Compound having brassinosteroid-like activity

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

[0001] The present invention relates to compounds having brassinosteroid-like activity.

[0002] Brassinosteroids (BRs) are plant growth hormones with a steroid skeleton whose structures were determined by Grove et al. in 1979. To date, over 70 BRs have been discovered in nature, and some 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 tolerance to abiotic stresses induced by high salinity, high temperature, heavy metals, and drought, as well as biotic stresses induced by bacteria, viruses, fungi, parasites, and insects. Therefore, BRs are promising molecules for agricultural applications.

[0003] Since the early 1980s, when the outline of BR's growth-regulating activity became clear, many researchers and agrochemical companies have been investigating its agricultural applications. However, while other plant hormones, such as gibberellins, auxins, cytokinins, and ethylene, have been put to practical use as pesticides, the use of BR-related compounds has remained limited even 40 years later. The reasons for the lack of progress in BR utilization include the high production costs and low profitability of BR, which has a steroid skeleton that is difficult to chemically synthesize, as well as the low metabolic stability and difficulty in maintaining BR's biological activity over a long period of time. For example, BR can only be extracted in trace amounts from plants, and it is prone to degradation and has poor stability. Furthermore, chemical synthesis of BR requires nine steps, making it extremely difficult even for those skilled in the art. When using plant hormones in agriculture, approaches such as developing synthetic plant hormone mimics are often used to control the synthetic complexity, redundancy, metabolic stability, and other factors that make application possible.

[0004] Since the steroid structure of BR contributes to the synthetic complexity, several molecules have been developed to date that have non-steroidal structures and activate BR signaling.

[0005] For example, in 1988, it was revealed that lithium targets the kinase BIN2 downstream of the BR receptor and causes BR signaling by inhibiting the enzymatic activity of BIN2. However, lithium is highly toxic, limiting its use.

[0006] In 1994, oleic acid monoglyceride isolated from the fungus Talaromyces trachysoerms was discovered to have BR-like activity. However, its activity was extremely weak, 1 / 100,000th of that of BR, and its interaction with the BR receptor, BRI1, was not confirmed.

[0007] Furthermore, in 2009, compound screening using an Arabidopsis hypocotyl elongation activity assay revealed that bikinin has the same activity as BR. Like lithium, bikinin induces BR signaling by inhibiting the enzyme activity of BIN2. Bikinin almost completely covers the genes expressed by BR and has been widely used as a tool in basic plant biology research. Its activity has been improved through derivatives, and research has also been conducted with a view to its potential agricultural applications. However, bikinin has low metabolic stability and is rapidly inactivated in vivo by binding to glutamate and malate.

[0008] Meanwhile, attempts are being made to synthesize non-steroidal BR mimetic molecules by targeting the BR receptor BRI1. The first example, a compound synthesized in 2001, 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.

[0009] Furthermore, 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, measurement of BR activity in rice bends showed that the activity of BL9 was 1 / 1000 of that of BR.

[0010] International Publication No. 2018 / 159827

[0011] As described above, the use of compounds with BR-like activity is still in the developmental 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.

[0012] The present invention is intended to solve the above-mentioned problems, and has as its object to provide a non-steroidal molecule having high brassinosteroid (BR)-like activity.

[0013]

[0009] As a result of intensive investigations in view of the above-mentioned object, the present inventors have found that, in particular, by replacing the piperazine ring at the central position of BL9 with a piperidine ring, i.e., by reducing the number of nitrogen atoms at the central position from two to one (changing from a piperazine ring to a piperidine ring), strong activity comparable to that of natural BR can be exhibited. Based on this finding, the present inventors have conducted further intensive research and completed the present invention. That is, the present invention encompasses the following configurations.

[0014] Item 1. General formula (1):

[0015] [wherein, ring A and ring B may be the same or different and represent a monocyclic aromatic ring or a non-aromatic ring. R １ , R ２ , R ３ , R ４ , R ５ and R ６ are the same or different and 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. ４ , R ５ and R ６ When two of the groups L are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. １ and L ２ are the same or different and represent a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O)２ - represents 0 or 1.] or a salt thereof.

[0016] Item 2. L １ and L ２ are the same or different and are a bond, —C(O)—, —CS—, —S(O)—, or —S(O) ２ Item 2. The compound or salt thereof according to Item 1, wherein - is -.

[0017] Item 3. L １ is —C(O)—, and L ２ Item 3. The compound or salt thereof according to Item 1 or 2, wherein is a bond.

[0018] 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.

[0019] Item 5. The compound or salt thereof according to any one of Items 1 to 4, wherein both ring A and ring B are benzene rings.

[0020] Item 6. The compound or salt thereof according to any one of Items 1 to 5, wherein n is 1.

[0021] Section 7. R １ , R ２ and R ３ are the same or different and represent 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; R ４ , R ５ and R ６ are the same or different and are 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 R ４ , R ５ and R ６ and two of the 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 heteroaromatic ring, or a salt thereof.

[0022] Section 8. General formula (1A):

[0023] [In the formula, R １ａ and R ２ａ are the same or different and 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. ４ａ represents a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyl group. 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.]

[0024] Item 9. An agricultural composition comprising the compound or salt thereof according to any one of Items 1 to 8.

[0025] 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.

[0026] Item 11. The agricultural composition according to Item 9 or 10, which is a plant growth regulator.

[0027] Item 12. The agricultural composition according to any one of Items 9 to 11, which is a plant growth promoter.

[0028] Item 13. The agricultural composition according to Item 12, wherein the plant is at least one species selected from the group consisting of vegetables and fruit trees.

[0029] Item 14. The agricultural composition according to any one of Items 9 to 11, which is a plant growth regulator.

[0030] Item 15. The agricultural composition according to Item 14, wherein the plant is a weed.

[0031] 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.

[0032] Section 17. General formula (6):

[0033] [wherein, ring B represents a monocyclic aromatic ring or a non-aromatic ring.４ , R ５ and R ６ are the same or different and 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. ４ , R ５ and R ６ When two of the groups R are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. ７ represents a substituted or unsubstituted alkyl group. ２ represents a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O) ２ - represents 0 or 1.]

[0034] Section 18. General formula (7):

[0035] [wherein, ring B represents a monocyclic aromatic ring or a non-aromatic ring. ４ , R ５ and R ６ are the same or different and 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. ４ , R ５ and R ６ When two of the groups L are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. ２ represents a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O) ２ - represents 0 or 1.]

[0036] According to the present invention, a non-steroidal molecule having high BR-like activity can be provided.

[0037] 1 is a diagram showing the results of Test Example 1. FIG. 2 is a diagram showing the results of Test Example 1. FIG. 3 is a diagram showing the results of Test Example 2. FIG. 4 is a diagram showing the results of Test Example 3.

[0038] In this specification, the term "containing" is a concept that encompasses all of "comprise," "consist essentially of," and "consist only of."

[0039] In addition, in this specification, when a numerical range is expressed as "A to B," it means A or more and B or less.

[0040] 1. Compounds having brassinosteroid-like activity The compounds of the present invention are represented by the general formula (1):

[0041] [wherein, ring A and ring B may be the same or different and represent a monocyclic aromatic ring or a non-aromatic ring. R １ , R ２ , R ３ , R ４ , R ５ and R ６ are the same or different and 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. ４ , R ５ and R ６ When two of the groups L are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. １ and L ２ are the same or different and represent a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O) ２ - represents 0 or 1.] or a salt thereof.

[0042] R １ , R ２ , R ３ , R ４ , R ５ and R ６ The halogen atom represented by 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.

[0043] R １ , R ２ , R ３ , R ４ , R ５ and R ６ The alkyl group represented by the formula (I) is not particularly limited, but is preferably a linear or branched saturated hydrocarbon group 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 As R, an alkyl group having 1 to 4 carbon atoms (C1-C4 alkyl group) is preferred, and an alkyl group having 1 to 3 carbon atoms (C1-C3 alkyl group) is more preferred. ４ , R ５ and R ６ As the alkyl group, an alkyl group having 2 to 6 carbon atoms (C2-C6 alkyl group) is preferred, and an alkyl group having 3 to 6 carbon atoms (C3-C6 alkyl group) is more preferred. 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, and a 1,1,2-trimethylpropyl group. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., R １ , R ２ and R ３ As R, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a tert-butyl group, etc. are preferred. ４ , R ５ and R ６Preferred examples of the alkyl group 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.

[0044] The alkyl group described above may have a substituent. The number of substituents is not particularly limited and may be, for example, one 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 optionally substituted with alkoxy groups described below. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., R １ , R ２ and R ３ The alkyl group represented by the formula (I) may have 1 to 3 substituents such as a hydroxyl group and an imino group which may be substituted with an alkoxy group as described below. ４ , R ５ and R ６ The substituents which the alkyl group represented by the formula (I) may have can be 1 to 3 hydroxyl groups.

[0045] R １ , R ２ , R ３ , R ４ , R ５ and R ６ The alkoxy group represented by the formula (I) 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 viewpoints of BR-like activity, ease of synthesis, etc., R １ , R ２ and R ３ As R, an alkoxy group having 1 to 4 carbon atoms (C1-C4 alkoxy group) is preferred, and an alkoxy group having 1 to 3 carbon atoms (C1-C3 alkoxy group) is more preferred. ４ , R ５ and R ６As for R, an alkoxy group having 2 to 6 carbon atoms (C2-C6 alkoxy group) is preferred, and an alkoxy group having 3 to 6 carbon atoms (C3-C6 alkoxy group) is more preferred. 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, and a 1,1,2-trimethylpropyloxy group. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., R １ , R ２ and R ３ As R, a methoxy group, an ethoxy group, etc. are preferred. ４ , R ５ and R ６ Preferred examples of the alkyl group 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.

[0046] The above-mentioned alkoxy group may also have a substituent. The number of substituents is not particularly limited and can 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 alkoxy group may have can be 1 to 5 halogen atoms (particularly fluorine atoms).

[0047] R １ , R ２ , R ３ , R ４ , R ５ and R ６The alkanoyl group represented by the formula (I) 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. Of 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. Of 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, a heptanoyl group, etc. are preferred.

[0048] The above-mentioned alkanoyl group may also have a substituent. The number of substituents is not particularly limited and can 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 alkanoyl group may have can be 1 to 5 halogen atoms (particularly fluorine atoms).

[0049] R １ , R ２ , R ３ , R ４ , R ５ and R ６The alkylsulfonyl group represented by the formula (I) means a monovalent group in which a sulfonyl group is bonded to the aforementioned alkyl group, and is preferably an alkylsulfonyl group having 1 to 6 carbon atoms (C1-C6 alkylsulfonyl group). Of 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, and a propylsulfonyl group. Of these, from the viewpoints of BR-like activity, ease of synthesis, etc., an ethylsulfonyl group, a propylsulfonyl group, etc. are preferred.

[0050] The alkylsulfonyl group described above may also have a substituent. The number of substituents is not particularly limited and can 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, and the like, the substituents that the alkylsulfonyl group may have can be 1 to 5 halogen atoms (particularly fluorine atoms).

[0051] R １ , R ２ , R ３ , R ４ , R ５ and R ６ The carbamoyl group represented by the formula (I) may have a substituent. The number of substituents is not particularly limited and can 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. In particular, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the carbamoyl group may have can be 1 to 2 of the above-mentioned alkyl groups (particularly 1 to 2 methyl groups).

[0052] R １ , R ２ , R ３ , R ４ , R５ and R ６ The amino group represented by the formula (I) may also have a substituent. The number of substituents is not particularly limited and can be, for example, 1 to 2, and the substituents may be the same or different. Examples of such substituents include the halogen atoms, hydroxyl groups, alkyl groups, alkanoyl groups, and optionally substituted carbamoyl groups. In particular, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the amino group may have can be one to two of the alkanoyl groups, a carbamoyl group optionally substituted with one or two of the alkyl groups, or the like (particularly a carbamoyl group optionally substituted with one to two acetyl groups or one to two methyl groups).

[0053] R １ , R ２ , R ３ , R ４ , R ５ and R ６ From the viewpoint of BR-like activity, ease of synthesis, etc., preferred examples of the alkyl group include a hydrogen atom; the halogen atoms described above; a hydroxyl group; a nitro group; the alkyl group (particularly, an imino group which may be substituted with the alkoxy group described above and an alkyl group which may be substituted with 1 to 3 hydroxyl groups); the alkoxy group; the alkanoyl group (particularly, an alkanoyl group which may be substituted with 1 to 5 halogen atoms described above); an alkylsulfonyl group (particularly, an alkylsulfonyl group which may be substituted with 1 to 5 halogen atoms described above); a substituted or unsubstituted carbamoyl group (particularly, a carbamoyl group which may be substituted with 1 to 2 alkyl groups described above); a substituted or unsubstituted amino group (particularly, an amino group which may be substituted with 1 to 2 of the alkanoyl group, the carbamoyl group, etc.); ４ , R ５ and R ６and two groups out of these 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, etc.);

[0054] In another embodiment, from the viewpoint of BR-like activity, ease of synthesis, etc., R １ , R ２ and R ３ is 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, a carbamoyl group which may be substituted with 1 to 2 alkyl groups), the above-mentioned 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.), or the like, and R ４ , R ５ and R ６ is a hydrogen atom, the above-mentioned halogen atom, the above-mentioned substituted or unsubstituted alkyl group (particularly the above-mentioned imino group optionally substituted with an alkoxy group and an alkyl group optionally substituted with 1 to 3 hydroxyl groups), the above-mentioned substituted or unsubstituted alkanoyl group (particularly the above-mentioned alkanoyl group optionally substituted with 1 to 5 halogen atoms), or the like, or R ４ , R ５ and R ６are bonded to adjacent atoms on ring B, and the two groups together with the atoms on ring B to which they are bonded preferably form a monocyclic heteroaromatic ring; １ , R ２ and R ３ is 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, a carbamoyl group which may be substituted with 1 to 2 alkyl groups), the above-mentioned 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.), or the like, and R ４ , R ５ and R ６ is more preferably a hydrogen atom, the above-mentioned halogen atom, the above-mentioned substituted or unsubstituted alkyl group (particularly, the above-mentioned imino group optionally substituted with an alkoxy group and an alkyl group optionally substituted with 1 to 3 hydroxyl groups), the above-mentioned substituted or unsubstituted alkanoyl group (particularly, an alkanoyl group optionally substituted with 1 to 5 halogen atoms), or the like.

[0055] In another embodiment, from the viewpoint of BR-like activity, ease of synthesis, etc., R １ , R ２ and R ３ is 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 optionally substituted with one methyl group, or the like, and R ４ , R ５ and R ６ is 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, or the like, or R ４ , R ５ and R ６are bonded to adjacent atoms on ring B, and the two groups, together with the atoms on ring B to which they are bonded, preferably form a monocyclic aromatic heterocycle (particularly, a pyrazole ring optionally substituted with 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, at least one of which is a hydrogen atom, and R ４ , R ５ and R ６ is a hydrogen atom, a hydroxyl group, a fluorine atom, a C2-C6 alkyl group optionally substituted with 1 to 3 hydroxyl groups (particularly an n-butyl group optionally substituted with one hydroxyl group), a C2-C6 alkoxy group optionally 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, etc.), or the like, or R ４ , R ５ and R ６ More preferably, two of the 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 aromatic heterocycle (particularly, a pyrazole ring optionally substituted with one alkyl group (particularly, an isobutyl group)), and R １ , R ２ and R ３ are a hydrogen atom, a hydroxyl group, a methoxy group, an acetylamino group, or the like, at least one of which is a hydrogen atom, and R ４ , R ５ and R ６ is more preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a C2-C6 alkyl group optionally substituted with 1 to 3 hydroxyl groups (particularly an n-butyl group optionally substituted with 1 hydroxyl group), a C2-C6 alkoxy group optionally 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, etc.), or the like.

[0056] L １ and L ２The alkylene group represented by the formula (I) means a divalent group obtained by removing one hydrogen atom from the alkyl group. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., alkylene groups having 1 to 3 carbon atoms (C1-C3 alkylene groups) are preferred, and alkylene groups having 1 to 2 carbon atoms (C1-C2 alkylene groups) are more preferred. Specific examples of the alkylene group include a methylene group, an ethylene group, a trimethylene group, and a propylene group. Among these, from the viewpoints of BR-like activity, ease of synthesis, etc., a methylene group is preferred.

[0057] L １ and L ２ From the viewpoint of BR-like activity, ease of synthesis, etc., the bond, -C(O)-, -CS-, -S(O)-, -S(O) ２ - and the like are preferred, a bond, -C(O)-, -CS-, -S(O)- and the like are more preferred, and L １ is —C(O)—, —CS—, —S(O)—, etc., and L ２ is more preferably a bond, and L １ is —C(O)—, and L ２ is particularly preferably a bond.

[0058] The monocyclic aromatic ring represented by ring A and ring B is not particularly limited, but includes a monocyclic aromatic carbocycle (benzene ring), a monocyclic aromatic heterocycle, and the like.

[0059] The monocyclic aromatic carbocycle (benzene ring) may also have a substituent. The number of substituents is not particularly limited and can 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, alkyl groups, alkanoyl groups, and carbamoyl groups optionally substituted with 1 to 2 alkyl groups. In particular, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic aromatic carbocycle (benzene ring) may have can be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and the like (particularly alkyl groups).

[0060] From the viewpoints of BR-like activity, ease of synthesis, etc., the monocyclic aromatic heterocycle is preferably a 5- or 6-membered monocyclic aromatic heterocycle containing, in addition to carbon and hydrogen atoms, 1 to 4 heteroatoms such as oxygen atoms, sulfur atoms, nitrogen atoms, etc. Specific examples of the monocyclic aromatic heterocycle include 5-membered monocyclic aromatic heterocycles such as a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, and a thiadiazole ring; and 6-membered monocyclic aromatic heterocycles such as a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiazine ring, and a triazine ring. Of these, from the viewpoints of BR-like activity, ease of synthesis, etc., a pyrazole ring is preferred.

[0061] The monocyclic aromatic heterocycle may also have a substituent. The number of substituents is not particularly limited and can 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, alkyl groups, alkanoyl groups, and carbamoyl groups optionally substituted with 1 to 2 alkyl groups. In particular, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic aromatic heterocycle may have can be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and the like (particularly alkyl groups).

[0062] The monocyclic non-aromatic ring represented by ring A and ring B includes a monocyclic non-aromatic carbocycle, a monocyclic non-aromatic heterocycle, and the like.

[0063] As the monocyclic non-aromatic carbocycle, a 5- or 6-membered monocyclic non-aromatic carbocycle is preferred from the viewpoints of BR-like activity, ease of synthesis, etc. 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. Of these, a 6-membered monocyclic non-aromatic carbocycle is preferred from the viewpoints of BR-like activity, ease of synthesis, etc.

[0064] The monocyclic non-aromatic carbocycle may also have a substituent. The number of substituents is not particularly limited and can 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, alkyl groups, alkanoyl groups, and carbamoyl groups optionally substituted with 1 to 2 alkyl groups. In particular, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic non-aromatic carbocycle may have can be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and the like (particularly alkyl groups).

[0065] 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, in addition to carbon and hydrogen atoms, for example, 1 to 4 heteroatoms such as oxygen atoms, sulfur atoms, nitrogen atoms, etc. Specific examples of the monocyclic non-aromatic heterocycle 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. Of these, from the viewpoints of BR-like activity, ease of synthesis, etc., a 6-membered monocyclic non-aromatic heterocycle is preferred.

[0066] The monocyclic non-aromatic heterocycle may also have a substituent. The number of substituents is not particularly limited and can 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, alkyl groups, alkanoyl groups, and carbamoyl groups optionally substituted with 1 to 2 alkyl groups. In particular, from the viewpoints of BR-like activity, ease of synthesis, and the like, the substituents that the monocyclic non-aromatic heterocycle may have can be 1 to 2 of the above-mentioned halogen atoms, hydroxyl groups, alkyl groups, and the like (particularly alkyl groups).

[0067] R ４ , R ５ and R ６When two of the groups 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, and the monocyclic aromatic ring and non-aromatic ring that can be formed in this case can also be those described above.

[0068] As ring A and ring B, from the viewpoints of BR-like activity, ease of synthesis, etc., a 6-membered monocyclic aromatic ring (a monocyclic aromatic carbocyclic ring (benzene ring), a 6-membered monocyclic aromatic heterocyclic ring, etc.), a 6-membered monocyclic non-aromatic ring (a 6-membered monocyclic non-aromatic carbocyclic ring, a 6-membered monocyclic non-aromatic heterocyclic ring), etc. are preferred. Specifically, from the viewpoints of BR-like activity, ease of synthesis, etc., ring A and ring B are preferably a cyclohexane ring, cyclohexene ring, piperidine ring, piperazine ring, tetrahydropyran ring, tetrahydrothiopyran ring, morpholine ring, thiomorpholine ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, thiazine ring, triazine ring, etc., with a benzene ring being more preferred.

[0069] n is 0 or 1, and is preferably 1 from the viewpoints of BR-like activity, ease of synthesis, and the like.

[0070] Examples of the compound of the present invention that satisfies the above conditions include compounds represented by the general formula (1A):

[0071] [In the formula, R １ａ and R ２ａ are the same or different and 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. ４ａ represents the above-mentioned halogen atom, the above-mentioned substituted or unsubstituted alkyl group, the above-mentioned substituted or unsubstituted alkoxy group, or the above-mentioned substituted or unsubstituted alkanoyl group.] or a salt thereof is preferred.

[0072] When the compound of the present invention has an asymmetric carbon atom in the molecule, it can exist as a plurality of 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 a mixture thereof.

[0073] The compounds of the present invention may contain isotopes (e.g., ２ H. ３ H. １３ C. １４ C. １５ N. １８ F. ３５ S. １２５ I, etc.), and deuterium conversions.

[0074] The compound of the present invention can exist in free form or in the form of a salt. Examples of the salt 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.

[0075] The compound of the present invention or a salt thereof includes any of its internal salts, adducts, solvates, hydrates, and the like.

[0076] 2. Agricultural Composition and Plant Growth Regulating Method The agricultural composition containing the compound of the present invention or a salt thereof can be formulated into an oil concentrate, an emulsifiable concentrate, a flowable concentrate, a wettable powder, a water dispersible granule, a dust concentrate, a granule concentrate, or the like by appropriately adding an inert carrier, a surfactant, other formulation adjuvants, or the like.

[0077] The inert carrier can 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.

[0078] Examples of surfactants include 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.

[0079] Examples of other formulation adjuvants include 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 (acid isopropyl phosphate); and stabilizers such as BHT.

[0080] The agricultural composition of the present invention can contain the compound of the present invention or a salt thereof in an amount of usually 0.01 to 99% by mass, particularly 0.1 to 95% by mass, and further particularly 0.5 to 90% by mass.

[0081] In the present invention, when the compound or salt thereof of the present invention, or the agricultural composition of the present invention is applied to a plant, it may be applied to the whole plant or a part of the plant (stems, leaves, buds, flowers, fruits, ears, seeds, roots, etc.), or may be applied to various growth stages of the plant (germination periods such as before or after emergence after sowing; vegetative growth periods such as during seedling raising, during seedling transplantation, during cuttings or cuttings, and during growth after planting; reproductive growth periods such as immediately before or during heading, etc.).

[0082] 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 spray treatments is usually 1 to 3 times.

[0083] Examples of application methods in the present invention include treatment of plant stems and leaves, flower organs, or panicles, such as spraying on stems and leaves (i.e., spraying treatment), treatment of plant seeds before sowing in soil or cultivation medium (i.e., seed treatment), treatment of soil (cultivation area) before or after planting plants (i.e., soil treatment), and treatment of seedlings (e.g., seedling box treatment, seedling tray treatment, etc.).

[0084] In the present invention, examples of spray treatments to the stems, leaves, floral organs, or panicles of plants include methods in which an effective amount of the compound of the present invention or a salt thereof, or the agricultural composition of the present invention is applied to the surface of the plant, such as by foliage spray, or to the panicles at the heading stage or to the entire plant. One embodiment of treatment to plants is treatment to plants growing in paddy fields. In addition, examples of the timing of spray treatment include the flowering period, including before, during, and after flowering.

[0085] Examples of plant seed treatments according to the present invention include methods in which an effective amount of the compound of the present invention or a salt thereof, or the agricultural composition of the present invention is applied to plant seeds before they are sown in soil or a culture medium. Specific treatment methods include spraying, smearing, dipping, impregnation, painting, 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 their surface and / or inside.

[0086] The soil treatment in the present invention can be exemplified by 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.Specific treatment methods include, for example, spraying on the soil, mixing into the soil, and irrigating the soil with a chemical solution (chemical solution irrigation, soil injection, chemical solution drip, etc.).The treatment location can be, for example, planting holes, rows, the vicinity of the planting holes, the vicinity of the rows, the entire cultivated area, the plant's soil edge, between plants, under the tree trunk, the main trunk ridge, soil, seedling box, seedling tray, seedbed, etc.The treatment time can be, for example, before sowing, at the time of sowing, immediately after sowing, during the seedling raising period, before planting, at the time of planting, or during 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 of the present invention or the agricultural composition of the present invention can also be applied to the soil. The compound of the present invention or a 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 of the present invention or a salt thereof, or the agricultural composition of the present invention can be mixed with an irrigation solution in advance, and then treated using, for example, the above-mentioned irrigation method or any other appropriate irrigation method such as sprinkling or flooding.

[0087] In the present invention, examples of treatments for seedlings include a spray treatment in which a diluted solution prepared by diluting the compound or salt thereof of the present invention, or the agricultural composition of the present invention with water to an appropriate active ingredient concentration is sprayed over the entire seedling, a dipping treatment in which the seedlings are immersed in the diluted solution, and a coating treatment in which the compound or salt thereof of the present invention, or the agricultural composition of the present invention, prepared as a dust, is applied to 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 salt thereof, or the agricultural composition of the present invention with water to an appropriate active ingredient concentration is sprayed over the seedlings and the surrounding soil after planting, and a method in which the compound or salt thereof of the present invention, prepared as a granule or a solid formulation such as granules, or the agricultural composition of the present invention, is sprayed over the surrounding soil after planting the seedlings.

[0088] 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, soybean, adzuki bean, kidney bean, peanut, buckwheat, sugar beet, rapeseed, sunflower, 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.), Cruciferous vegetables (radish, turnip, horseradish, kohlrabi, Chinese cabbage, cabbage, mustard greens, broccoli, cauliflower, etc.), Asteraceae vegetables (burdock, garland chrysanthemum, artichoke, lettuce, etc.), Liliaceae vegetables (green onion, onion, garlic, asparagus, etc.), Umbelliferae vegetables (carrot, parsley, celery, parsley, etc.), Chenopodiaceae vegetables (spinach, Swiss chard, etc.), Lamiaceae vegetables (perilla, mint, basil, etc.), strawberry, sweet potato, yam, taro, etc.; Fruit trees, for example, pome fruits (apple, European pear, Japanese pear, Chinese 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, macadamia nut, etc.), berries (blueberry, cranberry, blackberry, raspberry, etc.), grapes, persimmon, olive, loquat, banana, coffee, date palm, coconut palm, etc.;Weeds, such as redroot pigweed, wild rose, sowweed, American thistle, Bidens frondosa, American geranium, ragwort, ragweed, evening primrose, Japanese knotweed, dogwood, Japanese knotweed, Arabidopsis, dogwood, nightshade, chickweed, alfalfa, white buttercup, Chinese hackberry, giant ragweed, and giant ragweed Persianthus persica, Chinese holly, Chinese laurel, plantain, giant clover, buttercup, goosegrass, Dutch earwort, wood sorrel, sedge, vetch, Rumex species, yellow nutsedge, cucumber grass, shepherd's purse, nightshade, common laurel, chickweed, morning glory, white clover, sorrel, burdock, horsetail, Japanese laurel Dou, annual bluegrass, annual spurge, common purslane, tall goldenrod, common dandelion, bindweed, common morning glory, upright persimmon, upright violet, cardamom, Japanese tabira, Imperata lanceolata, water courgettes, water weed, Datura stramonium, clover, spurge, gooseberry, shepherd's purse, common sowberry, field daisy, flea bean, Examples of suitable plants include: daisy flower, chickweed, philly philly, nutsedge, knotweed, lamiaceous grass, daisy flower, fleabane, sorrel, mugwort, pigweed, Japanese mustard, Japanese ragwort, snakeberry, plantain, lanceolata, willow, lotus flower, purple wood sorrel, Japanese bush clover, crabgrass, American holly, Japanese laurel, mugwort, horsenettle, etc.; ornamental plants, etc. These plants may be genetically modified plants.

[0089] In one embodiment, the compound or salt thereof, or the agricultural composition of the present invention can be applied to, but is not limited to, rice. Examples of rice include japonica varieties such as Nipponbare, Hinohikari, Koshihikari, Akitakomachi, Haenuki, Sasanishiki, Hitomebore, Kinuhikari, Hoshinoyume, Kirara 397, Tsugaru Roman, Yumeakari, Hanaechizen, Yumetsukushi, Hatsushimo, Yukihikari, Nanatsuboshi, Mashiko, Asahi no Yume, Koshihibuki, Aichi no Kaori, Iro no Kagayaki, Oborozuki, and Yumehikari; indica varieties; Javanica varieties; Sally Queen, Basmati, Kitakaori, Princess Sally, Kao Hom Mali, Arborio, Carnaroli, and Viarone Nano.

[0090] The compound of the present invention or a salt thereof has brassinosteroid (BR)-like agonistic or antagonistic activity and is therefore useful as a plant growth regulator, for example, a growth promoter or growth inhibitor.

[0091] In one embodiment, the compound of the present invention or a salt thereof can be used as a plant growth promoter. As used herein, "promotion of plant growth" includes, for example, promoting seed germination, promoting rooting, promoting the development and elongation of branches, leaves, and stems, promoting flowering, promoting fruit set, promoting fruit maturation, promoting fruit enlargement, imparting disease resistance, and imparting tolerance to stress (e.g., high salt concentration, drought, high temperature, low temperature, nutrient deficiency, etc.). Plants to which the compound of the present invention or a salt thereof can be 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; and fruit trees such as 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, macadamia nut, etc.), berries (blueberry, cranberry, blackberry, raspberry, etc.), grape, persimmon, olive, loquat, banana, coffee, date palm, and coconut palm.

[0092] In another embodiment, the compound of the present invention or a salt thereof can be used as a growth inhibitor. As used herein, "inhibition of plant growth" includes, for example, inhibition of seed germination, inhibition of rooting, 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 the action as a herbicide. Examples of plants to which the compound of the present invention or a salt thereof can be applied as a growth inhibitor include: beetroot, redroot pigweed, sowweed, buttercup, American thistle, Bidens frondosa, American geranium, ragwort, ragweed, evening primrose, Japanese knotweed, Japanese mustard, Polygonum chinense, Arabidopsis thaliana, black nightshade, chickweed, alfalfa, white ragweed, Chinese hackberry, and oak. Aristome, common persimmon, common burdock, common iris, plantain, common tabby, common goosegrass, Dutch earwort, wood sorrel, sedge, vetch, Rumex, yellow nutsedge, cucumber grass, shepherd's purse, nightshade, common iris, chickweed, morning glory, convolvulus, white clover, sorrel, burdock, horsetail, annual pea, Japanese bellflower Poa annua, spurge, purslane, tall goldenrod, dandelion, bindweed, common knotweed, upright persimmon, upright violet, cardamom, Tabirako, Imperata lanceolata, water courgettes, water hyacinth, Datura stramonium, clover, spurge, gossypium, shepherd's purse, common sowberry, field daisy, flea bean, daisy, eggplant, buttercup, buttercup, beach daisy, sea dandelion, sea dandelion, beach dandelion, sea dandelion, beach dandelion Examples of weeds that can be used include, but are not limited to, sedges, knotweed, lamb's feet, daisy-foot weed, fleabane, sorrel, mugwort, pigweed, Japanese mustard, snakeweed, snakeberry, plantain, eggplant, willow, lotus flower, purple wood sorrel, Japanese bush clover, crabgrass, American holly, Japanese knotweed, mugwort, and horsenettle. (Particularly dicotyledonous plants)

[0093] 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:

[0094] [In the formula, ring A, ring B, R １ , R ２ , R３ , R ４ , R ５ , R ６ , L １ , L ２ and n are the same as above. ７ represents the above alkyl group. １ and X ２ and are the same or different and represent the above halogen atoms.]

[0095] (3-1) Compound (2) → Compound (4) The compound represented by the general formula (2) and the compound represented by the general formula (3) can be known or commercially available products, or can be synthesized from commercially available products by a known method.

[0096] A compound represented by general formula (4) can be obtained by coupling a compound represented by general formula (2) with a compound represented by general formula (3).

[0097] The coupling reaction of the compound represented by formula (2) with the compound represented by formula (3) can be carried out in a suitable solvent in the presence of a base according to a conventional method.

[0098] The solvent is not limited as long as it does not interfere with the reaction, and examples thereof 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, nitrile compounds such as acetonitrile, etc. These solvents can be used alone or in combination of two or more.

[0099] Examples of the base 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.

[0100] The amount of the compound represented by formula (3) used can be 1.5 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents in molar ratio to the compound represented by formula (2).

[0101] The amount of the base used can be 0.3 to 3.0 equivalents, preferably 0.5 to 2.0 equivalents, in molar ratio to the compound represented by formula (2).

[0102] This reaction can be carried out at 0 to 100° C., preferably 10 to 50° C. There is no particular limitation on the reaction time, and the reaction can be carried out sufficiently until completion.

[0103] After the reaction is complete, the compound represented by formula (4) can be obtained by purification in a conventional manner, if necessary. Alternatively, the compound can be subjected to the next step without purification.

[0104] (3-2) Compound (4) → Compound (6) The compound represented by the general formula (5) can be a known or commercially available product, or can be synthesized from a commercially available product by a known method.

[0105] A compound represented by general formula (6) can be obtained by coupling a compound represented by general formula (4) with a compound represented by general formula (5).

[0106] The coupling reaction of the compound represented by the general formula (4) with the compound represented by the general formula (5) can be carried out in a suitable solvent in the presence of a Lewis acid catalyst according to a conventional method.

[0107] The solvent is not limited as long as it does not interfere with the reaction, and examples thereof 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, nitrile compounds such as acetonitrile, etc. These solvents can be used alone or in combination of two or more.

[0108] 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.

[0109] The amount of the compound represented by formula (5) used can be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in molar ratio to the compound represented by formula (4).

[0110] 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 to the compound represented by formula (4).

[0111] 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 limitation on the reaction time, and the reaction can be carried out sufficiently until completion.

[0112] After the reaction is complete, the compound represented by formula (6) can be obtained by purification in a conventional manner, if necessary. Alternatively, the compound can be subjected to the next step without purification.

[0113] The general formula (6) thus obtained:

[0114] [In the formula, ring B, R ４ , R ５ , R ６ , R ７ , L２ and n is the same as above.] is a novel compound not described in any literature.

[0115] (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.

[0116] The reaction of the compound represented by formula (6) with an acid can be carried out in a suitable solvent according to a conventional method.

[0117] The solvent is not limited as long as it does not interfere with the reaction, and examples thereof 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, nitrile compounds such as acetonitrile, etc. These solvents can be used alone or in combination of two or more.

[0118] Examples of the acid 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.

[0119] The amount of the acid used can be an excess amount, and can be 5 to 200 equivalents, preferably 10 to 100 equivalents, in molar ratio to the compound represented by formula (6).

[0120] 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 limitation on the reaction time, and the reaction can be carried out sufficiently until completion.

[0121] After the reaction is complete, the compound represented by formula (7) can be obtained by purification in a conventional manner, if necessary. Alternatively, the compound can be subjected to the next step without purification.

[0122] The general formula (7) thus obtained:

[0123] [In the formula, ring B, R ４ , R ５ , R ６ , L ２ and n is the same as above.] is a novel compound not described in any literature.

[0124] (3-4) Compound (7) → Compound (1) The compound represented by the general formula (8) can be a known or commercially available product, or can be synthesized from a commercially available product by a known method.

[0125] 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).

[0126] The coupling reaction of the compound represented by the general formula (7) with the compound represented by the 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.

[0127] The solvent is not limited as long as it does not interfere with the reaction, and examples thereof 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, nitrile compounds such as acetonitrile, etc. These solvents can be used alone or in combination of two or more.

[0128] Examples of the condensing agent include 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' Examples of condensing agents include o-(benzotriazol-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), and o-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU). These condensing agents can be used alone or in combination of two or more.

[0129] Examples of the base 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.

[0130] The amount of the compound represented by formula (8) used can be 0.5 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio to the compound represented by formula (7).

[0131] 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 to the compound represented by formula (7).

[0132] The amount of the base used can be 0.5 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in molar ratio to the compound represented by formula (7).

[0133] This reaction can be carried out at 0 to 100° C., preferably 10 to 50° C. There is no particular limitation on the reaction time, and the reaction can be carried out sufficiently until completion.

[0134] After the reaction is completed, the reaction mixture is purified by a conventional method as needed to obtain the compound of the present invention represented by the general formula (1).

[0135] After the compound of the present invention represented by the general formula (1) is obtained in this manner, it is also possible to introduce a desired substituent by a conventional method. For example, when a compound (1) in which an alkanoyl group is introduced into ring B is obtained, the compound can be introduced by a conventional method using sodium borohydride (NaHBH ４ ) or the like, to obtain a compound (1) having an alkoxy group introduced into ring B.

[0136] The present invention will be specifically explained below by way of examples, but the present invention is not limited to these examples.

[0137] [Comparative Examples 1 and 2]

[0138]

[0139] Comparative Synthesis Example 1: 3,4-Difluoro-N-methoxy-N-methylbenzamide (Compound 1)

[0140]

[0141] In a 100 mL two-neck 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 (NEt) (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 NaSO. After filtration, the solvent was removed by evaporation. The resulting residue was purified by MPLC (hexane / ethyl acetate = 4:1 to 7:3) to give compound 1 as a yellow oil (1.17 g, 92%). 1 H NMR (400 MHz, CDCl3) 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 C9H9NO2Na [M+Na] + : 224.0494, found: 224.0490. 1 H NMR spectrum of 1 was identical to that reported in the literature.

[0142] Comparative Synthesis Example 2: 1-(3,4-difluorophenyl)butan-1-one (Compound 2)

[0143]

[0144] 3,4-Difluoro-N-methoxy-N-methylbenzamide (compound 1) (2.1 g, 9.5 mmol) and tetrahydrofuran (THF) (30 mL) were added to a 100 mL two-necked round-bottom flask equipped with a magnetic stir bar. The mixture was then cooled to 0 °C. Next, 2 M n-propylmagnesium bromide (6.3 mL, 13 mmol) in tetrahydrofuran (THF) 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, CDCl3) 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); HRMS (ESI+) m / z calcd for C 10 H 10 F2ONa [M+Na] + : 207.0592, found: 207.0593. 1 H NMR spectrum of 2 was identical to that reported in the literature.

[0145] Comparative Synthesis Example 3: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)butan-1-one (Compound 3)

[0146]

[0147] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were 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, CDCl3) 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), 3.08-3.03 (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 FN2O [M+H] + : 251.1554, found: 251.1554. 1 H NMR spectrum of 3 was identical to that reported in the literature.

[0148] Comparative Example 1: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-fluorophenyl)butan-1-one (BL8)

[0149]

[0150] In a Schlenk tube equipped with a magnetic stirrer, 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 Na2SO4. 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, CDCl3) 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, CDCl3) 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 Hz), 116.0 (d, J CF = 21.5 Hz), 50.3, 49.7, 47.6, 42.3, 40.2, 17.9, 13.9; HRMS (ESI+) m / z calcd for C 21 H 21 F3N2O2K [M+K] + : 429.1187, found: 429.1189. 1 H NMR spectrum of BL8 was identical to that reported in the literature.

[0151] Comparative Example 2: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-fluorophenyl)butan-1-one (NSBR1; BL9)

[0152]

[0153] In a Schlenk tube equipped with a magnetic stirrer, 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%). 1H NMR (400 MHz, CDCl3) 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, 2H), 4.10-3.60 (br, 4H), 3.23 (br s, 4H), 2.87 (t, J = 7.4 Hz, 2H), 1.75 (sext, J = 7.4 Hz, 2H), 1.62 (br s, 2H) 1.00 (t, J = 7.4 Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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 FN2O4Na [M+Na]+: 409.1534, found: 409.1532. 1 H NMR spectrum of NSBR1 was identical to that reported in the literature.

[0154] [Comparative Examples 3 to 16] Comparative Examples 1 to 2 described above were synthesized by the same method and each compound.

[0155]

[0156] Comparative synthesis example 4: 4-フルオロ-N-メトキシ-N-メチルベンゾアミド (compound 5ｽa)

[0157]

[0158] 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 Na2SO4. 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, CDCl3) 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 C9H 10 NO2Na [M+Na] + : 206.0587, found: 206.0588. 1 H NMR spectrum of 5a was identical to that reported in the literature.

[0159] Comparative Synthesis Example 5: 1-(4-fluorophenyl)butan-1-one (Compound 6a)

[0160]

[0161] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, 4-fluoro-N-methoxy-N-methylbenzamide (compound 5a) (933 mg, 5.1 mmol) and tetrahydrofuran (THF) (15 mL) were added. The mixture was then cooled to 0 °C. Next, 2 M n-propylmagnesium bromide (6.3 mL, 13 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 to give compound 6a as a yellow oil (750 mg, 88%). 1 H NMR (400 MHz, CDCl3) 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.

[0162] Comparative Synthesis Example 6: 1-(4-(piperazin-1-yl)phenyl)butan-1-one (Compound 7a)

[0163]

[0164] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were added 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). 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, CDCl3) 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), 1.75 (sext, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H), a NH proton peak was not observed.; 13 C NMR (150 MHz, CDCl3) 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 NO [M+H] + : 233.1648, found: 233.2647.

[0165] Comparative Example 3: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)phenyl)butan-1-one (8a)

[0166]

[0167] In a Schlenk tube equipped with a magnetic stirrer, 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 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 8a as a white solid (72 mg, 42%). 1 H NMR (400 MHz, CDCl3) 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, 4H), 2.87 (t, J = 7.4 Hz, 2H), 1.75 (sext, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), two NH proton peaks were not observed.; 13 C NMR (150 MHz, CDCl3) 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, three piperazine carbon peaks were not observed.; HRMS (ESI+) m / z calcd for C 21 H 24 N2O4Na [M+Na] + : 391.1628, found: 391.1624.

[0168] Comparative Synthesis Example 7: 3-chloro-4-fluoro-N-methoxy-N-methylbenzamide (Compound 5b)

[0169]

[0170] 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 (NEt) (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 NaSO. 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, CDCl3) 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, CDCl3) 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 C9H9FClNO2 [M+H] +: 218.0379, found: 218.0379.

[0171] Comparative Synthesis Example 8: 1-(3-chloro-4-fluorophenyl)butan-1-one (Compound 6b)

[0172]

[0173] To 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. Next, 2 M 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, CDCl3) 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, J = 7.4 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 197.7, 161.7 (d, J CF = 256 Hz), 134.2 (d, J CF = 2.9 Hz), 131.0, 128.4 (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 FClO2Na [M+Na] + : 223.0296, found: 223.0296.

[0174] Comparative Synthesis Example 9: 1-(3-chloro-4-(piperazin-1-yl)phenyl)butan-1-one (Compound 7b)

[0175]

[0176] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were added 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). 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 7b as a yellow solid (395 mg, 84%). 1 H NMR (400 MHz, CDCl3) 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, 4H), 2.88 (t, J = 7.3 Hz, 2H), 1.75 (sext, J = 7.4 Hz, 2H), 1.65 (br s, 1H), 1.00 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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 20ClNO [M+H] + : 267.1259, found: 267.1257.

[0177] Comparative Example 4: 1-(3-chloro-4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)phenyl)butan-1-one (8b)

[0178]

[0179] In a Schlenk tube equipped with a magnetic stirrer, 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 Na2SO4. 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, CDCl3) 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), 6.78 (s, 1H), 4.10-3.60 (br, 4H), 3.30-3.00 (br, 4H), 2.89 (t, J = 7.3 Hz, 2H), 1.76 (sext, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) 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, 114.7, 40.3, 17.8, 13.9, four piperazine carbon peaks were not observed.; HRMS (ESI+) m / z calcd for C 21 H 23 ClN2O4Na [M+Na] + : 425.1239, found: 425.1237.

[0180] Comparative Synthesis Example 10: 4-Fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (Compound 5c)

[0181]

[0182] 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 (NEt) (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 NaSO. 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%). 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 = 271 Hz), 118.2 (dd, J CF = 33.0, 13.0 Hz), 116.7 (d, J CF = 24.2 Hz), 61.2, 33.3; HRMS (ESI+) m / z calcd for C 10 H 10 F4NO2 [M+H] + : 252.0642, found: 252.0642.

[0183] Comparative synthesis example 11: 1-(4-フフルオロ-3-(トリフルオロメチル)フェニル)ブタン-1-オン (Compound 6c)

[0184]

[0185] To 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. Next, 2 M n-propylmagnesium bromide (1.5 mL, 3.0 mmol) in tetrahydrofuran (THF) 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, CDCl3) 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, CDCl3) 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), 127.6, 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; HRMS (ESI+) m / z calcd for C 11 H 11 F4NO [M+H] + : 235.0741, found: 235.0742.

[0186] Comparative Synthesis Example 12: 1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)butan-1-one (Compound 7c)

[0187]

[0188] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were added 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). 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, CDCl3) 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, CDCl3) 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 F3N2O [M+H] + : 301.1522, found: 301.1521.

[0189] Comparative Example 5: 1-(4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)butan-1-one (8c)

[0190]

[0191] In a screw-cap tube equipped with a magnetic stirrer, 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 Na2SO4. 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, CDCl3) 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, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H), two OH proton peaks were not observed.; 13 C NMR (150 MHz, CDCl3) δ 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 CFHRMS (ESI+) m / z calcd for C 22 H 24 F3N2O4 [M+H] + : 437.1683, found: 437.1685.

[0192] Comparative Synthesis Example 13: 1-(3,4-difluorophenyl)-3-methylbutan-1-one (Compound 6d)

[0193]

[0194] 3,4-Difluoro-N-methoxy-N-methylbenzamide (compound 1) (1.0 g, 5.0 mmol) and tetrahydrofuran (THF) (15 mL) were added to a 50 mL two-neck round-bottom flask equipped with a magnetic stir bar. The mixture was then cooled to -78 °C. Next, 0.9 M isobutylmagnesium bromide (8 mL, 7.5 mmol) in tetrahydrofuran (THF) 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, CDCl3) 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), 1.00 (d, J = 6.8 Hz, 6H); 13 C NMR (150 MHz, CDCl3) 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, 125.0 (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 F2ONa [M+Na] + : 221.0748, found: 211.0748.

[0195] Comparative Synthesis Example 14: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-methylbutan-1-one (Compound 7d)

[0196]

[0197] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were added 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). 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 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 7d as a yellow solid (267 mg, 77%). 1 H NMR (400 MHz, CDCl3) 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), 3.08-3.02 (m, 4H), 2.74 (d, J = 6.7 Hz, 2H), 2.27 (sep, J = 6.7 Hz, 1H), 0.98 (d, J = 6.7 Hz, 6H), a NH proton peak was not observed.;13 C NMR (150 MHz, CDCl3) 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, 50.98, 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 FN2O [M+H] + : 265.1711, found: 265.1709.

[0198] Comparative Example 6: 1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)-3-methyl-butan-1-one (9a)

[0199]

[0200] In a screw-cap tube equipped with a magnetic stirrer, 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 Na2SO4. 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%). 1H NMR (400 MHz, CDCl3) 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.; 13 C NMR (150 MHz, CDCl3) 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, 119.7, 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; HRMS (ESI+) m / z calcd for C 22 H 25 FN2O4Na [M+Na] + : 423.1691, found: 423.1688.

[0201] Comparative synthesis example 15: 1-(3,4-ジフルオロフェニル)ヘプタン-1-オン (Compound 6e)

[0202]

[0203] 3,4-Difluoro-N-methoxy-N-methylbenzamide (compound 1) (973 mg, 4.8 mmol) and tetrahydrofuran (THF) (15 mL) were added to a 100 mL two-necked round-bottom flask equipped with a magnetic stirrer. The mixture was then cooled to -78 °C. Next, 0.8 M n-hexylmagnesium bromide (10 mL, 7.5 mmol) in tetrahydrofuran (THF) 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, CDCl3) 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), 1.43-1.26 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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 = 3.6 Hz), 125.0 (dd, J CF = 7.2, 2.9 Hz), 117.4 (d, J CF = 17.3 Hz), 117.3 (d, J CF = 17.3 Hz), 38.5, 31.6, 28.9, 24.1, 22.5, 14.0; HRMS (ESI+) m / z calcd for C 13 H 16 F2ONa [M+Na] +: 249.1061, found: 249.1060.

[0204] Comparative Synthesis Example 16: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)heptan-1-one (Compound 7e)

[0205]

[0206] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were added 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). 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, CDCl3) 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), 3.08-3.02 (br, 4H), 2.87 (t, J = 7.5 Hz, 2H), 1.75 (br s, 1H) 1.74-1.66 (m, 2H), 1.42-1.26 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 198.4, 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; 17 H 26 FN2O [M+H] + : 293.2024, found: 293.2021.

[0207] Comparative Example 7: 1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)heptan-1-one (9b)

[0208]

[0209] 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 hours, 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%). 1H NMR (600 MHz, CDCl3) 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, CDCl3) 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, 38.3, 31.6, 29.0, 24.4, 22.5, 14.0; HRMS (ESI+) m / z calcd for C 24 H 29 FN2O4Na [M+Na]+: 451.2004, found: 451.2002.

[0210] Comparative synthesis example 17: 1-(3,4-ジフルオロフェニル)ノナン-1-オン (compound 6f)

[0211]

[0212] 3,4-Difluoro-N-methoxy-N-methylbenzamide (compound 1) (822 mg, 4.1 mmol) and tetrahydrofuran (THF) (12 mL) were added to a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar. The mixture was then cooled to -78 °C. Next, 0.5 M n-octylmagnesium bromide (1.3 mL, 6.2 mmol) in tetrahydrofuran (THF) 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 6f as a yellow oil (1.0 g, 97%). 1 H NMR (400 MHz, CDCl3) 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), 1.43-1.20 (m, 10H), 0.88 (t, J = 6.7 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 197.9, 153.5 (dd, J CF = 254, 12.9 Hz), 150.4 (dd, J CF = 249, 12.9 Hz), 134.1, (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; 15 H 20 F2ONa [M+Na] +: 277.1374, found: 277.1375.

[0213] Comparative Synthesis Example 18: 1-(3-fluoro-4-(piperazin-1-yl)phenyl)nonan-1-one (Compound 7f)

[0214]

[0215] To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar were added 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). 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 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 7f as a yellow solid (201 mg, 31%). 1 H NMR (400 MHz, CDCl3) 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), 3.08-3.03 (m, 4H), 2.87 (t, J = 7.5 Hz, 2H), 1.71 (quin, J = 7.3 Hz, 2H), 1.41-1.23 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H), a NH proton peak was not observed.; 13 C NMR (150 MHz, CDCl3) 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, JCF HRMS (ESI+) m / z calcd for C 19 H 19 FN2ONa [M+Na] + : 343.2156, found: 343.2157.

[0216] Comparative Example 8: 1-(4-(4-(3,4-dihydroxybenzoyl)piperazin-1-yl)-3-fluorophenyl)nonan-1-one (9c)

[0217]

[0218] In a Schlenk tube equipped with a magnetic stirrer, 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 Na2SO4. 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%). 1H NMR (400 MHz, CDCl3) 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, CDCl3) 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 FN2O4Na [M+Na] + : 479.2317, found: 479.2314.

[0219] Comparative synthesis example 19: tert-ブチル1-(3-フルオロ-4-(2,6-ジアザスピロ[3.3]ヘプタン-2-イル)フェニル)ブタン-1-オン(Compound 7g)

[0220]

[0221] To a screw cap containing a magnetic stir bar was added 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), CsCO (241 mg, 0.74 mmol), and dimethylformamide (DMF) (2 mL). 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 NaSO. 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, CDCl3) 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), 4.11 (s, 4H), 3.49 (d, J = 4.8 Hz, 1H), 2.82 (t, J = 7.4 Hz, 2H), 1.73 (sext, J = 7.2 Hz, 2H), 1.45 (s, 9H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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= 4.2 Hz), 79.9, 63.2, 40.0, 34.1, 28.3, 18.1, 13.9, a carbon peak was not observed or was overlap with solvent.; HRMS (ESI+) m / z calcd for C 20 H 28 FN2O3 [M+H] + : 363.2078, found: 363.2079.

[0222] Comparative Example 9: 1-(4-(6-(3,4-dihydroxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-3-fluorophenyl)butan-1-one (10a)

[0223]

[0224] 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 hour, 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.

[0225] In a 25 mL screw-cap tube equipped with 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, CD3OD) 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, CD3OD) 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 peak was not observed.; HRMS (ESI+) m / z calcd for C 22 H 24 FN2O4 [M+H] + : 399.1715, found: 399.1713.

[0226] Comparative Synthesis Example 20: tert-Butyl 5-(4-butyryl-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Compound 7h)

[0227]

[0228] To a screw-cap tube containing a magnetic stir bar were added 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), K2CO3 (92.4 mg, 0.67 mmol), and dimethylformamide (DMF) (1 mL). 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 Na2SO4. 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%). 1H NMR (600 MHz, CDCl3) 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 1.74 (sext, J = 7.6 Hz, 2H), 1.46 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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 FN2O3 [M+H] + : 377.2235, found: 377.2235.

[0229] Comparative Example 10: 1-(4-(5-(3,4-ジヒドロキシベンゾイル)ヘキサヒドロピロロ[3,4 -c】Floral-2(1H)-イル)-3-Floral(Compound 10b)

[0230]

[0231] 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.

[0232] In a 25 mL screw-cap tube equipped with a magnetic stir bar, the crude product Compound 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). 1H NMR (600 MHz, CD3OD) 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 calculation for C 23 H 25 FN2O4Na [M+Na] + : 435.1691, found: 435.1684.

[0233] Comparative Example 11: 1-(3-fluoro-4-(4-(2-hydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (Compound 11a)

[0234]

[0235] In a Schlenk tube equipped with a magnetic stirrer, 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 Na2SO4. 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, CD3OD) 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 = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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 FN2O3Na [M+Na] + : 393.1585, found: 393.1582.

[0236] Comparative Example 12: 1-(3-fluoro-4-(4-(3-hydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (Compound 11b)

[0237]

[0238] In a Schlenk tube equipped with a magnetic stirrer, 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 Na2SO4. 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%). 1H NMR (400 MHz, CDCl3) 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), 6.95-6.87 (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 = 7.4Hz, 3H); 13 C NMR (150 MHz, CDCl3) 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; HRMS (ESI+) m / z calcd for C 21 H 23 FN2O3Na [M+Na] + : 393.1585, found: 393.1584.

[0239] Comparative Example 13: 1-(3-フルオロ-4-(4-(4-ヒドロキシベンゾイル)Fructamine-1-イル)Fructamine-1-オン(Compound 11c)

[0240]

[0241] In a Schlenk tube equipped with a magnetic stirrer, 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 Na2SO4. 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, CDCl3) 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, CDCl3) 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.; HRMS (ESI+) m / z calcd for C 21 H 23 FN2O3Na [M+Na] + : 393.1585, found: 393.1584.

[0242] Comparative Example 14: 1-(3-fluoro-4-(4-(2,3,4-trihydroxybenzoyl)piperazin-1-yl)phenyl)butan-1-one (Compound 11d)

[0243]

[0244] In a Schlenk tube equipped with a magnetic stirrer, 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 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 11d as a white solid (29 mg, 18%). 1 H NMR (400 MHz, CD3OD) 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);13 C NMR (150 MHz, CD3OD) δ 200.5, 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 FN2O5K [M+K] + : 441.1223, found: 441.1223.

[0245] Comparative Example 15: (3,4-dihydroxyphenyl)(4-(2-fluoro-4-(1-hydroxybutyl)phenyl)piperazin-1-yl)methanone (Compound 12a)

[0246]

[0247] In a 5 mL screw-cap tube equipped with a magnetic stir bar, 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). The mixture was cooled to −10 °C. To the mixture was added a solution of NaBH (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 NaHCO and stirring for 5 min. The organic layer was washed with water and brine and dried over NaSO. 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%). 1H NMR (400 MHz, CDCl3) 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), 3.79-3.50 (br, 2H), 3.23-2.85 (br, 4H), 1.83-1.57 (m, 2H), 1.47-1.19 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), three NH proton peaks were not observed.; 13 C NMR (150 MHz, CD3OD) 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, 120.3 (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 FN2O4 [M+H] + : 425.1683, found: 425.1680.

[0248] Comparative Example 16: (3,4-dihydroxyphenyl)(4-(2-fluoro-4-(1-hydroxy-3-methylbutyl)phenyl)piperazin-1-yl)methanone (Compound 12b)

[0249]

[0250] In a 5 mL screw-cap tube equipped with a magnetic stir bar, 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). The mixture was cooled to 0 °C. To the mixture was added a solution of NaBH (7.0 mg, 0.19 mmol) in anhydrous methanol (1 mL). The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by adding ethyl acetate and saturated aqueous NaHCO and stirring for 5 min. The organic layer was washed with water and brine and dried over NaSO. 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, CDCl3) 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); 13 C NMR (150 MHz, CD3OD) δ 172.9, 157.1 (d, J CF = 244 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), 72.3, 52.1, 25.8, 23.5, 22.6, three piperazine carbon peaks were not observed.; HRMS (ESI+) m / z calcd for C 22 H 28FN2O4 [M+H] + : 403.2028, found: 403.2024.

[0251] [Example 1]

[0252]

[0253] Synthesis Example 1: Methyl 4-(4-butyrylphenyl)piperidine-1-carboxylate (Compound 15)

[0254]

[0255] In a 100 mL two-necked round-bottom flask equipped with a magnetic stir bar, 4-phenylpiperidine (Compound 13) (1.03 g, 6.4 mmol) was dissolved in dichloromethane (23 mL). Triethylamine (NEt) (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, 1 M aqueous HCl was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over NaSO. 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 further purification.

[0256] In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, AlCl3 (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 1 M aqueous HCl and extracted with dichloromethane. The organic layer was washed with water and dried over Na2SO4. 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). 1H NMR (400 MHz, CDCl3) 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 Hz, 1H), 1.87 (br, 2H), 1.78 (td, J = 14.6, 7.3 Hz, 2H), 1.68 (br, 2H), 1.03-1.00 (m, 3H); 13 C NMR (150 MHz, CDCl3) δ 200.0, 155.9, 150.8, 135.5, 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 NO3 [M+H] + : 290.1751, found: 290.1750.

[0257] Example 1: 1-(4-(1-(3,4-dihydroxybenzoyl)piperidin-4-yl)phenyl)butan-1-one (compound UA1)

[0258]

[0259] 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), 8 M aqueous HCl (4.7 mL), and ethanol (2 mL) were added. The reaction mixture was refluxed for 17 h. After adding 5 M 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 further purification.

[0260] 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: HO 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, CDCl3) 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, CDCl3) 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, 17.8, 13.9; HRMS (ESI+) m / z calcd for C 22 H 26 NO4 [M+H] + : 368.1856, found: 368.1858.

[0261] [Examples 2 and 3] Example 2: 4-(4-(4-(1-hydroxybutyl)phenyl)piperidine-1-carbonyl)benzene-1,2-diol (Compound 17)

[0262]

[0263] In a Schlenk tube equipped with a magnetic stirrer, Compound UA1 (101.3 mg, 0.28 mmol) was dissolved in methanol (1.5 mL). The mixture was cooled to 0 °C. A solution of NaBH (23.3 mg, 0.62 mmol) in anhydrous methanol (1.5 mL) was added to the mixture. The resulting mixture was stirred at 0 °C for 40 min. The reaction was quenched by adding ethyl acetate and saturated aqueous NaHCO and stirring for 5 min. The organic layer was washed with brine and dried over NaSO. 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%). 1H NMR (500 MHz, CDCl3) 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).

[0264] Example 3: 1-(4-(1-(3-hydroxybenzoyl)piperidin-4-yl)phenyl)butan-1-one (Compound 18)

[0265]

[0266] 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 in dioxane 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 Na2SO4. 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%). 1H NMR (500 MHz, CDCl3) 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), 1.91-1.60 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H).

[0267] [Example 4]

[0268]

[0269] Synthesis Example 2: Methyl-4-(4-(3-methylbutanoyl)phenyl)piperidine-1-carboxylate (Compound 19)

[0270]

[0271] In a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, AlCl3 (533 mg, 4.0 mmol) was dissolved in dichloromethane (5.0 mL) and cooled to 0 °C. Next, 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; obtained from the first step 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 1 M aqueous HCl 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 = 9:1 to 8:2) to give methyl-4-(4-(3-methylbutanoyl)phenyl)piperidine-1-carboxylate (Compound 19) (249.3 mg, 39%). 1H NMR (600 MHz, CDCl3) 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).

[0272] Synthesis Example 3: 3-methyl-1-(4-(piperidin-4-yl)phenyl)butan-1-one (Compound 20)

[0273]

[0274] To 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), 8 M aqueous HCl (5.0 mL), and ethanol (2 mL) were added. The reaction mixture was refluxed for 24 h. After adding 5 M 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 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, CDCl3) 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).

[0275] Example 4: 1-(4-(1-(3,4-dihydroxybenzoyl)piperidin-4-yl)phenyl)-3-methylbutan-1-one (Compound 21)

[0276]

[0277] 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 hours, 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=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, CDCl3) 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).

[0278] Experimental Example 1: Rice Lamina Joint Assay. The lamina joint assay was performed according to a bioprotocol. Seeds of the Taiwanese rice cultivar Taichung 65 were grown in a greenhouse by Professor Motoyuki Ashikari and Associate Professor Shiro Miya of the Tokai National Higher Education and Research System. Seeds were vacuum-packed and stored at 4°C before use, then heat-treated at 50°C for 2 days. After cooling to room temperature, the seeds were manually dehusked, 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. The seeds were then washed 10 times with sterile distilled water and allowed to dry on sterile filter paper in a clean bench. Sterilized seeds were sown in a 1 L glass beaker containing 1 / 2 MS medium supplemented with 2% water and adjusted to a pH of 5.7, and germinated in a growth chamber (PCBI Japan) at 28°C under long-day conditions (lights on for 16 hours).

[0279] Seedlings were harvested on day 8, and the same length (approximately 8 cm) at the third leaf stage was used for the assay. A 2-cm section from the second leaf joint was cut with a fresh razor blade and placed in sterile distilled water for 10 minutes. Three lamina joint sections were then placed in 55-millimeter Petri dishes containing 10 mL of sterile distilled water containing appropriate concentrations of epiBL (natural brassinosteroids) and brassinosteroid-like compounds diluted from a 10 mM stock in DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.). The same volume of DMSO served as a control. The lamina joint sections were incubated in the dark at 28°C for 2 days with periodic agitation before measurement. Photographs of the lamina joint sections were taken with a Canon digital camera and analyzed using the "measure angle" function in ImageJ 1.53k (NIH USA). This assay was independently repeated three times (a total of nine lamina joint sections per concentration).

[0280] The results are shown in Figures 1 to 3.

[0281] 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 brassinosteroid) and brassinosteroid-like compounds were diluted from 10 mM stocks in DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.) in 10 mL of sterile distilled water to the highest concentration. A 1:10 serial dilution was performed by vortexing the first dilution, removing 1 mL, and adding it to 9 mL of water in the next Petri dish. This process was repeated until all dilutions were completed, and the final 1 mL was discarded.

[0282] The results are shown in Figure 4.

[0283] Experimental 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 on 1 / 2 MS medium containing 0.8% Phytoagar and 1.5% sucrose for 7 days. 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 hours and then prepared in 1 / 2 MS medium without Phytoagar or 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).

[0284] The primers used were as follows: 5'-GTGATCTCAGCCGTACATTTGGA-3' and 5'-CACGTCGAAAAACTACCACTTCCT-3' for DWARF4, 5'-CAATAGTCTCAATGACGCAGT-3' and 5'-AACCGCAGCTATGTTG CATG-3' for BR6ox2, 5'-CCAAGATCCAGGACAAAGAAGGA-3' and 5'-TGGAGACGAGC ATAACTTGC-3' for UBQ2, and 5'-CGCCATCCAAGCTGTTCTC-3' and 5'-TCACGTCCAGC AAGGTCAAG-3' for ACT2.

[0285] UBQ2 and ACT2 were used as constitutive expression control genes.

[0286] The results are shown in Figure 5.

[0287] As described above, it can be seen that UA1 obtained in Example 1 has brassinosteroid-like activity comparable to that of the natural brassinosteroid EpiBL, and 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

1. General formula (1A): 【Chemistry 1】 [In the formula, R １ａ and R ２ａ are the same or different and 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 substituted alkyl group, a substituted 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. R ４ａ and R ５ａ In the case where the alkyl group is substituted, the substituent is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, or an imino group which may be substituted with an alkoxy group. ４ａ and R ５ａ In the case where the alkoxy group is substituted, the substituent is a halogen atom, a hydroxyl group, a cyano group, a nitro group, or an alkoxy group.] A compound represented by the formula (I) or a salt thereof.

2. (delete)

3. (delete)

4. (delete)

5. (delete)

6. (delete)

7. (delete)

8. (delete)

9. An agricultural composition comprising the compound or salt thereof according to claim 1.

10. 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.

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

12. 12. The agricultural composition according to claim 11, which is a plant growth promoter.

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

14. 12. The agricultural composition according to claim 11, which is a plant growth regulator.

15. 15. The agricultural composition of claim 14, wherein the plant is a weed.

16. A step of applying the compound or salt thereof according to claim 1 to a plant. A method for regulating plant growth comprising:

17. General formula (6): 【Chemistry 2】 [In the formula, Ring B is a monocyclic aromatic or non-aromatic ring. R ４ and R ５ are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro 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. ６ represents a substituted or unsubstituted alkanoyl group, or a substituted or unsubstituted alkylsulfonyl group. ４ , R ５ and R ６ When two of the groups are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. R ７ represents a substituted or unsubstituted alkyl group. L ２ represents a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O) ２ Indicates -. n represents 0 or 1. A compound represented by the formula:

18. General formula (7): 【Transformation 3】 [In the formula, Ring B is a monocyclic aromatic or non-aromatic ring. R ４ and R ５ represents a hydrogen atom. ６ represents a substituted or unsubstituted alkanoyl group. ４ , R ５ and R ６ When two of the groups are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. L ２ represents a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O) ２ Indicates -. n represents 0 or 1. A compound represented by the formula:

19. General formula (1): 【Chemistry 4】 [In the formula, Ring A and ring B may be the same or different and each represent 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 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. ４ , R ５ and R ６ When two of the groups are bonded to adjacent atoms on ring B, the two groups may be combined with the atoms on ring B to which they are bonded to form a monocyclic aromatic or non-aromatic ring. L １ and L ２ are the same or different and represent a bond, an alkylene group, —NH—, —O—, —S—, —C(O)—, —CS—, —S(O)—, or —S(O) ２ Indicates -. n represents 0 or 1. or a salt thereof, wherein the plant growth regulator is a plant growth promoter and / or a plant growth inhibitor, the plant growth promotion in the plant growth promoter is at least one selected from the group consisting of seed germination promotion; rooting promotion; rooting promotion; branch, leaf, and stem development and elongation promotion; fruit set promotion; fruit maturation promotion; fruit enlargement promotion; disease resistance impartation; and stress tolerance impartation; The plant growth inhibitor is at least one selected from the group consisting of seed germination inhibition; root growth inhibition; root establishment inhibition; branch, leaf and stem development and elongation inhibition; fruit set inhibition; fruit ripening inhibition; and fruit enlargement inhibition.

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