JP4834441B2 - Novel cyclic compounds having pyrimidinylalkylthio groups - Google Patents

Description

  The present invention relates to a novel cyclic compound having a pyrimidinylalkylthio group useful as a pharmaceutical or a salt thereof. These compounds are therapeutic agents for diseases involving angiogenesis, especially cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal angiopathy, diabetic macular edema, It is useful as a therapeutic agent for psoriasis vulgaris, atherosclerosis, etc.

  Angiogenesis is a phenomenon in which a new blood vessel network is formed from existing blood vessels, and is mainly observed in small blood vessels. Angiogenesis is inherently a physiological phenomenon and is essential for embryonic angiogenesis, but in adults it is usually only at limited times, such as in the endometrium, follicles, and in the wound healing process. Not observed. However, in diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis Angiogenesis is observed and is closely related to the pathological progression of these diseases. Angiogenesis is regulated by the balance between the promoting factor and the inhibitory factor, and it is considered that angiogenesis occurs when the balance is lost (see Non-Patent Document 1 and Non-Patent Document 2).

  Vascular endothelial growth factor (hereinafter referred to as “VEGF”) specifically acts on receptors (Flt-1, KDR / Flk-1, etc.) present on the surface of vascular endothelial cells to proliferate vascular endothelial cells. It is a factor that promotes the construction of capillary networks through migration and tube formation, and plays a very important role in the development of angiogenesis. Therefore, many attempts have been reported to treat diseases involving angiogenesis by inhibiting the VEGF and controlling the occurrence of angiogenesis. Examples of drugs used for such treatment include indoline-2-one derivatives (see Patent Document 1), phthalazine derivatives (see Patent Document 2), quinazoline derivatives (see Patent Document 3), anthranilic acid amide derivatives (Patent Document 4). Reference), 2-aminonicotinic acid derivatives (see Patent Document 5), 4-pyridylalkylthio derivatives (see Patent Document 6), and the like.

  However, these patent documents do not describe a cyclic compound having a pyrimidinylalkylthio group.

On the other hand, Patent Document 7 reports a cyclic compound having a pyrimidinylalkylthio group. Patent Document 7 relates to a pyrimidine derivative having HIV inhibitory activity. However, the patent document only discloses a huge number of chemical structures, and the cyclic compound having a pyrimidinylalkylthio group according to the present invention is disclosed. No specific disclosure has been made.
Molecular Medicine vol.35 Special issue “Molecular mechanisms of symptoms and pathologies”, Nakayama Shoten, 73-74 (1998) Protein Nucleic Acid Enzyme “Advanced Drug Discovery”, Kyoritsu Shuppan, 1182-1187 (2000) International Publication WO98 / 50356 Pamphlet International Publication WO98 / 35958 Pamphlet International Publication WO97 / 30035 pamphlet International Publication WO00 / 27819 Pamphlet International Publication WO01 / 55114 Pamphlet International Publication WO04 / 078723 Pamphlet International Publication WO03 / 016306 Pamphlet

  Synthetic studies of novel cyclic compounds having pyrimidinylalkylthio groups and finding the pharmacological actions of these compounds are very interesting issues.

  The present inventors have conducted synthetic studies on cyclic compounds having a pyrimidinylalkylthio group and have succeeded in creating many new compounds.

  Furthermore, various studies on the pharmacological action of these compounds revealed that these compounds have angiogenesis-inhibiting action and are therapeutic agents for diseases involving angiogenesis, particularly cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retina. And the present invention was completed. The present invention was found to be useful as a therapeutic agent for retinopathy of prematurity, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis, etc.

  The present invention provides a novel cyclic compound having a pyrimidinylalkylthio group useful as a pharmaceutical or a salt thereof. The novel cyclic compound according to the present invention has an excellent angiogenesis-inhibiting action, and diseases involving angiogenesis, such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retina It is useful as a therapeutic agent for venous occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis, etc.

The present invention relates to a compound represented by the general formula (1) or a salt thereof (hereinafter referred to as “the present compound” unless otherwise specified) and a pharmaceutical composition containing the present compound. The pharmaceutical use of the compound of the present invention will be described in more detail. The present invention relates to a therapeutic agent for a disease involving angiogenesis which comprises the compound of the present invention as an active ingredient. For example, cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy The present invention relates to therapeutic agents for retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis and the like.

[Wherein ring X is

May have one or more substituents selected from halogen atoms and alkyl groups;
R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group;
When R ¹ or R ² is an alkyl group, the alkyl group may have one or more substituents selected from an aryl group, a halogenoaryl group, an alkoxyaryl group and an alkylaryl group;
When R ¹ or R ² is an aryl group, the aryl group is selected from a halogen atom, a hydroxy group, an alkoxy group, a halogenoalkoxy group, an alkyl group, a halogenoalkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group, and an alkylaryl group. May have one or more selected substituents;
R ¹ and R ² together may form a non-aromatic heterocycle;
R ³ is a hydrogen atom, halogen atom, hydroxy group, alkoxy group, aryloxy group, alkyl group, aryl group, amino group, alkylamino group, cycloalkylamino group, arylamino group, alkylcarbonylamino group, arylcarbonylamino group Represents a mercapto group, an alkylthio group, an arylthio group, an alkylsulfinyl group or a non-aromatic heterocyclic group;
When R ³ is an alkylamino group or an alkylcarbonylamino group, the alkyl moiety is one or more substituents selected from a hydroxy group, an alkoxy group, an aryl group, an amino group, an alkylamino group and a non-aromatic heterocyclic group May have
When R ³ is a cycloalkylamino group, the cycloalkyl moiety may have one or more substituents selected from a hydroxy group and an alkoxy group;
When R ³ is a non-aromatic heterocyclic group, the ring may have one or more substituents selected from an alkyl group, a hydroxyalkyl group and an alkoxyalkyl group;
A ¹ represents a sulfur atom, a sulfinyl group or a sulfonyl group;
A ² represents an alkylene group. same as below. ]

  Each atom or group used in the claims and the specification shall have the following meanings throughout the claims and the specification.

  “Halogen atom” means fluorine, chlorine, bromine or iodine.

  “Alkyl” refers to linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like.

  “Cycloalkyl” refers to cycloalkyl having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

  “Aryl” refers to a monocyclic aromatic hydrocarbon or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. In addition, these monocyclic aromatic hydrocarbons or condensed polycyclic hydrocarbons formed by condensation of a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon and a cycloalkane ring are also “aryl” of the present invention. include. Specific examples of monocyclic aromatic hydrocarbons include phenyl, specific examples of condensed polycyclic aromatic hydrocarbons include naphthyl, anthryl, and phenanthryl. Specific examples of condensed polycyclic hydrocarbons include indanyl, tetrahydronaphthyl, and tetrahydro. Anthryl and the like.

  “Aromatic heterocycle” means a monocyclic aromatic heterocycle having one or more heteroatoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or a bicyclic or tricyclic condensed polycyclic aroma A group heterocycle is shown.

  Specific examples of monocyclic aromatic heterocycles include aromatic heterocycles having one heteroatom in the ring such as pyrrole, furan, thiophene, pyridine, etc .; imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, etc. Specific examples of fused polycyclic aromatic heterocycles having two or three rings such as an aromatic heterocycle having two nitrogen atoms in a ring such as pyrazine and pyrimidine And condensed aromatic heterocycles such as indole, isoindole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, thianthrene, phenoxatin, and phenanthroline.

  “Non-aromatic heterocycle” means a monocyclic non-aromatic heterocycle having one or more hetero atoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or a bicyclic or tricyclic condensed polycycle Represents a non-aromatic heterocycle of formula

  Specific examples of monocyclic non-aromatic heterocycles include saturated non-aromatic heterocycles having one hetero atom in the ring, such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, homopiperazine; imidazolidine, oxazolidine , Thiazolidine, pyrazolidine, piperazine, morpholine, thiomorpholine, homopiperidine, homomorpholine, etc., saturated non-aromatic heterocycles having two heteroatoms in the ring; pyrroline, dihydrofuran, dihydrothiophene, tetrahydropyridine, dihydropyridine, dihydro An unsaturated non-aromatic heterocyclic ring having one hetero atom in the ring such as pyran or pyran; an unsaturated non-aromatic heterocyclic ring having two hetero atoms such as imidazoline, oxazoline, thiazoline, pyrazoline, etc. Cyclic or tricyclic Specific examples of the coupling polycyclic aromatic heterocycle, chroman, indoline, isoindoline, xanthine and the like.

  “Alkoxy” represents straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy and the like.

  “Aryloxy” refers to monocyclic aromatic hydrocarbon oxy or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon oxy having 6 to 14 carbon atoms. Specific examples of monocyclic aromatic hydrocarbon oxy include phenoxy, and specific examples of condensed polycyclic aromatic hydrocarbon oxy include naphthyloxy, anthryloxy, phenanthryloxy and the like.

  “Alkylamino” refers to monoalkylamino having 1 to 6 carbon atoms or dialkylamino having 2 to 12 carbon atoms. Specific examples of monoalkylamino include methylamino, ethylamino, hexylamino and the like, and specific examples of dialkylamino include ethylmethylamino, dimethylamino, diethylamino, dihexylamino and the like.

  “Cycloalkylamino” refers to monocycloalkylamino having 3 to 22 carbon atoms or dicycloalkylamino having 6 to 16 carbon atoms. Specific examples of monocycloalkylamino include cyclopropylamino, cyclobutylaminoamino, cyclohexylamino, cyclopropylphenylamino and the like. Specific examples of dicycloalkylamino include dicyclopropylamino, dicyclobutylamino, dicyclopentylamino, dicyclohexyl. Amino, dicycloheptylamino, dicyclooctylamino and the like can be mentioned.

  “Arylamino” refers to monoarylamino having 6 to 20 carbon atoms or diarylamino having 12 to 28 carbon atoms. Specific examples of monoarylamino include phenylamino, naphthylamino, ethylphenylamino and the like, and specific examples of diarylamino include diphenylamino, dianthrylamino and the like.

  “Alkylcarbonylamino” refers to monoalkylcarbonylamino having 2 to 7 carbon atoms or dialkylcarbonylamino having 4 to 14 carbon atoms. Specific examples of monoalkylcarbonylamino include methylcarbonylamino, ethylcarbonylamino, hexylcarbonylamino and the like, and specific examples of dialkylcarbonylamino include ethylmethylcarbonylamino, dimethylcarbonylamino, diethylcarbonylamino, dihexylcarbonylamino and the like.

  “Arylcarbonylamino” refers to monoarylcarbonylamino having 7 to 21 carbon atoms or diarylcarbonylamino having 14 to 30 carbon atoms. Specific examples of monoarylcarbonylamino include phenylcarbonylamino, naphthylcarbonylamino, ethylphenylcarbonylamino, phenylcarbonylamino and the like, and specific examples of diarylamino include diphenylcarbonylamino, dianthrylcarbonylamino and the like.

  “Alkylthio” refers to a linear or branched alkylthio having 1 to 6 carbon atoms. Specific examples include methylthio, ethylthio, n-propylthio, n-butylthio, n-pentylthio, n-hexylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio and the like.

  “Arylthio” refers to monocyclic aromatic hydrocarbon thio or bicyclic or tricyclic fused polycyclic aromatic hydrocarbon thio having 6 to 14 carbon atoms. Specific examples of the monocyclic aromatic hydrocarbon thio include phenylthio, and specific examples of the condensed polycyclic aromatic hydrocarbon thio include naphthylthio, anthrylthio, phenanthrylthio and the like.

  “Alkylsulfinyl” refers to a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms. Specific examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl, n-pentylsulfinyl, n-hexylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, isopentylsulfinyl and the like. Can be mentioned.

  “Alkylene” refers to a linear or branched alkylene having 1 to 6 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, propylene, 2-methyltrimethylene and the like.

  “Halogenoalkoxy” refers to alkoxy having one or more halogen atoms as substituents.

  “Halogenoalkyl” refers to an alkyl having one or more halogen atoms as substituents.

  “Halogenoaryl” refers to aryl having the same or different halogen atoms as substituents.

  “Alkoxyaryl” refers to an aryl having the same or different alkoxy as a substituent.

  “Alkylaryl” refers to aryl having the same or different alkyl groups as a substituent.

When the compound of the present invention has a free hydroxy group, amino group, alkylamino group, cycloalkylamino group, arylamino group, alkylcarbonylamino group, arylcarbonylamino group or mercapto group as a substituent, these substituents are It may be protected with a protecting group. Moreover, also when an aromatic heterocyclic group or a non-aromatic heterocyclic ring has a free nitrogen atom, this nitrogen atom may be protected by the protecting group.

  “Protecting group for free hydroxy group” means a substituted or unsubstituted alkyl group such as a methyl group, a methoxymethyl group, a benzyl group, a 4-methoxyphenylmethyl group, an allyl group, or an unsubstituted alkenyl group; 3-bromotetrahydro Substituted or unsubstituted non-aromatic heterocyclic group such as pyranyl group, tetrahydropyranyl group, tetrahydrofuranyl group; substituted or unsubstituted alkylcarbonyl group such as acetyl group, trifluoroacetyl group, benzoyl group, 4-chlorobenzoyl group Or a substituted or unsubstituted arylcarbonyl group; methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group ,vinyl Substituted or unsubstituted alkyloxycarbonyl group, unsubstituted alkenyloxycarbonyl group, substituted or unsubstituted aryloxycarbonyl group such as xyloxycarbonyl group, allyloxycarbonyl group, phenyloxycarbonyl group, p-nitrophenyloxycarbonyl group; trimethylsilyl And those commonly used as protecting groups for free hydroxy groups such as substituted silyl groups such as a group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group;

  “Aromatic heterocyclic group having a free nitrogen group, a free amino group, a free alkylamino group, a free cycloalkylamino group, a free arylamino group, a free alkylcarbonylamino group, a free arylcarbonylamino group or Non-aromatic heterocyclic group having a free nitrogen atom ”means an unsubstituted alkenyl group such as an allyl group; a hydrocarbonyl group such as a formyl group; an acetyl group, a trichloroacetyl group, a trifluoroacetyl group, a benzoyl group , 4-chlorobenzoyl group, picolinoyl group or the like substituted or unsubstituted alkylcarbonyl group, substituted or unsubstituted arylcarbonyl group, or unsubstituted aromatic heterocyclic carbonyl group; methoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl Group 2,2,2-trichloroethoxycal Substituted or unsubstituted alkyloxycarbonyl such as nyl group, benzyloxycarbonyl group, diphenylmethoxycarbonyl group, phenoxycarbonyl group, m-nitrophenoxycarbonyl group, or substituted or unsubstituted aryloxycarbonyl group; methylsulfonyl group, benzylsulfonyl group A substituted or unsubstituted alkylsulfonyl group such as phenylsulfonyl group, 4-chlorophenylsulfonyl group, tolylsulfonyl group, 2,4,6-trimethylphenylsulfonyl group, or a substituted or unsubstituted arylsulfonyl group; A free alkylamino group, a free cycloalkylamino group, a free arylamino group, a free alkylcarbonylamino group, a free arylcarbonylamino group, an aromatic compound having a free nitrogen atom. It shows what is commonly used as a protecting group of a non-aromatic heterocyclic group having a ring group or a free nitrogen atom.

  The “protecting group for free mercapto group” means a substituted or unsubstituted alkyl group such as a methyl group, a methoxymethyl group, a benzyl group, a 4-methoxyphenylmethyl group, an allyl group, or an unsubstituted alkenyl group; 3-bromotetrahydro Substituted or unsubstituted non-aromatic heterocyclic group such as pyranyl group, tetrahydropyranyl group, tetrahydrofuranyl group; substituted or unsubstituted alkylcarbonyl group such as acetyl group, trifluoroacetyl group, benzoyl group, 4-chlorobenzoyl group Or a substituted or unsubstituted arylcarbonyl group; methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group ,vinyl A substituted or unsubstituted alkyloxycarbonyl group, an unsubstituted alkenyloxycarbonyl group, or a substituted or unsubstituted aryloxycarbonyl group such as a xoxycarbonyl group, an allyloxycarbonyl group, a phenyloxycarbonyl group, a p-nitrophenyloxycarbonyl group; And those commonly used as protecting groups for free mercapto groups.

  The substituted alkyl group, substituted non-aromatic heterocyclic group, substituted alkylcarbonyl group, substituted arylcarbonyl group, substituted alkyloxycarbonyl group, substituted aryloxycarbonyl group, substituted silyl group, substituted alkylsulfonyl group or substituted arylsulfonyl group are: , An alkyl group, a non-aromatic heterocyclic group, an alkyl group each substituted with one or more groups selected from a halogen atom, an alkoxy group, an alkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group and a nitro group A carbonyl group, an arylcarbonyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, a silyl group, an alkylsulfonyl group or an arylsulfonyl group;

  In the “multiple groups” in the present invention, each group may be the same or different, and preferably 2 or 3 groups, more preferably 2 groups.

  Further, the “group” in the present invention includes a hydrogen atom and a halogen atom.

  The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like. , Acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethione Acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid lauryl ester, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, etc. Salt of organic acid, quaternary ammonium salt with methyl bromide, methyl iodide, bromine ion, chloride ion, Salts with halogen ions such as urine ions, salts with alkali metals such as lithium, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, metal salts with iron and zinc, salts with ammonia , Triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3- Examples thereof include salts with organic amines such as propanediol, procaine and N, N-bis (phenylmethyl) -1,2-ethanediamine.

  When geometrical isomers or optical isomers exist in the compound of the present invention, these isomers are also included in the scope of the present invention.

  The compound of the present invention may take the form of a hydrate or a solvate.

  Furthermore, when proton tautomerism exists in this invention compound, those tautomers are also included in the scope of the present invention.

(A) Preferable examples of the compound of the present invention include a compound represented by the general formula (1), a compound wherein each group is a group shown below, or a salt thereof.

In general formula (1),
(a1) Ring X is

And / or
(a2) R ¹ represents an aryl group or an aromatic heterocyclic group; and / or
(a3) When R ¹ is an aryl group, the aryl group has one or more substituents selected from a halogen atom, a hydroxy group, an alkoxy group, a halogenoalkoxy group, an alkyl group, a halogenoalkyl group, and an aryl group And / or
(a4) R ² represents a hydrogen atom; and / or
(a5) R ³ represents a hydrogen atom, an amino group, an alkylamino group, a cycloalkylamino group, an arylamino group, an alkylcarbonylamino group, a mercapto group, an alkylthio group, an arylthio group, an alkylsulfinyl group or a non-aromatic heterocyclic group. Indication; and / or
(a6) when R ³ is an alkylamino group, the alkyl moiety may have one or more substituents selected from a hydroxy group, an alkoxy group, an aryl group, and a non-aromatic heterocyclic group; and / Or
(a7) when R ³ is a cycloalkylamino group, the cycloalkyl moiety may have one or more substituents selected from a hydroxy group and an alkoxy group; and / or
(a8) when R ³ is a non-aromatic heterocyclic group, the ring may have one or more substituents selected from an alkyl group, a hydroxyalkyl group and an alkoxyalkyl group; and / or
(a9) A ¹ represents a sulfur atom; and / or
(a10) A ² represents an alkylene group.

  That is, in the compound represented by the general formula (1), the above (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8), (a9) and A compound consisting of one or more combinations selected from (a10) or a salt thereof.

(B) As a more preferable example in the compound of the present invention, in the compound represented by the general formula (1), a compound in which each group is a group shown below or a salt thereof is mentioned.

(B1) Ring X is

And / or (b2) R ¹ represents an aryl group or an aromatic heterocyclic group; and / or (b3) when R ¹ is an aryl group, the aryl group is a halogen atom, an alkoxy group, a halogenoalkoxy group , May have one or more substituents selected from an alkyl group and a halogenoalkyl group; and / or (b4) R ² represents a hydrogen atom; and / or (b5) R ³ represents a hydrogen atom, An amino group, an alkylamino group, a cycloalkylamino group, an alkylcarbonylamino group, an alkylthio group or a non-aromatic heterocyclic group; and / or (b6) when R ³ is an alkylamino group, the alkyl moiety is a hydroxy group May have one or more substituents selected from an alkoxy group, an aryl group, and a non-aromatic heterocyclic group; and / or (b7) when R ³ is a cycloalkylamino group The cycloalkyl moiety may have one or more hydroxy groups as substituents; and / or (b8) when R ³ is a non-aromatic heterocyclic group, the ring is an alkyl group and a hydroxyalkyl group. And / or (b9) A ¹ represents a sulfur atom; and / or (b10) A ² represents an alkylene group.

  That is, in the compound represented by the general formula (1), the above (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9) and A compound consisting of one or more combinations selected from (b10) or a salt thereof.

(C) As a particularly preferred example of the compound of the present invention, in the compound represented by the general formula (1), a compound in which each group is a group shown below or a salt thereof is mentioned.

(C1) Ring X is

And / or (c2) R ¹ is phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-methoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-n-propylphenyl group, 3-isopropyl Phenyl group, 4-tert-butylphenyl group, 3-trifluoromethylphenyl group, 5-chloro-2,4-dimethoxyphenyl group, 3,5-dimethylphenyl group, indan-5-yl group, 1H-indazole- 6-yl group, quinolin-6-yl or isoquinolin-3-yl group; and / or (c3) R ² represents a hydrogen atom; and / or (c4) R ³ represents a hydrogen atom, amino group, methyl Amino group, n-butylamino group, dimethylamino group, 2-hydroxyethylamino group, 2-ethoxyethylamino group, 1-phenylethylamino group, 2-morpholinoethylamino group, cyclopropylamino group, cyclobutylamino 4-hydroxycyclohexylamino group, acetylamino group, diacetylamino group, methylthio group, morpholino group, piperazinyl group, 4-methylpiperazinyl group or 4- (2-hydroxyethyl) piperazinyl group; and / or ( c5) A ¹ represents a sulfur atom; and / or (c6) A ² represents a methylene group.

  That is, the compound represented by the general formula (1) is composed of one or more combinations selected from the above (c1), (c2), (c3), (c4), (c5) and (c6). Compound or salt thereof.

(D) Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.

2- (2-aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (3-isopropylphenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (quinolin-6-yl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (isoquinolin-3-yl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) benzamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) benzamide,
3- (2-aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) thiophene-2-carboxamide,
N- (3,5-dimethylphenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- (2-methylthiopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- (2-methylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
2- (2-dimethylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (indan-5-yl) pyridine-3-carboxamide,
2- (2-diacetylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (2-morpholinopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
2- (2-morpholinopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- (2-morpholinopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) -N- (3-trifluoromethylphenyl) pyridine-3-carboxamide,
2- (2-n-butylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- [2- (4-acetylpiperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- [2- (2-hydroxyethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide,
2- [2- (2-ethoxyethyl) aminopyrimidin-4-ylmethylthio] -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- [2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- [2- (4-methylpiperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide, and 2- [2- (piperazine- 1-yl) pyrimidin-4-ylmethylthio] -N- (3-trifluorophenyl) pyridine-3-carboxamide.

The compound of the present invention can be produced by the following method. In addition, each specific manufacturing method is demonstrated in detail by the below-mentioned Example [section of a manufacturing example]. Further, Hal used in the following synthesis route represents a halogen atom.

The main synthetic route of the compound of the present invention can be broadly divided into the following two routes (synthetic routes A and B), and the method can be appropriately selected according to the type of substituent.

The compound (I) of the present invention can be produced according to the synthesis route A. That is, O- (7-azabenzotriazol-1-yl) -1 in an organic solvent such as N, N-dimethylformamide (hereinafter abbreviated as DMF), compound (IV) and primary or secondary amine (V). In the presence of a condensing agent such as 1,3,3-tetramethyluronium hexafluorophosphate (hereinafter abbreviated as HATU) and a base such as N, N-diisopropylethylamine (hereinafter abbreviated as DIEA) at room temperature to 50 ° C. Compound (III) can be obtained by reacting for 1 to 24 hours. Subsequently, the compound (III) and the compound (II) are reacted in an organic solvent such as DMF in the presence of a base such as triethylamine (hereinafter abbreviated as TEA) at room temperature to 50 ° C. for 1 to 24 hours. (I) can be obtained.

Synthesis route A

  This invention compound (I) can also be manufactured according to the synthetic pathway B. That is, after obtaining compound (VI) by reacting compound (II) and compound (IV) in an organic solvent such as DMF in the presence of a base such as TEA at room temperature to 50 ° C. for 1 to 24 hours, Compound (VI) is reacted with primary or secondary amine (V) in an organic solvent such as DMF in the presence of a condensing agent such as HATU and a base such as DIEA at room temperature to 50 ° C. for 1 to 24 hours. To give the compound (I) of the present invention.

Synthesis route B

The compound (I) of the present invention obtained by the main synthetic route can further convert the R ^c group by the method shown below.

The compound (Ia) of the present invention in which the R ^c group is an amino (—NHR ^d ) group can introduce a R ^e CO group onto the amino (—NHR ^d ) group according to the synthesis route C. That is, the compound (Ia) obtained by the above-mentioned method and an acylating agent (VIIa, VIIb) such as acetic anhydride or acetyl chloride in an organic solvent such as DMF or without a solvent, in the presence of a base such as pyridine, from room temperature to 50 The compound (Ib) of the present invention can be obtained by reacting at 1 ° C. for 1 to 24 hours.

Synthesis route C

On the other hand, the present compound (Ic) in which the R ^c group is a methylsulfinyl (—S (═O) Me) group can be converted into an amino (—NR ^f R ^g ) group of the methylsulfinyl group according to the synthesis route D. That is, the present invention is carried out by reacting the compound (Ic) obtained by the above-described method with a primary or secondary amine (VIII) in an organic solvent such as DMF or without solvent at room temperature to 100 ° C. for 1 to 12 hours. Compound (Id) can be obtained.

Synthesis route D

Compound (II) used in the main synthetic route can be prepared by the following synthetic route E, F or G.

  Compound (IIa) can be produced according to synthetic route E. That is, compound (IX) was heated in an organic solvent such as benzene in the presence of a radical initiator such as 2,2′-azobisisobutyronitrile and a halogenating agent such as N-bromosuccinimide for 1 hour under heating and reflux. The compound (IIa) can be obtained by reacting for 12 hours.

Synthesis route E

  In addition, compound (IIa, b) is prepared by converting compound (X) into an alcohol form (XI) with a reducing agent such as sodium borohydride in an organic solvent such as methanol and then using a halogenating agent such as thionyl chloride. Halogen (IIa) is obtained by reacting in an organic solvent such as methylene at 0 to 50 ° C. for 1 to 24 hours, or obtained as a methanesulfonyl ether (IIb) by a base such as methanesulfonyl chloride and TEA. be able to.

Synthesis route F

The raw material compound (IId) in which the R ^c group is a methylsulfinyl (—S (═O) Me) group can be prepared by the method shown in the synthesis route G. That is, by oxidizing the compound (IIc, R ^c : -SMe) prepared by the synthesis route F with m-chloroperbenzoic acid in an organic solvent such as methylene chloride at 0 ° C. to 50 ° C. for 1 hour to 24 hours. compound ^{(IId, R c: -S (} = O) Me) can be obtained.

Synthesis route G

Compound (X) was prepared from the compound described in JP-A 2003-89690 “Production of 2-substituted thiopyridine-4-carboxylic acid ester” as shown in Synthesis route H. That is, the compound (Xa) in which the R ^c group is a methylthio group (—SMe) can be obtained by heating to reflux in an organic solvent such as propionitrile from the compound (XII) and methylisothiourea (XIII). On the other hand, the compound (Xb) in which the R ^c group is an amino group (—NR ^f R ^g ) can be obtained from the compound (XII) and various guanidines (XIV) under the same conditions.

Synthesis route H

Compound (Xc) can be prepared by the method shown in Synthesis Route I. That is, compound (XV) and compound (VIII) are reacted in an organic solvent such as methanol at room temperature to 80 ° C. for 15 minutes to 5 hours to obtain compound (XVI), followed by alkaline hydrolysis with a base such as sodium hydroxide. The intermediate (XVII) thus obtained can be obtained by reacting with an alkylating agent such as methyl iodide in a base such as sodium bicarbonate at room temperature for 1 to 24 hours.

Synthesis route I

This invention compound (I) can be converted into this invention compound (XVIII) which has a corresponding sulfoxide according to the synthetic pathway J. That is, the compound (I) of the present invention prepared by the main synthetic routes A and B and synthetic routes C and D is m-chloroperbenzoic acid in an organic solvent such as methylene chloride at 0 ° C. to 50 ° C. for 1 hour to 24 hours. The compound (XVIII) of the present invention can be obtained by oxidation.

Synthesis route J

The compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form by a widely used technique.

  In order to find the usefulness of the compound of the present invention, the VEGF-induced HUVEC proliferation reaction evaluation system (HUVEC: vascular endothelial cell derived from normal human umbilical vein), which is a method for evaluating the angiogenesis inhibitory effect of a drug, is used. A cell growth inhibitory effect test was performed, and the angiogenesis inhibitory effect was evaluated. Details thereof will be described in the following Examples [Pharmacological Test Items], and it has been found that the compound of the present invention exhibits an excellent cell growth inhibitory action and has an angiogenesis inhibitory effect.

  As mentioned above, angiogenesis is cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis It is reported that it is deeply related to diseases such as Therefore, the compound of the present invention is highly expected as a therapeutic agent for those diseases involving angiogenesis.

  The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, ointments, eye drops, eye ointments, and the like, and they can be formulated using a widely used technique.

  For example, oral preparations such as tablets, capsules, granules, powders are lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate and other excipients, stearic acid, magnesium stearate , Lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, calcium citrate, hydroxypropylmethylcellulose, macrogol, A coating agent such as a silicone resin, a stabilizer such as ethyl paraoxybenzoate and benzyl alcohol, a flavoring agent such as a sweetener, an acidulant, and a fragrance can be used as necessary.

  In addition, parenterals such as injections and eye drops are made of isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, sodium hydrogen phosphate, sodium acetate. , Buffers such as citric acid, glacial acetic acid, trometamol, surfactants such as polyoxyethylene sorbitan monooleate, polyoxy 40 stearate, polyoxyethylene hydrogenated castor oil, stabilizers such as sodium citrate and sodium edetate , Benzalkonium chloride, paraben, benzotonium chloride, paraoxybenzoate, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate PH adjusting agents such as Use in accordance with emissions benzyl alcohol soothing agent such as such as required, it may be prepared.

  The dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like. For example, in the case of an oral preparation, 0.01 to 1000 mg per day, preferably 1 to 100 mg can be administered once or divided into several times. In addition, the eye drops are usually administered in a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v) in one or several divided doses. it can.

The production examples, formulation examples and pharmacological test results of the compounds of the present invention are shown below. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

[Production example]
Reference example 1
2-Dimethylamino-4-trifluoromethylpyrimidine (Reference compound 1-1)

  2-Chloro-4-trifluoromethylpyrimidine (600 μL, 5.0 mmol) was dissolved in 2.0 M dimethylamine-methanol solution (10 mL) and stirred at 60 ° C. for 2 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 640 mg of the title reference compound as a colorless oil (yield 67%).

¹ H-NMR (400 MHz, CDCl ₃ )
δ 3.22 (s, 6H), 6.72 (d, J = 4.9 Hz, 1H), 8.48 (d, J = 4.9 Hz, 1H)

Reference example 2
2-Dimethylamino-4-methoxycarbonylpyrimidine (Reference compound 2-1)

  2-dimethylamino-4-trifluoromethylpyrimidine (320 mg, 1.7 mmol, reference compound 1-1) and sodium hydroxide (670 mg, 17 mmol) in a mixed solvent of methanol (5.0 mL) and water (5.0 mL) Then, the mixture was heated and stirred at 160 ° C. for 2 and a half hours while irradiating the microwave in the sealed tube. The reaction mixture was diluted with ethyl acetate (30 mL), and extracted sequentially with water (30 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The extracted aqueous layer was adjusted to pH 7 with 6M hydrochloric acid and then concentrated under reduced pressure. The residue was suspended in N, N-dimethylformamide (5.0 mL), sodium bicarbonate (1.3 g, 14 mmol) and methyl iodide (0.87 mL, 17 mmol) were added, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate (100 mL) and saturated brine (100 mL) twice, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 28 mg of the title reference compound as colorless needle crystals (yield 9.3%).

¹ H-NMR (500 MHz, CDCl ₃ )
δ 3.24 (s, 6H), 3.95 (d, J = 0.6 Hz, 3H), 7.07 (d, J = 4.8 Hz, 1H), 8.49 (dd, J = (4.8, 0.6 Hz, 1H)

Reference example 3
2-Amino-4-methoxycarbonylpyrimidine (Reference compound 3-1)

  Triethylamine (29 mL, 210 mmol) in a suspension of methyl 4-butoxy-2-oxo-3-butenoate (37 g, 200 mmol, JP-A-2003-89690) and guanidine hydrochloride (23 g, 240 mmol) in propionitrile (50 mL) And stirred at 100 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography. A mixture of the target product and the butyl ester of the target product was obtained as 18 g off-white solid (yield 60%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.85 (s, 3H), 6.99-7.06 (m, 3H), 8.48 (d, J = 4.8 Hz, 1H)

  Hereinafter, using compounds selected from commercially available compounds and known compounds, reference compounds 3-2 to 4 were obtained according to the production method of reference compound 3-1.

4-methoxycarbonyl-2-methylthiopyrimidine (reference compound 3-2)
¹ H-NMR (500 MHz, CDCl ₃ )
δ 2.62 (s, 3H), 4.00 (s, 3H), 7.61 (d, J = 4.9 Hz, 1H), 8.74 (d, J = 4.9 Hz, 1H)

2-Methylamino-4-methoxycarbonylpyrimidine (Reference compound 3-3)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.82 (d, J = 4.9 Hz, 3H), 3.85 (s, 3H), 7.04 (d, J = 4.9 Hz, 1H), 7.58 (brs, 1H) ), 8.52 (br s, 1H)

2-acetylamino-4-methoxycarbonylpyrimidine (reference compound 3-4)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.19 (s, 3H), 3.91 (s, 3H), 7.65 (d, J = 4.9 Hz, 1H), 8.91 (d, J = 4.9 Hz, 1H) , 10.90 (s, 1H)

Reference example 4
2-Amino-4-hydroxymethylpyrimidine (Reference compound 4-1)

2-Amino-4-methoxycarbonylpyrimidine (3.0 g, 20 mmol, Reference Compound 3-1) was suspended in a mixed solvent of ethanol (150 mL) and dichloromethane (20 mL), and sodium borohydride (2. 2 g, 59 mmol) was added and stirred for 24 hours. Acetone (20 mL) was gradually added under ice-cooling, and 2M hydrochloric acid was further added until no bubbles appeared. Saturated aqueous sodium bicarbonate was added to adjust the pH to 8, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, suspended in 10% methanol-chloroform solution, and filtered using silica gel (5.0 g). After the filtrate was concentrated under reduced pressure, the precipitated solid was collected by filtration with ethyl acetate and dried under reduced pressure to obtain 1.8 g of the title reference compound as a pale yellow solid (yield 73%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.30 (s, 2H), 5.35 (s, 1H), 6.48 (s, 2H), 6.65 (d, J = 4.9 Hz, 1H), 8.19 (d, J = 4.9 Hz, 1H)

  Hereinafter, reference compounds 4-2 to 4 were obtained according to the production method of reference compound 4-1, using compounds selected from reference compounds 3-1 to 4, commercially available compounds, and known compounds.

2-Dimethylamino-4-hydroxymethylpyrimidine (Reference compound 4-2)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 3.21 (s, 6H), 3.88 (s, 1H), 4.57 (s, 2H), 6.35 (d, J = 4.9 Hz, 1H), 8.24 (d, J = 4.9 Hz, 1H)

2-acetylamino-4-hydroxymethylpyrimidine (reference compound 4-3)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.17 (s, 3H), 4.48 (d, J = 5.4 Hz, 2H), 5.60 (t, J = 5.4 Hz, 1H), 7.22 (d, J = 4.9 Hz, 1H), 8.61 (d, J = 4.9 Hz, 1H), 10.46 (s, 1H)

4-Hydroxymethyl-2-methylthiopyrimidine (Reference compound 4-4)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 2.58 (s, 3H), 3.27 (t, J = 4.9 Hz, 1H), 4.70 (d, J = 4.9 Hz, 2H), 6.96 (d, J = 5.0 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H)

Reference Example 5
2-Amino-4- (tert-butyldimethylsilyloxymethyl) pyrimidine (Reference compound 5-1)

2-Amino-4-hydroxymethylpyrimidine (750 mg, 6.0 mmol, Reference compound 4-1) and tert-butyldimethylsilane chloride (990 mg, 6.6 mmol) were added to anhydrous N, N-dimethylformamide (8.0 mL). The suspension was added, imidazole (0.90 g, 13 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration with a 50% ethyl acetate-n-hexane solution and dried under reduced pressure to obtain 1.2 g of the title reference compound as a white solid (yield 84%).

¹ H-NMR (400 MHz, CDCl ₃ )
δ 0.11 (s, 6H), 0.95 (s, 9H), 4.59 (s, 2H), 5.03 (s, 2H), 6.87 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 5.1 Hz, 1H)

Reference Example 6
4-tert-butyldimethylsilyloxymethyl-2- (methylamino) pyrimidine (reference compound 6-1)

Under a nitrogen atmosphere, to a suspension of sodium hydride (60%, 37 mg, 0.92 mmol) in anhydrous tetrahydrofuran (1.0 mL) under ice-cooling, 2-amino-4- (tert-butyldimethylsilyloxymethyl) pyrimidine ( A solution of 200 mg, 0.84 mmol, reference compound 5-1) in anhydrous tetrahydrofuran (4.0 mL) was added dropwise. After stirring with ice cooling for 15 minutes, methyl iodide (57 μL, 0.92 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine (30 mL), and extracted with ethyl acetate (30 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 43 mg of the title reference compound as a colorless oil (yield 20%).

¹ H-NMR (500 MHz, CDCl ₃ )
δ 0.11 (s, 6H), 0.95 (s, 9H), 2.99 (d, J = 4.9 Hz, 3H), 4.59 (s, 2H), 5.06 (s, 1H), 6.77 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 4.9 Hz, 1H)

Reference Example 7
4-hydroxymethyl-2-methylaminopyrimidine (reference compound 7-1)

4-tert-Butyldimethylsilyloxymethyl-2-methylaminopyrimidine (40 mg, 0.16 mmol, Reference Compound 6-1) was dissolved in tetrahydrofuran (3.0 mL), and tetrabutylammonium fluoride trihydrate was added thereto. A solution of the product (55 mg, 0.17 mmol) in tetrahydrofuran (3.0 mL) was added and stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, suspended in a 25% methanol-chloroform solution, and filtered using silica gel (2.0 g). The filtrate was concentrated under reduced pressure to obtain 60 mg of a mixture of the title reference compound and tetrabutylammonium fluoride as a brown oily substance.

¹ H-NMR (500 MHz, CDCl ₃ )
δ 3.01 (s, 3H), 3.30 (m, 1H), 4.56 (s, 2H), 6.50 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 5.2 Hz, 1H)

Reference Example 8
2-Amino-4-methanesulfonyloxymethylpyrimidine (Reference compound 8-1)

Under ice-cooling, to a suspension of 2-amino-4-hydroxymethylpyrimidine (170 mg, 1.3 mmol, Reference Compound 4-1) in anhydrous tetrahydrofuran (5.0 mL) was added N, N-diisopropylethylamine (490 μL, 2. 9 mmol) and methanesulfonyl chloride (110 μL, 1.5 mmol) were sequentially added, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (300 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration with ethyl acetate and then dried under reduced pressure to obtain 140 mg of the title reference compound as a white solid (yield 53%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.30 (s, 3H), 5.06 (s, 2H), 6.63 (d, J = 5.2 Hz, 1H), 6.78 (s, 2H), 8.28 (d, J = 5.2 Hz, 1H)

  Hereinafter, using a compound selected from Reference Compound 4-4, a commercially available compound, and a known compound, Reference Compound 8-2 was obtained according to the production method of Reference Compound 8-1.

4-Methanesulfonyloxymethyl-2-methylthiopyrimidine (Reference compound 8-2)
¹ H-NMR (500 MHz, CDCl ₃ )
δ 2.57 (s, 3H), 3.14 (s, 3H), 5.22 (s, 2H), 7.13 (d, J = 4.9 Hz, 1H), 8.58 (d, J = 4.9 Hz, 1H)

Reference Example 9
4-Methanesulfonyloxymethyl-2-methylsulfinylpyrimidine (Reference compound 9-1)

Under ice cooling, m-chloroperbenzoic acid (75%, 2.4 g) was added to a solution of 4-methanesulfonyloxymethyl-2-methylthiopyrimidine (2.4 g, 10 mmol, Reference Compound 8-2) in anhydrous methylene chloride (30 mL). 10 mmol) was added and stirred for 15 minutes. Further, m-chloroperbenzoic acid (0.29 g, 1.3 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with saturated aqueous sodium hydrogen carbonate (30 mL), and then washed with saturated brine (30 mL). The aqueous layer was extracted twice with chloroform (100 mL), combined with the ethyl acetate layer, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 2.2 g of the title reference compound as a colorless oil (yield 88%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.97 (s, 3H), 3.21 (s, 3H), 5.42 (s, 2H), 7.62 (d, J = 4.9 Hz, 1H), 8.93 (d, J = 4.9 Hz, 1H)

Reference Example 10
4-Bromomethylpyrimidine (Reference compound 10-1)

To a solution of 4-methylpyrimidine (0.97 mL, 11 mmol) and N-bromosuccinimide (1.9 g, 11 mmol) in anhydrous benzene (25 mL), 2,2′-azobisisobutyronitrile (170 mg, 1. 0 mmol) was added and the mixture was stirred at 70 ° C. for 16 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of the title reference compound as a yellow oil (yield 21%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.65 (s, 2H), 7.67 (dd, J = 4.9, 1.5 Hz, 1H), 8.83 (d, J = 4.9 Hz, 1H), 9.18 ( d, J = 1.5 Hz, 1H)

Reference Example 11
2-acetylamino-4-chloromethylpyrimidine (reference compound 11-1)

To a suspension of 2-acetylamino-4-hydroxymethylpyrimidine (290 mg, 1.7 mmol, reference compound 4-3) in anhydrous methylene chloride (10 mL) at room temperature, thionyl chloride (0.18 mL, 2.4 mmol) was added. Added and stirred for 30 minutes. After evaporating the solvent under reduced pressure, water (50 mL) and ethyl acetate (100 mL) were added and partitioned, and the aqueous layer was further extracted twice with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 68 mg of the title reference compound as a yellow solid (yield 18%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.19 (s, 3H), 4.71 (s, 2H), 7.29 (d, J = 5.1 Hz, 1H), 8.69 (d, J = 5.1 Hz, 1H) , 10.64 (s, 1H)

Reference Example 12
2- (2-Aminopyrimidin-4-ylmethylthio) nicotinic acid (Reference Compound 12-1)

2-Amino-4-methanesulfonyloxymethylpyrimidine (580 mg, 2.9 mmol, Reference compound 8-1) was suspended in N, N-dimethylformamide (15 mL), and 2-mercaptonicotinic acid (400 mg, 2.6 mmol) and triethylamine (1.2 mL, 8.6 mmol) were added, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and extracted with water (50 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). 2M hydrochloric acid was added to the aqueous layer until no bubbles appeared, and the precipitated solid was collected by filtration. The solid was dried at 55 ° C. under reduced pressure to obtain 470 mg of the title reference compound as a white solid (yield 70%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.23 (s, 2H), 6.60 (s, 2H), 6.61 (d, J = 5.1 Hz, 1H), 7.25 (dd, J = 7.6, 4.9) Hz, 1H), 8.10 (d, J = 5.1 Hz.1H), 8.22 (dd, J = 7.6, 1.8 Hz, 1H), 8.60 (dd, J = 4) .9, 1.8 Hz, 1H), 13.48 (s, 1H)

  Hereinafter, Reference Compound 8-1 to 2, 9-1, 10-1, 11-1, a compound selected from commercially available compounds and known compounds is used in accordance with the production method of Reference Compound 12-1, Reference Compound 12 -2 to 6 were obtained.

2- (2-Aminopyrimidin-4-ylmethylthio) benzoic acid (Reference Compound 12-2)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.05 (s, 2H), 6.67-6.69 (m, 3H), 7.21 (td, J = 7.3, 1.4 Hz, 1H), 7.45-7.49. (M, 2H), 7.88 (dd, J = 7.3, 1.4 Hz, 1H), 8.16 (d, J = 5.0 Hz, 1H), 13.08 (s, 1H)

3- (2-Aminopyrimidin-4-ylmethylthio) thiophene-2-carboxylic acid (Reference compound 12-3)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.19 (s, 2H), 6.74 (d, J = 5.5 Hz, 1H), 7.01 (s, 2H), 7.22 (d, J = 5.5 Hz, 1H) 7.85 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 5.5 Hz, 1H), 13.00 (s, 1H)

2- (pyrimidin-4-ylmethylthio) nicotinic acid (reference compound 12-4)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.47 (s, 2H), 7.26 (dd, J = 7.6, 4.6 Hz, 1H), 7.59 (dd, J = 5.4, 1.5 Hz, 1H), 8.24 (dd, J = 7.6, 1.5 Hz, 1H), 8.59 (dd, J = 4.6, 1.5 Hz, 1H), 8.68 (d, J = 5. 4 Hz, 1H), 9.08 (d, J = 1.5 Hz, 1H), 13.52 (s, 1H)

2- (2-Methylthiopyrimidin-4-ylmethylthio) nicotinic acid (Reference Compound 12-5)
¹ H-NMR (500 MHz, CDCl ₃ )
δ 2.55 (s, 3H), 4.48 (s, 2H), 7.10-7.13 (m, 2H), 8.30 (dd, J = 7.6, 1.9 Hz, 1H ), 8.38 (d, J = 5.4 Hz, 1H), 8.56 (dd, J = 4.6, 1.9 Hz, 1H)

2- (2-Methylsulfinylpyrimidin-4-ylmethylthio) nicotinic acid (Reference Example 12-6)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.73 (s, 3H), 4.55 (s, 2H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.71 (d, J = 5.2) Hz, 1H), 8.25 (dd, J = 7.6, 1.5 Hz, 1H), 8.58 (dd, J = 4.9, 1.5 Hz, 1H), 8.85 (d , J = 5.2 Hz, 1H), 13.59 (brs, 1H)

Reference Example 13
N- (3,5-dimethylphenyl) -2-thioxo-1,2-dihydropyridine-3-carboxamide (Reference compound 13-1)
Under cooling with ice, 2-mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N, N-dimethylformamide (660 mL), carbonyldiimidazole (110 g, 0.70 mol) was added, and the mixture was stirred at room temperature for 2 hours. After adding water (5.4 mL) and stirring for 40 minutes, 3,5-xylidine (76 mL, 0.61 mol) was added, and the mixture was stirred at 60 ° C. for 16 hours. After allowing to cool, water (1.3 L) was added and the precipitated solid was collected by filtration and dried at 45 ° C. under reduced pressure to obtain 130 g of the title reference compound as a yellow solid (yield 89%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.27 (s, 6H), 6.77 (s, 1H), 7.10 (dd, J = 7.6, 6.0 Hz, 1H), 7.34 (s, 2H), 8. 03 (dd, J = 6.0, 1.8 Hz, 1H), 8.55 (dd, J = 7.6, 1.8 Hz, 1H), 12.90 (s, 1H), 14.18 (S, 1H)

  Hereinafter, using compounds selected from commercially available compounds and known compounds, reference compounds 13-2 to 4-4 were obtained according to the production method of reference compound 13-1.

2-Thioxo-N- (4-trifluoromethoxyphenyl) -1,2-dihydropyridine-3-carboxamide (Reference compound 13-2)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 7.08 (dd, J = 7.5, 5.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 8.03 (dd, J = 5.8, 1.8 Hz, 1H), 8.48 (dd, J = 7.5, 1.8 Hz, 1H), 12.91 (s, 1H) ), 14.19 (s, 1H)

N- (4-Chlorophenyl) -2-thioxo-1,2-dihydropyridine-3-carboxamide (Reference compound 13-3)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 7.08 (dd, J = 7.6, 6.1 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 8.03 (dd, J = 6.1, 1.8 Hz, 1H), 8.48 (dd, J = 7.6, 1.8 Hz, 1H), 12.90 (s, 1H) ), 14.19 (s, 1H)

N- (Indan-5-yl) -2-thioxo-1,2-dihydropyridine-3-carboxamide (Reference compound 13-4)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.98-2.06 (m, 2H), 2.81-2.89 (m, 4H), 7.09 (dd, J = 7.6, 4.8 Hz, 1H), 7.20 (D, J = 8.1 Hz, 1H), 7.43 (dd, J = 8.1, 2.0 Hz, 1H), 7.62 (s, 1H), 8.03 (dd, J = 4.8, 1.7 Hz, 1H), 8.55 (dd, J = 7.6, 1.7 Hz, 1H), 12.93 (s, 1H), 14.18 (s, 1H)

Example 1
2- (2-Aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 1-1)

  At room temperature, 2- (2-aminopyrimidin-4-ylmethylthio) nicotinic acid (60 mg, 0.24 mmol, Reference Compound 12-1), 3,5-dimethylaniline (33 μL, 0.27 mmol) and N, N— To a solution of diisopropylethylamine (0.93 μL, 0.53 mmol) in anhydrous N, N-dimethylformamide (1.0 mL) was added O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-. Tetrauronium hexafluorophosphate (110 mg, 0.29 mmol) was added and stirred for 18 hours. Ethyl acetate (30 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (50 mL) and saturated brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration and washed with a 50% diethyl ether-ethyl acetate solution. It dried under reduced pressure at 60 degreeC, and obtained 35 mg of target compounds as a light brown solid (yield 41%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 4.26 (s, 2H), 6.59 (s, 2H), 6.62 (d, J = 4.9 Hz, 1H), 6.76 (s, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.92 (dd, J = 7.6, 1.5 Hz, 1H) ), 8.11 (d, J = 4.9 Hz, 1H), 8.55 (dd, J = 4.9, 1.5 Hz, 1H), 10.32 (s, 1H)

  Hereinafter, using compounds selected from Reference Compounds 12-1 to 6, commercially available compounds, and known compounds, Compounds 1-2 to 34 were obtained according to the production method of Compound 1-1.

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide (Compound 1-2)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.27 (s, 2H), 6.60 (s, 2H), 6.62 (d, J = 5.1 Hz, 1H), 7.29 (dd, J = 7.6, 4.8) Hz, 1H), 7.42 (d, J = 9.0 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 7.97 (dd, J = 7.6, 1 .7 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 10.62 (s, 1H) )

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 1-3)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.27 (s, 2H), 6.60 (s, 2H), 6.62 (d, J = 5.2 Hz, 1H), 7.30 (dd, J = 7.8, 4.9) Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.98 (dd, J = 7.8, 1 .7 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 10.68 (s, 1H) )

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (indan-5-yl) pyridine-3-carboxamide (Compound 1-4)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.99-2.05 (m, 2H), 2.81-2.89 (m, 4H), 4.26 (s, 2H), 6.59 (s, 2H), 6.62 (d , J = 5.1 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.39. (D, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.92 (dd, J = 7.6, 1.5 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.56 (dd, J = 4.9, 1.5 Hz, 1H), 10.36 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (3-methylphenyl) pyridine-3-carboxamide (Compound 1-5)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 2.31 (s, 3H), 4.27 (s, 2H), 6.59 (s, 2H), 6.62 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.47 ( d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.93 (dd, J = 7.6, 1.7 Hz, 1H), 8.11 (d, J = 5) 0.0 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.40 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4-tert-butylphenyl) pyridine-3-carboxamide (Compound 1-6)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.28 (s, 9H), 4.26 (s, 2H), 6.59 (s, 2H), 6.62 (d, J = 4.9 Hz, 1H), 7.28 (dd, J = 7.4, 4.9 Hz, 1H), 7.37 (dd, J = 8.9, 2.0 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.93 (dd, J = 7.4, 1.9 Hz, 1H), 8.11 (d, J = 4.9 Hz, 1H), 8.56 (dd, J = 4.9, 1.H). 9 Hz, 1H), 10.41 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (3-isopropylphenyl) pyridine-3-carboxamide (Compound 1-7)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.20 (d, J = 9.1 Hz, 6H), 2.88 (m, 1H), 4.27 (s, 2H), 6.59 (s, 2H), 6.62 (d, J = 4.9 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 7.25-7.29 (m, 2H), 7.52 (d, J = 8.6). Hz, 1H), 7.60 (s, 1H), 7.95 (dd, J = 7.6, 1.9 Hz, 1H), 8.11 (d, J = 4.9 Hz, 1H), 8.56 (dd, J = 4.7, 1.9 Hz, 1H), 10.42 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (5-chloro-2,4-dimethoxyphenyl) pyridine-3-carboxamide (Compound 1-8)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.86 (s, 3H), 3.90 (s, 3H), 4.25 (s, 2H), 6.60 (s, 2H), 6.62 (d, J = 5.1 Hz, 1H), 6.88 (s, 1H), 7.26 (dd, J = 7.6, 4.9 Hz, 1H), 7.71 (s, 1H), 7.95 (d, J = 7) .6 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.55 (d, J = 4.9 Hz, 1H), 9.74 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4-methoxyphenyl) pyridine-3-carboxamide (Compound 1-9)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.74 (s, 3H), 4.26 (s, 2H), 6.60 (s, 2H), 6.62 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.61 (d, J = 9.0 Hz, 2H), 7.93 ( dd, J = 7.6, 1.7 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.55 (dd, J = 4.9, 1.7 Hz, 1H) ), 10.34 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4′-methoxyphenethyl) pyridine-3-carboxamide (Compound 1-10)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.75 (t, J = 7.3 Hz, 2H), 3.36-3.42 (m, 2H), 3.71 (s, 3H), 4.21 (s, 2H), 6. 59 (d, J = 5.1 Hz, 1H), 6.60 (s, 2H), 6.85 (dd, J = 8.1, 1.9 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 7.6, 4.9 Hz, 1H), 7.72 (dd, J = 7.6, 1.7 Hz, 1H), 8 .10 (d, J = 5.1 Hz, 1H), 8.50 (dd, J = 4.9, 1.7 Hz, 1H), 8.59 (t, J = 5.6 Hz, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (quinolin-6-yl) pyridine-3-carboxamide (Compound 1-11)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.28 (s, 2H), 6.59 (s, 2H), 6.63 (d, J = 5.7 Hz, 1H), 7.32 (dd, J = 7.6, 4.9) Hz, 1H), 7.51 (dd, J = 8.3, 4.1 Hz, 1H), 7.90 (m, 1H), 8.00-8.06 (m, 2H), 8.11 (D, J = 5.1 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.53 (s, 1H), 8.60 (dd, J = 4.9, 1.7 Hz, 1H), 8.82 (dd, J = 4.1, 1.4 Hz, 1H), 10.83 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (isoquinolin-3-yl) pyridine-3-carboxamide (Compound 1-12)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.28 (s, 2H), 6.60 (s, 2H), 6.63 (d, J = 4.9 Hz, 1H), 7.27 (dd, J = 7.6, 4.9) Hz, 1H), 7.58 (m, 1H), 7.75 (m, 1H), 7.99 (d, J = 8.1 Hz, 1H), 8.04 (dd, J = 7.6) , 1.7 Hz, 1H), 8.08-8.13 (m, 2H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 8.60 (s, 1H) , 9.20 (s, 1H), 11.18 (s, 1H)

[2- (2-Aminopyrimidin-4-ylmethylthio) pyridin-3-yl] morpholinomethanone (Compound 1-13)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.11 (br s, 2H), 3.50 (br s, 2H), 3.63 (d, J = 5.5 Hz, 4H), 4.31 (s, 2H), 6.56 ( d, J = 4.9 Hz, 1H), 6.61 (s, 2H), 7.24 (dd, J = 7.6, 4.9 Hz, 1H), 7.64 (dd, J = 7) .6, 1.8 Hz, 1H), 8.11 (d, J = 4.9 Hz, 1H), 8.51 (dd, J = 4.9, 1.8 Hz, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (indazol-6-yl) pyridine-3-carboxamide (Compound 1-14)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.28 (s, 2H), 6.60-6.64 (m, 3H), 7.25 (dd, J = 8.5, 1.4 Hz, 1H), 7.30 (dd, J = 7.6, 4.9 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.97-8.00 (m, 2H), 8.11 (d, J = 4.9 Hz, 1H), 8.23 (s, 1H), 8.58 (dd, J = 4.9, 1.6 Hz, 1H), 10.63 (s, 1H), 12.97 ( s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4-n-propylphenyl) pyridine-3-carboxamide (Compound 1-15)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.88 (t, J = 7.3 Hz, 3H), 1.55-1.60 (m, 2H), 2.50-2.54 (m, 2H), 4.26 (s, 2H) ), 6.60-6.63 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 7.27 (dd, J = 7.6, 4.7 Hz, 1H) 7.60 (d, J = 8.4 Hz, 2H), 7.93 (dd, J = 7.6, 1.8 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.56 (dd, J = 4.7, 1.8 Hz, 1H), 10.41 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) benzamide (Compound 1-16)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.25 (s, 6H), 4.06 (s, 2H), 6.60-6.63 (m, 3H), 6.74 (s, 1H), 7.27 (td, J = 7) .3,1.0 Hz, 1H), 7.35 (s, 2H), 7.42 (td, J = 7.3, 1.5 Hz, 1H), 7.47-7.51 (m, 2H), 8.13 (d, J = 4.9 Hz, 1H), 10.21 (s, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) benzamide (Compound 1-17)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.07 (s, 2H), 6.60-6.63 (m, 3H), 7.29 (td, J = 7.5, 1.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.45 (m, 1H), 7.52 (m, 2H), 7.75 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 4.9 Hz, 1H), 10.51 (s, 1H)

[2- (2-Aminopyrimidin-4-ylmethylthio) phenyl] morpholinomethanone (Compound 1-18)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.98-3.05 (m, 2H), 3.46-3.48 (m, 2H), 3.57-3.66 (m, 4H), 4.06 (s, 2H), 6 .52 (d, J = 4.8 Hz, 1H), 6.64 (s, 2H), 7.21 (dd, J = 7.6, 1.4 Hz, 1H), 7.27 (td, J = 7.3, 1.2 Hz, 1H), 7.36 (td, J = 7.3, 1.2 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 8.12 (d, J = 4.8 Hz, 1H)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (4′-methoxyphenethyl) benzamide (Compound 1-19)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.76 (t, J = 7.3 Hz, 2H), 3.36-3.41 (m, 2H), 3.72 (s, 3H), 4.01 (s, 2H), 6. 60 (d, J = 4.9 Hz, 1H), 6.64 (s, 2H), 6.85 (dd, J = 6.7, 2.1 Hz, 2H), 7.15-7.21 (M, 3H), 7.30-7.37 (m, 2H), 7.41 (d, J = 7.4 Hz, 1H), 8.13 (d, J = 4.9 Hz, 1H) , 8.39 (t, J = 5.6 Hz, 1H)

3- (2-Aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) thiophene-2-carboxamide (Compound 1-20)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 4.09 (s, 2H), 6.55 (d, J = 4.9 Hz, 1H), 6.60 (s, 2H), 6.75 (s, 1H), 7.25-7.28 (m, 3H), 7.82 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 9. 89 (s, 1H)

[3- (2-Aminopyrimidin-4-ylmethylthio) thiophen-2-yl] morpholinomethanone (Compound 1-21)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 3.39 (br s, 4H), 3.52-3.58 (m, 4H), 4.02 (s, 2H), 6.48 (d, J = 4.8 Hz, 1H), 6 .63 (s, 2H), 7.21 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 4. 8 Hz, 1H)

N- (3,5-dimethylphenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-22)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 4.51 (s, 2H), 6.77 (s, 1H), 7.28 (dd, J = 7.6, 4.6 Hz, 1H), 7. 33 (s, 2H), 7.59 (dd, J = 5.1, 1.2 Hz, 1H), 7.94 (dd, J = 7.6, 1.7 Hz, 1H), 8.54 (Dd, J = 4.6, 1.7 Hz, 1H), 8.69 (d, J = 5.1 Hz, 1H), 9.08 (d, J = 1.2 Hz, 1H), 10 .31 (s, 1H)

N- (4-Chlorophenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-23)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.51 (s, 2H), 7.29 (dd, J = 7.6, 4.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.59 ( dd, J = 5.1, 1.5 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.99 (dd, J = 7.6, 1.7 Hz, 1H) ), 8.55 (dd, J = 4.6, 1.7 Hz, 1H), 8.68 (d, J = 5.1 Hz, 1H), 9.07 (d, J = 1.5 Hz) , 1H), 10.62 (s, 1H)

N- (Indan-5-yl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-24)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.98-2.05 (m, 2H), 2.81-2.88 (m, 4H), 4.50 (s, 2H), 7.18 (d, J = 8.1 Hz, 1H ), 7.29 (m, 1H), 7.39 (m, 1H), 7.58-7.62 (m, 2H), 7.95 (dd, J = 7.6, 1.7 Hz, 1H), 8.53 (dd, J = 4.9, 1.7 Hz, 1H), 8.69 (d, J = 5.4 Hz, 1H), 9.07 (d, J = 1.2 Hz, 1H), 10.37 (s, 1H)

N- (4-tert-butylphenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-25)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.28 (s, 9H), 4.50 (s, 2H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.37 (dd, J = 6.8) , 2.0 Hz, 2H), 7.57-7.62 (m, 3H), 7.96 (dd, J = 7.6, 1.7 Hz, 1H), 8.54 (dd, J = 4.9, 1.7 Hz, 1H), 8.69 (d, J = 5.1 Hz, 1H), 9.08 (d, J = 1.2 Hz, 1H), 10.42 (s, 1H)

N- (3,5-dimethylphenyl) -2- (2-methylthiopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-26)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 2.33 (d, J = 0.5 Hz, 6H), 2.53 (s, 3H), 4.54 (s, 2H), 6.83 (s, 1H), 7.10 (d, J = 5.1 Hz, 1H), 7.15 (dd, J = 7.6, 4.9 Hz, 1H), 7.27 (s, 2H), 7.93 (dd, J = 7.6). , 1.7 Hz, 1H), 8.01 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 8.50 (dd, J = 4.9, 1.7 Hz) , 1H)

N- (3,5-dimethylphenyl) -2- (2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-27)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 2.84 (s, 3H), 4.58 (s, 2H), 6.77 (s, 1H), 7.29 (dd, J = 7.6, 4 .9 Hz, 1H), 7.33 (s, 2H), 7.71 (d, J = 5.2 Hz, 1H), 7.98 (dd, J = 7.6, 1.8 Hz, 1H) ), 8.53 (dd, J = 4.9, 1.8 Hz, 1H), 8.87 (d, J = 5.2 Hz, 1H), 10.33 (s, 1H)

N- (4-Chlorophenyl) -2- (2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-28)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.84 (s, 3H), 4.59 (s, 2H), 7.31 (dd, J = 7.6, 4.9 Hz, 1H), 7.43 (d, J = 8.8) Hz, 2H), 7.71 (d, J = 5.1 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 8.03 (dd, J = 7.6, 1 .7 Hz, 1H), 8.55 (dd, J = 4.9, 1.7 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H), 10.63 (s, 1H) )

2- (2-Methylsulfinylpyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 1-29)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.84 (s, 3H), 4.59 (s, 2H), 7.32 (dd, J = 7.6, 4.9 Hz, 1H), 7.39 (d, J = 8.2) Hz, 2H), 7.71 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 8.04 (dd, J = 7.6, 1 .8 Hz, 1H), 8.55 (dd, J = 4.9, 1.8 Hz, 1H), 8.87 (d, J = 4.9 Hz, 1H), 10.68 (s, 1H) )

N- (isoquinolin-3-yl) -2- (2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-30)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.84 (s, 3H), 4.60 (s, 2H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.59 (t, J = 7.6) Hz, 1H), 7.73 (d, J = 5.2 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 8.08-8.13 (m, 2H), 8.55 (dd, J = 4.9, 1.5 Hz, 1H), 8.60 (s, 1H), 8.87 (d , J = 5.2 Hz, 1H), 9.20 (s, 1H), 11.19 (s, 1H)

N- (3-chlorophenyl) -2- (2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-31)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.84 (s, 3H), 4.60 (s, 2H), 7.20 (m, 1H), 7.32 (dd, J = 7.6, 4.9 Hz, 1H), 7. 40 (m, 1H), 7.60 (m, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.90 (m, 1H), 8.04 (dd, J = 7) .6, 1.8 Hz, 1H), 8.55 (dd, J = 4.9, 1.8 Hz, 1H), 8.87 (d, J = 5.2 Hz, 1H), 10.67. (S, 1H)

2- (2-Methylsulfinylpyrimidin-4-ylmethylthio) -N- (3-trifluoromethylphenyl) pyridine-3-carboxamide (Compound 1-32)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.84 (s, 3H), 4.60 (s, 2H), 7.33 (dd, J = 7.6, 4.9 Hz, 1H), 7.49 (d, J = 7.6) Hz, 1H), 7.62 (dd, J = 7.9, 7.6 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 7) .9 Hz, 1H), 8.08 (dd, J = 7.6, 1.8 Hz, 1H), 8.19 (s, 1H), 8.56 (dd, J = 4.9, 1.H). 8 Hz, 1H), 8.87 (d, J = 5.2 Hz, 1H), 10.81 (s, 1H)

N- (3,5-dimethylphenyl) -2- (2-methylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 1-33)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 2.76 (d, J = 4.6 Hz, 3H), 4.28 (s, 2H), 6.61 (d, J = 4.9 Hz, 1H) , 6.76 (s, 1H), 7.04 (d, J = 4.3 Hz, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 ( s, 2H), 7.92 (dd, J = 7.6, 1.6 Hz, 1H), 8.15 (s, 1H), 8.56 (dd, J = 4.9, 1.6 Hz) , 1H), 10.32 (s, 1H)

2- (2-Dimethylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 1-34)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 2.32 (s, 6H), 3.12 (s, 6H), 4.46 (s, 2H), 6.55 (d, J = 5.0 Hz, 1H), 6.81 (s, 1H), 7.15 (dd, J = 7.6, 4.8 Hz, 1H), 7.23 (s, 2H), 7.96 (dd, J = 7.6, 1.8 Hz, 1H) ), 8.14 (s, 1H), 8.20 (d, J = 5.0 Hz, 1H), 8.53 (dd, J = 4.8, 1.8 Hz, 1H)

Example 2
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 2-1)

At room temperature, N- (3,5-dimethylphenyl) -2-thioxo-1,2-dihydropyridine-3-carboxamide (28 mg, 0.11 mmol, Reference compound 13-1), 2-acetylamino-4- (chloro To a solution of methyl) pyrimidine (18 mg, 0.10 mmol, Reference compound 11-1) in anhydrous N, N-dimethylformamide (1.0 mL) was added triethylamine (45 μL, 0.32 mmol), and the mixture was stirred for 16 hours. Ethyl acetate (30 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (30 mL) and saturated brine (30 mL), and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the precipitated solid was collected by filtration with diethyl ether and washed. It dried under reduced pressure at 50 degreeC, and obtained 21 mg of target compounds as light orange solid (yield 52%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.16 (s, 3H), 2.26 (s, 6H), 4.43 (s, 2H), 6.77 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.95 (dd, J = 7.6, 1.7 Hz, 1H) ), 8.52 (d, J = 4.9 Hz, 1H), 8.54 (dd, J = 4.9, 1.7 Hz, 1H), 10.33 (s, 1H), 10.49 (S, 1H)

  Hereinafter, using compounds selected from Reference Compounds 13-2 to 4, commercially available compounds, and known compounds, Compounds 2-2 to 4 were obtained according to the production method of Compound 2-1.

2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide (Compound 2-2)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.15 (s, 3H), 4.44 (s, 2H), 7.21 (d, J = 5.1 Hz, 1H), 7.30 (dd, J = 7.6, 4.9) Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.9 Hz, 2H), 8.00 (dd, J = 7.6, 1 .7 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.49 (s, 1H) ), 10.62 (s, 1H)

2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 2-3)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.15 (s, 3H), 4.44 (s, 2H), 7.22 (d, J = 5.1 Hz, 1H), 7.31 (dd, J = 7.6, 4.9) Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.82 (d, J = 8.7 Hz, 2H), 8.01 (dd, J = 7.6, 1 .7 Hz, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.49 (s, 1H) ), 10.68 (s, 1H)

2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (indan-5-yl) pyridine-3-carboxamide (Compound 2-4)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.97-2.04 (m, 2H), 2.15 (s, 3H), 2.80-2.88 (m, 4H), 4.43 (s, 2H), 7.18 (d , J = 8.2 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.39. (D, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.95 (dd, J = 7.6 Hz, 1H), 8.51 (d, J = 5.1 Hz) , 1H), 8.54 (dd, J = 4.9, 1.7 Hz, 1H), 10.37 (s, 1H), 10.49 (s, 1H)

Example 3
2- (2-Diacetylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 3-1)

2- (2-Aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (2.0 g, 5.5 mmol, compound 1-1) in acetic anhydride (20 mL) It was suspended and stirred at 100 ° C. for 4 hours. The reaction solution was diluted with ethyl acetate (1.0 L), washed with water (1.0 L), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.69 g of the target compound as a pale yellow solid (yield 30%).

¹ H-NMR (400 MHz, CDCl ₃ )
δ 2.17 (s, 6H), 2.32 (s, 6H), 4.60 (s, 2H), 6.82 (d, J = 0.7 Hz, 1H), 7.14 (dd, J = 7.6, 4.9 Hz, 1H), 7.25-7.27 (m, 2H), 7.53 (d, J = 5.2 Hz, 1H), 7.87 (dd, J = 7.6, 1.7 Hz, 1H), 8.08 (s, 1H), 8.46 (dd, J = 4.9, 1.7 Hz, 1H), 8.69 (d, J = (5.2 Hz, 1H)

  Hereinafter, using a compound selected from Compound 1-4, a commercially available compound, and a known compound, Compound 3-2 was obtained according to the production method of Compound 3-1.

2- (2-Diacetylaminopyrimidin-4-ylmethylthio) -N- (indan-5-yl) pyridine-3-carboxamide (Compound 3-2)
¹ H-NMR (400 MHz, CDCl ₃ )
δ 2.04-2.12 (m, 2H), 2.23 (s, 6H), 2.86-2.92 (m, 4H), 4.59 (s, 2H), 7.14 (dd , J = 7.6, 4.9 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.57 (S, 1H), 7.88 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H), 8.46 (dd, J = 4.9, 1.7 Hz, 1H) , 8.69 (d, J = 5.1 Hz, 1H), 8.89 (s, 1H)

Example 4
2- (2-Cyclopropylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 4-1)

N- (3,5-dimethylphenyl) -2- (2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (990 mg, 2.4 mmol, compound 1-27) was added to cyclopropylamine (6.0 mL). ) And stirred at 80 ° C. for 30 minutes. The reaction solution was diluted with ethyl acetate (80 mL), washed twice with water (50 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 650 mg (ethanol recrystallization) of the target compound as a colorless solid (yield 67%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.40-0.45 (m, 2H), 0.55-0.65 (m, 2H), 2.26 (s, 6H), 2.67 (m, 1H), 4.29 (s , 2H), 6.66 (d, J = 5.2 Hz, 1H), 6.76 (s, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7 .30-7.35 (m, 3H), 7.92 (dd, J = 7.6, 1.8 Hz, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8. 56 (dd, J = 4.9, 1.8 Hz, 1H), 10.32 (s, 1H)

  Hereinafter, compounds 4-2 to 36 were obtained according to the production method of compound 4-1, using compounds selected from compounds 1-27 to 32, commercially available compounds, and known compounds.

N- (4-chlorophenyl) -2- (2-morpholinopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 4-2)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.60-3.66 (m, 8H), 4.33 (s, 2H), 6.71 (d, J = 5.1 Hz, 1H), 7.29 (dd, J = 7.6) , 4.9 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.99 (dd, J = 7 .6, 1.7 Hz, 1H), 8.26 (d, J = 5.1 Hz, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 10.61. (S, 1H)

2- (2-morpholinopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 4-3)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.61-3.65 (m, 8H), 4.34 (s, 2H), 6.72 (d, J = 4.9 Hz, 1H), 7.31 (dd, J = 7.6) , 4.9 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.9 (dd, J = 7). .6, 1.7 Hz, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.58 (dd, J = 4.9, 1.7 Hz, 1H), 10.68. (S, 1H)

N- (3,5-dimethylphenyl) -2- (2-morpholinopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 4-4)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 3.61-3.66 (m, 8H), 4.33 (s, 2H), 6.71 (d, J = 4.9 Hz, 1H), 6. 77 (s, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.93 (dd, J = 7.6, 1. 7 Hz, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.32 (s, 1H)

N- (4-chlorophenyl) -2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 4-5)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.40-0.45 (m, 2H), 0.59-0.64 (m, 2H), 2.67 (m, 1H), 4.29 (s, 2H), 6.66 (d , J = 4.9 Hz, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.35 (m, 1H), 7.42 (d, J = 8. 8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.97 (dd, J = 7.6, 1.7 Hz, 1H), 8.19 (d, J = 4.9 Hz, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 10.62 (s, 1H)

2- (2-Cyclopropylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 4-6)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.40-0.45 (m, 2H), 0.58-0.64 (m, 2H), 2.67 (m, 1H), 4.29 (s, 2H), 6.66 (d , J = 4.9 Hz, 1H), 7.30 (dd, J = 7.6, 4.9 Hz, 1H), 7.35 (m, 1H), 7.38 (d, J = 8. 7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.98 (dd, J = 7.6, 1.7 Hz, 1H), 8.19 (d, J = 4.9 Hz, 1H), 8.58 (dd, J = 4.9, 1.7 Hz, 1H), 10.68 (s, 1H)

2- (2-Cyclopropylaminopyrimidin-4-ylmethylthio) -N- (isoquinolin-3-yl) pyridine-3-carboxamide (Compound 4-7)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.40-0.44 (m, 2H), 0.58-0.64 (m, 2H), 2.67 (m, 1H), 4.31 (s, 2H), 6.68 (d , J = 4.9 Hz, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.36 (brs, 1H), 7.58 (ddd, J = 8 .1, 7.8, 1.2 Hz, 1H), 7.75 (ddd, J = 8.1, 7.3, 1.2 Hz, 1H), 7.98 (d, J = 7.8) Hz, 1H), 8.05 (dd, J = 7.6, 1.7 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H), 8.19 (d, J = 4) .9 Hz, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 8.60 (brs, 1H), 9.20 (s, 1H), 11.18 ( s, 1H)

N- (3-chlorophenyl) -2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 4-8)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.40-0.45 (m, 2H), 0.59-0.64 (m, 2H), 2.67 (m, 1H), 4.30 (s, 2H), 6.66 (d , J = 4.9 Hz, 1H), 7.20 (ddd, J = 8.1, 7.1, 2.0 Hz, 1H), 7.30 (dd, J = 7.6, 4.9). Hz, 1H), 7.36 (m, 1H), 7.39 (dd, J = 8.3, 8.1 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.90 (t, J = 2.0 Hz, 1H), 7.9 (dd, J = 7.6, 1.7 Hz, 1H), 8.19 (d, J = 4.9 Hz, 1H) ), 8.58 (dd, J = 4.9, 1.7 Hz, 1H), 10.67 (s, 1H)

2- (2-Cyclopropylaminopyrimidin-4-ylmethylthio) -N- (3-trifluoromethylphenyl) pyridine-3-carboxamide (Compound 4-9)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.41-0.45 (m, 2H), 0.59-0.63 (m, 2H), 2.67 (m, 1H), 4.30 (s, 2H), 6.67 (d , J = 4.9 Hz, 1H), 7.31 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (m, 1H), 7.48 (d, J = 7. 6 Hz, 1H), 7.61 (dd, J = 1.9, 1.9 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 7.6, 1.8 Hz, 1H), 8.18-8.19 (m, 2H), 8.59 (dd, J = 4.9, 1.8 Hz, 1H), 10.81 (s) , 1H)

2- (2-n-Butylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 4-10)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.86 (t, J = 7.3 Hz, 3H), 1.25-1.33 (m, 2H), 1.43-1.50 (m, 2H), 2.26 (s, 6H) ), 3.19-3.24 (m, 2H), 4.27 (s, 2H), 6.59 (d, J = 4.9 Hz, 1H), 6.76 (s, 1H), 7 .12 (br s, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.92 (dd, J = 7.6, 1.8 Hz, 1H), 8.14 (d, J = 4.9 Hz, 1H), 8.55 (dd, J = 4.9, 1.8 Hz, 1H), 10.32 (s, 1H)

2- (2-n-Butylaminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide (Compound 45-11)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.86 (t, J = 7.3 Hz, 3H), 1.24-1.33 (m, 2H), 1.43-1.49 (m, 2H), 3.18-3.23 (M, 2H), 4.28 (s, 2H), 6.59 (d, J = 5.2 Hz, 1H), 7.12 (br s, 1H), 7.29 (dd, J = 7) .6, 4.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.97 (dd, J = 7.6, 1.8 Hz, 1H), 8.14 (d, J = 5.2 Hz, 1H), 8.57 (dd, J = 4.9, 1.8 Hz, 1H), 10 .61 (s, 1H)

2- (2-n-Butylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 4-12)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.85 (t, J = 7.3 Hz, 3H), 1.24-1.32 (m, 2H), 1.42-1.49 (m, 2H), 3.18-3.23 (M, 2H), 4.28 (s, 2H), 6.59 (d, J = 5.2 Hz, 1H), 7.11 (br s, 1H), 7.30 (dd, J = 7) .6, 4.9 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.98 (dd, J = 7.6, 1.8 Hz, 1H), 8.14 (d, J = 5.2 Hz, 1H), 8.58 (dd, J = 4.9, 1.8 Hz, 1H), 10 .68 (s, 1H)

2- (2-Cyclobutylaminopyrimidin-4-ylmethylthio) -N- (isoquinolin-3-yl) pyridine-3-carboxamide (Compound 4-13)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.50-1.65 (m, 2H), 1.85-2.00 (m, 2H), 2.15-2.20 (m, 2H), 4.28 (s, 2H), 4 .29 (m, 1H), 6.61 (d, J = 4.9 Hz, 1H), 7.31 (dd, J = 7.8, 4.9 Hz, 1H), 7.43-7. 50 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 8.02 (dd, J = 7.8) , 1.7 Hz, 1H), 8.14 (d, J = 4.9 Hz, 1H), 8.19 (s, 1H), 8.59 (dd, J = 4.9, 1.7 Hz). , 1H), 10.81 (s, 1H)

N- (3-chlorophenyl) -2- (2-cyclobutylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide (Compound 4-14)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.56-1.65 (m, 2H), 1.88-1.99 (m, 2H), 2.14-2.21 (m, 2H), 4.28 (s, 2H), 4 .29 (m, 1H), 6.61 (d, J = 4.9 Hz, 1H), 7.19 (m, 1H), 7.30 (dd, J = 7.6, 4.9 Hz, 1H), 7.37-7.42 (m, 2H), 7.60 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 7.98 (dd, J = 7) .6, 1.7 Hz, 1H), 8.14 (d, J = 4.9 Hz, 1H), 8.58 (dd, J = 4.9, 1.7 Hz, 1H), 10.66. (S, 1H)

2- [2- (4-Acetylpiperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (3,5-dimethylphenyl) pyridine-3-carboxamide (Compound 4-15)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.03 (s, 3H), 2.26 (s, 6H), 3.42 to 3.49 (m, 4H), 3.64 to 3.68 (m, 2H), 3.72-3 .75 (m, 2H), 4.33 (s, 2H), 6.71 (d, J = 4.9 Hz, 1H), 6.77 (s, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.94 (dd, J = 7.6, 1.7 Hz, 1H), 8.27 (d, J = 4) .9 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.33 (s, 1H)

2- [2- (4-Acetylpiperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (4-chlorophenyl) pyridine-3-carboxamide (Compound 4-16)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.03 (s, 3H), 3.46-3.50 (m, 4H), 3.64-3.67 (m, 2H), 3.72-3.75 (m, 2H), 4 .34 (s, 2H), 6.71 (d, J = 4.9 Hz, 1H), 7.30 (dd, J = 7.6, 4.9 Hz, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.9 Hz, 2H), 7.89 (dd, J = 7.6, 1.8 Hz, 1H), 8.27 ( d, J = 4.9 Hz, 1H), 8.58 (dd, J = 4.9, 1.8 Hz, 1H), 10.62 (s, 1H)

2- [2- (4-Acetylpiperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 4-17)
¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.03 (s, 3H), 3.48-3.50 (m, 4H), 3.64-3.67 (m, 2H), 3.72-3.75 (m, 2H), 4 .34 (s, 2H), 6.71 (d, J = 4.9 Hz, 1H), 7.31 (dd, J = 7.6, 4.9 Hz, 1H), 7.38 (d, J = 8.9 Hz, 2H), 7.82 (d, J = 8.9 Hz, 2H), 8.00 (dd, J = 7.6, 1.8 Hz, 1H), 8.27 ( d, J = 4.9 Hz, 1H), 8.59 (dd, J = 4.9, 1.8 Hz, 1H), 10.68 (s, 1H)

N- (3,5-dimethylphenyl) -2- [2- (1-phenylethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-18)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.40 (d, J = 7.1 Hz, 3H), 2.26 (s, 6H), 4.27 (s, 2H), 5.07 (m, 1H), 6.59 (d, J = 5.1 Hz, 1H), 6.77 (s, 1H), 7.13-7.16 (m, 1H), 7.22-7.38 (m, 7H), 7.69 (br s, 1H), 7.92 (dd, J = 7.6, 1.7 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.54 (dd, J = 4 .9, 1.7 Hz, 1H), 10.32 (s, 1H)

N- (3,5-dimethylphenyl) -2- [2- (2-hydroxyethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-19)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 3.27-3.31 (m, 2H), 3.38-3.50 (m, 2H), 4.27 (s, 2H), 4.65 (t , J = 5.6 Hz, 1H), 6.62 (d, J = 4.9 Hz, 1H), 6.77 (s, 1H), 7.00 (brs, 1H), 7.27 ( dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.92 (dd, J = 7.6, 1.7 Hz, 1H), 8.15 (d , J = 4.9 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.33 (s, 1H)

N- (3,5-dimethylphenyl) -2- [2- (2-ethoxyethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-20)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.07 (t, J = 6.8 Hz, 3H), 2.26 (s, 6H), 3.30-3.50 (m, 6H), 4.28 (s, 2H), 6. 62 (d, J = 4.9 Hz, 1H), 6.76 (s, 1H), 7.06 (brs, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.92 (dd, J = 7.6, 1.7 Hz, 1H), 8.15 (d, J = 4.9 Hz, 1H), 8. 56 (dd, J = 4.9, 1.7 Hz, 1H), 10.32 (s, 1H)

N- (3,5-dimethylphenyl) -2- [2- (2-morpholinoethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide monohydrochloride (Compound 4-21)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.26 (s, 6H), 3.27 (br s, 2H), 3.60-4.00 (m, 10H), 4.34 (s, 2H), 6.77 (d, J = 4.9 Hz, 1H), 6.77 (s, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.34 (s, 2H), 7.50 ( br s, 1H), 7.95 (dd, J = 7.6, 1.7 Hz, 1H), 8.25 (d, J = 4.9 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 10.20 (s, 1H), 10.36 (s, 1H)

2- [2- (2-Ethoxyethyl) aminopyrimidin-4-ylmethylthio] -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide (Compound 4-22)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.07 (t, J = 6.8 Hz, 3H), 3.30-3.50 (m, 6H), 4.29 (s, 2H), 6.63 (d, J = 4.9) Hz, 1H), 7.07 (brs, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H) , 7.82 (d, J = 8.3 Hz, 2H), 7.98 (dd, J = 7.6, 1.7 Hz, 1H), 8.15 (d, J = 4.9 Hz, 1H), 8.58 (dd, J = 4.9, 1.7 Hz, 1H), 10.68 (s, 1H)

N- (4-chlorophenyl) -2- [2- (2-morpholinoethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-23)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 2.30-2.50 (m, 8H), 3.53 (br s, 4H), 4.28 (s, 2H), 6.62 (d, J = 4.9 Hz, 1H), 6 .95 (S, 1H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.98 (dd, J = 7.6, 1.7 Hz, 1H), 8.15 (br s, 1H), 8.57 (dd, J = 4. 9, 1.7 Hz, 1H), 10.61 (br s, 1H)

N- (3,5-dimethylphenyl) -2- [2- (1,4-trans-4-hydroxycyclohexylamino) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-24)
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.15-1.20 (m, 4H), 1.76-1.88 (m, 4H), 2.26 (s, 6H), 3.35 (m, 1H), 3.60 (m , 1H), 4.26 (s, 2H), 4.50 (d, J = 4.3 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 6.76 (s). , 1H), 6.97 (br s, 1H), 7.27 (dd, J = 7.6, 4.9 Hz, 1H), 7.33 (s, 2H), 7.92 (dd, J = 7.6, 1.5 Hz, 1H), 8.14 (d, J = 5.2 Hz, 1H), 8.56 (dd, J = 4.9, 1.5 Hz, 1H), 10 .31 (s, 1H)

N- (3,5-dimethylphenyl) -2- [2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-25) ¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.32 (s, 6H), 2.54 (t, J = 5.1 Hz, 4H), 2.58 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.81 (t, J = 5.1 Hz, 4H), 4.44 (s, 2H), 6.61 (d, J = 5.0 Hz, 1H), 6 .81 (s, 1H), 7.15 (dd, J = 7.7, 4.8 Hz, 1H), 7.23 (s, 2H), 7.95 (dd, J = 7.7, 1 .8 Hz, 1H), 8.05 (br s, 1H), 8.20 (d, J = 5.0 Hz, 1H), 8.54 (dd, J = 4.8, 1.8 Hz, 1H)

2- [2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (isoquinolin-3-yl) pyridine-3-carboxamide (Compound 4-26)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.50-2.65 (m, 6H), 3.66 (t, J = 5.3 Hz, 2H), 3.83 (t, J = 5.1 Hz, 4H), 4.45 ( s, 2H), 6.64 (d, J = 5.0 Hz, 1H), 7.16 (dd, J = 7.7, 4.8 Hz, 1H), 7.52 (dd, J = 7) .2, 7.0 Hz, 1H), 7.68 (dd, J = 8.1, 7.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.91. (D, J = 8.6 Hz, 1H), 7.9 (dd, J = 7.7, 1.8 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 8 .56 (dd, J = 4.8, 1.8 Hz, 1H), 8.75 (s, 1H), 8.86 (s, 1H), 8.97 (s, 1H)

N- (3-chlorophenyl) -2- [2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-27)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.53 (t, J = 5.0 Hz, 4H), 2.58 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3 .79 (t, J = 5.0 Hz, 4H), 4.46 (s, 2H), 6.60 (d, J = 5.0 Hz, 1H), 7.10-7.20 (m, 2H), 7.28 (m, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 5.0 Hz, 1H), 8.31 (brs, 1H), 8.56 (d, J = 4.8 Hz, 1H)

2- [2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (3-trifluoromethylphenyl) pyridine-3-carboxamide (Compound 4-28)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.53 (t, J = 5.0 Hz, 4H), 2.58 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3 .79 (t, J = 5.0 Hz, 4H), 4.47 (s, 2H), 6.61 (d, J = 5.0 Hz, 1H), 7.19 (dd, J = 7. 7, 4.8 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.1, 7.9 Hz, 1H), 7.82 ( d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 8.01 (dd, J = 7.7, 1.8 Hz, 1H), 8.21 (d, J = 5) 0.0 Hz, 1H), 8.45 (br s, 1H), 8.57 (dd, J = 4.8, 1.8 Hz, 1H)

N- (3,5-dimethylphenyl) -2- [2- (4-methylpiperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-29)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.32 (s, 6H), 2.33 (s, 3H), 2.40-2.50 (m, 4H), 3.76-3.88 (m, 4H), 4.44 (s , 2H), 6.60 (d, J = 5.1 Hz, 1H), 6.81 (s, 1H), 7.15 (dd, J = 7.7, 4.8 Hz, 1H), 7 .23 (s, 2H), 7.95 (dd, J = 7.7, 1.8 Hz, 1H), 8.06 (br s, 1H), 8.20 (d, J = 5.0 Hz) , 1H), 8.53 (dd, J = 4.8, 1.8 Hz, 1H)

N- (isoquinolin-3-yl) -2- [2- (4-methylpiperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-30)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.34 (s, 3H), 2.40-2.51 (m, 4H), 3.80-3.90 (m, 4H), 4.45 (s, 2H), 6.65 (d , J = 5.0 Hz, 1H), 7.16 (dd, J = 7.7, 5.0 Hz, 1H), 7.52 (dd, J = 8.1, 7.2 Hz, 1H) , 7.68 (dd, J = 8.1, 7.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.9 (dd, J = 7.7, 1.8 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 8.56 (dd, J = 5.0 , 1.8 Hz, 1H), 8.74 (s, 1H), 8.83 (brs, 1H), 8.99 (s, 1H)

N- (3-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-31)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.34 (s, 3H), 2.44 (t, J = 5.0 Hz, 4H), 3.80 (t, J = 4.6 Hz, 4H), 4.46 (s, 2H) 6.59 (d, J = 5.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 7.7, 4.8 Hz, 1H) ), 7.30 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.72 (brs, 1H), 7.98 (dd, J = 7.7, 1.8 Hz, 1H), 8.21 (d, J = 5.0 Hz, 1H), 8.31 (brs, 1H), 8.56 (dd, J = 4. (8, 1.8 Hz, 1H)

2- [2- (4-Methylpiperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (3-trifluorophenyl) pyridine-3-carboxamide hydrochloride (Compound 4-32)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.74 (br.s, 3H), 2.90-3.10 (m, 2H), 3.25-3.50 (m, 4H), 4.36 (s, 2H), 4.63 (Brd, J = 4.1 Hz, 2H), 6.81 (d, J = 5.0 Hz, 1H), 7.30 (dd, J = 7.7, 4.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8. 07 (d, J = 7.6 Hz, 1H), 8.21 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 8.58 (brd, J = 4. 8 Hz, 1H), 10.91 (s, 1H), 11.06 (brs, 1H)

N- (3,5-dimethylphenyl) -2- [2- (piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-33)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.32 (s, 6H), 2.85-2.95 (m, 4H), 3.76-3.83 (m, 4H), 4.44 (s, 2H), 6.60 (d , J = 5.0 Hz, 1H), 6.81 (s, 1H), 7.16 (dd, J = 7.3, 5.0 Hz, 1H), 7.23 (s, 2H), 7 .95 (dd, J = 7.3, 1.8 Hz, 1H), 8.06 (brs, 1H), 8.19 (dd, J = 5.0 Hz, 1H), 8.54 (dd , J = 5.0, 1.8 Hz, 1H)

N- (isoquinolin-3-yl) -2- [2- (piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-34)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.91 (t, J = 5.0 Hz, 4H), 3.80 (t, J = 5.0 Hz, 4H), 4.45 (s, 2H), 6.65 (d, J = 5.1 Hz, 1H), 7.14 (dd, J = 7.7, 4.8 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.86-7.90 (m, 2H), 7.99 (dd, J = 7.7, 1.8 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 8.77 (s, 1H), 8.86 (s, 1H), 9.27 (Br s, 1H)

N- (3-chlorophenyl) -2- [2- (piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide (Compound 4-35)
¹ H-NMR (300 MHz, CDCl ₃ )
δ 2.92 (t, J = 5.0 Hz, 4H), 3.79 (t, J = 5.0 Hz, 4H), 4.45 (s, 2H), 6.59 (d, J = 5.0 Hz, 1H), 7.14-7.21 (m, 2H), 7.28 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz) 1H), 7.71 (s, 1H), 7.98 (dd, J = 7.5, 1.7 Hz, 1H), 8.20 (d, J = 5.0 Hz, 1H), 8. 31 (br s, 1H), 8.56 (dd, J = 4.8, 1.7 Hz, 1H)

2- [2- (Piperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (3-trifluorophenyl) pyridine-3-carboxamide (Compound 4-36)
¹ H-NMR (300 MHz, CDCl ₃ )

δ 2.84 (t, J = 5.0 Hz, 4H), 3.72 (t, J = 5.0 Hz, 4H), 4.45 (s, 2H), 6.58 (d, J = 5.0 Hz, 1H), 7.16 (dd, J = 7.7, 4.8 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.98 (dd, J = 7.7, 1.7) Hz, 1H), 8.20 (d, J = 5.0 Hz, 1H), 8.55 (m, 2H)

The chemical structures of the aforementioned compounds of the present invention are shown in Tables 1-6. In addition, the number described in R ³ in the table indicates the substitution position of R ³ with respect to the pyrimidine ring.

[Formulation example]
The typical formulation example of this invention compound is shown below.

1) Compound of the present invention 1 mg in 100 mg tablet
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.6mg

  A tablet having the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet. Moreover, a desired tablet can be obtained by changing suitably the kind and quantity of this invention compound and an additive.

2) Capsule Formulation 2 150 mg of the present compound 5 mg
Lactose 145mg

  A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.

3) Eye drop formulation 3 100 mg of the present compound in 100 mL
Sodium chloride 900mg
Polysorbate 80 200mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount

  Desired eye drops can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.

[Pharmacological test]
1. Evaluation Test for Angiogenesis Inhibitory Effect As one of the widely used methods for evaluating the angiogenesis inhibitory effect of drugs, a cell growth inhibitory action test using a VEGF-induced HUVEC proliferation reaction evaluation system is disclosed in Cancer Res. 59, 99-106 (1999). Therefore, according to the method described in the above-mentioned literature, the cell growth inhibitory action test of the compound of the present invention was performed, the cell growth inhibition rate was calculated, and the angiogenesis inhibitory effect of the compound of the present invention was evaluated using it as an index.

(Preparation of test compound solution)
The test compound was dissolved in dimethyl sulfoxide (hereinafter, DMSO), and the resulting solution was diluted with a commercially available phosphate buffer solution (hereinafter, PBS) to prepare a 20 μg / mL test compound solution.

(Preparation of HUVEC suspension)
HUVEC was suspended in F12K medium containing 0.5% fetal bovine serum (hereinafter, FBS) to prepare a HUVEC suspension at 2 × 10 ⁴ cells / mL.

(Preparation of VEGF solution)
VEGF was dissolved in PBS containing 0.1% bovine serum albumin, and the resulting solution was diluted with F12K medium containing 0.5% FBS to prepare a 400 ng / mL VEGF solution.

(Test method and measurement method)
1) 100 μL of HUVEC suspension was seeded in each well of a 96-well plate coated with type I collagen (2 × 10 ³ cells per well).

2) One day after sowing, 5 μL of the test compound solution was added per well.

3) One hour after the addition of the test compound solution, 5 μL of VEGF solution was added per well.

4) Three days after the addition of the VEGF solution, 10 μL of WST-8 assay reagent (Dojin Chemical) was added per well.

5) After 3 hours, the plate was attached to an absorptiometer (multi-label counter ARVO), and the absorbance of each well suspension (hereinafter referred to as test compound suspension) at 450 nm was measured.

6) In place of the test compound solution, 1.0% DMSO was used, and the others were tested in the same manner as in the above 1-5), and the result was used as a control.

In addition, between each said test process, it incubated in 37 degreeC, 5% carbon dioxide, and 95% oxygen conditions in the incubator.

(Calculation of cell growth inhibition rate)
The cell growth inhibition rate (%), which is an index of the angiogenesis inhibitory effect, was calculated from the following formula.

(a formula)
Cell growth inhibition rate (%)
= 100-{(absorbance of test compound suspension-A) / (absorbance of control-A)} × 100
A: Absorbance of only cell suspension (cell + medium)

(Test results and discussion)
As an example of the test results, test compounds (compound 1-1, compound 1-7, compound 1-12, compound 1-16, compound 1-20, compound 1-22, compound 1-26, compound 1-33, compound 2-1, compound 2-2, compound 2-4, compound 3-1, compound 4-1, compound 4-4, compound 4-6, compound 4-9, compound 4-19, compound 4-22, compound Table 7 shows the cell growth inhibition rates (%) of 4-25 and compound 4-36.

As shown in Table 7, the compound of the present invention exhibited an excellent cell growth inhibitory action. Therefore, the compound of the present invention has an excellent angiogenesis inhibitory effect.

Claims (8)

A compound represented by the following general formula (1) or a salt thereof.

[Wherein ring X is

May have one or more substituents selected from halogen atoms and alkyl groups;
R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group;
When R ¹ or R ² is an alkyl group, the alkyl group may have one or more substituents selected from an aryl group, a halogenoaryl group, an alkoxyaryl group and an alkylaryl group;
When R ¹ or R ² is an aryl group, the aryl group is selected from a halogen atom, a hydroxy group, an alkoxy group, a halogenoalkoxy group, an alkyl group, a halogenoalkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group, and an alkylaryl group. May have one or more selected substituents;
R ¹ and R ² together may form a non-aromatic heterocycle;
R ³ is a hydrogen atom, halogen atom, hydroxy group, alkoxy group, aryloxy group, alkyl group, aryl group, amino group, alkylamino group, cycloalkylamino group, arylamino group, alkylcarbonylamino group, arylcarbonylamino group Represents a mercapto group, an alkylthio group, an arylthio group, an alkylsulfinyl group or a non-aromatic heterocyclic group;
When R ³ is an alkylamino group or an alkylcarbonylamino group, the alkyl moiety is one or more substituents selected from a hydroxy group, an alkoxy group, an aryl group, an amino group, an alkylamino group and a non-aromatic heterocyclic group May have
When R ³ is a cycloalkylamino group, the cycloalkyl moiety may have one or more substituents selected from a hydroxy group and an alkoxy group;
When R ³ is a non-aromatic heterocyclic group, the ring may have one or more substituents selected from an alkyl group, a hydroxyalkyl group and an alkoxyalkyl group;
A ¹ represents a sulfur atom, a sulfinyl group or a sulfonyl group;
A ² represents an alkylene group. ] In general formula (1),
Ring X is

Indicates;
R ¹ represents an aryl group or an aromatic heterocyclic group;
When R ¹ is an aryl group, the aryl group may have one or more substituents selected from a halogen atom, a hydroxy group, an alkoxy group, a halogenoalkoxy group, an alkyl group, a halogenoalkyl group, and an aryl group. ;
R ² represents a hydrogen atom;
R ³ represents a hydrogen atom, amino group, alkylamino group, cycloalkylamino group, arylamino group, alkylcarbonylamino group, mercapto group, alkylthio group, arylthio group, alkylsulfinyl group or non-aromatic heterocyclic group;
When R ³ is an alkylamino group, the alkyl moiety may have one or more substituents selected from a hydroxy group, an alkoxy group, an aryl group and a non-aromatic heterocyclic group;
When R ³ is a cycloalkylamino group, the cycloalkyl moiety may have one or more substituents selected from a hydroxy group and an alkoxy group;
When R ³ is a non-aromatic heterocyclic group, the ring may have one or more substituents selected from an alkyl group, a hydroxyalkyl group and an alkoxyalkyl group;
A ¹ represents a sulfur atom;
The compound or a salt thereof according to claim 1, wherein A ² represents an alkylene group. In general formula (1),
Ring X is

Indicates;
R ¹ represents an aryl group or an aromatic heterocyclic group;
When R ¹ is an aryl group, the aryl group may have one or more substituents selected from a halogen atom, an alkoxy group, a halogenoalkoxy group, an alkyl group and a halogenoalkyl group;
R ² represents a hydrogen atom;
R ³ represents a hydrogen atom, an amino group, an alkylamino group, a cycloalkylamino group, an alkylcarbonylamino group, an alkylthio group or a non-aromatic heterocyclic group;
When R ³ is an alkylamino group, the alkyl moiety may have one or more substituents selected from a hydroxy group, an alkoxy group, an aryl group and a non-aromatic heterocyclic group;
When R ³ is a cycloalkylamino group, the cycloalkyl moiety may have one or more hydroxy groups as substituents;
When R ³ is a non-aromatic heterocyclic group, the ring may have one or more substituents selected from an alkyl group and a hydroxyalkyl group;
A ¹ represents a sulfur atom;
The compound or a salt thereof according to claim 1 or 2, wherein A ² represents an alkylene group. In general formula (1),
Ring X is

Indicates;
R ¹ is phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-methoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-n-propylphenyl group, 3-isopropylphenyl group, 4-tert-butylphenyl Group, 3-trifluoromethylphenyl group, 5-chloro-2,4-dimethoxyphenyl group, 3,5-dimethylphenyl group, indan-5-yl group, 1H-indazol-6-yl group, quinoline-6- Represents an yl or isoquinolin-3-yl group;
R ² represents a hydrogen atom;
R ³ is a hydrogen atom, amino group, methylamino group, n-butylamino group, dimethylamino group, 2-hydroxyethylamino group, 2-ethoxyethylamino group, 1-phenylethylamino group, 2-morpholinoethylamino group , Cyclopropylamino group, cyclobutylamino group, 4-hydroxycyclohexylamino group, acetylamino group, diacetylamino group, methylthio group, morpholino group, piperazinyl group, 4-methylpiperazinyl group or 4- (2-hydroxyethyl group) ) Represents a piperazinyl group;
A ¹ represents a sulfur atom;
The compound or a salt thereof according to claim 1, wherein A ² represents a methylene group. 2- (2-aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (3-isopropylphenyl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (quinolin-6-yl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (isoquinolin-3-yl) pyridine-3-carboxamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) benzamide,
2- (2-aminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) benzamide,
3- (2-aminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) thiophene-2-carboxamide,
N- (3,5-dimethylphenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- (2-methylthiopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- (2-methylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
2- (2-dimethylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (4-chlorophenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
2- (2-acetylaminopyrimidin-4-ylmethylthio) -N- (indan-5-yl) pyridine-3-carboxamide,
2- (2-diacetylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (2-morpholinopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
2- (2-morpholinopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- (2-morpholinopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
2- (2-cyclopropylaminopyrimidin-4-ylmethylthio) -N- (3-trifluoromethylphenyl) pyridine-3-carboxamide,
2- (2-n-butylaminopyrimidin-4-ylmethylthio) -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
2- [2- (4-acetylpiperazin-1-yl) pyrimidin-4-ylmethylthio] -N- (3,5-dimethylphenyl) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- [2- (2-hydroxyethyl) aminopyrimidin-4-ylmethylthio] pyridine-3-carboxamide,
2- [2- (2-ethoxyethyl) aminopyrimidin-4-ylmethylthio] -N- (4-trifluoromethoxyphenyl) pyridine-3-carboxamide,
N- (4-chlorophenyl) -2- (pyrimidin-4-ylmethylthio) pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- [2- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide,
N- (3,5-dimethylphenyl) -2- [2- (4-methylpiperazin-1-yl) pyrimidin-4-ylmethylthio] pyridine-3-carboxamide, and 2- [2- (piperazine- 1-yl) pyrimidin-4-ylmethylthio] -N- (3-trifluorophenyl) pyridine-3-carboxamide or a salt thereof. The pharmaceutical composition containing the compound or its salt of any one of Claims 1-5. A therapeutic agent for a disease involving angiogenesis, comprising the compound according to any one of claims 1 to 5 or a salt thereof. Diseases involving angiogenesis are cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris or saddle artery The therapeutic agent according to claim 7, which is cured.