WO2024172156A1 - Compound having brassinosteroid-like activity - Google Patents

Abstract

The present invention provides a nonsteroid molecule having a high brassinosteroid-like activity. Provided is a compound represented by general formula (1) [wherein: ring A and ring B each represent a monocyclic aromatic ring or a non-aromatic ring; R1-R6 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group; when two groups among R4-R6 are bound to an adjacent atom on ring B, the two groups may form a monocyclic aromatic ring or a non-aromatic ring together with the atom bound thereto on the ring B; L1 and L2 each represent a binding hand, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)-, or -S(O)2-; and n represents 0 or 1], or a salt thereof.

Description

Compounds with brassinosteroid-like activity

The present invention relates to compounds that have brassinosteroid-like activity.

Brassinosteroids (BRs) are plant growth hormones with a steroid skeleton that were isolated and structurally determined by Grove et al. in 1979. To date, over 70 BRs have been discovered in nature, and some BRs have been chemically synthesized. BRs play an important role in plant growth and development, primarily promoting cell elongation, cell division, bending, xylem differentiation, and seed germination. BRs are also involved in conferring resistance to abiotic stresses induced by high salinity, high temperature, heavy metals, drought, etc., as well as resistance to biotic stresses induced by bacteria, viruses, fungi, parasites, insects, etc., and are therefore molecules that are expected to be used in agriculture.

Since the early 1980s, when the outline of BR's growth-regulating action became clear, many researchers and agricultural chemical companies have been studying the agricultural use of BR in order to utilize its activity in agriculture. However, while other plant hormones such as gibberellin, auxin, cytokinin, and ethylene have been put to practical use as agricultural chemicals, the use of BR-related compounds has been limited even now, 40 years later. The reasons for the lack of progress in the use of BR include the high production cost and low profitability of BR, which has a steroid skeleton that is difficult to synthesize chemically, and the low metabolic stability and difficulty in maintaining biological activity for a long period of time. For example, even if BR is extracted from plants, only a very small amount can be obtained, and it is prone to decomposition and has stability problems. In addition, chemical synthesis of BR requires a nine-step process, which is extremely difficult even for those skilled in the art. When using plant hormones in agriculture, methods are often used to develop synthetic molecules that mimic plant hormones in order to control the synthetic complexity, redundancy, metabolic stability, etc., and make applications possible.

Because the steroid structure of BR is one of the reasons for its synthetic complexity, several molecules with non-steroidal structures that activate BR signaling have been developed.

For example, in 1988, it was discovered that lithium targets the kinase BIN2 downstream of the BR receptor, and inhibits the enzymatic activity of BIN2, thereby inducing BR signaling. However, lithium is highly toxic, and its use is limited.

In addition, in 1994, it was discovered that oleic acid monoglyceride isolated from the fungus Talaromyces trachysoerms had BR-like activity. However, its activity was extremely weak, 1/100,000th of that of BR, and no interaction with the BR receptor, BRI1, was confirmed.

In addition, in 2009, compound screening using an evaluation of Arabidopsis hypocotyl elongation activity revealed that bikinin has the same activity as BR. Like lithium, bikinin causes BR signaling by inhibiting the enzyme activity of BIN2. Bikinin covers almost all of the genes expressed by BR, and has been widely used as a tool to research basic botany. Its activity has been improved by using a group of derivatives, and research has also been conducted with a view to the prospect of agricultural applications. However, bikinin has low metabolic stability, and is rapidly inactivated in the body by binding to glutamic acid or malic acid.

Meanwhile, attempts are being made to synthesize non-steroidal BR mimetic molecules that target the BR receptor BRI1. The first example was a compound synthesized in 2001 that showed high BR activity when used in combination with auxin indole-3-acetic acid, which synergizes BR activity, but showed almost no BR activity on its own.

In addition, a non-steroidal BR mimetic molecule, BL9, has been synthesized through in silico screening of approximately 5 million non-steroidal compounds based on a pharmacophore model of BRI1 and BR, and molecular design based on structural comparison with BR (see, for example, Patent Document 1). However, measurements of BR activity in rice bending showed that the activity of BL9 was 1/1000 of that of BR.

WO 2018/159827

As mentioned above, the use of compounds with BR-like activity is still in the development stage, with many issues remaining. In particular, there has been little research on non-steroidal BRI1 agonist molecules that target BRI1, and their activity is weak.

The present invention aims to solve the problems described above and provide a non-steroidal molecule with high brassinosteroid (BR)-like activity.

As a result of intensive research in light of the above object, the inventors have found that by changing the piperazine ring at the central position in BL9 to a piperidine ring, in other words, by changing the number of nitrogen atoms at the central position from two to one (changing from a piperazine ring to a piperidine ring), it is possible to exhibit strong activity equivalent to that of natural BR. Based on this finding, the inventors have further intensively researched and completed the present invention. In other words, the present invention encompasses the following configurations.

Item 1. General formula (1):

［式中、
環Ａ及び環Ｂは同一又は異なって、単環式の芳香環又は非芳香族環を示す。
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は同一又は異なって、水素原子、ハロゲン原子、水酸基、シアノ基、ニトロ基、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、置換若しくは非置換アルカノイル基、置換若しくは非置換アルキルスルホニル基、置換若しくは非置換カルバモイル基、又は置換若しくは非置換アミノ基を示す。Ｒ^４、Ｒ^５及びＲ^６のうち２つの基が環Ｂ上の隣接する原子に結合している場合、該２つの基はそれらが結合する環Ｂ上の原子と一緒になって、単環式の芳香環又は非芳香族環を形成していてもよい。
Ｌ_１及びＬ_２は同一又は異なって、結合手、アルキレン基、－ＮＨ－、－Ｏ－、－Ｓ－、－Ｃ（Ｏ）－、－ＣＳ－、－Ｓ（Ｏ）－、又は－Ｓ（Ｏ）_２－を示す。
ｎは０又は１を示す。］
で表される化合物又はその塩。

[Wherein,
Ring A and ring B may be the same or different and each represents a monocyclic aromatic or non-aromatic ring.
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
L ₁ and L ₂ are the same or different and each represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)- or -S(O) ₂ -.
n represents 0 or 1.
A compound represented by the formula:

Item 2. The compound or salt thereof according to item 1, wherein L ₁ and L ₂ are the same or different and each represent a bond, —C(O)—, —CS—, —S(O)—, or —S(O) ₂ —.

Item 3. The compound or salt thereof according to item 1 or 2, wherein L ₁ is —C(O)— and L ₂ is a bond.

Item 4. The compound or salt thereof according to any one of items 1 to 3, wherein ring A and ring B are the same or different and are 6-membered monocyclic aromatic or non-aromatic rings.

Item 5. The compound or salt thereof according to any one of items 1 to 4, wherein ring A and ring B are both benzene rings.

Item 6. The compound or salt thereof according to any one of items 1 to 5, wherein n is 1.

Item 7. R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;
Items 7. The compound or salt thereof according to any one of Items 1 to 6, wherein R ⁴ , R ⁵ and R ⁶ are the same or different and each is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group, or two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, and the two groups, together with the atoms on ring B to which they are bonded, form a monocyclic heteroaromatic ring.

Section 8. General formula (1A):

［式中、
Ｒ^１ａ及びＲ^２ａは同一又は異なって、水素原子、水酸基、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、又は置換若しくは非置換カルバモイル基を示す。
Ｒ^４ａは、ハロゲン原子、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、又は置換若しくは非置換アルカノイル基を示す。
Ｒ^５ａは、水素原子、ハロゲン原子、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、又は置換若しくは非置換アルカノイル基を示す。］
で表される、項１～７のいずれか１項に記載の化合物又はその塩。

[Wherein,
R ^1a and R ^2a are the same or different and each represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted carbamoyl group.
R ^4a represents a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group.
R ^5a represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group.
Item 8. The compound or salt thereof according to any one of items 1 to 7, represented by the following formula:

Item 9. An agricultural composition containing the compound or salt thereof described in any one of items 1 to 8.

Item 10. The agricultural composition according to Item 9, which is applied to at least one species selected from the group consisting of agricultural crops, vegetables, fruit trees, weeds, and ornamental plants.

Item 11. The agricultural composition according to item 9 or 10, which is a plant growth regulator.

Item 12. The agricultural composition according to any one of items 9 to 11, which is a plant growth promoter.

Item 13. The agricultural composition according to Item 12, wherein the plant is at least one selected from the group consisting of vegetables and fruit trees.

Item 14. The agricultural composition according to any one of items 9 to 11, which is a plant growth inhibitor.

Item 15. The agricultural composition according to Item 14, wherein the plant is a weed.

Item 16. A method for regulating plant growth, comprising the step of applying the compound or salt thereof according to any one of Items 1 to 8, or the agricultural composition according to any one of Items 9 to 15, to a plant.

Section 17. General formula (6):

［式中、
環Ｂは単環式の芳香環又は非芳香族環を示す。
Ｒ^４、Ｒ^５及びＲ^６は同一又は異なって、水素原子、ハロゲン原子、水酸基、シアノ基、ニトロ基、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、置換若しくは非置換アルカノイル基、置換若しくは非置換アルキルスルホニル基、置換若しくは非置換カルバモイル基、又は置換若しくは非置換アミノ基を示す。Ｒ^４、Ｒ^５及びＲ^６のうち２つの基が環Ｂ上の隣接する原子に結合している場合、該２つの基はそれらが結合する環Ｂ上の原子と一緒になって、単環式の芳香環又は非芳香族環を形成していてもよい。
Ｒ^７は置換若しくは非置換アルキル基を示す。
Ｌ_２は結合手、アルキレン基、－ＮＨ－、－Ｏ－、－Ｓ－、－Ｃ（Ｏ）－、－ＣＳ－、－Ｓ（Ｏ）－、又は－Ｓ（Ｏ）_２－を示す。
ｎは０又は１を示す。］
で表される化合物。

[Wherein,
Ring B is a monocyclic aromatic or non-aromatic ring.
R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
^R7 represents a substituted or unsubstituted alkyl group.
_L2 represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)-, or -S(O) ₂ -.
n represents 0 or 1.
A compound represented by the formula:

Section 18. General formula (7):

［式中、
環Ｂは単環式の芳香環又は非芳香族環を示す。
Ｒ^４、Ｒ^５及びＲ^６は同一又は異なって、水素原子、ハロゲン原子、水酸基、シアノ基、ニトロ基、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、置換若しくは非置換アルカノイル基、置換若しくは非置換アルキルスルホニル基、置換若しくは非置換カルバモイル基、又は置換若しくは非置換アミノ基を示す。Ｒ^４、Ｒ^５及びＲ^６のうち２つの基が環Ｂ上の隣接する原子に結合している場合、該２つの基はそれらが結合する環Ｂ上の原子と一緒になって、単環式の芳香環又は非芳香族環を形成していてもよい。
Ｌ_２は結合手、アルキレン基、－ＮＨ－、－Ｏ－、－Ｓ－、－Ｃ（Ｏ）－、－ＣＳ－、－Ｓ（Ｏ）－、又は－Ｓ（Ｏ）_２－を示す。
ｎは０又は１を示す。］
で表される化合物。

[Wherein,
Ring B is a monocyclic aromatic or non-aromatic ring.
R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
_L2 represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)-, or -S(O) ₂ -.
n represents 0 or 1.
A compound represented by the formula:

The present invention provides a non-steroidal molecule with high BR-like activity.

FIG. 1 is a diagram showing the results of Test Example 1. FIG. 1 is a diagram showing the results of Test Example 1. FIG. 1 is a diagram showing the results of Test Example 1. FIG. 13 is a diagram showing the results of Test Example 2. FIG. 13 is a diagram showing the results of Test Example 3.

In this specification, "containing" is a concept that encompasses all of "comprise," "consist essentially of," and "consist of."

In addition, in this specification, when a numerical range is indicated as "A to B," it means A or more and B or less.

1. Compound having brassinosteroid-like activity The compound of the present invention is represented by the general formula (1):

［式中、
環Ａ及び環Ｂは同一又は異なって、単環式の芳香環又は非芳香族環を示す。
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は同一又は異なって、水素原子、ハロゲン原子、水酸基、シアノ基、ニトロ基、置換若しくは非置換アルキル基、置換若しくは非置換アルコキシ基、置換若しくは非置換アルカノイル基、置換若しくは非置換アルキルスルホニル基、置換若しくは非置換カルバモイル基、又は置換若しくは非置換アミノ基を示す。Ｒ^４、Ｒ^５及びＲ^６のうち２つの基が環Ｂ上の隣接する原子に結合している場合、該２つの基はそれらが結合する環Ｂ上の原子と一緒になって、単環式の芳香環又は非芳香族環を形成していてもよい。
Ｌ_１及びＬ_２は同一又は異なって、結合手、アルキレン基、－ＮＨ－、－Ｏ－、－Ｓ－、－Ｃ（Ｏ）－、－ＣＳ－、－Ｓ（Ｏ）－、又は－Ｓ（Ｏ）_２－を示す。
ｎは０又は１を示す。］
で表される化合物又はその塩である。

[Wherein,
Ring A and ring B may be the same or different and each represents a monocyclic aromatic or non-aromatic ring.
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
L ₁ and L ₂ are the same or different and each represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)- or -S(O) ₂ -.
n represents 0 or 1.
or a salt thereof.

The halogen atom represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is not particularly limited, and examples thereof include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a fluorine atom, a chlorine atom and a bromine atom are preferred, and a fluorine atom is more preferred.

The alkyl groups represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are not particularly limited, but are preferably linear or branched saturated hydrocarbon groups having 1 to 6 carbon atoms (C1-C6). Among them, from the viewpoints of BR-like activity, ease of synthesis, etc., R ¹ , R ² and R ³ are preferably alkyl groups having 1 to 4 carbon atoms (C1-C4 alkyl groups), and more preferably alkyl groups having 1 to 3 carbon atoms (C1-C3 alkyl groups). Furthermore, R ⁴ , R ⁵ and R ⁶ are preferably alkyl groups having 2 to 6 carbon atoms (C2-C6 alkyl groups), and more preferably alkyl groups having 3 to 6 carbon atoms (C3-C6 alkyl groups). Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isoamyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, an n-hexyl group, a 1,2,2-trimethylpropyl group, a 1,1,2-trimethylpropyl group, etc. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a tert-butyl group, etc. are preferred as R ¹ , R ² and R ³ . Furthermore, preferred examples of R ⁴ , R ⁵ and R ⁶ include an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isoamyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, an n-hexyl group, a 1,2,2-trimethylpropyl group and a 1,1,2-trimethylpropyl group.

The alkyl group described above may have a substituent. The number of the substituents is not particularly limited and may be, for example, 1 or more (for example, 1 to 5, particularly 1 to 3, etc.), and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, cyano groups, nitro groups, alkoxy groups described below, and imino groups which may be substituted with alkoxy groups described below. Among them, from the viewpoint of BR-like activity, ease of synthesis, etc., the substituents which the alkyl groups represented by R ¹ , R ² , and R ³ may have may be 1 to 3 hydroxyl groups, imino groups which may be substituted with alkoxy groups described below, and the substituents which the alkyl groups represented by R ⁴ , R ⁵ , and R ⁶ may have may be 1 to 3 hydroxyl groups.

The alkoxy group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means a monovalent group in which a hydrogen atom is bonded to at least one carbon atom in the alkyl group. Among them, from the viewpoint of BR-like activity, ease of synthesis, etc., R ¹ , R ² and R ³ are preferably alkoxy groups having 1 to 4 carbon atoms (C1-C4 alkoxy groups), more preferably alkoxy groups having 1 to 3 carbon atoms (C1-C3 alkoxy groups). Furthermore, R ⁴ , R ⁵ and R ⁶ are preferably alkoxy groups having 2 to 6 carbon atoms (C2-C6 alkoxy groups), more preferably alkoxy groups having 3 to 6 carbon atoms (C3-C6 alkoxy groups). More specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, a 1-hydroxybutyl group, an n-butyloxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, an n-pentyloxy group, an isoamyloxy group, a 1,2-dimethylpropyloxy group, a 2,2-dimethylpropyloxy group, an n-hexyloxy group, a 1,2,2-trimethylpropyloxy group, a 1,1,2-trimethylpropyloxy group, etc. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a methoxy group, an ethoxy group, etc. are preferred as R ¹ , R ² and R ³ . Furthermore, preferred examples of R ⁴ , R ⁵ and R ⁶ include a 1-hydroxybutyl group, an n-butyloxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, an n-pentyloxy group, an isoamyloxy group, a 1,2-dimethylpropyloxy group, a 2,2-dimethylpropyloxy group, an n-hexyloxy group, a 1,2,2-trimethylpropyloxy group and a 1,1,2-trimethylpropyloxy group.

The above-mentioned alkoxy group may also have a substituent. The number of the substituents is not particularly limited and may be, for example, one or more (e.g., 1 to 5, particularly 1 to 3, etc.), and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, cyano groups, nitro groups, and the above-mentioned alkoxy groups. Among these, from the viewpoint of BR-like activity, ease of synthesis, etc., the substituents that the alkoxy group may have may be 1 to 5 halogen atoms (particularly fluorine atoms).

The alkanoyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means a monovalent group in which a carbonyl group is bonded to the alkyl group, and an alkanoyl group having 2 to 7 carbon atoms (C2-C7 alkyl group) is preferred. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., an alkanoyl group having 3 to 7 carbon atoms (C3-C7 alkyl group) is preferred, and an alkanoyl group having 3 to 6 carbon atoms (C3-C6 alkyl group) is more preferred. Specific examples of the alkanoyl group include an acetyl group, a propionyl group, a pivaloyl group, a butanoyl group, a pentanoyl group, a hexanoyl group, and a heptanoyl group. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a propionyl group, a pivaloyl group, a butanoyl group, a pentanoyl group, a hexanoyl group, and a heptanoyl group are preferred.

The above-mentioned alkanoyl group may also have a substituent. The number of the substituents is not particularly limited and may be, for example, one or more (e.g., 1 to 5, particularly 1 to 3, etc.), and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, cyano groups, nitro groups, and the above-mentioned alkoxy groups. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., the substituents that the alkanoyl group may have may be 1 to 5 halogen atoms (particularly fluorine atoms).

The alkylsulfonyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means a monovalent group in which a sulfonyl group is bonded to the alkyl group, and an alkylsulfonyl group having 1 to 6 carbon atoms (C1-C6 alkylsulfonyl group) is preferred. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., an alkylsulfonyl group having 1 to 4 carbon atoms (C1-C4 alkylsulfonyl group) is preferred, and an alkylsulfonyl group having 1 to 3 carbon atoms (C1-C3 alkylsulfonyl group) is more preferred. Specific examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, etc. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., an ethylsulfonyl group, a propylsulfonyl group, etc. are preferred.

The above-mentioned alkylsulfonyl group may also have a substituent. The number of the substituents is not particularly limited and may be, for example, one or more (e.g., 1 to 5, particularly 1 to 3, etc.), and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, cyano groups, nitro groups, and alkoxy groups. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., the substituents that the alkylsulfonyl group may have may be 1 to 5 halogen atoms (particularly fluorine atoms).

The carbamoyl groups represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may also have a substituent. The number of the substituents is not particularly limited and may be, for example, 1 to 2, and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and alkanoyl groups. Among them, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the carbamoyl group may have may be 1 to 2 of the above-mentioned alkyl groups (particularly 1 to 2 methyl groups).

The amino group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may have a substituent. The number of the substituents is not particularly limited and may be, for example, 1 to 2, and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atom, hydroxyl group, alkyl group, alkanoyl group, and optionally substituted carbamoyl group. Among them, from the viewpoint of BR-like activity, ease of synthesis, and the like, the substituent that the amino group may have may be 1 to 2 of the above-mentioned alkanoyl groups, a carbamoyl group optionally substituted with 1 to 2 of the above-mentioned alkyl groups, and the like (particularly a carbamoyl group optionally substituted with 1 to 2 acetyl groups or 1 to 2 methyl groups).

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are, from the viewpoint of BR-like activity, ease of synthesis and the like, a hydrogen atom; the above-mentioned halogen atom; a hydroxyl group; a nitro group; the above-mentioned alkyl group (particularly, an imino group which may be substituted with the above-mentioned alkoxy group and an alkyl group which may be substituted with 1 to 3 hydroxyl groups); the above-mentioned alkoxy group; the above-mentioned alkanoyl group (particularly, an alkanoyl group which may be substituted with 1 to 5 halogen atoms); an alkylsulfonyl group (particularly, an alkylsulfonyl group which may be substituted with 1 to 5 halogen atoms); a substituted or unsubstituted carbamoyl group (particularly, a carbamoyl group which may be substituted with 1 to 2 alkyl groups); a substituted or unsubstituted amino group (particularly, an amino group which may be substituted with ¹ to 2 of ^the above-mentioned alkanoyl group, the above-mentioned carbamoyl group, etc.); It is preferable that two of ^{the six} groups are bonded to adjacent atoms on ring B, and the two groups, together with the atoms on ring B to which they are bonded, form a monocyclic non-aromatic carbocycle, a monocyclic non-aromatic heterocycle, a benzene ring, a monocyclic aromatic heterocycle, or the like, and more preferably a hydrogen atom; the above-mentioned halogen atom; a hydroxyl group; a nitro group; the above-mentioned alkyl group (particularly an imino group which may be substituted with the above-mentioned alkoxy group and an alkyl group which may be substituted with 1 to 3 hydroxyl groups); the above-mentioned alkoxy group; the above-mentioned alkanoyl group (particularly an alkanoyl group which may be substituted with 1 to 5 halogen atoms); an alkylsulfonyl group (particularly an alkylsulfonyl group which may be substituted with 1 to 5 halogen atoms); a substituted or unsubstituted carbamoyl group (particularly a carbamoyl group which may be substituted with 1 to 2 alkyl groups); a substituted or unsubstituted amino group (particularly an amino group which may be substituted with 1 to 2 of the above-mentioned alkanoyl groups, the above-mentioned carbamoyl groups, or the like).

In another embodiment, from the viewpoint of BR-like activity, ease of synthesis, etc., R ¹ , R ² and R ³ are a hydrogen atom, a hydroxyl group, the above-mentioned substituted or unsubstituted alkyl group (particularly, the above-mentioned imino group which may be substituted with an alkoxy group, and an alkyl group which may be substituted with 1 to 3 hydroxyl groups), the above-mentioned substituted or unsubstituted alkoxy group, the above-mentioned substituted or unsubstituted carbamoyl group (particularly, the carbamoyl group which may be substituted with 1 to 2 alkyl groups), the above-mentioned substituted or unsubstituted amino group (particularly, the above-mentioned alkanoyl group, the above-mentioned amino group which may be substituted with 1 to 2 carbamoyl groups, etc.), etc.; R ⁴ , R ⁵ and R ⁶ are a hydrogen atom, the above-mentioned halogen atom, the above-mentioned substituted or unsubstituted alkyl group (particularly, the above-mentioned imino group which may be substituted with an alkoxy group, and an alkyl group which may be substituted with 1 to 3 hydroxyl groups), the above-mentioned substituted or unsubstituted alkanoyl group (particularly, the alkanoyl group which may be substituted with 1 ^to 5 halogen atoms), etc.; or It is preferable that two groups among R ¹ , R 2 and R ³ are hydrogen atoms, hydroxyl groups, the above-mentioned substituted or unsubstituted alkyl groups (particularly, the above-mentioned imino groups which may be substituted with alkoxy groups and alkyl groups ^which may be substituted with ¹ to ³ hydroxyl groups), the above-mentioned substituted or unsubstituted alkoxy groups, the above-mentioned substituted or unsubstituted carbamoyl groups (particularly, the above-mentioned carbamoyl groups which may be substituted with 1 to 2 alkyl groups), the above-mentioned substituted or unsubstituted amino groups (particularly, the above-mentioned alkanoyl groups, the above-mentioned carbamoyl groups, or other amino groups which may be substituted with 1 to ² groups), etc ^.; It is more preferable that ⁶ is a hydrogen atom, the above-mentioned halogen atom, the above-mentioned substituted or unsubstituted alkyl group (particularly, the above-mentioned imino group which may be substituted with an alkoxy group and an alkyl group which may be substituted with 1 to 3 hydroxyl groups), the above-mentioned substituted or unsubstituted alkanoyl group (particularly, an alkanoyl group which may be substituted with 1 to 5 halogen atoms), or the like.

In another embodiment, from the viewpoint of BR-like activity, ease of synthesis, etc., R ¹ , R ² and R ³ are a hydrogen atom, a hydroxyl group, a fluorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, an amino group optionally substituted with one carbamoyl group which may be substituted with one methyl group, etc., and R ⁴ , R ⁵ and R ⁶ are a hydrogen atom, a hydroxyl group, a fluorine atom, a nitro group, a C2-C6 alkyl group optionally substituted with 1 to 3 hydroxyl groups, a C2-C6 alkoxy group optionally substituted with 1 to 5 fluorine atoms, a C3-C7 alkanoyl group optionally substituted with 1 to 5 fluorine atoms, a C1-C4 alkylsulfonyl group optionally substituted with 1 to 5 fluorine atoms, etc., or R ⁴ , R ⁵ and R It is preferred that two of the groups in ^{the formula (I} ) and (II) are bonded to adjacent atoms on ring B, and the two groups, together with the atoms on ring B to which they are bonded, form a monocyclic aromatic heterocycle (particularly, a pyrazole ring which may be substituted by 1 to 2 alkyl groups), and R ¹ , R ² and R ³ are a hydrogen atom, a hydroxyl group, a methoxy group, an acetylamino group, or the like, with at least one being a hydrogen atom, and R ⁴ , R ⁵ and R ⁶ are a hydrogen atom, a hydroxyl group, a fluorine atom, a C2-C6 alkyl group which may be substituted by 1 to 3 hydroxyl groups (particularly, an n-butyl group which may be substituted by 1 hydroxyl group), a C2-C6 alkoxy group which may be substituted by 1 to 5 fluorine atoms (particularly, a 1-hydroxybutyl group), a C3-C7 alkanoyl group (particularly, a butanoyl group, a 3-methylbutanoyl group, or the ^{like )} , or It is more preferable that two of the groups in ^{the formula (I} ) and (II) are bonded to adjacent atoms on ring B, and the two groups, together with the atoms on ring B to which they are bonded, form a monocyclic aromatic heterocycle (particularly a pyrazole ring which may be substituted with one alkyl group (particularly an isobutyl group)). It is further preferable that R ¹ , R ² and R ³ are a hydrogen atom, a hydroxyl group, a methoxy group, an acetylamino group, or the like, with at least one being a hydrogen atom, and R ⁴ , R ⁵ and R ⁶ are a hydrogen atom, a hydroxyl group, a fluorine atom, a C2-C6 alkyl group which may be substituted with 1 to 3 hydroxyl groups (particularly an n-butyl group which may be substituted with one hydroxyl group), a C2-C6 alkoxy group which may be substituted with 1 to 5 fluorine atoms (particularly a 1-hydroxybutyl group), a C3-C7 alkanoyl group (particularly a butanoyl group, a 3-methylbutanoyl group, or the like), or the like.

The alkylene group represented by _L1 and _L2 means a divalent group obtained by removing one hydrogen atom from the above alkyl group. Among them, from the viewpoints of BR-like activity, ease of synthesis, etc., an alkylene group having 1 to 3 carbon atoms (C1-C3 alkylene group) is preferred, and an alkylene group having 1 to 2 carbon atoms (C1-C2 alkylene group) is more preferred. Specific examples of the alkylene group include a methylene group, an ethylene group, a trimethylene group, a propylene group, etc. Among them, from the viewpoints of BR-like activity, ease of synthesis, etc., a methylene group is preferred.

From the viewpoints of BR-like activity, ease of synthesis, and the like, _L1 and _L2 are preferably a bond, -C(O)-, -CS-, -S(O)-, -S(O) _2- , etc., more preferably a bond, -C(O)-, -CS-, -S(O)-, etc., further preferably _L1 is -C(O)-, -CS-, -S(O)-, etc. and _L2 is a bond, and particularly preferably _L1 is -C(O)-, and _L2 is a bond.

The monocyclic aromatic rings represented by ring A and ring B include, but are not limited to, monocyclic aromatic carbon rings (benzene rings), monocyclic aromatic heterocycles, etc.

　The monocyclic aromatic carbocyclic ring (benzene ring) may have a substituent. The number of the substituents is not particularly limited and may be, for example, 1 to 4, and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, the above-mentioned alkyl groups, the above-mentioned alkanoyl groups, and carbamoyl groups which may be substituted with 1 to 2 of the above-mentioned alkyl groups. In particular, from the viewpoint of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic aromatic carbocyclic ring (benzene ring) may have may be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, etc. (particularly alkyl groups).

From the viewpoints of BR-like activity, ease of synthesis, etc., the monocyclic aromatic heterocycle is preferably a 5- to 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms such as oxygen atoms, sulfur atoms, nitrogen atoms, etc., in addition to carbon and hydrogen atoms. Specific examples of monocyclic aromatic heterocycles include 5-membered monocyclic aromatic heterocycles such as pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, triazole ring, tetrazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, and thiadiazole ring; and 6-membered monocyclic aromatic heterocycles such as pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, thiazine ring, and triazine ring. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a pyrazole ring is preferred.

　The monocyclic aromatic heterocycle may have a substituent. The number of the substituents is not particularly limited and may be, for example, 1 to 4, and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, the above-mentioned alkyl groups, the above-mentioned alkanoyl groups, and carbamoyl groups which may be substituted with 1 to 2 of the above-mentioned alkyl groups. In particular, from the viewpoint of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic aromatic heterocycle may have may be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and the like (particularly alkyl groups).

Examples of the monocyclic non-aromatic rings represented by ring A and ring B include monocyclic non-aromatic carbocycles and monocyclic non-aromatic heterocycles.

As the monocyclic non-aromatic carbocycle, from the viewpoints of BR-like activity, ease of synthesis, etc., a 5- to 6-membered monocyclic non-aromatic carbocycle is preferred. Specific examples of the monocyclic non-aromatic carbocycle include 5-membered monocyclic non-aromatic carbocycles such as a cyclopentane ring and a cyclopentene ring; and 6-membered monocyclic non-aromatic carbocycles such as a cyclohexane ring and a cyclohexene ring. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a 6-membered monocyclic non-aromatic carbocycle is preferred.

　The monocyclic non-aromatic carbocycle may have a substituent. The number of substituents is not particularly limited and may be, for example, 1 to 4, and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, the above-mentioned alkyl groups, the above-mentioned alkanoyl groups, and carbamoyl groups which may be substituted with 1 to 2 of the above-mentioned alkyl groups. In particular, from the viewpoint of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic non-aromatic carbocycle may have may be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, etc. (particularly alkyl groups).

From the viewpoints of BR-like activity, ease of synthesis, etc., the monocyclic non-aromatic heterocycle is preferably a 5- or 6-membered monocyclic non-aromatic heterocycle containing, for example, 1 to 4 heteroatoms such as oxygen atoms, sulfur atoms, nitrogen atoms, etc., in addition to carbon and hydrogen atoms. Specific examples of monocyclic non-aromatic heterocycles include 5-membered monocyclic non-aromatic heterocycles such as a pyrrolidine ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a thiazoline ring, and an oxazoline ring; and 6-membered monocyclic non-aromatic heterocycles such as a piperidine ring, a piperazine ring, a tetrahydropyran ring, a tetrahydrothiopyran ring, a morpholine ring, and a thiomorpholine ring. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a 6-membered monocyclic non-aromatic heterocycle is preferred.

　The monocyclic non-aromatic heterocycle may have a substituent. The number of the substituents is not particularly limited and may be, for example, 1 to 4, and the substituents may be the same or different. Examples of such substituents include the above-mentioned halogen atoms, hydroxyl groups, the above-mentioned alkyl groups, the above-mentioned alkanoyl groups, and carbamoyl groups which may be substituted with 1 to 2 of the above-mentioned alkyl groups. In particular, from the viewpoint of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic non-aromatic heterocycle may have may be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and the like (particularly alkyl groups).

When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic ring or a non-aromatic ring together with the atoms on ring B to which they are bonded. In this case, the monocyclic aromatic ring and the non-aromatic ring that may be formed may be as described above.

From the viewpoints of BR-like activity, ease of synthesis, etc., preferred rings A and B are 6-membered monocyclic aromatic rings (monocyclic aromatic carbocyclic rings (benzene rings), 6-membered monocyclic aromatic heterocyclic rings, etc.), 6-membered monocyclic non-aromatic rings (6-membered monocyclic non-aromatic carbocyclic rings, 6-membered monocyclic non-aromatic heterocyclic rings), etc. Specifically, from the viewpoints of BR-like activity, ease of synthesis, etc., preferred rings A and B are cyclohexane rings, cyclohexene rings, piperidine rings, piperazine rings, tetrahydropyran rings, tetrahydrothiopyran rings, morpholine rings, thiomorpholine rings, benzene rings, pyridine rings, pyrimidine rings, pyrazine rings, pyridazine rings, thiazine rings, triazine rings, etc., with a benzene ring being more preferred.

n is 0 or 1, and 1 is preferred from the standpoint of BR-like activity, ease of synthesis, etc.

The compound of the present invention that satisfies the above conditions is, for example, the compound represented by the general formula (1A):

［式中、
Ｒ^１ａ及びＲ^２ａは同一又は異なって、水素原子、水酸基、上記置換若しくは非置換アルキル基、上記置換若しくは非置換アルコキシ基、又は上記置換若しくは非置換カルバモイル基を示す。
Ｒ^４ａは、上記ハロゲン原子、上記置換若しくは非置換アルキル基、上記置換若しくは非置換アルコキシ基、又は上記置換若しくは非置換アルカノイル基を示す。］
で表される化合物又はその塩が好ましい。

[Wherein,
R ^1a and R ^2a are the same or different and each represent a hydrogen atom, a hydroxyl group, the above-mentioned substituted or unsubstituted alkyl group, the above-mentioned substituted or unsubstituted alkoxy group, or the above-mentioned substituted or unsubstituted carbamoyl group.
R ^4a represents the above halogen atom, the above substituted or unsubstituted alkyl group, the above substituted or unsubstituted alkoxy group, or the above substituted or unsubstituted alkanoyl group.
or a salt thereof is preferred.

When the compound of the present invention has an asymmetric carbon atom in the molecule, it may exist as multiple stereoisomers (i.e., diastereoisomers or optical isomers) based on the asymmetric carbon atom, and the compound of the present invention includes any one of these stereoisomers and any mixture thereof.

Compounds of the present invention include isotopically labeled compounds (e.g., ^2H , ^3H , ^13C , ^14C , ^15N , ^18F , ^35S , ^125I , etc.) and deuterium conversions.

The compounds of the present invention can exist in the free form or in the form of salts. Examples of salts include acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, formate, acetate, propionate, fumarate, oxalate, malonate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, maleate, lactate, malate, tartrate, citrate, and trifluoroacetate; metal salts such as lithium salt, potassium salt, calcium salt, magnesium salt, sodium salt, zinc salt, and aluminum salt; and base addition salts such as ammonium salt, diethanolamine salt, ethylenediamine salt, triethanolamine salt, and triethylamine salt.

The compounds of the present invention or their salts include their intramolecular salts, adducts, solvates, and hydrates.

2. Agricultural Compositions and Plant Growth Regulating Methods The agricultural compositions containing the compound of the present invention or a salt thereof can be formulated into oil concentrates, emulsifiable concentrates, flowable concentrates, wettable concentrates, water dispersible granules, dust concentrates, granules, and the like by appropriately adding inert carriers, surfactants, other formulation adjuvants, and the like.

The inert carrier may be either a solid carrier or a liquid carrier. Examples of the solid carrier include minerals such as kaolin clay, attapulgite clay, bentonite, montmorillonite, acid clay, pyrophyllite, talc, diatomaceous earth, and calcite; natural organic substances such as corncob flour and walnut shell flour; synthetic organic substances such as urea; salts such as calcium carbonate and ammonium sulfate; and synthetic inorganic substances such as synthetic hydrous silicon oxide, in the form of fine powders or granules. Examples of the liquid carrier include aromatic hydrocarbon compounds such as toluene, xylene, ethylbenzene, and methylnaphthalene; alcohol compounds such as methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, and ethylene glycol monoethyl ether; ketone compounds such as acetone, methyl ethyl ketone, and cyclohexanone; vegetable oils such as soybean oil and cottonseed oil; petroleum-based aliphatic hydrocarbon compounds; ester compounds; dimethyl sulfoxide; acetonitrile; and water.

Surfactants include, for example, nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, and polyethylene glycol fatty acid esters; and anionic surfactants such as alkyl sulfonates, alkylbenzene sulfonates, and alkyl sulfates.

Other formulation adjuvants include, for example, water-soluble polymers such as polyvinyl alcohol and polyvinylpyrrolidone; polysaccharides such as gum arabic, alginic acid and its salts, CMC (carboxymethylcellulose), and xanthan gum; inorganic substances such as aluminum magnesium silicate and alumina sol; preservatives; colorants; PAP (isopropyl acid phosphate); and stabilizers such as BHT.

The agricultural composition of the present invention can contain the compound of the present invention or its salt in an amount of usually 0.01 to 99% by mass, particularly 0.1 to 95% by mass, and furthermore 0.5 to 90% by mass, etc.

In the present invention, when the compound or salt thereof, or the agricultural composition of the present invention is applied to a plant, it may be applied to the whole or a part of the plant (stems, leaves, buds, flowers, fruits, ears, seeds, roots, etc.), and may be applied to various growth stages of the plant (germination period, such as before or after emergence after sowing; vegetative growth period, such as when raising seedlings, when transplanting seedlings, when taking cuttings or cuttings, and when growing after planting; reproductive growth period, such as just before or during heading, etc.).

The method of the present invention for regulating plant growth, for example, the method for promoting or inhibiting plant growth, can be carried out by applying an effective amount of the compound of the present invention or a salt thereof, or the agricultural composition of the present invention to the plant or its cultivation area. When applied to the plant or its cultivation area, the compound of the present invention or a salt thereof, or the agricultural composition of the present invention can be applied once or multiple times. For example, the number of times of spraying treatment is usually 1 to 3 times.

Application methods in the present invention include, for example, treatment of the stems and leaves, inflorescences, or spikes of plants, such as spraying the stems and leaves (i.e., spraying treatment), treatment of plant seeds before they are sown in soil or cultivation medium (i.e., seed treatment), treatment of the soil (cultivation area) before or after planting the plants (i.e., soil treatment), treatment of seedlings (for example, seedling box treatment, seedling tray treatment, etc.), etc.

In the present invention, examples of spray treatments on the stems, leaves, floral organs, or panicles of plants include methods of applying an effective amount of the compound of the present invention or a salt thereof, or the agricultural composition of the present invention to the surface of the plant, such as by spraying on the stems, or to the panicles at the heading stage or to the entire plant. One embodiment of treatment on plants is treatment on plants growing in paddy fields. In addition, examples of the time of spray treatment include the flowering period, including before, during, and after flowering.

In the present invention, examples of the plant seed treatment include a method of applying an effective amount of the compound of the present invention or a salt thereof, or the agricultural composition of the present invention to the seeds of a plant before they are sown in soil or a cultivation medium. Specific treatment methods include, for example, spraying, smearing, immersion, impregnation, coating, film coating, pellet coating, etc., and these methods can be used to prepare seeds that retain an effective amount of the compound of the present invention or a salt thereof, or the agricultural composition of the present invention on the surface and/or inside.

In the present invention, the soil treatment may be, for example, a method of applying an effective amount of the compound or salt thereof of the present invention, or the agricultural composition of the present invention to the soil before or after planting a plant. Specific treatment methods include, for example, spraying the soil, mixing the soil, and irrigating the soil with a chemical solution (chemical solution irrigation, soil injection, chemical solution drip, etc.). Treatment locations include, for example, planting holes, rows, near planting holes, near rows, the entire cultivated area, the plant edge, between plants, under the tree trunk, the main trunk ridge, soil, seedling boxes, seedling trays, seedling beds, etc. Treatment times include before sowing, at the time of sowing, immediately after sowing, the seedling period, before planting, at the time of planting, and the growth period after planting. In addition, in the above soil treatment, a solid fertilizer such as a paste fertilizer containing the compound or salt thereof or the agricultural composition of the present invention may be applied to the soil. The compound or salt thereof, or the agricultural composition of the present invention can also be mixed with an irrigation solution, for example, by injection into irrigation equipment (irrigation tubes, irrigation pipes, sprinklers, etc.), mixing into inter-row flooding solution, mixing into hydroponic solution, etc. Alternatively, the compound or salt thereof, or the agricultural composition of the present invention can be mixed with an irrigation solution in advance, and then treated using the above-mentioned irrigation method or other appropriate irrigation method such as sprinkling or flooding.

Examples of treatments for seedlings in the present invention include a spraying treatment in which a diluted solution prepared by diluting the compound or a salt thereof, or the agricultural composition of the present invention with water to an appropriate active ingredient concentration is sprayed over the entire seedling, an immersion treatment in which the seedlings are immersed in the diluted solution, and a coating treatment in which the compound or a salt thereof, or the agricultural composition of the present invention, prepared as a powder, is applied over the entire seedling. Examples of treatments for soil before or after planting the seedlings include a method in which a diluted solution prepared by diluting the compound or a salt thereof, or the agricultural composition of the present invention with water to an appropriate active ingredient concentration is sprayed over the seedlings and surrounding soil after planting the seedlings, and a method in which the compound or a salt thereof, or the agricultural composition of the present invention, prepared as a granule or a solid agent such as a granule, or the agricultural composition of the present invention, is sprayed over the surrounding soil after planting the seedlings.

Examples of plants to which the compound or a salt thereof, or the agricultural composition of the present invention can be applied include:
Agricultural crops, such as corn, rice, wheat, barley, rye, oats, sorghum, cotton, soybeans, adzuki beans, kidney beans, peanuts, buckwheat, sugar beets, rapeseed, sunflowers, sugarcane, tobacco, etc.;
Vegetables, for example, Solanaceae vegetables (eggplant, tomato, bell pepper, chili pepper, potato, etc.), Cucurbitaceae vegetables (cucumber, pumpkin, zucchini, watermelon, melon, squash, etc.), Cruciferae vegetables (radish, turnip, horseradish, kohlrabi, Chinese cabbage, cabbage, mustard, broccoli, cauliflower, etc.), Asteraceae vegetables (burdock, chrysanthemum, artichoke, lettuce, etc.), Liliaceae vegetables (green onion, onion, garlic, asparagus, etc.), Apiaceae vegetables (carrot, parsley, celery, American burdock, etc.), Chenopodiaceae vegetables (spinach, Swiss chard, etc.), Lamiaceae vegetables (perilla, mint, basil, etc.), strawberry, sweet potato, Chinese yam, taro, etc.;
Fruit trees, for example, pome fruits (apple, European pear, Japanese pear, quince, quince, etc.), stone fruits (peach, plum, nectarine, plum, cherry, apricot, prune, etc.), citrus fruits (Satsuma mandarin, orange, lemon, lime, grapefruit, etc.), nuts (chestnut, walnut, hazel, almond, pistachio, cashew nut, macadamia nut, etc.), berries (blueberry, cranberry, blackberry, raspberry, etc.), grape, persimmon, olive, loquat, banana, coffee, date palm, coconut palm, etc.;
Weeds, such as redroot pigweed, wild rose, sow thistle, American thistle, Bidens frondosa, American geranium, ragwort, ragweed, evening primrose, Japanese knotweed, barnyard millet, goldenrod, Japanese knotweed, horse chestnut, Japanese knotweed, Arabidopsis thaliana, barnyard millet, nightshade, cow chickweed, alfalfa, white chickweed, Chinese hackberry, giant ragweed, giant barnyard millet Veronica persica, Chinese knotweed, Japanese anemone, plantain, Japanese knotweed, Chinese poppy, goosegrass, Dutch earwort, wood sorrel, sedge, vetch, docks, yellow sedge, cucumber grass, shepherd's purse, nightshade, Japanese anemone, chickweed, morning glory, white clover, sorrel, burdock, horsetail, Japanese laurel Dou, annual grass, annual spurge, purslane, solid foxtail, common dandelion, bindweed, common morning glory, upright violet, upright violet, cardamom, Japanese laurel, Imperata japonica, water courgettes, water weeds, Datura serrata, clover, spurge, gooseberry, shepherd's purse, common sowberry, field daisy, flea bean, Aster, chickweed, phillyraeoides, nutsedge, knotweed, lamiaceae, dandelion, fleabane, dwarf sorrel, mugwort, hogweed, Japanese mustard, snakeberry, plantain, amplexicaule, willow, lotus grass, purple wood sorrel, meadowsweet, crabgrass, American laurel, Japanese knotweed, mugwort, horsenettle, etc.;
Houseplants, etc. These plants may be genetically modified plants.

In one embodiment, the compound or its salt, or the agricultural composition of the present invention may be applied to rice, but is not limited thereto. Examples of rice include japonica varieties such as Nipponbare, Hinohikari, Koshihikari, Akitakomachi, Haenuki, Sasanishiki, Hitomebore, Kinuhikari, Hoshino Yume, Kirara 397, Tsugaru Roman, Yumeakari, Hanaechizen, Yumetsukushi, Hatsushimo, Yukihikari, Nanatsuboshi, Masshigura, Asahi no Yume, Koshibuki, Aichi no Kaori, Iro no Kagayaki, Oborozuki, and Yumehikari; indica varieties; Javanica varieties; Sally Queen, Basmati, Kitakaori, Princess Sally, Khao Home Mali, Arborio, Carnaroli, and Vialone Nano.

The compound of the present invention or a salt thereof has brassinosteroid (BR)-like agonist or antagonist activity, and is therefore useful as a plant growth regulator, for example, a growth promoter or growth inhibitor.

In one embodiment, the compound of the present invention or a salt thereof can be used as a plant growth promoter. In this specification, "promotion of plant growth" can include, for example, promotion of seed germination; promotion of rooting; promotion of rooting; promotion of development and elongation of branches, leaves and stems; promotion of flowering; promotion of fruit set; promotion of fruit maturation; promotion of fruit enlargement; imparting disease resistance; imparting resistance to stress (for example, high salt concentration, dryness, high temperature, low temperature, nutritional deficiency, etc.), etc. Plants to which the compound or a salt thereof of the present invention is applied as a growth promoter include, but are not limited to, agricultural crops such as corn, rice, wheat, barley, rye, oats, sorghum, cotton, soybean, adzuki bean, kidney bean, peanut, buckwheat, sugar beet, rapeseed, sunflower, sugarcane, and tobacco; pome fruits (apple, European pear, Japanese pear, quince, quince, etc.), stone fruits (peach, plum, nectarine, plum, cherry, apricot, prune, etc.), citrus fruits (Satsuma mandarin, orange, lemon, lime, grapefruit, etc.), nuts (chestnut, walnut, hazel, almond, pistachio, cashew nut, macadamia nut, etc.), berries (blueberry, cranberry, blackberry, raspberry, etc.), grape, persimmon, olive, loquat, banana, coffee, date palm, coconut palm, and other fruit trees.

In another embodiment, the compound of the present invention or a salt thereof can be used as a growth inhibitor. In this specification, "inhibition of plant growth" refers to, for example, inhibition of seed germination, inhibition of root growth, inhibition of root establishment, inhibition of branch, leaf and stem development and elongation, inhibition of flowering, inhibition of fruit set, inhibition of fruit ripening, inhibition of fruit enlargement, and the like, and particularly includes an action as a herbicide. Plants to which the compound of the present invention or a salt thereof can be applied as a growth inhibitor include russet greens, russet rose, sowberry, thistle, Bidens frondosa, American geranium, ragweed, evening primrose, Japanese knotweed, Japanese mustard, Polygonum quinquefolia, Arabidopsis thaliana, ragweed, nightshade, chickweed, alfalfa, white-breasted hackberry, Chinese hackberry, Japanese laurel, and Japanese laurel. Roughweed, Veronica persica, Eucalyptus pratense, Western jasmine, Plantain, Common gooseberry, Common poppy, Goosegrass, Dutch earwort, Wood sorrel, Cyperus serrata, Vetch, Rumex, Yellow sedge, Cucumber grass, Shepherd's purse, Eggplant, Common jasmine, Common jasmine, Common chickweed, Common morning glory, White clover, Sorrel, Common burdock, Horsetail, Summer pea, Sparrow Wild rose, Japanese laurel, purslane, solid foxtail, common dandelion, bindweed, common knotweed, upright persimmon, upright violet, cardamom, Japanese tabby, Imperata japonica, water plantains, Japanese buttercup, Datura serrata, morning glory, clover, spurge, gooseberry, shepherd's purse, common sowberry, field daisy, flea bean, daisy, chickweed, chickweed, chickweed, shepherd's purse, common sowberry, field daisy, flea bean, chickweed, chickweed, buttercup, honeysuckle, seaweed Examples of weeds (particularly dicotyledonous plants) include, but are not limited to, Japanese knotweed, Lamium purpureum, Japanese knotweed, Elephant bean, Rumex gracilis, Artemisia anguicida, Buttercup, Japanese ragwort, Snakeberry, Plantain, Leptolepis lanceolata, Lamium amplexicaule, Willow, Lotus japonicus, Purple wood sorrel, Japanese bush clover, Digitaria ciliaris, American knotweed, Japanese knotweed, Artemisia anguicida, Horsenettle, and other weeds.

3. Method for Producing Compound The method for producing the compound of the present invention is not particularly limited, and the compound can be produced by various methods. For example, the compound can be produced by the following reaction scheme:

［式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｌ_１、Ｌ_２及びｎは前記に同じである。Ｒ^７は上記アルキル基を示す。Ｘ^１及びＸ^２は同一又は異なって、上記ハロゲン原子を示す。］
にしたがって合成することができる。

[In the formula, ring A, ring B, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , _L1 , _L2 and n are the same as those described above. ^R7 represents the above alkyl group. ^X1 and ^X2 may be the same or different and represent the above halogen atoms.]
It can be synthesized according to the following:

(3-1) Compound (2) → Compound (4)
The compound represented by the general formula (2) and the compound represented by the general formula (3) may be a known or commercially available product, or may be synthesized from a commercially available product by a known method.

The compound represented by general formula (4) can be obtained by coupling the compound represented by general formula (2) with the compound represented by general formula (3).

The coupling reaction between the compound represented by general formula (2) and the compound represented by general formula (3) can be carried out in a suitable solvent in the presence of a base according to a conventional method.

There are no limitations on the solvent as long as it does not interfere with the reaction, and examples include amide compounds such as N,N-dimethylformamide; ether compounds such as tetrahydrofuran; halogenated aliphatic hydrocarbon compounds such as chloroform and dichloromethane; aromatic hydrocarbon compounds such as toluene and xylene; and nitrile compounds such as acetonitrile. These solvents can be used alone or in combination of two or more.

Examples of bases include triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine (NMM), pyridine, lutidine, collidine, imidazole, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. These bases can be used alone or in combination of two or more.

The amount of the compound represented by general formula (3) used can be 1.5 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents, in molar ratio relative to the compound represented by general formula (2).

The amount of base used can be 0.3 to 3.0 equivalents, preferably 0.5 to 2.0 equivalents, in molar ratio relative to the compound represented by general formula (2).

This reaction can be carried out at 0 to 100°C, preferably 10 to 50°C. There is no particular limit to the reaction time, and the reaction can be carried out until completion.

After the reaction is complete, the compound represented by formula (4) can be obtained by purifying it in a conventional manner as necessary. Alternatively, the next step can be carried out without purification.

(3-2) Compound (4) → Compound (6)
The compound represented by formula (5) may be a known or commercially available product, or may be synthesized from a commercially available product by a known method.

The compound represented by general formula (6) can be obtained by coupling the compound represented by general formula (4) with the compound represented by general formula (5).

The coupling reaction between the compound represented by general formula (4) and the compound represented by general formula (5) can be carried out in a suitable solvent in the presence of a Lewis acid catalyst according to a conventional method.

There are no limitations on the solvent as long as it does not interfere with the reaction, and examples include amide compounds such as N,N-dimethylformamide; ether compounds such as tetrahydrofuran; halogenated aliphatic hydrocarbon compounds such as chloroform and dichloromethane; aromatic hydrocarbon compounds such as toluene and xylene; and nitrile compounds such as acetonitrile. These solvents can be used alone or in combination of two or more.

Examples of Lewis acid catalysts include aluminum chloride, aluminum bromide, aluminum iodide, iron chloride, gallium chloride, gallium bromide, indium chloride, indium bromide, tin chloride, titanium chloride, zirconium chloride, ruthenium chloride, antimony fluoride, antimony chloride, tungsten chloride, zinc chloride, boron trifluoride, boron trichloride, boron tribromide, niobium chloride, etc. These Lewis acid catalysts can be used alone or in combination of two or more.

The amount of the compound represented by general formula (5) used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio relative to the compound represented by general formula (4).

The amount of the oxidizing agent used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio relative to the compound represented by general formula (4).

This reaction can be carried out at 30 to 200°C, preferably 40 to 150°C, and particularly preferably under reflux. There is no particular limit to the reaction time, and the reaction can be carried out sufficiently until completion.

After the reaction is complete, the compound represented by general formula (6) can be obtained by purifying it in a conventional manner as necessary. Alternatively, the next step can be carried out without purification.

The general formula (6) obtained in this way:

［式中、環Ｂ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｌ_２及びｎは前記に同じである。］
で表される化合物は、文献未記載の新規化合物である。

[In the formula, ring B, R ⁴ , R ⁵ , R ⁶ , R ⁷ , L ₂ and n are the same as defined above.]
The compound represented by the formula (I) is a novel compound that has not been described in the literature.

(3-3) Compound (6) → Compound (7)
A compound represented by general formula (7) can be obtained by reacting a compound represented by general formula (6) with an acid.

The reaction of the compound represented by formula (6) with an acid can be carried out in a suitable solvent according to conventional methods.

There are no limitations on the solvent as long as it does not interfere with the reaction, and examples include alcohol compounds such as ethanol and n-propyl alcohol; amide compounds such as N,N-dimethylformamide; ether compounds such as tetrahydrofuran; halogenated aliphatic hydrocarbon compounds such as chloroform and dichloromethane; aromatic hydrocarbon compounds such as toluene and xylene; and nitrile compounds such as acetonitrile. These solvents can be used alone or in combination of two or more.

Examples of acids include hydrogen chloride (hydrochloric acid), sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, trifluoroacetic anhydride, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid, etc. These acids can be used alone or in combination of two or more.

The amount of acid used can be an excess amount, and can be 5 to 200 equivalents, preferably 10 to 100 equivalents, in molar ratio relative to the compound represented by formula (6).

This reaction can be carried out at 30 to 200°C, preferably 40 to 150°C, and particularly preferably under reflux. There is no particular limit to the reaction time, and the reaction can be carried out sufficiently until completion.

After the reaction is complete, the compound represented by general formula (7) can be obtained by purifying it in a conventional manner as necessary. Alternatively, the next step can be carried out without purification.

The general formula (7) obtained in this way is:

［式中、環Ｂ、Ｒ^４、Ｒ^５、Ｒ^６、Ｌ_２及びｎは前記に同じである。］
で表される化合物は、文献未記載の新規化合物である。

[In the formula, ring B, R ⁴ , R ⁵ , R ⁶ , L ₂ and n are the same as defined above.]
The compound represented by the formula (I) is a novel compound that has not been described in the literature.

(3-4) Compound (7) → Compound (1)
The compound represented by formula (8) may be a known or commercially available product, or may be synthesized from a commercially available product by a known method.

The compound represented by general formula (1) can be obtained by coupling the compound represented by general formula (7) with the compound represented by general formula (8).

The coupling reaction between the compound represented by general formula (7) and the compound represented by general formula (8) can be carried out in a suitable solvent in the presence of a condensing agent and a base according to a conventional method.

There are no limitations on the solvent as long as it does not interfere with the reaction, and examples include amide compounds such as N,N-dimethylformamide; ether compounds such as tetrahydrofuran; halogenated aliphatic hydrocarbon compounds such as chloroform and dichloromethane; aromatic hydrocarbon compounds such as toluene and xylene; and nitrile compounds such as acetonitrile. These solvents can be used alone or in combination of two or more.

Condensing agents include, for example, carbodiimide compounds (N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), diisopropylcarbodiimide, etc.), imidazole compounds (carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, etc.), triazine compounds (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, etc.), triazole compounds (1-hydroxybenzotriazole (HOBt), o-(7-azabenzotriazol-1-yl)-N,N,N',N '-tetramethyluronium hexafluorophosphate (HATU), o-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), o-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), o-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), o-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), etc. These condensing agents can be used alone or in combination of two or more.

Examples of bases include triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine (NMM), pyridine, lutidine, collidine, imidazole, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. These bases can be used alone or in combination of two or more.

The amount of the compound represented by general formula (8) used can be 0.5 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio relative to the compound represented by general formula (7).

The amount of the condensing agent used can be 1.0 to 10.0 equivalents, preferably 1.5 to 5.0 equivalents, in molar ratio relative to the compound represented by general formula (7).

The amount of base used can be 0.5 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio relative to the compound represented by general formula (7).

This reaction can be carried out at 0 to 100°C, preferably 10 to 50°C. There is no particular limit to the reaction time, and the reaction can be carried out until completion.

After the reaction is complete, purification can be performed by conventional methods as necessary to obtain the compound of the present invention represented by general formula (1).

After the compound of the present invention represented by the general formula (1) is thus obtained, it is also possible to introduce a desired substituent into the compound by a conventional method. For example, when a compound (1) having an alkanoyl group introduced into the ring B is obtained, the compound (1) having an alkoxy group introduced into the ring B can be obtained by reacting the compound with a known reducing agent such as sodium borohydride (NaHBH ₄ ).

The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these in any way.

[Comparative Examples 1-2]

Comparative Synthesis Example 1: 3,4-difluoro-N-methoxy-N-methylbenzamide (Compound 1)

In a 100 mL two-necked round bottom flask equipped with a magnetic stir bar, 3,4-difluorobenzoic acid (1.0 g, 6.3 mmol), N,O-dimethylhydroxylamine hydrochloride (1.3 g, 13 mmol), 1-hydroxybenzotriazole (HOBt) (1.5 g, 11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (1.9 g, 9.9 mmol), and triethylamine ( _NEt3 ) (4.5 mL, 32 mmol) were dissolved in dichloromethane (25 mL). After stirring at room temperature for 19 h, the mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 4:1 to 7:3) to obtain compound 1 as a yellow oil (1.17 g, 92%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65-7.57 (m, 1H), 7.56-7.50 (m, 1H), 7.25-7.19 (m, 1H), 3.56 (s, 3H), 3.37 (s, 3H); HRMS (ESI+) m/z calcd for C ₉ H ₉ NO ₂ Na [M+Na] ⁺ : 224.0494, found: 224.0490. ¹ H NMR spectrum of 1 was identical to that reported in the literature.

Comparative Synthesis Example 2: 1-(3,4-difluorophenyl)butan-1-one (Compound 2)

In a 100 mL two-necked round bottom flask equipped with a magnetic stir bar, 3,4-difluoro-N-methoxy-N-methylbenzamide (compound 1) (2.1 g, 9.5 mmol) and tetrahydrofuran (THF) (30 mL) were added. The mixture was then cooled to 0°C. Then, 2M n-propylmagnesium bromide in tetrahydrofuran (THF) (6.3 mL, 13 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 21 h. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 min. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:0 to 9:1) to give compound 2 as a yellow oil (1.6 g, 92%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.71 (m, 2H), 7.30-7.20 (m, 1H), 2.91 (t, J = 7.3 Hz, 2H),1.77 (sext, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H); (ESI+) m/z calcd for C ₁₀ H ₁₀ F ₂ ONa [M+Na] ⁺ : 207.0592, found: 207.0593. ¹ H NMR spectrum of 2 was identical to that reported in the literature.

Comparative Synthesis Example 3: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (Compound 3)

To a 50 mL two-necked round bottom flask equipped with a magnetic stir bar was added 1-(3,4-difluorophenyl)butan-1-one (compound 2) (599 mg, 3.1 mmol), piperazine (958 mg, 11 mmol), and acetonitrile (MeCN) (6 mL). After refluxing for 22 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation to give compound 3 as a yellow solid (747 mg, 96%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.69 (dd, J = 8.5, 2.0 Hz, 1H), 7.62 (dd, J = 13.9, 2.0 Hz, 1H), 6.92 (t, J = 8.5 Hz, 1H), 3.20-3.17 (m, 4H), 3 (m, 4H), 2.86 (t, J = 7.3 Hz, 2H), 1.75 (sext, J = 7.4 Hz, 2H), 1.70 (br s, 1H), 0.99 (t, J = 7.5 Hz, 3H); HRMS (ESI+) m/z calcd for C ₁₄ H ₂₀ FN ₂ O [M+H] ⁺ : 251.1554, found: 251.1554. ¹ H NMR spectrum of 3 was identical to that reported in the literature.

Comparative Example 1: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-fluorophenyl)butan-1-one (BL8)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 3) (103 mg, 0.41 mmol), 3,4-difluorobenzoic acid (77 mg, 0.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (154 mg, 0.81 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 18 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10 : 0 to 7 : 3) to give BL8 as a white solid (129 mg, 83%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.5, 2.0 Hz, 1H), 7.65 (dd, J = 13.8, 1.9 Hz, 1H), 7.33-7.30 (m, 1H), 7.25-7.19 (m, 2H), 6.92 (t, J = 8. 5 Hz, 1H), 4.10-3.50 (br, 4H), 3.22 (br s, 4H), 2.87 (t, J = 7.3 Hz, 2H), 3.31 (d, J = 1.8 Hz, 3H), 1.75 (sext, J = 7.4 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.2, 168.2, 154.7 (d, J _CF = 246 Hz), 151.4 (dd, J _CF = 251, 11.5 Hz), 150.2 (dd, J _CF = 250, 12.9 Hz), 143.3 (d, J _CF = 8.7 Hz), 132.1 (t, J _CF = 4.3 Hz), 131.7 (d, J _CF = 5.6 Hz), 125.2, 123.9 (dd, J _CF = 7.1, 4.3 Hz), 118.0, 117.7 (d, J _CF = 18.6 Hz), 117.1 (d, J _CF = 18.6 HRMS (ESI+) m/z calcd for C ₂₁ H ₂₁ F ₃ N ₂ O ₂ K [M+K] ⁺ : 429.1187, found: 429 .1189. ¹ H NMR spectrum _of BL8 was identical to that reported in the literature.

Comparative Example 2: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-fluorophenyl)butan-1-one (NSBR1; BL9)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 3) (295 mg, 1.2 mmol), 3,4-dihydroxybenzoic acid (231 mg, 1.5 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (461 mg, 2.4 mmol) were dissolved in dichloromethane (6 mL). After stirring at room temperature for 21 _h , the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10:0 to 9:1) to give NSBR1 (BL9) as a white solid (173 mg, 38%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.5, 2.0 Hz, 1H), 7.65 (dd, J = 13.7, 1.8 Hz, 1H), 6.99 (s, 1H), 6.92 (t, J = 8.4 Hz, 1H), 6.79-6.77 (m, ¹³ C NMR (150 MHz, _{CDCl 3} ) δ 198.3, 171.5, 155.4 (d, J _CF = 246 Hz), 146.9, 144.3, 143.2, 131.6, 125.9, 125.2, 119.7, 118.0, 116.1 (d, J _CF = 21.5 Hz), 115.3, 114.7, 50.2, 49.7, 48.1, 42.6, 40.2, 17.9, 13.9; HRMS (ESI+) m/z calcd for C ₂₁ H ₂₃ FN ₂ O ₄ Na [M+Na]+: 409.1534, found: 409.1532. ¹ H NMR spectrum of NSBR1 was identical to that reported in the literature.

[Comparative Examples 3 to 16]
Each compound was synthesized in the same manner as in Comparative Examples 1 and 2 above.

Comparative Synthesis Example 4: 4-Fluoro-N-methoxy-N-methylbenzamide (Compound 5a)

In a 100 mL two-necked round-bottom flask equipped with a magnetic stir bar, 4-fluorobenzoic acid (compound 4a) (1.0 g, 7.1 mmol), N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (2.1 g, 21 mmol) were dissolved in dichloromethane (12 mL). After stirring at room temperature for 13 h, the mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 9:1 to 7:3) to give compound 5a as a yellow oil (932 mg, 72%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77-7.21 (m, 2H), 7.08 (t, J = 8.6 Hz, 2H), 3.54 (s, 3H), 3.36 (s, 3H); HRMS (ESI+) m/z calcd for C ₉ H ₁₀ NO ₂ Na [M+Na] ⁺ : 206.0 587, found: 206.0588. ¹ H NMR spectrum of 5a was identical to that reported in the literature.

Comparative Synthesis Example 5: 1-(4-fluorophenyl)butan-1-one (Compound 6a)

To a 50 mL two-necked round bottom flask equipped with a magnetic stir bar was added 4-fluoro-N-methoxy-N-methylbenzamide (compound 5a) (933 mg, 5.1 mmol) and tetrahydrofuran (THF) (15 mL). The mixture was then cooled to 0°C. 2M n-propylmagnesium bromide in tetrahydrofuran (THF) (6.3 mL, 13 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 13 hours. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 minutes. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation to give compound 6a as a yellow oil (750 mg, 88%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (dd, J = 8.1, 6.9 Hz, 2H), 7.12 (t, J = 8.5 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H), 1.77 (sext, J = 7.3 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H); HRMS (ESI+) m/z calcd for C ₁₀ H ₁₁ FONa [M+Na] ⁺ : 189.0686, found: 189.0687. ¹ H NMR spectrum of 6a was identical to that reported in the literature.

Comparative Synthesis Example 6: 1-(4-(piperazin-1-yl)phenyl)butan-1-one (compound 7a)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 1-(4-fluorophenyl)butan-1-one (compound 6a) (677 mg, 4.1 mmol), piperazine (1.2 g, 14 mmol), and acetonitrile (MeCN) (7.6 mL) were added. After refluxing for 42 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10:0 to 9:1) to give compound 7a as a yellow solid (662 mg, 70%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 3.34-3.28 (m, 4H), 3.05-3.00 (m, 4H), 2.86 (t, J = 7.4 Hz, 2H), ^{1 13} C NMR (150 MHz, CDCl ₃ ) δ 198.9, 154.4, 130.1, 127.5, 113.4, 48.5, 45.8, 40 .0, 18.2, 14.0; HRMS (ESI+) m/z calcd for C ₁₄ H ₂₁ N ₂ O [M+H] ⁺ : 233.1648, found: 233.2647.

Comparative Example 3: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)phenyl)butan-1-one (8a)

In a Schlenk tube equipped with a magnetic stir bar, 1-(4-(piperazin-1-yl)phenyl)butan-1-one (compound 7a) (107 mg, 0.46 mmol), 3,4-dihydroxybenzoic acid (93 mg, 0.59 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (177 mg, 0.92 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 18 h, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10 : 0 to 9 : 1) to give compound 8a as a white solid (72 mg, 42%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (d, J = 9.0 Hz, 2H), 7.01 (br s, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.82-6.79 (m, 2H), 4.00-3.60 (br, 4H), 3.37 (br s ¹³ C NMR (150 MHz, CDCl ₃ ) δ 199.0, 171.3, 153. 5, 146.8, 144.2, 130.1, 128.4, 126.1, 119.8, 115.2, 114.7, _114.1 , 47.6, _40.1 , 18.1, 14.0; ₂ O ₄ Na [M+Na] ⁺ : 391.1628, found: 391.1624.

Comparative Synthesis Example 7: 3-chloro-4-fluoro-N-methoxy-N-methylbenzamide (Compound 5b)

In a 100 mL two-necked round bottom flask equipped with a magnetic stir bar, 3-chloro-4-fluorobenzoic acid (compound 4b) (593 mg, 3.4 mmol), N,O-dimethylhydroxylamine hydrochloride (680 mg, 7.0 mmol), 1-hydroxybenzotriazole (HOBt) (798 mg, 9.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (2.0 g, 5.9 mmol), and triethylamine ( _NEt3 ) (2.9 mL, 21 mmol) were dissolved in dichloromethane (21 mL). After stirring at room temperature for 18 h, the mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:0 to 4:1) to give compound 5b as a yellow oil (606 mg, 83%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (dd, J = 7.0, 1.9 Hz, 1H), 7.65 (ddd, J = 8.6, 4.8, 2.1 Hz, 1H), 7.17 (t, J = 8.7 Hz, 1H), 3.55 (s, 3H), 3.37 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 167.3, 159.4 (d, J _CF = 253 Hz), 131.4, 130.9 (d, J _CF = 4.4 Hz), 128.9 (d, J _CF = 7.2 Hz), 121.0 (d, J _CF = 18.6 Hz), 116.3 (d, J _CF = 21.6 Hz), 61.2, 33.5; HRMS (ESI+) m/z calcd for C ₉ H ₉ FClNO ₂ [M+H] ⁺ : 218.0379, found: 218.0379.

Comparative Synthesis Example 8: 1-(3-chloro-4-fluorophenyl)butan-1-one (Compound 6b)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 3-chloro-4-fluoro-N-methoxy-N-methylbenzamide (compound 5b) (708 mg, 3.3 mmol) and tetrahydrofuran (THF) (7.5 mL) were added. The mixture was then cooled to 0°C. Then, 2M n-propylmagnesium bromide (2.1 mL, 4.2 mmol) in tetrahydrofuran (THF) was added dropwise. The resulting mixture was stirred at room temperature for 13 h. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 min. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:1 to 4:1) to give compound 6b as a yellow oil (523 mg, 80%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (dd, J = 6.3, 2.1 Hz, 1H), 7.87 (ddd, J = 8.5, 4.5, 2.0 ^Hz , 1H), 7.22 (t, J = 8.5 Hz, 1H) _, 2.91 (t, _J = 7.3 Hz, 2H), 1.77 (sext. _8.4 (d, J _CF = 8.6 Hz), 121.8 (d, J _CF = 18.8 Hz), 116.7 (d, J _CF = 21.6 Hz), 40.4, 17.6, 13.8; HRMS (ESI+) m/z calcd for C ₁₀ H ₁₀ FClO ₂ Na [M+Na] ⁺ : 223.0296, found : 223.0296.

Comparative Synthesis Example 9: 1-(3-chloro-4-(piperazin-1-yl)phenyl)butan-1-one (Compound 7b)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 1-(3-chloro-4-fluorophenyl)butan-1-one (compound 6b) (355 mg, 1.8 mmol), piperazine (460 mg, 5.5 mmol), and acetonitrile (MeCN) (3 mL) were added. After refluxing for 21 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10 : 0 to 9 : 1) to give compound 7b as a yellow solid (395 mg, 84%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.17-3.09 (m, 4H), 3.09-3.00 (m, ^{4 13} C NMR (150 MHz, CDCl ₃ ) δ 198.3, 153.5, 131. 9, 130.9, 128.0, 127.8, 119.5, 52.0, 46.0, 40.2, 17.8, 13.9; HRMS (ESI+) m/z calcd for C ₁₄ H ₂₀ ClN ₂ O [M+H] ⁺ : 267.1259, found: 267.1257.

Comparative Example 4: 1-(3-chloro-4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)phenyl)butan-1-one (8b)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-chloro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 7b) (98 mg, 0.37 mmol), 3,4-dihydroxybenzoic acid (77 mg, 0.50 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (87 mg, 0.45 mmol) were dissolved in dichloromethane (2 mL). After stirring at room temperature for 45 h, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 3:1 to 3:2) to give compound 8b as a white solid (62 mg, 42%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.4, 2.1 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 7.00 (br s, 1H), 6.79 (s, 1H), ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.3, 171.6, 152.3, 146.9, 144.3, 132.8, 130.9, 128.4, 127.9, 126.0, 119.8, 119.7, 115.2, four piperazine carbon peak s were not observed.; HRMS (ESI+) m/z calcd for C ₂₁ H ₂₃ ClN ₂ O ₄ Na [M+Na] ⁺ : 425.1239, found: 425.1237.

Comparative Synthesis Example 10: 4-Fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (Compound 5c)

In a 100 mL two-necked round bottom flask equipped with a magnetic stir bar, 4-fluoro-3-trifluoromethylbenzoic acid (compound 4c) (1.0 g, 5.7 mmol), N,O-dimethylhydroxylamine hydrochloride (1.2 g, 12 mmol), 1-hydroxybenzotriazole (HOBt) (1.3 g, 9.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (2.0 g, 10 mmol), and triethylamine ( _NEt3 ) (4.8 mL, 35 mmol) were dissolved in dichloromethane (35 mL). After stirring at room temperature for 18 h, the mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:0 to 4:1) to give compound 5c as a yellow oil (1.1 g, 78%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (dd, J = 7.0, 1.9 Hz, 1H), 7.65 (ddd, J = 8.6, 4.8, 2.1 Hz, 1H), 7.17 (t, J = 8.7 Hz, 1H), 3.55 (s, 3H), 3.37 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 167.0, 160.9 (d, J _CF = 260 Hz), 134.5 (d, J _CF = 10.0 Hz), 130.1 (d, J _CF = 2.9 Hz), 128.1 (d, J _CF = 2.9 Hz), 122.2 (q , J _CF = HRMS (ESI+) m/z calcd for _{C 10} H ₁₀ F ₄ NO ₂ [M+H] ⁺ : 252.0642 _, found: 252.0 642.

Comparative Synthesis Example 11: 1-(4-fluoro-3-(trifluoromethyl)phenyl)butan-1-one (Compound 6c)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 4-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (compound 5c) (484 mg, 1.9 mmol) and tetrahydrofuran (THF) (7.5 mL) were added. The mixture was then cooled to 0°C. Then, 2M n-propylmagnesium bromide in tetrahydrofuran (THF) (1.5 mL, 3.0 mmol) was added _dropwise . The resulting mixture was stirred at room temperature for 21 h. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 min. The organic layer was washed with water and brine, and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:0 to 4:1) to give compound 6c as a yellow oil (352 mg, 78%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (dd, J = 6.8, 2.1 Hz, 1H), 8.21-8.15 (m, 1H), 7.30 (t, J = 9.2 Hz, 1H), 2.95 (t, J = 7.2 Hz, 2H), 1.79 (sext, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 197.5, 162.3 (d, J _CF = 261 Hz), 133.9 (d, J _CF = 10.0 Hz), 133.3 (d, JCF = 2.9 Hz), .6, 122.1 (q, J _CF = 271 Hz), 118.8 (dd, J _CF = _35.2 , 15.1 Hz), 117.3 (d, J _CF = 16.1 Hz ₎ , 40.4, 17.5, 13.7; _235.0741 , ^found : 235.0742.

Comparative Synthesis Example 12: 1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)butan-1-one (Compound 7c)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 1-(4-fluoro-3-(trifluoromethyl)phenyl)butan-1-one (compound 6c) (295 mg, 1.3 mmol), piperazine (460 mg, 5.5 mmol), and acetonitrile (MeCN) (3 mL) were added. After refluxing for 21 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10:0 to 9:1) to give compound 7c as a yellow solid (286 mg, 75%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 2.0Hz, 1H), 8.08 (dd, J = 8.5Hz, J = 2.0Hz, 1H), 7.30 (d, J = 8.5Hz, 1H), 3.04-3.00 (m, 8H), 2.92 (t, J = 7.3Hz, 2H), 1.77 (sext, J = 7.3Hz, 2H), 1.01 (t, J = 7.3Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.3, 156.2, 132.4, 132.1, 128.1 (dd, J _CF = 10.1, 5.9 Hz), 125.3 (d, J _CF = 30.2 Hz), 123.8 (d, J _CF = 271 Hz), 122.6, 54.1, 46.1, 40.3, 17.7, 13.8; HRMS (ESI+) m/z calcd for C ₁₅ H ₂₀ F ₃ N ₂ O [M+H] ⁺ : 301.15 22, found: 301.1521.

Comparative Example 5: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)butan-1-one (8c)

In a screw-cap tube containing a magnetic stir bar, 1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)butan-1-one (compound 7c) (69 mg, 0.23 mmol), 3,4-dihydroxybenzoic acid (75 mg, 0.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (81 mg, 0.42 mmol) were dissolved in dichloromethane (2 mL). After stirring at room temperature for 21 h, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 4:1 to 3:2) to give compound 8c as a white solid (57 mg, 57%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.3, 1.2 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.00 (s, 1H), 6.79 (s, 2H), 4.05-3 .55 (br, 4H), 3.20-2.90 (br, 4H), 2.98-2.88 (m, 2H), 1.77 ₍ sext ^. 198.3, 171.7, 155.0, 147.0, 144.4, 133.3, 132.6, 127.9 (d, J _CF = 5.7 Hz), 126.3 (d, J _CF = 30.2 Hz), 123.6 (d, J _CF = 271 Hz), 123.3, 119.6, 11 5.1, 114.7, 53.4, 52.7, 48.5, 42.9, 40.4, 17.6, 13.8; HRMS (ESI+) m/z calcd for C ₂₂ H ₂₄ F ₃ N ₂ O ₄ [M+H] ⁺ : 437.1683, found: 437.1685.

Comparative Synthesis Example 13: 1-(3,4-difluorophenyl)-3-methylbutan-1-one (Compound 6d)

In a 50 mL two-necked round bottom flask equipped with a magnetic stir bar, 3,4-difluoro-N-methoxy-N-methylbenzamide (compound 1) (1.0 g, 5.0 mmol) and tetrahydrofuran (THF) (15 mL) were added. The mixture was then cooled to -78 °C. Then, 0.9 M isobutylmagnesium bromide in tetrahydrofuran (THF) (8 mL, 7.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 23 h. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 min. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:0 to 9:1) to give compound 6d as a yellow oil (357 mg, 36%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.81-7.76 (m, 1H), 7.75-7.70 (m, 1H), 7.27-7.21 (m, 1H), 2.79 (d, J = 6.8 Hz, 2H), 2.28 (nonet, J = 6.7 Hz, 1H), (d, J = 6.8 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 197.5, 154.3 (d, J _CF = 12.9 Hz), 151.8 (dd, J _CF = 212, 13.1 Hz), 149.5 (d, J _CF = 12.9 Hz), 134.4, 1 25.0 (dd, J _CF = 7.2, 2.9 Hz), 117.4 (dd, J _CF = 18.0, 3.6 Hz), 47.3, 25.1, 22.7; HRMS (ESI+) m/z calcd for C ₁₁ H ₁₂ F ₂ ONa [M+Na] ⁺ : 221.0748, found: 211.0748.

Comparative Synthesis Example 14: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-methylbutan-1-one (Compound 7d)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 1-(3,4-difluorophenyl)-3-methylbutan-1-one (compound 6d) (261 mg, 1.3 mmol), piperazine (398 mg, 4.7 mmol), and acetonitrile (MeCN) (4 mL) were added. After refluxing for 20 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10 : 0 to 9 : 1) to give compound 7d as a yellow solid (267 mg, 77%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (dd, J = 8.6, 1.8 Hz, 1H), 7.61 (dd, J = 14.1, 1.8 Hz, 1H), 6.91 (t, J = 8.3 Hz, 1H), 3.21-3.16 (m, 4H), ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.1, 154.5 (d, J _CF = 246 Hz), 144.4 (d, J _CF = 8.6 Hz), 130.9 (d, J _CF = 5.9 Hz), 125.3 (d, J _CF = 2.9 Hz), 117.5 (d, J _CF = 3.0 Hz), 115.9 (d, J _CF = 21.6 Hz), 51.00, 5 0.98, 47.1, 46.0, 25.4, 22.7, a piperazine carbon peak were not observed.; HRMS (ESI+) m/z calcd for C ₁₅ H ₂₂ FN ₂ O [M+H] ⁺ : 265.1711, found: 265.1709.

Comparative Example 6: 1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)-3-methyl-butan-1-one (9a)

In a screw-cap tube containing a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-methylbutan-1-one (compound 7d) (90 mg, 0.34 mmol), 3,4-dihydroxybenzoic acid (75 mg, 0.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (110 mg, 0.57 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 22 h, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 7:3 to 1:1) to give compound 9a as a white solid (64 mg, 47%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.4, 2.1 Hz, 1H), 8.65 (dd, J = 13.7, 2.0 Hz, 1H), 7.01 (br s, 1H), 6.92 (t, J = 8.4 Hz, 1H), 6.79 (s, 1H) , 6.79 (s, 1H), 4.10-3.55 (m, 4H), 3.22 (br s, 4H), 2.76 (d, J = 7.0 Hz, 2H), 2.27 (sext, J = 6.7 Hz, 1H), 0.99 (d, J = 6.7 Hz, 6H), OH proton peaks were not observed. ; ^13C NMR (150 MHz, CDCl ₃ ) δ 198.2, 171.6, 154.5 (d, J _CF = 246 Hz), 147.0, 144.4, 143.3 (d, J _CF = 8.6 Hz), 131.8 (d, J _CF = 5.7 Hz), 125.6, 125.3, .7, 117.9, 116.1 (d, J _CF = 21.6 Hz), 114.9 (d, J _CF = 18.6 Hz), 50.1, 49.6, 48.0, _47.1 , _42.6 , 25.3, 22.7; _{4 Na} [M+Na] ⁺ : 423.1691, found: 423.1688.

Comparative Synthesis Example 15: 1-(3,4-difluorophenyl)heptan-1-one (Compound 6e)

In a 100 mL two-necked round-bottom flask equipped with a magnetic stir bar, 3,4-difluoro-N-methoxy-N-methylbenzamide (compound 1) (973 mg, 4.8 mmol) and tetrahydrofuran (THF) (15 mL) were added. The mixture was then cooled to -78 °C. Then, 0.8 M n-hexylmagnesium bromide in tetrahydrofuran (THF) (10 mL, 7.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 17 h. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 min. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10:0 to 9:1) to give compound 6e as a yellow oil (590 mg, 54%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.76 (m, 1H), 7.76-7.71 (m, 1H), 7.28-7.20 (m, 1H), 2.92 (t, J = 7.5 Hz, 2H), 1.72 (quint, J = 7.4 Hz, 2H), -1.26 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 197.9, 153.5 (dd, J _CF = 254, 12.9 Hz), 151.2 (dd, J _CF = 250, 12.9 Hz), 134.1 (t , J _CF = HRMS ₍ ESI+) m _/ z calcd for C ₁₃ H ₁₆ F ₂ ONa [M+Na] ⁺ : 249.1061 _, found: 249.1060.

Comparative Synthesis Example 16: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)heptan-1-one (compound 7e)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 1-(3,4-difluorophenyl)heptan-1-one (compound 6e) (499 mg, 2.2 mmol), piperazine (650 mg, 7.7 mmol), and acetonitrile (MeCN) (4.7 mL) were added. After refluxing for 37 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10:0 to 9:1) to give compound 7e as a yellow solid (593 mg, 92%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (dd, J = 8.3, 1.9 Hz, 1H), 7.62 (dd, J = 14.0, 2.0Hz, 1H), 6.92 (t, J = 8.5 Hz, 1H), 3.21-3.16 (br, 4H), ¹³ C NMR (150 MHz, CDCl ₃ ) δ 1 98.4, 154.5 (d, J _CF = 246 Hz), 144.4 (d, J _CF = 7.2 Hz), 130.6 (d, J _CF = 5.9 Hz), 125.2, 117.5, 115.9 (d, J _CF = 21.5 Hz), 51.04, 51.01, 46.0, 38. 3, 31.6, 29.0, 24.5, 22.5, 14.0, a piperazine carbon peak was not observed.; HRMS (ESI+) m/z calcd for C ₁₇ H ₂₆ FN ₂ O [M+H] ⁺ : 293.2024, found: 293.2021.

Comparative Example 7: 1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)heptan-1-one (9b)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)heptan-1-one (compound 7e) (102 mg, 0.35 mmol), 3,4-dihydroxybenzoic acid (65 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (98 mg, 0.51 mmol), and 1-hydroxybenzotriazole (HOBt) (73 mg, 0.54 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 18 h, the mixture was extracted with ethyl acetate. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 10:0 to 2:3) and PTLC (chloroform/ethyl acetate = 2:3) to give compound 9b as a white solid (47 mg, 31%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.69 (dd, J = 8.3, 2.1 Hz, 1H), 7.63 (dd, J = 13.4, 1.7 Hz, 1H), 6.99 (s, 1H), 6.90 (t, J = 8.6 Hz, 1H), 6.77 (s, 2H), 6.23 (s, 1H), 34.05-3.80 (br, 2H), 3.80-3.55 (br, 2H), 3.37-3.05 (br, 4H), 2.86 (t, J = 7.2 Hz, 2H), 1.70 (quin, J = 7.4 Hz, 2H), 1.39-1.32 (m, 2H), 1.32-1.26 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.4, 171.5, 154.6 (d, J _CF = 246 Hz), 146.9, 144.3 (d, J _CF = 7.1 Hz), 131.5 (d, J _CF = 5.7 Hz), 125.8, 125.2, 119.6, 118.0, 116.0 (d, J _CF = 21.5 Hz), 115.0, 114.8, 50.1, 49.6, 48.0, 42.6, 31.6, 29.0, 24.4, 22.5, 14.0; HRMS (ESI+) m/z calcd for C ₂₄ H ₂₉ FN ₂ O ₄ Na [M+Na]+: 451.2004, found: 451.2002.

Comparative Synthesis Example 17: 1-(3,4-difluorophenyl)nonan-1-one (Compound 6f)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 3,4-difluoro-N-methoxy-N-methylbenzamide (compound 1) (822 mg, 4.1 mmol) and tetrahydrofuran (THF) (12 mL) were added. The mixture was then cooled to -78 °C. 0.5 M n-octylmagnesium bromide in tetrahydrofuran (THF) (1.3 mL, 6.2 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 17 h. The reaction was quenched by adding ethyl acetate and saturated aqueous ammonium chloride solution and stirred at room temperature for 10 min. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 10 : 0 to 9 : 1) to give compound 6f as a yellow oil (1.0 g, 97 %).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.76 (m, 1H), 7.76-7.70 (m, 1H), 7.28-7.20 (m, 1H), 2.91 (t, J = 7.4 Hz, 2H), 1.72 (quin, J = 7.3 Hz, 2H), 1.20 (m, 10H), 0.88 (t, J = 6.7 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 197.9, 153.5 (dd, J _CF = 254, 12.9 Hz), 150.4 (dd, J _CF = 249, 12.9 Hz), t, J _CF = 3.6 Hz), 125.0 (dd, J _CF = 7.2, 4.2 Hz), 117.4 (d, J _CF = 18.8 Hz), 117.4 (d, J _CF = 17.3 Hz), 38.5, 31.8, 29.4, 29.3, 29.1, 24.2, 22.6, 14 .1; HRMS (ESI+) m/z calcd for C ₁₅ H ₂₀ F ₂ ONa [M+Na] ⁺ : 277.1374, found: 277.1375.

Comparative Synthesis Example 18: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)nonan-1-one (Compound 7f)

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 1-(3,4-difluorophenyl)nonan-1-one (compound 6f) (507 mg, 2.0 mmol), piperazine (589 mg, 7.0 mmol), and acetonitrile (MeCN) (4 mL) were added. After refluxing for 16 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10 : 0 to 9 : 1) to give compound 7f as a yellow solid (201 mg, 31%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.62 (dd, J = 14.0, 1.8 Hz, 1H), 6.92 (t, J = 8.4 Hz, 1H), 3.21-3.16 (m, 4H), ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.4, 154.5 (d, J _CF = 246 Hz), 144.4 (d, J _CF = 8.7 Hz), 130.6 ( _d , J _CF = 5.7 Hz), 125.2 (d, J _CF = 2.9 Hz), 117.5 (d, J _CF = 2.9 Hz), 115.9 (d, J HRMS (ESI+) m/z calcd for C ₁₉ H ₁₉ FN ₂ ONa [M+Na] ⁺ : 343.2156, found: 343.2157.

Comparative Example 8: 1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)nonan-1-one (9c)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)nonan-1-one (compound 7f) (100 mg, 0.31 mmol), 3,4-dihydroxybenzoic acid (61 mg, 0.40 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (104 mg, 0.54 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 19 h, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10 : 0 to 9 : 1) and PTLC (chloroform/ethyl acetate = 2 : 3) to give compound 9c as a white solid (28 mg, 20%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.4, 1.9 Hz, 1H), 7.65 (dd, J = 13.6, 1.9 Hz, 1H), 7.01 (br s, 1H), 6.92 (t, J = 8.4 Hz, 1H), 6.79 (s, 2H) , 4.10-3.60 (br, 4H), 3.23 (br s, 4H), 2.88 (t, J = 7.5 Hz, 2H), 1.71 (quin, J = 7.4 Hz, 2H), 1.40-1.20 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H), two OH proton peaks were not observed.; ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.5, 171.6, 154.6 (d, J _CF = 246 Hz), 147.0, 144.4, 143.2 (d, J _CF = 8.6 Hz), 131.5 (d, J _CF = 5.7 Hz), 125.6, 125.2, 119.7, 118.0, 116.0 (d, J _CF = 21.4 Hz), 115.0, 114.8, 50.2, 49.6, 48.0, 42.6, 38.3, 31.8, 29.4, 29.3, 29.1, 24.5, 22.6, 14.1; HRMS (ESI+) m/z calcd for C ₂₆ H ₃₃ FN ₂ O ₄ Na [M+Na] ⁺ : 479.2317, found: 479.2314.

Comparative Synthesis Example 19: tert-Butyl 1-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)butan-1-one (Compound 7g)

Into a screw cap containing a magnetic stir bar, 1-(3,4-difluorophenyl)butan-1-one (compound 2) (125 mg, 0.68 mmol), 2-(tert-butyloxycarbonyl)-2,6-diazaspiro[3.3]heptane (122 mg, 0.62 mmol), Cs ₂ CO ₃ (241 mg, 0.74 mmol), and dimethylformamide (DMF) (2 mL) were added. The mixture was stirred at 90° C. for 21 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 10:0 to 10:1) to give compound 7g as a white solid (164 mg, 74%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.63 (dd, J = 8.4, 1.9 Hz, 1H), 7.57 (dd, J = 13.6, 1.9 Hz, 1H), 6.38 (t, J = 8.6 Hz, 1H), 4.20 (d, J = 2.1 Hz, 4H), ¹³ C NMR (150 MHz, CDC) l ₃ ) δ 198.0, 156.0, 151.3 (d, J _CF = 240 Hz), 142.2 (d, J _CF = 11.4 Hz), 127.8 (d, J _CF = 4.4 Hz), 125.5, 115.6 (d, J _CF = 18.6 Hz), 112.7 (d, J _CF = 4. HRMS (ESI+) m/z calcd for C ₂₀ H ₂₈ FN ₂ O ₃ [M+H] ⁺ : 363.2078, found: 363.2079.

Comparative Example 9: 1-(4-(6-(3,4-dihydroxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-3-fluorophenyl)butan-1-one (10a)

In a 30 mL two-necked round bottom flask equipped with a magnetic stir bar, tert-butyl 1-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)butan-1-one (compound 7g) (150 mg, 0.41 mmol) was dissolved in dichloromethane/trifluoroacetic acid (TFA) (2:1) (9 mL). After stirring at room temperature for 1 h, the solvent was removed by evaporation. The residue was dissolved in toluene and the solvent was removed by evaporation. The crude product, compound 7g', was used in the next reaction without purification.

In a 25 mL screw-cap tube containing a magnetic stir bar, compound 7g' (100 mg, 0.38 mmol), 3,4-dihydroxybenzoic acid (66 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (111 mg, 0.58 mmol), 1-hydroxybenzotriazole (HOBt) (61 mg, 0.45 mmol), and 4-dimethylaminopyridine (DMAP) (61 mg, 0.49 mmol) were dissolved in dichloromethane/dimethylformamide (DMF) (5:1) (3 mL). After stirring at room temperature for 4 days, the mixture was extracted with ethyl acetate. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/methanol = 9:1) to give compound 10a as a white solid (3.9 mg, 4%, 2 steps).
¹ H NMR (600 MHz, CD ₃ OD) δ 7.69 (dd, J = 8.2, 1.4 Hz, 1H), 7.56 (dd, J = 13.7, 1.4 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 8. 2 Hz, 1H), 6.53 (t, J = 8.9 Hz, 1H), 4.58 (s, 2H), 4.31 (s, 2H), 4.26 (s, 4H), 2.86 (t, J = 7.2 Hz, 2H), 1.68 (sext, J = 7.3 Hz, 2H), 0.97 (t, J = 7.6 Hz, 3H); ¹³ C NMR (150 MHz, CD ₃ OD) δ 200.5, 172.5, 158.9, 152.8 (d, J _CF = 240 Hz), 144.4 (d, J _CF = 11.6 Hz), 128.5 (d, J _CF = 4.4 Hz), 127.2, 121. 7, 116.3, 116.13, 116.08, 115.6, 114.2 (d, _{J CF} = 4.4 Hz), 64.2, _40.8 , 35.9, _19.3 , 14.1, two carbon peaks were _not observed.; ] ⁺ : 399.1715, found: 399.1713.

Comparative Synthesis Example 20: tert-Butyl 5-(4-butyryl-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Compound 7h)

To a screw-cap tube containing a magnetic stir bar, 1-(3,4-difluorophenyl)butan-1-one (compound 2) (82.6 mg, 0.45 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (98.1 mg, 0.43 mmol), K ₂ CO ₃ (92.4 mg, 0.67 mmol), and dimethylformamide (DMF) (1 mL) were added. After stirring at 90°C for 23 h, the mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 15:85 to 3:7) to give compound 7h as a yellow solid (125.7 mg, 76%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.64 (dd, J = 8.6, 1.7 Hz, 1H), 7.61 (dd, J = 15.5, 1.7 Hz, 1H), 6.56 (t, J = 8.9 Hz, 1H), 3.76 (br s, 2H), 3.65 (t, J = 1 6.2 Hz, 2H), 3.45 (br s, 2H), 3.37 (d, J = 8.9 Hz, 1H), 3.27 (d, J = 7.6 Hz, 1H), 2.97 (br s, 2H), 2.83 (t, J = 7.2 Hz, 2H), 1.74 (sext, J = 7.6 Hz) , 2H), 1.46 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 197.9, 154.5, 150.6 (d, J _CF = 241 Hz), 140.4 (d, J _CF = 10.1 Hz), 126.5 (d, J _CF = 4.4 Hz), 125.8, 116.1 (d, J _CF = 21.6 Hz), 114.0 (d, J _CF = 5.7 Hz), 79.6, 53.8, 53.8, 50.1, 49.8, 42.0, 40.9, 39.9, 28.5, 18.2, 14. 0; HRMS (ESI+) m/z calcd for C ₂₁ H ₃₀ FN ₂ O ₃ [M+H] ⁺ : 377.2235, found: 377.2235.

Comparative Example 10: 1-(4-(5-(3,4-dihydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-fluorophenyl)butan-1-one (Compound 10b)

In a 30 mL two-necked round-bottom flask equipped with a magnetic stir bar, tert-butyl 5-(4-butyryl-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (compound 7h) (29 mg, 0.077 mmol) was dissolved in dichloromethane/trifluoroacetic acid (TFA) (1:1) (2 mL). After stirring at room temperature for 1 h, the solvent was removed by evaporation. The crude product, compound 7h', was used in the next reaction without purification.

In a 25 mL screw-cap tube containing a magnetic stir bar, the crude product 7h', 3,4-dihydroxybenzoic acid (21 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (25 mg, 0.13 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.14 mmol), and 4-dimethylaminopyridine (DMAP) (7.2 mg, 0.059 mmol) were dissolved in dichloromethane (1 mL). After stirring at room temperature for 3 days, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/methanol = 10:1) and HPLC (solvent A: water containing 0.1% trifluoroacetic acid, solvent B: acetonitrile containing 0.1% trifluoroacetic acid, solvent gradient = 0-65% gradient of solvent B over 65 min) to give compound 10b as a white solid (3.5 mg, 11%, 2 steps).
¹ H NMR (600 MHz, CD ₃ OD) δ 7.69 (dd, J = 8.9, 2.1 Hz, 1H), 7.59 (dd, J = 15.1, 2.1 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8. 2 Hz, 1H), 6.73 (t, J = 8.6 Hz, 1H), 3.87 (brs, 2H), 3.79 (brs, 1H), 3.71 (brs, 1H), 3.60 (brs, 3H), 3.40 (brs, 1H), 3.11 (brs, 1H), 3.04 (brs, 1H), 2.87 (t, J = 7.2 Hz, 2H), 1.69 (sext, J = 7.1 Hz, 2H), 0.97 (t, J = 7.6 Hz, 3H); HRMS (ESI+) m/z calcd for C ₂₃ H ₂₅ FN ₂ O ₄ Na [M+Na] ⁺ : 435.1691, found: 435.1684.

Comparative Example 11: 1-(3-fluoro-4-(4-(2-hydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (compound 11a)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 3) (104 mg, 0.42 mmol), 2-hydroxybenzoic acid (68 mg, 0.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (154 mg, 0.80 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 18 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 10 : 0 to 3 : 2) to give compound 11a as a white solid (64 mg, 41%).
¹ H NMR (400 MHz, CD ₃ OD) δ 9.57 (s, 1H), 7.71 (dd, J = 8.3, 2.0 Hz, 1H), 7.66 (dd, J = 13.7, 2.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.28 (dd, J = 7.7, 1 .7 Hz, 1H), 7.04 (dd, J = 8.4, 1.0Hz, 1H), 6.95-6.86 (m, 2H), 3.96-3.90 (m, 4H)3.29-3.30 (m, 4H), 2.87 (t, J = 7.4 Hz, 2H), 1.76 (sext, J = 7. 4Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.2, 171.1, 159.3, 154.6 (d, J _CF = 246 Hz), 143.2 (d, J _CF = 8.2 Hz), 133.0, 131.6 (d, J _CF = 5.7 Hz), 128.3, 125.2, 118.7, 118.3, 117.9 (d, J _CF = 3.0 Hz), 116.4, 116.1 (d, J _CF = 21.6 Hz), 50.0, 40.2, 17.9, 13.9, three piperazine carbon peaks were not observed. ;HRMS (ESI+) m/z calcd for C ₂₁ H ₂₃ FN ₂ O ₃ Na [M+Na] ⁺ : 393.1585, found: 393.1582.

Comparative Example 12: 1-(3-fluoro-4-(4-(3-hydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (Compound 11b)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 3) (108 mg, 0.43 mmol), 3-hydroxybenzoic acid (69 mg, 0.50 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (153 mg, 0.80 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 18 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 10 : 0 to 7 : 3) to give compound 11b as a white solid (64 mg, 41%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.4, 1.9 Hz, 1H), 7.65 (dd, J = 13.7, 2.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.00-6,98 (m, 1H), 6.95-6.8 7 (m, 3H), 6.79 (br s, 1H), 3.95 (br s, 2H), 3.64 (br s, 2H), 3.37-3.07 (br, 4H), 2.87 (t, J = 7.3 Hz, 2H), 1.75 (sext, J = 7.4Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.3, 170.7, 156.8, 154.6 (d, J _CF = 246 Hz), 143.3 (d, J _CF = 7.2 Hz), 135.9, 131.5 (d, J _CF = 5.7 Hz), 129.8, 125.2, 118.2, 118.0, 117.6, 116.0 (d, J _CF = 21.4 Hz), 114.6, 50.3, 49.7, 47.7, _42.2 , _40.2 , 17.9, 13.9; ₂ O ₃ Na [M+Na] ⁺ : 393.1585, found: 393.1584.

Comparative Example 13: 1-(3-fluoro-4-(4-(4-hydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (Compound 11c)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 3) (108 mg, 0.43 mmol), 4-hydroxybenzoic acid (67 mg, 0.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (153 mg, 0.80 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 13 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/ethyl acetate = 3:2 to 7:3) to give compound 11c as a white solid (75 mg, 47%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 8.5, 2.0 Hz, 1H), 7.65 (dd, J = 13.7, 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.02 (br s, 1H), 6.92 (t, J = 8 .4 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 6.60-6.20 (br, 2H) 3.82 (br s, 4H), 3.22 (br s, 4H), 2.87 (t, J = 7.3 Hz, 2H), 1.75 (sext, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 198.3, 170.6, 157.5, 154.6 (d, J _CF = 246 Hz), 143.4 (d, J _CF = 8.7 Hz), 131.5 (d, J _CF = 5.7 Hz), 129. 4, 127.1, 125.2 (d, J _CF = 2.9 Hz), 117.9, 116.0 (d, J _CF = 21.6 Hz), 115.4, 40.2, _17.9 , 13.9, four piperazine carbon peaks were not observed _{; 3 Na} [M+Na] ⁺ : 393.1585, found: 393.1584.

Comparative Example 14: 1-(3-fluoro-4-(4-(2,3,4-trihydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (Compound 11d)

In a Schlenk tube equipped with a magnetic stir bar, 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (compound 3) (99 mg, 0.40 mmol), 2,3,4-trihydroxybenzoic acid (82 mg, 0.48 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (142 mg, 0.74 mmol) were dissolved in dichloromethane (2 mL). After stirring at room temperature for 20 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (chloroform/methanol = 10 : 0 to 9 : 1) to give compound 11d as a white solid (29 mg, 18%).
¹ H NMR (400 MHz, CD ₃ OD) δ 7.77 (dd, J = 8.5, 2.0 Hz, 1H), 7.65 (dd, J = 14.0, 1.9 Hz, 1H), 7.09 (t, J = 8.6 Hz, 1H), 6.47 (s, 2H), 4.85 (s, 3H), 3.79 (br s, 4H), 3.25 (br s, 4H), 2.93 (t, J = 7.3 Hz, 2H), 1.71 (sext, J = 7.4 Hz, 2H), 0.99 (t, J = _7.4 Hz, 3H); ^, 173.2, 156.0 (d, J _CF = 244 Hz), 147.1, 145.2 (d, J _CF = 8.6 Hz), 136.6, 132.5, 126.7, 126.5, 119.5, 116.6 (d, J _CF = 21.5 Hz), 107.6, 41.0, 19. 0, 14.1, four piperazine carbon peaks were not observed.; HRMS (ESI+) m/z calcd for C ₂₁ H ₂₃ FN ₂ O ₅ K [M+K] ⁺ : 441.1223, found: 441.1223.

Comparative Example 15: (3,4-dihydroxyphenyl)(4-(2-fluoro-4-(1-hydroxybutyl)phenyl)piperazin-1-yl)methanone (Compound 12a)

1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-fluorophenyl)butan-1-one (NSBR1; BL9) (31 mg, 0.080 mmol) was dissolved in methanol (1 mL) in a 5 mL screw-cap tube equipped with a magnetic stir bar. The mixture was cooled to -10 °C. To the mixture was added a solution of _NaBH4 (9.2 mg, 0.24 mmol) in anhydrous methanol ( _{0.5 mL). The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched by adding ethyl acetate and saturated aqueous NaHCO3 solution to the mixture and stirring for 5 min. The organic layer was washed with water and brine, and dried over Na2SO4 . After} filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/ethyl acetate = 2:3) to give compound 12a as a white solid (20 mg, 61%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.09-7.00 (m, 2H), 6.94 (s, 1H), 6.88 (t, J = 8.4 Hz, 1H), 6.76 (s, 2H), 4.62 (t, J = 6.6 Hz, 1H), 4.02-3.80 (br, 2H) ¹³ C NMR (150 MHz, CD ₃ OD) δ 173.0, 157.1 (d, J _CF = 244 Hz), 148.8, 146.5, 142.6 (d, J _CF = 7.2 Hz), 139.8 (d, J _CF = 8.6 Hz), 127.5, 123.2 (d, J _CF = 2.9 Hz), 120.6, .3 (d, J _CF = 2.9 Hz), 116.1, 115.7, 114.6 (d, J _CF = 21.6 Hz), 74.0, 52.1, 42.3, 20.0, 14.3, three piperazine carbon peaks were not observed.; HRMS (ESI+) m/z calcd for C ₂₁ H ₂₆ FN ₂ O ₄ [M+H] ⁺ : 425.1683, found: 425.1680.

Comparative Example 16: (3,4-dihydroxyphenyl)(4-(2-fluoro-4-(1-hydroxy-3-methylbutyl)phenyl)piperazin-1-yl)methanone (Compound 12b)

1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)-3-methyl-butan-1-one (9a) (56.9 mg, 0.14 mmol) was dissolved in methanol (0.5 mL) in a 5 mL screw-cap tube equipped with a magnetic stir bar. The mixture was cooled to 0° C. A solution of NaBH ₄ (7.0 mg, 0.19 mmol) in anhydrous methanol (1 mL) was added to the mixture. The resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched by adding ethyl acetate and saturated aqueous NaHCO ₃ solution to the mixture and stirring for 5 min. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/methanol=9:1) to give compound 12b as a white solid (20 mg, 30%).
¹ H NMR (500 MHz, CDCl ₃ ) δ 6.92-7.13 (m, 3H), 6.87 (t, J = 7.5 Hz, 1H), 6.77 (s, 2H), 4.68 (s, 1H), 3.56-4.15 (m, 5H), 2.92-3.17 (br, 4H), 1 .66-1.70 (m, 2H), 1.43-1.49 (m, 1H) _, 1.25 (t, _J = 7.0 Hz, 1H), 0.94 (d, J = 4.0 Hz, 6H); Hz ⁾ , 148.8, 146.5, 142.8 (d, J _CF = 7.1 Hz), 139.8 (d, J _CF = 8.7 Hz), 127.5, 123.2, 120.6, 120.4, 116.1, 115.7, 114.6 (d, J _CF = 21.6 Hz), .3, 52.1, 25.8, 23.5, 22.6, three piperazine carbon peaks were not observed.; HRMS (ESI+) m/z calcd for C ₂₂ H ₂₈ FN ₂ O ₄ [M+H] ⁺ : 403.2028, found: 403.2024.

[Example 1]

Synthesis Example 1: Methyl 4-(4-butyrylphenyl)piperidine-1-carboxylate (Compound 15)

4-Phenylpiperidine (compound 13) (1.03 g, 6.4 mmol) was dissolved in dichloromethane (23 mL) in a 100 mL two-necked round-bottom flask equipped with a magnetic stir bar. Triethylamine (NEt ₃ ) (0.9 mL, 6.5 mmol) and methyl chloroformate (1.39 mL, 18 mmol) were added at 0°C. After stirring at room temperature for 21 h, 1M aqueous HCl was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The crude product, methyl 4-phenylpiperidine-1-carboxylate (compound 14) (1.49 g, quant.), was used in the next reaction without purification.

In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, AlCl ₃ (473 mg, 3.6 mmol) was dissolved in dichloromethane (5 mL). The mixture was then cooled to 0° C. Butyryl chloride (0.38 mL, 3.6 mmol) was then added dropwise. After stirring at 0° C. for 30 min, a solution of 4-phenylpiperidine-1-carboxylate (compound 14) (398 mg, 1.8 mmol) in dichloromethane (3 mL) was added dropwise. After refluxing for 21 h, the mixture was poured into ice containing 1M aqueous HCl and extracted with dichloromethane. The organic layer was washed with water and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 9:1 to 8:2) to give compound 15 as a yellow oil (286 mg, 55%, 2 steps).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 6.9 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 4.32 (br, 2H), 3.74 (s, 3H), 2.97-2.89 (m, 4H), 2.75 (t, J = 12.0 ¹³ C NMR (150 MHz, CDCl ₃ ) δ 200.0, 155.9, 150.8, 13 5.5, 128.4, 127.0, 52.6, 44.4, 42.6, 40.4, 32.8, 17.8, 13.9; HRMS (ESI+) m/z calcd for C ₁₇ H ₂₄ NO ₃ [M+H] ⁺ : 290.1751, found: 290.1750.

Example 1: 1-(4-(1-(3,4-dihydroxybenzoyl)piperidin-4-yl)phenyl)butan-1-one (compound UA1)

To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, methyl 4-(4-butyrylphenyl)piperidine-1-carboxylate (compound 15) (232 mg, 0.8 mmol), 8M aqueous HCl (4.7 mL), and ethanol (2 mL) were added. The reaction mixture was refluxed for 17 h, and after addition of 5M aqueous NaOH, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and _brine , and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The crude product 1-(4-(piperidin-4-yl)phenyl)butan-1-one (compound 16) (161 mg, crude yield: 87%) was used in the next reaction without purification.

In a screw-cap tube containing a magnetic stir bar, 1-(4-(piperidin-4-yl)phenyl)butan-1-one (compound 16) (34.7 mg, 0.15 mmol), 3,4-dihydroxybenzoic acid (33 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (57 mg, 0.21 mmol), 1-hydroxybenzotriazole (HOBt) (35.6 mg, 0.26 mmol), and 4-dimethylaminopyridine (DMAP) (24 mg, 0.20 mmol) were dissolved in dichloromethane (1.5 mL). After stirring at room temperature for 2 days, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and _brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/methanol = 10:1) and HPLC (conditions = solvent A: _H2O containing 0.1% trifluoroacetic acid, solvent B: acetonitrile containing 0.1% trifluoroacetic acid, solvent gradient = 0-65% gradient of solvent B over 65 minutes) to give compound UA1 as a white solid (12 mg, 22%, 2 steps).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.99 (s, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.77-6.75 (m, 1H), 4.79 (br , 1H), 4.04 (br, 1H), 3.15 (br, 1H), 2.96-2.84 (m, 4H), 2.00 (brs, 1H), 1.86 (brs, 1H), 1.76 (td, J = 14.7, 7.3 Hz, 4H), 1.02-0.99 (m, 3H) ; ^13C NMR (150 MHz, CDCl ₃ ) δ 200.2, 172.1, 149.4, 148.0, 144.5, 135.8, 128.6, 127.0, 126.9, 120.2, 115.2, 114.8, 42.3, 40.5, 33.1, 32.5, , 13.9; HRMS (ESI+) m/z calcd for C ₂₂ H ₂₆ NO ₄ [M+H] ⁺ : 368.1856, found: 368.1858.

[Examples 2 to 3]
Example 2: 4-(4-(4-(1-hydroxybutyl)phenyl)piperidine-1-carbonyl)benzene-1,2-diol (compound 17)

Compound UA1 (101.3 mg, 0.28 mmol) was dissolved in methanol (1.5 mL) in a Schlenk tube equipped with a magnetic stir bar. The mixture was cooled to 0°C. To the mixture was added a solution of _NaBH4 (23.3 mg, 0.62 mmol) in anhydrous methanol (1.5 mL). The resulting mixture was stirred at 0°C for 40 min. The reaction was quenched by adding ethyl acetate and saturated aqueous _NaHCO3 to the mixture and stirring for 5 min. The organic layer was washed with brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/ _methanol = 9:1) to give 4-(4-(4-(1-hydroxybutyl)phenyl)piperidine-1-carbonyl)benzene-1,2-diol (compound 17) (88.7 mg, 87%).
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.30 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.99 (s, 1H), 6.75 (s, 2H), 4.83 (s, 1H), 4.66 (t, J = 6.6 Hz, 1H) , 4.03 (s, 1H), 3.12 (s, 1H), 2.89-2.76 (m, 2H), 1.28-2.03 (9H), 0.93 (t, J = 7.4 Hz, 3H).

Example 3: 1-(4-(1-(3-hydroxybenzoyl)piperidin-4-yl)phenyl)butan-1-one (compound 18)

In a screw-cap tube equipped with a magnetic stir bar, 1-(4-(piperidin-4-yl)phenyl)butan-1-one hydrochloride (compound 16·HCl; a solid obtained by adding 4 M hydrochloric acid·dioxane solution and methanol to compound 16 obtained in Example 1 was used) (100.3 mg, 0.37 mmol), 3-hydroxybenzoic acid (63.6 mg, 0.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl·HCl) (109.3 mg, 0.57 mmol), 1-hydroxybenzotriazole (HOBt) (79.3 mg, 0.59 mmol), and diisopropylethylamine (0.26 mL, 1.45 mmol) were dissolved in dimethylformamide (DMF) (2.0 mL). After stirring at room temperature for 1 day, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO ₄ . After filtration, the solvent was removed by evaporation, and the resulting residue was purified by MPLC (chloroform/ethyl acetate = 8:2 to 6:4) to give 1-(4-(1-(3-hydroxybenzoyl)piperidin-4-yl)phenyl)butan-1-one (compound 18) (129.6 mg, 98%).
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.92 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.25-7.23 (m, 1H), 7.02-7.00 (m, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6 .87 (dd, J = 8.0, 2.6 Hz, 1H), 6.51-6.40 (m, 1H), 4.89 (brs, 1H), 3.95 (brs, 1H), 3.13 (brs, 1H), 2.95-2.81 (m, 4H), 2.00 (brs, 1H), .60 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H).

[Example 4]

Synthesis Example 2: Methyl-4-(4-(3-methylbutanoyl)phenyl)piperidine-1-carboxylate (Compound 19)

In a 50 mL two-necked round bottom flask equipped with a magnetic stir bar, AlCl ₃ (533 mg, 4.0 mmol) was dissolved in dichloromethane (5.0 mL) and cooled to 0°C. Then, isovaleryl chloride (0.49 mL, 4.0 mmol) was added dropwise. After stirring at 0°C, a solution of methyl 4-phenylpiperidine-1-carboxylate (compound 14; from step 1 of Synthesis Example 1) (458.4 mg, 2.0 mmol) in dichloromethane (3 mL) was added dropwise. After refluxing for 18 h, the mixture was poured into ice containing 1M aqueous HCl and extracted with dichloromethane. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane/ethyl acetate = 9:1 to 8:2) to give methyl-4-(4-(3-methylbutanoyl)phenyl)piperidine-1-carboxylate (compound 19) (249.3 mg, 39%).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.90 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.38-4.22 (m, 2H), 3.72 (s, 3H), 2.77-2.95 (m, 4H), 2.73 (tt, J = 12.3, 3.5 Hz, 1H), 2.32-2.25 (m, 1H), 1.88-1.81 (m, 2H), 1.67-1.60 (m, 2H), 0.99 (d, J = 6.9 Hz, 6H).

Synthesis Example 3: 3-methyl-1-(4-(piperidin-4-yl)phenyl)butan-1-one (Compound 20)

In a 50 mL two-necked round bottom flask equipped with a magnetic stir bar, methyl-4-(4-(3-methylbutanoyl)phenyl)piperidine-1-carboxylate (compound 19) (32.9 mg, 0.11 mmol), 8M aqueous HCl (5.0 mL), and ethanol (2 mL) were added. The reaction mixture was refluxed for 24 h, and after addition of 5M aqueous NaOH, the mixture was poured into water and extracted with ethyl _acetate . The organic layer was washed with brine and dried over _Na2SO4 . After filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/methanol = 9:1 with the addition of triethylamine) to give 3-methyl-1-(4-(piperidin-4-yl)phenyl)butan-1-one (compound 20) (12.0 mg, 45%).
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 3.32-3.22 (m, 2H), 3.01 (s, 2H), 2.83-2.67 (m, 4H), 2.38-2.19 ( 1H), 1.96-1.82 (m, 2H), 1.82-1.59 (m, 2H), 0.99 (d, J = 6.6 Hz, 6H).

Example 4: 1-(4-(1-(3,4-dihydroxybenzoyl)piperidin-4-yl)phenyl)-3-methylbutan-1-one (Compound 21)

In a screw-cap tube containing a magnetic stir bar, 3-methyl-1-(4-(piperidin-4-yl)phenyl)butan-1-one (compound 20) (12.0 mg, 48.9 μmol), 3,4-dihydroxybenzoic acid (14.6 mg, 94.7 μmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl) (18.6 mg, 97.0 μmol), 1-hydroxybenzotriazole (HOBt) (12.3 mg, 91.0 μmol), and diisopropylethylamine (40 μL, 0.22 mmol) were dissolved in dimethylformamide (DMF) (0.5 mL). After stirring at room temperature for 19 h, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na ₂ SO _4. After filtration, the solvent was removed by evaporation. The resulting residue was purified by PTLC (chloroform/methanol=9:1) to give 1-(4-(1-(3,4-dihydroxybenzoyl)piperidin-4-yl)phenyl)-3-methylbutan-1-one (compound 21) (10.5 mg, 56%).
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 7.01 (s, 1H), 6.76 (s, 2H), 5.06-4.62 (m, 1H), 4.30-3.85 (m, 1H) ), 3.24-2.63 (m, 7H), 2.38-2.17 (m, 1H), 2.12-1.41 (m, 2H), 0.98 (d, J = 6.6 Hz, 6H).

Test Example 1: Rice Lamina Joint Assay The lamina joint assay was adapted to the bioprotocol. Seeds of Taiwanese rice variety Taichung 65 were grown in a greenhouse by Professor Motoyuki Ashikari and Associate Professor Shiro Miya of the National University Corporation Tokai National Higher Education and Research System. Seeds were vacuum-packed and stored at 4°C before use, and heat-treated at 50°C for 2 days. After cooling to room temperature, the husks were removed manually, washed with 70% ethanol, rinsed with sterile distilled water, and sterilized with 20 mL of 5% sodium hypochlorite solution (Fujifilm Wako Pure Chemical Industries, Ltd.) and one drop of Tween 20 (Sigma-Aldrich) for 1 hour by stirring. Seeds were washed again 10 times with sterile distilled water and dried on sterile filter paper in a clean bench. The sterilized seeds were sown in a 1 L glass beaker containing 1/2 MS with 2% water added and the pH adjusted to 5.7, and germinated in a growth chamber (PCBI Japan) at 28°C under long-day conditions (lights on for 16 hours).

Seedlings were harvested on the 8th day and the same length (approximately 8 cm) at the third leaf stage was used for the assay. 2 cm from the second leaf joint was cut with a fresh razor and placed in sterile distilled water for 10 min. Three lamina joint sections were then placed in 55 mM diameter petri dishes containing 10 mL of sterile distilled water containing appropriate concentrations of epiBL (natural brassinosteroids) and brassinosteroid-like compounds diluted from 10 mM stocks in DMSO (Fujifilm Wako Pure Chemicals). An equal volume of DMSO was used as a control. Lamina joint sections were incubated in the dark at 28°C for 2 days with regular agitation before being measured. Photographs of lamina joint sections were taken with a Canon digital camera and analysed using the “measure angle” function in ImageJ 1.53k (NIH USA). The assay was independently repeated three times (total of 9 lamina joint sections per concentration).

The results are shown in Figures 1 to 3.

Test Example 2: Titration of EpiBL and UA1 by Lamina Joint Assay Lamina joint sections were prepared as described above. Appropriate concentrations of EpiBL (natural brassinosteroids) and brassinosteroid-like compounds diluted from 10 mM stocks in DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.) were added to 10 mL of sterile distilled water at the highest concentration. Serial dilutions of 1:10 were made by vortexing the first dilution, removing 1 mL, and adding it to 9 mL of water in the next concentration dish. This was repeated until all dilutions were completed, and the last 1 mL was discarded.

The results are shown in Figure 4.

Test Example 3: Quantitative real-time PCR
Hypocotyl elongation assays were performed according to the procedure proposed by Asami et al. Wild-type Arabidopsis (WT) plants were grown in the dark for 7 days on 1/2 MS medium containing 0.8% Phytoagar and 1.5% sucrose. They were immersed in a solution of 0.1% (v/v) DMSO (control), 0.1 μM EpiBL, 0.1 μM UA1, 1 μM UA1, or 10 μM UA1 for 3 h and prepared in 1/2 MS medium without Phytoagar and sucrose. Plant samples were removed and stored in liquid nitrogen for later RNA extraction. Total RNA was extracted from the samples using the RNeasy Plant Mini Kit (QIAGEN GmbH, Hilden, Germany). Complementary DNA (cDNA) was synthesized using ReverTra Ace (Toyobo Co., Ltd.) and used for quantitative real-time PCR (qRT-PCR). qRT-PCR was performed using the THUNDERBIRD SYBR qPCR system (Takara) according to the instructions provided with the LightCycler 96 System (Roche Diagnostics).

The following primers were used:
DWARF4 uses 5'-GTGATCTCAGCCGTACATTTGGA-3' and 5'-CACGTCGAAAAACTACCACTTCCT-3'.
BR6ox2 uses 5'-CAATAGTCTCAATGACGCAGT-3' and 5'-AACCGCAGCTATGTTG CATG-3';
UBQ2 uses 5'-CCAAGATCCAGGACAAAGAAGGA-3' and 5'-TGGAGACGAGC ATAACTTGC-3';
For ACT2, 5'-CGCCATCCAAGCTGTTCTC-3' and 5'-TCACGTCCAGC AAGGTCAAG-3' were used.

UBQ2 and ACT2 were used as constitutive expression control genes.

The results are shown in Figure 5.

As described above, UA1 obtained in Example 1 has brassinosteroid-like activity that is comparable to that of EpiBL, a natural brassinosteroid, and it can be understood that it is a compound with significantly higher brassinosteroid-like activity than conventional non-steroidal BRI1 agonist molecules. Furthermore, the compounds obtained in Examples 2 to 4 also had brassinosteroid-like activity equivalent to that of UA1 obtained in Example 1.

Claims (18)

General formula (1):

[Wherein,
Ring A and ring B may be the same or different and each represents a monocyclic aromatic or non-aromatic ring.
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
L ₁ and L ₂ are the same or different and each represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)- or -S(O) ₂ -.
n represents 0 or 1.
A compound represented by the formula: 2. The compound or salt thereof according to claim 1, wherein L ₁ and L ₂ are the same or different and each represent a bond, -C(O)-, -CS-, -S(O)-, or -S(O) ₂ -. The compound or a salt thereof according to claim 2, wherein L ₁ is -C(O)- and L ₂ is a bond. The compound or salt thereof according to claim 1, wherein ring A and ring B are the same or different and are 6-membered monocyclic aromatic or non-aromatic rings. The compound or salt thereof according to claim 4, wherein ring A and ring B are both benzene rings. The compound or salt thereof according to claim 1, wherein n is 1. R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;
The compound or salt thereof according to claim 1, wherein R ⁴ , R ⁵ and R ⁶ are the same or different and each is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group, or two of R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, and the two groups, together with the atoms on ring B to which they are bonded, form a monocyclic heteroaromatic ring. General formula (1A):

[Wherein,
R ^1a and R ^2a are the same or different and each represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted carbamoyl group.
R ^4a represents a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group.
R ^5a represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group.
The compound according to claim 7 or a salt thereof, An agricultural composition containing the compound or salt thereof according to any one of claims 1 to 8. The agricultural composition according to claim 9, which is applied to at least one species selected from the group consisting of agricultural crops, vegetables, fruit trees, weeds and ornamental plants. The agricultural composition according to claim 9, which is a plant growth regulator. The agricultural composition according to claim 11, which is a plant growth promoter. The agricultural composition according to claim 12, wherein the plant is at least one selected from the group consisting of vegetables and fruit trees. The agricultural composition according to claim 11, which is a plant growth inhibitor. The agricultural composition according to claim 14, wherein the plant is a weed. A method for regulating plant growth, comprising the step of applying the compound or a salt thereof according to any one of claims 1 to 8 to a plant. General formula (6):

[Wherein,
Ring B is a monocyclic aromatic or non-aromatic ring.
R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
^R7 represents a substituted or unsubstituted alkyl group.
_L2 represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)-, or -S(O) ₂ -.
n represents 0 or 1.
A compound represented by the formula: General formula (7):

[Wherein,
Ring B is a monocyclic aromatic or non-aromatic ring.
R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group. When two groups among R ⁴ , R ⁵ and R ⁶ are bonded to adjacent atoms on ring B, the two groups may form a monocyclic aromatic or non-aromatic ring together with the atoms on ring B to which they are bonded.
_L2 represents a bond, an alkylene group, -NH-, -O-, -S-, -C(O)-, -CS-, -S(O)-, or -S(O) ₂ -.
n represents 0 or 1.
A compound represented by the formula:

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