JP2001106673A - Biaryl urea derivatives - Google Patents

Abstract

(57) [Summary] The present invention relates to a compound represented by the general formula (I): [Wherein, Ar is a nitrogen-containing heteroaromatic group, X and Z are carbon atoms and the like, Y is CO and the like, R ₁ is a hydrogen atom and the like, R ₂ and R ₃ are hydrogen atoms and the like, R ₄ And R ₅ represent a hydrogen atom or the like, and have the formula: Represents a single bond or a double bond], and a method for producing the compound. According to the present invention, since the compound of the present invention has a remarkable inhibitory effect on the growth of tumor cells, it provides a Cdk4 and / or Cdk6 inhibitor for treating malignant tumors. Can be.

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] BACKGROUND OF THE INVENTION The present invention relates to a medicament,
Biaryl urea derivatives with disubstituted aromatic or heteroaromatic ring
Body, its production method and its use. [0001] 2. Description of the Related Art The growth of normal cells progresses according to the cell cycle.
Cell division and its arrest occur in an orderly manner
It is characterized by disordered growth of cancer cells.
That abnormalities in the cell cycle control mechanism
It is presumed to be directly related to malignant transformation. Mammal
The cell cycle of the vesicle is regulated by cyclin-dependent kinase
It is called “Cdk”. ) Serine / su called family
Cdk is regulated by leonine kinase.
A control called cyclin to express the enzyme activity of
It is necessary to form a complex with the subunit. Sa
Eclin also forms a family, with each Cd
The k molecule is a restricted cycle expressed in a cell cycle-specific manner
Form a complex with a cell molecule,
It is thought to control the line. For example, D type
Iculin binds to Cdk4 or Cdk6 and binds G1
Cyclin E-Cdk2 is G1 / S boundary
And cyclin A-Cdk2 promotes the progression of S phase.
Ecrine B-cdc2 controls the progression of G2 / M respectively
are doing. In addition, D1, D2,
D3 and three subtypes are known. Furthermore, Cdk
Is active not only in binding to cyclins, but also in Cdk molecules.
Phosphorylation / dephosphorylation, degradation of cyclin molecules and Cd
is thought to be regulated by binding to k-inhibitory protein
Advanced Cancer Research (Adva
nce Cancer Res. 66, 181
-P.212 (1995); Current Opinion I
Cell Biology (Current Opin.
  Cell Biol. ), Volume 7, 773-780
Page, (1995); Nature, No.
374, 131-134, (1995)]. [0001] Cdk inhibitory proteins in mammalian cells
Differs from the Cip / Kip family due to differences in structure and properties.
The INK4 family is roughly classified into two types. The former is broad
Inhibits the cyclin-Cdk complex, whereas the latter
Binds and specifically inhibits Cdk4 and Cdk6
You. [Nature, Vol. 366, 70
4-707, (1993); Molecular &
・ Cellular biology (Mol. Cell. B
iol. ), Vol. 15, pp. 2627-2681, (19
1995); Jeans and Development (Gen)
es Dev. 9), 1149-1163 (1
995)] A typical example of the former is, for example, p21 (Sdi1
/ Cip1 / Waf1), which is a cancer suppressor
RNA transcription is induced by the gene product p53 [G
And Developments (Genes De
v. 9, Vol. 935-944 (1995)].
On the other hand, for example, p16 (INK4a / MTS1 / CDK4
I / CDKN2) is one of the latter Cdk inhibitory proteins
One. The p16 gene is highly frequent in human cancer cells
Is present on human chromosome 9p21, which is abnormal in
Many p16 gene deletions have been reported in clinical practice
You. Also, onset of cancer in p16 knockout mice
It is reported that the frequency is high [Nature Gene
Tix (Nature Genet.), Volume 8, 2
7-32, (1994); Trends in Gene
Tix (Trends Genet.), Vol. 11,
136-140, (1995); Cell
l), Vol. 85, pp. 27-37, (1996)]. [0001] Each Cdk is a specific time in the cell cycle
Cell cycle progression by phosphorylating target proteins
Retinoblastoma (RB) protein
Is considered one of the most important target proteins.
RB protein is the key to progression from G1 phase to S phase
And undergoes rapid phosphorylation from late G1 to early S
You. Its phosphorylation is regulated by cyclin as the cell cycle progresses.
D-Cdk4 / Cdk6 complex followed by cyclin E-
It is believed that the Cdk2 complex is responsible. RB protein
If white matter becomes hyperphosphorylated, it will be low in early G1
Complex formed by oxidized form RB and transcription factor E2F
Coalescence dissociates. As a result, when E2F becomes a transcription activator,
Both suppress the promoter activity by the RB-E2F complex
Is released, and E2F-dependent transcription is activated. Current
At the same time, E2F and the RB protein that suppresses it,
Cdk4 / Cdk suppressively controls the function of RB protein
6. Cdk inhibitory proteins that regulate their kinase activity
Cdk-RB pathway consisting of and D-type cyclins
But important mechanisms that control the progression from G1 phase to S phase
[Cell, Vol. 58, 109
7-1105, (1989); Cell,
65, 1053-1061, (1991);
Oncogene, Vol. 7, 1067-
1074, (1992); Current opinion.
In Cell Biology (Current Opi
n. Cell Biol. ), Vol. 8, 805-81
Page 4, (1996); Molecular and Cellular
-Biology (Mol. Cell. Bio)
l. 18), 753-761, (1998).
Year)]. In fact, the binding DNA sequence of E2F
It is located upstream of many important cell growth related genes.
G1 late in E2F-dependent manner in multiple genes
It is reported that transcription is activated from to early S
[The Embo Journal (EMBO J.),
Vol. 9, pp. 2179-2184, (1990);
Cular and Cellular Biology (Mol.
  Cell. Biol. ), Volume 13, 1610-1
618, (1993)]. Any of the factors constituting the Cdk-RB route
Offspring abnormalities, such as deletion of functional p16 or cyclin D1
High expression, high expression of Cdk4, deletion of functional RB protein, etc.
Is frequently detected in human cancers [Science
Science, Vol. 254, 1138-114
6, (1991); Cancer Research (Can)
cer Res. ), Vol. 53, 5535-5541
Page, (1993); Current Opinion In
Le Biology (Current Opin. Cel)
l Biol. 8, Vol. 805-814, (19
1996)]. All of these progress from the G1 phase to the S phase.
Anomalies in the direction of promoting the line, this pathway is cancerous
Or play an important role in the abnormal growth of cancer cells
It is clear. A known compound having a Cdk family inhibitory action
As the compound, for example, flavopiridol (
A series of chromone derivatives represented by rabopyridol)
Are known. (WO 97/1647, 98/133
44). The compound of the present invention is structurally similar to the compound of the present invention.
As prior art, for example, WO96 / 25157
(Reference C), WO97 / 29743 (Reference B), Rice
Japanese Patent No. 5696138 (Reference C)
-115176 (Reference D). In Reference A and Reference B, the aryl group is N-
And N'-substituted urea or thiourea derivatives disclosed
Have been. However, references A and B
Between the substituted aryl group and the nitrogen-containing heteroaromatic group of the present invention
The structures are completely different from each other.
The compound is a compound that is not directly related to the present invention
It can be said. Further, the compounds described in Reference A and Reference B
Uses are related to chemokine receptor antagonists, for example,
Psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease,
It is intended as a therapeutic agent for diseases such as Zheimer's disease.
It is completely unrelated to the use of the present invention. Reference C may have one nitrogen atom.
Having an aromatic ring group and a benzene ring group which may be condensed
Urea or thiourea derivatives are disclosed. However
However, the main compound of the invention of Reference C is two phenyl
Is a urea derivative in which the N- and N'-substituted
Column 3 of the crab specification (line 11, line 13, and line 26
Line), column 5 (lines 17 and 19), column 7
(Line 13 and 15), column 17 (line 24)
And line 42), column 20 (line 14 from the bottom), etc.
Is a pyridyl group whose description is common in all places
Are N'-substituted three urea compounds.
It just does. The urea compound has an N-substituent
Are all phenyl groups, and the compound of the present invention
The structure is completely different. In the compounds of Reference C, the N-position
When the substituent is a fused benzene ring, the fused moiety is saturated and
Is defined as being either unsaturated or unsaturated
Of the fused ring portion is not mentioned, and unsubstituted
Is interpreted as a condensed ring (the present invention has an oxo group),
As can be seen from the specific disclosure of Reference C, the opening of the fused benzene ring
Since the examples shown are limited to naphthyl groups,
The compound has a different chemical structure from the compound of the present invention.
Is not directly related. Furthermore, the use of the compounds described in Reference C is
As described in column 16, potassium channelnenne
Activators, such as potassium channel dependence
For the treatment of convulsions, asthma, ischemia, etc.
It is completely unrelated to the application of the present invention.
is there. Reference D includes the triazine in Example 7.
The N-substituted group is N-substituted and the 9-fluorenone group is N-substituted.
Urea compounds have been disclosed. [0001] However, the invention of Reference D does not
The present invention relates to a photosensitive composition, that is, a photosensitive agent, and
Is an invention in which the technical field to which the invention belongs is completely different.
No compounds similar to Example 7 described above are mentioned.
Absent. The reason is that the compound of Reference D has a triazine nucleus.
A basic skeleton, in which the photoinitiating moiety contains a fluorenone group.
Several types of substituents are employed, and a photoinitiating moiety is added to the triazine nucleus.
More than ten kinds of linkages including urea
Because the combinations of groups are listed,
This is because an object group is illustrated. Therefore, the present invention
Compounds and uses of the present invention include the compounds of Example 7
Based on the description in Example D, nothing can be imagined,
Reference D can be said to be an invention not directly related to the present invention.
You. Therefore, the present invention provides a novel
Invention relating to a novel compound and a new use,
Examples which cannot be easily made based on Examples A to D
You. At the present time, Cdk6 inhibitors are
Not known physically. [0001] As described above, Cd
Compounds with k family inhibitory activity include
Conductors, but these compounds have a Cdk4
Inhibitory activity is not sufficient and compounds with even higher inhibitory activity
Things are required. For example, for Cdk6, etc.
New compounds with heterogeneous inhibitory activities are needed
I have. [0001] SUMMARY OF THE INVENTION The present inventors have developed an excellent C
Compounds having dk4 inhibitory activity or Cdk6 inhibitory activity
As a result of intensive research for the purpose of providing
A novel compound having an urea skeleton is Cdk4 and / or
Or the present invention has been found to exhibit Cdk6 inhibitory action,
Was completed. The present invention relates to a compound represented by the general formula (I): Embedded image [Wherein, Ar represents a pyridyl group, a pyrimidinyl group, a pyrazine
Nil, pyridazinyl, thiazolyl, isothiazoly
Group, oxazolyl group, isoxazolyl group, pyrazolyl
Group, pyrrolyl group, imidazolyl group, indolyl group, iso
Indolyl, quinolyl, isoquinolyl, benzothi
Selected from the group consisting of azolyl and benzoxazolyl
Selected nitrogen-containing heteroaromatic group, wherein (1) lower alkyl
Kill group, hydroxyl group, cyano group, halogen atom, nitro group,
Carboxyl, carbamoyl, formyl, lower
Lucanoyl group, lower alkanoyloxy group, hydroxy
Lower alkyl group, cyano lower alkyl group, halo lower alkyl
Kill group, carboxy lower alkyl group, 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, amino group,
Lower alkylamino group, di-lower alkylamino group, tri
Lower alkyl ammonium group, amino lower alkyl group, lower
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
Rukylsulfinyl group, lower alkylsulfonyl group, low
Primary alkylsulfonylamino group, hydroxyimino group and
Selected from the group consisting of
Substituent and formula: Y₁-W₁-Y₂-R_p(Where R
_pHas 1 to 3 hydrogen atoms or 1 to 3 substituents
Lower alkyl group, lower alkenyl group
Represents a lower alkynyl group or the substituent,
Pieces and even Embedded image A 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, isoindolyl group, indazolyl group
Group, indolyl group, indolizinyl group, isothiazolyl group
Group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazi
Nil group, pyrazolyl group, quinoxalinyl group, quinolyl
Group, dihydroisoindolyl group, dihydroindolyl
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, tetrahydropyranyl group, piperazinyl
Group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
Morpholino group, tetrahydroquinolinyl group and tetrahi
Aliphatic selected from the group consisting of droisoquinolinyl groups
Heterocyclic group, W₁Is a single bond, an oxygen atom, a sulfur atom, S
O, SO₂, NR_q, SO₂NR_q, N (R_q) SO₂
NR_r, N (R_q) SO₂, CH (OR_q), CONR
_q, N (R_q) CO, N (R_q) CONR_r, N
(R_q) COO, N (R_q) CSO, N (R_q) CO
S, C (R_q) = CR_r, C≡C, CO, CS, OC
(O), OC (O) NR_q, OC (S) NR_q, SC
(O), SC (O) NR_qOr C (O) O (here
And 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, carbamoyl group,
Formyl group, lower alkanoyl group, lower alkanoyl group
Xyl 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
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, amino group, lower alkylamino group, di-lower alkyl
Killamino group, tri-lower alkylammonio group, amino
Lower alkyl group, lower alkylamino lower alkyl group,
Di-lower alkylamino lower alkyl group, tri-lower alkyl
Luammonio lower alkyl group, lower alkanoylamino
Group, aroylamino group, lower alkanoylamidino lower
Alkyl group, lower alkylsulfinyl group, lower alkyl
Rusulfonyl group, lower alkylsulfonylamino group,
Consists of a droxyimino group and a lower alkoxyimino group
A substituent selected from the group or 1 to 3
A lower alkyl group or an aryl group which may have
Or an aralkyl group), Y₁And Y₂Are the same or
Differently, a single bond or said bicyclic or tricyclic fused ring
A linear or branched lower group which may have one
Represents an alkylene group)
Selected substituents, and optionally 1 to 3 identical or
Is a nitrogen-containing heteroaromatic ring optionally having a different substituent
Group, (2) lower alkyl group, lower alkanoyl group, lower
Alkanoyloxy group, hydroxy lower alkyl group,
Ano-lower alkyl group, halo-lower alkyl group, carboxy
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl group
Lucoxy group, lower alkoxycarbonyl group, lower alcohol
Xycarbonylamino group, lower alkoxycarbonyl group
Mino lower alkyl group, lower alkyl carbamoyl group, di
Lower alkylcarbamoyl group, carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylca
Rubamoyloxy group, lower alkylamino group, di-lower amino group
Alkylamino group, tri-lower alkylammonio group,
Lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, tri-lower alkyl group
Lucirmonio lower alkyl group, lower alkanoylua
Mino group, aroylamino group, lower alkylsulfinyl
Group, lower alkylsulfonyl group, lower alkylsulfonyl group
Ruamino group and lower alkanoylamidino lower alkyl
Substituents selected from the group consisting of
Abbreviated. ) To the carbon atom on the ring to which it is attached,
Carbon atom, oxygen atom and
And / or together with the nitrogen atom Embedded image Form a 5- to 7-membered ring selected from the group consisting of
A nitrogen-containing heteroaromatic group or the formula (3): Y₁-W₁-Y₂−
R_p(Where Y₁, W₁, Y₂And R_pHas the above meaning
A) a carbon atom on the ring to which the substituent represented by
A carbon atom on the adjacent carbon atom and the substituent,
Together with oxygen and / or nitrogen atoms, Embedded image Form a 5- to 7-membered ring selected from the group consisting of
The nitrogen-containing heteroaromatic group, X and Z are the same or different,
Represents a carbon atom or a nitrogen atom, or binds as appropriate;
R₁Or R₂And / or R₃Together with CH
Or a nitrogen atom, Y is CO, SO or SO₂, R₁Is
Hydrogen atom or formula: Y₃-W₂-Y₄-R_sWhere R
_sHas 1 to 3 hydrogen atoms or 1 to 3 substituents
Lower alkyl group, lower alkenyl group, lower
Alkynyl group, cyclo-lower alkyl group, aryl group,
Midazolyl group, isoxazolyl group, isoquinolyl group,
Isoindolyl, indazolyl, indolyl, i
Andridinyl group, isothiazolyl group, ethylenedioxy
Phenyl group, oxazolyl group, pyridyl group, pyrazinyl
Group, pyrimidinyl group, pyridazinyl group, pyrazolyl group,
Quinoxalinyl group, quinolyl group, dihydroisoindolini
, Dihydroindolyl, thionaphthenyl, naph
Tiridinyl group, phenazinyl group, benzimidazolyl
Group, benzoxazolyl group, benzothiazolyl group, ben
Zotriazolyl group, benzofuranyl group, thiazolyl group,
Thiadiazolyl, thienyl, pyrrolyl, furyl
Group, frazanyl group, triazolyl group, benzodioxani
Selected from the group consisting of
An aromatic heterocyclic group or isoxazolinyl group selected,
Isoxazolidinyl group, tetrahydropyridyl group, imi
Dazolidinyl group, tetrahydrofuranyl group, piperazini
Group, piperidinyl group, pyrrolidinyl group, pyrrolinyl
Group, morpholino group, tetrahydroquinolinyl group and tet
Fat selected from the group consisting of lahydroisoquinolinyl groups
Aliphatic heterocyclic group, W₂Is a single bond, an oxygen atom, a sulfur atom,
SO, SO₂, NR_t, SO₂NR_t, N (R_t) SO
₂NR_u, N (R_t) SO₂, CH (OR_t), CON
R_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), S
C (O) NR_tOr C (O) O (where R_tPassing
And R_uIs a hydrogen atom or a lower alkyl group, a hydroxyl group,
Cyano group, halogen atom, nitro group, carboxyl group,
Carbamoyl group, formyl group, lower alkanoyl group, low
Lower alkanoyloxy group, hydroxy lower alkyl group,
Cyano lower alkyl group, halo lower alkyl group, carboxyl
Lower alkyl group, carbamoyl lower alkyl group, lower
Alkoxy group, lower alkoxycarbonyl group, lower alkyl
Coxycarbonylamino group, lower alkoxycarbonyl
Amino lower alkyl group, lower alkyl carbamoyl group,
Di-lower alkylcarbamoyl group, carbamoyloxy
Group, lower alkylcarbamoyloxy group, di-lower alkyl
Rucarbamoyloxy group, amino group, lower alkylamido
Group, di-lower alkylamino group, tri-lower alkylan
Monio group, amino lower alkyl group, lower alkyl amino
Lower alkyl group, di-lower alkylamino lower alkyl
Group, tri-lower alkylammonio lower alkyl group, lower
Alkanoylamino group, aroylamino group, lower alk
Neuylamidino lower alkyl group, lower alkyl sulfy
Nyl group, lower alkyl sulfonyl group, lower alkyl sulf
Honylamino group, hydroxyimino group and lower alkoxy
A substituent selected from the group consisting of a simino group or the substitution
Lower alkyl optionally having 1 to 3 groups
Group, aryl group or aralkyl group), Y₃Passing
And Y₄Are the same or different and are a single bond or linear or
Represents 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: Y₃-W₂-Y₄-R_s
(Where R_s, W₂, Y₃And Y₄Has the meaning described above.
Selected from the group consisting of the substituents represented by
A group, and optionally 1 to 3 identical or different
A lower alkyl group which may have a substituent, or X
Form a nitrogen atom together with₂And R₃Are the same or different
Independently, a hydrogen atom, a hydroxyl group, a lower alkyl group,
Lower alkoxy group or formula: Y₃-W₂-Y₄-R_s
(Where R_s, W₂, Y₃And Y₄Has the meaning described above.
Or a substituent represented by₂And R₃Any of
One of them is R₁And together with X, Embedded image And Embedded image A saturated 5- to 8-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
Or together form a spirocyclo lower alkyl
Or an oxo group together with the bonding Z, or
Are the Z, R₁And a nitrogen atom, an oxygen atom and
One heteroatom selected from the group consisting of
Or a lower alkyl group,
A spirocyclo lower alkyl group which may have a substituent,
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 coxiimino groups; and
Formula: Y₁-W₁-Y₂-R_p(Where R_p, W₁, Y₁
And Y₂Has the meaning described above).
A substituent selected from the group consisting of 1 to
Three identical or different substituents, and optionally 1 to
Cyclo which may have three identical or different substituents
Lower alkyl group, aryl group, imidazolyl group, isothio
Xazolyl group, isoquinolyl group, isoindolyl group, i
Ndazolyl, indolyl, indolizinyl, iso
Thiazolyl group, ethylenedioxyphenyl group, oxazo
Ryl group, pyridyl group, pyrazinyl group, pyrimidinyl
Group, pyridazinyl group, pyrazolyl group, quinoxalinyl
Group, quinolyl group, dihydroisoindolyl group, dihydro
Indolyl, thionaphthenyl, naphthyridinyl,
Phenazinyl group, benzimidazolyl group, benzoxa
Zolyl, benzothiazolyl, benzotriazolyl
Group, benzofuranyl group, thiazolyl group, thiadiazolyl
Group, thienyl group, pyrrolyl group, furyl group, frazanyl
Group, triazolyl group, benzodioxanyl group and methyl
Aromatics selected from the group consisting of dioxyphenyl groups
Heterocyclic group, isoxazolinyl group, isoxazolidini
Group, tetrahydropyridyl group, imidazolidinyl group,
Tetrahydrofuranyl group, tetrahydropyranyl group,
Perazinyl group, piperidinyl group, pyrrolidinyl group, pyro
Linyl group, morpholino group, tetrahydroquinolinyl group and
And tetrahydroisoquinolinyl groups.
With a ring selected from the group consisting of aliphatic heterocyclic groups
May be, Embedded image And Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
Forming an 8-membered ring group;₄And R₅Are the same or different
Means hydrogen, halogen, hydroxyl, amino
Kuha formula: Y₃-W₂-Y₄-R_s(Where R_s, W₂,
Y₃And Y₄Has the meaning described above)
Or lower alkyl, cyano, nitro, carboxy
Group, carbamoyl group, formyl group, lower alkanoyl
Group, lower alkanoyloxy group, hydroxy lower alkyl
Group, cyano lower alkyl group, halo lower alkyl group,
Ruboxyl 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 coxiimino groups; and
Formula: Y₃-W₂-Y₄-R_s(Where R_s, W₂, Y₃
And Y₄Has the meaning described above)
A substituent selected from the group consisting of 1 to 3
Lower substituents which may have the same or different substituents
A alkyl group, an aryl group or an aralkyl group, Embedded image Represents a single bond or a double bond] or a compound represented by
The present invention relates to a salt thereof and a production method thereof. Next, the symbols and terms described in this specification
Will be described. A nitrogen-containing heteroaromatic group is at least
Also represents an aromatic ring group having one nitrogen atom,
Other than oxygen atoms and sulfur atoms
Represents an aromatic ring group having one or more heteroatoms.
You. Specifically, for example, a pyridyl group, a pyrimidinyl group,
Pyrazinyl, pyridazinyl, thiazolyl, isothiyl
Azolyl, oxazolyl, isoxazolyl, pyra
Zolyl, pyrrolyl, imidazolyl, indolyl
Group, isoindolyl group, quinolyl group, isoquinolyl group,
A benzothiazolyl group or a benzooxazolyl group;
And, for example, pyridyl group, pyrimidinyl group, pyrazi
Nil, pyridazinyl, thiazolyl, pyrazolyl
Or an imidazolyl group or the like, particularly, for example, pyridyl
Groups or pyrazolyl groups are particularly preferred. As the lower alkyl group, one having 1 to carbon atoms is used.
Six linear or branched alkyl groups are preferred, e.g.
For example, methyl group, ethyl group, propyl group, isopropyl
Group, butyl group, isobutyl group, sec-butyl group, t
tert-butyl group, butyl group, pentyl group, hexyl group
And the like, among which, for example, a methyl group, an ethyl group,
A tyl group and the like are preferred. A halogen atom is, for example, a fluorine atom, a salt
Atom, bromine atom, iodine atom, etc.
For example, a fluorine atom, a chlorine atom and the like are preferable. The lower alkanoyl group includes carbonyl
Substituted with an alkyl group having 1 to 5 carbon atoms
Groups, specifically, for example, acetyl, propio
Nil, butyryl, isobutyryl, valeryl, i
Sovaleryl, pivaloyl, pentanoyl and the like
For example, acetyl, propionyl, piva
Royl groups and the like are preferred. The lower alkanoyloxy group is an oxygen atom
Means a group substituted by the above lower alkanoyl group,
Physically, for example, an acetoxy group, a propionyloxy group,
Butyryloxy group, isobutyryloxy group, valerio
Xy group, isovaleryloxy group, pivaloyloxy group,
Pentanoyloxy group and the like;
Toxyl group, propionyloxy group, pivaloyloxy group
Are preferred. Hydroxy lower alkyl groups include hydroxyl
An alkyl group having 1 to 6 carbon atoms substituted by a group, etc.
Are preferred, specifically, for example, a hydroxymethyl group,
Hydroxymethyl group, trihydroxymethyl group, 1-h
Droxyethyl group, 2-hydroxyethyl group, 1-hydrido
Loxypropyl group, 2-hydroxypropyl group, 3-h
Droxypropyl group, 1-hydroxy-2-methylethyl
Group, 1-hydroxybutyl group, 1-hydroxy-2-
Methylpropyl group, 1-hydroxy-2,2-dimethyl
Ethyl group, 1-hydroxypentyl group, 1-hydroxy
-2-methylbutyl group, 1-hydroxyhexyl group, 1
-Hydroxy-2-methylpentyl group and the like;
However, for example, a hydroxymethyl group, 1-hydroxyethyl
Group, 2-hydroxyethyl group, 1-hydroxy-2-me
A tylethyl group is preferred. As the cyano lower alkyl group, a cyano group
Is substituted by an alkyl group having 1 to 6 carbon atoms, etc.
Preferably, specifically, for example, a cyanomethyl group, 1-cya
Noethyl group, 2-cyanoethyl group, 1-cyanopropyl
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-cy
Ano-2-methylbutyl group, 1-cyanohexyl group, 1
-Cyano-2-methylpentyl group and the like.
For example, a cyanomethyl group, a 1-cyanoethyl group, a 2-cya
Nosiethyl group, 1-cyano-2-methylethyl group and the like are preferred.
Good. The halo-lower alkyl group includes a halogen atom
A substituted or unsubstituted alkyl group having 1 to 6 carbon atoms
Are preferred, specifically, for example, a fluoromethyl group,
Romethyl group, bromomethyl group, iodomethyl group, difur
Oromethyl group, dichloromethyl group, trifluoromethyl
Group, 1-fluoroethyl group, 2-fluoroethyl group, 1
-Chloroethyl group, 2-chloroethyl group, 1-chlorop
Propyl 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-chloro
Lopentyl group, 1-chloro-2-methylbutyl group, 1-
Chlorohexyl group, 1-chloro-2-methylpentyl group
And the like, among which, for example, chloromethyl
Oromethyl group, 1-fluoroethyl group, 1-chloroethyl
And a 1-chloro-2-methylethyl group and the like are preferred. The carboxy lower alkyl group includes
Alkyl having 1 to 6 carbon atoms substituted by a boxy group
And specifically preferred are, for example, carboxymethyl
Group, 1-carboxyethyl group, 2-carboxyethyl
Group, 1-carboxypropyl group, 2-carboxypropyl
Group, 3-carboxypropyl group, 1-carboxy-2
-Methylethyl group, 1-carboxybutyl group, 1-cal
Boxy-2-methylpropyl group, 1-carboxy-2,
2-dimethylethyl group, 1-carboxypentyl group, 1
-Carboxy-2-methylbutyl group, 1-carboxy
A xyl group, a 1-carboxy-2-methylpentyl group, etc.
And, for example, carboxymethyl group, 1-cal
Boxyethyl group, 2-carboxyethyl group, 1-carbo
An xy-2-methylethyl group is preferred. The carbamoyl lower alkyl group includes
A group consisting of 1 to 6 carbon atoms substituted by a rubamoyl group
Preferred are alkyl groups and the like. Specifically, for example, carbamoyl
Methyl group, 1-carbamoylethyl group, 2-carbamoy
Ruethyl group, 1-carbamoylpropyl group, 2-carba
Moylpropyl group, 3-carbamoylpropyl group, 1-
Carbamoyl-2-methylethyl group, 1-carbamoyl
Butyl group, 1-carbamoyl-2-methylpropyl group,
1-carbamoyl-2,2-dimethylethyl group, 1-ca
Rubamoyl pentyl group, 1-carbamoyl-2-methyl
Butyl group, 1-carbamoylhexyl group, 1-carbamo
Yl-2-methylpentyl group and the like.
For example, a carbamoylmethyl group, a 1-carbamoylethyl group,
2-carbamoylethyl group, 1-carbamoyl-2-me
A tylethyl group is preferred. As the lower alkoxy group, a carbon atom is added to the oxygen atom.
A group substituted by an alkyl group consisting of 1 to 6 primes
Preferably, specifically, for example, a methoxy group, an ethoxy group,
Propoxy, isopropoxy, butoxy, isobut
Toxic group, sec-butoxy group, tert-butoxy
Group, pentyloxy group, neopentyloxy group, hexyl
And an isohexyloxy group.
Also for example, methoxy group, ethoxy group, isopropyloxy
Group, tert-butoxy group and the like. [0001] A lower alkoxycarbonyl group is
Means a group in which the above lower alkoxy group is substituted on the nyl group
Specifically, for example, methoxycarbonyl group, ethoxy
Carbonyl group, propoxycarbonyl group, isopropoxy
Cicarbonyl group, butoxycarbonyl group, isobutoxy
Carbonyl group, sec-butoxycarbonyl group, ter
t-butoxycarbonyl group, pentyloxycarbonyl
Group, neopentyloxycarbonyl group, hexyloxy
Carbonyl group, isohexyloxycarbonyl group, etc.
For example, methoxycarbonyl group, ethoxy
Carbonyl group, isopropyloxycarbonyl group, te
An rt-butoxycarbonyl group and the like are preferred. A lower alkylcarbamoyl group is
A substituent in which a moyl group is N-substituted by the above lower alkyl group
Represents, for example, N-methylcarbamoyl group, N-ethyl
Carbamoyl group, N-propylcarbamoyl group, N-a
Sopropylcarbamoyl group, N-butylcarbamoyl
Group, N-isobutylcarbamoyl group, N-tert-butyl
Tylcarbamoyl group, N-pentylcarbamoyl group, N
-Hexylcarbamoyl group and the like.
N-methylcarbamoyl group, N-ethylcarbamoyl
And an N-butylcarbamoyl group. The di-lower alkylcarbamoyl group is
The lower alkyl group is N, N-disubstituted to the bamoyl group.
Represents, for example, N, N-dimethylcarbamoyl
Group, N, N-diethylcarbamoyl group, N, N-dipro
Pyrcarbamoyl group, N, N-diisopropylcarbamo
Yl group, N, N-dibutylcarbamoyl group, N, N-di
Isobutylcarbamoyl group, N, N-ditert-butyl
Rucarbamoyl group, N, N-dipentylcarbamoyl
Group, N, N-dihexylcarbamoyl group, N-ethyl
-N-methylcarbamoyl group, N-methyl-N-propyl
And a carbamoyl group. Among them, for example, N, N-
Dimethylcarbamoyl group, N, N-diethylcarbamoy
Group, N, N-dibutylcarbamoyl group, N-ethyl-
N-methylcarbamoyl group, N-methyl-N-propyl
A carbamoyl group and the like are preferred. The lower alkylcarbamoyloxy group is
Oxygen atom substituted with the above lower alkylcarbamoyl group
Represents a substituent, for example, N-methylcarbamoyloxy
Group, N-ethylcarbamoyloxy group, N-propylca
Rubamoyloxy group, N-isopropylcarbamoylo
Xy group, N-butylcarbamoyloxy group, N-isobu
Tylcarbamoyloxy group, N-tert-butyl carb
Bamoyloxy group, N-pentylcarbamoyloxy
Group, N-hexylcarbamoyloxy group and the like,
Among them, for example, N-methylcarbamoyloxy group, N-E
Tylcarbamoyloxy group, N-butylcarbamoylo group
Xyl groups and the like are preferred. Di-lower alkylcarbamoyloxy group
Represents the above di-lower alkylcarbamoyl at the oxygen atom
Represents a substituted substituent, for example, N, N-dimethylcarbamo
Yloxy group, N, N-diethylcarbamoyloxy
Group, N, N-dipropylcarbamoyloxy group, N, N
-Diisopropylcarbamoyloxy group, N, N-dib
Tylcarbamoyloxy group, N, N-diisobutyl carb
Bamoyloxy group, N, N-ditert-butylcarba
Moyloxy group, N, N-dipentylcarbamoyloxy
N, N, N-dihexylcarbamoyloxy group, N
-Ethyl-N-methylcarbamoyloxy group, N-methyl
Ru-N-propylcarbamoyloxy group and the like,
Among them, for example, an N, N-dimethylcarbamoyloxy group,
N, N-diethylcarbamoyloxy group, N, N-dib
Tylcarbamoyloxy group, N-ethyl-N-methylca
Rubamoyloxy group, N-methyl-N-propylcarba
Moyloxy groups and the like are preferred. The term "lower alkylamino group" refers to an amino group
Represents a substituent in which the lower alkyl group is N-substituted, for example,
N-methylamino group, N-ethylamino group, N-pro
Pillamino group, N-isopropylamino group, N-butyl
Amino group, N-isobutylamino group, N-tert-butyl
Tylamino group, N-pentylamino group, N-hexylurea
Amino group and the like, among which, for example, N-methylamino
Group, N-ethylamino group, N-butylamino group and the like are preferable
It is. A di-lower alkylamino group refers to an amino group
A substituent in which the lower alkyl group is N, N-disubstituted;
For example, N, N-dimethylamino group, N, N-diethyl
Ruamino group, N, N-dipropylamino group, N, N-di
Isopropylamino 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-die
Tylamino group, N, N-dibutylamino group, N-ethyl
-N-methylamino group, N-methyl-N-propylamido
And the like are preferred. A tri-lower alkylammonio group is
The above lower alkyl group is N, N, N-trisubstituted to the
Represents a substituent, for example, N, N, N-trimethylammonium
O group, N, N, N-triethylammonio group, N, N,
N-tripropylammonio group, N, N, N-triiso
Propylammonio group, N, N, N-tributylammonium
Nio group, N, N, N-triisobutylammonio group,
N, N, N-tritert-butylammonio group, N,
N, N-tripentylammonio group, N, N, N-tri
Hexylammonio group, N-ethyl-N, N-dimethyl
Luammonio group, N, N-dimethyl-N-propylan
Monio group and the like, and among them, for example, N, N, N-tri
Methylammonio group, N, N, N-triethylammonium
O group, N, N, N-tributylammonio group, N-ethyl
Ru-N, N-dimethylammonio group, N, N-dimethyl
-N-propylammonio group and the like are preferable. As the amino lower alkyl group, an amino group
Is substituted by an alkyl group having 1 to 6 carbon atoms, etc.
Preferably, specifically, for example, aminomethyl group, diamino
Methyl group, triaminomethyl group, 1-aminoethyl group,
2-aminoethyl group, 1-aminopropyl group, 2-amino
Propyl group, 3-aminopropyl group, 1-amino-2
-Methylethyl group, 1-aminobutyl group, 1-amino-
2-methylpropyl group, 1-amino-2,2-dimethyl
Ethyl group, 1-aminocypentyl group, 1-amino-2-
Methylbutyl group, 1-aminohexyl group, 1-amino-
2-methylpentyl group and the like.
Nomethyl group, 1-aminoethyl group, 2-aminoethyl
And a 1-amino-2-methylethyl group and the like. The lower alkylamino lower alkyl group is
A lower alkyl group substituted with the above lower alkylamino group
Represents an N-methylaminomethyl group, N
-Ethylaminomethyl group, N-propylaminomethyl
Group, N-isopropylaminomethyl group, N-butylamido
Nomethyl group, N-isobutylaminomethyl group, N-te
rt-butylaminomethyl group, N-pentylaminomethyl
And an N-hexylaminomethyl group.
Also, for example, N-methylaminomethyl group, N-ethylamino
A methyl group, an N-butylaminomethyl group and the like are preferred. Di-lower alkylamino lower alkyl group
Is the above di-lower alkylamino group in the lower alkyl group
Represents a substituted substituent, for example, N, N-dimethylamino
Methyl group, N, N-diethylaminomethyl group, N, N-
Dipropylaminomethyl group, N, N-diisopropyla
Minomethyl group, N, N-dibutylaminomethyl group, N,
N-diisobutylaminomethyl group, N, N-ditert
-Butylaminomethyl group, N, N-dipentylaminomethyl
Tyl group, N, N-dihexylaminomethyl group, N-ethyl
Ru-N-methylaminomethyl group, N-methyl-N-pro
Pyraminomethyl group and the like.
-Dimethylaminomethyl group, N, N-diethylaminomethyl
Tyl group, N, N-dibutylaminomethyl group, N-ethyl
-N-methylaminomethyl group, N-methyl-N-propyl
Luminomethyl group and the like are preferred. Tri-lower alkyl ammonium lower alkyl
The group is defined as the above tri-lower alkyl
A substituent substituted by a monio group; for example, N, N, N-
Trimethylammoniomethyl group, N, N, N-triethyl
Luammoniomethyl group, N, N, N-tripropylan
Moniomethyl group, N, N, N-triisopropylammonium
Niomethyl group, N, N, N-tributylammoniomethy
Group, N, N, N-triisobutylammoniomethyl
Group, N, N, N-tritert-butylammoniomethy
A N, N, N-tripentylammoniomethyl group;
N, N, N-trihexylammoniomethyl group, N-E
Chill-N, N-dimethylammoniomethyl group, N, N-
And a dimethyl-N-propylammoniomethyl group.
Among them, for example, N, N, N-trimethylammoniome
A tyl group, an N, N, N-triethylammoniomethyl group,
N, N, N-tributylammoniomethyl group, N-ethyl
Ru-N, N-dimethylammoniomethyl group, N, N-di
A methyl-N-propylammoniomethyl group is preferred.
You. A lower alkanoylamino group is an amino group
Shows a substituent substituted by the lower alkanoyl group to the
For example, N-acetylamino group, N-propionylamino
Group, N-butyrylamino group and the like.
N-acetylamino group, N-propionylamino group, etc.
It is suitable. A lower aroylamino group is an amino group
A substituent substituted by a royl group;
Ruamino group, N-naphthylcarbonylamino group and the like.
Among them, for example, N-benzoylamino group is preferable.
is there. Lower alkanoylamidino lower alkyl group
Is the above-mentioned lower alkanoy in the amidino lower alkyl group.
And represents a substituent substituted with a N-acetyl group.
Dinomethyl group, N-propionylamidinomethyl group, N
-Butyrylamidinomethyl group and the like.
N-acetylamidinomethyl group, N-propionyl
A midinomethyl group and the like are preferred. [0001] The lower alkylsulfinyl group is
Represents a group in which the lower alkyl group is substituted on the ynyl group,
For example, N-methylsulfinyl group, N-ethylsphini
And an N-butylsulfinyl group.
For example, N-methylsulfinyl group, N-ethylsulfin
Nyl groups and the like are preferred. The term "lower alkylsulfonyl group" means a sulfonyl group.
Represents a group in which the lower alkyl group is substituted on the
N-methylsulfonyl group, N-ethylsulfonyl group, N
-Butylsulfonyl group and the like.
Preferred are a methylsulfonyl group, an N-ethylsulfonyl group and the like.
It is. A lower alkylsulfonylamino group is defined as
The above-mentioned lower alkylsulfonyl group is N-substituted for the amino group.
Represents, for example, N-methylsulfonylamino
Group, N-ethylsulfonylamino group, N-butylsulfonate
And an amino group such as N-methylsulfur.
Phonylamino group, N-ethylsulfonylamino group and the like are preferred.
Suitable. [0001] A lower alkoxyimino group refers to an imino group
Represents a substituent substituted by the lower alkoxy group, for example,
For example, methoxyimino group, ethoxyimino group, propoxyi
And a methoxyimino group, among others.
An ethoxyimino group and the like are preferred. The lower alkenyl group does not have 2 carbon atoms.
And preferably 6 straight-chain or branched alkenyl groups and the like.
For example, a vinyl group, a 1-propenyl group, an allyl group,
Sopropenyl group, 1-butenyl group, 3-butenyl group,
1,3-butanedienyl group, 2-pentenyl group, 4-pe
Pentenyl, 1-hexenyl, 3-hexenyl, 5
-Hexenyl group and the like.
Nil, allyl, isopropenyl, 1-butenyl
Etc. are preferred. The lower alkynyl group does not have 2 carbon atoms.
And 6 straight-chain or branched alkynyl groups are preferred.
For example, a 2-propynyl group, a 2-butynyl group,
And a 2-pentynyl group and the like.
For example, a 2-propynyl group, a 2-butynyl group and the like are preferable. As the cyclo-lower alkyl group, a compound having 3 carbon atoms
To 10 monocyclic or bicyclic alkyl groups are preferred.
For example, cyclopropyl group, cyclobutyl group,
Lopentyl group, cyclohexyl group, cycloheptyl group,
Cyclooctyl group and the like.
Methyl group, cyclohexyl group, cycloheptyl group,
A octyl group and the like are preferred. The aryl group may have 6 to 15 carbon atoms.
Are preferred, for example, a phenyl group,
Naphthyl group and the like, among them, for example, phenyl group and the like
preferable. The aromatic heterocyclic group includes, for example, imidazo
Ryl group, isoxazolyl group, isoquinolyl group, isoiyl group
Indolyl, indazolyl, indolyl, indole
Dinyl group, isothiazolyl group, ethylenedioxyphenyl
Group, oxazolyl group, pyridyl group, pyrazinyl group,
Limidinyl group, pyridazinyl group, pyrazolyl group, quinoki
Salinyl group, quinolyl group, dihydroisoindolyl group,
Dihydroindolyl group, thionaphthenyl group, naphthyridi
Nil, phenazinyl, benzimidazolyl, ben
Zoxazolyl group, benzothiazolyl group, benzotria
Zolyl, benzofuranyl, thiazolyl, thiadia
Zolyl, thienyl, pyrrolyl, furyl, furaza
Group, triazolyl group, benzodioxanyl group and
Tylenedioxyphenyl group and the like are preferable, and among them, for example,
Imidazolyl group, isoxazolyl group, isoquinolyl
Group, indolyl group, ethylenedioxyphenyl group, pyri
Jill group, pyrimidinyl group, pyridazinyl group, pyrazolyl
Group, quinolyl group, benzimidazolyl group, thiazolyl
Group, thienyl group and the like, particularly pyridyl group and pyrazo group.
Ryl groups and the like are more preferred. The term "aliphatic heterocyclic group" means a monocyclic or 2- or 2-cyclic group.
Represents an aliphatic heterocyclic group which is a condensed ring composed of three rings,
These are saturated aliphatic heterocyclic groups even if they are saturated aliphatic heterocyclic groups.
It may be a ring group. Specifically, for example, isoxazoly
Nil group, isoxazolidinyl group, tetrahydropyridyl
Group, imidazolidinyl group, tetrahydrofuranyl group,
Trahydropyranyl group, piperazinyl group, piperidinyl
Group, pyrrolidinyl group, pyrrolinyl group, morpholino group, t
Trahydroquinolinyl group, tetrahydroisoquinolinyl
And the like. Among them, for example, isoxazolinyl group,
Soxazolidinyl group, tetrahydropyridyl group, tetra
Hydrofuranyl group, tetrahydropyranyl group, piperazi
Nyl, piperidinyl, pyrrolidinyl, morpholino
Group, a tetrahydroisoquinolinyl group and the like are preferable, and in particular,
Isoxazolinyl group, tetrahydropyridyl group, pipera
Dinyl group, piperidinyl group, pyrrolidinyl group, morpholy
And a tetrahydroisoquinolinyl group are more preferred.
No. The aralkyl group has 7 to 15 carbon atoms.
Aralkyl groups and the like are preferred, and specifically, for example,
Benzyl group, α-methylbenzyl group, phenethyl group, 3
-Phenylpropyl group, 1-naphthylmethyl group, 2-na
Fthylmethyl group, α-methyl (1-naphthyl) methyl
Group, α-methyl (2-naphthyl) methyl group, α-ethyl
(1-naphthyl) methyl group, α-ethyl (2-naphthyl)
D) Methyl group, diphenylmethyl group, etc., dinaphthylmethyl
And particularly, for example, benzyl group, α-methyl
A benzyl group, a phenethyl group and the like are preferred. A linear or branched lower alkylene group
Is preferably an alkylene group having 1 to 6 carbon atoms,
Specifically, for example, methylene group, ethylene group, propylene
Group, tetramethylene group, dimethylmethylene group, diethyl
And methylene groups.
Tylene, propylene, dimethylmethylene, etc. are preferred
It is. The spirocyclo lower alkyl group includes carbon
An alkyl group or the like forming a spiro ring having a prime number of 3 to 6
Preferred, for example, spirocyclopropyl group, spirocycl
Robutyl, spirocyclopentyl, spirocyclo
Xyl groups and the like.
A tyl group, a spirocyclohexyl group and the like are preferred. Ar represents a pyridyl group, a pyrimidinyl group,
Pyrazinyl, pyridazinyl, thiazolyl, isothiyl
Azolyl, oxazolyl, isoxazolyl, pyra
Zolyl, pyrrolyl, imidazolyl, indolyl
Group, isoindolyl group, quinolyl group, isoquinolyl group,
Consists of benzothiazolyl and benzooxazolyl groups
A nitrogen-containing heteroaromatic group selected from the group
For example, pyridyl, pyrimidinyl, pyrazinyl, pyr
Dazinyl group, thiazolyl group, pyrazolyl group, imidazoly
And particularly preferably a pyridyl group and a pyrazolyl group.
Groups and the like are more preferred. The nitrogen-containing heteroaromatic group includes (1) a lower
Alkyl group, hydroxyl group, cyano group, halogen atom, nitro
Group, carboxyl group, carbamoyl group, formyl group, low
Lower alkanoyl group, lower alkanoyloxy group, hydro
Xy lower alkyl group, cyano lower alkyl group, halo lower
Alkyl group, carboxy lower alkyl group, carbamoyl
Lower alkyl group, lower alkoxy group, lower alkoxyca
Rubonyl group, lower alkylcarbamoyl group, di-lower alkyl
Kilcarbamoyl group, carbamoyloxy group, lower alkyl
Kill carbamoyloxy group, di-lower alkyl carbamoy
Luoxy group, amino group, lower alkylamino group, di-lower
Alkylamino group, tri-lower alkylammonio group,
Mino lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, tri-lower alkyl group
Lucirmonio lower alkyl group, lower alkanoylua
Mino group, aroylamino group, lower alkanoylamidino
Lower alkyl group, lower alkylsulfinyl group, lower alkyl group
Rukylsulfonyl group, lower alkylsulfonylamino
Group, hydroxyimino group and lower alkoxyimino group
And a substituent selected from the group consisting of:₁-W₁−
Y₂-R_p(Where R_pRepresents a hydrogen atom or the substituent
A lower alkyl group which may have 1 to 3
Lower alkenyl group or lower alkynyl group or
1 to 3 substituents as appropriate, Embedded image A 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, isoindolyl group, indazolyl group
Group, indolyl group, indolizinyl group, isothiazolyl group
Group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazi
Nil group, pyrazolyl group, quinoxalinyl group, quinolyl
Group, dihydroisoindolyl group, dihydroindolyl
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, tetrahydropyranyl group, piperazinyl
Group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
Morpholino group, tetrahydroquinolinyl group and tetrahi
Aliphatic selected from the group consisting of droisoquinolinyl groups
Heterocyclic group, W₁Is a single bond, an oxygen atom, a sulfur atom, S
O, SO₂, NR_q, SO₂NR_q, N (R_q) SO₂
NR_r, N (R_q) SO₂, CH (OR_q), CONR
_q, N (R_q) CO, N (R_q) CONR_r, N
(R_q) COO, N (R_q) CSO, N (R_q) CO
S, C (R_q) = CR_r, C≡C, CO, CS, OC
(O), OC (O) NR_q, OC (S) NR_q, SC
(O), SC (O) NR_qOr C (O) O (here
And 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, carbamoyl group,
Formyl group, lower alkanoyl group, lower alkanoyl group
Xyl 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
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, amino group, lower alkylamino group, di-lower alkyl
Killamino group, tri-lower alkylammonio group, amino
Lower alkyl group, lower alkylamino lower alkyl group,
Di-lower alkylamino lower alkyl group, tri-lower alkyl
Luammonio lower alkyl group, lower alkanoylamino
Group, aroylamino group, lower alkanoylamidino lower
Alkyl group, lower alkylsulfinyl group, lower alkyl
Rusulfonyl group, lower alkylsulfonylamino group,
Consists of a droxyimino group and a lower alkoxyimino group
A substituent selected from the group or 1 to 3
A lower alkyl group or an aryl group which may have
Or an aralkyl group), Y₁And Y₂Are the same or
Differently, a single bond or said bicyclic or tricyclic fused ring
A linear or branched lower group which may have one
Represents an alkylene group)
Selected substituents, and optionally 1 to 3 identical or
May have different substituents, and (2) lower alkyl
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 alkylcarbamoyl
Group, di-lower alkylcarbamoyl group, carbamoyloxy
Thio group, lower alkylcarbamoyloxy group, di-lower alkyl
Kill carbamoyloxy 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 alkyl sulf
Ynyl group, lower alkylsulfonyl group, lower alkyls
Ruphonylamino group and lower alkanoylamidino lower amine
Substituents selected from the group consisting of
Abbreviated as substituent. ) Carbon atom on the ring to which it is attached, adjacent
And the carbon atom on the substituent on the ring, oxygen
Together with atoms and / or nitrogen atoms, Embedded image Form a 5- to 7-membered ring selected from the group consisting of
Equation (3): Y₁-W₁-Y₂-R_p(formula
Medium, Y₁, W₁, Y₂And R_pHas the above meaning)
A carbon atom on the ring to which the substituent represented by
And the carbon and oxygen atoms on the substituent
And / or together with the nitrogen atom, Embedded image Form a 5- to 7-membered ring selected from the group consisting of
be able to. Here, the form of the substituent (1) will be described in detail.
To explain, specific substituents include (1-1) lower
Alkyl group, hydroxyl group, cyano group, halogen atom, nitro
Group, carboxyl group, carbamoyl group, formyl group, low
Lower alkanoyl group, lower alkanoyloxy group, hydro
Xy lower alkyl group, cyano lower alkyl group, halo lower
Alkyl group, carboxy lower alkyl group, carbamoyl
Lower alkyl group, lower alkoxy group, lower alkoxyca
Rubonyl group, lower alkylcarbamoyl group, di-lower alkyl
Kilcarbamoyl group, carbamoyloxy group, lower alkyl
Kill carbamoyloxy group, di-lower alkyl carbamoy
Luoxy group, amino group, lower alkylamino group, di-lower
Alkylamino group, tri-lower alkylammonio group,
Mino lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, tri-lower alkyl group
Lucirmonio lower alkyl group, lower alkanoylua
Mino group, aroylamino group, lower alkanoylamidino
Lower alkyl group, lower alkylsulfinyl group, lower alkyl group
Rukylsulfonyl group, lower alkylsulfonylamino
Group, hydroxyimino group and lower alkoxyimino group
And a substituent selected from the group consisting of:
₁-W₁-Y₂-R_p(Where R_pIs a hydrogen atom or low
Lower alkyl group, lower alkenyl group or lower alkynyl
Group or cyclo-lower alkyl group, aryl group, aromatic
An aromatic heterocyclic group or an aliphatic heterocyclic group, W₁Is a single bond,
Oxygen atom, sulfur atom, SO, SO₂, NR_q, SO₂N
R_q, N (R_q) SO₂NR_r, N (R_q) SO₂, C
H (OR_q), CONR_q, N (R_q) CO, N
(R_q) CONR_r, N (R_q) COO, N (R_q) C
SO, N (R_q) 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_qOr C
(O) O (where R_qAnd R_rIs a hydrogen atom,
Lower amines which may optionally have 1 to 3 substituents
Alkyl, aryl or aralkyl)), Y₁
And Y₂Are the same or different and are a single bond or the bicyclic group
Or a linear group which may have one tricyclic fused ring.
Or a branched lower alkylene group)
Substituents selected from the group consisting of substituents;
1 to 3 identical or different substituents are
It can be substituted with an aromatic ring group. In (1-1), preferred substituents are, for example,
For example, lower alkyl group, hydroxyl group, 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 alkylcarbamoy
Luoxy group, amino group, lower alkylamino group, di-lower
Alkylamino group, amino lower alkyl group, lower alkyl
L-amino lower alkyl group, di-lower alkyl amino lower group
Alkyl group, lower alkanoylamino group, aroylamino
Group, lower alkylsulfonylamino group, etc.
For example, a hydroxyl group, a halogen atom, a lower alkanoyloxy
Si group, hydroxy lower alkyl group, lower alkoxy group,
Lower alkoxycarbonyl group, amino group, lower alkyl
Amino lower alkyl groups and the like are more preferred. Formula of (1-2): Y₁-W₁-Y₂-R_p
In, R_pIs lower alkyl group or lower alkenyl group
Or a lower alkynyl group or a cyclo-lower alkyl group,
For reel, aromatic heterocyclic or aliphatic heterocyclic groups
Each of these substituents is a lower alkyl group, a hydroxyl group,
Ano group, halogen atom, nitro group, carboxyl group,
Rubamoyl group, formyl group, lower alkanoyl group, lower
Alkanoyloxy group, hydroxy lower alkyl group,
Ano-lower alkyl group, halo-lower alkyl group, carboxy
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl group
Alkoxy group, lower alkoxycarbonyl group, lower alkyl
Rucarbamoyl group, di-lower alkylcarbamoyl group,
Rubamoyloxy group, lower alkylcarbamoyloxy
Group, di-lower alkylcarbamoyloxy group, amino group,
Lower alkylamino group, di-lower alkylamino group, tri
Lower alkyl ammonium group, amino lower alkyl group, lower
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
Rukylsulfinyl group, lower alkylsulfonyl group, low
Primary alkylsulfonylamino group, hydroxyimino group and
Selected from the group consisting of
Where appropriate, one to three identical or different substituents are substituted.
The nitrogen-containing heteroaromatic group can be substituted. R_pIs cyclo lower alkyl group, aryl
Group, aromatic heterocyclic group or aliphatic heterocyclic group,
Each substituent is, in addition to the above substituents, Embedded image A bicyclic compound containing a partial structure selected from the group consisting of
Can have a tricyclic fused ring. Formula: Y₁-W₁-Y₂-R_pAt W
₁Is a single bond, an oxygen atom, a sulfur atom, SO, SO₂, N
R_q, SO₂NR_q, N (R_q) SO₂NR_r, N (R
_q) SO₂, CH (OR_q), CONR_q, N (R_q)
CO, N (R_q) CONR_r, N (R_q) COO, N
(R_q) CSO, N (R_q) 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_qAnd R_rIs hydrogen
Atom or lower alkyl group, cyclo 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
Represents a kill group, an aryl group or an aralkyl group)
And, for example, oxygen atom, sulfur atom, NR_q, SO₂
NR_q, N (R_q) SO₂, CONR_q, N (R_q) C
O, N (R_q) COO, C (R_q) = CR_r, OC
(O), OC (O) NR_q, C (O) O, etc. are preferred,
Especially, for example, NR_q, N (R_q) SO₂, CONR_q, N
(R_q) CO, N (R_q) COO, OC (O), C
(O) O and the like are preferable. Note that W₁R in_qAnd R_rIs a hydrogen atom
Or lower alkyl group, cyclo 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,
Ruboxyl 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
Represents a kill group, an aryl group or an aralkyl group. Said low
Secondary alkyl group, the aryl group or the aralkyl group
Represents a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom
Nitro, carboxyl, carbamoyl, phor
Mill 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 alkylcarbamoyl
Group, di-lower alkylcarbamoyl group, carbamoyloxy
Thio group, lower alkylcarbamoyloxy group, di-lower alkyl
Quilcarbamoyloxy group, amino group, lower alkyl group
Amino group, di-lower alkylamino group, tri-lower alkyl group
Ammonium group, amino lower alkyl group, lower alkyl amino group
Lower alkyl group, di-lower alkylamino lower alkyl
Group, tri-lower alkylammonio lower alkyl group, lower
Alkanoylamino group, aroylamino group, lower alk
Neuylamidino lower alkyl group, lower alkyl sulfy
Nyl group, lower alkyl sulfonyl group, lower alkyl sulf
Honylamino group, hydroxyimino group and lower alkoxy
Substituents selected from the group consisting of
There can be three chairs. Formula: Y₁-W₁-Y₂-R_pAt
One or different, a single bond or a linear or branched low
And a lower alkylene group. Said linear or branched lower
The alkylene group is Embedded image A bicyclic compound containing a partial structure selected from the group consisting of
Can have one tricyclic fused ring. Next, the form of the substituent (2) will be described in detail.
Then, the substituent is substituted on the nitrogen-containing heteroaromatic group.
Of the substituents, for example, lower alkyl group, lower alkanoyl
Group, lower alkanoyloxy group, hydroxy lower alkyl
Group, cyano lower alkyl group, halo lower alkyl group,
Ruboxyl lower alkyl group, carbamoyl lower alkyl
Group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkylcarbamoyl group, di-lower alkylcarbamo
Yl group, carbamoyloxy group, lower alkyl carbamo
Yloxy group, di-lower alkylcarbamoyloxy group,
Lower alkylamino group, di-lower alkylamino group, tri
Lower alkyl ammonium group, amino lower alkyl group, lower
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 alkylsulfo
Nil group, lower alkylsulfonylamino group, lower alka
Substitution of a noylamidino lower alkyl group or the like is involved,
The carbon atom on the ring to which these ring substituents are attached, next to
The carbon atom in contact with the carbon atom on the substituent on the ring, the acid
Together with elementary and / or nitrogen atoms, Embedded image Form a 5- to 7-membered ring selected from the group consisting of
It is a thing. The substituent on the ring includes, for example, lower
Alkyl group, lower alkanoyloxy group, hydroxy low
Lower alkyl group, halo lower alkyl group, carbamoyl lower
Alkyl group, lower alkoxy group, lower alkoxycarbo
Nyl group, lower alkylcarbamoyl group, lower alkyl group
Rubamoyloxy group, lower alkylamino group, di-lower amino group
Alkylamino group, amino lower alkyl group, lower alkyl
Amino lower alkyl group, di-lower alkylamino lower alkyl
Kill group, lower alkanoylamino group, aroylamino group
And the like, among which, for example, lower alkanoyloxy
Group, hydroxy lower alkyl group, lower alkoxy group, low
Lower alkoxycarbonyl group, lower alkylamino lower group
Alkyl groups and the like are more preferred. Next, the form of the substituent (3) will be described in detail.
Then, the present substituent has the formula: Y₁-W₁-Y₂-R_p(formula
Medium, Y₁, W₁, Y₂And R_pHas the above meaning)
A carbon atom on the ring to which the substituent represented by
And the carbon and oxygen atoms on the substituent
And / or formed together with a nitrogen atom, Embedded image A 5- to 7-membered ring selected from the group consisting of
You. The substituent or formation of the nitrogen-containing heteroaromatic group
The group is preferred in any of (1), (2) and (3).
However, the preferred form is (1 ') a 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 alkylcarbamoy
Group, lower alkylcarbamoyloxy group, amino group,
Lower alkylamino group, di-lower alkylamino group,
Lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, lower alk
Noylamino group, aroylamino group and lower alkyls
Substituents selected from the group consisting of rufonylamino groups
Formula: Y_1a-W_1a-Y_2a-R_pa(Where R_pa
Has 1 to 3 hydrogen atoms or 1 to 3 substituents
May be a lower alkyl group, a lower alkenyl group or
The lower alkynyl group or the substituent is appropriately 1 to 3
Pieces and even Embedded image A 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 group, pyrazolyl group, quinolyl group, 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
Oxygen atom, sulfur atom, NR_qa, SO₂NR_qa, N
(R_qa) SO₂, CONR_qa, N (R_qa) CO,
N (R_qa) COO, C (R_qa) = CR_ra, OC
(O), OC (O) NR_qaOr C (O) O (here
And R_qaAnd R_raIs a hydrogen atom, lower alkyl
Group, cyclo-lower alkyl group, hydroxyl group, halogen atom,
Lumyl group, lower alkanoyloxy group, hydroxy lower
Alkyl group, halo-lower alkyl group, carbamoyl-lower alkyl group
Alkyl group, lower alkoxy group, lower alkoxy carbonyl
Group, lower alkoxycarbonylamino group, lower alcohol
Xycarbonylamino lower alkyl group, lower alkyl group
Rubamoyl group, lower alkylcarbamoyloxy group,
Mino group, lower alkylamino group, di-lower alkylamino
Group, amino lower alkyl group, lower alkyl amino lower group
Alkyl group, di-lower alkylamino lower alkyl group, lower
Alkanoylamino group, aroylamino group and lower alkyl
Substitution selected from the group consisting of a killsulfonylamino group
Optionally having one to three groups or substituents,
Shows a lower alkyl group, aryl group or aralkyl group
Y)_1aAnd Y_2aAre the same or different and are a single bond
Or having one of said bicyclic or tricyclic fused rings
Represents a linear or branched lower alkylene group;
Substituted) selected from the group consisting of the substituents represented by
Group, (2 ') lower alkyl 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, lower alkyl
Amino group, di-lower alkylamino group, amino lower alkyl
Group, lower alkylamino lower alkyl group, di-lower alkyl
Killamino lower alkyl group, lower alkanoylamino group
And a substituent selected from the group consisting of aroylamino groups
Carbon atoms on the ring to which is attached, and adjacent carbon atoms
The carbon atom, oxygen atom and / or nitrogen
Together with elementary atoms, Embedded image Form a 5- or 6-membered ring selected from the group consisting of
A nitrogen-containing heteroaromatic group or the formula (3 '): Y_1a-W_1a−
Y_2a-R_pa(Where Y_1a, W_1a, Y_2aAnd R
_paHas the meaning described above).
Carbon atom on the ring, its adjacent carbon atoms and
Together with carbon, oxygen and / or nitrogen atoms on the substituents
Together Embedded image A 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(Where R_pbRepresents a hydrogen atom or the substituent
A lower alkyl group, a lower alkyl group,
Lucenyl group or lower alkynyl group or its substituent
1 to 3 as appropriate, Embedded image A bicyclic compound containing a partial structure selected from the group consisting of
Is a cyclo lower alkyl optionally having a tricyclic fused ring
From kill, aryl, pyridyl and pyrazolyl groups
An aromatic heterocyclic group or isoxa selected from the group consisting of
Zolinyl group, tetrahydropyridyl group, piperazinyl
Group, piperidinyl group, pyrrolidinyl group, morpholino group and
And tetrahydroisoquinolinyl groups.
Aliphatic heterocyclic group, W_1bIs NR_qb, N
(R_qb) SO₂, CONR_qb, N (R_qb) CO,
N (R_qb) COO, OC (O) or C (O) O (here
In, R_qbAnd R_rbIs a hydrogen atom or hydroxyl
Group, halogen atom, lower alkanoyloxy group, hydro
Xy lower alkyl group, lower alkoxy group, lower alkoxy
Cicarbonyl group, amino group and lower alkylamino lower
A substituent selected from the group consisting of alkyl groups or the substitution
Lower alkyl optionally having 1 to 3 groups
Group, aryl group or aralkyl group), Y_1b
And Y_2bAre the same or different and are a single bond or the bicyclic
Or a straight chain which may have one tricyclic fused ring
Represents a branched or branched lower alkylene group)
A substituent selected from the group consisting of:
Lower alkanoyloxy group, hydroxy lower alkyl
Group, lower alkoxy group, lower alkoxycarbonyl group and
Selected from the group consisting of lower alkylamino and lower alkyl groups
A carbon atom on the ring to which the selected substituent is attached,
Carbon atom, a carbon atom on the substituent on the ring, an oxygen atom
Together with the atom and / or the nitrogen atom, Embedded image A 5- or 6-membered ring selected from the group consisting of
Expression (3 ″): Y_1b-W_1b-Y_2b-R_pb(formula
Medium, Y_1b, W_1b, Y_2bAnd R_pbHas the above meaning
A) a carbon atom on the ring to which the substituent represented by
A carbon atom on the adjacent carbon atom and the substituent,
Together with oxygen and / or nitrogen atoms, Embedded image And a 5- or 6-membered ring selected from the group consisting of
is there. X and Z are the same or different and each represents a carbon atom
Or a nitrogen atom, or a bond as appropriate;₁Or
R₂And / or R₃Together with CH or nitrogen
Indicates an atom. Y is CO, SO or SO₂Is shown. R₁Is a hydrogen atom or a formula: Y₃-W₂
-Y₄-R_s(Where R_sRepresents a hydrogen atom or the substituent
A lower alkyl group optionally having 1 to 3 groups,
Lower alkenyl group, lower alkynyl group, cyclo lower alkenyl group
Kill group, aryl group, imidazolyl group, isoxazolyl
Group, isoquinolyl group, isoindolyl group, indazolyl group
Group, indolyl group, indolizinyl group, isothiazolyl group
Group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazi
Nil group, pyrazolyl group, quinoxalinyl group, quinolyl
Group, dihydroisoindolyl group, dihydroindolyl
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 of₂Is a single bond,
Oxygen atom, sulfur atom, SO, SO₂, NR_t, SO₂N
R_t, N (R_t) SO₂NR_u, N (R_t) SO₂, C
H (OR_t), CONR_t, N (R_t) CO, N
(R_t) CONR_u, N (R_t) COO, N (R_t) C
SO, 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_tOr C
(O) O (where R_tAnd R_uIs a hydrogen atom
Or lower alkyl group, hydroxyl group, cyano group, halogen source
Nitro, carboxyl, carbamoyl, phor
Mill 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 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
Selected substituents or one to three substituents
A lower alkyl group, an aryl group or
Aralkyl group), Y₃And Y₄Are the same or different
A single bond or a linear or branched lower alkyl
A substituent) 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 alkylcarbamoyl group, di-lower alkylcarbamo
Yl group, carbamoyloxy group, lower alkyl carbamo
Yloxy group, di-lower alkylcarbamoyloxy group,
Amino group, lower alkylamino group, di-lower alkylamino
Group, tri-lower alkylammonio group, amino-lower alkyl
Kill group, lower alkylamino lower alkyl group, di-lower alkyl group
Alkylamino lower alkyl group, tri-lower alkyl ammonium
Nio lower alkyl group, lower alkanoylamino group, allo
Ilamino group, lower alkanoylamidino lower alkyl
Group, lower alkylsulfinyl group, lower alkylsulfo
Nyl group, lower alkylsulfonylamino group, hydroxy
Selected from the group consisting of imino groups and lower alkoxyimino groups
Selected substituents and formula: Y₃-W₂-Y₄-R_s(formula
Medium, R_s, W₂, Y₃And Y₄Has 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 they form a nitrogen atom. Here, R₁Form is explained in detail
And R₁Is a hydrogen atom or a formula: Y₃-W₂-Y₄-R_s
(Where R_s, W₂, Y₃And Y₄Has the meaning described above.
) Or 1 to 3
Lower alkyl optionally having the same or different substituents
Is a group or forms a nitrogen atom with X
No. Formula: Y₃-W₂-Y₄-R_sIn, R
_sRepresents a lower alkyl group, a lower alkenyl group, a lower alkyl
Nil group, cyclo lower alkyl group, aryl group, aromatic compound
An aromatic ring group or an aliphatic heterocyclic group;
Represents a lower alkyl group, a hydroxyl group, a cyano group, a halogen atom
Nitro, carboxyl, carbamoyl, phor
Mill 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 alkylcarbamoyl
Group, di-lower alkylcarbamoyl group, carbamoyloxy
Thio group, lower alkylcarbamoyloxy group, di-lower alkyl
Quilcarbamoyloxy group, amino group, lower alkyl group
Amino group, di-lower alkylamino group, tri-lower alkyl group
Ammonium group, amino lower alkyl group, lower alkyl amino group
Lower alkyl group, di-lower alkylamino lower alkyl
Group, tri-lower alkylammonio lower alkyl group, lower
Alkanoylamino group, aroylamino group, lower alk
Neuylamidino lower alkyl group, lower alkyl sulfy
Nyl group, lower alkyl sulfonyl group, lower alkyl sulf
Honylamino group, hydroxyimino group and lower alkoxy
Substituents selected from the group consisting of
There can be three chairs. In addition, preferred substituent groups
Can be listed similarly to the substituents on Ar. Formula: Y₃-W₂-Y₄-R_sAt W
₂Is a single bond, an oxygen atom, a sulfur atom, SO, SO₂, N
R_t, SO₂NR_t, N (R_t) SO₂NR_u, N (R
_t) SO₂, 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_tAnd R
_uRepresents a hydrogen atom or a lower alkyl group, a hydroxyl group,
Group, halogen atom, nitro group, carboxyl group, cal
Bamoyl group, formyl group, lower alkanoyl group, lower
Lucanoyloxy group, hydroxy lower alkyl group, shea
Lower alkyl group, halo lower alkyl group, carboxy low
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl
Coxy group, lower alkoxycarbonyl group, lower alkoxy
Cicarbonylamino group, lower alkoxycarbonylamido
Lower alkyl group, lower alkyl carbamoyl group, di-lower
Lower alkylcarbamoyl group, carbamoyloxy group, low
Lower alkyl carbamoyloxy group, di-lower alkyl carb
Bamoyloxy 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
A lower alkyl group or an aralkyl group.
Each substituent of the group, the aryl group or the aralkyl group is R
_sAs in the above, it is possible to have 1 to 3 substituents as appropriate.
Wear. Formula: Y₃-W₂-Y₄-R_sIn, Y
₃And Y₄Are the same or different and are a single bond or linear
Or a 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
_saHas 1 to 3 hydrogen atoms or 1 to 3 substituents
A lower alkyl group, a lower alkenyl group,
From lower alkyl, aryl and indolyl groups
An aromatic heterocyclic group selected from the group consisting of
Dropypyridyl, piperazinyl, piperidinyl,
Selected from the group consisting of loridinyl and morpholino groups
An aliphatic heterocyclic group, W_2aIs a single bond, NR_ta, CH
(OR_ta), CONR_ta, N (R_ta) CO, N
(R_ta) COO, OC (O) NR_taOr C (O) O
(Where R_taAnd R_uaIs a hydrogen atom,
Lower alkyl optionally having 1 to 3 substituents
, An aryl group or an aralkyl group), Y_3aPassing
And Y_4aAre the same or different and are a single bond or linear or
Or branched lower alkylene group or lower alkyl group, water
Acid group, carbamoyl group, lower alkanoyloxy group,
Droxy lower alkyl group, lower alkoxy group, lower alkyl
Coxycarbonyl group, lower alkylcarbamoyl group, di
Lower alkylcarbamoyl group, carbamoyloxy group,
Lower alkylcarbamoyloxy group, lower alkylamido
Group, di-lower alkylamino group, amino-lower alkyl
Group, lower alkylamino lower alkyl group, di-lower alkyl
Ruamino lower alkyl group, lower alkanoylamino group
And substituents selected from the group consisting of aroylamino groups
Every formula: Y_3a-W_2a-Y_4a-R_sa(Where R
_sa, W_2a, Y_3aAnd Y_4aHas 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, especially a hydrogen atom
Or the formula: Y_3b-W_2b-Y_4b-R_sb(Where
R_sbHas 1 to 3 hydrogen atoms or the substituents as appropriate.
Optionally, 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 hydrogen
Atom, and optionally 1 to 3 substituents;
Represents a lower alkyl group, an aryl group or an aralkyl group
Y)_3bAnd Y_4bAre the same or different and are a single bond
Or a linear or branched lower alkylene group or hydride
Roxy 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).
1 to 3 substituents selected from the group
Lower alkyl optionally having the same or different substituents
Or forms a nitrogen atom together with X
Is mentioned. R₂And R₃Are the same or different,
(I) independently a hydrogen atom, a hydroxyl group, a lower alkyl group,
Higher alkoxy group or formula: Y₃-W₂-Y₄-R
_s(Where R_s, W₂, Y₃And Y₄Has the above meaning
Or (ii) R₂as well as
R₃Any one of R₁And form together with X
Make, Embedded image And Embedded image A saturated 5- to 8-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
Or (iii) or together,
A lower alkyl group, forming an oxo group together with the bound Z
Z or R₁And a nitrogen atom together with X,
Hetero selected from the group consisting of oxygen and sulfur
One or more atoms may be included,
Spirocyclo lower alkyl which may have a kill group or a substituent
Alkyl group, hydroxyl group, cyano group, halogen atom, nitro
Group, carboxyl group, carbamoyl group, formyl group, low
Lower alkanoyl group, lower alkanoyloxy group, hydro
Xy lower alkyl group, cyano lower alkyl group, halo lower
Alkyl group, carboxy lower alkyl group, carbamoyl
Lower alkyl group, lower alkoxy group, lower alkoxyca
Rubonyl group, lower alkoxycarbonylamino group, lower
Alkoxycarbonylamino lower alkyl group, lower alkyl
Kill carbamoyl group, di-lower alkylcarbamoyl group,
Carbamoyloxy group, lower alkylcarbamoyloxy
S, di-lower alkylcarbamoyloxy, 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
L-amino lower alkyl group, tri-lower alkyl ammonium
Lower alkyl group, lower alkanoylamino group, aroyl
Amino group, lower alkanoylamidino lower alkyl group,
Lower alkylsulfinyl group, lower alkylsulfonyl
Group, lower alkylsulfonylamino group, hydroxyimi
Selected from the group consisting of
Substituents and formula: Y₁-W₁-Y₂-R_p(Where
R_p, W₁, Y₁And Y₂Has the meaning given above)
A substituent selected from the group consisting of
And optionally 1 to 3 identical or different substituents, furthermore
Has 1 to 3 identical or different substituents as appropriate.
Cyclo lower alkyl group, aryl group, imida
Zolyl, isoxazolyl, isoquinolyl, iso
Indolyl, indazolyl, indolyl, India
Lysinyl group, isothiazolyl group, ethylenedioxyphen
Nil group, oxazolyl group, pyridyl group, pyrazinyl
Group, pyrimidinyl group, pyridazinyl group, pyrazolyl group,
Quinoxalinyl group, quinolyl group, dihydroisoindolini
, Dihydroindolyl, thionaphthenyl, naph
Tiridinyl group, phenazinyl group, benzimidazolyl
Group, benzoxazolyl group, benzothiazolyl group, ben
Zotriazolyl group, benzofuranyl group, thiazolyl group,
Thiadiazolyl, thienyl, pyrrolyl, furyl
Group, frazanyl group, triazolyl group, benzodioxani
Selected from the group consisting of
Selected aromatic heterocyclic group and isoxazolinyl group, a
Soxazolidinyl group, tetrahydropyridyl group, imida
Zolidinyl group, tetrahydrofuranyl group, tetrahydro
Pyranyl group, piperazinyl group, piperidinyl group, pylori
Dinyl group, pyrrolinyl group, morpholino group, tetrahydro
Quinolinyl and tetrahydroisoquinolinyl groups
Selected from the group consisting of aliphatic heterocyclic groups selected from
May be fused with the ring Embedded image And Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
It forms an 8-membered ring group. Here, R₂And R₃Explain concretely
And (i) R₂And R₃Are the same or different and are independent
(Ii) R₂And R₃Any one of
Form a substituent together with other substituents,
The substituent is combined with the other and further substituted
When forming a group and (iii) R₂And R₃Together
To form a substituent,₂And R₃Is another substituent
And the like, when forming a substituent together with
Included in the present invention. Next, R₂And R₃For each embodiment of the substituent of
Will be described. (I) R₂And R₃Is a hydrogen atom, hydroxyl
Group, lower alkyl group, lower alkoxy group or formula: Y₃−
W₂-Y₄-R_s(Where R_s, W₂, Y₃And Y
₄Has the meaning described above).
However, they may be the same or different,
And independent. (Ii) R₂And R₃Any one of R
₁And with X Embedded image And Embedded image Form a saturated 5- to 8-membered ring selected from the group consisting of
The other, together with the 5- or 8-membered ring,
A carbon or nitrogen atom on the ring, on a ring on the ring
Carbon atom, oxygen atom and / or nitrogen contained in the substituent
It can form a 5- to 7-membered ring with the atoms. (Iii) R₂And R₃Is (iii-
1) Together form a spirocyclo lower alkyl group
Or (iii-2) forms an oxo group with Z to be bonded.
Or (iii-3) Z, R₁And X
Selected from the group consisting of nitrogen, oxygen and sulfur
Containing one or more selected heteroatoms
Good Embedded imageAnd Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
An 8-membered ring group can be formed. The saturated or unsaturated 5- or 8-membered member
The ring group may be a lower alkyl group or an optionally substituted substituent.
Pyrocyclo lower alkyl group, hydroxyl group, cyano group, halogen
Atom, nitro group, carboxyl group, carbamoyl group,
Formyl group, lower alkanoyl group, lower alkanoyl group
Xyl 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
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, amino group, lower alkylamino group, di-lower alkyl
Killamino group, tri-lower alkylammonio group, amino
Lower alkyl group, lower alkylamino lower alkyl group,
Di-lower alkylamino lower alkyl group, tri-lower alkyl
Luammonio lower alkyl group, lower alkanoylamino
Group, aroylamino group, lower alkanoylamidino lower
Alkyl group, lower alkylsulfinyl group, lower alkyl
Rusulfonyl group, lower alkylsulfonylamino group,
Consists of a droxyimino group and a lower alkoxyimino group
A substituent selected from the group and the formula: Y₁-W₁-Y₂−
R_p(Where R_p, W₁, Y₁And Y₂Means the above
Selected from the group consisting of the substituents represented by
A substituent, suitably 1 to 3 identical or different
It can have a substituent. [0001] Substitution of a spirocyclo lower alkyl group
Examples of the group include a lower alkyl group and a lower alkoxy group.
Group, hydroxy lower alkyl group, aryl group and the like.
Among them, for example, lower alkyl group, lower alkoxy group, etc.
Is preferred. The saturated or unsaturated 5- or 8-membered member
The ring group further includes a cyclo lower alkyl group, an aryl
Group, imidazolyl group, isoxazolyl group, isoquinolyl
, Isoindolyl, indazolyl, indolyl
Group, indolizinyl group, isothiazolyl group, ethylenedi
Oxyphenyl group, oxazolyl group, pyridyl group,
Radinyl group, pyrimidinyl group, pyridazinyl group, pyrazo
Ryl group, quinoxalinyl group, quinolyl group, dihydroiso
Indolyl group, dihydroindolyl group, thionaphthenyl
Group, naphthyridinyl group, phenazinyl group, benzimida
Zolyl group, benzoxazolyl group, benzothiazolyl
Group, benzotriazolyl group, benzofuranyl group, thiazo
Ryl group, thiadiazolyl group, thienyl group, pyrrolyl group,
Furyl group, furzanyl group, triazolyl group, benzodio
Group consisting of a xanyl group and a methylenedioxyphenyl group
Aromatic heterocyclic groups selected from isoxazolinyl
Group, isoxazolidinyl group, tetrahydropyridyl group,
Imidazolidinyl group, tetrahydrofuranyl group, tetra
Hydropyranyl group, piperazinyl group, piperidinyl group,
Pyrrolidinyl group, pyrrolinyl group, morpholino group, tetra
Hydroquinolinyl and tetrahydroisoquinolinyl groups
A group consisting of an aliphatic heterocyclic group selected from the group consisting of
With the selected ring. The condensed ring may have 1 to 3 identical
Or different substituents. Concrete place
The substituent may be the same as the substituent on Ar.
it can. R₂And R₃Are (i), (ii) and
Preferred in any of (iii), but preferred forms
Are the same or different and independently represent a hydrogen atom, a hydroxyl group,
Lower alkyl group, lower alkoxy group or formula: Y_3a−
W_2a-Y_4a-R_sa(Where R_sa, W_2a, Y
_3aAnd Y_4aHas the meaning given above)
Is a substituent, R_2aAnd R_3aAny one of R
_1aAnd together with Xa, Embedded image And Embedded image A saturated 5- to 8-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
Or together form a spirocyclo lower alkyl
Or an oxo group together with the bonding Z, or
Is the connecting Z_a, R_1aNitrogen atom and oxygen together with Xa
Heteroatoms selected from the group consisting of atoms and sulfur atoms
May include one or more of
Spirocyclo lower alkyl optionally having a group or a substituent
Group, hydroxyl group, hydroxy lower alkyl group, lower alcohol
Xy group, lower alkoxycarbonyl group, lower alkoxy
Carbonylamino group, lower alkoxycarbonylamino
Lower alkyl group, lower alkylcarbamoyl group, lower alkyl group
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 and alloy
And a substituent selected from the group consisting of
Y_1a-W_1a-Y_2a-R_pa(Where R_pa, W
_1a, Y_1aAnd Y_2aHas the above meaning)
A substituent selected from the group consisting of
And optionally 1 to 3 identical or different substituents, furthermore
Has 1 to 3 identical or different substituents as appropriate.
Cyclo lower alkyl, aryl, pyridyl
Aromatic group selected from the group consisting of
From heterocyclic, piperidinyl and pyrrolidinyl groups
Selected from the group consisting of aliphatic heterocyclic groups selected from the group consisting of
May be fused with the selected ring, Embedded image And Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
And a case where an 8-membered ring group is formed. In particular, R_2bAnd R_3bAre the same or different
Independently, a hydrogen atom, a hydroxyl group, a lower alkyl group,
Lower alkoxy group or formula: Y_3b-W_2b-Y_4b
-R_sb(Where R_sb, W_2b, Y_3bAnd Y
_4bIs a substituent represented by the above meaning)
Or R_2bAnd R_3bAny one of R_1bAnd X_b
Form together with Embedded image And Embedded image To 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
Or together form a 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
Heteroatoms selected from the group consisting of atoms and sulfur atoms
May include one or more of
Spirocyclo lower alkyl optionally having a group or a substituent
Group, hydroxy lower alkyl group and lower alkoxy group
A substituent selected from the group consisting of a rubonyl group and a formula:
Y_1b-W_1b-Y_2b-R_pb(Where R_pb, W
_1b, Y_1bAnd Y_2bHas the above meaning)
A substituent selected from the group consisting of
And optionally 1 to 3 identical or different substituents, furthermore
Has 1 to 3 identical or different substituents as appropriate.
Cyclo-lower alkyl groups, aryl groups and
Selected from the group consisting of a peridinyl group and a pyrrolidinyl group
With a ring selected from the group consisting of aliphatic heterocyclic groups
May be, Embedded image And Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
It is preferable to form a 7-membered ring group. R₄And R₅Is the same or different and is hydrogen
Atom, halogen atom, hydroxyl group, amino group or formula: Y
₃-W₂-Y₄-R_S(Where R_s, W₂, Y₃And Y
₄Has the same meaning as described above) or the lower
Alkyl, cyano, nitro, carboxyl,
Bamoyl group, formyl group, lower alkanoyl group, lower
Lucanoyloxy group, hydroxy lower alkyl group, shea
Lower alkyl group, halo lower alkyl group, carboxy low
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl
Coxy group, lower alkoxycarbonyl group, lower alkoxy
Cicarbonylamino group, lower alkoxycarbonylamido
Lower alkyl group, lower alkyl carbamoyl group, di-lower
Lower alkylcarbamoyl group, carbamoyloxy group, low
Lower alkyl carbamoyloxy group, di-lower alkyl carb
Bamoyloxy 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
Substituents selected from the group consisting of:₃-W
₂-Y₄-R_s(Where R_s, W₂, Y₃And Y₄Is before
Selected from the group consisting of the substituents represented by
Selected substituents, optionally 1 to 3 identical or
A lower alkyl group, which may have a different substituent,
It represents a reel group or an aralkyl group. Here, R₄And R₅The form of the
If you clarify, R₄And R₅Is a hydrogen atom, a halogen atom,
Hydroxyl group, amino group or formula: Y₃-W₂-Y₄-R_s
(Where R_s, W₂, Y₃And Y₄Has the above meaning
May have a substituent or a substituent represented by
Shows a lower alkyl group, aryl group or aralkyl group
You. The lower alkyl group, the aryl group or the
The aralkyl group may have 1 to 3 identical or different
Can have groups. Specific examples of the substituent include, for example, lower
Kill, cyano, nitro, carboxyl, 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
Substituents selected from the group consisting of:₃-W
₂-Y₄-R_s(Where R_s, W₂, Y₃And Y₄Is before
Selected from the group consisting of the substituents represented by
Selected substituents. Formula Embedded image Represents a single bond or a double bond. Involved in the formula,
Z, R₁, R₂, R₃And any kind of bond depending on the type of X
Can be taken. Next, the compound of the general formula (I) of the present invention will be described.
Will be described. General formula (I) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the meaning described above. ] Has good Cdk
4 and / or Cdk6 inhibitory action.
General formula (Ia) Embedded image [Wherein, Ar_a, X_a, Y_a, Z_a, R_1a, R_2a,
R_3a, R_4a, R_5aAnd formula Embedded image Has the meaning described above. Are preferred, and
Having the general formula (Ib) Embedded image [Wherein, Ar_b, X_b, Y_b, Z_b, R_1b, R_2b,
R_3b, R_4b, R_5bAnd formula Embedded image Has the meaning described above. Are preferred. Incidentally, the general formula (Ip) Embedded image [Wherein, Ar_pIs a nitrogen-containing group which may have a substituent
An aromatic heterocyclic group, X_pRepresents a carbon atom (CH) or a nitrogen atom
Child, R_1pMay have a hydrogen atom or an appropriate substituent
Lower alkyl group, R_2pIs a hydrogen atom or an oxo group
Form a carbonyl group with the carbon atoms that combine)
Or a bonding carbon atom, R_1pAnd X_pWith nitrogen
Heteroatoms selected from the group consisting of atoms and sulfur atoms
May include one or more of
Saturated or unsaturated 5-membered or 6-membered
Forming a membered ring group;_4pAnd R_5pAre the same or different
A hydrogen atom, a halogen atom, a hydroxyl group, an amino group,
A lower alkyl group which may have a substituent, an aryl
Or a aralkyl group].
Is included in the compound of the general formula (I) and has good Cdk4
And / or a Cdk6 inhibitory effect. Hereinafter, the compound of the general formula (Ip)
To explain, Ar_pIs, for example, a pyridyl group, a pyrimidini
Group, pyrazinyl group, pyridazinyl group, thiazolyl group,
Isothiazolyl group, oxazolyl group, isoxazolyl
Group, pyrazolyl group, pyrrolyl group, imidazolyl group,
Drill group, isoindolyl group, quinolyl group, isoquinolyl
Group, benzothiazolyl group and benzooxazolyl group
A nitrogen-containing heteroaromatic group selected from the group consisting of
But for example pyridyl, pyrimidinyl, pyrazinyl
Group, pyridazinyl group, thiazolyl group, pyrazolyl group and
Nitrogen-containing heteroaryl selected from the group consisting of imidazolyl groups
Aromatic groups are preferred, especially pyridyl and pyrazolyl
Nitrogen-containing heteroaromatic groups selected from the group consisting of
Good. R_2pIs a carbon atom to which R_1pAnd X
Saturated or unsaturated 5- or 6-membered ring group formed with
As a specific example, Embedded image Or Embedded image And the like. In the compounds of the general formula (Ip), Ar_por
Is R_2pIs a carbon atom to which R_1pAnd X_pWith shape
Placement of saturated or unsaturated 5- or 6-membered ring group to be formed
When the substituent is a lower alkyl group, hydroxyl group, cyano group, halogen
Atom, nitro group, carboxyl group, carbamoyl group, e
Lumyl group, lower alkanoyl group, hydroxy lower alkyl
Group, cyano lower alkyl group, halo lower alkyl group,
Ruboxyl lower alkyl group, carbamoyl lower alkyl
Group, lower alkoxy group, lower alkoxycarbonyl group,
Lower alkylcarbamoyl group, di-lower alkylcarbamo
Yl group, carbamoyloxy group, lower alkyl carbamo
Yloxy group, di-lower alkylcarbamoyloxy group,
Amino group, lower alkylamino group, di-lower alkylamino
Group, tri-lower alkylammonio group, amino-lower alkyl
Kill group, lower alkylamino lower alkyl group, di-lower alkyl group
Alkylamino lower alkyl group, tri-lower alkyl ammonium
Nio lower alkyl group, lower alkanoylamino group, allo
Ilamino 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_ppIs a hydrogen atom or
Lower alkyl groups which may have a substituent, cyclo-lower
Alkyl group, lower alkenyl group, lower alkynyl group,
Reel group, aromatic heterocyclic group or aliphatic heterocyclic group, W
Is a single bond, an oxygen atom, a sulfur atom, a sulfinyl group,
Ruphonyl group, NR_qp, SO₂NR_qp, N (R_qp)
SO₂NR_rp, N (R_qp) SO₂, CH (O
R_qp), CONR_qp, N (R_qp) CO, N (R
_qp) CONR_rp, N (R_qp) COO, 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), S
C (O) NR_qpOr C (O) O (where R
_qpAnd R_rpIs a hydrogen atom, optionally substituted
Represents a lower alkyl group, an aryl group or an aralkyl group.
Y)_1pAnd Y_2pAre the same or different and are a single bond
Or a linear or branched lower alkylene group]
A substituent selected from the group consisting of
Compounds which may have three identical or different substituents
Are good compounds. The compound represented by the general formula (I) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the meaning described above. Wherein R is₄, R₅Passing
And -HNCONH-Ar is a benzene ring moiety,
Substitution can be performed at any substitution position. Therefore, the compound of the general formula (I)
(I-1) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the above-mentioned meaning], a compound of the general formula (I-2) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the above-mentioned meaning], a compound of the general formula (I-3) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the above-mentioned meaning] and a compound of the general formula (I-
4) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the above-mentioned meaning].
Among these compounds, compounds of the general formula (I-1) are preferred.
is there. Pharmaceutically acceptable compounds of general formula (I)
Salt means a conventional pharmaceutically acceptable salt
And when present as a substituent, a carboxyl group or
Refers to salts at bases or acidic residues on the side chains.
Can be. In the carboxyl group or acidic residue
Examples of basic addition salts include, for example, alkali metals.
Other than alkali metal salts such as sodium salt and potassium salt;
Alkaline earths such as calcium salts and magnesium salts
Metal salts; eg ammonium salts; eg trimethylamido
Salt, triethylamine salt; dicyclohexylamine
Salt, ethanolamine salt, diethanolamine salt, bird
Aliphatic amines such as ethanolamine salts and procaine salts
Salts; for example, aralkyl such as dibenzylethylenediamine
Amine salts; for example, pyridine salts, picoline salts, quinolines
Heterocyclic aromatic amine salts such as salts and isoquinoline salts;
Tetramethylammonium salt, tetraethylammonium
Salt, benzyltrimethylammonium salt, benzyl
Liethyl ammonium salt, benzyl tributyl ammonium
Salt, methyltrioctylammonium salt, tetrabu
Quaternary ammonium salts such as tyl ammonium salt;
Basic amino acid salts such as nin salts and lysine salts;
You. The acid addition salt of the base on the side chain includes:
For example, hydrochloride, sulfate, nitrate, phosphate, carbonate, charcoal
Inorganic acid salts such as oxyhydrogen salts and perchlorates;
Lopionate, lactate, maleate, fumarate,
Tartrate, malate, citrate, ascorbate
Organic acid salts such as methanesulfonate, isethion
Acid salt, benzenesulfonic acid salt, toluenesulfonic acid salt, etc.
Sulfonates; eg aspartate, glutamine
And acidic amino acid salts such as acid salts. Pharmaceutically acceptable compounds of general formula (I)
Non-toxic esters include those at the carboxyl group.
Means pharmaceutically acceptable conventional ones The compound of the formula (I) of the present invention is described below.
Among them, examples of suitable compounds will be mentioned,
A preferred group of compounds, including example compounds, is N '-(pyrroli
Dino [2,1-b] isoindoline-4-one-8-i
Ru) -N- (5- (2-octylaminomethyl) pyrazo
Yl-3-yl) urea (compound of 563), N'-
(Pyrrolidino [2,1-b] isoindoline-4-one
-8-yl) -N- (5- (2-methyl-4,4-dim
Tylpentylaminomethyl) pyrazol-3-yl) u
Rare (compound of 564), N '-(pyrrolidino [2,1
-B] isoindoline-4-one-8-yl) -N-
(5- (5-methoxyindan-2-ylaminomethyl)
B) pyrazol-3-yl) urea (compound of 581)
), N '-(pyrrolidino [2,1-b] isoindori
N-4-one-8-yl) -N- (5- (2-methyli
Ndan-2-ylaminomethyl) pyrazol-3-i
Le) urea (compound of 589), N '-(pyrrolidino
[2,1-b] isoindoline-4-one-8-yl)
-N- (5- (5-chloroindan-2-ylaminomethyl)
Tyl) pyrazol-3-yl) urea (compound of 595)
), N '-(pyrrolidino [2,1-b] isoindori
N-4-one-8-yl) -N- (5- (6-methylpi
Lysin-2-yl) pyrazol-3-yl) urea (6
05), N '-(pyrrolidino [2,1-b] i
Soindolin-4-one-8-yl) -N- (5- (pi
Loridin-2-yl) pyrazol-3-yl) urea
(Compound 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
Tyl) pyrazol-3-yl) urea (a compound of 572)
), N '-(pyrrolidino [2,1-b] -4-oxo
Isoindoline-8-yl) -N- (5- (Nt-butyl)
Tyl-N-methyl-aminomethyl) pyrazole-3-i
Urea (a compound of 596), N '-(pyrrolidino
[2,1-b] isoindoline-4-one-8-yl)
-N- (4- (N-benzyl-1,2,5,6-tetra
Hydropyridin-4-yl) pyridin-2-yl) uree
A (the compound of 254), N '-(pyrrolidino [2,1-
b] isoindoline-4-one-8-yl) -N- (4
-(N-benzyl-4-piperidyl) pyridine-2-i
Le) urea (compound of 255), N '-(pyrrolidino
[2,1-b] isoindoline-4-one-8-yl)
-N- (4- (N-benzyl-1,2,5,6-tetra
Hydropyridin-3-yl) pyridin-2-yl) uree
A (the compound of 256), N '-(pyrrolidino [2,1-
b] isoindoline-4-one-8-yl) -N- (4
-(N-benzyl-3-piperidyl) pyridine-2-i
Le) urea (compound of 257), N '-(pyrrolidino
[2,1-b] -4-oxoisoindoline-8-i
) -N- (4- (1,2,5,6-tetrahydropyri
Zin-3-yl) pyridin-2-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one
-8-yl) -N- (4- (N-acetyl-3-piperi
(Zyl) pyridin-2-yl) urea, N '-(pyrrolidide
No [2,1-b] isoindoline-4-one-8-i
Ru) -N- (piperidino [3,4-c] pyridine-6-
Il) urea (compound of 317), N '-(pyrrolidino
[2,1-b] isoindoline-4-one-8-yl)
-N- (pyrrolidino [3,4-c] pyridine-5-i
Ru) urea, N '-(pyrrolidino [2,1-b] isoy
Donlin-4-one-8-yl) -N- (4- (cyclo
Hexylaminoethyl) pyridin-2-yl) urea,
N '-(pyrrolidino [2,1-b] isoindoline-4
-On-8-yl) -N- (4- (N-cyclohexyl)
Pyrrolidin-3-yl) pyridin-2-yl) urea
(180 compounds), 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-cyclyl)
Lopentyl-3-methylisoindoline-1-one-4
-Yl) -N- (pyridin-2-yl) urea (428
N '-(3-t-butylisoindolino)
[3,2-b] oxazolidin-4-one-8-yl)
-N- (4- (N-benzylpyrrolidin-3-yl) pi
Lysin-2-yl) urea (compound of 526), N'-
(2-methylisoindolino [3,2-b] perhydro
-1,3-oxazin-5-one-9-yl) -N-
(4- (N-benzylpyrrolidin-3-yl) pyridine
-2-yl) urea (compound 541) and N '-(a
Soindolino [2,3-b] perhydro-1,4-meta
No-6,11a-benzoxazin-11-one-7-i
L) N- (pyridin-2-yl) urea (a compound of 476)
), Among which 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
L) pyrazol-3-yl) urea, N '-(pyrrolidium)
No [2,1-b] isoindoline-4-one-8-i
) -N- (5- (5-methoxyindan-2-ylua)
Minomethyl) 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
-On-8-yl) -N- (5- (5-chloroindan
-2-ylaminomethyl) pyrazol-3-yl) uree
A, N '-(pyrrolidino [2,1-b] isoindoline
-4-one-8-yl) -N- (4- (N-benzyl-
1,2,5,6-tetrahydropyridin-4-yl) pi
Lysin-2-yl) urea, N '-(pyrrolidino [2,
1-b] isoindoline-4-one-8-yl) -N-
(4- (N-benzyl-4-piperidyl) pyridine-2
-Yl) urea, N '-(pyrrolidino [2,1-b] i
Soindolin-4-one-8-yl) -N- (piperidi
No [3,4-c] pyridin-6-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one
-8-yl) -N- (4- (N-cyclohexylpyrroli)
Zin-3-yl) pyridin-2-yl) urea, N'-
(Pyrrolidino [2,1-b] isoindoline-4-one
-8-yl) -N- (4- (N-benzylpyrrolidine-
3-yl) pyridin-2-yl) urea, N '-(3-
t-butylisoindolino [3,2-b] oxazolidy
N-4-one-8-yl) -N- (4- (N-benzyl
Pyrrolidin-3-yl) pyridin-2-yl) urea;
N '-(2-methylisoindolino [3,2-b] per
Hydro-1,3-oxazin-5-one-9-yl)-
N- (4- (N-benzylpyrrolidin-3-yl) pyri
Zin-2-yl) urea and N '-(isoindolino)
[2,3-b] perhydro-1,4-methano-6,11
a-benzoxazin-11-one-7-yl) N- (pi
Lysin-2-yl) urea and the like are particularly preferred. Next, the preparation of the compound of the general formula (I) of the present invention is described.
The fabrication method will be described. The compound of the general formula (I) can be prepared by the following production method
A, can be manufactured by manufacturing method B or manufacturing method C
You. [0001]Manufacturing method A The compound of the general formula (I) has the general formula (III) Embedded image Wherein X and Z are the same or different and each represents
R represents a nitrogen atom or is bonded as appropriate.₁₀Or R
₂₀And / or R₃₀Together with CH or nitrogen
An element atom, Y is CO, SO or SO₂, R₁₀Is hydrogen
Atom or formula: Y₃₀-W₂₀-Y₄₀-R_s0(formula
Medium, R_s0Represents 1 to 3 hydrogen atoms or the substituents
Lower alkyl group, lower alkenyl which may have
Group, lower alkynyl group, cyclo lower alkyl group, aryl
Group, imidazolyl group, isoxazolyl group, isoquino
Ryl, isoindolyl, indazolyl, indori
Group, indolizinyl group, isothiazolyl group, ethylene
Dioxyphenyl group, oxazolyl group, pyridyl group,
Radinyl group, pyrimidinyl group, pyridazinyl group, pyrazo
Ryl group, quinoxalinyl group, quinolyl group, dihydroiso
Indolyl group, dihydroindolyl group, thionaphthenyl
Group, naphthyridinyl group, phenazinyl group, benzimida
Zolyl group, benzoxazolyl group, benzothiazolyl
Group, benzotriazolyl group, benzofuranyl group, thiazo
Ryl group, thiadiazolyl group, thienyl group, pyrrolyl group,
Furyl group, furzanyl group, triazolyl group, benzodio
Group consisting of a xanyl group and a methylenedioxyphenyl group
Aromatic heterocyclic group or isoxazolini selected from
Group, isoxazolidinyl group, tetrahydropyridyl
Group, imidazolidinyl group, tetrahydrofuranyl group,
Perazinyl group, piperidinyl group, pyrrolidinyl group, pyro
Linyl group, morpholino group, tetrahydroquinolinyl group and
And tetrahydroisoquinolinyl groups.
Aliphatic heterocyclic group, W₂₀Is a single bond, oxygen atom, sulfur
Yellow atom, SO, SO₂, NR_t0, SO₂NR_{t 0}, N
(R_t0) SO₂NR_u0, N (R_t0) SO₂, 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) = C
R_r0, C≡C, CO, CS, OC (O), OC (O)
NR_t0, OC (S) NR_t0, SC (O), SC
(O) NR_t0Or C (O) O (where R_t0
And R_u0Is a hydrogen atom or a lower alkyl group,
Hydroxyl group, cyano group, halogen atom,
Toro group, carboxyl group which may be protected, carba group
Moyl group, formyl group, lower alkanoyl group, lower alkyl
A canoyloxy group, an 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 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, optionally protected 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 alkylsulfinyl group, lower alkylsulfo
Nyl group, lower alkylsulfonylamino group, protected
Optionally hydroxyimino group and lower alkoxyimid
Or a substituent selected from the group consisting of
Optionally having 1 to 3 lower alkyl groups,
Represents a reel group or an aralkyl group), Y₃₀And Y
₄₀Are the same or different and are a single bond or a linear or
A branched lower alkylene group).
Or a lower alkyl group, an optionally protected hydroxyl group,
Ano group, halogen atom, nitro group, protected
Carboxyl group, carbamoyl group, formyl group, lower
Alkanoyl group, lower alkanoyloxy group, protected
Optionally a hydroxy lower alkyl group, a cyano lower alkyl group
Alkyl group, halo-lower alkyl group, which may be protected
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, which may be protected
Amino group, lower alkylamino group, di-lower alkylamino
Group, tri-lower alkylammonio group, amino-lower alkyl
Kill group, lower alkylamino lower alkyl group, di-lower alkyl group
Alkylamino lower alkyl group, tri-lower alkyl ammonium
Nio lower alkyl group, lower alkanoylamino group, allo
Ilamino group, lower alkanoylamidino lower alkyl
Group, lower alkylsulfinyl group, lower alkylsulfo
Nyl group, lower alkylsulfonylamino group, protected
Optionally hydroxyimino group and lower alkoxyimid
And a substituent selected from the group consisting of₃₀
-W₂₀-Y₄₀-R_s0(Where R_s0, W₂₀, Y
₃₀And Y₄₀Has the meaning given above)
A substituent selected from the group consisting of
May have from 3 to 3 identical or different substituents
It is a lower alkyl group or forms a nitrogen atom with X
And R₂₀And R₃₀Are the same or different and are independent
Hydrogen, optionally protected hydroxyl, lower alkyl
Group, lower alkoxy group or formula: Y₃₀-W₂₀−
Y₄₀-R_s0(Where R_s0, W₂₀, Y₃₀And Y
₄₀Is a substituent represented by the above meaning)
Or R₂₀And R₃₀Any one of R₁₀And X
Form together, Embedded image And Embedded image A saturated 5- to 8-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
Or together form a spirocyclo lower alkyl
Or an oxo group together with the bonding Z, or
Are the Z, R₁₀And nitrogen and oxygen together with X
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, optionally protected hydroxyl group, cyano group, halogen
Atom, nitro group, carboxyl which may be protected
Group, carbamoyl group, formyl group, lower alkanoyl
Group, lower alkanoyloxy group, optionally protected
Hydroxy lower alkyl group, cyano lower alkyl group, c
Lower alkyl group, optionally protected carboxy
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl
Coxy group, lower alkoxycarbonyl group, lower alkoxy
Cicarbonylamino group, lower alkoxycarbonylamido
Lower alkyl group, lower alkyl carbamoyl group, di-lower
Lower alkylcarbamoyl group, carbamoyloxy group, low
Lower alkyl carbamoyloxy group, di-lower alkyl carb
Bamoyloxy group, optionally protected amino group, low
Lower alkylamino group, di-lower alkylamino group, tri-lower
Primary alkylammonio group, optionally protected amino
Lower alkyl group, lower alkylamino lower alkyl group,
Di-lower alkylamino lower alkyl group, tri-lower alkyl
Luammonio lower alkyl group, lower alkanoylamino
Group, aroylamino group, lower alkanoylamidino lower
Alkyl group, lower alkylsulfinyl group, lower alkyl
Rusulfonyl group, lower alkylsulfonylamino group,
Protected hydroxyimino groups and lower alcohols
A substituent selected from the group consisting of a xyimino group; and
Formula: Y₁₀-W₁₀-Y₂₀-R_p0(Where R
_p0Has 1 to 3 hydrogen atoms or 1 to 3 substituents
A lower alkyl group or a lower alkenyl group which may be
Or a lower alkynyl group or the substituent
3 and even Embedded image A 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, isoindolyl group, indazolyl group
Group, indolyl group, indolizinyl group, isothiazolyl group
Group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazi
Nil group, pyrazolyl group, quinoxalinyl group, quinolyl
Group, dihydroisoindolyl group, dihydroindolyl
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, tetrahydropyranyl group, piperazinyl
Group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
Morpholino group, tetrahydroquinolinyl group and tetrahi
Aliphatic selected from the group consisting of droisoquinolinyl groups
Heterocyclic group, W₁₀Is a single bond, an oxygen atom, a sulfur atom, S
O, SO₂, NR_q0, SO₂NR_q0, N (R_q0)
SO₂NR_r0, N (R_q0) SO₂, CH (O
R_q0), CONR_q0, N (R_q0) CO, N (R
_q0) CONR_r0, N (R_q0) COO, N
(R_q0) CSO, N (R_q0) 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_q0Or C (O) O (where R
_q0And R_r0Is a hydrogen atom or a lower alkyl group,
A cyclo lower alkyl group, an optionally protected hydroxyl group,
Cyano group, halogen atom, nitro group, protected
Good carboxyl, carbamoyl, formyl, low
Lower alkanoyl group, lower alkanoyloxy group, protected
An optionally substituted hydroxy lower alkyl group, cyano lower alkyl group
Alkyl group, halo-lower alkyl group, protected
Carboxy lower alkyl group, carbamoyl lower alkyl
Group, lower alkoxy group, lower alkoxycarbonyl
Group, lower alkoxycarbonylamino group, lower alkoxy
Cicarbonylamino lower alkyl group, lower alkyl carb
Bamoyl group, di-lower alkylcarbamoyl group, carbamo
Yloxy group, lower alkylcarbamoyloxy group, di
Lower alkylcarbamoyloxy group, protected
Good amino group, lower alkylamino group, di-lower alkyl
Amino group, tri-lower alkylammonio group, protected
Optionally lower amino 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 alk
Neuylamidino lower alkyl group, lower alkyl sulfy
Nyl group, lower alkyl sulfonyl group, lower alkyl sulf
A honylamino group, an optionally protected hydroxyimi
Selected from the group consisting of amino groups and lower alkoxyimino groups
Substituent or one to three substituents as appropriate
Lower alkyl group, aryl group or aralkyl
Y)₁₀And Y₂₀Are the same or different
One single bond or one of the bicyclic or tricyclic fused rings
Linear or branched lower alkyl which may be present
Selected from the group consisting of the substituents represented by
Substituents, optionally 1 to 3 identical or different
Substituents, and optionally 1 to 3 identical or
Cyclo lower alkyl group optionally having different substituents,
Reel group, imidazolyl group, isoxazolyl group, iso
Quinolyl group, isoindolyl group, indazolyl group,
Drill group, indolizinyl group, isothiazolyl group, ethyl
Rangeoxyphenyl group, oxazolyl group, pyridyl
Group, pyrazinyl group, pyrimidinyl group, pyridazinyl group,
Pyrazolyl group, quinoxalinyl group, quinolyl group, dihydride
Loisoindolyl group, dihydroindolyl group, thionaph
Tenyl, naphthyridinyl, phenazinyl, benzo
Imidazolyl group, benzoxazolyl group, benzothiazo
Ryl group, benzotriazolyl group, benzofuranyl group,
Azolyl group, thiadiazolyl group, thienyl group, pyrrolyl
Group, furyl group, furazanyl group, triazolyl group, benzo
Dioxanyl group and methylenedioxyphenyl group
Aromatic heterocyclic groups selected from the group consisting of
Nil group, isoxazolidinyl group, tetrahydropyridyl
Group, imidazolidinyl group, tetrahydrofuranyl group,
Trahydropyranyl group, piperazinyl group, piperidinyl
Group, pyrrolidinyl group, pyrrolinyl group, morpholino group, t
Trahydroquinolinyl group and tetrahydroisoquinolini
Consisting of an aliphatic heterocyclic group selected from the group consisting of
May be fused with a ring selected from the group, Embedded imageAnd Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
Forming an 8-membered ring group;₄₀And R₅₀Are the same or
Differently, hydrogen, halogen, protected
A good hydroxyl group, an amino group which may be protected or
Formula: Y₃₀-W₂₀-Y₄₀-R_s0(Where R_s0,
W₂₀, Y₃₀And Y₄₀Has the above meaning)
Substituent or lower alkyl group, cyano group, nitro
Group, carboxyl group which may be protected, carbamoy
Group, formyl group, lower alkanoyl group, lower alkano
An yloxy group, an optionally protected hydroxy lower amine
Alkyl group, cyano lower alkyl group, halo lower alkyl
Group, an optionally protected 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, optionally protected amino group, lower alkylamino
Group, di-lower alkylamino group, tri-lower alkylan
Monio group, amino lower alkyl which may be protected
Group, lower alkylamino lower alkyl group, di-lower alkyl
L-amino lower alkyl group, tri-lower alkyl ammonium
Lower alkyl group, lower alkanoylamino group, aroyl
Amino group, lower alkanoylamidino lower alkyl group,
Lower alkylsulfinyl group, lower alkylsulfonyl
Group, lower alkylsulfonylamino group, protected
Hydroxyimino group and lower alkoxyimino group
And a substituent selected from the group consisting of:₃₀-W
₂₀-Y₄₀-R_s0(Where R_s0, W₂₀, Y₃₀
And Y₄₀Has the meaning described above)
A substituent selected from the group consisting of 1 to
A lower group which may have three identical or different substituents
Represents an alkyl group, an aryl group or an aralkyl group,
formula Embedded image Represents a single bond or a double bond];
General formula (IV) Embedded image [Wherein, Ar₀Represents a pyridyl group, a pyrimidinyl group, a pyra
Dinyl group, pyridazinyl group, thiazolyl group, isothiazo
Ryl, oxazolyl, isoxazolyl, pyrazolyl
Group, pyrrolyl group, imidazolyl group, indolyl group, i
Soindolyl, quinolyl, isoquinolyl, benzo
From the group consisting of thiazolyl and benzoxazolyl
A selected nitrogen-containing heteroaromatic group, wherein (1) a lower
Alkyl, optionally protected hydroxyl, cyano,
Logen atom, nitro group, carboxyl which may be protected
Sil group, carbamoyl group, formyl group, lower alkanoy
Or lower alkanoyloxy group, which may be protected
Hydroxy lower alkyl group, cyano lower alkyl group,
Halo-lower alkyl, optionally protected carboxy
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl group
Lucoxy group, lower alkoxycarbonyl group, lower alcohol
Xycarbonylamino group, lower alkoxycarbonyl group
Mino lower alkyl group, lower alkyl carbamoyl group, di
Lower alkylcarbamoyl group, carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylca
Rubamoyloxy group, an amino group which may be protected,
Lower alkylamino group, di-lower alkylamino group, tri
Lower alkyl ammonium group, amino lower alkyl group, lower
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
Rukylsulfinyl group, lower alkylsulfonyl group, low
Secondary alkylsulfonylamino group, which may be protected
A hydroxyimino group and a lower alkoxyimino group.
And a substituent selected from the group:₁₀-W₁₀−
Y₂₀-R_p0(Where R_p0, W₁₀, Y₁₀And Y
₂₀Has the meaning described above).
1 to 3 substituents selected from the group
Nitrogen-containing heterocyclic groups which may have the same or different substituents
Aromatic ring group, (2) lower alkyl group, lower alkanoyl
Group, lower alkanoyloxy group, optionally protected
Hydroxy lower alkyl group, cyano lower alkyl group, c
Lower alkyl group, optionally protected carboxy
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl
Coxy group, lower alkoxycarbonyl group, lower alkoxy
Cicarbonylamino group, lower alkoxycarbonylamido
Lower alkyl group, lower alkyl carbamoyl group, di-lower
Lower alkylcarbamoyl group, carbamoyloxy group, low
Lower alkyl carbamoyloxy group, di-lower alkyl carb
Bamoyloxy group, lower alkylamino group, di-lower alkyl
Killamino group, tri-lower alkylammonio group, protected
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
Killsulfinyl group, lower alkylsulfonyl group, lower
Alkylsulfonylamino group and lower alkanoylamino
Substituents selected from the group consisting of dino-lower alkyl groups
(Hereinafter abbreviated as a substituent on a ring which may be protected)
The carbon atom on the ring to which it is attached, its adjacent carbon atoms, and
A carbon atom on the substituent on the ring which may be protected, an acid
Together with elementary and / or nitrogen atoms, Embedded image 5 members that may be protected selected from the group consisting of
A nitrogen-containing heteroaromatic group forming a 7-membered ring, or (3)
Formula: Y₁₀-W₁₀-Y₂₀-R_p0(Where Y₁₀,
W₁₀, Y₂₀And R_p0Has the above meaning)
Carbon atom on the ring to which the substituent to be attached is adjacent
Carbon atoms and carbon atoms, oxygen atoms and
And / or together with the nitrogen atom, Embedded image 5 members that may be protected selected from the group consisting of
Shows a nitrogen-containing heteroaromatic group forming a 7-membered ring]
With the compound represented by the general formula (II) Embedded image [Wherein, Ar₀, X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] and a protecting group
By removing, general formula (I) Embedded image [Wherein, Ar represents a pyridyl group, a pyrimidinyl group, a pyrazine
Nil, pyridazinyl, thiazolyl, isothiazoly
Group, oxazolyl group, isoxazolyl group, pyrazolyl
Group, pyrrolyl group, imidazolyl group, indolyl group, iso
Indolyl, quinolyl, isoquinolyl, benzothi
Selected from the group consisting of azolyl and benzoxazolyl
Selected nitrogen-containing heteroaromatic group, wherein (1) lower alkyl
Kill group, hydroxyl group, cyano group, halogen atom, nitro group,
Carboxyl, carbamoyl, formyl, lower
Lucanoyl group, lower alkanoyloxy group, hydroxy
Lower alkyl group, cyano lower alkyl group, halo lower alkyl
Kill group, carboxy lower alkyl group, 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, amino group,
Lower alkylamino group, di-lower alkylamino group, tri
Lower alkyl ammonium group, amino lower alkyl group, lower
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
Rukylsulfinyl group, lower alkylsulfonyl group, low
Primary alkylsulfonylamino group, hydroxyimino group and
Selected from the group consisting of
Substituent and formula: Y₁-W₁-Y₂-R_p(Where R
_pHas 1 to 3 hydrogen atoms or 1 to 3 substituents
Lower alkyl group, lower alkenyl group
Represents a lower alkynyl group or the substituent,
Pieces and even Embedded image A 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, isoindolyl group, indazolyl group
Group, indolyl group, indolizinyl group, isothiazolyl group
Group, ethylenedioxyphenyl group, oxazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazi
Nil group, pyrazolyl group, quinoxalinyl group, quinolyl
Group, dihydroisoindolyl group, dihydroindolyl
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, tetrahydropyranyl group, piperazinyl
Group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group,
Morpholino group, tetrahydroquinolinyl group and tetrahi
Aliphatic selected from the group consisting of droisoquinolinyl groups
Heterocyclic group, W₁Is a single bond, an oxygen atom, a sulfur atom, S
O, SO₂, NR_q, SO₂NR_q, N (R_q) SO₂
NR_r, N (R_q) SO₂, CH (OR_q), CONR
_q, N (R_q) CO, N (R_q) CONR_r, N
(R_q) COO, N (R_q) CSO, N (R_q) CO
S, C (R_q) = CR_r, C≡C, CO, CS, OC
(O), OC (O) NR_q, OC (S) NR_q, SC
(O), SC (O) NR_qOr C (O) O (here
And 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, carbamoyl group,
Formyl group, lower alkanoyl group, lower alkanoyl group
Xyl 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
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, amino group, lower alkylamino group, di-lower alkyl
Killamino group, tri-lower alkylammonio group, amino
Lower alkyl group, lower alkylamino lower alkyl group,
Di-lower alkylamino lower alkyl group, tri-lower alkyl
Luammonio lower alkyl group, lower alkanoylamino
Group, aroylamino group, lower alkanoylamidino lower
Alkyl group, lower alkylsulfinyl group, lower alkyl
Rusulfonyl group, lower alkylsulfonylamino group,
Consists of a droxyimino group and a lower alkoxyimino group
A substituent selected from the group or 1 to 3
A lower alkyl group or an aryl group which may have
Or an aralkyl group), Y₁And Y₂Are the same or
Differently, a single bond or said bicyclic or tricyclic fused ring
A linear or branched lower group which may have one
Represents an alkylene group)
Selected substituents, and optionally 1 to 3 identical or
Is a nitrogen-containing heteroaromatic ring optionally having a different substituent
Group, (2) lower alkyl group, lower alkanoyl group, lower
Alkanoyloxy group, hydroxy lower alkyl group,
Ano-lower alkyl group, halo-lower alkyl group, carboxy
Lower alkyl group, carbamoyl lower alkyl group, lower alkyl group
Lucoxy group, lower alkoxycarbonyl group, lower alcohol
Xycarbonylamino group, lower alkoxycarbonyl group
Mino lower alkyl group, lower alkyl carbamoyl group, di
Lower alkylcarbamoyl group, carbamoyloxy group,
Lower alkylcarbamoyloxy group, di-lower alkylca
Rubamoyloxy group, lower alkylamino group, di-lower amino group
Alkylamino group, tri-lower alkylammonio group,
Lower alkyl group, lower alkylamino lower alkyl
Group, di-lower alkylamino lower alkyl group, tri-lower alkyl group
Lucirmonio lower alkyl group, lower alkanoylua
Mino group, aroylamino group, lower alkylsulfinyl
Group, lower alkylsulfonyl group, lower alkylsulfonyl group
Ruamino group and lower alkanoylamidino lower alkyl
Substituents selected from the group consisting of
Abbreviated. ) To the carbon atom on the ring to which it is attached,
Carbon atom, oxygen atom and
And / or together with the nitrogen atom Embedded image Form a 5- to 7-membered ring selected from the group consisting of
A nitrogen-containing heteroaromatic group or the formula (3): Y₁-W₁-Y₂−
R_p(Where Y₁, W₁, Y₂And R_pHas the above meaning
A) a carbon atom on the ring to which the substituent represented by
A carbon atom on the adjacent carbon atom and the substituent,
Together with oxygen and / or nitrogen atoms, Embedded image Form a 5- to 7-membered ring selected from the group consisting of
A nitrogen-containing heteroaromatic group, R₁Is a hydrogen atom or a formula: Y
₃-W₂-Y₄-R_s(Where R_sIs a hydrogen atom or the
Lower alkyl optionally having 1 to 3 substituents
Kill group, lower alkenyl group, lower alkynyl group, cyclo
Lower alkyl group, aryl group, imidazolyl group, isothio
Xazolyl group, isoquinolyl group, isoindolyl group, i
Ndazolyl, indolyl, indolizinyl, iso
Thiazolyl group, ethylenedioxyphenyl group, oxazo
Ryl group, pyridyl group, pyrazinyl group, pyrimidinyl group,
Pyridazinyl, pyrazolyl, quinoxalinyl,
Noryl group, dihydroisoindolyl group, dihydroindo
Ryl, thionaphthenyl, naphthyridinyl, phena
Dinyl group, benzimidazolyl group, benzoxazolyl
Group, benzothiazolyl group, benzotriazolyl group, ben
Zofuranyl group, thiazolyl group, thiadiazolyl group, thie
Nil, pyrrolyl, furyl, furazanyl, tria
Zolyl group, benzodioxanyl group and methylenedioxy
Aromatic heterocyclic groups selected from the group consisting of phenyl groups
Or isoxazolinyl group, isoxazolidinyl group,
Trahydropyridyl group, imidazolidinyl group, tetrahi
Drofuranyl, piperazinyl, piperidinyl,
Loridinyl group, pyrrolinyl group, morpholino group, tetrahi
Droquinolinyl and tetrahydroisoquinolinyl groups
An aliphatic heterocyclic group selected from the group consisting of: W₂Is simple
If oxygen, sulfur, SO, SO₂, NR_t, SO
₂NR_t, N (R_t) SO₂NR_u, N (R_t) S
O₂, CH (OR_t), CONR_t, N (R_t) CO,
N (R_t) CONR_u, N (Rt) 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_tOr C
(O) O (where R_tAnd R_uIs a hydrogen atom
Or lower alkyl group, hydroxyl group, cyano group, halogen source
Nitro, carboxyl, carbamoyl, phor
Mill 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 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
Selected substituents or one to three substituents
A lower alkyl group, an aryl group or
Aralkyl group), Y₃And Y₄Are the same or different
A single bond or a linear or branched lower alkyl
A substituent) 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 coxiimino groups; and
Formula: Y₃-W₂-Y₄-R_s(Where R_s, W₂, Y₃
And Y₄Has the meaning described above).
A substituent selected from the group consisting of 1 to
A lower radical which may have three identical or different substituents;
A nitrogen atom or forms a nitrogen atom with X;
R₂And R₃Are the same or different and are independently hydrogen
Hydroxyl group, lower alkyl group, lower alkoxy group
Is the formula: Y₃-W₂-Y₄-R_s(Where R_s, W₂, Y
₃And Y₄Has the same meaning as described above)
Or R₂And R₃Any one of R₁And X
Form together, Embedded image And Embedded image A saturated 5- to 8-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
Or together form a spiro lower alkyl group,
Forming an oxo group with the bonding Z, or
Z, R₁And nitrogen, oxygen and sulfur together with X
One heteroatom selected from the group consisting of atoms
May further include a lower alkyl group or a substituent.
Spirocyclo lower alkyl group which may have, 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,
Ruboxyl 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 coxiimino groups; and
Formula: Y₁-W₁-Y₂-R_p(Where R_p, W₁, Y₁
And Y₂Has the meaning described above).
A substituent selected from the group consisting of 1 to
Three identical or different substituents, and optionally 1 to
Cyclo which may have three identical or different substituents
Lower alkyl group, aryl group, imidazolyl group, isothio
Xazolyl group, isoquinolyl group, isoindolyl group, i
Ndazolyl, indolyl, indolizinyl, iso
Thiazolyl group, ethylenedioxyphenyl group, oxazo
Ryl group, pyridyl group, pyrazinyl group, pyrimidinyl
Group, pyridazinyl group, pyrazolyl group, quinoxalinyl
Group, quinolyl group, dihydroisoindolyl group, dihydro
Indolyl, thionaphthenyl, naphthyridinyl,
Phenazinyl group, benzimidazolyl group, benzoxa
Zolyl, benzothiazolyl, benzotriazolyl
Group, benzofuranyl group, thiazolyl group, thiadiazolyl
Group, thienyl group, pyrrolyl group, furyl group, frazanyl
Group, triazolyl group, benzodioxanyl group and methyl
Aromatics selected from the group consisting of dioxyphenyl groups
Heterocyclic group, isoxazolinyl group, isoxazolidini
Group, tetrahydropyridyl group, imidazolidinyl group,
Tetrahydrofuranyl group, tetrahydropyranyl group,
Perazinyl group, piperidinyl group, pyrrolidinyl group, pyro
Linyl group, morpholino group, tetrahydroquinolinyl group and
And tetrahydroisoquinolinyl groups.
With a ring selected from the group consisting of aliphatic heterocyclic groups
May be, Embedded imageAnd Embedded image A saturated or unsaturated 5-membered member selected from the group consisting of
Forming an 8-membered ring group;₄And R₅Are the same or different
Means hydrogen, halogen, hydroxyl, amino
Kuha formula: Y₃-W₂-Y₄-R_s(Where R_s, W₂,
Y₃And Y₄Has the meaning described above)
Or lower alkyl, cyano, nitro, carboxy
Group, carbamoyl group, formyl group, lower alkanoyl
Group, lower alkanoyloxy group, hydroxy lower alkyl
Group, cyano lower alkyl group, halo lower alkyl group,
Ruboxyl 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 coxiimino groups; and
Formula: Y₃-W₂-Y₄-R_s(Where R_s, W₂, Y₃
And Y₄Has the meaning described above)
A substituent selected from the group consisting of 1 to 3
Lower substituents which may have the same or different substituents
A alkyl group, an aryl group or an aralkyl group,
X, Y, Z and formula Embedded image Has the meaning described above].
And can be manufactured. The compound of the general formula (I) is
For the compound of II), for example, trichloroacetylation or
After performing p-nitrophenoxycarbonylation,
Also prepared by reacting with a compound of formula (VI).
Can be 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)
The compound of the general formula (IV) is preferably approximately
The reaction is carried out using 1 mole. Further, the compound of the general formula (III)
Trichloroacetylated or p-nitrophenoxycarbo
Nylation is carried out based on 1 mole of the compound of the general formula (III).
The corresponding halide is present in an amount of 1 to 5 moles, preferably about 1 mole.
This is done using Then, the obtained general formula (III)
Trichloroacetylated compound or p-nitrophen
The compound of the general formula (VI)
Reaction using 1-5 mol, preferably about 1 mol of compound
I do. [0004] The reaction is usually carried out, for example, in tetrahydrofura.
Ethers such as benzene and dioxane, such as benzene and tol
Aromatic hydrocarbons such as ene or their mixed solvents
It is performed in an active solvent. The reaction temperature depends on the starting compounds used.
The solvent used in the reaction is usually from 0 ° C.
, Preferably 20 to 100 ° C. The reaction time is usually from 20 minutes to 24 hours, preferably
It is preferably completed in 1 to 4 hours,
Can be. The compound of the general formula (III)
In the compound of the formula (IV), for example, a hydroxyl group, an amino group,
For example, a functional group such as a carboxyl group or containing the functional group
Hydroxy lower alkyl group, amino lower alkyl group,
When a substituent such as a ruboxyl lower alkyl group is present,
The hydroxyl group, amino group, carboxyl group, hydroxy lower
Alkyl group, amino lower alkyl group, carboxy lower alcohol
A substituent such as an alkyl group may be appropriately substituted with a hydroxyl-protecting group,
After protecting with a protecting group for a group or a protecting group for a carboxyl group.
It is preferable to take action. One obtained after the end of the reaction
By removing the protecting group of the compound of the general formula (II)
Thus, the compound of the general formula (I) can be produced. Examples of the hydroxyl-protecting group include, for example, 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, for example, benzyl
Aralkyl groups such as phenyl and p-nitrobenzyl groups;
Acyl groups such as formyl group and acetyl group; for example, ethoxy
Low carbonyl group, tert-butoxycarbonyl group, etc.
Higher alkoxycarbonyl group; for example, benzyloxycar
Carbonyl, p-nitrobenzyloxycarbonyl, etc.
And an aralkyloxycarbonyl group.
Nitrobenzyl group, tert-butoxycarbonyl group,
A benzyloxycarbonyl group and the like are preferred. Examples of carboxyl-protecting groups include, for example,
Lower alkyl such as methyl group, ethyl group and tert-butyl group
A kill group; for example, a benzyl group, a p-methoxybenzyl group, etc.
Aralkyl group and the like, especially methyl group, ethyl
Group, benzyl group and the like. Removal of the protecting group is a matter of stabilizing the kind and the compound.
The method described in the literature [Protective
Groups in Organic Synthesis (Pro
tive Groups in Organic
  Synthesis), T.W. W. Green (TW.
Greene), John Wiley & Son
Company (1981)] or an equivalent method.
Solvolysis using acids or bases, metal hydrides
Chemical reduction using a complex or palladium on carbon catalyst, la
Performing by catalytic reduction using a nickel catalyst, etc.
Can be. The compound of the formula (I) is a bicyclic fused ring group
For example, when R is formed, for example, R₂And R₃
Is a compound which forms an oxo group with Z, that is, a compound of the general formula
(I ') Embedded image [Wherein, Ar, X, Y, R₁, R₄And R₅Is the above
Has the meaning of the general formula (IV) Embedded image [Wherein, Ar₀Has the meaning described above]
Compound and general formula (III ′) Embedded image [Where X, Y, R₁₀, R₄₀And R₅₀Is the above
Having a meaning of the general formula (I)
I'-a) Embedded image [Wherein, Ar₀, X, Y, R₁₀, R₄₀And R
₅₀Has the above-mentioned meaning.]
It can be produced by removing a group. Each process
Can be performed in the same manner as in Production Method A. Note that this manufacturing method uses R₂And R₃Is a hydrogen source
For the production of a compound that is an atom, an alkyl group or an alkoxy group
Can also be applied. [0014]Manufacturing method B The compound of the general formula (I) has the general formula (V) Embedded image [Where X, Y, Z, R₁₀, R₂₀, R₃₀,
R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] and a compound represented by the general formula
(VI) Embedded image [Wherein, Ar₀Has the meaning described above]
And reacting the compound with a compound of the general formula (II) Embedded image[Wherein, Ar₀, X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] and a protecting group
By removing, general formula (I) Embedded image [Wherein, Ar, X, Y, Z, R₁, R₂, R₃, R₄,
R₅And formula Embedded image Has the above-mentioned meaning.]
Can be. The steps of the present production method are represented by the general formula of production method A
Preparation of the compound of the formula (I) and the compound of the formula (II)
It can be performed according to the method of the process. [0016]Manufacturing method C In the present production method, in general formula (I), Ar is pyrazolyl
This is a method for producing a compound as a base. That is, the general formula (VII) Embedded image Wherein L is converted to another functional group which may be protected
Reactive substituents with possible functional groups, T₁₀Is a single bond
Or, if appropriate, a linear group which may have a protected substituent.
Or branched lower alkylene, aryl,
An aromatic heterocyclic group, an aliphatic heterocyclic group or an aralkyl group;
Ar having a convertible functional group containing₀The compound of
And the general formula (VIII) H₂N-NH-R₆₀    (VIII) [Wherein, R₆₀Represents a protecting group for a hydrogen atom or an amino group.
To a compound of the general formula (IX) Embedded image [Where T is₁₀, R₆₀And L have the meaning described above.
And a compound of the general formula (III) Embedded image [Where X, Y, Z, R₁₀, R₂₀, R₃₀,
R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning.]
The reactive derivative is reacted appropriately in the presence of a base,
Formula (X) Embedded image [Where X, Y, Z, T₁₀, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀, R₆₀,formula Embedded image And L have the above-mentioned meanings].
Conversion reaction of the substituent L and / or removal of the protecting group.
And the general formula (I ″) Embedded image [Where T is₁Is a single bond or a linear or branched low
Lower alkylene group, aryl group, aromatic heterocyclic group, aliphatic
Convertible functional groups containing heterocyclic or aralkyl groups
Ar, Q having the formula:₁-Y₂-R_p(Here
And W₁, Y₂And R_pHas the meaning described above), X,
Y, Z, R, R₁, R₂, R₃, R₄, R₅And formula Embedded image Has the above-mentioned meaning].
Wear. The compound of the general formula (VII) and the compound of the general formula (VI)
By reacting the compound of formula II) with a compound of general formula (IX)
The reaction for producing the compound is performed by reacting 1 mole of the compound of the general formula (VII).
1 mol to excess of the compound of the general formula (VIII)
Moles, preferably 2-3 moles, e.g.
Performed by reacting in alcohol such as ethanol
be able to. The compound of the general formula (VIII) used is an acid
When a salt with, for example, a base such as triethylamine
2 to 5 mol per 1 mol of the compound of the general formula (VIII),
Preferably in the presence of a few moles of the formula (VIII)
Preferably, a free form of the compound is produced. The reaction temperature is usually from 20 ° C.
Up to the boiling point of the solvent
The reaction time is usually 1 hour to 48 hours, preferably
2 hours to 24 hours. Compounds of the general formula (IX),
The compound of I) and the reactive derivative of formate are optionally converted
By reacting in the presence of a base, a compound of general formula (X) is produced.
The reaction to be performed is 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
Preferably, 1 to 3 mol is used. Reactivity induction of formate
The conductor was used in an amount of 1 mol per 1 mol of the compound of the general formula (IX).
In excess of mol, preferably 1 to 3 mol,
1 mole to excess mole relative to the reactive derivative of stell,
Preferably, 1 to 3 mol is used. In addition, formic acid ester
Reactive derivatives form amide carboxylic esters.
There is no particular limitation as long as it is possible, but specific examples
For example, p-nitrophenyl chloroformate, methyl chloroformate
And the like. The reaction is usually carried out in an inert solvent.
Examples of the inert solvent include methylene chloride and chloroform.
Halogenated hydrocarbons such as ethyl ether;
Ethers such as tetrahydrofuran; for example, benzene,
Aromatic hydrocarbons such as toluene; for example, dimethylform
Aprotic polar solvents such as amide, acetone and ethyl acetate
And a mixed solvent thereof. The reaction temperature is determined by comparing the compound of formula (IX) with
In the reaction with a reactive derivative of an acid ester, the reaction is usually carried out at 20 ° C.
Or up to the boiling point of the solvent used in the reaction, preferably at 20 ° C.
~ 50 ° C, and the reaction time is usually 30 minutes ~ 24: 00
For 1 hour to 24 hours. This reaction is complete
Reacting with a compound of the general formula (III)
Is usually 20 ° C. to the boiling point of the solvent used for the reaction.
Up to the point, preferably 50 ° C to 100 ° C. Further, a metal complex is added to the compound of the general formula (X).
Carboxyl group is introduced as a catalyst and compared according to the usual method.
If necessary, after derivatization to amide, ester, etc.
To remove protecting groups such as hydroxyl, amino and carboxyl groups
By appropriately combining the removal reactions, the general formula
Compound (I '') can be produced. The compound of the general formula (X) is
A compound of the formula (IX), a compound of the general formula (III) and formic acid
Instead of using reactive derivatives of esters, for example,
For example, the compound of the general formula (III)
After reacting with phosgene to form an isocyanate, the general formula
It is also produced by reacting with the compound of (IX).
be able to. The reaction is usually carried out in an inert solvent.
Examples of the inert solvent include tetrahydrofuran and the like.
Can be The amount of each reagent used in the reaction is determined by the general formula (II)
Diphosgene is used in an amount of 1 mol to 1 mol of the compound of I).
The molar amount is in excess, preferably 1 mol.
The compound of the general formula (IX) is used in an amount of 1 mole to excess mole, preferably
Or 1 mole. The reaction temperature is usually from 20 ° C.
Up to the boiling point of the solvent
You. The reaction time is usually 30 minutes to 24 hours,
Preferably, it is 30 minutes to 6 hours. Conversion of the compound of the general formula (X) to another functional group
Converting reactive substituents L with possible functional groups
For example, when R is an aromatic ring and L is a halogen atom,
Phosphine ligands and salts using palladium complexes as catalysts
Example of a compound of general formula (X) and carbon monoxide in the presence of a group
For example, in an alcohol solvent such as methanol or ethanol,
To form an ester of the general formula (X)
The method of hydrolyzing the ester under neutral conditions is applicable.
You. An anti-functional compound having a functional group convertible to another functional group
The reactive substituent includes, for example, a hydroxyl group, an amino group,
Substituents such as a sil group, an ester group and a halogen atom;
It is. The amount of each reagent used in the reaction is represented by the general formula (X)
Per mole of the compound, for example, para
Didium complexes and, for example, 1,1-bis (diphenylphosphine)
Ino) Each of the phosphine ligands such as ferrocene
50% by weight, preferably 10-20% by weight;
For example, a base such as sodium bicarbonate is represented by the general formula (X).
2 mol to 10 mol, preferably 2 mol, per 1 mol of the compound
To 3 moles. The reaction temperature is usually from 20 ° C. to the reaction temperature.
Up to the boiling point of the solvent
The reaction time is usually 30 minutes to 24 hours, preferably
Is 5 hours to 24 hours. The carboxylic acid produced in this way is
The conversion method described below is a conversion method of the Ar substituent described below.
Can be performed in the same manner. After the completion of the reaction, necessary
Protection of hydroxyl group, amino group and carboxyl group etc.
By performing an appropriate combination of group removal reactions,
Compounds of formula (I ") can be prepared. The method for removing the protecting group depends on the type of the protecting group and
It depends on the stability of the target compound, etc.
Perform as appropriate according to the method described or a method equivalent thereto
Can be. Next, substitution of the compound of general formula (I) on Ar
A method for converting a substituent will be described. As described above, Ar represents various substituents.
Can have. For example, as shown in Production Method A and Production Method B
As such, a desired substituent was introduced into the initial starting compound.
Can be used to produce the desired compound.
You. However, in order to improve reactivity, yield, etc.,
For example -T₁-OR₇(Where R₇Is a hydroxyl group
A protecting group, T₁Has the meaning given above)
After the preparation of the compound of formula (II), further conversion of the functional groups is carried out.
(Conversion method A) or conversion of general formula (II)
Protect the urea part of the compound, then introduce the desired substituent
For example, the following conversion method B to conversion method H
Various conversion reactions can be performed as described above. [0038]Conversion method A This conversion method uses a functional group on Ar without protecting the urea moiety.
This is a method of performing group conversion. Various conversion methods are, for example,
General formula (II-c) Embedded image [Wherein, Ar_C0Is a substituent: -T₁-OR₇(here
Where R₇And T₁Has the meaning given above)
Ar₀X, Y, Z, R₁₀, R₂₀, R
₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
General formula (II-d) Embedded image [Wherein, Ar_d0Is a substituent: -T₁-OH (here
And T₁Has the above-mentioned meaning).₀To
X, Y, Z, R₁₀, R₂₀, R₃₀, R₄₀,
R₅₀And formula Embedded image Has the above-mentioned meaning] or a compound of the general formula
The compound of (II-d) is well known in synthetic organic chemistry.
Various synthetic methods for converting alcohols to amines
Using the general formula (II-e) Embedded image [Wherein, Ar_e0Is a substituent: -T₁-NH₂(here
Then T₁Has the above-mentioned meaning).
₀X, Y, Z, R₁₀, R₂₀, R₃₀, R
₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
You. The method for removing a protecting group for a hydroxyl group depends on the species of the protecting group.
And the stability of the target compound.
Appropriately according to the method described in the bibliography or a method analogous thereto.
I can. Various syntheses for converting alcohols to amines
Methods and reaction conditions include, for example, azodicarboxylic acid
Ethyl ester, triphenylphosphine and phthalate
Iwayu using amide (or diphenyl phosphate azide)
Mitsunobu reaction, or use of a base such as triethylamine
In the presence, a sulfonylating agent such as methanesulfonyl chloride
Sulfonylation and then phthalimide (also in the presence of a base)
Is the sodium phthalate
Treatment (or reduction) of imide (or azide) with hydrazine
Is preferred. The above reaction is usually carried out in an inert solvent,
As the inert solvent, for example, in the Mitsunobu reaction,
Trahydrofuran, chloroform, dimethoxyethane,
Benzene, toluene, etc., as well as sulfonylation and phthalate
In the reaction of imide (or sodium azide)
For example, methylene chloride, chloroform, tetrahi
Drofuran, benzene, ethyl acetate, dimethylforma
And the like. Further, the formation of a phthalimide group by hydrazine
In the removal reaction, for example, methanol, ethanol, etc.
Choles and the like further reduce hydrogen in the azide reduction reaction.
When using a metal halide complex, for example, ethyl ether, tet
Ethers such as lahydrofuran
When phosphine reduction is carried out with
In the reduction of hydrofuran or the like by catalytic reduction, for example,
Use alcohol such as ethanol or ethanol.
Is preferred. The amount of the reagent used is, for example,
In the reaction, 1 mole of the compound of the general formula (II-d) is
Zodicarboxylic acid diethyl ester, triphenylphosphine
And phthalimide (or diphenylphosphoric azide)
Is 1 mol to excess mol, preferably 1 to 5 mol
It is. Also, after sulfonylation, phthalimide (or
In the reaction for reacting sodium azide), the general formula (I)
One mole of the sulfonylating agent is used per mole of the compound of Id).
To excess mole, preferably 1 to 3 mole,
The base used is not 1 mol based on the sulfonylating agent.
Molar excess, preferably 1 to 3 mol. Next stage
Reaction to react talimide (or sodium azide)
In the above, phthalimide and
1 mole to excess mole of base or sodium azide, preferably
Preferably, 1 to 5 mol is used. Phthal with hydrazine
In the removal reaction of the imide group, one mole of the phthalimide compound was used.
And hydrazine is present in an amount of 1 mol to excess mol, preferably 1 mol.
To 10 moles, a metal hydride complex of an azide compound or tri
In the reduction reaction with phenylphosphine, one
1 mole to excess mole, preferably
1 to 2 mol. 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. Phthalimide with hydrazine
In the case of the group removal reaction, the reaction temperature is usually from 0 ° C.
Up to the boiling point of the solvent used, preferably from 20 ° C to 100 ° C.
° C, and the reaction time is usually 5 minutes to 48 hours, preferably
Or 30 minutes to 24 hours. Reduce the azide form
In the conversion to the amine form, metal hydride is used as a reducing agent.
When a complex is used, 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 triphenylphosphine was used as a reducing agent.
When using a reaction, the reaction temperature is usually from 20 ° C to the reaction temperature.
Up to the boiling point of the solvent used, preferably 30 ° C to 100 ° C
The reaction time is usually from 10 minutes to 48 hours, preferably
Or 30 minutes to 24 hours. Reduction by catalytic reduction
In the case of, the reaction temperature is usually 0 ° C to 100 ° C, preferably
Is 20 ° C to 50 ° C, and the reaction time is usually 10 minutes.
４８48 hours, preferably 10 minutes-24 hours. After completion of the reaction, necessary
Protection of hydroxyl group, amino group and carboxyl group etc.
By performing an appropriate combination of group removal reactions,
Compounds of formula (II-e) can be prepared. Among the compounds of the general formula (II-d),
Formula (II-d₁) Embedded image [Wherein, Ar_d1Is a substituent: -T₁-CH (R_d1)
—OH (where R_d1Is a hydrogen atom, as appropriate
A lower alkyl group which may have a protected substituent,
Aralkyl group, aromatic ring group, heteroaromatic ring group or nitrogen atom,
Hetero selected from the group consisting of oxygen and sulfur
One or more atoms may be included, and
A saturated or unsaturated aliphatic ring group which may have
Means T₁Has the above-mentioned meaning).
₀X, Y, Z, R₁₀, R₂₀, R₃₀, R
₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
An oxidation reaction is performed, and the compound represented by the general formula (II-d)₂) [Wherein, Ar_d2Is a substituent: -T₁-C (= O) -R
_d1(Where R_d1And T₁Has the above meaning
Ar)₀X, Y, Z, R
₁₀, R₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the meaning described above],
After the amination, the compound represented by the general formula (II-d)₃) [Wherein, Ar_d3Is a substituent: -T₁-CH (R_d1)
-NR_d2R_d3(Where R_d2And R
_d3Means that either one is a hydrogen atom or the same or different
May optionally have a protected substituent,
Lower alkyl group, aralkyl group, aromatic ring group, heteroaromatic ring
Consisting of a group or a nitrogen, oxygen, and sulfur atom
One or more heteroatoms selected from the group
Saturated or optionally substituted
Represents an unsaturated aliphatic ring group;_d1And T₁Is
Wherein Ar has the meaning₀Means X,
Y, Z, R_{1 0}, R₂₀, R₃₀, R₄₀, R₅₀as well as
formula Embedded image Has the above-mentioned meaning].
Wear. Formula (II-d)₁) To oxidize the compound
Formula (II-d₂The reaction for synthesizing the compound of
Above commonly known oxidation reactions can be applied
You. Formula (II-d)₂)) And R_d2R
_d3NH (where R_d2And R_d3Has the above meaning
The reductive amination reaction with the compound represented by
Formula (II-d₂)), 1 mole of the compound_d2R_d3
For 1 mol to excess mol of NH, preferably 3 to 5 mol
As a reducing agent, for example, sodium borohydride or
No 1 mol of sodium triacetoxyborohydride
Molar excess, preferably 3 to 5 mol, if necessary.
The molecular sieves 3A are represented by the general formula (II-d)₂)
Perform by adding 3 times the weight of the compound. The reaction is usually carried out in an inert solvent,
As the active solvent, chloroform, methanol or this
These mixed solvents are preferred. Reaction temperature is from 20 ℃
The boiling point of the inert solvent, preferably 20-60 ° C.
You. Formula (II-d)₁) From the general formula
(II-d₂) Through the compound of formula (II-d)₃)
In the step of synthesizing the compound of
Can be performed in the same way after protecting the
You. The thus obtained general formula (II-
The compound of c), the compound of general formula (II-d) and the general formula
The compound of (II-e) is obtained by removing a protecting group appropriately.
Thus, the compound of the general formula (I) can be produced.
The method for removing the protecting group depends on the type of the protecting group and the purpose of the purpose.
It depends on the stability of the compound, etc.
Can be carried out as appropriate according to the method or a method equivalent thereto.
You. [0052]Conversion method B In this production method, conversion is performed after protecting the urea portion.
Is the way. General formula (XI) Embedded image [Wherein, Ar_C0, X, Y, Z, R₁₀, R₂₀, R
₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning.] Is a compound of the general formula (II-
c) Embedded image [Wherein, Ar_C0Is a substituent: -T₁-OR₆(here
Where R₆And T₁Has the meaning given above)
Ar₀X, Y, Z, R₁₀, R₂₀, R
₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
In imines prepared from amines and paraformaldehyde
The starting compound for this conversion reaction
And the water of the compound of the general formula (XI)
By removing the protecting group for the acid group, the compound represented by the general formula (XII) Embedded image [Wherein, Ar_d0Is a substituent: -T₁-OH (here
And T₁Has the meaning described above).
₀X, Y, Z, R₁₀, R₂₀, R₃₀, R
₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
Wear. Reaction for producing compound of general formula (XI)
Is based on 1 mol of the compound of the general formula (II-c)
prepared from t-butylamine and paraformaldehyde
Using 3 to 5 moles, preferably 4 moles of imine
U. The above reaction is usually carried out in an inert solvent.
Chloroform, methyl chloride, etc.
Len, tetrahydrofuran and the like. The reaction temperature is usually from 50 ° C.
Up to the boiling point of the solvent
The reaction time is usually 12 hours to 72 hours, preferably
Is 24 hours to 72 hours. Encourage response as needed
One drop of a mineral acid such as sulfuric acid may be added to promote
No. The compound of the general formula (XII) is
Using the compound of I), the compound represented by the general formula (II-
The compound of the general formula (II-d) is produced from the compound of c)
Can be carried out according to the method of the step. The compound of the general formula (XII) has the general formula
A key intermediate for producing the compound of (I), for example
For example, as shown in the following conversion methods C to E, the general formula
Derivatization using the compound (XII) or a derivative thereof
It can be carried out. [0058]Conversion method C General formula (XII) Embedded image [Wherein, Ar_d0, X, Y, Z, R₁₀, R₂₀, R
₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] and a compound of the general formula (XII)
I) Embedded image [Wherein, Ar₂Is substituted by one or two nitro groups
A substituted phenyl group;₈Is one to three methoxy
Means a benzyl group substituted by a group]
By reacting with a compound, the compound represented by the general formula (XIV) Embedded image [Wherein, Ar_d1Is a substituent: -T₁−N (R₈) SO
₂Ar₂(Where T₁, R₈, Ar₂Is
Wherein Ar has the meaning₀Means X,
Y, Z, R₁₀, R₂₀, R₃₀, R₄₀, R₅₀as well as
formula Embedded image Has the above-mentioned meaning].
be able to. The reaction was carried out by reacting 1 mol of the compound of the formula (XII)
With respect to 1 mol of the compound of the general formula (XIII)
An excess mole, preferably 1 to 3 moles, is usually used for the Mitsunobu reaction.
It is done according to the law. For example, diethylazodicarboxy
Azodicarboxylic acid diesters such as
General formula (XII) by using phosphines such as luphosphine
To activate the compound of formula (XIII)
To give a compound of general formula (XIV)
be able to. The reaction is usually carried out in an inert solvent.
Examples of the inert solvent include methylene chloride and chloropho
Halogenated hydrocarbons such as Lum;
Ethers such as toluene and tetrahydrofuran or mixtures thereof.
Solvents and the like can be mentioned. The amount of the reagent used is determined according to the formula (XII)
Per mole of the compound of the formula
With diesters of azodicarboxylic acids such as xylates
Each of phosphines such as triphenylphosphine
Mole to excess mole, preferably 1 to 3 moles.
You. The reaction temperature is usually from 0 ° C. to the reaction temperature.
The solvent has a boiling point of preferably 20 ° C to 40 ° C. The reaction time is generally 1 hour to 24 hours, preferably
Preferably, it is 2 hours to 24 hours. After completion of the reaction, a usual treatment is carried out,
A crude product of the compound represented by (XIV) can be obtained.
Wear. The thus-obtained general formula (XIV)
Is purified by a conventional method to obtain a compound of the formula (XIV)
Can be obtained. From the compound of the general formula (XIV),
V) Embedded image[Wherein, Ar_d2Is a substituent: -T₁-NHSO₂Ar
₂(Where T₁, Ar₂Has the above meaning
Ar)₀X, Y, Z,
R₁₀, R₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
Normal removal of aralkyl groups, one of the amino-protecting groups
This is carried out according to the method described in the literature. From the compound of the general formula (XV), the compound of the general formula (XV)
I) Embedded image [Wherein, Ar_d3Is a substituent: -T₁−N (R_q) SO
₂Ar₂(Where R_q, T₁, Ar₂Is
Wherein Ar has the meaning₀Means X,
Y, Z, R₁₀, R₂₀, R₃₀, R₄₀, R₅₀as well as
formula Embedded image Has the above-mentioned meaning].
R per 1 mol of the compound of the general formula (XV)_q-OH (this
Where R_qHas the above meaning)
Using an excess mole, preferably 1 to 3 moles, of the general formula (X
Reaction of compound of formula II) with compound of general formula (XIII)
The reaction can be performed in the same manner as described above.
Similar conditions can be applied. The compound of the general formula (XVI)
VII) Embedded image [Wherein, Ar_d4Is a substituent: -T₁-NHR_q(here
In, R_q, T₁Has the aforementioned meaning)
The above Ar₀X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
For example, the hydrolysis of arylsulfonamide
Using thiophenol, sodium carbonate, etc.
Can be performed by acting in an inert solvent.
Wear. As the inert solvent, for example, dimethylforma
Mid and the like are preferred. R_qA synthetically convertible substituent
If present, it is necessary for the compound of general formula (XVI)
By introducing a substituent as appropriate by conducting a synthesis reaction according to
After that, the compound of the general formula (XVI) is converted from the compound of the general formula (XVI)
Conditions similar to those for the conversion to I) can be applied.
You. The reaction temperature is usually from 20 ° C.
Boiling point of the solvent used, preferably from 20C to 80C. The reaction time is usually from 2 hours to 48 hours, preferably
Preferably, it is 2 hours to 24 hours. General formula (XVII)
From the compound of general formula (II-f) Embedded image [Wherein, Ar_d4Is a substituent: -T₁-NHR_q(here
In, R_q, T₁Has the aforementioned meaning)
The above Ar₀X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula 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. Must
If necessary, use tetrahydrofuran, chloroform, etc.
The reaction can be carried out by mixing the active solvent and the acid. Ma
In addition, the compound of the general formula (XVI)
_qBy carrying out the conversion reaction of the above substituent,
A similar reaction can be performed for the compound into which
Wear. The compound of the general formula (II-f) is a compound of the general formula (XXI)
By subjecting the compound of II) to reductive amination,
Can be synthesized. In this synthesis method, a reductive
At an appropriate stage before and after the amination reaction, for example,
Urea by treatment with acid, trifluoroacetic acid, etc.
By removing the protecting group of the moiety, the compound represented by the general formula (II-
The compound of f) can be prepared. The compound in each step of the present production method is protected.
If any groups are present, then
Removal of these protecting groups and finally all
By removing the protecting group, the compound of general formula (I)
Can be manufactured. The method for removing the protecting group depends on the type of the protecting group and
It depends on the stability of the target compound, etc.
Perform as appropriate according to the method described or a method equivalent thereto
Can be. [0072]Conversion method D This conversion is a conversion of general formula (XVII) produced by conversion method C.
Using a compound represented by the general formula (XIX) Embedded image [Wherein, Ar_d5Is a substituent: -T₁-NR_q-T₂−
R_p(Where T₂Is a carbonyl group or a sulfo
A nyl group;_p, R_q, T₁, Ar₂Means the above
Ar as described above comprising₀X, Y,
Z, R₁₀, R₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the meaning given above], and then has the general formula
(II-g) Embedded image [Wherein, Ar_d5Is a substituent: -T₁-NR_q-T₂−
R_p(Where T₁, Ar₂, R_p, R_qAnd T
₂Has the meaning described above).₀Means
X, Y, Z, R₁₀, R₂₀, R₃₀, R₄₀, R
₅₀And formula Embedded image Has the above-mentioned meaning].
You. From the compound of the general formula (XVII)
The reaction for producing (XIX) is represented by the general formula (XVII)
Compound and general formula (XVIII) R_p-T₂-OH [R_pPassing
And T₂Has the meaning described above].
React with sulfonic acid or their reactive derivatives
It can be manufactured by the following. Formula (XVII
As a reactive derivative of carboxylic acid or sulfonic acid of I)
Are, for example, acid halides, mixed acid anhydrides, active esters
And active amides. Using a carboxylic acid of the general formula (XVIII)
, N, N'-dicyclohexylcarbodiimide
, 1-ethyl-3- (3-dimethylaminopropyl)
Carbodiimide, 2-chloro-1,3-dimethylimidazo
It is preferable to carry out the reaction in the presence of a condensing agent such as ril chloride.
Good. The compound of the formula (XVII) and the compound of the formula (XV)
The reaction with the compound of III) is carried out by the conversion of the general formula (XVII)
The compound of the general formula [(XVIII)
From 1 mol to excess mol, preferably from 1 to 5 mol
Done. The reaction is usually carried out in an inert solvent.
Examples of the inert solvent include methylene chloride and chloropho
Halogenated hydrocarbons such as Lum;
Ethers such as toluene and tetrahydrofuran;
Aromatic hydrocarbons such as toluene and toluene;
Aprotic poles such as lumamide, acetone and ethyl acetate
And a mixed solvent thereof. The reaction temperature is usually from -20 ° C to the reaction temperature.
The boiling point of the solvent used is preferably 0 ° C to 50 ° C. The reaction time is usually from 10 minutes to 48 hours,
Preferably, it is 30 minutes to 24 hours. In addition, the above reaction is performed in order to promote the reaction smoothly.
In the presence of a base. As the base
Is, for example, sodium hydroxide, potassium hydroxide,
Calcium, sodium carbonate, potassium carbonate, hydrogen carbonate
Inorganic bases such as sodium or, for example, triethylamido
, N-ethyldiisopropylamine, pyridine, 4-
Dimethylaminopyridine, N, N-dimethylaniline, etc.
Preferably, the reaction is performed in the presence of an organic base. The amount of the base used is represented by the general formula (XVII)
1 mole to excess mole, preferably 1 mole, relative to 1 mole of compound of I)
The preferred amount is 1 to 5 mol. Acid halide of the general formula (XVIII)
Is a carboxylic or sulfonic acid of the general formula (XVIII)
By reacting it with a halogenating agent according to a standard method.
Can be obtained. As the halogenating agent, for example, a salt
Thionyl chloride, phosphorus trichloride, phosphorus pentachloride,
, Phosphorus tribromide, oxalyl chloride, phosgene, etc.
Can be. Mixing of carboxylic acid of general formula (XVIII)
As the acid anhydride, a carboxylic acid of the general formula (XVIII) can be obtained by a conventional method.
According to the following, for example, ethyl chloroformate
Ter; aliphatic carboxylic acid chloride such as acetyl chloride
And the like. Activity of carboxylic acid of general formula (XVIII)
Esters can be prepared by a conventional method using a carboxylic acid of the general formula (XVIII).
For example, N, N'-dicyclohexylcarbodi
Imide, 1-ethyl-3- (3-dimethylaminopropyl
G) in the presence of a condensing agent such as carbodiimide,
Droxysuccinimide, N-hydroxyphthalimi
N-hydrocarbons such as 1-hydroxybenzotriazole
Xy compound; 4-nitrophenol, pentachlorophen
By reacting with phenol compounds such as phenol
Obtainable. Activity of carboxylic acid of general formula (XVIII)
The amide is prepared by using a carboxylic acid of the general formula [xviii] in a conventional manner.
Thus, for example, 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. Suitable acids for the compounds of the general formula (XIX), for example
For example, the compound of the general formula (I
The compound of Ig) can be prepared. If necessary
For example, inactive tetrahydrofuran, chloroform, etc.
The reaction can be carried out by mixing an ionic solvent and an acid. The compound of the general formula (II-g)
According to the method of the production method, the general formula (II-f) of the conversion method A
Can be produced as a starting material. [0088]Conversion method E This conversion method comprises the use of the compound of the general formula (XII)
General formula (XX) Embedded image [Wherein, Ar_h0Is a substituent: -T₁-OR_p(here
Where R_pAnd T₁Has the aforementioned meaning)
The above Ar₀X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula Embedded image Has the meaning given above], and then has the general formula
(II-h) Embedded image [Wherein, Ar_h0Is a substituent: -T₁-OR_p(here
In, R_pAnd T₁Has the above-mentioned meaning)
Ar₀X, Y, Z, R₁₀,
R₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
You. Using the compound of the general formula (XII)
The process for producing the compound of formula (XX) comprises the reaction of an alcohol with
Various synthesis methods and reaction conditions for converting to
Wear. For example, for the synthesis of aryl ethers,
Uses boronic acid diethyl ester and triphenylphosphine
React with aryl alcohol
It is preferable to carry out the reaction. Also, synthesis of alkyl ether
As a method, for example, in the presence of a base, a compound of the formula (XXI)
R_p-OH (wherein, R_pHas the meaning described above)
Halides obtained from alcohol (commercially available reagents are available
Commercially available reagents where possible) or sulfonic esters, eg
For example, there is a method of reacting methanesulfonic acid ester.
I can do it. Further alkyl ethers and aryl ethers
Examples of the method for synthesizing a compound represented by the general formula (XII)
To a halide or sulfonic ester
Then, in the presence of a base, a compound of the formula (XXI) R_pAl of -OH
And a method of reacting with a coal. The alcohol
Is converted to the halide by a conventional method, for example,
Use of carbon bromide or triphenylphosphine
It can be obtained by reacting in an active solvent.
Also, sulfonic esters such as methanesulfonic acid
Stele consists of methanesulfonyl chloride and triethylamido.
Reaction in an inert solvent such as ethyl acetate
Can be obtained. Compound of general formula (XX) thus obtained
If necessary, hydroxyl group, amino group and carboxyl group etc.
By appropriately combining the removal reactions of the protecting groups of
To produce a compound of the general formula (II-h)
You. The above reaction is usually carried out in an inert solvent,
As the inert solvent, for example, in the Mitsunobu reaction,
Trahydrofuran, chloroform, dimethoxyethane,
Benzene, toluene, etc. in halogenation
Halogenated hydrocarbons such as carbon tetrachloride and chloroform
In the sulfonylation, for example, methyl chloride
, Chloroform, tetrahydrofuran, benzene, vinegar
Ethyl acid and dimethylformamide are preferred. The amount of the reagent used is, for example,
In the reaction, azo is added to 1 mole of the compound of the general formula (XII).
Dicarboxylic acid diethyl ester, triphenyl phosphite
1 mole and excess of aryl alcohol and aryl alcohol, respectively
Mole, preferably 1 to 5 mole. 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 (XXI)
1 mole or more of halogenating agent to 1 mole of alcohol
Excess moles, preferably 1 to 3 moles, the general formula of the next stage
In the reaction for reacting the compound (XII), the compound represented by the general formula (X)
1 mole of the halide is used per 1 mole of the compound of II).
In excess of mol, preferably 1 to 5 mol,
1 mole to excess mole, preferably 1 mole,
Or 1 to 5 moles. Further, the compound represented by the general formula (XXI)
After converting the alcohol to the sulfonic ester, the general formula
In the reaction for reacting the compound (XII), the compound represented by the general formula (X)
The sulfonylating agent is added to 1 mole of the alcohol of XI).
Mole to excess mole, preferably 1 to 3 mole, and base
From 1 mole to excess mole per mole of sulfonylating agent.
, Preferably 1 to 5 moles, and the following general formula
In the reaction for reacting the compound (XII), the compound represented by the general formula (X)
The sulfonic acid ester is added to 1 mole of the compound of II).
Mole to excess mole, preferably 1 to 5 mole, and base
From 1 mole to excess per mole of sulfonic ester
Moles, preferably 1 to 5 moles. The compound of the general formula (XII) is converted to a halide
Alternatively, after conversion to sulfonic acid ester, presence of base
Below, when reacting with an alcohol of the general formula (XXI)
Can also be performed according to the 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. Alcohol of general formula (XXI)
After halogenation, the compound of the general formula (XII) is reacted
Reaction, the reaction temperature is usually 0 ° C.
Up to the boiling point of the solvent,
The reaction time is usually 5 minutes to 48 hours, preferably
30 minutes to 24 hours. Alcohol of general formula (XXI)
Is converted to a sulfonic acid ester, and then converted to a compound of the general formula (XI)
In the reaction for reacting the compound of I), the reaction temperature
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. The compound of the general formula (XII)
To a halide or sulfonic ester
After the reaction with an alcohol of the general formula (XXI) in the presence of a base.
The reaction can also be performed according to the above. After completion of the reaction, necessary
Protection of hydroxyl group, amino group and carboxyl group etc.
By performing an appropriate combination of group removal reactions,
The compound of formula (II-h) can be prepared,
By removing all protecting groups, the compound of the general formula (I)
Things can be manufactured. The method of removing the protecting group depends on the type of the protecting group and
It depends on the stability of the target compound, etc.
Perform as appropriate according to the method described or a method equivalent thereto
Can be. [0097]Conversion method F This conversion method comprises the use of the compound of the general formula (XII)
General formula (XXII) Embedded image [Wherein, Ar_i0Is a substituent: -T₁-CHO (here
Then T₁Has the above-mentioned meaning).
r₀X, Y, Z, R₁₀, R₂₀, R₃₀,
R₄₀, R₅₀And formula Embedded image Has the meaning described above], and then a compound of the general formula
(XXIII) Embedded image [Wherein, Ar_i2Is a substituent: -T₁-CH = R_v(This
Where T₁Has the meaning described above, and R_vIs es
The above Ar containing a ter group)₀X, Y,
Z, R₁₀, R₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
You. The reaction was carried out by reacting 1 mol of the compound of the general formula (XII)
Manganese dioxide in an amount of 1 mol to excess mol,
Or the reaction using 20 mol of a compound of the general formula (XXII)
Product, for example, dialkyl phosphonoacetic acid ester
And an appropriate base such as sodium hydride for 1
Reaction using mole to excess mole, preferably 3 to 5 mole
To obtain a compound of the general formula (XXIII).
Wear. The reaction is usually carried out in an inert solvent.
Examples of the inert solvent include tetrahydrofuran,
Diethyl ether and the like. The reaction temperature depends on whether the compound of the general formula (XII) is used.
In the reaction for synthesizing the compound of the general formula (XXII)
Is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably
More specifically, the temperature is from 20 ° C to 50 ° C. In addition, the general formula (XXI
Synthesis of compound of general formula (XXIII) from compound of I)
Reaction, usually at -78 ° C to 20 ° C, preferably
Or −78 ° C. to 0 ° C. The compound of the general formula (XXIII)
Diels-Alder reaction with a reactive diene compound, or
Performed well-known 1,3 dipole addition reactions
Then, by treating with an acid, the compound represented by the general formula (II-i) Embedded image [Wherein, Ar_i2Is a substituent: -T₁-Cy (here
And T₁Has the meaning described above, and Cy is optionally protected
Including a hetero atom, which may have a substituent
Ar having the formula (1) having an alicyclic group:₀Means
X, Y, Z, R₁₀, R₂₀, R₃₀, R₄₀, R
₅₀And formula Embedded image Has the above-mentioned meaning].
Wear. 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, methylene chloride, chloro
Halogenated hydrocarbons such as form, or acetonitrile
Are preferred. The reaction temperature ranges from 0 ° C. to the boiling point of the solvent used in the reaction.
To the point, preferably from 20C to 120C. After the reaction, the compound obtained is represented by the general formula
Compounds of general formula (II-f) from compounds of (XVII)
By applying the same conditions as in the process of manufacturing
The compound of the general formula (II-i) can be produced. [0106]Conversion method G General formula (XXIV) Embedded image [Wherein, Ar_j0Is a substituent: -Sn-R_w3(here
Where R_wRepresents a lower alkyl group).
Ar₀X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] with respect to the compound of the general formula (X
XV) R_x-L₁    (XXV) [Wherein, R_xOptionally has a protected substituent
Good, L₁Has an unsaturated bond
Aliphatic or aromatic ring, which may be cyclic or acyclic
Group or heteroaromatic group, L₁Is a halogen atom or trifle
Oromethanesulfonyloxy group]
By doing so, the general formula (II-j) Embedded image [Wherein, Ar_j1Is a substituent: -R_x(put it here,
R_xMay optionally have a protected substituent,
Ar_j1Having an unsaturated bond at the carbon atom bonded to
Or an aliphatic group, an aromatic ring group or
Represents a heteroaromatic ring group).₀Means
X, Y, Z, R₁₀, R₂₀, R₃₀, R₄₀, R₅₀
And formula Embedded image Has the above-mentioned meaning].
Wear. The reaction was carried out by reacting compound 1 of general formula (XXIV).
Of the compound of the general formula (XXV)
An excess mole, preferably 1 to 3 mole, is used, for example, tris (di
Benzylideneacetone) dipalladium (0) (Pd
₂(Dba)₃Palladium catalysts such as
Add phosphine ligands such as nylphosphine, and need
Add lithium chloride according to
U. The reaction is usually carried out in an inert solvent.
As the inert solvent, for example, dioxane, tetrahydro
Ethers such as furan, for example, aromatic carbonization such as toluene
And hydrogens. The reaction temperature is from 20 ° C.
The boiling point of the active solvent, preferably 50 to 130 ° C. [0109]Conversion method H General formula (XII-i) Embedded image [Wherein, Ar_k0Is a substituent:-(CH₂)₂-OH
Containing Ar₀X, Y, Z, R₁₀, R
₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] from the compound of the general formula (XXV
I) Embedded image [Wherein, Ar_k1Is a substituent: -CH = CH₂Before including
Ar₀X, Y, Z, R₁₀, R₂₀, R
₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning.]
Compound and general formula (XXVII) R_y-SH (XXVII) [Where R_yHas a protected substituent, as appropriate.
Represents an aliphatic group or an aromatic ring group, which may be
Reacting with a compound represented by the general formula (II-k): Embedded image [Wherein, Ar_k2Is a substituent:-(CH₂)₂-SR_y
(Where R_yHas the aforementioned meaning)
The above Ar₀X, Y, Z, R₁₀, R₂₀,
R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
Wear. From the compound of the general formula (XII-i),
In the reaction for synthesizing the compound of the formula (XXVI),
With respect to 1 mol of the compound (XII-i), for example,
1 to excess mole, preferably 1 to 3 moles
And a suitable base such as 1,8-diazabicyclo
Fats such as [5,4,0] undec-7-ene (DBU)
1 to an excess mole, preferably 1 to 3
Performed using moles. The reaction is usually carried out in an inert solvent.
As the inert solvent, tetrahydrofuran, ethyl acetate
And the like. The reaction temperature is inactive from 20 ℃
The boiling point of the solvent, preferably 20 to 50 ° C. From the compound of the general formula (XXVI),
In the reaction for synthesizing the compound of the formula (II-k),
R per 1 mol of the compound of (XXVI)_y-One SH
From 1 to 5 moles, preferably 1 to 5 moles.
1 mol to excess mol of a base such as um ethoxide is preferred.
After the completion of the reaction, treat with an acid such as hydrochloric acid.
By working up, a compound of general formula (II-k) is obtained. The reaction is usually carried out, for example, with methanol, ethanol,
This is performed in alcohol such as alcohol. Reaction temperature is from 0 ℃
The boiling point of the reaction, preferably from 0 to 50 ° C. With respect to the compound of the general formula (XXVI),
Conversion of the compound of the formula (XXIII) to the general formula (II-i)
The same reaction as in the step of synthesizing the compound is performed, and the compound represented by the general formula (II)
-I ') Embedded image [Wherein, Ar_i3Is a substituent: -T₁-Cy '(where
Then T₁Has the meaning described above, and Cy ′ is
It may have a protected substituent and contains a hetero atom.
Ar having an aliphatic ring group which may be₀To
Means X, Y, Z, R₁₀, R₂₀, R₃₀,
R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
Wear. The reaction is carried out from the compound of the general formula (XXIII)
Under the same conditions as in the step of synthesizing the compound of the formula (II-i)
More can be done. Next, the method for producing the starting compound of the present invention will be described.
Will be explained. The compounds of the general formula (I) of the present invention
As described above, the compound of the general formula (III) and the general formula
Compounds of the formula (IV), compounds of the general formula (V) and
Produced using a compound of formula (VI) as a starting compound.
Can be These starting compounds are known compounds.
Using a general synthesis method known per se.
The main production routes are described below.
You. The compound of the general formula (III)
Compounds of the general formula (IV)
Is a compound represented by the general formula:
The compound (V) can be produced by the method of Synthesis Method N.
Can be. Formula (III) used in Production Method A
Among the compounds, compounds wherein X is a nitrogen atom and Y is C ＝ O,
General formula (III-i) Embedded image [Where X₁Is a nitrogen atom, Y₁Represents CO, Z, R
₁₀, R₂₀, R₃₀, R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning] can be obtained by the following synthesis method A
Can be manufactured. [0118]Synthesis method A General formula (1) Embedded image [Wherein Q represents a halogen atom;₄₀And R₅₀
Has the meaning described above].
The active derivative (1 ') and the general formula (2) Embedded image [Where X₁, R₁₀, R₂₀, R₃₀And Z are
Having the meaning of the general formula (3) Embedded image [Where X₁, R₁₀, R₂₀, R₃₀, R₄₀, R
₅₀, Q and Z have the above-mentioned meaning].
Then, using a palladium complex as a catalyst, this compound
Is subjected to an intramolecular ring closure reaction to obtain a compound of the general formula (4) Embedded image [Where X₁, R₁₀, R₂₀, R₃₀, R₄₀, R
₅₀And Z have the above-mentioned meanings].
Can be manufactured by the action of a reducing agent.
You. Active derivatives of the carboxylic acids of the general formula (1)
The reaction between (1 ') and the compound of the general formula (2) is carried out by the conversion
In Method D, the compound of the general formula (XI) is converted from the compound of the general formula (XVII).
It can be carried out in the same manner as in the step of producing the compound of X).
Therefore, similar conditions can be applied to the reaction conditions and the like. From the compound of the general formula (3), the compound of the general formula (4)
The reaction for producing the compound is performed by reacting 1 mole of the compound of the general formula (3).
For example, tetrakistriphenylphosphine para
5 to 50% by weight of a palladium complex such as diium, preferably
Is 10 to 20% by weight, and a base such as potassium acetate
From 2 mol to 10 mol, preferably from 2 mol to 5 mol
Done. The reaction is usually carried out in an inert solvent.
Examples of the inert solvent include methylene chloride and chloropho
Halogenated hydrocarbons such as Lum;
Ethers such as toluene, tetrahydrofuran and dioxane;
For example, aromatic hydrocarbons such as benzene and toluene;
For example, dimethylformamide, acetone, ethyl acetate, etc.
Protic polar solvents or mixed solvents thereof and the like.
You. The reaction temperature is usually from 20 ° C. to the reaction temperature.
Up to the boiling point of the solvent
The reaction time is usually 30 minutes to 24 hours, preferably
Is 5 hours to 24 hours. The compound of the general formula (III-i)
By selecting appropriate conditions for the compound of (4), R
₂₀Is R₁₀And the 5- or 6-membered ring formed with X is unsaturated
Compound (III-i)_a) And compounds that are saturated
(III-i_b) Can be manufactured. The reaction is carried out with respect to 1 mol of the compound of the formula (4).
And, for example, 5 mol to 20 mol of iron powder under acidic conditions of hydrochloric acid,
By acting preferably 5 to 10 mol,
Compounds that are saturated (III-i_a) And the general formula
For example, 10% palladium per mole of the compound of (4)
5 to 50% by weight of carbon catalyst, preferably 10 to 20% by weight
% By using the catalytic reduction
Object (III-i_b) Can be obtained. The reaction is usually carried out in an inert solvent.
As the inert solvent, iron powder is allowed to act under acidic conditions of hydrochloric acid.
Reaction, for example, methanol, ethanol, etc.
Alcohols, and for catalytic reduction
For example, ethers such as ethyl ether and tetrahydrofuran
Alcohols such as methanol and ethanol
Or a mixed solvent thereof. The reaction temperature is usually adjusted to an iron reduction under acidic conditions of hydrochloric acid.
When performing the reaction, the temperature should be between 0 ° C and the boiling point of the solvent used for the reaction.
And preferably at 20 ° C. to 50 ° C.
Usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours
0 ° C. or less
Up to the boiling point of the medium, preferably between 20 ° C and 50 ° C,
The time is generally 1 hour to 48 hours, preferably 5 hours to
24 hours. After completion of the reaction, necessary
Protection of hydroxyl group, amino group and carboxyl group etc.
By performing an appropriate combination of group removal reactions,
Compounds of formula (III) can be prepared. The method for removing the protecting group depends on the type of the protecting group and
It depends on the stability of the target compound, etc.
Perform as appropriate according to the method described or a method equivalent thereto
Can be. The raw material of the production method A, represented by the general formula (III-
ii) Embedded image [Wherein, R₂₁Is a hydrogen atom or a hydroxyl group, R₃₁Is the water
Represents an elementary atom, R₁₀, R₄₀, R₅₀And X₁Is before
(Wherein X is a nitrogen atom,
Compounds wherein Y is CO and Z is a carbon atom)
It can be manufactured by a method. [0130]Synthesis method B The compound of the general formula (III-ii) has the general formula (5) Embedded image [Wherein, R₄₀And R₅₀Has the meaning given above]
After alkylating the compound by Mitsunobu reaction,
Reduction using sodium borohydride, general formula (6) Embedded image [Where X₁, R₁₀, R₄₀And R₅₀Means the above
Having a taste], and a palladium catalyst
It can be synthesized by performing catalytic reduction. The Mitsunobu reaction of the compound of the general formula (5)
Compound of general formula (XX) was prepared from compound of formula (XII)
It can be performed in the same manner as the method of manufacturing. After the Mitsunobu reaction,
Commonly known reduction using sodium borohydride
By applying the method, the compound of general formula (6) is synthesized.
To achieve. From the compound of the general formula (6), the compound of the general formula (III)
The reaction for synthesizing the compound of (ii) is, for example,
Catalytic reduction is performed using a palladium catalyst such as indium.
The reaction is usually performed in an inert solvent, and reacts with the inert solvent.
Examples include tetrahydrofuran, methanol and the like.
You. The reaction temperature is usually from 20 ° C. to the boiling point of the solvent used,
Preferably it is 20-50 degreeC. Adjusting the reaction conditions for catalytic reduction appropriately
By the general formula (III-ii)_a) (Where R
₂₁Represents a hydrogen atom; X₁, R₁₀, R₃₁, R₄₀
And R₅₀Has the meaning given above), and
Formula (III-ii)_b) (Where R₂₁Is hydroxyl
X represents a group₁, R₁₀, R₃₁, R₄₀And R
₅₀Has the meaning described above).
Can be. The raw material of the production method A, represented by the general formula (III-
iii) Embedded image [Where T is₃Is a single bond or a group having 1 to 3 carbon atoms.
An alkyl group which may have a protected substituent
Or an aralkyl group, R_10aAnd R_20aAre the same
Or different, if appropriate, having a protected substituent
A saturated or unsaturated hydrocarbon group, R₈₀Is a hydrogen atom
Or R_20aOr T₃To form a ring structure
May optionally have a protected substituent.
A saturated or unsaturated hydrocarbon group;₄₀And R
₅₀Has the above-mentioned meaning].
It can be manufactured by the following manufacturing method. [0135]Synthesis method C The compound of the general formula (III-iii) is a compound of the general formula (5)
The compound represented by the general formula (7) R_10a-CH (OH) -T₃-CO-R_20a    (7) [Where T is₃, R_10aAnd R_20aHas the above meaning
Hydrogenation after performing the Mitsunobu reaction using the compound
Reduction with sodium boron and cyclization under acidic conditions
By doing, the general formula (8) Embedded image [Where T is₃, R_10a, R_20a, R₄₀And R₅₀
Has the above-mentioned meaning].
By performing the reduction, the compound represented by the general formula (III-iii ') Embedded image [Where T is₃, R_10a, R_20a, R₄₀And R₅₀
Has the above-mentioned meaning.]
₈₀-L_iii(Where L_iiiIs a halogen field
Is used to introduce a substituent, and the general formula (II)
The compounds of I-iii) can be prepared. The Mitsunobu reaction of the compound of the general formula (5)
Compound of general formula (XX) was prepared from compound of formula (XII)
It can be performed in the same manner as the method of manufacturing. After the Mitsunobu reaction,
Commonly known reduction using sodium borohydride
Reduction is performed by the method. Then, for example, trifluorovinegar
Organic acids such as acid, acetic acid or formic acid
By performing the reaction in an inert solvent such as a run, the general formula
The compound of (8) can be synthesized. The reaction temperature is from 20 ° C. to the inert solvent used.
, Preferably 70 to 130 ° C. The catalytic reduction of the compound of the formula (8)
Compounds of general formula (III-ii) from compounds of formula (6)
By applying the same conditions as in the reaction for synthesizing
Compound (III-iii ') can be produced.
You. From the compound of the general formula (III-iii ')
The step of converting into a compound of the general formula (III-iii) comprises:
Synthetically, generally well-known amino group protecting groups, for example,
After protection with a tert-butoxycarbonyl group or the like,
Bases such as lithium hexamethyldisilazide
Now, R₈₀-L_iiiWith a protecting group for the amino group
To form a compound of the general formula [(III-iii)]
Compounds can be manufactured. The protection of the amino group is subject to the usual conditions.
Can be. R₈₀-L_iiiWith the general formula (I
For 1 mol of the protected compound of the compound of II-iii '), R
₈₀-L_iiiFrom 1 mole to an excess mole, preferably 3 moles.
Using a base such as lithium hexamethyldisilazide
The reaction is carried out using a mole to an excess mole, preferably 3 moles. reaction
The temperature is preferably from -78 to 20C. The amino group
The method for removing the protecting group can be according to a usual method. The compound represented by the general formula (8) is Embedded image [Wherein, R₄₀And R₅₀Has the meaning given above]
The compound is reduced to obtain a compound represented by the general formula (10) Embedded image [Wherein, R₄₀And R₅₀Has the meaning given above]
After forming the compound, the compound represented by the general formula (11) R_10a-CH (NH₂) -T₃-CH (OH) -R_20a    (11) [Where T is₃, R_10aAnd R_20aHas the above meaning
Also has a compound
be able to. The reduction of the compound of the general formula (9)
Sodium borohydride per mole of compound (9)
Using 0.5 mol of, for example, inactive tetrahydrofuran or the like.
It is preferable to carry out in a neutral solvent. 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)
Is reacted with 1 mol of the compound of the general formula (10)
On the other hand, the compound of the general formula (11) is added in an amount of 1 mol to excess,
Preferably, using 1 mol, molecular sieve 4A is
The reaction is performed by adding 3 times the weight of the compound of the general formula (10). The reaction is usually carried out in an inert solvent.
Inert solvents include tetrahydrofuran, dimethyl
Lumamide and the like are preferred. The reaction temperature is from 20 ° C. to an inert solvent used.
, Preferably from 100 to 120 ° C. The raw material of the production method A, represented by the general formula (III-
iv) Embedded image [Wherein, R_20bIs an optionally protected substitution
Having a group, represents a lower alkyl group or an aralkyl group,
R₁₀, R₄₀And R₅₀Has the meaning given above]
The compound was prepared by using the compound represented by the general formula (6) as a raw material,
It can be synthesized by a method. [0148]Synthesis method D The compound of the general formula (6) is represented by R_20b-OH (R_20bIs
Having the above meaning), followed by catalytic reduction
Thereby, the compound of the general formula (III-iv) is synthesized.
Can be The compound of the general formula (6) and R_20b-OH and
Is a reaction of a compound of the general formula (6) with R_20bSoluble in -OH
For example, p-toluenesulfonic acid is used in a catalytic amount,
Alternatively, p-toluene is used per mole of the compound of the general formula (6).
The reaction is performed by adding 0.1 mol of enesulfonic acid. The reaction temperature is from 20 ° C._20b−
OH (R_20bHas the meaning given above) up to the boiling point
Preferably, it is 90 to 100 ° C. Next, the compound of the general formula (6)
Conditions similar to the reaction for synthesizing compound (III-ii)
Is applied to perform catalytic reduction to obtain a compound represented by the general formula (III-iv):
Compounds can be synthesized. Using the compound of the general formula (III-iv) as a raw material
And represented by the general formula (II) synthesized according to the production method A.
The compound represented by the general formula (III-iv ′) Embedded image [Wherein, R₁₀, R₄₀And R₅₀Has the meaning described above.
And a compound of the general formula (IV)
With respect to the compound of general formula (II)
Compound and R_20bApply the same conditions as for the reaction with -OH
It can also be manufactured by the following. The raw material of the production method A, represented by the general formula (III-
v) Embedded image [Where T is₄Optionally has a protected substituent
Represents an alkylene group having 1 or 2 carbon atoms;
_10a, R_20a, R₄₀And R₅₀Has the above meaning
Has a compound of the general formula (1)
After cyclization, a general formula (12) Embedded image [Wherein, R₄₀And R₅₀Has the meaning given above]
After forming the compound, the compound represented by the general formula (13) R_10a-CH (L_a) -T₄-CH (L_a) -R_20a    (13) [Where L_aRepresents a halogen atom;₄, R_10a
And R_20aHas the above-mentioned meaning.]
And then performing catalytic reduction to synthesize
Can be. [0154]Synthesis method E The hydrazide of the compound of the general formula (1) is
The reaction is carried out in the same manner as in the reaction of the compound with the compound of the general formula (2).
Therefore, the compound of the general formula (1) can be prepared under the same conditions.
After activating with, react with hydrazine
It can be synthesized more. The amount of the reagent to be used depends on the amount of the compound represented by the general formula (1).
Hydrazine to 1 mol to an excess amount, preferably 1 mol
モ ル 3 mol. The reaction is usually carried out in an inert solvent.
As the inert solvent, for example, tetrahydrofuran,
Tilformamide and the like are preferred. The reaction temperature is from 20 ° C. to the inert solvent used.
, Preferably from 20 to 50 ° C. The thus obtained hydrazide is
Heating in an inert solvent such as methylformamide
Thus, the compound of the general formula (12) can be synthesized. The compound of the formula (12) and the compound of the formula (13)
Is reacted with 1 mole of the compound of the general formula (12)
On the other hand, the compound of the general formula (13) is used in a small excess from 1 mol,
Preferably, 1 mol is used, for example, dimethylformamide or the like.
In an inert solvent. Usually no need to add base
Is optionally a tertiary amine such as triethylamine.
The reaction can be performed in the presence. The reaction temperature is usually from room temperature to inert
The boiling point of the solvent, preferably 100 to 120 ° C. After performing the above reaction, the compound of general formula (6)
For synthesizing compounds of general formula (III-ii) from products
The catalytic reduction is performed by applying the same conditions as in
The compound of I-iv) can be synthesized. The general formula (III-v) which is a raw material of the production method A
i) Embedded image [Wherein, R₁₀, R₄₀And R₅₀Has the meaning described above.
Synthesis of the compound of the formula (12)
It can be performed by the following method as a charge. [0163]Synthesis method F The compound of the general formula (III-vi) is a compound of the general formula (12)
The compound represented by the general formula (14) R₁₀-L_a    (14) [Where L_aHas the meaning given above].
After that, it can be synthesized by performing catalytic reduction. The compound of the general formula (12) and the compound of the general formula (14)
From the compound of formula (III-vi)
Reaction of the compound of the general formula (12)
-V) by applying the same conditions as in the reaction for synthesizing the compound of
It can be carried out. The raw material of the production method A is represented by the general formula (III-v)
ii) Embedded image [Where P₁Represents a protecting group for a hydroxyl group;₄₀And R
₅₀Has the above-mentioned meaning] has the general formula
Performed by the method shown below using the compound of (1) as a raw material.
be able to. [0166]Synthesis method G Compound of general formula (1) and diethyl aminomalonate
After synthesizing an amide compound from
The decarboxylation reaction is performed under basic conditions. S of the obtained compound
Reduce the ter group and replace the newly generated hydroxyl group with a suitable protecting group.
After protection using a compound, catalytic reduction
Compound (III-vii) can be synthesized. Compounds of the general formula (1) and aminomalonic acid di
The reaction with ethyl ester can be carried out by reacting a compound of the general formula (XVII)
Same as the step of synthesizing the compound of the general formula (XIX) from the product
Can be performed by applying the following conditions. The cyclization reaction is carried out by using a suitable base such as hydrogenation.
Performed using sodium. The amount of reagent used for the reaction
1 mole of sodium hydride per mole of amide compound
And an excess mole, preferably 1 to 3 mole. The reaction is usually carried out in an inert solvent.
Inert solvents include tetrahydrofuran, dimethylform
Muamide or dimethyl sulfoxide. Anti
The reaction temperature is from 0 ° C. to the boiling point of the inert solvent used, preferably
Is 20 to 100 ° C. The subsequent decarboxylation reaction is carried out using a suitable base, for example,
For example, 1 mole of sodium hydroxide is added to 1 mole of the cyclized compound.
To an excess mole, preferably 3 to 5 moles. reaction
Is usually performed in an inert solvent, and as the inert solvent,
Is preferably an alcohol such as ethanol. Reaction temperature
Is from 20 ° C. to the boiling point of the inert solvent used, preferably 5
0-100 ° C is preferred. Ester reduction is commonly used in synthesis.
Methods for the reduction of esters, e.g. sodium borohydride
Can be carried out using a metal. The amount of reagent used
One mole of sodium borohydride is added to 1 mole of the stell
To an excess mole, preferably 3 to 10 mole. reaction
Is usually performed in an inert solvent, and as 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. Examples of the newly generated hydroxyl-protecting group include:
It is possible to use those listed in the manufacturing method A, but it is preferable.
Is a tert-butyldimethylsilyl group, tert-butyl
And a rudiphenylsilyl group. Reaction conditions are generally
Well-known conditions can be applied. After performing the above reaction, the compound of general formula (6)
For synthesizing compounds of general formula (III-ii) from products
The catalytic reduction is performed by applying the same conditions as in
The compound of I-vii) can be synthesized. The raw material of the production method A, represented by the general formula (III-
viii) Embedded image [Wherein, R_10aOptionally has a protected substituent
A saturated or unsaturated hydrocarbon group, R_20cIs
It may have a hydrogen atom or a protected substituent as appropriate.
A saturated or unsaturated hydrocarbon group;₄₀as well as
R₅₀Has the above-mentioned meaning] has the general formula
Using the compound of (1) as a raw material,
Can be achieved. [0175]Synthesis method H Esterifying a compound of the general formula (1)
Object and general formula (15) Embedded image [Wherein, R_zRepresents a methyl group or an ethyl group;
_20cHas the above-mentioned meaning]
And a general reaction (16) Embedded image [Wherein, R_z, R_20c, R₄₀And R₅₀Is the above
Significant] is obtained. Then, the general formula (1)
The compound of 6) is_10a-NH₂(R_10aIs the above
Amidated using) and cyclized under acidic conditions
And then reduce the alkoxy and nitro groups sequentially.
To synthesize a compound of the general formula (III-viii)
Can be. The compound of the formula (1) was dissolved in methanol in a small amount.
Addition of concentrated sulfuric acid and heating to make methyl ester
Is performed using generally well-known conditions in synthesis. The above methyl ester compound and the compound represented by the general formula (15)
The reaction with the compound is performed in one mole per mole of the methyl ester.
1 to an excess molar amount of the compound of the formula (15), preferably 1
~ 3 mol, using tetrakistriphenylphosphine para
A catalytic amount of palladium complex such as diium, preferably 3-5
Performed using mol%. The reaction is usually carried out in an inert solvent.
Tetrahydrofuran and the like as the inert solvent.
I can do it. The reaction temperature is from 50 to the boiling point of the solvent used, preferably
Or 70 to 100 ° C. The compound represented by the general formula (16) and R_10a-NH
₂The amidation of the compound of the formula (XVII)
The same conditions as in the step of synthesizing the compound of the formula (XIX) are applied.
Can be done using The cyclization reaction of the amide obtained by the above reaction
Under acidic conditions, for example, concentrated hydrochloric acid and ethanol
Reaction temperature in a mixed solvent with a neutral solvent is 20 ° C.
Boiling point of the inert solvent used, preferably 20 to 50 ° C
It is. The reduction of the alkoxy group can be performed, for example, by triethyl
The reaction can be carried out using silane and adding an appropriate acid.
The amount of the reagent used was determined based on 1 mol of the cyclized product and
The run is added in an amount of 1 mole to excess mole, preferably 3 to 5 moles.
As the acid to be added, for example, ether complex of borane trifluoride
1 mol to excess mol, preferably 3 to 5 mol
You. The reaction is usually performed in an inert solvent,
Examples of the medium include chloroform and methylene chloride.
I can do it. The reaction temperature is 0 to 50 ° C, preferably 20 ° C.
It is. The reduction reaction of the nitro group is carried out by the conversion of the general formula (6)
To synthesize a compound of the general formula (III-ii) from the compound
The catalytic reduction is carried out by applying the same conditions as in
The compound of II-viii) can be synthesized. Formula (III-viii ') Embedded image [Wherein, R_20c1Represents a hydrogen atom, and R_10a, R
₄₀And R₅₀Has the above-mentioned meaning.
The compound represented by the general formula (II) synthesized according to the production method A
-Viii ') Embedded image [Wherein, Ar₀, R_10a, R_20c1, R₄₀And R
₅₀Has the above-mentioned meaning].
It can also be synthesized by the following method. The compound of the general formula (III-vii)
After reacting with formula (14), the compound of general formula (IV) is
According to the production method A, using the general formula (II-viii '') Embedded image [Wherein, Ar₀, R_10a, P₁, R₄₀And R
₅₀Has the above-mentioned meaning].
You. Next, the protecting group of the hydroxyl group was removed, and methanesulfone was removed.
After acid esterification, treatment under basic conditions and catalytic reduction
To obtain a compound of the general formula (II-viii ')
Can be synthesized. The compound of the formula (II-viii '')
Removal of hydroxyl protecting groups is generally well known synthetically
The method can be applied. For example, if the protecting group is ter
When it is a t-butyldimethylsilyl group, use concentrated hydrochloric acid.
The reaction can be carried out in methanol. The methanesulfonic acid esterification is carried out by the above reaction.
1 mole of alcohol obtained in
1 mole to excess mole, preferably 1 to 3 moles
Methanesulfonyl chloride in 1 mole to excess mole, preferably
Or 1 to 3 mol. Use for subsequent base treatment
As the base, for example, 1,8-diazabicyclo [5,
4,0] undec-7-ene (DBU) from 1 mol
It is carried out using an excess mole, preferably 1 to 3 moles. reaction
Is usually carried out in an inert solvent and used as the inert solvent.
Dimethylformamide and the like are preferred. The reaction temperature is
The temperature is 0 to 50 ° C, preferably 0 to 20 ° C. With respect to the compound obtained by the above reaction,
Compounds of general formula (III-ii) from compounds of general formula (6)
Catalytic reduction is performed by applying the same conditions as in the reaction to synthesize the product.
To synthesize a compound of the general formula (II-viii ')
Can be. The raw material of production method A, represented by the general formula (III-
ix ') Embedded image [Wherein, R_10cOptionally has a protected substituent
Represents a saturated or unsaturated hydrocarbon group,₄₀
And R₅₀Has the above-mentioned meaning.]
Formula (III-ix ″) Embedded image [Wherein, R_10c, R₄₀And R₅₀Has the above meaning
Has the general formula (17) Embedded image [Wherein, R₄₀And R₅₀Has the meaning given above]
A known compound represented or known from the known compound.
Using the compound produced by the method as a raw material by the following method
Can be synthesized. [0189]Synthesis method I A compound of the general formula (17) and R_10c—OH [wherein R
_10cHas the meaning described above].
After that, catalytic reduction is carried out to obtain the compound represented by the general formula (III-
ix ′) and a compound of the general formula (III-ix ″)
Can be synthesized. The Mitsunobu reaction of the compound of the formula (17)
The compound of the general formula (XX) is converted from the compound of the general formula (XII)
It can be performed in the same manner as the manufacturing method. Catalytic reduction of the compound obtained by the above reaction
Is converted from the compound of the general formula (6) to 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 ")
Compound can be synthesized. The raw material of the production method A, represented by the general formula (III-
x) Embedded image [Wherein, R_10dOptionally has a protected substituent
Represents a saturated or unsaturated hydrocarbon group,₄₀
And R₅₀Has the above-mentioned meaning.
General formula (18) which is an intermediate in Method I Embedded image [Wherein, R_10c, R₄₀And R₅₀Has the above meaning
The compound is synthesized by the following method using the compound
Can be [0193]Synthesis method J The compound of the general formula (18) is reduced to give a compound of the general formula (19) Embedded image [Wherein, R₄₀And R₅₀Has the meaning given above]
A compound, R_10d—OH [wherein R_10cIs
After the Mitsunobu reaction, followed by catalytic reduction
To synthesize a compound of the general formula (III-x)
Can be The reduction of the compound of the general formula (18) is carried out by hydrogenation.
Sodium boron to 1 mole of the compound of the general formula (18)
On the other hand, 1 mol to excess mol, preferably 3 to 5 mol is used.
Do it. The reaction is usually performed in an inert solvent,
Tetrahydrofuran or the like is preferable as the ionic solvent. reaction
The temperature is between 0 ° C and 50 ° C, preferably 20 ° C. The Mitsunobu reaction of the compound of the general formula (19)
The compound of the general formula (XX) is converted from the compound of the general formula (XII)
It can be performed in the same manner as the manufacturing method. Next, the compound of the general formula (6)
Conditions similar to the reaction for synthesizing compound (III-ii)
Is applied to carry out catalytic reduction to convert the compound of the general formula (III-x)
Compounds can be synthesized. The compound of the general formula (1)
The compound of the formula (5) and the compound of the formula (15) are known compounds.
Or a chemical method known per se using a known compound
It can be manufactured by the method. Next, the other starting compound of Production Method A was used.
A method for producing a compound of the general formula (IV) will be described.
You. Compounds of general formula (IV) can be prepared according to the following synthesis methods K to
It can be produced by the synthesis method M. [0199]Synthesis method K The compound of the general formula (IV) is represented by the general formula (20) Embedded image [Wherein, R ′ represents a lower alkyl group;₀Is before
Having the meaning described above] with hydrazine
After the treatment, the nitric acid is treated with
(IV) Embedded image [Wherein, Ar₀Has the above-mentioned meaning]
Can be built. The compound of the formula (20) is treated with hydrazine.
After the treatment, the compound of the general formula (IV)
The amount of each reagent used in the reaction to convert
Hydrazine is 1 mol per 1 mol of the ester of (20).
10 to 10 mol, preferably 3 to 5 mol, in the next step
Of the general formula (20) by the reaction of nitrous acid
1 mol to 5 mol, preferably 1 mol to 5 mol, per 1 mol.
Preferably, it is 3 mol to 5 mol, and 1N hydrochloric acid is sodium nitrite.
1 L to 5 L, preferably 1 L to 3 per mole of lithium
L. The reaction is usually carried out in an inert solvent.
As the inert solvent, for the reaction with hydrazine
Is, for example, alcohols such as methanol, ethanol, etc.
In the reaction of nitrous acid, for example,
Water; for example, ethers such as tetrahydrofuran and dioxane
And halogens such as methylene chloride and chloroform
Hydrocarbons, or mixtures thereof. The reaction temperature is usually the same as that for the reaction with hydrazine.
On the other hand, the temperature is preferably from 0 ° C to the boiling point of the solvent used in the reaction.
The reaction time is usually 1 hour.
Between 48 hours, preferably 5 hours to 24 hours.
In the reaction with nitrous acid, 0 ° C to 50 ° C, preferably
The reaction time is usually 30 minutes.
５5 hours, preferably 30 minutes〜2 hours. The compound of the general formula (20) is
Compound, or manufactured according to the standard method of ester synthesis.
can do. [0204]Synthesis method L General formula (IV-i) Embedded image [Wherein, R ″ and R ″ ″ represent a carbon to which
A nitrogen atom may be included together with the elemental atom,
Saturated or unsaturated, which may have a substituted substituent
Which represents a 5- or 6-membered ring group]
Certain ethyl 1,2,4-triazine-5-carboxylates
Using ester as a raw material, general formula (21) Embedded image Wherein R ″ and R ″ ″ have the above-mentioned meanings.
Can be produced according to the synthesis method K after the synthesis of the compound of
it can. 1,2,4-triazine-5-carboxylic acid
The ethyl ester is represented by the general formula (22) Embedded image Wherein R ″ and R ″ ″ have the above-mentioned meanings.
To give a compound of the general formula (21)
You. The amount of the reagent used in the reaction is 1,2,4-
Per mole of riadin-5-carboxylic acid ethyl ester
The compound of the general formula (22) is used in an amount of 1 mol to excess mol, preferably
Preferably it is 1 to 5 mol. The reaction is usually inert
Medium, and the inert solvent is chloroform or the like.
No. The reaction temperature is from 20 ° C to an inert solvent used.
, Preferably 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 -i) is the general formula of the synthesis method K.
A compound of the general formula (IV) is produced from the compound of (20)
To produce a compound of the general formula (IV-i).
Can be built. Synthesis method M General formula (IV-ii) Embedded image [Wherein, Ar₁₀Is a substituent: -Sn (n-Bu)₃To
Containing Ar₀The compound of the general formula (23) Embedded image [Wherein, Ar_10iIs a substituent: -X₁₀(Here it is
And X₁₀Represents a halogen atom).
r₀R ′ has the above-mentioned meaning].
It can be synthesized as a raw material. The compound of the general formula (23) is converted to a palladium complex
Body, for example, tetrakistriphenylphosphine paradiu
With hexa-n-butylditin as a catalyst
By the general formula (24) Embedded image [Wherein, Ar₁₀And R 'have the above-mentioned meaning.
After the compound is synthesized, it can be produced according to the synthesis method K.
Wear. Compounds of the general formula (23) and hexa-n-butyl
In the reaction with tilgitin, a compound of the general formula (23)
1 mole of hexa-n-butylditin per mole
An excess mole, preferably 1.5 to 3 moles, is used.
Palladium complexes such as triphenylphosphine palladium
Using 0.05 to 0.2 mol, preferably 0.1 mol
You. The reaction is usually performed in an inert solvent,
Examples of the medium 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 -ii) is the general formula of the synthesis method K.
A compound of the general formula (IV) is produced from the compound of (20)
The compound of general formula (IV-ii)
Can be manufactured. Next, a compound represented by the general formula
(V) Embedded image [Where X, Y, Z, R₁₀, R₂₀, R₃₀,
R₄₀, R₅₀And formula Embedded image Has the meaning given above].
I will tell. The compound of the general formula (V) is prepared according to the following synthesis method N
It can be manufactured by the method. [0213]Synthesis method N The compound of the general formula (V) is represented by the general formula (25) Embedded image[Where X, Y, Z, R₁₀, R₂₀, R₃₀,
R₄₀, R₅₀And formula Embedded image Has the above-mentioned meaning].
Later, it is produced by the action of sodium azide
be able to. Conversion to the carboxylic acid chloride of the general formula (25)
In the step of substituting, the compound of the general formula (25) is
VIII) similar to the step of producing an acid halide from
The reaction conditions can be carried out under the same conditions.
Can be applied. For one mole of the acid chloride thus obtained,
And 1 mol to 5 mol of sodium azide, preferably 1 mol
To 3 moles of water or, if necessary, water and tetrahydrofuran.
The reaction is carried out in a mixed solvent of
Obtainable. The reaction temperature is usually between 0 ° C. and 50 ° C.
The reaction time is preferably 0 ° C to 20 ° C.
Usually 30 minutes to 12 hours, preferably 1 hour to 5 hours
is there. Further, the general formulas of the other starting compounds in Production Method B
The compound (VI) is a known compound or
It can be produced according to a standard method of synthesis of a product. Next, the usefulness of the present invention will be specifically described.
Therefore, the Cdk4 and Cdk6 activities and cell proliferation of the product of the present invention
50% inhibitory concentration (IC₅₀Value)
Was. [0001]Cdk4 inhibitory action (1) Cyclin D1-Cdk4 and cyclin D2-
Preparation of Cdk4 First, if Cdk4 and its activator cyclin D1,
Or cyclin D2 cDNA
Recombinant baculoyl incorporated into Rus expression vector
Was prepared. It was co-infected with insect cells Sf9 and
Iculin D1-Cdk4 or cyclin D2-Cdk4
Highly expressed as an active complex. Collect the cells and allow
After solubilization, purified by HPLC column chromatography
[The Embo Journal (EMBO J.), No.
15, 7060-7069, (1996)]. (2) Cyclin D1-Cdk4 and Cyclin
Activity measurement of Clin D2-Cdk4 Cyclin D1-Cdk4 and cyclin D2-Cdk
In the activity measurement of No. 4, the substrate was amino acid of RB protein
Synthetic peptide corresponding to acids 775 to 787 (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 is 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-mer
Captoethanol / 1 mM ethylene glycol bis
(Β-aminoethyl ether) -N, N, N ′, N′-
With Tetra Acetate Acid (EGTA)
Manufactured cyclin D1-Cdk4 or cyclin D
2-Cdk4, 100 μM substrate peptide and 50 μM
M unlabeled adenosine triphosphate (ATP) and 1 μm
[Γ-33P] -labeled ATP of Ci (2000-4000)
  Ci / mmole) at a reaction temperature of 30 ° C.
The reaction was performed for 5 minutes. Then 10 μl of 350 mM
Stop the reaction by adding phosphate buffer to the reaction system.
Was. After adsorbing the substrate peptide on P81 paper,
Radioactivity in a liquid scintillation counter
Was. [Γ-33P] labeled ATP was purchased from Daiichi Pure Chemicals.
Entered. The test compound is added to the reaction system by dimethyl
A solution dissolved in sulfoxide (DMSO) was prepared in 1.1.
Performed by adding μl. DMSO only to reaction system
Was added as a control group. Example 1 as a representative compound of the present invention
31, 165, 329, 579, and the
Cyclin D1-Cdk4 or cyclin D2-Cdk
IC50 values for 4 activities were determined. The result is
It is shown in the table. [0001] [Table 1] The compounds of the present invention, cyclin D1-Cdk
4 or cyclin D2-Cdk4 inhibitory activity is Cdk4
Known compound having inhibitory activity (±) flavopir
It is clear that it is significantly higher than that of idol.
You. [0001]Cdk6 inhibitory action (1) Cyclin D1-Cdk6 and cyclin D3-
Preparation of Cdk6 Like cyclin D1-Cdk4, Cdk6 and its
Activator cyclin D1 or cyclin D3
Each cDNA was assembled into a baculovirus expression vector.
To produce a recombinant baculovirus. Kon
Insect cells Sf9 were co-infected and cyclin D1-Cdk6
Or highly expressed as a cyclin D3-Cdk6 active complex
I let it. After the cells are collected and solubilized, the HPLC
Purified by ram chromatography. (2) Cyclin D1-Cdk6 and Cyclin
Activity measurement of Clin D3-Cdk6 In the activity measurement of cyclin D1-Cdk6, the substrate is
Synthetic peptide (Lys-Ala-Pro-Leu-Se
r-Pro-Lys-Lys-Ala-Lys)
In measuring the activity of cyclin D3-Cdk6,
The quality is 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 is 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 cycle
Phosphorus D3-Cdk6 and 100 μM substrate peptide
50 μM unlabeled ATP and 1 μCi [γ-33
P] Labeled ATP (2000-4000 Ci / mmol
e) at a reaction temperature of 30 ° C. for 20 minutes or 4
The reaction was performed for 5 minutes. Then 10 μl of 350 mM
  Stop the reaction by adding phosphate buffer to the reaction system.
Was. After adsorbing the substrate peptide on P81 paper,
Radioactivity in a liquid scintillation counter
Was. The compound of the present invention can be added to a reaction system by DMS
By adding 1.1 μl of a solution dissolved in O
went. Add 1.1 μl of DMSO to the reaction system
A control group was used. Example 1 as a representative compound of the present invention
31, 165, 329, 579, and the
Cyclin D1-Cdk6 or cyclin D3-Cdk
IC50 values for 6 activities were determined. The result is
It is shown in the table. [0001] [Table 1] The results show that the compound of the present invention has a strong cyclic property.
D1-Cdk6 or cyclin D3-Cdk6 inhibitory activity
It is clear that it has the property. [0001]Cell growth inhibitory action (1) Cell culture method Clinically isolated cancer cell line HCT116 supplemented with 10% fetal bovine serum
Clinically isolated cancer cells using Dulbecco's modified Eagle's medium
Strain MKN-1 was RPMI1640 supplemented with 10% fetal calf serum.
5% CO at 37 ° C using medium₂In the presence, saturated steam
The culture was carried out under the following conditions. (2) Measurement of cell growth inhibitory action The cell growth inhibitory effect is better for Skehan and others.
Law [Journal of National Cancer In
State (J. Natl. Cancer I)
nst. 82, 1107-1112, (19)
1990)]. HCT116 or
MKN-1 is 1 × 10³Each containing
100 μl of the culture medium for each cell was cultured in a 96-well cell culture medium.
The mixture was dispensed into a nutrient dish and cultured overnight. The next day, first
Of compound 131 and (±) flavopiridol
A dilution series with DMSO was prepared from the MSO solution.
Then use the dilution series or as a control without drug addition
Only DMSO was added to the culture medium for each cell.
Was. Finally, the cells cultured in the 96-well dish
Dilution series of each drug or culture with only added DMSO
Medium for 100 μl each, and further culture for 3 days
Was. [0001] 50% trichloroacetic acid was added to each well.
The cells were fixed by adding μl each. 0.4% sulforoda
After staining the cells with Min B, 10 mM Tris buffer
Was used to extract sulforhodamine B. 450 n
Measure optical density at 560 nm using m as control wavelength
And compared with the control group. Compound of Example 131 and (±)
Flavopiridol 50% cell growth inhibitory concentration
The results obtained for (IC50) are shown in the following table. [0001] [Table 1] The compound of the present invention has a Cdk inhibitory action
Compared to the known compound (±) flavopiridol
Clearly showing a strong cell growth inhibitory effect
Thus, they are useful as antitumor agents. Therefore, the therapeutic effect of the compound of the present invention is expected.
Suitable tumors include, for example, human colon cancer and the like.
Can be The compound of the present invention is used as an antitumor agent.
Pharmaceutically acceptable salts,
Can be Typical of pharmaceutically acceptable salts
For example, with alkali metals such as sodium and potassium
Salts and the like can be mentioned. [0001] The pharmaceutically acceptable salts of the compounds of the present invention
As the production method, a method usually used in the field of synthetic organic chemistry is applied.
It can be performed in any combination. Specifically, the present invention
Neutralize the free solution of the compound with an alkaline solution.
And the like. When the compound of the present invention is used as an antitumor agent
The dosage form can be selected from various forms, such as tablets
Oral preparations such as preparations, capsules, powders, granules, liquids, etc.
Examples include sterile liquid parenteral agents such as solutions and suspensions.
It is. [0001] Solid preparations are tablets, capsules
It can also be manufactured as a preparation, granule or powder
However, it can also be produced using appropriate additives. The
Examples of additives include sugars such as lactose and glucose, for example.
Starches such as corn, wheat, rice, etc.
Fatty acids such as acid, for example, sodium metasilicate, aluminum
Inorganic salts such as magnesium phosphate and anhydrous calcium phosphate,
For example, polyvinyl pyrrolidone, polyalkylene glycol
Synthetic polymers such as calcium stearate,
Fatty acid salts such as magnesium stearate, such as steari
Alcohols such as alcohol and benzyl alcohol,
For example, methyl cellulose, carboxymethyl cellulose
, Ethylcellulose, hydroxypropyl methylcell
Synthetic cellulose derivatives such as loin, other, water, gelatin
Oil, talc, vegetable oil, gum arabic, etc.
And the like. [0001] These tablets, capsules, granules, powders
Solid preparations are generally 0.1 to 100% by weight, preferably
Preferably it can contain 5 to 100% by weight of active ingredient
You. Liquid formulations include water, alcohols or soybean oil, for example.
In liquid preparations such as vegetable-derived oils such as peanut oil and sesame oil
Suspension, white
It can be manufactured in the form of tablets, injections and the like. In particular, parenteral intramuscular injection, intravenous injection
Examples of suitable solvents for administration by injection or subcutaneous injection include:
For example, distilled water for injection, lidocaine hydrochloride aqueous solution (intramuscular injection
), Saline, aqueous glucose solution, ethanol, vein
Liquid for internal injection (for example, citric acid, sodium citrate, etc.)
Aqueous solutions), electrolyte solutions (eg intravenous drip, intravenous injection)
For example) or a mixed solution thereof. Although these injections are dissolved in advance,
In addition, dissolve in powder form or with appropriate additives before use.
You can take a form to understand. These injections are
0.1 to 10% by weight, preferably 1 to 5% by weight
Components can be included. Also, a suspension or syrup for oral administration, etc.
Solutions may contain from 0.5 to 10% by weight of active ingredient.
Wear. [0001] Actually preferred dosages of the compounds according to the invention
Is the type of compound used and the type of compounded composition
Type, frequency of application, specific site to be treated and patient condition
Therefore, it can be appropriately increased or decreased. For example, per day
The dose per adult is 10 to
Parenteral administration, preferably intravenous injection
In the case of, it is 10 to 100 mg per day. In addition,
The frequency of administration depends on the administration method and symptoms,
Can be administered in 2 to 5 divided doses. [0001] BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below with reference to examples.
However, the present invention is not limited to these implementations.
It is not limited to only examples. [0001] Thin-layer chromatographs of Examples and Reference Examples
I use Silica gel as a plate₆₀F
₂₅₄(Merck) using a UV detector as a detection method
Was. As silica gel for column, WakogelT
MC-300 or C-200 (Wako Pure Chemical Industries) was used.
For high performance liquid chromatography, HP1100 series
Using Leeds (Hewlett-Packard (HP))
Was. The MS spectrum was measured by JMS-SX102A (Nippon Denki).
Child (JEOL)) or QUATTRO II (micro
Mass). The NMR spectrum is
When measuring with a chloroform solution, tet
Using Lamethylsilane (TMS) with heavy methanol solution
For measurement, use methanol as deuterated dimethyl sulfoxy
Use dimethyl sulfoxide when measuring with
Gemini-200 (200 MHz; Varia
n), Gemini-300 (300 MHz; Vari)
an) or VXR-300 (300 MHz; Var)
ian) using a spectrometer and calculating the total δ value
It was shown in ppm. The meanings of the abbreviations in the NMR measurement are shown below.
You. s: Singlet d: Doublet dd: Double doublet t: triplet dt: Double triplet q: quartet m: Multiplet br: Broad J: Coupling constant Hz: Hertz CDCl₃: Heavy chloroform D₂O: Heavy water DMSO-d₆: Heavy dimethyl sulfoxide CD₃OD: heavy methanol The meanings of the abbreviations in the reaction formulas are shown below.
You. 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 [0001] Next, the compounds of Examples according to the present invention are shown in the following Tables.
Specific examples are shown below. [0001] [Table 1][0001] [Table 2][0001] [Table 3][0001] [Table 4][0001] [Table 5][0001] [Table 6][0001] [Table 7][0001] [Table 8][0001] [Table 9][0001] [Table 10][0001] [Table 11][0001] [Table 12][0000] [Table 16][0000] [Table 17][0000] [Table 18][0000] [Table 19][0000] [Table 20][0000] [Table 21][0000] [Table 22][0000] [Table 23][0000] [Table 24][0000] [Table 25][0000] [Table 26][0000] [Table 27][0000] [Table 28][0000] [Table 29][0000] [Table 30][0000] [Table 31][0000] [Table 32][0000] [Table 33][0000] [Table 34][0000] [Table 35][0000] [Table 36][0000] [Table 37][0000] [Table 38][0000] [Table 39][0000] [Table 40][0000] [Table 41][0000] [Table 42][0000] [Table 43][0000] [Table 44][0000] [Table 45][0000] [Table 46][0000] [Table 47][0000] [Table 48][0000] [Table 49][0000] [Table 50][0000] [Table 51][0000] [Table 52][0000] [Table 53][0000] [Table 54][0000] [Table 55][0000] [Table 56][0000] [Table 57][0000] [Table 58][0000] [Table 59][0000] [Table 60][0000] [Table 61][0000] [Table 62][0000] [Table 63][0000] [Table 64][0000] [Table 65][0000] [Table 66][0000] [Table 67][0000] [Table 68][0000] [Table 69] [0000] [Table 70][0001]Example 1 29 mg of 4-amino-9-fluorenone (0.15 mm
ol) to 22 mg of 2-pyridinecarbonylazide (0.
15 mmol) in 0.5 ml of tetrahydrofuran
At room temperature, the reaction was refluxed for 2 hours. Reaction solution at room temperature
And mixed with hexane and ethyl acetate to crystallize.
Was. The obtained crude product is sequentially treated with ethyl acetate and methanol.
After the next washing, the precipitate was collected by filtration to give a yellow powder (34 mg, compound of Example 1).
Product).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 2-Example 8 According to the method of Example 1, conversion of Examples 2 to 8
A compound was produced.Example 2 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 3 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 4 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 5 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 6 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 7 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 8 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 9 Compound of Reference Example 1 and 2-amino-4- (N-ethoxy
Same as Example 26 using (carbonyl) aminopyridine
50 mg (0.12 mmol) of the compound prepared by the same procedure
l) was dissolved in 2 ml of ethanol.
2.0 ml (10 mmol) of sodium aqueous solution at room temperature
The reaction was refluxed for 1 hour. Return the reaction solution to room temperature and water
And extracted with ethyl acetate-tetrahydrofuran.
The organic layer was washed with brine, dried over magnesium sulfate, and filtered.
The filtrate was concentrated. The residue is purified by silica gel column chromatography.
Chromatography (chloroform-methanol, 100: 0-
95: 5) to give 8 mg of yellow crystals. [0001]¹H-NMR (DMSO-d₆) Δ: 6.
19 (1H, s), 6.25 (1H, d, J = 5.9H)
z), 6.28 (2H, s), 7.34-7.41 (3
H, m), 7.62-7.69 (2H, m), 7.74
(1H, d, J = 5.7 Hz), 8.15 (1H, d,
J = 7.1 Hz), 8.21 (1H, d, J = 7.1H)
z), 9.66 (1H, s), 12.3 (1H, b
r). mass: 331 (M + 1)⁺. [0001]Example 10 33 mg (0.10 mmol) of the compound of Example 9
Dissolve in 3 ml of lahydrofuran and add n-butyraldehyde
27 μl (0.30 mmol) and triacetoxy water
63 mg (0.30 mmol) of sodium borohydride
The reaction solution was stirred at the same temperature for 6 hours. Reaction liquid
Aqueous sodium bicarbonate solution and ethyl acetate-tetrahydrofuran
Extracted. The organic layer is washed with saturated saline and magnesium sulfate
After drying, the solution was filtered and the filtrate was concentrated. Residue thin layer chromatography
Raffy (chloroform-tetrahydrofuran, 70:
Purification by 30) gave 23 mg of yellow crystals.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 11 Using the compound of Example 80 (2), the compound of Example 80 (3)
Instead of the compound of Reference Example 3, 4-amino-
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 (CDCl₃) 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)⁺. [0001]Example 12-Example 17 According to the method of Embodiment 1, Embodiments 12 to 17
Was prepared.Example 12 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 13 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 14 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 15 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 16 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 17 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 18 (1) The compound of Reference Example 1 and 2-amino-5- (N-
using tert-butoxycarbonyl) aminopyridine
0.613 prepared by a procedure similar to that of Example 26.
g (1.40 mmol) with 10 ml of trifluoroacetic acid
The reaction solution was stirred at the same temperature for 6 hours. Reaction liquid
Aqueous sodium bicarbonate solution and ethyl acetate-tetrahydrofuran
Extracted. The organic layer is washed with saturated saline and magnesium sulfate
After drying, the solution was filtered and the filtrate was concentrated. Silica gel residue
Chromatography (chloroform-methanol, 1
00: 0 to 90:10) to obtain 0.431 g of crude crystals.
Obtained. This was washed with ether and yellow crystals 0.302
g was obtained. (2) 33 mg of the compound obtained in (1)
And 3.4 mg of yellow crystals were prepared according to the method of Example 10.
Obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 19-Example 20 Example 19 and Example 20 according to the method of Example 26
Was prepared.Example 19 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 20 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 21 Compound of Reference Example 1 and 2-amino-6- (N-tert
Example using (butoxycarbonyl) aminopyridine
The target compound was produced according to 18 (1).¹H-NM
R (DMSO-d₆) Δ: 6.07-6.10 (2H,
m), 6.28 (1H, d, J = 7.5 Hz), 7.3
4-7.41 (4H, m), 7.46-7.48 (1
H, m), 7.52-7.57 (1H, m), 7.65.
(1H, d, J = 6.7 Hz), 7.77 (1H, d,
J = 7.1 Hz), 7.93 (1H, d, J = 7.6H)
z), 9.55 (1H, s), 11.6 (1H, br)
s). mass: 331 (M + 1)⁺. [0001]Example 22 Using the compound of Example 21 for the purpose according to Example 10
A compound was produced.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 23-Example 25 According to the method of Embodiment 26, Embodiments 23 to 2
Compound 5 was prepared.Example 23 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 24 ¹ H-NMR (DMSO-d₆) 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, d, J = 7.5 Hz)
s), 11.4-11.5 (1H, br). mass: 344 (M + 1).⁺ [0001]Example 25 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 26 13 mg (0.14 mmol) of 2-aminopyrimidine
Compound of Reference Example 1 in tetrahydrofuran (1 ml) solution
1.25 mg (0.1 mmol) of tetrahydrofuran
(1 ml) solution was added and refluxed for 30 minutes. The precipitated crystals
The crystals are collected by filtration, washed with chloroform, and dried, and the target compound (10 mg)
Was obtained as yellow crystals.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 27-Example 53 According to the method of the twenty-sixth embodiment, the twenty-seventh to the fifth embodiments
Compound 3 was prepared.Example 27 ¹ H-NMR (DMSO-d₆) Δ: 7.36-7.9
5 (9H, m). mass: 333 (M + 1)⁺. [0001]Example 28 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 29 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 30 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 31 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 32 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 33 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 34 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 35 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 36 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 37 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 38 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 39 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 40 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 41 mass: 336 (M + 1)⁺. [0001]Example 42 mass: 422 (M + 1)⁺. [0001]Example 43 mass: 408 (M + 1)⁺. [0001]Example 44 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 45 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 46 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 47 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 48 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 49 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 50 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 51 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 52 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 53 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 54-Example 55 The compounds of Example 54 and Example 55 were prepared according to the method of Example 1.
Manufactured according to.Example 54 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 55 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 56 56 mg (0.20 mmol) of the compound of Example 55,
157 mg (0.6 mmol) of triphenylphosphine
And methanol 19 mg (0.60 mmol)
And dissolved in 5 ml
0.17 solution of dicarboxylate in toluene (60%)
ml (0.60 mmol), and react at the same temperature for 30 minutes.
Was stirred. Dilute the reaction with ethyl acetate and wash with water.
Was. The organic layer is separated, and the precipitated crystals are collected by filtration to give the desired compound.
41 mg were obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 57-Example 74 The compound of Example 57 to Example 74 is a compound of Example 56
Manufactured according to the method.Example 57 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 58 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 59 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 60 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 61 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 62 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 63 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 64 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 65 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 66 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 67 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 68 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 69 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 70 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 71 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 72 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 73 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 74 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 79 The compound of Reference Example 3 and 2-pyridinecarbonyl azide
And the target compound was produced according to the method of Example 1.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 80 (1) 4-hydroxymethylpicolinic acid ethyl ester
2.00 g (11.0 mmol) of dimethylformamide
And dissolved in 1.80 g of imidazole (27.
0 mmol), chloro-tert-butyldiphenyl
7.60 ml (27.0 mmol) of run was added at room temperature.
The reaction solution was stirred at the same temperature for 2 hours. Hexa
Diluted with ethyl acetate (1: 1) and washed with saturated saline.
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated. Residue
To silica gel column chromatography (hexane-vinegar)
Ethyl acid, 95: 5-70: 30), colorless solid
4.27 g were obtained. (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. Organic layer
Was washed with saturated saline, and the organic layer was concentrated to obtain an oily substance.
Was. This was used for the next reaction without purification. (3) The compound obtained in (2) is
22.2 ml of 1N hydrochloric acid when dissolved in 10 ml of LUM
(22.2 mmol) was added at room temperature. This mixture
Cool on ice and add 1.02 g of sodium nitrite (14.8 mmol
l) was added at the same temperature, and the reaction solution was further stirred at the same temperature for 30 minutes.
Stirred. Extract the reaction solution with chloroform and separate the organic layer
did. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After drying, the mixture was filtered and the filtrate was concentrated. The residue obtained was
0.622 g (3.30 mmol) of tetrahydric compound
A solution of lofuran (50 ml) was added at room temperature, and
Refluxed overnight. The reaction mixture is concentrated, and the residue is
Chromatography (chloroform-tetrahydrofura
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) in 10 ml of tetrahydrofuran
Dissolved and tetra-n-butylammonium fluoride
6.60 ml of lahydrofuran solution (1.0 M) (6.6
0 mmol) at room temperature, and the reaction solution is stirred at the same temperature for 1 hour.
Stirred. Dilute the reaction solution with tetrahydrofuran and ethyl acetate.
The mixture was washed with saturated saline. The organic layer was concentrated and precipitated
The pale yellow crystals were collected by filtration. The filtrate is subjected to silica gel column chromatography.
Chromatography (chloroform-methanol, 100: 0
~ 95: 5) to obtain yellow crystals. Knot filtered earlier
The crystals were combined with crystals to give 1.02 g of the desired compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 81 (1) 3.55 g of tetrahydrofura of the compound of Reference Example 5
(35 ml) solution in tetra-n-butylammonium fluoride
7.10 M in tetrahydrofuran (1.0 M)
ml (7.10 mmol) at room temperature.
Stirred at temperature for 1 hour. Concentrate the reaction and dilute with ether
did. Wash sequentially with water and saturated saline and dry with magnesium sulfate
After drying, the mixture was filtered and concentrated. The residue is washed with ether and dried.
1.66 g of the target compound was obtained as a colorless solid.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 82 (1) 45 mg of the compound of Example 80 (0.13 mmol
l) was dissolved in 1 ml of pyridine, and methanesulfonyl chloride was dissolved.
Lide (40 μl, 0.52 mmol) was added at room temperature.
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.
Issued. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline.
Wash sequentially, dry magnesium sulfate, filter and concentrate the filtrate.
Was. The residue was dissolved in 1 ml of dimethylformamide,
Add 85 mg (1.3 mmol) of sodium azide
Then, the reaction solution was stirred at 80 ° C. for 30 minutes. Chlorine reaction solution
It was diluted with form and washed with saturated saline. Separate the organic layer
Concentration gave 35 mg of a pale yellow solid. This one is used for purification
Used for the next reaction without any further work. (2) 35 mg of the compound obtained in (1)
Dissolved in 7 ml of methanol-tetrahydrofuran (5: 2)
And add 5 mg of 10% palladium carbon catalyst at room temperature
Was. 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 was filtered through celite and the filtrate was concentrated.
Was. The precipitated crystals were collected by filtration to obtain 13 mg of pale yellow crystals.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 83 260 mg of the compound of Reference Example 9
Dissolve in 10 ml of lofran (1: 1) and add 10% palladium
200 mg of carbon catalyst were added at room temperature. Inside the reaction vessel
The atmosphere was replaced with hydrogen, and the reaction solution was stirred at the same temperature overnight. Insoluble matter
And the filtrate was concentrated to give 105 mg of the title compound.¹ H-NMR (DMSO-d6) [delta]: 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)⁺. [0001]Example 84 (1) 1.02 g of the compound of Example 80 (3.02 mmol)
l) is dimethylformamide-tetrahydrofuran
(1: 8) Dissolve in 90 ml and manganese dioxide at room temperature
3.92 g (45.1 mmol) was added, and the reaction solution was heated at the same temperature.
And stirred for 6 hours. The reaction was filtered through celite. Filtration
The solution was concentrated, and the precipitated crystals were collected by filtration to give yellow crystals 0.21.
1 g was obtained. (2) 34 mg of the compound obtained in (1)
(0.10 mmol) and 22 mg of n-butylamine
(0.30 mmol) in 5 ml of chloroform,
212mg sodium triacetoxyborohydride
(1.0 mmol) was added at room temperature, and the reaction solution was added at the same temperature.
Stirred for 24 hours. The reaction solution is neutralized with 3N hydrochloric acid,
Extracted with LUM. Wash the organic layer with saturated saline
After drying with cesium, the mixture was filtered and the filtrate was concentrated. The precipitated crystals
Filtration gave 13 mg of the desired compound.¹ H-NMR (DMSO-d₆) Δ: 0.88 (3H,
t, J = 7.3 Hz), 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 (2
H, t, J = 7.2 Hz), 3.50-3.57 (1
H, m), 3.81 (2H, s), 4.83 (1H, d
d, J = 11 Hz, 5.5 Hz), 7.09 (1H,
d, J = 5.3 Hz), 7.31-7.33 (2H,
m), 7.47 (1H, t, J = 7.9 Hz), 8.2
6 (1H, d, J = 5.3 Hz), 8.31 (1H,
d, J = 8.1 Hz), 9.98 (1H, s), 11.
2 (1H, br). mass: 394 (M + 1)⁺. [0001]Examples 85-94 The compounds of Example 85 to Example 94 are the same as Example 84
Manufactured according to.Example 85 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 86 ¹ H-NMR (DMSO-d₆) Δ: 1.06-1.2
0 (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)⁺. [0001]Example 87 ¹ H-NMR (DMSO-d₆) Δ: 1.06-1.2
0 (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 (1
H, m), 3.64 (2H, s), 4.83 (1H, d
d, J = 11 Hz, 5.6 Hz), 4.91 (2H,
s), 6.51 (2H, d, J = 8.3 Hz), 6.9
9 (1H, d, J = 8.2 Hz), 7.04 (2H,
d, J = 5.4 Hz), 7.26 (1H, s), 7.3
2 (1H, d, J = 7.4 Hz), 7.47 (1H,
t, J = 7.8 Hz), 8.22 (1H, d, J = 5.
4Hz), 8.33 (1H, d, J = 8.1Hz),
9.94 (1H, s), 11.5 (1H, br). ma
ss: 443 (M + 1)⁺. [0001]Example 88 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 89 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 90 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 91 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 92 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 93 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 94 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 95 N- (2-aminoethyl) carbamic acid tert-butyl
The target compound was prepared according to Example 96 using
Built.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 96 (1) 844 m of 4-nitrobenzenesulfonyl chloride
g (3.81 mmol) in chloroform (9 ml)
0.531 ml of triethylamine
(3.81 mmol) and bring the reaction to room temperature.
Was. This solution (0.3 ml) was added at room temperature to n-propyl alcohol.
10 μl (0.122 mmol) of chloroform
0.3 ml solution was added and the reaction was stirred at the same temperature overnight.
Was. The reaction mixture was purified by thin-layer chromatography (chloroform
-Methanol, 19: 1) to give the desired compound.
Was. (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 diethylazodica was added to the reaction mixture.
0.047m of toluene solution of ruboxylate (40%)
1 (0.108 mmol) was added and the reaction solution was added at room temperature for 3 hours.
Stirred for days. Thin layer chromatography of the reaction mixture
(Chloroform-methanol, 19: 1). (3) The compound obtained in (2) is converted to dimethyl
35mg sodium carbonate dissolved in 1ml formamide
(0.330 mmol) and 11 μl of thiophenol
(0.107 mmol) was added at room temperature, and the reaction solution was heated at the same temperature.
And stirred for one day. The insolubles are filtered and the filtrate is tetrahydro
Dissolve in 3 ml of furan and add 1 ml of 1N hydrochloric acid to the reaction solution at room temperature
And the reaction solution was further stirred at room temperature for 1 hour. reaction
The solution was concentrated and the residue was azeotroped with toluene. Here Methaneau
Ru-ether was added to solidify to obtain the target compound.¹ H-NMR (DMSO-d₆) 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,
brs), 10.9 (1H, br). mass: 394 (M + 1)⁺. [0001]Example 97-Example 98 The compounds of Example 97 and Example 98 are equivalent to Example 96.
Manufactured.Example 97 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 98 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 99 Using glycol aldehyde diethyl acetal,
This was produced according to Example 96.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 100 Example 96 using glycine tert-butyl ester
Manufactured according to.¹H-NMR (DMSO-d₆)
δ: 1.03-1.10 (1H, m), 2.23-2.
40 (2H, brm), 2.54-2.65 (1H, b
rm), 2.97-3.05 (2H, brm), 3.1.
7-3.40 (3H, m), 3.50-3.59 (1
H, m), 3.94 (2H, brs), 4.81-4.
86 (1H, m), 7.03 (1H, d, J = 5.5H
z), 7.28-7.34 (2H, m), 7.46 (1
H, t, J = 7.8 Hz), 8.26 (2H, d, J =
6.5 Hz), 9.23 (2H, br), 10.4 (1
H, br), 10.9 (1H, br). mass: 466 (M + 1)⁺. [0001]Example 101-Example 108 The compounds of Examples 101 to 108 were prepared in Example 9
6 was prepared.Example 101 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 102 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 103 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 104 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 105 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 106 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 107 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 108 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 109 As described in Reference Example 8, 80 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 110 30 mg (0.038 mmol) of the compound of Reference Example 11
N-butanoyl chloride 6μ in chloroform (1ml) solution
l (0.058 mmol) and 13 μl of triethylamine
(0.093 mmol) at room temperature.
And stirred 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 kept at the same temperature.
And stirred for 10 minutes. 1 ml of water is added to the reaction solution, and the organic layer is separated.
separated. The organic layer is washed with 1 ml of water and washed with magnesium sulfate.
After drying, the mixture was filtered and the filtrate was concentrated. Residue is tetrahydrofura
Dissolved in 1 ml of 1N hydrochloric acid at room temperature.
In addition, the reaction was stirred at the same temperature for 15 minutes. Concentrate the reaction solution
The reaction mixture was added with 2 ml of trifluoroacetic acid
Was stirred at room temperature for 15 minutes. Concentrate the reaction mixture and add
The target compound was obtained by solidification with the addition of knol-ether.¹ H-NMR (DMSO-d₆) 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,
br), 11.1 (1H, br). mass: 422 (M + 1)⁺. [0001]Example 111-Example 114 The compounds of Examples 111 to 114 were prepared according to Example 1.
It was manufactured according to 10.Example 111 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 112 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 113 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 114 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 115 According to Example 96 (1) using the compound of Example 83
The target compound was prepared.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 116 Example 56 using phenol and the compound of Reference Example 7
The same operation as in Example 124 for the compound prepared in the same manner
Was carried out to produce a target compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 117 (1) 544 mg of 3-amino-5-phenylpyrazole
(3.4 mmol) of dimethylformamide (10 m
l) Add 164 mg (4.1 mmol) of sodium hydride 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. Add saturated ammonium chloride to the reaction mixture.
An aqueous ammonium solution was added, and the mixture was extracted with ethyl acetate. Organic
Separate the layers, wash with water and saturated saline, and wash with magnesium sulfate.
Dry and concentrate the filtrate. Silica gel column chromatography
Purify by chromatography (hexane-ethyl acetate, 4: 1)
To give 509 mg of the desired product. (2) 509 mg of the compound obtained in (1)
(2.0 mmol) in pyridine (5.0 ml).
0.19 ml (2.5 mmol) of methyl logoate was added.
Stirred at room temperature for 2 hours. 1N hydrochloric acid was added to the reaction solution, and
Extracted with chill. Separate the organic layer and add saturated aqueous sodium bicarbonate and saturated saline
After washing with water, magnesium sulfate was dried and the filtrate was concentrated.
The residue was analyzed by silica gel column chromatography (hexane
-Ethyl acetate, 4: 1 to 2: 1) to give the desired product 45
0 mg was obtained. (3) 440 mg of the compound obtained in (2)
(1.4 mmol) in toluene (5.0 ml).
0.40 ml (2.9 mmol) of liethylamine was added.
Stir at 80 ° C for 10 minutes, and add B-chlorocatechol borane.
Add 450mg (2.9mmol) at the same temperature for 10 minutes
Stirred. 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. B-chlorocate
Add 440 mg (2.9 mmol) of coal borane and add 10
Stirred at 0 ° C. for 1 hour. Add 1N hydrochloric acid to the reaction mixture and add
Extracted with Holm. Separate the organic layer and add 1N sodium hydroxide
Washed with saturated saline solution and dried over magnesium sulfate.
Concentrated. Chloroform-ether was added to the residue to precipitate
400 mg of the resulting crystals were collected by filtration. (4) 400 mg of the compound obtained in (3)
(0.87 mmol) in methanol-tetrahydrofura
(1: 1) in 20 ml. 10% palladium charcoal
200 mg of elementary catalyst was added, and the inside of the reaction
And stirred overnight. The reaction solution was filtered through celite, and the filtrate was concentrated.
Shrank. Crystallize by adding ether-ethyl acetate to the residue
Thus, 220 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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). [0001]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. Reaction solution at room temperature
After concentration, dissolve the residue in ether and wash with water
The extract was dried over magnesium sulfate and concentrated by filtration. Silica residue
Gel column chromatography (hexane-ethyl acetate
5: 1 to 2: 1) to yield 2.61 g of pale yellow crystals
I got (2) 1.23 g of the compound obtained in (1)
(3.27 mmol) and p-nitrophenyl chloroformate
0.859 mg (4.26 mmol), 4-dimethyla
Minopyridine 1.00 g (8.19 mmol), chloro
A mixture of 10 ml of form was stirred at room temperature for 30 minutes. reaction
0.920 g of the compound of Reference Example 3 (4.96 mmol
l) was added and the reaction was stirred at 100 ° C. overnight. Reaction liquid
With 1N sodium hydroxide, 1N
Wash sequentially with hydrochloric acid and saturated saline and dry with magnesium sulfate
The solution was concentrated by filtration. The residue is purified by silica gel column chromatography.
(Chloroform-methanol, 98: 2-97:
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 (diphenyl
Ruphosphino) ferrocene 30 mg (0.0541 mm)
ol) and 71 mg of sodium bicarbonate (0.845 m
mol) is mixed with 4 ml of methanol and the inside of the container is filled with carbon monoxide.
The reaction was refluxed for 7 hours. Sera the reaction solution
The filtrate was concentrated. Silica gel residue
Chromatography (chloroform-methanol, 9
8: 2 to 97: 3) to give 180 mg of a yellow solid
Was. (4) 40 mg of the compound obtained in (3)
It was dissolved in 5 ml of ethanol. Palladium hydroxide in the reaction solution
10 mg at room temperature, replace the inside of the vessel with hydrogen,
The solution was stirred at 70 ° C. overnight. Filter the reaction through Celite
The filtrate was concentrated. The residue is purified by silica gel column chromatography.
Purified by fee (chloroform-methanol, 10: 1)
Thus, 8.6 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]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) at room temperature, and the reaction solution is stirred at room temperature for a while.
After that, the mixture was further heated to 50 ° C. and stirred for 2 hours. Reaction liquid
Was acidified with 1N hydrochloric acid and then concentrated. Chloroform the residue
And washed with water. The water layer is more chloro
Extract twice with Holm, combine the organic layers and add magnesium sulfate
After drying, the solution was concentrated by filtration. Ether and chloroform in the residue
Was added, and 73 mg of precipitated crystals were collected by filtration. (2) 36 mg of the compound obtained in (1)
(0.0699 mmol) dissolved in 4 ml of ethanol
Then, 10 mg of palladium hydroxide was added to the reaction solution at room temperature.
And replace the inside of the vessel with hydrogen, and stir the reaction solution at 70 ° C. overnight.
Was. The reaction solution was filtered through celite, and the filtrate was concentrated. Residue
Add ether and chloroform to precipitate crystals
13 mg of the compound were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 120 (1) Using α-cyano-m-iodoacetophenone
The adjustment was performed according to the same procedure as in Examples 118 (1) to (3).
The prepared compound was reacted according to Example 119 (1).
Was carried out to obtain a target compound. (2) Using the compound obtained in (1),
The target compound was produced according to Example 119 (2).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 121 (1) 56 mg of the compound obtained in Example 120 (1)
(0.11 mmol) in 1.5 m of dimethylformamide
1 and 1,1'-carbonyl at room temperature.
Add 25 mg (0.15 mmol) of diimidazole,
The reaction was stirred at room temperature for 30 minutes. At room temperature,
42 μl (0.33 mmol) of nylethylamine was added.
The reaction solution was heated from room temperature to 70 ° C.
For 10 minutes. The reaction mixture is concentrated, and the residue is subjected to thin layer chromatography.
By chromatography (chloroform-methanol, 10: 1)
Purification gave a crude product. This thing is the next reaction as it is
used. (2) 51 mg of the compound obtained in (1)
(0.084 mmol) in methanol-tetrahydrof.
Dissolve in 3 ml of run (2: 1) and add hydroxylic acid to the reaction solution at room temperature.
Add 51 mg of palladium chloride and replace the inside of the vessel with hydrogen,
The reaction was stirred overnight at room temperature. Filter the reaction solution through Celite
After that, the filtrate was concentrated to obtain 25 mg of the desired compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 122 (1) 10.0 g of 2-bromo-3-nitrobenzoic acid (4
0.7 mmol), pyrrole-2-carboxyaldehyde
7.74 g (81.4 mmol) of triethylamine
20.0 ml (143 mmol) and thionyl chloride 30
ml, using the same procedure as in Reference Example 2 (1).
9.07 g of compound was obtained. (2) 9.07 g of the compound obtained in (1)
(28.0 mmol) of tetrahydrofuran (400 m
l) The solution was cooled to -78 ° C. Hydrogen in the reaction solution at the same temperature
Solution of diisopropylaluminum fluoride in toluene (1.0
M) 33.6 ml (33.6 mmol) were added and further
The reaction was stirred at the same temperature for 2 hours. At the same temperature for the reaction solution
Add 15 ml of a saturated aqueous solution of ammonium chloride and return to room temperature.
After stirring the reaction solution for 2 hours, the organic layer was washed with magnesium sulfate.
And the filtrate was concentrated. The resulting residue is
Dissolve in 200 ml of styrene and add chloro-t
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. Reaction solution
Dilute with ethyl acetate and saturate the organic layer with 200 ml of water three times
The extract was washed successively with brine, dried over magnesium sulfate, and the filtrate was concentrated.
Concentrated. The obtained residue is subjected to silica gel column chromatography.
Raffy (Wakogel C-300, hexane-ethyl acetate
10: 1 to 5: 1) to give 9.34 as a colorless oil.
g was obtained. (3) 9.34 g of the compound obtained in (2)
(21.3 mmol) and diisopropylethylamido
8.24 g (63.8 mmol) of dimethylforma
Dissolve in 200 ml of amide and replace the inside of the reaction vessel with nitrogen.
Was. Add tetrakistriphenylphosphine to the reaction solution at room temperature.
2.46 g (2.13 mmol) of palladium were added,
The reaction was stirred at 130 ° C. for 2 hours. Ethyl acetate
The mixture was added to 1 L of water and 500 ml of water, and the organic layer was separated. Water layer
Extract with 300 ml of ethyl acetate and combine the organic layers
Wash with water and saturated saline in that order, and dry with magnesium sulfate.
After drying, the filtrate was concentrated. The residue is purified by silica gel column chromatography.
Tography (Wakogel C-300, hexane-acetic acid
Ethyl, 20: 1 to 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) in methanol-tetrahydrofura
(1: 1) in 400 ml, and added to the reaction solution at room temperature.
500 mg of 0% palladium on carbon catalyst was added. Reaction vessel
The inside was replaced with hydrogen, and the reaction solution was stirred at room temperature for 2 hours. reaction
The liquid was filtered through Celite, and the filtrate was concentrated. Silica residue
Gel column chromatography (Wakogel C-30)
0, hexane-ethyl acetate, 2: 1 to 1: 1)
Was. 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 polarity substance)¹ H-NMR (CDCl₃) Δ: 0.14 (6H,
s), 0.95 (9H, s), 3.84 (2H, br)
s), 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 (1
H, t, J = 7.7 Hz), 7.14 (1H, d, J =
7.3 Hz). Fraction 2 (highly polar substance)¹ H-NMR (CDCl₃) Δ: 0.02 (6H,
s), 0.74 (9H, s), 1.60-1.70 (1
H, 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) Fraction 2 (highly polar substance) obtained in (4)
Example) using 2.40 g (7.23 mmol)
According to the same procedure as in Example 1, 2.71 g of a yellow solid was obtained. (6) 2.71 g of the compound obtained in (5)
(6.00 mmol) in methanol-tetrahydrofura
(1: 1) in 200 ml, and added to the reaction solution at room temperature.
N hydrochloric acid (10 ml) was added, and the reaction mixture was further incubated at the same temperature for 6 hours.
While stirring. The reaction mixture is concentrated, and the residue is
Dewatered by boiling. The obtained crude product is treated with hexane-ethyl acetate
-Recrystallized from tetrahydrofuran to obtain the target compound 1.8
5 g were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 123 (1) 4.50 g of the compound obtained in Example 131 (1)
(13.4 mmol) as in Example 122 (2).
According to the same procedure, 3.94 g of a yellow solid was obtained. (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-polar substance):¹ H-NMR (CDCl₃-CD₃OD) δ: 0.08
(3H, s), 0.11 (3H, s), 0.93 (9
H, s), 1.51 (3H, d, J = 6.2 Hz),
3.84 (2H, br), 5.26 (1H, m), 5.
96 (1H, d, J = 3.3 Hz), 6.10 (1H, d, J = 3.3 Hz)
dd, J = 3.1 Hz, 1.0 Hz), 6.78 (1
H, d, J = 8.0 Hz), 7.01 (1H, t, J =
7.7 Hz), 7.13 (1H, d, J = 7.3H)
z). Fraction 2 (highly polar substance):¹ H-NMR (CDCl₃) Δ: 0.07 (3H,
s), 0.11 (3H, s), 0.85-0.95 (1
H, m), 0.92 (9H, s), 1.24-1.35
(2H, m), 1.52 (3H, d, J = 6.3H
z), 1.52-1.55 (1H, m), 5.27 (1
H, q), 6.28 (1H, d, J = 3.4 Hz),
7.07 (1H, d, J = 3.6 Hz), 7.31 (1
H, dd, J = 8.5 Hz, 7.3 Hz), 7.92
(1H, dd, J = 7.3 Hz, 1.0 Hz), 8.2
8 (1H, dd, J = 8.5 Hz, 1.0 Hz). (3) Fraction 2 (highly polar substance) obtained in (2)
Example) using 300 mg (0.87 mmol)
According to the same procedure as in Example 1, 389 mg of a yellow solid was obtained. (4) 200 mg of the compound obtained in (3)
(0.429 mmol) using the same procedure as in Reference Example 7.
Thus, 92 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 124 Fraction 2 (highly polar substance) 1 obtained in Example 128 (5)
4 mg of methanol-tetrahydrofuran (1: 1) 2
and 1 ml of 1N hydrochloric acid was added to the reaction solution at room temperature.
In addition, the reaction solution was stirred at the same temperature for 30 minutes. Saturated reaction solution
Neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. Organic layer
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated. The residue
Thin layer chromatography (ethyl acetate-methanol, 3
0: 1) to give 4.1 mg of the desired compound and Example
3.8 mg of 127 were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 125 (1) 12.3 g of the compound of Example 128 (1) (38.
2 mmol) in 150 ml of tetrahydrofuran
Then, the reaction solution was cooled to -78 ° C. Water at the same temperature
Toluene solution of diisobutylaluminum iodide (1.0
M) 46.0 ml (46.0 mmol) were added and
The reaction was stirred for 15 minutes. Add saturated ammonium chloride to the reaction mixture.
25 ml of an aqueous solution of sodium was added, and the temperature was returned to room temperature. To the reaction solution
Magnesium sulfate was added and the mixture was filtered, and the filtrate was concentrated. Remaining
The residue is dissolved in 150 ml of chloroform, and imidazole is dissolved.
5.20 g (81.1 mmol) and chlorotriiso
9.40 ml (43.9 mmol) of propylsilane in the chamber
At room temperature, the atmosphere in the vessel was replaced with nitrogen, and the reaction solution was cooled to room temperature for 12 hours.
Stirred for hours. Dilute the reaction solution with ethyl acetate, add water,
Wash sequentially with Japanese saline, and dry the organic layer over magnesium sulfate
After filtration, the filtrate was concentrated. The residue is purified by silica gel column chromatography.
By chromatography (hexane-ethyl acetate, 10: 1)
Purification gave 17.2 g of a yellow solid. (2) 17.2 g of the compound obtained in (1)
(15.6 mmol) and according to (2) of Reference Example 2.
The reaction was carried out to obtain 4.90 g of a yellow solid. (3) 4.90 g of the compound obtained in (2)
(12.2 mmol) in 70 ml of tetrahydrofuran
Dissolve and add 20 ml of 6N hydrochloric acid to the reaction solution at room temperature.
The reaction solution was stirred at the same temperature for 1 hour. 1N sodium hydroxide
The reaction was made basic with um and extracted with ethyl acetate. Yes
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.
After drying, 2.94 g of a yellow solid was obtained. (4) 180 mg of the compound obtained in (3)
(0.73 mmol) in 5.0 ml of methanol and
Dissolve in 16 ml of trihydrofuran and add triethylamine
0.20 ml, 10% palladium on carbon catalyst 100 mg
In addition, the mixture was stirred at 50 ° C. for 1 hour under a hydrogen stream. Remove the reaction solution
The filtrate was concentrated to give 163 mg of a colorless solid.
Obtained. (5) 163 mg of the compound obtained in (4)
(0.75 mmol) and 2-pyridinecarbonyl azide
According to Example 1 using 107 mg (0.72 mmol)
Thus, 7 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 126 (1) 85 mg of the compound of Example 125 (0.251 mm
ol) and 132 mg (0.5 mg) of triphenylphosphine.
03mmol) in tetrahydrofuran (6ml)
0.140 ml of diphenylphosphate azide (0.65
0 mmol) and diethyl azodicarboxylate
0.220 ml of Ruen solution (40%) (0.505 mm
ol) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour.
Was. Dilute the reaction solution with ethyl acetate and add water and saturated saline.
After washing sequentially, the organic layer was dried over magnesium sulfate and filtered.
The filtrate was concentrated. The residue was purified by thin-layer chromatography
Purified with chloroform-methanol, 10: 1). Athe
Was added to obtain 24 mg of crystals. (2) 24 mg of the compound obtained in (1)
Dissolve in 2 ml of methanol-tetrahydrofuran (1: 1)
Then, at room temperature, 10% palladium on carbon catalyst 10
mg was added. Replace the inside of the vessel with hydrogen and react under a hydrogen stream
The liquid was stirred at room temperature until the starting material disappeared. Sera the reaction solution
The filtrate was concentrated. Add ether to the residue
Crystallized. The crystals were collected by filtration, and ethyl acetate and chloro
After washing with form, drying was performed to obtain 4.6 mg of the target compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 127 The target compound was obtained in the production reaction of Example 124.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 128 (1) Using pyrrole-3-carboxaldehyde
The same operation as in Example 2 (1) was performed 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),
Following the same procedure as in (2) of Example 2, 2:
1 was obtained. (4) Using the compound obtained in (3),
A purified mixture was obtained according to a procedure similar to (4) of Example 122.
Was. 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. Anti
The reaction solution is concentrated, and the residue is subjected to thin-layer chromatography (hex.
-Ethyl acetate, 1: 2) and fraction 1 (low polarity)
Substance) and fraction 2 (highly polar substance). (6) Fraction 1 (low-polarity substance) obtained in (5)
11 mg of methanol-tetrahydrofuran (1:
5) Dissolve in 1.2 ml and add 1N hydrochloric acid to the reaction solution at room temperature.
1.0 ml was added and the reaction was stirred at the same temperature. reaction
Concentrate the solution, dilute the residue with ethyl acetate, and add saturated aqueous sodium bicarbonate.
And saturated sodium chloride solution, and the organic layer was washed with magnesium sulfate.
After drying the solution, the filtrate was concentrated. Residue thin layer chromatography
By chromatography (chloroform-methanol, 10: 1)
Purification gave 3.1 mg of the desired compound.¹ H-NMR (acetone-d₆) Δ: 1.29
(1H, br), 2.52-2.61 (2H, m),
3.00-3.10 (2H, m), 3.29-3.41
(1H, m), 3.54-3.70 (2H, m), 5.
08 (1H, d, J = 5.4 Hz), 7.05-7.1
2 (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). [0001]Example 129 (1) 100 mg of the compound obtained in Reference Example 2 (2)
(0.467 mmol) in methanol (15 ml)
200 mg (3.58 mmol) of iron powder at room temperature, 6N
After adding 0.500 ml (3.00 mmol) of hydrochloric acid, the reaction was carried out.
The liquid was stirred at room temperature for 30 minutes. The reaction solution was treated with ethyl acetate 200
diluted with water, 100 ml of saturated aqueous sodium bicarbonate, water, saturated saline
The organic layer was dried over magnesium sulfate, and the filtrate was
Was concentrated. Silica gel column chromatography of the residue
-(Wakogel C-300, hexane-ethyl acetate,
5: 1) to give 71 mg of a pale green solid. (2) 50 mg of the compound obtained in (1)
65 mg of the target compound using the same procedure as in Example 1
I got¹ H-NMR (DMSO-d₆) 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). [0001]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 got¹ H-NMR (DMSO-d₆) 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). [0001]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) in the same manner as in Reference Example 2 (1).
According to the procedure, 9.20 g of a yellow solid was obtained. (2) 2.00 g of the compound obtained in (1)
(5.93 mmol) in the same manner as in Reference Example 2 (2).
According to the procedure, 941 mg of a pale green solid was obtained. (3) 300 mg of the compound obtained in (2)
(1.17 mmol) using the same procedure as in Example 129.
277 mg of the target compound was obtained according to the order.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 132 (1) 4.5 g of the compound obtained in Example 131 (1)
(13.4 mmol) using Example 122 (2)
3.94 g of the desired product was obtained in the stated order. (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) Fraction 1 (low-polarity substance) obtained in (2)
Example 1 using 200 mg (0.58 mmol)
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 same procedure as in Reference Example 7.
Thus, 85 mg of the desired compound was obtained.¹ H-NMR (DMSO-d₆) 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). BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below with reference to examples.
However, the present invention is not limited to these implementations.
It is not limited to only examples. [0001] Thin-layer chromatographs of Examples and Reference Examples
I use Silica gel as a plate₆₀F
₂₅₄(Merck) using a UV detector as a detection method
Was. As silica gel for column, WakogelT
MC-300 or C-200 (Wako Pure Chemical Industries) was used.
For high performance liquid chromatography, HP1100 series
Using Leeds (Hewlett-Packard (HP))
Was. The MS spectrum was measured by JMS-SX102A (Nippon Denki).
Child (JEOL)) or QUATTRO II (micro
Mass). The NMR spectrum is
When measuring with a chloroform solution, tet
Using Lamethylsilane (TMS) with heavy methanol solution
For measurement, use methanol as deuterated dimethyl sulfoxy
Use dimethyl sulfoxide when measuring with
Gemini-200 (200 MHz; Varia
n), Gemini-300 (300 MHz; Vari)
an) or VXR-300 (300 MHz; Var)
ian) using a spectrometer and calculating the total δ value
It was shown in ppm. The meanings of the abbreviations in the NMR measurement are shown below.
You. s: Singlet d: Doublet dd: Double doublet t: triplet dt: Double triplet q: quartet m: Multiplet br: Broad J: Coupling constant Hz: Hertz CDCl₃: Heavy chloroform D₂O: Heavy water DMSO-d₆: Heavy dimethyl sulfoxide CD₃OD: heavy methanol The meanings of the abbreviations in the reaction formulas are shown below.
You. 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 [0001] Next, the compounds of Examples according to the present invention are shown in the following Tables.
Specific examples are shown below. [0001] [Table 1][0001] [Table 2][0001] [Table 3][0001] [Table 4][0001] [Table 5][0001] [Table 6][0001] [Table 7][0001] [Table 8][0001] [Table 9][0001] [Table 10][0001] [Table 11][0001] [Table 12][0001]Example 1 29 mg of 4-amino-9-fluorenone (0.15 mm
ol) to 22 mg of 2-pyridinecarbonylazide (0.
15 mmol) in 0.5 ml of tetrahydrofuran
At room temperature, the reaction was refluxed for 2 hours. Reaction solution at room temperature
And mixed with hexane and ethyl acetate to crystallize.
Was. The obtained crude product is sequentially treated with ethyl acetate and methanol.
After the next washing, the precipitate was collected by filtration to give a yellow powder (34 mg, compound of Example 1).
Product).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 2-Example 8 According to the method of Example 1, conversion of Examples 2 to 8
A compound was produced.Example 2 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 3 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 4 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 5 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 6 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 7 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 8 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 9 Compound of Reference Example 1 and 2-amino-4- (N-ethoxy
Same as Example 26 using (carbonyl) aminopyridine
50 mg (0.12 mmol) of the compound prepared by the same procedure
l) was dissolved in 2 ml of ethanol.
2.0 ml (10 mmol) of sodium aqueous solution at room temperature
The reaction was refluxed for 1 hour. Return the reaction solution to room temperature and water
And extracted with ethyl acetate-tetrahydrofuran.
The organic layer was washed with brine, dried over magnesium sulfate, and filtered.
The filtrate was concentrated. The residue is purified by silica gel column chromatography.
Chromatography (chloroform-methanol, 100: 0-
95: 5) to give 8 mg of yellow crystals. [0001]¹H-NMR (DMSO-d₆) Δ: 6.
19 (1H, s), 6.25 (1H, d, J = 5.9H)
z), 6.28 (2H, s), 7.34-7.41 (3
H, m), 7.62-7.69 (2H, m), 7.74
(1H, d, J = 5.7 Hz), 8.15 (1H, d,
J = 7.1 Hz), 8.21 (1H, d, J = 7.1H)
z), 9.66 (1H, s), 12.3 (1H, b
r). mass: 331 (M + 1)⁺. [0001]Example 10 33 mg (0.10 mmol) of the compound of Example 9
Dissolve in 3 ml of lahydrofuran and add n-butyraldehyde
27 μl (0.30 mmol) and triacetoxy water
63 mg (0.30 mmol) of sodium borohydride
The reaction solution was stirred at the same temperature for 6 hours. Reaction liquid
Aqueous sodium bicarbonate solution and ethyl acetate-tetrahydrofuran
Extracted. The organic layer is washed with saturated saline and magnesium sulfate
After drying, the solution was filtered and the filtrate was concentrated. Residue thin layer chromatography
Raffy (chloroform-tetrahydrofuran, 70:
Purification by 30) gave 23 mg of yellow crystals.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 11 Using the compound of Example 80 (2), the compound of Example 80 (3)
Instead of the compound of Reference Example 3, 4-amino-
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 (CDCl₃) 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)⁺. [0001]Example 12-Example 17 According to the method of Embodiment 1, Embodiments 12 to 17
Was prepared.Example 12 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 13 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 14 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 15 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 16 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 17 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 18 (1) The compound of Reference Example 1 and 2-amino-5- (N-
using tert-butoxycarbonyl) aminopyridine
0.613 prepared by a procedure similar to that of Example 26.
g (1.40 mmol) with 10 ml of trifluoroacetic acid
The reaction solution was stirred at the same temperature for 6 hours. Reaction liquid
Aqueous sodium bicarbonate solution and ethyl acetate-tetrahydrofuran
Extracted. The organic layer is washed with saturated saline and magnesium sulfate
After drying, the solution was filtered and the filtrate was concentrated. Silica gel residue
Chromatography (chloroform-methanol, 1
00: 0 to 90:10) to obtain 0.431 g of crude crystals.
Obtained. This was washed with ether and yellow crystals 0.302
g was obtained. (2) 33 mg of the compound obtained in (1)
And 3.4 mg of yellow crystals were prepared according to the method of Example 10.
Obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 19-Example 20 Example 19 and Example 20 according to the method of Example 26
Was prepared.Example 19 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 20 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 21 Compound of Reference Example 1 and 2-amino-6- (N-tert
Example using (butoxycarbonyl) aminopyridine
The target compound was produced according to 18 (1).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 22 Using the compound of Example 21 for the purpose according to Example 10
A compound was produced.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 23-Example 25 According to the method of Embodiment 26, Embodiments 23 to 2
Compound 5 was prepared.Example 23 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 24 ¹ H-NMR (DMSO-d₆) 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, d, J = 7.5 Hz)
s), 11.4-11.5 (1H, br). mass: 344 (M + 1).^{+ Embodiment 25 1} H-NMR (DMSO-d₆) 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)⁺. [0001]Example 26 13 mg (0.14 mmol) of 2-aminopyrimidine
Compound of Reference Example 1 in tetrahydrofuran (1 ml) solution
1.25 mg (0.1 mmol) of tetrahydrofuran
(1 ml) solution was added and refluxed for 30 minutes. The precipitated crystals
The crystals are collected by filtration, washed with chloroform, and dried, and the target compound (10 mg)
Was obtained as yellow crystals.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 27-Example 53 According to the method of the twenty-sixth embodiment, the twenty-seventh to the fifth embodiments
Compound 3 was prepared.Example 27 ¹ H-NMR (DMSO-d₆) Δ: 7.36-7.9
5 (9H, m). mass: 333 (M + 1)⁺. [0001]Example 28 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 29 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 30 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 31 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 32 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 33 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 34 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 35 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 36 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 37 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 38 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 39 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 40 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 41 mass: 336 (M + 1)⁺. [0001]Example 42 mass: 422 (M + 1)⁺. [0001]Example 43 mass: 408 (M + 1)⁺. [0001]Example 44 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 45 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 46 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 47 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 48 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 49 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 50 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 51 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 52 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 53 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 54-Example 55 The compounds of Example 54 and Example 55 were prepared according to the method of Example 1.
Manufactured according to.Example 54 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 55 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 56 56 mg (0.20 mmol) of the compound of Example 55,
157 mg (0.6 mmol) of triphenylphosphine
And methanol 19 mg (0.60 mmol)
And dissolved in 5 ml
0.17 solution of dicarboxylate in toluene (60%)
ml (0.60 mmol), and react at the same temperature for 30 minutes.
Was stirred. Dilute the reaction with ethyl acetate and wash with water.
Was. The organic layer is separated, and the precipitated crystals are collected by filtration to give the desired compound.
41 mg were obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 57-Example 74 The compound of Example 57 to Example 74 is a compound of Example 56
Manufactured according to the method.Example 57 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 58 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 59 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 60 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 61 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 62 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 63 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 64 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 65 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 66 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 67 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 68 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 69 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 70 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 71 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 72 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 73 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 74 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 79 The compound of Reference Example 3 and 2-pyridinecarbonyl azide
And the target compound was produced according to the method of Example 1.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 80 (1) 4-hydroxymethylpicolinic acid ethyl ester
2.00 g (11.0 mmol) of dimethylformamide
And dissolved in 1.80 g of imidazole (27.
0 mmol), chloro-tert-butyldiphenyl
7.60 ml (27.0 mmol) of run was added at room temperature.
The reaction solution was stirred at the same temperature for 2 hours. Hexa
Diluted with ethyl acetate (1: 1) and washed with saturated saline.
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated. Residue
To silica gel column chromatography (hexane-vinegar)
Ethyl acid, 95: 5-70: 30), colorless solid
4.27 g were obtained. (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. Organic layer
Was washed with saturated saline, and the organic layer was concentrated to obtain an oily substance.
Was. This was used for the next reaction without purification. (3) The compound obtained in (2) is
22.2 ml of 1N hydrochloric acid when dissolved in 10 ml of LUM
(22.2 mmol) was added at room temperature. This mixture
Cool on ice and add 1.02 g of sodium nitrite (14.8 mmol
l) was added at the same temperature, and the reaction solution was further stirred at the same temperature for 30 minutes.
Stirred. Extract the reaction solution with chloroform and separate the organic layer
did. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After drying, the mixture was filtered and the filtrate was concentrated. The residue obtained was
0.622 g (3.30 mmol) of tetrahydric compound
A solution of lofuran (50 ml) was added at room temperature, and
Refluxed overnight. The reaction mixture is concentrated, and the residue is
Chromatography (chloroform-tetrahydrofura
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) in 10 ml of tetrahydrofuran
Dissolved and tetra-n-butylammonium fluoride
6.60 ml of lahydrofuran solution (1.0 M) (6.6
0 mmol) at room temperature, and the reaction solution is stirred at the same temperature for 1 hour.
Stirred. Dilute the reaction solution with tetrahydrofuran and ethyl acetate.
The mixture was washed with saturated saline. The organic layer was concentrated and precipitated
The pale yellow crystals were collected by filtration. The filtrate is subjected to silica gel column chromatography.
Chromatography (chloroform-methanol, 100: 0
~ 95: 5) to obtain yellow crystals. Knot filtered earlier
The crystals were combined with crystals to give 1.02 g of the desired compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 81 (1) 3.55 g of tetrahydrofura of the compound of Reference Example 5
(35 ml) solution in tetra-n-butylammonium fluoride
7.10 M in tetrahydrofuran (1.0 M)
ml (7.10 mmol) at room temperature.
Stirred at temperature for 1 hour. Concentrate the reaction and dilute with ether
did. Wash sequentially with water and saturated saline and dry with magnesium sulfate
After drying, the mixture was filtered and concentrated. The residue is washed with ether and dried.
1.66 g of the target compound was obtained as a colorless solid.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 82 (1) 45 mg of the compound of Example 80 (0.13 mmol
l) was dissolved in 1 ml of pyridine, and methanesulfonyl chloride was dissolved.
Lide (40 μl, 0.52 mmol) was added at room temperature.
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.
Issued. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline.
Wash sequentially, dry magnesium sulfate, filter and concentrate the filtrate.
Was. The residue was dissolved in 1 ml of dimethylformamide,
Add 85 mg (1.3 mmol) of sodium azide
Then, the reaction solution was stirred at 80 ° C. for 30 minutes. Chlorine reaction solution
It was diluted with form and washed with saturated saline. Separate the organic layer
Concentration gave 35 mg of a pale yellow solid. This one is used for purification
Used for the next reaction without any further work. (2) 35 mg of the compound obtained in (1)
Dissolved in 7 ml of methanol-tetrahydrofuran (5: 2)
And add 5 mg of 10% palladium carbon catalyst at room temperature
Was. 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 was filtered through celite and the filtrate was concentrated.
Was. The precipitated crystals were collected by filtration to obtain 13 mg of pale yellow crystals.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 83 260 mg of the compound of Reference Example 9
Dissolve in 10 ml of lofran (1: 1) and add 10% palladium
200 mg of carbon catalyst were added at room temperature. Inside the reaction vessel
The atmosphere was replaced with hydrogen, and the reaction solution was stirred at the same temperature overnight. Insoluble matter
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)⁺. [0001]Example 84 (1) 1.02 g of the compound of Example 80 (3.02 mmol)
l) is dimethylformamide-tetrahydrofuran
(1: 8) Dissolve in 90 ml and manganese dioxide at room temperature
3.92 g (45.1 mmol) was added, and the reaction solution was heated at the same temperature.
And stirred for 6 hours. The reaction was filtered through celite. Filtration
The solution was concentrated, and the precipitated crystals were collected by filtration to give yellow crystals 0.21.
1 g was obtained. (2) 34 mg of the compound obtained in (1)
(0.10 mmol) and 22 mg of n-butylamine
(0.30 mmol) in 5 ml of chloroform,
212mg sodium triacetoxyborohydride
(1.0 mmol) was added at room temperature, and the reaction solution was added at the same temperature.
Stirred for 24 hours. The reaction solution is neutralized with 3N hydrochloric acid,
Extracted with LUM. Wash the organic layer with saturated saline
After drying with cesium, the mixture was filtered and the filtrate was concentrated. The precipitated crystals
Filtration gave 13 mg of the desired compound.¹ H-NMR (DMSO-d₆) Δ: 0.88 (3H,
t, J = 7.3 Hz), 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 (2
H, t, J = 7.2 Hz), 3.50-3.57 (1
H, m), 3.81 (2H, s), 4.83 (1H, d
d, J = 11 Hz, 5.5 Hz), 7.09 (1H,
d, J = 5.3 Hz), 7.31-7.33 (2H,
m), 7.47 (1H, t, J = 7.9 Hz), 8.2
6 (1H, d, J = 5.3 Hz), 8.31 (1H,
d, J = 8.1 Hz), 9.98 (1H, s), 11.
2 (1H, br). mass: 394 (M + 1)⁺. [0001]Examples 85-94 The compounds of Example 85 to Example 94 are the same as Example 84
Manufactured according to.Example 85 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 86 ¹ H-NMR (DMSO-d₆) Δ: 1.06-1.2
0 (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)⁺. [0001]Example 87 ¹ H-NMR (DMSO-d₆) Δ: 1.06-1.2
0 (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 (1
H, m), 3.64 (2H, s), 4.83 (1H, d
d, J = 11 Hz, 5.6 Hz), 4.91 (2H,
s), 6.51 (2H, d, J = 8.3 Hz), 6.9
9 (1H, d, J = 8.2 Hz), 7.04 (2H,
d, J = 5.4 Hz), 7.26 (1H, s), 7.3
2 (1H, d, J = 7.4 Hz), 7.47 (1H,
t, J = 7.8 Hz), 8.22 (1H, d, J = 5.
4Hz), 8.33 (1H, d, J = 8.1Hz),
9.94 (1H, s), 11.5 (1H, br). mass: 443 (M + 1)⁺. [0001]Example 88 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 89 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 90 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 91 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 92 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 93 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 94 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 95 N- (2-aminoethyl) carbamic acid tert-butyl
The target compound was prepared according to Example 96 using
Built.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 96 (1) 844 m of 4-nitrobenzenesulfonyl chloride
g (3.81 mmol) in chloroform (9 ml)
0.531 ml of triethylamine
(3.81 mmol) and bring the reaction to room temperature.
Was. This solution (0.3 ml) was added at room temperature to n-propyl alcohol.
10 μl (0.122 mmol) of chloroform
0.3 ml solution was added and the reaction was stirred at the same temperature overnight.
Was. The reaction mixture was purified by thin-layer chromatography (chloroform
-Methanol, 19: 1) to give the desired compound.
Was. (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 diethylazodica was added to the reaction mixture.
0.047m of toluene solution of ruboxylate (40%)
1 (0.108 mmol) was added and the reaction solution was added at room temperature for 3 hours.
Stirred for days. Thin layer chromatography of the reaction mixture
(Chloroform-methanol, 19: 1). (3) The compound obtained in (2) is converted to dimethyl
35mg sodium carbonate dissolved in 1ml formamide
(0.330 mmol) and 11 μl of thiophenol
(0.107 mmol) was added at room temperature, and the reaction solution was heated at the same temperature.
And stirred for one day. The insolubles are filtered and the filtrate is tetrahydro
Dissolve in 3 ml of furan and add 1 ml of 1N hydrochloric acid to the reaction solution at room temperature
And the reaction solution was further stirred at room temperature for 1 hour. reaction
The solution was concentrated and the residue was azeotroped with toluene. Here Methaneau
Ru-ether was added to solidify to obtain the target compound.¹ H-NMR (DMSO-d₆) 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,
brs), 10.9 (1H, br). mass: 394 (M + 1)⁺. [0001]Example 97-Example 98 The compounds of Example 97 and Example 98 are equivalent to Example 96.
Manufactured.Example 97 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 98 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 99 Using glycol aldehyde diethyl acetal,
This was produced according to Example 96.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 100 Example 96 using glycine tert-butyl ester
Manufactured according to.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 101-Example 108 The compounds of Examples 101 to 108 were prepared in Example 9
6 was prepared.Example 101 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 102 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 103 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 104 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 105 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 106 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 107 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 108 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 109 As described in Reference Example 8, 80 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 110 30 mg (0.038 mmol) of the compound of Reference Example 11
N-butanoyl chloride 6μ in chloroform (1ml) solution
l (0.058 mmol) and 13 μl of triethylamine
(0.093 mmol) at room temperature.
And stirred 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 kept at the same temperature.
And stirred for 10 minutes. 1 ml of water is added to the reaction solution, and the organic layer is separated.
separated. The organic layer is washed with 1 ml of water and washed with magnesium sulfate.
After drying, the mixture was filtered and the filtrate was concentrated. Residue is tetrahydrofura
Dissolved in 1 ml of 1N hydrochloric acid at room temperature.
In addition, the reaction was stirred at the same temperature for 15 minutes. Concentrate the reaction solution
The reaction mixture was added with 2 ml of trifluoroacetic acid
Was stirred at room temperature for 15 minutes. Concentrate the reaction mixture and add
The target compound was obtained by solidification with the addition of knol-ether.¹ H-NMR (DMSO-d₆) 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,
br), 11.1 (1H, br). mass: 422 (M + 1)⁺. [0001]Example 111-Example 114 The compounds of Examples 111 to 114 were prepared according to Example 1.
It was manufactured according to 10.Example 111 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 112 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 113 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 114 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 115 According to Example 96 (1) using the compound of Example 83
The target compound was prepared.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 116 Example 56 using phenol and the compound of Reference Example 7
The same operation as in Example 124 for the compound prepared in the same manner
Was carried out to produce a target compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 117 (1) 544 mg of 3-amino-5-phenylpyrazole
(3.4 mmol) of dimethylformamide (10 m
l) Add 164 mg (4.1 mmol) of sodium hydride 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. Add saturated ammonium chloride to the reaction mixture.
An aqueous ammonium solution was added, and the mixture was extracted with ethyl acetate. Organic
Separate the layers, wash with water and saturated saline, and wash with magnesium sulfate.
Dry and concentrate the filtrate. Silica gel column chromatography
Purify by chromatography (hexane-ethyl acetate, 4: 1)
To give 509 mg of the desired product. (2) 509 mg of the compound obtained in (1)
(2.0 mmol) in pyridine (5.0 ml).
0.19 ml (2.5 mmol) of methyl logoate was added.
Stirred at room temperature for 2 hours. 1N hydrochloric acid was added to the reaction solution, and
Extracted with chill. Separate the organic layer and add saturated aqueous sodium bicarbonate and saturated saline
After washing with water, magnesium sulfate was dried and the filtrate was concentrated.
The residue was analyzed by silica gel column chromatography (hexane
-Ethyl acetate, 4: 1 to 2: 1) to give the desired product 45
0 mg was obtained. (3) 440 mg of the compound obtained in (2)
(1.4 mmol) in toluene (5.0 ml).
0.40 ml (2.9 mmol) of liethylamine was added.
Stir at 80 ° C for 10 minutes, and add B-chlorocatechol borane.
Add 450mg (2.9mmol) at the same temperature for 10 minutes
Stirred. 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. B-chlorocate
Add 440 mg (2.9 mmol) of coal borane and add 10
Stirred at 0 ° C. for 1 hour. Add 1N hydrochloric acid to the reaction mixture and add
Extracted with Holm. Separate the organic layer and add 1N sodium hydroxide
Washed with saturated saline solution and dried over magnesium sulfate.
Concentrated. Chloroform-ether was added to the residue to precipitate
400 mg of the resulting crystals were collected by filtration. (4) 400 mg of the compound obtained in (3)
(0.87 mmol) in methanol-tetrahydrofura
(1: 1) in 20 ml. 10% palladium charcoal
200 mg of elementary catalyst was added, and the inside of the reaction
And stirred overnight. The reaction solution was filtered through celite, and the filtrate was concentrated.
Shrank. Crystallize by adding ether-ethyl acetate to the residue
Thus, 220 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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). [0001]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. Reaction solution at room temperature
After concentration, dissolve the residue in ether and wash with water
The extract was dried over magnesium sulfate and concentrated by filtration. Silica residue
Gel column chromatography (hexane-ethyl acetate
5: 1 to 2: 1) to yield 2.61 g of pale yellow crystals
I got (2) 1.23 g of the compound obtained in (1)
(3.27 mmol) and p-nitrophenyl chloroformate
0.859 mg (4.26 mmol), 4-dimethyla
Minopyridine 1.00 g (8.19 mmol), chloro
A mixture of 10 ml of form was stirred at room temperature for 30 minutes. reaction
0.920 g of the compound of Reference Example 3 (4.96 mmol
l) was added and the reaction was stirred at 100 ° C. overnight. Reaction liquid
With 1N sodium hydroxide, 1N
Wash sequentially with hydrochloric acid and saturated saline and dry with magnesium sulfate
The solution was concentrated by filtration. The residue is purified by silica gel column chromatography.
(Chloroform-methanol, 98: 2-97:
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 (diphenyl
Ruphosphino) ferrocene 30 mg (0.0541 mm)
ol) and 71 mg of sodium bicarbonate (0.845 m
mol) is mixed with 4 ml of methanol and the inside of the container is filled with carbon monoxide.
The reaction was refluxed for 7 hours. Sera the reaction solution
The filtrate was concentrated. Silica gel residue
Chromatography (chloroform-methanol, 9
8: 2 to 97: 3) to give 180 mg of a yellow solid
Was. (4) 40 mg of the compound obtained in (3)
It was dissolved in 5 ml of ethanol. Palladium hydroxide in the reaction solution
10 mg at room temperature, replace the inside of the vessel with hydrogen,
The solution was stirred at 70 ° C. overnight. Filter the reaction through Celite
The filtrate was concentrated. The residue is purified by silica gel column chromatography.
Purified by fee (chloroform-methanol, 10: 1)
Thus, 8.6 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]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) at room temperature, and the reaction solution is stirred at room temperature for a while.
After that, the mixture was further heated to 50 ° C. and stirred for 2 hours. Reaction liquid
Was acidified with 1N hydrochloric acid and then concentrated. Chloroform the residue
And washed with water. The water layer is more chloro
Extract twice with Holm, combine the organic layers and add magnesium sulfate
After drying, the solution was concentrated by filtration. Ether and chloroform in the residue
Was added, and 73 mg of precipitated crystals were collected by filtration. (2) 36 mg of the compound obtained in (1)
(0.0699 mmol) dissolved in 4 ml of ethanol
Then, 10 mg of palladium hydroxide was added to the reaction solution at room temperature.
And replace the inside of the vessel with hydrogen, and stir the reaction solution at 70 ° C. overnight.
Was. The reaction solution was filtered through celite, and the filtrate was concentrated. Residue
Add ether and chloroform to precipitate crystals
13 mg of the compound were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 120 (1) Using α-cyano-m-iodoacetophenone
The adjustment was performed according to the same procedure as in Examples 118 (1) to (3).
The prepared compound was reacted according to Example 119 (1).
Was carried out to obtain a target compound. (2) Using the compound obtained in (1),
The target compound was produced according to Example 119 (2).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 121 (1) 56 mg of the compound obtained in Example 120 (1)
(0.11 mmol) in 1.5 m of dimethylformamide
1 and 1,1'-carbonyl at room temperature.
Add 25 mg (0.15 mmol) of diimidazole,
The reaction was stirred at room temperature for 30 minutes. At room temperature,
42 μl (0.33 mmol) of nylethylamine was added.
The reaction solution was heated from room temperature to 70 ° C.
For 10 minutes. The reaction mixture is concentrated, and the residue is subjected to thin layer chromatography.
By chromatography (chloroform-methanol, 10: 1)
Purification gave a crude product. This thing is the next reaction as it is
used. (2) 51 mg of the compound obtained in (1)
(0.084 mmol) in methanol-tetrahydrof.
Dissolve in 3 ml of run (2: 1) and add hydroxylic acid to the reaction solution at room temperature.
Add 51 mg of palladium chloride and replace the inside of the vessel with hydrogen,
The reaction was stirred overnight at room temperature. Filter the reaction solution through Celite
After that, the filtrate was concentrated to obtain 25 mg of the desired compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 122 (1) 10.0 g of 2-bromo-3-nitrobenzoic acid (4
0.7 mmol), pyrrole-2-carboxyaldehyde
7.74 g (81.4 mmol) of triethylamine
20.0 ml (143 mmol) and thionyl chloride 30
ml, using the same procedure as in Reference Example 2 (1).
9.07 g of compound was obtained. (2) 9.07 g of the compound obtained in (1)
(28.0 mmol) of tetrahydrofuran (400 m
l) The solution was cooled to -78 ° C. Hydrogen in the reaction solution at the same temperature
Solution of diisopropylaluminum fluoride in toluene (1.0
M) 33.6 ml (33.6 mmol) were added and further
The reaction was stirred at the same temperature for 2 hours. At the same temperature for the reaction solution
Add 15 ml of a saturated aqueous solution of ammonium chloride and return to room temperature.
After stirring the reaction solution for 2 hours, the organic layer was washed with magnesium sulfate.
And the filtrate was concentrated. The resulting residue is
Dissolve in 200 ml of styrene and add chloro-t
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. Reaction solution
Dilute with ethyl acetate and saturate the organic layer with 200 ml of water three times
The extract was washed successively with brine, dried over magnesium sulfate, and the filtrate was concentrated.
Concentrated. The obtained residue is subjected to silica gel column chromatography.
Raffy (Wakogel C-300) hexane-ethyl acetate
10: 1 to 5: 1) to give 9.34 as a colorless oil.
g was obtained. (3) 9.34 g of the compound obtained in (2)
(21.3 mmol) and diisopropylethylamido
8.24 g (63.8 mmol) of dimethylforma
Dissolve in 200 ml of amide and replace the inside of the reaction vessel with nitrogen.
Was. Add tetrakistriphenylphosphine to the reaction solution at room temperature.
2.46 g (2.13 mmol) of palladium were added,
The reaction was stirred at 130 ° C. for 2 hours. Ethyl acetate
The mixture was added to 1 L of water and 500 ml of water, and the organic layer was separated. Water layer
Extract with 300 ml of ethyl acetate and combine the organic layers
Wash with water and saturated saline in that order, and dry with magnesium sulfate.
After drying, the filtrate was concentrated. The residue is purified by silica gel column chromatography.
Tography (Wakogel C-300, hexane-acetic acid
Ethyl, 20: 1 to 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) in methanol-tetrahydrofura
(1: 1) in 400 ml, and added to the reaction solution at room temperature.
500 mg of 0% palladium on carbon catalyst was added. Reaction vessel
The inside was replaced with hydrogen, and the reaction solution was stirred at room temperature for 2 hours. reaction
The liquid was filtered through Celite, and the filtrate was concentrated. Silica residue
Gel column chromatography (Wakogel C-30)
0) Purification with hexane-ethyl acetate, 2: 1 to 1: 1)
Was. 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 polarity substance)¹ H-NMR (CDCl₃) Δ: 0.14 (6H,
s), 0.95 (9H, s), 3.84 (2H, br)
s), 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 (1
H, t, J = 7.7 Hz), 7.14 (1H, d, J =
7.3 Hz). Fraction 2 (highly polar substance)¹ H-NMR (CDCl₃) Δ: 0.02 (6H,
s), 0.74 (9H, s), 1.60-1.70 (1
H, 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) Fraction 2 (highly polar substance) obtained in (4)
Example) using 2.40 g (7.23 mmol)
According to the same procedure as in Example 1, 2.71 g of a yellow solid was obtained. (6) 2.71 g of the compound obtained in (5)
(6.00 mmol) in methanol-tetrahydrofura
(1: 1) in 200 ml, and added to the reaction solution at room temperature.
N hydrochloric acid (10 ml) was added, and the reaction mixture was further incubated at the same temperature for 6 hours.
While stirring. The reaction mixture is concentrated, and the residue is
Dewatered by boiling. The obtained crude product is treated with hexane-ethyl acetate
-Recrystallized from tetrahydrofuran to obtain the target compound 1.8
5 g were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 123 (1) 4.50 g of the compound obtained in Example 131 (1)
(13.4 mmol) as in Example 122 (2).
According to the same procedure, 3.94 g of a yellow solid was obtained. (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-polar substance):¹ H-NMR (CDCl₃-CD₃OD) δ: 0.08
(3H, s), 0.11 (3H, s), 0.93 (9
H, s), 1.51 (3H, d, J = 6.2 Hz),
3.84 (2H, br), 5.26 (1H, m), 5.
96 (1H, d, J = 3.3 Hz), 6.10 (1H, d, J = 3.3 Hz)
dd, J = 3.1 Hz, 1.0 Hz), 6.78 (1
H, d, J = 8.0 Hz), 7.01 (1H, t, J =
7.7 Hz), 7.13 (1H, d, J = 7.3H)
z). Fraction 2 (highly polar substance):¹ H-NMR (CDCl₃) Δ: 0.07 (3H,
s), 0.11 (3H, s), 0.85-0.95 (1
H, m), 0.92 (9H, s), 1.24-1.35
(2H, m), 1.52 (3H, d, J = 6.3H
z), 1.52-1.55 (1H, m), 5.27 (1
H, q), 6.28 (1H, d, J = 3.4 Hz),
7.07 (1H, d, J = 3.6 Hz), 7.31 (1
H, dd, J = 8.5 Hz, 7.3 Hz), 7.92
(1H, dd, J = 7.3 Hz, 1.0 Hz), 8.2
8 (1H, dd, J = 8.5 Hz, 1.0 Hz). (3) Fraction 2 (highly polar substance) obtained in (2)
Example) using 300 mg (0.87 mmol)
According to the same procedure as in Example 1, 389 mg of a yellow solid was obtained. (4) 200 mg of the compound obtained in (3)
(0.429 mmol) using the same procedure as in Reference Example 7.
Thus, 92 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 124 Fraction 2 (highly polar substance) 1 obtained in Example 128 (5)
4 mg of methanol-tetrahydrofuran (1: 1) 2
and 1 ml of 1N hydrochloric acid was added to the reaction solution at room temperature.
In addition, the reaction solution was stirred at the same temperature for 30 minutes. Saturated reaction solution
Neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. Organic layer
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated. The residue
Thin layer chromatography (ethyl acetate-methanol, 3
0: 1) to give 4.1 mg of the desired compound and Example
3.8 mg of 127 were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 125 (1) 12.3 g of the compound of Example 128 (1) (38.
2 mmol) in 150 ml of tetrahydrofuran
Then, the reaction solution was cooled to -78 ° C. Water at the same temperature
Toluene solution of diisobutylaluminum iodide (1.0
M) 46.0 ml (46.0 mmol) were added and
The reaction was stirred for 15 minutes. Add saturated ammonium chloride to the reaction mixture.
25 ml of an aqueous solution of sodium was added, and the temperature was returned to room temperature. To the reaction solution
Magnesium sulfate was added and the mixture was filtered, and the filtrate was concentrated. Remaining
The residue is dissolved in 150 ml of chloroform, and imidazole is dissolved.
5.20 g (81.1 mmol) and chlorotriiso
9.40 ml (43.9 mmol) of propylsilane in the chamber
At room temperature, the atmosphere in the vessel was replaced with nitrogen, and the reaction solution was cooled to room temperature for 12 hours.
Stirred for hours. Dilute the reaction solution with ethyl acetate, add water,
Wash sequentially with Japanese saline, and dry the organic layer over magnesium sulfate
After filtration, the filtrate was concentrated. The residue is purified by silica gel column chromatography.
By chromatography (hexane-ethyl acetate, 10: 1)
Purification gave 17.2 g of a yellow solid. (2) 17.2 g of the compound obtained in (1)
(15.6 mmol) and according to (2) of Reference Example 2.
The reaction was carried out to obtain 4.90 g of a yellow solid. (3) 4.90 g of the compound obtained in (2)
(12.2 mmol) in 70 ml of tetrahydrofuran
Dissolve and add 20 ml of 6N hydrochloric acid to the reaction solution at room temperature.
The reaction solution was stirred at the same temperature for 1 hour. 1N sodium hydroxide
The reaction was made basic with um and extracted with ethyl acetate. Yes
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.
After drying, 2.94 g of a yellow solid was obtained. (4) 180 mg of the compound obtained in (3)
(0.73 mmol) in 5.0 ml of methanol and
Dissolve in 16 ml of trihydrofuran and add triethylamine
0.20 ml, 10% palladium on carbon catalyst 100 mg
In addition, the mixture was stirred at 50 ° C. for 1 hour under a hydrogen stream. Remove the reaction solution
The filtrate was concentrated to give 163 mg of a colorless solid.
Obtained. (5) 163 mg of the compound obtained in (4)
(0.75 mmol) and 2-pyridinecarbonyl azide
According to Example 1 using 107 mg (0.72 mmol)
Thus, 7 mg of the target compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 126 (1) 85 mg of the compound of Example 125 (0.251 mm
ol) and 132 mg (0.5 mg) of triphenylphosphine.
03mmol) in tetrahydrofuran (6ml)
0.140 ml of diphenylphosphate azide (0.65
0 mmol) and diethyl azodicarboxylate
0.220 ml of Ruen solution (40%) (0.505 mm
ol) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour.
Was. Dilute the reaction solution with ethyl acetate and add water and saturated saline.
After washing sequentially, the organic layer was dried over magnesium sulfate and filtered.
The filtrate was concentrated. The residue was purified by thin-layer chromatography
Purified with chloroform-methanol, 10: 1). Athe
Was added to obtain 24 mg of crystals. (2) 24 mg of the compound obtained in (1)
Dissolve in 2 ml of methanol-tetrahydrofuran (1: 1)
Then, at room temperature, 10% palladium on carbon catalyst 10
mg was added. Replace the inside of the vessel with hydrogen and react under a hydrogen stream
The liquid was stirred at room temperature until the starting material disappeared. Sera the reaction solution
The filtrate was concentrated. Add ether to the residue
Crystallized. The crystals were collected by filtration, and ethyl acetate and chloro
After washing with form, drying was performed to obtain 4.6 mg of the target compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 127 The target compound was obtained in the production reaction of Example 124.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 128 (1) Using pyrrole-3-carboxaldehyde
The same operation as in Example 2 (1) was performed 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),
Following the same procedure as in (2) of Example 2, 2:
1 was obtained. (4) Using the compound obtained in (3),
A purified mixture was obtained according to a procedure similar to (4) of Example 122.
Was. 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. Anti
The reaction solution is concentrated, and the residue is subjected to thin-layer chromatography (hex.
-Ethyl acetate, 1: 2) and fraction 1 (low polarity)
Substance) and fraction 2 (highly polar substance). (6) Fraction 1 (low-polarity substance) obtained in (5)
11 mg of methanol-tetrahydrofuran (1:
5) Dissolve in 1.2 ml and add 1N hydrochloric acid to the reaction solution at room temperature.
1.0 ml was added and the reaction was stirred at the same temperature. reaction
Concentrate the solution, dilute the residue with ethyl acetate, and add saturated aqueous sodium bicarbonate.
And saturated sodium chloride solution, and the organic layer was washed with magnesium sulfate.
After drying the solution, the filtrate was concentrated. Residue thin layer chromatography
By chromatography (chloroform-methanol, 10: 1)
Purification gave 3.1 mg of the desired compound.¹ H-NMR (acetone-d₆) Δ: 1.29
(1H, br), 2.52-2.61 (2H, m),
3.00-3.10 (2H, m), 3.29-3.41
(1H, m), 3.54-3.70 (2H, m), 5.
08 (1H, d, J = 5.4 Hz), 7.05-7.1
2 (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). [0001]Example 129 (1) 100 mg of the compound obtained in Reference Example 2 (2)
(0.467 mmol) in methanol (15 ml)
200 mg (3.58 mmol) of iron powder at room temperature, 6N
After adding 0.500 ml (3.00 mmol) of hydrochloric acid, the reaction was carried out.
The liquid was stirred at room temperature for 30 minutes. The reaction solution was treated with ethyl acetate 200
diluted with water, 100 ml of saturated aqueous sodium bicarbonate, water, saturated saline
The organic layer was dried over magnesium sulfate, and the filtrate was
Was concentrated. Silica gel column chromatography of the residue
-(Wakogel C-300, hexane-ethyl acetate,
5: 1) to give 71 mg of a pale green solid. (2) 50 mg of the compound obtained in (1)
65 mg of the target compound using the same procedure as in Example 1
I got¹ H-NMR (DMSO-d₆) 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). [0001]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 got¹ H-NMR (DMSO-d₆) 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). [0001]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) in the same manner as in Reference Example 2 (1).
According to the procedure, 9.20 g of a yellow solid was obtained. (2) 2.00 g of the compound obtained in (1)
(5.93 mmol) in the same manner as in Reference Example 2 (2).
According to the procedure, 941 mg of a pale green solid was obtained. (3) 300 mg of the compound obtained in (2)
(1.17 mmol) using the same procedure as in Example 129.
277 mg of the target compound was obtained according to the order.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 132 (1) 4.5 g of the compound obtained in Example 131 (1)
(13.4 mmol) using Example 122 (2)
3.94 g of the desired product was obtained in the stated order. (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) Fraction 1 (low-polarity substance) obtained in (2)
Example 1 using 200 mg (0.58 mmol)
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 same procedure as in Reference Example 7.
Thus, 85 mg of the desired compound was obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 133 (1) 16 mg of the compound of Example 299 (1) was added.
3. 1-butanethiol in a solution of tanol (0.2 ml);
Add 2 μl and 2.6 mg of sodium ethoxide
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) 8 mg of the compound (1)
1N hydrochloric acid (1 ml) was added to drofuran (2 ml) solution,
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-d₆) 0.87 (3H, t, J = 7.2 Hz), 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)⁺. [0001]Example 134 (1) The compound of Example 289 was prepared using the compound of Reference Example 8.
The reaction was carried out according to (6) to obtain the desired compound. (2) 19 mg of the compound of (1), isop
15 μl of lopanol and 50 m of triphenylphosphine
g solution in tetrahydrofuran (0.2 ml) cooled to 0 ° C
And add 82 μl of azodicarboxylic acid diethyl ester.
Then, the mixture was stirred at room temperature for 30 minutes. Dilute the reaction solution with chloroform.
And washed with water and saturated saline, and dried over magnesium sulfate.
After drying, filtration and the filtrate were 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) Using 18 mg of the compound of (2)
The reaction was carried out according to Reference Example 11, and
The reaction was carried out according to (2) of the above to give the hydrochloride of the title compound.
Thus, 5 mg of a white solid was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Examples 135-136 The compound of Example 135 and Example 136 is a compound of Example 13
It was manufactured according to 4.Example 135 mass: 420 (M + 1)⁺. [0001]Example 136 mass: 434 (M + 1)⁺. [0001]Example 137 (1) t of the compound of Reference Example 8 and salicylaldehyde
Performed using tert-butyldiphenylsilyl ether
The target compound was obtained according to Example 84 (2). (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)⁺. [0001]Example 138 (1) Reference Example Using Compound (1) of Example 137
Reaction was carried out according to 7 to obtain the desired product. (2) Example 1 using the compound of (1)
The reaction was carried out according to 33 (2), and the hydrochloride of the title compound was obtained.
As a result, 4 mg of a white solid was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 139 (1) 29 mg of the compound of Example 137 (1), di-t
ert-butyl dicarbonate ((Boc)₂O) 16
mg, triethylamine 15 μl and chloroform 0.
2 ml of the mixture was stirred at room temperature for 3 hours. Concentrate the reaction solution
The residue was purified by TLC (Merch Art 5744,
Purification with chloroform-methanol (20: 1))
2 mg were obtained. (2) Using 35 mg of the compound of (1)
According to Reference Example 7, 24 mg of the desired product was obtained. (3) 24 mg of the compound of (2), 1-butane
According to (2) of Example 134, using 5 μl of ethanol.
3 mg of the desired product was obtained. (4) Using 8 mg of the compound of (3)
The reaction was carried out according to (133) of Example 133, and the title compound
3 mg of a white solid was obtained as the hydrochloride.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 140 (1) 30 mg of the compound of Reference Example 8 and o-anisual
Using 9 μl of aldehyde, the product was prepared in the same manner as in Example 84 (2).
16 mg of the alkyl (A) and 11 of the dialkyl (B)
mg was obtained. (2) 16 mg of the compound of (1) -A
The reaction was carried out according to (133) of Example 133, and the title was obtained.
12 mg of a pale yellow solid was obtained as a hydrochloride of the compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 141 Performed using 7 mg of the compound of (1) -B in Example 140.
The reaction was carried out according to (133) of Example 133, and the salt of the title compound was obtained.
4 mg of a pale yellow solid was obtained as an acid salt.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 142 (1) 30 mg of the compound of Example 164 (3)
Dissolved in 0.4 ml of tonitrile-methylene chloride (3: 1)
Then, after the inside of the reaction vessel is replaced with nitrogen, (Boc)₂O0.
12 ml, nitroethane 25 μl and 4-dimethylamido
4 mg of nopyridine was added, and the mixture was stirred at room temperature for 1 hour. reaction
Water was added to the solution and extracted with chloroform. The organic layer is saturated with water
Wash with sodium chloride solution, dry magnesium sulfate, filter, filter
The liquid was concentrated. The residue was purified by TLC (Merck Art 57).
44, purified with chloroform-methanol (30: 1))
Then, 32 mg of an adduct was obtained. 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), 12 mg of fraction (A) of 1.0 ml / min) and
13 mg of the fraction (B) with Rt = 14.58 min was obtained. (2) Compound of (1) -A and (1) -B
For each of the products, in accordance with (2) of Example 133,
(1) -A to pale yellow powder as compound of Example 142
From (1) -B as a compound of Example 143 in pale yellow
A powder was obtained. mass: 392 (M + 1)⁺. [0001]Example 143 Performed as a diastereomer of the compound of Example 142.
The compound of Example 143 was obtained. mass: 392 (M + 1)⁺. [0001]Examples 144-147 Examples 144 to 147 are similar to Example 142.
Manufactured.Example 144 ¹ H-NMR (CDCl₃) 1.18 (3H, t, J = 7.5 Hz), 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)⁺. [0001]Example 145 mass: 406 (M + 1)⁺. [0001]Example 146 mass: 406 (M + 1)⁺. [0001]Example 147 mass: 406 (M + 1)⁺. [0001]Examples 148-151 Examples 148 to 151 show the diastereoisomers.
This was a mixture and was produced according to Example 142.Example 148 mass: 420 (M + 1)⁺. [0001]Example 149 mass: 420 (M + 1)⁺. [0001]Example 150 mass: 448 (M + 1)⁺. [0001]Example 151 mass: 448 (M + 1)⁺. [0001]Examples 152-155 Examples 152-155 are single diastereomers
Yes, manufactured according to Example 156.Example 152 mass: 434 (M + 1)⁺. [0001]Example 153 mass: 434 (M + 1)⁺. [0001]Example 154 mass: 434 (M + 1)⁺. [0001]Example 155 mass: 434 (M + 1)⁺. [0001]Example 156 (1) 30 mg of the compound of (3) of Example 164, 1-
Pyroline N-oxide 59mg and chloroform 2ml
Was stirred at 80 ° C. for 23 hours. Bring the reaction to room temperature
It was returned and extracted with chloroform. The organic layer is water, saturated salt
After washing with water and drying over magnesium sulfate, filter and concentrate the filtrate
did. The residue was purified by TLC (Merch Art 5744,
Purified with roloform-methanol (20: 1)
24 mg of a colored oil are obtained. (2) Using 6 mg of the compound of (1),
The title compound (5 mg) was obtained according to Example 133 (2).¹ H-NMR (CDCl₃) 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)⁺. [0001]Example 157 Using the optical isomer of the compound of Example 164 (3),
This was produced according to Example 156. mass: 420 (M + 1)⁺. [0001]Example 158 (1) 30 mg of the compound of (3) of Example 164 and 2
-(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),
The title compound was a pale yellow solid according to Example 133 (2).
4 mg of body was obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Example 159 Using the optical isomer of the compound of Example 164 (3),
This was produced according to Example 158. mass: 408 (M + 1)⁺. [0001]Example 160 The compound of Example 160 is a mixture of diastereomers.
In accordance with Example 156. mass: 478 (M + 1)⁺. [0001]Example 161 The compound of Example 161 is a mixture of diastereomers.
The product was produced according to Example 157. mass: 478 (M + 1)⁺. [0001]Example 162 Example 16 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)⁺. [0001]Example 163 Performed as a diastereomer of the compound of Example 162.
The compound of Example 163 was obtained. mass: 468 (M + 1)⁺. [0001]Example 164 (1) 3.08 g of the compound of Reference Example 6 was optically analyzed by HPLC.
A division was performed 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)
-B 15.9 g, each of which was prepared according to Reference Example 7.
And 11.0 g of a colorless amorphous substance as (2) -A
And 10.9 g of a colorless amorphous substance as (2) -B was obtained.
Was. (3) 727 mg of the compound of (2) -A
Colorless amorphous substance 6 according to (1) of Example 299
06 mg was obtained. (4) Using 606 mg of the compound of (3)
In accordance with (1) of Example 300, 712 mg of the desired product was obtained.
Obtained. The diastereomer was analyzed for this using HPLC.
And Rt = 22.58 min (CHIRALPA
K AD (Daicel Chemical Industries, Ltd., 0.46φx25)
cm), ethanol, 0.5 ml / min)
(A) Fractionation of 360 mg and Rt = 38.84 minutes (B)
329 mg were obtained. (5) Regarding (4) -A and (4) -B
The reaction was carried out according to (133) of Example 133, and (4)-
A to pale yellow amorphous substance 2 as compound of Example 164
91 mg was used as the compound of Example 165 from (4) -B.
This gave 235 mg of a pale yellow amorphous substance. mass: 468 (M + 1)⁺. [0001]Example 165 Performed as a diastereomer of the compound of Example 164.
The compound of Example 165 was obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Examples 166 to 169 Examples 166 to 169 were manufactured according to Example 183.
Built.Example 166 mass: 392 (M + 1)⁺. [0001]Example 167 mass: 392 (M + 1)⁺. [0001]Example 168 mass: 392 (M + 1)⁺. [0001]Example 169 mass: 392 (M + 1)⁺. [0001]Example 170 The compound of Example 162 was used and produced according to Example 171.
Built. mass: 478 (M + 1)⁺. [0001]Example 171 291 mg of the compound of Example 164, (Boc)₂O
2.86 ml, 20% palladium hydroxide-carbon catalyst 15
0 mg, 30 ml of ethyl acetate and 5 ml of methanol
The mixture was stirred under a hydrogen stream at 60 ° C. for 15.5 hours. Anti
The reaction solution was filtered through celite, and the filtrate was concentrated. Residue
Kagel column chromatography (Wakogel C-30
0, purified with hexane-ethyl acetate (1: 1-1: 5))
This gave 183 mg of a colorless amorphous substance as the title compound.
Was.¹ H-NMR (CDCl₃) 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)⁺. [0001]Example 172 Using the compound of Example 165, it was prepared according to Example 171.
Built. mass: 478 (M + 1)⁺. [0001]Example 173 Using the compound of Example 163, and following the procedure of Example 171
Built. mass: 478 (M + 1)⁺. [0001]Example 174 25 mg of the compound of Example 170 and 4N hydrochloric acid-diox
The mixture of 6 ml of sun was stirred at room temperature for 15 minutes. Reaction solution
After concentrating, drying, 17 mg of a white solid was obtained as the title compound.
Obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 175 Using the compound of Example 173, it was prepared according to Example 174.
Built. mass: 378 (M + 1)⁺. [0001]Example 176 The compound of Example 171 was used and produced according to Example 174.
Built. mass: 378 (M + 1)⁺. [0001]Example 177 The compound of Example 172 was used and produced according to Example 174.
Built. mass: 378 (M + 1)⁺. [0001]Example 178 5 mg of the racemic hydrochloride salt of the compound of Example 174
tert-butyl N- (2-oxoethyl) carbame
Using 8 mg of the salt and according to Example 84, (2).
5 mg of the compound were obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Examples 179-182 The compounds of Examples 179 to 182 were prepared according to Example 1.
83.Example 179 mass: 460 (M + 1)⁺. [0001]Example 180 mass: 460 (M + 1)⁺. [0001]Example 181 mass: 460 (M + 1)⁺. [0001]Example 182 mass: 460 (M + 1)⁺. [0001]Example 183 7 mg of the compound of Example 177 and 7 butyraldehyde
using the same title compound as in Example 178
7 mg of a yellow oil were obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Examples 184-190 The compounds of Examples 184 to 190 were prepared according to Example 1.
83. Example 184 mass: 434 (M + 1)⁺. [0001]Example 185 mass: 434 (M + 1)⁺. [0001]Example 186 mass: 434 (M + 1)⁺. [0001]Example 187 mass: 561 (M + 1)⁺. [0001]Example 188 mass: 561 (M + 1)⁺. [0001]Example 189 mass: 561 (M + 1)⁺. [0001]Example 190 mass: 561 (M + 1)⁺. [0001]Example 191 Using the compound of Example 187, the preparation was carried out according to Example 193.
Built. mass: 461 (M + 1)⁺. [0001]Example 192 The compound of Example 188 was used and produced according to Example 193.
Built. mass: 461 (M + 1)⁺. [0001]Example 193 Using the compound of Example 189 (6 mg), the compound of Example 133 was used.
4m of a yellow solid which is the hydrochloride of the title compound according to (2)
g was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 194 Using the compound of Example 190, following the procedure of Example 193
Built. mass: 461 (M + 1)⁺. [0001]Example 195-210 The compounds of Examples 195 to 210 were prepared according to Example 1.
83.Example 195 mass: 488 (M + 1)⁺. [0001]Example 196 mass: 488 (M + 1)⁺. [0001]Example 197 mass: 488 (M + 1)⁺. [0001]Example 198 mass: 488 (M + 1)⁺. [0001]Example 199 mass: 504 (M + 1)⁺. [0001]Example 200 mass: 504 (M + 1)⁺. [0001]Example 201 mass: 504 (M + 1)⁺. [0001]Example 202 mass: 504 (M + 1)⁺. [0001]Example 203 mass: 494 (M + 1)⁺. [0001]Example 204 mass: 494 (M + 1)⁺. [0001]Example 205 mass: 494 (M + 1)⁺. [0001]Example 206 mass: 494 (M + 1)⁺. [0001]Example 207 mass: 551 (M + 1)⁺. [0001]Example 208 mass: 551 (M + 1)⁺. [0001]Example 209 mass: 551 (M + 1)⁺. [0001]Example 210 mass: 551 (M + 1)⁺. [0001]Examples 211-240 The compounds of Examples 211 to 240 were prepared in Example 1
78.Example 211 mass: 434 (M + 1)⁺. [0001]Example 212 mass: 448 (M + 1)⁺. [0001]Example 213 mass: 482 (M + 1)⁺. [0001]Example 214 mass: 462 (M + 1)⁺. [0001]Example 215 mass: 420 (M + 1)⁺. [0001]Example 216 mass: 518 (M + 1)⁺. [0001]Example 217 mass: 518 (M + 1)⁺. [0001]Example 218 mass: 448 (M + 1)⁺. [0001]Example 219 mass: 446 (M + 1)⁺. [0001]Example 220 mass: 474 (M + 1)⁺. [0001]Example 221 mass: 420 (M + 1)⁺. [0001]Example 222 mass: 462 (M + 1)⁺. [0001]Example 223 mass: 507 (M + 1)⁺. [0001]Example 224 mass: 512 (M + 1)⁺. [0001]Example 225 mass: 512 (M + 1)⁺. [0001]Example 226 mass: 484 (M + 1)⁺. [0001]Example 227 mass: 458 (M + 1)⁺. [0001]Example 228 mass: 504 (M + 1)⁺. [0001]Example 229 mass: 450 (M + 1)⁺. [0001]Example 230 mass: 432 (M + 1)⁺. [0001]Example 231 mass: 519 (M + 1)⁺. [0001]Example 232 mass: 457 (M + 1)⁺. [0001]Example 233 mass: 471 (M + 1)⁺. [0001]Example 234 mass: 469 (M + 1)⁺. [0001]Example 235 mass: 469 (M + 1)⁺. [0001]Example 236 mass: 469 (M + 1)⁺. [0001]Example 237 mass: 452 (M + 1)⁺. [0001]Example 238 mass: 472 (M + 1)⁺. [0001]Example 239 mass: 458 (M + 1)⁺. [0001]Example 240 mass: 522 (M + 1)⁺. [0001]Example 241 Using 4 mg of the compound of Example 178, the compound of Example 133 was used.
The reaction is carried out according to (2) to give the hydrochloride of the title compound.
4 mg were obtained.¹ H-NMR (CD₃OD) 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)⁺. [0001]Examples 242-247 The compounds of Examples 242 to 247 were prepared in Example 1
78.Example 242 mass: 500 (M + 1)⁺. [0001]Example 243 mass: 514 (M + 1)⁺. [0001]Example 244 mass: 514 (M + 1)⁺. [0001]Example 245 mass: 486 (M + 1)⁺. [0001]Example 246 mass: 472 (M + 1)⁺. [0001]Example 247 mass: 484 (M + 1)⁺. [0001]Example 248 Manufactured according to Example 249. mass: 496 (M + 1)⁺. [0001]Example 249 5 mg of racemic hydrochloride of the compound of Example 174
Ton-water (2: 1) (0.3 ml) was dissolved in sodium acetate.
After adding 4 mg of lithium and cooling to 0 ° C, 2,6-dichlorochloride was added.
2 μl of lorobenzoyl was added and stirred for 4 hours. Reaction liquid
Water and extract with chloroform, and the organic layer is saturated with water.
After washing with brine and drying over magnesium sulfate, filtration, filtrate
Was concentrated. The residue was purified by TLC (Merch Art 574).
4. Purified with chloroform-methanol (20: 1)
Then, 5 mg of a white solid was obtained as the title compound.¹ H-NMR (CDCl₃) 1.21-1.36 (1H, m), 2.06-1.18
(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)⁺. [0001]Examples 250-253 The compound of Example 250 to Example 253 was prepared according to Example 2.
49.Example 250 mass: 488 (M + 1)⁺. [0001]Example 251 mass: 483 (M + 1)⁺. [0001]Example 252 mass: 483 (M + 1)⁺. [0001]Example 253 mass: 483 (M + 1)⁺. [0001]Example 254 (1) 3.8 g of the compound of (1) of Example 264 and
Nortriflate (1-benzyl-4-piperidone,
Lithium diisopropylamide, N-phenyl trifur
Oromethanesulfonimide and tetrahydrofuran
Example with 2.8 g (adjusted according to normal method)
1.9 g of a brown oily substance was obtained according to the method of 264 (3).
Was. (2) Using 1.9 g of the compound of (1)
Example 80 A white solid 2 was prepared according to the method of (2) or (3).
30 mg were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 255 Reference Example 3 was repeated using 160 mg of the compound of Example 254.
Then, the reaction was carried out to obtain 52 mg of a white solid.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 256 Example 254 using 1-benzyl-3-piperidone
The reaction was carried out according to the procedure to obtain 52 mg of a white solid.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 257 According to Reference Example 3 using 30 mg of the compound of Example 256
The reaction was carried out to obtain 12 mg of a white solid.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 258 Example 260 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-d₆) 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)⁺. [0001]Example 259 Example 261, using 20 mg of the compound of Example 258
Thus, 5 mg of a white solid was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 260 (1) 280 mg of the compound of Example 254 in chloroform
Acid 1-chloroethyl ester 100 mg, triethyl alcohol
A mixture of 71 mg of min and 5 ml of chloroform at room temperature
Stir for 30 minutes. The reaction mixture is concentrated, and the residue is
Ram chromatography (Wakogel C-200, chromatograph
Refine in roform-methanol (100: 0 to 98: 2)
To give 295 mg of a solid. (2) 295 mg of the compound of (1)
Dissolved in ethanol (5 ml) and refluxed for 3 hours. Reaction solution
Return to room temperature, add saturated aqueous sodium bicarbonate, extract with chloroform.
Was. Wash the organic layer with saturated saline and dry over magnesium sulfate
After drying, the mixture was filtered and concentrated. The residue is purified by silica gel column chromatography.
Tography (FL60D (Fuji Silysia Limited),
Chloroform-methanol (100: 0 to 95: 5)
And 160 mg of a pale yellow solid was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 261 30 mg of the compound of Example 260, acetyl chloride 6.6
μl, triethylamine 13 μl and chloroform 3 m
The mixture was stirred at room temperature for 1 hour. Add saturated sodium bicarbonate to the reaction mixture
Water was added and extracted with chloroform. Organic layer is saturated saline
And dried over magnesium sulfate, filtered, and the filtrate was filtered.
Concentrated. The residue was purified by TLC (Merck Art 5744,
Purified with chloroform-methanol (9: 1), white
5 mg of crystals were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 262 Example 84 was prepared using 20 mg of the compound of Example 260.
3 mg of a white solid was obtained according to (2).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 263 The compound of Example 263 was prepared according to Example 262.
Was. mass: 506 (M + 1)⁺. [0001]Example 264 (1) methyl 4-chloropyridine-2-carboxylate
3 g of stele hydrochloride was added to 140 ml of dioxane.
8.4 g of xabutylditin and tetrakistriphenyl
Phosphine palladium is added and under a nitrogen stream for 12 hours
Refluxed. Return the reaction solution to room temperature, 10% potassium fluoride
After adding an aqueous solution and stirring for 30 minutes, dilute with ether and filter
did. The filtrate was washed with saturated saline and dried over magnesium sulfate.
After drying, the residue obtained by filtration is purified by silica gel column chromatography.
Chromatography (Wakogel C-200, hexane-acetic acid
Ethyl (1: 0 to 2: 1)) to give a colorless oil.
9 g were obtained. (2) Using 6.3 g of the compound of (1)
Oily substance 2. According to the method of Example 80 (2), (3).
8 g were obtained. (3) 60 mg of the compound of (2), 3-bu
Lomopyridine 47 mg, 2-dicyclohexyphosphite
No) Biphenyl 21 mg, lithium chloride 9 mg, Tris
21 mg of dibenzylidene dipalladium and tetrahydro
A mixture of 2 ml of furan was refluxed overnight. 10% in the reaction solution
An aqueous potassium fluoride solution and chloroform were added, and the organic layer was separated.
Released. The organic layer was washed with water and saturated saline,
After drying with sodium, filtration and concentration were performed. The residue was purified by TLC (Mer
ck Art 5744, chloroform-methanol
(9: 1)) to give 5 mg of white crystals.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Examples 265-277 The compound of Example 265 to Example 277 is a compound of Example 2
64.Example 265 mass: 385 (M + 1)⁺. [0001]Example 266 mass: 423 (M + 1)⁺. [0001]Example 267 mass: 386 (M + 1)⁺. [0001]Example 268 mass: 386 (M + 1)⁺. [0001]Example 269 mass: 392 (M + 1)⁺. [0001]Example 270 mass: 391 (M + 1)⁺. [0001]Example 271 mass: 465 (M + 1)⁺. [0001]Example 272 mass: 435 (M + 1)⁺. [0001]Example 273 mass: 435 (M + 1)⁺. [0001]Example 274 mass: 391 (M + 1)⁺. [0001]Example 275 mass: 389 (M + 1)⁺. [0001]Example 276 mass: 407 (M + 1)⁺. [0001]Example 277 mass: 445 (M + 1)⁺. [0001]Example 278 Using the compound of Example 82 and reacting according to Example 261
Was performed to obtain 9 mg of a white solid.¹ H-NMR (DMSO-d₆) 0.89 (3H, t, J = 7.3 Hz), 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)⁺. [0001]Example 279 30 mg of the compound of Example 80 and butanoyl chloride
It was dissolved in tilformamide and stirred at 90 ° C. for 30 minutes.
Dilute the reaction solution with chloroform, and add saturated aqueous sodium hydrogen carbonate and saturated saline.
After washing with water and drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated.
Shrank. The residue was purified by TLC (Merck Art 5744,
Purified with chloroform-tetrahydrofuran (7: 3)
Then, 8 mg of white crystals were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 280 The compound of Example 280 was prepared according to Example 279.
Was. mass: 449 (M + 1)⁺. [0001]Example 281 The compound of Example 281 was prepared according to Example 278.
Was. mass: 448 (M + 1)⁺. [0001]Example 282 1) 2-aminopyridine-4-carboxylic acid 1 g, chloride
A mixture of 2.8 ml of thionyl and 36 ml of methanol was prepared.
Refluxed overnight. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue.
And extracted with chloroform. Wash the organic layer with saturated saline
After filtration and drying over magnesium sulfate, the mixture is filtered and the filtrate is concentrated.
Was. The residue was subjected to silica gel column chromatography (Wako
-Gel C-200, chloroform-methanol (10
0: 0 to 98: 2)) to obtain 1.05 g of the desired product.
Was. (2) 1.8 g of the compound of Reference Example 3
0.35 ml of chloroacetic anhydride, 0.1 ml of triethylamine.
2 ml, methylene chloride 5 ml and tetrahydrofuran 1
0 ml of the mixture was stirred at room temperature for 2 hours. Saturated reaction solution
Aqueous sodium bicarbonate was added and extracted with chloroform. Saturate organic layer
Washed with brine, dried over magnesium sulfate, filtered, filtrate
Was concentrated. Silica gel column chromatography of the residue
-(Wakogel C-200, chloroform-tetrahydrode
Purified with lofran (9: 1 to 8: 2)), brown amorphous
2.92 g of quality were obtained. 1.77 g of the obtained compound,
1.05 g of the compound of (1), 1 ml of DBU and dimethyl
The mixture of 8 ml of sulfoxide was stirred at 100 ° C. for 3 hours.
Was. Dilute the reaction solution with chloroform and use water and saturated saline
After washing and drying over magnesium sulfate, filtration and concentration of the filtrate are carried out.
Was. The residue was subjected to silica gel column chromatography (Wako
-Gel 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 is 1N hydrochloric acid
After adjusting the pH to 4 with chloroform, the mixture was extracted with chloroform, and the organic layer was saturated.
Wash with brine, dry magnesium sulfate, filter,
The filtrate was concentrated. Wash the residue with chloroform-ethyl acetate
Purification gave 80 mg of a white solid. (4) Using 18 mg of the compound of (3)
The title compound, white, according to Example 409 (1)
5 mg of a solid was obtained.¹ H-NMR (DMSO-d₆) 0.92 (3H, t, J = 7.2 Hz), 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)⁺. [0001]Examples 283-286 The compound of Example 283 to Example 286 was prepared according to Example 2.
82.Example 283 mass: 434 (M + 1)⁺. [0001]Example 284 mass: 443 (M + 1)⁺. [0001]Example 285 mass: 443 (M + 1)⁺. [0001]Example 286 mass: 443 (M + 1)⁺. [0001]Example 287 (1) Using 90 mg of isoquinoline-3-carboxylic acid
In the same manner as in Reference Example 1, 14 mg of a yellow solid was obtained. (2) Using 14 mg of the compound of (1)
13 mg of the title compound as a white solid according to Example 79
I got¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 288 (1) 300 mg of isoquinoline-3-carboxylic acid, acid
30 mg of platinum chloride, 5 ml of 4N hydrochloric acid-dioxane and meta
5 ml of ethanol, and the inside of the vessel was replaced with hydrogen, and
Stirred for hours. The reaction solution was filtered through Celite, and the filtrate was concentrated.
This gave 32 mg of crude product. (2) Using 130 mg of the compound of (1)
The title compound was a white solid 23 according to Example 287.
mg was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 289 (1) Dimethyl of 4-pyridinecarboxaldehyde
Acetal 15g tetrahydrofuran (300ml)
The solution was cooled to −78 ° C.
-78 ° C to 0 ° C
The temperature rose. Tert-butyl 3-bromobutanol
Add 25 g of dimethylsilyl ether and stir at 0 ° C for 3 hours.
Stirred. The reaction solution is returned to room temperature, and saturated aqueous sodium hydrogen carbonate is added to
Extracted with Roholm. The organic layer is washed with a saturated saline solution,
After drying the magnesium acid salt, the mixture was filtered and the filtrate was concentrated. The residue
Silica gel column chromatography (Wakogel C-
200, hexane-ethyl acetate (2: 1))
17 g of an oil were obtained. (2) Reference using 7 g of the compound of (1)
3.9 g of an oil was obtained according to Example 7. (3) Reference using 3 g of the compound of (2)
According to Example 8, 7 g of a coloring oil was obtained. (4) 7 g of the compound of (3), triphenylene
5.8 g of luphosphine was added to water-tetrahydrofuran (1:
In addition to 10), the mixture was stirred at 50 ° C for 2 hours. Concentrate the reaction solution
And the residue is purified by silica gel column chromatography (FL).
60D (Fuji Silysia Ltd.), chloroform-meta
(100: 0 to 98: 2)) to give a brown oil
2.1 g of the product were obtained. (5) 2.1 g of chloro compound of the compound of (4)
Formic acid (5 ml) was added to form (10 ml) solution,
Stirred for hours. The reaction solution was concentrated, and the residue was treated with methanol (1
0ml) to the sodium borohydride
7.4 g was added and the mixture was stirred at room temperature for 1 hour. Chlorine reaction solution
Dilute with form, wash with saturated saline, and add magnesium sulfate
After drying, the mixture was filtered and the filtrate was concentrated. Silica gel residue
Chromatography (FL60D (Fuji Silysia Co., Ltd.)
Company), chloroform-methanol (100: 0-9)
8: 2)) to obtain 0.57 g. (6) 0.57 g of the compound of (5), chloride
1.7 g of p-nitrobenzenesulfonyl, dimethylamido
A mixture of 0.71 g of pyridine and 5 ml of chloroform
Was stirred at room temperature for 2 hours. Dilute the reaction solution with chloroform
And washed with saturated aqueous sodium hydrogen carbonate and saturated saline to remove magnesium sulfate.
After drying, the filtrate was concentrated. Silica gel residue
Ram chromatography (Wakogel C-200, chromatograph
Refine in roform-methanol (100: 0 to 98: 2)
To give 0.73 g of the desired product. (7) 0.73 g of the compound of (6), diacid
Manganese oxide 50mg, 30% hydrogen peroxide 5ml
A mixture of 20 ml of roloform was stirred at room temperature for 6 hours.
Dilute the reaction solution with chloroform, and add saturated aqueous sodium hydrogen carbonate and saturated saline.
After washing with water and drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated.
Shrank. Silica gel column chromatography of the residue
(Wakogel C-200, chloroform-methanol
(100: 0 to 98: 2)) and 0.78 g of crystals
I got (8) 0.78 g of the compound of (7),
0.71 ml of ethylamine, trimethylsilyl cyanide
Mixing of 0.66 ml and acetonitrile-chloroform
The material was stirred at 80 ° C. for 3 hours. Residue is silica gel column
Chromatography (Wakogel C-200, chloropho
Lum-methanol (100: 0 to 98: 2))
Thus, 0.71 g of a crystal was obtained. (9) Reference Example Using Compound (8)
75 mg of the desired product was obtained according to 4 and 5. (10) Using 75 mg of the compound of (9)
The pale yellow solid, which is the title compound, was
8 mg, and a yellow solid which is the compound of Example 292.
4 mg were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 290 7 mg of the compound of Example 289 was dissolved in 2 ml of methanol.
Then, add 50 μl of formalin and stir at room temperature for 4 hours.
Was. 3 ml of methanol is added to the reaction solution,
100 mg of thorium was added and the mixture was stirred at room temperature for 1 hour. Anti
After adding 1N hydrochloric acid to the reaction solution to decompose the excess reagent,
Aqueous sodium bicarbonate was added and extracted with chloroform. Saturate organic layer
After washing with brine and drying over magnesium sulfate, the filtrate and filtrate are filtered.
Concentrated. Silica gel column chromatography of the residue
(FL60D (Fuji Silysia Limited), chloroform
-Methanol (9: 1)) to give the title compound
3 mg of a yellow solid were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 291 7 mg of the compound of Example 289, 6 mg of acetic anhydride,
Mixing 5 mg of tylaminopyridine and 2 ml of chloroform
The mixture was stirred overnight at room temperature. Dilute the reaction solution with chloroform.
After washing with saturated aqueous sodium bicarbonate and saturated saline, magnesium sulfate
After drying, the filtrate was concentrated. The residue was purified by TLC (M
erck Art 5744, chloroform-methanol
(7: 3)) to give 3 mg of the title compound as a solid.
Was.¹ H-NMR (DMSO-d₆) 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). [0001]Example 292 The compound of Example 292 produces the compound of Example 289
Obtained in the final step.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 293 (1) Reference was made using 9 g of the compound of Example 80 (3).
8.5 g of a brown oil was obtained according to Example 6. (2) Using 8.5 g of the compound of (1)
According to (4) of Example 80, 4.7 g of a brown amorphous substance was obtained.
Obtained. (3) Using 250 mg of the compound of (2)
210 mg of the desired product was obtained according to (1) of Example 84.
Was. (4) di-o-toluylphosphonoacetic acid
38 mg of tyl ester in tetrahydrofuran (2 ml)
The solution was cooled to -78 ° C and 43 mg of the compound of (3) was added.
Add a solution of Trahydrofuran (1ml) and add 2 hours at -78 ° C
While stirring. A saturated aqueous ammonium chloride solution was added to the reaction solution.
And returned to room temperature. Extract with chloroform and saturate the organic layer.
Wash with brine and dry with magnesium sulfate, then filter, filter
The liquid was concentrated. The residue is purified by silica gel column chromatography.
E (Wakogel C-200, chloroform-methanol
(100: 0 to 97: 3)) and then TLC (Merc
h Art 5744, chloroform-tetrahydrofura
(9: 1)) to give 40 mg of a colorless oil. (5) 40 mg of the compound of (4), 6N salt
A mixture of 5 ml of acid and tetrahydrofuran was added at room temperature for 15 minutes.
Minutes. The reaction solution was extracted with chloroform,
After washing with water and drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated.
This was reduced to give 19 mg of a colorless solid as the title compound.¹ H-NMR (DMSO-d₆) 1.15 (3H, t, J = 7.1 Hz), 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)⁺. [0001]Example 294 (1) 22 mg of diethyl phosphonoacetic acid ethyl ester
The tetrahydrofuran (2 ml) solution is cooled on ice and
4 mg of thorium was added and stirred for 30 minutes. Example 293
43 mg of the compound of (3) in tetrahydrofuran (1 m
l) The solution was added and stirred for 2 hours. Add saturated ammonium chloride to the reaction mixture.
Add aqueous ammonium solution, bring to room temperature, and add chloroform.
Extracted. The organic layer was washed with saturated saline,
After drying, the filtrate was concentrated. Silica gel residue
Column chromatography (Wakogel C-200, K
With roloform-methanol (100: 0 to 97: 3)
Purification gave 42 mg of a white solid. (2) Using 42 mg of the compound of (1)
The title compound was white solid according to Example 293 (5).
21 mg of body was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 295 50 mg of the compound of Example 294 (1) in chloroform
(5 ml) To the solution was added 27 mg of zinc chloride and sodium borohydride.
7 mg of thorium was added, 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-d₆) 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)⁺. [0001]Example 296 30 mg of the compound of Example 294 (1) methanol
(10 ml) solution, 10 mg of copper (I) chloride and
Add 4mg of sodium iodide and stir until the ingredients disappear
Was. The same post-treatment as in Example 290 was carried out, and the title compound was used.
13 mg of a white solid was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 297 60 mg of the compound of Example 293 was added to 30 ml of chloroform.
Dissolved in toluene and diisopropyl aluminum hydride
0.9 ml of a solution (1.0 M) was added to -30 to -20.
Stirred at 30 ° C for 30 minutes. The same post-processing as in the embodiment 290 is performed.
Thus, 17 mg of a white solid as the title compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 298 40 mg of the compound of Example 294, 2N sodium hydroxide
Aqueous solution 5 ml, tetrahydrofuran 2 ml and methanol
Of the mixture were stirred at room temperature for 1 hour. To the reaction solution
The pH was adjusted to 3 by adding 1N hydrochloric acid and extracted with chloroform.
Was. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After drying, filtration and the filtrate were concentrated. The residue was purified by TLC (Merc
h Art 5744, chloroform-methanol (9:
After purification in 1)), recrystallization was performed and the title compound was white.
22 mg of a solid were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]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 ° C.
And methanesulfonyl chloride 0.310 ml
Add a solution of lahydrofuran (2 ml) and leave at room temperature for 11 hours
Stirred. Water was added to the reaction solution, and extracted with chloroform.
Was. The organic layer was washed with water and a saturated saline solution, and magnesium sulfate was washed.
After drying, the filtrate was concentrated. Silica gel residue
Ram chromatography (Wakogel C-200, Heki
Purified with sun-ethyl acetate (1: 1 to 0: 1), colorless
606 mg of amorphous material was obtained. (2) Table according to (2) of Example 133
The title compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 300 (1) Salification of 80 mg of the compound of Example 294 (1)
The methylene (5 ml) solution was cooled on ice and trifluoroacetic acid 2
74 mg and N- (methoxymethyl) -N-trimethyl
Add 190 mg of silylmethyl) benzylamine for 3 hours
Stirred. Dilute the reaction solution with chloroform and add saturated sodium bicarbonate
Wash with water and saturated saline, dry magnesium sulfate, and filter.
The filtrate was concentrated. The residue was purified by TLC (Merck Ar
t5744, chloroform-methanol (9: 1))
After purification, recrystallization was performed to obtain 91 mg of a pale yellow oil.
Was. (2) Using 91 mg of the compound of (1)
The title compound was white solid according to Example 293 (5).
50 mg of body was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 301 The compound of Example 301 is a compound of (4) of Example 293.
It was manufactured according to Example 300 using the product. mass: 540 (M + 1)⁺. [0001]Example 302 30 mg of tetrahydrofuran of the compound of Example 300
(3 ml) The solution was cooled on ice and lithium aluminum hydride
In tetrahydrofuran (2 M) and methano
0.22 ml of a tetrahydrofuran solution (1M) of
In addition, the mixture was stirred at room temperature for 30 minutes. After the same as in Example 290
After treatment, a white solid of the title compound (low-polar fraction) was obtained.
Example 2 mg and diastereomer of the title compound
2.3 mg of a white solid of compound 303 (high-polarity fraction)
Obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 303 The compound of Example 303 is the diastereomer of Example 302.
Obtained as a mer.¹ H-NMR (DMSO-d₆) 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)⁺. Embodiment 304 The compound of Example 304 uses the compound of Example 301.
And was produced according to Example 303. mass: 498 (M + 1)⁺. [0001]Example 305 (1) 50 mg of the compound of Example 293 (4),
A mixture of 34 mg of prene and 3 ml of toluene is placed in a sealed tube
The reaction was carried out at 120 ° C. overnight. The reaction solution was concentrated, and the residue was
LC (Merch Art 5744, chloroform-me
(9: 1)) to give 52 mg of the adduct.
Was. (2) Example 2 for the compound of (1)
The reaction was carried out according to 93 (5), and the title compound, white
18 mg of a colored solid were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 306 (1) Compound of Example 3 and 4-nitrobenzoy chloride
To obtain a yellow solid according to Example 261. (2) 22.1 g of the compound of (1) was converted to HP
LC (CHIRALPAK AD, hexane-ethanol)
(1: 1 to 1: 4)) and Rt = 22 minutes
Compound (A) of 11.2 g and Rt = 30 minutes
(B) 10.1 g was obtained. (3) 10 g of the compound of (2) -A, 6N
A mixture of 30 ml of hydrochloric acid and 30 ml of acetic acid at 80 ° C. for 3 days
While stirring. Return the reaction solution to room temperature, and add
After being made acidic, it was extracted with chloroform. Organic layer is 1N hydroxyl
Wash with aqueous potassium chloride solution and saturated saline
After drying, the filtrate was concentrated. Silica gel residue
Ram chromatography (Wakogel C-200, chromatograph
Refine in roform-methanol (100: 0 to 98: 2)
After the production, recrystallization from ethanol yielded 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)
Title compound (optical activity of compound of Example 91)
Body) A white solid was obtained. mass: 429 (M + 1)⁺. [0001]Example 307 Example 30 using the compound of (2) -B of Example 306
The title compound was a white solid according to 6 (3) to (5).
I got a body. mass: 429 (M + 1)⁺. [0001]Example 308 The compound of Example 308 was prepared according to Example 306.
Was. mass: 429 (M + 1)⁺. [0001]Example 309 The compound of Example 309 was produced according to Example 307.
Was. mass: 429 (M + 1)⁺. [0001]Example 310 The compound of Example 310 was prepared according to Example 307.
Was. mass: 469 (M + 1)⁺. [0001]Example 311 The compound of Example 311 was prepared according to Example 306.
Was. mass: 429 (M + 1)⁺. [0001]Example 312 The compound of Example 312 was prepared according to Example 307.
Was. mass: 429 (M + 1)⁺. [0001]Example 313 Example 290 was carried out using 51 mg of the compound of Example 91.
Thus, 12 mg of a white solid was obtained. mass: 429 (M + 1)⁺. [0001]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. Reaction mixture
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) Add the solution and stir at room temperature for 30 minutes and at 45 ° C. for 6 hours
Was. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography.
Chromatography (Wakogel C-200, hexane-acetic acid
(4: 1 to 1: 1)) to give a yellow oil 734.
mg was obtained. (2) Using 100 mg of the compound of (1)
The title compound was a white solid 101 m according to Reference Example 5.
g was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Examples 315-319 The compound of Example 315 to Example 319 is a compound of Example 3
It was manufactured according to No.14.Example 315 mass: 377 (M + 1)⁺. [0001]Example 316 mass: 378 (M + 1)⁺. [0001]Example 317 mass: 454 (M + 1)⁺. [0001]Example 318 mass: 454 (M + 1)⁺. [0001]Example 319 mass: 450 (M + 1)⁺. [0001]Example 320 100 mg of the compound of Example 319 in 4N hydrochloric acid-diox
A mixture of 5 ml of sun and 3 ml of methanol was stirred at room temperature for 30 minutes.
Stirred. After adding triethylamine to the reaction mixture, concentrate
And the residue is purified by silica gel column chromatography (FL).
60D (Fuji Silysia Ltd.), chloroform-meta
(100: 0 to 95: 5)) to give a white solid
72 mg were obtained. mass: 350 (M + 1)⁺. [0001]Example 321 17 mg of the compound of Example 320 and cyclopentanone
Using 12 mg of the title compound according to Example 84 (2)
I got something. mass: 418 (M + 1)⁺. [0001]Example 322 The compound of Example 322 was prepared according to Example 321.
Was. mass: 364 (M + 1)⁺. [0001]Example 323 (1) Using the compound of (2) -A of Example 164,
The target product was obtained according to 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-d₆) 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)⁺. [0001]Example 324 Example 32 Using the compound of (164) -B of Example 164
The hydrochloride of the title compound was obtained according to 3. mass: 352 (M + 1)⁺. [0001]Example 325 Example 13 using the compound of (2) -A of Example 164
The title compound was obtained according to 3 (2).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 326 Example 13 using the compound of (2) -B of Example 164
The title compound was obtained according to 3 (2). mass: 353 (M + 1)⁺. [0001]Example 327 (1) Example using the compound of (1) of Example 323
The desired product was obtained according to (1) of 96. (2) Example 1 using the compound of (1)
The title compound was obtained according to 33 (2).¹ H-NMR (DMSO-d₆) 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) +. [0001]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)⁺. [0001]Example 329 Using the compound of Example 327 (1) and 1-butanol
And the title compound according to (2) and (3) of Example 96.
Was obtained.¹ H-NMR (DMSO-d₆) 0.89 (3H, t, J = 7.8 Hz), 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)⁺. [0001]Example 330 (1) Example using the compound of (1) of Example 328
The desired product was obtained according to (327) (1). (2) Example 3 using the compound of (1)
The hydrochloride of the title compound was obtained according to 29. mass: 408 (M + 1)⁺. [0001]Example 331 Compound of Reference Example 8 and (R) -3- (tert-butoxy)
(Cicarbonylamino) -1,4-dimethanesulfonylo
Using xybutane, the title compound was prepared according to Example 334.
The hydrochloride was obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 332 15 mg of the compound of Example 331, 24 μl of acetyl chloride
l, triethylamine 92 μl and dimethylformamide
0.5 ml of the mixture was stirred at room temperature for 5 minutes. Reaction solution
Concentrate and concentrate the residue on TLC (Merck Art 5713,
Purified with chloroform-methanol (19: 1)
11 mg of a pale yellow solid, which was the title compound, was obtained.¹ H-NMR (CD₃OD) 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)⁺. [0001]Example 333 The compound of Example 96 was used using 20 mg of the compound of Example 331.
16 mg of the title compound, a pale yellow solid, was prepared according to (1).
Obtained.¹ H-NMR (DMSO-d₆) 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). [0001]Example 334 (1) 100 mg of the compound of (1) of Example 323,
(S) -3- (tert-butoxycarbonylamino)
34 mg of -1,4-dimethanesulfonyloxybutane,
46 mg of N, N-diisopropylethylamine and
Stir the mixture of 1 ml of tilformamide at 80 ° C for 1 hour
did. The reaction solution is returned to room temperature, diluted with chloroform and saturated.
Wash with aqueous sodium bicarbonate solution, water and saturated saline, and add magnesium sulfate
After drying, the mixture was filtered and the filtrate was concentrated. , Silica gel residue
Ram chromatography (Wakogel C-200, chromatograph
Purified with chloroform-methanol (1: 0 to 4: 1),
90 mg of the ester were obtained. (2) 100 mg of the compound of (1)
Hydrochloride of the title compound according to Example 133 (2).
Was obtained as a white solid (50 mg).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 335 Using (2) -B of Example 164, the
The obtained compound was reacted according to Example 334.
To give the hydrochloride of the title compound. mass: 421 (M + 1)⁺. [0001]Example 336 (1) 2- (N- (tert-butoxycarbonyl)
Amino) -4-methylpyridine 2.26 g of tetrahydride
The solution of lofran (100 ml) was cooled to -78 ° C and n-
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
-Add 1.48 ml of butyraldehyde and gradually warm to room temperature.
I got it. Water was added to the reaction solution, which was extracted with ethyl acetate. Organic
The layer was washed with saturated saline, dried over magnesium sulfate, and filtered.
The filtrate was concentrated. The residue is purified by silica gel column chromatography.
Chromatography (Wakogel C-300, hexane-acetic acid
Purification by chill (1: 0 to 1: 1) gave 1.37 as a white solid
g was obtained. (2) Using 1.00 g of the compound of (1)
700 mg of the target product was obtained according to (1) of Reference Example 8.
Was. (3) 700 mg of the compound of (2)
700 mg of phenylphosphine, 2 ml of water and tetrahi
A mixture of 30 ml of drofuran was stirred for 30 minutes. Reaction liquid
To room temperature, add toluene and methanol and concentrate.
Was. The residue was subjected to silica gel column chromatography (Wako
-Gel 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) 100 mg of the compound of (4)
The target substance 1 was obtained according to (2) of Example 96 using ethanol.
05 mg was obtained. (6) Using 53 mg of the compound of (5),
40 mg of a urea compound was obtained according to (2) of Example 118.
Was. 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) 20 mg of the compound of (6) -A
Colorless as the title compound according to Example 96 (3).
3.8 mg of an oil were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 337 Example 96 using a compound of (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)⁺. [0001]Example 338 (1) Compound of Reference Example 8 and 2,4-dimethoxyben
The purpose was as described in (2) of Example 84, using duzaldehyde.
I got something. (2) The compound of (1) and 1-propane
Using sulfonyl chloride and according to (1) of Example 96
To obtain the desired product. (3) Trifluoroacetic acid of the compound of (2)
The acid solution was stirred at room temperature for 15 minutes. Concentrate the reaction mixture to a residue
The residue was crystallized by adding ether-methanol to
I got mass: 458 (M + 1)⁺. [0001]Example 339 The compound of Example 339 was prepared according to Example 140.
Was. mass: 472 (M + 1)⁺. [0001]Example 340 The compound of Example 340 was prepared according to Example 138.
Was. mass: 458 (M + 1)⁺. [0001]Example 341 (1) Objective according to Reference Example 10 using o-anisidine
The compound was obtained. (2) Reference Example 1 Using Compound (1)
After performing the reaction according to 1, the crude product was dissolved in methanol.
Disassembled and treated with 1N hydrochloric acid. Filter the reaction solution through Celite
And the filtrate was concentrated. The residue was solidified with ether-methanol.
To give the title compound as a white solid. mass: 458 (M + 1)⁺. [0001]Examples 342-360 The compound of Example 342 to Example 360 was prepared in Example 3
41.Example 342 mass: 458 (M + 1)⁺. [0001]Example 343 mass: 419 (M + 1)⁺. [0001]Example 344 mass: 472 (M + 1)⁺. [0001]Example 345 mass: 485 (M + 1)⁺. [0001]Example 346 mass: 510 (M + 1)⁺. [0001]Example 347 mass: 435 (M + 1)⁺. [0001]Example 348 mass: 436 (M + 1)⁺. [0001]Example 349 mass: 479. (M + 1)⁺. [0001]Example 350 mass: 428 (M + 1)⁺. [0001]Example 351 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 352 mass: 430 (M + 1)⁺. [0001]Example 353 mass: 429 (M + 1)⁺. [0001]Example 354 mass: 429 (M + 1)⁺. [0001]Example 355 mass: 429 (M + 1)⁺. [0001]Example 356 mass: 479 (M + 1)⁺. [0001]Example 357 mass: 430 (M + 1)⁺. [0001]Example 358 mass: 468 (M + 1)⁺. [0001]Example 359 mass: 479 (M + 1)⁺. [0001]Example 360 mass: 430 (M + 1)⁺. [0001]Example 361 (1) Using 6-aminoquinoline,
The reaction was carried out according to Example 11, and sulfite was formed as a by-product.
I got a do body. (2) Using 64 mg of the compound of (1),
The title compound, a white solid, was prepared according to Example 133 (2).
21 mg of body was obtained. mass: 445 (M + 1)⁺. [0001]Example 362 (1) Using 6-aminoquinoline,
Reaction was carried out according to Reference Example 11, and chloride was used as a by-product.
Obtained. (2) Using 26 mg of the compound of (1),
The title compound, a white solid, was prepared according to Example 133 (2).
18 mg of body was obtained. mass: 371 (M + 1)⁺. [0001]Examples 363-364 Example 363 and Example 364 are based on Example 341.
Manufactured.Example 363 mass: 479 (M + 1)⁺. [0001]Example 364 mass: 418 (M + 1)⁺. [0001]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)
A yellow powder which is a hydrochloride of the title compound was obtained according to 39.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 366-375 The compound of Example 366 to Example 375 is a compound of Example 3
65.Example 366 mass: 549 (M + 1)⁺. [0001]Example 367 mass: 555 (M + 1)⁺. [0001]Example 368 mass: 569 (M + 1)⁺. [0001]Example 369 mass: 571 (M + 1)⁺. [0001]Example 370 mass: 549 (M + 1)⁺. [0001]Example 371 mass: 577 (M + 1)⁺. [0001]Example 372 mass: 549 (M + 1)⁺. [0001]Example 373 mass: 577 (M + 1)⁺. [0001]Example 374 mass: 583 (M + 1)⁺. [0001]Example 375 mass: 585 (M + 1)⁺. [0001]Example 376 (1) 510 mg of 2-pyridinecarboxaldehyde
Triphenylphosphorani in benzene (20 ml) solution
Add 1.70 g of methyl methyl acetate and add
Stirred for hours. The reaction mixture is concentrated, and the residue is
Chromatography (Wakogel C-300, hexa
-Ethyl acetate (4: 1 to 3: 1))
621 mg were obtained. (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, the yellow solid
24 mg was obtained.¹ H-NMR (CD₃OD) 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). [0001]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)
A white solid which was the hydrochloride of the title compound was obtained according to 39.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 378-387 The compound of Example 378 to Example 387 is a compound of Example 3
77.Example 378 mass: 549 (M + 1)⁺. [0001]Example 379 mass: 549 (M + 1)⁺. [0001]Example 380 mass: 577 (M + 1)⁺. [0001]Example 381 mass: 577 (M + 1)⁺. [0001]Example 382 mass: 529 (M + 1)⁺. [0001]Example 383 mass: 585 (M + 1)⁺. [0001]Example 384 mass: 571 (M + 1)⁺. [0001]Example 385 mass: 555 (M + 1)⁺. [0001]Example 386 mass: 569 (M + 1)⁺. [0001]Example 387 mass: 583 (M + 1)⁺. [0001]Example 388 The title was obtained according to Reference Example 3 using 19 mg of Example 376.
14 mg of the compound were obtained.¹ H-NMR (CD₃OD) 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). [0001]Example 389 (1) 1.01 g of 6-aminonicotinic acid, lithium hydride
Of aluminum 835 mg and tetrahydrofuran
The mixture 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. Concentrate the filtrate
And the residue is subjected to silica gel column chromatography (Wako
-Gel 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
332 mg of rt-butyldimethylchlorosilane, imida
A mixture of 244 mg of azole and 5 ml of dimethylformamide
The mixture was stirred at room temperature for 30 minutes. Add water to the reaction mixture,
Extracted with loroform. Wash the organic layer with saturated saline,
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated. Residue
To silica gel column chromatography (Wakogel C
-200, purified with hexane-ethyl acetate (3: 2),
341 mg of the desired product was obtained. (3) 320 mg of the compound of (2)
138 mg of the target product was prepared according to (2) of Example 118.
Obtained. (4) 103 mg of the compound of (3), acetic acid
Mixing 1ml, water 1ml and tetrahydrofuran 1ml
The material was stirred at room temperature for 3 days. The reaction solution was concentrated, and the residue was
LC (Merck Art 5744, chloroform-me
(10: 1), and the title compound was white.
44 mg of a colored powder were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 390 The compound of Example 390 was prepared according to Example 498.
Was. mass: 352 (M + 1)⁺. [0001]Example 391 (1) 103 mg of the compound of Example 389, triethyl
Luamine 0.6 ml and dimethyl sulfoxide 3 ml
Add 265 mg of sulfur trioxide pyridine complex to the mixture and add
Stirred at warm for 4 hours. Here, sulfur trioxide pyridine complex
195 mg was added and the mixture was stirred at room temperature for 1 hour. Remove the reaction solution
Dilute with roloform, wash with water and saturated saline, and wash with magnesium sulfate.
After drying with cesium, filtration and the filtrate were concentrated. Obtained crude
The product was used for the next reaction as it was. (2) 36 mg of the compound of (1) and ethyl
Using 2 ml of a methanol solution of ruamine (2.0 M),
White powder which is the title compound according to (84) of Example 84
20 mg were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 392 The compound of Example 392 was produced according to Example 391.
Was. mass: 380 (M + 1)⁺. [0001]Example 393 (1) 139 mg of 2-amino-5-nitropyridine
33 mg of the desired product was obtained according to Example 118 (2).
Was. (2) Using 33 mg of the compound of (1)
26 mg of the title compound was obtained as a white powder according to Example 3.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 394 (1) 643 mg of 2-amino-5-bromopyridine
Using 989 mg of the target compound in accordance with Example 118 (2)
Obtained. (2) Using 218 mg of the compound of (1)
150 mg of the desired product was obtained according to Reference Example 6. (3) 30 mg of the compound of (2)
10 μl of tilpiperazine, tris (dibenzylidene acetate
Ton) dipalladium (0) 3 mg, 1,1'-bis (di
Phenylphosphino) ferrocene 3 mg, 2,2'-bi
(Diphenylphosphino) -1,1'-binaphthyl 3
mg, sodium tert-butoxide 9 mg and tet
A mixture of 2 ml of lahydrofuran is placed in a sealed tube at 100 ° C. for 2 hours.
Allowed to react for hours. The reaction solution is returned to room temperature, and silica gel and
Filtered through celite. The filtrate is concentrated and the residue is concentrated in TL
C (Merck Art 5744, chloroform-meta
(10: 1)) to give 17 mg of the desired compound.
Obtained. (4) Using 17 mg of the compound of (3),
The hydrochloride of the title compound was prepared according to (133) of Example 133.
15 mg of a white solid was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 395-397 The compound of Example 395 to Example 397 is a compound of Example 3
94.Example 395 mass: 366 (M + 1)⁺. [0001]Example 396 mass: 352 (M + 1)⁺. [0001]Example 397 mass: 338 (M + 1)⁺. [0001]Example 398 (1) 2-amino-5-bromopyridine, tributyl
Reaction according to Example 429 (2) using vinyl tin
Was performed to obtain the desired product. (2) Using 6 mg of the compound of (1)
White powder which is the title compound according to Example 118 (2)
2 mg were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 399 According to Reference Example 3 using 4 mg of the compound of Example 398
3 mg of a white powder was obtained as the title compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 400 (1) 2-acetaminopyridine-4-carboxylic acid
19 mg of chill ester, 7 mg of sodium periodate,
Mix 12 mg of iodine, 25 μl of water and 0.12 ml of acetic acid
One drop of concentrated sulfuric acid was added to the mixture and stirred at 85 ° C for 23 hours.
Stirred. 5 ml of aqueous sodium thiosulfate solution was added to the reaction solution.
And extracted with chloroform. Magnesium sulfate organic layer
After drying, the solution was filtered and the filtrate was concentrated. The residue was purified by TLC (Mer
ck Art 5744, chloroform-methanol (2
0: 1)), and 15 mg of yellow powder was obtained as the target substance.
Obtained. (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-d₆) 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)⁺. [0001]Example 401 According to Reference Example 3 using 2 mg of the compound of Example 400
1 mg of a white powder was obtained as the title compound.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 402 Using 86 mg of 2-aminopyrimidine, Example 118
According to (2), 15 mg of the title compound, pale red powder,
Obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 403 (1) 2-amino-4,6-dichloropyrimidine
0 g, 1-methylpiperazine 733 mg, triethyl alcohol
A mixture of 1.3 ml of min and 15 ml of 1-butanol
Stirred at 80 ° C. for 22 hours. After concentrating the reaction solution,
Diluted with Lum-Methanol (10: 1), silica gel
(Wakogel C-200). Concentrate the filtrate
The product was reduced to obtain a crude product containing the desired product. (2) The compound of (1) is replaced with ethanol 18
of 390 mg of the desired product according to Reference Example 3.
Was. (3) Using 74 mg of the compound of (2),
The title compound, a white solid, was prepared according to Example 118 (2).
14 mg was obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Examples 404-405 The compound of Example 404 and Example 405 is a compound of Example 40
6 was prepared.Example 404 mass: 385 (M + 1)⁺. [0001]Example 405 mass: 359 (M + 1)⁺. [0001]Example 406 (1) Using Indole, the target product was prepared according to Reference Example 2.
Obtained. (2) Example 1 using the compound of (1)
The title compound was obtained according to 29. mass: 355 (M + 1)⁺. [0001]Example 407 The compound of Example 407 was prepared according to Example 408.
Was. mass: 363 (M + 1)⁺. [0001]Example 408 (1) Reference example using the compound of (1) of Example 406
The desired product was obtained according to 3. (2) Example 1 using the compound of (1)
The title compound was obtained according to the following procedure. mass: 357 (M + 1)⁺. [0001]Example 409 (1) 2-chloro-3-nitrobenzoic acid 3 g, amino
3.47 g of malonic acid diethyl ester hydrochloride, 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 stirred at room temperature for 3 hours.
Was. Dilute the reaction solution with 200 ml of ethyl acetate and add 1N salt
After washing with acid, saturated aqueous sodium bicarbonate and saturated saline, magnesium sulfate
, Dried and filtered to give a crude solid product. vinegar
After washing with ethyl acid, 2.49 g of primary crystals and secondary crystals
0.895 g was obtained. (2) The primary crystal 1.5 obtained in (1)
0 g of dimethyl sulfoxide (30 ml) solution was ice-cooled
And 230 mg of sodium hydride was added.
Minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution.
After diluting with 150 ml of ethyl acetate, the organic layer was separated.
did. The organic layer is washed with water and saturated saline,
After drying with sodium, filtration and concentration were performed to obtain 1.36 g of a crude product.
Was. (3) The crude product obtained in (2)
Add 47 g of ethanol solution (600 ml) to 100 ° C.
Heat and add 52 ml of 1N aqueous sodium hydroxide to add
Stirred for 0 minutes. The reaction solution was cooled on ice and filtered. The filtrate is concentrated
And the residue is subjected to silica gel column chromatography (wa
Kogel 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)
And suspended in ice-cooled water (90 ml).
Add 3.61 g of sodium borohydride in four portions and add 50
Minutes. Add 2 ml of saturated ammonium chloride and filter
And the resulting solid is washed with methanol to give a white powder.
3.48 g were obtained. (5) 1.00 g of the compound of (4),
650 mg of dazole 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. Reaction solution
Dilute with 200 ml of ethyl acetate and wash with water and saturated saline
After purification, dried over magnesium sulfate, filtered and concentrated to produce crude
I got something. The following reaction was performed without purification. (6) The total amount of the crude product of (5) is
Dissolved in 100 ml of toluene and performed the same reaction as in Reference Example 3.
Was. The obtained crude crystals were washed with ether-hexane,
1.13 g of min were obtained. (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) 1.48 g of the compound (7) in meta
Concentrated hydrochloric acid (4 ml) is added to the
Stir for 30 minutes at warm. The precipitated solid is collected by filtration, and
After washing with drofuran, 1.18 g of the title compound was obtained.¹ H-NMR (DMSO-d₆) 3.62 (1H, dd, J = 5.7 Hz, 11 Hz),
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)⁺. [0001]Examples 410-413 The compound of Example 410 to Example 413 is a compound of Example 4
It was manufactured according to No.14.Example 410 mass: 313 (M + 1)⁺. [0001]Example 411 mass: 327 (M + 1)⁺. Embodiment 412 mass: 341 (M + 1)⁺. Embodiment 413 mass: 355 (M + 1)⁺. [0001]Example 414 (1) 26 mg of the compound of Example 409 (6)
Tylformamide-tetrahydrofuran (1: 1) (1
ml), sodium hydride 5 mg, benzyl bromide
Then, the mixture was stirred at room temperature for 30 minutes. Reaction mixture
Filtration with silica gel and silica gel in hexane-ethyl acetate
Washed with (1: 1). Combine the filtrate and washings and concentrate.
And used for the next reaction. (2) The compound of (1) and 2-pyridineca
According to the method of Example 1 using rubonyl azide,
The compound was prepared. (3) Examples using the compound of (2)
Perform the same reaction as in (8) of 409, and convert the title compound to pale yellow
25 mg of a colored powder are obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Examples 415-423 The compound of Example 415 to Example 423 is a compound of Example 4
It was manufactured according to No.14.Example 415 mass: 338 (M + 1)⁺. [0001]Example 416 mass: 355 (M + 1)⁺. [0001]Example 417 mass: 369 (M + 1)⁺. [0001]Example 418 mass: 375 (M + 1)⁺. Embodiment 419 mass: 403 (M + 1)⁺. [0001]Example 420 mass: 409 (M + 1)⁺. [0001]Example 421 mass: 395 (M + 1)⁺. [0001]Example 422 mass: 379 (M + 1)⁺. [0001]Example 423 mass: 381 (M + 1)⁺. [0001]Examples 424-426 The compound of Example 424 to Example 426 is a compound of Example 4
27.Example 424 mass: 297 (M + 1)⁺. [0001]Example 425 mass: 311 (M + 1)⁺. [0001]Example 426 mass: 339 (M + 1)⁺. [0001]Example 427 (1) 11 mg of the compound of Example 414 in triethyl
Mixing 40 μl of amine and 10 μl of methanesulfonyl chloride
The mixture was stirred at room temperature for 20 minutes. Add 20μl of DBU
The mixture was stirred at room temperature for 25 minutes and at 80 ° C for 14.5 hours. Reaction liquid
To room temperature and filtered through silica gel.
Washed with sun-ethyl acetate (1: 1). Filtrate and washing solution
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) is converted to ethanol
Dissolved in a mixed solvent of trahydrofuran, 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-d₆) 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)⁺. [0001]Example 428 The compound of Example 428 was produced according to Example 427.
Was. mass: 365 (M + 1)⁺. [0001]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. Dilute the reaction solution with chloroform,
After washing with brine, dry over magnesium sulfate, filter and concentrate.
Shrank. 1.56 g of crude product was obtained. (2) 50 mg of the compound of (1) and tet
9 mg of laxtriphenylphosphine palladium
Suspended in 1 ml of lahydrofuran. After degassing,
Add 79 μl of butyl (1-ethoxyvinyl) tin,
Reflux at room temperature for 1 hour, at 50 ° C for 2 hours, and for an additional 2.5 hours
did. The reaction solution was returned to room temperature and filtered through silica gel. Shi
Rica gel washed with hexane-ethyl acetate (3: 1)
Then, the filtrate and the washing liquid were combined and concentrated. The residue was purified by TLC (M
erck Art 5744, hexane-ethyl acetate
(3: 1)).
mg was obtained. (3) Ethanol of 110 mg of the compound of (2)
437μ of 1N sodium hydroxide in a solution of ethanol (2ml)
and stirred at room temperature for 17 hours. Concentrate the reaction,
The residue was dissolved in 4 ml of water and washed with hexane. Water layer
Concentration afforded 95 mg of the desired product. (4) 45 mg of the compound of (3) and anil
The same reaction as (1) of Example 409 was performed using 18 μl of
Reaction gave 45 mg of the desired product. (5) 45 mg of the compound of (4), concentrated hydrochloric acid
Mix a mixture of 20 μl and 2 ml of ethanol at room temperature for 50 minutes
Stirred. The reaction mixture is concentrated, and the resulting solid is
Washed with ethyl acetate (3: 1). Washing liquid by TLC
(Merck Art 5744, hexane-ethyl acetate
(3: 1)) to give the desired product. (6) The compound of (5) and triethyl
The chloroform solution of 30 μl of the run was cooled on ice and
Add 23 µl of urine ether complex and add 2 hours 45 minutes at room temperature
Stirred. The reaction solution was subjected to TLC (Merck Art 574).
4, hexane-ethyl acetate (3: 1))
I got something. (7) Dissolve the compound of (6) in ethanol
Then, the same reaction as in Reference Example 3 was performed. (8) 7 mg of the compound of (7) and 2-py
Example 1 using 12 mg of lysine carbonyl azide
The reaction was performed according to the method. 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-d₆) 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)⁺. [0001]Example 430 The compound of Example 430 was produced according to Example 431.
Was. mass: 339 (M + 1)⁺. [0001]Example 431 (9) 12 mg of the compound of (8) and propionade
100 μl of diethyl diethyl acetal was added to chloroform-
Dissolve in 2 ml of tetrahydrofuran (1: 1) and add
Add 40μl of boron hydride ether complex and 6 hours at 120 ° C
While stirring. Propionaldehyde diethyl acetate
Add 50 μl of propional at 120 ° C for 3 hours.
Add 200 μl of diethyl diethyl acetal and add 120
Stirred at 2.5 ° 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-d₆) 0.98 (3H, t, J = 7.0 Hz), 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)⁺. [0001]Examples 432-437 The compounds of Examples 432 to 437 were prepared in Example 4
31.Example 432 mass: 387 (M + 1)⁺. [0001]Example 433 mass: 341 (M + 1)⁺. [0001]Example 434 mass: 311 (M + 1)⁺. [0001]Example 435 mass: 417 (M + 1)⁺. [0001]Example 436 mass: 417 (M + 1)⁺. [0001]Example 437 mass: 417 (M + 1)⁺. Embodiment 438 (1) 2.00 g of 3-nitrophthalimide, ethanol
Compound of interest was prepared according to Example 56 using 800 μl of
2.11 g were obtained. (2) 2.11 g of the compound (1)
Dissolved in 50 ml of nor-tetrahydrofuran (1: 4)
And cooled to -15 ° C.
360 mg was added and the mixture was stirred for 1 hour. Saturated ammonium chloride
Aqueous solution to bring the temperature to room temperature.
Extracted with LUM. After drying the organic layer over magnesium sulfate,
Filtration and concentration. The obtained solid was washed with hexane,
1.134 g of the target were obtained. (3) Using 120 mg of the compound of (2)
The same reaction as in Reference Example 3 was carried out to obtain 70 mg of the desired product.
Was. (4) 70 mg of the compound of (3) and 2-
Example 1 was prepared using 65 mg of pyridinecarbonyl azide.
According to the method, 26 mg of the title compound was obtained.¹ H-NMR (DMSO-d₆) 1.25 (3H, t, J = 7.2 Hz), 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)⁺. [0001]Example 439 Example 439 was produced according to Example 440. mass: 327 (M + 1)⁺. [0001]Example 440 13 mg of the compound of Example 438 was dissolved in 2 ml of ethanol.
And add a catalytic amount of p-toluenesulfonic acid at 90 ° C.
Stir for 1 hour. The reaction mixture is concentrated, and the resulting solid is
Recrystallization from ethyl acetate gave 7.3 mg of the title compound.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Examples 441-448 The compound of Example 441 to Example 448 is a compound of Example 4
Manufactured according to No. 40.Example 441 mass: 355 (M + 1)⁺. [0001]Example 442 mass: 369 (M + 1)⁺. [0001]Example 443 mass: 369 (M + 1)⁺. [0001]Example 444 mass: 383 (M + 1)⁺. [0001]Example 445 mass: 367 (M + 1)⁺. [0001]Example 446 mass: 395 (M + 1)⁺. [0001]Example 447 mass: 381 (M + 1)⁺. [0001]Example 448 mass: 403 (M + 1)⁺. [0001]Example 449 (1) (1) 2.02 g of 3-nitrophthalimide,
Example 56 using 1.20 ml of cyclopentanol
Accordingly, 2.27 g of the target compound was obtained. (2) Using 2.27 g of the compound of (1)
The reaction was carried out according to (2) of Example 438,
1.429 g were obtained. (3) Using 827 mg of the compound of (2)
The reaction was carried out according to Example 440, and the reaction solution was concentrated.
Used as such for 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
-Example using 600 mg of pyridinecarbonyl azide
According to the method of Example 1, 448 mg of the title compound was obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 450 25 mg of the compound of Example 449 was dissolved in ethanol
Then, the reaction was carried out in the same manner as in Example 440 to give the title compound as 1
8 mg were obtained.¹ H-NMR (DMSO-d₆) 0.99 <3H, t, J = 7.5 Hz>, 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)⁺. [0001]Examples 451-466 The compounds of Examples 451 to 466 were prepared according to Example 4.
67.Example 451 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 452 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 453 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 454 mass: 419 (M + 1)⁺. [0001]Example 455 mass: 419 (M + 1)⁺. [0001]Example 456 mass: 283 (M + 1)⁺. [0001]Example 457 mass: 297 (M + 1)⁺. [0001]Example 458 mass: 311 (M + 1)⁺. [0001]Example 459 mass: 311 (M + 1)⁺. [0001]Example 460 mass: 323 (M + 1)⁺. [0001]Example 461 mass: 337 (M + 1)⁺. [0001]Example 462 mass: 327 (M + 1)⁺. [0001]Example 463 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 464 mass: 331 (M + 1)⁺. [0001]Example 465 mass: 337 (M + 1)⁺. [0001]Example 466 mass: 337 (M + 1)⁺. [0001]Example 467 (1) Compound (20 mg, 20) of Example 449 (2)
% Palladium hydroxide-carbon catalyst 20 mg, methanol 1
mixture and 1 ml of tetrahydrofuran in a stream of hydrogen
The mixture was stirred at room temperature for 15 hours. Filter the reaction solution 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),
According to Example 1, the title compound was obtained as a pale yellow solid (2 mg).
Was. mass: 337 (M + 1)⁺. [0001]Example 468 The compound of Example 468 was prepared according to Example 467.
Was. mass: 339 (M + 1)⁺. [0001]Examples 469-492 The compound of Example 469 to Example 492 is the compound of Example 4
93.Example 469 mass: 365 (M + 1)⁺. [0001]Example 470 mass: 369 (M + 1)⁺. [0001]Example 471 mass: 387 (M + 1)⁺. [0001]Example 472 mass: 401 (M + 1)⁺. [0001]Example 473 mass: 407 (M + 1)⁺. [0001]Example 474 mass: 401 (M + 1)⁺. [0001]Example 475 mass: 379 (M + 1)⁺. [0001]Example 476 mass: 391 (M + 1)⁺. [0001]Example 477 mass: 325 (M + 1)⁺. [0001]Example 478 mass: 339 (M + 1)⁺. [0001]Example 479 mass: 353 (M + 1)⁺. [0001]Example 480 mass: 353 (M + 1)⁺. [0001]Example 481 mass: 401 (M + 1)⁺. [0001]Example 482 mass: 339 (M + 1)⁺. [0001]Example 483 mass: 461 (M + 1)⁺. [0001]Example 484 mass: 353 (M + 1)⁺. [0001]Example 485 mass: 367 (M + 1)⁺. [0001]Example 486 mass: 367 (M + 1)⁺. [0001]Example 487 mass: 367 (M + 1)⁺. [0001]Example 488 mass: 367 (M + 1)⁺. [0001]Example 489 mass: 367 (M + 1)⁺. [0001]Example 490 mass: 387 (M + 1)⁺. [0001]Example 491 mass: 401 (M + 1)⁺. [0001]Example 492 mass: 379 (M + 1)⁺. [0001]Example 493 (1) 125 g of 3-nitrophthalic anhydride
Cool the drofuran (2.5 L) solution to -78 ° C and add hydrogen
Add 48.8 g of sodium borohydride and stir for 1 hour
Was. 1N hydrochloric acid was added to the reaction solution, the temperature was returned to room temperature, and ethyl acetate was added.
Extracted. The organic layer is washed with water and saturated saline,
After drying with magnesium, the mixture was filtered and the filtrate was concentrated. Residue
Kagel column chromatography (Wakogel C-20)
0, purified with hexane-ethyl acetate (2: 1)
88.4 g of the product were obtained. (2) 200 mg of the compound of (1), 3-
Amino-1-propanol 90 mg, molecular sea
A mixture of 500 mg of bus 3A and 3 ml of tetrahydrofuran
The mixture was refluxed overnight. The reaction solution was filtered through celite,
After concentration, the residue was purified by TLC (Merch Art 574).
4, hexane-ethyl acetate (1: 1))
180 mg of the product were obtained. (3) 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-d₆) 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)⁺. [0001]Example 494 The compound of Example 494 to Example 492 is the compound of Example 493.
Manufactured according to.Example 494 mass: 339 (M + 1)⁺. [0001]Example 495 mass: 341 (M + 1)⁺. [0001]Example 496 mass: 341 (M + 1)⁺. [0001]Example 497 mass: 340 (M + 1)⁺. [0001]Example 498 mass: 325 (M + 1)⁺. [0001]Example 499 mass: 339 (M + 1)⁺. [0001]Example 500 mass: 387 (M + 1)⁺. [0001]Example 501 mass: 399 (M + 1)⁺. [0001]Example 502 mass: 369 (M + 1)⁺. [0001]Examples 503 to 530 The compound of Example 503 to Example 530 is the compound of Example 5
31.Example 503 mass: 498 (M + 1)⁺. [0001]Example 504 mass: 546 (M + 1)⁺. [0001]Example 505 mass: 558 (M + 1)⁺. [0001]Example 506 mass: 528 (M + 1)⁺. [0001]Example 507 mass: 524 (M + 1)⁺. [0001]Example 508 mass: 528 (M + 1)⁺. [0001]Example 509 mass: 546 (M + 1)⁺. [0001]Example 510 mass: 560 (M + 1)⁺. [0001]Example 511 mass: 566 (M + 1)⁺. [0001]Example 512 mass: 560 (M + 1)⁺. [0001]Example 513 mass: 538 (M + 1)⁺. [0001]Example 514 mass: 550 (M + 1)⁺. [0001]Example 515 mass: 484 (M + 1)⁺. [0001]Example 516 mass: 560 (M + 1)⁺. [0001]Example 517 mass: 498 (M + 1)⁺. [0001]Example 518 mass: 512 (M + 1)⁺. [0001]Example 519 mass: 512 (M + 1)⁺. [0001]Example 520 mass: 560 (M + 1)⁺. [0001]Example 521 mass: 512 (M + 1)⁺. [0001]Example 522 mass: 526 (M + 1)⁺. [0001]Example 523 mass: 526 (M + 1)⁺. [0001]Example 524 mass: 526 (M + 1)⁺. [0001]Example 525 mass: 526 (M + 1)⁺. [0001]Example 526 mass: 526 (M + 1)⁺. [0001]Example 527 mass: 546 (M + 1)⁺. [0001]Example 528 mass: 560 (M + 1)⁺. [0001]Example 529 mass: 538 (M + 1)⁺. [0001]Example 530 mass: 599 (M + 1)⁺. [0001]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.
After adding 200 ml, the mixture was diluted with ethyl acetate, and saturated sodium bicarbonate was added.
Water was added. Separate the organic layer and wash with water and saturated saline
After drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated.
The residue was subjected to silica gel column chromatography (Wakoge).
C-100, hexane-ethyl acetate (2: 1 to 1:
Purification was performed in 1)) to obtain 148 g of the desired product. (2) 18 g of the compound of (1) and trib
Using (35 g) of tyl vinyl tin in Example (429) (2)
The reaction was carried out according to the procedure to obtain 16 g of the desired product. (3) Using 16 g of the compound of (2),
19.7 g of the target product was obtained according to Example 300. (4) Using 19.7 g of the compound of (3)
14.1 g was obtained according to (1) and (2) of Reference Example 5.
Was.¹ H-NMR (CDCl₃) 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) 50 mg of the compound of (4) and
Example 1 was repeated using 30 mg of the compound of Example 493 (3).
According to the above, 41 mg of the title compound was obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Example 532 The compound of Example 532 was prepared according to Example 531.
Was. mass: 498 (M + 1)⁺. [0001]Example 533 (1) 2.00 g of 3-nitrophthalimide and 4-h
Example 43 using 1.37 g of droxy-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 a sieve 3A, 1 ml of trifluoroacetic acid
And a mixture of 25 ml of tetrahydrofuran at 100 ° C.
Stirred overnight. The reaction solution was returned to room temperature, filtered, and the filtrate was concentrated.
Shrank. Silica gel column chromatography of the residue
(Wakogel C-300, hexane-ethyl acetate (1:
Purification was performed in 1)) to obtain 963 mg of the desired product. (3) Refer to 963 mg of the compound of (2)
680 mg of the desired product was obtained according to Example 3. (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-d₆) 1.16 (3H, d, J = 7.0 Hz), 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)⁺. [0001]Example 534 mass: 353 (M + 1)⁺. [0001]Example 535 mass: 339 (M + 1)⁺. [0001]Example 536 mass: 353 (M + 1)⁺. [0001]Example 537 mass: 353 (M + 1)⁺. [0001]Example 538 mass: 367 (M + 1)⁺. [0001]Example 539 (1) 1.70 g of the compound of (3) of Example 493,
(Boc)₂O 5.50 g, 4-dimethylaminopyridi
Mixture of 3.00 g of tetrahydrofuran and 40 ml of tetrahydrofuran
Was stirred at room temperature overnight. The reaction solution is concentrated, and the residue is
Gel column chromatography (Wakogel C-30)
0, hexane-ethyl acetate (10: 1-5: 1))
Purification gave 2.56 g of the desired product. (2) 500 mg of the compound of (1)
Cool the solution of lahydrofuran (25 ml) to -78 ° C,
400 μl of butyl iodide and lithium hexamethyldisi
3.6m of azide in tetrahydrofuran (1.0M)
1 was added, and the temperature was gradually raised to room temperature. Saturated reaction solution
Add aqueous ammonium chloride solution and extract with ethyl acetate.
Was. The organic layer was washed with water and a saturated saline solution, and magnesium sulfate was washed.
After drying, the filtrate was concentrated. Silica gel residue
Ram chromatography (Wakogel C-300, Heki
Purification with sun-ethyl acetate (10: 1))
84 mg were obtained. (3) 484 mg of the compound of (2),
A mixture of 4 ml of fluoroacetic acid and 0.4 ml of water at room temperature
Stir for 10 minutes. The reaction mixture is concentrated, and the residue is
Ram chromatography (Wakogel C-300, Heki
Sun-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-d₆) 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)⁺. [0001]Example 540 The compound of Example 540 was prepared according to Example 541.
Was. mass: 498 (M + 1)⁺. [0001]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 were obtained.¹H-NMR (DMSO-d
₆) 1.17 (3H, d, J = 7.0 Hz), 1.20
-2.90 (10H, m), 3.66 (2H, s),
4.21 (2H, m), 5.94 (1H, s), 7.0
4 (1H, d, J = 5.0 Hz), 7.18 (1H,
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)⁺. [0001]Example 542-545 The compound of Example 542 to Example 545 is a compound of Example 5
41.Example 542 mass: 512 (M + 1)⁺. [0001]Example 543 mass: 512 (M + 1)⁺. [0001]Example 544 mass: 512 (M + 1)⁺. [0001]Example 545 mass: 526 (M + 1)⁺. [0001]Example 546 (1) 10.1 g of 2-chloro-3-nitrobenzoic acid
Example 12 using 4.85 ml of hydrazine monohydrate
9.00 g of the desired product was obtained according to 1 (1). (2) Ethanol of 9.00 g of the compound of (1)
Stir at 150 ° C for 15 hours in a sealed tube
did. The reaction solution was returned to room temperature, and the precipitated crystals were collected by filtration and dried.
After drying, 5.00 g of the desired product was obtained. (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. Bring the reaction to room temperature
And diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate, water, and saturated saline.
After washing and drying over magnesium sulfate, filter and concentrate the filtrate
did. The residue was purified by TLC (Merch Art 5744,
Purification with xan-ethyl acetate (1: 2)) gave the desired product 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-d₆) 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)⁺. [0001]Example 547 Compound of Example 546 (2) and 1,3-diiodop
Using lopan, according to (3) to (5) of Example 546.
This gave the title compound as a white solid.¹ H-NMR (DMSO-d₆) 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). [0001]Example 548 (1) 9.64 g of glycolic acid ethyl ester, chloride
13.2 ml of 4-methoxybenzyl, sodium hydride
Mixing of 3.89 g and 200 ml of dimethylformamide
Stirred at 0 ° C. overnight. Dilute the reaction solution with ethyl acetate
Wash with water and saturated saline and dry over magnesium sulfate.
Thereafter, the mixture was filtered and the filtrate was concentrated. Silica gel column residue
Chromatography (Wakogel C-200, hexane-
Purification with ethyl acetate (20: 1)) gave 16.0 g of the desired product.
I got (2) 4.11 ml of acetonitrile
Cool the solution of Trahydrofuran (400ml) to -78 ° C
And hexane solution of n-butyllithium (1.6M)
(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.
The temperature rises from -78 ° C to room temperature, and the raw materials disappear.
And stirred until the Add water to the reaction solution and acidify with 1N hydrochloric acid
After that, the mixture was extracted with ethyl acetate. Ethanol 2 in organic layer
After adding 00 ml, hydrazine monohydrate 20m
and refluxed overnight. The reaction mixture is concentrated and the residue
Ricagel column chromatography (Wakogel C-2
00, chloroform-methanol (98: 2))
Thus, 13.9 g of the desired product was obtained. (3) 13.9 g of the compound of (2), (B
oc)₂O15.1 ml, sodium hydride 2.62 g
And a mixture of dimethylformamide and 300 ml
Stirred at room temperature until disappeared. Add saturated ammonium chloride to the reaction mixture.
An aqueous solution of ammonium was added, and the mixture was extracted with ethyl acetate. Organic layer
After washing with saturated saline and drying over magnesium sulfate, filtration and filtration were performed.
The liquid was concentrated. The residue is purified by silica gel column chromatography.
E (Wakogel C-200, hexane-ethyl acetate
(10: 1 to 1: 1)), and 7.32 g of the desired product was obtained.
Obtained. (4) Using 7.32 g of the compound of (3)
In accordance with Example 118 (2), 4.16 g of the target product was obtained.
Obtained. (5) 4.16 g of the compound of (4), 10
% Pd-carbon catalyst 3 g, methanol-tetrahydrofura
140 ml of the mixture (1: 1) under a stream of hydrogen
C. and stirred for 3 hours. The reaction solution was filtered through celite,
Was concentrated. Silica gel column chromatography of the residue
-(Wakogel C-300, chloroform-methanol
(98: 2-80: 20)) and the Boc-protected form
(A) 602 mg and 593 mg of the title compound were obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 549 (1) Example using 510 mg of the compound of Example 548
295 mg of the desired product was obtained according to 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. Here
41 mg of sodium borohydride is added and the raw materials disappear
And stirred until the The reaction solution was filtered through celite, and the filtrate was concentrated.
Shrank. Silica gel column chromatography of the residue
(Wakogel C-300, chloroform-methanol
(20: 1 to 4: 1)) to give a racemic title compound.
139 mg of the body were obtained. (3) This product was purified by HPLC (CHIRA
Optical analysis with LPAK AD (Daicel Chemical Industries, Ltd.)
Rt = 8.3 min (CHIRALPAK AD
(Daicel Chemical Industries, Ltd., 0.46φx25cm),
(Ethanol, 0.5 ml / min) (A)
6 mg 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-d₆) 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)⁺. [0001]Example 550 The compound of Example 550 was replaced with the optical isomer of Example 549.
I got it. mass: 410 (M + 1)⁺. [0001]Example 551-591 The compound of Example 551 to Example 551 is the compound of Example 54
It was manufactured according to 9 (2).Example 551 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 552 mass: 383 (M + 1)⁺. [0001]Example 553 mass: 397 (M + 1)⁺. [0001]Example 554 mass: 397 (M + 1)⁺. [0001]Example 555 mass: 417 (M + 1)⁺. [0001]Example 556 mass: 417 (M + 1)⁺. [0001]Example 557 mass: 417 (M + 1)⁺. [0001]Example 558 mass: 445 (M + 1)⁺. [0001]Example 559 ¹ H-NMR (DMSO-d₆) 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). [0001]Example 560 mass: 445 (M + 1)⁺. [0001]Example 561 mass: 443 (M + 1)⁺. [0001]Example 562 mass: 431 (M + 1)⁺. [0001]Example 563 mass: 439 (M + 1)⁺. [0001]Example 564 mass: 439 (M + 1)⁺. [0001]Example 565 mass: 443 (M + 1)⁺. [0001]Example 566 mass: 461 (M + 1)⁺. [0001]Example 567 mass: 399 (M + 1)⁺. [0001]Example 568 mass: 399 (M + 1)⁺. [0001]Example 569 mass: 491 (M + 1)⁺. [0001]Example 570 mass: 438 (M + 1)⁺. [0001]Example 571 mass: 493 (M + 1)⁺. [0001]Example 572 mass: 425 (M + 1)⁺. [0001]Example 573 mass: 427 (M + 1)⁺. [0001]Example 574 mass: 500 (M + 1)⁺. [0001]Example 575 mass: 436 (M + 1)⁺. [0001]Example 576 mass: 413 (M + 1)⁺. [0001]Example 577 mass: 506 (M + 1)⁺. [0001]Example 578 mass: 503 (M + 1)⁺. [0001]Example 579 mass: 477 (M + 1)⁺. [0001]Example 580 mass: 473 (M + 1)⁺. [0001]Example 581 mass: 473 (M + 1)⁺. [0001]Example 582 mass: 489 (M + 1)⁺. [0001]Example 583 mass: 489 (M + 1)⁺. [0001]Example 584 mass: 443 (M + 1)⁺. [0001]Example 585 mass: 461 (M + 1)⁺. [0001]Example 586 mass: 522, 524 (M + 1)⁺. [0001]Example 587 mass: 477 (M + 1)⁺. [0001]Example 588 mass: 512 (M + 1)⁺. [0001]Example 589 mass: 457 (M + 1)⁺. [0001]Example 590 mass: 493 (M + 1)⁺. [0001]Example 591 mass: 493 (M + 1)⁺. [0001]Examples 592-595 The compound of Example 592 to Example 595 is a compound of Example 5
It was manufactured according to 49 (2) and (3).Example 592 mass: 477 (M + 1)⁺. [0001]Example 593 mass: 477 (M + 1)⁺. [0001]Example 594 mass: 477 (M + 1)⁺. [0001]Example 595 mass: 477 (M + 1)⁺. [0001]Example 596 Example 290 was carried out using 62 mg of the compound of Example 662.
15 mg of the title compound was obtained according to the above. mass: 397 (M + 1)⁺. [0001]Example 597 The compound of Example 597 was prepared according to Example 596.
Was. mass: 491 (M + 1)⁺. [0001]Example 598 The compound of Example 598 is a compound of (2) of Example 649.
The product was prepared according to Example 596. mass: 501 (M + 1)⁺. [0001]Example 599 (1) Using LN-benzylproline ethyl ester
The desired product was obtained according to (2) and (3) of Example 548.
Was. (2) Using 623 mg of the compound of (1)
408 mg of the desired product was prepared according to (2) of Example 118.
Obtained. (3) 288 mg of the compound of (2) and a salt
A mixture of 5 ml of acid-methanol was stirred at room temperature for 15 minutes.
Was. Concentrate the reaction mixture, dilute with chloroform, and add
After washing with water and saturated saline, drying over magnesium sulfate was performed.
The filtrate was concentrated. The residue is purified by silica gel column chromatography.
Chromatography (Wakogel C-200, chloroform-me
(99: 1)) to give a mixture of the title compounds.
119 mg were obtained. (4) The compound of (3) is separated by HPLC
And Rt = 14.6 minutes (CHIRALCEL OD (da
Isel Chemical Industry Co., Ltd., 0.46φx25cm)
Sun-ethanol (80:20), 0.6 ml / mi
38 mg of the title compound as fraction (A) in n) and Rt
= Compound of Example 600 as fraction (B) of 18.3 minutes
To give 39 mg. mass: 457 (M + 1)⁺. [0001]Example 600 The compound of Example 600 is the dia of the compound of Example 599.
Obtained as stereomers.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 601 Performed using DN-benzylproline ethyl ester
Rt = 14.0 min according to Example 599 and Example 600
(CHIRALCEL OD (Daicel Chemical Industries
0.46φx25cm), hexane-ethanol
(80:20), fraction (A) at 0.6 ml / min)
68 mg of the title compound and Rt = 16.8 min
64 mg of the compound of Example 602 was obtained as fraction (B)
Was. mass: 457 (M + 1)⁺. [0001]Example 602 The compound of Example 602 is a diamine of the compound of Example 601.
Obtained as stereomers. mass: 457 (M + 1)⁺. [0001]Examples 603 to 607 The compounds of Examples 603 to 607 were prepared in Example 5
It was manufactured according to 99 (1) to (3).Example 603 mass: 388 (M + 1)⁺. [0001]Example 604 mass: 424 (M + 1)⁺. [0001]Example 605 mass: 389 (M + 1)⁺. [0001]Example 606 mass: 424 (M + 1)⁺. [0001]Example 607 mass: 388 (M + 1)⁺. [0001]Example 608 610 mg of the compound of Example 599, 10% Pd-carbon
300 mg of catalyst, 800 mg of ammonium formate and eta
A mixture of 15 ml of phenol was refluxed for 4 hours. Reaction chamber
The mixture was returned to warm, filtered through Celite, and the filtrate was concentrated. The residue
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.
Obtained. mass: 367 (M + 1)⁺. [0001]Example 609 mass: 367 (M + 1)⁺. [0001]Example 610 mass: 367 (M + 1)⁺. [0001]Example 611 mass: 367 (M + 1)⁺. [0001]Example 612 The compound of Example 612 was obtained from (1) of Example 599.
It was manufactured according to (3). mass: 375 (M + 1)⁺. [0001]Example 613 (1) 1.87 g of 2-chloro-3-cyanopyridine
1.35 g of the target substance used according to (1) of Example 118
I got (2) Using 818 mg of the compound of (1)
N-protected body 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.
Was.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Examples 614-615 Example 614 and Example 615 correspond to Example 599.
It was manufactured according to (1) to (3).Example 614 mass: 468 (M + 1)⁺. [0001]Example 615 mass: 380 (M + 1)⁺. [0001]Examples 616-619 The compounds of Examples 616 to 619 were prepared according to Example 3.
Compound (06) and Compound (2) -B of Example 306
Using a compound synthesized according to (3) of Example 306.
Manufactured according to (1) to (3) of Example 599.
Was.Example 616 mass: 366 (M + 1)⁺. [0001]Example 617 mass: 366 (M + 1)⁺. [0001]Example 618 mass: 473 (M + 1)⁺. [0001]Example 619 mass: 473 (M + 1)⁺. [0001]Examples 620-621 The compound of Example 620 and Example 621 is a compound of 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)⁺. [0001]Example 621 mass: 383 (M + 1)⁺. [0001]Example 622-625 The compounds of Examples 622 to 625 were prepared according to Example 3.
Compound (06) and Compound (2) -B of Example 306
306 Compounds synthesized according to (3) of Example 306
Was obtained according to (1) to (3) of Example 599 using
The mixture of diastereomers obtained was purified by HPLC (CHIRA
LPAK AD (Daicel Chemical Industries, Ltd., 2φx25)
cm)).Example 622 mass: 471 (M + 1)⁺. [0001]Example 623 mass: 471 (M + 1)⁺. [0001]Example 624 mass: 471 (M + 1)⁺. [0001]Example 625 mass: 471 (M + 1)⁺. [0001]Example 626 The compound of Example 626 was obtained by converting (1) of Example 599.
It was manufactured according to (3). mass: 471 (M + 1)⁺. [0001]Example 627 The compound of Example 616 was prepared according to Example 622.
Was. mass: 424 (M + 1)⁺. [0001]Examples 628-629 The compound of Example 628 and the compound of Example 629
It was manufactured according to Example 622.Example 628 mass: 424 (M + 1)⁺. [0001]Example 629 mass: 424 (M + 1)⁺. [0001]Example 630 (1) Example using the compound of (3) of Example 599
The desired product was obtained according to 610. (2) 85 mg of the compound of (1), N-
(Diethylcarbamoyl) -N-methoxyformamide
A mixture of 81 μl and 2 ml of chloroform was added at 60 ° C. for 2 hours.
Stirred for hours. Return the reaction solution to room temperature and dilute with chloroform.
And washed with water and saturated saline, and dried over magnesium sulfate.
After drying, filtration and the filtrate were concentrated. The residue was purified by TLC (Merc
hArt5744, chloroform-methanol (10:
Purification in 1)) gave a mixture of diastereomers. This
Are divided in the same manner as in (3) of Example 549, and
4 mg of the title compound and 3 mg of the compound of Example 631 were obtained.
Was. mass: 395 (M + 1)⁺. [0001]Example 631 mass: 395 (M + 1)⁺. [0001]Example 632 (1) Using 171 mg of the compound of (1) of Example 630
A mixture of diastereomers 7 according to Example 295.
0 mg was obtained. (2) Example 5 for compound (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)⁺. [0001]Example 633 The compound of Example 633 is the diastereomer of Example 632
Obtained as a mer. mass: 381 (M + 1)⁺. [0001]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
Then, it is treated with 10% hydrochloric acid-methanol, dried and title
The hydrochloride of the compound was obtained in an amount of 22 mg. mass: 397 (M + 1)⁺. [0001]Example 635 The compound of Example 635 was prepared according to Example 634.
Was. [0001]Example 636 Using compound (20 g) of Example 639 (2)
After carrying out the reaction according to (1) of Example 84, Example 599 was carried out.
591 mg of the title compound were obtained according to (3). mass: 340 (M + 1)⁺. [0001]Example 637 The compound of Example 599 was used using the compound of (1) of Example 639.
708 mg of the title compound was obtained according to (3). mass: 432 (M + 1)⁺. [0001]Example 638 The compound of Example 638 was prepared according to Example 634.
Was. [0001]Example 639 (1) Ethyl 2-benzyloxypropionate
And the target substance according to (1) and (2) of Example 599.
I got (2) Using 4.30 g of the compound of (1)
The reaction was carried out according to (5) of Example 548. reaction
Add 10% hydrochloric acid-methanol to the solution to remove the Boc group
After that, ethyl acetate was added, and the precipitated crystals were collected by filtration and dried.
Drying afforded 2.21 g of the title compound. mass: 342 (M + 1)⁺. [0001]Examples 640-646 The compound of Example 640 to Example 646 is a compound of Example 6
34.Example 640 mass: 369 (M + 1)⁺. [0001]Example 641 mass: 383 (M + 1)⁺. [0001]Example 642 mass: 445 (M + 1)⁺. [0001]Example 643 mass: 409 (M + 1)⁺. [0001]Example 644 mass: 381 (M + 1)⁺. [0001]Example 645 mass: 383 (M + 1)⁺. [0001]Example 646 mass: 409 (M + 1)⁺. [0001]Example 647 (1) Using LN-benzylproline ethyl ester
The desired product was obtained according to (2) of Example 548. (2) 1.34 g of the compound of (1), hydrogen
243 mg of sodium iodide, 0.38 ml of methyl iodide
Raw material disappears from a mixture of dimethylformamide and 20 ml
Stir at room temperature until complete. Add saturated ammonium chloride to the reaction mixture.
Aqueous solution was added and extracted with ethyl acetate. Organic layer with water
After washing and drying over magnesium sulfate, filtration and concentration of the filtrate are carried out.
Was. The residue was subjected to silica gel column chromatography (Wako
-Gel C-300, chloroform-methanol (98:
Purification was performed under 2)) to obtain 350 mg of the title compound. (3) 340 mg of the compound of (2)
The reaction was carried out in accordance with (2) of Example 118,
252 mg were obtained. (4) Using 252 mg of the compound of (3)
A mixture of diastereomers 8 according to Example 610.
6 mg were obtained. This is the same as in Example 549.
Separation was performed according to the method, and 20 mg of the title compound and dia
17 mg of the compound of Example 648 which is a stereomer was obtained.
Was. mass: 381 (M + 1)⁺. [0001]Example 648 The compound of Example 648 was the same as the compound of Example 647.
Was obtained. mass: 381 (M + 1)⁺. [0001]Example 649 (1) Ethyl glycolate and benzyl bromide
And the purpose according to (1) and (2) of Example 548.
Was synthesized. (2) 1.31 mg of the compound of (1), water
271 mg of sodium iodide, 421 μl of methyl iodide
And 30 ml of dimethylformamide at 0 ° C for 60
Minutes. After the reaction, usual post-treatment is performed, and the obtained residue
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 target compound was prepared according to (2) of Example 118.
Obtained. (4) Example 5 using the compound of (3)
48 (5), followed by the purpose according to Example 84 (1)
176 mg of the product were obtained. (5) 30 mg of the compound of (4) and 2-
Using aminoindan 100 mg,
31 mg of the title compound according to (2)
11 mg of the compound and 12 mg of the compound of Example 651
Obtained.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 650 The compound of Example 650 is a by-product of the compound of Example 649.
Obtained as a product. mass: 386 (M + 1)⁺. [0001]Example 651 The compound of Example 651 is a by-product of the compound of Example 649.
Obtained as a product. mass: 342 (M + 1)⁺. [0001]Examples 652-656 The compound of Example 652 to Example 656 is a compound of Example 6
49.Example 652 mass: 487 (M + 1)⁺. [0001]Example 653 mass: 475 (M + 1)⁺. [0001]Example 654 mass: 535, 537 (M + 1)⁺. [0001]Example 655 mass: 491 (M + 1)⁺. [0001]Example 656 mass: 491 (M + 1)⁺. [0001]Examples 657-687 The compound of Example 657 to Example 687 is a compound of Example 5
It was manufactured according to 49 (2). [0000]Example 657 mass: 383 (M + 1)⁺. [0001]Example 658 mass: 409 (M + 1)⁺. [0001]Example 659 mass: 417 (M + 1)⁺. [0001]Example 660 mass: 369 (M + 1)⁺. [0001]Example 661 mass: 369 (M + 1)⁺. [0001]Example 662 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 663 mass: 355 (M + 1)⁺. [0001]Example 664 mass: 395 (M + 1)⁺. [0001]Example 665 mass: 381 (M + 1)⁺. [0001]Example 666 mass: 341 (M + 1)⁺. [0001]Example 667 mass: 324 (M + 1)⁺. [0001]Example 668 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 669 mass: 383 (M + 1)⁺. [0001]Example 670 mass: 397 (M + 1)⁺. [0001]Example 671 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 672 mass: 425 (M + 1)⁺. [0001]Example 673 mass: 439 (M + 1)⁺. [0001]Example 674 mass: 411 (M + 1)⁺. [0001]Example 675 mass: 397 (M + 1)⁺. [0001]Example 676 mass: 411 (M + 1)⁺. [0001]Example 677 mass: 445 (M + 1)⁺. [0001]Example 678 mass: 445 (M + 1)⁺. [0001]Example 679 mass: 445 (M + 1)⁺. [0001]Example 680 mass: 481 (M + 1)⁺. [0001]Example 681 mass: 481 (M + 1)⁺. [0001]Example 682 mass: 437 (M + 1)⁺. [0001]Example 683 mass: 468 (M + 1)⁺. [0001]Example 684 mass: 489 (M + 1)⁺. [0001]Example 685 mass: 484 (M + 1)⁺. [0001]Example 686 mass: 459 (M + 1)⁺. [0001]Example 687 mass: 399 (M + 1)⁺. [0001]Example 688 (1) 1.93 g of 2-aminoindane hydrochloride, bromine
Add 5.0 ml and 30 ml of acetic acid and stir at 50 ° C for 3 days.
Stirred. The reaction mixture was concentrated, and the residue was concentrated in 50 ml of chloroform.
Was dissolved. Here (Boc)₂O4ml and triethyl
Add 15 ml of Luamine and stir until the ingredients disappear.
Was. The reaction solution was washed with 1N hydrochloric acid, and the organic layer was concentrated. Remaining
The residue is subjected to silica gel column chromatography (Wakogel)
C-200) to give 1.38 g of the desired product. (2) 1.38 g of the compound of (1)
553 mg of the desired product was prepared according to (3) of Example 599.
Obtained. (3) 14 g of the compound of (2), bromovinegar
5.85 ml of ethyl acid, 14.7 ml of triethylamine
And a mixture of 100 ml of toluene were stirred at room temperature overnight.
Was. The reaction solution was diluted with ether-ethyl acetate,
After washing with water and drying over magnesium sulfate, the mixture was filtered and the filtrate was concentrated.
Shrank. The residue was dissolved in 150 ml of chloroform, and (B
oc)₂Add 12.6 ml of O.R. until the ingredients disappear
With stirring. The reaction mixture is concentrated, and the residue is
Chromatography (Wakogel C-200, hexane
-Ethyl acetate) to give 11.68 g of the desired product. (4) Using 10.13 g of the compound of (3)
In accordance with (2) of Example 548, 1.95 g of the target product was obtained.
Obtained. (5) 3-hydroxy-2-butanone
And synthesized according to (1) to (3) of Example 533.
Example 118 using the amine and the compound of (4)
A urea body was obtained according to (2). (6) The compound of (5) is converted to
Removal of the Boc protecting group by treatment with xane afforded the title compound
Obtained. mass: 551, 553 (M + 1)⁺. [0001]Example 689-690 The compound of Example 689 and Example 690 is a compound of Example 68
8 was prepared.Example 689 ¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 690 mass: 551, 553 (M + 1)⁺. [0001]Examples 691-692 The compound of Example 691 and Example 692 is a compound of Example 69
It was manufactured according to 3.Example 691 mass: 548 (M + 1)⁺. [0001]Example 692 mass: 474 (M + 1)⁺. [0001]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)₂Using O and chloroform,
56 mg) (according to (1) of Example 409).
Thus, 61 mg of the desired product was obtained. (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-d₆) 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)⁺. [0001]Example 694-700 The compound of Example 694 to Example 700 is the compound of Example 6
93.Example 694 mass: 490 (M + 1)⁺. [0001]Example 695 mass: 514 (M + 1)⁺. [0001]Example 696 mass: 514 (M + 1)⁺. [0001]Example 697 mass: 560 (M + 1)⁺. [0001]Example 698 mass: 527 (M + 1)⁺. [0001]Example 699 mass: 536 (M + 1)⁺. [0001]Example 700 mass: 528 (M + 1)⁺. [0001]Example 701 Example 118 was prepared using 100 mg of the compound of Example 703.
69 mg of the title compound were obtained according to (4). mass: 298 (M + 1)⁺. [0001]Example 702 (1) 3-amino-4-ethoxycarbonylpyrazo
To obtain the desired product in the same manner as in Example 703. (2) 300 mg of the compound of (1)
The title compound was obtained according to (118) of Example 118. mass: 370 (M + 1)⁺. [0001]Example 703 (1) 3.00 g of 3-aminopyrazole, benzyl bromide
5.60 g, 1.72 g of sodium hydride and dimethyl
The mixture of 30 ml of formamide was stirred at room temperature for 3 hours.
Was. A saturated aqueous ammonium chloride solution was added to the reaction solution, and acetic acid was added.
Extracted with ethyl. After drying the organic layer with magnesium sulfate,
Filtration and the filtrate were concentrated. The residue is purified by silica gel column chromatography.
Chromatography (Wakogel C-200, hexane-acetic acid
Purification with ethyl (3: 1 to 1: 1) gave the desired product in 2.8.
7 g were obtained. (2) Using 2.89 g of the compound of (1)
The title compound 989m was prepared according to Example 118 (2).
g was obtained. mass: 388 (M + 1)⁺. [0001]Example 704 (1) 300 mg of the compound of (1) of Example 702
The solution of trahydrofuran (20 ml) was cooled to 0 ° C.
Add 30 mg of lithium aluminum iodide and stir for 30 minutes
Was. 1N Hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate.
The organic layer is washed with saturated saline and dried over magnesium sulfate.
Thereafter, the mixture was filtered and the filtrate was concentrated. Silica gel column residue
Chromatography (Wakogel C-200, hexane-
Purify with ethyl acetate (1: 1-1: 2) to give the title compound
248 mg were obtained. mass: 418 (M + 1)⁺. [0001]Example 705 Using 100 mg of 3-amino-1-methylpyrazole,
196 mg of the title compound was prepared according to (2) of Example 118.
Obtained. mass: 312 (M + 1)⁺. [0001]Example 706 (1) 280 mg of chloroform of the compound of Reference Example 3
(5ml) Blow chlorine gas into the solution and filter
Was. This is treated with aqueous sodium hydroxide and chloroform.
The organic layer was separated and concentrated. Residue
To TLC (Merck Art 5744, chloroform
-Methanol (10: 1))
84 mg of (A) and 66 mg of dichloro form (B) were obtained.
Was. (2) Using 42 mg of the compound of (1) -A
The title compound was obtained as white crystals according to Example 1. mass: 343 (M + 1)⁺. [0001]Example 707 (1) A solution of 2.02 g of the compound of Reference Example 3 in chloroform
The liquid was cooled to −20 ° C., and 1.16 ml of bromine was added,
Minutes. The reaction solution was returned to room temperature, and the precipitated solid was collected by filtration.
did. This is treated with aqueous sodium hydroxide and chloropho
Dissolved in a mixture of lum and the organic layer was separated and concentrated. Remaining
The residue is subjected to silica gel column chromatography (Wakogel)
C-200, chloroform-methanol (99: 1)
1.30 g of the monobromo compound (A) and dibro
1.14 g of a molybdenum (B) was obtained. (2) 1.03 g of the compound (1) -A
The title compound was obtained in the same manner as in Example 1 to give 1.24 g.¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 708 Example 1 was repeated using the compound of (1) -B in Example 707.
The title compound was obtained accordingly. mass: 467, 469 (M + 1)⁺. [0001]Example 709 Example 37 was carried out using 37 mg of the compound of (1) -B.
The title compound was obtained according to Example 1. mass: 378 (M + 1)⁺. [0001]Example 710 (1) 4-nitro-1,2-benzisothiazole-
3-one 1,1, -dioxide 100 mg and 2-p
According to Example 56, two kinds of
121 mg of a pale yellow solid was obtained as a mixture of compounds. (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)
g and the O-alkyl compound (B) 20 mg were obtained. (3) 6 mg of the compound of (2) -A
2 mg of the title compound as a white solid according to Example 1.
I got¹ H-NMR (CDCl₃) 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)⁺. [0001]Example 711 Using compound (75 mg) of (2) -B of Example 710,
According to Example 1, 93 mg of the title compound as a pale yellow solid was obtained.
Obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001]Example 712-713 The compound of Example 712 to Example 713 is a compound of Example 7
10 and according to Example 711.Example 712 mass: 387 (M + 1)⁺. [0001]Example 713 mass: 387 (M + 1)⁺. [0001]Example 714 55 mg of the compound of Example 711 was added to tetrahydrofuran
Dissolved in 4 ml and added with 17 mg of sodium borohydride.
And stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate 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 was purified by TLC (Merck Art 5744, chloropho
(80: 1)) to give the title compound
Was obtained as a white solid (5 mg).¹ H-NMR (DMSO-d₆) 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)⁺. [0001]Example 715 5 mg of the compound of Example 714 and 2-propanol 7
of the title compound,
3 mg of a colored solid were obtained.¹ H-NMR (CDCl₃) 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)⁺. [0001] [Reference example]Reference Example 1 10.0 g of 9-fluorenone-4-carboxylic acid (44.
6 mmol), 50 ml of thionyl chloride and
A mixture of 1 ml of lumamide was refluxed for 1 hour. Reaction solution
Concentration gave the desired acid chloride as a yellow solid. this
The next reaction was performed without purification. [0001] 4.06 g of sodium azide (62.5 m
mol) was dissolved in 50 ml of water and ice-cooled.
The acid chloride was suspended in 200 ml of tetrahydrofuran
Those were 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,
Dried with gnesium. The filtrate was concentrated and the precipitated crystals
Filtration gave 10.3 g of the desired compound.¹ H-NMR (CDCl₃) Δ: 7.29-7.43
(2H, m), 7.56 (1H, dt, J = 7.7H
z, 1.3 Hz), 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)⁺. [0001]Reference example 2 (1) 2 g of 2-chloro-3-nitrobenzoic acid (10.
0 mmol) and thionyl chloride (30 ml) at room temperature.
And 4-dimethylaminopyridine 122 mg (1.0
0 mmol) was added and the reaction was refluxed for 12 hours. reaction
The solution was concentrated to obtain a crude acid chloride product. Pyrrole
3.5 ml (50.0 mmol) and triethylamine
7.0 ml (50.0 mmol) of methylene chloride (80
ml) The above acid chloride was added to the solution at room temperature.
Was stirred at the same temperature for 6 hours. Dilute the reaction solution with ethyl acetate
After washing with saturated saline, drying with magnesium sulfate, and filtration,
Concentration gave a crude product. Silica gel column chromatography
Fee (hexane-ethyl acetate, 1: 0 to 7: 3)
Purification 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 tetra
Kistriphenylphosphine palladium 1.10 g
(0.960 mmol) at room temperature
Was stirred overnight. The reaction solution was treated with ethyl acetate-ether (1:
Dilute with 2), wash with water and saturated saline solution in that order,
After drying, the mixture was filtered and concentrated to obtain a crude product. Silica gel
Ram chromatography (hexane-chloroform,
1: 0 to 1: 1) to give 2.24 g of a brown solid compound.
I got¹ H-NMR (CDCl₃) Δ: 6.34 (1H, t,
J = 3.2 Hz), 7.10 (1H, dd, J = 3.3)
Hz, 0.85 Hz), 7.21 (1H, m), 7.3
5 (1H, dd, J = 8.3 Hz, 7.3 Hz), 7.
94 (1H, dd, J = 7.3 Hz, 1.0 Hz),
8.28 (1H, dd, J = 8.5Hz, 1.0H
z). [0001]Reference Example 3 2.24 g of the compound of Reference Example 2 in methanol-tetrahydride
10% palladium on charcoal in 80 ml of lofran (1: 1)
0.200 g of an elementary catalyst was added at room temperature, and the reaction solution was flushed with hydrogen gas.
The mixture was stirred at room temperature for 12 hours. Celite filtration of insolubles
And the filtrate was concentrated. The obtained residue is applied to a silica gel column.
Chromatography (chloroform-methanol, 1:
0 to 98: 2 to 95: 5) to give a brown solid compound
(Compound of Reference Example 3) (1.03 g) was obtained.¹ H-NMR (DMSO-d₆) Δ: 0.80-0.9
3 (1H, m), 2.10-2.30 (2H, m),
2.43-2.51 (1H, m), 3.18-3.24
(1H, 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). [0001]Reference example 4 (1) Under a nitrogen stream, ethanol (90 ml) was ice-cooled.
500 mg (22 mmol) of sodium
Then, the reaction solution was stirred at room temperature for 50 minutes. The reaction was cooled on ice,
4- [2-[[(1,1-dimethylethyl) diphenyl
Silyl] 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).
20 mmol) to make it acidic and then at the same temperature
50 ml of water was added to the reaction solution, and extracted with ethyl acetate. Yes
Layer is washed with water, 1N sodium hydroxide and saturated saline solution
Clean, dry magnesium sulfate, filter, concentrate and remove brown oil
Obtained. Silka gel column chromatography (hexane
-Ethyl acetate, 2: 1 to 1: 1) to give a yellow oil
42 g were obtained.¹ H-NMR (CDCl₃) Δ: 1.00 (9H,
s), 1.45 (3H, t, J = 7.0 Hz), 2.8
9 (2H, t, J = 6.3 Hz), 3.90 (2H,
t, J = 6.3 Hz), 4.49 (2H, q, J = 7.
0 Hz), 7.28 (1H, d, J = 4.9 Hz),
7.32-7.45 (6H, m), 7.55 (4H, d
d), 7.99 (1H, s), 8.62 (1H, d, J
= 5.6 Hz). [0001]Reference Example 5 (1) Meta of compound 13 g (32 mmol) of Reference Example 4
Hydrazine monohydrate 7.8 in ethanol (200 ml) solution.
ml (160 mmol) was added at room temperature, and the reaction solution was kept at the same temperature.
And stirred for 19 hours. Dilute the reaction solution with chloroform
And washed with saturated saline. The organic layer is magnesium sulfate
After drying, filtration and concentration of the filtrate yielded 14 g of a yellow oil. This
Was used for the next reaction without purification. (2) The chlorophobe of the compound obtained in (1)
The solution (100 ml) was cooled on ice 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.
Was. Chloroform was added to the reaction solution, and the organic layer was separated.
After drying with cesium, the filtrate was concentrated 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
2mmol) solution in tetrahydrofuran (200ml)
2.00 g (10.6 mmol) of the compound of Reference Example 3
At room temperature, the reaction was stirred at 95 ° C. for 2.5 hours.
The reaction mixture is concentrated, and the residue is purified by silica gel column chromatography.
Fee (hexane-ethyl acetate, 1: 1 to 1: 2)
Purification yielded 8.0 g of pale yellow crystals.¹ H-NMR (CDCl₃) 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), 3.4
5 (1H, t, J = 10 Hz), 3.78 (1H, d
t), 3.90 (2H, t, J = 6.3 Hz), 4.8
0 (1H, dd), 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 = 7.3 Hz), 12.0 (1H, s). [0001]Reference example 6 8.0 g (14 mmol) of the compound of Reference Example 5 was
Paraformaldehyde when dissolved in 50 ml
71.44 g (2.38 mol) and tert-butyl alcohol
250 ml (2.38 mol) of min was stirred at room temperature and adjusted.
50 ml of the prepared imine and 1 drop of concentrated sulfuric acid were added thereto.
Was stirred at 95 ° C. for 3 days. The reaction mixture is concentrated and the residue is
Kagel column chromatography (hexane-ethyl acetate
3: 1 to 1: 1 to 1: 2) to give a colorless powder
7.0 g were obtained.¹ H-NMR (CDCl₃) Δ: 0.98 (9H,
s), 0.98-1.02 (1H, m), 1.28 (9
H, s), 2.20-2.35 (3H, m), 2.80.
(2H, t, J = 6.0 Hz), 3.33-3.42
(1H, 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), 5.0
5-5.15 (1H, br), 5.43-5.52 (1
H, 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). [0001]Reference Example 7 2.00 g of the compound of Reference Example 6 was added to tetrahydrofuran (2
0 ml) and tetra-n-butylammonium fluoride
3.5M solution of uranium in tetrahydrofuran (1.0M)
l (3.50 mmol) was added at room temperature, and the reaction solution was heated at the same temperature.
And stirred for 1 hour. Water is added to the reaction solution and extracted with ethyl acetate.
Issued. Combine the organic layers and wash with saturated saline, then add sulfuric acid.
The magnesium was dried and filtered. Crystals precipitated by concentrating the filtrate
Was collected by filtration. Concentrate the filtrate and silica gel column chromatography.
Raffy (hexane-ethyl acetate, 1: 2-0: 1-
Purification was carried out with chloroform-methanol (50: 1). Destination
700 mg of the target compound was obtained in combination with the crystals collected by filtration.
Was.¹ H-NMR (CDCl₃) 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). [0001]Reference Example 8 (1) 190 mg of the compound of Reference Example 7 was chloroform 2m
146 mg of triphenylphosphine (0.5 mg
6 mmol), 0.12 ml of diphenylphosphate azide
(0.56 mmol) and diethyl azodicarboxy
Rate of a toluene solution (40%) of 0.24 ml (0.5%)
5 mmol) at room temperature, and the reaction solution is kept at the same temperature for 15 hours.
While stirring. Water was added to the reaction mixture, which was extracted with ethyl acetate.
Was. The organic layers are combined, washed with water and saturated saline, and
After drying with cesium, the mixture was filtered and concentrated. Residue thin layer chromatography
Raffy (chloroform-methanol, 19: 1)
To obtain 130 mg of a pale yellow amorphous. (2) 130 mg of the compound obtained in (1)
To 2 ml of methanol-tetrahydrofuran (1: 1)
Dissolve and add 130 mg of 10% palladium on carbon catalyst at room temperature
The reaction solution was stirred at the same temperature for 2 hours under a hydrogen stream. Unfortunate
The solution was filtered through celite and the filtrate was concentrated. Thin residue
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-d₆) 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). [0001]Reference Example 9 Dissolve 800 mg of the compound of Example 81 in 25 ml of pyridine.
Dissolve and at room temperature 0.263 ml of methanesulfonic acid chloride
(3.40 mmol), and the reaction solution was heated at the same temperature for 1 hour.
Stirred. The insolubles were filtered and the filtrate was concentrated. Dummy residue
Dissolve in tylformamide and add sodium azide at room temperature
295 mg (4.54 mmol) were added, and the reaction solution was
Stirred at 30 ° C for 30 minutes. Return the reaction solution to room temperature, add water, and add vinegar.
Extracted with ethyl acid. Wash the organic layer with saturated saline and add sulfuric acid.
After drying with magnesium, the mixture was concentrated by filtration. Silica gel residue
Column chromatography (hexane-ethyl acetate,
1: 2 to 0: 1) to give 265 mg of the desired product.¹ H-NMR (CDCl₃) Δ: 1.23-1.37
(1H, m), 2.33-2.51 (2H, m), 2.
57-2.67 (1H, m), 2.90 (2H, t, J
= 6.4 Hz), 3.46 (1H, dt, J = 10H)
z, 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). [0001]Reference example 10 (1) p-nitrobenzenesulfonyl chloride 5.00
g (22.6 mmol) in chloroform (50 ml)
To the place where the liquid was cooled with ice, 4.72 ml of triethylamine was added.
(33.8 mmol) and 2,4-dimethoxybenzyl
5.05 g (30.1 mmol) of
The solution was stirred at room temperature for 1 hour. Water is added to the reaction solution and ethyl acetate is added.
Extracted. Combine the organic layers and add 1N hydrochloric acid, saturated sodium bicarbonate
Wash sequentially with water and saturated saline, dry magnesium sulfate, and filter.
And the filtrate was concentrated. It can be used in the next step without purification.
The reaction was performed. (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 diethyl azodicarboxylate
1.26 ml (2.89 mmol) of an ene solution (40%)
Was added at room temperature, and the reaction solution was stirred at the same temperature for 15 hours.
The reaction mixture is concentrated, and the residue is purified by silica gel column chromatography.
Clean with hexane (hexane-ethyl acetate, 1: 2-1: 4)
Thus, 1.54 g of a yellow amorphous product was obtained.¹ H-NMR (CDCl₃) Δ: 1.20-1.40
(1H, m), 1.30 (9H, s), 2.20-2.
43 (3H, m), 2.74 (2H, t, J = 7.6H
z), 3.33-3.45 (3H, m), 3.61 (3
H, s), 3.67-3.73 (1H, m), 3.73.
(3H, s), 4.36 (2H, s), 4.66 (1
H, 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, d
d, J = 8.0 Hz, 4.0), 6.73 (1H, d,
J = 4.0 Hz), 7.16 (1H, d, J = 8.0H)
z), 7.43-7.57 (3H, m), 7.67 (2
H, t), 7.77 (1H, d, J = 8.0 Hz),
7.80 (2H, d, J = 8.0 Hz), 8.19−
8.22 (3H, m). [0001]Reference Example 11 750 mg of the compound of Reference Example 10 was added to dimethylformamide
Dissolve in 7.5 ml and add 290 m of sodium carbonate at room temperature.
g (2.74 mmol) and thiophenol 0.120 m
1 (1.17 mmol) was added to the reaction solution,
Was stirred at room temperature for 4 days. Filter the insolubles and concentrate the filtrate
Was. The residue is purified by silica gel column chromatography (chromatography).
Roform-methanol, 50: 1 to 9: 1 to 4: 1)
The residue was purified to give 350 mg of a pale yellow amorphous product.¹ H-NMR (CDCl₃) 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). [0001] According to the present invention, the compound of the present invention is
It has a significant growth inhibitory effect on cells,
New Cdk4 inhibitor for the treatment of malignant tumors
can do.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 277/58 C07D 277/58 277/593 417/12 417/12 453/02 453/02 487/04 137 487/04 137 498/04 103 498/04 103 116 498/08 116 116 498/10 A 498/08 519/00 301 498/10 A61K 31/415 519/00 301 31/4155 // A61K 31/415 31 / 426 31/4155 31/437 31/426 31/439 31/437 31/4402 31/439 31/4436 31/4402 31/4439 31/4436 31/444 31/4439 31/4965 31/444 31/513 31 / 4965 31/5365 31/513 31/55 31/5365 31/553 31/55 A61P 35/00 31/553 43/00 111 A61P 35/00 C07D 498/04 112Q 43/00 111 277/46 (72) Inventor Ikuko Takahashi 3 Okubo, Tsukuba, Ibaraki Pref.

Claims (9)

[Claims] 1. A compound of the general formula (I) [Wherein Ar 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, 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 represents a hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may have 1 to 3 substituents or 1 to 3 substituents as appropriate.
Individual, and A cyclo-lower alkyl group, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, 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
( _Rq ) COO, N ( _Rq ) CSO, N ( _Rq ) CO
S, 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 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, 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, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino And a substituent selected from the group consisting of a lower alkoxyimino group or 1 to 3
Represents a lower alkyl group, an aryl group or an aralkyl group which may be present), Y ₁ and Y ₂ are the same or different and are each a single bond or one bicyclic or tricyclic fused ring A straight-chain or branched lower alkylene group which may be present), and optionally 1 to 3 identical or different substituents A nitrogen-containing heteroaromatic group which may have: (2) a lower alkyl 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 , Lower alkylcarbamoyl group, a 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 substituent selected from the group consisting of tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group and lower alkanoylamidino lower alkyl group ( (Hereinafter abbreviated as a substituent on the ring)), together with the carbon atom on the ring to which it is bonded, the adjacent carbon atom, and the carbon atom, oxygen atom and / or nitrogen atom on the substituent on the ring. 1) Or a nitrogen-containing heteroaromatic group forming a 5- to 7-membered ring selected from the group consisting of: or (3) Formula: Y ₁ -W ₁ -Y _2-
A carbon atom on a ring to which a substituent represented by R _p (wherein Y ₁ , W ₁ , Y ₂ and R _p have the above-mentioned meanings),
A carbon atom on the adjacent carbon atom and the substituent,
Together with an oxygen atom and / or a nitrogen atom, 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 is bonded 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
Hydrogen atom or the _{formula: Y 3 -W 2 -Y 4 -R} s ( in the formula,
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 the substituents as appropriate.
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, dihydroisoindolyl, dihydroindolyl, thionaphthenyl, naphthyridinyl, phenazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl , Thienyl group, pyrrolyl group,
A furyl group, a furazanyl group, a triazolyl group, an aromatic heterocyclic group or isoxazolinyl group selected from the group consisting of a benzodioxanyl group and a methylenedioxyphenyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, An aliphatic heterocyclic group selected from the group consisting of a tetrahydrofuranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₂ is a single bond , Oxygen atom, 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 ) CON
R _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 a 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 , 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 lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a substituent selected from the group consisting of 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 ₃ and Y ₄ are the same or different and each represents a single bond or a linear or branched lower alkylene group), 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,
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, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group,
Di-lower alkylcarbamoyl, carbamoyloxy, lower-alkylcarbamoyloxy, di-lower-alkylcarbamoyloxy, amino, lower-alkylamino, di-lower-alkylamino, tri-lower-alkylammonio, amino-lower-alkyl, 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 alkyl A substituent selected from the group consisting of a sulfonylamino group, a hydroxyimino group and a lower alkoxyimino group;
A substituent selected from the group consisting of substituents represented by Y ₃ -W ₂ -Y ₄ -R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meaning). Te, or an appropriate one to three identical or different substituents which may have a lower alkyl group, or a nitrogen atom to form together with X, 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:
A substituent represented by Y ₃ —W ₂ —Y ₄ —R _s (wherein, R _s , W ₂ , Y ₃ and Y ₄ have the above-mentioned meanings), 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 substituent on the ring 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 atoms 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 have the above-mentioned meanings) and are each a substituent selected from the group consisting of the substituents represented by the following formulas: 1 to 3 identical or different substituents, and optionally 1 to 3 Cyclo lower alkyl, aryl, imidazolyl, isoxazolyl, isoquinolyl, isoindolyl, indazolyl, indolyl, indolidyl, indolizinyl, isothiazolyl, ethylenedioxyphenyl, oxazolyl which may have the same or different substituents Group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group,
Phenazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl And an aromatic heterocyclic group selected from the group consisting of methylenedioxyphenyl group and isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group,
It consists of an aliphatic heterocyclic group selected from the group consisting of a tetrahydrofuranyl group, 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. Which may be condensed with a ring selected from the group: And Forming a saturated or unsaturated 5- or 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 compound represented by the formula: Y ₃ -W ₂ -Y ₄ -R _s (in the _formula, R _{s, W 2,}
Y ₃ and Y ₄ have the same meanings as described above) or 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, and 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 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 in 2 _-Y 4 -R _{s (wherein, R s, W 2, Y} 3
And Y ₄ have the meanings described above, and are each a substituent selected from the group consisting of
Represents a lower alkyl group, an aryl group or an aralkyl group which may have the same or different substituents, and has the formula Represents a single bond or a double bond], or a salt thereof. 2. A compound of the general formula (Ia) [Wherein, Ar _a is a nitrogen-containing heteroaromatic group selected from the group consisting of a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, a pyrazolyl group, and an imidazolyl group; Alkyl group, hydroxyl group, 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 alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group, lower alkylcarbamoyl group, lower alkylcarbamoyloxy group, amino group, lower alkylamino group, dilower alkylamino group, amino lower alkyl group,
A substituent selected from the group consisting of 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 formula: Y _1a -W _1a
-Y _2a -R _pa (wherein R _pa is a hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may have 1 to 3 substituents as appropriate, 1 to 3 and further A cyclo-lower alkyl group, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, indolyl group, ethylene which may have a bicyclic or tricyclic fused ring containing a partial structure selected from the group consisting of Aromatic heterocyclic group selected from the group consisting of dioxyphenyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinolyl group, benzimidazolyl group, thiazolyl group, thienyl group and triazolyl group or isoxazolinyl group, isoxazolin Jiniru group, tetrahydropyridyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, an aliphatic heterocyclic group selected from a morpholino group, and the group consisting of tetrahydroisoquinolinyl group, W _1a Is
Oxygen atom, sulfur atom, NR _qa , SO ₂ NR _qa , N
_{(R qa) SO 2, CONR} qa, N (R qa) CO,
N ( _Rqa ) COO, C ( _Rqa ) = _CRra , OC
(O), OC (O) NR _qa or C (O) O (where R _qa and R _ra represent a hydrogen atom or a lower alkyl group, a cyclo-lower alkyl group, a hydroxyl group, a halogen atom, a formyl group, a lower alkanoyloxy Group, hydroxy-lower alkyl group, halo-lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl 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 and lower alkylsulfo It 1 optionally a substituent or the substituent is selected from the group consisting of arylamino group which may have three, a lower alkyl group, an aryl group or an aralkyl group), Y _1a and Y _2a are the same or Differently, represents a linear or branched lower alkylene group which may have one single bond or one of the bicyclic or tricyclic condensed rings). A nitrogen-containing heteroaromatic group, which is a substituent selected and may have 1 to 3 identical or different substituents,
(2 ′) 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 alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group,
Lower alkylcarbamoyl 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,
A carbon atom on a ring to which a substituent selected from the group consisting of a lower alkanoylamino group and an aroylamino group is bonded;
Together with their adjacent carbon atoms and the carbon, oxygen and / or nitrogen atoms on the substituents on the ring, Or a nitrogen-containing heteroaromatic group forming a 5- or 6-membered ring selected from the group consisting of: or a formula (3 ′): Y _1a -W _1a −
Y _2a -R _pa (wherein, Y _1a , W _1a , Y _2a and R
_pa has the above-mentioned meaning) together with the carbon atom on the ring to which the substituent represented by the bond is attached, its adjacent carbon atom, and the carbon atom, oxygen atom and / or nitrogen atom on the substituent, Embedded image Nitrogen-containing to form a 5- to 6-membered ring selected from the group consisting of heteroaromatic ring group, X _a and Z _a are the same or different, and represent a carbon atom or a nitrogen atom, as appropriate, to bond, R _1a or together with _{R 2a} and / or _{R 3a,} CH or nitrogen atom, _{Y a} is, CO, SO or SO
₂ , R _1a is a hydrogen atom or a formula: Y _3a —W _2a —
Y _4a -R _sa (wherein, R _sa is a lower alkyl group, a lower alkenyl group, a cyclo-lower alkyl group, an aryl group, and an indolyl group which may have 1 to 3 hydrogen atoms or the substituents as appropriate. An aromatic heterocyclic group selected from the group consisting of or an aromatic heterocyclic group selected from the group consisting of a tetrahydropyridyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, and a morpholino group;
_2a is a single bond, NR _ta , CH (OR _ta ), CON
_Rta , N ( _Rta ) CO, N ( _Rta ) COO, OC
(O) NR _ta or C (O) O (where R _ta
Represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group optionally having 1 to 3 substituents), Y _3a and Y _4a are the same or different and are a single bond or A chain or branched lower alkylene group or lower alkyl group, hydroxyl group, carbamoyl group, lower alkanoyloxy group, hydroxy 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, lower alkylamino group, di-lower alkylamino group, amino-lower alkyl group,
A substituent selected from the group consisting of a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group and an aroylamino group; and 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), and may have 1 to 3 identical or different substituents as appropriate. R _2a and R _3a are the same or different and are independently a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a group represented by the formula: Y _3a -W _2a -Y _4a -R
_sa , wherein R _sa , W _2a , Y _3a and Y _4a have the same meaning as described above, or R _2a
And either one of R _3a and R _3a together with R _1a and Xa form: 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 substituent on the ring 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 with _a bonding Z _a , R _1a and Xa Atom, an oxygen atom and a sulfur atom, which may include one or more hetero atoms selected from the group consisting of a lower alkyl group, a spirocyclo lower alkyl group which may have a substituent, a hydroxyl group, and a hydroxy lower group. Alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino lower alkyl group Lower alkylcarbamoyl group, lower alkylcarbamoyl group, a lower alkylamino group,
A substituent selected from the group consisting of 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;
Y _1a -W _1a -Y _2a -R _pa (where R _pa , W
_1a , Y _1a and Y _2a have the same meaning as described above), and are 1 to 3 identical or different substituents, and 1 to 3 Or from 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 three or the same or different substituents, and a group consisting of a piperidinyl group and a pyrrolidinyl group. Which may be condensed with a ring selected from the group consisting of selected aliphatic heterocyclic groups. And Forming a saturated or unsaturated 5- to 8-membered ring group selected from the group consisting of: R _4a and R _5a 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 _3a -W _2a -Y _4a -R _sa (wherein,
R _sa , W _2a , Y _3a and Y _4a have the above-mentioned meanings) or a lower alkyl group, a hydroxy lower alkyl group, a halo lower alkyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl Group, lower alkylcarbamoyl group, lower alkylamino group, lower alkylamino lower alkyl group,
Substituents and wherein is selected from the group consisting of lower alkanoylamino group and aroylamino group: Y _3a -W _2a -
Y _4a -R _sa (wherein, R _sa , W _2a , Y _3a and Y
_4a is a substituent selected from the group consisting of the substituents represented by the above-mentioned), and may be a lower alkyl group or an aryl, which may have 1 to 3 identical or different substituents as appropriate. A group or an aralkyl group, having the formula Represents a single bond or a double bond], or a salt thereof. 3. A compound of the formula (Ib) Wherein Ar _b is a nitrogen-containing heteroaromatic group selected from the group consisting of a pyridyl group and a pyrazolyl group,
(1 ″) a substituent selected from the group consisting of 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 lower alkylamino lower alkyl group; Y _1b -W _1b -Y _2b -R _pb (wherein, R _pb represents a hydrogen atom or the substituent as appropriate, from 1 to 3
A lower alkyl group, a lower alkenyl group, a lower alkynyl group or a substituent
Or three, and 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 are a hydrogen atom or a hydroxyl group, a halogen atom, a cyclo-lower alkyl group, a lower alkanoyloxy group, a hydroxy-lower alkyl group A substituent selected from the group consisting of a lower alkoxy group, a lower alkoxycarbonyl group, an amino group and a lower alkylamino lower alkyl group, or a lower alkyl group, aryl optionally having 1 to 3 substituents; Y _1b and Y _2b are the same or different, and may have a single bond or one of the bicyclic or tricyclic condensed rings, and may be linear or branched. Selected from the group consisting of the substituents represented by the following formulas: 1 to 3 identical or different substituents. Which may be nitrogen-containing heteroaromatic ring group,
(2 ″) a carbon atom on a ring to which a substituent selected from the group consisting of a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group and a lower alkylamino lower alkyl group is bonded, and adjacent thereto Together with a carbon atom, an oxygen atom and / or a nitrogen atom on the ring substituent, Or a nitrogen-containing heteroaromatic group forming a 5- or 6-membered ring selected from the group consisting of: or (3 ″) formula: Y _1b -W _1b
—Y _2b —R _pb (wherein Y _1b , W _1b , Y _2b and R _pb have the above-mentioned meaning), a carbon atom on a ring to which a substituent is bonded, a carbon atom adjacent thereto, Together with the carbon, oxygen and / or nitrogen atoms on the substituents: Selected from the group consisting of the 5-membered to nitrogen-containing heteroaromatic ring group forming a 6-membered ring, X _b and Z _b are the same or different, and represent a carbon atom or a nitrogen atom, as appropriate, to bond, R _1b or R _2b and / or R _3a together, CH or a nitrogen atom, Y _b is CO, SO or SO
₂ , R _1b is a hydrogen atom or a formula: Y _3b -W _2b-
Y _4b -R _sb (wherein, R _sb is a lower alkyl group, a cyclo-lower alkyl group and an aryl group which may have 1 to 3 hydrogen atoms or the substituents as appropriate, W _2b is
A single bond, N (R _tb ) COO or C (O) O (where R _tb is a hydrogen atom,
A lower alkyl group, an aryl group or an aralkyl group which may be present), Y _3b and Y _4b are the same or different and represent a single bond or a linear or branched lower alkylene group) Or a hydroxy lower alkyl group represented by the formula: and Y _3b -W _2b -Y _4b -R _sb
(Wherein, R _sb , W _2b , Y _3b and Y _4b have the above-mentioned meanings), and are suitably 1 to 3 identical or different substituents A lower alkyl group which may have a substituent,
Or, forming a nitrogen atom together with X, R _2b and R
_3b is the same or different and independently represents 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 any one of R _2b and R _3b is formed together with R _1b and _Xb ; Formula 2 And A saturated 5- or 7-membered ring group selected from the group consisting of: a carbon atom or nitrogen atom on the ring, the carbon atom or the oxygen atom contained in the ring substituent on the ring; And / or a 5- to 7-membered ring with a nitrogen atom, or together with a spirocyclo lower alkyl group, an oxo group with a linking Z, or with a linking Z _b , R _1b and X _b It may contain one or more hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, lower alkyl group, spirocyclo lower alkyl group which may have a substituent, hydroxy lower alkyl And a substituent selected from the group consisting of a lower alkoxycarbonyl group and a formula:
Y _1b -W _1b -Y _2b -R _pb (where R _pb , W
_1b , Y _1b and Y _2b have the meanings described above), and are 1 to 3 identical or different substituents as appropriate; And condensed with a ring selected from the group consisting of an aliphatic heterocyclic group selected from the group consisting of a cyclo lower alkyl group, an aryl group, and a piperidinyl group and a pyrrolidinyl group which may have three or the same or different substituents May be used. And Forming a saturated or unsaturated 5- to 7-membered ring group selected from the group consisting of: R _4b and R _5b are the same or different and are a hydrogen atom, a halogen atom or a formula: Y _3b
-W _2b -Y _4b -R _sb (where R _sb , W _2b , Y
_3b and Y _4b have the above-mentioned meanings) or a lower alkyl group, a hydroxy lower alkyl group, a halo lower alkyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group,
Lower alkylcarbamoyl group, lower alkylamino group,
A substituent selected from the group consisting of lower alkylamino, lower alkyl, lower alkanoylamino and aroylamino, and the formula: Y _3b -W _2b -Y _4b -R
_sb (wherein, R _sb , W _2b , Y _3b and Y _4b have the above-mentioned meanings), and is suitably 1 to 3 identical or different substituents Represents a lower alkyl group, an aryl group or an aralkyl group which may have a substituent; Represents a single bond or a double bond], or the salt thereof. 4. A compound of the general formula (Ip) [In the formula, Ar _p is a nitrogen-containing heteroaromatic group which may have a substituent, X _p is a carbon atom (CH) or a nitrogen atom, R _1p is a hydrogen atom or has a substituent as appropriate. 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 be bonded) or a nitrogen atom and a sulfur atom together with the carbon atom to be bonded, R _1p and X _p A saturated or unsaturated 5- or 6-membered heteroatom, which may contain one or more heteroatoms selected from the group consisting of
R _4p and R _5p are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a lower alkyl group, an aryl group or an aralkyl group which may have a substituent. Is shown].
Or a salt thereof. 5. N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (5- (2-octylaminomethyl) pyrazol-3-yl) urea;
N '-(pyrrolidino [2,1-b] isoindoline-4
-On-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) pyrazole-
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- (5- (6-methylpyridin-2-yl) pyrazol-3-yl) urea, N '-(pyrrolidino [2,1
-B] isoindoline-4-one-8-yl) -N-
(5- (pyrrolidin-2-yl) pyrazol-3-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (5- (t- Butylaminomethyl) pyrazol-3-yl) urea;
N '-(pyrrolidino [2,1-b] isoindoline-4
-On-8-yl) -N- (5- (pyrazolo [5,4-
b] pyridin-3-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl)
-N- (5- (1-hydroxymethylcyclopentylaminomethyl) pyrazol-3-yl) urea, N'-
(Pyrrolidino [2,1-b] -4-oxoisoindoline-8-yl) -N- (5- (Nt-butyl-N-methyl-aminomethyl) pyrazol-3-yl) urea;
N '-(pyrrolidino [2,1-b] isoindoline-4
-On-8-yl) -N- (4- (N-benzyl-1,
2,5,6-tetrahydropyridin-4-yl) pyridin-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- (4- (N- Benzyl-1,2,5,6-tetrahydropyridine-3-
Yl) pyridin-2-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- (N-benzyl-3-piperidyl) pyridine- 2-yl) urea, N ′-(pyrrolidino [2,
1-b] -4-oxoisoindoline-8-yl) -N
-(4- (1,2,5,6-tetrahydropyridine-3
-Yl) pyridin-2-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (4- (N-acetyl-3-piperidyl) pyridine -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- (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-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) pyridine-2
-Yl) urea, N '-(N-cyclopentyl-3-methylisoindoline-1-one-4-yl) -N- (pyridin-2-yl) urea, N'-(3-t-butylisoindo Rino [3,2-b] oxazolidin-4-one-8-yl) -N- (4- (N-benzylpyrrolidin-
3-yl) pyridin-2-yl) urea, N '-(2-
Methyl isoindolino [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-6,11a-benzoxazin-11-one-7-yl) N- (pyridine-2
The compound according to claim 1, which is -yl) urea. 6. N '-(pyrrolidino [2,1-b] isoindoline-4-one-8-yl) -N- (5- (2-octylaminomethyl) pyrazol-3-yl) urea;
N '-(pyrrolidino [2,1-b] isoindoline-4
-On-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) pyrazole-
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-1,2,5,6-tetrahydropyridin-4-yl) pyridin-2-yl) urea, N '-(pyrrolidino [2,1-b] isoindoline-4 -On-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) pyridine-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-6,11a-benzoxazine-
The compound according to claim 1, which is 11-one-7-yl) N- (pyridin-2-yl) urea. 7. A compound of the general formula (III) Wherein, X and Z are the same or different, and represent a carbon atom or a nitrogen atom, as appropriate, bind, R ₁₀ or R
Together with ₂₀ and / or _{R 30,} CH or nitrogen atom, Y is CO, SO or _{SO 2, R 10} is a hydrogen atom or a _{formula: Y 30 -W 20 -Y 40 -R} s0 ( wherein , R _s0 represents a hydrogen atom or the substituent as appropriate, from 1 to 3
Lower alkyl group, lower alkenyl group, lower alkynyl group, cyclo lower alkyl group, 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, benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group,
A furyl group, a furazanyl group, a triazolyl group, an aromatic heterocyclic group or isoxazolinyl group selected from the group consisting of a benzodioxanyl group and a methylenedioxyphenyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, An aliphatic heterocyclic group selected from the group consisting of a tetrahydrofuranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, W ₂₀ is a single bond , Oxygen atom, sulfur atom, SO, SO ₂ , NR _t0 , SO ₂ NR _t0 , N
(R _t0 ) SO ₂ NR _u0 , N (R _t0 ) SO ₂ , CH
(OR _t0 ), CONR _t0 , N (R _t0 ) CO, N
(R _t0 ) CONR _u0 , N (R _t0 ) COO, N (R
_t0 ) CSO, N ( _Rt0 ) COS, C ( _Rv0 ) = C
R _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 _t0
And R _u0 are a hydrogen atom or a lower alkyl group, an _optionally protected hydroxyl group, a cyano group, a halogen atom, a nitro group, an optionally protected carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyl An oxy group, an optionally protected 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,
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, protected May be an 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, Tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkyl A substituent selected from the group consisting of a sulfonylamino group, an optionally protected hydroxyimino group and a lower alkoxyimino group, or a lower alkyl group or an aryl group optionally having 1 to 3 substituents; Or an aralkyl group), Y ₃₀ and Y
₄₀ is the same or different and represents a single bond or a linear or branched lower alkylene group);
Or lower alkyl group, optionally protected hydroxyl group, cyano group, halogen atom, nitro group, optionally protected carboxyl group, carbamoyl group, formyl group, lower alkanoyl group, lower alkanoyloxy group, protected 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 , 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 alkanoyl Amino group, aroylamino group, lower alkanoylamidino lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, optionally protected hydro Substituents and wherein is selected from the group consisting of Shiimino group and a lower alkoxyimino group: Y ₃₀
-W ₂₀ -Y ₄₀ -R _s0 (where R _s0 , W ₂₀ , Y
₃₀ and Y ₄₀ have the meanings described above), and are each a substituent selected from the group consisting of
Or 3 lower alkyl groups which may have the same or different substituents, or form a nitrogen atom with X, and R ₂₀ and R ₃₀ are the same or different and are each independently a hydrogen atom, hydroxyl group which may be protected, a lower alkyl group, a lower alkoxy group or the _formula: Y 30 _{-W 20} -
Y ₄₀ −R _s0 (wherein, R _s0 , W ₂₀ , Y ₃₀ and Y
₄₀ has the meaning described above), or one of R ₂₀ and R ₃₀ is formed together with R ₁₀ 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 substituent on the ring 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 ₁₀ and X A heteroatom selected from the group consisting of
Species or more may be included, a lower alkyl group,
Spirocyclo lower alkyl group which may have a substituent, a hydroxy group which may be protected, a cyano group, a halogen atom, a nitro group, a carboxyl group which may be protected, a carbamoyl group, a formyl group, a 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, protection Or unprotected amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, a protected or unprotected 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, protected A substituent selected from the group consisting of an optionally substituted hydroxyimino group and a lower alkoxyimino group; and a formula: 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, which may have 1 to 3 hydrogen atoms or 1 to 3 substituents as appropriate, or 1 to 3 substituents as appropriate; A cyclo-lower alkyl group, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, 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,
O, SO _2, NR _q0 , SO ₂ NR _q0 , N (R _q0 )
SO ₂ NR _r0 , N (R _q0 ) SO ₂ , CH (O
R _q0 ), CONR _q0 , N (R _q0 ) CO, N (R
_q0 ) CONR _r0 , N ( _Rq0 ) COO, N
( _Rq0 ) CSO, N ( _Rq0 ) COS, C ( _Rq0 )
= 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,
Cyano group, 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, di-lower group Alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, optionally protected amino group, lower alkylamino group, di-lower alkylamino group, tri-lower Rukylammonio group, optionally protected amino lower alkyl group, lower alkylamino lower alkyl group, dilower alkylamino lower alkyl group, trilower 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, an optionally protected hydroxyimino group and a lower alkoxyimino group, or 1 to 3 And a lower alkyl group, an aryl group or an aralkyl group which may have three), Y ₁₀ and Y ₂₀ are the same or different and are each a single bond or one of the bicyclic or tricyclic fused rings. Linear or branched, which may have A lower alkylene group), the substituent is selected from the group consisting of 1 to 3 identical or different substituents, and 1 to 3 identical or different substituents as appropriate. Cyclo-lower alkyl group, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedioxyphenyl group, oxazolyl group, pyridyl which may have a group 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, Aromatic heterocyclic group selected from the group consisting of thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group, furyl group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, and isoxazolinyl group, isoxa Zolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl May be combined ring condensed selected from the group consisting of aliphatic heterocyclic group selected from the group consisting of Le group, and tetrahydroisoquinolinyl group, ## STR2 ## And Forming a saturated or unsaturated 5- to 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 amino group or a formula: Y ₃₀ -W ₂₀ -Y ₄₀ -R _s0 (wherein, R _s0 ,
W ₂₀ , Y ₃₀ and Y ₄₀ have the above-mentioned meanings) 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, an optionally protected hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, an 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, 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 , A di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a 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, an optionally protected hydroxyimino group and a lower alkoxyimino group, and a formula: 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 are a lower alkyl group optionally having 1 to 3 identical or different substituents. Represents an aryl group or an aralkyl group,
Formula 1 Represents a single bond or a double bond];
General formula (IV) Wherein Ar ₀ 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, 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, 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 (where R _p0 , W ₁₀ , Y ₁₀ and Y
₂₀ is a substituent selected from the group consisting of the substituents represented by the above-mentioned meanings, and the nitrogen-containing heteroaromatic ring optionally having 1 to 3 identical or different substituents. A group, (2) a lower alkyl group, a lower alkanoyl group, a lower alkanoyloxy group, an optionally protected hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, an 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. And A nitrogen-containing heteroaromatic group forming a 5- or 7-membered ring which may be protected, selected from the group consisting of: or (3)
_{Wherein: Y 10 -W 10 -Y 20 -R} p0 ( _{wherein, Y 10,}
W ₁₀ , Y ₂₀ and R _p0 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, 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 general formulas (II): [Wherein, Ar ₀ , X, Y, Z, R ₁₀ , R ₂₀ ,
R ₃₀ , R ₄₀ , R ₅₀ and the formula Has the same meaning as described above], and the protecting group is removed as appropriate. [Wherein Ar 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, 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 represents a hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may have 1 to 3 substituents or 1 to 3 substituents as appropriate.
Individual, and A cyclo-lower alkyl group, aryl group, imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, 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
( _Rq ) COO, N ( _Rq ) CSO, N ( _Rq ) CO
S, 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 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, 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, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino And a substituent selected from the group consisting of a lower alkoxyimino group or 1 to 3
Represents a lower alkyl group, an aryl group or an aralkyl group which may be present), Y ₁ and Y ₂ are the same or different and are each a single bond or one bicyclic or tricyclic fused ring A straight-chain or branched lower alkylene group which may be present), and optionally 1 to 3 identical or different substituents A nitrogen-containing heteroaromatic group which may have: (2) a lower alkyl 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 , Lower alkylcarbamoyl group, a 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 substituent selected from the group consisting of tri-lower alkylammonio lower alkyl group, lower alkanoylamino group, aroylamino group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group and lower alkanoylamidino lower alkyl group ( (Hereinafter abbreviated as a substituent on the ring)), together with the carbon atom on the ring to which it is bonded, the adjacent carbon atom, and the carbon atom, oxygen atom and / or nitrogen atom on the substituent on the ring. 1) Or a nitrogen-containing heteroaromatic group forming a 5- to 7-membered ring selected from the group consisting of: or (3) Formula: Y ₁ -W ₁ -Y _2-
A carbon atom on a ring to which a substituent represented by R _p (wherein Y ₁ , W ₁ , Y ₂ and R _p have the above-mentioned meanings),
A carbon atom on the adjacent carbon atom and the substituent,
Together with an oxygen atom and / or a nitrogen atom, A nitrogen-containing heteroaromatic group forming a 5- to 7-membered ring selected from the group consisting of: R ₁ is a hydrogen atom or a formula: Y
₃ -W in ₂ -Y ₄ -R _s (wherein, _{R s} is to 1 suitably a hydrogen atom or the substituent may have three, a lower alkyl group, lower alkenyl group, lower alkynyl group, a cycloalkyl Lower alkyl group, 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, benzotriazolyl group, Benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolyl group, furyl group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, an aromatic heterocyclic group or isoxazolinyl group , Isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuranyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolinyl group Aliphatic heterocyclic group selected from the group consisting of finely 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 ) S
O 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 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; Represents three or more lower alkyl groups, aryl groups or aralkyl groups), Y ₃ and Y ₄ are the same or different and are each a single bond or a linear or branched lower alkylene group. Shown)), or a 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,
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 3 _-W in 2 _-Y 4 -R _{s (wherein, R s, W 2, Y} 3
And Y ₄ have the meanings described above, and are substituents selected from the group consisting of the substituents represented by the above formulas, and may be a lower alkyl group optionally having 1 to 3 identical or different substituents. Is or forms a nitrogen atom with X,
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 ₃ -W ₂ -Y ₄ -R _s (wherein, R _s and W ₂ , Y
₃ and Y ₄ have the meanings described above), or one of R ₂ and R ₃ is formed 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 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 have the above-mentioned meanings) and are each a substituent selected from the group consisting of the substituents represented by the following formulas: 1 to 3 identical or different substituents, and optionally 1 to 3 Cyclo lower alkyl, aryl, imidazolyl, isoxazolyl, isoquinolyl, isoindolyl, indazolyl, indolyl, indolidyl, indolizinyl, isothiazolyl, ethylenedioxyphenyl, oxazolyl which may have the same or different substituents Group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthenyl group, naphthyridinyl group,
Phenazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, furyl, furazanyl, triazolyl, benzodioxanyl And an aromatic heterocyclic group selected from the group consisting of methylenedioxyphenyl group and isoxazolinyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazolidinyl group,
It consists of an aliphatic heterocyclic group selected from the group consisting of a tetrahydrofuranyl group, 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. Which may be condensed with a ring selected from the group: And Forming a saturated or unsaturated 5- or 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 compound represented by the formula: Y ₃ -W ₂ -Y ₄ -R _s (in the _formula, R _{s, W 2,}
Y ₃ and Y ₄ have the same meanings as described above) or 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, and 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 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 in 2 _-Y 4 -R _{s (wherein, R s, W 2, Y} 3
And Y ₄ have the meanings described above, and are each a substituent selected from the group consisting of
May have the same or different substituents, represents a lower alkyl group, an aryl group or an aralkyl group,
X, Y, Z and the formula Has the above-mentioned meaning], or a salt thereof. 8. A compound of the general formula (V) [Wherein, X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and the formula Has the above-mentioned meaning] and a compound represented by the general formula (VI): Wherein Ar ₀ has the meaning described above, and reacts with the compound represented by the general formula (II). [Wherein, Ar ₀ , X, Y, Z, R ₁₀ , R ₂₀ ,
R ₃₀ , R ₄₀ , R ₅₀ and the formula Has the above-mentioned meaning], and the protecting group is removed as appropriate. [Wherein, Ar, X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ ,
R ₅ and the formula Has the above-mentioned meaning], or a salt thereof. 9. A compound of the general formula (VII) [Wherein, L is a reactive substituent having a functional group that can be converted to another functional group which may be protected, and T ₁₀ may be a single bond or may have a protected substituent as appropriate. good, linear or branched lower alkylene group, an aryl group, an aromatic heterocyclic group, the compounds of illustrating the Ar ₀ has a transformable functional group containing an aliphatic heterocyclic group or an aralkyl group] and the general formula (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). Wherein T ₁₀ , R ₆₀ and L have the same meanings as described above, and the compound represented by the general formula (III): [Wherein, X, Y, Z, R ₁₀ , R ₂₀ , R ₃₀ ,
R ₄₀ , R ₅₀ and the formula Has the above-mentioned meaning] and a reactive derivative of formic acid ester, where appropriate, in the presence of a base, to give a compound of the general formula (X) [Wherein, X, Y, Z, T ₁₀ , R ₁₀ , R ₂₀ , R
_30, R ₄₀ , R ₅₀ , R ₆₀ , formula And L have the above-mentioned meaning], and then the conversion of the substituent L and / or the removal of the protecting group are removed. [Wherein T ₁ represents a single bond or a linear or branched lower alkylene group, an aryl group, an aromatic heterocyclic group, an aliphatic heterocyclic group, or an Ar having an 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 above-mentioned meaning), X,
Y, Z, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and the formula Has the above-mentioned meaning], or a salt thereof.