WO2016175264A1 - Novel heteroaryl derivative having antimalarial activity - Google Patents

Abstract

Provided are: a compound that is a novel 2,4,6-substituted triazine derivative and a 2,4,6-substituted pyrimidine derivative, and is expressed by formula (I) (in the formula, A is CH or N, Z is an optionally substituted alkoxy group, an optionally substituted amino group, or the like, and R¹, R², and R³ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, or the like); or a pharmaceutically-acceptable salt thereof.

Description

Novel heteroaryl derivatives having antimalarial activity

The present invention relates to a novel heteroaryl derivative, specifically, a novel 2,4,6-substituted triazine derivative and a 2,4,6-substituted pyrimidine derivative. In addition, the present invention has an action of suppressing the growth of malaria parasites, and may be useful for the treatment, prevention and / or transmission of malaria parasite infections.

Malaria is a protozoal infection that is widely distributed from the tropics to the subtropics. Among the parasites that parasitize humans, infection with Plasmodium falciparum accounts for about 80% of malaria-infected persons and is a serious disease. In some cases it is a very dangerous infection leading to death. In addition, due to recent global warming, the malaria epidemic has a tendency to expand from tropical to subtropical developing countries as well as developed countries located in temperate regions.

For malaria parasites that parasitize humans, chloroquine and funcidal (a combination of pyrimesamine and sulfadoxine), which are called classic drugs developed in the 1930s and 1960s, have been used. Since then, artemisinin derivatives, which are active ingredients of herbal medicine blue grapes developed since 1980, are also used.
However, drug-resistant malaria parasites against chloroquine and fancidar have emerged, as well as resistant malaria parasites against multiple drugs including these drugs, and the emergence of resistant protozoa has also been reported in artemisinin derivatives developed later.

In response to the emergence of such resistant protozoa against existing drugs, attempts have been made around the world to develop antimalarial drugs effective against malaria parasites. However, in the development of antimalarial drugs, even if antimalarial activity is confirmed in vitro, there are many cases where the activity cannot be confirmed or toxicity is confirmed in vivo, effective for drug-resistant strains and in vivo. Few drugs that can confirm antimalarial activity have been found.

Up to now, triazine-2,4,6-substitute antimalarial active substance (Non-patent Document 1), triazine-2,4,6-substitute and pyrimidine-2,4,6-substitute An antitrypanosoma active substance (Non-patent Document 2) has been reported, but a compound having the structure of the compound of the present invention is not known.

An object of the present invention is to provide a novel compound that exhibits antimalarial activity against malaria parasites that are resistant to existing antimalarial drugs.

As a result of intensive studies to solve the above problems, the present inventors have found that the compound represented by the formula (I) and its pharmacology as a 2,4,6-substituted triazine derivative and a 2,4,6-substituted pyrimidine derivative. The present invention has been completed by finding that a chemically acceptable salt (hereinafter sometimes referred to as “the compound of the present invention”) has an inhibitory effect on the growth of malaria parasites. According to the present invention, human infectious malaria parasites such as Plasmodium falciparum, Plasmodium falciparum (P. vivax), Plasmodium falciparum (P. malariae), Plasmodium falciparum (P. ovale) and P. サ ル knowlesi infections can be treated, prevented and / or transmitted.

That is, the present invention provides the following aspects of the invention.
[1] The following formula (I):

(Where
A is CH or N;
Z represents an optionally substituted alkoxy group, an optionally substituted amino group, an optionally substituted alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl. And R ¹ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted group. Amino group, nitro group, hydroxy group, cyano group, heteroaryl group which may be substituted, acyl group which may be substituted, carbamoyl group which may be substituted, carboxyl group, acylamino which may be substituted Group, optionally substituted alkoxycarbonyl group, optionally substituted alkylsulfonyloxy group, and optionally substituted It is selected from the group consisting had ureido group, or if two of R ^1, R ² and R ³ is attached to a carbon atom adjacent on the benzene ring, together with the two carbon atoms to which they are attached And may form a 5-membered or 6-membered ring containing one or two oxygen atoms)
Or a pharmaceutically acceptable salt thereof.

[2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein A is CH.

[3] The compound according to [1], wherein A is N, or a pharmaceutically acceptable salt thereof.

[4] A pharmaceutical composition comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[5] A therapeutic agent for malaria parasite infection comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof as an active ingredient.

[6] The following formula (I):

(Where
A is CH or N;
Z represents a C _1-6 alkyl group, a C _1-6 haloalkyl group, a formula:

(Where
R ⁴ and R ⁵ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a —C _0-4 alkylene-CO—C _1-6 alkyl group, —C _1-4 Alkylene-O—C _1-6 alkyl group, —C _1-4 alkylene-NH—C _1-6 alkyl group, —C _1-4 alkylene-NH—CO—C _1-6 alkyl group, —C _1-4 Alkylene-NH-COO-C _1-6 alkyl group, -C _1-4 alkylene-N (same or different C _1-6 alkyl group) ₂ , -C _0-4 alkylene-COOH, -C _0-4 alkylene- A COO—C _1-6 alkyl group, —C _0-4 alkylene-CH═NH, —C _0-4 alkylene-CH═N—C _1-6 alkyl group, —C _0-4 alkylene-SO ₂ H, or —C _0-4 alkylene-SO ₂ —C _1-6 Alkyl (wherein the alkyl group, the alkenyl group, and the alkylene each independently represent a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group on a substitutable carbon atom. Group, C _1-6 haloalkoxy group, C _3-8 cycloalkyl group, hydroxy group, mercapto group, cyano group, nitro group, amino group, mono- or di-C _1-6 alkylamino group, carboxyl group, C One or more selected from the group consisting of a _1-4 acyl group and a C _1-4 acylamino group, or the same or different groups may be substituted.
Alternatively, R ⁴ and R ⁵ together with the N atom to which they are attached form a 3-8 membered heterocycloalkyl group or a 5-6 membered heteroaryl group;
R ⁶ is a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-8 cycloalkyl group, a _3-8 membered heterocycloalkyl group or an aryl group, wherein each group is In each independently substituted position, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a C _3-8 cycloalkyl group , Hydroxy group, mercapto group, cyano group, nitro group, amino group, mono- or di-C _1-6 alkylamino group, carboxyl group, C _1-4 acyl group and C _1-4 acylamino group Optionally substituted with two or more groups identical or different)
And R ¹ , R ² and R ³ each independently represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono- or di-C _{1- 6} alkylamino group, nitro group, hydroxy group, cyano group, C _3-6 cycloalkyl group, 5-membered to 6-membered heteroaryl group, heterocycloalkyl group, C _1-4 acyl group, C _1-4 acylamino group , Carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, carboxyl group, C _2-6 alkoxycarbonyl group, C _1-6 alkylsulfonyloxy group or —NHCONR ⁷ R ⁸ (wherein R ⁷ and R nitrogen ⁸ are each independently a hydrogen _atom, a _{C 1-6} alkyl group or _{C 2-6} alkenyl group, or, ^{R 7} and ^{R 8,} to which they are attached Atom taken together with to form a morpholinyl group, said morpholinyl group, at substitutable position, a halogen atom, C _1-6 alkyl, C _1-6 haloalkyl group, hydroxy group, a cyano group, a nitro group, An amino group, a mono- or di-C _1-6 alkylamino group and a carboxyl group, which may be substituted with one or two or more groups selected from the same or different).
Here, each group independently represents a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a C at a substitutable position. _1-6 haloalkoxy group, C _3-6 cycloalkyl group, hydroxy group, mercapto group, cyano group, nitro group, amino group, mono- or di-C _1-6 alkylamino group, carboxyl group, C _1-4 One or more selected from the group consisting of an acyl group and a C _1-4 acylamino group, which may be substituted with two or more identical or different groups)
Or a pharmaceutically acceptable salt thereof.

[7] Z is a C _1-6 haloalkyl group, an amino group, a mono- or di-C _1-6 alkylamino group, a C _1-6 alkoxy group, a C _3-8 cycloalkyloxy group, a phenoxy group,

(Wherein a is 1 to 7 and each ring is a substitutable position at a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy group, a hydroxymethyl group, a hydroxyethyl group, One or two or more groups selected from the group consisting of a cyano group, a nitro group, an amino group, a mono- or di-C _1-6 alkylamino group, a carboxyl group and a C _1-6 alkoxycarbonyl group May be substituted)
The compound according to [6] or a pharmaceutically acceptable salt thereof, which is a group selected from the group consisting of:

[8] R ¹ is a hydrogen atom,
R ² is bonded to the 3-position of the benzene ring, and is a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono- or di-C _1-6 alkylamino group, a nitro group, a hydroxy group Group, cyano group, imidazole group, triazole group, morpholinyl group, pyridyl group, C _1-4 acyl group, C _1-4 acylamino group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, carboxyl group, A C _1-6 alkoxycarbonyl group, a C _1-6 alkylsulfonyloxy group or a 4-morpholinecarboxamide group,
R ³ is bonded to the 5-position of the benzene ring and is a halogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group,
Here, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, imidazole group, triazole group, morpholinyl group, pyridyl group, C _1-4 acyl group, C _1-4 acylamino group , C _1-6 alkoxycarbonyl group, C _1-6 alkylsulfonyloxy group and 4-morpholinecarboxamide group each independently represent a halogen atom, C _1-6 alkyl group, C _1- One selected from the group consisting of a ₆ haloalkyl group, a C _2-6 alkenyl group, a C _3-8 cycloalkyl group, a hydroxy group, an amino group, a mono- or di-C _1-6 alkylamino group and a carboxyl group, or The compound according to [6] or [7], or a pharmaceutically acceptable salt thereof, which may be substituted with two or more groups which are the same or different.

[9] R ¹ is a hydrogen atom,
R ² is bonded to the 3-position of the benzene ring and is a halogen atom, an amino group, a mono- or di-C _1-6 alkylamino group or a nitro group;
R ³ is bonded to the 4-position of the benzene ring and is a halogen atom, a C _1-6 alkoxy group, an amino group, a mono- or di-C _1-6 alkylamino group or a nitro group, wherein C _{1 1- The 6} alkoxy group is selected from the group consisting of a halogen atom, a C _3-8 cycloalkyl group, a hydroxy group, an amino group, a mono- or di-C _1-6 alkylamino group and a carboxyl group at substitutable positions. The compound according to [6] or [7] or a pharmaceutically acceptable salt thereof, which may be substituted with one or two or more groups which are the same or different.

[10] R ¹ is a hydrogen atom;
R ² is bonded to the 2-position of the benzene ring and is a halogen atom;
R ³ is bonded to the 3-position of the benzene ring and is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is a halogen atom, hydroxy group, amino group, mono- Or a compound according to [6] or [7], which may be substituted with one or two or more groups selected from the group consisting of a di-C _1-6 alkylamino group and a carboxyl group; Its pharmaceutically acceptable salt.

[11] R ¹ is a hydrogen atom;
R ² is bonded to the 2-position of the benzene ring and is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is a halogen atom, a hydroxy group, an amino group, a mono- Or may be substituted with one or two or more groups selected from the group consisting of a di-C _1-6 alkylamino group and a carboxyl group,
The compound or a pharmaceutically acceptable salt thereof according to [6] or [7], wherein R ³ is bonded to the 4-position of the benzene ring and is a halogen atom.

[12] ^{Two of} R ¹ , R ² and R ³ are hydrogen atoms, and the remainder is bonded to the 3-position of the benzene ring and is a halogen atom or a C _1-6 alkyl group, wherein C _{1 The -6} alkyl group is a substitutable position, one selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a mono- or di-C _1-6 alkylamino group and a carboxyl group, or the same or different 2 The compound or a pharmaceutically acceptable salt thereof according to [6] or [7], which may be substituted with two or more groups.

[13] R ¹ , R ² and R ³ are each independently selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and a hydroxy group, wherein C _{1- The 6} alkyl group and the C _1-6 alkoxy group each independently represent a halogen atom, a C _1-6 alkoxy group, a hydroxy group, an amino group, a mono- or di-C _1-6 alkylamino group at a substitutable position. May be substituted with one or two or more groups selected from the group consisting of a group and a carboxyl group, or ^{two of} R ¹ , R ² and R ³ are adjacent on the benzene ring When bonded to a carbon atom, together with the two carbon atoms to which they are bonded, a 5- or 6-membered ring containing one or two oxygen atoms may be formed, [6] or [7 ]Record Or a pharmaceutically acceptable salt thereof.

[14] A pharmaceutical composition comprising the compound according to any one of [6] to [13] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[15] A therapeutic agent for malaria parasite infection comprising the compound according to any one of [6] to [13] or a pharmaceutically acceptable salt thereof as an active ingredient.

[16] A therapeutically effective amount of the compound according to any one of [1] to [3] or [6] to [13] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. A method for treating a malaria parasite infection characterized by the above.

[17] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3] or [6] to [13], which is used for treatment of malaria parasites.

[18] A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3] or [6] to [13] for producing a therapeutic agent for malaria parasite infections use.

[19] A malaria parasite growth inhibitor comprising the compound according to any one of [1] to [3] or [6] to [13] or a pharmaceutically acceptable salt thereof.

[20] A therapeutically effective amount of the compound according to any one of [1] to [3] or [6] to [13] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. A method for inhibiting the growth of malaria parasites.

The compound of the present invention has a suppressive action on malaria parasites and is useful as a novel therapeutic agent, preventive agent and / or propagation inhibitor for human infectious malaria parasites. Furthermore, it is also useful as a therapeutic agent, preventive agent and / or propagation inhibitor for malaria parasite infections which are resistant to existing antimalarial drugs such as chloroquine and funcidal. In addition, it can be used as a malaria parasite growth inhibitor in an experimental or research reagent.

Terms used in this specification will be described below.
“Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom, a chlorine atom or a bromine atom.

“Alkyl” or “alkylene” means a linear or branched, monovalent or divalent saturated hydrocarbon group having the specified number of carbon atoms, respectively. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Preferred alkyl includes C _1-6 alkyl, C _1-4 alkyl, and lower alkyl. For example, “C _1-6 alkyl” represents an alkyl group having 1 to 6 carbon atoms, and “lower alkyl” represents an alkyl group having 1 to 4 carbon atoms. “C ₀ alkylene” means a single bond, and “C _1-4 alkylene” means a divalent substituent having 1 to 4 carbon atoms, such as methylene, ethylene, propylene and butylene. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

“Alkenyl” means a straight or branched unsaturated hydrocarbon group having the specified number of carbon atoms containing one or more carbon-carbon double bonds. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Preferred alkenyl includes C _2-6 alkenyl and C _2-4 alkenyl. For example, “C _2-6 alkenyl” represents alkenyl having 2 to 6 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

“Alkynyl” means a straight or branched unsaturated hydrocarbon group having the specified number of carbon atoms containing one or more carbon-carbon triple bonds. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Preferred alkynyl includes C _2-6 alkynyl and C _2-4 alkynyl. For example, “C _2-6 alkynyl” refers to alkynyl having 2 to 6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl and the like.

“Haloalkyl” means an alkyl group as defined above having the indicated number of carbon atoms, wherein one or more hydrogen atoms have been replaced by halogen atoms. For example, “C _1-6 haloalkyl” refers to a haloalkyl having 1 to 6 carbon atoms. The number of hydrogen atoms replaced can range from one up to the total number of hydrogen atoms that may otherwise be present in the parent alkyl group. In the case of having a plurality of halogen atoms, they may be substituted with the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

“Hydroxyalkyl” means a hydroxy group to which an alkyl group as defined above having the specified number of carbon atoms is attached. In these, the alkyl part may be optionally substituted with one or more substituents included in the present invention. Preferred hydroxyalkyl includes C _1-6 hydroxyalkyl and C _1-4 hydroxyalkyl. For example, “C _1-6 hydroxyalkyl” represents a hydroxyalkyl having 1 to 6 carbon atoms. Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

“Alkoxy” means a group in which an alkyl group as defined above having the specified number of carbon atoms is bonded through an oxygen atom. In these, the alkyl part may be optionally substituted with one or more substituents included in the present invention. Preferable alkoxy includes C _1-6 alkoxy and C _1-4 alkoxy. For example, “C _1-6 alkoxy” represents alkoxy having 1 to 6 carbon atoms (—O—C _1-6 alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.

“Haloalkoxy” means alkoxy as defined above having the indicated number of carbon atoms, wherein one or more hydrogen atoms have been replaced by halogen atoms. For example, “C _1-6 haloalkoxy” represents haloalkoxy having 1 to 6 carbon atoms. The number of hydrogen atoms replaced can range from one up to the total number of hydrogen atoms that may otherwise be present in the parent alkyl group. In the case of having a plurality of halogen atoms, they may be substituted with the same or different halogen atoms. Examples of haloalkoxy include, but are not limited to, chloromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

“Cycloalkyl” means a mono- or polycyclic saturated hydrocarbon group having 3 or more carbon atoms. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Preferred cycloalkyl includes C _3-10 cycloalkyl, C _3-8 cycloalkyl, C _3-6 cycloalkyl. For example, “C _3-8 cycloalkyl” refers to cycloalkyl having 3 to 8 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the polycyclic saturated carbon hydrogen group include a bicyclic saturated carbon hydrogen group and a tricyclic saturated carbon hydrogen group, and examples thereof include decahydronaphthalene, bicyclo [2.1.0] pentane, and tricyclo [3.2. .1.0 ^2,7] octane, and the like.

“Heterocycloalkyl” means cycloalkyl as defined above, wherein at least one of the ring carbons has been replaced with a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Nitrogen and sulfur atoms may be oxidized if desired, and nitrogen atoms may be quaternized if desired. The fused ring leading to a bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Preferred heterocycloalkyl include 3 to 10 membered heterocycloalkyl, 3 to 8 membered heterocycloalkyl, and 3 to 6 membered heterocycloalkyl. For example, “3 to 8 membered heterocycloalkyl” refers to 3 to 8 membered cycloalkyl containing at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom. Examples of heterocycloalkyl include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine, tetrahydrofuran, tetrahydropyran, oxazolidinone, and the like.

“Aryl” means a monocyclic or bicyclic aromatic hydrocarbon group having 6 or more carbon atoms, excluding one hydrogen atom bonded to the aromatic ring. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Examples of aryl include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl and the like.

“Heteroaryl” means a monocyclic or bicyclic aromatic heterocyclic group in which at least one of the ring carbons has been replaced with a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. To do. These may be optionally substituted with one or more substituents included in the present invention at substitutable positions. Preferred heteroaryls include 3-10 membered heteroaryl, 3-6 membered heteroaryl, 5-6 membered heteroaryl. For example, “5-6 membered heteroaryl” refers to a 5-6 membered monocyclic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom or an oxygen atom. Examples of heteroaryl include, but are not limited to, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, purine, quinoline, And isoquinoline.

“Acyl” means a carbonyl group (—C (═O)) to which a hydrogen atom, an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group as defined above is attached. Preferred acyl includes C _1-7 acyl and C _1-4 acyl. For example, “C _1-4 acyl” refers to a carbonyl group to which an alkyl group having 1 to 3 carbon atoms is bonded. Examples of acyl include, but are not limited to, formyl, acetyl, propanoyl, petityl, isobutyryl, pivaloyl, cyclopentanecarbonyl, benzoyl and the like.

“Acylamino” means an amino group to which an acyl group as defined above is attached. Preferred acylamino includes C _1-7 acylamino and C _1-4 acylamino. For example, “C _1-4 acylamino” refers to an amino group to which an acyl group having 1 to 4 carbon atoms is bonded. Examples of acylamino include, but are not limited to, acetylamino, propionylamino, and the like.

“Alkoxycarbonyl” means a carbonyl group to which an alkoxy group as defined above is attached. Preferable alkoxycarbonyl includes C _1-6 alkoxycarbonyl and C _1-4 alkoxycarbonyl. For example, “C _1-6 alkoxycarbonyl” refers to a carbonyl group to which an alkoxy group having 1 to 6 carbon atoms is bonded. Examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

“Alkylsulfonyloxy” means a sulfonyloxy group to which an alkyl group as defined above is attached. In these, the alkyl part may be optionally substituted with one or more substituents included in the present invention. Preferable alkylsulfonyloxy includes C _1-6 alkylsulfonyloxy and C _1-4 alkylsulfonyloxy. For example, “C _1-6 alkylsulfonyloxy” refers to a sulfonyloxy group to which an alkyl group having 1 to 6 carbon atoms is bonded. Examples of alkylsulfonyloxy include, but are not limited to, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, and the like.

“Ureido” means a monovalent substituent (—NHCONH ₂ ) in which one hydrogen atom has been removed from urea. The terminal nitrogen may be optionally substituted with one or more substituents included in the present invention, and may be combined with the attached substituents to form a ring. Examples of ureido include, but are not limited to, ureido, methylureido, dimethylureido, 4-morpholinecarboxamide, and the like.

“Mono- or di-C _1-6 alkylamino” means an amino group in which one or two hydrogen atoms are replaced by alkyl groups as defined above having 1 to 6 carbon atoms. To do. When two alkyl groups are substituted, they may be substituted with the same or different alkyl groups. Examples of mono- or di-C _1-6 alkylamino include, but are not limited to, methylamino, ethylamino, dimethylamino, diethylamino and the like.

“Mono- or di-C _1-6 alkylcarbamoyl” has 1 or 2 hydrogen atoms bonded to a nitrogen atom replaced by an alkyl group as defined above having 1 to 6 carbon atoms , Means a carbamoyl group. When two alkyl groups are substituted, they may be substituted with the same or different alkyl groups. Examples of mono- or di-C _1-6 alkylcarbamoyl include, but are not limited to, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and the like.

“The term“ which may be substituted ”includes the case where the substitutable position of the group is not substituted (unsubstituted) and the case where it is substituted. “Unsubstituted” means that all substitutable positions of the group are hydrogen atoms. When substituted, it may be substituted with a plurality of substituents if possible, and the substituents may be the same or different. Substituents to be substituted include halogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, haloalkyl group, alkoxy group, haloalkoxy group, amino group, nitro group, cyano group, hydroxy group, mono- or di- -Alkylamino group, carbamoyl group, mono- or di-alkylcarbamoyl group, carboxyl group, morpholinyl group, formyl group, acetyl group, mesyl group, benzoyl group, acylamino group and the like.

“Pharmaceutically acceptable salt” means a salt formed with a compound of the present invention represented by formula (I) and a pharmaceutically acceptable acid or base. When the compound of the present invention represented by the formula (I) has a basic functional group such as an amino group, various acids and salts can be formed. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, oxalate, malonate, maleate , Fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, etc. Examples include organic acid salts and acidic amino acid salts such as glutamate and aspartate.
When the compound of the present invention represented by the formula (I) has an acidic functional group, salts with various bases can be formed. Examples of base addition salts include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, organic amine salts such as lower alkyl amine salts and lower alcohol amine salts, lysine, arginine, ornithine and the like. And basic amino acid salts and ammonium salts.
These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (I) with an acid or a base.
Since the compounds of the present invention may exist in the form of internal salts, hydrates and / or solvates, these internal salts, hydrates and / or solvates may also be compounds of the present invention. Is included. Examples of solvates include ethanol solvates.

“Treatment” means the healing and / or amelioration of malaria parasite infections in mammals, particularly humans. Examples include (a) preventing malaria parasite infections; (b) preventing the transmission of malaria infections; and (c) reducing and / or reducing malaria parasite infections. .

“Patient” means humans and animals such as dogs, cats, horses and the like. Among these, human is preferable.

A “therapeutically effective amount” is an amount that provides an improvement, cure, prevention, and / or alleviation of a disease, disorder, and / or side effects, or a delay in the progression of a disease and / or disorder, as compared to an untreated subject. Means the amount to bring. The term also includes within its scope an amount effective to promote normal physiological function. A therapeutically effective amount of a compound of the invention represented by formula (I) and pharmaceutically acceptable salts thereof can be administered as the active ingredient. Although not particularly limited, a range of about 1-1000 mg / kg (body weight) per day is generally effective as the compound represented by formula (I).
Such effective amounts include the amount of a compound of the invention alone, the amount of a combination of compounds of the invention and / or the amount of a compound of the invention in combination with other antimalarial agents.

Preferred embodiments of Z include a C _1-6 haloalkyl group, an amino group, a mono- or di-C _1-6 alkylamino group, a C _1-6 alkoxy group, a C _3-8 cycloalkyloxy group, a phenoxy group,

(Wherein a is 1 to 7 and each ring is a substitutable position at a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy group, a C _1-6 hydroxyalkyl group, One or the same selected from the group consisting of C _1-7 acyl group, cyano group, nitro group, amino group, mono- or di-C _1-6 alkylamino group, carboxyl group and C _1-6 alkoxycarbonyl group Or may be substituted with two or more different groups).

Preferred embodiments of R ¹ to R ³ are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a phenoxy group, an amino group, mono- or di-C _{1 -6} alkylamino group, nitro group, hydroxy group, cyano group, imidazole group, imidazole group substituted with C _1-3 alkyl, triazole group, triazole group substituted with C _1-3 alkyl, morpholinyl group, C ₁ Morpholinyl group substituted with _-3 alkyl, pyridyl group, pyridyl group substituted with C _1-3 alkyl, C _1-4 acyl group, C _1-4 acylamino group, carbamoyl group, mono- or di-C _{1- 6} alkylcarbamoyl group, a carboxyl _{group, C 1-6} alkoxycarbonyl group, a methanesulfonyloxy group or a 4-morpholin Cal An amide group. Further, when two of R ¹ to R ³ are bonded to adjacent carbon atoms on the benzene ring, a 5-membered ring containing one or two oxygen atoms together with the two carbon atoms to which they are bonded or A 6-membered ring may be formed. Preferably, a 1,3-dioxole ring or a 2,3-dihydro-1,4-dioxin ring is formed.

The compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples thereof include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization.

The compounds of the present invention represented by the formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality. Or it may exist as a stereoisomer. In the present invention, these optical or stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
Compound (I) of the present invention may have an isomer depending on, for example, the type of substituent. In this specification, the chemical structure of only one form of those isomers may be described, but the present invention includes all isomers (geometric isomers, optical isomers, tautomers) that can occur structurally. Etc.) and also includes isomers alone or a mixture thereof.

In addition, a deuterium converter obtained by converting any one or two or more ¹ H of the compounds of the present invention represented by the formula (I) into ² H (D) is also converted into the compound represented by the formula (I). Is included.
A crystalline polymorph may exist in the compound of the present invention represented by the formula (I) obtained as a crystal and a pharmaceutically acceptable salt thereof, and the crystalline polymorph is also included in the present invention.

The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced, for example, by the following method. In the production method shown below, when the defined group changes under the conditions of the implementation method or is unsuitable for carrying out the method, a method usually used in organic synthetic chemistry, for example, a functional group It can be easily manufactured by attaching means such as protection, deprotection [T. W. Greene, Protective Groups In Organic Synthesis 3rd Edition, John Wiley & Sons, Inc., 1999]. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.

The meanings of the abbreviations and symbols used in this specification are as follows.
THF: Tetrahydrofuran NMP: N-methylpyrrolidone 2-PrOH: 2-propanol DIEA: N, N-diisopropylethylamine DMSO: dimethylsulfoxide DMF: dimethylformamide TEA: triethylamine MeOH: methanol EtOH: ethanol CHCl _3: chloroform CDCl _3: deuterated chloroform DCM: Dichloromethane RuPhos: 2-Dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl BrettPhos Palladium: Chloro [2- (dicyclohexylphosphino) -3,6-dimethoxy-2'-4'-6'-tri -I-propyl-1,1'-biphenyl] [2- (2-aminoethyl) phenyl] palladium (II)
Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene Pd (dba) ₂ : bis (dibenzylideneacetone) palladium (0)

[Production Method of Compound of the Present Invention]
Among the compounds of the present invention represented by the formula (I), the triazine compound (Ia) in which A is N can be produced, for example, according to Scheme 1.
[Scheme 1]

(In the formula, R ¹ , R ² , R ³ and Z are as defined above.)

Compound (Ia) can be produced by reacting compound (II) with arylamine (III). That is, the compound (Ia) contains 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents of the arylamine (III), and an acid catalyst such as hydrochloric acid, if necessary, in a solvent. It can obtain by making it heat-react below. The solvent is not particularly limited as long as it is inert to the reaction. For example, a lower alcohol, preferably EtOH, 2-PrOH or 1-butanol can be used. The reaction can be carried out by heating at 80 to 150 ° C. for 3 to 24 hours. For example, the reaction can be carried out at 80 to 110 ° C. for 6 to 16 hours. In addition, this reaction can also be produced under commonly known coupling conditions with chlorotriazine, for example, basic conditions such as potassium carbonate.

Compound (III) can be obtained as a commercial product, or by a known method or a method analogous thereto.

Compound (II) used as a raw material of Scheme 1 can be produced, for example, by the method shown in Scheme 2.
[Scheme 2]

(In the formula, Z has the same meaning as described above.)

Compound (II) can be produced by reacting the dichloro compound (IV) with imidazo [1,2-a] pyridin-7-amine. That is, the compound (II) is obtained by mixing 0.5 to 2 molar equivalents, preferably 0.8 to 1.5 molar equivalents of imidazo [1,2-a] pyridin-7-amine with the dichloro compound (IV) in a solvent. , And 0.5 to 2 molar equivalents, preferably 0.8 to 1.5 molar equivalents, in the presence of a base catalyst such as DIEA. The solvent is not particularly limited as long as it is inert to the reaction, and THF can be preferably used. The reaction can be carried out by reacting at −40 to 60 ° C. for 1 to 24 hours, but preferably at −5 to 30 ° C. for 1 to 16 hours.

The dichloro form (IV) can be obtained as a commercially available product, or by a known method or a method analogous thereto.

The compound (Ia) of the present invention can also be produced, for example, according to Scheme 3.
[Scheme 3]

(In the formula, R ¹ , R ² , R ³ and Z are as defined above.)

Compound (Ia) can be obtained by subjecting compound (V) to 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents of compound (VI) by heating in a solvent. If necessary, an acid catalyst such as hydrochloric acid or a base can be added to the reaction, and the solvent is not particularly limited as long as it is inert to the reaction. For example, a polar solvent, Preferably, an alcohol solvent such as EtOH or 2-PrOH, or THF or DMF can be used. The reaction can be carried out by stirring for 3 to 24 hours under room temperature to solvent reflux conditions.

Compound (VI) which is one of the raw materials of Scheme 3 is a commercially available product, or can be produced by a known method or a method analogous thereto.

The compound (V) used as a raw material of Scheme 3 can be produced by the method shown in Scheme 4, for example.
[Scheme 4]

(In the formula, R ¹ , R ² and R ³ are as defined above.)

Compound (V) can be produced by reacting the dichloro compound (VII) with imidazo [1,2-a] pyridin-7-amine. That is, compound (V) comprises dichloro form (VII) and 0.5 to 2 molar equivalents, preferably 0.8 to 1.5 molar equivalents of imidazo [1,2-a] pyridin-7-amine in a solvent. It can obtain by making it react. If necessary, an acid catalyst such as hydrochloric acid or a base can be added to the reaction, and the solvent is not particularly limited as long as it is inert to the reaction. For example, a polar solvent, preferably Can be used EtOH, 2-PrOH alcohol solvent, THF, dioxane or the like. The reaction can be carried out by reacting at −40 ° C. to the reflux condition of the solvent for 1 to 24 hours. Preferably, the reaction can be carried out by reacting at room temperature to the reflux condition of the solvent for 1 to 16 hours. .

Compound (VII) used as a raw material of Scheme 4 can be obtained as a commercial product, or by a known method or a method analogous thereto.

Among the compounds of the present invention represented by the formula (I), the pyrimidine compound (Ib) of the present invention in which A is CH can be produced, for example, according to Scheme 5.
[Scheme 5]

(In the formula, R ¹ , R ² , R ³ and Z are as defined above.)

Compound (Ib) is obtained using chloro form (VIII) and imidazo [1,2-a] pyridin-7-amine under conditions well known for cross-coupling reactions such as Buchwald / Hartwig type reaction. Can be manufactured. That is, using an inert solvent such as toluene, THF or dioxane, a palladium catalyst such as Pd (dba) ₂ , a base such as sodium tert-butoxide, potassium carbonate or cesium carbonate and a ligand such as RuPhos, BrettPhos or Xantphos. To react. The imidazo [1,2-a] pyridin-7-amine is preferably used in an equivalent amount or an excess amount relative to the chloro compound (VIII), more preferably 1 equivalent to 10 equivalents. The reaction can be synthesized by reacting between 0 ° C. and 200 ° C. for several minutes to several days, preferably between 20 ° C. and 150 ° C. for 1 hour to 36 hours. Alternatively, the synthesis can also be performed by using a microwave synthesizer, for example, by reacting for several minutes to several hours under a temperature condition of 60 ° C. to 150 ° C.

The chloro compound (VIII) used as the raw material of Scheme 5 can be produced by, for example, the method shown in Scheme 6.
[Scheme 6]

(In the formula, R ¹ , R ² , R ³ and Z are as defined above.)

The chloro form (VIII) can be produced by reacting the dichloro form (IX) with the arylamine (III). That is, compound (VIII) can be obtained by reacting dichloro form (IX) with 0.5 to 2 molar equivalents, preferably 0.8 to 1.5 molar equivalents of arylamine (III) in a solvent. it can. If necessary, an acid catalyst such as hydrochloric acid or a base can be added to the reaction, and the solvent is not particularly limited as long as it is inert to the reaction. For example, a polar solvent, Preferably, EtOH, 2-PrOH alcohol solvent, THF, dioxane or the like can be used. The reaction can be carried out by reacting at −40 ° C. to the reflux condition of the solvent for 1 to 24 hours. Preferably, the reaction can be carried out by reacting at room temperature to the reflux condition of the solvent for 1 to 16 hours. .

The dichloro compound (IX) and arylamine (III) used as raw materials in Scheme 6 can be obtained as commercially available products, or by a known method or a method analogous thereto.

Further, the chloro compound (VIII) used as a raw material in Scheme 5 can also be produced, for example, by the method shown in Scheme 7.
[Scheme 7]

(Wherein R ¹ , R ² , R ³ , and Z are as defined above.)

Compound (VIII) can be obtained by reacting compound (X) with 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents of compound (VI) in a solvent. If necessary, an acid catalyst such as hydrochloric acid or a base can be added to the reaction, and the solvent is not particularly limited as long as it is inert to the reaction. For example, a polar solvent, Preferably, an alcohol solvent such as EtOH or 2-PrOH, or THF or DMF can be used. The reaction can be carried out by stirring for 0.5 to 24 hours under the condition of −20 ° C. to solvent reflux.

Compound (X) used as a raw material of Scheme 7 can be produced, for example, by the method shown in Scheme 8.
[Scheme 8]

(In the formula, R ¹ , R ² , and R ³ have the same meanings as described above.)

The chloro form (X) can also be produced by reacting the dichloro form (XI) and the arylamine (III). That is, compound (X) can be obtained by reacting dichloro form (XI) with 0.5 to 2 molar equivalents, preferably 0.8 to 1.5 molar equivalents of arylamine (III) in a solvent. it can. If necessary, an acid catalyst such as hydrochloric acid or a base can be added to the reaction, and the solvent is not particularly limited as long as it is inert to the reaction. For example, the polar solvent EtOH 2-PrOH alcohol solvent, THF, dioxane or the like can be used. The reaction can be carried out by reacting at -78 ° C to solvent reflux condition for 0.5 to 24 hours, but preferably by reacting at -78 ° C to -40 ° C for 0.5 to 2 hours. Can be implemented.

In addition, the above methods are appropriately combined, and methods commonly used in organic synthetic chemistry (for example, alkylation reaction of amino group, reaction of oxidizing alkylthio group to sulfoxide group or sulfone group, alkoxy group to hydroxyl group, or vice versa) By carrying out the reaction for conversion, the compound (I) of the present invention having a desired functional group at a desired position can be obtained.

[Use of Compound (I) of the Present Invention]
Compound (I) or a pharmaceutically acceptable salt thereof of the present invention can be prepared in the form of a conventional pharmaceutical preparation (pharmaceutical composition) suitable for oral administration, parenteral administration or topical administration.

Preparations for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as syrups. These formulations can be prepared by conventional methods. Solid preparations can be prepared by using conventional pharmaceutical carriers such as lactose, starch such as corn starch, crystalline cellulose such as microcrystalline cellulose, hydroxypropylcellulose, calcium carboxymethylcellulose, talc, magnesium stearate, etc. it can. Capsules can be prepared by wrapping the granules or powders thus prepared in capsules. A syrup can be prepared by dissolving or suspending the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethylcellulose and the like.

製 剤 Preparations for parenteral administration include infusions such as instillation. Injectable formulations can also be prepared by conventional methods, including isotonic agents (eg, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizers (eg, sodium sulfite, Albumin) and preservatives (eg, benzyl alcohol, methyl p-oxybenzoate).

The dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be varied according to the severity of the disease, the age and weight of the patient, the dosage form, etc., but is usually 1 mg per day in an adult. It is in the range of ~ 1,000 mg, which can be administered once or divided into two or three times by the oral or parenteral route.

In addition, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be used as an infection treatment, prevention, or transmission inhibition of infectious diseases caused by malaria parasites that are resistant to existing antimalarial agents such as chloroquine and fancidar. Useful. Moreover, it can also be used as a reagent for experiment and research as a malaria parasite growth inhibitor.

Hereinafter, the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to these examples.

The compound was identified by hydrogen nuclear magnetic resonance spectrum ( ¹ H-NMR) and mass spectrum (MS). ¹ H-NMR is measured at 400 MHz unless otherwise specified, and exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. In addition, br. Means a broad signal (broad).
For HPLC preparative chromatography, a commercially available ODS column was used, and water / methanol (including formic acid) was used as an eluent in a gradient mode unless otherwise specified.

For HPLC preparative chromatography, a commercially available ODS column was used, and water / MeOH (including formic acid) was used as an eluent in a gradient mode unless otherwise specified.

Reference example 1
Preparation of N- (4-chloro-6-morpholino-1,3,5-triazin-2-yl) imidazo [1,2-a] pyridin-7-amine

(First step)
An acetone solution (40 mL) of 2,4,6-trichloro-1,3,5-triazine (4 g, 21.69 mmol) was cooled to 0 ° C., and then morpholine (1.89 g, 21.69 mmol) and TEA (4 .51 mL, 32.5 mmol) was added. After stirring for 30 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 1.5 hours. The reaction mixture was poured into ice and stirred, and the precipitated solid was collected by filtration. The resulting solid was purified by column chromatography (silica gel, hexane / ethyl acetate) to give 4- (4,6-dichloro-1,3,5-triazin-2-yl) morpholine (2.72 g). Obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 3.93-3.85 (m, 4H), 3.79-3.72 (m, 4H); LCMS (m / z) 234.9 [M + H] ⁺ .

(Second step)
A THF solution (118 mL) of 4- (4,6-dichloro-1,3,5-triazin-2-yl) morpholine (2 g, 8.51 mmol) was cooled to −5 ° C., and then imidazo [1,2- a] A THF solution (43 mL) of pyridine-7-amine (0.94 g, 7.09 mmol) and DIEA (0.92 g, 7.09 mmol) was added dropwise. The mixture was stirred at room temperature overnight, and the precipitated solid was collected by filtration. The obtained solid was purified by column chromatography (silica gel, CHCl ₃ / MeOH) to obtain the title compound (1.82 g).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.55-8.45 (m, 1H), 8.40-8.32 (m, 1H), 8.24-7.84 (m, 2H), 7.77-7.69 (m, 1H) , 6.97 (dd, J = 7.4, 2.3 Hz, 1H), 4.00-3.90 (m, 2H), 3.89-3.80 (m, 2H), 3.79-3.67 (m, 4H); LCMS (m / z) 331.9 [ M + H] ⁺ .

Reference example 2
N2- [3- (1H-1,2,4-triazol-1-yl) -5- (trifluoromethyl) phenyl] -6-chloro-N4- (imidazo [1,2-a] pyridine-7- Yl) -1,3,5-triazine-2,4-diamine hydrochloride

(First step)
3-bromo-5- (trifluoromethyl) aniline (2 g, 8.33 mmol), copper (I) iodide (0.793 g, 4.17 mmol), potassium carbonate (3.45 g, 25 mmol) and 1,2, A suspension of 4-triazole (1.73 g, 25 mmol) in NMP (5.7 mL) was stirred at 195 ° C. for 2 hours. The insoluble material in the reaction mixture was filtered using a funnel covered with silica gel, and the insoluble material was washed with ethyl acetate. The organic layer obtained by washing the mother liquor with water and saturated brine was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, CHCl ₃ / MeOH) to give 3- (1H-1,2,4-triazol-1-yl) -5- ( Trifluoromethyl) aniline (1.37 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.31 (s, 1H), 8.23 (s, 1H), 7.33-7.26 (m, 2H), 6.91-6.85 (m, 1H), 6.02 (s , 2H); LCMS (m / z) 228.9 [M + H] ⁺ .

(Second process)
Acetone suspension (2.97 mL) of 2,4,6-trichloro-1,3,5-triazine (0.5 g, 2.71 mmol) was cooled to 0 ° C., and ice water (1.2 mL) was added. Then, an acetone solution (5 mL) of 3- (1H-1,2,4-triazol-1-yl) -5- (trifluoromethyl) aniline (0.62 g, 2.71 mmol) was added dropwise and stirred for 2 minutes. did. A saturated aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 7-8, and the mixture was further stirred at 0 ° C. for 20 minutes. After confirming disappearance of the raw materials, the precipitated solid was collected by filtration. The obtained solid was washed with water to give N- [3- (1H-1,2,4-triazol-1-yl) -5- (trifluoromethyl) phenyl] -4,6-dichloro-1, 3,5-Triazine-2-amine (954 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.63 (s, 1H), 9.47 (s, 1H), 8.51-8.45 (m, 1H), 8.33 (s, 1H), 8.13-8.10 (m , 1H), 8.10-8.07 (m, 1H); LCMS (m / z) 375.9 [M + H] ⁺ .

(3rd process)
N- [3- (1H-1,2,4-triazol-1-yl) -5- (trifluoromethyl) phenyl] -4,6-dichloro-1,3,5-triazin-2-amine (3 g , 8 mmol) and imidazo [1,2-a] pyridin-7-amine (0.85 g, 6.4 mmol) in a 1: 1 mixture of 1,4-dioxane / EtOH (54 mL) and concentrated hydrochloric acid Was added in a catalytic amount and refluxed for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration to obtain the title compound (2.3 g).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 12.17-11.54 (m, 1H), 9.52-9.44 (m, 1H), 8.89-7.71 (m, 10H), 7.01-6.93 (m, 1H) LCMS (m / z) 473.2 [M + H] ⁺ .

Example T1
N2- (imidazo [1,2-a] pyridin-7-yl) -N4- [3-methoxy-5- (trifluoromethyl) phenyl] -6-morpholino-1,3,5-triazine-2,4 -Production of diamines

Concentrated hydrochloric acid was added to a 2-PrOH suspension (15 mL) of 3-methoxy-5- (trifluoromethyl) aniline (0.28 g, 1.45 mmol) and the compound of Reference Example 1 (0.40 g, 1.21 mmol). A catalytic amount was added and stirred at 90 ° C. overnight. After cooling to room temperature, the precipitated solid was collected by filtration. The obtained solid was purified by column chromatography (CHCl ₃ / MeOH) to obtain the title compound (432 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.56 (s, 1H), 8.53-8.46 (m, 1H), 8.31-8.17 (m, 1H), 8.06-7.99 (m, 1H), 7.94 -7.81 (m, 1H), 7.78-7.63 (m, 3H), 6.97-6.89 (m, 2H), 3.95-3.88 (m, 2H), 3.88-3.81 (m, 5H), 3.78-3.70 (m, 4H); LCMS (m / z) 487.1 [M + H] ⁺ .

Example T2
N2- [3- (1H-1,2,4-triazol-1-yl) -5- (trifluoromethyl) phenyl] -6-cyclobutoxy-N4- (imidazo [1,2-a] pyridine-7 -Il) Production of 1,3,5-triazine-2,4-diamine

Sodium cyclobutoxide (0.64 mL, 0.64 mmol) was added to a cyclobutanol solution (10 mL) of the compound of Reference Example 2 (200 mg, 0.42 mmol) and refluxed for 1 hour. After confirming disappearance of the raw materials, the solvent was distilled off under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The organic layer obtained by washing the mother liquor with water was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by preparative HPLC to obtain the title compound (60 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.13 (s, 1H), 9.50 (s, 1H), 8.89-8.74 (m, 1H), 8.55-8.48 (m, 1H), 8.39-8.30 (m, 1H), 8.27-7.61 (m, 6H), 6.98-6.90 (m, 1H), 5.46-5.27 (m, 1H), 2.56-2.52 (m, 2H), 2.27-2.13 (m, 2H) , 1.92-1.78 (m, 1H), 1.78-1.59 (m, 1H); LCMS (m / z) 509.1 [M + H] ⁺ .

Examples T3 to T46
The following Example compounds [Table 1-1] to [Table 1-8] were prepared using the corresponding starting materials (commercially available products, or compounds derivatized from commercially available compounds by known methods or modifications thereof), respectively. According to the method described in the examples, the methods usually used in organic synthetic chemistry were appropriately combined as necessary.
The physicochemical data of each compound are shown in [Table 2-1] to [Table 2-5].

Reference example 3
Preparation of 4-chloro-N- [3-methoxy-5- (trifluoromethyl) phenyl] -6-morpholinopyrimidin-2-amine

(First step)
A solution of 2,4,6-trichloropyrimidine (3.76 ml, 32.7 mmol) and DIEA (8.46 g, 65.4 mmol) in EtOH (100 mL) was cooled to −20 ° C., and then morpholine (2.85 g, 32 0.7 mmol) of EtOH solution (33 mL) was added dropwise. The mixture was stirred at −20 ° C. for 30 minutes and then stirred at 0 ° C. for 1.5 hours. The mixture was further stirred overnight at room temperature, and the precipitated solid was collected by filtration. The obtained solid was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain 4- (2,6-dichloropyrimidin-4-yl) morpholine (3.23 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 6.40 (s, 1H), 3.81-3.74 (m, 4H), 3.73-3.56 (m, 4H); LCMS (m / z) 233.9 [M + H] ⁺ .

(Second process)
4-PrOH solution of 5- (2,6-dichloropyrimidin-4-yl) morpholine (732 mg, 3.14 mmol) and 3-methoxy-5- (trifluoromethyl) aniline (500 mg, 2.62 mmol) (5 mL) Concentrated hydrochloric acid was added in a catalytic amount and the mixture was stirred at 90 ° C. for 16 hours. The precipitated solid was collected by filtration, washed with ethyl acetate and dried to give the title compound (500 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.83 (s, 1H), 7.78-7.73 (m, 1H), 7.57-7.48 (m, 1H), 6.82-6.76 (m, 1H), 6.44 (s, 1H), 3.79 (s, 3H), 3.70-3.58 (m, 8H); LCMS (m / z) 389.2 [M + H] ⁺ .

Reference example 4
Preparation of 4-chloro-6-[(2S, 6R) -2,6-dimethylmorpholino] -N- [3-methoxy-5- (trifluoromethyl) phenyl] pyrimidin-2-amine

(First step)
To a THF solution (5.37 mL) of 3-methoxy-5- (trifluoromethyl) aniline (573 mg, 3 mmol), 1.9 M hexamethyldisilazane sodium THF solution (2.63 ml, 5 mmol) was added dropwise at −70 ° C. did. To this solution, a THF solution (3 mL) of 4,6-dichloro-2- (methylsulfonyl) pyrimidine (454 mg, 2 mmol) was added dropwise and stirred for 1 hour. After confirming that the reaction was complete, acetic acid was added to the reaction mixture and extracted with ethyl acetate. The mother liquor was washed sequentially with water and saturated brine, and the resulting organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, hexane / ethyl acetate) to give 4,6-dichloro-N- [3-methoxy-5- (trifluoromethyl) phenyl. Pyrimidin-2-amine (421 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.70 (s, 1H), 7.70-7.60 (m, 2H), 7.32 (s, 1H), 6.96-6.90 (m, 1H), 3.83 (s , 3H); LCMS (m / z) 339.7 [M + H] ⁺ .

(Second step)
To a DMF solution (1.479 mL) of 4,6-dichloro-N- (3-methoxy-5- (trifluoromethyl) phenyl) pyrimidin-2-amine (0.1 g, 0.296 mmol), (2S, 6R ) -2,6-dimethylmorpholine (0.034 g, 0.296 mmol) and sodium hydrogen carbonate (0.030 g, 0.355 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (73 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.85 (s, 1H), 7.91-7.85 (m, 1H), 7.47-7.41 (m, 1H), 6.84-6.78 (m, 1H), 6.47 (s, 1H), 4.52-3.96 (m, 2H), 3.80 (s, 3H), 3.65-3.52 (m, 2H), 2.65-2.54 (m, 2H), 1.14 (d, J = 6.2 Hz, 6H ).

Example P1
Preparation of N4- (imidazo [1,2-a] pyridin-7-yl) -N2- [3-methoxy-5- (trifluoromethyl) phenyl] -6-morpholinopyrimidine-2,4-diamine

The compound of Reference Example 3 (300 mg, 0.773 mmol) and imidazo [1,2-a] pyridin-7-amine (411 mg, 3.093 mmol) were dissolved in a degassed 1,4-dioxane solution (15 mL). Cesium carbonate (503 mg, 1.546 mmol), Xantphos (23 mg, 0.039 mmol) and Pd (dba) ₂ (23 mg, 0.039 mmol) were added at room temperature and the mixture was stirred at 120 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered through celite. The solid was washed with ethyl acetate, and the organic layer obtained by combining with the mother liquor was washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by column chromatography (silica gel, DCM / MeOH) to obtain the title compound (250 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.42 (s, 1H), 9.26 (s, 1H), 8.39-8.33 (m, 1H), 8.18-8.11 (m, 1H), 7.90-7.83 (m, 1H), 7.77-7.72 (m, 1H), 7.67-7.61 (m, 1H), 7.45-7.39 (m, 1H), 7.03 (dd, J = 7.6, 2.2 Hz, 1H), 6.76-6.71 (m, 1H), 5.62 (s, 1H), 3.78 (s, 3H), 3.74-3.67 (m, 4H), 3.54-3.46 (m, 4H); LCMS (m / z) 486.3 [M + H] ⁺ .

Example P96
6-[(2R, 6S) -2,6-dimethylmorpholino] -N4- (imidazo [1,2-a] pyridin-7-yl) -N2- [3-methoxy-5- (trifluoromethyl) phenyl Production of pyrimidine-2,4-diamine

The compound of Reference Example 4 (70 mg, 0.168 mmol), imidazo [1,2-a] pyridin-7-amine (44.7 mg, 0.336 mmol), and sodium tert-butoxide (32.3 mg, 0.336 mmol) To a dioxane suspension (2.5 mL), RuPhos (7.84 mg, 0.017 mmol) and BrettPhos Palladium (13.41 mg, 0.017 mmol) were added. The reaction was performed at 110 ° C. for 30 minutes using a microwave reactor under nitrogen gas. Unnecessary substances were removed by Celite filtration and washed with dioxane. The residue obtained by concentrating the mother liquor was purified by column chromatography (SNAP KP-NH Cartridge (manufactured by Biotage), chloroform) to obtain the title compound (51 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.45 (s, 1H), 9.27 (s, 1H), 8.37 (dd, J = 7.4, 0.8 Hz, 1H), 8.21-8.16 (m, 1H ), 8.04-7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.56-7.50 (m, 1H), 7.46-7.40 (m, 1H), 7.08-7.00 (m, 1H), 6.78-6.72 (m, 1H), 5.64 (s, 1H), 4.07-3.99 (m, 2H), 3.80 (s, 3H), 3.70-3.57 (m, 2H), 2.60-2.52 (m, 2H), 1.16 (d , J = 6.1 Hz, 6H); LCMS (m / z) 514.3 [M + H] ⁺ .

Examples P2 to P95, P97 to P116
The following Example compounds [Table 3-1] to [Table 3-19] were prepared by using the corresponding starting materials (commercially available products, or compounds derivatized from commercially available compounds by known methods or equivalent methods). According to the method described in the examples, the methods usually used in organic synthetic chemistry were appropriately combined as necessary.
The physicochemical data of each compound are shown in [Table 4-1] to [Table 4-15].

Test Example 1: In Vitro Antimalarial Activity Test The antimalarial activity of the compound of the present invention was evaluated by Plasmodium falciparum, a drug given by Professor Kiyoshi Kita of the University of Tokyo Graduate School of Medicine. The in vitro antimalarial activity of compounds against these malaria parasites was determined by the method of Otoguro et al. (Otoguro, K., Kohana, A., Manabe, C) using the resistant K1 strain and the drug-sensitive FCR3 strain. ., Ishiyama, A., Ui, H., Shiomi, K., Yamada, H. & Omura, S .: Potent antimalarial activity of polyether antibiotic, X-206. J. Antibiot., 54: 658-663, ( 2001)).

For the culture of the test protozoa, the method of Trager and Jensen (Trager, W. and Jensen, J .: Human malaria parasites in continuous culture, Science, 193: 673-677, (1976)) is slightly modified to maintain and transfer. The thing which performed the charge was used. That is, protozoa-infected erythrocytes subcultured using RPMI 1640 medium supplemented with 10% human plasma and fresh human erythrocytes in a culture dish were diluted (hematocrit value: 2-5%, protozoa-infected erythrocyte rate: 0.25 Culture at 37 ° C. under a mixed gas of 3% O ₂ -4% CO ₂ -93% N ₂ , and continuously culture by changing the medium and adding fresh erythrocytes every 2-3 days. went.

The drug susceptibility test was performed according to the method of Desjardins et al. (Desjardins, R. E., Canfield, C. J., Haynes, D. E. and Chulay, J. D .: Quantitative assessment of antimalarial activity in vitro by a semiautomated Antimicrob. Agents Chemother., 16: 710-718 (1979)). Specifically, protozoan suspension precultured in each well of a 96-well plate (hematocrit value: 2%, protozoa-infected erythrocyte rate: 0.5 or 1%) is 190 μL and the final concentration is 12.5 to 0.0001 μM. 10 μL of a test compound solution (5% DMSO solution) diluted in such a concentration step was added, mixed, and cultured for 72 hours under the above-mentioned mixed gas.

The measurement of protozoan growth was performed by the method of Makler et al. (Makler, M. T., Rise, J. M., Williams, J. A., Bancroft, J. E. . And Hinrichs, D. J .: Parasite lactate dehydrogenase as an Assay for Plasmodium falciparum drug sensitivity, Am. J. Med. Hyg., 48: 739-741 (1993)), Malstat Reagent, USA ) Was used for colorimetric determination of protozoan lactate dehydrogenase (p-LDH).

That is, after culturing for 72 hours, the 96-well plate was directly frozen at −20 ° C. for 18 hours and then thawed at 37 ° C. to hemolyze protozoa-infected erythrocytes and destroy the protozoa to prepare a crude enzyme solution. Add 100 μL of Malstat reagent and 20 μL of crude enzyme solution to each well of a new 96-well plate, mix and react for 15 minutes at room temperature, then nitroblue tetrazolium 2 mg / mL: phenazine ethosulfate 0 20 mg of a 1 mg / mL = 1: 1 solution was added to each well and allowed to react at room temperature for 2 hours under light-shielding conditions.
The blue formazan product produced by the reaction was colorimetrically determined by measuring the absorbance at a measurement wavelength of 655 nm using a microplate reader (Labostems, Finland). . The 50% protozoan growth inhibitory concentration (IC ₅₀ value) of the compound was determined from the compound concentration action curve.

(Evaluation results)
The compound of the present invention showed strong antimalarial activity in an in vitro antimalarial activity test. [Table 5-1] to [Table 5-7] show the antimalarial activity of the representative compounds of the present invention against cultured Plasmodium falciparum. The antimalarial activity was indicated by an IC ₅₀ value of less than 1 μM, **, 1 μM or more, but less than 5 μM, **, 5 μM or more, but less than 10 μM, *. When the test has not been performed, it is indicated by an NT (Not Tested) mark.

The compound (I) of the present invention shows the same strong antimalarial activity against the drug-resistant strain K1 and the drug-sensitive FCR3 strain. As a result, the compound (I) of the present invention is It shows that it has an excellent effect on the growth inhibition of the species.

Test Example 2: In vivo anti-malarial activity test The in vivo therapeutic effect of the compound of the present invention on the murine malaria parasite P. berghei N strain (drug-sensitive strain) infection experimental model and the aforementioned method of Otsukuro et al. (2001) and Peters et al. (Peters, W., Portus, JH and Robinson, BL: The chemotherapy of rodent malaria. XXII. The value of drug-resistant strains of P. berghei in Screening for blood schizonticidal activity. Ann. Trop. Med. Parasitol., 69: 155-171, (1975)). The murine malaria parasite P. berghei N strain was obtained from Dr. W. It was distributed by Peters (Northwick Park Institute for Medical Research, Meddlesex, UK).

As test animals, males of ICR mice (Nippon Charles River Co., Ltd.), 5 groups of 18 to 20 g were used. 2 × 10 ⁶ parasite-infected erythrocytes were prepared from the protozoa maintained and passaged by in vivo passage, and infected by tail vein inoculation. The treatment experiment was performed by a suppressive test for 4 days. On day 0 of infection, the test compound solution (solvent: 3% DMSO / 0.5% methylcellulose 400 solution or suspension) was administered intraperitoneally (i.p.) 2 hours after the infection. Administer once for 3 days (1st to 3rd day), prepare blood smears from the tail vein on the 4th day, observe parasitaemia of parasites, and treat from the infection rate of the non-compound group The effect (% inhibition) was determined. The significant difference test was performed by Dunnett's test.

Table 6 shows the in vivo antimalarial activity of the representative compounds of the present invention.

The compound (I) of the present invention has a significant inhibitory effect on the rate of erythrocyte-infected erythrocytes and the infection treatment effect on the experimental model of murine malaria parasite P. berghei N strain compared to the control group without any drug added. It was. This result is equivalent to the therapeutic effect equivalent to artesunate used as a positive control (suppression of erythrocytic erythrocyte rate of 83.9 to 91.2% at a dose of 10 mg / kg). (I) shows that it has excellent effectiveness as a remedy for malaria parasites.

The compound of the present invention is a therapeutic agent, prophylactic agent for infectious diseases of human infectious malaria parasites, for example, Plasmodium falciparum, Plasmodium falciparum, Plasmodium falciparum, Oval malaria parasite and Salmonaria parasite It is useful as a propagation inhibitor. Furthermore, it is useful in the treatment, prevention, and transmission prevention of infectious diseases caused by protozoan malaria that is resistant to existing antimalarial drugs such as chloroquine and fancidar. In addition, it can be used as a malaria parasite growth inhibitor in an experimental or research reagent.

Claims (5)

1. Formula (I):
   

   

   (Where
   A is CH or N;
   Z represents an optionally substituted alkoxy group, an optionally substituted amino group, an optionally substituted alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group. And R ¹ , R ² and R ³ each independently represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted amino group. Group, nitro group, hydroxy group, cyano group, heteroaryl group which may be substituted, acyl group which may be substituted, carbamoyl group which may be substituted, carboxyl group, acylamino group which may be substituted , An optionally substituted alkoxycarbonyl group, an optionally substituted alkylsulfonyloxy group and an optionally substituted It is selected from the group consisting of ureido group, or if two of R ^1, R ² and R ³ is attached to a carbon atom adjacent on the benzene ring, together with the two carbon atoms to which they are attached And may form a 5- or 6-membered ring containing one or two oxygen atoms)
   Or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein A is CH, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein A is N, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. A therapeutic agent for malaria parasite infection comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.