JP2002145778A - Grk inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new GRK inhibitor useful as a prophylactic or a therapeutic agent for cardiac insufficiency, etc. SOLUTION: This GRK inhibitor comprises a compound represented by the formula (I) [A denotes a nitrogen-containing heterocyclic ring which may further be substituted; R1 and R2 denote each amino group which may respectively be substituted; X denotes a spacer in which the number of atoms constituting the straight-chain part is 1-4; and R1 may be bound to R2 or/and X to form a ring], or its salt or a prodrug thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel GRK inhibitor useful as a prophylactic / therapeutic agent for heart failure and the like.

[0002]

2. Description of the Related Art G protein-coupled receptors represented by adrenergic receptors, acetylcholine receptors, opioid receptors, etc. are the most important receptors for maintaining physiological functions.
Degradation of these receptors leads to abnormal normal cellular responses and organ functions. G protein-coupled receptor kinase
(G protein-coupled receptor kinase, GRK) is an enzyme that phosphorylates G protein-coupled receptors activated by agonists, and GRK-phosphorylated receptors have reduced responsiveness to agonists Yes (desensitization). This GR
Numerous results have been reported suggesting that K acts as an exacerbating factor in various diseases. At the animal experiment level, many reports have shown that inhibiting the function of GRK using genetic modification techniques can prevent and treat conditions such as heart failure and arteriosclerosis (Lefkovitz, Nature Biotechnology, Vol. 14). Pp. 283-286;
Cork et al., Trends Incardiovascular Medicine, Vol. 9, pp. 77-81; Davis et al., Arteriosclerosis and Thrombosis Vascular Biology, Vol. 18, pp. 1275-1280; etc.). In addition, an increase in GRK2 has been reported in pathological animal models, human hypertensive patients and heart failure patients (Angrey et al., Circulation, 87, 454-463, etc.). From the above, GRK inhibitors are
In particular, it is expected to be developed as a prophylactic / therapeutic agent for cardiovascular diseases such as heart failure, hypertension, and atherosclerosis.
There is no report on a pyrimidine derivative having an inhibitory action. On the other hand, pyrimidine derivatives include, for example, Katritzky (AR), “Comprehensive heterocyclic chemistry” (COMPREHENS
IVE HETEROCYCLIC CHEMISTRY) Pergamon Press (PERGA
MON PRESS), 1984, Vol. 3, pp. 57-156, etc.
Compounds useful as anticancer agents and the like are disclosed. In addition, the USP3,016,380, useful as vitamin _{B 1} agent

Embedded image (R ^{4 ″} represents an optionally substituted alkyl group)
Is disclosed in Pharmaceutical Journal, 1972, Vol. 92, pp. 27-31, useful as a thiamine-related compound.

Embedded image

Embedded image Is disclosed, Russian Pharmacology and Toxicology Inc. New Drug
Screening Report (Khim. Farm. Zh.), 1969
Year 3, Volume 27, pages 30-30, as pyrimidine analogs of folic acid,

Embedded image Is disclosed, and Bio-Organic Chemistry (Bioor
g. Chem.), 1995, Vol. 23, pp. 512-518, useful for studying the reaction mechanism of thiaminase.

Embedded image Is disclosed, JP-B 33-5422,

Embedded image Although disclosed, it has not been reported at all that pyrimidine derivatives, including these compounds, have GRK inhibitory activity.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a drug which is useful as a prophylactic / therapeutic agent for heart failure or the like based on GRK inhibitory action.

[0004]

Means for Solving the Problems As a result of intensive studies on compounds having GRK inhibitory action, the present inventors have found that a compound represented by the following formula (I) or a salt thereof (hereinafter referred to as compound (I)): ) Or their prodrugs show excellent GRK inhibitory action,
Based on this, the present invention has been completed. That is, the present invention relates to (1) Formula (I)

Embedded imageWherein ring A is a nitrogen-containing heterocyclic group which may be further substituted.
A ring;¹And R ²Are each substituted
X represents a good amino group, and X represents the number of atoms constituting the linear portion.
Represents a spacer of 1 to 4;¹Is R²Or / and
And X may combine with each other to form a ring. ]
Compounds or their salts, or their prodrugs
A GRK inhibitor having the formula (1-1):

Embedded imageWherein ring A is a nitrogen-containing heterocyclic group which may be further substituted.
A ring;¹And R ²Are each substituted
X represents a good amino group, and X represents the number of atoms constituting the linear portion.
Indicates a spacer of 1 to 4. Or a compound represented by
Is a GR containing a salt thereof or a prodrug thereof.
K inhibitor; (1-2) the nitrogen-containing heterocycle is pyrimidine or pyridine
An agent according to the above (1) or (2); (2) a formula (I ′)

Embedded image [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, and R ¹ is bonded to R ³ or R ⁴ to form a ring. R ³ represents a hydrogen atom or an optionally substituted acyl group, and R ⁴ represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted Represents an acyl group; R ³ and R ⁴ may combine to form a cyclic amino group; n represents an integer of 1 to 4; Or a salt thereof, or a GRK inhibitor containing a prodrug thereof; (3) an alkyl group which may be substituted with R ^{4, a} cyclic hydrocarbon group which may be substituted, The agent according to the above (2), which is an optionally substituted heterocyclic group or an optionally substituted acyl group; (4) the agent according to the above (2), wherein R ⁴ is an optionally substituted alkyl group. (5) the agent according to (2), wherein R ⁴ is an optionally substituted aryl group; (6) the agent according to (2), wherein R ⁴ is an optionally substituted acyl group; 7) R ⁴ is a group represented by the formula-(C = O) -R,-(C = O) NR
_{R ', - SO 2 -R,} -SO 2 -NRR' or - (C
ＯO) O—R [R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ′
Represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R and R ′ are bonded to each other and may have a substituent together with an adjacent nitrogen atom. A nitrogen heterocyclic group may be formed. (8) the agent according to (2), wherein n is 1; (9) ring B is a group represented by the formula:

Embedded image [In the formula, R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group, and ring B ′ further has a substituent. Represents an optionally substituted pyrimidine ring. (10) the agent according to (9), wherein R ⁵ is an optionally substituted alkyl group or an optionally substituted aryl group; 11) The agent according to the above (9), wherein R ⁵ is methyl; (12) the agent according to the above (2), wherein R ¹ is amino;
3) The compound represented by the formula (I ′) is a compound represented by the formula (Ia)

Embedded image Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group; E represents an optionally substituted divalent cyclic hydrocarbon group or an optionally substituted divalent heterocyclic group;
, - - -O is _{S -, - SO -, -} SO 2 -, - S-S
—, —CO—NH—, —CO—O—, or C _1-4 alkylene; Ra represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Indicates an integer of 4. [Preferably, a compound represented by the formula (Ia ′):

Embedded image Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group, E ′ represents an optionally substituted divalent cyclic hydrocarbon group, and Ya ′ represents —O—, —S—, —SO—, -SO
_2- , -SS- or -CO-NH-;
a ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ^{5a ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. It shows an amino group, and n shows the integer of 1-4. The compound according to the above (2), which is a compound represented by the formula (Ib):

Embedded image Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and n represents an integer of 1 to 4. [Preferably, a compound represented by the formula (Ib ′):

Embedded image Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R ^{5b ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. Represents an amino group, and n represents an integer of 1 to 4. The compound according to the above (2), which is a compound represented by the formula (I ′):

Embedded image [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, F represents a nitrogen-containing heterocyclic group which may be further substituted, Rc represents a hydrocarbon group which may be substituted or an acyl group which may be substituted, and n represents an integer of 1 to 4. (16) the agent according to (1) or (2), which is a prophylactic or therapeutic agent for heart failure; (17) the agent according to (1) or (2), A method of inhibiting GRK in a mammal, which comprises administering an effective amount of the compound or a salt thereof, or a prodrug thereof to a mammal; (18) the compound or a salt thereof according to (1) or (2) above. Or a method for preventing or treating heart failure in a mammal, which comprises administering an effective amount of a prodrug thereof to the mammal; (19) The method according to (1) or (2) above, for producing a GRK inhibitor. (20) Use of a compound or a salt thereof, or a prodrug thereof;
Or use of the compound according to (2) or a salt thereof, or a prodrug thereof; (21) a compound of the formula (Ia ′)

Embedded image Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group, E ′ represents an optionally substituted divalent cyclic hydrocarbon group, and Ya ′ represents —O—, —S—, —SO—, -SO
_2- , -SS- or -CO-NH-;
a ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ^{5a ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. It shows an amino group, and n shows the integer of 1-4. However, when Ya 'is -O-, Ra' is not ethyl. A compound represented by the formula

Embedded image

Embedded image

Embedded image

Embedded image and

Embedded image Or a salt thereof; (22) a prodrug of the compound of (21) or a salt thereof; (22a) a drug containing the compound of (21) or a salt thereof, or a prodrug thereof [preferably (23) the compound according to (21), wherein R ³ is hydrogen; (24) the compound according to (21), wherein E ′ is an optionally substituted divalent aromatic hydrocarbon group. (25) The compound according to the above (21), wherein E 'is phenylene which may be substituted; (26) Ya' is -O-, -S-, -SO- or -S
(27) The compound according to (21), wherein O ′ is O ₂ —; (27) the compound according to ( ₂ ), wherein Ya ′ is —O— or —S—.
(28) The compound according to (2), wherein Ra ′ is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group.
(29) The compound according to (21), wherein Ra ′ is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group; (30) Ra ′. Is a phenyl which may be substituted; (31) a compound according to the above (21), wherein R ¹ is amino; (32) a compound according to the above (21), wherein n is 1. (33) ring B is of the formula

Embedded image Wherein R ^{5a ′} is as defined above. (34) The compound according to (21), wherein R ^{5a ′} is a lower alkyl group.
(35) The compound according to (33), wherein R ^{5a ′} is methyl; (36) (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (propyldisulfanyl) phenyl ] Formamide, N-[(4-amino-2-methyl-
5-pyrimidinyl) methyl] -N- [2- (phenylsulfanyl) phenyl] amine, N-[(4-amino-
2-methyl-5-pyrimidinyl) methyl] -N- [2-
(4-bromophenylsulfanyl) phenyl] amine, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(2-methoxyphenyl)
Sulfanyl] phenyl] amine, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2
-(4-methoxyphenoxy) phenyl] amine, N-
[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] phenyl] amine, N-[(4-amino-2-methyl-5-pyrimidinyl) ) Methyl] -N- [2-[(2
-Nitrophenyl) sulfanyl] phenyl] amine,
N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(3-methoxyphenyl) sulfanyl] phenyl] amine, 2-[[(4-amino-
2-methyl-5-pyrimidinyl) methyl] amino] -N
-(2,2-diphenylethyl) benzoic acid amide, (4
-Amino-2-methyl-5-pyrimidinyl) methyl (2
-Benzylsulfanylmethylsulfanylphenyl)
Formamide or a salt thereof or a prodrug thereof; (37) Formula (Ib ′)

Embedded image Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R ^{5b ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. Represents an amino group, and n represents an integer of 1 to 4. A compound represented by the formula

Embedded image and

Embedded image (38) a prodrug of the compound of (37) or a salt thereof; (38a) a medicament containing the compound of (37) or a salt thereof, or a prodrug thereof [preferably (39) R ^3b is a group represented by the formula — (C ＝ O) —R ′ [R ′ represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; . (40) The compound according to (39), wherein R ′ is an optionally substituted hydrocarbon group; (41) the compound according to (39), wherein R ′ is substituted. (42) the compound according to (39), wherein R ′ is an aromatic hydrocarbon group which may be substituted; (43) the compound according to (39), wherein R ′ is an optionally substituted cyclic hydrocarbon group; (44) The compound according to the above (39), which is an optionally substituted phenyl; (44) the compound according to the above (37), wherein Yb is an optionally substituted _C1-4 alkylene; (45) Yb is methylene. (46) The compound according to (37), wherein Rb is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group; Rb is an optionally substituted phenyl group (48) the compound of the above (37), wherein R ¹ is amino; (49) the compound of the above (37), wherein n is 1;

Embedded image Wherein R ^{5b ′} is as defined above. (51) The compound according to (37), wherein R ^{5b ′} is a lower alkyl group.
(52) The compound according to (50), wherein R ^{5b ′} is methyl; (53) N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N′-benzhydryl-N -Benzylterephthalamide, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-N'-
(1,2,3,4-tetrahydro-1-naphthalenyl)
Terephthalamide, N-[(4-amino-2-methyl-
5-pyrimidinyl) methyl] -N-benzyl-4-
[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide, N-[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] -N-benzyl-
6- (3,5-diphenyl-1H-pyrazol-1-yl) hexanamide, 4-[(allyloxy) methyl]
-N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-benzamide or a salt thereof or a prodrug thereof; (54) Formula (Ic)

Embedded image [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, F represents a nitrogen-containing heterocyclic group which may be further substituted, Rc represents a hydrocarbon group which may be substituted or an acyl group which may be substituted, and n represents an integer of 1 to 4. (55) a prodrug of the compound of (54) or a salt thereof; (55a) a medicament comprising the compound of (54) or a salt thereof, or a prodrug thereof. [Preferably a GRK inhibitor];

Embedded image [In the formula, F 'represents a 5- to 8-membered ring which may be further substituted, and Rc has the same meaning as described in the above (54). (57) wherein F is a group represented by the formula:

Embedded image [In the formula, F 'represents a benzene ring which may be further substituted, and Rc has the same meaning as described in the above (54). (58) a compound according to the above (54), wherein Rc is-(C = O) NRR '[R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ′ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R and R 'may combine with each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. (59) the compound according to (54), wherein R ¹ is amino; (60) the compound according to (54), wherein n is 1; 61) Ring B has the formula

Embedded image [Wherein, R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and ring B ′ represents a pyrimidine ring which may further have a substituent. . (62) The compound according to (61), wherein R ⁵ is an optionally substituted alkyl group or an optionally substituted aryl group; 63) The compound according to the above (61), wherein R ⁵ is methyl; (64) 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N, N-dibenzyl-1,3-dioxo- 5-isoindolinecarboxamide, 2-[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]-
N- (2,2-diphenylethyl) -1,3-dioxo-5-isoindolinecarboxamide, 2-[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -N
-(3,3-diphenylpropyl) -1,3-dioxo-5-isoindolinecarboxamide or a salt thereof or a prodrug thereof;

[0005] In the above formula, ring A represents a nitrogen-containing heterocyclic ring which may be substituted. The nitrogen-containing heterocycle of the “optionally substituted nitrogen-containing heterocycle” represented by ring A includes, for example, at least one nitrogen atom as an atom (ring atom) constituting a ring system, and further contains oxygen Nitrogen-containing aromatic heterocyclic group which may contain 1 to 3 (preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms selected from atoms, sulfur atoms and nitrogen atoms, etc. Examples include a ring, a saturated or unsaturated nitrogen-containing non-aromatic heterocycle (nitrogen-containing aliphatic heterocycle), and a nitrogen-containing aromatic heterocycle is preferably used. As the "nitrogen-containing aromatic heterocycle",
For example, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane,
1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine,
5- or 6-membered nitrogen-containing aromatic monocyclic heterocyclic ring such as pyrimidine, pyrazine, triazine and the like;
A 6- or 6-membered nitrogen-containing aromatic monocyclic heterocycle and a benzene ring are condensed or two or more of the same or different 5- or 6-membered nitrogen-containing aromatic monocyclic heterocycles are formed by condensation. An 8- to 12-membered condensed nitrogen-containing aromatic heterocycle or the like;
And the like. As the "non-aromatic heterocyclic group", for example, a 5- to 6-membered saturated or unsaturated (preferably saturated) nitrogen-containing non-aromatic heterocycle (eg, pyrrolidine, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, etc.) Nitrogen-containing aliphatic heterocycle), etc .;
Part or all of the double bonds of the nitrogen-containing aromatic monocyclic heterocyclic ring or the nitrogen-containing aromatic fused heterocyclic ring such as 3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline are Saturated non-aromatic heterocycles and the like. As the “nitrogen-containing heterocycle” of the “optionally substituted nitrogen-containing heterocycle” for ring A, a nitrogen-containing aromatic heterocycle is preferable, and a 5- or 6-membered nitrogen-containing aromatic monocyclic ring is particularly preferable. The formula heterocyclic ring is preferable, and a pyrimidine ring, a pyridine ring and the like are particularly preferable, and a pyrimidine ring is particularly preferably used.

[0006] The "nitrogen-containing heterocycle" of the "optionally substituted nitrogen-containing heterocycle" for ring A has a substituent in addition to the substituents specified in formula (I). Well,
Examples of such a substituent include a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an acyl group which may be substituted, an amino group which may be substituted, A hydroxyl group, a thiol group which may be substituted, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), a cyano group,
Examples thereof include a nitro group, an oxo group, and a thioxo group, and these substituents may be substituted at 1 to 5 (preferably 1 to 3) at any substitutable positions. Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent of the “optionally substituted nitrogen-containing heterocycle” for ring A include, for example, aliphatic chain hydrocarbons Groups, alicyclic hydrocarbon groups (non-aromatic cyclic hydrocarbon groups), aryl groups (aromatic hydrocarbon groups), and the like. Examples of the "aliphatic hydrocarbon group" as an example of a hydrocarbon group include:
Examples thereof include linear or branched aliphatic hydrocarbon groups such as an alkyl group, an alkenyl group, and an alkynyl group. Here, examples of the alkyl group include methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-
Examples thereof include a C _1-10 alkyl group such as methylheptyl and nonyl (preferably C _1-6 alkyl). Examples of the alkenyl group include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, and 2-methyl-
1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-
Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl,
-Hexenyl, 3-hexenyl, 4-hexenyl, 5-
And C _2-6 alkenyl groups such as hexenyl.
Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and a _{C 2-6} alkynyl group of 5-hexynyl and the like. Examples of the “alicyclic hydrocarbon group” as an example of the hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group. Here, as the “cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl, C _3-9 cycloalkyl such as cyclononyl and the like. As the “cycloalkenyl group”, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, - cyclopenten-1-cyclohexen-1-yl, and the like _{C 3-9} cycloalkenyl groups such as 1-cycloheptene-1-yl. As the “cycloalkadienyl group”, for example, 2,4-cyclopentadiene-1
-Yl, 2,4-cyclohexadien-1-yl, 2,5
And C _4-6 cycloalkadienyl groups such as -cyclohexadien-1-yl. Examples of the `` aryl group '' as an example of a hydrocarbon group include a monocyclic or fused polycyclic aromatic hydrocarbon group, for example, phenyl, naphthyl,
C such as anthryl, phenanthryl and acenaphthylenyl
_6-14 aryl groups and the like are preferable, and
-Naphthyl, 2-naphthyl and the like are particularly preferred. Examples of the hydrocarbon group include 1,2-dihydronaphthyl, 1,
Same or different two or three groups selected from the above-mentioned alicyclic hydrocarbon groups and aromatic hydrocarbon groups, such as 2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, fluorenyl, etc. And bicyclic or tricyclic hydrocarbon groups derived from the condensation of (preferably two or more groups).

[0007] The "optionally substituted substituent" represented by ring A
"Optionally substituted" as a substituent of "nitrogen heterocycle"
"Hydrocarbon group" in "hydrocarbon group"
Substituents include, for example, (i) halogenated
Lower alkyl group, lower (C_1-6) Alkoxy
-Lower (C_1-6) Alkyl group, lower (C_2-6) Al
Kenyloxy-lower (C_1-6) Alkyl groups, (ii)
Rogen atom (eg, fluoro, chloro, bromo, iodo)
And (iii) a lower alkylene dioxy group (eg,
For example, C such as methylenedioxy and ethylenedioxy
_1-3Alkylenedioxy group), (iv) nitro group,
(V) a cyano group, a thiocyano group, (vi) a hydroxy group,
Thiol group, oxo group, thioxo group, (vii) halogen
Lower alkoxy group, which may be
(C_1-6) Alkoxy-lower (C_1-6) Alkoxy
Group, phenoxy-lower (C_1-6) Alkoxy group, (vi
ii) lower cycloalkyl groups (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, etc.
C_3-6(Ix) halogenated
An optionally substituted lower alkylthio group, lower (C_1-6)
Alkoxy-lower (C_1-6) Alkylthio group, pheno
Kishi-low (C_1-6) Alkylthio group, (x) amino
Groups, (xi) mono-lower alkylamino groups (e.g.
Mono- such as ruamino, ethylamino, propylamino
C_1-6Alkylamino group), (xii) di-lower
Alkylamino group (for example, dimethylamino, diethyla
Di-C such as mino_{1 -6}Alkylamino group), (xi
ii) In addition to one nitrogen atom, nitrogen, oxygen and sulfur
Having one to three heteroatoms selected from yellow atoms
5- to 7-membered cyclic amino groups (for example, pyrrolidino,
5-oxo-1-pyrrolidinyl, piperidino, piperazi
No, morpholino, thiomorpholino, succinimide, 1
-Pyrazolyl, 5-oxo-l-pyrazolidinyl and the like;
Further, the cyclic amino group is condensed with a benzene ring to form a lid.
Or lower alkyl,
(Eg, methyl, ethyl, propyl, isopropyl,
, T-butyl, pentyl, hexyl, etc._1-6Al
Kill, etc.), aralkyl (eg, benzyl, phenethyl, etc.)
C_7-10Aralkyl, etc.), aryl (eg, phenyl,
C such as 1-naphthyl and 2-naphthyl_6-10Aryl
), Formyl, alkanoyl (eg, C such as acetyl)
_2-6Alkanoyl) or the like as a substituent
5 to 7-membered cyclic aminocarbonyl
Groups (specific examples of the 5- to 7-membered cyclic amino are the same as those described above);
To 7-membered cyclic aminocarbonyl-lower (C_1-6) Al
Specific examples of the kill group (5 to 7-membered cyclic amino are the same as described above.
Like) 5- to 7-membered cyclic amino-lower (C_{1 -6}) Archi
Carbonyl group (for specific examples of 5- to 7-membered cyclic amino, see
(Xiv) lower alkyl-carbonylamino
Groups (eg, acetylamino, propionylamino,
C such as tyrylamino_1-6Alkyl-carbonylamido
), Lower (C_1-6) Alkoxy-lower (C
_1-6) Alkyl-carbonylamino groups, benzoylua
Mino group, naphthoylamino group, (xv) aminocarbonyl
An oxy group, (xvi) a mono-lower alkylamino-carbo
Nyloxy group (for example, methylaminocarbonyloxy
Mono-C, such as ethylaminocarbonyloxy
_1-6Alkylamino-carbonyloxy group, etc.),
(Xvii) a di-lower alkylamino-carbonyloxy group
(For example, dimethylaminocarbonyloxy, diethyl
Di-C such as aminocarbonyloxy_1-6Alkyria
A mino-carbonyloxy group), (xviii) lower alkyl
Killsulfonylamino group (for example, methylsulfonyl
Mino, ethylsulfonylamino, propylsulfonylua
C such as mino _1-6Alkylsulfonylamino group
), (Xix) lower alkoxy-carbonyl group (eg,
For example, methoxycarbonyl, ethoxycarbonyl, propo
C such as xycarbonyl and isobutoxycarbonyl
_1-6Alkoxy-carbonyl group), (xx) carbo
Xyl group, (xxi) lower alkyl-carbonyl group (eg,
For example, methyl carbonyl, ethyl carbonyl, butyl carb
C such as Bonyl_1-6Alkyl-carbonyl group),
Lower alkyl-carbonyloxy groups (e.g., methyl
Rubonyloxy, ethylcarbonyloxy, butyl carb
C such as bonyloxy_1-6Alkyl-carbonyloxy
Group)), (xxii) lower cycloalkyl-carbonyl
(For example, cyclopropylcarbonyl, cyclobutylca
Rubonyl, cyclopentylcarbonyl, cyclohexyl
C such as carbonyl_3-6Cycloalkyl-carbonyl
Group), lower cycloalkyl-carbonyloxy (eg,
For example, cyclopropylcarbonyloxy, cyclobutyl
Carbonyloxy, cyclopentylcarbonyloxy,
C such as cyclohexylcarbonyloxy_3-6Cyclo
Alkyl-carbonyloxy group, etc.), (xxiii)
Bamoyl, carbamoyloxy, (xxiv) mono-low
Tertiary alkyl-carbamoyl groups (e.g., methyl carbamo
Yl, ethyl carbamoyl, propyl carbamoyl,
Mono-C such as tylcarbamoyl_1-6Alkyl-cal
Bamoyl group), mono-lower alkyl-carbamoyl
An oxy group (for example, methylcarbamoyloxy, ethyl
Carbamoyloxy, propylcarbamoyloxy,
Mono-C such as tylcarbamoyloxy_{1- 6}Alkyl
-Carbamoyloxy group, etc.), (xxv) di-lower alkyl
A kill-carbamoyl group (e.g., diethylcarbamoy
Di-C such as dibutylcarbamoyl _1-6Alkyl
-Carbamoyl group), di-lower alkyl-carbamo
An yloxy group (eg, diethylcarbamoyloxy,
Di-C such as dibutylcarbamoyloxy_1-6Archi
Carbamoyl group oxy, etc.), (xxvi) lower alkyl
Rusulfonyl group (for example, methylsulfonyl, ethyls
C such as ruphonyl and propylsulfonyl_1-6Alkyl
(Xxvii) lower cycloalkyls
Ruphonyl (eg, cyclopentylsulfonyl, cyclo
C such as hexylsulfonyl_3-6Cycloalkylsul
Fonyl), (xxviii) phenyl, (xxix) naphthyl
Group, (xxx) mono-phenyl-lower alkyl group (eg,
Mono-phenyl-C such as benzyl and phenylethyl
_1-6Alkyl group), mono-phenyl-lower alkyl
Monooxyphenyl such as benzyloxy
Le-C _1-6Alkyloxy group), mono-phenyl
-Lower (C_1-6) Alkyloxy-lower (C_1-6)
Alkyl group, (xxxi) di-phenyl-lower alkyl group
(For example, diphenylmethyl, diphenylethyl, etc.)
Di-phenyl-C_1-6Alkyl group), di-phenyl
A lower alkyloxy group (e.g., diphenylmethyl
Di-phenyl-C such as oxy_1-6Alkyloxy group
), Di-phenyl-lower (C_1-6) Alkyl oxy
Sea low (C_1-6) Alkyl group, (xxxii) mono-olefin
Enyl-lower alkyl-carbonyloxy groups (e.g.
Phenylmethylcarbonyloxy, phenylethylcarbo
Mono-phenyl-C such as niloxy _1-6Alkyl-
Carbonyloxy group), (xxxiii) di-phenyl-
Lower alkyl-carbonyloxy groups (e.g., diphenyl
Methylcarbonyloxy, diphenylethyl carbonyl
Di-phenyl-C such as ruoxy_1-6Alkyl-cal
Bonoxy group), (xxxiv) phenoxy group,
Nylthio group, phenoxy-C_1-6Alkyl group, phenyl
Lucio-C_1-6Alkyl group, (xxxv) mono-phenyl
A lower alkyl-carbonyl group (eg phenylmethyl
Mono-carbonyl such as carbonyl and phenylethylcarbonyl
Enyl-C_1-6Alkyl-carbonyl group), (xx
xvi) di-phenyl-lower alkyl-carbonyl group (eg
For example, diphenylmethylcarbonyl, diphenylethyl
Di-phenyl-C such as carbonyl _1-6Alkyl-ka
Rubynyl group), (xxxvii) benzoyl group, benzoi
Roxy group, benzoyl-C_1-6Alkyl group, benzo
Il-C_1-6Alkoxy group, di-benzoyl-C
_1-6Alkyl group, di-benzoyl-C_1-6Alkoki
Si group, (xxxviii) phenoxycarbonyl group, (xxxix)
(Mono or di) phenyl-lower alkyl-carbamoy
(E.g., phenyl-methylcarbamoyl, phenyl)
Ru-ethylcarbamoyl, diphenyl-methylcarbamo
Yl, diphenyl-ethylcarbamoyl, diphenyl-
(Mono or di) phenyl such as propylcarbamoyl
-C_1-6Alkyl-carbamoyl group, etc.)
Or di) phenyl-lower alkenyl-carbamoyl groups
(E.g., F (mono or di) phenyl-C_2-6Al
Enyl-carbamoyl group), amino-C_1-6Al
Kill-carbamoyl group, mono-C_1-6Alkylamino
-C_1-6Alkyl-carbamoyl group, di-C_1-6A
Lucylamino-C_1-6An alkyl-carbamoyl group,
(Xxxx) phenylcarbamoyl group, naphthylcarbamoy
Group, tetrahydronaphthylcarbamoyl group, (xxxx
i) phenyl-lower alkyl-carbonylamino group (eg
For example, phenyl-methylcarbonylamino, phenyl-
Phenyl-C such as ethylcarbonylamino_1-6Al
Kill-carbonylamino, etc.), diphenyl-lower
A kill-carbonylamino group (for example, diphenyl-methyl
Carbonylamino, diphenyl-ethylcarbonyla
Diphenyl-C such as mino_1-6Alkyl-carbonyl
Amino, etc.), (xxxxii) phenyl-lower alkylamido
(E.g., phenyl-methylamino, phenyl-ethyl)
Phenyl-C such as ruamino_1-6Alkyl amino
Etc.), phenyl-C_1-6Alkylamino-C_1-6A
Alkyl, phenylamino, (xxxxiii) phenyl-lower
Alkylsulfonyl group (for example, phenyl-methylsulfur
Phenyl such as phonyl, phenyl-ethylsulfonyl, etc.
C_1-6Alkylsulfonyl group), phenylsulfo
Nyl-lower alkyl group (for example, phenylsulfonyl-
Phenyls such as methyl and phenylsulfonyl-ethyl
Ruphonyl-C_1-6Alkyl group), (xxxxiv)
Nylsulfonyl group, phenylsulfinyl group, (xxxx
v) a phenyl-lower alkylsulfinyl group (e.g.,
Phenyl-methyl sulfinyl, phenyl-ethyl sulf
Phenyl-C such as finyl_1-6Alkylsulfini
Phenyl-lower alkylsulfo)
Nylamino group (for example, phenyl-methylsulfonylua)
Phenyl such as mino, phenyl-ethylsulfonylamino
Le-C_1-6Alkylsulfonylamino group), (xx
xxvii) phenylsulfonylamino group, (xxxxviii)
Rubonyl, carbonyloxy, carbonylamino, car
Bamoyl, C_1-4Alkyleneamino, C_1-4Archi
Lenoxy, C_1-4Alkylenethio, C_1-4Archi
"Heterocyclic group" which may be bonded via ren or the like
(E.g., "optionally substituted nitrogen-containing compound represented by ring A"
“Optionally substituted heterocycle” as a substituent of “primary ring”
The same as the "heterocyclic group" in the "group"; preferably
Is pyridyl, thienyl, furyl, tetrahydrofuryl
5- or 6-membered heterocyclic group, etc.), (xxxxix) lower
(C_1-4) May be linked via an alkylene
“Optionally substituted thiol group” (eg, represented by ring A)
Substituents of the "optionally substituted nitrogen-containing heterocycle"
The same as the "optionally substituted thiol group"
) And (xxxxx) lower (C_1-4) Alkylene
Which may be bonded through the "optionally substituted water
Acid group "(eg," optionally substituted
"Optionally substituted" as a substituent of "nitrogen heterocycle"
The same as the “hydroxyl group”) [(vii) phenoxy-
Low grade (C_1-6) Alkoxy group, (xxviii) phenyl
Group, (xxix) naphthyl group, (xxx) mono-phenyl-low
Lower alkyl group, mono-phenyl-lower alkyloxy
Group, (xxxi) di-phenyl-lower alkyl group, di-
Nyl-lower alkyloxy group, (xxxii) mono-phenyl
Ru-lower alkyl-carbonyloxy group, (xxxiii) di
-Phenyl-lower alkyl-carbonyloxy group, (xx
xiv) phenoxy group, phenylthio group, phenoxy-C
_1-6Alkyl group, phenylthio-C_1-6Alkyl
Group, (xxxv) mono-phenyl-lower alkyl-carboni
Group, (xxxvi) di-phenyl-lower alkyl-carbo
Nyl group, (xxxvii) benzoyl group, benzoyloxy
Group, benzoyl-C_1-6Alkyl group, benzoyl-C
_1-6Alkoxy group, di-benzoyl-C_1-6Archi
Group, di-benzoyl-C_1-6Alkoxy group, (xxxv
iii) phenoxycarbonyl group, (xxxix) (mono or
Di) phenyl-lower alkyl-carbamoyl group, (mono)
Or di) phenyl-lower alkenyl-carbamoyl
Group, (mono or di) phenyl-lower alkyl-carba
Moyl group, (xxxx) phenylcarbamoyl group, naphthyl
Carbamoyl group, tetrahydronaphthylcarbamoyl
Group, (xxxxi) phenyl-lower alkyl-carbonyl
Amino group, (xxxxii) phenyl-lower alkylamino,
Enyl-C_1-6Alkylamino-C_1-6Alkyl,
Phenylamino, (xxxxiii) phenyl-lower alkyl
Sulfonyl group, phenylsulfonyl-lower alkyl group,
(Xxxxiv) phenylsulfonyl group, phenylsulfini
Group, (xxxxv) phenyl-lower alkylsulfinyl
Group, (xxxxvi) phenyl-lower alkylsulfonylamido
A (xxxxvii) phenylsulfonylamino group and
(Xxxxviii) The heterocyclic group further includes, for example, a halogenated
Lower alkyl (eg, methyl, ethyl)
Propyl, isopropyl, butyl, sec-butyl, te
C such as rt-butyl, pentyl, hexyl, etc._1-6Archi
Lower alkoxy) which may be halogenated
(Eg, methoxy, ethoxy, propoxy, isopro
Poxy, n-butoxy, isobutoxy, sec-butoxy,
C such as tert-butoxy_1-6Alkoxy, etc.), halo
Gen atoms (eg, chlor, brom, iodine, etc.)
Droxy, benzyloxy, amino, mono-lower alkyl
Ruamino (eg, methylamino, ethylamino, pro
Mono-C such as pillamino_1-6Alkyl amino
), Di-lower alkylamino (eg, dimethylamido)
Di-C such as no, diethylamino, etc._1-6Alkylamino
Nitro), lower halogens which may be halogenated
Kill-carbonyl (eg, methylcarbonyl, ethyl
C such as carbonyl and butylcarbonyl_1-6Alkyl
-Carbonyl, etc.), benzoyl, phenyl, etc.
It may have one to four substituents. ]Such
Is raised.

As the above-mentioned "optionally lower alkyl group", for example, a lower alkyl group which may have 1 to 5 halogen atoms (eg, chloro, bromo, iodo, etc.) For example, methyl, ethyl,
Propyl, isopropyl, butyl, sec-butyl, tert-
And C _1-6 alkyl groups such as butyl, pentyl, hexyl and the like). Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2
2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4
-Trifluorobutyl, isobutyl, sec-butyl, tert
-Butyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, hexyl, 6,
6,6-trifluorohexyl and the like. Examples of the “optionally lower halogenated lower alkoxy group” include, for example, 1 to 5 halogen atoms (for example,
Lower alkoxy groups which may have chloro, bromo, iodo and the like (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, se)
and C _1-6 alkoxy groups such as c-butoxy and tert-butoxy). Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, and n. -Propoxy, isopropoxy, n-butoxy, 4,4,4-
Trifluorobutoxy, isobutoxy, sec-butoxy,
Examples include pentyloxy and hexyloxy. Examples of the “optionally lower halogenated lower alkylthio group” include, for example, a lower alkylthio group optionally having 1 to 5 halogen atoms (eg, chloro, bromo, iodo, etc.) (eg, methylthio group). , ethylthio, n- propylthio, isopropylthio, n- butylthio, isobutylthio, sec- butylthio, tert- a C _1-6 alkylthio group such as butylthio), and the like. specific examples include methylthio, difluoromethylthio, tri Fluoromethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, 4,4
4-trifluorobutylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

The “heterocyclic group” in the “optionally substituted heterocyclic group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” for ring A includes, for example, a ring system As a constituent atom (ring atom), a hetero atom 1 to 3 selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like.
At least one species (preferably one or two) (preferably one to four, more preferably one to two)
Aromatic heterocyclic groups, saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), and the like. As the "aromatic heterocyclic group", for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-
Oxadiazolyl, 1,2,4-oxadiazolyl, 1,
3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
5- or 6-membered aromatic monocyclic heterocyclic groups such as triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H- Indazolyl, benzindazolyl, benzoxazolyl, 1,2
-Benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl , Β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl , Imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,
2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like To a 12-membered aromatic condensed heterocyclic group (preferably, a heterocyclic ring in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, or a 5- or 6-membered aromatic monocyclic group as described above) A heterocyclic ring in which two identical or different heterocyclic groups of a heterocyclic group are fused, more preferably a heterocyclic ring in which a 5- or 6-membered aromatic monocyclic heterocyclic group is fused with a benzene ring)
And the like. Examples of the “non-aromatic heterocyclic group” include 3- to 8-membered (preferably 5 to 6) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4
A non-aromatic heterocyclic group in which a part or all of the above-mentioned aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group is saturated, such as tetrahydroisoquinolyl. Examples of the substituent which the “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent of the “optionally substituted nitrogen-containing heterocyclic ring” for ring A may have include For example, the substitution which the "hydrocarbon group" in the "optionally substituted hydrocarbon group" as a substituent of the "optionally substituted nitrogen-containing heterocyclic ring" for ring A may have And the same as the group.

In the ring A, "including optionally substituted substituents"
"Optionally substituted" as a substituent of "nitrogen heterocycle"
As the "acyl group", for example, a group represented by the formula-(C = O) -R,-
(C = O) NRR ',-(C = S) R,-(C = S) N
RR ', -SO-R, -SO ₂-R, -SO₂-NR
R ',-(C = O) OR or-(C = S) OR
[R and R 'are the same or different and each represents a hydrogen atom;
Or an optionally substituted hydrocarbon group or
Represents an optionally substituted heterocyclic group, or R and R ′ are
May have a substituent together with the adjacent nitrogen atom
Or a nitrogen-containing heterocyclic group. A group represented by
[Preferably, formulas-(C = O) -R,-(C = O) NR
R ', -SO₂-R, -SO₂-NRR ',-(C =
O) (C = O) OR or-(C = O) OR
Groups). In the above formula, R and
“Optionally substituted hydrocarbon group” represented by R ′
And "optionally substituted heterocyclic group"
"Optionally substituted nitrogen-containing heterocyclic group represented by ring A
"Optionally substituted hydrocarbon" as a substituent of "ring"
Group '' and `` optionally substituted heterocyclic group ''
Things. And R and R 'are linked to each other
Formed with an adjacent nitrogen atom
"Nitrogen-containing heterocyclic group"
As, for example, a nitrogen atom, an acid other than one nitrogen atom
1 to 1 heteroatoms selected from elementary atoms and sulfur atoms
5- to 7-membered cyclic amino group which may have three (eg,
For example, pyrrolidino, piperidino, piperazino, morpholi
Thiomorpholino, etc .; and the cyclic amino group is
Which may be condensed with a benzene ring).
As a substituent which the “nitrogen-containing heterocyclic group” may have
Is, for example, "including an optionally substituted group represented by ring A"
"Optionally substituted" as a substituent of "nitrogen heterocycle"
"Hydrocarbon group" in "hydrocarbon group"
And the same as the above substituents.
Lower alkyl (eg, methyl, ethyl, propyl, isop
Propyl, butyl, t-butyl, pentyl, hexyl, etc.
C_1-6Alkyl, etc.), aralkyl (eg, benzyl,
C such as enetyl_7-10Aralkyl etc.), aryl
(Examples include C such as phenyl, 1-naphthyl, and 2-naphthyl)
_6-10Aryl, etc.), formyl, alkanoyl (eg,
C such as acetyl_2-6Alkanoyl and the like are preferably used
Can be.

The “optionally substituted amino group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” for ring A includes, for example, a group represented by the formula —NR ^a R ^b [R ^a and R ^b is the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R ^a and R ^b are It may combine with each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. And the like. In the above formula, the “optionally substituted hydrocarbon group”, the “optionally substituted heterocyclic group” and the “optionally substituted acyl group” represented by R ^a and R ^b are the same as those described above. "Optionally substituted hydrocarbon group", "optionally substituted heterocyclic group", and "optionally substituted heterocyclic group" as substituents of "optionally substituted nitrogen-containing heterocycle" represented by ring A The same as the "optionally substituted acyl group". Examples of the “nitrogen-containing heterocyclic group” in the “optionally substituted nitrogen-containing heterocyclic group” formed by R ^a and R ^b being bonded to an adjacent nitrogen atom include, for example, one A 5- to 7-membered cyclic amino group optionally having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom (for example, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, Succinimide or the like; and the cyclic amino group is
Which may be condensed with a benzene ring to form a phthalimide or the like). Examples of the substituent which the “nitrogen-containing heterocyclic group” may have include, for example, “ As the substituents of the optionally substituted nitrogen-containing heterocycle, the same substituents as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have, and the like. Is, among others, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.),
Aralkyl (eg, C _7-10 such as benzyl, phenethyl, etc.)
Aryl and the like (eg, C _6-10 aryl such as phenyl, 1-naphthyl, and 2-naphthyl), formyl, alkanoyl (eg, C _2-6 alkanoyl such as acetyl) are preferably used.

The “optionally substituted hydroxyl group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” for ring A includes, for example, a group represented by the formula —O—R ^c [where R ^c is hydrogen Represents an atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted. And the like. In the above formula,
An “optionally substituted hydrocarbon group” for R ^c ,
As the "hydrocarbon group", "heterocyclic group" and "acyl group" in the "optionally substituted heterocyclic group" and "optionally substituted acyl group", the ""Optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" and "optionally substituted acyl group" as substituents of "optionally substituted nitrogen-containing heterocycle""Hydrocarbongroup" and "Heterocyclic group"
And the same as the “acyl group”. Here, "hydrocarbon group", "heterocyclic group" and "acyl group"
May have a substituent at any substitutable position,
Examples of such a substituent include a “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A described above. (I) exemplified as an optionally substituted substituent
To (xxxxviii).

In the ring A, "including optionally substituted substituents"
"Optionally substituted" as a substituent of "nitrogen heterocycle"
Examples of the "thiol group" include, for example, a group represented by the formula -SR^c(here
The sulfur atom may be oxidized, and -SO-, -SO₂
-Or the like) or -SS-R^c[R
^cIs a hydrogen atom, an optionally substituted hydrocarbon group,
An optionally substituted heterocyclic group or an optionally substituted
Shows an acyl group. And the like. Previous
In the formula, R^cA hydrocarbon which may be substituted
Element group "," optionally substituted heterocyclic group "and"
"Hydrocarbons" in the "Acyl group which may be substituted"
Groups, "heterocyclic group" and "acyl group"
"Optionally substituted nitrogen-containing heterocyclic group represented by ring A
"Optionally substituted hydrocarbon" as a substituent of "ring"
Group "," optionally substituted heterocyclic group "and" substituted
A "hydrocarbon group" in the "optionally substituted acyl group",
Examples of the same as "heterocyclic group" and "acyl group" include
It is. Here, "hydrocarbon group", "heterocyclic group" and
An “acyl group” has a substituent at any substitutable position.
Such a substituent may be represented by the aforementioned ring A.
Substituent of the "optionally substituted nitrogen-containing heterocycle"
In "optionally substituted hydrocarbon group"
Examples are given as substituents that the “hydrocarbon group” may have
(I) to (xxxxviii).
“Nitrogen-containing heterocycle optionally substituted” represented by ring A
As the substituent, an optionally substituted hydrocarbon group
Preferable is, among others, an optionally substituted C _1-6A
Alkyl groups are preferred, and methyl is particularly preferred.

In the above formula, R ¹ and R ² each represent an optionally substituted amino group. As the “optionally substituted amino group” represented by R ¹ and R ² , “optionally substituted amino group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A The same as the “amino group”, but the “optionally substituted amino group” for R ¹ may be substituted with 1 to 2 optionally substituted hydrocarbon groups. is preferable, also an amino group, more preferably an amino, R ²
The “optionally substituted amino group” represented by is one selected from a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, and an acyl group which may be substituted. And an amino group which may have an optionally substituted acyl group as a substituent. R ¹ is R ² and / or X
And may form a ring (eg, a 5- to 8-membered nitrogen-containing heterocyclic ring or the like).

In the above formula, X is an atom constituting the straight-chain portion.
The numbers 1 to 4 indicate spacers. X represents a “linear part”
As a spacer having 1 to 4 atoms constituting the component ",
(1)-(CH_Two)_f1-(F1 represents an integer of 1 to 4),
(2)-(CH_Two)_g1−X¹− (CH_Two)_g2− (G1 and g2 are the same
Or differently represent an integer of 0 to 3. Where the sum of g1 and g2
Is 0-3. X¹Is NH, O, S, SO or SO_TwoShows
), (3)-(CH_Two)_h1−X¹− (CH_Two)_h2−X^Two− (CH_Two)_h3−
(H1, h2 and h3 are the same or different and each represents an integer of 0 to 2
Show. However, the sum of h1, h2 and h3 is 0-2. X¹You
And X^TwoIs NH, O, S, SO or SO respectively_TwoIs shown. However
And when h2 is 0, X¹And X ^TwoAt least one of the preferred
Or NH. ) And some saturated divalent groups
A linear moiety such as a divalent group in which a bond has been converted to an unsaturated bond
Is a divalent group having 1 to 4 atoms.
Can be X is C_1-4Alkylene is preferred,
Among them, methylene and the like are preferably used. Indicated by X
The divalent group to be formed may be at any position (preferably a carbon atom
Above) may have a substituent.
Is, for example, "including an optionally substituted group represented by ring A"
"Optionally substituted" as a substituent of "nitrogen heterocycle"
"Hydrocarbon group" in "hydrocarbon group"
And the same as the above substituents.
Low grade (C_1-6) Alkyl (eg, methyl, ethyl, pro
Pill, isopropyl, butyl, isobutyl, sec-butyl
Chill, tert-butyl, pentyl, isopentyl, ne
Pentyl, hexyl, etc.), low grade (C_3-7) Cyclo
Alkyl (eg, cyclopropyl, cyclobutyl, cyclo
Pentyl, cyclohexyl, cycloheptyl, etc.), e
Lumil, low grade (C_2-7) Alkanoyl (eg, acetyl
, Propionyl, butyryl, etc.), lower (C_1-6)
Lower alkoxy-carbonyl, lower (C_1-6) Lower class
Lucoxy, hydroxyl, oxo and the like are preferred.

Among the compounds represented by the formula (I) or salts thereof (hereinafter sometimes referred to as compound (I)), the compounds represented by the formula (I ')

Embedded image [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, and R ¹ is bonded to R ³ or R ⁴ to form a ring. R ³ represents a hydrogen atom or an optionally substituted acyl group, and R ⁴ represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted Represents an acyl group; R ³ and R ⁴ may combine to form a cyclic amino group; n represents an integer of 1 to 4; Or a salt thereof (hereinafter may be referred to as compound (I ′)), and among the compounds (I ′), a compound represented by the formula (I ″)

Embedded imageWherein ring B is a pyrimidine which may be further substituted
A ring;¹Represents an amino group which may be substituted
Then R¹Is R³Or R⁴To form a ring
Well, R³Is a hydrogen atom or an optionally substituted
R represents a sil group;⁴Is an optionally substituted alkyl
Group, an optionally substituted cyclic hydrocarbon group,
An optionally substituted heterocyclic group or an optionally substituted
And R represents ³And R⁴Binds to form a cyclic amino group
N may be an integer of 1 to 4. ]
Or a salt thereof [hereinafter referred to as compound (I ″)
Is sometimes preferred).

The "pyrimidine ring" in the "optionally substituted pyrimidine ring" for ring B is represented by the formula (I ')
Or, in addition to the substituents specified in (I ″), the compound may further have a substituent, and examples of such a substituent include those of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A. The same substituents as the “nitrogen-containing heterocycle” may have are exemplified. In the above formula, ring B is a group represented by the formula

Embedded image [In the formula, R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group, and ring B ′ further has a substituent. Represents an optionally substituted pyrimidine ring. ] Is preferable. In the above formula, the “optionally substituted hydrocarbon group”, the “optionally substituted amino group” and the “optionally substituted heterocyclic group” represented by R ⁵ are represented by ring A. `` Optionally substituted hydrocarbon group '' as a substituent that the `` nitrogen-containing heterocycle '' of the `` optionally substituted nitrogen-containing heterocycle '' may have,
Examples include the same as the “optionally substituted amino group” and the “optionally substituted heterocyclic group”. Among them, as R ⁵ , an optionally substituted alkyl group, a substituted or unsubstituted alkyl group, And an aryl group which may be preferred,
Optionally substituted C _1-6 alkyl group, is preferable and a good C _6-10 aryl group which may be substituted, among others, methyl, phenyl (more preferably methyl) and the like are preferably used. R ⁵ is a hydrogen atom, a lower (C _1-6 ) alkyl group, or one or two lower (C
_An amino group which may be substituted with _1-6 ) alkyl is also preferably used, and a lower (C _1-6 ) alkyl group, particularly methyl is preferably used.

In the above formula, R ¹ represents an optionally substituted amino group, and R ¹ may be bonded to R ³ to form a ring. The “optionally substituted amino group” represented by R ^{1 includes the} “optionally substituted amino group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A And the like, but 1-2
And an amino group which may be substituted with a plurality of optionally substituted hydrocarbon groups. When R ¹ is bonded to R ³ to form a ring, compound (I ′) and compound (I ″) are represented by the formula

Embedded image [Wherein, ring D represents a 5- to 8-membered ring which may be substituted, and other symbols have the same meanings as described above] or a salt thereof.

When R ¹ is bonded to R ⁴ to form a ring, compound (I ′) and compound (I ″) have the formula

Embedded image [Wherein, ring D represents a 5- to 8-membered ring which may be substituted, and other symbols have the same meanings as described above] or a salt thereof. Here, as the substituent which the “5- to 8-membered ring” in the “optionally substituted 5- to 8-membered ring” for ring D may have, the “substituted or substituted” for ring A And the same substituents as those which the "nitrogen-containing heterocycle" of "optionally nitrogen-containing heterocycle" may have. Ring D may be bonded to R ³ or R ⁴ as a substituent to form a ring.

In the above formula, R ³ represents a hydrogen atom or an optionally substituted acyl group. In the above formula, the “optionally substituted acyl group” represented by R ³ may be a “substituted substituted” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” represented by the aforementioned ring A. And acyl groups which may be used. In the above formula, R ⁴ represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group (preferably an optionally substituted alkyl group, An optionally substituted aryl group, an optionally substituted acyl group, etc.), and more preferably an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted acyl group. And R ³ and R ⁴ may combine to form a cyclic amino group. In the above formula, the “optionally substituted hydrocarbon group”, the “optionally substituted heterocyclic group” and the “optionally substituted acyl group” represented by R ⁴ include the above-mentioned ring A `` Optionally substituted hydrocarbon group '', `` optionally substituted heterocyclic group '' and `` optionally substituted And the same as the "good acyl group". Also, R
As the "optionally substituted alkyl group" and "optionally substituted aryl group" as the ⁴ was exemplified as the "optionally substituted hydrocarbon group", "optionally substituted Specific examples include an “alkyl group” and an “optionally substituted aryl group”.
As the "optionally substituted alkyl group" and "hydrocarbon group which may be substituted cyclic" as ^4,
The “optionally substituted alkyl group” and the “optionally substituted alicyclic hydrocarbon group and the optionally substituted aryl group” exemplified as the “optionally substituted hydrocarbon group” Is a specific example. Among them, as R ⁴ , an alkyl group which may be substituted,
An aryl group which may be substituted, an acyl group which may be substituted and the like are preferable, and when R ⁴ is an aryl group which may be substituted (preferably a phenyl group which may be substituted), As the substituent of the “aryl group”, the “optionally substituted thiol group” as a substituent of the “optionally substituted nitrogen-containing heterocycle” represented by ring A (preferably a compound of the formula —S— Such as a group represented by R ^c ).

When R ³ and R ⁴ are combined to form a cyclic amino group, the “cyclic amino group” is, for example, selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to one nitrogen atom. 5- to 7-membered cyclic amino group optionally having 1 to 3 hetero atoms (for example, pyrrolidino,
Piperidino, piperazino, morpholino, thiomorpholino, succinimide and the like; and the cyclic amino group may be condensed with a benzene ring to form phthalimide and the like. Examples of the optionally substituted substituent include, for example, a “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A And the like may be the same as the substituents that may be possessed, among which lower alkyl (eg, methyl,
C _1-6 alkyl such as ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc., aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc.), aryl (eg, phenyl, 1- C _6-10 aryl such as naphthyl and 2-naphthyl, etc.), formyl, alkanoyl (eg, C _2-6 alkanoyl such as acetyl and the like) are preferably used.

When R ³ and R ⁴ do not combine to form a cyclic amino group, examples of the combination of R ³ and R ⁴ include a case where R ³ is a hydrogen atom and R ⁴ is substituted. When R ³ is a hydrogen atom and R ⁴ is an optionally substituted cyclic hydrocarbon group; when R ³ is a hydrogen atom and R ⁴ is an optionally substituted heterocyclic group; When R ³ is a hydrogen atom and R ⁴ is an optionally substituted acyl group;
R ³ is an optionally substituted acyl group and R ⁴ is an optionally substituted alkyl group; R ³ is an optionally substituted acyl group, and R ⁴ is R ³ is an optionally substituted acyl group, and R ⁴ is an optionally substituted heterocyclic group; R ³ is optionally substituted An acyl group, wherein R ⁴ is an optionally substituted acyl group; and the like. In the above formula, n is 1 to 4
(Preferably 1). Among the compounds represented by the formula (I ′) or salts thereof, the compounds represented by the formula (Ia)

Embedded image Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group; E represents an optionally substituted divalent cyclic hydrocarbon group or an optionally substituted divalent heterocyclic group;
, - - -O is _{S -, - SO -, -} SO 2 -, - S-S
—, —CO—NH—, —CO—O—, or C _1-4 alkylene; Ra represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Indicates an integer of 4. Or a salt thereof (hereinafter may be referred to as compound (Ia)); Formula (Ia ′)

Embedded image Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group, E ′ represents an optionally substituted divalent cyclic hydrocarbon group, and Ya ′ represents —O—, —S—, —SO—, -SO
_2- , -SS- or -CO-NH-;
a ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ^{5a ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. It shows an amino group, and n shows the integer of 1-4. However, when Ya 'is -O-, Ra' is not ethyl. Or a salt thereof [hereinafter may be referred to as compound (Ia ′)]; Formula (Ib)

Embedded image Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and n represents an integer of 1 to 4. Or a salt thereof (hereinafter may be referred to as compound (Ib)); Formula (Ib ′)

Embedded image Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R ^{5b ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. Represents an amino group, and n represents an integer of 1 to 4. Or a salt thereof (hereinafter may be referred to as compound (Ib ′)); Formula (Ic)

Embedded image [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, F represents a nitrogen-containing heterocyclic group which may be further substituted, Rc represents a hydrocarbon group which may be substituted or an acyl group which may be substituted, and n represents an integer of 1 to 4. Or a salt thereof (hereinafter, sometimes referred to as compound (Ic)); and the like.

In the above formula (Ia) or (Ia '), R ³
Is preferably a hydrogen atom. The formula (I)
In a), E represents an optionally substituted divalent cyclic hydrocarbon group or an optionally substituted divalent heterocyclic group.
Here, the “divalent cyclic hydrocarbon group” in the “optionally substituted divalent cyclic hydrocarbon group” represented by E includes the “optionally substituted cyclic hydrocarbon group” represented by the aforementioned ring A. In the “optionally substituted alicyclic hydrocarbon group” and the “optionally substituted aryl group” exemplified as the “optionally substituted hydrocarbon group” as the substituent of the “nitrogen heterocycle” A divalent group formed by removing one hydrogen atom from the “alicyclic hydrocarbon group” and the “aryl group”; and the “optionally substituted divalent cyclic hydrocarbon” represented by E The “divalent cyclic hydrocarbon group” in the “group” is a group represented by the formula —Y specified in the above formula (Ia).
aside from the group represented by a-Ra, the “alicyclic hydrocarbon group” and the “aryl group” in the above “optionally substituted alicyclic hydrocarbon group” and “optionally substituted aryl group” May further have the same substituents as the substituents that may have. The “divalent heterocyclic group” in the “optionally substituted divalent heterocyclic group” represented by E includes the “optionally substituted nitrogen-containing heterocyclic group” represented by the aforementioned ring A. And a divalent group formed by removing one hydrogen atom from the "heterocyclic group" in the "optionally substituted heterocyclic group" as a substituent of " The “divalent heterocyclic group” in the “optionally divalent heterocyclic group” is a group represented by the formula (I)
In addition to the group represented by the formula -Ya-Ra specified in a), the same substituent as the substituent which the "heterocyclic group" in the above-mentioned "optionally substituted heterocyclic group" may have It may further have a group. As E, a divalent aromatic hydrocarbon group which may be substituted, a divalent aromatic heterocyclic group which may be substituted, and the like are preferable, and among them, phenylene which may be substituted is preferable. Used. Examples of the C _1-4 alkylene represented by Ya include methylene, dimethylene, trimethylene, and tetramethylene, and among them, methylene is preferably used. As Ya, -O-, -S
-, - SO -, - SO 2 - is preferable, and among them,
-O-, -S- and the like are preferably used.

In the above formula (Ia '), E' represents an optionally substituted divalent cyclic hydrocarbon group. Here, as the “divalent cyclic hydrocarbon group” in the “optionally substituted divalent cyclic hydrocarbon group” represented by E ′, the “divalent cyclic hydrocarbon group” represented by the aforementioned ring A may be “optionally substituted”. "Optionally substituted alicyclic hydrocarbon group" and "optionally substituted aryl group" exemplified as "optionally substituted hydrocarbon group" as substituents of "nitrogen-containing heterocycle"
And a divalent group formed by removing one hydrogen atom from the “alicyclic hydrocarbon group” and the “aryl group”, and the “optionally substituted divalent cyclic group” represented by E ′ "Divalent cyclic hydrocarbon group" in "hydrocarbon group"
Is the formula -Ya'- specified in the formula (Ia ').
In addition to the group represented by Ra ′, “alicyclic hydrocarbon group” and “aryl group” in the above “optionally substituted alicyclic hydrocarbon group” and “optionally substituted aryl group” May further have the same substituent as the substituent which may have. E ′ is preferably a divalent aromatic hydrocarbon group which may be substituted, and the like.
Among them, phenylene which may be substituted is preferably used. Moreover, as Ya ', -O-, -S
-, - SO -, - SO 2 - is preferable, and among them,
-O-, -S- and the like are preferably used. In the above formula,
As the “hydrocarbon group” and “heterocyclic group” in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by Ra or Ra ′, The "optionally substituted hydrocarbon group" as a substituent of the "optionally substituted nitrogen-containing heterocyclic ring" and the "hydrocarbon group" and "optionally substituted heterocyclic group" And the same as the “heterocyclic group”. Here, "hydrocarbon group" and "heterocyclic group"
May have a substituent at any substitutable position,
Examples of such a substituent include a “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent of the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A described above. (I) exemplified as an optionally substituted substituent
To (xxxxviii). As Ra or Ra ′, a cyclic hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, and the like are preferable, and among them, an aromatic hydrocarbon group which may be substituted, And an aromatic heterocyclic group, and particularly preferably an optionally substituted phenyl. In the formula (Ia ′), R ^{5a ′} is a hydrogen atom,
And a lower alkyl group or an amino group which may be substituted with one or two lower alkyl groups. Represented by R ^{5a 'As} the "lower alkyl group" and "one or two lower alkyl optionally substituted amino group" represented by R ⁵ "lower alkyl group" and "1-2 The same as those for the "amino group optionally substituted with lower alkyl" are used. In addition, ring B has the formula

Embedded image Wherein R ^{5a ′} is as defined above. ] Is preferable.

In the above formula (Ib) or (Ib '), R
^3bRepresents an optionally substituted acyl group. here,
R^3bRepresented by the "optionally substituted acyl group"
Then R³Represented by an `` optionally substituted acyl
The same groups as those described above are used, but R ^3bAs the formula
-(C = O) -R '[R' is a hydrogen atom,
Hydrocarbon group or heterocyclic group which may be substituted
Is shown. And the like are preferred. Also, R '
Are preferably substituted hydrocarbon groups.
And further optionally substituted cyclic hydrocarbon groups
(Eg, alicyclic hydrocarbon group, aryl group, etc.) are preferred.
And optionally substituted aromatic hydrocarbon groups (eg,
And the like, and more preferably,
Phenyl which may be optionally used is preferably used. Previous
In the formula (Ib) or (Ib ′), Yb is a bond or
It represents alkylene which may be substituted. Where Yb
As "optionally substituted alkylene"
Is R⁴An alkyl which may be substituted
Divalent group formed by removing one hydrogen atom from the group
And the like.
"Alkylene" in "alkylene" is the above-mentioned formula (I
b) or Rb specified in (Ib ')
Other than the group⁴The “optionally substituted
The alkyl group in the alkyl group may have
It may further have the same substituent as the substituent. Yb
Represents an optionally substituted C_1-4Alkylene
Are preferred, and among them, methylene and the like are preferably used.
Can be In the formula (Ib) or (Ib ′), Rb is
An optionally substituted cyclic hydrocarbon group or substituted
Represents a heterocyclic group which may be substituted. "Substituted for Rb
Cyclic hydrocarbon group "
As the "group", the "substituted"
Optionally substituted as a substituent of a "nitrogen-containing heterocycle"
"Optionally substituted hydrocarbon group"
Optionally substituted alicyclic hydrocarbon group "and" substituted
Alicyclic hydrocarbon group '' and
And "aryl groups". Indicated by Rb
"Heterocycle" in "optionally substituted heterocyclic group"
As the "group", the "substituted"
Optionally substituted as a substituent of a "nitrogen-containing heterocycle"
The same as the "heterocyclic group" in the "optionally heterocyclic group"
Is included. Here, “cyclic hydrocarbon group” and
“Heterocyclic group” has a substituent at any substitutable position.
Such a substituent may be represented by the aforementioned ring A.
Substituent of the "optionally substituted nitrogen-containing heterocycle"
In "optionally substituted hydrocarbon group"
Examples are given as substituents that the “hydrocarbon group” may have
(I) to (xxxxx) substituents. Rb
As an aromatic hydrocarbon group which may be substituted,
An aromatic heterocyclic group which may be substituted is preferable, and
Or an optionally substituted phenyl group, etc.
Commonly used. In the above formula (Ib '), R^{5b '}Is hydrogen field
A lower alkyl group or one or two lower alkyl groups.
Shows an amino group which may be substituted. R^{5b '}Indicated by
"Lower alkyl group" and "1-2 lower alkyl groups"
An amino group which may be substituted with⁵Indicated by
"Lower alkyl group" and "1-2 lower alkyl
Amino group which may be substituted with a kill ''
Used. In addition, ring B has the formula

Embedded image Wherein R ^{5b ′} is as defined above. ] Is preferable.

In the above formula (Ic), F represents a nitrogen-containing heterocyclic group which may be further substituted. Here, as the “nitrogen-containing heterocyclic group” in the “nitrogen-containing heterocyclic group which may be further substituted” represented by F, a 5- to 6-membered monocyclic nitrogen-heterocyclic group, a 5- to 6-membered A nitrogen heterocyclic group formed from a condensed ring of a monocyclic nitrogen heterocycle and 5 to 8 members (preferably 5 to 6 members; more preferably a benzene ring and the like), and an atom constituting a ring system ( Ring atom) may contain, in addition to the specified carbon and nitrogen atoms, one or two heteroatoms selected from oxygen, sulfur, nitrogen and the like. It is preferable that the compound does not contain a hetero atom other than the carbon atom and the nitrogen atom. Among them, succinimide, phthalimide and the like are preferably used. More specifically, as the “nitrogen-containing heterocyclic group”, a succinimide which may further have a substituent other than the substituent Rc;

Embedded image [In the formula, F 'represents a 5- to 8-membered ring which may be further substituted. A group represented by the formula:

Embedded image [In the formula, F ′ represents a benzene ring which may be further substituted. 55. The compound according to claim 54, which is a group represented by the formula: The "nitrogen-containing heterocyclic group" may have a substituent other than the specified substituent Rc. Examples of such a substituent include "optionally substituted nitrogen-containing heterocyclic group" represented by ring A. As the substituent for the “heterocycle”, the same substituents as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have, and the like can be mentioned. In the formula (Ic), Rc represents a hydrocarbon group which may be substituted or an acyl group which may be substituted. Where R
As the “optionally substituted acyl group” for c, the “optionally substituted acyl group” for R ³
The same is used, but Rc is represented by the formula-(C
ＯO) NRR '[R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R' is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted R and R ′ may be bonded to each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. And the like are preferably used. The “optionally substituted hydrocarbon group” represented by Rc includes, for example, “optionally substituted hydrocarbon group” as a substituent of “optionally substituted nitrogen-containing heterocyclic ring” represented by ring A. And the same as the “hydrogen group”.

The compound (I) includes 2-methyl-5-({2-
[(2-nitrophenyl) sulfanyl] anilino} methyl) -4
-Pyrimidineamine; (4-amino-2-methyl-5-pyrimidinyl) methyl {2-[(4-methoxyphenyl) sulfanyl] phenyl} formamide; N-[(4-amino-2-methyl-5-pyrimidinyl) Methyl] -N-benzyl-4-[(3,5-diphenyl-4-isoxazolyl) methyl] benzamide; (4-amino-2
-Methyl-5-pyrimidinyl) methyl [2- (propyldisulfanyl) phenyl] formamide; N-[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]-
N- [2- (phenylsulfanyl) phenyl] amine; N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (4-bromophenylsulfanyl) phenyl] amine; N- [(4-amino-2-
Methyl-5-pyrimidinyl) methyl] -N- [2-
[(2-Methoxyphenyl) sulfanyl] phenyl]
Amine; N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (4-methoxyphenoxy) phenyl] amine; N-[(4-amino-2-methyl-5- Pyrimidinyl) methyl] -N- [2-[(4-
Methoxyphenyl) sulfanyl] phenyl] amine;
N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(2-nitrophenyl) sulfanyl] phenyl] amine; N-[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] -N- [2-
[(3-methoxyphenyl) sulfanyl] phenyl]
Amine; 2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] -N- (2,2-diphenylethyl) benzoic acid amide; (4-amino-2-methyl-5-pyrimidinyl) ) Methyl (2-benzylsulfanylmethylsulfanylphenyl) formamide; N-
[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N'-benzhydryl-N-benzyl terephthalamide; N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl −N ′ − (1, 2, 2,
3,4-tetrahydro-1-naphthalenyl) terephthalamide; N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(3,5-diphenyl-1H-pyrazole- 1-yl) methyl] benzamide; N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-6- (3,5-diphenyl-1H-pyrazol-1-yl) hexaneamide 4-[(allyloxy) methyl] -N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
Benzyl-benzamide; 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N, N-dibenzyl-1,3-dioxo-5-isoindolinecarboxamide; 2-[(4-amino-2 -Methyl-5-pyrimidinyl) methyl] -N- (2,2-diphenylethyl)-
1,3-dioxo-5-isoindolinecarboxamide; 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- (3,3-diphenylpropyl)-
1,3-dioxo-5-isoindolinecarboxamide; and the like, and salts thereof, are particularly preferably used.

Compound (I) wherein compound (I) is
Compound (I ′) and compound (I ″) or compound (Ia), compound (Ia ′), compound (Ib), compound (Ib ′) and compound (Ic) are included.
Is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, a compound that is converted into compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like. , A compound which undergoes hydrolysis by gastric acid or the like to be converted into the compound (I). As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated (for example, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.), Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Or dimethylaminomethylcarbonylated compound) or the carbohydrate of compound (I) Sill group is esterified,
An amidated compound (for example, the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) is available from Hirokawa Shoten 19
The compound may be converted to compound (I) under physiological conditions as described in “Development of Pharmaceuticals”, 1990, Vol. 7, Molecular Design, pp. 163 to 198.

Examples of the salt of the compound (I) include pharmacologically acceptable salts, such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, and the like.
Gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid,
Phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid,
Acid addition salts with acids such as sulfamic acid and sulfuric acid, for example, metal salts such as sodium, potassium, magnesium and calcium, for example, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine and the like Organic salts and the like. Compound (I) may be a hydrate. When an optically active form of compound (I) is required,
For example, it can be obtained using optically active starting materials or by resolving the racemic form of the compound using conventional methods.

Compound (I) can be prepared by a method known per se (for example, "New Vitaminology", The Vitamin Society of Japan, 1969,
On page 131-190) or a method analogous thereto. Compound (I) [among others, compound (I ″) or compound (Ia), compound (Ia ′), compound (Ib), compound (Ib ′) and compound (Ic) having a novel structure] For example, it can be manufactured by the following method. Each compound described in the following reaction formula, as long as it does not inhibit the reaction,
A salt may be formed, and examples of such a salt include those similar to the salt of compound (I). Reaction formula I (wherein, R ⁵ represents the same group as R ³ or R ⁴ described above;
⁶ to R ⁸ each represent the same group as the “hydrogen atom”, “optionally substituted hydrocarbon group” or “optionally substituted heterocyclic group” represented by R, and R ⁹ represents the aforementioned The same group as the "substituent which the hydrocarbon group in the optionally substituted hydrocarbon group as the substituent of the optionally substituted nitrogen-containing heterocyclic ring represented by ring A may have" And R ¹⁰ are the above-mentioned “substituents which the heterocyclic group which may be substituted in the optionally substituted heterocyclic group as a substituent of the optionally substituted nitrogen-containing heterocyclic ring represented by ring A” R ¹¹ represents the same group as R ^c described above; W represents a hydrogen atom removed from an acid (preferably a halogen atom); Z represents CO or SO ₂ ; ¹ to M ⁷ represent a leaving group, and other symbols have the same meanings as described above. )

Reaction formula I

Embedded image

Embedded image

Hereinafter, each step will be described in detail. (Step 1) Compound (II) can be produced by reacting compound (VIII) with compound (XI).
This condensation reaction is carried out without solvent or in an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, acetone, tert-butanol, hexane, toluene, benzene, dichloromethane or the like, or a mixed solvent thereof. It is carried out in the temperature range from 150C to 150C. Reaction times are from about 1 hour to about 100 hours. Compound (XI) is generally used in an amount of about 1 to 30 mol per 1 mol of compound (VIII). Further, by adding a base such as potassium carbonate, the reaction can be allowed to proceed smoothly.

(Step 2) The compound (IX) is reacted with the carbonyl compound (XII) and then reduced to give the compound (II)
Can be manufactured. This condensation reaction is carried out in an inert solvent,
For example, methanol, ethanol, benzene, toluene,
About 0 ° C. in chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof.
It is carried out in a temperature range from to 150 ° C. Reaction time is about 1
Hours to about 50 hours. Compound (XII) is generally used in an amount of about 1 to 5 mol per 1 mol of compound (IX). Further, by adding an acid and removing generated water, the reaction can proceed smoothly. The reduction reaction can be performed by a means known per se. For example,
When sodium triacetoxyborohydride or the like is used as the reducing agent, an inert solvent such as methanol, ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethyl The reaction is carried out in a temperature range of about 0 ° C. to 100 ° C. in formamide, dimethyl sulfoxide or the like, or a mixed solvent thereof. Reaction times are from about 1 hour to about 50 hours. The reducing agent is usually used in an amount of about 1 to 1 mol of the compound (IX).
To 5 mol. In addition, by performing a condensation reaction in the presence of a reducing agent, compound (II) can be obtained without isolating the imine derivative.

(Step 3) Compound (II) and compound (XII
Compound (IV) can be produced by reacting I) or compound (XIV). The condensation reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether,
Dimethoxyethane, hexane, toluene, benzene, dichloromethane, chloroform, 1,2-dichloroethane,
Ethyl acetate, dimethylformamide, dimethylsulfoxide, pyridine and the like, or a mixed solvent thereof,
It is performed in a temperature range of about 0 ° C to 130 ° C. Reaction times are from about 30 minutes to about 50 hours. Compound (XIII)
Alternatively, compound (XIV) is generally used in an amount of about 1 to 2 mol per 1 mol of compound (II). Optionally, as a base,
The reaction can proceed smoothly using pyridine, 4-dimethylaminopyridine, triethylamine, or the like.

(Step 4) Compound (IX) and compound (XII)
Compound (III) can be produced by reacting I) or compound (XIV). This condensation reaction is performed in step 3.
Is performed in the same manner as described above.

(Step 5) When Z = CO, the compound (II)
Compound (II) can be produced by reducing I). This reduction reaction can be carried out by a means known per se, and in the presence of a reducing agent, for example, lithium aluminum hydride or the like, an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, hexane, toluene, benzene, or the like, Alternatively, the reaction is performed in a temperature range of about 0 ° C. to 100 ° C. in a mixed solvent thereof.
Reaction times are from about 1 hour to about 50 hours. The reducing agent is usually used in an amount of about 1 to 5 mol per 1 mol of the compound (III).

(Step 6) Compound (III) and compound (X
By reacting V), compound (IV) can be produced. This condensation reaction is performed with an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane,
The reaction is carried out in acetone, methanol, ethanol, hexane, toluene, benzene, dichloromethane, dimethylformamide, dimethylsulfoxide or the like, or a mixed solvent thereof at a temperature of about 0 ° C to 130 ° C. Reaction times are from about 1 hour to about 100 hours. Compound (XV) is generally used in an amount of about 1 to 5 mol per 1 mol of compound (III). If necessary, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, or the like can be used as a base to allow the reaction to proceed smoothly.

(Step 7) Compound (IX) and Compound (XVI)
Is reacted, followed by ring closure to produce compound (V). This condensation reaction can be performed by a means known per se. For example, when an optionally substituted phthalic anhydride is used as the phthalimidating agent, about 0.5 to 5 times the optionally substituted phthalic anhydride is used, and an inert solvent such as tetrahydrofuran is used.
Dimethoxyethane, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide,
The reaction is performed in a temperature range of about 0 ° C. to 150 ° C. in dimethyl sulfoxide or the like, or a mixed solvent thereof. Reaction times are from about 10 minutes to about 10 hours. Compound (XVI) is generally used in an amount of about 1 to 5 per 1 mol of compound (IX).
Use moles. If necessary, pyridine, 4
-Dimethylaminopyridine, triethylamine and the like can be used. Subsequent ring closure reaction is carried out with inert solvent,
For example, tetrahydrofuran, diphenyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, acetic acid, etc.
Alternatively, the reaction is performed at a temperature of about 0 ° C. to 200 ° C. in the presence of an acid such as acetic acid in a mixed solvent thereof. Reaction times are from about 15 minutes to about 50 hours. Further, by adding an acid to the reaction solution after the completion of the condensation reaction and performing a ring closure reaction, the compound (V) can be obtained without isolating the intermediate.

(Step 8) Compound (IX) and compound (XVI
Compound (VI) can be produced by reacting I). The reaction is carried out in an inert solvent such as tetrahydrofuran, diphenyl ether, dimethoxyethane,
The reaction is carried out in methanol, ethanol, hexane, benzene, toluene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof at a temperature of about 0 ° C to 150 ° C. Reaction times are from about 1 hour to about 100 hours. Compound (XVII) is generally used in an amount of about 0.1 to 1 mol of compound (IX).
Use 8 to 5 moles. In addition, if necessary, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, or the like can be used as a base to allow the reaction to proceed smoothly.

(Step 9) Compound (VII) can be produced by treating compound (X) with a base to open the ring, and then reacting with compound (XVIII). The ring-opening reaction is carried out in an inert solvent such as water, tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof. In the temperature range of about 0 ° C to 100 ° C.
Reaction times are from about 30 minutes to about 20 hours. As the base, sodium hydroxide, lithium hydroxide, potassium carbonate, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used. The base is a compound (X)
Usually, about 3 to 5 mol is used per 1 mol. The subsequent condensation reaction is performed in an inert solvent such as water, tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof. The reaction is performed in a temperature range from room temperature to 100 ° C. Reaction times are from about 1 hour to about 50 hours. Further, by adding compound (XVIII) to the reaction solution after completion of the ring-opening reaction, compound (VII) can also be obtained without isolating the ring-opened product.

The compounds (II) to (VII) thus obtained may be subjected to a substituent conversion reaction, if desired, to convert those substituents to obtain a compound (I ″). The compound (I ") obtained in these steps can be used for the next reaction without isolation and purification. However, in all of the above production methods, when the compound has a carbonyl group, an amino group, a hydroxyl group, or a carboxyl group, a general protecting group may be introduced into the compound in advance by a method known per se. The desired product can be obtained by removing the protecting group after the reaction, if necessary. Here, as the protecting group for the carbonyl group, for example, a cyclic or acyclic acetal or ketal which may have a substituent; a cyclic or acyclic dithioacetal or a dithioketal which may have a substituent ; Etc. are used. Here, as the protecting group for the amino group, for example, lower (C _1-6 ) alkyl-carbonyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl and the like), benzoyl and the like are used. Examples of the hydroxyl-protecting group include methoxydimethylmethyl, trimethylsilyl, t-butyldimethylsilyl, trimethylsilylethoxymethyl (SEM), methoxymethyl, benzyloxymethyl, tetrahydropyranyl (THP) and the like. As the protecting group for the carboxyl group, for example, lower
(C _1-6 ) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, s-butyl, t-
Butyl, pentyl, hexyl, etc.), C _7-12 aralkyl (e.g. benzyl, phenethyl, 4-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, etc.) is used. Further, the carboxyl group may be converted to a 2-oxazoline ring for protection. As a method for introducing and removing the protecting group, a method known per se or a method analogous thereto (for example, a method described in Protective Groups in Organic Chemistry (JFW McOmie et al., Plenum Press)) is used. For example, a method of treating with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

The starting compounds used in the above-mentioned production method include, for example, Katritzky (AR),
"COMPREHENSIVE HETEROCYCLIC CHEMISTRY" (PERGAMON PRESS), 1984, Vol. 3, 57-156
Page, "New Vitamin Studies", The Vitamin Society of Japan, 1969,
It can be produced by the method described on pages 131 to 190 or a method analogous thereto. The other starting compounds can be produced by a method known per se or a method analogous thereto. When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, converted to a free form or another salt according to a conventional method. You can also. The compound (I) thus obtained can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, recrystallization,
Isolation and purification can be performed by using means such as column chromatography and thin-layer chromatography. The salt of compound (I) can be produced according to a means known per se, for example, by adding an inorganic acid or an organic acid to compound (I). When optical isomers can exist in compound (I), both of these individual optical isomers and mixtures thereof are, of course, included in the scope of the present invention. According to the means, it can be optically divided or manufactured individually. Compound (I) may be a hydrate, and both hydrates and non-hydrates are included in the scope of the present invention.

The compound (I) of the present invention has low toxicity and safety, and has a GRK inhibitory action, particularly a potent GRK2 inhibitory action, so that it can be used in animals, particularly mammals (eg, human, monkey,
Cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.), for example, heart failure, hypertension, pulmonary heart, arteriosclerosis, reduced heart function after cardiopulmonary bypass,
Coronary atherosclerosis after coronary artery reconstruction, graft failure after coronary artery bypass surgery, bronchial asthma, etc., and adrenaline beta
For diseases that are closely related to receptors and other G protein-coupled receptors, such as drug dependence, Parkinson's disease, dementia, peripheral arterial occlusion, diabetic nephropathy, urinary incontinence, depression, obesity, etc. It is useful, and it is particularly desirable to use it for prevention or treatment of heart failure and the like. Here, the concept of prevention of heart failure includes myocardial infarction, angina attack, cardiac bypass, thrombolytic therapy, and the treatment of prognosis after coronary revascularization, etc. It also includes the prevention of progression and worsening of heart failure and the maintenance of cardiac function during non-drug therapy (intra-aortic balloon pumping, ventricular assist, batista surgery, heart transplantation, etc.) for severe heart failure.

The compound (I) of the present invention can be administered orally or parenterally as it is or by mixing a pharmacologically acceptable carrier with appropriate excipients and diluents.
The formulation of the present invention containing compound (I) may be administered orally in the form of tablets (including sugar-coated tablets, film-coated tablets), pills, granules, powders, capsules (including soft capsules). ), Syrups, emulsions, suspensions, and the like. Examples of dosage forms for parenteral administration include injections, infusions, drops, suppositories, and inhalants (inhalation). Can be In addition, a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-
It is also effective to form a sustained-release preparation in combination with a glycolic acid copolymer, a mixture of a butyric acid polymer and a glycolic acid polymer, and a polyglycerol fatty acid ester. Although the content of compound (I) in the preparation of the present invention varies depending on the form of the preparation, it is usually 2 to 85 parts by weight based on the whole preparation.
%, Preferably 5 to 70% by weight.

As a method for producing the compound (I) into the above-mentioned dosage form, a known production method generally used in the art can be applied. In the case of producing the above-mentioned dosage form, if necessary, an excipient, a binder, a disintegrant, a lubricant, a sweetener, an interface, which are usually used in the field of formulation when producing the dosage form. It can be produced by appropriately containing an appropriate amount of an activator, a suspending agent, an emulsifier and the like. For example, when compound (I) is manufactured into a tablet, it can be manufactured by adding an excipient, a binder, a disintegrant, a lubricant, and the like. When manufactured into a pill and a granule, the compound (I) can be manufactured. , Excipients, binders, disintegrants and the like. In the case of powder and capsules, excipients and the like,
In the case of preparing a syrup, a sweetening agent and the like may be contained, and in the case of preparing an emulsion or a suspension, a suspending agent, a surfactant and an emulsifier may be contained.

Examples of the excipient include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder,
Mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like can be mentioned. Examples of binders include 5-10% by weight starch paste, 10-2%
0% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like. Examples of disintegrants include starch, calcium carbonate and the like. Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like. Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like. Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl stearate 40, and the like. Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite and the like. Examples of the emulsifier include gum arabic, tragacanth, gelatin, polysorbate 80 and the like. Further, when the compound (I) is produced in the above-mentioned dosage form, a colorant, a preservative, a fragrance, a flavoring agent, a stabilizer, a viscous agent and the like usually used in the field of purification may be used in an appropriate amount. Can be added.

The preparation of the present invention containing compound (I)
Stable, low toxicity and safe to use. Part 1
The daily dose varies depending on the condition and weight of the patient, the type of the compound, the administration route and the like. For example, in the case of oral administration to a patient with heart failure, the daily dose for an adult (body weight of about 60 kg) depends on the active ingredient (compound). (I) about 1 to 1000
mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg, which can be administered once or in two or three divided doses. When the compound (I) of the present invention is administered parenterally, it is usually administered in the form of a liquid (eg, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but for example, in the form of an injection, usually about 0.01 mg to about 100 mg per kg of body weight, preferably about 0.01 to about 100 mg.
Conveniently, about 50 mg, more preferably about 0.01 to about 20 mg, will be administered by intravenous injection. Injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like, and sustained-release preparations include iontophoresis transdermals. Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention in a sterile aqueous or oily liquid. Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents such as alcohols. (Eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50) and the like.
Examples of the oily liquid include sesame oil and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. In addition, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.). The prepared injection solution is usually filled into an ampoule. In addition, the preparation of the present invention (preparation containing compound (I)) may contain, as appropriate, drugs usually used for treatment of heart failure, for example, digitalis, catecholamine (eg, dobutamine, dopamine, denopamine, zamoterol, etc.), β-blocker ( Bisoprolol, carvedilol, etc.), nitrates (nitroglycerin, etc.), hydralazine,
Ca antagonists (e.g., amlodipine), ACE inhibitors (e.g., enalapril), AII antagonists (e.g., candesartan), diuretics (e.g., furosemide), PDE inhibitors (e.g., milrinone), Ca sensitivity enhancers
(Pimobendan, etc.), thrombolytics (t-PA, etc.), anticoagulants
(Heparin, warfarin, etc.), antiplatelet drugs (aspirin, etc.), antiarrhythmic drugs (amiodarone, etc.), HMG-CoA reductase inhibitors (atorovastatin, etc.), α-blockers (prazosin, etc.), atrial diuretic peptide, NEP inhibition Drugs (such as fasidotolyl), endothelin antagonists (such as bosentan), aldosterone antagonists (such as spironolactone), vasopressin antagonists (such as conivaptan), and the like, or a combination of these pharmaceutical ingredients as appropriate. I can do it. Furthermore, non-drug therapy for severe heart failure, such as assisted circulation (intra-aortic balloon pumping, assisted artificial heart, etc.),
It can be used in combination with batista surgery, heart transplantation and the like.

[0048]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to the following Examples, Preparation Examples and Experimental Examples, which are merely illustrative and do not limit the present invention. May be changed without departing from the range. Elution by column chromatography in Examples was performed by TLC.
(Thin Layer Chromatography). In the TLC observation, a TLC plate manufactured by Merck was used as a TLC plate.
F254 or NH manufactured by Fuji Silysia Chemical Ltd., a solvent used as an elution solvent in column chromatography as a developing solvent, and a UV detector as a detection method were used. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh) or Kieselgel 60 (230 to 400 mesh) manufactured by Merck, or Wakogel C-300 (45 to 75 μM) manufactured by Wako Pure Chemical Industries, Ltd. was used. As the basic silica gel for the column, basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silysia Chemical Ltd. was used. NMR spectra were measured on a Varian Gemini 200 type spectrometer using tetramethylsilane as an internal or external reference, and chemical shifts were indicated by δ values and coupling constants by Hz. The IR spectrum was measured with a Shimadzu FTZR-8200 spectrometer. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. The percentage in the solution represents the number of grams in 100 ml of the solution. The symbols in Reference Examples and Examples have the following meanings. s: singlet d: doublet t: triplet q: quartet dd: double doublet m: multiplet br: broad brs: broad singlet broad singlet) J: coupling constant WSC: water-soluble carbodiimide THF: tetrahydrofuran DMF: dimethylformamide DMSO: dimethylsulfoxide HOBt: 1-hydroxybenztriazole

[0049]

EXAMPLES Example 1 (Preparation of Compound 1) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (500
mg) was dissolved in water (5.0 ml), a 10% aqueous sodium hydroxide solution (1.43 ml) was added at room temperature, sodium chloride was added to saturate the reaction solution, and the mixture was stirred at room temperature for 0.5 hour. Sodium tetrahydro-2-furanylmethylthiosulfate (600 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Using ether and hydrochloride, (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(tetrahydro-2-furanylmethyl) disulfanyl] phenyl]
Formamide hydrochloride (Compound 1) (333 mg) was obtained as a colorless amorphous. Elemental analysis _{C 18 H 22 N 4 O 2} S 2 · HCl · 0.5H Calcd the ₂ O. : C, 49.59; H, 5.55; N, 12.85. Found: C, 49.36; H, 5.71; N, 12.88. ¹ H-NMR (DMSO-d ₆ ) δ: 1.46-1.6
2 (1H, m), 1.75-2.03 (3H, m),
2.50 (3H, s), 2.75-2.87 (2H,
m), 3.54-3.93 (3H, m), 4.75 (2
H, s), 7.25-7.57 (3H, m), 7.75.
7.88 (1H, m), 8.01 (1H, s), 8.
09-8.29 (1H, br), 8.22 (1H, br)
s), 9.24 (1H, br).

Example 2 (Preparation of Compound 2) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
00 mg) was dissolved in water (5.0 ml), a 10% aqueous sodium hydroxide solution (1.70 ml) was added at room temperature, and sodium chloride was added to saturate the reaction solution. The mixture was stirred at room temperature for 1 hour. Sodium 1-propylthiosulfate (500m
g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl).
Methyl [2- (propyldisulfanyl) phenyl] formamide (Compound 2) (295 mg) was obtained as colorless crystals. mp 115-117 ° C. Elemental analysis value: C ₁₆ H ₂₀ N ₄ OS ₂ Calcd. : C, 55.14; H, 5.78; N, 16.08. Found: C, 55.01; H, 5.72; N, 16.02. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.4 Hz), 1.63 (2H, nextet, J
= 7.3 Hz), 2.45 (3H, s), 2.63 (2
H, t, J = 7.2 Hz), 4.69 (2H, br)
s), 6.02 (2H, brs), 6.88 (1H, d
d, J = 7.6, 1.0 Hz), 7.21 (1H, t)
d, J = 7.6, 1.4 Hz), 7.43 (1H, t,
J = 7.7 Hz), 7.48 (1H, s), 7.87
(1H, dd, J = 8.1, 1.5 Hz), 8.12
(1H, s). IR (KBr) 1667, 1593, 1557, 147
0, 1435, 1372, 764 cm ^-1 .

Example 3 (Preparation of Compound 3) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
00 mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (1.70 ml) was added at room temperature.
The mixture was stirred at room temperature for 1 hour. 1-Iodobutane (2
A solution of 64 mg) in ethanol (5.0 ml) was added at room temperature and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5).
-Pyrimidinyl) methyl [2- (butylsulfanyl)
[Phenyl] formamide (compound 3) (334 mg) was obtained as colorless crystals. mp 115-117 ° C. Elemental analysis value C ₁₇ H ₂₂ N ₄ OS Calcd. : C, 61.79; H, 6.71; N, 16.95. Found: C, 61.53; H, 6.79; N, 16.93. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t,
J = 7.2 Hz), 1.34-1.67 (4H, m),
2.45 (3H, s), 2.86 (2H, t, J = 7.
2Hz), 4.69 (2H, br), 6.03 (2H,
brs), 6.84 (1H, d, J = 7.4 Hz),
7.07-7.16 (1H, m), 7.29-7.39
(2H, m), 7.49 (1H, s), 8.08 (1
H, s). IR (KBr) 1665, 1591, 1559, 147
2,1435,1372,762 cm ^-1 .

Example 4 (Production of Compound 4) 2-tetrahydro-2-furanylethanol (279 m
To a solution of g) in tetrahydrofuran (5.0 ml) was added triethylamine (1.0 ml) at room temperature, and methanesulfonyl chloride (0.28 ml) was added at 0 ° C. The mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and 2-tetrahydro-2-furanylethyl methanesulfonate (614 mg)
I got N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide Hydrobromide (500 mg) was dissolved in water (5.0 ml), and 1
A 0% aqueous sodium hydroxide solution (1.43 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. 2-tetrahydro-2-furanylethyl methanesulfonate (614m
A solution of g) in ethanol (5.0 ml) was added at room temperature and the mixture was stirred at room temperature for 13.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-tetrahydro- 2-
Furanylethyl) sulfanyl] phenyl] formamide (Compound 4) (302 mg) was obtained as colorless crystals. mp 122-124 ° C. Elemental analysis value: C ₁₉ H ₂₄ N ₄ O ₂ S Calcd. : C, 61.26; H, 6.49; N, 15.04. Found: C, 60.99; H, 6.47; N, 15.03. ¹ H-NMR (CDCl ₃ ) δ: 1.39-1.56
(1H, m), 1.73-2.10 (5H, m), 2.
45 (3H, s), 2.85-3.12 (2H, m),
3.68-3.98 (3H, m), 4.67 (2H, b
r), 6.01 (2H, br), 6.83 (1H, d,
J = 7.6 Hz), 7.07-7.17 (1H, m),
7.33-7.37 (2H, m), 7.49 (1H,
s), 8.08 (1H, s). IR (KBr) 1667, 1593, 1557, 147
2,1435,1372,1059,764,731c
m ^-1 .

Example 5 (Preparation of Compound 5) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (4
99 mg) was dissolved in water (4.0 ml), and a 10% aqueous sodium hydroxide solution (1.43 ml) was added at room temperature.
The mixture was stirred at room temperature for 30 minutes. Ethanol (2.0
ml) and 1-propyl iodide (0.17 ml) were added successively at room temperature. The mixture was further stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, and anhydrous magnesium sulfate was added for drying. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography,
Recrystallization from ethyl acetate-ether further gave (4-
Amino-2-methyl-5-pyrimidinyl) methyl [2-
(Propylsulfanyl) phenyl] formamide (compound 5) (164 mg) was obtained as colorless crystals. mp 132-135 ° C. Elemental analysis value: C ₁₆ H ₂₀ N ₄ OS: Calcd. : C, 60.73; H, 6.37; N, 17.71. Found: C, 60.60; H, 6.29; N, 17.77. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t,
J = 7.3 Hz), 1.64 (2H, sextet, J
= 7.4 Hz), 2.45 (3H, s), 2.84 (2
H, t, J = 7.3 Hz), 4.70 (2H, br),
6.01 (2H, br), 6.85 (1H, d, J =
6.8 Hz), 7.08-7.16 (1H, m), 7.
29-7.39 (2H, m), 7.49 (1H, s),
8.08 (1H, s). IR (KBr) 1665, 1591, 1564, 147
2,1435,1372 cm ^-1 .

Example 6 (Preparation of Compound 6) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (7
98 mg) was dissolved in water (8.0 ml), and a 10% aqueous sodium hydroxide solution (2.3 ml) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. A solution of 5-bromopentyl acetate (0.38 ml) in ethanol (5.0 ml) was added at room temperature. The mixture was further stirred at room temperature for 1 hour.
Ethyl acetate was added to the reaction mixture, and the organic layer was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(5-hydroxypentyl) ) Sulfanyl] phenyl] formamide (compound 6) (1
72 mg) were obtained as colorless crystals. mp 112-114 ° C. Elemental analysis value: C ₁₈ H ₂₄ N ₄ O ₂ S · 0.2H ₂ O Calcd. : C, 59.38; H, 6.75; N, 15.39. Found: C, 59.30; H, 6.82; N, 15.37. ¹ H-NMR (CDCl ₃ ) δ: 1.44-1.67
(6H, m), 2.45 (3H, s), 2.83 (2
H, t, J = 6.8 Hz), 3.66 (2H, t, J =
5.9 Hz), 4.70 (2H, s), 6.06 (2
H, br), 6.95 (1H, d, J = 7.2 Hz),
7.15 (1H, td, J = 7.1, 2.2 Hz),
7.25-7.38 (2H, m), 7.49 (1H,
s), 8.08 (1H, s). IR (KBr) 3333,1661,1593,155
9,1474,1435,1372,763,731c
m ^-1 .

Example 7 (Preparation of Compound 7) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (7
98 mg) was dissolved in water (8.0 ml), and a 10% aqueous sodium hydroxide solution (2.3 ml) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. A solution of 5-bromopentyl acetate (0.38 ml) in ethanol (5.0 ml) was added at room temperature. The mixture was further stirred at room temperature for 1 hour.
Ethyl acetate was added to the reaction mixture, and the organic layer was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ether-hexane to give acetic acid 5-[[2-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] pentyl (compound 7) (273 mg) was obtained as colorless crystals. mp 76 ° C. Elemental analysis value: C ₂₀ H ₂₆ N ₄ O ₃ S Calcd. : C, 59.68; H, 6.51; N, 13.92. Found: C, 59.47; H, 6.49; N, 14.00. ¹ H-NMR (CDCl ₃ ) δ: 1.43-1.73
(6H, m), 2.05 (3H, s), 2.45 (3
H, s), 2.86 (2H, t, J = 7.1 Hz),
4.07 (2H, t, J = 6.4 Hz), 4.67 (2
H, br), 6.01 (2H, br), 6.86 (1
H, d, J = 7.0 Hz), 7.13 (1H, td, J)
= 7.1, 2.4 Hz), 7.29-7.40 (2H,
m), 7.49 (1H, s), 8.08 (1H, s). IR (KBr) 1736, 1663, 1593, 155
9,1472,1435,1370,1246c
m ^-1 .

Example 8 (Preparation of Compound 8) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (9
97 mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (2.86 ml) was added at room temperature.
The mixture was stirred at room temperature for 1 hour. 2-Bromoethyl ethyl ether (1.0 ml) in ethanol (5.0 ml)
The solution was added at room temperature. The mixture was further stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further converted to a hydrochloride using 1N hydrochloric acid-ether.
(4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-ethoxyethyl) sulfanyl] phenyl] formamide hydrochloride (Compound 8) (274 mg) was obtained as a pale yellow amorphous. Elemental analysis _{C 17 H 22 N 4 O 2} S · HCl · 0.75H Calcd the ₂ O. : C, 51.51; H, 6.23; N, 14.13. Found: C, 51.15; H, 6.31; N, 14.79. ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.1
6 (3H, m), 2.50 (3H, s), 3.13 (2
H, t, J = 6.3 Hz), 3.33-3.53 (4
H, m), 4.70 (2H, s), 7.28-7.57.
(4H, m), 7.99 (1H, s), 8.17 (1
H, s), 8.21 (1H, br), 9.10-9.2.
1 (1H, br).

Example 9 (Preparation of Compound 9) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was added. ) And 2- (3-
A solution of (ethoxypropoxy) aniline (2.89 g) in acetone (20 ml) was added at room temperature. The mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (3-ethoxypropoxy) phenyl The amine (compound 9) (1.21 g) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t,
J = 7.0 Hz), 2.05 (2H, quint, J =
6.3 Hz), 2.53 (3H, s), 3.46 (2
H, q, J = 7.1 Hz), 3.55 (2H, t, J =
6.0 Hz), 4.10 (2H, t, J = 6.0H)
z), 4.17 (2H, brs), 5.51 (2H, b
rs), 6.73-6.94 (4H, m), 8.12.
(1H, s), NH were not identified. IR (KBr) 1597, 1561, 1508, 145
1,1248,1125 cm ^-1 .

Example 10 (Preparation of Compound 10) Formic acid (0.78 ml) was added to acetic anhydride (1.60 ml) at room temperature, and the mixture was stirred at 65 ° C. for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (3-ethoxypropoxy) phenyl] amine (1.19 g) in tetrahydrofuran (30
ml) solution was added at 0 ° C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (3- Ethoxypropoxy) phenyl] formamide (Compound 10)
(0.74 g) was obtained as colorless crystals. mp 102-103 ° C. Elemental analysis value: C ₁₈ H ₂₄ N ₄ O ₃ Calcd. : C, 62.77; H, 7.02; N, 16.27. Found: C, 62.60; H, 7.26; N, 16.24. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t,
J = 7.0 Hz), 1.96 (2H, quint, J =
6.1 Hz), 2.43 (3H, s), 3.47 (2
H, q, J = 6.5 Hz), 3.52 (2H, t, J =
5.7 Hz), 4.01 (2H, t, J = 6.2H)
z), 4.68 (2H, s), 6.01 (2H, br)
s), 6.87-6.99 (3H, m), 7.28-
7.36 (1H, m), 7.51 (1H, s), 8.1
2 (1H, s). IR (KBr) 1667, 1595, 1505, 145
6,1435,1273,1119 cm ^-1 .

Example 11 (Preparation of Compound 11) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
43 mg) was dissolved in water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.70 ml) was added at room temperature.
The mixture was stirred at room temperature for 0.5 hours. 1-bromo-2-
A solution of (2-methoxyethoxy) ethane (0.29 ml) in ethanol (6.0 ml) was added and the mixture was added at room temperature for 1 hour.
Stir for 3.5 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography) and further recrystallized from ethyl acetate-hexane.
(4-amino-2-methyl-5-pyrimidinyl) methyl [2-[[2- (2-methoxyethoxy) ethyl] sulfanyl] phenyl] formamide (compound 11) (4
94 mg) were obtained as colorless crystals. mp 85-86 ° C. Elemental analysis value: C ₁₈ H ₂₄ N ₄ O ₃ S Calcd. : C, 57.43; H, 6.43; N, 14.88. Found: C, 57.51; H, 6.32; N, 14.91. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 3.11 (2H, t, J = 6.8 Hz), 3.3
8 (3H, s), 3.51-3.67 (6H, m),
4.69 (2H, br), 6.02 (2H, br),
6.84 (1H, d, J = 8.4 Hz), 7.13 (1
H, td, J = 7.2, 2.1 Hz), 7.30-7.
41 (2H, m), 7.49 (1H, s), 8.06
(1H, s). IR (KBr) 1661, 1593, 1472, 143
5, 1103 cm ^-1 .

Example 12 (Preparation of Compound 12) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
03 mg) was dissolved in water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.59 ml) was added at room temperature.
The mixture was stirred at room temperature for 1.5 hours. A solution of benzyl 2-bromoethyl ether (0.32 ml) in ethanol (6.0 ml) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-hexane).
2-methyl-5-pyrimidinyl) methyl [2-[[2-
(Benzyloxy) ethyl] sulfanyl] phenyl]
Formamide (Compound 12) (515 mg) was obtained as colorless crystals. mp 108.5-109.5 ° C. Elemental analysis value: C ₂₂ H ₂₄ N ₄ O ₂ S Calcd. : C, 64.68; H, 5.92; N, 13.71. Found: C, 64.59; H, 5.94; N, 13.66. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.10 (2H, t, J = 6.7 Hz), 3.6
4 (2H, t, J = 6.6 Hz), 4.53 (2H,
s), 4.68 (2H, br), 6.01 (2H, b
r), 6.83 (1H, d, J = 7.8 Hz), 7.1
3 (1H, t, J = 6.8 Hz), 7.27-7.35
(7H, m), 7.47 (1H, s), 8.07 (1
H, s). IR (KBr) 1663, 1591, 1472, 143
5 cm ^-1 .

Example 13 (Preparation of Compound 13) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
24 mg) was suspended in ethanol (10 ml), and sodium methoxide (242 mg) was added at room temperature. The mixture was stirred at room temperature for 2 hours. Chloromethyl methyl sulfide (0.19 ml) was added and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give (4-amino-2-methyl-5).
-Pyrimidinyl) methyl [2-[[(methylsulfanyl) methyl] sulfanyl] phenyl] formamide (Compound 13) (26 mg) was obtained as colorless crystals. mp 130-132 ° C. Elemental analysis value: C ₁₅ H ₁₈ N ₄ OS ₂ .H ₂ O: Calcd. : C, 51.11; H, 5.72; N, 15.90. Found: C, 50.81; H, 5.42; N, 15.50. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H,
s), 2.46 (3H, s), 3.93 (2H, s),
4.71 (2H, br), 6.03 (2H, br),
6.91 (1H, d, J = 7.2 Hz), 7.22 (1
H, t, J = 7.2 Hz), 7.40 (1H, t, J =
7.5 Hz), 7.49 (1H, d-like), 7.
51 (1H, s), 8.13 (1H, s). IR (KBr) 1661, 1591, 1472, 143
5 cm ^-1 .

Example 14 (Preparation of Compound 14) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
47 mg) was dissolved in water (7.0 ml), and a 10% aqueous sodium hydroxide solution (1.71 ml) was added at room temperature.
The mixture was stirred at room temperature for 1 hour. Chloromethylpropyl sulfide (533 mg) in ethanol solution (7.0 m
l) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-
Pyrimidinyl) methyl [2-[[(propylsulfanyl) methyl] sulfanyl] phenyl] formamide (Compound 14) (219 mg) was obtained as yellow crystals. mp 114-117 ° C. Elemental analysis _{C 17 H 22 N 4 OS 2} · 1.5H Calcd the ₂ O. : C, 52.42; H, 6.47; N, 14.38. Found: C, 52.38; H, 6.17; N, 14.13. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, t,
J = 7.5 Hz), 1.63 (2H, nextet, J
= 7.1 Hz), 2.46 (3H, s), 2.63 (2
H, t, J = 7.2 Hz), 3.96 (2H, s),
4.69 (2H, br), 6.03 (2H, br),
6.88 (1H, dd, J = 7.6, 1.6 Hz),
7.21 (1H, t, J = 7.4 Hz), 7.39 (1
H, t, J = 6.9 Hz), 7.49-7.51 (1
H, m), 7.51 (1H, s), 8.12 (1H,
s). IR (KBr) 1663, 1591, 1472, 143
5 cm ^-1 .

Example 15 (Preparation of Compound 15) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (5
00 mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (1.43 ml) was added at room temperature.
The mixture was stirred at room temperature for 0.5 hours. A solution of benzylchloromethyl sulfide (309 mg, containing tetrahydrofuran) in ethanol (5.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and further converted to hydrochloride with 1N hydrochloric acid-ether to give (4-amino-2-methyl-5-
Pyrimidinyl) methyl (2-benzylsulfanylmethylsulfanylphenyl) formamide hydrochloride (Compound 15) (241 mg) was obtained as a colorless amorphous. ¹ H-NMR (DMSO-d ₆ ) δ: 2.44 (3H,
s), 3.82 (2H, s), 4.07 (2H, s),
4.73 (2H, br), 7.29-7.57 (11
H, m), 8.01 (1H, s), 8.21 (1H,
s).

Example 16 (Preparation of Compound 16) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
(40 mg) was suspended in ethanol (15 ml), and sodium methoxide (248 mg) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Chloromethyl thiocyanate (0.18 ml) was added and the mixture was stirred at room temperature for 17 hours and at 80 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively.
The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and [[2-[[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] methyl thiocyanate (compound 1
6) (76 mg) was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.69 (2H, br), 4.94 (2H, br).
s), 6.06 (2H, br), 6.89 (1H, d
d, J = 7.6, 1.4 Hz), 7.21 (1H, t)
d, J = 7.4, 1.5 Hz), 7.38 (1H, t)
d, J = 7.7, 1.4 Hz), 7.50 (1H,
s), 7.72 (1H, dd, J = 8.0, 1.4H)
z), 8.10 (1H, s). IR (KBr) 166
3,1593,1474,1435 cm ^-1 .

Example 17 (Preparation of Compound 17) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (6
24 mg) was suspended in ethanol (15 ml), and sodium methoxide (242 mg) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Chloromethylphenyl sulfide (0.30 ml) was added and the mixture was cooled at room temperature to 19.
Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-
2-Methyl-5-pyrimidinyl) methyl [2-[[(phenylsulfanyl) methyl] sulfanyl] phenyl] formamide (Compound 17) (228 mg) was obtained as colorless crystals. mp 119 ° C. Calcd As Elemental analysis _{C 20 H 20 N 4 OS 2} · 0.5H 2 O. : C, 59.23; H, 5.22; N, 13.82. Found: C, 59.38; H, 5.24; N, 13.59. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 4.29 (2H, s), 4.60 (2H, b
r), 5.94 (2H, br), 6.84 (1H, d,
J = 8.4 Hz), 7.16-7.52 (9H, m),
8.04 (1H, s). IR (KBr) 1661, 1591, 1474, 143
9 cm ^-1 .

Example 18 (Preparation of Compound 18) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was added. ) And 2-[(tetrahydro-2-furanylmethoxy) methyl] aniline (2.06 g) in acetone (20 ml) were added at room temperature. The mixture was stirred at 65 ° C. for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(tetrahydro-2-furan Nilmethoxy) methyl] phenyl] amine (compound 1
8) (772 mg) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.39-1.50
(1H, m), 1.70-1.92 (3H, m), 2.
51 (3H, s), 3.33 (1H, dd, J = 10.
4,7.6 Hz), 3.50 (1H, dd, J = 10.
4, 3.4 Hz), 3.61-3.73 (2H, m),
3.99 (1H, qd, J = 7.0, 3.4 Hz),
4.19 (2H, d, J = 4.4 Hz), 4.53 (1
H, d, J = 13.0 Hz), 4.59 (1H, d, J)
= 13.2 Hz), 5.23 (1H, t-like),
5.47 (2H, brs), 6.72-6.79 (2
H, m), 7.09 (1H, d, J = 6.6 Hz),
7.25 (1H, td, J = 7.7, 1.6 Hz),
8.14 (1H, s). IR (KBr) 1588, 1564, 1516, 145
4,1427,1076,748 cm ^-1 .

Example 19 (Preparation of Compound 19) Formic acid (0.60 ml) was added to acetic anhydride (1.23 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(tetrahydro-2-furanylmethoxy) methyl] phenyl] amine (0.95 g) in tetrahydrofuran (15 ml) was added to 0 Added at ° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ether to give (4-amino-
2-methyl-5-pyrimidinyl) methyl [2-[(tetrahydro-2-furanylmethoxy) methyl] phenyl]
Formamide (Compound 19) (762 mg) was obtained as colorless crystals. mp 99-100C. Elemental analysis value: C ₁₉ H ₂₄ N ₄ O ₃ Calcd. : C, 64.03; H, 6.79; N, 15.72. Found: C, 64.01; H, 6.76; N, 15.71. ¹ H-NMR (CDCl ₃ ) δ: 1.52-1.61
(1H, m), 1.81-2.00 (3H, m), 2.
46 (3H, s), 3.39 (1H, dd, J = 10.
0, 6.2 Hz), 3.44 (1H, dd, J = 10.
2,3.6 Hz), 3.70-3.91 (2H, m),
3.98-4.06 (1H, m), 4.26 (1H,
d, J = 14.8 Hz), 4.63 (1H, d, J = 1)
4.6 Hz), 4.74 (2H, s), 6.04 (2
H, br), 6.95 (1H, dd, J = 7.4, 1.
8Hz), 7.33 (1H, td, J = 7.4, 2.2)
Hz), 7.39 (1H, td, J = 7.4, 1.8H)
z), 7.50 (1H, dd, J = 7.2, 2.0H
z), 7.54 (1H, s), 8.17 (1H, s). IR (KBr) 1661, 1593, 1557, 145
6,1435, 1373, 1080 cm ^-1 .

Example 20 (Preparation of Compound 20) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (20 ml), and potassium carbonate (1.47 g) was added. ) And 2-[(benzylsulfanyl) methyl] aniline (2.03 g)
In acetone (30 ml) was added at room temperature.
The mixture was stirred at 65 ° C. for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -N
-[2- (Benzylsulfanylmethyl) phenyl] amine (compound 20) (708 mg) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H,
s), 3.58 (2H, s), 3.59 (2H, s),
4.11 (2H, s), 5.24 (1H, br), 5.
32 (2H, brs), 6.73-6.82 (2H,
m), 7.04 (1H, d, J = 7.4 Hz), 7.2
2-7.33 (6H, m), 8.11 (1H, s).

Example 21 (Preparation of Compound 21) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.0 g), (E) -3-phenyl-2
A mixture of -propenyl-2-aminobenzoic acid (0.9 g), potassium carbonate (1.1 g), and acetone (30 ml) was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-hexane to give (E) -3
-Phenyl-2-propenyl-2-[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] aminobenzoic acid (Compound 21) (0.65 g) was obtained as colorless crystals. mp 165-166 ° C Elemental analysis: C ₂₂ H ₂₂ N ₄ O ₂ Calcd. : C, 70.57; H, 5.92; N, 14.96. Found: C, 70.46; H, 5.82; N, 15.04. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 4.23 (2H, d, J = 4.8 Hz), 4.9
1 (1H, dd, J = 1.2, 6.6 Hz), 5.32
(2H, br), 6.36 (1H, dt, J = 6.2,
15.8Hz), 6.681 (1H, s), 6.63-
6.88 (2H, m), 7.12-7.55 (6H,
m), 7.72 (1H, t-like), 8.02 (1
H, dd, J = 1.4, 8 Hz), 8.14 (1H,
s).

Example 22 (Preparation of Compound 22) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (10.6 g) was added to acetone (250 ml).
And potassium carbonate (10.4 g) and methyl anthranilate (11.3 g) were added at room temperature, respectively.
The mixture was stirred at 70 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate.
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] methyl aminobenzoate (Compound 22) (4.98)
g) was obtained as colorless crystals. The mother liquor was concentrated, and the residue was purified by silica gel column chromatography. After concentration, the precipitated crystals were washed with ethyl acetate to give the compound (2.46).
g) was obtained as colorless crystals. Total yield: 7.44 g. mp 185-187 ° C (decomposition.). Elemental analysis value: C ₁₄ H ₁₆ N ₄ O ₂ Calcd. : C, 61.75; H, 5.92; N, 20.58. Found: C, 61.58; H, 5.91; N, 20.58. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 3.85 (3H, s), 4.24 (2H, d, J
= 5.2 Hz), 5.20 (2H, brs), 6.68
−6.79 (2H, m), 7.40 (1H, td, J =
7.8, 1.6 Hz), 7.70 (1H, t-like)
e), 7.95 (1H, dd, J = 8.2, 1.8H)
z), 8.15 (1H, s). IR (KBr) 3441, 1682, 1661, 160
1,1576,1514,1466,1456,142
7,1267,1242,741 cm ^-1 .

Example 23 (Preparation of Compound 23) 2-[(4-amino-2-methyl-5-pyrimidinyl)
A mixture of methyl [methyl] aminobenzoate (606 mg), 1-propylamine (12 ml) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.67 ml) was heated to reflux for 111 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. After concentration, the precipitated crystals were washed with ethyl acetate, and 2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl ] Amino]-
N-propylbenzoic acid amide (compound 23) (424 m
g) was obtained as colorless needle crystals. mp 197-198 ° C. Elemental analysis value: C ₁₆ H ₂₁ N ₅ O, Calcd. : C, 64.19; H, 7.07; N, 23.39. Found: C, 63.93; H, 7.18; N, 23.16. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.3 Hz), 1.62 (2H, sextet, J
= 7.2 Hz), 2.51 (3H, s), 3.36 (2
H, td, J = 7.2, 5.8 Hz), 4.20 (2
H, d, J = 5.2 Hz), 5.26 (2H, br)
s), 6.09 (1H, br), 6.71 (1H, t,
J = 7.5 Hz), 6.76 (1 H, d, J = 8.4 H)
z), 7.28-7.37 (2H, m), 7.58 (1
H, t-like), 8.13 (1H, s). IR (KBr) 1634, 1593, 1559, 151
6,1453,1424,1285,748 cm ^-1 .

Example 24 (Preparation of Compound 24) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (10 ml), and potassium carbonate (1.47 g) was added. ) And 2-aminophenylphenyl sulfide (2.13 g) in acetone (20 ml) were added at room temperature. Mix 6
Stirred at 5 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure,
Water was added to the residue and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. Combine the organic layers, wash with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- N- [2- (Phenylsulfanyl) phenyl] amine (Compound 24) (976 mg) was obtained as colorless crystals. mp 152-153 ° C. Elemental analysis value: C ₁₈ H ₁₈ N ₄ S · 0.17H ₂ O Calcd. : C, 66.42; H, 5.68; N, 17.21. Found: C, 66.71; H, 5.57; N, 16.91. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.11 (2H, d, J = 5.6 Hz), 4.7
7 (3H, br), 6.78 (1H, dd, J = 8.
0, 1.0 Hz), 6.86 (1H, td, J = 7.
5,1.1 Hz), 7.02-7.08 (2H, m),
7.12-7.22 (3H, m), 7.37 (1H, t
d, J = 7.9, 1.2 Hz), 7.57 (1H, d
d, J = 7.5, 1.7 Hz), 8.04 (1H,
s). IR (KBr) 1590, 1568, 1499, 147
8,1451,1420 cm ^-1 .

Example 25 (Production of Compound 25) Formic acid (1.1 ml) was added dropwise to acetic anhydride (2.2 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2- (phenylsulfanyl) phenyl] amine (6
43 mg) was dissolved in tetrahydrofuran (20 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from diisopropyl ether gave (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (phenylsulfanyl) phenyl] formamide (compound 2
5) (444 mg) was obtained as colorless crystals. mp 117-122 ° C. Elemental analysis value: C ₁₉ H ₁₈ N ₄ OS: Calcd. : C, 65.12; H, 5.18; N, 15.99. Found: C, 65.25; H, 5.30; N, 16.18. ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H,
s), 4.71 (2H, br), 5.95 (2H, b
r), 6.92-6.96 (1H, m), 7.12-
7.38 (8H, m), 7.53 (1H, s), 8.0
7 (1H, s). IR (KBr) 1663, 1593, 1474, 143
9 cm ^-1 .

Example 26 (Production of Compound 26) Formic acid (1.1 ml) was added dropwise to acetic anhydride (2.2 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2- (phenylsulfanyl) phenyl] amine (6
43 mg) was dissolved in tetrahydrofuran (20 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
The crystal was recrystallized from diisopropyl ether to give 5-[(formyl) [2- (phenylsulfanyl) anilino] methyl] -2-methyl-4-pyrimidinylformamide (Compound 26) (137 mg) as colorless crystals. mp 131-132 ° C. Elemental analysis _{C 20 H 18 N 4 O 2} S · 0.1H Calcd the ₂ O. : C, 63.17; H, 4.82; N, 14.73. Found: C, 63.04; H, 4.78; N, 14.64. ¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H,
s), 4.76 (2H, s), 6.97-7.02 (1
H, m), 7.15-7.35 (8H, m), 7.85
(1H, s), 8.07 (1H, s), 9.64 (1
H, d, J = 9.2 Hz), 10.01 (1H, br−)
d, J = 9.6 Hz). IR (KBr) 1705, 1659, 1599, 157
2,1476,1441,1429,1360,121
7 cm ^-1 .

Example 27 (Preparation of Compound 27) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.62 g) was suspended in acetone (20 ml), and potassium carbonate (1.58 g) was added. ) And 2-aminophenyl- (4-bromophenyl) sulfide (2.4
A solution of 0 g) in acetone (30 ml) was added at room temperature. The mixture was stirred at 70 ° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N -[2- (4-bromophenylsulfanyl) phenyl] amine (compound 27) (1.
08g) as colorless crystals. mp 137-138 ° C. Elemental analysis value: C ₁₈ H ₁₇ BrN ₄ S · 0.25H ₂ O Calcd. : C, 53.27; H, 4.35; N, 13.81. Found: C, 52.97; H, 4.61; N, 13.57. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 4.13 (2H, d, J = 5.4 Hz), 4.7.
8 (1H, t-like), 4.88 (2H, br),
6.80 (1H, d, J = 8.0 Hz), 6.85 −
6.93 (3H, m), 7.29-7.43 (3H,
m), 7.54 (1H, dd, J = 7.4, 1.8H)
z), 8.06 (1H, s). IR (KBr) 1640, 1590, 1566, 150
1,1471,1451,1422,1007,748
cm ^-1 .

Example 28 (Production of Compound 28) Formic acid (0.50 ml) was added dropwise to acetic anhydride (1.03 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling, the mixture was diluted with tetrahydrofuran (5.0 ml). N-[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -N
-[2- (4-Bromophenylsulfanyl) phenyl] amine (975 mg) was added to tetrahydrofuran (10
ml) and added dropwise at 0 ° C. Mix the mixture at room temperature for 1 hour.
Stir for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ether to give (4-amino-
2-methyl-5-pyrimidinyl) methyl [2- (4-bromophenylsulfanyl) phenyl] formamide (compound 28) (675 mg) was obtained as colorless crystals. mp 154-155 ° C. Elemental analysis value: C ₁₉ H ₁₇ BrN ₄ OS Calcd. : C, 53.15; H, 3.99; N, 13.05. Found: C, 53.01; H, 3.96; N, 12.92. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 4.72 (2H, s), 5.96 (2H, b
r), 6.99-7.10 (3H, m), 7.13-
7.18 (1H, m), 7.22-7.31 (2H,
m), 7.42-7.49 (2H, m), 7.52 (1
H, s), 8.07 (1H, s). IR (KBr) 1667, 1591, 1559, 147
2,1435,1009 cm ^-1 .

Example 29 (Production of Compound 29) Formic acid (0.50 ml) was added dropwise to acetic anhydride (1.03 ml) at room temperature, followed by stirring at 60 ° C. for 2 hours. After air cooling, the mixture was diluted with tetrahydrofuran (5.0 ml). N-[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -N
-[2- (4-Bromophenylsulfanyl) phenyl] amine (975 mg) was added to tetrahydrofuran (10
ml) and added dropwise at 0 ° C. Mix the mixture at room temperature for 1 hour.
Stir for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ether to give 5-[[2-
[(4-Bromophenylsulfanyl)] (formyl)
Anilino] methyl] -2-methyl-4-pyrimidinylformamide (Compound 29) (190 mg) was obtained as colorless crystals. mp 163 ° C. Elemental analysis value: C ₂₀ H ₁₇ BrN ₄ O ₂ S Calcd. : C, 52.52; H, 3.75; N, 12.25. Found: C, 52.50; H, 3.94; N, 12.02. ¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H,
s), 4.77 (2H, s), 6.98-7.09 (3
H, m), 7.15-7.20 (1H, m), 7.30
−7.35 (2H, m), 7.35-7.46 (2H,
m), 7.83 (1H, s), 8.08 (1H, s),
9.62 (1H, d, J = 9.2 Hz), 9.93 (1
H, d-like). IR (KBr) 1705, 1655, 1572, 147
4,1447,1427,1360,1217,73
1,667 cm ^-1 .

Example 30 (Preparation of Compound 30) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2- (4-bromophenylsulfanyl) phenyl]
Formamide (101 mg) in ethanol (10 ml)
And 1N hydrochloric acid was added. The mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure and ethanol-
The crystals were recrystallized from ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (4-bromophenylsulfanyl) phenyl] formamide hydrochloride (Compound 30) (40 mg) as colorless crystals. Was. mp 147-150 ° C. Elemental analysis value: C ₁₉ H ₁₇ BrN ₄ S.HCl.H ₂ O Calcd. : C, 47.17; H, 4.17; N, 11.58. Found: C, 47.27; H, 4.09; N, 11.49. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H,
s), 4.78 (2H, s), 7.06 (2H, d, J
= 8.4 Hz), 7.18-7.22 (1H, m),
7.38-7.39 (2H, m), 7.52 (2H,
d, J = 8.0 Hz), 7.66 (2H, br), 8.
10 (1H, s), 8.60 (2H, br). IR (KBr) 1661, 1601, 1472, 134
8 cm ^-1 .

Example 31 (Production of Compound 31) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (5.14 g) was suspended in acetone (40 ml), and potassium carbonate (5.02 g) was obtained. )) And 2-aminophenyl- (2-methoxyphenyl) sulfide (8.
A solution of 40 g) in acetone (80 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 64.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether.
N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(2-methoxyphenyl) sulfanyl] phenyl] amine (Compound 31) (2.94)
g) was obtained as colorless crystals. mp 127-128 ° C. Elemental analysis value: C ₁₉ H ₂₀ N ₄ OS: Calcd. : C, 64.75; H, 5.72; N, 15.90. Found: C, 64.56; H, 5.73; N, 15.64. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 3.85 (3H, s), 4.12 (2H, d, J
= 6.0 Hz), 4.87 (2H, br), 4.92
(1H, t-like), 6.64 (1H, dd, J =
7.9, 1.7 Hz), 6.74-6.89 (4H,
m), 7.12 (1H, td, J = 7.8, 1.6H)
z), 7.37 (1H, td, J = 7.8, 1.6H
z), 7.57 (1H, dd, J = 7.5, 1.7H)
z), 8.05 (1H, s). IR (KBr) 1588, 1572, 1499, 147
6,1451,1433,1240,748 cm ^-1 .

Example 32 (Production of Compound 32) Formic acid (3.4 ml) was added dropwise to acetic anhydride (6.9 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(2-methoxyphenyl) sulfanyl] phenyl] amine (4.03 g) was added to tetrahydrofuran (3
0 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (2 -Methoxyphenylsulfanyl) phenyl] formamide (Compound 32) (2.26 g) was obtained as colorless crystals. mp 128-130 ° C. Elemental analysis value: C ₂₀ H ₂₀ N ₄ O ₂ S Calcd. : C, 63.14; H, 5.30; N, 14.73. Found: C, 62.94; H, 5.36; N, 14.74. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.81 (3H, s), 4.80 (2H, b
r), 5.98 (2H, br), 6.85 (1H, d,
J = 7.2 Hz), 6.90-6.96 (2H, m),
7.07 (1H, td, J = 7.4, 1.9 Hz),
7.14-7.22 (3H, m), 7.36 (1H, t
d, J = 7.7, 1.8 Hz), 7.54 (1H,
s), 8.13 (1H, s). IR (KBr) 1663, 1591, 1476, 143
5,1275,1246,754,731 cm ^-1 .

Example 33 (Production of Compound 33) Formic acid (3.4 ml) was added dropwise to acetic anhydride (6.9 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(2-methoxyphenyl) sulfanyl] phenyl] amine (4.03 g) was added to tetrahydrofuran (3
0 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give [4- (formylamino) -2-methyl-5-pyrimidinyl] [2- [(2-methoxyphenyl) sulfanyl] phenyl] formamide (compound 33) (680
mg) as colorless crystals. mp 126 ° C. Elemental analysis value: C ₂₁ H ₂₀ N ₄ O ₃ S Calcd. : C, 61.75; H, 4.94; N, 13.72. Found: C, 61.78; H, 4.99; N, 13.68. ¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H,
s), 3.80 (3H, s), 4.84 (2H, s),
6.88-6.95 (3H, m), 7.07-7.17
(2H, m), 7.20-7.39 (3H, m), 7.
85 (1H, s), 8.12 (1H, s), 9.64
(1H, d, J = 9.2 Hz), 10.00 (1H, d
-Like). IR (KBr) 1707, 1659, 1574, 147
6,1447,1429,1275,1244,121
7 cm ^-1 .

Example 34 (Production of Compound 34) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (3.14 g) was suspended in acetone (30 ml), and potassium carbonate (3.07 g) was added. ) And 2-aminophenyl-4'-methoxyphenyl ether (4.78)
A solution of g) in acetone (60 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 63.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]-
N- [2- (4-Methoxyphenoxy) phenyl] amine (Compound 34) (1.94 g) was obtained as an amorphous. Elemental analysis value: C ₁₉ H ₂₀ N ₄ O ₂ .0.4H ₂ O Calcd. : C, 66.42; H, 6.10; N, 16.31. Found: C, 66.66; H, 6.36; N, 16.03. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 3.79 (3H, s), 4.20 (2H + 1H,
s), 5.35 (2H, brs), 6.69-6.94.
(7H, m), 7.03 (1H, td, J = 7.1,
2.4 Hz), 8.12 (1H, s). IR (KBr) 1593, 1561, 1505, 145
4,1441,1244,1213,739 cm ^-1 .

Example 35 (Preparation of Compound 35) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2- (4-methoxyphenoxy) phenyl] amine (0.96 g) was dissolved in acetone (15 ml), and 4-formyl-2-methyl-1,3,4-thiadiazoline-5-thione was dissolved. (1.38 g) was added at room temperature. The mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were washed with ethyl acetate-hexane (2: 1) to remove 2-methyl-1,3,4-thiadiazoline-5-thione. The solvent was distilled off from the filtrate under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (4-methoxypheninoxy)
Phenyl] formamide (Compound 35) (536 mg)
Was obtained as colorless crystals. mp 152-153 ° C. Calcd As Elemental analysis _{C 20 H 20 N 4 O 3} · 0.25H 2 O. : C, 65.12; H, 5.60; N, 15.19. Found: C, 65.09; H, 5.30; N, 14.91. ¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H,
s), 3.80 (3H, s), 4.75 (2H, s),
5.86 (2H, br), 6.69-6.75 (2H,
m), 6.80-6.86 (3H, m), 7.00-
7.10 (2H, m), 7.21-7.29 (1H,
m), 7.60 (1H, s), 8.24 (1H, s). IR (KBr) 1665, 1593, 1505, 149
5,1456,1439,1235,1209c
m ^-1 .

Example 36 (Preparation of Compound 36) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2- (4-methoxyphenoxy) phenyl] amine (0.96 g) was dissolved in acetone (15 ml), and 4-formyl-2-methyl-1,3,4-thiadiazoline-5-thione was dissolved. (1.38 g) was added at room temperature. The mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were washed with ethyl acetate-hexane (2: 1) to remove 2-methyl-1,3,4-thiadiazoline-5-thione. The solvent was distilled off from the filtrate under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give 5-[(formyl) [2- (4-methoxypheninoxy). Anilino] methyl] -2-methyl-
4-pyrimidinylformamide (Compound 36) (329
mg) as colorless crystals. mp 137-138 ° C. Elemental analysis value: C ₂₁ H ₂₀ N ₄ O ₄ Calcd. : C, 64.28; H, 5.14; N, 14.28. Found: C, 64.06; H, 5.10; N, 14.25. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H,
s), 3.80 (3H, s), 4.80 (2H, s),
6.60-6.66 (2H, m), 6.76-6.84
(2H, m), 6.86 (1H, d, J = 8.8H)
z), 7.06-7.17 (2H, m), 7.29 (1
H, ddd, J = 8.4, 6.0, 2.4 Hz), 7.
90 (1H, s), 8.25 (1H, s), 9.52
(1H, d, J = 9.6 Hz), 9.83 (1H, d−
like). IR (KBr) 1707, 1659, 1597, 157
2,1505,1495,1454,1429,136
4,1236,1213 cm ^-1 .

Example 37 (Production of Compound 37) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (10 ml), and potassium carbonate (1.47 g) was added. )) And 2-aminophenyl- (4-methoxyphenyl) sulfide (2.
A solution of 15 g) in acetone (20 ml) was added at room temperature. The mixture was stirred at 70 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. Combine the organic layers,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- N- [2
-[(4-Methoxyphenyl) sulfanyl] phenyl] amine (compound 37) (1.25 g) was obtained as colorless crystals. mp 129-130 ° C. Elemental analysis value: C ₁₉ H ₂₀ N ₄ OS: Calcd. : C, 64.75; H, 5.72; N, 15.90. Found: C, 64.53; H, 5.86; N, 15.82. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 3.76 (3H, s), 4.13 (2H, d, J
= 5.2 Hz), 4.79 (1H, t-like),
4.91 (2H, s), 6.73-6.85 (4H,
m), 7.03-7.09 (2H, m), 7.32 (1
H, t, J = 7.6 Hz), 7.51 (1H, dd, J)
= 7.7, 1.5 Hz), 8.06 (1H, s). IR (KBr) 1590, 1568, 1493, 145
6,1287,1244,750 cm ^-1 .

Example 38 (Production of Compound 38) Formic acid (1.1 ml) was added dropwise to acetic anhydride (2.2 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (15ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(4-Methoxyphenyl) sulfanyl] phenyl] amine (902 mg) was added to tetrahydrofuran (3
0 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[( 4-methoxyphenyl) sulfanyl]
Phenyl] formamide (compound 38) (670 mg)
Was obtained as colorless crystals. mp 165-166 ° C. Calcd As Elemental analysis _{C 20 H 20 N 4 O 2} S · 0.4H 2 O. : C, 61.96; H, 5.41; N, 14.45. Found: C, 62.22; H, 5.36; N, 14.17. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 3.84 (3H, s), 4.73 (2H, b
r), 6.02 (2H, br), 6.85-6.96.
(4H, m), 7.11 (1H, td, J = 7.3,
1.9 Hz), 7.20 (1H, td, J = 7.5)
1.6 Hz), 7.28-7.32 (2H, m), 7.
55 (1H, s), 8.12 (1H, s). IR (KBr) 1667, 1593, 1568, 155
9, 1495, 1472, 1439, 1287, 124
8 cm ^-1 .

Example 39 (Production of Compound 39) Formic acid (1.1 ml) was added dropwise to acetic anhydride (2.2 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (15ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(4-Methoxyphenyl) sulfanyl] phenyl] amine (902 mg) was added to tetrahydrofuran (3
0 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give [4- (formylamino) -2-methyl-5-pyrimidinyl] methyl [2 -(4-methoxyphenylsulfanyl) phenyl] formamide (compound 39) (21
7 mg) as colorless crystals. mp 134 ° C. Elemental analysis value: C ₂₁ H ₂₀ N ₄ O ₃ S · 0.1H ₂ O Calcd. : C, 61.48; H, 4.96; N, 13.66. Found: C, 61.31; H, 4.95; N, 13.66. ¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H,
s), 3.84 (3H, s), 4.77 (2H, s),
6.88-6.94 (4H, m), 7.12-7.23
(4H, m), 7.87 (1H, s), 8.12 (1
H, s), 9.68 (1H, d, J = 9.2 Hz), 1
0.07 (1H, d, J = 9.4 Hz). IR (KBr) 1707, 1659, 1593, 157
2,1495,1473,1443,1429,125
0,1215 cm ^-1 .

Example 40 (Preparation of compound 40) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (5.61 g) was suspended in acetone (40 ml), and potassium carbonate (5.48 g) was added. ) And 2-aminophenyl- (2-nitrophenyl) sulfide (7.5)
A solution of 2 g) in acetone (80 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 64 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N-[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] -N- [2-
[(2-Nitrophenyl) sulfanyl] phenyl] amine (compound 40) (2.36 g) was obtained as yellow crystals. mp 176-177 ° C. Elemental analysis _{C 18 H 17 N 5 O 2} S · 0.1H Calcd the ₂ O. : C, 58.55; H, 4.70; N, 18.97. Found: C, 58.63; H, 4.70; N, 18.67. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.15 (2H, d, J = 5.2 Hz), 4.8
5 (1H, br-t, J = 5.2 Hz), 4.88 (2
H, br), 6.78-6.86 (2H, m), 6.9.
1 (1H, td, J = 7.4, 1.2 Hz), 7.25
(1H, td, J = 7.7, 1.4 Hz), 7.34−
7.50 (2H, m), 7.55 (1H, dd, J =
7.4, 1.2 Hz), 8.04 (1H, s), 8.2
8 (1H, dd, J = 8.1, 1.5 Hz). IR (KBr) 1591, 1566, 1514, 145
1,1335,1306,733 cm ^-1 .

Example 41 (Production of Compound 41) Formic acid (3.0 ml) was added dropwise to acetic anhydride (6.0 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (15ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(2-Nitrophenyl) sulfanyl] phenyl] amine (2.18 g) was added to tetrahydrofuran (60
ml) and added dropwise at 0 ° C. Mix at room temperature 9
Stir for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether.
(4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-nitrophenyl) sulfanyl] phenyl] formamide (Compound 41) (1.38 g) was obtained as pale yellow crystals. mp 147 ° C. Elemental analysis _{C 19 H 17 N 5 O 3} S · 0.33H Calcd the ₂ O. : C, 56.86; H, 4.43; N, 17.45. Found: C, 56.96; H, 4.52; N, 17.19. ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 4.74 (2H, s), 5.92 (2H, b
r), 6.49-6.54 (1H, m), 7.23-
7.35 (3H, m), 7.45-7.67 (4H,
m), 8.06 (1H, s), 8.17-8.24 (1
H, m). IR (KBr) 1667, 1591, 1566, 147
4,1435,1337,1304,735 cm ^-1 .

Example 42 (Production of Compound 42) Formic acid (3.0 ml) was added dropwise to acetic anhydride (6.0 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (15ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(2-Nitrophenyl) sulfanyl] phenyl] amine (2.18 g) was added to tetrahydrofuran (60
ml) and added dropwise at 0 ° C. Mix at room temperature 9
Stir for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether.
[4- (Formylamino) -2-methyl-5-pyrimidinyl] methyl [2- (2-nitrophenylsulfanyl) phenyl] formamide (Compound 42) (741 m
g) was obtained as pale yellow crystals. mp 188-191 ° C. Elemental analysis _{C 20 H 17 N 5 O 4} S · 0.1H Calcd the ₂ O. : C, 56.49; H, 4.08; N, 16.47. Found: C, 56.40; H, 3.94; N, 16.35. ¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H,
s), 4.78 (2H, s), 6.62-6.67 (1
H, m), 7.16-7.21 (1H, m), 7.30
-7.39 (2H, m), 7.49-7.67 (3H,
m), 7.80 (1H, s), 8.00 (1H, s),
8.20-8.25 (1H, m), 9.59 (1H,
d, J = 9.6 Hz), 9.79 (1H, d, J = 9.
6 Hz). IR (KBr) 1705, 1659, 1570, 151
8, 1474, 1447, 1427, 1360, 133
7, 1304, 1217, 735 cm ^-1 .

Example 43 (Production of compound 43) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (3.77 g) was suspended in acetone (25 ml), and potassium carbonate (4.60 g) was obtained. ) And 2-aminophenyl- (4-methoxy-2-nitrophenyl) sulfide (7.36 g) in acetone (50 ml) were added at room temperature. The mixture was stirred at 70 ° C. for 17.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2 − [(4
-Methoxy-2-nitrophenyl) sulfanyl] phenyl] amine (compound 43) (1.75 g) was obtained as yellow crystals. mp 215-217 ° C. Elemental analysis value: C ₁₉ H ₁₉ N ₅ O ₃ S Calcd. : C, 57.42; H, 4.82; N, 17.62. Found: C, 57.46; H, 4.78; N, 17.57. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 3.85 (3H, s), 4.15 (2H, d, J
= 5.2 Hz), 4.87 (1H, br-t, J = 4.
8Hz), 4.92 (2H, s), 6.69 (1H,
d, J = 9.2 Hz), 6.83 (1H, d, J = 8.
4 Hz), 6.89 (1H, t, J = 8.2 Hz),
6.99 (1H, dd, J = 9.0, 3.2 Hz),
7.44 (1H, td, J = 7.5, 1.4 Hz),
7.55 (1H, dd, J = 7.7, 1.5 Hz),
7.77 (1H, d, J = 2.8 Hz), 8.05 (1
H, s). IR (KBr) 1590, 1561, 1518, 147
4,1453,1304 cm ^-1 .

Example 44 (Production of Compound 44) Formic acid (1.5 ml) was added dropwise to acetic anhydride (3.0 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(4-Methoxy-2-nitrophenyl) sulfanyl] phenyl] amine (613 mg) was dissolved in tetrahydrofuran (40 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 20.5 hours and at 80 ° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-methoxy -2-Nitrophenyl) sulfanyl] phenyl] formamide (Compound 44) (160 mg) was obtained as colorless crystals. mp 171.5-173.5 ° C. Elemental analysis value: C ₂₀ H ₁₉ N ₅ O ₄ S Calcd. : C, 56.46; H, 4.50; N, 16.46. Found: C, 56.17; H, 4.65; N, 16.20. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H,
s), 3.87 (3H, s), 4.74 (2H, s),
5.85 (2H, br), 6.58 (1H, d, J =
8.8 Hz), 6.93 (1H, dd, J = 8.8,
3.0 Hz), 7.14-7.18 (1H, m), 7.
40-7.48 (3H, m), 7.52 (1H, s),
7.65 (1H, d, J = 2.8 Hz), 8.06 (1
H, s). IR (KBr) 1667, 1591, 1563, 152
0, 1474, 1439, 1302 cm ^-1 .

Example 45 (Production of compound 45) Formic acid (1.5 ml) was added dropwise to acetic anhydride (3.0 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(4-Methoxy-2-nitrophenyl) sulfanyl] phenyl] amine (613 mg) was dissolved in tetrahydrofuran (40 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 20.5 hours and at 80 ° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give [4-formylamino-2-methyl-
5-pyrimidinyl] methyl [2- (4-methoxy-2-
[Nitrophenylsulfanyl) phenyl] formamide (compound 45) (413 mg) was obtained as colorless crystals. mp 167-168 ° C. Elemental analysis value: C ₂₁ H ₁₉ N ₅ O ₅ S Calcd. : C, 55.62; H, 4.22; N, 15.44. Found: C, 55.58; H, 4.22; N, 15.23. ¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H,
s), 3.88 (3H, s), 4.78 (2H, s),
6.76 (1H, d, J = 8.8 Hz), 6.99 (1
H, dd, J = 8.8, 3.0 Hz), 7.03-7.
10 (1H, m), 7.42-7.47 (3H, m),
7.64 (1H, d, J = 3.0 Hz), 7.83 (1
H, s), 8.02 (1H, s), 9.61 (1H,
d, J = 9.2 Hz), 9.85 (1H, d, J = 9.
8 Hz). IR (KBr) 1705, 1659, 1574, 152
0, 1474, 1427, 1221 cm ^-1 .

Example 46 (Preparation of compound 46) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-nitrophenyl) sulfanyl] phenyl] formamide (1.45 g) was added to tetrahydrofuran-methanol. (1: 1, 30 ml) and water (2
0 ml), potassium carbonate (3.04 g) and sodium hydrosulfite (80%: 3.19 g) were added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-amino Phenyl) sulfanyl] phenyl] formamide (compound 46) (393m
g) was obtained as colorless crystals. mp 189-190 ° C. Elemental analysis value: C ₁₉ H ₁₉ N ₅ OS · 0.1H ₂ O Calcd. : C, 62.14; H, 5.27; N, 19.07. Found: C, 62.16; H, 5.62; N, 18.68. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.07 (2H, s), 4.76 (2H, s),
6.05 (2H, br), 6.72-6.81 (3H,
m), 6.95 (1H, dd, J = 7.4, 1.8H)
z), 7.09-7.30 (4H, m), 7.56 (1
H, s), 8.20 (1H, s). IR (KBr) 1659, 1613, 1593, 156
1,1472,1437,1372,752,731c
m ^-1 .

Example 47 (Production of Compound 47) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (15 ml), and potassium carbonate (1.47 g) was added. ) And N- [2
-[(2-aminophenyl) sulfanyl] phenyl]
Acetamide (1.85 g) in acetone (30 m
l) was added at room temperature, respectively. The mixture was stirred at 65 ° C. for 6 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Under reduced pressure,
The solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
[2-[[2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] sulfanyl] phenyl] acetamide (compound 47) (974 m
g) was obtained as colorless crystals. mp 124-125 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H,
s), 2.45 (3H, s), 4.14 (2H, d, J
= 5.4 Hz), 4.94, (2H, br), 5.34
(1H, t-like), 6.67-6.78 (2H,
m), 7.01-7.08 (2H, m), 7.17-
7.31 (2H, m), 7.43-7.47 (2H,
m), 7.60 (1H, d, J = 8.0 Hz), 8.0
6 (1H, s). IR (KBr) 1645, 1591, 1566, 151
6,1470,1456,1435,1308,75
0,733 cm ^-1 .

Example 48 (Production of Compound 48) Formic acid (4.5 ml) was added dropwise to acetic anhydride (9.0 ml) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). N- [2-
[[2-[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] sulfanyl] phenyl] acetamide (550 mg) and triethylamine (0.61 ml) in tetrahydrofuran (25 ml)
And added dropwise at 0 ° C. The mixture was stirred at room temperature for 20 hours, and further heated to reflux for 16.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N- [2-[[2-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl]
Phenyl] acetamide (compound 48) (197 mg)
Was obtained as colorless crystals. mp 177-179 ° C. Elemental analysis _{C 21 H 21 N 5 O 2} S · 0.33H Calcd the ₂ O. : C, 61.01; H, 5.28; N, 16.94. Found: C, 61.23; H, 5.26; N, 16.60. ¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H,
s), 2.47 (3H, s), 4.73, (2H,
s), 6.03 (2H, br), 6.69-6.73.
(1H, m), 6.99-7.03 (1H, m), 7.
13 (1H, td, J = 7.6, 1.5 Hz), 7.1
9-7.25 (2H, m), 7.33 (1H, dd, J
= 7.6, 1.4 Hz), 7.47 (1H, td, J =
7.1, 2.0 Hz), 7.56 (1H, s), 7.8
3 (1H, br), 8.19 (1H, s), 8.41
(1H, br-d, J = 7.8 Hz). IR (KBr) 1667, 1591, 1578, 151
2,1472,1435 cm ^-1 .

Example 49 (Production of Compound 49) Formic acid (4.5 ml) was added dropwise to acetic anhydride (9.0 ml) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). N- [2-
[[2-[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] sulfanyl] phenyl] acetamide (550 mg) and triethylamine (0.61 ml) in tetrahydrofuran (25 ml)
And added dropwise at 0 ° C. The mixture was stirred at room temperature for 20 hours, and further heated to reflux for 16.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N- [2-[[2- [formyl [[4- (formylamino) -2-methyl-5-pyrimidinyl] methyl] amino] phenyl] sulfanyl] phenyl] acetamide (Compound 49) (62m
g) was obtained as colorless crystals. mp 167-168 ° C (decomposition). Elemental analysis _{C 22 H 21 N 5 O 3} S · 1.1H Calcd the ₂ O. : C, 58.03; H, 5.14; N, 15.38. Found: C, 57.85; H, 4.74; N, 14.99. ¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H,
s), 2.60 (3H, s), 4.76, (2H,
s), 6.73-6.77 (1H, m), 7.01-
7.28 (5H, m), 7.47 (1H, t, J = 8.
4 Hz), 7.78 (1H, brs), 7.89 (1
H, s), 8.20 (1H, s), 8.38 (1H,
d, J = 8.8 Hz), 9.68 (1H, d, J = 9.
2Hz), 10.03 (1H, br-d, J = 9.2H)
z). IR (KBr) 1705, 1661, 1574, 151
2,1474,1429,1219 cm ^-1 .

Example 50 (Production of Compound 50) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-aminophenyl) sulfanyl] phenyl] formamide (270 mg) was added to tetrahydrofuran (10 ml). Dissolve, pyridine (0.090 ml)
And benzoyl chloride (0.094 ml) were added at room temperature. The mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ether-hexane to give N- [2-[[2-[[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] phenyl] benzamide (Compound 50) (306 mg) was obtained as colorless crystals. mp 160-161 ° C. Elemental analysis value: C ₂₆ H ₂₃ N ₅ O ₂ S Calcd. : C, 66.50; H, 4.94; N, 14.91. Found: C, 66.41; H, 5.01; N, 14.78. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.4-5.1 (2H, br), 5.90 (2
H, br), 6.78 (1H, dd, J = 6.8, 2.
2 Hz), 7.11-7.23 (4H, m), 7.41
−7.60 (5H, m), 7.66-7.70 (2H,
m), 8.12 (1H, s), 8.66 (1H, d, J
= 7.6 Hz). IR (KBr) 1667, 1580, 1514, 149
1,1472,1433,1302 cm ^-1 .

Example 51 (Production of compound 51) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.85 g) was added to acetone (100 ml).
Suspended in potassium carbonate (2.71 g) and N- [2
-[(2-aminophenyl) sulfanyl] phenyl]
-N- (Methylsulfonyl) methanesulfonamide (3.65 g) was added at room temperature. Mix 70
Stirred at C for 22 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate-hexane to give N-
[2-[[2-[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] sulfanyl] phenyl] -N- (methylsulfonyl) methanesulfonylamide (Compound 51) (1.67 g) ) Was obtained as colorless crystals. mp 204 ° C (decomposition). Elemental analysis value: C ₂₀ H ₂₃ N ₅ O ₄ S ₃ Calcd. : C, 48.66; H, 4.70; N, 14.19. Found: C, 48.65; H, 4.87; N, 14.04. ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H,
s), 3.56 (6H, s), 4.08 (2H, d, J
= 5.2 Hz), 4.61, (2H, br), 5.45
(1H, t-like), 6.69 (1H, dd, J =
8.0, 0.6 Hz), 6.76-6.84 (2H,
m), 7.21-7.38 (4H, m), 7.54 (1
H, dd, J = 7.7, 1.5 Hz), 8.03 (1
H, s). IR (KBr) 1645, 1593, 1572, 150
8, 1464, 1366, 1345, 1327, 117
3,1157,903,760,561 cm ^-1 .

Example 52 (Production of Compound 52) Formic acid (5.4 ml) was added dropwise to acetic anhydride (10.8 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N- [2-
[[2-[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] sulfanyl] phenyl] -N- (methylsulfonyl) methanesulfonylamide (890 mg) in tetrahydrofuran (80 ml)
And added dropwise at 0 ° C. The mixture was stirred at 85 ° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate (AcOEt) to give N- [2-
[[2- [formyl [[4- (formylamino) -2-
Methyl-5-pyrimidinyl] methyl] amino] phenyl] sulfanyl] phenyl] -N- (methylsulfonyl) methanesulfonylamide (Compound 52) (877 m
g) was obtained as colorless crystals. mp 95-100 ° C. Elemental analysis value: C ₂₂ H ₂₃ N ₅ O ₆ S ₃ .AcOEt Calcd. : C, 48.97; H, 4.90; N, 10.98. Found: C, 48.87; H, 4.84; N, 10.92. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H,
s), 3.45 (6H, s), 4.78, (2H,
s), 6.84-6.89 (1H, m), 7.09-
7.13 (1H, m), 7.30-7.42 (6H,
m), 7.81 (1H, s), 8.17 (1H, s),
9.62 (1H, d, J = 9.2 Hz), 9.87 (1
H, d, J = 9.0 Hz). IR (KBr) 1705, 1659, 1574, 137
0,1161 cm ^-1 .

Example 53 (Preparation of Compound 53) N- [2-[[2- [Formyl [[4- (formylamino) -2-methyl-5-pyrimidinyl] methyl] amino] phenyl] sulfanyl] phenyl] -N- (methylsulfonyl) methanesulfonylamide (618 mg)
With tetrahydrofuran-methanol (1: 1, 10 m
l) and dissolved in a 1N aqueous sodium hydroxide solution (10 m
l) was added. The mixture was stirred at room temperature for 17 hours. A saturated saline solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N- [2-[[2-[[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] phenyl] methanesulfonylamide (Compound 53) (474 mg) was obtained as an amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 2.99 (3H, s), 4.74, (2H, b
r), 6.21 (2H, br), 6.74-6.80.
(1H, m), 6.98-7.04 (1H, m), 7.
10-7.36 (5H, m), 7.40-7.54 (1
H, m), 7.59 (1H, s), 7.70 (1H,
d, J = 8.4 Hz), 8.18 (1H, s). IR (KBr) 1651, 1590, 1472, 143
5,1331,1153,972,914,762,7
33 cm ^-1 .

Example 54 (Production of compound 54) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.70 g) was suspended in acetone (90 ml), and potassium carbonate (2.49 g) was added. ) And 2-[[4
-(2-Phenoxyethoxy) phenyl] sulfanyl] aniline (3.04 g) was added at room temperature.
The mixture was stirred at 65 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate.
The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ethanol to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N -[2-[[4- (2-phenoxyethoxy) phenyl] sulfanyl] phenyl]
The amine (compound 54) (1.50 g) was obtained as colorless crystals. mp 154-155 ° C. Elemental analysis value: C ₂₆ H ₂₆ N ₄ O ₂ S Calcd. : C, 68.10; H, 5.71; N, 12.22. Found: C, 67.95; H, 6.01; N, 12.08. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 4.13 (2H, d, J = 5.2 Hz), 4.2
5-4.33 (4H, m), 4.80 (1H, t, J =
5.8 Hz), 4.93 (2H, brs), 6.74-
6.86 (4H, m), 6.94-7.09 (5H,
m), 7.28-7.36 (3H, m), 7.52 (1
H, dd, J = 7.3, 1.5 Hz), 8.06 (1
H, s). IR (KBr) 1590, 1568, 1493, 145
3,1240 cm ^-1 .

Example 55 (Production of Compound 55) Formic acid (1.0 ml) was added dropwise to acetic anhydride (2.0 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[[4- (2-phenoxyethoxy) phenyl]
Sulfanyl] phenyl] amine (600 mg) was dissolved in tetrahydrofuran (30 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ethanol to give 4-amino-2-methyl-5-pyrimidinyl) methyl [2-[[4 -(2-phenoxyethoxy)
[Phenyl] sulfanyl] phenyl] formamide (compound 55) (402 mg) was obtained as colorless crystals. mp 166-167 ° C. Elemental analysis value: C ₂₇ H ₂₆ N ₄ O ₃ S Calcd. : C, 66.65; H, 5.39; N, 11.51. Found: C, 66.38; H, 5.38; N, 11.53. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.35 (4H, s), 4.72 (2H, b
r), 6.01 (2H, br), 6.85-7.02
(7H, m), 7.11 (1H, td, J = 7.4,
1.7 Hz), 7.19 (1H, dd, J = 7.8,
1.6Hz), 7.24-7.35 (4H, m), 7.
55 (1H, s), 8.12 (1H, s). IR (KBr) 1667, 1593, 1493, 147
2,1242 cm ^-1 .

Example 56 (Production of Compound 56) Formic acid (1.0 ml) was added dropwise to acetic anhydride (2.0 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[[4- (2-phenoxyethoxy) phenyl]
Sulfanyl] phenyl] amine (600 mg) was dissolved in tetrahydrofuran (30 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give [4- (formylamino)-
2-methyl-5-pyrimidinyl] methyl [2-[[4-
(2-phenoxyethoxy) phenyl] sulfanyl]
Phenyl] formamide (Compound 56) (184 mg)
Was obtained as colorless crystals. mp 94-95 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H,
s), 4.35 (4H, s), 4.77 (2H, s),
6.92-7.03 (7H, m), 7.12-7.36
(6H, m), 7.87 (1H, s), 8.12 (1
H, s), 9.68 (1H, d, J = 9.0 Hz), 1
0.08 (1H, d, J = 10.2 Hz). IR (KB
r) 1707, 1659, 1574, 1493, 124
2 cm ^-1 .

Example 57 (Production of Compound 57) 4-Amino-5-bromomethyl-2-phenylpyrimidine hydrobromide (700 mg) was suspended in tetrahydrofuran (30 ml), and potassium carbonate (701 mg) was obtained.
And (E) -3-phenyl-2-propenyl 2-aminobenzoic acid (1.03 g) were added at room temperature, respectively. The mixture was stirred at 75 ° C. for 14 hours. The reaction mixture is placed under reduced pressure
Concentrate and dilute the residue with ethyl acetate. The mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (E) -3-phenyl-2-propenyl 2-[[(4-amino-2- Phenyl-5-pyrimidinyl) methyl] amino] benzoic acid (Compound 57)
(621 mg) was obtained as colorless crystals. mp 163 ° C. Elemental analysis value: C ₂₇ H ₂₄ N ₄ O ₂ Calcd. : C, 74.29; H, 5.54; N, 12.84. Found: C, 74.15; H, 5.54; N, 12.66. ¹ H-NMR (CDCl ₃ ) δ: 4.33 (2H, d,
J = 4.8 Hz), 4.92 (2H, d, J = 6.2H)
z), 5.27 (2H, s), 6.38 (1H, dt,
J = 15.8, 6.2 Hz), 6.39-6.83 (3
H, m), 7.29-7.47 (9H, m), 7.79.
(1H, t-like), 8.03 (1H, dd, J =
8.0, 1.4 Hz), 8.33-8.37 (3H,
m). IR (KBr) 1682, 1613, 1578, 144
1,1408,1254,1225 cm ^-1 .

Example 58 (Preparation of Compound 58) N- (4-amino-2-phenyl-5-pyrimidinyl)
Methylbenzothiazolium bromide hydrobromide (73
0 mg) was suspended in water (9.0 ml), and a 10% aqueous sodium hydroxide solution (1.82 ml) and ethanol (9.0 ml) were added at room temperature. The mixture was stirred at room temperature for 1 hour. 2-bromoethyl ethyl ether (0.26
ml) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-phenyl-5-pyrimidinyl).
Methyl [2-[(2-ethoxyethyl) sulfanyl]
Phenyl] formamide (compound 58) (428 mg)
Was obtained as colorless crystals. mp 105 ° C. Elemental analysis value: C ₂₂ H ₂₄ N ₄ O ₂ S Calcd. : C, 64.68; H, 5.92; N, 13.71. Found: C, 64.61; H, 5.82; N, 13.59. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t,
J = 7.0 Hz), 3.07 (2H, t, J = 6.6H)
z), 3.43 (2H, q, J = 6.9 Hz), 3.5
3 (2H, t, J = 6.6 Hz), 4.78 (2H, b
r), 6.10 (2H, br), 6.90 (1H, d,
J = 7.8 Hz), 7.14 (1H, td, J = 7.
4,2.1 Hz), 7.35 (1H, td, J = 8.
2,1.5 Hz), 7.38-7.45 (4H, m),
7.68 (1H, s), 8.12 (1H, s), 8.2
9-8.34 (2H, m). IR (KBr) 1661, 1582, 1472, 144
5,1435,1408 cm ^-1 .

Example 59 (Production of Compound 59) To a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) was added a solution of methylamine in tetrahydrofuran (2.0 M, 2.5 ml) at 0 ° C. It was dropped over time. Furthermore, triethylamine (0.7m
A solution of 1) in tetrahydrofuran (5 ml) was added dropwise over 10 minutes, and the mixture was stirred at the same conditions for 90 minutes and at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and N, N-dimethylformamide (20 ml) and 4-dimethylaminopyridine (670 m
g) was added, and 4-amino-5-aminomethyl-2-methylpyrimidine (692 mg) was further added at 0 ° C. Stir for 1 hour under the same conditions, then at room temperature for 15 hours, 130
Stirred at C for 1 hour. Air-cool to room temperature, acetic acid (5 ml)
Was added and the mixture was heated and stirred at 160 ° C. for 3 hours and 30 minutes. The mixture was air-cooled to room temperature, and saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (300 ml) were added to carry out liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were collected and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-methyl-1,3-dioxo-
5-isoindolinecarboxamide (Compound 59) (4
74 mg). mp 267 ° C Elemental analysis value C ₁₆ H ₁₅ N ₅ O ₃ .0.1H ₂ O Calcd. C, 58.75; H, 4.68; N, 21.41. Found C, 58.84; H, 4.62; N, 21.18. ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 2.83 (3H, d, J = 4.2 Hz), 4.5
7 (2H, s), 6.72 (2H, s, br), 7.9
3 (1H, s), 7.99 (1H, d, J = 8.2H)
z), 8.26-8.30 (2H, m), 8.85 (1
H, d, J = 4.2 Hz).

Example 60 (Production of Compound 60) Anhydrous trimellitate chloride (1.06 g) was dissolved in tetrahydrofuran (10 ml), and diphenylmethylamine (915 mg) was added with stirring in an ice bath. Immediately, triethylamine (0.7 ml) was added, and the mixture was stirred under the same conditions for 0.5 hour. Tetrahydrofuran was distilled off under reduced pressure, and dimethylformamide (10 ml) was added to the residue to dissolve it. 4-dimethylaninopyridine (1.41
g) and 4-amino-5-aminomethyl-2-methylpyrimidine (690 mg) was added thereto while stirring in an ice bath.
The mixture was stirred in an ice bath for 1 hour and at a bath temperature of 60 ° C. for 15 minutes. Next, acetic acid (5 ml) was added, and the mixture was stirred at a bath temperature of 165 ° C. for 0.5 hour. Water (150 ml) and ethyl acetate (250 m
l) was added, shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate (50 ml), dried and dried to give 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzhydryl-1,3-dioxo-5-isoindolinecarboxamide (Compound 60). )
(1.57 g) was obtained as colorless crystals. Recrystallized from ethanol. mp 255-256 ° C. Elemental analysis value C ₂₈ H ₂₃ N ₅ O ₃ Calcd. : C, 70.43%; H, 4.85%; N, 14.67% Found: C, 70.27%; H, 4.79%; N, 14.56% ¹ H-NMR (DMSO- d ₆ ) δ: 2.30 (3H,
s), 4.57 (2H, s), 6.43 (1H, d),
6.74 (2H, br), 7.23-7.40 (10
H, m), 7.91 (1H, br), 8.00 (1H,
d), 8.36 (1H, dd), 8.45 (1H,
s), 9.70 (1H, d).

Example 61 (Production of Compound 61) 2-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzhydryl-1,3-dioxo-5
-Isoindolinecarboxamide (478 mg) was dissolved in ethanol (40 ml), 2N hydrochloric acid (0.5 ml) and concentrated under reduced pressure. Acetone was added to the residue, and the precipitated crystals were collected by filtration. This is crystallized from ethanol to give 2-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N-benzhydryl-1,3-dioxo-5-isoindolinecarboxamide hydrochloride (Compound 61) (3
10 mg) were obtained as colorless crystals. mp 188-190 ° C. Elemental analysis value C ₂₈ H ₂₄ N ₅ O ₃ Cl Calcd. : C, 65.43%; H, 4.71%; N, 13.63% Found: C, 65.19%; H, 4.62%; N, 13.46% ¹ H-NMR (DMSO- d ₆ ) δ: 2.50 (3H,
s), 4.63 (2H, s), 6.45 (1H, d),
7.25-7.39 (10H, m), 8.02 (1H,
d), 8.22 (1H, s), 8.40 (1H, d),
8.48 (1H, s), 9.20 (1H, br), 9.
73 (1H, d).

Example 62 (Production of Compound 62) Anhydrous trimellitate chloride (422 mg) was dissolved in tetrahydrofuran (5 ml), and dibenzylamine (394 mg) was added with stirring in an ice bath. 3 ml) and stirred under the same conditions for 0.5 hour. Tetrahydrofuran was distilled off under reduced pressure, and dimethylformamide (10 ml) was added to the residue to dissolve it. 4-Dimethylaninopyridine (366 mg) was added, and while stirring in an ice bath, 4-amino-5-aminomethyl-2-methylpyrimidine (300 mg) was added, and the mixture was added in an ice bath.
The mixture was stirred for 15 minutes at a bath temperature of 60 ° C. Next, acetic acid (3m
l) was added and the mixture was stirred at a bath temperature of 165 ° C for 0.5 hour. Aqueous sodium hydrogencarbonate (150 ml) and ethyl acetate (250 ml) were added to the reaction solution, shaken, and separated. The upper layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-[(4-amino-2-methyl-
5-pyrimidinyl) methyl] -N, N-dibenzyl-
1,3-Dioxo-5-isoindolinecarboxamide was obtained as a pale yellow candy (730 mg). This was dissolved in ethanol (30 ml) and 2N hydrochloric acid (0.75 m
l) was added and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N, N-dibenzyl-1,3-dioxo-5-isoindolinecarboxamide hydrochloride (Compound 62) ) (600 mg) as colorless crystals. mp 168-169 ° C Elemental analysis: C ₂₉ H ₂₆ N ₅ O ₃ Cl 1.5 H ₂ O Calcd. : C, 62.76%; H, 5.27%; N, 12.62% Found: C, 62.99%; H, 5.39%; N, 12.60% ¹ H-NMR (DMSO- d ₆ ) δ: 2.49 (3H,
s), 4.41 (2H, s), 4.60 (2H, s),
4.63 (2H, s), 7.17-7.43 (10H,
m), 7.93-7.99 (3H, m), 8.19 (1
H, s), 8.45 (1H, br), 9.20 (1H,
br).

Example 63 (Production of Compound 63) To a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) was added benzylamine (0.55 ml) and triethylamine (0.7 ml) at 0 ° C. The mixture was stirred under the same conditions for 50 minutes. After stirring at room temperature for further 40 minutes, the solvent was distilled off under reduced pressure. N, N-dimethylformamide (20 ml) was added thereto, and the mixture was further added at 0 ° C for 4 hours.
-Dimethylaminopyridine (671 mg) and 4-amino-5-aminomethyl-2-methylpyrimidine (691 m
g) was added. The mixture was stirred under the same conditions for 45 minutes, then at room temperature for 40 minutes and at 130 ° C. for 30 minutes. After cooling to room temperature, acetic acid (5 ml) was added, and the mixture was heated and stirred at 160 ° C. for 30 minutes. Air-cool to room temperature and add saturated aqueous sodium bicarbonate (1
50 ml) and ethyl acetate (200 ml) were added to carry out liquid separation. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 2-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-1,3-dioxo-5-isoindolinecarboxamide (Compound 63) (294 mg)
I got mp 249-250 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 4.52 (2H, d, J = 6.0 Hz), 4.5
7 (2H, s), 6.74 (2H, s, br), 7.2
5-7.36 (5H, m), 7.92 (1H, s),
8.01 (1H, d, J = 7.8 Hz), 8.33 −
8.37 (2H, m), 9.45 (1H, t, J = 6.
0 Hz).

Example 64 (Production of Compound 64) In a solution of anhydrous trimellitate acid chloride (1.1 g) in tetrahydrofuran (10 ml) at 0 ° C, 2,2-diphenylethylamine (986 mg) and triethylamine (0.
7 ml) and stirred under the same conditions for 30 minutes. After stirring at room temperature for further 20 minutes, the solvent was distilled off under reduced pressure. To this, N, N-dimethylformamide (20 ml) was added, and at 0 ° C., 4-dimethylaminopyridine (671 mg).
And 4-amino-5-aminomethyl-2-methylpyrimidine (692 mg) were added. The mixture was stirred for 40 minutes under the same conditions, and then for 40 minutes at room temperature and 30 minutes at 130 ° C.
Air-cool to room temperature, add acetic acid (5 ml), and add
The mixture was heated and stirred for 0 minutes. The mixture was air-cooled to room temperature, and saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (200 ml) were added to carry out liquid separation. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- (2,2-diphenylethyl).
-1,3-Dioxo-5-isoindolinecarboxamide (Compound 64) (237 mg) was obtained. mp 268-269 ° C (decomposition) Elemental analysis value C ₂₉ H ₂₅ N ₅ O ₃ Calcd. : C, 70.86; H, 5.13; N, 14.25. Found: C, 70.76; H, 5.16; N, 14.05. ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 3.92-3.98 (2H, m), 4.44 (1
H, t, J = 7.6), 4.54 (2H, s), 6.7.
1 (2H, s, br), 7.17-7.33 (10H,
m), 7.90 (1H, s), 7.95 (1H, d, J
= 8.4 Hz), 8.16 (1H, s), 8.17 (1
H, d, J = 8.4 Hz), 8.95 (1H, s, b)
r).

Example 65 (Preparation of Compound 65) N-benzhydryl-1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide (896)
mg) in N, N-dimethylformamide (10 ml) and 4-dimethylaminopyridine (336 mg).
-Amino-5-aminomethyl-2-phenylpyrimidine (501 mg) was added. 90 minutes at room temperature, 1 at 130 ° C
Stirred for hours. The mixture was air-cooled to room temperature, acetic acid (3 ml) was added, and the mixture was heated and stirred at 160 ° C for 1 hour. Air cool to room temperature,
Saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (300 ml) were added to carry out liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were collected and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was suspended in ethanol.
1N hydrochloric acid (2.5 ml) was added. This is dried under reduced pressure,
Ethanol-acetone was added to the residue, and the mixture was allowed to stand for 3 days. The resulting crystals were collected by filtration and 2-[(4-amino-2-phenyl-5-pyrimidinyl) methyl] -N-benzhydryl-1,3-dioxo- 5-isoindolinecarboxamide hydrochloride (compound 65) (262 mg) was obtained. mp 214-215 ° C. Elemental analysis value C ₃₃ H ₂₅ N ₅ O ₃ .HCl.3H ₂ O Calcd. : C, 62.90; H, 5.12; N, 11.11. Found: C, 63.07; H, 5.05; N, 11.00. ¹ H-NMR (DMSO-d ₆ ) δ: 4.67 (2H,
s), 6.44 (1H, d, J = 8.4 Hz), 6.9
5 (2H, s, br), 7.28-7.47 (13H,
m), 8.02 (1H, d, J = 7.8 Hz), 8.1
6 (1H, s), 8.26-8.29 (2H, m),
8.38 (1H, d, J = 7.8 Hz), 8.48 (1
H, s), 9.71 (1H, d, J = 8.4 Hz).

Example 66 (Production of Compound 66) In a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) was added 2-phenylethylamine (0.63 ml) and triethylamine (0.7 m2) at 0 ° C.
l) was added. The temperature was gradually raised from 0 ° C. to room temperature and stirred for 15 hours. The solvent was distilled off under reduced pressure, and N, N-dimethylformamide (20 ml) was added thereto.
-Dimethylaminopyridine (673 mg) and 4-amino-5-aminomethyl-2-methylpyrimidine (690 m
g) was added. The mixture was stirred for 1 hour under the same conditions, and then for 4 hours at room temperature and 1 hour at 130 ° C. Air cool to room temperature,
Acetic acid (5 ml) was added, and the mixture was heated and stirred at 160 ° C. for 1 hour. Air-cool to room temperature and add saturated aqueous sodium hydrogen carbonate (15
0 ml) and ethyl acetate (300 ml) were added, and the insoluble solid was collected by filtration. This was recrystallized from ethanol to give 2-
[(4-amino-2-methyl-5-pyrimidinyl) methyl] -1,3-dioxo-N- (2-phenylethyl)
-5-isoindolinecarboxamide (compound 66)
(285 mg). mp 256-257 ° C Elemental analysis: C ₂₃ H ₂₁ N ₅ O ₃ .0.5H ₂ O Calcd. : C, 65.08; H, 5.22; N, 16.50. Found: C, 65.25; H, 5.04; N, 16.26. ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 2.87 (2H, t, J = 6.6 Hz), 3.5
1-3.55 (2H, m), 4.56 (2H, s),
6.72 (2H, s, br), 7.20-7.34 (5
H, m), 7.92 (1H, s), 7.99 (1H,
d, J = 8.4 Hz), 8.27 (1H, d, J = 8.
4Hz), 8.29 (1H, s), 8.98 (1H,
s, br).

Example 67 (Preparation of Compound 67) In a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) at 0 ° C., 3,3-diphenylpropylamine (1.1 g) and triethylamine (1.0 g) were added. .
7 ml) was added. Gradually raise the temperature from 0 ° C to room temperature,
Stir for 5 hours. The solvent was distilled off under reduced pressure, N, N-dimethylformamide (20 ml) was added thereto, and 4-dimethylaminopyridine (672 mg) and 4-amino-5-aminomethyl-2-methylpyrimidine (690) were added at 0 ° C.
mg) was added. The mixture was stirred for 1 hour under the same conditions, and then for 4 hours at room temperature and 1 hour at 130 ° C. The mixture was air-cooled to room temperature, acetic acid (5 ml) was added, and the mixture was heated and stirred at 160 ° C. for 1 hour. Air-cool to room temperature and add saturated aqueous sodium bicarbonate (1
(50 ml) and ethyl acetate (300 ml). The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) and recrystallized from ethanol to give 2-[(4-amino-2-methyl-
[5-Pyrimidinyl) methyl] -N- (3,3-diphenylpropyl) -1,3-dioxo-5-isoindolinecarboxamide (Compound 67) (474 mg) was obtained. mp 255 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 2.29-2.40 (2H, m), 3.18-
3.25 (2H, m), 4.06 (1H, t, J = 8.
0 Hz), 4.57 (2H, s), 6.73 (2H,
s, br), 7.17-7.36 (10H, m), 7.
92 (1H, s), 7.98 (1H, d, J = 7.6H)
z), 8.28 (1H, d, J = 7.6 Hz), 8.3
0 (1H, s), 8.89 (1H, s, br).

Example 68 (Production of Compound 68) Benzylmethylamine (0.65 ml) and triethylamine (0.7 ml) were added to a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) at 0 ° C.
Were added in order. The temperature was gradually raised from 0 ° C. to room temperature and stirred for 15 hours. After further heating at 60 ° C. for 30 minutes, the solvent was distilled off under reduced pressure. N, N-dimethylformamide (20 ml) and 4-dimethylaminopyridine (672 m
g) was added, and 4-amino-5-aminomethyl-2-methylpyrimidine (690 mg) was further added at 0 ° C. Stir for 80 minutes under the same conditions, then at room temperature for 1 hour, 130 ° C
For 30 minutes. The mixture was air-cooled to room temperature, acetic acid (5 ml) was added, and the mixture was heated and stirred at 160 ° C. for 1 hour. The mixture was air-cooled to room temperature, and saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (300 ml) were added to carry out liquid separation. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 2-[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] -N-benzyl-N-methyl-1,3-dioxo-5-isoindolinecarboxamide (Compound 68) (90 mg). mp 201 ° C. Elemental analysis value C ₂₃ H ₂₁ N ₅ O ₃ .0.25 H ₂ O Calcd. : C, 65.78; H, 5.16; N, 16.68. Found: C, 65.58; H, 5.31; N, 16.43. ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 2.81 (3H, s), 4.57 (2H, s),
4.71 (2H, s), 6.72 (2H, s, br),
7.18-7.38 (5H, m), 7.89-7.99
(4H, m).

Example 69 (Preparation of Compound 69) To a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) at 0 ° C was added 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride ( 918 mg)
And triethylamine (1.4 ml) were added in order. The mixture was stirred under the same conditions for 2 hours, and further stirred at room temperature overnight (15 hours). The solvent was distilled off under reduced pressure, and N, N-dimethylformamide (20 ml) and 4-dimethylaminopyridine (67
1 mg), and 4-amino-5-aminomethyl-2-methylpyrimidine (691 mg) was further added at 0 ° C. Stir for 30 minutes under the same conditions, then at room temperature for 1 hour, 1 hour
Stirred at 30 ° C. for 1 hour. Air cool to room temperature and add acetic acid (5m
l) was added, and the mixture was heated and stirred at 160 ° C. for 1 hour. The mixture was air-cooled to room temperature, and saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (300 ml) were added to carry out liquid separation. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 2-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -1,3.
-Dioxo-N- (1,2,3,4-tetrahydro-1
-Naphthalenyl) -5-isoindolinecarboxamide (Compound 69) (92 mg) was obtained. mp 275-276 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.70-2.1
3 (4H, m), 2.29 (3H, s), 2.79 (2
H, s, br), 4.57 (2H, s), 5.25 (1
H, s, br), 6.74 (2H, s, br), 7.1
6-7.20 (4H, m), 7.91 (1H, s),
8.00 (1H, d, J = 7.4 Hz), 8.37 (1
H, d, J = 7.4 Hz), 8.39 (1H, s),
9.22 (1H, d, J = 8.0 Hz).

Example 70 (Preparation of Compound 70) To a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) at 0 ° C was added 1-benzyl-4-.
A solution of aminopiperidine (1.02 ml) in tetrahydrofuran (10 ml) was added dropwise over 2 hours. Subsequently, triethylamine (0.7 ml) in tetrahydrofuran (5 m
l) The solution was added and stirred for 4 hours under the same conditions. The mixture was further stirred at room temperature for 15 hours, and the solvent was distilled off under reduced pressure. N, N
-Dimethylformamide (20 ml) and 4-dimethylaminopyridine (671 mg) were added.
Amino-5-aminomethyl-2-methylpyrimidine (6
91 mg) was added. The mixture was stirred under the same conditions for 20 minutes, and then at room temperature for 2 hours and at 130 ° C. for 1 hour. The mixture was air-cooled to room temperature, acetic acid (5 ml) was added, and the mixture was heated and stirred at 160 ° C. for 1 hour. The mixture was air-cooled to room temperature, and saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (300 ml) were added to carry out liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were collected and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 2-[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] -N- (1-benzyl-4-piperidinyl) -1,3-dioxo-5-isoindolinecarboxamide (Compound 70) (667)
mg). mp 241-243 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.57-1.
7 (2H, m), 1.73-1.88 (2H, m),
1.95-2.13 (2H, m), 2.29 (3H,
s), 2.80-2.87 (2H, m), 3.48 (2
H, s), 3.79 (1H, s, br), 4.57 (2
H, s), 6.72 (2H, s, br), 7.10-
7.32 (5H, m), 7.91 (1H, s), 7.9
8 (1H, d, J = 7.8 Hz), 8.29 (1H,
d, J = 7.8 Hz), 8.33 (1H, s), 8.6
8 (1H, d, J = 8.0 Hz).

Example 71 (Production of Compound 71) To a solution of 4-amino-5-aminomethyl-2-methylpyrimidine (4.8 g) in pyridine (300 ml) was added 4-dimethylaminopyridine (4.9 g). Was. After cooling to 0 ° C., 1 g of monomethyl terephthalate chloride (7.0 g) was added.
Added over 5 minutes. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to carry out liquid separation, and the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from ethanol to give 4-
[[[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] amino] carbonyl) methyl benzoate (Compound 71) (5.5 g) was obtained. mp 236 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 3.88 (3H, s), 4.27 (2H, d, J
= 5.8 Hz), 6.78 (2H, s, br), 7.9
5 (1H, s) 7.97 (2H, d, J = 8.8H
z), 8.06 (2H, d, J = 8.8 Hz), 9.1
9 (1H, t, J = 5.8 Hz).

Example 72 (Preparation of Compound 72) A solution of methyl 4-([[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] carbonyl) benzoate (3.8 g) in tetrahydrofuran (60 ml) To the mixture was added a 2N aqueous sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 2 hours and at 80 ° C for 5 hours. A 2N aqueous sodium hydroxide solution (6 ml) was further added, and the mixture was added at 80 ° C for 30 minutes.
For 15 minutes at room temperature. 1N hydrochloric acid aqueous solution (13m
After l) was added and neutralized, the precipitated crystals were collected by filtration, washed with water,
After washing in the order of ethyl acetate, 4-([[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] amino] carbonyl) benzoic acid (1.3 g) was obtained. In addition, 10m of mother liquor
The resulting crystals were collected by filtration, washed with water and ethyl acetate in that order, and further washed with 4-[[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] carbonyl] benzoic acid ( Compound 72) (1.5 g) was obtained. mp 300 ° C. or higher ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 4.24 (2H, d, J = 5.0 Hz), 6.8
5 (2H, s, br), 7.7-7.8 (2H, m),
7.8-8.0 (3H, m), 9.07 (1H, s, b
r).

Example 73 (Preparation of Compound 73) N-[(4-amino-2-methyl-5-pyrimidinyl)
To a solution of [methyl] -N-benzylamine (3.0 g) in pyridine (60 ml) was added 4-dimethylaminopyridine (1.8 g). After cooling to 0 ° C., monomethyl terephthalate chloride (2.6 g) was added over 10 minutes. 0
After stirring at 90 ° C. for 90 minutes, water and ethyl acetate were added to carry out liquid separation.
The aqueous layer was extracted twice with ethyl acetate, and the organic layer was collected and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from ethanol to give 4-[[[(4-amino-
2-methyl-5-pyrimidinyl) methyl] (benzyl)
Amino] carbonyl] methyl benzoate (compound 73)
(3.0 g) was obtained. mp 194-196 ° C Elemental analysis: C ₂₂ H ₂₂ N ₄ O ₃ Calcd. : C, 67.68; H, 5.68; N, 14.35. Found: C, 67.72; H, 5.87; N, 14.09. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 3.92 (3H, s), 4.37 (2H, s),
4.55 (2H, s), 6.17 (2H, s, br),
7.19 (2H, d, J = 6.6 Hz), 7.35−
7.46 (3H, m), 7.51 (2H, d, J = 8.
4Hz), 7.76 (1H, s), 8.06 (2H,
d, J = 8.4 Hz).

Example 74 (Production of Compound 74) Methyl 4-[[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoate (3.0 g) in tetrahydrofuran ( 30m
1) Add 2N aqueous sodium hydroxide solution (4.3 m
l) was added and the mixture was stirred at room temperature for 15 hours. After neutralizing by adding a 1N aqueous hydrochloric acid solution (8.6 ml), the precipitated crystals are collected by filtration and 4-[[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl ]
Benzoic acid (1.3 g) was obtained. Further, the mother liquor was concentrated to 10 ml, and the generated crystals were collected by filtration.
[[[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] (benzyl) amino] carbonyl] benzoic acid (Compound 74) (1.3 g) was obtained. mp 223-224 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.32 (3H,
s), 4.42 (4H, s), 6.86 (2H, s, b
r), 7.12-7.16 (2H, m), 7.30-
7.34 (3H, m), 7.53 (2H, d, J = 8.
0 Hz), 7.80 (1H, s), 7.96 (2H,
d, J = 8.0 Hz).

Example 75 (Preparation of compound 75) 4-([[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] carbonyl) benzoic acid (1.3
g) in N, N-dimethylformamide (50 ml) solution, diphenylmethylamine (1.2 ml), 1-hydroxybenzotriazole monohydrate (1.1 g), 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.3 g) was sequentially added, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added, and the solid insoluble in both was collected by filtration, washed with water and ethyl acetate in this order, and washed with N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N'-.
Benzhydryl terephthalamide (Compound 75) (1.
5 g) were obtained. mp 300 ° C. or more Elemental analysis value C ₂₇ H ₂₅ N ₅ O ₂ .0.5H ₂ O Calcd. : C, 70.42; H, 5.69; N, 15.21. Found: C, 70.15; H, 5.62; N, 15.49. ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 4.26 (2H, d, J = 5.8 Hz), 6.4
2 (1H, d, J = 8.8 Hz), 6.79 (2H,
s, br), 7.26-7.37 (10H, m), 7.
93 (2H, d, J = 8.2 Hz), 7.94 (1H,
s), 8.02 (2H, d, J = 8.2 Hz), 9.0
8 (1H, t, J = 5.8 Hz), 9.41 (1H,
d, J = 8.8 Hz).

Example 76 (Preparation of Compound 76) 4-[[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoic acid (0.38 g) in dimethylformamide (0.38 g) 20ml)
Benzhydrylamine (0.28 g), 1-hydroxybenzotriazole monohydrate (0.23 g) 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added.
Washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-ethanol), and the obtained crystals were recrystallized from ethanol to give N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N'-benzhydryl-N-benzyl terephthalamide (Compound 76) (0.22 g) was obtained as colorless crystals. mp 231-232 ° C. Elemental analysis value C ₃₄ H ₃₁ N ₅ O ₂ Calcd. : C, 75.39; H, 5.77; N, 12.93. Found: C, 75.53; H, 5.62; N, 12.96. ¹ H-NMR (DMSO-d ₆ ) δ: 2.47 (3H,
s), 4.37 (2H, s), 4.54 (2H, s),
6.16 (2H, s, br), 6.42 (1H, d, J
= 7.8 Hz), 6.64 (1H, d, J = 8.6H)
z), 7.13-7.48 (1H, m), 7.51 (2
H, d, J = 8.4 Hz), 7.74 (1H, s),
7.83 (2H, d, J = 8.4 Hz).

Example 77 (Production of Compound 77) Sodium hydride (oil-based, 60%, 146 mg) was added to N,
Suspend in N-dimethylformamide (15 ml),
Diphenylmethanol (721 mg) was added and the mixture was added at room temperature for 1 hour.
Stirred for hours. N-[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl) benzamide and overnight at room temperature (15 hours)
Stirred. Water and ethyl acetate were added to carry out liquid separation, and the organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and recrystallized from ethanol to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4. -[(Benzhydryloxy) methyl] -N-benzylbenzamide (compound 7
7) (239 mg) was obtained. mp 162-163 ° C. Elemental analysis value C ₃₄ H ₃₂ N ₄ O ₂ Calcd. : C, 77.25; H, 6.10; N, 10.60. Found: C, 76.96; H, 6.21; N, 10.40. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 4.43 (2H, s), 4.53 (4H, s),
5.42 (1H, s), 6.24 (2H, s, br),
7.19-7.47 (19H, m), 7.73 (1H,
s).

Example 78 (Preparation of compound 78) N, N-dimethyl 4-[[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoic acid (377 mg) Formamide (1
0 ml) solution, 1,2-diphenylethylamine (0.29 ml), 1-hydroxybenzotriazole monohydrate (234 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (286 m2).
g) were sequentially added, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added and the solid insoluble in both was collected by filtration, washed with water and ethyl acetate in that order, and N-[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] -N-benzyl-N '-(1,
2-diphenylethyl) terephthalamide (compound 7
8) (395 mg) was obtained. mp 260-261 ° C Elemental analysis: C ₃₅ H ₃₃ N ₅ O ₂ .0.25H ₂ O Calcd. : C, 75.04; H, 6.03; N, 12.50. Found: C, 75.13; H, 6.02; N, 12.63. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 3.21 (2H, d, J = 7.4 Hz), 4.3
5 (2H, s), 4.53 (2H, s), 5.43 (1
H, dt, Jd = 7.4 Hz, Jt = 7.4 Hz),
6.17 (2H, s, br), 6.35 (1H, d, J
= 7.4 Hz), 7.06-7.49 (17H, m),
7.65 (1H, s), 7.71 (1H, d, J = 1
0.6 Hz).

Example 79 (Preparation of compound 79) N, N-dimethyl 4-[[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoic acid (377 mg) Formamide (1
0 ml) solution in 1,2,3,4-tetrahydro-1-
Naphthylamine (0.22 ml), 1-hydroxybenzotriazole monohydrate (232 mg), 1-ethyl-
3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (287 mg) was sequentially added, and the mixture was stirred at room temperature for 15 hours. Water was added and the insoluble solid was collected by filtration, washed with ethyl acetate, and washed with N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-N ′-(1,2,3,3). 4
-Tetrahydro-1-naphthalenyl) terephthalamide (89 mg) was obtained. The filtrate was extracted with ethyl acetate, and the organic layer was washed twice with water and once with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-
N '-(1,2,3,4-tetrahydro-1-naphthalenyl) terephthalamide (compound 79) (158 mg)
I got mp 220-221 ° C. Elemental analysis value C ₃₁ H ₃₁ N ₅ O ₂ · 0.25H ₂ O Calcd. : C, 72.99; H, 6.22; N, 13.73. Found: C, 72.95; H, 6.28; N, 13.57. ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.01
(3H, m), 2.09-2.15 (1H, m), 2.
50 (3H, s), 2.81 (2H, s, br), 4.
37 (2H, s), 4.54 (2H, s), 5.36
(1H, s, br), 6.20 (2H, s, br),
6.31 (1H, d, J = 8.0 Hz), 7.13-
7.41 (9H, m), 7.51 (2H, d, J = 8.
4 Hz), 7.74 (1H, s), 7.79 (2H,
d, J = 8.4 Hz).

Example 80 (Preparation of Compound 80) 4-[[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoic acid (375 mg) N, N-dimethyl Formamide (1
0 ml) solution, 1,2,3,4-tetrahydroisoquinoline (0.19 ml), 1-hydroxybenzotriazole monohydrate (230 mg), 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (2
(88 mg), and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to carry out liquid separation, and the organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give N-[(4-amino-2).
-Methyl-5-pyrimidinyl) methyl] -N-benzyl-4- (3,4-dihydro-2 (1H) -isoquinolinylcarbonyl) benzamide (Compound 80) (330 m
g) was obtained. mp 226 ° C. Elemental analysis value C ₃₀ H ₂₉ N ₅ O ₂ .0.5H ₂ O Calcd. : C, 71.98; H, 6.04; N, 13.99. Found: C, 71.71; H, 6.00; N, 13.85. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 2.84 (1H, s, br), 2.97 (1H,
s, br), 3.59 (1H, s, br), 3.98
(1H, s, br), 4.42 (2H, s), 4.56
(3H, s, br), 4.88 (1H, s, br),
6.20 (2H, s, br), 7.19-7.23 (6
H, m), 7.35-7.55 (7H, m), 7.76
(1H, s).

Example 81 (Production of Compound 81) 4-[[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoic acid (337 mg) in N, N-dimethyl Formamide (1
0 ml) solution and 1-aminoindan (0.17 m
l), 1-hydroxybenzotriazole monohydrate (2
08 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (259 mg) were sequentially added, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-
N ′-(2,3-Dihydro-1H-inden-1-yl) terephthalamide (Compound 81) (178 mg) was obtained. mp 208-210 ° C. Elemental analysis value C ₃₀ H ₂₉ N ₅ O ₂ .0.25 H ₂ O Calcd. : C, 72.63; H, 5.99; N, 14.12. Found: C, 72.47; H, 5.94; N, 14.35. ¹ H-NMR (CDCl ₃ ) δ: 1.82-1.96
(1H, m), 2.49 (3H, s), 2.63-2.
74 (1H, m), 2.90-3.03 (2H, m),
4.37 (2H, s), 4.54 (2H, s), 5.6
1-5.73 (1H, m), 6.20 (2H, s, b)
r), 6.31 (1H, d, J = 8.0 Hz), 7.1
6-7.46 (9H, m), 7.50 (2H, d, J =
8.2 Hz), 7.74 (1 H, s), 7.80 (2
H, d, J = 8.2 Hz).

Example 82 (Preparation of compound 82) N, N-dimethyl 4-[[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (benzyl) amino] carbonyl] benzoic acid (375 mg) Formamide (1
0 ml) solution, 1-naphthylamine (215 mg),
1-hydroxybenzotriazole monohydrate (153 m
g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (288 mg) were sequentially added.
Stirred at room temperature for 15 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give N-[(4-amino-2-methyl-
5-pyrimidinyl) methyl] -N-benzyl-N'-
(1-Naphthyl) terephthalamide (Compound 82) (1
78 mg). mp 259-260 ° C Elemental analysis: C ₃₁ H ₂₇ N ₅ O ₂ .0.75 H ₂ O Calcd. : C, 72.28; H, 5.58; N, 13.60. Found: C, 72.50; H, 5.62; N, 13.42. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 4.42 (2H, s), 4.56 (2H, s),
6.18 (2H, s, br), 7.22 (2H, dd,
J = 1.8 & 8.2 Hz), 7.37-7.61 (8
H, m), 7.75 (2H, d, J = 3.6 Hz),
7.77 (1H, d, J = 4.4 Hz), 7.84-
8.01 (5H, m), 8.25 (1H, s).

Example 83 (Production of Compound 83) 4-Amino-5-aminomethyl-2-methylpyrimidine (2.07 g) was dissolved in dimethylformamide (12 ml), and 4-dimethylaminopyridine (2.07 g) was dissolved. Was added, and 4-chloromethylbenzoyl chloride (3.20 g) was added with stirring in an ice bath, followed by stirring for 0.5 hour under the same conditions. Water (40 ml) was added, and saturated aqueous sodium hydrogen carbonate (10 ml) was further added. The precipitated crystals were collected by filtration, washed with water and dried, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- 4- (Chloromethyl) benzamide (compound 83) (2.46 g) was obtained as colorless crystals. mp 300 ° C. or higher ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 4.24 (2H, d), 4.82 (2H, s),
6.81 (2H, br), 7.54 (2H, d), 7.
86 (2H, d), 7.93 (1H, s), 9.01
(1H, br-t).

Example 84 (Production of compound 84) 4-Amino-5- (benzylaminomethyl) -2-methylpyrimidine (6.4 g), 4-dimethylaminopyridine (3.8 g) in dimethylformamide (50 ml) The solution was added at 0 ° C with 4-chloromethylbenzoyl chloride (5.8
g) in dimethylformamide (15 ml) was added dropwise. Stir at the same temperature for 3 hours, and add aqueous sodium hydrogen carbonate (1
l) was added and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with water and dried to give N-[(4-amino-2-methyl-
5-Pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl) benzamide (compound 84) (9.4 g)
Was obtained as colorless crystals. mp 177-179 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.5 (3H, s),
4.42 (2H, s), 4.54 (2H, s), 4.5
6 (2H, s), 6.15 (2H, br), 7.12-
7.43 (9H, m), 7.74 (1H, s).

Example 85 (Production of Compound 85) 2,4-Diphenylpyrazole (880 mg) was dissolved in dimethylformamide (6 ml), and 60% oily sodium hydride (176 mg) was added, followed by stirring for 15 minutes. .
Next, potassium iodide (100 mg), N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4-
(Chloromethyl) benzamide (1.16 g) was added, and the mixture was stirred at room temperature for 64 hours. Water (100 ml) was added to the reaction solution,
Ethyl acetate (200 ml) and hexane (50 ml) were added, shaken and separated. The upper layer is washed with water and concentrated under reduced pressure.
The residue (crystal) was washed with isopropyl ether and recrystallized from ethanol to give N-[(4-amino-2-methyl-5.
-Pyrimidinyl) methyl] -4-[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide (compound 85) was obtained as colorless crystals (1.13 g). mp 238-239 ° C. Elemental analysis value C ₂₉ H ₂₆ N ₆ O · 0.02 H ₂ O Calcd. : C, 73.34%; H, 5.53%; N, 17.70% Found: C, 73.06%; H, 5.66%; N, 17.74% ¹ H-NMR (DMSO- d ₆ ) δ: 2.28 (3H,
s), 4.21 (2H, d), 5.50 (2H, s),
6.78 (2H, br), 6.99 (1H, s), 7.
12 (2H, d), 7.28-7.46 (8H, m),
7.77 (2H, d), 7.86 (2H, d), 7.9
1 (1H, s), 8.93 (1H, br).

Example 86 (Preparation of Compound 86) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -4-[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide (474 mg)
Was dissolved in dimethylformamide (3 ml), 60% oily sodium hydride (40 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Next, potassium iodide (100 mg) and benzyl chloride (127 mg) were added, and the mixture was stirred at room temperature for 5 hours. The mixture was partitioned between water and ethyl acetate, the ethyl acetate layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
And N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(3,5-
Diphenyl-1H-pyrazol-1-yl) methyl] benzamide (Compound 86) (122 mg) was obtained as colorless crystals. mp 198-199 ° C Elemental analysis value C ₃₆ H ₃₂ N ₆ O · 0.1H ₂ O Calcd. : C, 76.33%; H, 5.73%; N, 14.84% Found: C, 76.25%; H, 5.70%; N, 14.68% ¹ H-NMR (DMSO- d ₆ ) δ: 2.30 (3H,
s), 4.0-4.65 (4H, m), 5.45 (2
H, s), 6.85 (1H, br), 6.96 (1H,
s), 7.05 (2H, d), 7.13 (1H, b
r), 7.25-7.45 (15H, m), 7.74
(1H, br), 7.85 (2H, d).

Example 87 (Preparation of Compound 87) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -4-[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide (474 mg)
Was dissolved in DMF (3 ml), 60% oily sodium hydride (40 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Next, potassium iodide (100 mg) and benzyl chloride (127 mg) were added, and the mixture was stirred at room temperature for 5 hours. The mixture was partitioned between water and ethyl acetate, the ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N
-[(4-Dibenzylamino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide (Compound 87) ( 50 mg) were obtained as colorless crystals. mp 180-181 ° C Elemental analysis value C ₄₃ H ₃₈ N ₆ O As Calcd. : C, 78.87%; H, 5.85%; N, 12.83% Found: C, 78.68%; H, 5.78%; N, 12.56% ¹ H-NMR (DMSO- d ₆ ) δ: 2.50 (3H,
s), 4.34 (2H, s), 4,48 (2H, s),
4,75 (2H, d), 5.37 (2H, s), 6.6
6 (1H, s), 7.01 (2H, d), 7.11-
7.25 (4H, m), 7.28-7.45 (16H,
m), 7.57 (1H, br), 7.62 (1H,
s), 7.82-7.87 (2H, m).

Example 88 (Preparation of Compound 88) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzyl-4-[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide (0.67 g) was dissolved in ethanol, and 1N hydrochloric acid (4 m
l) was added. The operation of evaporating the solvent under reduced pressure, adding ethanol and concentrating was repeated three times to obtain crystals. The obtained crystals are washed with acetone, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-.
[(3,5-Diphenyl-1H-pyrazol-1-yl) methyl] benzamide hydrochloride (Compound 88) (0.
69g) were obtained as colorless crystals. mp 168-173 ° C. Elemental analysis value C ₃₆ H ₃₂ N ₆ O.HCl.H ₂ O Calcd. : C, 69.83; H, 5.70; N, 13.57. Found: C, 69.57; H, 5.94; N, 13.65. ¹ H-NMR (DMSO-d ₆ ) δ: 2.49 (3H,
s), 3.9-5.0 (6H, m), 5.47 (2H,
s), 6.97 (1H, s), 7.02-7.17 (4
H, m), 7.20-7.56 (13H, m), 7.8.
−7.88 (2H, d, J = 7 Hz), 8.02 (1
H, brs), 8.12-9.2 (1H, br).

Example 89 (Production of Compound 89) Dibenzoylmethane (6.27 g) was dissolved in tetrahydrofuran (50 ml), 60% oily sodium hydride (840 mg) was added, and the mixture was stirred for 10 minutes. Next, potassium iodide (1 g), N-[(4-amino-2-methyl-
[5-Pyrimidinyl) methyl] -4- (chloromethyl) benzamide (2.04 g) was added, and the mixture was stirred for 2 hours and then stirred at a bath temperature of 90 to 95 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was ethyl acetate (40 ml) and water (40 ml).
Was added, and the precipitated crystals were collected by filtration, washed with water and ethyl acetate, dried, and dried to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4-[(2-benzoyl-3-oxo). -3-phenylpropyl) benzamide (compound 8
9) (2.05 g) was obtained as colorless crystals. mp 250-251 ° C Elemental analysis: C ₂₉ H ₂₆ N ₄ O ₃ Calcd. : C, 72.79%; H, 5.48%; N, 11.71% Found: C, 72.62%; H, 5.60%; N, 11.77% ¹ H-NMR (DMSO- d ₆ ) δ: 2.28 (3H,
s), 3.29 (2H, d), 4.20 (2H, d),
6.21 (1H, t), 6.79 (2H, br), 7.
40-7.52 (6H, m), 7.59-7.73 (4
H, m), 7.89-7.99 (5H, m), 8.87.
(1H, br).

Example 90 (Preparation of compound 90) N-[(4-Amino-2-methyl-5-pyrimidinyl)
Methyl] -4-[(2-benzoyl-3-oxo-3-
Phenylpropyl) benzamide (479 mg) and hydroxylamine hydrochloride (100 mg) were added to ethanol (1
The mixture was stirred at a bath temperature of 110 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was shaken with ethyl acetate (70 ml) and aqueous sodium hydrogen carbonate (20 ml) to separate the layers. The upper layer was washed with water and concentrated under reduced pressure. The residue (crystal) was washed with ethanol, dried and dried to give N-[(4-amino-2-methyl-
5-Pyrimidinyl) methyl] -4-[(3,5-diphenyl-4-isoxazolyl) methyl] benzamide (Compound 90) was obtained as colorless crystals (330 mg). mp 233-233 ° C. Elemental analysis value C ₂₉ H ₂₅ N ₆ O ₂ Calcd. : C, 73.25%; H, 5.30%; N, 14.73% Found: C, 73.11%; H, 5.26%; N, 14.80% ¹ H-NMR (DMSO- d ₆ ) δ: 2.29 (3H,
s), 4.19 (2H, s), 4.21 (2H, d),
6.79 (2H, br), 7.20 (2H, d), 7.
43-7.53 (8H, m), 7.67-7.78 (2
H, m), 7.91 (1H, s), 8.92 (1H, b
r).

Example 91 (Production of Compound 91) A suspension of 60% sodium hydride (0.32 g, washed with hexane) in tetrahydrofuran (20 ml) was treated with dibenzoylmethane (2.4 g) and potassium iodide (0.4 g). 44
g), N-[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl)
Benzamide (1.0 g) was added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added. The insoluble material was removed by filtration, and the organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography (ethyl acetate-ethanol) to obtain crystals (1.0 g). The crystals (0.5 g) were dissolved in ethanol (20 ml), and hydroxylamine hydrochloride (92 mg) was added to give 1
The mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the precipitated crystals were collected by filtration and dried. To this, ethanol (10 ml), 1N hydrochloric acid (1.0 ml)
Was added and heated to dissolve. After concentration, the residue was recrystallized from ethanol to give N-[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] -N-benzyl-4-[(3,
[5-Diphenyl-4-isoxazolyl) methyl] benzamide hydrochloride (Compound 91) (0.35 g) was obtained as colorless crystals. mp 247-248 ° C Elemental analysis value C ₃₆ H ₃₁ N ₅ O ₂ .HCl.0.2H ₂ O Calcd. : C, 71.38; H, 5.39; N, 11.56. Found: C, 71.37; H, 5.24; N, 11.37. ¹ H-NMR (DMSO-d ₆ ) δ: 2.48 (3H,
s), 3.85-4.83 (6H, m), 7.0-7.
18 (4H, m), 7.22-7.57 (15H,
m), 7.61-7.75 (2H, m), 8.0 (1
H, s), 8.6 (1H, br).

Example 92 (Preparation of compound 92) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -4-[(2-benzoyl-3-oxo-3-
(Phenylpropyl) benzamide (479 mg), hydrazine hydrochloride (83 mg) and potassium acetate (98 mg) were stirred in ethanol (8 ml) at a bath temperature of 110 ° C. for 15 hours. The crystals precipitated from the reaction solution are collected by filtration, and then washed with water and ethanol.
And dried, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4-[(3,5-
Diphenyl-1H-pyrazol-4-yl) methyl] benzamide (Compound 92) (390 mg) was obtained as colorless crystals. mp 295-296 ° C Elemental analysis value C ₂₉ H ₂₆ N ₆ O · 0.5H ₂ O Calcd. : C, 72.03%; H, 5.63%; N, 17.38% Found: C, 72.12%; H, 5.78%; N, 17.62% ¹ H-NMR (DMSO- d ₆ ) δ: 2.29 (3H,
s), 4.14 (2H, s), 4.21 (2H, d),
6.81 (2H, br), 7.20 (2H, s, b)
r), 7.26-7.37 (10H, m), 7.93
(2H, d, J = 8.2 Hz), 7.94 (2H,
d), 7.30-7.55 (10H, m), 7.76
(2H, d), 7.91 (1H, s), 8.92 (1
H, br).

Example 93 (Production of Compound 93) Sodium hydride (oil-based, 60%, 66 mg) was added to N, N
-Suspended in dimethylformamide (5 ml),
Phenylindole (290 mg) was added, and the mixture was stirred at room temperature for 1 hour. N-[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl) benzamide (571 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added, and the insoluble solid was collected by filtration, washed with ethyl acetate, and washed with N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4.
-[(2-Phenyl-1H-indol-1-yl) methyl] benzamide (315 mg) was obtained. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate.
1H-Indol-1-yl) methyl] benzamide (Compound 93) (105 mg) was obtained. mp 210-211 ° C. Elemental analysis value C ₃₅ H ₃₁ N ₅ O · 0.75 H ₂ O Calcd. : C, 76.27; H, 5.94; N, 12.71. Found: C, 76.17; H, 5.83; N, 12.79. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.41 (2H, s), 4.51 (2H, s),
5.36 (2H, s), 6.16 (2H, s, br),
6.64 (1H, s), 7.01 (2H, d, J = 8.
2Hz), 7.12-7.20 (6H, m), 7.2-
7.4 (9H, m), 7.6-7.7 (1H, m),
7.71 (1H, s).

Example 94 (Production of Compound 94) Sodium hydride (oil-based, 60%, 66 mg) was added to N, N
-Suspended in dimethylformamide (5 ml),
Add phenylimidazole (216 mg) and add 1 at room temperature.
Stirred for hours. N-[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl) benzamide (571 mg).
Stir for 5 hours. Water and ethyl acetate were added, the insoluble solid was collected by filtration, recrystallized from ethyl acetate, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(2 -Phenyl-1H-imidazole-1
-Yl) methyl] benzamide (compound 94) (289)
mg). mp 154-155 ° C Elemental analysis value C ₃₀ H ₂₈ N ₆ O.1.75 H ₂ O : C, 69.28; H, 6.10; N, 16.16. Found: C, 69.18; H, 6.08; N, 15.97. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 4.41 (2H, s), 4.53 (2H, s),
5.23 (2H, s), 6.17 (2H, s, br),
6.94 (1H, d, J = 1.4 Hz), 7.07 (2
H, d, J = 8.4 Hz), 7.18-7.22 (3
H, m), 7.27-7.51 (10H, m), 7.7.
3 (1H, s).

Example 95 (Preparation of Compound 95) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzyl-4-fluorobenzamide (229 mg) in N, N-dimethylformamide (2 m
l) To the solution, 2-phenylphenol (114 mg) and potassium carbonate (113 mg) were added, and the mixture was heated with stirring at 160 ° C for 14 hours. Water and ethyl acetate were added, the insoluble solid was collected by filtration, recrystallized from ethanol, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-([1, 1′-Biphenyl] -2-yloxy) benzamide (Compound 95) (93 mg) was obtained. mp 211-212 ° C. Elemental analysis value C ₃₂ H ₂₈ N ₄ O ₂ .0.25 H ₂ O Calcd. : C, 76.09; H, 5.69; N, 11.09. Found: C, 75.81; H, 5.56; N, 11.33. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.41 (2H, s), 4.50 (2H, s),
6.26 (2H, s, br), 6.819 (1H, d,
J = 8.8 Hz), 6.820 (1H, dd, J = 4.
4 & 9.2 Hz), 7.05 (1H, dd, J = 1.8)
& 7.6Hz), 7.18-7.47 (15H, m),
7.69 (1H, s).

Example 96 (Production of compound 96) Sodium hydride (oil-based, 60%, 66 mg) was added to N, N
-Suspended in dimethylformamide (5 ml),
[5- (2-Pyridinyl) -1H-pyrazol-3-yl] pyridine (333 mg) was added, and the mixture was stirred at room temperature for 1 hour. N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl)
Benzamide (571 mg) was added, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate are added, and the insoluble solid is collected by filtration.
The extract was washed with water and ethyl acetate in this order, recrystallized from ethanol, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[[3,5-di (2
-Pyridinyl) -1H-pyrazol-1-yl] methyl] benzamide (Compound 96) (476 mg). mp 249-250 ° C Elemental analysis value C ₃₄ H ₃₀ N ₈ O · 0.75 H ₂ O Calcd. : C, 70.39; H, 5.47; N, 19.31. Found: C, 70.30; H, 5.26; N, 19.38. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.35 (2H, s), 4.48 (2H, s),
6.0-6.3 (2H, br), 6.07 (2H,
s), 7.17-7.38 (14H, m), 7.56-
7.76 (3H, m), 8.00 (1H, d, J = 8.
4Hz), 8.56-8.64 (1H, m).

Example 97 (Production of Compound 97) 4-Dimethylaminopyridine (12.2 g) was added to a solution of 4-amino-5-aminomethyl-2-methylpyrimidine carbonate (14.0 g) in pyridine (200 ml). Was added. Cool to 0 ° C. and add 4-fluorobenzoic acid chloride (8.
4 ml) was added dropwise over 5 minutes. After stirring at 0 ° C. for 1 hour and at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added, and the insoluble solid was collected by filtration, washed with water and ethyl acetate in that order, and washed with N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4-fluorobenzamide (4 .
6 g) were obtained. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from ethanol to give N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -4-fluorobenzamide (compound 97) (2.
1 g). mp 262-263 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.49 (2H, d, J = 6.2 Hz), 6.0.
6 (2H, s, br), 6.74 (1H, s, br),
7.11 (1H, d, J = 8.4 Hz), 7.15 (1
H, d, J = 8.8 Hz), 7.78-7.85 (2
H, m), 7.98 (1H, s).

Example 98 (Production of Compound 98) Sodium hydride (oil-based, 60%, 174 mg) was added to N,
Suspend in N-dimethylformamide (10 ml),
N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -4-fluorobenzamide (1.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. After cooling to 0 ° C., a solution of benzyl chloride (4.7 ml) in N, N-dimethylformamide (5 ml) was added dropwise over 30 minutes. The temperature was gradually raised to room temperature and stirred for 15 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and further recrystallized from ethyl acetate to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- N-benzyl-4-fluorobenzamide (Compound 98) (2
23 mg). mp 152-154 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 4.43 (2H, s), 4.54 (2H, s),
6.22 (2H, s, br), 7.04 (1H, d, J
= 8.8 Hz), 7.09 (1H, d, J = 8.6H)
z), 7.21 (2H, dd, J = 2.2 & 8.0H)
z), 7.35-7.51 (5H, m), 7.73 (1
H, s).

Example 99 (Preparation of Compound 99) Formic acid (0.41 ml) was added to acetic anhydride (0.84 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (benzylsulfanylmethyl) phenyl] amine (708 mg) in tetrahydrofuran (1
0 ml) solution at 0 ° C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (benzylsulfanylmethyl) phenyl ] Formamide (Compound 99) (313m
g) was obtained as colorless crystals. mp 91-93 ° C. Elemental analysis value: C ₂₁ H ₂₂ N ₄ OS Calcd. : C, 66.64; H, 5.86; N, 14.80. Found: C, 66.41; H, 5.78; N, 14.68. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.38 (2H, s), 3.70 (2H, s),
4.58 (2H, br), 5.96 (2H, br),
6.86 (1H, d, J = 7.0 Hz), 7.20-
7.35 (8H, m), 7.48 (1H, s), 8.1
6 (1H, s). IR (KBr) 1661, 1593, 1559, 149
3,1472,1454,1433,1372,126
5,768,714 cm ^-1 .

Example 100 (Preparation of Compound 100) To a suspension of 4-amino-5-hydroxymethyl-2-methylpyrimidine (1.0 g) in dichloromethane (15 ml) was added methanesulfonyl chloride (0.82 g), followed by triethylamine. (0.76 g) was added, and the mixture was stirred at room temperature for 13 hours. The insolubles were collected by filtration and washed with dichloromethane.
The dichloromethane solutions were combined, toluidine (0.77 g) and triethylamine (1.1 ml) were added to the solution, and the mixture was heated under reflux for 3 hours. The organic layer was washed with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 2-methyl-5- (2-toluidinomethyl) -4-pyrimidineamine. A mixture of acetic anhydride (0.11 ml) and formic acid (0.053 ml) was stirred at 60 ° C. for 2 hours. Tetrahydrofuran (1m
l) and tetrahydrofuran (1) of 2-methyl-5- (2-toluidinomethyl) -4-pyrimidineamine.
5 ml) solution was added dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour and at 60 ° C. for 21 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-methylphenyl) formamide (compound 100) (80 m
g) was obtained as colorless crystals. mp 125-127 ° C Elemental analysis value C ₁₃ H ₁₆ N ₄ Calcd. : C, 68.39; H, 7.06; N, 24.54. Found: C, 68.24; H, 7.08; N, 24.54. ¹ H-NMR (CDCl ₃ ) δ: 2.12 (3H,
s), 2.45 (3H, s), 4.65 (2H, s),
6.51 (2H, br), 6.92 (1H, d, J =
7.4 Hz), 7.13-7.43 (3H, m), 7.
49 (1H, s), 8.12 (1H, s).

Example 101 (Production of Compound 101) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (0.48 g) was dissolved in ethanol (10 ml). Let
28% sodium methoxide methanol solution (0.66
g) was added at room temperature. The mixture was stirred at room temperature for 1 hour, allyl bromide (0.29 g) was added and the mixture was stirred at room temperature for 4 hours.
Stir for 1 hour. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-allylphenyl] formamide (Compound 101) (0.28 g) as yellow crystals. mp 133-135 ° C. Elemental analysis value C ₁₆ H ₁₈ N ₄ OS Calcd. : C, 61.12; H, 5.77; N, 17.82. Found: C, 60.97; H, 5.96; N, 17.65. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.5 (2H, d, J = 7 Hz), 5.08-
5.23 (2H, m), 5.67-5.92 (1H,
m), 6.06 (2H, br), 6.03-7.43.
(4H, m), 7.49 (1H, s) 8.09 (1H,
s).

Example 102 (Preparation of Compound 102) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (600
mg) was dissolved in water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.59 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethanol (6.0m
l), benzhydryl 2-chloroethyl ether (48
9 mg) and sodium iodide (297 mg) were added sequentially. The mixture was stirred at 85 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-
5-Pyrimidinyl) methyl [2-[(2-hydroxyethyl) sulfanyl] phenyl] formamide (Compound 102) (151 mg) was obtained as colorless crystals. mp 148 ° C. Elemental analysis value: C ₁₈ H ₁₈ N ₄ O ₂ S Calcd. : C, 56.58; H, 5.70; N, 17.60. Found: C, 56.29; H, 5.71; N, 17.39. ¹ H-NMR (CDCl ₃ ) δ: 2.23 (1H, b
r), 2.45 (3H, s), 3.05 (2H, t, J
= 6.3 Hz), 3.74 (2H, t, J = 6.2H)
z), 4.71 (2H, brs), 6.04 (2H, b
r), 6.93 (1H, dd, J = 7.8, 0.8H
z), 7.18 (1H, td, J = 7.1, 2.5H
z), 7.31-7.41 (2H, m), 7.49 (1
H, s), 8.10 (1H, s). IR (KBr) 1661, 1595, 1472, 143
5 cm ^-1 .

Example 103 (Preparation of Compound 103) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (840)
mg) was dissolved in water (8.0 ml), and a 10% aqueous sodium hydroxide solution (2.4 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. A solution of 3-chloropropyl acetate (412 mg) and sodium iodide (452 mg) in ethanol (8.0 ml) was added at room temperature, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography, recrystallized from ethyl acetate-ether, and treated with (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(3-hydroxypropyl)]. Sulfanyl] phenyl] formamide (Compound 103) (266
mg) as colorless crystals. mp 136-137 ° C. Elemental analysis value as C ₁₆ H ₂₀ N ₄ O ₂ S.0.3 H ₂ O, Calcd. : C, 56.89; H, 6.15; N, 16.58. Found: C, 57.06; H, 5.98; N, 16.31. ¹ H-NMR (CDCl ₃ ) δ: 1.76-1.89
(2H, m), 2.45 (3H, s), 2.96 (2
H, t, J = 7.1 Hz), 3.69 (2H, t, J =
6.0 Hz), 4.70 (2H, br), 6.06 (2
H, br), 6.92 (1H, d, J = 7.4 Hz),
7.11-7.20 (1H, m), 7.34-7.37
(2H, m), 7.50 (1H, s), 8.08 (1
H, s) and OH are not identified. IR (KBr) 1661, 1595, 1557, 147
2,1435,1372,764,733 cm ^-1 .

Example 104 (Preparation of Compound 104) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (749)
mg) was dissolved in water (7.5 ml), and a 10% aqueous sodium hydroxide solution (2.15 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. 4-bromobutyl acetate (3
A solution of 98 mg) in ethanol (5.0 ml) was added at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, recrystallized from ethyl acetate-hexane, and (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-hydroxybutyl) Sulfanyl] phenyl] formamide (compound 104) (16
8 mg) as colorless crystals. mp 98-99 ° C. Elemental analysis value: C ₁₇ H ₂₂ N ₄ O ₂ S Calcd. : C, 58.94; H, 6.40; N, 16.17. Found: C, 58.71; H, 6.36; N, 16.36. ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.69
(4H, m), 2.13 (1H, br), 2.45 (3
H, s), 2.87 (2H, t, J = 6.7 Hz),
3.64 (2H, t, J = 5.9 Hz), 4.70 (2
H, s), 6.07 (2H, br), 6.95 (1H,
d, J = 7.6 Hz), 7.12-7.20 (1H,
m), 7.30-7.35 (2H, m), 7.50 (1
H, s), 8.08 (1H, s). IR (KBr) 3318, 1659, 1595, 155
9,1472,1435 cm ^-1 .

Example 105 (Preparation of Compound 105) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (500
mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (1.43 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. A solution of 1-bromo-3-phenylpropane (238 mg) in ethanol (5.0 m
l) was added at room temperature and the mixture was stirred at room temperature for 13.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ether-hexane to give (4-amino-2).
-Methyl-5-pyrimidinyl) methyl [2-[(3-phenylpropyl) sulfanyl] phenyl] formamide (Compound 105) (377 mg) was obtained as colorless crystals. mp 89-90 ° C. Elemental analysis _{C 17 H 22 N 4 OS ·} 0.2H Calcd the ₂ O. : C, 66.71; H, 6.21; N, 14.14. Found: C, 66.72; H, 6.07; N, 14.08. ¹ H-NMR (CDCl ₃ ) δ: 1.94 (2H, qu
int, J = 7.3 Hz), 2.44 (3H, s),
2.73 (2H, t, J = 7.6 Hz), 2.84 (2
H, t, J = 7.5 Hz), 4.69 (2H, br)
s), 6.01 (2H, brs), 6.84 (1H,
d, J = 7.8 Hz), 7.08-7.34 (8H,
m), 7.48 (1H, s), 8.07 (1H, s). IR (KBr) 3324, 1663, 1591, 155
7,1472,1435,1370,762,733,
702 cm ^-1 .

Example 106 (Preparation of Compound 106) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (840)
mg) was dissolved in water (8.0 ml), and a 10% aqueous sodium hydroxide solution (2.4 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. A solution of 3-chloropropyl acetate (412 mg) and sodium iodide (452 mg) in ethanol (8.0 ml) was added at room temperature, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography, recrystallized with ethyl acetate-hexane, and acetic acid 3-[[2-[[(4-amino-2-methyl-
5-pyrimidinyl) methyl (formyl) amino] phenyl] sulfanyl] propyl (compound 106) (237
mg) as colorless crystals. mp 104-105 ° C. Elemental analysis value: C ₁₈ H ₂₂ N ₄ O ₃ S Calcd. : C, 57.73; H, 5.92; N, 14.96. Found: C, 57.48; H, 6.06; N, 14.68. ¹ H-NMR (CDCl ₃ ) δ: 1.93 (2H, qu
int, J = 6.8 Hz), 2.07 (3H, s),
2.46 (3H, s), 2.93 (2H, t, J = 7.
3 Hz), 4.15 (2H, t, J = 6.3 Hz),
4.69 (2H, br), 6.01 (2H, br),
6.88 (1H, d, J = 8.4 Hz), 7.15 (1
H, td, J = 7.1, 2.4 Hz), 7.31-7.
41 (2H, m), 7.49 (1H, s), 8.09
(1H, s). IR (KBr) 1736, 1663, 1591, 156
4,1474,1435,1242,1040,764
cm ^-1 .

Example 107 (Preparation of Compound 107) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (749)
mg) was dissolved in water (7.5 ml), and a 10% aqueous sodium hydroxide solution (2.15 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. 4-bromobutyl acetate (3
A solution of 98 mg) in ethanol (5.0 ml) was added at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and acetic acid 4-[[2-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl (formyl) amino] phenyl] sulfanyl] butyl (32
4 mg) as an oil. Acetic acid 4-[[2-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl (formyl) amino] phenyl] sulfanyl] butyl (324 mg) was dissolved in ethyl acetate (1.0 ml), 1N hydrochloric acid (ether) was added, and Stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure to obtain acetic acid 4-[[2-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl (formyl) amino] phenyl] sulfanyl] butyl hydrochloride (Compound 107) (170 mg) was obtained as an amorphous. Elemental analysis _{C 19 H 24 N 4 O 3} S · HCl · 0.5H Calcd the ₂ O. : C, 52.59; H, 6.04; N, 12.91. Found: C, 52.65; H, 6.11; N, 12.97. ¹ H-NMR (DMSO-d ₆ ) δ: 1.54-1.6
5 (4H, m), 1.99 (3H, s), 2.50 (3
H, s), 2.96 (2H, t, J = 7.0 Hz),
4.00 (2H, t, J = 6.0 Hz), 4.69 (2
H, s), 7.27-7.50 (4H, m), 7.99.
(1H, s), 8.16 (1H, s), around
8.2 (1H, br), 9.45 (1H, br). IR (KBr) 3285, 2683, 1730, 166
3,1601,1474,1348,1242,104
2 cm ^-1 .

Example 108 (Preparation of Compound 108) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (600
mg) was dissolved in water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.59 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethanol (6.0m
l), benzhydryl 2-chloroethyl ether (48
9 mg) and sodium iodide (297 mg) were added sequentially. The mixture was stirred at 85 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-5).
-Pyrimidinyl) methyl [2-[[2- (benzhydryloxy) ethyl] sulfanyl] phenyl] formamide (317 mg) was obtained. Ethanol (6.0m
l), fumaric acid (76 mg) was added, and the mixture was added at room temperature for 1 hour.
Stirred for hours. The reaction mixture was concentrated under reduced pressure, and further recrystallized from ethyl acetate-diisopropyl ether.
(4-amino-2-methyl-5-pyrimidinyl) methyl [2-[[2- (benzhydryloxy) ethyl] sulfanyl] phenyl] formamide fumarate (Compound 1
08) (329 mg) as colorless crystals. mp 172 ° C. Elemental analysis value: C ₂₈ H ₂₈ N ₄ O ₂ S. As C ₄ H ₄ O ₄ Calcd. : C, 63.98; H, 5.37; N, 9.33. Found: C, 63.94; H, 5.60; N, 9.34. ¹ H-NMR (DMSO-d ₆ ) δ: 2.23 (3H,
s), 3.18 (2H, t-like), 3.52 (2
H, t-like), 4.59 (2H, s), 5.50
(1H, s), 6.63 (2H, s), 6.74 (2
H, br), 7.22-7.47 (15H, m), 8.
09 (1H, s) and CO ₂ H were not identified.

Example 109 (Preparation of Compound 109) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (503)
mg) in water (5.0 ml) and a 10% aqueous sodium hydroxide solution (1.44 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. 2-chloroethyl carbamate (178 mg) and sodium iodide (270
mg) in ethanol solution (3.0 ml) at room temperature,
The mixture was stirred at 90 ° C. for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. Concentrate under reduced pressure,
The residue was purified by silica gel column chromatography,
Recrystallization from ethyl acetate gave 2-[[2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] ethyl carbamate and (4-amino-2- A mixture of methyl-5-pyrimidinyl) methyl [2-[(2-hydroxyethyl) sulfanyl] phenyl] formamide was obtained. This was suspended in dichloromethane (20 ml), and trichloroacetyl isocyanate (0.05 ml) was added. After stirring the mixture at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (15 ml) and water (1
5 ml) and potassium carbonate (182 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was slightly concentrated under reduced pressure,
Extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-[[2-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] ethyl carbamate (Compound 109) (148 mg) was obtained as colorless crystals. mp 185 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.11 (2H, t, J = 6.6 Hz), 4.1.
7 (2H, t, J = 6.6 Hz), 4.70 (2H, b
rs), 4.88 (2H, br), 6.00 (2H, b
r), 6.95 (1H, dd, J = 7.8, 1.0H
z), 7.19 (1H, td, J = 7.3, 2.1H
z), 7.37 (1H, td, J = 8.0, 1.4H
z), 7.44 (1H, dd, J = 8.0, 2.2H
z), 7.50 (1H, s), 8.09 (1H, s). IR (KBr) 1721, 1659, 1595, 147
4,1435,1404,1339,1074,733
cm ^-1 .

Example 110 (Preparation of Compound 110) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (500
mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (1.43 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. A solution of ethyl 3-bromopropionate (238 mg) in ethanol (5.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from hexane gave ethyl 3-[[2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] propionate (Compound 110) (336 mg). Obtained as colorless crystals. mp 133-134 ° C. Elemental analysis value: C ₁₈ H ₂₂ N ₄ O ₃ S Calcd. : C, 57.73; H, 5.92; N, 14.96. Found: C, 57.55; H, 5.91; N, 14.90. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t,
J = 7.1 Hz), 2.46 (3H, s), 2.57
(2H, t, J = 7.4 Hz), 3.15 (2H, t,
J = 7.3 Hz), 4.16 (2H, q, J = 7.2H)
z), 4.68 (2H, br), 6.00 (2H, b
r), 6.88 (1H, d, J = 7.8 Hz), 7.1
3-7.21 (1H, m), 7.36-7.39 (2
H, m), 7.50 (1H, s), 8.08 (1H,
s). IR (KBr) 1730, 1663, 1593, 147
4,1435, 1373, 1246 cm ^-1 .

Example 111 (Preparation of Compound 111) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (600
mg) was dissolved in water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.59 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethanol (6.0m
l), triethylamine (0.28 ml), 4-chloroethylmorpholine hydrochloride (369 mg) and sodium iodide (297 mg) were sequentially added. The mixture was stirred at 85 ° C. for 8.5 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[[ 2- (4-morpholinyl) ethyl] sulfanyl] phenyl] formamide (Compound 111) (422 mg) was obtained as colorless crystals. mp 135-136 ° C. Elemental analysis value: C ₁₉ H ₂₅ N ₅ O ₂ S Calcd. : C, 58.89; H, 6.50; N, 18.07. Found: C, 58.96; H, 6.48; N, 17.97. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 2.47 (4H, t, J = 4.8 Hz), 2.5
6 (2H, dd, J = 8.4, 6.2 Hz), 3.00
(2H, dd, J = 8.4, 6.2 Hz), 3.71
(4H, t, J = 4.6 Hz), 4.70 (2H, b
r), 6.01 (2H, br), 6.87 (1H, d,
J = 7.8 Hz), 7.15 (1H, dt, J = 7.
8, 4.4 Hz), 7.34-7.36 (2H, m),
7.48 (1H, s), 8.09 (1H, s). IR (KBr) 1661, 1591, 1472, 143
7,1115 cm ^-1 .

Example 112 (Preparation of Compound 112) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (620)
mg) was dissolved in water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.64 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Ethanol (6.0m
l), triethylamine (0.95 ml), benzhydryl chloromethyl sulfide (1.02 g), sodium iodide (614 mg) and tetrabutylammonium bromide (22 mg) were sequentially added. Mix the mixture at room temperature for 1 hour.
Stir for 2 hours. The reaction mixture was diluted with ethyl acetate.
The mixture was washed sequentially with water and saturated saline. The organic layer was 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 (4-amino-2-methyl-5-pyrimidinyl).
Methyl [2-[[((benzhydrylsulfanyl) methyl] sulfanyl] phenyl] formamide (706 m
g) was obtained as an oil. (4-amino-2-methyl-
5-Pyrimidinyl) methyl [2-[[(benzhydrylsulfanyl) methyl] sulfanyl] phenyl] formamide was dissolved in ethanol (12 ml) and fumaric acid (159 mg) was added. The mixture was stirred at room temperature for 15 hours. After addition of ether, the reaction mixture was concentrated under reduced pressure, and then recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[[(benzhi Drillsulfanyl) methyl] sulfanyl] phenyl] formamide 1/2 fumarate (Compound 112) (642 mg) was obtained as colorless crystals. mp 132 ° C. Elemental analysis value: C ₂₇ H ₂₆ N ₄ OS ₂・ C ₄ H ₄ O ₄ Calcd. : C, 63.95; H, 5.18; N, 10.29. Found: C, 63.79; H, 5.02; N, 10.26. ¹ H-NMR (DMSO-d ₆ ) δ: 2.23 (3H,
s), 3.89 (2H, s), 4.63 (2H, s),
5.38 (1H, s), 6.62 (1H, s), 6.7
9 (2H, brs), 7.15 (1H, d, J = 7.8)
Hz), 7.22-7.50 (14H, m), 8.12
(1H, s) and CO ₂ H have not been identified.

Example 113 (Production of compound 113) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.09 g) was suspended in acetone (30 ml), and 2-butoxyaniline (1 .40 g) at room temperature. The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was made basic using potassium carbonate, concentrated under reduced pressure, added with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N -(2-Butoxyphenyl) amine (compound 113) (548 mg) was obtained as colorless crystals. mp 124 ° C. Elemental analysis value: C ₁₆ H ₂₂ N ₄ O Calcd. : C, 67.11; H, 7.74; N, 19.56. Found: C, 66.98; H, 7.95; N, 19.59. ¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t,
J = 7.2 Hz), 1.45 (2H, sextet, J
= 7.4 Hz), 1.77 (2H, quint, J =
7.3 Hz), 2.53 (3H, s), 3.99 (2
H, t, J = 6.4 Hz), 4.17 (2H + 1H,
s), 5.48 (2H, brs), 6.73-6.93.
(4H, m), 8.12 (1H, s). IR (KBr) 1636, 1595, 1564, 150
8,1456,1246,1213,1125,737
cm ^-1 .

Example 114 (Compound 114) Formic acid (0.39 ml) was added to acetic anhydride (0.80 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Dilute with tetrahydrofuran (5.0 ml). N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- (2-butoxyphenyl) amine (436 m
g) in tetrahydrofuran (7.5 ml) was added at 0 ° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl (2-butoxyphenyl) Formamide (compound 114) (479 mg) was obtained as colorless crystals. mp 149 ° C. Elemental analysis value: C ₁₇ H ₂₂ N ₄ O ₂ .0.1 H ₂ O, Calcd. : C, 64.58; H, 7.08; N, 17.72. Found: C, 64.32; H, 6.90; N, 17.71. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t,
J = 6.9 Hz), 1.42 (2H, sextet, J
= 7.3 Hz), 1.69 (2H, quint, J =
7.1 Hz), 2.43 (3H, s), 3.90 (2
H, t, J = 6.4 Hz), 4.69 (2H, s),
6.02 (2H, br), 6.86-6.95 (3H,
m), 7.27-7.35 (1H, m), 7.50 (1
H, s), 8.12 (1H, s). IR (KBr) 1667, 1595, 1503, 147
2,1456,1433,1273 cm ^-1 .

Example 115 (Preparation of Compound 115) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (506)
mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (1.45 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. A solution of 2-iodopropane (226 mg) in ethanol (5.0 ml) was added. The mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-
Pyrimidinyl) methyl [2- [1- (methylethyl) sulfanyl] phenyl] formamide (Compound 115)
(324 mg) as colorless crystals. mp 154-155 ° C. Elemental analysis value: C ₁₆ H ₂₀ N ₄ OS · 0.1 H ₂ O Calcd. : C, 60.39; H, 6.40; N, 17.61. Found: C, 60.35; H, 6.40; N, 17.45. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d,
J = 6.6 Hz), 2.45 (3H, s), 3.42
(1H, septet-like (quint), J =
6.7 Hz), 4.70 (2H, br), 6.00 (2
H, br), 6.87 (1H, d, J = 8.8 Hz),
7.15 (1H, td, J = 7.9, 1.8 Hz),
7.30-7.43 (2H, m), 7.48 (1H,
s), 8.08 (1H, s). IR (KBr) 1667, 1591, 1557, 147
2,1435,1370 cm ^-1 .

Example 116 (Preparation of Compound 116) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (607)
mg) was dissolved in water (5.0 ml), and a 10% aqueous sodium hydroxide solution (1.75 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. A solution of N- (2-bromoethyl) phthalimide (443 mg) in ethanol (5.0 ml) was added, and the mixture was stirred at room temperature for 15.5 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[[ 2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] sulfanyl] phenyl] formamide (compound 116)
(111 mg) was obtained as colorless crystals. mp 151-152 ° C. Elemental analysis value: C ₂₃ H ₂₁ N ₅ O ₃ S Calcd. : C, 61.73; H, 4.73; N, 15.65. Found: C, 61.64; H, 4.76; N, 15.50. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.21 (2H, t, J = 7.0 Hz), 3.9
5 (2H, t, J = 7.0 Hz), 4.63 (2H, b
r), 6.01 (2H, br), 6.84 (1H, d
d, J = 7.8, 1.2 Hz), 7.13 (1H, t
d, J = 7.6, 1.4 Hz), 7.38 (1H, t)
d, J = 7.7, 1.5 Hz), 7.53 (1H, d
d, J = 7.8, 1.2 Hz), 7.57 (1H,
s), 7.72-7.78 (2H, m), 7.81-
7.87 (2H, m), 8.09 (1H, s). IR (KBr) 1715,1661,1472,143
5,1397,720 cm ^-1 .

Example 117 (Production of compound 117) Formic acid (0.70 ml) was added to acetic anhydride (1.44 ml) at room temperature, and the mixture was stirred at 65 ° C for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
A solution of [(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (2-tetrahydro-2-furanylethoxy) phenyl] amine (1.11 g) in tetrahydrofuran (20 ml) was added at 0 ° C. Added in. The mixture was stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane.
(4-Amino-2-methyl-5-pyrimidinyl) methyl [2- (2-tetrahydro-2-furanylethoxy) phenyl] formamide (Compound 117) (710 mg)
Was obtained as colorless crystals. mp 89-90 ° C. Elemental analysis value: C ₁₉ H ₂₄ N ₄ O ₃ Calcd. : C, 64.03; H, 6.79; N, 15.72. Found: C, 64.01; H, 6.75; N, 15.67. ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.60
(1H, m), 1.84-2.08 (5H, m), 2.
43 (3H, s), 3.67-4.07 (5H, m),
4.62 (1H, d, J = 15.0 Hz), 4.75
(1H, d, J = 15.0 Hz), 5.96 (2H, b
r), 6.86-6.98 (3H, m), 7.28-
7.35 (1H, m), 7.52 (1H, s), 8.1
2 (1H, s). IR (KBr) 1663, 1595,
1503, 1470, 1456, 1437, 1273c
m ^-1 .

Example 118 (Production of Compound 118) Formic acid (0.61 ml) was added to acetic anhydride (1.25 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
A solution of [(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (3-phenylpropoxy) phenyl] amine (1.03 g) in tetrahydrofuran (10 ml) was added at 0 ° C. The mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4
-Amino-2-methyl-5-pyrimidinyl) methyl [2
-(3-Phenylpropoxy) phenyl] formamide (compound 118) (808 mg) was obtained as colorless needle crystals. mp 141-142 ° C. Elemental analysis value: C ₂₂ H ₂₄ N ₄ O ₂ Calcd. : C, 70.19; H, 6.43; N, 14.88. Found: C, 70.10; H, 6.21; N, 14.83. ¹ H-NMR (CDCl ₃ ) δ: 2.03 (2H, d
q, J = 8.0, 6.6 Hz), 2.41 (3H,
s), 2.72 (2H, t, J = 7.5 Hz), 3.8
8 (2H, t, J = 6.2 Hz), 4.70 (2H,
s), 6.02 (2H, br), 6.86-7.01.
(3H, m), 7.15-7.33 (6H, m), 7.
51 (1H, s), 8.15 (1H, s). IR (KBr) 1661, 1595, 1501, 147
2,1454,1435,1271,1250,754
cm ^-1 .

Example 119 (Production of compound 119) Formic acid (0.78 ml) was added to acetic anhydride (1.60 ml) at room temperature, and the mixture was stirred at 65 ° C for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
A solution of [(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (3-ethoxypropoxy) phenyl] amine (1.19 g) in tetrahydrofuran (30 ml) was added at 0 ° C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-
Methyl-5-pyrimidinyl) methyl [2- (3-ethoxypropoxy) phenyl] formamide (Compound 11
9) (0.74 g) was obtained as colorless crystals. mp 102-103 ° C. Elemental analysis value: C ₁₈ H ₂₄ N ₄ O ₃ Calcd. : C, 62.77; H, 7.02; N, 16.27. Found: C, 62.60; H, 7.26; N, 16.24. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t,
J = 7.0 Hz), 1.96 (2H, quint, J =
6.1 Hz), 2.43 (3H, s), 3.47 (2
H, q, J = 6.5 Hz), 3.52 (2H, t, J =
5.7 Hz), 4.01 (2H, t, J = 6.2H)
z), 4.68 (2H, s), 6.01 (2H, br)
s), 6.87-6.99 (3H, m), 7.28-
7.36 (1H, m), 7.51 (1H, s), 8.1
2 (1H, s). IR (KBr) 1667, 1595, 1505, 145
6,1435,1273,1119 cm ^-1 .

Example 120 (Preparation of Compound 120) Formic acid (0.29 ml) was added to acetic anhydride (0.60 ml) at room temperature, and the mixture was stirred at 65 ° C. for 2.5 hours. After air cooling, the mixture was diluted with tetrahydrofuran (5.0 ml). N
-[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- [3- (benzyloxy) phenyl] amine (450 mg) in tetrahydrofuran (30 ml)
Was added at 0 ° C. The mixture was stirred at room temperature for 12.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from hexane gave (4-amino-2-methyl-5-pyrimidinyl) methyl [3- (benzyloxy) phenyl] formamide (Compound 120) (390 mg)
Was obtained as colorless crystals. mp 125-127 ° C. Elemental analysis value as C ₂₀ H ₂₀ N ₄ O ₂ Calcd. : C, 68.95; H, 5.79; N, 16.08. Found: C, 68.72; H, 5.75; N, 15.92. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 4.74 (2H, s), 5.03 (2H, s),
5.92 (2H, br), 6.64-6.69 (2H,
m), 6.91-6.97 (1H, m), 7.25-
7.29 (1H, m), 7.33-7.42 (5H,
m), 7.67 (1H, s), 8.32 (1H, s). IR (KBr) 1659, 1599, 1563, 148
9, 1470, 1454, 1435, 1372, 73
7,696 cm ^-1 .

Example 121 (Production of Compound 121) Formic acid (0.39 ml) was added to acetic anhydride (0.80 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- (3-ethoxyphenyl) amine (486 m
g) in tetrahydrofuran (10 ml) was added at 0 ° C. The mixture was stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl (3-ethoxyphenyl) Formamide (Compound 121) (461 mg) was obtained as colorless crystals. mp 136 ° C. Elemental analysis value: C ₁₅ H ₁₈ N ₄ O ₂ .1 / 6H ₂ O, Calcd. : C, 62.27; H, 6.39; N, 19.36. Found: C, 62.47; H, 6.28; N, 19.07. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t,
J = 7.0 Hz), 2.44 (3H, s), 3.99
(2H, q, J = 6.9 Hz), 4.75 (2H,
s), 5.94 (2H, br), 6.58-6.67.
(2H, m), 6.85 (1H, dd, J = 8.4,
2.6 Hz), 7.28 (1H, t, J = 8.1H)
z), 7.71 (1H, s), 8.33 (1H, s).
IR (KBr) 1661, 1601, 1561, 149
1,1476,1441,1370,1289,123
5 cm ^-1 .

Example 122 (Production of compound 122) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (40 ml), and potassium carbonate (1.47 g) was added. ) And 3-ethoxyaniline (1.45 g) in acetone (10 ml)
Was added at room temperature, respectively. The mixture was stirred at 65 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] -N- (3-ethoxyphenyl) amine (Compound 122) (475 mg)
Was obtained as colorless crystals. mp 109-110 ° C. Elemental analysis value: C ₁₄ H ₁₈ N ₄ O · 0.1H ₂ O, Calcd. : C, 64.64; H, 7.05; N, 21.54. Found: C, 64.68; H, 6.79; N, 21.55. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t,
J = 6.9 Hz), 2.52 (3H, s), 3.60
(1H, br-t, J = 5.2 Hz), 4.01 (2
H, q, J = 6.9 Hz), 4.14 (2H, d, J =
5.6 Hz), 5.41 (2H, brs), 6.28-
6.41 (3H, m), 7.13 (1H, t, J = 8.
1 Hz), 8.11 (1H, s). IR (KBr) 3328, 3166, 1615, 159
5,1563,1497,1456,1192,116
5 cm ^-1 .

Example 123 (Production of compound 123) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (3.87 g) was suspended in acetone (60 ml), and potassium carbonate (2.08 g) was added. ) And 3-
[[[Tert-butyl (dimethyl) silyl] oxy]
Methyl] aniline (6.50 g) in acetone (70
ml) was added at room temperature. The mixture was stirred at 65 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-methyl-
[5-Pyrimidinyl) methyl] -N- (3-hydroxymethyl) aniline (compound 123) (1.19 g) was obtained as colorless crystals. mp 127-128 ° C. Elemental analysis value C ₁₃ H ₁₆ N ₄ O · C ₃ H ₇ NO Calcd. : C, 60.55; H, 7.30; N, 22.07. Found: C, 60.52; H, 7.30; N, 21.88. ¹ H-NMR (CDCl ₃ ) δ: 2.15 (1H, b
r), 2.51 (3H, s), 3.67 (1H, tl)
ike), 4.16 (2H, d, J = 5.4 Hz),
4.65 (2H, s), 5.41 (2H, s), 6.6
4-6.68 (1H, m), 6.77-6.84 (2
H, m), 7.22 (1H, t, J = 7.6 Hz),
8.08 (1H, s). IR (KBr) 3322, 1607, 1564, 145
6,1435 cm ^-1 .

Example 124 (Production of compound 124) (4-Amino-2-methyl-5-pyrimidinyl) methyl [3-[[[tert-butyl (dimethyl) silyl] oxy] methyl] phenyl] formamide (4. 36g)
Was dissolved in tetrahydrofuran (100 ml) and 1M
Tetrabutylammonium fluoride (23 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was evaporated under reduced pressure, ethyl acetate was added to the residue, and anhydrous magnesium sulfate was added for drying. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl [3- (hydroxymethyl ) Phenyl] formamide (Compound 124) (2.40 g) as colorless crystals. mp 165-167 ° C. Elemental analysis value: C ₁₄ H ₁₆ N ₄ O ₂ .0.1H ₂ O, Calcd. : C, 61.35; H, 5.96; N, 20.44. Found: C, 61.36; H, 5.80; N, 20.32. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 2.64 (2H, br), 4.70 (2H, br).
s), 4.79 (2H, s), 6.06 (2H, b
r), 7.00 (1H, d, J = 7.4 Hz), 7.1
4 (1H, s), 7.27-7.42 (2H, m),
7.68 (1H, s), 8.33 (1H, s). IR (KBr) 3326, 3181, 1651, 159
3,1559,1456,1445,1372c
m ^-1 .

Example 125 (Production of Compound 125) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was added. ) And 2- (propoxymethyl) aniline (1.60 g) in acetone (20 ml) were added at room temperature, respectively. Mixture at 65 ° C
For 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give N-[(4-amino-2).
-Methyl-5-pyrimidinyl) methyl] -N- [2-
(Propoxymethyl) phenyl] amine (Compound 12
5) (599 mg) was obtained as colorless crystals. 172 mg was obtained as the second crystal. Total yield 771 mg. mp 112-113 ° C. Elemental analysis value: C ₁₆ H ₂₂ N ₄ O Calcd. : C, 67.11; H, 7.74; N, 19.56. Found: C, 66.84; H, 7.61; N, 19.30. ¹ H-NMR (CDCl ₃ ) δ: 0.80 (3H, t,
J = 7.4 Hz), 1.52 (2H, nextet, J
= 7.0 Hz), 2.52 (3H, s), 3.34 (2
H, t, J = 6.4 Hz), 4.18 (2H, d, J =
5.2 Hz), 4.50 (2H, s), 4.91 (1
H, t-like), 5.42 (2H, brs), 6.
74-6.81 (2H, m), 7.10 (1H, dd,
J = 7.8, 1.8 Hz), 7.22-7.30 (1
H, m), 8.12 (1H, s). IR (KBr) 3335, 3146, 1607, 158
8, 1564, 1514, 1456, 1426, 108
4 cm ^-1 .

Example 126 (Production of compound 126) Formic acid (0.49 ml) was added to acetic anhydride (0.99 ml) at room temperature, and the mixture was stirred at 60 ° C for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). N-
A solution of [(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (propoxymethyl) phenyl] amine (670 mg) in tetrahydrofuran (15 m
l) was added at 0 ° C. The mixture was stirred at room temperature for 14.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (propoxymethyl) ) Phenyl] formamide (Compound 126) (441
mg) as colorless crystals. mp 116 ° C. Elemental analysis value: C ₁₇ H ₂₂ N ₄ O ₂ Calcd. : C, 64.95; H, 7.05; N, 17.82. Found: C, 64.80; H, 7.09; N, 17.81. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t,
J = 7.5 Hz), 1.60 (2H, nextet, J
= 7.1 Hz), 2.46 (3H, s), 3.37 (2
H, t, J = 6.8 Hz), 4.19 (2H, s),
4.73 (2H, s), 6.07 (2H, br),
98 (1H, d, J = 7.4 Hz), 7.29-7.4
0 (2H, m), 7.46 (1H, td, J = 7.4,
2.2 Hz), 7.53 (1H, s), 8.17 (1
H, s). IR (KBr) 1661, 1593, 1557, 149
5,1462,1435,1373,1265,109
2 cm ^-1 .

Example 127 (Production of compound 127) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was added. ) And 3-benzyloxymethylaniline (2.11 g) in acetone (20 ml) were added at room temperature. Mixture at 65 ° C
For 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate-ethanol and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [3- (benzyloxymethyl) [Phenyl] amine (compound 127) (476 mg) was obtained as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and subjected to the same treatment to obtain the same compound (233 mg) as colorless crystals.
Total yield 709 mg. mp 188-189 ° C. Elemental analysis value: C ₁₉ H ₂₀ N ₄ O · 0.2 H ₂ O, Calcd. : C, 70.44; H, 6.35; N, 17.29. Found: C, 70.52; H, 6.44; N, 17.00. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 3.60 (1H, t-like), 4.13 (2
H, d, J = 5.2 Hz), 5.04 (2H, s),
5.36 (2H, s), 6.34-6.38 (2H,
m), 6.45-6.49 (1H, m), 7.14 (1
H, t, J = 8.3 Hz), 7.31-7.44 (5
H, m), 8.10 (1H, s). IR (KBr) 1615, 1593, 1563, 149
5,1454,1427,1188,1161,737
cm ^-1 .

Example 128 (Production of compound 128) Formic acid (0.29 ml) was added to acetic anhydride (0.60 ml) at room temperature, and the mixture was stirred at 65 ° C for 2.5 hours. After air cooling, the mixture was diluted with tetrahydrofuran (5.0 ml). N
At 0 ° C., a solution of-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [3- (benzyloxymethyl) phenyl] amine (450 mg) in tetrahydrofuran was added. Mix the mixture at room temperature for 12.5
Stirred for hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give (4-amino-
2-methyl-5-pyrimidinyl) methyl (3-benzyloxymethylphenyl) formamide (Compound 128)
(390 mg) as colorless crystals. mp 125-127 ° C. Elemental analysis value as C ₂₀ H ₂₀ N ₄ O ₂ Calcd. : C, 68.95; H, 5.79; N, 16.08. Found: C, 68.72; H, 5.75; N, 15.92. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 4.74 (2H, s), 5.03 (2H, s),
5.92 (2H, br), 6.64-6.69 (2H,
m), 6.91-6.97 (1H, m), 7.25-
7.29 (1H, m), 7.33-7.42 (5H,
m), 7.67 (1H, s), 8.32 (1H, s). IR (KBr) 1659, 1599, 1563, 148
9, 1470, 1454, 1435, 1372, 73
7,696 cm ^-1 .

Example 129 (Production of compound 129) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (3.87 g) was suspended in acetone (60 ml), and potassium carbonate (2.08 g) was obtained. ) And 3-
[[[Tert-butyl (dimethyl) silyl] oxy]
Methyl] aniline (6.50 g) in acetone (70
ml) was added at room temperature. The mixture was stirred at 65 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N -3-[[[tert-Butyl (dimethyl) silyl] oxy] methyl] aniline (Compound 129) (1.41 g) was obtained as off-white crystals. mp 102-104 ° C. Elemental analysis value: C ₁₉ H ₃₀ N ₄ OSi · 0.1H ₂ O Calcd. : C, 63.33; H, 8.45; N, 15.55. Found: C, 63.58; H, 8.54; N, 15.21. ¹ H-NMR (CDCl ₃ ) δ: 0.10 (6H,
s), 0.94 (9H, s), 2.52 (3H, s),
3.59 (1H, br), 4.16 (2H, s),
69 (2H, s), 5.39 (2H, brs), 6.6
0-6.64 (1H, m), 6.76-6.79 (2
H, m), 7.19 (1H, t, J = 7.9 Hz),
8.11 (1H, s). IR (KBr) 2955, 2930, 2857, 160
7, 1593, 1564, 1462, 1435, 125
6,1078 cm ^-1 .

Example 130 (Production of Compound 130) Formic acid (0.22 ml) was added to acetic anhydride (0.45 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Dilute with tetrahydrofuran (5.0 ml). N-
A solution of [(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-3-[[[tert-butyl (dimethyl) silyl] oxy] methyl] aniline (383 mg) in tetrahydrofuran (10 ml) was added at 0 ° C. added. The mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane.
(4-Amino-2-methyl-5-pyrimidinyl) methyl [3-[[[tert-butyl (dimethyl) silyl] oxy] methyl] phenyl] formamide (Compound 13
0) (268 mg) as colorless crystals. 112 mg was obtained as the second crystal. Total yield 380 mg. m
p109 ° C. Elemental analysis value: C ₂₀ H ₃₀ N ₄ O ₂ Si Calcd. : C, 62.14; H, 7.82; N, 14.49. Found: C, 61.88; H, 7.75; N, 14.24. ¹ H-NMR (CDCl ₃ ) δ: 0.09 (6H,
s), 0.93 (9H, s), 2.44 (3H, s),
4.72 (2H, s), 4.77 (2H, s), 5.9
4 (2H, br), 6.92-6.96 (1H, m),
7.08 (1H, s), 7.24-7.28 (1H,
m), 7.34 (1H, t, J = 7.5 Hz), 7.6
6 (1H, s), 8.32 (1H, s). IR (KBr) 1667, 1593, 1559, 146
4,1256,1107,1084,841,783c
m ^-1 .

Example 131 (Production of compound 131) (4-Amino-2-methyl-5-pyrimidinyl) methyl [3- (hydroxymethyl) phenyl] formamide (274 mg) was suspended in tetrahydrofuran (10 ml), and pyridine was added. (0.12 ml) and benzoyl chloride (0.13 ml) were added sequentially at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give 3-[[(4-amino-2-methyl-5-pyrimidinyl) methyl benzoate. ] (Formyl) amino] benzyl (Compound 131) (109 mg) as colorless crystals. mp 96-99 ° C. Elemental analysis value: C ₂₁ H ₂₀ N ₄ O ₃ .0.1 H ₂ O, Calcd. : C, 66.69; H, 5.38; N, 14.81. Found: C, 66.66; H, 5.38; N, 14.92. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 4.79 (2H, s), 5.35 (2H, s),
5.95 (2H, brs), 7.02-7.07 (1
H, m), 7.19 (1H, s), 7.37-7.63.
(5H, m), 7.69 (1H, s), 8.04-8.
08 (2H, m), 8.34 (1H, s). IR (KBr) 1719, 1663, 1591, 156
1,1451,1372,1273,1111,714
cm ^-1 .

Example 132 (Production of compound 132) (4-Amino-2-methyl-5-pyrimidinyl) methyl [3- (hydroxymethyl) phenyl] formamide (290 mg) and picolinic acid (197 mg) were added to N, N
-Dissolved in dimethylformamide (10 ml), and diethyl cyanophosphate (0.32 ml) and triethylamine (0.30 ml) were added at room temperature, respectively. The mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-isopropyl ether to give 3-[[(4-amino-2-methyl-5-pyrimidinyl) picolinic acid. Methyl] (formyl) amino] benzyl (compound 132) (188 mg) was obtained as colorless crystals. mp 134-135 ° C. Elemental analysis value: C ₂₀ H ₁₉ N ₅ O ₃ Calcd. : C, 63.65; H, 5.07; N, 18.56. Found: C, 63.41; H, 5.13; N, 18.61. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 4.78 (2H, s), 5.44 (2H, s),
5.93 (2H, brs), 7.02-7.07 (1
H, m), 7.40 (1H, t, J = 7.7 Hz),
7.44-7.54 (2H, m), 7.69 (1H,
s), 7.87 (1H, td, J = 7.7, 1.8H)
z), 8.15 (1H, d, J = 7.8 Hz), 8.3
3 (1H, s), 8.78 (1H, d, J = 4.0H)
z), 1H was hidden by CHCl ₃
(7.27). IR (KBr) 1726, 1669, 1591, 143
9,1306,1291,1246,1130c
m ^-1 .

Example 133 (Production of compound 133) (4-Amino-2-methyl-5-pyrimidinyl) methyl [3- (hydroxymethyl) phenyl] formamide (272 mg) and nicotinic acid (184 mg) were added to N, N
-Dissolved in dimethylformamide (5.0 ml), and diethyl cyanophosphate (0.30 ml) and triethylamine (0.28 ml) were added at room temperature, respectively. The mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give nicotinic acid 3-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] benzyl (Compound 133) (238m
g) was obtained as colorless crystals. mp 155 ° C. Elemental analysis value: C ₂₀ H ₁₉ N ₅ O ₃ Calcd. : C, 63.65; H, 5.07; N, 18.56. Found: C, 63.37; H, 5.02; N, 18.65. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 4.80 (2H, s), 5.38 (2H, s),
5.94 (2H, brs), 7.05-7.11 (1
H, m), 7.19 (1H, s), 7.39-7.45.
(3H, m), 7.69 (1H, s), 8.29-8.
35 (1H, m), 8.35 (1H, s), 8.81
(1H, dd, J = 4.9, 1.7 Hz), 9.25
(1H, d, J = 2.0 Hz). IR (KBr) 1725, 1659, 1591, 156
1,1466,1426,1373,1283,111
3,741 cm ^-1 .

Example 134 (Production of Compound 134) (4-Amino-2-methyl-5-pyrimidinyl) methyl [3- (hydroxymethyl) phenyl] formamide (300 mg) and isonicotinic acid (203 mg) were added to N, N -Dissolved in dimethylformamide (15 ml) and added diethyl cyanophosphate (0.50 ml) and triethylamine (0.48 ml) at room temperature, respectively.
The mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography,
Further recrystallization with ethyl acetate gave isonicotinic acid 3-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] benzyl (Compound 134)
(291 mg) was obtained as colorless crystals. mp 143 ° C. Elemental analysis value: C ₂₀ H ₁₉ N ₅ O ₃ Calcd. : C, 63.65; H, 5.07; N, 18.56. Found: C, 63.43; H, 5.12; N, 18.45. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 4.80 (2H, s), 5.37 (2H, s),
5.94 (2H, brs), 7.07-7.12 (1
H, m), 7.17 (1H, s), 7.42-7.45.
(2H, m), 7.68 (1H, s), 7.86 (2
H, dd, J = 4.3, 1.5 Hz), 8.34 (1
H, s), 8.81 (2H, dd, J = 4.4, 1.4)
Hz). IR (KBr) 1730, 1663, 1593, 156
1,1447,1408,1279,1121,73
4,706 cm ^-1 .

Example 135 (Production of Compound 135) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was obtained. ) And N-ethyl-2- (2-aminophenyl) acetamide (1.50
A solution of g) in acetone (25 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The precipitated crystals were washed with ether and 2- [2-[[(4
-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] -N-ethylacetamide (Compound 1
35) (838 mg) as colorless crystals. 79 mg was obtained as the second crystal. Total yield 917 mg. mp 191-192 ° C. Elemental analysis value: C ₁₆ H ₂₁ N ₅ O · 0.1 H ₂ O, Calcd. : C, 63.81; H, 7.09; N, 23.25. Found: C, 63.65; H, 7.00; N, 22.98. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t,
J = 7.3 Hz), 2.50 (3H, s), 3.21
(2H, qd, J = 7.2, 5.8 Hz), 3.45
(2H, s), 4.19 (2H, d, J = 5.0H
z), 5.40 (1H, t-like), 5.46 (2
H, brs), 5.61 (1H, br), 6.75 −
6.82 (2H, m), 7.06 (1H, dd, J =
7.7, 1.5 Hz), 7.22 (1H, td, J =
7.8, 2.0 Hz), 8.14 (1H, s). IR (KBr) 1636, 1599, 1559, 154
1,1520,1456 cm ^-1 .

Example 136 (Production of compound 136) Formic acid (0.51 ml) was added to acetic anhydride (1.05 ml) at room temperature, and the mixture was stirred at 65 ° C for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). 2- [2
-[[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] amino] phenyl] -N-ethylacetamide (739 mg) in tetrahydrofuran (30 ml)
Was added at 0 ° C. The mixture was stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from hexane gave colorless 2- [2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] -N-ethylacetamide (Compound 136) (621 mg). Obtained as crystals. mp 180 ° C. Elemental analysis value: C ₁₇ H ₂₁ N ₅ O ₂ .0.1H ₂ O, Calcd. : C, 62.03; H, 6.49; N, 21.27. Found: C, 61.92; H, 6.51; N, 21.05. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t,
J = 7.4 Hz), 2.47 (3H, s), 3.27
(2H, qd, J = 7.1, 5.2 Hz), 3.29
(2H, s), 4.90 (2H, br), 5.46 (1
H, br), 6.02 (2H, br), 6.94 (1
H, d, J = 7.4 Hz), 7.29-7.39 (3
H, m), 7.59 (1H, s), 8.14 (1H,
s). IR (KBr) 3312, 1657, 1595, 155
7, 1495, 1470, 1435 cm ^-1 .

Example 137 (Production of compound 137) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.53 g) was suspended in acetone (50 ml), and potassium carbonate (1.49 g) was added. ) And N, N-diethyl-2- (2-aminophenyl) acetamide (2.50 g) in acetone (20 ml) were added at room temperature. The mixture was stirred at 65 ° C. for 4.5 hours.
The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off, and the precipitated crystals were washed with ether,
2- [2-[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] -N, N-diethylacetamide (Compound 137) (0.81 g) was obtained as colorless crystals. 0.25 g was obtained as the second crystal. Total yield 1.06 g. mp 183-185 ° C. Elemental analysis value: C ₁₈ H ₂₅ N ₅ O · 0.1 H ₂ O, Calcd. : C, 65.67; H, 7.71; N, 21.27. Found: C, 65.59; H, 7.82; N, 21.00. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t,
J = 7.2 Hz), 1.19 (3H, t, J = 7.2H)
z), 2.50 (3H, s), 3.32 (2H, q, J
= 7.2 Hz), 3.47 (2H, q, J = 7.1H)
z), 3.63 (2H, s), 4.02 (2H, d, J
= 5.2 Hz), 5.47 (2H, brs), 6.12.
(1H, t-like), 6.72-6.78 (2H,
m), 7.05 (1H, dd, J = 8.0, 1.8H
z), 7.17 (1H, td, J = 7.9, 1.2H
z), 8.15 (1H, s). IR (KBr) 1620, 1597, 1561, 152
0,1458,748 cm ^-1 .

Example 138 (Production of Compound 138) Formic acid (0.53 ml) was added to acetic anhydride (1.09 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Dilute with tetrahydrofuran (5.0 ml). 2-
A solution of [2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] -N, N-diethylacetamide (841 mg) in tetrahydrofuran (40 ml) was added at 0 ° C. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give 2- [2-[[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]
(Formyl) amino] phenyl] -N, N-diethylacetamide (Compound 138) (814 mg) was obtained as colorless crystals. mp 126-129 ° C. Elemental analysis value: C ₁₉ H ₂₅ N ₅ O ₂ .0.1H ₂ O, Calcd. : C, 63.88; H, 7.11; N, 19.60. Found: C, 63.66; H, 7.12; N, 19.44. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t,
J = 7.0 Hz), 1.19 (3H, t, J = 7.1H)
z), 2.47 (3H, s), 3.29 (2H, q, J
= 7.2 Hz), 3.39 (2H, q, J = 7.2H)
z), 3.47 (2H, s), 4.52 (1H, b
r), 4.81 (1H, br), 5.99 (2H, b
r), 6.87-6.92 (1H, m), 7.23-
7.41 (3H, m), 7.68 (1H, s), 8.1
6 (1H, s). IR (KBr) 1655, 1593, 1561, 149
5,1435,1375,1352,1262,121
9 cm ^-1 .

Example 139 (Production of compound 139) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (50 ml), and potassium carbonate (1.47 g) was obtained. ) And 4- [2-
(2-Aminophenyl) acetyl] -1-piperazinecarbaldehyde (1.57 g) in acetone (20 m
l) was added at room temperature, respectively. The mixture was stirred at 65 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline, respectively. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. Under reduced pressure,
The solvent was distilled off, the residue was purified by silica gel column chromatography, and recrystallized from ethanol-ethyl acetate-hexane to give 4- [2- [2-[[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] amino] phenyl] acetyl] -1-piperazinecarbaldehyde (Compound 139) (599 mg) was obtained as colorless crystals. 2
189 mg were obtained as the number crystal. Total yield 788 mg. mp 187 ° C. Elemental analysis value: C ₁₉ H ₂₄ N ₆ O ₂ .0.5EtOH. : C, 61.36; H, 6.95; N, 21.47. Found: C, 61.26; H, 7.10; N, 21.20. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 3.29-3.34 (2H, m), 3.47-
3.50 (2H, m), 3.55-3.69 (4H,
m), 3.69 (2H, s), 4.19 (2H, d, J
= 5.4 Hz), 5.42 (2H, brs), 5.62
(1H, br), 6.74-6.79 (2H, m),
7.03-7.06 (1H, m), 7.20 (1H,
t, J = 7.7 Hz), 8.06 (1H, s), 8.1
5 (1H, s). IR (KBr) 1667, 1634, 1601, 156
4,1520,1454,1435,1281,100
3,733 cm ^-1 .

Example 140 (Production of Compound 140) Formic acid (0.42 ml) was added to acetic anhydride (0.86 ml) in a chamber.
Warm and the mixture was stirred at 65 ° C. for 2 hours. After air cooling,
Dilute with tetrahydrofuran (5.0 ml). 4-
[2- [2-[[(4-amino-2-methyl-5-pyri
Midinyl) methyl] amino] phenyl] acetyl] -1
-Tetra of piperazine carbaldehyde (618 mg)
Hydrofuran solution (50 ml) was added at 0 ° C. mixture
Was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure
And the residue is purified by silica gel column chromatography.
And then re-produced from ethyl acetate-diisopropyl ether.
After crystallization, (4-amino-2-methyl-5-pyrimidi
Nil) methyl [2- [2- (4-formyl-1-pipera)
Dinyl) -2-oxoethyl] phenyl] formamide
(Compound 140) (452 mg) was obtained as colorless crystals.
Was. mp 114-116 ° C.¹H-NMR (CDCl₃)
δ: 2.46 (3H, s), 3.34-3.44 (6
H, m), 3.57 (4H, br), 4.67 (2H,
s), 6.45 (2H, br), 7.00-7.09.
(1H, m), 7.24-7.26 (1H, m), 7.
36-7.40 (2H, m), 7.62 (1H, s),
8.11 (1H, s), 8.13 (1H, s). IR (KBr) 1659, 1597, 1559, 149
7, 1439, 1373, 1362, 1281, 125
0,1223,1200,1005,729cm ^-1.

Example 141 (Production of compound 141) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (20 ml), and potassium carbonate (1.47 g) was added. ) And 4-[(2
-Aminophenyl) acetyl] morpholine (1.40
A solution of g) in acetone (30 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give 4- [2- [2-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] acetyl] morpholine (Compound 141) (576 mg) was obtained as colorless crystals. mp 154 ° C. Elemental analysis value: C ₁₈ H ₂₃ N ₅ O ₂ Calcd. : C, 63.32; H, 6.79; N, 20.51. Found: C, 63.09; H, 6.61; N, 20.52. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 3.55-3.65 (10H, m), 4.20.
(2H, d, J = 5.2 Hz), 5.45 (2H, br
s), 5.77 (1H, t-like), 6.72-
6.79 (2H, m), 7.02 (1H, dd, J =
7.6, 1.6 Hz), 7.19 (1H, td, J =
7.8, 1.6 Hz), 8.15 (1H, s). IR (KBr) 1622, 1597, 1564, 152
0, 1454, 1304, 1271, 1256, 123
3,1115,733 cm ^-1 .

Example 142 (Preparation of Compound 142) Formic acid (0.29 ml) was added to acetic anhydride (0.59 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Dilute with tetrahydrofuran (5.0 ml). 4-
A solution of [2- [2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] phenyl] acetyl] morpholine (475 mg) in tetrahydrofuran (30
ml) at 0 ° C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from ethanol gave 4- [2- [2-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] acetyl] morpholine (Compound 142) (380 mg) was obtained as colorless crystals. mp 184 ° C. Elemental analysis value: C ₁₉ H ₂₃ N ₅ O ₃ .0.1H ₂ O Calcd. : C, 61.47; H, 6.30; N, 18.87. Found: C, 61.35; H, 6.24; N, 18.82. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 3.32 (2H, t, J = 5.0 Hz), 3.4
2 (2H, s), 3.62-3.67 (6H, m),
4.68 (2H, s), 5.99 (2H, br), 7.
00 (1H, dd, J = 7.0, 1.8 Hz), 7.3
4-7.42 (3H, m), 7.63 (1H, s),
8.14 (1H, s). IR (KBr) 1659, 1593, 1559, 143
5,1271,1233,1115,729 cm ^-1 .

Example 143 (Production of compound 143) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.52 g) was suspended in acetone (25 ml), and potassium carbonate (1.48 g) was obtained. ) And 4- (2-
A solution of (aminobenzoyl) morpholine (1.33 g) in acetone (25 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 46.5 hours. The reaction mixture is placed under reduced pressure
It was concentrated, diluted with ethyl acetate, and washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. Under reduced pressure,
The solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give 4- [2-[[(4-amino-2-methyl-5
-Pyrimidinyl) methyl] amino] benzoyl] morpholine (Compound 143) (935 mg) was obtained as colorless crystals. mp 197-198 ° C. Elemental analysis value: C ₁₇ H ₂₁ N ₅ O ₂ .0.1H ₂ O, Calcd. : C, 62.03; H, 6.49; N, 21.27. Found: C, 61.75; H, 6.76; N, 21.05. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 3.65-3.67 (8H, m), 4.16 (2
H, d, J = 5.0 Hz), 5.24 (1H, t, J =
4.8 Hz), 5.31 (2H, brs), 6.78
(1H, t, J = 7.4 Hz), 6.80 (1H, dJ
= 7.8 Hz), 7.10 (1H, dd, J = 7.6,
1.4Hz), 7.29 (1H, t, J = 7.7H)
z), 8.13 (1H, s). IR (KBr) 1620, 1597, 1566, 151
2,1462,1427,1279,1113,733
cm ^-1 .

Example 144 (Production of compound 144) Formic acid (0.47 ml) was added to acetic anhydride (0.96 ml) at room temperature, and the mixture was stirred at 60 ° C for 2 hours. After air cooling,
Diluted with tetrahydrofuran (10 ml). 4- [2
-[[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] amino] benzoyl] morpholine (739m
A solution of g) in tetrahydrofuran (40 ml) was added at 0 ° C. The mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ethanol to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (4- Morpholinylcarbonyl) phenyl] formamide (Compound 144) (651 mg)
Was obtained as colorless crystals. mp 211-213 ° C. Elemental analysis _{C 18 H 21 N 5 O 3} · 0.2H Calcd the ₂ O. : C, 60.22; H, 6.01; N, 19.51. Found: C, 60.37; H, 6.10; N, 19.29. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 2.92-3.08 (2H, br), 3.40-
3.73 (6H, m), 4.36 (1H, br), 5.
18 (1H, br), 5.93 (2H, br), 6.9
8-7.02 (1H, m), 7.28-7.33 (1
H, m), 7.36-7.48 (2H, m), 7.68
(1H, s), 8.24 (1H, s). IR (KBr) 1667, 1634, 1599, 156
4,1495,1464,1435,1281,126
4,1113,1020 cm ^-1 .

Example 145 (Production of Compound 145) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (894 mg) was added to tetrahydrofuran (3
0 ml), potassium carbonate (1.09 g) and 2-amino-N-benzhydrylbenzoic acid amide (1.
43 g) at room temperature. Mix at 75 ° C for 1
Stir for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give 2-[[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] amino] -N-
Benzhydrylbenzoic acid amide (Compound 145) (53
6 mg) as colorless crystals. mp 223-224 ° C. Elemental analysis value: C ₂₆ H ₂₅ N ₅ O Calcd. : C, 73.74; H, 5.95; N, 16.54. Found: C, 73.44; H, 5.60; N, 16.49. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 4.20 (2H, d, J = 5.2 Hz), 5.1.
8 (2H, brs), 6.32 (1H, d, J = 7.2)
Hz), 6.61 (1H, br-d, J = 7.0H)
z), 6.71 (1H, t, J = 7.5 Hz), 6.7
7 (1H, d, J = 8.0 Hz), 7.30-7.39
(11H, m), 7.46 (1H, d, J = 8.8H)
z), 7.66 (1H, t-like), 8.12 (1
H, s). IR (KBr) 1634, 1595, 1580, 151
6,1454 cm ^-1 .

Example 146 (Production of compound 146) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (830 mg) was added to tetrahydrofuran (3
0 ml), and potassium carbonate (1.01 g) and 2-amino-N- (2,2-diphenylethyl) benzoic acid amide (1.39 g) were added at room temperature. The mixture was stirred at 75 ° C. for 14.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline.
The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] -N- (2,2-diphenylethyl) benzoic acid amide (Compound 146) (878 mg) was obtained as colorless crystals. mp 129 ° C. Calcd As Elemental analysis _C 27 _H 27 _{N 5} O. : C, 73.12; H, 6.29; N, 15.79. Found: C, 73.25; H, 6.15; N, 15.46. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 4.03 (2H, dd, J = 8.0, 6.2H
z), 4.19 (2H, d, J = 4.8 Hz), 4.2
8 (1H, t, J = 8.1 Hz), 5.23 (2H, b
rs), 6.00 (1H, t-like), 6.60.
(1H, d, J = 7.0 Hz), 6.73 (1H, d,
J = 7.6 Hz), 7.01 (1H, dd, J = 8.
0, 1.4 Hz), 7.20-7.37 (11H,
m), 7.47 (1H, t-like), 8.13 (1
H, s). IR (KBr) 1634, 1516, 1451c
m ^-1 .

Example 147 (Production of compound 147) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (855 mg) was added to tetrahydrofuran (3
0 ml), and potassium carbonate (1.04 g) and 2-amino-N- (3,3-diphenylpropyl) benzoic acid amide (1.50 g) were added at room temperature. The mixture was stirred at 75 ° C. for 13.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
2-[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] amino] -N- (3,3-diphenylpropyl) benzoic acid amide (Compound 147) (761 mg)
Was obtained as colorless crystals. mp 171-172 ° C. Elemental analysis value: C ₂₈ H ₂₉ N ₅ O: Calcd. : C, 74.47; H, 6.47; N, 15.51. Found: C, 74.41; H, 6.56; N, 15.51. ¹ H-NMR (CDCl ₃ ) δ: 2.39 (2H, q,
J = 7.2 Hz), 2.50 (3H, s), 3.40
(2H, q, J = 6.5 Hz), 4.01 (1H, t,
J = 7.9 Hz), 4.18 (2H, d, J = 4.8H)
z), 5.23 (2H, brs), 5.95 (1H, t
-Like), 6.63 (1H, t, J = 7.5H)
z), 6.74 (1H, d, J = 8.6 Hz), 7.0
2 (1H, d, J = 6.6 Hz), 7.17-7.34
(11H, m), 7.63 (1H, t-like),
8.13 (1H, s). IR (KBr) 1634, 1595, 1580, 156
3,1516,1453 cm ^-1 .

Example 148 (Production of compound 148) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (836 mg) was added to tetrahydrofuran (3
0 ml), and potassium carbonate (1.02 g) and 2-amino-N-[(E) -3-phenyl-2-propenyl] benzoic acid amide (1.12 g) were added at room temperature. The mixture was stirred at 75 ° C. for 15 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give 2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino] -N -[(E) -3-phenyl-2-propenyl] benzoic acid amide (Compound 148)
(428 mg) as colorless crystals. mp 201-203 ° C. Elemental analysis value: C ₂₂ H ₂₃ N ₅ O Calcd. : C, 70.76; H, 6.21; N, 18.75. Found: C, 70.69; H, 6.04; N, 18.72. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 4.18 (2H, d, J = 6.0 Hz), 4.2
2 (2H, d, J = 4.8 Hz), 5.26 (2H, b
rs), 6.19-6.27 (1H, br), 6.26.
(1H, dt, J = 15.8, 6.2 Hz), 6.56
−6.80 (3H, m), 7.28-7.43 (7H,
m), 7.66 (1H, t-like), 8.14 (1
H, s). IR (KBr) 1636, 1595, 1580, 156
0, 1520, 1456 cm ^-1 .

Example 149 (Production of compound 149) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (804 mg) was added to tetrahydrofuran (3
0 ml), and potassium carbonate (982 mg) and 2-amino-N- (1,1'-biphenyl) -3-ylbenzoic acid amide (3.81 g) were added at room temperature, respectively. The mixture was stirred at 75 ° C. for 15.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give 2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] amino]- N- (1,1-biphenyl)
-3-ylbenzoic acid amide (compound 149) (1.00
g) was obtained as colorless crystals. mp 147-150 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H,
s), 4.23 (2H, d, J = 4.8 Hz), 5.2
4 (2H, s), 6.76-6.85 (2H, m),
7.36-7.63 (11H, m), 7.76 (1H,
brs), 7.84 (1H, brs), 8.15 (1
H, s). IR (KBr) 1644, 1597, 1568, 151
6,1451 cm ^-1 .

Example 150 (Production of Compound 150) Formic acid (0.32 ml) was added to acetic anhydride (0.66 ml) at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. After air cooling,
Dilute with tetrahydrofuran (5.0 ml). N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- (1,3-benzodioxo-5-yl) amine (400 mg) in tetrahydrofuran (15 m
l) was added at 0 ° C. The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give N-[(4-amino-2-methyl-5.
-Pyrimidinyl) methyl] -N- (1,3-benzodioxo-5-yl) formamide (Compound 150) (36
6 mg) as pale brown crystals. mp 180-182 ° C. Elemental analysis value: C ₁₄ H ₁₄ N ₄ O ₃ Calcd. : C, 58.73; H, 4.93; N, 19.57. Found: C, 58.62; H, 4.82; N, 19.46. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 4.68 (2H, s), 5.93 (2H, b
r), 6.02 (2H, s), 6.49 (1H, dd,
J = 8.2, 2.0 Hz), 6.55 (1H, d, J =
2.2Hz), 6.76 (1H, d, J = 8.0H)
z), 7.68 (1H, s), 8.24 (1H, s).
IR (KBr) 1667, 1632, 1595, 150
5,1487,1445,1427,1236,120
8,1036 cm ^-1 .

Example 151 (Production of compound 151) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.53 g) was suspended in acetone (50 ml), and potassium carbonate (1.49 g) was added. ) And 5-aminoquinoline (0.94 g) were added at room temperature, respectively. The mixture was stirred at 65 ° C. for 8 hours. Water is added to the reaction mixture,
Extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ethanol to give 5-[(4-amino-
2-methyl-5-pyrimidinyl) methyl] aminoquinoline (Compound 151) (405 mg) was obtained as yellow crystals. mp 272-276 ° C. Calcd As Elemental analysis _{C 15 H 15 N 5 · 0.75H} 2 O. : C, 64.61; H, 5.96; N, 25.12. Found: C, 64.48; H, 6.02; N, 24.96. ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H,
s), 4.25 (2H, d, J = 5.6 Hz), 6.4
8 (1H, d, J = 7.6 Hz), 6.77 (2H,
s), 6.89 (1H, t, J = 5.2 Hz), 7.2
1 (1H, d, J = 8.2 Hz), 7.39-7.50
(2H, m), 7.99 (1H, s), 8.60 (1
H, d, J = 8.4 Hz), 8.80 (1H, dd, J)
= 4.2, 1.6 Hz). IR (KBr) 1661, 1582, 1561, 149
1,1454,1418,1281,1111,78
9,669 cm ^-1 .

Example 152 (Production of compound 152) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.65 g) was suspended in acetone (20 ml), and potassium carbonate (1.61 g) was obtained. ) And 5-aminoisoquinoline (1.68 g) in acetone (30 m
l) was added at room temperature, respectively. 13. Mixing at 65 ° C.
Stir for 5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-ethanol to give 5-[(4-amino-2-methyl-
[5-Pyrimidinyl) methyl] aminoisoquinoline (Compound 152) (226 mg) was obtained as yellow crystals. mp 203-205 ° C. Calcd As Elemental analysis _{C 15 H 15 N 5 · 0.1H} 2 O. : C, 67.45; H, 5.74; N, 26.22. Found: C, 67.36; H, 5.70; N, 26.14. ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H,
s), 4.26 (2H, d, J = 5.2 Hz), 6.6.
4 (1H, d, J = 7.0 Hz), 6.78 (2H,
s), 6.89 (1H, t-like), 7.26 (1
H, d, J = 8.8 Hz), 7.40 (1H, t, J =
7.6 Hz), 7.99 (1H, s), 8.02 (1
H, d, J = 8.8 Hz), 8.43 (1H, d, J =
5.8 Hz), 9.13 (1H, s). IR (KBr) 3144, 1665, 1588, 156
3,1524,1449,1437,1412,138
7,1339,1281,799,754,667cm
^-1 .

Example 153 (Production of compound 153) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (2.49 g) was suspended in acetone (90 ml), and potassium carbonate (2.43 g) was added. ) And 2- (phenylsulfonyl) aniline (3.08 g) were added at room temperature, respectively. The mixture was stirred at 65 ° C. for 60.5 hours.
The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, respectively, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained crystals were washed with ethyl acetate,
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (phenylsulfonyl) phenyl] amine (compound 153) (469 mg) was obtained as colorless crystals. mp 221 ° C. Elemental analysis _{C 18 H 18 N 4 O 2} S · 0.2H Calcd the ₂ O. : C, 60.38; H, 5.18; N, 15.65. Found: C, 60.36; H, 5.13; N, 15.54. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 4.13 (2H, d, J = 4.8 Hz), 4.8
0 (2H, brs), 6.10 (1H, t-like
e), 6.75 (1H, d, J = 8.4 Hz), 6.9
3 (1H, t, J = 7.1 Hz), 7.41-7.63
(4H, m), 7.81-7.87 (2H, m), 8.
01 (1H, dd, J = 8.1, 1.9 Hz), 8.0
7 (1H, s). IR (KBr) 1597, 1568,
1514, 1462, 1323, 1289, 1148,
739,594 cm ^-1 .

Example 154 (Preparation of Compound 154) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-methoxyphenyl) sulfanyl] phenyl] formamide (505 mg) was added to methanol-tetrahydrofuran-water. (4: 1: 1, 12.0 ml) and sodium periodate (625 mg) was added at room temperature. The mixture was stirred at 95 ° C. for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-5-pyrimidyl) methyl [2- (2-methoxyphenyl) Sulfinyl) phenyl] formamide (Compound 15
4) (207 mg) was obtained as white crystals. mp 192-193 ° C. Calcd As Elemental analysis _{C 20 H 20 N 4 O 3} S · 0.1H 2 O. : C, 60.32; H, 5.11; N, 14.07. Found: C, 60.11; H, 5.18; N, 13.92. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 3.79 (3H, s), 4.62 (1H, b
r), 4.86 (1H, br), 5.95 (2H, b
r), 6.78 (1H, d, J = 7.6 Hz), 6.9
2 (1H, d, J = 7.6 Hz), 7.20 (1H, d, J = 7.6 Hz)
d, J = 7.5 Hz), 7.38-7.56 (3H,
m), 7.54 (1H, s), 7.74-7.83 (2
H, m), 7.91 (1H, s). IR (KBr) 1667, 1590, 1557, 147
8,1435,1277,1242,1038,101
5,762,729 cm ^-1 .

Example 155 (Preparation of Compound 155) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-methoxyphenyl) sulfanyl] phenyl] formamide (444 mg) was dissolved in dichloromethane (12 ml). Dissolve and add metachloroperbenzoic acid (70
%: 1583 mg) at 0 ° C. Stirred at room temperature for 16.5 hours. Further ethanol (4.0 ml) was added,
Stirred at room temperature for 6 hours. Sodium sulfite (809m
g) and water (10 ml) were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-1-oxide-5-pyrimidyl) methyl [2- [ (2-Methoxyphenyl) sulfonyl] phenyl] formamide (Compound 155)
(334 mg) was obtained as colorless crystals. mp 225-226 ° C. Calcd As Elemental analysis _{C 20 H 20 N 4 O 5} S. : C, 56.06; H, 4.70; N, 13.08. Found: C, 55.98; H, 4.62; N, 12.80. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H,
s), 3.69 (3H, s), 4.02 (1H, d, J
= 15.4 Hz), 5.20 (1H, d, J = 15.2)
Hz), 6.61 (1H, dd, J = 7.7, 1.1H)
z), 6.95 (1H, d, J = 7.8 Hz), 7.1
9-7.23 (2H, m), 7.32 (2H, br)
s), 7.35 (1H, s), 7.53 (1H, td,
J = 7.6, 1.6 Hz), 7.60-7.72 (2
H, m), 8.10 (1H, dd, J = 7.7, 1.9)
Hz), 8.44 (1H, dd, J = 8.0, 1.6H)
z). IR (KBr) 1667, 1626, 1590, 158
0,1481,1435,1316,1281,123
1,1155,735,592 cm ^-1 .

Example 156 (Preparation of Compound 156) (4-Amino-2-methyl-1-oxide-5-pyrimidyl) methyl [2-[(2-methoxyphenyl) sulfonyl] phenyl] formamide (200 mg) was dissolved in methanol. (15 ml), 10% palladium-carbon (180 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 66 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
(4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-methoxyphenyl) sulfonyl] phenyl] formamide (Compound 156) (119 mg) was obtained as colorless crystals. mp 227-228 ° C. Calcd As Elemental analysis _{C 20 H 20 N 4 O 4} S · 0.33H 2 O. : C, 57.41; H, 4.98; N, 13.39. Found: C, 57.64; H, 4.79; N, 13.08. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.61 (1H, d, J = 15.4 Hz);
69 (3H, s), 5.10, (1H, d, J = 15.
4Hz), 5.89 (2H, br), 6.61 (1H,
dd, J = 7.9, 1.3 Hz), 6.95 (1H, d
d, J = 8.4, 0.8 Hz), 7.23 (1H, t)
d, J = 7.8, 1.0 Hz), 7.41 (1H,
s), 7.45 (1H, s), 7.52 (1H, td,
J = 7.6, 1.7 Hz), 7.60-7.69 (2
H, m), 8.12 (1H, dd, J = 7.7, 1.9)
Hz), 8.43 (1H, dd, J = 8.0, 1.6H)
z). IR (KBr) 1667, 1591, 1480, 143
7,1316,1283,1155,733,592c
m ^-1 .

Example 157 (Production of compound 157) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.55 g) was suspended in acetone (10 ml), and potassium carbonate (1.51 g) was added. ) And 2-aminophenyl-3'-methoxyphenyl sulfide (2.5
A solution of 4 g) in acetone (20 ml) was added at room temperature. The mixture was stirred at 70 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(3-methoxyphenyl) sulfanyl] phenyl] amine (Compound 157) (1.21
g) was obtained as colorless crystals. mp 149-150 ° C. Elemental analysis value: C ₁₉ H ₂₀ N ₄ OS: Calcd. : C, 64.75; H, 5.72; N, 15.90. Found: C, 64.54; H, 5.84; N, 15.83. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 3.71 (3H, s), 4.13 (2H, d, J
= 4.8 Hz), 4.81 (1H, t, J = 4.9H)
z), 4.88 (2H, s), 6.59-6.69 (3
H, m), 6.78 (1H, d, J = 8.4 Hz),
6.85 (1H, td, J = 7.4, 1.3 Hz),
7.13 (1H, t, J = 7.8 Hz), 7.37 (1
H, td, J = 7.8, 1.7 Hz), 7.56 (1
H, dd, J = 7.5, 1.7 Hz), 8.06 (1
H, s). IR (KBr) 1590, 1574, 1501, 147
6,1453,1426,1283,1248,123
1,1040,748,735 cm ^-1 .

Example 158 (Production of Compound 158) Formic acid (1.2 ml) was added dropwise to acetic anhydride (2.4 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(3-Methoxyphenyl) sulfanyl] phenyl] amine (902 mg) was added to tetrahydrofuran (3
0 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[( 3-methoxyphenyl) sulfanyl]
Phenyl] formamide (Compound 158) (680 m
g) was obtained as colorless crystals. mp 155-156 ° C. Elemental analysis value: C ₂₀ H ₂₀ N ₄ O ₂ S Calcd. : C, 63.14; H, 5.30; N, 14.73. Found: C, 62.85; H, 5.43; N, 14.51. ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H,
s), 3.79 (3H, s), 4.71 (2H, b
r), 5.98 (2H, br), 6.80-6.88.
(3H, m), 6.92-6.97 (1H, m), 7.
18-7.30 (4H, m), 7.53 (1H, s),
8.07 (1H, s). IR (KBr) 1665, 1591, 1474, 143
9, 1285, 1248, 1039 cm ^-1 .

Example 159 (Production of compound 159) Formic acid (1.2 ml) was added dropwise to acetic anhydride (2.4 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2-[(3-Methoxyphenyl) sulfanyl] phenyl] amine (902 mg) was added to tetrahydrofuran (3
0 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give 5-[(formyl) [2-[(3-methoxyphenyl) sulfanyl] anilino. ] Methyl] -2-methyl-
4-pyrimidinylformamide (Compound 159) (18
0 mg) as colorless crystals. mp 127-128 ° C. Elemental analysis value: C ₂₁ H ₂₀ N ₄ O ₃ S Calcd. : C, 61.75; H, 4.94; N, 13.72. Found: C, 61.75; H, 4.97; N, 13.67. ¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H,
s), 3.78 (3H, s), 4.76 (2H, s),
6.72-6.76 (2H, m), 6.82-6.87
(1H, m), 6.98-7.03 (1H, m), 7.
19-7.37 (4H, m), 7.84 (1H, s),
8.07 (1H, s), 9.64 (1H, d, J = 9.
6 Hz), 9.97 (1H, d-like). IR (KBr) 1707, 1657, 1574, 147
6,1445,1427,1250,1219c
m ^-1 .

Example 160 (Preparation of Compound 160) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (1.0
0 g) was dissolved in water (10 ml), and a 10% aqueous sodium hydroxide solution (2.9 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Tetrabutylammonium bromide (39 mg) was added, a toluene solution of 4-fluoronitrobenzene (614 mg) (15 ml) was added at room temperature, and the mixture was stirred at 90 ° C. for 14 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography, recrystallized from ethyl acetate, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [ 2-[(4-nitrophenyl) sulfanyl] phenyl] amine (compound 16
0) (173 mg) as pale yellow crystals. mp 179 ° C. Elemental analysis _{C 18 H 17 N 5 O 2} S · 0.2H Calcd the ₂ O. : C, 58.27; H, 4.73; N, 18.88. Found: C, 58.57; H, 4.83; N, 18.55. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 4.16 (2H, d, J = 5.0 Hz), 4.7
8 (1H, t-like), 4.91 (2H, br),
6.87 (1H, d, J = 8.4 Hz), 6.90 (1
H, t, J = 7.5 Hz), 7.08 (2H, d, J =
9.2 Hz), 7.46 (1H, t, J = 7.2H)
z), 7.55 (1H, dd, J = 7.8, 1.6H
z), 8.06 (1H, s), 8.06 (2H, d, J
= 9.0 Hz). IR (KBr) 1642, 1591, 1574, 150
7, 1476, 1454, 1424, 1337, 85
3,743 cm ^-1 .

Example 161 (Preparation of Compound 161) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (1.0%)
0 g) was dissolved in water (10 ml), and a 10% aqueous sodium hydroxide solution (2.9 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Tetrabutylammonium bromide (39 mg) was added, a toluene solution of 4-fluoronitrobenzene (614 mg) (15 ml) was added at room temperature, and the mixture was stirred at 90 ° C. for 14 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[(4- Nitrophenyl) sulfanyl] phenyl] formamide (Compound 161)
(407 mg) was obtained as white crystals. mp 186-187 ° C. Elemental analysis value: C ₁₉ H ₁₇ N ₅ O ₃ S Calcd. : C, 57.71; H, 4.33; N, 17.71. Found: C, 57.58; H, 4.42; N, 17.41. ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 4.74 (2H, s), 5.87 (2H, b
r), 6.98-7.05 (2H, m), 7.27-
7.30 (1H, m), 7.42-7.57 (4H,
m), 8.03-8.09 (2H, m), 8.06 (1
H, s). IR (KBr) 1665, 1593, 1514, 147
6,1339 cm ^-1 .

Example 162 (Production of compound 162) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.94 g) was suspended in acetone (15 ml), and potassium carbonate (1.90 g) was obtained. ) And 2-aminophenyl 2-pyridinyl sulfide (2.78 g) in acetone (30 ml) were added at room temperature. The mixture was stirred at 65 ° C. for 16.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
2-Methyl-5-[[2- (2-pyridinylsulfanyl) anilino] methyl] -4-pyrimidineamine (Compound 162) (1.10 g) was obtained as colorless crystals. mp 139-143 ° C. Elemental analysis value: C ₁₇ H ₁₇ N ₅ S · 0.25 H ₂ O, Calcd. : C, 62.27; H, 5.38; N, 21.36. Found: C, 62.07; H, 5.52; N, 21.38. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.16 (2H, d, J = 5.4 Hz), 4.9
8 (2H, br), 5.02 (1H, t-like),
6.78-6.90 (3H, m), 7.01 (1H, d
dd, J = 7.0, 5.4, 1.1 Hz), 7.36 −
7.45 (1H, m), 7.46 (1H, td, J =
7.7, 1.6 Hz), 7.59 (1H, dd, J =
7.6, 1.6 Hz), 8.06 (1H, s), 8.3
8-8.41 (1H, m). IR (KBr) 1591, 1574, 1563, 150
5,1451,1418 cm ^-1 .

Example 163 (Production of compound 163) Formic acid (0.85 ml) was added dropwise to acetic anhydride (1.7 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). 2-methyl-5
-[[2- (2-pyridinylsulfanyl) anilino]
Methyl] -4-pyrimidineamine (1.09 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (2- Pyridinylsulfanyl) phenyl] formamide (compound 163) (694)
mg) as colorless crystals, mp 121 ° C. Elemental analysis value C ₁₈ H ₁₇ N ₅ OS Calcd. : C, 61.52; H, 4.88; N, 19.93. Found: C, 61.25; H, 5.14; N, 19.75. ¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H,
s), 4.73 (2H, s), 5.93 (2H, b
r), 6.98-7.09 (3H, m), 7.38-
7.54 (3H, m), 7.55 (1H, s), 7.6
6 (1H, dd, J = 6.1, 3.1 Hz), 8.09
(1H, s), 8.36 (1H, ddd, J = 4.8,
1.8, 0.6 Hz). IR (KBr) 1663, 1591, 1574, 156
1,1474,1447,1418 cm ^-1 .

Example 164 (Production of compound 164) Formic acid (0.85 ml) was added dropwise to acetic anhydride (1.7 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (10ml). 2-methyl-5
-[[2- (2-pyridinylsulfanyl) anilino]
Methyl] -4-pyrimidineamine (1.09 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise at 0 ° C. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and [4- (formylamino) -2-methyl-5-pyrimidinyl] methyl [2- (2-pyridinylsulfanyl) phenyl] formamide (Compound 164)
(328 mg) was obtained as amorphous. Elemental analysis value: C ₁₉ H ₁₇ N ₅ O ₂ S. 0.17 H ₂ O. : C, 59.66; H, 4.57; N, 18.31. Found: C, 60.02; H, 4.90; N, 17.95. ¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H,
s), 4.86 (2H, brs), 6.98-7.11.
(2H, m), 7.15 (1H, d, J = 8.0H
z), 7.40-7.45 (2H, m), 7.55 (1
H, td, J = 7.7, 1.9 Hz), 7.65-7.
70 (1H, m), 8.02 (1H, s), 8.09
(1H, s), 8.34-8.36 (1H, m), 9.
59 (1H, d, J = 9.6 Hz), 10.02 (1
H, br-d, J = 9.6 Hz). IR (KBr) 1707, 1659, 1574, 144
9,1427,1217 cm ^-1 .

Example 165 (Preparation of Compound 165) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (570
mg) was suspended in ethanol (15 ml), and sodium methoxide (221 mg) was added at room temperature. The mixture was stirred at room temperature for 1 hour. 2-chloropyrimidine (614
mg) at room temperature and the mixture was stirred at 90 ° C. for 87 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from diisopropyl ether gave (4-amino-2-methyl-5-pyrimidinyl) methyl [2-
[(2-Pyrimidinyl) sulfanyl] phenyl] formamide (compound 165) (244 mg) was obtained as colorless crystals. mp 161-164 ° C. Elemental analysis value: C ₁₇ H ₁₆ N ₆ OS · 0.33 H ₂ O Calcd. : C, 56.98; H, 4.69; N, 23.45. Found: C, 56.69; H, 4.69; N, 23.17. ¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H,
s), 4.74 (2H, br), 5.90 (2H, b
r), 7.01 (1H, t, J = 4.8 Hz), 7.0
3-7.08 (1H, m), 7.46 (1H, d, J =
5.8 Hz), 7.48 (1H, d, J = 6.4H)
z), 7.53 (1H, s), 7.73-7.77 (1
H, m), 8.14 (1H, s), 8.45 (2H,
d, J = 4.8 Hz). IR (KBr) 1661,15
91,1561,1553,1474,1429,13
81 cm ^-1 .

Example 166 (Production of compound 166) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (2.73 g) was suspended in acetone (30 ml), and potassium carbonate (4.00 g) was obtained. ) And 2-aminophenyl 2-thienyl sulfide (4.00 g) in acetone (60 ml) were added at room temperature. The mixture was stirred at 70 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give 2-methyl-5-[[2- (2-
Thienylsulfanyl) anilino] methyl] -4-pyrimidineamine (compound 166) (1.87 g) was obtained as colorless crystals. mp 141-143 ° C. Elemental analysis value as C ₁₆ H ₁₆ N ₄ S ₂ Calcd. : C, 58.51; H, 4.91; N, 17.06. Found: C, 58.42; H, 5.03; N, 17.02. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 4.17 (2H, d, J = 5.2 Hz), 4.8
1 (1H, br), 5.10 (2H, brs), 6.7
5 (1H, d, J = 8.0 Hz), 6.79 (1H, t
d, J = 7.5, 1.2 Hz), 6.93 (1H, d
d, J = 5.3, 3.5 Hz), 7.04 (1H, d
d, J = 7.5, 1.3 Hz), 7.24-7.32
(2H, m), 7.52 (1H, dd, J = 7.6,
1.4 Hz), 8.10 (1H, s). IR (KBr) 1636, 1588, 1566, 149
9,1451,1422,747 cm ^-1 .

Example 167 (Production of compound 167) Formic acid (1.8 ml) was added dropwise to acetic anhydride (3.6 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (15ml). 2-methyl-5
[[2- (2-Thienylsulfanyl) anilino] methyl] -4-pyrimidineamine (786 mg) was dissolved in tetrahydrofuran (25 ml) and added dropwise at 0 ° C.
The mixture was stirred at room temperature for 18.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2- (2-thienylsulfanyl) phenyl] formamide (compound 167) ( 586mg)
Was obtained as amorphous. Elemental analysis value: C ₂₁ H ₂₁ N ₅ O ₂ S · 0.25AcOEt. : C, 57.12; H, 4.79; N, 14.80. Found: C, 57.00; H, 4.80; N, 14.54. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.75 (2H, br), 6.03 (2H, b
r), 6.86 (1H, dd, J = 7.5, 1.3H)
z), 6.98 (1H, dd, J = 7.8, 1.8H)
z), 7.09-7.29 (4H, m), 7.53-
7.55 (1H, m), 7.55 (1H, s), 8.1
5 (1H, s). IR (KBr) 1667, 1591, 1472, 143
5 cm ^-1 .

Example 168 (Production of compound 168) Formic acid (1.8 ml) was added dropwise to acetic anhydride (3.6 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (15ml). 2-methyl-5
[[2- (2-Thienylsulfanyl) anilino] methyl] -4-pyrimidineamine (786 mg) was dissolved in tetrahydrofuran (25 ml) and added dropwise at 0 ° C.
The mixture was stirred at room temperature for 18.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
[4- (Formylamino) -2-methyl-5-pyrimidinyl] methyl [2- (2-thienylsulfanyl) phenyl] formamide (Compound 168) (199 mg) was obtained as colorless crystals. mp 195-199 ° C. Elemental analysis value: C ₁₈ H ₁₆ N ₄ O ₂ S ₂ Calcd. : C, 56.23; H, 4.19; N, 14.57. Found: C, 56.08; H, 4.48; N, 14.25. ¹ H-NMR (CDCl ₃ ) δ: 2.62 (3H,
s), 4.79 (2H, brs), 6.90 (1H,
d, J = 8.0 Hz), 6.99 (1H, dd, J =
8.0, 1.6 Hz), 7.09-7.33 (4H,
m), 7.55 (1H, dd, J = 5.3, 1.3H
z), 7.87 (1H, s), 8.16 (1H, s),
9.70 (1H, d, J = 9.2 Hz), 10.04
(1H, d-like). IR (KBr) 1707,1
661,1572,1474,1429,1217cm
^-1 .

Example 169 (Production of compound 169) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-nitrophenyl) sulfanyl] phenyl] formamide (0.74 g) was added to 85% ethanol (50 ml), and reduced iron (0.94 g) and calcium chloride (0.10 g) were added thereto. The mixture was stirred at 95 ° C. for 3 hours. After air cooling, the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate. The mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-methyl-
5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (Compound 1
69) (612 mg) as colorless crystals. mp 181-182 ° C. Elemental analysis value: C ₁₉ H ₁₉ N ₅ OS: Calcd. : C, 62.44; H, 5.24; N, 19.16. Found: C, 62.42; H, 5.50; N, 19.03. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 3.89 (2H, brs), 4.74 (2H, b
r), 6.01 (2H, br), 6.67-6.71.
(2H, m), 6.82 (1H, dd, J = 7.7,
1.5 Hz), 6.87 (1H, dd, J = 7.8,
1.6 Hz), 7.06 (1H, td, J = 7.4,
1.5 Hz), 7.14-7.22 (3H, m), 7.
55 (1H, s), 8.13 (1H, s). IR (KBr) 1661, 1595, 1497, 147
0 cm ^-1 .

Example 170 (Production of compound 170) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (186 mg) was added to tetrahydrofuran (10.0 ml). ) And pyridine (0.062m
l) and benzoyl chloride (0.065 ml) were each added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give N- [4-[[2-
[[(4-Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl]
Phenyl] benzoic acid amide (compound 170) (271 m
g) was obtained as colorless crystals. mp 214 ° C. Elemental analysis value: C ₂₆ H ₂₃ N ₅ O ₂ S Calcd. : C, 66.50; H, 4.94; N, 14.91. Found: C, 66.19; H, 4.96; N, 14.68. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 4.73 (2H, br), 5.99 (2H, b
r), 6.91 (1H, dd, J = 7.2, 2.0H
z), 7.05 (1H, dd, J = 7.4, 1.8H
z), 7.13-7.36 (4H, m), 7.46-
7.59 (4H, m), 7.69 (2H, d, J = 8.
8 Hz), 7.85-7.91 (3H, m), 8.10
(1H, s). IR (KBr) 1661, 1591, 1526, 149
7,1472,1316 cm ^-1 .

Example 171 (Production of Compound 171) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (201 mg) was added to N, N-dimethyl It was dissolved in formamide (10 ml), and isonicotinic acid (204 mg) and diethyl cyanophosphate (90%: 0.1%) were dissolved.
38 ml) and triethylamine (0.30 ml) were added sequentially. The mixture was stirred at room temperature for 23 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N- [4-[[2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] [Phenyl] sulfanyl] phenyl] isonicotinamide (Compound 171) (157 mg) was obtained as an amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 4.74 (2H, br), 6.01 (2H, b
r), 6.95 (1H, dd, J = 7.4, 1.8H)
z), 7.00 (1H, dd, J = 7.4, 1.8H)
z), 7.17-7.34 (4H, m), 7.35 (1
H, s), 7.65-7.73 (4H, m), 8.03.
(1H, s), 8.08 (1H, s), 8.83 (2
H, dd, J = 4.4, 1.8 Hz). IR (KBr) 1663, 1591, 1528, 149
5,1472 cm ^-1 .

Example 172 (Preparation of compound 172) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (219 mg) was added to N, N-dimethyl After dissolving in formamide (10 ml), 3-ethoxypropionic acid (0.20 ml) and diethyl cyanophosphate (9
0%: 0.40 ml) and triethylamine (0.34
ml) were added sequentially. The mixture was stirred at room temperature for 21.5 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give N- [4-[[2-[[(4-amino-
2-methyl-5-pyrimidinyl) methyl] (formyl)
Amino] phenyl] sulfanyl] phenyl] -3-ethoxypropionamide (Compound 172) (120 m
g) was obtained as colorless crystals. mp 137-138 ° C. Elemental analysis _{C 24 H 27 N 5 O 3} S · 0.5H Calcd the ₂ O. : C, 60.74; H, 5.95; N, 14.76. Found: C, 60.52; H, 5.77; N, 14.55. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t,
J = 7.0 Hz), 2.46 (3H, s), 2.65
(2H, t, J = 5.5 Hz), 3.62 (2H, q,
J = 7.1 Hz), 3.77 (2H, t, J = 5.6H)
z), 4.72 (2H, br), 6.00 (2H, b
r), 6.90 (1H, dd, J = 7.5, 1.7H)
z), 7.00 (1H, dd, J = 7.7, 1.9H)
z), 7.11-7.23 (2H, m), 7.28 (2
H, d, J = 8.6 Hz), 7.54 (1H, s),
7.54 (2H, d, J = 8.8 Hz), 8.10 (1
H, s), 8.69 (1H, s). IR (KBr) 1663, 1595, 1532, 147
2 cm ^-1 .

Example 173 (Production of compound 173) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (25 ml), and potassium carbonate (1.83 g) was obtained. ) And 2-[[4
-(2-ethoxyethoxy) phenyl] sulfanyl]
Aniline (2.23 g) was added at room temperature, respectively. The mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- N-
[2-[[4- (2-ethoxyethoxy) phenyl] sulfanyl] phenyl] amine (compound 173) (84
0 mg) as colorless crystals. mp 95 ° C. Elemental analysis value: C ₂₂ H ₂₆ N ₄ O ₂ S Calcd. : C, 64.36; H, 6.38; N, 13.65. Found: C, 64.32; H, 6.51; N, 13.66. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t,
J = 6.9 Hz), 2.49 (3H, s), 3.60
(2H, q, J = 7.1 Hz), 3.77 (2H, q,
J = 7.1 Hz), 4.07 (2H, d, J = 4.9H)
z), 4.13 (2H, d, J = 5.2 Hz), 4.7
8 (1H, t-like), 4.92 (2H, br
s), 6.73-6.86 (4H, m), 7.02-
7.07 (2H, m), 7.31 (1H, t, J = 7.
0 Hz), 7.51 (1H, dd, J = 7.5, 1.7)
Hz), 8.06 (1H, s). IR (KBr) 1591, 1568, 1493, 145
4,1246 cm ^-1 .

Example 174 (Production of compound 174) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (203 mg) was added to tetrahydrofuran (10.0 ml). ) And pyridine (0.067 m
l) and 2- (3,4-dimethoxyphenyl) acetyl chloride (143 mg) were added, respectively. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether.
N- [4-[[2-[[(4-amino-2-methyl-5
-Pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] phenyl] -2- (3,4-dimethoxyphenyl) acetamide (compound 174) (264)
mg) as colorless crystals. mp 109 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H,
s), 3.70 (2H, s), 3.90 (3H, s),
3.91 (3H, s), 4.70 (2H, br), 5.
99 (2H, br), 6.83-6.92 (4H,
m), 6.99 (1H, dd, J = 7.4, 1.8H)
z), 7.12-7.25 (5H, m), 7.45 (2
H, d, J = 8.4 Hz), 7.52 (1H, s),
8.06 (1H, s). IR (KBr) 1663, 15
95, 1532, 1472 cm ^-1 .

Example 175 (Production of compound 175) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (213 mg) was treated with 1,2-dichloroethane (12 ml), 2-thiazolecarbaldehyde (0.084 ml) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water, a saturated aqueous solution of sodium bicarbonate, water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
2-methyl-5-pyrimidinyl) methyl [2-[[4-
[[(E)-or (Z) -1,3-thiazole-2-
Ilmethylidene] amino] phenyl] sulfanyl] phenyl] formamide (Compound 175) (220 mg)
Was obtained as pale yellow crystals. mp 176-178 ° C. Elemental analysis value: C ₂₃ H ₂₀ N ₆ OS ₂ Calcd. : C, 59.98; H, 4.38; N, 18.25. Found: C, 59.80; H, 4.26; N, 18.04. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 4.73 (2H, brs), 5.98 (2H, b
r), 6.98 (1H, dd, J = 7.4, 1.6H)
z), 7.15-7.34 (7H, m), 7.54 (1
H, s), 7.54-7.56 (1H, m), 8.03.
(1H, d, J = 3.2 Hz), 8.10 (1H,
s), 8.70 (1H, s). IR (KBr) 1663, 1593, 1472, 143
7,731 cm ^-1 .

Example 176 (Preparation of compound 176) N- (4-amino-2-phenyl-5-pyrimidinyl)
Methylbenzothiazolium bromide hydrobromide (62
0 mg) was dissolved in tetrahydrofuran (6.0 ml) and water (6.0 ml), and a 10% aqueous sodium hydroxide solution (1.55 ml) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Triethylamine (0.90m
l), benzylchloromethyl sulfide (669 m
g), sodium iodide (581 mg) and tetrabutylammonium bromide (21 mg) were added, and the mixture was stirred at room temperature for 15.5 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane.
(4-amino-2-phenyl-5-pyrimidinyl) methyl [2-[[(benzylsulfanyl) methyl] sulfanyl] phenyl] formamide (compound 176)
39 mg) as colorless crystals. mp 127-128 ° C. Elemental analysis value C ₂₆ H ₂₄ N ₄ OS ₂ Calcd. : C, 66.07; H, 5.12; N, 11.85. Found: C, 65.70; H, 5.22; N, 11.79. ¹ H-NMR (CDCl ₃ ) δ: 3.79 (4H,
s), 4.80 (2H, br), 6.09 (2H, b
r), 6.93 (1H, dd, J = 7.6, 1.4H
z), 7.20 (1H, td, J = 7.5, 1.9H
z), 7.29-7.44 (10H, m), 7.71
(1H, s), 8.16 (1H, s), 8.28-8.
32 (2H, m). IR (KBr) 1661, 1636, 1582, 147
2,1410 cm ^-1 .

Example 177 (Production of compound 177) 4-Amino-5-aminomethyl-2-methylpyrimidine (1.38 g) was dissolved in pyridine (10 ml) to give 4-
Dimethylaminopyridine (500 mg) was added and 1-octanesulfonyl chloride (2.1
7g) and stirred at room temperature for 15 hours. Pyridine was distilled off under reduced pressure, water (30 ml) was added to the residue, and the precipitated crystals were collected by filtration, washed with water and ethyl acetate, dried and dried to give 4-amino-2-methyl-5- (octane-1-). Ylsulfonylaminomethyl) pyrimidine (compound 177) (2.3
g) was obtained as colorless crystals. mp. 199-201 ° C Elemental analysis: C ₁₄ H ₂₆ N ₄ O ₂ S Calcd. : C, 53.47; H, 8.33; N, 17.82 Found: C, 53.36; H, 8.30; N, 17.52 ¹ H-NMR (DMSO-d ₆ ) δ: 0 .86 (3
H, t), 1.25 (10H, br), 1.55-
1.70 (2H, m), 2.30 (3H, s), 2.9
4-3.02 (2H, m), 3.92 (2H, d),
6.60 (2H, br.), 7.39 (1H, t),
7.93 (1H, s).

Example 178 (Preparation of Compound 178) 4-Amino-2-methyl-5- (octan-1-ylsulfonylaminomethyl) pyrimidine (220 mg) was dissolved in dimethylformamide (1.5 ml) to give a 60% oily solution. Sodium hydride (30 mg), sodium iodide (7
0 mg) and benzyl chloride (130 mg) were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (40m
l), water (20 ml) and hexane (30 ml) were added, shaken and separated. Wash the upper layer with diluted sodium hydroxide water,
After washing with water, the mixture was concentrated under reduced pressure. The residue (crystal) was washed with ethanol and dried to obtain 4-amino-5- [benzyl- (octan-1-ylsulfonyl) amino] methyl-methylpyrimidine (compound 178) (100 mg) as colorless crystals. . mp. 125-126 ° C. Elemental analysis value C ₂₁ H ₃₂ N ₄ O ₂ S Calcd. : C, 62.34; H, 7.97; N, 13.85 Found: C, 62.28; H, 8.07; N, 13.82 ¹ H-NMR (DMSO-d ₆ ) δ: 0 .89 (3H,
t), 1.27 (10H, br), 2.43 (3H,
s), 2.89-2.97 (2H, m), 4.24 (2
H, s), 4.33 (2H, s), 5.84 (2H, b
r), 7.23-7.33 (5H, m), 7.81 (1
H, s).

Example 179 (Preparation of compound 179) 4-Amino-5- [benzyl- (octan-1-ylsulfonyl) amino] methyl-2-methylpyrimidine (5
3 mg) in 2N hydrochloric acid (0.1 m) in ethanol (4 ml).
l) was added to dissolve and concentrate under reduced pressure. Acetone (2 ml) was added to the residue, and the precipitated crystals were collected by filtration, washed with acetone and dried, and dried with 4-amino-5- [benzyl- (octan-1-ylsulfonyl) amino] methyl-2-methylpyrimidine hydrochloride. (Compound 179) (50 mg) was obtained as colorless crystals. mp. 196-197 ° C Elemental analysis: C ₂₁ H ₃₃ N ₄ O ₂ SCl. : C, 57.19; H, 7.54 ; N, 12.70 Found: C, 57.04; H, 7.62; N, 12.68 1 H-NMR (DMSO-d 6) δ: 0 .87 (3
H, t), 1, 27 (10H, br), 1.64-1.
80 (2H, m), 2.38 (3H, s), 3.24-
3.31 (2H, m), 4.35 (2H, s), 4, 4
6 (2H, s), 7.25 (5H, s), 7.90 (1
H, s), 9.10 (1H, br).

Example 180 (Production of compound 180) 4-Amino-5- (octan-1-ylsulfonyl) aminomethyl-2-methylpyrimidine (314 mg) was dissolved in methanol (4 ml), and 28% sodium methoxide was added. Methanol solution (193 mg) was added and 4-chlorophenacyl bromide (234 mg) with stirring at room temperature.
Was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was partitioned between water and ethyl acetate, the ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-amino-5- [N-4 -Chlorobenzoylmethyl-N- (octan-1-ylsulfonyl) amino] methyl-2-methylpyrimidine (Compound 180)
(98 mg) as a pale yellow candy. This was crystallized from isopropyl ether, dried and dried to obtain crystals. mp. 110-111 ° C. Elemental analysis _{C 22 H 31 N 4 O 3} Calcd as SCl. : C, 56.58; H, 6.69; N, 12.00 Found: C, 56.49; H, 6.54; N, 11.87 ¹ H-NMR (DMSO-d ₆ ) δ: 0 .89 (3H,
t), 1.20-1.60 (10H, m), 1.85-
2.05 (2H, m), 2.47 (3H, s), 3.2
3-3.32 (2H, m), 4.42 (2H, s),
4.62 (2H, s), 5.92 (2H, br), 7.
46 (2H, d), 7.71 (1H, s), 7.80
(2H, d).

Example 181 (Production of compound 181) 4-Amino-5-aminomethyl-2-methylpyrimidine (1.38 g) and 4- {methylaminopyridine (1.5
3g) was dissolved in DMF (10 ml) and stirred in an ice bath with naphthalene-2-sulfonyl chloride (2.27).
g) was added. After 15 minutes, it was removed from the bath and stirred for 2 hours. Water (100 ml) was added, and the precipitated crystals were collected by filtration, washed with water, and dried to give 4-amino-5- (naphthalen-2-ylsulfonyl) aminomethyl-2-methylpyrimidine (compound 181) (2.9 g) as colorless. Obtained as crystals. mp. Calcd the 231 - 232 ° C. Elemental analysis _{C 16 H 16 N 4 O 2} S. : C, 58.52; H, 4.91; N, 17.06 Found: C, 58.30; H, 4.87; N, 17.01 ¹ H-NMR (DMSO-d ₆ ) δ: 2 .18 (3
H, s), 3.82 (2H, d), 6.54 (2H, b
r), 7.63-7.83 (4H, m), 8.03-
8.15 (4H, m), 8.40 (1H, s).

Example 182 (Preparation of compound 182) 4-Amino-5- (naphthalen-2-ylsulfonyl)
Aminomethyl-2-methylpyrimidine (462 mg) was dissolved in DMF (10 ml) and stirred at room temperature for 60%.
Oily sodium hydride (52 mg) was added. Next, potassium iodide (100 mg) and benzyl chloride (16
5 mg) and stirred at room temperature for 4 hours. Water (40m
1) and ethyl acetate (60 ml) were added, shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-amino-5- [N
-Benzyl- (N-naphthalen-2-ylsulfonyl)
Amino] methyl 2-methylpyrimidine (compound 182)
(260 mg) as colorless crystals. mp. 153-154 ° C Elemental analysis value As C ₂₃ H ₂₂ N ₄ O ₂ S, Calcd. : C, 66.01; H, 5.30; N, 13.39 Found: C, 65.87; H, 5.41; N, 13.41 ¹ H-NMR (DMSO-d ₆ ) δ: 2 .38 (3H,
s), 4.19 (2H, s), 4.37 (2H, s),
5.78 (2H, br), 7.00-7.15 (5H,
m), 7.54 (1H, s), 7.62-7.74 (2
H, m), 7.82 (1H, dd), 7.94-8.0.
5 (3H, m), 8.43 (1H, s).

Example 183 (Preparation of compound 183) 4-Amino-5- (naphthalen-1-ylsulfonyl)
Aminomethyl-2-methylpyrimidine (492 mg) was dissolved in tetrahydrofuran (4 ml), 60% oily sodium hydride (62 mg) was added, and the mixture was stirred for 15 minutes.
Next, potassium iodide ((100 g), 4- (benzophenone-2-ylaminocarbonyl) benzyl chloride (560 mg) was added, and the mixture was stirred at room temperature for 15 hours.The reaction solution was mixed with water (40 ml) and ethyl acetate (150 ml). The upper layer was washed with water, concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml).
l) was added to dryness under reduced pressure. The residue was crystallized from acetone and recrystallized from ethanol to give 4-amino-5- [N-
4- (benzophenon-2-ylaminocarbonylbenzyl) -N- (naphthalen-2-ylsulfonyl) amino] methyl-2-methylpyrimidine hydrochloride (compound 18
3) (860 mg) was obtained as colorless crystals. mp. 219-220 ° C Elemental analysis: C ₃₇ H ₃₂ N ₅ O ₄ SCl. : C, 65.53; H, 4.76; N, 10.33 Found: C, 65.31; H, 4.67; N, 10.21 ¹ H-NMR (DMSOd ₆ ) δ: 2.32. (3H,
s), 4.32 (2H, s), 4.57 (2H, s),
7.26-7.83 (16H, m), 7.94 (8.2
6 (4H, m), 8.64 (1H, s), 9.20 (1
H, br), 10.26 (1H, s).

Example 184 (Production of compound 184) 4-Amino-5-aminomethyl-2-methylpyrimidine (414 mg), 4-dimethylaminopyridine (427)
mg) was dissolved in DMF (2 ml), and 474 mg of butyric anhydride was added thereto with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours, saturated saline (30 ml), sodium hydrogen carbonate (200 mg), ethyl acetate (60 ml), tetrahydrofuran (40 ml) were added, and the mixture was shaken and separated. The upper layer was concentrated under reduced pressure, purified by silica gel column chromatography, and recrystallized from ethanol / ethyl to give 4-amino-5- (butyroylaminomethyl) -2-methylpyrimidine (compound 184) (360 mg). Was obtained as colorless crystals. mp. 178-179 ° C. Elemental analysis value C ₁₀ H ₁₆ N ₄ O Calcd. : C, 57.67; H, 7.74; N, 26.90 Found: C, 57.66; H, 7.85; N, 26.91 ¹ H-NMR (DMSO-d ₆ ) δ: 0 .84 (3
H, t), 1.42-1.60 (2H, m), 2.10
(3H, t), 2.28 (3H, s), 4.03 (2
H, d), 6.74 (2H, br), 7.85 (1H,
s), 8.31 (1H, br).

Example 185 (Preparation of compound 185) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -4- (chloromethyl) benzamide (Compound 83) (1.46 g), 2-aminothiophenol (8
75 mg), anhydrous potassium carbonate (1.38 g) and potassium iodide (200 mg) were stirred in DMF (7 ml) at room temperature for 16 hours. A mixed solvent (300 ml) of ethyl acetate and hexane (4: 1) and water (100 ml) were added to the reaction solution, and the mixture was shaken and separated. The upper layer was washed with dilute sodium hydroxide, washed with water, and concentrated under reduced pressure. The residue (crystal) is washed with ethanol (10 ml), dried and dried to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4-.
[[(2-Aminophenyl) sulfanylmethyl]] benzamide (Compound 185) (1.05 g) was obtained as pale yellow crystals. mp. 195-196 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 3.80 (2H, s), 4.22 (2H, d),
5.31 (2H, br), 6.38-6.46 (1H,
m), 6.69 (1H, d), 6.81 (2H, b
r), 6.96-7.05 (2H, m), 7.26 (2
H, d), 7.73 (2H, d), 7.92 (1H,
s), 8.92 (1H, br).

Example 186 (Production of compound 186) N- (4-Amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide Hydrobromide (0.6 g) was dissolved in ethanol (10 ml). Let 2
8% sodium methoxide methanol solution (0.83
g) was added at room temperature. The mixture was stirred at room temperature for 1 hour, phenacyl bromide (0.29 g) was added and the mixture was stirred at room temperature for 23 hours. After concentration under reduced pressure, the residue was diluted with ethyl acetate and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give [4-[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]]
[4H-1,4-benzothiazin-2-yl] (phenyl) methanone (compound 186) (0.5 g) was obtained as yellow crystals. mp 123-125 ° C. Elemental analysis value: C ₂₁ H ₁₈ N ₄ OS. EtOH: Calcd. : C, 65.69; H, 5.75; N, 13.32. Found: C, 65.54; H, 5.83; N, 13.30. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t,
J = 7.0 Hz), 1.34 (1H, s), 2.53
(3H, s), 3.73 (2H, m), 4.41 (2
H, s), 5.20 (2H, br), 6.56-6.6.
5. 3 (1H, m), 6.8-7.08 (3H, m), 6.
84 (1H, s) 7.15-7.55 (5H, m),
8.11 (1H, s).

Example 187 (Preparation of compound 187) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.0 g), 1-phenyl-1,3-dihydro-2H-benzimidazole- 2-one (0.7
4 g), potassium carbonate (1.1 g), acetone (30 m
The mixture of 1) was heated at reflux for 13 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was extracted with 1N hydrochloric acid. The aqueous layer was made basic with 1N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 1-[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]-
3-Phenyl-1,3-dihydro-2H-benzimidazol-2-one (compound 187) (0.23 g) was obtained as colorless crystals. mp 205 ° C. Elemental analysis value C ₁₉ H ₁₇ N ₅ O · 0.2 H ₂ O Calcd. : C, 68.13; H, 5.24; N, 20.91. Found: C, 67.90; H, 5.14; N, 21.17. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.95 (2H, s), 6.1 (2H, br),
6.9-7.66 (9H, m), 8.34 (1H,
s).

Example 188 (Production of compound 188) Formic acid (2.1 ml) was added dropwise to acetic anhydride (4.2 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (5.0 ml). 2-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] amino] -N-propylbenzoic acid amide (552 mg) was dissolved in tetrahydrofuran (30 ml) and added dropwise at 0 ° C. The mixture was further stirred at 50 ° C for 17 hours at 60 ° C.
Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether.
9-methyl-6-propyl-6,6a, 7,12-tetrahydro-5H-pyrimido [4 ′, 5 ′: 4,5] pyrimido [1,2-a] quinazolin-5-one (compound 18
8) (168 mg) was obtained as colorless crystals. mp 101-102 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t,
J = 7.5 Hz), 1.74 (2H, quint, J =
7.1 Hz), 2.41 (3H, s), 3.40 (1
H, dt, J = 14.0, 7.2 Hz), 3.84 (1
H, dt, J = 14.0, 7.2 Hz), 4.53 (1
H, d, J = 17.2 Hz), 4.81 (1H, d, J)
= 17.2 Hz), 5.51 (1H, s), 6.11
(1H, s), 6.79 (1H, d, J = 8.2H
z), 6.99 (1H, t, J = 7.6 Hz), 7.3
7 (1H, td, J = 7.9, 1.8 Hz), 8.03
(1H, dd, J = 7.7, 1.5 Hz), 8.11
(1H, s). IR (KBr) 1657, 1607, 1568, 151
8,1481,1435,1310,1061c
m ^-1 .

Example 189 (Preparation of compound 189) N- (4-amino-2-methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (625
mg) was suspended in ethanol (15 ml), and sodium methoxide (223 mg) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate-hexane to give 2-methyl-11a, 12-dihydro-5H-pyrimido [4 ′,
5 ′: 4,5] Pyrimido [2,1-b] [1,3] benzothiazole (compound 189) (213 mg) was obtained as pale pink crystals. mp 176-177 ° C. Elemental analysis value: C ₁₃ H ₁₂ N ₄ S · 0.1H ₂ O, Calcd. : C, 60.49; H, 4.76; N, 21.70. Found: C, 60.70; H, 4.77; N, 21.41. ¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H,
3.s), 4.51 (1H, d, J = 17.2 Hz),
65 (1H, d, J = 16.8 Hz), 5.35 (1
H, br), 6.51 (1H, s), 6.60 (1H,
d, J = 7.6 Hz), 6.84 (1H, td, J =
7.7, 1.1 Hz), 7.06 (1H, td, J =
7.7, 1.4 Hz), 7.19 (1H, d, J = 8.
8Hz), 8.02 (1H, s). IR (KBr) 1667, 1593, 1557, 152
6, 1472, 1429, 1373, 731 cm ^-1 .

Example 190 (Production of compound 190) 4-Amino-5-aminomethyl-2-methylpyrimidine (1.38 g) was dissolved in pyridine (10 ml), 4-dimethylaminopyridine (500 mg) was added, and ice was added. Benzoyl chloride (1.83 g) was added while stirring in the bath, and the mixture was stirred for 0.5 hours under the same conditions. Pyridine was distilled off under reduced pressure, water (30 ml) and ethyl acetate (100 ml) were added to the residue, and the mixture was shaken and separated. The upper layer was washed with aqueous sodium hydrogen carbonate. The aqueous layer and the washing solution were combined and allowed to stand at room temperature for 20 hours. The precipitated crystals were collected by filtration, washed with a small amount of water, and dried.
-Amino-5- (benzoylaminomethyl) -2-methylpyrimidine was obtained as colorless crystals (1.15 g). The ethyl acetate layer was concentrated under reduced pressure, and the residue (crystal) was washed with ethyl acetate (10 ml).
(Benzoylaminomethyl) -2-methylpyrimidine (compound 190) (0.54 g) was obtained as colorless crystals. mp. 224-225 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H,
s), 4.24 (2H, d), 6.81 (2H, b
r), 7.43-7.60 (3H, m), 7.83-
7.88 (2H, m), 7.93 (1H, s), 8.9
8 (1H, br).

Example 191 (Production of compound 191) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was obtained. ) And 2- (2-
Tetrahydro-2-furanylethoxy) aniline (2.
A solution of 60 g) in acetone (20 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (2-tetrahydro-2- Furanylethoxy) phenyl] amine (Compound 1
91) (1.13 g) was obtained as amorphous. ¹ H
_{-NMR (CDCl 3) δ: 1.42-1.60} (1
H, m), 1.77-2.11 (5H, m), 2.52
(3H, s), 3.60-3.71 (1H, m), 3.
77-3.88 (1H, m), 3.91-4.05 (1
H, m), 4.07-4.20 (2H, m), 4.16
(2H, s), 4.33 (1H, br), 5.51 (2
H, brs), 6.72-6.94 (4H, m), 8.
12 (1H, s). IR (KBr) 1628, 1597, 1561, 151
2,1451,1248,1213,1125,105
5,741 cm ^-1 .

Example 192 (Production of compound 192) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was added. ) And 2- (3-
A solution of phenylpropoxy) aniline (2.66 g) in acetone (20 ml) was added at room temperature. The mixture was stirred at 65 ° C. for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-
2-methyl-5-pyrimidinyl) methyl] -N- [2-
(3-Phenylpropoxy) phenyl] amine (compound 192) (1.05 g) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.13 (2H, qu
int, J = 7.0 Hz), 2.53 (3H, s),
2.78 (2H, t, J = 7.5 Hz), 4.01 (2
H, t, J = 6.4 Hz), 4.16 (1H + 2H,
s), 5.44 (2H, br), 6.72-6.79.
(3H, m), 6.85-6.93 (1H, m), 7.
16-7.30 (5H, m), 8.12 (1H, s). IR (KBr) 1595, 1508, 1453, 124
8,739 cm ^-1 .

Example 193 (Production of compound 193) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was obtained. ) And 2- (3-
A solution of (ethoxypropoxy) aniline (2.89 g) in acetone (20 ml) was added at room temperature. The mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2- (3-ethoxypropoxy) phenyl Amine (Compound 193) (1.21
g) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t,
J = 7.0 Hz), 2.05 (2H, quint, J =
6.3 Hz), 2.53 (3H, s), 3.46 (2
H, q, J = 7.1 Hz), 3.55 (2H, t, J =
6.0 Hz), 4.10 (2H, t, J = 6.0H)
z), 4.17 (2H, brs), 5.51 (2H, b
rs), 6.73-6.94 (4H, m), 8.12.
(1H, s), NH were not identified. IR (KBr) 1597, 1561, 1508, 145
1,1248,1125 cm ^-1 .

Example 194 (Production of compound 194) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was obtained. ) And 3-benzyloxyaniline (2.11 g) in acetone (20 m
l) was added at room temperature, respectively. The mixture was stirred at 65 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethanol-ethyl acetate.
N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [3- (benzyloxy) phenyl] amine (Compound 194) (476 mg) was obtained as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the same compound (233 mg) as colorless crystals. Total yield 709 mg. mp 188-189 ° C. Elemental analysis value: C ₁₉ H ₂₀ N ₄ O · 0.2 H ₂ O, Calcd. : C, 70.44; H, 6.35; N, 17.29. Found: C, 70.52; H, 6.44; N, 17.00. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 3.60 (1H, t-like), 4.13 (2
H, d, J = 5.2 Hz), 5.04 (2H, s),
5.36 (2H, s), 6.34-6.38 (2H,
m), 6.45-6.49 (1H, m), 7.14 (1
H, t, J = 8.3 Hz), 7.31-7.44 (5
H, m), 8.10 (1H, s). IR (KBr) 1615, 1593, 1563, 149
5,1454,1427,1188,1161,737
cm ^-1 .

Example 195 (Production of compound 195) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.50 g) was suspended in acetone (30 ml), and potassium carbonate (1.47 g) was added. ) And 3,4-
An acetone solution (20 ml) of (methylenedioxy) aniline (1.45 g) was added at room temperature. The mixture was stirred at 65 ° C. for 4.5 hours. Water is added to the reaction mixture,
Extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
(1,3-benzodioxo-5-yl) amine (compound 195) (407 mg) was obtained as an amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 3.42 (1H, br), 4.10 (2H, d,
J = 1.8 Hz), 5.49 (2H, br), 5.89
(2H, s), 6.18 (1H, dd, J = 8.3,
2.3Hz), 6.35 (1H, d, J = 2.6H)
z), 6.70 (1H, d, J = 8.4 Hz), 8.0
9 (1H, s). IR (KBr) 1636, 1597, 1563, 150
5,1489,1458,1208,1038c
m ^-1 .

Example 196 (Production of compound 196) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (4.02 g), 2-[(2-ethoxyethyl) sulfanyl] aniline (5. 61 g) and potassium carbonate (4.91 g) were suspended in acetone (100 ml) and stirred at 65 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (600 ml) was added. The mixture was washed with water (200 ml × 2) and saturated saline (75 ml).
And washed. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- N-
[2-[(2-Ethoxyethyl) sulfanyl] phenyl] amine (compound 196) (2.93 g) was obtained as colorless crystals. mp 119 ° C. Elemental analysis value: C ₁₆ H ₂₂ N ₄ OS: Calcd. : C, 60.35; H, 6.96; N, 17.59. Found: C, 60.29; H, 7.09; N, 17.68. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t,
J = 7.0 Hz), 2.53 (3H, s), 2.87
(2H, t, J = 6.5 Hz), 3.44 (2H, q,
J = 7.1 Hz), 3.50 (2H, t, J = 6.2H)
z), 4.19 (2H, d, J = 5.2 Hz), 5.2
5 (1H, t-like), 5.38 (2H, br
s), 6.72 (1H, d, J = 7.6 Hz), 6.7.
4 (1H, t, J = 7.1 Hz), 7.24 (1H,
t, J = 7.2 Hz), 7.46 (1H, dd, J =
7.9, 1.3 Hz), 8.15 (1H, s). IR (KBr) 1588, 1568, 1499, 145
3 cm ^-1 .

Example 197 (Production of compound 197) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (217 mg) was added to THF (5. 0ml)
And pyridine (0.072 ml) and diphenylacetic chloride (164 mg) were added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate (2
00 ml), water (75 ml) and saturated saline (5 ml).
0 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give N- [4-[[2-[[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]
(Formyl) amino] phenyl] sulfanyl] phenyl] -2,2-diphenylacetic acid amide (compound 197)
(57.7 mg) was obtained as colorless crystals. mp 185-186 ° C. Elemental analysis _{C 33 H 29 N 5 O 2} Calcd as S · _{H 2} O. : C, 68.61; H, 5.41; N, 12.12. Found: C, 68.86; H, 5.45; N, 12.50. ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H,
s), 4.71 (2H, br), 5.09 (1H,
s), 5.97 (2H, br), 6.90 (1H, d,
J = 9.8 Hz), 7.04 (1H, d, J = 9.0H)
z), 7.16-7.38 (15H, m), 7.50
(2H, d, J = 8.8 Hz), 7.52 (1H,
s), 8.08 (1H, s). IR (KBr) 1667, 1591, 1532, 149
5,1472,733 cm ^-1 .

Example 198 (Production of compound 198) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(4-aminophenyl) sulfanyl] phenyl] formamide (206 mg) was added to THF (10. 0m
1) and pyridine (0.21 ml) and 2-naphthoyl chloride (258 mg) were added at room temperature. The mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction mixture, and ethyl acetate (3 mL) was added.
00 ml). The mixture was combined with a 1N aqueous sodium hydroxide solution (75 ml × 4) and a saturated aqueous sodium carbonate solution (7 mL).
5 ml × 2), water (100 ml) and saturated saline (50
ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give N- [4-[[2-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] phenyl]
-2-Naphthamide (Compound 198) (179.4m
g) was obtained as colorless crystals. mp 212-213 ° C (decomposition). Elemental analysis value: C ₃₀ H ₂₅ N ₅ O ₂ S Calcd. : C, 69.34; H, 4.85; N, 13.48. Found: C, 69.14; H, 4.72; N, 13.43. ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H,
s), 4.73 (2H, s), 6.76-7.30 (9
H, m), 7.59-7.67 (3H, m), 7.88.
(2H, d, J = 8.8 Hz), 8.03-8.13
(3H, m), 8.19 (1H, s), 8.58 (1
H, s), 10.60 (1H, s).

Example 199 (Production of compound 199) 4-Amino-5-bromomethyl-2-phenylpyrimidine hydrobromide (602 mg) was added to acetone (25 ml).
Suspended in potassium carbonate (603 mg) and 2-
[(4-aminophenyl) sulfanyl] aniline (8
07 mg) was added. The mixture was stirred at 65 ° C. for 14 hours. Ethyl acetate (300 ml) was added, and water (100 m
l) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether-hexane to give N-[(4-amino-2-phenyl-5-pyrimidinyl) methyl ] -N- [2-[(4
-Methoxyphenyl) sulfanyl] phenyl] amine (Compound 199) (610.0 mg) was obtained as pale yellow crystals. mp 58-60 ° C. Elemental analysis value C ₂₄ H ₂₂ N ₄ OS Calcd. : C, 69.54; H, 5.35; N, 13.52. Found: C, 69.57; H, 5.74; N, 13.25. ¹ H-NMR (CDCl ₃ ) δ: 3.77 (3H,
s), 4.19 (2H, d, J = 5.2 Hz), 4.8.
5 (1H, t-like), 5.04 (2H, br
s), 6.76-6.85 (4H, m), 7.04-7.
10 (2H, m), 7.32 (1H, td, J = 7.
8, 1.6 Hz), 7.43-7.46 (3H, m),
7.52 (1H, dd, J = 7.2, 1.4 Hz),
8.24 (1H, s), 8.30-8.34 (2H,
m). IR (KBr) 1613, 1590, 1551, 149
3,1441,1406,1244 cm ^-1 .

Example 200 (Production of compound 200) 4-Amino-5-bromomethyl-2-isopropylpyrimidine hydrobromide (604 mg) was added to acetone (40 m
l), potassium carbonate (671 mg) and 2-
[(4-Methoxyphenyl) sulfanyl] aniline (898 mg) was added. The mixture was stirred at 65 ° C. for 18 hours. Ethyl acetate (200 ml) was added, and water (100
ml) and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane.
N-[(4-Amino-2-isopropyl-5-pyrimidinyl) methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] phenyl] amine (Compound 200)
(184.5 mg) was obtained as colorless crystals. mp 94 ° C. Elemental analysis value: C ₂₁ H ₂₄ N ₄ OS Calcd. : C, 66.29; H, 6.36; N, 14.72. Found: C, 66.10; H, 6.19; N, 14.72. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d,
J = 7.0 Hz), 2.88-3.02 (1H, m),
3.77 (3H, s), 4.13 (2H, d, J = 4.
8 Hz), 4.80 (1H, t-like), 4.93
(2H, brs), 6.74-6.85 (4H, m),
7.04-7.11 (2H, m), 7.31 (1H, t
d, J = 7.7, 1.4 Hz), 7.50 (1H, d
d, J = 7.6, 1.6 Hz), 8.11 (1H,
s). IR (KBr) 1590, 1557, 1493, 145
6,1244 cm ^-1 .

Example 201 (Production of Compound 201) Formic acid (1.3 ml) was added to acetic anhydride (2.6 ml). After stirring at room temperature for 1 hour, THF (5.0 ml) was added, and N-[(4-amino-2-phenyl-5-pyrimidinyl) methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] was added. A solution of [phenyl] amine (540 mg) in THF (10 ml) was added at 0 ° C. The mixture was stirred at room temperature for 13.5 hours. The reaction mixture was treated with ethyl acetate (2
50 ml), and washed sequentially with water (100 ml), a saturated aqueous solution of sodium carbonate (75 ml), water (100 ml) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and methanol-THF-water (1: 1: 1, 15.0 m) was added to the residue.
l) and sodium hydroxide (156 mg) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (250 ml), and washed sequentially with water (100 ml), a saturated aqueous solution of sodium carbonate (75 ml), water (100 ml) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography,
Further, recrystallization from ethyl acetate-diisopropyl ether gave (4-amino-2-phenyl-5-pyrimidinyl) methyl [2-[(4-methoxyphenyl) sulfanyl] phenyl] formamide (compound 201) (35
8.7 mg) as colorless crystals. mp 141 ° C. Elemental analysis value: C ₂₅ H ₂₂ N ₄ O ₂ S Calcd. : C, 67.85; H, 5.01; N, 12.66. Found: C, 67.87; H, 5.07; N, 12.73. ¹ H-NMR (CDCl ₃ ) δ: 3.77 (3H,
s), 4.82 (2H, br), 6.08 (2H, b
r), 6.83-6.94 (4H, m), 7.06-7.
28 (4H, m), 7.42-7.45 (3H, m),
7.74 (1H, s), 8.15 (1H, s), 8.2
9-8.33 (2H, m). IR (KBr) 1663, 1591, 1493, 147
0,1408,1248 cm ^-1 .

Example 202 (Production of Compound 202) Formic acid (0.68 ml) was added to acetic anhydride (1.36 ml). After stirring at room temperature for 1 hour, THF (2.0 ml)
And N-[(4-amino-2-isopropyl-5-
Pyrimidinyl) methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] phenyl] amine (260 m
g) in THF (5.0 ml) was added at 0 ° C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and a saturated aqueous sodium carbonate solution (75 ml), water (100 ml) and saturated saline (75 ml) were used.
ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and methanol-T
HF-water (1: 1: 1, 15.0 ml) and sodium hydroxide (82 mg) were added. The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and water (75 ml), a saturated aqueous solution of sodium carbonate (50 ml), water (75 ml) and saturated saline (50 ml) were used.
Washing was performed sequentially in 1). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
Recrystallization from hexane gave (4-amino-2-isopropyl-5-pyrimidinyl) methyl [2-[(4-methoxyphenyl) sulfanyl] phenyl] formamide (compound 202) (180.0 mg) as colorless crystals. Obtained. mp 145 ° C. Elemental analysis value: C ₂₂ H ₂₄ N ₄ O ₂ S Calcd. : C, 67.68; H, 5.92; N, 13.71. Found: C, 64.77; H, 6.13; N, 13.94. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d,
J = 6.6 Hz), 2.85-2.99 (1H, m),
3.83 (3H, s), 4.72 (2H, br), 5.
99 (2H, br), 6.84-6.93 (4H,
m), 7.06-7.19 (2H, m), 7.29 (2
H, d, J = 8.4 Hz), 7.60 (1H, s),
8.13 (1H, s). IR (KBr) 1663, 1591, 1495, 147
2,1250 cm ^-1 .

Example 203 (Production of compound 203) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.13 g), 2-([1,1'-biphenyl] -4-yl Sulfanyl) aniline (2.22
g) and potassium carbonate (1.38 g) in acetone (30
ml) and stirred at 65 ° C. for 16 hours. Ethyl acetate (300 ml) was added to the reaction mixture. The mixture was washed with water (100 ml) and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
5-[[2-([1,1′-biphenyl] -4-ylsulfanyl) anilino] methyl] -2-methyl-4-pyrimidineamine (Compound 203) (782 mg) was obtained as colorless crystals. mp 196-197 ° C. Elemental analysis value: C ₂₄ H ₂₂ N ₄ S Calcd. : C, 72.33; H, 5.56; N, 14.06. Found: C, 71.97; H, 5.31; N, 13.93. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 4.14 (2H, d, J = 4.6 Hz), 4.8
1 (3H, brs), 6.78-6.91 (2H,
m), 7.09-7.13 (2H, m), 7.34-7.
61 (9H, m), 8.06 (1H, s). IR (KBr) 1588, 1568, 1499, 147
8,1449,760 cm ^-1 .

Example 204 (Production of compound 204) Formic acid (1.0 ml) was added to acetic anhydride (2.0 ml).
Was. After stirring at room temperature for 1 hour, THF (5.0 ml) was added.
In addition, 5-[[2-([1,1'-biphenyl] -4-
Ylsulfanyl) anilino] methyl] -2-methyl-
4-pyrimidineamine (425 mg) in THF (20 m
l) The solution was added at 0 ° C. Mixture at room temperature for 13.5 hours
Stirred. Dilute the reaction mixture with ethyl acetate (200 ml).
And saturated aqueous sodium carbonate (75 ml), water (1
00 ml) and saturated saline (50 ml). Yes
The organic layer was dried with anhydrous magnesium sulfate. Decompress the solvent
Under reduced pressure, methanol-THF-water (1: 1:
1, 21.0 ml) and sodium hydroxide (128 m
g) was added. The mixture was stirred at room temperature for 2 hours. Reaction mixture
The mixture was diluted with ethyl acetate (200 ml) and water (75 m
l), saturated aqueous sodium carbonate solution (50 ml), water (7
5 ml) and saturated saline (50 ml). Organic
The layer was dried with anhydrous magnesium sulfate. Solvent under reduced pressure
The residue is purified by silica gel column chromatography.
Purification and recrystallization from ethyl acetate gave 4-
[[2-[[(4-amino-2-methyl-5-pyrimidi
Nyl) methyl] (formyl) amino] phenyl] sulf
Phenyl] -1,1'-biphenyl (compound 204) (3
65 mg) were obtained as colorless crystals. mp 164-165 ° C (decomposition). Elemental analysis value C₂₅H₂₂N₄Calcd. : C, 70.40; H, 5.20; N, 13.14. Found: C, 70.68; H, 5.28; N, 13.22.¹ H-NMR (CDCl₃) Δ: 2.44 (3H,
s), 4.75 (2H, brs), 6.00 (2H, b
r), 6.97 (1H, dd, J = 7.6, 1.8H)
z), 7.17-7.50 (8H, m), 7.56-7.
61 (5H, m), 8.11 (1H, s). IR (KBr) 1663, 1593, 1478, 143
5,762,733cm ^-1.

Example 205 (Preparation of Compound 205) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (0.96 g), 2- (2'-methoxy [1,1'-biphenyl] -4-ylsulfanyl) aniline (1.83 g) and potassium carbonate (1.17 g)
Was suspended in acetone (25 ml) and stirred at 65 ° C. for 17 hours. Ethyl acetate (300 ml) was added to the reaction mixture. The mixture was mixed with water (100 ml) and saturated saline (50 ml).
ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give 5-[[2-[(2'-methoxy [1,
1′-Biphenyl] -4-yl) sulfanyl] anilino] methyl] -2-methyl-4-pyrimidineamine (Compound 205) (667 mg) was obtained as colorless crystals. mp 197-198 ° C (decomposition). Elemental analysis value: C ₂₅ H ₂₄ N ₄ OS · 0.75 H ₂ O Calcd. : C, 67.92; H, 5.81; N, 12.67. Found: C, 68.08; H, 5.56; N, 12.78. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H,
s), 3.93 (3H, s), 4.10 (2H, d, J
= 4.4 Hz), 4.73 (1H, br), 4.80.
(2H, br), 6.77 (1H, d, J = 7.8H)
z), 6.87 (1H, t, J = 7.3 Hz), 6.9
9-7.12 (4H, m), 7.23-7.37 (5H,
m), 7.63 (1H, d, J = 7.4 Hz), 8.0
5 (1H, s). IR (KBr) 1595,1561,1505,147
8, 1454, 1427, 756 cm ^-1 .

Example 206 (Preparation of compound 206) 4-Amino-5-bromomethyl-2-phenylpyrimidine hydrobromide (581 mg) was suspended in THF (20 ml), and potassium carbonate (582 mg) and 2- (2-amino-5-bromopyridine) were added. [(2
-Nitrophenyl) sulfanyl] aniline (829 m
g) was added. The mixture was stirred at 75 ° C. for 72 hours. Ethyl acetate (200 ml) was added, and the mixture was washed with water (75 ml) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
[(4-Amino-2-phenyl-5-pyrimidinyl) methyl] -N- [2-[(2-nitrophenyl) sulfanyl] phenyl] amine (Compound 206) (510 m
g) was obtained as a yellow amorphous. Elemental analysis _{C 23 H 19 N 5 O 2} S · 0.4H Calcd the ₂ O. : C, 63.26; H, 4.57; N, 16.04. Found: C, 63.62; H, 4.45; N, 15.65. ¹ H-NMR (CDCl ₃ ) δ: 4.23 (2H, d,
J = 5.2 Hz), 4.94 (1H, t-like),
5.00 (2H, s), 6.80-6.95 (3H,
m), 7.22-7.30 (1H, m), 7.35-7.
49 (5H, m), 7.53-7.57 (1H, m),
8.24 (1H, s), 8.26-8.32 (3H,
m). IR (KBr) 1615, 1591, 1568, 155
3,1512,1441,1408,1335,130
6,733 cm ^-1 .

Example 207 (Preparation of compound 207) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] phenyl] amine (378 mg) in THF
Potassium carbonate (489 mg) and acetyl bromide (0.20 ml) were added to the (15 ml) solution. The mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with ethyl acetate (200
ml) and a saturated aqueous solution of sodium carbonate (50 m
l), water (100 ml) and saturated saline (50 ml) sequentially. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2).
-Methyl-5-pyrimidinyl) methyl [2-[(4-methoxyphenyl) sulfanyl] phenyl] acetic acid amide (Compound 207) (248 mg) was obtained as colorless crystals. mp 136-137 ° C. Elemental analysis value: C ₂₁ H ₂₂ N ₄ O ₂ S Calcd. : C, 63.94; H, 5.62; N, 14.20. Found: C, 63.71; H, 5.77; N, 14.14. ¹ H-NMR (CDCl ₃ ) δ: 1.91 (3H,
s), 2.47 (3H, s), 3.85 (3H, s),
4.40 (1H, d, J = 15.0 Hz), 5.03
(1H, d, J = 15.0 Hz), 6.20 (2H, b
r), 6.75-6.80 (2H, m), 6.95 (2
H, d, J = 8.8 Hz), 7.03-7.19 (2
H, m), 7.36 (2H, d, J = 8.8 Hz),
7.42 (1H, s). IR (KBr) 1645, 15
93, 1495, 1470, 1250 cm ^-1 .

Example 208 (Production of Compound 208) Formic acid (1.1 ml) was added to acetic anhydride (2.2 ml). After stirring at room temperature for 1 hour, THF (5.0 ml) was added, and 5-[[2-[(2′-methoxy [1,1′-biphenyl] -4-yl) sulfanyl] anilino] methyl] -2 was added. -Methyl-4-pyrimidineamine (480 m
g) in THF (35 ml) was added at 0 ° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and a saturated aqueous sodium carbonate solution (50 ml), water (75 ml) and saturated saline (50 ml) were used.
Washing was performed sequentially in 1). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give 4-[[2-[[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] (formyl) amino] phenyl] sulfanyl] -2′-methoxy-1,
1′-biphenyl (compound 208) (222 mg) was obtained as colorless crystals. mp 167-170 ° C. Elemental analysis value: C ₂₆ H ₂₄ N ₄ O ₂ S · 0.1 H ₂ O, Calcd. : C, 68.13; H, 5.32; N, 12.22. Found: C, 67.96; H, 5.35; N, 12.10. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H,
s), 3.83 (3H, s), 4.73 (2H, b
r), 6.00 (2H, br), 6.91-7.08
(3H, m), 7.17-7.39 (7H, m), 7.
54 (2H, d, J = 8.4 Hz), 7.56 (1H,
s), 8.13 (1H, s). IR (KBr) 1665, 1591, 1480, 143
7, 1254, 756, 733 cm ^-1 .

Example 209 (Production of compound 209)
Amino-5-bromomethyl-2-isopropylpyrimidine hydrobromide (936 mg) was suspended in THF (30 ml), and potassium carbonate (1.04 g) and 2-[(2-nitrophenyl) sulfanyl] aniline (1 .48 g) was added.
The mixture was stirred at 75 ° C. for 72 hours. Ethyl acetate (30
0 ml), water (100 ml) and saturated saline (5 ml).
0 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, recrystallized from ethyl acetate, and N-[(4-amino-2-isopropyl-5-
Pyrimidinyl) methyl] -N- [2-[(2-nitrophenyl) sulfanyl] phenyl] amine (compound 20
9) (420 mg) was obtained as yellow crystals. mp 156-157 ° C. Elemental analysis value: C ₂₀ H ₂₁ N ₅ O ₂ S Calcd. : C, 60.74; H, 5.35; N, 17.71. Found: C, 60.64; H, 5.40; N, 17.51. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d,
J = 7.0 Hz), 2.87-3.00 (1H, m),
4.15 (2H, d, J = 5.2 Hz), 4.85 (2
H + 1H, brs), 6.78-6.95 (3H,
m), 7.22-7.56 (4H, m), 8.10 (1
H, s), 8.30 (1H, dd, J = 8.1, 1.5
Hz). IR (KBr) 1591, 1561, 1514, 145
1,1335,1306,735 cm ^-1 .

Example 210 (Production of Compound 210) Formic acid (0.80 ml) was added to acetic anhydride (1.6 ml). After stirring at room temperature for 1 hour, THF (5.0 ml) was added, and N-[(4-amino-2-isopropyl-5-pyrimidinyl) methyl] -N- [2-[(2-nitrophenyl) sulfanyl] was added. Phenyl] amine (317 mg)
Was added at 0 ° C. in THF (10 ml). The mixture was stirred at room temperature for 22 hours. The reaction mixture was treated with ethyl acetate (15
0 ml) and a saturated aqueous solution of sodium carbonate (50 m
l), water (75 ml) and saturated saline (50 ml) sequentially. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and methanol-THF was added to the residue.
-Water (1: 1: 1, 15.0 ml) and sodium hydroxide (96 mg) were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (150 ml),
Water (50 ml), saturated sodium carbonate aqueous solution (50 m
l), water (50 ml) and saturated saline (50 ml) sequentially. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-isopropyl-5-pyrimidinyl) methyl [2-[(2-nitro Phenyl) sulfanyl] phenyl] formamide (Compound 210) (3
05 mg) as yellow crystals. mp 128-129 ° C. Elemental analysis value: C ₂₁ H ₂₁ N ₅ O ₃ S Calcd. : C, 59.56; H, 5.00; N, 16.54. Found: C, 59.51; H, 5.04; N, 16.53. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d,
J = 7.0 Hz), 2.76-2.90 (1H, m),
4.71 (2H, s), 5.83 (2H, br), 6.
65 (1H, dd, J = 7.6, 1.4 Hz), 7.1
5-7.19 (1H, m), 7.22-7.38 (2H,
m), 7.47-7.55 (3H, m), 7.61-7.
65 (1H, m), 8.02 (1H, s), 8.21
(1H, dd, J = 7.6, 2.0 Hz). IR (KBr) 1667, 1591, 1518, 147
2,1337,735 cm ^-1 .

Example 211 (Production of compound 211) Formic acid (1.0 ml) was added to acetic anhydride (2.0 ml). After stirring at room temperature for 1 hour, THF (5.0 ml) was added, and N-[(4-amino-2-phenyl-5-pyrimidinyl) methyl] -N- [2-[(2-nitrophenyl) sulfanyl] was added. A solution of [phenyl] amine (412 mg) in THF (15 ml) was added at 0 ° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was treated with ethyl acetate (200
ml) and a saturated aqueous solution of sodium carbonate (50 m
l), water (75 ml) and saturated saline (50 ml) sequentially. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and methanol-THF was added to the residue.
-Water (1: 1: 1, 21.0 ml) and sodium hydroxide (115 mg) were added. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate (200 ml), water (50 ml) and a saturated aqueous solution of sodium carbonate (5 ml).
0 ml), water (50 ml) and saturated saline (30 ml)
Was sequentially washed. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give (4-amino-2-phenyl-5-pyrimidinyl) methyl [2-[(2-nitro Phenyl) sulfanyl] phenyl] formamide (compound 211) (28
7 mg) as yellow crystals. mp 160-161 ° C. Elemental analysis value: C ₂₄ H ₁₉ N ₅ O ₃ S Calcd. : C, 63.01; H, 4.19; N, 15.31. Found: C, 62.93; H, 4.11; N, 15.48. ¹ H-NMR (CDCl ₃ ) δ: 4.82 (2H,
s), 5.85 (2H, br), 6.42 (1H, d
d, J = 8.3, 1.3 Hz), 6.90 (1H, t)
d, J = 7.8, 1.3 Hz), 7.10 (1H, t)
d, J = 7.7, 1.5 Hz), 7.31-7.67
(7H, m), 7.69 (1H, s), 8.08-8.
13 (1H, m), 8.13 (1H, s), 8.16-
8.23 (2H, m). IR (KBr) 1663, 1591, 1518, 141
0,1337,733 cm ^-1 .

Example 212 (Production of compound 212) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(2-nitrophenyl) sulfanyl] phenyl] amine (403 mg) in THF (2
0 ml) solution, potassium carbonate (1.50 g) and acetyl bromide (0.60 ml) were added. The mixture was stirred at room temperature for 42.5 hours. The reaction mixture was treated with ethyl acetate (20
0 ml) and a saturated aqueous solution of sodium carbonate (50 m
l), water (75 ml) and saturated saline (50 ml) sequentially. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2).
-Methyl-5-pyrimidinyl) methyl [2-[(2-nitrophenyl) sulfanyl] phenyl] acetic acid amide (Compound 212) (159 mg) was obtained as pale yellow crystals. mp 162-169 ° C (decomposition). Elemental analysis _{C 20 H 19 N 5 O 3} S · 0.1H Calcd the ₂ O. : C, 58.41; H, 4.71; N, 17.03. Found: C, 58.11; H, 4.71; N, 16.71. ¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H,
s), 2.33 (3H, s), 4.44 (1H, d, J
= 15.0 Hz), 4.91 (1H, d, J = 15.0)
Hz), 6.07 (2H, br), 6.89 (1H, d
d, J = 7.6, 1.4 Hz), 7.05-7.10.
(1H, m), 7.32-7.53 (6H, m), 8.
19 (1H, dd, J = 7.6, 2.0 Hz). IR (KBr) 1645, 1593, 1566, 151
8,1474,1431,1400,1337,735
cm ^-1 .

Example 213 (Production of compound 213) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.38 g), 2- (4'-ethoxy [1,1'-biphenyl] -4-ylsulfanyl) aniline (1.57 g) and potassium carbonate (1.69 g)
Was suspended in THF (50 ml) and stirred at 70 ° C. for 14.5 hours. The reaction mixture was concentrated under reduced pressure, and water (100 m
l) was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give 5-[[2
-[(4'-ethoxy [1,1'-biphenyl] -4-
Yl) sulfanyl] anilino] methyl] -2-methyl-4-pyrimidineamine (compound 213) (379 m
g) was obtained as colorless crystals. mp 164-165 ° C. Elemental analysis value: C ₂₆ H ₂₆ N ₄ OS: Calcd. : C, 70.56; H, 5.92; N, 12.66. Found: C, 70.26; H, 5.85; N, 12.49. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t,
J = 6.9 Hz), 2.47 (3H, s), 4.08
(2H, q, J = 7.0 Hz), 4.13 (2H, d,
J = 5.2 Hz), 4.82 (2H, br + 1H, t-
like), 6.79 (1H, d, J = 8.4 Hz),
6.86 (1H, td, J = 7.5, 1.4 Hz),
6.93-6.99 (2H, m), 7.07-7.11
(2H, m), 7.34-7.47 (5H, m), 7.
59 (1H, dd, J = 7.7, 1.5 Hz), 8.0
6 (1H, s). IR (KBr) 1607, 1588, 1568, 148
7, 1476, 1451, 1246 cm ^-1 .

Example 214 (Production of compound 214) N-[(4-amino-2-chloro-5-pyrimidinyl)
Methyl] -N- [2-[(2-nitrophenyl) sulfanyl] phenyl] amine (56 mg) was suspended in methanol (10 ml), and 2N dimethylaminemethanol (0.75 ml) was added. Mix at room temperature for 3.5
Stirred for hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 ml) was added. The mixture was washed with water (15 ml x 2)
And a saturated saline solution (10 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography,
Further, recrystallization from ethyl acetate-ether-diisopropyl ether gave N, N, 2-trimethyl-5-.
[[2-[(2-nitrophenyl) sulfanyl] anilino] methyl] -4-pyrimidineamine (compound 21
4) (16 mg) was obtained as yellow crystals. mp 83-86 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 2.97 (6H, s), 4.19 (2H, d, J
= 4.8 Hz), 5.08 (1H, br), 6.67
(1H, d, J = 8.4 Hz), 6.78-6.86
(2H, m), 7.34-7.52 (4H, m), 7.
95 (1H, s), 8.27 (1H, dd, J = 8.
0, 1.4 Hz). IR (KBr) 1590, 1568, 1541, 151
6,1451,1420,1397,1337,130
6,735 cm ^-1 .

Example 215 (Production of compound 215) Formic acid (0.8 ml) was added to acetic anhydride (1.6 ml). After stirring at room temperature for 2 hours, THF (5.0 ml) was added, and 5-[[2-[(4'-ethoxy [1,1'-biphenyl] -4-yl) sulfanyl] anilino] methyl] -2 was added. -Methyl-4-pyrimidineamine (352 m
g) in THF (15 ml) was added at 0 ° C. The mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and a saturated aqueous solution of sodium carbonate (50 ml), water (50 ml) and saturated saline (25 ml) were used.
Washing was performed sequentially in 1). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
THF-water (1: 1: 1, 15.0 ml) and sodium hydroxide (95 mg) were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and 4-[[2-[[(4
-Amino-2-methyl-5-pyrimidinyl) methyl]
(Formyl) amino] phenyl] sulfanyl] -4 '
-Ethoxy-1,1'-biphenyl (compound 215)
(182 mg) was obtained as colorless crystals. mp 200-201 ° C. Elemental analysis _{C 27 H 26 N 4 O 2} S · 0.25H Calcd the ₂ O. : C, 68.26; H, 5.62; N, 11.79. Found: C, 68.07; H, 5.40; N, 11.79. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t,
J = 7.0 Hz), 2.44 (3H, s), 4.09
(2H, q, J = 6.9 Hz), 4.74 (2H, b
r), 5.98 (2H, br), 6.92-7.00
(3H, m), 7.13-7.33 (5H, m), 7.
49-7.56 (5H, m), 8.11 (1H, s). IR (KBr) 1661, 1474, 1250c
m ^-1 .

Example 216 (Preparation of Compound 216) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] phenyl] amine (452 mg) in THF
(15 ml) To the solution were added potassium carbonate (585 mg) and ethyl chloroglyoxyate (0.36 ml). The mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate (200 ml), and a saturated aqueous solution of sodium carbonate (50 ml), water (50 ml) and saturated saline (25 ml) were used.
Washing was performed sequentially in 1). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
After recrystallization from diisopropyl ether, [[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -2
-[(4-methoxyphenyl) sulfanyl] anilino] (oxo) ethyl acetate (Compound 216) (510 m
g) was obtained as colorless crystals. mp 140-141 ° C. Elemental analysis value: C ₂₃ H ₂₄ N ₄ O ₄ S Calcd. : C, 61.05; H, 5.35; N, 12.38. Found: C, 61.08; H, 5.27; N, 12.57. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t,
J = 7.1 Hz), 2.47 (3H, s), 3.85
(3H, s), 4.05 (2H, q, J = 7.1H
z), 4.52 (1H, d, J = 14.6 Hz), 5.
15 (1H, d, J = 15.0 Hz), 5.97 (2
H, br), 6.81 (1H, dd, J = 7.6, 1.
3 Hz), 6.85 (1H, dd, J = 7.6, 1.1)
Hz), 6.92-6.96 (2H, m), 7.02
(1H, td, J = 7.5, 1.6 Hz), 7.16
(1H, td, J = 7.5, 1.5 Hz), 7.36-
7.40 (2H, m), 7.49 (1H, s). IR (KBr) 1744,1661,1591,149
5,1472,1250,1202 cm ^-1 .

Example 217 (Preparation of compound 217) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(2-methoxyphenyl) sulfanyl] phenyl] amine (393 mg) in THF
(15 ml) To the solution were added potassium carbonate (616 mg) and acetyl bromide (0.24 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with ethyl acetate (200
ml) and a saturated aqueous solution of sodium carbonate (50 m
l), water (50 ml) and saturated saline (25 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give (4-amino-2-methyl-5-pyrimidinyl) methyl [2-[( 2-methoxyphenyl) sulfanyl] phenyl] acetic acid amide (Compound 217) (370 mg) was obtained as colorless crystals. mp158-162 ° C. Elemental analysis value: C ₂₁ H ₂₂ N ₄ O ₂ S Calcd. : C, 63.94; H, 5.62; N, 14.20. Found: C, 63.73; H, 5.62; N, 13.95. ¹ H-NMR (CDCl ₃ ) δ: 1.92 (3H,
s), 2.46 (3H, s), 3.78 (3H, s),
4.33 (1H, d, J = 15.0 Hz), 5.21
(1H, d, J = 14.6 Hz), 6.20 (2H, b
r), 6.71 (1H, dd, J = 7.5, 1.5H
z), 6.88 (1H, dd, J = 8.0, 1.6H
z), 6.94-7.11 (3H, m), 7.16 (1
H, td, J = 7.3, 1.7 Hz), 7.37-7.
46 (2H, m), 7.42 (1H, s). IR (KBr) 1645, 1586, 1472, 143
3,1402,1277 cm ^-1 .

Example 218 (Production of compound 218) 4-Amino-5-bromomethyl-2-isopropylpyrimidine hydrobromide (952 mg) was added to THF (30 m2).
l), potassium carbonate (1.06 g) and 2-
[(2-Methoxyphenyl) sulfanyl] aniline (1.42 g) was added. The mixture was stirred at 75 ° C. for 12.5 hours. Ethyl acetate (300 ml) was added, and water (1
00 ml) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, recrystallized from ethyl acetate-diisopropyl ether, and N-[(4-amino-2-isopropyl-
5-Pyrimidinyl) methyl] -N- [2-[(2-methoxyphenyl) sulfanyl] phenyl] amine (Compound 218) (648 mg) was obtained as colorless crystals. mp 147-148 ° C. Elemental analysis value: C ₂₁ H ₂₄ N ₄ OS Calcd. : C, 66.29; H, 6.36; N, 14.72. Found: C, 66.24; H, 6.32; N, 14.80. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d,
J = 7.0 Hz), 2.93 (1H, septet, J
= 6.9 Hz), 3.84 (3H, s), 4.12 (2
H, d, J = 4.8 Hz), 4.85 (2H, br)
s), 4.93 (1H, t-like), 6.67 (1
H, dd, J = 7.6, 1.8 Hz), 6.75-6.
87 (4H, m), 7.13 (1H, td, J = 7.
2,1.6 Hz), 7.37 (1H, t, J = 7.7H)
z), 7.57 (1H, dd, J = 8.4, 1.0H
z), 8.10 (1H, s). IR (KBr) 1588, 1559, 1501, 147
6,1449,1240,748cm ^-1 .

Example 219 (Production of compound 219) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.98 g) was suspended in THF (70 ml), and potassium carbonate (2.42 g) was added. ) And 5-chloro-
2-[(4-Methoxyphenyl) sulfanyl] aniline (3.71 g) was added. 13.5 at 70 ° C.
Stirred for hours. Ethyl acetate (350 ml) was added, and the mixture was washed with water (100 ml × 2) and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
5-[[5-chloro-2-[(4-methoxyphenyl)
Sulfanyl] anilino] methyl] -2-methyl-4-
Pyrimidineamine (Compound 219) (1.05 g) was obtained as colorless crystals. mp 119-120 ° C. Elemental analysis value: C ₁₉ H ₁₉ ClN ₄ OS Calcd. : C, 58.98; H, 4.95; N, 14.48. Found: C, 58.60; H, 5.03; N, 14.22. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 3.77 (3H, s), 4.09 (2H, d, J
= 5.0 Hz), 4.80 (3H, br), 6.71-
6.82 (4H, m), 7.02-7.07 (2H,
m), 7.43 (1H, d, J = 8.2 Hz), 8.0
6 (1H, s). IR (KBr) 1582,1563,1493,146
0.1246 cm ^-1 .

Example 220 (Production of compound 220) (4-Amino-2-methyl-5-pyrimidinyl) methyl [2-[(2-methoxyphenyl) sulfinyl] phenyl] formamide (126 mg) was added to THF (5. 0m
1) sodium hydroxide solution (5.
0 ml) was added. The mixture was stirred at 60 ° C. for 1 hour.
Water (50 ml) was added and extracted with dichloromethane (50 ml). The organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethanol to give 5-[[2-[(2-methoxyphenyl) sulfinyl] anilino] methyl] -2-methyl 4-Pyrimidineamine (production of compound 220) (103 mg) was obtained as colorless crystals. mp 205-206 ° C (decomposition). Elemental analysis _{C 19 H 20 N 4 O 2} S · 0.75H Calcd As 2 O · 0.5EtOH. : C, 59.31; H, 6.10; N, 13.83. Found: C, 59.28; H, 6.22; N, 13.55. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 3.71 (3H, s), 4.12 (2H, d, J
= 4.6 Hz), 4.89 (2H, brs), 6.34.
(1H, t-like), 6.69 (1H, d, J =
8.8 Hz), 6.82 (1H, t, J = 7.2H)
z), 6.87 (1H, d, J = 8.0 Hz), 7.1
5 (1H, t, J = 7.1 Hz), 7.26-7.31
(1H, m), 7.43 (1H, t, J = 7.1H
z), 7.58 (1H, d, J = 7.8 Hz), 7.8
4 (1H, dd, J = 7.4, 1.6 Hz), 8.07
(1H, s). IR (KBr) 1593, 1566, 1478, 145
8,1435,1020,752,733 cm ^-1 .

Example 221 (Preparation of compound 221) 5-Bromomethyl-2-methyl-4- (1-pyrrolidinyl) pyrimidine hydrobromide (1.30 g) was added to THF.
(40 ml) and potassium carbonate (2.67 g)
And 2- (phenylsulfanyl) aniline (2.33)
g) was added. The mixture was stirred at 70 ° C. for 14 hours. Ethyl acetate (350 ml) was added, and the mixture was washed with water (75 ml × 2) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give N-[[2-methyl-
4- (1-Pyrrolidinyl) -5-pyrimidinyl] methyl] -2- (phenylsulfanyl) aniline (compound 221) (859 mg) was obtained as colorless crystals. mp 124 ° C. Elemental analysis value: C ₂₂ H ₂₄ N ₄ S Calcd. : C, 70.18; H, 6.42; N, 14.88. Found: C, 70.37; H, 6.47; N, 15.04. ¹ H-NMR (CDCl ₃ ) δ: 1.70-1.77
(4H, m), 2.47 (3H, s), 3.51-3.
57 (4H, m), 4.14 (2H, d, J = 4.8H)
z), 4.92 (1H, t, J = 4.4 Hz), 6.7
1 (1H, d, J = 8.8 Hz), 6.77 (1H, t
d, J = 7.6, 1.6 Hz), 6.97-7.02
(2H, m), 7.05-7.23 (3H, m), 7.
36 (1H, td, J = 7.6, 1.8 Hz), 7.5
2 (1H, dd, J = 7.6, 1.6 Hz), 7.88
(1H, s). IR (KBr) 1586, 1537, 1499, 147
8,1439,743 cm ^-1 .

Example 222 (Production of Compound 222) 5-Bromomethyl-2-methyl-4- (1-pyrrolidinyl) pyrimidine hydrobromide (0.70 g) was added to THF.
(20 ml) and potassium carbonate (1.44 g)
And 2-[(4-methoxyphenyl) sulfanyl] aniline (0.96 g) were added. Mix at 70 ° C. for 13
Stirred for hours. Ethyl acetate (250 ml) was added, and the mixture was washed with water (75 ml × 2) and saturated saline (50 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
-[[2-Methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methyl] -2-[(4-methoxyphenyl) sulfanyl] aniline (634 mg) was obtained as an oil. 4N hydrochloric acid-ethyl acetate (0.38 mg) was added to an ethyl acetate solution (15 ml) of the obtained oil (623 mg).
ml) and stirred at room temperature for 13 hours. The reaction mixture was filtered and N-[[2-methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methyl] -2-[(4-methoxyphenyl) sulfanyl] aniline hydrochloride (Compound 222) (646 mg) Was obtained as colorless crystals. mp 200 ° C (decomposition). Elemental analysis value: C ₂₃ H ₂₆ N ₄ OS.HCl. : C, 62.36; H, 6.14; N, 12.65. Found: C, 62.04; H, 6.10; N, 12.59. ¹ H-NMR (DMSO-d ₆ ) δ: 1.81 (4H,
br), 2.51 (3H, s), 3.72 (3H, s +
4H, br), 4.45 (2H, d, J = 5.2H)
z), 5.81 (1H, t-like), 6.67-6.
74 (2H, m), 6.88-6.94 (2H, m),
7.08-7.14 (2H, m), 7.26 (1H, t
d, J = 7.7, 1.8 Hz), 7.39 (1H, d
d, J = 7.8, 1.6 Hz), 7.85 (1H,
s).

Example 223 (Production of compound 223) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (520 mg) was suspended in THF (20 ml), and potassium carbonate (1.02 g) and 2-[(4-
Fluorophenyl) sulfanyl] aniline (1.01
g) was added. The mixture was stirred at 70 ° C. for 12 hours. Ethyl acetate (300 ml) was added and water (100 ml × 2)
And saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography,
The mixture was recrystallized from ethyl acetate-diisopropyl ether to give 5-[[2-[(4-fluorophenyl) sulfanyl] anilino] methyl] -2-methyl-4-pyrimidineamine (compound 223) (243 mg) as colorless crystals. As obtained. mp 157-158 ° C. Elemental analysis value: C ₁₈ H ₁₇ FN ₄ S · 0.1 H ₂ O. : C, 63.17; H, 5.07; N, 16.37. Found: C, 63.00; H, 5.03; N, 16.14. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 4.13 (2H, d, J = 5.2 Hz), 4.8
0 (1H, t-like), 4.88 (2H, br)
s), 6.76-7.08 (6H, m), 7.36 (1
H, td, J = 7.5, 1.6 Hz), 7.54 (1
H, dd, J = 7.6, 1.4 Hz), 8.06 (1
H, s). IR (KBr) 1590, 1568, 1489, 145
3 cm ^-1 .

Example 224 (Production of compound 224) 2-[(4-Chlorophenyl) sulfanyl] aniline (305 mg) was dissolved in HMPA (4.0 ml).
Sodium hydride (60%: 169 mg) and copper (I) iodide (335 mg) were added. The mixture was stirred at room temperature for 2 hours. The mixture was added to 2-iodo-N-[[2-methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methyl] aniline (694 mg). Mix 80
Stirred at 150C for 15 hours. Water (100 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give N- [2-
[(4-Chlorophenyl) sulfanyl] phenyl]-
N-[[2-Methyl-4- (1-pyrrolidinyl) -5-
Pyrimidinyl] methyl] amine (compound 224) (47
mg) as colorless crystals. mp 128-130 ° C. Elemental analysis value: C ₂₂ H ₂₃ ClN ₄ S Calcd. : C, 64.30; H, 5.64; N, 13.63. Found: C, 63.91; H, 5.68; N, 13.51. ¹ H-NMR (CDCl ₃ ) δ: 1.71-1.78
(4H, m), 2.48 (3H, s), 3.49-3.
56 (4H, m), 4.14 (2H, d, J = 4.8H)
z), 4.87 (1H, t-like), 6.71 (1
H, d, J = 9.0 Hz), 6.78 (1H, td, J)
= 7.4, 1.0 Hz), 6.89-6.95 (2H,
m), 7.10-7.16 (2H, m), 7.37 (1
H, td, J = 7.7, 1.4 Hz), 7.50 (1
H, dd, J = 7.8, 1.4 Hz), 7.93 (1
H, s). IR (KBr) 1586, 1539, 1501, 147
4,1447 cm ^-1 .

Example 225 (Preparation of Compound 225) N-[(4-amino-2-methyl-5-pyrimidinyl)
To a solution of [methyl] -N-benzylamine (1.3 g) in pyridine (30 ml) was added 4-dimethylaminopyridine (0.76 g). After cooling to 0 ° C., a solution of 4-methoxybenzoic acid chloride (0.97 g) in pyridine (5 m
l) was added dropwise over 15 minutes. The mixture was stirred at 0 ° C. for 90 minutes, 300 ml of water was added, and the precipitated crystals were collected by filtration. The crystals are washed with water and isopropyl ether, and N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-methoxybenzamide (compound 225)
(1.3 g) as colorless crystals. On the other hand, the filtrate was extracted with ethyl acetate, and the organic layer was washed twice with water and once with saturated saline and dried over sodium sulfate. After concentrating to dryness, the precipitated crystals were recrystallized from ethyl acetate to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
Benzyl-4-methoxybenzamide (Compound 225)
(0.38 g) was obtained as colorless crystals. mp. 155-156 ° C Elemental analysis value As C ₂₁ H ₂₂ N ₄ O ₂ Calcd. C, 69.59; H, 6.12; N, 15.46. Found C, 69.72; H, 6.19; N, 15.49. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 3.80 (3H, s), 4.49 (2H, s),
4.53 (2H, s), 6.36 (2H, brs),
6.87 (2H, d, J = 8.6 Hz), 7.22-
7.27 (2H, m), 7.35-7.47 (5H,
m), 7.70 (1H, s).

Example 226 (Production of compound 226) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzyl-4- (chloromethyl) benzamide (571 mg) and N, N of phthalimide potassium
Dimethylformamide (5 ml) solution at room temperature for 90
The mixture was stirred at 60 ° C. for 4 hours and at 100 ° C. for 90 minutes. Water was added and the precipitated crystals were collected by filtration, recrystallized from ethyl acetate-ethanol, and N-[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] -N-benzyl-4-[(1,3
-Dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] benzamide (Compound 226)
(274 mg) was obtained. mp. 253-254 ° C. Elemental analysis value C ₂₉ H ₂₅ N ₅ O ₃ .0.75 H ₂ O Calcd. C, 68.97; H, 5.29; N, 13.87. Found C, 68.62; H, 5.31; N, 13.84. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 4.39 (2H, s), 4.50 (2H, s),
4.83 (2H, s), 6.17 (2H, brs),
7.18 (2H, d, J = 6.2 Hz), 7.32-
7.43 (7H, m), 7.702 (1H, s), 7.
704 (2H, d, J = 8.4 Hz), 7.79-7.
86 (2H, m).

Example 227 (Production of compound 227) Sodium hydride (oil-based, 60%, 37 mg) was added to N, N
-Suspension in dimethylformamide (4 ml), 3,
Add 5-dimethylpyrazole (78 mg) and add 1 at room temperature.
Stirred for hours. N-[(4-amino-2-methyl-5-
Pyrimidinyl) methyl] -N-benzyl-4- (chloromethyl) benzamide (305 mg) was added at room temperature.
Stirred for hours. Water and ethyl acetate were added to carry out liquid separation, and the organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(3,5-dimethyl [1H-pyrazol-1-yl) methyl] benzamide (compound 227) (148 mg) was obtained as colorless crystals. mp. 169-171 ° C. Elemental analysis value C ₂₆ H ₂₈ N ₆ O.0.35 H ₂ O As Calcd. C, 69.89; H, 6.47; N, 18.81. Found C, 70.13; H, 6.57; N, 18.55. ¹ H-NMR (CDCl ₃ ) δ: 2.12 (3H,
s), 2.22 (3H, s), 2.49 (3H, s),
4.40 (2H, s), 4.51 (2H, s), 5.2
0 (2H, s), 5.84 (1H, s), 6.21 (2
H, brs), 7.04 (2H, d, J = 8.2H)
z), 7.19 (2H, dd, J = 1.8, 7.6H
z), 7.33-7.42 (5H, m), 7.71 (1
H, s).

Example 228 (Production of Compound 228) Sodium hydride (oil-based, 60%, 37 mg) was added to N, N
-Suspension in dimethylformamide (4 ml), 3,
5-Diisopropylpyrazole (122 mg) was added, and the mixture was stirred at room temperature for 45 minutes. N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4
-(Chloromethyl) benzamide (305 mg) was added, and the mixture was stirred at room temperature for 12 hours. Water was added, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(3,5- Diisopropyl-1H-pyrazol-1-yl) methyl] benzamide (Compound 22
8) (108 mg) was obtained as colorless crystals. mp. 194 ° -195 ° C. Elemental analysis value As C ₃₀ H ₃₆ N ₆ O · 2H ₂ O, Calcd. C, 69.64; H, 7.57; N, 15.78. Found C, 67.80; H, 7.29; N, 15.60. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (6H, d,
J = 7.0 Hz), 1.24 (6H, d, J = 7.0 H)
z), 2.49 (3H, s), 2.67-2.80 (1
H, m), 2.87-2.97 (1H, m), 4.40.
(2H, s), 4.51 (2H, s), 5.26 (2
H, s), 5.90 (1H, s), 6.23 (2H, b
rs), 6.99 (2H, d, J = 8.0 Hz), 7.
19 (2H, d, J = 5.8 Hz), 7.34-7.4
1 (5H, m), 7.72 (1H, s).

Example 229 (Preparation of compound 229) Sodium hydride (oil-based, 60%, 36 mg) was added to N, N
-Suspended in dimethylformamide (4 ml), 1-
Phenyl-3-pyrazolidone (130 mg) was added and the mixture was stirred at room temperature for 30 minutes. N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-
(Chloromethyl) benzamide (305 mg) was added,
Stirred at room temperature for 12 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with saturated saline, and dried over sodium sulfate. After concentration, the precipitated crystals were recrystallized from ethyl acetate-isopropyl ether to give N-[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -N
-Benzyl-4-[(5-oxo-2-phenyl 1-pyrazolidinyl) methyl] benzamide (Compound 229)
(194 mg) was obtained as colorless crystals. mp. 186-187 ° C. Elemental analysis value C ₃₀ H ₃₀ N ₆ O ₂ .0.5H ₂ O Calcd. C, 69.88; H, 6.06; N, 16.30. Found C, 69.77; H, 5.99; N, 16.30. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 2.52 (2H, t, J = 7.6 Hz), 3.7
0 (2H, t, J = 7.6 Hz), 4.41 (1H,
s), 4.52 (2H, s), 4.55 (2H, s),
6.23 (2H, brs), 6.94 (2H, d, J =
7.2 Hz), 7.08 (1 H, t, J = 7.2 H)
z), 7.19-7.49 (11H, m), 7.73
(1H, s).

Example 230 (Production of Compound 230) Sodium hydride (oil-based, 60%, 38 mg) was added to N, N
-Suspended in dimethylformamide (4 ml),
5-Diphenylimidazole (176 mg) was added, and the mixture was stirred at room temperature for 1 hour. N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-
(Chloromethyl) benzamide (305 mg) was added,
The mixture was stirred at room temperature for 150 minutes. Water and ethyl acetate were added to carry out liquid separation, and the organic layer was washed with saturated saline and dried over sodium sulfate. After concentration, the precipitated crystals were recrystallized from ethyl acetate to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-4-[(4,5-diphenyl-1H-imidazole. -1-yl) methyl] benzamide (compound 230) (101 mg) was obtained as colorless crystals. mp. 186-187 ° C Elemental analysis: C ₃₆ H ₃₂ N ₆ O 0.75H ₂ O Calcd. C, 74.78; H, 5.84; N, 14.53. Found C, 74.53; H, 5.67; N, 14.46. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 4.36 (2H, s), 4.51 (2H, s),
4.99 (2H, s), 6.14 (2H, brs),
6.94 (2H, d, J = 8.4 Hz), 7.11-
7.49 (17H, m), 7.64 (1H, s), 7.
73 (1H, s).

Example 231 (Preparation of compound 231) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzyl-4-methoxybenzamide (200 mg) was dissolved in dichloromethane (5 ml),
Boron bromide at 0 ° C (dichloromethane solution, 1M, 3m
l) was added. The mixture was stirred at 0 ° C for 3 hours and at room temperature for 2 hours.
Water was added thereto, and the precipitated crystals were collected by filtration, recrystallized from ethanol-ethyl acetate to give N-[(4-amino-2-methyl-
5-pyrimidinyl) methyl] -N-benzyl-4-hydroxybenzamide hydrobromide (Compound 231) (1
44 mg) were obtained as colorless crystals. mp. 252-254 ° C (decomposition) Elemental analysis value As C ₂₀ H ₂₀ N ₄ O ₂ · HBr · 0.46H ₂ O Calcd. C, 54.89; H, 5.05; N, 12.80. Found C, 55.26; H, 4.87; N, 12.40. ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 4.31 (2H, s), 4.53 (2H, s),
6.67 (2H, d, J = 8.4 Hz), 6.82 (2
H, brs), 7.19-7.40 (7H, m), 7.
73 (1H, brs).

Example 232 (Preparation of Compound 232) N-[(4-amino-2-methyl-5-pyrimidinyl)
To a solution of [methyl] -N-benzylamine (367 mg) in pyridine (10 ml) was added 4-dimethylaminopyridine (221 mg). After cooling to 0 ° C., 6-bromohexanoyl chloride (0.25 ml) was added dropwise. 0 ° C
The mixture was stirred for 30 minutes, 300 ml of water was added, and the precipitated crystals were collected by filtration. The crystals are washed with water and washed with N-[(4-amino-
2-methyl-5-pyrimidinyl) methyl] -N-benzyl-6-bromohexanamide (Compound 232) (53
4 mg) as colorless crystals. mp. 127 ° C. Elemental analysis value As C ₁₉ H ₂₅ BrN ₄ O · 0.2 H ₂ O, Calcd. C, 55.80; H, 6.26; N, 13.70. Found C, 55.98; H, 6.53; N, 13.72. ¹ H-NMR (CDCl ₃ ) δ: 1.38-1.52
(2H, m), 1.63-1.74 (2H, m), 1.
78-1.93 (2H, m), 2.43 (2H, t, J
= 7.4 Hz), 2.48 (3H, s), 3.39 (2
H, t, J = 6.6 Hz), 4.39 (2H, s),
4.44 (2H, s), 6.16 (2H, brs),
7.15-7.19 (2H, m), 7.34-7.41
(3H, m), 7.80 (1H, s).

Example 233 (Production of compound 233) Sodium hydride (oil-based, 60%, 36 mg) was added to N, N
-Suspension in dimethylformamide (4 ml), 3,
5-Diphenylpyrazole (176 mg) was added, and the mixture was stirred at room temperature for 40 minutes. N-[(4-amino-2-methyl-
[5-Pyrimidinyl) methyl] -N-benzyl-6-bromohexaneamide (324 mg) was added, and the mixture was stirred at room temperature for 12 hours and at 60 ° C for 5 hours. After cooling to room temperature, sodium iodide (12 mg) was added, and the mixture was further stirred at 60 ° C. for 150 minutes. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with saturated saline, and dried over sodium sulfate. The mixture was subjected to silica gel column chromatography.
After concentration, the precipitated crystals were recrystallized from isopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-6- (3,5-diphenyl-1H-pyrazole- 1-yl) hexaneamide (compound 233) (321 mg) was obtained as colorless crystals. mp. 100-103 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.24-1.32.
(2H, m), 1.53-1.91 (4H, m), 2.
33 (2H, t, J = 7.6 Hz), 2.47 (3H,
s), 4.14 (2H, t, J = 7.0 Hz), 4.3
3 (2H, s), 4.36 (2H, s), 6.11 (2
H, brs), 6.55 (1H, s), 7.09-7.
13 (2H, m), 7.28-7.49 (11H,
m), 7.76-7.84 (3H, m).

Example 234 (Preparation of compound 234) N-[(4-amino-2-methyl-5-pyrimidinyl)
N, N of methyl] -N-benzylamine (114 mg)
-Dimethylformamide (5 ml) solution was added with 3- (3-
Methoxyphenyl) propionic acid (90 mg), 1-hydroxybenzotriazole monohydrate (115 mg),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (144 mg) was sequentially added, and 1
Stir for 2 hours. Saturated aqueous sodium bicarbonate and ethyl acetate were added to carry out liquid separation, and the organic layer was separated twice with water and once with saturated saline.
Washed twice and dried over sodium sulfate. It was concentrated and subjected to silica gel column chromatography. The crystals precipitated by concentration are recrystallized from isopropyl ether to give N-
[(4-Amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-3- (3-methoxyphenyl) propanamide (Compound 234) (131 mg) was obtained as colorless crystals. mp. 101-102 ° C. Elemental analysis value C ₂₃ H ₂₆ N ₄ O ₂ .0.5H ₂ O Calcd. C, 69.15; H, 6.81; N, 14.02. Found C, 69.11; H, 6.95; N, 14.12. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 2.71 (2H, t, J = 7.6 Hz), 2.9
8 (2H, t, J = 7.6 Hz), 3.75 (3H,
s), 4.34 (2H, s), 4.36 (2H, s),
6.20 (2H, brs), 6.69-6.76 (3
H, m), 7.05-7.09 (2H, m), 7.12.
(1H, t, J = 8.0 Hz), 7.31-7.41
(3H, m), 7.77 (1H, s).

Example 235 (Preparation of compound 235) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzylamine (457 mg) in N, N
-Dimethylformamide (5 ml) solution was added with 3- (4-
Methoxyphenyl) propionic acid (360 mg), 1-
Hydroxybenzotriazole monohydrate (460m
g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (575 mg) was sequentially added,
Stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate and ethyl acetate were added and the layers were separated, and the organic layer was washed twice with water and once with saturated brine, and dried over sodium sulfate. The crystals precipitated by concentration were recrystallized from ethyl acetate to give N-[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] -N
-Benzyl-3- (4-methoxyphenyl) propanamide (Compound 235) (420 mg) was obtained as colorless crystals. mp. 134-135 ° C. Elemental analysis value C ₂₃ H ₂₆ N ₄ O ₂ .0.1H ₂ O Calcd. C, 70.42; H, 6.73; N, 14.28. Found C, 70.38; H, 6.69; N, 14.35. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 2.67 (2H, t, J = 7.4 Hz), 2.9
5 (2H, t, J = 7.4 Hz), 3.77 (3H,
s), 4.31 (2H, s), 4.35 (2H, s),
6.22 (2H, brs), 6.74-6.80 (2
H, m), 7.04-7.09 (4H, m), 7.31.
-7.41 (3H, m), 7.76 (1H, s).

Example 236 (Preparation of compound 236) N-[(4-Amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzyl-3- (3-methoxyphenyl) propanamide (170 mg) was dissolved in dichloromethane (2 ml), and boron bromide (dichloromethane solution, 1M, 4.4 ml) was added at 0 ° C. Stirred at 0 ° C. for 30 minutes. Saturated aqueous sodium hydrogen carbonate and dichloromethane were added, and the layers were separated, and the organic layer was dried over sodium sulfate. Concentrated crystals were recrystallized from ethyl acetate to give N-
[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-3- (3-hydroxyphenyl)
Propanamide (Compound 236) (112 mg) was obtained as colorless crystals. mp. Calcd a 180-181 ° C. Elemental analysis _{C 22 H 24 N 4 O 2} . C, 70.19; H, 6.43; N, 14.88. Found C, 70.08; H, 6.68; N, 14.92. ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H,
s), 2.56-2.64 (2H, m), 2.70-
7.77 (2H, m), 4.30 (2H, s), 4.5
2 (2H, s), 6.54-6.65 (3H, m),
6.89 (2H, brs), 6.96-7.04 (1
H, m), 7.09-7.13 (2H, m), 7.26
-7.36 (3H, m), 7.80 (1H, s), 9.
22 (1H, s).

Example 237 (Preparation of compound 237) Sodium hydride (oil-based, 60%, 25 mg) was added to N, N
-Suspended in dimethylformamide (2 ml), N-
[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-3- (3-hydroxyphenyl)
Propanamide (188 mg) was added, and the mixture was stirred at room temperature for 40 minutes. Benzyl chloride (0.06 ml) was added, and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with saturated saline, and dried over sodium sulfate. The mixture was subjected to silica gel column chromatography. After concentration, the precipitated crystals were recrystallized from diethyl ether to give N-[(4-amino-2-methyl-5
-Pyrimidinyl) methyl] -N-benzyl-3- [3-
(Benzyloxy) phenyl] propanamide (Compound 237) (100 mg) was obtained as colorless crystals. mp. 113-114 ° C Elemental analysis value As C ₂₉ H ₃₀ N ₄ O ₂ Calcd. C, 74.65; H, 6.48; N, 12.01. Found C, 74.49; H, 6.42; N, 11.90. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H,
s), 2.70 (2H, t, J = 7.0 Hz), 2.9
8 (2H, t, J = 7.0 Hz), 4.34 (2H,
s), 4.35 (2H, s), 5.01 (2H, s),
6.14 (2H, brs), 6.77-6.83 (3
H, m), 7.06 (2H, dd, J = 2.6, 7.8)
Hz), 7.16 (1H, t, J = 8.0 Hz), 7.
30-7.42 (8H, m), 7.77 (1H, s).

Example 238 (Preparation of Compound 238) N-[(4-amino-2-methyl-5-pyrimidinyl)
To a solution of [methyl] -N-benzylamine (367 mg) in pyridine (10 ml) was added 4-dimethylaminopyridine (221 mg). After cooling to 0 ° C., 6-bromopentanoyl chloride (0.22 ml) was added dropwise. 0 ° C
The mixture was stirred for 90 minutes, 100 ml of water was added, and the precipitated crystals were collected by filtration. The crystals were washed with water and isopropyl ether and recrystallized from ethyl acetate-isopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl).
Methyl] -N-benzyl-6-bromopentanamide (Compound 238) (291 mg) was obtained as colorless crystals. mp. 139-140 ° C Elemental analysis: C ₁₈ H ₂₃ BrN ₄ O Calcd. C, 55.25; H, 5.92; N, 14.32. Found C, 55.50; H, 6.00; N, 14.56. ¹ H-NMR (CDCl ₃ ) δ: 1.84-1.88
(4H, m), 2.44 (2H, t, J = 6.6H
z), 2.48 (3H, s), 3.89 (2H, t, J
= 6.2 Hz), 4.39 (2H, s), 4.44 (2
H, s), 6.14 (2H, brs), 7.16 (2
H, d, J = 6.6 Hz), 7.34-7.46 (3
H, m), 7.80 (1H, s). Example 239 (Preparation of compound 239) Sodium hydride (oily, 60%, 53 mg) was added to N, N
-Suspended in dimethylformamide (5 ml), N-
[(4-Amino-2-methylpyrimidin-5-yl) methyl] -4-[(3,5-diphenyl-1H-pyrazol-1-yl) methyl] benzamide (570 mg) was added, and the mixture was stirred at room temperature for 30 minutes. did. 1-Bromo-3-phenylpropane (0.2 ml) was added, and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate are added and the mixture is separated.
The extract was washed once with a saturated saline solution and dried over sodium sulfate. The mixture was subjected to silica gel column chromatography. The solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -4-[(3,5-diphenyl-1H-pyrazole-1. -Yl) methyl] -N- (3-phenylpropyl) benzamide (compound 239) (91 mg) was obtained as colorless crystals. mp. 145-146 ° C Elemental analysis value C ₃₈ H ₃₆ N ₆ O · 0.2H ₂ O Calcd. C, 76.54; H, 6.15; N, 14.09. Found C, 76.49; H, 5.93; N, 14.14. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.87
(2H, m), 2.41 (2H, t, J = 7.0H
z), 2.49 (3H, s), 3.06-3.13 (2
H, m), 4.53 (2H, s), 5.42 (2H,
s), 6.16 (2H, brs), 6.70 (1H,
s), 6.96-6.99 (2H, m), 7.07-
7.25 (6H, m), 7.30-7.47 (9H,
m), 7.80 (1H, s), 7.87-7.91 (2
H, m).

Example 240 (Production of Compound 240) Sodium hydride (oil-based, 60%, 17 mg) was added to N, N
-Suspension in dimethylformamide (3 ml),
5-Diphenylpyrazole (84 mg) was added, and the mixture was stirred at room temperature for 15 minutes. N-[(4-amino-2-methyl-5
-Pyrimidinyl) methyl] -N-benzyl-6-bromopentanamide (150 mg) and sodium iodide (1
14 mg), and the mixture was stirred at room temperature for 3 days and at 80 ° C for 24 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with saturated saline, and dried over sodium sulfate. The mixture was subjected to silica gel column chromatography. After concentration, the precipitated crystals were recrystallized from isopropyl ether to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-6- (3,5-diphenyl-1H-pyrazole- 1-yl) pentanamide (Compound 240) (110 mg) was obtained as colorless crystals. mp. 125-126 ° C. Elemental analysis C ₃₃ H ₃₄ N ₆ Calcd as O · 0.2AcOEt. C, 74.04; H, 6.54; N, 15.33. Found C, 73.94; H, 6.60; N, 15.19. ¹ H-NMR (CDCl ₃ ) δ: 1.57-1.91
(4H, m), 2.32 (2H, t, J = 7.4H
z), 2.47 (3H, s), 4.16 (2H, t, J
= 7.0 Hz), 4.33 (4H, s), 6.11 (2
H, brs), 6.54 (1H, s), 7.07-7.
11 (2H, m), 7.30-7.50 (11H,
m), 7.78-7.82 (3H, m).

Example 241 (Preparation of Compound 241) Sodium hydride (oil, 60%, 32 mg) was washed with hexane and suspended in N, N-dimethylformamide (5 ml). 3,5-diphenylpyrazole (0.1
6g) and stirred at room temperature for 15 minutes. N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
(4-Fluorobenzyl) -6-bromohexaneamide (0.3 g) and sodium iodide (45 mg) were added,
Stirred at 60 ° C. for 12 hours. The mixture was concentrated, water and ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with water and once with a saturated saline solution, and dried over magnesium sulfate. Silica gel column chromatography (ethyl acetate: ethanol = 1
Eluted at 0: 1). Concentrate to give N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -6- (3,5-diphenyl-1H-pyrazol-1-yl) -N- (4-
Fluorobenzyl) hexaneamide (Compound 241)
(0.15 g) as colorless crystals. mp. 63-65 ° C. Elemental analysis value: C ₃₄ H ₃₆ FN ₆ O · 0.3H ₂ O C, 71.88; H, 6.32; N, 14.79. Found C, 71.91; H, 6.35; N, 14.70. ¹ H-NMR (CDCl ₃ ) δ: 1.17-1.32
(2H, m), 1.53-1.69 (2H, m), 1.
76-1.91 (2H, m), 2.32 (2H, t, J
= 7.6 Hz), 2.47 (3H, s), 4.15 (2
H, t, J = 7.0 Hz), 4.32 (4H, s),
6.07 (2H, brs), 6.56 (1H, s),
6.98-7.18 (4H, m), 7.28-7.52
(8H, m), 7.75 (1H, s), 7.78-7.
84 (2H, m).

Example 242 (Production of compound 242) 4-[[[(4-Amino-2-methylpyrimidine-5-
Yl) methyl] (4-fluorobenzyl) amino] carbonyl] methyl benzoate (1.20 g) was dissolved in tetrahydrofuran (12 ml), an aqueous sodium hydroxide solution (2N, 1.6 ml) was added, and the mixture was stirred at room temperature for 12 hours. . Hydrochloric acid (1N, 3.2 ml) was added, and ethyl acetate was added to carry out liquid separation. Extract the organic layer with water three times, collect the aqueous layer,
Concentration gave a crude product of 4-[[[(4-amino-2-methylpyrimidin-5-yl) methyl] (4-fluorobenzyl) amino] carbonyl] benzoic acid (1.04
g). Of these, 0.50 g was dissolved in N, N-dimethylformamide (10 ml) and 1-hydroxybenzotriazole monohydrate (0.23 g), 1,2,3,4-tetrahydro-1-naphthylamine (0.22 ml) ), 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g) was added successively,
Stirred for hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed with saturated saline and dried over magnesium sulfate. The mixture was subjected to silica gel column chromatography. Concentrate,
The precipitated crystals are recrystallized from isopropyl ether to give N
-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- (4-fluorobenzyl) -N '-(1,
2,3,4-Tetrahydro-1-naphthalenyl) terephthalamide (Compound 242) (0.33 g) was obtained as colorless crystals. mp. 230-231 ° C Elemental analysis: C ₃₁ H ₃₀ N ₅ O ₂ F Calcd. C, 71.11; H, 5.78; N, 13.38. Found C, 70.92; H, 5.70; N, 13.29. ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.20
(4H, m), 2.49 (3H, s), 2.81 (2
H, brs), 4.34 (2H, s), 4.52 (2
H, s), 5.36 (1H, brs), 6.16 (2
H, brs), 6.35 (1H, d, J = 8.4H)
z), 7.04-7.31 (8H, m), 7.48 (2
H, d, J = 8.0 Hz), 7.73 (1H, s),
7.80 (2H, d, J = 8.0 Hz).

Example 243 (Production of compound 243) 5-[[(4-Fluorobenzyl) amino] methyl]-
To a solution of 2-methylpyrimidin-4-amine (1.2 g) in pyridine (20 ml) was added 4-dimethylaminopyridine (0.66 g). After cooling to 0 ° C., terephthalic acid monomethyl ester chloride (0.97 g) was added.
The mixture was stirred at 0 ° C for 7 hours and 30 minutes. The mixture was concentrated, and water and ethyl acetate were added thereto to carry out liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the organic layer was collected, washed with brine, and dried over magnesium sulfate. Subjected to silica gel column chromatography,
4-[[[(4-amino-2-methylpyrimidine-5-
Yl) methyl] (4-fluorobenzyl) amino] carbonyl] methyl benzoate (compound 243) (1.43
g) was obtained as colorless crystals. mp. 189-190 ° C. Elemental analysis value: C ₂₂ H ₂₁ N ₄ O ₃ F Calcd. C, 64.70; H, 5.18; N, 13.72. Found C, 64.64; H, 5.26; N, 13.68. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H,
s), 3.95 (3H, s), 4.34 (2H, s),
4, 54 (2H, s), 6.14 (2H, brs),
7.05-7.19 (4H, m), 7.47-7.51
(2H, m), 7.75 (1H, s), 8.04-8.
09 (2H, m).

Example 244 (Production of compound 244) 5-[[(4-Fluorobenzyl) amino] methyl]-
To a solution of 2-methylpyrimidin-4-amine (0.5 g) in pyridine (10 ml) was added 4-dimethylaminopyridine (0.27 g). After cooling to 0 ° C., 6-bromohexanoyl chloride (0.30 ml) was added dropwise. 0 ° C
For 150 minutes. Water and ethyl acetate are added and the mixture is separated.
The organic layer was washed twice with water and once with a saturated saline solution, and dried over magnesium sulfate. The crystals precipitated after concentration were washed with isopropyl ether and N-[(4-amino-2-methyl-
5-Pyrimidinyl) methyl] -N- (4-fluorobenzyl) -6-bromohexanamide (Compound 244)
(0.67 g) as colorless crystals. mp. 100-102 ° C Elemental analysis value As C ₁₉ H ₂₄ BrN ₄ OF Calcd. C, 53.91; H, 5.71; N, 13.24. Found C, 53.93; H, 5.73; N, 13.05. ¹ H-NMR (CDCl ₃ ) δ: 1.41-1.53
(2H, m), 1.63-1.78 (2H, m), 1.
79-1.93 (2H, m), 2.41 (2H, t, J
= 7.2 Hz), 2.47 (3H, s), 3.40 (2
H, t, J = 6.6 Hz), 4.37 (2H, s),
4,41 (2H, s), 6.15 (2H, brs),
7.04-7.18 (4H, m), 7.78 (1H,
s).

Example 245 (Production of Compound 245) N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N-benzylamine (197 mg) in pyridine (5 ml) was added to 4-dimethylaminopyridine (1
15 mg). After cooling to 0 ° C., ethyl chloroglyoxylate (0.1 ml) was added dropwise. After stirring at 0 ° C. for 3 hours, water and ethyl acetate were added to carry out liquid separation. The organic layer was washed twice with water and once with a saturated saline solution, and dried over sodium sulfate. The residue was subjected to silica gel column chromatography, concentrated and ethyl [[(4-amino-2-methylpyrimidin-5-yl) methyl] (benzyl) amino] (oxo)
Acetate (compound 245) (138 mg) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t,
J = 7.2 Hz), 2.49 (3H, s), 4.30
(2H, s), 4.34 (2H, q, J = 7.2H
z), 4,36 (2H, s), 5.96 (2H, br)
s), 7.30-7.47 (5H, m), 7.81 (1
H, s).

Example 246 (Preparation of compound 246) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.0 g), 4-phenoxyaniline (0.98 g), acetone (20 ml) The mixture was heated at reflux for 9 hours. The mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and the obtained crystal was recrystallized from ethyl acetate-hexane to give 2-methyl-5-[[(4-phenoxyphenyl) amino]. Methyl] pyrimidine-4-
The amine (compound 246) (0.46 g) was obtained as colorless crystals. mp 174-175 ° C. Elemental analysis value: C ₁₈ H ₁₈ N ₄ O. Calcd. : C, 70.57; H, 5.92; N, 18.29. Found: C, 70.37; H, 6.01; N, 18.39. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 3.58 (1H, br), 4.15 (2H,
s), 5.55 (2H, br), 6.4-7.34 (9
H, m), 8.10 (1H, s).

Example 247 (Production of compound 247) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.0 g), N- [2- (diethylamino) ethyl] benzamide (1.4 g) ), Acetone (2
0 ml) was heated to reflux for 9 hours, and ethanol (1
0 ml), and the mixture was further heated under reflux for 13 hours. The mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was washed with ethyl acetate. The water tank was concentrated, ethanol was added to the residue, and insolubles were removed by filtration. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and 4-[[(4-amino-2-
Methylpyrimidin-5-yl) methyl] amino] -N-
[2- (Diethylamino) ethyl] benzamide (compound 247) (0.98 g) was obtained as colorless crystals. mp 211-214 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, t,
J = 7.4 Hz), 2.53 (3H, S), 2.5-
2.76 (2H, m), 2.64 (4H, q, J = 7.
4Hz), 3.43-3.56 (2H, m), 3.87
-3.99 (1H, m), 4.19 (2H, d, J =
4.8 Hz), 5.27 (2H, br), 6.72 (2
H, d, J = 8.8 Hz), 7.02 (1H, br),
7.72 (2H, d, J = 8.8 Hz), 8.13 (1
H, s).

Example 248 (Preparation of compound 248) 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (1.0 g), 2-phenoxyaniline (0.98 g), acetone (20 ml) Mix 10
Heated to reflux for an hour. The mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. Water the organic layer,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 2-methyl-5-[[(2
-Phenoxyphenyl) amino] methyl]] pyrimidin-4-amine (Compound 248) (0.43 g) was obtained as colorless crystals. mp 125-126 ° C. Elemental analysis value: C ₁₈ H ₁₈ N ₄ O. Calcd. : C, 70.57; H, 5.92; N, 18.29. Found: C, 70.38; H, 5.85; N, 18.47. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 4.1 (1H, br), 4.18 (2H, s),
5.23 (2H, br), 6.7-6.98 (5H,
m), 7.02-7.13 (2H, m), 7.23-
7.37 (2H, m), 8.09 (1H, s).

Example 249 (Preparation of compound 249) 4-[[[(4-Amino-2-methylpyrimidine-5-
Yl) methyl] amino] carbonyl] benzoic acid (1.0
g), benzhydrylamine (0.85 g) and dimethylformamide (30 ml) were added to a solution of HOBt (0.71 g).
g) and WSC (0.89 g) were added and stirred at room temperature for 24 hours. Concentrate under reduced pressure, add ethyl acetate and water to the residue,
The precipitated crystals are washed with ethyl acetate and 4-[[(4-amino-2-methylpyrimidin-5-yl) methyl] amino] -N-benzhydrylamide (Compound 249)
(1.0 g) was obtained as colorless crystals. mp 251-281 ° C. Elemental analysis _{C 26 H 25 N 5 O ·} 0.5H Calcd the ₂ O. : C, 72.20; H, 6.06; N, 16.19. Found: C, 71.99; H, 5.99; N, 16.09. ¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H,
s), 4.08 (2H, d, J = 5.4 Hz), 6.3
8 (1H, d, J = 8.8 Hz), 6.5-6.7 (1
H, m), 6.57 (2H, d, J = 8.8 Hz),
6.69 (2H, br), 7.17-7.4 (10H,
m), 7.73 (2H, d, J = 8.8 Hz), 7.9
4 (1H, s), 8.79 (1H, d, J = 8.8H)
z).

Example 250 (Preparation of Compound 250) 4-[[[(4-Amino-2-methylpyrimidine-5-
Yl) methyl] amino] carbonyl] benzoic acid (1.0
g), 3,3-diphenylpropylamine (0.98
g), HO in a solution of dimethylformamide (30 ml)
Bt (0.71 g) and WSC (0.89 g) were added, and the mixture was stirred at room temperature for 23 hours. The mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the precipitated crystals were washed with ethyl acetate.
[[(4-amino-2-methylpyrimidin-5-yl)
Methyl] amino] -N- (3,3-diphenylpropyl) benzamide (Compound 250) (0.96 g) was obtained as colorless crystals. mp 189-190 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.17-2.32
(2H, m), 2.28 (3H, s), 3.04-3.
27 (2H, m), 4.0-4.12 (3H, m),
6.44-6.60 (3H, m), 6.70 (2H, b
r), 7.11-6.37 (10H, m), 7.59
(2H, d, J = 8.6 Hz), 7.94 (1H,
s), 8.05 (1H, t, J = 4.4 Hz).

Example 251 (Production of compound 251) Formic acid (0.29 ml) was added dropwise to acetic anhydride (0.58 ml) at room temperature, and the mixture was stirred at 60 ° C for 2 hours. Tetrahydrofuran (2 ml) was added, followed by 4-[[(4-amino-
2-methylpyrimidin-5-yl) methyl] amino]-
A solution of N-benzhydrylamide (0.5 g) in tetrahydrofuran (5 ml) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The operation of adding toluene to the residue and concentrating was repeated twice, and the obtained crystals were recrystallized from ethanol-ethyl acetate to give 4-[[(4-amino-2-methylpyrimidin-5-yl) methyl]].
(Formyl) amino] -N-benzhydrylbenzamide (Compound 251) (0.38 g) was obtained as colorless crystals. mp 213-214 ° C. Elemental analysis _{C 27 H 25 N 5 O 2} · 0.2H Calcd the ₂ O. : C, 71.25; H, 5.63; N, 15.39. Found: C, 71.21; H, 5.59; N, 15.39. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 4.82 (2H, s), 5.85 (2H, b
r), 6.43 (1H, d, J = 7.5 Hz), 6.6
3 (1H, d, J = 7.5 Hz), 7.17 (1H,
d, J = 8.4 Hz), 7.23-7.42 (10H,
m), 7.69 (1H, s), 7.85 (1H, d, J
= 8.4 Hz), 8.37 (1H, s).

Example 252 (Production of compound 252) Formic acid (0.27 ml) was added dropwise to acetic anhydride (0.54 ml) at room temperature, and the mixture was stirred at 60 ° C for 2 hours. Tetrahydrofuran (5 ml) was added, followed by 4-[[(4-amino-
2-Methylpyrimidin-5-yl) methyl] amino]
A solution of -N- (3,3-diphenylpropyl) benzamide (0.5 g) in tetrahydrofuran (5 ml) was added to 0
It was added dropwise at ° C. The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The operation of adding toluene to the residue and concentrating
The resulting crystals were recrystallized from ethanol-ethyl acetate to give 4-[[(4-amino-2-methylpyrimidin-5-yl) methyl]] (formyl) amino]-
N- (3,3-diphenylpropyl) benzamide (compound 252) (0.42 g) was obtained as colorless crystals. mp 156-158 ° C. Elemental analysis value: C ₂₉ H ₂₉ N ₅ O ₂ .0.2H ₂ O: Calcd. : C, 72.09; H, 6.13; N, 14.49. Found: C, 72.06; H, 6.08; N, 14.38. ¹ H-NMR (CDCl ₃ ) δ: 2.35-2.49
(2H, m), 2.44 (3H, s), 3.49 (2
H, q, J = 6.2 Hz), 4.02 (1H, t, J =
7.6 Hz), 4.81 (2H, s), 5.88 (3
H, br), 6.43 (1H, d, J = 7.5 Hz),
6.63 (1H, d, J = 7.5 Hz), 7.06-
7.63 (14H, m), 7.68 (1H, s), 8.
36 (1H, s).

Example 253 (Production of Compound 253) A solution of 5-aminomethyl-4-dimethylamino-2-methylpyrimidine (0.93 g) and 4-dimethylaminopyridine (0.75 g) in dimethylformamide (10 ml) was added. 4-chloromethylbenzoyl chloride (0.degree.
g) in dimethylformamide (10 ml) was added,
The mixture was stirred for 0.5 hours under the same conditions. Water (40 ml) was added, and saturated aqueous sodium hydrogen carbonate (10 ml) was further added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-[(4-dimethylamino-2-methylpyrimidin-5-yl) methyl] -4- (chloromethyl) benzamide (1.6 g). Sodium hydride (oil, 60%, 0.1 g) was suspended in N, N-dimethylformamide (15 ml), 2,4-diphenylpyrazole (0.48 g) was added, and the mixture was stirred at room temperature for 1 hour. did.
Then, N-[(4-dimethylamino-2-methylpyrimidin-5-yl) methyl] -4- (chloromethyl) benzamide (0.7 mg) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was washed with water and ethyl acetate sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane.
[(4-Dimethylamino-2-methylpyrimidine-5
Yl) methyl] -4-[(3,5-diphenyl-1H-
Pyrazol-1-yl) methyl] benzamide (0.7
6 g) were obtained. Sodium hydride (oil, 60%, 39
mg) was suspended in N, N-dimethylformamide (10 ml), and N-[(4-dimethylamino-2-methylpyrimidin-5-yl) methyl] -4-[(3,5-diphenyl-1H- A solution of pyrazol-1-yl) methyl] benzamide (0.45 g) in N, N-dimethylformamide (5 ml) was added, the mixture was stirred at room temperature for 25 minutes, and benzyl chloride (0.11 ml) in N, N-dimethylformamide ( 5 ml) solution was added dropwise. 40 minutes at room temperature for 80 minutes
For 20 hours. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added to carry out liquid separation. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give N-benzyl-N-[[4- (dimethylamino) -2-methylpyrimidin-5-yl] methyl] -4- ( 3,5-Diphenyl-1H-pyrazol-1-yl) benzamide (Compound 253) (300 mg) was obtained. mp 153-155 ° C. Elemental analysis value: C ₃₈ H ₃₆ N ₆ O · 0.1H ₂ O Calcd. : C, 76.77; H, 6.14; N, 14.14. Found: C, 76.63; H, 6.32; N, 14.19. ¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H,
s), 2.97 (6H, s), 4.2-4.8 (4H,
m), 5.41 (2H, s), 6.67 (1H, s),
6.93-7.5 (17H, m), 7.78-8.2
(3H, m).

Example 254 (Production of compound 254) 60% oily sodium hydride (0.53 g) was added to allyl alcohol (15 ml), and potassium iodide (200 mg) was added at room temperature with stirring, followed by 4-amino- 5-
(4-Chloromethylbenzoylaminomethyl) -2-methylpyrimidine (1.1 g) was added. Reaction solution at 60 ° C
And concentrated under reduced pressure. Water was added to the residue, and the precipitated crystals were collected by filtration, washed with water and dried to give 4-amino-5-N
-(4-Allyloxymethylbenzoyl) aminomethyl-2-methylpyrimidine (1.0 g) was obtained as colorless crystals. 4-amino-5- (4-allyloxymethylbenzoyl) aminomethyl-2-methylpyrimidine (0.35 g)
Was dissolved in a mixed solvent of tetrahydrofuran (12 ml) and N, N-dimethylformamide (1 ml), and 60% oily sodium hydride (48 mg) was added. While stirring at room temperature, potassium iodide (200 mg) and benzyl chloride were added. (0.15 g) was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, and the organic layer was concentrated and subjected to silica gel column chromatography. The obtained crystals are ethanol (10 ml)
And 2N hydrochloric acid (0.1 ml) was added, and the mixture was concentrated under reduced pressure. The residue (crystal) was washed with acetone, dried and dried to give 4-amino-5- (N-4-allyloxymethylbenzoyl-N- Benzyl) aminomethyl-2-methylpyrimidine hydrochloride (Compound 254) was obtained as colorless crystals (40 mg). mp 208-210 ° C. Elemental analysis value C ₂₄ H ₂₇ ClN ₄ O ₂ .0.3H ₂ O Calcd. : C, 64.87; H, 6.26; N, 12.61. Found: C, 64.83; H, 6.12; N, 12.68. ¹ H-NMR (DMSO-d ₆ ) δ: 2.51 (3H,
s), 4.00 (2H, d, J = 4.8 Hz), 4.5
0 (4H, s), 4.62 (2H, br), 5.14-
5.35 (2H, m), 5.83-6.03 (1H,
m), 7.11-7.55 (9H, m), 8, 05 (1
H, br), 9.12 (1H, br).

Reference Example 1 2-nitrophenol (5.03 g) and triphenylphosphine (9.48 g) were added to tetrahydrofuran (50
ml), 3-ethoxy-1-propanol (3.77 g) was added at room temperature, and a toluene solution of diethyl azodicarboxylate (40%, 15.7 g) was added at 0 ° C. The mixture was stirred at room temperature for 13.5 hours. The reaction mixture was diluted with ethyl acetate, and washed sequentially with water, a 1N aqueous sodium hydroxide solution, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
-(3-Ethoxypropoxy) -2-nitrobenzene (7.62 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t,
J = 6.9 Hz), 2.09 (2H, quint, J =
6.1 Hz), 3.50 (2H, q, J = 7.1H)
z), 3.63 (2H, t, J = 6.1 Hz), 4.2
2 (2H, t, J = 6.1 Hz), 7.01 (1H, t
d, J = 7.6, 0.8 Hz), 7.10 (1H, d,
J = 8.4 Hz), 7.52 (1H, td, J = 7.
9, 1.7 Hz), 7.83 (1H, dd, J = 8.
1,1.5 Hz). IR (KBr) 1609, 1526, 1489, 135
4,1281,1258,1117,745 cm ^-1 .

Reference Example 2 1- (3-ethoxypropoxy) -2-nitrobenzene (3.30 g) was dissolved in methanol (50 ml).
0% Palladium on carbon (300 mg) was added. The mixture was stirred vigorously under a hydrogen atmosphere at room temperature for 13 hours. The reaction mixture was filtered through celite, the filtrate was concentrated and 2- (3-
Ethoxypropoxy) aniline (2.89 g) was obtained as a red-brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t,
J = 7.1 Hz), 2.08 (2H, quint, J =
6.3 Hz), 3.36 (2H, br), 3.50 (2
H, q, J = 6.9 Hz), 3.61 (2H, t, J =
6.2 Hz), 4.10 (2H, t, J = 6.2H)
z), 6.66-6.82 (4H, m). IR (KB
r) 2870, 1615, 1507, 1277, 122
1,1115,741 cm ^-1 .

Reference Example 3 Sodium hydride (60%: 0.88 g) was washed with hexane and suspended in tetrahydrofuran (15 ml). Then, 1-propanethiol (1.81 ml) was added. A suspension of the produced 1-propanethiol sodium salt in tetrahydrofuran is added to bromochloromethane (1).
2.9 g) at 0 ° C. over 5 minutes. Mix 0
Stirred at C for 1 hour. The reaction mixture was filtered, washed with ether, and the filtrate was concentrated to give chloromethylpropyl sulfide (1.81 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t,
J = 7.3 Hz), 1.70 (2H, nextet, J
= 7.3 Hz), 2.74 (2H, t, J = 7.3H)
z), 4.75 (2H, s).

Reference Example 4 Sodium hydride (60%: 0.80 g) was washed with hexane and suspended in tetrahydrofuran (15 ml). Then, benzylthiol (2.48 g) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the resulting suspension of benzylthiol sodium salt in tetrahydrofuran was added dropwise to bromochloromethane (12.9 g) at 0 ° C over 15 minutes. The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was filtered, washed with ether, and the filtrate was concentrated to give benzyl chloromethyl sulfide (3.88 g, containing tetrahydrofuran) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.92 (2H,
s), 4.55 (2H, s), 7.29-7.36 (5
H, m).

Reference Example 5 2-Nitrobenzyl bromide (10.77 g) was dissolved in cyclohexane (400 ml), and tetrahydrofurfuryl alcohol (50.9 g) and silver oxide (I) were added thereto. The mixture was stirred at 90 ° C. for 38 hours. The reaction mixture was filtered through celite. The filtrate was diluted with ethyl acetate and washed with water and saturated saline, respectively. The organic layer was 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 2-nitrobenzyltetrahydro-2-furanylmethyl ether (5.20 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.75
(1H, m), 1.82 to 2.09 (3H, m), 3.
59 (1H, d, J = 1.4 Hz), 3.62 (1H,
s), 3.75-3.97 (2H, m), 4.10-
4.22 (1H, m), 4.95 (2H, s), 7.3
9-7.47 (1H, m), 7.65 (1H, td, J
= 7.7, 1.2 Hz), 7.82 (1H, dd, J =
7.8, 0.8 Hz), 8.06 (1H, dd, J =
8.2, 1.2 Hz).

Reference Example 6 2-Nitrobenzyltetrahydro-2-furanylmethyl ether (2.45 g) was dissolved in methanol (50 ml), and 10% palladium-carbon (250 mg) and ammonium formate (4.89 g) were respectively added. added. The mixture was stirred at room temperature for 23 hours. The reaction mixture was poured into ether, stirred for a while, and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-[(tetrahydro-2-furanylmethoxy) methyl] aniline (2.06 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.52-1.64
(1H, m), 1.78-2.02 (3H, m), 3.
40 (1H, dd, J = 10.0, 6.4 Hz);
48 (1H, dd, J = 10.6, 4.4 Hz);
71-3.93 (2H, m), 4.01-4.08 (1
H, m), 4.25 (2H, brs), 4.55 (1
H, d, J = 15.0 Hz), 4.61 (1H, d, J)
= 15.0 Hz), 6.67 (1H, d, J = 7.8H)
z), 6.69 (1H, td, J = 7.5, 1.0H
z), 7.03-7.08 (1H, m), 7.12 (1
H, td, J = 7.8, 1.5 Hz).

Reference Example 7 2-Nitrobenzyl bromide (5.38 g) was dissolved in dimethylformamide (100 ml), and benzylthiol (2.9 ml) and potassium carbonate (5.2 g) were added, respectively. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ether and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain benzyl 2-nitrobenzyl sulfide (6.24 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 3.65 (2H,
s), 3.95 (2H, s), 7.23-7.56 (8
H, m), 7.96 (1H, dd, J = 7.9, 1.3)
Hz).

Reference Example 8 Benzyl 2-nitrobenzyl sulfide (5.80 g)
And potassium carbonate (18.5 g) in water: tetrahydrofuran: methanol (3: 1: 1, 250 ml) and sodium hydrosulfite (80%: 19.
5 g) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was 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 2-[(benzylsulfanyl) methyl] aniline (2.05 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 3.0-3.9 (2
H, br), 3.618 (2H, s), 3.623 (2
H, s), 6.69 (1H, d, J = 7.6 Hz),
6.71 (1H, td, J = 7.8, 1.2 Hz),
6.96 (1H, d, J = 7.6 Hz), 7.10 (1
H, td, J = 7.7, 1.5 Hz), 7.22-7.
37 (5H, m).

Reference Example 9 Sodium hydride (60%: 0.88 g) was suspended in dimethylformamide (30 ml), and a solution of 4-bromothiophenol (3.78 g) in dimethylformamide (20 ml) was added dropwise at 0 ° C. did. After stirring the mixture at 0 ° C for 15 minutes, 1-fluoro-2-nitrobenzene (2.82 g) was added dropwise at 0 ° C. Mix at room temperature for 30 minutes.
Stirred for minutes. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate to give 4-bromophenyl-
2′-Nitrophenyl sulfide (6.32 g) was obtained as yellow needles. mp 110-113 ° C ¹ H-NMR (CDCl ₃ ) δ: 6.87 (1H, d
d, J = 8.0, 1.4 Hz), 7.24 (1H, dd)
d, J = 8.3, 7.1, 1.4 Hz), 7.38 (1
H, ddd, J = 8.2, 7.0, 1.7 Hz), 7.
42-7.47 (2H, m), 7.58-7.65 (2
H, m), 8.24 (1H, dd, J = 8.0, 1.4)
Hz).

Reference Example 10 4-Bromophenyl-2'-nitrophenyl sulfide (5.28 g) was dissolved in tetrahydrofuran: methanol (1: 1, 70 ml), and water (100 ml) was added. Then, potassium carbonate (14.1 g) and sodium hydrosulfite (80%: 14.8 g) were added at room temperature. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added, the organic layer was separated and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate to give 2-aminophenyl-4'-bromophenyl sulfide (3.77 g) as yellow needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.28 (2H, b
r), 6.76 (1H, td, J = 7.4, 1.2H
z), 6.80 (1H, dd, J = 8.3, 0.9H
z), 6.90-6.97 (2H, m), 7.21-
7.36 (3H, m), 7.44 (1H, dd, J =
7.4, 1.4 Hz).

Reference Example 11 Sodium hydride (60%: 3.24 g) was suspended in dimethylformamide (100 ml), and a solution of 2-methoxythiophenol (10.3 g) in dimethylformamide (50 ml) was added at 40 ° C. at 40 ° C. It was added dropwise over a period of minutes. 1-
Fluoro-2-nitrobenzene (10.4 g) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to give 2-methoxyphenyl-2'-
Nitrophenyl sulfide (including dimethylformamide,
20.7 g) were obtained as yellow crystals. mp 119-122 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.79 (3H,
s), 6.81 (1H, dd, J = 8.3, 1.3H
z), 7.01-7.10 (2H, m), 7.19 (1
H, td, J = 7.7, 1.5 Hz), 7.32 (1
H, ddd, J = 8.0, 7.4, 1.4 Hz), 7.
51 (1H, ddd, J = 7.9, 7.5, 1.4H
z), 7.60 (1H, dd, J = 7.5, 1.7H)
z), 8.25 (1H, dd, J = 8.1, 1.5H
z).

Reference Example 12 2-methoxyphenyl-2'-nitrophenyl sulfide (5.37 g) was dissolved in tetrahydrofuran: methanol (1: 1, 100 ml), and water (100 ml) was dissolved.
Was added. Then, potassium carbonate (17.0 g) and sodium hydrosulfite (80%: 17.9 g)
Was added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed with water and saturated saline, respectively. The organic layer was 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 2-aminophenyl-2'-methoxyphenyl sulfide (3.07 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H,
s), 4.31 (2H, brs), 6.64 (1H, d
d, J = 7.6, 1.8 Hz), 6.72-6.88.
(4H, m), 7.11 (1H, ddd, J = 8.1,
7.3, 1.8 Hz), 7.25 (1H, ddd, J =
8.0, 7.4, 1.4 Hz), 7.46 (1H, d
d, J = 7.8, 1.4 Hz).

Reference Example 13 Sodium hydride (60%: 2.39 g) was suspended in dimethylformamide (70 ml), and a solution of 4-methoxyphenol (6.74 g) in dimethylformamide (3
5 ml) was added dropwise at 0 ° C. After the mixture was stirred at 0 ° C. for 15 minutes, 1-fluoro-2-nitrobenzene (7.6) was used.
6 g) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was recrystallized from diisopropyl ether-hexane, and 4-methoxyphenyl-2′-nitrophenyl ether (12.5
g) was obtained as pale brown crystals. mp 76-77 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.82 (3H,
s), 6.89-6.95 (3H, m), 6.99-
7.05 (2H, m), 7.12 (1H, td, J =
8.1, 1.6 Hz), 7.45 (1H, td, J =
8.0, 1.9 Hz), 7.92 (1H, dd, J =
8.3, 1.7 Hz).

Reference Example 14 4-methoxyphenyl-2'-nitrophenyl ether (9.01 g) was dissolved in tetrahydrofuran: methanol (1: 1, 80 ml), and water (80 ml) was added. Then, potassium carbonate (30.5 g) and sodium hydrosulfite (80%: 32.0 g) were added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was 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 2-aminophenyl-4'-methoxyphenyl ether (4.82 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 3.79 (3H,
s), 3.83 (2H, br), 6.63-6.97.
(8H, m).

Reference Example 15 Sodium hydride (60%: 1.27 g) was suspended in dimethylformamide (15 ml), and a solution of 4-methoxythiophenol (4.05 g) in dimethylformamide (30 ml) was added dropwise at 0 ° C. did. After the mixture was stirred at 0 ° C for 20 minutes, 1-fluoro-2-nitrobenzene (4.08 g) was added dropwise at 0 ° C. Further, dimethylformamide (10 ml) was added. Mix the mixture at 0 ° C for 1.5
Stirred for hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diisopropyl ether-hexane to give 4-methoxyphenyl-2'-nitrophenyl sulfide (6.
03g) were obtained as yellow crystals. mp99-101 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.88 (3H,
s), 6.83 (1H, dd, J = 8.0, 1.4H
z), 6.97-7.05 (2H, m), 7.19 (1
H, ddd, J = 8.2, 7.0, 1.3 Hz), 7.
34 (1H, ddd, J = 8.0, 7.4, 1.5H
z), 7.47-7.55 (2H, m), 8.24 (1
H, dd, J = 8.0, 1.4 Hz).

Reference Example 16 4-methoxyphenyl-2'-nitrophenyl sulfide (4.68 g) was dissolved in tetrahydrofuran: methanol (1: 1, 60 ml), and water (40 ml) was added. Then, potassium carbonate (14.9 g) and sodium hydrosulfite (80%: 15.6 g) were added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-aminophenyl-4'-methoxyphenyl sulfide (2.17 g) as an orange oil. ¹ H-NMR (CDCl ₃ ) δ: 3.76 (3H,
s), 4.26 (2H, br), 6.68-6.84.
(4H, m), 7.09-7.22 (3H, m), 7.
40 (1H, dd, J = 7.5, 1.7 Hz).

Reference Example 17 Tetrabutylammonium bromide (0.48 g) was added to a mixture of 2-aminothiophenol (3.76 g) and a 10% aqueous sodium hydroxide solution (50 ml), and the mixture was stirred at room temperature for 5 minutes. A toluene solution (50 ml) of 1-fluoro-2-nitrobenzene (4.23 g) was added, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-aminophenyl-2'-nitrophenyl sulfide (7.53 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 4.29 (2H, br
s), 6.78-6.88 (3H, m), 7.19-
7.47 (4H, m), 8.27 (1H, dd, J =
8.3, 1.7 Hz).

Reference Example 18 Tetrabutylammonium bromide (0.55 g) was added to a mixture of 2-aminothiophenol (4.26 g) and a 10% aqueous sodium hydroxide solution (30 ml), and the mixture was stirred at room temperature for 5 minutes. A toluene solution (30 ml) of 4-chloro-3-nitroanisole (6.37 g) was added, and the mixture was stirred at room temperature for 19 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was 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 2-aminophenyl-4′-methoxy-2′-nitrophenyl sulfide (7.38 g) as a brown oil. A part of the compound was collected and recrystallized from ethyl acetate-hexane to obtain 2-aminophenyl-4′-methoxy-2′-nitrophenyl sulfide as dark yellow crystals. mp 117-119 ° C. Elemental analysis value: C ₁₃ H ₁₂ N ₂ O ₃ S Calcd. : C, 56.51; H, 4.38; N, 10.14. Found: C, 56.76; H, 4.44; N, 9.94. ¹ H-NMR (CDCl ₃ ) δ: 3.81 (3H,
s), 4.28 (2H, brs), 6.75 (1H,
d, J = 8.8 Hz), 6.81 (1H, t, J = 7.
9Hz), 6.83 (1H, d, J = 7.8Hz),
6.99 (1H, dd, J = 9.0, 2.6 Hz),
7.32 (1H, td, J = 8.1, 1.5 Hz),
7.46 (1H, dd, J = 8.1, 1.5 Hz),
7.77 (1H, d, J = 2.4 Hz). IR (KBr) 1613, 1520, 1480, 133
7,1304 cm ^-1 .

Reference Example 19 2-aminophenyl-2'-nitrophenyl sulfide (3.65 g) was dissolved in tetrahydrofuran (150 ml), and acetyl chloride (1.16 ml) was added at 0 ° C. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate, and N- [2
-[(2-nitrophenyl) sulfanyl] phenyl]
Acetamide (3.25 g) was obtained as yellow crystals. Further, the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and treated in the same manner as described above to obtain the same compound (0.76 g) as yellow crystals. Total yield: 4.01 g. mp 137-138 ° C. Elemental analysis value: C ₁₄ H ₁₂ N ₂ O ₃ S Calcd. : C, 58.32; H, 4.20; N, 9.72. Found: C, 58.30; H, 4.15; N, 9.69. ¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H,
s), 6.71 (1H, dd, J = 8.1, 1.5H)
z), 7.21 (1H, td, J = 7.5, 1.2H
z), 7.29 (1H, td, J = 7.7, 1.5H
z), 7.39 (1H, td, J = 7.6, 1.6H
z), 7.52-7.62 (2H, m), 8.09 (1
H, s), 8.29 (1H, dd, J = 8.0, 1.6)
Hz), 8.53 (1H, d, J = 8.0 Hz). IR (KBr) 1696, 1591, 1578, 151
4,1435,1337,1296 cm ^-1 .

Reference Example 20 N- [2-[(2-nitrophenyl) sulfanyl] phenyl] acetamide (5.97 g) was dissolved in tetrahydrofuran: methanol (1: 1, 80 ml), and water (80 ml) was added. . Then, potassium carbonate (17.
2g) and sodium hydrosulfite (80%:
18.0 g) were added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
-[2-[(2-Aminophenyl) sulfanyl] phenyl] acetamide (1.87 g) was obtained as an orange oil. ¹ H-NMR (CDCl ₃ ) δ: 2.16 (3H,
s), 4.26 (2H, br), 6.68-6.78.
(2H, m), 7.00-7.34 (5H, m), 7.
90 (1H, br), 8.17 (1H, d, J = 8.0)
Hz).

Reference Example 21 2-aminophenyl-2'-nitrophenyl sulfide (7.14 g) was dissolved in tetrahydrofuran (200 ml), and methanesulfonyl chloride (4.94 ml) was dissolved.
And triethylamine (8.90 ml) were added. The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 1N hydrochloric acid, water, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate, and N- (methylsulfonyl) -N-
[2-[(2-Nitrophenyl) sulfanyl] phenyl] methanesulfonamide (9.91 g) was obtained as dark yellow crystals. mp 195-197 ° C. Elemental analysis value as C ₁₄ H ₁₄ N ₂ O ₆ S ₃ Calcd. : C, 41.78; H, 3.51; N, 6.96. Found: C, 41.98; H, 3.49; N, 6.94. ¹ H-NMR (CDCl ₃ ) δ: 3.45 (6H,
s), 7.03 (1H, dd, J = 8.0, 1.6H
z), 7.28 (1H, td, J = 7.7, 1.5H
z), 7.41 (1H, td, J = 7.6, 1.5H
z), 7.47-7.66 (4H, m), 8.21 (1
H, dd, J = 8.0, 1.8 Hz). IR (KBr)
1520, 1370, 1354, 1339, 1161,
909, 760, 735 cm ^-1 .

Reference Example 22 N- (methanesulfonyl) -N- [2-[(2-nitrophenyl) sulfanyl] phenyl] methanesulfonamide (8.93 g) and tin (II) chloride dihydrate (20.
0 g) in ethyl acetate (500 ml),
For 1.5 hours. The reaction mixture was neutralized with a 1N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N- [2-[(2-aminophenyl) sulfanyl] phenyl] -N- (methylsulfonyl) methanesulfonamide (4.26 g) was used. Was obtained as white crystals. mp 187-188 ° C. Elemental analysis value as C ₁₄ H ₁₆ N ₂ O ₄ S ₃ Calcd. : C, 45.14; H, 4.33; N, 7.52. Found: C, 44.83; H, 4.05; N, 7.36. ¹ H-NMR (CDCl ₃ ) δ: 3.60 (6H,
s), 4.36 (2H, s), 6.67-6.87 (3
H, m), 7.15-7.33 (4H, m), 7.46.
(1H, dd, J = 7.8, 1.6 Hz). IR (KBr) 1368, 1352, 1161, 89
9,7585 cm ^-1 .

Reference Example 23 1-Bromo-2-nitrobenzene (24.4 g) and triphenylphosphine (50.1 g) were suspended in dimethylformamide: methanol (1: 1, 200 ml), and 4-hydroxythiophenol ( 16.1 g) and 3N aqueous sodium hydroxide solution (45 ml) were added successively. The mixture was stirred at room temperature for 13 hours. The reaction mixture was slightly concentrated under reduced pressure, and 1N hydrochloric acid and ethyl acetate were added to the residue. The mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give 4-[(2-nitrophenyl) sulfanyl] phenol (23.4 g) as yellow crystals. As obtained.
The second crystal (5.66 g) was obtained as yellow crystals. Total yield: 29.1 g. mp 133-134 ° C. Elemental analysis value as C ₁₂ H ₉ NO ₃ S. Calcd. : C, 58.29; H, 3.67; N, 5.66. Found: C, 58.15; H, 3.42; N, 5.56. ¹ H-NMR (CDCl ₃ ) δ: 5.12 (1H,
s), 6.84 (1H, dd, J = 8.1, 1.5H)
z), 6.92-6.99 (2H, m), 7.16-
7.24 (1H, m), 7.30-7.39 (1H,
m), 7.43-7.51 (2H, m), 8.24 (1
H, dd, J = 8.0, 1.4 Hz). IR (KBr) 1591, 1510, 1495, 133
9,1304 cm ^-1 .

Reference Example 24 4-[(2-Nitrophenyl) sulfanyl] phenol (3.67 g) was added to dimethylformamide (50 ml).
And potassium carbonate (2.26 g) and β-bromophenetol (3.13 g) were added, respectively. The mixture was stirred at room temperature for 14.5 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, a 1N aqueous solution of sodium hydroxide, water, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate and 1-nitro-2-[[4- (2-phenoxyethoxy) phenyl].
[Sulfanyl] benzene (4.38 g) was obtained as yellow crystals. The mother liquor was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the same treatment as described above was performed to obtain the compound (0.49 g) as yellow crystals.
Total yield: 4.87 g. mp 137-138 ° C. Elemental analysis value: C ₂₀ H ₁₇ NO ₄ S Calcd. : C, 65.38; H, 4.66; N, 3.81. Found: C, 65.14; H, 4.42; N, 3.79. ¹ H-NMR (CDCl ₃ ) δ: 4.39 (4H,
s), 6.83 (1H, dd, J = 8.1, 1.5H
z), 6.95-7.10 (5H, m), 7.15-
7.38 (4H, m), 7.50-7.56 (2H,
m), 8.24 (1H, dd, J = 8.2, 1.6H)
z). IR (KBr) 1593, 1514, 1493, 133
9, 1304, 1242 cm ^-1 .

Reference Example 25 1-nitro-2-[[4- (2-phenoxyethoxy)
Phenyl] sulfanyl] benzene (3.98 g), calcium chloride (0.60 g) and reduced iron (5.44 g)
Was mixed with 85% ethanol (200 ml),
For 3 hours. After air cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate-hexane to obtain 2-[[4- (2-phenoxyethoxy) phenyl] sulfanyl] aniline (3.09 g) as off-white crystals. . The second crystal (0.33 g) was obtained as colorless crystals. Total yield: 3.
42g. mp 101-102 ° C. Elemental analysis value as C ₂₀ H ₁₉ NO ₂ S Calcd. : C, 71.19; H, 5.68; N, 4.15. Found: C, 70.98; H, 5.90; N, 4.01. ¹ H-NMR (CDCl ₃ ) δ: 4.28 (6H,
s), 6.69-7.00 (7H, m), 7.10-
7.42 (6H, m). IR (KBr) 1601, 1493, 1480, 124
0 cm ^-1 .

Reference Example 26 Benzamidine hydrochloride (9.23 g) was added to ethanol (2
5 ml) and sodium methoxide (3.18).
g) was added. The mixture was stirred at room temperature for 5 minutes. The reaction mixture was filtered to remove the precipitated sodium chloride. α
-Methoxymethylene-β-formylaminopropionitrile (4.13 g) was dissolved in ethanol (30 ml), and the above-mentioned filtrate was added. The mixture was stirred at room temperature for 19.5 hours and at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The mixture was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethanol to give (4-amino-2-phenyl-5-
Pyrimidinyl) methylformamide (2.57 g) was obtained as white crystals. mp 216-217 ° C. Elemental analysis value: C ₁₂ H ₁₂ N ₄ O, Calcd. : C, 63.14; H, 5.30; N, 24.55. Found: C, 63.03; H, 5.44; N, 24.42. ¹ H-NMR (CDCl ₃ ) δ: 4.17 (2H, d,
J = 6.2 Hz), 6.89 (2H, brs), 7.4
2-7.48 (3H, m), 8.13-8.15 (2
H, m), 8.24-8.33 (2H, m), 8.49.
(1H, t-like). IR (KBr) 1659, 1537, 1406, 124
6 cm ^-1 .

Reference Example 27 (4-Amino-2-phenyl-5-pyrimidinyl) methylformamide (9.51 g) was suspended in methanol-tetrahydrofuran (1: 1, 160 ml), and sodium hydroxide (16.7 g) was added. And water (80 ml) were added. The mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated in half under reduced pressure and extracted five times with ether. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-diisopropyl ether-hexane to obtain 5- (aminomethyl) -2-phenyl-4-pyrimidineamine (4.91 g) as white crystals. The same treatment was carried out from the filtrate, and the second crystal (2.7)
8 g) were obtained. Total yield: 7.69 g. mp 94-95 ° C. Elemental analysis value C ₁₁ H ₁₂ N ₄ Calcd. : C, 65.98; H, 6.04; N, 27.98. Found: C, 65.91; H, 5.88; N, 28.00. ¹ H-NMR (CDCl ₃ ) δ: 3.91 (2H,
s), 6.09 (2H, brs), 7.41-7.47.
(3H, m), 8.13 (1H, s), 8.30-8.
35 (2H, m) and 2H were not identified. IR (KB
r) 1593, 1582, 1557, 1442, 141
0 cm ^-1 .

Reference Example 28 5- (Aminomethyl) -2-phenyl-4-pyrimidineamine (6.36 g) was dissolved in water (50 ml), and concentrated hydrochloric acid (9.3 ml) was added. Sodium nitrite (2.
41 g) aqueous solution (10 ml) was added at 60 ° C. The mixture was stirred at 60 ° C. for 1.5 hours. Sodium hydroxide (5.1 g) was added at 0 ° C. to make the reaction mixture basic. This mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ether to obtain (4-amino-2-phenyl-5-pyrimidinyl) methanol (5.25 g) as pale yellow crystals. mp 134 ° C. Elemental analysis value as C ₁₁ H ₁₁ N ₃ O, Calcd. : C, 65.66; H, 5.51; N, 20.88. Found: C, 65.59; H, 5.59; N, 20.77. ¹ H-NMR (CDCl ₃ ) δ: 4.61 (2H,
s), 5.51 (2H, brs), 7.44-7.48.
(3H, m), 8.09 (1H, s), 8.28-8.
33 (2H, m) and 1H have not been identified. IR (KB
r) 1622, 1595, 1557, 1445, 141
0 cm ^-1 .

Reference Example 29 (4-Amino-2-phenyl-5-pyrimidinyl) methanol (4.42 g) was suspended in acetic acid (45 ml).
25% HBr-acetic acid (30 ml) was added. Mix 1
Stirred at 10 ° C. for 3 hours. The reaction mixture was air-cooled and ether was slowly added. The precipitated crystals were collected by filtration and washed with methanol to give 4-amino-5-bromomethyl-2-phenylpyrimidine hydrobromide (3.95 g) as white crystals. After allowing the mother liquor to stand, the same treatment as described above was performed to obtain the same compound (2.19 g) as white crystals. Total yield: 6.14 g. mp197-200 ° C ¹ H-NMR (DMSO-d ₆ ) δ: around4
(2H, br), 4.77 (2H, s), 7.61-
7.72 (3H, m), 8.14-8.19 (2H,
m), 8.59 (1H, s).

Reference Example 30 4-Amino-5-bromomethyl-2-phenylpyrimidine hydrobromide (3.93 g) was suspended in acetone: toluene (4: 1, 30 ml), and benzothiazole (3.87 g) was added. ) Was added. The mixture was boiled at 80 ° C. for 22 hours. After air cooling, ether was gradually added, and the reaction mixture was filtered. The solid was recrystallized from water to give N- (4-amino-2-phenyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (3.15 g) as pale reddish brown crystals. mp 263-267 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 5.96 (2H,
s), 7.61-7.72 (4H, m), 7.89-
8.07 (3H, m), 8.25-8.62 (5H,
m), 10.52 (1H, s).

Reference Example 31 5- (aminomethyl) -2-methyl-4-pyrimidineamine carbonate (10.0 g) was dissolved in 6N hydrochloric acid (20 ml). Sodium nitrite (3.80 g) aqueous solution (1
5 ml) at 0 ° C. and the mixture is left at room temperature for 3.5 hours at 6 ° C.
Stirred at 0 ° C. for 0.5 hour. An aqueous solution of sodium bicarbonate was added at 0 ° C. to make the reaction mixture basic. The mixture was concentrated under reduced pressure. Ethanol was added to the residue, and after heating, filtration was performed to remove generated salts. The filtrate was concentrated under reduced pressure to obtain (4-amino-2-methyl-5-pyrimidinyl) methanol (6.18 g) as pale yellow crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3
H, s), 4.36 (2H, s), 8.07 (1H,
s), NH ₂ and OH were not identified.

Reference Example 32 (4-Amino-2-methyl-5-pyrimidinyl) methanol (35.7 g) was added to 10% hydrogen bromide-acetic acid (750 m 2).
l). The mixture was stirred at 110 ° C. for 3.5 hours. The reaction mixture was air-cooled and ether was slowly added.
The precipitated crystals were collected by filtration and washed with methanol-ether to give 4-amino-5-bromomethyl-2-methylpyrimidine hydrobromide (61.4 g) as white crystals. mp 201-204 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3H,
s), 4.66 (2H, s), 8.51 (1H, s),
8.66 (1H, s), 9.36 (1H, s).

Reference Example 33 4-Amino-5-bromomethyl-2-methylpyrimidine hydrobromide (14.8 g) was suspended in acetone: toluene (1: 1, 50 ml), and benzothiazole (21.4 g) was used. ) Was added. The mixture was boiled at 75 ° C. for 22 hours. After air cooling, the reaction mixture was filtered. Water to solid
It was dissolved in ethanol and decolorized using activated carbon. Further, recrystallization was performed with water-ethanol, and N- (4-amino-
2-Methyl-5-pyrimidinyl) methylbenzothiazolium bromide hydrobromide (16.5 g) was obtained as pale reddish brown crystals. mp 287-290 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.57 (3H,
s), 5.91 (2H, s), 7.88-8.04 (2
H, m), 8.41-8.62 (3H, m), 8.98
(1H, brs), 9.38 (1H, brs), 10.
59 (1H, s).

Reference Example 34 To a solution of anhydrous trimellitate chloride (1.1 g) in tetrahydrofuran (10 ml) was added dropwise a solution of benzhydrylamine (0.88 ml) in tetrahydrofuran (3 ml) at 0 ° C. over 1 hour. Subsequently, triethylamine (0.
7 ml) and stirred under the same conditions for 2 hours. After stirring at room temperature overnight (15 hours), water and ethyl acetate were added to carry out liquid separation. The organic layer was washed twice with water and once with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was washed with ethyl acetate, and N-benzohydryl-1,3-
Dioxo-1,3-dihydro-2-benzofuran-5
Carboxamide (1.6 g) was obtained. mp 220-222 ° C ¹ H-NMR (CDCl ₃ ) δ: 6.44 (1H, d,
J = 7.6 Hz), 6.95 (1H, d, J = 7.6H)
z), 7.2-7.4 (10H, m), 8.08 (1
H, d, J = 8.4 Hz), 8.36 (1H, s),
8.38 (1H, d, J = 8.4 Hz).

Reference Example 35 A small amount of lithium aluminum hydride (19.6 g) was added to a solution of 4-amino-5- (benzoylaminomethyl) -2-methylpyrimidine (25.0 g) in anhydrous tetrahydrofuran (500 ml) at 0 ° C. The mixture was heated at reflux for 18 hours. After cooling, ice was added little by little, and tetrahydrofuran was distilled off under reduced pressure. An aqueous solution of sodium hydroxide was added, insolubles were removed by filtration, and the organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: ethanol: triethylamine / 50: 10: 1).
-Amino-5- (benzylaminomethyl) -2-methylpyrimidine (11.5 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H,
s), 3.74 (4H, s), 6.14 (2H, b
r), 7.2-7.42 (5H, m), 7.93 (1
H, s).

Reference Example 36 In a solution of 1,3-di (2-pyridyl) -1,3-propanedione (2.0 g) in ethanol (20 ml), hydrazine hydrochloride (0.67 g) and sodium acetate (0.80 g) were added.
g) was added. After heating under reflux for 2 hours, water and ethyl acetate were added to carry out liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were collected and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with methanol to obtain 2- [5- (2-pyridinyl) -1H-pyrazol-3-yl] pyridine (1.4 g). mp 190-191 ° C ¹ H-NMR (CDCl ₃ ) δ: 7.26 (1H,
s), 7.23-7.42 (2H, m), 7.74-
7.82 (2H, m), 7.92 (2H, d, J = 8.
0 Hz), 8.67 (2H, dd, J = 0.8 & 4.6)
Hz).

Reference Example 37 2-chloroethanol (24.2 g) was added to toluene (25
After adding concentrated sulfuric acid (3.5 ml) at room temperature, a toluene solution (50 ml) of benzhydrol (36.8 g) was added dropwise over 30 minutes. The mixture was further stirred at 100 ° C. for 1.5 hours. After air cooling, the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and benzhydryl 2-chloroethyl ether (56.40 g) was used.
I got ¹ H-NMR (CDCl ₃ ) δ: 3.66 to 3.76
(4H, m), 5.43 (1H, s), 6.98-7.
39 (10H, m).

Reference Example 38 Bromodiphenylmethane (3.89 g) and thiourea (1.32 g) were mixed with ethanol (50 ml).
The mixture was stirred at 90 ° C. for 6.5 hours. Then, a 12N aqueous solution of sodium hydroxide (12 ml) was added, and the mixture was added at 90 ° C.
Stir for 5 hours. After air cooling, the reaction solution was acidified by adding concentrated hydrochloric acid, and then diluted with water. The mixture was extracted with ethyl acetate. The organic layer was 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 benzhydrylthiol (2.93).
g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.28 (1H, d,
J = 5.0 Hz), 5.45 (1H, d, J = 5.2H)
z), 7.19-7.44 (10H, m).

Reference Example 39 Sodium hydride (60%: 0.63 g) was suspended in tetrahydrofuran (5.0 ml), and a solution of benzhydrylthiol (2.63 g) in tetrahydrofuran (15%) was obtained.
ml) was added. The mixture was stirred at room temperature for 1 hour. The resulting sodium salt suspension in tetrahydrofuran was added to bromochloromethane (8.49 g) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The generated salt was removed by filtration, and the filtrate was concentrated to obtain benzhydryl chloromethyl sulfide (3.45 g). ¹ H-NMR (CDCl ₃ ) δ: 4.49 (2H,
s), 5.50 (1H, s), 7.29-7.47 (1
0H, m).

Reference Example 40 2-Nitrophenol (4.00 g), 1-iodobutane (5.82 g) and potassium carbonate (4.77 g) were mixed with N, N-dimethylformamide, and the mixture was added at room temperature.
Stir for 8.5 hours. The reaction mixture was diluted with ethyl acetate. The mixture was mixed with water, 1N aqueous sodium hydroxide,
Washed sequentially with water and saturated saline. The organic layer was 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 butyl 2-nitrophenyl ether (5.50 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.3 Hz), 1.43-1.61 (2H, m),
1.75-1.89 (2H, m), 4.11 (2H,
t, J = 6.4 Hz), 6.96-7.09 (2H,
m), 7.51 (1H, ddd, J = 8.7, 7.3,
1.5 Hz), 7.81 (1H, dd, J = 8.0,
1.4 Hz).

Reference Example 41 Butyl 2-nitrophenyl ether (5.22 g) was dissolved in water: ethanol (1: 2, 180 ml), and sodium hydrosulfite (80%: 23.3 g) was dissolved.
Was added. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was slightly concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was 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 2-butoxyaniline (1.37 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.4 Hz), 1.51 (2H, sextet, J
= 7.4 Hz), 1.81 (2H, quint, J =
6.8 Hz), 3.79 (2H, brs), 4.00
(2H, t, J = 6.4 Hz), 6.66-6.83
(4H, m).

Reference Example 42 2-nitrophenol (4.24 g) and 2-tetrahydro-2-furanylethyl methanesulfonate (7.11)
g) and potassium carbonate (5.06 g) were mixed with N, N-dimethylformamide (60 ml) and stirred at 65 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed successively with water, a 1N aqueous solution of sodium hydroxide, water and saturated saline. The organic layer was 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 2- [2- (2
-Nitrophenoxy) ethyl] tetrahydrofuran (6.30 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.48-1.65
(1H, m), 1.82-2.18 (5H, m), 3.
68-3.93 (2H, m), 4.01-4.17 (1
H, m), 4.24 (2H, dd, J = 7.2, 5.6)
Hz), 7.00 (1H, td, J = 7.7, 1.2H)
z), 7.10 (1H, dd, J = 8.4, 1.0H
z), 7.51 (1H, ddd, J = 8.6, 7.4,
1.4 Hz), 7.82 (1H, dd, J = 8.0,
1.8 Hz). IR (KBr) 1609, 1526, 1489, 135
4,1281,1256,1088,747 cm ^-1 .

Reference Example 43 2- [2- (2-Nitrophenoxy) ethyl] tetrahydrofuran (3.20 g) was dissolved in methanol (50 ml), and 10% palladium-carbon (320 mg) was added. The reaction system was replaced with hydrogen and stirred vigorously at room temperature for 13 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 2- (2-tetrahydro-2-furanylethoxy) aniline (2.62 g) as a red oil. ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.64
(1H, m), 1.81-2.15 (5H, m), 3.
69-4.15 (7H, m), 6.65-6.83 (4
H, m).

Reference Example 44 2-Nitrophenol (4.00 g), 3-phenylpropyl bromide (5.72 g) and potassium carbonate (4.
37 g) in N, N-dimethylformamide (50 ml)
And stirred at room temperature for 20.5 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
-Phenylpropyl ether (7.13 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.16 (2H, d
q, J = 8.0, 6.4 Hz), 2.86 (2H, t,
J = 7.3 Hz), 4.08 (2H, t, J = 6.0H)
z), 6.97-7.04 (2H, m), 7.15-7.
33 (5H, m), 7.44-7.52 (1H, m),
7.84 (1H, dd, J = 8.4, 2.0 Hz).

Reference Example 45 2-Nitrophenyl 3-phenylpropyl ether (3.54 g) was dissolved in methanol (50 ml).
10% palladium on carbon (350 mg) was added. The reaction system was purged with hydrogen and stirred vigorously at room temperature for 15 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 2- (3-phenylpropoxy) aniline (2.6
8g) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 2.15 (2H, d
q, J = 8.6, 6.5 Hz), 2.83 (2H, t,
J = 7.7 Hz), 3.40 (2H, br), 4.01
(2H, t, J = 6.2 Hz), 6.65-6.83
(4H, m), 7.16-7.33 (5H, m).

Reference Example 46 2-Nitrophenol (5.03 g) and triphenylphosphine (9.48 g) were added to tetrahydrofuran (50
ml), and 3-ethoxypropanol (3.7).
7 g) at room temperature, followed by the addition of a toluene solution of diethyl azodicarboxylate (40%: 15.7 g) at 0 ° C. The mixture was stirred at room temperature for 13.5 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water, a 1N aqueous solution of sodium hydroxide, water, and saturated saline.
The organic layer was 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 1- (3-ethoxypropoxy) -2-nitrobenzene (7.62 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t,
J = 6.9 Hz), 2.09 (2H, quint, J =
6.1 Hz), 3.50 (2H, q, J = 7.1H)
z), 3.63 (2H, t, J = 6.1 Hz), 4.2
2 (2H, t, J = 6.1 Hz), 7.01 (1H, t
d, J = 7.6, 0.8 Hz), 7.10 (1H, d,
J = 8.4 Hz), 7.52 (1H, td, J = 7.
9, 1.7 Hz), 7.83 (1H, dd, J = 8.
1,1.5 Hz). IR (KBr) 1609, 1526, 1489, 135
4,1281,1258,1117,745 cm ^-1 .

Reference Example 47 1- (3-Ethoxypropoxy) -2-nitrobenzene (3.30 g) was dissolved in methanol (50 ml).
10% Palladium on carbon (300 mg) was added. The reaction system was replaced with hydrogen and stirred vigorously at room temperature for 13 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 2- (3-ethoxypropoxy) aniline (2.8
9g) was obtained as a red-brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t,
J = 7.1 Hz), 2.08 (2H, quint, J =
6.3 Hz), 3.36 (2H, br), 3.50 (2
H, q, J = 6.9 Hz), 3.61 (2H, t, J =
6.2 Hz), 4.10 (2H, t, J = 6.2H)
z), 6.66-6.82 (4H, m). IR (KBr) 2870, 1615, 1507, 127
7,1221,1115,741 cm ^-1 .

Reference Example 48 3-Hydroxymethylaniline (10.0 g) and imidazole (6.08 g) were dissolved in N, N-dimethylformamide, and tert-butyl (dimethyl) silyl chloride (13.5 g) was dissolved in N, N-dimethylformamide. A solution of N-dimethylformamide (50 ml) was added at 0 ° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
[[[Tert-butyl (dimethyl) silyl] oxy]
Methyl] aniline (17.68 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.10 (6H,
s), 0.94 (9H, s), 3.64 (2H, br)
s), 4.66 (2H, s), 6.54-6.59 (1
H, m), 6.68-6.72 (2H, m), 7.11.
(1H, t, J = 7.9 Hz). IR (KBr) 2955, 2930, 2857, 162
0, 1464, 1254, 1096, 1069, 83
7,775 cm ^-1 .

Reference Example 49 2-Nitrobenzyl bromide (4.25 g) was dissolved in dichloromethane (100 ml), and 1-propanol (11.8 g) and silver (I) oxide (4.56 g) were added. The mixture was stirred at room temperature for 69 hours. The reaction mixture was filtered through celite. The solvent was distilled off under reduced pressure of the filtrate,
The residue was purified by silica gel column chromatography,
2-Nitrobenzylpropyl ether (1.61 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.3 Hz), 1.69 (2H, nextet, J
= 7.1 Hz), 3.54 (2H, t, J = 6.7H)
z), 4.88 (2H, s), 7.39-7.46 (1
H, m), 7.64 (1H, td, J = 7.6, 1.2)
Hz), 7.82 (1H, d, J = 8.0 Hz), 8.
06 (1H, dd, J = 8.1, 1.1 Hz).

Reference Example 50 2-Nitrobenzylpropyl ether (2.02 g) was dissolved in methanol (50 ml), and 10% palladium-carbon (200 mg) and ammonium formate (4.89) were used.
g) was added. The mixture was stirred at room temperature for 64.5 hours.
The reaction mixture was poured into ether and filtered using celite. The solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2- (propoxymethyl) aniline (1.61 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t,
J = 7.3 Hz), 1.62 (2H, sextet, J
= 7.1 Hz), 3.40 (2H, t, J = 6.6H)
z), 4.18 (2H, br), 4.52 (2H,
s), 6.68 (1H, d, J = 7.6 Hz), 6.7.
0 (1H, td, J = 7.8, 1.0 Hz), 7.06
(1H, d, J = 8.4 Hz), 7.13 (1H, t
d, J = 7.7, 1.6 Hz).

Reference Example 51 2- (2-nitrophenyl) acetic acid (2.70 g), ethylamine hydrochloride (6.08 g) and 1-ethyl-3-
(3-Dimethylaminopropyl) -carbodiimide hydrochloride (3.14 g) was added to N, N-dimethylformamide (3
0 ml) and diisopropylethylamine (1
3.0 ml) was added at room temperature. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated saline, respectively. The organic layer was 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 N-ethyl-2- (2-nitrophenyl) acetamide (1.11 g) as colorless crystals. mp 138-139 ° C. Elemental analysis value as C ₁₀ H ₁₂ N ₂ O ₃ Calcd. : C, 57.68; H, 5.81; N, 13.45. Found: C, 57.67; H, 5.76; N, 13.40. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t,
J = 7.2 Hz), 3.29 (2H, qd, J = 7.
2,5.6 Hz), 3.82 (2H, s), 5.81
(1H, br), 7.41-7.65 (3H, m),
8.04 (1H, dd, J = 8.3, 1.3 Hz).

Reference Example 52 N-ethyl-2- (2-nitrophenyl) acetamide (1.87 g) was dissolved in methanol (50 ml).
10% Palladium on carbon (200 mg) and ammonium formate (4.25 g) were added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ether and filtered using celite. The solvent was distilled off from the filtrate under reduced pressure, and the precipitated crystals were washed with ethyl acetate-hexane and washed with N-ethyl-hexane.
2- (2-aminophenyl) acetamide (1.52
g) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t,
J = 7.3 Hz), 2.7-4.1 (2H, br),
3.24 (2H, qd, J = 7.3, 5.8 Hz),
5.46 (2H, s), 5.64 (1H, br),
72 (1H, d, J = 7.6 Hz), 6.74 (1H,
t, J = 7.5 Hz), 7.03 (1H, d, J = 7.
0 Hz), 7.11 (1H, td, J = 7.6, 1.5)
Hz).

Reference Example 53 2- (2-nitrophenyl) acetic acid (4.92 g) and 1
-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (5.73 g) was mixed with N, N-dimethylformamide (55 ml) and diethylamine (5.6 ml) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give N, N-diethyl-2-.
(2-Nitrophenyl) acetamide (2.97 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t,
J = 7.1 Hz), 1.30 (3H, t, J = 7.1H)
z), 3.40 (2H, q, J = 6.9 Hz), 3.4
4 (2H, q, J = 6.9 Hz), 4.05 (2H,
s), 7.35 (1H, d, J = 7.4 Hz), 7.4
3 (1H, td, J = 7.8, 1.5 Hz), 7.57
(1H, td, J = 7.3, 1.5 Hz), 8.09
(1H, dd, J = 8.1, 1.5 Hz).

Reference Example 54 N, N-diethyl-2- (2-nitrophenyl) acetamide (2.95 g) was dissolved in methanol (50 ml), and 10% palladium-carbon (295 mg) and ammonium formate (5.91 g) were dissolved. ) Was added. The mixture was stirred at room temperature for 63.5 hours. Pour the reaction mixture into ether,
It was filtered using Celite. The solvent was distilled off from the filtrate under reduced pressure, and the precipitated crystals were washed with ethyl acetate-hexane.
N, N-Diethyl-2- (2-aminophenyl) acetamide (2.52 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t,
J = 7.2 Hz), 1.16 (3H, t, J = 7.1H)
z), 2.9-4.0 (2H, br), 3.36 (2
H, q, J = 7.1 Hz), 3.45 (2H, q, J =
7.2 Hz), 3.63 (2H, s), 6.66-6.
72 (2H, m), 6.99-7.10 (2H, m).

Reference Example 55 2- (2-nitrophenyl) acetic acid (3.90 g) and 1
-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (4.95 g) is suspended in N, N-dimethylformamide (35 ml), and the N, N of 1-piperazinecarbaldehyde (3.69 g) is suspended. -Dimethylformamide solution (10 ml) was added at room temperature. The mixture was stirred at room temperature for 42.5 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was 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 4- [2- (2-nitrophenyl).
Acetyl] -1-piperazinecarbaldehyde (3.7
7g) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 3.42 to 3.69
(8H, m), 4.10 (2H, s), 7.35 (1
H, d, J = 7.4 Hz), 7.48 (1H, td, J)
= 7.8, 1.5 Hz), 7.61 (1H, td, J =
7.5, 1.6 Hz), 8.12 (1H, s), 8.1
4 (1H, dd, J = 7.4, 1.4 Hz).

Reference Example 56 4- [2- (2-Nitrophenyl) acetyl] -1-piperazinecarbaldehyde (3.75 g) was dissolved in methanol (65 ml), and 10% palladium-carbon (3
75 mg) and ammonium formate (4.26 g). The mixture was stirred at room temperature for 26 hours. The reaction mixture was poured into ether and filtered using celite. The solvent was distilled off from the filtrate under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate-hexane to give 4- [2- (2-aminophenyl) acetyl] -1.
-Piperazine carbaldehyde (2.60 g) was obtained as colorless crystals. mp 132-135 ° C. Elemental analysis value: C ₁₃ H ₁₇ N ₃ O ₂ Calcd. : C, 63.14; H, 6.93; N, 16.99. Found: C, 62.98; H, 6.85; N, 16.77. ¹ H-NMR (CDCl ₃ ) δ: 3.17 (1H, t,
J = 5.1 Hz), 3.30-3.41 (2H, m),
3.50-3.66 (5H, m), 3.69 (2H,
s), 4.37 (2H, brs), 6.70 (1H,
d, J = 7.8 Hz), 6.72 (1H, t, J = 7.
0 Hz), 7.01 (1H, d, J = 7.6 Hz),
7.09 (1H, td, J = 7.7, 1.4 Hz),
8.05 (1H, s).

Reference Example 57 2-Nitrophenylacetic acid (4.75 g) and 1-ethyl-
3- (3-Dimethylaminopropyl) -carbodiimide hydrochloride (6.03 g) was suspended in N, N-dimethylformamide (50 ml), and morpholine (2.74 g) was added at room temperature. The mixture was stirred at room temperature for 64.5 hours.
The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to give 4-[(2-nitrophenyl) acetyl] morpholine (4.61 g) as pale yellow crystals. Obtained. mp 137 ° C. Elemental analysis value: C ₁₂ H ₁₄ N ₂ O ₄ Calcd. : C, 57.59; H, 5.64; N, 11.19. Found: C, 57.60; H, 5.77; N, 11.08. ¹ H-NMR (CDCl ₃ ) δ: 3.59-3.80
(8H, m), 4.06 (2H, s), 7.35 (1
H, dd, J = 7.3, 1.5 Hz), 7.46 (1
H, td, J = 7.7, 1.5 Hz), 7.60 (1
H, td, J = 7.4, 1.3 Hz), 8.12 (1
H, dd, J = 8.0, 1.4 Hz).

Reference Example 58 4-[(2-Nitrophenyl) acetyl] morpholine (2.46 g) was dissolved in methanol (40 ml).
10% Palladium on carbon (250 mg) and ammonium formate (3.10 g) were added at room temperature, respectively. The mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into ether and stirred at room temperature. The mixture was filtered using celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-hexane to give 4-[(2-aminophenyl) acetyl] morpholine (1.89 g) as colorless crystals. Obtained. mp 102 ° C. Elemental analysis value: C ₁₂ H ₁₆ N ₂ O ₂ Calcd. : C, 65.43; H, 7.32; N, 12.72. Found: C, 65.42; H, 7.24; N, 12.55. ¹ H-NMR (CDCl ₃ ) δ: 3.59-3.65
(10H, m), 4.43 (2H, br), 6.67-
6.74 (2H, m), 6.90 (1H, dd, J =
7.0, 0.8 Hz), 7.07 (1H, t, J = 7.
7 Hz).

Reference Example 59 Anthranilic acid (3.92 g) and 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide hydrochloride (6.58 g) was added to N, N-dimethylformamide (55
ml) and morpholine (2.99 g) was added at room temperature. The mixture was stirred at room temperature for 64 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed sequentially with water and saturated saline. The aqueous layer was extracted with ethyl acetate. These organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate to obtain 4- (2-aminobenzoyl) morpholine (4.95 g) as colorless crystals. mp 75-76 ° C. Elemental analysis value as C ₁₁ H ₁₄ N ₂ O ₂ Calcd. : C, 64.06; H, 6.84; N, 13.58. Found: C, 64.02; H, 7.06; N, 13.44. ¹ H-NMR (CDCl ₃ ) δ: 3.66-3.73
(8H, m), 4.34 (2H, brs), 6.68-
6.75 (2H, m), 7.07 (1H, dd, J =
7.8, 1.6 Hz), 7.18 (1H, td, J =
7.7, 1.7 Hz).

Reference Example 60 Anthranilic acid (4.11 g), 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide hydrochloride
(6.89 g) and 1-hydroxy-1H-benzotri
Azole monohydrate (5.51 g) was added to N, N-dimethylphos.
Dissolve it in Lumamide (60ml) and add benzhydryl alcohol
Min (6.59 g) was added. Mixture at room temperature for 27 hours
Stirred. The reaction mixture was concentrated under reduced pressure.
Chill added. The mixture is washed with water, saturated sodium bicarbonate
Washed sequentially with an aqueous solution of water, water and saturated saline. Organic layer
It was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure
The precipitated crystals were washed with ethyl acetate-hexane,
Further, recrystallization with ethanol-ethyl acetate
No-N-benzhydrylbenzoic acid amide (5.65 g)
Was obtained as colorless crystals. mp 155-156 ° C. Elemental analysis value C₂₀H₁₈N₂O as Calcd. : C, 79.44; H, 6.00; N, 9.26. Found: C, 79.13; H, 5.98; N, 9.29.¹ H-NMR (CDCl₃) Δ: 5.56 (2H, br)
s), 6.37 (1H, d, J = 7.2 Hz), 6.5.
6 (1H, d-like), 6.65 (1H, t, J =
7.9 Hz), 6.68 (1H, d, J = 8.2H)
z), 7.18-7.42 (12H, m). IR (KBr) 1634, 1618, 1586, 151
6,750,700cm ^-1.

Reference Example 61 Anthranilic acid (2.74 g), 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide hydrochloride (4.60 g) and 1-hydroxy-1H-benzotriazole monohydrate (3.67 g) were dissolved in N, N-dimethylformamide (40 ml). Diphenylethylamine (4.73 g) was added. The mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then recrystallized from ethyl acetate-hexane to give 2-amino-N- (2,2
-Diphenylethyl) benzoic acid amide (5.57 g) was obtained as colorless crystals. mp 142-143 ° C. Elemental analysis value: C ₂₁ H ₂₀ N ₂ O Calcd. : C, 79.72; H, 6.37; N, 8.85. Found: C, 79.53; H, 6.46; N, 8.79. ¹ H-NMR (CDCl ₃ ) δ: 4.05 (2H, d
d, J = 7.7, 5.9 Hz), 4.30 (1H, t,
J = 8.1 Hz), 5.40 (2H, brs), 5.9
7 (1H, br), 6.54 (1H, t, J = 7.5H)
z), 6.64 (1H, d, J = 8.0 Hz), 6.9
8 (1H, d, J = 8.0 Hz), 7.15 (1H, t
d, J = 7.6, 1.4 Hz), 7.19-7.37
(10H, m). IR (KBr) 1634, 1615, 1586, 152
6,1495,1451,1262,752,700c
m ^-1 .

Reference Example 62 Anthranilic acid (2.74 g), 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide hydrochloride
(4.60 g) and 1-hydroxy-1H-benzotri
Azole monohydrate (3.67 g) was added to N, N-dimethylphos.
Dissolved in lumamide (40 ml).
Lepropylamine (5.07 g) was added. Mix room
Stirred at room temperature for 15 hours. Dilute the reaction mixture with ethyl acetate
Water, saturated aqueous sodium bicarbonate solution, water and saturated
Washed sequentially with brine. Organic layer with anhydrous magnesium sulfate
Dried. The solvent was distilled off under reduced pressure, and then ethyl acetate was added.
And recrystallized with 2-amino-N- (3,3-diphenyl
(Propyl) benzoic acid amide (4.65 g) as colorless crystals
As obtained. mp 118 ° C. Elemental analysis value C₂₂H₂₂N₂O as Calcd. : C, 79.97; H, 6.71; N, 8.48. Found: C, 79.79; H, 6.84; N, 8.44.¹ H-NMR (CDCl₃) Δ: 2.40 (2H, q,
J = 7.2 Hz), 3.42 (2H, q, J = 6.5H)
z), 4.03 (1H, t, J = 8.1 Hz), 5.4
8 (2H, br), 5.90 (1H, br), 6.58
(1H, t, J = 7.8 Hz), 6.65 (1H, d,
J = 8.4 Hz), 7.00 (1H, d, J = 7.8H)
z), 7.14-7.38 (11H, m). IR (KBr) 1636, 1584, 1526, 149
3,748,702cm ^-1.

Reference Example 63 Sodium hydride (60%: 3.96 g) was suspended in N, N-dimethylformamide (100 ml), and phthalimide (16.2 g) was added at 0 ° C. After the mixture was stirred at 0 ° C. for 30 minutes, cinnamyl chloride (95%: 1)
6.1 g) at 0 ° C. over 15 minutes. N, N-dimethylformamide (50 ml) was added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate to give 2-[(E) -3-phenyl-2.
-Propenyl] -1H-isoindole-1,3 (2
H) -dione (20.17 g) was obtained as colorless crystals.
4.91 g of the second crystal was obtained. Total yield: 25.08
g. mp 154-155 ° C. Elemental analysis value as C ₁₇ H ₁₃ NO ₂ Calcd. : C, 77.55; H, 4.98; N, 5.32. Found: C, 77.43; H, 5.15; N, 5.25. ¹ H-NMR (CDCl ₃ ) δ: 4.45 (2H, d
d, J = 6.2, 1.2 Hz), 6.26 (1H, d
t, J = 15.8, 6.4 Hz), 6.67 (1H,
d, J = 16.2 Hz), 7.22-7.39 (5H,
m), 7.70-7.77 (2H, m), 7.83-7.
89 (2H, m). IR (KBr) 1771, 1705, 1427, 139
2,1107,955,727 cm ^-1 .

Reference Example 64 2-[(E) -3-phenyl-2-propenyl] -1H
-Isoindole-1,3 (2H) -dione (7.91
g) was suspended in ethanol (150 ml) and hydrazine monohydrate (4.51 g) was added. The mixture was stirred at 90 ° C. for 1.5 hours. After adding a saturated aqueous solution of sodium hydrogen carbonate and water to the reaction mixture, the mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain cinnamylamine (containing ether, 5.82).
g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.48 (2H, d
d, J = 5.7, 1.3 Hz), 6.32 (1H, d
t, J = 16.0, 5.7 Hz), 6.51 (1H,
d, J = 16.0 Hz), 7.18-7.40 (5H,
m), NH ₂ has not been identified.

Reference Example 65 Anthranilic acid (2.74 g) was dissolved in N, N-dimethylformamide (20 ml), and a cinnamylamine (all amounts described above) in N, N-dimethylformamide (4.
0 ml), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (11.5 g) and 1-
Hydroxy-1H-benzotriazole monohydrate (3.
67g) was added. The mixture was stirred at room temperature for 15.5 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 2-amino-N-[(E) -3-phenyl-2-propenyl] benzoic acid amide (3.72 g) as colorless crystals. Obtained. mp 120-121 ° C. Elemental analysis value: C ₁₆ H ₁₆ N ₂ O Calcd. : C, 76.16; H, 6.39; N, 11.10. Found: C, 76.15; H, 6.25; N, 11.14. ¹ H-NMR (CDCl ₃ ) δ: 4.21 (2H, t
d, J = 6.0, 1.2 Hz), 5.55 (2H, br)
s), 6.19 (1H, br), 6.29 (1H, d
t, J = 15.8, 6.3 Hz), 6.56-6.71.
(3H, m), 7.18-7.41 (7H, m). IR (KBr) 1634, 1615, 1584, 152
0,1260,748 cm ^-1 .

Reference Example 66 Anthranilic acid (2.54 g), 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide hydrochloride (5.75 g) and 1-hydroxy-1H-benzotriazole monohydrate (4.59 g) were dissolved in N, N-dimethylformamide (50 ml), and 3-aminobiphenyl (3.45 g) was added. The mixture was stirred at room temperature for 61 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then recrystallized from ethyl acetate-hexane to remove unnecessary substances. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-amino-N- (1,1'-biphenyl) -3-
Ilbenzoic acid amide (3.81 g) was obtained as colorless crystals. Further, a part of the compound was recrystallized from ethyl acetate-diisopropyl ether-hexane to give the same compound (1.3).
9g) were obtained as colorless crystals. mp 114 ° C. Elemental analysis value: C ₁₉ H ₁₆ N ₂ O Calcd. : C, 79.14; H, 5.59; N, 9.72. Found: C, 79.00; H, 5.59; N, 9.53. ¹ H-NMR (CDCl ₃ ) δ: 5.52 (2H, br
s), 6.70-6.77 (2H, m), 7.23-7.
64 (10H, m), 7.82 (1H, brs), 7.
82 (1H, brs). IR (KBr) 1651, 1613, 1584, 153
7,1481 cm ^-1 .

Reference Example 67 Sodium hydride (60%: 1.22 g) was suspended in N, N-dimethylformamide (15 ml), and a solution of 3-methoxythiophenol (3.90 g) in N, N-dimethylformamide was obtained. (30 ml) was added dropwise at 0 ° C. After the mixture was stirred at 0 ° C for 10 minutes, 1-fluoro-2-nitrobenzene (3.92 g) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 3-methoxyphenyl-2'-nitrophenyl sulfide (6.99).
g) was obtained as yellow crystals. mp 121-122 ° C. Elemental analysis value as C ₁₃ H ₁₁ NO ₃ S Calcd. : C, 59.76; H, 4.24; N, 5.36. Found: C, 59.68; H, 4.12; N, 5.45. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H,
s), 6.92 (1H, dd, J = 8.3, 1.3H)
z), 7.03 (1H, ddd, J = 8.4, 2.6,
1.1 Hz), 7.11-7.26 (3H, m), 7.
31-7.44 (2H, m), 8.23 (1H, dd,
J = 8.1, 1.5 Hz).

Reference Example 68 3-Methoxyphenyl-2'-nitrophenyl sulfide (5.05 g) was dissolved in tetrahydrofuran: methanol (1: 1, 60 ml), and water (50 ml) was added. Then, potassium carbonate (16.0 g) and sodium hydrosulfite (80%: 16.8 g) were added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-aminophenyl-3'-methoxyphenyl sulfide (2.56 g) as an orange oil. ¹ H-NMR (CDCl ₃ ) δ: 3.72 (3H,
s), 4.0-4.5 (2H, br), 6.63-6.8.
1 (5H, m), 7.13 (1H, td, J = 7.6,
1.5 Hz), 7.24 (1H, ddd, J = 8.0,
7.4, 1.5 Hz), 7.45 (1H, dd, J =
7.6, 1.4 Hz).

Reference Example 69 Sodium hydride (60%: 1.21 g) was suspended in N, N-dimethylformamide (15 ml), and a solution of 2-mercaptopyridine (3.05 g) in N, N-dimethylformamide ( 30 ml) was added dropwise at room temperature. After stirring the mixture at room temperature for 15 minutes, 1-fluoro-2-nitrobenzene (3.87 g) was added dropwise at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to obtain 2-nitrophenyl 2-pyridinyl sulfide (5.47 g) as yellow crystals. 0.43 g was obtained as the second crystal. Total yield: 5.90 g. mp 72 ° C. Elemental analysis value: C ₁₁ H ₈ N ₂ O ₂ S Calcd. : C, 56.88; H, 3.47; N, 12.06. Found: C, 56.74; H, 3.62; N, 11.97. ¹ H-NMR (CDCl ₃ ) δ: 7.23-7.53
(5H, m), 7.71 (1H, td, J = 7.7,
1.9 Hz), 8.14 (1H, dd, J = 7.6,
1.8 Hz), 8.60 (1H, ddd, J = 4.8,
1.9, 0.8 Hz).

Reference Example 70 2-nitrophenyl 2-pyridinyl sulfide (3.7
2 g) in tetrahydrofuran: methanol (1: 1, 5
0 ml) and water (50 ml) was added. Then, potassium carbonate (13.3 g) and sodium hydrosulfite (80%: 13.9 g) were added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
Pyridinyl sulfide (1.26 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 4.37 (2H, br
s), 6.72-6.85 (3H, m), 6.99 (1
H, ddd, J = 7.4, 4.8, 1.1 Hz), 7.
24-7.33 (1H, m), 7.43 (1H, td,
J = 7.8, 2.0 Hz), 7.50 (1H, dd, J
= 7.7, 1.5 Hz), 8.42 (1H, ddd, J)
= 4.9, 1.9, 0.9 Hz).

Reference Example 71 Thiophene-2-thiol (10.47 g) and 10%
To a mixture of aqueous sodium hydroxide solution (100 ml) was added tetrabutylammonium bromide (1.45 g),
Stir at room temperature for 5 minutes. A toluene solution (100 ml) of 1-fluoro-2-nitrobenzene (12.7 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline, respectively. The organic layer was 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 2-nitrophenyl 2-thienyl sulfide (21.15 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 6.96 (1H, d
d, J = 8.3, 1.3 Hz), 7.20 (1H, d
d, J = 5.4, 3.6 Hz), 7.20-7.31
(1H, m), 7.36-7.47 (2H, m), 7.
66 (1H, dd, J = 5.3, 1.3 Hz), 8.2
6 (1H, dd, J = 8.0, 1.4 Hz).

Reference Example 72 2-nitrophenyl 2-thienyl sulfide (11.0
0 g) was dissolved in acetic acid (88 ml) and reduced iron (33.
0g) was added at 0 ° C. The reaction was completed immediately upon stirring the mixture at room temperature. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was washed with a 1N aqueous sodium hydroxide solution, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated saline solution. The organic layer was 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 2-aminophenyl 2-thienyl sulfide (8.23 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 4.33 (2H, b
r), 6.68 (1H, dd, J = 7.4, 1.6H)
z), 6.72 (1H, d, J = 7.4 Hz), 6.9
4 (1H, dd, J = 5.3, 3.5 Hz), 7.10
-7.18 (2H, m), 7.26-7.29 (1H,
m), 7.38-7.42 (1H, m).

Reference Example 73 4-[(2-Nitrophenyl) sulfanyl] phenol (2.48 g) was converted to N, N-dimethylformamide (2
0 ml), and potassium carbonate (3.32 g) and bromoethyl ethyl ether (2.86 ml) were added, respectively. The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, a 1 N aqueous solution of sodium hydroxide, water, and saturated saline, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 1-nitro-2-[[4- (2-ethoxyethoxy) phenyl] sulfanyl] benzene (3.01 g) as a yellow oil. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t,
J = 6.9 Hz), 3.63 (2H, q, J = 6.9H)
z), 3.84 (2H, t, J = 4.8 Hz), 4.1
8 (2H, t, J = 4.8 Hz), 6.81 (1H, d
d, J = 8.4, 1.4 Hz), 7.00-7.07
(2H, m), 7.15 (1H, td, J = 7.7,
1.4 Hz), 7.33 (1H, td, J = 7.7,
1.8Hz), 7.46-7.53 (2H, m), 8.
23 (1H, dd, J = 8.1, 1.5 Hz). IR (KBr) 1593, 1516, 1493, 133
9, 1304, 1250 cm ^-1 .

Reference Example 74 1-Nitro-2-[[4- (2-ethoxyethoxy) phenyl] sulfanyl] benzene (2.99 g), calcium chloride (0.52 g) and reduced iron (3.66 g) were mixed in 85 parts by weight. % Ethanol (100 ml) and stirred at 95 ° C. for 3 hours. After air cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and saturated saline, respectively. The organic layer was 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 2-[[4- (2-ethoxyethoxy) phenyl] sulfanyl] aniline (2.25 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t,
J = 6.8 Hz), 3.58 (2H, q, J = 7.1H)
z), 3.76 (2H, t, J = 4.7 Hz), 4.0
7 (2H, t, J = 4.8 Hz), 4.26 (2H, b
r), 6.69-6.86 (4H, m), 7.01-7.
22 (3H, m), 7.39 (1H, d, J = 7.2H
z).

Reference Example 75 Tetrabutylammonium bromide (1.61 g) was added to a mixture of 2-aminothiophenol (12.5 g) and a 10% aqueous sodium hydroxide solution (100 ml).
A toluene solution (100 ml) of -bromoethyl ethyl ether (16.1 g) was added dropwise. Mixture at room temperature for 1.
Stir for 5 hours. The reaction mixture was neutralized with 1N hydrochloric acid, and ethyl acetate (500 ml) was added. The organic layer was separated and washed sequentially with water (150 ml × 2) and saturated saline (75 ml). The organic layer was 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 2-[(2-ethoxyethyl) sulfanyl] aniline (17.41 g) as an orange oil. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t,
J = 6.9 Hz), 2.91 (2H, t, J = 6.6H)
z), 3.48 (2H, q, J = 6.9 Hz), 3.5
3 (2H, t, J = 6.6 Hz), 4.41 (2H, b
r), 6.68 (1H, td, J = 7.4, 1.3H)
z), 6.72 (1H, dd, J = 8.0, 1.2H
z), 7.13 (1H, td, J = 7.7, 1.4H
z), 7.40 (1H, dd, J = 7.6, 1.4H
z).

Reference Example 76 Benzamidine hydrochloride (9.23 g) was added to ethanol (2
5 ml) and sodium methoxide (3.18).
g) was added. The mixture was stirred at room temperature for 5 minutes. The reaction mixture was filtered to remove the precipitated sodium chloride. α
-Methoxymethylene-β-formylaminopropionitrile (4.13 g) was dissolved in ethanol (30 ml) and a solution of benzamidine was added. Mix the mixture at room temperature for 1 hour.
The mixture was stirred for 9.5 hours and 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The mixture was washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethanol to give (4-amino-2-phenyl-5-pyrimidinyl) methylformamide (2.57
g) was obtained as white crystals. mp 216-217 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 4.17 (2H,
d, J = 6.2 Hz), 6.89 (2H, brs),
7.42-7.48 (3H, m), 8.13-8.15
(2H, m), 8.24-8.33 (2H, m), 8.
49 (1H, t-like). IR (KBr) 1659, 1537, 1406, 124
6 cm ^-1 .

Reference Example 77 (4-Amino-2-phenyl-5-pyrimidinyl) methylformamide (9.51 g) was obtained by adding methanol-THF.
(1: 1, 160 ml) and sodium hydroxide (16.7 g) and water (80 ml) were added. The mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and extracted five times with ether. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-IPE-hexane to give 5- (aminomethyl) -2-phenyl-4-pyrimidineamine (4.9).
1 g) were obtained as white crystals. The same treatment was carried out from the filtrate to obtain the second crystal (2.78 g). mp 94-95 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.91 (2H,
s), 6.09 (2H, brs), 7.41-7.47.
(3H, m), 8.13 (1H, s), 8.30-8.
35 (2H, m). IR (KBr) 1593, 1582, 1557, 144
2,1410 cm ^-1 .

Reference Example 78 5- (Aminomethyl) -2-phenyl-4-pyrimidineamine (6.36 g) was dissolved in water (50 ml), and concentrated hydrochloric acid (9.3 ml) was added. Sodium nitrite (2.
41 g) of an aqueous solution (10 ml) was added at 60 ° C. The mixture was stirred at 60 ° C. for 1.5 hours. Sodium hydroxide (5.1 g) was added at 0 ° C. to make the reaction mixture basic. The mixture was extracted three times with ether. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, recrystallized from ether, and (4-amino-2-phenyl-5-pyrimidinyl) methanol (5.25 g)
Was obtained as pale yellow crystals. mp 134 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.61 (2H,
s), 5.51 (2H, brs), 7.44-7.48.
(3H, m), 8.09 (1H, s), 8.28-8.
33 (2H, m). IR (KBr) 1622, 1595, 1557, 144
5,1410 cm ^-1 .

Reference Example 79 (4-Amino-2-phenyl-5-pyrimidinyl) methanol (4.42 g) was suspended in acetic acid (45 ml).
25% HBr-acetic acid (30 ml) was added. Mix 1
Stirred at 10 ° C. for 3 hours. The reaction mixture was air-cooled and ether was slowly added. The precipitated crystals were collected by filtration and washed with methanol to give 4-amino-5-bromomethyl-2-phenylpyrimidine hydrobromide (3.95 g) as white crystals. After allowing the mother liquor to stand, the same treatment as described above was performed to obtain the same compound (2.19 g) as white crystals. mp 197-200 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: around4
(2H, br), 4.77 (2H, s), 7.61-
7.72 (3H, m), 8.14-8.19 (2H,
m), 8.59 (1H, s).

Reference Example 80 Isopropylamidine hydrochloride (8.75 g) was dissolved in ethanol (20 ml), sodium methoxide (3.85 g) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove the precipitated sodium chloride. α-methoxymethylene-β-formylaminopropionitrile (5.00 g) was added to ethanol (2
5 ml) and a solution of isopropylamidine was added. The mixture was stirred at 60 C for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was allowed to stand for a while. The precipitated crystals were collected by filtration, and (4-amino-2-isopropyl-5-pyrimidinyl) methylformamide (3.09 g) was used.
Was obtained as crystals. mp 186-187 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.14 (3H,
t, J = 7.0 Hz), 2.53 (3H, s), 2.8
7 (2H, t, J = 6.5 Hz), 3.44 (2H,
q, J = 7.1 Hz), 3.50 (2H, t, J = 6.
2 Hz), 4.19 (2H, d, J = 5.2 Hz),
5.25 (1H, t-like), 5.38 (2H, b
rs), 6.72 (1H, d, J = 7.6 Hz), 6.
74 (1H, t, J = 7.1 Hz), 7.24 (1H,
t, J = 7.2 Hz), 7.46 (1H, dd, J =
7.9, 1.3 Hz), 8.15 (1H, s). IR (KBr) 1588, 1568, 1499, 145
3 cm ^-1 .

Reference Example 81 (4-amino-2-isopropyl-5-pyrimidinyl)
Methyl formic amide (5.13 g) was added to methanol-THF.
(1: 1, 80 ml), and an aqueous solution (40 ml) of sodium hydroxide (3.17 g) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to about half under reduced pressure, and extracted with ether (150 ml × 4).
The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 5-aminomethyl-2-isopropyl-4.
-Pyrimidineamine (4.27 g) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d,
J = 7.0 Hz), 2.88-3.02 (1H, m),
3.83 (2H, s), 5.99 (2H, br), 7.
98 (1H, s).

Reference Example 82 5-Aminomethyl-2-isopropyl-4-pyrimidineamine (4.25 g) was suspended in water (30 ml), and concentrated hydrochloric acid (4.3 ml) was added. Sodium nitrite (1.
94 g) of an aqueous solution (10 ml) was added at 60 ° C. over 15 minutes. The mixture was stirred at 60 ° C. for 1 hour. Sodium hydroxide (2.6 g) was added to make the reaction mixture basic,
Extracted with ether (150 ml × 5). The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
(4-amino-2-isopropyl-5-pyrimidinyl)
Methanol (3.98 g) was obtained as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d,
J = 6.8 Hz), 2.87-3.01 (1H, m),
4.58 (2H, s), 5.47 (2H, brs),
7.94 (1H, s.

Reference Example 83 (4-amino-2-isopropyl-5-pyrimidinyl)
10% HBr-acetic acid (50%) was added to methanol (3.96 g).
ml) and stirred at 110 ° C. for 3 hours. The reaction mixture was air-cooled, and the precipitated crystals were collected by filtration and dried to give 4-amino-5-bromomethyl-2-isopropylpyrimidine hydrobromide (4.99 g) as pale yellow crystals. mp 191-193 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 1.26 (6H,
t, J = 6.8 Hz), 2.97-3.11 (1H,
m), 4.68 (2H, s), 8.51 (1H, s),
8.70 (1H, brs), 9.38 (1H, br)
s).

Reference Example 84 4-Bromophenyl 2-nitrophenyl sulfide (4.65 g), phenylboronic acid (2.74 g) and potassium carbonate (4.97 g) were dissolved in toluene-water-ethanol (10: 1: 1, 180 ml) and stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakistriphenylphosphine palladium (0.87 g) was added and the mixture was stirred at 95 ° C. for 13.5 hours under an argon atmosphere.
Ethyl acetate (500 ml) was added, and the mixture was washed with water (150 ml) and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The organic layer was passed through silica gel, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to give [1,1′-biphenyl] -4-yl2-nitrophenyl sulfide (2.96 g). ) Was obtained as yellow crystals. Reduce the mother liquor under reduced pressure
After concentration, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to obtain the same compound (0.62 g) as yellow crystals. mp 112-113 ° C. ¹ H-NMR (CDCl ₃ ) δ: 6.97 (1H, d
d, J = 8.1, 1.1 Hz), 7.19-7.26
(1H, m), 7.33-7.53 (4H, m), 7.
62-7.73 (6H, m), 8.25 (1H, dd,
J = 8.4, 1.4 Hz). IR (KBr) 1593, 1514, 1478, 133
7, 1304, 762, 733 cm ^-1 .

Reference Example 85 [1,1′-Biphenyl] -4-yl2-nitrophenyl sulfide (3.48 g), calcium chloride (0.60 g)
3g) and reduced iron (4.43 g) were mixed in 85% ethanol (100 ml) and stirred at 95 ° C for 3 hours.
After air cooling, filtration was performed using Celite, and the precipitated crystals were collected by filtration to obtain 2-([1,1′-biphenyl] -4-ylsulfanyl) aniline (1.68 g) as pale yellow crystals. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were washed successively with water, methanol and ether to give the same compound (1.26).
g) was obtained as pale yellow crystals. mp 97-98 ° C (decomposition). ¹ H-NMR (CDCl ₃ ) δ: 4.33 (2H, br)
s), 6.80-6.84 (2H, m), 7.13-7.
52 (11H, m). IR (KBr) 1609, 1480, 760 cm ^-1 .

Reference Example 86 4-bromophenyl 2-nitrophenyl sulfide (5.00 g), 2-methoxyphenylboronic acid (2.
94g) and potassium carbonate (5.35g) in toluene
Water-ethanol (10: 1: 1, 120 ml)
The mixture was stirred at room temperature for 20 minutes under an argon atmosphere. Tetrakistriphenylphosphine palladium (0.93 g) was added and the mixture was stirred at 95 ° C. for 108 hours under an argon atmosphere. Ethyl acetate (600 ml) was added, and water (15
0 ml × 2) and saturated saline (75 ml × 2). The organic layer was 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 2′-methoxy [1,1′-biphenyl] -4-yl 2-nitrophenyl sulfide.
2'-methoxy [1,1'-biphenyl] -4 obtained
-Yl 2-nitrophenyl sulfide (total), calcium chloride (0.89 g) and reduced iron (6.29 g) in 8
Mix in 5% ethanol (150 ml),
Stirred for hours. After air cooling, the mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (500ml). The mixture was washed with water (150 ml × 2) and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 2- (2'-
Methoxy [1,1′-biphenyl] -4-ylsulfanyl) aniline (1.85 g) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.79 (3H,
s), 4.34 (2H, brs), 6.73-6.87.
(2H, m), 6.94-7.04 (2H, m), 7.
08-7.14 (2H, m), 7.21-7.51 (6
H, m).

Reference Example 87 4-bromophenyl 2-nitrophenyl sulfide (4.95 g), 4-ethoxyphenylboronic acid (5.
30 g) and potassium carbonate (5.29 g) in toluene.
Water-ethanol (10: 1: 1, 180 ml)
The mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakistriphenylphosphine palladium (0.74 g) was added and the mixture was stirred at 95 ° C. for 23.5 hours under an argon atmosphere. Ethyl acetate (500 ml) was added, and the mixture was washed successively with a 1N aqueous sodium hydroxide solution (100 ml), a saturated aqueous sodium carbonate solution (100 ml), water (150 ml × 2), and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate-diisopropyl ether and washed with 4'-methoxy [1,1'-biphenyl].
-4-yl 2-nitrophenyl sulfide (4.37
g) was obtained as yellow crystals. mp 169-170 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, t,
J = 7.0 Hz), 4.10 (2H, q, J = 7.0H)
z), 6.93-7.04 (3H, m), 7.22 (1
H, td, J = 7.6, 1.2 Hz), 7.36 (1
H, td, J = 7.6, 1.7 Hz), 7.54-7.
69 (6H, m), 8.24 (1H, dd, J = 8.
4,1.4 Hz).

Reference Example 88 4'-ethoxy [1,1'-biphenyl] -4-yl-
2-nitrophenyl sulfide (3.45 g), calcium chloride (0.54 g) and reduced iron (3.84 g)
Mix in 5% ethanol (150 ml),
Stir for 9 hours. The mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The precipitated crystals are collected by filtration, washed with water,
-(4'-Ethoxy [1,1'-biphenyl] -4-ylsulfanyl) aniline (1.68 g) was obtained as colorless crystals. mp 145-147 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t,
J = 7.0 Hz), 4.06 (2H, q, J = 6.9H)
z), 4.31 (2H, brs), 6.74-6.82
(2H, m), 6.91-6.95 (2H, m), 7.
11-7.16 (2H, m), 7.21-7.29 (1
H, m), 7.38-7.50 (5H, m). IR (K
Br) 3480, 3378, 1605, 1480, 12
52,1049 cm ^-1 .

Reference Example 89 To 2-methyl-5-[[2-[(2-nitrophenyl) sulfanyl] anilino] methyl] -4-pyrimidineamine (1.80 g) was added concentrated hydrochloric acid (15 ml).
Stirred at C for 6 hours. The reaction mixture was neutralized with a 12 N aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution, and water (150 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give 2-methyl-5-
[[2-[(2-Nitrophenyl) sulfanyl] anilino] methyl] -4-pyrimidinol (284 mg) was obtained as yellow crystals. mp 200-206 ° C (decomposition). ¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H,
s), 4.22 (2H, d, J = 6.6 Hz), 5.5
6 (1H, t, J = 6.2 Hz), 6.73-6.82
(3H, m), 7.12-7.19 (1H, m), 7.
31-7.48 (3H, m), 7.78 (1H, s),
8.18 (1H, dd, J = 8.0, 1.4 Hz). IR (KBr) 1661, 1591, 1514, 133
7, 1306, 735 cm ^-1 .

Reference Example 90 2-methyl-5-[[2-[(2-nitrophenyl) sulfanyl] anilino] methyl] -4-pyrimidinol (223 mg) was suspended in dimethylaniline (10 ml). (0.6 ml) was added. The mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was added to ice water (1
0 g), water (150 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N-[(4-amino-2-
Chloro-5-pyrimidinyl) methyl] -N- [2-
[(2-Nitrophenyl) sulfanyl] phenyl] amine (61 mg) was obtained as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H,
s), 4.43 (2H, t, J = 6.2 Hz), 5.4
4 (1H, t, J = 6.5 Hz), 6.56 (1H,
d, J = 8.4 Hz), 6.78-6.88 (2H,
m), 7.16-7.43 (3H, m), 7.53 (1
H, dd, J = 7.4, 1.2 Hz), 8.28 (1
H, s), 8.30 (1H, d, J = 5.8 Hz).

Reference Example 91 4-methoxythiophenol (5.61 g) and 20%
To a mixture of aqueous sodium hydroxide solution (30 ml) was added tetrabutylammonium bromide (0.65 g).
The mixture was stirred at room temperature for 5 minutes. Toluene solution (30 ml) of 2,5-dichloronitrobenzene (7.68 g)
Was added. The mixture was stirred at room temperature for 1 hour. Ethyl acetate (400 ml) was added, and the mixture was washed sequentially with water (150 ml), a saturated aqueous solution of sodium carbonate (100 ml), water (100 ml), and saturated saline (75 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was recrystallized from ethyl acetate-diisopropyl ether to give 4-[(4-chloro-2-nitrophenyl) sulfanyl] phenylmethyl ether (10.0 g) as orange crystals. mp 96-97 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.88 (3H,
s), 6.76 (1H, d, J = 8.8 Hz), 7.0
1 (2H, d, J = 8.4 Hz), 7.29 (1H, d
d, J = 8.8, 2.2 Hz), 7.49 (2H, d,
J = 8.6 Hz), 8.23 (1H, d, J = 2.2H)
z).

Reference Example 92 4-[(4-Chloro-2-nitrophenyl) sulfanyl] phenyl methyl ether (4.22 g), calcium chloride (0.77 g) and reduced iron (5.45 g) were mixed with 85
% Ethanol (70 ml) and stirred at 95 ° C. for 4 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and ethyl acetate (300 ml) was added. The mixture was washed with water (100 ml × 2) and saturated saline (75 ml).
And washed. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-2-[(4-
Methoxyphenyl) sulfanyl] aniline (3.73
g) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 3.77 (3H,
s), 4.34 (2H, brs), 6.65-6.83.
(4H, m), 7.09-7.14 (2H, m), 7.
32 (1H, d, J = 8.0 Hz).

Reference Example 93 (4-Chloro-2-methyl-5-pyrimidinyl) methylcarbamate benzyl (5.00 g) was dissolved in ethanol (85 ml), and pyrrolidine (4.3 ml) and triethylamine (7.2 ml). Was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water (200 ml) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate.
[2-Methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methylcarbamatebenzyl (5.09 g) was obtained as colorless crystals. mp 125 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.88-1.95
(4H, m), 2.47 (3H, s), 3.59-3.
66 (4H, m), 4.37 (2H, d, J = 5.0H
z), 4.78 (1H, br), 5.13 (2H,
s), 7.35 (5H, s), 7.98 (1H, s). IR (KBr) 1717, 1588, 1537, 145
4,1441 cm ^-1 .

Reference Example 94 [2-Methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methylcarbamatebenzyl (4.86 g) was dissolved in methanol (100 ml), and 10% palladium-carbon (0.73 g) was dissolved. Was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give [2-methyl-4-
(1-Pyrrolidinyl) -5-pyrimidinyl] methanamine (2.81 g) was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.93-2.00
(4H, m), 2.48 (3H, s), 3.70-3.
77 (4H, m), 3.83 (2H, s), 7.96
(1H, s). IR (KBr) 1590, 1539, 1445c
m ^-1 .

Reference Example 95 [2-Methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methanamine (2.79 g) was added to concentrated hydrochloric acid (2.4).
ml) and water (25 ml), and an aqueous solution (7.0 ml) of sodium nitrite (1.10 g) was added at 60 ° C for 5 minutes.
Then, the mixture was stirred for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and the mixture was saturated with potassium carbonate. The mixture was extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ether.
Methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methanol (2.77 g) was obtained as colorless crystals. mp 129-131 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.93-1.99
(4H, m), 2.46 (3H, s), 3.75-3.
82 (4H, m), 4.57 (2H, s), 7.81
(1H, s). IR (KBr) 1590, 1539, 1474, 143
7 cm ^-1 .

Reference Example 96 [2-Methyl-4- (1-pyrrolidinyl) -5-pyrimidinyl] methanol (2.57 g) was dissolved in 10% hydrobromic acid-acetic acid (30 ml), and the mixture was dissolved at 110 ° C. for 3 hours. Stirred. The reaction mixture was concentrated under reduced pressure to obtain 5-bromomethyl-2-methyl-4- (1-pyrrolidinyl) pyrimidine hydrobromide (4.36 g) as a black solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.98 (4H,
br), 2.51 (3H, s), 3.96 (4H, b
r), 4.91 (2H, s), 8.50 (1H, s).

Reference Example 97 5-Bromomethyl-2-methyl-4- (1-pyrrolidinyl) pyrimidine hydrobromide (2.12 g) was added to THF.
(60 ml) and potassium carbonate (4.35 g)
And 2-iodoaniline (2.76 g) were added. The mixture was stirred at 70 ° C. for 12 hours. Ethyl acetate (600m
l), water (150 ml × 2) and saturated saline (1
00 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and further recrystallized from ethyl acetate-diisopropyl ether to give 2-iodo-N-[[2-methyl-4- (1-pyrrolidinyl). -5
-Pyrimidinyl] methyl] aniline (1.67 g) was obtained as colorless crystals. mp 107 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.88-1.95
(4H, m), 2.52 (3H, s), 3.67-3.
73 (4H, m), 4.19 (3H, brs), 6.5
1 (1H, t, J = 7.7 Hz), 6.61 (1H,
d, J = 8.2 Hz), 7.25 (1H, t, J = 7.
9Hz), 7.69 (1H, dd, J = 7.6, 1.6)
Hz), 8.05 (1H, s). IR (KBr) 1586, 1539, 1497, 144
9,1439cm ^-1 .

Reference Example 98 A solution of 4-fluorobenzylamine (15 ml) in tetrahydrofuran (40 ml) was cooled to 0 ° C., and 4-amino-5-bromomethyl-2-methylpyrimidine hydrobromide (3.8 g) was added. Added over 15 minutes. The temperature was gradually raised to room temperature and stirred for 12 hours. After concentration, the residue was subjected to silica gel chromatography. Crystals formed by adding isopropyl ether are collected by filtration and 5-[[(4-fluorobenzyl) amino] methyl] -2-methylpyrimidine-4.
-The amine (2.20 g) was obtained as colorless crystals. mp. 111-112 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.49 (3H,
s), 3.71 (2H, s), 3.72 (2H, s),
6.12 (1H, s, broad), 6.98-7.0
8 (2H, m), 7.21-7.27 (2H, m),
7.93 (1H, s).

Reference Example 99 2,6-dimethyl-3,5-heptanedione (2.1 m
To a solution of 1) in ethanol (30 ml) was added hydrazine hydrochloride (0.91 g) and sodium acetate (1.10 g). The mixture was heated under reflux for 2 hours. The mixture was concentrated, and water and ethyl acetate were added thereto to carry out liquid separation. The organic layer was dried with sodium sulfate. The residue was subjected to silica gel column chromatography to obtain 3,5-diisopropylpyrazole (1.30 g) as colorless crystals. mp. 89-90 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.27 (12H,
d, J = 7.0 Hz) 2.91 (1H, q, J = 7.0)
Hz), 2.98 (1H, q, J = 7.0 Hz), 5.
88 (1H, s).

Formulation Example 1 A GRK inhibitor containing a compound represented by the formula (I) or a salt thereof according to the present invention as an active ingredient (eg, a therapeutic agent for heart failure, etc.) can be produced, for example, by the following formulation. Can be. After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule. 2/3 of (1), (2), (3), (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Formulation Example 2 50 mg of the compound obtained in Example 15 was dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection.
Make it 00 ml. The solution is filtered under sterile conditions, then 1 ml each of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.

Experimental Example 1 In order to evaluate the GRK-dependent phosphorylation inhibitory action of a compound, an in vitro phosphorylation assay was performed. The experimental method was performed by partially modifying the method of Cork et al. (Journal of Biological Chemistry, vol. 268, pages 8256-8260). That is, as the phosphorylation substrate, rhodopsin in ROS (rod visual cell outer segment) prepared from bovine retina was used, and as human GRK2, human GRK2 gene was added to COS-7 cells (Benovic et al., FEBS Letter, vol. 283). , Pp. 122-126), and used as a cytoplasmic fraction, using G protein bg subunit (G _bg ).
Was used as a 5 mM EDT
A, including 5 mM MgCl ₂ , 0.3 mM ATP (including 20 μCi [γ- ³² P] -ATP), 14 μg GRK2, 20 μg ROS, 200 nM G _βγ 5
The phosphorylation of rhodopsin by GRK2 was induced by irradiating light to a 0 mM Tris-HCl buffer (30 μl) and incubating at room temperature for 10 minutes. The compound is N,
It was dissolved in N-dimethylformamide (DMF) and added to a final 1% DMF. The reaction was stopped by adding 30 μl of SDS sample buffer, and the sample was solubilized by treating with a sonicator for 10 minutes. SDS-PAGE was performed using a 10% polyacrylamide gel, and the gel was dried after CBB staining. [Γ-
³² P] -ATP was imaged and phosphorylated rhodopsin was quantified. GRK-dependent phosphorylation inhibitory action of the compounds was expressed by inhibition ratio is 100 to solvent treatment in the presence of 0,200nM _G βγ a solvent treatment with G _{[beta] [gamma]} absence.

Experimental Results Table 1 shows the results. From this, it is clear that the compound of the present invention exhibits an excellent GRK inhibitory action.

[Table 1]

[0405]

The compound (I) of the present invention or a salt thereof is
It has an excellent GRK inhibitory activity and is advantageously used for the prevention and treatment of various diseases such as heart failure.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61P 9/04 A61P 9/04 9/10 9/10 101 101 9/12 9/12 11/06 11 / 06 13/00 13/00 13/12 13/12 25/16 25/16 25/24 25/24 25/28 25/28 25/30 25/30 43/00 111 43/00 111 C07D 239/42 C07D 239/42 Z 403/06 403/06 403/12 403/12 405/12 405/12 F term (reference) 4C063 AA01 BB03 BB07 BB09 CC29 CC73 DD07 DD12 DD29 EE01 4C086 AA01 AA02 BC42 GA02 GA07 GA08 MA01 MA04 NA14 NA15 ZA02 ZA12 ZA15 ZA36 ZA40 ZA42 ZA45 ZA59 ZA70 ZB11 ZC20 ZC35 ZC39 ZC41

Claims (65)

[Claims] 1. A compound of the formula (I)Wherein ring A is a nitrogen-containing heterocyclic group which may be further substituted.
A ring;¹And R ²Are each substituted
X represents a good amino group, and X represents the number of atoms constituting the linear portion.
Represents a spacer of 1 to 4;¹Is R²Or / and
And X may combine with each other to form a ring. ]
Compounds or their salts, or their prodrugs
GRK inhibitors. 2. The agent according to claim 1, wherein R ¹ and R ² are each an optionally substituted amino group, and X is a spacer having 1 to 4 atoms constituting a straight chain portion. 3. The agent according to claim 1, wherein the nitrogen-containing heterocycle is pyrimidine or pyridine. 4. The compound represented by the formula (I) is a compound represented by the formula (I ′): [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, and R ¹ is bonded to R ³ or R ⁴ to form a ring. R ³ represents a hydrogen atom or an optionally substituted acyl group, and R ⁴ represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted Represents an acyl group; R ³ and R ⁴ may combine to form a cyclic amino group; n represents an integer of 1 to 4; The agent according to claim 1, which is a compound represented by the formula: 5. The method according to claim 1, wherein R ⁴ is an optionally substituted alkyl group, an optionally substituted cyclic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group. Item 7. The agent according to Item 4. 6. The agent according to claim 4, wherein R ⁴ is an optionally substituted alkyl group. 7. The agent according to claim 4, wherein R ⁴ is an optionally substituted aryl group. 8. The agent according to claim 4, wherein R ⁴ is an optionally substituted acyl group. 9. R⁴Is the formula-(C = O) -R,-(C =
O) NRR ', -SO ₂-R, -SO₂-NRR '
Is-(C = O) O-R [R is an optionally substituted cyclic
Represents a hydrocarbon group or an optionally substituted heterocyclic group.
R ′ is a hydrogen atom, an optionally substituted hydrocarbon group
Or an optionally substituted heterocyclic group, wherein R and
R 'is bonded to each other to form a substituent together with an adjacent nitrogen atom.
A nitrogen-containing heterocyclic group which may be possessed may be formed. ]
The agent according to claim 4, which is a group represented by the formula: 10. The agent according to claim 4, wherein n is 1. 11. Ring B is of the formula [In the formula, R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group, and ring B ′ further has a substituent. Represents an optionally substituted pyrimidine ring. The agent according to claim 4, which has a structure represented by the formula: 12. The agent according to claim 11, wherein R ⁵ is an optionally substituted alkyl group or an optionally substituted aryl group. 13. The agent according to claim 4, wherein R ¹ is amino. 14. A compound represented by the formula (I):
a) embedded image Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group; E represents an optionally substituted divalent cyclic hydrocarbon group or an optionally substituted divalent heterocyclic group;
, - - -O is _{S -, - SO -, -} SO 2 -, - S-S
—, —CO—NH—, —CO—O—, or C _1-4 alkylene; Ra represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Indicates an integer of 4. The agent according to claim 1, which is a compound represented by the formula: 15. A compound represented by the formula (I):
b) embedded image Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and n represents an integer of 1 to 4. The agent according to claim 1, which is a compound represented by the formula: 16. The compound represented by the formula (I) is a compound represented by the formula (I)
c) embedded image [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, F represents a nitrogen-containing heterocyclic group which may be further substituted, Rc represents a hydrocarbon group which may be substituted or an acyl group which may be substituted, and n represents an integer of 1 to 4. The agent according to claim 1, which is a compound represented by the formula: 17. The method according to claim 1, which is an agent for preventing or treating heart failure.
Agents as described. 18. The compound according to claim 1, or a salt thereof,
Or a method of inhibiting GRK in a mammal, which comprises administering an effective amount of a prodrug thereof to the mammal. 19. The compound according to claim 1, or a salt thereof,
Alternatively, a method for preventing and treating heart failure in a mammal, which comprises administering an effective amount of a prodrug thereof to the mammal. 20. The method for producing a GRK inhibitor according to claim 1.
Use of the described compound or a salt thereof, or a prodrug thereof. 21. Use of the compound according to claim 1, a salt thereof, or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for heart failure. 22. The formula (Ia ′) Wherein ring B may be further substituted showed good pyrimidine ring, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ³ , R
³ represents a hydrogen atom or an optionally substituted acyl group, E ′ represents an optionally substituted divalent cyclic hydrocarbon group, and Ya ′ represents —O—, —S—, —SO—, -SO
_2- , -SS- or -CO-NH-;
a ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ^{5a ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. It shows an amino group, and n shows the integer of 1-4. However, when Ya 'is -O-, Ra' is not ethyl. (Provided that: Embedded image Embedded image Embedded image And Or its salts). 23. A prodrug of the compound according to claim 22 or a salt thereof. 24. A medicament comprising the compound according to claim 22, or a salt thereof, or a prodrug thereof. 25. The compound according to claim 22, wherein R ³ is hydrogen. 26. The compound according to claim 22, wherein E ′ is an optionally substituted divalent aromatic hydrocarbon group. 27. The compound according to claim 22, wherein E ′ is phenylene which may be substituted. 28. The compound according to claim 22, wherein Ya ′ is —O—, —S—, —SO— or —SO ₂ —. 29. The compound according to claim 22, wherein Ya 'is -O- or -S-. 30. The compound according to claim 22, wherein Ra ′ is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. 31. The compound according to claim 22, wherein Ra ′ is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group. 32. The compound according to claim 22, wherein Ra ′ is an optionally substituted phenyl. 33. The compound according to claim 22, wherein R ¹ is amino. 34. The compound according to claim 22, wherein n is 1. 35. Ring B is of the formula Wherein R ^{5a ′} is as defined above. 23. The compound according to claim 22, which has a structure represented by the formula: 36. The compound according to claim 35, wherein R ^{5a ′} is a lower alkyl group. 37. (4-Amino-2-methyl-5-pyrimidinyl) methyl [2- (propyldisulfanyl) phenyl] formamide, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- N- [2- (phenylsulfanyl) phenyl] amine, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-
[2- (4-bromophenylsulfanyl) phenyl]
Amine, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(2-methoxyphenyl) sulfanyl] phenyl] amine, N-[(4-amino-2-methyl -5-pyrimidinyl) methyl] -N-
[2- (4-methoxyphenoxy) phenyl] amine,
N-[(4-amino-2-methyl-5-pyrimidinyl)
Methyl] -N- [2-[(4-methoxyphenyl) sulfanyl] phenyl] amine, N-[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] -N- [2-
[(2-nitrophenyl) sulfanyl] phenyl] amine, N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- [2-[(3-methoxyphenyl) sulfanyl] phenyl] amine, 2-[[(4-
Amino-2-methyl-5-pyrimidinyl) methyl] amino] -N- (2,2-diphenylethyl) benzoic acid amide, (4-amino-2-methyl-5-pyrimidinyl) methyl (2-benzylsulfanylmethylsulfanyl) Phenyl) formamide or a salt thereof or a prodrug thereof. 38. The formula (Ib ′) Wherein ring B is further substituted showed good pyrimidine ring optionally, R ¹ is shows the amino group which may be substituted, R ¹ is may form a ring with R ^3b ,
R ^3b represents an optionally substituted acyl group; Yb represents a bond or an optionally substituted alkylene;
Rb represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R ^{5b ′} may be substituted with a hydrogen atom, a lower alkyl group or one or two lower alkyl groups. Represents an amino group, and n represents an integer of 1 to 4. (Provided that: And Or its salts). 39. A prodrug of the compound according to claim 38 or a salt thereof. 40. A medicament comprising the compound according to claim 38, a salt thereof, or a prodrug thereof. 41. R ^3b is of the formula-(C = O) -R '[R'
Represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. 39. The compound according to claim 38, which is a group represented by the formula: 42. The compound according to claim 41, wherein R ′ is an optionally substituted hydrocarbon group. 43. The compound according to claim 41, wherein R ′ is an optionally substituted cyclic hydrocarbon group. 44. The compound according to claim 41, wherein R ′ is an optionally substituted aromatic hydrocarbon group. 45. The compound according to claim 41, wherein R ′ is an optionally substituted phenyl. 46. C _{1-4 wherein} Yb may be substituted.
39. The compound according to claim 38, which is an alkylene. 47. The compound according to claim 38, wherein Yb is methylene. 48. The compound according to claim 38, wherein Rb is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group. 49. The compound according to claim 38, wherein Rb is an optionally substituted phenyl group. 50. The compound according to claim 38, wherein R ¹ is amino. 51. The compound according to claim 38, wherein n is 1. 52. Ring B is of the formula Wherein R ^{5b ′} is as defined above. 39. The compound according to claim 38, which has a structure represented by the formula: 53. The compound according to claim 52, wherein R ^{5b ′} is a lower alkyl group. 54. N-[(4-amino-2-methyl-5
-Pyrimidinyl) methyl] -N'-benzhydryl-N
-Benzylterephthalamide, N-[(4-amino-2
-Methyl-5-pyrimidinyl) methyl] -N-benzyl-N '-(1,2,3,4-tetrahydro-1-naphthalenyl) terephthalamide, N-[(4-amino-2-
Methyl-5-pyrimidinyl) methyl] -N-benzyl-
4-[(3,5-diphenyl-1H-pyrazole-1-
Yl) methyl] benzamide, N-[(4-amino-2)
-Methyl-5-pyrimidinyl) methyl] -N-benzyl-6- (3,5-diphenyl-1H-pyrazole-1-
Yl) hexaneamide, 4-[(allyloxy) methyl] -N-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N-benzyl-benzamide or a salt thereof or a prodrug thereof. 55. The formula (Ic) [In the formula, ring B represents a pyrimidine ring which may be further substituted, R ¹ represents an amino group which may be substituted, F represents a nitrogen-containing heterocyclic group which may be further substituted, Rc represents a hydrocarbon group which may be substituted or an acyl group which may be substituted, and n represents an integer of 1 to 4. Or a salt thereof. 56. A prodrug of the compound of claim 55 or a salt thereof. 57. A medicament comprising the compound according to claim 55, a salt thereof, or a prodrug thereof. 58. F is a compound of the formula [In the formula, F 'represents a 5- to 8-membered ring which may be further substituted, and Rc has the same meaning as defined in claim 55. The compound according to claim 55, which is a group represented by the formula: 59. F is of the formula [In the formula, F 'represents a benzene ring which may be further substituted, and Rc has the same meaning as defined in claim 55. The compound according to claim 55, which is a group represented by the formula: 60. Rc is-(C = O) NRR '[R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R' represents a hydrogen atom, A hydrocarbon group or a heterocyclic group which may be substituted, and R and R ′ are bonded to each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. Is also good. The compound according to claim 55, which is a group represented by the formula: 61. The compound according to claim 55, wherein R ¹ is amino. 62. The compound according to claim 55, wherein n is 1. 63. Ring B is of the formula [Wherein, R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and ring B ′ represents a pyrimidine ring which may further have a substituent. . The compound according to claim 55, which has a structure represented by the following formula: 64. The compound according to claim 63, wherein R ⁵ is an optionally substituted alkyl group or an optionally substituted aryl group. 65. 2-[(4-amino-2-methyl-5
-Pyrimidinyl) methyl] -N, N-dibenzyl-1,
3-dioxo-5-isoindolinecarboxamide, 2
-[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- (2,2-diphenylethyl) -1,3-
Dioxo-5-isoindolinecarboxamide, 2-
[(4-amino-2-methyl-5-pyrimidinyl) methyl] -N- (3,3-diphenylpropyl) -1,3-
Dioxo-5-isoindolinecarboxamide or a salt thereof or a prodrug thereof.