JP2002220338A - Cdk4 AND/OR Cdk6 INHIBITOR INCLUDING BIARYLUREA COMPOUND OR ITS SALT AS ACTIVE INGREDIENT - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a Cdk4 and/or Cdk6 inhibitor or the like that is aimed at treating malignant tumor. SOLUTION: This Cdk4 and/or Cdk6 inhibitor includes a compound represented by formula (I) [wherein, Ar is a N-including heteroaromatic; X and Z are each C or the like; Y is CO or the like; R1 is H or the like; R2 and R3 are each H or the like; R4 and R5 are each H or the like ; and a partial structure (...) represents a single or double bond] or its salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a Cdk4 containing a biarylurea derivative or a salt thereof, which is useful as a medicament, which is disubstituted with an aromatic ring or a heteroaromatic ring, as an active ingredient.
And / or use as Cdk6 inhibitors.

[0002]

2. Description of the Related Art The growth of normal cells is characterized by the fact that cell division progressing according to the cell cycle and its arrest occur in an orderly manner, whereas the growth of cancer cells is characterized by being disordered. It is presumed that abnormalities in control mechanisms are directly related to carcinogenesis or malignancy of cancer. The cell cycle of mammalian cells is controlled by cyclin-dependent kinases (hereinafter, referred to as cyclin-dependent kinases).
It is called “Cdk”. ) Is regulated by a serine / threonine kinase called the family, and Cdk needs to form a complex with a regulatory subunit called cyclin in order to express its enzymatic activity. Cyclin also forms a family, and each Cd
The k molecule is thought to control the progress of a specific cell cycle by forming a complex with a limited cyclin molecule that is specifically expressed in the cell cycle. For example, D-type cyclin binds to Cdk4 or Cdk6 and
Cyclin E-Cdk2 controls the progression of the G1 / S boundary, cyclin A-Cdk2 controls the progression of the S phase, and cyclin B-cdc2 controls the progression of G2 / M. In addition, D1, D2,
D3 and three subtypes are known. Furthermore, Cdk
Is active in not only binding to cyclin, but also phosphorylation / dephosphorylation of Cdk molecule, degradation of cyclin molecule and Cd
It is thought to be controlled by binding to k-inhibitory proteins [Advanced Cancer Research (Adva)
nce Cancer Res. 66, 181
-212 (1995); Current Opinion in Cell Biology (Current Opin.
Cell Biol. ), Volume 7, 773-780
Page, (1995); Nature, 374, 131-134, (1995)].

[0003] Cdk-inhibiting proteins in mammalian cells are roughly classified into two types, the Cip / Kip family and the INK4 family, based on differences in structure and properties. The former broadly inhibits the cyclin-Cdk complex, while the latter binds and specifically inhibits Cdk4 and Cdk6. [Nature, Volume 366, 7
04-707, (1993); Molecular and Cellular Biology (Mol. Cell.
Biol. ), Vol. 15, pp. 2627-2681, (1
995); Jeans and Development (Ge
nes Dev. 9), 1149-1163 (1995)]

A typical example of the former is, for example, p21 (Sdi1
/ Cip1 / Waf1), whose RNA transcription is induced by the tumor suppressor gene product p53 [Jeans and Development (Genes De).
v. 9, Vol. 935-944 (1995)].

On the other hand, for example, p16 (INK4a / MTS
1 / CDK4I / CDKN2) is one of the Cdk inhibitory proteins belonging to the latter. The p16 gene is present on human chromosome 9p21, which is frequently found abnormal in human cancer cells, and in fact, many p16 gene deletions have been reported in clinical practice. In addition, it has been reported that the incidence of cancer in p16 knockout mice is high [Nature Genetics.
8, 27-32, (1994); Trends Genet.,
11, 136-140, (1995); Cell, 85, 27-37, (1996).
Year)].

[0006] Each Cdk controls the progress of the cell cycle by phosphorylating a target protein at a specific stage of the cell cycle. Among them, the retinoblastoma (RB) protein is one of the most important target proteins. It is considered one.
The RB protein is a key protein in progressing from the G1 phase to the S phase, and is rapidly phosphorylated from late G1 to early S. The phosphorylation of the cyclin D-Cdk4 / Cdk6 complex followed by cyclin E-
It is believed that the Cdk2 complex is responsible. When the RB protein becomes hyperphosphorylated, the complex previously formed by the hypophosphorylated RB and the transcription factor E2F in the early stage of G1 is dissociated. As a result, E2F becomes a transcriptional activator, and the suppression of the promoter activity by the RB-E2F complex is released, so that E2F-dependent transcription is activated. At present, E2F, RB protein that suppresses it, and Cdk4 / Cd that suppresses the function of RB protein
The Cdk-RB pathway, consisting of k6, a Cdk inhibitory protein that regulates their kinase activity and D-type cyclins, is regarded as an important mechanism controlling the progression from G1 phase to S phase [Cell, No. 58 volumes, 109
7-1105, (1989); Cell,
65, 1053-1061, (1991); Oncogene, 7, 1067-.
1074, (1992); Current opinion.
In Cell Biology (Current Opi
n. Cell Biol. ), Vol. 8, 805-81
4, (1996); Molecular and Cellular Biology (Mol. Cell. Bio).
l. 18), 753-761, (1998).
Year)]. Actually, the binding DNA sequence of E2F exists upstream of many cell growth-related genes important in, for example, the S phase, and among these, transcription is activated from late G1 to early S by E2F in a plurality of genes. [EMBO J. (EMBO J.),
9, pp. 2179-2184 (1990); Molecular and Cellular Biology (Mol.
Cell. Biol. ), Volume 13, 1610-1
618, (1993)].

[0007] Abnormality of any factor constituting the Cdk-RB pathway, such as deletion of functional p16 or cyclin D1
High expression, high Cdk4 expression and deletion of functional RB protein are frequently detected in human cancers [Science, vol. 254, 1138-114].
6, (1991); Cancer Research (Can)
cer Res. ), Vol. 53, 5535-5541
Page, (1993); Current Opinion in Cell Biology (Current Opin. Cel).
l Biol. 8, pp. 805-814, (19)
1996)]. These are all abnormalities in the direction of promoting the progression from the G1 phase to the S phase, and it is clear that this pathway plays an important role in canceration or abnormal proliferation of cancer cells.

As a known compound having a Cdk family inhibitory action, for example, a series of chromone derivatives represented by flavopiridol (flavopyridol) are known. (WO 97/1647, 98/133
44).

As prior arts which are structurally similar to the compounds of the present invention, for example, WO96 / 25157 (Reference A), WO97 / 29743 (Reference B), US Pat. No. 5,696,138 (Reference C) and JP 2
-115176 (Reference D).

In Reference A and Reference B, the aryl group is N-
And N′-substituted urea or thiourea derivatives are disclosed. However, since the aryl groups described in References A and B and the nitrogen-containing heteroaromatic group of the present invention have completely different chemical structures, the compounds described in References A and B are not directly related to the present invention. It can be said that the compound is not related to. Furthermore, the use of the compounds described in References A and B relates to chemokine receptor antagonists, and is intended as a therapeutic agent for diseases such as psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, and Alzheimer's disease. It is completely unrelated to the use of the present invention.

Reference C discloses urea or thiourea derivatives having an aromatic ring group which may have one nitrogen atom and a benzene ring group which may be condensed. However, the main compound of the invention of Reference C is a urea derivative in which two phenyl groups are N- and N′-substituted, and slightly described in column 3 (line 11, line 13, and line 26).
Line), column 5 (lines 17 and 19), column 7 (lines 13 and 15), column 17 (lines 24 and 42), In column 20 (the 14th line from the bottom), etc., only three types of urea compounds having a pyridyl group N′-substituted are described, which are common in any place. The N-substituents of the urea compound are all phenyl groups, and have a completely different chemical structure from the compound of the present invention. In the compound of Reference C, when the N-substituent is a condensed benzene ring, the condensed portion may be saturated or unsaturated, but the substituent of the condensed ring portion is not mentioned. However, it is understood that the fused benzene ring is an unsubstituted condensed ring (the present invention has an oxo group). Further, as far as the specific disclosure of Reference C is concerned, the disclosed example of the condensed benzene ring is limited to a naphthyl group. Thus, it can be said that the compound of Reference C has a different chemical structure from the compound of the present invention, and the two inventions are not directly related.

Further, the use of the compounds described in Reference C is
As described in Column 16, the present invention relates to a potassium channelenenel activator, for example, a therapeutic agent for diseases against potassium channel-dependent convulsions, asthma, ischemia, etc. Is completely unrelated.

Reference D discloses a urea compound in which the triazine group is N-substituted and the 9-fluorenone group is N'-substituted in Example 7.

However, the invention of Reference D relates to a radiation-sensitive composition, that is, an invention relating to a photosensitizer, which is an invention which is completely different from the present invention in the technical field to which the invention belongs. No analogous compounds are mentioned. The reason is that the compound of Reference D has a triazine nucleus as a basic skeleton, and a photoinitiating moiety employs a dozen or more types of substituents including a fluorenone group, and as a group connecting the photoinitiating moiety to the triazine nucleus, This is because a group of compounds having various structures is exemplified by the relationship in which ten or more combinations of linking groups including urea are listed. Therefore, the compound of the present invention and the use of the present invention cannot be conceived at all based on the description in Reference D including the compound of Example 7,
Reference D can be said to be an invention not directly related to the present invention.

Therefore, the present invention is an invention relating to a novel compound and a novel use which are not described in the literature, and cannot be easily achieved based on the above-mentioned References A to D.

[0016] At present, Cdk6 inhibitors are not specifically known.

[0017]

As described above, Cd
Compounds having k-family inhibitory activity include chromone derivatives, but the inhibitory activity of these compounds on Cdk4 is not sufficient, and the compounds have a higher inhibitory activity, and further have a heterogeneous inhibitory activity on, for example, Cdk6 and the like. Cd containing a new compound as an active ingredient
There is a need for k4 and / or Cdk6 inhibitors.

[0018]

SUMMARY OF THE INVENTION The present inventors have developed an excellent C
As a result of intensive studies aimed at providing a compound having a dk4 inhibitory action or a Cdk6 inhibitory action, a novel compound having a biaryl urea skeleton was found to have Cdk4 and / or
Alternatively, they have found that they exhibit Cdk6 inhibitory action, and thus completed the present invention.

The present invention relates to a compound of the formula (I)

[0020]

Embedded image [Wherein, Ar represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, isoquinolyl] A nitrogen-containing heteroaromatic group selected from the group consisting of a benzothiazolyl group and a benzooxazolyl group, wherein (1) a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group,
Carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl Group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group,
Lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl ammonium lower alkyl group, lower alkanoylamino A substituent selected from the group consisting of a group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a formula: Y ₁ -W ₁ -Y ₂ -R _p (wherein R _p is a lower alkyl group, a lower alkenyl group or a lower alkynyl group or a substituted group thereof, which may have 1 to 3 hydrogen atoms or 1 to 3 substituents as appropriate) 1 to 3 groups as appropriate,

[0021]

Embedded image A cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of Group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group,
Selected from the group consisting of benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl. Aromatic heterocyclic group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
An aliphatic heterocyclic group selected from the group consisting of a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₁ is a single bond, an oxygen atom, a sulfur atom,
O, SO _{2 ,} NR _q , SO ₂ NR _q , N (R _q ) SO ₂ NR _r ,
_{N (R q) SO 2,} CH (OR q), CONR q, N
_{(R q) CO, N (} R q) CONR r, N (R q) COO,
N ( _Rq ) CSO, N ( _Rq ) COS, C ( _Rq ) = C
R _r , C≡C, CO, CS, OC (O), OC (O) N
R _q , OC (S) NR _q , SC (O), SC (O) NR _q
Or C (O) O (where R _q and R _r represent a hydrogen atom or a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower group) Alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group, or A lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 substituents as appropriate), Y
₁ and Y ₂ are the same or different and represent a single bond or a linear or branched lower alkylene group which may have one bicyclic or tricyclic fused ring) A substituent selected from the group consisting of the substituents shown, and optionally having 1 to 3 identical or different substituents, a nitrogen-containing heteroaromatic group, (2) a lower alkyl group, a lower Alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxy Carbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group , A tri-lower alkylammonio lower alkyl group,
A substituent selected from the group consisting of a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group and a lower alkanoylamidino lower alkyl group (hereinafter abbreviated as an on-ring substituent); Together with the carbon atom on the ring to which it is attached, its adjacent carbon atoms and the carbon, oxygen and / or nitrogen atoms on said ring substituents,

[0022]

Embedded image Or a nitrogen-containing heteroaromatic group forming a 5- to 7-membered ring selected from the group consisting of: or (3) Y ₁ -W ₁ -Y ₂ -R _p
Wherein Y ₁ , W ₁ , Y ₂ and R _p have the above-mentioned meaning.
Together with the carbon atom on the ring to which the substituent represented by bonds, the adjacent carbon atom and the carbon atom, oxygen atom and / or nitrogen atom on the substituent,

[0023]

Embedded image The nitrogen-containing heteroaromatic ring group forming a 5- to 7-membered ring selected from the group consisting of, X and Z are the same or different,
Represents a carbon atom or a nitrogen atom, or binds as appropriate;
Together with R ₁ or R ₂ and / or R ₃ , CH or a nitrogen atom, Y is CO, SO or SO ₂ , R ₁ is a hydrogen atom or a formula: Y ₃ —W ₂ —Y ₄ —R _s (where R _s is
A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoquinolyl group which may have 1 to 3 hydrogen atoms or the above substituents as appropriate. , Indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group,
Dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group, furyl group, Furananyl group, triazolyl group, benzodioxanyl group, methylenedioxyphenyl group, aromatic heterocyclic group selected from the group consisting of methylenedioxyphenyl group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group , piperazinyl group, a piperidinyl group, pyrrolidinyl group, pyrrolinyl group, a morpholino group, an aliphatic heterocyclic group selected from the group consisting tetrahydroquinolinyl group and tetrahydroisoquinolinyl group, W ₂ is a single bond Oxygen atom, a sulfur atom, SO, S
_{O 2, NR t, SO 2} NR t, N (R t) SO 2 NR u, N
(R _t ) SO ₂ , CH (OR _t ), CONR _t , N (R _t )
CO, N (R _t ) CONR _u , N (R _t ) COO, N
_{(R t) CSO, N (} R t) COS, C (R v) = CR r,
C≡C, CO, CS, OC (O), OC (O) NR _t ,
OC (S) NR _t , SC (O), SC (O) NR _t or C
(O) O (wherein, R _t and R _u is a hydrogen atom or a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group A hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group,
Carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di Lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl group Ammonio lower alkyl group, lower alkanoylamino group,
A substituent selected from the group consisting of an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or 1 to 3 Or 3 or less, which represents a lower alkyl group, an aryl group or an aralkyl group), Y ₃ and Y ₄ are the same or different and are each a single bond or a linear or branched lower alkylene group. Or a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group Group, halo lower alkyl group, carboxy lower alkyl A kill group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group; : Y ₃ -W ₂ -Y ₄ -R _s (where R _s , W ₂ , Y ₃ and Y ₄
Is a substituent selected from the group consisting of the substituents represented by the above), and is a lower alkyl group optionally having 1 to 3 identical or different substituents, or Or a nitrogen atom is formed together with X, and R ₂ and R ₃ are the same or different and are independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a formula: Y
A substituent represented by _3- W ₂ -Y ₄ -R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the same meaning as described above), or any of R ₂ and R ₃ One forms together with R ₁ and X,

[0024]

Embedded image And

[0025]

Embedded image And a saturated 5- or 8-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, a carbon atom or an oxygen atom contained in a ring substituent on the ring. And / or forms a 5- to 7-membered ring with a nitrogen atom, or together forms a spirocyclo lower alkyl group, an oxo group with a bonding Z, or a nitrogen atom with a bonding Z, R ₁ and X May include one or more hetero atoms selected from the group consisting of oxygen and sulfur atoms, a lower alkyl group, a spirocyclo lower alkyl group which may have a substituent,
Hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group,
A carboxy lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group; : Y ₁ -W ₁ -Y ₂ -R _p (wherein, R _p , W ₁ , Y ₁ and Y ₂
Is a substituent selected from the group consisting of the substituents represented by the above), and is suitably 1 to 3 identical or different substituents, and further 1 to 3 identical or different as appropriate Cyclo lower alkyl group which may have a substituent, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group, Benzothiazolyl group Aromatic selected from the group consisting of benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl Heterocyclic group and isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
A morpholino group, which may be condensed with a ring selected from the group consisting of an aliphatic heterocyclic group selected from the group consisting of a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group,

[0026]

Embedded image And

[0027]

Embedded image Forming a saturated or unsaturated 5- to 8-membered ring group selected from the group consisting of: R ₄ and R ₅ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a group represented by the formula: Y ₃ -W _{(wherein, R s, W 2, Y} 3 and Y ₄ are as defined above) ₂ -Y ₄ -R _s substituent group or a lower alkyl group represented by a cyano group, a nitro group, a carboxyl group, Carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower Alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkyl A carbamoyl group, a carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino Lower alkyl group,
Tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino group and lower alkoxyimino group A substituent selected from the group and the formula: Y ₃
—W ₂ —Y ₄ —R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the meaning described above), and are appropriately selected from the group consisting of A lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 same or different substituents,

[0028]

Embedded image Represents a single bond or a double bond], or a salt thereof as an active ingredient, as a Cdk4 and / or Cdk6 inhibitor.

Next, the symbols and terms described in this specification will be described.

The term "nitrogen-containing heteroaromatic group" refers to an aromatic ring group having at least one nitrogen atom. In addition to the above-mentioned nitrogen atom, one nitrogen atom selected from the group consisting of an oxygen atom and a sulfur atom
Indicates an aromatic ring group having one or more heteroatoms.
Specifically, for example, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyrazolyl group, pyrrolyl group, imidazolyl group, indolyl group, isoindolyl group, quinolyl group, isoquinolyl group And a benzothiazolyl group or a benzoxazolyl group, among which, for example, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, a pyrazolyl group, or an imidazolyl group are preferable, and a pyridyl group or a pyrazolyl group is particularly preferable. .

The lower alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl group, t
Examples thereof include an tert-butyl group, a butyl group, a pentyl group, and a hexyl group. Among them, for example, a methyl group, an ethyl group, and a butyl group are preferable.

The halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and among them, a fluorine atom, a chlorine atom and the like are preferable.

As the lower alkanoyl group, a group in which a carbonyl group is substituted by an alkyl group having 1 to 5 carbon atoms is preferable. Specifically, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl Groups, a pivaloyl group, a pentanoyl group and the like. Among them, for example, an acetyl group, a propionyl group, a pivaloyl group and the like are preferable.

The lower alkanoyloxy group means a group in which the above-mentioned lower alkanoyl group is substituted for an oxygen atom, and specifically, for example, an acetoxy group, a propionyloxy group,
Butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group,
Examples thereof include a pentanoyloxy group, and among them, for example, an acetoxy group, a propionyloxy group, a pivaloyloxy group, and the like are preferable.

The hydroxy lower alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted by a hydroxyl group. Specific examples include a hydroxymethyl group, a dihydroxymethyl group, a trihydroxymethyl group and a 1-hydroxyethyl group. Group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-2-methylethyl group, 1-hydroxybutyl group, 1-hydroxy-2-
Methylpropyl group, 1-hydroxy-2,2-dimethylethyl group, 1-hydroxypentyl group, 1-hydroxy-2-methylbutyl group, 1-hydroxyhexyl group, 1
And a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, and a 1-hydroxy-2-methylethyl group.

As the cyano lower alkyl group, an alkyl group having 1 to 6 carbon atoms and the like, which is substituted by a cyano group, is preferred. Propyl group, 2-cyanopropyl group, 3-cyanopropyl group, 1
-Cyano-2-methylethyl group, 1-cyanobutyl group,
1-cyano-2-methylpropyl group, 1-cyano-2,
2-dimethylethyl group, 1-cyanopentyl group, 1-cyano-2-methylbutyl group, 1-cyanohexyl group, 1
And a cyanomethyl group, a 1-cyanoethyl group, a 2-cyanosiethyl group, and a 1-cyano-2-methylethyl group.

The halo-lower alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted by a halogen atom, and specifically, for example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, a iodomethyl group, a difluoromethyl group Group, dichloromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1
-Chloroethyl group, 2-chloroethyl group, 1-chloropropyl group, 2-chloropropyl group, 1-fluoro-2-
Methylethyl group, 1-chloro-2-methylethyl group, 1
-Chlorobutyl group, 1-chloro-2-methylpropyl group, 1-chloro-2,2-dimethylethyl group, 1-chloropentyl group, 1-chloro-2-methylbutyl group, 1-
Examples thereof include a chlorohexyl group and a 1-chloro-2-methylpentyl group. Among them, for example, chloromethyl group, trifluoromethyl group, 1-fluoroethyl group, 1-chloroethyl group, 1-chloro-2-methylethyl group and the like Is preferred.

As the carboxy lower alkyl group, an alkyl group having 1 to 6 carbon atoms and the like substituted by a carboxy group and the like are preferable. 1-carboxypropyl group, 2-carboxypropyl group, 3-carboxypropyl group, 1-carboxy-2
-Methylethyl group, 1-carboxybutyl group, 1-carboxy-2-methylpropyl group, 1-carboxy-2,
2-dimethylethyl group, 1-carboxypentyl group, 1
-Carboxy-2-methylbutyl group, 1-carboxyhexyl group, 1-carboxy-2-methylpentyl group and the like. Among them, carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group, 1-carboxy- A 2-methylethyl group is preferred.

The carbamoyl lower alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted by a carbamoyl group, and specifically, for example, a carbamoylmethyl group, a 1-carbamoylethyl group, a 2-carbamoylethyl group, 1-carbamoylpropyl group, 2-carbamoylpropyl group, 3-carbamoylpropyl group, 1-
A carbamoyl-2-methylethyl group, a 1-carbamoylbutyl group, a 1-carbamoyl-2-methylpropyl group,
1-carbamoyl-2,2-dimethylethyl group, 1-carbamoylpentyl group, 1-carbamoyl-2-methylbutyl group, 1-carbamoylhexyl group, 1-carbamoyl-2-methylpentyl group and the like. Among them, for example, carbamoyl Methyl group, 1-carbamoylethyl group,
A 2-carbamoylethyl group, a 1-carbamoyl-2-methylethyl group and the like are preferable.

The lower alkoxy group is preferably a group in which an oxygen atom is substituted by an alkyl group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, and the like.
Propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, neopentyloxy group, hexyloxy group, isohexyloxy group, and the like. An ethoxy group, an isopropyloxy group, a tert-butoxy group and the like are preferable.

The term "lower alkoxycarbonyl group" means a group in which a carbonyl group is substituted by the above-mentioned lower alkoxy group. Group, isobutoxycarbonyl group, sec-butoxycarbonyl group, ter
t-butoxycarbonyl group, pentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, isohexyloxycarbonyl group and the like, among which methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group, te
An rt-butoxycarbonyl group and the like are preferred.

The term "lower alkylcarbamoyl group" means a substituent in which the above lower alkyl group is N-substituted on a carbamoyl group, such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,
Isopropylcarbamoyl group, N-butylcarbamoyl group, N-isobutylcarbamoyl group, N-tert-butylcarbamoyl group, N-pentylcarbamoyl group, N
-Hexylcarbamoyl group and the like. Among them, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-butylcarbamoyl group and the like are preferable.

The term "di-lower alkylcarbamoyl group" means a substituent in which the above lower alkyl group is N, N-disubstituted on a carbamoyl group, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, , N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group, N, N-diisobutylcarbamoyl group, N, N-ditert-butylcarbamoyl group, N, N-dipentylcarbamoyl group , N, N-dihexylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-methyl-N-propylcarbamoyl group and the like.
Dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dibutylcarbamoyl group, N-ethyl-
N-methylcarbamoyl, N-methyl-N-propylcarbamoyl and the like are preferred.

The lower alkylcarbamoyloxy group is
A substituent in which the above-mentioned lower alkylcarbamoyl group is substituted by an oxygen atom, for example, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-propylcarbamoyloxy group, N-isopropylcarbamoyloxy group, N-butylcarbamoyloxy Group, N-isobutylcarbamoyloxy group, N-tert-butylcarbamoyloxy group, N-pentylcarbamoyloxy group, N-hexylcarbamoyloxy group, and the like,
Among them, for example, N-methylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-butylcarbamoyloxy group and the like are preferable.

The term "di-lower alkylcarbamoyloxy group" refers to a substituent in which the above-mentioned di-lower alkylcarbamoyloxy group is substituted by an oxygen atom, for example, N, N-dimethylcarbamoyloxy group, N, N-diethylcarbamoyloxy group, N, N N-dipropylcarbamoyloxy group, N, N
-Diisopropylcarbamoyloxy group, N, N-dibutylcarbamoyloxy group, N, N-diisobutylcarbamoyloxy group, N, N-ditert-butylcarbamoyloxy group, N, N-dipentylcarbamoyloxy group, N, N-dihexyl Carbamoyloxy group, N
-Ethyl-N-methylcarbamoyloxy group, N-methyl-N-propylcarbamoyloxy group and the like,
Among them, for example, an N, N-dimethylcarbamoyloxy group,
N, N-diethylcarbamoyloxy, N, N-dibutylcarbamoyloxy, N-ethyl-N-methylcarbamoyloxy, N-methyl-N-propylcarbamoyloxy and the like are preferred.

The term "lower alkylamino group" means a substituent in which the above-mentioned lower alkyl group is N-substituted on an amino group, such as N-methylamino group, N-ethylamino group, N-propylamino group, N-isopropyl. Amino group, N-butylamino group, N-isobutylamino group, N-tert-butylamino group, N-pentylamino group, N-hexylamino group and the like. Among them, for example, N-methylamino group, N-ethyl Amino groups and N-butylamino groups are preferred.

The term "di-lower alkylamino group" means a substituent in which the above lower alkyl group is N, N-disubstituted on an amino group, such as N, N-dimethylamino group, N, N-diethylamino group, N, N-diethylamino group. N-dipropylamino group, N, N-diisopropylamino group, N, N-dibutylamino group,
N, N-diisobutylamino group, N, N-ditert-
Butylamino group, N, N-dipentylamino group, N, N
-Dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group and the like,
Among them, for example, N, N-dimethylamino group, N, N-diethylamino group, N, N-dibutylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group and the like are preferable.

The term "tri-lower alkylammonio group" refers to a substituent in which the above lower alkyl group is N, N, N-trisubstituted on the amino group, such as N, N, N-trimethylammonio group, N, N , N-triethylammonio group, N, N,
N-tripropylammonio group, N, N, N-triisopropylammonio group, N, N, N-tributylammonio group, N, N, N-triisobutylammonio group,
N, N, N-tritert-butylammonio group, N,
N, N-tripentylammonio group, N, N, N-trihexylammonio group, N-ethyl-N, N-dimethylammonio group, N, N-dimethyl-N-propylammonio group, etc. And an N, N, N-trimethylammonio group, N, N, N-triethylammonio group, N, N, N-tributylammonio group, N-ethyl-N, N-dimethylammonio group. , N, N-dimethyl-N-propylammonio and the like are preferred.

As the amino lower alkyl group, an alkyl group having 1 to 6 carbon atoms substituted by an amino group and the like are preferable. Specific examples thereof include an aminomethyl group, a diaminomethyl group, a triaminomethyl group and a 1-amino group. Ethyl group,
2-aminoethyl group, 1-aminopropyl group, 2-aminopropyl group, 3-aminopropyl group, 1-amino-2
-Methylethyl group, 1-aminobutyl group, 1-amino-
2-methylpropyl group, 1-amino-2,2-dimethylethyl group, 1-aminocypentyl group, 1-amino-2-
Methylbutyl group, 1-aminohexyl group, 1-amino-
Examples thereof include a 2-methylpentyl group, and among them, for example, an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 1-amino-2-methylethyl group, and the like are preferable.

The lower alkylamino lower alkyl group is
A lower alkyl group is a substituent in which the above lower alkylamino group is substituted, for example, N-methylaminomethyl group, N
-Ethylaminomethyl group, N-propylaminomethyl group, N-isopropylaminomethyl group, N-butylaminomethyl group, N-isobutylaminomethyl group, N-te
rt-butylaminomethyl group, N-pentylaminomethyl group, N-hexylaminomethyl group and the like, among which N-methylaminomethyl group, N-ethylaminomethyl group, N-butylaminomethyl group and the like are preferable. It is.

The term "di-lower alkylamino lower alkyl group" means a substituent in which a lower alkyl group is substituted by the above-mentioned di-lower alkylamino group, such as N, N-dimethylaminomethyl group, N, N-diethylaminomethyl group, N, N-
Dipropylaminomethyl group, N, N-diisopropylaminomethyl group, N, N-dibutylaminomethyl group,
N-diisobutylaminomethyl group, N, N-ditert
-Butylaminomethyl group, N, N-dipentylaminomethyl group, N, N-dihexylaminomethyl group, N-ethyl-N-methylaminomethyl group, N-methyl-N-propylaminomethyl group, and the like, Among them, for example, N, N
-Dimethylaminomethyl, N, N-diethylaminomethyl, N, N-dibutylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl and the like are preferred.

The term "tri-lower alkylammonio lower alkyl group" means a substituent in which a lower alkyl group is substituted by the above-mentioned tri-lower alkylammonio group. For example, N, N, N-
Trimethylammoniomethyl group, N, N, N-triethylammoniomethyl group, N, N, N-tripropylammoniomethyl group, N, N, N-triisopropylammoniomethyl group, N, N, N- Tributylammoniomethyl group, N, N, N-triisobutylammoniomethyl group, N, N, N-tritert-butylammoniomethyl group, N, N, N-tripentylammoniomethyl group,
N, N, N-trihexylammoniomethyl group, N-ethyl-N, N-dimethylammoniomethyl group, N, N-
And a dimethyl-N-propylammoniomethyl group.
N, N, N-tributylammoniomethyl, N-ethyl-N, N-dimethylammoniomethyl, N, N-dimethyl-N-propylammoniomethyl and the like are preferred.

The lower alkanoylamino group is a substituent in which the above-mentioned lower alkanoyl group is substituted on an amino group,
Examples thereof include an N-acetylamino group, an N-propionylamino group, an N-butyrylamino group and the like. Among them, for example, an N-acetylamino group and an N-propionylamino group are preferable.

The lower aroylamino group is a substituent in which an amino group is substituted with an aroyl group, and examples thereof include N-benzoylamino group and N-naphthylcarbonylamino group. It is.

The lower alkanoylamidino lower alkyl group refers to a substituent in which the above lower alkanoyl group is substituted for the amidino lower alkyl group, for example, N-acetylamidinomethyl group, N-propionylamidinomethyl group,
-Butyrylamidinomethyl group and the like, and among them, for example, N-acetylamidinomethyl group, N-propionylamidinomethyl group and the like are preferable.

The lower alkylsulfinyl group means a sulfinyl group substituted by the above lower alkyl group,
Examples thereof include an N-methylsulfinyl group, an N-ethylsulfinyl group, an N-butylsulfinyl group and the like. Among them, for example, an N-methylsulfinyl group and an N-ethylsulfinyl group are preferable.

The lower alkylsulfonyl group is a group in which a sulfonyl group is substituted by the above-mentioned lower alkyl group.
-Butylsulfonyl group and the like.
A methylsulfonyl group, an N-ethylsulfonyl group and the like are preferred.

The term "lower alkylsulfonylamino group" means a substituent in which the above-mentioned lower alkylsulfonyl group is N-substituted on an amino group. Amino groups and the like are mentioned, and among them, for example, N-methylsulfonylamino group, N-ethylsulfonylamino group and the like are preferable.

The lower alkoxyimino group is a substituent in which the above-mentioned lower alkoxy group is substituted on the imino group, and examples thereof include a methoxyimino group, an ethoxyimino group, and a propoxyimino group.
An ethoxyimino group is preferred.

The lower alkenyl group is preferably a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, A 3-butenyl group,
1,3-butanedienyl group, 2-pentenyl group, 4-pentenyl group, 1-hexenyl group, 3-hexenyl group, 5
-Hexenyl group and the like. Among them, for example, 1-propenyl group, allyl group, isopropenyl group, 1-butenyl group and the like are preferable.

The lower alkynyl group is preferably a linear or branched alkynyl group having 2 to 6 carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and the like. Among them, for example, a 2-propynyl group, a 2-butynyl group and the like are preferable.

The cyclo-lower alkyl group may have 3 carbon atoms.
To 10 monocyclic or bicyclic alkyl groups and the like are preferable, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group,
Examples thereof include a cyclooctyl group, and among them, for example, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like are preferable.

The aryl group includes C 6 to C 15
Aryl groups are preferred, for example, a phenyl group,
Examples include a naphthyl group and the like, among which a phenyl group and the like are preferable.

Examples of the aromatic heterocyclic group include imidazolyl, isoxazolyl, isoquinolyl, isoindolyl, indazolyl, indolyl, indolizinyl, isothiazolyl, ethylenedioxyphenyl, oxazolyl, pyridyl, pyrazinyl and the like. , Pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group,
Dihydroindolyl, thionaphthenyl, naphthyridinyl, phenazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, Frazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group and the like are preferable. Pyrazolyl, quinolyl, benzimidazolyl, thiazolyl, thienyl and the like are preferred, and pyridyl and pyrazolyl are particularly preferred.

The term "aliphatic heterocyclic group" means an aliphatic heterocyclic group which is a monocyclic ring or a condensed ring composed of two or three rings, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group. It may be a group. Specifically, for example, isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl group Preferred are, for example, isoxazolinyl, isoxazolidinyl, tetrahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholino, and the like. Tetrahydroisoquinolinyl group and the like are preferable, particularly isoxazolinyl group, tetrahydropyridyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, morpholino group, tetrahydroisoquinolinyl group and the like. More preferable.

The aralkyl group is preferably an aralkyl group having 7 to 15 carbon atoms, such as benzyl, α-methylbenzyl, phenethyl and 3
-Phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, α-methyl (1-naphthyl) methyl group, α-methyl (2-naphthyl) methyl group, α-ethyl (1-naphthyl) methyl group, Examples include an α-ethyl (2-naphthyl) methyl group, a diphenylmethyl group, a dinaphthylmethyl group, and the like, and particularly preferably a benzyl group, an α-methylbenzyl group, a phenethyl group, and the like.

The linear or branched lower alkylene group is preferably an alkylene group having 1 to 6 carbon atoms.
Specific examples include a methylene group, an ethylene group, a propylene group, a tetramethylene group, a dimethylmethylene group, a diethylmethylene group, and the like.

The spirocyclo-lower alkyl group is preferably an alkyl group forming a spiro ring having 3 to 6 carbon atoms, such as a spirocyclopropyl group, a spirocyclobutyl group, a spirocyclopentyl group and a spirocyclohexyl group. Among them, for example, a spirocyclopentyl group and a spirocyclohexyl group are preferable.

Ar represents a pyridyl group, a pyrimidinyl group,
Pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl,
A nitrogen-containing heteroaromatic group selected from the group consisting of a benzothiazolyl group and a benzooxazolyl group is shown. Particularly, for example, a pyridyl group and a pyrazolyl group are more preferable.

The nitrogen-containing heteroaromatic group includes (1) lower alkyl, hydroxyl, cyano, halogen, nitro, carboxyl, carbamoyl, formyl, lower alkanoyl, lower alkanoyloxy, and hydroxy lower. Alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkyl carbamoyl group, di-lower alkyl carbamoyl group, carbamoyloxy group, lower alkyl carbamoyl Oxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower-alkylamino lower-alkyl group, di-lower alkyl Mino lower alkyl group, tri lower alkyl ammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino group and lower A substituent selected from the group consisting of an alkoxyimino group and the formula: Y ₁ -W ₁ -Y
_2- R _p (wherein, R _p is a hydrogen atom or the substituent
And optionally 1 to 3 lower alkyl groups, lower alkenyl groups or lower alkynyl groups or said substituents,

[0071]

Embedded image A cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of Group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group,
Selected from the group consisting of benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl. Aromatic heterocyclic group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
An aliphatic heterocyclic group selected from the group consisting of a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₁ is a single bond, an oxygen atom, a sulfur atom,
O, SO _{2 ,} NR _q , SO ₂ NR _q , N (R _q ) SO ₂ NR _r ,
_{N (R q) SO 2,} CH (OR q), CONR q, N
_{(R q) CO, N (} R q) CONR r, N (R q) COO,
N ( _Rq ) CSO, N ( _Rq ) COS, C ( _Rq ) = C
R _r , C≡C, CO, CS, OC (O), OC (O) N
R _q , OC (S) NR _q , SC (O), SC (O) NR _q
Or C (O) O (where R _q and R _r represent a hydrogen atom or a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower group) Alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group, or A lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 substituents as appropriate), Y
₁ and Y ₂ are the same or different and represent a single bond or a linear or branched lower alkylene group which may have one bicyclic or tricyclic fused ring) A substituent selected from the group consisting of the substituents shown, which may have 1 to 3 identical or different substituents, and (2) a lower alkyl group, a lower alkanoyl group, a lower alkanoyloxy Group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkyl carbamoyl group, di-lower alkyl carbamoyl group, carbamoyloxy group A lower alkylcarbamoyloxy group, a lower alkylcarbamoyloxy group, a lower alkylamino group, Alkylamino group, a tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, a di-lower alkylamino-lower alkyl group, a tri-lower alkylammonio lower alkyl group,
A substituent selected from the group consisting of a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group and a lower alkanoylamidino lower alkyl group (hereinafter abbreviated as an on-ring substituent); Together with the carbon atom on the ring to which it is attached, its adjacent carbon atoms and the carbon, oxygen and / or nitrogen atoms on said ring substituents,

[0072]

Embedded image A 5- or 7-membered ring selected from the group consisting of: (3) Formula: Y ₁ -W ₁ -Y ₂ -R _p (where Y is
₁ , W ₁ , Y ₂ and R _p have the above-mentioned meanings), the carbon atom on the ring to which the substituent is bonded, the carbon atom adjacent thereto, and the carbon atom, oxygen atom and / or Or together with the nitrogen atom,

[0073]

Embedded image A 5- to 7-membered ring selected from the group consisting of

Here, the form of the substituent (1) will be described in detail. Specific examples of the substituent include (1-1) a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group and a carboxyl group. A carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, Lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino Lower alkyl Lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, A substituent selected from the group consisting of a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a formula (1-2): Y
_1- W ₁ -Y ₂ -R _p (wherein, R _p is a hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group or a cyclo lower alkyl group, an aryl group, an aromatic heterocyclic group or an aliphatic hetero group) A ring group, W ₁ is a single bond, an oxygen atom, a sulfur atom, SO, SO _{2 ,} NR _q , SO ₂ NR _q , N
_{(R q) SO 2 NR r} , N (R q) SO 2, CH (OR q),
CONR _q , N (R _q ) CO, N (R _q ) CONR _r , N
( _Rq ) COO, N ( _Rq ) CSO, N ( _Rq ) COS,
C (R _q ) = CR _r , C≡C, CO, CS, OC (O),
OC (O) NR _q , OC (S) NR _q , SC (O), SC
(O) NR _q or C (O) O (where R _q and R
_r represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group optionally having 1 to 3 substituents), Y ₁ and Y ₂ are the same or different and are a single bond or A linear or branched lower alkylene group which may have one bicyclic or tricyclic condensed ring, or a substituent selected from the group consisting of And one to three identical or different substituents can be substituted on the nitrogen-containing heteroaromatic group as appropriate.

In (1-1), suitable substituents are, for example, lower alkyl, hydroxyl, halogen, formyl, lower alkanoyloxy, hydroxy lower alkyl, halo lower alkyl, carbamoyl lower alkyl, lower An alkoxy group, a lower alkoxycarbonyl group,
Lower alkylcarbamoyl group, lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, lower alkanoylamino group, Aroylamino group, lower alkylsulfonylamino group and the like, particularly, for example, a hydroxyl group, a halogen atom, a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group,
A lower alkoxycarbonyl group, an amino group, a lower alkylamino lower alkyl group and the like are more preferable.

[0076] Formula (1-2): In _{Y 1 -W 1 -Y 2 -R p} , R p is lower alkyl, lower alkenyl or lower alkynyl group or a lower cycloalkyl group, an aryl group, an aromatic heterocyclic In the case of a cyclic group or an aliphatic heterocyclic group,
Each of these substituents is a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, Halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkyl carbamoyl group, di-lower alkyl carbamoyl group, carbamoyloxy group, lower alkyl carbamoyloxy group,
Di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower Alkyl ammonium lower alkyl group, lower alkanoylamino group, aroylamino group,
A substituent selected from the group consisting of a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group is appropriately substituted with 1 to 3 identical or Different substituents can be substituted on the nitrogen-containing heteroaromatic group.

When R _p is a cyclo lower alkyl group, an aryl group, an aromatic heterocyclic group or an aliphatic heterocyclic group, each of these substituents is

[0078]

Embedded image And a condensed bicyclic or tricyclic ring containing a partial structure selected from the group consisting of:

Formula: Y₁-W₁-Y_Two-R_pAt W
₁Is a single bond, an oxygen atom, a sulfur atom, SO, SO_{Two ,}N
R_q, SO_TwoNR_q, N (R_q) SO_TwoNR_r, N (R_q) S
O_Two, CH (OR_q), CONR_q, N (R_q) CO, N
(R_q) CONR_r, N (R_q) COO, N (R_q) CS
O, N (R_q) COS, C (R_q) = CR_r, C≡C, C
O, CS, OC (O), OC (O) NR_q, OC (S)
NR_q, SC (O), SC (O) NR _qOr C (O) O
(Where R_qAnd R_rIs a hydrogen atom or lower
Alkyl group, cyclo lower alkyl group, hydroxyl group, cyano
Group, halogen atom, nitro group, carboxyl group, carba
Moyl group, formyl group, lower alkanoyl group, lower alkyl
Canoyloxy group, hydroxy lower alkyl group, cyano
Lower alkyl group, halo lower alkyl group, carboxy lower
Alkyl group, carbamoyl lower alkyl group, lower alcohol
Xy group, lower alkoxycarbonyl group, lower alkoxy
Carbonylamino group, lower alkoxycarbonylamino
Lower alkyl group, lower alkylcarbamoyl group, di-lower
Alkylcarbamoyl group, carbamoyloxy group, lower
Alkylcarbamoyloxy group, di-lower alkylcarba
Moyloxy group, amino group, lower alkylamino group, di
Lower alkylamino group, tri-lower alkyl ammonium
Group, amino lower alkyl group, lower alkyl amino lower group
Alkyl group, di-lower alkylamino lower alkyl group, tri
Lower alkylammonio lower alkyl group, lower alkano
Ylamino group, aroylamino group, lower alkanoylua
Midino lower alkyl group, lower alkylsulfinyl group,
Lower alkylsulfonyl group, lower alkylsulfonyl group
Mino group, hydroxyimino group and lower alkoxyimino
A substituent selected from the group consisting of
Lower alkyl group, ant which may have 1 to 3
Or an aralkyl group).
For example, oxygen atom, sulfur atom, NR_q, SO_TwoNR_q, N
(R_q) SO_Two, CONR_q, N (R_q) CO, N (R_q)
COO, C (R_q) = CR_r, OC (O), OC (O) N
R_q, C (O) O and the like are preferable, and particularly, for example, NR_q, N
(R_q) SO_Two, CONR_q, N (R_q) CO, N (R_q)
COO, OC (O), C (O) O and the like are preferred.

R _q and R _r in W ₁ are a hydrogen atom or a lower alkyl group, a cyclo-lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group. Group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group, or It represents a lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 substituents as appropriate. The lower alkyl group, the aryl group or the aralkyl group is a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, or a hydroxy lower alkyl. Group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group,
Carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkyl carbamoyl group, di-lower alkyl carbamoyl group, carbamoyloxy group, lower alkyl carbamoyloxy group, di-lower alkyl carbamoyloxy group, amino group, lower alkyl amino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, A lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group It 1 optionally a substituent more selected may have three.

In the formula: Y ₁ -W ₁ -Y ₂ -R _p are the same or different and each represents a single bond or a linear or branched lower alkylene group. The straight-chain or branched lower alkylene group is

[0082]

Embedded image May have one bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of

Next, the form of the substituent (2) will be described in detail. This substituent is, for example, a lower alkyl group, a lower alkanoyl group or a lower alkanoyl group among the substituents on the nitrogen-containing heteroaromatic ring group. Oxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group,
Lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl ammonium lower alkyl group, lower alkanoylamino Group, aroylamino group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, lower alkanoylamidino lower alkyl group, etc.
Together with the carbon atom on the ring to which these ring substituents are attached, their adjacent carbon atoms and the carbon, oxygen and / or nitrogen atoms on the ring substituent,

[0084]

Embedded image A 5- or 7-membered ring selected from the group consisting of

The substituent on the ring includes, for example, a lower alkyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a halo lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl carbamoyl group. Group, lower alkylcarbamoyloxy group, lower alkylamino group, di-lower alkylamino group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, lower alkanoylamino group, aroylamino group, and the like, Among them, for example, a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylamino lower alkyl group and the like are more preferable.

Next, the form of the substituent (3) will be described in detail. This substituent is represented by the formula: Y ₁ -W ₁ -Y ₂ -R _p (wherein
Y ₁ , W ₁ , Y ₂ and R _p have the above-mentioned meanings), a carbon atom on the ring to which the substituent is bonded, a carbon atom adjacent thereto, a carbon atom on the substituent, an oxygen atom, / Or formed together with a nitrogen atom,

[0087]

Embedded image And a 5- to 7-membered ring selected from the group consisting of

The substituent or the forming group of the nitrogen-containing heteroaromatic group is preferably any of (1), (2) and (3), but the preferred form is (1 ′) a lower alkyl group, a hydroxyl group. A halogen atom, formyl group, lower alkanoyloxy group, hydroxy lower alkyl group, halo lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group,
Lower alkoxycarbonyl group, lower alkylcarbamoyl group, lower alkylcarbamoyloxy group, amino group,
Selected from the group consisting of a lower alkylamino group, a di-lower alkylamino group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group, an aroylamino group and a lower alkylsulfonylamino group. And a substituent represented by the formula: Y _1a -W _1a -Y _2a -R _pa (wherein R _pa may have a hydrogen atom or 1 to 3 substituents as appropriate,
1 to 3 lower alkyl groups, lower alkenyl groups or lower alkynyl groups or the substituents as appropriate,

[0089]

Embedded imageA bicyclic compound containing a partial structure selected from the group consisting of
Is a cyclo lower alkyl optionally having a tricyclic fused ring
Kill group, aryl group, imidazolyl group, isoxazolyl
Group, isoquinolyl group, indolyl group, ethylene diox
Cyphenyl group, pyridyl group, pyrimidinyl group, pyridazi
Nil, pyrazolyl, quinolyl, benzimidazoly
Group, thiazolyl group, thienyl group and triazolyl group
An aromatic heterocyclic group selected from the group consisting of
Sazolinyl group, isoxazolidinyl group, tetrahydropi
Lysyl group, tetrahydrofuranyl group, tetrahydropyra
Nil, piperazinyl, piperidinyl, pyrrolidini
Group, morpholino group and tetrahydroisoquinolinyl group
An aliphatic heterocyclic group selected from the group consisting of_1aIs an acid
Elemental atom, sulfur atom, NR_qa, SO_TwoNR_qa, N (R_qa)
SO_Two, CONR_qa, N (R_qa) CO, N (R_qa) CO
O, C (R_qa) = CR_ra, OC (O), OC (O) NR
_qaOr C (O) O (where R_qaAnd R_raIs the water
Elemental atom, lower alkyl group, cyclo-lower alkyl group, hydroxyl
Group, halogen atom, formyl group, lower alkanoyloxy
Si group, hydroxy lower alkyl group, halo lower alkyl
Group, carbamoyl lower alkyl group, lower alkoxy group,
Lower alkoxycarbonyl group, lower alkoxycarbonyl
Ruamino group, lower alkoxycarbonylamino lower alkyl
Kill group, lower alkyl carbamoyl group, lower alkyl group
Rubamoyloxy group, amino group, lower alkylamino
Group, di-lower alkylamino group, amino-lower alkyl group,
Lower alkylamino lower alkyl group, di-lower alkyl group
Mino lower alkyl group, lower alkanoylamino group, allo
From ylamino group and lower alkylsulfonylamino group
A substituent selected from the group consisting of
A lower alkyl group or an aryl group which may have three
Or an aralkyl group), Y_1aAnd Y _2aAre the same
Or differently, a single bond or said bicyclic or tricyclic condensed
Linear or branched, which may have one fused ring
Which represents a lower alkylene group)
A substituent selected from the group consisting of (2 ') a lower alkyl group and a lower
Alkanoyloxy group, hydroxy lower alkyl group, c
(B) lower alkyl group, carbamoyl lower alkyl group, lower
Alkoxy group, lower alkoxycarbonyl group, lower alkyl
Kill carbamoyl group, lower alkyl carbamoyloxy
Group, lower alkylamino group, di-lower alkylamino group,
Amino lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, lower alkyl
From the group consisting of canoylamino and aroylamino groups
Carbon atom on the ring to which the selected substituent is attached, adjacent
And the carbon atom on the substituent on the ring, oxygen
Together with atoms and / or nitrogen atoms,

[0090]

Embedded image Or a nitrogen-containing heteroaromatic group forming a 5- or 6-membered ring selected from the group consisting of: or (3 ′) Formula: Y _1a -W _1a -Y _2a
—R _pa (wherein, Y _1a , W _1a , Y _2a and R _pa have the above-mentioned meanings), the carbon atom on the ring to which the substituent is bonded, the carbon atom adjacent thereto and the carbon atom on the substituent. Together with the carbon, oxygen and / or nitrogen atoms of

[0091]

Embedded imageA 5- or 6-membered ring selected from the group consisting of
And (1 ") a hydroxyl group, a halogen atom, a lower
Noyloxy group, hydroxy lower alkyl group, lower alkyl
Coxy group, lower alkoxycarbonyl group, amino group and
Select from the group consisting of lower alkylamino and lower alkyl groups
Substituents as well as formulas: Y _1b-W_1b-Y_2b-R_pb(formula
Medium, R_pbRepresents 1 to 3 hydrogen atoms or 1 to 3
May have a lower alkyl group or a lower alkenyl group
Or a lower alkynyl group or the substituent
3 chairs and even

[0092]

Embedded image An aromatic group selected from the group consisting of a cyclo-lower alkyl group, an aryl group, a pyridyl group and a pyrazolyl group, which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of An aliphatic heterocyclic group selected from the group consisting of an aromatic heterocyclic group or an isoxazolinyl group, a tetrahydropyridyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, a morpholino group and a tetrahydroisoquinolinyl group, W _1b is NR _qb , N (R _qb ) SO
₂ , CONR _qb , N (R _qb ) CO, N (R _qb ) COO,
OC (O) or C (O) O (where R _qb and R
_rb is a hydrogen atom or a hydroxyl group, a halogen atom, a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an amino group and a substituent selected from the group consisting of a lower alkylamino lower alkyl group or A lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 substituents as appropriate), Y _1b and Y _2b are the same or different and are a single bond or the bicyclic or tricyclic A straight-chain or branched lower alkylene group which may have one fused condensed ring), and (2 ″) lower alkanoyl Selected from the group consisting of an oxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group and a lower alkylamino lower alkyl group. Taken together with the carbon atom on the ring to which the selected substituent is attached, its adjacent carbon atoms and the carbon, oxygen and / or nitrogen atoms on the ring substituent;

[0093]

Embedded image A 5- or 6-membered ring selected from the group consisting of or a (3 ″) formula: Y _1b -W _1b -Y _2b -R _pb (wherein, Y _1b ,
W _1b , Y _2b and R _pb have the above-mentioned meanings), the carbon atom on the ring to which the substituent is bonded, the carbon atom adjacent thereto, and the carbon atom, oxygen atom and / or nitrogen on the substituent Together with the atoms,

[0094]

Embedded image And a 5- or 6-membered ring selected from the group consisting of

X and Z are the same or different and each represent a carbon atom or a nitrogen atom, or, when appropriate, together with R ₁ or R ₂ and / or R ₃ , represents a CH or nitrogen atom.

Y represents CO, SO or SO ₂ .

R ₁ is a hydrogen atom or a formula: Y ₃ —W ₂ —
Y ₄ —R _s (wherein, R _s is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo-lower alkyl group, an aryl group, which may have 1 to 3 hydrogen atoms or 1 to 3 substituents as appropriate) Group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, Quinoxalinyl group, quinolyl group,
Dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group,
Benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group, furyl group, furazanyl group, triazolyl group,
Aromatic heterocyclic group selected from the group consisting of benzodioxanyl group and methylenedioxyphenyl group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, piperazinyl group, piperidinyl group A pyrrolidinyl group, a pyrrolinyl group, a morpholino group, an aliphatic heterocyclic group selected from the group consisting of a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₂ is a single bond, an oxygen atom, a sulfur atom, SO, SO ₂ , NR _t , SO ₂ NR _t , N
_{(R t) SO 2 NR u} , N (R t) SO 2, CH (OR t),
CONR _t , N (R _t ) CO, N (R _t ) CONR _u , N
_{(R t) COO, N (} R t) CSO, N (R t) COS,
C (R _v ) = CR _r , C≡C, CO, CS, OC (O),
OC (O) NR _t , OC (S) NR _t , SC (O), SC
(O) NR _t or C (O) O (where R _t and R
_u is a hydrogen atom or lower alkyl group, hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo Lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy Group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group,
Di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, Lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group,
A substituent selected from the group consisting of a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or a lower alkyl group, aryl optionally having 1 to 3 substituents, A aralkyl group), Y ₃ and Y ₄ are
The same or different, a single bond or a linear or branched lower alkylene group) or a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, Formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkyl carbamoyl group , Di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl Lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, A substituent selected from the group consisting of a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group; and a formula: Y ₃ -W ₂ -Y
_4- R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meanings), and are suitably 1 to 3 substituents Is a lower alkyl group which may have the same or different substituents, or
Form a nitrogen atom with X.

[0098] Here, the form R _1, will be described in detail, R ₁ is a hydrogen atom or the formula: Y ₃ -W in ₂ -Y ₄ -R _s (wherein, R _s, W _2, Y ₃ and Y ₄ has the meaning described above), is a lower alkyl group optionally having 1 to 3 identical or different substituents, or forms a nitrogen atom together with X It is mentioned.

In the formula: Y ₃ -W ₂ -Y ₄ -R _s ,
_s is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group, an aryl group, an aromatic heterocyclic group or an aliphatic heterocyclic group, etc., and each of these substituents is a lower alkyl group, , Cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group,
Carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkyl carbamoyl group, di-lower alkyl carbamoyl group, carbamoyloxy group, lower alkyl carbamoyloxy group, di-lower alkyl carbamoyloxy group, amino group, lower alkyl amino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, A lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group It 1 optionally a substituent more selected may have three. Preferred substituent groups can be listed in the same manner as the substituents on Ar.

In the formula: Y ₃ -W ₂ -Y ₄ -R _s , W
₂ is a single bond, an oxygen atom, a sulfur atom, SO, SO ₂ , NR
_{t, SO 2 NR t, N} (R t) SO 2 NR u, N (R t) S
O ₂ , CH (OR _t ), CONR _t , N (R _t ) CO, N
(R _t ) CONR _u , N (R _t ) COO, N (R _t ) CS
O, N (R _t ) COS, C (R _v ) = CR _r , C≡C, C
O, CS, OC (O), OC (O) NR _t , OC (S)
NR _t , SC (O), SC (O) NR _t or C (O) O. Wherein, R _t and R _u is a hydrogen atom or a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group,
Hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group,
Lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group,
Amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group, A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group, or it 1 appropriately substituents may be three, a lower alkyl group, an aryl group or an aralkyl group, lower alkyl group, each substituent for the aryl group or the aralkyl group, as well as the R _s , 1 to 3 substituents as appropriate It can be.

In the formula: Y ₃ —W ₂ —Y ₄ —R _s , Y ₃ and Y ₄ are the same or different and represent a single bond or a linear or branched lower alkylene group.

R₁Preferred examples are, for example, a hydrogen atom or
Kuha formula: Y_3a-W_2a-Y_4a-R_sa(Where R_saIs hydrogen
Optionally having 1 to 3 atoms or substituents.
Lower alkyl, lower alkenyl, cyclo-lower
From the group consisting of alkyl, aryl and indolyl groups
Selected aromatic heterocyclic group or tetrahydropyridi
Group, piperazinyl group, piperidinyl group, pyrrolidinyl
Group selected from the group consisting of
Ring group, W_2aIs a single bond, NR_ta, CH (OR_ta), C
ONR_ta, N (R_ta) CO, N (R_ta) COO, OC
(O) NR_taOr C (O) O (where R_taas well as
R_uaHas a hydrogen atom and optionally 1 to 3 substituents
Lower alkyl group, aryl group or aralkyl
Y)_3aAnd Y_4aAre the same or different,
A bond or a linear or branched lower alkylene group or
Lower alkyl group, hydroxyl group, carbamoyl group, lower alk
Noyloxy group, hydroxy lower alkyl group, lower alkyl
Coxy group, lower alkoxycarbonyl group, lower alkyl
Carbamoyl group, di-lower alkylcarbamoyl group, carb
Bamoyloxy group, lower alkylcarbamoyloxy
Group, lower alkylamino group, di-lower alkylamino group,
Amino lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, lower alkyl
From the group consisting of canoylamino and aroylamino groups
Selected substituents and formula: Y_3a-W_2a-Y _4a-R
_sa(Where R_sa, W_2a, Y_3aAnd Y_4aHas the above meaning
Having a substituent selected from the group consisting of
A substituent, suitably 1 to 3 identical or different
A lower alkyl group which may have a substituent, or
X may form a nitrogen atom, especially hydrogen
Atom or formula: Y_3b-W_2b-Y_4b-R_sb(Where R_sb
Has 1 to 3 hydrogen atoms or 1 to 3 substituents
May be a lower alkyl group, a cyclo lower alkyl group and
Aryl group, W_2bIs a single bond, N (R_tb) COO or
C (O) O (where R_tbIs a hydrogen atom, the substitution
Lower alkyl optionally having 1 to 3 groups
Group, aryl group or aralkyl group), Y_3bAnd Y
_4bAre the same or different and are a single bond or a linear or
Branched lower alkylene group or hydroxy lower alkyl group
And formula: Y_3b-W_2b-Y_4b-R_sb(Where R_sb, W_2b,
Y_3bAnd Y_4bHas the meaning described above)
A substituent selected from the group consisting of
Low molecular weight which may have three identical or different substituents
Is a lower alkyl group or forms a nitrogen atom with X
To do so.

R ₂ and R ₃ are the same or different, and (i)
Independently, a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a formula: Y ₃ -W ₂ -Y ₄ -R _s (wherein,
R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meanings) or (ii) one of R ₂ and R ₃ together with R ₁ and X Form

[0104]

Embedded image And

[0105]

Embedded image And a saturated 5- or 8-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, a carbon atom or an oxygen atom contained in a ring substituent on the ring. And / or form a 5- to 7-membered ring with a nitrogen atom, (iii) or together form a spirocycloalkyl group, an oxo group with a bonding Z, or Z, R ₁ and X With a nitrogen atom,
One or more hetero atoms selected from the group consisting of oxygen and sulfur may be included, and lower alkyl, spirocyclo lower alkyl which may have a substituent, hydroxyl, cyano, halogen Atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy Group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group,
Carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group,
Tri lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, dilower alkylamino lower alkyl group, tri lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group ,
A substituent selected from the group consisting of a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group; and a formula: Y ₁ -W ₁ -Y ₂ -R _p (wherein ,
R _p , W ₁ , Y ₁ and Y ₂ have the above-mentioned meanings) and are each a substituent selected from the group consisting of
1 to 3 identical or different substituents as appropriate, furthermore
Cyclo lower alkyl, aryl, imidazolyl, isoxazolyl, isoquinolyl, isoindolyl, indazolyl, indolyl, indolizinyl, isothiazolyl, ethylene optionally having 1 to 3 identical or different substituents Dioxyphenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group,
Dihydroindolyl, thionaphthenyl, naphthyridinyl, phenazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, An aromatic heterocyclic group selected from the group consisting of a furazanyl group, a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, and an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imidazolidinyl group, and a tetrahydrofuranyl group An aliphatic compound selected from the group consisting of a tetrahydropyranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group May be combined ring condensed selected from the group consisting of cyclic groups,

[0106]

Embedded image And

[0107]

Embedded image Forming a saturated or unsaturated 5- or 8-membered ring group selected from the group consisting of

Here, R ₂ and R ₃ will be specifically described. (I) When R ₂ and R ₃ are the same or different and independently carry a substituent, (ii) R ₂ and R ₃ Is formed together with another substituent to form a substituent, and the formed substituent and the other together form a further substituent; and (iii) R ₂ and R ₃ are Any case where R ₂ and R ₃ together with other substituents and the like form a substituent together and form a substituent is included in the present invention.

Next, each embodiment of the substituents of R ₂ and R ₃ will be described. (I) R ₂ and R _{3 each} represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a formula: Y ₃ —W ₂ —Y ₄ —R _s (where R _s , W ₂ , Y ₃ and Y ₄ has the same meaning as described above), which may be the same or different, and is independent of each other. (Ii) one of R ₂ and R ₃ together with R ₁ and X

[0110]

Embedded image And

[0111]

Embedded image Form a saturated 5- to 8-membered ring selected from the group consisting of: and, together with the 5- to 8-membered ring,
A 5- to 7-membered ring can be formed together with a carbon atom or nitrogen atom on the ring and a carbon atom, oxygen atom and / or nitrogen atom contained in the substituent on the ring on the ring. (Iii) R ₂ and R ₃ together form (iii-1) a spirocyclo lower alkyl group, or (ii)
i-2) forming an oxo group together with Z to be bound, or (i)
ii-3) a nitrogen atom together with Z, R ₁ and X to be bonded;
One or more hetero atoms selected from the group consisting of oxygen atoms and sulfur atoms may be included.

[0112]

Embedded image And

[0113]

Embedded image And a saturated or unsaturated 5- to 8-membered ring group selected from the group consisting of:

The 5- or 8-membered saturated or unsaturated ring group may be a lower alkyl group, a spirocyclo lower alkyl group which may have a substituent, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, Carbamoyl group,
Formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group,
Lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, A lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group,
Di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino And substituents selected from the group consisting of lower alkoxyimino groups and the formula: Y ₁ -W ₁ -Y ₂ -R _p
(Wherein, R _p , W ₁ , Y ₁ and Y ₂ have the same meaning as described above), and are suitably 1 to 3 identical or different substituents It can have a substituent.

The substituent of the spirocyclo lower alkyl group includes, for example, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an aryl group and the like. Among them, for example, a lower alkyl group and a lower alkoxy group are preferable.

The saturated or unsaturated 5- or 8-membered ring group further includes a cyclo lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, Isothiazolyl, ethylenedioxyphenyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, quinoxalinyl, quinolyl, dihydroisoindolyl, dihydroindolyl, thionaphthenyl, naphthyridinyl , Phenazinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group,
Furyl group, furazanyl group, triazolyl group, aromatic heterocyclic group selected from the group consisting of benzodioxanyl group and methylenedioxyphenyl group and isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group,
Imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group,
It can be condensed with a ring selected from the group consisting of an aliphatic heterocyclic group selected from the group consisting of a pyrrolidinyl group, a pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group.

This condensed ring can have 1 to 3 identical or different substituents as appropriate. Specific substituents can be the same as the substituents on Ar.

R ₂ and R ₃ are (i), (ii) and (i)
Although ii) is preferred, preferred forms are the same or different and are independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, or a formula: Y _3a -W _2a -Y
_4a- R _sa (wherein, R _sa , W _2a , Y _3a and Y _4a have the above-mentioned meanings) or R _2a and R _2a
Either one of _3a forms together with R _1a and Xa

[0119]

Embedded image And

[0120]

Embedded image And a saturated 5- or 8-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, a carbon atom or an oxygen atom contained in a ring substituent on the ring. And / or forms a 5- to 7-membered ring with a nitrogen atom, or together forms a spirocyclo lower alkyl group, an oxo group with a bonding Z, or _a nitrogen with _a bonding Z _a , R _1a and Xa One heteroatom selected from the group consisting of atom, oxygen atom and sulfur atom
Species or more may be included, a lower alkyl group,
Spirocyclo lower alkyl group which may have a substituent, hydroxyl group, hydroxy lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, lower Selected from the group consisting of an alkylcarbamoyloxy group, a lower alkylamino group, a di-lower alkylamino group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group and an aroylamino group Substituent and formula: Y
During _1a -W _1a -Y _2a -R _{pa (wherein, R pa, W 1a, Y} 1a and Y
_2a is a substituent selected from the group consisting of the substituents represented by the above-mentioned meanings), and 1 to 3 identical or different substituents as appropriate, and further 1 to 3 identical or different as appropriate. An aromatic heterocyclic group selected from the group consisting of a cyclo lower alkyl group, an aryl group, a pyridyl group and a pyrazolyl group which may have different substituents, and an aliphatic heterocyclic group selected from the group consisting of a piperidinyl group and a pyrrolidinyl group May be fused with a ring selected from the group consisting of ring groups,

[0121]

Embedded image And

[0122]

Embedded image A saturated or unsaturated 5- or 8-membered ring group selected from the group consisting of

Among them, R _2b and R _3b are the same or different and are independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a formula: Y _3b -W _2b -Y _4b -R _sb (wherein, R _sb , W _2b , Y _3b and Y _4b have the above-mentioned meanings, or one of R _2b and R _3b is formed together with R _1b and X _b Do

[0124]

Embedded image And

[0125]

Embedded imageTo a saturated 5- to 7-membered ring group selected from the group consisting of
The other is bonded to a carbon atom or nitrogen on the ring
Atom, carbon atom, acid contained in the ring substituent on the ring
5- or 7-membered ring with elementary and / or nitrogen atoms
Spirocyclo lower alkyl
Or an oxo group together with the bonding Z, or
Is the connecting Z_b, R_1bAnd X_bWith nitrogen atom, oxygen atom
And a hetero atom selected from the group consisting of
Species or more may be included, a lower alkyl group,
Spirocyclo lower alkyl optionally having substituent (s)
Group, hydroxy lower alkyl group and lower alkoxy carb
A substituent selected from the group consisting of a bonyl group;
_1b-W_1b-Y_2b-R_pb(Where R_pb, W_1b, Y_1bAnd Y
_2bHas the above-mentioned meaning)
A substituent selected from the group;
The same or different substituents, and optionally 1 to 3
Cyclo lower amines which may have the same or different substituents
Alkyl, aryl, piperidinyl, and pyrrolidyl groups
From an aliphatic heterocyclic group selected from the group consisting of dinyl groups
May be fused with a ring selected from the group consisting of:

[0126]

Embedded image And

[0127]

Embedded image It is preferable to form a saturated or unsaturated 5- or 7-membered ring group selected from the group consisting of

R ₄ and R ₅ are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a group represented by the formula: Y ₃
A substituent or a lower alkyl group, a cyano group, a nitro group, a carboxyl group, represented by -W ₂ -Y ₄ -R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the same meaning as described above); Carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower Alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, dialkyl Lower alkylamino Group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower A substituent selected from the group consisting of an alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group; and a formula: Y ₃ -W ₂ -Y
_4- R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meanings), and are suitably 1 to 3 substituents It represents a lower alkyl group, an aryl group or an aralkyl group which may have the same or different substituents.

[0129] Here, the form of R ₄ and R _5, will be described in detail, R ₄ and R ₅ are a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or the _{formula: Y 3 -W 2 -Y 4 -R} s (Where
R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meanings) or a lower alkyl group, an aryl group or an aralkyl group which may have a substituent.

The lower alkyl group, the aryl group or the aralkyl group may have 1 to 3 identical or different substituents as appropriate.

Specific examples of the substituent include a lower alkyl group, a cyano group, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, Halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyl Oxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl Group, a lower alkylamino-lower alkyl group, a di-lower alkylamino-lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, aroylamino group, a lower alkanoyl amidino lower alkyl group, a lower alkylsulfinyl group,
A substituent selected from the group consisting of a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a formula: Y ₃ -W _{2
(Wherein, R s, W 2, Y} 3 and Y ₄ are as defined above) -Y ₄ -R _s include substituents selected from the group consisting of substituents represented by.

Expression

[0133]

Embedded image Represents a single bond or a double bond. Involved in the formula,
Any bond can be taken depending on the types of Z, R ₁ , R ₂ , R ₃ and X.

Next, the compound of the general formula (I) which is the active ingredient according to the present invention will be described.

Formula (I)

[0136]

Embedded image [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0137]

Embedded image Has the above-mentioned meaning. Are good Cdk4
And / or has a Cdk6 inhibitory action, and particularly, of the general formula (Ia)

[0138]

Embedded image _{Wherein, Ar a, X a, Y} a, Z a, R 1a, R 2a, R 3a, R
_4a , R _5a and the formula

[0139]

Embedded image Has the above-mentioned meaning. The compound of the formula (Ib)

[0140]

Embedded image [Wherein, Ar _b , X _b , Y _b , Z _b , R _1b , R _2b , R _3b , R
_4b , R _5b and the formula

[0141]

Embedded image Has the meaning described above. Are preferred.

The formula (Ip)

[0143]

Embedded image Wherein, Ar _p is optionally substituted group nitrogen-containing heteroaromatic ring group optionally having, X _p is a carbon atom (CH) or a nitrogen atom, R _1p is have a hydrogen atom or an optionally substituted group A lower alkyl group, R _{2p which} may be a hydrogen atom or an oxo group (forming a carbonyl group together with the carbon atom to which it is bonded);
Or one or more hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom together with the carbon atom to be bonded, R _1p and X _p , and may optionally have a substituent; R _4p and R _5p are the same or different and form a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a lower alkyl group which may have a substituent, if _desired , which forms an unsaturated 5- or 6-membered ring group. Which represents a group, an aryl group or an aralkyl group], is included in the compound of the general formula (I), and exhibits a good Cdk4 and / or Cdk6 inhibitory action.

[0144] Explaining the compounds of general formula _(I-p), Ar p is, for example pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, a thiazolyl group,
A nitrogen-containing heteroaromatic ring selected from the group consisting of isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzothiazolyl and benzoxazolyl groups. Group, among which, for example, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, a nitrogen-containing heteroaromatic group selected from the group consisting of a pyrazolyl group and an imidazolyl group are preferable, and particularly, for example, a pyridyl group and a pyrazolyl group. A nitrogen-containing heteroaromatic group selected from the group consisting of:

Specific examples of the saturated or unsaturated 5- or 6-membered ring group formed together with the carbon atom to which R _2p is bonded, R _1p and X include:

[0146]

Embedded image Or

[0147]

Embedded image And the like.

Among the compounds of the general formula (Ip), Ar_por
Is R_2pIs a carbon atom to which R_1pAnd X_pForm with
Saturated or unsaturated 5- or 6-membered substituents
Is a lower alkyl group, hydroxyl group, cyano group, halogen atom
Nitro, carboxyl, carbamoyl, phor
Mill group, lower alkanoyl group, hydroxy lower alkyl
Group, cyano lower alkyl group, halo lower alkyl group,
Boxy lower alkyl group, carbamoyl lower alkyl group,
Lower alkoxy group, lower alkoxycarbonyl group, lower
Alkyl carbamoyl group, di-lower alkyl carbamoyl
Group, carbamoyloxy group, lower alkylcarbamoyl
Oxy group, di-lower alkylcarbamoyloxy group,
Group, lower alkylamino group, di-lower alkylamino
Group, tri-lower alkylammonio group, amino-lower alkyl
Group, lower alkylamino lower alkyl group, di-lower alkyl
Killamino lower alkyl group, tri-lower alkyl ammonium
O lower alkyl group, lower alkanoylamino group, alloy
Ruamino group, lower alkanoylamidino lower alkyl
Group, lower alkylsulfonylamino group, hydroxyimi
And a lower alkoxyimino group and a formula: Y_1p-W-Y
_2p-R_pp[Wherein, R_ppHas a hydrogen atom or an appropriate substituent
Optionally, a lower alkyl group, a cyclo lower alkyl
Group, lower alkenyl group, lower alkynyl group, aryl
Group, aromatic heterocyclic group or aliphatic heterocyclic group, W is
Bond, oxygen atom, sulfur atom, sulfinyl group, sulfoni
Group, NR_qp, SO_TwoNR_qp, N (R_qp) SO_TwoNR_rp,
N (R_qp) SO _Two, CH (OR_qp), CONR_qp, N
(R_qp) CO, N (R_qp) CONR_rp, N (R_qp) CO
O, N (R_qp) CSO, N (R_qp) COS, C (R_qp)
= CR_rp, C≡C, CO, CS, OC (O), OC
(O) NR_qp, OC (S) NR_qp, SC (O), SC
(O) NR_qpOr C (O) O (where R_qpas well as
R_rpIs a hydrogen atom, optionally substituted lower alkyl
A kill group, an aryl group or an aralkyl group), Y_1p
And Y_2pAre the same or different and are a single bond or linear
Or a branched lower alkylene group].
Selected substituents, and optionally 1 to 3 identical or
Are compounds that may have different substituents
Things.

The compound represented by the general formula (I)

[0150]

Embedded image [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0151]

Embedded image Has the above-mentioned meaning. R ₄ , R ₅ and-
HNCONH-Ar can be substituted at any substitution position as long as it is a benzene ring portion.

Accordingly, the compound of the general formula (I) is a compound of the general formula (I-1)

[0153]

[Of 60] [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0154]

Embedded image Has the above-mentioned meaning], a compound of the general formula (I-2)

[0155]

Embedded image [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0156]

Embedded image Has the above-mentioned meaning], a compound of the general formula (I-3)

[0157]

Embedded image [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0158]

Embedded image Has the above-mentioned meaning] and a compound of the general formula (I-4)

[0159]

Embedded image [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0160]

Embedded image Has the above-mentioned meaning], and among these compounds, the compound of the general formula (I-1) is preferable.

The pharmaceutically acceptable salt of the compound of the formula (I) means a conventional pharmaceutically acceptable salt, and when present as a substituent, a carboxyl group or a base or a base on a side chain. Salts at acidic residues can be mentioned.

Examples of the basic addition salt at the carboxyl group or acidic residue include alkali metal salts such as alkali metal salts such as sodium salt and potassium salt;
Alkaline earth metal salts such as, for example, calcium salts and magnesium salts; ammonium salts; for example, trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts; For example, an aralkylamine salt such as dibenzylethylenediamine; a heterocyclic aromatic amine salt such as a pyridine salt, a picoline salt, a quinoline salt, an isoquinoline salt; Quaternary ammonium salts such as benzyltributylammonium salt, methyltrioctylammonium salt and tetrabutylammonium salt; salts such as arginine salt and lysine salt Gender amino acid salts and the like.

The acid addition salt of the base on the side chain includes
Inorganic salts such as, for example, hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetates, propionate, lactate, maleate, fumarate,
Organic acid salts such as tartrate, malate, citrate, and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and toluenesulfonate; for example, aspartate; Examples include acidic amino acid salts such as glutamate.

The non-toxic pharmaceutically acceptable ester of the compound of the formula (I) means a conventional pharmaceutically acceptable one at the carboxyl group.

In the following, among the compounds of the general formula (I) of the present invention, preferred examples of the compounds will be mentioned. Preferred examples of the compounds, including the compounds of the examples described below, include N ′-(pyrrolidino [2, 1-b] isoindoline-4-one-8-yl) -N- (5- (2-octylaminomethyl) pyrazol-3-yl) urea (compound of 563), N'-
(Pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (5- (2-methyl-4,4-dimethylpentylaminomethyl) pyrazol-3-yl) urea (564 Compound), N ′-(pyrrolidino [2,1
-B] isoindoline-4-one-8-yl) -N-
(5- (5-methoxyindan-2-ylaminomethyl) pyrazol-3-yl) urea (compound of 581), N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl ) -N- (5- (2-methylindan-2-ylaminomethyl) pyrazol-3-yl) urea (compound of 589), N '-(pyrrolidino [2,1-b] isoindoline-4-one -8-yl)
-N- (5- (5-chloroindan-2-ylaminomethyl) pyrazol-3-yl) urea (a compound of 595), N '-(pyrrolidino [2,1-b] isoindoline-4-one- 8-yl) -N- (5- (6-methylpyridin-2-yl) pyrazol-3-yl) urea (6
05), N ′-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (5- (pyrrolidin-2-yl) pyrazol-3-yl) urea (611) ), N ′-(pyrrolidino [2,1-
b] isoindoline-4-one-8-yl) -N- (5
-(T-butylaminomethyl) pyrazol-3-yl)
Urea (compound of 662), N ′-(pyrrolidino [2,
1-b] isoindoline-4-one-8-yl) -N-
(5- (pyrazolo [5,4-b] pyridin-3-yl)
Urea (compound of 613), N ′-(pyrrolidino [2,
1-b] isoindoline-4-one-8-yl) -N-
(5- (1-hydroxymethylcyclopentylaminomethyl) pyrazol-3-yl) urea (compound of 572), N ′-(pyrrolidino [2,1-b] -4-oxoisoindoline-8-yl) -N -(5- (Nt-butyl-N-methyl-aminomethyl) pyrazol-3-yl) urea (596 compound), N '-(pyrrolidino [2,1-b] isoindoline-4-one-8- Ill)
-N- (4- (N-benzyl-1,2,5,6-tetrahydropyridin-4-yl) pyridin-2-yl) urea (compound of 254), N '-(pyrrolidino [2,1-
b] isoindoline-4-one-8-yl) -N- (4
-(N-benzyl-4-piperidyl) pyridin-2-yl) urea (a compound of 255), N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl)
-N- (4- (N-benzyl-1,2,5,6-tetrahydropyridin-3-yl) pyridin-2-yl) urea (a compound of 256), N '-(pyrrolidino [2,1-
b] isoindoline-4-one-8-yl) -N- (4
-(N-benzyl-3-piperidyl) pyridin-2-yl) urea (a compound of 257), N '-(pyrrolidino [2,1-b] -4-oxoisoindoline-8-yl) -N- ( 4- (1,2,5,6-tetrahydropyridin-3-yl) pyridin-2-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- (N-acetyl-3-piperidyl) pyridin-2-yl) urea, N ′-(pyrrolidino [2 , 1-b] Isoindolin-4-one-8-yl) -N- (piperidino [3,4-c] pyridin-6-
Yl) urea (compound of 317), N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl)
-N- (pyrrolidino [3,4-c] pyridin-5-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- ( Cyclohexylaminoethyl) pyridin-2-yl) urea,
N '-(pyrrolidino [2,1-b] isoindoline-4
-On-8-yl) -N- (4- (N-cyclohexylpyrrolidin-3-yl) pyridin-2-yl) urea (a compound of 180), N '-(pyrrolidino [2,1-
b] isoindoline-4-one-8-yl) -N- (4
-(N-benzylpyrrolidin-3-yl) pyridine-2
-Yl) urea (compound of 165), N '-(N-cyclopentyl-3-methylisoindoline-1-one-4
-Yl) -N- (pyridin-2-yl) urea (428
Compound), N ′-(3-t-butylisoindolino [3,2-b] oxazolidin-4-one-8-yl)
-N- (4- (N-benzylpyrrolidin-3-yl) pyridin-2-yl) urea (compound 526), N'-
(2-methylisoindolino [3,2-b] perhydro-1,3-oxazin-5-one-9-yl) -N-
(4- (N-benzylpyrrolidin-3-yl) pyridin-2-yl) urea (compound 541) and N ′-(isoindolino [2,3-b] perhydro-1,4-methano-6,11a- Benzoxazin-11-one-7-yl) N- (pyridin-2-yl) urea (compound of 476), and among them, for example, N ′-(pyrrolidino [2,
1-b] isoindoline-4-one-8-yl) -N-
(5- (2-octylaminomethyl) pyrazole-3-
Yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (5- (2-
Methyl-4,4-dimethylpentylaminomethyl) pyrazol-3-yl) urea, N ′-(pyrrolidino [2,
1-b] isoindoline-4-one-8-yl) -N-
(5- (5-methoxyindan-2-ylaminomethyl) pyrazol-3-yl) urea, N ′-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- ( 5- (2-methylindan-2-ylaminomethyl) pyrazol-3-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8
-Yl) -N- (5- (5-chloroindan-2-ylaminomethyl) pyrazol-3-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- (N-benzyl-1,2,2,
5,6-tetrahydropyridin-4-yl) pyridine-
2-yl) urea, N '-(pyrrolidino [2,1-b]
Isoindoline-4-one-8-yl) -N- (4-
(N-benzyl-4-piperidyl) pyridin-2-yl) urea, N ′-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (piperidino [3,4- c] pyridin-6-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- (N-cyclohexylpyrrolidin-3-yl) pyridin-2-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- (N-benzylpyrrolidin-
3-yl) pyridin-2-yl) urea, N '-(3-
t-butylisoindolino [3,2-b] oxazolidin-4-one-8-yl) -N- (4- (N-benzylpyrrolidin-3-yl) pyridin-2-yl) urea;
N '-(2-methylisoindolino [3,2-b] perhydro-1,3-oxazin-5-one-9-yl)-
N- (4- (N-benzylpyrrolidin-3-yl) pyridin-2-yl) urea and N '-(isoindolino [2,3-b] perhydro-1,4-methano-6,11
a-benzoxazin-11-one-7-yl) N- (pyridin-2-yl) urea and the like are particularly preferred.

Next, a method for producing the compound of the general formula (I) according to the present invention will be described.

The compound of the general formula (I) can be produced by the following production method A, production method B or production method C.

Production Method A The compound of the general formula (I) can be prepared by reacting the compound of the general formula (III)

[0169]

Embedded imageWherein X and Z are the same or different and each represents
R represents a nitrogen atom or is bonded as appropriate._TenOr R₂₀
And / or R₃₀Together with CH or nitrogen source
Child, Y is CO, SO or SO_Two, R_TenIs a hydrogen atom
Or the formula: Y₃₀-W_{Two 0}-Y₄₀-R_s0(Where R_s0Is the water
Optionally having 1 to 3 element atoms or the substituents.
Lower alkyl group, lower alkenyl group, lower alkynyl
Group, cyclo-lower alkyl group, aryl group, imidazoly
Group, isoxazolyl group, isoquinolyl group, isoyne
Drill group, indazolyl group, indolyl group, indoliz
Nyl group, isothiazolyl group, ethylenedioxyphenyl
Group, oxazolyl group, pyridyl group, pyrazinyl group, pyri
Midinyl group, pyridazinyl group, pyrazolyl group, quinoxa
Linyl, quinolyl, dihydroisoindolyl, di
Hydroindolyl group, thionaphthenyl group, naphthyridini
Group, phenazinyl group, benzimidazolyl group, benzo
Oxazolyl group, benzothiazolyl group, benzotriazo
Ryl, benzofuranyl, thiazolyl, thiadiazo
Ryl, thienyl, pyrrolyl, furyl, furazani
Group, triazolyl group, benzodioxanyl group and methyl
Aroma selected from the group consisting of rangeoxyphenyl groups
Group heterocyclic group or isoxazolinyl group, isoxazolyl
Dinyl group, tetrahydropyridyl group, imidazolidinyl
Group, tetrahydrofuranyl group, piperazinyl group, piperi
Dinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino
Group, tetrahydroquinolinyl group and tetrahydroiso
An aliphatic heterocyclic group selected from the group consisting of a norinyl group,
W₂₀Is a single bond, an oxygen atom, a sulfur atom, SO, SO_Two,
NR_t0, SO_TwoNR_t0, N (R_t0) SO_TwoNR_u0, N (R
_t0) SO_Two, CH (OR_t0), CONR_t0, N (R_t0)
CO, N (R_t0) CONR_u0, N (R_t0) COO, N
(R_t0) CSO, N (R_t0) COS, C (R_v0) = CR
_r0, C≡C, CO, CS, OC (O), OC (O) NR
_t0, OC (S) NR_t0, SC (O), SC (O) NR_t0
Or C (O) O (where R _t0And R_u0Is hydrogen
Atom or lower alkyl group, water which may be protected
Acid group, cyano group, halogen atom, nitro group, protected
Carboxyl group, carbamoyl group, formyl
Group, lower alkanoyl group, lower alkanoyloxy group,
An optionally protected hydroxy lower alkyl group, shea
Lower alkyl, halo-lower alkyl, protected
Carboxy lower alkyl, carbamoyl lower
Alkyl group, lower alkoxy group, lower alkoxycarbo
Nyl group, lower alkoxycarbonylamino group, lower alkyl
Coxycarbonylamino lower alkyl group, lower alkyl
Carbamoyl group, di-lower alkylcarbamoyl group, carb
Bamoyloxy group, lower alkylcarbamoyloxy
Group, di-lower alkylcarbamoyloxy group, protected
Amino group, lower alkylamino group, di-lower
Alkylamino group, tri-lower alkyl ammonium group, protection
Optionally substituted amino lower alkyl group, lower alkyl
Amino lower alkyl group, di-lower alkylamino lower alkyl
A kill group, a tri-lower alkylammonio lower alkyl group,
Lower alkanoylamino group, aroylamino group, lower
Lucanoylamidino lower alkyl group, lower alkyl sulf
Finyl group, lower alkylsulfonyl group, lower alkyl
Sulfonylamino group, optionally protected hydroxy
Selected from the group consisting of imino groups and lower alkoxyimino groups
Selected substituent or one to three substituents as appropriate
A lower alkyl group, an aryl group or
Represents a alkyl group), Y₃₀And Y₄₀Are the same or different
A single bond or a linear or branched lower alkylene
A substituent) or a lower alkyl group,
A protected hydroxyl group, a cyano group, a halogen atom,
Nitro group, carboxyl group which may be protected,
Bamoyl group, formyl group, lower alkanoyl group, lower
Lucanoyloxy group, hydroxy which may be protected
Lower alkyl group, cyano lower alkyl group, halo lower alkyl
Kill group, optionally protected carboxy lower alkyl
Group, carbamoyl lower alkyl group, lower alkoxy group,
Lower alkoxycarbonyl group, lower alkoxycarbonyl
Ruamino group, lower alkoxycarbonylamino lower alkyl
Kill group, lower alkylcarbamoyl group, di-lower alkyl
Carbamoyl group, carbamoyloxy group, lower alkyl
Carbamoyloxy group, di-lower alkylcarbamoyl
Xy group, optionally protected amino group, lower alkyl
Amino group, di-lower alkylamino group, tri-lower alkyl
Ammonio group, amino lower alkyl group, lower alkyl group
Mino lower alkyl group, di-lower alkylamino lower alkyl
Group, tri-lower alkyl ammonium lower alkyl group, low
Lower alkanoylamino group, aroylamino group, lower alkyl
Canoylamidino lower alkyl group, lower alkyl sulf
Ynyl group, lower alkylsulfonyl group, lower alkyls
A rufonylamino group, an optionally protected hydroxy group
Selected from the group consisting of amino groups and lower alkoxyimino groups
Substituents as well as formulas: Y₃₀-W₂₀-Y₄₀-R_s0(formula
Medium, R_s0, W₂₀, Y₃₀And Y₄₀Has the above meaning
Substituents selected from the group consisting of
And optionally 1 to 3 identical or different substitutions
A lower alkyl group which may have a group, or X and
Together form a nitrogen atom, R₂₀And R₃₀Are the same or different
Independently represents a hydrogen atom, an optionally protected hydroxyl
Group, lower alkyl group, lower alkoxy group or formula: Y
₃₀-W₂₀-Y₄₀-R_s0(Where R_s0, W₂₀, Y₃₀And Y
₄₀Has the above-mentioned meaning)
Or R₂₀And R₃₀Any one of R_TenAnd with X
Form around

[0170]

Embedded image And

[0171]

Embedded image And a saturated 5- or 8-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, a carbon atom or an oxygen atom contained in a ring substituent on the ring. And / or form a 5- to 7-membered ring with a nitrogen atom, or together form a spirocyclo lower alkyl group, an oxo group with a bonding Z, or a nitrogen atom with a bonding Z, R ₁₀ and X May include one or more hetero atoms selected from the group consisting of oxygen and sulfur atoms, and may include a lower alkyl group, a spirocyclo lower alkyl group which may have a substituent,
An optionally protected hydroxyl group, a cyano group, a halogen atom, a nitro group, an optionally protected carboxyl group,
Carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, optionally protected hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, optionally protected carboxy lower alkyl group, carbamoyl lower alkyl group Group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyl An oxy group, an optionally protected amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an optionally protected amino-lower alkyl group, Killamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonyl amino group, substituent and the formula is selected from a protected consisting also good hydroxyimino group and a lower alkoxyimino group optionally the group: Y ₁₀
—W ₁₀ —Y ₂₀ —R _p0 (wherein, R _p0 is a lower alkyl group, a lower alkenyl group or a lower alkynyl group or a substituted group thereof, which may have 1 to 3 hydrogen atoms or 1 to 3 substituents as appropriate) 1 to 3 groups as appropriate,

[0172]

Embedded image A cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of Group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group,
Selected from the group consisting of benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl. Aromatic heterocyclic group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
An aliphatic heterocyclic group selected from the group consisting of a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₁₀ is a single bond, an oxygen atom, a sulfur atom, S
O, SO _{2 ,} NR _q0 , SO ₂ NR _q0 , N (R _q0 ) SO ₂ NR
_{r0, N (R q0) SO} 2, CH (OR q 0), CONR q0,
_{N (R q0) CO, N} (R q0) CONR r0, N (R q0) C
OO, N ( _Rq0 ) CSO, N ( _Rq0 ) COS, C
(R _q0 ) = CR _r0 , C≡C, CO, CS, OC (O),
OC (O) NR _q0 , OC (S) NR _q0 , SC (O), S
C (O) NR _q0 or C (O) O (where R _q0 and R _r0 represent a hydrogen atom or a lower alkyl group, a cyclo-lower alkyl group, an optionally protected hydroxyl group, a cyano group, a halogen atom, a nitro Group, optionally protected carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, optionally protected hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, protected A carboxy lower alkyl group, a carbamoyl lower alkyl group,
Lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group An optionally protected amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, optionally protected amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino Lower alkyl group, tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group,
It may have a substituent selected from the group consisting of a lower alkylsulfonyl group, a lower alkylsulfonylamino group, an optionally protected hydroxyimino group and a lower alkoxyimino group, or may have 1 to 3 substituents as appropriate. ,
A lower alkyl group, an aryl group or an aralkyl group), Y ₁₀ and Y ₂₀ are the same or different and each may have a single bond or one of the bicyclic or tricyclic fused rings. Which represents a chain or branched lower alkylene group)
Is a substituent selected from the group consisting of the substituents represented by and may have 1 to 3 identical or different substituents as appropriate, or 1 to 3 identical or different substituents as appropriate. Cyclo-lower alkyl, aryl, imidazolyl, isoxazolyl, isoquinolyl, isoindolyl, indazolyl, indolyl, indolizinyl, isothiazolyl, ethylenedioxyphenyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl , Pyridazinyl group, pyrazolyl group,
Quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, thiazolyl group,
An aromatic heterocyclic group selected from the group consisting of thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl, and isoxazolinyl and isoxazolidinyl Group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolinyl group and tetrahydroisoquinolinyl group May be fused with a ring selected from the group consisting of an aliphatic heterocyclic group,

[0173]

Embedded image And

[0174]

Embedded image Forming a saturated or unsaturated 5- or 8-membered ring group selected from the group consisting of: R ₄₀ and R ₅₀ are the same or different and are a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, An optionally substituted amino group or formula: Y
₃₀ -W ₂₀ -Y ₄₀ -R _{s0 (wherein, R s0, W 20, Y} 30 and Y
₄₀ has the above-mentioned meaning), a substituent or a lower alkyl group, a cyano group, a nitro group, an optionally protected carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, May be a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, an optionally protected carboxy lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, optionally protected amino group A lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an optionally protected amino-lower alkyl group, a lower alkylamino-lower alkyl group, a di-lower alkylamino-lower alkyl group, and a tri-lower alkylammonio Lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, protected Substituents and wherein also be selected from the group consisting of good hydroxyimino group and a lower alkoxyimino _{group: Y 30 -W 20 -Y 40 -R} s0 ( wherein,
R _s0 , W ₂₀ , Y ₃₀ and Y ₄₀ have the same meaning as described above), and have 1 to 3 identical or different substituents as appropriate. May represent a lower alkyl group, an aryl group or an aralkyl group;

[0175]

Embedded image Represents a single bond or a double bond];
General formula (IV)

[0176]

[Of 75] Wherein Ar ₀ is a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, A nitrogen-containing heteroaromatic group selected from the group consisting of an isoquinolyl group, a benzothiazolyl group and a benzooxazolyl group, wherein (1) a lower alkyl group, an optionally protected hydroxyl group, a cyano group, a halogen atom, nitro Group, optionally protected carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, optionally protected hydroxy lower alkyl group, cyano lower alkyl group,
Halo-lower alkyl group, optionally protected carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, dialkyl Lower alkylcarbamoyl group, carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, optionally protected amino group,
Lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl ammonium lower alkyl group, lower alkanoylamino Group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, optionally protected hydroxyimino group and lower alkoxyimino group. Group and formula: Y ₁₀ -W ₁₀ -Y ₂₀
-R _p0 (wherein, R _p0 , W ₁₀ , Y ₁₀ and Y ₂₀ have the above-mentioned meanings), and are suitably 1 to 3 substituents A nitrogen-containing heteroaromatic group optionally having the same or a different substituent, (2)
Lower alkyl group, lower alkanoyl group, lower alkanoyloxy group, optionally protected hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group,
Optionally protected carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group,
Lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group,
Lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, optionally protected amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl ammonium lower group A substituent selected from the group consisting of an alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group and a lower alkanoylamidino lower alkyl group (hereinafter, even if protected, Together with the carbon atom on the ring to which it is attached, the adjacent carbon atom and the carbon, oxygen and / or nitrogen atom on the optionally protected ring substituent. Become,

[0177]

Embedded image A nitrogen-containing heteroaromatic group forming a 5- or 7-membered ring which may be protected, selected from the group consisting of: or (3)
Formula: Y ₁₀ -W ₁₀ -Y ₂₀ -R _p0 (where Y ₁₀ , W ₁₀ , Y ₂₀
And R _p0 have the meaning described above) together with the carbon atom on the ring to which the substituent is bonded, the adjacent carbon atom, and the carbon atom, oxygen atom and / or nitrogen atom on the substituent. hand,

[0178]

Embedded image And a nitrogen-containing heteroaromatic group forming a 5- or 7-membered ring which may be protected, selected from the group consisting of the following:

[0179]

Embedded image [Wherein, Ar ₀ , X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0180]

Embedded image Has the above-mentioned meaning], and the protecting group is appropriately removed to give a compound of the general formula (I)

[0181]

Embedded image [Wherein, Ar represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, isoquinolyl] A nitrogen-containing heteroaromatic group selected from the group consisting of a benzothiazolyl group and a benzooxazolyl group, wherein (1) a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group,
Carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl Group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group,
Lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl ammonium lower alkyl group, lower alkanoylamino A substituent selected from the group consisting of a group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a formula: Y ₁ -W ₁ -Y ₂ -R _p (wherein R _p is a lower alkyl group, a lower alkenyl group or a lower alkynyl group or a substituted group thereof, which may have 1 to 3 hydrogen atoms or 1 to 3 substituents as appropriate) 1 to 3 groups as appropriate,

[0182]

Embedded image A cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of Group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group,
Selected from the group consisting of benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl. Aromatic heterocyclic group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
An aliphatic heterocyclic group selected from the group consisting of a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₁ is a single bond, an oxygen atom, a sulfur atom,
O, SO _{2 ,} NR _q , SO ₂ NR _q , N (R _q ) SO ₂ NR _r ,
_{N (R q) SO 2,} CH (OR q), CONR q, N
_{(R q) CO, N (} R q) CONR r, N (R q) COO,
N ( _Rq ) CSO, N ( _Rq ) COS, C ( _Rq ) = C
R _r , C≡C, CO, CS, OC (O), OC (O) N
R _q , OC (S) NR _q , SC (O), SC (O) NR _q
Or C (O) O (where R _q and R _r represent a hydrogen atom or a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower group) Alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group, or A lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 substituents as appropriate), Y
₁ and Y ₂ are the same or different and represent a single bond or a linear or branched lower alkylene group which may have one bicyclic or tricyclic fused ring) A substituent selected from the group consisting of the substituents shown, and optionally having 1 to 3 identical or different substituents, a nitrogen-containing heteroaromatic group, (2) a lower alkyl group, a lower Alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxy Carbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group , A tri-lower alkylammonio lower alkyl group,
A substituent selected from the group consisting of a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group and a lower alkanoylamidino lower alkyl group (hereinafter abbreviated as an on-ring substituent); Together with the carbon atom on the ring to which it is attached, its adjacent carbon atoms and the carbon, oxygen and / or nitrogen atoms on said ring substituents,

[0183]

Embedded image Or a nitrogen-containing heteroaromatic group forming a 5- to 7-membered ring selected from the group consisting of: or (3) Y ₁ -W ₁ -Y ₂ -R _p
Wherein Y ₁ , W ₁ , Y ₂ and R _p have the above-mentioned meaning.
Together with the carbon atom on the ring to which the substituent represented by bonds, the adjacent carbon atom and the carbon atom, oxygen atom and / or nitrogen atom on the substituent,

[0184]

Embedded imageForm a 5- to 7-membered ring selected from the group consisting of
Nitrogen-containing heteroaromatic group, R ₁Is a hydrogen atom or a formula: Y_Three
-W_Two-Y_Four-R_s(Where R_sIs a hydrogen atom or the substituent
Lower alkyl, which may optionally have 1 to 3
Group, lower alkenyl group, lower alkynyl group, cyclo-lower
Alkyl group, aryl group, imidazolyl group, isoxa
Zolyl group, isoquinolyl group, isoindolyl group,
Zolyl group, indolyl group, indolizinyl group, isothia
Zolyl group, ethylenedioxyphenyl group, oxazolyl
Group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyri
Dazinyl group, pyrazolyl group, quinoxalinyl group, quinolinyl group
Group, dihydroisoindolyl group, dihydroindolyl group
Group, thionaphthenyl group, naphthyridinyl group, phenazini
Group, benzimidazolyl group, benzoxazolyl group,
Benzothiazolyl group, benzotriazolyl group, benzofu
Ranyl, thiazolyl, thiadiazolyl, thienyl
Group, pyrrolyl group, furyl group, furazanyl group, triazolyl group
Group, benzodioxanyl group and methylenedioxyphen
An aromatic heterocyclic group selected from the group consisting of
Are isoxazolinyl, isoxazolidinyl, tetra
Hydropyridyl group, imidazolidinyl group, tetrahydro
Furanyl group, piperazinyl group, piperidinyl group, pylori
Dinyl group, pyrrolinyl group, morpholino group, tetrahydro
Quinolinyl and tetrahydroisoquinolinyl groups
An aliphatic heterocyclic group selected from the group consisting of_TwoIs a single bond,
Oxygen atom, sulfur atom, SO, SO_Two, NR_t, SO_TwoN
R _t, N (R_t) SO_TwoNR_u, N (R_t) SO_Two, CH (O
R_t), CONR_t, N (R _t) CO, N (R_t) CONR
_u, N (R_t) COO, N (R_t) CSO, N (R_t) CO
S, C (R_v) = CR_r, C≡C, CO, CS, OC
(O), OC (O) NR _t, OC (S) NR_t, SC
(O), SC (O) NR_tOr C (O) O (here
And R_tAnd R_uIs a hydrogen atom or a lower alkyl group,
Hydroxyl group, cyano group, halogen atom, nitro group, carboxy
Sil group, carbamoyl group, formyl group, lower alkanoy
Group, lower alkanoyloxy group, hydroxy lower alkyl
A kill group, a cyano lower alkyl group, a halo lower alkyl group,
Carboxy lower alkyl group, carbamoyl lower alkyl
Group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxyca
Rubonylamino lower alkyl group, lower alkyl carbamo
Yl group, di-lower alkylcarbamoyl group, carbamoyl
Oxy group, lower alkylcarbamoyloxy group, di-lower
Alkylcarbamoyloxy group, amino group, lower alkyl
Ruamino group, di-lower alkylamino group, tri-lower alkyl
Luammonio group, amino lower alkyl group, lower alkyl
Amino lower alkyl group, di-lower alkylamino lower alkyl
A kill group, a tri-lower alkylammonio lower alkyl group,
Lower alkanoylamino group, aroylamino group, lower
Lucanoylamidino lower alkyl group, lower alkyl sulf
Finyl group, lower alkylsulfonyl group, lower alkyl
Sulfonylamino group, hydroxyimino group and lower alkyl
A substituent selected from the group consisting of a coxiimino group or
Lower alkyl optionally having 1 to 3 substituents
A kill group, an aryl group or an aralkyl group), Y
_ThreeAnd Y_FourAre the same or different and are a single bond or linear or
Or a branched lower alkylene group)
Group, or lower alkyl group, hydroxyl group, cyano group, halogen
Atom, nitro group, carboxyl group, carbamoyl group, e
Lumyl group, lower alkanoyl group, lower alkanoyl oxo
Si group, hydroxy lower alkyl group, cyano lower alkyl
Group, halo lower alkyl group, carboxy lower alkyl group,
Carbamoyl lower alkyl group, lower alkoxy group, lower
Alkoxycarbonyl group, lower alkoxycarbonyl group
Mino group, lower alkoxycarbonylamino lower alkyl
Group, lower alkylcarbamoyl group, di-lower alkyl carb
Bamoyl group, carbamoyloxy group, lower alkyl carb
Bamoyloxy group, di-lower alkylcarbamoyloxy
Group, amino group, lower alkylamino group, di-lower alkyl
Amino group, tri-lower alkylammonio group, amino lower
Alkyl group, lower alkylamino lower alkyl group, di-low
Lower alkylamino lower alkyl group, tri-lower alkyl group
Lower ammonium group, lower alkanoylamino group,
Aroylamino group, lower alkanoylamidino lower al
Kill group, lower alkylsulfinyl group, lower alkyls
Ruphonyl group, lower alkylsulfonylamino group, hydro
A group consisting of a xyimino group and a lower alkoxyimino group
And a substituent selected from the formula: Y_Three-W_Two-Y_Four-R_s(formula
Medium, R_s, W_Two, Y_ThreeAnd Y_FourHas the meaning given above)
A substituent selected from the group consisting of
With one to three identical or different substituents
Or a lower alkyl group which may be
Form an elementary atom, R _TwoAnd R_ThreeAre the same or different
Standing hydrogen atom, hydroxyl group, lower alkyl group, lower alcohol
Xy group or formula: Y_Three-W_Two-Y_Four-R_s(Where R_s,
W_Two, Y_ThreeAnd Y_FourHas the meaning described above)
A substituent or R_TwoAnd R_ThreeAny one of R₁as well as
Together with X,

[0185]

Embedded image And

[0186]

Embedded image And a saturated 5- or 8-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, a carbon atom or an oxygen atom contained in a substituent on the ring on the ring. And / or form a 5- to 7-membered ring with the nitrogen atom or together form a spiro lower alkyl group,
It may form an oxo group together with the bonding Z, or may include one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur together with the bonding Z, R ₁ and X; Lower alkyl group, optionally substituted spirocyclo lower alkyl group, hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl Group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group; : Y ₁ -W ₁ -Y ₂ -R _p (wherein, R _p , W ₁ , Y ₁ and Y ₂
Is a substituent selected from the group consisting of the substituents represented by the above), and is suitably 1 to 3 identical or different substituents, and further 1 to 3 identical or different as appropriate Cyclo lower alkyl group which may have a substituent, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group, Benzothiazolyl group Aromatic selected from the group consisting of benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl Heterocyclic group and isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
A morpholino group, which may be condensed with a ring selected from the group consisting of an aliphatic heterocyclic group selected from the group consisting of a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group,

[0187]

Embedded image And

[0188]

Embedded image Forming a saturated or unsaturated 5- to 8-membered ring group selected from the group consisting of: R ₄ and R ₅ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a group represented by the formula: Y ₃ -W _{(wherein, R s, W 2, Y} 3 and Y ₄ are as defined above) ₂ -Y ₄ -R _s substituent group or a lower alkyl group represented by a cyano group, a nitro group, a carboxyl group, Carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower Alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkyl A carbamoyl group, a carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino Lower alkyl group,
Tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino group and lower alkoxyimino group A substituent selected from the group and the formula: Y ₃
—W ₂ —Y ₄ —R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meanings), and are appropriately selected from the group consisting of X represents a lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 same or different substituents;

[0189]

Embedded image Has the meaning described above].

The compound of the general formula (I) is
It can also be produced by subjecting the compound of II) to, for example, trichloroacetylation or p-nitrophenoxycarbonylation, and then reacting with the compound of the general formula (VI).

The compound of the formula (III) and the compound of the formula (I)
The reaction with the compound of V) is carried out by reacting the compound 1 of the general formula (III)
It is carried out using preferably about 1 mol of the compound of the general formula (IV) per mol.

The trichloroacetylation or p-nitrophenoxycarbonylation of the compound of the general formula (III) is carried out by adding 1 to 5 moles, preferably approximately 1 mole, of the corresponding halide to 1 mole of the compound of the general formula (III). It is carried out using 1 mole. Then, the obtained general formula (III)
The reaction is carried out using 1 to 5 mol, preferably about 1 mol of the compound of the general formula (VI) per 1 mol of the trichloroacetylated compound or the p-nitrophenoxycarbonylated compound of the compound of the formula (1).

The reaction is usually carried out in an inert solvent such as an ether such as tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene or toluene, or a mixed solvent thereof.

The reaction temperature is appropriately selected according to the starting compounds used, and is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 to 100 ° C.

The reaction time is usually completed in 20 minutes to 24 hours, preferably 1 hour to 4 hours, but can be appropriately increased or decreased.

In the compound of the general formula (III) and the compound of the general formula (IV), for example, a hydroxyl group, an amino group,
When a functional group such as a carboxyl group or a substituent containing the functional group such as a hydroxy lower alkyl group, an amino lower alkyl group, or a carboxy lower alkyl group is present, the hydroxyl group, an amino group, a carboxyl group, a hydroxy lower alkyl group, The reaction is preferably performed after protecting a substituent such as an amino lower alkyl group and a carboxy lower alkyl group with a protecting group for a hydroxyl group, a protecting group for an amino group, and a protecting group for a carboxyl group. By removing the protecting group of the compound of the general formula (II) obtained after the completion of the reaction,
Compounds of general formula (I) can be prepared.

Examples of the hydroxyl-protecting group include tert.
-Butyldimethylsilyl group, tert-butyldiphenyl
A lower alkylsilyl group such as a lucyl group; for example, methoxy
Lower alkyl such as methyl group and 2-methoxyethoxymethyl group
Coxymethyl group; for example, benzyl group, p-methoxybenz
Aralkyl groups such as a zyl group; for example, formyl group, acetyl
And an acyl group such as a tert-butyldiene group.
A methylsilyl group, an acetyl group and the like are preferred.

Examples of the amino-protecting group include aralkyl groups such as benzyl group and p-nitrobenzyl group; acyl groups such as formyl group and acetyl group; lower alkoxy groups such as ethoxycarbonyl group and tert-butoxycarbonyl group. A carbonyl group; for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group;
Nitrobenzyl group, tert-butoxycarbonyl group,
A benzyloxycarbonyl group and the like are preferred.

Examples of the carboxyl-protecting group include a lower alkyl group such as a methyl group, an ethyl group and a tert-butyl group; an aralkyl group such as a benzyl group and a p-methoxybenzyl group; Ethyl, benzyl and the like are preferred.

The removal of the protecting group depends on the type and the stability of the compound.
Groups in Organic Synthesis (Pro
tive Groups in Organic
Synthesis), T.M. W. Green (TW.
Greene), John Wiley & Son
Co., Ltd. (1981)] or a method analogous thereto, for example, by solvolysis using an acid or a base, chemical reduction using a metal hydride complex, or catalytic reduction using a palladium carbon catalyst, Raney nickel catalyst, or the like. Can be.

When the compound of the formula (I) forms a bicyclic fused ring group, for example, a compound in which R ₂ and R ₃ together with Z forms an oxo group, that is, a compound of the formula (I ′) )

[0202]

Embedded image Wherein Ar, X, Y, R ₁ , R ₄ and R ₅ have the meaning described above,

Formula (IV)

[0204]

Embedded image Wherein Ar ₀ has the meaning described above, and a compound represented by the general formula (III ′):

[0205]

Embedded image Wherein X, Y, R ₁₀ , R ₄₀ and R ₅₀ have the same meanings as defined above, to give a compound of the general formula (II′-
a)

[0206]

Embedded image [Wherein, Ar ₀ , X, Y, R ₁₀ , R ₄₀ and R ₅₀ have the above-mentioned meanings], and can be produced by appropriately removing a protecting group. The reaction conditions in each step can be performed in the same manner as in Production Method A.

This production method can be applied to the production of a compound in which R ₂ and R ₃ are a hydrogen atom, an alkyl group or an alkoxy group.

Production Method B The compound of the general formula (I) can be prepared by reacting the compound of the general formula (V)

[0209]

Embedded image [Wherein, X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0210]

Embedded image Has the above-mentioned meaning], and a compound represented by the general formula (VI) H ₂ N—Ar ₀ [wherein, Ar ₀ has the above-mentioned meaning]. Formula (II)

[0211]

Embedded image [Wherein, Ar ₀ , X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0212]

Embedded image Has the above-mentioned meaning], and the protecting group is appropriately removed to give a compound of the general formula (I)

[0213]

Embedded image [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅
And formula

[0214]

Embedded image Has the above-mentioned meaning].

The step of this production method can be carried out according to the method of the step of producing the compound of the general formula (I) and the compound of the general formula (II) in the production method A.

Production Method C This production method is a method for producing a compound of the formula (I) wherein Ar is a pyrazolyl group. That is, the general formula (VI
I)

[0219]

Embedded image Wherein, L is the reactive substituent having a transformable functional group to other functional groups may be protected, T ₁₀ also have a single bond or optionally protected substituents And Ar ₀ having a convertible functional group containing a linear or branched lower alkylene group, aryl group, aromatic heterocyclic group, aliphatic heterocyclic group or aralkyl group.] (VIII) H ₂ N—NH—R ₆₀ (VIII) wherein R ₆₀ represents a hydrogen atom or an amino-protecting group, and reacted with a compound of the general formula (IX)

[0218]

Embedded image Wherein T ₁₀ , R ₆₀ and L have the same meanings as described above, and the compound represented by the general formula (III)

[0219]

Embedded image [Wherein, X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0220]

Embedded image

Embedded image [Where X, Y, Z, T ₁₀ , R ₁₀ , R ₂₀ , R _{30 ,} R ₄₀ ,
R ₅₀ , R ₆₀ , Formula

[0221]

Embedded image And L have the same meaning as described above], and the conversion of the substituent L and / or the removal of the protecting group to give a compound of the general formula (I '')

[0222]

Embedded image [Wherein T ₁ is Ar having a single bond or a linear or branched lower alkylene group, an aryl group, an aromatic heterocyclic group, an aliphatic heterocyclic group, or a convertible functional group containing an aralkyl group. _, Q represent W ₁ -Y ₂ -R _p (where W
₁ , Y ₂ and R _p have the meanings given above), X, Y, Z,
R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and the formula

[0223]

Embedded image Has the above-mentioned meaning] can be produced.

The compound of the general formula (VII) and the compound of the general formula (VI)
The reaction of producing the compound of the general formula (IX) by reacting the compound of the general formula (IX) with 1 mol of the compound of the general formula (VIII) is preferably 1 mol to excess mol, preferably 1 mol of the compound of the general formula (VII). The reaction can be carried out by reacting 2 to 3 moles in an alcohol such as ethanol or butanol. When the compound of the general formula (VIII) used is a salt with an acid, for example, 2 to 5 mol of a base such as triethylamine is used per 1 mol of the compound of the general formula (VIII).
It is preferable to form a free form of the compound of the general formula (VIII) in the presence of preferably 2 to 3 mol.

The reaction temperature is generally from 20 ° C. to the boiling point of the solvent used in the reaction, preferably from 50 ° C. to 150 ° C. The reaction time is usually from 1 hour to 48 hours, preferably from 2 hours to 24 hours. is there.

The compound of the general formula (IX),
The reaction for producing the compound of the general formula (X) by reacting the compound of the formula (I) and the reactive derivative of the formate with an appropriate base in the presence of a base is carried out based on 1 mol of the compound of the general formula (IX)
The compound of the formula (III) is used in an amount of 1 mol to excess mol, preferably 1 to 3 mol. The reactive derivative of formate is 1 mol to excess mole, preferably 1 to 3 mol, per 1 mol of the compound of the general formula (IX).
Preferably, 1 to 3 mol is used. The reactive derivative of formate is not particularly limited as long as it can form an amide carboxylate, and specific examples thereof include p-nitrophenyl chloroformate and methyl chloroformate.

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride and chloroform;
Ethers such as tetrahydrofuran; for example, benzene,
Aromatic hydrocarbons such as toluene; for example, aprotic polar solvents such as dimethylformamide, acetone, and ethyl acetate; and mixed solvents thereof.

The reaction temperature is usually 20 ° C. for the reaction of the compound of the formula (IX) with a reactive derivative of formate.
Or up to the boiling point of the solvent used in the reaction, preferably at 20 ° C.
To 50 ° C, and the reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 24 hours. After the reaction is completed, in the step of reacting with the compound of the general formula (III), the temperature is usually from 20 ° C to the boiling point of the solvent used in the reaction, preferably from 50 ° C to 100 ° C.

Further, a carboxyl group is introduced into the compound of the general formula (X) using a metal complex as a catalyst and derivatized into, for example, an amide compound or an ester compound according to a conventional method. The compound of the general formula (I ″) can be produced by appropriately combining the removal reactions of the protecting groups such as above.

The compound of the general formula (X) may be replaced with, for example, a compound of the general formula (III), instead of using the compound of the general formula (IX), the compound of the general formula (III) and the reactive derivative of formate. Can also be produced by reacting a compound of the formula (I) with diphosgene in the presence of activated carbon to give an isocyanate, and then reacting with a compound of the general formula (IX).

The reaction is usually performed in an inert solvent, and examples of the inert solvent include tetrahydrofuran.

The amount of each reagent used in the reaction is represented by the general formula (II)
The amount of diphosgene is 1 mol to excess mol, preferably 1 mol, the activated carbon is 5 g, and the compound of the formula (IX) is 1 mol to excess mol, preferably 1 mol, per 1 mol of the compound of I).

The reaction temperature is usually from 20 ° C. to the boiling point of the solvent used in the reaction, preferably from 30 ° C. to 100 ° C.

The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

In the compound of the general formula (X), the step of converting the reactive substituent L having a functional group convertible to another functional group may be performed, for example, when R is an aromatic ring and L is a halogen atom.
The compound of the general formula (X) is reacted with a compound of the general formula (X) and carbon monoxide in an alcohol solvent such as methanol or ethanol using a palladium complex as a catalyst in the presence of a phosphine ligand and a base. , And then a method of hydrolyzing the ester under basic conditions can be applied.

The reactive substituent having a functional group that can be converted into another functional group includes, for example, a substituent such as a hydroxyl group, an amino group, a carboxyl group, an ester group, and a halogen atom.

The amount of each reagent used in the reaction is represented by the general formula (X)
And a phosphine ligand such as 1,1-bis (diphenylphosphino) ferrocene, for example, in an amount of 5 to 1 mol of the compound
The base is used in an amount of 50% by weight, preferably 10 to 20% by weight, and, for example, a base such as sodium hydrogen carbonate is used in an amount of 2 to 10 mol, preferably 2 to 3 mol, per 1 mol of the compound of the formula (X).

The reaction temperature is usually from 20 ° C. to the boiling point of the solvent used in the reaction, preferably from 50 ° C. to 100 ° C. The reaction time is usually from 30 minutes to 24 hours, preferably from 5 hours to 24 hours. is there.

The method for further converting the carboxylic acid thus produced can be carried out in the same manner as the method for converting the Ar substituent described below.

After completion of the reaction, a usual treatment is carried out, and if necessary, a reaction for removing a protecting group such as a hydroxyl group, an amino group and a carboxyl group is appropriately combined, whereby the compound of the formula (I '') is obtained. Can be manufactured.

The method for removing the protecting group varies depending on the type of the protecting group, the stability of the target compound, and the like, but can be appropriately performed according to, for example, the method described in the above-mentioned literature or a method analogous thereto.

Next, a method for converting a substituent on Ar in the compound of the formula (I) will be described.

As described above, Ar can have various substituents. For example, as shown in Production Method A and Production Method B, a desired compound can be produced by using a compound obtained by introducing a desired substituent into an initial raw material compound. However, in order to improve reactivity, yield, etc.,
For example, after producing a compound of the general formula (II) having -T ₁ -OR ₇ (where R ₇ is a protecting group for a hydroxyl group and T ₁ has the above-mentioned meaning), a further functional group conversion reaction is carried out. (Conversion Method A), or in order to protect the urea portion of the compound of the general formula (II) and then introduce a desired substituent, for example, various conversions as shown in the following Conversion Methods B to H The reaction can be performed.

Conversion Method A This conversion method is a method for converting a functional group on Ar without protecting the urea portion. Various conversion methods are described in, for example, general formula (II-c).

[0245]

Embedded image [Wherein Ar _C0 is the above-mentioned A containing a substituent: -T ₁ -OR ₇ (where R ₇ and T ₁ have the above-mentioned meanings)
indicates _{r 0, X, Y, Z} , R 10, R 20, R 30, R 4 0, R
₅₀ and formula

[0246]

Embedded image Has the above-mentioned meaning].
General formula (II-d)

[0247]

Embedded image [Wherein, Ar _d0 represents the above-mentioned Ar ₀ containing a substituent: —T ₁ —OH (where T ₁ has the above-mentioned meaning), and X, Y, Z, R ₁₀ , R ₂₀ , R _30, R _40, R ₅₀ and the formula

[0248]

Embedded image Has the meaning described above], or the compound of the general formula (II-d) can be obtained by using various synthetic methods well known in organic synthetic chemistry for converting an alcohol to an amine. II-e)

[0249]

Embedded image [Wherein, Ar _e0 represents the above Ar ₀ containing a substituent: -T ₁ -NH ₂ (where T ₁ has the above-mentioned meaning), and X, Y, Z, R ₁₀ , R _{20 , R 30, R 40, R} 5 0 and equation

[0250]

Embedded image Has the meaning described above].

The method for removing the protecting group for the hydroxyl group varies depending on the kind of the protecting group, the stability of the target compound, and the like.

As various synthesis methods and reaction conditions for converting an alcohol into an amine, for example, a so-called Mitsunobu reaction using diethyl azodicarboxylate, triphenylphosphine and phthalimide (or diphenylphosphoric azide) may be carried out, or triethylamine may be used. Sulfonation with a sulfonylating agent such as methanesulfonyl chloride in the presence of a base such as methanesulfonyl chloride, and then reacting with phthalimide (or sodium azide) in the presence of a base. Is preferred.

The above reaction is usually carried out in an inert solvent,
As the inert solvent, in the Mitsunobu reaction, for example, tetrahydrofuran, chloroform, dimethoxyethane,
In the reaction in which benzene, toluene or the like reacts with sulfonylation and phthalimide (or sodium azide), examples include methylene chloride, chloroform, tetrahydrofuran, benzene, ethyl acetate, dimethylformamide and the like.

In the reaction for removing the phthalimide group with hydrazine, alcohols such as methanol and ethanol are used, and when a metal hydride complex is used in the azide reduction reaction, ethers such as ethyl ether and tetrahydrofuran are used. In the case of performing phosphine reduction with triphenylphosphine or the like, it is preferable to use, for example, aqueous tetrahydrofuran or the like, and in the reduction by catalytic reduction, for example, alcohols such as methanol or ethanol are used.

The amount of the reagent used is, for example, in the above-mentioned Mitsunobu reaction, with respect to 1 mol of the compound of the general formula (II-d), diethyl azodicarboxylate, triphenylphosphine and phthalimide (or diphenylphosphoric azide).
Is 1 mol to excess mol, preferably 1 to 5 mol. In the reaction of reacting phthalimide (or sodium azide) after sulfonylation, the compound represented by the general formula (I)
The sulfonylating agent is used in an amount of 1 mol to excess, preferably 1 to 3 mol, per 1 mol of the compound of Id), and the base used in this case is 1 mol to excess, preferably 1 mol, of the sulfonylating agent. Is 1 to 3 mol. In the reaction for reacting phthalimide (or sodium azide) in the next step, phthalimide and a base or sodium azide are used in an amount of 1 mol to excess mol, preferably 1 to 5 mol, per mol of the sulfonylating agent. In the removal reaction of the phthalimide group with hydrazine, hydrazine is used in an amount of 1 mol to excess mol, preferably 1 mol, per 1 mol of the phthalimide compound.
In the reduction reaction of the azide compound with a metal hydride complex or triphenylphosphine, the reducing agent is used in an amount of 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol of the azide compound.

In the Mitsunobu reaction, the reaction temperature is usually-
70 ° C to 100 ° C, preferably 20 ° C to 50 ° C,
The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes.
Minutes to 24 hours. In the case of the reaction for removing the phthalimide group with hydrazine, the reaction temperature is usually from 0 ° C to the boiling point of the solvent used in the reaction, preferably from 20 ° C to 100 ° C.
° C, and the reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours. When a metal hydride complex is used as a reducing agent in a reaction for converting an azide compound to an amine compound, the reaction temperature is usually from -70 ° C to 15 ° C.
0 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 1 hour.
0 hours, and when using triphenylphosphine as the reducing agent, the reaction temperature is usually from 20 ° C to the boiling point of the solvent used in the reaction, preferably from 30 ° C to 100 ° C.
The reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 24 hours. In the case of reduction by catalytic reduction, the reaction temperature is usually 0 ° C to 100 ° C, preferably 20 ° C to 50 ° C, and the reaction time is generally 10 minutes to 48 hours, preferably 10 minutes to 24 hours. .

After completion of the reaction, the reaction product is subjected to a usual treatment, and if necessary, a reaction for removing a protecting group such as a hydroxyl group, an amino group, and a carboxyl group is appropriately combined, thereby obtaining a compound of the formula (II-e). Can be manufactured.

Among the compounds of the general formula (II-d), those of the general formula (II-d ₁ )

[0259]

Embedded image [In the formula, Ar _d1 is a substituent: -T ₁ -CH (R _d1 ) -O
H (where R _d1 is a hydrogen atom, a lower alkyl group, an aralkyl group, an aromatic ring group, a heteroaromatic ring group or a nitrogen atom, an oxygen atom and a sulfur A saturated or unsaturated aliphatic ring group which may contain one or more hetero atoms selected from the group consisting of atoms and may have a substituent as appropriate, and T ₁ has the above-mentioned meaning. means Ar ₀ of the containing a has), X, Y, Z, R 10, R 20, R 3 0, R 40, R 50 and the formula

[0260]

Embedded image Has the above-mentioned meaning].
After performing an oxidation reaction, the compound represented by the general formula (II-d ₂ )

[0261]

Embedded image [ _Wherein , Ar _d2 represents a substituent: —T ₁ -C (＝ O) —R _d1
(Where R _d1 and T ₁ have the above meanings)
Means Ar ₀ as described above, and X, Y, Z, R ₁₀ ,
R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0262]

Embedded image Has the above-mentioned meaning], and is subjected to reductive amination to give a compound of the general formula (II-d ₃ )

[0263]

Embedded image [Wherein, Ar _d3 represents a substituent: —T ₁ —CH (R _d1 ) —N
R _d2 R _d3 (where R _d2 and R _d3 are each a hydrogen atom, or a lower alkyl group, an aralkyl group, which may be the same or different and may optionally have a protected substituent, An aromatic ring group, a heteroaromatic ring group or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom may contain one or more heteroatoms, and may have a substituent, if necessary. X represents an unsaturated aliphatic ring group, and R _d1 and T ₁ have the same meaning as defined above, and Ar ₀ includes X, Y, Z, R ₁₀ , R ₂₀ ,
R ₃₀ , R ₄₀ , R ₅₀ and formula

[0264]

Embedded image Has the above-mentioned meaning] can be produced.

As the reaction for oxidizing the compound of the formula (II-d ₁ ) to synthesize the compound of the formula (II-d ₂ ), an oxidation reaction generally well known in the synthesis can be applied.

Formula (II-d)_Two)) And R_d2R_d3
NH (where R_d2And R_d3Has the above meaning)
The reductive amination reaction with the compound represented by the general formula (II)
-D _Two)), 1 mole of the compound_d2R_d31 mol of NH
To an excess mole, preferably 3 to 5 moles,
For example, sodium borohydride or thoria hydride
1 mole to excess mole of sodium cetoxyboron,
Preferably, 3 to 5 mol is used, and if necessary, molecular
Sieves 3A has the general formula (II-d)_Two) Of the weight of the compound
Perform by adding 3 times the amount.

The reaction is usually performed in an inert solvent, and as the inert solvent, chloroform, methanol, a mixed solvent thereof or the like is preferable. The reaction temperature is from 20 ° C to the boiling point of the inert solvent used, preferably from 20 to 60 ° C.

The step of synthesizing the compound of the general formula (II-d ₃ ) from the compound of the general formula (II-d ₁ ) through the compound of the general formula (II-d ₂ ) The same procedure can be performed after the urea portion is protected.

The thus obtained general formula (II-
The compound of general formula (I) can be produced from the compound of c), the compound of general formula (II-d) and the compound of general formula (II-e) by appropriately removing the protecting group.
The method for removing the protective group varies depending on the type of the protective group, the stability of the target compound, and the like, and can be appropriately performed according to, for example, the method described in the above-mentioned literature or a method analogous thereto.

Conversion Method B This production method is a method in which the urea moiety is protected and then converted. General formula (XI)

[0271]

Embedded image [Wherein, Ar _C0 , X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0272]

Embedded image Has the above-mentioned meaning.] Is a compound of the general formula (II-
c)

[0273]

Embedded image [Wherein Ar _C0 is the above-mentioned A containing a substituent: -T ₁ -OR ₆ (wherein R ₆ and T ₁ have the above-mentioned meanings)
r ₀ means X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ ,
R ₅₀ and formula

[0274]

Embedded image Has the above-mentioned meaning] can be used as a starting compound for the present conversion reaction by stirring a compound of the formula (XI) in an imine prepared from tert-butylamine and paraformaldehyde. By removing the hydroxyl-protecting group of the general formula (XII)

[0275]

Embedded image [Wherein, Ar _d0 represents the above Ar ₀ containing a substituent: —T ₁ —OH (where T ₁ has the above meaning), and X, Y, Z, R ₁₀ , R _{20, R 30, R 40,} R 50 and the formula

[0276]

Embedded image Has the above-mentioned meaning] can be produced.

The reaction for producing the compound of the general formula (XI) is performed based on 1 mol of the compound of the general formula (II-c)
The reaction is carried out using 3 to 5 mol, preferably 4 mol, of the imine prepared from t-butylamine and paraformaldehyde.

The above reaction is usually carried out in an inert solvent, and examples of the inert solvent include chloroform, methylene chloride, tetrahydrofuran and the like.

The reaction temperature is usually from 50 ° C. to the boiling point of the solvent used in the reaction, preferably from 80 ° C. to 150 ° C. The reaction time is usually from 12 hours to 72 hours, preferably from 24 hours to 72 hours. is there. If necessary, one drop of a mineral acid such as sulfuric acid may be added to accelerate the reaction.

The compound of the general formula (XII) has the general formula (XII)
Using the compound of I), the compound represented by the general formula (II-
It can be carried out according to the method of the step of producing the compound of the general formula (II-d) from the compound of c).

The compound of the general formula (XII) is a key intermediate for producing the compound of the general formula (I), for example, as shown in the following conversion methods C to E, The derivatization can be carried out using the compound of (1) or a derivative thereof.

Conversion Method C General Formula (XII)

[0283]

Embedded image [Wherein, Ar _d0 , X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0284]

Embedded image Has the above-mentioned meaning] and a compound of the general formula (XII)
I)

[0285]

Embedded image Wherein Ar ₂ represents a phenyl group substituted by 1 to 2 nitro groups, and R ₈ represents a benzyl group substituted by 1 to 3 methoxy groups. By the reaction, the compound represented by the general formula (XIV)

[0286]

Embedded image [In the formula, Ar _d1 is a substituent: -T ₁ -N (R ₈ ) SO ₂ A
R ₂ (where T ₁ , R ₈ , and Ar ₂ have the above-mentioned meanings), and the above-mentioned Ar ₀ means X, Y, Z, R
_{10, R 20, R 30,} R 40, R 50 and the formula

[0287]

Embedded image Has the meaning described above] can be produced.

The reaction is carried out according to a conventional method of the Mitsunobu reaction using 1 mol to an excess, preferably 1 to 3 mol, of the compound of the general formula (XIII) relative to 1 mol of the compound of the general formula (XII). . For example, a diester of azodicarboxylic acid such as diethyl azodicarboxylate and a phosphine such as triphenylphosphine are represented by the general formula (XII):
By activating the compound of formula (XIII) and reacting with the compound of formula (XIII), the compound of formula (XIV) can be obtained.

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as ethyl ether and tetrahydrofuran or a mixed solvent thereof. And the like.

The amount of the reagent to be used is represented by the formula (XII)
For each mole of the compound of formula (I), a diester of azodicarboxylic acid such as diethylazodicarboxylate and a phosphine such as triphenylphosphine are each added in an amount of 1 mole.
The amount is from mol to excess mol, preferably from 1 mol to 3 mol.

The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 ° C. to 40 ° C.

The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 24 hours.

After completion of the reaction, a usual treatment is performed to obtain a crude product of the compound represented by the general formula (XIV). The compound represented by the general formula (XIV) thus obtained is purified according to a conventional method to obtain a compound represented by the general formula (XIV)
Can be obtained.

From the compound of the general formula (XIV), the compound of the general formula (X
V)

[0295]

Embedded image[Wherein, Ar_d2Is a substituent: -T₁-NHSO_TwoAr
_Two(Where T₁, Ar _TwoHas the above meaning
Ar)₀X, Y, Z, R_Ten,
R ₂₀, R₃₀, R₄₀, R₅₀And formula

[0296]

Embedded image Has the above-mentioned meaning].
It is carried out according to a usual method for removing an aralkyl group, which is one of the amino-protecting groups, for example, the method described in the above-mentioned literature.
From the compound of the general formula (XV) to the general formula (XVI)

[0297]

Embedded image [In the formula, Ar _d3 represents a substituent: —T ₁ —N (R _q ) SO ₂ A
r _{2 (wherein, R q, T 1, Ar} 2 are as defined above) refers to Ar ₀ of the containing, X, Y, Z, R
_{10, R 20, R 30,} R 40, R 50 and the formula

[0298]

Embedded image Has the above-mentioned meaning].
Using 1 mol to excess mol, preferably 1 to 3 mol of R _q —OH (where R _q has the above-mentioned meaning) to 1 mol of the compound of the general formula (XV),
The reaction can be carried out in the same manner as in the reaction of the compound of the formula II) with the compound of the general formula (XIII). Accordingly, the same reaction conditions and the like can be applied.

From the compound of the general formula (XVI), the compound of the general formula (XVI)
VII)

[0300]

Embedded image [Wherein, Ar _d4 represents the above-mentioned Ar ₀ including a substituent: -T ₁ -NHR _q (where R _q and T ₁ have the above-mentioned meanings), and X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0301]

Embedded image Has the above-mentioned meaning].
For example, the reaction can be carried out according to a conventional method for hydrolysis of arylsulfonamide, for example, by using thiophenol, sodium carbonate and the like in an inert solvent. As the inert solvent, for example, dimethylformamide and the like are preferable.

When a substituent which can be converted in R _q is present in the synthesis, the compound of the formula (XVI) is subjected to a synthesis reaction, if necessary, to introduce a substituent appropriately, followed by the addition of a compound of the formula (XVI). From the compound of the formula (XVI), a compound of the general formula (XVII)
The same conditions as in the reaction for converting to can be applied.

The reaction temperature is usually from 20 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 ° C. to 80 ° C.

The reaction time is generally from 2 hours to 48 hours, preferably from 2 hours to 24 hours.

From the compound of the general formula (XVII), the compound of the general formula (II-f)

[0306]

Embedded image [Wherein, Ar _d4 represents the above-mentioned Ar ₀ including a substituent: -T ₁ -NHR _q (where R _q and T ₁ have the above-mentioned meanings), and X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0307]

Embedded image Has the above-mentioned meaning].
Acids suitable for compounds of general formula (XVII), such as hydrochloric acid,
The reaction can be performed with trifluoroacetic acid or the like. If necessary, the reaction can be carried out by mixing an acid with an inert solvent such as tetrahydrofuran or chloroform.

Further, for the compound of the general formula (XVI),
By performing a conversion reaction of a substituent on _{Rq as} needed, the same reaction can be performed on a compound into which a substituent is appropriately introduced.

The compound of the general formula (II-f) can also be synthesized by subjecting the compound of the general formula (XXIII) to reductive amination. In this synthesis method,
At an appropriate stage before and after the reductive amination reaction, for example, by treatment with hydrochloric acid, trifluoroacetic acid and the like,
By removing the protecting group of the urea moiety, the compound represented by the general formula (I)
The compound of If) can be produced.

When a protecting group is present in the compound in each step of the present production method, these protecting groups are removed at an appropriate stage of the above steps, and finally, all the protecting groups are removed. The compound of the general formula (I) can be produced.

The method for removing the protecting group varies depending on the kind of the protecting group, the stability of the target compound, and the like.

Conversion Method D In this conversion, the compound of the formula (XVII) produced by the conversion method C was used to convert the compound of the formula (XIX)

[0313]

Embedded image [ _Wherein , Ar _d5 is a substituent: -T ₁ -NR _q -T ₂ -R
_p (wherein, T ₂ represents a carbonyl group or a sulfonyl _{group, R p, R q, T} 1, Ar 2 are as defined above) refers to Ar ₀ of the containing, X, Y, Z, R ₁₀ ,
R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0314]

Embedded image Has the meaning described above], and then has the general formula (II-g)

[0315]

Embedded image [ _Wherein , Ar _d5 is a substituent: -T ₁ -NR _q -T ₂ -R
_{p (wherein, T 1, Ar 2, R} p, R q and T ₂ are as defined above) refers to Ar ₀ of the containing, X,
Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and formula

[0316]

Embedded image Has the above-mentioned meaning].

In the reaction for producing the general formula (XIX) from the compound of the general formula (XVII), the compound of the general formula (XVII) and the general formula (XVIII) R _p -T ₂ -OH [R _p and T ₂ Having the meaning of the above]], or a carboxylic acid, a sulfonic acid, or a reactive derivative thereof represented by the formula: General formula (XVIII)
As the reactive derivative of the carboxylic acid or sulfonic acid,
For example, acid halides, mixed acid anhydrides, active esters,
Active amides and the like are used. When the carboxylic acid of the general formula (XVIII) is used, condensation of N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 2-chloro-1,3-dimethylimidazolyl chloride, etc. The reaction is preferably performed in the presence of an agent.

The compound of the formula (XVII) and the compound of the formula (XV)
The reaction with the compound of the formula III) is carried out using 1 mol to excess, preferably 1 to 5 mol of the compound of the formula [(XVIII), based on 1 mol of the compound of the formula (XVII).

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as ethyl ether and tetrahydrofuran; And aromatic hydrocarbons such as dimethylformamide, acetone, ethyl acetate and the like, or a mixed solvent thereof.

The reaction temperature is usually from -20 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C. The reaction time is generally 10 minutes to 48 hours, preferably 30 minutes.
Minutes to 24 hours.

The above reaction can be carried out in the presence of a base in order to smoothly carry out the reaction. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and the like, or triethylamine, N-ethyldiisopropylamine, pyridine,
It is preferable to carry out the reaction in the presence of an organic base such as dimethylaminopyridine and N, N-dimethylaniline.

The amount of the base used is represented by the general formula (XVII)
The amount is from 1 mol to an excess mol, preferably from 1 to 5 mol, per 1 mol of the compound of I).

The acid halide of the general formula (XVIII) can be obtained by reacting a carboxylic acid or a sulfonic acid of the general formula (XVIII) with a halogenating agent according to a conventional method. As the halogenating agent, for example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene and the like are used.

The mixed acid anhydride of the carboxylic acid of the general formula (XVIII) can be obtained by converting a carboxylic acid of the general formula (XVIII) according to a conventional method, for example, a chloroformate such as ethyl chloroformate; an aliphatic carboxylic acid chloride such as acetyl chloride. And can be obtained by reacting

The active ester of the carboxylic acid of the general formula (XVIII) can be prepared by converting the carboxylic acid of the general formula (XVIII) according to a conventional method, for example, N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) By reacting in the presence of a condensing agent such as carbodiimide with an N-hydroxy compound such as N-hydroxysuccinimide, N-hydroxyphthalimide and 1-hydroxybenzotriazole; and a phenol compound such as 4-nitrophenol and pentachlorophenol. Obtainable.

The active amide of a carboxylic acid of the general formula (XVIII) can be obtained by converting a carboxylic acid of the general formula [xviii] according to a conventional method, for example, with 1,1′-carbonyldiimidazole,
1,1'-carbonylbis (2-methylimidazole)
And the like.

The thus obtained general formula (XIX)
The compound of the formula (II-)
By obtaining the compound of g) and further removing the protecting group,
Compounds of general formula (I) can be prepared.

The compound of the formula (XIX) is reacted with a suitable acid such as hydrochloric acid, trifluoroacetic acid and the like to give the compound of the formula (IIX)
The compound of Ig) can be prepared. If necessary, the reaction can be carried out by mixing an acid with an inert solvent such as tetrahydrofuran or chloroform.

In addition, the compound of the general formula (II-g) can be obtained by converting the compound of the general formula (II-f) of the conversion method A according to the method of the present production method.
Can be produced as a starting material.

Conversion Method E In this conversion method, a compound of the general formula (XX) is prepared using a compound of the general formula (XII).

[0331]

Embedded image [Wherein, Ar _h0 represents the above-mentioned Ar ₀ including a substituent: —T ₁ —OR _p (where R _p and T ₁ have the above-mentioned meanings), and X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and formula

[0332]

Embedded image Has the meaning described above], and then has the general formula (II-h)

[0333]

Embedded image [Wherein, Ar _h0 represents the above Ar ₀ including a substituent: —T ₁ —O—R _p (where R _p and T ₁ have the above meanings), and X, Y, _{Z, R 10, R 20,} R 3 0, R
_40, R ₅₀ and the formula

[0334]

Embedded image Has the above-mentioned meaning].

As the method for producing the compound of the general formula (XX) using the compound of the general formula (XII), various synthesis methods and reaction conditions for converting an alcohol into an ether can be used. For example, in the synthesis of an aryl ether, it is preferable to carry out a reaction with aryl alcohol using azodicarboxylic acid diethyl ester and triphenylphosphine, that is, a so-called Mitsunobu reaction. As a method for synthesizing an alkyl ether, for example, a compound represented by the general formula (XXI)
Reacting a halide (a commercially available reagent if a commercially available reagent is available) obtained from an alcohol of R _p —OH (where R _p has the above-mentioned meaning) or a sulfonic acid ester such as methanesulfonic acid ester And the like. Further, as a method for synthesizing an alkyl ether and an aryl ether, for example, a compound of the general formula (XII) is converted into a halide or a sulfonic acid ester and then reacted with an alcohol of the general formula (XXI) R _p -OH in the presence of a base. Method and the like. The conversion of the alcohol to the halide can be obtained by a conventional method, for example, by reacting carbon tetrabromide or triphenylphosphine in an inert solvent such as carbon tetrachloride. Sulfonates, for example, methanesulfonates, can be obtained by reacting methanesulfonyl chloride with a base such as triethylamine in an inert solvent such as ethyl acetate.

The compound of the general formula (II-h) is obtained by appropriately combining the thus obtained compound of the general formula (XX) with a reaction for removing protecting groups such as a hydroxyl group, an amino group and a carboxyl group. Can be manufactured.

The above reaction is usually carried out in an inert solvent,
As the inert solvent, in the Mitsunobu reaction, for example, tetrahydrofuran, chloroform, dimethoxyethane,
Benzene, toluene and the like are preferable for halogenation, for example, halogenated hydrocarbons such as carbon tetrachloride and chloroform, and for sulfonylation, for example, methylene chloride, chloroform, tetrahydrofuran, benzene, ethyl acetate, dimethylformamide and the like are preferable.

The amount of the reagent to be used is, for example, in the Mitsunobu reaction, 1 mol to excess mol of diethyl azodicarboxylate, triphenylphosphine and aryl alcohol per 1 mol of the compound of the general formula (XII), preferably Is 1 to 5 mol. In addition, the general formula (X
After halogenating the alcohol of XI), the compound of the general formula (XII)
In the reaction for reacting the compound of the formula (I), the halogenating agent is used in an amount of 1 mol to excess mol, preferably 1 to 3 mol, per 1 mol of the alcohol of the general formula (XXI). In the reaction to be reacted, the general formula (X
The halide is used in an amount of 1 mol to excess, preferably 1 to 5 mol, and the base is used in an amount of 1 mol to excess, preferably 1 to 5 mol, per 1 mol of the compound, per 1 mol of the compound of II). Further, in the reaction of converting the alcohol of the general formula (XXI) into a sulfonic acid ester and then reacting the compound of the general formula (XII),
The sulfonylating agent is added to 1 mole of the alcohol of XI).
The compound is used in an amount of from 1 mol to an excess, preferably from 1 to 3 mol, and from 1 mol to an excess, preferably from 1 to 5 mol, of the base per mol of the sulfonylating agent. In the reaction to be reacted, the general formula (X
The sulfonic acid ester is added to 1 mole of the compound of II).
The base is used in an amount of 1 mol to an excess, preferably 1 to 5 mol, and 1 mol to an excess of the base, preferably 1 to 5 mol, per 1 mol of the sulfonic acid ester.

When the compound of the general formula (XII) is converted into a halide or a sulfonic acid ester and then reacted with an alcohol of the general formula (XXI) in the presence of a base, the reaction can be carried out as described above.

In the Mitsunobu reaction, the reaction temperature is usually-
70 ° C to 100 ° C, preferably 20 ° C to 50 ° C,
The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes.
Minutes to 24 hours. In the reaction of reacting the compound of the general formula (XII) after halogenating the alcohol of the general formula (XXI), the reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 ° C. to 100 ° C. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours. After converting the alcohol of the general formula (XXI) to a sulfonic ester, the compound of the general formula (XI)
In the reaction for reacting the compound of I), the reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to 30 ° C,
The reaction time is generally 5 minutes to 48 hours, preferably 10 minutes.
Minutes to 10 hours. When the compound of the general formula (XII) is converted into a halide or a sulfonic ester and then reacted with an alcohol of the general formula (XXI) in the presence of a base, the reaction can be carried out according to the above.

After completion of the reaction, a usual treatment is carried out, and if necessary, a reaction for removing a protecting group such as a hydroxyl group, an amino group and a carboxyl group is appropriately combined, whereby the compound of the formula (II-h) is obtained. Can be produced, and the compound of the general formula (I) can be produced by further removing all protecting groups.

The method for removing the protecting group varies depending on the kind of the protecting group, the stability of the target compound, and the like.

Conversion Method F This conversion method uses a compound of the general formula (XXII)

[0344]

Embedded image [Wherein, Ar _i0 is the above Ar ₀ containing a substituent: -T ₁ -CHO (where T ₁ has the above-mentioned meaning)]
X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀
And formula

[0345]

Embedded image Has the above-mentioned meaning], and then represented by the general formula (XXIII)

[0346]

Embedded image [In the formula, Ar _i2 represents the above Ar ₀ containing a substituent: —T ₁ —CH ＝ R _v (where T ₁ has the above-mentioned meaning, and R _v represents an ester group) Means X, Y, Z, R
_{10, R 20, R 30,} R 40, R 50 and the formula

[0347]

Embedded image Has the above-mentioned meaning].

The reaction is carried out using 1 mol to excess mol, preferably 20 mol, of manganese dioxide with respect to 1 mol of the compound of the general formula (XII) to give a compound of the general formula (XXII). Acetic acid ester and a suitable base, for example sodium hydride, each in 1
The reaction is carried out using a mole to an excess mole, preferably 3 to 5 moles, to obtain a compound of the general formula (XXIII).

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include tetrahydrofuran,
Diethyl ether and the like.

In the reaction for synthesizing the compound of the general formula (XXII) from the compound of the general formula (XII), the reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 ° C. to 50 ° C. is there. In addition, the general formula (XXI
In the reaction for synthesizing the compound of the general formula (XXIII) from the compound of I), the temperature is usually -78 ° C to 20 ° C, preferably -78 ° C to 0 ° C.

The compound of the formula (XXIII) is subjected to a Diels-Alder reaction with a reactive diene compound or a generally well-known 1,3 dipole addition reaction, followed by treatment with an acid. General formula (II-i)

[0352]

Embedded image [In the formula, Ar _i2 represents a substituent: -T ₁ -Cy (where T ₁ has the above-mentioned meaning, and Cy may have a protected substituent, if necessary, hetero, Ar ₀ ) having X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0353]

Embedded image Has the above-mentioned meaning] can be produced.

The amount of each reagent used in the reaction is represented by the general formula (XX)
The reactive diene compound 1 is used per mole of the compound III).
It is from mole to excess mole, preferably 10 mole.

The above reaction is usually carried out in an inert solvent,
As the inert solvent, for example, halogenated hydrocarbons such as methylene chloride and chloroform, and acetonitrile are preferable.

The reaction temperature is from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 ° C. to 120 ° C.

After the reaction, to the obtained compound, the same conditions as in the step of producing the compound of the general formula (II-f) from the compound of the general formula (XVII) are applied, whereby the compound of the general formula (II-i) ) Can be produced.

Conversion Method G General Formula (XXIV)

[0359]

Embedded image [In the formula, Ar _j0 represents the above-mentioned A containing a substituent: —Sn—R _w 3 (where R _w represents a lower alkyl group);
means _{r 0, X, Y, Z} , R 10, R 20, R 30, R 4 0,
R ₅₀ and formula

[0360]

Embedded image Has the above-mentioned meaning] with respect to the compound of the general formula (X
XV) R _x -L ₁ (XXV) [wherein, R _x is a cyclic or non-cyclic bond having a carbon atom to which L ₁ has an unsaturated bond, which may have a protected substituent. An aliphatic group, an aromatic ring group or a heteroaromatic group, L ₁ represents a halogen atom or a trifluoromethanesulfonyloxy group], which may be cyclic, to obtain a compound of the general formula (II-j)

[0361]

Embedded image [In the formula, Ar _j1 is a substituent: -R _x (where R _{x is}
May optionally have a protected substituent, Ar
X represents the above-mentioned Ar ₀ , which represents an aliphatic group, an aromatic ring group or a heteroaromatic group, in which the carbon atom bonded to _j1 may be cyclic or acyclic having an unsaturated bond. ,
Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and formula

[0362]

Embedded image Has the above-mentioned meaning] can be produced.

In the reaction, the compound of the general formula (XXV) is used in an amount of 1 mol to an excess, preferably 1 to 3 mol, per 1 mol of the compound of the general formula (XXIV). For example, tris (dibenzylideneacetone) dipalladium ( 0) (Pd
_The reaction is carried out in an inert gas by adding a palladium catalyst such as ₂ (dba) ₃ ), for example, a phosphine ligand such as triphenylphosphine, and, if necessary, lithium chloride.

The reaction is usually performed in an inert solvent, and examples of the inert solvent include ethers such as dioxane and tetrahydrofuran, and aromatic hydrocarbons such as toluene. The reaction temperature is from 20 ° C to the boiling point of the inert solvent used, preferably from 50 to 130 ° C.

Conversion Method H General Formula (XII-i)

[0366]

Embedded image [In the formula, Ar _k0 means the above Ar ₀ containing a substituent: — (CH ₂ ) ₂ —OH, and X, Y, Z, R ₁₀ , R ₂₀ ,
R ₃₀ , R ₄₀ , R ₅₀ and formula

[0367]

Embedded image Has the above-mentioned meaning] from the compound of the general formula (XXV
I)

[0368]

Embedded image [In the formula, Ar _k1 means the above-mentioned Ar ₀ containing a substituent: —CH ＝ CH ₂ , and X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R
_40, R ₅₀ and the formula

[0369]

Embedded image Has the above-mentioned meaning] after synthesizing a compound of the formula (XXVII) R _y -SH (XXVII) wherein R _y has a protected substituent Which represents an aliphatic group or an aromatic ring group], and reacts with a compound of the general formula (II-k)

[0370]

Embedded image [Wherein, Ar _k2 represents the above-mentioned Ar ₀ containing a substituent: — (CH ₂ ) ₂ —SR _y (where R _y has the above-mentioned meaning), and X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R
_40, R ₅₀ and the formula

[0371]

Embedded image Has the above-mentioned meaning] can be produced.

In the reaction for synthesizing the compound of the general formula (XXVI) from the compound of the general formula (XII-i), for example, 1 to 1 mol of methanesulfonyl chloride is added per 1 mol of the compound of the general formula (XII-i). Preferably, 1 to 3 moles are used, and a suitable base, for example, 1 to excess mole, preferably 1 to excess mole of an aliphatic tertiary amine such as 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU). 1-3
Performed using moles.

The reaction is usually performed in an inert solvent, and examples of the inert solvent include tetrahydrofuran, ethyl acetate and the like. The reaction temperature is from 20 ° C to the boiling point of the inert solvent used, preferably from 20 to 50 ° C.

In the reaction for synthesizing the compound of the general formula (II-k) from the compound of the general formula (XXVI), R _y -SH is used in an amount of 1 mol to excess mol, preferably 1 mol, of 1 mol of the compound of the general formula (XXVI). Is used in an amount of 1 to 5 mol, a base such as sodium ethoxide or the like is added in an amount of 1 mol to an excess mol, preferably 1 to 5 mol. Obtain the compound.

The reaction is usually performed in an alcohol such as methanol or ethanol. The reaction temperature is from 0 ° C. to the boiling point of the reaction used, preferably from 0 to 50 ° C.

The compound of the general formula (XXVI) was subjected to the same reaction as in the step of synthesizing the compound of the general formula (II-i) from the compound of the general formula (XXIII).
-I ')

[0377]

Embedded image [In the formula, Ar _i3 is a substituent: -T ₁ -Cy ′ (where T ₁ has the above-mentioned meaning, and Cy ′ may have a protected substituent as appropriate. means Ar ₀ of the containing having those aliphatic cyclic group contains a hetero atom), X, Y, Z, R 1 0, R 20, R 30, R 40, R 50 and the formula

[0378]

Embedded image Has the above-mentioned meaning] can be produced. The reaction can be performed under the same conditions as in the step of synthesizing the compound of the general formula (II-i) from the compound of the general formula (XXIII).

Next, a method for producing the starting compound of the present invention will be described. As described above, the compound of the general formula (I) of the present invention mainly comprises a compound of the general formula (III), a compound of the general formula (IV), a compound of the general formula (V) and a compound of the general formula (VI) as a raw material. It can be manufactured by using as a compound. These starting compounds can be produced from known compounds by using a general synthesis method known per se, and the main production routes will be described below.

The compound of the general formula (III) can be prepared by the methods of Synthesis Methods A to J, and the compound of the general formula (IV) can be prepared by the methods of Synthesis Methods K to M. Can be produced by the method of synthesis method N.

Of the compounds of the general formula (III) used in the production method A, compounds wherein X is a nitrogen atom and Y is C ＝ O, that is, a compound of the general formula (III-i)

[0382]

Embedded image [Wherein, X ₁ represents a nitrogen atom, Y ₁ represents CO, Z, R ₁₀ ,
R ₂₀ , R ₃₀ , R _{40 ,} R ₅₀ and the formula

[0383]

Embedded image Has the above-mentioned meaning] can be obtained by the following synthesis method A
Can be manufactured.

Synthesis method A General formula (1)

[0385]

Embedded image [Wherein Q represents a halogen atom, and R ₄₀ and R ₅₀ are
A carboxylic acid represented by the formula (2) having the above-mentioned meaning;

[0386]

Embedded image Wherein X ₁ , R ₁₀ , R ₂₀ , R ₃₀ and Z have the meanings described above, and reacting with a compound of the general formula (3)

[0387]

Embedded image [Wherein X ₁ , R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ , Q and Z have the same meanings as above], and the compound is converted to a compound using a palladium complex as a catalyst. By subjecting the compound to an intramolecular ring closure reaction, the compound represented by the general formula (4)

[0388]

Embedded image [Wherein X ₁ , R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and Z
Has the above-mentioned meaning] and then reacting with a reducing agent.

The reaction between the active derivative (1 ′) of the carboxylic acid of the general formula (1) and the compound of the general formula (2) can be carried out by converting the compound of the general formula (XVII) by the conversion method D to the compound of the general formula (XI)
The reaction can be carried out in the same manner as in the step of producing the compound of X).

In the reaction for producing the compound of the general formula (4) from the compound of the general formula (3), for example, 5 to 50 mol of a palladium complex such as tetrakistriphenylphosphine palladium is used per 1 mol of the compound of the general formula (3). %, Preferably 10 to 20% by weight, and 2 to 10 mol, preferably 2 to 5 mol of a base such as potassium acetate.

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as ethyl ether, tetrahydrofuran and dioxane;
For example, aromatic hydrocarbons such as benzene and toluene; aprotic polar solvents such as dimethylformamide, acetone, and ethyl acetate;

The reaction temperature is generally from 20 ° C. to the boiling point of the solvent used in the reaction, preferably from 50 ° C. to 100 ° C. The reaction time is usually from 30 minutes to 24 hours, preferably from 5 hours to 24 hours. is there.

The compound of the general formula (III-i) can be prepared by converting the compound of the general formula (4) into R
₂₀ Compound 5-membered or 6-membered ring formed with R ₁₀ and X is an unsaturated (III-i _a) and saturated compounds wherein (II
_Iib ) can be prepared.

In the reaction, for example, 5 mol to 20 mol of iron powder is added to 1 mol of the compound of the formula (4) under acidic conditions of hydrochloric acid.
Preferably by action of 5 mol to 10 mol, 5 to 50 weight relative to 1 mole of the compound, for example, 10% palladium carbon catalyst compounds are unsaturated and (III-i _a), also the general formula (4) %, Preferably 10% to 20% by weight, and performing a catalytic reduction to obtain a saturated compound (III- _ib ).

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include alcohols such as methanol and ethanol in the reaction of iron powder under acidic conditions of hydrochloric acid. For the catalytic reduction, for example, ethers such as ethyl ether and tetrahydrofuran; alcohols such as methanol and ethanol;

The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably from 20 ° C. to 50 ° C. when the iron reduction is carried out under acidic conditions of hydrochloric acid, and the reaction time is usually from 30 minutes to 30 minutes. The reaction time is 24 hours, preferably 30 minutes to 2 hours, 0 ° C. to the boiling point of the solvent used for the reaction, preferably 20 ° C. to 50 ° C. for the catalytic reduction, and the reaction time is usually 1 hour to 48 hours. Time, preferably 5 hours to
24 hours.

After completion of the reaction, a usual treatment is carried out, and if necessary, a reaction of removing a protecting group such as a hydroxyl group, an amino group and a carboxyl group is appropriately combined, thereby producing a compound of the general formula (III). can do.

The method for removing the protecting group varies depending on the kind of the protecting group, the stability of the target compound, and the like.

The raw material of the production method A, represented by the general formula (III-
ii)

[0400]

Embedded image [Wherein, R ₂₁ represents a hydrogen atom or a hydroxyl group, R ₃₁ represents a hydrogen atom, and R ₁₀ , R ₄₀ , R ₅₀ and X ₁ have the same meaning as above] (where X is nitrogen Atom, Y is CO,
The compound in which Z is a carbon atom) can be produced by the following production method.

Synthetic Method B The compound of the general formula (III-ii) can be prepared by reacting the compound of the general formula (5)

[0402]

Embedded image [Wherein R ₄₀ and R ₅₀ have the same meaning as above], alkylation is performed by Mitsunobu reaction, and then reduced using sodium borohydride to obtain a compound represented by the general formula (6):

[0403]

Embedded image [Wherein X _{1 ,} R ₁₀ , R ₄₀ and R ₅₀ have the same meanings as above], and can be further synthesized by catalytic reduction using a palladium catalyst.

The Mitsunobu reaction of the compound of the general formula (5) can be carried out in the same manner as in the production of the compound of the general formula (XX) from the compound of the general formula (XII). After the Mitsunobu reaction,
The compound of the general formula (6) is synthesized by applying a generally known reduction method using sodium borohydride.

From the compound of the general formula (6), the compound of the general formula (III)
In the reaction for synthesizing the compound of -ii), catalytic reduction is performed using a palladium catalyst such as palladium hydroxide.
The reaction is usually performed in an inert solvent, and examples of the inert solvent include tetrahydrofuran, methanol and the like. The reaction temperature is usually from 20 ° C. to the boiling point of the solvent used,
Preferably it is 20-50 degreeC.

By appropriately adjusting the reaction conditions for the catalytic reduction, the general formula (III-ii _a ) (wherein R
₂₁ represents a hydrogen atom, and X ₁ , R ₁₀ , R ₃₁ , R ₄₀ and R ₅₀
Has the meaning described above) and a compound of the general formula (III)
-Ii _b ) (wherein, R ₂₁ represents a hydroxyl group,
X ₁ , R ₁₀ , R ₃₁ , R ₄₀ and R ₅₀ have the meanings described above).

The raw material of the production method A, represented by the general formula (III-
iii)

[0408]

Embedded image [Wherein T ₃ is a single bond or an alkyl group or an aralkyl group having 1 to 3 carbon atoms, which may have a protected substituent, and R _10a and R _20a are the same or different. May optionally have a protected substituent,
A saturated or unsaturated hydrocarbon group, R ₈₀ is a hydrogen atom or R
Coupled with _20a or T ₃ may form a ring structure, as appropriate, may have protected substituent, saturated or show an unsaturated hydrocarbon group, R ₄₀ and R ₅₀ is the The compound represented by the following formula] can be produced by the following production method.

Synthesis Method C The compound of the general formula (III-iii) is different from the compound of the general formula (5) by the general formula (7) R _10a —CH (OH) —T ₃ —CO—R _20a (7) In the above formula, T ₃ , R _10a and R _20a have the same meaning as above, a Mitsunobu reaction is carried out, followed by reduction with sodium borohydride and cyclization under acidic conditions, whereby Equation (8)

[0410]

Embedded image [Wherein T ₃ , R _10a , R _20a , R ₄₀ and R ₅₀ have the above-mentioned meanings], and then subjected to catalytic reduction to give a compound of the general formula (III-iii ′)

[0411]

Embedded image Wherein T ₃ , R _10a , R _20a , R ₄₀ and R ₅₀ have the same meaning as described above, and further, R ₈₀ -L _iii
(Where L _iii represents a halogen atom) to introduce a substituent, whereby a compound of the general formula (III-iii) can be produced.

The Mitsunobu reaction of the compound of the general formula (5) can be carried out in the same manner as in the production of the compound of the general formula (XX) from the compound of the general formula (XII). After the Mitsunobu reaction,
The reduction is carried out by a generally known reduction method using sodium borohydride. Next, the compound of the general formula (8) can be synthesized by adding an organic acid such as trifluoroacetic acid, acetic acid or formic acid and performing a reaction in an inert solvent such as tetrahydrofuran.

The reaction temperature is from 20 ° C. to the boiling point of the inert solvent used, preferably from 70 to 130 ° C.

The catalytic reduction of the compound of the general formula (8) is carried out under the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6). -Iii ') can be prepared.

The step of converting a compound of the general formula (III-iii ′) into a compound of the general formula (III-iii) comprises
Synthesis, generally well-known amino-protecting group, after protecting, for example tert- butoxycarbonyl, suitable base, for example, in the presence of a such as lithium hexamethyldisilazide, is reacted with R ₈₀ -L _iii By removing the protecting group for the amino group, the compound of the general formula [(III-iii)] can be produced.

The protection of the amino group can be carried out according to ordinary conditions.

[0417] reaction with R ₈₀ -L _iii the general formula (III
-Iii ') per mole of protected compound of R ₈₀ -L
_iii is used in an amount of 1 mol to excess mol, preferably 3 mol, and a base such as lithium hexamethyldisilazide is used in an amount of 1 mol to excess mol, preferably 3 mol. The reaction temperature is-
78-20 ° C is preferred. The method for removing the protecting group for the amino group can be in accordance with a usual method.

The compound of the general formula (8) can be obtained by converting the compound of the general formula (9)

[0419]

Embedded image Wherein R ₄₀ and R ₅₀ have the same meaning as described above, to give a compound of the general formula (10)

[0420]

Embedded image Wherein, R ₄₀ and R ₅₀ is as defined above] was a compound of the general formula _{(11) R 10a -CH (NH} 2) -T 3 -CH (OH) -R 20a (11) [Wherein T ₃ , R _10a and R _20a have the same meaning as above].

The reduction of the compound of the general formula (9) is preferably carried out in an inert solvent such as tetrahydrofuran using 0.5 mol of sodium borohydride with respect to 1 mol of the compound of the general formula (9). . The reaction temperature is 0 ° C. or less,
Preferably it is -78 ° C.

The compound of the formula (10) and the compound of the formula (11)
In the reaction with the compound of the formula, the compound of the general formula (11) is added in an amount of 1 mol to an excess amount relative to 1 mol of the compound of the general formula (10).
Preferably, using 1 mol, molecular sieve 4A is
The reaction is performed by adding three times the weight of the compound of the general formula (10).

The reaction is usually performed in an inert solvent, and the inert solvent is preferably tetrahydrofuran, dimethylformamide or the like.

The reaction temperature is preferably from 100 to 120 ° C. from 20 ° C. to the boiling point of the inert solvent used.

The raw material of the production method A, which is represented by the general formula (III-
iv)

[0426]

Embedded image [Wherein, R _20b represents a lower alkyl group or an aralkyl group optionally having a substituent which may be protected;
_10, R ₄₀ and R ₅₀ is a compound of having] the meaning of a compound of the general formula (6) as a starting material can be synthesized by the following method.

[0427] Synthetic Method D General Formula (6) R _20b -OH The compound of (R _20b is as defined above) was reacted with, by performing catalytic reduction, the general formula (III-iv) Compounds can be synthesized.

[0428] The reaction of the compound of the general formula (6) and R _20b -OH, the compounds of general formula (6) was dissolved in R _{2 0b} -OH, for example, a catalytic amount of p- toluenesulfonic acid, preferably The reaction is carried out by adding 0.1 mol of p-toluenesulfonic acid to 1 mol of the compound of the general formula (6).

The reaction temperature is from 20 ° C. to R _20b —O
It is preferably from 90 to 100 ° C. up to the boiling point of H (R _20b has the above-mentioned meaning).

Next, catalytic reduction is carried out by applying the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6), whereby the compound of the general formula (III-iv) is synthesized. can do.

The compound represented by the general formula (II) synthesized according to the production method A using the compound of the general formula (III-iv) as a starting material is represented by the general formula (III-iv ′)

[0432]

Embedded image [Wherein R ₁₀ , R ₄₀ and R ₅₀ have the above-mentioned meaning]
To the compound of the general formula (II) synthesized from the compound of the general formula (IV) and the compound of the general formula (IV) by applying the same conditions as in the reaction of the compound of the general formula (6) with R _20b —OH. Can be manufactured.

The raw material of the production method A, represented by the general formula (III-
v)

[0434]

Embedded image [Wherein T ₄ represents an alkylene group having 1 or 2 carbon atoms which may have a protected substituent, and
_10a , R _20a , R ₄₀ and R ₅₀ have the above-mentioned meanings] can be obtained by converting the compound of the general formula (1) into a hydrazide and then cyclizing the compound of the general formula (12)

[0435]

Embedded image Wherein, R ₄₀ and R ₅₀ is as defined above] was a compound of the general formula _{(13) R 10a -CH (L} a) -T 4 -CH (L a) -R 20a (13 Wherein L _a represents a halogen atom, and T ₄ , R _10a and R _20a have the same meaning as described above, followed by catalytic reduction.

[0436] hydrazide compounds syntheses E general formula (1) has the general formula (1) compounds with the general formula (2) compound with the reaction and can be carried out in the same manner in, therefore, the general formula (1) After activating the compound under the same conditions, the compound can be synthesized by reacting with hydrazine.

The amount of the reagent to be used is such that hydrazine is used in an amount of 1 mol to an excess amount, preferably 1 mol, based on the compound of the general formula (1).
モ ル 3 mol.

The reaction is usually carried out in an inert solvent. As the inert solvent, for example, tetrahydrofuran, dimethylformamide and the like are preferable.

The reaction temperature is from 20 ° C. to the boiling point of the inert solvent used, preferably from 20 to 50 ° C.

The compound of the general formula (12) can be synthesized by heating the thus obtained hydrazide in an inert solvent such as dimethylformamide.

The compound of the general formula (12) and the compound of the general formula (13)
In the reaction with the compound of the formula (1), the compound of the formula (13) is used in an inert solvent such as dimethylformamide using a small excess of the compound of the formula (13), preferably 1 mole, per mole of the compound of the formula (12). Do. Usually, it is not necessary to add a base, but the reaction can be carried out appropriately in the presence of a tertiary amine such as, for example, triethylamine.

The reaction temperature is usually from room temperature to the boiling point of the inert solvent used, preferably from 100 to 120 ° C.

After performing the above reaction, catalytic reduction is carried out by applying the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6), thereby obtaining the compound of the general formula (II)
The compound of I-iv) can be synthesized.

The raw material of the production method A is represented by the general formula (III-v)
i)

[0445]

Embedded image [Wherein R ₁₀ , R ₄₀ and R ₅₀ have the above-mentioned meaning]
Can be carried out by the following method using the compound of the general formula (12) as a raw material.

[0446] Compounds of synthesis F general formula (III-vi) is the compound of the general formula (12), the general formula _{(14) R 10 -L a (} 14) [ wherein, L _a is defined above Having the following formula], followed by catalytic reduction.

The compound of the general formula (12) and the compound of the general formula (14)
The reaction for synthesizing the compound of the general formula (III-vi) from the compound of the general formula (III-vi)
The reaction can be performed under the same conditions as in the reaction for synthesizing the compound of -v).

The starting material for the production method A is represented by the general formula (III-v)
ii)

[0449]

Embedded image [Wherein, P ₁ represents a protecting group for a hydroxyl group, and R ₄₀ and R ₅₀
Has the above-mentioned meaning] can be carried out by the following method using the compound of the general formula (1) as a raw material.

Synthetic Method G After synthesizing an amide compound from the compound of the general formula (1) and aminomalonic acid diethyl ester, the compound is cyclized and then subjected to a decarboxylation reaction under basic conditions. The compound of the general formula (III-vii) can be synthesized by reducing the ester group of the obtained compound, protecting the newly generated hydroxyl group with an appropriate protecting group, and then performing catalytic reduction. .

The reaction of the compound of the general formula (1) with the aminomalonic acid diethyl ester is carried out under the same conditions as in the step of synthesizing the compound of the general formula (XIX) from the compound of the general formula (XVII). Can be.

The cyclization reaction is carried out using a suitable base, for example, sodium hydride. The amount of the reagent used in the reaction is 1 mol to excess mol, preferably 1 to 3 mol, of sodium hydride per 1 mol of the amide compound.

The reaction is usually performed in an inert solvent, and examples of the inert solvent include tetrahydrofuran, dimethylformamide and dimethylsulfoxide. The reaction temperature is from 0 ° C to the boiling point of the inert solvent used, preferably from 20 to 100 ° C.

The subsequent decarboxylation reaction is carried out using a suitable base, for example, sodium hydroxide, in an amount of 1 mol to an excess, preferably 3 to 5 mol, per 1 mol of the cyclized compound. The reaction is usually performed in an inert solvent, and the inert solvent is preferably an alcohol such as ethanol. The reaction temperature is from 20 ° C. to the boiling point of the inert solvent used, preferably 5
0-100 ° C is preferred.

The ester can be reduced by an ester reduction method generally used in the synthesis, for example, using sodium borohydride. The amount of the reagent used is 1 mol to excess mol, preferably 3 to 10 mol, of sodium borohydride per 1 mol of the ester. The reaction is usually performed in an inert solvent, and the inert solvent is preferably methanol, ethanol, or the like. The reaction temperature is
The temperature is from 0 ° C to 20 ° C, preferably 0 ° C.

As the protecting group for the newly generated hydroxyl group, those described in Production method A can be used, and preferably a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group. As the reaction conditions, generally well-known conditions can be applied.

After performing the above reaction, catalytic reduction is carried out by applying the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6), thereby obtaining the compound of the general formula (II)
The compound of I-vii) can be synthesized.

The starting material for the production method A, which is represented by the general formula (III-
viii)

[0459]

Embedded image [Wherein, R _10a is a saturated or unsaturated hydrocarbon group optionally having a protected substituent, and R _20c is a hydrogen atom or an optionally protected substituent. Good,
Represents a saturated or unsaturated hydrocarbon group, R ₄₀ and R
_50, the compounds of the 'have the meanings indicated above, Formula (1)
Can be synthesized by using the following compound as a raw material by the method shown below.

Synthesis method H The compound of the general formula (1) is esterified, and the ester compound and a compound of the general formula (15)

[0461]

Embedded image [Wherein, R _z represents a methyl group or an ethyl group;
_20c has the above-mentioned meaning], and a coupling reaction with a compound of the general formula (16)

[0462]

Embedded image Wherein R _z , R _20c , R ₄₀ and R ₅₀ have the meaning given above. Next, the compound of the general formula (16) is amidated using R _10a —NH ₂ (R _10a has the above-mentioned meaning), cyclized under acidic conditions, and then an alkoxy group and a nitro group are sequentially formed. After reduction, the compound represented by the general formula (III)
The compound of -viii) can be synthesized.

The reaction of adding a small amount of concentrated sulfuric acid to a compound of the formula (1) in methanol and heating to give a methyl ester is performed under generally well-known conditions in synthesis.

In the reaction of the above methyl ester compound with the compound of the general formula (15), the compound of the general formula (15) is used in an amount of 1 to excess mole, preferably 1 to 1 mole of the methyl ester body.
To 3 moles of a palladium complex such as tetrakistriphenylphosphine palladium in a catalytic amount, preferably 3 to 5 moles.
Performed using mol%.

The reaction is usually performed in an inert solvent, and examples of the inert solvent include tetrahydrofuran. The reaction temperature is from 50 to the boiling point of the solvent used, preferably from 70 to 100 ° C.

The amidation of the compound of the general formula (16) and R _10a —NH ₂ is performed under the same conditions as in the step of synthesizing the compound of the general formula (XIX) from the compound of the general formula (XVII). Can be.

The cyclization of the amide obtained by the above reaction is carried out under acidic conditions, for example, in a mixed solvent of concentrated hydrochloric acid and an inert solvent such as ethanol.
Boiling point of the inert solvent used, preferably 20 to 50 ° C
It is.

The reduction of the alkoxy group can be carried out, for example, by using triethylsilane and adding an appropriate acid.
The amount of the reagent to be used is 1 mol to excess mol, preferably 3 to 5 mol, of triethylsilane per mol of the cyclized product, and as an acid to be added, for example, 1 mol to excess mol of an ether complex of borane trifluoride. And preferably 3 to 5 mol. The reaction is usually performed in an inert solvent, and examples of the inert solvent include chloroform and methylene chloride. The reaction temperature is 0 to 50 ° C, preferably 20 ° C.
It is.

In the reduction reaction of the nitro group, catalytic reduction is carried out by applying the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6),
The compound of II-viii) can be synthesized.

Formula (III-viii ')

[0471]

Embedded image [ _Wherein R _20c1 represents a hydrogen atom, and R _10a , R ₄₀ and R ₅₀ have the above-mentioned meanings]
General formula (II-vii) synthesized according to production method A
i ')

[0472]

Embedded image [Wherein Ar ₀ , R _10a , R _20c1 , R ₄₀ and R ₅₀ have the above-mentioned meanings] can also be synthesized by the following method.

After reacting the compound of the general formula (III-vii) with the general formula (14), the compound of the general formula (II-viii ″) is prepared according to the production method A using the compound of the general formula (IV).

[0474]

Embedded image [Wherein Ar ₀ , R _10a , P ₁ , R ₄₀ and R ₅₀ have the above-mentioned meanings]. Next, the protecting group of the hydroxyl group was removed, and after methanesulfonic acid esterification,
By treating under basic conditions and performing catalytic reduction,
The compound of the general formula (II-viii ′) can be synthesized.

The removal of the protecting group for the hydroxyl group of the compound of the formula (II-viii '') can be carried out by a generally well-known method in synthesis. For example, if the protecting group is ter
In the case of a t-butyldimethylsilyl group or the like, the reaction can be performed in methanol using concentrated hydrochloric acid.

In the methanesulfonic acid esterification, triethylamine is used in an amount of 1 to excess mole, preferably 1 to 3 moles, and methanesulfonyl chloride is used in an amount of 1 to excess mole, preferably 1 mole, relative to 1 mole of the alcohol obtained in the above reaction. Is performed using 1 to 3 mol. As the base used for the subsequent base treatment, for example, 1,8-diazabicyclo [5,
[0,0] Undec-7-ene (DBU) is used in an amount of 1 mol to an excess mol, preferably 1 to 3 mol. The reaction is usually performed in an inert solvent, and dimethylformamide or the like is preferable as the inert solvent. The reaction temperature is
The temperature is 0 to 50 ° C, preferably 0 to 20 ° C.

The compound obtained by the above reaction is subjected to catalytic reduction under the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6), and The compound of II-viii ') can be synthesized.

The starting material for the production method A, which is represented by the general formula (III-
ix ')

[0479]

Embedded image [Wherein, R _10c represents a saturated or unsaturated hydrocarbon group optionally having a protected substituent, and R ₄₀ and R ₅₀ have the above-mentioned meanings] Formula (I
II-ix '')

[0480]

Embedded image [Wherein R _10c , R ₄₀ and R ₅₀ have the above-mentioned meanings], a compound of the general formula (17)

[0481]

Embedded image [Wherein R ₄₀ and R ₅₀ have the above-mentioned meanings] or a compound produced from the known compound by a method known per se as a raw material, and can be synthesized by the following method.

Synthesis Method I After conducting a Mitsunobu reaction using a compound of the general formula (17) and R _10c —OH, wherein R _10c has the above-mentioned meaning,
By performing the catalytic reduction, the compound represented by the general formula (III-ix ′)
And the compound of the general formula (III-ix ″) can be synthesized.

The Mitsunobu reaction of the compound of the general formula (17) can be carried out in the same manner as in the production of the compound of the general formula (XX) from the compound of the general formula (XII).

The catalytic reduction of the compound obtained by the above reaction can be carried out by converting the compound of the general formula (6) to the compound of the general formula (III-ii)
Is performed by applying the same conditions as in the reaction for synthesizing the compound of
By purifying and separating under appropriate conditions, general formula (III)
-Ix ′) and the compound of the general formula (III-ix ″) can be synthesized.

The raw material of production method A, represented by the general formula (III-
x)

[0486]

Embedded image Wherein R _10d represents a saturated or unsaturated hydrocarbon group optionally having a protected substituent, and R ₄₀ and R ₅₀ have the above-mentioned meanings. General formula (18) which is an intermediate in synthesis method I

[0487]

Embedded image [Wherein R _10c , R ₄₀ and R ₅₀ have the meanings described above], and can be synthesized by the following method using the compound as a raw material.

Synthesis Method J The compound of the formula (18) is reduced to give the compound of the formula (19)

[0489]

Embedded image [Wherein R ₄₀ and R ₅₀ have the above-mentioned meanings], and after performing a Mitsunobu reaction with R _10d -OH [wherein R _10c has the above-mentioned meanings], catalytic reduction is carried out. By performing, the compound of the general formula (III-x) can be synthesized.

The reduction of the compound of the general formula (18) is carried out using sodium borohydride in an amount of 1 mol to an excess, preferably 3 to 5 mol, per 1 mol of the compound of the general formula (18). The reaction is usually performed in an inert solvent, and the inert solvent is preferably tetrahydrofuran or the like. The reaction temperature is from 0 ° C to 50 ° C, preferably 20 ° C.

The Mitsunobu reaction of the compound of the general formula (19) can be carried out in the same manner as in the production of the compound of the general formula (XX) from the compound of the general formula (XII).

Then, catalytic reduction is carried out by applying the same conditions as in the reaction for synthesizing the compound of the general formula (III-ii) from the compound of the general formula (6), whereby the compound of the general formula (III-x) is synthesized. can do.

The compound of the general formula (1), the compound of the general formula (5) and the compound of the general formula (15) are known compounds or are prepared by known chemical methods using the known compounds. can do.

Next, a process for producing the compound of the general formula (IV), which is the other starting compound of the process A, will be described. The compound of the general formula (IV) can be produced by the following synthesis methods K to M.

Synthetic Method K The compound of the general formula (IV) can be prepared by reacting the compound of the general formula (20)

[0496]

Embedded image [Wherein, R ′ represents a lower alkyl group, and Ar ₀ has the above-mentioned meaning.] The ester represented by the general formula (IV) is treated with hydrazine and then treated with nitrous acid.

[0497]

Embedded image [Wherein Ar ₀ has the meaning described above].

In the reaction of treating the compound of the general formula (20) with hydrazine and then reacting it with nitrous acid to convert it to the compound of the general formula (IV), the amount of each reagent used is determined by the amount of the ester of the general formula (20) The hydrazine is used in an amount of 1 mol to 10 mol, preferably 3 mol to 5 mol, per 1 mol, and sodium nitrite is added in an amount of 1 mol of the ester of the general formula (20) in the next step of reacting with nitrous acid. Mol to 5 mol, preferably 3 mol to 5 mol, and 1N hydrochloric acid is 1 L to 5 L, preferably 1 L to 3 mol per mol of sodium nitrite.
L.

The reaction is usually carried out in an inert solvent. Examples of the inert solvent include alcohols such as methanol and ethanol for the reaction with hydrazine. Examples of the reaction include water; ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; and mixtures thereof.

The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used for the reaction with hydrazine, preferably from 20 ° C. to 50 ° C. The reaction time is usually from 1 hour to 48 hours, The reaction time is preferably from 5 hours to 24 hours, and in the reaction with nitrous acid, the reaction temperature is from 0 ° C to 50 ° C, preferably from 0 ° C to 20 ° C, and the reaction time is usually from 30 minutes to 5 hours, preferably from 30 minutes. Minutes to 2 hours.

The compound of the general formula (20) is a known compound or can be produced according to a usual method of ester synthesis.

Synthesis method L General formula (IV-i)

[0503]

Embedded image [In the formula, R ″ and R ′ ″ may include a nitrogen atom together with a carbon atom to which each is bonded, and may have a protected substituent, if necessary, saturated or unsaturated. A 5- or 6-membered ring group of formula (21) using a known compound, 1,2,4-triazine-5-carboxylic acid ethyl ester as a raw material.

[0504]

Embedded image Wherein R ″ and R ′ ″ have the meaning described above.
After synthesizing the compound of formula (I), it can be produced according to synthesis method K. 1,2,4-triazine-5-carboxylic acid ethyl ester is represented by the general formula (22)

[0505]

Embedded image Wherein R ″ and R ′ ″ have the meaning described above.
To give a compound of the general formula (21).

The amount of the reagent used in the reaction is 1 mol to excess mol, preferably 1 to 5 mol of the compound of the formula (22) per mol of 1,2,4-triazine-5-carboxylic acid ethyl ester. It is. The reaction is usually performed in an inert solvent, and examples of the inert solvent include chloroform. The reaction temperature is from 20 ° C to the boiling point of the inert solvent used, preferably from 20 to 70 ° C.

From the compound of the general formula (21), the compound of the general formula (IV)
The reaction for synthesizing the compound of the general formula (IV) is carried out in the same manner as in the step of producing the compound of the general formula (IV) from the compound of the general formula (20) in the synthesis method K. can do.

Synthesis method M General formula (IV-ii)

[0509]

Embedded image Wherein, Ar ₁₀ is a substituted group: -Sn (n-Bu) ₃ shows the Ar ₀ of the containing] compounds of the general formula (23)

[0510]

Embedded image [Wherein, Ar _10i is a substituent: -X ₁₀ (wherein,
X ₁₀ represents a halogen atom), and R ₀ has the above-mentioned meaning, and R ′ has the above-mentioned meaning.

By reacting the compound of the general formula (23) with hexa-n-butylditin using a palladium complex, for example, tetrakistriphenylphosphine palladium as a catalyst, the compound of the general formula (24)

[0512]

Embedded image Wherein Ar ₁₀ and R ′ have the meaning described above, and then can be produced according to Synthesis Method K.

In the reaction of the compound of the general formula (23) with hexa-n-butylditin, 1 mol of the hexa-n-butylditin is added to 1 mol of the compound of the general formula (23) in an excess mole, preferably 1.5 moles. And a palladium complex such as tetrakistriphenylphosphine palladium in an amount of 0.05 to 0.2 mol, preferably 0.1 mol. The reaction is usually performed in an inert solvent, and examples of the inert solvent include dioxane. The reaction temperature is 5
0 ° C to the boiling point of the inert solvent used, preferably 70 to 1
30 ° C.

From the compound of the general formula (24), the compound of the general formula (IV)
The reaction for synthesizing the compound of the general formula (IV) is carried out in the same manner as in the step of producing the compound of the general formula (IV) from the compound of the general formula (20) in the synthesis method K to produce the compound of the general formula (IV-ii) can do. Next, the compound represented by the general formula (V),

[0515]

Embedded image [Wherein, X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0516]

Embedded image Has the meaning described above]. The compound of the general formula (V) can be produced by the following synthesis method N.

Synthetic Method N The compound of the general formula (V) is prepared by converting the compound of the general formula (25)

[0518]

Embedded image [Wherein, X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ , R ₄₀ , R ₅₀ and the formula

[0519]

Embedded image Has the above-mentioned meaning] to obtain a chloride, followed by the action of sodium azide.

In the step of converting into a carboxylic acid chloride of the general formula (25), the compound of the general formula (25) is converted to a compound of the general formula (X)
The reaction can be performed in the same manner as in the step of producing an acid halide from VIII), and thus, the same conditions can be applied to the reaction conditions and the like. 1 mol to 5 mol, preferably 1 mol to 3 mol, of sodium azide is reacted with 1 mol of the acid chloride thus obtained in water or, if necessary, a mixed solvent of water and tetrahydrofuran to obtain a compound represented by the general formula (V) ) Can be obtained.

The reaction temperature is generally 0 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C., and the reaction time is generally 30 minutes to 12 hours, preferably 1 hour to 5 hours.

The compound of the general formula (VI), which is another starting compound of the production method B, is a known compound or can be produced according to a conventional method for synthesizing an amino compound.

Next, in order to specifically demonstrate the usefulness of the present invention, the Cdk4 and Cdk6 activities of the product of the present invention and the 50% inhibitory concentration (IC ₅₀ value) on cell growth inhibition were determined.

Cdk4 Inhibitory Action (1) Cyclin D1-Cdk4 and Cyclin D2
-Preparation of Cdk4 First, cDNAs of Cdk4 and its activator cyclin D1 or cyclin D2 were respectively incorporated into a baculovirus expression vector to prepare a recombinant baculovirus. It was co-infected with insect cells Sf9 and cyclin D1-Cdk4 or cyclin D2-Cdk.
Highly expressed as a 4-active complex. After the cells were collected and solubilized, they were purified by HPLC column chromatography [Embo Journal (EMBO J.),
15, 7060-7069, (1996)].

(2) Activity measurement of cyclin D1-Cdk4 and cyclin D2-Cdk4: cyclin D1-Cdk4 and cyclin D2-Cdk
In the activity measurement of No. 4, the substrate was a synthetic peptide corresponding to amino acids 775 to 787 of the RB protein (Ar
g-Pro-Pro-Thr-Leu-Ser-Pro
-Ile-Pro-His-Ile-Pro-Arg)
The Embo Journal (EMBO
J. 15), pp. 7060-7069, (1996)
Year)].

The reaction was carried out according to the method of Kitagawa et al. [Oncogene (On).
cogene), Vol. 7, pp. 1067-1074, (1
992)] with some modifications. The reaction solution volume is 21.
In 1 μl, the composition of the reaction buffer (R buffer) is 2
0 mM Tris-HCl buffer (pH 7.4) / 1
0 mM magnesium chloride / 4.5 mM 2-mercaptoethanol / 1 mM ethylene glycol bis (β-aminoethyl ether) -N, N, N ′, N′-
Cyclin D1-Cdk4 or cyclin D purified therefrom with tetraacetic acid (EGTA)
2-Cdk4 with 100 μM substrate peptide and 50 μM
M unlabeled adenosine triphosphate (ATP) and 1 μM
[Γ-33P] -labeled ATP of Ci (2000-400
0 Ci / mmole) and reacted at a reaction temperature of 30 ° C. for 45 minutes. Then 10 μl of 350 m
The reaction was stopped by adding M phosphate buffer to the reaction system. After adsorbing the substrate peptide on P81 paper,
The radioactivity was measured with a liquid scintillation counter. [Γ-33P] -labeled ATP was purchased from Daiichi Pure Chemicals.

The test compound was added to the reaction system by adding a solution dissolved in dimethyl sulfoxide (DMSO) to 1.1.
Performed by adding μl. A control system was prepared by adding 1.1 μl of DMSO alone to the reaction system.

Example 1 as a typical compound of the present invention
31, 165, 329, 579 and the cyclin D1-Cdk4 or cyclin D2-Cdk of this compound
IC50 values for 4 activities were determined. The results are shown in the table below.

[0529]

[Table 1]

The compounds of the present invention, cyclin D1-Cdk
4 or cyclin D2-Cdk4 inhibitory activity
4 known compounds having inhibitory activity (±) flavopi
It is clear that it is significantly higher than that of ridol.

Cdk6 Inhibitory Action (1) Cyclin D1-Cdk6 and Cyclin D3
-Preparation of Cdk6 Similar to cyclin D1-Cdk4, cDNA of Cdk6 and its activator cyclin D1 or cyclin D3 was incorporated into a baculovirus expression vector to prepare a recombinant baculovirus. It was co-infected with insect cells Sf9 and cyclin D1-Cdk
6 or cyclin D3-Cdk6. After collecting and solubilizing the cells, HPLC
Purified by column chromatography.

(2) Activity measurement of cyclin D1-Cdk6 and cyclin D3-Cdk6 In the activity measurement of cyclin D1-Cdk6, the substrate was a synthetic peptide (Lys-Ala-Pro-Leu-Se).
In the measurement of the activity of cyclin D3-Cdk6 using r-Pro-Lys-Lys-Ala-Lys, the substrate was a synthetic peptide (Arg-Pro-Pro-Thr-).
Leu-Ser-Pro-Ile-Pro-His-I
le-Pro-Arg).
Naru (EMBO J.), Vol. 15, 7060-706
9 (1996)].

The reaction was carried out according to the method of Kitagawa et al. [Oncogene (On).
cogene), Vol. 7, pp. 1067-1074, (1
992)] with some modifications. The reaction solution volume is 21.
1 μl of cyclin D1-C purified in R buffer
dk6 and 400 μM substrate peptide, or cyclin D3-Cdk6 and 100 μM substrate peptide, 50 μM unlabeled ATP and 1 μCi [γ-3
3P] labeled ATP (2000-4000 Ci / mmo
le) was added and reacted at a reaction temperature of 30 ° C. for 20 minutes or 45 minutes. Then 10 μl of 350 m
The reaction was stopped by adding M phosphate buffer to the reaction system. After adsorbing the substrate peptide on P81 paper,
The radioactivity was measured with a liquid scintillation counter.

The compound of the present invention is added to the reaction system by DMS
This was performed by adding 1.1 μl of a solution dissolved in O. A control group was prepared by adding 1.1 μl of DMSO to the reaction system.

Example 1 as a typical compound of the present invention
31, 165, 329, 579 and the cyclin D1-Cdk6 or cyclin D3-Cdk of this compound
IC50 values for 6 activities were determined. The results are shown in the table below.

[0536]

[Table 2]

From these results, it is clear that the compound of the present invention has a strong cyclin D1-Cdk6 or cyclin D3-Cdk6 inhibitory activity.

Cell Growth Inhibitory Action (1) Cell Culture Method The clinically isolated cancer cell line HCT116 was prepared using Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum, and the clinically isolated cancer cell line MKN-1 was cultured with 10% bovine serum. RPMI1640 with fetal serum
The culture was performed using a medium at 37 ° C. in the presence of 5% CO _{2 in} a saturated steam environment.

(2) Measurement of Cell Growth Inhibitory Effect Cell growth inhibitory effect was measured by the method of Skehan et al. [Journal of National Cancer Institute (J. Natl. Cancer I).
nst. 82, 1107-1112, (19)
1990)]. 100 μl of a culture medium for each cell containing 1 × 10 ³ HCT116 or MKN-1 as viable cells was dispensed into a 96-well cell culture dish and cultured overnight. The next day, a dilution series with DMSO was prepared from a DMSO solution of compound 131 and (±) flavopiridol. Then, the dilution series or DMSO alone was added to the culture medium of each cell as a control without drug addition. Finally, to the cells cultured in a 96-well dish, 100 μl of a dilution series of each drug or a culture medium containing only DMSO was added, and the cells were further cultured for 3 days.

In each well, 50% of 50% trichloroacetic acid was added.
The cells were fixed by adding μl each. After staining the cells with 0.4% sulforo-damine B, the sulfolo-damine B was extracted using 10 mM Tris buffer. 450 n
The optical density at 560 nm was measured using m as a control wavelength and compared with the control group. Compound of Example 131 and (±)
The results of determination of the 50% inhibitory concentration (IC50) of flavopiridol for cell growth are shown in the following table.

[0541]

[Table 3]

The compound of the present invention is clearly useful as an antitumor agent because it shows a clearly stronger cell growth inhibitory effect as compared with the known compound (±) flavopiridol having Cdk inhibitory activity.

Therefore, suitable tumors in which the therapeutic effect of the compound of the present invention is expected include, for example, human colon cancer.

When the compound of the present invention is used as an antitumor agent, it can be used as a pharmaceutically acceptable salt thereof. Typical examples of pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium.

The method for producing a pharmaceutically acceptable salt of the compound of the present invention can be carried out by appropriately combining methods generally used in the field of synthetic organic chemistry. Specific examples include neutralization titration of a free solution of the compound of the present invention with an alkaline solution.

When the compound of the present invention is used as an antitumor agent, various forms can be selected, for example, oral preparations such as tablets, capsules, powders, granules, and liquids, such as solutions and suspensions. And sterilized liquid parenteral preparations.

The solid preparation can be produced as it is in the form of tablets, capsules, granules or powder, but it can also be produced using appropriate additives. Examples of the additive include sugars such as lactose and glucose, for example, starches such as corn, wheat, and rice, fatty acids such as stearic acid, such as sodium metasilicate, magnesium aluminate, and inorganic salts such as anhydrous calcium phosphate.
For example, polyvinylpyrrolidone, synthetic polymers such as polyalkylene glycol, for example, calcium stearate, fatty acid salts such as magnesium stearate, for example, stearyl alcohol, alcohols such as benzyl alcohol,
Examples thereof include synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose, and hydroxypropylmethylcellulose, and other commonly used additives such as water, gelatin, talc, vegetable oil, and gum arabic.

These tablets, capsules, granules, powders and other solid preparations can generally contain 0.1 to 100% by weight, preferably 5 to 100% by weight, of the active ingredient. Liquid formulations include water, alcohols or soybean oil, for example.
It can be produced in the form of suspensions, syrups, injections and the like using appropriate additives usually used in liquid preparations such as vegetable-derived oils such as peanut oil and sesame oil.

Particularly suitable solvents for parenteral administration by intramuscular injection, intravenous injection or subcutaneous injection include, for example, distilled water for injection, lidocaine hydrochloride aqueous solution (for intramuscular injection), physiological saline, Examples thereof include an aqueous glucose solution, ethanol, a liquid for intravenous injection (eg, an aqueous solution of citric acid, sodium citrate, etc.), an electrolyte solution (eg, intravenous drip, intravenous injection), and the like, or a mixed solution thereof.

These injections may be in the form of a powder which has been dissolved in advance or a powder to which an appropriate additive has been added and which is dissolved at the time of use. These injections can usually contain 0.1 to 10% by weight, preferably 1 to 5% by weight of the active ingredient.

A liquid preparation such as a suspension or a syrup for oral administration may contain 0.5 to 10% by weight of an active ingredient.

The practically preferred dosage of the compound of the present invention may be appropriately adjusted depending on the kind of the compound to be used, the kind of the compounded composition, the frequency of application, the specific site to be treated, and the condition of the patient. For example, the daily dose per adult per day is 10 to 500 mg for oral administration, and 10 to 100 mg per day for parenteral administration, preferably intravenous injection. In addition,
The number of times of administration varies depending on the administration method and symptoms, but it can be administered once or divided into 2 to 5 times.

[0553]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

[0554] Thin-layer chromatography of Examples and Reference Examples, Silica gel ₆₀ F ₂₅₄ as a plate
(Merck) using a UV detector as a detection method.
As silica gel for column, WakogelTM C
-300 or C-200 (Wako Pure Chemical Industries) was used. As the high performance liquid chromatography, HP1100 series (Hewlett-Packard (HP)) was used.
The MS spectrum was measured using JMS-SX102A (JEOL) or QUATTRO II (micromass). The NMR spectrum is determined by using tetramethylsilane (TMS) as an internal standard when measuring with a heavy chloroform solution, methanol when measuring with a heavy methanol solution, and dimethylsulfoxide when measuring with a heavy dimethyl sulfoxide solution. Using
Gemini-200 (200 MHz; Varia
n), Gemini-300 (300 MHz; Vari)
an) or VXR-300 (300 MHz; Var)
Measurement was performed using an ian) spectrometer, and all δ values were shown in ppm.

The meanings of the abbreviations in NMR measurement are as follows. s: singlet d: doublet dd: double doublet t: triplet dt: double triplet q: quartet m: multiplet br: broad J: coupling constant Hz: Hertz CDCl _3: deuterated chloroform D ₂ O: deuterium oxide DMSO-d _6: Heavy dimethyl sulfoxide CD ₃ OD: Heavy methanol

The meanings of the abbreviations in the reaction formulas and the like are shown below. Ac: acetyl group Et: ethyl group n-Bu: n-butyl group Bn: benzyl group n-Pr: n-propyl group i-Pr: isopropyl group Me: methyl group Ph: phenyl group Py: pyridyl group TEA: triethylamine

[0557]

EXAMPLES The compounds of the present invention are specifically illustrated in the following tables.

[0558]

[Table 4]

[0559]

[Table 5]

[0560]

[Table 6]

[0561]

[Table 7]

[0562]

[Table 8]

[0563]

[Table 9]

[0564]

[Table 10]

[0565]

[Table 11]

[0566]

[Table 12]

[0567]

[Table 13]

[0568]

[Table 14]

[0569]

[Table 15]

[0570]

[Table 16]

[0571]

[Table 17]

[0572]

[Table 18]

[0573]

[Table 19]

[0574]

[Table 20]

[0575]

[Table 21]

[0576]

[Table 22]

[0577]

[Table 23]

[0578]

[Table 24]

[0579]

[Table 25]

[0580]

[Table 26]

[0581]

[Table 27]

[0582]

[Table 28]

[0583]

[Table 29]

[0584]

[Table 30]

[0585]

[Table 31]

[0586]

[Table 32]

[0587]

[Table 33]

[0588]

[Table 34]

[0589]

[Table 35]

[0590]

[Table 36]

[0591]

[Table 37]

[0592]

[Table 38]

[0593]

[Table 39]

[0594]

[Table 40]

[0595]

[Table 41]

[0596]

[Table 42]

[0597]

[Table 43]

[0598]

[Table 44]

[0599]

[Table 45]

[0600]

[Table 46]

[0601]

[Table 47]

[0602]

[Table 48]

[0603]

[Table 49]

[0604]

[Table 50]

[0605]

[Table 51]

[0606]

[Table 52]

[0607]

[Table 53]

[0608]

[Table 54]

[0609]

[Table 55]

[0610]

[Table 56]

[0611]

[Table 57]

[0612]

[Table 58]

[0613]

[Table 59]

[0614]

[Table 60]

[0615]

[Table 61]

[0616]

[Table 62]

[0617]

[Table 63]

[0618]

[Table 64]

[0619]

[Table 65]

[0620]

[Table 66]

[0621]

[Table 67]

[0622]

[Table 68]

[0623]

[Table 69]

[0624]

[Table 70]

Example 1 29 mg of 4-amino-9-fluorenone (0.15 mm
ol) to 22 mg of 2-pyridinecarbonylazide (0.
A solution of 15 mmol) in 0.5 ml of tetrahydrofuran was added at room temperature, and the reaction solution was refluxed for 2 hours. The reaction solution was returned to room temperature, and a mixed solution of hexane and ethyl acetate was added for crystallization. The obtained crude product was washed successively with ethyl acetate and methanol, and then collected by filtration to obtain 34 mg of a yellow powder (the compound of Example 1). ¹ H-NMR (DMSO-d ₆ ) δ: 7.07 (1H,
J = 8.3 Hz, 5.1 Hz), 7.34-7.45
(4H, m), 7.64-7.69 (2H, m), 7.
78-7.84 (1H, m), 8.04 (1H, d, J
= 7.9 Hz), 8.08 (1H, d, J = 7.7H)
z), 8.29 (1H, dd, J = 5.0 Hz, 1.2
Hz), 10.0 (1H, s), 11.1 (1H, br)
s). mass: 316 (M + 1) ⁺ .

Example 2- Example 8 The compounds of Examples 2 to 8 were prepared according to the method of Example 1. Example 2 ¹ H-NMR (DMSO-d ₆ ) δ: 2.35 (3H,
s), 7.02-7.11 (1H, m), 7.34-
7.48 (3H, m), 7.60-7.74 (3H,
m), 8.02-8.22 (3H, m), 8.19 (1
H, m), 8.92 (1H, m), 12.1 (1H,
m). mass: 330 (M + 1) ⁺ .

Example 3 ¹ H-NMR (DMSO-d ₆ ) δ: 7.01 (1H,
dd, J = 5.6 Hz, 8.0 Hz), 7.26 (1
H, dd, J = 2.0 Hz, 8.0 Hz), 7.35−
7.46 (3H, m), 7.67 (2H, d, J = 7.
3 Hz), 7.81 (1H, dd, J = 2.0 Hz,
5.6 Hz), 8.11 (1H, dd, J = 1.8H)
z, 7.3 Hz), 8.15 (1H, d, J = 7.3H)
z), 8.40 (1H, s), 11.8 (1H, s). mass: 332 (M + 1) ⁺ .

Example 4 ¹ H-NMR (DMSO-d ₆ ) δ: 3.28 (2H,
s), 7.36-7.46 (6H, m), 7.56 (3
H, d, J = 7.6 Hz), 7.62-7.70 (2
H, m), 7.69 (1H, dd, J = 5.0 Hz,
8.0 Hz), 7.88 (1H, d, J = 5.0H)
z), 8.04-8.14 (2H, m), 8.48 (1
H, s), 11.8 (1H, s). mass: 422 (M + 1) ⁺ .

Example 5 ¹ H-NMR (DMSO-d ₆ ) δ: 7.23-7.2
8 (1H, m), 7.39-7.48 (3H, m),
7.65-7.70 (2H, m), 8.07-8.10
(2H, m), 8.48 (1H, dt, J = 7.8H
z, 1.6 Hz), 8.56 (1H, d, J = 5.0H)
z). mass: 360 (M + 1) ⁺ .

Example 6 ¹ H-NMR (DMSO-d ₆ ) δ: 2.35 (3H,
s), 6.96 (1H, d, J = 5.0 Hz), 7.1
5 (1H, s), 7.36-7.49 (3H, m),
7.64-7.74 (2H, m), 8.08-8.15
(2H, m), 8.19 (1H, d, J = 5.0H
z), 10.0 (1H, s), 11.3 (1H, br)
s). mass: 330 (M + 1) ⁺ .

Example 7 ¹ H-NMR (DMSO-d ₆ ) δ: 7.18 (1H,
d, J = 6.0 Hz), 7.35-7.45 (3H,
m), 7.57 (1H, s), 7.62-7.67 (2
H, m), 7.93 (1H, d, J = 7.0 Hz),
7.98 (1H, d, J = 7.0 Hz), 8.28 (1
H, d, J = 4.0 Hz), 10.1 (1H, s), 1
0.4 (1H, s).

Example 8 ¹ H-NMR (DMSO-d ₆ ) δ: 2.97 (6H,
s), 6.43 (1H, s), 6.43 (1H, dd,
J = 7.3 Hz, 2.0 Hz), 7.33-7.41
(3H, m), 7.62-7.67 (2H, m), 7.
88 (1H, d, J = 6.0 Hz), 8.14 (1H,
d, J = 6.7 Hz), 8.20 (1H, d, J = 6.
7 Hz), 9.63 (1H, s).

Example 9 Using the compound of Reference Example 1 and 2-amino-4- (N-ethoxycarbonyl) aminopyridine in the same procedure as in Example 26, 50 mg (0.12 mmol) of compound
When 1) was dissolved in 2 ml of ethanol, 2.0 ml (10 mmol) of a 5N aqueous sodium hydroxide solution was added at room temperature, and the reaction solution was refluxed for 1 hour. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate-tetrahydrofuran.
The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (chloroform-methanol, 100: 0 to 100).
95: 5) to give 8 mg of yellow crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 6.19 (1H,
s), 6.25 (1H, d, J = 5.9 Hz), 6.2
8 (2H, s), 7.34-7.41 (3H, m),
7.62-7.69 (2H, m), 7.74 (1H,
d, J = 5.7 Hz), 8.15 (1H, d, J = 7.
1Hz), 8.21 (1H, d, J = 7.1Hz),
9.66 (1H, s), 12.3 (1H, br). mass: 331 (M + 1) ⁺ .

Example 10 33 mg (0.10 mmol) of the compound of Example 9 was dissolved in 3 ml of tetrahydrofuran, and 27 μl (0.30 mmol) of n-butyraldehyde and 63 mg (0.30 mmol) of sodium triacetoxyborohydride were added at room temperature. In addition, the reaction solution was stirred at the same temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by thin-layer chromatography (chloroform-tetrahydrofuran, 70:
Purification by 30) gave 23 mg of yellow crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H,
t, J = 7.2 Hz), 1.31-1.40 (2H,
m), 1.48-1.53 (2H, m), 2.98-
3.02 (2H, m), 6.19 (1H, s), 6.2
8 (1H, d, J = 6.1 Hz, 1.9 Hz), 6.7
9 (1H, dt), 7.31-7.40 (3H, m),
7.62-7.68 (2H, m), 7.75 (1H,
d, J = 6.2 Hz), 8.14 (1H, dd, J =
7.1 Hz, 1.9 Hz), 8.20 (1H, d, J =
8.2 Hz), 9.60 (1H, s), 12.3 (1
H, br). mass: 387 (M + 1) ⁺ .

Example 11 Using the compound of Example 80 (2), the compound of Reference Example 3 was replaced with 4-amino-amino acid according to the method of Example 80 (3).
For the compound prepared by reacting with 9-fluorenone,
The same operation as in Example 80 (4) was carried out to obtain colorless crystals 21
mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 4.52 (2H, d,
J = 5.3 Hz), 5.47 (1H, t, J = 5.3H)
z), 7.00 (1H, d, J = 4.7 Hz), 7.2
8-7.69 (6H, m), 8.05-8.22 (3
H, m), 10.0 (1H, s), 11.4 (1H,
s). mass: 346 (M + 1) ⁺ .

Examples 12 to 17 Examples 12 to 17 were carried out according to the method of Example 1.
Was prepared. Example 12 ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H,
s), 7.25 (1H, d, J = 7.6 Hz), 7.1
6-7.45 (3H, m), 7.63-7.72 (3
H, m), 8.04-8.14 (3H, m), 9.92.
(1H, s), 11.1 (1H, br). mass: 330 (M + 1) ⁺ .

Example 13 ¹ H-NMR (DMSO-d ₆ ) δ: 7.34-7.4
7 (3H, m), 7.58 (1H, d, J = 8.9H)
z), 7.66 (2H, m), 7.95 (1H, d, J
= 7.8 Hz), 7.99 (2H, m), 8.31 (1
H, d, J = 2.6 Hz), 10.0 (1H, br). mass: 350, 352 (M + 1) ⁺ .

Example 14 ¹ H-NMR (DMSO-d ₆ ) δ: 7.35-7.4
8 (3H, m), 7.54 (1H, d, J = 8.9H)
z), 7.62-7.72 (2H, m), 7.93 (1
H, d, J = 9.2 Hz), 7.96 (1H, d, J =
5.1 Hz), 8.00 (1H, dd, J = 8.9H)
z, 2.2 Hz), 8.39 (1H, d, J = 2.8H)
z), 10.1 (1H, m). mass: 394, 396 (M + 1) ⁺ .

Example 15 ¹ H-NMR (DMSO-d ₆ ) δ: 7.36-7.5
6 (4H, m), 7.64-7.74 (2H, m),
7.96 (2H, t, J = 8.6 Hz), 7.94-
8.02 (1H, m), 8.60 (1H, m), 9.1
6 (1H, m). mass: 361 (M + 1) ⁺ .

Example 16 ¹ H-NMR (DMSO-d ₆ ) δ: 7.39-7.4
9 (6H, m), 7.68-7.73 (3H, m),
7.99-8.08 (3H, m), 8.23-8.26
(1H, m), 8.80 (1H, s). mass: 359 (M + 1) ⁺ .

Example 17 ¹ H-NMR (DMSO-d ₆ ) δ: 7.37-7.4
8 (3H, m), 7.55 (1H, d, J = 8.8H
z), 7.62-7.69 (2H, m), 7.95 (1
H, d, J = 7.9 Hz), 8.02 (1H, d, J =
6.9 Hz), 8.25 (1H, dd, J = 8.8H)
z, 2.3 Hz), 8.79 (1H, d, J = 2.2H)
z). mass: 360 (M + 1) ⁺ .

Example 18 (1) The compound of Reference Example 1 and 2-amino-5- (N-
Compound 0.613 prepared in a similar manner to Example 26 using (tert-butoxycarbonyl) aminopyridine.
10 ml of trifluoroacetic acid was added to g (1.40 mmol) at room temperature, and the reaction solution was stirred at the same temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (chloroform-methanol, 1
(00: 0 to 90:10) to obtain 0.431 g of crude crystals. This was washed with ether and yellow crystals 0.302
g was obtained. (2) 3.4 mg of yellow crystals were obtained according to the method of Example 10 using 33 mg of the compound obtained in (1). ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H,
t, J = 7.2 Hz), 1.37-1.43 (2H,
m), 1.50-1.57 (2H, m), 2.97-
3.03 (2H, m), 5.59 (1H, t), 7.1
1-7.13 (2H, m), 7.35-7.45 (3
H, m), 7.64-7.70 (3H, m), 8.11.
-8.16 (2H, m), 9.61 (1H, s). mass: 387 (M + 1) ⁺ .

Examples 19 to 20 According to the method of Example 26, Examples 19 and 20 were carried out.
Was prepared. Example ^{19 1 H-NMR (DMSO- d} 6) δ: 3.81 (3H,
s), 7.05 (2H, d, J = 8.8 Hz), 7.3
8-7.47 (4H, m), 7.64-7.70 (4
H, m), 8.02-8.13 (3H, m), 8.54.
(1H, d, J = 2.6 Hz), 10.1 (0.3H,
s), 11.0 (0.2H, br). mass: 422 (M + 1) ⁺ .

Example 20 ¹ H-NMR (DMSO-d ₆ ) δ: 2.51 (3H,
s), 7.04 (1H, d, J = 7.1 Hz), 7.2
1-7.27 (1H, m), 7.47-7.59 (3
H, m), 7.72-7.84 (3H, m), 8.00.
−8.04 (1H, m), 8.17 (1H, d, J =
7.6 Hz), 10.1 (1H, s), 11.3 (1
H, brs). mass: 330 (M + 1) ⁺ .

Example 21 The compound of Reference Example 1 and 2-amino-6- (N-tert
The target compound was produced according to Example 18 (1) using (-butoxycarbonyl) aminopyridine. ¹ H-NMR (DMSO-d ₆ ) δ: 6.07-6.1
0 (2H, m), 6.28 (1H, d, J = 7.5H
z), 7.34-7.41 (4H, m), 7.46-
7.48 (1H, m), 7.52-7.57 (1H,
m), 7.65 (1H, d, J = 6.7 Hz), 7.7
7 (1H, d, J = 7.1 Hz), 7.93 (1H,
d, J = 7.6 Hz), 9.55 (1H, s), 11.
6 (1H, brs). mass: 331 (M + 1) ⁺ .

Example 22 The target compound was prepared in the same manner as in Example 10 except for using the compound of Example 21. ¹ H-NMR (DMSO-d ₆ ) δ: 0.68 (3H,
t, J = 7.4 Hz), 1.03-1.15 (2H,
m), 1.32-1.42 (2H, m), 2.99-
3.05 (2H, m), 6.07 (1H, d, J = 8.
2Hz), 6.31 (1H, d, J = 7.8Hz),
6.65 (1H, t, J = 5.4 Hz), 7.34-
7.40 (3H, m), 7.48 (1H, d, J = 6.
3 Hz), 7.55 (1H, dd, J = 7.6 Hz,
6.4 Hz), 7.65 (1H, d, J = 7.3H)
z), 7.70 (1H, d, J = 7.2 Hz), 7.8
1 (1H, d, J = 7.4 Hz), 9.56 (1H,
s), 11.4 (1H, br). mass: 387 (M + 1) ⁺ .

Examples 23 to 25 Examples 23 to 2 were carried out according to the method of Example 26.
Compound 5 was prepared. Example 23 ¹ H-NMR (DMSO-d ₆ ) δ: 1.16 (3H,
t, J = 7.4 Hz), 2.36 (3H, s), 2.7
3 (2H, q, J = 7.6 Hz), 6.94 (1H,
d, J = 7.7 Hz), 7.36-7.47 (3H,
m), 7.57-7.68 (3H, m), 7.88 (1
H, d, J = 7.9 Hz), 8.06 (1H, d, J =
7.0 Hz). mass: 358 (M + 1) ⁺ .

Example 24 ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (3H,
s), 2.34 (3H, s), 6.77 (1H, s),
6.89 (1H, s), 7.38-7.43 (3H,
m), 7.63-7.68 (2H, m), 7.90 (1
H, dd, J = 8.0 Hz, 1.9 Hz), 8.05
(1H, d, J = 7.5 Hz), 9.92 (1H,
s), 11.4-11.5 (1H, br). mass: 344 (M + 1). ⁺

Example 25 ¹ H-NMR (DMSO-d ₆ ) δ: 2.39 (3H,
s), 2.41 (3H, s), 6.94 (1H, s),
7.37-7.48 (3H, m), 7.60-7.69
(2H, m), 7.88 (1H, d, J = 7.9H)
z), 8.04 (1H, d, J = 7.6 Hz), 8.1
1 (2H, brs), 8.77 (0.7H, s), 9.
02 (0.3H, s). mass: 387 (M + 1) ⁺ .

Example 26 To a solution of 2-aminopyrimidine (13 mg, 0.14 mmol) in tetrahydrofuran (1 ml) was added a solution of 1.25 mg (0.1 mmol) of the compound of Reference Example 1 in tetrahydrofuran (1 ml), and the mixture was refluxed for 30 minutes. The precipitated crystals were collected by filtration, washed with chloroform and dried, and 10 mg of the desired compound was obtained.
Was obtained as yellow crystals. _{^{1 H-NMR (DMSO- d 6}} ) δ: 7.23 (1H,
t, J = 4.9 Hz), 7.38-7.50 (3H,
m), 7.67-7.72 (2H, m), 8.06-
8.10 (2H, m), 8.74 (2H, d, J = 4.
9Hz), 10.6 (0.3H, s), 11.6 (0.
3H, s). mass: 317 (M + 1) ⁺ .

Examples 27 to 53 According to the method of Example 26, Examples 27 to 5 were carried out.
Compound 3 was prepared. Example ^{27 1 H-NMR (DMSO- d} 6) δ: 7.36-7.9
5 (9H, m). mass: 333 (M + 1) ⁺ .

Example 28 ¹ H-NMR (DMSO-d ₆ ) δ: 3.28 (3H,
s), 7.07 (1H, d, J = 5.3 Hz), 7.3
6-7.97 (6H, m), 8.05 (1H, d, J =
7.3 Hz), 8.53 (1H, d). mass: 331 (M + 1) ⁺ .

Example 29 ¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (3H,
s), 2.52 (3H, s), 7.27-7.35 (3
H, m), 7.53-7.57 (2H, m), 7.81
(1H, d, J = 7.9 Hz), 7.90 (1H, d,
J = 7.6 Hz), 9.00 (1H, s). mass: 373 (M + 1) ⁺ .

Example 30 ¹ H-NMR (DMSO-d ₆ ) δ: 2.27 (3H,
s), 2.38 (3H, s), 7.36-7.48 (3
H, m), 7.65-7.70 (2H, m), 7.75
−7.78 (1H, m), 7.92 (1H, d, J =
7.4 Hz), 9.02 (1H, brs). mass: 345 (M + 1) ⁺ .

Example 31 ¹ H-NMR (DMSO-d ₆ ) δ: 3.34 (3H,
s), 3.92 (3H, s), 7.39-7.51 (4
H, m), 7.69-7.81 (3H, m), 7.99.
(1H, d, J = 7.6 Hz). mass: 377 (M + 1) ⁺ .

Example 32 ¹ H-NMR (DMSO-d ₆ ) δ: 2.19 (3H,
s), 5.95 (1H, br), 6.75 (1H, b
r), 7.39-7.44 (2H, m), 7.49-
7.52 (1H, m), 7.63-7.69 (2H,
m), 7.78-7.81 (1H, m), 7.94-
7.97 (1H, m). mass: 347 (M + 1) ⁺ .

Example 33 ¹ H-NMR (DMSO-d ₆ ) δ: 1.76, 1.8
9 (3H, sx2), 2.01, 2.18 (3H, sx
2), 7.37-7.50 (5H, m), 7.61-
7.67 (2H, m), 7.77-7.80 (1H,
m), 7.93-7.97 (1H, m). mass: 361 (M + 1) ⁺ .

[0658] Example ^{34 1 H-NMR (DMSO- d} 6) δ: 7.43-7.5
3 (3H, m), 7.68-7.73 (2H, m),
7.94-8.02 (2H, m), 8.34-8.39
(2H, m), 8.99 (1H, s). mass: 317 (M + 1) ⁺ .

Example 35 ¹ H-NMR (DMSO-d ₆ ) δ: 6.60 (1H,
brs), 7.33-7.49 (7H, m), 7.63.
−7.75 (4H, m), 7.91 to 8.05 (2H,
m). mass: 381 (M + 1) ⁺ .

[0660] Example ^{36 1 H-NMR (DMSO- d} 6) δ: 5.85 (2H,
brs), 7.30-7.45 (5H, m), 7.61.
−7.69 (2H, m), 8.13-8.20 (1H,
m). mass: 321 (M + 1) ⁺ .

Example 37 ¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (3H,
t, J = 7.5 Hz), 4.05 (2H, q, J = 7.
5Hz), 6.18 (1H, m), 7.33-7.46
(4H, m), 7.63-7.73 (3H, m), 7.
84 (1H, d, J = 7.5 Hz). mass: 333 (M + 1) ⁺ .

Example 38 ¹ H-NMR (DMSO-d ₆ ) δ: 6.45 (1H,
s), 7.31-7.47 (4H, m), 7.54-
7.63 (8H, m), 7.69 (1H, d, J = 7.
5Hz), 8.79 (1H, s), 8.95 (1H,
s). mass: 381 (M + 1) ⁺ .

Example 39 ¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (3H,
s), 5.45 (1H, s), 6.49-6.61 (4
H, m), 6.69-6.85 (8H, m), 7.91
(1H, brs), 8.06 (1H, brs). mass: 395 (M + 1) ⁺ .

Example 40 ¹ H-NMR (DMSO-d ₆ ) δ: 6.33 (1H,
d, J = 3.8 Hz), 6.55-6.66 (4H,
m), 6.81-6.85 (2H, m), 7.00-
7.04 (1H, m), 7.08 (1H, d, J = 7.
6 Hz), 8.03 (1H, brs). mass: 322 (M + 1) ⁺ .

Example 41 mass: 336 (M + 1) ⁺ .

Example 42 mass: 422 (M + 1) ⁺ .

Example 43 mass: 408 (M + 1) ⁺ .

Example 44 ¹ H-NMR (DMSO-d ₆ ) δ: 1.30 (3H,
t, J = 7.5 Hz), 4.31 (2H, q, J = 7.
5Hz), 7.36-7.50 (4H, m), 7.60
−7.69 (1H, m), 7.83 (1H, d, J =
7.5Hz), 7.90 (1H, d, J = 7.5H)
z), 8.72 (1H, s). mass: 437 (M + 1) ⁺ .

Example 45 ¹ H-NMR (DMSO-d ₆ ) δ: 7.29-7.5
0 (6H, m), 7.55 (1H, s), 7.60-
7.66 (2H, m), 7.81-7.94 (4H,
m). mass: 398 (M + 1) ⁺ .

Example 46 ¹ H-NMR (DMSO-d ₆ ) δ: 7.40 (2H,
t), 7.49 (3H, d), 7.60-7.66 (3
H, m), 7.83 (1H, d, J = 7.6 Hz),
7.91 (3H, d, J = 7.6 Hz). mass: 432 (M + 1) ⁺ .

Example 47 ¹ H-NMR (DMSO-d ₆ ) δ: 7.35-7.4
3 (2H, m), 7.48-7.52 (1H, m),
7.60-7.66 (2H, m), 7.72 (1H,
d, J = 7.6 Hz), 7.81 (1H, d, J = 7.
6 Hz), 8.20-8.28 (3H, m), 8.38
−8.44 (2H, m), 8.89−9.02 (0.2
H, br). mass: 507 (M + 1) ⁺ .

Example 48 ¹ H-NMR (DMSO-d ₆ ) δ: 2.45 (3H,
s), 6.51-6.70 (3H, m), 6.79-
6.97 (4H, m), 7.13-7.37 (1H,
m), 7.80 (0.3H, s), 8.20 (0.3
H, s). mass: 336 (M + 1) ⁺ .

Example 49 ¹ H-NMR (DMSO-d ₆ ) δ: 7.36-7.4
3 (2H, m), 7.47 (2H, d, J = 7.5H
z), 7.61-7.65 (2H, m), 7.77 (1
H, d, J = 7.5 Hz), 7.84 (1H, d, J =
7.5 Hz). mass: 400, 402 (M + 1) ⁺ .

Example 50 ¹ H-NMR (DMSO-d ₆ ) δ: 7.35-7.4
5 (2H, m), 7.52 (1H, d, J = 6.9H)
z), 7.60-7.67 (2H, m), 7.77 (1
H, d, J = 8.0 Hz), 7.85 (1H, d, J =
7.5Hz), 8.60 (1H, s). mass: 367 (M + 1) ⁺ .

[0675] Example ^{51 1 H-NMR (DMSO- d} 6) δ: 7.25 (1H,
t), 7.40 (3H, t), 7.48 (1H, d, J
= 7.6 Hz), 7.60-7.68 (3H, m),
7.86-7.93 (3H, m), 9.15 (0.5
H, br). mass: 372 (M + 1) ⁺ .

Example 52 ¹ H-NMR (DMSO-d ₆ ) δ: 1.49 (3H,
s), 6.41 (1H, d, J = 7.5 Hz), 6.5.
7-6.90 (7H, m), 7.00-7.05 (1
H, brm), 7.10-7.15 (1H, brm). mass: 386 (M + 1) ⁺ .

Example 53 ¹ H-NMR (DMSO-d ₆ ) δ: 6.45 (1H,
dt), 6.60 (2H, t), 6.70 (1H, d,
J = 7.6 Hz), 6.80-6.90 (3H, m),
7.00-7.10 (3H, m). mass: 390 (M + 1) ⁺ .

Examples 54 to 55 The compounds of Examples 54 and 55 were prepared according to the method of Example 1. Example ^{54 1 H-NMR (DMSO- d} 6) δ: 7.07-7.1
1 (1H, m), 7.34-7.38 (1H, m),
7.53 (1H, s), 7.78-7.84 (2H,
m), 7.92-7.95 (1H, m), 8.07 (1
H, d, J = 8.3 Hz), 8.32 (1H, d, J =
1.8Hz), 8.38 (1H, s).

Example 55 ¹ H-NMR (DMSO-d ₆ ) δ: 7.06 (1H,
dd, J = 7.2 Hz, 5.1 Hz), 7.20-7.
23 (1H, m), 7.42 (1H, d, J = 7.3H
z), 7.71-7.80 (2H, m), 8.35 (1
H, dd, J = 5.0 Hz, 1.9 Hz), 8.74
(1H, d, J = 8.5 Hz), 12.0 (0.4H,
s), 11.3 (0.4H, brs), 12.6 (b
r).

[0680] Compounds 56mg of Example 56 Example 55 (0.20 mmol), triphenylphosphine 157 mg (0.6 mmol) and methanol 19mg of (0.60 mmol) was dissolved in dimethylformamide 5 ml, diethylazodicarboxylate at room temperature Rate toluene solution (60%) 0.17
ml (0.60 mmol) was added, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was separated, and the precipitated crystals were collected by filtration to obtain 41 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 3.03 (3H,
s), 7.04-7.09 (1H, m), 7.19 (1
H, brd, J = 7.9 Hz), 7.45 (1H, d
d, J = 7.2 Hz, 0.8 Hz), 7.70-7.8
1 (2H, m), 8.39 (1H, dd, J = 5.0H
z, 1.9 Hz), 8.74 (1H, d, J = 8.6H)
z), 10.2 (0.3H, s), 12.7 (0.3
H, br).

[0681] Example 57 - compound of Example 74 Example 57 through Example 74 were prepared according to the method of Example 56. Example 57 ¹ H-NMR (DMSO-d ₆ ) δ: 1.18 (3H,
t, J = 7.2 Hz), 3.60 (2H, q, J = 7.
2 Hz), 7.07 (1H, dd, J = 7.3 Hz,
5.0 Hz), 7.19-7.21 (1H, m), 7.
42 (1H, d, J = 7.2 Hz), 7.71-7.8
1 (2H, m), 8.39 (1H, m), 8.75 (1
H, d, J = 8.6 Hz), 10.2 (0.3H,
s), 12.7 (0.3H, br).

Example 58 ¹ H-NMR (DMSO-d ₆ ) δ: 0.87 (3H,
t, J = 7.4 Hz), 1.62 (2H, q, J = 7.
3Hz), 3.53 (2H, t, J = 7.1 Hz),
7.07 (1H, dd, J = 7.3 Hz, 5.1H
z), 7.22 (1H, m), 7.46 (1H, d, J
= 7.3 Hz), 7.71-7.81 (2H, m),
8.38 (1H, m), 8.75 (1H, d, J = 8.
5 Hz), 10.2 (0.3 H, s), 12.6 (0.
3H, br).

Example 59 ¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (6H,
d, J = 6.9 Hz), 4.37-4.42 (1H,
m), 7.05-7.09 (1H, m), 7.21-
7.23 (1H, brm), 7.43 (1H, d, J =
7.2 Hz), 7.70-7.81 (2H, m), 8.
39 (1H, m), 8.74 (1H, d, J = 8.5H
z), 10.2 (0.2H, s), 12.6 (0.2
H, br).

Example 60 ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H,
t, J = 7.3 Hz), 1.26-1.36 (2H,
m), 1.54-1.63 (2H, m), 3.57 (2
H, t, J = 7.0 Hz), 7.07 (1H, ddd,
J = 7.3 Hz, 5.0 Hz, 1.0 Hz), 7.20
(1H, d, J = 7.9 Hz), 7.46 (1H, d,
J = 7.2 Hz), 7.71-7.81 (2H, m),
8.38 (1H, dd, J = 5.0 Hz, 1.8H
z), 8.75 (1H, d, J = 8.5 Hz), 10.
2 (1H, s), 12.6 (1H, br).

[0685] Example ^{61 1 H-NMR (DMSO- d} 6) δ: 1.40-1.4
7 (2H, m), 1.61-1.68 (2H, m),
3.39 (2H, t, J = 6.4 Hz), 3.58 (2
H, t, J = 6.8 Hz), 4.38 (0.3H,
m), 7.04-7.09 (1H, m), 7.19-
7.22 (1H, m), 7.41-7.47 (1H,
m), 7.71-7.82 (2H, m), 8.34-
8.39 (1H, m), 8.75 (1H, d, J = 8.
2Hz), 10.2 (0.5H, s), 12.6 (0.
4H, br).

Example 62 ¹ H-NMR (DMSO-d ₆ ) δ: 3.34-3.4
8 (3H, m), 3.59 (2H, d, J = 7.5H
z), 4.43 (2H, m), 7.05-7.09 (1
H, m), 7.20 (1H, d, J = 8.2 Hz),
7.46 (1H, d, J = 6.9 Hz), 7.71-
7.81 (2H, m), 8.38 (1H, dd, J =
4.8 Hz, 1.6 Hz), 8.74 (1H, d, J =
8.6 Hz), 10.2 (1 H, s), 12.6 (1
H, br).

Example 63 ¹ H-NMR (DMSO-d ₆ ) δ: 1.21 (3H,
t, J = 7.1 Hz), 4.16 (2H, q, J = 7.
1 Hz), 4.42 (2H, s), 7.07 (1H, d
d, J = 7.2 Hz, 5.1 Hz), 7.18-7.2
1 (1H, m), 7.54 (1H, d, J = 7.3H
z), 7.75-7.83 (2H, m), 8.35-
8.38 (1H, m), 8.81 (1H, d, J = 8.
6 Hz), 10.2 (0.5 H, s), 12.7 (0.
4H, br).

Example 64 ¹ H-NMR (DMSO-d ₆ ) δ: 4.78 (2H,
s), 7.06 (1H, ddd, J = 7.3 Hz, 5.
0 Hz, 1.0 Hz), 7.19-7.36 (6H,
m), 7.50 (1H, d, J = 7.1 Hz), 7.7
4-7.80 (2H, m), 8.36 (1H, dd, J
= 4.9 Hz, 1.9 Hz), 8.77 (1H, d, J)
= 8.6 Hz), 10, 2 (0.3 H, s), 12.6
(0.3H, br).

Example 65 ¹ H-NMR (DMSO-d ₆ ) δ: 2.94 (2H,
t, J = 7.3 Hz), 3.81 (2H, t, J = 7.
3 Hz), 7.08 (1H, dd, J = 7.2 Hz,
5.0 Hz), 7.15-7.33 (6H, m), 7.
43 (1H, d, J = 7.3 Hz), 7.70-7.8
1 (2H, m), 8.37 (1H, dd, J = 4.8H
z, 1.4 Hz), 8.73 (1H, d, J = 8.6H)
z), 10.2 (0.3H, s), 12.6 (0.3
H, br).

Example 66 ¹ H-NMR (DMSO-d ₆ ) δ: 4.61 (2H,
s), 6.50 (1H, t, J = 7.2 Hz), 6.6.
7 (1H, d, J = 7.7 Hz), 6.93-7.09
(4H, m), 7.17-7.22 (1H, m), 7.
41-7.71 (2H, m), 7.74-7.80 (2
H, m), 8.36 (1H, d, J = 4.7 Hz),
8.78 (1H, d, J = 8.6 Hz), 10.2
(0.5H, s), 12.6 (0.5H, br).

Example 67 ¹ H-NMR (DMSO-d ₆ ) δ: 4.62 (2H,
s), 6.41-6.46 (3H, m), 6.95 (1
H, t, J = 7.9 Hz), 7.06 (1H, dd, J)
= 7.2 Hz, 5.0 Hz), 7.19-7.22 (1
H, m), 7.50 (1H, d, J = 7.2 Hz),
7.74-7.80 (2H, m), 8.37 (1H,
d, J = 5.6 Hz), 8.77 (1H, d, J = 8.
4 Hz), 10.2 (0.3 H, s), 12.6 (0.
3H, br).

Example 68 ¹ H-NMR (DMSO-d ₆ ) δ: 4.91 (2H,
s), 7.03 (1H, dt, J = 6.3 Hz, 1.1
Hz), 7.17-7.29 (2H, m), 7.42
(1H, dd, J = 7.9 Hz, 1.0 Hz), 7.5
2 (1H, d, J = 7.2 Hz), 7.73-7.82
(3H, m), 8.31 (1H, dd, J = 4.5H
z, 1.5 Hz), 8.44 (1H, dd, J = 4.5)
Hz, 1.8 Hz), 8.79 (1H, d, J = 8.6)
Hz), 10.2 (0.3 H, s), 12.6 (0.2
H, br).

Example 69 ¹ H-NMR (DMSO-d ₆ ) δ: 4.81 (2H,
s), 7.06 (1H, dd, J = 7.2 Hz, 5.0
Hz), 7.09-7.22 (1H, m), 7.35
(1H, dd, J = 7.8 Hz, 4.8 Hz), 7.4
9 (1H, d, J = 6.9 Hz), 7.72-7.80
(3H, m), 8.37 (1H, d, J = 3.9H
z), 8.48 (1H, dd, J = 4.8 Hz, 1.6)
Hz), 8.60 (1H, s), 8.76 (1H, d,
J = 8.0 Hz), 10.2 (0.3 H, s), 12.
6 (0.3H, br).

Example 70 ¹ H-NMR (DMSO-d ₆ ) δ: 4.81 (2H,
s), 7.04 (1H, dd, J = 6.9 Hz, 5.5)
Hz), 7.18-7.21 (1H, m), 7.33
(2H, d, J = 5.7 Hz), 7.51 (1H, d,
J = 7.2 Hz), 7.74-7.81 (2H, m),
8.33 (1H, d, J = 3.9 Hz), 8.51 (2
H, d, J = 6.0 Hz), 8.78 (1H, d, J =
8.6 Hz), 10.2 (0.4 H, s), 12.6
(0.3H, br).

Example 71 ¹ H-NMR (DMSO-d ₆ ) δ: 3.82 (3H,
s), 4.85 (2H, s), 7.04 (1H, dd,
J = 6.2 Hz, 1.1 Hz), 7.07-7.21
(1H, m), 7.47 (2H, d, J = 8.5H
z), 7.51 (1H, d, J = 7.3 Hz), 7.7
4-7.80 (2H, m), 7.92 (2H, d, J =
8.5Hz), 8.34 (1H, d, J = 4.0H)
z), 8.78 (1H, d, J = 8.6 Hz), 10.
2 (0.2H, s), 12.6 (0.2H, br).

Example 72 ¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.6
8 (1H, brm), 1.82-1.98 (2H, br
m), 2.04-2.14 (3H, brm), 4.72.
-4.76 (1H, brm), 5.61 (1H, dd,
J = 10 Hz, 1.2 Hz), 5.82-5.86 (1
H, m), 7.03-7.06 (1H, brm), 7.
21-7.27 (1H, brm), 7.42-7.45
(1H, m), 7.70-7.80 (2H, m), 8.
36 (1H, brs), 8.72-8.74 (1H,
m), 10.2 (0.4H, brs), 12.4 (0.
4H, br).

Example 73 ¹ H-NMR (DMSO-d ₆ ) δ: 0.93-1.1
1 (2H, brm), 1.13-1.16 (3H, br
m), 1.63-1.74 (6H, brm), 3.42.
(2H, d, J = 6.9 Hz), 7.08 (1H, d
t, J = 6.2 Hz, 1.1 Hz), 7.19-7.2
3 (1H, brm), 7.47 (1H, d, J = 7.1)
Hz), 7.72-7.82 (2H, m), 8.38
(1H, d, J = 4.9 Hz), 8.75 (1H, d,
J = 8.6 Hz), 10.2 (0.5 H, s), 12.
7 (0.4H, br).

Example 74 ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (4H,
m), 2.49 (4H, m), 4.49 (3H, s),
5.76-5.85 (1H, m), 7.04-7.09
(1H, m), 7.17-7.21 (1H, brm),
7.48 (1H, d, J = 7.2 Hz), 7.71-
7.80 (2H, m), 8.35 (1H, d, J = 4.
2 Hz), 8.76 (1H, d, J = 8.6 Hz), 1
0.2 (0.5H, s), 12.6 (0.5H, b
r).

Example 79 The target compound was prepared according to the method of Example 1 using the compound of Reference Example 3 and 2-pyridinecarbonylazide. ¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.2
0 (1H, m), 2.30-2.43 (2H, br
m), 2.52-2.57 (1H, m), 3.28-
3.35 (1H, m), 3.50-3.60 (1H,
m), 4.83 (1H, dd, J = 10 Hz, 5.7H
z), 7.06 (1H, dd, J = 7.2 Hz, 5.1)
Hz), 7.28-7.33 (2H, m), 7.46
(1H, t, J = 7.7 Hz), 7.76-7.82
(1H, m), 8.29-8.32 (2H, m), 9.
95 (1H, s), 11.2 (1H, br). mass: 309 (M + 1) ⁺ .

Example 80 (1) 2.00 g (11.0 mmol) of ethyl 4-hydroxymethylpicolinate was dissolved in 80 ml of dimethylformamide, and 1.88 g of imidazole (27.
0 mmol) and 7.60 ml (27.0 mmol) of chloro-tert-butyldiphenylsilane were added at room temperature, and the reaction solution was stirred at the same temperature for 2 hours. The reaction solution was diluted with hexane-ethyl acetate (1: 1), washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 95: 5-70: 30) to obtain 4.27 g of a colorless solid.

(2) 3.14 g of the compound obtained in (1)
(7.40 mmol) in 60 ml of methanol,
1.80 ml (37.0 mmol) of hydrazine monohydrate
Was added at room temperature, and the reaction solution was stirred at the same temperature for 12 hours.
The reaction solution was concentrated, and the residue was dissolved in chloroform. The organic layer was washed with saturated saline, and the organic layer was concentrated to obtain an oil. This was used for the next reaction without purification.

(3) The compound obtained in (2) was dissolved in 10 ml of chloroform, and 22.2 ml of 1N hydrochloric acid was added.
(22.2 mmol) was added at room temperature. The mixture was cooled on ice and 1.02 g of sodium nitrite (14.8 mmol)
1) was added at the same temperature, and the reaction solution was further stirred at the same temperature for 30 minutes. The reaction solution was extracted with chloroform, and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. To the obtained residue, a solution of 0.622 g (3.30 mmol) of the compound of Reference Example 3 in 50 ml of tetrahydrofuran was added at room temperature, and the reaction solution was added as 1
Refluxed overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform-tetrahydrofuran, 10: 0 to 9: 1) to obtain a pale brown amorphous.
3 g were obtained.

(4) 2.03 g of the compound obtained in (3)
(3.30 mmol) was dissolved in 10 ml of tetrahydrofuran, and 6.60 ml (6.6 M) of a tetrahydrofuran solution of tetra-n-butylammonium fluoride (1.0 M) was used.
0 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was diluted with tetrahydrofuran and ethyl acetate, and washed with saturated saline. The organic layer was concentrated, and the precipitated pale yellow crystals were collected by filtration. The filtrate was subjected to silica gel column chromatography (chloroform-methanol, 100: 0).
~ 95: 5) to obtain yellow crystals. 1.02 g of the target compound was obtained in combination with the crystals previously collected by filtration. ¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.2
0 (1H, m), 2.31-2.44 (2H, m),
2.45-2.58 (1H, m), 3.28-3.35
(1H, m), 3.50-3.60 (1H, m), 4.
52 (2H, d, J = 5.6 Hz), 4.83 (1H,
dd, J = 10 Hz, 5.3 Hz), 5.47 (1H,
t, J = 5.7 Hz), 6.99 (1H, d, J = 4.
7Hz), 7.26 (1H, s), 7.32 (1H,
d, J = 7.5 Hz), 7.47 (1H, t, J = 7.
8Hz), 8.23 (1H, d, J = 5.3Hz),
8.33 (1H, d, J = 7.6 Hz), 9.96 (1
H, s), 11.4 (1H, br). mass: 339 (M + 1) ⁺ .

Example 81 (1) To a solution of 3.50 g of the compound of Reference Example 5 in 35 ml of tetrahydrofuran was added a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.0 M) 7.10
ml (7.10 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. The reaction was concentrated and diluted with ether. The extract was washed successively with water and saturated saline, dried over magnesium sulfate, and concentrated by filtration. The residue was washed with ether and dried to give 1.66 g of the desired compound as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.2
2 (1H, m), 2.26-2.31 (2H, br
m), 2.46-2.62 (1H, m), 2.70 (2
H, t, J = 6.3 Hz), 3.22-3.40 (1
H, m), 3.48-3.71 (3H, m), 4.71.
(1H, brt), 4.79-4.90 (1H, m),
6.95 (1H, d, J = 6.3 Hz), 7.11 (1
H, s), 7.30 (1H, d, J = 6.3 Hz),
7.44 (1H, t, J = 7.9 Hz), 8.19 (1
H, d, J = 6.3 Hz), 8.30 (1H, d, J =
7.9 Hz), 9.86 (1H, s), 11.4 (1
H, br). mass: 353 (M + 1) ⁺ .

Example 82 (1) 45 mg (0.13 mmol) of the compound of Example 80
l) was dissolved in 1 ml of pyridine, 40 μl (0.52 mmol) of methanesulfonyl chloride was added at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was acidified with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in 1 ml of dimethylformamide, 85 mg (1.3 mmol) of sodium azide was added at room temperature, and the reaction solution was stirred at 80 ° C. for 30 minutes. The reaction solution was diluted with chloroform and washed with saturated saline. The organic layer was separated and concentrated to give 35 mg of a pale yellow solid. This was used for the next reaction without purification.

(2) 35 mg of the compound obtained in (1) was dissolved in 7 ml of methanol-tetrahydrofuran (5: 2), and 5 mg of a 10% palladium on carbon catalyst was added at room temperature. The inside of the container is replaced with hydrogen, and the reaction solution is added at room temperature under a hydrogen stream.
Stirred overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. The precipitated crystals were collected by filtration to obtain 13 mg of pale yellow crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.1
0 (1H, m), 2.21-2.60 (4H, m),
3.45-3.52 (2H, m), 4.06-4.09
(2H, m), 4.79-4.85 (1H, m), 5.
16-5.20 (1H, m), 6.93 (1H, d, J
= 5.9 Hz), 7.20 (1H, s), 7.26 (1
H, d, J = 7.6 Hz), 7.39-7.45 (1
H, m), 8.10 (1H, d, J = 4.9 Hz),
8.27 (1H, d, J = 7.7 Hz), 10.3 (1
H, br), 11.7 (1H, br). mass: 338 (M + 1) ⁺ .

Example 83 260 mg of the compound of Reference Example 9 was dissolved in 10 ml of methanol-tetrahydrofuran (1: 1), and 200 mg of a 10% palladium on carbon catalyst was added at room temperature. The inside of the reaction vessel was replaced with hydrogen, and the reaction solution was stirred at the same temperature overnight. The insolubles were filtered off and the filtrate was concentrated to give 105 mg of the title compound. ¹ H-NMR (DMSO-d6) δ: 1.01-1.2
2 (1H, m), 2.28-2.40 (3H, br
m), 2.62-2.72 (2H, m), 2.80-
2.88 (2H, m), 3.18 (2H, s), 3.4
5-3.60 (2H, m), 4.82 (1H, dd, J
= 9.8 Hz, 6.2 Hz), 6.95 (1H, d, J)
= 6.2 Hz), 7.12 (1H, s), 7.30 (1
H, d, J = 6.8 Hz), 7.45 (1H, t, J =
7.4Hz), 8.20 (1H, d, J = 5.5H)
z), 8.30 (1H, d, J = 6.2 Hz), 9.9
4 (1H, br), 11.4 (1H, br). mass: 352 (M + 1) ⁺ .

Example 84 (1) 1.02 g (3.02 mmol) of the compound of Example 80
l) was dissolved in 90 ml of dimethylformamide-tetrahydrofuran (1: 8), 3.92 g (45.1 mmol) of manganese dioxide was added at room temperature, and the reaction solution was stirred at the same temperature for 6 hours. The reaction was filtered through celite. The filtrate was concentrated, and the precipitated crystals were collected by filtration to obtain yellow crystals 0.21.
1 g was obtained.

(2) 34 mg of the compound obtained in (1)
(0.10 mmol) and n-butylamine 22 mg
(0.30 mmol) in 5 ml of chloroform,
212mg sodium triacetoxyborohydride
(1.0 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 24 hours. The reaction solution was neutralized with 3N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The precipitated crystals were collected by filtration to obtain 13 mg of the desired compound. ¹ H-NMR (D
_{MSO- d 6) δ: 0.88 (} 3H, t, J = 7.3H
z), 1.08-1.17 (1H, m), 1.28-
1.38 (2H, m), 1.42-1.51 (2H,
m), 2.31-2.39 (3H, m), 2.47-
2.54 (2H, m), 2.59 (2H, t, J = 7.
2Hz), 3.50-3.57 (1H, m), 3.81
(2H, s), 4.83 (1H, dd, J = 11 Hz,
5.5 Hz), 7.09 (1H, d, J = 5.3H)
z), 7.31-7.33 (2H, m), 7.47 (1
H, t, J = 7.9 Hz), 8.26 (1H, d, J =
5.3 Hz), 8.31 (1H, d, J = 8.1H)
z), 9.98 (1H, s), 11.2 (1H, b
r). mass: 394 (M + 1) ⁺ .

[0710] The compound of Example 85-94 Example 85 to Example 94, was prepared analogously to Example 84. Example ^{85 1 H-NMR (DMSO- d} 6) δ: 1.11-1.1
8 (1H, m), 2.22-2.44 (5H, m),
2.58 (2H, t, J = 5.8 Hz), 3.46 −
3.58 (3H, m), 3.73 (2H, s), 4.5
1 (1H, t, J = 5.4 Hz), 4.84 (1H, d
d, J = 10 Hz, 5.6 Hz), 7.05 (1H,
d, J = 5.4 Hz), 7.26 (1H, s), 7.3
3 (1H, d, J = 7.4 Hz), 7.48 (1H,
t, J = 7.9 Hz), 8.24 (1H, d, J = 5.
3 Hz), 8.34 (1H, d, J = 8.2 Hz),
9.93 (1H, s), 11.4 (1H, br). mass: 382 (M + 1) ⁺ .

Example 86 ¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.20
(1H, m), 2.28-2.43 (2H, m), 2.
48-2.60 (1H, m), 3.00 (1H, b
r), 3.28-3.40 (1H, m), 3.50-
3.60 (1H, m), 3.71 (4H, s), 4.8
3 (1H, m), 7.06 (1H, d, J = 4.6H
z), 7.25 (1H, d, J = 7.4 Hz), 7.2
9-7.39 (6H, m), 7.46 (1H, t, J =
7.4 Hz), 8.23 (1H, d, J = 5.5H)
z), 8.34 (1H, d, J = 7.4 Hz), 9.9
7 (1H, s), 11.5 (1H, br). mass: 428 (M + 1) ⁺ .

Example 87 ¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.20
(1H, m), 2.29-2.43 (2H, m), 2.
49-2.60 (1H, m), 3.32 (2H, s),
3.49 (2H, s), 3.53-3.60 (1H,
m), 3.64 (2H, s), 4.83 (1H, dd,
J = 11 Hz, 5.6 Hz), 4.91 (2H, s),
6.51 (2H, d, J = 8.3 Hz), 6.99 (1
H, d, J = 8.2 Hz), 7.04 (2H, d, J =
5.4 Hz), 7.26 (1H, s), 7.32 (1
H, d, J = 7.4 Hz), 7.47 (1H, t, J =
7.8 Hz), 8.22 (1H, d, J = 5.4H)
z), 8.33 (1H, d, J = 8.1 Hz), 9.9
4 (1H, s), 11.5 (1H, br). mass: 443 (M + 1) ⁺ .

[0713] Example ^{88 1 H-NMR (DMSO- d} 6) δ: 1.07-1.1
8 (1H, m), 2.32-2.44 (2H, m),
2.51-2.66 (5H, m), 3.28-3.40
(2H, m), 3.54-3.61 (1H, m), 3.
72 (2H, s), 4.82 (3H, s), 6.48
(2H, d, J = 8.2 Hz), 6.86 (2H, d,
J = 8.2 Hz), 7.03 (1H, d, J = 5.2H)
z), 7.24 (1H, s), 7.32 (1H, d, J
= 7.3 Hz), 7.48 (1H, t, J = 7.6H)
z), 8.22 (1H, d, J = 5.0 Hz), 8.3
4 (1H, d, J = 8.3 Hz), 9.94 (1H, d, J = 8.3 Hz)
s), 11.4 (1H, br). mass: 457 (M + 1) ⁺ .

Example 89 ¹ H-NMR (DMSO-d ₆ ) δ: 1.12-1.2
1 (1H, m), 2.33-2.42 (2H, m),
2.50-2.59 (2H, m), 2.90-3.15
(1H, br), 3.51-3.58 (1H, m),
3.70 (2H, s), 3.77 (2H, s), 4.8
4 (1H, dd, J = 11 Hz, 5.6 Hz), 7.0
8 (1H, d, J = 5.3 Hz), 7.28-7.46
(4H, m), 7.48 (1H, t, J = 7.8H
z), 7.57 (2H, d, J = 8.2 Hz), 7.7
9 (2H, d, J = 8.3 Hz), 8.25 (1H,
d, J = 5.3 Hz), 8.34 (1H, d, J = 8.
2 Hz), 9.96 (1H, s), 11.4 (1H, b
r). mass: 507 (M + 1) ⁺ .

[0715] Example ^{90 1 H-NMR (DMSO- d} 6) δ: 1.08-1.1
5 (1H, m), 2.30-2.57 (5H, m),
2.71-2.83 (4H, m), 3.48-3.55
(1H, m), 3.71 (2H, s), 4.78-4.
83 (1H, m), 6.99 (1H, d, J = 5.3H
z), 7.23-7.25 (3H, m), 7.30 (1
H, d, J = 7.6 Hz), 7.39 (2H, d, J =
8.0 Hz), 7.45 (1H, t, J = 7.8H)
z), 7.71 (2H, d, J = 7.9 Hz), 8.2
0 (1H, d, J = 4.9 Hz), 8.31 (1H,
d, J = 8.0 Hz), 9.91 (1H, s), 11.
4 (1H, br). mass: 521 (M + 1) ⁺ .

[0716] Example ^{91 1 H-NMR (DMSO- d} 6) δ: 1.05-1.1
8 (1H, m), 2.26-2.40 (2H, m),
2.46-2.60 (2H, m), 3.00 (1H, b
r), 3.50-3.58 (1H, m), 3.69 (2
H, s), 3.71 (2H, s), 4.82 (1H, d
d, J = 10 Hz, 5.9 Hz), 7.05 (1H,
d, J = 5.3 Hz), 7.31 (2H, d, J = 7.
5 Hz), 7.38 (2H, d, J = 5.5 Hz),
7.46 (1H, t, J = 7.9 Hz), 8.23 (1
H, d, J = 5.4 Hz), 8.32 (1H, d, J =
8.1 Hz), 8.50 (2H, d, J = 5.9H)
z), 9.95 (1H, s), 11.4 (1H, b
r). mass: 429 (M + 1) +.

[0717] Example ^{92 1 H-NMR (DMSO- d} 6) δ: 1.03-1.1
7 (1H, m), 2.28-2.40 (3H, m),
2.47-2.54 (1H, m), 2.73 (4H,
s), 3.26-3.34 (1H, m), 3.50-
3.58 (1H, m), 3.70 (2H, s), 4.8
0 (1H, dd, J = 11 Hz, 5.6 Hz), 6.9
8 (1H, d, J = 5.5 Hz), 7.23 (2H,
d, J = 6.1 Hz), 7.23 (1H, s), 7.2
9 (1H, d, J = 6.6 Hz), 7.44 (1H,
t, J = 7.8 Hz), 8.19 (1H, d, J = 5.
3 Hz), 8.30 (1H, d, J = 7.3 Hz),
8.42 (2H, d, J = 5.9 Hz), 9.91 (1
H, s), 11.4 (1H, br). mass443 (M + 1) ⁺ .

Example 93 ¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.2
5 (1H, m), 2.27-1.64 (4H, m),
3.20-3.41 (3H, m), 3.49-3.60
(2H, m), 4.24 (2H, brm), 4.84-
4.92 (1H, m), 7.33-7.63 (6H,
m), 8.29 (1H, d, J = 7.7 Hz), 8.4
0 (1H, d, J = 5.5 Hz), 9.08 (1H,
s), 9.85 (2H, brm), 10.3 (1H,
s), 10.7 (1H, brm). mass: 432 (M + 1) ⁺ .

[0719] Example ^{94 1 H-NMR (DMSO- d} 6) δ: 0.99-1.1
4 (5H, m), 1.75-1.85 (4H, m),
2.25-2.38 (3H, m), 2.47-2.55
(1H, m), 3.26-3.35 (2H, m), 3.
48-3.57 (1H, m), 3.71 (2H, s),
4.44 (1H, d, J = 4.4 Hz), 4.81 (1
H, dd, J = 10 Hz, 5.6 Hz), 7.02 (1
H, d, J = 5.5 Hz), 7.23 (1H, s),
7.29 (1H, d, J = 7.4 Hz), 7.45 (1
H, t, J = 7.7 Hz), 8.19 (1H, d, J =
5.3Hz), 8.30 (1H, d, J = 8.2H)
z), 9.90 (1H, s), 11.4 (1H, b
r). mass: 436 (M + 1) ⁺ .

Example 95 The target compound was prepared according to Example 96, using tert-butyl N- (2-aminoethyl) carbamic acid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.01-1.1
5 (1H, m), 2.25-2.61 (3H, br
m), 2.97-3.03 (2H, brm), 3.14.
-3.55 (6H, brm), 3.50-3.59 (1
H, m), 3.80-4.00 (1H, brm), 4.
80-4.86 (1H, m), 7.05 (1H, br)
d), 7.25-7.34 (2H, m), 7.46 (1
H, dd), 8.21-8.30 (4H, m), 9.4.
8 (2H, br), 10.2 (1H, brs), 10.
9 (1H, br). mass: 395 (M + 1) ⁺ .

Example 96 (1) 4-nitrobenzenesulfonyl chloride 844m
g (3.81 mmol) in chloroform (9 ml) was ice-cooled and triethylamine (0.531 ml) was added thereto.
(3.81 mmol) was added and the reaction was allowed to come to room temperature. This solution (0.3 ml) was added to a solution of 10 μl (0.122 mmol) of n-propylamine in 0.3 ml of chloroform at room temperature, and the reaction solution was stirred at the same temperature overnight. The reaction mixture was purified by thin-layer chromatography (chloroform-methanol, 19: 1) to obtain the target compound.

(2) Refer to Example 7 for the compound obtained in (1).
38 mg of compound and 29 mg of triphenylphosphine
(0.111 mmol) chloroform (0.6 ml)
The solution was added at room temperature, and a toluene solution of diethyl azodicarboxylate (40%) 0.047 m was added to the reaction solution.
1 (0.108 mmol) was added and the reaction solution was added at room temperature for 3 hours.
Stirred for days. The reaction mixture was purified by thin layer chromatography (chloroform-methanol, 19: 1).

(3) The compound obtained in (2) was dissolved in 1 ml of dimethylformamide, and 35 mg of sodium carbonate was dissolved.
(0.330 mmol) and 11 μl of thiophenol
(0.107 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 1 day. The insoluble material was filtered, the filtrate was dissolved in 3 ml of tetrahydrofuran, 1 ml of 1N hydrochloric acid was added to the reaction solution at room temperature, and the reaction solution was further stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was azeotroped with toluene. Methanol-ether was added thereto to solidify to obtain the target compound. ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H,
t, J = 7.5 Hz), 1.03-1.17 (1H,
m), 1.58-1.70 (2H, m), 2.26-
2.40 (2H, brm), 2.55-2.65 (1
H, brm), 2.85-2.95 (2H, brm),
2.96-3.03 (2H, m), 3.12-3.22
(2H, brm), 2.28-2.35 (1H, m),
3.50-3.60 (1H, m), 4.80-4.86
(1H, m), 7.06 (1H, d, J = 5.2H
z), 7.30-7.35 (2H, m), 7.48 (1
H, t, J = 7.9 Hz), 8.27-8.32 (2
H, m), 8.86 (2H, br), 10.4 (1H,
br), 10.9 (1H, br). mass: 394 (M + 1) ⁺ .

[0724] The compound of Example 97- Example 98 Example 97 and Example 98 were prepared analogously to Example 96. Example 97 ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (3H,
t, J = 7.8 Hz), 1.01-1.17 (1H,
m), 2.26-2.40 (2H, m), 2.52-
2.63 (2H, m), 2.26-2.39 (2H,
m), 2.50-2.61 (1H, m), 2.88-
3.00 (4H, m), 3.10-3.21 (2H,
m), 3.26-3.34 (1H, m), 3.50-
3.60 (1H, m), 4.80-4.86 (1H,
m), 7.02 (1H, d, J = 4.6 Hz), 7.2
6-7.34 (2H, m), 7.46 (1H, t, J =
7.8 Hz), 8.26-8.30 (2H, m), 8.
80 (2H, m), 10.2 (1H, s), 11.0
(1H, br). mass: 408 (M + 1) ⁺ .

Example 98 ¹ H-NMR (DMSO-d ₆ ) δ: 0.86 (3H,
t), 1.00-1.20 (1H, m), 1.21-
1.34 (4H, m), 1.54-1.66 (2H,
m), 2.26-2.38 (2H, m), 2.40-
2.63 (1H, m), 2.85-3.00 (4H,
m), 3.08-3.23 (2H, m), 3.26-
3.35 (1H, m), 3.50-3.60 (1H,
m), 4.80-4.86 (1H, m), 7.03 (1
H, d, J = 4.3 Hz), 7.26-7.35 (2
H, m), 7.46 (1H, t, J = 7.8 Hz),
8.26-8.30 (2H, m), 8.81 (2H, b
rm), 10.3 (1H, s), 11.0 (1H, b
r). mass: 422 (M + 1) ⁺ .

Example 99 Production was carried out according to Example 96 using glycolaldehyde diethyl acetal. ¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.1
5 (1H, m), 2.25-2.40 (3H, m),
2.43-2.63 (1H, m), 2.90-3.37
(6H, m), 3.48-3.60 (1H, m), 4.
77-4.85 (1H, m), 6.97-7.02 (1
H, m), 7.23-7.34 (2H, m), 7.40.
−7.50 (1H, m), 8.23−8.32 (2H,
m), 8.66 (0.5H, brm), 9.00-9.
23 (1H, brm), 10.1 (1H, s), 11.
0 (1H, br). mass: 394 (M + 1) ⁺ .

Example 100 Example 96 was repeated using glycine tert-butyl ester.
Manufactured according to. ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.1
0 (1H, m), 2.23-2.40 (2H, br
m), 2.54-2.65 (1H, brm), 2.97
-3.05 (2H, brm), 3.17-3.40 (3
H, m), 3.50-3.59 (1H, m), 3.94
(2H, brs), 4.81-4.86 (1H, m),
7.03 (1H, d, J = 5.5 Hz), 7.28-
7.34 (2H, m), 7.46 (1H, t, J = 7.
8 Hz), 8.26 (2H, d, J = 6.5 Hz),
9.23 (2H, br), 10.4 (1H, br), 1
0.9 (1H, br). mass: 466 (M + 1) ⁺ .

[0728] Compounds of Example 101 - Example 108 Example 101 to Example 108, Example 9
6 was prepared. Example ^{101 1 H-NMR (DMSO- d} 6) δ: 1.03-1.1
5 (1H, m), 2.25-2.63 (3H, m),
2.95-3.05 (2H, m), 3.19-3.37
(3H, m), 3.50-3.61 (1H, m), 4.
10-4.19 (2H, m), 4.80-4.86 (1
H, m), 5.26 (2H, s), 7.00 (1H,
d, J = 5.5 Hz), 7.28-7.49 (8H,
m), 8.26-8.32 (2H, m), 9.37 (2
H, brm), 10.2 (1H, s), 10.9 (1
H, br). mass: 500 (M + 1) ⁺ .

Example 102 ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.1
7 (1H, m), 2.26-2.63 (3H, br
m), 2.97-3.05 (2H, brm), 3.10
-3.21 (2H, brm), 3.26-3.37 (1
H, brm), 3.50-3.60 (1H, m), 3.
78 (3H, s), 4.06-4.17 (2H, br
m), 4.80-4.88 (1H, m), 6.98-
7.03 (3H, m), 7.26 (1H, brm),
7.34 (1H, d, J = 8.3 Hz), 7.43-
7.50 (3H, m), 8.25-8.30 (2H,
m), 9.18 (2H, brm), 10.3 (1H, b
rs), 10.9 (1H, br).

[0730] Example ^{103 1 H-NMR (DMSO- d} 6) δ: 1.02-1.1
8 (1H, m), 2.25-2.40 (3H, m),
2.44-2.63 (2H, m), 3.06-3.09
(2H, m), 3.25-3.35 (3H, m), 3.
50-3.59 (1H, m), 4.82-4.88 (1
H, m), 7.04 (1H, dd, J = 6.0 Hz,
1.1Hz), 7.30-7.35 (2H, m), 7.
45-7.55 (3H, m), 7.92 (1H, t),
8.28 (2H, d, J = 7.0 Hz), 8.67 (1
H, m), 9.39 (2H, brm), 10.4 (1
H, brm), 10.9 (1H, br). mass: 443 (M + 1) ⁺ .

Example 104 ¹ H-NMR (DMSO-d ₆ ) δ: 1.01-1.1
5 (1H, m), 2.30-2.40 (3H, m),
2.41-2.56 (1H, m), 2.57-2.64
(1H, m), 3.04-3.11 (2H, m), 3.
20-3.36 (3H, m), 3.50-3.59 (1
H, m), 4.82-4.87 (1H, m), 7.07
(1H, d, J = 6.6 Hz), 7.31-7.35
(2H, m), 7.48 (1H, t, J = 7.8H
z), 7.83-7.90 (1H, m), 8.25-
8.29 (2H, m), 8.46 (1H, d), 8.8
7. (1H, dd, J = 5.3 Hz, 1.3 Hz);
98 (1H, s), 9.79 (2H, brm), 10.
3 (1H, br), 10.9 (1H, br). mass: 443 (M + 1) ⁺ .

Example 105 ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.1
7 (1H, m), 2.26-2.40 (2H, m),
2.50-2.65 (1H, m), 3.05-3.15
(2H, m), 3.21-3.37 (3H, m), 3.
50-3.61 (1H, m), 4.40-4.45 (2
H, m), 4.81-4.89 (1H, m), 7.05.
(1H, d, J = 4.6 Hz), 7.25-7.35
(2H, m), 7.46 (1H, t, J = 8.3H
z), 7.99 (2H, d, J = 7.4 Hz), 8.2
8 (2H, d, J = 7.4 Hz), 8.86 (2H,
d, J = 6.5 Hz), 9.90-10.0 (2H,
m), 10.3 (1H, s), 10.9 (1H, b
r). mass: 443 (M + 1) ⁺ .

[0733] Example ^{106 1 H-NMR (DMSO- d} 6) δ: 1.03-1.1
7 (1H, m), 2.25-2.37 (2H, m),
2.40-2.60 (1H, m), 2.91-3.01
(4H, m), 3.14-3.35 (5H, m), 3.
49-3.59 (1H, m), 4.80-4.85 (1
H, m), 7.02 (1H, d, J = 5.3 Hz),
7.26-7.37 (7H, m), 7.46 (1H,
t), 8.26-8.29 (2H, m), 8.94 (2
H, brm), 10.2 (1H, s), 11.0 (1
H, br). mass: 456 (M + 1) ⁺ .

Example 107 ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.1
7 (1H, m), 2.26-2.50 (3H, br
m), 2.54-2.63 (1H, brm), 2.83
(2H, t), 3.00 (2H, t), 3.06-3.
23 (3H, brm), 3.26-3.37 (1H,
m), 3.50-3.58 (1H, m), 4.80-
4.86 (1H, m), 6.72 (2H, d, J = 8.
3 Hz), 7.05 (3H, d, J = 8.3 Hz),
7.28-7.35 (2H, m), 7.46 (1H,
t, J = 7.8 Hz), 8.26-8.32 (2H,
m), 8.94 (2H, brm), 10.3 (1H,
s), 11.0 (1H, br). mass: 472 (M + 1) ⁺ .

Example 108 ¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.1
5 (1H, m), 2.26-2.40 (2H, br
m), 2.43-2.63 (2H, brm), 2.98
-3.06 (2H, m), 3.20-3.43 (6H,
brm), 3.50-3.65 (1H, m), 4.81.
-4.88 (1H, m), 7.03 (1H, d, J =
5.5Hz), 7.30-7.35 (2H, m), 3.
45-3.50 (1H, m), 7.95 (2H, d, J
= 5.5 Hz), 8.28 (2H, d, J = 5.5H)
z), 8.86 (2H, d, J = 5.5 Hz), 8.7
2 (2H, brm), 10.2 (1H, s), 10.9
(1H, br). mass: 457 (M + 1) ⁺ .

Example 109 As described in Reference Example 8, 80 mg of the desired compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.2
5 (2H, m), 2.26-2.43 (2H, br
m), 2.50-2.65 (1H, m), 2.57 (6
H, s), 2.88-3.06 (3H, m), 3.26.
-3.40 (1H, m), 3.50-3.59 (1H,
m), 4.82-4.86 (1H, m), 7.00 (1
H, d, J = 5.5 Hz), 6.26-6.34 (2
H, m), 7.46 (1H, t, J = 7.8 Hz),
8.23 (1H, d, J = 5.5 Hz), 8.30 (1
H, d, J = 8.3 Hz), 10.0 (1H, s), 1
0.5 (0.5H, br), 11.1 (1H, br). mass: 380 (M + 1) ⁺ .

Example 110 To a solution of 30 mg (0.038 mmol) of the compound of Reference Example 11 in 1 ml of chloroform was added 6 μl of n-butanoyl chloride.
l (0.058 mmol) and 13 μl of triethylamine
(0.093 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. N-Butanoyl chloride 6 μl was added to the reaction solution.
l (0.058 mmol) and 10 μl of triethylamine
(0.072 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 10 minutes. 1 ml of water was added to the reaction solution, and the organic layer was separated. The organic layer was washed with 1 ml of water, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in 1 ml of tetrahydrofuran, 1 ml of 1N hydrochloric acid was added to the reaction solution at room temperature, and the reaction solution was stirred at the same temperature for 15 minutes. The reaction solution was concentrated, 2 ml of trifluoroacetic acid was added to the residue, and the reaction solution was stirred at room temperature for 15 minutes. The reaction solution was concentrated, and methanol-ether was added to the residue to solidify to obtain the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 0.80 (3H,
t, J = 7.8 Hz), 1.03-1.15 (1H,
m), 1.42-1.54 (2H, m), 2.00 (2
H, t, J = 6.9 Hz), 2.25-2.40 (2
H, brm), 2.55-2.63 (1H, brm),
2.70-2.78 (2H, brm), 3.28-3.
39 (3H, brm), 3.50-3.60 (1H, b
rq), 4.80-4.86 (1H, m), 7.01.
(1H, d, J = 4.6 Hz), 7.14 (1H,
s), 7.34 (1H, d, J = 8.3 Hz), 7.4
8 (1H, t, J = 7.8 Hz), 7.88 (2H, b
rm), 8.23 (1H, d, J = 4.6 Hz), 8.
26 (1H, d, J = 8.3 Hz), 10.4 (1H, d, J = 8.3 Hz)
br), 11.1 (1H, br). mass: 422 (M + 1) ⁺ .

[0738] The compound of Example 111- Example 114 Example 111 to Example 114, Example 1
It was manufactured according to No.10. Example 111 ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.2
3 (1H, m), 2.26-2.60 (3H, m),
2.70 (2H, br), 3.15 (2H, br),
3.40-3.60 (2H, m), 4.34 (2H,
s), 4.80-4.90 (1H, m), 6.97 (1
H, d, J = 4.9 Hz), 7.15 (1H, s),
7.30 (1H, d, J = 8.0 Hz), 7.40−
7.52 (6H, m), 8.23 (1H, d, J = 4.
3 Hz), 8.30 (1H, d, J = 8.0 Hz),
8.54-8.63 (1H, m), 9.94 (1H,
s), 11.4 (1H, br). mass: 470 (M + 1) ⁺ .

Example 112 ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.2
0 (1H, m), 2.26-2.40 (2H, m),
2.41-2.60 (1H, m), 2.83 (2H, b
rt), 3.15 (1H, s), 3.20-3.40.
(1H, m), 3.43-3.57 (2H, m), 4.
75-4.86 (1H, m), 6.97 (1H, d, J
= 7.6 Hz), 7.15 (1H, s), 7.30 (1
H, d, J = 11 Hz), 7.40-7.52 (4H,
m), 7.80 (2H, d, J = 10 Hz), 8.21
(1H, d, J = 6.7 Hz), 8.30 (1H, d,
J = 11 Hz), 8.59 (1H, brt), 9.94
(1H, s), 11.4 (1H, br). mass: 456 (M + 1) ⁺ .

Example 113 ¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.2
0 (1H, m), 2.25-2.41 (2H, m),
2.72 (2H, t), 3.10-3.20 (2H,
m), 3.26-3.42 (1H, m), 3.48-
3.60 (1H, m), 3.75-3.90 (1H,
m), 4.36 (2H, s), 4.80-4.86 (1
H, m), 6.99 (1H, d, J = 5.7 Hz),
7.13 (1H, s), 7.19-7.40 (7H,
m), 7.46 (1H, t, J = 7.6 Hz), 8.2
3 (1H, d, J = 3.8 Hz), 8.28 (1H,
d, J = 8.6 Hz), 10.0 (1H, s), 11.
2 (1H, br).

Example 114 ¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.6
0 (1H, m), 2.50-3.00 (3H, br
m), 3.03-3.15 (2H, brm), 3.34.
-3.48 (2H, brm), 3.65-3.80 (1
H, brm), 3.85-4.00 (1H, m), 5.
17-5.26 (1H, m), 7.31 (1H, d, J
= 5.4 Hz), 7.46 (1H, s), 7.72 (1
H, dd, J = 6.8 Hz, 0.6 Hz), 7.87
(1H, t), 7.94-8.03 (3H, m), 8.
10-8.20 (3H, m), 8.58 (1H, d, J
= 4.7 Hz), 8.70 (1H, d, J = 8.1H)
z), 10.4 (1H, s), 11.7 (1H, b
r). mass: 492 (M + 1) ⁺ .

Example 115 Using the compound of Example 83, the desired compound was prepared according to Example 96 (1). ¹ H-NMR (DMSO-d ₆ ) δ: 1.04-1.1
9 (1H, m), 2.26-2.41 (2H, m),
2.48-2.60 (1H, m), 2.66-2.74
(2H, m), 3.10-3.20 (2H, m), 3.
28-3.39 (1H, m), 3.51-3.59 (1
H, m), 4.79-4.82 (1H, m), 6.90
(1H, d, J = 4.6 Hz), 7.01 (1H,
s), 7.32 (1H, d, J = 8.3 Hz), 7.4
6 (1H, t, J = 8.3 Hz), 7.97 (2H,
d, J = 9.2 Hz), 8.17 (2H, m), 8.2
9-8.37 (3H, m), 9.90 (1H, s), 1
1.2 (1H, br). mass: 537 (M + 1) ⁺ .

Example 116 The same procedures as in Example 124 were carried out on the compound prepared according to Example 56 using phenol and the compound of Reference Example 7 to produce the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (1H,
t, J = 7.4 Hz), 2.25-2.40 (2H,
m), 2.60-2.69 (1H, m), 3.10 (2
H, t, J = 5.5 Hz), 3.25-3.35 (1
H, m), 3.54 (1H, q, J = 9.2 Hz),
4.25 (2H, t, J = 5.5 Hz), 4.80 −
4.86 (1H, m), 6.92 (1H, d, J = 12
Hz), 6.94 (2H, d, J = 7.4 Hz), 7.
20 (1H, d, J = 5.5 Hz), 7.25-7.3
7 (4H, m), 7.48 (1H, t, J = 7.4H
z), 8.23-8.28 (2H, m), 10.5-1
1.0 (2H, br). mass: 429 (M + 1) +.

Example 117 (1) 544 mg of 3-amino-5-phenylpyrazole
(3.4 mmol) of dimethylformamide (10 m
l) 164 mg (4.1 mmol) of sodium hydride was added to the solution.
l), 0.45 ml of benzyl bromide (3.8 mmol)
l) was added and the mixture was stirred at room temperature for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over magnesium sulfate, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 4: 1) to obtain 509 mg of the desired product.

(2) 509 mg of the compound obtained in (1)
To a solution of (2.0 mmol) in pyridine (5.0 ml) was added 0.19 ml (2.5 mmol) of methyl chloroformate, and the mixture was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated.
The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 4: 1 to 2: 1) to obtain the target compound 45.
0 mg was obtained.

(3) 440 mg of the compound obtained in (2)
To a solution of (1.4 mmol) in toluene (5.0 ml) was added 0.40 ml (2.9 mmol) of triethylamine, and the mixture was stirred at 80 ° C. for 10 minutes. Stirred for minutes. 290 mg of the compound of Reference Example 3 (1.5 mmol
l) was added and the mixture was stirred at the same temperature for 30 minutes. 440 mg (2.9 mmol) of B-chlorocatecholborane was added, and 1
The mixture was stirred at 00 ° C for 1 hour. 1N Hydrochloric acid was added to the reaction solution, and extracted with chloroform. The organic layer was separated, washed with 1N sodium hydroxide and saturated saline, dried over magnesium sulfate, and concentrated. Chloroform-ether was added to the residue, and 400 mg of the precipitated crystals were collected by filtration.

(4) 400 mg of the compound obtained in (3)
(0.87 mmol) was dissolved in 20 ml of methanol-tetrahydrofuran (1: 1). 200 mg of a 10% palladium carbon catalyst was added, and the inside of the reaction vessel was replaced with hydrogen, and 50 ° C
And stirred overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was crystallized by adding ether-ethyl acetate to obtain 220 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.1
0 (1H, m), 2.27-1.37 (2H, br
m), 2.62-2.67 (1H, brm), 3.26.
-3.37 (1H, m), 3.48-3.57 (1H,
m), 4.75 (1H, dd, J = 11 Hz, 5.7H
z), 6.60 (1H, brs), 7.28 (1H,
d, J = 7.5 Hz), 7.30-7.48 (4H,
m), 7.73 (2H, d, J = 7.3 Hz), 8.2
6 (1H, d, J = 8.2 Hz), 9.61 (1H,
s), 12.8 (1H, br).

Example 118 (1) α-cyano-o-iodoacetophenone 3.81
g (13.3 mmol), benzylhydrazine dihydrochloride 7.80 g (40.0 mmol), triethylamine 1
8.0 ml (129 mmol) and n-butanol 50
The ml mixture was stirred at 120 ° C. overnight. The reaction solution was returned to room temperature and concentrated, and the residue was dissolved in ether, washed with water, dried over magnesium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 5: 1 to 2: 1) to obtain 2.61 g of pale yellow crystals.
I got

(2) 1.23 g of the compound obtained in (1)
A mixture of (3.27 mmol), 0.859 mg (4.26 mmol) of p-nitrophenyl chloroformate, 1.00 g (8.19 mmol) of 4-dimethylaminopyridine and 10 ml of chloroform was stirred at room temperature for 30 minutes. 0.920 g (4.96 mmol) of the compound of Reference Example 3 was added to the reaction solution.
l) was added and the reaction was stirred at 100 ° C. overnight. The reaction solution was diluted with chloroform, and 1N sodium hydroxide, 1N
The extract was washed sequentially with hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated by filtration. The residue was subjected to silica gel column chromatography (chloroform-methanol, 98: 2 to 97:
Purification was performed in 3) to obtain 1.60 g of a yellow solid.

(3) 236 mg of the compound obtained in (2)
(0.461 mmol) and 11 mg of palladium acetate
(0.0490 mmol) 1,1′-bis (diphenylphosphino) ferrocene 30 mg (0.0541 mm
ol) and 71 mg of sodium bicarbonate (0.845 m
mol) was mixed with 4 ml of methanol, the inside of the vessel was replaced with carbon monoxide, and the reaction solution was refluxed for 7 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (chloroform-methanol, 9
8: 2 to 97: 3) to obtain 180 mg of a yellow solid.

(4) 40 mg of the compound obtained in (3) was dissolved in 5 ml of ethanol. 10 mg of palladium hydroxide was added to the reaction solution at room temperature, the atmosphere in the vessel was replaced with hydrogen, and the reaction solution was stirred at 70 ° C. overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol, 10: 1) to obtain 8.6 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.1
5 (1H, m), 2.25-2.40 (2H, m),
2.62-2.77 (1H, m), 3.43-3.58
(2H, m), 3.73 (3H, s), 4.74-4.
78 (1H, m), 6.25 (1H, m), 7.27
(1H, d, J = 7.6 Hz), 7.41-7.74
(5H, m), 8.23-8.26 (1H, m), 8.
31 (1H, s), 9.59 (1H, s). mass: 432 (M + 1) ⁺ .

Example 119 (1) 140 mg of the compound obtained in Example 118 (3)
(0.268 mmol) in 3 ml of methanol,
1.00 ml of 1N sodium hydroxide (1.00 ml) was added to the reaction solution.
mmol) was added at room temperature, and the reaction solution was stirred for a while at room temperature, and then further heated to 50 ° C. and stirred for 2 hours. The reaction solution was acidified with 1N hydrochloric acid and then concentrated. The residue was dissolved in chloroform and washed with water. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, dried over magnesium sulfate, and concentrated by filtration. Ether and chloroform were added to the residue, and 73 mg of precipitated crystals were collected by filtration.

(2) 36 mg of the compound obtained in (1)
(0.0699 mmol) was dissolved in 4 ml of ethanol, 10 mg of palladium hydroxide was added to the reaction solution at room temperature, the atmosphere in the vessel was replaced with hydrogen, and the reaction solution was stirred at 70 ° C. overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. Ether and chloroform were added to the residue to precipitate crystals, thereby obtaining 13 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.01-1.1
4 (1H, m), 2.25-2.34 (2H, m),
2.65-2.68 (1H, m), 3.35-3.53
(2H, m), 4.74 (1H, dd, J = 10 Hz,
5.8 Hz), 6.34 (1H, br), 7.27 (2
H, d, J = 7.5 Hz), 7.43 (2H, t, J =
7.8 Hz), 7.54 (1H, d, J = 3.8H)
z), 7.70 (1H, d, J = 7.4 Hz), 8.2
6 (1H, d, J = 8.1 Hz), 9.59 (1H,
s). mass: 418 (M + 1) ⁺ .

Example 120 (1) A compound prepared according to the same procedure as in Examples 118 (1) to (3) using α-cyano-m-iodoacetophenone according to Example 119 (1) The reaction was performed to obtain the target compound.

(2) Using the compound obtained in (1),
The target compound was produced according to Example 119 (2). ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.1
7 (1H, m), 2.25-2.40 (1H, m),
2.63-2.72 (2H, m), 3.34-3.41
(2H, m), 4.74-4.80 (1H, m), 6.
65 (1H, br), 7.28 (1H, d, J = 7.6)
Hz), 7.44 (1H, t, J = 7.6 Hz), 7.
58 (1H, t, J = 7.7 Hz), 7.91 (1H,
d, J = 8.0 Hz), 7.97 (1H, d, J = 7.
9Hz), 8.25 (1H, d, J = 8.2Hz),
8.30 (1H, d, J = 4.3 Hz), 9.68 (1
H, s). mass: 418 (M + 1) ⁺ .

Example 121 (1) 56 mg of the compound obtained in Example 120 (1)
(0.11 mmol) in 1.5 m of dimethylformamide
l, and 1,1′-carbonyldiimidazole (25 mg, 0.15 mmol) was added to the reaction solution at room temperature.
The reaction was stirred at room temperature for 30 minutes. At room temperature, 42 μl (0.33 mmol) of phenylethylamine was added to the reaction solution, the reaction temperature was heated from room temperature to 70 ° C., and the reaction solution was further stirred for 10 minutes. The reaction solution was concentrated, and the residue was purified by thin-layer chromatography (chloroform-methanol, 10: 1) to obtain a crude product. This was used for the next reaction as it was.

(2) 51 mg of the compound obtained in (1)
(0.084 mmol) was dissolved in 3 ml of methanol-tetrahydrofuran (2: 1), 51 mg of palladium hydroxide was added to the reaction solution at room temperature, and the atmosphere in the vessel was replaced with hydrogen.
The reaction was stirred overnight at room temperature. After the reaction solution was filtered through Celite, the filtrate was concentrated to obtain 25 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.1
0 (1H, m), 2.25-2.36 (2H, m),
2.43-2.56 (1H, m), 2.65 (2H,
t, J = 7.1 Hz), 2.87 (2H, t, J = 7.
5Hz), 3.16-3.25 (2H, m), 4.73
-4.79 (1H, m), 6.70 (1H, br),
7.16-7.33 (7H, m), 7.44 (1H,
t, J = 7.9 Hz), 7.54 (1H, t, J = 7.5 Hz).
7 Hz), 7.79 (1H, d, J = 7.0 Hz),
7.87 (1H, d, J = 6.3 Hz), 8.19 (1
H, s), 8.26 (1H, d, J = 7.7 Hz),
8.72 (1H, br), 9.69 (1H, br). mass: 521 (M + 1) ⁺ .

Example 122 (1) 10.0 g of 2-bromo-3-nitrobenzoic acid (4
0.7 mmol), 7.74 g (81.4 mmol) of pyrrole-2-carboxaldehyde, 20.0 ml (143 mmol) of triethylamine and thionyl chloride 30
According to the same procedure as in Reference Example 2 (1) using 9.0 ml, 9.07 g of the target compound was obtained.

(2) 9.07 g of the compound obtained in (1)
(28.0 mmol) in tetrahydrofuran (400 m
l) The solution was cooled to -78 ° C. At the same temperature, a toluene solution of diisopropyl aluminum hydride (1.0
M) 33.6 ml (33.6 mmol) was added, and the reaction solution was further stirred at the same temperature for 2 hours. After adding 15 ml of a saturated aqueous solution of ammonium chloride to the reaction solution at the same temperature, returning the mixture to room temperature and stirring the reaction solution for 2 hours, the organic layer was dried over magnesium sulfate, and the filtrate was concentrated. The obtained residue was dissolved in 200 ml of methylene chloride, and chlorot was added to the reaction solution at room temperature.
tert-butyldimethylsilane 6.32 g (41.9 m
mol) and 3.80 g (55.8 mm) of imidazole
ol) was added and the reaction was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and the organic layer was sequentially washed with 200 ml of water three times and saturated saline, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate, 10: 1-5: 1) to obtain a colorless oil 9.34.
g was obtained.

(3) 9.34 g of the compound obtained in (2)
(21.3 mmol) and 8.24 g (63.8 mmol) of diisopropylethylamine were dissolved in 200 ml of dimethylformamide, and the atmosphere in the reaction vessel was replaced with nitrogen. At room temperature, 2.46 g (2.13 mmol) of tetrakistriphenylphosphine palladium was added to the reaction solution,
The reaction was stirred at 130 ° C. for 2 hours. The reaction solution was added to 1 L of ethyl acetate and 500 ml of water, and the organic layer was separated. The aqueous layer was further extracted with 300 ml of ethyl acetate, and the organic layers were combined, washed sequentially with water and saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate, 20: 1-5: 1) to give a yellow solid 4.7.
3 g were obtained.

(4) 4.73 g of the compound obtained in (3)
(13.2 mmol) was dissolved in 400 ml of methanol-tetrahydrofuran (1: 1).
500 mg of 0% palladium on carbon catalyst was added. The inside of the reaction vessel was replaced with hydrogen, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue is subjected to silica gel column chromatography (Wakogel C-30).
0, hexane-ethyl acetate, 2: 1 to 1: 1). Pyrole derivative 1.20 as fraction 1 (low polarity substance)
g, pyrrolidine derivative 2.40 as fraction 2 (highly polar substance)
g was obtained. Fraction 1 (low-polar substance) ¹ H-NMR (CDCl ₃ ) δ: 0.14 (6H, s),
0.95 (9H, s), 3.84 (2H, brs),
4.88 (2H, s), 5.98 (1H, d, J = 3.
1 Hz), 6.09-6.11 (1H, m), 6.78
(1H, d, J = 7.1 Hz), 7.02 (1H, t,
J = 7.7 Hz), 7.14 (1H, d, J = 7.3H)
z). Fraction 2 (highly polar substance) ¹ H-NMR (CDCl ₃ ) δ: 0.02 (6H, s),
0.74 (9H, s), 1.60-1.70 (1H,
m), 2.15-2.23 (1H, m), 2.42-
2.50 (2H, m), 3.68 (2H, brs),
3.95-4.02 (2H, m), 4.36 (1H, d
d, J = 10 Hz, 5.2 Hz), 4.63 (1 H, d
d, J = 12 Hz, 5.5 Hz), 6.80 (1H,
d, J = 7.0 Hz), 7.20-7.24 (2H,
m).

(5) 2.71 g of a yellow solid was obtained according to the same procedure as in Example 1 using 2.40 g (7.23 mmol) of fraction 2 (highly polar substance) obtained in (4).

(6) 2.71 g of the compound obtained in (5)
(6.00 mmol) was suspended in 200 ml of methanol-tetrahydrofuran (1: 1).
10 ml of N hydrochloric acid was added, and the reaction solution was further stirred at the same temperature for 6 hours. The reaction solution was concentrated, and the residue was azeotropically dehydrated twice with toluene. The obtained crude product was recrystallized from hexane-ethyl acetate-tetrahydrofuran to obtain the desired compound 1.8.
5 g were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27-1.4
0 (1H, m), 1.72-1.78 (1H, m),
2.20-2.27 (1H, m), 2.40-2.50
(1H, m), 2.53-2.62 (1H, m), 3.
59 (1H, t, J = 7.5 Hz), 3.85-3.9
3 (1H, m), 4.90 (1H, dd, J = 8.0H)
z, 5.5 Hz), 5.97 (1H, br), 7.17
−7.22 (1H, m), 7.33 (1H, d, J =
8.0 Hz), 7.40 (1H, d, J = 9.0H)
z), 7.47 (1H, t, J = 7.5 Hz), 7.9
8 (1H, t, J = 8.0 Hz), 8.18 (1H,
d, J = 7.0 Hz), 8.30 (1H, d, J = 4.
0 Hz), 10.6 (1H, br), 11.0 (1H,
br). mass: 339 (M + 1) ⁺ .

Example 123 (1) 4.50 g of the compound obtained in Example 131 (1)
(13.4 mmol) and 3.94 g of a yellow solid was obtained in the same procedure as in Example 122 (2).

(2) 3.94 g of the compound obtained in (1)
Example 122 (3) using (8.47 mmol)
According to the same procedure as in (4), fraction 1 (low-polar substance) 23
8 mg and fraction 2 (highly polar substance) 1.14 g were obtained. Fraction 1 (low polarity substance): ¹ H-NMR (CDCl ₃ -CD
₃ OD) δ: 0.08 (3H, s), 0.11 (3H,
s), 0.93 (9H, s), 1.51 (3H, d, J
= 6.2 Hz), 3.84 (2H, br), 5.26
(1H, m), 5.96 (1H, d, J = 3.3H
z), 6.10 (1H, dd, J = 3.1 Hz, 1.0
Hz), 6.78 (1H, d, J = 8.0 Hz), 7.
01 (1H, t, J = 7.7 Hz), 7.13 (1H,
d, J = 7.3 Hz). Fraction 2 (highly polar substance): ¹ H-NMR (CDCl ₃ ) δ:
0.07 (3H, s), 0.11 (3H, s), 0.8
5-0.95 (1H, m), 0.92 (9H, s),
1.24-1.35 (2H, m), 1.52 (3H,
d, J = 6.3 Hz), 1.52-1.55 (1H,
m), 5.27 (1H, q), 6.28 (1H, d, J
= 3.4 Hz), 7.07 (1H, d, J = 3.6H)
z), 7.31 (1H, dd, J = 8.5 Hz, 7.3)
Hz), 7.92 (1H, dd, J = 7.3 Hz, 1.
0 Hz), 8.28 (1H, dd, J = 8.5 Hz,
1.0 Hz).

(3) 389 mg of a yellow solid was obtained in the same manner as in Example 1 using 300 mg (0.87 mmol) of the fraction 2 (highly polar substance) obtained in (2).

(4) 200 mg of the compound obtained in (3)
(0.429 mmol) and 92 mg of the target compound were obtained in the same procedure as in Reference Example 7. ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-0.9
5 (1H, m), 1.14 (3H, d, J = 6.3H
z), 1.17-1.28 (1H, m), 2.25-
2.40 (2H, m), 3.70-3.74 (1H,
m), 3.80-3.90 (1H, m), 4.78-
4.85 (2H, m), 7.06 (1H, dd, J =
7.2 Hz, 5.0 Hz), 7.33 (2H, t, J =
7.4 Hz), 7.46 (1H, t, J = 7.9H)
z), 7.76-7.82 (1H, m), 8.26-
8.30 (2H, m), 9.90 (1H, s), 11.
0 (1H, br).

Example 124 Fraction 2 (highly polar substance) 1 obtained in Example 128 (5)
4 mg of methanol-tetrahydrofuran (1: 1) 2
The reaction solution was added with 1.0 ml of 1N hydrochloric acid at room temperature, and stirred at the same temperature for 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by thin-layer chromatography (ethyl acetate-methanol, 3
0: 1) to give 4.1 mg of the desired compound and 3.8 mg of the compound of Example 127. ¹ H-NMR (DMSO-d ₆ ) δ: 0.92-1.0
9 (1H, m), 1.18 (2H, d, J = 6.6H
z), 1.60-1.74 (1H, br), 2.68-
2.76 (1H, m), 2.80-3.00 (1H,
m), 3.28 (1H, dd, J = 11 Hz, 9.0H)
z), 3.63 (1H, dd, J = 11 Hz, 8.5H
z), 4.87 (1H, dd, J = 11 Hz, 5.2H
z), 6.97 (1H, d, J = 4.6 Hz), 6.9
9-7.05 (1H, m), 7.45-7.60 (2
H, m), 7.68-7.76 (1H, m), 8.19.
−8.23 (1H, m), 8.32 (1H, dd, J =
7.7 Hz, 1.3 Hz), 8.94 (1H, br),
12.00 (1H, br). mass: 323 (M + 1) ⁺ .

Example 125 (1) 12.3 g of the compound of Example 128 (1) (38.
2 mmol) was dissolved in 150 ml of tetrahydrofuran, and the reaction solution was cooled to -78 ° C. At the same temperature, a toluene solution of diisobutylaluminum hydride (1.0 mL) was added to the reaction solution.
M) 46.0 ml (46.0 mmol) was added, and the reaction solution was stirred as it was for 15 minutes. 25 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the temperature was returned to room temperature. Magnesium sulfate was added to the reaction solution, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in 150 ml of chloroform, 5.20 g (81.1 mmol) of imidazole and 9.40 ml (43.9 mmol) of chlorotriisopropylsilane were added at room temperature, and the atmosphere in the vessel was replaced with nitrogen.
Stirred for hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated saline, and the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 10: 1) to obtain 17.2 g of a yellow solid.

(2) 17.2 g of the compound obtained in (1)
Using (15.6 mmol), the reaction was carried out according to (2) of Reference Example 2 to obtain 4.90 g of a yellow solid.

(3) 4.90 g of the compound obtained in (2)
(12.2 mmol) was dissolved in 70 ml of tetrahydrofuran, and 20 ml of 6N hydrochloric acid was added to the reaction solution at room temperature.
The reaction solution was stirred at the same temperature for 1 hour. The reaction was basified with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated.
The precipitated crystals were collected by filtration, washed with hexane-ethyl acetate, and dried to obtain 2.94 g of a yellow solid.

(4) 180 mg of the compound obtained in (3)
(0.73 mmol) was dissolved in 5.0 ml of methanol and 16 ml of tetrahydrofuran, 0.20 ml of triethylamine and 100 mg of 10% palladium on carbon catalyst were added, and the mixture was stirred at 50 ° C. for 1 hour under a hydrogen stream. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain 163 mg of a colorless solid.

(5) 163 mg of the compound obtained in (4)
(0.75 mmol) and 107 mg (0.72 mmol) of 2-pyridinecarbonylazide were used to obtain 7 mg of the desired compound according to Example 1. ¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.1
0 (1H, m), 3.02-3.21 (1H, m),
3.30-3.65 (4H, m), 3.87-3.89
(1H, m), 4.95-5.02 (1H, m), 7.
06-8.45 (7H, m), 9.02 (1H, b
r), 11.9 (1H, br). mass: 339 (M + 1) ⁺ .

Example 126 (1) 85 mg (0.251 mm) of the compound of Example 125
ol) and 132 mg of triphenylphosphine (0.5
03 mmol) in tetrahydrofuran (6 ml) was added to 0.140 ml (0.65 ml) of diphenylphosphoric azide.
0 mmol) and 0.220 ml (0.505 mm) of a toluene solution of diethyl azodicarboxylate (40%).
ol) at room temperature and the reaction was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and the organic layer was dried over magnesium sulfate and filtered.
The filtrate was concentrated. The residue was purified by thin-layer chromatography (chloroform-methanol, 10: 1). Ether was added to obtain 24 mg of crystals.

(2) 24 mg of the compound obtained in (1) was dissolved in 2 ml of methanol-tetrahydrofuran (1: 1), and a 10% palladium-carbon catalyst 10% was added to the reaction solution at room temperature.
mg was added. The inside of the vessel was replaced with hydrogen, and the reaction solution was stirred under a hydrogen stream at room temperature until the raw materials disappeared. The reaction solution was filtered through celite, and the filtrate was concentrated. Ether was added to the residue for crystallization. The crystals were collected by filtration, washed with ethyl acetate and chloroform, and dried to obtain 4.6 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 0.97-1.1
0 (1H, m), 2.72-2.82 (1H, m),
2.87-3.00 (2H, m), 3.10-3.20
(1H, m), 3.30-3.60 (2H, m), 4.
96-5.01 (1H, m), 7.03-7.14 (1
H, m), 7.31-7.34 (1H, m), 7.40.
−7.50 (2H, m), 7.77-7.83 (1H,
m), 8.16 (2H, br), 8.26 (1H, d,
J = 8.1 Hz), 8.37 (1H, d, J = 4.0H)
z), 10.1 (1H, s), 11.2 (1H, b
r). mass: 338 (M + 1) ⁺ .

Example 127 The objective compound was obtained by the production reaction of Example 124. ¹ H-NMR (DMSO-d ₆ ) δ: 0.45 (2H,
d, J = 7.0 Hz), 1.55-1.70 (1H, b
r), 2.08-2.19 (1H, m), 2.48-
2.68 (1H, m), 2.88-3.02 (1H,
m), 3.41-3.53 (1H, m), 3.66-
3.80 (1H, m), 4.96 (1H, d, J = 5.
3 Hz), 6.92 (1H, d, J = 8.3 Hz),
6.99-7.05 (1H, m), 7.46-7.60
(2H, m), 7.72-7.77 (1H, m), 8.
20-8.23 (1H, m), 8.32-8.37 (1
H, m), 8.66 (1H, br), 12.00 (1
H, br). mass: 323 (M + 1) ⁺ .

Example 128 (1) The same procedure as in (1) of Reference Example 2 was carried out using pyrrole-3-carboxaldehyde to obtain the desired product.

(2) 139 mg of the compound obtained in (1)
(0.433 mmol) of Example 122 (2)
The target compound was obtained according to the same procedure as described above.

(3) Using the compound obtained in (2) according to the same procedure as in (2) of Reference Example 2, the compound 2 with the regioisomer:
1 was obtained.

(4) Using the compound obtained in (3), a purified mixture was obtained according to the same procedure as (4) in Example 122. This was used for the next reaction as it was.

(5) 22 m of the purified mixture obtained in (4)
g and 26 mg of 2-pyridinecarbonylazide (0.17
(mmol) using the same procedure as in Example 1. The reaction solution was concentrated, and the residue was purified by thin-layer chromatography (hexane-ethyl acetate, 1: 2) to obtain Fraction 1 (low-polar substance) and Fraction 2 (high-polar substance).

(6) 11 mg of the fraction 1 (low-polar substance) obtained in (5) was dissolved in methanol-tetrahydrofuran (1: 1).
5) The mixture was dissolved in 1.2 ml, and 1.0 ml of 1N hydrochloric acid was added to the reaction solution at room temperature, and the reaction solution was stirred at the same temperature. The reaction solution was concentrated, the residue was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by thin-layer chromatography (chloroform-methanol, 10: 1) to obtain 3.1 mg of the desired compound. ¹ H-NMR (acetone-d ₆ ) δ: 1.29 (1
H, br), 2.52-2.61 (2H, m), 3.0.
0-3.10 (2H, m), 3.29-3.41 (1
H, m), 3.54-3.70 (2H, m), 5.08
(1H, d, J = 5.4 Hz), 7.05-7.12
(1H, m), 7.23 (1H, d, J = 8.4H
z), 7.32-7.36 (1H, m), 7.45 (1
H, t, J = 7.7 Hz), 7.78-7.87 (1
H, m), 8.36-8.42 (2H, m), 8.96
(1H, br), 11.9 (1H, br).

Example 129 (1) 100 mg of the compound obtained in Reference Example 2 (2)
(0.467 mmol) in a methanol (15 ml) solution at room temperature, iron powder 200 mg (3.58 mmol), 6N
0.500 ml (3.00 mmol) of hydrochloric acid was added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was treated with ethyl acetate 200
The organic layer was diluted with 100 ml of a saturated aqueous solution of sodium bicarbonate, water and saturated saline in this order, dried over magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate,
5: 1) to give 71 mg of a pale green solid.

(2) 65 mg of the desired compound was prepared according to the same procedure as in Example 1 using 50 mg of the compound obtained in (1).
I got ¹ H-NMR (DMSO-d ₆ ) δ: 6.34 (1H,
t, J = 3.1 Hz), 6.65 (1H, d, J = 3.
1 Hz), 7.08 (1H, dd, J = 6.7 Hz,
5.6 Hz), 7.24-7.29 (3H, m), 7.
38 (1H, d, J = 7.3 Hz), 7.77-7.8
3 (1H, m), 8.27 (1H, d, J = 8.2H
z), 8.31 (1H, dd, J = 5.1 Hz, 1.1)
Hz), 10.1 (1H, brs), 11.0 (1H,
br).

Example 130 Fraction 1 (low-polar substance) obtained in Example 122 (4),
Example 122 using 300 mg (0.91 mmol)
(5) Following the same procedure as in (6), 216 mg of the desired compound
I got ¹ H-NMR (DMSO-d ₆ ) δ: 4.60 (2H,
s), 5.65 (1H, br), 6.20 (1H,
s), 6.68 (1H, s), 7.14-7.20 (1
H, m), 7.25 (1H, t, J = 7.4 Hz),
7.35-7.43 (2H, m), 7.94 (1H,
t, J = 6.9 Hz), 8.20 (1H, d, J = 7.
4 Hz), 8.34 (1 H, d, J = 5.5 Hz), 1
0.8 (2H, br).

Example 131 (1) 10.0 g of 2-bromo-3-nitrobenzoic acid (4
0.7 mmol), 8.90 g of 2-acetylpyrrole
(81.6 mmol) and 9.20 g of a yellow solid were obtained in the same procedure as in Reference Example 2 (1).

(2) 2.00 g of the compound obtained in (1)
(5.93 mmol) and according to the same procedure as in Reference Example 2 (2), 941 mg of a pale green solid was obtained.

(3) 300 mg of the compound obtained in (2)
(1.17 mmol) and 277 mg of the desired compound were obtained in the same procedure as in Example 129. ¹ H-NMR (DMSO-d ₆ ) δ: 6.32-6.3
5 (1H, m), 6.74 (1H, s), 7.07 (1
H, dd, J = 7.2 Hz, 5.2 Hz), 7.19
(1H, s), 7.26 (1H, s), 7.40 (1
H, t, J = 8.0 Hz), 7.47 (1H, d, J =
8.6 Hz), 7.66 (1H, dd, J = 7.9H)
z, 1.5 Hz), 7.78-7.83 (1H, m),
8.25 (1H, dd, J = 5.2 Hz, 1.6H
z), 8.47 (1H, dd, J = 8.0 Hz, 1.6)
Hz), 10.1 (1H, s), 10.8 (1H, br)
s), 12.0 (1H, s). mass: 347 (M + 1) ⁺ .

Example 132 (1) 4.5 g of the compound obtained in Example 131 (1)
(13.4 mmol) and 3.94 g of the desired product was obtained according to the procedure of Example 122 (2).

(2) 3.94 g of the compound obtained in (1)
Example 122 (3) using (8.47 mmol)
Fraction 1 (low-polar substance) 238 according to the same procedure as (4)
mg and fraction 2 (highly polar substance) 1.14 g.

(3) Example 1 using 200 mg (0.58 mmol) of fraction 1 (low-polar substance) obtained in (2)
According to the same procedure as in the above, 247 mg of crystals were obtained.

(4) 247 mg of the compound obtained in (3)
(0.53 mmol) and the procedure of Reference Example 7 was followed to obtain 85 mg of the desired compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.58 (3H,
d, J = 7 Hz), 5.02 (1H, q, J = 7H)
z), 6.07 (1H, d, J = 3 Hz), 6.55
(1H, d, J = 3Hz), 6.96 (1H, brd,
J = 8 Hz), 7.06 (1 H, t, J = 5 Hz),
7.22 (1H, t, J = 7 Hz), 7.43 (1H,
d, J = 7 Hz), 7.69-7.75 (1H, m),
8.23-8.27 (2H, m).

Example 133 (1) The compound of Example 299 (1) was added to a solution of 16 mg of ethanol (0.2 ml) in 1-butanethiol.
2 μl and 2.6 mg of sodium ethoxide were added, and the mixture was stirred at room temperature for 15 hours. Concentrate the reaction mixture and remove the residue by TLC
(Merck Art 5744, hexane-ethyl acetate (1: 5)) to give 8 mg of the desired product.

(2) To a solution of 8 mg of the compound (1) in tetrahydrofuran (2 ml) was added 1 ml of 1N hydrochloric acid, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated, and the residue was washed with ether-
Crystallize from methanol to give the title compound, a white solid 4
mg was obtained. ^{1 H-NMR (DMSO-d} 6) 0.87 (3H, t, J = 7.2Hz), 1.07-
1.24 (1H, m), 1.28-1.40 (2H,
m), 1.49 (2H, tt, J = 7.3, 7.7H
z), 2.25-2.58 (5H, m), 2.71-
2.88 (4H, m), 3.27-3.34 (1H,
m), 3.38-3.82 (1H, m), 4.82 (1
H, dd, J = 5.4, 11 Hz), 7.03 (1H,
d, J = 5.4 Hz), 7.17 (1H, s), 7.3
2 (1H, d, J = 7.5 Hz), 7.47 (1H,
t, J = 7.8 Hz), 8.22 (1H, d, J = 5.
4 Hz), 8.28 (1H, d, J = 8.4 Hz), 1
0.1 (1H, br), 11.1 (1H, br). mass: 425 (M + 1) ⁺ .

Example 134 (1) The compound of Reference Example 8 was reacted according to Example 289 (6) to give the desired compound.

(2) 19 mg of the compound of (1), 15 μl of isopropanol and 50 m of triphenylphosphine
g solution of tetrahydrofuran (0.2 ml) was cooled to 0 ° C., and 82 μl of azodicarboxylic acid diethyl ester was added, followed by stirring at room temperature for 30 minutes. The reaction solution was diluted with chloroform, washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merc
k Art 5744, chloroform-methanol (2
0: 1)) to give 18 mg of the desired product.

(3) A reaction was carried out according to Reference Example 11 using 18 mg of the compound (2).
The reaction was carried out according to (2) to give 5 mg of a white solid as a hydrochloride of the title compound. ^{1 H-NMR (DMSO-d} 6) 1.06-1.20 (1H, m), 1.24 (6H, s
x2), 2.25-2.44 (3H, m), 2.93-
2.99 (2H, m), 3.11-3.16 (2H,
m), 3.21-3.36 (2H, m), 3.49-
3.59 (1H, m), 4.80-4.86 (1H,
m), 7.04-7.06 (1H, m), 7.26-
7.33 (2H, m), 7.46 (1H, t, J = 7.
8 Hz), 8.26-8.29 (2H, m), 8.78
(2H, br), 10.2 (1H, s), 10.9 (1
H, br). mass: 394 (M + 1) ⁺ .

Examples 135-136 The compounds of Examples 135 and 136 were prepared according to Example 13.
It was manufactured according to 4. Example 135 mass: 420 (M + 1) ⁺ .

Example 136 mass: 434 (M + 1) ⁺ .

Example 137 (1) t of the compound of Reference Example 8 and salicylaldehyde
The target compound was obtained according to Example 84 (2) using tert-butyldiphenylsilyl ether.

(2) Example 1 using the compound of (1)
3 mg of the title compound as a white solid according to 33 (2)
I got mass: 696 (M + 1) ⁺ .

Example 138 (1) Using the compound of Example 137 (1), a reaction was carried out according to Reference Example 7 to obtain the desired product.

(2) Example 1 using the compound of (1)
The reaction was carried out according to 33 (2) to give 4 mg of a white solid as a hydrochloride of the title compound. ^{1 H-NMR (DMSO-d} 6) 1.06-1.24 (1H, m), 2.25-2.48
(2H, m), 2.49-2.63 (1H, m), 2.
98-3.03 (2H, m), 3.13-3.37 (2
H, m), 3.27-3.35 (1H, m), 3.45
-3.79 (1H, m), 4.11-4.14 (2H,
m), 4.80-4.85 (1H, m), 6.83-
7.01 (3H, m), 7.22-7.38 (3H,
m), 7.44-7.49 (1H, m), 8.25-
8.29 (2H, m), 8.90 (2H, br), 1
0.1 (1H, br), 10.2 (1H, br), 1
1.0 (1H, br). mass: 458 (M + 1) ⁺ .

Example 139 (1) 29 mg of the compound of Example 137 (1)
tert-butyl dicarbonate ((Boc) ₂ O) 16
mg, triethylamine 15 μl and chloroform 0.
2 ml of the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by TLC (Merck Art 5744, chloroform-methanol (20: 1)) to obtain the target compound 3.
2 mg were obtained.

(2) 24 mg of the desired product was obtained according to Reference Example 7 using 35 mg of the compound of (1).

(3) Using 24 mg of the compound of (2) and 5 μl of 1-butanol, 3 mg of the desired product was obtained according to (2) of Example 134.

(4) Using 8 mg of the compound of (3), the reaction was carried out according to (2) of Example 133 to obtain 3 mg of a white solid as a hydrochloride of the title compound. ¹ H-NMR (DMSO-d ₆ ) 0.91 (3H, t, J = 7.5 Hz), 1.06-
1.24 (1H, m), 1.43 (2H, tt, J =
6.6, 7.5 Hz), 1.73 (2H, tt, J =
6.6, 6.6 Hz), 2.25-2.59 (3H,
m), 2.98-3.05 (2H, m), 3.14-
3.24 (2H, m), 3.27-3.35 (1H,
m), 3.43-3.65 (1H, m), 4.03 (2
H, t, J = 6.6 Hz), 4.15 (2H, brt,
J = 5.4 Hz), 4.79-4.86 (1H, m),
6.97-7.10 (3H, m), 7.27-7.49
(5H, m), 8.25-8.29 (2H, m), 9.
01 (1H, br), 10.1 (1H, br), 10.
9 (1H, br). mass: 514 (M + 1) ⁺ .

Example 140 (1) Using 30 mg of the compound of Reference Example 8 and 9 μl of o-anisaldehyde, according to (2) of Example 84, 16 mg of the monoalkyl compound (A) and 11 mg of the dialkyl compound (B) 11
mg was obtained.

(2) The reaction was carried out according to (2) of Example 133 using 16 mg of the compound (1) -A to obtain 12 mg of a pale yellow solid as a hydrochloride of the title compound. ^{1 H-NMR (DMSO-d} 6) 1.05-1.12 (1H, m), 2.26-2.61
(3H, m), 2.99-3.05 (2H, m), 3.
14-3.21 (2H, m), 3.22-3.35 (1
H, m), 3.49-3.84 (1H, m), 3.85
(3H, s), 4.13-4.17 (2H, m), 4.
81-4.86 (1H, m), 6.98-7.03 (2
H, m), 7.10 (1H, d, J = 4.8 Hz),
7.27-7.34 (2H, m), 7.40-7.49
(3H, m), 8.26-8.29 (2H, m), 9.
01 (2H, br), 10.3 (1H, br), 10.
9 (1H, br). mass: 472 (M + 1) ⁺ .

Example 141 A reaction was carried out according to Example 133 (2) using 7 mg of the compound (1) -B of Example 140 to obtain 4 mg of a pale yellow solid as a hydrochloride of the title compound. ^{1 H-NMR (DMSO-d} 6) 1.03-1.10 (1H, m), 2.26-2.81
(3H, m), 3.16-3.40 (4H, m), 3.
70 (3H, s), 3.75 (3H, s), 3.43-
3.99 (2H, m), 4.29-4.46 (4H,
m), 4.81-4.86 (1H, m), 6.90-
7.13 (5H, m), 7.27-7.35 (2H,
m), 7.42-7.51 (5H, m), 8.22-
8.28 (2H, m), 8.93 (1H, br), 1
0.3 (1H, br), 10.8 (1H, br). mass: 592 (M + 1) ⁺ .

Example 142 (1) 30 mg of the compound of (3) of Example 164 was dissolved in 0.4 ml of acetonitrile-methylene chloride (3: 1), the atmosphere in the reaction vessel was replaced with nitrogen, and (Boc) ₂ O0 .
12 ml, 25 μl of nitroethane and 4 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merck Art 57).
44, chloroform-methanol (30: 1)) to obtain 32 mg of an adduct. HPLC about this
The diastereomer is separated by Rt = 9.64 minutes (CH
IRALPAK AD (Daicel Chemical Industries, Ltd.
46φx25cm), hexane-ethanol (20: 8
0), a fraction (A) of 1.0 ml / min) (12 mg) and a fraction (R) of 14.58 min (B) of 13 mg were obtained.

(2) Compounds (1) -A and (1) -B were obtained according to (2) of Example 133, respectively.
A pale yellow powder was obtained as a compound of Example 142 from (1) -A, and a pale yellow powder as a compound of Example 143 from (1) -B. mass: 392 (M + 1) ⁺ .

[0813] As diastereomer of a compound of Example 143 Example 142, to give the compound of Example 143. mass: 392 (M + 1) ⁺ .

[0814] Example 144-147 Example 144 to Example 147 were prepared analogously to Example 142. Example _{^{144 1 H-NMR (CDCl 3}} ) 1.18 (3H, t, J = 7.5Hz), 1.16-
1.44 (1H, m), 2.40 (2H, q, J = 7.
5Hz), 2.36-2.44 (2H, m), 2.57
-2.65 (1H, m), 2.87 (1H, dd, J =
7.2, 17 Hz), 3.42-3.53 (2H,
m), 3.73-3.82 (1H, m), 4.80 (1
H, dd, J = 5.7, 11 Hz), 5.54 (1H,
dd, J = 7.2, 11 Hz), 6.97 (1H, d,
J = 9.0 Hz), 6.98 (1H, br), 7.56
−7.57 (2H, m), 8.20 (1H, d, J =
5.1Hz), 8.37 (1H, d, J = 7.2H)
z), 9.05 (1H, br), 11.9 (1H, b
r). mass: 406 (M + 1) ⁺ .

Example 145 mass: 406 (M + 1) ⁺ .

Example 146 mass: 406 (M + 1) ⁺ .

Example 147 mass: 406 (M + 1) ⁺ .

[0818] Example 148-151 Example 148 to Example 151 was a mixture of diastereomers, was prepared analogously to Example 142. Example 148 mass: 420 (M + 1) ⁺ .

Example 149 mass: 420 (M + 1) ⁺ .

Example 150 Mass: 448 (M + 1) ⁺ .

Example 151 mass: 448 (M + 1) ⁺ .

[0822] Example 152-155 Example 152 to 155 is a single diastereomer, was prepared analogously to Example 156. Example 152 mass: 434 (M + 1) ⁺ .

Example 153 mass: 434 (M + 1) ⁺ .

Example 154 mass: 434 (M + 1) ⁺ .

Example 155 mass: 434 (M + 1) ⁺ .

Example 156 (1) 30 mg of the compound of (3) of Example 164
Pyroline N-oxide 59mg and chloroform 2ml
Was stirred at 80 ° C. for 23 hours. The reaction solution was returned to room temperature and extracted with chloroform. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merck Art 5744, chloroform-methanol (20: 1)) to obtain 24 mg of a pale yellow oil.

(2) The title compound (5 mg) was obtained according to Example 133 (2) using (1) compound (6 mg). ¹ H-NMR (CDCl ₃ ) 1.22-1.35 (1H, m), 1.58-1.86
(3H, m), 1.99-2.17 (2H, m), 2.
35-2.62 (4H, m), 3.13-3.22 (1
H, m), 3.33-3.49 (2H, m), 3.72
-3.84 (2H, m), 4.79 (1H, dd, J =
5.7, 11 Hz), 5.08 (1H, t, J = 7.2)
Hz), 6.95-7.01 (2H, m), 7.47
(1H, t, J = 7.5 Hz), 7.54 (1H, d,
J = 6.3 Hz), 8.09 (1H, s), 8.16
(1H, d, J = 5.1 Hz), 8.32 (1H, d,
J = 6.6 Hz), 11.9 (1H, s). mass: 420 (M + 1) ⁺ .

Example 157 The compound of Example 164 (3) was prepared according to Example 156, using the optical isomer. mass: 420 (M + 1) ⁺ .

Example 158 (1) 30 mg and 2 mg of the compound of Example 164 (3)
-(2-nitroethoxy) tetrahydropyran 53 µl
To obtain 39 mg of the desired product in the same manner as in Example 142.

(2) Using 7 mg of the compound of (1), 4 mg of the title compound, a pale yellow solid, was obtained according to (2) of Example 133. ¹ H-NMR (CDCl ₃ ) 1.22-1.39 (1H, m), 2.35-2.62
(3H, m), 3.04 (1H, dd, J = 6.9, 1
7 Hz), 3.42-3.82 (3H, m), 4.47
(1H, d, J = 14 Hz), 4.54 (1H, d, J)
= 14 Hz), 4.79 (1H, dd, J = 5.7,1
0 Hz), 5.66-5.73 (1H, m), 6.85
-6.88 (1H, m), 6.99 (1H, s), 7.
22-7.26 (1H, m), 7.48 (1H, t, J
= 7.8 Hz), 7.54 (1H, d, J = 7.5H)
z), 8.19 (1H, d, J = 5.4 Hz), 8.2
5-8.30 (1H, m), 9.16 (1H, br),
11.9 (1H, s). mass: 408 (M + 1) ⁺ .

Example 159 The compound of Example 164 (3) was prepared according to Example 158 using the optical isomer of the compound. mass: 408 (M + 1) ⁺ .

[0832] The compound of Example 160 Example 160 is a mixture of diastereomers, was prepared analogously to Example 156. mass: 478 (M + 1) ⁺ .

[0833] The compound of Example 161 Example 161 is a mixture of diastereomers, was prepared analogously to Example 157. mass: 478 (M + 1) ⁺ .

Example 162 Example 16 was repeated using the compound of (2) -B of Example 164.
The reaction was carried out according to (3) to (5) of Example 4 to obtain Example 162.
7 mg of a pale yellow amorphous substance as the compound of Example 16
9 mg of a pale yellow amorphous substance was obtained as compound 3. mass: 468 (M + 1) ⁺ .

[0835] As diastereomer of a compound of Example 163 Example 162, to give the compound of Example 163. mass: 468 (M + 1) ⁺ .

Example 164 (1) 3.08 g of the compound of Reference Example 6 was subjected to optical resolution by HPLC, and Rt = 14.54 minutes (CHIRALCEL)
OD (Daicel Chemical Industries, Ltd., 0.46φx25c)
m), hexane-isopropanol (60:40),
0.47 ml / min) of fraction (A) 1.37 g and Rt
= 1.25 g of fraction (B) = 25.58 min.

(2) 15.6 g of (1) -A and (1)
15.9 g of -B was reacted according to Reference Example 7 to obtain 11.0 g of a colorless amorphous substance as (2) -A.
And 10.9 g of a colorless amorphous substance as (2) -B.

(3) A colorless amorphous substance 6 using 727 mg of the compound (2) -A according to (1) of Example 299.
06 mg was obtained.

(4) Using 606 mg of the compound of (3), 712 mg of the desired product was obtained according to (1) of Example 300. The diastereomer was separated from this using HPLC, and Rt = 22.58 minutes (CHIRALPA
K AD (Daicel Chemical Industries, Ltd., 0.46φx25)
cm), ethanol, 0.5 ml / min) (A) 360 mg and Rt = 38.84 min (B)
329 mg were obtained.

(5) The reaction of (4) -A and (4) -B was carried out according to (2) of Example 133, and (4) -A
A to pale yellow amorphous substance 2 as compound of Example 164
91 mg of 235 mg of a pale yellow amorphous substance was obtained as the compound of Example 165 from (4) -B. mass: 468 (M + 1) ⁺ .

[0841] As diastereomer of a compound of Example 165 Example 164, to give the compound of Example 165. _{^{1 H-NMR (CDCl 3)}} 1.24-1.31 (1H, m), 1.82-1.99
(1H, m), 2.30-2.45 (3H, m), 2.
58-2.74 (3H, m), 2.82 (1H, dt,
J = 5.4, 9 Hz), 2.90 (1H, t, J = 8.
7Hz), 3.29-3.34 (1H, m), 3.41
-3.50 (1H, m), 3.62-3.81 (3H,
m), 6.79 (1H, dd, J = 6,11 Hz),
6.80 (1H, s), 6.95 (1H, d, J = 5.
1Hz), 7.23-7.36 (5H, m), 7.45
(1H, t, J = 7.2 Hz), 7.53 (1H, d,
J = 7.5 Hz), 8.09 (1H, d, J = 5.4H)
z), 8.25 (1H, s), 8.33 (1H, d, J
= 9 Hz), 12.0 (1H, s). mass: 468 (M + 1) ⁺ .

[0842] Example 166-169 Example 166 to 169, was prepared according to Example 183. Example 166 mass: 392 (M + 1) ⁺ .

Example 167 mass: 392 (M + 1) ⁺ .

Example 168 mass: 392 (M + 1) ⁺ .

Example 169 mass: 392 (M + 1) ⁺ .

Example 170 Using the compound of Example 162, it was prepared according to Example 171. mass: 478 (M + 1) ⁺ .

Example 171 (291 mg) of the compound of Example 164 (Boc) ₂ O
2.86 ml, 20% palladium hydroxide-carbon catalyst 15
A mixture of 0 mg, 30 ml of ethyl acetate and 5 ml of methanol was stirred at 60 ° C. for 15.5 hours under a hydrogen stream. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wako-Gel C-30).
0, hexane-ethyl acetate (1: 1-1: 5)) to give 183 mg of a colorless amorphous substance as the title compound. ¹ H-NMR (CDCl ₃ ) 1.22-1.44 (1H, m), 1.49 (9H,
s), 1.96-2.04 (1H, m), 2.27-
2.47 (3H, m), 2.58-2.64 (1H,
m), 3.30-3.34 (2H, m), 3.41-
3.49 (2H, m), 3.57-3.89 (3H,
m), 4.79 (1H, dd, J = 5.7, 11H
z), 6.81 (1H, s), 6.88 (1H, d, J
= 5.4 Hz), 7.46-7.57 (2H, m),
8.15 (1H, d, J = 5.1 Hz), 8.34 (1
H, d, J = 6.9 Hz), 8.76 (0, 5H, b)
r), 8.88 (0.5H, br), 12.0 (1H,
br). mass: 478 (M + 1) ⁺ .

Example 172 The compound of Example 165 was used and produced according to Example 171. mass: 478 (M + 1) ⁺ .

Working Example No.173 According to the procedure described in the working example No.171, the compound of the working example No.163 was used. mass: 478 (M + 1) ⁺ .

Example 174 A mixture of 25 mg of the compound of Example 170 and 6 ml of 4N hydrochloric acid-dioxane was stirred at room temperature for 15 minutes. The reaction solution was concentrated and dried to obtain 17 mg of a white solid as the title compound. ¹ H-NMR (DMSO-d ₆ ) 1.07-1.14 (1H, m), 1.89-1.97
(1H, m), 2.25-2.41 (3H, m), 2.
42-2.58 (1H, m), 3.04-3.79 (7
H, m), 4.80-4.86 (1H, m), 7.09
−7.11 (1H, m), 7.31−7.34 (2H,
m), 7.47 (1H, t, J = 7.8 Hz), 8.2
6-8.29 (2H, m), 9.16 (2H, br),
10.1 (1H, s), 10.9 (1H, br). mass: 378 (M + 1) ⁺ .

Example 175 The compound of Example 173 was used and produced according to Example 174. mass: 378 (M + 1) ⁺ .

Working Example No.176 According to the procedure described in the working example No.174, the compound of the working example No.171 was used. mass: 378 (M + 1) ⁺ .

Example 177 Using the compound of Example 172, this was prepared according to Example 174. mass: 378 (M + 1) ⁺ .

Example 178 Using 5 mg of racemic hydrochloride of the compound of Example 174 and 8 mg of tert-butyl N- (2-oxoethyl) carbamate, 5 mg of the title compound was obtained according to (2) of Example 84. Was. ¹ H-NMR (CDCl ₃ ) 1.22-1.42 (1H, m), 1.45 (9H,
s), 1.82-1.89 (1H, m), 2.29-
2.49 (3H, m), 2.51-2.80 (4H,
m), 2.81-2.98 (2H, m), 3.22-
3.34 (3H, m), 3.41-3.49 (1H,
m), 3.71-3.81 (1H, m), 4.79 (1
H, dd, J = 5.4, 11 Hz), 5.04 (1H,
br), 6.82 (1H, s), 6.93 (1H, d,
J = 5.7 Hz), 7.46 (1H, t, J = 7.8H)
z), 7.54 (1H, d, J = 7.2 Hz), 8.1
0 (1H, d, J = 5.4 Hz), 8.30 (1H,
d, J = 7.8 Hz), 8.48 (1H, br), 1
2.0 (1H, br). mass: 521 (M + 1) ⁺ .

[0855] The compound of Example 179-182 Example 179 to Example 182, Example 1
83. Example 179 mass: 460 (M + 1) ⁺ .

Example 180 Mass: 460 (M + 1) ⁺ .

Example 181 mass: 460 (M + 1) ⁺ .

Example 182 mass: 460 (M + 1) ⁺ .

Example 183 7 mg of the compound of Example 177 and 7 μ of butyraldehyde
Using 1 to give 7 mg of the title compound as a pale yellow oil according to Example 178. ¹ H-NMR (CDCl ₃ ) 0.93 (3H, t, J = 7.2 Hz), 1.25-
1.43 (3H, m), 1.52 (2H, quinte
t, J = 7.8 Hz), 1.71-1.91 (1H,
m), 2.32-2.66 (8H, m), 2.75 (1
H, t, J = 7.2 Hz), 2.96 (1H, t, J =
8.7 Hz), 3.30-3.35 (1H, m),
42-3.48 (1H, m), 3.72-3.82 (1
H, m), 4.79 (1H, dd, J = 5.4, 11H)
z), 6.80 (1H, br), 6.96 (1H, d,
J = 5.7 Hz), 7.47 (1H, t, J = 7.5H)
z), 7.54 (1H, d, J = 7.5 Hz), 8.1
0 (1H, d, J = 5.7 Hz), 8.34 (1H,
d, J = 8.1 Hz), 8.38 (1H, br), 1
2.0 (1H, br). mass: 434 (M + 1) ⁺ .

[0860] The compound of Example 184-190 Example 184 to Example 190, Example 1
83. Example 184 mass: 434 (M + 1) ⁺ .

Example 185 mass: 434 (M + 1) ⁺ .

Example 186 mass: 434 (M + 1) ⁺ .

Example 187 mass: 561 (M + 1) ⁺ .

Example 188 mass: 561 (M + 1) ⁺ .

Example 189 mass: 561 (M + 1) ⁺ .

Example 190 mass: 561 (M + 1) ⁺ .

Example 191 The compound of Example 187 was used and produced according to Example 193. mass: 461 (M + 1) ⁺ .

Example 192 The compound of Example 188 was used and prepared according to Example 193. mass: 461 (M + 1) ⁺ .

Example 193 Using 6 mg of the compound of Example 189, 4 m of a yellow solid which was the hydrochloride of the title compound according to Example 133, (2)
g was obtained. ¹ H-NMR (DMSO-d ₆ ) 1.04-1.11 (1H, m), 1.65-2.03
(3H, m), 2.19-2.59 (9H, m), 3.
13-3.34 (3H, m), 3.36-4.03 (6
H, m), 4.84 (1H, dd, J = 5.4, 10H
z), 7.33 (1H, d, J = 7.2 Hz), 7.4
7 (1H, t, J = 7.8 Hz), 7.16-7.55
(2H, m), 8.26 (1H, d, J = 7.8H
z), 8.31 (1H, d, J = 5.4 Hz), 9.5
2 (1H, br), 10.3 (1H, brd, J = 10
Hz), 10.8 (1H, br), 11.7 (1H, b
r). mass: 461 (M + 1) ⁺ .

Example 194 The compound of Example 190 was prepared according to Example 193. mass: 461 (M + 1) ⁺ .

[0871] The compound of Example 195-210 Example 195 to Example 210, Example 1
83. Example 195 mass: 488 (M + 1) ⁺ .

Example 196 mass: 488 (M + 1) ⁺ .

Example 197 mass: 488 (M + 1) ⁺ .

Example 198 mass: 488 (M + 1) ⁺ .

Example 199 mass: 504 (M + 1) ⁺ .

Example 200 mass: 504 (M + 1) ⁺ .

Example 201 mass: 504 (M + 1) ⁺ .

Example 202 mass: 504 (M + 1) ⁺ .

Example 203 mass: 494 (M + 1) ⁺ .

Example 204 mass: 494 (M + 1) ⁺ .

Example 205 mass: 494 (M + 1) ⁺ .

Example 206 mass: 494 (M + 1) ⁺ .

Example 207 mass: 551 (M + 1) ⁺ .

Example 208 mass: 551 (M + 1) ⁺ .

Example 209 mass: 551 (M + 1) ⁺ .

Example 210 mass: 551 (M + 1) ⁺ .

[0887] The compound of Example 211-240 Example 211 to Example 240, Example 1
78. Example 211 mass: 434 (M + 1) ⁺ .

Example 212 mass: 448 (M + 1) ⁺ .

Example 213 mass: 482 (M + 1) ⁺ .

Example 214 mass: 462 (M + 1) ⁺ .

Example 215 mass: 420 (M + 1) ⁺ .

Example 216 mass: 518 (M + 1) ⁺ .

Example 217 mass: 518 (M + 1) ⁺ .

Example 218 mass: 448 (M + 1) ⁺ .

Example 219 mass: 446 (M + 1) ⁺ .

Example 220 mass: 474 (M + 1) ⁺ .

Example 221 mass: 420 (M + 1) ⁺ .

Example 222 mass: 462 (M + 1) ⁺ .

Example 223 mass: 507 (M + 1) ⁺ .

Example 224 mass: 512 (M + 1) ⁺ .

Example 225 mass: 512 (M + 1) ⁺ .

Example 226 mass: 484 (M + 1) ⁺ .

Example 227 mass: 458 (M + 1) ⁺ .

Example 228 mass: 504 (M + 1) ⁺ .

Example 229 mass: 450 (M + 1) ⁺ .

Example 230 mass: 432 (M + 1) ⁺ .

Example 231 mass: 519 (M + 1) ⁺ .

Example 232 mass: 457 (M + 1) ⁺ .

Example 233 mass: 471 (M + 1) ⁺ .

Example 234 mass: 469 (M + 1) ⁺ .

Example 235 mass: 469 (M + 1) ⁺ .

Example 236 mass: 469 (M + 1) ⁺ .

Example 237 mass: 452 (M + 1) ⁺ .

Example 238 mass: 472 (M + 1) ⁺ .

Example 239 mass: 458 (M + 1) ⁺ .

Example 240 mass: 522 (M + 1) ⁺ .

Example 241 Using 4 mg of the compound of Example 178, the reaction was carried out according to Example 133 (2) to obtain 4 mg of the hydrochloride of the title compound. ¹ H-NMR (CD ₃ OD) 1.14-1.28 (1H, m), 1.51-1.76
(1H, m), 2.30-2.48 (3H, m), 2.
62-2.75 (2H, m), 3.42-3.76 (1
0H, m), 4.95 (1H, dd, J = 5.7, 11
Hz), 7.55 (1H, br), 7.57-7.59
(3H, m), 8.04-8.07 (1H, m), 8.
30 (1H, d, J = 6.6 Hz). mass: 421 (M + 1) ⁺ .

[0918] The compound of Example 242-247 Example 242 to Example 247, Example 1
78. Example 242 mass: 500 (M + 1) ⁺ .

Example 243 mass: 514 (M + 1) ⁺ .

Example 244 mass: 514 (M + 1) ⁺ .

Example 245 mass: 486 (M + 1) ⁺ .

Example 246 mass: 472 (M + 1) ⁺ .

Example 247 mass: 484 (M + 1) ⁺ .

Example 248 The production was carried out according to Example 249. mass: 496 (M + 1) ⁺ .

Example 249 5 mg of a racemic hydrochloride of the compound of Example 174 was dissolved in acetone-water (2: 1) (0.3 ml), 4 mg of sodium acetate was added thereto, and the mixture was cooled to 0 ° C. , 6-dichlorobenzoyl (2 μl) was added and stirred for 4 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merck Art 574).
4, chloroform-methanol (20: 1)) to give 5 mg of a white solid as the title compound. _{^{1 H-NMR (CDCl 3)}} 1.21-1.36 (1H, m), 2.06-2.18
(1H, m), 2.33-2.64 (4H, m), 3.
24-4.03 (6H, m), 4.21-4.27 (1
H, m), 4.74-4.83 (1H, m), 6.74
(0.5H, s), 6.82 (0.5H, s), 6.8
8 (0.5 H, d, J = 5.7 Hz), 6.94 (0.
5H, d, J = 5.7 Hz), 7.23-7.38 (3
H, m), 7.45-7.77 (2H, m), 8.16
(1H, dd, J = 5.4, 12 Hz), 8.31 (1
H, t, J = 8.4 Hz), 8.53 (1H, s), 1
1.8 (0.5H, s), 11.9 (0.5H, s). mass: 550 (M + 1) ⁺ .

[0926] The compound of Example 250-253 Example 250 to Example 253, Example 2
49. Example 250 mass: 488 (M + 1) ⁺ .

Example 251 mass: 483 (M + 1) ⁺ .

Example 252 mass: 483 (M + 1) ⁺ .

Example 253 mass: 483 (M + 1) ⁺ .

Example 254 (1) 3.8 g of the compound of Example 264 (1) and enol triflate (1-benzyl-4-piperidone,
According to the method of Example 264 (3), 1.9 g of a brown oil was obtained using 2.8 g of lithium diisopropylamide, prepared from N-phenyltrifluoromethanesulfonimide and tetrahydrofuran according to a conventional method.

(2) A white solid 2 was prepared according to the method of Example 80 (2) or (3) using 1.9 g of the compound (1).
30 mg were obtained. ^{1 H-NMR (DMSO-d} 6) 1.28 (1H, m), 2.20-2.80 (7H,
m), 3.22 (1H, d, J = 2.6 Hz), 3.4
5 (1H, m), 3.67 (2H, s), 3.78 (1
H, m), 4.79 (1H, dd, J = 5.6, 11H
z), 6.36 (1H, br), 6.88 (1H,
s), 7.00 (1H, d, J = 5.6 Hz), 7.2
0-7.50 (6H, m), 7.50 (1H, d, J =
7.9 Hz), 8.10 (1H, d, J = 5.6H)
z), 8.35 (1H, d, J = 7.9 Hz), 8.8
6 (1H, s), 12.0 (1H, br). mass: 480 (M + 1) ⁺ .

Example 255 Using 160 mg of the compound of Example 254, the reaction was carried out according to Reference Example 3 to obtain 52 mg of a white solid. ¹ H-NMR (DMSO-d ₆ ) 1.32 (1H, m), 1.70-2.00 (4H,
m), 2.03 (2H, m), 2.25-2.80 (4
H, m) 3.08 (2H, m), 3.49 (1H,
m), 3.60 (2H, s), 3.81 (1H, m),
4.82 (1H, dd, J = 5.6, 11 Hz);
72 (1H, s), 6.92 (1H, d, J = 5.2H
z), 7.20-7.50 (5H, m), 7.49 (1
H, t, J = 7.9 Hz), 7.55 (1H, d, J =
7.9 Hz), 8.07 (1H, s,), 8.15 (1
H, d, J = 5.2 Hz), 8.40 (1H, d, J =
7.9 Hz), 12.0 (1H, br). mass: 482 (M + 1) ⁺ .

Example 256 A reaction was carried out using 1-benzyl-3-piperidone according to Example 254 to obtain 52 mg of a white solid. ¹ H-NMR (DMSO-d ₆ ) 1.30 (1H, m), 2.20-2.80 (7H,
m), 3.35 (1H, d, J = 2.0 Hz), 3.4
8 (1H, m), 3.72 (2H, s), 3.76 (1
H, m), 4.81 (1H, dd, J = 5.7, 11H
z), 6.44 (1H, m), 6.78 (1H, s),
6.95 (1H, d, J = 5.6 Hz), 7.20-
7.40 (5H, m), 7.49 (1H, d, J = 7.
9Hz), 7.53 (1H, d, J = 7.9Hz),
8.11 (1H, d, J = 5.6 Hz), 8.35 (1
H, d, J = 7.9 Hz), 8.52 (1H, s), 1
2.0 (1H, br). mass: 480 (M + 1) ⁺ .

Example 257 The reaction was carried out according to Reference Example 3 using 30 mg of the compound of Example 256 to obtain 12 mg of a white solid. ^{1 H-NMR (DMSO-d} 6) 1.20-1.40 (1H, m), 1.60-2.20
(5H, m), 2.20-2.70 (3H, m), 2.
80-3.00 (3H, m), 3.45 (1H, m),
3.55 (2H, s), 3.75 (1H, m), 4.7
8 (1H, dd, J = 5.6, 11 Hz), 6.71
(1H, s), 6.87 (1H, d, J = 5.2H
z), 7.10-7.40 (5H, m), 7.47 (1
H, t, J = 7.5 Hz), 7.54 (1H, d, J =
7.9 Hz), 8.08 (1H, d, J = 5.2H)
z), 8.12 (1H, s), 8.34 (1H, d, J
= 5.2 Hz), 12.0 (1H, br). mass: 482 (M + 1) ⁺ .

Example 258 Example 260 was repeated using 180 mg of the compound of Example 256.
17 mg of a yellow solid was obtained according to the following procedure. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 2.20-2.70 (5H,
m), 3.01 (2H, m), 3.45 (1H, m),
3.70 (2H, s), 3.75 (1H, m), 4.7
9 (1H, dd, J = 5.6, 11 Hz), 6.48
(1H, m), 6.67 (1H, s), 6.98 (1
H, d, J = 5.2 Hz), 7.46 (1H, t, J =
7.9 Hz), 7.52 (1H, s), 7.58 (1
H, d, J = 7.9 Hz), 8.30 (1H, d, J =
7.9 Hz), 12.0 (1H, br). mass: 390 (M + 1) ⁺ .

Example 259 According to Example 261, 5 mg of a white solid was obtained using 20 mg of the compound of Example 258. ¹ H-NMR (DMSO-d ₆ ) 1.25 (1H, m), 2.20 (3H, s), 2.3
0-2.80 (5H, m), 3.40-3.90 (4
H, m), 4.42 (2H, m), 4.81 (1H, d
d, J = 5.6, 11 Hz), 6.50 (1H, m),
5.82 (1H, s), 7.00 (1H, d, J = 5.
2Hz), 7.48 (1H, t, J = 7.9Hz),
7.55 (1H, d, J = 7.9 Hz), 8.20 (2
H, m), 8.35 (1H, d, J = 7.9 Hz), 1
1.9 (1H, br). mass: 432 (M + 1) ⁺ .

Example 260 (1) A mixture of 280 mg of the compound of Example 254, 100 mg of chloroformic acid 1-chloroethyl ester, 71 mg of triethylamine and 5 ml of chloroform was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (100: 0 to 98: 2)) to obtain 295 mg of a solid.

(2) 295 mg of the compound of (1) was dissolved in methanol (5 ml) and refluxed for 3 hours. The reaction solution was returned to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (FL60D (Fuji Silysia),
Chloroform-methanol (100: 0 to 95: 5)
And 160 mg of a pale yellow solid was obtained. ^{1 H-NMR (DMSO-d} 6) 1.28 (1H, m), 2.40 (3H, m), 2.6
2 (1H, m), 3.12 (2H, m), 3.45 (1
H, m), 3.59 (2H, s), 3.77 (1H,
m), 4.80 (1H, dd, J = 5.6, 11H
z), 6.42 (1H, m), 6.81 (1H, s),
7.02 (1H, d, J = 5.3 Hz), 7.26 (1
H, s), 7.46 (1H, t, J = 7.9 Hz),
7.55 (1H, d, J = 7.9 Hz), 8.13 (1
H, d, J = 5.3 Hz), 8.33 (1H, s,),
8.35 (1H, d, J = 7.9 Hz), 12.0 (1
H, br). mass: 390 (M + 1) ⁺ .

Example 261 30 mg of the compound of Example 260 was used, and acetyl chloride 6.6 was used.
μl, triethylamine 13 μl and chloroform 3 m
The mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merck Art 5744,
Purification with chloroform-methanol (9: 1) yielded 5 mg of white crystals. ¹ H-NMR (DMSO-d ₆ ) 1.25 (1H, m), 2.22 (3H, s), 2.2
0-2.80 (5H, m), 3.40-3.95 (4
H, m), 4.35 (2H, m), 4.82 (1H, d
d, J = 5.6, 11 Hz), 6.40 (1H, m),
6.80 (1H, s), 7.03 (1H, d, J = 5.
6Hz), 7.49 (1H, t, J = 7.9Hz),
7.57 (1H, t, J = 7.9 Hz), 8.20 (2
H, m), 8.33 (1H, d, J = 7.9 Hz), 1
1.9 (1H, br). mass: 432 (M + 1) ⁺ .

Example 262 A white solid (3 mg) was obtained according to Example 84 (2) using 20 mg of the compound of Example 260. ^{1 H-NMR (DMSO-d} 6) 1.05-2.20 (14H, m), 2.20-2.9
0 (6H, m), 3.22-3.50 (3H, m),
3.70-3.82 (1H, m), 4.78 (1H, d
d, J = 5.8, 11 Hz), 6.37 (1H, m),
6.77 (1H, s), 7.01 (1H, d, J = 5.
4 Hz), 7.54 (1H, d, J = 7.8 Hz),
8.12 (1H, d, J = 5.4 Hz), 8.32 (1
H, d, J = 7.8 Hz), 12.0 (1H, s). mass: 472 (M + 1) ⁺ .

[0941] The compound of Example 263 Example 263 was prepared analogously to Example 262. mass: 506 (M + 1) ⁺ .

Example 264 (1) 3 g of 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride was added to 140 ml of dioxane, 8.4 g of hexabutylditin and palladium tetrakistriphenylphosphine were added, and the mixture was added under a stream of nitrogen. And refluxed for 12 hours. The reaction solution was returned to room temperature, a 10% aqueous potassium fluoride solution was added, and the mixture was stirred for 30 minutes, diluted with ether and filtered. The filtrate was washed with saturated saline, dried over magnesium sulfate, and the residue obtained by filtration was purified by silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate (1: 0 to 2: 1)). Colorless oil 0.
9 g were obtained.

(2) Using 6.3 g of the compound of (1), according to the method of Example 80 (2), (3), to obtain an oily substance 2.
8 g were obtained.

(3) A mixture of 60 mg of the compound of (2), 47 mg of 3-bromopyridine, 21 mg of 2-dicyclohexyphosphino) biphenyl, 9 mg of lithium chloride, 21 mg of trisdibenzylidene dipalladium and 2 ml of tetrahydrofuran was refluxed overnight. 10% in the reaction solution
An aqueous potassium fluoride solution and chloroform were added, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered and concentrated. The residue was purified by TLC (Mer
Purification with ck Art 5744, chloroform-methanol (9: 1) yielded 5 mg of white crystals. ¹ H-NMR (DMSO-d ₆ ) 1.10-1.20 (1H, m), 2.33-2.40
(1H, m), 2.40-2.78 <2H, m>, 3.
28-3.33 (1H, m), 3.53 (1H, m),
4.84 (1H, m), 7.31 (1H, d, J = 7.
7Hz), 7.43-7.49 (1H, m), 7.56
(1H, dd, J = 4.5, 7.7 Hz), 7.61
(1H, s), 8.10 (1H, dd, J = 2.3,
7.7 Hz), 8.30 (1H, d, J = 7.7H)
z), 8.41 (1H, d, J = 5.5 Hz), 8.6
8 (1H, d, J = 5.5 Hz), 8.91 (1H,
d, J = 2.3 Hz), 10.0 (1H, s), 11.
0 (1H, br). mass: 386 (M + 1) ⁺ .

[0945] The compound of Example 265-277 Example 265 to Example 277, Example 2
64. Example 265 mass: 385 (M + 1) ⁺ .

Example 266 mass: 423 (M + 1) ⁺ .

Example 267 mass: 386 (M + 1) ⁺ .

Example 268 mass: 386 (M + 1) ⁺ .

Example 269 mass: 392 (M + 1) ⁺ .

Example 270 mass: 391 (M + 1) ⁺ .

Example 271 mass: 465 (M + 1) ⁺ .

Example 272 mass: 435 (M + 1) ⁺ .

Example 273 mass: 435 (M + 1) ⁺ .

Example 274 mass: 391 (M + 1) ⁺ .

Example 275 mass: 389 (M + 1) ⁺ .

Example 276 mass: 407 (M + 1) ⁺ .

Example 277 mass: 445 (M + 1) ⁺ .

Example 278 Using the compound of Example 82, a reaction was carried out according to Example 261 to obtain 9 mg of a white solid. ^{1 H-NMR (DMSO-d} 6) 0.89 (3H, t, J = 7.3Hz), 1.15 (1
H, m), 1.57 (2H, q, J = 7.3 Hz),
2.15 (2H, q, J = 7.3 Hz), 2.20−
2.60 (3H, m), 3.30 (1H, m), 3.5
5 (1H, m), 4.24 (1H, d, J = 6.0H)
z), 4.82 (1H, dd, J = 5.6, 11H
z), 6.92 (1H, d, J = 5.6 Hz), 7.1
3 (1H, s), 7.46 (1H, t, J = 7.9H)
z), 7.48 (1H, d, J = 7.9 Hz), 8.2
3 (1H, d, J = 5.6 Hz), 8.30 (1H,
d, J = 7.9 Hz), 8.42 (1H, t, J = 6.
0 Hz), 9.97 (1H, s), 11.3 (1H, b
r). mass: 408 (M + 1) ⁺ .

Example 279 30 mg of the compound of Example 80 and butanoyl chloride were dissolved in dimethylformamide, and the mixture was stirred at 90 ° C for 30 minutes.
The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merck Art 5744,
Purification with chloroform-tetrahydrofuran (7: 3) yielded 8 mg of white crystals. ¹ H-NMR (DMSO-d ₆ ) 0.97 (3H, t, J = 7.3 Hz), 1.25 (1
H, m), 1.70 (2H, q, J = 7.3 Hz),
2.30-2.60 (1H, m), 2.40 (2H,
q, J = 7.4 Hz), 2.30-2.55 (2H,
m), 2.60 (1H, m), 3.45 (1H, m),
3.79 (1H, m), 4.80 (1H, dd, J =
5.6, 11 Hz), 5.13 (2H, s), 6.84
(1H, s), 6.96 (1H, d, J = 5.5H)
z), 7.49 (1H, t, J = 7.9 Hz), 7.5
5 (1H, d, J = 7.9 Hz), 8.19 (1H,
d, J = 5.5 Hz), 8.31 (1H, d, J = 7.
9Hz), 11.9 (1H, br). mass: 409 (M + 1) ⁺ .

[0960] The compound of Example 280 Example 280, was prepared analogously to Example 279. mass: 449 (M + 1) ⁺ .

[0961] The compound of Example 281 Example 281 was prepared analogously to Example 278. mass: 448 (M + 1) ⁺ .

Example 282 1) A mixture of 1 g of 2-aminopyridine-4-carboxylic acid, 2.8 ml of thionyl chloride and 36 ml of methanol was used.
Refluxed overnight. The reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-200, chloroform-methanol (10
0: 0 to 98: 2)) to obtain 1.05 g of the desired product.

(2) 1.8 g of the compound of Reference Example 3, 0.35 ml of trichloroacetic anhydride, 0.1 g of triethylamine.
2 ml, methylene chloride 5 ml and tetrahydrofuran 1
0 ml of the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-tetrahydrofuran (9: 1 to 8: 2)) to obtain 2.92 g of a brown amorphous substance. 1.77 g of the obtained compound,
A mixture of 1.05 g of the compound of (1), 1 ml of DBU and 8 ml of dimethyl sulfoxide was stirred at 100 ° C. for 3 hours. The reaction solution was diluted with chloroform, washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-200, chloroform-methanol (97:
Purification was performed in 3)) to obtain 1.21 g of the desired product.

(3) 300 mg of the compound of (2), 1N
Sodium hydroxide aqueous solution 10ml and methanol 3ml
Was stirred at 90 ° C. for 1 hour. The reaction solution was adjusted to pH 4 with 1N hydrochloric acid, extracted with chloroform, the organic layer was washed with brine, dried over magnesium sulfate, filtered,
The filtrate was concentrated. The residue was washed with chloroform-ethyl acetate to obtain 80 mg of a white solid.

(4) According to (1) of Example 409, 18 mg of the compound (3) was used to give 5 mg of the title compound as a white solid. ^{1 H-NMR (DMSO-d} 6) 0.92 (3H, t, J = 7.2Hz), 1.13 (1
H, m), 1.32 (1H, m), 1.53 (2H,
m), 2.20-2.70 (3H, m), 3.20-
3.70 (4H, m), 4.85 (1H, dd, J =
5.6, 11 Hz), 7.32 (1H, d, J = 7.9)
Hz), 7.38 (1H, d, J = 5.2 Hz), 7.
49 (1H, t, J = 7.9 Hz), 7.75 (1H,
s), 8.30 (1H, d, = 7.9 Hz), 8.43
(1H, d, J = 5.2 Hz), 8.70 (1H, t,
J = 6.7 Hz), 10.1 (1H, s), 10.8
(1H, br). mass: 408 (M + 1) ⁺ .

[0966] The compound of Example 283-286 Example 283 to Example 286, Example 2
82. Example 283 mass: 434 (M + 1) ⁺ .

Example 284 mass: 443 (M + 1) ⁺ .

Example 285 mass: 443 (M + 1) ⁺ .

Example 286 mass: 443 (M + 1) ⁺ .

Example 287 (1) A yellow solid (14 mg) was obtained according to Reference Example 1 using isoquinoline-3-carboxylic acid (90 mg).

(2) 13 mg of the title compound, a white solid, according to Example 79 using 14 mg of the compound of (1)
I got ¹ H-NMR (DMSO-d ₆ ) 1.10-1.20 (1H, m), 2.25-2.50
(2H, m), 2.58-2.70 (1H, m), 3.
20-3.40 (1H, m), 3.48-3.62 (1
H, m), 4.83 (1H, dd, J = 5.6, 10H)
z), 7.33 (1H, d, J = 7.9 Hz), 7.4
9 (2H, m), 7.70 (1H, t, J = 7.9H)
z), 7.87 (1H, d, J = 7.9 Hz), 8.0
2 (1H, s), 8.07 (1H, d, J = 7.9H)
z), 8.31 (1H, d, J = 7.9 Hz), 9.1
8 (1H, s), 9.70 (1H, br), 9.90
(1H, s). mass: 359 (M + 1) ⁺ .

Example 288 (1) 300 mg of isoquinoline-3-carboxylic acid, 30 mg of platinum oxide, 5 ml of 4N hydrochloric acid-dioxane and 5 ml of methanol were mixed, the atmosphere in the vessel was replaced with hydrogen, and the mixture was treated at room temperature with 6 mg
Stirred for hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain 32 mg of a crude product.

(2) The title compound, a white solid 23, was prepared according to Example 287 using 130 mg of the compound of (1).
mg was obtained. ¹ H-NMR (DMSO-d ₆ ) 1.00-1.20 (1H, m), 1.60-1.80
(4H, m), 2.20-2.70 (7H, m), 3.
20-3.35 (1H, m), 3.45-3.60 (1
H, m), 4.77 (1H, dd, J = 5.5, 10H)
z), 6.95 (1H, s), 7.28 (1H, d, J
= 7.9 Hz), 7.43 (1H, t, J = 7.9H)
z), 8.00 (1H, s), 8.29 (1H, d, J
= 7.9 Hz), 9.71 (1H, s), 11.2 (1
H, br). mass: 363 (M + 1) ⁺ .

Example 289 (1) 15 g of dimethyl acetal of 4-pyridinecarboxaldehyde in tetrahydrofuran (300 ml)
The solution was cooled to −78 ° C., and 73 ml of a hexane solution of n-butyllithium (1.6 M) was added, and the temperature was changed from −78 ° C. to 0 ° C.
The temperature rose. 25 g of tert-butyldimethylsilyl ether of 3-bromobutanol was added, and the mixture was stirred at 0 ° C for 3 hours. The reaction solution was returned to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-
200, hexane-ethyl acetate (2: 1))
17 g of an oil were obtained.

(2) 3.9 g of an oil was obtained according to Reference Example 7 using 7 g of the compound of (1).

(3) 7 g of a brown oil was obtained according to Reference Example 8 using 3 g of the compound of (2).

(4) 7 g of the compound of (3) and 5.8 g of triphenylphosphine were added to water-tetrahydrofuran (1: 9).
In addition to 10), the mixture was stirred at 50 ° C for 2 hours. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (FL)
Purification with 60D (Fuji Silysia KK) and chloroform-methanol (100: 0 to 98: 2)) gave 2.1 g of a brown oil.

(5) Formic acid (5 ml) was added to a chloroform (10 ml) solution of the compound (4) (2.1 g) at 80 ° C.
Stirred for hours. The reaction solution was concentrated, and the residue was treated with methanol (1
0 ml), and 7.4 g of sodium borohydride was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with chloroform, washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (FL60D (Fuji Silysia)), chloroform-methanol (100: 0 to 9).
8: 2)) to obtain 0.57 g.

(6) A mixture of 0.57 g of the compound of (5), 1.7 g of p-nitrobenzenesulfonyl chloride, 0.71 g of dimethylaminopyridine and 5 ml of chloroform was stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (100: 0 to 98: 2)) to obtain 0.73 g of the desired product.

(7) A mixture of 0.73 g of the compound of (6), 50 mg of manganese dioxide, 5 ml of 30% hydrogen peroxide solution and 20 ml of chloroform was stirred at room temperature for 6 hours.
The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (100: 0 to 98: 2)) to give 0.78 g of crystals.
I got

(8) A mixture of 0.78 g of the compound (7), 0.71 ml of triethylamine, 0.66 ml of trimethylsilyl cyanide and acetonitrile-chloroform was stirred at 80 ° C. for 3 hours. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (100: 0 to 98: 2)) to obtain 0.71 g of crystals.

(9) Using the compound of (8), 75 mg of the desired product was obtained according to Reference Examples 4 and 5.

(10) The title compound, a pale yellow solid, was obtained in the same manner as in Reference Example 11 by using 75 mg of the compound of (9).
8 mg, and a yellow solid which is the compound of Example 292.
4 mg were obtained. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 1.60-2.00 (3H,
m), 2.20-2.60 (4H, m), 2.64 (1
H, m), 3.15 (2H, m), 3.45 (1H,
m), 3.78 (1H, m), 4.18 (1H, t, J
= 7.2 Hz), 4.80 (1H, dd, J = 5.6,
11 Hz), 6.98 (1H, s), 6.99 (1H,
d, J = 5.6 Hz), 7.46 (1H, t, J = 7.
9Hz), 4.55 (1H, d, J = 7.9Hz),
8.11 (1H, d, J = 5.6 Hz), 8.39 (1
H, d, J = 7.9 Hz), 8.40 (1H, s), 1
2.0 (1H, br). mass: 378 (M + 1) ⁺ .

Example 290 7 mg of the compound of Example 289 was dissolved in 2 ml of methanol, 50 μl of formalin was added, and the mixture was stirred at room temperature for 4 hours. 3 ml of methanol was added to the reaction solution, 100 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. After adding 1N hydrochloric acid to the reaction solution to decompose the excess reagent, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (FL60D (Fuji Silysia Ltd.), chloroform-methanol (9: 1)) to obtain 3 mg of the title compound as a yellow solid. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 1.55-2.10 (4H,
m), 2.22 (3H, s), 2.20-2.40 (3
H, m), 2.65 (1H, m), 3.14 (1H,
m), 3.25 (1H, m), 3.50 (1H, m),
3.79 (1H, m), 4.82 (1H, dd, J =
5.6, 11 Hz), 6.89 (1H, s), 7.03
(1H, d, J = 5.6 Hz), 7.49 (1H, t,
J = 7.9 Hz), 7.56 (1H, d, J = 7.9H)
z), 8.05 (1H, s), 8.15 (1H, d, J
= 5.6 Hz), 8.35 (1H, d, J = 7.9H)
z), 12.0 (1H, br). mass: 392 (M + 1) ⁺ .

Example 291 A mixture of the compound of Example 289 (7 mg), acetic anhydride (6 mg), dimethylaminopyridine (5 mg) and chloroform (2 ml) was stirred at room temperature overnight. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (M
Purification with erck Art 5744, chloroform-methanol (7: 3)) gave 3 mg of the title compound as a solid. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 1.80-2.10 (3H,
m), 2.11 (3H, s), 2.20-2.70 (4
H, m), 3.30-3.80 (4H, m), 4.60
−5.20 (2H, m), 6.60−6.90 (1H,
m), 7.40-7.60 (2H, m), 8.00-
8.40 (2H, m), 9.10 (1H, br), 1
1.9 (1H, br).

[0986] The compound of Example 292 Example 292 was obtained in the final step of producing the compound of Example 289. ^{1 H-NMR (DMSO-d} 6) 1.20-1.60 (3H, m), 2.10 (2H,
m), 2.40 (2H, m), 2.60 (1H, m),
2.90 (2H, m), 3.45 (1H, m), 3.7
8 (1H, m), 4.80 (1H, dd, J = 5.6,
11 Hz), 7.10-7.60 (4H, m), 8.0
0-8.40 (3H, m), 11.8 (1H, br). mass: 376 (M + 1) ⁺ .

Example 293 (1) 8.5 g of a brown oily substance was obtained according to Reference Example 6 using 9 g of the compound of Example 80 (3).

(2) Using 8.5 g of the compound of (1), 4.7 g of a brown amorphous substance was obtained according to (4) of Example 80.

(3) 210 mg of the desired product was obtained according to (1) of Example 84 using 250 mg of the compound of (2).

(4) 38 mg of ethyl di-o-toluylphosphonoacetate in tetrahydrofuran (2 ml)
The solution was cooled to -78 ° C, a solution of 43 mg of the compound (3) in tetrahydrofuran (1 ml) was added, and the mixture was stirred at -78 ° C for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the temperature was returned to room temperature. After extraction with chloroform, the organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-200, chloroform-methanol (100: 0 to 97: 3)) and then TLC (Merc
Purification with k Art 5744, chloroform-tetrahydrofuran (9: 1) yielded 40 mg of a colorless oil.

(5) A mixture of 40 mg of the compound of (4), 6N hydrochloric acid and 5 ml of tetrahydrofuran was added at room temperature for 15 minutes.
Minutes. The reaction solution was extracted with chloroform, washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 19 mg of a colorless solid as the title compound. ^{1 H-NMR (DMSO-d} 6) 1.15 (3H, t, J = 7.1Hz), 1.09-
1.15 (1H, m), 2.30-3.38 (2H,
m), 2.48-2.56 (1H, m), 3.20-
3.31 (1H, m), 3.51-3.55 (1H,
m), 4.11 (2H, q, J = 7.1 Hz), 4.7
9-4.85 (1H, m), 6.23 (1H, d, J =
13 Hz), 7.04 (2H, m), 7.30-7.3
2 (2H, m), 7.46 (1H, t, J = 7.7H
z), 8.28-8.30 (2H, m), 9.99 (1
H, s), 11.0 (1H, br). mass: 407 (M + 1) ⁺ .

Example 294 (1) 22 mg of ethyl ethyl diethylphosphonoacetate
Was cooled in ice, 4 mg of sodium hydride was added, and the mixture was stirred for 30 minutes. Example 29
43 mg of compound (3) in tetrahydrofuran (1
ml) solution and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, the temperature was returned to room temperature, and extraction was performed with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-200,
Chloroform-methanol (100: 0 to 97: 3))
Purification gave 42 mg of a white solid.

(2) 21 mg of the title compound was obtained as a white solid using 42 mg of the compound of (1) according to (5) of Example 293. ¹ H-NMR (DMSO-d ₆ ) 1.00-1.20 (1H, m), 1.28 (3H,
t, J = 7.1 Hz), 2.20-2.40 (2H,
m), 2.40-2.60 (1H, m), 3.20-
3.40 (1H, m), 3.45-3.60 (1H,
m), 4.23 (1H, q, J = 7.1 Hz), 4.8
4 (1H, m), 6.78 (1H, d, J = 16H
z), 7.33 (1H, d, J = 7.9 Hz), 7.4
0-7.50 (3H, m), 7.57 (1H, d, J =
16 Hz), 8.30 (1H, d, J = 7.9 Hz),
8.36 (1H, d, J = 5.6 Hz), 10.0 (1
H, s), 10.8 (1H, br). mass: 407 (M + 1) ⁺ .

Example 295 To a solution of 50 mg of the compound of Example 294 (1) in chloroform (5 ml) were added 27 mg of zinc chloride and 7 mg of sodium borohydride, and the mixture was refluxed for 3 hours. Example 290
The same post-treatment as described above was carried out to give the title compound, a white solid 32.
mg was obtained. ¹ H-NMR (DMSO-d ₆ ) 1.00-1.20 (1H, m), 2.20-2.60
(3H, m), 3.20-3.60 (2H, m), 4.
17 (2H, m), 4.84 (1H, dd, J = 5.
6,11 Hz), 5.04 (1H, t, J = 6.3H)
z), 6.53 (1H, d, J = 16 Hz), 6.66
(1H, d, J = 16 Hz), 7.15 (1H, d, J
= 5.3 Hz), 7.22 (1H, s), 7.31 (1
H, d, J = 7.9 Hz), 7.47 (1H, t, J =
7.9 Hz), 8.24 (1H, d, J = 5.3H)
z), 8.32 (1H, d, J = 7.9 Hz), 9.9
4 (1H, s), 11.3 (1H, br). mass: 365 (M + 1) ⁺ .

Example 296 To a solution of 30 mg of the compound of Example 294 (1) in methanol (10 ml) were added 10 mg of copper (I) chloride and 4 mg of sodium borohydride, and the mixture was stirred until the raw materials disappeared. The same post-treatments as in Example 290 were performed to obtain 13 mg of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) 1.05-1.25 (1H, m), 1.15 (3H,
t, J = 7.1 Hz), 2.20-2.60 (3H,
m), 2.64 (2H, t, J = 7.1 Hz), 2.8
3 (2H, t, J = 7.1 Hz), 3.20-3.40
(1H, m), 3.45-3.60 (1H, m), 4.
04 (2H, q, J = 7.1 Hz), 4.81 (1H,
m), 6.96 (1H, d, J = 5.3 Hz), 7.1
1 (1H, s), 7.30 (1H, d, J = 7.9H)
z), 7.45 (1H, d, J = 7.9 Hz), 8.1
9 (1H, d, J = 5.4 Hz), 8.30 (1H,
d, J = 7.9 Hz), 9.90 (1H, s), 12.
3 (1H, br). mass: 409 (M + 1) ⁺ .

Example 297 60 mg of the compound of Example 293 was added to 30 ml of chloroform.
, And 0.9 ml of a toluene solution of diisopropylaluminum hydride (1.0 M) was added thereto.
Stirred at 30 ° C for 30 minutes. The same post-treatments as in Example 290 were performed to obtain 17 mg of the title compound as a white solid. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 2.20-2.70 (3H,
m), 3.30 (1H, m), 3.53 (1H, m),
4.15-4.40 (2H, m), 4.81 (1H, d
d, J = 5.6, 11 Hz), 5.00 (1H, m),
6.00 (1H, m), 6.38 (1H, m), 6.8
9 (1H, d, J = 5.4 Hz), 7.12 (1H,
s), 7.31 (1H, d, J = 7.9 Hz), 7.4
5 (1H, t, J = 7.9 Hz), 8.28 (2H,
m), 9.90 (1H, s), 11.1 (1H, b
r). mass: 365 (M + 1) ⁺ .

Example 298 A mixture of 40 mg of the compound of Example 294, 5 ml of a 2N aqueous sodium hydroxide solution, 2 ml of tetrahydrofuran and 2 ml of methanol was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merc
k Art 5744, chloroform-methanol (9:
After purification in 1)), recrystallization was performed to obtain 22 mg of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) 1.00-1.20 (1H, m), 2.20-2.60
(3H, m), 3.15 (1H, m), 3.45-3.
60 (1H, m), 4.82 (1H, m), 6.68
(1H, d, J = 16 Hz), 7.20-7.60 (5
H, m), 8.28 (1H, d, J = 7.9 Hz),
8.35 (1H, d, J = 5.6 Hz), 10.2 (1
H, s), 10.9 (1H, br), 12.8 (1H,
br). mass: 379 (M + 1) ⁺ .

Example 299 (1) 727 mg of the compound of Example 7; DBU 1.49
A mixture of 6 ml and 10 ml of tetrahydrofuran was added at 0 °
Then, a solution of 0.310 ml of methanesulfonyl chloride in tetrahydrofuran (2 ml) was added, and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate (1: 1 to 0: 1)) to obtain 606 mg of a colorless amorphous substance.

(2) The title compound was obtained according to Example 133, (2). ¹ H-NMR (DMSO-d ₆ ) 1.07-1.14 (1H, m), 2.29-12.57
(3H, m), 3.24-3.88 (2H, m), 4.
79-4.85 (1H, m), 5.58 (1H, d, J
= 11 Hz), 6.08 (1H, d, J = 18 Hz),
6.74 (1H, dd, J = 11, 18 Hz), 7.2
2-7.24 (1H, m), 7.29-7.34 (2
H, m), 7.47 (1H, t, J = 7.5 Hz),
8.22-8.27 (2H, m), 10.1 (1H,
s), 11.0 (1H, br). mass: 335 (M + 1) ⁺ .

Example 300 (1) A solution of 80 mg of the compound of Example 294 (1) in methylene chloride (5 ml) was ice-cooled, and trifluoroacetic acid 2
74 mg and 190 mg of N- (methoxymethyl) -N-trimethylsilylmethyl) benzylamine were added and stirred for 3 hours. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merck Ar
After purification with t5744, chloroform-methanol (9: 1), recrystallization was performed to obtain 91 mg of a pale yellow oil.

(2) Using 91 mg of the compound of (1), 50 mg of the title compound was obtained as a white solid according to Example 293 (5). ^{1 H-NMR (DMSO-d} 6) 1.24 (1H, m), 1.24 (3H, t, H = 7.
4Hz), 2.20-2.75 (3H, m), 2.80
(1H, m), 2.95 (1H, m), 3.05 (1
H, m), 3.19 (1H, m), 3.45 (1H,
m), 3.60-3.90 (4H, m), 4.18 (2
H, q, J = 7.4 Hz), 4.78 (1H, dd, J)
= 5.6, 11 Hz), 6.93 (1H, s), 7.0
3 (1H, d, J = 5.6 Hz), 7.10-7.45
(5H, m), 7.50 (1H, t, J = 7.9H)
z), 7.55 (1H, d, J = 7.9 Hz), 8.1
3 (1H, d, J = 5.6 Hz), 8.37 (1H,
d, J = 7.9 Hz), 8.82 (1H, s), 12.
0 (1H, br). mass: 540 (M + 1) ⁺ .

[1002] The compound of Example 301 Example 301, using the compound of (4) of Example 293, was prepared analogously to Example 300. mass: 540 (M + 1) ⁺ .

Example 302 A solution of the compound of Example 300 in 30 mg of tetrahydrofuran (3 ml) was ice-cooled, and 56 μl of lithium aluminum hydride in tetrahydrofuran (2 M) and 0.22 ml of methanol in tetrahydrofuran (1 M) were added. For 30 minutes. The same post-treatment as in Example 290 was carried out to give the title compound (low-polar fraction) as a white solid.
2.3 mg of a white solid of the compound of Example 303 (highly polar fraction), which is a diastereomer of the title compound, was obtained in an amount of 2 mg. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 2.20-2.60 (3H,
m), 3.30-4.40 (12H, m), 4.78
(1H, m), 6.60-7.00 (2H, m), 7.
20-7.80 (7H, m), 8.10-8.40 (2
H, m), 11.8 (1H, br). mass: 498 (M + 1) ⁺ .

[1004] The compound of Example 303 Example 303 was obtained as a diastereomer of Example 302. ^{1 H-NMR (DMSO-d} 6) 1.25 (1H, m), 2.00-2.70 (3H,
m), 2.80-4.40 (12H, m), 4.78
(1H, m), 6.75 (1H, s), 6.98 (1
H, d, J = 5.4 Hz), 7.20-7.70 (7
H, m), 8.10 (1H, d, J = 5.4 Hz),
8.28 (1H, d, J = 7.9 Hz), 11.8 (1
H, br). mass: 498 (M + 1) ⁺ .

Example 304 The compound of Example 304 was produced according to Example 303 using the compound of Example 301. mass: 498 (M + 1) ⁺ .

Example 305 (1) A mixture of 50 mg of the compound of Example 293 (4), 34 mg of isoprene and 3 ml of toluene was reacted in a sealed tube at 120 ° C. overnight. The reaction solution was concentrated, and the residue was
Purification by LC (Merck Art 5744, chloroform-methanol (9: 1)) gave 52 mg of the adduct.

(2) Example 2 for the compound of (1)
The reaction was carried out according to 93 (5) to give 18 mg of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) 1.03 (3H, t, J = 7.3 Hz), 1.25 (1
H, m), 1.68 (s), 1.72 (s), 1.68
-1.72 (3H), 2.00-3.20 (9H,
m), 3.42 (1H, m), 3.78 (1H, m),
3.98 (2H, q, J = 7.3 Hz), 4.80 (1
H, dd, J = 5.6, 11 Hz), 5.49 (1H,
m), 6.84 (2H, m), 7.46 (1H, d, J
= 7.9 Hz), 7.55 (1H, d, J = 7.9H)
z), 8.10 (1H, d, J = 5.2 Hz), 8.4
0 (1H, d, J = 7.9 Hz), 9.25 (1H,
s), 12.0 (1H, br). mass: 475 (M + 1) ⁺ .

Example 306 (1) A yellow solid was obtained in the same manner as in Example 261, using the compound of Example 3 and 4-nitrobenzoyl chloride.

(2) 22.1 g of the compound of (1) was converted to HP
After optical resolution with LC (CHIRALPAK AD, hexane-ethanol (1: 1 to 1: 4)), 11.2 g of compound (A) with Rt = 22 minutes and 10.1 g of compound (B) with Rt = 30 minutes I got

(3) 10 g of the compound of (2) -A, 6N
A mixture of 30 ml of hydrochloric acid and 30 ml of acetic acid was stirred at 80 ° C. for 3 days. The reaction solution was returned to room temperature, made basic with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with a 1N aqueous solution of potassium hydroxide and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (100: 0 to 98: 2)) and recrystallized from ethanol to give a white solid.
1 g (98% ee) was obtained.

(4) Example 8 using the compound of (3)
A white solid was obtained according to 0.

(5) Example 8 using the compound of (4)
The title compound (optically active compound of the compound of Example 91) was obtained in the same manner as in Example 4 to obtain a white solid. mass: 429 (M + 1) +.

Example 307 Example 30 was repeated using the compound of (2) -B of Example 306.
According to 6 (3) to (5), a white solid as the title compound was obtained. mass: 429 (M + 1) +.

[1014] The compound of Example 308 Example 308, was prepared analogously to Example 306. mass: 429 (M + 1) +.

[1015] The compound of Example 309 Example 309, was prepared analogously to Example 307. mass: 429 (M + 1) +.

[1016] The compound of Example 310 Example 310 was prepared analogously to Example 307. mass: 469 (M + 1) ⁺ .

[1017] The compound of Example 311 Example 311 was prepared analogously to Example 306. mass: 429 (M + 1) +.

[1018] The compound of Example 312 Example 312 was prepared analogously to Example 307. mass: 429 (M + 1) +.

Example 313 12 mg of a white solid was obtained according to Example 290 using 51 mg of the compound of Example 91. mass: 429 (M + 1) +.

Example 314 (1) Cyclopentanone 504 mg, pyrrolidine 49
8 mg, molecular sieves 4A 2 g and toluene 3
0 ml of the mixture was stirred at room temperature overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. Residue is chloroform 20
ml, dissolved in 1,2,4-triazine-5.
-Chloroform of carboxylic acid ethyl ester (10 m
l) The solution was added, and the mixture was stirred at room temperature for 30 minutes and at 45 ° C for 6 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate (4: 1 to 1: 1)) to give a yellow oil 734.
mg was obtained.

(2) Using 100 mg of the compound of (1) and according to Reference Example 5, 101 m of the title compound as a white solid
g was obtained. ^{1 H-NMR (DMSO-d} 6) 1.30 (1H, m), 2.14 (2H, quinte
t, J = 7.5 Hz), 2.40 (2H, m), 2.6
2 (1H, m), 2.92 (4H, t, J = 7.5H
z), 3.42 (1H, m), 3.75 (1H, m),
4.79 (1H, dd, J = 5.6, 11 Hz);
68 (1H, s), 7.48 (1H, t, J = 7.4H
z), 7.53 (1H, d, J = 7.4 Hz), 7.6
6 (1H, s), 8.03 (1H, s), 8.33 (1
H, d, J = 7.4 Hz), 12.1 (1H, s). mass: 349 (M + 1) ⁺ .

[1022] The compound of Example 315-319 Example 315 to Example 319, Example 3
It was manufactured according to No.14. Example 315 mass: 377 (M + 1) ⁺ .

Example 316 mass: 378 (M + 1) ⁺ .

Example 317 mass: 454 (M + 1) ⁺ .

Example 318 mass: 454 (M + 1) ⁺ .

Example 319 mass: 450 (M + 1) ⁺ .

Example 320 A mixture of 100 mg of the compound of Example 319, 5 ml of 4N hydrochloric acid-dioxane and 3 ml of methanol was stirred at room temperature for 30 minutes. After adding triethylamine to the reaction solution, the mixture was concentrated, and the residue was subjected to silica gel column chromatography (FL).
Purification with 60D (Fuji Silysia Ltd.), chloroform-methanol (100: 0 to 95: 5)) gave 72 mg of a white solid. mass: 350 (M + 1) ⁺ .

Example 321 The title compound was obtained according to Example 84 (2) using 17 mg of the compound of Example 320 and 12 mg of cyclopentanone. mass: 418 (M + 1) ⁺ .

Working Example No.322 According to the procedure described in the working example No.321, the compound of the working example No.322 was prepared. mass: 364 (M + 1) ⁺ .

Example 323 (1) Using the compound of (2) -A of Example 164, the desired product was obtained according to Reference Example 8.

(2) Example 1 using the compound of (1)
The hydrochloride of the title compound was obtained according to 33 (2). ^{1 H-NMR (DMSO-d} 6) 1.00-1.23 (1H, m), 2.20-2.90
(7H, m), 3.40-3.61 (2H, m), 4.
81 (1H, m), 6.90-7.51 (4H, m),
8.08-8.37 (2H, m), 9.95 (1H, b
rs), 11.4 (1H, brs). mass: 352 (M + 1) ⁺ .

Example 324 Example 32 was repeated using the compound of (2) -B of Example 164.
The hydrochloride of the title compound was obtained according to 3. mass: 352 (M + 1) ⁺ .

Example 325 Example 13 was repeated using the compound of (2) -A of Example 164.
The title compound was obtained according to 3 (2). ¹ H-NMR (DMSO-d ₆ ) 1.00-1.21 (1H, m), 2.25-2.79
(5H, m), 3.21-3.72 (4H, m), 4.
65-4.90 (2H, m), 6.90-7.52 (4
H, m), 8.13-8.38 (2H, m), 9.85
(1H, s), 11.4 (1H, brs). mass: 353 (M + 1) ⁺ .

Example 326 Example 13 was repeated using the compound of (2) -B of Example 164.
The title compound was obtained according to 3 (2). mass: 353 (M + 1) ⁺ .

Example 327 (1) Using the compound of (1) of Example 323, the desired product was obtained according to (1) of Example 96.

(2) Example 1 using the compound of (1)
The title compound was obtained according to 33 (2). ¹ H-NMR (DMSO-d ₆ ) 1.01-1.20 (1H, m), 2.22-2.78
(5H, m), 3.08-3.20 (2H, m), 3.
32 (1H, m), 3.55 (1H, m), 4.81
(1H, m), 6.85-7.52 (4H, m), 7.
92-8.40 (7H, m), 9.90 (1H, s),
11.2 (1H, brs). mass: 538 (M + 1) ⁺ .

Example 328 (1) Using the compound of (2) -B of Example 164, the desired product was obtained according to (1) of Example 323.

(2) Example 3 using the compound of (1)
The title compound was obtained according to 27. mass: 538 (M + 1) ⁺ .

Example 329 Using the compound of Example 327 (1) and 1-butanol, a hydrochloride of the title compound was obtained according to Example 96 (2) and (3). ^{1 H-NMR (DMSO-d} 6) 0.89 (3H, t, J = 7.8Hz), 1.01-
1.17 (1H, m), 1.25-1.41 (2H,
m), 1.52-1.64 (2H, m), 2.26-
2.40 (2H, m), 2.52-2.63 (1H,
m), 2.85-3.00 (4H, m), 3.08-
3.23 (2H, m), 3.26-3.35 (1H,
m), 3.50-3.60 (1H, m), 4.80-
4.86 (1H, m), 7.03 (1H, d, J = 4.
3 Hz), 7.26-7.35 (2H, m), 7.56
(1H, t, J = 7.8 Hz), 8.26-8.30
(2H, m), 8.81 (2H, m), 10.3 (1
H, s), 11.0 (1H, brs). mass: 408 (M + 1) ⁺ .

Example 330 (1) Using the compound of (1) of Example 328, the desired product was obtained according to (1) of Example 327.

(2) Example 3 using the compound of (1)
The hydrochloride of the title compound was obtained according to 29. mass: 408 (M + 1) ⁺ .

Example 331 Using the compound of Reference Example 8 and (R) -3- (tert-butoxycarbonylamino) -1,4-dimethanesulfonyloxybutane, the hydrochloride of the title compound was prepared in the same manner as in Example 334. Obtained. ¹ H-NMR (DMSO-d ₆ ) 1.05 (1H, m), 2.00-2.75 (5H,
m), 3.05-4.95 (11H, m), 7.12-
7.52 (4H, m), 8.21-8.80 (4H,
m), 10.5-11.8 (4H, m).

Example 332 15 mg of the compound of Example 331, 24 μl of acetyl chloride
l, a mixture of 92 µl of triethylamine and 0.5 ml of dimethylformamide were stirred at room temperature for 5 minutes. The reaction solution was concentrated, and the residue was purified by TLC (Merck Art 5713,
Purification with chloroform-methanol (19: 1) gave 11 mg of the title compound as a pale yellow solid. ¹ H-NMR (CD ₃ OD) 1.10-1.30 (1H, m), 1.65 (1H,
m), 1.90 (3H, s), 2.22 (1H, m),
2.40-2.92 (11H, m), 3.45 (1H,
m), 3.65 (1H, m), 4.29 (1H, m),
4.86 (1H, m), 6.87-7.00 (2H,
m), 7.39-7.52 (2H, m), 8.14-
8.30 (2H, m). mass: 463 (M + 1) ⁺ .

Example 333 Using 20 mg of the compound of Example 331, 16 mg of the title compound was obtained as a pale yellow solid according to Example 96 (1). ^{1 H-NMR (DMSO-d} 6) 1.12 (1H, m), 1.45 (1H, m), 1.8
9 (1H, m), 2.20-2.75 (10H, m),
3.25-3.75 (4H, m), 4.75-4.85
(1H, m), 6.87-7.50 (4H, m), 8.
00-8.43 (6H, m).

Example 334 (1) 100 mg of the compound of (1) of Example 323
(S) -3- (tert-butoxycarbonylamino)
34 mg of -1,4-dimethanesulfonyloxybutane,
A mixture of 46 mg of N, N-diisopropylethylamine and 1 ml of dimethylformamide was stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (1: 0 to 4: 1).
90 mg of the ester were obtained.

(2) Using 100 mg of the compound of (1), 50 mg of a white solid as a hydrochloride of the title compound was obtained according to (2) of Example 133. ¹ H-NMR (DMSO-d ₆ ) 1.05 (1H, m), 2.00-2.75 (5H,
m), 3.05-4.95 (11H, m), 7.12-
7.52 (4H, m), 8.21-8.80 (4H,
m), 10.5-11.8 (4H, m). mass: 421 (M + 1) ⁺ .

Example 335 Using (2) -B of Example 164, a compound synthesized according to Reference Example 8 was reacted according to Example 334 to obtain a hydrochloride of the title compound. mass: 421 (M + 1) ⁺ .

Example 336 (1) 2- (N- (tert-butoxycarbonyl)
A solution of 2.26 g of amino) -4-methylpyridine in tetrahydrofuran (100 ml) was cooled to −78 ° C.
Butyllithium hexane solution (1.5M) 18.2m
was added and the temperature was raised to room temperature. The reaction was cooled to -78 ° C and n
1.48 ml of -butyraldehyde was added, and the temperature was gradually raised to room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate (1: 0-1: 1)) to give a white solid 1.37.
g was obtained.

(2) Using 1.00 g of the compound of (1), 700 mg of the desired product was obtained according to (1) of Reference Example 8.

(3) A mixture of 700 mg of the compound of (2), 700 mg of triphenylphosphine, 2 ml of water and 30 ml of tetrahydrofuran was stirred for 30 minutes. The reaction solution was returned to room temperature, and concentrated by adding toluene and methanol. The residue was subjected to silica gel column chromatography (Wakogel C-300, chloroform-methanol (1: 0)
To 4: 1) to obtain 600 mg of the desired product.

(4) Example 9 using the compound of (3)
The intended product was obtained according to 6 (1).

(5) Using 100 mg of the compound of (4) and ethanol, the desired product 1 was obtained according to (2) of Example 96.
05 mg was obtained.

(6) Using 53 mg of the compound of (5),
40 mg of a urea compound was obtained according to Example 118 (2). This was purified by HPLC (CHIRALPAK AD)
And 19 mg as compound A in ascending order of Rt,
19 mg was obtained as compound B.

(7) Using 20 mg of the compound (6) -A, 3.8 mg of the title compound was obtained as a colorless oil according to (3) of Example 96. ^{1 H-NMR (DMSO-d} 6) 0.70-1.42 (11H, m), 2.10-2.8
2 (8H, m), 3.05-3.81 (2H, m),
4.37-4.88 (1H, m), 6.90-6.97
(1H, m), 7.10 (1H, s), 7.28-7.
51 (2H, m), 8.15-8.37 (2H, m),
9.88 (1H, s), 11.8 (1H, s). mass: 422 (M + 1) ⁺ .

Example 337 Example 96 was repeated using the compound (6) -B of Example 336.
5.7 m of the title compound as a colorless oil according to (3)
g was obtained. mass: 422 (M + 1) ⁺ .

Example 338 (1) Using the compound of Reference Example 8 and 2,4-dimethoxybenzaldehyde, the desired product was obtained according to Example 84 (2).

(2) Using the compound of (1) and 1-propanesulfonyl chloride, the desired product was obtained according to (1) of Example 96.

(3) A solution of the compound of (2) in trifluoroacetic acid was stirred at room temperature for 15 minutes. The reaction solution was concentrated, and the residue was crystallized by adding ether-methanol to obtain the title compound. mass: 458 (M + 1) ⁺ .

[1059] The compound of Example 339 Example 339 was prepared analogously to Example 140. mass: 472 (M + 1) ⁺ .

[1060] The compound of Example 340 Example 340 was prepared analogously to Example 138. mass: 458 (M + 1) ⁺ .

Example 341 (1) The target compound was obtained according to Reference Example 10 using o-anisidine.

(2) Reference Example 1 using the compound of (1)
After performing the reaction according to 1, the crude product was dissolved in methanol and treated with 1N hydrochloric acid. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was solidified with ether-methanol to obtain the title compound as a white solid. mass: 458 (M + 1) ⁺ .

Examples 342-360 The compounds of Examples 342 to 360 were prepared according to Example 3.
41. Example 342 mass: 458 (M + 1) ⁺ .

Example 343 mass: 419 (M + 1) ⁺ .

Example 344 mass: 472 (M + 1) ⁺ .

Example 345 mass: 485 (M + 1) ⁺ .

Example 346 mass: 510 (M + 1) ⁺ .

Example 347 mass: 435 (M + 1) ⁺ .

Example 348 mass: 436 (M + 1) ⁺ .

Example 349 mass: 479. (M + 1) ⁺ .

Example 350 mass: 428 (M + 1) ⁺ .

Example 3511 ¹ H-NMR (DMSO-d ₆ ) 1.07 (1H, m), 2.25-2.35 (2H,
m), 2.58 (1H, m), 2.93 (2H, t, J
= 6.9 Hz), 3.29 (1H, m), 3.53 (1
H, m), 3.86 (2H, t, J = 6.9 Hz),
4.82 (1H, dd, J = 5.6, 11 Hz);
90 (1H, d, J = 5.5 Hz), 7.08 (1H,
s), 7.32 (1H, d, J = 7.6 Hz), 7.4
6 (1H, t, J = 7.6 Hz), 7.97 (2H,
d, J = 8.9 Hz), 8.17 (1H, s), 8.2
1 (1H, d, J = 5.5 Hz), 8.26 (1H,
d, J = 7.6 Hz), 8.35 (2H, d, J = 8.
9Hz), 10.3 (1H, br), 11.0 (1H,
br), 13.0 (1H, br). mass: 620 (M + 1) ⁺ .

Example 352 mass: 430 (M + 1) ⁺ .

Example 353 mass: 429 (M + 1) ⁺ .

Example 354 mass: 429 (M + 1) ⁺ .

Example 355 mass: 429 (M + 1) ⁺ .

Example 356 mass: 479 (M + 1) ⁺ .

Example 357 mass: 430 (M + 1) ⁺ .

Example 358 mass: 468 (M + 1) ⁺ .

Example 359 mass: 479 (M + 1) ⁺ .

Example 360 mass: 430 (M + 1) ⁺ .

Example 361 (1) A reaction was carried out using 6-aminoquinoline according to Reference Examples 10 and 11, to obtain a sulfide form as a by-product.

(2) Using 64 mg of the compound of (1),
According to (133) of Example 133, 21 mg of the title compound was obtained as a white solid. mass: 445 (M + 1) ⁺ .

Example 362 (1) A reaction was carried out using 6-aminoquinoline according to Reference Examples 10 and 11, to obtain a chloride as a by-product.

(2) Using 26 mg of the compound of (1),
18 mg of the title compound was obtained as a white solid according to Example 133 (2). mass: 371 (M + 1) ⁺ .

[1086] Example 363-364 Example 363 and Example 364 were prepared analogously to Example 341. Example 363 mass: 479 (M + 1) ⁺ .

Example 364 mass: 418 (M + 1) ⁺ .

Example 365 (1) Tert- of 4-hydroxybenzaldehyde
Example 137 using butyldiphenylsilyl ether
The desired product was obtained according to (1).

(2) Example 1 using the compound of (1)
According to 39, a yellow powder which was a hydrochloride of the title compound was obtained. ^{1 H-NMR (DMSO-d} 6) 1.07-1.16 (1H, m), 2.26-2.61
(3H, m), 2.80 (3H, s), 2.83 (3
H, s), 3.00-3.17 (3H, m), 3.25.
-3.34 (1H, m), 3.45-3.56 (3H,
m), 4.11 (2H, t, J = 4.2 Hz), 4.3
6 (2H, t, J = 4.3 Hz), 4.82 (2H, d
d, J = 6.2, 12 Hz), 6.97-7.07 (3
H, m), 7.25-7.54 (5H, m), 8.23.
−8.28 (2H, m), 9.37 (2H, br), 1
0.2 (1H, br), 10.4 (1H, br), 1
0.9 (1H, br). mass: 529 (M + 1) ⁺ .

[1090] The compound of Example 366-375 Example 366 to Example 375, Example 3
65. Example 366 mass: 549 (M + 1) ⁺ .

Example 367 mass: 555 (M + 1) ⁺ .

Example 368 mass: 569 (M + 1) ⁺ .

Example 369 mass: 571 (M + 1) ⁺ .

Example 370 mass: 549 (M + 1) ⁺ .

Example 371 mass: 577 (M + 1) ⁺ .

Example 372 mass: 549 (M + 1) ⁺ .

Example 373 mass: 577 (M + 1) ⁺ .

Example 374 mass: 583 (M + 1) ⁺ .

Example 375 mass: 585 (M + 1) ⁺ .

Example 376 (1) 510 mg of 2-pyridinecarboxaldehyde
1.70 g of triphenylphosphoranylidene acetic acid methyl ester was added to a benzene (20 ml) solution of
Stirred for hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate (4: 1 to 3: 1)) to obtain 621 mg of the desired product.

(2) Using 621 mg of the compound of (1), 252 mg of the desired product was obtained according to Example 297.

(3) Using 20 mg of the compound of (2),
According to Example 365, 24 mg of a yellow solid which was a hydrochloride of the title compound was obtained. ¹ H-NMR (CD ₃ OD) 1.13 (1H, m), 2.42 (2H, m), 2.7
0 (1H, m), 3.60-3.82 (2H, m),
3.37-3.47 (3H, m), 4.03 (1H,
m), 4.20-4.38 (3H, m), 4.96 (2
H, m), 6.81-8.72 (16H, m).

Example 377 (1) Tert- of 3-hydroxybenzaldehyde
Example 137 using butyldiphenylsilyl ether
The desired product was obtained according to (1).

(2) Example 1 using the compound of (1)
According to 39, a white solid which was a hydrochloride of the title compound was obtained. ¹ H-NMR (DMSO-d ₆ ) 1.04 (1H, m), 2.23-2.34 (2H,
m), 2.70 (1H, m), 3.07-3.20 (4
H, m), 3.28 (1H, m), 3.51 (1H,
m), 4.16 (2H, m), 4.84 (1H, dd,
J = 6.4, 10 Hz), 5.39 (2H, s), 7.
08-7.20 (2H, m), 7.28-7.39 (4
H, m), 7.43-7.52 (2H, m), 7.71
(1H, m), 7.86 (1H, d, J = 8.6H)
z), 8.20-8.28 (2H, m), 8.77 (1
H, m), 9.64 (2H, br), 10.7 (1H,
br), 11.1 (1H, br). mass: 549 (M + 1) ⁺ .

Examples 378-387 The compounds of Examples 378 to 387 were prepared in Example 3
77. Example 378 mass: 549 (M + 1) ⁺ .

Example 379 mass: 549 (M + 1) ⁺ .

Example 380 mass: 577 (M + 1) ⁺ .

Example 381 mass: 577 (M + 1) ⁺ .

Example 382 mass: 529 (M + 1) ⁺ .

Example 383 mass: 585 (M + 1) ⁺ .

Example 384 mass: 571 (M + 1) ⁺ .

Example 385 mass: 555 (M + 1) ⁺ .

Example 386 mass: 569 (M + 1) ⁺ .

Example 387 mass: 583 (M + 1) ⁺ .

Example 388 According to Reference Example 3, 14 mg of the title compound was obtained using 19 mg of Example 376. ¹ H-NMR (CD ₃ OD) 1.12 (1H, m), 2.24-2.41 (3H,
m), 2.70 (1H, m), 3.32-3.41 (4
H, m), 3.55-3.75 (2H, m), 4.02
-4.32 (5H, m), 4.92 (3H, m), 6.
88 (2H, m), 7.22 (2H, m), 7.30
(1H, m), 7.40-7.50 (3H, m), 7.
89 (1H, m), 8.03 (2H, m), 8.22
(1H, m), 8.43 (1H, m), 8.69 (1
H, m).

Example 389 (1) A mixture of 1.01 g of 6-aminonicotinic acid, 835 mg of lithium aluminum hydride and tetrahydrofuran was refluxed for 23 hours. The reaction solution is returned to room temperature, and water 8
40 μl, 840 μl of 1 N sodium hydroxide and water 84
0 μl was added sequentially, and the mixture was filtered through Celite. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (Wakogel C-200, chloroform-methanol (50:
Purification was carried out by 1-10: 1) to obtain 223 mg of the desired product.

(2) 223 mg of the compound of (1), te
A mixture of 332 mg of rt-butyldimethylchlorosilane, 244 mg of imidazole and 5 ml of dimethylformamide was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and extracted with chloroform. Wash the organic layer with saturated saline,
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated. The residue is subjected to silica gel column chromatography (Wakogel C
-200, purified with hexane-ethyl acetate (3: 2),
341 mg of the desired product was obtained.

(3) Using 320 mg of the compound of (2), 138 mg of the desired product was obtained according to (2) of Example 118.

(4) A mixture of the compound (3) (103 mg), acetic acid (1 ml), water (1 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 3 days. The reaction solution was concentrated, and the residue was
Purification by LC (Merck Art 5744, chloroform-methanol (10: 1)) afforded 44 mg of a white powder as the title compound. ^{1 H-NMR (DMSO-d} 6) 1.07 (1H, m), 2.22-2.57 (3H,
m), 3.30 (1H, m), 3.53 (1H, m),
4.46 (2H, d, J = 5.0 Hz), 4.82 (1
H, dd, J = 5.6, 10 Hz), 5.23 (1H,
t, J = 5.0 Hz), 7.25 (1H, d, J = 8.
6Hz), 7.31 (1H, dd, J = 0.9, 8.0)
Hz), 7.46 (1H, t, J = 8.0 Hz), 7.
73 (1H, dd, J = 2.3, 8.6 Hz), 8.2
3 (1H, d, J = 2.3 Hz), 8.31 (1H, d
d, J = 0.9, 8.0 Hz), 9.92 (1H,
s), 11.2 (1H, br). mass: 339 (M + 1) ⁺ .

[1120] The compound of Example 390 Example 390, was prepared analogously to Example 498. mass: 352 (M + 1) ⁺ .

Example 391 (1) To a mixture of 103 mg of the compound of Example 389, 0.6 ml of triethylamine and 3 ml of dimethyl sulfoxide was added 265 mg of a sulfur trioxide pyridine complex, and the mixture was stirred at room temperature for 4 hours. To this, 195 mg of sulfur trioxide pyridine complex was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with chloroform, washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was directly used for the next reaction.

(2) Using 36 mg of the compound of (1) and 2 ml of a methanol solution of ethylamine (2.0 M),
According to (84) of Example 84, 20 mg of a white powder as the title compound was obtained. ¹ H-NMR (DMSO-d ₆ ) 1.15 (1H, m), 1.20 (3H, t, J = 7.
3Hz), 2.32-2.38 (2H, m), 2.53
(1H, m), 3.00 (2H, q, J = 7.3H
z), 3.30 (1H, m), 3.55 (1H, m),
4.14 (2H, s), 4.79 (1H, dd, J =
5.6, 10 Hz), 7.33 (1H, d, J = 7.9)
Hz), 7.46 (1H, d, J = 8.8 Hz), 7.
48 (1H, t, J = 7.9 Hz), 7.88 (1H,
dd, J = 2.3, 8.8 Hz), 8.27 (1H,
d, J = 7.9 Hz), 8.36 (1H, d, J = 2.
3 Hz), 10.1 (0.2 H, s), 10.6 (0.
3H, br). mass: 366 (M + 1) ⁺ .

[1123] The compound of Example 392 Example 392 was prepared analogously to Example 391. mass: 380 (M + 1) ⁺ .

Example 393 (1) 33 mg of the desired product was obtained according to Example 118 (2) using 139 mg of 2-amino-5-nitropyridine.

(2) According to Reference Example 3, 26 mg of the title compound was obtained as a white powder using 33 mg of the compound of (1). ^{1 H-NMR (DMSO-d} 6) 1.12 (1H, m), 2.31-2.45 (3H,
m), 2.55 (1H, m), 3.53 (1H, m),
4.77 (1H, dd, J = 4.5, 10 Hz);
05 (2H, s), 6.99 (1H, m), 7.07
(1H, dd, J = 3.1, 8.8 Hz), 7.27
(1H, d, J = 7.8 Hz), 7.43 (1H, t,
J = 7.8 Hz), 7.67 (1H, d, J = 3.1H)
z), 8.32 (1H, d, J = 7.8 Hz), 9.4
7 (1H, s). mass: 324 (M + 1) ⁺ .

Example 394 (1) 989 mg of the desired compound was obtained according to Example 118 (2) using 2-amino-5-bromopyridine (643 mg).

(2) 150 mg of the desired product was obtained according to Reference Example 6 using 218 mg of the compound of (1).

(3) 30 mg of the compound of (2), 10 μl of 1-methylpiperazine, 3 mg of tris (dibenzylideneacetone) dipalladium (0), 3 mg of 1,1′-bis (diphenylphosphino) ferrocene, 2,2 ′ -Bis (diphenylphosphino) -1,1'-binaphthyl 3
mg, sodium tert-butoxide 9 mg and tetrahydrofuran 2 ml in a sealed tube at 100 ° C. for 2 hours.
Allowed to react for hours. The reaction was returned to room temperature and filtered through silica gel and celite. The filtrate is concentrated and the residue is concentrated in TL
Purification with C (Merck Art 5744, chloroform-methanol (10: 1)) afforded 17 mg of the desired compound.

(4) Using 17 mg of the compound of (3),
15 mg of a white solid, which was the hydrochloride of the title compound, was obtained according to Example 133 (2). ¹ H-NMR (DMSO-d ₆ ) 1.04 (1H, m), 2.23-2.38 (2H,
m), 2.58 (1H, m), 2.80 (s), 2.8
1 (s), 2.80-2.81 (3H), 3.06-
3.22 (4H, m), 3.30 (1H, m), 3.4
8-3.58 (3H, m), 3.75-3.79 (2
H, m), 4.83 (1H, dd, J = 5.6, 10H)
z), 7.30 (1H, dd, J = 0.9, 8.1H)
z), 7.36 (1 Hbrd, J = 9.2 Hz), 7.
45 (1H, t, J = 8.1 Hz), 7.65 (1H,
dd, J = 2.7, 9.2 Hz), 7.99 (1H,
d, J = 2.7 Hz), 8.24 (1H, dd, J =
0.9, 8.1 Hz), 10.1 (1H, br), 1
0.8 (1H, br). mass: 407 (M + 1) ⁺ .

Examples 395-397 The compounds of Examples 395 to 397 were prepared in Example 3
94. Example 395 mass: 366 (M + 1) ⁺ .

Example 396 mass: 352 (M + 1) ⁺ .

Example 397 mass: 338 (M + 1) ⁺ .

Example 398 (1) The reaction was carried out according to Example 429 (2) using 2-amino-5-bromopyridine and tributylvinyltin to obtain the desired product.

(2) Using 6 mg of the compound of (1), 2 mg of the title compound as a white powder was obtained according to (2) of Example 118. ¹ H-NMR (DMSO-d ₆ ) 0.80-0.92 (1H, m), 2.35-2.50
(2H, m), 2.55-2.65 (1H, m), 3.
02-3.50 (1H, m), 3.72-3.82 (1
H, m), 4.77-4.84 (1H, m), 5.35.
(1H, d, J = 9.0 Hz), 5.73 (1H, d,
J = 18 Hz), 6.68 (1H, dd, J = 9.0,
18Hz), 6.72-7.00 (1H, m), 7.4
5-7.60 (3H, m), 7.80 (1H, m),
8.17 (1H, m), 8.27 (1H, d, J = 7.
0 Hz), 11.8 (1H, br). mass: 335 (M + 1) ⁺ .

Example 399 Using 4 mg of the compound of Example 398, 3 mg of the title compound, a white powder, was obtained according to Reference Example 3. ^{1 H-NMR (DMSO-d} 6) 0.80-0.90 (1H, m), 1.22 (3H,
t, J = 7.4 Hz), 2.40-2.50 (2H,
m), 2.58-2.65 (1H, m), 2.62 (2
H, q, J = 7.4 Hz), 3.42-3.50 (1
H, m), 3.70-3.82 (1H, m), 4.80
(1H, m), 6.70 (1H, d, J = 9.0H
z), 7.46 (1H, t, J = 7.0 Hz), 7.5
0-7.60 (2H, m), 8.04 (1H, d),
8.30 (1H, d, J = 7.4 Hz), 11.9 (1
H, br). mass: 337 (M + 1) +.

Example 400 (1) 2-Acetaminopyridine-4-carboxylic acid methyl ester 19 mg, sodium periodate 7 mg,
One drop of concentrated sulfuric acid was added to a mixture of 12 mg of iodine, 25 μl of water and 0.12 ml of acetic acid, and the mixture was stirred at 85 ° C. for 23 hours. To the reaction solution was added 5 ml of an aqueous solution of sodium thiosulfate, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Mer
ck Art 5744, chloroform-methanol (2
0: 1)) to give 15 mg of the desired product as a yellow powder.

(2) Example 3 using the compound of (1)
The reaction was carried out according to the procedure described in Example 98, and the title compound was white powder 2
mg was obtained. ^{1 H-NMR (DMSO-d} 6) 0.85-0.92 (1H, m), 2.37-2.47
(2H, m), 2.55-2.59 (1H, m), 3.
43-3.51 (1H, m), 3.74-3.81 (1
H, m), 3.97 (3H, s), 4.82 (1H,
m), 5.43 (1H, d, J = 10 Hz), 5.66
(1H, dd, J = 1.0, 10 Hz), 7.22-
7.32 (1H, m), 7.49 (1H, t, J = 7.
8Hz), 7.58 (1H, m), 8.05 (1H,
s), 8.26 (1H, d, J = 8.0 Hz), 8.4
3 (1H, s), 11.5 (1H, br). mass: 393 (M + 1) ⁺ .

Example 401 According to Reference Example 3, 2 mg of the compound of Example 400 was used to obtain 1 mg of the title compound as a white powder. ¹ H-NMR (DMSO-d ₆ ) 0.70-0.80 (1H, m), 1.25 (3H,
t, J = 7.5 Hz), 2.30-2.50 (2H,
m), 2.94 (2H, q, J = 7.5 Hz), 3.4
1-3.50 (1H, m), 3.74-3.82 (1
H, m), 3.98 (3H, s), 4.24-4.30.
(1H, m), 4.78-4.820 (1H, m),
7.20 (1H, s), 7.43-7.60 (2H,
m), 7.67-7.76 (1H, m), 8.17 (1
H, s), 8.26 (1H, d, J = 7.2 Hz), 1
1.6 (1H, br). mass: 395 (M + 1) ⁺ .

Example 402 Using 86 mg of 2-aminopyrimidine, 15 mg of a pale red powder as the title compound was obtained according to Example 118 (2). ^{1 H-NMR (DMSO-d} 6) 1.17 (1H, m), 2.24-2.40 (2H,
m), 2.52 (1H, m), 3.30 (1H, m),
3.54 (1H, m), 4.87 (1H, dd, J =
5.0, 10 Hz), 7.18 (1H, t, J = 5.0)
Hz), 7.34 (1H, dd, J = 0.9, 7.8H)
z), 7.49 (1H, t, J = 7.8 Hz), 8.3
0 (1H, dd, J = 0.9, 7.8 Hz), 8.71
(2H, d, J = 5.0 Hz), 10.4 (1H,
s), 11.6 (1H, s). mass: 310 (M + 1) ⁺ .

Example 403 (1) 2-Amino-4,6-dichloropyrimidine
A mixture of 0 g, 733 mg of 1-methylpiperazine, 1.3 ml of triethylamine and 15 ml of 1-butanol was stirred at 80 ° C. for 22 hours. After concentration, the reaction solution was diluted with chloroform-methanol (10: 1) and filtered through silica gel (Wakogel C-200). The filtrate was concentrated to obtain a crude product containing the desired product.

(2) The compound of (1) was converted to ethanol 18
The resulting product was dissolved in the same amount as in Example 1 to obtain 390 mg of the desired product according to Reference Example 3.

(3) Using 74 mg of the compound of (2),
According to Example 118 (2), 14 mg of a white solid was obtained as the title compound. ¹ H-NMR (CDCl ₃ ) 1.27 (1H, m), 2.35 (3H, m), 2.3
4-2.60 (7H, m), 3.42 (1H, m),
3.64-3.80 (5H, m), 4.76 (1H, d
d, J = 5.3, 11 Hz), 5.22 (1H, d, J)
= 6.4 Hz), 7.36 (1H, s), 7.45 (1
H, t, J = 7.7 Hz), 7.52 (1H, dd, J)
= 1.1, 7.7 Hz), 7.94 (1H, d, J =
6.4 Hz), 8.26 (1H, dd, J = 1.1,
7.7 Hz), 11.8 (1H, s). mass: 408 (M + 1) ⁺ .

Examples 404-405 The compounds of Example 404 and Example 405 were prepared according to Example 40.
6 was prepared. Example 404 mass: 385 (M + 1) ⁺ .

Example 405 mass: 359 (M + 1) ⁺ .

Example 1406 (1) The target compound was obtained using indole according to Reference Example 2.

(2) Example 1 using the compound of (1)
The title compound was obtained according to 29. mass: 355 (M + 1) ⁺ .

[1147] The compound of Example 407 Example 407 was prepared analogously to Example 408. mass: 363 (M + 1) ⁺ .

Example 408 (1) Using the compound of (1) in Example 406, the intended product was obtained according to Reference Example 3.

(2) Example 1 using the compound of (1)
The title compound was obtained according to the following procedure. mass: 357 (M + 1) ⁺ .

Example 409 (1) 2-Chloro-3-nitrobenzoic acid 3 g, aminomalonic acid diethyl ester hydrochloride 3.47 g, HOBt
Monohydrate 2.51 g, triethylamine 3.11 ml
And a mixture of 36 ml of dimethylformamide and ice-cooled,
3.37 g of WSC hydrochloride was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with 200 ml of ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated to obtain a crude solid product. After washing with ethyl acetate, 2.49 g of primary crystals and 0.895 g of secondary crystals were obtained.

(2) Primary crystal 1.5 obtained in (1)
A solution of 0 g of dimethyl sulfoxide (30 ml) was cooled on ice, and 230 mg of sodium hydride was added.
Minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was diluted with 150 ml of ethyl acetate, and then the organic layer was separated. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered and concentrated to obtain 1.36 g of a crude product.

(3) Crude product obtained in (2)
47 g of an ethanol solution (600 ml) is heated to 100 ° C.
Stirred for 0 minutes. The reaction solution was cooled on ice and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate (1: 1 to 1)).
3: 5) to obtain 5.76 g of an ester.

(4) 5.76 g of the compound of (3) was suspended in methanol (90 ml), and after cooling with ice, 3.61 g of sodium borohydride was added in four portions.
Minutes. 2 ml of saturated ammonium chloride was added and the mixture was filtered, and the obtained solid was washed with methanol to obtain 3.48 g of a white powder.

(5) 1.00 g of the compound of (4), 650 mg of imidazole and 16 ml of dimethylformamide
Tert-butyldimethylchlorosilane 1.
50 g was added and the mixture was stirred at room temperature for 1 hour and 25 minutes. The reaction solution was diluted with 200 ml of ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate, filtered and concentrated to obtain a crude product. The following reaction was performed without purification.

(6) The whole amount of the crude product of (5) was dissolved in 100 ml of ethanol, and the same reaction as in Reference Example 3 was performed. The obtained crude crystals were washed with ether-hexane to obtain 1.13 g of an amine.

(7) 1.13 g of the compound of (6) and 2-
Example 1 using 650 mg of pyridinecarbonyl azide
1.48 g of the target compound was produced according to the method described in the above.

(8) To a solution of 1.48 g of the compound (7) in methanol (30 ml) was added concentrated hydrochloric acid (4 ml), and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed with tetrahydrofuran to obtain 1.18 g of the title compound. ^{1 H-NMR (DMSO-d} 6) 3.62 (1H, dd, J = 5.7Hz, 11Hz),
3.94 (1H, dd, J = 3.9 Hz, 11 Hz),
4.75 (1H, m), 7.09 (1H, m), 7.3
6 (2H, m), 7.44 (1H, t, J = 7.7H)
z), 7.85 (1H, m), 8.14 (1H, d, J
= 7.7 Hz), 8.31 (1H, m), 8.60 (1
H, s), 10.18 (1H, s), 10.92 (1
H, s). mass: 299 (M + 1) ⁺ .

[1158] The compound of Example 410-413 Example 410 to Example 413, Example 4
It was manufactured according to No.14. Example 410 mass: 313 (M + 1) ⁺ .

Example 411 mass: 327 (M + 1) ⁺ .

Example 412 mass: 341 (M + 1) ⁺ .

Example 413 mass: 355 (M + 1) ⁺ .

Example 414 (1) 26 mg of the compound of (6) in Example 409 was treated with dimethylformamide-tetrahydrofuran (1: 1) (1
ml), 5 mg of sodium hydride and 12 μl of benzyl bromide were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through silica gel, and the silica gel was washed with hexane-ethyl acetate (1: 1). The combined filtrate and washings were concentrated and used for the next reaction.

(2) The target compound was produced according to the method of Example 1 using the compound of (1) and 2-pyridinecarbonyl azide.

(3) The same reaction as in (8) of Example 409 was carried out using the compound of (2) to obtain 25 mg of the title compound as a pale yellow powder. ¹ H-NMR (DMSO-d ₆ ) 3.92-4.00 (2H, m), 4.34 (1H,
d, J = 11 Hz), 4.58 (1H, t, J = 4.5)
Hz), 5.20 (1H, d, J = 11 Hz), 7.1
0 (1H, m), 7.25-7.38 (5H, m),
7.43-7.50 (3H, m), 7.86 (1H,
m), 8.08 (1H, m), 8.20 (1H, m),
10.2 (1H, s), 10.5 (1H, s). mass: 389 (M + 1) ⁺ .

Examples 415-423 The compounds of Examples 415 to 423 were prepared in Example 4
It was manufactured according to No.14. Example 415 mass: 338 (M + 1) ⁺ .

Example 416 mass: 355 (M + 1) ⁺ .

Example 417 mass: 369 (M + 1) ⁺ .

Example 418 mass: 375 (M + 1) ⁺ .

Example 419 mass: 403 (M + 1) ⁺ .

Example 420 mass: 409 (M + 1) ⁺ .

Example 421 mass: 395 (M + 1) ⁺ .

Example 422 mass: 379 (M + 1) ⁺ .

Example 423 mass: 381 (M + 1) ⁺ .

[1174] The compound of Example 424-426 Example 424 to Example 426, Example 4
27. Example 424 mass: 297 (M + 1) ⁺ .

Example 425 mass: 311 (M + 1) ⁺ .

Example 426 mass: 339 (M + 1) ⁺ .

Example 427 (1) A mixture of 11 mg of the compound of Example 414, 40 μl of triethylamine and 10 μl of methanesulfonyl chloride was stirred at room temperature for 20 minutes. DBU (20 μl) was added, and the mixture was stirred at room temperature for 25 minutes and at 80 ° C. for 14.5 hours. The reaction solution was returned to room temperature, filtered through silica gel, and the silica gel was washed with hexane-ethyl acetate (1: 1). The filtrate and washings were combined and concentrated. The residue was purified by TLC (Merck Ar
t5744, chloroform-methanol (20: 1))
Then, 6.4 mg of the target compound was obtained.

(2) The compound of (1) was dissolved in a mixed solvent of ethanol and tetrahydrofuran, and the same reaction as in Reference Example 3 was performed. The obtained crude product was subjected to TLC (Merc
k Art 5744, chloroform-methanol (2
0: 1)) to give 3.8 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) 1.45 (3H, d, J = 6.6 Hz), 4.40 (1
H, d, J = 16 Hz), 4.55 (1H, q, J =
6.6 Hz), 5.08 (1H, d, J = 16 Hz),
7.02 (1H, ddd, J = 0.9, 5.1, 7.2)
Hz), 7.24-7.39 (6H, m), 7.42-
7.51 (2H, m), 7.75 (1H, ddd, J =
2.1, 7.2, 8.7 Hz), 8.13-8.17
(2H, m), 9.72 (1H, s), 10.73 (1
H, s). mass: 373 (M + 1) ⁺ .

[1179] The compound of Example 428 Example 428 was prepared analogously to Example 427. mass: 365 (M + 1) ⁺ .

Example 429 (1) 1.49 g of 2-chloro-3-nitrobenzoic acid,
A mixture of 50 μl of concentrated sulfuric acid and 50 ml of methanol was added to 22
Refluxed for hours. The reaction solution was diluted with chloroform, washed with water and saturated saline, dried over magnesium sulfate, filtered and concentrated. 1.56 g of crude product was obtained.

(2) 50 mg of the compound of (1) and 9 mg of tetrakistriphenylphosphine palladium were suspended in 1 ml of tetrahydrofuran. After degassing, 79 μl of tributyl (1-ethoxyvinyl) tin was added,
The mixture was refluxed at room temperature for 1 hour, at 50 ° C for 2 hours, and further for 2.5 hours. The reaction solution was returned to room temperature and filtered through silica gel. The silica gel was washed with hexane-ethyl acetate (3: 1), and the filtrate and the washing were combined and concentrated. The residue was purified by TLC (M
erck Art 5744, hexane-ethyl acetate (3: 1)).
mg was obtained.

(3) 1N sodium hydroxide (437 μm) was added to a solution of the compound (2) (110 mg) in ethanol (2 ml).
and stirred at room temperature for 17 hours. Concentrate the reaction,
The residue was dissolved in 4 ml of water and washed with hexane. The aqueous layer was concentrated to give 95 mg of the desired product.

(4) The same reaction as in (1) of Example 409 was carried out using 45 mg of the compound of (3) and 18 μl of aniline to obtain 45 mg of the desired product.

(5) A mixture of 45 mg of the compound of (4), 20 μl of concentrated hydrochloric acid and 2 ml of ethanol was stirred at room temperature for 50 minutes. The reaction solution was concentrated, and the obtained solid was washed with chloroform-ethyl acetate (3: 1). Washing liquid by TLC
(Merck Art 5744, hexane-ethyl acetate (3: 1)) to obtain the desired product.

(6) A chloroform solution of the compound of (5) and 30 μl of triethylsilane was cooled with ice, 23 μl of boron trifluoride etherate was added, and the mixture was stirred at room temperature for 2 hours and 45 minutes. The reaction solution was subjected to TLC (Merck Art 574).
4, hexane-ethyl acetate (3: 1)) to obtain the desired product.

(7) The compound of (6) was dissolved in ethanol, and the same reaction as in Reference Example 3 was performed.

(8) A reaction was carried out according to the method of Example 1 using 7 mg of the compound of (7) and 12 mg of 2-pyridinecarbonylazide. The crude product was purified by TLC (Mer
ckArt 5744, hexane-ethyl acetate (1:
Purification was performed under 1)) to obtain 4 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) 1.43 (3H, d, J = 6.6 Hz), 5.60 (1
H, q, J = 6.6 Hz), 7.05 (1H, m),
7.24-7.33 (2H, m), 7.46-7.57
(4H, m), 7.68-7.82 (2H, m), 8.
28-8.33 (2H, m), 9.92 (1H, s),
11.3 (1H, s). mass: 359 (M + 1) ⁺ .

[1188] The compound of Example 430 Example 430, was prepared analogously to Example 431. mass: 339 (M + 1) ⁺ .

[1189] Example 431 (9) chloroform compound 12mg and diethyl acetal 100μl of propionaldehyde (8) -
It was dissolved in 2 ml of tetrahydrofuran (1: 1), added with boron trifluoride ether complex (40 μl), and stirred at 120 ° C. for 6 hours. Add 50 μl of propionaldehyde diethyl acetal and add 200 μl of propionaldehyde diethyl acetal at 120 ° C. for 3 hours.
Stirred at ℃ ° C for 2.5 hours. The reaction solution was subjected to TLC (Merck
Art 5744, chloroform-methanol (10:
Purification by 1)) afforded 2.3 mg of the title compound. ^{1 H-NMR (DMSO-d} 6) 0.98 (3H, t, J = 7.0Hz), 1.75 (2
H, m), 3.19 (1H, t, J = 10 Hz), 4.
49 (1H, t, J = 10 Hz), 5.18 (2H,
m), 7.05 (1H, m), 7.35-7.58 (3
H, m), 7.78 (1H, m), 8.29 (2H,
m), 9.88 (1H, s), 10.8 (1H, s). mass: 339 (M + 1) ⁺ .

[1190] The compound of Example 432-437 Example 432 to Example 437, Example 4
31. Example 432 mass: 387 (M + 1 ) +.

Example 433 mass: 341 (M + 1) ⁺ .

Example 434 mass: 311 (M + 1) ⁺ .

Example 435 mass: 417 (M + 1) ⁺ .

Example 436 mass: 417 (M + 1) ⁺ .

Example 437 mass: 417 (M + 1) ⁺ .

Example 438 (1) According to Example 56, 2.00 g of 3-nitrophthalimide and 800 μl of ethanol were used to obtain 2.11 g of the target compound.

(2) 2.11 g of the compound of (1) was dissolved in 50 ml of methanol-tetrahydrofuran (1: 4) and cooled to -15 ° C., to which 360 mg of sodium borohydride was added and stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to bring the temperature to room temperature, water was added, and the mixture was extracted with chloroform. After drying the organic layer over magnesium sulfate,
Filtration and concentration. The obtained solid was washed with hexane to obtain 1.134 g of the desired product.

(3) The same reaction as in Reference Example 3 was carried out using 120 mg of the compound of (2) to obtain 70 mg of the desired product.

(4) 70 mg of the compound of (3) and 2-
26 mg of the title compound was obtained according to the method of Example 1 using 65 mg of pyridinecarbonyl azide. ^{1 H-NMR (DMSO-d} 6) 1.25 (3H, t, J = 7.2Hz), 3.42 (1
H, m), 3.71 (1H, m), 6.00 (1H,
d, J = 9.0 Hz), 6.63 (1H, d, J = 9.
0 Hz), 7.10 (1H, ddd, J = 1.0, 5.
0, 7.0 Hz), 7.30 (1H, d, J = 7.5H)
z), 7.37 (1H, dd, J = 1.0, 7.0H
z), 7.54 (1H, t, J = 7.5 Hz), 7.8
2 (1H, ddd, J = 2.1, 7.0, 7.5H
z), 8.36-8.39 (2H, m), 9.98 (1
H, s), 11.7 (1H, s). mass: 313 (M + 1) ⁺ .

Example 439 Example 439 was prepared according to Example 440. mass: 327 (M + 1) ⁺ .

Example 440 13 mg of the compound of Example 438 was dissolved in 2 ml of ethanol, and a catalytic amount of p-toluenesulfonic acid was added, followed by stirring at 90 ° C. for 1 hour. The reaction solution was concentrated, and the obtained solid was recrystallized from hexane-ethyl acetate to obtain 7.3 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) 1.01 (3H, t, J = 6.9 Hz), 1.20 (3
H, t, J = 7.1 Hz), 2.85 (1H, m),
2.60 (1H, m), 3.25 (1H, m), 3.6
4 (1H, m), 6.15 (1H.s), 7.04 (1
H, dd, J = 5.4, 6.6 Hz), 7.21 (1
H, d, J = 8.0 Hz), 7.36 (1H, d, J =
7.2Hz), 7.53 (1H, t, J = 8.0H)
z), 7.77 (1H, ddd, J = 2.1, 6.6,
7.2 Hz), 8.28 (1H, dd, J = 2.7,
5.4 Hz), 8.36 (1 H, d, J = 8.0 H)
z), 9.97 (1H, s), 11.8 (1H, s). mass: 341 (M + 1) ⁺ .

[1202] The compound of Example 441-448 Example 441 to Example 448, Example 4
Manufactured according to No. 40. Example 441 mass: 355 (M + 1) ⁺ .

Example 442 mass: 369 (M + 1) ⁺ .

Example 443 mass: 369 (M + 1) ⁺ .

Example 444 mass: 383 (M + 1) ⁺ .

Example 445 mass: 367 (M + 1) ⁺ .

Example 446 mass: 395 (M + 1) ⁺ .

Example 447 mass: 381 (M + 1) ⁺ .

Example 448 mass: 403 (M + 1) ⁺ .

Example 449 (1) (1) 2.02 g of 3-nitrophthalimide,
2.27 g of the target compound was obtained according to Example 56 using 1.20 ml of cyclopentanol.

(2) Using 2.27 g of the compound of (1), the reaction was carried out according to (2) of Example 438 to obtain 1.429 g of the desired product.

(3) A reaction was carried out according to Example 440 using 827 mg of the compound of (2), and the reaction solution was concentrated and used as it is in the next reaction.

(4) Reference Example 3 using the compound of (3)
Was carried out to obtain 772 mg of the desired product.

(5) 772 mg of the compound of (4) and 2
According to the method of Example 1 using 600 mg of -pyridinecarbonyl azide, 448 mg of the title compound was obtained. ^{1 H-NMR (DMSO-d} 6) 1.52 <8H, m>, 2.81 <3H, s>, 4.2
1 (1H, m), 6.24 (1H, s), 7.04 (1
H, ddd, J = 1.0, 5.0, 7.5 Hz), 7.
23 (1H, d, J = 7.5 Hz), 7.34 (1H,
dd, J = 1.0, 7.0 Hz), 7.52 (1H,
t, J = 7.5 Hz), 7.76 (1H, m), 8.2
4 (1H, m), 8.34 (1H, m), 9.95 (1
H, s), 11.6 (1H, s). mass: 335 (M-MeOH) +.

Example 450 25 mg of the compound of Example 449 was dissolved in ethanol, and the reaction was carried out according to Example 440.
8 mg were obtained. ^{1 H-NMR (DMSO-d} 6) 0.99 <3H, t, J = 7.5Hz>, 1.55-
2.00 <8H, m>, 2.78 (1H, m), 3.1
2 (1H, m), 4.22 (1H, m), 6.21 (1
H, s), 7.04 (1H, ddd, J = 1.0, 5.
0, 7.5 Hz), 7.20 (1H, d, J = 7.5H)
z), 7.33 (1H, d, J = 7.0 Hz), 7.5
1 (1H, t, J = 7.5 Hz), 7.77 (1H,
m), 8.27 (1H, m), 8.37 (1H, d, J
= 7.5 Hz), 9.96 (1H, s), 11.8 (1
H, s). mass: 381 (M + 1) ⁺ .

[1216] The compound of Example 451-466 Example 451 to Example 466, Example 4
67. Example 451 ¹ H-NMR (DMSO-d ₆ ) 1.55-1.99 (14H, m), 4.30 (1H,
m), 4.45 (2H, s), 7.03 (1H, m),
7.32-7.50 (3H, m), 7.76 (1H,
m), 8.15 (1H, d, J = 7.8 Hz), 8.2
8 (1H, m), 9.73 (1H, s), 10.7 (1
H, br). mass: 379 (M + 1) ⁺ .

Example 452 ¹ H-NMR (DMSO-d ₆ ) 1.10-1.70 (12H, m), 1.95 (1H,
m), 3.38 (2H, d, J = 7.8 Hz), 4.4
7 (2H, s), 7.05 (2H, m), 7.33-
7.51 (3H, m), 7.78 (1H, m), 8.0
8 (1H, d, J = 7.5 Hz), 9.75 (1H, d, J = 7.5 Hz)
s), 10.8 (1H, br). mass: 379 (M + 1) ⁺ .

Example 453 ¹ H-NMR (DMSO-d ₆ ) 1.10-1.25 (4H, m), 1.79-1.92
(4H, m), 2.10-2.22 (4H, m), 4.
12 (1H, m), 4.45 (2H, s), 7.05
(1H, m), 7.33-7.57 (3H, m), 7.
78 (1H, m), 8.18 (1H, d, J = 7.5H
z), 8.28 (1H, d, J = 2.1 Hz), 9.6
9 (1H, s), 10.6 (1H, br).

Example 454 mass: 419 (M + 1) ⁺ .

Example 455 mass: 419 (M + 1) ⁺ .

Example 456 mass: 283 (M + 1) ⁺ .

Example 457 mass: 297 (M + 1) ⁺ .

Example 458 mass: 311 (M + 1) ⁺ .

Example 459 mass: 311 (M + 1) ⁺ .

Example 460 mass: 323 (M + 1) ⁺ .

Example 461 mass: 337 (M + 1) ⁺ .

Example 462 mass: 327 (M + 1) ⁺ .

Example 463 ¹ H-NMR (DMSO-d ₆ ) 3.62 (2H, t, J = 7.5 Hz), 3.91 (3
H, s), 4.34 (2H, t, J = 7.5 Hz),
4.60 (2H, s), 7.02 (1H, m), 7.3
8-7.51 (3H, m), 7.99 (1H, m),
8.20 (1H, d, J = 7.8 Hz), 8.39 (1
H, d, J = 2.1 Hz), 9.80 (1H, s), 1
1.0 (1H, br).

Example 464 mass: 331 (M + 1) ⁺ .

Example 465 mass: 337 (M + 1) ⁺ .

Example 466 mass: 337 (M + 1) ⁺ .

Example 467 (1) Compound (20 mg, 20) of Example 449 (2)
% Palladium hydroxide-carbon catalyst 20 mg, methanol 1
A mixture of 1 ml of tetrahydrofuran and 1 ml of tetrahydrofuran was stirred at room temperature for 15 hours under a hydrogen stream. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by TLC (Merck Ar
t5744, chloroform-methanol (19: 1))
Then, 5 mg of the desired product was obtained.

(2) Using 5 mg of the compound of (1), 2 mg of the title compound was obtained as a pale yellow solid according to Example 1. mass: 337 (M + 1) +.

[1234] The compound of Example 468 Example 468 was prepared analogously to Example 467. mass: 339 (M + 1) ⁺ .

Examples 469-492 The compounds of Examples 469 to 492 were prepared according to Example 4.
93. Example 469 mass: 365 (M + 1) ⁺ .

Example 470 mass: 369 (M + 1) ⁺ .

Example 471 mass: 387 (M + 1) ⁺ .

Example 472 mass: 401 (M + 1) ⁺ .

Example 473 mass: 407 (M + 1) ⁺ .

Example 474 mass: 401 (M + 1) ⁺ .

Example 475 mass: 379 (M + 1) ⁺ .

Example 476 mass: 391 (M + 1) ⁺ .

Example 477 mass: 325 (M + 1) ⁺ .

Example 478 mass: 339 (M + 1) ⁺ .

Example 479 mass: 353 (M + 1) ⁺ .

Example 480 mass: 353 (M + 1) ⁺ .

Example 481 mass: 401 (M + 1) ⁺ .

Example 482 mass: 339 (M + 1) ⁺ .

Example 483 mass: 461 (M + 1) ⁺ .

Example 484 mass: 353 (M + 1) ⁺ .

Example 485 mass: 367 (M + 1) ⁺ .

Example 486 mass: 367 (M + 1) ⁺ .

Example 487 mass: 367 (M + 1) ⁺ .

Example 488 mass: 367 (M + 1) ⁺ .

Example 489 mass: 367 (M + 1) ⁺ .

Example 490 mass: 387 (M + 1) ⁺ .

Example 491 mass: 401 (M + 1) ⁺ .

Example 492 mass: 379 (M + 1) ⁺ .

[1259] cooling the tetrahydrofuran (2.5L) solution of Example 493 (1) 3-nitrophthalic anhydride 125g to -78 ° C., was added sodium borohydride 48.8 g, was stirred for 1 hour. 1N Hydrochloric acid was added to the reaction solution, the temperature was returned to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-20).
0, and purified with hexane-ethyl acetate (2: 1) to obtain 88.4 g of the desired product.

(2) 200 mg of the compound of (1), 3-
A mixture of 90 mg of amino-1-propanol, 500 mg of molecular sieves 3A and 3 ml of tetrahydrofuran was refluxed overnight. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was subjected to TLC (Merck Art 574).
4, hexane-ethyl acetate (1: 1)) to obtain 180 mg of the desired product.

(3) Using 180 mg of the compound of (2), 139 mg of the desired product was obtained according to Reference Example 3.

(4) Using 30 mg of the compound of (3),
36 mg of the title compound were obtained according to Example 1. ^{1 H-NMR (DMSO-d} 6) 1.50-4.30 (6H, m), 5.86 (1H,
s), 7.05 (1H, t, J = 5.0 Hz), 7.1
9 (1H, d, J = 8.0 Hz), 7.36 (1H,
d, J = 6.0 Hz), 7.53 (1H, t, J = 8.
0 Hz), 7.78 (1H, t, J = 8.0 Hz),
8.32 (1H, d, J = 5.0 Hz), 8.38 (1
H, d, J = 8.0 Hz), 9.99 (1H, s). mass: 325 (M + 1) ⁺ .

[1263] The compound of Example 494-502 Example 494 to Example 502, Example 4
93. Example 494 mass: 339 (M + 1) ⁺ .

Example 495 mass: 341 (M + 1) ⁺ .

Example 496 mass: 341 (M + 1) ⁺ .

Example 497 mass: 340 (M + 1) ⁺ .

Example 498 mass: 325 (M + 1) ⁺ .

Example 499 mass: 339 (M + 1) ⁺ .

Example 500 mass: 387 (M + 1) ⁺ .

Example 501 mass: 399 (M + 1) ⁺ .

Example 502 mass: 369 (M + 1) ⁺ .

[1272] The compound of Example 503-530 Example 503 to Example 530, Example 5
31. Example 503 mass: 498 (M + 1) ⁺ .

Example 504 mass: 546 (M + 1) ⁺ .

Example 505 mass: 558 (M + 1) ⁺ .

Example 506 mass: 528 (M + 1) ⁺ .

Example 507 mass: 524 (M + 1) ⁺ .

Example 508 mass: 528 (M + 1) ⁺ .

Example 509 mass: 546 (M + 1) ⁺ .

Example 510 mass: 560 (M + 1) ⁺ .

Example 511 mass: 566 (M + 1) ⁺ .

Example 512 mass: 560 (M + 1) ⁺ .

Example 513 mass: 538 (M + 1) ⁺ .

Example 514 mass: 550 (M + 1) ⁺ .

Example 515 mass: 484 (M + 1) ⁺ .

Example 516 mass: 560 (M + 1) ⁺ .

Example 517 mass: 498 (M + 1) ⁺ .

Example 518 mass: 512 (M + 1) ⁺ .

Example 519 mass: 512 (M + 1) ⁺ .

Example 520 mass: 560 (M + 1) ⁺ .

Example 521 mass: 512 (M + 1) ⁺ .

Example 522 mass: 526 (M + 1) ⁺ .

Example 523 mass: 526 (M + 1) ⁺ .

Example 524 mass: 526 (M + 1) ⁺ .

Example 525 mass: 526 (M + 1) ⁺ .

Example 526 mass: 526 (M + 1) ⁺ .

Example 527 mass: 546 (M + 1) ⁺ .

Example 528 mass: 560 (M + 1) ⁺ .

Example 529 mass: 538 (M + 1) ⁺ .

Example 530 mass: 599 (M + 1) ⁺ .

Example 531 (1) Picolinic acid 150 g, dimethylformamide 2
0 ml and a mixture of 500 ml of thionyl chloride at 100 ° C.
For 1 hour. The reaction solution was cooled to 0 ° C., 200 ml of methanol was added, and the mixture was diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated, washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated.
The residue was subjected to silica gel column chromatography (Wakogel C-100, hexane-ethyl acetate (2: 1 to 1:
Purification was performed in 1)) to obtain 148 g of the desired product.

(2) Using 18 g of the compound of (1) and 35 g of tributylvinyltin, the reaction was carried out according to (2) of Example 429 to obtain 16 g of the desired product.

(3) 19.7 g of the desired product was obtained according to Example 300 using 16 g of the compound of (2).

(4) Using 19.7 g of the compound (3), 14.1 g was obtained according to (1) and (2) of Reference Example 5. ¹ H-NMR (CDCl ₃ ) 1.85 (1H, m), 2.30-2.90 (5H,
m), 3.48 (1H, quintet, J = 7.0H)
z), 3.68 (2H, d, J = 7.0 Hz), 7.2
0-7.40 (5H, m), 7.45 (1H, d, J =
8.0 Hz), 8.09 (1H, s), 8.59 (1
H, d, J = 8.0 Hz).

(5) Using 50 mg of the compound of (4) and 30 mg of the compound of (3) in Example 493, 41 mg of the title compound was obtained according to Example 1. ¹ H-NMR (CDCl ₃ ) 1.60-4.60 (15H, m), 5.69 (1H,
s), 6.83 (1H, s), 6.91 (1H, d, J
= 5.0 Hz), 7.20-7.60 (6H, m),
8.13 (1H, d, J = 5.0 Hz), 8.45 (1
H, d, J = 5.0 Hz), 8.77 (1H, s). mass: 484 (M + 1) ⁺ .

[1305] The compound of Example 532 Example 532 was prepared analogously to Example 531. mass: 498 (M + 1) ⁺ .

Example 533 (1) Example 43 using 2.00 g of 3-nitrophthalimide and 1.37 g of 4-hydroxy-2-butanone
1.78 g of the target product was obtained according to 8 (1) and (2).

(2) 1.78 g of the compound of (1), 5 g of molecular sieves 3A, 1 ml of trifluoroacetic acid
And 25 ml of tetrahydrofuran were stirred at 100 ° C. overnight. The reaction solution was returned to room temperature, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate (1: 1)).
Purification was performed in 1)) to obtain 963 mg of the desired product.

(3) According to Reference Example 3, 680 mg of the target compound was obtained from 963 mg of the compound of (2).

(4) Using 30 mg of the compound of (3),
According to Example 1, 28 mg of the title compound was obtained. ^{1 H-NMR (DMSO-d} 6) 1.16 (3H, d, J = 7.0Hz), 1.70-
4.30 (5H, m), 5.95 (1H, s), 6.9
0-8.70 (7H, m), 10.0 (1H, s), 1
1.6 (1H, br). mass: 339 (M + 1) ⁺ .

Example 534 mass: 353 (M + 1) ⁺ .

Example 535 mass: 339 (M + 1) ⁺ .

[1312] Example 536 mass: 353 (M + 1 ) +.

Example 537 mass: 353 (M + 1) ⁺ .

Example 538 mass: 367 (M + 1) ⁺ .

Example 539 (1) 1.70 g of the compound of Example 493 (3)
A mixture of 5.50 g of (Boc) ₂ O, 3.00 g of 4-dimethylaminopyridine and 40 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (Wakogel C-30).
0, hexane-ethyl acetate (10: 1 to 5: 1)) to obtain 2.56 g of the desired product.

(2) A solution of 500 mg of the compound of (1) in tetrahydrofuran (25 ml) was cooled to -78 ° C.
400 μl of butyl iodide and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M) 3.6 m
1 was added, and the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate (10: 1)) to give the desired product 4
84 mg were obtained.

(3) A mixture of 484 mg of the compound of (2), 4 ml of trifluoroacetic acid and 0.4 ml of water was stirred at room temperature for 10 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (Wakogel C-300, hexane-ethyl acetate (10: 1)) to give the desired product 2
49 mg were obtained.

(4) Using 50 mg of the compound of (3),
48 mg of the title compound were obtained according to Example 1. ^{1 H-NMR (DMSO-d} 6) 0.61 (1H, m), 0.63 (3H, t, J = 7.
0 Hz), 1.00-3.80 (8H, m), 3.95
(1H, brd, J = 11 Hz), 4.18 (1H, b
rd, J = 11 Hz), 4.39 (1H, dt, J =
2.0, 11 Hz), 7.00-7.20 (2H,
m), 7.37 (1H, d, J = 7.0 Hz), 7.5
0 (1H, t, J = 8.0 Hz), 7.78 (1H,
t, J = 8.0 Hz), 8.23 (1H, d, J = 5.
0 Hz), 8.38 (1H, d, J = 8.0 Hz), 1
0.0 (1H, s), 11.8 (1H, br). mass: 381 (M + 1) ⁺ .

[1319] The compound of Example 540 Example 540, was prepared analogously to Example 541. mass: 498 (M + 1) ⁺ .

Example 541 30 mg of the compound (3) of Example 533 and Example 531
Using 50 mg of the compound of (4), 48 mg of the title compound was obtained according to Example 1. ^{1 H-NMR (DMSO-d} 6) 1.17 (3H, d, J = 7.0Hz), 1.20-
2.90 (10H, m), 3.66 (2H, s), 4.
21 (2H, m), 5.94 (1H, s), 7.04
(1H, d, J = 5.0 Hz), 7.18 (1H, d, J = 5.0 Hz)
s), 7.20-7.40 (6H, m), 7.56 (1
H, t, J = 8.0 Hz), 8.22 (1H, d, J =
5.0 Hz), 8.45 (1H, d, J = 8.0H)
z), 9.96 (1H, s), 11.7 (1H, b
r). mass: 498 (M + 1) ⁺ .

[1321] The compounds of Example 542-545 Example 542 to Example 545, Example 5
41. Example 542 mass: 512 (M + 1) ⁺ .

Example 543 mass: 512 (M + 1) ⁺ .

Example 544 mass: 512 (M + 1) ⁺ .

Example 545 mass: 526 (M + 1) ⁺ .

Example 546 (1) Example 12 was prepared using 10.1 g of 2-chloro-3-nitrobenzoic acid and 4.85 ml of hydrazine monohydrate.
9.00 g of the desired product was obtained according to 1 (1).

(2) A solution of 9.00 g of the compound of (1) in ethanol (1 L) was stirred at 150 ° C. for 15 hours in a sealed tube. The reaction solution was returned to room temperature, and the precipitated crystals were collected by filtration and dried to obtain 5.00 g of the desired product.

(3) 40 mg of the compound of (2), 1,4
29 μl of diiodobutane and dimethylformamide 1
The mixture of ml was refluxed for 15 hours. The reaction solution was returned to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by TLC (Merck Art 5744, hexane-ethyl acetate (1: 2)) to obtain the target compound 44.
mg was obtained.

(4) Using 49 mg of the compound of (3),
25 mg of the desired product was obtained according to Reference Example 3.

(5) Using 25 mg of the compound of (4),
A white solid as the title compound was obtained according to Example 1. ^{1 H-NMR (DMSO-d} 6) 1.65-1.78 (2H, m), 1.88-2.11
(2H, m), 3.39-3.50 (2H, m), 3.
80-3.96 (2H, m), 7.00-7.13 (1
H, m), 7.20-7.39 (2H, m), 7.40.
−7.49 (1H, m), 7.75-7.85 (1H,
m), 8.15-8.22 (1H, m), 8.32 (1
H, s), 9.93 (1H, s), 11.1 (1H,
s). mass: 324 (M + 1) ⁺ .

Example 547 Using the compound of Example 546 (2) and 1,3-diiodopropane, a white solid was obtained as the title compound according to Example 546 (3) to (5). ¹ H-NMR (DMSO-d ₆ ) 2.49 (2H, m), 3.55-3.71 (2H,
m), 3.71-3.81 (2H, m), 7.01-
7.10 (1H, m), 7.18-7.22 (1H,
m), 7.28-7.40 (2H, m), 7.76-
7.82 (1H, m), 8.08-8.35 (2H,
m), 9.97 (1H, s), 11.1 (1H, s).

Example 548 (1) A mixture of 9.64 g of glycolic acid ethyl ester, 13.2 ml of 4-methoxybenzyl chloride, 3.89 g of sodium hydride and 200 ml of dimethylformamide was stirred at 0 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-200, hexane-
Purification with ethyl acetate (20: 1)) gave 16.0 g of the desired product.
I got

(2) A solution of 4.11 ml of acetonitrile in 400 ml of tetrahydrofuran was cooled to −78 ° C., and a hexane solution of n-butyllithium (1.6 M) was obtained.
(46.3 ml) was added, and the compound 1 of (1) was added.
A solution of 6.0 g of tetrahydrofuran (150 ml) was added, and the temperature was raised from −78 ° C. to room temperature, followed by stirring until the raw materials disappeared. Water was added to the reaction solution, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. Ethanol 2 in organic layer
After adding 00 ml, hydrazine monohydrate 20m
and refluxed overnight. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (Wakogel C-2).
00, chloroform-methanol (98: 2)) to give 13.9 g of the desired product.

(3) 13.9 g of the compound of (2), (B
oc) ₂ O 15.1 ml, sodium hydride 2.62 g
And 300 ml of dimethylformamide were stirred at room temperature until the raw materials disappeared. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate (10: 1 to 1: 1)) to obtain 7.32 g of the desired product.

(4) Using 7.32 g of the compound of (3), 4.16 g of the desired product was obtained according to (2) of Example 118.

(5) 4.16 g of the compound of (4), 10
% Pd-carbon catalyst (3 g) and methanol-tetrahydrofuran (1: 1) (140 ml) were mixed in a hydrogen stream at 50 g.
C. and stirred for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-300, chloroform-methanol (98: 2 to 80:20)) to obtain 602 mg of the protected Boc (A) and 593 mg of the title compound. ¹ H-NMR (DMSO-d ₆ ) 0.98-1.18 (1H, m), 2.20-2.41
(2H, m), 2.60-2.78 (1H, m), 3.
03-3.60 (2H, m), 4.44 (2H, d, J
= 5.5 Hz), 4.61-4.79 (1H, m),
5.29 (1H, t, J = 5.5 Hz), 6.00 (1
H, s), 7.26 (1H, d, J = 6.7 Hz),
7.42 (1H, dd, J = 6.7, 7.9 Hz),
8.27 (1H, d, J = 7.9 Hz), 9.41 (1
H, s), 12.3 (1H, s). mass: 328 (M + 1) ⁺ .

Example 549 (1) Using 510 mg of the compound of Example 548, 295 mg of the desired product was obtained according to Example 84, (1).

(2) 121 mg of the compound of (1), 1-
Methyl piperazine 414 μl, molecular sieves 3
A 100 mg and chloroform-methanol (1:
1) 4 ml of the mixture was stirred at room temperature for 12 hours. To this, 41 mg of sodium borohydride was added and stirred until the raw materials disappeared. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-300, chloroform-methanol (20: 1 to 4: 1)) to obtain 139 mg of a racemic form of the title compound.

(3) This product was purified by HPLC (CHIRA
Optical resolution was performed by LPAK AD (Daicel Chemical Industries, Ltd.), and Rt = 8.3 min (CHIRALPAK AD).
(Daicel Chemical Industries, Ltd., 0.46φx25cm),
Ethanol, 0.5 ml / min) 6 mg of the compound of (A) as the title compound, and Rt = 11.1 min.
19 mg of the compound of (B) as the compound of Example 550
Obtained. ^{1 H-NMR (DMSO-d} 6) 0.98-1.13 (1H, m), 2.13 (3H,
s), 2.22-2.47 (10H, m), 2.51-
2.72 (1H, m), 3.42 (2H, s), 3.2
3-3.60 (2H, m), 4.62-4.78 (1
H, m), 5.96 (1H, s), 7.26 (1H,
d, J = 7.5 Hz), 7.42 (1H, dd, J =
7.5, 7.9 Hz), 8.26 (1H, d, J = 7.
9Hz), 9.44 (1H, s), 12.3 (1H,
s). mass: 410 (M + 1) ⁺ .

[1339] The compound of Example 550 Example 550, was obtained as an optical isomer of Example 549. mass: 410 (M + 1) ⁺ .

[1340] The compound of Example 551-591 Example 551 to Example 591 Example 54
It was manufactured according to 9 (2). Example 551 ¹ H-NMR (DMSO-d ₆ ) 0.82 (6H, t, J = 7.5 Hz), 0.98−
1.14 (1H, m), 1.36 (4H, dq, J =
7.2, 7.5 Hz), 2.21-2.40 (2H,
m), 2.48-2.65 (2H, m), 3.23-
3.60 (2H, m), 3.67 (2H, s), 4.6
3-4.74 (1H, m), 6.02 (1H, s),
7.26 (1H, d, J = 6.7 Hz), 7.42 (1
H, dd, J = 6.7, 8.0 Hz), 8.26 (1
H, d, J = 8.0 Hz), 9.41 (1H, s), 1
2.2 (1H, s). mass: 397 (M + 1) ⁺ .

Example 552 mass: 383 (M + 1) ⁺ .

Example 553 mass: 397 (M + 1) ⁺ .

Example 554 mass: 397 (M + 1) ⁺ .

Example 555 mass: 417 (M + 1) ⁺ .

Example 556 mass: 417 (M + 1) ⁺ .

Example 557 mass: 417 (M + 1) ⁺ .

Example 558 mass: 445 (M + 1) ⁺ .

Example 559 ¹ H-NMR (DMSO-d ₆ ) 0.98-1.14 (1H, m), 1.14 (6H,
d, J = 6.9 Hz), 2.24-2.40 (2H,
m), 2.59-2.70 (1H, m), 2.74 (1
H, dq, J = 6.9, 6.9 Hz), 3.22-3.
60 (2H, m), 4.22 (1H, d, J = 6.0H)
z), 4.64-4.73 (1H, m), 5.94 (1
H, t, J = 6.0 Hz), 6.08 (1H, s),
6.40 (1H, d, J = 7.0 Hz), 6.44 (1
H, d, J = 7.1 Hz), 6.51 (1H, s),
6.98 (1H, dd, J = 7.0, 7.1 Hz),
7.26 (1H, d, J = 7.0 Hz), 7.42 (1
H, dd, J = 7.0, 8.2 Hz), 8.25 (1
H, d, J = 8.2 Hz), 9.40 (1H, s), 1
2.3 (1H, s).

Example 560 mass: 445 (M + 1) ⁺ .

Example 561 mass: 443 (M + 1) ⁺ .

Example 562 mass: 431 (M + 1) ⁺ .

Example 563 mass: 439 (M + 1) ⁺ .

Example 564 mass: 439 (M + 1) ⁺ .

Example 565 mass: 443 (M + 1) ⁺ .

Example 566 mass: 461 (M + 1) ⁺ .

[1356] Example 567 mass: 399 (M + 1 ) +.

Example 568 mass: 399 (M + 1) ⁺ .

Example 569 mass: 491 (M + 1) ⁺ .

Example 570 mass: 438 (M + 1) ⁺ .

Example 571 mass: 493 (M + 1) ⁺ .

Example 572 mass: 425 (M + 1) ⁺ .

Example 573 mass: 427 (M + 1) ⁺ .

Example 574 mass: 500 (M + 1) ⁺ .

Example 575 mass: 436 (M + 1) ⁺ .

[1365] Example 576 mass: 413 (M + 1 ) +.

Example 577 mass: 506 (M + 1) ⁺ .

Example 578 mass: 503 (M + 1) ⁺ .

[1368] Example 579 mass: 477 (M + 1 ) +.

[1369] Example 580 mass: 473 (M + 1 ) +.

Example 581 mass: 473 (M + 1) ⁺ .

Example 582 mass: 489 (M + 1) ⁺ .

Example 583 mass: 489 (M + 1) ⁺ .

Example 584 mass: 443 (M + 1) ⁺ .

Example 585 mass: 461 (M + 1) ⁺ .

Example 586 mass: 522, 524 (M + 1) ⁺ .

Example 587 mass: 477 (M + 1) ⁺ .

Example 588 mass: 512 (M + 1) ⁺ .

Example 589 mass: 457 (M + 1) ⁺ .

Example 590 mass: 493 (M + 1) ⁺ .

Example 591 mass: 493 (M + 1) ⁺ .

Examples 592-595 The compounds of Examples 592 to 595 were prepared in Example 5
It was manufactured according to 49 (2) and (3). Example 592 mass: 477 (M + 1) ⁺ .

Example 593 mass: 477 (M + 1) ⁺ .

Example 594 mass: 477 (M + 1) ⁺ .

Example 595 mass: 477 (M + 1) ⁺ .

Example 596 Using the compound of Example 662 (62 mg), the title compound (15 mg) was obtained according to Example 290. mass: 397 (M + 1) ⁺ .

[1386] The compound of Example 597 Example 597, was prepared analogously to Example 596. mass: 491 (M + 1) ⁺ .

[1387] The compound of Example 598 Example 598, using the compound of (2) of Example 649, was prepared analogously to Example 596. mass: 501 (M + 1) ⁺ .

Example 599 (1) Using LN-benzylproline ethyl ester, the desired product was obtained according to (2) and (3) of Example 548.

(2) Using 623 mg of the compound of (1), 408 mg of the desired product was obtained according to (2) of Example 118.

(3) A mixture of 288 mg of the compound of (2) and 5 ml of hydrochloric acid-methanol was stirred at room temperature for 15 minutes. The reaction solution was concentrated, diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (99: 1)) to obtain 119 mg of a mixture of the title compounds.

(4) The compound of (3) was separated by HPLC, and Rt = 14.6 minutes (CHIRALCEL OD (Daicel Chemical Industries, Ltd., 0.46φ × 25 cm), hexane-ethanol (80:20), 0.1%). 6ml / mi
38 mg of the title compound as fraction (A) in n) and Rt
39 mg of the compound of Example 600 was obtained as a fraction (B) of = 18.3 minutes. mass: 457 (M + 1) ⁺ .

[1392] The compound of Example 600 Example 600 was obtained as a diastereomer of the compound of Example 599. ^{1 H-NMR (DMSO-d} 6) 0.98-1.04 (1H, m), 1.64-1.80
(3H, m), 2.04-2.40 (4H, m), 2.
59-2.90 (2H, m), 3.16 (1H, d, J
= 13 Hz), 3.42-3.60 (3H, m), 3.
76 (1H, d, J = 13 Hz), 4.62-4.68
(1H, m), 6.09 (1H, brs), 7.20-
7.36 (6H, m), 7.42 (1H, dd, J =
7.9, 8.0 Hz), 8.26 (1H, d, J = 7.
9Hz), 9.43 (1H, s), 12.4 (1H,
s). mass: 457 (M + 1) ⁺ .

Example 601 Using DN-benzylproline ethyl ester, Rt = 14.0 minutes (CHIRALCEL OD (Daicel Chemical Industries, Ltd., 0.46φ × 25 cm)) according to Example 599 and Example 600, Fractionation of hexane-ethanol (80:20), 0.6 ml / min) (A)
As a result, 68 mg of the title compound and 64 mg of the compound of Example 602 were obtained as a fraction (B) with an Rt of 16.8 minutes. mass: 457 (M + 1) ⁺ .

[1394] The compound of Example 602 Example 602 was obtained as a diastereomer of the compound of Example 601. mass: 457 (M + 1) ⁺ .

[1395] The compound of Example 603-607 Example 603 to Example 607, Example 5
It was manufactured according to 99 (1) to (3). Example 603 mass: 388 (M + 1) ⁺ .

Example 604 mass: 424 (M + 1) ⁺ .

Example 605 mass: 389 (M + 1) ⁺ .

Example 606 mass: 424 (M + 1) ⁺ .

[1399] Example 607 mass: 388 (M + 1 ) +.

Example 608 A mixture of 610 mg of the compound of Example 599, 300 mg of 10% Pd-carbon catalyst, 800 mg of ammonium formate and 15 ml of ethanol was refluxed for 4 hours. The reaction solution was returned to room temperature, filtered through Celite, and the filtrate was concentrated. The residue is purified by silica gel column chromatography (Silica).
gel 60N (spherical neutral)
(Kanto Chemical Co., Ltd.), chloroform-methanol (9
8: 2 to 5: 1)) to give 290 mg of the title compound. mass: 367 (M + 1) ⁺ .

Example 609 mass: 367 (M + 1) ⁺ .

Example 610 mass: 367 (M + 1) ⁺ .

Example 611 mass: 367 (M + 1) ⁺ .

[1404] The compound of Example 612 Example 612 was prepared analogously to Example 599 from (1) to (3). mass: 375 (M + 1) ⁺ .

Example 613 (1) Using 1.87 g of 2-chloro-3-cyanopyridine, 1.35 g of the desired product according to (1) of Example 118
I got

(2) Using 818 mg of the compound of (1) and N-protected compound 618 according to (3) of Example 548.
mg was obtained.

(3) Using 294 mg of the compound of (2), 45 mg of the title compound was obtained according to (2) of Example 118. ^{1 H-NMR (DMSO-d} 6) 1.04-1.20 (1H, m), 2.30-2.41
(2H, m), 2.62-2.71 (1H, m), 3.
28-3.35 (1H, m), 3.48-3.59 (1
H, m), 4.74-4.82 (1H, m), 7.12.
−7.20 (1H, m), 7.33 (1H, d, J =
7.6 Hz), 7.48 (1H, dd, J = 7.6,
7.9 Hz), 8.32 (1H, d, J = 7.9H)
z), 8.51-8.54 (2H, m), 9.80 (1
H, s), 10.2 (1H, s). mass: 349 (M + 1) ⁺ .

Examples 614 to 615 Examples 614 and 615 were produced according to (1) to (3) of Example 599. Example 614 mass: 468 (M + 1) ⁺ .

Example 615 mass: 380 (M + 1) ⁺ .

[1410] The compound of Example 616-619 Example 616 to Example 619, Example 3
It was manufactured according to (1) to (3) of Example 599 using a compound of (3) of Example 06 and a compound synthesized according to (3) of Example 306 from (2) -B of Example 306. . Example 616 mass: 366 (M + 1) ⁺ .

Example 617 mass: 366 (M + 1) ⁺ .

Example 618 mass: 473 (M + 1) ⁺ .

Example 619 mass: 473 (M + 1) ⁺ .

Examples 620-621 The compounds of Examples 620 and 621 were prepared according to Example 61.
Example 5 using the compound of Example 8 and the compound of Example 619
It was produced according to 48 (5). Example 620 mass: 383 (M + 1) ⁺ .

Example 621 mass: 383 (M + 1) ⁺ .

[1416] The compound of Example 622-625 Example 622 to Example 625, Example 3
The compound of Example 599 was obtained according to (3) from (1) using a compound of (3) of Example 06 and a compound synthesized from (2) -B of Example 306 according to (3) of Example 306. The mixture of diastereomers was analyzed by HPLC (CHIRALP).
AK AD (Daicel Chemical Industries, Ltd., 2φx25c)
m)). Example 622 mass: 471 (M + 1) ⁺ .

Example 623 mass: 471 (M + 1) ⁺ .

Example 624 mass: 471 (M + 1) ⁺ .

Example 625 mass: 471 (M + 1) ⁺ .

[1420] The compound of Example 626 Example 626, was prepared analogously to Example 599 from (1) to (3). mass: 471 (M + 1)
⁺ .

Example 627 The compound of Example 616 was produced according to Example 622. mass: 424 (M + 1) ⁺ .

Examples 628-629 The compounds of Example 628 and 629 were produced according to Example 622. Example 628 mass: 424 (M + 1) ⁺ .

Example 629 mass: 424 (M + 1) ⁺ .

Example 630 (1) The target compound was obtained in the same manner as in Example 610, using the compound of (3) in Example 599.

(2) 85 mg of the compound of (1), N-
A mixture of 81 µl of (diethylcarbamoyl) -N-methoxyformamide and 2 ml of chloroform was added at 60 ° C for 2 hours.
Stirred for hours. The reaction solution was returned to room temperature, diluted with chloroform, washed with water and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC (Merc
kArt5744, chloroform-methanol (10:
Purification in 1)) gave a mixture of diastereomers. This was separated in the same manner as in Example 549 (3) to give 4 mg of the title compound and 3 mg of the compound of Example 631. mass: 395 (M + 1) ⁺ .

Example 631 mass: 395 (M + 1) ⁺ .

Example 632 (1) A mixture of diastereomers 7 was prepared according to Example 295 using 171 mg of the compound of (1) of Example 630.
0 mg was obtained.

(2) Example 5 for the compound of (1)
The image is divided in the same manner as in (3) of 49, and
mg and Example 633 were obtained. mass: 381 (M + 1) ⁺ .

[1429] The compound of Example 633 Example 633, was obtained as a diastereomer of Example 632. mass: 381 (M + 1) ⁺ .

Example 634 42 mg of Example 636 and 120 μl of 1-butylamine
The reaction was carried out according to (2) of Example 549 using 1 and then treated with 10% hydrochloric acid-methanol and dried to obtain 22 mg of the hydrochloride of the title compound. mass: 397 (M + 1) ⁺ .

[1431] The compound of Example 635 Example 635 was prepared analogously to Example 634.

Example 636 Using 1.20 g of the compound of (6) of Example 639, the reaction was carried out according to (1) of Example 84, and then the procedure of Example 599 was carried out.
591 mg of the title compound were obtained according to (3). mass: 340 (M + 1) ⁺ .

Example 637 Using the compound of (1) of Example 639, 708 mg of the title compound was obtained according to (3) of Example 599. mass: 432 (M + 1) ⁺ .

[1434] The compound of Example 638 Example 638 was prepared analogously to Example 634.

Example 639 (1) Using ethyl 2-benzyloxypropionate, the desired product was obtained according to (1) and (2) of Example 599.

(2) Using 4.30 g of the compound of (1), a reaction was carried out according to (5) of Example 548. After removing the Boc group by adding 10% hydrochloric acid-methanol to the reaction solution, ethyl acetate was added, and the precipitated crystals were collected by filtration and dried to obtain 2.21 g of the title compound. mass: 342 (M + 1) ⁺ .

[1437] The compound of Example 640-646 Example 640 to Example 646, Example 6
34. Example 640 mass: 369 (M + 1) ⁺ .

Example 641 mass: 383 (M + 1) ⁺ .

Example 642 mass: 445 (M + 1) ⁺ .

Example 643 mass: 409 (M + 1) ⁺ .

Example 644 mass: 381 (M + 1) ⁺ .

Example 645 mass: 383 (M + 1) ⁺ .

Example 646 mass: 409 (M + 1) ⁺ .

Example 647 (1) The target compound was obtained according to Example 548 (2) using LN-benzylproline ethyl ester.

(2) A mixture of 1.34 g of the compound of (1), 243 mg of sodium hydride, 0.38 ml of methyl iodide and 20 ml of dimethylformamide was stirred at room temperature until the starting materials disappeared. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-300, chloroform-methanol (98:
Purification was performed under 2)) to obtain 350 mg of the title compound.

(3) Using 340 mg of the compound of (2), the reaction was carried out according to (2) of Example 118 to obtain 252 mg of the desired product.

(4) Diastereomer mixture 8 according to Example 610 using 252 mg of the compound (3)
6 mg were obtained. This was subjected to resolution in the same manner as in Example 549 to obtain 20 mg of the title compound and 17 mg of the diastereomer of the compound of Example 648. mass: 381 (M + 1) ⁺ .

[1448] The compound of Example 648 Example 648, was obtained with the compound of Example 647. mass: 381 (M + 1) ⁺ .

Example 649 (1) Using ethyl glycolate and benzyl bromide, the desired product was synthesized according to (1) and (2) of Example 548.

(2) A mixture of 1.31 mg of the compound (1), 271 mg of sodium hydride, 421 μl of methyl iodide and 30 ml of dimethylformamide was added at 60 ° C. for 60 hours.
Minutes. After the reaction, ordinary post-treatment is performed, and the obtained residue is subjected to silica gel column chromatography (Wakogel C).
-200, chloroform-methanol (99: 1 to 9
8: 2)) to give 593 mg of the desired product.

(3) Using 593 mg of the compound of (2), 535 mg of the desired product was obtained according to (2) of Example 118.

(4) Example 5 using the compound of (3)
48 (5), and subsequently, 176 mg of the desired product were obtained according to Example 84 (1).

(5) 30 mg of the compound of (4) and 2-
Using 100 mg of aminoindane, 31 mg of the title compound, 11 mg of the compound of Example 650 and 12 mg of the compound of Example 651 according to (2) of Example 549.
Obtained. ^{1 H-NMR (DMSO-d} 6) 0.93-1.10 (1H, m), 2.24-2.38
(2H, m), 2.52-2.63 (1H, m), 2.
67 (1H, d, J = 6.6 Hz), 2.72 (1H,
d, J = 6.6 Hz), 3.02 (1H, d, J = 7.
0 Hz), 3.08 (1H, d, J = 7.0 Hz),
3.28-3.58 (3H, m), 3.72 (3H,
s), 3.74 (2H, s), 4.71-4.80 (1
H, m), 6.08 (1H, s), 7.06-7.18.
(4H, m), 7.26 (1H, d, J = 7.4H
z), 7.43 (1H, dd, J = 7.4, 7.9H
z), 8.26 (1H, d, J = 7.9 Hz), 9.4
3 (1H, s). mass: 457 (M + 1) ⁺ .

[1454] The compound of Example 650 Example 650 was obtained as a by-product of the compound of Example 649. mass: 386 (M + 1) ⁺ .

[1455] The compound of Example 651 Example 651 was obtained as a by-product of the compound of Example 649. mass: 342 (M + 1) ⁺ .

[1456] The compound of Example 652-656 Example 652 to Example 656, Example 6
49. Example 652 mass: 487 (M + 1) ⁺ .

Example 653 mass: 475 (M + 1) ⁺ .

Example 654 mass: 535, 537 (M + 1) ⁺ .

Example 655 mass: 491 (M + 1) ⁺ .

Example 656 mass: 491 (M + 1) ⁺ .

Examples 657-687 The compounds of Examples 657 to 687 were prepared according to Example 5.
It was manufactured according to 49 (2). Example 657 mass: 383 (M + 1) ⁺ .

Example 658 mass: 409 (M + 1) ⁺ .

Example 659 mass: 417 (M + 1) ⁺ .

Example 660 mass: 369 (M + 1) ⁺ .

Example 661 mass: 369 (M + 1) ⁺ .

Example 662 ¹ H-NMR (DMSO-d ₆ ) 0.95-1.12 (1H, m), 1.36 (9H,
s), 2.22-2.38 (2H, m), 2.62-
2.75 (1H, m), 3.23-3.37 (1H,
m), 3.42-3.60 (1H, m), 4.10 (2
H, m), 4.79 (1H, dd, J = 5.9, 10H)
z), 6.47 (1H, s), 7.29 (1H, d, J
= 7.3 Hz), 7.45 (1H, t, J = 7.3H)
z), 8.22 (1H, d, J = 7.3 Hz), 9.0
9 (3H, br), 9.91 (1H, s). mass: 383 (M + 1) ⁺ .

Example 663 mass: 355 (M + 1) ⁺ .

Example 664 mass: 395 (M + 1) ⁺ .

Example 665 mass: 381 (M + 1) ⁺ .

Example 666 mass: 341 (M + 1) ⁺ .

Example 667 mass: 324 (M + 1) ⁺ .

Example 668 ¹ H-NMR (DMSO-d ₆ ) 0.90-1.20 (1H, m), 1.20-2.00
(8H, m), 2.20-2.70 (4H, m), 3.
00-3.40 (1H, m), 3.40-3.60 (1
H, m), 3.74 (2H, m), 4.69 (1H,
m), 7.25 (1H, d, J = 7.9 Hz), 7.4
1 (1H, t, J = 7.9 Hz), 8.21 (1H,
d, J = 7.9 Hz), 9.44 (1H, br), 1
2.2 (1H, br). mass: 395 (M + 1) ⁺ .

Example 669 mass: 383 (M + 1) ⁺ .

Example 670 mass: 397 (M + 1) ⁺ .

Example 671 ¹ H-NMR (DMSO-d ₆ ) 0.70-0.95 (6H, m), 0.95-1.15
(1H, m), 1.15 to 1.50 (8H, m), 2.
10-2.70 (4H, m), 3.10-3.40 (1
H, m), 3.40-3.60 (1H, m), 3.66.
(2H, s), 4.70 (1H, dd, J = 6.0, 1
1Hz), 6.01 (1H, br), 7.27 (1H,
d, J = 7.9 Hz), 7.43 (1H, t, J = 7.
9 Hz), 8.27 (1H, d, J = 7.9 Hz),
9.40 (1H, s), 12.1 (1H, br). mass: 425 (M + 1) ⁺ .

Example 672 mass: 425 (M + 1) ⁺ .

[1477] Example 673 mass: 439 (M + 1 ) +.

Example 674 mass: 411 (M + 1) ⁺ .

Example 675 mass: 397 (M + 1) ⁺ .

Example 676 mass: 411 (M + 1) ⁺ .

Example 677 mass: 445 (M + 1) ⁺ .

Example 678 mass: 445 (M + 1) ⁺ .

Example 679 mass: 445 (M + 1) ⁺ .

Example 680 mass: 481 (M + 1) ⁺ .

Example 681 mass: 481 (M + 1) ⁺ .

Example 682 mass: 437 (M + 1) ⁺ .

Example 683 mass: 468 (M + 1) ⁺ .

Example 684 mass: 489 (M + 1) ⁺ .

Example 685 mass: 484 (M + 1) ⁺ .

Example 686 mass: 459 (M + 1) ⁺ .

Example 687 mass: 399 (M + 1) ⁺ .

Example 688 (1) 1.93 g of 2-aminoindane hydrochloride, 5.0 ml of bromine and 30 ml of acetic acid were added, and the mixture was stirred at 50 ° C. for 3 days. The reaction mixture was concentrated, and the residue was concentrated in 50 ml of chloroform.
Was dissolved. To this, 4 ml of (Boc) ₂ O and 15 ml of triethylamine were added and stirred until the raw materials disappeared. The reaction solution was washed with 1N hydrochloric acid, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200) to obtain 1.38 g of the desired product.

(2) Using 1.38 g of the compound (1), 553 mg of the desired product was obtained according to Example 599 (3).

(3) 14 g of the compound of (2), 5.85 ml of ethyl bromoacetate, 14.7 ml of triethylamine
And 100 ml of toluene were stirred overnight at room temperature. The reaction solution was diluted with ether-ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in 150 ml of chloroform, and (B
oc) was stirred at room temperature until ₂ O12.6Ml addition the starting material disappeared. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate) to obtain 11.68 g of the desired product.

(4) Using 10.13 g of the compound (3), 1.95 g of the desired product was obtained according to (2) of Example 548.

(5) An amine synthesized according to (1) to (3) of Example 533 using 3-hydroxy-2-butanone and the compound of (4) were used to prepare (2) of Example 118. A urea body was obtained according to the procedure.

(6) The compound of (5) was treated with 4N hydrochloric acid-dioxane to remove the Boc protecting group to obtain the title compound. mass: 551, 553 (M + 1) ⁺ .

Examples 689-690 The compounds of Example 689 and Example 690 were prepared according to Example 68.
8 was prepared. Example 689 ¹ H-NMR (DMSO-d ₆ ) 0.78-1.20 (7H, m), 2.24-2.78
(4H, m), 2.89-3.10 (2H, m), 3.
40-3.59 (1H, m), 3.72 (2H, s),
4.10-4.22 (1H, m), 4.78 (1H,
s), 6.10 (1H, brs), 7.27 (1H,
d, J = 6.5 Hz), 7.29 (1H, d, J = 7.
7Hz), 7.35 (1H, d, J = 6.5Hz),
7.40 (1H, s), 7.48 (1H, dd, J =
7.7, 8.5 Hz), 8.32 (1H, d, J = 8.
5Hz), 9.55 (1H, s), 12.1 (1H, b
rs). mass: 565, 567 (M + 1) ⁺ .

Example 690 mass: 551, 553 (M + 1) ⁺ .

Examples 691-692 The compounds of Example 691 and Example 692 are prepared according to Example 69.
It was manufactured according to 3. Example 691 mass: 548 (M + 1) ⁺ .

Example 692 mass: 474 (M + 1) ⁺ .

Example 693 (1) 54 mg of the compound of Example 120, trans-
Mono-Boc protected form of 1,4-diaminocyclohexane (trans-1,4-diaminocyclohexane, (Bo
c) using ₂ O and chloroform were synthesized according to the usual method) using 56 mg, of the desired product was obtained 61mg according to (1) of Example 409.

(2) Using 61 mg of the compound of (1),
37 mg of the desired product was obtained according to (2) of Example 548. ¹ H-NMR (DMSO-d ₆ ) 0.98-1.20 (1H, m), 1.48-1.53
(4H, m), 1.88-2.09 (4H, m), 2.
26-2.43 (2H, m), 2.63-2.71 (1
H, m), 2.90-3.08 (1H, m), 3.23.
-3.83 (3H, m), 4.74-4.85 (1H,
m), 6.71 (1H, s), 7.26 (1H, d, J
= 7.4 Hz), 7.44 (1H, dd, J = 7.4,
7.9 Hz), 7.54 (1H, dd, J = 7.7,
8.3 Hz), 7.80 (1H, d, J = 8.3H)
z), 7.88 (1H, d, J = 7.7 Hz), 8.0
2-8.13 (2H, br), 8.23 (1H, s),
8.26 (1H, d, J = 6.6 Hz), 8.48 (1
H, d, J = 7.9 Hz), 9.20-9.40 (1
H, br), 9.84 (1H, s). mass: 514 (M + 1) ⁺ .

[1504] The compound of Example 694-700 Example 694 to Example 700, Example 6
93. Example 694 mass: 490 (M + 1) ⁺ .

Example 695 mass: 514 (M + 1) ⁺ .

Example 696 mass: 514 (M + 1) ⁺ .

Example 697 mass: 560 (M + 1) ⁺ .

Example 698 mass: 527 (M + 1) ⁺ .

Example 699 mass: 536 (M + 1) ⁺ .

Example 700 mass: 528 (M + 1) ⁺ .

Example 701 Example 100 was repeated using 100 mg of the compound of Example 703.
69 mg of the title compound were obtained according to (4). mass: 298 (M + 1) ⁺ .

Example 702 (1) Using 3-amino-4-ethoxycarbonylpyrazole, the desired product was obtained in the same manner as in Example 703.

(2) Using 300 mg of the compound of (1), the title compound was obtained according to (4) of Example 118. mass: 370 (M + 1) ⁺ .

Example 703 (1) A mixture of 3.00 g of 3-aminopyrazole, 5.60 g of benzyl bromide, 1.72 g of sodium hydride and 30 ml of dimethylformamide was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer with magnesium sulfate,
Filtration and the filtrate were concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, hexane-ethyl acetate (3: 1 to 1: 1), and the target compound was purified to 2.8.
7 g were obtained.

(2) Using 2.89 g of the compound of (1), 989 m of the title compound according to (2) of Example 118
g was obtained. mass: 388 (M + 1) ⁺ .

Example 704 (1) A solution of 300 mg of the compound of Example 702 (1) in tetrahydrofuran (20 ml) was cooled to 0 ° C., 30 mg of lithium aluminum hydride was added, and the mixture was stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-200, hexane-
Purification with ethyl acetate (1: 1 to 1: 2) gave 248 mg of the title compound. mass: 418 (M + 1) ⁺ .

Example 705 Using 100 mg of 3-amino-1-methylpyrazole,
196 mg of the title compound was obtained according to (2) of Example 118. mass: 312 (M + 1) ⁺ .

Example 706 (1) Chlorine gas was blown into a solution of 280 mg of the compound of Reference Example 3 in chloroform (5 ml), and the resulting product was collected by filtration. This was dissolved in a mixture of aqueous sodium hydroxide and chloroform, and the organic layer was separated and concentrated. The residue was purified by TLC (Merck Art 5744, chloroform-methanol (10: 1)) to obtain 84 mg of a monochloro form (A) and 66 mg of a dichloro form (B).

(2) The title compound, a white crystal, was obtained according to Example 1 using 42 mg of the compound (1) -A. mass: 343 (M + 1) ⁺ .

Example 707 (1) A chloroform solution of 2.02 g of the compound of Reference Example 3 was cooled to −20 ° C., and 1.16 ml of bromine was added thereto.
Minutes. The reaction solution was returned to room temperature, and the precipitated solid was collected by filtration. This was dissolved in a mixture of aqueous sodium hydroxide and chloroform, and the organic layer was separated and concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, chloroform-methanol (99: 1)) to obtain 1.30 g of a monobromo compound (A) and 1.14 g of a dibromo compound (B).

(2) 1.24 g of the title compound was obtained according to Example 1 using 1.03 g of the compound (1) -A. ¹ H-NMR (DMSO-d ₆ ) 0.98-1.14 (1H, m), 2.22-2.40
(2H, m), 2.43-2.60 (1H, m), 3.
27-3.40 (1H, m), 3.49-3.60 (1
H, m), 4.73-4.80 (1H, m), 7.06
(1H, dd, J = 7.2, 12 Hz), 7.26 (1
H, d, J = 8.7 Hz), 7.59 (1H, d, J =
8.4 Hz), 7.79 (1H, ddd, J = 2.1,
8.7, 12 Hz), 8.30 (1H, dd, J = 2.
1,7.2 Hz), 8.26 (1H, d, J = 8.4H)
z), 10.0 (1H, s), 11.3 (1H, s). mass: 387, 389 (M + 1) ⁺ .

Example 708 The title compound was obtained according to Example 1 using the compound of (1) -B of Example 707. mass: 467, 469 (M + 1) ⁺ .

Example 709 The title compound was obtained according to Example 1, using 37 mg of the compound of (1) -B in Example 706. mass: 378 (M + 1) ⁺ .

Example 710 (1) 4-Nitro-1,2-benzisothiazole-
Using 100 mg of 3-one 1,1, -dioxide and 67 μl of 2-propanol, 121 mg of a pale yellow solid was obtained as a mixture of two compounds according to Example 56.

(2) Using 30 mg of the mixture of (1),
The reaction was carried out according to Reference Example 3. The crude product was purified by TLC (M
erck Art 5744, chloroform-methanol (80: 1)) to give the N-alkyl compound (A) in 6 m.
g and the O-alkyl compound (B) 20 mg were obtained.

(3) 2 mg of the title compound, a white solid, was prepared according to Example 1, using 6 mg of the compound of (2) -A.
I got ¹ H-NMR (CDCl ₃ ) 1.65 (6H, d, J = 7.8 Hz), 4.55 (1
H, dq, J = 7.8, 7.8 Hz), 6.95 (1
H, d, J = 7.8 Hz), 7.04 (1H, t, J =
6.3 Hz), 7.47 (1H, d, J = 7.5H)
z), 7.61 (1H, br), 7.66-7.78
(1H, m), 8.47 (1H, d, J = 5.7H
z), 9.00 (1H, d, J = 8.4 Hz), 13.
1 (1H, br). mass: 361 (M + 1) ⁺ .

Example 711 Using 75 mg of the compound of (2) -B of Example 710, 93 mg of the title compound was obtained as a pale yellow solid according to Example 1. ¹ H-NMR (CDCl ₃ ) 1.45 (6H, d, J = 6 Hz), 5.49 (1H,
dq, J = 6.6 Hz, 6.85 (1H, d, J =
8.1 Hz), 7.03-7.07 (1H, m), 7.0.
59-7.75 (3H, m), 8.27-8.30 (1
H, m), 8.36 (1H, d, J = 9.3 Hz), 1
1.8 (1H, br). mass: 361 (M + 1) ⁺ .

[1528] The compound of Example 712-713 Example 712 to Example 713, Example 7
10 and according to Example 711. Example 712 mass: 387 (M + 1) ⁺ .

Example 713 mass: 387 (M + 1) ⁺ .

Example 714 55 mg of the compound of Example 711 was added to tetrahydrofuran 4
The mixture was dissolved in ml, and 17 mg of sodium borohydride was added, followed by stirring at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated.
The residue was purified by TLC (Merck Art 5744, chloroform-methanol (80: 1)) to give 5 mg of the title compound as a white solid. ¹ H-NMR (DMSO-d ₆ ) 4.41 (2H, br), 7.04 (1H, t, J = 6)
Hz), 7.40 (1H, d, J = 7.2 Hz), 7.
47 (1H, d, J = 8.1 Hz), 7.56 (1H,
t, J = 8.1 Hz), 7.75-7.87 (2H,
m), 8.25-8.33 (2H, m), 9.84 (1
H, s), 10.9 (1H, br). mass: 305 (M + 1) ⁺ .

Example 715 5 mg of the compound of Example 714 and 2-propanol 7
Using μl and according to Example 56, 3 mg of the title compound was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) 1.46 (3H, t, J = 7.2 Hz), 4.47 (2
H, q, J = 7.2 Hz), 4.94 (2H, s),
6.83 (1H, d, J = 8.1 Hz), 7.04 (1
H, t, J = 8.4 Hz), 7.54 (1H, d, J =
6.9 Hz), 7.61 (1H, t, J = 8.1H)
z), 7.73 (1H, t, J = 8.7 Hz), 7.9
7 (1H, s), 8.33 (1H, d, J = 3.3H
z), 8.46 (1H, d, J = 7.8 Hz), 12.
5 (1H, s). mass: 377 (M + 1) ⁺ .

[1532]

Reference Example Reference Example 1 10.0 g of 9-fluorenone-4-carboxylic acid (44.
6 mmol), 50 ml of thionyl chloride and 1 ml of dimethylformamide were refluxed for 1 hour. The reaction solution was concentrated to obtain the desired acid chloride as a yellow solid. This was subjected to the following reaction without purification.

[1335] 4.06 g (62.5 m) of sodium azide
mol) was dissolved in 50 ml of water and cooled with ice, the acid chloride suspended in 200 ml of tetrahydrofuran was added all at once, and the reaction solution was stirred at the same temperature for 1 hour.
The reaction solution was treated with tetrahydrofuran-ethyl acetate (10: 1)
The organic layer was separated, washed with saturated saline and dried over magnesium sulfate. The filtrate was concentrated, and the precipitated crystals were filtered to obtain 10.3 g of the desired compound. ¹ H-NMR (CDCl ₃ ) δ: 7.29-7.43 (2
H, m), 7.56 (1H, dt, J = 7.7 Hz,
1.3Hz), 7.75 (1H, d, J = 7.5H)
z), 7.90 (1H, dd, J = 7.3 Hz, 1.3)
Hz), 8.02 (1H, dd, J = 7.9 Hz, 1.
2Hz), 8.43 (1H, d, J = 7.9Hz). mass: 250 (M + 1) ⁺ .

Reference Example 2 (1) 2 g of 2-chloro-3-nitrobenzoic acid (10.
0 mmol) and thionyl chloride (30 ml) at room temperature.
0 mmol) was added and the reaction was refluxed for 12 hours. The reaction solution was concentrated to obtain a crude acid chloride product. 3.5 ml (50.0 mmol) of pyrrole and 7.0 ml (50.0 mmol) of triethylamine in methylene chloride (80
ml) The above acid chloride was added to the solution at room temperature, and the reaction solution was stirred at the same temperature for 6 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and filtered.
Concentration gave a crude product. Purification by silica gel column chromatography (hexane-ethyl acetate, 1: 0 to 7: 3) gave 2.43 g of a yellow oil.

(2) The yellow oil obtained in (1) 2.4
0 g (9.60 mmol) of dimethylacetamide (1
1.80 g (19.2 m) of potassium acetate was added to the solution.
mol) was added and the system was replaced with nitrogen. Here, 1.10 g of tetrakistriphenylphosphine palladium
(0.960 mmol) was added at room temperature, and the reaction solution was stirred at 130 ° C. overnight. The reaction solution was treated with ethyl acetate-ether (1:
Diluted in 2), washed successively with water and saturated saline, dried over magnesium sulfate, filtered and concentrated to obtain a crude product. Silica gel column chromatography (hexane-chloroform,
1: 0 to 1: 1) to give 2.24 g of a brown solid compound.
I got ¹ H-NMR (CDCl ₃ ) δ: 6.34 (1 H, t, J
= 3.2 Hz), 7.10 (1H, dd, J = 3.3H)
z, 0.85 Hz), 7.21 (1H, m), 7.35
(1H, dd, J = 8.3 Hz, 7.3 Hz), 7.9
7. 4 (1H, dd, J = 7.3 Hz, 1.0 Hz);
28 (1H, dd, J = 8.5 Hz, 1.0 Hz).

Reference Example 3 To a solution of 2.24 g of the compound of Reference Example 2 in 80 ml of methanol-tetrahydrofuran (1: 1) was added 0.200 g of a 10% palladium-carbon catalyst at room temperature, and the reaction mixture was added at room temperature under a hydrogen stream at room temperature. Stirred for hours. The insolubles were filtered through celite, and the filtrate was concentrated. The obtained residue is subjected to silica gel column chromatography (chloroform-methanol, 1: 1,
0 to 98: 2 to 95: 5) to obtain 1.03 g of a brown solid compound (the compound of Reference Example 3). ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-0.93
(1H, m), 2.10-2.30 (2H, m), 2.
43-2.51 (1H, m), 3.18-3.24 (1
H, m), 3.38-3.47 (1H, m), 4.50
(1H, dd, J = 10 Hz, 5.5 Hz), 5.34
(2H, s), 6.72 (1H, d, J = 7.9H)
z), 6.76 (1H, d, J = 7.4 Hz), 7.1
1 (1H, t, J = 7.6 Hz).

Reference Example 4 (1) Under a nitrogen stream, ethanol (90 ml) was ice-cooled, 500 mg (22 mmol) of sodium was added, and the reaction solution was stirred at room temperature for 50 minutes. The reaction was cooled on ice,
4- [2-[[(1,1-dimethylethyl) diphenylsilyl] oxy] ethyl] -2-pyridinecarbonitrile 45 g (120 mmol) of ethanol (150 m
l) The solution was added over 15 minutes and the reaction was allowed to come to room temperature and
Stirred for hours. The reaction mixture was cooled with ice to 120 ml of 1N hydrochloric acid (1 ml).
After adding 20 mmol), the reaction solution was further added with 50 ml of water at the same temperature and extracted with ethyl acetate. The organic layer was washed sequentially with water, 1N sodium hydroxide and saturated saline, dried over magnesium sulfate, filtered and concentrated to obtain a brown oil. Purification by silica gel column chromatography (hexane-ethyl acetate, 2: 1 to 1: 1) gave 42 g of a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (9H, s),
1.45 (3H, t, J = 7.0 Hz), 2.89 (2
H, t, J = 6.3 Hz), 3.90 (2H, t, J =
6.3 Hz), 4.49 (2H, q, J = 7.0H)
z), 7.28 (1H, d, J = 4.9 Hz), 7.3
2-7.45 (6H, m), 7.55 (4H, dd),
7.99 (1H, s), 8.62 (1H, d, J = 5.
6 Hz).

Reference Example 5 (1) Hydrazine monohydrate 7.8 was added to a solution of 13 g (32 mmol) of the compound of Reference Example 4 in methanol (200 ml).
ml (160 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 19 hours. The reaction solution was diluted with chloroform and washed with saturated saline. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to obtain 14 g of a yellow oil. This was used for the next reaction without purification.

(2) A chloroform (100 ml) solution of the compound obtained in (1) was ice-cooled, and 97 ml of 1N hydrochloric acid was added.
(97 mmol) and 4.5 g of sodium sulfite (6
5 mmol), and the reaction solution was stirred at the same temperature for 40 minutes. Chloroform was added to the reaction solution, the organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to 14 g of a yellow oil.
I got This was used for the next reaction without purification.

(3) 14 g of the compound obtained in (2) (3
2.00 g (10.6 mmol) of the compound of Reference Example 3 was added to a solution of 2 mmol) in tetrahydrofuran (200 ml) at room temperature, and the reaction solution was stirred at 95 ° C. for 2.5 hours.
The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 1 to 1: 2) to obtain 8.0 g of pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s),
1.22-1.37 (1H, m), 2.33-2.47
(2H, m), 2.58-2.65 (1H, m), 2.
81 (2H, t, J = 6.3 Hz), 3.45 (1H,
t, J = 10 Hz), 3.78 (1H, dt), 3.9
0 (2H, t, J = 6.3 Hz), 4.80 (1H, d
d), 6.53 (1H, s), 6.82 (1H, d, J
= 5.2 Hz), 7.30-7.47 (8H, m),
7.53-7.58 (5H, m), 8.07 (1H,
d, J = 4.2 Hz), 8.32 (1H, d, J = 7.
3Hz), 12.0 (1H, s).

Reference Example 6 When 8.0 g (14 mmol) of the compound of Reference Example 5 was dissolved in 50 ml of chloroform, 71.44 g (2.38 mol) of paraformaldehyde and 250 ml (2.38 mol) of tert-butylamine were stirred at room temperature. 50 ml of the imine prepared above and 1 drop of concentrated sulfuric acid were added, and the reaction solution was stirred at 95 ° C. for 3 days. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 3: 1 to 1: 1 to 1: 2) to obtain 7.0 g of a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (9H, s),
0.98-1.02 (1H, m), 1.28 (9H,
s), 2.20-2.35 (3H, m), 2.80 (2
H, t, J = 6.0 Hz), 3.33-3.42 (1
H, m), 3.64-3.73 (1H, m), 3.86
(2H, t, J = 7.2 Hz), 4.67 (1H, d,
J = 12 Hz), 4.73-4.80 (1H, m),
4.85 (1H, d, J = 8.8 Hz), 5.05-
5.15 (1H, br), 5.43-5.52 (1H,
br), 6.86 (1H, d, J = 5.6 Hz), 7.
30-7.41 (6H, m), 7.49 (1H, d
d), 7.54-7.60 (5H, m), 7.76 (2
H, d, J = 12 Hz), 8.23 (1H, d, J =
4.8 Hz).

Reference Example 7 2.00 g of the compound of Reference Example 6 was added to tetrahydrofuran (2
0 ml), and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.0 M) 3.50 m
1 (3.50 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the precipitated crystals were collected by filtration. The filtrate was concentrated and purified by silica gel column chromatography (hexane-ethyl acetate, 1: 2-0: 1-chloroform-methanol, 50: 1). 700 mg of the target compound was obtained in combination with the crystals collected by filtration. ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.35 (1
H, m), 1.30 (9H, s), 2.20-2.40.
(3H, m), 2.83 (2H, t, J = 6.6H
z), 3.33-3.45 (1H, m), 3.61-
3.74 (1H, m), 3.78 (2H, t, J = 6.
6 Hz), 4.64-4.89 (3H, m), 5.07
−5.20 (1H, m), 5.42−5.55 (1H,
m), 6.91 (1H, d, J = 5.3 Hz), 7.4
5-7.59 (2H, m), 7.74-7.81 (2
H, m), 8.28 (1H, d, J = 5.3 Hz).

Reference Example 8 (1) 190 mg of the compound of Reference Example 7 was added to chloroform 2m
146 mg of triphenylphosphine (0.5 mg
6 mmol), 0.12 ml of diphenylphosphate azide
(0.56 mmol) and 0.24 ml (0.5%) of a toluene solution of diethyl azodicarboxylate (40%).
5 mmol) was added at room temperature, and the reaction solution was stirred at the same temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over magnesium sulfate, and concentrated by filtration. The residue was purified by thin-layer chromatography (chloroform-methanol, 19: 1) to obtain 130 mg of a pale yellow amorphous.

(2) 130 mg of the compound obtained in (1)
Was dissolved in 2 ml of methanol-tetrahydrofuran (1: 1), 130 mg of a 10% palladium carbon catalyst was added at room temperature, and the reaction solution was stirred at the same temperature for 2 hours under a hydrogen stream. The insolubles were filtered through celite and the filtrate was concentrated. The residue was purified by thin-layer chromatography (chloroform-methanol, 19:
Purify in 1) to give the title compound as a pale yellow oil (32 mg)
And 80 mg of the compound of Example 109 were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.23-1.3
5 (1H, m), 1.29 (9H, s), 2.21-
2.41 (3H, m), 2.89 (2H, brt),
3.00 (2H, brt), 3.34-3.41 (1
H, m), 3.62-3.71 (1H, m), 4.65
(1H, d, J = 12 Hz), 4.73-4.80 (1
H, m), 4.83 (1H, d, J = 12 Hz), 5.
00-5.20 (1H, br), 5.40-5.50
(1H, br), 6.81 (1H, d, J = 5.6H)
z), 7.50 (2H, t), 7.71 (2H, d, J
= 8.8 Hz), 8.26 (1H, d, J = 5.6H)
z).

Reference Example 9 800 mg of the compound of Example 81 was dissolved in 25 ml of pyridine, and 0.263 ml of methanesulfonic acid chloride was added at room temperature.
(3.40 mmol) was added, and the reaction solution was stirred at the same temperature for 1 hour. The insolubles were filtered and the filtrate was concentrated. The residue was dissolved in dimethylformamide, and 295 mg (4.54 mmol) of sodium azide was added at room temperature.
Stirred at 30 ° C for 30 minutes. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (hexane-ethyl acetate,
1: 2 to 0: 1) to give 265 mg of the desired product. ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.37 (1
H, m), 2.33-2.51 (2H, m), 2.57
-2.67 (1H, m), 2.90 (2H, t, J =
6.4 Hz), 3.46 (1 H, dt, J = 10 Hz,
3.2 Hz), 3.61 (2H, t, J = 6.4H)
z), 3.77 (1H, q), 4.77-4.84 (1
H, m), 6.81 (1H, s), 6.90 (1H,
d, J = 6.4 Hz), 7.50 (1H, t, J = 8.
0 Hz), 7.57 (1H, d, J = 4.8 Hz),
8.17 (1H, d, J = 4.8 Hz), 8.34 (1
H, d, J = 7.2 Hz), 8.76 (1H, s).

Reference Example 10 (1) p-Nitrobenzenesulfonyl chloride 5.00
g (22.6 mmol) in chloroform (50 ml) was ice-cooled and triethylamine (4.72 ml) was added.
(33.8 mmol) and 5.05 g (30.1 mmol) of 2,4-dimethoxybenzylamine were added, and the reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layers were combined, washed sequentially with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated. This was subjected to the following reaction without purification.

(2) 1.12 g of the compound obtained in (1)
And 1.00 g of the compound of Reference Example 7 in 10 ml of chloroform
Was dissolved in 758 mg of triphenylphosphine (2.8 mg).
9 mmol) and 1.26 ml (2.89 mmol) of a toluene solution of diethyl azodicarboxylate (40%)
Was added at room temperature, and the reaction solution was stirred at the same temperature for 15 hours.
The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 2-1: 4) to obtain 1.54 g of a yellow amorphous product. ¹ H-NMR (C
DCl ₃ ) δ: 1.20-1.40 (1H, m), 1.
30 (9H, s), 2.20-2.43 (3H, m),
2.74 (2H, t, J = 7.6 Hz), 3.33-
3.45 (3H, m), 3.61 (3H, s), 3.6
7-3.73 (1H, m), 3.73 (3H, s),
4.36 (2H, s), 4.66 (1H, d, J = 12
Hz), 4.71-4.80 (1H, m), 4.84
(1H, d, J = 12 Hz), 6.29 (1H, d, J)
= 4.0 Hz), 6.40 (1H, dd, J = 8.0H)
z, 4.0), 6.73 (1H, d, J = 4.0H)
z), 7.16 (1H, d, J = 8.0 Hz), 7.4
3-7.57 (3H, m), 7.67 (2H, t),
7.77 (1H, d, J = 8.0 Hz), 7.80 (2
H, d, J = 8.0 Hz), 8.19-8.22 (3
H, m).

Reference Example 11 750 mg of the compound of Reference Example 10 was dissolved in 7.5 ml of dimethylformamide, and 290 ml of sodium carbonate was added at room temperature.
g (2.74 mmol) and thiophenol 0.120 m
l (1.17 mmol) was added to the reaction solution, and the reaction solution was further stirred at room temperature for 4 days. The insolubles were filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol, 50: 1 to 9: 1 to 4: 1) to obtain 350 mg of a pale yellow amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (10H,
s), 2.10-2.37 (3H, m), 2.75-
2.90 (4H, m), 3.34-3.43 (1H,
m), 3.73-3.77 (9H, m), 4.67 (1
H, d, J = 9.6 Hz), 4.77 (1H, dd),
4.85 (1H, d, J = 9.6 Hz), 5.05-
5.15 (1H, br), 5.40-5.50 (1H,
br), 6.39 (2H, d, J = 8.0 Hz), 6.
87 (1H, d, J = 6.4 Hz), 7.09 (1H,
dd), 7.47-7.57 (2H, m), 7.75.
(2H, d, J = 6.4 Hz), 8.25 (1H, d,
J = 4.8 Hz).

[1549]

[Formulation Examples] Formulation examples of the compound of the present invention are shown below, but the formulation of the compound of the present invention is not limited to these formulation examples.

Formulation Example 1 Compound 45 (part) of Example 131, heavy magnesium oxide 15 and lactose 75 are uniformly mixed to give a powder or fine powder of 350 μm or less. This powder was placed in a capsule container to obtain a capsule.

Formulation Example 2 Compound 45 of Example 131 (part) Starch 15 Lactose 16 Crystalline cellulose 21 Polyvinyl alcohol 3 Distilled water 30 After uniformly mixed, crushed and granulated, dried, and then sieved to 1410 The granules were 177 μm in size.

Formulation Example 3 A granule was prepared in the same manner as in Formulation Example 2, and 96 parts of the granule was added with 4 parts of calcium stearate and compression-molded to prepare a tablet having a diameter of 10 mm.

Formulation Example 4 To 90 parts of the granules obtained by the method of Formulation Example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate were added and compression-molded to obtain tablets having a diameter of 8 mm. To this, a syrup gelatin and a precipitated calcium carbonate mixed suspension were added to prepare a sugar-coated tablet.

Formulation Example 5 Compound 0.6 of Example 131 (part) Nonionic surfactant 2.4 Physiological saline 97 was heated and mixed, put into an ampoule, sterilized, and injected. Produced.

[1555]

According to the present invention, the compound of the active ingredient according to the present invention has a remarkable inhibitory effect on the growth of tumor cells, and therefore, Cdk4 and / or Cdk6 for the treatment of malignant tumors. Inhibitors and the like can be provided.
According to the present invention, the composition of the present invention exhibits a remarkable growth inhibitory effect on tumor cells, and thus provides a novel Cdk4 and / or Cdk6 inhibitor for treating malignant tumors. Can be.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/426 A61K 31/426 4C072 31/428 31/428 4C086 31/437 31/437 31/4375 31 / 4375 31/44 31/44 31/4409 31/4409 31/4427 31/4427 31/4439 31/4439 31/444 31/444 31/4523 31/4523 31/454 31/454 31/496 31/496 31 / 4965 31/4965 31/505 31/505 31/506 31/506 31/5365 31/5365 31/5377 31/5377 31/553 31/553 31/695 31/695 A61P 35/00 A61P 35/00 43 / 00 111 43/00 111 C07D 453/02 C07D 453/02 // C07D 213/75 213/75 213/79 213/79 213/80 213/80 213/82 213/82 231/38 231/38 Z 231 / 52 231/52 239/42 239/42 241/20 241/20 277/48 277/48 277/82 277/82 405/12 405/12 409/12 409/12 417/12 417/12 487/04 137 487/04 137 498/04 103 498/04 103 116 116 116 498/10 A 498/10 519/00 301 519/00 301 311 311 498/04 112Q (72) Inventor Ikuko Takahashi 3 Okubo Tsukuba, Ibaraki Pref. AE14 AE20 4C050 AA01 BB04 CC04 EE01 FF05 FF10 GG01 HH04 4C055 AA01 BA02 BA03 BA06 BA52 BA53 BA58 BB02 BB17 CA02 CA06 CA08 CA16 CA42 CA51 CA52 CA57 CA58 CB02 DA01 DA06 DA13 DA52 DB02 EA01 4C063A01 CC073A01 FF01 GG20 4C072 AA01 AA04 AA06 BB02 BB06 BB07 CC01 CC11 EE03 EE06 EE09 FF03 GG07 GG08 HH02 HH07 MM01 MM02 UU01 4C086 AA01 BC17 BC36 BC42 BC48 BC50 BC80 BC82 BC84 CB03 MA05 GA05 GA05 GA05 GA05

Claims (1)

[Claims] 1. A compound of the general formula (I) [Wherein, Ar represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, isoquinolyl] A nitrogen-containing heteroaromatic group selected from the group consisting of a benzothiazolyl group and a benzooxazolyl group, 1) a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, Formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group,
Carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di Lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl group Ammonio lower alkyl group, lower alkanoylamino group,
A substituent selected from the group consisting of an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group; and a formula: Y ₁ -W during ₁ -Y ₂ -R _p (wherein, R _p is to 1 suitably a hydrogen atom or the substituent may have three, a lower alkyl group, a lower alkenyl group or a lower alkynyl group or the substituent 1 to 3 as appropriate, and furthermore A cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of Group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group,
Selected from the group consisting of benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl. Aromatic heterocyclic group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
An aliphatic heterocyclic group selected from the group consisting of a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₁ is a single bond, an oxygen atom, a sulfur atom,
O, SO _{2 ,} NR _q , SO ₂ NR _q , N (R _q ) SO ₂ NR _r ,
_{N (R q) SO 2,} CH (OR q), CONR q, N
_{(R q) CO, N (} R q) CONR r, N (R q) COO,
N ( _Rq ) CSO, N ( _Rq ) COS, C ( _Rq ) = C
R _r , C≡C, CO, CS, OC (O), OC (O) N
R _q , OC (S) NR _q , SC (O), SC (O) NR _q
Or C (O) O (where R _q and R _r represent a hydrogen atom or a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower group) Alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group, or A lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 substituents as appropriate), Y
₁ and Y ₂ are the same or different and represent a single bond or a linear or branched lower alkylene group which may have one bicyclic or tricyclic fused ring) A nitrogen-containing heteroaromatic group optionally having 1 to 3 identical or different substituents, 2) a lower alkyl group, a lower alkanoyl Group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonyl Amino lower alkyl group, lower alkyl carbamoyl group, di-lower alkyl carbamoyl group, carbamoyloxy group, Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group , A tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
On the ring to which a substituent selected from the group consisting of an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, and a lower alkanoylamidino lower alkyl group (hereinafter abbreviated as on-ring substituent) is bonded. , Its adjacent carbon atoms and carbon atoms, oxygen atoms and / or
Or together with the nitrogen atom, Or a nitrogen-containing heteroaromatic group forming a 5- to 7-membered ring selected from the group consisting of: or 3) a formula: Y ₁ -W ₁ -Y ₂ -R _p (wherein, Y ₁ , W ₁ , Y ₂₎ And R _p have the meaning described above) together with the carbon atom on the ring to which the substituent is bonded, the adjacent carbon atom, and the carbon atom, oxygen atom and / or nitrogen atom on the substituent. And The nitrogen-containing heteroaromatic ring group forming a 5- to 7-membered ring selected from the group consisting of, X and Z are the same or different,
Represents a carbon atom or a nitrogen atom, or binds as appropriate;
Together with R ₁ or R ₂ and / or R ₃ , CH or a nitrogen atom, Y is CO, SO or SO ₂ , R ₁ is a hydrogen atom or a formula: Y ₃ —W ₂ —Y ₄ —R _s (where R _s is
A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo-lower alkyl group, an aryl group, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoquinolyl group which may have 1 to 3 hydrogen atoms or the above substituents as appropriate. , Indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group,
Dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group, furyl group, Furananyl group, triazolyl group, benzodioxanyl group, methylenedioxyphenyl group, aromatic heterocyclic group selected from the group consisting of methylenedioxyphenyl group or isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group , piperazinyl group, a piperidinyl group, pyrrolidinyl group, pyrrolinyl group, a morpholino group, an aliphatic heterocyclic group selected from the group consisting tetrahydroquinolinyl group and tetrahydroisoquinolinyl group, W ₂ is a single bond Oxygen atom, a sulfur atom, SO, S
_{O 2, NR t, SO 2} NR t, N (R t) SO 2 NR u, N
(R _t ) SO ₂ , CH (OR _t ), CONR _t , N (R _t )
CO, N (R _t ) CONR _u , N (R _t ) COO, N
_{(R t) CSO, N (} R t) COS, C (R v) = CR r,
C≡C, CO, CS, OC (O), OC (O) NR _t ,
OC (S) NR _t , SC (O), SC (O) NR _t or C
(O) O (wherein, R _t and R _u is a hydrogen atom or a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group A hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group,
Carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di Lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, tri-lower alkyl group Ammonio lower alkyl group, lower alkanoylamino group,
A substituent selected from the group consisting of an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or 1 to 3 Or 3 or less, which represents a lower alkyl group, an aryl group or an aralkyl group), Y ₃ and Y ₄ are the same or different and are each a single bond or a linear or branched lower alkylene group. Or a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group Group, halo lower alkyl group, carboxy lower alkyl A kill group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group; : Y ₃ -W ₂ -Y ₄ -R _s (where R _s , W ₂ , Y ₃ and Y ₄
Is a substituent selected from the group consisting of the substituents represented by the above), and is a lower alkyl group optionally having 1 to 3 identical or different substituents, or Or a nitrogen atom is formed together with X, and R ₂ and R ₃ are the same or different and are independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a formula: Y
A substituent represented by _3- W ₂ -Y ₄ -R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the same meaning as described above), or any of R ₂ and R ₃ One forms together with R ₁ and X, And And a saturated 5- or 8-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, a carbon atom or an oxygen atom contained in a ring substituent on the ring. And / or forms a 5- to 7-membered ring with a nitrogen atom, or together forms a spirocyclo lower alkyl group, an oxo group with a bonding Z, or a nitrogen atom with a bonding Z, R ₁ and X May include one or more hetero atoms selected from the group consisting of oxygen and sulfur atoms, a lower alkyl group, a spirocyclo lower alkyl group which may have a substituent,
Hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group,
A carboxy lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group,
Lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, Di-lower alkylamino group, tri-lower alkylammonio group, amino-lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkyl-ammonio lower alkyl group,
A lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a substituent selected from the group consisting of a hydroxyimino group and a lower alkoxyimino group; : Y ₁ -W ₁ -Y ₂ -R _p (wherein, R _p , W ₁ , Y ₁ and Y ₂
Is a substituent selected from the group consisting of the substituents represented by the above), and is suitably 1 to 3 identical or different substituents, and further 1 to 3 identical or different as appropriate Cyclo lower alkyl group which may have a substituent, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group, phenazinyl group, benzimidazolyl group, benzoxazolyl group, Benzothiazolyl group Aromatic selected from the group consisting of benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl and methylenedioxyphenyl Heterocyclic group and isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
Which may be condensed with a ring selected from the group consisting of an aliphatic heterocyclic group selected from the group consisting of a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group; And Forming a saturated or unsaturated 5- to 8-membered ring group selected from the group consisting of: R ₄ and R ₅ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a group represented by the formula: Y ₃ -W _{(wherein, R s, W 2, Y} 3 and Y ₄ are as defined above) ₂ -Y ₄ -R _s substituent group or a lower alkyl group represented by a cyano group, a nitro group, a carboxyl group, Carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, hydroxy lower alkyl group, cyano lower alkyl group, halo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower Alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, di-lower alkyl A carbamoyl group, a carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino lower alkyl group, di-lower alkylamino Lower alkyl group,
Tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino group and lower alkoxyimino group A substituent selected from the group and the formula: Y ₃
-W ₂ -Y ₄ -R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the same meaning as described above), and are appropriately selected from the group consisting of Represents a lower alkyl group, an aryl group or an aralkyl group which may have 1 to 3 same or different substituents, and has the formula: Represents a single bond or a double bond] or Cdk4 and / or Cdk containing a compound thereof as an active ingredient.
dk6 inhibitors.