WO2017135471A1 - INTEGRIN α4β7 INHIBITOR - Google Patents

Abstract

Provided is a compound having an excellent integrin α4 inhibiting action. A sulfonamide derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, R1-R5, e-h, D, and B are as defined in the specification.)

Description

α4β7 integrin inhibitor

The present invention relates to a sulfonamide derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing these compounds as active ingredients. In particular, the present invention relates to a compound useful as a therapeutic or prophylactic agent for inflammatory diseases in which an α4 integrin-dependent adhesion process is involved in the disease state.

An orally administrable compound having an α4 integrin inhibitory action useful as a therapeutic or prophylactic agent for inflammatory diseases in which an α4 integrin-dependent adhesion process is involved in the pathological state is already known. For example, Patent Document 1 discloses a phenylalanine derivative represented by the following formula or a pharmaceutically acceptable salt thereof, and a typical compound thereof has the following chemical structure.

Patent Document 1 shows the results of VCAM inhibitory activity (VCAM-1 / α4β1 binding assay) and (VCAM-1 / α4β7 binding assay).
Further, Patent Document 2 discloses a phenylalanine derivative represented by the following formula having a terminal R12 (R13) N—X1-group or a pharmaceutically acceptable salt thereof.

This compound has been shown to have a higher VCAM-1 / α4β1 integrin inhibitory activity in the presence of serum than the compound of Example 1 of Patent Document 1. Patent Document 3 also discloses a compound having an α4 integrin inhibitory action.

Patent Document 4 (WO2005 / 077915) describes a phenylalanine derivative having an α4 integrin inhibitory action as represented by the following formula, but a 2,6-dichlorobenzoyl group or amino acid residue is present at the N-terminus of phenylalanine. A group is bound.

Patent Document 5 (Japanese Patent Application Laid-Open No. 2003-321358) describes a phenylalanine derivative having an α4 integrin inhibitory activity represented by the following formula. Are joined.

Patent Document 6 (WO01 / 56994) describes a phenylalanine derivative having an α4 integrin inhibitory action represented by the following formula, and proline and the like are bonded to the N-terminus of phenylalanine.

Patent Document 7 (WO 2006/127584) describes a phenylalanine derivative having an α4 integrin inhibitory action represented by the following formula, and a pyrimidine ring or the like is directly bonded to the N-terminus of phenylalanine.

Patent Document 8 (WO01 / 42215) describes a phenylalanine derivative having an α4 integrin inhibitory action represented by the following formula, and the phenylalanine has an N-terminus such as a 2-chloro-6-methylbenzoyl group. Are joined.

Patent Document 9 (WO2013 / 161904) describes a phenylalanine derivative having an α4β7 integrin inhibitory action represented by the following formula. This document shows the results of a VCAM-1 / α4β1 integrin binding inhibitory activity evaluation of a specific phenylalanine derivative and a MAdCAM-1 / α4β7 integrin binding inhibitory activity evaluation test in the presence of serum. Has a low effect and is described as having a high effect on α4β7 integrin.

Patent Document 10 (WO2015 / 064580) describes a phenylalanine derivative having an α4β7 integrin inhibitory action represented by the following formula. This document also shows the results of VCAM-1 / α4β1 integrin binding inhibitory activity evaluation of specific phenylalanine derivatives and MAdCAM-1 / α4β7 integrin binding inhibitory activity evaluation test in the presence of serum. Has a low effect and is described as having a high effect on α4β7 integrin.

WO02 / 16329 WO05 / 061466 WO03 / 070709 WO2005 / 077915 JP 2003-321358 A WO01 / 56994 WO2006 / 127484 WO01 / 42215 WO2013 / 161904 WO2015 / 064580

An object of the present invention is to provide a novel compound having a chemical structural formula that has not been known so far and having an excellent α4 integrin inhibitory action.
In particular, an object of the present invention is to provide a novel compound having an α4 integrin inhibitory action with high selectivity, which has a low effect on α4β1 and a high effect on α4β7.
Another object of the present invention is to provide a compound having an excellent α4 integrin inhibitory action that can be administered orally.
Another object of the present invention is to provide a compound having an α4 integrin inhibitory activity excellent in safety.
Another object of the present invention is to provide a compound having a long-lasting α4 integrin inhibitory activity.
Another object of the present invention is to provide a novel compound having an excellent α4 integrin inhibitory action in human whole blood.
Another object of the present invention is to provide a pharmaceutical composition containing the above novel compound and a pharmaceutically acceptable carrier.
Another object of the present invention is to provide a medicament containing the novel compound.
Another object of the present invention is to provide a therapeutic or prophylactic agent for inflammatory diseases in which an α4β7 integrin-dependent adhesion process is involved in the disease state.
Another object of the present invention is to provide an α4 integrin inhibitor.

The present inventors examined the inhibitory activity of α4β7 integrin in human whole blood for compounds having various structures. As a result, a sulfonamide derivative having a specific chemical structure having a heterocyclic group having an aminocarbonyl group as a substituent or a sulfonamide group to which a phenyl group is bonded or a pharmaceutically acceptable salt thereof is excellent in human whole blood. It was found to have α4β7 integrin inhibitory activity.

That is, the present invention includes the following aspects [1] to [17].
[1] A sulfonamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(In the formula

Represents a single bond or a double bond,
R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, lower alkenyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, hydroxy group, or a hydroxy lower alkyl group, R ₁ And R ₂ are bonded to each other to form a benzene ring which may have a substituent, an alicyclic hydrocarbon having 4 to 7 carbon atoms which may have a substituent, or a heteroaryl ring which may have a substituent Or may form a heterocyclic ring which may have a substituent,
R ₃ represents a lower alkyl group,
e, f, g, and h each independently represent C—H or a nitrogen atom;
B represents a hydroxy group, an alkoxy group having 1 to 10 carbon atoms, an —O-heterocyclic group, a cilexetyloxy group, or a medoxomiloxy group;
D represents a benzene ring or a heteroaryl ring which may have a substituent,
R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a phenyl group which may have a substituent, Or it represents the heterocyclic group which may have a substituent, R < ₄ > and R < ₅ > may couple | bond together and it may form the heterocyclic ring which may have a substituent. )
[2]

The sulfonamide derivative according to the above [1], or a pharmaceutically acceptable salt thereof, wherein represents a double bond.
[3] R ₁ and R ₂ are bonded to each other to have a benzene ring which may have a substituent, an alicyclic hydrocarbon having 4 to 7 carbon atoms which may have a substituent, and a substituent. A heteroaryl ring or a hetero ring that may have a substituent, and the substituent is a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and The sulfonamide derivative described in the above [1] or [2], or a pharmaceutically acceptable salt thereof, selected from a lower alkylamino lower alkyl group.
[4] R ₁ and R ₂ each independently represent a hydrogen atom, a lower alkyl group, or a lower alkoxymethyl group, and R ₁ and R ₂ may be bonded to each other to have a substituent. The alicyclic hydrocarbon of formula 4 to 7, a heteroaryl ring which may have a substituent, or a heterocycle which may have a substituent may be formed, and the substituent is a lower alkyl group And a sulfonamide derivative described in the above [1] or [2], or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
[5] The sulfonamide derivative according to [1] or [2] above, wherein R ₁ and R ₂ each independently represents a hydrogen atom, a lower alkyl group, or a lower alkoxymethyl group, or a pharmaceutical thereof Acceptable salt.
[6] R ₁ and R ₂ are bonded to each other to have a cyclohexene which may have a substituent, pyridine which may have a substituent, dihydropyran which may have a substituent, or a substituent. A tetrahydropyridine may be formed, and the substituent is selected from a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and a lower alkylamino lower alkyl group, The sulfonamide derivative according to 1] or [2], or a pharmaceutically acceptable salt thereof.
[7] The sulfonamide derivative according to any one of the above [1] to [6], wherein e represents a nitrogen atom, and f, g, and h represent CH, or a pharmaceutically acceptable derivative thereof Possible salt.
[8] The sulfonamide derivative according to any one of [1] to [7], or a pharmaceutically acceptable salt thereof, wherein B represents a hydroxy group or an alkoxy group having 1 to 6 carbon atoms salt.
[9] The sulfonamide derivative according to any one of [1] to [8] above, wherein the substituent of D is selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group, or a pharmaceutical Acceptable salt.
[10] D represents an benzene ring which may have a substituent, and the substituent is selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group. Or a pharmaceutically acceptable salt thereof.
[11] R ₄ and R ₅ may each independently have a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, or a substituent. Represents a phenyl group or a heterocyclic group which may have a substituent, and the substituent is a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a heterocyclic ring; R ₄ and R ₅ may be bonded to form a heterocyclic group which may have a substituent, and the substituent is a lower alkyl group, a lower alkoxy group, or a hydroxy group. The sulfonamide derivative according to any one of [1] to [10], or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
[12] R ₄ and R ₅ each independently represent a hydrogen atom, a lower alkyl group which may have a substituent, or a heterocyclic group which may have a substituent, wherein the substituent is , A halogen atom, a cyano group, a hydroxy group, a lower alkoxy group, a trifluoromethyl group, and a heterocyclic group, R ₄ and R ₅ may be bonded to each other to have a lower alkyl group as a substituent. The sulfonamide derivative according to any one of [1] to [10], or a pharmaceutically acceptable salt thereof, which may form a heterocyclic group.
[13] R ₁ and R ₂ each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkoxy lower alkyl group, and R ₁ and R ₂ are bonded to form a carbon number of 4 to 7 alicyclic hydrocarbons, heteroaryl rings, or heterocycles that may be substituted with lower alkyl groups,
D represents a benzene ring or a heteroaryl ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, and R ₄ and R ₅ are each independently Represents a hydrogen atom or a lower alkyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a heterocyclic group, a hydroxy group, a cyano group and a halogen atom, provided that R ₄ and R _{4 5} may be bonded to form a heterocyclic group which may be substituted with a lower alkyl group;
However,
When D represents a benzene ring substituted with a halogen atom, R ₁ and R ₂ each represent a lower alkyl group,
When D is a benzene ring having a lower alkyl group, a lower alkoxy group or a hydroxy group as a substituent, the substituent is bonded to D at a carbon atom adjacent to the carbon atom bonded to S;
When R ₄ or R ₅ represents a lower alkyl group substituted with a hydroxy group, the lower alkyl group substituted with the hydroxy group is represented by the following formula (a) or (b):

However, when R ₄ or R ₅ is represented by the formula (b), R ₁ and R ₂ each represent a lower alkyl group,
When R ₄ or R ₅ is a lower alkyl group substituted with a cyano group, D represents a benzene ring, or the sulfonamide derivative according to the above [1], or a pharmaceutically acceptable salt thereof.
[14] The sulfonamide derivative of the above-mentioned [1] represented by the following formula or a pharmaceutically acceptable salt thereof.

(Wherein R1, R2, R3, e, f, g, h and B are as defined in [1] above)
[15] The sulfonamide derivative according to the above [1] represented by the following formula, or a pharmaceutically acceptable salt thereof.

(Wherein B is as defined in [1])
[16] A pharmaceutical composition comprising the sulfonamide derivative according to any one of [1] to [15], or a pharmaceutically acceptable salt thereof.
[17] Treatment of an inflammatory disease in which an α4β7 integrin-dependent adhesion process containing the sulfonamide derivative according to any one of the above [1] to [15] or a pharmaceutically acceptable salt thereof is involved in a disease state Agent or preventive agent.
[18] An α4β7 integrin inhibitor comprising the sulfonamide derivative according to any one of [1] to [15] above or a pharmaceutically acceptable salt thereof.

According to the present invention, a novel compound having a chemical structural formula that has not been known so far and having an excellent α4 integrin inhibitory action is provided.
In particular, according to the present invention, there is provided a novel compound having an α4 integrin inhibitory action with high selectivity, which is low in effect on α4β1 and high in effect on α4β7.
The present invention also provides a compound having an excellent α4 integrin inhibitory action that can be administered orally.
According to the present invention, a compound having α4 integrin inhibitory activity excellent in safety is also provided.
According to the present invention, a compound having a long-lasting α4 integrin inhibitory activity is also provided.
The present invention also provides a novel compound having an excellent α4 integrin inhibitory action in human blood.
According to the present invention, there is also provided a pharmaceutical composition comprising the novel compound and a pharmaceutically acceptable carrier.
According to this invention, the pharmaceutical containing the said novel compound is also provided.
The present invention also provides a therapeutic or prophylactic agent for inflammatory diseases in which an α4β7 integrin-dependent adhesion process is involved in the disease state.
According to the present invention, an α4 integrin inhibitor is also provided.

In the present specification, “may have a substituent” means “substituted or unsubstituted”. Unless otherwise specified, the position and number of substituents are arbitrary and are not particularly limited. When substituted with two or more substituents, these substituents may be the same or different. Examples of the substituent include a halogen atom, a nitro group, a cyano group, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a hydroxy lower alkyl group, a hydroxy lower alkenyl group, and a hydroxy lower group. Alkoxy group, lower alkoxyalkyl group, halogeno lower alkyl group, halogeno lower alkenyl group, halogeno lower alkoxy group, halogeno lower alkylthio group, amino group, lower alkylamino group, lower alkylaminocarbonyl group, carboxy group, lower alkyloxycarbonyl group Carbamoyl group, lower alkanoyl group, aroyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, sulfamoyl group, ammonium group, aryl group, heterocyclic group, aryl lower alkyl group, hete Ring lower alkyl group, aryloxy group, heterocyclic oxy group, arylsulfonyl group, heterocyclic sulfonyl group, dihydroxyboryl group, lower alkylamino lower alkyl group, aryl lower alkoxycarbonyl group, lower alkenyloxy group, lower acyloxy group, and And lower acylamino group.

In this specification, the term “lower” means a group having 1 to 6 carbon atoms, and the “lower alkyl group” means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, tert-pentyl Group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclopropylethyl group, etc. And preferably a methyl group, an ethyl group, or an n-propyl group.

The “lower alkenyl group” refers to a linear or branched alkenyl group having 2 to 6 carbon atoms including each isomer. Examples thereof include a vinyl group, an allyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group, and a vinyl group, an allyl group, and a propenyl group are preferable.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom and a chlorine atom.

The “lower alkoxy group” refers to an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexyloxy group, isopropoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, cyclopropyloxy Group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group, and a methoxy group, an ethoxy group, and an n-propoxy group are preferable.

The “lower alkoxymethyl group” refers to a methyl group that is mono-substituted or further substituted with the above-mentioned “lower alkoxy group”. Examples thereof include a methoxymethyl group, an ethoxymethyl group, an isopropoxymethyl group, a tert-butoxymethyl group, and the like, and a methoxymethyl group and an ethoxymethyl group are preferable.

The “hydroxy lower alkyl group” refers to a lower alkyl group substituted with a hydroxyl group, and examples thereof include a hydroxymethyl group and a hydroxyethyl group, and a hydroxymethyl group is preferred.

The “lower alkylamino lower alkyl group” refers to a lower alkyl group substituted with the above-mentioned “lower alkyl group” mono- or di-substituted amino group. Examples include a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group, an isopropylaminomethyl group, a methylaminoethyl group, an ethylaminoethyl group, a dimethylaminomethyl group, and a methylethylaminomethyl group, preferably methyl An aminomethyl group, an ethylaminomethyl group, and a methylaminoethyl group;

The “alicyclic hydrocarbon” refers to a cyclic structure composed of carbon atoms and hydrogen atoms, and includes cycloalkanes that are all formed by single bonds and cycloalkenes that may contain double bonds. For example, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexene and the like can be mentioned, and cyclohexane and cyclohexene are preferable.

The “heteroaryl ring” refers to a 4- to 10-membered aromatic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms. For example. Pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, furan ring, thiophene ring, pyrrole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, pyrazole ring, imidazole ring, oxadiazole ring, thiadiazole ring, triazole Ring, tetrazole ring, benzofuran ring, benzothiophene ring, indole ring, isoindole ring, benzoxazole ring, benzisoxazole ring, benzthiazole ring, benzisothiazole ring, benzimidazole ring, indazole ring, purine ring, quinoline ring , Isoquinoline ring, cinnoline ring, phthalazine ring, quinazoline ring, quinoxaline ring, and pteridine ring, preferably a pyridine ring and a pyrimidine ring.

“Heterocycle” refers to a 4- to 10-membered monocyclic to bicyclic heterocycle containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring atoms. In addition, any carbon atom which is a ring atom may be substituted with an oxo group, and a sulfur atom or a nitrogen atom may be oxidized to form an oxide. Further, it may be condensed with a benzene ring. For example, oxetane ring, tetrahydrofuran ring, dihydropyran ring, tetrahydropyran ring, dioxolane ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, thiazolidine ring, azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, homopiperidine ring, homopiperazine ring , Pyrazolidine ring, imidazolidine ring, tetrahydropyridine ring, tetrahydropyrimidine ring, morpholine ring, thiomorpholine ring, indoline ring, isoindoline ring, chroman ring, isochroman ring, azaindoline ring, piperidinone ring, imidazoloxazine ring, imidazolothiazoline ring , Pyrimidone ring, hydantoin ring, quinuclidine ring and the like, and piperidine ring, piperazine ring, tetrahydropyran ring and morpholine ring are preferable.

“Heterocyclic group” refers to a 4- to 10-membered monocyclic to bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms. . In addition, any carbon atom which is a ring atom may be substituted with an oxo group, and a sulfur atom or a nitrogen atom may be oxidized to form an oxide. Further, it may be condensed with a benzene ring. Oxetanyl group, tetrahydrofuranyl group, dihydropyranyl group, tetrahydropyranyl group, dioxolanyl group, tetrahydrothiophenyl group, tetrahydrothiopyranyl group, thiazolidinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, homopiperidinyl group, homopiperazinyl group Group, pyrazolidinyl group, imidazolidinyl group, tetrahydropyridyl group, tetrahydropyrimidyl group, morpholinyl group, thiomorpholinyl group, indolinyl group, isoindolinyl group, chromanyl group, isochromanyl group, azaindolyl group, piperidinonyl group, imidazoloxazolyl group, imidazolothia A zolyl group, a pyrimidinyl group, a hydantoinyl group, a quinuclidinyl group, etc., preferably a piperidinyl group, a piperazinyl group, a teto Hidoropiraniru group, a morpholinyl group, piperidinonyl group, a hydantoinyl group.

In the present invention, the sulfonamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably the following:
In general formula (I), R ₁ and R ₂ are each independently preferably a hydrogen atom, a lower alkyl group or a lower alkoxymethyl group, more preferably a hydrogen atom or a lower alkyl group, a hydrogen atom or a methyl group. Is particularly preferred.
In the general formula (I), the ring formed by combining R ₁ and R ₂ is preferably pyridine, cyclohexene, dihydropyran and tetrahydropyridine, more preferably cyclohexene, dihydropyran and tetrahydropyridine, and dihydropyran. And tetrahydropyridine are particularly preferred.
In general formula (I), R ₃ is preferably a lower alkyl group, particularly preferably a methyl group.
In the general formula (I), e, f, g and h are preferably C—H 2 or _a nitrogen atom, more preferably any one is a nitrogen atom, and particularly preferably e or f is a nitrogen atom. preferable.
In general formula (I), B is preferably a hydroxy group or a lower alkoxy group, more preferably a hydroxy group, a methoxy group, an ethoxy group, an isopropoxy group, or a cyclohexyl group, and a hydroxy group, a methoxy group, an ethoxy group, or an isopropoxy group. Is particularly preferred.
In general formula (I), D is preferably a benzene ring which may have a substituent or a heteroaryl ring which may have a substituent, more preferably a benzene ring or a pyridine ring, and particularly preferably a benzene ring.
In general formula (I), the substituent of D is preferably a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group, more preferably a fluorine atom, a methyl group, a methoxy group or a hydroxy group.
In the general formula (I), when D represents a benzene ring or a pyridine ring, the substitution position of the aminosulfonyl group and aminocarbonyl group bonded to D is preferably the para position.
In the general formula (I), R ₄ and R ₅ are each independently a lower alkyl group which may have a substituent or a heterocyclic group which may have a substituent, preferably a methyl group or an ethyl group. Tert-butyl group, cyclopropyl group, 2-isopentyl group, 3,3-dimethyl-2-butyl group and tetrahydropyranyl group are more preferable, and ethyl group, tert-butyl group and cyclopropyl group are particularly preferable.
In the general formula (I), the substituents of R ₄ and R ₅ are preferably a methoxy group, a morpholino group, a trifluoromethyl group, a hydroxy group or a cyano group, and particularly preferably a morpholino group, a trifluoromethyl group or a cyano group.
In the general formula (I), the ring formed by combining R ₄ and R ₅ is preferably a heterocyclic ring which may have a substituent, and morpholine and piperazine are particularly preferable.

In the general formula (I),
R ₁ and R ₂ each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkoxy lower alkyl group, and R ₁ and R ₂ are bonded to form an alicyclic group having 4 to 7 carbon atoms. May form a hydrocarbon, heteroaryl ring, or heterocycle optionally substituted with a lower alkyl group,
D represents a benzene ring or a heteroaryl ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, and R ₄ and R ₅ are each independently Represents a hydrogen atom or a lower alkyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a heterocyclic group, a hydroxy group, a cyano group and a halogen atom, provided that R ₄ and R _{4 5} may be bonded to form a heterocyclic group which may be substituted with a lower alkyl group;
However,
When D represents a benzene ring substituted with a halogen atom, R ₁ and R ₂ each represent a lower alkyl group,
When D is a benzene ring having a lower alkyl group, a lower alkoxy group or a hydroxy group as a substituent, the substituent is bonded to D at a carbon atom adjacent to the carbon atom bonded to S;
When R ₄ or R ₅ represents a lower alkyl group substituted with a hydroxy group, the lower alkyl group substituted with the hydroxy group is represented by the following formula (a) or (b):

However, when R ₄ or R ₅ is represented by the formula (b), R ₁ and R ₂ each represent a lower alkyl group,
When R ₄ or R ₅ is a lower alkyl group substituted with a cyano group, D represents a benzene ring;
Compounds are preferred. Such compounds have a particularly high selectivity.

When the compound represented by the general formula (I) of the present invention can be in the form of a salt, the salt may be pharmaceutically acceptable, for example, for an acidic group such as a carboxyl group in the formula Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, organic salts such as aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine Examples thereof include salts with amines and salts with basic amino acids such as arginine and lysine. When a basic group is present in the formula, for a basic group, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid Examples thereof include salts with organic carboxylic acids such as acids and salts with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. As a method for forming a salt, a compound of the general formula (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersing agent, or cation exchange or anion is performed based on other salt forms. It can also be obtained by ion exchange.

The compound of the present invention may also contain a solvate of the compound represented by the general formula (I), for example, a hydrate, an alcohol adduct and the like.
The compound of the present invention includes a prodrug form of the compound represented by formula (I). The prodrug of the compound of the present invention is a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically causes oxidation, reduction, hydrolysis, etc. A compound that changes to a compound represented by the general formula (I), a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to a compound represented by the general formula (I). Examples of the prodrug of the compound represented by the general formula (I) are not limited to those exemplified in the compounds of Examples. For example, when the compound represented by the general formula (I) has an amino group, the prodrug may be a compound in which the amino group is acylated, alkylated or phosphorylated (eg, a compound represented by the general formula (I) The amino group of eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2monooxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylated pivaloyloxy Examples thereof include methylated, tert-butylated compounds, etc. When the compound represented by the general formula (I) has hydroxy, the prodrug includes acylated, alkylated, phosphorylated, borated. Of the compound represented by the general formula (I) is acetylated, palmitoylated, propano And a compound having a carboxy group as a prodrug, such as a compound having a carboxy group, and a pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compound, etc. Compounds in which the carboxy group is esterified or amidated (eg, carboxyl of the compound represented by the general formula (I) is methyl esterified, ethyl esterified, normal propyl esterified, phenyl esterified, or isopropyl esterified. , Isobutyl esterification, cyclobutyl esterification, cyclopentyl esterification, cyclohexyl esterification, cycloheptyl esterification, cyclobutylmethyl esterification, cyclohexylmethyl esterification, normal hexyl esterification, sec-butyl esterification, tert-butyl Stealization, (4-tetrahydropyranyl) methyl esterification, (4-tetrahydropyranyl) esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, Examples include phthalidyl esterification, (5-methyl-2 monooxo-1,3-dioxolen-4 monoyl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc. When the compound represented by the formula (I) has a carboxy group, the prodrug includes a compound in which the carboxy group is esterified with a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. These compounds are preferably represented by the formula (I) by a method known per se. ).
The prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.

The present invention includes all isotopes of the compounds represented by formula (I). The isotope of the compound of the present invention is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the present compound, a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, include a chlorine atom, ^{respectively, 2 H, 3 H, 13} C , ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and the like. In particular, unstable radioisotopes that emit radioactivity and emit neutrons, such as ³ H and ¹⁴ C, are useful in tests of tissue distribution of drugs or compounds. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity. The isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.

The compound represented by the general formula (I) or a salt thereof is administered as it is or as various pharmaceutical compositions. As a dosage form of such a pharmaceutical composition, for example, it may be a tablet, powder, pill, granule, capsule, suppository, solution, sugar coating, devoted, or syrup, and a usual formulation aid. Can be produced according to a conventional method.
For example, tablets may contain phenylalanine derivatives, which are the active ingredients of the present invention, known auxiliary substances such as inert diluents such as lactose, calcium carbonate or calcium phosphate, binders such as gum arabic, corn starch or gelatin, alginic acid, corn starch or the like Gelatinized starch and other leavening agents, sweeteners such as sucrose, lactose and saccharin, flavoring agents such as peppermint, red mono oil and cherry, lubricants such as magnesium stearate, talc and carboxymethylcellulose, fats, waxes and semi-solids And liquid gelatin, soft gelatin capsules such as natural or hardened oils and excipients for suppositories, water, alcohol, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Obtained by.

An inhibitor comprising a compound represented by the general formula (I) or a salt thereof as an active ingredient can be used as a therapeutic or prophylactic agent for inflammatory diseases in which an α4 integrin-dependent adhesion process is involved in the pathological state. Such inflammatory diseases include, for example, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular disease, arteriosclerosis, relapse Examples include stenosis, tumor growth, tumor metastasis, transplant rejection, and / or human immunodeficiency virus infection (see Non-Patent Document 1).
The dose to be used for the above purpose is determined by the intended therapeutic effect, administration method, treatment period, age, weight, etc., but it is usually given orally as a daily dose for adults by the oral or parenteral route. In the case of administration, 1 μg to 5 g may be used, and in the case of parenteral administration, 0.01 μg to 1 g may be used.

According to the sulfonamide derivative represented by the general formula (I), an aminocarbonyl group is provided as a substituent of D. By adopting such a structure, excellent α4β7 integrin inhibitory activity can be obtained in human whole blood. In addition, since the sulfonamide derivative of the present invention has a high concentration to the portal vein and the amount of exposure in the circulating blood increases, a stronger effect can be obtained. From this viewpoint, the α4β7 integrin-dependent adhesion process is useful as a therapeutic or prophylactic agent for inflammatory diseases in which the disease state is involved. Furthermore, in the sulfonamide derivative of general formula (I), the 2-position and 5-position of phenyl in the phenylalanine moiety are substituted with fluorine atoms. Thereby, the effect is low with respect to α4β1 integrin, and high inhibitory activity can be selectively obtained with respect to α4β7 integrin.

The compound represented by the general formula (I) of the present invention includes, for example, an intermediate having a carboxyl group at the terminal represented by the general formula (MI) and an amino group at the terminal represented by the general formula (M-II). And an intermediate having an amidation reaction.
The amidation reaction is known, and examples thereof include (1) a method using a condensing agent and (2) a method using an acid halide.

(1) A method using a condensing agent is, for example, a method in which a carboxylic acid and an amine or a salt thereof are mixed with, for example, dichloromethane, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF) or acetonitrile. In a solvent that does not adversely influence the reaction, for example, in the presence or absence of a base such as pyridine, triethylamine or N, N-diisopropylethylamine, for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7 In the presence or absence of condensation aids such as azabenzotriazole (HOAt) or N-hydroxysuccinimide (HOSu), for example 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSC) ), 1,3-dicyclohexylcarbodiimide (DCC) Or (7-azabenzotriazole-1-yl) -N, N, N ', is carried out by reacting with a condensing agent such as N'- tetramethyluronium hexafluorophosphate (HATU).

(2) In the method using an acid halide, the carboxylic acid is used in a solvent that does not adversely influence the reaction, such as dichloromethane, or in the absence or presence of a catalyst such as DMF in the absence of a solvent. For example, an acid halide obtained by reacting with thionyl chloride, oxalyl chloride, thionyl bromide, etc., for example, dichloromethane, THF, etc., in a solvent that does not adversely affect this reaction, for example, pyridine, triethylamine, or The reaction is carried out by reacting with an amine or a salt thereof in the presence of a base such as N, N-diisopropylethylamine.

Among these, the intermediate having a carboxyl group at the terminal represented by the general formula (MI) can be produced, for example, by the following method.

The production method of a representative compound among the intermediates having a carboxyl group at the terminal represented by the general formula (MI) which is the compound of the present invention is shown below. In the following description, unless otherwise specified, symbols in the formula are the same as defined in the formula (I).
In the general formula (MI), D is a phenyl group that may have a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, and a halogen atom, or a pyridyl group. The intermediate body (S8) which has a carboxyl group at the terminal is compoundable by using the method (manufacturing method A, B, and C) etc. which are described below, for example.

<Production method A>

In the formula, D ₁ represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection, and R ₂₁ represents, for example, a lower alkyl group or the like. It represents a general ester substituent, and in the formula, X ₁ represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as trifluoromethanesulfonyloxy group.
The sulfonyl chloride derivative (S1) and the aniline derivative (S2) are reacted in a solvent that does not adversely affect the reaction such as dichloromethane, acetonitrile, THF, or DMF, for example, in the presence of a base such as pyridine or triethylamine. To synthesize the sulfonamide derivative (S3). The obtained sulfonamide derivative (S3) is obtained in the presence of a base such as triethylamine or N, N-diisopropylethylamine in a solvent that does not adversely affect the reaction such as DMF or N-methylpyrrolidone (NMP). For example, the aldehyde derivative (S4) can be synthesized by performing a coupling reaction in a carbon dioxide atmosphere using a metal catalyst such as 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II). The obtained aldehyde derivative (S4) can synthesize a carboxylic acid derivative (S5) by performing an oxidation reaction such as Pinnick oxidation. The obtained carboxylic acid derivative (S5) and amine derivative (S6) or a salt thereof, for example, pyridine, in a solvent that does not adversely affect the reaction, such as dichloromethane, THF, 1,4-dioxane, DMF, or acetonitrile. In the presence or absence of a base such as triethylamine or N, N-diisopropylethylamine, for example, in the presence or absence of a condensation aid such as HOBt, HOAt or HOSu, for example, WSC, By reacting with a condensing agent such as DCC or HATU, it can be derived into the corresponding amide derivative (S7). Subsequently, the amide derivative (S7) is used in a solvent that does not adversely influence the reaction such as THF, 1,4-dioxane, methanol or ethanol, for example, using a base such as sodium hydroxide or lithium hydroxide. The target carboxylic acid derivative (S8) can be produced by performing alkaline hydrolysis or acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.

<Production method B>

In the formula, D ₁ represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection, and R ₂₁ represents, for example, a lower alkyl group or the like. Represents a general ester substituent.
The sulfonyl chloride derivative (S9) and the aniline derivative (S2) are reacted in a solvent that does not adversely affect the reaction such as dichloromethane, acetonitrile, THF, or DMF, for example, in the presence of a base such as pyridine or triethylamine. To synthesize a sulfonamide derivative (S5). The obtained sulfonamide derivative (S5) and amine derivative (S6) or a salt thereof in a solvent that does not adversely affect the reaction, such as dichloromethane, THF, 1,4-dioxane, DMF or acetonitrile, for example, In the presence or absence of a base such as pyridine, triethylamine, or N, N-diisopropylethylamine, for example, in the presence or absence of a condensation aid such as HOBt, HOAt or HOSu, for example WSC By reacting with a condensing agent such as DCC or HATU, it can be derived into the corresponding amide derivative (S7). Subsequently, the amide derivative (S7) is used in a solvent that does not adversely influence the reaction such as THF, 1,4-dioxane, methanol or ethanol, for example, using a base such as sodium hydroxide or lithium hydroxide. The target carboxylic acid derivative (S8) can be produced by performing alkaline hydrolysis or acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.

<Manufacturing method C>

In the formula, D ₁ represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection, and R ₂₁ represents, for example, a lower alkyl group or the like. Represents a general ester substituent.
The sulfonyl chloride derivative (S10) and the aniline derivative (S2) are reacted in a solvent that does not adversely influence the reaction such as dichloromethane, acetonitrile, THF, or DMF, for example, in the presence of a base such as pyridine or triethylamine. To synthesize a sulfonamide derivative (S7). Subsequently, the sulfonamide derivative (S7) is treated with a base such as sodium hydroxide or lithium hydroxide in a solvent that does not adversely affect the reaction such as THF, 1,4-dioxane, methanol or ethanol. The target carboxylic acid derivative (S8) can be produced by carrying out the alkaline hydrolysis used or acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.

In the general formula (MI), D is a phenyl group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group and a halogen atom, or a pyridyl group, The intermediate (S8) having a carboxyl group at the terminal where R ₅ is a hydrogen atom can be synthesized by using, for example, the method described below (Production Method D).

<Manufacturing method D>

In the formula, D ₁ represents the above-described substituent represented by D, or a substituent that can be easily converted to D by an operation such as deprotection, and R ₂₁ represents, for example, a lower alkyl group or the like. It represents a general ester substituent, and in the formula, X ₁ represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as trifluoromethanesulfonyloxy group.
The halogenaryl derivative (S3) and the isocyanide reagent (S11) are mixed with, for example, a base such as cesium carbonate in a solvent that does not adversely affect the reaction such as DMSO, for example, in the presence or absence of water. The tert-butylamide derivative (S12) can be synthesized by reacting in the presence using, for example, a metal catalyst such as bistriphenylphosphine dichloropalladium (II). The obtained tert-butylamide derivative (S12) is used in a solvent that does not adversely influence the reaction such as THF, 1,4-dioxane, methanol or ethanol, for example, a base such as sodium hydroxide or lithium hydroxide. The target carboxylic acid derivative (S8) can be produced by carrying out alkaline hydrolysis using, acid hydrolysis using, for example, hydrochloric acid or trifluoroacetic acid.

Each process can be synthesized by using generally replaceable reaction conditions, and should be selected in a timely manner according to the type of raw material compound. In addition, the compound of the present invention obtained by the above method can be purified using techniques such as extraction, distillation, crystallization, column chromatography and the like usually used in organic synthesis.

The intermediate (S17) having an amino group at the terminal represented by the general formula (M-II), which is the compound of the present invention, may be produced by, for example, the following production methods (Production Methods E, F, and G). It can be synthesized by using. In the following description, unless otherwise specified, symbols in the formula are the same as defined in the formula (I).

<Manufacturing method E>

Wherein R ₃₁ is, for example, tert- butoxycarbonyl group, such as benzyloxycarbonyl group, for example, a substituent of the general amines which can removed by manipulation of deprotection such as, wherein X ₃ is, for example, chlorine, bromine, represents a leaving group such as a halogen atom or for example, trifluoromethanesulfonyloxy group iodine, wherein B ₁ represents, by operation of deprotection such, represents a readily converted can substituents B.
The halogenated aryl derivative (S13) and a borane derivative such as bis (pinacolato) diborane, for example, in a solvent that does not adversely affect the reaction such as DMF, for example, in the presence of a base such as potassium acetate, for example, By performing a coupling reaction using a metal catalyst such as 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II), the corresponding boronic acid ester derivative is derived, and then the boronic acid obtained The boronic ester is deprotected by treating the ester derivative with, for example, sodium periodate or ammonium acetate and water in a solvent that does not adversely affect the reaction, such as acetone. The corresponding boronic acid derivative (S14) can be synthesized. The obtained boronic acid derivative (S14) and uracil derivative (S15) are mixed with a solvent that does not adversely affect the reaction, such as dichloromethane, dimethyl sulfoxide (DMSO), or DMF, such as pyridine or triethylamine. The amino acid derivative (S16) can be synthesized by performing a coupling reaction using a metal catalyst such as copper (II) acetate or copper (II) trifluoromethanesulfonate in the presence of a base. Subsequently, the amino acid derivative (S16) is subjected to deprotection such as acid hydrolysis using hydrochloric acid or trifluoroacetic acid or hydrogenolysis to produce the target carboxylic acid derivative (S17). be able to.

<Manufacturing method F>

Wherein R ₃₁ is, for example, tert- butoxycarbonyl group, such as benzyloxycarbonyl group, for example, a substituent of the general amines which can removed by manipulation of deprotection such as, wherein R ₃₂ and R ₃₃ Each independently represents, for example, a lower alkyl group or a substituent of a general ester such as a benzene ring which may have a substituent, wherein B ₁ is converted to B by an operation such as deprotection. Represents a substituent that can be easily converted.
The nitro derivative (S18) is, for example, a catalytic reduction reaction using a metal catalyst such as palladium carbon, palladium hydroxide, or Raney nickel in a solvent that does not adversely affect the reaction such as methanol, ethanol, or isopropyl alcohol. Alternatively, the aniline derivative (S19) can be synthesized by reacting a metal such as zinc under acidic conditions (for example, hydrochloric acid, acetic acid, or ammonium chloride). The obtained aniline derivative (S19) and carbamate derivative (S20) are mixed with triethylamine, pyridine, or diaza in a solvent that does not adversely affect the reaction, such as dichloromethane, 1,4-dioxane, THF, or DMF. The amino acid derivative (S16) can be synthesized by reacting with a base such as bicycloundecene (DBU). Subsequently, the target carboxylic acid derivative (S17) is produced by deprotecting the amino acid derivative (S16) by, for example, acid hydrolysis using hydrochloric acid or trifluoroacetic acid or hydrogenolysis. Can do.

<Manufacturing method G>

In the formula, R ₃₁ represents a general amine substituent which can be removed by an operation such as deprotection, for example, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, etc., wherein X ₃ , X ₄ and X ₅ each independently represents, for example, a halogen atom such as chlorine, bromine, iodine or the like, or a leaving group such as trifluoromethanesulfonyloxy group, wherein B ₁ represents B by the operation such as deprotection. Represents a substituent which can be easily converted into
The halogenated aryl derivative (S21) and the uracil derivative (S15) are mixed in a solvent that does not adversely influence the reaction, such as DMSO, NMP, or DMF, for example, triethylamine, N, N-diisopropylethylamine, DBU, or the like. In the presence of a base, for example, a compound (S22) is synthesized by performing a coupling reaction using a metal catalyst such as copper (I) iodide, copper (I) bromide, or copper (I) chloride. Can do. The obtained compound (S22) and halide (S23) are treated with, for example, tris (di-acid) in the presence of zinc powder activated with, for example, iodine in a solvent that does not adversely affect the reaction such as DMF. Negishi coupling using a metal catalyst such as benzylideneacetone) dipalladium (0) and a ligand commonly used in organic synthesis such as 2-dicyclohexyl-2 ′, 6′-dimethoxybiphenyl (SPhos). By carrying out the reaction, an amino acid derivative (S16) can be synthesized. Subsequently, the amino acid derivative (S16) is subjected to deprotection such as acid hydrolysis using hydrochloric acid or trifluoroacetic acid or hydrogenolysis to produce the target carboxylic acid derivative (S17). be able to.

The present invention will be described in more detail based on the following synthesis examples, examples and test examples. These are preferred embodiments of the present invention, and the present invention is not limited by the synthesis examples, examples and test examples, and may be changed without departing from the scope of the present invention. In addition, the reagents, devices, and materials used in the present invention are commercially available unless otherwise specified.

The common intermediate methyl 4-amino-2,5-difluoro-benzoate can be synthesized by the method described in the patent document (WO2013 / 161904).

Below, the synthesis example of the intermediate body used for the synthesis | combination of an Example compound is shown.
[Synthesis Example 1]
4-[[4- (tert-butylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

(Process 1)
Synthesis of Methyl 2,5-difluoro-4-[(4-iodophenyl) sulfonylamino] benzoate

Methyl 4-amino-2,5-difluoro-benzoate (3.0 g, 16.0 mmol) was dissolved in pyridine (30 ml), 4-iodobenzenesulfonyl chloride (12.1 g, 40.1 mmol) was added, and the mixture was mixed at 50 ° C. Stir overnight. Concentrated under reduced pressure, and the resulting residue was slurry washed with acetonitrile and vacuum dried to give methyl 4- [bis [(4-iodophenyl) sulfonyl] amino] -2,5-difluoro-benzoate (11.6 g) Got. THF (24 mL) was added, cooled to 0 ° C., 1M tetrabutylammonium fluoride / THF solution (24 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride solution was added and concentrated under reduced pressure to remove THF. The mixture was diluted with ethyl acetate, washed 4 times with 0.5 M hydrochloric acid, once with 1 M hydrochloric acid, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was slurry-washed with hexane / ethyl acetate = 7: 3. Vacuum drying gave the title compound (5.9 g, yield: 82%).
(Process 2)
Synthesis of Methyl 2,5-difluoro-4-[(4-formylphenyl) sulfonylamino] benzoate

The compound (1.0 g, 2.2 mmol) obtained in (Step 1) was dissolved in DMF (20 mL), and 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II) (0.16 g, 0 .22 mmol) was added, and the mixture was stirred at 70 ° C. for 10 minutes under an argon atmosphere. After returning to room temperature, N, N-diisopropylethylamine (1.1 ml, 6.6 mmol) and triethylsilane (0.88 mL, 5.5 mmol) were added, and the mixture was replaced with carbon monoxide, followed by stirring at 70 ° C. overnight. The residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid, The desired fraction was lyophilized to give the title compound (0.53 g, 68%).
(Process 3)
Synthesis of 4-[(2,5-difluoro-4-methoxycarbon-phenyl) sulfamoyl] benzoic acid

To the compound obtained in (Step 2) (0.53 g, 1.5 mmol), tert-butyl alcohol (15.6 ml) and water (3.7 mL) were added, and 2-methyl-2-butene (1.6 ml, 15 mmol) was added and stirred at room temperature. Disodium hydrogen phosphate (1.1 g, 7.5 mmol) dissolved in water (4.5 mL) and sodium chlorite (0.41 g, 4.5 mmol) dissolved in water (4.5 mL) in this order In addition, the mixture was stirred overnight at room temperature. The reaction solution was adjusted to about pH 6 with 2M hydrochloric acid, and extracted with ethyl acetate. After washing with saturated brine and drying over anhydrous magnesium sulfate, the residue was slurry washed with acetonitrile to give the title compound (0.56 g, quant.).
(Process 4)
Synthesis of 4-[[4- (tert-butylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

The compound obtained in (Step 3) (0.56 g, 1.5 mmol), WSC hydrochloride (0.58 g, 3.0 mmol), HOBt (0.20 g, 1.5 mmol), DMF (1 mL), dichloromethane ( 5 mL) was added and stirred at room temperature for 2 hours. After diluting with dichloromethane, saturated brine was added, extracted with dichloromethane and a small amount of methanol, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1,4-dioxane (4 mL), 2M aqueous lithium hydroxide solution (2.3 mL) was added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction mixture was neutralized with 1M aqueous trifluoroacetic acid solution, and the solvent was distilled off under reduced pressure. The residue was purified in the same manner as in (Step 2), and the desired fraction was lyophilized to give the title compound (0.38 g, 61%).

[Synthesis Example 2] to [Synthesis Example 8], [Synthesis Example 11], [Synthesis Example 13], [Synthesis Example 14], [Synthesis Example 20], and [Synthesis Example 23] to [Synthesis Example 26] Can be synthesized in the same manner as the compound of [Synthesis Example 1] by allowing the corresponding amine reagent to act on the compound obtained in (Step 3) of [Synthesis Example 1].

[Synthesis Example 2]
2,5-difluoro-4-[[[4- (morpholine-4-carbonyl) phenyl] sulfonylamino] benzoic acid

[Synthesis Example 3]
2,5-difluoro-4-[[4- (4-isopropylpiperazine-1-carbonyl) phenyl] sulfonylamino] benzoic acid

[Synthesis Example 4]
4-[[4- (cyclopropylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 5]
2,5-difluoro-4-[[[4- (methylcarbamoyl) phenyl] sulfonylamino] benzoic acid

[Synthesis Example 6]
2,5-difluoro-4-[[[4- (ethylcarbamoyl) phenyl] sulfonylamino] benzoic acid

[Synthesis Example 7]
2,5-difluoro-4-[[[4- (2-methoxyethylcarbamoyl) phenyl] sulfonylamino] benzoic acid

[Synthesis Example 8]
2,5-difluoro-4-[[[4- (2-morpholinoethylcarbamoyl) phenyl] sulfonylamino] benzoic acid

The compounds of [Synthesis Example 9], [Synthesis Example 10], [Synthesis Example 22], and [Synthesis Example 27] are methyl 4-amino-2, 5-difluoro in [Synthesis Example 1] (Step 1). It can be synthesized in the same manner as the compound of [Synthesis Example 1] by allowing 5-benzopyridin-2-sulfonyl chloride or 6-iodopyridine-3-sulfonyl chloride to act on -benzoate.

[Synthesis Example 9]
4-[[5- (tert-butylcarbamoyl) -2-pyrylyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 10]
2,5-difluoro-4-[[[5- (tetrahydropyran-4-ylcarbamoyl) -2-pyrylyl] sulfonylamino] benzoic acid

[Synthesis Example 11]
2,5-difluoro-4-[[[4- (tetrahydropyran-4-ylcarbamoyl) phenyl] sulfonylamino] benzoic acid

[Synthesis Example 12]
4-[[4- (tert-butylcarbamoyl) -3-methoxy-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

(Process 1)
Synthesis of Methyl 4-[(4-bromo-3-methoxy-phenyl) sulfonylamino] -2,5-difluoro-benzoate

Methyl 4-amino-2,5-difluoro-benzoate (1.5 g, 18.0 mmol) is dissolved in pyridine (15 ml), and 4-bromo-3-methoxybenzenesulfonyl chloride (4.6 g, 16 mmol) is added at room temperature. After stirring overnight, ethyl acetate (20 ml) and water (50 ml) were added. The mixture was extracted twice with ethyl acetate, and the organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was dissolved in THF (10 mL), cooled to 0 ° C., tetrabutylammonium fluoride (3.0 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (50 ml) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and the resulting residue was slurry washed with diethyl ether to give the title compound (2.0 g, yield: 57%).
1H NMR (CDCl ₃ , 300 MHz): δ 7.69-7.59 (m, 2H), 7.47-7.41 (m, 1H), 7.34-7.31 (m, 2H), 7.03 (s, 1H), 3.93 (s, 3H ), 3.90 (s, 3H)
(Process 2)
Synthesis of Methyl 4-[[4- (tert-butylcarbamoyl) -3-methoxy-phenyl] sulfonylamino] -2,5-difluoro-benzoate

In a DMSO solution (0.90 ml) of the compound (0.10 g, 0.23 mmol) obtained in (Step 1), water (0.10 ml), tert-butyl isocyanide (57 mg, 0.69 mmol), cesium carbonate ( 75 mg, 0.23 mmol) and bistriphenylphosphine dichloropalladium (II) (8.0 mg, 0.012 mmol) were sequentially added, and the mixture was stirred at 180 ° C. for 30 minutes in a sealed tube. Cool to room temperature and add saturated aqueous ammonium chloride (30 ml). The mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative thin layer chromatography to obtain the title compound (24 mg, 23%).
1H NMR (DMSO-d ₆ , 300 MHz): δ 11.12 (s, 1H), 7.86 (s, 1H), 7.69-7.64 (m, 2H), 7.51-7.46 (m, 2H), 7.33-7.2 (m , 1H), 3.87 (s, 3H), 3.81 (s, 3H), 1.33 (s, 9H).
(Process 3)
Synthesis of 4-[[4- (tert-butylcarbamoyl) -3-methoxy-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

To a methanol solution (6.0 ml) of the compound (0.48 g, 1.1 mmol) obtained in (Step 2) was added 4M lithium hydroxide aqueous solution (2.0 ml), and the mixture was stirred at room temperature for 2 hours. Hydrochloric acid was added to adjust the pH to 1.0 to 2.0, and the solid was collected by filtration to give the title compound (0.42 g, 90%).
1H NMR (DMSO-d6, 300 MHz): δ 11.07 (s, 1H), 7.87 (s, 1H), 7.67-7.61 (m, 2H), 7.50-7.46 (m, 2H), 7.28-7.24 (m, 1H), 3.87 (s, 3H), 1.33 (s, 9H).

[Synthesis Example 13]
2,5-difluoro-4-[[4-[[1- (trifluoromethyl) cyclopropyl] carbamoyl] phenyl] sulfonylamino] benzoic acid

[Synthesis Example 14]
2,5-difluoro-4-[[4-[(2-hydroxy-1,1-dimethyl-ethyl) carbamoyl] phenyl] sulfonylamino] benzoic acid

The compounds of [Synthesis Example 15] to [Synthesis Example 18] have the corresponding aryl bromide reagent acting on Methyl 4-amino-2,5-difluoro-benzoate in (Step 1) of [Synthesis Example 12]. Can be synthesized in the same manner as the compound of [Synthesis Example 12].

[Synthesis Example 15]
4-[[4- (tert-butylcarbamoyl) -2-methyl-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 16]
4-[[4- (tert-butylcarbamoyl) -3-methyl-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 17]
4-[[4- (tert-butylcarbamoyl) -3-fluoro-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 18]
4-[[4- (tert-butylcarbamoyl) -2-methoxy-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 19]
4-[[4- (tert-butylcarbamoyl) -3-hydroxy-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

A 1M tribromoborane / dichloromethane solution (15 ml) was added to a dichloromethane solution (3.0 ml) of the compound (0.24 g, 0.54 mmol) obtained in (Step 2) of [Synthesis Example 12], and at room temperature. Stir for 18 hours. Ice water was added, and the mixture was stirred at room temperature for 15 minutes, and then extracted with ethyl acetate three times. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurry washed with ethyl acetate / diethyl ether (3/1) to give the title compound (85 mg, 37%).
1H NMR (DMSO-d ₆ , 300 MHz): δ 12.27 (s, 1H), 11.08 (s, 1H), 8.24 (s, 1H), 7.98-7.95 (m, 1H), 7.65-7.59 (m, 1H ), 7.32-7.20 (m, 3H), 1.40 (s, 9H)
[Synthesis Example 20]
4-[[4-[(1-Cyanocyclopropyl) carbamoyl] phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

The compound of [Synthesis Example 21] can be synthesized in the same manner as the compound of [Synthesis Example 19] by using the compound of [Synthesis Example 18].

[Synthesis Example 21]
4-[[4- (tert-butylcarbamoyl) -2-hydroxy-phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 22]
4-[[6- (tert-butylcarbamoyl) -3-pyrylyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 23]
4-[[4-[(2-Cyano-1,1-dimethyl-ethyl) carbamoyl] phenyl] sulfonylamino] -2,5-difluoro-benzoic acid

[Synthesis Example 24]
2,5-difluoro-4-[[4-[[(1S) -1- (hydroxymethyl) -2-methyl-propyyl] carbamoyl] phenyl] sulfonylamino] benzoic acid

[Synthesis Example 25]
2,5-difluoro-4-[[4-[[(1R) -1- (hydroxymethyl) -2-methyl-propyyl] carbamoyl] phenyl] sulfonylamino] benzoic acid

[Synthesis Example 26]
2,5-difluoro-4-[[4-[[(1S) -1- (hydroxymethyl) -2,2-dimethyl-propyyl] carbamoyl] phenyl] sulfonylamino] benzoic acid

[Synthesis Example 27]
4-[[5-[(1-Cyanocyclopropyl) carbamoyl] -2-pyrylyl] sulfonylamino] -2,5-difluoro-benzoic acid

The compounds of [Synthesis Example 28] to [Synthesis Example 30], [Synthesis Example 35] to [Synthesis Example 37], [Synthesis Example 41], and [Synthesis Example 45] are described in Patent Document (WO2013 / 161904). It can be synthesized by the method.

[Synthesis Example 28]
Methyl (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-pyrido [3,4-d] pyrimidin-3-yl) phenyl] propanoate

[Synthesis Example 29]
Methyl (2S) -2-amino-3- [6- (1-methyl-2,4-dioxo-pyrido [3,4-d] pyrimidin-3-yl) -3-pyrylyl] propanoate

[Synthesis Example 30]
Methyl (2S) -2-amino-3- [4- (3-methyl-2,6-dioxo-pyrimidin-1-yl) phenyl] propanoate

[Synthesis Example 31]
Methyl (2S) -2-amino-3- [4- (3,4,5-trimethyl-2,6-dioxo-pyrimidin-1-yl) phenyl] propanoate

(Process 1)
Synthesis of Methyl (2S) -2- (tert-butoxycarbonylamino) -3- [4- (5,6-dimethyl-2,4-dioxo-1H-pyrimidin-3-yl) phenyl] propanoate

The manufacturing method is described in a patent document (WO2013 / 161904) [4-[(2S) -2- (tert-butycarbonylamino) -3-methoxy-3-propoxy] phenyl] bornic acid (9.2 g, 29 mmol). ) In dichloromethane solution (100 ml), copper acetate (5.2 g, 29 mmol), 5,6-dimethyluracil (4.0 g, 29 mmol), and triethylamine (10 ml) were sequentially added and stirred at room temperature for 18 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1: 1) to give the title compound (0.83 g, 7%).
1H NMR (CDCl ₃ , 400 MHz) δ 8.90 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 5.06 (d, J = 8.7 Hz, 1H), 4.64-4.59 (m, 1H), 3.72 (s, 3H), 3.15 (d, J = 6.3 Hz, 2H), 2.16 (s, 3H), 1.95 (s, 3H), 1.44 (s, 9H ) .; MS (ESI) m / z 418 [M + H] +
(Process 2)
Synthesis of Methyl (2S) -2- (tert-butoxycarbonylamino) -3- [4- (3,4,5-trimethyl-2,6-dioxo-pyrimidin-1-yl) phenyl] propanoate

To a DMF solution (15 ml) of the compound (0.83 g, 2.0 mmol) obtained in (Step 1), potassium carbonate (0.85 g, 6.0 mmol) and methyl iodide (0.4 ml) were sequentially added. The mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure, and water (20 ml) and ethyl acetate (30 ml) were added. Extraction was performed three times with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.64 g, 75%).
1H NMR (CDCl ₃ , 400 MHz) δ 8.02 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 4.63-4.58 (m, 1H), 3.71 (s, 3H), 3.47 (s, 3H), 3.13 (d, J = 6.0 Hz, 2H), 2.33 (s, 3H), 2.02 (s, 3H ), 1.43 (s, 9H) .; MS (ESI) m / z 432 [M + H] +
(Process 3)
Synthesis of Methyl (2S) -2-amino-3- [4- (3,4,5-trimethyl-2,6-dioxo-pyrimidin-1-yl) phenyl] propanoate

The compound (0.64 g, 1.5 mmol) obtained in (Step 2) was dissolved in 4M hydrochloric acid / ethyl acetate solution (40 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate (30 ml) was added. After stirring at room temperature for 30 minutes, the solid was collected by filtration to give the hydrochloride of the title compound (0.46 g, 93%).
1H NMR (CD ₃ OD, 400 MHz) δ 7.31 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.31-4.27 (m, 1H), 3.78 (s, 3H) , 3.38 (s, 3H), 3.37-3.32 (m, 1H), 3.09-3.03 (m, 1H), 2.30 (s, 3H), 1.91 (s, 3H) .; MS (ESI) m / z 332 [ M + H] +

[Synthesis Example 32]
Methyl (2S) -2-amino-3- [6- (3-methyl-2,6-dioxo-pyrimidin-1-yl) -3-pyridine] propanoate

(Process 1)
Synthesis of tert-butyl 3-benzoyl-2,4-dioxo-pyrimidine-1-carboxylate

To an acetonitrile solution (50 ml) of uracil (5.0 g, 45 mmol), di-tert-butyl dicarbonate (10.2 g, 47 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) were sequentially added and brought to room temperature. And stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was slurry washed with ethyl acetate. The obtained solid was dissolved in dichloromethane (50 ml), and N, N-diisopropylethylamine (7.9 ml, 45 mmol) was added. Under ice-cooling, benzoyl chloride (5.3 g, 37 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction twice with dichloromethane. The organic layer was washed successively with 0.5M hydrochloric acid and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was slurry washed with ethyl acetate to give the title compound (9.4 g, 66%).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (dd, J = 8.5, 1.6 Hz, 1H), 8.11-8.04 (m, 2H), 7.87-7.76 (m, 1H), 7.68-7.56 (m , 2H), 5.98 (dd, J = 8.4, 1.7 Hz, 1H), 1.54 (d, J = 1.6 Hz, 9H); MS (ESI) m / z 317 [M + H] ⁺
(Process 2)
Synthesis of 3-benzoyl-1-methyl-pyrimidine-2,4-dione

Trifluoroacetic acid (8.0 ml) was added to a dichloromethane solution (5.0 ml) of the compound (9.4 g, 30 mmol) obtained in (Step 1), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (50 ml). Potassium carbonate (4.5 g, 33 mmol) and methyl iodide (2.8 ml, 45 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Water (30 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The title compound was obtained by filtering the solid (7.4 g, quant.).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (dd, J = 8.0, 1.3 Hz, 2H), 7.87 (d, J = 7.9 Hz, 1H), 7.83-7.72 (m, 1H), 7.60 ( dd, J = 8.4, 7.2 Hz, 2H), 5.81 (dd, J = 7.9, 0.6 Hz, 1H), 3.32 (s, 3H); MS (ESI) m / z 231 [M + H] ⁺ .
(Process 3)
Synthesis of 1-methyluracil

To the compound (7.4 g, 30 mmol) obtained in (Step 2), 8M ammonia / methanol solution (50 ml) was added and stirred at room temperature for 5 hours. After filtering the solid (first crystal), the filtrate was concentrated under reduced pressure. The residue was slurry washed with ethyl acetate (second crystal), and the resulting solid was collected to give the title compound (4.2 g, quant.).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 5.51 (d, J = 7.8 Hz, 1H), 3.22 (s, 3H) ; MS (ESI) m / z 127 [M + H] ⁺ .
(Process 4)
Mixtures of 3- (5-bromo-2-pyridyl) -1-methyl-pyrimidine-2,4-dione and 3- (5-iodo-2-pyridyl) -1-methyl-pyrimidine-2,4-dione Synthesis of

To a DMF solution (5.0 ml) of the compound (0.22 g, 1.7 mmol) obtained in (Step 3), 5-bromo-2-iodopyridine (0.74 g, 2.6 mmol), copper iodide ( 0.50 g, 2.6 mmol) and triethylamine (1.0 ml, 6.9 mmol) were sequentially added, and the mixture was stirred at 140 ° C. for 18 hours. The reaction solution was cooled to room temperature, and water (25 ml) and dichloromethane (25 ml) were added. After filtration through celite and extraction twice with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound mixture (1: 1) (0.29 g).
(Process 5)
Synthesis of Methyl (2S) -2- (tert-butycarbonylcarbonyl) -3- [6- (3-methyl-2,6-dioxo-pyrimidin-1-yl) -3-pyridine] propanoate

Zinc powder (96 mg, 1.5 mmol) was suspended in DMF (2.0 ml), iodine (26 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. methyl (2R) -2- (tert-butycarbonylcarbonyl) -3-iodo-propanoate (0.19 g, 0.59 mmol) and iodine (26 mg, 0.10 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes.
In a separate container, the mixture (0.29 g) obtained in (Step 4) was placed and dissolved in DMF (1.0 ml). Tris (dibenzylideneacetone) dipalladium (0) (22 mg, 0.024 mmol) and SPhos (20 mg, 0.049 mmol) were sequentially added and stirred for 10 minutes. This mixed solution was added to the previously prepared mixed solution, degassed and purged with argon three times, and then stirred at 60 ° C. for 18 hours. The reaction solution was cooled to room temperature, and water (25 ml) and dichloromethane (25 ml) were added. After filtration through celite and extraction twice with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.21 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J = 2.3 Hz, 1H), 7.92-7.72 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 7.9 Hz, 1H), 4.35-4.20 (m, 1H), 3.64 (s, 3H), 3.31 (s, 3H), 3.11 (dd, J = 13.9 , 4.8 Hz, 1H), 2.94 (dd, J = 14.1, 10.6 Hz, 1H), 1.34 (s, 9H); MS (ESI) m / z 405 [M + H] ⁺ .
(Step 6)
Synthesis of Methyl (2S) -2-amino-3- [6- (3-methyl-2,6-dioxo-pyrimidin-1-yl) -3-pyridine] propanoate

The compound (0.21 g, 0.52 mmol) obtained in (Step 5) was dissolved in 1,4-dioxane (2.0 ml) and methanol (1.0 ml). 4M Hydrochloric acid / 1,4-dioxane solution (2.0 ml) was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure to give the hydrochloride of the title compound (0.18 g, quant.).
MS (ESI) m / z 305 [M + H] ⁺ .

The compound of [Synthesis Example 33] can be synthesized in the same manner as the compound of [Synthesis Example 32] by using thymine in (Step 1) of [Synthesis Example 32].

[Synthesis Example 33]
Isopropyl (2S) -2-amino-3- [6- (3,5-dimethyl-2,6-dioxo-pyrimidin-1-yl) -3-pyrylyl] propanoate

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (s, 3H), 8.45 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.1, 2.4 Hz, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 4.91 (p, J = 6.2 Hz, 1H), 4.40 (s, 1H), 3.29 (s, 3H), 3.24 (dd, J = 14.3, 5.9 Hz, 1H), 3.11 (dd, J = 14.3, 8.6 Hz, 1H), 1.83 (d, J = 1.0 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H), 1.06 ( d, J = 6.2 Hz, 3H); MS (ESI) m / z 437 [M + H] ⁺ .

The compound of [Synthesis Example 34] is the same as the compound of [Synthesis Example 31] by using 6- (ethoxymethyl) -1H-pyrimidine-2,4-dione in (Step 1) of [Synthesis Example 31]. It can synthesize | combine by the method of.

[Synthesis Example 34]
Methyl (2S) -2-amino-3- [4- [4- (ethoxymethyl) -3-methyl-2,6-dioxo-pyrimidin-1-yl] phenyl] propanoate

MS (ESI) m / z 362 [M + H] ⁺ .
[Synthesis Example 35]
Methyl (2S) -2-amino-3- [5- (3-methyl-2,6-dioxo-pyrimidin-1-yl) -2-pyrylyl] propanoate

[Synthesis Example 36]
Methyl (2S) -2-amino-3- [4- (3,5-dimethyl-2,6-dioxo-pyrimidin-1-yl) phenyl] propanoate

[Synthesis Example 37]
Methyl (2S) -2-amino-3- [5- (3,5-dimethyl-2,6-dioxo-pyrimidin-1-yl) -2-pyrylyl] propanoate

[Synthesis Example 38]
Isopropyl (2S) -2-amino-3- [4- (1,7-dimethyl-2,4-dioxo-6,8-dihydro-5H-pyrido [3,4-d] pyrimidin-3-yl) phenyl ] Propanoate

(Process 1)
Synthesis of Ethyl 1-benzyl-5-[(4-nitrophenoxy) carbonylamino] -3,6-dihydro-2H-pyridine-4-carboxylate

Ammonium acetate (5.2 g, 67 mmol) was added to an ethanol solution (20 ml) of hydrochloride of hydrochloride (2.0 g, 6.7 mmol) of Ethyl 1-benzyl-3-piperidine-4-carboxylate at room temperature, and 18% at room temperature. Stir for hours. The reaction solution was concentrated under reduced pressure, and dichloromethane and saturated multistory water were added. Extraction was performed twice with dichloromethane, and the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 ml). Pyridine (0.6 ml) was added, and 4-nitrophenyl chloroformate (1.4 g, 6.7 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.49 g, 16%).
(Process 2)
Synthesis of Isopropyl (2S) -3- (4-aminophenyl) -2- (tert-butoxycarbonylamino) propanoate

To a DMF solution (15 ml) of (2S) -2- (tert-butoxycarbonylamino) -3- (4-nitrophenyl) propanoic acid (2 g, 6.4 mmol), potassium carbonate (3 g, 22 mmol), and 2-iodopropane ( 2.0 ml) was sequentially added and stirred at room temperature for 18 hours. Water was added to the reaction solution, followed by extraction three times with a mixed solution of ethyl acetate and hexane (1: 1), and the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (40 ml) and water (4.0 ml). Zinc powder (3.5 g, 54 mmol) and ammonium chloride (0.52 g, 9.7 mmol) were sequentially added, and the mixture was stirred at 70 ° C. for 1 hour 30 minutes. The reaction solution was filtered through Celite and then concentrated under reduced pressure. The residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. The desired fraction was freeze-dried to obtain the trifluoroacetate salt of the title compound.
(Process 3)
isopropyl (2S) -3- [4- (7-benzyl-2,4-dioxo-1,5,6,8-tetrahydropyrido [3,4-d] pyrimidin-3-yl) phenyl] -2- (tert -Butoxycarbonylamino) propanoate synthesis

To a 1,4-dioxane solution (20 ml) of the compound (0.49 g, 1.2 mmol) obtained in (Step 1), the compound (0.50 g, 1.1 mmol) obtained in (Step 2), and DBU (0.42 ml) was sequentially added and stirred at 60 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added. Extraction was performed twice with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler and purified in the same manner as in (Step 2) to obtain the trifluoroacetate salt of the title compound (0.40 g, 51%).
(Process 4)
Isopropyl (2S) -3- [4- (7-benzyl-1,7-dimethyl-2,4-dioxo-6,8-dihydro-5H-pyrido [3,4-d] pyrimidin-7-ium-3 -Yl) phenyl] -2- (tert-butoxycarbonylamino) propanoate synthesis

To a DMF solution (3.5 ml) of the compound (0.40 g, 0.59 mmol) obtained in (Step 3), potassium carbonate (0.30 g, 2.2 mmol) and methyl iodide (0.22 ml, 3 0.5 mmol) was added sequentially, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, and purified by the same method as in (Step 2) to obtain the trifluoroacetate salt of the title compound (0 .30 g, 71%).
(Process 5)
Isopropyl (2S) -2-amino-3- [4- (1,7-dimethyl-2,4-dioxo-6,8-dihydro-5H-pyrido [3,4-d] pyrimidin-3-yl) phenyl ] Synthesis of propanoate

10% palladium carbon (50 mg) was added to an isopropyl alcohol solution (5.0 ml) of the compound (0.30 g, 0.43 mmol) obtained in (Step 4), and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. . The reaction solution was filtered through Celite and concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (2.0 ml) and isopropyl alcohol (1.0 ml). 4M Hydrochloric acid / 1,4-dioxane solution (2.0 ml) was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure to give the hydrochloride of the title compound (0.15 g, 74%).
MS (ESI) m / z 401 [M + H] ⁺

For the compounds of [Synthesis Example 39], [Synthesis Example 40], [Synthesis Example 42], and [Synthesis Example 44], the corresponding 1,2-ketoester reagent is used in (Step 1) of [Synthesis Example 38]. Thus, it can be synthesized in the same manner as in the compound of [Synthesis Example 38].

[Synthesis Example 39]
Isopropyl (2S) -2-amino-3- [4- (1,6-dimethyl-2,4-dioxo-7,8-dihydro-5H-pyrido [4,3-d] pyrimidin-3-yl) phenyl ] Propanoate

MS (ESI) m / z 401 [M + H] ⁺
[Synthesis Example 40]
Isopropyl (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-5,6,7,8-tetrahydroquinazolin-3-yl) phenyl] propanoate

MS (ESI) m / z 386 [M + H] ⁺

[Synthesis Example 41]
Methyl (2S) -2-amino-3- [4- (3,4-dimethyl-2,6-dioxo-pyrimidin-1-yl) phenyl] propanoate

[Synthesis Example 42]
Isopropyl (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-6,8-dihydro-5H-pyrano [3,4-d] pyrimidin-3-yl) phenyl] propanoate

MS (ESI) m / z 388 [M + H] ⁺

[Synthesis Example 43]
Methyl (2S) -2-amino-3- [6- (1-methyl-2,4-dioxo-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-3-yl) -3- pyrylyl] propanoate

(Process 1)
Synthesis of Ethyl 4-amino-3,6-dihydro-2H-pyran-5-carboxylate

Ammonium acetate (2.4 g, 31 mmol) was added to an ethanol solution (10 ml) of ethyl 4-oxotetrahydropyran-3-carboxylate (0.54 g, 3.1 mmol), and the mixture was stirred at 60 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane and saturated multistory water were added. Extraction was performed twice with dichloromethane, and the organic layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the title compound was obtained by concentration under reduced pressure (0.49 g, quant.).
(Process 2)
Synthesis of 1,5,7,8-tetrahydropyrano [4,3-d] pyrimidine-2,4-dione

Trichloroacetyl isocyanate (0.74 ml, 6.2 mmol) was added to an acetonitrile solution (6.0 ml) of the compound (0.49 g, 3.1 mmol) obtained in (Step 1), and the mixture was stirred at room temperature for 30 minutes. . The solid was collected by filtration and suspended in an 8M ammonia / methanol solution (5.0 ml). The mixture was stirred at 70 ° C. for 18 hours, and the solid was collected by filtration to give the title compound (0.30 g, 57%).
(Process 3)
Synthesis of 3- (5-bromo-2-pyridyl) -1,5,7,8-tetrahydropyrano [4,3-d] pyrimidine-2,4-dione

To the acetonitrile solution (10.0 ml) of the compound (0.53 g, 3.2 mmol) obtained in (Step 2), 5-bromo-2-iodopyridine (1.1 g, 3.7 mmol), copper iodide ( 0.30 g, 1.6 mmol) and DBU (0.93 ml, 6.4 mmol) were sequentially added, and the mixture was stirred at 70 ° C. for 18 hours. The reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC using ODS as a filler, and water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solution and lyophilization of the desired fraction (0.26 g, 26%).
(Process 4)
Synthesis of 3- (5-bromo-2-pyridyl) -1-methyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidine-2,4-dione
To a DMF solution (2.0 ml) of the compound (0.26 g, 0.80 mmol) obtained in (Step 3), potassium carbonate (0.33 g, 2.4 mmol) and methyl iodide (0.25 ml) were added. Sequentially added and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. Lyophilization gave the title compound (0.20 g, 74%).
(Process 5)
Methyl (2S) -2- (tert-butoxycarbonylamino) -3- [6- (1-methyl-2,4-dioxo-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-3-yl ) -3-pyridyl] propanoate synthesis

Zinc powder (0.12 g, 1.8 mmol) was suspended in DMF (2.0 ml), iodine (34 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. methyl (2R) -2- (tert-butycarbonylcarbonyl) -3-iodo-propanoate (0.23 g, 0.70 mmol) and iodine (34 mg, 0.13 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes.
In a separate container, the compound obtained in (Step 4) (0.20 g, 0.59 mmol) was placed and dissolved in DMF (1.0 ml). Tris (dibenzylideneacetone) dipalladium (0) (14 mg, 0.015 mmol) and SPhos (24 mg, 0.058 mmol) were sequentially added and stirred for 10 minutes. This mixed solution was added to the previously prepared mixed solution, degassed and purged with argon three times, and then stirred at 60 ° C. for 18 hours. After cooling the reaction solution to room temperature and concentrating under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. The desired fraction was lyophilized to give the title compound (0.12 g, 45%).
(Step 6)
Methyl (2S) -2-amino-3- [6- (1-methyl-2,4-dioxo-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-3-yl) -3- pyridyl] propanoate

The compound obtained in (Step 5) (0.12 g, 0.26 mmol) was dissolved in 1,4-dioxane (1.0 ml) and methanol (1.0 ml). 4M Hydrochloric acid / 1,4-dioxane solution (1.0 ml) was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure to give the hydrochloride of the title compound (0.10 g, quant.).
MS (ESI) m / z 361 [M + H] ⁺

[Synthesis Example 44]
Isopropyl (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-3-yl) phenyl] propanoate

MS (ESI) m / z 388 [M + H] ⁺
[Synthesis Example 45]
Methyl (2S) -2-amino-3- [4- (6-methoxy-1-methyl-2,4-dioxo-pyrido [3,4-d] pyrimidin-3-yl) phenyl] propanoate

The compound of [Synthesis Example 46] and [Synthesis Example 47] is obtained by using 6-methyluracil or 5,6-dimethyluracil in [Step 3] of [Synthesis Example 43]. It can be synthesized by a method similar to that of the compound.

[Synthesis Example 46]
Methyl (2S) -2-amino-3- [6- (3,4-dimethyl-2,6-dioxo-pyrimidin-1-yl) -3-pyrylyl] propanoate

MS (ESI) m / z 319 [M + H] ⁺
[Synthesis Example 47]
Methyl (2S) -2-amino-3- [6- (3,4,5-trimethyl-2,6-dioxo-pyrimidin-1-yl) -3-pyrylyl] propanoate

MS (ESI) m / z 333 [M + H] ⁺

[Synthesis Example 48]
Isopropyl (2S) -2-amino-3- [5- (1-methyl-2,4-dioxo-5,6,7,8-tetrahydroquinazolin-3-yl) -2-pyrylyl] propanoate

(Process 1)
Synthesis of Ethyl 2-[(4-nitrophenoxy) carbonyllamino] cyclohexene-1-carboxylate

Ethyl 2-oxocyclohexane carbonate (1.5 mL, 8.823 mmol) was dissolved in methanol (90 mL). Ammonium acetate (6.80 g, 88.23 mmol) was added to the solution and stirred at 60 ° C. for 14 hours. After removing the solvent of the reaction solution under reduced pressure, ethyl acetate was added to the residue, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and the obtained organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue was dissolved in dichloromethane (45 mL). After adding pyridine (0.86 mL, 10.65 mmol) to the solution and cooling to 0 ° C., (4-nitrophenyl) carbonochloridate (1.879 g, 9.322 mmol) was added and stirred for 14 hours while gradually returning to room temperature. did. The solvent of the reaction solution was removed under reduced pressure, and the obtained residue was purified using silica gel column chromatography (SiO2, hexane / ethyl acetate) to give the title compound as a pale yellow solid (2.72 g, 94.0). %).
MS (ESI) m / z 335 [M + H] +
(Process 2)
Synthesis of 3- (6-bromo-3-pyridyl) -5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione

The compound obtained in (Step 1) (1.47 g, 4.401 mmol) was dissolved in 1,4-dioxane (45 mL), and 6-bromopyridin-3-amine (0.795 g, 4.621 mmol) and 1, 8-diazabiccyclo [5.4.0] undec-7-ene (1.31 mL, 8.802 mmol) was added, and the mixture was stirred at room temperature for 17 hours. After removing the solvent of the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase HPLC using ODS as a filler and purified in the same manner as in (Synthesis Example 1) (Step 2) to give the title compound. (719 mg, 30.2%) was obtained.
MS (ESI) m / z 322 [M + H] +
(Process 3)
Synthesis of 3- (6-bromo-3-pyridyl) -1-methyl-5,6,7,8-tetrahydroquinazoline-2,4-dione

The compound obtained in (Step 2) (719 mg, 2.232 mmol) is dissolved in dimethylformamide (8 mL), and potassium carbonate (770 mg, 5.580 mmol) and methyl iodide (207 uL, 3.348 mmol) are added to room temperature. For 3 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the insoluble matter, the solvent was removed under reduced pressure to obtain a residue. The obtained residue was subjected to reverse phase HPLC using ODS as a filler and purified in the same manner as in (Synthesis Example 1) (Step 2) to give the title compound (269 mg, 35.9%). Obtained.
MS (ESI) m / z 336 [M + H] +
(Process 4)
Isopropyl (2S) -2- (tert-butyoxycarbonylamino) -3- [5- (1-methyl-2,4-dioxo-5,6,7,8-tetrahydroquinazolin-3-yl) -2-pyrylyl] propanoate Composition

Zinc powder (157 mg, 2.40 mmol) was suspended in DMF (2.0 ml), iodine (46.3 mg, 0.18 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Methyl (2R) -2- (tert-butycarbonylcarbonyl) -3-iodo-propanoate (269 mg, 0.801 mmol) and iodine (46.3 mg, 0.18 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes.
In a separate container, the compound obtained in (Step 3) (256 mg, 0.801 mmol) was placed and dissolved in DMF (2.0 ml). Tris (dibenzylideneacetone) dipalladium (0) (18.3 mg, 0.020 mmol) and SPhos (32.9 mg, 0.0801 mmol) were sequentially added and stirred for 10 minutes. This mixed solution was added to the previously prepared mixed solution, degassed and purged with argon three times, and then stirred at 60 ° C. for 15 hours. The reaction solution was cooled to room temperature, and water (25 ml) and dichloromethane (25 ml) were added. After filtration through celite and extraction twice with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (223 mg, 57.3%).
MS (ESI) m / z 487 [M + H] +
(Process 5)
Synthesis of Isopropyl (2S) -2-amino-3- [5- (1-methyl-2,4-dioxo-5,6,7,8-tetrahydroquinazolin-3-yl) -2-pyrylyl] propanoate hydrochloride

The compound obtained in (Step 4) (223 mg, 0.459 mmol) was dissolved in ethyl acetate (3 mL). A 4N hydrochloric acid / ethyl acetate solution (1.2 mL) was added to the solution, and the mixture was stirred at room temperature for 7 hours. After removing the solvent under reduced pressure, the title compound (219 mg, quant.) Was obtained by lyophilization.
MS (ESI) m / z 387 [M + H] +

[Example 1]
(2S) -2-[[4-[[4- (tert-butylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoyl] amino] -3- [6- (1-methyl-2,4-dioxo -Pyrido [3,4-d] pyrimidin-3-yl) -3-pyrylyl] propanoic acid

(Process 1)
Methyl (2S) -2-[[4-[[4- (tert-butylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoyl] amino] -3- [6- (1-methyl-2,4- synthesis of dioxo-pyrido [3,4-d] pyrimidin-3-yl) -3-pyrylyl] propanoate

In a DMF solution (1.5 ml) of the compound of [Synthesis Example 1] (40 mg, 0.097 mmol) and the hydrochloride of the compound of [Synthesis Example 29] (42 mg, 0.11 mmol), HATU (44 mg, 0.12 mmol) was added. ) And N, N-diisopropylamine (58 μl, 0.34 mmol) were sequentially added and stirred at room temperature for 5 hours.
Concentrate under reduced pressure, subject the residue to reverse phase HPLC using ODS as a filler, elute with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid, and freeze-dry the desired fraction. This gave the title compound (47 mg, 67%).
(Process 2)
(2S) -2-[[4-[[4- (tert-butylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoyl] amino] -3- [6- (1-methyl-2,4-dioxo Synthesis of pyrido [3,4-d] pyrimidin-3-yl) -3-pyrylyl] propanoic acid

To a 1,4-dioxane solution (1.0 ml) of the compound (47 mg, 0.063 mmol) obtained in (Step 1), water (1.0 ml) and 1M aqueous sodium hydroxide solution (0.19 ml) were added. Sequentially added and stirred at room temperature for 5 hours. After neutralizing with 1M hydrochloric acid and concentrating under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, and a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. And the desired fraction was lyophilized to give the title compound (40 mg, 87%).
1H NMR (400 MHz, DMSO-d6) δ 10.92 (brs, 1H), 8.99 (s, 1H), 8.69 (dd, J = 8.1, 2.2 Hz, 1H), 8.57 (d, J = 5.0 Hz, 1H) , 8.46 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.97-7.81 (m, 6H), 7.40 (d, J = 8.0 Hz, 1H), 7.32-7.17 (m, 2H), 4.72-4.63 (m, 1H), 3.60 (s, 3H), 3.33-3.26 (m, 1H), 3.14-3.04 (m, 1H), 1.35 (s, 9H) .; MS (ESI) m / z 736 [M + H] +

The compound shown in Table 1 is any one selected from [Synthesis Example 1] to [Synthesis Example 27], any carboxylic acid intermediate, and [Synthesis Example 28] to [Synthesis Example 48]. Can be synthesized in the same manner as the compound of [Example 1].

[Example 2]
Isopropyl (2S) -2-[[4-[[4- (tert-butylcarbamoyl) phenyl] sulfonylamino] -2,5-difluoro-benzoyl] amino] -3- [4- (1-methyl-2,4- dioxo-pyrido [3,4-d] pyrimidin-3-yl) phenyl] propanoate

A solution of A4 (35 mg, 0.048 mmol) in isopropyl alcohol (2.0 ml was added with 4M hydrochloric acid / 1,4-dioxane solution (1.0 ml) and stirred for 5 hours at 60 ° C. The reaction solution was allowed to reach room temperature. After cooling and concentration under reduced pressure, the residue was subjected to reverse phase HPLC using ODS as a filler, eluting with a mixed solution of water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. Fractions were lyophilized to give the title compound (34 g, 91%).

The compound shown in Table 2 is a method similar to the compound of [Example 2] by using any sulfonamide derivative selected from A1 to A58 and the corresponding alcohol (isopropyl alcohol or cyclohexyl alcohol). Can be synthesized.

Test example 1
(1) VCAM-1 / α4β1 integrin binding inhibitory activity evaluation test Measures the ability of a test substance to inhibit binding of human T cell line Jurkat, which is known to express α4β1 integrin, to VCAM-1 did.
To a 96-well microtiter plate, 50 μL / well of recombinant human VCAM-1 / Fc (R & D systems) solution (1 μg / mL) diluted with buffer A (carbonate buffer, pH 9.6) was added at 4 ° C. Incubated overnight. After washing once with PBS, Block Ace (Snow Brand Milk Products) was added at 150 μL / well and incubated at room temperature for 2 hours.
After removal, washing was performed once with PBS.
Various concentrations of test substances diluted in binding buffer (DMEM containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl ₂ ) and Jurkat cells (2 × 10 ⁶ cells / mL) were 100 μL each of VCAM-1 / Fc Was added to the coated plate (5 × 10 ⁵ cells / well) and incubated at 30 ° C. for 15-30 minutes. After binding the cells to the wells, unbound cells were removed by washing with PBS. Buffer C (PBS containing 1.5% Triton X-100) was added to the plate at 50 μL / well to lyse the bound Jurkat cells. 30 μL of Substrate Buffer (Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay) was added to 30 μL of the cell lysate and allowed to react at room temperature in the dark for 30 minutes. 30 μL each of Stop Solution (Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay) was added, and the absorbance at 490 nm was measured using a plate reader. The absorbance obtained here was obtained by detecting lactate dehydrogenase (LDH) activity eluted in the supernatant of each well, that is, proportional to the number of Jurkat cells remaining on the plate after binding to VCAM-1. To do. The test was performed in duplicate, and the cell binding rate at various concentrations when the absorbance of wells not containing the test substance was taken as 100% was determined, and the concentration IC ₅₀ that caused 50% binding inhibition was calculated. The results obtained are summarized in Table 3.

Test example 2
(2) MAdCAM-1 / α4β7 integrin binding inhibitory activity evaluation test Ability of test substance to inhibit binding of human B cell line cell line RPMI-8866 known to express α4β7 integrin to MAdCAM-1 Was measured.
50 μL / well of a recombinant mouse MAdCAM-1 / Fc (R & D systems) solution (1 μg / mL) diluted with buffer A (carbonate buffer, pH 9.6) was added to a 96-well microtiter plate at 4 ° C. Incubated overnight. After washing once with PBS, Block Ace (Snow Brand Milk Products) was added at 150 μL / well and incubated at room temperature for 2 hours. After removal, washing was performed once with PBS.
Various concentrations of test substances diluted in binding buffer (DMEM containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl ₂ ) and RPMI-8866 cells (2 × 10 ⁶ cells / mL) in 100 μL MAdCAM-1 / Fc was added to the coated plate (5 × 10 ⁵ cells / well) and incubated at 30 ° C. for about 60 minutes. After binding the cells to the wells, unbound cells were removed by washing with PBS. Buffer C (PBS containing 1.5% Triton X-100) was added to the plate at 50 μL / well to lyse bound RPMI-8866 cells. 30 μL of Substrate Buffer (Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay) was added to 30 μL of the cell lysate and allowed to react at room temperature in the dark for 30 minutes. 30 μL each of Stop Solution (Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay) was added, and the absorbance at 490 nm was measured using a plate reader. The absorbance obtained here was obtained by detecting the lactate dehydrogenase (LDH) activity eluted in the supernatant of each well, that is, the number of RPMI-8866 cells remaining on the plate after binding to MAdCAM-1. Is proportional to The test was performed in duplicate, and the cell binding rate at various concentrations when the absorbance of wells not containing the test substance was taken as 100% was determined, and the concentration IC ₅₀ that caused 50% binding inhibition was calculated. The results obtained are summarized in Table 3.

Test example 3
(3) MAdCAM-1 / α4β7 integrin binding inhibitory activity evaluation test in the presence of serum (1)
The ability of test substances to inhibit binding of human B cell line cell line RPMI-8866, known to express α4β7 integrin, to MAdCAM-1 was determined.
50 μL / well of a recombinant mouse MAdCAM-1 / Fc (R & D systems) solution (1 μg / mL) diluted with buffer A (carbonate buffer, pH 9.6) was added to a 96-well microtiter plate at 4 ° C. Incubated overnight. After washing once with PBS, Block Ace (Snow Brand Milk Products) was added at 150 μL / well and incubated at room temperature for 2 hours. After removal, washing was performed once with PBS.
Various concentrations of test substances and RPMI-8866 cells (2 × 10 ⁶ cells / mL) diluted in binding buffer (DMEM containing 40 mM HEPES, 0.2% BSA and 4 mM MnCl ₂ ) were added at 50% final concentration. 100 μL each was added to a plate coated with MAdCAM-1 / Fc to contain human serum (7.5 × 10 ⁵ cells / well) and incubated at 30 ° C. for about 60 minutes. After binding the cells to the wells, unbound cells were removed by washing with PBS. Buffer C (PBS containing 1.5% Triton X-100) was added to the plate at 50 μL / well to lyse bound RPMI-8866 cells. 30 μL of Substrate Buffer (Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay) was added to 30 μL of the cell lysate and allowed to react at room temperature in the dark for 30 minutes. 30 μL each of Stop Solution (Promega, CytoTox 96 Non-Radioactive Cytotoxicity Assay) was added, and the absorbance at 490 nm was measured using a plate reader. The absorbance obtained here was obtained by detecting the lactate dehydrogenase (LDH) activity eluted in the supernatant of each well, that is, the number of RPMI-8866 cells remaining on the plate after binding to MAdCAM-1. Is proportional to The test was performed in duplicate, and the cell binding rate at various concentrations when the absorbance of wells not containing the test substance was taken as 100% was determined, and the concentration IC ₅₀ that caused 50% binding inhibition was calculated. The results obtained are summarized in Table 3.

As a result of comparison with the results of Test Example (1) and Test Example (2), it was found that the compound of the present invention has high selectivity such that the effect on α4β1 is low and the effect on α4β7 is high. . Thus, the high selectivity for α4β1 is low and the effect is high for α4β7 reduces the effect on α4β1 which suppresses the infiltration of lymphocytes around the whole body and is expressed specifically in the intestinal tract. Since the action on α4β7 can be greatly suppressed, there is an advantage that the adaptive disease can be treated more efficiently.

Test example 4
(4) MAdCAM-1 / α4β7 integrin binding inhibitory activity evaluation test in human whole blood The binding inhibitory activity of T cell α4β7 integrin and MAdCAM-1 in human whole blood was measured by a test substance. Blood samples were obtained by donating blood from healthy volunteers.
4 mM MnCl2 solution and various test substance dilutions were added to human whole blood and incubated for 10 minutes. 10 μg / mL recombinant mouse MAdCAM-1 / Fc (R & D Systems) was added and incubated for a total volume of 50 μL for 30 minutes. 950 μL of Lyse / Fix (BD Biosciences) was added, and hemolysis and fixation were performed at 37 ° C. for 10 minutes. After centrifugation for 5 minutes, the supernatant was removed, and 600 μL of 10% inactivated fetal bovine serum-added RPMI-1640 medium (hereinafter referred to as medium) was added. After centrifugation for 5 minutes, the supernatant was removed and washed. After washing with the medium again, 0.625 μg / mL Rat Anti-Mouse MAdCAM-1 antibody (Southern Biotech) was added and incubated for 30 minutes or more. After washing with the medium, 50 μg / mL Goat Anti-Rat IgG (H + L) Antibody, FITC (Life Technologies) was added and incubated for 30 minutes or more. After washing with the medium, 10 μg / mL PE Rat Anti-Mouse CD4 (BD Pharmigen) was added and incubated for 30 minutes or more. After washing with the medium, the ratio of the MAdCAM-1-positive cell ratio in the CD4-positive cells was measured using flow cytometry.
Tests are based on the results of independent tests using 2 to 3 different blood samples. From wells containing no test substance, the absence of ligand is 100% inhibition and the presence of ligand is 0% inhibition. The inhibition rate of MAdCAM-1 binding was determined and the concentration IC ₅₀ resulting in 50% binding inhibition was calculated.

Test Example 5
The mouse portal vein concentration of the test substance was measured and the oral absorbability was evaluated.
The test substance was dissolved or uniformly suspended in a 0.5% (w / v) aqueous solution of methylcellulose, and 3 compounds (3 mg / 10 mL / kg) were added to female mice (BALB / cAnNCrlCrlj, 7-9 weeks old) using a gastric tube. ) Was orally administered in a cassette.
30 minutes after administration, the abdomen was opened under isoflurane anesthesia, and about 0.2 mL of blood was collected from the portal vein using a syringe treated with DDVP (esterase inhibitor) and heparin sodium, and stored on ice.
The collected blood was centrifuged at 18,000 g × 3 minutes using a refrigerated centrifuge to obtain a plasma sample. After extracting the test substance with acetonitrile, the plasma concentration was quantified by LC / MS / MS.
The plasma concentration was the sum of the test substance and its active metabolite. The calculated plasma concentrations are shown in Table 5.

Claims (18)

1. A sulfonamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
   

   

   (In the formula
   

   

   Represents a single bond or a double bond,
   R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, lower alkenyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, hydroxy group, or a hydroxy lower alkyl group, R ₁ And R ₂ are bonded to each other to form a benzene ring which may have a substituent, an alicyclic hydrocarbon having 4 to 7 carbon atoms which may have a substituent, or a heteroaryl ring which may have a substituent Or may form a heterocyclic ring which may have a substituent,
   R ₃ represents a lower alkyl group,
   e, f, g, and h each independently represent C—H or a nitrogen atom;
   B represents a hydroxy group, an alkoxy group having 1 to 10 carbon atoms, an —O-heterocyclic group, a cilexetyloxy group, or a medoxomiloxy group;
   D represents a benzene ring or a heteroaryl ring which may have a substituent,
   R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a phenyl group which may have a substituent, Or it represents the heterocyclic group which may have a substituent, R < ₄ > and R < ₅ > may couple | bond together and it may form the heterocyclic ring which may have a substituent. )
2. 

   The sulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a double bond.
3. R ₁ and R ₂ are bonded to each other to form a benzene ring which may have a substituent, an alicyclic hydrocarbon having 4 to 7 carbon atoms which may have a substituent, or a hetero ring which may have a substituent. An aryl ring or a heterocyclic ring which may have a substituent is formed, and the substituent is a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and a lower alkylamino. The sulfonamide derivative according to claim 1 or 2, which is selected from lower alkyl groups, or a pharmaceutically acceptable salt thereof.
4. R ₁ and R ₂ each independently represents a hydrogen atom, a lower alkyl group, or a lower alkoxymethyl group, and R ₁ and R ₂ may be bonded to each other to have a substituent. 7 an alicyclic hydrocarbon, a heteroaryl ring which may have a substituent, or a heterocycle which may have a substituent may be formed, and the substituent may be a lower alkyl group and a lower alkoxy group. The sulfonamide derivative according to claim 1 or 2, which is selected from a group, or a pharmaceutically acceptable salt thereof.
5. The sulfonamide derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₂ each independently represents a hydrogen atom, a lower alkyl group, or a lower alkoxymethyl group. .
6. R ₁ and R ₂ may be bonded to each other to have an optionally substituted cyclohexene, an optionally substituted pyridine, an optionally substituted dihydropyran, or an optionally substituted group. 3. A good tetrahydropyridine is formed, and the substituent is selected from a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a lower alkylamino group, and a lower alkylamino lower alkyl group. Or a pharmaceutically acceptable salt thereof.
7. The sulfonamide derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein e represents a nitrogen atom, and f, g, and h represent C—H.
8. The sulfonamide derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein B represents a hydroxy group or an alkoxy group having 1 to 6 carbon atoms.
9. The sulfonamide derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, wherein the substituent of D is selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group.
10. 9. D represents an optionally substituted benzene ring, and the substituent is selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group. Sulfonamide derivatives, or pharmaceutically acceptable salts thereof.
11. R ₄ and R ₅ are each independently a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, a phenyl group that may have a substituent, Alternatively, it represents a heterocyclic group which may have a substituent, and the substituent is selected from a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, and a heterocyclic group. R ₄ and R ₅ may combine to form a heterocyclic group which may have a substituent, and the substituent is selected from a lower alkyl group, a lower alkoxy group and a hydroxy group The sulfonamide derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
12. R ₄ and R ₅ each independently represents a hydrogen atom, a lower alkyl group which may have a substituent, or a heterocyclic group which may have a substituent, wherein the substituent is a halogen atom , A cyano group, a hydroxy group, a lower alkoxy group, a trifluoromethyl group, and a heterocyclic group, and R ₄ and R ₅ may be bonded to each other to have a lower alkyl group as a substituent. The sulfonamide derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
13. R ₁ and R ₂ each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkoxy lower alkyl group, and R ₁ and R ₂ are bonded to form an alicyclic group having 4 to 7 carbon atoms. May form a hydrocarbon, heteroaryl ring, or heterocycle optionally substituted with a lower alkyl group,
    D represents a benzene ring or a heteroaryl ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, and R ₄ and R ₅ are each independently Represents a hydrogen atom or a lower alkyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a heterocyclic group, a hydroxy group, a cyano group and a halogen atom, provided that R ₄ and R _{4 5} may be bonded to form a heterocyclic group which may be substituted with a lower alkyl group;
    However,
    When D represents a benzene ring substituted with a halogen atom, R ₁ and R ₂ each represent a lower alkyl group,
    When D is a benzene ring having a lower alkyl group, a lower alkoxy group or a hydroxy group as a substituent, the substituent is bonded to D at a carbon atom adjacent to the carbon atom bonded to S;
    When R ₄ or R ₅ represents a lower alkyl group substituted with a hydroxy group, the lower alkyl group substituted with the hydroxy group is represented by the following formula (a) or (b):
    

    

    However, when R ₄ or R ₅ is represented by the formula (b), R ₁ and R ₂ each represent a lower alkyl group,
    The sulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein when R ₄ or R ₅ is a lower alkyl group substituted with a cyano group, D represents a benzene ring.
14. The sulfonamide derivative according to claim 1, which is represented by the following formula, or a pharmaceutically acceptable salt thereof.
    

    

    (Wherein R1, R2, R3, e, f, g, h and B are as defined in claim 1).
15. The sulfonamide derivative according to claim 1, which is represented by the following formula, or a pharmaceutically acceptable salt thereof.
    

    

    (Wherein B is as defined in claim 1)
16. A pharmaceutical composition comprising the sulfonamide derivative according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.
17. A therapeutic or prophylactic agent for inflammatory diseases in which an α4β7 integrin-dependent adhesion process involving the sulfonamide derivative according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof is involved in a disease state.
18. An α4β7 integrin inhibitor comprising the sulfonamide derivative according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.