JP2000169475A - Pyrazole derivative and salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having structure with a substituted condensed tricycloheterocyclic ring, also effective against 5-FU drug-resistant tumors and P-glycoprotein-expressive multidrug-resistant strains, and useful as an active ingredient of highly efficacious antitumor agents. SOLUTION: This new compound is a compound of formula I [R1 and R2 are each H, a halogen, hydroxyl or the like; R3 and R4 are each H, a halogen, alkoxyl or the like; R5 is H, an alkyl, alkenyl, or the like; Q is an amidino, cycloalkyl, phenyl or a monocycloheterocyclic group; G is a (substituted) condensed tricycloheterocyclic ring], e.g. 3- 3-[1-(4-amino-2-pyrimidinyl)-5-methyl-4- pyrazolyl]-2-trans-propen-1-yl}-9fluoro-2,3,4,4a,5,6-hexahydro-1H-pyra zino[1, 2- a]quinoline hydrochloride. The compound of formula I is obtained by subjecting a compound of formula II and a basic compound: H-G to Mannich reaction to form a compound of formula III which is then reduced into a compound of formula IV which is subsequently dehydrated.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound having a chemical structure different from that of a conventionally used antitumor agent and an antitumor agent containing the compound as an active ingredient.
The present invention relates to a highly effective antitumor agent which is effective also for system drug resistant tumors.

[0002]

2. Description of the Related Art At present, many 5-FU drugs are used as an orally administrable antitumor agent, but they are not sufficiently effective, and some tumors are resistant to 5-FU drugs. It has been desired to develop a drug that has appeared, is more effective, and is also effective against 5-FU drug-resistant tumors. The antitumor effects of the pyrazole derivatives related to the present invention are described in JP-A-9-48776 and WO98.
/ 32739. The present invention provides a pyrazole derivative having a novel structure substituted by a condensed tricyclic heterocyclic ring.
No. 48776, pyrimidinyl group, WO 98/327
It is intended to provide a novel compound in which a novel substituent is introduced into a cycloalkyl group, a phenyl group, a monocyclic heterocyclic group or the like in JP-A-39.

[0003] An object of the present invention is to provide a highly effective antitumor agent having a chemical structure different from that of a conventionally used antitumor agent and exhibiting efficacy even for 5-FU drug-resistant tumors.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a pyrazole derivative having a novel structure is also effective against 5-FU drug-resistant tumors and has a strong antitumor effect. I found In addition, they have found that this compound also has an effect on P-glycoprotein-expressing multidrug-resistant strains, which are clinically problematic, and completed the present invention. The present invention relates to a compound of the formula (I)

[0005]

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[Wherein R ¹ is a hydrogen atom, a halogen atom,
A hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent. You may have. R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group, an alkyl group or a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are a halogen atom, It may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group.

R ³ represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group, It may have an alkoxyl group, thiol group or alkylthio group. R ⁴ is a hydrogen atom, a halogen atom,
Means an alkoxyl group, amino group, alkylamino group, aryl group or alkyl group, and the alkyl group has a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group as a substituent. You may. R ⁵ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an arylalkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or It may have an alkylthio group.

Q represents an amidino group, a cycloalkyl group, a phenyl group or a monocyclic heterocyclic group, and these amidino groups, cycloalkyl groups, phenyl groups and monocyclic heterocyclic groups are alkyl groups as substituents. Group (may be substituted by a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group), halogen atom, hydroxyl group, alkoxyl group, alkoxylalkoxyl group, amino group, alkyl group Amino group, acylamino group, alkylaminoalkylamino group, nitro group, cyano group, carbamoyl group,
A group selected from the group consisting of thiol, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl and aryl It may have one or more.

G represents a condensed tricyclic heterocyclic ring, and the condensed tricyclic heterocyclic ring has, as a substituent, an alkyl group (halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or An alkylthio group may be substituted.), A halogen atom, a hydroxyl group,
It may have one or more substituents selected from the group consisting of alkoxyl, thiol, alkylthio, amino, alkylamino, acylamino, nitro, cyano, carbamoyl and aryl groups. Further, the fused tricyclic heterocyclic ring may have an epoxy group. Further, the condensed tricyclic heterocyclic ring may contain a carbonyl group as a ring constituent. And a salt thereof.

Alternatively, in the compound represented by the above general formula (I) and a salt thereof, ([Q is a pyrimidinyl group, which is bonded to a pyrazole group at a position other than the 2-position, and G is
Condensed tricyclic heterocyclic ring, wherein the saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by a saturated hydrocarbon ring or a saturated heterocyclic ring having no substituent] and a salt thereof. ) Compounds and salts thereof.

Further, the present invention provides a compound represented by the general formula (Ia):

Embedded image [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q have the same meanings as those in claim 1, G ¹ means a condensed tricyclic heterocyclic ring, The cyclic heterocyclic ring is composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring.

The nitrogen-containing heterocyclic ring constituting the condensed tricyclic heterocyclic ring is substituted by an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group). ), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group. May be one or more. In addition, the nitrogen-containing heterocyclic ring may include a carbonyl group as a component of the ring.

The saturated or unsaturated hydrocarbon or heterocyclic ring constituting the condensed tricyclic heterocyclic ring may be substituted by an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group). Or an alkylthio group may be substituted.), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group,
It may have one or more substituents selected from the group consisting of an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, and may form a ring It may have an epoxy group over two atoms. Further, the saturated or unsaturated hydrocarbon ring or heterocyclic ring may contain a carbonyl group as a component of the ring.

The benzene ring constituting the condensed tricyclic heterocyclic ring may be substituted by an alkyl group (even if it is substituted by a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group). A) a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group. It may have one or more. And a salt thereof.

Alternatively, in the compound represented by the above general formula (I) and a salt thereof, ([Q is a pyrimidinyl group and is bonded to a pyrazole group at a position other than the 2-position, and G ¹ is
Condensed tricyclic heterocyclic ring, wherein the saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by a saturated hydrocarbon ring or a saturated heterocyclic ring having no substituent] and a salt thereof. ) Compounds and salts thereof.

In the compound represented by the above general formula (I) or (Ia), Q is a pyrimidinyl group;
Compounds which bind to the pyrazole ring at the 1-position and salts thereof are preferred.

In the compound represented by the above general formula (I) or (Ia), the saturated or unsaturated hydrocarbon ring or the heterocyclic ring constituting the condensed tricyclic heterocyclic ring has a substituent. Compounds and salts thereof are preferred.

Further, the present invention provides a compound represented by the general formula (1b):

[0019]

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Where R is¹, R^Two, R^Three, R^FourAnd R
^FiveIs synonymous with that described in claim 1, and G^TwoIs a group -Z
¹-Z^Two [Wherein, Z¹Is

[0021]

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(X represents a nitrogen atom or CH.)
And a nitrogen-containing saturated heterocyclic structure represented by the formula: wherein a ketone moiety may be contained. As a substituent on this ring, an alkyl group (which may be substituted with a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group , An alkoxyl group, an amino group, an alkylamino group and an aryl group.

Z ² represents a phenyl group or a heterocyclic group, and these phenyl group and heterocyclic group are
An alkyl group (which may be substituted by a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group), halogen atom, hydroxyl group, alkoxyl group, thiol group,
It may have one or more substituents selected from the group consisting of alkylthio, amino, alkylamino, acylamino, nitro, cyano, carbamoyl and aryl groups. ]

Or a condensed tricyclic heterocyclic group, wherein said condensed tricyclic heterocyclic group is an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group) Or an alkylthio group may be substituted.), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group,
It may have one or more substituents selected from the group consisting of amino group, alkylamino group, acylamino group, nitro group, cyano group, carbamoyl group and aryl group. Further, the fused tricyclic heterocyclic group may have an epoxy group. Further, the condensed tricyclic heterocyclic ring may contain a carbonyl group as a ring constituent.

Q ¹ represents a cycloalkyl group, a phenyl group or a monocyclic heterocyclic group, and these cycloalkyl group, phenyl group and monocyclic heterocyclic group are substituted as the following (A) It may have one or more groups selected, and may have one or more groups selected from (B).

(A) an alkyl group having a substituent (substituents of the alkyl group include a trialkylammonio group, a cyano group, a ureido group, an alkylureido group, an amidino group,
Selected from the group consisting of guanidino, hydroxyalkoxyl, alkoxylalkoxyl, aminoalkoxyl, hydroxyalkylamino, aminoalkylamino, carboxyl, carbamoyl, sulfamoyl, alkylsulfamoyl and arylsulfamoyl And may further have one or more groups selected from this group. ),

The group -R⁷¹-R⁷  [R⁷Is a monocyclic nitrogen-containing heterocyclic group or cycloalkyl
A group, R⁷¹Is a single bond or an alkyl having 1 to 3 carbon atoms
Means a kylene group, R⁷And R⁷¹(Except for single bond)
Good. ) Each independently represents an alkyl group (halo
Gen atom, hydroxyl group, amino group, alkylamino
Group, trialkylammonio group, cyano group, ureido
Group, alkyl ureido group, amidino group, guanidino group,
Alkoxyl group, hydroxyalkoxyl group, alkoxy
Silalkoxyl group, aminoalkoxyl group, hydroxy
Silalkylamino group, aminoalkylamino group, carbo
Xyl, carbamoyl, sulfamoyl, alkyl
Rusulfamoyl group, arylsulfamoyl group, thio
Or a group selected from the group consisting of
It may have one or more substituents. ), Haloge
Atom, hydroxyl group, amino group, alkylamino
Group, trialkylammonio group, cyano group, ureido
Group, alkyl ureido group, amidino group, guanidino group,
Alkoxyl group, hydroxyalkoxyl group, alkoxy
Silalkoxyl group, aminoalkoxyl group, hydroxy
Silalkylamino group, aminoalkylamino group, carbo
Xyl, carbamoyl, sulfamoyl, alkyl
Rusulfamoyl group, arylsulfamoyl group, thio
Group selected from the group consisting of a thiol group and an alkylthio group
May be provided singly or plurally. ]

Group -R⁷²-R⁷³-R⁷⁴-R⁷  [R⁷Is a monocyclic nitrogen-containing heterocyclic group or cycloalkyl
A group, R⁷²And R⁷⁴Are each independently a single bond or
Represents an alkylene group having 1 to 3 carbon atoms;⁷³Is oxygen
Atom or sulfur atom,

R ⁷ , R ⁷² (excluding the case of a single bond) and R ⁷⁴ (excluding the case of a single bond) each independently represent an alkyl group (a halogen atom, a hydroxyl group,
Amino group, alkylamino group, trialkylammonio group, cyano group, ureido group, alkylureido group, amidino group, guanidino group, alkoxyl group, hydroxyalkoxyl group, alkoxylalkoxyl group, aminoalkoxyl group, hydroxyalkylamino group, amino It may have one or more substituents selected from the group consisting of an alkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group. . ), A halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group,
Cyano group, ureido group, alkylureido group, amidino group, guanidino group, alkoxyl group, hydroxyalkoxyl group, alkoxylalkoxyl group, aminoalkoxyl group, hydroxyalkylamino group, aminoalkylamino group, carboxyl group, carbamoyl group, sulfamoyl group, It may have one or more substituents selected from the group consisting of an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group. ]

The group -R⁷²-NR⁷⁵-R⁷⁴-R⁸  [R⁷²And R⁷⁴Are each independently a single bond or 1 carbon atom
To 3 alkylene groups;⁷⁵Is an alkyl group (C
Logen atom, hydroxyl group, amino group, alkylamido
Group, trialkylammonio group, cyano group, ureide
Group, alkyl ureido group, amidino group, guanidino group,
Alkoxyl group, hydroxyalkoxyl group, alkoxy
Silalkoxyl group, aminoalkoxyl group, hydroxy
Silalkylamino group, aminoalkylamino group, carbo
Xyl, carbamoyl, sulfamoyl, alkyl
Rusulfamoyl group, arylsulfamoyl group, thio
Or a group selected from the group consisting of
It may have one or more substituents. ), Hydrogen source
, A hydroxyl group, an alkoxyl group or -R⁷⁴-R
⁸Means

R ⁸ represents an alkylsulfonyl group, an arylsulfonyl group, a monocyclic nitrogen-containing heterocyclic group or a cycloalkyl group, and R ⁸ (excluding alkylsulfonyl and arylsulfonyl groups), R ⁷² (Excluding the case of a single bond) and R ⁷⁴ (excluding the case of a single bond) each independently represent an alkyl group (a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio) Group, cyano group, ureido group, alkylureido group, amidino group, guanidino group, alkoxyl group, hydroxyalkoxyl group, alkoxylalkoxyl group, aminoalkoxyl group, hydroxyalkylamino group, aminoalkylamino group, carboxyl group, carbamoyl group, sulfamoyl Group, alkylsulfamoyl group, aryl May have one or more substituents selected from the group consisting of a rusulfamoyl group, a thiol group and an alkylthio group.), A halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, Cyano group, ureido group, alkylureido group, amidino group, guanidino group, alkoxyl group, hydroxyalkoxyl group, alkoxylalkoxyl group, aminoalkoxyl group, hydroxyalkylamino group, aminoalkylamino group, carboxyl group, carbamoyl group, sulfamoyl group, It may have one or more substituents selected from the group consisting of an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group. ]

The group -R⁸¹-R⁸²-R⁹  [R⁸¹Represents a single bond or an alkylene group having 1 to 3 carbon atoms
Means R⁸²Represents an oxygen atom or a sulfur atom;⁸¹
(Excluding the case of a single bond) is an alkyl group as a substituent
(Halogen, hydroxyl, amino, alkyl
Amino group, trialkylammonio group, cyano group, urea
Id group, alkyl ureide group, amidino group, guanidino
Group, alkoxyl group, hydroxyalkoxyl group,
Coxylalkoxyl group, aminoalkoxyl group, hydr
Loxyalkylamino group, aminoalkylamino group,
Ruboxyl group, carbamoyl group, sulfamoyl group,
Rukylsulfamoyl group, arylsulfamoyl group,
Selected from the group consisting of thiol groups and alkylthio groups
May have one or more substituents. ), C
Logen atom, hydroxyl group, amino group, alkylamido
Group, trialkylammonio group, cyano group, ureide
Group, alkyl ureido group, amidino group, guanidino group,
Alkoxyl group, hydroxyalkoxyl group, alkoxy
Silalkoxyl group, aminoalkoxyl group, hydroxy
Silalkylamino group, aminoalkylamino group, carbo
Xyl, carbamoyl, sulfamoyl, alkyl
Rusulfamoyl group, arylsulfamoyl group, thio
Or a group selected from the group consisting of
It may have one or more substituents.

R ⁹ represents an alkyl group having a substituent, and the substituent of the alkyl group may be a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, a ureido group, an alkyl group. Ureido, amidino, guanidino, alkoxyl, hydroxyalkoxyl, alkoxylalkoxyl, aminoalkoxyl, hydroxyalkylamino, aminoalkylamino, carboxyl, carbamoyl, sulfamoyl, alkylsulfamoyl, aryl It is a group selected from the group consisting of a sulfamoyl group, a thiol group and an alkylthio group, and may further have one or more groups selected from this group. ]

Or a group -R⁸¹-NR⁸³-R⁹  [R⁸¹Represents a single bond or an alkylene group having 1 to 3 carbon atoms
Means R⁸¹(Excluding the case of a single bond) is a substituent
The alkyl group (halogen atom, hydroxyl group,
Group, alkylamino group, trialkylammonio group,
Cyano group, ureido group, alkyl ureide group, amidino
Group, guanidino group, alkoxyl group, hydroxyalco
Xyl group, alkoxyl alkoxyl group, amino alcohol
Xyl group, hydroxyalkylamino group, aminoalkyl
Amino group, carboxyl group, carbamoyl group, sulf
Amoyl group, alkylsulfamoyl group, arylsulfo
Famoyl, thiol and alkylthio groups
Having one or more substituents selected from the group
Is also good. ), Halogen atom, hydroxyl group, amino
Group, alkylamino group, trialkylammonio group,
Ano group, ureido group, alkyl ureide group, amidino
Group, guanidino group, alkoxyl group, hydroxyalco
Xyl group, alkoxyl alkoxyl group, amino alcohol
Xyl group, hydroxyalkylamino group, aminoalkyl
Amino group, carboxyl group, carbamoyl group, sulf
Amoyl group, alkylsulfamoyl group, arylsulfo
Famoyl, thiol and alkylthio groups
Having one or more substituents selected from the group
Is also good.

R ⁸³ represents an alkyl group (halogen atom, hydroxyl group, amino group, alkylamino group, trialkylammonio group, cyano group, ureido group, alkylureido group, amidino group, guanidino group, alkoxyl group, hydroxyalkoxyl group , An alkoxyl alkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group May have one or more substituents), a hydrogen atom, a hydroxyl group or an alkoxyl group,

R ⁹ represents an alkyl group having a substituent, and the substituent of the alkyl group is a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, a ureido group, an alkyl group. Ureido, amidino, guanidino, alkoxyl, hydroxyalkoxyl, alkoxylalkoxyl, aminoalkoxyl, hydroxyalkylamino, aminoalkylamino, carboxyl, carbamoyl, sulfamoyl, alkylsulfamoyl, aryl It is a group selected from the group consisting of a sulfamoyl group, a thiol group and an alkylthio group, and may further have one or more groups selected from this group (provided that
R ⁸¹ is a single bond, R ⁸³ is a hydrogen atom, and R ⁹ is an alkylamino group). ]

(B) an alkyl group (which may be substituted by a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group), halogen atom, hydroxyl group, alkoxyl group, alkoxyl Alkoxyl, amino, alkylamino, acylamino, alkylaminoalkylamino, nitro, cyano, carbamoyl, thiol, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, aryl The present invention relates to a compound represented by a sulfonyl group, an aminosulfonyl group, an alkylaminosulfonyl group, an arylaminosulfonyl group and an aryl group｝ and a salt thereof.

The compound represented by the general formula (I), (Ia) or (I
The compound of the present invention represented by b) includes both cis and trans alkenyl double bond moieties. Further, these compounds of the present invention include arbitrary stereoisomers. Next, terms used in the present specification will be described. "Cis (form)" means that R ³ and R ⁴ are attached to the same side of the double bond; "trans (form)" means that R ³ and R ⁴ are double It means that the bond is on the opposite side to the bond.

A "hydroxyl group" may be protected with a protecting group. An "amino group" may be protected by a protecting group. The “alkyl group”, “alkenyl group” and “alkynyl group” may be linear or branched, and have from 1 carbon atom (2 carbon atoms in the case of alkenyl and alkynyl groups) to 6 carbon atoms, unless otherwise specified. Are preferred.
The alkyl portion of the “alkoxyl group” preferably has 1 to 6 carbon atoms. “Aryl group” means a monovalent group obtained by removing one hydrogen atom from the nucleus of an aromatic hydrocarbon,
For example, phenyl, tolyl, biphenylyl, naphthyl and the like can be mentioned.

The amino group of the "aminoalkyl group" may be bonded to any position of the alkyl group. Further, the alkyl group preferably has 1 to 6 carbon atoms. The term “alkylamino group” means a group in which one amino group is substituted for an amino group or a group in which two amino groups are substituted for an amino group (the two alkyl groups may be the same or different). . The alkyl group preferably has 1 to 6 carbon atoms.
The “alkyl ureido group” means a ureido group substituted with one alkyl group, or a ureido group substituted with two alkyl groups (the two alkyl groups may be the same or different). . The alkyl group preferably has 1 to 6 carbon atoms.

An "acyl group" is a carbonyl group (-CO
-) To which a hydrogen atom, an alkyl group or an aryl group is bonded, such as formyl, acetyl, propanoyl, benzoyl and the like. The alkyl group to be bonded preferably has 1 to 6 carbon atoms,
A phenyl group is preferable as the aryl group to be bonded.

The term "heterocyclic group" refers to a group derived from a monocyclic or bicyclic saturated or unsaturated heterocyclic compound, and includes, as ring structure atoms, an oxygen atom, a nitrogen atom and a sulfur atom. It contains one or more atoms selected from the group consisting of one or more atoms. Examples of the monocyclic heterocyclic group include, for example, aziridine, azetidine, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, Dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, triazine, piperazine,
Examples include groups derived from monocyclic heterocyclic compounds such as dioxane, pyran, morpholine, and thiomorpholine. Examples of the bicyclic heterocyclic group include groups derived from a bicyclic heterocyclic compound such as benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, and chroman.

The term "nitrogen-containing heterocyclic ring" means a saturated or unsaturated heterocyclic ring which always contains one nitrogen atom as a constituent atom of the heterocyclic ring, and further includes, as constituent atoms, an oxygen atom, a nitrogen atom and a sulfur atom. It may contain one or more atoms selected from the group consisting of one or more atoms. For example, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, homopiperazine,
Tetrahydropyridine, morpholine, thiomorpholine,
Examples include pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like.

The "nitrogen-containing heterocyclic group" means a group derived from the above "nitrogen-containing heterocycle". The “nitrogen-containing saturated heterocycle” means a saturated one of the above “nitrogen-containing heterocycle”. “Fused tricyclic heterocyclic group” means a fused ring group composed of three rings including at least one heterocyclic ring. The fused tricyclic heterocyclic group is preferably a group derived from an ortho-fused compound. Ortho-condensation refers to a structure in which two rings constituting a polycyclic compound have only two atoms in common, and this kind of compound has one or more shared surfaces in the structural formula. And the number of shared planes 2
There are twice as many shared atoms.

[0045] By "single bond" means a single bond, for example, when the -R ⁷¹ -R ⁷ R ⁷¹ is a single bond, results in no substantial R ^71, a -R ⁷ as a whole . In the specification of the present application, when "having a substituent" and "may have a substituent" are described, the bonding position of the substituent is not particularly limited.

Next, the compound represented by the general formula (I), (Ia) or (I
Each substituent of the compound represented by b) (hereinafter, also referred to as “the compound (I), (Ia) or (Ib) of the present invention). The same applies to other formulas.”

R ¹ is preferably a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, a phenyl group or an alkyl group, and the alkyl group is an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol as a substituent. Or an alkylthio group.

R ² is a hydroxyl group, an alkoxyl group,
An amino group, an alkyl group or a cycloalkyl group is preferable, and the alkyl group and the cycloalkyl group have a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent. Is also good.

R ³ is preferably a hydrogen atom or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.

R ⁴ is preferably a hydrogen atom or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.

R ⁵ is preferably a hydrogen atom or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.

G represents a condensed tricyclic heterocyclic group. The fused tricyclic heterocyclic group is not particularly limited, but is preferably a group composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring.

G may or may not have a substituent, but preferably has a substituent.

G ¹ of the compound (Ia) of the present invention is a condensed tricyclic heterocyclic group G, whose constituent is a nitrogen-containing heterocyclic ring,
It is limited to a saturated or unsaturated hydrocarbon ring or hetero ring, and a benzene ring. The nitrogen-containing heterocyclic ring constituting G ¹ may or may not have a substituent,
It is preferred to have. Examples of such a substituent include those described below.

Next, G of the compound (Ib) of the present invention^TwoAbout
Will be explained. Group-Z¹-Z^Two  Then the expression

[0056]

Embedded image

(Wherein X represents a nitrogen atom or CH), the nitrogen-containing saturated heterocyclic structure Z ¹ represented by 5
Alternatively, those having a 6-membered ring size are preferred, and those derived from piperazine and piperidine are particularly preferred.

The heterocyclic group represented by Z ² is preferably a monocyclic group having a 5- or 6-membered ring, and more preferably an unsaturated group. Specifically, a pyridyl group, a pyridazyl group, a pyrazyl group, a pyrimidyl group, and a triazyl group are preferred.

Z ² is preferably a phenyl group or a pyrimidinyl group. The phenyl group and pyrimidinyl group may have a substituent, a halogen atom, a hydroxyl group,
Cyano group and alkyl group (halogen atom, amino group,
Alkylamino group, hydroxyl group, alkoxyl group,
A thiol group or an alkylthio group may be substituted. It is preferred that the compound has two identical or different substituents selected from the group consisting of

As Z ² , a halogen atom, a hydroxyl group, a cyano group and an alkyl group (may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) Most preferred is a phenyl group having two identical or different substituents selected from the group consisting of

When G ² is a condensed tricyclic heterocyclic group, the condensed tricyclic heterocyclic ring is composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring. Are preferred. The condensed tricyclic heterocyclic group of G, G ¹ or G ² preferably has a nitrogen atom as a free valence of a nitrogen-containing heterocyclic ring constituting the condensed tricyclic heterocyclic group.

The nitrogen-containing heterocyclic ring constituting the condensed tricyclic heterocyclic group of G, G ¹ or G ² is preferably a 6-membered ring, specifically, piperazine, piperidine and tetrahydropyridine. Is preferred. Further, those in which the piperazine, piperidine, and tetrahydropyridine rings contain a carbonyl group as a constituent element can also be mentioned as preferable examples.

The saturated or unsaturated hydrocarbon ring or hetero ring constituting the condensed tricyclic heterocyclic group of G, G ¹ or G ² is preferably a 5- to 7-membered ring. Those having a 6-membered ring are preferred. Further, those containing a carbonyl group as a component of the ring can also be mentioned as preferred examples.

The specific structure of the fused tricyclic heterocyclic group of G, G ¹ or G ² is

[0065]

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(Wherein X ¹ is an oxygen atom, a sulfur atom, N
M and n each representing H, CH ₂ or C = O independently represent 0 or an integer of 1 to 2; Also,

[0067]

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The partial structure represented by the formula includes a double bond.
It may be an unsaturated ring. Note that X¹ And adjacent carbon source
X forms a double bond,¹Is N or CH
Become. ) Are preferred.

Further,

[0070]

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Specific examples of the structure represented by the following can be given.

[0072]

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[0073]

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[0074]

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[0075]

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Of these specific examples, the following are preferred.

[0077]

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As the substituent for the nitrogen-containing heterocyclic moiety constituting the condensed tricyclic heterocyclic group of G, G ¹ or G ² , an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group) , A thiol group or an alkylthio group may be substituted), a hydroxyl group,
Alkoxyl and amino groups are preferred.

As the substituent for the saturated or unsaturated hydrocarbon ring or heterocyclic moiety constituting the condensed tricyclic heterocyclic group of G, G ¹ or G ² , an alkyl group (amino group, alkylamino group, A hydroxyl group or an alkoxyl group may be substituted.), A hydroxyl group, an alkoxyl group, an amino group and an alkylamino group are preferred.

Further, those having an epoxy group over two carbon atoms forming a ring are also preferable.
As a substituent of the benzene ring constituting the condensed tricyclic heterocyclic group of G, G ¹ or G ² , an alkyl group (an amino group, an alkylamino group, a hydroxyl group or an alkoxyl group may be substituted). , A halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group and a cyano group.

M and n are preferably such that the sum of m and n is 0, 1 and 2, and particularly preferably 1 and 2.

Q or Q ¹ is preferably a monocyclic heterocyclic group. The monocyclic heterocyclic group represented by Q or Q ¹ is preferably an unsaturated one, more preferably a 5- or 6-membered ring.

The monocyclic heterocyclic group represented by Q or Q ¹ is an unsaturated monocyclic heterocyclic group having a 5- or 6-membered ring and having one or more nitrogen atoms as constituent atoms of the heterocyclic ring. Nitrogen-containing heterocyclic groups are most preferred, and specific examples include those derived from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. However, in the invention of claim 2 or 5, when Q is pyrimidine, G or G ¹ is a condensed tricyclic heterocyclic ring, and the condensed ring is a saturated or unsaturated hydrocarbon ring or heterocyclic ring. Are represented by a saturated hydrocarbon ring or a saturated heterocyclic ring having no substituent (except when Q is a pyrimidinyl group and bonded at the 2-position), and the compounds thereof and the compounds (I) and (I) of the present invention. Not included in Ia).

Q ¹ must be a substituent selected from (A)
And may have a substituent selected from (B). Among (B), an alkyl group, an amino group, an alkylamino group, a hydroxyl group or an alkoxyl group is preferable, and the alkyl group is a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, Ureido group, alkyl ureido group, amidino group, guanidino group, alkoxyl group, hydroxyalkoxyl group, alkoxylalkoxyl group,
Aminoalkoxyl group, hydroxyalkylamino group,
Aminoalkylamino group, carboxyl group, carbamoyl group, sulfamoyl group, alkylsulfamoyl group,
It may have one or more substituents selected from the group consisting of an arylsulfamoyl group, a thiol group and an alkylthio group.

Compounds (I), (Ia) or (I) of the present invention
As b), a trans form (when R ³ and R ⁴ are bonded on the opposite side to a double bond) is preferable. The compound (I) of the present invention can be produced by various methods. Representative production methods are shown below.

[0086]

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(R ¹ , R ² , R ⁴ , Q and G are the same as described above.) That is, the compound (III) obtained by subjecting the compound (II) and the basic compound HG to a Mannich reaction is reduced. To the compound (IV), followed by dehydration to obtain the desired compound (I). Each reaction will be described in detail.

Mannich reaction Compound (III) can be obtained by treating compound (II) and basic compound HG in a solvent in the presence of a condensing agent. The basic compound HG is preferably used as a salt such as hydrochloride or hydrobromide. Examples of the condensing agent include paraformaldehyde and formaldehyde.

Examples of usable solvents include alcohol solvents such as methanol, ethanol and propanol;
Amide solvents such as N, N-dimethylformamide, acetamide and dimethylacetamide; halogenated hydrocarbon solvents such as chloroform, dichloromethane and carbon tetrachloride; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; benzene, toluene and xylene And the like. Moreover, you may use these mixed solvents.

The reaction temperature may be generally in the range of -20 ° C to 150 ° C, preferably in the range of 0 ° C to 100 ° C. The reaction time may usually be in the range from 5 minutes to 120 hours, preferably in the range from 30 minutes to 72 hours.

Reduction reaction The corresponding compound (IV) can be obtained by reducing the compound (III). The reduction may be performed by a method usually used in this field. For example, a method of performing treatment in the presence of a reducing agent, a method of performing hydrogenation in the presence of a catalyst, and the like can be given.

Examples of the reducing agent include borohydride compounds and aluminum hydride compounds, such as sodium borohydride, sodium cyanoborohydride and lithium aluminum hydride. Also,
Examples of the catalyst include palladium, Raney nickel, platinum oxide and the like.

The solvent that can be used is appropriately selected depending on the reducing agent. Examples of the solvent include alcohol solvents such as methanol, ethanol and propanol, amide solvents such as N, N-dimethylformamide, acetamide and dimethylacetamide, chloroform, dichloromethane, and the like. Examples thereof include halogenated hydrocarbon solvents such as carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, and aromatic hydrocarbon solvents such as benzene, toluene and xylene. Moreover, you may use these mixed solvents.

The reaction temperature is usually from -20 ° C to 150 ° C.
And preferably in the range of 0 ° C to 100 ° C. The reaction time may usually be in the range from 5 minutes to 72 hours, preferably in the range from 10 minutes to 24 hours.

Dehydration Reaction The desired compound (I) can be obtained by subjecting compound (IV) to a dehydration reaction. The dehydration may be performed by a method generally used in this field, for example, a method of heating in the presence of an acid, and the like.

The acid which can be used in this method may be either an organic acid or an inorganic acid. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, and potassium hydrogen sulfate, and examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, and oxalic acid. As the acid, an inorganic acid is preferred. In addition, alumina can also be used.

The reaction may be carried out using a solvent, for example, an amide solvent such as N, N-dimethylformamide, acetamide, dimethylacetamide, chloroform,
Examples thereof include halogenated hydrocarbon solvents such as dichloromethane and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, and aromatic hydrocarbon solvents such as benzene, toluene and xylene. Moreover, you may use these mixed solvents.

The reaction temperature is usually from -20 ° C to 150 ° C.
And preferably in the range of 0 ° C to 100 ° C. The reaction time may usually be in the range from 5 minutes to 72 hours, preferably in the range from 10 minutes to 24 hours. In the synthesis method shown above, with R ³ is a hydrogen atom, a compound alkenyl group moiety is trans form can be synthesized, Compound Compound or alkenyl group moiety R ³ is an alkyl group is cis, the following Can be synthesized by the following method.

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(A represents a chlorine atom, a bromine atom or an iodine atom, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and G
Is the same as above. That is, the compound represented by the general formula (I) can be obtained by subjecting the compound (IIa) to a Wittig reaction with the compound (V).

The production method shown in the above figure will be described in detail. The compound (I) can be obtained by reacting the compound (V) with a tertiary phosphine in a solvent, treating the resulting phosphonium salt with a base in a solvent, and then adding the compound (IIa).

Examples of the tertiary phosphine used include triphenylphosphine, tri-n-butylphosphine and the like. As the base, n-butyllithium, phenyllithium, sodium hydride, potassium t-butoxide, sodium ethoxide, 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU)
Is mentioned.

Examples of usable solvents include ether solvents such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; alcohol solvents such as methanol, ethanol and propanol; Amide solvents such as dimethylformamide, acetamide and dimethylacetamide; and halogenated hydrocarbon solvents such as chloroform, dichloromethane and carbon tetrachloride. Moreover, you may use these mixed solvents.

The reaction temperature may be generally in the range of 30 ° C. to 150 ° C., preferably in the range of 50 ° C. to 100 ° C. The reaction time may usually be in the range from 5 minutes to 72 hours, preferably in the range from 10 minutes to 24 hours.

In the above process for producing compound (I) of the present invention,
The compound (Ia) of the present invention can be produced in the same manner as described above by using a compound in which G ¹ is substituted for G in the basic compounds HG and compound (V). In the compounds (II) and (IIa),
The compound of the present invention (Ib) is replaced with the compound of the present invention by replacing Q with Q ¹ and using a compound obtained by substituting G ^{2 for} G in the basic compound HG or compound (V). It can be manufactured in the same manner as (I).

The starting compounds (II) and (IIa), basic compounds HG and (V)
Are known compounds or known methods, for example, JP-A-9-48776, JP-B-54-17760, JP-B-50-5198, and JP-A-8-269.
No. 057, JP-A-6-279442, JP-A-9-504789, JP-A-50-58234, JP-A-52-83397, JP-B-46-33.
No. 032, Indian Journal of Chemistry, Vol. 13, p. 462 (1975), Indian Journal of Chemistry, Sect.
B, 25B (12), pp. 1231-1233 (1986
Year), Indian Journal of Chemistry, Sect. B, 17B (3), pages 244-245 (1979), Journal of Medicinal Chemistry, Vol. 13, 516 (1970), Indian Journal of Chemistry, Volume 7,
833 (1969), Helvetica Hemika Acta, Vol. 20, p. 1388 (1937), WO 98 /
No. 00134, WO98 / 00401, US
These compounds are easily synthesized according to a method commonly used by those skilled in the art according to, for example, US Pat.

Further, after the allylation shown below, the desired product (I) can be obtained through a reductive amination reaction or a substitution reaction. Similarly, the basic compound H-
In G, the compound of the present invention (Ia) can be produced in the same manner as the above-mentioned compound of the present invention (I) by using a compound wherein G is substituted by G ¹ , and compound (IIa)
Wherein Q is replaced with Q ¹ and the basic compound HG
In the above, the compound of the present invention (Ib) can be produced in the same manner as in the above-mentioned compound (I) of the present invention by using a compound in which G ² is substituted in place of G.

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(M represents a metal, for example, an alkali metal, an alkaline earth metal, tin, zinc, nickel, etc., R represents a protecting group for a hydroxyl group, and R ¹ , R ² , R ³ ,
R ⁵ , Q and G are the same as above. )

That is, the compound (IIa) is reacted with an appropriate allyl metal compound, or is subjected to an addition reaction with allylsilane in the presence of a Lewis acid to protect the hydroxyl group of the compound (VI) to give the compound (II). VII)
This is oxidized to give compound (VIII).
The compound (I) can be obtained by subjecting the obtained compound (VIII) and the basic compound HG to a reductive amination reaction, followed by deprotection if necessary and subjecting to a dehydration reaction. Further, the compound (X) is obtained by subjecting the compound (VIII) to a reduction reaction or reacting with an alkyl metal compound to give a compound (IX), further converting a hydroxyl group into a leaving group, It can also be obtained by a substitution reaction. Each reaction step will be described.

Addition reaction Compound (VIa) is obtained by reacting compound (IIa) with an appropriate allyl metal compound in a solvent or by subjecting compound (IIa) to an addition reaction with allylsilane in the presence of a Lewis acid (such as titanium tetrachloride). be able to.

The allyl metal compound which can be used in the reaction includes, for example, allyl lithium, allyl magnesium halide and allyl tin compound. Examples of the allylsilane that can be used include, for example, allyltrialkylsilane and allyltriarylsilane. Examples of usable Lewis acids include titanium tetrachloride and the like. Solvents that can be used for the reaction include diethyl ether, tetrahydrofuran, ether solvents such as dioxane, hexane, pentane, benzene, toluene,
Examples thereof include hydrocarbon solvents such as xylene and mixtures thereof. When an allyltin compound is used, water or a hydrated ether solvent may be used.

The reaction temperature may be generally in the range of -78 to 100 ° C, preferably in the range of -78 to 70 ° C. The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Hydroxyl group protection reaction The hydroxyl group of compound (VI) can be protected with a protecting group commonly used in this field. Examples of the protecting group include substituted methyl ether-based protecting groups such as methoxymethyl ether, methylthiomethyl ether and benzyloxymethyl ether; 1-methoxyethyl ether;
Substituted ethyl ether-based protecting groups such as 2-trichloroethyl ether, substituted benzyl ether-based protecting groups such as benzyl ether and p-methoxybenzyl ether, silyl ether-based protecting groups such as triethylsilyl and t-butyldimethylsilyl, and acetyl and the like. Examples include ester-based protecting groups, and carbonate-based protecting groups such as methoxycarbonyl and 2,2,2-trichloroethoxycarbonyl.

Oxidation Reaction To obtain compound (VIII) from compound (VII),
The method may be carried out by a method usually used in this field. For example, after subjecting to a stoichiometric oxidation using an oxidizing agent such as osmium tetraoxide or a catalytic oxidation reaction using a co-oxidizing agent, once passing through a diol, , By subjecting it to a general oxidation reaction such as periodate decomposition.
I) can be obtained. Compound (VIII) can also be obtained by subjecting compound (VII) to general ozonolysis involving reductive treatment in a solvent.

Examples of the oxidizing agent that can be used in the diolation reaction include potassium permanganate and osmium tetroxide. Examples of the co-oxidizing agent include hydrogen peroxide, an aqueous solution of hydrogen peroxide, and the like.
Perchlorates such as perchloric acid and sodium perchlorate;
Methylmorpholine-N-oxide, hexacyanoiron (I
II) Potassium acid and the like.

Solvents that can be used in the diolation reaction include, for example, alcohol solvents such as methanol, ethanol and t-butanol, ketone solvents such as acetone and methyl ethyl ketone, chlorine solvents such as dichloromethane and dichloroethane, diethyl ether and tetrahydrofuran. And hydrocarbon solvents such as hexane, pentane and benzene, or water, and mixed solvents thereof. The reaction temperature of the diolation may be usually in the range of -78 to 100 ° C, preferably -7.
It ranges from 8 to room temperature. Reaction time is usually from 5 minutes to 12
It can range from 0 hours, preferably from 30 minutes to 48 hours.

The periodate decomposition of the diol is carried out by using periodic acid, periodate, or the like as an oxidizing agent, using an alcoholic solvent such as methanol, ethanol, or t-butanol; a ketone solvent such as acetone or methyl ethyl ketone;
It may be treated in a solvent such as a chlorine-based solvent such as dichloromethane or dichloroethane, an ether-based solvent such as diethyl ether, tetrahydrofuran or dioxane, a hydrocarbon-based solvent such as hexane, pentane or benzene, or water, or a mixed solvent thereof. .

The reaction temperature for periodate decomposition may be usually in the range of -20 to 100 ° C, and preferably in the range of 0 ° C to room temperature. The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Solvents usable for ozonolysis include, for example, alcohol solvents such as methanol, ethanol and propanol, ketone solvents such as acetone and methyl ethyl ketone, chlorine solvents such as dichloromethane and dichloroethane, diethyl ether, tetrahydrofuran and dioxane. Ether solvents, hydrocarbon solvents such as hexane and pentane, and mixed solvents thereof.

The ozonolysis may be carried out usually at a temperature of -78 to 100 ° C., preferably at a temperature of -78 to room temperature.
The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Reductive Amination Reaction The compound (X) can be obtained from the compound (VIII) by a method generally used in this field. For example,
After reacting compound (VIII) with basic compound HG, compound (X) can be obtained by further treating with a reducing agent.

Examples of usable reducing agents include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diborane, and hydrogenation in the presence of a catalyst such as Raney nickel or palladium carbon. You may. Examples of the solvent that can be used include alcohol solvents such as methanol, ethanol, and propanol; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as hexane, pentane, benzene, toluene, and xylene; A mixed solvent is mentioned.

The reductive amination reaction may be carried out usually at a temperature of from -78 ° C to 100 ° C, preferably at a temperature of from -10 ° C to room temperature. The reaction time may be generally from 5 minutes to 120 hours, preferably from 30 minutes to 48 hours.

Reduction reaction Compound (IX) in which R ⁵ is a hydrogen atom is compound (VI)
It can be obtained by reducing the carbonyl group of II). The reduction may be performed by a method usually used in this field. For example, a method of performing treatment in the presence of a reducing agent or a method of performing hydrogenation in the presence of a catalyst can be used.

Examples of the reducing agent include borohydride compounds and aluminum hydride compounds, such as sodium borohydride and lithium aluminum hydride. Examples of the catalyst include palladium, Raney nickel, platinum oxide and the like.

In this reaction, a solvent may be used. The solvent may be appropriately selected depending on the reducing agent. Examples thereof include alcohol solvents such as methanol, ethanol and propanol, and amide solvents such as N, N-dimethylformamide, acetamide and dimethylacetamide. , Chloroform, dichloromethane,
Examples thereof include chlorine solvents such as carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as hexane, pentane, benzene, toluene and xylene, and mixed solvents thereof.

The reaction temperature may be generally in the range of -78 ° C to 100 ° C, preferably in the range of -78 ° C to room temperature.
The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Addition reaction of alkyl group Compound (IX) in which R ⁵ is other than a hydrogen atom can be obtained by reacting compound (VIII) with an alkyl metal compound.

The addition reaction of the alkyl group may be performed by a method usually used in this field. For example, a method of treating with alkyllithium, alkylmagnesium halide or the like can be mentioned. Examples of the alkyl metal compound include alkyl lithium such as methyl lithium and ethyl lithium, and alkyl magnesium halide such as methyl magnesium iodide and ethyl magnesium bromide.

In this reaction, a solvent may be used. For example, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as hexane, pentane, benzene, toluene and xylene, or mixed solvents thereof are used. No. Reaction temperature is usually -78 ° C
To 100 ° C, and preferably from -78 ° C to room temperature. The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Amino Group Substitution Reaction After the hydroxyl group of compound (IX) is converted to a leaving group such as halogen or sulfonic acid ester, it is subjected to a substitution reaction with basic compound HG to give the corresponding compound (IX). X) can be obtained.

In order to convert the hydroxyl group into a leaving group such as a halogen or a sulfonic acid ester, a method generally used in this field may be used. As the halogenation method, for example, a method of treating with phosphorus trihalide, phosphorus pentahalide or the like in a solvent such as dichloromethane or chloroform, or a method of chlorinating or brominating in a solvent such as N, N-dimethylformamide or dioxane. A method of treating with a Vilsmeier reagent such as N, N-dimethylchloroforminium is mentioned. Examples of the sulfonylation method include a method of treating with methanesulfonyl chloride or p-toluenesulfonyl chloride in a solvent in the presence of an appropriate base.

Compound (IX) derivative and basic compound H
The substitution reaction with -G may be performed by a method usually used in this field. For example, the substituted compound (X) can be obtained by heating a mixture of the derivative of the compound (IX) and the basic compound HG in a solvent such as acetonitrile in the presence of a base such as potassium carbonate.

Deprotection Reaction The protecting group for the hydroxyl group of compound (X) can be deprotected under the deprotection reaction conditions usually used for the used protecting group. Dehydration reaction The target compound (I) can be obtained by dehydrating the compound (XI). Dehydration may be performed by a method usually used in this field. For example, there is a method of heating in the presence of an acid.

The acid which can be used may be either an organic acid or an inorganic acid. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, potassium hydrogen sulfate, and the like.As the organic acid, p-toluenesulfonic acid, methanesulfonic acid,
Oxalic acid and the like can be mentioned. As the acid, an inorganic acid is preferred. In addition, alumina can also be used.

In this reaction, a solvent may be used. For example, amide solvents such as N, N-dimethylformamide, acetamide, dimethylacetamide, chloroform,
Examples thereof include halogenated hydrocarbon solvents such as dichloromethane and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, and aromatic hydrocarbon solvents such as benzene, toluene and xylene. Moreover, you may use these mixed solvents.

The reaction temperature is usually from -20 ° C to 150 ° C.
And preferably in the range of 0 ° C to 100 ° C. The reaction time may usually be in the range from 5 minutes to 72 hours, preferably in the range from 10 minutes to 24 hours. Further, a compound in which the alkenyl group is in the trans form can also be obtained by the following method.

[0139]

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(X^TwoIs a trialkylphosphonium group, di
An alkylphosphoryl group, a dialkylphosphono group or
R is a trialkylphosphoranylidene group;¹, R^Two, R
^Three, R^Four , R^Five, Q and G are the same as above. )

That is, compound (IIa) was converted to compound (XI)
The compound (I) can be obtained by subjecting the α, β unsaturated carbonyl compound (XIII) obtained by subjecting I) to a Wittig reaction to a reductive amination reaction with a basic compound HG. Compound (XII
When I) is an α, β unsaturated aldehyde (where R ⁵ =
H), the α, β unsaturated carboxyl compound (XIIIa) obtained by subjecting the compound (IIa) to the compound (XIIa) by a Wittig reaction is subjected to a reduction reaction, and then the obtained compound (XIV) is oxidized. Can also be obtained. Compound (I) is obtained by subjecting compound (XIII) to a reduction reaction to give compound (XIV), and further converting a hydroxyl group to a leaving group to give basic compound H
It can also be obtained by a substitution reaction with -G. Each reaction step will be described.

Wittig Reaction To obtain compound (XIII) from compound (IIa),
What is necessary is just to carry out by the method usually used in this field. For example, compound (XIII) can be obtained by treating compound (IIa) with (XII) in a solvent, under basic reaction conditions, or under neutral reaction conditions. Examples of the base include n-butyllithium, phenyllithium, sodium hydride, potassium t-butoxide, sodium ethoxide, 1,8-diazabicyclo [5.4.0] undes-
7-ene (DBU).

Examples of usable solvents include ether solvents such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; alcohol solvents such as methanol, ethanol and propanol; Amide solvents such as dimethylformamide, acetamide and dimethylacetamide; and halogenated hydrocarbon solvents such as chloroform, dichloromethane and carbon tetrachloride. Moreover, you may use these mixed solvents.

The reaction temperature may be generally in the range of 30 ° C. to 150 ° C., preferably in the range of 50 ° C. to 100 ° C. The reaction time may usually be in the range from 5 minutes to 72 hours, preferably in the range from 10 minutes to 24 hours.

Reductive Amination Reaction The compound (I) can be obtained from the compound (XIII) by a method usually used in this field. For example,
After reacting compound (XIII) with basic compound HG, compound (I) can be obtained by further treating with a reducing agent.

As a reducing agent that can be used, complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride and the like may be used. Examples of the solvent that can be used include alcohol solvents such as methanol, ethanol, and propanol; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as hexane, pentane, benzene, toluene, and xylene; A mixed solvent is mentioned.

The reductive amination reaction may be carried out usually at a temperature in the range of -78 ° C to 100 ° C, preferably in the range of -10 ° C to room temperature. The reaction time may be generally from 5 minutes to 120 hours, preferably from 30 minutes to 48 hours.

Reduction Reaction The carbonyl group of compound (XIII) or compound (X
The corresponding alcohol (XIV) can be obtained by reducing the ester group of IIIa). The reduction may be performed by a method usually used in this field. For example, a method of performing treatment in the presence of a reducing agent may be mentioned. Examples of the reducing agent include a borohydride compound and an aluminum hydride compound, and preferably include diisobutylaluminum hydride. In this reaction, a solvent may be used, and is appropriately selected depending on the reducing agent.
Alcoholic solvents such as ethanol and propanol, N,
Amide solvents such as N-dimethylformamide, acetamide and dimethylacetamide; chlorine solvents such as chloroform, dichloromethane and carbon tetrachloride; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; hexane, pentane, benzene, toluene and xylene Or a mixed solvent thereof. The reaction temperature may be generally in the range of -78C to 100C, preferably in the range of -78C to room temperature. The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Oxidation Reaction To obtain compound (XIII) from compound (XIV),
What is necessary is just to carry out by the method usually used in this field. For example, a method of performing treatment in the presence of an oxidizing agent may be mentioned. Examples of the oxidizing agent include silver oxide, lead tetraacetate, a chromium-based oxidizing agent, and a manganese-based oxidizing agent, and preferably include manganese dioxide. In this reaction, a solvent may be used and appropriately selected depending on the reducing agent. For example, ketone solvents such as acetone and ethyl methyl ketone, amide solvents such as N, N-dimethylformamide, acetamide and dimethylacetamide, chloroform, dichloromethane , Chlorinated solvents such as carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, hydrocarbon solvents such as hexane, pentane, benzene, toluene, xylene, basic solvents such as pyridine, acetic acid, phosphoric acid, etc. Or a mixed solvent thereof. The reaction temperature may usually be in the range of -78C to 100C. The reaction time may be generally in the range of 5 minutes to 120 hours, preferably in the range of 30 minutes to 48 hours.

Amino Group Substitution Reaction After converting the hydroxyl group of compound (XIV) to a leaving group such as halogen or a sulfonic acid ester, the compound (XIV) is subjected to a substitution reaction with a basic compound HG to give the corresponding compound (XIV). I) can be obtained. In order to convert the hydroxyl group into a leaving group such as a halogen or a sulfonic acid ester, a method generally used in this field may be used.

Examples of the halogenation method include a method of treating with phosphorus trihalide, phosphorus pentahalide, or the like in a solvent such as dichloromethane or chloroform, or a method of treating hexachloroacetone in a solvent such as dichloromethane or chloroform.
Or a method of treating with carbon tetrachloride and triphenylphosphine, or a method of treating with a Vilsmeier reagent such as N, N-dimethylchloroforminium chloride or bromide in a solvent such as N, N-dimethylformamide or dioxane. Can be

Examples of the sulfonylation method include a method of treating with methanesulfonyl chloride or p-toluenesulfonyl chloride in a solvent in the presence of an appropriate base. The substitution reaction between the derivative of compound (XIV) and basic compound HG may be performed by a method generally used in this field. For example, compound (I) can be obtained by heating a mixture of a derivative of compound (XIV) and basic compound HG in a solvent such as acetonitrile in the presence of a base such as potassium carbonate.

The compound of the present invention can be converted into a physiologically acceptable salt by converting it with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid or an organic acid such as formic acid, acetic acid or methanesulfonic acid, if desired. . The free form or salt of the compound of the present invention may exist as a hydrate.

The antitumor agent of the present invention can be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, or by various methods such as oral administration. Among these administration methods, intravenous administration by an aqueous preparation and oral administration are preferred. Aqueous preparations can be prepared as acid adducts with pharmacologically acceptable acids. In the case of oral administration, it may be in a free form or in a salt form. As for the preparation method of the preparation, an appropriate preparation is selected according to the administration method, and the preparation can be prepared by a commonly used preparation method of various preparations.

The oral preparations of the antitumor preparations of the present invention include, for example, tablets, powders, granules, capsules,
Examples include solutions, syrups, elixirs, oily and aqueous suspensions, and the like. Injectables may use stabilizers, preservatives, and solubilizers in the formulation, and may contain solutions that may contain these auxiliaries in a container, and then be prepared as a solid formulation by freeze-drying etc. May be prepared as a preparation. One dose may be stored in a container, or multiple doses may be stored in the same container. Liquid preparations include solutions, suspensions, emulsions, and the like. When preparing these preparations, suspending agents, emulsifiers, and the like can also be used as additives.

The antitumor agent containing the compound of the present invention is preferably administered as a compound once a day per adult and repeated at appropriate intervals. Also, the dose ranges from 1 mg to 3 g, preferably from 5 mg to 2 g. Next, the antitumor effect of the compound of the present invention obtained as described above will be shown by experimental examples.

Experimental Example 1 10% fetal bovine serum, 2 mM L-glutamine, 100%
RPMI 1640 containing μg / ml kanamycin sulfate
1.0 × 10 ³ c of human lung cancer strain PC-12 passaged in
cells were seeded in a 96-well microplate at a concentration of cells / 150 μl / well.
0 μl / well was added. Thereafter, the cells were cultured for 3 days.
TT (3- (4,5-dimethylthiazol-2-yl)
(2,5-diphenyl-2H-tetrazolium bromide) was added at 20 μl / well. After 4 hours, the culture solution was removed, dimethyl sulfoxide was added at 150 μl / well, and the absorbance was measured at 540 nm. The antitumor effect was expressed as a GI ₅₀ value (ng / ml), which was the drug concentration at which the cell proliferation of the drug-added group was 50% of that of the control group.

[0158]

[Table 1]

The compounds synthesized in the present invention show antitumor activity as shown in Table 1, and can be applied as antitumor agents for treating various tumors.

Test Example 2 << Cooperative Movement Inhibition Test >> A rotating rod (diameter 3 cm) of a rota-rod device (Natsume Seisakusho) was set at a rotation speed of 10 rpm, and a mouse (Balb / c) that remained on the rod for 60 seconds or more was selected. . After 1, 4 and 24 hours after the oral administration of the test substance, the mouse was placed on a rotating rod, and the mouse that fell within 60 seconds was determined to have a positive effect on the coordination.
Table 2 shows the results.

[0161]

[Table 2]

*: Mouse fibrosarcoma Meth A was subcutaneously transplanted into mice (d0), and the test substance was orally administered in 4 doses (d7-10) or 5 doses (d7-11). Tumor effect (I
R) was determined. **: Number of mice with positive cooperative movement inhibition / Number of test mice ***: Not performed.

The compound of the present invention was applied to a previously filed patent (Japanese Patent Application
7-247096) The compound represented by Example 31 is orally administered to mice at a single dose near the maximum tolerated dose that exhibits an antitumor effect (10 m in Example 31 of Japanese Patent Application No. 7-247096).
g dose), a strong inhibitory effect on coordination was observed. On the other hand, the series of compounds filed in this patent is IR58%
A dose showing the above efficacy or a higher dose
A single dose showed no or only a very weak effect on coordination.

[0164]

The present invention will be described in more detail with reference to the following Examples (in the structural formulas of Examples, Me represents a methyl group,
Represents a t-butoxycarbonyl group).

Example 1 3- [3- [1- (4-amino-2-pyrimidinyl)-
5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a,
5,6-hexahydro-1H-pyrazino [1,2-a]
Quinoline hydrochloride (isomer A)

[0166]

Embedded image

(1) 2-hydrazino-4- (4-methoxybenzylamino) pyrimidine 2,5.7-dichloropyrimidine 15.7 cooled to 0 ° C
g, potassium carbonate (14.4 g) and dimethylformamide (60 ml) were added with 4-methoxybenzylamine (21 ml), and the mixture was stirred at room temperature for 48 hours.
The reaction solution was poured into ice water, stirred for 1 hour, and the precipitate was collected by filtration. The obtained solid was dissolved in 280 ml of tetrahydrofuran, 44 ml of an 80% aqueous hydrazine solution and 23.5 g of potassium carbonate were added, and the mixture was heated under reflux for 24 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was stirred at room temperature for 1 hour. The insolubles were collected by filtration, washed with water, and dried to give the title compound 17.
1 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 3 H), 4.45
(br, 2 H), 5.00-5.20 (br, 1 H), 5.78 (d, 1 H, J =
6Hz), 6.16 (br, 1 H), 6.88 (d, 2 H, J = 9 Hz), 7.
24 (d, 2 H, J = 9 Hz), 7.87 (d, 1 H, J = 6 Hz).

(2) Ethyl 1- [4- (4-methoxybenzylamino) -2-pyrimidinyl] -5-methyl-4-pyrazolecarboxylate 6.70 g of ethyl ethoxymethyleneacetoacetate
7.35 g of the compound obtained in Example 1- (1) was added to 60 ml of an ethanol solution containing, and the mixture was stirred at room temperature for 30 minutes.
The mixture was heated under reflux for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (1: 2), and the fraction containing the desired product was concentrated. Yielded 8.64 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (t, 3 H, J = 7 Hz), 2.92
(s, 3 H), 3.81 (s, 3 H), 4.31 (q, 2 H, J = 7 Hz),
4.51 (br, 2 H), 6.30 (d, 1 H, J = 6 Hz), 6.89 (d,
2H, J = 9 Hz), 7.25 (d, 2 H, J = 9 Hz), 8.05 (s,
1H), 8.25 (d, 1H, J = 6 Hz).

(3) 1- [4- (4-Methoxybenzylamino) -2-pyrimidinyl] -5-methyl-4-pyrazolecarbaldehyde Compound obtained in Example 1- (2) under a nitrogen atmosphere. 0g
Was cooled to -78 ° C, 76 ml of diisobutylaluminum hydride (1M hexane solution) was added over 30 minutes, and the mixture was stirred at the same temperature for 5 hours. Add 10% aqueous potassium tartrate solution 100
After adding ml, the mixture was stirred at room temperature for 15 hours. After extracting the reaction solution with a mixed solvent of methanol-chloroform (1: 9), the organic layer was dried, and the solvent was distilled off under reduced pressure. Dioxane (120 ml) and activated manganese dioxide (14.9) were added to the residue.
After adding g, the mixture was stirred at room temperature for 24 hours. After removing insolubles by Celite filtration, the filtrate was concentrated. Ether was added to the residue, the mixture was stirred at room temperature for 3 hours, and the precipitate was collected by filtration to obtain 5.38 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.92 (s, 3 H), 3.81 (s, 3 H),
4.40-4.60 (br, 2 H), 6.33 (d, 1 H, J = 6 Hz), 6.90
(d, 2 H, J = 9 Hz), 7.25 (d, 2 H, J = 9 Hz), 8.10
(s, 1 H), 8.26 (d, 1 H, J = 6 Hz), 10.00 (s, 1 H).

(4) 3- [1- [4- (4-methoxybenzylamino) -2-pyrimidinyl] -5-methyl-4
-Pyrazolyl] -2-trans-ethyl propenoate 5.38 g of the compound obtained in Example 1- (3), 6.95 g of (carboethoxymethylene) triphenylphosphorane,
And 80 ml of toluene at 80 ° C. for 16
Stirred for hours. After the reaction solution was stirred at room temperature for 24 hours, the precipitate was collected by filtration to obtain 4.45 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hz), 2.71
(s, 3 H), 3.81 (s, 3 H), 4.25 (q, 2 H, J = 7 Hz),
4.45-4.60 (br, 2 H), 6.26 (d, 1 H, J = 16 Hz), 6.2
8 (d, 1 H, J = 6 Hz), 6.89 (d, 2 H, J = 8 Hz), 7.2
5 (d, 2 H, J = 8 Hz), 7.61 (d, 1 H, J = 16 Hz), 7.9
2 (s, 1 H), 8.24 (d, 1 H, J = 6 Hz).

(5) 3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-tr
ans-Ethyl propenoate 5.83 g of the compound obtained in Example 1- (4) was dissolved in 150 ml of trifluoroacetic acid, and the mixture was heated under reflux for 19 hours.
The reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added, extracted with 10% methanol-chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with ether to obtain 2.07 g of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (t, 3 H, J = 7 Hz), 2.75
(s, 3H), 3.15 (br s, 2H), 4.25-4.27 (m, 2 H), 6.27
(d, 1 H, J = 16 Hz), 6.47 (d, 1 H, J = 6 Hz), 7.6
0 (d, 1 H, J = 16 Hz), 7.94 (s, 1 H), 8.14 (d, 1
(H, J = 6 Hz).

(6) 3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-tr
ans-Propenal To 2.07 g of the compound obtained in Example 1- (5), 100 ml of dichloromethane was added, and diisobutylaluminum hydride (1M hexane solution) was added at 25 ° C. under a nitrogen atmosphere at −78 ° C.
Then, the mixture was stirred at the same temperature for 15 minutes and at ice temperature for 30 minutes. A saturated aqueous potassium tartrate solution was added to the reaction solution, stirred at room temperature, extracted with 10% methanol-chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The aqueous layer was further subjected to HP-20 column chromatography.
It was eluted with methanol and concentrated together with the above extract. 100 ml of 1,4-dioxane and 5.27 g of active manganese dioxide were added to the residue, and the mixture was stirred at 50 ° C. for 16 hours.
The insolubles were filtered through celite, washed with an organic layer of chloroform-methanol-water (7: 3: 1), and the solvent was distilled off. The residue was recrystallized from ethanol-ether to give 1.00 g of the title compound as a slightly brown powder. ¹ H-NMR (CD ₃ O
D-CDCl ₃ ) δ: 2.78 (s, 3 H), 6.39 (d, 1 H, J = 5 H
z), 6.56 (dd, 1 H, J = 16 Hz, 8 Hz), 7.44 (d, 1 H,
J = 16 Hz), 7.96 (s, 1 H), 8.14 (d, 1 H, J = 5 H
z), 9.62 (d, 1 H, J = 8 Hz).

(7) 7-Fluoro-2-quinolinecarboxylic acid 9.64 g of 7-fluoroquinaldine, sodium acetate 3
0 g and 60 ml of acetic acid at 70 ° C.
At 20.degree. C., a mixture consisting of 9.1 ml of bromine and 8 ml of acetic acid is added.
Added over a minute. The reaction solution was stirred at 90 ° C. for 1 hour, cooled to room temperature, and then concentrated under reduced pressure. After adding water to the residue, the insoluble matter was collected by filtration and washed with water to obtain 20.0 g of 7-fluoro-2-tribromoquinoline. 200 ml of concentrated sulfuric acid was added to the obtained compound,
After stirring for 0 hours, the reaction solution was poured into about 600 ml of ice. A 28% aqueous ammonia solution was added to the obtained acidic aqueous solution to make it alkaline, and then a 1N aqueous phosphoric acid solution was added to add p
H was adjusted to around 4, and extracted with chloroform. The organic layer was dried and concentrated, and the obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (9: 1), and the fraction containing the desired compound was concentrated to give the title compound. 9.04 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.52 (t, 1 H, J = 9 Hz), 7.80
(d, 1 H, J = 9 Hz), 7.97 (dd, 1 H, J = 6 Hz, 9 H
z), 8.27 (d, 1 H, J = 8 Hz), 8.43 (d, 1 H, J = 8 H
z).

(8) 7-Fluoro-2- [N- (1-phenylethyl) carbamoyl] -1,2,3,4-tetrahydroquinoline (diastereoisomer A and diastereoisomer B) 9.04 g of the compound obtained in (7) was treated with 300 parts of acetic acid.
After adding 1.0 g of platinum oxide, catalytic hydrogenation was performed for 6 hours. After removing the insoluble matter by filtration and concentrating the filtrate to dryness, the residue was dissolved in ethyl acetate,
Washed with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 300 ml of dichloromethane, and (s)-
8.5 g of (-)-1-phenylethylamine, 8.6 g of dimethylaminopyridine, and 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride 17
After adding g, the mixture was stirred at room temperature for 20 hours. The reaction solution is water,
After sequentially washing with a 1N aqueous solution of phosphoric acid and saturated saline, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of ethyl acetate-hexane (2: 5), and 5.78 g of a low-polar isomer (diastereoisomer A) and a high-polar isomer (diastereoisomer) of the title compound were obtained. 5.17 g of isomer B) were obtained. Diastereoisomer A; ¹ H-NMR (CDCl ₃ ) δ: 1.45 (d, 3 H, J = 7 Hz), 1.85-
1.94 (m, 1 H), 2.30-2.38 (m, 1 H), 2.50-2.59 (m, 1
H), 2.65-2.75 (m, 1 H), 3.96 (q, 1 H, J = 5Hz),
4.19 (d, 1 H, J = 5 Hz), 5.12-5.20 (m, 1 H), 6.32
(dd, 1 H, J = 2 Hz, 10 Hz), 6.41 (dt, 1 H, J = 2 H
z, 8 Hz), 6.88 (d, 1 H, J = 8 Hz), 6.93 (t, 1 H, J
= 8 Hz), 7.25-7.40 (m, 5 H). Diastereoisomer B; ¹ H-NMR (CDCl ₃ ) δ: 1.49 (d, 3 H, J = 7 Hz), 1.83-
1.91 (m, 1 H), 2.24-2.32 (m, 1 H), 2.37-2.45 (m, 1
H), 2.60-2.67 (m, 1 H), 4.01 (q, 1 H, J = 5Hz),
4.24 (d, 1 H, J = 5 Hz), 5.10-5.17 (m, 1 H), 6.36
(dd, 1 H, J = 2 Hz, 10 Hz), 6.42 (dt, 1 H, J = 2 H
z, 8 Hz), 6.90 (t, 1 H, J = 8 Hz), 6.85-6.95 (br,
1H), 7.15-7.30 (m, 5H). (9) 7-Fluoro-2- [N- (1-phenylethyl) -N-tert-butoxycarbonylaminomethyl] -1,2,3,4 -Tetrahydroquinoline (diastereoisomer A)

5.78 g of the diastereoisomer A obtained in Example 1- (8) was dissolved in 80 ml of tetrahydrofuran, and the mixture was stirred at 0 ° C. with borane-dimethylsulfide complex 16
After adding ml, the mixture was stirred at room temperature for 3 days. A 6N hydrochloric acid aqueous solution was added, and the mixture was stirred for 1 hour. After extraction with chloroform, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 56 ml of dioxane, 5.5 g of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 40 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, developing with a mixed solvent of ethyl acetate-hexane (1: 9) and concentrating the fraction containing the desired product to give the title compound 7. 61 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.30 (m, 1 H), 1.53 (s, 9
H), 1.54 (d, 3 H, J = 9 Hz), 1.79-1.82 (m, 1 H), 2.
50-2.70 (m, 2 H), 2.95-3.10 (br, 1 H), 3.18 (dd, 1
H, J = 14 Hz, 3 Hz), 3.25-3.45 (br, 1 H), 5.70-5.8
5 (br, 1 H), 6.19 (td, 1 H, J = 8 Hz, 2 Hz), 6.77
(dd, 1 H, J = 8 Hz, 7 Hz), 7.30-7.45 (m, 6 H).

(10) 9-Fluoro-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1-oxopyrazino [1,2-a] quinoline (diastereoisomer A 7.61 g of the compound obtained in Example 1- (9) is dissolved in 50 ml of tetrahydrofuran, and 2.45 ml of pyridine and 1.75 m of chloroacetyl chloride are stirred at 0 ° C.
After adding l, the mixture was stirred at room temperature for 30 minutes. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was washed with tetrahydrofuran 20
Then, the mixture was dissolved in trifluoroacetic acid (25 ml), and the mixture was stirred at room temperature for 2 hours and further at 50 ° C for 1 hour. After the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in dimethylformamide (50 ml), potassium carbonate (4.6 g) was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
9) The mixture was developed with a mixed solvent, and the fraction containing the desired compound was concentrated to obtain 5.09 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (d, 3 H, J = 7 Hz), 1.75-
1.95 (m, 2 H), 2.25 (dd, 1 H, J = 12 Hz, 9 Hz), 2.
80 (dd, 1 H, J = 8 Hz, 5 Hz), 2.96 (ddd, 1 H, J = 1
2 Hz, 5 Hz, 2 Hz), 3.07 (d, 1 H, J = 17 Hz), 3.37
(q, 1 H, J = 7 Hz), 3.58-3.65 (m, 1 H), 3.78 (dd,
1 H, J = 17 Hz, 2 Hz), 6.77 (td, 1 H, J = 8 Hz, 2 H
z), 7.03 (dd, 1 H, J = 8 Hz, 6 Hz), 7.25-7.40 (m,
5 H), 7.93 (dd, 1 H, J = 12 Hz, 2 Hz).

(11) 9-Fluoro-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (diastereoisomer A 5.9 g of the compound obtained in Example 1- (10) was added to a diborane solution prepared by suspending 5.9 g of sodium borohydride in 20 ml of tetrahydrofuran and adding 25.6 ml of a boron trifluoride diethyl ether complex. A tetrahydrofuran solution (30 ml) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to 0 ° C., and a 6N aqueous hydrochloric acid solution was added, followed by stirring at 80 ° C. for 1 hour and further at room temperature for 48 hours.
After neutralization with a saturated aqueous sodium hydrogen carbonate solution and extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of ethyl acetate-hexane (1: 9), and the fraction containing the desired product was concentrated. 2.52 g of the title compound were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (d, 3 H, J = 6 Hz), 1.56-
1.81 (m, 3 H), 2.18-2.25 (m, 1 H), 2.57-2.63 (m, 1
H), 2.70-2.78 (m, 2 H), 2.78-2.98 (m, 2 H), 3.18
(dd, 1 H, J = 11 Hz, 3 Hz), 3.35 (q, 1 H, J = 7 H
z), 3.66 (d, 1 H, J = 11 Hz), 6.34 (td, 1 H, J = 8
Hz, 2 Hz), 6.46 (dd, 1 H, J = 13 Hz, 2Hz), 6.85
(t, 1 H, J = 8 Hz), 7.23-7.33 (m, 5 Hz).

(12) 9-Fluoro-2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [1,2-
a] Quinoline (enantiomer A) 40 ml of 2.52 g of the compound obtained in Example 1- (11)
2.54 g of ammonium formate
After adding 2.5 g of 10% palladium on carbon, 1.
The mixture was refluxed for 5 hours. After removing insoluble matter by filtration,
The filtrate was concentrated under reduced pressure. Saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of methanol and chloroform (7:10), and the fraction containing the desired compound was concentrated to give the title compound 1.56.
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.67-1.78 (m, 1 H), 1.89-1.96
(m, 1 H), 2.63-2.72 (m, 2 H), 2.76-2.84 (m, 1 H),
2.95-3.04 (m, 2 H), 3.13-3.32 (m, 2 H), 3.67-3.76
(m, 1 H), 6.40 (td, 1 H, J = 8 Hz, 2 Hz), 6.47 (d
d, 1 H, J = 12 Hz, 2 Hz), 6.90 (t, 1 H, J = 8 Hz).

(13) 3- [3- [1- (4-amino-
2-pyrimidinyl) -5-methyl-4-pyrazolyl]-
2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer A) -120 mg of the compound obtained in (12), Example 1
-A mixture of 133 mg of the aldehyde obtained in (6) and 20 ml of ethanol was stirred at 80 ° C. for 1 hour, cooled to room temperature, 0.33 ml of acetic acid was added, and 110 mg of sodium cyanoborohydride was divided into three portions. And added every hour. After stirring at room temperature for 13 hours, water and a saturated aqueous solution of sodium carbonate were added to the reaction solution, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, the resulting residue was subjected to silica gel column chromatography to give methanol-
The mixture was developed with a mixed solvent of chloroform (2:98), and the fraction containing the target compound was concentrated. The obtained residue (166 mg) was dissolved in isopropyl alcohol (10 ml) by heating. After hot addition of 1N hydrochloric acid-ethanol (0.45 ml), the mixture was allowed to stand at room temperature for 10 hours, and the precipitate was collected by filtration to give 105 mg of the title compound. Obtained. Melting point: 188-194 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.55 (m, 1 H), 1.98-2.10 (m,
1H), 2.57 (s, 3 H), 2.60-3.00 (m, 2 H), 3.00-3.20
(m, 2 H), 3.25-3.45 (m, 4 H), 3.50-3.60 (m, 1H),
3.85-3.95 (m, 1 H), 4.05-4.15 (m, 1 H), 6.17 (dt,
1 H, J = 16 Hz, 7 Hz), 6.41 (d, 1 H, J = 6 Hz), 6.4
7 (td, 1 H, J = 8 Hz, 2 Hz), 6.78 (d, 1 H, J = 16 H
z), 6.78-6.80 (m, 1 H), 6.98 (t, 1 H, J = 8 Hz),
7.34 (brs, 2 H), 7.96 (s, 1 H), 8.11 (d, 1 H, J = 6
Hz), 10.6-10.7 (br, 1 H).

Example 2 3- [3- [1- (4-amino-2-pyrimidinyl)-
5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a,
5,6-hexahydro-1H-pyrazino [1,2-a]
Quinoline hydrochloride (isomer B)

[0181]

Embedded image

(1) 7-Fluoro-2- [N- (1-phenylethyl) -N-tert-butoxycarbonylaminomethyl] -1,2,3,4-tetrahydroquinoline (diastereoisomer B) Diastereomer B5.17 obtained in Example 1- (8)
g was reacted in the same manner as in Example 1- (9) and worked up to give 6.93 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.60 (m, 1 H), 1.47 (s, 9
H), 1.54 (d, 3 H, J = 9 Hz), 2.50-2.55 (m, 2 H), 3.
00-3.20 (m, 3 H), 5.25-5.45 (br, 1 H), 6.10 (dd, 1
H, J = 11 Hz, 2 Hz), 6.23 (td, 1 H, J = 8 Hz, 2 H
z), 6.78 (dd, 1H, J = 8 Hz, 7 Hz), 7.20-7.40 (m, 5
H).

(2) 9-fluoro-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-
1-oxopyrazino [1,2-a] quinoline (diastereoisomer B) 6.93 g of the compound obtained in Example 2- (1) was prepared in Example 1
The reaction was carried out in the same manner as in (10), and post-treatment was carried out to obtain 5.28 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (d, 3 H, J = 7 Hz), 1.83-
1.90 (m, 2 H), 2.02-2.15 (m, 1 H), 2.50 (dd, 1 H,
J = 12 Hz, 6 Hz), 2.79-2.94 (m, 2 H), 3.33 (s, 2
H), 3.42 (q, 1 H, J = 6 Hz), 3.50-3.62 (m, 1 H),
6.78 (td, 1 H, J = 8 Hz, 2 Hz), 7.04 (dd, 1 H, J =
8 Hz, 7 Hz), 7.26-7.40 (m, 5 H), 7.81 (dd, 1 H, J
= 12 Hz, 2 Hz).

(3) 9-fluoro-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-
1H-pyrazino [1,2-a] quinoline (diastereoisomer B) 5.28 g of the compound obtained in Example 2- (2) was prepared in Example 1
The reaction was carried out in the same manner as in (11), and post-treatment was performed to obtain 2.45 g of the title compound. ¹ H-NMR (CDCl ₃ ) d: 1.39 (d, 3 H, J = 6 Hz), 1.68-1.8
0 (m, 1 H), 1.86-2.13 (m, 3 H), 2.63-2.70 (m, 1 H),
2.74-2.85 (m, 2 H), 3.04-3.12 (m, 2 H), 3.35-3.40
(m, 1 H), 3.48-3.53 (m, 1 H), 6.34 (td, 1 H, J =
8 Hz, 2 Hz), 6.40 (dd, 1 H, J = 13 Hz, 2 Hz), 6.87
(t, 1 H, J = 8 Hz), 7.24-7.33 (m, 5 Hz).

(4) 9-fluoro-2,3,4,4a,
5,6-hexahydro-1H-pyrazino [1,2-a]
Quinoline (enantiomer B) 2.45 g of the compound obtained in Example 2- (3) was prepared in Example 1-
The reaction was carried out in the same manner as in (12), and the mixture was worked up to obtain 1.57 g of the title compound. ^{The 1} H-NMR spectrum completely coincided with the spectrum of the compound obtained in Example 1- (12).

(5) 3- [3- [1- (4-amino-2)
-Pyrimidinyl) -5-methyl-4-pyrazolyl] -2
-Trans-propen-1-yl] -9-fluoro-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer B) 128 mg of the compound obtained in Example 2- (4) and Example 1- ( 142-mg of the aldehyde obtained in 6)
The reaction was carried out in the same manner as in (13), and the mixture was worked up to obtain 104 mg of the title compound. Melting point: 192-194 ° C (decomposition) The ¹ H-NMR spectrum completely coincided with the spectrum of the compound obtained in Example 1- (13).

Example 3 (+/-)-3- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-tr
ans-propen-1-yl] -9-fluoro-2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride

[0188]

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(1) 1- (4-Fluoro-2-nitrophenoxy) -2,3-epoxypropane 31.4 g of 4-fluoro-2-nitrophenol, 100 ml of epichlorohydrin, 9.1 sodium hydroxide
g, 40 ml of water and 900 ml of ethanol were stirred at 80 ° C. for 10 hours. After the reaction solution was cooled to room temperature, insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with ether-hexane (1: 1)
It was dissolved in a mixed solvent, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform and hexane (3: 1), and the fraction containing the desired product was concentrated to obtain 27.9 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.84 (dd, 1 H, J = 5 Hz, 2 Hz),
2.93 (t, 1 H, J = 5 Hz), 3.36-3.40 (m, 1 H), 4.10
(dd, 1 H, J = 11 Hz, 5 Hz), 4.41 (dd, 1 H, J = 11
Hz, 3 Hz), 7.14 (dd, 1 H, J = 9 Hz, 4 Hz), 7.24-7.
30 (m, 1 H), 7.60 (dd, 1 H, J = 8 Hz, 3 Hz).

(2) 1- (4-Fluoro-2-nitrophenoxy) -2-hydroxy-3-phthalimidopropane 4.49 g of the compound obtained in Example 3- (1), 3.10 g of phthalimide, 0.1% of pyridine. After heating a mixture consisting of 21 ml and 20 ml of butanol to reflux for 16 hours,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and methanol-chloroform (2:
98) The mixture was developed with a mixed solvent, and the fraction containing the desired product was concentrated to give 3.90 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.07 (d, 1 H, J = 6 Hz), 3.99
(dd, 1 H, J = 14 Hz, 5Hz), 4.03 (dd, 1 H, J = 14 H
z, 6 Hz), 4.14 (dd, 1 H, J = 9 Hz, 5 Hz), 4.22 (d
d, 1 H, J = 9 Hz, 4 Hz), 4.30-4.40 (m, 1 H), 7.10
(dd, 1 H, J = 9 Hz, 4 Hz), 7.25-7.31 (m, 1 H), 7.6
5 (dd, 1 H, J = 8 Hz, 3 Hz), 7.74 (2 H, dd, J = 5 H
z, 3 Hz), 7.87 (dd, 2 H, J = 5 Hz, 3 Hz).

(3) 6-Fluoro-3-phthalimidomethyl-1,4-benzoxazine 3.85 g of the compound obtained in Example 3- (2) was treated with acetone 1
2 ml, Jones reagent 10 ml (chromic acid 4 g, concentrated sulfuric acid 2 m) while maintaining the internal temperature at 15 to 20 ° C.
and 8 ml of water), and the mixture was stirred at room temperature for 3 hours. After water was added to the reaction solution to dilute it, insolubles were collected by filtration. The obtained compound was dissolved in 200 ml of ethanol and subjected to catalytic hydrogenation in the presence of Raney nickel for 24 hours. After removing insoluble matter by filtration, the filtrate was concentrated to dryness, and the obtained crystalline residue was dissolved by heating in 50 ml of ethanol. After cooling to room temperature, 6.1 ml of acetic acid
And 1.3 g of sodium cyanoborohydride were added,
Stir for 1 hour. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, developed with chloroform, and the fraction containing the desired product was concentrated to obtain 1.79 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.75-3.97 (m, 4 H), 4.19-4.24
(m, 2 H), 6.27-6.32 (m, 1 H), 6.66-6.70 (m, 1 H),
7.75 (dd, 2 H, J = 5 Hz, 3 Hz), 7.87 (dd, 2 H, J =
(5 Hz, 3 Hz).

(4) 3-aminomethyl-6-fluoro-
1,4-Benzoxazine 1.79 g of the compound obtained in Example 3- (3) was dissolved in 40 ml of ethanol, 0.9 ml of hydrazine monohydrate was added, and the mixture was heated under reflux for 3 hours. The residue obtained by distilling off the solvent was dissolved in water, 6 ml of acetic acid was added, and the mixture was stirred at room temperature for 30 minutes and then at 0 ° C. for 30 minutes. The insolubles were removed by filtration, the filtrate was made alkaline with a 10% aqueous sodium hydroxide solution, and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 972 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (dd, 1 H, J = 12 Hz, 8 H
z), 2.92 (dd, 1 H, J = 12 Hz, 5 Hz), 3.30 (m, 1
H), 3.93 (dd, 1 H, J = 11 Hz, 7 Hz), 4.17 (dd, 1H,
J = 11 Hz, 4 Hz), 4.35 (brs, 1 H), 6.28-6.35 (m,
2 H), 6.68 (dd, 1H, J = 8 Hz, 5 Hz).

(5) 3-benzylaminomethyl-6-fluoro-1,4-benzoxazine 972 mg of the compound obtained in Example 3- (4) and 553 mg of benzaldehyde were dissolved in 30 ml of ethanol, and the mixture was stirred at 50 ° C. for 1 hour. After that, the reaction solution was concentrated to dryness. The residue was dissolved in 30 ml of newly added ethanol, 1.53 ml of acetic acid was added, and then 1.0 g of sodium cyanoborohydride was added, followed by stirring at room temperature for 2 hours. After the reaction solution was concentrated, a 1N aqueous solution of sodium hydroxide was added to the residue, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography, developed with a methanol-chloroform mixed solvent (2:98), and containing the target compound. The fraction was concentrated to give the title compound (1.03 g). ¹ H-NMR (CDCl ₃ ) δ: 2.61 (dd, 1 H, J = 12 Hz, 9 H
z), 2.80 (dd, 1 H, J = 12Hz, 4 Hz), 3.40-3.48 (m, 1
H), 3.80, 3.81 (ABq, 2 H, J = 13 Hz), 3.87 (dd, 1
H, J = 10 Hz, 7 Hz), 4.16 (ddd, J = 10 Hz, 3 Hz,
1 Hz), 4.41 (brs, 1 H), 6.25-6.32 (m, 2 H), 6.64-6.
70 (m, 1 H), 6.64-6.70 (m, 1 H), 7.20-7.36 (m, 5
H).

(6) 3-benzyl-1,2-dioxo-
9-fluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine 1.02 g of the compound obtained in Example 3- (5) 2 ml of diethyl oxalate are added, at 110 ° C. for 11 hours, and then for 15 hours.
Heat at 0 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ether to obtain 777 mg of the title compound as a slightly pink powder.

(7) 3-benzyl-9-fluoro-2,
3,4,4a, 5,6, -Hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine 942 mg of sodium borohydride are suspended in 15 ml of tetrahydrofuran, and boron trifluoride diethyl ether is added at room temperature. The complex was added dropwise and stirred for 1 hour. Next, Example 3
-The compound (677 mg) obtained in (6) was added to the reaction solution in several portions, and the mixture was heated under reflux for 2 hours. The reaction solution was poured little by little into 60 ml of concentrated hydrochloric acid under ice cooling and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to make the liquid alkaline, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline.
The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, eluted with a mixed solvent of ethyl acetate-hexane (1: 6-1: 5), and the fraction containing the desired product was concentrated. This gave 575 mg of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.82 (t, 1 H, J = 11 Hz), 2.28
(dt, 1 H, J = 4 Hz, 12 Hz), 2.79-2.89 (m, 2 H), 2.9
5-2.98 (m, 2 H), 3.18-3.20 (m, 2 H), 3.52-3.54 (m,
1H), 3.51, 3.59 (ABq, 2 H, J = 13 Hz), 3.92 (dd,
1 H, J = 9 Hz, 11 Hz), 4.10 (dd, 1 H, J = 3 Hz, 11
Hz), 6.36 (dt, 1 H, J = 3 Hz, 9 Hz), 6.47 (dd, 1 H,
J = 3 Hz, 11 Hz), 6.66 (dd, 1 H, J = 5 Hz, 9 Hz)
7.33-7.34 (m, 5H).

(8) 9-Fluoro-2,3,4,4a,
5,6, -Hexahydro-1H-pyrazino [2,1-
c] -1,4-Benzoxazine 575 mg of the compound obtained in Example 3- (7) was dissolved in 20 ml of methanol, 608 mg of ammonium formate and 580 mg of 10% palladium on carbon were added, and the mixture was heated under reflux for 1 hour. After filtering off the insoluble matter, the solvent was distilled off. To the obtained residue, saturated saline was added, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off.
g were obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.48
(dd, 1 H, J = 11 Hz, 12 Hz), 2.70 (dt, 1 H, J = 3
Hz, 12 Hz), 2.88-3.00 (m, 2 H), 3.05-3.15 (m, 2
H), 3.51 (ddd, 1 H, J = 2 Hz, 3 Hz, 12 Hz), 3.92
(dd, 1 H, J = 9 Hz, 11 Hz), 4.13 (dd, 1 H, J = 3 Hz,
11 Hz), 6.37 (ddd, 1 H, J = 3 Hz, 8 Hz, 9 Hz), 6.4
7 (dd, 1 H, J = 3 Hz, 11 Hz), 6.66 (dd, 1 H, J = 5
Hz, 9 Hz).

(9) (+/-)-3- [3- [1- (4
-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9
-Fluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride 190 mg of the compound obtained in Example 3- (8) and 209 mg of the aldehyde obtained in Example 1- (6) was used in Example 1-
The reaction was carried out in the same manner as in (13), and post-treatment was carried out to obtain 307 mg of the title compound as a white powder. Melting point: 192-199 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.69 (s, 3 H), 2.82-2.88 (m,
1 H), 3.05-3.12 (m, 1H), 3.26 (t, 1 H, J = 12 H
z), 3.56 (d, 2 H, J = 18 Hz), 3.69-3.72 (m, 1H),
3.88-4.00 (m, 3 H), 4.09 (d, 1 H, J = 13 Hz), 4.31
(dd, 1 H, J = 3Hz, 12 Hz), 6.30 (dt, 1 H, J = 16
Hz, 7 Hz), 6.50 (dt, 1 H, J = 3 Hz, 8 Hz), 6.58 (d,
1 H, J = 7 Hz), 6.75 (dd, J = 6 Hz, 8 Hz), 6.82
(d, 1 H, J = 16 Hz), 6.89 (dd, 1 H, J = 3 Hz, 12 H
z), 8.07 (d, 1 H, J = 7 Hz), 8.25 (s, 1 H), 11.79
(br s, 1 H).

Example 4 (+/-)-2- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-tr
ans-propen-1-yl] -1,2,3,4,1
0,10a-hexahydropyrazino [1,2-a] indole hydrochloride

[0199]

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(+/-)-1,2,3,4,10,10
a-Hexahydropyrazino [1,2-a] indole 7
6 mg and 77 m of the aldehyde obtained in Example 1- (6)
g was reacted in the same manner as in Example 1- (13) and worked up to give 100 mg of the title compound as a white powder. Melting point: 173-176 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.65 (s, 3 H), 2.6-2.7 (m, 1
H), 2.9-3.1 (m, 1 H), 3.3-3.6 (m, 5 H), 3.8-4.0
(m, 4 H), 6.16 (dt, 1 H, J = 16, 7 Hz), 6.29 (s, 1
H), 6.65 (d, 1 H, J = 7 Hz), 6.42 (d, 1 H, J = 5 H
z), 6.67 (t, 1 H, J = 7 Hz), 6.75 (d, 1 H, J = 16
Hz), 7.07 (t, 1 H, J = 7 Hz), 7.12 (d, 1 H, J = 7 H
z), 7.3-7.4 (bs, 2 H), 7.94 (s, 1 H), 8.11 (d, 1
H, J = 5 Hz), 11.0-10.9 (m, 1H).

Example 5 3- [3- [1- (2-amino-6-dimethylamino-
4-pyrimidinyl) -5-methyl-4-pyrazolyl]-
2-trans-propen-1-yl] -2,3,4
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline hydrochloride (isomer A)

[0202]

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(1) 1- (2-amino-6-chloro-4)
-Pyrimidinyl) -5-methyl-4-pyrazolecarboxylic acid ethyl 2-amino-4,6-dichloropyrimidine 16.4 g,
Hydrazine monohydrate 25 ml, potassium carbonate 13.8
g and 300 ml of ethanol were heated under reflux for 2 hours, then cooled to room temperature, and the reaction solution was concentrated under reduced pressure. After adding water to the residue, the precipitate was collected by filtration, and 14.0 g of a white powder obtained by filtration was mixed with 300 m of ethanol.
l and ethoxymethylene acetoacetic acid ethyl ester 1
6.3 g was added, and the mixture was stirred at room temperature for 40 minutes, and then heated and refluxed for 2 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain 21.9 g of the title compound as colorless crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (t, 3 H, J = 7 Hz), 3.00
(s, 3 H), 4.33 (q, 2 H, J = 7 Hz), 5.26 (brs, 2 H),
7.33 (s, 1 H), 8.02 (s, 1 H).

(2) 1- (2-amino-6-chloro-4)
-Pyrimidinyl) -5-methyl-4-pyrazolecarbaldehyde 5.00 g of the compound obtained in Example 5- (1) was obtained in Example 1-
The reaction was carried out in the same manner as in (3), and post-treatment was performed to obtain 3.90 g of the title compound as a white solid. ¹ H-NMR (CDCl
₃ ) δ: 3.01 (s, 3H, s, CH3), 5.61 (br, 0.5H), 7.
32 (s, 1 H), 8.08 (s, 1 H), 10.00 (s, 1 H).

(3) Ethyl 3- [1- (2-amino-6-chloro-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenoate Obtained in Example 5- (2) 3.90 g of the compound obtained in Example 1
The same reaction as in (4) was performed and post-treatment was performed to obtain 4.11 g of the title compound as a white solid. ¹ H-NMR (CDCl
₃ ) δ: 1.34 (t, 3H, J = 7Hz), 2.79 (s, 3H), 4.2
6 (q, 2 H, J = 7 Hz), 5.58 (br, 0.5 H), 5.38 (s, 2
H), 6.27 (d, 1 H, J = 16 Hz), 7.31 (s, 1 H), 7.59
(d, 1 H, J = 16 Hz), 7.91 (s, 1 H).

(4) Ethyl 3- [1- (2-amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenoate In Example 5- (3) 1.0 g of the obtained compound, 1.2 ml of a 50% aqueous dimethylamine solution, and 30 ml of ethanol
Was stirred at 50 ° C. for 16.5 hours. During this time, 0.6 ml of a 50% aqueous dimethylamine solution was added to the reaction solution. The reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, water was added to the residue, and the precipitate was collected by filtration to obtain 999 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hzt), 2.73
(s, 3 H), 3.10 (s, 6 H), 4.25 (q, 2 H, J = 7 Hz),
4.76 (brs, 2 H), 6.23 (d, 1 H, J = 16 Hz), 6.37
(s, 1 H), 7.60 (d, 1 H, J = 16 Hz), 7.84 (s, 1 H).

(5) 3- [1- (2-Amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenal Obtained in Example 5- (4). Compound 1.00 g was prepared in Example 1
The reaction was carried out in the same manner as in (6), and the mixture was worked up to give 756 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (s, 3 H), 3.12 (s, 6 H),
4.75 (brs, 2 H), 6.40 (s, 1 H), 6.53 (dd, 1 H, J =
16Hz, 8 Hz), 7.40 (d, 1 H, J = 16 Hz), 7.88 (s, 1
H), 9.63 (d, 1 H, J = 8 Hz).

(6) 3- [3- [1- (2-amino-6)
-Dimethylamino-4-pyrimidinyl) -5-methyl-
4-pyrazolyl] -2-trans-propen-1-yl] -2,3,4,4a, 5,6-hexahydro-1H
-Pyrazino [1,2-a] quinoline hydrochloride (isomer A) (+)-2,3,4,4a, 5,6-hexahydro-1
H-pyrazino [1,2-a] quinoline hydrochloride 206 mg
Then, 50 mg of the aldehyde obtained in Example 5- (5) was suspended in 10 ml of ethanol, 40 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 24 hours. Then, water and a saturated aqueous solution of sodium carbonate were added to the reaction solution, and chloroform was added. Extracted. The organic layer is dried over anhydrous sodium sulfate,
After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography {developed with a mixed solvent of methanol and chloroform (2:98)}. After adding 1N hydrochloric acid-ethanol to 10 mg of the obtained free form of the title compound, the solvent was distilled off, and the residue was recrystallized from isopropyl alcohol to give 5 mg of the title compound.
I got Melting point: 198 ° C. or more (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.80 (m, 1 H), 1.95-2.10
(m, 1 H), 2.67 (s, 3H), 2.60-3.00 (m, 3 H), 3.00-
3.20 (m, 2 H), 3.19 (s, 6 H), 3.30-3.70 (m, 4 H),
3.85-4.00 (m, 1 H), 4.10-4.20 (m, 1 H), 6.26 (dt,
1 H, J = 16 Hz, 7 Hz), 6.41 (s, 1 H), 6.70 (t, 1 H,
J = 8 Hz), 6.82 (d, 1 H, J = 16 Hz), 6.90 (d, 1
H, J = 8 Hz), 6.98 (d, 1 H, J = 6 Hz), 7.04-7.08
(m, 1 H), 8.12 (s, 1 H).

Example 6 3- [3- [1- (2-amino-6-dimethylamino-
4-pyrimidinyl) -5-methyl-4-pyrazolyl]-
2-trans-propen-1-yl] -2,3,4
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline hydrochloride (isomer B)

[0210]

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(-)-2,3,4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (206 mg) and the aldehyde obtained in Example 5- (5) (50 mg) were used. The reaction was carried out in the same manner as in Example 5- (6), and the mixture was worked up to obtain 20 mg of the title compound. Melting point: 191 ° C. or higher (decomposition) The ¹ H-NMR spectrum completely coincided with the spectrum of the compound obtained in Example 5- (6).

Example 7 3- [3- [1- (2-amino-6-dimethylamino-
4-pyrimidinyl) -5-methyl-4-pyrazolyl]-
2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer A)

[0213]

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Amine 198m obtained in Example 1- (12)
g and 261 mg of the aldehyde obtained in Example 5- (5).
Was reacted in the same manner as in Example 1- (13) and post-treated to obtain 120 mg of the title compound. Melting point: 208 ° C. or more (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.70 (m, 1 H), 1.95-2.05
(m, 1 H), 2.67 (s, 3H), 2.60-3.00 (m, 3 H), 3.00-
3.20 (m, 2 H), 3.19 (s, 6 H), 3.30-3.70 (m, 4 H),
3.80-4.00 (m, 1 H), 4.11 (d, 1 H, J = 13 Hz), 6.26
(dt, 1 H, J = 16 Hz, 7 Hz), 6.41 (s, 1 H), 6.47 (t
d, J = 8 Hz, 2 Hz), 6.76 (dd, 1 H, J = 13 Hz, 2 H
z), 6.81 (d, 1 H, J = 16 Hz), 6.98 (t, 1 H, J = 8
Hz), 8.15 (s, 1H), 11.10-11.25 (br, 1H).

Example 8 3- [3- (1- (2-amino-6-dimethylamino-
4-pyrimidinyl) -5-methyl-4-pyrazolyl)-
2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer B)

[0216]

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210 mg of the amine obtained in Example 2- (4)
Further, 277 mg of the aldehyde obtained in Example 5- (5) was reacted in the same manner as in Example 1- (13), and was subjected to post-treatment to obtain 140 mg of the title compound. Melting point: 205 ° C. or more (decomposition) The ¹ H-NMR spectrum completely coincided with that of the compound obtained in Example 7.

Example 9 (+/-)-3- [3- [1- (2-Amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene- 1-yl]-
9-Fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride

[0219]

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175 mg of the amine obtained in Example 3- (8)
Further, 229 mg of the aldehyde obtained in Example 5- (5) was reacted in the same manner as in Example 1- (13), and post-treated to obtain 238 mg of the title compound. Melting point: 197-208 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3 H), 2.83-2.85 (m,
1 H), 3.09-3.28 (m, 2H), 3.19 (s, 6 H), 3.55 (d, 2
H, J = 11 Hz), 3.63-3.68 (m, 1 H), 3.80-4.00 (m,
3 H), 4.09 (d, 1 H, J = 13 Hz), 4.30 (dd, 1 H, J =
3 Hz, 11 Hz), 6.24 (dt, 1 H, J = 8 Hz, 16 Hz), 6.4
2 (d, 1 H, J = 7 Hz), 6.50 (dt, 1 H, J = 3 Hz, 9 H
z),, 6.75 (dd, J = 6 Hz, 9 Hz), 6.81 (d, 1 H, J =
16 Hz), 6.88 (dd, 1 H, J = 3 Hz, 12 Hz), 8.14 (s,
1 H), 11.69 (brs, 1 H).

Example 10 (+/-)-2- [3- [1- (2-Amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene- 1-yl]-
1,2,3,4,10,10a-Hexahydropyrazino [1,2-a] indole hydrochloride

[0222]

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(+/-)-1,2,3,4,10,10
a-Hexahydropyrazino [1,2-a] indole 5
0 mg and 38 m of the aldehyde obtained in Example 5- (5)
g was reacted as in Example 1- (13) and worked up to give 30 mg of the title compound. Melting point: 200-204 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.5-2.6 (m, 1 H), 2.65 (s, 3)
H), 2.9-3.0 (m, 1 H), 3.07 (s, 6 H), 3.3-3.6 (m, 5
H), 3.8-4.0 (m, 4 H), 6.16 (dt, 1 H, J = 16Hz, 7 H
z), 6.29 (s, 1 H), 6.65 (d, 1 H, J = 7 Hz), 6.67
(t, 1 H, J = 7 Hz), 6.75 (d, 1 H, J = 16 Hz), 7.07
(t, 1 H, J = 7 Hz), 7.12 (d, 1 H, J = 7 Hz), 8.00
(s, 1 H), 11.1-11.0 (m, 1 H).

Example 11 2- [3- [1- (2-amino-6-dimethylamino-
4-pyrimidinyl) -5-methyl-4-pyrazolyl]-
2-trans-propen-1-yl] -1,2,3,
4-tetrahydropyrazino [1,2-a] indole

[0225]

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(1) 3- [1- (2-Amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenol Example 5- (5) under a nitrogen atmosphere. 0.7) ester obtained in
30 ml of a dichloromethane solution containing 8 g was cooled to −78 ° C., and 8.0 ml of diisobutylaluminum hydride (1M hexane solution) was added over 20 minutes, followed by stirring at the same temperature for 1 hour. After adding a saturated aqueous potassium tartrate solution to the reaction solution, the mixture was stirred at room temperature for 2 hours. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to give the title compound 0.4.
4 g were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.62 (s, 3 H), 3.02 (s, 6 H),
4.08 (bs, 2 H), 6.13 (dt, 1 H, J = 16 Hz, 6 Hz),
6.22 (s, 1 H), 6.40 (d, 1 H, J = 16 Hz), 7.86 (s,
1 H).

(2) 2-amino-4-dimethylamino-
6- [4- (3-chloro-1-trans-propene-
1-yl) -5-methyl-1-pyrazolyl] pyrimidine 100 mg of the compound obtained in Example 11- (1) was suspended in 1 ml of dichloromethane, and 1 ml of hexachloroacetone and 100 mg of triphenylphosphine were added thereto under ice-cooling. Stirred for hours. The reaction solution was concentrated, and the obtained residue was purified using silica gel column chromatography {developed with a mixed solvent of methanol and chloroform (2:98)} to give 30 mg of the title compound.
I got ¹ H-NMR (CDCl ₃ ) δ: 2.64 (s, 3 H), 3.10 (s,
6 H), 4.06 (d, 2 H, J = 6 Hz), 4.73 (bs, 2 H), 6.
06 (dt, 1 H, J = 16 Hz, 6 Hz), 6.37 (s, 1 H), 6.45
(d, 1 H, J = 16 Hz), 7.74 (s, 1 H).

(3) 2- [3- [1- (2-amino-6)
-Dimethylamino-4-pyrimidinyl) -5-methyl-
4-pyrazolyl] -2-trans-propen-1-yl] -1,2,3,4-tetrahydropyrazino [1,2
-A] indole 30 mg of the compound obtained in Example 11- (2) was dissolved in 30 ml of tetrahydrofuran, 400 mg of 1,2,3,4-tetrahydropyrazino [1,2-a] indole and 10 ml of triethylamine were added, and 3 The mixture was heated under reflux for a day. The reaction solution was diluted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography / methanol-chloroform (2: 9
8) The residue was purified with a mixed solvent using a developing｝ to obtain 7 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.64 (s, 3 H), 3.01 (s, 6 H),
3.36 (d, 2 H, J = 6 Hz), 3.59 (d, 2 H, J = 6 Hz),
3.69 (d, 2 H, J = 6 Hz), 4.09 (s, 2 H), 4.71 (bs, 2
H) 6.05 (dt, 1 H, J = 16, 6 Hz), 6.19 (s, 1 H),
6.45 (d, 1 H, J = 16 Hz), 7.09 (t, 1 H, J = 7 Hz),
7.14 (t, 1 H, J = 7 Hz), 7.32 (d, 1 H, J = 7 Hz),
7.67 (d, 1 H, J = 7 Hz), 7.73 (s, 1 H).

Example 12 3- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -7,9-difluoro- 2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer A)

[0230]

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7,9-Difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (enantiomer A)
101 mg, 3- [1- (4-amino-2-pyrimidinyl) -5-methyl-4-
After stirring a mixture of 103 mg of pyrazolyl] -2-trans-propenal and 20 ml of ethanol at 80 ° C. for 1 hour,
After cooling to room temperature, 0.26 ml of acetic acid was added, and then 135 mg of sodium cyanoborohydride was added in three portions every hour. After stirring at room temperature for 16 hours, water and a saturated aqueous solution of sodium carbonate were added to the reaction solution, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography (270-400 mesh, 25 g) to give methanol-chloroform (2.5: 97.5). The mixture was developed with a mixed solvent, and the fraction containing the target compound was concentrated. 212 mg of the obtained residue was dissolved in 5 ml of isopropyl alcohol by heating.
After adding 0.5 ml of N hydrochloric acid-ethanol, the mixture was allowed to stand at room temperature for 3 hours, and the precipitate was collected by filtration to obtain 157 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.75 (m, 1 H), 2.00-2.15
(m, 1 H), 2.60 (s, 3 H), 2.6-2.8 (m, 1 H), 2.8-3.0
(m, 1 H), 3.0-3.15 (m, 1 H), 3.15-3.3 (m, 1H), 3.
4-3.65 (m, 4 H), 3.8-4.0 (m, 2 H), 4.13 (d, 1 H, J
= 13 Hz), 6.21 (dt, 1 H, J = 16 Hz, 7 Hz), 6.46
(d, 1 H, J = 6 Hz), 6.49 (dt, 1 H, J = 9 Hz, 2 Hz),
6.69 (d, 1 H, J = 12 Hz), 6.79 (d, 1 H, J = 16 H
z), 7.60 (brs, 2 H), 7.99 (s, 1 H), 8.10 (d, 1 H,
J = 6 Hz), 11.42 (brs, 1 H)

Example 13 3- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -7,9-difluoro- 2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer B)

[0233]

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7,9-Difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (enantiomer B)
106 mg, 3- [1- (4-amino-2-pyrimidinyl) -5-methyl-4-
The reaction and post-treatment were carried out in the same manner as in Example 12 using 108 mg of [pyrazolyl] -2-trans-propenal to give 140 mg of the title compound.
I got ¹ H-NMR (DMSO-d ₆ ) δ: consistent with the data of Example 12.

Example 14 3- [3- [1- (2-amino-6-dimethylamino-4-pyrimidinyl)
-5-Methyl-4-pyrazolyl] -2-trans-propen-1-yl]-
7,9-difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer A)

[0236]

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7,9-Difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (enantiomer A)
101 mg, 3- [1- (2-amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenal 1
The reaction and post-treatment were carried out in the same manner as in Example 12 using 22 mg to obtain 72 mg of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.75 (m, 1 H), 2.0-2.1 (m,
1 H), 2.67 (s, 3 H), 3.11 (s, 6 H), 2.4-3.6 (m, 9
H), 3.8-4.0 (m, 2 H), 4.13 (d, 1 H, J = 14Hz), 6.2
1 (dt, 1 H, J = 16 Hz, 7 Hz), 6.32 (s, 1 H), 6.50
(dt, 1 H, J = 9 Hz, 2 Hz), 6.69 (d, 1 H, J = 12 H
z), 6.79 (d, 1 H, J = 16 Hz), 8.04 (s, 1 H), 11.24
(brs, 1 H)

Example 15 3- [3- [1- (2-Amino-6-dimethylaminomethyl-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene-1-
Yl] -7,9-difluoro-2,3,4,4a, 5,6-hexahydro-1H-
Pyrazino [1,2-a] quinoline hydrochloride (isomer B)

[0239]

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7,9-Difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (enantiomer B)
104 mg, 3- [1- (2-amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenal 1
Using 26 mg, the reaction and post-treatment were carried out in the same manner as in Example 12 to obtain the title compound (76 mg) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ: consistent with the data of Example 14.

Example 16 (+/-)-2- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4
-Pyrazolyl] -2-trans-propen-1-yl] -7-fluoro-
1,2,3,4,10,10a-Hexahydropyrazino- [1,2-a] indole hydrochloride

[0242]

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(1) (3-Fluorophenyl) hydrazine 10 g of 3-fluoroaniline was suspended in 100 ml of concentrated hydrochloric acid.
After slowly adding 50 ml of a 13% aqueous solution of sodium nitrite under ice cooling, the mixture was stirred at the same temperature for 10 minutes. Then, a suspension composed of 75 g of tin chloride dihydrate and 50 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour while gradually returning to room temperature. Sodium hydroxide was added to the reaction mixture under ice cooling to adjust the pH to about 9, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and recrystallized from a mixed solvent of ether and ethanol to obtain 11 g of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 6.7-6.9 (m, 3 H), 7.29 (q, 1
H, J = 8 Hz), 8.46 (brs, 1 H), 10.11 (brs, 3 H).

(2) 2- (3-Fluoro-1-hydrazinine)
Ethyl propanoate A mixture consisting of 10 g of the compound obtained in Example 16- (1), 7.2 g of ethyl pyruvate and 30 ml of pyridine was heated under reflux for 10 hours. The reaction solution was cooled to room temperature, diluted with water, and the precipitate was collected by filtration to obtain 13 g of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (t, 3 H, J = 7 Hz), 2.11
(s, 3 H), 4.32 (q, 2 H, J = 7 Hz), 6.65 (dt, 1 H,
J = 8 Hz, 2 Hz), 6.89 (dd, 1 H, J = 8 Hz, 2 Hz), 7.
02 (dt, 1 H, J = 11 Hz, 2 Hz), 7.22 (m, 1 H), 7.72
(s, 1 H).

(3) Ethyl 4-fluoro-2-indolecarboxylate and ethyl 6-fluoro-2-indolecarboxylate 14.2 g of the compound obtained in Example 16- (2) was added to polyphosphate 50.
g was added and heated and stirred at 120 ° C. for 10 minutes. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of hexane-ethyl acetate (20: 1), and mixed with 3.0 g of ethyl 4-fluoro-2-indolecarboxylate and 6-fluoro-2-indolecarboxylic acid 1.0 g of ethyl were each obtained. Ethyl 4-fluoro-2-indolecarboxylate: ¹ H-NMR (C
DCl ₃ ) δ: 1.43 (t, 3 H, J = 7 Hz), 4.43 (q, 2 H, J
= 7 Hz), 6.91 (dd, 1 H, J = 10 Hz, 8 Hz), 7.22
(d, 1 H, J = 8 Hz), 7.38 (s, 1 H), 7.39 (dt, 1 H,
J = 8 Hz, 5 Hz). Ethyl 6-fluoro-2-indolecarboxylate: ¹ H-NMR (C
DCl ₃ ) δ: 1.42 (t, 3H, J = 7 Hz), 4.41 (q, 2 H, J
= 7 Hz), 6.93 (dt, 1 H, J = 9 Hz, 2 Hz), 7.09 (d
d, 1 H, J = 9 Hz, 2 Hz), 7.21 (s, 1 H), 7.61 (dd,
1 H, J = 9 Hz, 5 Hz), 9.08 (brs, 1 H).

(4) Ethyl 6-fluoro-1- (2-phthalimidoethyl) -2-indolecarboxylate 1.0 g of ethyl 6-fluoro-2-indolecarboxylate was dissolved in 50 ml of dimethylformamide, and dissolved in ice-cooled 60 ml. % Sodium hydride and 10 ml of dimethylformamide were added, and the mixture was stirred at the same temperature for 30 minutes.
5.0 g of (bromoethyl) phthalimide was added, and the mixture was stirred for 24 hours while gradually returning to room temperature. After stopping the reaction by adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and developed with a mixed solvent of hexane-ethyl acetate (9: 1) to obtain 0.74 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (t, 3 H, J = 7 Hz), 4.12
(t, 2 H, J = 6 Hz), 4.31 (q, 2 H, J = 7 Hz), 4.79
(t, 2 H, J = 6 Hz), 6.76 (dt, 1 H, J = 9 Hz, 2 Hz),
6.98 (dd, 1 H, J = 9 Hz, 2 Hz), 7.30 (s, 1 H), 7.
51 (dd, 1 H, J = 9 Hz, 5 Hz), 7.64 (dt, 2 H, J = 7
Hz, 2 Hz), 7.73 (dd, 2 H, J = 7 Hz, 2 Hz).

(5) 7-Fluoro-1,2,3,4-tetrahydropyrazino- [1,2-a] indol-1-one 1.0 g of the compound obtained in Example 16- (4) was dissolved in ethanol 50
hydrazine monohydrate 0.5 ml, add 50 ml
For 18 hours. The reaction solution was cooled to room temperature, diluted with chloroform, and washed sequentially with a 1N aqueous sodium hydroxide solution and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the title compound was 0.48 g.
I got ¹ H-NMR (DMSO-d ₆ ) δ: 3.6-3.7 (m, 2 H), 4.24 (t, 2
H, J = 6 Hz), 6.98 (dt, 1 H, J = 9 Hz, 2 Hz), 7.0
5 (s, 1 H), 7.43 (dd, 1 H, J = 9 Hz, 2 Hz), 7.69 (d
d, 1 H, J = 9 Hz, 5 Hz), 8.14 (brs, 1 H).

(6) 7-Fluoro-1,2,3,4-tetrahydropyrazino- [1,2-a] indole 0.47 g of the compound obtained in Example 16- (5) was suspended in 50 ml of tetrahydrofuran. Lithium aluminum hydride
0.2 g was added, and the mixture was stirred at 60 ° C for 8 hours. The reaction solution was cooled to 0 ° C., carefully added with a saturated aqueous solution of potassium tartrate to terminate the reaction, and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 0.46 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.36 (t, 2 H, J = 6 Hz), 3.95
(t, 2 H, J = 6 Hz), 4.19 (s, 2 H), 6.16 (s, 1 H),
6.86 (ddd, 1 H, J = 9 Hz, 8 Hz, 2 Hz), 6.94 (dd, 1
H, J = 9 Hz, 2 Hz), 7.43 (dd, 1 H, J = 8 Hz, 5 H
z).

(7) 2-tert-butoxycarbonyl-7-fluoro-1,2,3,4-tetrahydropyrazino- [1,2-a] indole 0.46 g of the compound obtained in Example 16- (6) The methylene chloride
Dissolve in 50 ml and di-tert-butyl dicarbonate 0.63 g under ice-cooling
Was added, and 0.4 ml of triethylamine was added dropwise. After the reaction solution was stirred for 8 hours while gradually returning to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, developed with a mixed solvent of ethyl acetate: hexane (6: 1), and the fraction containing the desired product was concentrated to obtain 0.62 g of the title compound as a yellow oily substance. . ¹ H-NMR (CDCl ₃ ) δ: 1.50 (s, 9 H), 3.92 (t, 2 H, J
= 6 Hz), 4.02 (t, 2 H, J = 6 Hz), 4.78 (s, 2 H),
6.23 (s, 1 H), 6.87 (ddd, 1 H, J = 9 Hz, 8 Hz, 2 H
z), 6.94 (dd, 1 H, J = 9 Hz, 2 Hz), 7.45 (dd, 1 H,
J = 8 Hz, 5 Hz).

(8) (+/-)-2-tert-butoxycarbonyl-
7-fluoro-1,2,3,4,10,10a-hexahydropyrazino- [1,
2-a] Indole 0.62 g of the compound obtained in Example 16- (7) was added to methanol 20
After dissolving in 1.4 ml of acetic acid, 1.4 ml of acetic acid was added, and 1.3 g of sodium cyanoborohydride was added, followed by stirring at room temperature for 4 days.
After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, ethanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 0.66 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (s, 9 H), 2.54 (dd, 1 H,
J = 15 Hz, 8 Hz), 2.9-3.0 (m, 4 H), 3.4-3.5 (m, 2
H), 4.0-4.2 (m, 2 H), 6.14 (dd, 1 H, J = 10Hz, 2 H
z), 6.32 (ddd, 1 H, J = 10 Hz, 8 Hz, 2 Hz), 6.96
(dd, 1 H, J = 8 Hz, 6 Hz).

(9) (+/-)-2- [3- [1- (4-amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene-1-
Yl] -7-fluoro-1,2,3,4,10,10a-hexahydropyrazino- [1,2-a] indole hydrochloride 200 mg of the compound obtained in Example 16- (8) 10 ml
Was added and stirred for 10 minutes. The reaction solution was diluted with water, adjusted to pH 9 by adding sodium hydrogen carbonate, and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 115 mg of the obtained residue was dissolved in 20 ml of ethanol, and 3- [1- (4-amino-2-pyrimidinyl)-
5-methyl-4-pyrazolyl] -2-trans-propenal 80 mg
Was added and stirred at room temperature for 2 hours. Then, after adding 100 μl of acetic acid, 50 mg of sodium cyanoborohydride was added,
Stirred at room temperature for 3 days. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, ethanol was distilled off under reduced pressure and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel chromatography.
The mixture was developed with a mixed solvent of 9: 1), and the fraction containing the target compound was concentrated. After the residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol,
Recrystallization from ethanol gave the title compound (50 mg) as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.53 (s, 3 H), 2.57 (dd, 1 H, J
= 15 Hz, 8 Hz), 2.9-3.0 (m, 4 H), 3.4-3.5 (m, 2
H), 4.0-4.2 (m, 4 H), 6.11 (dt, 1 H, J = 16 Hz, 7
Hz), 6.39 (ddd, 1 H, J = 10 Hz, 8 Hz, 2 Hz), 6.40
(d, 1 H, J = 6 Hz), 6.51 (dd, 1 H, J = 10 Hz, 2 H
z), 6.71 (d, 1 H, J = 16 Hz), 6.07 (dd, 1 H, J = 8
Hz, 6 Hz), 7.29 (brs, 2 H), 7.90 (s, 1 H), 8.10
(d, 1 H, J = 6 Hz), 10.93 (brs, 1 H)

Example 17 (+/-)-2- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4
-Pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-
1,2,3,4,10,10a-Hexahydropyrazino- [1,2-a] indole hydrochloride

[0253]

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(1) 1.0 g of ethyl 9-fluoro-1,2,3,4-tetrahydropyrazino- [1,2-a] indol-1-one 4-fluoro-2-indolecarboxylate was
The reaction and post-treatment were carried out in the same manner as in Example 16- (4) and (5) to obtain 0.3 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.79 (t, 2 H, J = 6 Hz), 4.31
(t, 2 H, J = 6 Hz), 6.81 (dd, 1 H, J = 10 Hz, 7 H
z), 7.2-7.3 (m, 3 H).

(2) 9-Fluoro-1,2,3,4-tetrahydropyrazino- [1,2-a] indole 0.3 g of the compound obtained in Example 17- (1) was added to Example 16
-Reaction and work-up were carried out in the same manner as in (6), and 0.3 g of the title compound was obtained.
I got ¹ H-NMR (CDCl ₃ ) δ: 3.37 (t, 2 H, J = 6 Hz), 4.02
(t, 2 H, J = 6 Hz), 4.22 (s, 2 H), 6.27 (s, 1 H),
6.77 (ddd, 1 H, J = 10 Hz, 7 Hz, 2 Hz), 7.0-7.1
(m, 2 H).

(3) 2-tert-butoxycarbonyl-9-fluoro-1,2,3,4-tetrahydropyrazino- [1,2-a] indole 0.3 g of the compound obtained in Example 17- (2) From Example 16
-The reaction and post-treatment were carried out in the same manner as in (7), and the title compound (0.5 g) was obtained.
Was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.53 (s, 9 H), 3.93 (t, 2 H, J
= 6 Hz), 4.09 (t, 2 H, J = 6 Hz), 4.81 (s, 2 H),
6.36 (s, 1 H), 6.78 (ddd, 1 H, J = 11 Hz, 7 Hz, 2 H
z), 7.0-7.1 (m, 2 H).

(4) (+/-)-2-tert-butoxycarbonyl-
9-Fluoro-1,2,3,4,10,10a-hexahydropyrazino- [1,
2-a] Indole 0.5 g of the compound obtained in Example 17- (3) was used in Example 16
-The reaction and work-up were carried out in the same manner as in (8), and 0.35 g of the title compound was obtained.
I got ¹ H-NMR (CDCl ₃ ) δ: 1.63 (s, 9 H), 2.54 (dd, 1 H,
J = 15 Hz, 9 Hz), 2.7-3.1 (m, 6 H), 3.4-3.6 (m, 2
H), 6.19 (d, 1 H, J = 8 Hz), 6.35 (t, 1 H, J = 8 H
z), 6.9-7.0 (m, 1 H).

(5) (+/-)-2- [3- [1- (4-amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene-1-
Yl] -9-fluoro-1,2,3,4,10,10a-hexahydropyrazino- [1,2-a] indole hydrochloride The compound obtained in Example 17- (4) 350 mg, 3- [1- (4-amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans
Using 160 mg of -propenal, the reaction and post-treatment were carried out in the same manner as in Example 16- (9) to obtain 50 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.57 (s, 3 H), 2.7-4.2 (m, 10
H), 4.35-4.45 (m, 1 H), 6.15 (dt, 1 H, J = 16 Hz, 7
Hz), 6.42 (d, 1 H, J = 6 Hz), 6.64 (t, 1 H, J = 9
Hz), 6.7-6.8 (m, 2 H), 7.39 (brs, 2 H), 7.94 (s, 1
H), 8.11 (d, 1H, J = 6 Hz)

Example 18 (+/-)-3- [3- [1- (4-Amino-2-pyrimidinyl) -5-methyl-4
-Pyrazolyl] -2-trans-propen-1-yl] -7,9-difluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1-c]-
1,4-benzoxazine hydrochloride

[0260]

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(1) 1- (2,4-difluoro-6-nitrophenoxy) -2,3-epoxypropane 12.62 g of 2,4-difluoro-6-nitrophenol, 36 ml of epichlorohydrin, 3.3 g of sodium hydroxide, 15 m water
l and a mixture of 320 ml of ethanol at 80 ° C 2
Stir for 4 hours. After the reaction solution was cooled to room temperature, insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in a mixed solvent of ether-hexane (1: 2), washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of ethyl acetate-hexane (1: 9), and the fraction containing the desired product was concentrated to obtain 11.28 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.69 (dd, 1 H, J = 5 Hz, 3 H
z), 2.88 (t, 1 H, J = 5 Hz), 3.3-3.45 (m, 1 H), 4.1
5 (ddd, 1 H, J = 12 Hz, 6 Hz, 1 Hz), 4.40 (dd, 1
H, J = 12 Hz, 3 Hz), 7.15 (ddd, 1 H, J = 11 Hz, 7
Hz, 3 Hz), 7.40 (ddd, 1 H, J = 7 Hz, 3 Hz, 2 Hz).

(2) 1- (2,4-Difluoro-6-nitrophenoxy) -2-hydroxy-3-phthalimidopropane 11.28 g of the compound obtained in Example 18- (1), 14.4 g of phthalimide, 0.5 ml of pyridine , And 50 ml of butanol were heated under reflux for 20 hours, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (270-400 mesh, 300 g), developed with a mixed solvent of ethyl acetate-hexane (1: 4), and the fraction containing the desired compound was concentrated to give 6.2 g of the title compound. I got ¹ H-NMR (CDCl ₃ ) δ: 3.05 (d, 1 H, J = 6 Hz), 3.96
(dd, 1 H, J = 14 Hz, 4Hz), 4.00 (dd, 1 H, J = 14 H
z, 7 Hz), 4.2-4.4 (m, 3 H), 7.16 (ddd, 1 H, J = 10
Hz, 7 Hz, 3 Hz), 7.43 (dt, 1 H, J = 8 Hz, 3 Hz),
7.74 (dd, 2 H, J = 5 Hz, 3 Hz), 7.88 (dd, 2 H, J =
(5 Hz, 3 Hz).

(3) 6,8-Difluoro-3-phthalimidomethyl-3,4-dihydro-2H-1,4-benzoxazine 16.2 g of the compound obtained in Example 18- (2) was treated with 30 m of acetone.
20 ml of Jones reagent (8.2 g of chromic acid, 4 ml of concentrated sulfuric acid, and water) while maintaining the internal temperature at 15 to 20 ° C.
(Adjusted from 16 ml), and the mixture was stirred at room temperature for 2 hours. After water was added to the reaction solution to dilute it, insolubles were collected by filtration. The obtained compound was dissolved in ethanol (200 ml) and subjected to catalytic hydrogenation in the presence of Raney nickel for 8 hours. After removing insoluble matter by filtration, the filtrate was concentrated to dryness, and the obtained crystalline residue was dissolved in 70 ml of ethanol by heating. After cooling to room temperature, 10 ml of acetic acid and 3.0 g of sodium cyanoborohydride were added, and the mixture was stirred for 4 hours. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (20
0g), developed with chloroform, and concentrated the fraction containing the desired product to obtain 2.79 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.75-4.00 (m, 4 H), 4.29 (dd,
1 H, J = 11 Hz, 3 Hz), 4.43 (brs, 1 H), 6.12 (dt, 1
H, J = 10 Hz, 2 Hz), 6.20 (ddd, 1 H, J = 11 Hz, 9
Hz, 2 Hz), 7.76 (dd, 2 H, J = 5 Hz, 3 Hz), 7.88
(dd, 2 H, J = 5 Hz, 3 Hz).

(4) 3-aminomethyl-6,8-difluoro-3,
4-Dihydro-2H-1,4-benzoxazine 12.78 g of the compound obtained in Example 18- (3) was added to ethanol 6
After dissolving in 0 ml and adding 1.32 ml of hydrazine monohydrate, the mixture was heated under reflux for 5 hours. The residue obtained by evaporating the solvent was dissolved in water, acetic acid (10 ml) was added, and the mixture was added
Then, the mixture was stirred at 0 ° C for 2 hours. The insolubles were removed by filtration, the filtrate was made alkaline with a 5% aqueous sodium hydroxide solution, and then extracted with a mixed solvent of methanol and chloroform (1:99). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.61 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (dd, 1 H, J = 13 Hz, 8 H
z), 2.95 (dd, 1 H, J = 13 Hz, 5 Hz), 3.37-3.44 (m,
1H), 3.97 (dd, 1 H, J = 11 Hz, 6 Hz), 4.23 (dd, 1
H, J = 11 Hz, 3 Hz), 4.45-4.70 (m, 1 H), 6.14 (dt,
1 H, J = 10 Hz, 3 Hz), 6.21 (ddd, 1 H, J = 11 Hz,
(8 Hz, 3 Hz).

(5) 3-benzylaminomethyl-6,8-difluoro-3,4-dihydro-2H-1,4-benzoxazine 1.61 g of the compound 1 obtained in Example 18- (4) and 833 mg of benzaldehyde Was dissolved in 50 ml of ethanol,
After stirring at for 0.5 hour, the reaction solution was concentrated to dryness. The residue was dissolved in 50 ml of newly added ethanol, 2.3 ml of acetic acid was added, and then 1.7 g of sodium cyanoborohydride was added.
Stirred at room temperature for 2 hours. After concentrating the reaction solution, 1
An N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, developed with a methanol-chloroform mixed solvent (2:98), and containing the target compound. The fraction was concentrated to give 1.85 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.61 (dd, 1 H, J = 12 Hz, 10 H
z), 2.83 (dd, 1 H, J = 12 Hz, 4 Hz), 3.45-3.50 (m,
1H), 3.81 and 3.82 (ABq, 2 H, J = 14 Hz), 3.90 (d
d, 1 H, J = 11 Hz, 7 Hz), 4.23 (dd, 1 H, J = 11 H
z, 3 Hz), 4.60 (brs, 1 H), 6.11 (dt, 1 H, J = 10 H
z, 2 Hz), 6.20 (ddd, 1 H, J = 11 Hz, 9Hz, 2 Hz),
7.25-7.40 (m, 5 H).

(6) 3-benzyl-1,2-dioxo-7,9-difluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1-
c] -1,4-benzoxazine To 3.5 g of the compound obtained in Example 18- (5) was added 3.5 ml of diethyl oxalate, and the mixture was heated at 110 ° C. for 22 hours and then at 150 ° C. for 5 hours.
Heated for hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ether to give 1.49 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 3.31 (dd, 1 H, J = 12 Hz, 4 H
z), 3.45 (t, 1 H, J = 12 Hz), 3.85 (dd, 1 H, J = 1
2 Hz, 10 Hz), 4.32-4.45 (m, 3 H), 4.67 and 4.71 (A
Bq, 2 H, J = 15 Hz), 6.71 (m, 1 H), 7.25-7.45 (m,
5H), 8.47 (m, 1H). (7) 3-benzyl-7,9-difluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1-c]- 1,4-benzoxazine 1.97 g of sodium borohydride in tetrahydrofuran 30
Then, 8.3 ml of boron trifluoride diethyl ether complex was added dropwise at room temperature, and the mixture was stirred for 1 hour. Next, Example 1
11.45 g of the compound obtained in 8- (6) was added to the reaction solution in several portions, and the mixture was heated under reflux for 4 hours. The reaction solution is concentrated under ice-cooled concentrated hydrochloric acid 3
The mixture was poured little by little into 0 ml and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to make the liquid alkaline, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline.
After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (100 g), eluted with a mixed solvent of ethyl acetate-hexane (1: 4), and the fraction containing the desired product was concentrated. This gave 1.54 g of the title compound as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (t, 1 H, J = 11 Hz), 2.26
(dt, 1 H, J = 12 Hz, 3 Hz), 2.80-2.84 (m, 1 H), 2.
89 (dt, 1 H, J = 12 Hz, 3 Hz), 2.94-3.00 (m, 1 H),
3.23-3.30 (m, 1 H), 3.51, 3.58 (ABq, 2 H, J = 13
Hz), 3.65-3.72 (m, 1 H), 3.92 (dd, 1 H, J = 10 Hz,
9 Hz), 4.20 (dd, 1 H, J = 10 Hz, 3 Hz), 6.25-6.32
(m, 2 H), 7.25-7.36 (m, 5 H).

(8) 7,9-Difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine Example 18- (7 11.54 g of the compound obtained in
The mixture was dissolved in 0 ml, and thereto were added 1.53 g of ammonium formate and 1.5 g of 10% palladium on carbon (containing 50% water), and the mixture was refluxed for 3 hours. After filtering off the insoluble matter, the solvent was distilled off, and a saturated saline solution was added to the obtained residue, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (270-400 mesh, 70 g), and eluted with a mixed solvent of methanol-chloroform (7:93). Concentrate the fractions containing
mg was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (t, 1 H, J = 11 Hz), 2.75
(dt, 1 H, J = 12 Hz, 3 Hz), 2.93 (dt, 1 H, J = 12
Hz, 3 Hz), 3.02 (dt, 1 H, J = 11 Hz, 2 Hz), 3.10-3.
25 (m, 2 H), 3.51 (dt, 1 H, J = 11 Hz, 2 Hz), 3.96
(dd, 1 H, J = 11 Hz, 9 Hz), 4.24 (dd, 1 H, J = 11
Hz, 3 Hz), 6.26-6.35 (m, 2 H).

(9) (+/-)-3- [3- [1- (4-amino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene-1-
Yl] -7,9-difluoro-2,3,4,4a, 5,6, -hexahydro-1H
-Pyrazino [2,1-c] -1,4-benzoxazine hydrochloride 118 mg of the compound obtained in Example 18- (8), 3- [1- (4-amino-2-pyrimidinyl) -5-methyl -4-pyrazolyl] -2-tran
The reaction and post-treatment were conducted using 119 mg of s-propenal in the same manner as in Example 12 to obtain 176 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.57 (s, 3 H), 2.7-4.2 (m, 1
0 H), 4.35-4.45 (m, 1 H), 6.15 (dt, 1 H, J = 16 Hz,
7 Hz), 6.42 (d, 1 H, J = 6 Hz), 6.64 (t, 1 H, J =
9 Hz), 6.7-6.8 (m, 2 H), 7.39 (brs, 2 H), 7.94 (s,
1 H), 8.11 (d, 1H, J = 6 Hz)

Example 19 (+/-)-3- [3- [1- (2-Amino-6-dimethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propene- 1-
Yl] -7,9-difluoro-2,3,4,4a, 5,6, -hexahydro-1H
-Pyrazino [2,1-c] -1,4-benzoxazine hydrochloride

[0270]

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7,9-Difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine 80 m
g, 3- [1- (2-amino-6-dimethylamino-4-pyrimidinyl)
-5-Methyl-4-pyrazolyl] -2-trans-propenal 96 mg
The reaction and post-treatment were carried out in the same manner as in Example 12 to obtain 61 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3 H), 2.80-2.95 (m, 1
H), 3.0-4.2 (m, 9 H), 3.16 (s, 6 H), 4.38 (d, 1 H,
J = 9 Hz), 6.22 (dt, 1 H, J = 16 Hz, 7 Hz), 6.38
(s, 1 H), 6.65 (t, 1 H, J = 9 Hz), 6.80 (d, 1 H, J
= 16 Hz), 6.77-6.82 (m, 1 H), 8.10 (s, 1 H), 11.4
7 (brs, 1 H)

Example 20 1- [1- [2-Amino-6- (2-hydroxyethyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1-piperazinyl] -1-trans-propene

[0273]

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(1) 1- [1- (2-Amino-6-chloro-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1
-Piperazinyl] -1-trans-propene 1- [1- (2-amino-6-benzyloxy-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -3-
After adding 12 ml of trifluoroacetic acid and 0.6 ml of thioanisole to 2.2 g of [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, diethyl ether was added to the residue, and the mixture was stirred at room temperature, and the precipitate was collected by filtration. Phosphorus oxychloride 12
Then, the mixture was stirred at 60 to 80 ° C for 3 hours. After concentrating the reaction solution, ice chips were gradually added to the residue under ice cooling, chloroform was added, and the reaction solution was neutralized with sodium hydrogen carbonate. Chloroform-methanol (9:
After extracting 5 times in 1), the organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (49: 1), and the fraction containing the desired product was concentrated. A mixed solvent of ether-hexane was added to the residue, and the precipitate was collected by filtration to obtain 970 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 2.60-2.65 (m, 4 H), 2.70 (s, 3
H), 3.15-3.25 (m, 6 H), 5.15 (brs, 2 H), 6.09 (dt,
1 H, J = 16 Hz, 7 Hz), 6.26 (tt, 1 H, J = 9 Hz, 2
Hz), 6.37 (dd, 2 H, J = 11 Hz, 2 Hz), 6.39 (d, 1
H, J = 16 Hz), 7.32 (s, 1 H), 7.81 (s, 1 H).

(2) 1- [1- [2-amino-6- (2
-Hydroxyethyl) amino-4-pyrimidinyl] -5
-Methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-tra
ns-propene 455 mg of the compound obtained in Example 20- (1) was suspended in 30 ml of ethanol, 5 ml of ethanolamine was added, and the mixture was heated under reflux for 30 hours. After the reaction solution was cooled to room temperature and concentrated under reduced pressure, water and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue, and the mixture was extracted ten times with a mixed solvent of chloroform-methanol (9: 1). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained solid was washed with a chloroform-ether mixed solvent to obtain 458 mg of the title compound as a white powder. Melting point: 176-181 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (s, 3 H), 3.12 (d, 2 H, J
= 6 Hz), 3.15-3.25 (m, 4 H), 3.25-3.40 (m, 6 H),
3.45-3.55 (m, 2 H), 4.70 (t, 1 H, J = 5 Hz), 6.06
(dt, 1 H, J = 16 Hz, 7 Hz), 6.14 (s, 2 H), 6.15
(s, 1 H), 6.41 (d, 1 H, J = 16 Hz), 6.44 (tt, 1 H,
J = 9 Hz, 2 Hz), 6.59 (dd, 2 H, J = 11 Hz, 2 Hz),
7.04 (brs, 1H), 7.88 (s, 1H).

Example 21 1- [1- [2-Amino-6-di (2-hydroxyethyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5 -Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0277]

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Compound 446m obtained in Example 20- (1)
was suspended in 20 ml of ethanol, 265 mg of 2,2′-iminodiethanol was added, and the mixture was heated under reflux for 16 hours. 265 mg of 2,2′-iminodiethanol was added, and the mixture was further heated under reflux for 6 hours.
mg, and the mixture was heated under reflux for 17 hours. After the reaction solution was cooled to room temperature and concentrated under reduced pressure, saturated saline was added to the residue and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off, the obtained residue was subjected to silica gel column chromatography, and developed with a mixed solvent of chloroform-methanol (19: 1 to 9: 1). The fractions containing the product were concentrated. The residue was diluted with 1N hydrochloric acid /
After hydrochlorination with ethanol, recrystallization from ethanol gave 218 mg of the title compound as a white powder. Melting point: 184-187 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.64 (s, 3H), 3.09-3.18 (m, 4
H), 3.44-3.98 (m, 14 H), 6.21 (dt, 1 H, J = 16 Hz, 8
Hz), 6.43 (s, 1 H), 6.58 (t, 1 H, J = 9 Hz), 6.73 (d,
2 H, J = 9 Hz), 6.80 (d, 2 H, J = 16 Hz), 8.11 (s,
1 H), 10.70 (brs, 1 H).

Example 22 1- [1- [2-amino-6- (3-hydroxy-1-)
Azetidinyl) -4-pyrimidinyl] -5-methyl-4
-Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0280]

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552 mg of N-benzhydryl-3-hydroxyazetidine hydrochloride was dissolved in 80% aqueous ethanol, and 10% palladium on carbon (water 50.1%) 500
mg, and catalytic hydrogenation was performed at 5 atm for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 ml of ethanol, and Example 20- (1) was used.
Was added and the mixture was heated under reflux for 2 days.
The reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel chromatography, developed with a mixed solvent of chloroform-methanol (19: 1), and the fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and recrystallized from ethanol to give 367 mg of the title compound.
Was obtained as a white powder. Melting point: 195-199 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 3.05-3.13 (m, 2
H), 3.22-3.25 (m, 2 H), 3.49 (d, 2 H, J = 10 Hz), 3.9
2-3.97 (m, 6 H), 4.35-4.45 (m, 2 H), 4.60-4.66 (m, 1
H), 6.15 (s, 1 H), 6.25 (dt, 1 H, J = 16 Hz, 8 Hz),
6.57 (t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.8
0 (d, 2 H, J = 16 Hz), 7.73 (brs, 2 H), 8.14 (s, 1 H),
11.34 (brs, 2 H).

Example 23 1- [1- [2-Amino-6- (2-tert-butoxycarbonylaminoethyl) amino-4-pyrimidinyl] -5-methyl-pyrazolyl] -3- [4- (3 5
-Difluorophenyl) -1-piperazinyl] -1-t
ran-propene

[0283]

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(1) 1- (2-amino-6-chloro-4)
Ethyl-pyrimidinyl) -5-methyl-4-pyrazolecarboxylate After adding 300 ml of ethanol to 16.4 g of 2-amino-4,6-dichloropyrimidine, 25 ml of hydrazine monohydrate and 13.8 g of potassium carbonate were added. The mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the precipitate was collected by filtration. To 14.0 g of the obtained white powder of 2-amino-6-chloro-4-hydrazinopyrimidine, 300 ml of ethanol and 16.3 g of ethoxymethylene acetoacetic acid ethyl ester were added.
After stirring at room temperature for 40 minutes, the mixture was heated under reflux for 2 hours. After the reaction solution was cooled to room temperature, the precipitate was collected by filtration to obtain 21.9 g of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (t, 3 H, J = 7 Hz), 3.00
(s, 3 H), 4.33 (q, 2 H, J = 7 Hz), 5.26 (brs, 2 H),
7.33 (s, 1 H), 8.02 (s, 1 H).

(2) 1- (2-amino-6-chloro-4)
-Pyrimidinyl) -5-methyl-4-pyrazolecarbaldehyde 14.1 g of the compound obtained in Example 23- (1) was dissolved in 600 ml of methylene chloride, cooled to -78 ° C under a nitrogen atmosphere, and then diisobutylaluminum hydride. (1M
Hexane solution (200 ml) was added, and the mixture was stirred at the same temperature for 5 hours. To the reaction solution was added 1 L of a 10% aqueous potassium tartrate solution, and the mixture was stirred at room temperature for 4 hours. Then, 500 ml of methanol was added, and the mixture was further stirred for 1 hour. After separating the organic layer, the aqueous layer was extracted three times with chloroform and ten times with a mixed solvent of chloroform-methanol (9: 1). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is 600 m in 1,4-dioxane.
After adding 42 g of active manganese dioxide,
Stirred at room temperature for 12 hours. After removing insolubles by Celite filtration, the filtrate was concentrated to obtain 9.8 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 3.01 (s, 3 H), 5.61 (brs, 1 H),
7.32 (s, 1 H), 8.08 (s, 1 H), 10.00 (s, 1 H).

(3) Ethyl 3- [1- (2-amino-6-chloro-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenoate Obtained in Example 23- (2) 3.90 g of the compound, (carboethoxymethylene) triphenylphosphorane 6.86
g and 150 ml of toluene at 80 ° C.
For 19 hours. The reaction solution was left at room temperature for 8 hours, and the precipitate was collected by filtration to give the title compound 4.11.
g was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (t, 3 H, J = 7 Hz), 2.79
(s, 3 H), 4.26 (q, 2 H, J = 7 Hz), 5.58 (brs, 1 H),
5.38 (s, 2 H), 6.27 (d, 1 H, J = 16 Hz), 7.31 (s,
1H), 7.59 (d, 1 H, J = 16 Hz), 7.91 (s, 1 H).

(4) 3- [1- [2-amino-6- (2
-Tert-butoxycarbonylaminoethyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl]
-2-trans-Ethyl propenoate 300 mg of the compound obtained in Example 23- (3) was suspended in 100 ml of ethanol, and 1.3 ml of ethylenediamine was suspended.
And heated under reflux for 4 days. After the solvent was distilled off under reduced pressure, the residue was dissolved in 20 ml of methylene chloride, 1.06 g of di-tert-butyl dicarbonate was added, and 163 μl of triethylamine was added dropwise. After the reaction solution was stirred at room temperature for 3 days, the solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel chromatography, and developed with a mixed solvent of ethyl acetate: hexane (4: 1) to give the desired product. The fractions containing were concentrated to obtain 386 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hz), 1.43
(s, 9 H), 2.73 (s, 3 H), 3.31-3.38 (m, 2 H), 3.45-
3.49 (m, 2 H), 4.25 (q, 2 H, J = 7 Hz), 4.77 (brs,
2H), 4.96 (brs, 1H), 5.27 (brs, 1H), 6.22 (d,
1H, J = 16 Hz), 6.29 (s, 1 H), 7.59 (d, 1 H, J = 1
6 Hz), 7.83 (s, 1 H).

(5) 3- [1- [2-amino-6- (2
-Tert-butoxycarbonylaminoethyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl]
-2-trans-propenal 386 mg of the compound obtained in Example 23- (4) was dissolved in 20 ml of methylene chloride, cooled to -78 ° C under a nitrogen atmosphere, and 5 ml of diisobutylaluminum hydride (1M hexane solution) was added. The mixture was stirred at the same temperature for 3 hours.
A 10% aqueous potassium tartrate solution was added to the reaction solution, and the mixture was added at room temperature for 4 hours.
After stirring for an hour, the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (20 ml). After adding activated manganese dioxide (619 mg), the mixture was stirred at room temperature for 15 hours. After removing insolubles by Celite filtration, the filtrate was concentrated to give the title compound 341.
mg was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (s, 9 H), 2.77 (s, 3 H), 3.
33-3.37 (m, 2 H), 3.43-3.49 (m, 2 H), 4.78 (brs, 2
H), 4.95 (brs, 1 H), 5.32 (brs, 1 H), 6.31 (s, 1
H), 6.52 (dd, 1 H, J = 16 Hz, 8 Hz), 7.38 (d, 1 H,
J = 16 Hz), 7.86 (s, 1 H), 9.63 (d, 1 H, J = 8 Hz).

(6) 1- [1- [2-amino-6- (2
-Tert-butoxycarbonylaminoethyl) amino-4-pyrimidinyl] -5-methyl-pyrazolyl] -3
-[4- (3,5-Difluorophenyl) -1-piperazinyl] -1-trans-propene 341 mg of the compound obtained in Example 23- (5) was dissolved in 25 ml of ethanol, and 1- (3,5-difluoro 248 mg of phenyl) piperazine hydrochloride and 147 μl of triethylamine were added, followed by stirring at room temperature for 4 hours. Next, 364 μl of acetic acid was added, and 138 mg of sodium cyanoborohydride was added, followed by stirring at room temperature for 14.5 hours.
After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, ethanol was distilled off under reduced pressure and extracted with chloroform.
The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel chromatography.
The mixture was developed with a mixed solvent of chloroform-methanol (49: 1), and the fraction containing the desired product was concentrated to obtain 217 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (s, 9 H), 2.49-2.64 (m, 4
H), 2.63 (s, 3 H), 3.17 (d, 2 H, J = 7 Hz), 3.20-3.
23 (m, 4 H), 3.29-3.33 (m, 2 H), 3.38-3.45 (m, 2
H), 4.97 (brs, 2 H), 5.23 (brs, 1 H), 5.53 (brs, 1
H), 6.03 (dt, 1H, J = 16 Hz, 7 Hz), 6.24 (t, 1 H,
J = 9 Hz), 6.26 (s, 1 H), 6.35-6.39 (m, 3 H), 7.7
3 (s, 1 H).

Example 24 1- [1- [2-Amino-6- (2-aminoethyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1
-Piperazinyl] -1-trans-propene hydrochloride

[0291]

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Compound 23m obtained in Example 23- (6)
g was dissolved in methylene chloride (20 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction solution, saturated aqueous sodium hydrogen carbonate was added to the residue, and chloroform-
The mixture was extracted with a mixed solvent of methanol (9: 1). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and 1N hydrochloric acid / ethanol was added to the resulting residue to form a hydrochloride, which was recrystallized from ethanol to obtain 159 mg of the title compound as a white powder. Was. Melting point: 237-251 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.65 (s, 3 H), 3.05-3.16 (m, 4
H), 3.25 (t, 2 H, J = 12 Hz), 3.50 (t, 2 H, J = 11
Hz), 3.62 (brs, 2 H), 3.91-3.97 (m, 4 H), 6.24 (d
t, 1 H, J = 16 Hz, 7 Hz), 6.43 (s, 1 H), 6.56 (t,
1 H, J = 9 Hz), 6.72 (d, 2 H, J = 9 Hz), 6.80 (d, 1
H, J = 16 Hz), 8.12 (s, 1 H), 8.17 (brs, 3 H), 11.
27 (brs, 1 H).

Example 25 1- [1- [2-Amino-6- (6-tert-butoxycarbonylaminohexyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl]
-1-trans-propene

[0294]

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(1) 3- [1- [2-amino-6- (6
-Tert-Butoxycarbonylaminohexyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-ethyl propenoate Example 23 The ethylenediamine of (4) was changed to hexamethylenediamine. Compound 30 obtained in Example 23- (3) by performing the same reaction and post-treatment as in 23- (4).
From 0 mg, 299 mg of the title compound was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hz), 1.36-1.
49 (m, 4 H), 1.44 (s, 9 H), 1.56-1.63 (m, 4 H), 2.7
3 (s, 3 H), 3.09-3.13 (m, 2 H), 3.28-3.31 (m, 2
H), 4.25 (q, 2 H, J = 7 Hz), 4.53 (brs, 1 H), 4.74
(brs, 2 H), 4.87 (brs, 1 H), 6.22 (d, 1 H, J = 16
Hz), 6.27 (s, 1 H), 7.59 (d, 1 H, J = 16 Hz), 7.84
(s, 1 H).

(2) 3- [1- [2-amino-6- (6
-Tert-butoxycarbonylaminohexyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal Using the compound (299 mg) obtained in Example 25- (1), Example 23- (5 The same reaction and post-treatment as in) were carried out to obtain 278 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.37-1.61 (m, 8 H), 1.44 (s, 9
H), 2.78 (s, 3 H), 3.08-3.16 (m, 2 H), 3.26-3.33
(m, 2 H), 4.53 (brs, 1 H), 4.75 (brs, 2 H), 4.88
(brs, 1 H), 6.29 (s, 1 H), 6.53 (dd, 1 H, J = 16 H
z, 8 Hz), 7.39 (d, 1 H, J = 16 Hz), 7.87 (s, 1 H),
9.63 (d, 1 H, J = 8 Hz).

(3) 1- [1- [2-amino-6- (6
-Tert-butoxycarbonylaminohexyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1
-Piperazinyl] -1-trans-propene Using 278 mg of the compound obtained in Example 25- (2), the same reaction and post-treatment as in Example 23- (6) were performed to obtain 305 mg of the title compound as a white solid. . ¹ H-NMR (CDCl ₃ ) δ: 1.34 (brs, 4 H), 1.44 (s, 9 H),
1.55-1.59 (m, 2 H), 2.55-2.68 (m, 4 H), 2.64 (s, 3
H), 3.08-3.11 (m, 2 H), 3.18 (d, 2 H, J = 7Hz),
3.21-3.22 (m, 4 H), 3.23-3.28 (m, 2 H), 4.64 (brs,
1 H), 4.85 (brs, 2 H), 5.00 (brs, 1 H), 6.03 (dt, 1
H, J = 16 Hz, 7 Hz), 6.24 (t, 1 H, J = 9 Hz), 6.26
(s, 1 H), 6.35-6.40 (m, 3 H), 7.74 (s, 1 H).

Example 26 1- [1- [2-amino-6- (6-aminohexyl)]
Amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl)-
1-piperazinyl] -1-trans-propene hydrochloride

[0299]

Embedded image

Compound 25 obtained in Example 25- (3)
Using g, the same reaction and post-treatment as in Example 24 were performed, followed by recrystallization from ethanol-isopropanol to obtain 195 mg of the title compound as a white-pink solid. Melting point: 212-217 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.26-1.38 (m, 4 H), 1.51-1.60
(m, 4 H), 2.65 (s, 3 H), 2.74-2.79 (m, 2 H), 3.05-3.
17 (m, 2 H), 3.25 (t, 2 H, J = 12 Hz), 3.51-3.72
(m, 4 H), 3.92-3.97 (m, 4 H), 6.25 (dt, 1 H, J = 1
6 Hz, 7 Hz), 6.55-6.59 (m, 2 H), 6.72 (d, 2 H, J =
11 Hz), 6.80 (d, 1 H, J = 16 Hz), 7.92 (brs, 3 H),
8.14 (s, 1 H), 11.32 (brs, 1 H).

Example 27 1- [1- [2-Amino-6- (3-tert-butoxycarbonylamino-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4 −
(3,5-difluorophenyl) -1-piperazinyl]
-1-trans-propene

[0302]

Embedded image

(1) 3- [1- [2-amino-6- (3
-Tert-butoxycarbonylamino-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-ethyl propenoate 628 mg of N-benzhydryl-3-tert-butoxycarbonylaminoazetidine in 50 ml of ethanol And 10% palladium on carbon (water 50.1%) 6
00 mg was added and catalytic hydrogenation was performed at 5 atm for 19 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of ethanol.
-286 mg of the compound obtained in (3) and triethylamine 2
59 μl was added, and the mixture was heated under reflux for 2 days. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography to give chloroform-methanol (4.
The mixture was developed with a mixed solvent of 9: 1), and the fraction containing the desired product was concentrated to obtain 593 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hz), 1.45
(s, 9 H), 2.73 (s, 3 H), 3.86 (dd, 2 H, J = 5 Hz, 9
Hz), 4.25 (q, 2 H, J = 7 Hz), 4.37 (t, 2 H, J = 8
Hz), 4.61 (brs, 1 H), 4.78 (brs, 2 H), 4.97 (brs,
1H), 6.13 (s, 1H), 6.22 (d, 1H, J = 16 Hz), 7.59
(d, 1 H, J = 16 Hz), 7.38 (s, 1 H).

(2) 3- [1- [2-amino-6- (3
-Tert-butoxycarbonylamino-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal Using the compound 593 mg obtained in Example 27- (1), Example 23- The same reaction and post-treatment as in (5) were performed to obtain 575 mg of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9 H), 2.78 (s, 3 H), 3.
87 (dd, 2 H, J = 5 Hz, 9 Hz), 4.38 (t, 2 H, J = 5 H
z), 4.58-4.68 (m, 1 H), 4.81 (brs, 2 H), 5.97 (br
s, 1 H), 6.15 (s, 1 H), 6.52 (d, 1 H, J = 16 Hz, 8
Hz), 7.38 (d, 1H, J = 16 Hz), 7.87 (s, 1 H), 9.63
(d, 1 H, J = 8 Hz).

(3) 1- [1- [2-amino-6- (3
-Tert-butoxycarbonylamino-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl)-
1-Piperazinyl] -1-trans-propene Using 534 mg of the compound obtained in Example 27- (2), the same reaction and post-treatment as in Example 23- (6) were performed to obtain 378 mg of the title compound as a white powder. Was. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (s, 9 H), 1.55-1.59 (m, 2
H), 2.55-2.68 (m, 4 H), 2.64 (s, 3 H), 3.08-3.11
(m, 2 H), 3.18 (d, 2 H, J = 7 Hz), 3.21-3.22 (m, 4
H), 3.23-3.28 (m, 2 H), 4.64 (brs, 1 H), 4.85 (br
s, 2 H), 5.00 (brs, 1 H), 6.03 (dt, 1H, J = 16 Hz,
7 Hz), 6.24 (t, 1 H, J = 9 Hz), 6.26 (s, 1 H), 6.35
-6.40 (m, 3 H), 7.74 (s, 1 H).

Example 28 1- [1- [2-Amino-6- (3-amino-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3 5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0307]

Embedded image

Compound 378m obtained in Example 27- (3)
Using g, the same reaction and post-treatment as in Example 24 were performed to obtain 282 mg of the title compound as a white-pink solid. Melting point: 218-224 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.68 (s, 3 H), 3.09 (dd, 2 H,
J = 10 Hz, 21 Hz), 3.26 (t, 2 H, J = 12 Hz), 3.49
(d, 2 H, J = 11 Hz), 3.90-3.98 (m, 4 H), 4.18-4.25
(m, 3 H), 4.42-4.46 (m, 2 H), 6.20 (s, 1 H), 6.23
(dt, 1 H, J = 16 Hz, 8 Hz), 6.57 (dt, 1 H, J = 2 H
z, 9 Hz), 6.72 (d, 2 H, J = 9 Hz), 6.76 (d, 1 H, J
= 18 Hz), 8.32 (s, 1 H), 8.76 (brs, 3 H), 11.43
(brs, 1 H).

Example 29 1- [1- [4-Amino-6- (2-hydroxyethyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0310]

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(1) 2,6-Dichloro-4- (4-methoxybenzyl) aminopyrimidine and 4,6-dichloro-2- (4-methoxybenzyl) aminopyrimidine 2,4,6-trichloropyrimidine 27.5 g Was suspended in a mixed solvent of 200 ml of ethanol and 200 ml of methylene chloride, and 30 ml of 4-methoxybenzylamine was added under ice cooling.
Was added dropwise. After stirring at the same temperature for 19 hours,
10 ml of methoxybenzylamine was added dropwise and stirred for 18 hours. After adding 200 ml of a 0.5 N phosphoric acid aqueous solution to the reaction solution and extracting with chloroform, the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue obtained was subjected to silica gel chromatography, and developed with a mixed solvent of chloroform-hexane (3: 1) to develop 4,6-dichloro- 13.3 g of 2- (4-methoxybenzyl) aminopyrimidine was obtained and then developed with a mixed solvent of chloroform-ethyl acetate (1: 3) to give 2,6-dichloro-4- (4-methoxybenzyl) aminopyrimidine 24 .2 g were obtained. 2,6-dichloro-4- (4-methoxybenzyl) aminopyrimidine ¹ H-NMR (CDCl ₃ ) δ: 3.81 (s, 1 H), 4.40 (brs, 2 H),
6.26 (s, 1 H), 6.89 (d, 2 H, J = 9 Hz), 7.22 (d, 2
H, J = 8 Hz). 4,6-dichloro-2- (4-methoxybenzyl) aminopyrimidine ¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 1 H), 4.54 (d, 2 H, J =
6 Hz), 5.68 (brs, 1 H), 6.62 (s, 1 H), 6.87 (d, 2
H, J = 8 Hz), 7.25 (d, 2 H, J = 9 H).

(2) Ethyl 1- [4-chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolecarboxylate 2,6-dichloro-4- (4-methoxy 5.57 g of benzyl) aminopyrimidine in 20 ml of tetrahydrofuran
And hydrazine monohydrate (3.0 ml) was added thereto.
Heated to reflux for an hour. After evaporating the solvent under reduced pressure, water was added to the residue, and the precipitate was collected by filtration to give 4-chloro-2.
5.06 g of -hydrazino-6- (4-methoxybenzyl) aminopyrimidine was obtained as a white solid. This was suspended in 150 ml of ethanol, 3.37 g of ethoxymethylene acetoacetic acid ethyl ester was added at room temperature, and the mixture was stirred for 1 hour and then heated and refluxed for 15 hours. The reaction solution was concentrated under reduced pressure and dried to give 7.22 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (t, 3 H, J = 7 Hz), 2.92
(s, 3 H), 3.80 (s, 3 H), 4.31 (q, 2 H, J = 7 Hz),
4.45 (brs, 2 H), 6.32 (s, 1 H), 6.89 (d, 2 H, J = 7
Hz), 7.22 (d, 2 H, J = 7 Hz), 8.03 (s, 1 H).

(3) 1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolecarbaldehyde Compound obtained in Example 29- (2) 5. The same reaction and post-treatment as in Example 23- (2) were performed using 77 g to obtain 5.31 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.93 (s, 3 H), 3.81 (s, 3 H), 4.4
5 (brs, 2 H), 6.35 (s, 1 H), 6.90 (d, 2 H, J = 8 H
z), 7.23 (d, 2 H, J = 8 Hz), 8.09 (s, 1 H), 10.00
(s, 1 H).

(4) Ethyl 3-[[4-chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propanoate Example 29- ( 5.11 g of the compound obtained in 3) was dissolved in 130 ml of toluene, 5.22 g of (carboethoxymethylene) triphenylphosphorane was added, and the mixture was heated under reflux in a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, developed with a mixed solvent of ethyl acetate-hexane (1: 2), and the fraction containing the desired compound was concentrated to give the title compound 5. 3
4 g were obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, 3 H, J = 7 Hz), 2.71
(s, 3 H), 3.81 (s, 3 H), 4.25 (q, 2 H, J = 7 Hz),
4.46 (brs, 2 H), 5.90 (brs, 1 H), 6.26 (d, 1 H, J
= 16 Hz), 6.29 (s, 1 H), 6.89 (d, 2 H, J = 8 Hz),
7.23 (d, 2 H, J = 8 Hz), 7.58 (d, 1 H, J = 16 Hz),
7.92 (s, 1 H).

(5) 3-[[4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal Example 29- (4) Using 5.34 g of the compound obtained in the above, the same reaction and post-treatment as in Example 23- (5) were performed to obtain 3.38 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.76 (s, 3 H), 3.81 (s, 3 H), 4.
26 (brs, 2 H), 6.32 (s, 1 H), 6.55 (dd, 1 H, J = 8
Hz, 16 Hz), 6.90 (d, 2 H, J = 8 Hz), 7.24 (d, 2
H, J = 9 Hz), 7.39 (d, 1 H, J = 16 Hz), 7.96 (s, 1
H), 9.65 (d, 1 H, J = 9 Hz).

(6) 1- [1- [4-Chloro-6- (4
-Methoxybenzyl) amino-2-pyrimidinyl] -5
-Methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-tra
ns-propene Using 398 mg of the compound obtained in Example 29- (5), the same reaction and post-treatment as in Example 23- (6) were performed to obtain 378 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.55-2.65 (m, 7 H), 3.17-3.21
(m, 6 H), 3.79 (s, 3 H), 4.40 (brs, 2 H), 6.06 (dt,
1 H, J = 16 Hz, 7 Hz), 6.21 (t, 1 H, J = 9 Hz),
6.25 (s, 1 H), 6.35-6.39 (m, 3 H), 6.87 (d, 2 H, J
= 8 Hz), 7.20 (d, 2 H, J = 8 Hz), 7.80 (s, 1 H).

(7) 1- [1- (4-Amino-6-chloro-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1
-Piperazinyl] -1-trans-propene 780 mg of the compound obtained in Example 29- (6) was dissolved in 30 ml of trifluoroacetic acid, and 500 µl of anisole was added, followed by heating under reflux for 15 hours. The solvent is distilled off under reduced pressure,
After 100 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the residue, the mixture was extracted with a mixed solvent of chloroform-methanol (9: 1). After drying the organic layer over anhydrous sodium sulfate,
The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel chromatography, and chloroform-methanol (4
The mixture was developed with a mixed solvent of 9: 1 to 19: 1), and the fraction containing the desired compound was concentrated to obtain 502 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 2.61-2.65 (m, 7 H), 3.17-3.23
(m, 6 H), 5.79 (brs, 2 H), 6.07 (dt, 1 H, J = 16 H
z, 7 Hz), 6.24 (t, 1 H, J = 8 Hz), 6.32 (s, 1H),
6.34-6.40 (m, 3 H), 7.82 (s, 1 H).

(8) 1- [1- [4-amino-6- (2
-Hydroxyethyl) amino-2-pyrimidinyl] -5
-Methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-tra
ns-propene hydrochloride After suspending 584 mg of the compound obtained in Example 29- (7) in 50 ml of ethanol, 790 μm of ethanolamine was used.
and heated under reflux for 4 days. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with a mixed solvent of chloroform-methanol (9: 1). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and developed with a mixed solvent of chloroform-methanol (9: 1) to obtain a fraction containing the target compound. Was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and then recrystallized from a mixed solvent of ethanol and isopropanol to obtain 107 mg of the title compound as a white powder. Melting point: 198-208 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 3.09-3.78 (m, 1
0 H), 3.95-3.98 (m, 4H), 5.58 (s, 1 H), 6.31 (dt,
1H, J = 16 Hz, 8 Hz), 6.57 (t, 1 H, J = 9 Hz), 6.7
3 (d, 2 H, J = 9 Hz), 6.83 (d, 2 H, J = 16 Hz), 8.
31 (s, 1 H), 11.08 (brs, 1 H).

Example 30 1- [1- [4-amino-6- (3-hydroxy-1-)
Azetidinyl) -2-pyrimidinyl] -5-methyl-4
-Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0320]

Embedded image

Compound 29 obtained in Example 29- (7), 500m
Using g, the same reaction and post-treatment as in Example 22 were performed to obtain 150 mg of the title compound as a white solid. Melting point: 213-220 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.64 (s, 3 H), 3.09-3.11 (m, 2
H), 3.25 (t, 2 H, J = 12 Hz), 3.51 (t, 2 H, J = 12
Hz), 3.85-3.98 (m, 6 H), 4.30-4.34 (m, 2 H), 4.61
-4.66 (m, 1 H), 5.28 (s, 1 H), 6.31 (dt, 1 H, J =
15 Hz, 7 Hz), 6.56 (t, 1 H, J = 9 Hz), 6.72 (d, 2
H, J = 9 Hz), 6.83 (d, 2 H, J = 15 Hz), 7.50 (brs,
2 H), 8.27 (s, 1 H), 11.33 (brs, 2 H).

Example 31 1- [1- [4-Amino-6- (1-pyrrolidinyl)-
2-pyrimidinyl] -5-methyl-4-pyrazolyl]-
3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0323]

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Compound 29 mg obtained in Example 29- (7)
Is suspended in 10 ml of ethanol, and 21 μl of pyrrolidine is suspended.
Was added and heated under reflux for 24 hours. The residue obtained by evaporating the solvent under reduced pressure was subjected to preparative TLC, and developed and separated and purified in a lower layer of chloroform: methanol: water = 20: 3: 1. The obtained compound was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and then crystallized from ethanol-ether to obtain 25 mg of the title compound as a white solid. Melting point: 195-201 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.99 (brs, 4 H), 2.70 (s, 3)
H), 3.07-3.98 (m, 12 H), 5.45 (s, 1 H), 6.36 (dt, 1
H, J = 16 Hz, 7 Hz), 6.56 (t, 1 H, J = 8 Hz), 6.7
2 (d, 2 H, J = 10 Hz), 6.85 (d, 2 H, J = 16 Hz),
8.33 (s, 1 H), 11.4 (brs, 1 H).

Example 32 1- [1- [4-Amino-6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] -5-methyl-pyrazolyl] -3- [4- (3,5- Difluorophenyl)-
1-piperazinyl] -1-trans-propene hydrochloride

[0326]

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Compound 24 obtained in Example 29- (7) except that pyrrolidine in Example 31 was changed to N-methylpiperazine.
Using mg, the same reaction and post-treatment as in Example 31 were performed,
26 mg of the title compound were obtained as a white solid. Melting point: 235-243 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (s, 3 H), 2.79 (s, 3 H),
3.09-3.18 (m, 4 H), 3.25 (t, 2 H, J = 3 Hz), 3.44-
3.98 (m, 10 H), 4.31 (d, 2 H), 5.78 (s, 1 H), 6.25
(dt, 1 H, J = 16 Hz, 7 Hz), 6.57 (t, 1 H, J = 10
Hz), 6.72 (d, 2H, J = 10 Hz), 6.82 (d, 2H, J = 16
Hz), 7.35 (brs, 2 H), 8.12 (s, 1 H), 11.32 (brs, 2 H
H).

Example 33 1- [1- (4-Amino-6-morpholino-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl]
-1-trans-propene hydrochloride

[0329]

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Compound 293m obtained in Example 29- (7)
g was suspended in 100 ml of ethanol, 287 μl of morpholine was added, and the mixture was heated under reflux for 5 days. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, developed with a mixed solvent of chloroform-methanol (97: 3), and the fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and then recrystallized from a mixed solvent of ethanol and isopropanol to give the title compound 22
5 mg was obtained as a white powder. Melting point: 234-238 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (s, 3 H), 3.09-3.98 (m, 1
8 H), 5.68 (s, 1 H), 6.27 (dt, 1 H, J = 16 Hz, 8 H
z), 6.58 (t, 1 H, J = 10 Hz), 6.73 (d, 2 H, J = 10
Hz), 6.81 (d, 2 H, J = 16 Hz), 8.17 (s, 1 H), 10.9
0 (brs, 2 H).

Example 34 1-[[4- (1-Azetidinyl) -6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,3 5-difluorophenyl) -1-piperazinyl] -1-trans-propene

[0332]

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(1) 3-[[4- (1-azetidinyl)
-6- (4-Methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-tran
Ethyl s-propenoate After suspending 428 mg of the compound obtained in Example 29- (4) in 100 ml of ethanol, azetidine hydrochloride 468 was used.
mg and heated in a sealed tube at 100 ° C. for 3 days. After the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give the title compound 4
03 mg was obtained as a light brown powder. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, 3 H, J = 7 Hz), 2.35-2.
43 (m, 2 H), 2.69 (s, 3 H), 3.80 (s, 3 H), 4.03-4.0
6 (m, 4 H), 4.23 (q, 2 H, J = 7 Hz), 4.35 (d, 2 H,
J = 5 Hz), 4.97 (s, 1 H), 5.38 (brs, 1 H), 6.22
(d, 1 H, J = 16 Hz), 6.87 (d, 2 H, J = 7 Hz), 7.24
(d, 2 H, J = 7 Hz), 7.60 (d, 1 H, J = 16 Hz), 7.87
(s, 1 H).

(2) 3-[[4- (1-azetidinyl)
-6- (4-Methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-tran
s-Propenal Using 403 mg of the compound obtained in Example 34- (1), the same reaction and post-treatment as in Example 23- (5) were performed to obtain 375 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.35-2.46 (m, 2 H), 2.74 (s, 3
H), 3.80 (s, 3 H), 4.03-4.06 (m, 4 H), 4.36 (brs,
2 H), 4.99 (s, 1 H), 5.35 (brs, 1 H), 6.47-6.58
(m, 1 H), 6.84-6.89 (m, 2 H), 7.23-7.27 (m, 2 H),
7.35-7.43 (m, 1 H), 7.90 (s, 1 H), 9.63 (brs, 1 H).

(3) 1-[[4- (1-azetidinyl)
-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl]
-1-trans-propene Using 363 mg of the compound obtained in Example 34- (2), the same reaction and post-treatment as in Example 23- (6) were performed to obtain 255 mg of the title compound as a slightly brown oil. ¹ H-NMR (CDCl ₃ ) δ: 2.35-2.39 (m, 2 H), 2.53-2.66
(m, 4 H), 2.61 (s, 3 H), 3.18-3.24 (m, 6 H), 3.79
(s, 3 H), 4.03 (t, 4 H, J = 9 Hz), 4.34 (d, 2H, J
= 5 Hz), 4.95 (s, 1 H), 5.49 (brs, 1 H), 6.01 (d
t, 1 H, J = 16 Hz, 7 Hz), 6.24 (dt, 1 H, J = 2.9 H)
z), 6.36 (d, 2 H, J = 9 Hz), 6.38 (d, 1H, J = 16 H
z), 6.86 (d, 2 H, J = 8 Hz), 7.23 (d, 2 H, J = 9 H
z), 7.76 (s, 1 H).

Example 35 1-[[4-Amino-6- (1-azetidinyl) -2-]
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3-
[4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0337]

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Compound 34m obtained in Example 34- (3)
g was dissolved in 30 ml of trifluoroacetic acid, 2 ml of anisole was added, and the mixture was refluxed for 23 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with a mixed solvent of chloroform-methanol (9: 1). After the organic layer was dried over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was subjected to silica gel chromatography, and chloroform-methanol (98:
The mixture was developed with the mixed solvent in 2), and the fraction containing the target compound was concentrated. After the residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol,
Recrystallization from ethanol gave 54 mg of the title compound as a white powder. Melting point: 190-196 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.37-2.41 (m, 2 H), 2.63 (s, 3)
H), 3.08-3.49 (m, 6 H), 3.95-3.98 (m, 4 H), 4.09-
4.12 (m, 4 H), 5.23 (s, 1 H), 6.29 (dt, 1 H, J = 16
Hz, 8 Hz), 6.57 (t, 1 H, J = 9 Hz), 6.73 (d, 1 H,
J = 9 Hz), 6.82 (d, 1 H, J = 16 Hz), 8.23 (s, 1 H),
11.17 (brs, 1 H).

Example 36 3- [3- [1- [2-Amino-6- (2-hydroxyethyl) amino-4-pyrimidinyl] -5-methyl-4
-Pyrazolyl] -2-trans-propen-1-yl] -7,9-difluoro-2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride

[0340]

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(1) 2-Tribromomethyl-5,7-difluoroquinoline A mixture consisting of 33 g of 5,7-difluoroquinaldine, 94 g of sodium acetate and 190 ml of acetic acid was added with 70
At C, a mixture consisting of 28.4 ml of bromine and 25 ml of acetic acid was added over 30 minutes. The reaction solution was stirred at 90 ° C. for 1 hour, cooled to room temperature, added with water, and extracted twice with ethyl acetate. The organic layer is 10% aqueous sodium thiosulfate,
After washing with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline solution in that order, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 71.9 g of the title compound.
Was obtained as a brown solid. ¹ H-NMR (CDCl ₃ ) δ: 7.15 (td, 1 H, J = 9 Hz, 2 Hz),
7.69 (d, 1 H, J = 9 Hz), 8.25 (d, 1 H, J = 9 Hz),
8.49 (d, 1 H, J = 9 Hz).

(2) 5,7-Difluoro-2-quinolinecarboxylic acid Concentrated sulfuric acid was added to 17.4 g of the compound obtained in Example 36- (1).
Add 80 ml and keep at 150 ° C for 20 hours at 130 ° C
After stirring for 20 hours at, the reaction solution was poured into about 800 ml of ice. A 28% aqueous ammonia solution was added to the obtained acidic aqueous solution to make it alkaline, and then a 1N aqueous phosphoric acid solution was added to adjust the pH to around 4, followed by extraction with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (9: 1), and the fraction containing the desired product was concentrated to obtain 2.58 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.96 (t, 1 H, J = 10 Hz), 7.84
(d, 1 H, J = 8 Hz), 8.16 (d, 1 H, J = 8 Hz), 8.63
(d, 1 H, J = 8 Hz).

(3) 5,7-difluoro-2- [N-
(1-phenylethyl) carbamoyl] -1,2,3
4-tetrahydroquinoline (diastereoisomer A and diastereoisomer B) 2.58 g of the compound obtained in Example 36- (2) was treated with acetic acid 10
0 ml, and after adding 300 mg of platinum oxide, 6
Time catalytic hydrogenation was performed. The insolubles were removed by filtration, the filtrate was concentrated to dryness, the residue was dissolved in chloroform, washed with half-saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 80 ml of dichloromethane, and (s)-(-)-1
-Phenylethylamine 2.20 g, dimethylaminopyridine 2.24 g, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 4.44 g
Was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was washed successively with a 1N aqueous phosphoric acid solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography and developed with a mixed solvent of ethyl acetate-hexane (1: 4) to give a low-polar isomer (diastereoisomer A) of the title compound (1.0).
5 g was obtained and then developed with a mixed solvent of ethyl acetate-hexane (1: 2) to obtain 1.22 g of a highly polar isomer (diastereoisomer B). Diastereoisomer A; ¹ H-NMR (CDCl ₃ ) δ: 1.46 (d, 3 H, J = 7 Hz), 1.85-1.
93 (m, 1 H), 2.25-2.33 (m, 1H), 2.41-2.50 (m, 1 H),
2.71-2.81 (m, 1 H), 3.95 (q, 1 H, J = 5 Hz), 4.36
(d, 1 H, J = 4 Hz), 5.16 (m, 1 H), 6.13 (dt, 1 H,
J = 10 Hz, 2 Hz), 6.21 (td, 1 H, J = 9 Hz, 2 Hz),
6.67 (d, 1 H, J = 8 Hz), 7.25-7.40 (m, 5 H). Diastereoisomer B; ¹ H-NMR (CDCl ₃ ) δ: 1.49 (d, 3 H, J = 7 Hz) ), 1.83-1.
92 (m, 1 H), 2.20-2.37 (m, 2H), 2.66-2.73 (m, 1 H),
3.98 (q, 1 H, J = 5 Hz), 4.42 (d, 1 H, J = 4 Hz),
5.13 (m, 1 H), 6.13-6.26 (m, 2 H), 6.70 (d, 1 H, J
= 6 Hz), 7.15-7.31 (m, 5 H).

(4) 5,7-difluoro-2- [N-
(1-Phenylethyl) -N-tert-butoxycarbonylaminomethyl] -1,2,3,4-tetrahydroquinoline (diastereoisomer B) Diastereoisomer B1 obtained in Example 36- (3). 2
2 g was dissolved in 15 ml of tetrahydrofuran, 3.9 ml of borane-dimethylsulfide complex was added under stirring at 0 ° C., and the mixture was stirred at room temperature for 3 days. 6N hydrochloric acid aqueous solution 10
After stirring for 2 hours, the mixture was neutralized using a saturated aqueous solution of sodium hydrogen carbonate. After extraction with chloroform, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Residue 1,4
-Dissolve in 10 ml of dioxane and di-tert-dicarbonate
After adding 1.06 ml of -butyl, the mixture was stirred at room temperature for 39 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, developing with a mixed solvent of ethyl acetate-hexane (1: 9) and concentrating the fraction containing the desired compound to give the title compound 1. 39 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.40 (m, 1 H), 1.48 (s, 9
H), 1.53 (d, 3 H, J = 7Hz), 2.25-2.40 (m, 1 H), 2.
50-2.65 (m, 1 H), 3.00-3.20 (m, 3 H), 5.25-5.50
(m, 1 H), 5.92 (d, 1 H, J = 10 Hz), 6.02 (td, 1 H,
J = 9 Hz, 2 Hz), 7.25-7.40 (m, 5 H).

(5) 7,9-Difluoro-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1-oxopyrazino [1,2-a] quinoline (diastereoisomer Compound B) 1.39 g of the compound obtained in Example 36- (4) is dissolved in 10 ml of tetrahydrofuran, and 0.43 ml of pyridine and 0.31 of chloroacetyl chloride are stirred at 0 ° C.
After adding ml, the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 30 minutes. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in 4 ml of tetrahydrofuran, 5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes and further at 50 ° C. for 2 hours. After the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 10 ml of dimethylformamide, 0.9 g of potassium carbonate was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-
The mixture was developed with a mixed solvent of hexane (1: 4), and the fraction containing the desired product was concentrated to obtain 935 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (d, 3 H, J = 7 Hz), 1.88-2.
10 (m, 2 H), 2.52 (dd, 1 H, J = 12 Hz, 6 Hz), 2.65-
3.00 (m, 3 H), 3.33 and 3.34 (ABq, 2 H, J = 17 Hz),
3.42 (q, 1 H, J = 7 Hz), 3.50-3.60 (m, 1 H), 6.59
(td, 1 H, J = 10 Hz, 2 Hz), 7.25-7.40 (m, 5 H), 7.
69 (dt, 1 H, J = 11 Hz, 2 Hz).

(6) 7,9-Difluoro-3- (1-phenylethyl) -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (diastereoisomer Form B) 930 mg of the compound obtained in Example 36- (5) was dissolved in 14 ml of tetrahydrofuran, 3 ml of borane-dimethylsulfide complex was added, and the mixture was stirred for 5 days. Reaction solution 6
After pouring into 20 ml of a normal hydrochloric acid aqueous solution and stirring at room temperature for 1 hour, sodium hydrogen carbonate was added to adjust the pH to about 9, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and developed with a mixed solvent of ethyl acetate-hexane (1: 9) to give the desired compound. Was concentrated to obtain 722 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (d, 3 H, J = 6 Hz), 1.55-1.
75 (m, 1 H), 1.89-1.95 (m, 2 H), 2.04-2.11 (m, 1
H), 2.54-2.64 (m, 1 H), 2.73-2.83 (m, 3 H), 3.05-
3.11 (m, 2 H), 3.38 (q, 1 H, J = 6 Hz), 3.46-3.52
(m, 1 H), 6.13-6.23 (m, 2 H), 7.23-7.40 (m, 5 Hz).

(7) 7,9-difluoro-2,3,4
4a, 5,6-hexahydro-1H-pyrazino [1,2
-A] Quinoline (enantiomer B) 10 ml of 722 mg of the compound obtained in Example 36- (6)
Dissolved in methanol, and 0.69 g of ammonium formate
And 0.68 g of 10% palladium on carbon,
The mixture was refluxed for 1.5 hours. After removing insolubles by filtration, the filtrate was concentrated under reduced pressure. Saturated saline was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of methanol and chloroform (1: 9), and the fraction containing the desired compound was concentrated to give the title compound 41
2 mg were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.72 (m, 1 H), 1.87-1.95
(m, 1 H), 2.54-2.63 (m, 2 H), 2.70-2.81 (m, 2 H),
2.85-2.97 (m, 2 H), 3.01-3.06 (m, 1 H), 3.10-3.15
(m, 1 H), 3.60 (brd, 1 H, J = 12 Hz), 6.18 (td, 1
H, J = 9 Hz, 2 Hz), 6.28 (d, 1 H, J = 13 Hz).

(8) 3- [3- [1- [2-amino-6
-(4-Methoxybenzyloxy) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans
-Propen-1-yl] -7,9-difluoro-2,
3,4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline (isomer B) 220 mg of the compound obtained in Example 36- (7), 3-
[[2-amino-6- (4-methoxybenzyloxy)
-4-pyrimidinyl] -5-methyl-4-pyrazolyl]
A mixture consisting of 357 mg of 2-trans-propenal and 20 ml of ethanol was stirred at 60 ° C. for 20 minutes, cooled to room temperature, and 0.56 ml of acetic acid was added.
Then 286 mg of sodium cyanoborohydride were added in two portions every 3 hours. After stirring at room temperature for 15 hours, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and developed with a mixed solvent of methanol and chloroform (1:99) to give the desired compound. The fractions containing were concentrated to obtain 428 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.55-1.75 (m, 1 H), 1.85-2.00
(m, 2 H), 2.66 (s, 3H), 2.50-3.20 (m, 8 H), 3.63 (b
rd, 1 H, J = 12 Hz), 4.93 (brs, 2 H), 5.34 (s, 2
H), 6.04 (dt, 1 H, J = 16 Hz, 7 Hz), 6.19 (td, 1
H, J = 9 Hz, 2 Hz), 6.25-6.32 (m, 1 H), 6.38 (d, 1
H, J = 16 Hz), 6.67 (s, 1 H), 7.25-7.50 (m, 5 H),
7.77 (s, 1 H).

(9) 3- [3- [1- (2-amino-6)
-Chloro-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl]-
7,9-difluoro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline (isomer B) To compound 428 mg obtained in Example 36- (8), 10 ml of trifluoroacetic acid and 0.11 ml of thioanisole
Was added and stirred at room temperature for 2 hours. Concentrate the reaction,
After adding diethyl ether to the residue and stirring at room temperature, the precipitate was collected by filtration. 10 ml of phosphorus oxychloride was added to 439 mg of the obtained compound, and the mixture was stirred at 90 ° C. for 6 hours. After concentrating the reaction solution, water and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue, and chloroform-methanol (9:
Extracted 4 times in 1). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (99: 1), and the fraction containing the desired product was concentrated to obtain 177 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.80 (m, 1 H), 1.90-2.00
(m, 2 H), 2.20-2.30 (m, 1 H), 2.50-3.30 (m, 8 H),
2.70 (s, 3 H), 3.64 (brd, 1 H, J = 12 Hz), 5.15
(s, 2 H), 6.08 (dt, 1 H, J = 16 Hz, 7 Hz), 6.19 (t
d, 1 H, J = 9 Hz, 2 Hz), 6.29 (d, 1 H, J = 13 Hz),
6.39 (d, 1 H, J = 16 Hz), 7.31 (s, 1 H), 7.81 (s, 1
H).

(10) 3- [3- [1- [2-amino-
6- (2-hydroxyethyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans
-Propen-1-yl] -7,9-difluoro-2,
3,4,4a, 5,6-Hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer B) 18 mg of the compound obtained in Example 36- (9) was dissolved in 5 ml of ethanol, and ethanol was added. After 1 ml of the amine was added, the mixture was heated under reflux for 26 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off, the obtained residue was subjected to preparative TLC, developed with a mixed solvent of chloroform / methanol (95: 5), and the title compound was obtained from the fraction containing the target compound. To give 15 mg of the free form.
The obtained compound was dissolved in hot ethanol (2 ml), 1N hydrochloric acid / ethanol was added, the mixture was cooled, and the precipitated powder was collected by filtration to obtain 6 mg of the title compound. Melting point: 200 ° C. or more (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.70 (m, 1H), 2.00-2.10
(m, 1 H), 2.50-2.75 (m. 2 H), 2.65 (s, 3 H), 2.80-
2.95 (m, 1 H), 3.00-3.30 (m, 2 H), 3.30-3.65 (m, 7
H), 3.80-4.00 (m, 2 H), 4.13 (brd, 1 H, J = 13 H
z), 6.24 (dt, 1 H, J = 16 Hz, 7 Hz), 6.45 (s, 1
H), 6.50 (td, 1 H, J = 9 Hz, 2 Hz), 6.69 (d, 1 H, J
= 13 Hz), 6.80 (d, 1 H, J = 16 Hz), 8.12 (s, 1
H), 11.25 (brs, 1 H).

Example 37 3- [3- [1- [2-amino-6- [N-methyl-N]
-(2-Hydroxyethyl)] amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans
-Propen-1-yl] -7,9-difluoro-2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer B)

[0352]

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Example 36 18 mg of the compound obtained in (9)
Using the ethanolamine of Example 36- (10) with N
The same reaction and post-treatment as in Example 36- (10) were performed, except that -methyl-N- (2-hydroxyethyl) amine was used, to obtain 5 mg of the title compound. Melting point: 206-211 ° C
(Decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.70 (m, 1H), 2.00-2.10
(m, 1 H), 2.45-2.75 (m. 2 H), 2.67 (s, 3 H), 2.80-
2.95 (m, 1 H), 3.07 (s, 3 H), 3.00-3.65 (m, 9 H),
3.80-4.00 (m, 2 H), 4.13 (brd, 1 H, J = 12 Hz), 6.
17 (dt, 1 H, J = 16 Hz, 7 Hz), 6.27 (s, 1 H), 6.48
(td, 1 H, J = 9 Hz, 2 Hz), 6.67 (d, 1H, J = 13 H
z), 6.77 (d, 1 H, J = 16 Hz), 7.95 (s, 1 H), 11.0
8 (brs, 1H).

Example 38 3- [3- [1- [2-Amino-6-di (2-hydroxyethyl) amino-4-pyrimidinyl] -5-methyl-
4-pyrazolyl] -2-trans-propen-1-yl] -7,9-difluoro-2,3,4,4a, 5,6
-Hexahydro-1H-pyrazino [1,2-a] quinoline hydrochloride (isomer B)

[0355]

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Compound 36 mg obtained in Example 36- (9)
Was used to replace ethanolamine of Example 36- (10) with 2,2′-iminodiethanol.
The same reaction and post-treatment as in (10) were performed to give the title compound 6m
g was obtained. Melting point: 161-166 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.70 (m, 1H), 2.00-2.10
(m, 1 H), 2.50-2.75 (m. 2 H), 2.66 (s, 3 H), 2.80-
3.70 (m, 12 H), 3.67 (t, 2 H, J = 5 Hz), 3.80-4.00
(m, 2 H), 4.13 (brd, 1 H, J = 13 Hz), 6.16 (dt, 1
H, J = 16 Hz, 7Hz), 6.30 (s, 1 H), 6.51 (td, 1 H,
J = 9 Hz, 2 Hz), 6.69 (d, 1 H, J = 13 Hz), 6.78
(d, 1 H, J = 16 Hz), 7.97 (s, 1 H), 8.55 (brs, 1
H). Example 39 (+/-)-3- [3- [1- [2-amino-6- (3-hydroxy-1-azetidinyl) -4-pyrimidinyl] -2-trans-propen-1- Il] -7,9
-Difluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino
[2,1-c] -1,4-benzoxazine hydrochloride

[0357]

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3- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2
83 mg of -trans-propenal was suspended in 11 ml of ethanol, and (+/-)-7,9-difluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1- c] -1,4-Benzoxazine 63 mg was added and the mixture was stirred at 80 ° C. for 1 hour. After cooling the reaction solution to room temperature, 158 μl of acetic acid was added, and then 52 mg of sodium cyanoborohydride was added, followed by stirring at room temperature for 14 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted four times with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (270-400 mesh, 80 g), developed with a mixed solvent of chloroform-methanol (95: 5), and the fraction containing the desired product was concentrated. Residue (102 m
g) was treated with 1N hydrochloric acid / ethanol and recrystallized from isopropyl alcohol to obtain 77 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 2.80-4.45 (m,
15 H), 4.55-4.65 (m, 1 H), 6.03 (s, 1 H), 6.17 (dt,
1 H, J = 16 Hz, 7 Hz), 6.65 (t, 1 H, J = 9 Hz), 6.
75-6.80 (m, 3 H), 8.01 (s, 1 H), 11.19 (brs, 1 H)

Example 40 1- [1- [4-Amino-6- (2-hydroxyethylamino) -1,3,5
-Triazin-2-yl] -5-methyl-4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0360]

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(1) 2-chloro-4- (2-hydroxyethylamino) -6- (4-methoxybenzylamino) -1,3,5-triazine 2,4-dichloro-6- (4-methoxybenzyl) Amino) -1,3,5-
1.43 g (5.01 mmol) of triazine was suspended in 100 ml of ethanol, 303 μl (5.01 mmol) of 2-aminoethanol and 693 mg of potassium carbonate were added, and the mixture was stirred at 45 ° C. for 1 day. After evaporating the solvent under reduced pressure, water was added to the residue and the precipitate was collected by filtration to obtain 1.56 g (quantitative) of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 3.57-3.61 (m, 2 H), 3.76-3.79
(m, 2 H), 3.80 (s, 3 H), 4.47-4.54 (m, 2 H), 6.86
(d, 2 H, J = 9 Hz), 7.21 (d, 2 H, J = 8 Hz).

(2) 1- [4- (2-hydroxyethylamino)-
6- (4-methoxybenzylamino) -1,3,5-triazine-2-
Ethyl] -5-methyl-4-pyrazolecarboxylate 1.55 g (5.00 mmol) of the compound obtained in Example 40- (1) was suspended in 30 ml of ethanol, and 1.56 ml of hydrazine monohydrate was obtained.
(50.1 mmol) and 692 mg (5.00 mmol) of potassium carbonate were added, and the mixture was heated under reflux for 21 hours. After distilling off the solvent under reduced pressure,
Water was added to the residue and chloroform-methanol (9: 1)
Extracted with a mixed solvent. After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of ethanol, and ethyl 2- (ethoxymethylene) acetoacetate (582 mg, 3.13 mmol) was added.
After stirring for 2 hours, the mixture was heated under reflux for 16 hours. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel chromatography, developed with a mixed solvent of chloroform-methanol (97: 3), and the fraction containing the desired product was concentrated to give the title compound 1.
10 g (51%) were obtained as a pale white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (t, 3 H, J = 7 Hz), 1.65
(brs, 1 H), 2.93, 2.98 (each s, 3 H), 3.56-3.64 (m,
2 H), 3.79 (s, 3 H), 3.75-3.86 (m, 2 H), 4.30 (q,
2 H, J = 7 Hz), 4.51-4.59 (m, 2 H), 5.63-6.03 (m,
2H), 6.87 (d, 2 H, J = 8 Hz), 7.23 (d, 2 H, J = 8
Hz), 8.00, 8.02 (each s, 1 H).

(3) 1- [4- (2-hydroxyethylamino)-
6- (4-methoxybenzylamino) -1,3,5-triazine-2-
Yl] -5-methyl-4-pyrazolecarbaldehyde 1.10 g (2.57 mmol) of the compound obtained in Example 40- (2) was dissolved in methylene chloride (100 ml), and the mixture was dissolved at -78 ° C under a nitrogen atmosphere.
And then cooled to diisobutylaluminum hydride (1
M hexane solution), and stirred at the same temperature for 1 hour.
5 ml of diisobutylaluminum hydride (1M hexane solution) was added, and the mixture was stirred for 1 hour. To the reaction solution was added 500 ml of a 10% aqueous potassium tartrate solution, and the mixture was stirred at room temperature for 16 hours.
After separating the organic layer, the aqueous layer was extracted twice with chloroform and five times with a mixed solvent of chloroform-methanol (9: 1). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (100 ml), activated manganese dioxide (1.79 g) was added, and the mixture was stirred at room temperature for 2 days. After removing insolubles by filtration through celite, the filtrate was concentrated to obtain 686 mg (70%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.83-2.94 (m, 3 H), 3.53-3.88
(m, 7 H), 4.47-4.63 (m, 2 H), 5.99-6.52 (m, 2 H),
6.81-6.87 (m, 2 H), 7.18-7.23 (m, 2 H), 7.99-8.07
(m, 1 H), 10.02 (s, 1 H).

(4) 3-[[4- (2-hydroxyethylamino)
-6- (4-methoxybenzylamino) -1,3,5-triazine-2-
Ethyl] -5-methyl-4-pyrazolyl] -2-trans-propenoate From the compound 686 mg obtained in Example 40- (3), 653 mg of (carboethoxymethylene) triphenylphosphorane, and 100 ml of toluene The resulting mixture was heated at reflux for 19 hours.
After evaporating the solvent under reduced pressure, the mixture was cooled to room temperature, and the precipitate was collected by filtration to obtain 440 mg (54%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, 3 H, J = 7 Hz), 2.69-
2.75 (m, 3 H), 3.55-3.64 (m, 2 H), 3.78-3.82 (m, 5
H), 4.24 (q, 2 H, J = 7 Hz), 4.52-4.59 (m, 2H), 5.
55-5.91 (m, 2 H), 6.25 (d, 1 H, J = 16 Hz), 6.87
(d, 2 H, J = 8 Hz), 7.25 (d, 2 H, J = 8 Hz), 7.57
(d, 1 H, J = 16 Hz), 7.89-7.91 (m, 1 H).

(5) 3-[[4- (2-hydroxyethylamino)
-6- (4-methoxybenzylamino) -1,3,5-triazine-2-
Yl] -5-methyl-4-pyrazolyl] -2-trans-propenal 440 mg of the compound obtained in Example 40- (4) was methylene chloride
After dissolving in 40 ml and cooling to -78 ° C under nitrogen atmosphere,
5.0 ml of diisobutylaluminum hydride (1M hexane solution) was added, and the mixture was stirred at the same temperature for 30 minutes and at 0 ° C. for 1 hour. After cooling the reaction solution to −78 ° C., a 10% aqueous solution of potassium tartrate was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. 9: 1) Extracted 10 times with a mixed solvent.
After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is 1,4-dioxane
It was dissolved in 50 ml, and after adding 844 mg of active manganese dioxide, the mixture was stirred at room temperature for 18 hours. After removing insolubles by Celite filtration, the filtrate was concentrated to give the title compound.
784 mg (97%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.68-2.76 (m, 3 H), 3.53-3.78
(m, 7 H), 4.50-5.56 (m, 2 H), 5.86-6.39 (m, 2 H),
6.48-6.54 (m, 1H), 6.83-6.87 (m, 2H), 7.21-7.25
(m, 2 H), 7.33 (d, 1 H, J = 16 Hz), 7.85-7.91 (m,
1 H), 9.61 (d, 1H, J = 8 Hz).

(6) 1- [1- [4- (2-hydroxyethylamino) -6- (4-methoxybenzylamino) -1,3,5-triazine-
2-yl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene Compound 384 obtained in Example 40- (5) mg of ethanol 50
Then, 291 mg of 1- (3,5-difluorophenyl) piperazine was added, and the mixture was stirred at room temperature for 16 hours. Then acetic acid 53
After adding 7 μl, sodium cyanoborohydride 147 mg
Was added in three portions over 4 hours, and the mixture was stirred at room temperature for 2 days. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, ethanol was distilled off under reduced pressure and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel chromatography, and developed with a mixed solvent of chloroform-methanol (49: 1),
By concentrating the fraction containing the target compound, the title compound 36 was obtained.
5 mg (66%) was obtained as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 2.61-2.63 (m, 3 H), 3.16-3.23
(m, 6 H), 3.53-3.79 (m, 7 H), 4.54-4.58 (m, 2 H),
6.03-6.12 (m, 1H), 6.24 (dt, 1 H, J = 9 Hz, 2 Hz),
6.34-6.37 (m, 2 H), 6.86 (d, 2H, J = 8 Hz), 7.23
(d, 2H, J = 8 Hz), 7.81 (s, 1 H).

(7) 1- [1- [4-Amino-6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride To 365 mg of the compound obtained in Example 40- (6), 50 ml of trifluoroacetic acid and 1 ml of thioanisole were added. After adding, 2
Heated to reflux for days. The solvent was distilled off under reduced pressure, 100 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with a mixed solvent of chloroform-methanol (9: 1). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel chromatography, and developed with a mixed solvent of chloroform-methanol (19: 1) to obtain the desired product. The containing fraction was concentrated. 1 residue
After hydrochlorination with normal hydrochloric acid / ethanol, recrystallization from ethanol gave 188 mg (54%) of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.68 (s, 3 H), 3.10 (dd, 2 H,
J = 21 Hz, 9 Hz), 3.24 (t, 2 H, J = 8 Hz), 3.38-
3.43 (m, 2 H), 3.49-3.57 (m, 4 H), 3.94-3.98 (m, 4
H), 6.21-6.30 (m, 1 H), 6.57 (t, 1 H, J = 9 Hz),
6.72 (d, 2 H, J = 9 Hz), 6.81 (d, 1 H, J = 16 Hz),
8.20 (s, 1 H), 11.25 (brs, 1 H)

Example 41 1- [1- [4-Amino-6- (3-hydroxy-1-azetidinyl) -1,
3,5-triazin-2-yl] -5-methyl-4-pyrazolyl] -3- [4
-(3,5-Difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0369]

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(1) 2-chloro-4- (3-hydroxy-1-azetidinyl) -6- (4-methoxybenzylamino) -1,3,5-triazine 2,4-dichloro-6- (4- (Methoxybenzylamino) -1,3,5-
1.47 g (5.16 mmol) of triazine was suspended in 100 ml of ethanol, and 568 mg of 3-hydroxyazetidine hydrochloride (5.18 mmol)
mmol) and 1.43 g of potassium carbonate, and the mixture was stirred at room temperature for 7 hours. After evaporating the solvent under reduced pressure, water was added to the residue and the precipitate was collected by filtration to obtain 1.54 g (93%) of the title compound as a white powder. ¹ H-NMR (CDCl ₃ / CD ₃ OD) δ: 3.80 (s, 3 H), 3.83-4.
01 (m, 2H), 4.28-4.50 (m, 2H), 4.64 (brs, 1H),
6.83-6.85 (m, 2 H), 7.22 (m, 1 H, J = 9 Hz).

(2) 1- [4- (3-hydroxy-1-azetidinyl) -6- (4-methoxybenzylamino) -1,3,5-triazine
Ethyl-2-yl] -5-methyl-4-pyrazolecarboxylate Using 1.54 g (4.79 mmol) of the compound obtained in Example 41- (1), the reaction was carried out in the same manner as in Example 40- (2). Work-up provided 1.80 g (85%) of the title compound as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (t, 3 H, J = 7 Hz), 2.95
(s, 3 H), 3.79 (s, 3 H), 4.03 (dd, 2 H, J = 10 H
z, 4 Hz), 4.30 (q, 2 H, J = 7 Hz), 4.41 (t, 2H, J
= 7 Hz), 4.55 (d, 2 H, J = 6 Hz), 4.77 (brs, 1 H),
5.76 (brs, 1 H), 6.85 (d, 2 H, J = 9 Hz), 7.24
(d, 2 H, J = 9 Hz), 8.00 (s, 1 H).

(3) 1- [4- (3-hydroxy-1-azetidinyl) -6- (4-methoxybenzylamino) -1,3,5-triazine
2--2-yl] -5-methyl-4-pyrazole carbaldehyde Using 1.80 g (4.10 mmol) of the compound obtained in Example 41- (2), the reaction was carried out in the same manner as in Example 40- (3). Treatment provided 1.24 g (77%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.95 (s, 3 H), 3.80 (s, 3 H),
4.04 (dd, 2H, J = 10Hz, 4Hz), 4.42 (t, 2H, J =
7 Hz), 4.55 (d, 2 H, J = 6 Hz), 4.797 (brs, 1 H),
5.75 (brs, 1 H), 6.86 (d, 2 H, J = 9 Hz), 7.24
(d, 2 H, J = 9 Hz), 8.10 (s, 1 H), 10.00 (s, 1 H).

(4) 3-[[4- (3-hydroxy-1-azetidinyl) -6- (4-methoxybenzylamino) -1,3,5-triazine-
Ethyl 2-yl] -5-methyl-4-pyrazolyl] -2-trans-propenoate Using 1.24 g of the compound obtained in Example 41- (3) and 1.15 g of (carboethoxymethylene) triphenylphosphorane,
After the reaction, post-treatment was carried out in the same manner as in Example 40- (4) to give 1.08 g (74%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, 3 H, J = 7 Hz), 2.72
(s, 3 H), 3.80 (s, 3 H), 4.03 (d, 2 H, J = 7 Hz),
4.24 (q, 2 H, J = 7 Hz), 4.41 (t, 2 H, J = 7 Hz),
4.55 (d, 2 H, J = 6 Hz), 4.78 (brs, 1 H), 5.71 (br
s, 1 H), 6.24 (d, 1H, J = 16 Hz), 6.85 (d, 2 H, J
= 9 Hz), 7.24 (d, 2 H, J = 9 Hz), 7.58 (d, 1 H, J =
16 Hz), 7.94 (s, 1 H).

(5) 3-[[4- (3-hydroxy-1-azetidinyl) -6- (4-methoxybenzylamino) -1,3,5-triazine-
2-yl] -5-methyl-4-pyrazolyl] -2-trans-propenal Using 1.08 g of the compound obtained in Example 41- (4), the reaction was carried out in the same manner as in Example 40- (5). Treatment provided 784 mg (80%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.77 (s, 3 H), 3.80 (s, 3 H),
4.04 (dd, 2H, J = 10Hz, 4Hz), 4.42 (t, 2H, J =
7 Hz), 4.55 (d, 2 H, J = 6 Hz), 4.80 (brs, 1H), 5.
75 (brs, 1 H), 6.55 (dd, 1 H, J = 16 Hz, 8 Hz), 6.
86 (d, 2 H, J = 9 Hz), 7.24 (d, 2 H, J = 9 Hz), 7.3
7 (d, 1 H, J = 16 Hz), 7.96 (s, 1 H), 9.63 (d, 1
(H, J = 8 Hz).

(6) 1- [1- [4- (3-hydroxy-1-azetidinyl) -6- (4-methoxybenzylamino) -1,3,5-triazin-2-yl] -5-methyl -4-Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene Using the compound 577 mg obtained in Example 41- (5), Example 40- After the reaction, post-treatment was conducted in the same manner as in (6) to obtain 627 mg (56%) of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 2.61-2.63 (m, 3 H), 3.20-3.23
(m, 6 H), 3.78 (s, 3 H), 3.96-4.01 (m, 2 H), 4.38
(t, 2 H, J = 7 Hz), 4.54 (d, 2 H, J = 6 Hz), 4.75
(brs, 1 H), 5.77 (brs, 1 H), 6.05 (dt, 1H, J = 16
Hz, 8 Hz), 6.24 (dt, 1 H, J = 9 Hz, 2 Hz), 6.36
(d, 2 H, J = 9 Hz), 6.38 (d, 2 H, J = 9 Hz), 6.84
(d, 2 H, J = 8 Hz), 7.24 (d, 2 H, J = 8 Hz), 7.83
(s, 1 H).

(7) 1- [1- [4-amino-6- (3-hydroxy-1
-Azetidinyl) -1,3,5-triazin-2-yl] -5-methyl-4
-Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride Using the compound 627 mg obtained in Example 41- (6), Example 40- ( After the reaction, post-treatment was conducted in the same manner as in 7) to obtain 360 mg (59%) of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.62 (s, 3 H), 3.08-3.23 (m, 4
H), 3.51 (d, 2 H, J = 11 Hz), 3.88-3.98 (m, 6 H),
4.22-4.30 (m, 2 H), 4.54-4.60 (m, 1 H), 6.22 (dt,
1H, J = 16 Hz, 8 Hz), 6.57 (t, 1 H, J = 9 Hz), 6.7
3 (d, 2 H, J = 9 Hz), 6.79 (d, 1 H, J = 16 Hz), 8.0
7 (s, 1 H), 1 0.88 (brs, 1 H).

Example 42 1- [1- [2-Amino-6- (3-hydroxy-1-pyrrolidinyl) -4-
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0378]

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The compound obtained in Example 20- (1) 23 mg (0.
05 mmol) was suspended in 2 ml of ethanol, and 13.5 mg of 3-hydroxypyrrolidine was added, followed by heating under reflux for 6 days. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (1
The mixture was developed with a mixed solvent of 9: 1), and the fraction containing the desired compound was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and recrystallized from a mixed solvent of ethanol and ether to obtain 10 mg of the title compound as a slightly brown powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.94-2.03 (m, 2 H), 2.67 (s,
3 H.), 3.07-3.71 (m, 10 H), 3.94-3.98 (m, 4 H), 4.4
2 (s, 1 H), 6.25-6.40 (m, 2 H), 6.58 (t, 1H, J = 9
Hz), 6.73 (d, 2 H, J = 9 Hz), 6.80 (d, 2 H, J = 16
Hz), 8.14 (s, 1 H), 1 1.08 (brs, 1 H)

Example 43 1- [1- [2-Amino-6-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-
[4- (3,5-difluorophenyl) -1-piperazinyl] -1-tran
s-propene hydrochloride

[0381]

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Compound 20 obtained in Example 20- (1) 23 mg
(0.05 mmol), (S) -2-hydroxymethylpyrrolidine 15.7
Using mg, the reaction and post-treatment were carried out in the same manner as in Example 42 to obtain 6 mg of the title compound as a slightly brown powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.99-2.08 (m, 3 H), 2.66 (s,
3 H), 3.08-3.52 (m, 10 H), 3.94-3.98 (m, 4 H), 6.2
1 (dt, 1 H, J = 16 Hz, 8 Hz), 6.59 (t, 1 H, J = 9 H
z), 6.73 (d, 2 H, J = 9 Hz), 6.80 (d, 2 H, J = 16
Hz), 8.12 (s, 1 H), 1 0.83 (brs, 1 H)

Example 44 1- [1- [2-Amino-6- [N-methyl- (2-hydroxyethyl) amino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4 -
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0384]

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The compound obtained in Example 20- (1) 446 mg
(1.0 mmol), using 803 μl of N-methyl-2-aminoethanol, and reacted and post-treated in the same manner as in Example 42 to give the title compound
230 mg were obtained as a light pink powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.65 (s, 3 H), 3.08-3.26 (m,
7 H), 3.50 (d, 2 H, J = 12 Hz), 3.63-3.79 (m, 4 H),
3.94-3.98 (m, 4 H), 6.24 (dt, 1 H, J = 16Hz, 8 Hz
), 6.47 (brs, 1 H), 6.58 (t, 1 H, J = 9 Hz), 6.73
(d, 2 H, J = 9 Hz), 6.81 (d, 2 H, J = 16 Hz), 8.15
(s, 1 H), 11.19 (brs, 1 H)

Example 45 1- [1- [2-Amino-6- (3-hydroxypropyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0387]

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Example 20-23 mg of the compound obtained in (1) (0.
After performing a reaction and treating in the same manner as in Example 42 using 201 mmol of 3-aminopropanol and 201 μl of 3-aminopropanol, 27 mg of the title compound was obtained as a slightly brown powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.73 (m, 2 H), 2.64 (s,
3 H), 3.08-3.66 (m, 10 H), 3.94-3.98 (m, 4 H), 6.2
4 (dt, 1 H, J = 16 Hz, 8 Hz), 6.43 (brs, 1 H), 6.57
(t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.80
(d, 2 H, J = 16 Hz), 8.15 (s, 1 H), 11.03 (brs, 1
H)

Example 46 1- [1- [2-Amino-6- (4-hydroxybutyl) amino-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0390]

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Compound 20 mg obtained in Example 20- (1)
(0.05 mmol) and 238 μl of 4-aminobutanol, and after the reaction, post-treatment was carried out in the same manner as in Example 42 to give 22 mg of the title compound.
Was obtained as a light brown powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.48-1.61 (m, 4 H), 2.64 (s,
3 H), 3.08-3.52 (m, 10 H), 3.94-3.98 (m, 4 H), 6.2
3 (dt, 1 H, J = 16 Hz, 8 Hz), 6.42 (brs, 1H), 6.57
(t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.80
(d, 2 H, J = 16 Hz), 8.16 (s, 1 H), 10.95 (brs, 1
H)

Example 47 1- [1- [2-Amino-6-[(3S, 4S) -3,4-dihydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl]- Three
-[4- (3,5-Difluorophenyl) -1-piperazinyl] -1-tra
ns-propene hydrochloride

[0393]

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(3S, 4S) -1-Benzyl-3,4-dihydroxypyrrolidine (650 mg, 3.36 mmol) was dissolved in ethanol (100 ml), and palladium hydroxide-carbon (500 mg) was added.
Contact hydrogenation for 16 hours. After filtering off the insoluble matter and distilling off the solvent under reduced pressure, the residue was dissolved in 50 ml of ethanol, and 500 mg (1.12 mmol) of the compound obtained in Example 20- (1) was added. did. After distilling off the solvent under reduced pressure,
The residue was subjected to silica gel chromatography, developed with an organic layer of chloroform-methanol-water (20: 3: 1),
The fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 485 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.51 (s, 3 H), 3.09-3.68 (m,
10 H), 3.95-3.98 (m, 4 H), 4.09 (s, 2 H), 6.23 (dt,
1 H, J = 16 Hz, 8 Hz), 6.27 (brs, 1 H), 6.58 (t,
1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.81 (d,
2 H, J = 16 Hz), 8.16 (s, 1 H), 10.79 (brs, 1 H)

Example 48 1- [1- [2-Amino-6- (3-hydroxypiperidino) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5 -Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0396]

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Compound 20 obtained in Example 20- (1) 23 mg
(0.05 mmol) and 26 mg of 3-hydroxypiperidine, followed by a post-treatment after the reaction in the same manner as in Example 42 to give 24 m of the title compound.
g was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.35-1.49 (m, 2 H), 1.68-1.75
(m, 1 H), 1.83-1.92 (m, 1 H), 2.63 (s, 3 H.), 3.07
-3.55 (m, 10 H), 3.90-3.97 (m, 5 H), 6.25 (dt, 1 H,
J = 16 Hz, 8 Hz), 6.43 (s, 1 H.), 6.59 (t, 1 H, J
= 9 Hz), 6.74 (d, 2 H, J = 9 Hz), 6.79 (d, 2 H, J =
16 Hz), 8.09 (s, 1 H), 10.59 (brs, 1 H).

Example 49 1- [1- [2-Amino-6- (4-hydroxypiperidino) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5 -Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0399]

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The compound obtained in Example 20- (1) 23 mg
(0.05 mmol), using 26 mg of 4-hydroxypiperidine, after the reaction and post-treatment in the same manner as in Example 42 to give the title compound 24 m
g was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.36-1.48 (m, 2 H), 1.78-1.87
(m, 2 H), 2.63 (s, 3H.), 3.07-3.97 (m, 15 H), 6.2
5 (dt, 1 H, J = 16 Hz, 8 Hz), 6.55 (s, 1 H), 6.58
(t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.80
(d, 2 H, J = 16 Hz), 8.14 (s, 1 H), 11.42 (brs, 1
H)

Example 50 1- [1- [2-Amino-6-[(2R) -2-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-
[4- (3,5-difluorophenyl) -1-piperazinyl] -1-tran
s-propene hydrochloride

[0402]

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The compound obtained in Example 20- (1) 23 mg
(0.05 mmol), (R) -2-hydroxymethylpyrrolidine 15.7
After the reaction, a post-treatment was carried out using mg in the same manner as in Example 42 to obtain 20 mg of the title compound as a slightly brown powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.96-2.07 (m, 4 H), 2.65 (s,
3 H), 3.06-3.50 (m, 10 H), 3.93-3.97 (m, 4 H), 6.2
1-6.23 (m, 2 H), 6.58 (t, 1 H, J = 9 Hz), 6.72 (d,
2H, J = 9 Hz), 6.79 (d, 2 H, J = 16 Hz), 8.12
(s, 1 H), 11.00 (brs, 1 H)

Example 51 1- [1- (2-Amino-6-carboxymethylamino-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl)- 1-piperazinyl] -1-trans-propene hydrochloride

[0405]

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The compound obtained in Example 20- (1) 23 mg
(0.05 mmol) was suspended in 2 ml of an 80% aqueous ethanol solution, and then 19.4 mg of glycine and 40 μl of triethylamine were added.
The mixture was refluxed for 7 days. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, and chloroform was added.
It was developed and purified with an organic layer of -methanol-water (7: 3: 1). The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and then crystallized from a mixed solvent of ethanol and ether to obtain 14 mg of the title compound as a slightly brown powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 3.07-3.58 (m,
6 H), 3.95-3.98 (m, 4H), 4.10 (s, 2 H), 6.12-6.23
(m, 1 H), 6.29 (brs, 1 H), 6.59 (t, 1 H, J = 9 Hz),
6.73 (d, 2 H, J = 9 Hz), 6.79 (d, 2 H, J = 16 H
z), 8.10 (s, 1 H), 10.78 (brs, 1 H)

Example 52 1- [1- [2-Amino-6-[(3R) -3-hydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4 -
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0408]

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Example 20 After suspending 500 mg of the compound obtained in (1) in 50 ml of ethanol, 416 mg of (R)-(-)-3-hydroxypyrrolidine hydrochloride and 1.56 ml of triethylamine were added. Heated to reflux for an hour. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography and developed with a mixed solvent of chloroform-methanol (19: 1),
The fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 440 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.94-2.02 (m, 2 H), 2.67 (s,
3 H), 3.07-3.19 (m, 4H), 3.46-3.58 (m, 4 H), 3.92-
3.98 (m, 4 H), 4.41 (s, 1 H), 6.13-6.28 (m, 2 H),
6.59 (t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz),
6.80 (d, 2 H, J = 16 Hz), 8.13 (s, 1 H), 10.92 (brs,
1 H)

Example 53 1- [1- [2-Amino-5-methoxy-6- (3-hydroxy-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-
[4- (3,5-difluorophenyl) -1-piperazinyl] -1-tran
s-propene hydrochloride

[0411]

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(1) A mixture consisting of 12 g of 2-amino-4,6-dihydroxy-5-methoxypyrimidine guanidine hydrochloride, 9 g of sodium ethoxide and 100 ml of ethanol was heated under reflux for 1 hour, and then the reaction solution was cooled to room temperature. Then, 10 g of dimethyl methoxymalonate was added, and the mixture was heated under reflux for 48 hours. The reaction solution was cooled to room temperature, the pH was adjusted to around 4 by adding a 1 N hydrochloric acid solution, and the powder precipitated after stirring was collected by filtration to obtain 2.0 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 3.32 (s, 3 H), 6.31 (brs, 2
H), 10.41 (brs, 2 H).

(2) 2-amino-4-chloro-6-hydrazino-5
-Methoxypyrimidine To 2.0 g of the compound obtained in Example 53- (1), 10 ml of phosphorus oxychloride was added, and the mixture was stirred at 60 to 80 ° C for 5 hours. The reaction solution was gradually added to ice water, and after stirring, the precipitate was collected by filtration. The obtained 2-amino-4,6-dichloro-5-methoxypyrimidine 0.45
After adding 20 ml of ethanol to the g, 0.14 g of hydrazine monohydrate and 0.5 g of potassium carbonate were added, and the mixture was heated under reflux for 72 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with a mixed solvent of chloroform-methanol (9: 1). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 0.39 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 3.31 (s, 2 H), 3.55 (s, 3
H), 4.24 (brs, 1 H), 6.24 (brs, 2 H).

(3) 1- (2-amino-6-chloro-5-methoxy-
Ethyl 4-pyrimidinyl) -5-methyl-4-pyrazolecarboxylate Ethanol 50 was added to 0.39 g of the compound obtained in Example 53- (2).
ml and ethyl 2- (ethoxymethylene) acetoacetate 0.4
After adding 2 g and stirring at room temperature for 20 minutes, the mixture was heated under reflux for 24 hours. The residue obtained by concentrating the reaction solution was subjected to silica gel chromatography, developed with a mixed solvent of hexane-ethyl acetate (6: 1), and the fraction containing the desired compound was concentrated to give 0.36 g of the title compound. I got ¹ H-NMR (CDCl ₃ ) δ: 1.38 (t, 3 H, J = 7 Hz), 2.58
(s, 3 H), 3.59 (s, 3 H), 4.33 (q, 2 H, J = 7 Hz),
5.20 (brs, 2 H), 8.09 (s, 1 H).

(4) 1- (2-amino-6-chloro-5-methoxy-
4-Pyrimidinyl) -5-methyl-4-pyrazolecarbaldehyde Using 0.36 g of the compound obtained in Example 53- (3), the reaction was followed by post-treatment as in Example 40- (3) to give the title compound
0.17 g was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.62 (s, 3 H), 3.64 (s, 3 H),
5.21 (brs, 2 H), 8.12 (s, 1 H), 10.00 (s, 1 H).

(5) 3- [1- (2-Amino-6-chloro-5-methoxy-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-
Ethyl propenoate Using 170 mg of the compound obtained in Example 53- (4) and 270 mg of (carboethoxymethylene) triphenylphosphorane,
After the reaction, post-treatment was conducted in the same manner as in Example 40- (4) to obtain 30 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (t, 3 H, J = 7 Hz), 2.40
(s, 3 H), 3.59 (s, 3 H), 4.26 (q, 2 H, J = 7 Hz),
5.23 (brs, 2 H), 6.29 (d, 1 H, J = 16 Hz), 7.58
(d, 1 H, J = 16 Hz), 7.95 (s, 1 H).

(6) 3- [1- [2-amino-6- (3-hydroxy-1
-Azetidinyl) -5-methoxy-4-pyrimidinyl] -5-methyl
4-Pyrazolyl] -2-trans-ethyl propenoate suspended in 20 ml of the compound obtained in Example 53- (5),
Hydroxyazetidine hydrochloride 20 mg and potassium carbonate 3
0 mg was added, and the mixture was heated under reflux for 18 hours. After the reaction solution was cooled to room temperature and concentrated under reduced pressure, saturated saline was added to the residue and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off, the obtained residue was subjected to silica gel column chromatography to give chloroform.
The mixture was developed with a mixed solvent of -methanol (49: 1), and the fraction containing the desired product was concentrated to obtain 30 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hz), 2.37
(s, 3 H), 3.25 (s, 3 H), 4.09 (dd, 2 H, J = 10 Hz,
4 Hz), 4.25 (q, 2 H, J = 7 Hz), 4.47 (t, 2H, J =
10 Hz), 4.7-4.8 (m, 3 H), 6.21 (d, 1 H, J = 16 H
z), 7.58 (d, 1 H, J = 16 Hz), 7.90 (s, 1 H).

(7) 3- [1- [2-amino-6- (3-hydroxy-1
-Azetidinyl) -5-methoxy-4-pyrimidinyl] -5-methyl
4-Pyrazolyl] -2-trans-propenal Using 30 mg of the compound obtained in Example 53- (6), the reaction was followed by post-treatment as in Example 40- (5) to give the title compound
20 mg was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.42 (s, 3 H), 3.29 (s, 3 H),
4.10 (dd, 2 H, J = 10Hz, 4 Hz), 4.48 (t, 2 H, J =
10 Hz), 4.7-4.8 (m, 3 H), 6.52 (dd, 1 H, J = 16 Hz,
8 Hz), 7.37 (d, 1 H, J = 16 Hz), 7.94 (s, 1 H),
9.62 (d, 1 H, J = 8 Hz).

(8) 1- [1- [2-Amino-5-methoxy-6- (3-
Hydroxy-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-
Piperazinyl] -1-trans-propene hydrochloride 20 mg of the compound obtained in Example 53- (7), 16 mg of 1- (3,5-difluorophenyl) piperazine hydrochloride, and 10 μl of acetic acid
Using l, the reaction was followed by post-treatment as in Example 40- (6) to give 11 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (s, 3 H), 3.0-3.1 (m, 2
H), 3.1-3.2 (m, 2 H), 3.21 (s, 3 H), 3.50 (d, 2 H,
J = 7 Hz), 3.8-4.0 (m, 6H), 3.3-3.5 (m, 2H), 3.5-
3.6 (m, 1 H), 6.15 (dt, 1 H, J = 16 Hz, 7 Hz), 6.5
7 (tt, 1 H, J = 9 Hz, 2 Hz), 6.72 (dd, 2 H, J = 9 H
z, 2 Hz), 6.74 (d, 1 H, J = 16 Hz), 8.03 (s, 1 H),
10.97 (brs, 1 H)

Example 54 1- [1- [2-Amino-6- (N-hydroxy-N-methylamino) -4-
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0421]

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The compound obtained in Example 20- (1) 23 mg
(0.05 mmol) was suspended in 50 ml of ethanol.
22 mg of methylhydroxylammonium and potassium carbonate 3
6 mg was added, and the mixture was heated under reflux for 7 days. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography,
It was developed and purified with an organic layer of chloroform-methanol-water (7: 3: 1). The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and recrystallized from a mixed solvent of ether and ethanol to obtain 14 mg of the title compound as a dark gray powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 3.07-3.12 (m,
2 H), 3.24 (t, 2 H, J = 12 Hz), 3.41 (s, 3 H), 3.49
(d, 2 H, J = 10 Hz), 3.85-3.97 (m, 4 H), 6.24 (dt,
1 H, J = 16 Hz, 8 Hz), 6.55 (s, 1 H), 6.58 (t, 1
H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.80 (d, 2
H, J = 16 Hz), 8.13 (s, 1 H), 11.36 (brs, 1 H)

Example 55 1- [1- [2-Amino-6-[(2S) -1-hydroxy-2-propylamino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [ Four-
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0424]

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The compound obtained in Example 20- (1) 446 mg
Example 4 using (1.0 mmol) and 751 mg of L-alaninol
In the same manner as in 2, the reaction was followed by post-treatment to obtain 454 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (d, 3 H, J = 6 Hz), 2.63
(s, 3 H), 3.08 (d, 2H, J = 11 Hz), 3.25 (t, 2 H,
J = 12 Hz), 3.39-3.50 (m, 4 H), 3.93-3.97 (m, 4
H,), 4.16 (brs, 1 H), 6.25 (dt, 1 H, J = 16 Hz, 8
Hz), 6.51 (s, 1H), 6.58 (t, 1 H, J = 9 Hz), 6.73
(d, 2 H, J = 10 Hz), 6.81 (d, 2 H, J = 16 Hz), 8.16
(s, 1 H), 11.45 (brs, 1 H)

Example 56 1- [1- [2-Amino-6- (2-hydroxyethoxy) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluoro Phenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0427]

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Compound 446 mg obtained in Example 20- (1)
(1.0 mmol) and 558 μl of ethylene glycol were suspended in 40 ml of tert-butanol, and 691 mg of potassium carbonate was added, followed by heating under reflux for 7 days. After distilling off the solvent under reduced pressure,
The residue was subjected to silica gel chromatography, developed with an organic layer of chloroform-methanol (19: 1), and the fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 290 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.69 (s, 3 H), 3.08 (d, 2 H,
J = 11 Hz), 3.20 (t, 2 H, J = 12 Hz), 3.50 (d, 2 H,
J = 12 Hz), 3.68 (t, 2 H, J = 5 Hz), 3.91-3.98
(m, 4 H), 4.27 (t, 2 H, J = 5 Hz), 6.17 (dt, 1 H,
J = 16 Hz, 8 Hz), 6.33 (s, 1 H), 6.59 (t, 1 H, J =
9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.79 (d, 2 H, J =
16 Hz), 8.03 (s, 1 H), 10.99 (brs, 1 H)

Example 57 1- [1- [2-Amino-6-[(2S) -1-hydroxy-3-methyl-2-butylamino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl]
-3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-t
rans-propene hydrochloride

[0430]

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Compound 20 mg obtained in Example 20- (1)
(0.05 mmol) and 27 mg of D-valinol were reacted and post-treated in the same manner as in Example 42 to obtain 13 mg of the title compound as a slightly pink powder. ¹ H-NMR (DMSO-d ₆ ) δ: 0.92 (t, 6H, J = 7 Hz), 1.87-
2.00 (m, 1 H), 2.64 (s, 3 H), 3.10-3.97 (m, 13 H),
6.23-6.29 (m, 1 H), 6.52-6.61 (m, 2 H), 6.73 (d,
2 H, J = 9 Hz), 6.80 (d, 2 H, J = 16 Hz), 8.15 (s,
1 H), 11.22 (brs, 1 H)

Example 58 1- [1- [2-Amino-6-[(1S) -2-hydroxy-1-phenyl-1-]
Ethylamino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl]-
1-trans-propene hydrochloride

[0433]

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Compound 20 obtained in Example 20- (1) 23 mg
(0.05 mmol) and 35 mg of (S)-(+)-phenylglycinol were reacted and post-treated in the same manner as in Example 42 to obtain 13 mg of the title compound as a slightly pink powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (s, 3 H), 3.07-3.97 (m,
13 H), 5.23-5.31 (m, 1 H), 6.18-6.27 (m, 1 H), 6.59
(t, 2 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.79
(d, 2 H, J = 16 Hz), 7.27 (d, 1 H, J = 7 Hz), 7.3
5 (t, 2 H, J = 8 Hz), 7.41 (d, 2 H, J = 6 Hz), 8.14
(s, 1 H), 11.07 (brs, 1 H)

Example 59 1- [1- [2-Amino-6- (1,3-dihydroxy-2-propylamino) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0436]

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Compound 20 mg obtained in Example 20- (1)
(0.05 mmol) and 24 mg of serinol, followed by post-treatment in the same manner as in Example 42 to obtain 13 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.63 (s, 3 H), 3.01-3.11 (m,
2 H), 3.25 (t, 2 H, J = 12 Hz), 3.47-3.55 (m, 6 H),
3.93-3.97 (m, 4 H,), 4.08 (brs, 1 H), 6.25 (dt, 1
H, J = 16 Hz, 8 Hz), 6.51 (s, 1 H), 6.58 (t, 2 H,
J = 9 Hz), 6.73 (d, 2 H, J = 10 Hz), 6.81 (d, 2
H, J = 16 Hz), 8.16 (s, 1 H), 11.43 (brs, 1 H)

Example 60 1- [1- [2-Amino-6-[(3R) -3- (1-hydroxy-1-methyl) ethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl- 4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0439]

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(3R) -3- (1-hydroxy-1-methyl) ethyl-1
Dissolve 1.6 g of-[(1S) -1-phenyl-1-ethyl] pyrrolidine in 20 ml of 80% aqueous ethanol, add 2.0 g of 10% palladium on carbon (water 50.1%), and apply Time catalytic hydrogenation was performed. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml), the compound (0.45 g) obtained in Example 20- (1) and potassium carbonate (0.5 g) were added, and the mixture was heated under reflux for 2 days. After the reaction solution was cooled to room temperature and concentrated under reduced pressure, saturated saline was added to the residue and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off, the obtained residue was subjected to silica gel column chromatography, and developed with a mixed solvent of chloroform-methanol (19: 1).
The fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 0.4 g of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (s, 3 H), 1.13 (s, 3 H),
1.9-2.0 (m, 2 H), 2.2-2.3 (m, 1 H), 2.66 (s, 3
H), 3.1-3.2 (m, 2 H), 3.2-3.3 (m, 2 H), 3.3-3.5
(m, 6 H), 3.9-4.0 (m, 4 H), 6.0-6.2 (m, 2 H), 6.58
(t, 1 H, J = 10 Hz), 6.73 (d, 2 H, J = 10 Hz), 6.
77 (d, 1 H, J = 16 Hz), 8.02 (s, 1 H), 10.85 (bs,
1 H)

Example 61 1- [1- [2-Amino-6-[(3R, 4R) -3,4-dihydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl]- Three
-[4- (3,5-Difluorophenyl) -1-piperazinyl] -1-tra
ns-propene hydrochloride

[0442]

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(3R, 4R) -1-benzyl-3,4-dihydroxypyrrolidine (387 mg, 2.00 mmol) was dissolved in ethanol (50 ml), and 1N hydrochloric acid (3 ml) and palladium hydroxide on carbon
00 mg was added and the mixture was catalytically hydrogenated at 50 ° C. for 3 days. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was ethanol 40.
400 mg of the compound obtained in Example 20- (1).
(0.90 mmol) and 625 μl of triethylamine were added, and the mixture was heated under reflux for one day. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, developed with an organic layer of chloroform-methanol-water (20: 3: 1), and the fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and crystallized from ethanol to give the title compound 375.
mg was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 3.07-3.72 (m,
10 H), 3.92-3.98 (m, 4 H), 4.10 (s, 2 H), 6.25 (dt,
1 H, J = 16 Hz, 8 Hz), 6.32 (brs, 1 H), 6.59 (t,
1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.81 (d,
2 H, J = 16 Hz), 8.17 (s, 1 H), 11.38 (brs, 1 H)

Example 62 1- [1- [2-Amino-6- [cis-3,4-dihydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4 -
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0445]

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As in Example 42, 580 mg (3.00 mmol) of cis-1-benzyl-3,4-dihydroxypyrrolidine and 400 mg (0.90 mmol) of the compound obtained in Example 20- (1) were used.
After the reaction, post-treatment was performed to obtain 121 mg of the title compound as a slightly pink powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3 H), 3.07-3.70 (m,
10 H), 3.92-3.98 (m, 4 H), 4.16 (s, 2 H), 6.21-6.28
(m, 1 H), 6.59 (t, 1 H, J = 9 Hz), 6.73 (d, 2 H,
J = 9 Hz), 6.81 (d, 2 H, J = 16 Hz), 8.15 (s, 1
H), 11.22 (brs, 1 H)

Example 63 1- [1- [2-Amino-6- (3-hydroxy-3-methyl-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4 -
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0448]

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After dissolving 329 mg (1.30 mmol) of 1-benzhydryl-3-hydroxy-3-methylazetidine in 50 ml of ethanol, 300 mg of 10% palladium-carbon (water 50.1%) was dissolved.
Was added and hydrogenated catalytically at 6 atm for 18 hours. After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethanol, and 400 mg (0.90 mmol) of the compound obtained in Example 20- (1) and 625 μl of triethylamine were added. Heated to reflux for one day. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, developed with a mixed solvent of chloroform-methanol (97: 3), and the fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 246 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3 H), 3.06-3.11 (m,
2 H), 3.19-3.22 (m, 2H), 3.48 (d, 2 H, J = 12 Hz),
3.90-4.06 (m, 6 H), 6.13 (s, 1 H), 6.23 (dt, 1 H,
J = 16 Hz, 8 Hz), 6.57 (t, 1 H, J = 9 Hz), 6.72
(d, 2 H, J = 9 Hz), 6.79 (d, 2 H, J = 16 Hz), 8.12
(s, 1 H)

Example 64 1- [1- [2-Amino-6-[(3S) -3-hydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4 -
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0451]

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936 mg (5.00 mmol) of (3S) -1-tert-butoxycarbonyl-3-hydroxypyrrolidine was treated with methylene chloride 10
solution, add 5 ml of trifluoroacetic acid and add
Stir for 15 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethanol, and 400 mg (0.90 mmol) of the compound obtained in Example 20- (1) and 691 mg of potassium carbonate were used. After the reaction, post-treatment was performed to obtain 451 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.96-2.03 (m, 2 H), 2.67 (s,
3 H), 3.07-3.12 (m, 2H), 3.24 (t, 2H, J = 12 Hz),
3.50 (d, 2 H, J = 12 Hz), 3.62 (s, 2 H), 3.92-3.98
(m, 4 H), 4.43 (s, 1 H), 6.25 (dt, 1 H, J = 16 H
z, 8 Hz), 6.33 (s, 1 H), 6.58 (t, 1 H, J = 9 Hz),
6.73 (d, 2 H, J = 9 Hz), 6.81 (d, 2 H, J = 16 Hz),
8.16 (s, 1 H), 11.30 (brs, 1 H)

Example 65 1- [1- [2-Amino-6- [3-[(1-hydroxy-1-methyl) -1-ethyl] -1-azetidinyl] -4-pyrimidinyl] -5-methyl -Four-
Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0454]

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After dissolving 421 mg (1.50 mmol) of 1-benzhydryl-3-[(1-hydroxy-1-methyl) -1-ethyl] azetidine in 50 ml of ethanol, 10% palladium-carbon (water content) was dissolved.
(50.1%), and 400 mg was added thereto, followed by catalytic hydrogenation at 50 ° C for 13 hours.
After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of ethanol.
300 mg (0.67 mmol) of the compound obtained in (1) and potassium carbonate 9
3 mg was added, and the mixture was heated under reflux for 1 day. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography,
Expand with chloroform-methanol (19: 1) mixed solvent,
The fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 361 mg of the title compound as a pale flesh-colored powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (s, 6 H), 2.67 (s, 3 H),
2.75-2.79 (m, 1 H), 3.07-3.12 (m, 2 H), 3.23 (t, 2
H, J = 12 Hz), 3.50 (d, 2 H, J = 11 Hz), 3.91-3.97
(m, 4 H), 4.13 (s, 4 H), 6.13 (s, 1 H), 6.25 (dt,
1 H, J = 16 Hz, 8 Hz), 6.58 (t, 1 H, J = 9 Hz), 6.
73 (d, 2 H, J = 9 Hz), 6.80 (d, 2 H, J = 16 Hz),
8.15 (s, 1 H), 11.27 (brs, 1 H)

Example 66 1- [1- [2-Amino-6- (3-hydroxymethyl-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0457]

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After dissolving 477 mg (1.88 mmol) of 1-benzhydryl-3-hydroxymethylazetidine in 100 ml of ethanol, 500 mg of 10% palladium-carbon (water 50.1%) was added, and contact hydrogenation was performed at 7 atm for 19 hours. did. After removing the insoluble matter by filtration and distilling off the solvent under reduced pressure, the residue was dissolved in 30 ml of ethanol to obtain the compound obtained in Example 20- (1).
300 mg (0.67 mmol) and 93 mg of potassium carbonate were added, and the mixture was heated under reflux for 1 day. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, developed with an organic layer of chloroform-methanol (19: 1), and the fraction containing the desired product was concentrated. The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 336 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3 H), 2.75-2.82 (m,
1 H), 3.07-3.12 (m, 2H), 3.24 (t, 2 H, J = 12 Hz),
3.49 (d, 2 H, J = 11 Hz), 3.56 (d, J = 6 Hz), 3.91
-3.97 (m, 6 H), 4.23 (s, 2 H), 6.13 (s, 1 H), 6.25
(dt, 1 H, J = 16 Hz, 8 Hz), 6.58 (t, 1 H, J = 9 H
z), 6.73 (d, 2 H, J = 9 Hz), 6.80 (d, 2 H, J = 16
Hz), 8.15 (s, 1 H), 11.33 (brs, 1 H)

Example 67 1- [1- [2-Amino-6-[(2S, 4S) -4-hydroxy-2-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-
4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0460]

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446 mg of the compound obtained in Example 20- (1)
(2S, 4S) -4-hydroxy-2-hydroxymethylpyrrolidine
Using 1.43 g, the reaction was followed by post-treatment as in Example 42 to obtain 348 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.00 (m, 1 H), 2.10-2.20
(m, 1 H), 2.67 (s, 3H), 3.00-4.05 (m, 15 H), 4.40
-4.50 (m, 1 H), 6.21 (dt, 1 H, J = 16 Hz, 7 Hz), 6.
20-6.50 (br, 1 H), 6.50-6.65 (m, 1 H), 6.73 (d, 2
H, J = 11 Hz), 6.80 (d, 1 H, J = 16 Hz), 8.07 (s,
1 H), 11.24 (brs, 1 H)

Example 68 1- [1- [2-Amino-6-[(3R) -3-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-
[4- (3,5-difluorophenyl) -1-piperazinyl] -1-tran
s-propene hydrochloride

[0463]

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The compound obtained in Example 20- (1) 446 mg,
Using 503 mg of (3R) -3-hydroxymethylpyrrolidine, the reaction was followed by post-treatment as in Example 42 to give the title compound 452.
mg was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.90 (m, 1 H), 2.00-2.15
(m, 1 H), 2.68 (s, 3H), 3.00-4.05 (m, 17 H), 6.26
(dt, 1 H, J = 16 Hz, 7 Hz), 6.32 (s, 1 H), 6.57
(t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.81
(d, 1 H, J = 16Hz), 8.15 (s, 1 H), 11.34 (brs, 1
H)

Example 69 1- [1- [2-Amino-6-[(3S) -3-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-
[4- (3,5-difluorophenyl) -1-piperazinyl] -1-tran
s-propene hydrochloride

[0466]

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446 mg of the compound obtained in Example 20- (1)
Using 567 mg of (3S) -3-hydroxymethylpyrrolidine, the reaction was followed by post-treatment as in Example 42 to give the title compound 458.
mg was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.90 (m, 1 H), 2.00-2.15
(m, 1 H), 2.69 (s, 3H), 3.00-4.05 (m, 17 H), 6.26
(dt, 1 H, J = 16 Hz, 7 Hz), 6.31 (s, 1 H), 6.57
(t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 Hz), 6.81
(d, 1 H, J = 16Hz), 8.15 (s, 1 H), 11.18 (brs, 1
H)

Example 70 1- [1- [2-Amino-6-[(3R, 4R) -3-hydroxy-4-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-
4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0469]

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(3R, 4R) -1-[(1S) -1-phenethyl] -3-hydroxy-4- (tert-butyldimethylsiloxymethyl) pyrrolidin-2-one 1.59 g of dry tetrahydrofuran (50 ml)
After adding 18 ml of borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) to the solution at 0 ° C,
Stirred at room temperature for 30 hours. 30 ml of aqueous ethanol in the reaction solution
(Water: ethanol = 1: 4) and triethylamine 5
After adding ml, the mixture was heated under reflux for 1 hour. After concentrating the reaction solution, water was added, extracted three times with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue (1.05 g), 40 ml of ethanol and 1.0 g of 10% palladium-carbon (water 50.1%) were added, and subjected to catalytic hydrogenation under a pressure of 4.5 atm for 28 hours. The insoluble matter was removed by filtration, and the residue obtained by concentration under reduced pressure was subjected to Example 2
Using 446 mg of the compound obtained in 0- (1), the reaction was followed by post-treatment in the same manner as in Example 42, and the fraction containing the desired product was concentrated. 6 ml of acetic acid, 3 ml of water and 3 ml of tetrahydrofuran were added to the obtained residue, and the mixture was stirred at 80 ° C for 6 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted five times with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel chromatography, developed with a mixed solvent of chloroform-methanol (92: 8), and containing the target compound. Fractions were concentrated. The residue was converted into a hydrochloride with 1 N hydrochloric acid / ethanol, and recrystallized from ethanol to obtain 326 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.25-2.40 (m, 1 H), 2.68 (s,
3 H), 3.00-4.05 (m, 16 H), 4.25-4.30 (m, 1 H), 6.2
6 (dt, 1 H, J = 16 Hz, 7 Hz), 6.33 (brs, 1H), 6.58
(t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 11 Hz), 6.8
2 (d, 1 H, J = 16 Hz), 8.16 (s, 1 H), 11.25 (brs, 1
H)

Example 71 1- [1- [2-Amino-6-[(3R) -3-[(1R or S) -1-hydroxyethyl] -1-pyrrolidinyl] -4-pyrimidinyl] -5- Methyl-4-
Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride (isomer A)

[0472]

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(3R) -3-[(1R or S) -1-hydroxyethyl]-
0.95 g of 1-[(S) -1-phenethyl] pyrrolidine, Example 20-
Using 0.4 g of the compound obtained in (1) and 0.2 g of potassium carbonate, the reaction was carried out and post-treated in the same manner as in Example 60 to obtain 0.35 g of the title compound (isomer of Example 72) as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (d, 3 H, J = 7 Hz), 1.7-
1.8 (m, 1 H), 2.0-2.1 (m, 1 H), 2.1-2.2 (m, 1 H),
2.65 (s, 3 H), 3.0-3.1 (m, 4 H), 3.2-3.4 (m, 3 H),
3.5-3.6 (m, 3 H), 3.9-4.0 (m, 4 H), 4.5-4.7 (m, 1
H), 6.07 (s, 1H), 6.13 (dt, 1 H, J = 16 Hz, 7 H
z), 6.28 (brs, 2 H), 6.58 (t, 1 H, J = 10 Hz), 6.72
(d, 2 H, J = 10 Hz), 6.76 (d, 1 H, J = 16 Hz), 7.
97 (s, 1H), 10.56 (brs, 1 H)

Example 72 1- [1- [2-Amino-6-[(3R) -3-[(1S or R) -1-hydroxyethyl] -1-pyrrolidinyl] -4-pyrimidinyl] -5- Methyl-4-
Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride (isomer B)

[0475]

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(3R) -3-[(1S or R) -1-hydroxyethyl]-
1-[(S) -1-phenethyl] pyrrolidine 0.62 g, Example 20-
Using 0.4 g of the compound obtained in (1) and 0.2 g of potassium carbonate, the reaction was carried out and post-treated in the same manner as in Example 60 to obtain 0.3 g of the title compound (isomer of Example 71) as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10 (d, 3 H, J = 7 Hz), 1.5-
1.7 (m, 1 H), 1.8-1.9 (m, 1 H), 2.0-2.1 (m, 1 H),
2.66 (s, 3 H), 3.0-3.2 (m, 4 H), 3.2-3.4 (m, 3 H),
3.4-3.5 (m, 3 H), 3.9-4.0 (m, 4 H), 4.6-4.7 (m, 1
H), 6.06 (s, 1H), 6.13 (dt, 1 H, J = 16 Hz, 7 H
z), 6.24 (brs, 2 H), 6.57 (t, 1 H, J = 10 Hz), 6.71
(d, 2 H, J = 10 Hz), 6.75 (d, 1 H, J = 16 Hz), 7.
96 (s, 1H), 10.69 (brs, 1 H)

Example 73 1- [1- [2-Amino-6-[(3S, 4S) -3-hydroxy-4-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-
4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0478]

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1.87 mg of (3S, 4S) -1-[(1S) -1-phenethyl] -3-hydroxy-4- (tert-butyldimethylsiloxymethyl) -2-pyrrolidone in Example 20- (1) Obtained compound 300 m
Using g, the reaction was followed by post-treatment as in Example 70 to give 30 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.25-2.40 (m, 1 H), 2.67 (s,
3 H), 3.00-4.05 (m, 16H), 4.15-4.25 (m, 1 H), 6.22
(dt, 1 H, J = 16 Hz, 7 Hz), 6.20-6.35 (br, 1 H),
6.58 (t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 11 Hz),
6.81 (d, 1 H, J = 16 Hz), 8.15 (s, 1 H), 10.95 (br
s, 1 H)

Example 74 1- [1- [2-Amino-6-[(2S, 4S) -2-carbamoyl-4-hydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-4-pyrazolyl ] -3- [4- (3,5-Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0481]

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(2S, 4S) -1-benzyloxycarbonyl-4-
Hydroxypyrrolidine-2-carboxamide 116 mg (0.44 m
mol), 89 mg (0.2 mmo) of the compound obtained in Example 20- (1).
l) and 28 mg of potassium carbonate, the reaction was followed by post-treatment as in Example 65, to give 4 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.99-4.36 (m, 19 H), 6.03 (s,
1 H), 6.15 (dt, 1 H, J = 16 Hz, 8 Hz), 6.58 (t, 1
H, J = 9 Hz), 6.72 (d, 2 H, J = 9 Hz), 6.78 (d, 2
H, J = 16 Hz), 8.03 (s, 1 H), 10.63 (brs, 1 H)

Example 75 1- [1- [2-Amino-6-[(3R, 4S) -3-hydroxy-4-[(1-hydroxy-1-methyl) -1-ethyl] -1-pyrrolidinyl ] -4-Pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0484]

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(3R, 4S) -3-hydroxy-4-[(1-hydroxy-
1-methyl) -1-ethyl] -1-[(S) -1-phenethyl] pyrrolidine
Using 0.42 g, 0.25 g of the compound obtained in Example 20- (1) and 0.4 g of potassium carbonate, the reaction was followed by post-treatment in the same manner as in Example 60 to obtain 0.11 g of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.13 (s, 3 H), 1.14 (s, 3 H),
2.0-2.1 (m, 1 H), 2.66 (s, 3 H), 3.0-3.2 (m, 4
H), 3.2-3.4 (m, 4 H), 3.51 (d, 2 H, J = 7 Hz), 3.9
-4.0 (m, 4 H), 4.2-4.3 (m, 1 H), 6.0-6.2 (m, 2 H),
6.58 (t, 1 H, J = 10 Hz), 6.72 (d, 2 H, J = 10 H
z), 6.74 (d, 1 H, J = 16 Hz), 8.01 (s, 1H)

Example 76 1- [1- [2-Amino-6-[(2S, 4S) -2- (N-methylcarbamoyl) -4-hydroxy-1-pyrrolidinyl] -4-pyrimidinyl] -5
-Methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0487]

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N-methyl- (2S, 4S) -1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxamide 231
mg (0.83 mmol), 178 m of the compound obtained in Example 20- (1)
g (0.4 mmol) and 55 mg of potassium carbonate, Example 6
After the reaction, post-treatment was carried out in the same manner as in Example 5 to obtain 33 mg of the title compound as an orange powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.02-2.31 (m, 2 H), 2.59 (d,
3 H, J = 4 Hz), 2.62 (s, 3 H), 3.08 (d, 2 H, J = 4
Hz), 3.25 (t, 2H, J = 12 Hz), 3.48 (d, 2H, J = 12
Hz), 3.74-3.77 (m, 2 H), 3.92-3.96 (m, 4 H), 4.41
-4.64 (m, 4 H), 6.14 (s, 1 H), 6.24 (dt, 1 H, J =
16 Hz, 8 Hz), 6.56 (t, 1 H, J = 9 Hz), 6.72 (d, 2
H, J = 9 Hz), 6.80 (d, 2 H, J = 16 Hz), 8.15 (s, 1
H), 11.51 (brs, 1 H)

Example 77 1- [1- [2-Amino-6-[(2S, 4S) -2- (N, N-dimethylcarbamoyl) -4-hydroxy-1-pyrrolidinyl] -4-pyrimidinyl]
-5-Methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0490]

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N, N-dimethyl- (2S, 4S) -1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxamide
374 mg (1.28 mmol) of the compound 2 obtained in Example 20- (1)
Using 23 mg (0.5 mmol) and 69 mg of potassium carbonate, the reaction was followed by post-treatment as in Example 65 to give 162 mg of the title compound.
Was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.99-2.39 (m, 2 H), 2.64 (s,
3 H), 2.82 (s, 3 H), 3.06-3.12 (m, 5 H), 3.22-3.28
(m, 2 H), 3.47-4.41 (m, 10 H), 6.21-6.25 (m, 2 H),
6.57 (t, 1 H, J = 9 Hz), 6.72 (d, 2 H, J = 9 Hz),
6.80 (d, 2 H, J = 16 Hz), 8.14 (s, 1 H), 11.21 (br
s, 1 H)

Example 78 1- [1- [2-Amino-6-[(3R, 4S) -3-hydroxy-4-hydroxymethyl-1-pyrrolidinyl] -4-pyrimidinyl] -5-methyl-
4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0493]

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(3R, 4S) -3-hydroxy-4- (hydroxymethyl) -1-((S) -1-phenethyl) pyrrolidine 0.19 g, Example 2
0.2 g of the compound obtained in 0- (1) and 0.2 g of potassium carbonate
Using g, the reaction was followed by post-treatment in the same manner as in Example 60 to obtain 0.11 g of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.2-2.3 (m, 1 H), 2.66 (s, 3
H), 3.0-3.2 (m, 4 H), 3.3-3.4 (m, 2 H), 3.4-3.6 (m,
2 H), 3.67 (d, 2 H, J = 7 Hz), 3.9-4.0 (m, 6 H),
4.2-4.3 (m, 1 H), 6.0-6.2 (m, 2 H), 6.58 (t, 1 H,
J = 10 Hz), 6.74 (d, 2 H, J = 10 Hz), 6.78 (d, 1
H, J = 16 Hz), 8.04 (s, 1 H), 10.75 (brs, 1 H)

Example 79 1- [1- [2-Amino-6-[(3R, 4R) -3-hydroxy-4- (1-hydroxy-1-methyl-1-ethyl) -1-pyrrolidinyl]- 4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0496]

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(3R, 4R) -3-hydroxy-4- (1-hydroxy-1
-Methyl-1-ethyl) -1-[(S) -1-phenethyl] pyrrolidine
Using 5 g, 0.25 g of the compound obtained in Example 20- (1) and 0.3 g of potassium carbonate, the reaction was followed by post-treatment in the same manner as in Example 60 to obtain 0.26 g of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (s, 3 H), 1.31 (s, 3 H),
2.0-2.2 (m, 1 H), 2.66 (s, 3 H), 3.0-3.1 (m, 2
H), 3.1-3.2 (m, 2 H), 3.2-3.4 (m, 4 H), 3.50 (d, 2
H, J = 7 Hz), 3.9-4.0 (m, 4 H), 4.4-4.5 (m, 1 H),
6.0-6.2 (m, 2 H), 6.58 (dt, 1 H, J = 10 Hz, 2 Hz),
6.72 (dd, 2 H, J = 10 Hz), 6.77 (d, 1H, J = 16 H
z), 8.02 (s, 1 H), 10.84 (brs, 1 H)

Example 80 1- [2-Amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-
Pyrimidinyl] -5-methyl-4-pyrazolyl) -3-[(2S) -4- (3,
5-difluorophenyl) -2-methylpiperazin-1-yl] -1
-trans-propene hydrochloride

[0499]

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(1) (3S) -1- (3,5-difluorophenyl)-
3-methylpiperazine (S) -2-methylpiperazine 2.48 g, 3,5-difluorobromobenzene 3.97 g, sodium tert-butoxide 2.76 g,
A mixture of 326 mg of dichlorobis [(tri-ortho-tolyl) phosphine] palladium (II) (PdCl2 [P (o-tolyl) 3] 2) and 100 ml of toluene was heated at 100 ° C. under a nitrogen atmosphere.
For 24 hours. After removing insoluble matter by filtration, the filtrate was washed with water and then with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (270-400 me
sh, 100 g) and methanol-chloroform (6: 9
4) The mixture was developed with a mixed solvent, and the fraction containing the desired compound was concentrated to obtain 1.89 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (d, 3 H, J = 6 Hz), 2.38
(dd, 1 H, J = 12 Hz, 10 Hz), 2.74 (td, 1 H, J = 12
Hz, 3 Hz), 2.90-3.01 (m, 1 H), 2.98 (td, 1H, J =
12 Hz, 3 Hz), 3.11 (ddd, 1 H, J = 12 Hz, 3 Hz, 2 H
z), 3.48 (dm, 2H, J = 10 Hz), 6.24 (tt, 1 H, J = 9
Hz, 2 Hz), 6.36 (dd, 2 H, J = 11 Hz, 2 Hz).

(2) 3- [1- [2-Amino-6-chloro-4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal 3- [1- [2-amino-6 -Chloro-4-pyrimidinyl] -5-methyl-4
The reaction was followed by a post-treatment using 11.3 g of ethyl [-pyrazolyl] -2-trans-propenoate in the same manner as in Example 40- (5).
4.04 g of the title compound were obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.83 (s, 3 H), 5.24 (bs, 2 H),
6.56 (dd, 1 H, J = 16Hz, 9 Hz), 7.35 (s, 1 H), 7.
39 (d, 1 H, J = 16 Hz), 7.93 (s, 1 H), 9.66 (d, 1
(H, J = 9 Hz).

(3) 1-[(2-Amino-6-chloro-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -3-[(2S) -4- (3,5-difluorophenyl)- 2-methylpiperazin-1-yl] -1-trans
-Propene Compound 418 mg obtained in Example 80- (2), Example 80-
Using 420 mg of the compound obtained in (1) and 1.13 ml of acetic acid,
After the reaction, post-treatment was carried out in the same manner as in Example 40- (6) to obtain 71 mg of the title compound from the fraction containing the desired product. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, 3 H, J = 6 Hz), 2.35-2.
45 (m, 1 H), 2.50-2.80 (m, 2 H), 2.69 (s, 3 H), 2.9
5-3.10 (m, 3 H), 3.35-3.50 (m, 2 H), 3.60-3.70 (m.
1 H), 5.18 (s, 2 H), 6.09 (ddd, 1 H, J = 16 Hz, 8
Hz, 6 Hz), 6.24 (tt, 1 H, J = 9 Hz, 2 Hz), 6.33-
6.38 (m, 2 H), 6.38 (d, 1 H, J = 16 Hz), 7.31 (s,
1 H), 7.80 (s, 1 H).

(4) 1- [2-Amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2S) -4- (3,5-difluorophenyl) -2-methylpiperazin-1-yl] -1-trans-propene hydrochloride 71 mg of the compound obtained in Example 80- (2) and 49 mg of (3S, 4S) -dihydroxypyrrolidine were used. Using, as in Example 42,
After the reaction, post-treatment was performed to obtain 62 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (d, 3 H, J = 3 Hz), 2.69
(s, 3 H), 3.00-4.20 (m, 15 H), 6.20-6.40 (m, 2 H),
6.55 (t, 1 H, J = 9 Hz), 6.74 (d, 2 H, J = 10 Hz),
6.89 (d, 1 H, J = 16 Hz), 8.21 (s, 1 H), 11.43 (b
rs, 1 H)

Example 81 1- [2-Amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-
Pyrimidinyl] -5-methyl-4-pyrazolyl) -3-[(2R) -4- (3,
5-difluorophenyl) -2-methylpiperazin-1-yl] -1
-trans-propene hydrochloride

[0505]

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(1) (3R) -1- (3,5-difluorophenyl)-
3-Methylpiperazine After reaction, post-treatment was carried out in the same manner as in Example 80- (1) using (R) -2-methylpiperazine instead of (S) -2-methylpiperazine to obtain the title compound. . ¹ H-NMR (CDCl ₃ ) δ: 1.13 (d, 3 H, J = 6 Hz), 2.38
(dd, 1 H, J = 12 Hz, 10 Hz), 2.74 (td, 1 H, J = 12
Hz, 3 Hz), 2.90-3.01 (m, 1 H), 2.98 (td, 1H, J =
12 Hz, 3 Hz), 3.11 (ddd, 1 H, J = 12 Hz, 3 Hz, 2 H
z), 3.48 (dm, 2H, J = 10 Hz), 6.24 (tt, 1 H, J = 9
Hz, 2 Hz), 6.36 (dd, 2 H, J = 11 Hz, 2 Hz).

(2) 1-[(2-Amino-6-chloro-4-pyrimidinyl) -5-methyl-4-pyrazolyl] -3-[(2R) -4- (3,5-difluorophenyl)- 2-methylpiperazin-1-yl] -1-trans
-Propene The compound obtained in Example 20- (1) 145 mg, Example 40-
Using 145 mg of the compound obtained in (6) and 394 μl of acetic acid, the reaction was followed by post-treatment in the same manner as in Example 42 to give the title compound 33 m
g was obtained. The NMR spectrum was consistent with that of the compound obtained in Example 80- (2).

(3) 1- [2-Amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl) -3-[(2R) -4- (3,5-difluorophenyl) -2-methylpiperazin-1-yl] -1-trans-propene hydrochloride 33 mg of the compound obtained in Example 81- (2) and (3S, 4S)-
After reaction, post-treatment was carried out using 23 mg of dihydroxypyrrolidine in the same manner as in Example 42 to obtain 22 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: consistent with that of the compound obtained in Example 80- (3).

Example 82 1- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2S) -4- (3,
5-difluorophenyl) -2-methyl-1-piperazinyl] -1-t
rans-propene hydrochloride

[0510]

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(1) 3- [1- [2-amino-6- (3-hydroxy-1
-Azetidinyl) -4-pyrimidinyl] -5-ethyl-4-pyrazolyl] -2-trans-ethyl propenoate 3- [1- [2-amino-6-chloro-4-pyrimidinyl] -5-ethyl-4
4.14 g of ethyl [-pyrazolyl] -2-trans-propenoate were suspended in 150 ml of ethanol, and 3.07 g of 3-hydroxyazetidine hydrochloride and 7.8 ml of totiethylamine were added.
Heated to reflux for days. After allowing the reaction solution to stand at room temperature, the precipitate was collected by filtration to give 4.10 g of the title compound as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (t, 3 H, J = 7 Hz), 2.7
2 (s, 3 H), 3.72 (dd, 2 H, J = 9 Hz, 4 Hz), 4.10-4.
25 (m, 4 H), 4.50-4.60 (m, 1 H), 5.73 (d, 1H, J =
6 Hz), 5.96 (s, 1 H), 6.41 (s, 2 H), 6.42 (d, 1 H,
J = 16 Hz), 7.52 (d, 1 H, J = 16 Hz), 8.19 (s, 1
H).

(2) 3- [1- [2-amino-6- (3-hydroxy-1
-Azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal Using 4.0 g of the compound obtained in Example 82- (1), a compound similar to that of Example 40- (5) was used. The reaction and after-treatment were performed to obtain 1.76 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 2.81 (s, 3 H), 3.73 (dd, 2
H, J = 9 Hz, 4 Hz), 4.19 (dd, 2 H, J = 6 Hz, 7 H
z), 4.50-4.60 (m, 1 H), 5.74 (d, 1 H, J = 7 Hz),
5.90 (s, 1 H), 6.43 (s, 2 H), 6.66 (dd, 1 H, J = 1
6 Hz, 8 Hz), 7.72 (d, 1 H, J = 16 Hz), 8.22 (s, 1
H), 9.61 (d, 1 H, J = 8 Hz).

(3) 1- [1- [2-amino-6- (3-hydroxy-1
-Azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2S) -4- (3,5-difluorophenyl) -2-methyl-1-
Piperazinyl] -1-trans-propene hydrochloride 450 mg of the compound obtained in Example 82- (2), Example 80-
Using 414 mg of the compound obtained in (1) and 688 μl of acetic acid, the reaction was carried out and post-treated in the same manner as in Example 39 to give the title compound 113
mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.45 (d, 3 H, J = 6 Hz), 2.68
(s, 3 H), 3.00-4.20 (m, 11 H), 4.30-4.40 (m, 2 H),
4.55-4.70 (m, 1 H), 6.09 (s, 1 H), 6.24 (dt, 1 H,
J = 16 Hz, 7 Hz), 6.55 (t, 1 H, J = 9 Hz), 6.74
(d, 2 H, J = 10 Hz), 6.87 (d, 1 H, J = 16 Hz), 8.12
(s, 1 H), 11.16 (brs, 1 H)

Example 83 1- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2R) -4- (3,
5-difluorophenyl) -2-methyl-1-piperazinyl] -1-t
rans-propene hydrochloride

[0515]

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3- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2
Example 39 using 450 mg of -trans-propenal, 414 mg of the compound obtained in Example 81- (1), and 688 μl of acetic acid.
The reaction and post-treatment were carried out in the same manner as in the above to give 213 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (d, 3 H, J = 6 Hz), 2.68
(s, 3 H), 3.00-4.20 (m, 11 H), 4.25-4.35 (m, 2 H),
4.55-4.70 (m, 1 H), 6.02 (s, 1 H), 6.20 (dt, 1 H,
J = 16 Hz, 7 Hz), 6.56 (t, 1 H, J = 9 Hz), 6.74
(d, 2 H, J = 10 Hz), 6.86 (d, 1 H, J = 16 H), 8.06
(s, 1 H), 10.92 (brs, 1 H)

Example 84 1- [1- [4-Amino-6- (3-hydroxy-1-azetidinyl) -2-
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2S) -4- (3,
5-difluorophenyl) -2-methyl-1-piperazinyl] -1-t
rans-propene hydrochloride

[0518]

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(1) 1- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl]
-3-[(2S) -4- (3,5-difluorophenyl) -2-methyl-1-piperazinyl] -1-trans-propene 3-[[4-chloro-6- (4-methoxybenzyl) amino Using 590 mg of 2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal, 180 mg of the compound obtained in Example 80- (1) and 688 μl of acetic acid, Example 40- (6) was used. Similarly, after the reaction, post-treatment was performed to obtain 288 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, 3 H, J = 6 Hz), 2.40-2.
50 (m, 1 H), 1.50-2.80 (m, 2 H), 2.64 (s, 3 H), 2.9
0-3.15 (m, 3 H), 3.35-3.50 (m, 2 H), 3.60-3.70 (m.
1 H), 3.81 (s, 3 H), 4.30-4.60 (brs, 2 H), 6.08
(dt, 1 H, J = 16 Hz, 7 Hz), 6.20-6.30 (m, 1 H), 6.2
5 (s, 1 H), 6.30-6.45 (m, 2 H), 6.38 (d, 1 H, J = 1
6 Hz), 6.89 (d, 2 H, J = 8 Hz), 7.23 (d, 2 H, J =
8 Hz), 7.83 (s, 1 H).

(2) 1- [1- (4-Amino-6-chloro-2-pyrimidinyl) -5-propyl-4-pyrazolyl] -3-[(2S) -4- (3,5-difluorophenyl ) -2-Methyl-1-piperazinyl] -1-trans
-Propene Using 288 mg of the compound obtained in Example 84- (1), the reaction was followed by post-treatment in the same manner as in Example 40- (7) to give the title compound
230 mg were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, 3 H, J = 6 Hz), 2.30-2.
50 (m, 1 H), 2.55-2.80 (m, 2 H), 2.69 (s, 3 H), 2.9
0-3.10 (m, 3 H), 3.35-3.50 (m, 2 H), 3.65 (dd, 1
H, J = 13 Hz, 5 Hz), 5.18 (s, 2 H), 6.09 (ddd, 1
H, J = 16 Hz, 8 Hz, 6 Hz), 6.24 (tt, 1 H, J = 9 H
z, 2 Hz), 6.33-6.38 (m, 2 H), 6.38 (d, 1H, J = 16
Hz), 7.31 (s, 1 H), 7.80 (s, 1 H).

(3) 1- [1- [4-amino-6- (3-hydroxy-1
-Azetidinyl) -2-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2S) -4- (3,5-difluorophenyl) -2-methyl-1-
Piperazinyl] -1-trans-propene hydrochloride 230 mg of the compound obtained in Example 84- (2), 3-hydroxy
-1-azetidine hydrochloride 164 mg and potassium carbonate 138 mg
After the reaction, post-treatment was carried out in the same manner as in Example 54 to obtain 213 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (d, 3 H, J = 6 Hz), 2.64
(s, 3 H), 3.00-4.20 (m, 11 H), 4.25-4.40 (m, 2 H),
4.60-4.70 (m, 1 H), 5.29 (s, 1 H), 6.35 (dt, 1 H,
J = 16 Hz, 7 Hz), 6.56 (t, 1 H, J = 9 Hz), 6.74
(d, 2 H, J = 11 Hz), 6.91 (d, 1 H, J = 16 Hz), 8.30
(s, 1 H), 11.59 (brs, 1 H)

Example 85 1- [1- [4-Amino-6- (3-hydroxy-1-azetidinyl) -2-
Pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2R) -4- (3,
5-difluorophenyl) -2-methyl-1-piperazinyl] -1-t
rans-propene hydrochloride

[0523]

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(1) 1- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-methyl-4-pyrazolyl]
-3-[(2R) -4- (3,5-difluorophenyl) -2-methyl-1-piperazinyl] -1-trans-propene 3-[[4-chloro-6- (4-methoxybenzyl) amino 2-Pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propenal 590 mg and the compound obtained in Example 81- (1) 180 mg
, A reaction and a post-treatment in the same manner as in Example 40- (6).
By performing purification, 286 mg of the title compound was obtained. NMR
The spectrum was consistent with that of the compound obtained in Example 84- (1).

(2) 1- [1- (4-amino-6-chloro-2-pyrimidinyl) -5-propyl-4-pyrazolyl] -3-[(2R) -4- (3,5-difluorophenyl ) -2-Methyl-1-piperazinyl] -1-trans
-Propene The compound obtained in Example 85- (1) was treated with Example 286 mg.
By conducting the reaction, post-treatment and purification in the same manner as (7),
220 mg of the title compound were obtained. The NMR spectrum is shown in Example 84.
-It was consistent with that of the compound obtained in (2).

(3) 1- [1- [4-amino-6- (3-hydroxy-1
-Azetidinyl) -2-pyrimidinyl] -5-methyl-4-pyrazolyl] -3-[(2R) -4- (3,5-difluorophenyl) -2-methyl-1-
Piperazinyl] -1-trans-propene hydrochloride 230 mg of the compound obtained in Example 85- (1) was reacted, worked up and purified in the same manner as in Example 54 to give 154 mg of the title compound as a white powder. Was. ¹ H-NMR (DMSO-d ₆ ) δ: 1.47 (d, 3 H, J = 6 Hz), 2.65
(s, 3 H), 3.00-4.20 (m, 11 H), 4.30-4.40 (m, 2 H),
4.60-4.70 (m, 1 H), 5.30 (s, 1 H), 6.37 (dt, 1 H,
J = 16 Hz, 7 Hz), 6.55 (t, 1 H, J = 9 Hz), 6.74
(d, 2 H, J = 11 Hz), 6.92 (d, 1 H, J = 16 Hz), 8.34
(s, 1 H), 11.77 (brs, 1 H)

Example 86 3- [3- [1- [2-Amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans
-Propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride (isomer A )

[0528]

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(1) 2- (4-Fluoro-2-nitrophenoxy) -1,1-dimethoxyethane To a suspension of sodium hydride (4.32 g) in dry DMF (60 ml) was added
A solution of 16.7 g of 2-dimethoxyethanol in DMF (50 ml) was added over 20 minutes at room temperature. After stirring at room temperature for 1 hour, the reaction was cooled to 0 ° C. and 2,5-difluoronitrobenzene 23.
A solution of 9 g of DMF (20 ml) was added, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was poured into 700 ml of ice water, and hexane-ethyl acetate (9: 9) was added.
1) The mixture was extracted twice with a mixed solvent. The organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 35.88 g of the title compound as a pale red oil. ¹ H-NMR (CDCl ₃ ) δ: 3.49 (s, 6 H), 4.10 (d, 2 H, J
= 5 Hz), 4.70 (t, 1 H, J = 5 Hz), 7.09 (dd, 1 H,
J = 9 Hz), 7.28 (dt, 1 H, J = 3 Hz, 8 Hz), 7.60 (d
d, 1 H, J = 8 Hz, 3 Hz).

(2) 2- (2-acetylamino-4-fluorophenoxy) -1,1-dimethoxyethane 35.88 g of the compound obtained in Example 86- (1) was treated with methanol 50
Dissolved in 0 ml, 10% palladium-carbon (50% water-containing) 7.0 g
Was added thereto, and the mixture was subjected to catalytic hydrogenation under pressure (4 atm) for 5 hours. Then, insolubles were removed by filtration and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. After 400 ml of ether and 32 ml of diisopropylethylamine were added to the residue, a solution of 12.8 ml of acetyl chloride in 30 ml of ether was added over 10 minutes while stirring at room temperature. After stirring at room temperature for 2 hours, insolubles were removed by filtration, and the filtrate was washed with water, 1N aqueous hydrochloric acid, saturated sodium bicarbonate, water and saturated saline in this order, and then dried over anhydrous sodium sulfate. The obtained solution was concentrated under reduced pressure and dried to give 36.01 g of the title compound as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (s, 3 H), 3.46 (s, 6 H),
4.00 (d, 2 H, J = 5 Hz), 4.68 (t, 1 H, J = 5 Hz),
6.69 (dt, 1 H, J = 9 Hz, 4 Hz), 6.88 (dd, 1H, J =
9 Hz, 5 Hz), 8.22 (dd, 1 H, J = 11 Hz, 3 Hz), 8.20
-8.30 (brs, 1 H).

(3) 4-acetyl-6-fluoro-3-methoxy
[1,4] benzoxazine To 130 ml of toluene was added 80 mg of p-toluenesulfonic acid.
Dehydration was performed azeotropically using an ean-Stark apparatus. 2.3 g of the compound obtained in Example 86- (2) was added to the solution cooled to room temperature.
Was added, and the mixture was stirred at 75 ° C. for 15 hours. After the reaction solution was cooled, 100 ml of ethyl acetate was added for dilution, and the mixture was washed with saturated sodium bicarbonate, water, and saturated saline in this order. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and developed with a mixed solvent of ethyl acetate-hexane (1: 4) to give the desired compound. The fractions containing were concentrated to give 1.07 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.38 (s, 3 H), 3.35 (s, 3 H),
4.13 (dd, 1 H, J = 11Hz, 2 Hz), 4.46 (dd, 1 H, J =
11 Hz, 2 Hz), 5.4-6.0 (m, 1 H), 6.80-7.20 (m, 3
H).

(4) 4-acetyl-3-cyano-6-fluoro
[1,4] benzoxazine 1.058 g of the compound obtained in Example 86- (3), ether 38
0.63 ml of cyanotrimethylsilane was added to a mixture consisting of 0.094 ml of BF3-ether complex and stirred at room temperature for 8 hours. 0.094 ml of BF3-ether complex and 0.63 ml of cyanotrimethylsilane were added to the reaction solution, and the mixture was further stirred at room temperature for 24 hours, diluted with 100 ml of ethyl acetate, and diluted with saturated sodium hydrogen carbonate, water and saturated saline in this order. And washed. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.034 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.41 (s, 3 H), 4.18 (dd, 1 H,
J = 11 Hz, 3 Hz), 4.62 (dd, 1 H, J = 11 Hz, 2 Hz),
5.90-6.15 (m, 1 H), 6.90-7.10 (m, 3 H).

(5) N-[(S) -1-phenylethyl] -6-fluoro [1,4] benzoxazine-3-carboxamide (isomer A
And isomer B) 1.034 g of the compound obtained in Example 86- (4) was treated with 6N hydrochloric acid 3
After the mixture was stirred at 100 ° C. for 13 hours, the reaction solution was concentrated to dryness under reduced pressure. After water was added to the residue and extracted with a mixed solvent of methanol and chloroform (5:95), the organic layer was dried over anhydrous sodium sulfate. Dichloromethane in the residue
40 ml, (S)-(-)-phenethylamine 0.94 ml, dimethylaminopyridine 1.19 g, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 1.4 g were added, and the mixture was stirred at room temperature for 5 days. The reaction solution was diluted with chloroform, washed with water, a 1N aqueous solution of phosphoric acid, water, and saturated saline in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography, and developed with a mixed solvent of ethyl acetate-hexane (2: 3) to obtain 347 mg of the isomer A of the title compound as colorless crystals from the low-polar fraction. . Further, 367 mg of isomer B of the title compound was obtained as a colorless syrup from the highly polar fraction. Isomer A ¹ H-NMR (CDCl ₃ ) δ: 1.43 (d, 3 H, J = 6.8 Hz), 3.9
6 (dd, 1 H, J = 10.7 Hz, 3.4 Hz), 4.04 (dt, 1 H, J
= 5.9 Hz, 3.4 Hz), 4.18 (d, 1 H, J = 5.9 Hz), 4.53
(dd, 1 H, J = 10.7 Hz, 3.4 Hz), 5.09-5.17 (m, 1
H), 6.42-6.47 (m, 2 H), 6.80 (dd, 1 H, 9.8 Hz, 5.4
Hz), 6.88 (d, 1 H, J = 7.8 Hz), 7.27-7.37 (m. 5
H). Isomer B ¹ H-NMR (CDCl ₃ ) δ: 1.49 (d, 3 H, J = 6.8 Hz), 3.9
5 (dd, 1 H, J = 10.7 Hz, 3.4 Hz), 4.09 (dt, 1 H, J
= 5.9 Hz, 3.4 Hz), 4.26 (d, 1 H, J = 5.9 Hz), 4.4
9 (dd, 1 H, J = 10.7 Hz, 3.4 Hz), 5.09-5.17 (m, 1
H), 6.42-6.49 (m, 2 H), 6.79 (dd, 1 H, 8.8 Hz, 5.4
Hz), 6.88 (d, 1 H, J = 7.8 Hz), 7.12-7.28 (m. 5
H).

(6) N-tert-butoxycarbonyl-N-[(S)
1-phenylethyl] aminomethyl-6-fluoro [1,4] benzoxazine (isomer A) 2.08 g of isomer A obtained in Example 86- (5) was dissolved in 30 ml of tetrahydrofuran, and the mixture was stirred at 0 ° C. 10 regulation borane-
After adding 6.93 ml of the dimethylsulfide complex, the mixture was stirred at room temperature for 1 day. A 6N aqueous hydrochloric acid solution was added, and the mixture was stirred for 1 hour, and then neutralized with a saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of dioxane, and 3.18 ml of di-tert-butyl dicarbonate was added, followed by stirring at room temperature for 6 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, developing with a mixed solvent of ethyl acetate-hexane (1: 4) and concentrating the fraction containing the desired product to give 2.05 g of the title compound. I got ¹ H-NMR (CDCl ₃ ) δ: 1.49 (s, 9 H), 1.52 (d, 3 H, J
= 7 Hz), 2.96 (brs, 1H), 3.18 (dd, 1 H, J = 15 Hz,
4 Hz), 3.40 (brs, 1 H), 3.79 (dd, 1 H, J = 11 Hz,
6 Hz), 4.03 (dd, 1 H, J = 11 Hz, 2 Hz), 5.89 (brs,
1 H), 6.22 (dt, 1 H, J = 8 Hz, 3 Hz), 6.59 (dd, 1
H, J = 9 Hz, 5 Hz), 7.33-7.39 (m.5H).

(7) 9-fluoro-3-[(S) -1-phenylethyl] -2,3,4,4a, 5,6-hexahydro-2-oxopyrazino [2,1
-c] benzoxazine (isomer A) 2.05 g of the compound obtained in Example 86- (6) was dissolved in 15 ml of tetrahydrofuran, 644 μl of pyridine was added, and 0 ° C.
Under stirring, a solution of 465 μl of chloroacetyl chloride in 1.5 ml of tetrahydrofuran was added dropwise. After stirring at room temperature for 2.5 hours, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in 15 ml of tetrahydrofuran, 20 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour and further at 50 ° C. for 3 hours.
After the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in dimethylformamide (15 ml), potassium carbonate (1.32 g) was added, and the mixture was stirred at 50 ° C for 1 hour. Cool the reaction to room temperature,
After dilution with water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with a mixed solvent of ethyl acetate-hexane (1: 9), and the fraction containing the desired product was concentrated to obtain 1.88 g of the title compound as a slightly brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (d, 3 H, J = 7 Hz), 2.09
(dd, 1 H, J = 12 Hz, 9 Hz), 2.97 (ddd, 1 H, J = 12
Hz, 5 Hz, 2 Hz), 3.08 (d, 1 H, J = 17 Hz), 3.39
(q, 1 H, J = 7 Hz), 3.84-3.87 (m, 2 H), 4.14 (d, 1
H, J = 8 Hz), 6.74-6.81 (m, 2 H), 7.27-7.37 (m, 5
H), 8.19 (dd, 1 H, J = 12 Hz, 2 Hz).

(8) 9-fluoro-3- [1- (S) phenylethyl] -2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] benzoxazine (isomer A) 1.88 g of the compound obtained in Example 86- (7) was dissolved in 30 ml of tetrahydrofuran, and 10N borane was stirred under stirring at 0 ° C.
After adding 6 ml of the dimethylsulfide complex, the mixture was stirred at room temperature for 3 days. Ethanol was added, followed by 6N aqueous hydrochloric acid. After stirring for 1 hour, the mixture was neutralized using a saturated aqueous solution of sodium hydrogen carbonate. After extraction with chloroform, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, developed with a mixed solvent of chloroform-methanol (98: 2), and the fraction containing the desired product was concentrated to give 1.33 g of the title compound as a white powder. . ¹ H-NMR (CDCl ₃ ) δ: 1.39 (d, 3 H, J = 6 Hz), 1.68
(t, 1 H, J = 11 Hz), 2.24 (dt, 1H, J = 12 Hz, 3H
z), 2.66-2.70 (m, 1 H), 2.87 (dt, 1 H, J = 12Hz, 3
Hz), 3.06-3.13 (m, 1 H), 3.18-3.22 (m, 1 H), 3.38
(q, 1 H, J = 7 Hz), 3.57 (d, 1 H, J = 13 Hz), 3.83
(dd, J = 11 Hz, 9Hz), 4.01 (dd, 1 H, J = 11 Hz, 3
Hz), 6.35 (dt, 1 H, J = 11 Hz, 3 Hz), 6.47 (dd, 1
H, J = 11 Hz, 3 Hz), 6.64 (dd, 1 H, J = 8 Hz, 5H
z), 7.23-7.35 (m, 5 H).

(9) 9-Fluoro-2,3,4,4a, 5,6-hexahydro- (1H) -pyrazino [2,1-c] benzoxazine (isomer A) In Example 86- (8) 1.33 g of the obtained compound was dissolved in 50 ml of methanol, and 1.34 g of ammonium formate and 10%
After adding 1.35 g of palladium carbon, the mixture was heated under reflux for 2 hours. After removing insolubles by filtration, the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.56 g of the title compound as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (t, 1 H, J = 11 Hz), 2.71
(dt, 1 H, J = 12 Hz, 3Hz), 2.93 (dt, 1 H, J = 16 Hz,
3 Hz), 3.00 (d, 1 H, J = 12 Hz), 3.07-3.16 (m, 2
H), 3.52 (d, 1 H, J = 12 Hz), 3.93 (dd, 1 H, J = 1
1 Hz, 9 Hz), 4.14 (dd, 1 H, J = 11 Hz, 3 Hz), 6.38
(dt, 1 H, J = 9 Hz, 3 Hz), 6.48 (dd, 1 H, J = 11 H
z, 3 Hz), 6.67 (dd, 1 H, J = 9 Hz, 6 Hz).

(10) 3- [3- [1- (2-amino-4-chloro-6-
Pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro
-1H-pyrazino [2,1-c] -1,4-benzoxazine (isomer A) 229 mg of the compound obtained in Example 86- (9) was treated with ethanol 2
0-ml, and 3- [1- (2-amino-4-chloro-6-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenal 2
64 mg and 286 μl of acetic acid were added, and the mixture was stirred at room temperature for 4 hours. Next, 157 mg of sodium cyanoborohydride was added, and the mixture was added at room temperature.
Stir for 2 days. Ethanol was distilled off under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was subjected to silica gel chromatography, and developed with a mixed solvent of chloroform-methanol (97: 3). Concentration gave 248 mg of the title compound as a white powder. H-NMR (CDCl ₃ ) δ: 1.85 (t, 1 H, J = 11 Hz), 2.27
(dt, 1 H, J = 12 Hz, 3 Hz), 2.68 (s, 3 H), 2.81-2.9
5 (m, 2 H), 3.07 (d, 1 H, J = 12 Hz), 3.14-3.27
(m, 3 H), 3.57 (d, 1 H, J = 12 Hz), 3.95 (dd, 1 H,
J = 10 Hz, 9 Hz), 4.17 (dd, 1 H, J = 11 Hz, 3 Hz),
5.43 (brs, 2 H), 6.07 (dt, 1 H, J = 16 Hz, 7 Hz),
6.36-6.40 (m, 2 H), 6.49 (dd, 1 H, J = 11 Hz, 3 H
z), 6.68 (dd, 1 H, J = 9 Hz, 6 Hz), 7.29 (s, 1 H),
7.80 (s, 1 H).

(11) 3- [3- [1- [2-amino-6-[(3S, 4S)-
Dihydroxypyrrolidino] -4-pyrimidinyl] -5-methyl-4
-Pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-
2,3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-
Benzoxazine hydrochloride (isomer A) In the same manner as in Example 42, using 37 mg (0.08 mmol) of the compound obtained in Example 86- (10) and 25 mg of (3S, 4S) -3,4-dihydroxypyrrolidine. After the reaction, post-treatment was performed to obtain 27 mg of the title compound as white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3 H), 2.83 (q, 1 H,
J = 10 Hz), 3.05-3.08 (m, 1 H), 3.24 (t, 1 H, J = 1
2 Hz), 3.54 (d, 1 H, J = 12 Hz), 3.62-3.70 (m, 4
H), 3.87-3.98 (m, 3 H), 4.06-4.09 (m, 3 H), 4.29
(dd, 1 H, J = 11 Hz, 3 Hz), 6.24 (dt, 2 H, J = 16 H
z, 7 Hz), 6.31 (s, 1 H), 6.49 (dt, 1H, J = 9 Hz, 3
Hz), 6.73 (dd, 1 H, J = 9 Hz, 6 Hz), 6.80 (d, 1
H, J = 16 Hz), 6.87 (dd, 1 H, J = 12 Hz, 3 Hz), 8.1
4 (s, 1 H), 11.80 (brs, 1 H)

Example 87 3- [3- [1- [2-Amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans
-Propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride (isomer B )

[0541]

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(1) N-tert-butoxycarbonyl-N-[(S)
1-phenylethyl] aminomethyl-6-fluoro [1,4] benzoxazine (isomer B) Using 2.43 g of isomer B obtained in Example 86- (5), the procedure of Example 86- (6) was repeated. The reaction, work-up and purification were carried out in the same manner to obtain 2.69 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (s, 9 H), 1.48 (s, 3 H),
3.02-3.11 (m, 2 H), 3.32 (s, 1 H), 3.54 (dd, 1 H,
J = 11 Hz, 4 Hz), 3.69 (d, 1 H, J = 10 Hz), 4.03 (d
d, 1 H, J = 11 Hz, 2 Hz), 5.41 (brs, 1 H), 6.21-6.2
8 (m, 2 H), 6.61 (dd, 1 H, J = 9 Hz), 7.27-7.36
(m. 5 H).

(2) 9-Fluoro-3- [1- (S) phenylethyl] -2,3,4,4a, 5,6-hexahydro-2-oxopyrazino [2,1
-c] Benzoxazine (isomer B) Using 2.69 g of the compound obtained in Example 87- (1), the reaction, work-up and purification were carried out in the same manner as in Example 86- (7) to give 1.45 g of the title compound. Was obtained as a light brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (d, 3 H, J = 6 Hz), 2.09
(dd, 1 H, J = 12 Hz, 7Hz), 3.04 (dd, 1 H, J = 12 H
z, 3 Hz), 3.24 (d, 1 H, J = 17 Hz), 3.41 (d, 1 H,
J = 17 Hz), 3.47 (q, 1 H, J = 7 Hz), 3.85 (dt, 1
H, J = 6 Hz, 3 Hz), 4.05 (t, 1 H, J = 10 Hz), 4.19
(dd, 1 H, J = 10 Hz, 3 Hz), 6.73-6.82 (m, 2 H), 7.2
8-7.37 (m, 5 H), 8.06 (dd, 1 H, J = 11 Hz, 3 Hz).

(3) 9-Fluoro-3- [1- (S) phenylethyl] -2,3,4,4a, 5,6-hexahydro- (1H) -pyrazino [2,1-c]
Benzoxazine (isomer B) Using 1.45 g of the compound obtained in Example 87- (2), the reaction, post-treatment, and purification were carried out in the same manner as in Example 86- (8), to give 1.52 g of the title compound as a white powder. As obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (d, 3 H, J = 7 Hz), 1.83
(t, 1 H, J = 11 Hz), 2.14 (dt, 1 H, J = 11 Hz, 3
Hz), 2.74 (dt, 1 H, J = 11 Hz, 3 Hz), 2.82-2.86
(m, 1 H), 2.99-3.03 (m, 1 H), 3.18-3.25 (m, 1 H),
3.39-3.44 (m, 2 H), 3.94 (d, 1 H, J = 11 Hz, 9 H
z), 4.16 (dd, 1 H, J = 11 Hz, 3 Hz), 6.35 (dt, 1 H,
J = 11 Hz, 3 Hz), 6.42 (dd, 1 H, J = 11 Hz, 3 H
z), 6.66 (dd, 1H, J = 9 Hz, 5 Hz), 7.23-7.33 (m, 5
Hz).

(4) 9-Fluoro-2,3,4,4a, 5,6-hexahydro- (1H) -pyrazino [2,1-c] benzoxazine (isomer B) In Example 87- (3) Using 1.52 g of the obtained compound, the reaction, work-up and purification were carried out in the same manner as in Example 86- (9) to obtain 762 mg of the title compound as a dark brown oil. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (t, 1 H, J = 11 Hz), 2.71
(t, 1 H, J = 12 Hz), 2.96 (dt, 1 H, J = 16 Hz, 3 H
z), 3.04 (d, 1 H, J = 13 Hz), 3.19 (d, 2 H, J = 11
Hz), 3.56 (d, 1 H, J = 12 Hz), 3.94 (t, 1 H, J = 1
1 Hz), 4.15 (dd, 1 H, J = 11 Hz, 3 Hz), 6.39 (dt,
1 H, J = 9 Hz, 3 Hz), 6.49 (dd, 1 H, J = 11 Hz, 3 H
z), 6.68 (dd, 1 H, J = 9 Hz, 6 Hz). (5) 3- [3- [1- (2-amino-4-chloro-6-pyrimidinyl) -5
-Methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-
Fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2,
1-c] -1,4-benzoxazine (isomer B) 229 mg of the compound obtained in Example 87- (4) and 3- [1- (2-
Using 264 mg of amino-4-chloro-6-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-2-propenal, the reaction, work-up and purification were carried out in the same manner as in Example 86- (10). Was carried out to obtain 248 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.88 (t, 1 H, J = 11 Hz), 2.29
(dt, 1 H, J = 12 Hz, 3 Hz), 2.68 (s, 3 H), 2.91 (d
t, 1 H, J = 12 Hz, 3 Hz), 2.97 (d, 1 H, J = 11 Hz),
3.11 (d, 1 H, J = 11 Hz), 3.20-3.27 (m, 3 H), 3.5
8 (d, 1 H, J = 12 Hz), 3.95 (dd, 1 H, J = 11 Hz, 9
Hz), 4.17 (dd, 1 H, J = 11 Hz, 3 Hz), 5.52 (brs, 2
H), 6.07 (dt, 1 H, J = 16 Hz, 7 Hz), 6.36-6.40
(m, 2 H), 6.49 (dd, 1 H, J = 11 Hz, 3 Hz), 6.68 (d
d, 1 H, J = 9 Hz, 6 Hz), 7.29 (s, 1 H), 7.81 (s, 1
H).

(6) 3- [3- [1- [2-amino-6-[(3S, 4S) -dihydroxypyrrolidino] -4-pyrimidinyl] -5-methyl-4-
Pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,
3,4,4a, 5,6-hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride (isomer B) 32 mg of the compound obtained in Example 87- (5) And (3S, 4S)-
Example 4 using 22 mg of 3,4-dihydroxypyrrolidine
The reaction, post-treatment and purification were carried out in the same manner as 2 to give 27 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3 H), 2.83 (q, 1 H,
J = 10 Hz), 3.05-3.08 (m, 1 H), 3.25 (t, 1 H, J = 1
2 Hz), 3.54 (d, 1 H, J = 12 Hz), 3.63-3.71 (m, 4
H), 3.87-3.98 (m, 3 H), 4.06-4.10 (m, 3 H), 4.29
(dd, 1 H, J = 11 Hz, 3 Hz), 6.24 (dt, 2 H, J = 16 H
z, 7 Hz), 6.32 (s, 1 H), 6.49 (dt, 1H, J = 9 Hz,
3 Hz), 6.74 (dd, 1 H, J = 9 Hz, 6 Hz), 6.80 (d, 1
H, J = 16 Hz), 6.87 (dd, 1 H, J = 12 Hz, 3 Hz), 8.
14 (s, 1 H), 11.87 (brs, 1 H)

Example 88 3- [3- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl)-
4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2, 1-c] -1,4-benzoxazine hydrochloride (isomer A)

[0548]

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The compound obtained in Example 86- (10), 248 m
g, 179 mg of 3-hydroxyazetidine hydrochloride and 150 mg of potassium carbonate were reacted and worked up in the same manner as in Example 54 to obtain 241 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.65 (s, 3 H), 2.82 (q, 1 H,
J = 10 Hz), 3.05-3.08 (m, 1 H), 3.22 (t, 1 H, J = 1
2 Hz), 3.54 (d, 1 H, J = 12 Hz), 3.62-3.67 (m, 1
H), 3.86-3.98 (m, 5 H), 4.08 (d, 1 H, J = 14 Hz),
4.29 (dd, 1 H, J = 11 Hz, 3 Hz), 4.39-4.41 (m, 2
H), 4.58-4.64 (m, 1 H), 6.12 (s, 1 H), 6.22 (dt, 2
H, J = 16 Hz, 7 Hz), 6.49 (dt, 1 H, J = 8 Hz, 3 H
z), 6.74 (dd, 1 H, J = 9 Hz, 6 Hz), 6.78 (d, 1 H,
J = 16 Hz), 6.88 (dd, 1 H, J = 12 Hz, 3 Hz), 8.11
(s, 1 H), 11.60 (brs, 1 H)

Example 89 3- [3- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl)-
4-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2, 1-c] -1,4-benzoxazine hydrochloride (isomer B)

[0551]

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The compound obtained in Example 87- (5), 188 m
g, 136 mg of 3-hydroxyazetidine hydrochloride and 114 mg of potassium carbonate were reacted and post-treated in the same manner as in Example 54 to obtain 209 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.65 (s, 3 H), 2.82 (q, 1 H,
J = 10 Hz), 3.04-3.07 (m, 1 H), 3.22 (t, 1 H, J = 1
2 Hz), 3.54 (d, 1 H, J = 12 Hz), 3.62-3.67 (m, 1
H), 3.86-3.98 (m, 5 H), 4.08 (d, 1 H, J = 14 Hz),
4.29 (dd, 1 H, J = 11 Hz, 3 Hz), 4.39-4.41 (m, 2
H), 4.58-4.64 (m, 1 H), 6.13 (s, 1 H), 6.22 (dt, 2
H, J = 16 Hz, 7 Hz), 6.49 (dt, 1 H, J = 8 Hz, 3 H
z), 6.74 (dd, 1 H, J = 9 Hz, 6 Hz), 6.80 (d, 1 H, J
= 16 Hz), 6.88 (dd, 1 H, J = 11 Hz, 2 Hz), 8.11
(s, 1 H), 11.67 (brs, 1 H)

Example 90 3- [3- [1- [4-amino-6- (3-hydroxy-1-azetidinyl)-]
2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2, 1-c] -1,4-benzoxazine hydrochloride (isomer A)

[0554]

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(1) 3- [3- [1- [4-Chloro6- (4-methoxybenzylamino) -2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propene-1- Il] -9-fluoro-2,3,4,4a,
5,6, -Hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine (isomer A) 386 mg of the compound obtained in Example 86- (9) was treated with ethanol 35
dissolved in 3-ml and 3- [1- (4-chloro-6- (4-methoxybenzylamino) -2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2
Using 644 mg of -trans-propenal and 480 μl of acetic acid, the reaction and post-treatment were carried out in the same manner as in Example 86- (10) to give the title compound
897 mg were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.88 (t, 1 H, J = 11 Hz), 2.22
-2.31 (m, 1 H), 2.64 (s, 3 H), 2.88-2.93 (m, 2 H),
3.09 (d, 1 H, J = 12 Hz), 3.19-3.27 (m, 3 H), 3.5
8 (d, 1 H, J = 12 Hz), 3.81 (s, 3 H), 3.96 (t, 1
H, J = 9 Hz), 4.18 (dd, 1 H, J = 11 Hz, 3 Hz), 4.4
3 (brs, 2 H), 6.05 (dt, 1 H, J = 16 Hz, 7 Hz), 6.25
(s, 1 H), 6.37-6.40 (m, 2 H), 6.49 (dd, 1 H, J =
11 Hz, 3 Hz), 6.68 (dd, 1 H, J = 9 Hz, 6 Hz), 6.89
(d, 2H, J = 9 Hz), 7.22 (d, 2H, J = 9 Hz), 7.82
(s, 1 H).

(2) 3- [3- [1- (6-Amino-4-chloro-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9- Fluoro-2,3,4,4a, 5,6, -hexahydro-1
H-pyrazino [2,1-c] -1,4-benzoxazine (isomer A) Using 897 mg of the compound obtained in Example 90- (1), the reaction was carried out in the same manner as in Example 40- (7). After work-up, the title compound 49
5 mg was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (t, 1 H, J = 11 Hz), 2.26
-2.34 (m, 1 H), 2.67 (s, 3 H), 2.85-2.95 (m, 2 H),
3.07 (d, 1 H, J = 11 Hz), 3.16-3.26 (m, 3 H), 3.5
8 (d, 1 H, J = 12 Hz), 3.96 (dd, 1 H, J = 11 Hz, 9
Hz), 4.18 (dd, 1 H, J = 11 Hz, 3 Hz), 5.28 (brs, 1
H), 6.07 (dt, 1 H, J = 16 Hz, 7 Hz), 6.34 (s, 1
H), 6.35-6.41 (m, 2 H), 6.49 (dd, 1 H, J = 11 Hz,
3 Hz), 6.68 (dd, 1 H, J = 9 Hz, 6 Hz), 7.84 (s, 1
H).

(3) 3- [3- [1- [4-amino-6- (3-hydroxy-1-azetidinyl) -2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propene -1-yl] -9-fluoro-2,3,4,
4a, 5,6-Hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride (isomer A) 357 mg of the compound obtained in Example 90- (2), 3-hydroxy Using 357 mg of azetin hydrochloride and 300 mg of potassium carbonate, the reaction and post-treatment were carried out in the same manner as in Example 54 to give the title compound
390 mg were obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.62 (s, 3 H), 2.79-284 (m, 1
H), 3.05-3.08 (m, 1H), 3.26 (t, 1 H, J = 12 Hz),
3.54 (d, 1 H, J = 11 Hz), 3.69-3.71 (m, 1H), 3.83-
3.98 (m, 5 H), 4.08 (d, 1 H, J = 13 Hz), 4.28-4.32
(m, 3 H), 4.59-4.65 (m, 1 H), 5.27 (s, 1 H), 6.30
(dt, 2 H, J = 16 Hz, 7 Hz), 6.49 (dt, 1 H, J = 8
Hz, 3 Hz), 6.74 (dd, 1 H, J = 9 Hz, 6 Hz), 6.81
(d, 1 H, J = 16 Hz), 6.88 (dd, 1 H, J = 12 Hz, 3 H
z), 8.25 (s, 1 H), 11.93 (brs, 1 H)

Example 91 3- [3- [1- [4-amino-6- (3-hydroxy-1-azetidinyl)-]
2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9-fluoro-2,3,4,4a, 5,6, -hexahydro-1H-pyrazino [2, 1-c] -1,4-benzoxazine hydrochloride (isomer B)

[0559]

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(1) 3- [3- [1- [4-Chloro-6- (4-methoxybenzylamino) -2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propene-1 -Yl] -9-fluoro-2,3,4,4
a, 5,6-Hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine (isomer B) 487 mg of the compound obtained in Example 87- (4) and 3- [1- (Four-
Chloro-6- (4-methoxybenzylamino) -2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propenal 813
Using mg, the reaction, post-treatment, and purification were carried out in the same manner as in Example 90- (1) to obtain 588 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.90 (t, 1 H, J = 11 Hz), 2.25
-2.32 (m, 1 H), 2.63 (s, 3 H), 2.90-3.00 (m, 2 H),
3.12 (d, 1 H, J = 11 Hz), 3.20-3.31 (m, 3 H), 3.5
8 (d, 1 H, J = 11 Hz), 3.81 (s, 3 H), 3.96 (t, 1
H, J = 9 Hz), 4.18 (dd, 1 H, J = 11 Hz, 3 Hz), 4.4
8 (brs, 2 H), 6.05 (dt, 1 H, J = 16 Hz, 7 Hz), 6.25
(s, 1 H), 6.37-6.43 (m, 2 H), 6.49 (dd, 1 H, J =
11 Hz, 3 Hz), 6.68 (dd, 1 H, J = 9 Hz, 6 Hz), 6.89
(d, 2H, J = 9 Hz), 7.23 (d, 2H, J = 9 Hz), 7.84
(s, 1 H).

(2) 3- [3- [1- (6-amino-4-chloro-2-pyrimidinyl) -5-methyl-4-pyrazolyl] -2-trans-propen-1-yl] -9- Fluoro-2,3,4,4a, 5,6, -hexahydro-1
H-pyrazino [2,1-c] -1,4-benzoxazine (isomer B) Using 588 mg of the compound obtained in Example 91- (1), reacted in the same manner as in Example 40- (7). After work-up and purification, 277 mg of the title compound was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (t, 1 H, J = 11 Hz), 2.26
(dt, 1 H, J = 12 Hz, 3 Hz), 2.67 (s, 3 H), 2.84-2.
95 (m, 2 H), 3.07 (d, 1 H, J = 10 Hz), 3.13-3.26
(m, 3 H), 3.57 (d, 1 H, J = 12 Hz), 3.96 (t, 1 H,
J = 9 Hz), 4.18 (dd, 1 H, J = 10 Hz, 3 Hz), 5.33 (b
rs, 1 H), 6.06 (dt, 1 H, J = 16 Hz, 7 Hz), 6.34 (s,
1 H), 6.35-6.41 (m, 2 H), 6.49 (dd, 1 H, J = 11 H
z, 3 Hz), 6.68 (dd, 1 H, J = 9 Hz, 6 Hz), 7.84 (s,
1 H).

(3) 3- [3- [1- [4-amino-6- (3-hydroxy-1-azetidinyl) -2-pyrimidinyl] -5-methyl-4-pyrazolyl] -2-trans-propene -1-yl] -9-fluoro-2,3,4,
4a, 5,6-Hexahydro-1H-pyrazino [2,1-c] -1,4-benzoxazine hydrochloride (isomer B) 277 mg of the compound obtained in Example 91- (2), 3-hydroxy Using 200 mg of azetidine hydrochloride and 170 mg of potassium carbonate, the reaction and post-treatment were carried out in the same manner as in Example 54 to give the title compound
212 mg were obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 2.62 (s, 3 H), 2.79-284 (m, 1
H), 3.05-3.08 (m, 1H), 3.26 (t, 1 H, J = 12 Hz),
3.54 (d, 1 H, J = 12 Hz), 3.68-3.71 (m, 1H), 3.84-
3.98 (m, 5 H), 4.08 (d, 1 H, J = 14 Hz), 4.28-4.32
(m, 3 H), 4.59-4.62 (m, 1 H), 5.27 (s, 1 H), 6.30
(dt, 2 H, J = 16 Hz, 7 Hz), 6.49 (dt, 1 H, J = 8
Hz, 3 Hz), 6.74 (dd, 1 H, J = 9 Hz, 6 Hz), 6.81
(d, 1 H, J = 16 Hz), 6.88 (dd, 1 H, J = 12 Hz, 3 H
z), 8.25 (s, 1 H), 12.00 (brs, 1 H)

Example 92 1- [1- [4-Amino-6- (3-hydroxyazetidino) -2-pyrimidinyl] -5-ethyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0564]

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(1) Methyl 1- [4-chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-ethyl-4-pyrazolecarboxylate Methyl 2- (methoxymethylene) propionylacetate (Methyl
2-methoxymethylene-3-oxopentanoate) in 1.72 g of ethanol solution (20 ml) was added at room temperature to 4-chloro-2-hydrazino-6.
2.8 g of-(4-methoxybenzyl) aminopyrimidine was added,
After stirring for 30 minutes, the mixture was heated under reflux for 3 hours. After concentrating the reaction solution under reduced pressure, ether and hexane were added to the residue,
The precipitate was collected by filtration to give 2.53 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (t, 3 H, J = 7 Hz), 3.47
(q, 2 H, J = 7 Hz), 3.82 (s, 3 H), 3.86 (s, 3 H),
4.3-4.7 (brs, 2 H), 6.34 (s, 1 H), 6.90 (d, 2H, J
= 9 Hz), 7.24 (d, 2 H, J = 9 Hz), 8.05 (s, 1 H).

(2) 1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-ethyl-4-pyrazolecarbaldehyde 2.52 g of the compound obtained in Example 92- (1) Was used to carry out the same reaction and post-treatment as in Example 40- (3), thereby obtaining 2.52 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, 3 H, J = 7 Hz), 3.45
(q, 2 H, J = 7 Hz), 3.82 (s, 3 H), 4.35-4.80 (br, 2
H), 6.36 (s, 1 H), 6.90 (d, 2 H, J = 9 Hz), 7.24
(d, 2 H, J = 9 Hz), 8.09 (s, 1 H), 10.00 (s, 1 H).

(3) 3- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-ethyl-4-pyrazolyl]
-2-trans-Ethyl propenoate Using 2.52 g of the compound obtained in Example 92- (2) and 2.62 g of (carboethoxymethylene) triphenylphosphorane, the reaction was carried out in the same manner as in Example 40- (4). Treatment gave 3.24 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (t, 3 H, J = 7 Hz), 1.33
(t, 3 H, J = 7 Hz), 3.25 (q, 2 H, J = 7 Hz), 3.82
(s, 3 H), 4.25 (q, 2 H, J = 7 Hz), 6.27 (d, 1H, J
= 16 Hz), 6.30 (s, 1 H), 6.90 (d, 2 H, J = 9 Hz),
7.24 (d, 2 H, J = 9 Hz), 7.59 (d, 1 H, J = 16 Hz),
7.93 (s, 1 H).

(4) 3- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-ethyl-4-pyrazolyl]
-2-trans-propenal Using 3.24 g of the compound obtained in Example 92- (3), the same reaction and post-treatment as in Example 40- (5) were performed to obtain 1.78 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (t, 3 H, J = 7 Hz), 3.27
(q, 2 H, J = 7 Hz), 3.82 (s, 3 H), 4.3-4.7 (br, 2
H), 6.33 (s, 1 H), 6.56 (dd, 1 H, J = 16 Hz, 8 Hz),
6.91 (d, 2 H, J = 9 Hz), 7.24 (d, 2 H, J = 9 Hz),
7.38 (d, 1 H, J = 16 Hz), 7.95 (s, 1 H), 9.65 (d,
1 H, J = 8 Hz).

(5) 1- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-ethyl-4-pyrazolyl]
-3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-t
rans-propene 796 mg of the compound obtained in Example 92- (4) was added to ethanol 20
After dissolving in 1 ml, 1- (3,5-difluorophenyl) piperazine hydrochloride (515 mg) was added, and sodium cyanoborohydride (500 mg) was added, followed by stirring at room temperature for 24 hours. After adding water and a saturated aqueous solution of sodium hydrogen carbonate to the reaction solution, the mixture was extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel chromatography.
The mixture was developed with a mixed solvent of 8.5: 1.5), and the fraction containing the desired product was concentrated to obtain 712 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (t, 3 H, J = 7 Hz), 2.63
(t, 4 H, J = 5 Hz), 3.10-3.25 (m, 8 H), 3.82 (s, 3
H), 4.30-4.70 (brs, 2 H), 6.08 (dt, 1 H, J = 16 H
z, 7 Hz), 6.20-6.30 (m, 1 H), 6.25 (s, 1 H), 6.35-
6.45 (m, 3 H), 6.90 (d, 2 H, J = 9 Hz), 7.24 (d, 2
H, J = 9 Hz), 7.83 (s, 1 H).

(6) 1- [1- (4-Amino-6-chloro-2-pyrimidinyl) -5-ethyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1- Piperazinyl] -1-trans-propene Using 58 mg of the compound obtained in Example 92- (5), the reaction and post-treatment were carried out in the same manner as in Example 40- (7) to give the title compound 46.
mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (t, 3 H, J = 7 Hz), 2.66
(t, 4 H, J = 5 Hz), 3.20 (q, 2 H, J = 7 Hz), 3.21
(d, 2 H, J = 7 Hz), 3.24 (t, 4 H, J = 5 Hz), 5.35
(brs, 2 H), 6.09 (dt, 1 H, J = 16 Hz, 7 Hz), 6.25
(tt, 1 H, J = 9 Hz, 2 Hz), 6.36 (s, 1 H), 6.35-6.4
2 (m, 2 H), 6.40 (d, 1 H, J = 16 Hz), 6.90 (d, 2
H, J = 9 Hz), 7.83 (s, 1 H).

(7) 1- [1- [4-amino-6- (3-hydroxy-1
-Azetidinyl) -2-pyrimidinyl] -5-ethyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl]-
1-trans-propene hydrochloride Using 46 mg of the compound obtained in Example 92- (6), 44 mg of 3-hydroxyazetidine hydrochloride and 55 mg of potassium carbonate, the reaction and post-treatment were carried out in the same manner as in Example 54. , The title compound
28 mg were obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.18 (t, 3 H, J = 7 Hz), 3.00
-3.30 (m, 6 H), 3.50-3.60 (m, 2 H), 3.70-3.80 (m,
2 H), 3.90-4.05 (m, 4 H), 4.21 (t, 2 H, J = 8 Hz),
4.55-4.65 (m, 1 H), 5.24 (s, 1 H), 6.20 (dt, 1 H,
J = 16 Hz, 7 Hz), 6.58 (t, 1 H, J = 9 Hz), 6.73 (d
d, 2 H, J = 11 Hz, 2 Hz), 6.78 (d, 1H, J = 16 Hz),
8.02 (s, 1 H), 10.98 (brs, 1 H)

Example 93 1- [1- [4-Amino-6- (3-hydroxy-1-azetidinyl) -2-
Pyrimidinyl] -5-propyl-4-pyrazolyl] -3- [4- (3,5-
Difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0573]

Embedded image

(1) Ethyl 1- [4-chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-propyl-4-pyrazolecarboxylate Ethyl 2- (ethoxymethylene) butyryl acetate (Ethyl 2 -et
hoxymethylene-3-oxohexanoate) 1.11 g and 4-chloro
Using 1.32 g of -2-hydrazino-6- (4-methoxybenzyl) aminopyrimidine, the same reaction and post-treatment as in Example 92-1 (1) were performed to obtain 1.57 g of the title compound as a milky white solid. . ¹ H-NMR (CDCl ₃ ) δ: 0.97 (t, 3 H, J = 7 Hz), 1.37
(t, 3 H, J = 7 Hz), 1.70 (m, 2 H), 3.45 (m, 2 H),
3.81 (s, 3 H), 4.32 (q, 2 H, J = 7 Hz), 4.3-4.7 (b
r, 2 H), 6.32 (s, 1 H), 6.90 (d, 2 H, J = 9 Hz),
7.24 (d, 2 H, J = 9 Hz), 8.05 (s, 1 H).

(2) 1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-propyl-4-pyrazolecarbaldehyde 1.24 g of the compound obtained in Example 93- (1) The above compound was subjected to the same reaction and post-treatment as in Example 40- (3) to give 0.97 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (t, 3 H, J = 7 Hz), 1.73
(m, 2 H), 3.42 (t, 2 H, J = 7 Hz), 3.82 (s, 3 H),
4.35-4.70 (br, 2 H), 6.35 (s, 1 H), 6.90 (d, 2H, J
= 9 Hz), 7.24 (d, 2 H, J = 9 Hz), 8.10 (s, 1 H),
9.99 (s, 1 H).

(3) Ethyl 3- [1- [4-chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-propyl-4-pyrazolyl] -2-trans-propenoate Example 93 Using 0.94 g of the compound obtained in (2) and 1.11 g of (carboethoxymethylene) triphenylphosphorane, the reaction was carried out and post-treated in the same manner as in Example 40- (4) to give 1.10 g of the title compound in white Obtained as a solid. ¹ H-NMR (CDCl ₃ ) δ: 0.96 (t, 3 H, J = 7 Hz), 1.33
(t, 3 H, J = 7 Hz), 1.65 (m, 2 H), 3.21 (t, 2 H, J
= 7 Hz), 3.81 (s, 3 H), 4.25 (q, 2 H, J = 7 Hz), 4.
35-4.70 (br, 2 H), 6.27 (d, 1 H, J = 16 Hz), 6.29
(s, 1 H), 6.90 (d, 2 H, J = 9 Hz), 7.24 (d, 2 H, J
= 9 Hz), 7.58 (d, 1 H, J = 16 Hz), 7.93 (s, 1 H).

(4) 3- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-propyl-4-pyrazolyl] -2-trans-propenal Example 93- ( Using 1.10 g of the compound obtained in 3), the reaction was followed by post-treatment in the same manner as in Example 40- (5) to obtain 0.76 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (t, 3 H, J = 7 Hz), 1.70
(m, 2 H), 3.24 (t, 2 H, J = 7 Hz), 3.82 (s, 3 H),
4.3-4.7 (br, 2 H), 6.32 (s, 1 H), 6.56 (dd, 1H, J
= 16 Hz, 8 Hz), 6.90 (d, 2 H, J = 9 Hz), 7.24 (d,
2 H, J = 9 Hz), 7.38 (d, 1 H, J = 16 Hz), 7.96 (s,
1 H), 9.65 (d, 1 H, J = 8 Hz).

(5) 1- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5-propyl-4-pyrazolyl] -3- [4- (3,5- Difluorophenyl) -1-piperazinyl]-
1-trans-propene Example 9 was repeated using 41 mg of the compound obtained in Example 93- (4) and 30 mg of 1- (3,5-difluorophenyl) piperazine.
After the reaction, post-treatment was carried out in the same manner as in 2- (5), to give the title compound 61
mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, 3 H, J = 7 Hz), 1.60-1.
70 (m, 2 H), 2.64 (t, 4 H, J = 5 Hz), 3.13 (t, 2 H,
J = 7 Hz), 3.20 (d, 2 H, J = 7 Hz), 3.23 (t, 4 H,
J = 5 Hz), 3.81 (s, 3 H), 4.30-4.60 (brs, 2 H),
6.07 (dt, 1 H, J = 16 Hz, 7 Hz), 6.20-6.30 (m, 1
H), 6.24 (s, 1 H), 6.35-6.40 (m, 2 H), 6.38 (d, 1
H, J = 16 Hz), 6.89 (d, 2 H, J = 8 Hz), 7.23 (d, 2
H, J = 8 Hz), 7.84 (s, 1 H).

(6) 1- [1- (4-Amino-6-chloro-2-pyrimidinyl) -5-propyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1- Piperazinyl] -1-trans-propene After the reaction, a post-treatment was conducted using 61 mg of the compound obtained in Example 93- (5) in the same manner as in Example 40- (7) to obtain 47 mg of the title compound. . ¹ H-NMR (CDCl ₃ ) δ: 0.98 (t, 3 H, J = 7 Hz), 1.60-1.
70 (m, 2 H), 2.65 (t, 4 H, J = 5 Hz), 3.13 (t, 2 H,
J = 7 Hz), 3.21 (d, 2 H, J = 7 Hz), 3.24 (t, 4 H,
J = 5 Hz), 5.36 (brs, 2 H), 6.08 (dt, 1 H, J = 16
Hz, 7 Hz), 6.25 (tt, 1 H, J = 9 Hz, 2 Hz), 6.35
(s, 1 H), 6.35-6.40 (m, 2 H), 6.39 (d, 1 H, J = 16
Hz), 7.84 (s, 1 H).

(7) 1- [1- [4-amino-6- (3-hydroxy-1
-Azetidinyl) -2-pyrimidinyl] -5-propyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride Example 93- (6 Using 61 mg of the compound obtained in), 44 mg of 3-hydroxyazetidine hydrochloride and 55 mg of potassium carbonate, the reaction was carried out and post-treated in the same manner as in Example 54 to obtain 29 mg of the title compound as a white powder. . ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (t, 3 H, J = 7 Hz), 1.50
-1.65 (m, 2 H), 3.00-3.30 (m, 6 H), 3.45-3.55 (m, 2
H), 3.70-3.80 (m, 2 H), 3.90-4.05 (m, 4 H), 4.15-
4.25 (m, 2 H), 4.55-4.65 (m, 1 H), 5.22 (s, 1 H),
6.18 (dt, 1 H, J = 16 Hz, 7 Hz), 6.58 (t, 1 H, J =
9 Hz), 6.73 (d, 2 H, J = 10 Hz), 6.77 (d, 1 H, J =
16 Hz), 8.00 (s, 1 H), 10.81 (brs, 1 H)

Example 94 1- [1- [4-Amino-6- (3-hydroxy-1-azetidinyl) -2-
Pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0582]

Embedded image

(1) Ethyl 1- [4-chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5- (2-propyl) -4-pyrazolecarboxylate 2- (ethoxymethylene) isobutyrylacetic acid Ethyl
2-ethoxymethylene-4-methyl-3-oxopentanoate) 1.07 g
1.40 g of 4-chloro-2-hydrazino-6- (4-methoxybenzyl) aminopyrimidine at room temperature in an ethanol solution (10 ml) of
Was added and heated under reflux for 5 days. After concentrating the reaction solution under reduced pressure, the residue was subjected to silica gel chromatography,
Elute with a mixed solvent of ethyl acetate-hexane (3: 7),
By concentrating the fraction containing the target compound, the title compound 1.
18 g were obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (t, 3 H, J = 7 Hz), 1.42
(d, 6 H, J = 7 Hz), 3.81 (s, 3 H), 3.95 (quint., 1
H, J = 7 Hz), 4.31 (q, 2 H, J = 7 Hz), 4.3-4.7 (b
r, 2 H), 6.37 (s, 1 H), 6.90 (d, 2 H, J = 9 Hz),
7.23 (d, 2 H, J = 9 Hz), 8.03 (s, 1 H).

(2) 1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5- (2-propyl) -4-pyrazolecarbaldehyde Obtained in Example 94- (1) The compound was reacted and worked up in the same manner as in Example 40- (3) using 1.18 g of the title compound to obtain 1.00 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (d, 6 H, J = 7 Hz), 3.82
(s, 3 H), 3.99 (quint., 1 H, J = 7 Hz), 4.30-4.70
(br, 2 H), 6.39 (s, 1 H), 6.90 (d, 2 H, J = 9 Hz),
7.23 (d, 2 H, J = 9 Hz), 8.11 (s, 1 H), 10.16 (s,
1 H).

(3) 3- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -2-trans-propenoic acid Ethyl Using 1.00 g of the compound obtained in Example 94- (2), the reaction was followed by post-treatment in the same manner as in Example 40- (4) to obtain 1.10 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, 3 H, J = 7 Hz), 1.41
(d, 6 H, J = 7 Hz), 3.82 (s, 3 H), 3.98 (quint., 1
H, J = 7 Hz), 4.25 (q, 2 H, J = 7 Hz), 4.35-4.65
(br, 2 H), 6.21 (d, 1 H, J = 16 Hz), 6.33 (s, 1
H), 6.90 (d, 2 H, J = 9 Hz), 7.23 (d, 2 H, J = 9 H
z), 7.83 (d, 1 H, J = 16 Hz), 7.88 (s, 1 H).

(4) 3- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -2-trans-propenal The reaction and post-treatment were carried out in the same manner as in Example 40- (5) using 1.07 g of the compound obtained in Example 94- (3) to obtain 0.87 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (d, 6 H, J = 7 Hz), 3.81
(s, 3 H), 4.02 (quint., 1 H, J = 7 Hz), 4.35-4.70
(br, 2 H), 6.36 (s, 1 H), 6.50 (dd, 1 H, J = 16 H
z, 8 Hz), 6.90 (d, 2 H, J = 9 Hz), 7.25 (d, 2 H, J
= 9 Hz), 7.63 (d, 1 H, J = 16 Hz), 7.90 (s, 1 H),
9.63 (d, 1 H, J = 8 Hz).

(5) 1- [1- [4-Chloro-6- (4-methoxybenzyl) amino-2-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3- [4- ( 3,5-Difluorophenyl) -1-piperazinyl] -1-trans-propene The procedure was carried out using 41 mg of the compound obtained in Example 94- (4) and 30 mg of 1- (3,5-difluorophenyl) piperazine. Example 9
After the reaction, post-treatment was carried out in the same manner as in 2- (5), to give the title compound 62
mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (d, 6 H, J = 7 Hz), 2.64
(t, 4 H, J = 5 Hz), 3.19 (d, 2 H, J = 7 Hz), 3.24
(t, 4 H, J = 5 Hz), 3.81 (s, 3 H), 3.98 (quint., 1
H, J = 7 Hz), 4.30-4.70 (brs, 2 H), 6.00 (dt, 1
H, J = 16 Hz, 7 Hz), 6.25 (tt, 1 H, J = 9 Hz, 2 H
z), 6.29 (s, 1 H), 6.36 (dd, 2 H, J = 11 Hz, 2 H
z), 6.62 (d, 1 H, J = 16 Hz), 6.89 (d, 2 H, J = 9
Hz), 7.22 (d, 2H, J = 9 Hz), 7.77 (s, 1 H).

(6) 1- [1- (4-amino-6-chloro-2-pyrimidinyl) -5- (2-propyl) -4-pyrazolyl] -3- [4- (3,5-difluorophenyl ) -1-Piperazinyl] -1-trans-propene Using 62 mg of the compound obtained in Example 94- (5), the reaction was followed by post-treatment as in Example 40- (7) to give the title compound 47. mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (d, 6 H, J = 7 Hz), 2.66
(t, 4 H, J = 5 Hz), 3.20 (d, 2 H, J = 7 Hz), 3.24
(t, 4 H, J = 5 Hz), 4.00 (quint., 1 H, J = 7 Hz),
5.45 (brs, 2 H), 6.01 (dt, 1 H, J = 16 Hz, 7 Hz),
6.25 (tt, 1 H, J = 9 Hz, 2 Hz), 6.37 (dd, 2 H, J =
11 Hz, 2 Hz), 6.38 (s, 1 H), 6.63 (d, 1H, J = 16 H
z), 7.78 (s, 1 H).

(7) 1- [1- [4-amino-6- (3-hydroxy-1
-Azetidinyl) -2-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride The reaction was carried out in the same manner as in Example 54 using 47 mg of the compound obtained in 94- (6), 44 mg of 3-hydroxyazetidine hydrochloride and 55 mg of potassium carbonate to give 32 mg of the title compound in white. Obtained as a powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.32 (d, 6 H, J = 7 Hz), 3.00
-3.30 (m, 4 H), 3.45-3.60 (m, 2 H), 3.65-3.85 (m,
3 H), 3.90-4.05 (m, 4 H), 4.10-4.25 (m, 2 H), 4.55
-4.65 (m, 1 H), 5.25 (s, 1 H), 6.11 (dt, 1 H, J =
16 Hz, 7 Hz), 6.57 (t, 1 H, J = 9 Hz), 6.74 (dd, 2
H, J = 11 Hz, 2 Hz), 6.97 (d, 1 H, J = 16 Hz), 7.9
1 (s, 1 H), 10.90 (brs, 1 H)

Example 95 1- [1- [2-Amino-6- (3-hydroxy-3-methyl-1-azetidinyl) -4-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl]
-3-[(2R) -4- (3,5-difluorophenyl) -2-methyl-1-piperazinyl] -1-trans-propene hydrochloride

[0591]

Embedded image

(1) Methyl 1- (2-amino-6-chloro-4-pyrimidinyl) -5- (2-propyl) -4-pyrazolecarboxylate 3.9 2-amino-4-chloro-6-hydrazinopyrimidine g was suspended in 50 ml of ethanol, and then 2- (ethoxymethylene)
5.8 g of ethyl isobutyryl acetate was added, and the mixture was stirred at room temperature for 20 minutes and further at 80 ° C. for 48 hours. After cooling the reaction solution to room temperature, 50 ml of hexane was added, and the mixture was further stirred for 24 hours. The precipitate was collected by filtration, washed with hexane, and dried to give the title compound (5.4 g) as a pale-brown solid. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, 3 H, J = 7 Hz), 1.45
(d, 6 H, J = 7 Hz), 4.15-4.26 (m, 1 H), 4.33 (q, 2
H, J = 7 Hz), 5.27 (brs, 2 H), 7.17 (s, 1 H), 8.0
2 (s, 1 H).

(2) Ethyl 3- [1- (2-amino-6-chloro-4-pyrimidinyl) -5- (2-propyl) -4-pyrazolyl] -2-trans-propenoate Using 5.27 g of methyl (amino-6-chloro-4-pyrimidinyl) -5-ethyl-4-pyrazolecarboxylate, Example 40-
After the reaction, post-treatment was carried out in the same manner as in (3) to obtain 3.99 g of a white solid. Using this solid and 6.28 g of (carboethoxymethylene) triphenylphosphorane, Example 40- (4)
After the reaction, post-treatment was carried out in the same manner as in to give 2.34 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (t, 3 H, J = 7 Hz), 1.44
(d, 6 H, J = 7 Hz), 4.22-4.28 (m, 3 H), 5.24 (brs,
2 H), 6.21 (d, 1 H, J = 16 Hz), 7.23 (s, 1H), 7.8
3 (d, 1 H, J = 16 Hz), 7.85 (s, 1 H).

(3) 3- [1- (2-Amino-6-chloro-4-pyrimidinyl) -5- (2-propyl) -4-pyrazolyl] -2-trans-propenal Example 95- (2) Using 2.15 g of the compound obtained in the above and the same reaction and post-treatment as in Example 40- (5), 1.90 g of the title compound was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (d, 6 H, J = 7 Hz), 4.32
(quint., 1 H, J = 7 Hz), 5.22 (brs, 2 H), 6.50 (d
d, 1 H, J = 16 Hz, 8 Hz), 7.24 (s, 1 H), 7.63 (d, 1
H, J = 16 Hz), 7.88 (s, 1 H), 9.64 (d, 1 H, J = 8
Hz).

(4) 1- [1- (2-Amino-6-chloro-4-pyrimidinyl) 5- (2-propyl) -4-pyrazolyl] -3-[(2R) -4-
(3,5-difluorophenyl) -2-methyl-1-piperazinyl]-
1-trans-propene 583 mg of the compound obtained in Example 95- (3) was added to ethanol 80
of the compound obtained in Example 81- (1).
g and 630 μl of acetic acid, followed by post-treatment after reaction in the same manner as in Example 86- (10) to obtain 755 mg of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (d, 3 H, J = 6 Hz), 1.39
(d, 6 H, J = 7 Hz), 2.41-2.46 (m, 1 H), 2.57-2.72
(m, 2 H), 2.94-3.08 (m, 3 H), 3.38-3.50 (m, 2 H),
3.60-3.65 (m, 1 H), 4.25 (quint., 1 H, J = 7 Hz),
5.16 (brs, 2 H), 6.02 (dt, 1 H, J = 16 Hz, 7 Hz),
6.21-6.26 (m, 1 H), 6.35 (dd, 2 H, J = 11 Hz, 2 H
z), 6.61 (d, 1 H, J = 16 Hz), 7.23 (s, 1 H), 7.74
(s, 1 H).

(5) 1- [1- [2-amino-6- (3-hydroxy-3
-Methyl-1-azetidinyl) -4-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3-[(2R) -4- (3,5-difluorophenyl) -2-methyl-1- Piperazinyl] -1-trans-propene hydrochloride 377 mg of the compound obtained in Example 95- (4) was treated with ethanol 30
suspended in 3-ml 3-methyl-3-hydroxyazetidine 150
After the reaction, a post-treatment was carried out in the same manner as in Example 54 using mg and 107 mg of potassium carbonate to obtain 155 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (d, 3 H, J = 6 H), 1.33
(d, 6 H, J = 7 Hz), 1.44 (s, 3 H), 2.98-4.10 (m, 1
4 H), 5.94 (s, 1 H), 6.16 (dt, 1 H, J = 16Hz, 7 H
z), 6.55 (t, 1 H, J = 9 Hz), 6.70-6.75 (m, 2 H),
7.06 (d, 1 H, J = 16 Hz), 8.01 (s, 1 H), 10.92 (br
s, 1 H)

Example 96 1- [1- [2-Amino-6- (3-hydroxy-3-methyl-1-azetidinyl) -4-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl]
-3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-t
rans-propene hydrochloride

[0598]

Embedded image

(1) 1- [1- (2-Amino-6-chloro-4-pyrimidinyl) -5- (2-propyl) -4-pyrazolyl] -3- [4- (3,5-difluorophenyl ) -1-Piperazinyl] -1-trans-propene 583 mg of the compound obtained in Example 95- (3) and 1- (3,5-
The reaction was followed by a post-treatment using 801 mg of (difluorophenyl) piperazine in the same manner as in Example 86- (10) to give 1.35 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (d, 6 H, J = 7 Hz), 2.63
(t, 4 H, J = 5 Hz), 3.18-3.25 (m, 6 H), 4.25 (qui
nt., 1 H, J = 7 Hz), 5.19 (brs, 2 H), 6.01 (dt, 1
H, J = 16, 7 Hz), 6.25 (tt, 1 H, J = 9 Hz, 2 Hz),
6.37 (dd, 2 H, J = 11 Hz, 2 Hz), 6.61 (d, 1 H, J =
16 Hz), 7.23 (s, 1 H), 7.75 (s, 1 H).

(2) 1- [1- [2-amino-6- (3-hydroxy-3
-Methyl-1-azetidinyl) -4-pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3- [4- (3,5-difluorophenyl)-
1-piperazinyl] -1-trans-propene hydrochloride The compound obtained in Example 96- (1), 398 mg, 3-methyl-3-
Hydroxyazetidine 150 mg and potassium carbonate 116 mg
After the reaction, post-treatment was carried out in the same manner as in Example 54 to obtain 231 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (d, 6 H, J = 7 Hz), 1.44
(s, 3 H), 3.08-3.3 (m, 4H), 3.3-3.7 (m, 4 H), 3.8
-4.2 (m, 7 H), 5.90 (s, 1 H), 6.11 (dt, 1 H, J = 1
6 Hz, 7 Hz), 6.54-6.60 (m, 1 H), 6.73 (dd, 2 H, J
= 9 Hz, 2 Hz), 6.98 (d, 1 H, J = 16 Hz), 7.95 (s, 1
H), 10.82 (brs, 1 H)

Example 97 1- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-
Pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3-[(2R)
-4- (3,5-Difluorophenyl) -2-methyl-1-piperazinyl] -1-trans-propene hydrochloride

[0602]

Embedded image

The compound obtained in Example 95- (4), 377 mg,
The same reaction and post-treatment as in Example 54 were carried out using 180 mg of 3-hydroxyazetidine hydrochloride and 226 mg of potassium carbonate to obtain 362 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (d, 6 H, J = 7 Hz), 1.44
(s, 3 H), 3.08-3.3 (m, 4 H), 3.3-3.7 (m, 4 H), 3.
8-4.2 (m, 7 H), 5.90 (s, 1 H), 6.11 (dt, 1H, J = 1
6 Hz, 7 Hz), 6.54-6.60 (m, 1 H), 6.73 (dd, 2 H, J
= 9 Hz, 2 Hz), 6.98 (d, 1 H, J = 16 Hz), 7.95 (s, 1
H), 10.82 (brs, 1 H)

Example 98 1- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-
Pyrimidinyl] -5- (2-propyl) -4-pyrazolyl] -3- [4-
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0605]

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The compound obtained in Example 96- (1), 474 mg,
The same reaction and post-treatment as in 35 were performed using 328 mg of 3-hydroxyazetidine hydrochloride and 276 mg of potassium carbonate to obtain 435 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (d, 6 H, J = 7 Hz), 3.0-
3.2 (m, 2 H), 3.2-3.3 (m, 2 H), 3.45-3.60 (m, 2 H),
3.8-4.2 (m, 7 H), 4.3-4.5 (m, 2 H), 4.55-4.70 (m,
1 H), 6.01 (s, 1 H), 6.16 (dt, 1 H, J = 16 Hz, 7
Hz), 6.57 (t, 1 H, J = 9 Hz), 6.73 (d, 2 H, J = 9 H
z), 7.00 (d, 1 H, J = 16 Hz), 8.03 (s, 1 H), 11.07
(brs, 1 H)

Example 99 1- [1- [2-Amino-6- (3-hydroxy-3-methyl-1-azetidinyl) -4-pyrimidinyl] -5-ethyl-4-pyrazolyl] -3-[( Two
R) -4- (3,5-Difluorophenyl) -2-methyl-1-piperazinyl] -1-trans-propene hydrochloride

[0608]

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(1) Methyl 1- (2-amino-6-chloro-4-pyrimidinyl) -5-ethyl-4-pyrazolecarboxylate 7.79 g of 2-amino-4-chloro-6-hydrazinopyrimidine was added to 100 parts of ethanol. After suspending the suspension in 1 ml, 10.7 g of methyl methoxymethylenepropionylacetate was added, and the mixture was stirred at room temperature for 20 minutes and further at 80 ° C. for 3 hours. After leaving the reaction solution at 0 ° C. for 48 hours, the precipitate was collected by filtration and dried to give the title compound.
12.88 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (t, 3 H, J = 7 Hz), 3.55
(q, 2 H, J = 7 Hz), 3.87 (s, 3 H), 5.22 (brs, 2
H), 7.33 (s, 1 H), 8.01 (s, 1 H).

(2) 1- (2-Amino-6-chloro-4-pyrimidinyl) -5-ethyl-4-pyrazolecarbaldehyde Using 99 g of the compound obtained in Example 99- (1), By performing the same reaction and post-treatment as in 40- (3), 3.0 g of the title compound was obtained as a white solid ¹ H-NMR (CDCl ₃ ) δ: 1.36 (t, 3 H, J = 7 Hz) , 3.53
(q, 2 H, J = 7 Hz), 5.30 (brs, 2 H), 7.34 (s, 1
H), 8.06 (s, 1 H), 10.00 (s, 1 H).

(3) Ethyl 3- [1- (2-amino-6-chloro-4-pyrimidinyl) -5-ethyl-4-pyrazolyl] -2-trans-propenoate Obtained in Example 99- (2) The same reaction and post-treatment as in Example 40- (4) were performed using 2.95 g of the obtained compound to obtain 2.1 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (t, 3 H, J = 7 Hz), 1.33
(t, 3 H, J = 7 Hz), 3.30 (q, 2 H, J = 7 Hz,), 4.26
(q, 2 H, J = 7 Hz), 5.23 (brs, 2 H), 6.27 (dd, 1
H, J = 16 Hz), 7.33 (s, 1 H), 7.57 (d, 1 H, J = 16
Hz), 7.88 (s, 1H).

(4) 3- [1- (2-Amino-6-chloro-4-pyrimidinyl) -5-ethyl-4-pyrazolyl] -2-trans-propenal The compound obtained in Example 99- (3) The same reaction and post-treatment as in Example 40- (5) were carried out using 2.1 g to give 1.6 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, 3 H, J = 8 Hz), 3.33
(q, 2 H, J = 8 Hz), 5.25 (brs, 2 H), 6.56 (dd, 1
H, J = 16 Hz, 9 Hz), 7.36 (s, 1 H), 7.37 (d, 1 H, J
= 16 Hz), 7.91 (s, 1 H), 9.66 (d, 1 H, J = 9 Hz).

(5) 1- [1- [2-Amino-6-chloro-4-pyrimidinyl] -5-ethyl-4-pyrazolyl] -3-[(2R) -4- (3,5-difluorophenyl ) -2-Methyl-1-piperazinyl] -1-trans-
Propene Using Example 99- (4), the reaction was followed by post-treatment as in Example 86- (10) to give 860 mg of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (d, 3 H, J = 6 Hz), 1.23
(t, 3 H, J = 7 Hz), 2.3-2.4 (m, 1 H), 2.5-2.6 (m,
1 H), 2.69 (dd, 1 H, J = 12 Hz, 10 Hz), 2.9-3.0
(m, 3 H), 3.20 (q, 2 H, J = 7 Hz), 3.4-3.5 (m, 2
H), 3.64 (dd, 1 H, J = 16 Hz, 6 Hz), 5.14 (brs, 2
H), 6.10 (dt, 1 H, J = 16 Hz, 7 Hz), 6.23 (tt, 1 H,
J = 9 Hz, 2 Hz), 6.35 (dd, 2 H, J = 9 Hz, 2 Hz),
6.37 (d, 1 H, J = 16 Hz), 7.31 (s, 1 H), 7.78 (s,
1 H).

(6) 1- [2-amino-4- [4- [3-[(2R) -4- (3,5
-Difluorophenyl) -2-methylpiperazino] -1-propenyl] -5-ethyl-1H-1-pyrazolyl] -6-pyridinyl] -3-
Methyl-3-hydroxyazetidine hydrochloride 400 mg of the compound obtained in Example 99- (5), 3-methyl-3-
After performing the same reaction, post-treatment, and purification as in Example 42 using 0.15 g of hydroxyazetidine and 0.1 ml of acetic acid, recrystallization from ethanol gave 0.26 g of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.13 (t, 3 H, J = 7 Hz), 1.41
(s, 3 H), 1.42 (d, 3H, J = 6 Hz), 2.9-3.0 (m, 2
H), 3.0-3.5 (m, 6 H), 3.7-4.1 (m, 7 H), 5.99 (s, 1
H), 6.17 (dt, 1 H, J = 16 Hz, 7 Hz), 6.56 (t, 1
H, J = 10 Hz), 6.73 (d, 2 H, J = 10 Hz), 6.83 (d,
1 H, J = 16 Hz), 8.00 (s, 1 H), 10.97 (brs, 1 H)

Example 100 1- [1- [2-Amino-6- (3-hydroxy-3-methyl-1-azetidinyl) -4-pyrimidinyl] -5-ethyl-4-pyrazolyl] -3- [4 -
(3,5-difluorophenyl) -1-piperazinyl] -1-trans-
Propene hydrochloride

[0616]

Embedded image

(1) 1- [1- (2-Amino-6-chloro-4-pyrimidinyl) -5-ethyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1- Piperazinyl] -1-trans-propene 800 mg of the compound obtained in Example 99- (4) and 1- (3,5-
The same reaction and post-treatment as in Example 86- (10) were carried out using 630 mg of difluorophenyl) piperazine to obtain 1.1 g of the title compound as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (t, 3 H, J = 7 Hz), 2.63
(t, 4 H, J = 5 Hz), 3.1-3.2 (m, 8 H), 5.14 (brs, 2
H), 6.11 (dt, 1 H, J = 16 Hz, 7 Hz), 6.25 (tt, 1
H, J = 9 Hz, 2 Hz), 6.36 (dd, 2 H, J = 9 Hz, 2 H
z), 6.39 (d, 1 H, J = 16 Hz), 7.32 (s, 1 H), 7.79
(s, 1 H).

(2) 1- [1- [2-amino-6- (3-hydroxy-3
-Methyl-1-azetidinyl) -4-pyrimidinyl] -5-ethyl-4
-Pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride 400 mg of the compound obtained in Example 100- (1) and 3-methyl-3- Example 4 using 150 mg of hydroxyazetidine
The same reaction and post-treatment as in Example 2 were performed to give 210 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (t, 3 H, J = 7 Hz), 1.43
(s, 3 H), 3.0-3.1 (m, 2 H), 3.2-3.3 (m, 4 H), 3.5
8 (d, 2 H, J = 7 Hz), 3.8-4.0 (m, 8 H), 6.06 (s, 1
H), 6.18 (dt, 1 H, J = 16 Hz, 7 Hz), 6.58 (tt, 1
H, J = 9 Hz, 2 Hz), 6.72 (dd, 2 H, J = 9 Hz, 2 Hz),
6.78 (d, 1 H, J = 16 Hz), 8.04 (s, 1 H), 10.99 (br
s, 1 H)

Example 101 1- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-
Pyrimidinyl] -5-ethyl-4-pyrazolyl] -3-[(2R) -4- (3,
5-difluorophenyl) -2-methyl-1-piperazinyl] -1-t
rans-propene hydrochloride

[0620]

Embedded image

The compound obtained in Example 99- (5), 400 mg,
The same reaction and post-treatment as in Example 54 were carried out using 180 mg of 3-hydroxyazetidine hydrochloride and 0.12 g of potassium carbonate to obtain 300 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (t, 3 H, J = 7 Hz), 1.41
(d, 3 H, J = 6 Hz), 2.9-3.0 (m, 2 H), 3.1-3.5 (m,
8 H), 3.73 (dd, 2 H, J = 9 Hz, 4 Hz), 3.8-4.1 (m,
3 H), 4.20 (t, 2 H, J = 9 Hz), 4.5-4.6 (m, 1 H),
5.95 (s, 1 H), 6.18 (dt, 1 H, J = 16 Hz, 7 Hz), 6.
42 (brs, 2 H), 6.56 (t, 1 H, J = 10 Hz), 6.73 (d,
2 H, J = 10 Hz), 6.83 (d, 1 H, J = 16 Hz), 8.00
(s, 1 H), 10.99 (brs, 1 H)

Example 102 1- [1- [2-Amino-6- (3-hydroxy-1-azetidinyl) -4-
Pyrimidinyl] -5-ethyl-4-pyrazolyl] -3- [4- (3,5-difluorophenyl) -1-piperazinyl] -1-trans-propene hydrochloride

[0623]

Embedded image

The compound obtained in Example 100- (1), 400 m
g, 180 mg of 3-hydroxyazetidine hydrochloride and 0.12 g of potassium carbonate were subjected to the same reaction and post-treatment as in Example 54 to obtain 260 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (t, 3 H, J = 7 Hz), 2.9-
3.0 (m, 2 H), 3.1-3.3 (m, 6 H), 3.51 (d, 2 H, J = 7
Hz), 3.72 (dd, 2 H, J = 9 Hz, 4 Hz), 3.8-4.0 (m,
4 H), 4.18 (t, 2 H, J = 9 Hz), 4.5-4.6 (m, 1 H),
5.94 (s, 1 H), 6.14 (dt, 1 H, J = 16 Hz, 7 Hz), 6.4
0 (brs, 2 H), 6.58 (t, 1 H, J = 10 Hz), 6.72 (d, 2
H, J = 10 Hz), 6.75 (d, 1 H, J = 16 Hz), 7.96 (s,
1 H), 10.55 (brs, 1 H)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31/535 601 A61K 31/535 601 608 608 C07D 403/04 C07D 403/04 403/14 403/14 487 / 04 140 487/04 140 491/044 491/044 498/04 498/04 112T (72) Inventor Jin Oki 1-16-13 Kitakasai, Tokyo, Japan 72) Inventor Hiroyuki Naito 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 1st Pharmaceutical Co., Ltd.Tokyo R & D Center Tokyo R & D Center Co., Ltd.

Claims (22)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, and the alkyl group is a halogen atom, an amino group, an alkylamino group as a substituent. ,
It may have a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group. R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group, an alkyl group or a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are a halogen atom, an amino group as a substituent. , An alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group. R ³
Represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, and the alkyl group is a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group as a substituent. Alternatively, it may have an alkylthio group. R ⁴ represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group,
It may have an alkoxyl group, thiol group or alkylthio group. R ⁵ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an arylalkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or It may have an alkylthio group. Q represents an amidino group, a cycloalkyl group, a phenyl group, or a monocyclic heterocyclic group, and these amidino groups, cycloalkyl groups, phenyl groups, and monocyclic heterocyclic groups have an alkyl group (halogen) as a substituent. atom,
An amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group may be substituted. ), A halogen atom, a hydroxyl group, an alkoxyl group, an alkoxyl alkoxyl group, an amino group,
Alkylamino group, acylamino group, alkylaminoalkylamino group, nitro group, cyano group, carbamoyl group, thiol group, alkylthio group, arylthio group, alkylsulfinyl group, arylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, aminosulfonyl group , An alkylaminosulfonyl group, an arylaminosulfonyl group and an aryl group. G represents a condensed tricyclic heterocyclic ring, and the condensed tricyclic heterocyclic ring is a substituent having an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) May be substituted.), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group. May have one or more substituents. Further, the fused tricyclic heterocyclic ring may have an epoxy group. In addition, the fused tricyclic heterocyclic ring is
A carbonyl group may be contained as a component of the ring. And a salt thereof. 2. A compound of the general formula (I) [Wherein, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, and the alkyl group is a halogen atom, an amino group, an alkylamino group as a substituent. ,
It may have a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group. R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group, an alkyl group or a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are a halogen atom, an amino group as a substituent. , An alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group. R ³
Represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, and the alkyl group is a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group as a substituent. Alternatively, it may have an alkylthio group. R ⁴ represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group,
It may have an alkoxyl group, thiol group or alkylthio group. R ⁵ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an arylalkyl group, wherein the alkyl group is a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or It may have an alkylthio group. Q represents an amidino group, a cycloalkyl group, a phenyl group, or a monocyclic heterocyclic group, and these amidino groups, cycloalkyl groups, phenyl groups, and monocyclic heterocyclic groups have an alkyl group (halogen) as a substituent. atom,
An amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group may be substituted. ), A halogen atom, a hydroxyl group, an alkoxyl group, an alkoxyl alkoxyl group, an amino group,
Alkylamino group, acylamino group, alkylaminoalkylamino group, nitro group, cyano group, carbamoyl group, thiol group, alkylthio group, arylthio group, alkylsulfinyl group, arylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, aminosulfonyl group , An alkylaminosulfonyl group, an arylaminosulfonyl group and an aryl group. G represents a condensed tricyclic heterocyclic ring, and the condensed tricyclic heterocyclic ring is a substituent having an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) May be substituted.), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group. May have one or more substituents. Further, the fused tricyclic heterocyclic ring may have an epoxy group. Further, the condensed tricyclic heterocyclic ring may contain a carbonyl group as a ring constituent. And a salt thereof (provided that, in the compound and its salt, [G is a condensed tricyclic heterocyclic ring and the saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring is Represented by a saturated hydrocarbon ring or a saturated heterocyclic ring having no substituent (Q is a pyrimidinyl group,
Excludes the case where the position is combined. )] Excluding compounds and their salts. ). 3. The compound according to claim 1, wherein the fused tricyclic heterocyclic ring is composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring. Its salt. 4. A compound of the general formula (Ia) [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q have the same meanings as those in claim 1, G ¹ means a condensed tricyclic heterocyclic ring, The cyclic heterocyclic ring is composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring. The nitrogen-containing heterocyclic ring constituting the condensed tricyclic heterocyclic ring may be substituted by an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) .), A halogen atom, a hydroxyl group,
It may have one or more substituents selected from the group consisting of alkoxyl, thiol, alkylthio, amino, alkylamino, acylamino, nitro, cyano, carbamoyl and aryl groups. In addition, the nitrogen-containing heterocyclic ring may include a carbonyl group as a component of the ring. The saturated or unsaturated hydrocarbon ring or hetero ring constituting the condensed tricyclic hetero ring may be substituted with an alkyl group (halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group). May be substituted.), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group,
It may have one or more substituents selected from the group consisting of an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, and has an epoxy group extending between two atoms forming a ring. May be. Further, the saturated or unsaturated hydrocarbon ring or heterocyclic ring may contain a carbonyl group as a component of the ring. The benzene ring constituting the condensed tricyclic heterocyclic ring has, as a substituent, an alkyl group (which may be substituted with a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group). , A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group,
It may have one or more substituents selected from the group consisting of alkylthio, amino, alkylamino, acylamino, nitro, cyano, carbamoyl and aryl groups. And a salt thereof. 5. A compound of the general formula (Ia) [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q have the same meanings as those in claim 1, G ¹ means a condensed tricyclic heterocyclic ring, The cyclic heterocyclic ring is composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring. The nitrogen-containing heterocyclic ring constituting the condensed tricyclic heterocyclic ring may be substituted by an alkyl group (a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) .), A halogen atom, a hydroxyl group,
It may have one or more substituents selected from the group consisting of alkoxyl, thiol, alkylthio, amino, alkylamino, acylamino, nitro, cyano, carbamoyl and aryl groups. In addition, the nitrogen-containing heterocyclic ring may include a carbonyl group as a component of the ring. The saturated or unsaturated hydrocarbon ring or hetero ring constituting the condensed tricyclic hetero ring may be substituted with an alkyl group (halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group). May be substituted.), A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group,
It may have one or more substituents selected from the group consisting of an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, and has an epoxy group extending between two atoms forming a ring. May be. Further, the saturated or unsaturated hydrocarbon ring or heterocyclic ring may contain a carbonyl group as a component of the ring. The benzene ring constituting the condensed tricyclic heterocyclic ring has, as a substituent, an alkyl group (which may be substituted with a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group). , A halogen atom, a hydroxyl group, an alkoxyl group, a thiol group,
It may have one or more substituents selected from the group consisting of alkylthio, amino, alkylamino, acylamino, nitro, cyano, carbamoyl and aryl groups. ] Represented by compounds and their salts (however, in this compound and its salts, [G ^1,
A condensed tricyclic heterocyclic ring, wherein the saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by an unsubstituted saturated hydrocarbon ring or saturated heterocyclic ring (Q is a pyrimidinyl group, Excludes the case of binding at the 2-position.)] Except for compounds and salts thereof. ). 6. The compound according to any one of claims 3 to 5, wherein Q is a pyrimidinyl group, and the compound is bonded to the pyrazole ring at the 2-position. 7. The compound according to any one of claims 3 to 5, wherein the saturated or unsaturated hydrocarbon ring or the heterocyclic ring constituting the condensed tricyclic heterocyclic ring has a substituent. 8. A compound of the general formula (Ib)中 where R¹, R^Two, R^Three, R^FourAnd R^FiveIs described in claim 1
G is synonymous with^TwoIs a group -Z¹-Z^Two [Wherein, Z¹
Is(X represents a nitrogen atom or CH.)
A nitrogen-saturated heterocyclic structure, which includes a ketone moiety.
It may be rare. Also, as a substituent on this ring,
Alkyl group (halogen atom, amino group, alkylamino
Group, hydroxyl group, alkoxyl group, thiol group or
May be substituted by an alkylthio group. ),halogen
Atom, hydroxyl group, alkoxyl group, amino group,
Selected from the group consisting of alkylamino and aryl
May have one or more groups. Z^TwoIs phenyl
Group or heterocyclic group.
The ring group is an alkyl group (halogen atom, a
Amino group, alkylamino group, hydroxyl group, alkoxy
Substituted with a sil, thiol or alkylthio group
You may. ), Halogen atom, hydroxyl group, alcohol
Xyl group, thiol group, alkylthio group, amino group,
Alkylamino, acylamino, nitro, cyano
Group, carbamoyl group and aryl group
It may have one or more substituents. ]Also
Represents a condensed tricyclic heterocyclic group, and the condensed tricyclic heterocyclic ring
The group is an alkyl group (halogen atom, amino
Group, alkylamino group, hydroxyl group, alkoxyl
Group, thiol group or alkylthio group
Good. ), Halogen atom, hydroxyl group, alkoxy
Group, thiol group, alkylthio group, amino group, alkyl
Ruamino group, acylamino group, nitro group, cyano group,
Selected from the group consisting of rubamoyl and aryl groups
It may have one or more substituents. Also, this contraction
The combined tricyclic heterocyclic group may have an epoxy group. Further
In addition, a fused tricyclic heterocycle is a carbon
May contain a hydroxyl group. Q¹Is a cycloalkyl group,
Phenyl group or monocyclic heterocyclic group.
Loalkyl, phenyl and monocyclic heterocyclic groups
As a substituent, one or more groups selected from the following (A)
And one or more groups selected from (B)
May be. (A) an alkyl group having a substituent (replacement of this alkyl group)
Substituents include trialkylammonio, cyano, urea
Group, alkyl ureido group, amidino group, guanidino
Group, hydroxyalkoxyl group, alkoxylalkoxy
Sil group, aminoalkoxyl group, hydroxyalkyl group
Amino group, aminoalkylamino group, carboxyl group,
Rubamoyl group, sulfamoyl group, alkyl sulfamo
From the group consisting of yl and arylsulfamoyl groups
Group selected, one more group selected from this group
It may have the above. ), Group -R⁷¹-R⁷  [R⁷Is a monocyclic nitrogen-containing heterocyclic group or cycloalkyl
A group, R⁷¹Represents a single bond or an alkylene group having 1 to 3 carbon atoms.
Taste, R⁷And R⁷¹(Excluding the case of single bond)
Alkyl group (halogen atom, hydroxy)
Sil group, amino group, alkylamino group, trialkyl group
Ammonium, cyano, ureido, alkylureido
Group, amidino group, guanidino group, alkoxyl group, hydrid
Roxyalkoxyl group, alkoxylalkoxyl group,
Aminoalkoxyl group, hydroxyalkylamino group,
Aminoalkylamino group, carboxyl group, carbamoy
, A sulfamoyl group, an alkylsulfamoyl group,
Arylsulfamoyl group, thiol group and alkyl
One or more substituents selected from the group consisting of thio groups
You may have one. ), Halogen atom, hydroxyl
Group, amino group, alkylamino group, trialkylammonium
Nio group, cyano group, ureido group, alkyl ureide group,
Amidino group, guanidino group, alkoxyl group, hydroxy
Alkoxyl group, alkoxyl alkoxyl group, amide
Alkoxyl group, hydroxyalkylamino group, amide
Noalkylamino group, carboxyl group, carbamoyl
Group, sulfamoyl group, alkylsulfamoyl group,
Reel sulfamoyl, thiol and alkylthio
Having one or more groups selected from the group consisting of
May be. ] Group -R⁷²-R⁷³-R⁷⁴-R⁷  [R⁷Is a monocyclic nitrogen-containing heterocyclic group or cycloalkyl
A group, R⁷²And R⁷⁴Are each independently a single bond or
Represents an alkylene group having 1 to 3 carbon atoms;⁷³Represents an oxygen atom or a sulfur atom;⁷, R⁷²(Excluding the case of a single bond) and R⁷⁴(Single connection
Except in the case of ) Is each independently a substituent
Kill group (halogen atom, hydroxyl group, amino group,
Alkylamino group, trialkylammonio group, cyano
Group, ureido group, alkyl ureide group, amidino group,
Anidino group, alkoxyl group, hydroxyalkoxyl
Group, alkoxyl alkoxyl group, aminoalkoxyl
Group, hydroxyalkylamino group, aminoalkylamido
Group, carboxyl group, carbamoyl group, sulfamoi
Group, alkylsulfamoyl group, arylsulfamo
Group consisting of yl, thiol and alkylthio groups
May have one or more substituents selected from
No. ), Halogen atom, hydroxyl group, amino group,
Alkylamino group, trialkylammonio group, cyano
Group, ureido group, alkyl ureide group, amidino group,
Anidino group, alkoxyl group, hydroxyalkoxyl
Group, alkoxyl alkoxyl group, aminoalkoxyl
Group, hydroxyalkylamino group, aminoalkylamido
Group, carboxyl group, carbamoyl group, sulfamoi
Group, alkylsulfamoyl group, arylsulfamo
Group consisting of yl, thiol and alkylthio groups
May have one or more substituents selected from
No. ] Group -R⁷²-NR⁷⁵-R⁷⁴-R⁸  [R⁷²And R⁷⁴Are each independently a single bond or 1 carbon atom
To 3 alkylene groups; R⁷⁵Represents an alkyl group (halogen atom, hydroxyl group,
Mino group, alkylamino group, trialkylammonio
Group, cyano group, ureido group, alkyl ureide group,
Dino group, guanidino group, alkoxyl group, hydroxya
Lucoxyl group, alkoxyl alkoxyl group, amino group
Lucoxyl group, hydroxyalkylamino group, amino group
Alkylamino group, carboxyl group, carbamoyl group,
Rufamoyl group, alkylsulfamoyl group, aryl
Sulfamoyl, thiol and alkylthio groups
Having one or more substituents selected from the group consisting of
May be. ), Hydrogen atom, hydroxyl group, alkoxy
A sil group or -R⁷⁴-R⁸Means R⁸Is an alkylsulfonyl group, an arylsulfonyl group,
Means a monocyclic nitrogen-containing heterocyclic group or cycloalkyl group
Then R⁸(Alkylsulfonyl group and arylsulfo
Excludes the case of a nyl group. ), R⁷²(Except for single bond)
Good. ) And R⁷⁴(Except for single bond)
As a substituent, an alkyl group (halogen atom, hydro
Xyl group, amino group, alkylamino group, trialkyl
Ammonio group, cyano group, ureide group, alkyl urea
Groups, amidino groups, guanidino groups, alkoxyl groups,
Droxyalkoxyl group, alkoxylalkoxyl
Group, aminoalkoxyl group, hydroxyalkylamino
Group, aminoalkylamino group, carboxyl group, carba
Moyl group, sulfamoyl group, alkylsulfamoyl
Group, arylsulfamoyl group, thiol group and
One or more substituents selected from the group consisting of
You may have two or more. ), Halogen atom, hydroxy
Sil group, amino group, alkylamino group, trialkyl group
Ammonium, cyano, ureido, alkylureido
Group, amidino group, guanidino group, alkoxyl group, hydrid
Roxyalkoxyl group, alkoxylalkoxyl group,
Aminoalkoxyl group, hydroxyalkylamino group,
Aminoalkylamino group, carboxyl group, carbamoy
, A sulfamoyl group, an alkylsulfamoyl group,
Arylsulfamoyl group, thiol group and alkyl
One or more substituents selected from the group consisting of thio groups
You may have one. ] Group -R⁸¹-R⁸²-R⁹  [R⁸¹Represents a single bond or an alkylene group having 1 to 3 carbon atoms
Means R⁸²Represents an oxygen atom or a sulfur atom;⁸¹(Excluding the case of a single bond) is an alkyl
Group (halogen atom, hydroxyl group, amino group,
Killamino group, trialkylammonio group, cyano group,
Ureido group, alkyl ureide group, amidino group, guani
Dino group, alkoxyl group, hydroxyalkoxyl group,
Alkoxyl alkoxyl group, amino alkoxyl group,
Hydroxyalkylamino group, aminoalkylamino
Group, carboxyl group, carbamoyl group, sulfamoyl
Group, alkylsulfamoyl group, arylsulfamoy
From the group consisting of thiol, thiol and alkylthio groups
May have one or more substituents selected
No. ), Halogen atom, hydroxyl group, amino group,
Alkylamino group, trialkylammonio group, cyano
Group, ureido group, alkyl ureide group, amidino group,
Anidino group, alkoxyl group, hydroxyalkoxyl
Group, alkoxyl alkoxyl group, aminoalkoxyl
Group, hydroxyalkylamino group, aminoalkylamido
Group, carboxyl group, carbamoyl group, sulfamoi
Group, alkylsulfamoyl group, arylsulfamo
Group consisting of yl, thiol and alkylthio groups
May have one or more substituents selected from
No. R⁹Represents an alkyl group having a substituent.
The substituent of the alkyl group is a halogen atom, a hydroxyl group,
Amino group, alkylamino group, trialkylammonio
Group, cyano group, ureido group, alkyl ureide group,
Dino group, guanidino group, alkoxyl group, hydroxya
Lucoxyl group, alkoxyl alkoxyl group, amino group
Lucoxyl group, hydroxyalkylamino group, amino group
Alkylamino group, carboxyl group, carbamoyl group,
Rufamoyl group, alkylsulfamoyl group, aryl
Sulfamoyl, thiol and alkylthio groups
Group selected from the group consisting of
May be further included. Or a group -R⁸¹-NR⁸³-R⁹  [R⁸¹Represents a single bond or an alkylene group having 1 to 3 carbon atoms
Means, R⁸¹(Excluding the case of a single bond) is an alkyl
Group (halogen atom, hydroxyl group, amino group,
Killamino group, trialkylammonio group, cyano group,
Ureido group, alkyl ureide group, amidino group, guani
Dino group, alkoxyl group, hydroxyalkoxyl group,
Alkoxyl alkoxyl group, amino alkoxyl group,
Hydroxyalkylamino group, aminoalkylamino
Group, carboxyl group, carbamoyl group, sulfamoyl
Group, alkylsulfamoyl group, arylsulfamoy
From the group consisting of thiol, thiol and alkylthio groups
May have one or more substituents selected
No. ), Halogen atom, hydroxyl group, amino group,
Alkylamino group, trialkylammonio group, cyano
Group, ureido group, alkyl ureide group, amidino group,
Anidino group, alkoxyl group, hydroxyalkoxyl
Group, alkoxyl alkoxyl group, aminoalkoxyl
Group, hydroxyalkylamino group, aminoalkylamido
Group, carboxyl group, carbamoyl group, sulfamoi
Group, alkylsulfamoyl group, arylsulfamo
Group consisting of yl, thiol and alkylthio groups
May have one or more substituents selected from
No. R⁸³Is an alkyl group (halogen atom, hydroxyl
Group, amino group, alkylamino group, trialkylammonium
Nio group, cyano group, ureido group, alkyl ureide group,
Amidino group, guanidino group, alkoxyl group, hydroxy
Alkoxyl group, alkoxyl alkoxyl group, amide
Alkoxyl group, hydroxyalkylamino group, amide
Noalkylamino group, carboxyl group, carbamoyl
Group, sulfamoyl group, alkylsulfamoyl group,
Reel sulfamoyl, thiol and alkylthio
One or more substituents selected from the group consisting of
You may have. ), Hydrogen atom, hydroxyl group or
Represents an alkoxyl group, and R⁹Represents an alkyl group having a substituent.
Substituents on the halogen group, a hydroxyl group,
Group, alkylamino group, trialkylammonio group,
Cyano group, ureido group, alkyl ureide group, amidino
Group, guanidino group, alkoxyl group, hydroxyalco
Xyl group, alkoxyl alkoxyl group, amino alcohol
Xyl group, hydroxyalkylamino group, aminoalkyl
Amino group, carboxyl group, carbamoyl group, sulf
Amoyl group, alkylsulfamoyl group, arylsulfo
Famoyl, thiol and alkylthio groups
Group selected from the group
May have one or more (provided that R⁸¹Is a single bond, R
⁸³Is a hydrogen atom, R⁹Is an alkylamino group
H). (B) alkyl group (halogen atom, amino group, alkyl
Amino group, hydroxyl group, alkoxyl group, thiol
Groups or alkylthio groups may be substituted. ), C
Halogen atom, hydroxyl group, alkoxyl group, alcohol
Xylalkoxyl group, amino group, alkylamino group,
Acylamino group, alkylaminoalkylamino group, d
Toro, cyano, carbamoyl, thiol, al
Kirthio group, arylthio group, alkylsulfinyl
Group, arylsulfinyl group, alkylsulfonyl group,
Arylsulfonyl group, aminosulfonyl group, alkyl
Aminosulfonyl group, arylaminosulfonyl group and
And a salt thereof and a salt thereof. 9. The fused tricyclic heterocyclic group represented by G ² is a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or a heterocyclic ring,
9. The compound according to claim 8, which comprises a benzene ring, and a salt thereof. 10. The compound according to any one of claims 3 to 9, wherein G, G ¹ or G ² has, as a free valence, a nitrogen atom of a nitrogen-containing heterocyclic ring constituting a condensed tricyclic heterocyclic ring. Its salt. 11. The compound according to any one of claims 3 to 10, wherein the nitrogen-containing heterocyclic ring constituting the fused tricyclic heterocyclic group of G, G ¹ or G ² has a size of a 6-membered ring. Its salt. 12. The compound according to any one of claims 3 to 11, wherein the nitrogen-containing heterocycle constituting the fused tricyclic heterocyclic group of G, G ¹ or G ² is piperazine, piperidine or tetrahydropyridine. Its salt. 13. The saturated or unsaturated hydrocarbon or heterocyclic ring constituting the fused tricyclic heterocyclic group of G, G ¹ or G ² has a size of 5 to 7 members. The compound according to any one of claims 1 to 4, and a salt thereof. 14. The fused tricyclic heterocyclic ring of G, G ¹ or G ² is (Wherein, X ¹ represents an oxygen atom, a sulfur atom, NH, CH _2, or CＯO. M and n each independently represent 0 or an integer of 1 to 2. ] The partial structure represented by may be an unsaturated ring containing a double bond. The compound according to any one of claims 3 to 13 and a salt thereof. 15. The compound according to any one of claims 3 to 14, wherein Q or Q ¹ is a monocyclic heterocyclic group, and a salt thereof. 16. The monocyclic heterocyclic group represented by Q or Q ¹ is
The compound according to any one of claims 3 to 15, which is a nitrogen-containing heterocyclic group, and a salt thereof. 17. The monocyclic heterocyclic group for Q or Q ¹ is
17. A 3- to 6-membered nitrogen-containing heterocyclic group.
A compound and a salt thereof according to any one of the above. 18. The monocyclic heterocyclic group for Q or Q ¹ is
4. A 5- to 6-membered unsaturated nitrogen-containing heterocyclic group.
18. The compound according to any one of to 17 and a salt thereof. 19. The monocyclic heterocyclic group represented by Q or Q ¹ is
19. The compound according to any one of claims 3 to 18, which is derived from pyridine, piperazine, pyridazine, pyrazine or triazine, and a salt thereof. 20. The compound according to claim 8, wherein Z ¹ is piperazine or piperidine, and a salt thereof. 21. Z ² is a phenyl group, and as a substituent of the phenyl group, an alkyl group (even when a halogen atom, amino group, alkylamino group, hydroxyl group, alkoxyl group, thiol group or alkylthio group is substituted) One) a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group. 9. The compound according to claim 8 or a salt thereof having a plurality thereof. 22. Z ² is a phenyl group, and a substituent of the phenyl group is a halogen atom, a hydroxyl group,
Cyano group and alkyl group (halogen atom, amino group,
Alkylamino group, hydroxyl group, alkoxyl group,
A thiol group or an alkylthio group may be substituted. The same or different groups selected from the group consisting of
9. The compound according to claim 8, which has a salt thereof, and a salt thereof.