KR100213510B1 - Imidazopyridine derivatives and their use - Google Patents

Abstract

Triethylamine in a suspension of 5-mercaptoimidazo [1,2-a] pyridine (5.02 g, 33.4 mmol) and 1-bromo-3-chloropropane (5.26 g, 33.4 mmol) in ethanol (100 ml) (4.66 ml, 33.4 mmol) is added and the mixture is stirred at rt for 17 h. After distilling off the solvent, chloroform is added to the residue, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 5.46 g (72.0%, light brown oily product) of the desired product.

Description

Imidazo pyridine derivatives and uses thereof

The present invention relates to imidazo pyridine derivatives and their use. In particular, the present invention relates to imidazo [1,2-a] pyridine derivatives useful as medicaments and calmodulin inhibitors containing the derivatives.

In recent years, various cerebrovascular anemia or cardiovascular anemia diseases have increased with the increase of the elderly population. Currently, calcium channel blocker, one of the medicines for treating this disease, has been widely used clinically, and cerebrovascular disease caused by hypertension has been reduced. However, cardiovascular anemia has not been reduced, and there is a need for the development of medicines with excellent mechanism activity.

On the other hand, chlorpromazine, which has an inhibitory activity against intracellular calcium-binding protein calmodulin, has been reported to be effective in experimental anemia. [G. E. Thomas, S. Levitsky and H. Feinberg, J. Med. Cell Cardiol., 15, 621 (1983); J. I. Dahlager and T. Bilde, Scand. J. Urol Nephrol., 10, 126 (1976); And in K. R. Chien, J. Adams, R. G. Pfan and J. L. Farber, Am. J. Pathol., 88 539 (1977). And it has also been reported that calmodulin plays an important role in anemia [S. W. Schaffer, R. S. Roy and J. M. McMcord, Eur. Heart J., 4 (Suppl. H), 81 (1983)]. However, phenothiadines such as chlorpomarine have a strong central nerve inhibitory activity, and therefore have disadvantages in use as a medicine for circulatory machines. Therefore, there is a need for development of better calmodulin inhibitors.

There are many reports on imidazo [1,2-a] pyridine derivatives. However, there are few reports on the pharmacological activity of compounds in which a hydrocarbon with functional groups binds to position 5 via S, S (O), S (O) ₂ , O or N. For example, European patent application P87108189.9 reports such compounds as starting materials for the synthesis of cefem compounds. Japanese Patent Laid-Open Nos. 277393/1987 and 10792/1988 report it as a cefem compound. EP-1-6614 and DE280938 report as hypotensive agents. However, none of them are intervening the inhibitory activity which is calmodul.

Under these circumstances, the present inventors are concerned with the synthesis and activity of imidazo [1,2-a] pyridine derivatives in which a hydrocarbon group having a functional group binds to position 5 via S, S (O), S (O) ₂ , O or N. Has been intensively studied. As a result, certain derivatives with excellent calmodulin suppression activity have been found. Thus, this invention was completed.

According to the present invention there is provided a calmodulin inhibitor composition comprising a compound of formula (I) or a salt thereof (including a solvate).

[Formula I]

Wherein X is S, S (O), S (O) ₂ , O or NR ³ (R ³ is hydrogen or optionally substituted hydrocarbon group); A may also contain ether oxygen in any possible position, and ₁ ~ C ₁₅ hydrocarbon group which may have a bivalent substituent in a part of the hydrocarbon-based group; B is an acylated amino group or an acylated hydroxy group or an etherified hydroxy group and the nitrogen atom of the amino group of B may form a ring together with the carbon atom of A or R ³ ; R ¹ and R ² are the same or different and are hydrogen, optionally substituted hydrocarbon group, halogen, nitro group, nitroso group, optionally protected amino group, lower alkoxycarbonyl group or lower alkyl carbamoyl group.

In formula (I), X is S, S (O), S (O) ₂ , O or NR ³ (R ³ is hydrogen or optionally substituted hydrocarbon group). Preferably X is S or O. Examples of the optionally substituted hydrocarbon group represented by R ³ are a lower alkyl group, an aralkyl group and the like.

An example of one of the ether may contain an oxygen and a hydrocarbon group ₁ ~ C ₁₅ divalent hydrocarbon group which may have a substituent of a part of the represented by A in any possible position is a group represented by the formula:

Wherein L, m and n are each an integer from 0 to 5; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen, an optionally substituted loweralkyl, aralkyl or aryl group R ⁴ and R ⁵ , R ⁶ and R ⁷ or R ⁸ and R ⁹ may be bonded together to form a ring, or R ⁴ or R ⁶ may be combined together with R ⁸ or R ⁹ to form a ring.) , A group represented by the following formula or a group represented by the following formula:

(Wherein o and p are each an integer of 0 to 5).

Examples of the optionally substituted hydrocarbon group represented by R ¹ and R ² include an optionally substituted lower alkyl, aralkyl or aryl group.

Examples of the acylated amino group represented by B include a group represented by the formula of -NR ¹⁰ R ¹¹ .

[Wherein, R ¹⁰ is hydrogen, optionally substituted alkyl, aralkyl or aryl group, or the following formula:

-CO-R ¹² (wherein R ¹² is hydrogen or optionally substituted alkyl, aralkyl or aryl group), -SO ₂ R ¹³ (wherein R ¹³ is optionally substituted alkyl, aralkyl or aryl group) , -CO-NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are hydrogen or an optionally substituted alkyl, aralkyl or aryl group and R ¹⁴ and R ¹⁵ may be bonded together to form a ring) or -CS- NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same as defined above); R ¹¹ is the following formula; -CO-R ¹⁶ (wherein R ¹⁶ is an optionally substituted alkyl, aralkyl or aryl group), -COOR ¹⁶ (R ¹⁶ is as defined above), -SO ₂ R ¹⁷ (wherein R ¹⁷ is optionally substituted) One alkyl, aralkyl or aryl group, -CO-NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are as defined above, or -CS-NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are Same as the definition); R ¹⁰ may be combined with R ³ , R ⁴ , R ⁶ , R ⁸ , R ¹¹ , R ¹⁶ or R ¹⁷ to form a ring. Examples of acylated or etherified hydroxy groups include the following formulas; A group represented by -OR ¹⁸ wherein R ¹⁸ is an optionally substituted alkyl, aralkyl or aryl group, or a group represented by the following formula; -CO-NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same as defined above) or -CO-R ¹⁹ (wherein R ¹⁹ is an optionally substituted alkyl, aralkyl or aryl group).

As a lower alkyl group in each substituent in Formula (I), C1-C6 linear form, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, or There is a branched alkyl group. The alkyl group may have an unsaturated bond, and examples of the unsaturated alkyl group include an alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, and 3-butenyl. Lower alkyl groups include one to four halogen, nitro, amino, lower alkylamino, cyclic amino, lower alkoxy, aryloxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxycarbonoyl, and the like. It may have a substituent. Examples of halogens include fluorine, bromine, chlorine and iodine.

Examples of the lower alkylamino group as the substituent include an N-monoalkylamino group having 1 to 6 carbon atoms such as methylamino, ethylamino, propylamino and butylamino, and an alkyl portion of dimethylamino, diethylamino, dibutylamino, It contains C1-C6 N, N-dialkylamino groups, such as methyl ethyl amino.

Examples of the cyclic amino group as the substituent include 4-7 membered cyclic amino groups such as N-pyrrolidinyl, piperidino, piperazinyl, morpholino and homopiperazino.

Examples of the lower alkoxy group as the substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy.

Examples of the aryloxy group as the above substituent include a C ₆ ~ ₁₀ aryloxy, such as phenoxy, 1-naphthoxy, 2-naphthoxy.

Examples of the lower alkoxycarbonyl group as the substituent include an alkoxycarbonyl group having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.

Examples of lower alkylcarbamoyl groups as the substituent include N-monoalkylcarbamoyl groups and alkyl moieties having 1 to 6 carbon atoms such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and butylcarbamoyl. N, N-dialkylcarbamoyl groups having 1 to 6 carbon atoms, such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl and methylethylcarbamoyl.

As the alkyl group of formula (I), for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, Octadecyl, nonadecyl, eicosanyl, henicosanyl, docosanyl, tricosanyl, tetracosanyl, pentacosanyl, hexacosanyl, heptaconic acid, octacosanyl, nonacosanyl, triacontanyl, farnesyl, Linear or branched alkyl groups having 1 to 30 carbon atoms, preferably 1 to 10 carbon atoms such as dihydrophytyl; Cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; Norbornyl, bicyclo [2. 2. 2] octyl, bicyclo [3. 3. 1] nonyl, bicyclo [3. 3. 0] octyl, perhydropentalenyl, perhydroindenyl, perhydroazulenyl, perhydrocyclopentacyclooctenyl, perhydronaphthyl, perhydrobenzocycloheptenyl, perhydrobenzocyclooctenyl, Saturated bicyclic hydrocarbon groups formed by bonding a 5 to 8 membered ring with each other such as perhydroheptalenyl and perhydrocycloheptacyclooctenyl; And saturated tricyclic hydrocarbon groups formed by combining 5- to 8-membered rings with each other such as adamantyl perhydroindasenyl (as, s), perhydroacenaphthyl enyl, perhydrophenmantril, and perhydroantryl; have.

The alkyl group may have an unsaturated bond, and examples of the alkyl group having an unsaturated bond include alkenyl groups having 2 to 30 carbon atoms, such as vinyl, allyl, and 9-octadecenyl; Cycloalkenyl groups having 5 to 8 carbon atoms such as cyclopentenyl and cyclohexenyl; Bicyclo [2. 2. 2] oct-2-enyl, in single (eg 1-in single, 2-in single, etc.), indenyl (eg 1H-inden-1-yl, 1H-inden-2-yl, 1H-indene) -3-yl, etc.), dihydronaphthyl (eg, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, etc.), tetrahydronaphthyl (eg, 5,6 , 7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, etc., 5H-benzocycloheptenyl (e.g. 5H-5-benzocycloheptenyl, 5H -8-benzocycloheptenyl, etc.), dihydro-5H-benzocycloheptenyl (eg, 6,7-dihydro-5H-8-benzohydrocycloheptenyl, etc.), tetrahydrobenzocyclooctenyl (eg, Unsaturated bicyclic hydrocarbon groups such as 5,6,7,8-tetrahydro-9-benzocyclooctenyl and the like; Unsaturated tricyclic hydrocarbon groups such as acenaphthenyl (eg, 1-acenaphthenyl) and tetrahydroantryl (eg, 1,2,3,4-tetrahydro-1-antryl and the like).

The alkyl group having 1 to 30 carbon atoms and the alkenyl group having 2 to 30 carbon atoms include a cycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopropyl), phenyl, naphthyl, halogen (e.g., Br, Cl, etc.), cyano, oxo And, for example, about 1 to 4 carbon atoms, such as a lower alkoxy group, preferably substituted with one or two substituents. As a substituent of the alkyl and alkenyl group, the phenyl group may be substituted with 1 to 4 substituents such as a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms, hydroxy, nitro and halogen.

The cycloalkyl group, the bicyclic hydrocarbon group, the tricyclic hydrocarbon group and the group having an unsaturated bond included in the alkyl group include lower alkyl group, halogeno lower alkyl group, hydroxy lower alkyl group, acyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy group, Halogeno lower alkoxy group, lower alkoxycarbonyl-lower alkoxy group, lower alkenyloxy group, aralkyloxy group, lower alkoxy-lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, carbamoyl group, N, N-di lower alkylalkylbamo Diary, N-lower alkylcarbamoyl group, halogen, cyano, nitro, hydroxy, acyloxy group, amino group, lower alkylsulfonylamino group, acylamino group, lower alkoxycarbonylamino group, acyl group, mercapto, lower alkyl tea 1-4, preferably 1 or 2 substituents, such as a group, a lower alkyl sulfinyl group, a lower alkyl sulfonyl group, oxo, etc. can be substituted. When they are substituted with two or more substituents, the substituents may be the same or different.

Examples of the lower alkyl group as the substituent include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like.

As a halogeno lower alkyl group, there exists a C1-C6 alkyl group substituted by 1-3 halogen atoms, such as trifluoromethyl, fluoromethyl, chloroethyl, fluoroethyl, for example.

As a hydroxy lower alkyl group, there exists a C1-C6 hydroxy alkyl group, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, for example.

As an acyloxy lower alkyl group, there exists a C1-C6 alkyl group substituted by C2-C6 lower alkanoyloxy or benzoyloxy group, such as acetoxy ethyl and benzoyloxy ethyl, for example.

As a lower alkoxy-lower alkyl group, For example, C1-C6 alkoxy, such as methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, methoxybutyl, ethoxypropyl, ethoxybutyl, There is a C1-C6 alkyl group substituted by the group.

As a lower alkoxy group, there exists a C1-C6 alkoxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, for example.

Halogen number lower alkoxy group, for example, carbon number substituted with 1 to 3 halogen atoms such as chloroethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, chloropropoxy and chlorobutoxy There is an alkoxy group of ˜6.

As the lower alkoxycarbonyl-lower alkoxy group, for example, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, butoxycarbonylmethoxy, methoxycarbonylpropoxy, ethoxycarbonylethoxy and the like There is an alkoxy group having 1 to 6 carbon atoms substituted with an alkoxycarbonyl group having an alkoxy portion having 1 to 6 carbon atoms.

As a lower alkenyloxy group, there exists a C2-C6 alkenyloxy group, such as vinyloxy, allyloxy, butenyloxy, for example.

As the aralkyloxy group, for example, the lower alkyl moiety is benzyloxy, phenethyloxy, 3-phenylpropyloxy, α-methylphenethyloxy, α-methylbenzyloxy, α-ethylbenzyloxy, β-ethylphenethyl And phenyl lower alkyloxy groups such as oxy and β-methylphenethyloxy.

As an example of a lower alkoxy-lower alkoxy group, there exists a C1-C6 alkoxy group substituted by the C1-C6 alkoxy group, such as ethoxymethoxy, methoxyethoxy, butoxyethoxy, ethoxy propoxy, for example. .

As lower alkoxycarbonyl, there exists a C1-C6 alkoxycarbonyl group which has C1-C6, such as a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, for example.

As the N, N-di lower alkylcarbamoyl group, for example, the alkyl moiety is N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl and the like, N, N-dialkylcarbamoyl group having 1 to 6 carbon atoms and the alkyl moiety is bonded together to form a 5- or 6-membered ring structure N, N-di lower alkylcarbamoyl groups (eg, N-pyrrolidinylcarbonyl, piperidino carbonyl, etc.).

As the N-lower alkylcarbamoyl group, for example, the alkyl moiety has 1 to 6 carbon atoms such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, and N-butylcarbamoyl. N-alkylcarbamoyl groups.

Examples of halogens include chlorine, fluorine, bromine and iodine.

As an acyloxy group, there exist a C2-C6 alkanoyloxy group and benzoyloxy group, such as acetoxy, a propanoyloxy, butyloxy, pivaloyloxy, for example.

As a lower alkylsulfonylamino group, there exists a C1-C6 alkylsulfonylamino group, such as methanesulfonylamino and an ethanesulfonylamino, for example.

As an acylamino group, there exist C2-C6 alkanoylamino and benzamide groups, such as acetamide, a propanoylamino, a butylylamino, pivaloylamino, for example.

As the lower alkoxycarbonylamino group, for example, the alkoxy moiety includes an alkoxycarbonylamino group having 1 to 6 carbon atoms such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, and the like. .

As an acyl group, there exist an alkanoyl group and a benzoyl group of C2-C6 of acetyl, propane oil, butylyl, and pivaloyl, for example.

As a lower alkylthio group, there exists a C1-C6 alkylthio group, such as methylthio, ethylthio, propylthio, and butylthio, for example.

As a lower alkyl sulfonyl group, there exists a C1-C6 alkyl sulfonyl group, such as methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, and butyl sulfonyl, for example.

As a lower alkyl sulfinyl group, there exist C1-C6 alkyl sulfinyl groups, such as methyl sulfinyl, ethyl sulfinyl, propyl sulfinyl, and butyl sulfinyl, for example.

As the aralkyl group in formula (I), for example, the alkyl moiety is a phenyl lower alkyl group having 1 to 6 carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, etc., and the alkyl moiety is (1-naphthyl) methyl. And naphthyl-lower alkyl having 1 to 6 carbon atoms, such as 2- (1-naphthyl) ethyl and 2- (2-naphthyl) ethyl.

The phenyl portion of the phenyl-lower alkyl group and the naphthyl portion of the naphthyl lower alkyl group include one of halogen, lower alkyl group, lower alkoxy group, nitro, cyano, hydroxy, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group and the like. It may be substituted with ˜4 substituents.

Examples of halogens include fluorine, bromine, chlorine and iodine. As a lower alkyl group, there exists a lower alkyl group similar to the thing of the said Formula (I), for example.

As a lower alkoxy group, there exist C1-C6 linear or branched alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy, for example.

As a lower alkoxycarbonyl group, there exists a C1-C6 alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, for example.

As the lower alkyl carbamoyl group, for example, the alkyl moiety is an N-alkyl carbamoyl group having 1 to 6 carbon atoms such as methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, butyl carbamoyl, and alkyl moiety. And C1-C6 N, N-dialkylcarbamoyl groups such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl and methylethylcarbamoyl.

As an aryl group in Formula (I), it is preferable that it is C4-C24. For example, aromatic monocyclic, bicyclic or tricyclic hydrocarbon groups such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl, thienyl, furyl, benzothienyl, benzofuranyl and the like Aromatic monocyclic or bicyclic heterocyclic groups.

The aryl group is 1 to 4, preferably 1 or 2, such as halogen, lower alkyl group, lower alkoxy group, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl group, carbamoyl, lower alkylcarbamoyl group, etc. It may be substituted with a substituent.

Examples of halogens include fluorine, bromine, chlorine and iodine.

As a lower alkyl group, there exists a lower alkyl group which can have a C1-C6 alkyl group or an unsaturated bond, for example.

As a lower alkyl group which has an unsaturated bond, there exists a lower alkenyl group of C2-C6, for example.

As a C1-C6 alkyl group and C2-C6 lower alkenyl group, there exists a group similar to the lower alkyl group of said Formula (I), for example.

Examples of lower alkoxy groups include alkoxy groups having 1 to 6 carbon atoms, examples of lower alkoxycarbonyl groups include an alkoxy moiety containing an alkoxycarbonyl group having 1 to 6 carbon atoms and an alkyl moiety having 1 to 6 carbon atoms. The N-alkylcarbamoyl group and the alkyl moiety of N include N, N-dialkylcarbamoyl groups having about 1 to 6 carbon atoms. Examples of such groups include the same groups as the lower alkoxy, lower alkoxy carbonyl and lower alkylcarbamoyl substituents of the phenyl moiety in the aralkyl group.

As an aryl group containing oxo, there exist benzoquinolyl, naphthoquinolyl, anthraquinolyl, etc., for example.

Examples of halogen in R ¹ and R ² include fluorine, bromine, chlorine and iodine.

As the lower alkoxycarbonyl group and the lower alkylcarbamoyl group in R ¹ and R ² , there are, for example, the same groups as the lower alkoxycarbonyl and lower alkylcarbamoyl substituents of the phenyl portion of the aralkyl group.

Examples of groups in which R ¹⁰ and R ³ join together to form a ring include a group represented by the following formula:

Wherein q is 2 or 3 and A and R are as defined above.

Examples of groups in which R ¹⁰ is bonded to R ⁴ , R ⁶ or R ⁸ to form a ring include a group represented by the following formula:

Wherein q and r are each 2 or 3; R ¹¹ is as defined above.

Examples of groups wherein —NR ¹⁰ R ¹¹ forms a ring in B include groups represented by the following formulae:

The hetero ring is a lower alkyl group, a halogeno lower alkyl group, a hydroxy lower alkyl group, an acyloxy lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkoxycarbonyl group-a lower alkoxyl group, a lower alkenyloxy group , Aralkyloxy group, lower alkoxy-lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, carbamoyl group, N, N-di lower alkylcarbamoyl group, N-lower alkylcarbamoyl group, halogen, cyano, nitro, hydroxy 1-4, such as an acyloxy group, an amino, a lower alkyl sulfonyl amino group, an acyl amino group, a lower alkoxycarbonylamino group, an acyl group, a mercapto group, a lower alkylthio group, a lower alkyl sulfinyl group, a lower alkyl pure ponyl group, oxo, etc. May be substituted with one, preferably one or two substituents. When they are substituted with two or more substituents, the substituents may be the same or different.

Examples of the lower alkyl group as the substituent include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like.

As a halogeno lower alkyl group, there exists a C1-C6 alkyl group substituted by 1-3 halogen atoms, such as trifluoromethyl, fluoromethyl, chloromethyl, chloroethyl, fluoroethyl, for example.

As a hydroxy lower alkyl group, there exists a C1-C6 hydroxyalkyl group, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, for example.

As an acyloxy lower alkyl group, there exists a C1-C6 alkyl group substituted by C2-C6 lower alkanoyloxy or benzoyloxy group, such as acetoxy ethyl and benzoyloxy ethyl, for example.

As a lower alkoxy-lower alkyl group, For example, C1-C6 alkoxy, such as methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, methoxybutyl, ethoxypropyl, ethoxybutyl, There is a substituted or substituted alkyl group having 1 to 6 carbon atoms.

As a lower alkoxy group, there exists a C1-C6 alkoxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, for example.

A halogeno lower alkoxy group having 1 to 3 halogen atoms such as chloroethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, chloropropoxy, chlorobutoxy, etc. There is an alkoxy group of ˜6.

Lower alkoxycarbonyl-lower alkoxy groups, for example, the alkoxy moiety is methoxycarbonylmethoxy, ethoxycarbonylmethoxy, butoxycarbonylmethoxy, methoxycarbonylpropoxy, ethoxycarbonyl There exists a C1-C6 alkoxy group substituted by C1-C6 alkoxycarbonyl groups, such as oxy.

As a lower alkenyloxy group, there exists a C2-C6 alkenyloxy group, such as vinyloxy, allyloxy, butenyloxy, for example.

As the aralkyloxy group, for example, the lower alkyl moiety is benzyloxy, phenethyloxy, 3-phenylpropyloxy, α-methylphenethyloxy, α-methylbenzyloxy, α-ethylbenzyloxy, β-ethyleneethyloxy and a phenyl lower alkyloxy group having 1 to 6 carbon atoms such as β-methylphenethyloxy.

Examples of lower alkoxy-lower alkoxy groups include, for example, carbon atoms substituted with an alkoxy group substituted with an alkoxy group having 1 to 6 carbon atoms such as ethoxymethoxy, methoxyethoxy, butoxyethoxy and ethoxypropoxy. There is an alkoxy group of 6.

Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groups having 1 to 6 carbon atoms in the alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.

Examples of N, N-di lower alkylcarbamoyl groups include N, N-dialkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety such as N, N-dimethylcarbamoyl, N, N-diethylcarba Moyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl, and the like, and N, wherein the alkyl moieties are joined together to form a five or six membered ring. , N-disubstituted alkyl carbamoyl groups such as N-pyrrolidinylcarbonyl, piperidinocarbonyl and the like.

Examples of N-lower alkylcarbamoyl groups include N-alkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N- Butylcarbamoyl and the like.

Examples of halogen include chloro, fluoro, bromo and iodo.

Examples of the acyloxy group include an alkoxyyloxy group and a benzoyloxy group having 2 to 6 carbon atoms such as acetoxy, propanoyloxy, butylyloxy and pivaloyloxy.

Examples of the lower alkylsulfonylamino group include alkylsulfonylamino groups having 1 to 6 carbon atoms such as methanesulfonylamino and ethanesulfonylamino.

Examples of the acylamino group include an alkanoylamino group having 1 to 6 carbon atoms and a benzamide group such as acetamide, propanoylamino, butylylamino, pivaloylamino and the like.

Examples of lower alkoxycarbonylamino groups include alkoxycarbonylamino groups having 1 to 6 carbon atoms in the alkoxy moiety such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like.

Examples of the acyl group include C2-C6 alkanoyl groups and benzoyl groups such as acetyl, propanoyl, butylyl and pivaloyl.

Examples of lower alkylthio groups include alkylthio groups having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, and butylthio.

Examples of lower alkylsulfonyl groups include alkylsulfonyl groups having 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, and butylsulfinyl.

Examples of lower alkylsulfinyl groups include alkylsulfinyl groups having 1 to 6 carbon atoms such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, and butylsulfinyl.

In —NR ¹⁴ R ¹⁵ , examples of the group where R ¹⁴ and R ¹⁵ combine with an adjacent nitrogen atom to form a ring include 1-aziridinyl, 1-azetidinyl, piperidino, perhydro-1-a 3- to 8-membered monocyclic heterocyclic groups such as zefinyl, perhydro-1-azonoyl, morpholino, thiomorpholino, 1-piperazinyl, 3-thiazolidinyl; 1-indolyl, perhydro-1-indolyl, 2-isoindolyl, perhydro-2-isoindolyl, 1,2,3,4-tetrahydro-1-quinolyl, 1,2,3, 4-tetrahydro-2-isoquinolyl, perhydro-1-quinolyl, perhydro-2-isoquinolyl, 3-azabicyclo [3. 2. 2] condensed bicyclic or bridged bicyclic heterocyclic groups such as non-3-yl; 9-carbazolyl, 10-acridanyl, , 10,11-dihydro-5H-5-dibenz [b, f] azepinyl, 5,6,11,12-tetrahydro-5-dibenz [b, f] azocinyl, 1,2 Condensed tricyclic heterocyclic groups such as, 3,4, -tetrahydro-9-carbazolyl, 10-phenoxadinyl, 10-phenothiadinyl and the like.

Examples of the substituent of the heterocyclic group include the same groups as those of -NR ¹⁰ R ¹¹ .

Examples of optionally protected amino groups of R ¹ and R ² include amino groups, acylamino groups and trimethylamino groups, and examples of acyl groups include the same groups as those of R ¹¹ .

Examples of the ring formed by connecting R ⁴ and R ⁵ or R ⁶ and R ⁷ or R ⁸ and R ⁹ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Examples of the ring formed by connecting R ⁴ or R ⁶ and R ⁸ or R ⁹ , respectively, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Compounds of formula (I) form salts such as acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or organic acids such as acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, lactic acid, and the like. . Examples of the solvent of the solvent compound include alcohols such as methanol, ethanol, propanol and isopropanol; Ketones such as acetone; Ethers such as tetrahydrofuran and dioxane.

The compound of formula (I) may contain a subsidiary carbon in the molecule. Where two stereoisomers of R- and S-configuration exist, each isomer as well as mixtures thereof are included within the scope of the present invention.

Among the compounds represented by the formula (I), the compounds of the formula (I '), the compounds of the formula (I), the compounds of the formula (I') and the acid addition salts and solvent compounds of these compounds are known in the art. It is not described in.

[Formula I ']

[Formula I '']

[Formula I '' ']

[Wherein X, A, R ¹ and R ² are the same as defined above; B ¹ is an amino group acylated by an acyl group of carboxylic acid, sulfonic acid, carbamic acid or thiocarbamic acid having 2 or more carbon atoms; B ² is an acylated amino group, and the nitrogen atom of the amino group of B ² is linked to a carbon atom of A or R ³ to form a ring; B ³ is a hydroxyl group acylated by an acyl group of carboxylic acid or N-hydrocarbon substituted carbamic acid]

Accordingly, the present invention also provides these novel compounds.

Examples of amino groups acylated by acyl groups of carboxylic acid, sulfonic acid, carbamic acid or thiocarbamic acid having 2 or more carbon atoms include the formula -NR ^{10 '} R ^11' wherein R ^{10 '} is hydrogen or optionally substituted alkyl, aral A che or aryl group, or a group of the formula -CO-R ¹² , -SO ₂ R ¹³ , -CO-NR ¹⁴ R ¹⁵ or -CS-NR ¹⁴ R ¹⁵ ; R ^{11 '} is a group of the formula -CO-R ¹⁶ , -SO ₂ R ¹⁷ , -CO-NR ¹⁴ R ¹⁵ or -CS-NR ¹⁴ R ¹⁵ (as defined above for all other symbols). . Preferred as R ^{10 '} are hydrogen or an optionally substituted alkyl, aralkyl or aryl group, or a group of the formula -SO ₂ R ¹³ , -CO-NR ¹⁴ R ¹⁵ or -CS-NR ¹⁴ R ¹⁵ . Preferred as R ^{11 '} are groups of the formula -SO ₂ R ¹⁷ , -CO-NR ¹⁴ R ¹⁵ or -CS-NR ¹⁴ R ¹⁵ . Particularly preferred is that R ^{10 '} is hydrogen and R ^11' is a group of the formula -SO ₂ R ¹³ (the definition of all symbols is as defined above).

Examples of the ring formed by linking the nitrogen atom of the acylated amino group of B ² with the carbon atom of A or R ³ include the ring formed by linking R ¹⁰ with R ³ , R ⁴ , R ⁶ or R ⁸ .

Examples of the hydroxyl group acylated by the acyl group of the carboxylic acid or N-hydrocarbon substituted carbamic acid include the formula -O-CO-NO ¹⁵ R ¹⁶ or -O-CO-R ¹⁹ (wherein the definition of all symbols is Group).

Preferred as B ³ is a group of the formula -O-CO-NHR ¹⁶ wherein R ¹⁶ is the same as defined above.

Among the compounds of formula (I), preferred are those wherein X is S or O, and B is (1) an amino group acylated by an acyl group of sulfonic acid, carbamic acid or thiocarbamic acid, (2) acyl of carboxylic acid or carbamic acid It is a ring formed by connecting the nitrogen atom of the hydroxyl group acylated by the group or (3) the acylated amino group of B with the carbon atom of A or R ³ . As the group B, an amino group acylated by an acyl group of sulfonic acid is particularly preferable.

Starting materials or intermediates for the preparation of the final product represented by formula (I) are readily prepared by known methods or methods known per se.

Imidazo [1,2-a] pyridine derivatives (I) and salts thereof of the present invention can be synthesized, for example, by the following method:

(A) When X in Formula (I) is S, O or NR ³ , the compound of formula (II) or a salt thereof is reacted with a compound of formula (III) to give compound (I).

Formula II

Formula III

[Wherein E is a halogen such as chloro, bromo or iodine; X ¹ is S, O or NR ³ and other substituents and symbols are the same as defined above]

(B) When X in formula (I) is S or O, the compound of formula (IV) or a salt thereof is reacted with a compound of formula (V) to give compound (I).

Formula IV

Formula V

[Wherein X ² is S or O; E ¹ is a leaving group such as halogen (ie, chloro, bromo, iodine, etc.), toluenesulfonyl group or methanesulfonyl group; The other symbols are the same as defined above]

(C) B in formula (I) , or In this case, the compound of formula (VI) or a salt thereof is reacted with a compound of formula (VII) or a salt thereof to obtain compound (I).

Formula VI

Formula VII

[Wherein B ¹ is —O— or —NR ¹⁰ —;

Q ¹ is PhO-CO-, G-CO- or G-CS- (wherein Ph is a phenyl group; G is a halogen such as chloro); The other symbols are the same as defined above]

(D) B in formula (I) or In this case, the compound of formula (VIII) or a salt thereof is reacted with a compound of formula (IX) or a salt thereof to obtain compound (I).

Formula VIII

Formula IX

[Wherein, Q ² is Or G-CO-C-; The other symbols are the same as defined above]

(E) When X in Formula (I) is S (O) or S (O) ₂ , the compound of formula (Ia) or a salt thereof is reacted with an oxidizing agent to obtain compound (I).

[Wherein, all symbols are the same as defined above]

(F) When R ² in the formula (I) is halogen such as chloro, bromo, iodine or the like, the compound of formula (Ib) or a salt thereof is reacted with a halogenating agent to obtain a compound (I).

[Wherein, all symbols are the same as defined above]

(G) When R ² in the formula (I) is nitro, the compound of formula (Ib) or a salt thereof is nitrided to obtain compound (I).

(H) When R ² in the formula (I) is a nitroso group, the compound of formula (Ib) or a salt thereof is nitrosized to obtain compound (I).

(I) In the formula (I), when R ² is CH ₂ R ^2a (wherein R ^2a is a lower dialkylamino group or a cyclic amino group), the compound (I) can be produced by the following reaction.

(J) A compound of formula (X) or a salt thereof is reacted with a compound of formula (XI) to give compound (I).

Formula X

Formula XI

[Wherein, all symbols are the same as defined above]

(K) When R ¹¹ in formula (I) is COR ¹⁶ , the compound of formula (XII) or a salt thereof is reacted with a compound of formula (XIII) to give compound (I).

Formula XII

Formula XIII

[Wherein, G ¹ is halogen such as chloro or R ¹⁶ (O) q—CO—O—, wherein q is 0 or 1; All other symbols are the same as defined above]

(L) Compound (XII) or a salt thereof is reacted with a compound of formula (XIV) to give compound (I).

[Expression XIV]

[Wherein, G ² is halogen such as chloro or R ¹⁷ SO ₂ O—; All other symbols are the same as defined above]

(M) When R ² in the formula (I) is an amino group, the compound of formula (I) or a salt thereof in which R ² is nitro or nitroso is reduced to obtain a compound (I) in which R ² in the formula is an amino group. In the case of protected amino groups, these amino groups are further acylated or tritylated.

In the above methods A to M, the compounds capable of forming salts can be used in the form of salts, and examples of such salts include those described in the above compound (I). Salts of each compound may be included in the following description of methods A-M.

In method A, the reaction between compound (II) and compound (III) is carried out at -10 to + 200 ° C, in a solvent, from 1 equivalent to excess (1-10 equivalent) of compound (III) per 1 equivalent of compound (II). In the presence of basic compounds such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate and the like. Examples of the solvent used include water; Lower alcohols such as methanol, ethanol and propanol; Ketones such as acetone and metal ethyl ketone; Ethers such as tetrahydrofuran; And aprotic polar solvents such as N, N-dimethylformamide, diethyl sulfoxide and the like. Reaction time

Is usually 1 hour to 2 days, preferably 1 to 8 hours.

The reaction of compound (IV) with compound (V) in method B is carried out under similar conditions to the reaction of compound (II) with compound (III) in method A.

The reaction with compound (VII) with compound (VI) in Method C is carried out at -10 to + 150 ° C, with a solvent (e.g. ether, toluene, benzene, chloroform, dichloromethane, dioxane, tetrahydrofuran, dimethyl In the absence or presence of formamide). Tertiary amines (eg triethylamine, pyridine, diethylaminopyridine, N-methylpiperidine, etc.) may be added to promote the reaction. Compound (VII) is used in the amount of 1 to 10 equivalents per compound (VI) equivalent.

The reaction of compound (VII) with compound (VII) in method D is carried out under similar conditions to the reaction of compound (VI) with compound (VII) in method C. In addition, when Q ² is -NCO-, boron trifluoride-ethyl ether (BF ₃ · Et ₂ O) can be added. The reaction time is usually 0.5 to 24 hours, preferably 0.5 to 6 hours.

Oxidation of compound (Ia) in method E can be carried out using from 1 to 10 equivalents of oxidizing agent per equivalent of compound (Ib) in the presence of a solvent at -30 to + 100 ° C. Examples of the solvent used include water, methanol, ethanol, dichloromethane, chloroform and the like. Examples of oxidizing agents include m-chloroperbenzoic acid, sodium metaperiodate, hydrogen peroxide and the like. The reaction time is usually 0.5 hours to 2 days, preferably 0.5 to 12 hours.

The reaction of compound (Ib) with halogenating agent in Method F is carried out using from 1 to 10 equivalents of halogenating agent per equivalent of compound (Ib) in the absence or presence of a solvent at -20 to + 150 ° C. can do. Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and carbon tetrachloride; Acetic acid; Propionic acid and the like. Examples of the halogenating agent include halogen molecules such as chlorine and bromine; N-halogenosuccinimides, such as N-chlorosuccinimide and N-bromosuccinimide, are included. Moreover, radical reaction initiators, such as benzoyl peroxide, can be added to the said reaction. The reaction time is usually 0.5 hours to 2 days, preferably 1 to 12 hours.

The nitrification of compound (Ib) in method G can be carried out at -20 to + 100 ° C., in the absence or presence of a solvent, using from 1 to 10 equivalents of nitriding per equivalent of compound (Ib) Can be. Examples of the solvent used include acetic acid, acetic anhydride, sulfuric acid and the like. Examples of nitriding agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, fuming nitric acid, phosphoric or acetic anhydride and nitric acid) and the like. The reaction time is usually 0.5 to 24 hours, preferably 0.5 to 6 hours.

The nitrification reaction of compound (Ib) in method H can be carried out using from 1 to 10 equivalents of a nitrosizing agent per equivalent of compound (Ib) in the absence or presence of a solvent at -20 to + 100 ° C. Can be. Examples of the solvent used include water; Lower fatty acids such as acetic acid and propionic acid; Ethers such as tetrahydrofuran and dioxane; Aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide are included. Examples of nitrosizing agents include potassium nitrite, sodium nitrite and the like. This reaction is carried out in the presence of acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and the like. The reaction time is usually 0.5 to 24 hours, preferably 0.5 to 6 hours.

The Mannich reaction of compound (Ib) with lower dialkylamines or cyclic amines and formalin in process I is carried out at -20 to + 100 ° C, in the presence of a solvent, from 1 to 1 excess of Mannich reagent per equivalent of compound (Ib) 1 to 10 equivalents). Examples of the solvent used include water; Lower alcohols such as methanol, ethanol, propanol and isopropanol; And lower fatty acids such as acetic acid and propionic acid. The reaction time is usually 30 minutes to 1 day, preferably 1 to 12 hours.

In method J, the reaction between compound (XI) and compound (XI) is carried out at 1 to 10 equivalents of compound (XI) per 1 equivalent of compound (X) in the absence or presence of a solvent at 0 to + 200 ° C. This can be done using Examples of the solvent used include water; Lower alcohols such as methanol, ethanol and propanol; Ethers such as tetrahydrofuran, dimethoxyethane and dioxane; Nitriles such as acetonitrile and propionitrile; Aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide are included. In the above reaction, an inorganic base such as potassium carbonate or sodium bicarbonate or an organic base such as triethylamine, pyridine or dimethylaniline can be added as an acid-trapping agent. The reaction time is usually 10 minutes to 7 days, preferably 1 hour to 2 days.

In method K, the reaction between compound (XII) and compound (XIII) is carried out at -30 to + 200 ° C, in a solvent, an inorganic base such as potassium carbonate, sodium bicarbonate, or triethylamine, pyridine, dimenylaniline, 1,4 In the absence or presence of an organic base such as diazabicyclo [2,2,2,] octane (DABCO), using from 1 to 10 equivalents of compound (XIII) per equivalent of compound (XII) Can be done. Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane; Esters such as methyl acetate and ethyl acetate; Aprotic polar solvents, such as N, N-dimethyl chilformamide and dimethyl sulfoxide, are included. The reaction time is usually 10 minutes to 24 hours, preferably 0.5 to 6 hours.

The reaction of compound (XII) with compound (XIV) in method L is carried out under conditions similar to those of the reaction of compound (XII) with compound (XIII) in method K.

In method M, the reduction reaction of compound (I) wherein R ² in the formula is a nitro group or a nitroso group is carried out at -20 to + 200 ° C. in the presence of a solvent, from 1 to 10 equivalents of reducing agent per equivalent of compound (I). Can be used. Examples of the solvent used include water, methanol, ethanol, propanol, isopropanol, acetic acid and the like. Examples of reducing agents include mixtures of iron and hydrochloric acid or mixtures of zinc and acetic acid. In addition, this reaction can be carried out using a hydrogenation catalyst such as palladium black, palladium carbon, Raney nickel and the like at -20 to +20 DEG C under hydrogen normal pressure. Examples of the solvent used include water, methanol, ethanol, propanol, isopropanol, acetic acid and the like. The reaction time is usually 10 minutes to 24 hours, preferably 0.5 to 6 hours. When the protected amino group is -NH-CO-NR ¹⁴ R ¹⁵ or -NH-CS-NR ¹⁴ R ¹⁵ , it can be obtained by reacting a compound of formula (I) with a compound (VII), wherein R ² in the formula is an amino group. . This reaction is carried out under conditions similar to the reaction conditions of compound (VI) and compound (VII) in Method C. When the protected amino group is a tritylamino group, it can be obtained by reacting a compound of formula (I) in which R ² is an amino group with trityl chloride. This reaction is a known reaction and can be carried out under known conditions.

Compound (II) can be obtained, for example, by the following process.

The reaction of compound (XV) with compound (XI) is carried out under conditions similar to those of compound (X) and compound (XI).

Compound (IV) can be obtained, for example, by the following process.

[Wherein, Y is NaS-, KS-, NaO- or KO-.]

The reaction of compound (II) with compound (XVI) can be carried out using 1 equivalent to an excess of compound (XVI) per 1 equivalent of compound (II) in the presence of a solvent at 0 to + 250 ° C. Examples of the solvent used include water; Lower alcohols such as methanol, ethanol and propanol; Ethers such as tetrahydrofuran, dimethicethane and dioxane; Aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like.

Compound (VI) can be obtained, for example, by the following process:

(Iii) when X is S or 0,

[Wherein, all symbols are the same as defined above]

(Ii) when X is S, O or NR ³ ,

[Wherein, all symbols are the same as defined above]

(Iii) when X is S or O and B ¹ is NR ¹⁰ ,

(Wherein T is an amino protecting group such as benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl, trityl, benzyl, B ¹ T is phthalimide, and other symbols are as defined above.)

(Iii) when X is S (0) or S (0) ₂ and B ¹ is NR ¹⁰ , treat compound (XX) with an oxidant and then remove any protecting groups;

(Iii) when X is S or O and B ¹ is NR ¹⁰ ,

(Wherein, the symbols are as defined above.)

(Iii) when X is S, O or NR ³ and B ¹ is NR ¹⁰ ,

(Wherein, symbols are as defined above.)

The reaction of compound (IV) with compound (XVII) in process (iii) is carried out under similar conditions as in reaction of compound (IV) and compound (V) in Method B.

The reaction of compound (II) with compound (XVIII) in process (ii) is carried out under similar conditions as in the reaction of compound (II) with compound (III) in Method A.

The reaction of compound (IV) with compound (XIX) in process (iii) is carried out under similar conditions as in reaction of compound (IV) and compound (V) in Method B.

The reaction of compound (XX) with the oxidant in process (iii) is carried out under similar conditions as in the reaction of compound (Ia) with oxidant.

The reaction of compound (IV) with compound (XXI) in process (iii) is carried out under similar conditions as in reaction of compound (IV) and compound (V) in Method B.

The reaction of compound (II) with compound (XXIII) in process (iii) is carried out under similar conditions as in reaction of compound (II) with compound (III) in Method A.

Process (ⅴ) and is for converting the hydroxyl group of compound (XXII) in (ⅵ) as E ¹ E ¹ in this case a halogen, formula (XXII) Compound halogenated phosphorus (e.g., phosphorus trichloride, phosphorus oxychloride and the, Phosphorus pentachloride, phosphorus tribromide, etc.), red phosphorus and a halogenating agent such as halogen, thionyl chloride and the like. When E ¹ is a toluenesulfonyl group or a methanesulfonyloxy group, this can be obtained by reacting compound (XXII) with toluenesulfonyl chloride or methanesulfonylchloride. The reaction with R ¹⁰ NH following the reaction is carried out at 0-200 ° C. in the absence of solvent or in the presence of a suitable solvent.

These reactions are all known and can be carried out according to known conditions.

Compound (VIII) can be obtained, for example, by the following procedure.

(Iii) when Q ² is OCN-,

Wherein the symbols are as defined above.

(Ii) when Q ² is OCN-,

Wherein the symbols are as defined above.

(Iii) when Q ² is SCN-,

(Iii) when Q ² is SCN-,

Wherein Y ¹ is Na or K

(Iii) when Q ² is PhO-CO-O,

(Iii) when Q ² is G-CO-NR ¹⁰ ,

(Iii) when Q ² is G-CO-O-,

That is, (iii) compound (XXIV) is reacted with phosgene, and then the reaction product is heated to dehydrogenated.

(Ii) The compound (XXV) is reacted with silver cyanate.

(Iii) Compound (XXIV) is reacted with CS ₂ , further with chlorocarbonate, and the reaction product is heated.

(Iii) The compound (XXV) is reacted with the compound (XXVI).

(Iii) Compound (XXII) is reacted with phenyl chlorocarbonate.

(Iii) Compound (XII) is reacted with phosgene.

(Iii) The compound (XXII) is reacted with phosgene.

These reactions are all known and can be carried out according to known conditions.

All reactions for removing the protecting group are known, and can be carried out according to known conditions.

For example, the benzyloxycarbonyl group or benzyl group as an amino protecting group is present in a solvent (e.g., alcohol, acetic acid, water, tetrahydrofuran, and a mixed solvent thereof, etc.) and the presence of a catalyst (e.g., palladium on carbon, platinum oxide, etc.) Under catalytic reduction (reaction temperature: room temperature to + 100 ° C.).

In the case of trityl or t-butoxycarbonyl groups, solvents (e.g., water, alcohols, tetrahydrofuran, Dioxane and the like).

Trifluoroacetyl groups can be easily removed by alkali (eg, sodium hydroxide, sodium bicarbonate solution, etc.) treatment.

The phthalamide group can be removed by reaction with hydrazine hydrate in a solvent (eg methanol, ethanol, etc.).

The starting compound can be removed from the desired product (I) obtained by the above process or a salt thereof by the following conventional separation means. Or the reaction mixture itself can be used as starting material for the next step without purification.

Separation and purification of compound (I) or salts thereof from the reaction mixture is carried out according to known separation methods (e.g., extraction, concentration, filtration, recrystallization, column chromatography, thin layer chromatography, etc.).

Compound (I) or a salt thereof of the present invention has calmodulin inhibitory activity, hypertension, ischemic diseases (eg, angina pectoris, myocardial infarction, arrhythmia, renal failure, etc.), arteriosclerosis, vasoconstriction after subarachnoid hemorrhage, and It is useful as a safe medicine for various diseases of mammals such as inflammatory diseases (eg nephritis, asthma, hepatitis, etc.).

When the compound (I) or a salt thereof of the present invention is used in the above medicines, it is mixed with a pharmaceutically acceptable carrier, excipient, diluent, orally in a dosage form such as powder, granules, tablets, capsules, injections, and the like. Or parenteral administration. Dosage may vary depending on the particular route of administration, condition to be treated, age and weight of the patient. For example, when administered orally to an adult patient, the dosage is 0.2-50 mg / kg / day, preferably 0.5-30 mg / kg / day, more preferably 1-20 mg / kg / day, once a day or It may be administered several times.

As described above, the compound (I) and salts of the present invention have excellent calmodulin inhibitory activity and are used as antihypertensive agents, drugs for treating ischemic diseases, anti-arteriosclerosis, drugs for treating vasoconstriction after subarachnoid hemorrhage, and anti-inflammatory agents in humans and mammals. useful.

The present invention is described in more detail with reference to the following examples, examples, preparations and experimental examples, which should not be construed as limiting the scope of the invention. In these examples, room temperature means 15 to 30 ° C.

Reference Example 1

(1) Synthesis of 2-ethoxycarbonyl-5-chloroimidazo [1,2-a] pyridine

A solution of 2-amino-6-chloropyridine (6.43 g, 50 mmol) and ethyl bromopyruvate (9.75 g, 50 mmol) in ethanol (150 ml) was heated under reflux for 4 hours. After removal of the solvent, chloroform is added to the residue, which is washed sequentially with saturated sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After concentrating the solvent, n-hexane is added to the mixture. The precipitated crystals are then filtered off and washed with n-hexane to afford 7.60 g of the desired product (67.6%, pale yellow crystals).

Melting Point: 143 ~ 145 ℃

Elemental Analysis C ₁₀ H ₉ N ₂ O ₂ Cl

Calculated: C, 53.47; H, 4.04; N, 12.47

Found: C, 53.45; H, 3.99; N, 12.59

The following compound is obtained by the same method as described in Reference Example 1 (1).

(2) 5-chloro-2-methylimidazo [1,2-a] pyridine

(3) 3-ethoxycarbonyl-5-chloro-2-methylimidazo- [1,2-a] pyridine

(4) 2-ethoxycarbonylmethyl-5-chloroimidazo- [1,2-a] pyridine

Reference Example 2

(1) Synthesis of 5- [2- (amino) ethylthio] -2-methylimidazo [1,2-a] pyridine

To a ethanol (100 ml) suspension of cysteamine hydrochloride (2.95 g, 26 mmol) is added 60% sodium hydride (in oil; 2.08 g, 26 mmol) with stirring under ice cooling and the mixture is stirred for 5 minutes. 5-Chloro-2-methylimidazo [1,2-a] pyridine (3.33 g, 20 mmol) was added to the mixture, which was then heated under reflux for 3 hours. After distilling off the solvent, coloform was added to the residue, which was washed with 1N-NaOH and dried over anhydrous potassium carbonate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate / ethanol / triethylamine = 6: 2: 1) to give 2.2 g of the desired product (53.6%, brown oil phase).

Reference Example 2 The following compounds were obtained in the same manner as described in (1).

(2) 5- [2- (amino) ethylthio] -2-ethoxycarbonylimidazo [1,2-a] pyridine

Elemental Analysis C ₁₂ H ₁₅ N ₃ O ₂ S.O.3H ₂ O

Calculated: C, 53.24; H, 5.81; N, 15.52

Found: C, 53.43; H, 5.61; N, 15.54

(3) 5- [2- (amino) ethylthio] -3-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine

(4) 5- [2- (amino) ethylthio] -2-ethoxycarbonylmethylimidazo [1,2-a] pyridine

(5) 5-[(4-piperidyl) thio] imidazo [1,2-a] pyridine

Reference Example 3

(1) Synthesis of 5- [4- (amino) butoxy] imidazo [1,2-a] pyridine

50chloroimidazo [1,2-a] pyridine (4.59 g, 30.1 mmol) and 4-aminobutanol (2.68 g, 30.1 mmol) in a DMF (60 ml) suspension of 60% sodium hydride (in oil; 1.32 g, 33 mmol) A solution of DMF (60 ml) is added at room temperature with stirring, and the mixture is stirred at the same temperature for 5 hours. T-butyl dicarbonate (9.83 g, 45 mmol) was added to the reaction solution, which was stirred for 13 hours at room temperature. After distilling off the solvent, water is added to the residue, which is extracted twice with ether, washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is dissolved in methanol (20 ml) and then concentrated hydrochloric acid (20 ml) is added and stirred at room temperature for 1 hour. After distilling off the solvent, chloroform is added to the residue, which is washed with 3N NaOH. After drying over anhydrous potassium carbonate, the solvent is distilled off. The residue is purified by column chromatography (eluent: methanol / chloroform = 1: 5) to afford 2.53 g of the desired product (40.9%, light brown oil phase).

Reference Example 3 The following compound is obtained by the same method as described in (1).

(2) 5- [5- (amino) pentyloxy] imidazo [1,2-a] pyridine

(3) 5- [6- (amino) hexyloxy] imidazo [1,2-a] pyridine

(4) 5- [2- [1- (imino) propoxy]] imidazo [1,2-a] pyridine

(5) 5- [2- (amino) -1- (phenyl) ethoxy] imidazo- [1,2-a] pyridine

(6) 5-[(4-piperidinyl) oxy] imidazo [1,2-a] pyridine

Reference Example 4

Synthesis of 5- [2- (phenoxycarbonyloxy) ethylthio] imidazo [1,2-a] pyridine

Phenyl chloroformate in a solution of methylene chloride (120 ml) of 5- [2- (hydroxy) ethylthio] imidazo [1,2-a] pyridine (5.83 g, 30 mmol) and pyridine (4.36 ml, 60 mmol) (7.53 ml, 60 mmol) is added with stirring under ice cooling and the mixture is stirred for 30 minutes under ice cooling. The reaction solution was washed sequentially with 5% aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by column chromatography (eluent: ethyl acetate) to give 8.61 g of the desired product (91.3%, oil phase).

Reference Example 5

Synthesis of 5- [2- (methylsulfonyloxy) ethylthio] imidazo [1,2-a] pyridine

Methanesulphate in a solution of methylene chloride (300 ml) of 5- [2- (hydroxy) ethylthio] imidazo [1,2-a] pyridine (9.71 g, 50 mmol) and triethylamine (10.5 ml, 75.3 mmol) Ponyl chloride (4.26 ml, 55 mmol) is added with stirring under ice cooling and the mixture is stirred under ice cooling for 2 hours. The reaction solution is washed in order of saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is then distilled off to yield 13.6 g of the desired product (quantitative yield, brown oil phase).

Reference Example 6

(1) Synthesis of 5- [2- (methylamino) ethylthio] imidazo [1,2-a] pyridine

5- [2- (methylsulfonyloxy) ethylthio] imidazo [1,2-a] pyridine (2.18 g, 8 mmol), triethylamine (2.24 ml, 16 mmol) and 40% methylamine-methanol solution (20 ml) of chloroform (20 ml) solution is heated under reflux for 3 hours. The reaction solution is washed with 3N aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: methanol / chloroform = 1: 10) to give 781 mg of the desired product (47.1%, light brown oil phase).

Reference Example 6 The following compound was obtained by the same method as described in (1).

(2) 5- [2- (ethylamino) ethylthio] imidazo [1,2-a] pyridine

Reference Example 7

(1) Synthesis of 5- [3 (amino) propoxy) imidazo [1,2-a] pyridine

To a methanol (10 ml) solution of 5- [3- (t-butoxycarbonylamino) propoxy] imidazo [1,2-a] pyridine was added concentrated hydrochloric acid (5 ml) and the mixture was stirred at room temperature for 1 hour. do. After distilling off the solvent, chloroform (30 ml) and 3N-NaOH (10 ml) are added to the residue, which is extracted with chloroform and dried over anhydrous potassium carbonate. The solvent is then distilled off to yield 687 mg of the desired product (78.7%, light yellow oil phase).

The following compound is obtained by the same method as described in Reference Example 7 (1).

(2) 5- [2- (amino) ethoxy] imidazo [1,2-a] pyridine

(3) 5- [2- (amino) ethylamizo] imidazo [1,2-a] pyridine

(4) 5- [3- (amino) propylamino] imidazo [1,2-a] pyridine

Reference Example 8

Synthesis of 5- [3- (amino) propylamino] imidazo [1,2-a] pyridine dihydrochloride

Hydrogen chloride-methanol (6 ml) was added to a suspension of methylene chloride (40 ml) of 5- [3- (t-butoxycarbonylamino) propylamino] idamazo [1,2-a] pyridine (1.742 g, 6 mmol). The mixture is stirred at rt for 20 h. After distilling off the solvent, ethanol (15 ml) and ether (30 ml) are added to the residue. The precipitated crystals are then filtered off and washed sequentially with ether and a small amount of ethanol to yield 1.311 g of the desired product (83.0%, pale yellow crystals).

Elemental Analysis C ₁₀ H ₁₄ N ₄ O · 2HCl · 0.2H ₂ O

Calculated: C, 45.02; H, 6. 20; N, 21.00

Found: C, 45.15; H, 6. 25; N, 21.17

Reference Example 9

Synthesis of 5- [3- (amino) propylthio] imidazo [1,2-a] pyridine

To a mixed solution of 10% potassium hydroxide (63.3 g, 105 mmol) and dimethyl sulfoxide (50 ml) was added S- [3- (amino) propyl] isothiourea dihydrobromide (8.85 g, 39 mmol) and the mixture was Stir at room temperature for 1.5 hours.

5-chloroimidazo [1,2-a] pyridine (3.05 g, 20 mmol) was added to the reaction solution, which was then stirred at room temperature for 1.5 hours and further at 65 ° C for 20 hours.

Water is added to the reaction solution, which is extracted with chloroform, washed several times with 1N-sodium chloride and dried over anhydrous magnesium sulfate.

The solvent is distilled off to give 2.66 g of the desired product (64.3%, light yellow oil phase).

Reference Example 10

In the same manner as described in Reference Example 8, the following compound was obtained.

(1) 5- [2- (amino) ethylsulfonyl] imidazo [1,2-a] pyridinedihydrochloride

Melting Point: 210 ~ 220 ℃ (Decomposition)

Elemental Analysis C ₉ H ₁₁ N ₃ O ₂ S · 2HCl · 0.5H ₂ O,

Calculated Value: C, 35.19: H, 4.59: N, 13.68

Found: C, 35.18: H, 4.49: N, 13.98

(2) 5- [2- (amino) ethylsulfinyl] imidazo [1,2-a] pyridinedihydrochloride

Melting Point: 195 ~ 205 ℃ (Decomposition)

Elemental Analysis C ₉ H ₁₁ N ₃ OS · 2HCl · 0.3H ₂ O,

Calculated Value: C, 37.59: H, 4.77: N, 14.61

Found: C, 37.76: H, 4.77: N, 14.60

(3) 5- [2- (amino) ethoxy] imidazo [1.2-a] pyridine dihydrochloride

Melting Point: 209 ~ 220 ℃ (Decomposition)

Elemental Analysis C ₉ H ₁₁ N ₃ O · 2HCl · H ₂ O,

Calculated Value: C, 40.31: H, 5.64: N, 15.67

Found: C, 40.20: H, 5.65: N, 15.58

(4) 5- [4- (piperidyl) thio] imidazo [1,2-a] pyridine dihydrochloride

Melting Point: 204 ~ 218 ℃ (Decomposition)

Elemental analysis C ₁₂ H ₁₅ N ₃ S.2HCl,

Calculated Value: C, 47.06: H, 5.59: N, 13.72

Found: C, 47.00: H, 5.63: N, 13.56

Reference Example 11

Synthesis of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine

A suspension of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine dihydrochloride (13.31 g, 50 mmol) in chloroform (200 ml) was washed with 3N-sodium hydroxide (50 ml) The aqueous layer is extracted with chloroform and the combined chloroform layers are dried over anhydrous magnesium sulfate. After distilling off the solvent, 9.63 g (99.7% pale yellow oily product) of the desired product are obtained.

NMR (200 Hz, CDCl ₃ ) δ: 1.67 (2H, br), 2.95 (2H, m), 3.08 (2H, m), 6.95 (1H, d, J = 7 Hz), 7.15 (1H, dd, J = 9.2 , 7Hz), 7.59 (1H, d, J = 9, 2Hz), 7.71 (1H, s), 7.88 (1H, s)

Reference Example 12

Synthesis of 5- [3- (chloro) propylthio] imidazo [1,2-a] pyridine.

Triethylamine in a suspension of 5-mercaptoimidazo [1,2-a] pyridine (5.02 g, 33.4 mmol) and 1-bromo-3-chloropropane (5.26 g, 33.4 mmol) in ethanol (100 ml) (4.66 ml, 33.4 mmol) is added and the mixture is stirred at rt for 17 h. After distilling off the solvent, chloroform is added to the residue, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 5.46 g (72.0%, light brown oily product) of the desired product.

NMR (200 Hz, CDCl ₃ ) δ: 2.09 (2H, m), 3.17 (2H, t, J = 7 Hz), 3.68 (2H, t, J = 6 Hz), 6.94 (1H, dd, J = 7.2, 1 Hz) , 7.16 (1H, dd, J = 9.2, 7.2 Hz), 7.60 (1H, m), 7.72 (1H, d, J = 1.2 Hz), 7.86 (1H, m)

Example 1

Synthesis of 5- [2- (methylsulfonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 1).

Methanesulfonyl in a solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (9.63 g, 49.8 mmol) and triethylamine (7.64 ml) dissolved in methylene chloride (150 ml) Chloride (3.85 ml, 49.7 mmol) is added with stirring under ice cooling and stirred for 1 hour under ice cooling. The reaction solution is poured into water and stirred. The precipitated crystals are then filtered off, washed with water and dried to afford 10.53 g (77.9%, colorless crystals) of the desired product.

Melting Point: 130 ~ 131 ℃ (Decomposition)

Elemental Analysis C ₁₀ H ₁₃ N ₃ O ₂ S ₂ ,

Calculated Value: C, 44.26: H, 4.83: N, 15.48

Found: C, 44.05: H, 4.82: N, 15.31

NMR (90 MHz, CMSO-d ₆ ) δ: 2.96 (3H, s), 3.22 (4H, s), 7.10 (1H, dd, J = 7, 1.5 Hz), 7.26 (1H, dd, J = 9, 7 Hz ), 7.31 (1H, br), 7.56 (1H, d, J = 9 Hz), 7.68 (1H, d, J = 1 Hz), 7.97 (1H, s)

IR (KBr) cm ^-1 : 3450, 3140, 2930, 1620, 1490, 1315, 1155

Example 2

Synthesis of 5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 2).

A suspension of 5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (543 g, 2 mmol) dissolved in methanol (20 ml) is treated with hydrogen chloride-methanol. After distilling off the solvent, the residue is crystallized from chloroform ether. The crystals obtained are then washed with ether and dried to give 550 mg (89.3%, colorless crystals) of the desired product.

Melting Point: 154 ~ 160 ℃

Example 3

(1) Synthesis of 5- [2- (ethylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 3).

To a solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (1.93 g, 10 mmol) and triethylamine (1.53 ml, 11 mmol) dissolved in methylene chloride (100 ml) Ethanesulfonyl chloride (0.95 ml, 10 mmol) is added with stirring at room temperature and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed successively with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography (eluent: ethanol / ethyl acetate = 1: 5) to give 2.23 g (78.2%, colorless crystals) of the desired product.

Elemental analysis _{C 11 H 15 N 3 O 2} S 2 · 0.1H 2 O,

Calculated Value: C, 46.01: H, 5.34: N, 14.63

Found: C, 45.74: H, 5.26: N, 14.36

NMR (90 MHz, CMSO-d ₆ ) δ: 1.16 (3H, t, J = 7 Hz), 2.99 (2H, q, J = 7 Hz), 3.21 (4H, m), 7.11 (1H, dd, J = 7, 1.5 Hz), 7.28 (1H, dd, J = 8.5, 7 Hz), 7.33 (1H, br), 7.59 (1H, d, J = 8.5 Hz), 7.71 (1H, s), 7.99 (1H, s)

In the same manner as described in Example 3 (1), the following compounds are obtained.

(2) 5- [2- (propylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 4)

Elemental Analysis C ₁₂ H ₁₇ N ₃ O ₂ S.0.2H ₂ O,

Calculated Value: C, 47.57: H, 5.79: N, 13.87

Found: C, 47.62: H, 5.74: N, 14.03

NMR (200 Hz, CDCl ₃ ) δ: 1.04 (3H, t, J = 7.4 Hz), 1.83 (2H, m), 2.98 (2H, m), 3.19 (2H, m), 3.33 (2H, m), 4.93 (1H, br), 7.02 (1H, dd, J = 7, 1.2 Hz), 7.17 (1H, dd, J = 9, 7 Hz), 7.63 (1H, m), 7.70 (1H, d, J = 1.4 Hz ), 7.85 (1 H, m)

(3) 5- [2- (isopropylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 5)

NMR (200 Hz, CDCl ₃ ) δ: 1.36 (6H, d, J = 6.8 Hz), 3.16 (1H, hepet, J = 6.8 Hz), 3.19 (2H, t, J = 6.4 Hz), 3.36 (2H, m ), 4.80 (1H, br), 7.02 (1H, dd, J = 7, 1.2 Hz), 7.17 (1H, dd, J = 9, 7 Hz), 7.62 (1H, d, J = 9 Hz), 7.70 (1H) , s), 7.86 (1 H, m)

(4) 5- [2- (butylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 6)

Elemental Analysis C ₁₃ H ₁₉ N ₃ O ₂ S _2,

Calculated Value: C, 49.82: H, 6.11: N, 13.41

Found: C, 49.76: H, 6.15: N, 13.40

NMR (200 Hz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.43 (2H, m), 1.76 (2H, m), 3.00 (2H, m), 3.19 (2H, m), 3.33 (2H, m), 5.06 (1H, br), 7.01 (1H, dd, J = 7, 1.2 Hz), 7.16 (1H, dd, J = 9, 7 Hz), 7.61 (1H, d, J = 9 Hz ), 7.69 (1H, d, J = 1.2 Hz), 7.84 (1H, m)

(5) 5- [2- (octylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 7)

NMR (90 MHz, CDCl ₃ ) δ: 0.73-2.00 (15H, m), 2.88-3.52 (6H, m), 6.24 (1H, br), 7.00 (1H, dd, J = 7, 1.5 Hz), 7.13 ( 1H, dd, J = 9, 7 Hz), 7.58 (1H, d, J = 9 Hz), 7.63 (1H, s), 7.81 (1H, s)

(6) 5- [2- [3- (chloro) propylsulfoninamino] ethylthio] imidazo [1,2-a] pyridine (Compound 8)

Elemental Analysis C ₁₂ H ₁₆ N ₃ O ₂ S ₂ Cl

Calculated Value: C, 43.17: H, 4.83: N, 12.59

Found: C, 43.41: H, 4.83: N, 12.47

NMR (90 MHz, CDCl _3- DMSO-d ₆ ) δ: 2.22 (2H, m), 2.97-3.46 (6H, m), 3.66 (2H, t, J = 6.5 Hz), 7.07 (1H, dd, J = 7.5 2 Hz), 7.19 (1H, dd, J = 9, 7.5 Hz), 7.26 (1H, br), 7.59 (1H, m), 7.69 (1H, s), 7.90 (1H, s)

(7) 5- [2- (hexadecylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 9)

NMR (200 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 6.8 Hz), 1.25 (26H, m), 1.78 (2H, m), 3.00 (2H, m), 3.18 (2H, m), 3.33 (2H, m), 4.73 (1H, br), 7.02 (1H, dd, J = 7.1 Hz), 7.17 (1H, dd, J = 9, 7 Hz), 7.64 (1H, d, J = 9 Hz), 7.72 (1H, d, J = 1.2 Hz), 7.87 (1H, s)

Example 4

(1) 3-chloro-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 10) and 3-chloro-5- [2- (methylsulfonylamino ) Ethylthio] -2-succinimide-imidazo [1,2-a] pyridine (Compound 11).

N-chloro succinamide (267 mg, 2) in a suspension of 5- [2- (methylsulfonylamino) ethylthio] imidazo- [1,2-a] pyridine (534 mg, 2 mmol) in chloroform (60 ml) Mmol) is added with stirring at room temperature and the mixture is stirred at room temperature for 24 hours. The reaction mixture is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography (eluent: ethanol / ethyl acetate = 1: 10) to give 245 mg of the desired product (compound 10, 40.4%, gray crystals) as fraction 1.

Elemental Analysis C ₁₀ H ₁₂ N ₃ O ₂ S ₂ Cl,

Calculated Value: C, 39.28: H, 3.96: N, 13.74

Found: C, 39.47: H, 4.00: N, 13.61

NMR (90 MHz, DMSO-d ₆ ) δ: 2.90 (3H, s), 3.22 (4H, m), 7.06 (1H, dd,, J = 1.5 Hz), 7.23 (1H, dd, J = 9, 7 Hz) , 7.53 (1H, dd, J = 9, 1.5 Hz), 7.66 (1H, s)

As fraction 2, 96 mg of the desired product (compound 11, 11.9%, colorless crystals) were obtained.

NMR (90 MHz, DMSO-d ₆ ) δ: 2.94 (3H, s), 2.97 (4H, s), 3.23 (4H, m), 7.19 (1H, dd, J = 7, 2 Hz), 7.40 (1H, dd , J = 7 Hz), 7.59 (1H, dd, J = 9 1.5 Hz)

In the same manner as described in Example 4 (1), the following compounds are obtained.

(2) 3-bromo-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 12)

Elemental Analysis C ₁₀ H ₁₂ N ₃ O ₂ S ₂ Br,

Calculated Value: C, 34.29: H, 3.45: N, 12.00

Found: C, 34.26: H, 3.45: N, 11.94

NMR (90 MHz, DMSO-d ₆ ) δ: 2.90 (3H, s), 3.19 (4H, m), 7.07 (1H, dd,, J = 7, 1.5 Hz), 7.23 (1H, dd, J = 9, 7 Hz), 7.56 (1H, dd, J = 9, 1.5 Hz), 7.66 (1H, s)

(3) 3-iodine-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 13)

NMR (90 MHz, DMSO-d ₆ ) δ: 2.98 (3H, s), 3.17 (4H, m), 7.07 (1H, dd,, J = 7, 1.5 Hz), 7.24 (1H, dd, J = 9, 7 Hz), 7.60 (1H, dd, J = 9, 1.5 Hz), 7.68 (1H, s)

Example 5

Synthesis of 5- [2- (methylsulfonylamino) ethylthio] -3-morpholinomethyl imidazo [1,2-a] pyridine (Compound 14).

To a solution of 37% formalin (178 mg, 2.2 mmol) in acetic acid (2 ml) is added morpholine (192 μl , 2.2 mmol) with stirring under ice cooling, and the mixture is stirred at room temperature for 30 minutes. 5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (543 mg, 2 mmol) is added to the reaction mixture and then stirred at 60 ° C. for 2 hours. After distilling off the solvent, the residue is dissolved in chloroform (50 ml) and washed with 1N NaOH (10 ml). The aqueous layer is then extracted with chloroform (30 ml x 3), the combined chloroform layers are dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography (eluent: ethanol / ethyl acetate = 1: 10 → 1: 5) to give 530 mg (71.5%, colorless solid) of the desired product.

NMR (90 MHz, CDCl ₃ ) δ: 2.94 (4H, m), 2.67 (3H, s), 3.27 (4H, m), 3.67 (4H, m), 4.08 (2H, s), 6.62 (1H, br) , 6.94 (2H, m), 7.50 (1H, s), 7.57 (1H, dd, J = 8, 5 Hz)

Example 6

In the same manner as described in Example 4 (1), the following compounds are obtained.

5- [2- (methylmethylsulfonylamino) ethylthio] -3-morpholinomethylimidazo [1,2-a] pyridinedihydrochloride (Compound 15)

NMR (200 MHz, DMSO-d6) δ: 2.92 (3H, s), 3.15-4.20 (14H, m), 5.08 (1H, br), 7.44 (1H, M), 7.69 (1H, dd, J = 7, 1.4 Hz), 7.83 (1H, dd, J = 8.7, 7 Hz), 7.94 (1H, dd, J = 8.8, 1.4 Hz), 8.40 (1H, s)

Example 7

In the same manner as described in Examples 2 and 5, the following compounds are obtained.

3-dimethylaminomethyl-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine dihydrochloride (Compound 16)

Elemental analysis: C ₁₃ H ₂₀ N ₄ O ₂ S ₂ 2HC1,

Calc .: C, 38.05; H, 5.65; N, 13.65

Found: C, 38.33; H, 5.65; N, 13.61

NMR (90 MHz, DMSO-d ₆ -D ₂ 0) δ: 2.95 (9H, s), 3.30 (4H, m), 5.08 (2H, s), 7.68-8.06 (3H, m), 8.43 (1H, s )

Example 8

In the same manner as described in Example 3, the following compounds were obtained.

(1) 2-methyl-5- (2-methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 17)

Melting Point: 179-181 ℃

Elemental analysis: C ₁₁ H ₁₅ N ₃ O ₂ S ₂ ,

Calc .: C, 46.29; H, 5. 30; N, 14.72

Found: C, 46.03; H, 5. 27; N, 14.39

(2) 2-ethoxycarbonylmethyl-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 18)

NMR (90 MHz, CDC1 ₃ ) δ: 1.29 (3H, t, J = 7 Hz), 2.95 (3H, s), 3.05-3.48 (4H, m), 3.88 (2H, s), 4.22 (2H, q, J = 7 Hz), 5.61 (1H, br), 6.97 (1H, dd, J = 7, 1.5 Hz), 7.12 (1H, dd, J = 9, 7 Hz), 7.53 (1H, d, J = 9 Hz), 7.86 (1H, s)

(3) 3-ethoxycarbonyl-2-methyl-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 19)

NMR (90MHz, CDC1 ₃ ) δ: 1.40 (3H, t, J = 7Hz), 2.60 (3H, s), 2.85 (3H, s), 3.21 (4H, m), 4.43 (2H, q, J = 7Hz ), 5.20 (1H, br), 7.07 (1H, dd, J = 7, 1.5 Hz), 7.33 (1H, dd, J = 9, 7 Hz), 7.51 (1H, dd, J = 9, 1.5 Hz)

(4) 2-ethoxycarbonyl-5- [2-methylsulfonylamino) -ethylthio] imidazo [1,2-a] pyridine (Compound 20)

NMR (90 MHz, DMSO-d ₆ ) δ: 1.34 (3H, t, J = 7 Hz), 2.92 (3H, s), 3.26 (4H, m), 4.30 (2H, q, J = 7 Hz), 7.23 (1H , dd, J = 7, 1Hz), 7.30 (1H, br), 7.39 (1H, dd, J = 9, 7Hz), 7.64 (1H, d, J = 9Hz), 8.43 (1H, s)

Example 9

Synthesis of 2-carboxymethyl-5- [2- (methylsulfonylamino) ethylthio] imidazo [1.2-a] pyridine (Compound 21).

1NNaOH (6.93ml) in a solution of 2-ethoxycarbonyl-5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (1.65g, 4.62 mmol) in methanol (5m1) , 6.93 mmol), and the mixture is stirred at room temperature for 2.5 hours. After the reaction mixture is washed with methylene chloride, 1N HCl (17.39 ml, 17.39 mmol) is added thereto and the solvent is distilled off. Water is added to the residue and the solid obtained is washed with water and dried to give 777 mg (51. 1%, colorless solid) of the desired product.

Elemental analysis: C ₁₂ H ₁₅ N ₃ O ₄ S ₂

Calc .: C, 43.76; H, 4.59; N, 12.76

Found: C, 43.68; H, 4. 60; N, 12.64

NMR (200 MHz, DMSO-d ₆ ) δ: 2.92 (3H, s), 3.24 (4H, s), 3.75 (2H, s), 7.09 (1H, dd, J = 7.2, 1 Hz), 7.27 (1H, dd , J = 9, 7.2 Hz), 7.36 (1H, br), 7.48 (1H, d, J = 9 Hz), 7.86 (1H, s)

Example 10

Following the same manner as described in Examples 2 and 3 (1), the following compounds were obtained.

(1) 5- [2- (N-methyl-N-methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 22)

NMR (200 MHz, CDC1 ₃ ) δ: 2.82 (3H, s), 2.89 (3H, s), 3.22 (2H, m), 3.40 (2H, m), 7.03 (1H, dd, J = 7, 1 Hz), 7.19 (1H, dd, J = 9, 7 Hz), 7.62 (1H, d, J = 9 Hz), 7.72 (1H, d, J = 1.2 Hz), 7.86 (1H, s)

(2) 5- [2- (N-methyl-N-methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridinehydrochloride (Compound 23)

Melting Point: 152 ~ 154 ℃

(3) 5- [2- (methylsulfonylamino) ethyl sulfinyl] imidazo [1,2-a] pyridine (Compound 24)

Elemental analysis: C ₁₀ H ₁₃ N ₃ O ₃ S _{2 ·} 2H ₂ O,

Calc .: C, 41.28; H, 4. 64; N, 14.44

Found: C, 41.48; H, 4.57; N, 14.66

NMR (200 MHz, CDC1 ₃ -d ₆ ) δ: 2.98 (3H, s), 3.16-3.33 (1H, m), 3.39-3.76 (3H, m), 7.33-7.47 (3H, m), 7.33-7.84 ( 2H, m), 8.03 (1H, m)

(4) 5- [2- (methylsulfonylamino) ethylsulfonyl] imidazo [1,2-a] pyridine (Compound 25)

Elemental analysis: C ₁₀ H ₁₃ N ₃ O ₄ S ₂ ,

Calculated Value: C, 39.59; H, 4. 32; N, 13.85

Found: C, 39.31; H, 4.33; N, 13.78

NMR (200 MHz, CDC1 ₃ -DMSO-d ₆ ) δ: 2.88 (3H, s), 3.45-3.66 (4H, m), 7.40 (1H, d, J = 9, 7 Hz), 7.71 (1H, dd, J = 7, 1.2 Hz), 7.85 (1H, d, J = 1.2 Hz), 7.96 (1H, d, J = 9 Hz), 8.30 (1H, s)

(5) 5- [2- (trifluoromethylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 26)

NMR (90 MHz, DMSO-d ₆ ) δ: 3.12-3.52 (4H, m), 7.13 (1H, dd, J = 7, 1.5 Hz), 7.28 (1H, dd, J = 9, 7 Hz), 7.61 (1H , d, J = 9 Hz), 7.71 (1H, d, J = 1.5 Hz), 8.02 (1H, s)

(6) 5- [3- (methylsulfonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 27)

Elemental analysis: C ₁₁ H ₁₅ N ₃ O ₂ S ₂ ,

Calc .: C, 46.29; H, 5. 30; N, 14.72

Found: C, 46.35; H, 5. 34; N, 14.71

NMR (90 MHz, CDCl ₃ ) δ: 1.90 (2H, m), 2.93 (2H, s), 3.07 (2H, m), 3.27 (2H, m), 5.54 (1H, br), 6.90 (1H, dd, J = 7, 1 Hz), 7.11 (1H, dd, J = 9, 7 Hz), 7.57 (1H, d, J = 9 Hz), 7.65 (1H, d, J = 1.5 Hz), 7.82 (1H, s)

(7) 5- [3- (trifluoromethylsulfonylamino) -propylthio] imidazo [1,2-a] pyridine (Compound 28)

Elemental analysis: C ₁₁ H ₁₂ N ₃ O ₂ S ₂ F ₃ ,

Calc .: C, 38.93; H, 3.56; N, 12.38

Found: C, 38.91; H, 3. 64; N, 12.27

NMR (200 MHz, CDC1 ₃ -DMSO-d ₆ ) δ: 1.91 (2H, m), 3.09 (2H, t, J = 7.2 Hz), 3.36 (2H, t, J = 6.2 Hz), 6.97 (1H, dd , J = 7, 1Hz), 7.19 (1H, dd, J = 9, 7Hz), 7.58 (1H, dd, J = 9, 1Hz), 7.70 (1H, d, J = 1.2Hz), 7.88 (1H, s)

(8) 5- [1- (methylsulfonyl) -4-piperidylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 29)

Melting Point: 191 ~ 200 ℃

NMR (200 Hz, CDCl3) δ of the free compound: 1.70-2.13 (4H, m), 2.79 (3H, s), 2.90 (2H, m), 3.35 (1H, m), 3.69 (2H, m), 7.05 ( 1H, dd, J = 7, 1.2 Hz), 7.17 (1H, dd, J = 8.8, 7 Hz), 7.67 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 1.2 Hz), 7.96 (1H, s)

(9) 5- [2- (phenylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 30)

Elemental analysis: C ₁₅ H ₁₅ N ₃ O ₂ S _2,

Calc .: C, 54.03; H, 4.53; N, 12.60

Found: C, 53.88; H, 4.53; N, 12.43

NMR (200 MHz, CDC1 ₃ ) δ: 3.01-3.23 (4H, m), 5.05 (1H, br), 6.84 (1H, d, J = 7 Hz), 7.08 (1H, dd, J = 9, 7 Hz), 7.41 -7.63 (4H, m), 7.68 (1H, d, J = 1.4 Hz), 7.75-7.83 (3H, m)

(10) 5- [2- [4- (methyl) phenylsulfonylamino] ethylthio] imidazo- [1,2-a] pyridine (Compound 31)

Elemental _{analysis: C 16 H 17 N 3 O} 2 S 2 · 0.5H 2 O,

Calc .: C, 53.91; H, 5.0 9; N, 11.79

Found: C, 54.13; H, 4.94; N, 11.57

NMR (90 MHz, CDC1 ₃ -DMSO-d ₆ ) δ: 2.39 (3H, s), 3.16 (4H, m), 6.90-7.33 (3H, m), 7.47-7.90 (7H, m)

(11) 5- [2- [4- (acetamido) phenylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 32)

Elemental _{analysis: C 17 H 18 N 3 O} 2 S 2 · 1H 2 O,

Calc .: C, 49.98; H, 4.93; N, 13.72

Found: C, 50.16; H, 4. 60; N, 13.60

NMR (200 MHz, DMSO-d6) δ: 2.09 (3H, s), 2.98 (2H, m), 3.13 (2H, m), 6.99 (1H, dd, J = 1 Hz), 7.23 (1H, dd, J = 9, 7 Hz), 7.52-7.77 (6H, m), 7.83 (1H, br), 7.90 (1H, m)

(12) 5- [2- [4- (acetamido) phenylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 33)

Melting Point: 126 ~ 130 ℃

(13) 5- [2- [4- (chloro) phenylsulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 34)

Elemental analysis: C ₁₅ H ₁₄ N ₃ O ₂ S ₂ C10.5 H ₂ O,

Calc .: C, 47.80; H, 4.0 1; N, 11.15

Found: C, 48.03; H, 3.63; N, 11.18

NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) δ: 3.68 (4H, m), 6.98 (1H, d, J = 7 Hz), 7.18 (1H, dd, J = 9, 7 Hz), 7.44 (2H, m ), 7.56 (1H, d, J = 9 Hz), 7.67 (1H, d, J = 1.2 Hz), 7.74 (2H, m), 7.83 (1H, s), 7.87 (1H, br)

(14) 5- [2- [4- (fluoro) phenylsulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 35)

Elemental analysis: C ₁₅ H ₁₄ N ₃ O ₂ S ₂ F

Calc .: C, 51.27; H, 4.02; N, 11.96

Found: C, 51.16; H, 4.05; N, 12.05

NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) δ: 3.08 (4H, m), 6.95 (1H, dd, J = 7, 1 Hz), 7.07-7.20 (3H, m), 7.48 (1H, br), 7.58 (1H, d, J = 9 Hz), 7.68 (1H, d, J = 1.2 Hz), 7.77-7.86 (3H, m)

(15) 5- [2- [4- (methoxy) phenylsulfonylamino] ethylthio] -imidazo- [1,2-a] pyridine (Compound 36)

Elemental _{analysis: C 16 H 17 N 3 O} 2 S 2 · 0.3H 2 O,

Calculated Value: C, 51.10; H, 4.81; N, 11.39

Found: C, 51.25; H, 4.73; N, 11.47

NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) δ: 3.07 (4H, m), 3.86 (3H, s), 6.86-6.97 (3H, m), 7.15 (1H, dd, J = 9, 7 Hz), 7.20 (1 H, br), 7.57 (1 H, d, J = 9 Hz), 7.64-7.76 (3 H, m), 7.81 (1 H, s)

(16) 5- [2- [2,4,5- (trichloro) phenylsulfonylamino] ethylthio] -imidazo [1,2-a] pyridine (Compound 37)

Elemental _{analysis: C 15 H 12 N 3 O} 2 S 2 CL 3 · 0.5H 2 O,

Calc .: C, 40.42; H, 2.94; N, 9.43

Found: C, 40.65; H, 2. 74; N, 9.50

NMR (200 Hz, CDCl ₃ -DMSO-d ₆ ) δ: 3.07-3.25 (4H, m), 6.95 (1H, dd, J = 7, 1 Hz), 7.16 (1H, dd, J = 9, 7 Hz), 7.57 (1H, d, J = 9 Hz), 7.59 (1H, s), 8.07 (1H, s)

(17) 5- [2- [2,4,6- (trimethyl) phenylsulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 38)

Elemental analysis: C ₁₈ H ₂₁ N ₃ O ₂ S ₂ ,

Calc .: C, 57.57; H, 5.65; N, 11.19

Found: C, 57.32; H, 5.65; N, 11.09

NMR (200 Hz, CDCl ₃ ) δ: 2.30 (3H, s), 2.58 (6H, s), 2.98-3.20 (4H, m), 5.00 (1H, br), 6.81 (1H, d, J = 7 Hz), 6.92 (2H, s), 7.08 (1H, dd, J = 9, 7 Hz), 7.60 (1H, d, J = 9 Hz), 7.68 (1H, s), 7.77 (1H, s)

(18) 5- [2- [2,4,6- (triisopropyl) phenylsulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 39)

Elemental analysis: C ₂₄ H ₃₃ N ₃ O ₂ S ₂ ,

Calc .: C, 62.71; H, 7. 24; N, 9.14

Found: C, 62.65; H, 7. 15; N, 9.07

NMR (200 Hz, CDCl ₃ ) δ: 1.24 (12H, d, J = 6.8 Hz), 1.26 (6H, d, J = 7 Hz), 2.94 (1H, heptet, J = 7 Hz), 3.06-3.25 (4H, m ), 4.10 (2H, heptet, J = 6.8 Hz), 4.90 (1H, br), 6.83 (1H, dd, J = 7, 1 Hz), 7.08 (1H, dd, J = 9, 7 Hz), 7.59 (1H , d, J = 9 Hz), 7.68 (1H, d, J = 1.2 Hz), 7.80 (1H, m)

(19) 5- [2-[(2-thienyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 40)

Elemental analysis: C ₁₃ H ₁₃ N ₃ O ₂ S ₃ ,

Calc .: C, 46.00; H, 3. 86; N, 12.38

Found: C, 45.71; H, 3.88; N, 12.30

NMR (200 Hz, DMSO-d6) δ: 3.03-3.20 (4H, m), 7.04 (1H, dd, J = 7, 1 Hz), 7.12 (1H, m), 7.26 (1H, dd, J = 9, 7 Hz ), 7.50-7.61 (2H, m), 7.69 (1H, d, J = 1.4 Hz), 7.89 (1H, m), 7.93 (1H, m), 8.16 (1H, br)

(20) 5- [2-[(2-thienyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 41)

Melting Point: 140 ~ 143 ℃

Elemental analysis: C ₁₃ H ₁₃ N ₃ O ₂ S ₃ · HCl,

Calc .: C, 41.54; H, 3.75; N, 11.18

Found: C, 41.25; H, 3.80; N, 11.05

(21) 5- [2-[(1-naphthyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 42)

Elemental analysis: C ₁₉ H ₁₇ N ₃ O ₂ S ₂ ,

Calculated Value: C, 59.51; H, 4. 47; N, 10.96

Found: C, 59.73; H, 4.61; N, 10.77

NMR (200 Hz, CDCl ₃ ) δ: 2.97 (2H, m), 3.07 (2H, m), 5.55 (1H, br), 6.56 (1H, dd, J = 7, 1 Hz), 6.92 (1H, dd, J = 9, 7 Hz), 7.44-7.72 (6H, m), 7.96 (1H, m), 8.06 (1H, d, J = 8.2 Hz), 8.20 (1H, dd, J = 7.4, 1.2 Hz), 8.64 ( 1H, m)

(22) 5- [2-[(1- (naphthyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 43)

Melting Point: 179 ~ 185 ℃

(23) 5- [2-[(2-naphthyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 44)

Melting Point: 179 ~ 185 ℃

Elemental _{analysis: C 19 H 17 N 3 O} 2 S 3 · 0.2H 2 O,

Calc .: C, 58.95; H, 4.53; N, 10.86

Found: C, 59.15; H, 4.78; N, 10.55

NMR (200 Hz, CDCl ₃ ) δ: 3.07 (2H, m), 3.20 (2H, m), 5.31 (1H, br), 6.74 (1H, dd, J = 7, 1 Hz), 6.89 (1H, dd, J = 9,7 Hz), 7.51 (1H, d, J = 9 Hz), 7.58-7.85 (5H, m), 7.88-7.97 (3H, m), 8.39 (1H, d, J = 1.6 Hz)

(24) 5- [2-[(2-naphthyl) sulfonylamino] -ethylthio] -imidazo [1,2-a] pyridine hydrochloride (Compound 45)

Melting Point: 170 ~ 175 ℃

(25) 5- [2-[(8-quinolyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 46)

Elemental analysis: C ₁₈ H ₁₆ N ₄ O ₂ S ₂

Calculated Value: C, 56.23; H, 4. 19; N, 14.57

Found: C, 56.39; H, 4. 23; N, 14.69

NMR (200 Hz, CDCl ₃ ) δ: 3.00-3.22 (4H, m), 6.65 (1H, dd, J = 7, 1 Hz), 6.81 (1H, br), 6.97 (1H, dd, J = 9, 7 Hz) , 7.47-7.74 (5H, m), 8.06 (1H, dd, J = 8.4, 1.4 Hz), 8.26 (1H, dd, J = 8.4, 1.8 Hz), 8.40 (1H, dd, J = 7.2, 1.4 Hz ), 8.95 (1H, dd, J = 4.2, 1.8Hz)

(26) 5- [2- [8- (quinolyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 47)

Melting Point: 190 ~ 196 ℃

(27) 5- [2- [5- (dimethylamino)-(1-naphthylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 48)

NMR (200 MHz, CDCl ₃ ) δ: 2.90 (H, s), 2.93-3.12 (4H, m), 5.46 (1H, br), 6.56 (1H, dd, J = 7, 1 Hz), 6.92 (1H, dd , J = 9, 7 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.43-7.63 (4H, m), 7.67 (1H, s), 8.18 (1H, dd, J = 7.4, 1.2 Hz), 8.27 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 8.6 Hz)

(28) 5- [2-[(E) -styrylsulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 49)

Elemental analysis: C ₁₇ H ₁₇ N ₃ O ₂ S _2,

Calculated Value: C, 56.80; H, 4.77; N, 11.69

Found: C, 56.95; H, 4. 84; N, 11.62

NMR (200 MHz, CDCl ₃ ) δ: 3.14-3.34 (4H, m), 4.95 (1H, br), 6.70 (1H, d, J = 15.4 Hz), 6.98 (1H, dd, J = 7, 1 Hz), 7.09 (1H, dd, J = 9, 7 Hz), 7.43 (5H, m), 7.46 (1H, d, J = 15.4 Hz), 7.59 (1H, d, J = 9 Hz), 7.68 (1H, d, J = 1.4 Hz), 7.84 (1H, s)

(29) 5- [2- [N, N-di- (E) -styrylsulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 50)

Elemental analysis: C ₂₅ H ₂₃ N ₃ O ₄ S _3,

Calc .: C, 57.12; H, 4.41; N, 7.99

Found: C, 57.07; H, 4. 48; N, 7.81

NMR (200 MHz, CDCl ₃ ) δ: 3.33 (2H, m), 3.91 (2H, m), 7.05 (1H, dd, J = 7, 1 Hz), 7.12 (2H, d, J = 15.4 Hz), 7.18 ( 1H, dd, J = 8.8, 7Hz), 7.38-7.56 (12H, m), 7.61 (1H, d, J = 8.8Hz), 7.66 (1H, d, J = 1.2Hz), 7.77 (1H, s)

(30) 5- [2- [2- (acetylamino) -4- (methyl)-(5-thiazolyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 51)

NMR (200 MHz, DMSO-d ₆ ) δ: 2.17 (3H, s), 2.38 (3H, s), 3.07-3.49 (4H, m), 7.02 (1H, d, J = 7.2 Hz), 7.23 (1H, dd, J = 8.8, 7.2 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.67 (1H, s), 7.90 (1H, s), 8.20 (1H, br)

(31) 5- [3- (1-naphthylsulfonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 52)

Melting Point: 140 ~ 141 ℃

Elemental analysis: C ₂₀ H ₁₉ N ₃ O ₂ S _2,

Calc .: C, 60.43; H, 4. 82; N, 10.57

Found: C, 60.58; H, 4. 85; N, 10.60

(32) 5- [2- [N-methyl-N- (1-naphthylsulfonylamino)] ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 53)

Melting Point: 161 ~ 164 ℃

Elemental _{analysis: C 20 H 19 N 3 O} 2 S 2 · HCl,

Calc .: C, 55.35; H, 4.65; N, 9.68

Found: C, 55.31; H, 4. 69; N, 9.55

NHz (200 MHz, CDCl ₃ ) δ: 2.90 (3H, s), 3.12 (2H, m), 3.42 (2H, m), 6.92 (1H, dd, J = 7, 1Hz), 7.14 (1H) , dd, J = 9, 7Hz), 7.45 (1H, dd, J = 8.4, 7.4Hz), 7.53 to 7.71 (5H, m), 7.90 (1H, m), 8.02 (1H, d, J = 8.4Hz ), 8.09 (1H, dd, J = 7.4, 1.2 Hz), 8.60 (1H, m)

(33) 5- [2- [N-ethyl-N- (1-naphthylsulfonylamino)] ethylthio] imidazo [1,2-a] pyridinehydrochloride (Compound 54)

Melting Point: 178 ~ 185 ℃

Elemental _{analysis: C 21 H 21 N 3 O} 2 S 2 · HCl,

Calc .: C, 56.30; H, 4.95; N, 9.38

Found: C, 56.27; H, 4.97; N, 9.29

NMR of the free compound (200 MHz, CDCl 3) δ: 1.06 (3H, t, J = 7.2 Hz), 3.06 (2H, m), 3.30 to 3.50 (4H, m), 6.90 (1H, d, J = 7.2 Hz) , 7.15 (1H, dd, J = 9, 7.41 (1H, m), 7.53-7.71 (5H, m), 7.86-8.

(34) 5- [2- [2-hydroxyethyl) -N- (1-niphthylsulfonylamino)] ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 55)

Melting Point: 172 ~ 176 ℃

Elemental _{analysis: C 21 H 21 N 3 O} 3 S 2 · HCI

Calculated: C, 54.36: H, 4.78: N, 9.06

Found: C, 54.74: H, 4.85: N, 8.88

NMR (200 MH _Z, CDC1 ₃ ) δ: 2.10 (1H, br), 3.18 (2H, m), 3.41 ~ 3.62 (4H, m), 3.74 (2H, t, J = 5.2H _Z ) of free compounds, 6.90 (1H, dd, J = 7.1H _Z ) _, 7.12 (1H, dd, J = 9, 7H _Z ), 7.42 (1H, m), 7.85-8.10 (3H, m), 7.85-8.10 (3H, m ), 8.56 (1 H, m)

(35) 2-Methyl-5- [2- (1-naphthylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 56)

Elemental Analysis: C ₂₀ H ₁₉ N ₃ O ₂ S ₂

Calculated: C, 60.43: H, 4.82: N, 10.57

Found: C, 60.24: H, 4.84: N, 10.52

NMR (200 MH _Z, CDC1 ₃ ) δ: 2.44 (3H, s), 2.89 ~ 3.11 (4H, m), 5.30 (1H, br), 6.47 (1H, dd, J = 7, 1.2H _Z ), 6.85 (1H, dd, J = 9, 7H _Z ), 7.36-7.53 (3H, m), 7.96 (1H, dd, J = 6.8, 1.8H _Z ), 8.06 (1H, d, J = 8.2H _Z ), 8.19 (1H, doublet, J = 7.4, 1.2H _Z ), 8.63 (1H, d, J = 8.4H _Z )

(36) 3-ethoxycarbonyl-2-methyl-5- [2- [1- (naphthyl) sulfonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 57)

Elemental Analysis: C ₂₃ H ₂₃ N ₃ O ₄ S _{2 ·} 0.5 H ₂ O,

Calculated: C, 57.72: H, 5.05: N, 8.78

Found: C, 57.85: H, 5.02: N, 8.63

NMR (200MH _Z , CDC1 ₃ ) δ: 1.41 (3H, t, J = 7.2H _Z ), 2.61 (3H, _S ), 2.95 ~ 3.05 (4H, m), 4.42 (2H, q, J = 7.2H _Z ), 7.42 ~ 7.66 (4H, m), 7.91 (1H, m), 8.04 (1H, d, J = 8H Z), 8.16 (1H, dd, J = 7.4, 1.4H Z), 8.54 (1H, m )

(37) 2-ethoxycarbonyl-5- [2- (1-naphthylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 58)

Elemental Analysis: C ₂₂ H ₂₁ N ₃ O ₄ S ₂

Calculated: C, 58.00: H, 4.65: N, 9.22

Found: C, 57.79: H, 4.63: N, 9.24

NMR (200MH _Z , CDC1 ₃ ) δ: 1.45 (3H, t, J = 7.2H _Z ), 2.98 (2H, m), 3.12 (2H, m), 4.47 (2H, q, J = 7.2H _Z ), 5.26 (1H, br), 6.65 (1H, dd, J = 7,1H _Z ), 7.03 (1H, dd, J = 9,7H _Z ), 7.44 ~ 7.73 (4H, m), 7.95 (1H, dd, J = 7.2, 1.2H _Z ), 8.24 (1H, s), 8.62 (1H, m)

Example 11

In the same manner as described in Example 4 (1), the following compounds were obtained.

3-bromo-5- [2- (1- (naphthyl) sulfonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 59)

Elemental Analysis: C ₁₉ H ₁₆ N ₃ O ₂ S ₂ Br

Calculated Value: C, 49.35: H,

3.49: N, 9.09

Found: C, 49.39: H, 3.47: N, 8.98

Example 12

The following compounds are obtained in the same manner as described in Example 3 (1).

(1) 5- [2- (methylsulfonylamino) ethylamino] imidazo [1,2-a] pyridine (Compound 60)

(2) 5- [3- (methylsulfonylamino) propylamino] imidazo [1,2-a] pyridine (Compound 61)

NMR (90MH _Z , CDC1 ₃ -DMSO-d ₆ ) δ: 1.97 (2H, m), 2.90 (3H, s), 3.17 (2H, m), 3.46 (2H, m), 6.19 (1H, d, J = 8H _Z ), 6.91-7.20 (2H, m). 7.37 ~ 7.63 (2H, m), 7.71 (1H, d, J = 2H _Z ), 8.36 (1H, d, J = 2H _Z )

(3) 5- [2- (methylsulfonylamino) ethyloxy] imidazo [1,2-a] pyridine (Compound 62)

Elemental Analysis: C ₁₀ H ₁₃ N ₃ O ₃ S

Calculated: C, 47.05: H, 5.13: N, 16.46

Found: C, 46.95: H, 5.17: N, 16.38

NMR (200MH _Z , DMSO-d ₆ ) δ: 2.98 (3H, s), 3.49 (2H, m), 4.35 (2H, t, J = 5.2H _Z ), 6.34 (1H, dd, J = 6, 1.6 H _Z ), 7.16-7.32 (2H, m), 7.50 (1H, br), 7.57 (1H, d, J = 1.2H _Z ), 7.91 (1H, s)

(4) 5- [2- (trifluoromethylsulfonylamino) ethyloxy] imidazo [1,2-a] pyridine (Compound 63)

NMR (200MH _Z , DNSO-d ₆ ) δ: 3.71 (2H, m), 4.38 (2H, t, J = 5H _Z ) 6.38 (1H, dd, J = 6.6, 1.6H _Z ), 7.19 ~ 7.34 (2H , m), 7.60 (1 H, s), 7.87 (1 H, s)

(5) 5- [3- (methylsulfonylamino) propyloxy] imidazo [1,2-a] pyridine (Compound 64)

NMR (200MH _Z , CDC1 ₃ -DMSO-d ₆ ) δ: 2.2 (2H, m), 2.93 (3H, s), 3.35 (2H, m), 4.39 (2H, t, J = 6.2H _Z ), 6.11 (1H, dd, J = 6.8, 1.6H _Z ), 6.91 (1H, br), 7.14 ~ 7.29 (2H, m), 7.57 (1H, d, J = 1.4H _Z ), 7.67 (1H, m)

(6) 5- [3- (trifluoromethylsulfonylamino) propyloxy] imidazo [1,2-a] pyridine (Compound 65)

NMR (200MH _Z , DMSO-d ₆ ) δ: 2.05 (2H, m), 2.91 (3H, s), 3.21 (3H, m), 4.38 (2H, t, J = 6H _Z ), 6.35 (1H, dd , J = 7, 1.2H _Z ), 7.10 ~ 7.32 (3H, m), 7.56 (1H, d, J = 1.4H _Z ), 7.78 (1H, s)

(7) 5- [4- (methylsulfonylamino) butyloxy] imidazo [1,2-a] pyridine (Compound 66)

Elemental Analysis: C ₁₂ H ₁₇ N ₃ O ₃ S

Calculated: C, 50.87: H, 6.05: N, 14.83

Found: C, 50.60: H, 6.11: N, 14.78

NMR (200MH _Z , CDC1 ₃ ) δ: 1.87 (2H, m), 2.04 (2h, m), 2.99 (3H, s), 3.28 (2H, m), 4.29 (2H, t, J = 6.2H _Z ) , 4.58 (1H, br), 6.04 (1H, d, J = 7.2H _Z ), 7.29 (1H, d, J = 9H _Z ), 7.59 (1H, d, J = 1.4H _Z ), 7.63 (1H, m)

(8) 5- [4- (trifluoromethylsulfonylamino) butyloxy] imidazo [1,2-a] pyridine (Compound 67)

Elemental Analysis: C ₁₂ H ₁₄ N ₃ O ₃ SF ₃

Calculated: C, 42.73: H, 4.18: N, 12.56

Found: C, 42,53: H, 4.27: MN, 12.25

NMR (200MH _Z , CDC1 ₃ -DMSO-d ₆ ) δ: 1.87 (2H, m), 2.03 (2H, m), 3.30 (2H, m), 4.30 (2H, t, J = 6H _Z ), 6.08 ( 1H, dd, J = 6.4, 1.4H _Z ), 7.14 ~ 7.28 (2H, m), 7.57 (1H, s), 7.68 (1H, s)

(9) 5- [5- (methinesulfonylamino) pentyloxy] imidazo [1,2-a] pyridine (Compound 68)

Elemental Analysis: C ₁₃ H ₁₉ N ₃ O ₃ S

Calculated: C, 52.51: H, 6.44: N. 14.13

Found: C, 52.22: H, 6.53: N, 13.83

NMR (200MH _Z , CDC1 ₃ ) δ: 1.54-1.80 (4H, m), 1.97 (2H, m), 3.20 (2H, m), 4.25 (2H, t, J = 6.2H _Z ), 4.59 (1H, br), 6.02 (1H, dd, J = 7.2, 1H _Z ), 7.17 (1H, dd, J = 9, 7H _Z ), 7.28 (1H, d, J = 9H _Z ), 7.59 (1H, d, J = 1.4H _Z ) 7.63 (1H, m)

(10) 5- [5- (trifluoromethylsulfonylamino) pentyloxy] imidazo [1,2-a] pyridine (Compound 69)

Elemental Analysis: C ₁₃ H ₁₆ N ₃ O ₃ SF ₃

Calculated Value: C, 44.44: H, 4.59: N, 11.96

Found: C, 44.47: H, 4.63: N, 11.71

NMR (200MH _Z , CDC1 ₃ ) δ: 1.63 ~ 2.02 (6H, m), 3.42 (2H, m), 4.18 (2H, t, J = 6H _Z ), 5.94 (1H, d, J = 7H _Z ), 7.12 (1H, dd, J = 9, 7H _Z ), 7.23 (1H, d, J = 9H _Z ), 7.30 (1H, d, J = 1H _Z ), 7.41 (1H, d, J = 1H _Z )

(11) 5- [6- (methylsulfonylamino) hexyloxy] imidazo [1,2-a] pyridine (Compound 70)

Elemental analysis: C ₁₄ H ₂₁ N ₃ O ₃ S · 0.2H ₂ 0

Calculated Value: C, 53.38: H, 6.85: N, 13.34

Found: C, 53.67: H, 7.04: N, 13.28

NMR (200MH _Z, CDC1 ₃ ) δ: 1.40 ~ 1.73 (6H, m), 1.91 (2H, m), 3.17 (2H, m), 4.24 (2H, t, J = 6.2H _Z ), 4.61 (1H, br), 6.02 (1H, dd, J = 7, 1H _Z ), 7.17 (1H, dd, J = 9,7H _Z ), 7.28 (1H, d, J = 9H _Z ), 7.59 (1H, d, J = 1.4H _Z ), 7.65 (1H, m)

(12) 5- [6- (trifluoromethylsulfonylamino) hexyloxy] imidazo [1,2-a] pyridine (Compound 71)

NMR (200MH _Z , CDC1 ₃ ) δ: 1.32 ~ 2.03 (8H, m), 3.37 (2H, t, J = 6.6H _Z ), 4.17 (2H, t, J = 6.2H _Z ), 5.97 (1H, d , J = 7H _Z ), 7.16 (1H, dd, J = 9,7H _Z ), 7.21 (1H, br), 7.25 (1H, d, J = 9H _Z ), 7.51 (1H, d, J = 1.1H _Z ), 7.54 (1H, s)

(13) 5- [2- (methylsulfoniamino) propyloxy] -imidazo [1,2-a] pyridine (Compound 72)

Melting Point: 171 ~ 172 ℃

(14) 5- [1- (methylsulfonylamino)-(2-propyloxy)] imidazo [1,2-a] pyridine (Compound 73)

Elemental Analysis: C ₁₁ H ₁₅ N ₃ O ₃ S

Calculated: C, 49.06: H, 5.61: N, 15.60

Found: C, 48.81: H, 5.63: N, 15.59

NMR (200MH _Z , CDC1 ₃ ) δ: 1.47 (3H, d, J = 6.2H _Z ), 3.01 (3H, s), 3.50 (2H, m), 4.84 (1H, m), 6.10 (1H, d, J = 7.4H _Z ), 6.38 (1H, br), 7.09 (1H, DD, J = 9, 7.4H _Z ), 7.21 (1H, d, J = 9H _Z ), 7.41 (1H, d, J = 1.4 H _Z )

(15) 5- [2- (methylsulfonylamino) -1- (phenyl) -ethyloxy] imidazo [1,2-a] pyridine (Compound 74)

NMR (200MH _Z , CDC1 ₃ ) δ: 2.94 (3H, s), 3.61 ~ 3.83 (2H, m) 5.33 (1H, br), 5.58 (1H, dd, J = 7, 4.6H _Z ), 5.91 (1H , d, J = 7.4Hz), 7.00 (1h, dd, J = 9, 7.4H _Z ), 7.24 (1H, d, J = 9H _Z ), 7.40 (5H, m), 7.60 (1H, d, J = 1.4H _Z ), 7.73 (1H, s)

(16) 5-[[1- (phenyl) -2-trifluoromethylsulfonylamino)] ethyloxy] imidazo [1,2, -a] pyridine (Compound 75)

(17) 5- [1- (methylsulfonyl) -4-piperidyloxy] imidazo [1,2-a] riridine (Compound 76)

(18) 5- [1- (trifluoromethylsulfonyl) -4-piperidyloxy] imidazo [1,2-a] pyridine (Compound 77)

NMR (200MHz, CDC1 ₃ ) δ: 2.18 (4H, m), 3.71 (4H, s), 4.99 (1H, m), 6.08 (1H, d, J = 7Hz), 7.19 (1H, dd, J = 9 , 7 Hz), 7.33 (1H, d, J = 9 Hz), 7.64 (1H, s), 7.65 (1H, s)

(19) 5- [2- (1- (naphthyl) sulfonylamino) ethyloxy] imidazo [1,2-a] pyridine (Compound 78)

Elemental Analysis: C ₁₉ H ₁₇ N ₃ O ₃ S

Calculated: C, 62.11: H, 4.66: N, 11.44

Found: C, 62.04: H, 4.57: N, 11.41

NMR (200 MHz, DMSO-d ₆ ) δ: 3.38 (2H, m), 4.11 (2H, t, J = 5.2 Hz), 6.06 (1H, m), 7.08-7.20 (2H, m), 7.46-7.85 ( 5H, m), 8.00 (1H, m), 8.16 (1H, s), 8.20 (1H, s), 8.47 (1H, br), 8.64 (1H, m)

(20) 5- [3- (1- (naphthyl) sulfonylamino) propyloxy] imidazo [1,2-a] pyridine (Compound 79)

Elemental Analysis: C ₂₀ H ₁₉ N ₃ O ₃ S

Calculated: C, 62.97: H, 5.02: N, 11.02

Found: C, 62.82: H, 4.98: N, 11.14

NMR (200 MHz, CDC1 ₃ -DMSO-d ₆ ) δ: 1.98 (2H, m), 3.19 (2H, m), 3.98 (2H, t, J = 6 Hz), 5.59 (1H, d, J = 7.2 Hz) , 6.99 to 7.35 (4H, m), 7.43 to 7.63 (3H, m), 7.67 to 7.80 (3H, m), 8.14 (1H, d, J = 7.4 Hz), 8.68 (1H, d, J = 8.2 Hz )

(21) 5- [6- (1- (naphthyl) sulfonylamino) hexyloxy] imidazo [1,2-a] pyridine (Compound 80)

Elemental Analysis: C ₂₃ H ₂₅ N ₃ O ₃ S · O.3H ₂ O

Calculated: C, 64.40: H, 6.02: N, 9.80

Found: C, 64.66: H, 6.07: N, 9.68

(22) 5- [2- (1-naphthyl (sulfonylamino) propyloxy] imidazo [1,2-a] pyridine (Compound 81)

Melting Point: 188 ~ 190 ℃

(23) 5- [1- (1-taphthylsulfonyl))-(4-piperidyl) oxy] imidazo [1,2-a] pyridine (Compound 82)

Example 13

(1) Synthesis of 5- [2- (acetylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 83)

5- [2-(amino) ethylthio] imidazo [1,2-a] pyridine dihydrochloride (2.66 g, 10 mmol) and triethylamine (4.32) dissolved in N, N-dimethylformamide (24 ml) acetyl chloride (0.71 ml, 10 mmol) is added to the solution of ml, 31 mmol) with stirring under ice cooling, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is poured into water and extracted with chloroform. The chloroform layer is washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethanol / ethyl acetate = 1: 3) to give 1.57 g (66.8%, colorless crystals) of the desired product.

Elemental Analysis: C ₁₁ H ₁₃ N ₈ OS · O.3H ₂ O

Calculated: C, 54.89: H, 5.69: N, 17.46

Found: C, 55.29: H, 5.52: N, 17.42

According to the same manner as described in Examples 2 and 13 (1), the following compounds are obtained.

(2) 5- [2- (trifluoroacetylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 84)

(3) 5- [2- (decanoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 85)

(4) 5- [2- (aminoacetylamino) ethylthio] imidazo [1,2-a] pyridine dihydrochloride (Compound 86)

(5) 5- [2- (benzoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 87)

(6) 5- [2- [3 (2H) -pyridazinone-6-carbonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 88)

(7) 5- [2-[(2-tenoylamino)] ethylthio] imidazo [1,2-a] pyridine (Compound 89)

(8) 5- [2- (1-naphthoyl) aminoethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 90)

(9) 5- [2- (2-naphthoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 91)

(10) 5- [2- (nicotinoylamino} ylthio] imidazo [1,2-a] pyridine (Compound 92)

(11) 5- [2- (isonicothiylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 93)

(12) 5- [2-3,4- (dimethoxy) phenylacetylamino] ethylthio] imidazo [1,2-a] pyridine dihydrate chloride (Compound 94)

(13) 5- [2- [3- (3-pyridyl) acryloylamino) ethylthio] imidazo [1,2-a] pyridine dihydrochloride (Compound 95)

(14) 5- [3- (benzoylamino) propylamino] imidazo [1,2-a] pyridine (Compound 96)

(15) 5- [3- (decanoylamino) propylamino] imidazo {1,2-a] pyridine (Compound 97)

Example 14

(1) Synthesis of 5- [2- [2- (carboxy) benzoylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 98).

Phthalic anhydride (1.12 g, 7.56 mmol) was added to a solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (1.12 g, 5.8 mmol) in chloroform (58 ml), and the mixture was The mixture is stirred at room temperature for 14 hours and then heated at reflux for 5 hours. The reaction mixture is left to cool. The precipitated crystals are filtered off, washed with chloroform and dried to give 1.68 g (84.8%, colorless crystals) of the desired product.

Example 15

(1) Synthesis of 5- [2- (phthalimide) ethylthio] imidazo [1,2-a] pyridine (Compound 99).

Hydrogen chloride-methanol solution (40 ml) was added to 5- [2- [2- (carboxy) benzoylamino] ethylthio] imidazo [1,2-a] pyridine dihydrochloride (638 mg, 2 mmol), and the mixture was Heat at reflux for 24 hours. After distilling off the solvent, the residue is dissolved in chloroform, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 530 mg (81.9%, yellow crystals) of the desired product.

Example 16

(1) Synthesis of 5- [2- (methylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 100).

To the solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (1.93 g, 10 mmol) in methylene chloride (30 ml) was stirred methyl isocyanate (0.59 ml, 10 mmol) under ice cooling While adding, the mixture is stirred for 1 hour under ice-cooling. After distilling off the solvent, the residue is purified by column chromatography eluent: ethanol / ethyl acetate = 1: 5) to give 2.15 g (86.0%. Pale yellow crystals) of the desired product.

In the same manner as described in Example 16 (1), the following compounds were obtained.

(2) 5- [2- (ethylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 101)

(3) 5- [2- (propylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 102)

(4) 5- [2- (isopropylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 103)

(5) 5- [2- (butylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 104)

(6) 5- [2- (cyclohexylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 105)

(7) 5- [2- (phenylcarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 106)

Example 17

(1) Synthesis of 5- [2- (methylthiocarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 107).

To a solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (2.96 g, 15.3 mmol) in methylene chloride (50 ml), methyl isocyanate (1.12 ml, 15.3 mmol) was stirred under ice cooling Adding while stirring the mixture at room temperature for 3 hours. After the solvent is concentrated, ether is added. The precipitated crystals are then filtered off and washed with ether to yield 2.76 g (67.6%, colorless crystals) of the desired product.

Elemental Analysis: C ₁₁ H ₁₄ N ₄ S ₂

Calculated: C, 49.60: H, 5.30: N, 21.03

Found: C, 49.63; H, 5. 34; N, 21.03

In the same manner as described in Example 17 (1), the following compounds were obtained.

(2) 5- [2- (phenylthiocarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 108)

(3) 5- [2- [4- (methoxy) phenylthiocarbamoylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 109)

(4) 5- [2- [4- (methyl) phenylthiocarbamoylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 110)

(5) 5- [2- [4- (chloro) phenylthiocarbamoylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 111)

(6) 5- [2-[(1-naphthyl) thiocarbamoylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 112)

(7) 2-ethoxycarbonylmethyl-5- [2- (phenylthiocarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 113]

(8) 2-ethoxycarbonyl-5- [2- (phenylthiocarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 114)

(9) 2-methyl-5- [2- (phenylthiocarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 115)

(10) 3-ethoxycarbonyl-2-methyl-5- [2- (phenylthiocarbamoylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 116)

(11) 5- [3- (phenylthiocarbamoylamino) propylthio] imidazo [1,2-a] pyridine (Compound 117)

Example 18

(1) Synthesis of 5- [2- (methylcarbamoyloxy) ethylthio] imidazo [1,2-a] pyridine (Compound 118).

Methyl isocyanate in a solution of 5- [2- (hydroxy) ethylthio] imidazo [1,2-a] pyridine (971 mg, 5 mmol) and triethylamine (0.91 ml, 6.53 mmol) in methylene chloride (40 ml) (0.65 ml, 11 mmol) is added with stirring under ice cooling and the mixture is stirred at room temperature for 12 hours. The reaction mixture is washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: methanol / chloroform = 1: 20) to obtain 1.07 g of the desired product (85.2%, colorless crystals).

The following compounds are obtained according to the same method as described in Example 18 (1).

(2) 5- [2- (butylcarbamoyloxy) ethylthio] imidazo [1,2-a] pyridine (Compound 119)

(3) 5- [2- (phenylcarbamoyloxy) ethylthio] imidazo [1,2-a] pyridine (Compound 120)

(4) 5- [2-[(1-naphthyl) carbamoyloxy) ethylthio] imidazo [1,2-a] pyridine (Compound 121)

(5) 5- [2- (benzylcarbamoyloxy) ethylthio] imidazo [1,2-a] pyridine (Compound 122)

Example 19

(1) Synthesis of 5- [2- [3- (hydroxy) propylcarbamoyloxy] ethylthio] imidazo [1,2-a] pyridine (Compound 123)

The mixture obtained by adding 3-aminopropanol (0.27 ml, 3.52 mmol) to 5- [2- (phenoxycarbonyloxy) ethylthio] imidazo [1,2-a] pyridine (1.10 g, 3.50 mmol) Stir at 120 ° C. for 1.5 h. The reaction mixture is left to cool, chloroform is added thereto, washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue is then purified by column chromatography (eluent: methanol / chloroform = 1: 20) to give 575 g of the desired product (55.6%, colorless crystals).

Elemental analysis: C ₁₃ H ₁₇ N ₃ O ₃ S, 0.2H ₂ O,

Calculated: C, 52.23; H, 5.87; N, 14.06

Found: C, 52.46; H, 5.78; N, 14.26

According to the same method as described in Example 19 (1), the following compounds are obtained.

(2) 5- [2- [6- (hydroxy) hexylcarbamoyloxy] ethylthio] imidazo [1,2-a] pyridine (Compound 124)

Elemental analysis: C ₁₆ H ₂₃ N ₃ O ₃ S, 0.2H ₂ O,

Calculated: C, 56.35; H, 6.92; N, 12.32

Found: C, 56.63; H, 6.89; N, 12.43

(3) 5- [2- [3- (morpholino) propylcarbamoyloxy] ethylthio] imidazo [1,2-a] pyridine (Compound 125)

(4) 5- [2- [3- (1-imidazolyl) propylcarbamoyloxy] ethylthio] imidazo [1,2-a] pyridine (Compound 126)

(5) 5- [2- [4- (pyridyl) methylcarbamoyloxy] ethylthio] imidazo [1,2-a] pyridine (Compound 127)

Example 20

(1) Synthesis of 5- [2- (methoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 128).

While stirring in a solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (1.93 g, 10 mmol) and triethylamine (1.53 ml, 11 mmol) in methylene chloride (30 ml) Methyl chloroformate (0.77 ml, 10 mmol) is added under ice cooling and the resulting mixture is stirred at room temperature for 20 minutes. The reaction mixture is washed sequentially with aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography (eluent: ethanol / ethyl acetate = 1: 10) to give 1.68 g of the desired product (66.9%, colorless crystals).

Melting Point: 198.0 ~ 200.0 ℃

Elemental analysis: C ₁₁ H ₁₃ N ₃ O ₂ S,

Calc .: C, 52.57; H, 5. 21; N, 16.72

Found: C, 52.68; H, 5. 22; N, 16.60

NMR (200MHz, CDCl ₃ ) δ: 3.12 (2H, m), 3.40 (2H, m), 3.68 (3H, s), 5.10 (1H, br), 7.00 (1H, d, J = 7Hz), 7.16 ( 1H, dd, J = 9, 7 Hz), 7.61 (1H, d, J = 9 Hz), 7.72 (1H, s), 7.87 (1H, s)

According to the same method as described in Examples 2 and 20 (1), the following compounds are obtained.

(2) 5- [2- (ethoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 129)

Melting Point: 68 ~ 70 ℃

Elemental analysis: C ₁₄ H ₁₉ N ₃ O ₂ S,

Calc .: C, 54.32; H, 5. 70; N, 15.84

Found: C, 54.43; H, 5.75; N, 15.83

(3) 5- [2- (propyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 130)

Melting Point: 62 ~ 64 ℃

Elemental Analysis: C ₁₃ H ₁₇ N ₃ O ₂ S

Calc .: C, 55.89; H, 6. 13; 15.04

Found: C, 55.87; H, 6.09; 14.96

(4) 5- [2- (butyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 131)

Melting Point: 75 ~ 76 ℃

Elemental Analysis: C ₁₄ H ₁₉ N ₃ O ₂ S

Calc .: C, 57.31; H, 6.53; N, 14.32

Found: C, 57.32; H, 6. 55; N, 14.23

NMR (200 MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7 Hz), 1.35 (2H, m), 1.58 (2H, m), 3.14 (2H, t, J = 6.4 Hz), 3.41 (2H, m), 4.05 (2H, t, J = 6.6 Hz), 5.04 (1H, br), 7.16 (1H, dd, J = 9, 7 Hz), 7.60 (1H, d, J = 9 Hz), 7.71 (1H, d, J = 1.2 Hz), 7.85 (1 H, s)

IR (KBr) cm ^-1 : 3490, 3210, 2970, 1695, 1615, 1500, 1285

(5) 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 132)

Melting Point: 80.0∼81.0 ℃

Elemental analysis: C ₁₃ H ₁₇ N ₃ O ₂ S,

Calc .: C, 55.89; H, 6. 13; N, 15.04

Found: C, 55.85; H, 6. 14; N, 14.96

NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, t, J = 6.2 Hz), 3.14 (2H, t, J = 6.4 Hz), 3.41 (2H, m), 4.94 (1H, br), 7.02 (1H , d, J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9Hz), 7.71 (1H, d, J = 1.4Hz), 7.86 (1H, s)

IR (KBr) cm ^-1 : 3220, 3025, 2970, 1705, 1630, 1545, 1300, 1240

(6) 5- [2- (isopropyloxycarbonyl) ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 133)

Melting Point: 145 ~ 150 ℃

(7) 5- [2- (isobutyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 134)

Melting Point: 75 ~ 76 ℃

Elemental analysis: C ₁₄ H ₁₉ N ₃ O ₂ S,

Calc .: C, 57.31: H, 6.53; N, 14.32

Found: C, 57.29; H, 6.53; N, 14.41

NMR (200 MHz, CDCl ₃ ) δ: 0.91 (6H, d, J = 6.8 Hz), 1.89 (1H, m), 3.14 (2H, t, J = 6.4 Hz), 3.42 (2H, m), 3.84 (2H , d, J = 6.6 Hz), 5.15 (1H, br), 7.01 (1H, d, J = 7 Hz), 7.16 (1H, dd, J = 9, 7 Hz), 7.59 (1H, d, J = 9 Hz) , 7.70 (1H, d, J = 1.2 Hz), 7.85 (1H, s)

(8) 5- [2- (allyloxycarbonylamino) ethylthio] imidazo [1,2-a], pyridine (Compound 135)

Melting Point: 72.5 ~ 73.5 ℃

Elemental analysis: C ₁₃ H ₁₅ N ₃ O ₂ S,

Calc .: C, 56.30; H, 5. 45; N, 15.15

Found: C, 56.34; H, 5. 44; N, 15.04

NMR (200 MHz, CDCl ₃ ) δ: 3.15 (2H, t, J = 6.4 Hz), 3.43 (2H, m), 4.56 (2H, m), 5.07 (1H, br), 5.18-5.36 (2H, m) , 5.90 (1H, m), 7.02 (1H, d, J = 7 Hz), 7.17 (1H, dd, J = 9, 7 Hz), 7.61 (1H, d, J = 9 Hz), 7.72 (1H, d, J = 1.4 Hz), 7.86 (1 H, m)

IR (KBr) cm ^-1 : 3205, 3020, 1700, 1625, 1570, 1490, 1270

(9) 5- [2- [2,2,2- (trichloro) ethoxycarbonylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 136)

Melting Point: 113 ~ 114.0 ℃

Elemental analysis: C ₁₂ H ₁₂ N ₃ O ₂ SCl ₃ ,

Calculated Value: C, 39.10; H, 3. 28; N, 11.40

Found: C, 39.23; H, 3. 27; N, 11.25

NMR (200 MHz, CDCl ₃ ) δ: 3.17 (2H, t, J = 6.4 Hz), 3.48 (2H, m), 4.73 (2H, s), 5.52 (1H, br), 7.03 (1H, d, J = 7 Hz), 7.17 (1H, dd, J = 9, 7 Hz), 7.62 (1H, d, J = 9 Hz), 7.71 (1H, d, J = 1.2 Hz), 7.87 (1H, m)

IR (KBr) cm ^-1 : 3195, 2975, 1725, 1615, 1545, 1485, 1260, 1210

(10) 5- [2- (benzyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 137)

Melting Point: 52∼53 ℃

Elemental analysis: C ₁₇ H ₁₇ N ₃ O ₂ S,

Calc .: C, 62.36; H, 5. 23; N, 12.83

Found: C, 62.34; H, 5. 22; N, 12.75

NMR (200 MHz, CDCl ₃ ) δ: 3.14 (2H, t, J = 6.4 Hz), 3.43 (2H, m), 5.09 (2H, s), 5.17 (1H, br), 6.99 (1H, d, J = 6.8 Hz), 7.13 (1H, dd, J = 9.2, 6.8 Hz), 7.35 (5H, s), 7.59 (1H, d, J = 9.2 Hz), 7.69 (1H, s), 7.84 (1H, s)

(11) 5- [2-[(9- (fluoroenyl) methyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 138)

Melting Point: 105.0 ~ 108.0 ℃

Elemental analysis: C ₂₅ H ₂₁ N ₃ O ₂ S, 0.4H ₂ O,

Calc .: C, 69.07; H, 5.05; N, 9.67

Found: C, 69.14; H, 5. 23; N, 9.96

NMR (200 MHz, CDCl ₃ ) δ: 3.13 (2H, t, J = 6 Hz), 3.42 (2H, m), 4.21 (1H, t, J = 6.6 Hz), 4.43 (2H, d, J = 6.6 Hz) , 5.17 (1H, br), 7.01 (1H, d, J = 7.4Hz), 7.15 (1H, dd, J = 8.6, 7.4Hz), 7.29-7.46 (4H, m), 7.53-7.75 (3H, m ), 7.60-7.87 (4H, m)

IR (KBr) cm ^-1 : 3205, 3020, 1710, 1625, 1550, 1485, 1450, 1270

(12) 5- [2- (phenoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 139)

Melting Point: 96.0∼ 97.0 ℃

Elemental analysis: C ₁₆ H ₁₅ N ₃ O ₂ S,

Calc .: C, 61.32; H, 4. 82; N, 13.41

Found: C, 61.35; H, 4. 86; N, 13.30

IR (KBr) cm ^-1 : 3200, 3005, 1725, 1615, 1555, 1485, 1270, 1210

(13) 5- [2- (N-methyl-N-isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 140)

NMR (200 MHz, CDCl ₃ ) δ: 1.02 to 1.35 (6H, m), 2.91 (3H, s), 3.05 to 3.26 (2H, m), 3.38 to 3.60 (2H, m), 4.89 (1H, m), 7.01 (1H, br), 7.18 (1H, dd, J = 9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.71 (1H, s), 7.84 (1H, s)

IR (KBr) cm ^-1 : 3220, 3025, 2970, 1705, 1630, 1545

(14) 5- [2- (N-ethyl-N-isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 141)

NMR (200 MHz, CDCl ₃ ) δ: 0.95 to 1.35 (9H, m), 3.02 to 3.68 (6H, m), 4.90 (1H, m), 7.04 (1H, m), 7.19 (1H, dd, J = 9 , 7Hz), 7.60 (1H, d, J = 9Hz), 7.72 (1H, s), 7.83 (1H, s)

IR (KBr) cm ^-1 : 3220, 3025, 2970, 1705, 1630, 1545

Example 21

Example 4 Following the same method as described in (1), the following compounds were obtained.

(1) 3-bromo-5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 142)

Melting Point: 103.0 ~ 104.0 ℃

Elemental analysis: C ₁₃ H ₁₆ N ₃ O ₂ SBr,

Calc .: C, 43.58; H, 4.50; N, 11.73

Found: C, 43.60; H, 4.53; N, 11.74

NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J = 6.2 Hz), 3.11 (2H, t, J = 6.6 Hz), 3.42 (2H, m), 4.90 (1H, heptet, J = 6.2 Hz ), 4.96 (1H, br), 7.00 (1H, dd, J = 7, 1.2 Hz), 7.14 (1H, dd, J = 8.8, 7 Hz), 7.57 (1H, dd, J = 8.8, 1.2 Hz), 7.59 (1H, s)

(2) 3-chloro-5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 143)

Melting Point: 113.0 ~ 114.0 ℃

Elemental analysis: C ₁₃ H ₁₆ N ₃ O ₂ SCl · 0.2H ₂ O,

Calc .: C, 49.19; H, 5. 21; N, 13.24

Found: C, 49.38; H, 5. 26; N, 13.22

NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J = 6.4 Hz), 3.12 (2H, t, J = 6.4 Hz), 3.43 (2H, m), 4.90 (1H, heptet, J = 6.4 Hz ), 4.96 (1H, br), 6.99 (1H, dd, J = 7.2, 1.2 Hz), 7.10 (1H, dd, J = 8.8, 7.2 Hz), 7.53 (1H, dd, J = 8.8, 1.2 Hz) , 7.54 (1H, s)

Example 22

According to the same method as described in Example 5, the following compounds were obtained.

5- [2- (isopropyloxycarbonylamino) ethylthio] -3- (morpholinomethyl) imidazo [1,2-a] pyridine (Compound 144)

NMR (200 MHz, CDCl ₃ ) δ: 0.96 (6H, d, J = 6.2 Hz), 2.56 (4H, m), 3.26 (2H, m), 3.36 (2H, m), 3.65 (4H, m), 4.10 (2H, s), 4.59 (1H, heptet, J = 6.2 Hz), 6.85 (1H, br), 7.01 (1H, d, J = 5 Hz), 7.13 (1H, dd, J = 8.6, 6.6 Hz), 7.51 (1H, s), 7.53 (1H, d, J = 8.6Hz)

Example 23

In the same manner as in the method described in Example 20 (1), the following compounds were obtained.

(1) 5- [3- (methoxycarbonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 145)

Melting Point: 69.0 ~ 70.0 ℃

Elemental analysis: C ₁₂ H ₁₅ N ₃ O ₂ S,

Calc .: C, 54.32; H, 5. 70; N, 15.84

Found: C, 54.48; H, 5. 74; N, 15.72

NMR (200MHz, CDCl ₃ ) δ: 1.85 (2H, m), 3.02 (2H, t, J = 7 Hz), 3.32 (2H, m), 3.67 (3H, s), 4.85 (1H, br), 6.91 (1H, dd, J = 7, 1.2 Hz), 7.15 (1H, dd, J = 9, 7 Hz), 7.58 (1H, d, J = 9 Hz), 7.70 (1H, d, J = 1.2 Hz), 7.84 (1H, s)

(2) 5- [3- (isopropyloxycarbonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 146)

NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J = 6.2 Hz), 1.85 (2H, m), 3.03 (2H, m), 3.31 (2H, m), 4.82 (1H, br), 4.90 (1H, heptet, J = 6.2 Hz), 6.90 (1H, dd, J = 7, 1 Hz), 7.15 (1H, dd, J = 9, 7 Hz), 7.57 (1H, m), 7.69 (1H, d, J = 1.4 Hz), 7.84 (1 H, m)

IR (KBr) cm ^-1 : 3210, 3025, 2965, 1695, 1620, 1545, 1490, 1275

(3) 5- [1- (t-butoxycarbonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (Compound 147)

NMR (200 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.50 to 1.98 (4H, m), 2.90 (2H, m), 3.36 (1H, m), 3.98 (2H, m), 7.03 (1H, dd, J = 7, 1.2 Hz), 7.15 (1H, dd, J = 9, 7 Hz), 7.64 (1H, m), 7.70 (1H, d, J = 1.2 Hz), 7.96 (1H, m)

(4) 5- [1- (isopropyloxycarbonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (Compound 148)

NMR (200 MHz, CDCl ₃ ) δ: 1.23 (6H, d, J = 6.2 Hz), 1.50-1.98 (4H, m), 2.94 (2H, m), 3.37 (1H, m), 4.03 (2H, m) , 4.91 (1H, heptet, J = 6.2 Hz), 7.03 (1H, dd, J = 7, 1.2 Hz), 7.16 (1H, dd, J = 9, 7 Hz), 7.65 (1H, d, J = 9 Hz) , 7.71 (1H, d, J = 1.2 Hz), 7.97 (1H, s)

Example 24

(1) Synthesis of 5 [2- (tert-butoxycarbonylamino) ethoxy] imidazo [1,2-a] pyridine (Compound 149)

To a suspension of 60% sodium hydride (oil phase: 4.8 g, 0.12 mmol) in DMF (150 ml) with 5-chloroimidazo [1,2-a] pyridine (15.26 g, 0.1 mol) in DMF (120 ml) with stirring at room temperature. ) And 2-aminoethanol (6.72 g, 0.11 mol) were added and the resulting mixture was stirred at the same temperature for 33 hours. Di-tert-butyl dicarbonate (32.74 g, 0.15 mol) is added to the reaction mixture, which is then stirred at room temperature for 13 hours. After distilling off the solvent, water (800 ml) is added to the residue, which is extracted twice with ether. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated, then ether is added.

The precipitated crystals are filtered off and washed with ether to give 10.77 g of the desired product (38.8%, colorless crystals). As a second crystal, 1.31 g of the desired product (4.7%, colorless crystals) were obtained.

NMR (200MHz, CDCl ₃ ) δ: 1.46 (9H, s), 3.68 (2H, s), 4.31 (2H, t, J = 5.2Hz), 5.00 (1H, br), 6.06 (1H, d, J = 7 Hz), 7.17 (1H, dd, J = 9, 7 Hz), 7.30 (1H, d, J = 9 Hz), 7.60 (1H, d, J = 1.2 Hz), 7.66 (1H, s)

In the same manner as in the method described in Example 24 (1), the following compound is obtained.

(2) 5- [3- (tert-butoxycarbonyl) propoxy] imidazo [1,2-a] pyridine (Compound 150)

NMR (200 MHz, CDCl ₃ ) δ: 1.44 (9H, S), 2.14 (2H, q, J = 6.2 Hz), 3.40 (2H, m), 4.31 (2H, t, J = 6.2 Hz), 4.83 (1H , br), 6.04 (1H, d, J = 7.2 Hz), 7.16 (1H, dd, J = 9, 7.2 Hz), 7.28 (1H, d, J = 9 Hz), 7.59 (1H, d, J = 1.2 Hz), 7.66 (1 H, s)

Example 25

(1) 5- [2- (tert-butoxycarbonylamino) ethylsulfonyl] imidazo [1,2-a] pyridine (Compound 151) and 5- [2- (tert-butoxycarbonylamino) Synthesis of ethylsulfinyl] imidazo [1,2-a] pyridine (Compound 152)

85% m- under ice-cooling with stirring to a solution of 5- [2- (tert-butoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (2.93 g, 10 mmol) in chloroform (50 ml). Chloroperbenzoic acid (5.08 g, 25 mmol) is added and the resulting mixture is stirred at room temperature for 4 hours. Chloroform (50 ml) is then added to the mixture, which in turn is washed with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 5- [2- (tert-butoxycarbonylamino) ethylsulfonyl] imidazo [1,2-a] pyridine (Compound 151: Fraction 1). 17.2%, colorless crystals), 560 mg is obtained.

Elemental analysis: C ₁₄ H ₁₉ N ₃ O ₄ S · 0.3H ₂ O,

Calc .: C, 50.83; H, 5.97; N, 12.70

Found: C, 50.97; H, 5.91; N, 12.80

NMR (200 MHz, CDCl ₃ ) δ: 1.37 (9H, s), 3.42 to 3.63 (4H, m), 5.03 (1H, br), 7.36 (1H, dd, J = 9.7 Hz), 7.68 (1H, dd, J = 1.5Hz), 7.85 (1H, d, J = 1.5Hz), 7.96 (1H, d, J = 9Hz), 8.25 (1H, m)

As fraction 2, 5- [2- (tert-butoxycarbonylamino) ethylsulfinyl] imidazo [1,2-a], pyridine (Compound 152: 27.5%, colorless crystals) were obtained.

Elemental analysis: C ₁₄ H ₁₉ N ₃ O ₂ S · 0.4H ₂ O,

Calc .: C, 53.11; H, 6. 30; N, 13.27

Found: C, 53.27; H, 6. 18; N, 13.36

NMR (200MHz, CDCl ₃ ) δ: 1.43 (9H, s), 3.14-3.75 (4H, m), 5.07 (1H, br), 7.30-7.41 (2H, m), 7.73-7.87 (3H, m)

Example 26

Synthesis of 5- (phthalimidomethylthio) imidazo [1,2-a] pyridine (Compound 153) 5-mercaptoimidazo [1,2-a] pyridine (3.00 g, 20 mmol) in ethanol (200 ml) Triethylamine (4.2 ml, 30 mmol) is added to a suspension of N-bromomethylphthalimide (5.28 g, 22 mmol) and the resulting mixture is stirred at room temperature for 1 hour. The solvent is distilled off, chloroform is added to the residue, which is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is then purified by column chromatography (eluent: ethyl acetate) to give 4.29 g of the desired product (63.4%, light yellow crystals).

NMR (200 MHz, CDCl ₃ ) δ: 5.10 (2H, s), 7.02 to 7.13 (2H, m), 7.61 to 7.84 (6H, m), 7.99 (1H, m)

Example 27

Synthesis of 5- [2- (phthalimido) ethylthio] imidazo [1,2-a] pyridine (Compound 99)

Of 5-mercaptoimidazo [1,2-a] pyridine (3.00 g, 20 mmol) and N- [2- (bromo) ethyl] phthalimide (5.59 g, 22 mmol) in ethanol (200 ml) Triethylamine (4.2 ml, 30 mmol) is added to the suspension and the resulting mixture is stirred at room temperature for 3 hours and heated at reflux for 4 hours. After distilling off the solvent, chloroform is added to the residue, which is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is then purified by column chromatography (eluent: ethyl acetate) to give 3.95 g of the desired product (61.1%, yellow crystals).

NMR (200 MHz, CDCl ₃ ) δ: 3.33 (2H, t, J = 6.6 Hz), 3.97 (2H, t, J = 6.6 Hz), 7.11 to 7.21 (2H, m), 7.55 (1H, m), 7.67 7.87 (6 H, m)

Example 28

Synthesis of 5- [3- (phthalimido) propylthio)] imidazo [1,2-a] pyridine (Compound 154)

Of 5-mercaptoimidazo [1,2-a] pyridine (3.00 g, 20 mmol) and N- [3- (bromo) propyl] phthalimide (5.90 g, 22 mmol) in ethanol (200 ml) Triethanamine (4.2 ml, 30 mmol) is added to the suspension and the resulting mixture is stirred at room temperature for 1 hour and heated at reflux for 1 hour. The solvent is distilled off, chloroform is added to the residue, which is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is then purified by column chromatography (eluent: ethyl acetate) to give 4.79 g of the desired product (71.1%, colorless crystals).

NMR (200 MHz, CDCl ₃ ) δ: 2.02 (2H, m), 3.02 (2H, t, J = 7.2 Hz), 3.85 (2H, t, J = 6.8 Hz), 6.98 (1H, dd, J = 7, 1 Hz), 7.16 (1H, dd, J = 9, 7 Hz), 7.58 (1H, m), 7.67-7.88 (6H, m)

Example 29

Synthesis of 5- [4- (phthalimido) butylthio] imidazo [1,2-a] pyridine (Compound 155)

Of 5-mercaptoimidazo [1,2-a] pyridine (3.00 g, 20 mmol) and N- [4- (bromo) butyl] phthalimide (6.21 g, 22 mmol) in ethanol (200 ml) Triethylamine (4.2 ml, 30 mmol) is added to the suspension and the resulting mixture is stirred at room temperature for 1 hour and heated at reflux for 45 minutes. The solvent is distilled off, chloroform is added to the residue, which is washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is then purified by column chromatography (eluent: ethyl acetate) to give 4.50 g of the desired product (64.1%, light yellow crystals).

NMR (200 MHz, CDCl ₃ ) δ: 1.62-1.95 (4H, m), 3.04 (2H, t, J = 7 Hz), 3.71 (2H, t, J = 6.8 Hz), 6.89 (1H, dd, J = 7 , 1 Hz), 7.10 (1H, dd, J = 9, 7 Hz), 7.54 (1H, d, J = 9 Hz), 7.65-7.86 (6H, m)

Example 30

Synthesis of 5- [6- (phthalimido) hexylthio] imidazo [1,2-a] pyridine (Compound 156)

Of 5-mercaptoimidazo [1,2-a] pyridine (1.50 g, 10 mmol) and N- [6- (bromo) hexyl] phthalimide (3.10 g, 10 mmol) in ethanol (100 ml) Triethylamine (2.1 ml, 15 mmol) is added to the suspension, and the obtained mixture is stirred at room temperature for 12 hours. The solvent is distilled off, chloroform is added to the residue, which is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is then purified by column chromatography (eluent: ethyl acetate) to give 2.86 g of the desired product (75.5%, light tan crystals).

NMR (200 MHz, CDCl ₃ ) δ: 1.24-1.77 (8H, m), 2.99 (2H, t, J = 7.2 Hz), 3.68 (2H, t, J = 7.2 Hz), 6.87 (1H, dd, J = 7, 1 Hz), 7.15 (1H, dd, J = 9, 7 Hz), 7.56 (1H, d, J = 9 Hz), 7.65-7.88 (6H, m)

Example 31

5- [2-2- (phthalimido) ethyloxy] ethylthio)] Synthesis of imidazo [1,2-a] pyridine (Compound 157).

5-mercaptoimidazo [1,2-a] pyridine (3.00 g, 20 mmol) and N- [2- [2- (bromo) ethyloxy] ethyl] phthalimide (5.96) in ethanol (200 ml) g, 20 mmol) is added triethylamine (4.2 ml, 30 mmol) and the resulting mixture is stirred at room temperature for 12 hours and heated at reflux for 3 hours. The solvent is distilled off, chloroform is added to the residue, which is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is then purified by column chromatography (eluent: ethyl acetate) to give 4.00 g of the desired product (54.5%, light tan crystals).

NMR (200 MHz, CDCl ₃ ) δ: 3.12 (2H, t, J = 6.4 Hz), 3.64-3.77 (4H, m), 3.89 (2H, t, J = 5.4 Hz), 6.91 (1H, dd, J = 7.1 Hz), 7.20 (1H, dd, J = 9, 7 Hz), 7.56 (1H, d, J = 9 Hz), 7.63-7.88 (6H, m)

Example 32

In the same manner as described in Example 31, the following compounds are obtained.

(1) 5- [3-[[2- (anilino) ethyl] -N- (acetyl) amino] propylthio] imidazo [1,2-a] pyridine (Compound 158)

NMR (200MHz, CDCl ₃ ) δ: 1.89 (2H, m), 2.05 (1.5H, s), 2.09 (1.5H, s), 2.97 (2H, m), 3.25-3.60 (6H, m), 6.53 ~ 6.63 (2H, m), 6.63 ~ 6.80 (1H, m), 6.89 (1H, m), 7.07 ~ 7.25 (3H, m), 7.59 (1H, m), 7.70 (1H, m), 7.83 (1H, s)

(2) 5- [3-[[2- [N- (acetyl) anilino] ethyl] -N- (acetyl) amino] propylthio] imidazo [1,2-a] pyridine (Compound 159)

NMR (200 MHz, CDCl ₃ ) δ: 1.70 to 2.07 (8H, m), 2.88-3.06 (2H, m), 3.32 to 3.58 (4H, m), 3.70 to 3.85 (2H, m), 6.88 to 7.00 (1H m), 7.08 to 7.26 (3H, m), 7.32 to 7.50 (3H, m), 7.57 to 7.08 (1H, m), 7.68 to 7.74 (1H, m), 7.80 to 7.88 (1H, m)

(3) 5- [3-[[2- (anilino) ethyl] -N- (tert-butoxycarbonyl) amino] propylthio] imidazo [1,2-a] pyridine (Compound 160)

NMR (200MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.87 (2H, m), 2.96 (2H, t, J = 7.2Hz), 3.27 (2H, m), 3.34 (2H, m), 6.52 -6.62 (2H, m), 6.69 (1H, dd, J = 0, 7.4 Hz), 6.85 (1H, d, J = 7.4 Hz), 7.07-7.22 (3H, m), 7.56 (1H, m), 7.69 (1H, d, J = 1.4 Hz), 7.81 (1H, s)

(4) 5- [3-[[2-N- (acetyl) anilino] ethyl] -N- (tert-butoxycarbonyl) amino] propylthio] imidazo [1,2-a] pyridine (compound 161)

NMR (200 MHz, CDCl ₃ ) δ: 1.13 to 1.48 (9H, m), 1.72 to 1.98 (5H, m), 2.97 (2H, t, J = 7.2 Hz), 3.38 (4H, m), 3.75 (2H, m), 6.94 (1H, d, J = 7 Hz), 7.08-7.47 (6H, m), 7.61 (1H, d, J = 9 Hz), 7.70 (1H, d, J = 1.2 Hz), 7.85 (1H, m)

Example 33

Synthesis of 5- [2- [2- (hydroxy) benzoylamino] ethylthio] imidazo [1,2-a] pyridine (Compound 162)

To a solution of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine (3.87 g, 20 mmol) and triethylamine (5.59 ml, 40 mmol) in methylene chloride (200 ml) with stirring O-acetylsalicyloyl chloride (4.77 g, 24 mmol) is added under ice cooling, and the resulting mixture is stirred at room temperature for 30 minutes. The solvent is distilled off and ethanol (60 ml) and 1N NaOH (40 ml) are added to the residue and stirred for 1 hour. 1N HC1 (40 ml) is added and ethanol is distilled off, and the residue is extracted with chloroform and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate / ethanol = 10: 1) to give 3.51 g of the desired product (56.0%, colorless solid).

Melting Point: 156 ~ 157 ℃

Elemental analysis: C ₁₆ H ₁₅ N ₃ O ₂ S,

Calc .: C, 61.32; H, 4. 82; N, 13.41

Found: C, 61.44; H, 5.0 4; N, 13.45

NMR (200 MHz, CDCl ₃ ) δ: 3.34 (2H, m), 3.58 (2H, m), 6.83-6.63 (2H, m0, 7.18 (1H, dd, J = 7, 1.2 Hz), 7.27 (1H, dd , J = 8.6, 7.0Hz), 7.39 (1H, m), 7.54 (1H, m), 7.68 (1H, d, J = 1.2Hz), 7.77 (1H, m), 7.95 (1H, d, J = 1.2 Hz), 9.04 (1 H, br)

Example 34

Synthesis of 5- [2- [2H-1, 3-benzoxazine- 2-thione-4 (3H) -one-3-yl] ethylthio] imidazo [1,2-a] pyridine (Compound 163)

1.1'-thiocarbo in 5- [2- [2- (hydroxy) benzoylamino] ethylthio] imidazo [1,2-a] pyridine (627 mg, 2.00 mmol) suspension in anhydrous tetrahydrofuran (30 ml). Nyldiimidazole (713 mg, 4.00 mmol) is added and the mixture is stirred for 46 hours at room temperature. After distilling off the solvent, chloroform is added to the residue, which is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 600 mg of the desired product. The product was recrystallized from methylene chloride-ethyl acetate to give 448 mg of the desired product (63.0%, pale red powder).

NMR (200 MHz, CDCl ₃ ) δ: 3.45 (2H, m), 4.73 (2H, m), 7.15-7.47 (4H, m), 7.60 (1H, m), 7.71 (1H, d, J = 1.4 Hz) , 7.75 (1H, m), 7.85 (1H, m), 8.04 (1H, m)

Example 35

Synthesis of 5- [2- [2H-1,3-benzooxazine-2,4 (3H) -dione-3-yl] ethylthio] imidazo [1,2-a] pyridine (Compound 164)

1,1'- in a solution of 5- [2- [2- (hydroxy) benzoyl amino] ethylthio] imadazo [1,2-a] pyridine (627 mg, 2.00 mmol) in anhydrous tetra hydrofuran (30 ml). Carbonyldiimidazole (649 mg, 4.00 mmol) is added and the mixture is stirred at room temperature for 15 hours. After distilling off the solvent, chloroform is added to the residue, which is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 528 mg of the desired product (77.8%, colorless crystals).

NMR (200 MHz, CDCl ₃ ) δ: 3.38 (2H, m), 4.34 (2H, m), 7.13-7.73 (3H, M), 7.39 (1H, m), 7.57 (1H, m), 7.67 -7.78 ( 2H, m), 7.83 (1H, s), 8.05 (1H, dd, J = 7.8, 1.8 Hz)

Example 36

Synthesis of 5- [1- (trifluoromethanesulfonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (Compound 165)

Ice in a solution of 5- (4-piperidylthio) imidazo [1,2-a] pyridine dihydrochloride (919 mg, 3 mmol) and triethylamine (1.39 ml, 9.89 mmol) in methylene chloride (40 ml) Under cold stirring, trifluoromethanesulfonic anhydride (0.61 ml, 3.63 mmol) is added and the mixture is stirred at room temperature for 1 hour. The residue is washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate / n-hexane = 1: 1) to give 0.66 g of the desired product (60.2%, colorless solid).

Melting Point: 102 ~ 103 ℃

NMR (200 MHz, CDCl ₃ ) δ: 1.68 to 1.90 (2H, m), 1.97 to 2.13 (2H, m), 3.22 (2H, m), 3.41 (1H, m), 3.89 (2H, m), 7.05 ( 1H, dd, J = 7, 1.2 Hz, 7.17 (1H, dd, J = 8.8, 7 Hz), 7.68 (1H, m), 7.72 (1H, d, J = 1.2 Hz), 7.95 (1H, m)

Example 37

Synthesis of 5- [4- (methanesulfonamido) butylthio] imidazo [1,2-a] pyridine (Compound 166)

Ice-cooled and stirred in a solution of 5- [4- (amino) butylthio] imidazo [1,2-a] pyridine (440 mg, 1.99 mmol) and triethylamine (0.42 ml, 3.01 mmol) in methylene chloride (20 ml) Methanesulfonyl chloride (0.19 ml, 2.45 mmol) is added and the mixture is stirred for 1 hour under ice-cooling. The reaction mixture is washed in order of saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 302 mg of the desired product (50.8%, pale reddish brown solid).

NMR (200MHz, CDCl ₃ ) δ: 1.74 (4H, m), 2.94 (3H, s), 3.02 (2H, m), 3.15 (2H, m), 4.53 (1H, br), 6.92 (1H, dd, J = 7.1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.59 (1H, m), 7.70 (1H, d, J = 1.2Hz), 7.84 (1H, m)

Example 38

Synthesis of 5- [4- (trifluoromethanesulfonamido) butylthio] imidazo [1,2-a] pyridine (Compound 167)

Ice-cooled and stirred in a solution of 5- [4- (amino) butylthio] imidazo [1,2-a] pyridine (460 mg, 2.08 mmol) and triethylamine (0.44 ml, 3.16 mmol) in methylene chloride (20 ml) Trifluoromethanesulfonic anhydride (0.38 ml, 2.26 mmol) is added thereto and the mixture is stirred for 30 minutes under ice-cooling. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 277 mg of the desired product (37.7%, colorless crystals).

NMR (200 MHz, CDCl ₃ ) δ: 1.74 (4H, m), 3.04 (2H, m), 3.22 (2H, m), 6.94 (1H, dd, J = 7, 1 Hz), 7.19 (1H, dd, J = 9, 7 Hz), 7.56 (1H, d, J = 9 Hz), 7.69 (1H, d, J = 1.2 Hz), 7.86 (1H, m), 8.71 (1H, br)

Example 39

Synthesis of 5- [4- (1-naphthalenesulfonylamino) butylthio] imidazo [1,2-a] pyridine (Compound 168)

In a solution of 5- [4- (amino) butylthio] imidazo [1,2-a] pyridine (300 mg, 1.36 mmol) and triethylamine (0.29 ml, 2.08 mmol) in methylene chloride (15 ml), 1-naphthalenesulfonyl chloride (307 mg, 1.35 mmol) is added under stirring and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed in the order of aqueous sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (eluent: ethyl acetate) to give 296 mg of the desired product (53.0%, colorless solid).

NMR (200MHz, CDCl ₃ ) δ: 1.55 (4H, m), 2.81 (2H, m), 2.92 (2H, m), 4.83 (1H, br), 6.78 (1H, dd, J = 7.1Hz), 7.11 (1H, dd, J = 9, 7 Hz), 7.45 to 7.75 (6H, m), 7.93 (1H, m), 8.05 (1H, d, J = 8.4 Hz), 8.25 (1H, dd, J = 7.2, 1.2 Hz), 8.62 (1 H, m)

Example 40

Synthesis of 5- [4- (isopropoxycarbonylamino) butylthio] imidazo [1,2-a] pyridine (Compound 169)

Ice-cooled and stirred in a solution of 5- [4- (amino) butylthio] imidazo [1,2-a] pyridine (370 mg, 1.67 mmol) and triethylamine (0.35 ml, 2.51 mmol) in methylene chloride (20 ml) Isopropyl chloroformate (0.25 g, 2.04 mmol) is added and the mixture is stirred under ice cooling for 1 hour. The reaction mixture is washed in order of aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 215 mg of the desired product (41.8%, light tan oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J = 6.2 Hz), 1.54 to 1.72 (4H, m), 3.02 (2H, m), 3.18 (2H, m), 4.66 (1H, br) , 4.90 (1H, hept, J = 6.2 Hz), 6.90 (1H, dd, J = 7, 1 Hz), 7.15 (1H, dd, J = 9, 71 Hz), 7.58 (1H, d, J = 9 Hz), 7.84 (1 H, m)

Example 41

Synthesis of 5- [3- (benzenesulfonamido) propyloxy] imidazo [1,2-a] pyridine (Compound 170)

5- [3- (amino) propyloxy] imidazo [1,2-a] pyridine dihydrochloride (2.64 g, 10 mmol) and triethylamine (4.88 ml) in methylene chloride (100 ml) -acetonitrile (30 ml) To a suspension of 35 mmol), benzenesulfonyl chloride (1.53 ml, 12 mmol) is added under ice-cooling and stirring, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed in order of aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained crude product is recrystallized from methylene-ethanol to give 1.97 g of the desired product (59.5%, light brown crystals).

Melting Point: 155 ~ 156 ℃

NMR (200 MHz, CDCl ₃ ) δ: 2.14 (2H, m), 3.26 (2H, m), 4.27 (2H, t, J = 5.8 Hz), 5.93 (1H, dd, J = 7, 1.2 Hz), 6.08 (1H, br), 7.11 (1H, dd, J = 9, 7 Hz), 7.17 (1H, m), 7.33 (1H, m), 7.37 to 7.56 (4H, m), 7.84 to 7.72 (2H, m)

Example 42

Synthesis of 5- [2- [2- (methanesulfonamido) ethyloxy] ethylthio] imidazo [1,2-a] pyridine (Compound 171)

Hydrazine monohydrate (0.44 ml) in a suspension of 5- [2- [2- (phthalimido) ethyloxy] ethylthio] imidazo [1,2-a] pyridine (1.10 g, 3 mmol) in ethanol (15 ml) 9.1 mmol) is added and the mixture is heated to reflux for 1 h. After the mixture is left to cool, methylene chloride (30 ml) is added and the insoluble product is filtered off and the solvent is distilled off from the filtrate. To the residue is added methylene chloride (30 ml) and triethylamine (0.84 ml, 6 mmol), and methanesulfonic anhydride (679 mg, 3.9 mmol) is added thereto under ice cooling and stirring, and the mixture is stirred at room temperature for 1 hour. Then washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate / ethanol = 10: 1) to give 0.82 g of the desired product (86.9%, light yellow oil product).

NMR (200 MHz, CDCl ₃ ) δ: 2.96 (3H, s), 3.16 (2H, t, J = 6 Hz), 3.22 (2H, m), 3.54 (2H, t, J = 5 Hz), 3.68 (2H, t , J = 6 Hz, 5.12 (1H, br), 6.99 (1H, dd, J = 7, 6 Hz), 7.16 (1H, dd, J = 9, 7 Hz), 7,61 (1H, m), 7.70 ( 1H, d, J = 1.2 Hz), 7.88 (1H, m)

Example 43

5- [3- [1,2-benzisothiazole-3 (2H) -one-1,1-dioxydo-2-yl] propylthio] imidazo [1,2-a] pyridine (Compound 172 ) Synthesis

1,8-dia in a solution of 5- [3- (chloro) propylthio] imidazo [1,2-a] pyridine (1.17 g, 5.16 mmol) and saccharin (1.50 g, 8.19 mmol) in DMF (30 ml) Zacyclocyclo [5. 4. Add 0] -7-undecene (0.78 ml, 5.22 mmol) and stir the mixture at 80 ° C. for 24 h. The reaction mixture is poured into aqueous sodium bicarbonate solution and it is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 658 mg of the desired product (34.1%, colorless crystals).

Melting Point: 99 ~ 100 ℃

NMR (200 MHz, CDCl ₃ ) δ: 2.17 (2H, m), 3.09 (2H, t, J = 7 Hz), 3.95 (2H, t, J = 6.8 Hz), 7.00 (1H, dd, J = 7, 1 Hz ), 7.61 (1H, dd, J = 8.8, 7 Hz), 7.60 (1H, m), 7.69 (1H, d, J = 1.2 Hz), 7.80-7.97 (4H, m), 8.06 (1H, m)

Example 44

Synthesis of 5- [3- (methanesulfonamido) benzyl] imidazo [1,2-a] pyridine (Compound 173)

To a solution of 3-aminobenzyl alcohol (1.23 g, 10 mmol) and triethylamine (3.07 ml, 22 mmol) in methylene chloride (50 ml) was added methanesulfonyl (1.55 ml, 20 mmol) under ice cooling and stirring and the mixture was Stir at room temperature for 1 hour. Then 5-mercapto imidazo [1,2-a] pyridine (1.50 g, 10 mmol) and triethylamine (1.40 ml, 10 mmol) were added and stirred for 5 hours. The reaction product is washed in the order of saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 0.88 g of the desired product (26.4%, light brown powder).

NMR (200MHz, CDCl ₃ ) δ: 2.91 (3H, s), 4.13 (2H, s), 6.52 (1H, m), 6.81 (1H, m), 6.92-7.28 (4H, m), 7.58 (1H, m), 7.66 (1 H, m), 7.86 (1 H, m)

Example 45

Synthesis of 5- [3- (acetyloxy) propylthio] imidazo [1,2-a] pyridine (Compound 174)

Solution of 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (2.00 g, 9.60 mmol) and triethylamine (1.60 ml, 11.5 mil: rimol) in methylene chloride (50 ml) To this was added acetic anhydride (1.10 ml, 11.6 mmol) under stirring at room temperature and the mixture was stirred for additional 7.5 hours at room temperature. The reaction mixture is washed with 1N aqueous sodium hydroxide solution and dried. After distilling off the solvent, the residue is purified by column chromatography (eluent: hexane / acetone = 1: 1) to afford 2.40 g of the desired product (100%, brown oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.98 (2H, quint, J = 6.6 Hz), 2.04 (3H, s), 3.06 (2H, t, J = 7.0 Hz), 4.19 (2H, t, J = 6.2 Hz ), 6.94 (1H, d, J = 6.8 Hz), 7.17 (1H, dd, J = 8.8, 6.8 Hz), 7.62 (1H, d, J = 8.8 Hz), 7.71 (1H, s), 7.85 (1H , s)

IR (Neat) cm ^-1 : 1740, 1488, 1240

Example 46

Synthesis of 5- [3- (acetyloxy) propylthio] imidazo [1,2-a] pyridine (Compound 174)

To a solution of 3-bromo-1-propanol (0.50 g, 3.60 mmol) and triethylamine (0.60 ml, 0.40 mmol) in methylene chloride (15 ml) was added acetic anhydride (0.40 ml, 4.24 mmol) at room temperature with stirring. The mixture is stirred further overnight at room temperature. The reaction mixture is washed with 1N aqueous sodium hydroxide solution and dried.

After distilling off the solvent, ethanol (10 ml) and triethylamine (1.00 ml, 7.17 mmol) were added to the residue. 5-mercaptopyridine (0.49 g, 3.26 mmol) is added to the mixture under stirring at room temperature and the mixture is stirred at room temperature for 5 minutes. The solvent is distilled off and the residue is purified by column chromatography (eluent: hexane / acetone = 1: 1) to give 0.54 g of the desired product (66.3%, brown oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.98 (2H, quint, J = 6.6 Hz), 2.04 (3H, s), 3.06 (2H, t, J = 7.0 Hz), 4.19 (2H, t, J = 6.2 Hz ), 6.94 (1H, d, J = 6.8 Hz), 7.17 (1H, dd, J = 8.8, 6.8 Hz), 7.62 (1H, d, J = 8.8 Hz), 7.71 (1H, s), 7.85 (1H , s)

IR (Neat) cm ^-1 : 1740, 1488, 1240

Example 47

Synthesis of 5- [3- (benzoyloxy) propylthio] imidazo [1,2-a] pyridine (Compound 175)

Stir in a solution of 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (1.00 g, 4.80 mmol) and triethylamine (0.80 ml, 5.74 mmol) in methylene chloride (25 ml) At room temperature benzoyl chloride (1.10 ml, 11.6 mmol) is added and the mixture is stirred for an additional 30 minutes at room temperature. The reaction mixture is washed with 1N aqueous sodium hydroxide solution and dried. After distilling off the solvent, the residue is purified by column chromatography [eluent: hexane / acetone = 1: 1] to give 1.32 g of the desired product (88.1%, white solid).

Melting Point: 60 ~ 61 ℃

Elemental analysis: C ₁₇ H ₁₆ N ₂ O ₂ S,

Calc .: C, 65.36; H, 5. 16; N, 8.97

Found: C, 65.52; H, 5. 17; N, 8.84

NMR (200 MHz, CDCl ₃ ) δ: 2,13 (2H, quint, J = 6.6 Hz), 3.16 (2H, t, J = 7.2 Hz), 4.46 (2H, t, J = 6.2 Hz), 6.96 (1H , d, J = 7.0 Hz, 7.15 (1H, dd, J = 9.2, 7.0 Hz), 7.38-7.7.6 (4H, m), 7.69 (1H, s), 7.86 (1H, s), 7.99 (2H, dd, J = 7.2, 1.6 Hz)

IR (Neat) cm ^-1 : 1713, 1487, 1280

Example 48

Synthesis of 5- [3- [2- (phenyl) ethylcarbonyloxy] propylthio] imidazo [1,2-a] pyridine (Compound 176).

In a solution of 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (1.00 g, 4.80 mmol) and triethylamine (0.80 ml, 5.74 mmol) in methylene chloride (25 ml) at room temperature 3-phenylpropionyl chloride (1.01 g, 5.99 mmol) is added under stirring at and the mixture is stirred for an additional 2 hours at room temperature. The reaction mixture is washed with 1N aqueous sodium hydroxide solution and dried. After distilling off the solvent, the residue is purified by column chromatography [eluent: hexane / acetone = 1: 1] to give 1.37 g of the desired product (84.2%, yellow oil product).

Elemental analysis: C ₁₉ H ₂₀ N ₂ O ₂ S,

Calculated Value: C, 67.03; H, 5.92; N, 8.23

Found: C, 66.86; H, 6.01; N, 7.81

NMR (200 MHz, CDCl ₃ ) δ: 1.92 (2H, quint, J = 6.6 Hz), 2.63 (2H, t, J = 7.7 Hz), 2.94 (4H, t, J = 7.2 Hz), 4.19 (2H, t , J = 6.2 Hz, 6.91 (1H, d, J = 7.2 Hz), 7.10-7.35 (6H, m), 7.61 (1H, d, J = 9.0 Hz), 7.72 (1H, s), 7.84 (1H , s)

IR (Neat) cm ^-1 : 1730, 1487, 1288

Example 49

5- [3- (acetyloxy) propylsulfinyl] imidazo [1,2-a] pyridine (Compound 177) and 5- [3- (acetyloxy) propylsulfonyl] imidazo [1,2-a] Synthesis of Pyridine (Compound 178)

To a solution of 5- [3- (acetyloxy) propylthio] imidazo [1,2-a] pyridine (1.00 g, 3.99 mmol) in chloroform (25 ml) under ice-cooling and stirring, m-chloroperbenzoic acid (1.47 g, 5.96 mmol) is added and the mixture is stirred for an additional 1.5 h under ice cooling. The reaction mixture is washed and dried in the order of 20% aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution. After distilling off the solvent, the residue was purified by column chromatography [eluent: hexane / acetone = 1: 1] to give 0.19 g of 5- [3- (acetyloxy) propylsulfinyl] imidazo [1,2-a ] Pyridine (compound 177) (34.6%, yellow oil product) and 0.19 g of 5- [3- (acetyloxy) propylsulfonyl] imidazo [1, 2-a] pyridine (compound 178) (16.5%, yellow Oil product).

5- [3- (acetyloxy) propylsulfinyl] imidazo [1,2-a] pyridine (Compound 177)

NMR (200 MHz, CDCl ₃ ) δ: 1.90 to 2.30 (2H, m), 2.02 (3H, s), 3.05 to 3.30 (2H, m), 4.10 to 4.30 (2H, m), 7.31 to 7.38 (2H, m ), 7.47-7.87 (2H, m), 7.92 (1H, s)

IR (Neat) cm ^-1 : 1740, 1240, 1063, 1033

5- [3- (acetyloxy) propylsulfonyl] imidazo [1,2-a] pyridine (Compound 178)

NMR (200 MHz, CDCl ₃ ) δ: 1.98 (3H, s), 2.03 to 2.20 (2H, m), 3.30 to 3.40 (2H, m), 4.13 (2H, t, J = 6.2 Hz), 7.36 (1H, dd, J = 9.0, 7.2 Hz), 7.68 (1H, dd, J = 7.2, 1.2 Hz), 7.86 (1H, s), 7.96 (1H, d, J = 0.9 Hz), 8.28 (1H, s)

IR (Neat) cm ^-1 : 1740, 1325, 1240, 1130

Example 50

Synthesis of 5- [3- (methoxy) propylthio] imidazo [1,2-a] pyridine (Compound 179)

To a solution of 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (803 mg, 3.86 mmol) in tetrahydrofuran (30 ml), 60% sodium hydride in oil (0.19) under ice cooling and stirring g, 4.6 mmol) is added and the mixture is stirred for an additional 30 minutes under ice-cooling. Methyl iodide (0.36 ml, 5.8 mmol) is added to the reaction mixture, which is then stirred at room temperature overnight. The reaction mixture is poured into water and extracted with methylene chloride (30 ml x 3). The methylene chloride layer is mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 308 mg of the desired product (35.9%, light brown, oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.92 (2H, tt, J = 6.0, 7.2 Hz), 3.10 (2H, t, J = 7.3 Hz), 3.32 (3H, s), 3.48 (2H, t, J = 5.8 Hz), 6.91 (1H, dd, J = 1.2, 7.0 Hz), 7.15 (1H, dd, J = 7.2, 9.0 Hz), 7.57 (1H, td, J = 1.0, 9.0 Hz), 7.70 (1H, d, J = 1.2 Hz), 7.84 (1H, t, J = 0.8 Hz)

Example 51

Synthesis of 5- [3- (phenoxy) propylthio] imidazo [1,2-a] pyridine (Compound 180)

(1) Synthesis of 5- [3- (methanesulfonyloxy) propylthio] imidazo [1,2-a] pyridine

Ice in a solution of 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (1.030 g, 4.95 mmol) and triethylamine (1.03 ml, 7.4 mmol) in methylene chloride (30 ml) Methanesulfonyl chloride (0.46 ml, 5.9 mmol) is added under cooling and stirring and the mixture is stirred for 10 additional minutes under ice cooling. The reaction mixture is washed with water and the aqueous layer is extracted with methylene chloride (30 ml x 3). The methylene chloride layers are mixed and dried over anhydrous magnesium sulfate. The solvent is then distilled off to yield the crude product 5- [3- (methanesulfonyloxy) propylthio] imidazo [1, 2-a] pyridine as a yellow oil product.

(2) Synthesis of 5- [3- (phenoxy) propylthio] imidazo [1,2-a] pyridine (Compound 180)

To a solution of phenol (0.70 g, 7.4 mmol) in tetrahydrofuran (20 ml) is added 60% sodium hydride (0.30 ml, 7.4 mmol) in oil under ice cooling and stirring and the mixture is stirred for an additional 30 minutes under ice cooling. To the reaction mixture was added a solution of 5- [3- (methanesulfonyloxy) propylthio] imidazo [1,2-a] pyridine, a crude product in tetrahydrofuran (10 ml) obtained in (1), under reflux. Heat overnight. The reaction mixture is poured into water and extracted with methylene chloride (30 ml x 4). The methylene chloride layer is mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 1.220 g of the desired product (86.8%, light brown oil product).

NMR (200 MHz, CDCl ₃ ) δ: 2.13 (2H, tt, J = 5.9, 7.1 Hz), 3.22 (2H, t, J = 7.2 Hz), 4.09 (2H, t, J = 5.8 Hz), 6.85-7.00 (4H, m), 7.13 (1H, dd, J = 7.0, 9.0 Hz), 7.25-7.33 (2H, m), 7.57 (1H, td, J = 08, 9.0 Hz), 7.71 (1H, d, J = 1.4 Hz), 7.85 (1 H, s)

Example 52

Synthesis of 5- [3- [2- (phenoxy) ethyloxy] propylpio] imidazo [1,2-a] pyridine (Compound 181)

(1) Synthesis of 1-methanesulfonyloxy-2- (phenoxy) ethane

To a solution of 2- (phenoxy) ethanol (1.35 g, 9.78 mmol) and triethylamine (2.04 ml, 14.7 mmol) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmol) under ice cooling and stirring. The mixture is stirred for an additional 10 minutes under ice-cooling. The reaction solution is washed with water and the aqueous layer is extracted with methylene chloride (30 ml x 3). The methylene chloride layers are mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was column chromatographed [eluent: hexane / methyl = 1: 1] to give crude product 1-methanesulfonyloxy-2- (phenoxy) ethane as a pale yellow oil product.

(2) Synthesis of 5- [3- (phenoxy) ethyloxy] propylthio] imidazo [1,2-a] pyridine (Compound 181)

60% sodium hydride (0.30) in oil under ice-cooling and stirring in a 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (1.018 g, 4.89 mmol) solution in tetrahydrofuran (20 ml) ml, 7.4 mmol) and the mixture is stirred for an additional 30 minutes under ice cooling. To the reaction mixture was added a solution of the crude product 1-methanesulfonyloxy- (phenoxy) ethane in tetrahydrofuran (10 ml) obtained in (1), followed by heating under reflux for 4.5 hours. The reaction solution is poured into water and extracted with methylene chloride (30 ml x 4). The methylene chloride layer is mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 0.870 g of the desired product (54.2%, light brown oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.96 (2H, tt, J = 6.1, 7.1 Hz), 3.13 (2H, t, J = 7.2 Hz), 3.66 (2H, t, J = 5.9 Hz), 3.78 (2H , dd, J = 3.3, 6.1 Hz), 4.11 (2H, dd, J = 3.9, 5.5 Hz), 6.88-7.00 (4H, m), 7.13 (1H, dd, J = 7.0, 9.0 Hz), 7.24- 7.32 (2H, m), 7.56 (1H, td, J = 0.9, 9.0 Hz), 7.69 (1H, d, J = 1.2 Hz), 7.83 (1H, t, J = 0.8 Hz)

[53 of implementation]

Synthesis of 5- [3- [3- (phenyl) propyloxy] propylthio] imidazo [1,2-a] pyridine (Compound 182)

60% sodium hydride (0.25 in oil) under ice-cooling and stirring in a 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (1.070 g, 5.137 mmol) solution in tetrahydrofuran (20 ml) g, 6.2 mmol) and the mixture is stirred for an additional 30 minutes under ice-cooling. Methyl iodide (1.53 g, 7.71 mmol) was added to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture is poured into water and extracted with methylene chloride (30 ml x 3). The methylene chloride layer is mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 0.987 g of the desired compound (58.9%, light brown oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.81 to 1.99 (4H, m), 2.68 (2H, t, J = 7.6 Hz), 3.12 (2H, t, J = 7.2 Hz), 3.41 (2H, t, J = 6.4 Hz), 3.51 (2H, t, J = 5.8 Hz), 6.91 (1H, dd, J = 1.1, 7.1 Hz), 7.10 to 7.32 (6H, m), 7.56 (1H, td, J = 1.0, 9.9 Hz), 7.69 (1H, d, J = 1.4 Hz), 7.84 (1H, t, J = 1.0 Hz)

Example 54

Synthesis of 5- [3- [2- (anilino) ethyloxy] propylthio] imidazo [1,2-a] pyridine (Compound 183)

(1) Synthesis of 5- [3- (methylsulfonyloxy) propylthio] imidazo [1,2-a] pyridine

To a solution of 5- [3- (hydroxy) propylthio] imidazo [1,2-a] pyridine (2.003 g, 9.62 mmol) and triethylamine (2.01 ml, 14.4 mmol) in methylene chloride (30 ml) Methanesulfonyl chloride (0.89 ml, 12 mmol) is added under cooling and stirring and the mixture is stirred for an additional 10 minutes under ice cooling. The reaction mixture is washed with water and the aqueous layer is extracted with methylene chloride (30 ml x 3). The methylene chloride layers are mixed and dried over anhydrous magnesium sulfate. The solvent is then distilled off to yield the crude product [5- [3- (methanesulfonyloxy) propylthio] imidazo [1,2-a] pyridine as a yellow oil product.

(2) Synthesis of 5- [3- [2- (anilino) ethyloxy] propylthio] imidazo [1,2-a] pyridine (Compound 183)

To a solution of 2-anilinoethanol (1.98 g, 14.4 mmol) in tetrahydrofuran (20 ml) was added 60% sodium hydride (1.15 ml, 28.9 mmol) in oil under ice cooling and stirring and the mixture was stirred for an additional 30 minutes under ice cooling. do. To the reaction mixture was added a solution of the crude product 5- [3- (methanesulfonyloxy) propylthio] imidazo [1,2-a] pyridine in tetrahydrofuran (10 ml) obtained in (1) above, followed by 1 at reflux. Heat for hours. The reaction mixture is poured into water and extracted with methylene chloride (30 ml x 4). The methylene chloride layer is mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to yield 0.951 g of the desired product (30.2%, pale green crystals).

NMR (200 MHz, CDCl ₃ ) δ: 1.94 (2H, tt, J = 5.9, 7.1 Hz), 3.10 (2H, t, J = 7.2 Hz), 3.28 (2H, t, J = 5.2 Hz), 3.57 (2H , t, J = 6.0 Hz), 3.62 (2H, t, J = 5.1 Hz), 3.98 (1H, br, s), 6.63 (2H, d, J = 7.3 Hz), 6.72 (1H, t, J = 7.3 Hz), 6.89 (2H, dd, J = 1.0, 7.4 Hz), 7.10-7.22 (3H, m), 7.57 (1H, d, J = 9.0 Hz), 7.70 (1H, d, J = 1.4 Hz) , 7.83 (1H, s)

Example 55

Synthesis of 5- [3- [2- (N-methanesulfonylanilino) ethyloxy] propylthio] imidazo [1, 2-a] pyridine (Compound 184)

5- [3- [2- (phenylamino) ethyloxy] propylthio] imidazo [1,2-a] pyridine (1.034 g, 3.158 mmol) and triethylamine (0.88 ml) dissolved in methylene chloride (30 ml) , 6.3 mmol) is added methanesulfonyl chloride (0.37 ml, 4.7 mmol) with stirring under ice cooling, and the mixture is further stirred under ice cooling for 10 minutes. The reaction mixture is washed with water and the aqueous layer is extracted with methylene chloride (30 ml x 3). The methylene chloride layers are mixed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 16 mg of the desired product (brown oil product).

NMR (200 MHz, CDCl ₃ ) δ: 1.86 (2H, tt, J = 5.9, 7.2 Hz), 2.92 (3H, s), 3.03 (2H, t, J = 7.2 Hz), 3.50 (2H, t, J = 5.3 Hz), 3.50 (2H, t, J = 5.8 Hz), 3.84 (2H, t, J = 5.7 Hz), 6.89 (1H, dd, J = 1.0, 7.0 Hz), 7.15 (1H, dd, J = 7.0, 9.0 Hz), 7.31-7.40 (5H, m), 7.57 (1H, d, J = 9.0 Hz), 7.70 (1H, d, J = 1.0 Hz), 7.82 (1H, s)

Example 56

Synthesis of 5- [1- (2-thienylcarbonyl) -4-piperidyloxy] imidazo [1,2-a] pyridine (Compound 185)

To a 60% sodium hydride (0.40 g, 10 mmol) suspension in oil suspended in dimethylformamide (30 ml), 1- (2-thienylcarbonyl) -4-hydroxypiperidine (2.11 g, 10 mmol) was added. While stirring under ice-cooling, the mixture is stirred for 30 minutes at room temperature To this reaction mixture, 5-chloroimidazo [1,2-a] pyridine (1.53 g, 10 mmol) is added with stirring under ice-cooling and then at room temperature Stir for 7 hours Water is added to the reaction mixture, which is extracted with ethyl acetate and dried The solvent is distilled off and the residue is purified by column chromatography [eluent: ethyl acetate / hexane (1: 1)-> ethyl acetate / Hexane (2: 1) → ethyl acetate / ethanol (50: 1)] to afford 0.15 g (4.6%, pale yellow oily product) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 2.03 to 2.16 (4H, m), 3.85 to 3.96 (4H, m), 4.84 to 4.93 (1H, m), 6.09 (1H, d, J = 7.0 Hz), 7.06 ( 1H, dd, J = 3.6, 5.0 Hz), 7.12 to 7.35 (3H, m), 7.47 (1H, dd, J = 1.2, 5.0 Hz), 7.62 (1H, d, J = 1.2 Hz), 7.67 (1H) , d, J = 0.8 Hz)

Example 57

Synthesis of 5- [2- (N-benzylmethylsulfonylamino) ethyloxy] imidazo [1,2-a] pyridine (Compound 186)

(1) Synthesis of 2- (N-benzylmethylsulfonylamino) -1-ethanol

To a solution of N-benzylamino ethanol (7.10 ml, 50 mmol) and triethylamine (7.67 ml, 55 mmol) dissolved in dichloromethane (100 ml), methylsulfonyl chloride (4.26 ml, 55 mmol) was stirred under ice-cooling Add and stir the mixture at room temperature for 30 minutes. The reaction mixture is washed sequentially with saturated aqueous sodium bicarbonate solution and water and then dried. After distilling off the solvent, the residue was purified by column chromatography [eluent: ethyl acetate / hexane (1: 1)-> ethyl acetate / hexane (2: 1)-> ethyl acetate] to give 1.99 g (17.4%) of the desired product. Pale yellow oily product).

NMR (200MHz, CDCl ₃ ) δ: 1.89 (1H, bs), 2.94 (3H, s), 3.37 (2H, t, J = 5.0Hz), 3.65 (2H, t, J = 5.0Hz), 4.47 (2H , s), 7.35-7.39 (5H, m)

IR (Neat) cm ^-1 : 3520, 3030, 2930, 1600, 1595, 1455, 1320, 1140

(2) Synthesis of 5- [2- (N-benzylmethylsulfonylamino) ethyloxy] imidazo [1,2-a] pyridine (Compound 186)

To 60% sodium hydride (0.20 g, 5 mmol) suspension in oil suspended in dimethylformamide (20 ml), 2- (N-benzylmethylsulfonylamino) -1-ethanol (1.14 g, 5 mmol) was ice-cooled. It is added with stirring, and the mixture is stirred at room temperature for 30 minutes. 5-chloroimidazo [1,2-a] pyridine (0.763 g, 5 mmol) was added to the reaction mixture with stirring under ice cooling, followed by stirring at 80 ° C. for 16 hours. After cooling, water is added to the reaction mixture, which is extracted with ethyl acetate and then dried. After distilling off the solvent, the residue was purified by column chromatography [eluent: ethyl acetate / hexane (1: 1)-> ethyl acetate / hexane (2: 1)] to give 0.68 g (39.4%, pale yellow oily product) of the desired product. To obtain.

NMR (200 MHz, CDCl ₃ ) δ: 2.94 (3H, s), 3.72 (2H, t, J = 6.0 Hz), 4.23 (2H, t, J = 5.8 Hz), 4.52 (2H, s), 5.87 (1H , d, J = 6.8 Hz), 7.11 (1H, d, J = 7.2, 9.0 Hz), 7.25-7.40 (6H, m), 7.58 (2H, s)

IR (Neat) cm ^-1 : 3150, 3030, 2930, 1640, 1540

Example 58

Synthesis of 5- [3- (methylsulfonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 27)

(1) Synthesis of 3-methylsulfonylamino-1-methylsulfonyloxypropane

Ice-cooled methylsulfonyl chloride (25.5 ml, 330 mmol) in a solution of 3-amino-1-propanol (11.47 ml, 150 mmol) and triethylamine (46 ml, 330 mmol) dissolved in tichloromethane (250 ml) Under stirring, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is washed sequentially with aqueous sodium bicarbonate solution and water and then dried. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 24.22 g (69.8%, white crystals) of the desired product.

Melting Point: 53.5 ~ 55.5 ℃

NMR (200 MHz, CDl3) δ: 2.02 (2H, quint, J = 6.4 Hz), 2.98 (3H, s), 3.05 (3H, s), 3.31 (2H, q, J = 6.4 Hz), 4.37 (2H, t, J = 5.8 Hz), 4.68 (1H, bs)

(2) Synthesis of 5- [3- (methylsulfonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 27)

3-Methylponylamino- in a solution of 5-mercaptoimidazo [1,2-a] pyridine (1.50 g, 10 mmol) and 4M sodium methylate (2.93 ml, 12 mmol) dissolved in ethanol (50 ml) 1-methylsulfonyloxypropane (2.77 g, 12 mmol) is added at room temperature and the mixture is heated at reflux for 16 h. After cooling, the solvent is distilled off. The residue is dissolved in chloroform, washed with saturated aqueous sodium bicarbonate solution and then dried. After distilling off the solvent, the residue is purified by column chromatography [eluent: ethyl acetate / ethanol (50: 1)] to give 1.34 g (47.5%, pale yellow crystals) of the desired product.

Melting Point: 114 ~ 116 ℃

NMR (200 MHz, CDCl ₃ ) δ: 1.92 (2H, quint, J = 6.8 Hz), 2.95 (3H, s), 3.09 (2H, t, J = 7.0 Hz), 3.30 (2H, q, J = 6.6 Hz ), 4.82 (1H, bs), 6.94 (1H, d, J = 7.0 Hz), 7.15 (1H, dd, J = 7.0, 9.0 Hz), 7.60 (1H, d, J = 9.0 Hz), 7.69 (1H , s), 7.84 (1H, s)

1R (KBr) cm ^-1 : 3440, 3080, 2850, 1615. 1485, 1315, 1140

Example 59

5- [1- (methylsulfonyl) -4-piperidylsulfinyl] imidazo [1,2-a] pyridine (Compound 187) and 5- [1- (methylsulfonyl) -4-piperidylsulfodil Synthesis of Imidazo [1,2-a] pyridine (Compound 188)

M-chloroperbenzoic acid in a solution of 5- [1- (methylsulfonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (0.934 ml, 3.0 mmol) dissolved in chloroform (30 ml) (0.914 g, 4.5 mmol) is added while stirring under ice cooling, and the mixture is stirred at room temperature for 2 hours. To this reaction mixture is added m-chloroperbenzoic acid (0.609 g, 3.0 mmol) with stirring under ice cooling, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed with 1N aqueous sodium hydroxide solution and dried. After distilling off the solvent, the residue was purified by column chromatography [eluent: ethyl acetate / ethanol (25: 1-> 10: 1)] to give 0.272 g of a sulfone compound (24.2%, white crystals) as a fraction 1, a fraction 2 0.273 g of a sulfoxide compound (26.5%, white crystals) is obtained.

5- [1- (methylsulfonyl) -4-piperidylsulfonyl] imidazo- [1, 2-a] pyridine (Compound 188)

Melting Point: 224 ~ 226 ℃

NMR (200 MHz, CDCl ₃ ) δ: 1.96 to 2.12 (4H, m), 2.68 to 2.82 (1H, m), 2,79 (3H, s), 3.22 (1H, m), 3.85 to 3.97 (2H, m ), 7.36 (1H, dd, J = 7.2, 8.8 Hz), 7.64 (1H, d, J = 7.2 Hz), 7.86 (1H, bs), 7.98 (1H, d, J = 9.0 Hz), 8.34 (1H , bs)

5- [1- (methylsulfonyl) -4-piperidylsulfinyl] imidazo- [1, 2-a] pyridine (Compound 189)

Melting Point: 205 ℃ (Decomposition)

NMR (200 MHz, CDCl ₃ ) δ: 1.69 to 2.08 (4H, m), 2.66 to 2.85 (1H, m), 2,79 (3H, s), 3.29 (1H, m), 3.82 to 3.79 (2H, m ), 7.25 to 7.38 (2H, m), 7.81 to 7.86 (2H, m), 8.09 (1H, bs)

Example 60

Synthesis of 5- [2- [3- (hydroxy) isoindolin-1-on-2-yl] ethylthio] imidazo [1,2-a] pyridine (Compound 189)

5-mercaptoimidazo [1,2-a] pyridine (159 mg, 1 mmol) and 2- [2- (bromo) ethyl] -3-hydroxyindolin-1-suspended in ethanol (15 ml) Trimethylamine (0.21 ml, 1.5 mmol) is added to a suspension of warm (256 mg, 1 mmol) and the mixture is stirred at room temperature for 12 hours and then heated at reflux for 2 hours.

After distilling off the solvent, chloroform is added to the residue, which is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography [eluent: ethyl acetate / ethanol (10: 1)] to give 11.9 g (36.6%, pale yellow solid) of the desired product.

NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) δ: 3.38 (4H, m), 3.88 (2H, m), 5,82 (1H, m), 6.47 (1H, m), 7.14-7.67 (2H, m), 7.44 to 7.67 (5H, m), 7.67 (1H, m), 7.85 (1H, m)

Example 61

Synthesis of 5- [2- (isoindolin-1-one-2-yl] ethylthio] imidazo [1,2-a] pyridine (Compound 190)

5-mercaptoimidazo [1,2-a] pyridine (150 mg, 1 mmol) and 2- [2- (bromo) ethyl] isoindolin-1-one (240 mg, suspended in ethanol (15 ml) Trimethylamine (0.21 ml, 1.5 mmol) is added to the suspension, and the mixture is stirred at room temperature for 12 hours and then heated at reflux for 2 hours. After distilling off the solvent, chloroform is added to the residue, which is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography [eluent: ethyl acetate / ethanol (15: 1)] to give 234 mg (77.0%, light brown solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 3.32 (2H, t, J = 6.8 Hz), 3.89 (2H, t, J = 6.8 Hz), 4.39 (2H, s), 705-7.18 (2H, m), 7.37 ~ 7.60 (4H, m), 7.70 (1H, d, J = 1.2 Hz), 7.82 ~ 7.88 (2H, m)

Example 62

Synthesis of 5- [2- (phenylsulfonylamino) ethylsulfinyl] imidazo [1,2-a] pyridine (Compound 191)

M-chloroperbenzoic acid (913 mg, 4.5 mmol) was added to a suspension of 5- [2- (phenylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine (600 mg, 1.8 mmol) in chloroform (50 ml). Add with stirring under ice cooling, and the mixture is stirred at rt for 22 h. The reaction mixture is washed sequentially with 1N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography [eluent: ethyl acetate / ethanol (10: 1)] to give 200 g (31.8%, light brown solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 3.16 (1H, m), 3.35-3.65 (3H, m), 5,96 (1H, br), 7.28-7.36 (2H, m), 7.48-7.67 (3H, m ), 7.75 ~ 7.90 (5H, m)

Example 63

Synthesis of 5- [2- (tert-butoxycarbonylamino) ethylthio] -3-nitroimidazo [1,2-a] pyridine (Compound 192)

To a solution of cysteamine (2.95 g, 38.2 mmol) in DMF (50 ml) is added with stirring under ice cooling of 60% sodium hydride (1.53 g, 38.2 mmol) in oil, and the mixture is stirred at room temperature for 10 minutes. 5-Chloro-3-nitroimidazo [1,2-a] pyridine (5.81 g, 29.4 mmol) is added to the mixture, which is then stirred under ice cooling for 30 minutes and further stirred at room temperature for 30 minutes. Di-tert-butyl dicarbonate (9.63 g, 44 mmol) is added and then stirred at room temperature for 4 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 2.06 g (20.7%, tan solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 1.41 (9H, m), 3.17 to 3.41 (4H, m), 5,00 (1H, br), 7.36 (1H, dd, J = 6.2, 2.6 Hz), 7.59 to 7.71 (2H, m), 8.54 (1H, s)

Example 64

Synthesis of 5- [2- (methylsulfonylamino) ethylthio] -3-nitroimidazo [1,2-a] pyridine (Compound 193)

(1) Synthesis of 5- [2- (amino) ethylthio] -3-nitroimidazo [1,2-a] pyridine dihydrochloride

Concentrated hydrochloric acid (2 ml) in a solution of 5- [2- (tert-butoxycarbonylamino) ethylthio] -3-nitroimidazo [1,2-a] pyridine (364 mg, 1.08 mmol) in methanol (3 ml) Is added and the mixture is stirred at rt for 1 h. The solvent is then distilled off to yield 340 mg (quantitative, brown solid) of the desired product.

(2) Synthesis of 5- [2- (methylsulfonylamino) ethylthio] -3-nitroimidazo [1,2-a] pyridine (Compound 193)

5- [2- (amino) ethylthio] -3-nitroimidazo [1,2-a] pyridine dihydrochloride (221 mg, 0.71 mmol) and triethylamine (0.33 ml, dissolved in methylene chloride (30 ml) Methanesulfonyl chloride (0.08 ml, 1.03 mmol) is added to the solution of 2.37 mmol) with stirring under ice cooling, and the mixture is further stirred at the same temperature for 10 minutes. After washing with water, the reaction mixture is dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 108 mg (48.0%, orange solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 2.84 (3H, s), 3.09 (2H, s), 3,33 (2H, m), 7.24 (1H, br), 7.65 (1H, m), 7.77 to 7.90 ( 2H, m), 8.78 (1H, s)

Example 65

Synthesis of 5- [1- (methylsulfonyl) -4-piperidyloxy] -3-nitroimidazo [1,2-a] pyridine (Compound 194)

To a solution of 4-hydroxy-1-methylsulfonyl-piperidine (2.15 g, 12 mmol) in dimethylformamide (3 ml) was added 60% sodium hydride (0.48 g, 12 mmol) in oil with stirring under ice cooling The mixture is stirred for 10 minutes at room temperature. 5-Chloro-3-nitroimidazo [1,2-a] pyridine (1.976 g, 10 mmol) is added to the reaction mixture with stirring under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is poured into water and it is extracted with ethyl acetate. The precipitate is filtered off, washed with water and dried to give 1.862 g (54.7%, yellow solid) of the desired product. The organic layer is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude crystals thus obtained are recrystallized from methylene-n-hexane to give the desired product (460 mg, tan solid).

NMR (200 MHz, CDCl ₃ ) δ: 2.02 to 2.23 (3H, s), 2.90 (3H, s), 3,29 (2H, m), 3.66 (2H, m), 4.95 (1H, m), 6.44 ( 1H, d, J = 7.6Hz), 7.43 (1H, d, J = 8.8Hz), 7.58 (1H, dd, J = 8.8, 7.6Hz), 8.40 (1H, s)

Example 66

Synthesis of 3-amino-5- [1- (methylsulfonyl) -4-pyreridyloxy] imidazo [1,2-a] pyridine (Compound 195)

10% carbon phase in a solution of 5- [1- (methylsulfonyl) -4-piperidyloxy] -3-nitroimidazo [1,2-a] pyridine (70 mg, 0.226 mmol) in methylene chloride (10 ml) Palladium (50 ml) is added and the mixture is stirred for 1.5 h at room temperature in a hydrogen atmosphere. After treating the reaction mixture with Celite, the solvent is distilled off. Chloroform is added to the residue, washed successively with saturated aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography [eluent: chloroform / methanol (15: 1)] to give 93 mg (30.0%, brown oily product) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 2.17 (4H, m), 2.84 (3H, s), 3.28-3.53 (4H, m), 4.70 (1H, m), 5.87 (1H, dd, J = 7.2 Hz) , 6.87 (1H, dd, J = 9, 7.2 Hz), 7.07 (1H, d, J = 9 Hz), 7.27 (1H, s)

Example 67

Synthesis of 2-isobutylcarbamoyl-5- [2- (methylsulfonylamino) ethylthio] [1, 2-a] pyridine (Compound 196)

2-ethoxycarbonyl-5- [2- (methylsulfonyl) amino) ethylthio] [1, 2-a] pyridine (148 mg, 0.431 mmol), isobutylamine (0.86 ml, 8.65 mmol) and ethanol (10 ml) is heated at reflux for 18 h. Further isobutylamine (1.72 ml, 17.3 mmol) is added to the mixture and the mixture is heated at reflux for 17 hours. Further isobutylamine (1.72 ml, 17.3 mmol) is added to the mixture and the mixture is heated under reflux for 8 hours. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 139 mg (86.9%, pale yellow solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.93 (1H, nonet, J = 6.6 Hz), 2.98 (3H, s), 3.15 to 3.43 (6H, m), 5.51 (1H, brt, J = 6 Hz), 7.10 (1H, dd, J = 1.2 Hz), 7.24 (1H, dd, J = 9, 7 Hz), 7.49 (1H, br), 7.55 (1H, m), 8.47 (1H, s)

Example 68

According to the same manner as described in Example 31, the following compounds are obtained.

5- [3- [N- (methylsulfonyl) -3- (phenyl) propylamino] propylthio] imidazo [1, 2-a] pyridine (Compound 197)

NMR (200 MHz, CDCl ₃ ) δ: 1.80 to 2.00 (4H), 2.62 (2H, t, J = 7.6 Hz), 2.80 (3H, s), 3.02 (2H, t, J = 7 Hz) 3.17 (2H, m ), 3.28 (2H, m), 6.91 (1H, dd, J = 7, 1 Hz), 7.07-7.34 (6H, m), 7.59 (1H, d, J = 9 Hz), 7.85 (1H, m)

Example 69

Synthesis of 5- [1- (methylsulfonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (free compound of compound 29)

(1) Synthesis of 1-methylsulfonyl-4-methylsulfonyloxypiperidine

To a solution of 4-hydroxypiperidine (5.10 g, 50 mmol) and triethylamine (20.9 ml, 150 mmol) in methylene chloride (150 ml) was added methanesulfonyl chloride (8.54 ml, 110 mmol) with stirring under ice cooling And the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed sequentially with saturated aqueous sodium bicarbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is solidified with ethyl acetate-n-hexane to give 11.45 g (88.3%, pale yellow solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 2.07 (4H, s), 2.81 (3H, s), 3.36 (4H, m), 4.93 (1H, m)

(2) Synthesis of 5- [1- (methylsulfonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (free compound of compound 29)

To a suspension of 5-methcaptoimidazo [1,2-a] pyridine (1.50 g, 10 mmol) in ethanol (100 ml) is added a solution of 4.1 M sodium methylate (2.44 ml, 10 mmol) in methanol, The mixture is stirred for 10 minutes at room temperature. At room temperature 1-methylsulfonyl-4-methylsulfonyloxypiperidine (2.83 g, 11 mmol) is added to the reaction mixture and the mixture is heated at reflux for 14 hours. After distilling off the solvent, the residue is dissolved in chloroform, washed successively with 1N aqueous sodium hydroxide solution and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography [eluent: ethyl acetate / ethanol (10: 1)] to give 1.27 g (40.8%, light brown solid) of the desired product.

NMR (200 MHz, CDCl ₃ ) δ: 1.70 to 2.13 (4H, m), 2.79 (3H, s), 2,90 (2H, m), 3.35 (2H, m), 3.69 (2H, m), 7.05 ( 1H, dd, J = 7, 1.2 Hz), 7.17 (1H, dd, J = 8.8, 7 Hz), 7.67 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 1.2 Hz), 7.96 (1H, s)

[Production Example 1]

(1) 100 g of compound 1

(2) 50 g of lactose

(3) 15 g of corn starch

(4) Carboxymethyl cellulose calcium 44g

(5) 210 g of magnesium stearate

1,000 tablets

All of components (1), (2) and (3) and 30 g of component (4) are kneaded with water, dried under vacuum and then granulated. The granular powder is mixed with 14 g of component (4) and 1 g of component (5) and the mixture is placed in a tablet molding machine to obtain 1,000 tablets containing 100 mg of component (1) per tablet.

[Production Example 2]

(1) 10 g of compound 1

(2) 4.5g lactose

(3) 4.5g corn starch

(4) 1 g of magnesium stearate

100 capsules 20 g

All the above ingredients are thoroughly mixed and filled into suitable gelatin capsules to obtain 100 capsules containing 100 mg of component (1) per capsule.

[Manufacture example 3]

(1) 10 g of compound 1

(2) 1.8 g sodium chloride

(3) appropriate amount of distilled water for injection

Total amount 200 ml

Component (3) is added to the starch of components (1) and (2) to dissolve them, and the total amount of solution is adjusted to 200 ml. The solution is then sterilized and filled into ampoules of the appropriate size to yield 100 ampoules containing 100 mg of component (1) per ampoule.

Experimental Example 1

Calmodulin Inhibitory Activity

(Experimental method)

50 mM Tris-HCl buffer (pH 7.4), 5 mM MgCl ₂ , 10 μM CaCl ₂ and calmodulin [2 units; Sigma Corporation, p-0270] or 3 mM EGTA, cyclic nucleotide phosphodiesterase [0.01 units; Sigma Corporation, p-0520], and a reaction system (0.45 ml) consisting of 1 μM cGMP ([ ³ H] cGMP, containing ³ nCi), the compounds of the present invention obtained in the above examples (0.11% DMSO solution, 50 μl) Was added and the reaction was carried out at 37 ° C. for 15 minutes. The reaction is then terminated by boiling the tube for 2 minutes. [ ³ H] 5'-GMP product was converted to [ ³ H] guanosine by further incubation at 37 ° C. for 10 min using 50 μg of snake venom solution (C. atrox) as 5′-nucleotidase. Switch. Carrier guanosine is added, then Doex 1 × 8 resin is added to the reaction tube, and the tube is centrifuged for 1 minute. Radioactivity in 250 μl of supernatant is measured. The inhibition rate is measured according to the following formula.

% Inhibition = 100- (measured in the presence of drug-measured in the presence of EGTA) /

(Measured value in the absence of drug -EGTA) * 100

The results are shown in Table 1.

As shown in Table 1 above, the compounds of the present invention have excellent calmodulin inhibitory activity.

Experimental Example 2

Hypotensive activity in spontaneous hypertensive rats (SHR)

(Experimental method)

SHR male mice at 20 weeks of age are used. They are warmed in a thermostat at 37 ° C. for 5 minutes and the measurement is carried out according to the blood volume measurement method. The agent (compound obtained in the above example) is suspended in gum arabic-water and administered orally in an amount of 2.5 ml / kg. Blood pressure is measured before and after drug administration at 1 hour and 5 hours, and the change in value is calculated from the blood pressure value before administration, respectively.

The results are shown in Table 2.

As shown in Table 2, the compound of the present invention has excellent blood pressure lowering activity.

Experimental Example 3

Effect on the development of arrhythmias caused by ischemia and subsequent reperfusion in the rat heart

(Experimental method)

Male Sprague Dawley rats (Japan Clea) 9 to 10 weeks of age are anesthetized with 50 mg / kg (ip) of sodium pentobarbital. The heart is exposed to the left thoracotomy under artificial ventilation with room air and sutured under the main left coronary artery (LAD) for ligation for 5 minutes. Then unscrew the ligation for reperfusion. The occurrence of ventricular tachycardia (VT), ventricular fibrillation (VF), and cardiac arrest (CA) occur until 10 minutes after reperfusion is recorded. The agent (the compound obtained in the above example) is orally administered (5 ml / kg) 1 hour before strongly ligation. According to the X ² -test, the effect of the drug is assessed against the frequency of the groups receiving the excipients.

The results are shown in Table 3 below.

As shown in Table 3, the compounds of the present invention reduce the frequency of arrhythmia caused by occlusion of 5 minutes prior to reperfusion.

Experimental Example 4

Effect on Acute Renal Failure Caused by Ischemia and Subsequent Reperfusion in Rat Kidney

(Experimental method)

SD rats (males) 6 to 7 weeks of age are anesthetized with pentobarbital sodium (50 mg / kg, i.p.) and ligation of the left and right renal arteries. After 45 minutes, the clip is removed and religated. After 20 hours, blood is collected from the abdominal aorta as measured by pentobarbital sodium anesthesia and blood urea nitrogen (BUN) is measured.

The drug (compound obtained in the above example) is orally administered (5 ml / kg) 1 hour before occlusion of the renal artery.

The results are shown in Table 4.

As shown in Table 4, the compounds of the present invention inhibit the increase of BUN in ischemic kidney / reperfusion in rats.

Another aspect of the invention is to provide a novel angiogenesis inhibitor.

Vascular formation occurs in normal physiological conditions of humans or mammals, such as menstruation and ovulation or placental formation, restorative healing, and methods of restoring inflammation, and rapid formation and increase of capillaries to cells as shown below. It is known that angiogenesis occurs at various morbidity rates causing various serious damages. Capillaries are diseases caused by pathological increase, for example, in the field of ophthalmology, diabetic retinopathy, posterior capsular fibrosis, angiogenesis with cornea transplantation, glaucoma, ocular tumors and granular conjunctivitis and the like; Psoriasis, purulent granulomas, etc. in the field of dermatology; Angiopathy, fibrovascular disease and the like in the field of pediatrics; Hypertrophy scars, granulation etc. in the field of surgery; Arthritis rheumatoiditis, edematous sclerosis and the like in the field of internal medicine; Atherosclerosis and the like in heart disease; Various tumors and the like are known.

In particular, many people have been blinded by an abnormal increase in angiogenesis in diabetic retinopathy and granuloconjunctivitis. In addition, a large number of people suffer from cartilage rupture due to abnormal angiogenesis in the joint due to arthritis rheumatoiditis. Therefore, there has been a need for the development of compounds useful as agents for the prevention or treatment of diseases involving an increase in angiogenesis. Moreover, it is believed that rapid proliferation and expansion of tumors is caused by angiogenesis induced by angiogenic factors produced by tumor cells. Therefore, angiogenesis inhibitors will be novel drugs for the treatment of various tumors and it is expected that studies on angiogenesis inhibitors will be initiated [J. Folkman, Advance in Cancer Research, 43, 175 (1985), published by George Klein and Sidney Weinhouse.

It has already been known that heparin or heparin segments in combination with so-called hemostatic steroids (antiangiogenic steroids) such as cortisone can inhibit angiogenesis [J. Folkman et al., Science, 221, 719 (1983); J. Folkman et al., Annals of Surgery, 206, 374 (1981).

Furthermore, the use of sulfated α, β and γ-cyclodextrins, in particular β-cyclodextrin tetradecasulfate or heparin, in combination with hemostatic steroids, fumagillins, collagen synthesis inhibitors, etc., results in synergistic angiogenesis. Has been recognized [D. Ingber and J. Folkman, Laboratory Investigation, 59, 44 (1988).

On the other hand, US Patent Nos. 4, 599, 331 disclose that angiogenesis inhibitory activity is observed even by using only a steroid (ethian acid derivative). However, this steroid also has a strong adrenocorticos-teroid hormone activity, which makes it difficult to use it as a medicament.

There are a number of reports related to imidazo [1,2-a] pyridine derivatives. However, there are very few reports on the pharmacological activity of compounds having an alkylthio group having a functional group at the 5-position. In particular, with respect to such compounds having carbamate esters as functional groups, only 5- (2-t-butoxy carbonylaminoethylthio) imidazo [1,2-a] pyridine and 5- [2- (N- Chloroacetylcarbamoyloxy) -ethylthio] imidazo [1,2-a] pyridine is reported in European patent application P 87108189.9 as starting material for the synthesis of cefem compounds with excellent antimicrobial activity. But there is no specification for its pharmacological activity.

In this situation, the inventors have synthesized various imidazo [1,2-a] pyridine derivatives having substituents at the 5-position and extensively studied their pharmacological activity. As a result, several of them were found to possess excellent angiogenesis inhibitory activity.

Accordingly, the present invention also provides a novel angiogenesis inhibiting composition containing a compound of formula (1):

Wherein A ′ is a divalent C _1-15 hydrocarbon group which may contain ether oxygen at any possible position, and the side chain portions of the hydrocarbon group may be substituted; R ^a and R ^b are the same or different and hydrogen , An optionally substituted hydrocarbon group, a halogen, a nitro group, a nitroso group, an optionally protected amino group, a lower alkoxycarbonyl group or a lower alkyl carbamoyl group; R ^c is hydrogen or an optionally substituted hydrocarbon group or may form a ring with a carbon atom of A R ^d is an optionally substituted hydrocarbon group.)

Examples of the group represented by A ′ in the general formula (1) include groups of the following formula:

Wherein x, y and z are each an integer from 0 to 5; R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j are hydrogen or optionally substituted lower alkyl, lower alkenyl, aralkyl, Aryl or a heterocyclic group; R ^e and R ^f or R ^g and R ^h or R ⁱ and R ^j may be bonded together to form a ring or R ^e or R ^g may be bonded together with R ⁱ or R ^j Ring;), -CH ₂ CH ₂ OCH ₂ CH ₂ -or a group of the following formula and the like.

(Wherein a and b are each an integer of 0 to 5)

Examples of lower alkyl groups represented by R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, Linear or branched alkyl groups of 1 to 6 carbon atoms such as hexyl and the like. Examples of lower alkenyl groups represented by R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j include lower alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, and the like. Groups are included. Lower alkyl and lower alkenyl groups may have from 1 to 5 substituents, such as halogen, nitro, amino, lower alkylamino, cyclic amino, lower alkoxy, aryloxy, carbamoyl, cyano, hydroxy, Carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl and the like. Examples of halogens include fluoro, bromo, chloro and iodine. As the substituent, examples of lower alkylamino groups include N-monoalkylamino groups having 1 to 6 carbon atoms in the alkyl moiety such as methylamino, ethylamino, propylamino, butylamino and the like and dimethylamino, diethylamino, dibutylamino, methyl N, N-dialkylamino groups where the alkyl moiety has 1 to 6 carbon atoms, such as ethylamino and the like, are included.

As the substituent, examples of the cyclic amino group include 4 to 7 membered cyclic amino groups such as N-pyrrolidino, piperazino, piperadinyl, morpholino, homopiperazino and the like.

As the substituent, examples of lower alkoxy groups include straight or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like. As the substituent, examples of the aryloxy group include C _6-10 aryloxy groups such as phenoxy, 1-naphthoxy, 2-naphthoxy and the like. As the substituent, examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 1 to 6 alkoxy moieties such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Examples of the lower alkyl carbamoyl group include N-monoalkyl carbamoyl having 1 to 6 alkyl moieties, such as methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, butyl carbamoyl, etc. Likewise, N, N-dialkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety are included.

Examples of the aralkyl group represented by R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j include alkyl groups such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, and the like having 1 to 6 carbon atoms. Naphthyl-lower alkyl having an alkyl moiety of 1 to 6 carbon atoms, such as a phosphorus phenyl lower alkyl group and (1-naphthyl) methyl, 2- (1-naphthyl) ethyl, 2- (2-nathryl) ethyl and the like. . The phenyl portion of the phenyl-lower alkyl group and the naphthyl portion of the naphthyl-lower alkyl group are selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl, and the like. It may be substituted with 1 to 4 substituents. Examples of halogens include fluoro, bromo, chloro and iodo. Examples of lower alkyl groups and lower alkenyl groups include groups similar to lower alkyl groups and lower alkenyl groups represented by R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j . For example, lower alkoxy groups include straight or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like. Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groups having 1 to 6 alkoxy moieties, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Examples of lower alkylcarbamoyl groups are N-alkylcarbamoyl groups having 1 to 6 carbon atoms and dimethylcarbamoyl, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, and the like. And N, N-dialkylcarbamoyl having an alkyl moiety of 1 to 6 carbon atoms, such as diethylcarbamoyl, dibutylcarbamoyl, methylethylcarbamoyl and the like.

Examples of the aryl group represented by R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j include aromatic rings such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl, etc. Or a cyclic hydrocarbon group, and examples of heterocyclic groups include 1 to 4 heteroatoms such as sulfur, oxygen, nitrogen, and the like, wherein the heterocyclic ring is bonded via a carbon atom, thienyl, furyl, benzothienyl, benzofuranyl Aromatic ring groups or ring groups such as the like. Aryl groups and heterocyclic groups are 1 to 4, preferably 1, such as halogen, lower alkyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, and the like. Or two substituents. Examples of halogen in such substituents include fluoro, bromo, chloro and iodo. Examples of lower alkenyl groups are alkyl groups having 1 to 6 carbon atoms as described above and examples of lower alkyl groups are lower alkenyl groups having 1 to 6 carbon atoms as described above. Examples of the alkoxy group include an alkoxy group having 1 to 6 carbon atoms, and examples of the alkoxycarbonyl group include an alkoxycarbonyl group having an alkoxy moiety of 1 to 6 carbon atoms. Examples of lower alkylcarbamoyl groups are N-monoalkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety and N, N-dialkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety. Examples of these groups include groups similar to lower alkoxy groups, lower alkoxycarbonyl groups and lower alkylcarbamoyl groups as substituents for the phenyl moiety in the aralkyl group. Examples of the aryl group having an oxo group include benzoquinolyl, naphthoquinolyl, anthraquinolyl and the like.

Examples of rings formed by combining R ^e and R ^f , R ^g and R ^h or R ⁱ and R ^j include C _3-8 cycloalkanes such as cyclopropane, cyclobutane, cyclohexane and the like.

Examples of rings formed by combining R ^e or R ^g with R ^h or R ⁱ include C _3-8 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like.

Examples of the optionally substituted hydrocarbon group in R ^a and R ^b are a lower alkyl group, a lower alkenyl group, an aralkyl group and an aryl group optionally substituted with a substituent in the group represented by A ′. In addition, examples of halogen include fluoro, chloro, bromo and iodo. Examples of the optionally protected amino group include an amino group, an acylamino group, and the like.

Examples of the acyl group of the acylamino group include lower alkylcarbonyl groups (e.g., C _1-6 alkylcarbonyl groups such as acetyl), aralkylcarbonyl groups (e.g., C _7-10 arralcarbonyl groups such as benzylcarbonyl, etc.), arylcarbonyl groups ( Eg, _C6-10 arylcarbonyl groups such _as benzoyl, etc., lower alkyloxycarbonyl groups (eg _C1-4 alkyloxycarbonyl groups such as methoxycarbonyl, etc.), aralkyloxycarbonyl groups (eg _C7-10 such as benzyloxycarbonyl, etc.) aralkyloxy group), aryloxycarbonyl group (eg, has a group represented by -COR ^d or ^d -CO2R, such as _C6-10 aryloxycarbonyl group), such as phenoxycarbonyl.

Examples of lower alkoxycarbonyl groups and lower alkylcarbamoyl groups in R ^a and R ^b are lower alkoxy as substituents for the phenyl moiety in the aralkyl group represented by R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j . Groups similar to carbonyl and lower alkylcarbamoyl groups.

Examples of the optionally substituted hydrocarbon group of R ^c and R ^d include an optionally substituted lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aralkyl group, an aryl group, and the like. Examples of the optionally substituted lower alkyl group, lower alkenyl group, aralkyl group and aryl group include groups similar to those described for the group represented by A '. Examples of the cycloalkyl group include a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the substituent of the cycloalkyl group include those similar to those of the optionally substituted lower alkyl group as described in A ', and the number is 1 to 5. Examples of groups in which R ^C is connected to R ^e , R ^f , R ^g , R ^h , R ⁱ , and R ^j in A ′ to form a ring include groups of the general formula:

Wherein Q and R are 2 or 3, respectively

Compounds of the general formula (1) include, for example, acid addition salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and organic acids such as acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, lactic acid, and the like. Can be formed.

Compound (1) or a salt thereof may be a solvent compound and examples of the solvent of the solvent compound include alcohols such as methanol, ethanol, propanol, isopropanol and the like; Ketones such as acetone and the like; Ethers such as tetrahydrofuran, dioxane and the like.

Examples of preferred embodiments of the compound of formula (1) or a salt thereof include a compound represented by the following formula or a salt thereof:

(Wherein R ^{a '} is hydrogen or lower alkyl group; R ^b' is hydrogen or optionally substituted lower alkyl group; R ^{d '} is optionally substituted lower alkyl group, cycloalkyl group or lower alkenyl group)

In general formula (1 '), the lower alkyl group represented by R ^a' , the optionally substituted lower alkyl group represented by R ^{b '} , and the lower alkyl group and lower alkenyl group represented by R ^d' include R ^e , R ^f , and R Included are those described with respect to groups represented by ^g , R ^h , R ⁱ , and R ^j . Examples of the optionally substituted lower alkyl group represented by R ^{d '} include those described above for R ^d . R ^{d '} is preferably C _1-6 alkyl or C _1-6 alkenyl.

Compound (1) may contain subsidiary carbon in the molecule. When stereoisomers of the R- and S-configuration exist, these isomers as well as mixtures thereof are within the scope of the present invention.

The imidazo [1,2-a] pyridine derivative (1) or salts thereof of the present invention can be synthesized according to the following method, for example.

(A) the compound of the following general formula (2):

Wherein X 'is halogen such as chloro, bromo, iodine and the like and R ^a and R ^b are as defined above. Reaction with a compound of the general formula (3):

Wherein A ', R ^c and R ^d are as defined above.

(B) the compound of the following general formula (4) or a salt thereof:

Wherein R ^a and R ^b are as defined above. Reaction with a compound of formula (5):

Wherein A ', R ^c and R ^d are as defined above and X ¹ is halogen (e.g. chloro, bromo, iodo and the like), an arylsulfonyloxy group or methane sulfonyloxy such as toluene sulphonyloxy group Leaving groups such as alkylsulfonyloxy groups such as groups).

(C) the compound of the following general formula (6) or a salt thereof:

Wherein A ', R ^a , R ^b and R ^c are as defined above. Reaction with a compound of formula (7)

Wherein R ^d and X 'are as defined above.

(D) the compound of the following general formula (8) or a salt thereof:

Wherein A ', R ^a , R ^b and R ^d are as defined above) and react with a compound of formula (9):

Wherein X ¹ is as defined above and R ^{c ′} is an optionally substituted hydrocarbon group.

(E) the compound of the following general formula (10)

Wherein A ', R ^a , R ^b are as defined above

Reaction with the compound of the general formula (11)

Wherein R ^d is as defined above

(F) the compound of formula 12) or a salt thereof:

(Wherein X ² is a leaving group such as halogen (eg chloro etc.), phenoxy group, imidazolyl, etc., and A ′ R ^a , R ^b and R ^c are as defined above). React with compounds of:

Wherein Rd is as defined above

Wherein A ', Ra, C and Rd are as defined above. Reaction with a halogenating agent yields a compound of formula (1b) or a salt thereof.

(G) the compound of the following general formula (1a) or a salt thereof:

Wherein A ', R ^a , R ^c and R ^d are as defined above and X' is halogen.

(H) Nitrosing the compound of formula (1a) or a salt thereof yields the compound of formula (1c) or a salt thereof:

Wherein A ', R ^a , R ^b and R ^d are as defined above

(I) Nitrosation of the compound of formula (1a) affords the compound of formula (1d) or a salt thereof:

Wherein A ', R ^a , R ^c and R ^d are as defined above.

(J) the compound of formula (1c) or (1d) or a salt thereof is reduced to yield a compound of formula (1e) or a salt thereof:

Wherein A ', R ^a , R ^c and R ^d are as defined above. The compound of formula (1e) or a salt thereof is a compound of formula (7) or X'COR ^d (where X' and R ^d is as defined above) to further react to give a compound of formula (1f) or a salt thereof:

Wherein R ^k is —CO ₂ R ^d or —COR ^d and A ′, R ^a , R ^c and R ^d are as defined above.

(K) According to the following scheme, a compound of the general formula (1 g) or a salt thereof is obtained.

Wherein R ^2a is a lower dialkylamino group or a cyclic amino group, and A ', R ^a , R ^c and R ^d are as defined above.

In the presence of a basic compound such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate and the like, in a solvent, from -10 ° C to + 200 ° C, 1 equivalent to excess per equivalent of Compound (2) or a salt thereof, provided that Reaction of Compound (2) or a salt thereof with Compound (3) in Method A can be carried out by using Compound (3). Examples of the solvent used include water; Lower alcohols such as methanol, ethanol, propanol and the like; Ketones such as acetone, methyl ethyl ketone and the like; Ethers such as tetrahydrofuran and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like. The reaction time is usually 1 hour to 2 days, preferably 1 to 8 hours.

The reaction of Compound (4) or a salt thereof with Compound (5) in Method B can be carried out under conditions similar to those of Compound (2) and Compound (3) in Method A.

At −30 ° C. to + 200 ° C. in the presence of an inorganic base such as potassium carbonate, sodium bicarbonate, or an organic base such as triethylamine, pyridine, dimethylaniline, 1,4-azabicyclo [2.2.2] octane (DABCO), The reaction of compound (6) or a salt thereof with compound (7) can be carried out in Method C by using from 1 equivalent to significant excess of compound (7) relative to compound (6) or salts thereof in a solvent.

Examples of the solvent used include water; Lower alcohols such as methanol, ethanol, propanol and the like; Ketones such as acetone, methyl ethyl ketone and the like; Ethers such as tetrahydrofuran and the like, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like. The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 6 hours.

Method D by using in the solvent in the presence of a base such as potassium hydride, sodium hydride, sodium amide and the like in an amount of from 1 equivalent to significant excess of compound (9) relative to compound (8) or salt thereof Reaction of Compound (8) or a salt thereof with Compound (9) can be carried out. Examples of the solvent used include ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and the like. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

Reaction of compound (10) with compound (11) in Method E by using from 1 equivalent to significant excess of compound (11) relative to compound (10) at -10 ° C to + 150 ° C, with or without solvent Can be performed. Examples of the solvent used include ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like; Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like. To promote the reaction, tertiary amines such as triethylamine, pyridine, dimethylaminopyridine, N-methylpiperidine or the like or boron trifluoride ether (BF ₃ Et ₂ O) can be added. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

Compound (12) or a salt thereof and a compound in Method F by using from 1 equivalent to a substantial excess of Compound (11) relative to Compound (12) or a salt thereof at -30 ° C to + 200 ° C, with or without solvent The reaction with (11) can be carried out. Examples of the solvent used include ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like; Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and the like. To accelerate the reaction, tertiary amines such as triethylamine, pyridine, dimethylaminopyridine, N-methylpiperidine and the like can be added.

The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

Reaction of Compound (1a) or its salts with halogenating agents in Method G by using from 1 equivalent to significant excess of halogenating agent relative to Compound (1a) or a salt thereof at -20 to + 150 ° C., with or without solvent. Can be performed. Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, carbon tetrachloride, etc., acetic acid, propionic acid and the like. Examples of halogenating agents include halogen molecules such as chlorine, bromine and the like; N-halogenated succinimides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. Moreover, during the reaction, radical reaction initiators such as benzoyl peroxide and the like can be added. The reaction time is usually 30 minutes to 12 hours, preferably 1 to 12 hours.

In the presence or absence of a solvent, at -20 to + 100 ° C., nitration of Compound (1a) or its salts can be carried out in Method H by using from 1 equivalent to significant excess of the nitrating agent relative to Compound (1a) or salts thereof. Can be. Examples of the solvent used include acetic acid, acetic anhydride, sulfuric acid and the like. Examples of nitrating agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, phosphoric acid or mixed acids of acetic anhydride with nitric acid) and the like. The reaction time is 30 minutes to 1 day, preferably 30 minutes to 6 hours.

In the presence or absence of a solvent, at -20 to + 100 ° C., nitration of compound (1a) or salts thereof is carried out in method I by using an excess of 1 to 1 excess of nitrating agent relative to compound (1a) or salts thereof can do. Examples of the solvent used include water: lower fatty acids such as acetic acid, propionic acid and the like; Ethers such as tetrahydrofuran, dioxane and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like. Examples of nitrating agents include potassium nitrite, sodium nitrite and the like. The reaction is carried out in the presence of acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and the like. The reaction time is usually 30 minutes to 1 day, preferably 30 minutes to 6 hours.

Reduction of compound (1c) or (1d) or salt thereof in Method J by using from 1 equivalent to significant excess of reducing agent relative to compound (1c) or (1d) in the presence of a solvent at -20 to + 200 ° C. can do. Examples of the solvent used include water, methanol, ethanol, propanol, acetic acid and the like. Examples of reducing agents include iron, hydrochloric acid, a mixture of zinc and acetic acid, and the like. Moreover, the reaction can also be carried out by using hydrogenation catalysts such as palladium, palladium black on carbon, Raney-nickel and the like under the atmospheric pressure of hydrogen at -20 to + 200 ° C in the presence of a solvent.

The reaction time is usually 30 minutes to 2 days, preferably 1 to 12 hours.

Furthermore, in Method C, the reaction of Compound (1e) or a salt thereof with Compound (7) or Compound (1e) or a salt thereof under conditions similar to those of the reaction of Compound (6) or a salt thereof with Compound (7) The reaction with X'COR ⁴ can be carried out.

In the presence of a solvent, at -20 to + 10 ° C., in a method K by using from 1 equivalent to a significant excess of Mannich's reagent relative to compound (1a) or a salt thereof, low dialkyl Reactions of amines and formalin or cyclic amines with formalin can be carried out. Examples of the solvent used include water; Lower alcohols such as methanol, ethanol, propanol, isopropanol and the like; Lower fatty acids such as acetic acid and lopionic acid are included. The reaction time is usually 30 minutes to 1 day, preferably 1 to 12 hours.

In the above methods A to K, the compounds which form the salts can be used in the form of salts and examples of such salts include those described in the salt of compound (1).

In the starting materials used in the methods A to K, compound (2) can be obtained by the following method.

The reaction of compound (13) with compound (14) can be carried out by using from 1 equivalent to significant excess of compound (14) relative to compound (13) at 0 to + 200 ° C with or without solvent. Examples of the solvent used include water; Lower alcohols such as methanol, ethanol, propanol and the like; Ethers such as tetrahydrofuran, dimethoxyethane, dioxane and the like; Nitriles such as acetonitrile, propionitrile and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like. Furthermore, in the reaction, inorganic bases such as potassium carbonate, potassium bicarbonate and the like or organic bases such as triethylamine, pyridine, dimethylaniline and the like can be added as the acid-trapping agent. The reaction time is usually 10 minutes to 7 days, preferably 1 hour to 2 days.

Compound (4) can be obtained, for example, by the following method.

(Half in the scheme, Y is sodium or potassium, and R ^a and R ^b are as defined above.)

(In the reaction scheme, T is ^a protecting group such as p-methoxybenzyl, benzyl, etc. and R ^a and R ^b are as defined above.)

Compound (2) is reacted with YSH under conditions similar to those for reacting compound (2) with compound (3).

Compound (15) is reacted with compound (14) under conditions similar to those of the reaction between compound (13) and compound (14).

Compound (16) is reacted with compound (14) under conditions similar to those for reacting compound (13) with compound (14).

Compound (6) can be obtained by the following method, for example.

(A ', R ^a , R ^b , R ^c , and R ^d are as defined above in the scheme.)

(In the reaction scheme, T ¹ is an amino protecting group such as benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl, trityl, benzyl, etc .; A ', R ^a , R ^b , and R ^c are the definitions above As it is.)

(In the reaction scheme, A ', T ¹ and R ^c are as defined above, but further include those wherein -NT ¹ R ^c is phthalimide.)

(In the reaction scheme, A ', R ^a , R ^b , R ^c , R ^d and X ¹ are as defined above.)

(In the reaction scheme, X ¹ and R ^c are as defined above.)

(In the reaction diagram TRL, A ', R ^c and T ¹ are as defined above but further include those in which -NT ¹ R ^c is phthalimide.)

Reaction of compound (2) with compound (18), reaction of compound (2) with compound (19) under conditions similar to those for reacting compound (2) with compound (3) in Method A, compound (4) Reaction with Compound (21), Compound (2) with Compound (22), and Compound (4) with Compound (25).

Phosphorus halides such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide and the like when X ¹ is halogen; Halogenating agents such as red phosphorus and halogens; The hydroxyl group of compound (22) is converted to X ¹ by treating compound (23) with thionyl chloride or the like. When X ¹ is a toluenefonyloxy group or a methanesulfonyloxy group, it can be obtained by treating compound (23) with toluenesufonylchloride or methanesulfonyl chloride. Subsequent reaction with compound (24) is carried out at 0-200 ° C., with or without suitable solvent. All of these reactions are known and can be carried out according to known conditions.

Compound (26) is reacted with Compound (14) under conditions similar to those of the above reaction of Compound (13) and Compound (14).

Compound (10) is obtained by the following method, for example.

i) The compound (17) is reacted with phosgene and the reaction mixture is heated to dehydrogenation.

ii) React compound (28) with silver cyanate.

All these reactions are also known and can be carried out according to known conditions.

(In the reaction scheme, A ', R ^a and R ^b are as defined above.)

(In the reaction scheme, A ', R ^a and R ^b are as defined above.)

Compound (12) can be obtained by the following method, for example.

i) When X ² is C 1, the compound (6) is reacted with phosgene.

ii) When X ² is phenoxy, compound (6) is reacted with phenylchlorocarbonate.

iii) When X ² is imidazole, compound (6) is reacted with carbonyldiimidazole.

All these reactions are known and can be carried out according to known conditions.

All reactions for removing the protecting group are known and can be carried out according to known conditions. For example, p-methoxybenzyl group which is a protecting group of a mercapto group can be removed by treating with trifluoroacetic acid at acetic acid water temperature and treating with hydrogen sulfide or 2-mercaptoethanol. The benzyl group can be removed by sodium metal in liquid ammonia.

For example, in the presence of a catalyst (e.g. palladium on carbon, platinum oxide, etc.), catalytic reduction (reaction temperature; 0 to 100) in a solvent (e.g. alcohol, acetic acid, water, tetrahydrofuran, mixed solvents thereof, etc.) Benzyloxycarbonyl group and benzyl group which are protecting groups of an amino group can be removed by performing (degree. C.).

In the case of trityl and t-butoxycarbonyl groups, in the presence of an acid (e.g. inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, etc .; organic acids such as toluenesulfonic acid, methanesulfonic acid, acetic acid, etc.), solvents (e.g., water, alcohol, tetrahydro In furan, dioxane and the like), it may be removed at 0 to 150 ° C. Trifluorolock acetyl groups are alkali examples; It can be easily removed by treating with sodium hydroxide, sodium bicarbonate solution, etc.).

Phthalimide groups can be removed by treatment with hydrazine hydrate in a solvent (eg methanol, ethanol, etc.).

Compounds (2), (4), (6), (10) and (12) can be separated by the following conventional separation methods, but in the form of a reaction mixture as starting material for preparing the required compound (1) or salts thereof. Can also be used. Furthermore, for example, Shinzikken Kagak Koza, Vol 14, synthesis and Reaction of Organic compounds I-V. (Japan Chemical Society; published by Maruzen K.K. Tokyo); To Shinji-ku, Vol. 15, Oxidation and Reduction I-V, published by Japan Chemical Society; Maruzen K.K., Tokyo; Organic Syntheses, (John Wiley and Sons, Inc., New York); According to the method described in Theilheimer's Synthetic Methods of rganic Chemistry, (Basel, New York, Karger) or the like or a modification thereof, among the above compounds, compounds (3), (5), (7), (13), (14), ( 18), (19), (21), (22), (24) and (25) can be prepared.

Compound (1) or salts thereof are separated and purified from the reaction mixture according to conventional separation methods (e.g., extraction, concentration, filtration, recrystallization, color chromatography, membrane chromatography, etc.).

The compound (1) of the present invention or a salt thereof has an angiogenic inhibitory activity and is useful as an angiogenesis inhibitor such as, for example, nephrogenic inhibitors, anti-inflammatory agents, antirheumatic arthritis agents, antidiabetic retinopathy agents and the like.

Compound (1) or salts thereof are low toxicity and therefore orally or parenterally to mammals (eg, humans, rabbits, dogs, cats, mice, fish, guinea pigs, etc.) as is, as pharmaceutical compositions or powders in suitable dosage forms. May be administered. Dosage will vary depending on the particular route of administration, the disease being treated, the age and weight of the patient. When using compound (1) or a salt thereof as a nephrogenic inhibitor, such a preparation can be obtained by mixing compound (1) or a salt thereof with a pharmaceutically acceptable carrier. Compound (1) or a salt thereof can be used by formulating in a suitable dosage form such as red wine, injection, capsule, tablet, suppository, solution, emulsion, suspension and other suitable dosage forms.

Dosage forms for parenteral administration, e.g. when injections are prepared, isotonic agents (e.g. glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (e.g. benzyl alcohol, chlorobutanol, methyl parahydroxybenzo Ate, propyl parahydroxybenzoate and the like), anticoagulants (eg dextran sulfate, heparin and the like) and buffers (eg phosphate buffer, sodium acetate buffer) can be used. Moreover, the dosage form for oral administration may be used as a capsule in which Compound (1) or a salt thereof is mixed with lactose or the like or may be used as a dragee prepared by a conventional method.

For example, when parenteral administration of Compound (1) or a salt thereof to the lesion (s.c, i.v. or i.m.) by injection, the dosage is about 0.05-50 mg / kg / day,

Preferably about 0.2 to 20 mg / kg / day, more preferably about 0.5 to 10 mg / kg / day. In the case of oral administration, the dosage may be about 0.1 to 500 mg / kg / day, preferably about 1 to 100 mg / kg / day, more preferably 5 to 50 mg / kg / day. Furthermore, compound (I) or salts thereof can be used for topical application. For example, the lesions of the body such as the head, chest, abdomen, limbs, etc. may be washed with a solution in which compound (I) or a salt thereof is dissolved in an isotonic solution at a concentration of 0.01 to 2 w / v%, or compound (I) or a Ointments containing salts in an amount of about 0.1 to 50 mg / Lg can be applied to the lesions so that Compound (I) or salts thereof can be used to prevent and treat tumors at these sites.

As described above, the angiogenesis inhibiting composition containing the compound (I) or a salt thereof of the present invention has excellent activity and in view of this activity, it is used for the prevention and treatment of tumors of humans and mammals, rheumatoid arthritis and the like. It is useful as a medicament.

The following Reference Examples, Examples, Formulation Examples and Experimental Examples describe the present invention in more detail and do not limit the scope of the present invention. In Reference Examples, Examples, and Formulation Examples, room temperature is 15-25 ° C.

[Reference Example 1 ']

(1) Synthesis of 5- [2- (methylsulfonyloxy) -ethylthio] imidazo [1,2-a] pyridine.

Methanesulfonyl in a solution of 5- (2-hydroxy) ethylthioimidazo [1,2-a] pyridine (9.71 g, 50 mmol) and triethylamine (10.5 ml, 75.3 mmol) in methylene chloride (300 ml) Chloride (4.26 ml, 55 mmol) is added with stirring under cold cooling and the mixture is stirred for 2 hours under ice cooling. The reaction mixture is washed sequentially with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is then evaporated off to give 13.6 g of the required product (quantitative, brown oily product).

[Reference Example 2 ']

(1) Synthesis of 5- [2- (methylamino) -ethylthio] imidazo [1,2-a] pyridine.

5- [2- (methylsulfonyloxy) ethylthio] -imidazo [1,2-a] pyridine (2.18 g, 8 mmol), triethylamine (2.24 ml, 16 mmol) in chloroform (20 ml) and 40 A solution of% methylamine-methanol solution (20 ml) is heated under reflux for 3 hours.

The reaction mixture is washed with 3N NaOH and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography to give 781 mg of the desired product (eluent: methanol / chloroform (1:10)) (47.1%, pale brown oily product).

The following compounds are obtained in the same manner as described in Reference Example 2 '(1).

(2) 5- [2- (ethylamino) ethylthio] imidazo- [1,2-a] pyridine

[Reference Example 3 ']

(1) Synthesis of 5- [2- (amino) ethylthio] imidazo- [1,2-a] pyridine.

A 5- [2- (amino) ethylthio] imidazo- [1,2-a] pyridine dihydrochloride (13.31 g, 50 mmol) suspension in chloroform (200 ml) was washed with 3N sodium hydroxide (50 ml). The aqueous layer is extracted with chloroform and the combined chloroform layers are dried over anhydrous magnesium sulfate. The solvent is then distilled off to yield 9.63 g of the desired product (99.7% pale yellow oily product).

[Reference Example 4 ']

Synthesis of 5- [3- (amino) propylthio] imidazo- [1,2-a] pyridine.

To a mixed solution of 10% (w / w) potassium hydroxide (69.3 g, 105 mmol) and dimethyl sulfoxide (50 ml) was added S- (3-aminopropyl) isothiourea dihydrobromide (8.85 g, 39 mmol) The mixture is stirred at rt for 1.5 h. 5-chloroimidazo [1,2-a] pyridine (3.05 g, 20 mmol) is added to the reaction mixture, which is stirred at room temperature and further stirred at 65 ° C. for 20 hours. Water is added to the reaction mixture, the solution is extracted with chloroform, washed several times with 1N sodium hydroxide and dried over anhydrous magnesium sulfate. The solvent is then distilled off to give 2.66 g of the desired product (64.3%, pale yellow oily product).

Example 1

(1) Synthesis of 5- [2- (methoxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 1 ')

5- [2- (amino) ethylthio] imidazo- [1,2-a] pyridine (1.93 g, 10 mmol) in methylene chloride (30 ml) is added with stirring under ice cooling and the mixture is stirred at room temperature for 20 minutes. . The reaction mixture is washed with aqueous sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography [eluent: ethanol / ethyl acetate (1:10)] to give 1.68 g of the desired product (66.9% colorless crystals).

Melting Point: 198 ~ 200.0 ℃

Elemental analysis: C ₁₁ H ₁₃ N ₃ O ₂ S,

Calculated: C, 52.57; H, 5. 21; N, 16.72

Found: C, 52.68; H, 5. 22; N, 16.60

In the same manner as described in Example 1 ', the following compounds were obtained.

(2) 5- [2- (ethoxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 2 ')

Melting Point: 68 ~ 70 ℃

Elemental Analysis: C ₁₂ H ₁₅ N ₃ O ₂ S

Calculated: C, 54.32; H, 5. 70; N, 15.84

Found: C, 54.33; H, 5.75; N, 15.83

(3) 5- [2- (propylcarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 3 ')

Melting Point: 62 ~ 64 ℃

Elemental Analysis: C ₁₃ H ₁₇ N ₃ O ₂ S

Calculated: C, 55.89; H, 6. 13; N, 15.04

Found: C, 55.87; H, 6.09; N, 14.96

(4) 5- [2- (butyloxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 4 ')

Melting Point: 75 ~ 76 ℃

Elemental Analysis: C ₁₄ H ₁₉ N ₃ O ₂ S

Calculated: C, 57.31; H, 6.53; N, 14.32

Found: C, 57.32; H, 6.55; N, 14.23

(5) 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 5 ')

Melting Point: 80.0 ~ 71.0 ℃

Elemental Analysis: C ₁₃ H ₁₇ N ₃ O ₂ S

Calculated: C, 55.89; H, 6. 13; N, 15.04

Found: C, 55.85; H, 6. 14; N, 14.96

(6) 5- [2- (isobutyloxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 6 ')

Melting Point: 75 ~ 76 ℃

Elemental Analysis: C ₁₄ H ₁₉ N ₃ O ₂ S

Calculated: C, 57.31; H, 6.53; N, 14.32

Found: C, 57.29; H, 6.53; N, 14.41

(7) 5- [2- (allyloxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 7 ')

Melting Point: 72.5 ~ 73.5 ℃

Elemental Analysis: C ₁₃ H ₁₅ N ₃ O ₂ S

Calculated: C, 56.30; H, 5. 45; N, 15.15

Found: C, 56.34; H, 5. 44; N, 15.04

(8) 5- [2- [2,2,2- (trichloro) ethoxycarbonylamino] ethylthio] imidazo- [1,2-a] pyridine (Compound 8 ')

Melting Point: 113.0 ~ 114.0 ℃

Elemental Analysis: C ₁₂ H ₁₂ N ₃ O ₂ SCl ₃

Calculated: C, 39.10; H, 3. 28; N, 11.4

Found: C, 39.23; H, 3. 27; N, 11.25

(9) 5- [2- (benzyloxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 9 ')

Melting Point: 52.0 ~ 53.0 ℃

Elemental Analysis: C ₁₇ H ₁₇ N ₃ O ₂ S

Calculated: C, 62.36; H, 5. 23; N, 12.83

Found: C, 62.34; H, 5. 22; N, 12.75

(10) 5- [2-[(9-fluoroenyl) methyloxycarbonylamino) ethylthioimidazo- [1,2-a] pyridine (Compound 10 ')

Melting Point: 105.0 ~ 108.0 ℃

Elemental _{analysis: C 24 H 21 N 3 O} 2 S. 0.4H ₂ O

Calculated: C, 69.07; H, 5.05; N, 9.67

Found: C, 69.14; H, 5. 23; N, 9.96

(11) 5- [2- (phenoxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 11 ')

Melting Point: 96.0 ~ 97.0 ℃

Elemental analysis: C ₁₆ H ₁₅ N ₃ O ₂ S

Calculated: C, 61.32; H, 4. 82; N, 13.41

Found: C, 61.35; H, 4.86; N, 13.30

(12) 5- [2- (N-methyl-N-isopropyloxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 12 ')

(13) 5- [2- (N-ethyl-N-isopropiooxycarbonylamino) ethylthio] imidazo- [1,2-a] pyridine (Compound 13 ')

(14) 5- [3- (methoxycarbonylamino) propylthio] imidazo- [1,2-a] pyridine (Compound 14 ')

Melting Point: 69.0 ~ 70.0 ℃

Elemental Analysis: C ₁₂ H ₁₅ N ₃ O ₂ S

Calculated: C, 54.32; H, 5. 70; N, 15.84

Found: C, 54.48; H, 5. 74; N, 15.72

(15) 5- [3- (isopropyloxycarbonylamino) propylthio] imidazo [1,2-a] pyridine (Compound 15 ')

(16) 5- [1- (t-butoxycarbonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (Compound 16 ')

(17) 5- [1- (isopropyloxycarbonylamino) -4-piperidylthio] imidazo [1,2-a] pyridine (Compound 17 ')

Example 2

(1) Synthesis of 3-bromo-5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 18 ')

N-promosuccinimide (187 ml, 1.05) in a solution of 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (279 mg, 1 mmol) in chloroformin (5 ml) Mmol) is added and the mixture is stirred at room temperature for 1 hour. The reaction solution is washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (eluent: ethyl acetate) to give 296 mg of the desired product (82.7%, colorless solid).

Melting Point: 103 ~ 104.0 ℃

Elemental analysis: C ₁₃ H ₁₆ N ₃ O ₂ SBr

Calculated: C, 43.58; H, 4.50; N, 11.73

Found: C, 43.60; H, 4.53; N, 11.74

In the same manner as described in Example 2 '(1), the following compounds were obtained.

(3) 3-chloro-5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (Compound 19 ')

Melting Point: 113.0 ~ 114.0 ℃

Elemental Analysis: C ₁₃ H ₁₆ N ₃ O ₂ SCl ^. 0.2H ₂ O

Calculated: C, 49.19; H, 5. 21; N, 13.24

Found: C, 49.38; H, 5. 26; N, 13.22

Example 3

(1) Synthesis of 5- [2- (isopropyloxycarbonylamino) ethylthio] -3-morpholinomethylimidazo [1,2-a] pyridine (Compound 20 ')

To a solution of 37% aqueous formalin solution (210 mg, 2.59 mmol) in acetic acid (2 mL) is added under ice cooling to morpholine (226 μL, 2.59 mmol) and the mixture is stirred at room temperature for 45 minutes. 5- [3- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (651 mg, 2.33 mmol) is added and stirred at 60 ° C. for 2 hours. After distilling off the solvent, the residue is diluted with chloroform, washed with 1N aqueous NaOH solution and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography [eluent: ethanol / ethyl acetate = 1: 10] to give 442 mg of the desired product (50.1%, light brown solid).

Example 4

Synthesis of 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine hydrochloride (Compound 21 ')

A 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (279 mg, 1 mmol) solution in methanol (10 ml) is treated with hydrogen chloride-methanol. After distilling off the solvent, the residue is recrystallized from isopropanol-ethylacetate-methanol. The crystals thus obtained are washed with water and dried to give 290 mg of the desired product (92.1%, colorless crystals).

Melting Point: 145 ~ 150 ℃

Elemental _{analysis: C 13 H 17 N 3 O} 2 S. HCl

Calculated: C, 49.44; H, 5. 74; N, 13.30

Found: C, 49.51; H, 5. 64; N, 13.14

Example 5

Synthesis of 5- [4- (isopropyloxycarbonylamino) butylthio] imidazo [1,2-a] pyridine (Compound 22 ')

To 5- [4- (isopropyloxycarbonylamino) butylthio imidazo [1,2-a] pyridine (370 mg, 1.67 mmol) and triethylamine (0.35 ml, 2.51 mmol) in methylene chloride (20 ml) Isopropyl chloroformate (0.25 g, 2.04 mmol) is added with stirring under ice cooling, and the mixture is stirred under ice cooling for 1 hour. The reaction mixture is washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by column chromatography (eluent: ethyl acetate) to give 215 mg of the desired product (41.8% light tan oily product).

[Manufacture example 1 ']

(1) 50 g of compound 5 '

(2) 100 g of lactose

(3) 15 g of corn starch

(4) carboxymethyl cellulose calcium 44g

(5) 1 g of magnesium stearate

1000 tablets 210 g

30 g of all components (1), (2), (3) and (4) are kneaded with water, dried under vacuum to granulate. The granulated powder is mixed with 14 g of component (4) and 1 g of component (5) and the mixture is filled in a tableting machine to prepare 1000 tablets containing 50 mg of component (1) per tablet.

[Production Example 2 ']

The following ingredients are kneaded uniformly to prepare an ointment.

Compound 5 '0.5 g

1 g of liquid paraffin

Suitable quantity of white mineral oil g

100 g of whole quantity

[Production Example 3 ']

Compound 5 '1g

19 g of cacao oil

Ingredients (1) and (2) are kneaded in a 60 DEG C water bath. The mixture is then placed in suppository molds and cooled to yield ten suppositories each containing 2 g of the mixture.

[Production Example 4 ']

(1) 10 g of compound 5 '

(2) 4.5 g lactose

(3) 4.55 g of corn starch

(4) 1 g of magnesium stearate

1000 capsules 20 g

All ingredients are thoroughly mixed and the mixture is filled into suitable gelatin capsules to prepare 100 capsules containing 100 mg of ingredient (1) per capsule.

[Production example 5 ']

The injection solution filled in ampoule is prepared by mixing and dissolving the following components.

Per ampoule

Compound 21 '50mg

Sodium Chloride 18mg

Suitable amount of distilled water for injection

2 ml total amount

Experimental Example 1 '

Effect of the target compound on the growth of endothelial cells

The experiment is carried out using endothelial cells (HUVE cells) obtained from human umbilical vein. 2 × 10 ³ HUVE cells are suspended in complete medium prepared by adding 2.5% FBS (fetal bovine serum) to GIT medium (manufactured by Nihon Seiyaku Co., Ltd.). The suspension is then distributed in 96-well microtiter plates and incubated at 37 ° C. in 5% carbon dioxide-7% oxygen-88% nitrogen atmosphere. After 24 hours, human recombination base FGF (embedded cell growth element) is added to the culture within the range of the final concentration of 2 ng / ml and further test compound is added followed by incubation for 3 days. Growth rate of HUVE cells after culture is measured by MTT method [Canser Treatment Reports, Vol. 71, p1141-1149, 1987].

Test compounds inhibit the growth of human navel endothelial cells.

The IC ₅₀ value of the test compound (the concentration of test compound that inhibits the growth of endothelial cells by 50%) is determined from the graph of the growth curve of HUVE cells. The results are shown in Table 1 'below.

As shown in Table 5, the compounds of the present invention have an excellent inhibitory effect on endothelial cell growth.

Experimental Example 2

Effect of the target compound on the growth of small arterial endothelial cells

This experiment is done using endothelial cells (BAE cells) derived from the bovine aorta. 5 × 10 BAE cells are suspended in complete medium prepared by adding 5% FBS (fetal bovine serum) to Dulbecco's modified Eagle's minmum essential medium (D-MEM medium). The suspension is then distributed in 96-well microtiter plates and incubated at 37 ° C. in an atmosphere of 5% carbon dioxide-95% air. After 24 hours, human recombination base FGF (endothelial cell growth factor) is added to the culture within the range of the final concentration of 2 ng / ml, and further test compound is added and cultured for 3 days. The growth rate of BAE cells after culture was measured by MTT method [Canser Treatment Repots, Vol. 71, p1141--1149, 1987].

The test compound inhibits the growth of small arterial endothelial cells.

The IC value of Compound 1 '(the concentration of test compound that inhibits endothelial cell growth by 50%) is 48 μΜ.

Experimental Example 3 '

Effect of Target Compounds on Growth of Human Navel Venous Endothelial Cells by Phorbol Ester

This experiment is done using endothelial cells (HUVE cells) obtained from human umbilical vein. 2 × 10 HUVE cells are suspended in complete medium prepared by adding 2.5% FBS (fetal bovine serum) to GIT medium (manufactured by Nihon Seiyaku Co., Ltd.). The suspension is then distributed in 96-well microtiter plates and incubated at 37 ° C. in 5% carbon dioxide-7% oxygen-88% nitrogen atmosphere. After 24 hours, 12-0-tetradecanoylphorball 13-acetate (TPA) is added to the culture in the range of the last concentration of 1 nM and incubated for 3 days after the addition of the test compound. After incubation, growth rate of HUVE cells is measured by MTT method [Canser Treatment Reports, Vol. 71, p1141-1149, 1987].

Test compounds inhibit the growth of human navel endothelial cells by phorbol esters.

The IC value of Compound 1 (concentration of test compound that inhibits endothelial cell growth by 50%) is 15 μΜ.

Experimental Example 4 '

Effect of the target compound on the inhibition of calcium concentrations in endothelial cells by phorbol esters

Bovine aortic endothelial cells (BAE cells) are cultured on a cover glass loaded with 4 μM Flar 2 (manufactured by Dlijin Kagaku Kenkyusho) and inserted into a quartz cuvette containing 2.5 ml of HEPES buffer (pH 7.5).

The quartz cuvette is fixed so that the covering glass is positioned diagonally at an angle of 45 ° to the direction of incidence of the excited light.

Fluorescence analysis is performed with a spectrophotometer F-4000 (manufactured by Hitachi Seisakusho Co., Ltd.). It was excited at 340 nm and 380 nm and fluorescence of 505 nm was recorded.

Fmax was measured by ionomicine (2 μM, manufactured by Carbairochen Co.), a calcium ion permeation carrier, and Fmin was measured by EGTA (8 mM), a chelating agent of calcium ions.

Intracellular Calcium Ion Concentration [Ca ] i is calculated by the following formula;

[Wherein D (W ₁ ): measured value of excited wavelength W ₁ ; D (W ₂ ): measured value of excited wavelength W ₂ ; AutoF ₁ : autofluorescence at W ₁ ; Auto F ₂ : magnetic fluorescence at W ₂ ;

Fluorescence intensity in free state at; Sb ₂ : Fluorescence intensity during Ca ⁺⁺ binding at W ₂ ]

The above formula can be obtained by correcting the following formula of Zehn et al., Taking Kd as 224 nM.

The experiment is carried out by adding various concentrations of the test compound to the solution in the cuvette and incubating for 5 minutes. Then 12-o-tetradecanoylphorball 13-acetate (TPA) with a final concentration of 2 nM is added and the change in fluorescence intensity is observed.

The test compound was found to inhibit the increase in calcium concentration in internal cells by phorbol ester (TPA).

The change of the inhibitory effect by the change of the concentration of compound 1 'is shown in Table 2'.

Toxicity Test Results

Test Methods: Mice are injected 300 mg / kg orally or 100 mg / kg intravenously with Compound 1 (compound of Example 1) to observe acute toxicity symptoms or autonomic neurological symptoms for 72 hours. If no symptoms appear, pharmacological evaluation is continued using each dose and concentration, with appropriate increases in dosage to the amounts required by the appropriate control compound. On the other hand, if acute toxicity is observed initially, the maximum tolerated dose is determined and the pharmacological test dose is proportionally reduced.

Reference (Irwin, S., Psychopharmacologia. 13: 222-257, 1968)

Results: Sudden toxicity symptoms and autonomy at 300 mg / kg oral or 100 mg / kg intravenous, 300 mg / kg oral and 100 mg / kg intravenous injections of Compound 1 (compound of Example 1) in mice No neurological symptoms were seen. Thus, it has been demonstrated that the compounds of the present invention are low toxicity.

Claims (26)

Hypertension, ischemic disease, arteriosclerosis, vasoconstriction after subarachnoid hemorrhage and inflammatory, containing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient Calmodulin inhibitor composition useful for the disease: Wherein X is S, S (O), S (O) ₂ , O or NR ³ (R ³ is hydrogen, or C _1-6 alkyl, phenyl-C _1-6 alkyl or naph which may have 1 to 4 substituents Til-C is _1-6 alkyl) and: A is (a) a group of the formula: (Wherein l, m and n are each an integer of 0 to 5; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each (1) hydrogen or (2) 1-4) C _1-6 alkyl, C _2-6 alkenyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or C _4-24 aryl which may have two substituents, or R ⁴ and R ⁵ or R ⁶ and R ⁷ or R ⁸ and R ⁹ may be bonded to each other to form a ring, or R ⁴ or R ⁶ may be individually bonded to R ⁸ or R ⁹ to form a ring), (b) a group of the formula -CH ₂ CH ₂ OCH ₂ CH _2- , or (c) a group of the formula: (Wherein O and P are each an integer of 0 to 5); B is (a) a group of the formula: -NR ¹⁰ R ¹¹ (wherein R ¹⁰ is (1) hydrogen, or (2) C _1-30 linear or branched alkyl which may have from _{1 to} 4 substituents, C _3-8 cycloalkyl, saturated non- or tricyclic hydrocarbon groups formed by the fusion of 5--8 membered rings, C _2-30 alkenyl, phenyl-C _1-6 alkyl, naphthyl-C _{1- ~ 6} alkyl or C _{4 -24} aryl or (3) a member selected from the group consisting of -CO-R ¹² , -SO ₂ R ¹³ , -CO-NR ¹⁴ R ¹⁵ and -CS-NR ¹⁴ R ¹⁵ ; R ¹¹ Is -CO-R ¹⁶ , -CO-OR ¹⁶ , -SO ₂ R ¹⁷ , -CO-NR ¹⁴ R ¹⁵ or -CS-NR ¹⁴ R ¹⁵ ) or (b) a group of the formula: -OR ¹⁸ (wherein , R ¹⁸ is (1) a saturated non- or tricyclic hydrocarbon formed by fusing C _1-30 straight or branched alkyl, C _3-8 cycloalkyl, 5-8 membered ring which may have 1-4 substituents group, C _{2 ~ 30} alkenyl, phenyl -C _1-6 alkyl, naphthyl, -C _1-6 alkyl, or a C _{4 ~ 24} aryl, or ^{(2) -CO-NR 14 R} 15 or -CO-R ¹⁹ Wherein R ¹² , R ¹⁴ and R ¹⁵ Is independently (1) hydrogen, or (2) a saturation ratio formed by fusion of C _1-30 straight or branched alkyl, C _3-8 cycloalkyl, 5-8 membered ring, which may have 1-4 substituents -or tricyclic hydrocarbon group, C _{2 ~ 30} alkenyl, phenyl -C _{1 ~ 6} alkyl, naphthyl _{~~ 1} -C ₆ alkyl or C _{4 ~ 24} aryl; R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently saturated, non- or tricys formed by the fusion of C _1-30 straight or branched alkyl, C _3-8 cycloalkyl, 5-8 membered rings cyclic hydrocarbon group, C _{2 ~ 30} alkenyl, phenyl -C _{1 ~ 6} alkyl, naphthyl -C _{1 ~ 6} alkyl, or C _{4 ~ 24} aryl, R ¹⁰ and R ³ form a ring of the formula in combination with You can do it: Wherein q is an integer of 2 or 3 and A and R ¹¹ are as defined above, or R ¹⁰ may be combined with R ⁴ , R ⁶ or R ⁸ to form a ring of the formula below; (Wherein q and r are each an integer of 2 or 3; R ¹¹ is as defined above), or R ¹⁰ may be bonded to R ¹¹ to form a ring of the following formula; R ¹⁴ and R ¹⁵ together with adjacent nitrogen atoms are 1-aziridinyl, 1-azetidinyl, piperidino, perhydro-1-azinyl, perhydro-1-azonoyl, morpholino, thio Morpholino, 1-piperazinyl, 3-thiazolidinyl, 1-indolyl, perhydro-1-indolyl, 2-isoindolyl, perhydro-2-isoindolyl, 1,2,3, 4-tetrahydro-1-quinolyl, 1,2,3,4-tetrahydro-2-isoquinolyl, perhydro-1-quinolyl, perhydro-2-isoquinolyl, 3-azabicyclo [3.2 .2] non-3-yl, 9-carbozolyl, 10-acridanyl, , 10, 11-dihydro-5H-5-dibenz [b, f] azinyl, 5,6,11,12-tetrahydro-5-dibenz [b, f] azonoyl, 1,2 Can form 3,4-tetrahydro-9-carbazolyl, 10-phenoxadinyl or 10-phenothiadinyl; R ¹ and R ² are the same or different and are hydrogen, C _1-6 alkyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or C _4-24 aryl, which may have _1-4 substituents, Halogen, nitro group, nitroso group, optionally protected amino group, lower alkoxycarbonyl group or lower alkylcarbamoyl group; The C _1-6 alkyl substituents mentioned are halogen, nitro, amino, N-mono C _1-6 alkylamino, N, N-di C _1-6 alkylamino, 4-7 membered cyclicamino, C _1-6 Alkoxy, C _6-10 aryloxy, carbamoyl, cyano, hydroxy, carboxy, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl; The mentioned substituents of C _1-30 alkyl alkenyl are 1-4 selected from (1) C _3-8 cycloalkyl, (2) C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro and halogen Phenyl optionally substituted with substituents (3) naphthyl, (4) halogen, (5) cyano, (6) oxo or (7) C _1-6 alkoxy; The substituents mentioned for C _3-8 cycloalkyl or saturated non- or tricyclic hydrocarbons are C _1-6 alkyl, halogeno C _1-6 alkyl, hydroxy C _1-6 alkyl, acyloxy C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halogeno C _1-6 alkoxy, C _1-6 alkoxy-carbonyl -C _1-6 alkoxy, C _1-6 alkenyloxy, aralkyl Oxy, C _1-6 alkoxy-C _1-6 alkoxy, C _1-6 alkoxycarbonyl, carboxy, carbamoyl, N, N-di C _1-6 alkylcarbamoyl, NC _1-6 alkylcarbamoyl , Halogen, cyano, nitro, hydroxy, acyloxy, amino, C _1-6 alkylsulfonylamino, acylamino, C _1-6 alkoxycarbonylamino, acyl, mercapto, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl or oxo; The mentioned substituents of phenyl-C _1-6 alkyl or naphthyl C _1-6 alkyl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, hydroxy, C _1-6 alkoxy carbonyl, carbamoyl Or C _1-6 alkylcarbamoyl; The substituents mentioned for C _{4 -24} aryl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, oxo, hydroxy, amino, C _1-6 alkoxycarbonyl, carbamoyl or C _{1 ~ 6} alkyl-carbamoyl. The compound of claim 1, wherein the optionally protected amino group of R ¹ and R ² is amino, acylamino (acyl group is the same as that of R ¹¹ in claim 1) or tritylamino; The lower alkoxycarbonyl and lower alkylcarbamoyl of R ¹ and R ² are C _1-6 alkoxycarbonyl and C _1-6 alkylcarbamoyl, respectively. Compounds of formula (I ') or salts or solvates thereof: Wherein X is S, S (O), S (O) 2, O or NR ³ (R ³ is C _{1 ~ 6} alkyl, phenyl -C _{1 ~ 6} alkyl, which may have a hydrogen, or 1 to 4 substituents Naphthyl-C _1-6 alkyl); A is a group of the formula: (Wherein all symbols are as defined in claim ₁ ), -CH ₂ CH ₂ OCH ₂ CH ₂ -or a group of the following formula: (Wherein O and P are integers of 0 to 5); B ¹ is an amino group acylated with an acyl group derived from a carboxylic acid having 2 or more carbon atoms, sulfonic acid, carbamic acid or thiocarbamic acid; R ¹ and R ² are the same or different and are hydrogen, C _1-6 alkyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or C _4-24 aryl, which may have _1-4 substituents, Halogen, nitro group, nitroso group, optionally protected amino group, lower alkoxy carbonyl group or lower alkylcarbamoyl group; Substituents for C _1-6 alkyl mentioned are halogen, nitro, amino, N-mono C _1-6 alkylamino, N, N-di C _1-6 alkylamino, 4-7 membered cyclicamino, C _1-6 Alkoxy, C _6-10 aryloxy, carbamoyl, cyano, hydroxy, carboxy, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl; The mentioned substituents of phenyl-C _1-6 alkyl or naphthyl-C _1-6 alkyl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, hydroxy, C _1-6 alkoxycarbonyl , Carbamoyl or C _1-6 alkylcarbamoyl; The substituents mentioned for C _{4 -24} aryl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, oxo, hydroxy, amino, C _1-6 alkoxycarbonyl, carbamoyl or C _{1 ~ 6} alkyl-carbamoyl. 4. A straight chain according to claim 3, wherein B ¹ is a group of the formula: -NR ¹⁰ R ¹¹ (wherein R ^{10 '} is (1) hydrogen or (2) C _1-30 straight or which may have 1 to 4 substituents) branched alkyl, C _{3 ~ 8} cycloalkyl, 5 - 8 membered saturated ring formed by the fusion of a non-or tricyclic hydrocarbon group, C _{2 ~ 30} alkaryl carbonyl, phenyl -C _{1 ~ 6} alkyl, -C _{1 ~} naphthyl ₆ alkyl or C _{4 -24} aryl or (3) -CO-R ¹² , -SO ₂ R ¹³ , -CO-NR ¹⁴ R ¹⁵ and -CS-NR ¹⁴ R ¹⁵ ; phenyl -C _1-6 alkyl or The mentioned substituents of naphthyl-C _1-6 alkyl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, hydroxy, C _1-6 alkoxycarbonyl, carbamoyl or C _{1-6 6} alkylcarbamoyl; the mentioned substituents of C _{4 -24} aryl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, oxo, hydroxy, amino, C _1-6 alkoxycarbonyl , Carbamoyl or C _1-6 alkylcarbamoyl; R ^{11 '} is -CO-R ¹⁶ , -SO ₂ R ¹⁷ , -CO-NR ¹⁴ R ¹⁵ or -CS-NR ¹⁴ R ¹⁵ ); R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in claim ^{1 wherein} the optionally protected amino groups of R ¹ and R ² are amino, acylamino (acyl groups are those of R ¹¹ of claim 1 Same) or tritylamino; And lower alkoxycarbonyl and lower alkylcarbamoyl of R ¹ and R ² are C _1-6 alkoxycarbonyl and C _1-6 alkylcarbamoyl, respectively. The compound of claim 3, wherein B ¹ is —NH—SO ₂ R ¹⁷ (R ¹⁷ is as defined in claim 1). The compound of claim 3, wherein X is S or O and B ¹ is —NH—SO ₂ R ¹⁷ (R ¹⁷ is as defined in claim 1). 4. A 5- [2- (methylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine, 5- [2- (trifluoromethylsulfonylamino) ethylthio] imidazo [1,2-a] pyridine, 5- [3- (methylsulfonylamino) propyloxy] imidazo [1,2-a] pyridine, 5- [3- (trifluoromethylsulfonylamino) propyloxy ] Imidazo [1,2-a] pyridine, 5- [3- (methylsulfonylamino) propylthio] imidazo [1,2-a] pyridine, or 5- [3- (trifluoromethylsulfonyl Amino) propylthio] imidazo [1,2-a] pyridine. Blood vessels after hypertension, ischemic disease, arteriosclerosis, subarachnoid hemorrhage, containing a compound of formula (I ′) as defined in claim 3 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, diluent or excipient Calmodulin inhibitory composition useful for contractile and inflammatory diseases. A compound of formula (I), or a salt or solvate thereof: wherein X is S, S (O), S (O) ₂ , O or NR ³ (R ³ is hydrogen, or has 1 to 4 substituents C _1-6 alkyl, phenyl-C _1-6 alkyl or naphthyl-C _1-6 alkyl); A is a group of the following formula; (Wherein all symbols are as defined in claim 1), a group of the formula -CH ₂ CH ₂ OCH ₂ CH ₂ -or a group of the formula: (Wherein O and P are integers of 0 to 5); B ² is a group of the formula: . . (All symbols in the formula are the same as defined in claim 1); R ¹ and R ² are the same or different and are hydrogen, C _1-6 alkyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or C _4-24 aryl, which may have _1-4 substituents, Halogen, nitro group, nitroso group, optionally protected amino group, lower alkoxycarbonyl group or lower alkylcarbamoyl group; Substituents for C _1-6 alkyl mentioned are halogen, nitro, amino, N-mono C _1-6 alkylamino, N, N-di C _1-6 alkylamino, 4-7 membered cyclicamino, C _1-6 Alkoxy, C _6-10 aryloxy, carbamoyl, cyano, hydroxy, carboxy, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl; The mentioned substituents of phenyl-C _1-6 alkyl or naphthyl-C _1-6 alkyl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, hydroxy, C _1-6 alkoxycarbonyl , Carbamoyl or C _1-6 alkylcarbamoyl; The substituents mentioned for C _{4 -24} aryl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, oxo, hydroxy, amino, C _1-6 alkoxycarbonyl, carbamoyl or C _{1 ~ 6} alkyl-carbamoyl. The optionally protected amino group of R ¹ and R ² is amino, acylamino (acyl group is the same as that of R ¹¹ ) or tritylamino, and lower alkoxycarbonyl and lower alkylcarbons of R ¹ and R ² . Barmoyl is C _1-6 alkoxycarbonyl and C _1-6 alkylcarbamoyl, respectively. The compound of claim 9, wherein X is S or 0. The compound of claim 9, wherein 5- [1- (methylsulfonyl) -4-piperidylthio] imidazo [1,2-a] pyridine, 5- [1- (trifluoromethyl) -4-pi A compound that is ferridylthio] imidazo [1,2-a] pyridine. After hypertension, ischemic disease, arteriosclerosis, subarachnoid bleeding, comprising a compound of formula (I) as defined in claim 9, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient Calmodulin inhibitory compositions useful for vasoconstriction and inflammatory diseases. A compound of formula (I '), or a salt or solvate thereof Wherein X is S, S (O), S (O) ₂ or NR ³ (R ³ is hydrogen, or C _1-6 alkyl, phenyl-C _1-6 alkyl or naphthyl which may have 1 to 4 substituents -C _1-6 alkyl); A is a group of the formula: (Wherein all symbols are as defined in claim ₁ ), a group of the formula -CH ₂ CH ₂ OCH ₂ CH ₂ -or a group of the following formula (Wherein O and P are integers of 0 to 5); R ¹ and R ² are the same or different and are hydrogen, C _1-6 alkyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or C _4-24 aryl, which may have _1-4 substituents, Halogen, nitro group, nitroso group, optionally protected amino group, lower alkoxycarbonyl group or lower alkylcarbamoyl group; Substituents for C _1-6 alkyl mentioned are halogen, nitro, amino, N-mono C _1-6 alkylamino, N, N-di C _1-6 alkylamino, 4-7 membered cyclicamino, C _1-6 Alkoxy, C _6-10 aryloxy, carbamoyl, cyano, hydroxy, carboxy, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl; The mentioned substituents of phenyl-C _1-6 alkyl or naphthyl-C _1-6 alkyl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, hydroxy, C _1-6 alkoxycarbonyl , Carbamoyl or C _1-6 alkylcarbamoyl; The substituents mentioned for C _{4 -24} aryl are halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, cyano, oxo, hydroxy, amino, C _1-6 alkoxycarbonyl, carbamoyl or C _{1 6} alkyl-carbamoyl and; B ³ is a hydroxy group acylated with an acyl group derived from carboxylic acid or N-hydrocarbon substituted carbamic acid. The compound of claim 14, wherein B ³ is —O—CO—NR ¹⁵ R ¹⁶ or —O—CO—R ¹⁹ , wherein R ¹⁵ , R ¹⁶ and R ¹⁹ are as defined in claim ^1, and R ¹ and R The optionally protected amino group of ² is amino, acylamino (acyl group is the same as that of R ¹¹ ) or tritylamino; And lower alkoxycarbonyl and lower alkylcarbamoyl of R ¹ and R ² are C _1-6 alkoxycarbonyl and C _1-6 alkylcarbamoyl, respectively. 15. The compound of claim 14, wherein X is S or O and B ³ is -O-CONHR ¹⁶ (R ¹⁶ is as defined in claim 1). 15. The compound of claim 14, wherein 5- [2- (methylcarbamoyloxy) ethylthio] imidazo [1,2-a] pyridine, or 5- [2- [3- (hydroxy) propylcarbamoyloxy ] Ethylthio] amidazo [1,2-a] pyridine. Hypertension, ischemic disease, arteriosclerosis, subarachnoid bleeding, comprising a compound of formula (I ′) as defined in claim 14 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient Calmodulin inhibitory compositions useful for vasoconstriction and inflammatory diseases. Compounds of the formula A compound of claim 3 or 9 or a salt or solvate thereof, consisting of reacting with one compound of formula Q ¹ -NR ¹⁴ R ¹⁵ , G ¹ -CO (O) _q- R ¹⁶ or G ² -SO ₂ R ¹⁷ . Manufacturing Method [Wherein, Q ¹ is PhO—CO—, G—CO— or G-CS (Ph is a phenyl group, G is a halogen), and G ¹ is halogen or R ¹⁶ (O) _q —CO—O— ( q is 0 or 1), q is 0 or 1, G ² is halogen or R ¹⁷ SO ₂ O-, and the other symbols are as defined in claim 1]. Compounds of the formula React with a compound of the formula HX ¹ -AB ¹ , or when X is S or 0, When reacted with a compound of formula E ¹ -AB ¹ , or when X is S (O) or S (O) ₂ , a compound of the formula A process for producing the compound of claim 4, or a salt or solvate thereof, which comprises oxidizing. (Wherein E is halogen, X ¹ is S, O or NR ³ , X ² is S or 0, E ¹ is a leaving group and the other substituents and symbols are as defined in claim 4) Compounds of the formula When reacted with a compound of the formula HX ¹ -AB ² or when the nitrogen atom of the amino group of B ² and the carbon atom of A form a ring, the compound of the following formula When reacted with a compound of formula E ¹ -AB ² or when X is S (O) or S (O) ₂ , a compound of the formula A method for producing the compound of claim 9 or a salt or solvate thereof, which comprises oxidizing. (Wherein E is halogen, X ¹ is S, O or NR ³ , X ² is S or O, E ¹ is a leaving group and other symbols are as defined in claim 9). Compounds of the formula Reacting with one compound of the formula Q ¹ -NR ¹⁵ R ¹⁶ or G ¹ -CO (O) _q- R ¹⁹ , or Reacting with a compound of the formula HX ¹ -AB ³ , or React with a compound of the formula E ¹ -AB ³ , or when X is S (O) or S (O) ₂ , A process for preparing the compound of claim 14, or a salt or solvate thereof, consisting of oxidizing: (Wherein E is halogen, X ¹ is S, O or NR ³ , X ² is S or O, E ¹ is a leaving group, Q ¹ , G ¹ and q are as defined in claim 19, R ¹⁵ , R ¹⁶ and R ¹⁹ are as defined in claim 1 and other symbols are as defined in claim 14). Vascular useful as an anti-tumor, anti-inflammatory, anti- chronic joint rheumatoid and anti-diabetic retinopathy, comprising a compound of formula (1): or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient Angiogenesis Inhibition Compositions: Wherein A 'is (a) a group of the general formula: Wherein x, y and z are each an integer from 0 to 5; each of R ^e , R ^f , R ^g , R ^h , R ⁱ and R ^j is (1) hydrogen, (2) 1 to 5 substituents C _1-6 alkyl, C _2-6 alkenyl, or (3) Phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl, C _{6 which} may have 1 to 4 substituents _-14 allyl or an aromatic monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from sulfur, oxygen and nitrogen, or R ^e and R ^f or R ^g and R ^h or R ⁱ and R ^j Or combine together to form a C _3-8 cycloalkaline ring, or R ^e or R ^g combine with R ⁱ or R ^j to form a C _3-8 cycloalkane ring), (b) general formula —CH ₂ CH _{A group of 2} OCH ₂ CH _2- , or (c) a group of the general formula: (Wherein a and b are each an integer of 0 to 5); R ^a and R ^b are the same or different and are hydrogen, C _1-6 alkyl, C _2-6 alkenyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl, which may have _{1 to 4} substituents Or a C _6-14 aryl group, halogen, nitro group, nitroso group, optionally protected amino group, lower alkoxycarbonyl group or lower alkylcarbamoyl group; R ^c is hydrogen or C _1-6 alkyl C _3-8 cycloalkyl, C _2-6 alkenyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl which may have _{1 to 5} substituents Or C _6-14 aryl; R ^d is C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or C which may have _{1 to 5} substituents _6-14 aryl, R ^c and R ^e or R ^f , or R ^c and R ^g or R ^h , or R ^c and R ⁱ or R ^j are joined together to form a group of the general formula , (Wherein Q and R are each an integer of 2 or 3); The substituents of C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl are halogen, nitro, amino, N-mono C _1-6 alkylamino, N, N-di C _1-6 alkylamino , C _4-7 cyclic amino, C _1-6 alkoxy, phenoxy, 1-naproxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, C _1-6 alkoxycarbonyl or C _{1 6} alkyl-carbamoyl and; The substituents of phenyl-C _1-6 alkyl, naphthyl-C _1-6 alkyl or heterocyclic groups are halogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, nitro, cyano, Oxo, hydroxy, amino, C _1-6 alkoxycarbonyl, carbamoyl or C _1-6 alkylcarbamoyl. The compound of claim 23, wherein the lower alkoxycarbonyl and lower alkylcarbamoyl of R ^a and R ^b are C _1-6 alkoxycarbonyl and C _1-6 alkylcarbamoyl, respectively; The optionally protected amino group of R ^a or R ^b is imino or acylamino (here, the acyl group is C _1-6 alkylcarbonyl, C _7-10 aralkylcarbonyl, C _6-10 arylcarbonyl, C _1-4 Alkoxycarbonyl, C _7-10 aralkyloxycarbonyl or C _6-10 aryloxycarbonyl. The composition of claim 23, wherein A ′ is ethylene, R ^c is hydrogen, and R ^d is C _1-6 alkyl or C _2-6 alkenyl. 24. The compound of claim 23 wherein the compound is 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine, 5- [2- (ethoxycarbonylamino) ethylthio] Imidazo [1,2-a] pyridine, 5- [2- (methoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine, 5- [2- (propyloxycarbonylamino) ethyl Thio] imidazo [1,2-a] pyridine or 5- [2- (allyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine.