JP7148769B2 - Heterocyclic compound or its salt, GPR35 agonist and pharmaceutical composition - Google Patents

Description

The present invention relates to heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions.

Among G protein-coupled receptors (GPCRs), GPR35, which belongs to the rhodopsin-like class AGPCR, is an orphan receptor that is expressed in the immune system, digestive system and other visceral tissues. Although much of the action of GPR35 has not been clarified, it has been reported to be associated with blood pressure, pain sensation, immune response, inflammatory bowel disease, diabetes, arteriosclerosis, and the like. Therefore, agonists of GPR35 are expected as therapeutic agents for various diseases, and candidate compounds are being searched for.

Compounds such as zaprinast, dicoumarol, disodium cromoglycate (DSCG), pamoic acid, and quercetin have been reported as GPR35 agonists. In addition, Non-Patent Document 1 reports that a compound having the following formula or a structure similar thereto has activity as a GPR35 agonist.

J. Med. Chem. 2013, 56, 7084-7099

It is believed that the discovery of new candidate compounds for GPR35 agonists that have not been reported thus far will contribute to the elucidation of the actions of GPR35, the development of therapeutic methods for diseases in which GPR35 is involved, and the like.
Furthermore, GPR35 is characterized by large species differences in ligand responsiveness compared to other GPCRs. For example, the compound described in Non-Patent Document 1 has been confirmed to have activity against human GPR35, but its activity against rat GPR35 is extremely weak and there are species differences.

Considering that it is essential to undergo animal tests in the process of drug development, finding a candidate compound as a GPR35 agonist that exhibits activity in animals other than humans is an important consideration with a view to its practical use as a drug. Considered to be a great advantage.
The present invention has been made in view of the above circumstances, and an object of an embodiment of the present invention is to provide a heterocyclic compound or a salt thereof, a GPR35 agonist and a pharmaceutical composition.

Means for solving the above problems include the following embodiments.
<1> A heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.

[In general formula (I), X represents O or NH, R ¹ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl group, OR ⁴ (R ⁴ is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic alkyl group ), NR ⁵ R ⁶ (R ⁵ and R ⁶ are each independently the same as R ⁴ and may be joined together to form a ring), NR ⁷ COR ⁸ (R ⁷ and R ⁸ are each independently as defined for R ⁴ ), NR ⁹ SO ₂ R ¹⁰ (R ⁹ and R ¹⁰ are each independently defined as R ⁴ ), S(O) _n R ¹¹ (n is 0, 1 or 2; and R ¹¹ has the same meaning as R ⁴ ), COR ¹² (R ¹² has the same meaning as R ⁴ ), COOR ¹³ (R ¹³ has the same meaning as R ⁴ ), OCOR ¹⁴ (R ¹⁴ has the same meaning as R ⁴ are synonymous), CONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are each independently synonymous with R ⁴ ), SO ₂ NR ¹⁷ R ¹⁸ (R ¹⁷ and R ¹⁸ are each independently synonymous with R ⁴ ) , OCH ₂ COOR ¹⁹ (R ¹⁹ has the same meaning as R ⁴ ), OSO ₂ R ²⁰ (R ²⁰ has the same meaning as R ⁴ ), SR ²¹ (R ²¹ has the same meaning as R ⁴ ), a nitro group, represents a cyano group or a halogen atom, and R ³ represents COOR ²² (R ²² has the same meaning as R ⁴ ). n attached to R ² represents the number of R ² and is an integer of 0-3. ]
<2> The heterocyclic compound or the heterocyclic compound according to <1>, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-1) pharmacologically acceptable salts.

[In general formula (I-1), R ¹ , R ² , R ³ , X and n have the same definitions as R ¹ , R ² , R ³ , X and n in general formula (I). ]
<3> The heterocyclic compound or the heterocyclic compound according to <1>, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-2) pharmacologically acceptable salts.

[In general formula (I-2), R ¹ , R ² , R ³ , X and n have the same definitions as R ¹ , R ² , R ³ , X and n in general formula (I). ]
<4> The heterocyclic compound according to any one of <1> to <3>, wherein X is O, or a pharmacologically acceptable salt thereof.
<5> The heterocyclic compound according to any one of <1> to <4>, wherein R ² is NR ⁵ R ⁶ or NR ⁷ COR ⁸ , or a pharmacologically acceptable salt of the heterocyclic compound. .
<6> R ¹ has no substituent, substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH ₂ COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OR (R is a hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group ), CONRR (R are each independently hydrogen atoms or substituted or unsubstituted alkyl groups), SO ₂ R (R is substituted or unsubstituted alkyl groups), SO ₂ NRR (R are each independently hydrogen atoms or substituted or unsubstituted alkyl group), SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom as a substituent, the heterocycle according to any one of <1> to <5> compound or a pharmaceutically acceptable salt of said heterocyclic compound.
<7> The heterocyclic compound according to any one of <1> to <6>, wherein R ³ is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), or the pharmacological properties of the heterocyclic compound permissible salt.
<8> The heterocyclic compound according to any one of <1> to <7>, wherein R ² is NH ₂ or NHCOR ⁸ , or a pharmacologically acceptable salt thereof.
<9> The heterocyclic compound according to any one of <1> to <8>, wherein R ² is NHCOAr (Ar is a substituted or unsubstituted aryl group) or the pharmacologically acceptable heterocyclic compound salt.
<10> The heterocyclic compound according to any one of <1> to <9> or a pharmacologically acceptable salt thereof, which has activity as a GPR35 agonist.
<11> The heterocyclic compound according to <10> or a pharmacologically acceptable salt thereof, which has activity against at least one of human GPR35 and non-human animal GPR35.
<12> The heterocyclic compound according to <10> or <11> or a pharmacologically acceptable salt thereof, which has activity against both human GPR35 and non-human animal GPR35.
<13> The heterocyclic compound or the pharmacologically acceptable salt of the heterocyclic compound according to <11> or <12>, wherein the non-human animal is a rodent.
<14> A GPR35 agonist, which is a heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.

[In general formula (I), X represents O or NH, R ¹ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl group, OR ⁴ (R ⁴ is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic alkyl group ), NR ⁵ R ⁶ (R ⁵ and R ⁶ are each independently the same as R ⁴ and may be joined together to form a ring), NR ⁷ COR ⁸ (R ⁷ and R ⁸ are each independently as defined for R ⁴ ), NR ⁹ SO ₂ R ¹⁰ (R ⁹ and R ¹⁰ are each independently defined as R ⁴ ), S(O) _n R ¹¹ (n is 0, 1 or 2; and R ¹¹ has the same meaning as R ⁴ ), COR ¹² (R ¹² has the same meaning as R ⁴ ), COOR ¹³ (R ¹³ has the same meaning as R ⁴ ), OCOR ¹⁴ (R ¹⁴ has the same meaning as R ⁴ are synonymous), CONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are each independently synonymous with R ⁴ ), SO ₂ NR ¹⁷ R ¹⁸ (R ¹⁷ and R ¹⁸ are each independently synonymous with R ⁴ ) , OCH ₂ COOR ¹⁹ (R ¹⁹ has the same meaning as R ⁴ ), OSO ₂ R ²⁰ (R ²⁰ has the same meaning as R ⁴ ), SR ²¹ (R ²¹ has the same meaning as R ⁴ ), a nitro group, represents a cyano group or a halogen atom, and R ³ represents COOR ²² (R ²² has the same meaning as R ⁴ ). n attached to R ² represents the number of R ² and is an integer of 0-3. ]
<15> The GPR35 agonist according to <14>, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-1).

［一般式（Ｉ－１）において、Ｒ^１、Ｒ^２、Ｒ^３、Ｘ及びｎは一般式（Ｉ）におけるＲ^１、Ｒ^２、Ｒ^３、Ｘ及びｎと同義である。］
＜１６＞ 前記一般式（Ｉ－１）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－２）で表される、＜１４＞に記載のＧＰＲ３５作動薬。

[In general formula (I-1), R ¹ , R ² , R ³ , X and n have the same definitions as R ¹ , R ² , R ³ , X and n in general formula (I). ]
<16> The GPR35 agonist according to <14>, wherein the heterocyclic compound represented by the general formula (I-1) or the heterocyclic compound is represented by the following general formula (I-2).

[In general formula (I-2), R ¹ , R ² , R ³ , X and n have the same definitions as R ¹ , R ² , R ³ , X and n in general formula (I). ]
<17> The GPR35 agonist according to any one of <14> to <16>, wherein X is O.
<18> The GPR35 agonist according to any one of <14> to <17>, wherein R ² is NR ⁵ R ⁶ or NR ⁷ COR ⁸ .
<19> R ¹ has no substituent, substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH ₂ COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OR (R is a hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group ), CONRR (R are each independently hydrogen atoms or substituted or unsubstituted alkyl groups), SO ₂ R (R is substituted or unsubstituted alkyl groups), SO ₂ NRR (R are each independently hydrogen atoms or substituted or unsubstituted Alkyl group), SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom as a substituent, GPR35 operation according to any one of <14> to <18> medicine.
<20> The GPR35 agonist according to any one of <14> to <19>, wherein R ³ is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group).
<21> The GPR35 agonist according to any one of <14> to <20>, wherein R ² is NH ₂ or NHCOR ⁸ .
<22> The GPR35 agonist according to any one of <14> to <21>, wherein R ² is NHCOAr (Ar is a substituted or unsubstituted aryl group).
<23> The GPR35 agonist according to any one of <14> to <22>, which has activity against at least one of human GPR35 and non-human animal GPR35.
<24> The GPR35 agonist of any one of <14> to <23>, which has activity against both human GPR35 and non-human animal GPR35.
<25> The GPR35 agonist according to <23> or <24>, wherein the non-human animal is a rodent.
<26> The GPR35 agonist according to any one of <14> to <25>, for use in treating symptoms or diseases associated with GPR35.
<27> The heterocyclic compound according to any one of <1> to <13> or a pharmacologically acceptable salt of the heterocyclic compound, or any one of <14> to <26> A pharmaceutical composition comprising the described GPR35 agonist as an active ingredient.

According to the present invention, heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions are provided.

It is the result of measuring the expression of rat GPR35 mRNA by quantitative RT-PCR. Data comparing the degranulation response of RBL-2H3 cells expressing rat GPR35 and RBL-2H3 cells not expressing rat GPR35.

<First embodiment>
A first embodiment of the present disclosure is a heterocyclic compound represented by general formula (I) described above or a pharmacologically acceptable salt of the heterocyclic compound.

In formula (I), the aryl group represented by R ¹ includes a phenyl group, a naphthyl group and the like, preferably a phenyl group. The aromatic heterocyclic group represented by R ¹ includes an aromatic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably pyridyl group, furanyl group, thienyl group or pyrrolyl group.

When the aryl group or aromatic heterocyclic group represented by R ¹ has a substituent, the type of the substituent is not particularly limited. For example, it can be selected from substituents represented by R ² in general formula (I).

In general formula (I), the alkyl group represented by R ² or R ⁴ includes an alkyl group having 1 to 10 carbon atoms (excluding substituents), preferably having 1 to 10 carbon atoms (excluding substituents). is an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms (excluding substituents), still more preferably a methyl group, an ethyl group, a propyl group or a butyl group. Alkyl groups may be straight or branched. When the alkyl group has a substituent, the substituent includes a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxyl group, a methyl ester group, an amino group and the like. Halogen atoms include fluorine, chlorine, bromine and iodine atoms, and so on.

In general formula (I), the cycloalkyl group represented by R ² or R ⁴ includes cycloalkyl groups having 3 to 10 carbon atoms (excluding substituents), preferably cycloalkyl groups having 3 to 10 carbon atoms (excluding substituents). ) is a 3-6 cycloalkyl group. When the cycloalkyl group has a substituent, examples thereof include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxyl group, a methyl ester group and an amino group.

In general formula (I), the alkenyl group represented by R ² or R ⁴ includes an alkenyl group having 1 to 10 carbon atoms (excluding substituents), preferably having 1 to 10 carbon atoms (excluding substituents). is an alkenyl group having 1 to 5 carbon atoms, more preferably an alkenyl group having 1 to 3 carbon atoms (excluding substituents). When the alkenyl group has a substituent, examples thereof include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxyl group, a methyl ester group, an amino group and the like.

In general formula (I), the alkynyl group represented by R ² or R ⁴ includes an alkynyl group having 1 to 10 carbon atoms (excluding substituents), preferably having 1 to 10 carbon atoms (excluding substituents). is an alkynyl group having 1 to 5 carbon atoms, more preferably an alkynyl group having 1 to 3 carbon atoms (excluding substituents). When the alkynyl group has a substituent, examples of the substituent include a trialkylsilyl group (the alkyl group has the same meaning as the above alkyl group) and the like.

In general formula (I), the alicyclic heterocyclic group represented by R ² or R ⁴ includes an alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom, It is an alicyclic heterocyclic group having 2 to 6 carbon atoms (excluding substituents) including an oxygen atom or a sulfur atom. Examples of substituents when the alicyclic heterocyclic group has a substituent include an alkyl group (the alkyl group is synonymous with the alkyl group), an alkoxy group (the alkyl group in the alkoxy group is synonymous with the alkyl group ), nitro group, cyano group, halogen atom, hydroxyl group, carboxy group, methyl ester group, amino group and the like.

In formula (I), the aryl group represented by R ² or R ⁴ includes a phenyl group and a naphthyl group, preferably a phenyl group. Examples of substituents when the aryl group has a substituent include an alkyl group (the alkyl group is synonymous with the alkyl group), an alkoxy group (the alkyl group in the alkoxy group is synonymous with the alkyl group), and a nitro group. , a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group, and the like.

In the general formula (I), the aralkyl group represented by R ² or R ⁴ is an aralkyl group having 1 to 6 carbon atoms (excluding substituents) substituted with one of the above-mentioned aryl groups. groups. Examples of substituents when the aralkyl group has a substituent include an alkyl group (the alkyl group is synonymous with the alkyl group), an alkoxy group (the alkyl group in the alkoxy group is synonymous with the alkyl group), and a nitro group. , a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group, and the like.

In general formula (I), the aromatic heterocyclic group represented by R ² or R ⁴ includes an aromatic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom or an oxygen atom. or an aromatic heterocyclic group having 2 to 9 carbon atoms (excluding substituents) including a sulfur atom. Examples of substituents when the aromatic heterocyclic group has a substituent include an alkyl group (the alkyl group is synonymous with the above alkyl group) and an alkoxy group (the alkyl group in the alkoxy group is synonymous with the above alkyl group). , nitro group, cyano group, halogen atom, hydroxyl group, carboxy group, methyl ester group, amino group and the like.

In the general formula (I), the aromatic heterocyclic alkyl group represented by R ² or R ⁴ is an alkyl group having 1 to 6 carbon atoms (excluding substituents) in which one of the carbon atoms is the above-mentioned aromatic An aromatic heterocyclic alkyl group substituted with a heterocyclic ring can be mentioned. Examples of substituents when the aromatic heterocyclic alkyl group has a substituent include an alkyl group (the alkyl group is synonymous with the alkyl group), an alkoxy group (the alkyl group in the alkoxy group is synonymous with the alkyl group ), nitro group, cyano group, halogen atom, hydroxyl group, carboxy group, methyl ester group, amino group and the like.

In general formula (I), when R ¹ is a substituted aryl group or aromatic heterocyclic group, the number of substituents is not particularly limited, but may be 1 to 3, or 1 Alternatively, the number may be two or one.

When R ¹ is an aryl group or aromatic heterocyclic group having a substituent, R ¹ is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH ₂ COOR as a substituent. (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO ₂ R (R is a substituted or unsubstituted alkyl group), SO ₂ NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom. Furthermore, R ¹ is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH ₂ COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OR (R is a hydrogen atom, a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom.

In general formula (I), the number of R ² is preferably 1 or 2, more preferably 1.
R ² is preferably NR ⁵ R ⁶ or NR ⁷ COR ⁸ , more preferably NH ₂ or NHCOR ⁸ , even more preferably NH ₂ or NHCOAr (Ar is a substituted or unsubstituted aryl group) .
Ar includes a phenyl group and a naphthyl group, preferably a phenyl group. Examples of substituents when the aryl group has a substituent include an alkyl group (the alkyl group is synonymous with the alkyl group), an alkoxy group (the alkyl group in the alkoxy group is synonymous with the alkyl group), and a nitro group. , a cyano group, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, and the like. Among them, an alkoxy group and a halogen atom are preferred, and a methoxy group and a chloro group are more preferred.
When R ² is NHCOAr and Ar is a substituted aryl group, Ar preferably has a substituent at the para position.

R3 is preferably COOR ⁽ R is a hydrogen atom or a substituted or unsubstituted alkyl group), more preferably COOH.

In certain embodiments, heterocyclic compounds represented by general formula (I) are those in which X is O, R ¹ is a substituted or unsubstituted aryl group, and R ² is NR ⁵ R ⁶ or NR ⁷ COR ⁸ It may be a heterocyclic compound.
In the above heterocyclic compound, R ¹ further has no substituent, a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH ₂ COOR (R is a hydrogen atom or a substituted or unsubstituted unsubstituted alkyl group), OR (R is a hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO ₂ R (R is a substituted or unsubstituted alkyl group), SO ₂ NRR (R is each independently a hydrogen atom or a substituted or unsubstituted unsubstituted alkyl group), SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), an aryl group or an aromatic heterocyclic group having a nitro group, a cyano group or a halogen atom as a substituent, and R ² is NHCOAr ( Ar is a substituted or unsubstituted aryl group) ^, R3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), and n is 1.

In one embodiment, the heterocyclic compound represented by general formula (I) may be a heterocyclic compound represented by general formula (I-1) below. The definitions of X, R ¹ to R ³ and n in general formula (I-1) are the same as in general formula (I), and preferred examples are also the same.

In one embodiment, the heterocyclic compound represented by general formula (I) may be a heterocyclic compound represented by general formula (II) below. The definitions of X and R ¹ to R ³ in general formula (I-2) are the same as in general formula (I), and preferred examples are also the same.

When the heterocyclic compound represented by general formula (I) has positional isomers, geometric isomers, optical isomers or tautomers, any of these or a mixture thereof is also represented by general formula (I). It is included in the heterocyclic compound that is used.
The pharmacologically acceptable salts of the heterocyclic compound represented by general formula (I) may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. be.

The pharmacologically acceptable salts of the heterocyclic compound represented by formula (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. are mentioned. Acid addition salts include inorganic acid salts such as hydrochlorides, sulfates and phosphates, and organic acid salts such as acetates, maleates, fumarates, tartrates, citrates and methanesulfonates. mentioned. Examples of metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and zinc salts. Ammonium salts include salts such as ammonium and tetramethylammonium. Examples of organic amine addition salts include addition salts of morpholine, piperidine and the like. Amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.

When obtaining a salt of the heterocyclic compound represented by general formula (I), when the heterocyclic compound is obtained in the form of a salt, it can be purified as it is, and when it is obtained in the free form, The heterocyclic compound may be dissolved or suspended in a suitable organic solvent, and acid or base may be added to form a salt by a conventional method.

The heterocyclic compound represented by general formula (I) may exhibit activity as a GPR35 agonist. In certain embodiments, the heterocyclic compound represented by general formula (I) may have activity against at least one of human GPR35 and non-human animal GPR35. It may have activity against both GPR35 of animals other than GPR35. Non-human animals include, but are not limited to, rodents such as mice and rats.

Specific examples (CI-1 to CI-127) of heterocyclic compounds represented by the general formula (I) where X is O are shown below. Heterocyclic compounds are not limited to these.

The structures of specific examples (CII-1 to CII-22) of the heterocyclic compound represented by the general formula (I) in which X is NH are shown below, which are represented by the general formula (I) Heterocyclic compounds are not limited to these.

<Second embodiment>
A second embodiment of the present disclosure is a GPR35 agonist, which is a heterocyclic compound represented by the above general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.

When a GPR35 agonist is used for purposes such as pharmaceuticals that require animal testing for practical use, the GPR35 agonist is human GPR35 and non-human animals (e.g., rodents such as mice and rats) GPR35 preferably exhibit activity against both

The use of GPR35 agonists is not particularly limited, and is intended for treatment of all conditions and diseases associated with GPR35.
Symptoms and diseases associated with GPR35 include, but are not limited to, allergic diseases, inflammatory bowel disease, diabetes, arteriosclerosis, and the like.

A GPR35 agonist may be one that is used as an antiallergic agent.
GPR35 is known to suppress IL-4 secretion from iNKT cells upon activation. Therefore, application of a GPR35 agonist to GPR35 is thought to suppress differentiation induction from Th0 cells to Th2 cells. As a result, chemical mediators released from Th2 cells are expected to have the effect of suppressing allergic reactions caused by binding to receptors. Anti-allergic drugs using GPR35 agonists are a means of achieving more fundamental alleviation and elimination of symptoms compared to existing anti-allergic drugs that target the binding of chemical mediators released from Th2 cells to receptors. It is considered useful as

GPR35 agonists may be used in the form of supplements, foods, beverages, etc., as well as drugs, and may be used for purposes other than medical practices such as research.

A GPR35 agonist can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. Also, these pharmaceutical formulations are for veterinary and human use.
As the route of administration, it is preferable to use the most effective route for treatment, and oral or parenteral routes such as enteral, buccal, subcutaneous, intramuscular, and intravenous routes can be mentioned.
Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like.
The effective dose and frequency of administration of GPR35 agonists vary depending on the dosage form, age of the patient, body weight, nature of symptoms to be treated, severity, etc., but usually the dosage is 0.01 to 1000 mg/day. The dose is preferably 5 to 500 mg/person, and the administration frequency is preferably once a day or in divided doses.

<Third Embodiment>
A third embodiment of the present disclosure is a pharmaceutical composition comprising the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment as an active ingredient. be.

When the pharmaceutical composition contains components other than the above active ingredients, such components include media and formulation additives commonly used in the preparation of drugs. Media include solid media (eg, gelatin, lactose) and liquid media (eg, alcohol, water, saline). Pharmaceutical additives include excipients, disintegrants, binders, lubricants, surfactants, buffers, solubilizers, stabilizers, tonicity agents and the like. The blending amount of these components is as long as the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment can act as an active ingredient. There are no particular restrictions.

The form of the pharmaceutical composition is not particularly limited and can be selected depending on the application. Examples include forms suitable for oral administration such as tablets, granules, powders, capsules, suspensions, syrups, emulsions and limonades, and forms suitable for parenteral administration such as suppositories and injections.

Preparations in a form suitable for oral administration, for example, liquid preparations such as emulsions and syrups, include water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, soybean oil and the like. oils, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor and peppermint flavor, and the like. In addition, capsules, tablets, powders, granules, etc. contain excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl It can be produced using a binder such as alcohol, hydroxypropyl cellulose, or gelatin, a surfactant such as fatty acid ester, or a plasticizer such as glycerin.
Formulations in forms suitable for parenteral administration preferably consist of sterile aqueous preparations containing the active compound which are isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier consisting of a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
Topical formulations are prepared by dissolving or suspending the active compound in one or more vehicles such as mineral oil, petroleum, polyhydric alcohols, etc. or other bases used in topical pharmaceutical formulations.
Formulations for enteral administration are prepared using conventional carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids and the like, and presented as suppositories.
In addition, in these parenteral formulations, glycols, oils, flavors, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants exemplified for oral formulations , plasticizers and the like may also be added.

<Fourth Embodiment>
A fourth embodiment of the present disclosure comprises the step of contacting GPR35 with the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of said heterocyclic compound, or the GPR35 agonist of the second embodiment, Methods of activating GPR35 or treating diseases involving GPR35.

The method of contacting GPR35 with the heterocyclic compound or pharmacologically acceptable salt of the heterocyclic compound of the first embodiment, or the GPR35 agonist of the second embodiment is not particularly limited, and oral administration, intravenous administration , surgical treatment such as indwelling, and the like. Alternatively, GPR35 may be brought into contact with the pharmaceutical composition of the third embodiment described above.

The GPR35 to be contacted with the heterocyclic compound or the pharmacologically acceptable salt of the heterocyclic compound of the first embodiment, or the GPR35 agonist of the second embodiment may be human GPR35 or non-human GPR35. GPR35 of animals (laboratory animals, livestock animals, pet animals, etc.) may also be used. Moreover, it may be GPR35 in vivo or GPR35 in vitro.

The method for activating GPR35 may be intended for treatment of a disease in which GPR35 is involved, or may be intended for research, examination, or the like other than treatment.

When the method for activating GPR35 is intended to treat diseases associated with GPR35, the diseases associated with GPR35 to be treated include allergic diseases, inflammatory bowel diseases, diabetes, arteriosclerosis, and the like. but not limited to these.

Hereinafter, embodiments of the present disclosure will be specifically described based on synthetic examples and identification data of heterocyclic compounds, evaluation of activity as GPR35 agonists, and formulation examples, but the present disclosure is not limited to these do not have.
Compounds that are heterocyclic compounds of the present disclosure and are not included in the specific examples of the heterocyclic compounds described above, or compounds that are not described in the synthesis examples below among the specific examples described above, refer to the synthesis examples described later. It can be synthesized within the scope of ordinary technical knowledge of those skilled in the art.

Synthesis of Methyl 8-amino-6-phenyl-4-oxo-4H-chromene-2-carboxylate (CI-1)

(1) After adding (COOEt) ₂ (3.21 mL, 23.6 mmol) to a solution of commercially available 3-bromo-6-hydroxy-5-nitroacetophenone (2.50 g, 9.61 mmol) in dimethylformamide (60 mL), cool with ice. ^t BuOK (4.32 g, 38.5 mmol) was slowly added below and stirred overnight. 0.4 M hydrochloric acid was slowly added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure. Then, it was dissolved in methanol (100 mL), concentrated sulfuric acid (7.00 mL) was slowly added under ice-cooling, and the mixture was heated under reflux overnight. The reaction solution was concentrated, and the residue was slowly added dropwise to a saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain methyl 6-bromo-8-nitro-4-oxo-4H-chromene-2-carboxylate (2.90 g, 8.85 mmol) (yield 92%). .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.57 (1H, d, J = 2.4 Hz), 8.46 (1H, d, J = 2.8 Hz), 7.20 (1H, s), 4.03 (3H, s) .

(2) SnCl ₂ (6.01 g, 31.7 mmol) and 4 M hydrochloric acid (21.8 mL) were added, and the mixture was heated and stirred at 65°C for 4 hours. The reaction mixture was concentrated, the residue was slowly added dropwise to a saturated aqueous sodium hydrogencarbonate solution, chloroform was added, and the mixture was stirred overnight at room temperature. Celite is added to the reaction solution, insoluble matter is filtered off, the chloroform layer is isolated, dried over anhydrous sodium sulfate, and the solvent is distilled off to give methyl 8-amino-6-bromo-4-oxo-4H-chromene- 2-carboxylate (1.67 g, 5.61 mmol) was obtained (yield 71%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.63 (1H, d, J = 2.4 Hz), 7.16 (1H, d, J = 2.0 Hz), 7.09 (1H, s), 4.41 (2H, br) , 4.02 (3H, s). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.22 (1H, d, J = 2.0 Hz), 7.20 (1H, d, J = 2.4 Hz), 6.92 (1H , s), 5.92 (2H, _brs ), 3.94 ⁽ 3H, s). , 114.73, 53.60.

(3) 1,4-dioxane (5.0 mL) of methyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (200 mg, 0.671 mmol) obtained in (2) above and dimethyl PdCl ₂ (dppf) (49 mg, 0.0671 mmol), K ₃ PO ₄ (284 mg, 1.34 mmol), and phenylboronic acid (123 mg, 1.01 mmol) were added to a mixed solution of formamide (2.0 mL) under an argon atmosphere. Heated to reflux overnight. The reaction mixture was concentrated, saturated saline solution and chloroform were added to the residue, and the precipitated insoluble matter was filtered off, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain CI-1 (137 mg, 0.464 mmol) (yield 69%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.64 (2H, d, J = 7.5 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.42-7.39 (3H, m), 6.92 ( 1H, s), 5.70 (2H, brs), 3.96 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-4-oxo-6-phenyl-4H-chromene-2-carboxylate (CI-2)

(1) CH ₂ Cl ₂ (1.68 mL) of methyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (100 mg, 0.335 mmol) synthesized during the synthesis of CI-1 and A solution of N,N-diisopropylethylamine (0.080 mL, 0.446 mmol) and 4-methoxybenzoyl chloride (0.060 mL, 0.446 mmol) in CH ₂ Cl ₂ (1.12 mL) was added to a mixed solution of tetrahydrofuran (0.56 mL) under ice cooling. It was slowly added and stirred at room temperature for 4 days. Furthermore, a solution of N,N-diisopropylethylamine (0.080 mL, 0.446 mmol) and 4-methoxybenzoyl chloride (0.060 mL, 0.446 mmol) in CH ₂ Cl ₂ (1.12 mL) was slowly added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to give methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (144 mg, 0.332 mmol). obtained (yield 99%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.16 (1H, d, J = 2.4 Hz), 8.76 (1H, brs), 8.03 (1H, d, J = 2.8 Hz), 7.98 (2H, d, J = 9.1 Hz), 7.16 (1H, s), 7.08 (2H, d, J = 9.1 Hz), 4.08 (3H, s), 3.93 (3H, s).

(2) 1,4-dioxane (13 mL) and dimethylformamide (7 mL) under argon atmosphere, PdCl ₂ (dppf) (13 mg, 0.0174 mmol), K ₃ PO ₄ (74 mg, 0.347 mmol), phenylboronic acid (85 mg, 0.694 mmol) mmol) was added, and the mixture was heated and stirred at 85° C. overnight. Furthermore, phenylboronic acid (85 mg, 0.694 mmol) was added, and the mixture was heated and stirred at 85°C overnight. The reaction mixture was concentrated, saturated saline solution and chloroform were added to the residue, and the precipitated insoluble matter was filtered off, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain CI-2 (143 mg, 0.333 mmol) (yield 72%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.42 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.78 (2H, d, J = 7.9 Hz), 7.54 (2H, t, J = 7.5 Hz), 7.45 (1H, t, J = 7.5 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.93 (3H, s), 3.89 (3H, s).

Synthesis of 8-(4-Methoxybenzamido)-4-oxo-6-phenyl-4H-chromene-2-carboxylic acid (CI-3)

4 M NaOH aqueous solution (0.146 mL) was added to a solution of CI-2 (50 mg, 0.116 mmol) in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CI-3 (44 mg, 0.106 mmol) (yield 91%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.19 (1H, brs), 8.43 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.77 (2H, d, J = 7.5 Hz), 7.54 (2H, t, J = 7.5 Hz), 7.45 (1H, t, J = 7.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.97 (1H, s), 3.87 (3H, s). EI-MS (m/z): 416 [M] ⁺ .

Synthesis of Methyl 8-amino-6-methoxycarbonylphenyl-4-oxo-4H-chromene-2-carboxylate (CI-4)

Argon Add PdCl ₂ (dppf) (49 mg, 0.0671 mmol), K ₃ PO ₄ (284 mg, 1.34 mmol), and 4-(methoxycarbonyl)phenylboronic acid (181 mg, 1.01 mmol) under atmosphere and heat overnight at 80 °C. Stirred. Further, PdCl ₂ (dppf) (49 mg, 0.0671 mmol) and 4-(methoxycarbonyl)phenylboronic acid (181 mg, 1.01 mmol) were added, and the mixture was heated and stirred at 80° C. overnight. Further, dimethylformamide (2.0 mL) was added and the mixture was heated under reflux for 7 hours and then concentrated. The reaction mixture was concentrated, saturated saline solution and chloroform were added to the residue, and the precipitated insoluble matter was separated by filtration. Then, it was extracted with chloroform and dried with anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain CI-4 (193 mg, 0.546 mmol) (yield 81%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.06 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.47 (1H, d, J = 2.4 Hz) , 7.47 (1H, d, J = 2.4 Hz), 6.94 (1H, s), 5.76 (2H, brs), 3.96 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-amino-6-(3-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-5)

Using 3-(methoxycarbonyl)phenylboronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, CI-5 was obtained in the same manner as CI-4 (yield 64%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.18 (1H, t, J = 2.0 Hz), 8.00-7.94 (2H, m), 7.65 (1H, t, J = 7.5 Hz), 7.47 ( 1H, d, J = 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 6.94 (1H, s), 5.76 (2H, brs), 3.96 (3H, s), 3.91 (3H, s).

Synthesis of Methyl 8-amino-6-(2-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-6)

Using 2-(methoxycarbonyl)phenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-5 was obtained in the same manner as CI-4 (yield 38%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.75 (1H, dd, J = 7.5 Hz, 1.2 Hz), 7.64 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.52 (1H, dt , J = 7.5 Hz, 1.2 Hz), 7.45 (1H, dd, J = 7.9 Hz, 0.8 Hz), 7.06-7.04 (2H, m), 6.92 (1H, s), 5.69 (2H, d, J = 7.5 Hz), 3.96 (3H, s), 3.60 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-methoxycarbonylphenyl-4-oxo-4H-chromene-2-carboxylate (CI-7)

1,4-dioxane (5 mL) and dimethylformamide (3 mL) under an argon atmosphere, PdCl ₂ (dppf) (13 mg, 0.0174 mmol), K ₃ PO ₄ (74 mg, 0.347 mmol), 4-(methoxycarbonyl)phenylboronic acid (47 mg, 0.260 mmol) was added, and the mixture was heated and stirred at 85° C. for 2 days. The reaction mixture was concentrated, saturated saline solution and chloroform were added to the residue, and the precipitated insoluble matter was filtered off, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain CI-7 (16 mg, 0.0373 mmol) (yield 21%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.25 (1H, brs), 8.50 (1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 2.4 Hz), 8.10 (2H, d, J = 8.7 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.96 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.06 (1H, s) , 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s). EI-MS (m/z): 487 [M] ⁺ .

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-8)

Using 3-(methoxycarbonyl)phenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-8 was obtained in the same manner as CI-7 (yield 46%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.25 (1H, brs), 8.47 (1H, d, J = 2.4 Hz), 8.27 (1H, s), 8.13 (1H, d, J = 2.0 Hz), 8.11-8.03 (4H, m), 7.70 (1H, t, J = 7.9 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 487[M] ⁺ .

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(2-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-9)

N,N _- diisopropylethylamine (0.057 mL, _0.327 mmol) and 4-methoxybenzoyl chloride (0.044 mL, 0.327 mmol) in CH ₂ Cl ₂ (0.5 mL) was added slowly under ice-cooling, and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain CI-9 (100 mg, 0.233 mmol) (yield 95%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.18 (1H, brs), 8.07 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.86 (1H, dd, J = 7.9 Hz, J = 1.2 Hz), 7.75 (1H, d, J = 2.4 Hz), 7.70 (1H, dt, J = 7.5 Hz, J = 1.2 Hz), 7.60-7.55 (2H, m) , 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.94 (3H, s), 3.87 (3H, s), 3.64 (3H, s). 487 [M] ⁺ .

Synthesis of Methyl 8-amino-6-carboxyphenyl-4-oxo-4H-chromene-2-carboxylate (CI-10)

Using 4-carboxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-10 was obtained in the same manner as in the synthesis of CI-4 (yield 32%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.05 (2H, J = 7.9 Hz), 7.77 (2H, m), 7.47 (1H, d, J = 2.0 Hz), 7.45 (1H, J = 1.6 Hz), 6.93 (1H, s), 5.74 (2H, brs), 3.96 (3H, s). EI-MS (m/z): 339 [M] ⁺ .

Synthesis of 4-[8-(4-Methoxybenzamide)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]benzoic acid (CI-11)

Using 4-carboxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-11 was obtained in the same manner as in the synthesis of CI-7 (yield 74%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.25 (1H, brs), 8.49 (1H, s), 8.18 (1H, s), 8.08 (2H, d, J = 8.3 Hz), 8.05 ( 2H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.88 ( 3H, s). EI-MS (m/z): 473 [M] ⁺ .

Synthesis of 4-[2-Ethoxycarbonyl-8-(4-methoxybenzamide)-4-oxo-4H-chromen-6-yl]benzoic acid (CI-12)

In place of Methyl 8-(4-Methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate, ethyl 8-(4-methoxybenzamido which can be synthesized by the method described in J. Med. Chem. )-4-oxo-4H-chromene-2-carboxylate was used to obtain CI-12 in the same manner as in the synthesis of CI-11 (yield 59%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.25 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 2.0 Hz), 8.08 (2H, d, J = 7.9 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.13 (2H, d, J = 9.1 Hz), 7.05 (1H, s) , 4.36 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 1.27 (3H, t, J = 7.1 Hz).

Synthesis of 3-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]benzoic acid (CI-13)

Using 3-carboxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-13 was obtained in the same manner as in the synthesis of CI-7 (yield 48%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.24 (1H, brs), 8.48 (1H, d, J = 2.4 Hz), 8.27 (1H, s), 8.13 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 7.9 Hz), 7.95 (1H, d, J = 8.3 Hz), 7.67 (1H, t, J = 7.9 Hz) , 7.15 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.80 (3H, s). EI-MS (m/z): 473 [M] ⁺ .

Synthesis of 2-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]benzoic acid (CI-14)

Using 2-carboxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-14 was obtained in the same manner as in the synthesis of CI-7 (yield 4%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 8.13 (1H, d, J = 2.4 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.85 (1H, d, J = 8.7 Hz), 7.77 (1H, d, J = 2.4 Hz), 7.65 (1H, m), 7.58-7.46 (2H, m), 7.13 (2H, d, J = 9.1 Hz), 7.04 ( 1H, s), 3.94 (3H, s), 3.87 (3H, s). EI-MS (m/z): 473 [M] ⁺ .

Synthesis of 6-(4-Methoxycarbonylphenyl)-8-(4-methoxybenzamide)-4-oxo-4H-chromene-2-carboxylic acid (CI-15)

LiI (41 mg, 0.308 mmol) was added to a solution of CI-7 (50 mg, 0.103 mmol) in tetrahydrofuran (3.0 mL), and the mixture was heated under reflux for 7 hours. Further, LiI (41 mg, 0.308 mmol) was added, and after heating under reflux overnight, the reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure, and CI-15 was obtained. (35 mg, 0.0739 mmol) was obtained (72% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.51 (1H, d, J = 2.0 Hz), 8.16 (1H, d, J = 2.4 Hz), 8.10 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz), 7.95 (2H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz), 6.93 (1H, s) , 3.90 (3H, s), 3.87 (3H, s). EI-MS (m/z): 473[M] ⁺ .

Synthesis of 6-(3-Methoxycarbonylphenyl)-8-(4-methoxybenzamide)-4-oxo-4H-chromene-2-carboxylic acid (CI-16)

4 M NaOH aqueous solution (0.058 mL, 0.233 mmol) was added to a solution of CI-8 (50 mg, 0.116 mmol) in 1,4-dioxane (2.5 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated, 1M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give CI-16 (51 mg, 0.108 mmol) (yield 93%). The position of hydrolyzed carboxylic acid was determined by HMBC correlation.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.21 (1H, brs), 8.48 (1H, d, J = 2.0 Hz), 8.27 (1H, s), 8.11 (1H, d, J = 2.0 Hz), 8.10-8.02 (4H, m), 7.70 (1H, m), 7.11 (2H, d, J = 9.1 Hz), 6.96 (1H, s), 3.92 (3H, s), 3.87 (3H, s ¹³ C-NMR (100 MHz, DMSO-D ₆ ) Delta: 177.52, 166.95, 162.29, 161.17, 154.18, 148.81, 138.75, 136.05, 131.69, 130.57 , 125.93, 124.56, 118.40, 113.83, 112.95, 55.49, 52.36. EI-MS (m/z): 473 [M] ⁺ .

Synthesis of 6-Carboxyphenyl-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-17)

LiI (44 mg, 0.329 mmol) was added to a solution of CI-11 (52 mg, 0.110 mmol) in tetrahydrofuran (4.0 mL), and the mixture was heated under reflux overnight. After LiI (44 mg, 0.329 mmol) was added and heated under reflux for 2 days, LiI (44 mg, 0.329 mmol) was further added and heated under reflux overnight. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure, and then recrystallized from methanol to obtain CI-17 (28 mg, 0.0610 mmol). (56% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.26 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.08 (2H, d, J = 8.4 Hz), 8.06 (2H, d, J = 8.8 Hz), 7.92 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.8 Hz), 6.99 (1H, s) , 3.87 (3H, s). EI-MS (m/z): 459 [M] ⁺ .

Synthesis of 6-(3-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-18)

LiI (66 mg, 0.493 mmol) was added to a solution of CI-13 (71 mg, 0.164 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 100° C. for 10 hours under microwave irradiation. LiI (66 mg, 0.493 mmol) was added and stirred at 100 °C for 10 hours under microwave irradiation. (44 mg, 0.329 mmol) was added and stirred at 100° C. for 2 hours under microwave irradiation. The reaction mixture was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure, and recrystallized from methanol to obtain CI-18 (41 mg, 0.0950 mmol) ( Yield 58%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 9.65 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.13 (1H, s), 7.12 (2H, d, J = 9.1 Hz), 6.97 (1H, s), 6.84 (1H, m), 3.87 (3H, s). EI-MS (m/z): 459 [M] ⁺ .

Synthesis of 6-(2-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-19)

LiI (67 mg, 0.502 mmol) was added to a solution of CI-14 (80 mg, 0.167 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 100° C. for 6 hours under microwave irradiation. Furthermore, LiI (67 mg, 0.502 mmol) was added, and the mixture was stirred at 100° C. for 13 hours under microwave irradiation. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure. ) was obtained (55% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.04 (1H, brs), 8.21 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.79 (1H, d, J = 7.1 Hz), 7.70 (1H, d, J = 2.0 Hz), 7.65 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.52 (1H, m), 7.48 (1H, d, J = 7.5 Hz), 7.09 (2H, d, J = 8.3 Hz), 6.69 (1H, s), 3.86 (3H, s). EI-MS (m/z): 459 [M] ⁺ .

Synthesis of 6-(2-Carboxyphenyl)-8-(4-hydroxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-20)

LiI (31 mg, 0.234 mmol) was added to a solution of CI-14 (19 mg, 0.0390 mmol) in tetrahydrofuran (2.0 mL), and the mixture was stirred at 200° C. for 2 hours under microwave irradiation. LiI (31 mg, 0.234 mmol) was added and stirred at 200°C for 2.5 hours under microwave irradiation, then LiI (31 mg, 0.234 mmol) was further added and stirred at 200°C for 6 hours under microwave irradiation. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CI-20 (4 mg, 0.00898 mmol) (yield 23%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.27 (1H, br), 10.01 (1H, brs), 8.14 (1H, d, J = 2.4 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.84 (1H, dd, J = 7.5 Hz, 1.2 Hz), 7.75 (1H, d, J = 2.0 Hz), 7.65 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.54 (1H, dt , J = 7.5 Hz, 1.2 Hz), 7.48 (1H, d, J = 7.1 Hz), 6.98 (1H, s), 6.91 (2H, d, J = 8.7 Hz).

Synthesis of Methyl 6-(4-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-21)

Using 4-hydroxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-21 was obtained in the same manner as in the synthesis of CI-7 (yield 72%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.18 (1H, brs), 9.73 (1H, brs), 8.33 (1H, d, J = 2.0 Hz), 8.04 (2H, d, J = 9.1 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.01 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 445 [M] ⁺ .

Synthesis of Ethyl 6-hydroxyphenyl-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-22)

In place of Methyl 8-(4-Methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate, ethyl 8-(4-methoxybenzamido which can be synthesized by the method described in J. Med. Chem. )-4-oxo-4H-chromene-2-carboxylate, CI-22 was obtained in the same manner as in the synthesis of CI-21 (yield 25%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 9.73 (1H, brs), 8.33 (1H, d, J = 2.0 Hz), 8.04 (2H, d, J = 9.1 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 7.01 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 4.35 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 1.26 (3H, m).

Synthesis of Methyl 6-(3-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-23)

Using 3-hydroxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-23 was obtained in the same manner as in the synthesis of CI-7 (yield 51%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.20 (1H, brs), 9.67 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 9.1 Hz), 8.03 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.14 (2H, d, J = 9.1 Hz) , 7.13 (1H, s), 7.03 (1H, s), 6.84 (1H, m), 3.94 (3H, s), 3.88 (3H, s). EI-MS (m/z): 445 [M] ⁺ .

Synthesis of Methyl 6-(2-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-24)

Using 2-hydroxyphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-24 was obtained in the same manner as in the synthesis of CI-7 (yield 64%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.20 (1H, brs), 9.85 (1H, s), 8.26 (1H, d, J = 1.6 Hz), 8.07 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.38 (1H, dd, J = 7.9 Hz, 1.6 Hz), 7.32 (1H, m), 7.13 (2H, d, J = 9.1 Hz), 7.02 (1H, s), 7.01 (1H, m), 6.95 (1H, m), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 445 [M] ⁺ .

Synthesis of 6-(4-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-25)

Using CI-21 instead of CI-13, CI-25 was obtained in the same manner as in the synthesis of CI-18 (yield 51%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.19 (1H, brs), 9.74 (1H, brs), 8.32 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.7 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 6.97 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 3.87 (3H, s). EI-MS (m/z): 431 [M] ⁺ .

Synthesis of 6-(3-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-26)

Using CI-23 instead of CI-13, CI-26 was obtained in the same manner as in the synthesis of CI-18 (yield 58%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 9.65 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.13 (1H, s), 7.12 (2H, d, J = 9.1 Hz), 6.97 (1H, s), 6.84 (1H, m), 3.87 (3H, s). EI-MS (m/z): 431 [M] ⁺ .

Synthesis of 6-(2-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-27)

Using CI-24 instead of CI-13, CI-27 was obtained in the same manner as in the synthesis of CI-18 (yield 86%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.51 (1H, brs), 9.82 (1H, brs), 8.28 (1H, d, J = 2.0 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.37 (1H, m), 7.24 (1H, m), 7.11 (2H, d, J = 8.7 Hz), 7.01 (1H, d, J = 7.1 Hz), 6.97 (1H, s), 6.94 (1H, t, J = 7.5 Hz), 3.87 (3H, s). EI-MS (m/z): 431 [M] ⁺ .

Synthesis of Methyl 6-(4-tert-butoxycarbonylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-28)

To a solution of CI-21 (233 mg, 0.523 mmol) in dimethylformamide (3.5 mL) was added K ₂ CO ₃ (94 mg, 0.680 mmol) and tert-butyl 2-bromoacetate (0.092 mL, 0.628 mmol) under an argon atmosphere. The mixture was added and stirred at room temperature for 2 days. The reaction mixture was concentrated, saturated brine was added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain CI-28 (211 mg, 0.377 mmol) (yield 72%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.20 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.05 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.05 (2H, d, J = 9.1 Hz), 7.05 (1H, s) , 4.73 (2H, s), 3.92 (3H, s), 3.88 (3H, s), 1.45 (9H, s). EI-MS (m/z): 559 [M] ⁺ .

Synthesis of Methyl 6-(3-tert-butoxycarbonylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-29)

Using CI-23 instead of CI-21, CI-29 was obtained in the same manner as in the synthesis of CI-28 (yield 48%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.23 (1H, brs), 8.40 (1H, d, J = 2.0 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.46 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.25 (1H, s), 7.14 (2H, d, J = 8.7 Hz), 7.04 (1H, s), 7.00 (1H, dd, J = 7.9 Hz, 2.0 Hz), 4.79 (2H, s), 3.92 (3H, s), 3.88 (3H, s), 1.46 (9H, s).

Synthesis of Methyl 6-(2-tert-butoxycarbonylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-30)

Using CI-24 instead of CI-21, CI-30 was obtained in the same manner as in the synthesis of CI-28 (yield 63%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 8.28 (1H, d, J = 1.6 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.42 (1H, m), 7.39 (1H, t, J = 7.9 Hz), 7.13 (2H, J = 9.1 Hz), 7.14-7.02 (2H, m), 7.02 (1H, s), 4.74 (2H, s), 3.92 (3H, s), 3.87 (3H, s), 1.38 (9H, s). EI-MS (m/z): 559 [M] ⁺ .

Synthesis of 4-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]phenoxyacetic acid (CI-31)

Dioxane (6.4 mL, 25.6 mmol) containing 4 M HCl was added to CI-28 (191 mg, 0.341 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated to give CI-31 (165 mg, 0.328 mmol) (yield 96%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.37 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.3 Hz), 8.04 (1H, d, J = 2.0 Hz), 7.72 (2H, d, J = 9.1 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.7 Hz), 7.03 (1H, s) , 4.76 (2H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 503 [M] ⁺ .

Synthesis of 3-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]phenoxyacetic acid (CI-32)

CI-32 was obtained in a manner similar to the synthesis of CI-31, substituting CI-29 for CI-28 (quantitative yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.23 (1H, brs), 8.40 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.45 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 7.00 (1H, dd, J = 7.9 Hz, 2.4 Hz), 4.82 (2H, s), 3.92 (3H, s), 3.88 (3H, s). -MS (m/z): 503 [M] ⁺ .

Synthesis of 2-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]phenoxyacetic acid (CI-33)

CI-33 was obtained in a manner similar to the synthesis of CI-31, substituting CI-30 for CI-28 (quantitative yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 8.28 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 9.5 Hz), 7.42 (1H, m), 7.39 (1H, t, J = 8.3 Hz), 7.13 (2H, J = 9.1 Hz), 7.14-7.04 (2H, m), 7.02 (1H, s), 4.77 (2H, s), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 503 [M] ⁺ .

Synthesis of 6-(4-Carboxylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-34)

Using CI-31 instead of CI-13, CI-34 was obtained in the same manner as in the synthesis of CI-18 (yield 64%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.18 (1H, brs), 8.36 (1H, d, J = 2.4 Hz), 8.04 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.71 (2H, d, J = 9.1 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 9.1 Hz), 6.98 (1H, s) , 4.76 (2H, s), 3.87 (3H, s).

Synthesis of 6-(3-Carboxylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-35)

Using CI-32 instead of CI-13, CI-35 was obtained in the same manner as in the synthesis of CI-18 (yield 73%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.20 (1H, brs), 8.40 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.44 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.27 (1H, s), 7.12 (2H, d, J = 8.3 Hz) , 7.00 (1H, m), 6.99 (1H, s), 4.82 (2H, s), 3.87 (3H, s). EI-MS (m/z): 489 [M] ⁺ .

Synthesis of 6-(2-Carboxylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-36)

Using CI-33 instead of CI-13, CI-36 was obtained in the same manner as in the synthesis of CI-18 (yield 84%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.15 (1H, brs), 8.28 (1H, d, J = 2.4 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.42 (1H, dd, J = 7.9 Hz, 2.0 Hz), 7.38 (1H, m), 7.11 (2H, d, J = 8.7 Hz), 7.11 (1H, m), 7.05 (1H, d, J = 8.7 Hz), 7.02 (1H, s), 4.77 (2H, s), 3.86 (3H, s). EI-MS (m/z): 489 [M] ⁺ .

Synthesis of Methyl 6-[4-(methoxycarbonylmethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-37)

Using 4-(methoxycarbonylmethyl)phenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-37 was obtained in the same manner as in the synthesis of CI-7 (yield 20%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.23 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s) , 3.92 (3H, s), 3.88 (3H, s), 3.77 (2H, s), 3.64 (3H, s).

Synthesis of Methyl 6-[3-(methoxycarbonylmethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-38)

Using 3-(methoxycarbonylmethyl)phenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-38 was obtained in the same manner as in the synthesis of CI-7 (yield 44%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.24 (1H, brs), 8.41 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.71 (1H, s), 7.68 (1H, m), 7.49 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.87 (3H, s), 3.82 (2H, s), 3.38 (3H, s).

Synthesis of 6-[4-(Carboxymethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-39)

Using CI-37 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 75%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.24 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.8 Hz), 8.06 (2H, d, J = 9.2 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 9.2 Hz), 6.98 (1H, s) , 3.87 (3H, s), 3.77 (2H, s).

Synthesis of 6-[3-(Carboxymethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-40)

Using CI-38 instead of CI-13, CI-40 was obtained in the same manner as in the synthesis of CI-18 (yield 74%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.69 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.48 (1H, t, J = 7.5 Hz), 7.34 (1H, d, J = 7.5 Hz) , 7.12 (2H, d, J = 9.1 Hz), 6.98 (1H, s), 3.87 (3H, s), 3.71 (2H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-41)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 52%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.40 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.45 (1H, m), 7.33 (1H, d, J = 7.9 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.14 (2H, m), 7.04 (1H, s), 7.03 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3.86 (3H, s). EI-MS (m/z): 459 [M] ⁺ .

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(4-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-42)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 32%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.18 (1H, brs), 8.37 (1H, d, J = 2.0 Hz), 8.04 (2H, d, J = 8.7 Hz), 8.04 (1H, m), 7.72 (2H, d, J = 9.1 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 7.02 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 3.83 (3H, s).

Synthesis of Methyl 6-(3-cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-43)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 46%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.27 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.31 (1H, s), 8.19 (1H, d, J = 2.0 Hz), 8.14 (1H, m), 8.05 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.73 (1H, t, J = 7.9 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 454 [M] ⁺ .

Synthesis of Methyl 6-(4-cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-44)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 54%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.27 (1H, brs), 8.49 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.00 (2H, d, J = 9.1 Hz), 7.98 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.06 (1H, s) , 3.93 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 6-(3-formylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-45)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 59%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.26 (1H, brs), 10.14 (1H, s), 8.52 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 8.20 ( 1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.0 Hz), 8.06 (2H, d, J = 8.8 Hz), 7.98 (1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 8.8 Hz) t, J = 8.0 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 457 [M] ⁺ .

Synthesis of Methyl 6-(4-formylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-46)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 16%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.30 (1H, brs), 10.09 (1H, s), 8.52 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 2.4 Hz), 8.06 (2H, d, J = 8.7 Hz), 8.07-8.05 (4H, m), 7.15 (2H, d, J = 8.7 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 6-(3-fluorophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-47)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 28%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.23 (1H, brs), 8.44 (1H, d, J = 2.0 Hz), 8.13 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.66-7.63 (2H, m), 7.57 (1H, m), 7.29 (1H, m), 7.14 (2H, d, J = 8.7 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 447 [M] ⁺ .

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-trifluoromethoxyphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-48)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 66%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.25 (1H, brs), 8.46 (1H, d, J = 2.0 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.0 Hz), 7.78 (1H, s), 7.67 (1H, t, J = 8.0 Hz), 7.46 (1H, d, J = 8.4 Hz) , 7.14 (2H, d, J = 8.8 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 513 [M] ⁺ .

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-nitrophenyl)-4-oxo-4H-chromene-2-carboxylate (CI-49)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 3%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.30 (1H, brs), 8.54 (1H, d, J = 2.4 Hz), 8.33-8.28 (3H, m), 8.22 (1H, d, J = 2.8 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.83 (1H, t, J = 7.9 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.07 (1H, s), 3.93 ( 3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(4-nitrophenyl)-4-oxo-4H-chromene-2-carboxylate (CI-50)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 5%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.30 (1H, brs), 8.54 (1H, s), 8.36 (2H, d, J = 8.8 Hz), 8.23 (1H, s), 8.10 ( 2H, d, J = 8.8 Hz), 8.05 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.89 ( 3H, s).

Synthesis of Methyl 6-(3-acetylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-51)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 14%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.27 (1H, brs), 8.48 (1H, d, J = 2.4 Hz), 8.28 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 8.0 Hz), 8.06 (1H, m), 8.06 (2H, d, J = 8.8 Hz), 7.70 (1H, t, J = 8.0 Hz) , 7.15 (2H, d, J = 8.8 Hz), 7.06 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.69 (3H, s).

Synthesis of Methyl 6-(3-dimethylaminophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-52)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 26%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.36 (1H, d, J = 2.4 Hz), 8.06 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.8 Hz), 8.03 (1H, m), 7.33 (1H, t, J = 8.0 Hz), 7.14 (2H, d, J = 9.2 Hz), 7.03 (1H, s), 7.00 (1H, d, J = 8.8 Hz), 6.81 (1H, d, J = 8.4 Hz), 3.91 (3H, s), 3.88 (3H, s), 2.99 (6H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-pyridyl)-4-oxo-4H-chromene-2-carboxylate (CI-53)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 6%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.30 (1H, brs), 8.99 (1H, d, J = 2.0 Hz), 8.65 (1H, dd, J = 5.1 Hz, 1.6 Hz), 8.46 (1H, m), 8.30 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.98 (1H, dd, J = 8.3 Hz, 5.1 Hz), 7.11 (2H, d, J = 9.1 Hz), 7.06 (1H, s), 3.92 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(4-pyridyl)-4-oxo-4H-chromene-2-carboxylate (CI-54)

Using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, it was obtained in the same manner as in the synthesis of CI-7 (yield 15%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.29 (1H, brs), 8.73 (2H, d, J = 4.4 Hz), 8.52 (1H, d, J = 2.4 Hz), 8.25 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.84 (2H, d, J = 4.4 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.07 (1H, s) , 3.93 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-methylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-55)

Using 3-methylphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-55 was obtained in the same manner as in the synthesis of CI-7 (yield 34%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.23 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 2.8 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.60 (1H, s), 7.56 (1H, d, J = 7.9 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.27 (1H, d, J = 7.5 Hz) , 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.42 (3H, s).

Synthesis of Methyl 6-(3-tert-butylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-57)

Using 3-tert-butylphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-57 was obtained in the same manner as in the synthesis of CI-7 (yield 59%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.21 (1H, brs), 8.39 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.71 (1H, s), 7.56 (1H, d, J = 6.7 Hz), 7.50 (1H, d, J = 6.3 Hz), 7.46 (1H, m), 7.14 (2H, d, J = 8.3 Hz), 7.03 (1H, s), 3.92 (3H, s), 3.87 (3H, s), 1.36 (9H, s). EI-MS (m/z): 485 [M] ⁺ .

Synthesis of Methyl 6-(3-carbamoylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-58)

Using 3-carbamoylphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-58 was obtained in the same manner as in the synthesis of CI-7 (yield 18%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.04 (1H, brs), 8.50 (1H, d, J = 2.4 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.92 (1H, d, J = 8.3 Hz), 7.86 (1H, m), 7.60 (1H, t, J = 7.9 Hz), 7.29 (1H, br), 7.13 (2H, d, J = 9.1 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-methylthiophenyl)-4-oxo-4H-chromene-2-carboxylate (CI-59)
Using 3-methylthiophenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-59 was obtained in the same manner as in the synthesis of CI-7 (yield 52%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.00 (1H, brs), 8.44 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.58 (1H, s), 7.51 (1H, d, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.35 (1H, d, J = 7.5 Hz) , 7.12 (2H, d, J = 8.7 Hz), 7.01 (1H, s), 3.93 (3H, s), 3.88 (3H, s), 2.56 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-methylsulfonylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-60)

Using 3-methylsulfonylphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-60 was obtained in the same manner as in the synthesis of CI-7 (yield 23%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.29 (1H, brs), 8.51 (1H, d, J = 2.0 Hz), 8.29 (1H, t, J = 2.0 Hz), 8.23 (1H, d, J = 2.8 Hz), 8.17 (1H, d, J = 8.3 Hz), 8.06 (2H, d, J = 9.1 Hz), 8.00 (1H, d, J = 7.5 Hz), 7.82 (1H, t, J = 7.5 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s).

Synthesis of 8-(4-Methoxybenzamido)-6-(3-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-61)

Using CI-41 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 91%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.18 (1H, brs), 8.40 (1H, d, J = 2.0 Hz), 8.09 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.45 (1H, t, J = 8.3 Hz), 7.32 (1H, d, J = 7.9 Hz), 7.27 (1H, t, J = 2.0 Hz), 7.12 (2H, m) , 7.02 (1H, dd, J = 8.3 Hz, 1.6 Hz), 6.99 (1H, s), 3.87 (3H, s), 3.86 (3H, s). ¹³ C-NMR (100 MHz, DMSO-d ₆ ) δ: 177.47, 164.96, 162.28, 161.21, 159.92, 152.94, 148.87, 139.76, 137.33, 130.35, 129.72, 129.21, 129.05, 125.96, 124.50, 119.23, 118.52, 114.06, 113.83, 113.38, 112.18, 55.50, 55.27. EI- MS (m/z): 445 [M] ⁺ .

Synthesis of 8-(4-Methoxybenzamido)-6-(4-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-62)

Using CI-42 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 75%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.16 (1H, brs), 8.37 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.3 Hz), 8.04 (1H, d, J = 2.8 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 7.08 (2H, d, J = 8.3 Hz), 6.97 (1H, s) , 3.87 (3H, s), 3.83 (3H, s). EI-MS (m/z): 445 [M] ⁺ .

Synthesis of 6-(3-Cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-63)

Using CI-43 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 89%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.26 (1H, brs), 8.49 (1H, d, J = 2.4 Hz), 8.31 (1H, s), 8.19 (1H, d, J = 2.0 Hz), 8.14 (1H, m), 8.06 (2H, d, J = 9.1 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.73 (1H, t, J = 7.9 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 440 [M] ⁺ .

Synthesis of 6-(4-Cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-64)

Using CI-44 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 87%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.26 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.01 (2H, d, J = 9.1 Hz), 7.98 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 6.99 (1H, s) , 3.87 (3H, s). EI-MS (m/z): 440 [M] ⁺ .

Synthesis of 6-(3-Formylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-65)

Using CI-45 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 73%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.26 (1H, brs), 10.14 (1H, s), 8.51 (1H, d, J = 2.0 Hz), 8.33 (1H, s), 8.20 ( 1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 7.6 Hz), 8.06 (2H, d, J = 9.2 Hz), 7.96 (1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 7.6 Hz) t, J = 7.6 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.01 (1H, s), 3.87 (3H, s). EI-MS (m/z): 443 [M] ⁺ .

Synthesis of 6-(3-Fluorophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-67)

Using CI-47 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 72%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.23 (1H, brs), 8.43 (1H, d, J = 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.66-7.55 (3H, m), 7.28 (1H, m), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 433 [M] ⁺ .

Synthesis of 8-(4-Methoxybenzamido)-6-(3-trifluoromethoxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-68)

Using CI-48 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 70%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.24 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 7.67 (1H, t, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz) , 7.12 (2H, d, J = 8.8 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 499 [M] ⁺ .

Synthesis of 8-(4-Methoxybenzamido)-6-(4-nitrophenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-70)

Using CI-50 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 51%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.27 (1H, brs), 8.54 (1H, d, J = 2.4 Hz), 8.36 (2H, d, J = 8.3 Hz), 8.22 (1H, m), 8.09 (2H, d, J = 8.7 Hz), 8.06 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s).

Synthesis of 6-(3-Acetylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-71)

Using CI-51 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 76%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.17 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.25 (1H, s), 8.09 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 7.5 Hz), 8.01 (1H, d, J = 7.5 Hz), 7.70 (1H, t, J = 7.9 Hz) , 7.11 (2H, d, J = 8.7 Hz), 6.78 (1H, s), 3.87 (3H, s), 2.68 (3H, s).

Synthesis of 8-(4-Methoxybenzamido)-6-(4-pyridyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-74)

Using CI-54 instead of CI-13, it was obtained in the same manner as the synthesis of CI-18 (yield 39%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.30 (1H, brs), 9.07 (2H, d, J = 6.8 Hz), 8.66 (1H, d, J = 2.8 Hz), 8.54 (2H, d, J = 6.8 Hz), 8.28 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 9.2 Hz), 7.07 (1H, s) , 3.88 (3H, s).

Synthesis of 6-(3-tert-Butylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-77)

Using CI-57 instead of CI-13, CI-77 was obtained in the same manner as in the synthesis of CI-18 (yield 81%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.40 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.08 (2H, d, J = 8.7 Hz), 7.98 (1H, d, J = 2.4 Hz), 7.68 (1H, s), 7.52 (1H, d, J = 6.3 Hz), 7.47 (1H, t, J = 6.7 Hz), 7.46 (1H, m), 7.09 (2H, d, J = 9.1 Hz), 6.73 (1H, s), 3.87 (3H, s), 1.37 (9H, s).

Synthesis of 8-(4-Methoxybenzamido)-6-(3-methylsulfonylphenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-80)

Using CI-60 instead of CI-13, CI-80 was obtained in the same manner as in the synthesis of CI-18 (yield 89%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.29 (1H, brs), 8.51 (1H, d, J = 2.4 Hz), 8.28 (1H, s), 8.22 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 7.9 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.81 (1H, t, J = 7.9 Hz) , 7.12 (2H, d, J = 9.1 Hz), 7.00 (1H, s), 3.87 (3H, s).

Synthesis of Methyl 6-(3-furyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-82)

Using 3-furylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-82 was obtained in the same manner as in the synthesis of CI-7 (yield 24%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.21 (1H, brs), 8.41 (1H, s), 8.30 (1H, d, J = 2.4 Hz), 8.08 (1H, d, J = 2.4 Hz), 8.04 (2H, dd, J = 9.1 Hz, 2.4 Hz), 7.81 (1H, m), 7.13 (1H, d, J = 2.0 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.01 (1H, s), 3.90 (3H, s), 3.87 (3H, d, J = 2.0 Hz).

Synthesis of Methyl 6-(5-acetyl-2-thienyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-83)

Using 5-acetyl-2-thienylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-83 was obtained in the same manner as in the synthesis of CI-7 (yield 36%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.02 (1H, brs), 8.53 (1H, d, J = 2.0 Hz), 8.13 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.3 Hz), 7.95 (1H, d, J = 4.4 Hz), 7.76 (1H, d, J = 4.0 Hz), 7.13 (2H, m), 7.02 (1H, s), 3.93 (3H, s), 3.88 (3H, s), 2.56 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(2-methoxy-4-pyridyl)-4-oxo-4H-chromene-2-carboxylate (CI-85)

Using 2-methoxy-4-pyridylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-85 was obtained in the same manner as CI-7 (yield 34%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.06 (1H, brs), 8.50 (1H, d, J = 2.0 Hz), 8.29 (1H, d, J = 5.5 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.03 (2H, d, J = 9.1 Hz), 7.37 (1H, dd, J = 5.5 Hz, 1.6 Hz), 7.14 (1H, s), 7.13 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.93 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(2-methylthio-5-pyridyl)-4-oxo-4H-chromene-2-carboxylate (CI-87)

Using 2-methylthio-5-pyridylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-87 was obtained in the same manner as in the synthesis of CI-7 (yield 30%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.26 (1H, brs), 8.85 (1H, d, J = 2.0 Hz), 8.42 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.08 (1H, dd, J = 8.4 Hz, 2.4 Hz), 8.05 (2H, d, J = 9.2 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.14 (2H , d, J = 9.2 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.58 (3H, s).

Synthesis of Methyl 6-(2-amino-5-pyridyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-88)

Using 2-amino-5-pyridylboronic acid pinacol ester instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-88 was obtained in the same manner as in the synthesis of CI-7 (yield 7%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.24 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.85-7.75 (2H, m), 7.71-7.50 (3H, m), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.92 (3H, s ), 3.88 (3H, s).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-trifluoromethylphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-89)

Using 3-trifluoromethylphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-89 was obtained in the same manner as in the synthesis of CI-7 (yield 48%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.06 (1H, brs), 8.51 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 7.1 Hz), 8.04 (2H, d, J = 8.3 Hz), 8.04 (1H, s), 7.81 (1H, m), 7.77 (1H, t, J = 7.5 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 497 [M] ⁺ .

Synthesis of Methyl 6-(3-hydroxymethylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-91)

Using 3-hydroxymethylphenylboronic acid instead of 4-(Methoxycarbonyl)phenylboronic acid, CI-91 was obtained in the same manner as in the synthesis of CI-7 (yield 37%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.22 (1H, brs), 8.43 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 1.6 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 7.9 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.39 (1H, d, J = 7.1 Hz) , 7.14 (2H, d, J = 8.7 Hz), 7.04 (1H, s), 5.31 (1H, brm), 4.61 (2H, d, J = 5.9 Hz), 3.93 (3H, s), 3.88 (3H, s).

Synthesis of Methyl 8-(4-chlorobenzamido)-6-(3-hydroxyphenyl)-4-oxo-4H-chromene-2-carboxylate (CI-96)

(1) Using 4-chlorobenzoyl chloride instead of 4-Methoxybenzoyl chloride, methyl 6-bromo-8-(4-chlorobenzamido)-4-oxo-4H-chromene was synthesized in the same manner as in Synthesis of CI-2 (1). -2-carboxylate was obtained (quantitative yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.53 (1H, brs), 8.28 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.3 Hz), 8.01 (1H, d, J = 2.4 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.05 (1H, s), 3.91 (3H, s).

(2) Methyl 6-bromo-8-(4-chlorobenzamido)-4-oxo-4H-chromene instead of Methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate Using 2-carboxylate and using 3-hydroxyphenylboronic acid instead of 4-(methoxycarbonyl)phenylboronic acid, CI-96 was obtained in the same manner as in the synthesis of CI-7 (yield 17%).

¹ H-NMR (400 MHz, DMSO-d6) δ: 10.52 (1H, brs), 9.68 (1H, brs), 8.32 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 8.7 Hz ), 8.07 (1H, m), 7.70 (2H, d, J = 8.3 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.13 (1H, t , J = 2.0 Hz), 7.04 (1H, s), 6.85 (1H, dd, J = 8.3 Hz, 2.0 Hz), 3.94 (3H, s).

Synthesis of Methyl 8-(4-chlorobenzamido)-6-(3-cyanophenyl)-4-oxo-4H-chromene-2-carboxylate (CI-98)

Using 3-cyanophenylboronic acid instead of 3-hydroxyphenylboronic acid, CI-98 was obtained in the same manner as in the synthesis of CI-96 (yield 30%).

¹ H-NMR (400 MHz, DMSO-d6) δ: 10.58 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.32 (1H, t, J = 1.6 Hz), 8.24 (1H, d , J = 2.4 Hz), 8.15 (1H, dt, J = 8.7 Hz, 1.2 Hz), 8.08 (2H, d, J = 8.3 Hz), 7.91 (1H, dt, J = 7.9 Hz, 1.6 Hz), 7.73 (1H, m), 7.71 (2H, d, J = 8.3 Hz), 7.06 (1H, s), 3.92 (3H, s).

Synthesis of 6-(3-Furyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (CI-105)

Using CI-82 instead of CI-13, CI-105 was obtained in the same manner as in the synthesis of CI-18 (yield 94%).

1H ^- NMR (400 MHz, DMSO _- d6) 10.19 (1H, brs), 8.40 (1H, s), 8.29 (1H, d, J = 2.4 Hz), 8.08 (1H, m), 8.05 (2H, d, J = 9.1 Hz), 7.81 (1H, d, J = 2.0 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.11 (1H, m), 6.96 (1H, s), 3.87 (3H, s).

Synthesis of 8-(4-Methoxybenzamido)-6-(3-trifluoromethylphenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-112)

Using CI-89 instead of CI-13, CI-112 was obtained in the same manner as in the synthesis of CI-18 (yield 91%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.25 (1H, brs), 8.49 (1H, d, J = 2.4 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 7.1 Hz), 8.09 (1H, s), 8.06 (2H, d, J = 9.1 Hz), 7.82 (1H, d, J = 7.9 Hz), 7.77 (1H, t, J = 7.5 Hz) , 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 483 [M] ⁺ .

Synthesis of 6-(3-Hydroxymethylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid (CI-114)

Using CI-91 instead of CI-13, CI-114 was obtained in the same manner as in the synthesis of CI-18 (yield 89%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.20 (1H, brs), 8.42 (1H, m), 8.11 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 7.5 Hz), 7.48 (1H, t, J = 7.5 Hz), 7.38 (1H, d, J = 7.1 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.99 (1H, s), 5.29 (1H, br), 4.61 (2H, s), 3.87 (3H, s).

Synthesis of 8-(4-Chlorobenzamido)-6-(3-hydroxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid (CI-119)

Using CI-96 instead of CI-13, CI-119 was obtained in the same manner as in the synthesis of CI-18 (yield 75%).

¹ H-NMR (400 MHz, DMSO-d6) δ: 10.48 (1H, brs), 9.65 (1H, brs), 8.31 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 8.7 Hz ), 8.05 (1H, m), 7.67 (2H, d, J = 8.3 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.17 (1H, d, J = 7.9 Hz), 7.12 (1H, t , J = 2.0 Hz), 6.98 (1H, s), 6.84 (1H, dd, J = 7.5 Hz, J = 1.6 Hz).

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(4-methoxycarbonylphenyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-1)

(1) 4-methoxybenzoylchloride (3.62 mL, 26.8 mmol) was slowly added dropwise to a solution of commercially available 5-bromo-2-nitroaniline (4.84 g, 22.3 mmol) in pyridine (30.0 mL), and the mixture was stirred at room temperature for 40 hours. Precipitated crystals were collected by filtration, washed with methanol, and dried under reduced pressure to obtain N-(4-bromo-2-nitrophenyl)-4-methoxybenzamide. The filtrate was concentrated, washed with a mixed solvent of chloroform/methanol = 1/1, and dried under reduced pressure to obtain N-(4-bromo-2-nitrophenyl)-4-methoxybenzamide (7.65 g, 21.8 mmol). (Yield 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 11.36 (1H, brs), 9.31 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 9.1 Hz), 7.96 (2H, d, J = 9.1 Hz), 7.33 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.03 (2H, d, J = 9.1 Hz), 3.90 (3H, s).

(2) N-(4-bromo-2-nitrophenyl)-4-methoxybenzamide (3.70 g, 10.5 mmol) obtained above in EtOH (50 mL), THF (50 mL) and H ₂ O (5.0 mL) Na ₂ S ₂ O ₄ (11.0 g, 105 mmol) was added to the mixed solution of and heated under reflux for 22 hours under an argon atmosphere. The reaction mixture was concentrated, saturated aqueous sodium chloride solution was added to the residue, extraction was performed with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography, and N-(2-amino-4-bromophenyl)-4-methoxybenzamide (2.70 g, 8.40 mmol) was obtained from the hexane/ethyl acetate = 1/1 fraction. ) was obtained (80% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.85 (2H, d, J = 8.7 Hz), 7.77 (1H, brs), 7.53 (1H, d, J = 2.4 Hz), 7.17 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.97 (2H, d, J = 9.1 Hz), 6.72 (1H, d, J = 8.7 Hz), 3.88 (3H, s), 3.85 (2H, br).

(3) DMAD (0.0809 mL, 0.495 mmol) was added to a 1,4-dioxane (5.0 mL) solution of N-(2-amino-4-bromophenyl)-4-methoxybenzamide (106 mg, 0.330 mmol) obtained above. ) was added, and the mixture was heated and stirred at 140° C. for 90 minutes under microwave irradiation. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography, and dimethyl 2-[4-bromo-2-(4-methoxybenzamido)anilino]-2- was isolated from the hexane/ethyl acetate = 4/1 fraction. Butenedioate (114 mg, 0.244 mmol) was obtained (yield 74%).

¹H-NMR (400 MHz, CDCl₃) δ: 9.04 (1H, brs), 8.53 (1H, d, J = 2.4 Hz), 8.35 (1H, br), 7.86 (2H, d, J = 9.1 Hz), 7.17 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.99 (2H, d, J = 8.7 Hz), 6.81 (1H, d, J = 8.3 Hz), 5.69 (1H, s), 3.88 (3H, s), 3.77 (3H, s) , 3.66 (3H, s) .

(4) A solution of dimethyl 2-[4-bromo-2-(4-methoxybenzamido)anilino]-2-butenedioate (121 mg, 0.261 mmol) obtained above in xylene (5.0 mL) was irradiated with 200 The mixture was heated and stirred at ℃ for 24 hours. The precipitated crystals were collected by filtration, washed with xylene, dried under reduced pressure, purified by silica gel column chromatography, and methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo -1,4-dihydroquinoline-2-carboxylate (64 mg, 0.148 mmol) was obtained (57% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.67 (1H, brs), 8.82 (1H, brs), 7.99 (1H, m), 7.98 (2H, d, J = 8.6 Hz), 7.57 ( 1H, brs), 7.20 (2H, d, J = 8.6 Hz), 3.99 (3H, s), 3.89 (3H, s). EI-MS (m/z): 432 [ ⁸¹ BrM] ⁺ , 430 [ ⁷⁹ BrM] ⁺ .

(5) Methyl 6-bromo-8-(4-methoxybenzamido)-4- obtained above instead of Methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate Using oxo-1,4-dihydroquinoline-2-carboxylate, CII-1 was obtained in the same manner as in the synthesis of CI-7 (yield 46%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.68 (1H, brs), 9.09 (1H, brs), 8.12 (2H, d, J = 8.3 Hz), 8.12 (1H, m), 8.00 ( 2H, d, J = 8.3 Hz), 7.94 (2H, d, J = 8.7 Hz), 7.59 (1H, brs), 7.19 (2H, d, J = 9.1 Hz), 4.00 (3H, s), 3.91 ( 3H, s), 3.89 (3H, s).

In the synthesis of compounds CII-2 to CII-5 below, the methyl 6- Similar to the synthesis of CII-1, using bromo-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate and using the corresponding boronic acid instead of 4-(methoxycarbonyl)phenylboronic acid. obtained by the method of

Synthesis of Methyl 8-(4-methoxybenzamido)-6-(3-methoxycarbonylphenyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-2) (18% yield)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.67 (1H, brs), 9.05 (1H, brs), 8.29 (1H, s), 8.06 (2H, d, J = 7.5 Hz), 8.06 ( 1H, m), 8.00 (2H, d, J = 7.9 Hz), 7.70 (1H, t, J = 7.9 Hz), 7.57 (1H, brs), 7.18 (2H, m), 4.00 (3H, s), 3.93 (3H, s), 3.89 (3H, s).

Synthesis of Methyl 6-(4-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-3) (yield 4%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 12.19 (1H, br), 10.70 (1H, brs), 9.75 (1H, brs), 8.99 (1H, brs), 8.01 (2H, d, J = 8.7 Hz), 8.01 (1H, m), 7.64 (2H, d, J = 8.7 Hz), 7.54 (1H, brs), 7.21 (2H, d, J = 9.1 Hz), 6.95 (2H, d, J = 8.7 Hz), 3.99 (3H, s), 3.89 (3H, s).

Synthesis of Methyl 6-(3-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-4) (yield 54%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.71 (1H, brs), 9.69 (1H, brs), 9.07 (1H, brs), 8.02 (1H, brs), 8.02 (2H, d, J = 8.7 Hz), 7.60 (1H, brs), 7.36 (1H, t, J = 7.5 Hz), 7.23-7.20 (2H, m), 7.21 (2H, d, J = 8.7 Hz), 6.86 (1H, m ), 4.00 (3H, s), 3.89 (3H, s). EI-MS (m/z): 444 [M] ⁺ .

Synthesis of Methyl 6-(2-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-5) (23% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 12.17 (1H, br), 10.70 (1H, brs), 9.74 (1H, brs), 9.01 (1H, brs), 8.00 (1H, m), 8.00 (2H, d, J = 8.3 Hz), 7.60 (1H, brs), 7.40 (1H, d, J = 7.5 Hz), 7.26 (1H, t, J = 7.1 Hz), 7.20 (2H, d, J = 8.7 Hz), 7.02 (1H, d, J = 7.9 Hz), 6.96 (1H, t, J = 7.5 Hz), 4.00 (3H, s), 3.89 (3H, s). ): 444 [M] ⁺ .

Synthesis of 6-(4-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-6)

To a 1,4-dioxane (2.0 mL) solution of CII-1 (20 mg, 0.0411 mmol) was added 4 M NaOH aqueous solution (0.153 mL, 0.603 mmol), stirred at room temperature for 12 hours, and then incubated at 50 °C for 3 days. The mixture was heated and stirred. The reaction mixture was concentrated, 1 M hydrochloric acid was slowly added dropwise until crystals precipitated, the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CIII-6 (14 mg, 0.0305 mmol) (yield 74%). ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.70 (1H, brs), 10.23 (1H, brs), 8.29 (1H, d, J = 2.4 Hz), 8.12 (2H, d, J = 8.3 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.01 (2H, d, J = 8.3 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.13 (2H, m), 6.55 (1H, s), 3.88 (3H, s).

Synthesis of 6-(3-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-7)

Using CII-2 instead of CII-1, CII-7 was obtained in the same manner as in the synthesis of CII-6 (yield 91%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.77 (1H, brs), 10.28 (1H, brs), 8.31 (1H, s), 8.28 (1H, d, J = 2.0 Hz), 8.11 ( 2H, d, J = 8.3 Hz), 8.03 (1H, brs), 7.90 (1H, d, J = 7.5 Hz), 7.71 (1H, d, J = 7.5 Hz), 7.41 (1H, t, J = 7.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.54 (1H, s), 3.87 (3H, s). EI-MS (m/z): 458 [M] ⁺ .

Synthesis of 6-(4-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-8)

Using CII-3 instead of CII-1, CII-8 was obtained in the same manner as in the synthesis of CII-6 (yield 44%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 12.18 (1H, br), 10.75 (1H, br), 9.72 (1H, brs), 9.12 (1H, br), 8.01 (1H, brs), 8.01 (2H, d, J = 9.1 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.54 (1H, brs), 7.16 (2H, d, J = 8.3 Hz), 6.93 (2H, d, J = 8.3 Hz), 3.88 (3H, s).

Synthesis of 6-(3-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-9)

Using CII-4 instead of CII-1, CII-9 was obtained in the same manner as in the synthesis of CII-6 (yield 71%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.68 (1H, brs), 9.63 (1H, brs), 8.20 (1H, d, J = 2.4 Hz), 8.09 (2H, d, J = 8.7 Hz), 8.02 (1H, brs), 7.30 (1H, t, J = 7.5 Hz), 7.17 (1H, brs), 7.13 (1H, m), 7.13 (2H, d, J = 9.1 Hz), 6.79 ( 1H, m), 6.58 (1H, brs), 3.87 (3H, s). EI-MS (m/z): 430 [M] ⁺ .

Synthesis of 6-(2-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-10)

Using CII-5 instead of CII-1, CII-10 was obtained in the same manner as in the synthesis of CII-6 (yield 94%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 10.71 (1H, brs), 9.80 (1H, brs), 8.70 (1H, brs), 8.09 (1H, brs), 8.02 (2H, d, J = 9.1 Hz), 7.38 (1H, dd, J = 7.9 Hz, 1.6 Hz), 7.23 (1H, t, J = 8.3 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, d, J = 7.9 Hz), 6.94 (1H, m), 3.87 (3H, s). EI-MS (m/z): 430 [M] ⁺ .

<Evaluation of activity as a GPR35 agonist>
The following tests were performed to evaluate activity as a GPR35 agonist. Tests were performed on the compounds numbered in Tables 1 and 2 and, as positive controls, Zaprinast and DSCG, which are known to have activity against rat GPR35.

(1) The expression vector pCAGGS contains alkaline phosphatase-fused TGF-α gene (see J. Cell Biol. 151, 209-220, 2000 for details) and trimeric G proteins G _i1 , G _i3 , G _o , G ₁₂ , G ₁₃ , G _z , G _s , and G ₁₆ α subunits and G _αq fusion genes (for details, see Nat. Methods, 9, 1021-1029, 2012.) and human The GPR35 or rat GPR35 gene was integrated and transfected into HEK293 cells using polyethyleneimine "Max" reagent (Polyscience, Inc.).

(2) Hank's buffer (5 mM HEPES-NaOH, pH 7.4, 137 mM NaCl, 5.3 mM KCl, 1.26 mM CaCl ₂ , 0.44 mM MgCl ₂ , 0.34 mM NaH for transfected HEK293 cells Compounds or positive controls were added at concentrations of 1000 nM, 10000 nM in ₂ PO _{4 ,} 0.41 mM MgSO ₄ , 5.6 mM glucose) and incubated at 37° C. for 30 minutes.

(3) After incubation, buffer and cell surface alkaline phosphatase activity are liberated using paranitrophenyl phosphate solution (40 mM Tris-HCl, pH 9.5, 40 mM NaCl, 10 mM MgCl ₂ , 10 mM p-nitrophenol). It was calculated from the concentration of p-nitrophenol (see Nat. Methods, 9, 1021-1029, 2012 for details). Specifically, the sum of the alkaline phosphatase activities of both fractions was defined as the total activity, and the shedding rate (%) was expressed as (activity in buffer/total activity)×100. The results are shown in Table 1 (human GPR35) and Table 2 (rat GPR35) (n=3).

<Evaluation using rat GPR35-expressing RBL-2H3 cells>
A rat mast cell line RBL-2H3 was used to establish cells constitutively expressing a gene encoding rat GPR35 with a hemagglutinin (HA) epitope tag sequence added to the N-terminal side, and used for the following evaluations.

FIG. 1 shows the results of measurement of rat GPR35 mRNA expression by quantitative RT-PCR. RBL-2H3 cells (RBL) show substantially no expression of rat GPR35 compared to rat peritoneal mast cells (pMC). In addition, it was confirmed from the results of flow cytometry using a fluorescently labeled anti-HA antibody that stable expression of rat GPR35 was detected.

FIG. 2 shows experimental data comparing the degree of degranulation between RBL-2H3 cells expressing rat GPR35 and RBL-2H3 cells not expressing rat GPR35.
RBL-2H3 cells stably expressing HA-tagged rat GPR35 were sensitized with 50 ng/ml anti-DNPIgE antibody (clone SPE-7) for 24 hours. Thereafter, washing was performed twice to remove free IgE antibodies. Cells were then treated with dinitrophenol-human serum albumin (DNP-HSA) (30 ng/ml) in the presence of zaprinast (1 μM) as a positive control, or compound CI-18 or compound CI-26 at the concentrations shown in FIG. β-hexosaminidase activity (%) was examined as an index of the degree of degranulation by the cells. The results are shown in FIG. For comparison, FIG. 2 shows the results of performing the same treatment as above on RBL-2H3 cells (mock) not expressing rat GPR35.
In FIG. 2, error bars indicate standard errors (n=3), and when *p<0.05 and **p<0.01, it is judged that there is a significant difference. Statistical processing was performed by one-way analysis of variance and Dunnett's test.

As shown in FIG. 2, rat GPR35-expressing RBL-2H3 cells significantly reduced β-hexosaminidase activity in the presence of CI-18 or CI-26 in a dose-dependent manner. This result suggests that CI-18 or CI-26 suppresses the degranulation response induced by IgE-mediated antigen stimulation and exhibits antiallergic activity.

<Evaluation using rat peritoneal mast cells>
Using rat peritoneal mast cells, the effects of compounds on the degranulation response to antigen stimulation mediated by IgE were examined.

Rat peritoneal cells harvested from Wistar rats (male, 7 weeks old) were fractionated by density gradient centrifugation to obtain purified mast cells of 90-95% purity. The obtained cells were sensitized with an anti-DNP IgE antibody (clone SPE-7) (10 μg/ml) at 37° C. for 3 hours. Thereafter, washing was performed twice to remove free IgE antibodies. A degranulation response was then induced by stimulation with lysophosphatidylserine (2 μM) and dinitrophenol-conjugated human serum albumin (DNP-HSA) (100 ng/ml).
In addition, zaprinast (1 μM) or compounds CI-16, 18, 26 or 63 at concentrations shown in Table 3 were added simultaneously with DNP-HAS in the same procedure as above. The degree of degranulation response was measured using β-hexosaminidase activity (%) as an indicator. Table 3 shows the results. In Table 3, SD indicates standard deviation (n=3).

As shown in Table 3, β-hexosaminidase activity was significantly decreased in the presence of CI-16, 18, 26, 63 in a dose-dependent manner. These results suggest that CI-16, 18, 26, and 63 suppress the degranulation response induced by IgE-mediated antigen stimulation and exhibit antiallergic activity.

<Formulation example 1>
Using the synthesized CI-16, tablets having the following composition were prepared by a conventional method.
CI-16 100mg
Lactose 60mg
Potato starch 30mg
Polyvinyl alcohol 2mg
Magnesium stearate 1 mg
Tar pigment trace amount

<Formulation example 2>
Using the synthesized CI-16, a powder having the following composition was prepared by a conventional method.
CI-16 150mg
Lactose 280mg

<Formulation Example 3>
Using the synthesized CI-16, a syrup having the following composition was prepared by a conventional method.
CI-16 100mg
40 mg refined sucrose
Ethyl p-hydroxybenzoate 40 mg
10 mg of propyl p-hydroxybenzoate
Strawberry flavor 0.1cc
Add water to the above ingredients to make a total volume of 100 cc.

The disclosures of Japanese Patent Application Nos. 2017-174799 and 2018-146961 are incorporated herein by reference in their entireties.
All publications, patent applications and technical standards mentioned herein are to the same extent as if each individual publication, patent application and technical standard were specifically and individually noted to be incorporated by reference. incorporated herein by reference.

Claims (27)

A heterocyclic compound represented by the following general formula (1-2) or a pharmacologically acceptable salt of the heterocyclic compound.

[In general formula (1-2), X represents O or NH, R ¹ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, R ² represents OH, NR ⁵ R ⁶ ( R ⁵ and R ⁶ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted alicyclic heterocyclic ring a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group, which together form a ring good), NR ⁷ COR ⁸ (R ⁷ and R ⁸ are each independently synonymous with R ⁵ ), NR ⁹ SO ₂ R ¹⁰ (R ⁹ and R ¹⁰ are each independently synonymous with R ⁵ ), S (O) _n R ¹¹ (n is 0, 1 or 2, R ¹¹ has the same meaning as R ⁵ ), COR ¹² (R ¹² has the same meaning as R ⁵ ), COOR ¹³ (R ¹³ has the same meaning as R ⁵ ), OCOR ¹⁴ (R ¹⁴ is synonymous with R ⁵ ), CONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are each independently synonymous with R ⁵ ), SO ₂ NR ¹⁷ R ¹⁸ (R ¹⁷ and R ¹⁸ are each independently the same as R ⁵ ), OCH ₂ COOR ¹⁹ (R ¹⁹ is the same as R ⁵ ), OSO ₂ R ²⁰ (R ²⁰ is the same as R ⁵ ), SR ²¹ (R ²¹ has the same definition as R ⁵ ), a nitro group, a cyano group or a halogen atom, and R ³ represents COOR ²² (R ²² has the same definition as R ⁵ ). ] (delete) (delete) 2. The heterocyclic compound according to claim 1, wherein X is O, or a pharmaceutically acceptable salt thereof. 5. The heterocyclic compound according to claim ¹ or ⁴ , or a pharmaceutically acceptable salt thereof, wherein ^R2 is ^NR5R6 or ^NR7COR8 . R ¹ has no substituent, substituted or unsubstituted alkyl group, COOR (R is hydrogen atom or substituted or unsubstituted alkyl group), OCH ₂ COOR (R is hydrogen atom or substituted or unsubstituted alkyl group) , OR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), NRR (each R is independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), CONRR (R are each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO ₂ R (R is a substituted or unsubstituted alkyl group), SO ₂ NRR (each R is independently a hydrogen atom or a substituted or unsubstituted alkyl group) , SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom as a substituent, the heterocyclic compound according to any one of claims 1, 4 and 5, or the A pharmacologically acceptable salt of a heterocyclic compound. 7. The heterocyclic compound according to any one of claims 1, 4, 5, and 6, wherein R ³ is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), or the pharmacologically acceptable salt. ^8. The heterocyclic compound according to any one of claims 1, 4, 5, 6, 7, or a pharmaceutically acceptable salt thereof, wherein ^R2 is _NH2 or NHCOR8. 9. The heterocyclic compound according to any one of claims 1, 4, 5, 6, 7, 8, wherein ^R2 is NHCOAr (Ar is a substituted or unsubstituted aryl group) or the pharmacological permissible salt. 10. The heterocyclic compound according to any one of claims 1, 4, 5, 6, 7, 8, 9, or a pharmaceutically acceptable salt thereof, having activity as a GPR35 agonist. 11. The heterocyclic compound according to claim 10, or a pharmaceutically acceptable salt thereof, which has activity against human GPR35 and/or non-human animal GPR35. 12. The heterocyclic compound according to claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, having activity against both human GPR35 and non-human animal GPR35. 13. The heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 11 or 12, wherein said non-human animal is a rodent. A GPR35 agonist, which is a heterocyclic compound represented by the following general formula (1-2) or a pharmacologically acceptable salt of the heterocyclic compound.

[In general formula (1-2), X represents O or NH, R ¹ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, R ² represents OH, NR ⁵ R ⁶ ( R ⁵ and R ⁶ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted alicyclic heterocyclic ring a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group, which together form a ring good), NR ⁷ COR ⁸ (R ⁷ and R ⁸ are each independently synonymous with R ⁵ ), NR ⁹ SO ₂ R ¹⁰ (R ⁹ and R ¹⁰ are each independently synonymous with R ⁵ ), S (O) _n R ¹¹ (n is 0, 1 or 2, R ¹¹ has the same meaning as R ⁵ ), COR ¹² (R ¹² has the same meaning as R ⁵ ), COOR ¹³ (R ¹³ has the same meaning as R ⁵ ), OCOR ¹⁴ (R ¹⁴ is synonymous with R ⁵ ), CONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are each independently synonymous with R ⁵ ), SO ₂ NR ¹⁷ R ¹⁸ (R ¹⁷ and R ¹⁸ are each independently the same as R ⁵ ), OCH ₂ COOR ¹⁹ (R ¹⁹ is the same as R ⁵ ), OSO ₂ R ²⁰ (R ²⁰ is the same as R ⁵ ), SR ²¹ (R ²¹ has the same definition as R ⁵ ), a nitro group, a cyano group or a halogen atom, and R ³ represents COOR ²² (R ²² has the same definition as R ⁵ ). (delete) (delete) 15. The GPR35 agonist of claim 14, wherein X is O. 18. The ^GPR35 agonist according to claim ¹⁴ or 17, wherein ^R2 is ^NR5R6 or ^NR7COR8 . R ¹ has no substituent, substituted or unsubstituted alkyl group, COOR (R is hydrogen atom or substituted or unsubstituted alkyl group), OCH ₂ COOR (R is hydrogen atom or substituted or unsubstituted alkyl group) , OR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), NRR (each R is independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), CONRR (R are each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO ₂ R (R is a substituted or unsubstituted alkyl group), SO ₂ NRR (each R is independently a hydrogen atom or a substituted or unsubstituted alkyl group) , SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom as a substituent. 20. The GPR35 agonist according to any one of claims 14, 17, 18, 19, wherein R3 is COOR ⁽ R is a hydrogen atom or a substituted or unsubstituted alkyl group). 21. A GPR35 agonist according to any one of claims 14, 17, 18, 19, 20, wherein ^R2 is _NH2 or ^NHCOR8 . 22. A GPR35 agonist according to any one of claims 14, 17, 18, 19, 20, 21, wherein ^R2 is NHCOAr (Ar is a substituted or unsubstituted aryl group). 23. The GPR35 agonist of any one of claims 14, 17, 18, 19, 20, 21, 22, which has activity against human GPR35 and/or non-human animal GPR35. 24. The GPR35 agonist of any one of claims 14, 17, 18, 19, 20, 21, 22, 23, which has activity against both human GPR35 and non-human animal GPR35. 25. The GPR35 agonist of claim 23 or claim 24, wherein said non-human animal is a rodent. 26. A GPR35 agonist according to any one of claims 14, 17, 18, 19, 20, 21, 22, 23, 24, 25 for use in treating a condition or disease in which GPR35 is mediated. 14. The heterocyclic compound according to any one of claims 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or a pharmaceutically acceptable salt thereof, or A pharmaceutical composition comprising the GPR35 agonist according to any one of claims 14, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26 as an active ingredient.

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