JP2003261566A - Drugs containing quinolizine - Google Patents

Abstract

(57) [Summary] [PROBLEMS] To provide a novel medicine. SOLUTION: General formula (I) [Wherein, R ¹ represents an alkyl group or the like, R ² represents an alkyl group, a C ₁ -C ₆ alkoxy group, or the like, R ³ represents a hydrogen atom or a halogen atom, and R ⁴ represents a hydrogen atom or a halogen atom. R ⁵ represents a general formula (a) Wherein cyclic group A represents a heteroaryl ring or the like; cyclic group G represents a cycloalkene ring or the like;
^{7a to} R ^7d represent a hydrogen atom, a halogen atom, or the like. ). Or a pharmacologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention has excellent antibacterial activity.
The present invention relates to a novel quinolidine-containing drug. [0002] 2. Description of the Related Art It contains quinolidine which has an antibacterial action.
Pharmaceuticals include EP 308 019, WO 9116
No. 894, WO9510519, WO963
No. 9407, WO9907696, WO01
No. 2935 is known.
You. However, at the 8-position of quinolidine, the compound of the general formula
Those having the substituent (b) are described in The 39th Interscie
nce Conference on Antimicrobial Agents & Ch
emotherapy. (1999. ) Limited to one compound described,
Its antibacterial activity was not strong either. Also, mushrooms
In the 8-position of gin, the compound of the general formula (a) or (b)
Drugs containing a compound having a substituent have hitherto been known
did not exist. [0003] SUMMARY OF THE INVENTION Synthetic quinolone antibacterial agents
Is widely used clinically as a therapeutic drug for infectious diseases. And
In recent years, however, the emergence of quinolone-resistant bacteria has become a major problem.
Novel synthetic antibacterial agent effective against these resistant bacteria
The development of was desired. [0004] Means for Solving the Problems The inventors have antibacterial activity.
As a result of diligent research on pharmaceuticals that are
New quinolizine compound with high safety and high safety
Thus, the present invention has been accomplished. That is, the present invention provides a compound represented by the general formula (I) [0006] Embedded image [Wherein, R¹Is a hydrogen atom, C₁-C₆Archi
Substituted with 1 or 2 or more halogen atoms or halogen atoms₁-C₆
Alkyl group, C_Three-C₇Cycloalkyl group, C₁-C₆Al
C substituted one or more times by kill_Three-C₇Cycloalkyl
Substituted with 1 or 2 or more halogen atoms_Three-C₇Shi
Chloroalkyl, aryl, heteroaryl, or
Are the same or different selected from halogen atoms and amino
Or an aryl group substituted by one or more substituents
Represents a heteroaryl group;^TwoIs a hydrogen atom, halogen
Atom, cyano group, hydroxy group, C₁-C₆Alkyl
Substituted with 1 or 2 or more halogen atoms₁-C₆A
Alkyl group, C₁-C₆Alkoxy group or halogen atom
Substituted by one or more of₁-C₆Table showing alkoxy groups
Then R^ThreeIs a hydrogen atom (however, the following R^FiveGeneral formula in
(B) a group formed by a phenyl ring and a cyclic group G in the group is a
In the case of a soindolin ring, R^ThreeIs limited to halogen atoms
You. ) Or a halogen atom;^FourIs a hydrogen atom, halo
Gen atom, nitro group, amino group or C₁-C₆Alkyl group
And R^FiveIs the general formula (a) [0008] Embedded image Wherein the cyclic group A is a heterocyclic group
Represents an aryl ring, and the cyclic group G optionally has a carbon atom
5 carbon atoms which may be replaced by an atom, an oxygen atom or a sulfur atom
To 8 cycloalkene rings or 5 to 8 carbon atoms
Represents a cycloalkane ring of^6aOr R^6cAre the same or
Differently, a hydrogen atom, a halogen atom, a hydroxy group,
Toro group, amino group, cyano group, C₁-C_FourAlkyl group, C
₁-C_Four1 or 2 or more substitution by alkoxy group or halogen atom
Done C₁-C_FourAn alkyl group or a halogen atom
Is C substituted with 2 or more₁-C_FourRepresents an alkoxy group;^7a
Or R^7dAre the same or different and represent a hydrogen atom, a halogen atom
, Hydroxy, nitro, cyano, hydroxy
Mino group, C₁-C_FourAlkyl group, C₁-C_FourAn alkoxy group,
C substituted by one or more halogen atoms₁-C_FourArchi
Substituted with 1 or 2 or more halogen atoms or halogen atoms₁-C_Four
Alkoxy group, hydroxy C₁-C_FourAlkyl group, C₁−
C_FourAlkyloxyimino group, amino group, C₁-C_FourAl
Kill and C_Three-C₇Identical or selected from cycloalkyl
Is an amino group substituted by one or more different substituents,
C substituted with mino₁-C_FourAlkyl group, C₁-C_FourArchi
And C_Three-C₇The same or selected from cycloalkyl
Substituted with amino group substituted by one or more different substituents
Done C₁-C_FourAn alkyl group, an oxo group, or a bond
C with carbon atoms_Three-C_FiveGroup forming a cycloalkane ring
Represents ) Or general formula (b) [0010] Embedded image Wherein the cyclic group G is
Wherein the phenyl ring and the cyclic group G are
When the condensed ring to be formed is a tetrahydroisoquinoline ring
R)^6aOr R^6c, R^7aOr R^7dIs as defined above
Represents ). A quinolizine derivative having the formula
Pharmaceuticals containing esters or pharmacologically acceptable salts thereof
It is. In the general formula (I), preferably, (1)
R¹Is C₁-C_FourWith an alkyl group, fluorine atom or chlorine atom
C substituted by 1 or 2 or more₁-C_ThreeAlkyl group, C_Three-C_Four
Cycloalkyl group, C₁-C_TwoC substituted with alkyl_Three
-C_Four1 in cycloalkyl group, fluorine atom or chlorine atom
Or two or more substituted C_Three-C_FourCycloalkyl group, 2,
4-difluorophenyl group, 2-thiazolyl group, 2-f
Fluorophenyl group, 4-fluorophenyl group, 3-amido
No-4,6-difluorophenyl group, 5-fluoro-2
A pyridyl group, a 2,6-difluoro-3-pyridyl group or
Is a 6-amino-3,5-difluoro-2-pyridyl group
Certain compounds, their esters or their pharmacologically acceptable
Medicine containing salt, (2) R¹Is C₁-C_FourAlkyl group,
C substituted by 1 or 2 or more fluorine atoms or chlorine atoms₁
-C_ThreeAlkyl group, C_Three-C_FourCycloalkyl group, C₁-C
_TwoC substituted with alkyl_Three-C_FourCycloalkyl group,
C substituted by 1 or 2 or more nitrogen atoms or chlorine atoms_Three−
C_FourCycloalkyl group, 2,4-difluorophenyl
Group, 2-thiazolyl group, 2,6-difluoro-3-pyri
A zyl group or 6-amino-3,5-difluoro-2-pyri
A compound that is a zyl group, its ester or its pharmacologically acceptable
(3) R containing a salt containing¹Is an ethyl group,
Propyl group, isopropyl group, 2-fluoroethyl group, 2
-Chloroethyl group, 2,2,2-trifluoroethyl
Group, cyclopropyl group, cyclobutyl group, 2-methylcyclyl
Ropropyl group, 2-fluorocyclopropyl group, 2,2
-Difluorocyclopropyl group or 2,3-difluoro
Compounds that are cyclopropyl groups, esters thereof, or
Pharmaceuticals containing a pharmacologically acceptable salt, (4) R¹But d
A tyl group, a 2-fluoroethyl group, a cyclopropyl group or
Compounds which are 2-fluorocyclopropyl groups,
Medicine containing ter or a pharmacologically acceptable salt thereof,
(5) R^TwoIs hydrogen, fluorine, chlorine, bromine
Atom, cyano group, hydroxy group, C₁-C_ThreeAlkyl group,
C substituted by 1 or 2 or more fluorine atoms or chlorine atoms₁
-C_ThreeAlkyl group, C₁-C_ThreeAn alkoxy group or
C substituted by 1 or 2 or more elementary atoms₁-C_ThreeAlkoxy group
A compound, an ester thereof, or a pharmacologically acceptable compound thereof.
(6) R-containing pharmaceutical,^TwoIs hydrogen atom, fluorine
Atom, chlorine atom, methyl group, ethyl group, fluoromethyl
Group, difluoromethyl group, trifluoromethyl group, 1-
Fluoroethyl group, 2-fluoroethyl group, methoxy
Group, ethoxy group, fluoromethoxy group, difluorometh
A compound which is a xy group or a trifluoromethoxy group,
Doctors containing esters or pharmacologically acceptable salts thereof
Medicine, (7) R^TwoIs a fluorine atom, a chlorine atom, a methyl group,
Fluoromethyl group, difluoromethyl group, trifluoro
A methyl group, a methoxy group or a difluoromethoxy group
Compound, its ester or its pharmacologically acceptable salt
Containing medicine, (8) R^ThreeIs a hydrogen atom, a fluorine atom or
Is a chlorine atom, its ester or its pharmacology
(9) R-containing pharmaceutically acceptable salt,^ThreeBut hydrogen field
Compound which is an atom or a fluorine atom, its ester or its
Pharmaceuticals containing a pharmacologically acceptable salt, (10) R
^FourIs a hydrogen atom, an amino group, a fluorine atom, a chlorine atom or
Compounds that are methyl groups, their esters or their pharmacology
A medicament containing an acceptable salt, (11) R^FourBut hydrogen field
, An amino group or a methyl group, or an ester thereof
Or a medicament containing a pharmacologically acceptable salt thereof, (1
2) R^FourIs a hydrogen atom, its ester or
(13) a drug containing a pharmacologically acceptable salt thereof,
^FiveAnd the cyclic group A and the cyclic group G in the general formula (a)
The condensed ring to be formed is a tetrahydrothienopyridine ring,
Hydrothienopyrrole ring, dihydrocyclopentathiof
Benzene ring, tetrahydrobenzothiophene ring, tetrahydrogen
Rotiazolopyridine ring, tetrahydropyrrolopyridine
Ring, tetrahydroindole ring, dihydropyrrolo pillow
Ring, dihydrocyclopentapyrrole ring, dihydrothier
Nothiopyran ring, dihydrothienopyran ring, tetrahydrogen
Rothienoazepine ring, tetrahydrobenzofuran ring or
A dihydropyrrolopyridine ring, or R^FiveIn
Formation of the phenyl ring and the cyclic group G in the group of the general formula (b)
Condensed ring is an indane ring, tetrahydronaphthalene
A ring, an indoline ring or an isoindoline ring, and
R^6aIs a hydrogen atom and R^6bAnd R^6cAre the same or
Differently hydrogen, fluorine, chlorine, cyano,
Methyl group, ethyl group, methoxy group, ethoxy group, fluoro
Romethyl group, difluoromethyl group, trifluoromethyl
Or a difluoromethoxy group, and R^7aIs hydrogen
An atom and R^7bOr R^7dBut the same or different
Hydrogen atom, fluorine atom, chlorine atom, hydroxy group, methyl
Group, ethyl group, methoxy group, ethoxy group, hydroxy
Imino group, fluoromethyl group, difluoromethyl group,
Trifluoromethyl group, 2-fluoroethyl group, fluoro
Methoxy, difluoromethoxy, trifluorometh
Xy group, C₁-C_ThreeAlkylimino group, hydroxy C₁−
C_ThreeAlkyl group, amino group, C₁-C_TwoAlkyl and C_Three−
C_FourSame or different substitution selected from cycloalkyl
Amino group substituted with 1 or 2 groups, substituted with amino
C₁-C_ThreeAlkyl group, C₁-C_FourAlkyl and C_Three-C_FourShi
1 with the same or different substituents selected from
Or C substituted with two or more substituted amino groups₁-C_FourA
Alkyl group, oxo group, or C
_Three-C_FourA compound that is a group forming a cycloalkane ring;
Containing an ester or a pharmacologically acceptable salt thereof
Medicine, (14) R^FiveA cyclic group A in the general formula (a) group
And the condensed ring group formed by the cyclic group G are 4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Group, 4,5,6,7-tetrahydrothieno [2,3-
c] pyridin-2-yl group, 5,6-dihydro-4H-
Thieno [2,3-c] pyrrol-2-yl group, 5,6-
Dihydro-4H-cyclopenta [b] thiophen-2-
Yl group, 4,5,6,7-tetrahydro-1H-pyrrolo
[3,2-c] pyridin-2-yl group, 4,5,6,7
A tetrahydro-1H-indol-2-yl group, 4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group, 4,5,6,7-tetrahydrobenzo [b]
Furan-2-yl group, 5,6,7,8-tetrahydro-
A 4H-thieno [2,3-d] azepin-2-yl group,
4,7-dihydro-5H-thieno [2,3-c] pyran
-2-yl group, 4,7-dihydro-5H-thieno [2,
3-c] thiopyran-2-yl group or 5,6-dihi
Dro-4H-thieno [2,3-b] thiopyran-2-i
Or a group represented by R^FiveIn the general formula (b) group
The fused ring group formed by the phenyl ring and the cyclic group G is
-5-yl group, 5,6,7,8-tetrahydronaphtha
A ren-2-yl group or an isoindoline-5-yl group;
And R^6aAnd R^6bIs a hydrogen atom, and R^6c
Is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group,
Methoxy group, difluoromethyl group, trifluoro group
A methyl group or a difluoromethoxy group, and R^7a
And R^7bIs a hydrogen atom, and R^7cAnd R^7dBut the same
One or different, a fluorine atom, a chlorine atom, a hydroxy
Group, methyl group, ethyl group, methoxy group, hydroxyimi
Group, fluoromethyl group, difluoromethyl group, trif
Fluoromethyl group, difluoromethoxy group, methoxyimi
Groups, ethoxyimino groups, hydroxymethyl groups, 1-
Droxyethyl group, 2-hydroxyethyl group, 1-hydrido
Roxypropyl group, amino group, methylamino group, dimethyl
Ruamino group, ethylamino group, cyclopropylamino
Group, aminomethyl group, 1-aminoethyl group, 2-amino
Ethyl group, C ₁-C_TwoChoose from alkyl and cyclopropyl
A or 1-substituted with the same or different substituents
C substituted with a mino group₁-C_TwoAlkyl group, oxo group, or
Forms a cyclopropane ring with the carbon atom to which it is attached.
Compound, its ester or its pharmacologically acceptable group
(15) R.^FiveGeneral formula in
(A) condensed ring group formed by cyclic group A and cyclic group G in the group
Is 4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl group, 4,5,6,7-tetrahi
Drothieno [2,3-c] pyridin-2-yl group, 5,
6-dihydro-4H-thieno [2,3-c] pyrrole-
2-yl group, 5,6-dihydro-4H-cyclopenta
[B] thiophen-2-yl group, 4,5,6,7-tet
Lahydro-1H-pyrrolo [3,2-c] pyridine-2-
Yl group, 4,5,6,7-tetrahydro-1H-india
2-yl group 4,5,6,7-tetrahydrobenzo
[B] thiophen-2-yl group, 4,5,6,7-tet
Lahydrobenzo [b] furan-2-yl group, 5,6
7,8-tetrahydro-4H-thieno [2,3-d] a
Zepin-2-yl group, 4,7-dihydro-5H-thieno
[2,3-c] pyran-2-yl group, 4,7-dihydro
-5H-thieno [2,3-c] thiopyran-2-yl
Group or 5,6-dihydro-4H-thieno [2,3-
b] a thiopyran-2-yl group, or R^FiveIn
Of a phenyl ring and a cyclic group G in the group of the general formula (b)
Is an indan-5-yl group, 5,6,7,
8-tetrahydronaphthalen-2-yl group or isoin
A dolin-5-yl group and R^6aAnd R^6bIs hydrogen
An atom and R^6cIs hydrogen atom, fluorine atom, methyl
A methoxy group or a difluoromethoxy group; and
One, R^7aOr R^7bIs a hydrogen atom, and R^7cAnd R
^7dAre the same or different and are a hydrogen atom, a fluorine atom,
Methoxy group, hydroxyimino group, fluoromethyl
Group, difluoromethoxy group, methoxyimino group,
Droxymethyl group, 1-hydroxyethyl group, amino
Group, methylamino group, dimethylamino group, aminomethyl
Group, 1-aminoethyl group, N-methylaminomethyl group,
1- (N-methylamino) ethyl group, N-ethylamino
Methyl group, N, N-dimethylaminomethyl group, 1-
(N, N-dimethylamino) ethyl group, N, N-diethyl
Aminomethyl group, N-cyclopropylaminomethyl group
Or a 1- (N-cyclopropylamino) ethyl group, oxo
A cyclopropane ring together with an azo group or a bonding carbon atom
Which is a group forming, its ester or its pharmacology
Pharmaceuticals containing a physiologically acceptable salt, (16) R^FiveSmell
The cyclic group A and the cyclic group G in the general formula (a) form
The fused ring group is 4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl group, 4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-2-i
Group, 5,6-dihydro-4H-thieno [2,3-c]
Pyrrol-2-yl group, 5,6-dihydro-4H-cycl
Lopenta [b] thiophen-2-yl group, 4,5,6
7-tetrahydro-1H-pyrrolo [3,2-c] pyridi
2-yl group, 4,5,6,7-tetrahydro-1H
-Indol-2-yl group 4,5,6,7-tetrahydrido
Lobenzo [b] thiophen-2-yl group, 4,5,6
A 7-tetrahydrobenzo [b] furan-2-yl group,
5,6,7,8-tetrahydro-4H-thieno [2,3
-D] azepin-2-yl group, 4,7-dihydro-5H
-Thieno [2,3-c] pyran-2-yl group, 4,7-
Dihydro-5H-thieno [2,3-c] thiopyran-2
-Yl group or 5,6-dihydro-4H-thieno [2,
3-b] thiopyran-2-yl group and R^7aNo
To R^7bIs a hydrogen atom, and R^7cAnd R^7dBut the same
Or differently, hydrogen atom, fluorine atom, methyl group, meth
Xy, hydroxyimino, fluoromethyl, dif
Fluoromethoxy group, methoxyimino group, hydroxymethyl
Group, 1-hydroxyethyl group, amino group, methylamino
Group, dimethylamino group, aminomethyl group, 1-amino
Ethyl group, N-methylaminomethyl group, 1- (N-methyl
Ruamino) ethyl group, N-ethylaminomethyl group, N,
N-dimethylaminomethyl group, 1- (N, N-dimethyl
Amino) ethyl group, N, N-diethylaminomethyl group,
N-cyclopropylaminomethyl group, 1- (N-cyclo
Propylamino) ethyl group, oxo group, or bond
A compound that forms a cyclopropane ring with a carbon atom
Compounds, esters or pharmacologically acceptable salts thereof.
Medicine. In the general formula (I), (1) to (1)
(4), (5) to (7), (8) to (9), (10)
Toshi (12) and (13) to (16) have large numbers
As shown, more preferred compounds are represented by the general formula (I)
In, R¹Arbitrarily selected from the above (1) to (4)
Then R^TwoIs arbitrarily selected from (5) to (7), and R^ThreeTo
(8) or (9), R^FourFrom (10)
Arbitrarily selected from (12), R^FiveFrom (13) to (16)
Arbitrarily, and arbitrarily combine these
The obtained compound, its ester or its pharmacologically acceptable
Also suitable are medicaments which contain salts. In the medicament of the present invention, preferably, an antibacterial agent and
It is used as a medicine. In the general formula (I), R¹"C₁-C₆Alkyl
As the `` group '', for example, a methyl group, an ethyl group, a propyl
Group, isopropyl group, butyl group, isobutyl group, s-butyl group
Tyl group, t-butyl group, pentyl group, isopentyl group,
Neopentyl group, t-pentyl group, 1-methylbutyl
Group, hexyl group, 1-methylpentyl group, 2-methylpe
Methyl group, 3-methylpentyl group, 1-ethylbutyl group
Or a linear or branched alkyl such as a 2-ethylbutyl group.
And preferably a methyl group and an ethyl group.
Group, propyl group, isopropyl group, butyl group, isobutyl
C, such as benzyl, s-butyl or t-butyl,<sub>1</sub>-C<sub>Four</sub>
Alkyl group, more preferably ethyl group, propyl
Group or isopropyl group, particularly preferably an ethyl group
It is. In the general formula (I), R<sup>1</sup>"Halogen atom is 1
Or two or more substituted C<sub>1</sub>-C<sub>6</sub>Alkyl group "
“Halogen atom” means, for example, a fluorine atom, a chlorine atom
Atom, bromine atom or iodine atom, preferably fluorine
Atom, chlorine atom or bromine atom, more preferably
A nitrogen atom or a chlorine atom, particularly preferably a fluorine atom.
I am a child. R<sup>1</sup>"Substituted 1 or 2 or more times with a halogen atom
Done C<sub>1</sub>-C<sub>6</sub>The “alkyl group” refers to the aforementioned “C<sub>1</sub>-C<sub>6</sub>Al
A group in which a "halogen atom" is substituted for a "kill group".
Such groups include, for example, fluoromethyl group, difur
Oromethyl group, trifluoromethyl group, 1-fluoro
Tyl group, 2-fluoroethyl group, 1,1-difluoroe
Tyl group, 2,2,2-trifluoroethyl group, pentaf
Fluoroethyl group, 1-fluoropropyl group, 2-fluoro
Ropropyl group, 3-fluoropropyl group, 3,3,3-
Trifluoropropyl group, perfluoropropyl group, 1
-Fluoromethylethyl group, 1-difluoromethylethyl
Group, 1-trifluoromethylethyl group, 1-fluoro
-1-methylethyl group, hexafluoroisopropyl
Group, 4-fluorobutyl group, perfluorobutyl group, 5
-Fluoropentyl group, perfluoropentyl group, 6-
Such as fluorohexyl and perfluorohexyl
C in which one or more fluorine atoms are substituted<sub>1</sub>-C<sub>6</sub>Alkyl
Group: chloromethyl group, dichloromethyl group, trichloromethyl
Butyl, 1-chloroethyl and 2-chloroethyl groups
With one or more substituted chlorine atoms<sub>1</sub>-C<sub>6</sub>Alkyl
Group: bromomethyl group, dibromomethyl group, 1-bromoe
1 or a bromine atom such as a 2-bromoethyl group or
C substituted by 2 or more<sub>1</sub>-C<sub>6</sub>Alkyl group or methyl iodide
Group, diiodomethyl group, 1-iodoethyl group, 2-yo
One or more iodine atoms such as
C<sub>1</sub>-C<sub>6</sub>Alkyl groups can be mentioned.
Fluoromethyl, difluoromethyl, trifluoromethyl
Tyl group, 1-fluoroethyl group, 2-fluoroethyl
Group, 1,1-difluoroethyl group, 2,2,2-trif
Fluoroethyl group, hexafluoroisopropyl group, 1-
Fluoromethylethyl group or 1-difluoromethylethyl
Substituted with one or more fluorine atoms such as<sub>1</sub>−
C<sub>Three</sub>Alkyl group or chloromethyl group, 2-chloroe
C substituted by one or more chlorine atoms such as tyl group<sub>1</sub>−
C<sub>Three</sub>Alkyl group, more preferably 2-fluoro
Tyl group, 2-chloroethyl group or 2,2,2-trifur
Oroethyl group, particularly preferably 2-fluoroethyl
Group. In the general formula (I), R<sup>1</sup>"C<sub>Three</sub>-C<sub>7</sub>Cycloa
Examples of the "alkyl group" include a cyclopropyl group and a cycloalkyl group.
Robutyl group, cyclopentyl group, cyclohexyl group or
A cycloheptyl group can be mentioned.
Propyl group or cyclobutyl group, particularly preferably,
It is a cyclopropyl group. In the general formula (I), R<sup>1</sup>"C<sub>1</sub>-C<sub>6</sub>Alkyl
Substituted by one or more of<sub>Three</sub>-C<sub>7</sub>Cycloalkyl group "
Means “C<sub>1</sub>-C<sub>6</sub>Alkyl group "<sub>Three</sub>-C<sub>7</sub>Shi
A group substituted by one or more chloroalkyl groups,
As a group such as, for example, 1-methylcyclopropyl
Group, 1-ethylcyclopropyl group, 2-methylcyclo
Propyl group, 2-ethylcyclopropyl group, 2-propyl
Rucyclopropyl group, 2-butylcyclopropyl group, 2
-Pentylcyclopropyl group, 2-hexylcyclopro
Pill group, 2,2-dimethylcyclopropyl group, 2,3-
Dimethylcyclopropyl group, 1-methylcyclobutyl
Group, 1-ethylcyclobutyl group, 2-methylcyclobutyi group
Group, 2-ethylcyclobutyl group, 2-propylcyclo
Butyl group, 2-butylcyclobutyl group, 2-pentylcyl
Cyclobutyl group, 2-hexylcyclobutyl group, 3-methyl
Rucyclobutyl group, 3-ethylcyclobutyl group, 3-p
Propylcyclobutyl group, 3-butylcyclobutyl group, 3
-Pentylcyclobutyl group, 3-hexylcyclobutyl
Group, 2,3-dimethylcyclobutyl group, cyclopentyl
Group, 1-methylcyclopentyl group, 1-ethylcyclope
Methyl group, 2-methylcyclopentyl group, 2-ethyl
Clopentyl group, 2-propylcyclopentyl group, 2-
Butylcyclopentyl group, 2-pentylcyclopentyl
Group, 2-hexylcyclopentyl group, 3-methylcyclo
Pentyl group, 3-ethylcyclopentyl group, 3-propyl
Rucyclopentyl group, 3-butylcyclopentyl group, 3
-Pentylcyclopentyl group, 3-hexylcyclopen
Tyl group, 3,4-dimethylcyclopentyl group, 1-methyl
Rucyclohexyl group, 2-methylcyclohexyl group, 3
-Methylcyclohexyl group or 4-methylcyclohexyl
And preferably a methyl group or an ethyl group.
Substituted with a group<sub>Three</sub>-C<sub>Four</sub>A cycloalkyl group, especially
Preferably, it is a 2-methylcyclopropyl group. In the general formula (I), R<sup>1</sup>"Halogen atom is 1
Or two or more substituted C<sub>Three</sub>-C<sub>7</sub>Cycloalkyl group "
Means that the “halogen atom” is the “C<sub>Three</sub>-C<sub>7</sub>Cycloal
A group obtained by substituting 1 or 2 or more to
Examples of the group include a 1-fluorocyclopropyl group,
2-fluorocyclopropyl group, 2,2-difluorosi
Chloropropyl group, 2,3-difluorocyclopropyl
Group, 1-fluorocyclobutyl group, 2-fluorocyclo
Butyl group, 3-fluorocyclobutyl group, 1-fluoro
Cyclopentyl group, 2-fluorocyclopentyl group, 2
-Fluorocyclohexyl group, 2-fluorocyclohep
C in which one or more fluorine atoms such as a tyl group are substituted<sub>Three</sub>
-C<sub>7</sub>Cycloalkyl group or 2-chlorocyclopro
Salts such as pill group and 2,3-dichlorocyclopropyl group
C in which one or more elementary atoms are substituted<sub>Three</sub>-C<sub>7</sub>Cycloalkyl
And preferably 2-fluorocyclopropyl.
Ropyl group, 2,2-difluorocyclopropyl group, 2,
3-difluorocyclopropyl group, 2-fluorocyclo
Fluorine such as butyl group and 3-fluorocyclobutyl group
C in which one or more atoms are substituted<sub>Three</sub>-C<sub>Four</sub>Cycloalkyl
Group or 2-chlorocyclopropyl group, 2,3-dic
1 or more chlorine atoms such as lolocyclopropyl
C replaced on<sub>Three</sub>-C<sub>Four</sub>A cycloalkyl group, more preferably
Has a 2-fluorocyclopropyl group, 2,2-difur
Orocyclopropyl group or 2,3-difluorocyclopropyl
A propyl group, particularly preferably 2-fluorocyclopropyl
It is a ropyl group. In the general formula (I), R<sup>1</sup>"Aryl group"
For example, phenyl group, indenyl group, naphthyl
Group, such as a phenanthrenyl group or an anthracenyl group
An aromatic hydrocarbon group having 6 to 14 carbon atoms may be mentioned.
And preferably a phenyl group. In the general formula (I), R<sup>1</sup>Heteroaryl
A `` group '' is selected from nitrogen, oxygen and sulfur.
5- to 10-membered complex containing one or two heteroatoms
An aromatic ring group; examples of such a heteroaromatic ring group include, for example,
For example, a pyridyl group, a pyrimidinyl group, a pyridazinyl group,
Pyrazinyl group, thiazolyl group, thienyl group, furyl group,
Pyrrolyl, imidazolyl, oxazolyl or quino
Ril groups can be mentioned, preferably a pyridyl group or a pyridyl group.
A midinyl group or a thiazolyl group;
It is a lysyl group or a thiazolyl group. In the general formula (I), R¹"Halogen atom and
1 or 2 with the same or different substituents selected from amino
Specific examples of the above-substituted aryl group include, for example,
For example, a 2-aminophenyl group, a 3-aminophenyl group,
4-aminophenyl group, 2-fluorophenyl group, 3-
Fluorophenyl group, 4-fluorophenyl group, 2-c
Lolophenyl group, 3-chlorophenyl group, 4-chlorophenyl
Phenyl, 2-bromophenyl, 3-bromophenyl
Group, 4-bromophenyl group, 2,4-difluorophenyl
Group, 2,4-dichlorophenyl group, 2,4-dibromo
Phenyl group, 2-fluoro-1-naphthyl group, 1-fur
Oro-2-naphthyl group or 3-amino-4,6-difur
Orophenyl group can be mentioned, preferably, 2-fur
Orophenyl group, 4-fluorophenyl group, 2-chloro
Phenyl group, 4-chlorophenyl group, 2,4-difluoro
Rophenyl group, 2,4-dichlorophenyl group or 3-A
Mino-4,6-difluorophenyl group, more preferred
Includes a 2-fluorophenyl group and a 4-fluorophenyl
Group, 2,4-difluorophenyl group or 3-amino-
4,6-difluorophenyl group, particularly preferably,
2,4-difluorophenyl group. In the general formula (I), R¹Heteroaryl
Group "and" the same selected from a halogen atom and amino
Or a hetero ant substituted by one or more different substituents
Specific examples of the phenyl group "include, for example, 2-pyridyl
Group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidyl
Group, 4-pyrimidyl group, 5-pyrimidyl group, 3-pyrida
Dinyl group, 4-pyridazinyl group, 2-pyrazinyl group, 2
-Thiazolyl group, 4-thiazolyl group, 5-thiazolyl
Group, 2-thienyl group, 3-thienyl group, 2-furyl group,
3-furyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-
Pyrrolyl group, 2-imidazolyl group, 4-imidazolyl
Group, 2-oxazolyl group, 4-oxazolyl group, 5-O
Xazolyl group, 5-fluoro-2-pyridyl group, 2,6
-Difluoro-3-pyridyl group, 3-fluoro-2-thio
Enyl group, 4-fluoro-2-thienyl group, 5-fluoro
B-2-thienyl group, 2-fluoro-3-thienyl group,
5-fluoro-3-thienyl group, 3-fluoro-2-f
Ryl group, 4-fluoro-2-furyl group, 5-fluoro-
2-furyl group, 2-fluoro-3-furyl group, 5-fur
Oro-3-furyl group, 3-fluoro-1-pyrrolyl group,
4-fluoro-2-pyrrolyl group, 4-fluoro-2-thio
Azolyl group, 4-fluoro-2-imidazolyl group, 5-
Chloro-2-pyridyl group, 2,6-dichloro-3-pyri
Jyl group, 3-chloro-2-thienyl group, 4-chloro-2
-Thienyl group, 5-chloro-2-thienyl group, 2-chloro
B-3-thienyl group, 5-chloro-3-thienyl group, 3
-Chloro-2-furyl group, 4-chloro-2-furyl group,
5-chloro-2-furyl group, 2-chloro-3-furyl
Group, 5-chloro-3-furyl group, 3-chloro-1-pyrro
Ryl group, 4-chloro-2-pyrrolyl group, 4-chloro-2
-Thiazolyl group, 4-chloro-2-imidazolyl group, 6
-Amino-2-pyridyl group, 6-amino-3,5-dic
Loro-2-pyridyl group or 6-amino-3,5-difur
Oro-2-pyridyl group can be mentioned.
-Pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-
Thiazolyl group, 5-fluoro-2-pyridyl group, 2,6
-Difluoro-3-pyridyl group, 6-amino-3,5-
Difluoro-2-pyridyl group, 2,6-dichloro-3-
Pyridyl group or 6-amino-3,5-dichloro-2-pi
A lysyl group, more preferably a 2-thiazolyl group, 5
-Fluoro-2-pyridyl group, 2,6-difluoro-3
-Pyridyl group or 6-amino-3,5-difluoro-2
-Pyridyl group, particularly preferably 2-thiazolyl
Group, 2,6-difluoro-3-pyridyl group or 6-amido
No-3,5-difluoro-2-pyridyl group. In the general formula (I), R^TwoThe "halogen atom" of
Has the same meaning as above, preferably a fluorine atom, a chlorine atom
Or a bromine atom, particularly preferably a fluorine atom or a salt
Elementary atom. In the general formula (I), R^Two"C₁-C₆Alkyl
Group "and" C substituted by one or more halogen atoms "₁
-C₆"Alkyl group" has the same meaning as described above, and "C₁-C
₆As the “alkyl group”, preferably C₁-C_ThreeAlkyl group
And more preferably a methyl group or an ethyl group,
Particularly preferably, it is a methyl group, and "a halogen atom is one or more.
Is C substituted with 2 or more₁-C₆Alkyl groups are preferably
Suitably fluoro or chloro C₁-C_ThreeAn alkyl group
More preferably, a fluoromethyl group, a difluoromethyl
Group, trifluoromethyl group, 1-fluoroethyl group or
Is a 2-fluoroethyl group, particularly preferably
Romethyl group, difluoromethyl group or trifluoromethyl
Group. In the general formula (I), R^Two"C₁-C₆Alkoki
Examples of the `` group '' include a methoxy group, an ethoxy group,
Loxy, isopropoxy, butoxy, isobut
Xyl, s-butoxy, t-butoxy, pentyl
A xy group or a hexyloxy group;
Is C<sub>1</sub>-C<sub>Three</sub>Alkoxy group, more preferably
Xy or ethoxy, particularly preferably methoxy
Group. In the general formula (I), R<sup>Two</sup>"Halogen atom is 1
Or two or more substituted C<sub>1</sub>-C<sub>6</sub>"Alkoxy group"
The “halogen atom” is the same as the “C<sub>1</sub>-C<sub>6</sub>Alkoxy group "
A group substituted by 1 or 2 or more.
Is, for example, a fluoromethoxy group, a difluoromethoxy
Group, trifluoromethoxy group, 2-fluoroethoxy
Group, 1-fluoroethoxy group, 2,2,2-trifluoro
Roethoxy group, perfluoroethoxy group, 3-fluoro
Propoxy group, 3,3,3-trifluoropropoxy
Group, perfluoropropoxy group, hexafluoroisop
Loxy group, 4-fluorobutoxy group, perfluorobut
Toxyl group, 5-fluoropentyloxy group, 6-fluoro
1 or 2 or more fluorine atoms such as rohexyloxy group
Replaced C<sub>1</sub>-C<sub>6</sub>Alkoxy group or 2-chloroe
1 or a chlorine atom such as a toxic group or a chloromethoxy group
C substituted by 2 or more<sub>1</sub>-C<sub>6</sub>Alkoxy groups can be mentioned
Preferably a fluoromethoxy group, difluoromethoxy
Si group, trifluoromethoxy group, 1-fluoroethoxy
Group, 2,2,2-trifluoroethoxy group or 3-fur
One or more fluorine atoms such as olopropoxy groups
Replaced C<sub>1</sub>-C<sub>Three</sub>An alkoxy group, more preferably,
Fluoromethoxy group, difluoromethoxy group or trif
A fluoromethoxy group, particularly preferably a difluoromethyl group.
It is a toxic group. In the general formula (I), R<sup>Three</sup>"Halogen atom"
Is as defined above, preferably a fluorine atom or a salt
And is particularly preferably a fluorine atom. In the general formula (I), R<sup>Four</sup>The "halogen atom" of
It has the same meaning as above, and is preferably a fluorine atom or a chlorine atom.
I am a child. In the general formula (I), R<sup>Four</sup>"C<sub>1</sub>-C<sub>Four</sub>Alkyl
The `` group '' has the same meaning as described above, and is preferably a methyl group
You. In the general formula (I), R^FiveGeneral formula (a)
The “heteroaryl ring” for A in the group is the same as defined above for 5
Represents a 10 to 10-membered heteroaromatic ring, preferably pyridine
Ring, thiophene ring, pyrimidine ring, thiazole ring, fura
Ring, pyrrole ring, imidazole ring or oxazole ring
More preferably, a pyridine ring, a thiophene ring,
Limidine ring, furan ring, pyrrole ring or imidazole ring
And particularly preferably a furan ring, a pyridine ring and a thiof ring.
Ene ring, pyrimidine ring or pyrrole ring. In the general formula (I), R^FiveGeneral formula (a)
In the group represented by the cyclic group G, "arbitrarily a carbon atom is a nitrogen atom,
5 to 5 carbon atoms which may be replaced by an elemental atom or a sulfur atom
8 cycloalkene rings or 6 to 8 carbon atoms
As the "loalkane ring", for example, a cyclopentane ring,
Cyclohexane ring, cycloheptane ring, cyclooctane
Ring, cyclopentene ring, cyclohexene ring, cycloheptane
Ten ring, cyclooctene ring, pyrrolidine ring, piperidine
Ring, hexahydro-1H-azepine ring, azocan ring, a
Midazolidine ring, pyrazolidine ring, piperazine ring, hex
Sahydropyridazine ring, hexahydropyrimidine ring, di
Hydropyrimidine ring, morpholine ring, thiomorpholine
Ring, tetrahydrofuran ring, tetrahydropyran ring,
Trahydrothiopyran ring, dihydropyrrole ring, dihydric
Loimidazole ring, dihydropyrazole ring, tetrahydride
Rothiophene ring, 1,3-dithiane ring, oxazolidine
And a thiazolidine ring.
Clopentane ring, cyclopentene ring, cyclohexane
Ring, cyclohexene ring, pyrrolidine ring, piperidine ring,
Imidazolidine ring, pyrazolidine ring, tetrahydrofura
Ring, tetrahydropyran ring, tetrahydrothiopyran
Or a hexahydro-1H-azepine ring,
Preferably, cyclopentane ring, cyclohexane ring, pyro
Lysine ring, piperidine ring, tetrahydropyran ring, tet
Lahydrothiopyran ring or hexahydro-1H-aze
It is a pin ring. In the general formula (I), R^FiveGeneral formula (a)
Examples of the condensed ring represented by the cyclic group A and the cyclic group G in the group include
For example, tetrahydrothienopyridine ring, dihydrothieno
Pyrrole ring, tetrahydrothiazolopyridine ring, dihydric
Lopirolothiazole ring, tetrahydropyridopyridine
Ring, tetrahydropyridopyrimidine ring, dihydropyrrolo
Pyridine ring, dihydropyrrolopyrimidine ring, dihydrocy
Clopentathiophene ring, tetrahydrobenzothiophene
Ring, dihydrocyclopentapyridine ring, tetrahydro
Quinazolidine ring, tetrahydroquinoxaline ring, dihydric
Rocyclopentathiazole ring, tetrahydropyrrolopyri
Gin ring, tetrahydroindole ring, dihydropyrrolopi
Roll ring, dihydrocyclopentapyrrole ring tetrahydride
Lobenzothiazole ring, dihydrothienothiopyran ring,
Dihydrothienopyran ring, dihydrothienoazepine ring,
And a tetrahydrobenzofuran ring.
Suitably, a tetrahydrothienopyridine ring,
Nopyrrole ring, dihydrocyclopentathiophene ring,
Trahydrobenzothiophene ring, tetrahydrothiazolo
Pyridine ring, tetrahydropyrrolopyridine ring, tetrahi
Droindole ring, dihydropyrrolopyrrole ring, dihydric
Rocyclopentapyrrole ring, dihydrothienothiopyran
Ring, dihydrothienopyran ring, dihydrothienoazepine
Ring, tetrahydrobenzofuran ring or dihydropyrrolopi
It is a lysine ring. In the general formula (I), R^FiveGeneral formula (a)
Specific examples of the fused ring group represented by the cyclic group A and the cyclic group G in the group
By way of example, and preferably, 4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl group, 4,5
6,7-tetrahydrothieno [3,2-c] pyridine-
3-yl group, 4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl group, 4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-3-i
Group, 4,5,6,7-tetrahydrothieno [3,4-
c] pyridin-1-yl group, 4,5,6,7-tetrahi
Drothieno [3,4-c] pyridin-3-yl group, 5,
6-dihydro-4H-thieno [2,3-c] pyrrole-
2-yl group, 5,6-dihydro-4H-thieno [2,3
-C] pyrrol-3-yl group, 5,6-dihydro-4H
-Thieno [3,4-c] pyrrol-1-yl group, 5,6
-Dihydro-4H-thieno [3,2-b] pyrrole-2
-Yl group, 5,6-dihydro-4H-thieno [2,3-
b] pyrrol-2-yl group, 5,6-dihydro-4H-
Cyclopenta [b] thiophen-2-yl group, 5,6-
Dihydro-4H-cyclopenta [b] thiophen-3-
Yl group, 4,5,6,7-tetrahydrobenzo [b] thi
Offen-2-yl group, 5,6-dihydro-4H-cycl
Lopenta [c] thiophen-1-yl group, 4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl group, 4,5,6,7-tetrahydro-1H-pyro
B [3,2-c] pyridin-2-yl group, 4,5,6
7-tetrahydro-1H-pyrrolo [3,2-c] pyridi
N-3-yl group, 4,5,6,7-tetrahydro-1H
-Pyrrolo [2,3-c] pyridin-2-yl group, 4,
5,6,7-tetrahydro-1H-pyrrolo [2,3-
c] pyridin-3-yl group, 4,5,6,7-tetrahi
Dro-1H-indol-2-yl group, 4,5,6,7
-Tetrahydro-1H-indol-3-yl group, 1,
4,5,6-tetrahydropyrrolo [3,4-b] pillow
Ru-2-yl group, 1,4,5,6-tetrahydropyrrolo
[3,4-b] pyrrole-3-yl group, 1,4,5,6
-Tetrahydrocyclopenta [b] pyrrol-2-yl
Group, 1,4,5,6-tetrahydrocyclopenta [b]
Pyrrol-3-yl group, 6,7-dihydro-5H-pyro
B [3,4-b] pyridin-3-yl group, 4,5,6
A 7-tetrahydrobenzo [b] furan-2-yl group,
5,6,7,8-tetrahydro-4H-thieno [2,3
-D] azepin-2-yl group, 4,7-dihydro-5H
-Thieno [2,3-c] pyran-2-yl group, 4,7-
Dihydro-5H-thieno [2,3-c] thiopyran-2
-Yl group or 5,6-dihydro-4H-thieno [2,
3-b] thiopyran-2-yl group, more preferably
Is 4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl group, 4,5,6,7-tetrahi
Drothieno [2,3-c] pyridin-2-yl group, 4,
5,6,7-tetrahydrothieno [3,4-c] pyridi
1-yl group, 5,6-dihydro-4H-thieno
[2,3-c] pyrrole-2-yl group, 5,6-dihydride
B-4H-thieno [3,4-c] pyrrol-1-yl
Group, 5,6-dihydro-4H-thieno [2,3-c] pi
Roll-3-yl group, 5,6-dihydro-4H-cyclo
Penta [b] thiophen-2-yl group, 4,5,6,7
A tetrahydrobenzo [b] thiophen-2-yl group,
4,5,6,7-tetrahydro-1H-pyrrolo [3,2
-C] pyridin-2-yl group, 4,5,6,7-tetra
Hydro-1H-pyrrolo [2,3-c] pyridine-2-i
Group, 4,5,6,7-tetrahydro-1H-indole
Ru-2-yl group, 1,4,5,6-tetrahydropyrrolo
[3,4-b] pyrrole-2-yl group, 1,4,5,6
-Tetrahydrocyclopenta [b] pyrrol-2-yl
Group, 5,6-dihydro-4H-cyclopenta [c] thio
Phen-1-yl group, 4,5,6,7-tetrahydrobe
Nzo [b] furan-2-yl group, 5,6,7,8-tet
Lahydro-4H-thieno [2,3-d] azepine-2-
Yl group, 4,7-dihydro-5H-thieno [2,3-
c] pyran-2-yl group, 4,7-dihydro-5H-thio
An eno [2,3-c] thiopyran-2-yl group, or 5,
6-dihydro-4H-thieno [2,3-b] thiopyran
-2-yl group, particularly preferably 4,5,6,7-tetra
A hydrothieno [3,2-c] pyridin-2-yl group,
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl group, 5,6-dihydro-4H-thieno
[2,3-c] pyrrole-2-yl group, 5,6-dihydride
B-4H-Cyclopenta [b] thiophen-2-yl
Group, 4,5,6,7-tetrahydro-1H-pyrrolo
[3,2-c] pyridin-2-yl group, 4,5,6,7
A tetrahydro-1H-indol-2-yl group, 4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group, 4,5,6,7-tetrahydrobenzo [b]
Furan-2-yl group, 5,6,7,8-tetrahydro-
A 4H-thieno [2,3-d] azepin-2-yl group,
4,7-dihydro-5H-thieno [2,3-c] pyran
-2-yl group, 4,7-dihydro-5H-thieno [2,
3-c] thiopyran-2-yl group or 5,6-dihydrido
B-4H-thieno [2,3-b] thiopyran-2-yl
Group. In the general formula (I), R^FiveGeneral formula (b)
The cyclic group G in the group has the same meaning as described above. In the general formula (I), R^FiveGeneral formula (b)
As a condensed ring formed by the phenyl ring in the group and the cyclic group G
Is, for example, an indane ring, a tetrahydronaphthalene ring,
Indoline ring, isoindoline ring, 2,3-dihydrobe
Nsimidazole ring or 2,3-dihydroindazole
A ring, preferably an indane ring,
Dronaphthalene ring, indoline ring or isoindoline ring
And even more preferably a tetrahydronaphthalene ring
Or an isoindoline ring. In the general formula (I), R^FiveGeneral formula (b)
A fused ring group formed by a phenyl ring and a cyclic group G in the group
As a specific example, preferably, an indan-4-yl group,
Indan-5-yl group, 5,6,7,8-tetrahydro
Naphthalen-1-yl group, 5,6,7,8-tetrahydrid
Ronaphthalen-2-yl group, indoline-4-yl group,
An indoline-5-yl group, an indoline-6-yl group,
A ndolin-7-yl group, an isoindoline-4-yl group or
Is an isoindoline-5-yl group, more preferably,
An indan-4-yl group, an indan-5-yl group, 5,
6,7,8-tetrahydronaphthalen-2-yl group, i
A ndolin-5-yl group, an isoindoline-4-yl group or
Is an isoindoline-5-yl group, particularly preferably
Indan-5-yl group, 5,6,7,8-tetrahydro
Naphthalen-2-yl group or isoindoline-5-yl
Group. In the general formula (I), R^FiveGeneral formula (a)
R in the group or the general formula (b)^6aOr R^6c, And R^7aNo
To R^7d"Halogen atom", "C₁-C_FourAlkyl group ",
"C ₁-C_FourAlkoxy group ", 1 or 2 halogen atoms
C replaced above₁-C_FourAlkyl group ”and“ halogen atom ”
C substituted by 1 or 2 or more₁-C_FourAlkoxy group "
Is as defined above. In the general formula (I), R^FiveGeneral formula (a)
R in the group or the general formula (b)^7aOr R^7d"Hydroxy
C₁-C_FourThe “alkyl group” means that the hydroxy group is the aforementioned “C₁
-C_FourA group substituted with an "alkyl group";
As, for example, a hydroxymethyl group, 1-hydroxy
Siethyl group, 2-hydroxyethyl group, 1-hydroxy
Propyl group, 2-hydroxypropyl group, 3-hydroxy
Cypropyl group, 1-hydroxy-1-methylethyl group,
1-hydroxybutyl group, 2-hydroxybutyl group, 3
A -hydroxybutyl group or a 4-hydroxybutyl group;
Preferably a hydroxymethyl group,
Droxyethyl group, 2-hydroxyethyl group, 1-hydrido
Loxypropyl group, 2-hydroxypropyl group or 1-
Hydroxy C, such as a hydroxy-1-methylethyl group
₁-C_ThreeAn alkyl group, more preferably a hydroxy group.
Tyl group, 1-hydroxyethyl group, 2-hydroxyethyl
And a 1-hydroxypropyl group, particularly preferably
Is a hydroxymethyl group or a 1-hydroxyethyl group
is there. In the general formula (I), R^FiveGeneral formula (a)
R in the group or the general formula (b)^7aOr R^7d"C₁-C_FourA
The "alkyloxyimino group" refers to the aforementioned "C₁-C_FourAlkoki
A group in which the "si group" is substituted with an imino group.
For example, methoxyimino group, ethoxyimino
Group, propoxyimino group, isopropoxyimino group,
Toxiimino group, isobutoxyimino group, s-butoxy
An imino group or a t-butoxyimino group;
Preferably, a methoxyimino group, an ethoxyimino group,
C such as a poxyimino group or an isopropoxyimino group₁−
C_ThreeAn alkyloxyimino group, more preferably
A xyimino group or an ethoxyimino group, particularly preferably
Is a methoxyimino group. In the general formula (I), R^FiveGeneral formula (a)
R in the group or the general formula (b)^7aOr R^7d"C₁-C_FourA
Lucil and C_Three-C₇Identical selected from cycloalkyl
Or an amino group substituted by one or more different substituents "
Means “C₁-C_FourAlkyl group "and" C_Three-C₇
Same or different substitution selected from "cycloalkyl group"
Refers to an amino group substituted by one or more groups
Examples of the group include a methylamino group and a dimethylamino group.
No group, ethylamino group, diethylamino group, N-ethyl
-N-methylamino group, propylamino group, isopropyl
Ruamino group, butylamino group, cyclopropylamino
Group, dicyclopropylamino group, cyclobutylamino
Group, cyclopentylamino group, cyclohexylamino
Group, cycloheptylamino group, N-cyclopropyl-N
-Methylamino group or N-cyclopropyl-N-ethyl
An amino group can be mentioned, preferably, methylamino
Group, dimethylamino group, ethylamino group, diethylamino
Group, N-ethyl-N-methylamino group, cyclopropyl
Amino group, cyclobutylamino group, N-cyclopropyl
Ru-N-methylamino group or N-cyclopropyl-N-
C such as ethylamino group₁-C_TwoAlkyl or C_Three
-C_FourAn amino group mono- or di-substituted by cycloalkyl
Yes, more preferably methylamino group, dimethylamino
Group, ethylamino group or cyclopropylamino group.
And even more preferably a methylamino group or a dimethylamine group.
A mino group, particularly preferably a methylamino group. In the general formula (I), R^FiveGeneral formula (a)
R in the group or the general formula (b)^7aOr R^7d"In the amino group
Replaced C₁-C_Four`` Alkyl group '' is substituted with amino group
"C<sub>1</sub>-C<sub>Four</sub>Alkyl group "
Examples of such a group include, for example, an aminomethyl group, 1-amido
Noethyl group, 2-aminoethyl group, 1-aminopropyl
Group, 2-aminopropyl group, 3-aminopropyl group, 1
-Amino-1-methylethyl group, 1-aminobutyl group,
2-aminobutyl group, 3-aminobutyl group or 4-amino
And a nonbutyl group.
Group, 1-aminoethyl group, 2-aminoethyl group, 1-A
Minopropyl group, 2-aminopropyl group or 1-amino
C-substituted by an amino group such as -1-methylethyl group
<sub>1</sub>-C<sub>Three</sub>Alkyl group, more preferably aminomethyl
Group, 1-aminoethyl group or 2-aminoethyl group
Substituted with an amino group<sub>1</sub>-C<sub>Two</sub>An alkyl group.
More preferably, an aminomethyl group or 1-aminoethyl
And particularly preferably an aminomethyl group. In the general formula (I), R<sup>Five</sup>General formula (a)
R in the group or the general formula (b)<sup>7a</sup>Or R<sup>7d</sup>"C<sub>1</sub>-C<sub>Four</sub>A
Lucil and C<sub>Three</sub>-C<sub>7</sub>Identical selected from cycloalkyl
Or an amino group substituted by one or more different substituents
Replaced C<sub>1</sub>-C<sub>Four</sub>The “alkyl group” refers to the aforementioned “C<sub>1</sub>-C<sub>Four</sub>
Alkyl and C<sub>Three</sub>-C<sub>7</sub>The same selected from cycloalkyl
Amino substituted by one or more substituents with one or different substituents
"C" substituted with "group"<sub>1</sub>-C<sub>Four</sub>Alkyl "
Such groups include, for example, N-methylamino
Methyl group, 1- (N-methylamino) ethyl group, 2-
(N-methylamino) ethyl group, 1- (N-methylamino
No) propyl group, 2- (N-methylamino) propyl
Group, 3- (N-methylamino) propyl group, 1- (N-
Methylamino) -1-methylethyl group, 1- (N-methyl
L-amino) butyl group, 2- (N-methylamino) butyl
Group, 3- (N-methylamino) butyl group, 4- (N-methyl
Butylamino) butyl group, N-ethylaminomethyl group, 1
-(N-ethylamino) ethyl group, 2- (N-ethylamino)
Mino) ethyl group, 1- (N-ethylamino) propyl
Group, 2- (N-ethylamino) propyl group, 3- (N-
Ethylamino) propyl group, 1- (N-ethylamino)
-1-methylethyl group, 4- (N-ethylamino) buty
Group, N-propylaminomethyl group, 1- (N-propyl
L-amino) ethyl group, 2- (N-propylamino) ethyl
Group, N-isopropylaminomethyl group, 1- (NI
Isopropylamino) ethyl group, 2- (N-isopropyl)
Amino) ethyl group, N-butylaminomethyl group, 1-
(N-butylamino) ethyl group, 2- (N-butylamino)
No) ethyl group, N, N-dimethylaminomethyl group, 1-
(N, N-dimethylamino) ethyl group, 2- (N, N-
Dimethylamino) ethyl group, 1- (N, N-dimethyla
Mino) propyl group, 2- (N, N-dimethylamino) propyl
Propyl group, 3- (N, N-dimethylamino) propyl
Group, 1- (N, N-dimethylamino) -1-methylethyl
Group, 4- (N, N-dimethylamino) butyl group, N,
N-diethylaminomethyl group, 1- (N, N-diethyl
Amino) ethyl group, 2- (N, N-diethylamino)
Tyl group, N-cyclopropylaminomethyl group, 1- (N
-Cyclopropylamino) ethyl group, 2- (N-cyclo
Propylamino) ethyl group, 1- (N-cyclopropyl)
Amino) propyl group, 2- (N-cyclopropylamido)
No) propyl group, 3- (N-cyclopropylamino) p
Propyl group, 1- (N-cyclopropylamino) -1-me
Tylethyl group, 4- (N-cyclopropylamino) buty
Group, N-cyclobutylaminomethyl group, 1- (N-
Clobutylamino) ethyl group, 2- (N-cyclobutyl)
Amino) ethyl group, N-cyclopentylaminomethyl
Group, 1- (N-cyclopentylamino) ethyl group, 2-
(N-cyclopentylamino) ethyl group, N-cyclo
Xylaminomethyl group or 2- (N-cyclohexylurea)
A mino) ethyl group can be mentioned, and N-methyl is preferred.
L-aminomethyl group, 1- (N-methylamino) ethyl
Group, 2- (N-methylamino) ethyl group, 1- (N-
Tylamino) propyl group, 2- (N-methylamino) propyl
Ropyl group, 1- (N-methylamino) -1-methylethyl
Group, N-ethylaminomethyl group, 1- (N-ethyl
A mino) ethyl group, a 2- (N-ethylamino) ethyl group,
1- (N-ethylamino) propyl group, 2- (N-ethyl
Ruamino) propyl group, N-propylaminomethyl group,
1- (N-propylamino) ethyl group, N-isopropyl
L-aminomethyl group, 1- (N-isopropylamino)
Tyl group, N-butylaminomethyl group, 1- (N-butyl
Amino) ethyl group, N, N-dimethylaminomethyl group,
1- (N, N-dimethylamino) ethyl group, 2- (N,
N-dimethylamino) ethyl group, N, N-diethylamido
Nomethyl group, 1- (N, N-diethylamino) ethyl
Group, N-cyclopropylaminomethyl group, 1- (N-
Chloropropylamino) ethyl group, 2- (N-cyclopro
Pyramino) ethyl group, 1- (N-cyclopropylamido)
No) propyl group, 2- (N-cyclopropylamino) p
Such as a propyl group or an N-cyclobutylaminomethyl group
C<sub>1</sub>-C<sub>Four</sub>Alkyl group and C<sub>Three</sub>-C<sub>Four</sub>From the cycloalkyl group
1 or 2 substituted by the same or different substituents selected
C substituted with an amino group<sub>1</sub>-C<sub>Three</sub>An alkyl group,
Preferably, an N-methylaminomethyl group, 1- (N-methyl
L-amino) ethyl group, 2- (N-methylamino) ethyl
Group, N-ethylaminomethyl group, 1- (N-ethylamino
No) ethyl group, N, N-dimethylaminomethyl group, 1-
(N, N-dimethylamino) ethyl group, 2- (N, N-
Dimethylamino) ethyl group, N, N-diethylaminomethyl
A tyl group, an N-cyclopropylaminomethyl group or 1-
C such as (N-cyclopropylamino) ethyl group<sub>1</sub>−
C<sub>Two</sub>An alkyl group or a cyclopropyl group;
An amino group which is mono- or di-substituted by one or different substituents
Replaced C <sub>1</sub>-C<sub>Two</sub>An alkyl group, even more preferably
Represents an N-methylaminomethyl group, 1- (N-methylamino
G) ethyl group, N-ethylaminomethyl group, N, N-di
Methylaminomethyl group, 1- (N, N-dimethylamino
No) ethyl group, N, N-diethylaminomethyl group, N-
Cyclopropylaminomethyl group or 1- (N-cyclopropyl
Ropylamino) ethyl group, particularly preferably N-methyl group.
Tylaminomethyl group or N, N-dimethylaminomethyl
Group. In the general formula (I), R<sup>Five</sup>General formula (a)
R in the group or the general formula (b)<sup>7a</sup>Or R<sup>7d</sup>The charcoal that binds
C with elementary atoms<sub>Three</sub>-C<sub>Five</sub>A group forming a cycloalkane ring "
Is C<sub>Three</sub>-C<sub>Five</sub>The cycloalkane ring is a carbon atom on cyclic group A
Is a group that forms a spiro ring by bonding
Preferably, C<sub>Three</sub>-C<sub>Four</sub>Group forming a cycloalkane ring
And more preferably a group forming a cyclopropane ring
It is. In the general formula (I), R<sup>Five</sup>As a specific group of
Is preferably 4,5,6,7-tetrahydrothieno
[3,4-c] pyridin-4-yl group, 3-trifluoro
Romethyl-4,5,6,7-tetrahydrothieno [3,
4-c] pyridin-4-yl group, 3-chloro-4,5,
6,7-tetrahydrothieno [3,4-c] pyridine-
4-yl group, 3-cyano-4,5,6,7-tetrahydrid
Rothieno [3,4-c] pyridin-4-yl group,
Fluoro-5-methyl-4,5,6,7-tetrahydrothi
Eno [3,4-c] pyridin-4-yl group, 3-fluoro
B-4,5,6,7-tetrahydrothieno [3,4-
c] pyridin-4-yl group, 3-methyl-4,5,6,
7-tetrahydrothieno [3,4-c] pyridine-4-
Yl group, 3-difluoromethoxy-4,5,6,7-tet
A lahydrothieno [3,4-c] pyridin-4-yl group,
3-methoxy-4,5,6,7-tetrahydrothieno
[3,4-c] pyridin-4-yl group, 4-methyl-
4,5,6,7-tetrahydrothieno [3,4-c] pi
Lysin-4-yl group, 5-methyl-4,5,6,7-te
Trahydrothieno [3,4-c] pyridin-4-yl
Group, 6- (1-hydroxyethyl) -4,5,6,7-
Tetrahydrothieno [3,4-c] pyridin-4-yl
Group, 6-aminomethyl-4,5,6,7-tetrahydro
Thieno [3,4-c] pyridin-4-yl group, 6-cyclo
Ropropylaminomethyl-4,5,6,7-tetrahydride
Rothieno [3,4-c] pyridin-4-yl group, 6-meth
Tylaminomethyl-4,5,6,7-tetrahydrothier
No [3,4-c] pyridin-4-yl group, 6-dimethyl
Aminomethyl-4,5,6,7-tetrahydrothieno
[3,4-c] pyridin-4-yl group, 6-hydroxy
Methyl-4,5,6,7-tetrahydrothieno [3,4
-C] pyridin-4-yl group, 6-methyl-4,5,
6,7-tetrahydrothieno [3,4-c] pyridine-
4-yl group, spiro [4,5,6,7-tetrahydrothio
Eno [3,4-c] pyridine-6,1'-cyclopropa
4-N-yl group, 7-methyl-4,5,6,7-tetra
A lahydrothieno [3,4-c] pyridin-4-yl group,
7-amino-4,5,6,7-tetrahydrothieno
[3,4-c] pyridin-4-yl group, 7-hydroxy
Imino-4,5,6,7-tetrahydrothieno [3,4
-C] pyridin-4-yl group, 7-methoxyimino-
4,5,6,7-tetrahydrothieno [3,4-c] pi
Lysin-4-yl group, 7-hydroxy-4,5,6,7
-Tetrahydrothieno [3,4-c] pyridine-4-i
Group, 7-methoxy-4,5,6,7-tetrahydrothio
Eno [3,4-c] pyridin-4-yl group, 4,5
6,7-tetrahydrothieno [4,3-c] pyridine-
4-yl group, 5-methyl-4,5,6,7-tetrahydrid
Rothieno [4,3-c] pyridin-4-yl group, 7-meth
Cyl-4,5,6,7-tetrahydrothieno [4,3-
c] pyridin-4-yl group, 4-amino-4,5,6,
7-tetrahydrothieno [4,3-c] pyridine-4-
Yl group, 4-aminomethyl-4,5,6,7-tetrahi
Drobenzo [b] thiophen-4-yl group, 4-methyl
Aminomethyl-4,5,6,7-tetrahydrobenzo
[B] thiophen-4-yl group, 4-amino-3-chloro
B-4,5,6,7-Tetrahydrobenzo [b] thiof
Ene-4-yl group, 4-amino-3-cyano-4,5,
6,7-tetrahydrobenzo [b] thiophen-4-i
Group, 4-amino-3-fluoro-4,5,6,7-te
Trahydrobenzo [b] thiophen-4-yl group, 4-
Amino-3-methyl-4,5,6,7-tetrahydrobe
Benzo [b] thiophen-4-yl group, 4-amino-3-
Difluoromethoxy-4,5,6,7-tetrahydroben
Zo [b] thiophen-4-yl group, 4-amino-3-meth
Toxi-4,5,6,7-tetrahydrobenzo [b] thi
Offen-4-yl group, 4-amino-6-hydroxymethyl
Tyl-4,5,6,7-tetrahydrobenzo [b] thio
Phen-4-yl group, 4-amino-6-methyl-4,
5,6,7-tetrahydrobenzo [b] thiophene-4
-Yl group, 4-amino-6-methoxy-4,5,6,7
A tetrahydrobenzo [b] thiophen-4-yl group,
4-amino-7-fluoromethyl-4,5,6,7-te
Trahydrobenzo [b] thiophen-4-yl group, 4-
Amino-7-aminomethyl-4,5,6,7-tetrahi
Drobenzo [b] thiophen-4-yl group, 4-amino
-7-cyclopropylaminomethyl-4,5,6,7-
Tetrahydrobenzo [b] thiophen-4-yl group, 4
-Amino-7-methyl-4,5,6,7-tetrahydro
Benzo [b] thiophen-4-yl group, 4,7-diamido
No-4,5,6,7-tetrahydrobenzo [b] thiof
Ene-4-yl group, 4-amino-7-hydroxy-4,
5,6,7-tetrahydrobenzo [b] thiophene-4
-Yl group, 4-amino-7-methoxy-4,5,6,7
A tetrahydrobenzo [b] thiophen-4-yl group,
4-amino-4,5,6,7-tetrahydrobenzo
[B] thiophen-4-yl group, 4-cyclopropyla
Mino-4,5,6,7-tetrahydrobenzo [b] thio
Phen-4-yl group, 4-methylamino-4,5,6
7-tetrahydrobenzo [b] thiophen-4-yl
Group, 4-dimethylamino-4,5,6,7-tetrahydrido
Lobenzo [b] thiophen-4-yl group, 4-hydroxy
Simino-4,5,6,7-tetrahydrobenzo [b]
Thiophen-4-yl group, 4-methoxyimino-4,
5,6,7-tetrahydrobenzo [b] thiophene-4
-Yl group, 4-hydroxy-4,5,6,7-tetrahi
Drobenzo [b] thiophen-4-yl group, 5-amino
-4,5,6,7-tetrahydrobenzo [b] thiophene
-4-yl group, 5-amino-3-fluoro-4,5,
6,7-tetrahydrobenzo [b] thiophen-4-i
Group, 6-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-4-yl group, 7-amino-4,
5,6,7-tetrahydrobenzo [b] thiophene-4
-Yl group, 5,6-dihydro-4H-thieno [4,3-
c] pyrrol-4-yl group, 3-chloro-5,6-dihi
Dro-4H-thieno [4,3-c] pyrrol-4-yl
Group, 3-cyano-5,6-dihydro-4H-thieno
[4,3-c] pyrrol-4-yl group, 3-fluoro-
6-methyl-5,6-dihydro-4H-thieno [4,3
-C] pyrrol-4-yl group, 3-fluoro-5,6-
Dihydro-4H-thieno [4,3-c] pyrrol-4-
Yl group, 3-methyl-5,6-dihydro-4H-thieno
[4,3-c] pyrrol-4-yl group, 3-difluorome
Toxic-5,6-dihydro-4H-thieno [4,3-
c] pyrrol-4-yl group, 3-methoxy-5,6-di
Hydro-4H-thieno [4,3-c] pyrrol-4-i
Group, 4-methyl-5,6-dihydro-4H-thieno
[4,3-c] pyrrol-4-yl group, 5-methyl-
5,6-dihydro-4H-thieno [4,3-c] pyro-
Ru-4-yl group, 6-aminomethyl-5,6-dihydro
-4H-thieno [4,3-c] pyrrol-4-yl group,
6-cyclopropylaminomethyl-5,6-dihydro-
4H-thieno [4,3-c] pyrrol-4-yl group, 6
-Methylaminomethyl-5,6-dihydro-4H-thie
No [4,3-c] pyrrol-4-yl group, 6-dimethyl
Aminomethyl-5,6-dihydro-4H-thieno [4,
3-c] pyrrol-4-yl group, 6-hydroxymethyl
-5,6-dihydro-4H-thieno [4,3-c] pyro
-Lu-4-yl group, 6-methyl-5,6-dihydro-4
H-thieno [4,3-c] pyrrol-4-yl group, spin
B [5,6-dihydro-4H-thieno [4,3-c] pi
Roll-6,1'-cyclopropane] -4-yl group, 4
-Amino-5,6-dihydro-4H-cyclopenta
[B] thiophen-4-yl group, 4-amino-3-chloro
B-5,6-dihydro-4H-cyclopenta [b] thio
Phen-4-yl group, 4-amino-3-cyano-5,6
-Dihydro-4H-cyclopenta [b] thiophene-4
-Yl group, 4-amino-3-methyl-5,6-dihydro
-4H-cyclopenta [b] thiophen-4-yl group,
4-amino-3-difluoromethoxy-5,6-dihydride
B-4H-Cyclopenta [b] thiophen-4-yl
Group, 4-amino-3-methoxy-5,6-dihydro-4
H-cyclopenta [b] thiophen-4-yl group, 4-
Amino-5-trifluoromethyl-5,6-dihydro-
4H-cyclopenta [b] thiophen-4-yl group, 4
-Amino-5-hydroxymethyl-5,6-dihydro-
4H-cyclopenta [b] thiophen-5-yl group, 4
-Amino-5-methyl-5,6-dihydro-4H-cycl
Lopenta [b] thiophen-4-yl group, 4-amino-
6-fluoromethyl-5,6-dihydro-4H-cyclo
Penta [b] thiophen-4-yl group, 4-amino-6
-Aminomethyl-5,6-dihydro-4H-cyclopen
[B] thiophen-4-yl group, 4-amino-6-cy
Clopropylaminomethyl-5,6-dihydro-4H-
Cyclopenta [b] thiophen-4-yl group, 4-amido
No-6-methyl-5,6-dihydro-4H-cyclopen
[B] thiophen-4-yl group, 4,6-diamino-
5,6-dihydro-4H-cyclopenta [b] thiophene
4-Nyl group, 4-amino-6-hydroxy-5,6
-Dihydro-4H-cyclopenta [b] thiophene-4
-Yl group, 4-amino-6-methoxy-5,6-dihydride
B-4H-Cyclopenta [b] thiophen-4-yl
Group, 5-amino-5,6-dihydro-4H-cyclopen
[B] thiophen-4-yl group, 6-amino-5,6
-Dihydro-4H-cyclopenta [b] thiophene-4
-Yl group, 4-amino-6-methyl-4,5,6,7-
Tetrahydrothieno [4,3-c] pyridin-4-yl
The group 4-amino-6-methyl-5-oxo-4,5,
6,7-tetrahydrothieno [4,3-c] pyridine-
4-yl group, 4-methylamino-4,5,6,7-tetra
A lahydrothieno [4,3-c] pyridin-4-yl group,
4-amino-7,7-dimethyl-4,5,6,7-tet
A lahydrothieno [4,3-c] pyridin-4-yl group,
4-methylamino-7,7-dimethyl-4,5,6,7
-Tetrahydrothieno [4,3-c] pyridine-4-i
Group, spiro [4-amino-4,5,6,7-tetrahi
Dorothieno [4,3-c] pyridine-7,1'-cycloprop
Lopan] -4-yl group, spiro [4-methylamino-4,
5,6,7-tetrahydrothieno [4,3-c] pyridi
-7,1'-cyclopropane] -4-yl group, 7-amino
-4,4-dimethyl-4,5,6,7-tetrahydrothi
Eno [3,4-c] pyridin-4-yl group, 7-methyl
Amino-4,4-dimethyl-4,5,6,7-tetrahi
Drothieno [3,4-c] pyridin-4-yl group, spino
B [7-amino-4,5,6,7-tetrahydrothieno
[3,4-c] pyridine-4,1′-cyclopropane] -4
-Yl group, spiro [7-methylamino-4,5,6,7
-Tetrahydrothieno [3,4-c] pyridine-4,1 '
-Cyclopropane] -4-yl group, 7-amino-5-
Cyl-4,5,6,7-tetrahydrothieno [3,4-
c] pyridin-4-yl group, 4-methylamino-4,5
Thiopyran-4-yl group, 4-amino-4,7-dihydride
B-5H-thieno [4,3-c] thiopyran-4-yl
Group, 4-methylamino-4,7-dihydro-5H-thiene
No [4,3-c] thiopyran-4-yl group, 4-amino-
4,7-dihydro-5H-thieno [4,3-c, 6,7-
Tetrahydrothieno [3,4-c] pyridin-4-yl
Group, 4-amino-5-methyl-4,5,6,7-tetra
Hydrobenzo [b] thiophen-4-yl group, 4-amido
No-5,6-dihydro-4H-thieno [4,3-b] thio
Pyran-4-yl group, 4-methylamino-5,6-dihi
Dro-4H-thieno [4,3-b]] pyran-4-yl
Group, 4-methylamino-4,7-dihydro-5H-thiene
No [4,3-c] pyran-4-yl group, 4-amino-5
6,7,8-tetrahydro-4H-thieno [4,3-
d] azepin-4-yl group, 4-methylamino-5,
6,7,8-tetrahydro-4H-thieno [4,3-
d] azepin-4-yl group, 4-amino-4,5,6,
7-tetrahydrobenzo [b] furan-4-yl group, 4
-Methylamino-5,6,7,8-tetrahydrobenzo
[b] furan-4-yl group, isoindoline-5-yl
Group, 1-methylisoindoline-5-yl group, 2-methyl
Luisoindoline-5-yl group, 7-methylisoindo
Phosphorus-5-yl group, 1,7-dimethylisoindoline
5-yl group, 7-fluoroisoindolin-5-yl
Group, 7-fluoro-1-methylisoindoline-5-i
A 1,1-dimethylisoindoline-5-yl group,
Spiro [isoindoline-1,1'-cyclopropane]
-5-yl group, 6-fluoroisoindolin-5-yl
Group, 6-fluoro-1-methylisoindoline-5-i
Group, 4-fluoroisoindoline-5-yl group, 4-
Fluoro-1-methylisoindoline-5-yl group, 7
-Chloroisoindoline-5-yl group, 7-methoxyi
Soindolin-5-yl group, 7-difluoromethoxyiso
Indoline-5-yl group, 7-trifluoromethyliso
Indoline-5-yl group, 7-cyanoisoindoline-
5-yl group, 1-hydroxymethylisoindoline-5
-Yl group, 1-aminomethylisoindoline-5-yl
Group, 1-methylaminomethylisoindoline-5-yl
Group, 1-dimethylaminomethylisoindoline-5-i
Group, 1-cyclopropylaminomethylisoindoline
-5-yl group, 1-aminoindan-5-yl group, 2-
Aminoindan-5-yl group, 3-aminoindan-5
-Yl group, 1-aminoindan-4-yl group, 3-methyl
Ruaminoindan-5-yl group, 3-dimethylaminoi
Ndan-5-yl group, 3-amino-7-methylindan
-5-yl group, 3-amino-7-fluoroindan-5
-Yl group, 3-amino-7-chloroindan-5-yl
A 3-amino-7-methoxyindan-5-yl group,
3-amino-7-difluoromethoxyindan-5-yl
Group, 3-aminomethylindan-5-yl group, 3-methyl
Ruaminomethylindan-5-yl group, 3-dimethyla
Minomethylindan-5-yl group, 6-amino-5,
6,7,8-tetrahydronaphthalen-2-yl group, 5
-Amino-5,6,7,8-tetrahydronaphthalene-
2-yl group, 4-amino-5,6,7,8-tetrahydride
Ronaphthalen-2-yl group, 7-amino-5,6,7,
8-tetrahydronaphthalen-2-yl group, 8-amino
-5,6,7,8-tetrahydronaphthalen-2-yl
Group, 8-amino-4-methyl-5,6,7,8-tetra
Hydronaphthalen-2-yl group, 8-amino-4-metho
Xy-5,6,7,8-tetrahydronaphthalene-2-
Yl group, 8-amino-4-fluoro-5,6,7,8-
Tetrahydronaphthalen-2-yl group, 8-amino-4
-Trifluoromethyl-5,6,7,8-tetrahydro
Naphthalen-2-yl group, 5-amino-5,6,7,8
-Tetrahydronaphthalen-1-yl group, 8-aminomethyl
Cyl-5,6,7,8-tetrahydronaphthalene-2-
Yl group, 8-cyclopropylamino-5,6,7,8-
Tetrahydronaphthalen-2-yl group, 8-amino-6
-Methoxy-5,6,7,8-tetrahydronaphthalene
-2-yl group or 6-amino-6-difluoromethoxy
C-5,6,7,8-tetrahydronaphthalene-2-i
And more preferably 4,5,6,7-tetrahi
Drothieno [3,2-c] pyridin-2-yl group, 3-
Trifluoromethyl-4,5,6,7-tetrahydrothi
Eno [3,2-c] pyridin-2-yl group, 3-fluoro
B-5-Methyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl group, 3-fluoro-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl group, 3-methyl-4,5,6,7-te
Trahydrothieno [3,2-c] pyridin-2-yl
Group, 4-methyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl group, 5-methyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl group, 6-aminomethyl-4,5,6
7-tetrahydrothieno [3,2-c] pyridine-2-
Yl group, 6-hydroxymethyl-4,5,6,7-tetra
A lahydrothieno [3,2-c] pyridin-2-yl group,
6-methyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl group, 7-methyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl group, 7-amino-4,5,6,7-te
Trahydrothieno [3,2-c] pyridin-2-yl
Group, 7-hydroxyimino-4,5,6,7-tetrahi
Drothieno [3,2-c] pyridin-2-yl group, 7-
Methoxyimino-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl group, 7-hydroxy
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl group, 4,5,6,7-tetrahydro
Thieno [2,3-c] pyridin-2-yl group, 5-methyl
-4,5,6,7-tetrahydrothieno [2,3-
c] pyridin-2-yl group, 7-methyl-4,5,6,
7-tetrahydrothieno [2,3-c] pyridine-2-
Yl group, 4-amino-4,5,6,7-tetrahydrothio
Eno [2,3-c] pyridin-2-yl group, 4-amino
-3-fluoro-4,5,6,7-tetrahydrobenzo
[B] thiophen-2-yl group, 4-amino-7-methyl
-4,5,6,7-tetrahydrobenzo [b] thiof
En-2-yl group, 4-amino-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl group, 5-a
Mino-4,5,6,7-tetrahydrobenzo [b] thio
Phen-2-yl group, 5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl group, 3-fluoro-
6-methyl-5,6-dihydro-4H-thieno [2,3
-C] pyrrol-2-yl group, 3-fluoro-5,6-
Dihydro-4H-thieno [2,3-c] pyrrol-2-
Yl group, 3-methyl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl group, 4-methyl-
5,6-dihydro-4H-thieno [2,3-c] pyro-
Ru-2-yl group, 6-methyl-5,6-dihydro-4H
-Thieno [2,3-c] pyrrol-2-yl group, spiro
[5,6-dihydro-4H-thieno [2,3-c] pyro
-Yl-6,1'-cyclopropane] -2-yl group, 4-
Amino-5,6-dihydro-4H-cyclopenta [b]
Thiophen-2-yl group, 4-amino-6-methyl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl group, 4-amino-6-methyl-5-o
Xo-4,5,6,7-tetrahydrothieno [2,3-
c] pyridin-2-yl group, 4-methylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
2--2-yl group, 4-amino-7,7-dimethyl-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
-2-yl group, 4-methylamino-7,7-dimethyl
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridin-2-yl group, spiro [4-amino-4,5,
6,7-tetrahydrothieno [2,3-c] pyridine-
7,1′-cyclopropane] -2-yl group, spiro [4-me
Tylamino-4,5,6,7-tetrahydrothieno
[2,3-c] pyridine-7,1′-cyclopropane] -2
-Yl group, 7-amino-5-methyl-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Group, 4-methylamino-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl group, 4-amido
No-5-methyl-4,5,6,7-tetrahydrobenzo
[B] thiophen-2-yl group, 4-amino-5,6-
Dihydro-4H-thieno [2,3-b] thiopyran-2
-Yl group, 4-methylamino-5,6-dihydro-4H
-Thieno [2,3-b] thiopyran-2-yl group, 4-
Amino-4,7-dihydro-5H-thieno [2,3-
c] thiopyran-2-yl group, 4-methylamino-4,
7-dihydro-5H-thieno [2,3-c] thiopyran
-2-yl group, 4-amino-4,7-dihydro-5H-
Thieno [2,3-c] pyran-2-yl group, 4-methyl
Amino-4,7-dihydro-5H-thieno [2,3-
c] pyran-2-yl group, 4-amino-5,6,7,8
-Tetrahydro-4H-thieno [2,3-d] azepine
-2-yl group, 4-methylamino-4,5,6,7-te
Trahydrobenzo [b] furan-2-yl group, isoin
Dolin-5-yl group, 1-methylisoindoline-5
Yl group, 2-methylisoindoline-5-yl group, 7-
Methylisoindoline-5-yl group, 7-fluoroiso
Indoline-5-yl group, 1,1-dimethylisoindo
Phosphorus-5-yl group, 6-fluoroisoindoline-5
Yl group, 4-fluoroisoindoline-5-yl group, 7
-Difluoromethoxyisoindoline-5-yl group, 3-
Aminoindan-5-yl group, 3-methylaminoinda
-5-yl group, 3-dimethylaminoindan-5-i
A 3-amino-7-methylindan-5-yl group;
3-amino-7-fluoroindan-5-yl group, 3-
An amino-7-difluoromethoxyindan-5-yl group,
3-aminomethylindan-5-yl group, 3-methyla
Minomethylindan-5-yl group, 3-dimethylamino
Methylindan-5-yl group, 8-amino-5,6,
7,8-tetrahydronaphthalen-2-yl group, 8-A
Mino-4-methyl-5,6,7,8-tetrahydronaph
Taren-2-yl group, 8-amino-4-fluoro-5,
6,7,8-tetrahydronaphthalen-2-yl group, 8
-Amino-4-trifluoromethyl-5,6,7,8-
Tetrahydronaphthalen-2-yl group, 5-amino-
5,6,7,8-tetrahydronaphthalen-1-yl
Group or 8-aminomethyl-5,6,7,8-tetra
A hydronaphthalen-2-yl group; In the above, “the ester” refers to the book
The compounds of the invention can be converted into esters, so
And such esters include, for example,
Ester of droxy group and ester of carboxy group
And each ester residue is a "general protecting group" or
"Cleaved in vivo by chemical or enzymatic hydrolysis.
Ester "which is the" protecting group obtained ". "General protecting group" means hydrogenolysis, hydrolysis,
Cleavage by chemical methods such as decomposition, electrolysis, photolysis
A protecting group that can be
Such "general protecting groups" include, for example, formyl,
Cetyl, propionyl, butyryl, isobutyryl, pen
Tanoyl, pivaloyl, valeryl, isovaleryl, oct
Tanoyl, nonanoyl, decanoyl, 3-methylnonano
Yl, 8-methylnonanoyl, 3-ethyloctanoy
3,3,7-dimethyloctanoyl, undecanoyl,
Dodecanoyl, tridecanoyl, tetradecanoyl, pe
Nantadecanoyl, hexadecanoyl, 1-methylpentane
Decanoyl, 14-methylpentadecanoyl, 13,1
3-dimethyltetradecanoyl, heptadecanoyl, 1
5-methylhexadecanoyl, octadecanoyl, 1-
Methylheptadecanoyl, nonadecanoyl, eicosano
Alkyl carbonyls such as yl and henicosanoyl
Groups, such as succinoyl, glutaroyl, adipoyl
Carboxylated alkylcarbonyl group, chloroacetyl
, Dichloroacetyl, trichloroacetyl, trifur
1 or 2 or more substitution by halogen atom such as oroacetyl
Lower carbonyl group, cyclopropyl group
Rubonyl, cyclobutylcarbonyl, cyclopentylca
Rubonyl, cyclohexylcarbonyl, cycloheptyl
Saturated rings such as carbonyl and cyclooctylcarbonyl
Hydrocarbon-carbonyl groups, such as methoxyacetyl
Lower alkoxy lower alkyl group carbonyl group, (E)-
Unsaturated alkyl groups such as 2-methyl-2-butenoyl
“Aliphatic acyl group” such as rubonyl group; benzoyl, naph
A like toil, pyridoyl, thienoyl, floyl
Reel carbonyl group, 2-bromobenzoyl, 4-chloro
Substituted by 1 or 2 or more halogen atoms such as lobenzoyl
Arylcarbonyl group, 2,4,6-trimethyl
Lower alkyl groups such as benzoyl and 4-toluoyl
Lower alkyl such as arylcarbonyl group and 4-anisoyl
Alkoxylated arylcarbonyl group, 2-carboxy group
Nzoyl, 3-carboxy group benzoyl, 4-carboxy
Carboxylated aryl carboxyls such as benzoyl groups
Nyl group, 4-nitrobenzoyl, 2-nitrobenzoyl
A nitrated arylcarbonyl group such as 2- (methoxy)
Lower alkoxycars such as benzoyl) benzoyl
Bonylated arylcarbonyl group, 4-phenylbenzoyi
Fragrances such as arylated arylcarbonyl groups such as
Group acyl group "; phenylacetyl, α-naphthylpropyl
Onyl, β-naphthylbutyryl, diphenylisobutylyl
, Triphenylacetyl, α-naphthyldiphenyli
One such as sobutyryl, 9-anthryl pentanoyl
Lower alkyl group carboxy substituted with up to three aryl groups
Nyl group, 4-methylphenylacetyl, 2,4,6-to
Limethylphenylformyl, 3,4,5-trimethylf
Enylbutyryl, 4-methoxyphenylisobutyryl,
4-methoxyphenyldiphenylpivaloyl, 2-nitro
Rophenylacetyl, 4-nitrophenylpropioni
4-chlorophenylbutyryl, 4-bromophenyl
Low as acetyl, 4-cyanophenylpentanoyl
Lower alkyl group, lower alkoxy group, nitro group, halogen
1 to 3 aryl atoms substituted with an atom or cyano group
Lower alkyl group substituted with aryl group, carbonyl group, etc.
"Aralkylcarbonyl group"; tetrahydropyran-
2-yl, 3-bromotetrahydropyran-2-yl,
4-methoxytetrahydropyran-4-yl, tetrahi
Dorothiopyran-2-yl, 4-methoxytetrahydro
"Tetrahydropyranyl" such as thiopyran-4-yl
Or tetrahydrothiopyranyl group "; tetrahydrofura
2-Nyl and tetrahydrothiofuran-2-yl
Such as tetrahydrofuranyl or tetrahydrothiofura
Nyl group ”; trimethylsilyl, triethylsilyl, iso
Propyldimethylsilyl, t-butyldimethylsilyl,
Methyl diisopropylsilyl, methyl di-t-butyl
Tri-lower alkyls such as silyl and triisopropylsilyl
Kill group silyl group, diphenylmethylsilyl, diphenyl
Butylsilyl, diphenylisopropylsilyl, phenyl
One or two aryls, such as rudiisopropylsilyl
Tri-lower alkyl-substituted silyl groups such as silyl groups
Methoxymethyl, 1,1-dimethyl-1-methoate
Xymethyl, ethoxymethyl, propoxymethyl, iso
Propoxymethyl, butoxymethyl, t-butoxymethyl
A lower alkoxymethyl group such as
Lower alkoxylated lower alkoxymethacrylates such as xymethyl
Tyl group, 2,2,2-trichloroethoxymethyl, bis
A halogen atom such as (2-chloroethoxy) methyl
"A" such as lower alkoxymethyl substituted by 1 or 2 or more
1-ethoxyethyl 1- (isopropoxymethyl group);
Lower alkoxylated ethyl groups such as (ropoxy) ethyl,
Halogen atomization such as 2,2,2-trichloroethyl
“Substituted ethyl group” such as ethyl group; benzyl, α-naphthy
Methyl, β-naphthylmethyl, diphenylmethyl,
Riphenylmethyl, α-naphthyldiphenylmethyl, 9
-With one to three aryl groups such as anthrylmethyl
Substituted lower alkyl group, 4-methylbenzyl, 2,
4,6-trimethylbenzyl, 3,4,5-trimethyl
Benzyl, 4-methoxybenzyl, 4-methoxyphenyl
Rudiphenylmethyl, 2-nitrobenzyl, 4-nitro
Benzyl, 4-chlorobenzyl, 4-bromobenzyl,
A lower alkyl group such as 4-cyanobenzyl,
Ali by oxy group, nitro group, halogen atom, cyano group
Substituted with 1 to 3 substituted aryl groups
"Aralkyl group" such as lower alkyl group; methoxycarbo
Nil, ethoxycarbonyl, t-butoxycarbonyl,
Lower alkoxycarbo such as isobutoxycarbonyl
A nyl group, 2,2,2-trichloroethoxycarbonyl,
Halo such as 2-trimethylsilylethoxycarbonyl
Substituted with a gen atom or a tri-lower alkyl silyl group
“Alkoxycarboni” such as lower alkoxycarbonyl group
Group "; vinyloxycarbonylallyloxycarboni
An `` alkenyloxycarbonyl group '' such as
Benzyloxycarbonyl, 4-methoxybenzyloxy
Cicarbonyl, 3,4-dimethoxybenzyloxycal
Bonyl, 2-nitrobenzyloxycarbonyl, 4-ni
1 to 2 such as trobenzyloxycarbonyl
An aryl ring is substituted by a lower alkoxy group or a nitro group;
"Aralkyloxycarbonyl group" which may be
On the other hand, "ester of carboxy group"
As such a “general protecting group”, preferably, methyl,
Chill, propyl, isopropyl, butyl, isobutyl,
s-butyl, t-butyl, pentyl, isopentyl, 2
-Methylbutyl, neopentyl, 1-ethylpropyl,
Hexyl, isohexyl, 4-methylpentyl, 3-methyl
Chillpentyl, 2-methylpentyl, 1-methylpentyl
3,3-dimethylbutyl, 2,2-dimethylbutyl
1,1-dimethylbutyl, 1,2-dimethylbutyl
1,3-dimethylbutyl, 2,3-dimethylbutyl
"Lower alkyl groups" such as 2-ethylbutyl;
Thenyl, 1-propenyl, 2-propenyl, 1-methyl
-2-propenyl, 1-methyl-1-propenyl, 2-
Methyl-1-propenyl, 2-methyl-2-propenyl
2-ethyl-2-propenyl, 1-butenyl, 2-
Butenyl, 1-methyl-2-butenyl, 1-methyl-1
-Butenyl, 3-methyl-2-butenyl, 1-ethyl-
2-butenyl, 3-butenyl, 1-methyl-3-butenyl
2-methyl-3-butenyl, 1-ethyl-3-butene
Nil, 1-pentenyl, 2-pentenyl, 1-methyl-
2-pentenyl, 2-methyl-2-pentenyl, 3-pe
Unenyl, 1-methyl-3-pentenyl, 2-methyl-
3-pentenyl, 4-pentenyl, 1-methyl-4-pe
Pentenyl, 2-methyl-4-pentenyl, 1-hexenyl
, 2-hexenyl, 3-hexenyl, 4-hexenyl
Alkenyl groups, such as 5-hexenyl; ethynyl
2-propynyl, 1-methyl-2-propynyl, 2
-Methyl-2-propynyl, 2-ethyl-2-propini
2-butynyl, 1-methyl-2-butynyl, 2-methyl
Tyl-2-butynyl, 1-ethyl-2-butynyl, 3-
Butynyl, 1-methyl-3-butynyl, 2-methyl-3
-Butynyl, 1-ethyl-3-butynyl, 2-pentini
1-methyl-2-pentynyl, 2-methyl-2-pe
Pentynyl, 3-pentynyl, 1-methyl-3-pentini
, 2-methyl-3-pentynyl, 4-pentynyl, 1
-Methyl-4-pentynyl, 2-methyl-4-pentini
, 2-hexynyl, 3-hexynyl, 4-hexynyl
An “alkynyl group” such as 5-hexynyl;
Fluoromethyl, trichloromethyl, difluoromethyl,
Dichloromethyl, dibromomethyl, fluoromethyl,
2,2,2-trifluoroethyl, 2,2,2-tric
Loroethyl, 2-bromoethyl, 2-chloroethyl, 2
-Fluoroethyl, 2-iodoethyl, 3-chloropro
Pill, 4-fluorobutyl, 6-iodohexyl, 2,
"1 or 2 halogen atoms" such as 2-dibromoethyl
Lower alkyl group substituted above "; 2-hydroxyethyl
, 2,3-dihydroxypropyl, 3-hydroxyp
Ropyl, 3,4-dihydroxybutyl, 4-hydroxy
"Hydroxy lower alkyl" such as butyl; acetyl
"Aliphatic acyl" such as
A group "; benzyl, phenethyl, 3-phenylpropyl,
α-naphthylmethyl, β-naphthylmethyl, diphenyl
Methyl, triphenylmethyl, 6-phenylhexyl,
α-naphthyldiphenylmethyl, 9-anthrylmethyl
"Lower radicals substituted with one to three aryl groups such as
Alkyl group ”, 4-methylbenzyl, 2,4,6-trime
Tylbenzyl, 3,4,5-trimethylbenzyl, 4-
Methoxybenzyl, 4-methoxyphenyldiphenylme
Tyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-
Chlorobenzyl, 4-bromobenzyl, 4-cyanoben
Jyl, 4-cyanobenzyldiphenylmethyl, bis (2
-Nitrophenyl) methyl, piperonyl, 4-methoxy
Lower alkyl such as carbonylbenzyl, lower alkyl
Coxy group, nitro group, halogen atom, cyano group, alcohol
1 to 3 aryl rings substituted with an oxycarbonyl group
"Arals" such as lower alkyl groups substituted with aryl groups of
Kill group '' or trimethylsilyl, triethylsilyl
, Isopropyldimethylsilyl, t-butyldimethyl
Silyl, methyldiisopropylsilyl, methyl di-t
-Butylsilyl, triisopropylsilyl, methyldiph
Enylsilyl, isopropyldiphenylsilyl, butyl
Diphenylsilyl and phenyldiisopropylsilyl
Such a “silyl group” can be mentioned. "In vivo, for chemical or enzymatic hydrolysis
Thus, a "cleavable protecting group" refers to a substance such as hydrolysis in the human body.
It is cleaved by biological methods to produce free acid or its salt.
Refers to the protective group that is formed.
Administered to laboratory animals such as mice and mice by intravenous injection,
Subsequent examination of the body fluid of the animal reveals the original compound or its drug.
Can be determined by the ability to detect a physically acceptable salt
You. The “raw” of “ester of hydroxy group”
Can be cleaved by chemical or enzymatic hydrolysis in the body
As the "protecting group", for example, formyloxymethyl, a
Sethoxymethyl, dimethylaminoacetoxymethyl,
Lopionyloxymethyl, butyryloxymethyl, piva
Loyloxymethyl, valeryloxymethyl, isovale
Ryloxymethyl, hexanoyloxymethyl, 1-e
Lumyloxyethyl, 1-acetoxyethyl, 1-pro
Pionyloxyethyl, 1-butyryloxyethyl, 1
-Pivaloyloxyethyl, 1-valeryloxyethyl
, 1-isovaleryloxyethyl, 1-hexanoyl
Oxyethyl, 1-formyloxypropyl, 1-ace
Toxipropyl, 1-propionyloxypropyl, 1
-Butyryloxypropyl, 1-pivaloyloxypro
Pill, 1-valeryloxypropyl, 1-isovaleryl
Oxypropyl, 1-hexanoyloxypropyl, 1
-Acetoxybutyl, 1-propionyloxybutyl,
1-butyryloxybutyl, 1-pivaloyloxybuty
1-acetoxypentyl, 1-propionyloxy
Pentyl, 1-butyryloxypentyl, 1-pivaloy
Like loxypentyl and 1-pivaloyloxyhexyl
Una 1-("aliphatic acyl" oxy) "lower alkyl
Group "; formylthiomethyl, acetylthiomethyl, dime
Tylaminoacetylthiomethyl, propionylthiomethy
, Butyrylthiomethyl, pivaloylthiomethyl, barre
Rylthiomethyl, isovalerylthiomethyl, hexanoy
Luthiomethyl, 1-formylthioethyl, 1-acetyl
Thioethyl, 1-propionylthioethyl, 1-butylene
Luthioethyl, 1-pivaloylthioethyl, 1-valeri
Luthioethyl, 1-isovalerylthioethyl, 1-hexyl
Sanoylthioethyl, 1-formylthiopropyl, 1-
Acetylthiopropyl, 1-propionylthiopropyl
1-butyrylthiopropyl, 1-pivaloylthiop
Ropyl, 1-valerylthiopropyl, 1-isovaleryl
Thiopropyl, 1-hexanoylthiopropyl, 1-a
Cetylthiobutyl, 1-propionylthiobutyl, 1-
Butyrylthiobutyl, 1-pivaloylthiobutyl, 1-
Acetylthiopentyl, 1-propionylthiopent
1-butyrylthiopentyl, 1-pivaloylthiope
1-, such as methyl, 1-pivaloylthiohexyl
("Aliphatic acyl" thio) "lower alkyl group"; cyclo
Pentylcarbonyloxymethyl, cyclohexylcal
Bonyloxymethyl, 1-cyclopentylcarbonylo
Xyl, 1-cyclohexylcarbonyloxyethyl
1-cyclopentylcarbonyloxypropyl, 1
-Cyclohexylcarbonyloxypropyl, 1-cyclohexyl
Lopentylcarbonyloxybutyl, 1-cyclohexyl
1- (such as cyclocarbonyloxybutyl
Kill ”carbonyloxy)“ lower alkyl group ”, benzo
1-("aromatic acyl" oxo, such as yloxymethyl
B) 1- (acyloxy) "low" such as "lower alkyl group"
Lower alkyl group "; methoxycarbonyloxymethyl, d
Toxycarbonyloxymethyl, propoxycarbonyl
Oxymethyl, isopropoxycarbonyloxymethyl
, Butoxycarbonyloxymethyl, isobutoxyca
Rubonyloxymethyl, pentyloxycarbonyloxy
Cimethyl, hexyloxycarbonyloxymethyl,
Clohexyloxycarbonyloxymethyl, cyclohexyl
Xyloxycarbonyloxy (cyclohexyl) methyl
1- (methoxycarbonyloxy) ethyl, 1-
(Ethoxycarbonyloxy) ethyl, 1- (propoxy
Cicarbonyloxy) ethyl, 1- (isopropoxy)
Rubonyloxy) ethyl, 1- (butoxycarbonyl)
Xy) ethyl, 1- (isobutoxycarbonyloxy)
Ethyl, 1- (t-butoxycarbonyloxy) ethyl
1- (pentyloxycarbonyloxy) ethyl,
1- (hexyloxycarbonyloxy) ethyl, 1-
(Cyclopentyloxycarbonyloxy) ethyl, 1
-(Cyclopentyloxycarbonyloxy) propyl
1- (cyclohexyloxycarbonyloxy) p
Ropyl, 1- (cyclopentyloxycarbonyloxy)
B) butyl, 1- (cyclohexyloxycarbonyl)
Xy) butyl, 1- (cyclohexyloxycarbonyl)
Oxy) ethyl, 1- (ethoxycarbonyloxy) p
Ropyl, 2- (methoxycarbonyloxy) ethyl, 2
-(Ethoxycarbonyloxy) ethyl, 2- (propo
Xycarbonyloxy) ethyl, 2- (isopropoxy)
Carbonyloxy) ethyl, 2- (butoxycarbonyl)
Oxy) ethyl, 2- (isobutoxycarbonyloxy)
B) Ethyl, 2- (pentyloxycarbonyloxy)
Ethyl, 2- (hexyloxycarbonyloxy) ethyl
1- (methoxycarbonyloxy) propyl, 1-
(Ethoxycarbonyloxy) propyl, 1- (propo
Xycarbonyloxy) propyl, 1- (isopropoxy)
Cicarbonyloxy) propyl, 1- (butoxycarbo)
Nyloxy) propyl, 1- (isobutoxycarbonyl)
Oxy) propyl, 1- (pentyloxycarbonyl)
Xy) propyl, 1- (hexyloxycarbonyloxy)
B) propyl, 1- (methoxycarbonyloxy) buty
1- (ethoxycarbonyloxy) butyl, 1-
(Propoxycarbonyloxy) butyl, 1- (isoprop
Ropoxycarbonyloxy) butyl, 1- (butoxyca)
Rubonyloxy) butyl, 1- (isobutoxycarbonyl)
Ruoxy) butyl, 1- (methoxycarbonyloxy)
Pentyl, 1- (ethoxycarbonyloxy) pliers
1- (methoxycarbonyloxy) hexyl, 1-
(Alcohol) such as (ethoxycarbonyloxy) hexyl
Coxycarbonyloxy) alkyl group; phthalidyl, di
"F" such as methylphthalidyl and dimethoxyphthalidyl
Talidyl group "; (5-phenyl-2-oxo-1,3-
Dioxolen-4-yl) methyl, [5- (4-methyl
Phenyl) -2-oxo-1,3-dioxolen-4-
Yl] methyl, [5- (4-methoxyphenyl) -2-
Oxo-1,3-dioxolen-4-yl] methyl,
[5- (4-fluorophenyl) -2-oxo-1,3
-Dioxolen-4-yl] methyl, [5- (4-chloro
L-phenyl) -2-oxo-1,3-dioxolen-4
-Yl] methyl, (2-oxo-1,3-dioxolene
-4-yl) methyl, (5-methyl-2-oxo-1,
3-dioxolen-4-yl) methyl, (5-ethyl-
2-oxo-1,3-dioxolen-4-yl) methyl
(5-propyl-2-oxo-1,3-dioxole)
N-4-yl) methyl, (5-isopropyl-2-oxo)
So-1,3-dioxolen-4-yl) methyl, (5-
Butyl-2-oxo-1,3-dioxolen-4-i
O) oxodioxorenylmethyl groups such as methyl
“Carbonyloxyalkyl group”; the above “aliphatic acyl”
Group "; the above-mentioned" aromatic acyl group ";
“Steel salt residue”; “Phosphate salt residue”; “Amino acid
Carbamoyl group; 1 to 2 residues
A carbamoyl group substituted by a lower alkyl group represented by the formula:
Ruboxyethyldithioethyl, 3-carboxypropyl
Dithioethyl, 4-carboxybutyldithioethyl, 5
-Carboxypentyldithioethyl, 6-carboxy
Carboxy "lower alkyl" such as xyldithioethyl
Le) dithioethyl group, or methyldithioethyl, ethyl
Rudithioethyl, propyldithioethyl, butyldithio
Ethyl, pentyldithioethyl, hexyldithioethyl
Dithioethyl groups such as "lower alkyl groups" such as
While the “ester of carboxy group”
"Cleaved in vivo by chemical or enzymatic hydrolysis.
As the `` obtaining protecting group '', specifically, methoxymethyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl
, 1- (isopropoxy) ethyl, 2-methoxyethyl
, 2-ethoxyethyl, 1,1-dimethyl-1-meth
Xymethyl, ethoxymethyl, propoxymethyl, iso
Propoxymethyl, butoxymethyl, t-butoxymethyl
A lower alkoxy lower alkyl group such as
Lower alkoxylated lower alcohols such as ethoxymethyl
Xy lower alkyl groups, such as phenoxymethyl
Oxy "lower alkyl group", 2,2,2-tri
Chloroethoxymethyl, bis (2-chloroethoxy) meth
Halogenated lower alkoxy lower alkyl such as tyl
"Alkoxy lower alkyl group" such as methoxy group
"Lower alkoxy" carbonyls such as bonylmethyl
"Lower alkyl group"; cyanomethyl, 2-cyanoethyl
Cyano "lower alkyl group" such as methylthiomethyl
Thio, "lower alkyl" such as ethylthiomethyl
Methyl group ;; phenylthiomethyl, naphthylthiomethyl
An "aryl group" such as a thiomethyl group; 2-methanesulfur
Phonylethyl, 2-trifluoromethanesulfonylethyl
Lower alkyl which may be substituted with a halogen atom such as
A “alkyl group” a sulfonyl a “lower alkyl group”; 2-benzene
Like sulfonylethyl and 2-toluenesulfonylethyl
“Aryl group” sulfonyl “lower alkyl group”;
Lumyloxymethyl, acetoxymethyl, propionyl
Oxymethyl, butyryloxymethyl, pivaloyloxy
Cimethyl, valeryloxymethyl, isovaleryloxy
Methyl, hexanoyloxymethyl, 1-formyloxy
Siethyl, 1-acetoxyethyl, 1-propionylo
Xyethyl, 1-butyryloxyethyl, 1-pivaloy
Ruoxyethyl, 1-valeryloxyethyl, 1-iso
Valeryloxyethyl, 1-hexanoyloxyethyl
, 2-formyloxyethyl, 2-acetoxyethyl
, 2-propionyloxyethyl, 2-butyryloxy
Ciethyl, 2-pivaloyloxyethyl, 2-valeryl
Oxyethyl, 2-isovaleryloxyethyl, 2-he
Xanoyloxyethyl, 1-formyloxypropyl
1-acetoxypropyl, 1-propionyloxy
Propyl, 1-butyryloxypropyl, 1-pivaloy
Ruoxypropyl, 1-valeryloxypropyl, 1-
Isovaleryloxypropyl, 1-hexanoyloxy
Propyl, 1-acetoxybutyl, 1-propionyl
Xybutyl, 1-butyryloxybutyl, 1-pivaloy
Loxybutyl, 1-acetoxypentyl, 1-propyl
Onyloxypentyl, 1-butyryloxypentyl,
1-pivaloyloxypentyl, 1-pivaloyloxy
Hexyl-like "aliphatic acyl" oxy "lower alkyl"
), Cyclopentylcarbonyloxymethyl, cyclo
Rohexylcarbonyloxymethyl, 1-cyclopentene
Carbonyloxyethyl, 1-cyclohexylcarbo
Nyloxyethyl, 1-cyclopentylcarbonyloxy
Cypropyl, 1-cyclohexylcarbonyloxypro
Pill, 1-cyclopentylcarbonyloxybutyl, 1
-"Si" such as cyclohexylcarbonyloxybutyl
Chloroalkyl) carbonyloxy "lower alkyl group",
"Aromatic acyl" oxo, such as benzoyloxymethyl
Acyloxy "lower alkyl" such as "lower alkyl"
Group "; methoxycarbonyloxymethyl, ethoxycal
Bonyloxymethyl, propoxycarbonyloxymethyl
, Isopropoxycarbonyloxymethyl, butoxy
Carbonyloxymethyl, isobutoxycarbonyloxy
Cimethyl, pentyloxycarbonyloxymethyl, f
Xyloxycarbonyloxymethyl, cyclohexyl
Oxycarbonyloxymethyl, cyclohexyloxy
Carbonyloxy (cyclohexyl) methyl, 1- (meth
Toxylcarbonyloxy) ethyl, 1- (ethoxy)
Bonyloxy) ethyl, 1- (propoxycarbonyl)
Xy) ethyl, 1- (isopropoxycarbonyloxy)
B) Ethyl, 1- (butoxycarbonyloxy) ethyl
1- (isobutoxycarbonyloxy) ethyl, 1
-(T-butoxycarbonyloxy) ethyl, 1- (pe
Ethyloxycarbonyloxy) ethyl, 1- (hexyl
Ruoxycarbonyloxy) ethyl, 1- (cyclopen
Tyloxycarbonyloxy) ethyl, 1- (cyclope
1- (cyclohexyloxycarbonyloxy) propyl
Rohexyloxycarbonyloxy) propyl, 1-
(Cyclopentyloxycarbonyloxy) butyl, 1
-(Cyclohexyloxycarbonyloxy) butyl,
1- (cyclohexyloxycarbonyloxy) ethyl
1- (ethoxycarbonyloxy) propyl, 2-
(Methoxycarbonyloxy) ethyl, 2- (ethoxy)
Carbonyloxy) ethyl, 2- (propoxycarbonyl)
Ruoxy) ethyl, 2- (isopropoxycarbonyl)
Xy) ethyl, 2- (butoxycarbonyloxy) ethyl
2- (isobutoxycarbonyloxy) ethyl, 2
-(Pentyloxycarbonyloxy) ethyl, 2-
(Hexyloxycarbonyloxy) ethyl, 1- (meth
Toxicarbonyloxy) propyl, 1- (ethoxyca)
Rubonyloxy) propyl, 1- (propoxycarbonyl)
Loxy) propyl, 1- (isopropoxycarbonyl)
Oxy) propyl, 1- (butoxycarbonyloxy)
Propyl, 1- (isobutoxycarbonyloxy) pro
Pill, 1- (pentyloxycarbonyloxy) propyl
1- (hexyloxycarbonyloxy) propyl
1- (methoxycarbonyloxy) butyl, 1-
(Ethoxycarbonyloxy) butyl, 1- (propoxy
(Cyclocarbonyloxy) butyl, 1- (isopropoxy)
Rubonyloxy) butyl, 1- (butoxycarbonyl)
Xy) butyl, 1- (isobutoxycarbonyloxy)
Butyl, 1- (methoxycarbonyloxy) pentyl,
1- (ethoxycarbonyloxy) pentyl, 1- (meth
Toxylcarbonyloxy) hexyl, 1- (ethoxy)
(Alkoxycarbo) such as rubonyloxy) hexyl
(Nyloxy) alkyl group; (5-phenyl-2-oxo)
-1,3-dioxolen-4-yl) methyl, [5-
(4-methylphenyl) -2-oxo-1,3-dioxo
Solen-4-yl] methyl, [5- (4-methoxy
Nyl) -2-oxo-1,3-dioxolen-4-i
] Methyl, [5- (4-fluorophenyl) -2-o
Xo-1,3-dioxolen-4-yl] methyl, [5
-(4-chlorophenyl) -2-oxo-1,3-dio
Xoxolen-4-yl] methyl, (2-oxo-1,3-
Dioxolen-4-yl) methyl, (5-methyl-2-
Oxo-1,3-dioxolen-4-yl) methyl,
(5-ethyl-2-oxo-1,3-dioxolen-4
-Yl) methyl, (5-propyl-2-oxo-1,3)
-Dioxolen-4-yl) methyl, (5-isopropyl)
2-oxo-1,3-dioxolen-4-yl) me
Chill, (5-butyl-2-oxo-1,3-dioxole
Oxodioxolenylmethyl such as (n-4-yl) methyl
“Carbonyloxyalkyl group” such as tyl group;
Like dimethylphthalidyl, dimethoxyphthalidyl
"Phthalidyl group"; such as phenyl and indanyl
“Aryl group”; the above “lower alkyl group” or
Tilthio, ethylthio, propylthio, isopropylthio
E, butylthio, isobutylthio, s-butylthio, t
-Butylthio, pentylthio, isopentylthio, 2-
Methylbutylthio, neopentylthio, 1-ethylpro
Pilthio, hexylthio, isohexylthio, 4-methyl
Rupentylthio, 3-methylpentylthio, 2-methyl
Pentylthio, 1-methylpentylthio, 3,3-dimethyl
Butylbutylthio, 2,2-dimethylbutylthio, 1,1
-Dimethylbutylthio, 1,2-dimethylbutylthio,
1,3-dimethylbutylthio, 2,3-dimethylbutyl
1 to 6 carbon atoms such as thio and 2-ethylbutylthio
Represents a straight-chain or branched-chain alkylthio group of
A number 1 to 4 "alkylthio group"; a carboxy group methyl
"Carboxy group alkyl group" such as
`` Amide-forming residues of amino acids '' such as lualanine
You. The compound (I) of the present invention has an asymmetric carbon atom in the molecule.
Optical isomers based on elemental atoms (including diastereomers)
Exists, and the geometric isomer based on the ring structure exists
However, each of these isomers is also included in the present invention. The “pharmacologically acceptable salt” is defined as
The clear compound (I) can be converted into a salt,
A salt, preferably such a salt as sodium
Alkali metals such as potassium, potassium and lithium salts
Alkaline earth such as salt, calcium salt, magnesium salt
Metal salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts
Metal salts such as Kell salt and cobalt salt; like ammonium salts
Inorganic salt, t-octylamine salt, dibenzylamine
Salt, morpholine salt, glucosamine salt, phenylglycine
Alkyl ester salt, ethylenediamine salt, N-methyl
Glucamine salt, guanidine salt, diethylamine salt, bird
Ethylamine salt, dicyclohexylamine salt, N, N '
-Dibenzylethylenediamine salt, chloroprocaine
Salt, procaine salt, diethanolamine salt, N-benzyl
Le-phenethylamine salt, piperazine salt, tetramethyl
Ammonium salt, tris (hydroxymethyl) aminometh
Amine salts such as organic salts such as tan salts; hydrofluoric acid salts;
Halogen such as hydrochloride, hydrobromide, hydroiodide
Hydrogenate, nitrate, perchlorate, sulfate, phosphoric acid
Inorganic salts such as salts; methanesulfonate, trifluoromethane
Lower grades such as tansulfonate and ethanesulfonate
Lucane sulfonate, benzene sulfonate, p-tolue
Aryl sulfonates such as sulfonic acid salts, acetic acid
Salt, malate, fumarate, succinate, citric acid
Organic salts such as salts, tartrate, oxalate, and maleate, and
Is glycine salt, lysine salt, arginine salt, ornithine
Amino such as salt, glutamate, aspartate
Acid salt. The compound (I) of the present invention is
Can still exist. Preferred compounds in the general formula (I)
Specific examples of the compounds shown in Tables 1 and 2 below
You. However, the compounds of the present invention are not limited to these.
is not. In Table 1, the meanings of the abbreviations are as follows.
It is on the street. That is, Me: methyl group, Et: ethyl group F-Et: 2-fluoroethyl group cPr: Cyclopropyl group F-cPr: 2-fluorocyclopropyl group dF-Ph: 2,4-difluorophenyl group dF-Py: 2,6-difluoro-3-pyridyl group NH_Two-dF-Py: 6-amino-3,5-difluoro-2-pi
Lysyl group Thiazo: 2-thiazolyl group THT (32c) P-2-yl: 4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl group 3-CF_Three-THT (32c) P-2-yl: 3-trifluoromethyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
N-2-yl group 3-Cl-THT (32c) P-2-yl: 3-chloro-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 3-CN-THT (32c) P-2-yl: 3-cyano-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 3-F-5-Me-THT (32c) P-2-yl: 3-fluoro-5-methyl
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl group 3-F-THT (32c) P-2-yl: 3-fluoro-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 3-Me-THT (32c) P-2-yl: 3-methyl-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 3-OCHF_Two-THT (32c) P-2-yl: 3-difluoromethoxy-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
N-2-yl group 3-OMe-THT (32c) P-2-yl: 3-methoxy-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridine-2-i
Le group 4-Me-THT (32c) P-2-yl: 4-methyl-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 5-Me-THT (32c) P-2-yl: 5-methyl-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 6-CH (OH) Me-THT (32c) P-2-yl: 6- (1-hydroxyd
Tyl) -4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl group 6-CH_TwoNH_Two-THT (32c) P-2-yl: 6-aminomethyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
N-2-yl group 6-CH_TwoNHcPr-THT (32c) P-2-yl: 6-cyclopropylamido
Nomethyl-4,5,6,7-tetrahydrothieno [3,
2-c] pyridin-2-yl group 6-CH_TwoNHMe-THT (32c) P-2-yl: 6-methylaminomethyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl group 6-CH_TwoNMe_Two-THT (32c) P-2-yl: 6-dimethylaminomethyl
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl group 6-CH_TwoOH-THT (32c) P-2-yl: 6-hydroxymethyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
N-2-yl group 6-Me-THT (32c) P-2-yl: 6-methyl-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 6-scPr-THT (32c) P-2-yl: spiro [4,5,6,7-te
Trahydrothieno [3,2-c] pyridine-6,1'-
Cyclopropane] -2-yl 7-Me-THT (32c) P-2-yl: 7-methyl-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 7-NH_Two-THT (32c) P-2-yl: 7-amino-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridin-2-yl
Base 7-NOH-THT (32c) P-2-yl: 7-hydroxyimino-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
N-2-yl group 7-NOMe-THT (32c) P-2-yl: 7-methoxyimino-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
N-2-yl group 7-OH-THT (32c) P-2-yl: 7-hydroxy-4,5,6
7-tetrahydrothieno [3,2-c] pyridine-2-
Il group 7-OMe-THT (32c) P-2-yl: 7-methoxy-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridine-2-i
Le group THT (23c) P-2-yl: 4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl group 5-Me-THT (23c) P-2-yl: 5-methyl-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridin-2-yl
Base 7-Me-THT (23c) P-2-yl: 7-methyl-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridin-2-yl
Base 4-NH_Two-THT (23c) P-2-yl: 7-amino-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridin-2-yl
Base 4-CH_TwoNH_Two-THBT-2-yl: 4-aminomethyl-4,5,6
7-tetrahydrobenzo [b] thiophen-2-yl group 4-CH_TwoNHMe-THBT-2-yl: 4-methylaminomethyl-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NH_Two-3-Cl-THBT-2-yl: 4-amino-3-chloro-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NH_Two-3-CN-THBT-2-yl: 4-amino-3-cyano-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NH_Two-3-F-THBT-2-yl: 4-amino-3-fluoro-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl group 4-NH_Two-3-Me-THBT-2-yl: 4-amino-3-methyl-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NH_Two-3-OCHF_Two-THBT-2-yl: 4-amino-3-difluoro
Methoxy-4,5,6,7-tetrahydrobenzo [b]
Thiophene-2-yl group 4-NH_Two-3-OMe-THBT-2-yl: 4-amino-3-methoxy-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl group 4-NH_Two-6-CH_TwoOH-THBT-2-yl: 4-amino-6-hydroxy
Cimethyl-4,5,6,7-tetrahydrobenzo [b]
Thiophene-2-yl group 4-NH_Two-6-Me-THBT-2-yl: 4-amino-6-methyl-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NH_Two-6-OMe-THBT-2-yl: 4-amino-6-methoxy-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl group 4-NH_Two-7-CH_TwoF-THBT-2-yl: 4-amino-7-fluorome
Tyl-4,5,6,7-tetrahydrobenzo [b] thio
Phen-2-yl group 4-NH_Two-7-CH_TwoNH_TwoTHBT-2-yl: 4-amino-7-aminomethyl
Tyl-4,5,6,7-tetrahydrobenzo [b] thio
Phen-2-yl group 4-NH_Two-7-CH_TwoNHcPr-THBT-2-yl: 4-amino-7-cyclo
Propylaminomethyl-4,5,6,7-tetrahydro
Benzo [b] thiophen-2-yl group 4-NH_Two-7-Me-THBT-2-yl: 4-amino-7-methyl-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4,7-dNH_Two-THBT-2-yl: 4,7-diamino-4,5,6
7-tetrahydrobenzo [b] thiophen-2-yl group 4-NH_Two-7-OH-THBT-2-yl: 4-amino-7-hydroxy-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl group 4-NH_Two-7-OMe-THBT-2-yl: 4-amino-7-methoxy-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl group 4-NH_Two-THBT-2-yl: 4-amino-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl group 4-NHcPr-THBT-2-yl: 4-cyclopropylamino-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NHMe-THBT-2-yl: 4-methylamino-4,5,6,7
-Tetrahydrobenzo [b] thiophen-2-yl group 4-NMe_Two-THBT-2-yl: 4-dimethylamino-4,5,6
7-tetrahydrobenzo [b] thiophen-2-yl group 4-NOH-THBT-2-yl: 4-hydroxyimino-4,5
6,7-tetrahydrobenzo [b] thiophen-2-i
Le group 4-NOMe-THBT-2-yl: 4-methoxyimino-4,5,6
7-tetrahydrobenzo [b] thiophen-2-yl group 4-OH-THBT-2-yl: 4-hydroxy-4,5,6,7-te
Trahydrobenzo [b] thiophen-2-yl group 5-NH_Two-THBT-2-yl: 5-amino-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl group 5-NH_Two-3-F-THBT-2-yl: 5-amino-3-fluoro-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl group 6-NH_Two-THBT-2-yl: 6-amino-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl group 7-NH_Two-THBT-2-yl: 7-amino-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl group DHT (23c) P-2-yl: 5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl group 3-Cl-DHT (23c) P-2-yl: 3-chloro-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 3-CN-DHT (23c) P-2-yl: 3-cyano-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 3-F-6-Me-DHT (23c) P-2-yl: 3-fluoro-6-methyl
-5,6-dihydro-4H-thieno [2,3-c] pyro
-L-2-yl group 3-F-DHT (23c) P-2-yl: 3-fluoro-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 3-Me-DHT (23c) P-2-yl: 3-methyl-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 3-OCHF_Two-DHT (23c) P-2-yl: 3-difluoromethoxy-5
6-dihydro-4H-thieno [2,3-c] pyrrol-
2-yl group 3-OMe-DHT (23c) P-2-yl: 3-methoxy-5,6-dihydride
B-4H-thieno [2,3-c] pyrrol-2-yl group 4-Me-DHT (23c) P-2-yl: 4-methyl-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 5-Me-DHT (23c) P-2-yl: 5-methyl-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 6-CH_TwoNH_Two-DHT (23c) P-2-yl: 6-aminomethyl-5,6
-Dihydro-4H-thieno [2,3-c] pyrrol-2
-Yl group 6-CH_TwoNHcPr-DHT (23c) P-2-yl: 6-cyclopropylamido
Nomethyl-5,6-dihydro-4H-thieno [2,3-
c] pyrrol-2-yl group 6-CH_TwoNHMe-DHT (23c) P-2-yl: 6-methylaminomethyl-
5,6-dihydro-4H-thieno [2,3-c] pyro-
Ru-2-yl group 6-CH_TwoNMe_Two-DHT (23c) P-2-yl: 6-dimethylaminomethyl
-5,6-dihydro-4H-thieno [2,3-c] pyro
-L-2-yl group 6-CH_TwoOH-DHT (23c) P-2-yl: 6-hydroxymethyl-5,
6-dihydro-4H-thieno [2,3-c] pyrrol-
2-yl group 6-Me-DHT (23c) P-2-yl: 6-methyl-5,6-dihydro
-4H-thieno [2,3-c] pyrrol-2-yl group 6-scPr-DHT (23c) P-2-yl: spiro [5,6-dihydro-
4H-thieno [2,3-c] pyrrol-6,1'-cycl
Lopropane] -2-yl group 4-NH_Two-DHCPT-2-yl: 4-amino-5,6-dihydro-4
H-cyclopenta [b] thiophen-2-yl group 4-NH_Two-3-Cl-DHCPT-2-yl: 4-amino-3-chloro-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 4-NH_Two-3-CN-DHCPT-2-yl: 4-amino-3-cyano-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 4-NH_Two-3-Me-DHCPT-2-yl: 4-amino-3-methyl-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 4-NH_Two-3-OCHF_Two-DHCPT-2-yl: 4-amino-3-difluoro
Romethoxy-5,6-dihydro-4H-cyclopenta
[B] Thiophene-2-yl group 4-NH_Two-3-OMe-DHCPT-2-yl: 4-amino-3-methoxy-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 4-NH_Two-5-CF_Three-DHCPT-2-yl: 4-amino-5-trifluoro
Romethyl-5,6-dihydro-4H-cyclopenta
[B] thiophen-4-yl group 4-NH_Two-5-CH_TwoOH-DHCPT-2-yl: 4-amino-5-hydroxy
Cimethyl-5,6-dihydro-4H-cyclopenta
[B] Thiophene-5-yl group 4-NH_Two-5-Me-DHCPT-2-yl: 4-amino-5-methyl-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 4-NH_Two-6-CH_TwoF-DHCPT-2-yl: 4-amino-6-fluoro
Methyl-5,6-dihydro-4H-cyclopenta [b]
Thiophene-2-yl group 4-NH_Two-6-CH_TwoNH_Two-DHCPT-2-yl: 4-amino-6-amino
Methyl-5,6-dihydro-4H-cyclopenta [b]
Thiophene-2-yl group 4-NH_Two-6-CH_TwoNHcPr-DHCPT-2-yl: 4-amino-6-cycl
Propylaminomethyl-5,6-dihydro-4H-cy
Clopenta [b] thiophen-2-yl group 4-NH_Two-6-Me-DHCPT-2-yl: 4-amino-6-methyl-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 4,6-dNH_Two-DHCPT-2-yl: 4,6-diamino-5,6-di
Hydro-4H-cyclopenta [b] thiophen-2-i
Le group 4-NH_Two-6-OH-DHCPT-2-yl: 4-amino-6-hydroxy
-5,6-dihydro-4H-cyclopenta [b] thiof
En-2-yl group 4-NH_Two-6-OMe-DHCPT-2-yl: 4-amino-6-methoxy-
5,6-dihydro-4H-cyclopenta [b] thiophene
N-2-yl group 5-NH_Two-DHCPT-2-yl: 5-amino-5,6-dihydro-4
H-cyclopenta [b] thiophen-2-yl group 6-NH_Two-DHCPT-2-yl: 6-amino-5,6-dihydro-4
H-cyclopenta [b] thiophen-2-yl group 4-NH_Two-6-Me-THT (23c) P-2-yl: 4-amino-6-methyl
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridin-2-yl group 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl: 4-amino-6-me
Cyl-5-oxo-4,5,6,7-tetrahydrothier
No [2,3-c] pyridin-2-yl group 4-NHMe-THT (23c) P-2-yl: 4-methylamino-4,5
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl group 4-NH_Two-7-DMe-THT (23c) P-2-yl: 4-amino-7,7-di
Methyl-4,5,6,7-tetrahydrothieno [2,3
-C] pyridin-2-yl group 4-NHMe-7-DMe-THT (23c) P-2-yl: 4-methylamino-7,
7-dimethyl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl group 4-NH_Two-7-scPr-THT (23c) P-2-yl: spiro [4-amino-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysine-7,1'-cyclopropane] -2-yl group 4-NHMe-7-scPr-THT (23c) P-2-yl: spiro [4-methyla
Mino-4,5,6,7-tetrahydrothieno [2,3-
c] pyridine-7,1'-cyclopropane] -2-yl group 7-NH_Two-4-DMe-THT (32c) P-2-yl: 7-amino-4,4-di
Methyl-4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl group 7-NHMe-4-DMe-THT (32c) P-2-yl: 7-methylamino-
4,4-dimethyl-4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl group 7-NH_Two-4-scPr-THT (32c) P-2-yl: spiro [7-amino-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysine-4,1'-cyclopropane] -2-yl group 7-NHMe-4-scPr-THT (32c) P-2-yl: spiro [7-methyla
Mino-4,5,6,7-tetrahydrothieno [3,2-
c] pyridine-4,1'-cyclopropane] -2-yl group 7-NH_Two-5-Me-THT (32c) P-2-yl: 7-amino-5-methyl
-4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl group 4-NHMe-THT (32c) P-2-yl: 4-methylamino-4,5
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl group 4-NH_Two-5-Me-THBT-2-yl: 4-amino-5-methyl-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl group 4-NH_Two-DHT (23b) TP-2-yl: 4-amino-5,6-dihydride
B-4H-thieno [2,3-b] thiopyran-2-yl group 4-NHMe-DHT (23b) TP-2-yl: 4-methylamino-5,6-
Dihydro-4H-thieno [2,3-b] thiopyran-2-
Il group 4-NH_Two-DHT (23c) TP-2-yl; 4-amino-4,7-dialdehyde
B-5H-thieno [2,3-c] thiopyran-2-yl group 4-NHMe-DHT (23c) TP-2-yl: 4-methylamino-4,7-
Dihydro-5H-thieno [2,3-c] thiopyran-2-
Il group 4-NH_Two-DHT (23c) P-2-yl: 4-amino-4,7-dihydro
-5H-thieno [2,3-c] pyran-2-yl group 4-NHMe-DHT (23c) P-2-yl: 4-methylamino-4,7-
Dihydro-5H-thieno [2,3-c] pyran-2-yl
Base 4-NH_Two-THT (23d) A-2-yl: 4-amino-5,6,7,8-
Tetrahydro-4H-thieno [2,3-d] azepine-
2-yl group 4-NHMe-THT (23d) A-2-yl: 4-methylamino-
5,6,7,8-tetrahydro-4H-thieno [2,3
-D] azepin-2-yl group 4-NH_Two-THBF-2-yl: 4-amino-4,5,6,7-tet
Lahydrobenzo [b] furan-2-yl group 4-NHMe-THBF-2-yl: 4-methylamino-4,5,6,7
-Tetrahydrobenzo [b] furan-2-yl group
You. [0055] Embedded image [0056] [Table 1] Compound Number R¹           R^Two     R^Three  R^Four      R^Five  1-1 Et H H H THT (32c) P-2-yl  1-2 F-Et H H H THT (32c) P-2-yl  1-3 cPr H H H THT (32c) P-2-yl  1-4 F-cPr H H H THT (32c) P-2-yl  1-5 dF-Ph H H H THT (32c) P-2-yl  1-6 dF-Py H H H THT (32c) P-2-yl  1-7 NH_Two-dF-Py H H H THT (32c) P-2-yl  1-8 Thiazo H H H THT (32c) P-2-yl  1-9 Et Me H H THT (32c) P-2-yl  1-10 F-Et Me H H THT (32c) P-2-yl  1-11 cPr Me H H THT (32c) P-2-yl  1-12 F-cPr Me H H THT (32c) P-2-yl  1-13 dF-Ph Me H H THT (32c) P-2-yl  1-14 dF-Py Me H H THT (32c) P-2-yl  1-15 NH_Two-dF-Py Me H H THT (32c) P-2-yl  1-16 Thiazo Me H H THT (32c) P-2-yl  1-17 Et CH_TwoF H H THT (32c) P-2-yl  1-18 F-Et CH_TwoF H H THT (32c) P-2-yl  1-19 cPr CH_TwoF H H THT (32c) P-2-yl  1-20 F-cPr CH_TwoF H H THT (32c) P-2-yl  1-21 dF-Ph CH_TwoF H H THT (32c) P-2-yl  1-22 dF-Py CH_TwoF H H THT (32c) P-2-yl  1-23 NH_Two-dF-Py CH_TwoF H H THT (32c) P-2-yl  1-24 Thiazo CH_TwoF H H THT (32c) P-2-yl  1-25 Et CHF_Two    H H THT (32c) P-2-yl  1-26 F-Et CHF_Two    H H THT (32c) P-2-yl  1-27 cPr CHF_Two    H H THT (32c) P-2-yl  1-28 F-cPr CHF_Two    H H THT (32c) P-2-yl  1-29 dF-Ph CHF_Two    H H THT (32c) P-2-yl  1-30 dF-Py CHF_Two    H H THT (32c) P-2-yl  1-31 NH_Two-dF-Py CHF_Two    H H THT (32c) P-2-yl  1-32 Thiazo CHF_Two    H H THT (32c) P-2-yl  1-33 Et CF_Three     H H THT (32c) P-2-yl  1-34 F-Et CF_Three     H H THT (32c) P-2-yl  1-35 cPr CF_Three     H H THT (32c) P-2-yl  1-36 F-cPr CF_Three     H H THT (32c) P-2-yl  1-37 dF-Ph CF_Three     H H THT (32c) P-2-yl  1-38 dF-Py CF_Three     H H THT (32c) P-2-yl  1-39 NH_Two-dF-Py CF_Three     H H THT (32c) P-2-yl  1-40 Thiazo CF_Three     H H THT (32c) P-2-yl  1-41 Et OH H H THT (32c) P-2-yl  1-42 F-Et OH H H THT (32c) P-2-yl  1-43 cPr OH H H THT (32c) P-2-yl  1-44 F-cPr OH H H THT (32c) P-2-yl  1-45 dF-Ph OH H H THT (32c) P-2-yl  1-46 dF-Py OH H H THT (32c) P-2-yl  1-47 NH_Two-dF-Py OH H H THT (32c) P-2-yl  1-48 Thiazo OH H H THT (32c) P-2-yl  1-49 Et OMe H H THT (32c) P-2-yl  1-50 F-Et OMe H H THT (32c) P-2-yl  1-51 cPr OMe H H THT (32c) P-2-yl  1-52 F-cPr OMe H H THT (32c) P-2-yl  1-53 dF-Ph OMe H H THT (32c) P-2-yl  1-54 dF-Py OMe H H THT (32c) P-2-yl  1-55 NH_Two-dF-Py OMe H H THT (32c) P-2-yl  1-56 Thiazo OMe H H THT (32c) P-2-yl  1-57 Et OCHF_Two   H H THT (32c) P-2-yl  1-58 F-Et OCHF_Two   H H THT (32c) P-2-yl  1-59 cPr OCHF_Two   H H THT (32c) P-2-yl  1-60 F-cPr OCHF_Two   H H THT (32c) P-2-yl  1-61 dF-Ph OCHF_Two   H H THT (32c) P-2-yl  1-62 dF-Py OCHF_Two   H H THT (32c) P-2-yl  1-63 NH_Two-dF-Py OCHF_Two   H H THT (32c) P-2-yl  1-64 Thiazo OCHF_Two   H H THT (32c) P-2-yl  1-65 Et CN H H THT (32c) P-2-yl  1-66 F-Et CN H H THT (32c) P-2-yl  1-67 cPr CN H H THT (32c) P-2-yl  1-68 F-cPr CN H H THT (32c) P-2-yl  1-69 dF-Ph CN H H THT (32c) P-2-yl  1-70 dF-Py CN H H THT (32c) P-2-yl  1-71 NH_Two-dF-Py CN H H THT (32c) P-2-yl  1-72 Thiazo CN H H THT (32c) P-2-yl  1-73 Et Cl H H THT (32c) P-2-yl  1-74 F-Et Cl H H THT (32c) P-2-yl  1-75 cPr Cl H H THT (32c) P-2-yl  1-76 F-cPr Cl H H THT (32c) P-2-yl  1-77 dF-Ph Cl H H THT (32c) P-2-yl  1-78 dF-Py Cl H H THT (32c) P-2-yl  1-79 NH_Two-dF-Py Cl H H THT (32c) P-2-yl  1-80 Thiazo Cl H H THT (32c) P-2-yl  1-81 Et H F H THT (32c) P-2-yl  1-82 F-Et H F H THT (32c) P-2-yl  1-83 cPr H F H THT (32c) P-2-yl  1-84 F-cPr H F H THT (32c) P-2-yl  1-85 dF-Ph H F H THT (32c) P-2-yl  1-86 dF-Py H F H THT (32c) P-2-yl  1-87 NH_Two-dF-Py H F H THT (32c) P-2-yl  1-88 Thiazo H F H THT (32c) P-2-yl  1-89 Et Me F H THT (32c) P-2-yl  1-90 F-Et Me F H THT (32c) P-2-yl  1-91 cPr Me F H THT (32c) P-2-yl  1-92 F-cPr Me F H THT (32c) P-2-yl  1-93 dF-Ph Me F H THT (32c) P-2-yl  1-94 dF-Py Me F H THT (32c) P-2-yl  1-95 NH_Two-dF-Py Me F H THT (32c) P-2-yl  1-96 Thiazo Me F H THT (32c) P-2-yl  1-97 Et CH_TwoF F H THT (32c) P-2-yl  1-98 F-Et CH_TwoF F H THT (32c) P-2-yl  1-99 cPr CH_TwoF F H THT (32c) P-2-yl  1-100 F-cPr CH_TwoF F H THT (32c) P-2-yl  1-101 dF-Ph CH_TwoF F H THT (32c) P-2-yl  1-102 dF-Py CH_TwoF F H THT (32c) P-2-yl  1-103 NH_Two-dF-Py CH_TwoF F H THT (32c) P-2-yl  1-104 Thiazo CH_TwoF F H THT (32c) P-2-yl  1-105 Et CHF_Two    F H THT (32c) P-2-yl  1-106 F-Et CHF_Two    F H THT (32c) P-2-yl  1-107 cPr CHF_Two    F H THT (32c) P-2-yl  1-108 F-cPr CHF_Two    F H THT (32c) P-2-yl  1-109 dF-Ph CHF_Two    F H THT (32c) P-2-yl  1-110 dF-Py CHF_Two    F H THT (32c) P-2-yl  1-111 NH_TwodF-Py CHF_Two    F H THT (32c) P-2-yl  1-112 Thiazo CHF_Two    F H THT (32c) P-2-yl  1-113 Et CF_Three     F H THT (32c) P-2-yl  1-114 F-Et CF_Three     F H THT (32c) P-2-yl  1-115 cPr CF_Three     F H THT (32c) P-2-yl  1-116 F-cPr CF_Three     F H THT (32c) P-2-yl  1-117 dF-Ph CF_Three     F H THT (32c) P-2-yl  1-118 dF-Py CF_Three     F H THT (32c) P-2-yl  1-119 NH_Two-dF-Py CF_Three     F H THT (32c) P-2-yl  1-120 Thiazo CF_Three     F H THT (32c) P-2-yl  1-121 Et OH F H THT (32c) P-2-yl  1-122 F-Et OH F H THT (32c) P-2-yl  1-123 cPr OH F H THT (32c) P-2-yl  1-124 F-cPr OH F H THT (32c) P-2-yl  1-125 dF-Ph OH F H THT (32c) P-2-yl  1-126 dF-Py OH F H THT (32c) P-2-yl  1-127 NH_Two-dF-Py OH F H THT (32c) P-2-yl  1-128 Thiazo OH F H THT (32c) P-2-yl  1-129 Et OMe F H THT (32c) P-2-yl  1-130 F-Et OMe F H THT (32c) P-2-yl  1-131 cPr OMe F H THT (32c) P-2-yl  1-132 F-cPr OMe F H THT (32c) P-2-yl  1-133 dF-Ph OMe F H THT (32c) P-2-yl  1-134 dF-Py OMe F H THT (32c) P-2-yl  1-135 NH_Two-dF-Py OMe F H THT (32c) P-2-yl  1-136 Thiazo OMe F H THT (32c) P-2-yl  1-137 Et OCHF_Two   F H THT (32c) P-2-yl  1-138 F-Et OCHF_Two   F H THT (32c) P-2-yl  1-139 cPr OCHF_Two   F H THT (32c) P-2-yl  1-140 F-cPr OCHF_Two   F H THT (32c) P-2-yl  1-141 dF-Ph OCHF_Two   F H THT (32c) P-2-yl  1-142 dF-Py OCHF_Two   F H THT (32c) P-2-yl  1-143 NH_Two-dF-Py OCHF_Two   F H THT (32c) P-2-yl  1-144 Thiazo OCHF_Two   F H THT (32c) P-2-yl  1-145 Et CN F H THT (32c) P-2-yl  1-146 F-Et CN F H THT (32c) P-2-yl  1-147 cPr CN F H THT (32c) P-2-yl  1-148 F-cPr CN F H THT (32c) P-2-yl  1-149 dF-Ph CN F H THT (32c) P-2-yl  1-150 dF-Py CN F H THT (32c) P-2-yl  1-151 NH_Two-dF-Py CN F H THT (32c) P-2-yl  1-152 Thiazo CN F H THT (32c) P-2-yl  1-153 Et Cl F H THT (32c) P-2-yl  1-154 F-Et Cl F H THT (32c) P-2-yl  1-155 cPr Cl F H THT (32c) P-2-yl  1-156 F-cPr Cl F H THT (32c) P-2-yl  1-157 dF-Ph Cl F H THT (32c) P-2-yl  1-158 dF-Py Cl F H THT (32c) P-2-yl  1-159 NH_Two-dF-Py Cl F H THT (32c) P-2-yl  1-160 Thiazo Cl F H THT (32c) P-2-yl  1-161 cPr Me H NH_Two    THT (32c) P-2-yl  1-162 F-cPr Me H NH_Two    THT (32c) P-2-yl  1-163 cPr OCHF_Two   H NH_Two    THT (32c) P-2-yl  1-164 F-cPr OCHF_Two   H NH_Two    THT (32c) P-2-yl  1-165 cPr Me F NH_Two    THT (32c) P-2-yl  1-166 F-cPr Me F NH_Two    THT (32c) P-2-yl  1-167 cPr OCHF_Two   F NH_Two    THT (32c) P-2-yl  1-168 F-cPr OCHF_Two   F NH_Two    THT (32c) P-2-yl  1-169 cPr Me H Me THT (32c) P-2-yl  1-170 F-cPr Me H Me THT (32c) P-2-yl  1-171 cPr Me F Me THT (32c) P-2-yl  1-172 F-cPr Me F Me THT (32c) P-2-yl  1-173 cPr Me H H 3-CF_Three-THT (32c) P-2-yl  1-174 F-cPr Me H H 3-CF_Three-THT (32c) P-2-yl  1-175 cPr OMe H H 3-CF_Three-THT (32c) P-2-yl  1-176 F-cPr OMe H H 3-CF_Three-THT (32c) P-2-yl  1-177 cPr OCHF_Two    H H 3-CF_Three-THT (32c) P-2-yl  1-178 F-cPr OCHF_Two    H H 3-CF_Three-THT (32c) P-2-yl  1-179 cPr Me H NH_Two    3-CF_Three-THT (32c) P-2-yl  1-180 cPr OCHF_Two    H NH_Two   3-CF_Three-THT (32c) P-2-yl  1-181 cPr Me F H 3-CF_Three-THT (32c) P-2-yl  1-182 F-cPr Me F H 3-CF_Three-THT (32c) P-2-yl  1-183 cPr OCHF_Two    F H 3-CF_Three-THT (32c) P-2-yl  1-184 F-cPr OCHF_Two    F H 3-CF_Three-THT (32c) P-2-yl  1-185 cPr Me F NH_Two    3-CF_Three-THT (32c) P-2-yl  1-186 cPr OCHF_Two    F NH_Two   3-CF_Three-THT (32c) P-2-yl  1-187 cPr Me H H 3-Cl-THT (32c) P-2-yl  1-188 F-cPr Me H H 3-Cl-THT (32c) P-2-yl  1-189 cPr OCHF_Two    H H 3-Cl-THT (32c) P-2-yl  1-190 F-cPr OCHF_Two    H H 3-Cl-THT (32c) P-2-yl  1-191 cPr Me F H 3-Cl-THT (32c) P-2-yl  1-192 F-cPr Me F H 3-Cl-THT (32c) P-2-yl  1-193 cPr OCHF_Two    F H 3-Cl-THT (32c) P-2-yl  1-194 F-cPr OCHF_Two    F H 3-Cl-THT (32c) P-2-yl  1-195 cPr Me H H 3-CN-THT (32c) P-2-yl  1-196 F-cPr Me H H 3-CN-THT (32c) P-2-yl  1-197 cPr OCHF_Two    H H 3-CN-THT (32c) P-2-yl  1-198 F-cPr OCHF_Two    H H 3-CN-THT (32c) P-2-yl  1-199 cPr Me F H 3-CN-THT (32c) P-2-yl  1-200 F-cPr Me F H 3-CN-THT (32c) P-2-yl  1-201 cPr OCHF_Two    F H 3-CN-THT (32c) P-2-yl  1-202 F-cPr OCHF_Two    F H 3-CN-THT (32c) P-2-yl  1-203 cPr Me H H 3-F-5-Me-THT (32c) P-2-yl  1-204 F-cPr Me H H 3-F-5-Me-THT (32c) P-2-yl  1-205 cPr OMe H H 3-F-5-Me-THT (32c) P-2-yl  1-206 F-cPr OMe H H 3-F-5-Me-THT (32c) P-2-yl  1-207 cPr OCHF_Two    H H 3-F-5-Me-THT (32c) P-2-yl  1-208 F-cPr OCHF_Two    H H 3-F-5-Me-THT (32c) P-2-yl  1-209 cPr Me H NH_Two    3-F-5-Me-THT (32c) P-2-yl  1-210 cPr OCHF_Two    H NH_Two   3-F-5-Me-THT (32c) P-2-yl  1-211 cPr Me F H 3-F-5-Me-THT (32c) P-2-yl  1-212 F-cPr Me F H 3-F-5-Me-THT (32c) P-2-yl  1-213 cPr OCHF_Two    F H 3-F-5-Me-THT (32c) P-2-yl  1-214 F-cPr OCHF_Two    F H 3-F-5-Me-THT (32c) P-2-yl  1-215 cPr Me F NH_Two    3-F-5-Me-THT (32c) P-2-yl  1-216 cPr OCHF_Two    F NH_Two   3-F-5-Me-THT (32c) P-2-yl  1-217 cPr Me H H 3-F-THT (32c) P-2-yl  1-218 F-cPr Me H H 3-F-THT (32c) P-2-yl  1-219 cPr OMe H H 3-F-THT (32c) P-2-yl  1-220 F-cPr OMe H H 3-F-THT (32c) P-2-yl  1-221 cPr OCHF_Two    H H 3-F-THT (32c) P-2-yl  1-222 F-cPr OCHF_Two    H H 3-F-THT (32c) P-2-yl  1-223 cPr Me H NH_Two    3-F-THT (32c) P-2-yl  1-224 cPr OCHF_Two    H NH_Two   3-F-THT (32c) P-2-yl  1-225 cPr Me F H 3-F-THT (32c) P-2-yl  1-226 F-cPr Me F H 3-F-THT (32c) P-2-yl  1-227 cPr OCHF_Two    F H 3-F-THT (32c) P-2-yl  1-228 F-cPr OCHF_Two    F H 3-F-THT (32c) P-2-yl  1-229 cPr Me F NH_Two    3-F-THT (32c) P-2-yl  1-230 cPr OCHF_Two    F NH_Two   3-F-THT (32c) P-2-yl  1-231 cPr Me H H 3-Me-THT (32c) P-2-yl  1-232 F-cPr Me H H 3-Me-THT (32c) P-2-yl  1-233 cPr OMe H H 3-Me-THT (32c) P-2-yl  1-234 F-cPr OMe H H 3-Me-THT (32c) P-2-yl  1-235 cPr OCHF_Two    H H 3-Me-THT (32c) P-2-yl  1-236 F-cPr OCHF_Two    H H 3-Me-THT (32c) P-2-yl  1-237 cPr Me H NH_Two    3-Me-THT (32c) P-2-yl  1-238 cPr OCHF_Two    H NH_Two   3-Me-THT (32c) P-2-yl  1-239 cPr Me F H 3-Me-THT (32c) P-2-yl  1-240 F-cPr Me F H 3-Me-THT (32c) P-2-yl  1-241 cPr OCHF_Two    F H 3-Me-THT (32c) P-2-yl  1-242 F-cPr OCHF_Two    F H 3-Me-THT (32c) P-2-yl  1-243 cPr Me F NH_Two    3-Me-THT (32c) P-2-yl  1-244 cPr OCHF_Two    F NH_Two   3-Me-THT (32c) P-2-yl  1-245 cPr Me H H 3-OCHF_Two-THT (32c) P-2-yl  1-246 F-cPr Me H H 3-OCHF_Two-THT (32c) P-2-yl  1-247 cPr OCHF_Two    H H 3-OCHF_Two-THT (32c) P-2-yl  1-248 F-cPr OCHF_Two    H H 3-OCHF_Two-THT (32c) P-2-yl  1-249 cPr Me F H 3-OCHF_Two-THT (32c) P-2-yl  1-250 F-cPr Me F H 3-OCHF_Two-THT (32c) P-2-yl  1-251 cPr OCHF_Two    F H 3-OCHF_Two-THT (32c) P-2-yl  1-252 F-cPr OCHF_Two    F H 3-OCHF_Two-THT (32c) P-2-yl  1-253 cPr Me H H 3-OMe-THT (32c) P-2-yl  1-254 F-cPr Me H H 3-OMe-THT (32c) P-2-yl  1-255 cPr OCHF_Two    H H 3-OMe-THT (32c) P-2-yl  1-256 F-cPr OCHF_Two    H H 3-OMe-THT (32c) P-2-yl  1-257 cPr Me F H 3-OMe-THT (32c) P-2-yl  1-258 F-cPr Me F H 3-OMe-THT (32c) P-2-yl  1-259 cPr OCHF_Two    F H 3-OMe-THT (32c) P-2-yl  1-260 F-cPr OCHF_Two    F H 3-OMe-THT (32c) P-2-yl  1-261 cPr Me H H 4-Me-THT (32c) P-2-yl  1-262 F-cPr Me H H 4-Me-THT (32c) P-2-yl  1-263 cPr OCHF_Two    H H 4-Me-THT (32c) P-2-yl  1-264 F-cPr OCHF_Two    H H 4-Me-THT (32c) P-2-yl  1-265 cPr Me F H 4-Me-THT (32c) P-2-yl  1-266 F-cPr Me F H 4-Me-THT (32c) P-2-yl  1-267 cPr OCHF_Two    F H 4-Me-THT (32c) P-2-yl  1-268 F-cPr OCHF_Two    F H 4-Me-THT (32c) P-2-yl  1-269 cPr Me H H 5-Me-THT (32c) P-2-yl  1-270 F-cPr Me H H 5-Me-THT (32c) P-2-yl  1-271 cPr OCHF_Two    H H 5-Me-THT (32c) P-2-yl  1-272 F-cPr OCHF_Two    H H 5-Me-THT (32c) P-2-yl  1-273 cPr Me F H 5-Me-THT (32c) P-2-yl  1-274 F-cPr Me F H 5-Me-THT (32c) P-2-yl  1-275 cPr OCHF_Two    F H 5-Me-THT (32c) P-2-yl  1-276 F-cPr OCHF_Two    F H 5-Me-THT (32c) P-2-yl  1-277 cPr Me H H 6-CH (OH) Me-THT (32c) P-2-yl  1-278 F-cPr Me H H 6-CH (OH) Me-THT (32c) P-2-yl  1-279 cPr OCHF_Two    H H 6-CH (OH) Me-THT (32c) P-2-yl  1-280 F-cPr OCHF_Two    H H 6-CH (OH) Me-THT (32c) P-2-yl  1-281 cPr Me F H 6-CH (OH) Me-THT (32c) P-2-yl  1-282 F-cPr Me F H 6-CH (OH) Me-THT (32c) P-2-yl  1-283 cPr OCHF_Two    F H 6-CH (OH) Me-THT (32c) P-2-yl  1-284 F-cPr OCHF_Two    F H 6-CH (OH) Me-THT (32c) P-2-yl  1-285 cPr Me H H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-286 F-cPr Me H H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-287 cPr OMe H H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-288 F-cPr OMe H H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-289 cPr OCHF_Two    H H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-290 F-cPr OCHF_Two    H H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-291 cPr Me H NH_Two    6-CH_TwoNH_Two-THT (32c) P-2-yl  1-292 cPr OCHF_Two    H NH_Two   6-CH_TwoNH_Two-THT (32c) P-2-yl  1-293 cPr Me F H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-294 F-cPr Me F H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-295 cPr OCHF_Two    F H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-296 F-cPr OCHF_Two    F H 6-CH_TwoNH_Two-THT (32c) P-2-yl  1-297 cPr Me F NH_Two    6-CH_TwoNH_Two-THT (32c) P-2-yl  1-298 cPr OCHF_Two    F NH_Two   6-CH_TwoNH_Two-THT (32c) P-2-yl  1-299 cPr Me H H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-300 F-cPr Me H H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-301 cPr OCHF_Two    H H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-302 F-cPr OCHF_Two    H H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-303 cPr Me F H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-304 F-cPr Me F H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-305 cPr OCHF_Two    F H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-306 F-cPr OCHF_Two    F H 6-CH_TwoNHcPr-THT (32c) P-2-yl  1-307 cPr Me H H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-308 F-cPr Me H H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-309 cPr OCHF_Two    H H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-310 F-cPr OCHF_Two    H H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-311 cPr Me F H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-312 F-cPr Me F H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-313 cPr OCHF_Two    F H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-314 F-cPr OCHF_Two    F H 6-CH_TwoNHMe-THT (32c) P-2-yl  1-315 cPr Me H H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-316 F-cPr Me H H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-317 cPr OCHF_Two    H H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-318 F-cPr OCHF_Two    H H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-319 cPr Me F H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-320 F-cPr Me F H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-321 cPr OCHF_Two    F H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-322 F-cPr OCHF_Two    F H 6-CH_TwoNMe_Two-THT (32c) P-2-yl  1-323 cPr Me H H 6-CH_TwoOH-THT (32c) P-2-yl  1-324 F-cPr Me H H 6-CH_TwoOH-THT (32c) P-2-yl  1-325 cPr OCHF_Two    H H 6-CH_TwoOH-THT (32c) P-2-yl  1-326 F-cPr OCHF_Two    H H 6-CH_TwoOH-THT (32c) P-2-yl  1-327 cPr Me F H 6-CH_TwoOH-THT (32c) P-2-yl  1-328 F-cPr Me F H 6-CH_TwoOH-THT (32c) P-2-yl  1-329 cPr OCHF_Two    F H 6-CH_TwoOH-THT (32c) P-2-yl  1-330 F-cPr OCHF_Two    F H 6-CH_TwoOH-THT (32c) P-2-yl  1-331 cPr Me H H 6-Me-THT (32c) P-2-yl  1-332 F-cPr Me H H 6-Me-THT (32c) P-2-yl  1-333 cPr OCHF_Two    H H 6-Me-THT (32c) P-2-yl  1-334 F-cPr OCHF_Two    H H 6-Me-THT (32c) P-2-yl  1-335 cPr Me F H 6-Me-THT (32c) P-2-yl  1-336 F-cPr Me F H 6-Me-THT (32c) P-2-yl  1-337 cPr OCHF_Two    F H 6-Me-THT (32c) P-2-yl  1-338 F-cPr OCHF_Two    F H 6-Me-THT (32c) P-2-yl  1-339 cPr Me H H 6-scPr-THT (32c) P-2-yl  1-340 F-cPr Me H H 6-scPr-THT (32c) P-2-yl  1-341 cPr OCHF_Two    H H 6-scPr-THT (32c) P-2-yl  1-342 F-cPr OCHF_Two    H H 6-scPr-THT (32c) P-2-yl  1-343 cPr Me F H 6-scPr-THT (32c) P-2-yl  1-344 F-cPr Me F H 6-scPr-THT (32c) P-2-yl  1-345 cPr OCHF_Two    F H 6-scPr-THT (32c) P-2-yl  1-346 F-cPr OCHF_Two    F H 6-scPr-THT (32c) P-2-yl  1-347 cPr Me H H 7-Me-THT (32c) P-2-yl  1-348 F-cPr Me H H 7-Me-THT (32c) P-2-yl  1-349 cPr OMe H H 7-Me-THT (32c) P-2-yl  1-350 F-cPr OMe H H 7-Me-THT (32c) P-2-yl  1-351 cPr OCHF_Two    H H 7-Me-THT (32c) P-2-yl  1-352 F-cPr OCHF_Two    H H 7-Me-THT (32c) P-2-yl  1-353 cPr Me H NH_Two    7-Me-THT (32c) P-2-yl  1-354 cPr OCHF_Two    H NH_Two   7-Me-THT (32c) P-2-yl  1-355 cPr Me F H 7-Me-THT (32c) P-2-yl  1-356 F-cPr Me F H 7-Me-THT (32c) P-2-yl  1-357 cPr OCHF_Two    F H 7-Me-THT (32c) P-2-yl  1-358 F-cPr OCHF_Two    F H 7-Me-THT (32c) P-2-yl  1-359 cPr Me F NH_Two    7-Me-THT (32c) P-2-yl  1-360 cPr OCHF_Two    F NH_Two   7-Me-THT (32c) P-2-yl  1-361 cPr Me H H 7-NH_Two-THT (32c) P-2-yl  1-362 F-cPr Me H H 7-NH_Two-THT (32c) P-2-yl  1-363 cPr OMe H H 7-NH_Two-THT (32c) P-2-yl  1-364 F-cPr OMe H H 7-NH_Two-THT (32c) P-2-yl  1-365 cPr OCHF_Two    H H 7-NH_Two-THT (32c) P-2-yl  1-366 F-cPr OCHF_Two    H H 7-NH_Two-THT (32c) P-2-yl  1-367 cPr Me H NH_Two    7-NH_Two-THT (32c) P-2-yl  1-368 cPr OCHF_Two    H NH_Two   7-NH_Two-THT (32c) P-2-yl  1-369 cPr Me F H 7-NH_Two-THT (32c) P-2-yl  1-370 F-cPr Me F H 7-NH_Two-THT (32c) P-2-yl  1-371 cPr OCHF_Two    F H 7-NH_Two-THT (32c) P-2-yl  1-372 F-cPr OCHF_Two    F H 7-NH_Two-THT (32c) P-2-yl  1-373 cPr Me F NH_Two    7-NH_Two-THT (32c) P-2-yl  1-374 cPr OCHF_Two    F NH_Two   7-NH_Two-THT (32c) P-2-yl  1-375 cPr Me H H 7-NOH-THT (32c) P-2-yl  1-376 F-cPr Me H H 7-NOH-THT (32c) P-2-yl  1-377 cPr OMe H H 7-NOH-THT (32c) P-2-yl  1-378 F-cPr OMe H H 7-NOH-THT (32c) P-2-yl  1-379 cPr OCHF_Two    H H 7-NOH-THT (32c) P-2-yl  1-380 F-cPr OCHF_Two    H H 7-NOH-THT (32c) P-2-yl  1-381 cPr Me H NH_Two    7-NOH-THT (32c) P-2-yl  1-382 cPr OCHF_Two    H NH_Two   7-NOH-THT (32c) P-2-yl  1-383 cPr Me F H 7-NOH-THT (32c) P-2-yl  1-384 F-cPr Me F H 7-NOH-THT (32c) P-2-yl  1-385 cPr OCHF_Two    F H 7-NOH-THT (32c) P-2-yl  1-386 F-cPr OCHF_Two    F H 7-NOH-THT (32c) P-2-yl  1-387 cPr Me F NH_Two    7-NOH-THT (32c) P-2-yl  1-388 cPr OCHF_Two    F NH_Two   7-NOH-THT (32c) P-2-yl  1-389 cPr Me H H 7-NOMe-THT (32c) P-2-yl  1-390 F-cPr Me H H 7-NOMe-THT (32c) P-2-yl  1-391 cPr OMe H H 7-NOMe-THT (32c) P-2-yl  1-392 F-cPr OMe H H 7-NOMe-THT (32c) P-2-yl  1-393 cPr OCHF_Two    H H 7-NOMe-THT (32c) P-2-yl  1-394 F-cPr OCHF_Two    H H 7-NOMe-THT (32c) P-2-yl  1-395 cPr Me H NH_Two    7-NOMe-THT (32c) P-2-yl  1-396 cPr OCHF_Two    H NH_Two   7-NOMe-THT (32c) P-2-yl  1-397 cPr Me F H 7-NOMe-THT (32c) P-2-yl  1-398 F-cPr Me F H 7-NOMe-THT (32c) P-2-yl  1-399 cPr OCHF_Two    F H 7-NOMe-THT (32c) P-2-yl  1-400 F-cPr OCHF_Two    F H 7-NOMe-THT (32c) P-2-yl  1-401 cPr Me F NH_Two    7-NOMe-THT (32c) P-2-yl  1-402 cPr OCHF_Two    F NH_Two   7-NOMe-THT (32c) P-2-yl  1-403 cPr Me H H 7-OH-THT (32c) P-2-yl  1-404 F-cPr Me H H 7-OH-THT (32c) P-2-yl  1-405 cPr OCHF_Two    H H 7-OH-THT (32c) P-2-yl  1-406 F-cPr OCHF_Two    H H 7-OH-THT (32c) P-2-yl  1-407 cPr Me F H 7-OH-THT (32c) P-2-yl  1-408 F-cPr Me F H 7-OH-THT (32c) P-2-yl  1-409 cPr OCHF_Two    F H 7-OH-THT (32c) P-2-yl  1-410 F-cPr OCHF_Two    F H 7-OH-THT (32c) P-2-yl  1-411 cPr Me H H 7-OMe-THT (32c) P-2-yl  1-412 F-cPr Me H H 7-OMe-THT (32c) P-2-yl  1-413 cPr OCHF_Two    H H 7-OMe-THT (32c) P-2-yl  1-414 F-cPr OCHF_Two    H H 7-OMe-THT (32c) P-2-yl  1-415 cPr Me F H 7-OMe-THT (32c) P-2-yl  1-416 F-cPr Me F H 7-OMe-THT (32c) P-2-yl  1-417 cPr OCHF_Two    F H 7-OMe-THT (32c) P-2-yl  1-418 F-cPr OCHF_Two    F H 7-OMe-THT (32c) P-2-yl  1-419 cPr Me H H THT (23c) P-2-yl  1-420 F-cPr Me H H THT (23c) P-2-yl  1-421 cPr OCHF_Two    H H THT (23c) P-2-yl  1-422 F-cPr OCHF_Two    H H THT (23c) P-2-yl  1-423 cPr Me F H THT (23c) P-2-yl  1-424 F-cPr Me F H THT (23c) P-2-yl  1-425 cPr OCHF_Two    F H THT (23c) P-2-yl  1-426 F-cPr OCHF_Two    F H THT (23c) P-2-yl  1-427 cPr Me H H 5-Me-THT (23c) P-2-yl  1-428 F-cPr Me H H 5-Me-THT (23c) P-2-yl  1-429 cPr OCHF_Two    H H 5-Me-THT (23c) P-2-yl  1-430 F-cPr OCHF_Two    H H 5-Me-THT (23c) P-2-yl  1-431 cPr Me F H 5-Me-THT (23c) P-2-yl  1-432 F-cPr Me F H 5-Me-THT (23c) P-2-yl  1-433 cPr OCHF_Two    F H 5-Me-THT (23c) P-2-yl  1-434 F-cPr OCHF_Two    F H 5-Me-THT (23c) P-2-yl  1-435 cPr Me H H 7-Me-THT (23c) P-2-yl  1-436 F-cPr Me H H 7-Me-THT (23c) P-2-yl  1-437 cPr OCHF_Two    H H 7-Me-THT (23c) P-2-yl  1-438 F-cPr OCHF_Two    H H 7-Me-THT (23c) P-2-yl  1-439 cPr Me F H 7-Me-THT (23c) P-2-yl  1-440 F-cPr Me F H 7-Me-THT (23c) P-2-yl  1-441 cPr OCHF_Two    F H 7-Me-THT (23c) P-2-yl  1-442 F-cPr OCHF_Two    F H 7-Me-THT (23c) P-2-yl  1-443 cPr Me H H 4-NH_Two-THT (23c) P-2-yl  1-444 F-cPr Me H H 4-NH_Two-THT (23c) P-2-yl  1-445 cPr OMe H H 4-NH_Two-THT (23c) P-2-yl  1-446 F-cPr OMe H H 4-NH_Two-THT (23c) P-2-yl  1-447 cPr OCHF_Two    H H 4-NH_Two-THT (23c) P-2-yl  1-448 F-cPr OCHF_Two    H H 4-NH_Two-THT (23c) P-2-yl  1-449 cPr Me H NH_Two    4-NH_Two-THT (23c) P-2-yl  1-450 cPr OCHF_Two    H NH_Two   4-NH_Two-THT (23c) P-2-yl  1-451 cPr Me F H 4-NH_Two-THT (23c) P-2-yl  1-452 F-cPr Me F H 4-NH_Two-THT (23c) P-2-yl  1-453 cPr OCHF_Two    F H 4-NH_Two-THT (23c) P-2-yl  1-454 F-cPr OCHF_Two    F H 4-NH_Two-THT (23c) P-2-yl  1-455 cPr Me F NH_Two    4-NH_Two-THT (23c) P-2-yl  1-456 cPr OCHF_Two    F NH_Two   4-NH_Two-THT (23c) P-2-yl  1-457 cPr Me H H 4-CH_TwoNH_Two-THBT-2-yl  1-458 cPr OCHF_Two    H H 4-CH_TwoNH_Two-THBT-2-yl  1-459 cPr Me F H 4-CH_TwoNH_Two-THBT-2-yl  1-460 cPr OCHF_Two    F H 4-CH_TwoNH_Two-THBT-2-yl  1-461 cPr Me H H 4-CH_TwoNHMe-THBT-2-yl  1-462 cPr OCHF_Two    H H 4-CH_TwoNHMe-THBT-2-yl  1-463 cPr Me F H 4-CH_TwoNHMe-THBT-2-yl  1-464 cPr OCHF_Two    F H 4-CH_TwoNHMe-THBT-2-yl  1-465 cPr Me H H 4-NH_Two-3-Cl-THBT-2-yl  1-466 F-cPr Me H H 4-NH_Two-3-Cl-THBT-2-yl  1-467 cPr OCHF_Two    H H 4-NH_Two-3-Cl-THBT-2-yl  1-468 F-cPr OCHF_Two    H H 4-NH_Two-3-Cl-THBT-2-yl  1-469 cPr Me F H 4-NH_Two-3-Cl-THBT-2-yl  1-470 F-cPr Me F H 4-NH_Two-3-Cl-THBT-2-yl  1-471 cPr OCHF_Two    F H 4-NH_Two-3-Cl-THBT-2-yl  1-472 F-cPr OCHF_Two    F H 4-NH_Two-3-Cl-THBT-2-yl  1-473 cPr Me H H 4-NH_Two-3-CN-THBT-2-yl  1-474 F-cPr Me H H 4-NH_Two-3-CN-THBT-2-yl  1-475 cPr OCHF_Two    H H 4-NH_Two-3-CN-THBT-2-yl  1-476 F-cPr OCHF_Two    H H 4-NH_Two-3-CN-THBT-2-yl  1-477 cPr Me F H 4-NH_Two-3-CN-THBT-2-yl  1-478 F-cPr Me F H 4-NH_Two-3-CN-THBT-2-yl  1-479 cPr OCHF_Two    F H 4-NH_Two-3-CN-THBT-2-yl  1-480 F-cPr OCHF_Two    F H 4-NH_Two-3-CN-THBT-2-yl  1-481 cPr Me H H 4-NH_Two-3-F-THBT-2-yl  1-482 F-cPr Me H H 4-NH_Two-3-F-THBT-2-yl  1-483 cPr OMe H H 4-NH_Two-3-F-THBT-2-yl  1-484 F-cPr OMe H H 4-NH_Two-3-F-THBT-2-yl  1-485 cPr OCHF_Two    H H 4-NH_Two-3-F-THBT-2-yl  1-486 F-cPr OCHF_Two    H H 4-NH_Two-3-F-THBT-2-yl  1-487 cPr Me H NH_Two    4-NH_Two-3-F-THBT-2-yl  1-488 cPr OCHF_Two    H NH_Two   4-NH_Two-3-F-THBT-2-yl  1-489 cPr Me F H 4-NH_Two-3-F-THBT-2-yl  1-490 F-cPr Me F H 4-NH_Two-3-F-THBT-2-yl  1-491 cPr OCHF_Two    F H 4-NH_Two-3-F-THBT-2-yl  1-492 F-cPr OCHF_Two    F H 4-NH_Two-3-F-THBT-2-yl  1-493 cPr Me F NH_Two    4-NH_Two-3-F-THBT-2-yl  1-494 cPr OCHF_Two    F NH_Two   4-NH_Two-3-F-THBT-2-yl  1-495 cPr Me H H 4-NH_Two-3-Me-THBT-2-yl  1-496 F-cPr Me H H 4-NH_Two-3-Me-THBT-2-yl  1-497 cPr OCHF_Two    H H 4-NH_Two-3-Me-THBT-2-yl  1-498 F-cPr OCHF_Two    H H 4-NH_Two-3-Me-THBT-2-yl  1-499 cPr Me F H 4-NH_Two-3-Me-THBT-2-yl  1-500 F-cPr Me F H 4-NH_Two-3-Me-THBT-2-yl  1-501 cPr OCHF_Two    F H 4-NH_Two-3-Me-THBT-2-yl  1-502 F-cPr OCHF_Two    F H 4-NH_Two-3-Me-THBT-2-yl  1-503 cPr Me H H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-504 F-cPr Me H H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-505 cPr OCHF_Two    H H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-506 F-cPr OCHF_Two    H H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-507 cPr Me F H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-508 F-cPr Me F H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-509 cPr OCHF_Two    F H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-510 F-cPr OCHF_Two    F H 4-NH_Two-3-OCHF_Two-THBT-2-yl  1-511 cPr Me H H 4-NH_Two-3-OMe-THBT-2-yl  1-512 cPr OCHF_Two    H H 4-NH_Two-3-OMe-THBT-2-yl  1-513 cPr Me F H 4-NH_Two-3-OMe-THBT-2-yl  1-514 cPr OCHF_Two    F H 4-NH_Two-3-OMe-THBT-2-yl  1-515 cPr Me H H 4-NH_Two-6-CH_TwoOH-THBT-2-yl  1-516 cPr OCHF_Two    H H 4-NH_Two-6-CH_TwoOH-THBT-2-yl  1-517 cPr Me F H 4-NH_Two-6-CH_TwoOH-THBT-2-yl  1-518 cPr OCHF_Two    F H 4-NH_Two-6-CH_TwoOH-THBT-2-yl  1-519 cPr Me H H 4-NH_Two-6-Me-THBT-2-yl  1-520 cPr OCHF_Two    H H 4-NH_Two-6-Me-THBT-2-yl  1-521 cPr Me F H 4-NH_Two-6-Me-THBT-2-yl  1-522 cPr OCHF_Two    F H 4-NH_Two-6-Me-THBT-2-yl  1-523 cPr Me H H 4-NH_Two-6-OMe-THBT-2-yl  1-524 cPr OCHF_Two    H H 4-NH_Two-6-OMe-THBT-2-yl  1-525 cPr Me F H 4-NH_Two-6-OMe-THBT-2-yl  1-526 cPr OCHF_Two    F H 4-NH_Two-6-OMe-THBT-2-yl  1-527 cPr Me H H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-528 F-cPr Me H H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-529 cPr OCHF_Two    H H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-530 F-cPr OCHF_Two    H H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-531 cPr Me F H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-532 F-cPr Me F H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-533 cPr OCHF_Two    F H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-534 F-cPr OCHF_Two    F H 4-NH_Two-7-CH_TwoF-THBT-2-yl  1-535 cPr Me H H 4-NH_Two-7-CH_TwoNH_Two-THBT-2-yl  1-536 cPr OCHF_Two    H H 4-NH_Two-7-CH_TwoNH_Two-THBT-2-yl  1-537 cPr Me F H 4-NH_Two-7-CH_TwoNH_Two-THBT-2-yl  1-538 cPr OCHF_Two    F H 4-NH_Two-7-CH_TwoNH_Two-THBT-2-yl  1-539 cPr Me H H 4-NH_Two-7-CH_TwoNHcPr-THBT-2-yl  1-540 cPr OCHF_Two    H H 4-NH_Two-7-CH_TwoNHcPr-THBT-2-yl  1-541 cPr Me F H 4-NH_Two-7-CH_TwoNHcPr-THBT-2-yl  1-542 cPr OCHF_Two    F H 4-NH_Two-7-CH_TwoNHcPr-THBT-2-yl  1-543 cPr Me H H 4-NH_Two-7-Me-THBT-2-yl  1-544 F-cPr Me H H 4-NH_Two-7-Me-THBT-2-yl  1-545 cPr OMe H H 4-NH_Two-7-Me-THBT-2-yl  1-546 F-cPr OMe H H 4-NH_Two-7-Me-THBT-2-yl  1-547 cPr OCHF_Two    H H 4-NH_Two-7-Me-THBT-2-yl  1-548 F-cPr OCHF_Two    H H 4-NH_Two-7-Me-THBT-2-yl  1-549 cPr Me H NH_Two    4-NH_Two-7-Me-THBT-2-yl  1-550 cPr OCHF_Two    H NH_Two   4-NH_Two-7-Me-THBT-2-yl  1-551 cPr Me F H 4-NH_Two-7-Me-THBT-2-yl  1-552 F-cPr Me F H 4-NH_Two-7-Me-THBT-2-yl  1-553 cPr OCHF_Two    F H 4-NH_Two-7-Me-THBT-2-yl  1-554 F-cPr OCHF_Two    F H 4-NH_Two-7-Me-THBT-2-yl  1-555 cPr Me F NH_Two    4-NH_Two-7-Me-THBT-2-yl  1-556 cPr OCHF_Two    F NH_Two   4-NH_Two-7-Me-THBT-2-yl  1-557 cPr Me H H 4,7-dNH_Two-THBT-2-yl  1-558 cPr OCHF_Two    H H 4,7-dNH_Two-THBT-2-yl  1-559 cPr Me F H 4,7-dNH_Two-THBT-2-yl  1-560 cPr OCHF_Two    F H 4,7-dNH_Two-THBT-2-yl  1-561 cPr Me H H 4-NH_Two-7-OH-THBT-2-yl  1-562 cPr OCHF_Two    H H 4-NH_Two-7-OH-THBT-2-yl  1-563 cPr Me F H 4-NH_Two-7-OH-THBT-2-yl  1-564 cPr OCHF_Two    F H 4-NH_Two-7-OH-THBT-2-yl  1-565 cPr Me H H 4-NH_Two-7-OMe-THBT-2-yl  1-566 F-cPr Me H H 4-NH_Two-7-OMe-THBT-2-yl  1-567 cPr OCHF_Two    H H 4-NH_Two-7-OMe-THBT-2-yl  1-568 F-cPr OCHF_Two    H H 4-NH_Two-7-OMe-THBT-2-yl  1-569 cPr Me F H 4-NH_Two-7-OMe-THBT-2-yl  1-570 F-cPr Me F H 4-NH_Two-7-OMe-THBT-2-yl  1-571 cPr OCHF_Two    F H 4-NH_Two-7-OMe-THBT-2-yl  1-572 F-cPr OCHF_Two    F H 4-NH_Two-7-OMe-THBT-2-yl  1-573 Et H H H 4-NH_Two-THBT-2-yl  1-574 F-Et H H H 4-NH_Two-THBT-2-yl  1-575 cPr H H H 4-NH_Two-THBT-2-yl  1-576 F-cPr H H H 4-NH_Two-THBT-2-yl  1-577 dF-Ph H H H 4-NH_Two-THBT-2-yl  1-578 dF-Py H H H 4-NH_Two-THBT-2-yl  1-579 NH_Two-dF-Py H H H 4-NH_Two-THBT-2-yl  1-580 Thiazo H H H 4-NH_Two-THBT-2-yl  1-581 Et Me H H 4-NH_Two-THBT-2-yl  1-582 F-Et Me H H 4-NH_Two-THBT-2-yl  1-583 cPr Me H H 4-NH_Two-THBT-2-yl  1-584 F-cPr Me H H 4-NH_Two-THBT-2-yl  1-585 dF-Ph Me H H 4-NH_Two-THBT-2-yl  1-586 dF-Py Me H H 4-NH_Two-THBT-2-yl  1-587 NH_Two-dF-Py Me H H 4-NH_Two-THBT-2-yl  1-588 Thiazo Me H H 4-NH_Two-THBT-2-yl  1-589 Et CH_TwoF H H 4-NH_Two-THBT-2-yl  1-590 F-Et CH_TwoF H H 4-NH_Two-THBT-2-yl  1-591 cPr CH_TwoF H H 4-NH_Two-THBT-2-yl  1-592 F-cPr CH_TwoF H H 4-NH_Two-THBT-2-yl  1-593 dF-Ph CH_TwoF H H 4-NH_Two-THBT-2-yl  1-594 dF-Py CH_TwoF H H 4-NH_Two-THBT-2-yl  1-595 NH_Two-dF-Py CH_TwoF H H 4-NH_Two-THBT-2-yl  1-596 Thiazo CH_TwoF H H 4-NH_Two-THBT-2-yl  1-597 Et CHF_Two    H H 4-NH_Two-THBT-2-yl  1-598 F-Et CHF_Two    H H 4-NH_Two-THBT-2-yl  1-599 cPr CHF_Two    H H 4-NH_Two-THBT-2-yl  1-600 F-cPr CHF_Two    H H 4-NH_Two-THBT-2-yl  1-601 dF-Ph CHF_Two    H H 4-NH_Two-THBT-2-yl  1-602 dF-Py CHF_Two    H H 4-NH_Two-THBT-2-yl  1-603 NH_Two-dF-Py CHF_Two    H H 4-NH_Two-THBT-2-yl  1-604 Thiazo CHF_Two    H H 4-NH_Two-THBT-2-yl  1-605 Et CF_Three     H H 4-NH_Two-THBT-2-yl  1-606 F-Et CF_Three     H H 4-NH_Two-THBT-2-yl  1-607 cPr CF_Three     H H 4-NH_Two-THBT-2-yl  1-608 F-cPr CF_Three     H H 4-NH_Two-THBT-2-yl  1-609 dF-Ph CF_Three     H H 4-NH_Two-THBT-2-yl  1-610 dF-Py CF_Three     H H 4-NH_Two-THBT-2-yl  1-611 NH_Two-dF-Py CF_Three     H H 4-NH_Two-THBT-2-yl  1-612 Thiazo CF_Three     H H 4-NH_Two-THBT-2-yl  1-613 Et OH H H 4-NH_Two-THBT-2-yl  1-614 F-Et OH H H 4-NH_Two-THBT-2-yl  1-615 cPr OH H H 4-NH_Two-THBT-2-yl  1-616 F-cPr OH H H 4-NH_Two-THBT-2-yl  1-617 dF-Ph OH H H 4-NH_Two-THBT-2-yl  1-618 dF-Py OH H H 4-NH_Two-THBT-2-yl  1-619 NH_Two-dF-Py OH H H 4-NH_Two-THBT-2-yl  1-620 Thiazo OH H H 4-NH_Two-THBT-2-yl  1-621 Et OMe H H 4-NH_Two-THBT-2-yl  1-622 F-Et OMe H H 4-NH_Two-THBT-2-yl  1-623 cPr OMe H H 4-NH_Two-THBT-2-yl  1-624 F-cPr OMe H H 4-NH_Two-THBT-2-yl  1-625 dF-Ph OMe H H 4-NH_Two-THBT-2-yl  1-626 dF-Py OMe H H 4-NH_Two-THBT-2-yl  1-627 NH_Two-dF-Py OMe H H 4-NH_Two-THBT-2-yl  1-628 Thiazo OMe H H 4-NH_Two-THBT-2-yl  1-629 Et OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-630 F-Et OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-631 cPr OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-632 F-cPr OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-633 dF-Ph OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-634 dF-Py OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-635 NH_Two-dF-Py OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-636 Thiazo OCHF_Two   H H 4-NH_Two-THBT-2-yl  1-637 Et CN H H 4-NH_Two-THBT-2-yl  1-638 F-Et CN H H 4-NH_Two-THBT-2-yl  1-639 cPr CN H H 4-NH_Two-THBT-2-yl  1-640 F-cPr CN H H 4-NH_Two-THBT-2-yl  1-641 dF-Ph CN H H 4-NH_Two-THBT-2-yl  1-642 dF-Py CN H H 4-NH_Two-THBT-2-yl  1-643 NH_Two-dF-Py CN H H 4-NH_Two-THBT-2-yl  1-644 Thiazo CN H H 4-NH_Two-THBT-2-yl  1-645 Et Cl H H 4-NH_Two-THBT-2-yl  1-646 F-Et Cl H H 4-NH_Two-THBT-2-yl  1-647 cPr Cl H H 4-NH_Two-THBT-2-yl  1-648 F-cPr Cl H H 4-NH_Two-THBT-2-yl  1-649 dF-Ph Cl H H 4-NH_Two-THBT-2-yl  1-650 dF-Py Cl H H 4-NH_Two-THBT-2-yl  1-651 NH_Two-dF-Py Cl H H 4-NH_Two-THBT-2-yl  1-652 Thiazo Cl H H 4-NH_Two-THBT-2-yl  1-653 Et H F H 4-NH_Two-THBT-2-yl  1-654 F-Et H F H 4-NH_TwoTHBT-2-yl  1-655 cPr H F H 4-NH_Two-THBT-2-yl  1-656 F-cPr H F H 4-NH_Two-THBT-2-yl  1-657 dF-Ph H F H 4-NH_Two-THBT-2-yl  1-658 dF-Py H F H 4-NH_Two-THBT-2-yl  1-659 NH_Two-dF-Py H F H 4-NH_Two-THBT-2-yl  1-660 Thiazo H F H 4-NH_Two-THBT-2-yl  1-661 Et Me F H 4-NH_Two-THBT-2-yl  1-662 F-Et Me F H 4-NH_Two-THBT-2-yl  1-663 cPr Me F H 4-NH_Two-THBT-2-yl  1-664 F-cPr Me F H 4-NH_Two-THBT-2-yl  1-665 dF-Ph Me F H 4-NH_Two-THBT-2-yl  1-666 dF-Py Me F H 4-NH_Two-THBT-2-yl  1-667 NH_Two-dF-Py Me F H 4-NH_Two-THBT-2-yl  1-668 Thiazo Me F H 4-NH_Two-THBT-2-yl  1-669 Et CH_TwoF F H 4-NH_Two-THBT-2-yl  1-670 F-Et CH_TwoF F H 4-NH_Two-THBT-2-yl  1-671 cPr CH_TwoF F H 4-NH_Two-THBT-2-yl  1-672 F-cPr CH_TwoF F H 4-NH_Two-THBT-2-yl  1-673 dF-Ph CH_TwoF F H 4-NH_Two-THBT-2-yl  1-674 dF-Py CH_TwoF F H 4-NH_Two-THBT-2-yl  1-675 NH_Two-dF-Py CH_TwoF F H 4-NH_Two-THBT-2-yl  1-676 Thiazo CH_TwoF F H 4-NH_Two-THBT-2-yl  1-677 Et CHF_Two    F H 4-NH_Two-THBT-2-yl  1-678 F-Et CHF_Two    F H 4-NH_Two-THBT-2-yl  1-679 cPr CHF_Two    F H 4-NH_Two-THBT-2-yl  1-680 F-cPr CHF_Two    F H 4-NH_Two-THBT-2-yl  1-681 dF-Ph CHF_Two    F H 4-NH_Two-THBT-2-yl  1-682 dF-Py CHF_Two    F H 4-NH_Two-THBT-2-yl  1-683 NH_Two-dF-Py CHF_Two    F H 4-NH_Two-THBT-2-yl  1-684 Thiazo CHF_Two    F H 4-NH_Two-THBT-2-yl  1-685 Et CF_Three     F H 4-NH_Two-THBT-2-yl  1-686 F-Et CF_Three     F H 4-NH_Two-THBT-2-yl  1-687 cPr CF_Three     F H 4-NH_Two-THBT-2-yl  1-688 F-cPr CF_Three     F H 4-NH_Two-THBT-2-yl  1-689 dF-Ph CF_Three     F H 4-NH_Two-THBT-2-yl  1-690 dF-Py CF_Three     F H 4-NH_Two-THBT-2-yl  1-691 NH_Two-dF-Py CF_Three     F H 4-NH_Two-THBT-2-yl  1-692 Thiazo CF_Three     F H 4-NH_Two-THBT-2-yl  1-693 Et OH F H 4-NH_Two-THBT-2-yl  1-694 F-Et OH F H 4-NH_Two-THBT-2-yl  1-695 cPr OH F H 4-NH_Two-THBT-2-yl  1-696 F-cPr OH F H 4-NH_Two-THBT-2-yl  1-697 dF-Ph OH F H 4-NH_Two-THBT-2-yl  1-698 dF-Py OH F H 4-NH_Two-THBT-2-yl  1-699 NH_Two-dF-Py OH F H 4-NH_Two-THBT-2-yl  1-700 Thiazo OH F H 4-NH_Two-THBT-2-yl  1-701 Et OMe F H 4-NH_Two-THBT-2-yl  1-702 F-Et OMe F H 4-NH_Two-THBT-2-yl  1-703 cPr OMe F H 4-NH_Two-THBT-2-yl  1-704 F-cPr OMe F H 4-NH_Two-THBT-2-yl  1-705 dF-Ph OMe F H 4-NH_Two-THBT-2-yl  1-706 dF-Py OMe F H 4-NH_Two-THBT-2-yl  1-707 NH_Two-dF-Py OMe F H 4-NH_Two-THBT-2-yl  1-708 Thiazo OMe F H 4-NH_Two-THBT-2-yl  1-709 Et OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-710 F-Et OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-711 cPr OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-712 F-cPr OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-713 dF-Ph OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-714 dF-Py OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-715 NH_Two-dF-Py OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-716 Thiazo OCHF_Two   F H 4-NH_Two-THBT-2-yl  1-717 Et CN F H 4-NH_Two-THBT-2-yl  1-718 F-Et CN F H 4-NH_Two-THBT-2-yl  1-719 cPr CN F H 4-NH_Two-THBT-2-yl  1-720 F-cPr CN F H 4-NH_Two-THBT-2-yl  1-721 dF-Ph CN F H 4-NH_Two-THBT-2-yl  1-722 dF-Py CN F H 4-NH_Two-THBT-2-yl  1-723 NH_Two-dF-Py CN F H 4-NH_Two-THBT-2-yl  1-724 Thiazo CN F H 4-NH_Two-THBT-2-yl  1-725 Et Cl F H 4-NH_Two-THBT-2-yl  1-726 F-Et Cl F H 4-NH_Two-THBT-2-yl  1-727 cPr Cl F H 4-NH_Two-THBT-2-yl  1-728 F-cPr Cl F H 4-NH_Two-THBT-2-yl  1-729 dF-Ph Cl F H 4-NH_Two-THBT-2-yl  1-730 dF-Py Cl F H 4-NH_Two-THBT-2-yl  1-731 NH_Two-dF-Py Cl F H 4-NH_Two-THBT-2-yl  1-732 Thiazo Cl F H 4-NH_Two-THBT-2-yl  1-733 cPr Me H NH_Two    4-NH_Two-THBT-2-yl  1-734 F-cPr Me H NH_Two    4-NH_Two-THBT-2-yl  1-735 cPr OCHF_Two   H NH_Two    4-NH_Two-THBT-2-yl  1-736 F-cPr OCHF_Two   H NH_Two    4-NH_Two-THBT-2-yl  1-737 cPr Me F NH_Two    4-NH_Two-THBT-2-yl  1-738 F-cPr Me F NH_Two    4-NH_Two-THBT-2-yl  1-739 cPr OCHF_Two   F NH_Two    4-NH_Two-THBT-2-yl  1-740 F-cPr OCHF_Two   F NH_Two    4-NH_Two-THBT-2-yl  1-741 cPr Me H Me 4-NH_Two-THBT-2-yl  1-742 F-cPr Me H Me 4-NH_Two-THBT-2-yl  1-743 cPr Me F Me 4-NH_Two-THBT-2-yl  1-744 F-cPr Me F Me 4-NH_Two-THBT-2-yl  1-745 cPr Me H H 4-NHcPr-THBT-2-yl  1-746 F-cPr Me H H 4-NHcPr-THBT-2-yl  1-747 cPr OCHF_Two    H H 4-NHcPr-THBT-2-yl  1-748 F-cPr OCHF_Two    H H 4-NHcPr-THBT-2-yl  1-749 cPr Me F H 4-NHcPr-THBT-2-yl  1-750 F-cPr Me F H 4-NHcPr-THBT-2-yl  1-751 cPr OCHF_Two    F H 4-NHcPr-THBT-2-yl  1-752 F-cPr OCHF_Two    F H 4-NHcPr-THBT-2-yl  1-753 cPr Me H H 4-NHMe-THBT-2-yl  1-754 F-cPr Me H H 4-NHMe-THBT-2-yl  1-755 cPr OCHF_Two    H H 4-NHMe-THBT-2-yl  1-756 F-cPr OCHF_Two    H H 4-NHMe-THBT-2-yl  1-757 cPr Me F H 4-NHMe-THBT-2-yl  1-758 F-cPr Me F H 4-NHMe-THBT-2-yl  1-759 cPr OCHF_Two    F H 4-NHMe-THBT-2-yl  1-760 F-cPr OCHF_Two    F H 4-NHMe-THBT-2-yl  1-761 cPr Me H H 4-NMe_Two-THBT-2-yl  1-762 F-cPr Me H H 4-NMe_Two-THBT-2-yl  1-763 cPr OCHF_Two    H H 4-NMe_Two-THBT-2-yl  1-764 F-cPr OCHF_Two    H H 4-NMe_Two-THBT-2-yl  1-765 cPr Me F H 4-NMe_Two-THBT-2-yl  1-766 F-cPr Me F H 4-NMe_Two-THBT-2-yl  1-767 cPr OCHF_Two    F H 4-NMe_Two-THBT-2-yl  1-768 F-cPr OCHF_Two    F H 4-NMe_Two-THBT-2-yl  1-769 cPr Me H H 4-NOH-THBT-2-yl  1-770 F-cPr Me H H 4-NOH-THBT-2-yl  1-771 cPr OCHF_Two    H H 4-NOH-THBT-2-yl  1-772 F-cPr OCHF_Two    H H 4-NOH-THBT-2-yl  1-773 cPr Me F H 4-NOH-THBT-2-yl  1-774 F-cPr Me F H 4-NOH-THBT-2-yl  1-775 cPr OCHF_Two    F H 4-NOH-THBT-2-yl  1-776 F-cPr OCHF_Two    F H 4-NOH-THBT-2-yl  1-777 cPr Me H H 4-NOMe-THBT-2-yl  1-778 F-cPr Me H H 4-NOMe-THBT-2-yl  1-779 cPr OCHF_Two    H H 4-NOMe-THBT-2-yl  1-780 F-cPr OCHF_Two    H H 4-NOMe-THBT-2-yl  1-781 cPr Me F H 4-NOMe-THBT-2-yl  1-782 F-cPr Me F H 4-NOMe-THBT-2-yl  1-783 cPr OCHF_Two    F H 4-NOMe-THBT-2-yl  1-784 F-cPr OCHF_Two    F H 4-NOMe-THBT-2-yl  1-785 cPr Me H H 4-OH-THBT-2-yl  1-786 F-cPr Me H H 4-OH-THBT-2-yl  1-787 cPr OCHF_Two    H H 4-OH-THBT-2-yl  1-788 F-cPr OCHF_Two    H H 4-OH-THBT-2-yl  1-789 cPr Me F H 4-OH-THBT-2-yl  1-790 F-cPr Me F H 4-OH-THBT-2-yl  1-791 cPr OCHF_Two    F H 4-OH-THBT-2-yl  1-792 F-cPr OCHF_Two    F H 4-OH-THBT-2-yl  1-793 cPr Me H H 5-NH_Two-THBT-2-yl  1-794 F-cPr Me H H 5-NH_Two-THBT-2-yl  1-795 cPr OMe H H 5-NH_Two-THBT-2-yl  1-796 F-cPr OMe H H 5-NH_Two-THBT-2-yl  1-797 cPr OCHF_Two    H H 5-NH_Two-THBT-2-yl  1-798 F-cPr OCHF_Two    H H 5-NH_Two-THBT-2-yl  1-799 cPr Me H NH_Two    5-NH_Two-THBT-2-yl  1-800 cPr OCHF_Two    H NH_Two   5-NH_Two-THBT-2-yl  1-801 cPr Me F H 5-NH_Two-THBT-2-yl  1-802 F-cPr Me F H 5-NH_Two-THBT-2-yl  1-803 cPr OCHF_Two    F H 5-NH_Two-THBT-2-yl  1-804 F-cPr OCHF_Two    F H 5-NH_Two-THBT-2-yl  1-805 cPr Me F NH_Two    5-NH_Two-THBT-2-yl  1-806 cPr OCHF_Two    F NH_Two   5-NH_Two-THBT-2-yl  1-807 cPr Me H H 5-NH_Two-3-F-THBT-2-yl  1-808 cPr OCHF_Two    H H 5-NH_Two-3-F-THBT-2-yl  1-809 cPr Me F H 5-NH_Two-3-F-THBT-2-yl  1-810 cPr OCHF_Two    F H 5-NH_Two-3-F-THBT-2-yl  1-811 cPr Me H H 6-NH_Two-THBT-2-yl  1-812 cPr OCHF_Two    H H 6-NH_Two-THBT-2-yl  1-813 cPr Me F H 6-NH_Two-THBT-2-yl  1-814 cPr OCHF_Two    F H 6-NH_Two-THBT-2-yl  1-815 cPr Me H H 7-NH_Two-THBT-2-yl  1-816 cPr OCHF_Two    H H 7-NH_Two-THBT-2-yl  1-817 cPr Me F H 7-NH_Two-THBT-2-yl  1-818 cPr OCHF_Two    F H 7-NH_Two-THBT-2-yl  1-819 Et H H H DHT (23c) P-2-yl  1-820 F-Et H H H DHT (23c) P-2-yl  1-821 cPr H H H DHT (23c) P-2-yl  1-822 F-cPr H H H DHT (23c) P-2-yl  1-823 dF-Ph H H H DHT (23c) P-2-yl  1-824 dF-Py H H H DHT (23c) P-2-yl  1-825 NH_Two-dF-Py H H H DHT (23c) P-2-yl  1-826 Thiazo H H H DHT (23c) P-2-yl  1-827 Et Me H H DHT (23c) P-2-yl  1-828 F-Et Me H H DHT (23c) P-2-yl  1-829 cPr Me H H DHT (23c) P-2-yl  1-830 F-cPr Me H H DHT (23c) P-2-yl  1-831 dF-Ph Me H H DHT (23c) P-2-yl  1-832 dF-Py Me H H DHT (23c) P-2-yl  1-833 NH_Two-dF-Py Me H H DHT (23c) P-2-yl  1-834 Thiazo Me H H DHT (23c) P-2-yl  1-835 Et CH_TwoF H H DHT (23c) P-2-yl  1-836 F-Et CH_TwoF H H DHT (23c) P-2-yl  1-837 cPr CH_TwoF H H DHT (23c) P-2-yl  1-838 F-cPr CH_TwoF H H DHT (23c) P-2-yl  1-839 dF-Ph CH_TwoF H H DHT (23c) P-2-yl  1-840 dF-Py CH_TwoF H H DHT (23c) P-2-yl  1-841 NH_Two-dF-Py CH_TwoF H H DHT (23c) P-2-yl  1-842 Thiazo CH_TwoF H H DHT (23c) P-2-yl  1-843 Et CHF_Two    H H DHT (23c) P-2-yl  1-844 F-Et CHF_Two    H H DHT (23c) P-2-yl  1-845 cPr CHF_Two    H H DHT (23c) P-2-yl  1-846 F-cPr CHF_Two    H H DHT (23c) P-2-yl  1-847 dF-Ph CHF_Two    H H DHT (23c) P-2-yl  1-848 dF-Py CHF_Two    H H DHT (23c) P-2-yl  1-849 NH_Two-dF-Py CHF_Two    H H DHT (23c) P-2-yl  1-850 Thiazo CHF_Two    H H DHT (23c) P-2-yl  1-851 Et CF_Three     H H DHT (23c) P-2-yl  1-852 F-Et CF_Three     H H DHT (23c) P-2-yl  1-853 cPr CF_Three     H H DHT (23c) P-2-yl  1-854 F-cPr CF_Three     H H DHT (23c) P-2-yl  1-855 dF-Ph CF_Three     H H DHT (23c) P-2-yl  1-856 dF-Py CF_Three     H H DHT (23c) P-2-yl  1-857 NH_Two-dF-Py CF_Three     H H DHT (23c) P-2-yl  1-858 Thiazo CF_Three     H H DHT (23c) P-2-yl  1-859 Et OH H H DHT (23c) P-2-yl  1-860 F-Et OH H H DHT (23c) P-2-yl  1-861 cPr OH H H DHT (23c) P-2-yl  1-862 F-cPr OH H H DHT (23c) P-2-yl  1-863 dF-Ph OH H H DHT (23c) P-2-yl  1-864 dF-Py OH H H DHT (23c) P-2-yl  1-865 NH_Two-dF-Py OH H H DHT (23c) P-2-yl  1-866 Thiazo OH H H DHT (23c) P-2-yl  1-867 Et OMe H H DHT (23c) P-2-yl  1-868 F-Et OMe H H DHT (23c) P-2-yl  1-869 cPr OMe H H DHT (23c) P-2-yl  1-870 F-cPr OMe H H DHT (23c) P-2-yl  1-871 dF-Ph OMe H H DHT (23c) P-2-yl  1-872 dF-Py OMe H H DHT (23c) P-2-yl  1-873 NH_Two-dF-Py OMe H H DHT (23c) P-2-yl  1-874 Thiazo OMe H H DHT (23c) P-2-yl  1-875 Et OCHF_Two   H H DHT (23c) P-2-yl  1-876 F-Et OCHF_Two   H H DHT (23c) P-2-yl  1-877 cPr OCHF_Two   H H DHT (23c) P-2-yl  1-878 F-cPr OCHF_Two   H H DHT (23c) P-2-yl  1-879 dF-Ph OCHF_Two   H H DHT (23c) P-2-yl  1-880 dF-Py OCHF_Two   H H DHT (23c) P-2-yl  1-881 NH_Two-dF-Py OCHF_Two   H H DHT (23c) P-2-yl  1-882 Thiazo OCHF_Two   H H DHT (23c) P-2-yl  1-883 Et CN H H DHT (23c) P-2-yl  1-884 F-Et CN H H DHT (23c) P-2-yl  1-885 cPr CN H H DHT (23c) P-2-yl  1-886 F-cPr CN H H DHT (23c) P-2-yl  1-887 dF-Ph CN H H DHT (23c) P-2-yl  1-888 dF-Py CN H H DHT (23c) P-2-yl  1-889 NH_Two-dF-Py CN H H DHT (23c) P-2-yl  1-890 Thiazo CN H H DHT (23c) P-2-yl  1-891 Et Cl H H DHT (23c) P-2-yl  1-892 F-Et Cl H H DHT (23c) P-2-yl  1-893 cPr Cl H H DHT (23c) P-2-yl  1-894 F-cPr Cl H H DHT (23c) P-2-yl  1-895 dF-Ph Cl H H DHT (23c) P-2-yl  1-896 dF-Py Cl H H DHT (23c) P-2-yl  1-897 NH_Two-dF-Py Cl H H DHT (23c) P-2-yl  1-898 Thiazo Cl H H DHT (23c) P-2-yl  1-899 Et H F H DHT (23c) P-2-yl  1-900 F-Et H F H DHT (23c) P-2-yl  1-901 cPr H F H DHT (23c) P-2-yl  1-902 F-cPr H F H DHT (23c) P-2-yl  1-903 dF-Ph H F H DHT (23c) P-2-yl  1-904 dF-Py H F H DHT (23c) P-2-yl  1-905 NH_Two-dF-Py H F H DHT (23c) P-2-yl  1-906 Thiazo H F H DHT (23c) P-2-yl  1-907 Et Me F H DHT (23c) P-2-yl  1-908 F-Et Me F H DHT (23c) P-2-yl  1-909 cPr Me F H DHT (23c) P-2-yl  1-910 F-cPr Me F H DHT (23c) P-2-yl  1-911 dF-Ph Me F H DHT (23c) P-2-yl  1-912 dF-Py Me F H DHT (23c) P-2-yl  1-913 NH_Two-dF-Py Me F H DHT (23c) P-2-yl  1-914 Thiazo Me F H DHT (23c) P-2-yl  1-915 Et CH_TwoF F H DHT (23c) P-2-yl  1-916 F-Et CH_TwoF F H DHT (23c) P-2-yl  1-917 cPr CH_TwoF F H DHT (23c) P-2-yl  1-918 F-cPr CH_TwoF F H DHT (23c) P-2-yl  1-919 dF-Ph CH_TwoF F H DHT (23c) P-2-yl  1-920 dF-Py CH_TwoF F H DHT (23c) P-2-yl  1-921 NH_Two-dF-Py CH_TwoF F H DHT (23c) P-2-yl  1-922 Thiazo CH_TwoF F H DHT (23c) P-2-yl  1-923 Et CHF_Two    F H DHT (23c) P-2-yl  1-924 F-Et CHF_Two    F H DHT (23c) P-2-yl  1-925 cPr CHF_Two    F H DHT (23c) P-2-yl  1-926 F-cPr CHF_Two    F H DHT (23c) P-2-yl  1-927 dF-Ph CHF_Two    F H DHT (23c) P-2-yl  1-928 dF-Py CHF_Two    F H DHT (23c) P-2-yl  1-929 NH_Two-dF-Py CHF_Two    F H DHT (23c) P-2-yl  1-930 Thiazo CHF_Two    F H DHT (23c) P-2-yl  1-931 Et CF_Three     F H DHT (23c) P-2-yl  1-932 F-Et CF_Three     F H DHT (23c) P-2-yl  1-933 cPr CF_Three     F H DHT (23c) P-2-yl  1-934 F-cPr CF_Three     F H DHT (23c) P-2-yl  1-935 dF-Ph CF_Three     F H DHT (23c) P-2-yl  1-936 dF-Py CF_Three     F H DHT (23c) P-2-yl  1-937 NH_Two-dF-Py CF_Three     F H DHT (23c) P-2-yl  1-938 Thiazo CF_Three     F H DHT (23c) P-2-yl  1-939 Et OH F H DHT (23c) P-2-yl  1-940 F-Et OH F H DHT (23c) P-2-yl  1-941 cPr OH F H DHT (23c) P-2-yl  1-942 F-cPr OH F H DHT (23c) P-2-yl  1-943 dF-Ph OH F H DHT (23c) P-2-yl  1-944 dF-Py OH F H DHT (23c) P-2-yl  1-945 NH_Two-dF-Py OH F H DHT (23c) P-2-yl  1-946 Thiazo OH F H DHT (23c) P-2-yl  1-947 Et OMe F H DHT (23c) P-2-yl  1-948 F-Et OMe F H DHT (23c) P-2-yl  1-949 cPr OMe F H DHT (23c) P-2-yl  1-950 F-cPr OMe F H DHT (23c) P-2-yl  1-951 dF-Ph OMe F H DHT (23c) P-2-yl  1-952 dF-Py OMe F H DHT (23c) P-2-yl  1-953 NH_Two-dF-Py OMe F H DHT (23c) P-2-yl  1-954 Thiazo OMe F H DHT (23c) P-2-yl  1-955 Et OCHF_Two   F H DHT (23c) P-2-yl  1-956 F-Et OCHF_Two   F H DHT (23c) P-2-yl  1-957 cPr OCHF_Two   F H DHT (23c) P-2-yl  1-958 F-cPr OCHF_Two   F H DHT (23c) P-2-yl  1-959 dF-Ph OCHF_Two   F H DHT (23c) P-2-yl  1-960 dF-Py OCHF_Two   F H DHT (23c) P-2-yl  1-961 NH_Two-dF-Py OCHF_Two   F H DHT (23c) P-2-yl  1-962 Thiazo OCHF_Two   F H DHT (23c) P-2-yl  1-963 Et CN F H DHT (23c) P-2-yl  1-964 F-Et CN F H DHT (23c) P-2-yl  1-965 cPr CN F H DHT (23c) P-2-yl  1-966 F-cPr CN F H DHT (23c) P-2-yl  1-967 dF-Ph CN F H DHT (23c) P-2-yl  1-968 dF-Py CN F H DHT (23c) P-2-yl  1-969 NH_Two-dF-Py CN F H DHT (23c) P-2-yl  1-970 Thiazo CN F H DHT (23c) P-2-yl  1-971 Et Cl F H DHT (23c) P-2-yl  1-972 F-Et Cl F H DHT (23c) P-2-yl  1-973 cPr Cl F H DHT (23c) P-2-yl  1-974 F-cPr Cl F H DHT (23c) P-2-yl  1-975 dF-Ph Cl F H DHT (23c) P-2-yl  1-976 dF-Py Cl F H DHT (23c) P-2-yl  1-977 NH_Two-dF-Py Cl F H DHT (23c) P-2-yl  1-978 Thiazo Cl F H DHT (23c) P-2-yl  1-979 cPr Me H NH_Two    DHT (23c) P-2-yl  1-980 F-cPr Me H NH_Two    DHT (23c) P-2-yl  1-981 cPr OCHF_Two   H NH_Two    DHT (23c) P-2-yl  1-982 F-cPr OCHF_Two   H NH_Two    DHT (23c) P-2-yl  1-983 cPr Me F NH_Two    DHT (23c) P-2-yl  1-984 F-cPr Me F NH_Two    DHT (23c) P-2-yl  1-985 cPr OCHF_Two   F NH_Two    DHT (23c) P-2-yl  1-986 F-cPr OCHF_Two   F NH_Two    DHT (23c) P-2-yl  1-987 cPr Me H Me DHT (23c) P-2-yl  1-988 F-cPr Me H Me DHT (23c) P-2-yl  1-989 cPr Me F Me DHT (23c) P-2-yl  1-990 F-cPr Me F Me DHT (23c) P-2-yl  1-991 cPr Me H H 3-Cl-DHT (23) P-2-yl  1-992 F-cPr Me H H 3-Cl-DHT (23) P-2-yl  1-993 cPr OCHF_Two    H H 3-Cl-DHT (23) P-2-yl  1-994 F-cPr OCHF_Two    H H 3-Cl-DHT (23) P-2-yl  1-995 cPr Me F H 3-Cl-DHT (23) P-2-yl  1-996 F-cPr Me F H 3-Cl-DHT (23) P-2-yl  1-997 cPr OCHF_Two    F H 3-Cl-DHT (23) P-2-yl  1-998 F-cPr OCHF_Two    F H 3-Cl-DHT (23) P-2-yl  1-999 cPr Me H H 3-CN-DHT (23) P-2-yl 1-1000 F-cPr Me H H 3-CN-DHT (23) P-2-yl 1-1001 cPr OCHF_Two    H H 3-CN-DHT (23) P-2-yl 1-1002 F-cPr OCHF_Two    H H 3-CN-DHT (23) P-2-yl 1-1003 cPr Me F H 3-CN-DHT (23) P-2-yl 1-1004 F-cPr Me F H 3-CN-DHT (23) P-2-yl 1-1005 cPr OCHF_Two    F H 3-CN-DHT (23) P-2-yl 1-1006 F-cPr OCHF_Two    F H 3-CN-DHT (23) P-2-yl 1-1007 cPr Me H H 3-F-6-Me-DHT (23) P-2-yl 1-1008 F-cPr Me H H 3-F-6-Me-DHT (23) P-2-yl 1-1009 cPr OMe H H 3-F-6-Me-DHT (23) P-2-yl 1-1010 F-cPr OMe H H 3-F-6-Me-DHT (23) P-2-yl 1-1011 cPr OCHF_Two    H H 3-F-6-Me-DHT (23) P-2-yl 1-1012 F-cPr OCHF_Two    H H 3-F-6-Me-DHT (23) P-2-yl 1-1013 cPr Me H NH_Two    3-F-6-Me-DHT (23) P-2-yl 1-1014 cPr OCHF_Two    H NH_Two   3-F-6-Me-DHT (23) P-2-yl 1-1015 cPr Me F H 3-F-6-Me-DHT (23) P-2-yl 1-1016 F-cPr Me F H 3-F-6-Me-DHT (23) P-2-yl 1-1017 cPr OCHF_Two    F H 3-F-6-Me-DHT (23) P-2-yl 1-1018 F-cPr OCHF_Two    F H 3-F-6-Me-DHT (23) P-2-yl 1-1019 cPr Me F NH_Two    3-F-6-Me-DHT (23) P-2-yl 1-1020 cPr OCHF_Two    F NH_Two   3-F-6-Me-DHT (23) P-2-yl 1-1021 cPr Me H H 3-F-DHT (23) P-2-yl 1-1022 F-cPr Me H H 3-F-DHT (23) P-2-yl 1-1023 cPr OMe H H 3-F-DHT (23) P-2-yl 1-1024 F-cPr OMe H H 3-F-DHT (23) P-2-yl 1-1025 cPr OCHF_Two    H H 3-F-DHT (23) P-2-yl 1-1026 F-cPr OCHF_Two    H H 3-F-DHT (23) P-2-yl 1-1027 cPr Me H NH_Two    3-F-DHT (23) P-2-yl 1-1028 cPr OCHF_Two    H NH_Two   3-F-DHT (23) P-2-yl 1-1029 cPr Me F H 3-F-DHT (23) P-2-yl 1-1030 F-cPr Me F H 3-F-DHT (23) P-2-yl 1-1031 cPr OCHF_Two    F H 3-F-DHT (23) P-2-yl 1-1032 F-cPr OCHF_Two    F H 3-F-DHT (23) P-2-yl 1-1033 cPr Me F NH_Two    3-F-DHT (23) P-2-yl 1-1034 cPr OCHF_Two    F NH_Two   3-F-DHT (23) P-2-yl 1-1035 cPr Me H H 3-Me-DHT (23) P-2-yl 1-1036 F-cPr Me H H 3-Me-DHT (23) P-2-yl 1-1037 cPr OMe H H 3-Me-DHT (23) P-2-yl 1-1038 F-cPr OMe H H 3-Me-DHT (23) P-2-yl 1-1039 cPr OCHF_Two    H H 3-Me-DHT (23) P-2-yl 1-1040 F-cPr OCHF_Two    H H 3-Me-DHT (23) P-2-yl 1-1041 cPr Me H NH_Two    3-Me-DHT (23) P-2-yl 1-1042 cPr OCHF_Two    H NH_Two   3-Me-DHT (23) P-2-yl 1-1043 cPr Me F H 3-Me-DHT (23) P-2-yl 1-1044 F-cPr Me F H 3-Me-DHT (23) P-2-yl 1-1045 cPr OCHF_Two    F H 3-Me-DHT (23) P-2-yl 1-1046 F-cPr OCHF_Two    F H 3-Me-DHT (23) P-2-yl 1-1047 cPr Me F NH_Two    3-Me-DHT (23) P-2-yl 1-1048 cPr OCHF_Two    F NH_Two   3-Me-DHT (23) P-2-yl 1-1049 cPr Me H H 3-OCHF_Two-DHT (23) P-2-yl 1-1050 F-cPr Me H H 3-OCHF_Two-DHT (23) P-2-yl 1-1051 cPr OCHF_Two    H H 3-OCHF_Two-DHT (23) P-2-yl 1-1052 F-cPr OCHF_Two    H H 3-OCHF_Two-DHT (23) P-2-yl 1-1053 cPr Me F H 3-OCHF_Two-DHT (23) P-2-yl 1-1054 F-cPr Me F H 3-OCHF_Two-DHT (23) P-2-yl 1-1055 cPr OCHF_Two    F H 3-OCHF_Two-DHT (23) P-2-yl 1-1056 F-cPr OCHF_Two    F H 3-OCHF_Two-DHT (23) P-2-yl 1-1057 cPr Me H H 3-OMe-DHT (23) P-2-yl 1-1058 F-cPr Me H H 3-OMe-DHT (23) P-2-yl 1-1059 cPr OCHF_Two    H H 3-OMe-DHT (23) P-2-yl 1-1060 F-cPr OCHF_Two    H H 3-OMe-DHT (23) P-2-yl 1-1061 cPr Me F H 3-OMe-DHT (23) P-2-yl 1-1062 F-cPr Me F H 3-OMe-DHT (23) P-2-yl 1-1063 cPr OCHF_Two    F H 3-OMe-DHT (23) P-2-yl 1-1064 F-cPr OCHF_Two    F H 3-OMe-DHT (23) P-2-yl 1-1065 cPr Me H H 4-Me-DHT (23) P-2-yl 1-1066 F-cPr Me H H 4-Me-DHT (23) P-2-yl 1-1067 cPr OMe H H 4-Me-DHT (23) P-2-yl 1-1068 F-cPr OMe H H 4-Me-DHT (23) P-2-yl 1-1069 cPr OCHF_Two    H H 4-Me-DHT (23) P-2-yl 1-1070 F-cPr OCHF_Two    H H 4-Me-DHT (23) P-2-yl 1-1071 cPr Me H NH_Two    4-Me-DHT (23) P-2-yl 1-1072 cPr OCHF_Two    H NH_Two   4-Me-DHT (23) P-2-yl 1-1073 cPr Me F H 4-Me-DHT (23) P-2-yl 1-1074 F-cPr Me F H 4-Me-DHT (23) P-2-yl 1-1075 cPr OCHF_Two    F H 4-Me-DHT (23) P-2-yl 1-1076 F-cPr OCHF_Two    F H 4-Me-DHT (23) P-2-yl 1-1077 cPr Me F NH_Two    4-Me-DHT (23) P-2-yl 1-1078 cPr OCHF_Two    F NH_Two   4-Me-DHT (23) P-2-yl 1-1079 cPr Me H H 5-Me-DHT (23) P-2-yl 1-1080 F-cPr Me H H 5-Me-DHT (23) P-2-yl 1-1081 cPr OCHF_Two    H H 5-Me-DHT (23) P-2-yl 1-1082 F-cPr OCHF_Two    H H 5-Me-DHT (23) P-2-yl 1-1083 cPr Me F H 5-Me-DHT (23) P-2-yl 1-1084 F-cPr Me F H 5-Me-DHT (23) P-2-yl 1-1085 cPr OCHF_Two    F H 5-Me-DHT (23) P-2-yl 1-1086 F-cPr OCHF_Two    F H 5-Me-DHT (23) P-2-yl 1-1087 cPr Me H H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1088 F-cPr Me H H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1089 cPr OCHF_Two    H H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1090 F-cPr OCHF_Two    H H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1091 cPr Me F H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1092 F-cPr Me F H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1093 cPr OCHF_Two    F H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1094 F-cPr OCHF_Two    F H 6-CH_TwoNH_Two-DHT (23) P-2-yl 1-1095 cPr Me H H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1096 F-cPr Me H H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1097 cPr OCHF_Two    H H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1098 F-cPr OCHF_Two    H H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1099 cPr Me F H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1100 F-cPr Me F H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1101 cPr OCHF_Two    F H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1102 F-cPr OCHF_Two    F H 6-CH_TwoNHcPr-DHT (23) P-2-yl 1-1103 cPr Me H H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1104 F-cPr Me H H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1105 cPr OCHF_Two    H H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1106 F-cPr OCHF_Two    H H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1107 cPr Me F H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1108 F-cPr Me F H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1109 cPr OCHF_Two    F H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1110 F-cPr OCHF_Two    F H 6-CH_TwoNHMe-DHT (23) P-2-yl 1-1111 cPr Me H H 6-CH_TwoNMe_TwoDHT (23) P-2-yl 1-1112 F-cPr Me H H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1113 cPr OCHF_Two    H H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1114 F-cPr OCHF_Two    H H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1115 cPr Me F H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1116 F-cPr Me F H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1117 cPr OCHF_Two    F H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1118 F-cPr OCHF_Two    F H 6-CH_TwoNMe_Two-DHT (23) P-2-yl 1-1119 cPr Me H H 6-CH_TwoOH-DHT (23) P-2-yl 1-1120 F-cPr Me H H 6-CH_TwoOH-DHT (23) P-2-yl 1-1121 cPr OCHF_Two    H H 6-CH_TwoOH-DHT (23) P-2-yl 1-1122 F-cPr OCHF_Two    H H 6-CH_TwoOH-DHT (23) P-2-yl 1-1123 cPr Me F H 6-CH_TwoOH-DHT (23) P-2-yl 1-1124 F-cPr Me F H 6-CH_TwoOH-DHT (23) P-2-yl 1-1125 cPr OCHF_Two    F H 6-CH_TwoOH-DHT (23) P-2-yl 1-1126 F-cPr OCHF_Two    F H 6-CH_TwoOH-DHT (23) P-2-yl 1-1127 cPr Me H H 6-Me-DHT (23) P-2-yl 1-1128 F-cPr Me H H 6-Me-DHT (23) P-2-yl 1-1129 cPr OMe H H 6-Me-DHT (23) P-2-yl 1-1130 F-cPr OMe H H 6-Me-DHT (23) P-2-yl 1-1131 cPr OCHF_Two    H H 6-Me-DHT (23) P-2-yl 1-1132 F-cPr OCHF_Two    H H 6-Me-DHT (23) P-2-yl 1-1133 cPr Me H NH_Two    6-Me-DHT (23) P-2-yl 1-1134 cPr OCHF_Two    H NH_Two   6-Me-DHT (23) P-2-yl 1-1135 cPr Me F H 6-Me-DHT (23) P-2-yl 1-1136 F-cPr Me F H 6-Me-DHT (23) P-2-yl 1-1137 cPr OCHF_Two    F H 6-Me-DHT (23) P-2-yl 1-1138 F-cPr OCHF_Two    F H 6-Me-DHT (23) P-2-yl 1-1139 cPr Me F NH_Two    6-Me-DHT (23) P-2-yl 1-1140 cPr OCHF_Two    F NH_Two   6-Me-DHT (23) P-2-yl 1-1141 cPr Me H H 6-scPr-DHT (23) P-2-yl 1-1142 F-cPr Me H H 6-scPr-DHT (23) P-2-yl 1-1143 cPr OMe H H 6-scPr-DHT (23) P-2-yl 1-1144 F-cPr OMe H H 6-scPr-DHT (23) P-2-yl 1-1145 cPr OCHF_Two    H H 6-scPr-DHT (23) P-2-yl 1-1146 F-cPr OCHF_Two    H H 6-scPr-DHT (23) P-2-yl 1-1147 cPr Me H NH_Two    6-scPr-DHT (23) P-2-yl 1-1148 cPr OCHF_Two    H NH_Two   6-scPr-DHT (23) P-2-yl 1-1149 cPr Me F H 6-scPr-DHT (23) P-2-yl 1-1150 F-cPr Me F H 6-scPr-DHT (23) P-2-yl 1-1151 cPr OCHF_Two    F H 6-scPr-DHT (23) P-2-yl 1-1152 F-cPr OCHF_Two    F H 6-scPr-DHT (23) P-2-yl 1-1153 cPr Me F NH_Two    6-scPr-DHT (23) P-2-yl 1-1154 cPr OCHF_Two    F NH_Two   6-scPr-DHT (23) P-2-yl 1-1155 cPr Me H H 4-NH_Two-DHCPT-2-yl 1-1156 F-cPr Me H H 4-NH_Two-DHCPT-2-yl 1-1157 cPr OCHF_Two    H H 4-NH_Two-DHCPT-2-yl 1-1158 F-cPr OCHF_Two    H H 4-NH_Two-DHCPT-2-yl 1-1159 cPr Me F H 4-NH_Two-DHCPT-2-yl 1-1160 F-cPr Me F H 4-NH_Two-DHCPT-2-yl 1-1161 cPr OCHF_Two    F H 4-NH_Two-DHCPT-2-yl 1-1162 F-cPr OCHF_Two    F H 4-NH_Two-DHCPT-2-yl 1-1163 cPr Me H H 4-NH_Two-3-Cl-DHCPT-2-yl 1-1164 cPr OCHF_Two    H H 4-NH_Two-3-Cl-DHCPT-2-yl 1-1165 cPr Me F H 4-NH_Two-3-Cl-DHCPT-2-yl 1-1166 cPr OCHF_Two    F H 4-NH_Two-3-Cl-DHCPT-2-yl 1-1167 cPr Me H H 4-NH_Two-3-CN-DHCPT-2-yl 1-1168 cPr OCHF_Two    H H 4-NH_Two-3-CN-DHCPT-2-yl 1-1169 cPr Me F H 4-NH_Two-3-CN-DHCPT-2-yl 1-1170 cPr OCHF_Two    F H 4-NH_Two-3-CN-DHCPT-2-yl 1-1171 cPr Me H H 4-NH_Two-3-Me-DHCPT-2-yl 1-1172 cPr OCHF_Two    H H 4-NH_Two-3-Me-DHCPT-2-yl 1-1173 cPr Me F H 4-NH_Two-3-Me-DHCPT-2-yl 1-1174 cPr OCHF_Two    F H 4-NH_Two-3-Me-DHCPT-2-yl 1-1175 cPr Me H H 4-NH_Two-3-OCHF_Two-DHCPT-2-yl 1-1176 cPr OCHF_Two    H H 4-NH_Two-3-OCHF_Two-DHCPT-2-yl 1-1177 cPr Me F H 4-NH_Two-3-OCHF_Two-DHCPT-2-yl 1-1178 cPr OCHF_Two    F H 4-NH_Two-3-OCHF_Two-DHCPT-2-yl 1-1179 cPr Me H H 4-NH_Two-3-OMe-DHCPT-2-yl 1-1180 cPr OCHF_Two    H H 4-NH_Two-3-OMe-DHCPT-2-yl 1-1181 cPr Me F H 4-NH_Two-3-OMe-DHCPT-2-yl 1-1182 cPr OCHF_Two    F H 4-NH_Two-3-OMe-DHCPT-2-yl 1-1183 cPr Me H H 4-NH_Two-5-CF_Three-DHCPT-2-yl 1-1184 cPr OCHF_Two    H H 4-NH_Two-5-CF_Three-DHCPT-2-yl 1-1185 cPr Me F H 4-NH_Two-5-CF_Three-DHCPT-2-yl 1-1186 cPr OCHF_Two    F H 4-NH_Two-5-CF_Three-DHCPT-2-yl 1-1187 cPr Me H H 4-NH_Two-5-CH_TwoOH-DHCPT-2-yl 1-1188 cPr OCHF_Two    H H 4-NH_Two-5-CH_TwoOH-DHCPT-2-yl 1-1189 cPr Me F H 4-NH_Two-5-CH_TwoOH-DHCPT-2-yl 1-1190 cPr OCHF_Two    F H 4-NH_Two-5-CH_TwoOH-DHCPT-2-yl 1-1191 cPr Me H H 4-NH_Two-5-Me-DHCPT-2-yl 1-1192 F-cPr Me H H 4-NH_Two-5-Me-DHCPT-2-yl 1-1193 cPr OCHF_Two    H H 4-NH_Two-5-Me-DHCPT-2-yl 1-1194 F-cPr OCHF_Two    H H 4-NH_Two-5-Me-DHCPT-2-yl 1-1195 cPr Me F H 4-NH_Two-5-Me-DHCPT-2-yl 1-1196 F-cPr Me F H 4-NH_Two-5-Me-DHCPT-2-yl 1-1197 cPr OCHF_Two    F H 4-NH_Two-5-Me-DHCPT-2-yl 1-1198 F-cPr OCHF_Two    F H 4-NH_Two-5-Me-DHCPT-2-yl 1-1199 cPr Me H H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1200 F-cPr Me H H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1201 cPr OCHF_Two    H H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1202 F-cPr OCHF_Two    H H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1203 cPr Me F H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1204 F-cPr Me F H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1205 cPr OCHF_Two    F H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1206 F-cPr OCHF_Two    F H 4-NH_Two-6-CH_TwoF-DHCPT-2-yl 1-1207 cPr Me H H 4-NH_Two-6-CH_TwoNH_Two-DHCPT-2-yl 1-1208 cPr OCHF_Two    H H 4-NH_Two-6-CH_TwoNH_Two-DHCPT-2-yl 1-1209 cPr Me F H 4-NH_Two-6-CH_TwoNH_Two-DHCPT-2-yl 1-1210 cPr OCHF_Two    F H 4-NH_Two-6-CH_TwoNH_Two-DHCPT-2-yl 1-1211 cPr Me H H 4-NH_Two-6-CH_TwoNHcPr-DHCPT-2-yl 1-1212 cPr OCHF_Two    H H 4-NH_Two-6-CH_TwoNHcPr-DHCPT-2-yl 1-1213 cPr Me F H 4-NH_Two-6-CH_TwoNHcPr-DHCPT-2-yl 1-1214 cPr OCHF_Two    F H 4-NH_Two-6-CH_TwoNHcPr-DHCPT-2-yl 1-1215 cPr Me H H 4-NH_Two-6-Me-DHCPT-2-yl 1-1216 F-cPr Me H H 4-NH_Two-6-Me-DHCPT-2-yl 1-1217 cPr OCHF_Two    H H 4-NH_Two-6-Me-DHCPT-2-yl 1-1218 F-cPr OCHF_Two    H H 4-NH_Two-6-Me-DHCPT-2-yl 1-1219 cPr Me F H 4-NH_Two-6-Me-DHCPT-2-yl 1-1220 F-cPr Me F H 4-NH_Two-6-Me-DHCPT-2-yl 1-1221 cPr OCHF_Two    F H 4-NH_Two-6-Me-DHCPT-2-yl 1-1222 F-cPr OCHF_Two    F H 4-NH_Two-6-Me-DHCPT-2-yl 1-1223 cPr Me H H 4,6-dNH_Two-DHCPT-2-yl 1-1224 cPr OCHF_Two    H H 4,6-dNH_Two-DHCPT-2-yl 1-1225 cPr Me F H 4,6-dNH_Two-DHCPT-2-yl 1-1226 cPr OCHF_Two    F H 4,6-dNH_Two-DHCPT-2-yl 1-1227 cPr Me H H 4-NH_Two-6-OH-DHCPT-2-yl 1-1228 cPr OCHF_Two    H H 4-NH_Two-6-OH-DHCPT-2-yl 1-1229 cPr Me F H 4-NH_Two-6-OH-DHCPT-2-yl 1-1230 cPr OCHF_Two    F H 4-NH_Two-6-OH-DHCPT-2-yl 1-1231 cPr Me H H 4-NH_Two-6-OMe-DHCPT-2-yl 1-1232 cPr OCHF_Two    H H 4-NH_Two-6-OMe-DHCPT-2-yl 1-1233 cPr Me F H 4-NH_Two-6-OMe-DHCPT-2-yl 1-1234 cPr OCHF_Two    F H 4-NH_Two-6-OMe-DHCPT-2-yl 1-1235 cPr Me H H 5-NH_Two-DHCPT-2-yl 1-1236 cPr OCHF_Two    H H 5-NH_Two-DHCPT-2-yl 1-1237 cPr Me F H 5-NH_Two-DHCPT-2-yl 1-1238 cPr OCHF_Two    F H 5-NH_Two-DHCPT-2-yl 1-1239 cPr Me H H 6-NH_Two-DHCPT-2-yl 1-1240 cPr OCHF_Two    H H 6-NH_Two-DHCPT-2-yl 1-1241 cPr Me F H 6-NH_Two-DHCPT-2-yl 1-1242 cPr OCHF_Two    F H 6-NH_Two-DHCPT-2-yl 1-1243 cPr Me H H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1244 F-cPr Me H H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1245 cPr OMe H H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1246 F-cPr OMe H H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1247 cPr OCHF_Two     H H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1248 F-cPr OCHF_Two     H H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1249 cPr Me H NH_Two   4-NH_Two-6-Me-THT (23c) P-2-yl 1-1250 cPr OCHF_Two     H NH_Two   4-NH_Two-6-Me-THT (23c) P-2-yl 1-1251 cPr Me F H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1252 F-cPr Me F H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1253 cPr OCHF_Two     F H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1254 F-cPr OCHF_Two     F H 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1255 cPr Me F NH_Two  4-NH_Two-6-Me-THT (23c) P-2-yl 1-1256 cPr OCHF_Two     F NH_Two 4-NH_Two-6-Me-THT (23c) P-2-yl 1-1257 cPr Me H H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1258 F-cPr Me H H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1259 cPr OMe H H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1260 F-cPr OMe H H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1261 cPr OCHF_Two     H H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1262 F-cPr OCHF_Two     H H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1263 cPr Me H NH_Two   4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1264 cPr OCHF_Two     H NH_Two   4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1265 cPr Me F H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1266 F-cPr Me F H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1267 cPr OCHF_Two     F H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1268 F-cPr OCHF_Two     F H 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1269 cPr Me F NH_Two  4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1270 cPr OCHF_Two     F NH_Two 4-NH_Two-6-Me-7-O-THT (23c) P-2-yl 1-1271 cPr Me H H 4-NHMe-THT (23c) P-2-yl 1-1272 F-cPr Me H H 4-NHMe-THT (23c) P-2-yl 1-1273 cPr OCHF_Two    H H 4-NHMe-THT (23c) P-2-yl 1-1274 F-cPr OCHF_Two    H H 4-NHMe-THT (23c) P-2-yl 1-1275 cPr Me F H 4-NHMe-THT (23c) P-2-yl 1-1276 F-cPr Me F H 4-NHMe-THT (23c) P-2-yl 1-1277 cPr OCHF_Two    F H 4-NHMe-THT (23c) P-2-yl 1-1278 F-cPr OCHF_Two    F H 4-NHMe-THT (23c) P-2-yl 1-1279 cPr Me H H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1280 F-cPr Me H H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1281 cPr OMe H H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1282 F-cPr OMe H H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1283 cPr OCHF_Two     H H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1284 F-cPr OCHF_Two     H H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1285 cPr Me H NH_Two   4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1286 cPr OCHF_Two     H NH_Two   4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1287 cPr Me F H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1288 F-cPr Me F H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1289 cPr OCHF_Two     F H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1290 F-cPr OCHF_Two     F H 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1291 cPr Me F NH_Two  4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1292 cPr OCHF_Two     F NH_Two 4-NH_Two-7-DMe-THT (23c) P-2-yl 1-1293 cPr Me H H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1294 F-cPr Me H H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1295 cPr OMe H H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1296 F-cPr OMe H H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1297 cPr OCHF_Two     H H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1298 F-cPr OCHF_Two     H H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1299 cPr Me H NH_Two   4-NHMe-7-DMe-THT (23c) P-2-yl 1-1300 cPr OCHF_Two     H NH_Two   4-NHMe-7-DMe-THT (23c) P-2-yl 1-1301 cPr Me F H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1302 F-cPr Me F H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1303 cPr OCHF_Two     F H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1304 F-cPr OCHF_Two     F H 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1305 cPr Me F NH_Two  4-NHMe-7-DMe-THT (23c) P-2-yl 1-1306 cPr OCHF_Two     F NH_Two 4-NHMe-7-DMe-THT (23c) P-2-yl 1-1307 cPr Me H H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1308 F-cPr Me H H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1309 cPr OMe H H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1310 F-cPr OMe H H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1311 cPr OCHF_Two     H H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1312 F-cPr OCHF_Two     H H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1313 cPr Me H NH_Two   4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1314 cPr OCHF_Two     H NH_Two   4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1315 cPr Me F H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1316 F-cPr Me F H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1317 cPr OCHF_Two     F H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1318 F-cPr OCHF_Two     F H 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1319 cPr Me F NH_Two  4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1320 cPr OCHF_Two     F NH_Two 4-NH_Two-7-scPr-THT (23c) P-2-yl 1-1321 cPr Me H H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1322 F-cPr Me H H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1323 cPr OCHF_Two    H H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1324 F-cPr OCHF_Two    H H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1325 cPr Me F H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1326 F-cPr Me F H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1327 cPr OCHF_Two    F H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1328 F-cPr OCHF_Two    F H 4-NHMe-7-scPr-THT (23c) P-2-yl 1-1329 cPr Me H H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1330 F-cPr Me H H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1331 cPr OCHF_Two    H H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1332 F-cPr OCHF_Two    H H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1333 cPr Me F H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1334 F-cPr Me F H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1335 cPr OCHF_Two    F H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1336 F-cPr OCHF_Two    F H 7-NH_Two-4-DMe-THT (32c) P-2-yl 1-1337 cPr Me H H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1338 F-cPr Me H H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1339 cPr OCHF_Two    H H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1340 F-cPr OCHF_Two    H H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1341 cPr Me F H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1342 F-cPr Me F H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1343 cPr OCHF_Two    F H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1344 F-cPr OCHF_Two    F H 7-NHMe-4-DMe-THT (32c) P-2-yl 1-1345 cPr Me H H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1346 F-cPr Me H H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1347 cPr OCHF_Two    H H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1348 F-cPr OCHF_Two    H H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1349 cPr Me F H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1350 F-cPr Me F H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1351 cPr OCHF_Two    F H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1352 F-cPr OCHF_Two    F H 7-NH_Two-4-scPr-THT (32c) P-2-yl 1-1353 cPr Me H H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1354 F-cPr Me H H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1355 cPr OCHF_Two    H H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1356 F-cPr OCHF_Two    H H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1357 cPr Me F H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1358 F-cPr Me F H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1359 cPr OCHF_Two    F H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1360 F-cPr OCHF_Two    F H 7-NHMe-4-scPr-THT (32c) P-2-yl 1-1361 cPr Me H H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1362 F-cPr Me H H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1363 cPr OMe H H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1364 F-cPr OMe H H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1365 cPr OCHF_Two     H H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1366 F-cPr OCHF_Two     H H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1367 cPr Me H NH_Two   7-NH_Two-5-Me-THT (32c) P-2-yl 1-1368 cPr OCHF_Two     H NH_Two   7-NH_Two-5-Me-THT (32c) P-2-yl 1-1369 cPr Me F H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1370 F-cPr Me F H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1371 cPr OCHF_Two     F H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1372 F-cPr OCHF_Two     F H 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1373 cPr Me F NH_Two  7-NH_Two-5-Me-THT (32c) P-2-yl 1-1374 cPr OCHF_Two     F NH_Two 7-NH_Two-5-Me-THT (32c) P-2-yl 1-1375 cPr Me H H 4-NHMe-THT (32c) P-2-yl 1-1376 F-cPr Me H H 4-NHMe-THT (32c) P-2-yl 1-1377 cPr OCHF_Two    H H 4-NHMe-THT (32c) P-2-yl 1-1378 F-cPr OCHF_Two    H H 4-NHMe-THT (32c) P-2-yl 1-1379 cPr Me F H 4-NHMe-THT (32c) P-2-yl 1-1380 F-cPr Me F H 4-NHMe-THT (32c) P-2-yl 1-1381 cPr OCHF_Two    F H 4-NHMe-THT (32c) P-2-yl 1-1382 F-cPr OCHF_Two    F H 4-NHMe-THT (32c) P-2-yl 1-1383 cPr Me H H 4-NH_Two-5-Me-THBT-2-yl 1-1384 F-cPr Me H H 4-NH_Two-5-Me-THBT-2-yl 1-1385 cPr OMe H H 4-NH_Two-5-Me-THBT-2-yl 1-1386 F-cPr OMe H H 4-NH_Two-5-Me-THBT-2-yl 1-1387 cPr OCHF_Two     H H 4-NH_Two-5-Me-THBT-2-yl 1-1388 F-cPr OCHF_Two     H H 4-NH_Two-5-Me-THBT-2-yl 1-1389 cPr Me H NH_Two   4-NH_Two-5-Me-THBT-2-yl 1-1390 cPr OCHF_Two     H NH_Two   4-NH_Two-5-Me-THBT-2-yl 1-1391 cPr Me F H 4-NH_Two-5-Me-THBT-2-yl 1-1392 F-cPr Me F H 4-NH_Two-5-Me-THBT-2-yl 1-1393 cPr OCHF_Two     F H 4-NH_Two-5-Me-THBT-2-yl 1-1394 F-cPr OCHF_Two     F H 4-NH_Two-5-Me-THBT-2-yl 1-1395 cPr Me F NH_Two  4-NH_Two-5-Me-THBT-2-yl 1-1396 cPr OCHF_Two     F NH_Two 4-NH_Two-5-Me-THBT-2-yl 1-1397 cPr Me H H 4-NH_Two-DHT (23b) TP-2-yl 1-1398 F-cPr Me H H 4-NH_Two-DHT (23b) TP-2-yl 1-1399 cPr OMe H H 4-NH_Two-DHT (23b) TP-2-yl 1-1400 F-cPr OMe H H 4-NH_Two-DHT (23b) TP-2-yl 1-1401 cPr OCHF_Two     H H 4-NH_Two-DHT (23b) TP-2-yl 1-1402 F-cPr OCHF_Two     H H 4-NH_Two-DHT (23b) TP-2-yl 1-1403 cPr Me H NH_Two   4-NH_Two-DHT (23b) TP-2-yl 1-1404 cPr OCHF_Two     H NH_Two   4-NH_Two-DHT (23b) TP-2-yl 1-1405 cPr Me F H 4-NH_Two-DHT (23b) TP-2-yl 1-1406 F-cPr Me F H 4-NH_Two-DHT (23b) TP-2-yl 1-1407 cPr OCHF_Two     F H 4-NH_Two-DHT (23b) TP-2-yl 1-1408 F-cPr OCHF_Two     F H 4-NH_Two-DHT (23b) TP-2-yl 1-1409 cPr Me F NH_Two  4-NH_Two-DHT (23b) TP-2-yl 1-1410 cPr OCHF_Two     F NH_Two 4-NH_Two-DHT (23b) TP-2-yl 1-1411 cPr Me H H 4-NHMe-DHT (23b) TP-2-yl 1-1412 F-cPr Me H H 4-NHMe-DHT (23b) TP-2-yl 1-1413 cPr OCHF_Two    H H 4-NHMe-DHT (23b) TP-2-yl 1-1414 F-cPr OCHF_Two    H H 4-NHMe-DHT (23b) TP-2-yl 1-1415 cPr Me F H 4-NHMe-DHT (23b) TP-2-yl 1-1416 F-cPr Me F H 4-NHMe-DHT (23b) TP-2-yl 1-1417 cPr OCHF_Two    F H 4-NHMe-DHT (23b) TP-2-yl 1-1418 F-cPr OCHF_Two    F H 4-NHMe-DHT (23b) TP-2-yl 1-1419 cPr Me H H 4-NH_Two-DHT (23c) TP-2-yl 1-1420 F-cPr Me H H 4-NH_Two-DHT (23c) TP-2-yl 1-1421 cPr OMe H H 4-NH_Two-DHT (23c) TP-2-yl 1-1422 F-cPr OMe H H 4-NH_Two-DHT (23c) TP-2-yl 1-1423 cPr OCHF_Two     H H 4-NH_Two-DHT (23c) TP-2-yl 1-1424 F-cPr OCHF_Two     H H 4-NH_Two-DHT (23c) TP-2-yl 1-1425 cPr Me H NH_Two   4-NH_Two-DHT (23c) TP-2-yl 1-1426 cPr OCHF_Two     H NH_Two   4-NH_Two-DHT (23c) TP-2-yl 1-1427 cPr Me F H 4-NH_Two-DHT (23c) TP-2-yl 1-1428 F-cPr Me F H 4-NH_Two-DHT (23c) TP-2-yl 1-1429 cPr OCHF_Two     F H 4-NH_Two-DHT (23c) TP-2-yl 1-1430 F-cPr OCHF_Two     F H 4-NH_Two-DHT (23c) TP-2-yl 1-1431 cPr Me F NH_Two  4-NH_Two-DHT (23c) TP-2-yl 1-1432 cPr OCHF_Two     F NH_Two 4-NH_Two-DHT (23c) TP-2-yl 1-1433 cPr Me H H 4-NHMe-DHT (23c) TP-2-yl 1-1434 F-cPr Me H H 4-NHMe-DHT (23c) TP-2-yl 1-1435 cPr OMe H H 4-NHMe-DHT (23c) TP-2-yl 1-1436 F-cPr OMe H H 4-NHMe-DHT (23c) TP-2-yl 1-1437 cPr OCHF_Two     H H 4-NHMe-DHT (23c) TP-2-yl 1-1438 F-cPr OCHF_Two     H H 4-NHMe-DHT (23c) TP-2-yl 1-1439 cPr Me H NH_Two   4-NHMe-DHT (23c) TP-2-yl 1-1440 cPr OCHF_Two     H NH_Two   4-NHMe-DHT (23c) TP-2-yl 1-1441 cPr Me F H 4-NHMe-DHT (23c) TP-2-yl 1-1442 F-cPr Me F H 4-NHMe-DHT (23c) TP-2-yl 1-1443 cPr OCHF_Two     F H 4-NHMe-DHT (23c) TP-2-yl 1-1444 F-cPr OCHF_Two     F H 4-NHMe-DHT (23c) TP-2-yl 1-1445 cPr Me F NH_Two  4-NHMe-DHT (23c) TP-2-yl 1-1446 cPr OCHF_Two     F NH_Two 4-NHMe-DHT (23c) TP-2-yl 1-1447 cPr Me H H 4-NH_Two-DHT (23c) P-2-yl 1-1448 F-cPr Me H H 4-NH_Two-DHT (23c) P-2-yl 1-1449 cPr OMe H H 4-NH_Two-DHT (23c) P-2-yl 1-1450 F-cPr OMe H H 4-NH_Two-DHT (23c) P-2-yl 1-1451 cPr OCHF_Two     H H 4-NH_Two-DHT (23c) P-2-yl 1-1452 F-cPr OCHF_Two     H H 4-NH_Two-DHT (23c) P-2-yl 1-1453 cPr Me H NH_Two   4-NH_Two-DHT (23c) P-2-yl 1-1454 cPr OCHF_Two     H NH_Two   4-NH_Two-DHT (23c) P-2-yl 1-1455 cPr Me F H 4-NH_Two-DHT (23c) P-2-yl 1-1456 F-cPr Me F H 4-NH_Two-DHT (23c) P-2-yl 1-1457 cPr OCHF_Two     F H 4-NH_Two-DHT (23c) P-2-yl 1-1458 F-cPr OCHF_Two     F H 4-NH_Two-DHT (23c) P-2-yl 1-1459 cPr Me F NH_Two  4-NH_Two-DHT (23c) P-2-yl 1-1460 cPr OCHF_Two     F NH_Two 4-NH_Two-DHT (23c) P-2-yl 1-1461 cPr Me H H 4-NHMe-DHT (23c) P-2-yl 1-1462 F-cPr Me H H 4-NHMe-DHT (23c) P-2-yl 1-1463 cPr OCHF_Two    H H 4-NHMe-DHT (23c) P-2-yl 1-1464 F-cPr OCHF_Two    H H 4-NHMe-DHT (23c) P-2-yl 1-1465 cPr Me F H 4-NHMe-DHT (23c) P-2-yl 1-1466 F-cPr Me F H 4-NHMe-DHT (23c) P-2-yl 1-1467 cPr OCHF_Two    F H 4-NHMe-DHT (23c) P-2-yl 1-1468 F-cPr OCHF_Two    F H 4-NHMe-DHT (23c) P-2-yl 1-1469 cPr Me H H 4-NH_Two-THT (23d) A-2-yl 1-1470 F-cPr Me H H 4-NH_Two-THT (23d) A-2-yl 1-1471 cPr OMe H H 4-NH_Two-THT (23d) A-2-yl 1-1472 F-cPr OMe H H 4-NH_Two-THT (23d) A-2-yl 1-1473 cPr OCHF_Two     H H 4-NH_Two-THT (23d) A-2-yl 1-1474 F-cPr OCHF_Two     H H 4-NH_Two-THT (23d) A-2-yl 1-1475 cPr Me H NH_Two   4-NH_Two-THT (23d) A-2-yl 1-1476 cPr OCHF_Two     H NH_Two   4-NH_Two-THT (23d) A-2-yl 1-1477 cPr Me F H 4-NH_Two-THT (23d) A-2-yl 1-1478 F-cPr Me F H 4-NH_Two-THT (23d) A-2-yl 1-1479 cPr OCHF_Two     F H 4-NH_Two-THT (23d) A-2-yl 1-1480 F-cPr OCHF_Two     F H 4-NH_Two-THT (23d) A-2-yl 1-1481 cPr Me F NH_Two  4-NH_Two-THT (23d) A-2-yl 1-1482 cPr OCHF_Two     F NH_Two 4-NH_Two-THT (23d) A-2-yl 1-1483 cPr Me H H 4-NHMe-THT (23d) A-2-yl 1-1484 F-cPr Me H H 4-NHMe-THT (23d) A-2-yl 1-1485 cPr OCHF_Two    H H 4-NHMe-THT (23d) A-2-yl 1-1486 F-cPr OCHF_Two    H H 4-NHMe-THT (23d) A-2-yl 1-1487 cPr Me F H 4-NHMe-THT (23d) A-2-yl 1-1488 F-cPr Me F H 4-NHMe-THT (23d) A-2-yl 1-1489 cPr OCHF_Two    F H 4-NHMe-THT (23d) A-2-yl 1-1490 F-cPr OCHF_Two    F H 4-NHMe-THT (23d) A-2-yl 1-1491 cPr Me H H 4-NH_Two-THBF-2-yl 1-1492 F-cPr Me H H 4-NH_Two-THBF-2-yl 1-1493 cPr OCHF_Two    H H 4-NH_Two-THBF-2-yl 1-1494 F-cPr OCHF_Two    H H 4-NH_Two-THBF-2-yl 1-1495 cPr Me F H 4-NH_Two-THBF-2-yl 1-1496 F-cPr Me F H 4-NH_Two-THBF-2-yl 1-1497 cPr OCHF_Two    F H 4-NH_Two-THBF-2-yl 1-1498 F-cPr OCHF_Two    F H 4-NH_Two-THBF-2-yl 1-1499 cPr Me H H 4-NHMe-THBF-2-yl 1-1500 F-cPr Me H H 4-NHMe-THBF-2-yl 1-1501 cPr OMe H H 4-NHMe-THBF-2-yl 1-1502 F-cPr OMe H H 4-NHMe-THBF-2-yl 1-1503 cPr OCHF_Two     H H 4-NHMe-THBF-2-yl 1-1504 F-cPr OCHF_Two     H H 4-NHMe-THBF-2-yl 1-1505 cPr Me H NH_Two   4-NHMe-THBF-2-yl 1-1506 cPr OCHF_Two     H NH_Two   4-NHMe-THBF-2-yl 1-1507 cPr Me F H 4-NHMe-THBF-2-yl 1-1508 F-cPr Me F H 4-NHMe-THBF-2-yl 1-1509 cPr OCHF_Two     F H 4-NHMe-THBF-2-yl 1-1510 F-cPr OCHF_Two     F H 4-NHMe-THBF-2-yl 1-1511 cPr Me F NH_Two  4-NHMe-THBF-2-yl 1-1512 cPr OCHF_Two     F NH_Two 4-NHMe-THBF-2-yl In Table 2, the meanings of the respective abbreviations are as follows.
That is, Me: methyl group Et: ethyl group F-Et: 2-fluoroethyl group cPr: Cyclopropyl group F-cPr: 2-fluorocyclopropyl group dF-Ph: 2,4-difluorophenyl group dF-Py: 2,6-difluoro-3-pyridyl group NH_Two-dF-Py: 6-amino-3,5-difluoro-2-pi
Lysyl group Thiazo: 2-thiazolyl group iIDL-5-yl: isoindoline-5-yl group 1-Me-iIDL-5-yl: 1-methylisoindoline-5-yl
Base 2-Me-iIDL-5-yl: 2-methylisoindoline-5-yl
Base 7-Me-iIDL-5-yl: 7-methylisoindoline-5-yl
Base 1,7-dMe-iIDL-5-yl: 1,7-dimethylisoindoline-
5-yl group 7-F-iIDL-5-yl: 7-fluoroisoindoline-5-yl
Le group 7-F-1-Me-iIDL-5-yl: 7-fluoro-1-methylisoyi
Ndlin-5-yl group 1,1-dMe-iIDL-5-yl: 1,1-dimethylisoindoline-
5-yl group 1-scPr-iIDL-5-yl: spiro [isoindoline-1,1 '
-Cyclopropane] -5-yl group 6-F-iIDL-5-yl: 6-fluoroisoindoline-5-yl
Base 6-F-1-Me-iIDL-5-yl: 6-fluoro-1-methylisoyi
Ndlin-5-yl group 4-F-iIDL-5-yl: 4-fluoroisoindoline-5-yl
Base 4-F-1-Me-iIDL-5-yl: 4-fluoro-1-methylisoyi
Ndlin-5-yl group 7-Cl-iIDL-5-yl: 7-chloroisoindoline-5-yl
Base 7-OMe-iIDL-5-yl: 7-methoxyisoindoline-5-yl
Le group 7-OCHF_Two-iIDL-5-yl: 7-difluoromethoxyisoindo
Phosphorus-5-yl group 7-CF_Three-iIDL-5-yl: 7-trifluoromethylisoindori
N-5-yl group 7-CN-iIDL-5-yl: 7-cyanoisoindoline-5-yl
Base 1-CH_TwoOH-iIDL-5-yl: 1-hydroxymethylisoindo
Phosphorus-5-yl group 1-CH_TwoNH_Two-iIDL-5-yl: 1-aminomethylisoindoline
-5-yl group 1-CH_TwoNHMe-iIDL-5-yl: 1-methylaminomethylisoy
Ndlin-5-yl group 1-CH_TwoNMe_Two-iIDL-5-yl: 1-dimethylaminomethyliso
Indoline-5-yl group 1-CH_TwoNHcPr-iIDL-5-yl: 1-cyclopropylaminomethyl
Luisoindolin-5-yl group 1-NH_Two-IDN-5-yl: 1-aminoindan-5-yl group 2-NH_Two-IDN-5-yl: 2-aminoindan-5-yl group 3-NH_Two-IDN-5-yl: 3-aminoindan-5-yl group 1-NH_Two-IDN-4-yl: 1-aminoindan-4-yl group 3-NHMe-IDN-5-yl: 3-methylaminoindan-5-y
3-group NMe₂-IDN-5-yl: 3-dimethyla
Minoindan-5-yl group 3-NH_Two-7-Me-IDN-5-yl: 3-amino-7-methylinda
N-5-yl group 3-NH_Two-7-F-IDN-5-yl: 3-amino-7-fluoroinda
N-5-yl group 3-NH_Two-7-Cl-IDN-5-yl: 3-amino-7-chloroinda
N-5-yl group 3-NH_Two-7-OMe-IDN-5-yl: 3-amino-7-methoxyin
Dan-5-yl group 3-NH_Two-7-OCHF_Two-IDN-5-yl: 3-amino-7-difluoro
Methoxyindan-5-yl group 3-CH_TwoNH_Two-IDN-5-yl: 3-aminomethylindane-5
Il group 3-CH_TwoNHMe-IDN-5-yl: 3-methylaminomethylindane
-5-yl group 3-CH_TwoNMe_Two-IDN-5-yl: 3-dimethylaminomethylinda
N-5-yl group 6-NH_Two-THN-2-yl: 6-amino-5,6,7,8-tetra
Hydronaphthalen-2-yl group 5-NH_Two-THN-2-yl: 5-amino-5,6,7,8-tetra
Hydronaphthalen-2-yl group 4-NH_Two-THN-2-yl: 4-amino-5,6,7,8-tetra
Hydronaphthalen-2-yl group 7-NH_Two-THN-2-yl: 7-amino-5,6,7,8-tetra
Hydronaphthalen-2-yl group 8-NH_Two-THN-2-yl: 8-amino-5,6,7,8-tetra
Hydronaphthalen-2-yl group 8-NH_Two-4-Me-THN-2-yl: 8-amino-4-methyl-5,
6,7,8-tetrahydronaphthalen-2-yl group 8-NH_Two-4-OMe-THN-2-yl: 8-amino-4-methoxy-
5,6,7,8-tetrahydronaphthalen-2-yl group 8-NH_Two-4-F-THN-2-yl: 8-amino-4-fluoro-5,
6,7,8-tetrahydronaphthalen-2-yl group 8-NH_Two-4-CF_Three-THN-2-yl: 8-amino-4-trifluoro
Methyl-5,6,7,8-tetrahydronaphthalene-2
-Yl group 5-NH_Two-THN-1-yl: 5-amino-5,6,7,8-tetra
Hydronaphthalen-1-yl group 8-CH_TwoNH_Two-THN-2-yl: 8-aminomethyl-5,6,7,
8-tetrahydronaphthalen-2-yl group 8-NHcPr-THN-2-yl: 8-cyclopropylamino-5
6,7,8-tetrahydronaphthalen-2-yl group 8-NH_Two-6-OMe-THN-2-yl: 8-amino-6-methoxy-
5,6,7,8-tetrahydronaphthalen-2-yl group 8-NH_Two-6-OCHF_Two-THN-2-yl: 6-amino-6-difluoro
Methoxy-5,6,7,8-tetrahydronaphthalene-
2-yl group It is. [0057] Embedded image[0058] [Table 2] Compound Number R¹            R^Two     R^Three   R^Four    R^Five 2-1 Et H F H iIDL-5-yl 2-2 F-Et H F H iIDL-5-yl 2-3 cPr H F H iIDL-5-yl 2-4 F-cPr H F H iIDL-5-yl 2-5 dF-Ph H F H iIDL-5-yl 2-6 dF-Py H F H iIDL-5-yl 2-7 NH_Two-dF-Py H F H iIDL-5-yl 2-8 Thiazo H F H iIDL-5-yl 2-9 Et Me F H iIDL-5-yl 2-10 F-Et Me F H iIDL-5-yl 2-11 cPr Me F H iIDL-5-yl 2-12 F-cPr Me F H iIDL-5-yl 2-13 dF-Ph Me F H iIDL-5-yl 2-14 dF-Py Me F H iIDL-5-yl 2-15 NH_Two-dF-Py Me F H iIDL-5-yl 2-16 Thiazo Me F H iIDL-5-yl 2-17 Et CH_TwoF F H iIDL-5-yl 2-18 F-Et CH_TwoF F H iIDL-5-yl 2-19 cPr CH_TwoF F H iIDL-5-yl 2-20 F-cPr CH_TwoF F H iIDL-5-yl 2-21 dF-Ph CH_TwoF F H iIDL-5-yl 2-22 dF-Py CH_TwoF F H iIDL-5-yl 2-23 NH_Two-dF-Py CH_TwoF F H iIDL-5-yl 2-24 Thiazo CH_TwoF F H iIDL-5-yl 2-25 Et CHF_Two   F H iIDL-5-yl 2-26 F-Et CHF_Two   F H iIDL-5-yl 2-27 cPr CHF_Two   F H iIDL-5-yl 2-28 F-cPr CHF_Two   F H iIDL-5-yl 2-29 dF-Ph CHF_Two   F H iIDL-5-yl 2-30 dF-Py CHF_Two   F H iIDL-5-yl 2-31 NH_Two-dF-Py CHF_Two   F H iIDL-5-yl 2-32 Thiazo CHF_Two   F H iIDL-5-yl 2-33 Et CF_Three    F H iIDL-5-yl 2-34 F-Et CF_Three    F H iIDL-5-yl 2-35 cPr CF_Three    F H iIDL-5-yl 2-36 F-cPr CF_Three    F H iIDL-5-yl 2-37 dF-Ph CF_Three    F H iIDL-5-yl 2-38 dF-Py CF_Three    F H iIDL-5-yl 2-39 NH_Two-dF-Py CF_Three    F H iIDL-5-yl 2-40 Thiazo CF_Three    F H iIDL-5-yl 2-41 Et OH F H iIDL-5-yl 2-42 F-Et OH F H iIDL-5-yl 2-43 cPr OH F H iIDL-5-yl 2-44 F-cPr OH F H iIDL-5-yl 2-45 dF-Ph OH F H iIDL-5-yl 2-46 dF-Py OH F H iIDL-5-yl 2-47 NH_Two-dF-Py OH F H iIDL-5-yl 2-48 Thiazo OH F H iIDL-5-yl 2-49 Et OMe F H iIDL-5-yl 2-50 F-Et OMe F H iIDL-5-yl 2-51 cPr OMe F H iIDL-5-yl 2-52 F-cPr OMe F H iIDL-5-yl 2-53 dF-Ph OMe F H iIDL-5-yl 2-54 dF-Py OMe F H iIDL-5-yl 2-55 NH_Two-dF-Py OMe F H iIDL-5-yl 2-56 Thiazo OMe F H iIDL-5-yl 2-57 Et OCHF_Two  F H iIDL-5-yl 2-58 F-Et OCHF_Two  F H iIDL-5-yl 2-59 cPr OCHF_Two  F H iIDL-5-yl 2-60 F-cPr OCHF_Two  F H iIDL-5-yl 2-61 dF-Ph OCHF_Two  F H iIDL-5-yl 2-62 dF-Py OCHF_Two  F H iIDL-5-yl 2-63 NH_Two-dF-Py OCHF_Two  F H iIDL-5-yl 2-64 Thiazo OCHF_Two  F H iIDL-5-yl 2-65 Et CN F H iIDL-5-yl 2-66 F-Et CN F H iIDL-5-yl 2-67 cPr CN F H iIDL-5-yl 2-68 F-cPr CN F H iIDL-5-yl 2-69 dF-Ph CN F H iIDL-5-yl 2-70 dF-Py CN F H iIDL-5-yl 2-71 NH_Two-dF-Py CN F H iIDL-5-yl 2-72 Thiazo CN F H iIDL-5-yl 2-73 Et Cl F H iIDL-5-yl 2-74 F-Et Cl F H iIDL-5-yl 2-75 cPr Cl F H iIDL-5-yl 2-76 F-cPr Cl F H iIDL-5-yl 2-77 dF-Ph Cl F H iIDL-5-yl 2-78 dF-Py Cl F H iIDL-5-yl 2-79 NH_Two-dF-Py Cl F H iIDL-5-yl 2-80 Thiazo Cl F H iIDL-5-yl 2-81 cPr Me F NH_Two  iIDL-5-yl 2-82 F-cPr Me F NH_Two  iIDL-5-yl 2-83 cPr OCHF_Two  F NH_Two  iIDL-5-yl 2-84 F-cPr OCHF_Two  F NH_Two  iIDL-5-yl 2-85 cPr Me F Me iIDL-5-yl 2-86 F-cPr Me F Me iIDL-5-yl 2-87 Et H F H 1-Me-iIDL-5-yl 2-88 F-Et H F H 1-Me-iIDL-5-yl 2-89 cPr H F H 1-Me-iIDL-5-yl 2-90 F-cPr H F H 1-Me-iIDL-5-yl 2-91 dF-Ph H F H 1-Me-iIDL-5-yl 2-92 dF-Py H F H 1-Me-iIDL-5-yl 2-93 NH_Two-dF-Py H F H 1-Me-iIDL-5-yl 2-94 Thiazo H F H 1-Me-iIDL-5-yl 2-95 Et Me F H 1-Me-iIDL-5-yl 2-96 F-Et Me F H 1-Me-iIDL-5-yl 2-97 cPr Me F H 1-Me-iIDL-5-yl 2-98 F-cPr Me F H 1-Me-iIDL-5-yl 2-99 dF-Ph Me F H 1-Me-iIDL-5-yl 2-100 dF-Py Me F H 1-Me-iIDL-5-yl 2-101 NH_Two-dF-Py Me F H 1-Me-iIDL-5-yl 2-102 Thiazo Me F H 1-Me-iIDL-5-yl 2-103 Et CH_TwoF F H 1-Me-iIDL-5-yl 2-104 F-Et CH_TwoF F H 1-Me-iIDL-5-yl 2-105 cPr CH_TwoF F H 1-Me-iIDL-5-yl 2-106 F-cPr CH_TwoF F H 1-Me-iIDL-5-yl 2-107 dF-Ph CH_TwoF F H 1-Me-iIDL-5-yl 2-108 dF-Py CH_TwoF F H 1-Me-iIDL-5-yl 2-109 NH_Two-dF-Py CH_TwoF F H 1-Me-iIDL-5-yl 2-110 Thiazo CH_TwoF F H 1-Me-iIDL-5-yl 2-111 Et CHF_Two   F H 1-Me-iIDL-5-yl 2-112 F-Et CHF_Two   F H 1-Me-iIDL-5-yl 2-113 cPr CHF_Two   F H 1-Me-iIDL-5-yl 2-114 F-cPr CHF_Two   F H 1-Me-iIDL-5-yl 2-115 dF-Ph CHF_Two   F H 1-Me-iIDL-5-yl 2-116 dF-Py CHF_Two   F H 1-Me-iIDL-5-yl 2-117 NH_Two-dF-Py CHF_Two   F H 1-Me-iIDL-5-yl 2-118 Thiazo CHF_Two   F H 1-Me-iIDL-5-yl 2-119 Et CF_Three    F H 1-Me-iIDL-5-yl 2-120 F-Et CF_Three    F H 1-Me-iIDL-5-yl 2-121 cPr CF_Three    F H 1-Me-iIDL-5-yl 2-122 F-cPr CF_Three    F H 1-Me-iIDL-5-yl 2-123 dF-Ph CF_Three    F H 1-Me-iIDL-5-yl 2-124 dF-Py CF_Three    F H 1-Me-iIDL-5-yl 2-125 NH_Two-dF-Py CF_Three    F H 1-Me-iIDL-5-yl 2-126 Thiazo CF_Three    F H 1-Me-iIDL-5-yl 2-127 Et OH F H 1-Me-iIDL-5-yl 2-128 F-Et OH F H 1-Me-iIDL-5-yl 2-129 cPr OH F H 1-Me-iIDL-5-yl 2-130 F-cPr OH F H 1-Me-iIDL-5-yl 2-131 dF-Ph OH F H 1-Me-iIDL-5-yl 2-132 dF-Py OH F H 1-Me-iIDL-5-yl 2-133 NH_Two-dF-Py OH F H 1-Me-iIDL-5-yl 2-134 Thiazo OH F H 1-Me-iIDL-5-yl 2-135 Et OMe F H 1-Me-iIDL-5-yl 2-136 F-Et OMe F H 1-Me-iIDL-5-yl 2-137 cPr OMe F H 1-Me-iIDL-5-yl 2-138 F-cPr OMe F H 1-Me-iIDL-5-yl 2-139 dF-Ph OMe F H 1-Me-iIDL-5-yl 2-140 dF-Py OMe F H 1-Me-iIDL-5-yl 2-141 NH_Two-dF-Py OMe F H 1-Me-iIDL-5-yl 2-142 Thiazo OMe F H 1-Me-iIDL-5-yl 2-143 Et OCHF_Two  F H 1-Me-iIDL-5-yl 2-144 F-Et OCHF_Two  F H 1-Me-iIDL-5-yl 2-145 cPr OCHF_Two  F H 1-Me-iIDL-5-yl 2-146 F-cPr OCHF_Two  F H 1-Me-iIDL-5-yl 2-147 dF-Ph OCHF_Two  F H 1-Me-iIDL-5-yl 2-148 dF-Py OCHF_Two  F H 1-Me-iIDL-5-yl 2-149 NH_Two-dF-Py OCHF_Two  F H 1-Me-iIDL-5-yl 2-150 Thiazo OCHF_Two  F H 1-Me-iIDL-5-yl 2-151 Et CN F H 1-Me-iIDL-5-yl 2-152 F-Et CN F H 1-Me-iIDL-5-yl 2-153 cPr CN F H 1-Me-iIDL-5-yl 2-154 F-cPr CN F H 1-Me-iIDL-5-yl 2-155 dF-Ph CN F H 1-Me-iIDL-5-yl 2-156 dF-Py CN F H 1-Me-iIDL-5-yl 2-157 NH_Two-dF-Py CN F H 1-Me-iIDL-5-yl 2-158 Thiazo CN F H 1-Me-iIDL-5-yl 2-159 Et Cl F H 1-Me-iIDL-5-yl 2-160 F-Et Cl F H 1-Me-iIDL-5-yl 2-161 cPr Cl F H 1-Me-iIDL-5-yl 2-162 F-cPr Cl F H 1-Me-iIDL-5-yl 2-163 dF-Ph Cl F H 1-Me-iIDL-5-yl 2-164 dF-Py Cl F H 1-Me-iIDL-5-yl 2-165 NH_Two-dF-Py Cl F H 1-Me-iIDL-5-yl 2-166 Thiazo Cl F H 1-Me-iIDL-5-yl 2-167 cPr Me F NH_Two  1-Me-iIDL-5-yl 2-168 F-cPr Me F NH_Two  1-Me-iIDL-5-yl 2-169 cPr OCHF_Two  F NH_Two  1-Me-iIDL-5-yl 2-170 F-cPr OCHF_Two  F NH_Two  1-Me-iIDL-5-yl 2-171 cPr Me F Me 1-Me-iIDL-5-yl 2-172 F-cPr Me F Me 1-Me-iIDL-5-yl 2-173 cPr Me F H 2-Me-iIDL-5-yl 2-174 F-cPr Me F H 2-Me-iIDL-5-yl 2-175 cPr OCHF_Two  F H 2-Me-iIDL-5-yl 2-176 F-cPr OCHF_Two  F H 2-Me-iIDL-5-yl 2-177 cPr Me F NH_Two   2-Me-iIDL-5-yl 2-178 cPr OCHF_Two  F NH_Two   2-Me-iIDL-5-yl 2-179 cPr Me F H 7-Me-iIDL-5-yl 2-180 F-cPr Me F H 7-Me-iIDL-5-yl 2-181 cPr OCHF_Two  F H 7-Me-iIDL-5-yl 2-182 F-cPr OCHF_Two  F H 7-Me-iIDL-5-yl 2-183 cPr Me F NH_Two   7-Me-iIDL-5-yl 2-184 cPr OCHF_Two  F NH_Two   7-Me-iIDL-5-yl 2-185 cPr Me F H 1,7-dMe-iIDL-5-yl 2-186 F-cPr Me F H 1,7-dMe-iIDL-5-yl 2-187 cPr OCHF_Two  F H 1,7-dMe-iIDL-5-yl 2-188 F-cPr OCHF_Two  F H 1,7-dMe-iIDL-5-yl 2-189 cPr Me F NH_Two   1,7-dMe-iIDL-5-yl 2-190 cPr OCHF_Two  F NH_Two   1,7-dMe-iIDL-5-yl 2-191 cPr Me F H 7-F-iIDL-5-yl 2-192 F-cPr Me F H 7-F-iIDL-5-yl 2-193 cPr OCHF_Two  F H 7-F-iIDL-5-yl 2-194 F-cPr OCHF_Two  F H 7-F-iIDL-5-yl 2-195 cPr Me F NH_Two   7-F-iIDL-5-yl 2-196 cPr OCHF_Two  F NH_Two   7-F-iIDL-5-yl 2-197 cPr Me F H 7-F-1-Me-iIDL-5-yl 2-198 F-cPr Me F H 7-F-1-Me-iIDL-5-yl 2-199 cPr OCHF_Two  F H 7-F-1-Me-iIDL-5-yl 2-200 F-cPr OCHF_Two  F H 7-F-1-Me-iIDL-5-yl 2-201 cPr Me F NH_Two   7-F-1-Me-iIDL-5-yl 2-202 cPr OCHF_Two  F NH_Two   7-F-1-Me-iIDL-5-yl 2-203 cPr Me F H 1,1-dMe-iIDL-5-yl 2-204 F-cPr Me F H 1,1-dMe-iIDL-5-yl 2-205 cPr OCHF_Two  F H 1,1-dMe-iIDL-5-yl 2-206 F-cPr OCHF_Two  F H 1,1-dMe-iIDL-5-yl 2-207 cPr Me F NH_Two   1,1-dMe-iIDL-5-yl 2-208 cPr OCHF_Two  F NH_Two   1,1-dMe-iIDL-5-yl 2-209 cPr Me F H 1-scPr-iIDL-5-yl 2-210 F-cPr Me F H 1-scPr-iIDL-5-yl 2-211 cPr OCHF_Two  F H 1-scPr-iIDL-5-yl 2-212 F-cPr OCHF_Two  F H 1-scPr-iIDL-5-yl 2-213 cPr Me F NH_Two   1-scPr-iIDL-5-yl 2-214 cPr OCHF_Two  F NH_Two   1-scPr-iIDL-5-yl 2-215 cPr Me F H 6-F-iIDL-5-yl 2-216 F-cPr Me F H 6-F-iIDL-5-yl 2-217 cPr OCHF_Two  F H 6-F-iIDL-5-yl 2-218 F-cPr OCHF_Two  F H 6-F-iIDL-5-yl 2-219 cPr Me F NH_Two   6-F-iIDL-5-yl 2-220 cPr OCHF_Two  F NH_Two   6-F-iIDL-5-yl 2-221 cPr Me F H 6-F-1-Me-iIDL-5-yl 2-222 F-cPr Me F H 6-F-1-Me-iIDL-5-yl 2-223 cPr OCHF_Two  F H 6-F-1-Me-iIDL-5-yl 2-224 F-cPr OCHF_Two  F H 6-F-1-Me-iIDL-5-yl 2-225 cPr Me F NH_Two   6-F-1-Me-iIDL-5-yl 2-226 cPr OCHF_Two  F NH_Two   6-F-1-Me-iIDL-5-yl 2-227 cPr Me F H 4-F-iIDL-5-yl 2-228 F-cPr Me F H 4-F-iIDL-5-yl 2-229 cPr OCHF_Two  F H 4-F-iIDL-5-yl 2-230 F-cPr OCHF_Two  F H 4-F-iIDL-5-yl 2-231 cPr Me F NH_Two   4-F-iIDL-5-yl 2-232 cPr OCHF_Two  F NH_Two   4-F-iIDL-5-yl 2-233 cPr Me F H 4-F-1-Me-iIDL-5-yl 2-234 F-cPr Me F H 4-F-1-Me-iIDL-5-yl 2-235 cPr OCHF_Two  F H 4-F-1-Me-iIDL-5-yl 2-236 F-cPr OCHF_Two  F H 4-F-1-Me-iIDL-5-yl 2-237 cPr Me F NH_Two   4-F-1-Me-iIDL-5-yl 2-238 cPr OCHF_Two  F NH_Two   4-F-1-Me-iIDL-5-yl 2-239 cPr Me F H 7-Cl-iIDL-5-yl 2-240 F-cPr Me F H 7-Cl-iIDL-5-yl 2-241 cPr OCHF_Two  F H 7-Cl-iIDL-5-yl 2-242 F-cPr OCHF_Two  F H 7-Cl-iIDL-5-yl 2-243 cPr Me F NH_Two   7-Cl-iIDL-5-yl 2-244 cPr OCHF_Two  F NH_Two   7-Cl-iIDL-5-yl 2-245 cPr Me F H 7-OMe-iIDL-5-yl 2-246 F-cPr Me F H 7-OMe-iIDL-5-yl 2-247 cPr OCHF_Two  F H 7-OMe-iIDL-5-yl 2-248 F-cPr OCHF_Two  F H 7-OMe-iIDL-5-yl 2-249 cPr Me F NH_Two   7-OMe-iIDL-5-yl 2-250 cPr OCHF_Two  F NH_Two   7-OMe-iIDL-5-yl 2-251 cPr Me F H 7-OCHF_Two-iIDL-5-yl 2-252 F-cPr Me F H 7-OCHF_Two-iIDL-5-yl 2-253 cPr OCHF_Two  F H 7-OCHF_Two-iIDL-5-yl 2-254 F-cPr OCHF_Two  F H 7-OCHF_Two-iIDL-5-yl 2-255 cPr Me F NH_Two   7-OCHF_Two-iIDL-5-yl 2-256 cPr OCHF_Two  F NH_Two   7-OCHF_Two-iIDL-5-yl 2-257 cPr Me F H 7-CF_Three-iIDL-5-yl 2-258 F-cPr Me F H 7-CF_Three-iIDL-5-yl 2-269 cPr OCHF_Two  F H 7-CF_Three-iIDL-5-yl 2-260 F-cPr OCHF_Two  F H 7-CF_Three-iIDL-5-yl 2-261 cPr Me F H 7-CN-iIDL-5-yl 2-262 F-cPr Me F H 7-CN-iIDL-5-yl 2-263 cPr OCHF_Two  F H 7-CN-iIDL-5-yl 2-264 F-cPr OCHF_Two  F H 7-CN-iIDL-5-yl 2-265 cPr Me F H 1-CH_TwoOH-iIDL-5-yl 2-266 cPr OCHF_Two  F H 1-CH_TwoOH-iIDL-5-yl 2-267 cPr Me F H 1-CH_TwoNH_Two-iIDL-5-yl 2-268 cPr OCHF_Two  F H 1-CH_TwoNH_Two-iIDL-5-yl 2-269 cPr Me F H 1-CH_TwoNHMe-iIDL-5-yl 2-270 cPr OCHF_Two  F H 1-CH_TwoNHMe-iIDL-5-yl 2-271 cPr Me F H 1-CH_TwoNMe_Two-iIDL-5-yl 2-272 cPr OCHF_Two  F H 1-CH_TwoNMe_Two-iIDL-5-yl 2-273 cPr Me F H 1-CH_TwoNHcPr-iIDL-5-yl 2-274 cPr OCHF_Two  F H 1-CH_TwoNHcPr-iIDL-5-yl 2-275 cPr Me H H 1-NH_Two-IDN-5-yl 2-276 cPr OCHF_Two  H H 1-NH_Two-IDN-5-yl 2-277 cPr Me F H 1-NH_Two-IDN-5-yl 2-278 cPr OCHF_Two  F H 1-NH_Two-IDN-5-yl 2-279 cPr Me H H 2-NH_Two-IDN-5-yl 2-280 cPr OCHF_Two  H H 2-NH_Two-IDN-5-yl 2-281 cPr Me F H 2-NH_Two-IDN-5-yl 2-282 cPr OCHF_Two  F H 2-NH_Two-IDN-5-yl 2-283 cPr Me H H 3-NH_Two-IDN-5-yl 2-284 F-cPr Me H H 3-NH_Two-IDN-5-yl 2-285 cPr OMe H H 3-NH_Two-IDN-5-yl 2-286 F-cPr OMe H H 3-NH_Two-IDN-5-yl 2-287 cPr OCHF_Two  H H 3-NH_Two-IDN-5-yl 2-288 F-cPr OCHF_Two  H H 3-NH_Two-IDN-5-yl 2-289 cPr Me H NH_Two   3-NH_Two-IDN-5-yl 2-290 cPr OCHF_Two  H NH_Two   3-NH_Two-IDN-5-yl 2-291 cPr Me F H 3-NH_Two-IDN-5-yl 2-292 F-cPr Me F H 3-NH_Two-IDN-5-yl 2-293 cPr OCHF_Two  F H 3-NH_Two-IDN-5-yl 2-294 F-cPr OCHF_Two  F H 3-NH_Two-IDN-5-yl 2-295 cPr Me F NH_Two   3-NH_Two-IDN-5-yl 2-296 cPr OCHF_Two  F NH_Two   3-NH_Two-IDN-5-yl 2-297 cPr Me H H 1-NH_Two-IDN-4-yl 2-298 cPr OCHF_Two  H H 1-NH_Two-IDN-4-yl 2-299 cPr Me F H 1-NH_Two-IDN-4-yl 2-300 cPr OCHF_Two  F H 1-NH_Two-IDN-4-yl 2-301 cPr Me H H 3-NHMe-IDN-5-yl 2-302 F-cPr Me H H 3-NHMe-IDN-5-yl 2-303 cPr OMe H H 3-NHMe-IDN-5-yl 2-304 F-cPr OMe H H 3-NHMe-IDN-5-yl 2-305 cPr OCHF_Two  H H 3-NHMe-IDN-5-yl 2-306 F-cPr OCHF_Two  H H 3-NHMe-IDN-5-yl 2-307 cPr Me H NH_Two   3-NHMe-IDN-5-yl 2-308 cPr OCHF_Two  H NH_Two   3-NHMe-IDN-5-yl 2-309 cPr Me F H 3-NHMe-IDN-5-yl 2-310 F-cPr Me F H 3-NHMe-IDN-5-yl 2-311 cPr OCHF_Two  F H 3-NHMe-IDN-5-yl 2-312 F-cPr OCHF_Two  F H 3-NHMe-IDN-5-yl 2-313 cPr Me F NH_Two   3-NHMe-IDN-5-yl 2-314 cPr OCHF_Two  F NH_Two   3-NHMe-IDN-5-yl 2-315 cPr Me H H 3-NMe_Two-IDN-5-yl 2-316 F-cPr Me H H 3-NMe_Two-IDN-5-yl 2-317 cPr OMe H H 3-NMe_Two-IDN-5-yl 2-318 F-cPr OMe H H 3-NMe_Two-IDN-5-yl 2-319 cPr OCHF_Two  H H 3-NMe_Two-IDN-5-yl 2-320 F-cPr OCHF_Two  H H 3-NMe_Two-IDN-5-yl 2-321 cPr Me H NH_Two   3-NMe_Two-IDN-5-yl 2-322 cPr OCHF_Two  H NH_Two   3-NMe_Two-IDN-5-yl 2-323 cPr Me F H 3-NMe_Two-IDN-5-yl 2-324 F-cPr Me F H 3-NMe_Two-IDN-5-yl 2-325 cPr OCHF_Two  F H 3-NMe_Two-IDN-5-yl 2-326 F-cPr OCHF_Two  F H 3-NMe_Two-IDN-5-yl 2-327 cPr Me F NH_Two   3-NMe_Two-IDN-5-yl 2-328 cPr OCHF_Two  F NH_Two   3-NMe_Two-IDN-5-yl 2-329 cPr Me H H 3-NH_Two-7-Me-IDN-5-yl 2-330 F-cPr Me H H 3-NH_Two-7-Me-IDN-5-yl 2-331 cPr OMe H H 3-NH_Two-7-Me-IDN-5-yl 2-332 F-cPr OMe H H 3-NH_Two-7-Me-IDN-5-yl 2-333 cPr OCHF_Two  H H 3-NH_Two-7-Me-IDN-5-yl 2-334 F-cPr OCHF_Two  H H 3-NH_Two-7-Me-IDN-5-yl 2-335 cPr Me H NH_Two   3-NH_Two-7-Me-IDN-5-yl 2-336 cPr OCHF_Two  H NH_Two   3-NH_Two-7-Me-IDN-5-yl 2-337 cPr Me F H 3-NH_Two-7-Me-IDN-5-yl 2-338 F-cPr Me F H 3-NH_Two-7-Me-IDN-5-yl 2-339 cPr OCHF_Two  F H 3-NH_Two-7-Me-IDN-5-yl 2-340 F-cPr OCHF_Two  F H 3-NH_Two-7-Me-IDN-5-yl 2-341 cPr Me F NH_Two   3-NH_Two-7-Me-IDN-5-yl 2-342 cPr OCHF_Two  F NH_Two   3-NH_Two-7-Me-IDN-5-yl 2-343 cPr Me H H 3-NH_Two-7-F-IDN-5-yl 2-344 F-cPr Me H H 3-NH_Two-7-F-IDN-5-yl 2-345 cPr OMe H H 3-NH_Two-7-F-IDN-5-yl 2-346 F-cPr OMe H H 3-NH_Two-7-F-IDN-5-yl 2-347 cPr OCHF_Two  H H 3-NH_Two-7-F-IDN-5-yl 2-348 F-cPr OCHF_Two  H H 3-NH_Two-7-F-IDN-5-yl 2-349 cPr Me H NH_Two   3-NH_Two-7-F-IDN-5-yl 2-350 cPr OCHF_Two  H NH_Two   3-NH_Two-7-F-IDN-5-yl 2-351 cPr Me F H 3-NH_Two-7-F-IDN-5-yl 2-352 F-cPr Me F H 3-NH_Two-7-F-IDN-5-yl 2-353 cPr OCHF_Two  F H 3-NH_Two-7-F-IDN-5-yl 2-354 F-cPr OCHF_Two  F H 3-NH_Two-7-F-IDN-5-yl 2-355 cPr Me F NH_Two   3-NH_Two-7-F-IDN-5-yl 2-356 cPr OCHF_Two  F NH_Two   3-NH_Two-7-F-IDN-5-yl 2-357 cPr Me H H 3-NH_Two-7-Cl-IDN-5-yl 2-358 F-cPr Me H H 3-NH_Two-7-Cl-IDN-5-yl 2-359 cPr OMe H H 3-NH_Two-7-Cl-IDN-5-yl 2-360 F-cPr OMe H H 3-NH_Two-7-Cl-IDN-5-yl 2-361 cPr OCHF_Two  H H 3-NH_Two-7-Cl-IDN-5-yl 2-362 F-cPr OCHF_Two  H H 3-NH_Two-7-Cl-IDN-5-yl 2-363 cPr Me H NH_Two   3-NH_Two-7-Cl-IDN-5-yl 2-364 cPr OCHF_Two  H NH_Two   3-NH_Two-7-Cl-IDN-5-yl 2-365 cPr Me F H 3-NH_Two-7-Cl-IDN-5-yl 2-366 F-cPr Me F H 3-NH_Two-7-Cl-IDN-5-yl 2-367 cPr OCHF_Two  F H 3-NH_Two-7-Cl-IDN-5-yl 2-368 F-cPr OCHF_Two  F H 3-NH_Two-7-Cl-IDN-5-yl 2-369 cPr Me F NH_Two   3-NH_Two-7-Cl-IDN-5-yl 2-370 cPr OCHF_Two  F NH_Two   3-NH_Two-7-Cl-IDN-5-yl 2-371 cPr Me H H 3-NH_Two-7-OMe-IDN-5-yl 2-372 F-cPr Me H H 3-NH_Two-7-OMe-IDN-5-yl 2-373 cPr OMe H H 3-NH_Two-7-OMe-IDN-5-yl 2-374 F-cPr OMe H H 3-NH_Two-7-OMe-IDN-5-yl 2-375 cPr OCHF_Two  H H 3-NH_Two-7-OMe-IDN-5-yl 2-376 F-cPr OCHF_Two  H H 3-NH_Two-7-OMe-IDN-5-yl 2-377 cPr Me H NH_Two   3-NH_Two-7-OMe-IDN-5-yl 2-378 cPr OCHF_Two  H NH_Two   3-NH_Two-7-OMe-IDN-5-yl 2-379 cPr Me F H 3-NH_Two-7-OMe-IDN-5-yl 2-380 F-cPr Me F H 3-NH_Two-7-OMe-IDN-5-yl 2-381 cPr OCHF_Two  F H 3-NH_Two-7-OMe-IDN-5-yl 2-382 F-cPr OCHF_Two  F H 3-NH_Two-7-OMe-IDN-5-yl 2-383 cPr Me F NH_Two   3-NH_Two-7-OMe-IDN-5-yl 2-384 cPr OCHF_Two  F NH_Two   3-NH_Two-7-OMe-IDN-5-yl 2-385 cPr Me H H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-386 F-cPr Me H H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-387 cPr OMe H H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-388 F-cPr OMe H H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-389 cPr OCHF_Two  H H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-390 F-cPr OCHF_Two  H H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-391 cPr Me H NH_Two   3-NH_Two-7-OCHF_Two-IDN-5-yl 2-392 cPr OCHF_Two  H NH_Two   3-NH_Two-7-OCHF_Two-IDN-5-yl 2-393 cPr Me F H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-394 F-cPr Me F H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-395 cPr OCHF_Two  F H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-396 F-cPr OCHF_Two  F H 3-NH_Two-7-OCHF_Two-IDN-5-yl 2-397 cPr Me F NH_Two   3-NH_Two-7-OCHF_Two-IDN-5-yl 2-398 cPr OCHF_Two  F NH_Two   3-NH_Two-7-OCHF_Two-IDN-5-yl 2-399 cPr Me H H 3-CH_TwoNH_Two-IDN-5-yl 2-400 F-cPr Me H H 3-CH_TwoNH_Two-IDN-5-yl 2-401 cPr OMe H H 3-CH_TwoNH_Two-IDN-5-yl 2-402 F-cPr OMe H H 3-CH_TwoNH_Two-IDN-5-yl 2-403 cPr OCHF_Two  H H 3-CH_TwoNH_Two-IDN-5-yl 2-404 F-cPr OCHF_Two  H H 3-CH_TwoNH_Two-IDN-5-yl 2-405 cPr Me H NH_Two   3-CH_TwoNH_Two-IDN-5-yl 2-406 cPr OCHF_Two  H NH_Two   3-CH_TwoNH_Two-IDN-5-yl 2-407 cPr Me F H 3-CH_TwoNH_Two-IDN-5-yl 2-408 F-cPr Me F H 3-CH_TwoNH_Two-IDN-5-yl 2-409 cPr OCHF_Two  F H 3-CH_TwoNH_Two-IDN-5-yl 2-410 F-cPr OCHF_Two  F H 3-CH_TwoNH_Two-IDN-5-yl 2-411 cPr Me F NH_Two   3-CH_TwoNH_Two-IDN-5-yl 2-412 cPr OCHF_Two  F NH_Two   3-CH_TwoNH_Two-IDN-5-yl 2-413 cPr Me H H 3-CH_TwoNHMe-IDN-5-yl 2-414 F-cPr Me H H 3-CH_TwoNHMe-IDN-5-yl 2-415 cPr OMe H H 3-CH_TwoNHMe-IDN-5-yl 2-416 F-cPr OMe H H 3-CH_TwoNHMe-IDN-5-yl 2-417 cPr OCHF_Two  H H 3-CH_TwoNHMe-IDN-5-yl 2-418 F-cPr OCHF_Two  H H 3-CH_TwoNHMe-IDN-5-yl 2-419 cPr Me H NH_Two   3-CH_TwoNHMe-IDN-5-yl 2-420 cPr OCHF_Two  H NH_Two   3-CH_TwoNHMe-IDN-5-yl 2-421 cPr Me F H 3-CH_TwoNHMe-IDN-5-yl 2-422 F-cPr Me F H 3-CH_TwoNHMe-IDN-5-yl 2-423 cPr OCHF_Two  F H 3-CH_TwoNHMe-IDN-5-yl 2-424 F-cPr OCHF_Two  F H 3-CH_TwoNHMe-IDN-5-yl 2-425 cPr Me F NH_Two   3-CH_TwoNHMe-IDN-5-yl 2-426 cPr OCHF_Two  F NH_Two   3-CH_TwoNHMe-IDN-5-yl 2-427 cPr Me H H 3-CH_TwoNMe_Two-IDN-5-yl 2-428 F-cPr Me H H 3-CH_TwoNMe_Two-IDN-5-yl 2-429 cPr OMe H H 3-CH_TwoNMe_Two-IDN-5-yl 2-430 F-cPr OMe H H 3-CH_TwoNMe_Two-IDN-5-yl 2-431 cPr OCHF_Two  H H 3-CH_TwoNMe_Two-IDN-5-yl 2-432 F-cPr OCHF_Two  H H 3-CH_TwoNMe_Two-IDN-5-yl 2-433 cPr Me H NH_Two   3-CH_TwoNMe_Two-IDN-5-yl 2-434 cPr OCHF_Two  H NH_Two   3-CH_TwoNMe_Two-IDN-5-yl 2-435 cPr Me F H 3-CH_TwoNMe_Two-IDN-5-yl 2-436 F-cPr Me F H 3-CH_TwoNMe_Two-IDN-5-yl 2-437 cPr OCHF_Two  F H 3-CH_TwoNMe_Two-IDN-5-yl 2-438 F-cPr OCHF_Two  F H 3-CH_TwoNMe_Two-IDN-5-yl 2-439 cPr Me F NH_Two   3-CH_TwoNMe_Two-IDN-5-yl 2-440 cPr OCHF_Two  F NH_Two   3-CH_TwoNMe_Two-IDN-5-yl 2-441 cPr Me H H 6-NH_Two-THN-2-yl 2-442 cPr OCHF_Two  H H 6-NH_Two-THN-2-yl 2-443 cPr Me F H 6-NH_Two-THN-2-yl 2-444 cPr OCHF_Two  F H 6-NH_Two-THN-2-yl 2-445 cPr Me H H 5-NH_Two-THN-2-yl 2-446 cPr OCHF_Two  H H 5-NH_Two-THN-2-yl 2-447 cPr Me F H 5-NH_Two-THN-2-yl 2-448 cPr OCHF_Two  F H 5-NH_Two-THN-2-yl 2-449 cPr Me H H 4-NH_Two-THN-2-yl 2-450 cPr OCHF_Two  H H 4-NH_Two-THN-2-yl 2-451 cPr Me F H 4-NH_Two-THN-2-yl 2-452 cPr OCHF_Two  F H 4-NH_Two-THN-2-yl 2-453 cPr Me H H 7-NH_Two-THN-2-yl 2-454 cPr OCHF_Two  H H 7-NH_Two-THN-2-yl 2-455 cPr Me F H 7-NH_Two-THN-2-yl 2-456 cPr OCHF_Two  F H 7-NH_Two-THN-2-yl 2-457 cPr Me H H 8-NH_Two-THN-2-yl 2-458 F-cPr Me H H 8-NH_Two-THN-2-yl 2-459 cPr OMe H H 8-NH_Two-THN-2-yl 2-460 F-cPr OMe H H 8-NH_Two-THN-2-yl 2-461 cPr OCHF_Two  H H 8-NH_Two-THN-2-yl 2-462 F-cPr OCHF_Two  H H 8-NH_Two-THN-2-yl 2-463 cPr Me H NH_Two   8-NH_Two-THN-2-yl 2-464 cPr OCHF_Two  H NH_Two   8-NH_Two-THN-2-yl 2-465 cPr Me F H 8-NH_Two-THN-2-yl 2-466 F-cPr Me F H 8-NH_Two-THN-2-yl 2-467 cPr OCHF_Two  F H 8-NH_Two-THN-2-yl 2-468 F-cPr OCHF_Two  F H 8-NH_Two-THN-2-yl 2-469 cPr Me F NH_Two   8-NH_Two-THN-2-yl 2-470 cPr OCHF_Two  F NH_Two   8-NH_Two-THN-2-yl 2-471 cPr Me H H 8-NH_Two-4-Me-THN-2-yl 2-472 F-cPr Me H H 8-NH_Two-4-Me-THN-2-yl 2-473 cPr OMe H H 8-NH_Two-4-Me-THN-2-yl 2-474 F-cPr OMe H H 8-NH_Two-4-Me-THN-2-yl 2-475 cPr OCHF_Two  H H 8-NH_Two-4-Me-THN-2-yl 2-476 F-cPr OCHF_Two  H H 8-NH_Two-4-Me-THN-2-yl 2-477 cPr Me H NH_Two   8-NH_Two-4-Me-THN-2-yl 2-478 cPr OCHF_Two  H NH_Two   8-NH_Two-4-Me-THN-2-yl 2-479 cPr Me F H 8-NH_Two-4-Me-THN-2-yl 2-480 F-cPr Me F H 8-NH_Two-4-Me-THN-2-yl 2-481 cPr OCHF_Two  F H 8-NH_Two-4-Me-THN-2-yl 2-482 F-cPr OCHF_Two  F H 8-NH_Two-4-Me-THN-2-yl 2-483 cPr Me F NH_Two   8-NH_Two-4-Me-THN-2-yl 2-484 cPr OCHF_Two  F NH_Two   8-NH_Two-4-Me-THN-2-yl 2-485 cPr Me H H 8-NH_Two-4-OMe-THN-2-yl 2-486 F-cPr Me H H 8-NH_Two-4-OMe-THN-2-yl 2-487 cPr OMe H H 8-NH_Two-4-OMe-THN-2-yl 2-488 F-cPr OMe H H 8-NH_Two-4-OMe-THN-2-yl 2-489 cPr OCHF_Two  H H 8-NH_Two-4-OMe-THN-2-yl 2-490 F-cPr OCHF_Two  H H 8-NH_Two-4-OMe-THN-2-yl 2-491 cPr Me H NH_Two   8-NH_Two-4-OMe-THN-2-yl 2-492 cPr OCHF_Two  H NH_Two   8-NH_Two-4-OMe-THN-2-yl 2-493 cPr Me F H 8-NH_Two-4-OMe-THN-2-yl 2-494 F-cPr Me F H 8-NH_Two-4-OMe-THN-2-yl 2-495 cPr OCHF_Two  F H 8-NH_Two-4-OMe-THN-2-yl 2-496 F-cPr OCHF_Two  F H 8-NH_Two-4-OMe-THN-2-yl 2-497 cPr Me F NH_Two   8-NH_Two-4-OMe-THN-2-yl 2-498 cPr OCHF_Two  F NH_Two   8-NH_Two-4-OMe-THN-2-yl 2-499 cPr Me H H 8-NH_Two-4-F-THN-2-yl 2-500 F-cPr Me H H 8-NH_Two-4-F-THN-2-yl 2-501 cPr OMe H H 8-NH_Two-4-F-THN-2-yl 2-502 F-cPr OMe H H 8-NH_Two-4-F-THN-2-yl 2-503 cPr OCHF_Two  H H 8-NH_Two-4-F-THN-2-yl 2-504 F-cPr OCHF_Two  H H 8-NH_Two-4-F-THN-2-yl 2-505 cPr Me H NH_Two   8-NH_Two-4-F-THN-2-yl 2-506 cPr OCHF_Two  H NH_Two   8-NH_Two-4-F-THN-2-yl 2-507 cPr Me F H 8-NH_Two-4-F-THN-2-yl 2-508 F-cPr Me F H 8-NH_Two-4-F-THN-2-yl 2-509 cPr OCHF_Two  F H 8-NH_Two-4-F-THN-2-yl 2-510 F-cPr OCHF_Two  F H 8-NH_Two-4-F-THN-2-yl 2-511 cPr Me F NH_Two   8-NH_Two-4-F-THN-2-yl 2-512 cPr OCHF_Two  F NH_Two   8-NH_Two-4-F-THN-2-yl 2-513 cPr Me H H 8-NH_Two-4-CF_Three-THN-2-yl 2-514 F-cPr Me H H 8-NH_Two-4-CF_Three-THN-2-yl 2-515 cPr OMe H H 8-NH_Two-4-CF_Three-THN-2-yl 2-516 F-cPr OMe H H 8-NH_Two-4-CF_Three-THN-2-yl 2-517 cPr OCHF_Two  H H 8-NH_Two-4-CF_Three-THN-2-yl 2-518 F-cPr OCHF_Two  H H 8-NH_Two-4-CF_Three-THN-2-yl 2-519 cPr Me H NH_Two   8-NH_Two-4-CF_Three-THN-2-yl 2-520 cPr OCHF_Two  H NH_Two   8-NH_Two-4-CF_Three-THN-2-yl 2-521 cPr Me F H 8-NH_Two-4-CF_Three-THN-2-yl 2-522 F-cPr Me F H 8-NH_Two-4-CF_Three-THN-2-yl 2-523 cPr OCHF_Two  F H 8-NH_Two-4-CF_Three-THN-2-yl 2-524 F-cPr OCHF_Two  F H 8-NH_Two-4-CF_Three-THN-2-yl 2-525 cPr Me F NH_Two   8-NH_Two-4-CF_Three-THN-2-yl 2-526 cPr OCHF_Two  F NH_Two   8-NH_Two-4-CF_Three-THN-2-yl 2-527 cPr Me H H 5-NH_Two-THN-1-yl 2-528 cPr OCHF_Two  H H 5-NH_Two-THN-1-yl 2-529 cPr Me F H 5-NH_Two-THN-1-yl 2-530 cPr OCHF_Two  F H 5-NH_Two-THN-1-yl 2-531 cPr Me H H 8-CH_TwoNH_Two-THN-2-yl 2-532 F-cPr Me H H 8-CH_TwoNH_Two-THN-2-yl 2-533 cPr OMe H H 8-CH_TwoNH_Two-THN-2-yl 2-534 F-cPr OMe H H 8-CH_TwoNH_Two-THN-2-yl 2-535 cPr OCHF_Two  H H 8-CH_TwoNH_Two-THN-2-yl 2-536 F-cPr OCHF_Two  H H 8-CH_TwoNH_Two-THN-2-yl 2-537 cPr Me H NH_Two   8-CH_TwoNH_Two-THN-2-yl 2-538 cPr OCHF_Two  H NH_Two   8-CH_TwoNH_Two-THN-2-yl 2-539 cPr Me F H 8-CH_TwoNH_Two-THN-2-yl 2-540 F-cPr Me F H 8-CH_TwoNH_Two-THN-2-yl 2-541 cPr OCHF_Two  F H 8-CH_TwoNH_Two-THN-2-yl 2-542 F-cPr OCHF_Two  F H 8-CH_TwoNH_Two-THN-2-yl 2-543 cPr Me F NH_Two   8-CH_TwoNH_Two-THN-2-yl 2-544 cPr OCHF_Two  F NH_Two   8-CH_TwoNH_Two-THN-2-yl 2-545 cPr Me H H 8-NHcPr-THN-2-yl 2-546 F-cPr Me H H 8-NHcPr-THN-2-yl 2-547 cPr OMe H H 8-NHcPr-THN-2-yl 2-548 F-cPr OMe H H 8-NHcPr-THN-2-yl 2-549 cPr OCHF_Two  H H 8-NHcPr-THN-2-yl 2-550 F-cPr OCHF_Two  H H 8-NHcPr-THN-2-yl 2-551 cPr Me H NH_Two   8-NHcPr-THN-2-yl 2-552 cPr OCHF_Two  H NH_Two   8-NHcPr-THN-2-yl 2-553 cPr Me F H 8-NHcPr-THN-2-yl 2-554 F-cPr Me F H 8-NHcPr-THN-2-yl 2-555 cPr OCHF_Two  F H 8-NHcPr-THN-2-yl 2-556 F-cPr OCHF_Two  F H 8-NHcPr-THN-2-yl 2-557 cPr Me F NH_Two   8-NHcPr-THN-2-yl 2-558 cPr OCHF_Two  F NH_Two   8-NHcPr-THN-2-yl 2-559 cPr Me H H 8-NH_Two-6-OMe-THN-2-yl 2-560 cPr OCHF_Two  H H 8-NH_Two-6-OMe-THN-2-yl 2-561 cPr Me F H 8-NH_Two-6-OMe-THN-2-yl 2-562 cPr OCHF_Two  F H 8-NH_Two-6-OMe-THN-2-yl 2-563 cPr Me H H 8-NH_Two-6-OCHF_Two-THN-2-yl 2-564 cPr OCHF_Two  H H 8-NH_Two-6-OCHF_Two-THN-2-yl 2-565 cPr Me F H 8-NH_Two-6-OCHF_Two-THN-2-yl 2-566 cPr OCHF_Two  F H 8-NH_Two-6-OCHF_Two-THN-2-yl Preferred Compounds Among the Exemplary Compounds of Table 1 or Table 2
Is a compound number 1-3, 1-4, 1-9, 1-10, 1-11, 1-12, 1-13, 1-1
4,1-15,1-16,1-19,1-20,1-27,1-28,1-35,1-36,1-43,1-4
4,1-51,1-52,1-57,1-58,1-59,1-60,1-61,1-62,1-63,1-6
4,1-67,1-68,1-75,1-76,1-83,1-84,1-89,1-90,1-91,1-9
2,1-93,1-94,1-95,1-96,1-99,1-100,1-107,1-108,1-11
5,1-116,1-123,1-124,1-131,1-132,1-139,1-140,1-147,
1-148,1-155,1-156,1-161,1-162,1-163,1-164,1-165,1-
166,1-167,1-168,1-169,1-170,1-171,1-172,1-173,1-17
4,1-177,1-178,1-179,1-180,1-181,1-182,1-183,1-184,
1-185,1-186,1-187,1-188,1-189,1-190,1-191,1-192,1-
193,1-194,1-195,1-196,1-197,1-198,1-199,1-200,1-20
1,1-202,1-203,1-204,1-207,1-208,1-209,1-210,1-211,
1-212,1-213,1-214,1-215,1-216,1-217,1-218,1-221,1-
222,1-223,1-224,1-225,1-226,1-227,1-228,1-229,1-23
0,1-231,1-232,1-235,1-236,1-237,1-238,1-239,1-240,
1-241,1-242,1-243,1-244,1-245,1-246,1-247,1-248,1-
249,1-250,1-251,1-252,1-253,1-254,1-255,1-256,1-25
7,1-258,1-259,1-260,1-261,1-262,1-263,1-264,1-265,
1-266,1-267,1-268,1-269,1-270,1-271,1-272,1-273,1-
274,1-275,1-276,1-277,1-278,1-279,1-280,1-281,1-28
2,1-283,1-284,1-285,1-286,1-289,1-290,1-291,1-292,
1-293,1-294,1-295,1-296,1-297,1-298,1-299,1-300,1-
301,1-302,1-303,1-304,1-305,1-306,1-307,1-308,1-30
9,1-310,1-311,1-312,1-313,1-314,1-315,1-316,1-317,
1-318,1-319,1-320,1-321,1-322,1-323,1-324,1-325,1-
326,1-327,1-328,1-329,1-330,1-331,1-332,1-333,1-33
4,1-335,1-336,1-337,1-338,1-339,1-340,1-341,1-342,
1-343,1-344,1-345,1-346,1-347,1-348,1-351,1-352,1-
353,1-354,1-355,1-356,1-357,1-358,1-359,1-360,1-36
1,1-362,1-365,1-366,1-367,1-368,1-369,1-370,1-371,
1-372,1-373,1-374,1-375,1-376,1-379,1-380,1-381,1-
382,1-383,1-384,1-385,1-386,1-387,1-388,1-389,1-39
0,1-393,1-394,1-395,1-396,1-397,1-398,1-399,1-400,
1-401,1-402,1-403,1-404,1-405,1-406,1-407,1-408,1-
409,1-410,1-411,1-412,1-413,1-414,1-415,1-416,1-41
7,1-418,1-419,1-420,1-421,1-422,1-423,1-424,1-425,
1-426,1-427,1-428,1-429,1-430,1-431,1-432,1-433,1-
434,1-435,1-436,1-437,1-438,1-439,1-440,1-441,1-44
2,1-443,1-444,1-447,1-448,1-449,1-450,1-451,1-452,
1-453,1-454,1-455,1-456,1-457,1-458,1-459,1-460,1-
461,1-462,1-463,1-464,1-465,1-466,1-467,1-468,1-46
9,1-470,1-471,1-472,1-473,1-474,1-475,1-476,1-477,
1-478,1-479,1-480,1-481,1-482,1-485,1-486,1-487,1-
488,1-489,1-490,1-491,1-492,1-493,1-494,1-495,1-49
6,1-497,1-498,1-499,1-500,1-501,1-502,1-503,1-504,
1-505,1-506,1-507,1-508,1-509,1-510,1-511,1-512,1-
513,1-514,1-515,1-516,1-517,1-518,1-519,1-520,1-52
1,1-522,1-523,1-524,1-525,1-526,1-527,1-528,1-529,
1-530,1-531,1-532,1-533,1-534,1-535,1-536,1-537,1-
538,1-539,1-540,1-541,1-542,1-543,1-544,1-547,1-54
8,1-549,1-550,1-551,1-552,1-553,1-554,1-555,1-556,
1-557,1-558,1-559,1-560,1-561,1-562,1-563,1-564,1-
565,1-566,1-567,1-568,1-569,1-570,1-571,1-572,1-57
5,1-576,1-581,1-582,1-583,1-584,1-585,1-586,1-587,
1-588,1-591,1-592,1-599,1-600,1-607,1-608,1-615,1-
611-6,1-623,1-624,1-629,1-630,1-631,1-632,1-633,1-
634,1-635,1-636,1-639,1-640,1-647,1-648,1-655,1-65
6,1-661,1-662,1-663,1-664,1-665,1-666,1-667,1-668,
1-671,1-672,1-679,1-680,1-687,1-688,1-695,1-696,1-
703,1-704,1-711,1-712,1-719,1-720,1-727,1-728,1-73
3,1-734,1-735,1-736,1-737,1-738,1-739,1-740,1-741,
1-742,1-743,1-744,1-745,1-746,1-747,1-748,1-749,1-
750,1-751,1-752,1-753,1-754,1-755,1-756,1-757,1-75
8,1-759,1-760,1-761,1-762,1-763,1-764,1-765,1-766,
1-767,1-768,1-769,1-770,1-771,1-772,1-773,1-774,1-
775,1-776,1-777,1-778,1-779,1-780,1-781,1-782,1-78
3,1-784,1-785,1-786,1-787,1-788,1-789,1-790,1-791,
1-792,1-793,1-794,1-797,1-798,1-799,1-800,1-801,1-
802,1-803,1-804,1-805,1-806,1-807,1-808,1-809,1-81
0,1-811,1-812,1-813,1-814,1-815,1-816,1-817,1-818,
1-821,1-822,1-827,1-828,1-829,1-830,1-831,1-832,1-
833,1-834,1-837,1-838,1-845,1-846,1-853,1-854,1-86
1,1-862,1-869,1-870,1-875,1-876,1-877,1-878,1-879,
1-880,1-881,1-882,1-885,1-886,1-893,1-894,1-901,1-
902,1-907,1-908,1-909,1-910,1-911,1-912,1-913,1-91
4,1-917,1-918,1-925,1-926,1-933,1-934,1-941,1-942,
1-949,1-950,1-957,1-958,1-965,1-966,1-973,1-974,1-
979,1-980,1-981,1-982,1-983,1-984,1-985,1-986,1-98
7,1-988,1-989,1-990,1-991,1-992,1-993,1-994,1-995,
1-996,1-997,1-998,1-999,1-1000,1-1001,1-1002,1-100
3,1-1004,1-1005,1-1006,1-1007,1-1008,1-1011,1-101
2,1-1013,1-1014,1-1015,1-1016,1-1017,1-1018,1-101
9,1-1020,1-1021,1-1022,1-1025,1-1026,1-1027,1-102
8,1-1029,1-1030,1-1031,1-1032,1-1033,1-1034,1-103
5,1-1036,1-1039,1-1040,1-1041,1-1042,1-1043,1-104
4,1-1045,1-1046,1-1047,1-1048,1-1049,1-1050,1-105
1,1-1052,1-1053,1-1054,1-1055,1-1056,1-1057,1-105
8,1-1059,1-1060,1-1061,1-1062,1-1063,1-1064,1-106
5,1-1066,1-1069,1-1070,1-1071,1-1072,1-1073,1-107
4,1-1075,1-1076,1-1077,1-1078,1-1079,1-1080,1-108
1,1-1082,1-1083,1-1084,1-1085,1-1086,1-1087,1-108
8,1-1089,1-1090,1-1091,1-1092,1-1093,1-1094,1-109
5,1-1096,1-1097,1-1098,1-1099,1-1100,1-1101,1-110
2,1-1103,1-1104,1-1105,1-1106,1-1107,1-1108,1-110
9,1-1110,1-1111,1-1112,1-1113,1-1114,1-1115,1-111
6,1-1117,1-1118,1-1119,1-1120,1-1121,1-1122,1-112
3,1-1124,1-1125,1-1126,1-1127,1-1128,1-1131,1-113
2,1-1133,1-1134,1-1135,1-1136,1-1137,1-1138,1-113
9,1-1140,1-1141,1-1142,1-1145,1-1146,1-1147,1-114
8,1-1149,1-1150,1-1151,1-1152,1-1153,1-1154,1-115
5,1-1156,1-1157,1-1158,1-1159,1-1160,1-1161,1-116
2,1-1163,1-1164,1-1165,1-1166,1-1167,1-1168,1-116
9,1-1170,1-1171,1-1172,1-1173,1-1174,1-1175,1-117
6,1-1177,1-1178,1-1179,1-1180,1-1181,1-1182,1-118
3,1-1184,1-1185,1-1186,1-1187,1-1188,1-1189,1-119
0,1-1191,1-1192,1-1193,1-1194,1-1195,1-1196,1-119
7,1-1198,1-1199,1-1200,1-1201,1-1202,1-1203,1-120
4,1-1205,1-1206,1-1207,1-1208,1-1209,1-1210,1-121
1,1-1212,1-1213,1-1214,1-1215,1-1216,1-1217,1-121
8,1-1219,1-1220,1-1221,1-1222,1-1223,1-1224,1-122
5,1-1226,1-1227,1-1228,1-1229,1-1230,1-1231,1-123
2,1-1233,1-1234,1-1235,1-1236,1-1237,1-1238,1-123
9,1-1240,1-1241,1-1242,1-1243,1-1244,1-1247,1-124
8,1-1249,1-1250,1-1251,1-1252,1-1253,1-1254,1-125
5,1-1256,1-1257,1-1258,1-1261,1-1262,1-1263,1-126
4,1-1265,1-1266,1-1267,1-1268,1-1269,1-1270,1-127
1,1-1272,1-1273,1-1274,1-1275,1-1276,1-1277,1-127
8,1-1279,1-1280,1-1283,1-1284,1-1285,1-1286,1-128
7,1-1288,1-1289,1-1290,1-1291,1-1292,1-1293,1-129
4,1-1297,1-1298,1-1299,1-1300,1-1301,1-1302,1-130
3,1-1304,1-1305,1-1306,1-1307,1-1308,1-1311,1-131
2,1-1313,1-1314,1-1315,1-1316,1-1317,1-1318,1-131
9,1-1320,1-1321,1-1322,1-1323,1-1324,1-1325,1-132
6,1-1327,1-1328,1-1329,1-1330,1-1331,1-1332,1-133
3,1-1334,1-1335,1-1336,1-1337,1-1338,1-1339,1-134
0,1-1341,1-1342,1-1343,1-1344,1-1345,1-1346,1-134
7,1-1348,1-1349,1-1350,1-1351,1-1352,1-1353,1-135
4,1-1355,1-1356,1-1357,1-1358,1-1359,1-1360,1-136
1,1-1362,1-1365,1-1366,1-1367,1-1368,1-1369,1-137
0,1-1371,1-1372,1-1373,1-1374,1-1375,1-1376,1-137
7,1-1378,1-1379,1-1380,1-1381,1-1382,1-1383,1-138
4,1-1387,1-1388,1-1389,1-1390,1-1391,1-1392,1-139
3,1-1394,1-1395,1-1396,1-1397,1-1398,1-1401,1-140
2,1-1403,1-1404,1-1405,1-1406,1-1407,1-1408,1-140
9,1-1410,1-1411,1-1412,1-1413,1-1414,1-1415,1-141
6,1-1417,1-1418,1-1419,1-1420,1-1423,1-1424,1-142
5,1-1426,1-1427,1-1428,1-1429,1-1430,1-1431,1-143
2,1-1433,1-1434,1-1437,1-1438,1-1439,1-1440,1-144
1,1-1442,1-1443,1-1444,1-1445,1-1446,1-1447,1-144
8,1-1451,1-1452,1-1453,1-1454,1-1455,1-1456,1-145
7,1-1458,1-1459,1-1460,1-1461,1-1462,1-1463,1-146
4,1-1465,1-1466,1-1467,1-1468,1-1469,1-1470,1-147
3,1-1474,1-1475,1-1476,1-1477,1-1478,1-1479,1-148
0,1-1481,1-1482,1-1483,1-1484,1-1485,1-1486,1-148
7,1-1488,1-1489,1-1490,1-1491,1-1492,1-1493,1-149
4,1-1495,1-1496,1-1497,1-1498,1-1499,1-1500,1-150
3,1-1504,1-1505,1-1506,1-1507,1-1508,1-1509,1-151
0,1-1511,1-1512,2-3,2-4,2-9,2-10,2-11,2-12,2-13,2-
14,2-15,2-16,2-19,2-20,2-27,2-28,2-35,2-36,2-43,2-
44,2-51,2-52,2-59,2-60,2-67,2-68,2-75,2-76,2-80,2-
81,2-82,2-83,2-84,2-85,2-86,2-89,2-90,2-95,2-96,2-
97,2-98,2-99,2-100,2-101,2-102,2-105,2-106,2-113,2
-114,2-121,2-122,2-129,2-130,2-137,2-138,2-145,2-1
46,2-153,2-154,2-161,2-162,2-166,2-167,2-168,2-16
9,2-170,2-171,2-172, 2-173,2-174,2-175,2-176,2-17
7,2-178,2-179,2-180,2-181,2-182,2-183,2-184, 2-18
5,2-186,2-187,2-188,2-189,2-190,2-191,2-192,2-193,
2-194,2-195,2-196,2-197,2-198,2-199,2-200,2-201,2-
202,2-203,2-204,2-205,2-206,2-207,2-208,2-209,2-21
0,2-211,2-212,2-213,2-214,2-215,2-216,2-217,2-218,
2-219,2-220,2-221,2-222,2-223,2-224,2-225,2-226,2-
227,2-228,2-229,2-230,2-231,2-232,2-233,2-234,2-23
5,2-236,2-237,2-238,2-239,2-240,2-241,2-242,2-243,
2-244,2-245,2-246,2-247,2-248,2-249,2-250,2-251,2-
252,2-253,2-254,2-255,2-256,2-257,2-258,2-259,2-26
0,2-261,2-262,2-263,2-264,2-265,2-266,2-267,2-268,
2-269,2-270,2-271,2-272,2-273,2-274,2-275,2-276,2-
277,2-278,2-279,2-280,2-281,2-282,2-283,2-284,2-28
7,2-288,2-289,2-290,2-291,2-292,2-293,2-294,2-295,
2-296,2-297,2-298,2-299,2-300,2-301,2-302,2-305,2-
306,2-307,2-308,2-309,2-310,2-311,2-312,2-313,2-31
4,2-315,2-316,2-319,2-320,2-321,2-322,2-323,2-324,
2-325,2-326,2-327,2-328,2-329,2-330,2-333,2-334,2-
335,2-336,2-337,2-338,2-339,2-340,2-341,2-342,2-34
3,2-344,2-347,2-348,2-349,2-350,2-351,2-352,2-353,
2-354,2-355,2-356,2-357,2-358,2-361,2-362,2-363,2-
364,2-365,2-366,2-367,2-368,2-369,2-370,2-371,2-37
2,2-375,2-376,2-377,2-378,2-379,2-380,2-381,2-382,
2-383,2-384,2-385,2-386,2-389,2-390,2-391,2-392,2-
393,2-394,2-395,2-396,2-397,2-398,2-399,2-400,2-40
3,2-404,2-405,2-406,2-407,2-408,2-409,2-410,2-411,
2-412,2-413,2-414,2-417,2-418,2-419,2-420,2-421,2-
422,2-423,2-424,2-425,2-426,2-427,2-428,2-431,2-43
2,2-433,2-434,2-435,2-436,2-437,2-438,2-439,2-440,
2-441,2-442,2-443,2-444,2-445,2-446,2-447,2-448,2-
449,2-450,2-451,2-452,2-453,2-454,2-455,2-456,2-45
7,2-458,2-461,2-462,2-463,2-464,2-465,2-466,2-467,
2-468,2-469,2-470,2-471,2-472,2-475,2-476,2-477,2-
478,2-479,2-480,2-481,2-482,2-483,2-484,2-485,2-48
6,2-489,2-490,2-491,2-492,2-493,2-494,2-495,2-496,
2-497,2-498,2-499,2-500,2-503,2-504,2-505,2-506,2-
507,2-508,2-509,2-510,2-511,2-512,2-513,2-514,2-51
7,2-518,2-519,2-520,2-521,2-522,2-523,2-524,2-525,
2-526,2-527,2-528,2-529,2-530,2-531,2-532,2-535,2-
536,2-537,2-538,2-539,2-540,2-541,2-542,2-543,2-54
4,2-545,2-546,2-549,2-550,2-551,2-552,2-553,2-554,
2-555,2-556,2-557,2-558,2-559,2-560,2-561,2-562,2-
563, 2-564, 2-565 or 2-566, more preferably
Is the compound number 1-3, 1-4, 1-11, 1-12, 1-19, 1-20, 1-27, 1-2
8,1-35,1-36,1-43,1-44,1-51,1-52,1-59,1-60,1-67,1-6
8,1-75,1-76,1-83,1-84,1-91,1-92,1-99,1-100,1-107,1
-108,1-115,1-116,1-123,1-124,1-131,1-132,1-139,1-1
40,1-147,1-148,1-155,1-156,1-161,1-162,1-163,1-16
4,1-165,1-166,1-173,1-174,1-177,1-178,1-179,1-181,
1-182,1-183,1-184,1-185,1-187,1-188,1-189,1-190,1-
191,1-192,1-193,1-194,1-195,1-196,1-197,1-198,1-19
9,1-200,1-201,1-202,1-203,1-204,1-207,1-208,1-209,
1-211,1-212,1-213,1-214,1-215,1-217,1-218,1-221,1-
222,1-223,1-225,1-226,1-227,1-228,1-229,1-231,1-23
2,1-235,1-236,1-237,1-239,1-240,1-241,1-242,1-243,
1-245,1-246,1-247,1-248,1-249,1-250,1-251,1-252,1-
253,1-254,1-255,1-256,1-257,1-258,1-259,1-260,1-26
1,1-262,1-263,1-264,1-265,1-266,1-267,1-268,1-269,
1-270,1-271,1-272,1-273,1-274,1-275,1-276,1-277,1-
278,1-279,1-280,1-281,1-282,1-283,1-284,1-285,1-28
6,1-289,1-290,1-291,1-293,1-294,1-295,1-296,1-297,
1-299,1-300,1-301,1-302,1-301-3,1-304,1-305,1-306,
1-307,1-308,1-309,1-310,1-311,1-312,1-311-3,1-314,
1-315,1-316,1-317,1-318,1-319,1-320,1-321,1-322,1-
323,1-324,1-325,1-326,1-327,1-328,1-329,1-330,1-33
1,1-332,1-333,1-334,1-335,1-336,1-337,1-338,1-339,
1-340,1-341,1-342,1-343,1-344,1-345,1-346,1-347,1-
348,1-351,1-352,1-353,1-355,1-356,1-357,1-358,1-35
9,1-361,1-362,1-365,1-366,1-367,1-369,1-370,1-371,
1-372,1-373,1-375,1-376,1-379,1-380,1-381,1-383,1-
384,1-385,1-386,1-387,1-389,1-390,1-393,1-394,1-39
5,1-397,1-398,1-399,1-400,1-401,1-403,1-404,1-405,
1-406,1-407,1-408,1-409,1-410,1-411,1-412,1-413,1-
414,1-415,1-416,1-417,1-418,1-419,1-420,1-421,1-42
2,1-423,1-424,1-425,1-426,1-427,1-428,1-429,1-430,
1-431,1-432,1-433,1-434,1-435,1-436,1-437,1-438,1-
439,1-440,1-441,1-442,1-443,1-444,1-447,1-448,1-44
9,1-451,1-452,1-453,1-454,1-455,1-457,1-458,1-459,
1-460,1-461,1-462,1-463,1-464,1-465,1-466,1-467,1-
468,1-469,1-470,1-471,1-472,1-473,1-474,1-475,1-47
6,1-477,1-478,1-479,1-480,1-481,1-482,1-485,1-486,
1-487,1-489,1-490,1-491,1-492,1-493,1-495,1-496,1-
497,1-498,1-499,1-500,1-501,1-502,1-503,1-504,1-50
5,1-506,1-507,1-508,1-509,1-510,1-511,1-512,1-513,
1-514,1-515,1-516,1-517,1-518,1-519,1-520,1-521,1-
522,1-523,1-524,1-525,1-526,1-527,1-528,1-529,1-53
0,1-531,1-532,1-533,1-534,1-535,1-536,1-537,1-538,
1-539,1-540,1-541,1-542,1-543,1-544,1-547,1-548,1-
549,1-551,1-552,1-553,1-554,1-555,1-557,1-558,1-55
9,1-560,1-561,1-562,1-563,1-564,1-565,1-566,1-567,
1-568,1-569,1-570,1-571,1-572,1-575,1-576,1-583,1-
584,1-591,1-592,1-599,1-600,1-607,1-608,1-615,1-61
6,1-623,1-624,1-631,1-632,1-639,1-640,1-647,1-648,
1-655,1-656,1-663,1-664,1-671,1-672,1-679,1-680,1-
687,1-688,1-695,1-696,1-703,1-704,1-711,1-712,1-71
9,1-720,1-727,1-728,1-733,1-734,1-735,1-736,1-737,
1-738,1-745,1-746,1-747,1-748,1-749,1-750,1-751,1-
752,1-753,1-754,1-755,1-756,1-757,1-758,1-759,1-76
0,1-761,1-762,1-763,1-764,1-765,1-766,1-767,1-768,
1-769,1-770,1-771,1-772,1-773,1-774,1-775,1-776,1-
777,1-778,1-779,1-780,1-781,1-782,1-783,1-784,1-78
5,1-786,1-787,1-788,1-789,1-790,1-791,1-792,1-793,
1-794,1-797,1-798,1-799,1-801,1-802,1-803,1-804,1-
805,1-807,1-808,1-809,1-810,1-811,1-812,1-813,1-81
4,1-815,1-816,1-817,1-818,1-821,1-822,1-829,1-830,
1-837,1-838,1-845,1-846,1-853,1-854,1-861,1-862,1-
869,1-870,1-877,1-878,1-885,1-886,1-893,1-894,1-90
1,1-902,1-901-9,1-910,1-917,1-918,1-925,1-926,1-93
3,1-934,1-941,1-942,1-949,1-950,1-957,1-958,1-965,
1-966,1-973,1-974,1-979,1-980,1-981,1-982,1-983,1-
984,1-991,1-992,1-993,1-994,1-995,1-996,1-997,1-99
8,1-999,1-1000,1-1001,1-1002,1-1003,1-1004,1-1005,
1-1006,1-1007,1-1008,1-1011,1-1012,1-1013,1-1015,1
-1016,1-1017,1-1018,1-1019,1-1021,1-1022,1-1025,1-
1026,1-1027,1-1029,1-1030,1-1031,1-1032,1-1033,1-1
035,1-1036,1-1039,1-1040,1-1041,1-1043,1-1044,1-10
45,1-1046,1-1047,1-1049,1-1050,1-1051,1-1052,1-105
3,1-1054,1-1055,1-1056,1-1057,1-1058,1-1059,1-106
0,1-1061,1-1062,1-1063,1-1064,1-1065,1-1066,1-106
9,1-1070,1-1071,1-1073,1-1074,1-1075,1-1076,1-107
7,1-1079,1-1080,1-1081,1-1082,1-1083,1-1084,1-108
5,1-1086,1-1087,1-1088,1-1089,1-1090,1-1091,1-109
2,1-1093,1-1094,1-1095,1-1096,1-1097,1-1098,1-109
9,1-1100,1-1101-11102,1-1103,1-1104,1-1105,1-1106,
1-1107,1-1108,1-1109,1-1110,1-1111,1-1112,1-1113,1
-1114,1-1115,1-1116,1-1117,1-1118,1-1119,1-1120,1-
1121,1-1122,1-1123,1-1124,1-1125,1-1126,1-1127,1-1
128,1-1131,1-1132,1-1133,1-1135,1-1136,1-1137,1-11
38,1-1139,1-1141,1-1142,1-1145,1-1146,1-1147,1-114
9,1-1150,1-1151,1-1152,1-1153,1-1155,1-1156,1-115
7,1-1158,1-1159,1-1160,1-1161,1-1162,1-1163,1-116
4,1-1165,1-1166,1-1167,1-1168,1-1169,1-1170,1-117
1,1-1172,1-1173,1-1174,1-1175,1-1176,1-1177,1-117
8,1-1179,1-1180,1-1181,1-1182,1-1183,1-1184,1-118
5,1-1186,1-1187,1-1188,1-1189,1-1190,1-1191,1-119
2,1-1193,1-1194,1-1195,1-1196,1-1197,1-1198,1-119
9,1-1200,1-1201,1-1202,1-1203,1-1204,1-1205,1-120
6,1-1207,1-1208,1-1209,1-1210,1-1211,1-1212,1-121
3,1-1214,1-1215,1-1216,1-1217,1-1218,1-1219,1-122
0,1-1221,1-1222,1-1223,1-1224,1-1225,1-1226,1-122
7,1-1228,1-1229,1-1230,1-1231,1-1232,1-1233,1-123
4,1-1235,1-1236,1-1237,1-1238,1-1239,1-1240,1-124
1,1-1242,1-1243,1-1244,1-1247,1-1248,1-1249,1-125
1,1-1252,1-1253,1-1254,1-1255,1-1257,1-1258,1-126
1,1-1262,1-1263,1-1265,1-1266,1-1267,1-1268,1-126
9,1-1271,1-1272,1-1273,1-1274,1-1275,1-1276,1-127
7,1-1278,1-1279,1-1280,1-1283,1-1284,1-1285,1-128
7,1-1288,1-1289,1-1290,1-1291,1-1293,1-1294,1-129
7,1-1298,1-1299,1-1301,1-1302,1-1303,1-1304,1-130
5,1-1307,1-1308,1-1311,1-1312,1-1313,1-1315,1-131
6,1-1317,1-1318,1-1319,1-1321,1-1322,1-1323,1-132
4,1-1325,1-1326,1-1327,1-1328,1-1329,1-1330,1-133
1,1-1332,1-1333,1-1334,1-1335,1-1336,1-1337,1-133
8,1-1339,1-1340,1-1341,1-1342,1-1343,1-1344,1-134
5,1-1346,1-1347,1-1348,1-1349,1-1350,1-1351,1-135
2,1-1353,1-1354,1-1355,1-1356,1-1357,1-1358,1-135
9,1-1360,1-1361,1-1362,1-1365,1-1366,1-1367,1-136
9,1-1370,1-1371,1-1372,1-1373,1-1375,1-1376,1-137
7,1-1378,1-1379,1-1380,1-1381,1-1382,1-1383,1-138
4,1-1387,1-1388,1-1389,1-1391,1-1392,1-1393,1-139
4,1-1395,1-1397,1-1398,1-1401,1-1402,1-1403,1-140
5,1-1406,1-1407,1-1408,1-1409,1-1411,1-1412,1-141
3,1-1414,1-1415,1-1416,1-1417,1-1418,1-1419,1-142
0,1-1423,1-1424,1-1425,1-1427,1-1428,1-1429,1-143
0,1-1431,1-1433,1-1434,1-1437,1-1438,1-1439,1-144
1,1-1442,1-1443,1-1444,1-1445,1-1447,1-1448,1-145
1,1-1452,1-1453,1-1455,1-1456,1-1457,1-1458,1-145
9,1-1461,1-1462,1-1463,1-1464,1-1465,1-1466,1-146
7,1-1468,1-1469,1-1470,1-1473,1-1474,1-1475,1-147
7,1-1478,1-1479,1-1480,1-1481,1-1483,1-1484,1-148
5,1-1486,1-1487,1-1488,1-1489,1-1490,1-1491,1-149
2,1-1493,1-1494,1-1495,1-1496,1-1497,1-1498,1-149
9,1-1500,1-1503,1-1504,1-1505,1-1507,1-1508,1-150
9,1-1510,1-1511,2-3,2-4,2-11,2-12,2-19,2-20,2-27,2
-28,2-35,2-36,2-43,2-44,2-51,2-52,2-59,2-60,2-67,2
-68,2-75,2-76,2-81,2-82,2-89,2-90,2-97,2-98,2-105,
2-106,2-113,2-114,2-121,2-122,2-129,2-130,2-137,2-
138,2-145,2-146,2-153,2-154,2-161,2-162,2-167,2-16
8,2-173,2-174,2-175,2-176,2-179,2-180,2-181,2-182,
2-185,2-186,2-187,2-188,2-191,2-192,2-193,2-194,2-
197,2-198,2-199,2-200,2-203,2-204,2-205,2-206,2-20
9,2-210,2-211,2-212,2-215,2-216,2-217,2-218,2-221,
2-222,2-223,2-224,2-227,2-228,2-229,2-230,2-233,2-
234,2-235,2-236,2-239,2-240,2-241,2-242,2-245,2-24
6,2-247,2-248,2-251,2-252,2-253,2-254,2-257,2-258,
2-259,2-260,2-261,2-262,2-263,2-264,2-265,2-266,2-
267,2-268,2-269,2-270,2-271,2-272,2-273,2-274,2-27
5,2-276,2-277,2-278,2-279,2-280,2-281,2-282,2-283,
2-284,2-287,2-288,2-289,2-291,2-292,2-293,2-294,2-
295,2-297,2-298,2-299,2-300,2-301,2-302,2-305,2-30
6,2-307,2-309,2-310,2-311,2-312,2-313,2-315,2-316,
2-319,2-320,2-321,2-323,2-324,2-325,2-326,2-327,2-
329,2-330,2-333,2-334,2-335,2-337,2-338,2-339,2-34
0,2-341,2-343,2-344,2-347,2-348,2-349,2-351,2-352,
2-353,2-354,2-355,2-357,2-358,2-361,2-362,2-363,2-
365,2-366,2-367,2-368,2-369,2-371,2-372,2-375,2-37
6,2-377,2-379,2-380,2-381,2-382,2-383,2-385,2-386,
2-389,2-390,2-391,2-393,2-394,2-395,2-396,2-397,2-
399,2-400,2-403,2-404,2-405,2-407,2-408,2-409,2-41
0,2-411,2-413,2-414,2-417,2-418,2-419,2-421,2-422,
2-423,2-424,2-425,2-427,2-428,2-431,2-432,2-433,2-
435,2-436,2-437,2-438,2-439,2-441,2-442,2-443,2-44
4,2-445,2-446,2-447,2-448,2-449,2-450,2-451,2-452,
2-453,2-454,2-455,2-456,2-457,2-458,2-461,2-462,2-
463,2-465,2-466,2-467,2-468,2-469,2-471,2-472,2-47
5,2-476,2-477,2-479,2-480,2-481,2-482,2-483,2-485,
2-486,2-489,2-490,2-491,2-493,2-494,2-495,2-496,2-
497,2-499,2-500,2-503,2-504,2-505,2-507,2-508,2-50
9,2-510,2-511,2-513,2-514,2-517,2-518,2-519,2-521,
2-522,2-523,2-524,2-525,2-527,2-528,2-529,2-530,2-
531,2-532,2-535,2-536,2-537,2-539,2-540,2-541,2-54
2,2-543,2-545,2-546,2-549,2-550,2-551,2-553,2-554,
2-555,2-556,2-557,2-559,2-560,2-561,2-562,2-563,2-
564, 2-565 or 2-566 compound, even more preferably
Is the compound number 1-3,1-4,1-11,1-12,1-51,1-52,1-59,1-6
0,1-91,1-92,1-139,1-140,1-161,1-165,1-173,1-177,1-
181,1-183,1-185,1-203,1-207,1-211,1-213,1-215,1-21
7,1-221,1-225,1-227,1-229,1-231,1-235,1-239,1-241,
1-243,1-261,1-265,1-269,1-273,1-285,1-289,1-293,1-
295,1-297,1-323,1-327,1-331,1-335,1-347,1-351,1-35
5,1-357,1-359,1-361,1-365,1-369,1-371,1-373,1-375,
1-379,1-383,1-385,1-387,1-389,1-393,1-397,1-399,1-
401,1-403,1-407,1-411,1-415,1-419,1-423,1-427,1-43
1,1-435,1-439,1-443,1-447,1-451,1-453,1-455,1-481,
1-485,1-489,1-491,1-493,1-543,1-547,1-551,1-553,1-
555,1-575,1-576,1-583,1-584,1-623,1-624,1-631,1-63
2,1-663,1-664,1-711,1-712,1-733,1-737,1-793,1-797,
1-801,1-803,1-805,1-815,1-817,1-821,1-822,1-829,1-
830,1-869,1-870,1-877,1-878,1-909,1-910,1-957,1-95
8,1-979,1-983,1-1007,1-1011,1-1015,1-1017,1-1019,1
-1021,1-1025,1-1029,1-1031,1-1033,1-1035,1-1039,1-
1043,1-1045,1-1047,1-1065,1-1069,1-1073,1-1075,1-1
077,1-1127,1-1131,1-1135,1-1137,1-1139,1-1141,1-11
45,1-1149,1-1151,1-1153,1-1155,1-1157,1-1159,1-116
1,1-1243,1-1247,1-1251,1-1253,1-1255,1-1257,1-126
1,1-1265,1-1267,1-1269,1-1271,1-1275,1-1279,1-128
3,1-1287,1-1289,1-1291,1-1293,1-1297,1-1301,1-130
3,1-1305,1-1307,1-1311,1-1315,1-1317,1-1319,1-132
1,1-1325,1-1361,1-1365,1-1369,1-1371,1-1373,1-137
5,1-1379,1-1383,1-1387,1-1391,1-1393,1-1395,1-139
7,1-1401,1-1405,1-1407,1-1409,1-1411,1-1415,1-141
9,1-1423,1-1427,1-1429,1-1431,1-1433,1-1437,1-144
1,1-1443,1-1445,1-1447,1-1451,1-1455,1-1457,1-145
9,1-1461,1-1465,1-1469,1-1473,1-1477,1-1479,1-148
1,1-1499,1-1503,1-1507,1-1509,1-1511,2-11,2-12,2-5
9,2-60,2-81,2-97,2-98,2-145,2-146,2-167,2-173,2-17
4,2-175,2-176,2-179,2-180,2-181,2-182,2-191,2-192,
2-193,2-194,2-203,2-204,2-205,2-206,2-215,2-216,2-
217,2-218,2-227,2-228,2-229,2-230,2-251,2-252,2-25
3,2-254,2-283,2-287,2-291,2-293,2-301,2-305,2-309,
2-311,2-315,2-319,2-323,2-325,2-329,2-333,2-337,2-
339,2-343,2-347,2-351,2-353,2-385,2-389,2-393,2-39
5,2-399,2-403,2-407,2-409,2-413,2-417,2-421,2-423,
2-427,2-431,2-435,2-437,2-457,2-461,2-465,2-467,2-
471,2-475,2-479,2-481,2-499,2-503,2-507,2-509,2-51
3,2-517,2-521,2-523,2-527,2-529,2-531,2-535,2-539
Or a compound of 2-541, particularly preferably, Compound No. 1-11: 1-cyclopropyl-9-methyl-4
-Oxo-8- [4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
-3-carboxylic acid, Compound No. 1-51: 1-cyclopropyl-9-methoxy-
4-oxo-8- [4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -4H-quinoli
Gin-3-carboxylic acid, Compound No. 1-59: 1-cyclopropyl-9-difluoro
Methoxy-4-oxo-8- [4,5,6,7-tetra
Hydrothieno [3,2-c] pyridin-2-yl] -4
H-quinolidine-3-carboxylic acid, Compound No. 1-91: 1-cyclopropyl-7-fluoro-
9-methyl-4-oxo-8- [4,5,6,7-tet
Lahydrothieno [3,2-c] pyridin-2-yl]-
4H-quinolidine-3-carboxylic acid, Compound No. 1-161: 6-amino-1-cyclopropyl-
9-methyl-4-oxo-8- [4,5,6,7-tet
Lahydrothieno [3,2-c] pyridin-2-yl]-
4H-quinolidine-3-carboxylic acid, Compound number 1-165: 6-amino-1-cyclopropyl-
7-fluoro-9-methyl-4-oxo-8- [4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
2-Nyl] -4H-quinolizin-3-carboxylic acid, Compound number 1-173: 1-cyclopropyl-9-methyl-
4-oxo-8- [3-trifluoromethyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl] -4H-quinolidine-3-carboxylic acid, Compound number 1-217: 1-cyclopropyl-8- [3-f
Luoro-4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -9-methyl-4-oxo
-4H-quinolidine-3-carboxylic acid, Compound number 1-225: 1-cyclopropyl-7-fluoro
-8- [3-Fluoro-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -9-methyl
Ru-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-231: 1-cyclopropyl-9-methyl-
8- [3-methyl-4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -4-oxo-
4H-quinolidine-3-carboxylic acid, Compound number 1-239: 1-cyclopropyl-7-fluoro
-9-methyl-8- [3-methyl-4,5,6,7-te
Trahydrothieno [3,2-c] pyridin-2-yl]
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-265: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methyl-4,5,6,7-te
Trahydrothieno [3,2-c] pyridin-2-yl]
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-269: 1-cyclopropyl-9-methyl-
8- [5-methyl-4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -4-oxo-
4H-quinolidine-3-carboxylic acid, Compound number 1-323: 1-cyclopropyl-8- [6-h
Droxymethyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -9-methyl-4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-335: 1-cyclopropyl-7-fluoro
-9-methyl-8- [6-methyl-4,5,6,7-te
Trahydrothieno [3,2-c] pyridin-2-yl]
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-361: 8- [7-amino-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridine-2-i
1] -cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid Compound number 1-369: 8- [7-amino-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridine-2-i
1] -cyclopropyl-7-fluoro-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid Compound No. 1-403: 1-cyclopropyl-8- [7-h
Droxy-4,5,6,7-tetrahydrothieno [3,
2-c] pyridin-2-yl] -9-methyl-4-oxo
So-4H-quinolidine-3-carboxylic acid, Compound number 1-411: 1-cyclopropyl-8- [7-me
Toxi-4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -9-methyl-4-oxo
-4H-quinolidine-3-carboxylic acid, Compound No. 1-415: 1-cyclopropyl-7-fluoro
-8- [7-methoxy-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -9-methyl
Ru-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-423: 1-cyclopropyl-7-fluoro
-9-methyl-4-oxo-8- (4,5,6,7-te
Trahydrothieno [2,3-c] pyridin-2-yl)
-4H-quinolidine-3-carboxylic acid, Compound number 1-431: 1-cyclopropyl-7-fluoro
-9-methyl-8- [5-methyl-4,5,6,7-te
Trahydrothieno [2,3-c] pyridin-2-yl]
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-439: 1-cyclopropyl-7-fluoro
-9-methyl-8- [7-methyl-4,5,6,7-te
Trahydrothieno [2,3-c] pyridin-2-yl]
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-443: 8- [4-amino-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridine-2-i
1] -cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid, Compound No. 1-583: 8- [4-amino-4,5,6,7-
Tetrahydrobenzo [b] thiophen-2-yl] -1
-Cyclopropyl-9-methyl-4-oxo-4H-ki
Noridine-3-carboxylic acid, Compound No. 1-623: 8- [4-amino-4,5,6,7-
Tetrahydrobenzo [b] thiophen-2-yl] -1
-Cyclopropyl-9-methoxy-4-oxo-4H-
Quinolidine-3-carboxylic acid, Compound No. 1-631: 8- [4-amino-4,5,6,7-
Tetrahydrobenzo [b] thiophen-2-yl] -1
-Cyclopropyl-9-difluoromethoxy-4-oxo
So-4H-quinolidine-3-carboxylic acid, Compound No. 1-663: 8- [4-amino-4,5,6,7
-Tetrahydrobenzo [b] thiophen-2-yl]-
1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-733: 6-amino-8- [4-amino-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -1-cyclopropyl-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-737: 6-amino-8- [4-amino-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Acid, Compound No. 1-829: 1-cyclopropyl-8- [5,6
-Dihydro-4H-thieno [2,3-c] pyrrole-2
-Yl] -9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid, Compound No. 1-909: 1-cyclopropyl-8- [5,6
-Dihydro-4H-thieno [2,3-c] pyrrole-2
-Yl] -7-fluoro-9-methyl-4-oxo-4
H-quinolidine-3-carboxylic acid, Compound No. 1-979: 6-amino-1-cyclopropyl-
8- [5,6-dihydro-4H-thieno [2,3-c]
Pyrrole-2-yl] -9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid, Compound No. 1-983: 6-amino-1-cyclopropyl-
8- [5,6-dihydro-4H-thieno [2,3-c]
Pyrrole-2-yl] -7-fluoro-9-methyl-4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-1021: 1-cyclopropyl-8- [3-f
Fluoro-5,6-dihydro-4H-thieno [2,3-
c] Pyrol-2-yl] -9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid, Compound number 1-1029: 1-cyclopropyl-7-fluoro
-8- [3-Fluoro-5,6-dihydro-4H-thier
No [2,3-c] pyrrol-2-yl] -9-methyl-
4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1035: 1-cyclopropyl-9-methyl-
8- [3-methyl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid, Compound number 1-1043: 1-cyclopropyl-7-fluoro
-9-methyl-8- [3-methyl-5,6-dihydro-
4H-thieno [2,3-c] pyrrol-2-yl] -4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1065: 1-cyclopropyl-9-methyl-
8- [4-methyl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid, Compound number 1-1073: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methyl-5,6-dihydro-
4H-thieno [2,3-c] pyrrol-2-yl] -4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1127: 1-cyclopropyl-9-methyl-
8- [6-methyl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid, Compound number 1-1135: 1-cyclopropyl-7-fluoro
-9-methyl-8- [6-methyl-5,6-dihydro-
4H-thieno [2,3-c] pyrrol-2-yl] -4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1139: 6-amino-1-cyclopropyl-
7-fluoro-9-methyl-8- [6-methyl-5,6
-Dihydro-4H-thieno [2,3-c] pyrrole-2
-Yl] -4-oxo-4H-quinolizin-3-carbo
Acid, Compound number 1-1141: 1-cyclopropyl-9-methyl-
4-oxo-8- [spiro [5,6-dihydro-4H-
Thieno [2,3-c] pyrrole-6,1'-cyclopro
Pan] -2-yl] -4H-quinolidine-3-carboxyl
acid, Compound number 1-1149: 1-cyclopropyl-7-fluoro
-9-methyl-4-oxo-8- [spiro [5,6-di
Hydro-4H-thieno [2,3-c] pyrrole-6
1'-cyclopropane] -2-yl] -4H-quinolizi
-3-carboxylic acid, Compound number 1-1155: 8- [4-amino-5,6-dihydride
B-4H-Cyclopenta [b] thiophen-2-yl]
-1-cyclopropyl-9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid, Compound No. 1-1159: 8- [4-amino-5,6-dihydride
B-4H-Cyclopenta [b] thiophen-2-yl]
-1-cyclopropyl-7-fluoro-9-methyl-4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1243: 8- [4-amino-6-methyl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl] -1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-1251: 8- [4-amino-6-methyl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl] -1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
carboxylic acid, Compound number 1-1257: 8- [4-amino-6-methyl-5
-Oxo-4,5,6,7-tetrahydrothieno [2,
3-c] pyridin-2-yl] -1-cyclopropyl-
9-methyl-4-oxo-4H-quinolizin-3-cal
Boric acid, Compound number 1-1265: 8- [4-amino-6-methyl-5
-Oxo-4,5,6,7-tetrahydrothieno [2,
3-c] pyridin-2-yl] -1-cyclopropyl-
7-Fluoro-9-methyl-4-oxo-4H-quinoli
Gin-3-carboxylic acid, Compound number 1-1271: 1-cyclopropyl-9-methyl-
8- [4-methylamino-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridin-2-yl] -4-o
Xo-4H-quinolidine-3-carboxylic acid, Compound number 1-1275: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-4,5,6,
7-tetrahydrothieno [2,3-c] pyridine-2-
Yl] -4-oxo-4H-quinolidine-3-carboxyl
acid, Compound number 1-1279: 8- [4-amino-7,7-dimethyl
-4,5,6,7-tetrahydrothieno [2,3-
c] pyridin-2-yl] -1-cyclopropyl-9-
Methyl-4-oxo-4H-quinolidine-3-carboxyl
acid, Compound No. 1-1287: 8- [4-amino-7,7-dimethyl
-4,5,6,7-tetrahydrothieno [2,3-
c] pyridin-2-yl] -1-cyclopropyl-7-
Fluoro-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid, Compound number 1-1293: 8-1-cyclopropyl-9-methyl
Ru- [4-methylamino-7,7-dimethyl-4,5,
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -4-oxo-4H-quinolizin-3-cal
Boric acid, Compound number 1-1301: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-7,7-dimension
Cyl-4,5,6,7-tetrahydrothieno [2,3-
c] pyridin-2-yl] -4-oxo-4H-quinoli
Gin-3-carboxylic acid, Compound number 1-1307: 1-cyclopropyl-9-methyl-
4-oxo-8- [spiro [4-amino-4,5,6,
7-tetrahydrothieno [2,3-c] pyridine-7,
1′-Cyclopropane] -2-yl] -4H-quinolizi
-3-carboxylic acid, Compound number 1-1315: 1-cyclopropyl-7-fluoro
-9-methyl-4-oxo-8- [spiro [4-amino
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridin-7,1'-cyclopropane] -2-yl]-
4H-quinolidine-3-carboxylic acid, Compound number 1-1321: 1-cyclopropyl-9-methyl-
4-oxo-8- [spiro [4-methylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
-7,1'-Cyclopropane] -2-yl] -4H-
Quinolidine-3-carboxylic acid, Compound number 1-1325: 1-cyclopropyl-7-fluoro
-9-methyl-4-oxo-8- [spiro [4-methyl
Amino-4,5,6,7-tetrahydrothieno [2,3
-C] pyridine-7,1'-cyclopropane] -2-a
Ru] -4H-quinolidine-3-carboxylic acid, Compound number 1-1361: 8- [7-amino-5-methyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-1369: 8- [7-amino-5-methyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
carboxylic acid, Compound number 1-1375: 1-cyclopropyl-9-methyl-
8- [4-methylamino-4,5,6,7-tetrahydride
Rothieno [3,2-c] pyridin-2-yl] -4-o
Xo-4H-quinolidine-3-carboxylic acid, Compound number 1-1379: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-4,5,6
7-tetrahydrothieno [3,2-c] pyridine-2-
Yl] -4-oxo-4H-quinolidine-3-carboxyl
acid, Compound number 1-1383: 8- [4-amino-5-methyl-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -1-cyclopropyl-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1391: 8- [4-amino-5-methyl-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Acid, Compound No. 1-1397: 8- [4-amino-5,6-dihydride
B-4H-thieno [2,3-b] thiopyran-2-i
1] -cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid, Compound No. 1-1405: 8- [4-amino-5,6-dihydride
B-4H-thieno [2,3-b] thiopyran-2-i
1] -cyclopropyl-7-fluoro-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1411: 1-cyclopropyl-9-methyl-
8- [4-methylamino-5,6-dihydro-4H-thio
Eno [2,3-b] thiopyran-2-yl] -4-oxo
So-4H-quinolidine-3-carboxylic acid, Compound number 1-1415: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-5,6-dihi
Dro-4H-thieno [2,3-b] thiopyran-2-i
4-oxo-4H-quinolidine-3-carboxyl
acid, Compound No. 1-1419: 8- [4-amino-4,7-dihydrido
B-5H-thieno [2,3-c] thiopyran-2-i
1] -cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid, Compound No. 1-1427: 8- [4-amino-4,7-dihydride
B-5H-thieno [2,3-c] thiopyran-2-i
1] -cyclopropyl-7-fluoro-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1433: 1-cyclopropyl-9-methyl-
8- [4-methylamino-4,7-dihydro-5H-thio
Eno [2,3-c] thiopyran-2-yl] -4-oxo
So-4H-quinolidine-3-carboxylic acid, Compound number 1-1441: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-4,7-dihi
Dro-5H-thieno [2,3-c] thiopyran-2-i
4-oxo-4H-quinolidine-3-carboxyl
acid, Compound No. 1-1447: 8- [4-amino-4,7-dihydrido
B-5H-thieno [2,3-c] pyran-2-yl]-
1-cyclopropyl-9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid, Compound No. 1-1455: 8- [4-amino-4,7-dihydrido
B-5H-thieno [2,3-c] pyran-2-yl]-
1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid, Compound number 1-1461: 1-cyclopropyl-9-methyl-
8- [4-methylamino-4,7-dihydro-5H-thio
Eno [2,3-c] pyran-2-yl] -4-oxo-
4H-quinolidine-3-carboxylic acid, Compound number 1-1465: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-4,7-dihi
Dro-5H-thieno [2,3-c] pyran-2-yl]
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-1469: 8- [4-amino-5,6,7,8
-Tetrahydro-4H-thieno [2,3-d] azepine
-2-yl] -1-cyclopropyl-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid, Compound No. 1-1477: 8- [4-amino-5,6,7,8
-Tetrahydro-4H-thieno [2,3-d] azepine
-2-yl] -1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Acid, Compound number 1-1499: 1-cyclopropyl-9-methyl-
8- [4-methylamino-4,5,6,7-tetrahydride
Lobenzo [b] furan-2-yl] -4-oxo-4H
-Quinolidine-3-carboxylic acid, Compound number 1-1507: 1-cyclopropyl-7-fluoro
-9-methyl-8- [4-methylamino-4,5,6
7-tetrahydrobenzo [b] furan-2-yl] -4
-Oxo-4H-quinolidine-3-carboxylic acid, Compound No. 2-11: 1-cyclopropyl-7-fluoro-
8- (isoindoline-5-yl) -9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid, Compound number 2-12: 7-fluoro-1- (2-fluorosi
Clopropyl) -8- (isoindoline-5-yl)-
9-methyl-4-oxo-4H-quinolizin-3-cal
Boric acid, Compound No. 2-59: 1-cyclopropyl-9-difluoro
Methoxy-7-fluoro-8- (isoindoline-5-
Yl) -4-oxo-4H-quinolidine-3-carboxyl
acid, Compound No. 2-81: 6-amino-1-cyclopropyl-7
-Fluoro-8- (isoindoline-5-yl) -9-
Methyl-4-oxo-4H-quinolidine-3-carboxyl
acid, Compound No. 2-97: 1-cyclopropyl-7-fluoro-
9-methyl-8- (1-methylisoindoline-5-i
Ru) -4-oxo-4H-quinolidine-3-carboxyl
acid, Compound number 2-98: 7-fluoro-1- (2-fluorosi
Chloropropyl) -9-methyl-8- (1-methylisoyi)
Ndrin-5-yl) -4-oxo-4H-quinolizine
-3-carboxylic acid, Compound No. 2-145: 1-cyclopropyl-9-difluoro
Romethoxy-7-fluoro-8- (1-methylisoin
Dolin-5-yl) -4-oxo-4H-quinolizine-
3-carboxylic acid, Compound No. 2-167: 6-amino-1-cyclopropyl-
7-fluoro-9-methyl-8- (1-methylisoin
Dolin-5-yl) -4-oxo-4H-quinolizine-
3-carboxylic acid, Compound No. 2-283: 8- (3-aminoindan-5-i
L) -1-cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid, Compound No. 2-291: 8- (3-aminoindan-5-i
Ru) -1-cyclopropyl-7-fluoro-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid, Compound No. 2-457: 8- (8-amino-5,6,7,8
-Tetrahydronaphthalen-2-yl) -1-cycloprop
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid, Compound No. 2-465: 8- (8-amino-5,6,7,8
-Tetrahydronaphthalen-2-yl) -1-cycloprop
Ropyl-7-fluoro-9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid, Compound No. 2-527: 8- (5-amino-5,6,7,8
-Tetrahydronaphthalen-1-yl) -1-cycloprop
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid, or Compound No. 2-529: 8- (5-amino-5,6,7,8
-Tetrahydronaphthalen-1-yl) -1-cycloprop
Ropyl-7-fluoro-9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid. [0059] BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention is described below.
It can be manufactured by the method A described above. [0060] Embedded image[0061]Method A In method A, R¹, R^Two, R^Three, R^FourRepresents a group having the same meaning as above.
Then R^5aIs R^FiveOr R^FiveUpper hydroxy group
Or R in which the amino group is optionally protected with a protecting group
^FiveAnd R⁸Represents a protecting group for a carboxy group, and X represents a leaving group.
Represents a group, Y represents a hydrogen atom or a halogen atom, and M represents
Represents a tin atom or a boron atom, and Z represents a ligand of M
You. R^5aThe protecting group of the hydroxy group in
If it can stably protect the hydroxy group during the reaction
Although there is no particular limitation, specifically, hydrogenolysis, hydrolysis
Opening by chemical methods such as decomposition, electrolysis and photolysis
Refers to a protecting group that can be cleaved, for example, the above-mentioned “aliphatic acyl”
Group "; the above-mentioned" aromatic acyl group ";
A lofuranyl or tetrahydrothiofuranyl group ";
"Silyl group"; "alkoxymethyl group" described above;
"Substituted ethyl group"; "aralkyl group" described above;
“Alkoxycarbonyl group”; the above “alkenyloxy”
A "cyclocarbonyl group" or the above-mentioned "aralkyloxyca"
Rubonyl group ". R^5aThe protecting group for the amino group in
In particular, if it can stably protect the amino group,
Although not limited, specific examples include hydrogenolysis, hydrolysis, and electrolysis.
Can be cleaved by chemical methods such as gasolysis and photolysis
A protecting group, for example, the aforementioned “aliphatic acyl group”;
The above-mentioned “aromatic acyl group”;
The above-mentioned “alkenyloxycarbonyl group”;
“Aralkyloxycarbonyl group”;
Aralkyl group "; N, N-dimethylamido
Nomethylene, benzylidene, 4-methoxybenzylidene
4-nitrobenzylidene, salicylidene, 5-chloro
Losalicylidene, diphenylmethylene or (5-chloro
-2-hydroxyphenyl) phenylmethylene
"Substituted methylene groups" forming Schiff bases; benzenes
Arylsulfonyl groups such as rufonyl, p-toluene
Sulfonyl, pentamethylbenzenesulfonyl, p-meth
Toxibenzenesulfonyl, 2,4,6-trimethoxy
Benzenesulfonyl or 3-methoxy-4-t-butyl
Lower alkyl, lower alcohol such as benzenesulfonyl
“Aromatic sulfonyl groups such as arylsulfonyl groups substituted with xy
Ruphonyl group ”or methanesulfonyl, t-butyls
Alkylsulfonyl groups such as rufonyl, trifluoro
Methylsulfonyl, trisilylethanesulfonyl or
Halogen atoms such as benzylsulfonyl, silyl groups,
"Aliphatic" such as alkylsulfonyl substituted with a reel group
Sulfonyl group "can be mentioned. R⁸The protecting group for the carboxy group in
If it can stably protect the carboxy group during the reaction
Although there is no particular limitation, specifically, hydrogenolysis, hydrolysis
Opening by chemical methods such as decomposition, electrolysis and photolysis
Refers to a protecting group that can be cleaved, for example, the aforementioned “lower alkyl”
The above-mentioned “alkenyl group”; the above-mentioned “alkynyl”
Group "; the above" substituted by one or more halogen atoms
"Lower alkyl group"; the above "hydroxy lower alkyl"
Group "; the above-mentioned" aliphatic acyl "-" lower alkyl group ";
The above-mentioned “aralkyl group”; the above-mentioned “silyl group”
be able to. The leaving group for X reacts with a nucleophile.
There is no particular limitation as long as the functional group undergoes a substitution reaction.
However, as such a group, for example, the aforementioned “halogen”
Atom "; methanesulfonyloxy or ethanesulfonyl
A "lower alkylsulfonyloxy group" such as oxy;
"Halogens such as trifluoromethanesulfonyloxy
Substituted lower alkylsulfonyloxy group '' or
Arylsulfonyloxy such as zensulfonyloxy
Thio group, lower alkyl such as p-toluenesulfonyloxy
Killed arylsulfonyloxy group or p-chloroben
Halogen-substituted aryls such as zensulfonyloxy
"Aromatic sulfonyloxy group" such as a rufonyloxy group
I can list them. The halogen atom in Y is as defined above.
Represents The ligand of M in Z is defined as
There is no particular limitation as long as it can coordinate, but
Examples of such groups include, for example, when M is a tin atom,
G) methyl, (tris) ethyl or (tris) hexyl
"(Tris) C₁-C₆Alkyl group "
And (bis) hydroxy when M is a boron atom
A group of (bis) methyloxy or (bis) ethyloxy
Like "(screw) C₁-C₆Alkyloxy group "; tetra
"C such as methylethylenedioxy group₁-C _FourAlkyl
Substituted with a group_Two-C₈Alkylenedioxy group ", or
Is an arylene dioxy group such as a phenylenedioxy group
Group ". Hereinafter, each step of the method A will be described in detail.
I do. (Method A) (Step A1) The step A1 is known or a known method.
(For example, in WO9907682, WO9921849, etc.
Can be easily obtained according to the method described in
Compound (II) obtained by Method A to Method G
This is a step of producing compound (III). In this step, Y is a hydrogen atom or a halogen atom
(Preferably a chlorine, bromine or iodine atom)
(II) in an inert solvent under an inert gas atmosphere (eg,
For example, argon gas, nitrogen gas or helium gas), lithium
After derivatization to a lithio compound using an
React with ruthenium halide or borate ester
Compound (III) wherein M is a tin atom or a boron atom
(Method A1a) or Y is a halogen atom
(Preferably a chlorine, bromine or iodine atom)
(II) in an inert solvent under an inert gas atmosphere
Reaction with a tin or borating agent in the presence of an aluminum catalyst.
Thus, M is a tin atom or a boron atom, respectively.
Production of a certain compound (III) (Method A1b)
Be done. (Method A1a) The solvent used is one that inhibits the reaction.
If the raw material can be dissolved to some extent,
Not specified, for example, benzene, toluene, xylene or
Aromatic hydrocarbons such as mesitylene; pentane, hexane
Or aliphatic hydrocarbons such as cyclohexane; 1,2-di
Methokiethane, diethyl ether, diisopropyl ate
Ter, tetrahydrofuran, anisole, diglyme or
Is an ether such as dioxane, or a mixed solvent thereof
And the like, and preferably ethers.
Preferably, it is tetrahydrofuran. The lithiating agent used includes, for example,
Methyl lithium, butyl lithium, s-butyl lithium
Or alkyl lithiums such as t-butyl lithium;
Aryl lithiums such as nil lithium, or lithium
Diisopropylamide or lithium bis (trimethyl
Lithium) amides such as ril) amide;
Preferably, butyllithium, s-butyllithium, t-
Butyllithium or phenyllithium. Lithiation
The amount of the agent to be used is generally 1 part per compound (II).
Three to three moles are used, preferably one to two moles.
You. The reaction temperature of the lithiation reaction depends on the starting compound,
Although it varies depending on the reagent or solvent, it is usually −100 ° C.
To 50 ° C, preferably -70 ° C to 0 ° C.
You. The reaction time depends on the starting material, reaction temperature, reagent
Or 5 minutes to 5 o'clock, depending on the solvent, etc.
Between 10 minutes and 1 hour. The lithiation reaction solution obtained above is then
Reaction with trialkyltin halides or borate esters
To the desired tin derivative or boric acid derivative, respectively.
Guided by the body. The trialkyltin halide used is
Trimethyltin chloride, tripropyltin chloride, salt
Tributyltin bromide, trimethyltin bromide, triethyl bromide
Rutin or tributyltin bromide
Tripropyltin or tributyltin chloride. As the borate ester used, for example,
For example, trimethyl borate, triethyl borate, triborate
Isopropyl, tributyl borate or 2-isopropoxy
C-4,4,5,5-tetramethyl-1,3,2-di
Xaborolane, preferably triboric acid
Methyl or 2-isopropoxy-4,4,5,5-tetra
Lamethyl-1,3,2-dioxaborolane. Trialkyltin halide or boric acid ester
The amount of tellurium is usually 1 to compound (II).
To 5 moles are used, preferably 1 to 2 moles.
is there. The reaction temperature depends on the starting compound, reagent, solvent, etc.
The temperature is usually -100 ° C to 50 ° C,
Suitably, it is between -70 ° C and 0 ° C. The reaction time is based on the starting compound, reaction temperature, reagent
Or 5 minutes to 5 o'clock, depending on the solvent, etc.
Between 10 minutes and 24 hours. Note that Y is a halogen atom (preferably a salt
Compound (II), which is a hydrogen, bromine or iodine atom)
Reaction with Gnesium to prepare Grignard reagent
Perform the same reaction using
Compound (III) can also be produced by the above. (Method A1b) The solvent used is one that inhibits the reaction.
If the raw material can be dissolved to some extent,
Not specified, for example, benzene, toluene or xylene
Aromatic hydrocarbons; 1,2-dimethoxyethane, diethyl
Ether, diisopropyl ether, tetrahydrof
An agent such as orchid, anisole, diglyme or dioxane
Ters; nitrites such as acetonitrile or propionitrile
Ryls: N, N-dimethylformamide, N, N-dimethyl
Tilacetamide, N-methyl-2-pyrrolidone or f
Amides such as xamethylphosphorylamide; dimethyls
Sulfoxides such as rufoxide or a mixed solution thereof
And aromatic hydrocarbons.
And particularly preferably benzene or toluene. As the palladium catalyst used, for example,
For example, palladium-activated carbon or palladium black
Radiums; palladium chloride or palladium acetate
Radium salts or tetrakis (triphenylphosph
In) palladium (0), bis (triphenylphosphine)
N) palladium (II) chloride or bis (dibenzyl)
Organic palladium complexes such as denacetone) palladium (0)
And organic palladium complexes.
And particularly preferably tetrakis (triphenylphosphine).
In) palladium (0). Use of palladium catalyst
The amount is usually 0.00001 to the raw material (II).
Times to 2 times, preferably 0.001 to 0.5 times.
It is twice the mole. As the tinning agent used, for example,
Xamethyldistannane, hexaethyldistannane, hex
Such as sapropyldistannane or hexabutyldistannane
Hexaalkyldistannane can be mentioned, preferably
Is hexabutyldistanane. Examples of the boronizing agent used include, for example,
4,4,5,5-tetramethyl-1,3,2-dioxa
Dialkoxy borane such as borane or catechol borane,
Or 4,4,5,5-tetramethyl-1,3,2-di
Oxaboran-2-yl-4 ', 4', 5 ', 5'-te
A, such as tramethyl-1 ', 3', 2'-dioxaborane;
Lucoxydiborane can be mentioned, preferably 4,
4,5,5-tetramethyl-1,3,2-dioxabora
It is. The amount of the above-mentioned tin or boronizing agent used is
Usually, it is 1 to 10 times the molar amount of the raw material (II),
Suitably, it is 1 to 3 moles. The reaction temperature depends on the starting compound, reagent, solvent, etc.
Is usually 0 ° C. to 180 ° C.,
Preferably, it is 50 ° C to 150 ° C. The reaction time is based on the starting compound, reaction temperature, reagent
Or, it changes depending on the solvent or the like, but usually from 1 hour to 72 hours.
Hours, preferably from 2 hours to 48 hours. In the case of the reaction with the boronating agent,
Is preferably carried out in the presence of
Is, for example, potassium acetate, potassium t-butoxide,
Triethylamine, diisopropylethylamine, triethylamine
Butylamine, pyridine or 1,8-diazabicyclo
[5,4,0] -7-undecene, etc.
Suitably, triethylamine, diisopropylethylamine
Or pyridine. The amount of base used is based on the amount of raw material (II).
Is 0.5 to 10 times equimolar, preferably 1
It is up to 3 times the mole. The compound obtained by the above (Method A1a) or (Method A1b)
After completion of the reaction, for example, the reaction mixture is concentrated.
And add a water-immiscible organic solvent such as ethyl acetate.
After washing with water, the organic phase containing the target compound is separated and
After drying over magnesium acid, etc., the solvent is distilled off.
It is. The obtained compound may be used in a conventional manner, if necessary.
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. The borate ester derivative obtained above
Is hydrolyzed to form a boric acid derivative (Z is a hydroxy group).
Compound (III)), the resulting boric acid derivative
The body can be used as a raw material for the next step. The reaction
Is a known method [for example, Experimental Chemistry Course, 4th edition, 24
Vol. 61, (1992), J. Org. Chem.,55, 4622
(1990), Tetrahedron Letter,twenty five, 1781 (1984), J. Org.
Chem.,62, 6458 (1997), etc.]. (Step A2) Step A2 is obtained by step A1.
Compound (III) and a known method (WO9639407, U.S. Pat.
S5693813) or the method B described below.
The compound (IV) thus obtained is reacted with the compound (V)
This is the step of manufacturing. Compound (IV) and compound wherein M is a tin atom
The coupling reaction (Still reaction) with (III)
Known methods, for example, Organic Reactions,
Vol. 50, p. 1 (1997), WO9729102, etc.
Performed with reference to argon, nitrogen or helium, etc.
Using a metal catalyst in an inert solvent under an inert gas atmosphere
Done. The solvent used in the reaction is one that inhibits the reaction.
If it does not harm and dissolves the raw material to some extent,
Not limited to, for example, benzene, toluene, xylene
Or aromatic hydrocarbons such as mesitylene; pentane, hexene
Aliphatic hydrocarbons such as sun or cyclohexane;
Halogen such as Tylene, chloroform or dichloroethane
Hydrocarbons; 1,2-dimethoxyethane, diethyl ether
Ter, diisopropyl ether, tetrahydrofuran,
Ethers such as anisole, diglyme or dioxane
Esters; esters such as ethyl acetate or butyl acetate; aceto
Nitriles such as nitrile or propionitrile: N, N
-Dimethylformamide, N, N-dimethylacetamide
, N-methyl-2-pyrrolidone or hexamethylphos
Amides such as phosphorylamide; dimethylsulfoxide and the like
Sulfoxides, or mixtures of these, etc.
Preferably, aromatic hydrocarbons, ethers or
Amides, particularly preferably toluene, tetrahydride
Lofuran or N, N-dimethylformamide. Examples of the metal catalyst used include, for example,
Radium-activated carbon, palladium black, palladium chloride,
Palladium acetate, tetrakis (triphenylphosphine
N) palladium (0), bis (triphenylphosphine)
N) palladium (II) chloride or bis (dibenzyl)
Palladium catalysts such as denacetone) palladium (0),
Or a nickel catalyst such as nickel chloride or nickel acetate
And preferably a palladium catalyst,
Particularly preferably, tetrakis (triphenylphosphine)
Palladium (0) or bis (triphenylphosphine)
Palladium (II) chloride. Usage of metal catalyst
As 0.00001 to 1 with respect to compound (IV)
Mole, preferably 0.001 to 0.3 mole.
is there. The amount of the tin compound (III) used is
It is usually 1 to 10 moles per mole of the raw material (IV),
Is 1 to 3 moles. The reaction temperature depends on the starting compound, the reagent, and the metal catalyst.
Or, it varies depending on the solvent or the like, but is usually from 0 ° C.
° C, preferably 50 ° C to 150 ° C. The reaction time depends on the starting compound, the reaction temperature,
It varies depending on the drug, metal catalyst, solvent, etc.
Hours to 72 hours, preferably 2 hours to 48 hours
Between. Further, compound (IV) and M are boron atoms
Reaction with compound (III) (Suzuki Coupling Co., Ltd.)
Reaction) is carried out by a known method (for example, fine chemical
26 (6), 5 (1997), Fine
Chemical, 26 (7), 13 (1997), W
O9729102), argon,
In an inert gas atmosphere such as nitrogen or helium, in an inert solvent
In the presence or absence of a base, using a metal catalyst
It is. The solvent used for the reaction is
If it does not harm and dissolves the raw material to some extent,
But not limited to, for example, water; methanol, eta
Knol, propanol, isopropanol or butanol
Alcohols such as benzene, toluene, xylene or
Is an aromatic hydrocarbon such as mesitylene; pentane, hexa
Aliphatic hydrocarbons such as butane or cyclohexane; methyl chloride
Benzene, chloroform or 1,2-dichloroethane
Hydrogenated hydrocarbons; 1,2-dimethoxyethane, diethyl
Ether, diisopropyl ether, tetrahydrof
An agent such as orchid, anisole, diglyme or dioxane
Esters; esters such as ethyl acetate or butyl acetate;
Nitriles such as setonitrile or propionitrile:
N, N-dimethylformamide, N, N-dimethylacetate
Toamide, N-methyl-2-pyrrolidone or hexamethyi
Amides such as diphosphorylamide; dimethyl sulfoxy
And sulfoxides such as
And preferably mixed with toluene / ethanol / water.
Solvent, tetrahydrofuran, dioxane or N, N-
Dimethylformamide, particularly preferably toluene
/ Ethanol / water mixed solvent. Examples of the base used include, for example,
Titanium, sodium bicarbonate, sodium carbonate, carbonated water
Alkali metal carbonates such as potassium potassium or potassium carbonate,
Or triethylamine, tributylamine or diiso
Amines such as propylethylamine;
Preferably, it is an alkali metal carbonate, particularly preferably,
Sodium carbonate. The amount of the base used is usually based on the amount of the raw material (IV).
1 to 10 moles, preferably 2 to 3 moles
It is. Examples of the metal catalyst used include, for example,
Radium-activated carbon or metal palladium such as palladium black
Palladium such as palladium chloride or palladium acetate
Salt or tetrakis (triphenylphosphine)
Palladium (0), bis (triphenylphosphine)
Radium (II) chloride or bis (dibenzylidenea)
Organic palladium complexes such as seton) palladium (0)
And preferably, an organic palladium complex
And particularly preferably tetrakis (triphenylphosphine).
In) palladium (0) or bis (triphenylphosphine)
In) palladium (II) chloride. The amount of the metal catalyst used is based on the amount of the raw material (IV).
0.00001 to 1 mole, preferably 0.0
It is 01 to 0.3 times mol. The amount of the boron compound (III) to be used depends on the amount of the raw material (I
0.5 to 5 moles, preferably 1 to 2 moles, relative to V)
Is a mole. The reaction temperature depends on the starting compound, the reagent, and the metal catalyst.
Or it varies depending on the solvent or the like, but is usually 0 ° C to 180 ° C.
° C, preferably 50 ° C to 150 ° C. The reaction time depends on the starting compound, the reaction temperature,
It varies depending on the drug, metal catalyst, solvent, etc.
Hours to 48 hours, preferably 2 hours to 24:00
Between. After completion of the reaction, the target compound (V) of this reaction is
For example, concentrate the reaction mixture and add water such as ethyl acetate.
Add immiscible organic solvent, wash with water, contain target compound
The organic phase is separated, dried over anhydrous magnesium sulfate, etc.
It is obtained by distilling off the agent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step A3) The step A3 is a compound obtained in the step A2.
Deprotecting the compound (V) to produce the compound (I).
You. In this step, the carboxy group of compound (V)
Removing the protecting group; and R^5aThe protecting group contained in
This is done by removing. The reaction for removing the protecting group of the carboxy group is as follows:
Known methods (eg, “ProtectiveGroups in Organic
Synthesis ”(Theodora W. Greene, Peter G. M. Wuts
Author, 1999, A Wiley-Interscience Publication)
Etc.). Low protecting group
When it is a lower alkyl group, for example, under acidic conditions
Using hydrochloric acid, sulfuric acid or p-toluenesulfonic acid,
Water or water and an organic solvent (preferably methanol or ethanol
Alcohols such as knol; tetrahydrofuran or geo
In a mixed solvent with ethers such as xane;
In the case of basic conditions, lithium hydroxide, water
Using sodium oxide or potassium hydroxide in water or
Water and organic solvent (preferably methanol or ethanol
Alcohols, or tetrahydrofuran or dioxo
And an ether such as sun. R^5a
As a method for removing the protecting group contained in the compound, a known method (eg,
For example, “ProtectiveGroups in Organic Synthesis” (T
heodora W. Greene, by Peter G. M. Wuts, 1999, A Wi
ley-Interscience Publication))
With reference to, for example, an acid (preferably hydrochloric acid or
Method using chloroacetic acid, a base (preferably,
Using potassium, sodium hydroxide or potassium hydroxide)
Method, hydrogen reduction method, etc., as appropriate.
You. It should be noted that the reaction for removing the protecting group of the carboxy group
Response and R^5aThe order of the reaction for removing the protecting group contained in
The reaction may be performed first, and the reaction conditions must be appropriately selected.
And the reaction to remove the protecting group of the carboxy group and R^5a
Removal reaction of the protecting group contained in
You. In the compound (I), R^FiveGrade 1 or 2 inside
Compounds containing a secondary amino group or a hydroxy group
And an alkyl group on the nitrogen atom and / or the oxygen atom
Can be introduced. The alkylation reaction is a known reaction.
Methods, for example, using formaldehyde / formic acid,
Easy by appropriately adopting a method using alkyl halide
Can be done. Also, this alkylation is an ester
It may be performed before hydrolysis of the group. The target compound of each reaction described above can be prepared by a conventional method.
Is taken from the reaction mixture according to For example, insoluble matter
If is present, after appropriate filtration, the solvent is distilled off under reduced pressure.
Or by distilling off the solvent under reduced pressure to remove the residue.
Add water and extract with a water-immiscible organic solvent such as ethyl acetate
And, if necessary, after drying over anhydrous sodium sulfate or the like,
It can be obtained by removing the solvent, and
If so, use standard methods, such as recrystallization, column chromatography
Further purification can be carried out by using a gel. Compound (I) is an optically heterogeneous compound based on asymmetric carbon.
Isomer (including diastereomer) or ring structure, unsaturated carbon
There may be geometric isomers based on primes,
In some cases, the raw materials separated by optical resolution or geometric isomers
By using a compound, the desired optical properties of
Only isomers or geometric isomers can be obtained. Also,
At appropriate stages of the manufacturing process, racemic or geometric
The body mixture is subjected to conventional optical resolution or separation methods (eg,
Crystallization, resolution with diastereomeric salts, optical resolution
Column chromatography using a column)
Thus, it is also possible to obtain each isomer. Compound (I) can be prepared according to a conventional method.
Or a pharmacologically acceptable salt by treating with a base.
Can be converted to For example, an inert solvent (preferably
Is an ether, tetrahydrofuran or dioxane, etc.
Ethers: methanol, ethanol, propanol,
Alcohols such as isopropanol or butanol, or
Is a halogenated carbon such as methylene chloride or chloroform.
Hydrogen)) and react with the desired acid or base, and evaporate the solvent
Or by filtering the precipitated crystals
Thereby, the desired salt can be obtained. Also,
The salt can be separated directly from the reaction mixture in the final reaction step.
You can also. The starting compound (IV) in Method A was obtained from WO96
No. 39407, WO0129035, US5693813
It can be manufactured according to the method described in
Can be. [0114] Embedded image In the method B, R¹, R^Two, R^Three, R^Four, R⁸, X is
Represents the same meaning as above,⁹Is C₁-C₆An alkyl group, or
C_Three-C₇Represents a cycloalkyl group. Hereinafter, each step of the method B will be described in detail.
I do. (Step B1) In step B1, compound (VI) is treated with R^TwoLead the group
To produce compound (VII). In this step, compound (VI) is dissolved in an inert solvent
After treatment with a lithiating agent to derive a lithio compound, C₁
-C_Four1 or 2 or more alkyl halides or halogen atoms
Replaced C₁-C₆Reacting an alkyl halide to form R
^TwoIs C₁-C₆1 or 2 or more alkyl or halogen atoms
Replaced C₁-C₆Compound (VII) which is an alkyl group
To obtain a lithio compound and a halogenating agent (Method B1a)
Respond, R^TwoIs a halogen atom, to obtain a compound (VII)
(Method B1b) or the reaction of a lithio compound with a formylating agent
Let R^TwoIs a formyl group to obtain a compound (VII)
R, which converts a formyl group to a nitrile^TwoIs Nitori
To obtain a compound (VII) which is a benzyl group (Method B1c)
The compound is reacted with a borate ester,
Reacting with an oxidizing agent in the presence of R^TwoIs a hydroxy group
Compound (VII) is obtained (Method B1d) or Method B1d
R obtained by^TwoIs a hydroxy group (VI
I) and C₁-C₆An alkyl halide or halogen atom
Is C substituted with 2 or more₁-C₆Reacted alkyl halide
Let's R^TwoIs C₁-C₆1 with an alkoxy group or a halogen atom
Or two or more substituted C₁-C₆Compounds that are alkoxy groups
This is carried out by obtaining the product (VII) (Method B1e). (Method B1a) The lithiation reaction of compound (VI)
A1 above except that compound (VI) is used instead of (II)
The reaction is performed in the same manner as the method described in the step A1a.
The second-stage reaction is performed by adding 1 to 10 to the obtained lithiation reaction solution.
Times mole (preferably 1 to 5 times mole) of C₁-C₆Archi
Luhalide (preferably C₁-C₆Alkyl bromide or
C ₁-C₆Alkyl iodide) or 1 or
C substituted by 2 or more₁-C₆Alkyl halide (preferably
Is C 1 or 2 or more substituted with a halogen atom₁-C₆A
1 or 2 or more substituted with alkyl bromide or halogen atom
Replaced C₁-C₆Alkyl iodide)
The reaction conditions and the like are described in, for example, J. Org.56,
 The procedure is performed with reference to the conditions described in 4793 (1991). (Method B1b) As the halogenating agent used, for example,
For example, N-chlorosuccinimide, N-bromosuccinimide
Mid, cyanogen bromide, 1,2-dibromoethane, chlorine, odor
And iodine, etc., and preferably, bromide
, 1,2-dibromoethane, N-chlorosuccinimi
Or N-bromosuccinimide. Halogenated
Reaction conditions include, for example, J. Org.55, 1311 (199
0) J.Organomet.Chem.,325, 13 (1987).
It is done with consideration. (Method B1c) As the formylating agent used, for example,
For example, N, N-dimethylformamide, N-formylpyrro
Lysine or N-formylpiperidine may be mentioned.
Preferably, N, N-dimethylformamide or N-
Formylpyrrolidine. Formylation reaction conditions
For example, Synthesis,Ten, 803 (1988), Helv. Chi
m.Acta.,68, 584, 1985 etc.
Done. (Method B1c) Reaction for converting formyl group to nitrile group
Can be prepared by known methods (eg, Synthesis,Four, 586 (1999), Te
trahedron Letter,39, 4047 (1998), Experimental Chemistry Course No. 4
Method described in 20th edition, page 451, etc.)
First, R^Two(VII) wherein is a formyl group and a hydr
Roxylamine (preferably hydroxylamine hydrochloride
Salt) to induce aldoxime, followed by dehydration
Agents (eg, acid anhydrides such as acetic anhydride or phthalic anhydride;
Phosphorus chloride such as phosphorus oxychloride or phosphorus pentachloride, or
N, N-carbonyldiimidazole or N, N-dicyc
Rohexyl carbodiimide, etc., preferably, anhydrous vinegar.
(Which is an acid). (Method B1d) Lithium compound of compound (VI) and boric acid ester
The reaction leading to the boron compound by reacting the ter
A1 above except that compound (VI) is used instead of (II)
The reaction is performed in the same manner as the method described in the step A1a.
The resulting boron compound is then oxidized in the presence of a base.
React with the agent^TwoIs a hydroxy group (VII)
Led to. After the reaction, the boron compound is extracted, crystallized,
It is isolated and purified according to a conventional method such as column purification.
After extraction from the mixture, the crude product obtained by evaporating the solvent, or
Alternatively, the reaction mixture can be used as is for the next oxidation.
Wear. Solvents used in the reaction include those that inhibit the reaction.
If it does not harm and dissolves the raw material to some extent,
But not limited to, for example, water; methanol, ethanol,
Alcohol such as propanol, isopropanol, butanol
Coals; 1,2-dimethyokeethane, diethyl ether
, Diisopropyl ether, tetrahydrofuran,
Ethers such as nisole, diglyme or dioxane,
Or a mixed solvent thereof, and the like.
Is water or ethers, particularly preferably water, tet
Lahydrofuran or dioxane. Examples of the base used include, for example,
Titanium, sodium bicarbonate, sodium carbonate, carbonated water
Alkali metal carbonates such as potassium potassium or potassium carbonate,
Or lithium hydroxide, sodium hydroxide or potassium hydroxide
And alkali metal hydroxides such as lium.
Preferably, it is an alkali metal hydroxide, particularly preferably
Is sodium hydroxide. The amount of the base used is usually based on the amount of the raw material (VI).
1 to 10 moles, preferably 2 to 3 moles
It is. The oxidizing agent used is, for example, peracid
Hydrogen chloride, peracetic acid or t-butyl hydroperoxide, etc.
Of peroxide or triethylamine N-oxide, etc.
N-oxides and the like can be mentioned.
Hydrogen. The reaction temperature depends on the starting compound, solvent and the like.
Is usually 0 ° C. to 100 ° C., preferably
Is from 20 ° C. to 50 ° C. The reaction time depends on the starting compound, the reaction temperature or the solution temperature.
Depends on the medium, etc., usually 30 minutes to 72 hours
And preferably for 1 to 24 hours. (B1e method) R obtained by B1d method^TwoIs hydroxy
Compounds (VII) and C₁-C₆Alkyl halide
(Preferably C₁-C₆Alkyl bromide or C₁-C₆A
Substituted by 1 or 2 or more with alkyl iodide) or a halogen atom
Done C₁-C₆Alkyl halide (preferably halogen
C substituted by one or more atoms₁-C_FourAlkyl bromine
Or C substituted by 1 or 2 or more halogen atoms₁−
C_FourReaction with an alkyl iodide) in an inert solvent
It is performed in the presence of a group. The solvent used for the reaction is one that inhibits the reaction.
If it does not harm and dissolves the raw material to some extent,
But not limited to, for example, water; methanol, eta
Knol, propanol, isopropanol or butanol
Alcohols such as benzene, toluene, xylene or
Is an aromatic hydrocarbon such as mesitylene; pentane, hexa
Aliphatic hydrocarbons such as butane or cyclohexane; methyl chloride
Benzene, chloroform or 1,2-dichloroethane
Hydrogenated hydrocarbons; 1,2-dimethoxyethane, diethyl
Ether, diisopropyl ether, tetrahydrof
An agent such as orchid, anisole, diglyme or dioxane
Esters; esters such as ethyl acetate or butyl acetate;
Nitriles such as setonitrile or propionitrile:
N, N-dimethylformamide, N, N-dimethylacetate
Toamide, N-methyl-2-pyrrolidone or hexamethyi
Amides such as diphosphorylamide; dimethyl sulfoxy
Sulfoxides such as chlorides, or mixed solvents thereof.
Preferably alcohols, ethers or
Amides, particularly preferably tetrahydrofuran,
Dioxane or N, N-dimethylformamide. Examples of the base used include, for example,
Titanium, sodium bicarbonate, sodium carbonate, carbonated water
Alkali metal carbonates such as potassium potassium or potassium carbonate;
Sodium methoxide, sodium ethoxide or potassium
Alkali metal alkoxides such as um t-butoxide;
Lithium hydride, sodium hydride or potassium hydride
Such as alkali metal hydride, or triethylamine,
Tributylamine or diisopropylethylamine
Examples thereof include amines and the like.
It is a carbonate, particularly preferably sodium carbonate.
The amount of the base to be used is generally 1 to 10 based on the raw material (VI).
The molar amount is 2 times, preferably 2 to 3 times. The reaction temperature depends on the starting compound, base or solvent.
Is usually 0 ° C. to 150 ° C.,
Preferably, it is between 20 ° C and 100 ° C. The reaction time depends on the starting compound, reaction temperature, base
Or, it varies depending on the solvent and the like, but usually 30 minutes to 7 minutes
2 hours, preferably 1 hour to 24 hours. After completion of the reaction, the desired compound (VII)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound may be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step B2) Step B2 is a step in the presence of a strong base in an inert solvent.
(VII) and compound (V) obtained in the step B1 in the presence of
III) to produce compound (IX)
This is the step of doing. The solvent used in the reaction is one that inhibits the reaction.
If it does not harm and dissolves the raw material to some extent,
Not limited to, for example, benzene, toluene or xylene
Aromatic hydrocarbons such as methane and mesitylene; pentane, hexene
Aliphatic hydrocarbons such as sun or cyclohexane; 1,2
-Dimethokiethane, diethyl ether, diisopropyl
Ether, tetrahydrofuran, anisole, digly
Or ethers such as dioxane; N-methyl-2-pi
Amides such as lolidone or hexamethylphosphorylamide
Sulphoxides such as dimethylsulphoxide, or
These mixed solvents and the like can be mentioned.
Ters or amides, particularly preferably
Lofran, dioxane or hexamethylphosphorylamido
Is. The strong base used is, for example,
Lithium, s-butyllithium or t-butyllithium
Alkyl lithiums such as phenyllithium
Lithium; lithium diisopropylamide or lithium
Lithium ion such as titanium bis (trimethylsilyl) amide
Amides; alkali metal alkoxides such as potassium t-butoxide
Coxides, or lithium hydride, sodium hydride
Or an alkali metal hydride such as potassium hydride
And preferably lithium diisopropylamide
Or lithium bis (trimethylsilyl) amide. The amount of compound (VIII) used is usually
It is 1 to 5 moles compared to (VII), preferably 1.
The amount of the strong base used, which is 5 to 3 moles, is usually
It is 1 to 3 moles compared to (VIII), and preferably 1 mole.
To 1.5 times mol. The reaction temperature depends on the starting compound, strong base or solvent.
It usually varies between -70 ° C and 50 ° C.
Preferably, it is -70 ° C to 0 ° C. The reaction time is based on the starting compound, reaction temperature, strong salt
It varies depending on the group or solvent, etc., but usually from 30 minutes to
48 hours, preferably 1 to 24 hours
You. After completion of the reaction, the target compound (IX) of this reaction was
For example, concentrate the reaction mixture and add water such as ethyl acetate.
Add immiscible organic solvent, wash with water, contain target compound
The organic phase is separated, dried over anhydrous magnesium sulfate, etc.
It is obtained by distilling off the agent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step B3) Step B3 is a step contained in compound (IX).
This is a step of converting a tolyl group to a formyl group. In this step, compound (IX) is dissolved in an inert solvent,
Compound (X) directly obtained by treatment with a reducing agent (Method B3a)
Or, first, the nitrile group contained in the compound (IX)
To an ester group and then reducing the ester group
Is converted to a hydroxymethyl group, and the hydroxymethyl group is further converted to a hydroxymethyl group.
Oxidation gives compound (X) (B3b
Method). (Method B3a) The solvent used in the reaction
If it does not harm and dissolves the raw material to some extent,
Not limited to, for example, for example, benzene, toluene,
Aromatic hydrocarbons such as xylene or mesitylene; penta
Aliphatic hydrocarbons such as hexane, hexane or cyclohexane
And 1,2-dimethoxyethane, diethyl ether, dii
Sopropyl ether, tetrahydrofuran, aniso
Ethers such as dimethyl, diglyme or dioxane, or
Examples thereof include a mixed solvent thereof.
Ene, hexane or tetrahydrofuran. As the reducing agent, for example, lithium hydride
Aluminum or diisobutylaluminum hydride
And preferably, diisobutylaluminum hydride.
Nium. The amount of the reducing agent used is usually based on the amount of the raw material (IX).
1 to 3 times, preferably 1 to 1.5 times
Is a mole. The reaction temperature depends on the starting compound or the solvent.
Is usually -70 ° C to 50 ° C, and is preferably
Is from -70 ° C to 0 ° C. The reaction time depends on the starting compound, the reaction temperature or the solution temperature.
Depends on the medium, etc., usually 10 minutes to 24 hours
And preferably for 30 minutes to 12 hours. (Method B3b) The conversion of a nitrile group to an ester group is carried out
Known methods, for example, alcohols (preferably methanol
, Ethanol, propanol, isopropanol or
Butanol) in a solvent, acid (preferably hydrochloric acid or sulfuric acid)
This is easily performed by processing in Reduction of ester group to hydroxymethyl group
Is a known method, for example, using the B3a method as a reducing agent
Reducing agent, lithium borohydride or borohydride described in
Sodium hydrogen (preferably, lithium aluminum hydride
Or diisobutylaluminum hydride)
This can be easily performed. Oxidation of hydroxymethyl group to formyl group
Is a known method, for example, manganese dioxide
Chromic anhydride, pyridinium chlorochromate,
Pyridinium romate, dimethyl sulfoxide / anhydride
(Eg, acetic anhydride or trifluoroacetic anhydride), or
Is a dimethyl sulfoxide / acid chloride (eg,
Cetyl or oxalyl chloride) (preferably, dimethyls
Rufoxide / acid chloride)
It is. After completion of the reaction, the target compound (X) of this reaction is
For example, concentrate the reaction mixture and add water such as ethyl acetate.
Add immiscible organic solvent, wash with water, contain target compound
The organic phase is separated, dried over anhydrous magnesium sulfate, etc.
It is obtained by distilling off the agent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step B4) Step B4 is another step of producing compound (X).
Known method, for example, US Pat.
The compound (VII) and the compound (XI) were
The reaction is carried out in the presence of This step was carried out in place of compound (VIII).
Except that the product (XI) was used.
Be done. (Step B5) The step B5 is a step B3 or a step B4.
Compound (X) obtained by the above-mentioned method,
Is a compound (XII) easily obtained from a known compound
Is reacted in an inert solvent to give compound (IV).
This is the manufacturing process. Solvents used in the reaction include those that inhibit the reaction.
If it does not harm and dissolves the raw material to some extent,
Not limited to, for example, benzene, toluene, xylene
Or aromatic hydrocarbons such as mesitylene; pentane, hexene
Aliphatic hydrocarbons such as sun or cyclohexane; 1,2
-Dimethokiethane, diethyl ether, diisopropyl
Ether, tetrahydrofuran, anisole, digly
Ethers such as methanol or dioxane; methanol, ethanol
, Propanol, isopropanol or butanol
Alcohols such as N; N-dimethylformamide;
N, N-dimethylacetamide, N-methyl-2-pyro
Amides such as lidone or hexamethylphosphorylamide
Sulphoxides such as dimethylsulphoxide, or
These solvents and the like can be mentioned.
Group hydrocarbons, alcohols or amides, especially
Preferably, it is xylene, ethanol or butanol.
You. The reaction temperature depends on the starting compound, solvent and the like.
Is usually 20 ° C. to 200 ° C.
Is 50 ° C. to 150 ° C. The reaction time depends on the starting compound, the reaction temperature or the solution temperature.
Varies depending on the medium, but usually 10 minutes to 48 hours
And preferably for 30 minutes to 24 hours. What
For the purpose of accelerating the reaction, piperidine / acetate, pyro
Additives such as lysine / acetate or morpholine / acetate
Where appropriate, piperidine / acetate may be added.
The intermediate produced in the reaction was once separated,
A cyclization reaction of the body can also be performed.
m.,39, 3070 (1996). After completion of the reaction, the target compound (IV) of this reaction was
For example, concentrate the reaction mixture and add water such as ethyl acetate.
Add immiscible organic solvent, wash with water, contain target compound
The organic phase is separated, dried over anhydrous magnesium sulfate, etc.
It is obtained by distilling off the agent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. The starting compound (II) in Method A was prepared according to WO99
No. 07682, WO9921849, WO0132665
Etc. or according to the methods C to G described below.
Can be manufactured. [0153] Embedded imageIn methods C to G, A, R^6COr R^6c,
X and Y are as defined above, and p and q are the same or different
And represents an integer of 1 to 3;⁷α¹Or R⁷α^Three, R⁷
β and R⁷β¹Or R⁷β^ThreeAre the same or different,
R^7aOr R^7d, Or R^7aOr R^7dAny of
Hydroxy or amino groups on the
R protected by a protecting group^7aOr R^7dRepresents any of R^Ten,
R^10aAnd R^10bAre the same or different and each represents a hydrogen atom, C₁−
C_FourSubstituted with one or more alkyl groups or halogen atoms
C₁-C_FourRepresents a protecting group for an alkyl group or an amino group;
¹¹Is C₁-C_FourY represents an alkyl group^aIs the same as Y
Group of C or C₁-C_FourRepresents an alkoxycarbonyl group. R⁷α¹Or R⁷α^Three, R⁷β, R⁷β¹Or R⁷
β^Three, And R^TenA protecting group for a hydroxy group and a
The protecting group for the amino group has the same meaning as described above. R^Ten1 or 2 or more halogen atoms
Replaced C₁-C_FourThe alkyl group has the same meaning as described above.
You. Hereinafter, each of the steps C to G will be described in detail.
I will explain. (Method C) (Step C1) The step C1 is a known method or a known method.
Compound (XIII) and Compound (XI) easily obtained according to
V) or compound (XV) in the presence of an acid to form a compound
This is a step of producing the product (IIa). The solvent used is one that inhibits the reaction.
If the raw material can be dissolved to some extent,
Not specified, for example, benzene, toluene, xylene or
Aromatic hydrocarbons such as mesitylene; pentane, hexane
Or aliphatic hydrocarbons such as cyclohexane; N, N-di
Methylformamide, N, N-dimethylacetamide,
N-methyl-2-pyrrolidone or hexamethyl phosphoryl
Amides such as luamide; methylene chloride, chloroform,
Halogenation of carbon tetrachloride or 1,2-dichloroethane
Preferred are hydrocarbons and carbon disulfide.
Suitably, N, N-dimethylformamide, methylene chloride
Or chloroform. Examples of the acid used include hydrochloric acid and odor.
Mineral acids such as hydrofluoric acid, sulfuric acid or phosphoric acid, or aluminum chloride
Louis such as titanium, titanium tetrachloride, zinc chloride or tin chloride
And hydrochloric acid or sulfuric acid.
You. The amount of the acid used is usually the same as that of the compound (XII
1 to 10 times mol (preferably 1 to 3 times) relative to I)
Mol) is used, but when a mineral acid is used, the solvent and
A large excess can also be used. The reaction temperature depends on the starting compound, reagent, solvent, etc.
It usually varies between -10 ° C and 150 ° C.
Preferably, it is 20 ° C to 110 ° C. The reaction time depends on the starting compound, reaction temperature, reagent
Or, it changes depending on the solvent and the like, but usually from 5 minutes
Time, preferably 10 minutes to 12 hours. After completion of the reaction, the desired compound (IIa)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Method D) (Step D1) The step D1 is a known method or a known method.
Compound (XIII), which can be obtained easily according to
Under ambient atmosphere (for example, argon gas, nitrogen gas or helium
Gas), derived to lithio compounds using lithiating agents
Then, by reacting with the compound (XIV), the compound (XV
This is the step of manufacturing I). The solvents and lithiation agents used are as described above.
The same as (A1a method) is used.
The reaction, the reaction time, etc. are performed under the same conditions. Compound (XI
The amount of V) to be used is generally based on the compound (XIII).
1 to 3 moles, preferably 1 to 1.5 moles
It is. The reaction temperature depends on the starting compound, reagent, solvent, etc.
It usually varies between -100 ° C and 0 ° C.
Preferably, it is -70 ° C to 0 ° C. The reaction time is based on the starting material, reaction temperature, reagent
Or, it changes depending on the solvent or the like, but usually from 5 minutes
Time, preferably 10 minutes to 5 hours. Note that R⁷Compounds in which β is a hydrogen atom (XV
As an alternative to the preparation of I)
Carbon dioxide, alkoxycarbonylating agent or formylating agent
To react with a carboxyl group and an alkoxy group, respectively.
After introducing a carbonyl or formyl group, these groups
Can also be reduced to a hydroxymethyl group,⁷
It is possible to produce compound (XVI) where β is a hydrogen atom.
Wear. In this case, the lithio compound and carbon dioxide gas,
Coxycarbonylating agent (eg, methyl chlorocarbonate or
Chloroformates such as ethyl chlorocarbonate, or charcoal
Carbonic acid esters such as dimethyl acid or diethyl carbonate
Preferably, ethyl chlorocarbonate or diethyl carbonate.
You. ) Or a formylating agent (eg, N, N-dim
Tylformamide, N-formylpyrrolidine or N-
And N, N-dimethyl.
Ruformamide or N-formylpyrrolidine. )
Reacts with carbon dioxide gas,
Using a oxycarbonylating agent or a formylating agent,
Can be performed in the same manner as described above. Further, a carboxyl group, an alkoxycarbo
Reduction of Nyl or Formyl to Hydroxymethyl
Are known methods, for example, lithium borohydride, hydrogen
Sodium borohydride, lithium aluminum hydride or
Diisobutylaluminum hydride or the like (preferably hydrogenated
Lithium borohydride, sodium borohydride or lithium hydride
Titanium aluminum. Easily done using
You. After completion of the reaction, the desired compound (XVI)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step D2) The step D2 is a compound obtained in the step D1.
(XVI) with halogenating or sulfonylating agent
To convert the hydroxy group of compound (XVI) to a halogen atom
Or after converting to a sulfonyloxy group, treating with a base
This is the step of producing compound (IIa). The solvent used is one that inhibits the reaction.
If the raw material can be dissolved to some extent,
Not specified, for example, 1,2-dimethoxyethane, diethyl
Ether, diisopropyl ether, tetrahydrof
An agent such as orchid, anisole, diglyme or dioxane
Ters: methylene chloride, chloroform, carbon tetrachloride or
Halogenated hydrocarbons such as 1,2-dichloroethane;
Nitriles such as setonitrile or propionitrile:
N, N-dimethylformamide, N, N-dimethylacetate
Toamide, N-methyl-2-pyrrolidone or hexamethyi
Amides such as phosphorylamide, or dimethylsulfur
Sulfoxides such as foxides can be mentioned, and preferably
Are ethers, halogenated hydrocarbons or amides
Yes, particularly preferably, tetrahydrofuran, methylene chloride
Or N, N-dimethylformamide. As the halogenating agent, for example, thiochloride
Nil, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, oxy
Phosphorus chloride or phosphorus oxybromide can be mentioned.
Is thionyl chloride; examples of sulfonylating agents include
For example, methanesulfonyl chloride, trifluoromethane chloride
Sulfonyl, trifluoromethanesulfonic anhydride, chloride
Benzenesulfonyl or paratoluenesulfonyl chloride
And preferably methanesulfonyl chloride or
Trifluoromethanesulfonyl chloride. Examples of the base include lithium carbonate and charcoal.
Sodium hydrogen oxy, sodium carbonate, potassium hydrogen carbonate
Or alkali metal carbonates such as potassium carbonate; triethyl
Amine, tributylamine, diisopropylethylamine
, Pyridine or 1,8-diazabicyclo [5,4,0]
Amines such as -7-undecene; sodium methoxy
, Sodium ethoxide, sodium t-butoxide
Or alkali metal alkoxy such as potassium t-butoxide
Sids, or lithium hydride, sodium hydride or
Alkali metal hydrides such as potassium hydride
And preferably sodium t-butoxide or potassium
Tert-butoxide. The amount of the base to be used is generally different from that of compound (XVI).
1 to 10 moles, preferably 1 to 3 moles
Is a mole. The reaction temperature depends on the starting compound, reagent, solvent, etc.
It usually varies between -20 ° C and 80 ° C.
Preferably, the temperature is −0 ° C. to 25 ° C. The reaction time is based on the starting compound, reaction temperature, reagent
Or, it changes depending on the solvent or the like, but usually from 5 minutes
Time, preferably 10 minutes to 5 hours. After completion of the reaction, the desired compound (IIa)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Method E) (Step E1) The step E1 is a known step or a known method.
(XIII) and compound (XVI) easily obtained according to
I) or its reactive derivative (eg, acid halide, acid
An anhydride or an active ester) to react with the compound (XV
III). This step includes a known method,
For example, a method using a condensing agent, or a compound (XVII)
Reactive derivatives of carboxyl groups of
, Acid anhydrides or active esters).
The selection is performed as appropriate. The solvent used is preferably benzene
Aromatic hydrocarbons such as zen, toluene or xylene
And methylene chloride, chloroform, carbon tetrachloride, di
Of chloroethane, chlorobenzene or dichlorobenzene
Such halogenated hydrocarbons; ethyl formate, ethyl acetate
Propyl acetate, butyl acetate or diethyl carbonate
Esters: diethyl ether, diisopropyl ether
Ter, tetrahydrofuran, dioxane, dimethoxye
Like tan or diethylene glycol dimethyl ether
Ethers: acetone, methyl ethyl ketone, methyl
Isobutyl ketone, isophorone or cyclohexanone
Ketones such as nitroethane or nitrobenzene
Nitro compounds such as acetonitrile or isobutyroni
Nitriles such as tolyl; formamide, N, N-di
Methylformamide, dimethylacetamide or hexa
Amides such as methyl phosphorotriamide; dimethyl
Sulfoxides such as sulfoxide or sulfolane;
Trimethylamine, triethylamine or N-methylamine
Aliphatic tertiary amines such as ruphorin, or pyridine or
Aromatic amines such as picoline, and more preferably
Means halogenated hydrocarbons (especially methylene chloride) or
Is an aromatic amine, especially pyridine. The base used in the present method is, for example, carbonic acid
Lithium, sodium carbonate or potassium carbonate
Lucali metal carbonates; lithium bicarbonate, sodium bicarbonate
Alkali metal bicarbons such as lithium or potassium bicarbonate
Acid salts; lithium hydride, sodium hydride or hydride
Alkali metal hydrides such as potassium; lithium hydroxide
Aluminum, sodium hydroxide or potassium hydroxide.
Lucali metal hydroxides; lithium methoxide, sodium
Mumethoxide, sodium ethoxide or potassium t-
Alkali metal alkoxides such as butoxide, or
Is triethylamine, tributylamine, diisopro
Pyrethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-di
Methylaniline, N, N-diethylaniline, 1,5-
Diazabicyclo [4.3.0] non-5-ene, 1,4
-Diazabicyclo [2.2.2] octane (DABC
O) or 1,8-diazabicyclo [5.4.0] -7-
Organic amines such as undecene (DBU)
Suitably, organic amines (particularly preferably triethylamido
). If a condensing agent is used, the condensation used
As the agent, for example, N, N'-dicyclohexylcal
Bodiimide, 1-ethyl-3- (3-dimethylaminop
Ropyl) carbodiimide hydrochloride, N, N'-carbodiimid
Dazole, diphenyl phosphate azide, cyanophosphate die
Benzotriazole-1 butyl or hexafluorophosphate
-Yloxy-tris- (dimethylamino) phosphonium
And the like, and preferably 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride or
N, N'-carbodiimidazole. The reaction temperature depends on the starting compound used,
Agent, catalyst, carboxylic acid or carboxylic acid chloride
Different, but usually between 0 ° C. and 150 ° C., preferably
20 to 100 ° C. The reaction time depends on the starting compound used,
Agent, catalyst, carboxylic acid, carboxylic acid chloride, acid anhydride
Depending on the product or the reaction temperature, it is usually 10 minutes to 1
2 hours, preferably 30 minutes to 3 hours. After completion of the reaction, the desired compound (XVIII)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (Step E2) The step E2 is a compound obtained in the step E1.
The product (XVIII) is reacted with a dehydrating agent,
Compound (IIa) is obtained by reacting the product with a reducing agent.
This is the step of manufacturing. The solvent used may inhibit the reaction.
If the raw material can be dissolved to some extent,
Not specified, for example, benzene, toluene, xylene or
Aromatic hydrocarbons such as mesitylene; pentane, hexane
Or aliphatic hydrocarbons such as cyclohexane; methyl chloride
, Chloroform, carbon tetrachloride or 1,2-dichloroe
Halogenated hydrocarbons such as tan or acetonitrile
Or nitriles such as propionitrile
Preferably, aromatic hydrocarbons or halogenated hydrocarbons
And particularly preferably toluene. As a dehydrating agent, for example, oxychloride
, Phosphorus pentachloride or polyphosphoric acid.
Suitably, it is phosphorus oxychloride. The amount of the dehydrating agent to be used is generally the same as that of compound (XIII)
1 to 10 times mol (preferably 2 to 5 times mol)
Is used, but when the dehydrating agent is a liquid,
A large excess can also be used. The reaction temperature depends on the starting compound, reagent, solvent, etc.
It usually varies between 20 ° C and 180 ° C
Preferably, it is 50 ° C to 150 ° C. The reaction time is based on the starting compound, reaction temperature, reagent
Or, it varies depending on the solvent, etc.
It is 2 hours, preferably 1 hour to 5 hours. Up
Used in the reaction of the product obtained in
The solvent used does not hinder the reaction,
It is not particularly limited as long as it is soluble to a certain degree.
Aromatics such as benzene, toluene, xylene or mesitylene
Hydrocarbons; 1,2-dimethoxyethane, diethyl ate
Ter, diisopropyl ether, tetrahydrofuran,
Ethers such as anisole, diglyme or dioxane
Class: methylene chloride, chloroform, carbon tetrachloride or 1,
Halogenated hydrocarbons such as 2-dichloroethane; aceto
Nitriles such as nitrile or propionitrile; methano
, Ethanol, propanol, isopropanol or
Are alcohols such as butanol, or N, N-dimethyl
Ruformamide, N, N-dimethylacetamide, N-
Methyl-2-pyrrolidone or hexamethylphosphoryla
And amides such as amides.
Coals or ethers, particularly preferably methanoic acid.
Or ethanol. As the reducing agent, for example, borohydride
Titanium or sodium borohydride may be mentioned.
And preferably sodium borohydride. The amount of the reducing agent to be used is generally the same as that of compound (XIII)
0.5 to 10 moles, preferably 0.1 to 10 moles.
(5 to 5 times mol). The reaction temperature depends on the starting compound, reagent, solvent, etc.
Is usually 0 ° C. to 150 ° C.,
Preferably, it is between 20 ° C and 100 ° C. The reaction time is based on the starting compound, reaction temperature, reagent
Or, it varies depending on the solvent, etc.
It is 2 hours, preferably 1 hour to 8 hours. After completion of the reaction, the desired compound (IIa)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound may be used in a conventional manner, if necessary.
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. (F method) (Step F1) The step F1 is a known method or a known method.
(XIX) and compound (XX) easily obtained according to
With the compound (II) in the presence of a base.
This is the step of manufacturing b). The solvent used is one that inhibits the reaction.
If the raw material can be dissolved to some extent,
Not specified, for example, benzene, toluene, xylene or
Aromatic hydrocarbons such as mesitylene; 1,2-dimethoxy
Ethane, diethyl ether, diisopropyl ether,
Tetrahydrofuran, anisole, diglyme or geo
Ethers such as xane, or N, N-dimethylform
Amide, N, N-dimethylacetamide, N-methyl-
2-pyrrolidone or hexamethylphosphorylamide
Amides and the like, and preferably, ethers or
Are amides, particularly preferably N, N-dimethylpho
Lumamide. Examples of the base include lithium carbonate and charcoal.
Sodium hydrogen oxy, sodium carbonate, potassium hydrogen carbonate
Or alkali metal carbonates such as potassium carbonate; triethyl
Amine, tributylamine, diisopropylethylamine
, Pyridine or 1,8-diazabicyclo [5,4,0]
Amines such as -7-undecene; sodium methoxy
, Sodium ethoxide or potassium t-butoxide
And alkali metal alkoxides, or lithium hydride
Alkali such as sodium hydride, potassium hydride
Metal hydrides can be mentioned, and preferably,
Lium or potassium hydride. The amount of the base to be used is generally the same as that of the compound (XI
II) 2 to 10 times mol (preferably 2 to 5 times)
Mol) is used, but when amines are used,
A large excess can be used also as a medium. The reaction temperature depends on the starting compound, reagent, solvent, etc.
It usually varies between -10 ° C and 150 ° C.
Preferably, it is -10 ° C to 60 ° C. The reaction time is based on the starting compound, reaction temperature, reagent
Or, it changes depending on the solvent, etc.
4 hours, preferably 1 hour to 12 hours. After the completion of the reaction, the target compound (IIb)
Is, for example, concentrating the reaction mixture, such as ethyl acetate
Add an organic solvent immiscible with water, wash with water, and remove the target compound.
Separate the organic phase containing and dry over anhydrous magnesium sulfate etc.
Thereafter, it is obtained by distilling off the solvent. The obtained compound can be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. In the above methods C to F, Y^aIs C
Compound (IIb) which is a 1-C4 alkoxycarbonyl group
Is a known method, for example, disclosed in Japanese Patent Laid-Open No.
According to the method described in the report, Y^aIs a hydrogen atom
It can be converted to compound (IIb). Further, compound (IIa) or compound (IIb)
Primary or secondary amino or hydroxy groups are present
In such a case, a known method (for example, “Protective Groups”
in Organic Synthesis ”(Theodora W. Greene, Peter
Written by G. M. Wuts, 1999, A Wiley-Interscience Publica
Introduce the desired protecting group according to the method described in
And a deprotection reaction can be performed. (G method) (Step G1) The step G1 is publicly known or performed by a known method.
The carbonyl group of the compound (XXI) easily obtained according to the
Converting the amino group to produce a compound (IIc).
You. In this step, compound (XXI) is converted to amine (R^10aR^10bN
H) to produce imine or iminium ions
To give compound (IIc) (reductive amination reaction
A) (Method G1a) or Compound (XXI)
(R^10aR^10bNHCHO) or ammonium formate
To give compound (IIc) via N-formyl derivative
(Leuckart-Wallach reaction) (G1b method)
Product (XXI) reduced alcohol or reduced alcohol
Halogen and alkyl easily derived from rucohol
A sulfonyloxy form or an arylsulfonyloxy form
Amine (R^10aR^10bNH) to give compound (IIc)
(G1c method). (Method G1a) The reductive amination reaction is carried out by a known method (eg,
For example, Organic Reactions, 4,174 (1948), Synthesis, 135 (1
975), Experimental Chemistry Course, 4th Edition, Volume 20, page 300, etc.)
The method is performed with reference to the solvent used as the reaction.
Does not hinder
If not specifically limited, for example, methanol, ethanol
Or alcohols such as propanol; benzene, tolue
Aromatic hydrocarbons such as xylene, xylene or mesitylene;
Aliphatic hydrocarbons such as hexane, hexane or cyclohexane
Elements: methylene chloride, chloroform or dichloroethane
Halogenated hydrocarbons such as 1,2-dimethoxyethane,
Diethyl ether, diisopropyl ether, tetrahi
Drofuran, anisole, diglyme or dioxane
Ethers; esters such as ethyl acetate or butyl acetate
: Nitriles such as acetonitrile: N, N-dimethyl
Formamide, N, N-dimethylacetamide, N-meth
Tyl-2-pyrrolidone or hexamethylphosphoramido
Amides such as sulfide; sulfoxy such as dimethyl sulfoxide
And mixed solvents thereof.
Suitably, they are alcohols or ethers. Used
Lithium aluminum hydride, hydrogen
Sodium borohydride, sodium cyanoborohydride,
Metallic water such as diisobutylaluminum hydride or borane
Species or metals such as sodium or zinc
And preferably sodium borohydride or hydrogen
Sodium cyanoborohydride. The reaction temperature depends on the starting compound, reagent, solvent, etc.
It usually varies between -10 ° C and 150 ° C.
Preferably, it is 20 ° C to 110 ° C. Reaction time
Varies depending on the starting compound, reagent, solvent, etc.,
Usually 1 hour to 48 hours, preferably 2 hours
It takes 24 hours. Alternatively, Raney Nickel, Para
The catalytic reduction method using a metal catalyst such as
Compound (IIc) can be produced from the isomer. (G1b method) The conditions for the Leuckart-Wallach reaction are public
Known methods (eg, Organic Reactions, 5,301 (1949),
Experimental Chemistry Course, 4th Edition, Volume 20, p. 302, etc.)
Performed for reference. (Method G1c) Alcohol derived from compound (XXI)
Body and amine (R^10aR^10bNH) to react with the compound (II
reaction to obtain c), and halogenation derived from alcohol
, Alkylsulfonyloxy or arylsulfonate
The honyloxy compound is converted to an amine (R^{Ten a}R^10bNH)
The reaction conditions for obtaining the compound (IIc) can be determined by known methods (for example,
Experimental Chemistry Course, 4th Edition, Volume 20, 284, 288 pages, etc.
Performed for reference. In addition, R^10aAnd R^10bSeparate if both are hydrogen
As a method, compound (XXI) is treated with hydroxyamine hydrochloride or
Reacts with alkoxyamine hydrochloride to form oxy
To give compound (IIc) (Method G1d)
Compound (XXI) is reduced to give an alcohol form, and then
Reaction with a diating agent to give the azide derivative, and finally reducing
Compound (IIc) is obtained (Method G1e) or compound (XXI) is
Reduced alcohol or reduced alcohol
Halogen, alkylsulfonylo easily derived from
Xyl or arylsulfonyloxy is phthalimide
Or reacting with a salt thereof to form an N-substituted phthalimide
After hydrolysis, or hydrazine or methylamine
To give compound (IIc) (Gabrie
l method) (G1f method). (Method G1d) The solution used in the oximation reaction
As a medium, it does not hinder the reaction and dissolves some starting materials
There is no particular limitation as long as it does, for example, water;
Alcohols such as ethanol, ethanol or propanol
Such as benzene, toluene or xylene mesitylene
Aromatic hydrocarbons; pentane, hexane or cyclohexa
Aliphatic hydrocarbons such as methylene chloride, chloroform
Or halogenated hydrocarbons such as dichloroethane; 1,2
-Dimethokiethane, diethyl ether, diisopropyl
Ether, tetrahydrofuran, anisole, digly
Or ethers such as dioxane; ethyl acetate or vinegar
Esters such as butyl acid; nitriles such as acetonitrile
Class: N, N-dimethylformamide, N, N-dimethyl
Acetamide, N-methyl-2-pyrrolidone or
Amides such as tyl phosphoryl amide; dimethyl sulfoxy
Sulfoxides such as sides, or a mixed solvent thereof.
Water or alcohols.
And particularly preferably ethanol. Hydroxyamido
Hydrochloride or alkoxyamine hydrochloride is used in the reaction system.
Neutralization is carried out using a group.
For example, lithium carbonate, sodium hydrogen carbonate, sodium carbonate
Alkaline such as ium, potassium bicarbonate or potassium carbonate
Limetal carbonates; sodium acetate or potassium acetate
Lucali metal acetate; lithium hydroxide, sodium hydroxide
Or alkali metal hydroxides such as potassium hydroxide;
Um methoxide, sodium ethoxide or potassium t
Alkali metal alkoxides such as butoxide; hydrogenation
Lithium, sodium hydride or potassium hydride
Lucali metal hydride, or triethylamine, trib
Amines such as tylamine or diisopropylethylamine
And preferably, alkali metal acetate or
Is an alkali metal hydroxide, particularly preferably sodium acetate.
Thorium or sodium hydroxide. The amount of the base to be used is usually 0.1 to the starting material.
1 to 2 moles, preferably 0.5 to 1.5 times
Is a mole. The reaction temperature may vary depending on the starting compound, reagent, solvent, etc.
It usually varies between -10 ° C and 150 ° C.
Preferably, it is 20 ° C to 110 ° C. The reaction time depends on the starting compound, reagent, solvent, etc.
It usually varies from 1 hour to 48 hours
And preferably for 2 to 24 hours. After the completion of the reaction, the oxime compound is, for example,
The mixture is concentrated and is immiscible with water such as ethyl acetate.
After adding organic solvent and washing with water, the organic phase containing the target compound is separated.
And dried over anhydrous magnesium sulfate etc., and then the solvent is distilled off.
And, if necessary, conventional methods, such as
Purified by silica gel, silica gel column chromatography, etc.
Can be manufactured. (Method G1d) Used in the reduction reaction of an oxime compound
Solvent that does not hinder the reaction
There is no particular limitation as long as it dissolves.
Alcohols such as ethanol, ethanol or propanol
Organic acids such as acetic acid or propionic acid; benzene, tol
Aromatic hydrocarbons such as ene, xylene or mesitylene;
Aliphatic hydrocarbons such as hexane or cyclohexane; salts
Halogenated hydrocarbons such as methylene chloride or chloroform
And the like; 1,2-dimethoxyethane, diethyl ether, tet
Lahydrofuran, anisole, diglyme or dioxa
Ethers such as ethyl acetate;
Teres; nitriles such as acetonitrile: N, N-dimer
Tylformamide, N, N-dimethylacetamide, N
-Methyl-2-pyrrolidone or hexamethylphosphoryl
Amides such as amides; sulfo such as dimethyl sulfoxide
Oxides or a mixed solvent thereof may be mentioned.
Preferably ethers, more preferably tet
Lahydrofuran or diglyme. As the reducing agent, lithium aluminum hydride
, Diisobutylaluminum hydride or borane
Metal hydrides; metals such as sodium or zinc
And preferably lithium aluminum hydride or
Boran. The amount of the reducing agent used is usually 1 to the raw material.
To 10 times mole, preferably 1 to 1.5 times mole
It is. The reaction temperature depends on the starting compound, solvent and the like.
Is usually 0 ° C. to 150 ° C., preferably
Is 50 ° C to 120 ° C. The reaction time depends on the starting compound, the solvent and the like.
It usually varies from 1 hour to 48 hours, preferably
2 hours to 12 hours. As an alternative, Raney nickel or acid
Oxygen can also be generated by catalytic reduction using a metal catalyst such as platinum
Compound (IIc) can be produced from the compound. (Method G1e) Reduction reaction of carbonyl group to hydroxy group
Is performed under the same conditions as in the reduction method in the step E2. Obtained
Used in the reaction between the alcohol
The solvent used does not hinder the reaction,
It is not particularly limited as long as it is soluble to a certain degree.
Alcohols such as tanol, ethanol or propanol
Such as benzene, toluene, xylene or mesitylene
Aromatic hydrocarbons; fats such as hexane or cyclohexane
Aliphatic hydrocarbons; such as methylene chloride or chloroform;
Hydrogenated hydrocarbons; 1,2-dimethoxyethane, diethyl
Ruether, tetrahydrofuran, anisole, jigula
Ethers such as im or dioxane; ethyl acetate or vinegar
Esters such as butyl acid; nitriles such as acetonitrile
Class: N, N-dimethylformamide, N, N-dimethyl
Acetamide, N-methyl-2-pyrrolidone or hexa
Amides such as methylphosphorylamide; dimethyl sulfo
Sulfoxides such as oxides, or a mixed solvent thereof
And preferably, toluene or tetrahydride.
Lofran. As the azidating agent, for example, lithiated azide
Metal or azide such as sodium or sodium azide;
Silicon azide compounds such as lucyrilazide or azide
Phosphoryl azide compounds such as diphenylphosphoryl
Diphenyl phosphoryl azide
It is. This reaction is carried out in the presence or absence of a base.
And the base is, for example, triethylamido.
, Tributylamine, diisopropylethylamine or
Is 1,8-diazabicyclo [4.3.0] -7-unde
Examples thereof include amines such as cene.
8-diazabicyclo [4.3.0] -7-undecene
is there. The amount of the azidating agent to be used is usually
1 to 3 times, preferably 1 to 1.5 times
It is. The amount of the base used is usually about 1
The molar amount is from 3 to 3 times, preferably from 1 to 1.5 times.
You. The reaction temperature depends on the starting compound, the solvent and the like.
Usually, the temperature is between -10 ° C and 150 ° C.
Suitably, it is between 0 ° C and 80 ° C. The reaction time depends on the starting compound, solvent and the like.
It usually varies from 1 hour to 48 hours, preferably
2 hours to 24 hours. After completion of the reaction, the azide compound is, for example, mixed with the reaction mixture.
Concentrate the mixture and use a water-immiscible organic such as ethyl acetate
After adding the solvent and washing with water, the organic phase containing the target compound is separated.
And dried over anhydrous magnesium sulfate etc., and then the solvent is distilled off.
It can be obtained by: The obtained compound may be used in a conventional manner,
For example, recrystallization, silica gel column chromatography, etc.
Can be further purified. In addition, instead of the above base, Mitsunobu reaction strip
(Eg, diethyl azodicarboxylate-triphenyl
(Phosphine) also produces azide form from alcohol form
be able to. As another method, alcoholic
Halide or sulfonic acid
After stellating, react with the above azidating agent in the presence of a base
Can produce azide form
You. (Method G1e) Used in the reduction reaction of azide form
As a solvent, it does not hinder the reaction and dissolves some starting materials.
There is no particular limitation as long as it is understood.
Alcohols such as alcohol, ethanol or propanol;
Organic acids such as acetic acid or propionic acid; benzene, tolue
Aromatic hydrocarbons such as ethylene, xylene or mesitylene;
Aliphatic hydrocarbons such as xane or cyclohexane; chloride
Halogenated hydrocarbons such as methylene or chloroform;
1,2-dimethoxyethane, diethyl ether, tetrahi
Drofuran, anisole, diglyme or dioxane
Ethers; esters such as ethyl acetate or butyl acetate
: Nitriles such as acetonitrile: N, N-dimethyl
Formamide, N, N-dimethylacetamide, N-meth
Tyl-2-pyrrolidone or hexamethylphosphoramido
Amides such as sulfide; sulfoxy such as dimethyl sulfoxide
Or a mixed solvent thereof.
Is tetrahydrofuran. As the reducing agent, for example, borohydride
Titanium, sodium borohydride, lithium hydride
Metals such as minium or diisobutylaluminum hydride
Hydrides, preferably lithium hydride
Aluminum. The amount of the reducing agent used is usually 1 to the raw material.
To 3 times mole, preferably 1 to 1.5 times mole.
is there. The reaction temperature depends on the starting compound, the solvent and the like.
Usually, the temperature is between -10 ° C and 150 ° C.
Suitably, it is between 0 ° C and 80 ° C. The reaction time depends on the
It varies depending on the substance or the solvent, etc.
24 hours, preferably 1 hour to 12 hours
You. Alternatively, a metal catalyst such as Pd-carbon was used.
Catalytic reduction method, reduction method using triphenylphosphine, etc.
However, compound (IIc) can be produced from azide form
You. (G1f method) The reaction conditions in the Gabriel method are, for example, An
gew.Chem., Int.Ed.Engl., 7,919 (1968)
Performed for reference. Further, the above G1a or G1c to G1f methods
In the reduction reaction, an asymmetric ligand is used
Of the compound (XXI), imine or oxime
Easy reduction to optically active target compound (IIc) by reduction
Can lead. The asymmetric ligands include, for example, optically active
Optically active amino acids such as diphenylprolinol
Rucol ligand; optically active 2,2'-bis [diphenyl
Ruphosfuino] -1,1'-binaphthyl
Phosphine ligand; optically active menthol, 1,
Optically active compounds such as 1'-bi (2,2'-naphthol)
Alcohol ligand or optically active B-chlorodiiso
Optically active boron coordination such as pinocanephenylborane
A child can be mentioned. In addition, asymmetric reduction using enzymes or microorganisms
Easily lead to the target compound (IIc) which is optically active
Can be. The target compounds obtained by the above methods G1a to G1f
(IIc), for example, after the completion of the reaction, concentrate the reaction mixture
Water and an immiscible organic solvent such as ethyl acetate.
After washing with water, the organic phase containing the target compound is separated and
After drying over magnesium acid, etc., the solvent is distilled off.
It is. If necessary, conventional methods such as recrystallization, silica
Can be further purified by gel column chromatography, etc.
You. The target compounds obtained by the above methods G1a to G1f
(IIc) is optionally R^10aOr R ^10bIs the desired protecting group
The reaction conditions and the like, known methods,
(For example, “Protective Groups in Organic Synthesis
 "(Theodora W. Greene, Peter G.M.Wuts, 1999,
A Wiley-Interscience Publication)
Method). Compound (IIc) has a primary or secondary
When a mino group or a hydroxy group is present, a known group
Law (eg, “Protective Groups in Organic Synthes
is ”(Theodora W. Greene, Peter G. M. Wuts, 1999
Year, published in A Wiley-Interscience Publication etc.
Method) to introduce a desired protecting group and a deprotection reaction.
It can be performed. Compound (I) of the present invention or a pharmaceutically acceptable compound thereof
Salts that are used are, for example, staphylococci, S. pyogenes, pneumonia
Gram-positive bacteria such as cocci and enterococci; Neisseria gonorrhoeae and catarrh spheres
Bacteria, Escherichia coli, Klebsiella pneumoniae, Shigella, Salmonella, Serachi
A, deformed bacteria, Enterobacter, Citrobacter, Pseudomonas
Bacteria, Gram-negative bacteria such as Haemophilus influenzae; Mycobacterium tuberculosis,
Mycobacteria such as atypical mycobacteria; Peptostreptococca
Anaerobic, such as chromosome, Clostridium, Bacteroides
Bacteria: methicillin-resistant Staphylococcus aureus (MRSA), methicillin
Resistant staphylococcus epidermidis (MRSE), quinolone-resistant staphylococci
Bacteria, drug-resistant enterococci (vancomycin-resistant bacteria: VRE,
Noron-resistant bacteria), drug-resistant pneumococci (penicillin-resistant)
Bacteria: PRSP, penicillin-insensitive bacteria: PISP), drug-resistant bacteria
N. fluenzae (ampicillin resistant, not producing β-lactamase)
Bacilli: BLNAR, β-lactamase producing bacteria)
Resistant bacteria; including mycoplasma and chlamydia
Strong and balanced antibacterial activity against a wide range of pathogens
Shows sex. Further, the compound (I) of the present invention has a biodistribution,
Excellent in pharmacokinetics such as half-life in blood, organs such as kidney and liver
Toxicity to is low. Therefore, compound (I) of the present invention,
Pharmacologically acceptable salts or esters thereof are
Is useful as a medicine, especially bacteria caused by various pathogens
Useful as an antibacterial agent for treating or preventing infectious diseases
You. In the above description, various drug-resistant bacteria
Include multidrug-resistant bacteria that have acquired resistance to multiple drugs.
I will. In the above, quinolone resistance refers to
The MIC for rofloxacin is 4 μg / ml or more
Say. As the administration form of the compound (I) of the present invention
Is, for example, a tablet, capsule, granule, powder or
Oral administration by syrup, injection or suppository, etc.
Parenteral administration, and these formulations contain excipients (eg,
For example, lactose, white sugar, glucose, mannitol, sorbitol
Sugar derivatives such as corn starch, potato
Starch induction like starch, alpha starch, dextrin
Body; cellulose derivatives such as crystalline cellulose;
Organic gums such as gum agar; dextran; pullulan
Agent: light anhydrous silicic acid, synthetic aluminum silicate, silicic acid
Like calcium, magnesium metasilicate aluminate
Silicate derivatives; phosphates such as calcium hydrogen phosphate; charcoal
Carbonates such as calcium sulfate; such as calcium sulfate
Examples include inorganic excipients such as sulfates. ), Luscious
Agents (eg, stearic acid, calcium stearate,
Metal stearate such as magnesium stearate
Salt; talc; colloidal silica; like veegum, gay wax
Waxes; boric acid; adipic acid; sodium sulfate
Such sulfates; glycols; fumaric acid; sodium benzoate
Um; DL leucine; fatty acid sodium salt; lauryl sulfate
Such as sodium silicate and magnesium lauryl sulfate
Ril sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and
And the above-mentioned starch derivatives. ), Binder
(Eg, hydroxypropylcellulose, hydroxy
Propyl methylcellulose, polyvinylpyrrolidone,
Crogor, and compounds similar to the above-mentioned excipients
Can do things. ), Disintegrants (eg, low substituted hydroxy
Propylcellulose, carboxy group methylcellulose,
Carboxy group methylcellulose calcium, internally crosslinked
Cellulos, such as sodium ruboxyl methylcellulose
Carboxy group methyl starch, carboxy
Sodium methyl starch, cross-linked polyvinyl pyrrolide
Starches and celluloses that have been chemically modified
I can do it. ), Stabilizers (methylparaben, propyl
Paraoxybenzoic acid esters such as leparaben;
Lolobutanol, benzyl alcohol, phenylethyl
Alcohols such as alcohol; benzalkoniu chloride
Phenols such as phenol and cresol;
Melosal; dehydroacetic acid; and sorbic acid
Can do things. ), Flavoring agents (eg, commonly used
And sweeteners, acidulants, flavors and the like. ),
It is manufactured by a known method using additives such as a diluent. The amount of use depends on the symptoms, age, administration method, etc.
For example, in the case of oral administration,
0.1 mg / kg body weight (preferably 1 mg / kg body weight)
Weight), with an upper limit of 100 mg / kg body weight (preferably 10 mg / kg
kg body weight), in the case of intravenous administration,
As 0.1 mg / kg body weight (preferably 1 mg / kg body weight),
100 mg / kg body weight (preferably 10 mg / kg body weight)
One or several times a day depending on the symptoms
desirable. The following Examples, Reference Examples, Formulation Examples and Test Examples
The present invention will be described in further detail with reference to the drawings. [Example] (Example 1)1-cyclopropyl-9-methyl-4-oxo
So-8- [4,5,6,7-tetrahydrothieno [3,
2-c] pyridin-2-yl] -4H-quinolidine-3
-Carboxylic acid(Exemplified Compound No. 1-11) (A) Ethyl 1-cyclopropyl-9-methyl-4-
Oxo-8- [5-trityl-4,5,6,7-tetra
Hydrothieno [3,2-c] pyridin-2-yl] -4
H-quinolidine-3-carboxylate Under an argon atmosphere, 5-trityl-4,5,6,7-te
1.86 g of trahydrothieno [3,2-c] pyridine
(4.88 mol) in 50 ml of tetrahydrofuran
3. butyl lithium (1.5 M hexane solution)
0 ml (6.00 mmol) at -70 ° C or lower for 5 minutes
The solution was dropped. After stirring for 1 hour, tributyltin chloride
1.5 ml (5.54 mmol) was added dropwise over 5 minutes.
Was. After stirring for 10 minutes, hexane and saturated ammonium chloride
After adding the aqueous solution, the mixture was extracted three times with hexane. Organic phase
Was dried over anhydrous sodium sulfate, and the solvent was distilled off.
3.87 g of the compound was obtained as a pale yellow oil. Under an argon atmosphere, the obtained tin compound,
Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
0.50 g of bis (triphenylphosphine)
Um (II) chloride and 0.35 g of toluene in 50 ml
And heated and stirred at 100 ° C. for 2 hours. After the completion of the reaction, the pressure was reduced from the obtained reaction solution.
Under the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: hexane / ethyl acetate
= 1/1) and 0.74 g of the title compound was obtained as a yellow solid
As obtained. (70% yield) NMR spectrum (CDC
l_Three, Δ): 0.70-0.72 (m, 2H), 1.00-1.02 (m, 2H), 1.
43 (t, J = 7.2Hz, 3H), 2.30-2.35 (m, 1H), 2.65-2.70
(m, 2H), 2.97 (s, 3H), 3.01-3.11 (m, 2H), 3.45-3.50
 (m, 2H), 4.42 (q, J = 7.2Hz, 2H), 6.92 (s, 1H), 7.15
-7.60 (m, 16H), 8.38 (s, 1H), 9.34 (d, J = 7.2Hz, 1H) (B) ethyl 1-cyclopropyl-9-methyl-4-
Oxo-8- [4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
3-carboxylate p-toluenesulfonate Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
0.73 g of noridine-3-carboxylate (1.12
mmol) in 33 ml of tetrahydrofuran and p
220 mg (1.16 mmol) of toluenesulfonic acid
Was added. Stir at room temperature for 7 hours, then at 40 ° C for 4 hours
Thereafter, the formed precipitate was collected by filtration. Filter the resulting filter
After washing with tyl ether, 0.59 g of the title compound was
Obtained as a body. (91% yield) NMR spectrum (CDCl_Three, Δ): 0.74-0.78 (m, 2
H), 1.03-1.08 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 2.28-
2,38 (m, 4H), 2.95 (s, 3H), 3.20-3.24 (m, 2H), 3.6
2-3.66 (m, 2H), 4.38-4.46 (m, 4H), 6.98 (s, 1H),
7.06 (d, J = 7.2Hz, 1H), 7.15 (d, J = 7.8Hz, 2H), 7.64
 (d, J = 7.8Hz, 2H), 8.41 (s, 1H), 9.35 (d, J = 7.2Hz,
1H) (C) 1-cyclopropyl-9-methyl-4-oxo-
8- [4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl] -4H-quinolizin-3-ca
Rubonic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylate p-toluenesulfonate 0.59
g (1.02 mmol) dissolved in chloroform and saturated
An aqueous solution of sodium hydrogen carbonate was added. Separated
The aqueous phase was extracted three times with chloroform. Chloro combined
Dry the solution over anhydrous sodium sulfate and evaporate the solvent.
And ethyl 1-cyclopropyl-9-methyl-4-o
Xo-8- (4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl) -4H-quinolizi
0.48 g of -3-carboxylate as an orange foam
I got it. The obtained foam was washed with tetrahydrofuran 20
dissolved in 1 ml of 1N sodium hydroxide aqueous solution 2.5 ml
(2.5 mmol) and 4 ml of ethanol
Was. After stirring for 6 hours, 10 ml of water was added, and 1N hydrochloric acid was further added.
In addition, the pH was adjusted to neutral. The generated precipitate is collected by filtration.
And washed with water to give 0.37 g of the title compound as an orange solid.
Was. (96% yield) Melting point: 220-223 ° C NMR spectrum (CDCl_Three, Δ): 0.78-0.83 (m, 2
H), 1.06-1.13 (m, 2H), 2.35-2.45 (m, 1H), 2.88-2.9
3 (m, 2H), 3.06 (s, 3H), 3.20-3.25 (m, 2H), 4.00
(d, J = 1.8Hz, 2H), 7.04 (s, 1H), 7.35 (d, J = 7.5Hz,
1H), 8.56 (s, 1H), 9.27 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 381 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3412, 17
29, 1653, 1436 (Example 2)1-cyclopropyl-9-methyl-8- [5-methyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -4-oxo-4H-quinolidine-
3-carboxylic acid (Exemplary Compound No. 1-269) 1-cyclopropyl-9-methyl-4-oxo-8-
[4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl] -4H-quinolizin-3-carbo
Dissolve 80 mg of acid in 3 ml of formic acid and add 3 ml of formalin
And heated to 60 ° C. Obtained after stirring for 10 hours.
The solvent was distilled off from the reaction solution under reduced pressure, and 1N sodium hydroxide was added.
Aqueous solution to make a homogeneous solution, and then add 1N hydrochloric acid.
The pH was adjusted to neutral. The generated precipitate is collected by filtration and washed with water.
This gave 34 mg of the title compound as an orange solid. (yield
41%) Melting point: 210-215 ° C (decomposition) NMR spectrum (CDCl_Three, Δ): 0.78-0.83 (m, 2
H), 1.06-1.13 (m, 2H), 2.35-2.45 (m, 1H), 2.55
(s, 3H), 2.84-2.88 (m, 2H), .3.02-3.08 (m, 5H), 3.
61 (s, 2H), 7.03 (s, 1H), 7.35 (d, J = 7.5Hz, 1H),
8.56 (s, 1H), 9.27 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3425, 17
18, 1626, 1430 (Example 3)1-cyclopropyl-9-methoxy-4-oxo-8-
[4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl] 4H-quinolidine-3-carboxyl
acid (Exemplified Compound No.1-51) (A) Ethyl 1-cyclopropyl-9-methoxy-4
-Oxo-8- [5-trityl-4,5,6,7-tet
Lahydrothieno [3,2-c] pyridin-2-yl]-
4H-quinolidine-3-carboxylate Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
Instead of ethyl 8-chloro-1-cyclopropyl
Le-9-methoxy-4-oxo-4H-quinolidine-3
0.48 g (1.49 mmol) of carboxylate
The reaction was carried out in the same manner as in Example 1 (a), except that
0.77 g of compound was obtained as an orange solid. (Yield 78
%) NMR spectrum (CDCl_Three, Δ): 0.73-0.76 (m, 2
H), 0.97-1.01 (s, 2H), 1.44 (t, J = 5.1Hz, 3H), 2.53
-2.71 (m, 3H), 3.04-3.10 (m, 2H), 3.45-3.51 (m, 2
H), 3.75 (s, 3H), 4.41 (q, J = 5.1Hz, 2H), 7.16-7.58
 (m, 16H), 8.15 (s, 1H), 9.22 (d, J = 6.0Hz, 1H) (B) ethyl 1-cyclopropyl-9-methyl-4-
Oxo-8- [4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
3-carboxylate p-toluenesulfonate Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-9-methoxy-4-oxo-8-
[5-Trityl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
0.77 g (1.16 mmol) of -3-carboxylate
The reaction was carried out in the same manner as in Example 1 (b) except that l) was used.
This gave 0.84 g of the title compound as an orange solid. (Income
94%) NMR spectrum (CDCl_Three, Δ): 0.72-0.76 (m, 2
H), 0.98-1.02 (m, 2H), 1.41 (t, J = 7.2Hz, 3H), 2.30
 (s, 3H), 2.51-2.61 (m, 1H), 3.11-3.17 (m, 2H), 3.6
0-3.66 (m, 2H), 3.68 (s, 3H), 4.40 (q, J = 7.2Hz, 2
H), 4.46-4.52 (m, 2H), 7.12 (d, J = 8.1Hz, 2H), 7.29
(d, J = 7.8Hz, 1H), 7.69 (d, J = 8.1Hz, 2H), 8.11 (s, 1
H), 9.18 (d, J = 7.8Hz, 1H), 9.52-9.64 (br, 1H) MS spectrum (CI, m / z) 425 (M⁺+1) (C) 1-cyclopropyl-9-methoxy-4-oxo
-8- (4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl) -4H-quinolizin-3-
carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-9-methoxy-4-
Oxo-8- [4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
3-carboxylate p-toluenesulfonate
Except that 0.20 g (0.34 mmol) was used,
Reaction was carried out in the same manner as in 1 (c) to give 0.11 g of the title compound.
Obtained as an orange solid. (80% yield) Melting point: 200-205 ° C (decomposition) NMR spectrum (CDCl_Three, Δ): 0.80-0.86 (m, 2
H), 1.04-1.09 (m, 2H), 2.66-2.76 (m, 1H), 2.91-2.9
7 (m, 2H), 3.20-3.26 (m, 2H), 3.80 (s, 3H), 4.03
(s, 2H), 7.48 (s, 1H), 7.53 (d, J = 7.8Hz, 1H), 8.33
 (s, 1H), 9.16 (d, J = 7.8Hz, 1H) MS spectrum (FAB +, m / z) 397 (M⁺+
1) IR spectrum (KBr, ν_max  cm^-1): 3402, 17
18, 1647, 1458 (Example 4)1-cyclopropyl-7-fluoro-9-methyl-8-
[4-Methyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid (Exemplary Compound No. 1-2
65) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [4-methyl-5-trityl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl] -4-oxo-4H-quinolizin-3-cal
Boxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 4-methyl-5-
Trityl-4,5,6,7-tetrahydrothieno [3,
2-c] pyridine 1.10 g (2.78 mmol)
Ethyl 8-chloro-1-cyclopropyl-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Ethyl 8-chloro-1-cyclopropyl
Ropyl-7-fluoro-9-methyl-4-oxo-4H
-Quinolidine-3-carboxylate 0.40 g (1.
Except for using 24 mmol), the same as in Example 1 (a)
Reaction yielded 0.49 g of the title compound as a yellow solid.
Was. (58% yield) NMR spectrum (CDCl_Three, Δ): 0.75-0.76 (m, 2
H), 1.02-1.05 (m, 2H), 1.40 (d, J = 6.8Hz, 3H), 1.43 (t, J =
7.1Hz, 3H), 1.69-1.80 (m, 1H), 2.06-2.22 (m, 1H), 2.28
-2.37 (m, 1H), 2.93 (s.3H), 3.47-3.72 (m, 2H), 4.42 (q,
J = 7.1Hz, 2H), 4.47 (q, J = 6.8Hz, 1H), 6.69 (s, 1H), 7.1
1-7.52 (m, 15H), 8.37 (s, 1H), 9.39 (d, J = 6.3Hz, 1H) MS spectrum (FAB, m / z) 683 (M⁺+1) (B) ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [4-methyl-4,5,6,7-tetra
Hydrothieno [3,2-c] pyridin-2-yl] -4
-Oxo-4H-quinolizin-3-carboxylate
p-toluenesulfonic acid salt Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-7-fluoro-9-methyl-8-
[4-Methyl-5-trityl-4,5,6,7-tetra
Hydrothieno [3,2-c] pyridin-2-yl] -4
-Oxo-4H-quinolizin-3-carboxylate
Except that 0.49 g (0.72 mmol) was used,
The reaction was carried out in the same manner as in 1 (b) to give 0.41 g of the title compound.
Obtained as an orange foam. (93% yield) NMR spectrum (CDCl_Three, Δ): 0.76-0.81 (m, 2
H), 1.03-1.09 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.78 (d, J =
6.8Hz, 3H) 2.31-2.36 (m, 1H), 2.36 (s, 3H), 2.92 (s, 3
H), 3.10-3.17 (m, 1H), 3.25-3.40 (m, 1H), 3.45-3.56 (m,
1H), 3.78-3.91 (m, 1H), 4.43 (q, J = 7.1Hz, 2H), 4.59-4.71
(m, 1H), 6.90 (s, 1H), 7.18 (d, J = 7.8Hz, 2H), 7.68 (d, J =
7.8Hz, 2H), 8.39 (s, 1H), 9.26 (brs, 1H), 9.41 (d, J = 6.3
Hz, 1H), 9.80 (brs, 1H) MS spectrum (CI, m / z) 441 (M⁺+1) (C) 1-cyclopropyl-7-fluoro-9-methyl
-8- [4-methyl-4,5,6,7-tetrahydrothio
Eno [3,2-c] pyridin-2-yl] -4-oxo
-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-7-fluoro-9-
Methyl-8- [4-methyl-4,5,6,7-tetrahi
Dorothieno [3,2-c] pyridin-2-yl] -4-
Oxo-4H-quinolidine-3-carboxylate p
0.41 g of toluenesulfonate (0.68 mmol
Reaction was carried out in the same manner as in Example 1 (c), except that l) was used.
This gave 0.23 g of the title compound as an orange solid. (Income
Rate 82%) Melting point: 255 ℃ (decomposition) NMR spectrum (DMSO-d₆, δ): 0.75-0.79 (m,
2H), 1.04-1.10 (m, 2H), 1.34 (d, J = 6.6Hz, 3H), 2.49-2.
96 (m, 3H), 2.96 (s, 3H), 3.10-3.20 (m, 1H overlapped wi
th H2O), 3.94 (q, J = 6.6Hz, 1H), 7.25 (s, 1H), 8.23 (s,
1H), 9.31 (d, J = 6.3Hz, 1H) MS spectrum (CI, m / z) 413 (M⁺+1) IR spectrum (KBr, ν_maxcm^-1) 3410, 1664,
1465 (Example 5)1-cyclopropyl-7-fluoro-9-methyl-8-
[7-methyl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid (Exemplary Compound No. 1-4
39) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [7-methyl-6-trityl-4,5
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -4-oxo-4H-quinolizin-3-cal
Boxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 7-methyl-6-
Trityl-4,5,6,7-tetrahydrothieno [2,
3-c] pyridine 1.10 g (2.78 mmol)
Ethyl 8-chloro-1-cyclopropyl-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Ethyl 8-chloro-1-cyclopropyl
Ropyl-7-fluoro-9-methyl-4-oxo-4H
0.39 g of -quinolidine-3-carboxylate (1.
Except that 20 mmol) was used.
Reaction gave 0.41 g of the title compound as a yellow solid.
Was. (Yield 50%) NMR spectrum (CDCl_Three, Δ): 0.74-0.77 (m, 2
H), 1.01-1.05 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.5
5 (d, J = 6.6Hz, 3H), 1.56-1.68 (m, 1H), 1.94-2.03
(m, 1H), 2.28-2.35 (m, 1H), 2.90 (s, 3H), 3.53-
3.68 (m, 2H), 4.28 (q, J = 7.1Hz, 2H), 4.68 (q, J = 6.6
Hz, 1H), 6.41 (s, 1H), 7.10-7.52 (m, 15H), 8.36
(s, 1H), 9.38 (d, J = 5.6Hz, 1H) MS spectrum (FAB, m / z) 683 (M⁺+1) (B) ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [7-methyl-4,5,6,7-tetra
Hydrothieno [2,3-c] pyridin-2-yl] -4
-Oxo-4H-quinolizin-3-carboxylate
p-toluenesulfonic acid salt Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-7-fluoro-9-methyl-8-
[7-methyl-5-trityl-4,5,6,7-tetra
Hydrothieno [2,3-c] pyridin-2-yl] -4
-Oxo-4H-quinolizin-3-carboxylate
Except that 0.40 g (0.59 mmol) was used,
The reaction was carried out in the same manner as in 1 (b) to give 0.45 g of the title compound.
Obtained almost quantitatively as an orange foam. The NMR spectrum (CDCl_Three, Δ): 0.7
6-0.81 (m, 2H), 1.03-1.10 (m, 2H), 1.43 (t, J = 7.1Hz, 3H),
 1.84 (d, J = 6.8Hz, 3H) 2.32-2.36 (m, 1H), 2.36 (s, 3H),
2.92 (s, 3H), 2.92-3.00 (m, 1H), 3.09-3.24 (m, 1H), 3.3
0-3.50 (m, 1H), 3.82-3.91 (m, 1H), 4.43 (q, J = 7.1Hz, 2H),
 4.68-4.80 (m, 1H), 6.91 (s, 1H), 7.18 (d, J = 7.8Hz, 2H),
7.68 (d, J = 7.8Hz, 2H), 8.40 (s, 1H), 9.31 (brs, 1H),
9.41 (d, J = 6.3Hz, 1H), 9.90 (brs, 1H) MS spectrum (CI, m / z) 441 (M⁺+1) (C) 1-cyclopropyl-7-fluoro-9-methyl
-8- [7-methyl-4,5,6,7-tetrahydrothio
Eno [2,3-c] pyridin-2-yl] -4-oxo
-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-7-fluoro-9-
Methyl-8- [7-methyl-4,5,6,7-tetrahi
Drothieno [2,3-c] pyridin-2-yl] -4-
Oxo-4H-quinolidine-3-carboxylate p
-0.43 g of toluenesulfonate (0.59 mmol)
The reaction was carried out in the same manner as in Example 1 (c), except that
This gave 0.18 g of the title compound as a yellow solid. (Income
Rate 74%) Melting point: 235-236 ° C NMR spectrum (DMSO-d₆, Δ): 0.74-0.79
(m, 2H), 1.04-1.10 (m, 2H), 1.38 (d, J = 6.6Hz, 3H) 2.49-
2.90 (m, 2H), 2.96 (s, 3H), 3.15-3.20 (m, 2H), 4.09 (q, J
= 6.6Hz, 1H), 7.17 (s, 1H), 8.25 (s, 1H), 9.31 (d, J =
(6.1Hz, 1H) MS spectrum (CI, m / z) 413 (M⁺+1) IR spectrum (KBr, ν_maxcm^-1) 3420, 1734,
1668, 1441 (Example 6)1-cyclopropyl-7-fluoro-9-methyl-8-
[6-Methyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid (Exemplified Compound No. 1-3
55) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [6-methyl-5-trityl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl] -4-oxo-4H-quinolizin-3-cal
Boxylate 5-trityl-4,5,6,7-tetrahydrothieno
6-methyl-5 instead of [3,2-c] pyridine
Trityl-4,5,6,7-tetrahydrothieno [3,
2-c] pyridine 1.11 g (2.81 mmol)
Ethyl 8-chloro-1-cyclopropyl-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Ethyl 8-chloro-1-cyclopropyl
Ropyl-7-fluoro-9-methyl-4-oxo-4H
-0.50 g of quinolidine-3-carboxylate (1.
Except for using 54 mmol), the same as in Example 1 (a)
Reaction yielded 0.71 g of the title compound as a yellow solid.
Was. (Yield 68%) NMR spectrum (CDCl_Three, Δ): 0.32 (d, J = 6.3Hz,
3H), 0.72-0.79 (m, 2H), 1.00-1.05 (m, 2H), 1.43 (t, J = 7.
1Hz, 3H), 2.27-2.36 (m, 1H), 2.47 (d, J = 15.4Hz, 1H), 2.9
6 (s.3H), 3.31-3.50 (m, 2H), 3.91-4.00 (m, 1H), 4.19 (d,
J = 15.4Hz, 1H), 4.43 (q, J = 7.1Hz, 2H), 6.83 (s, 1H), 7.17
-7.58 (m, 15H), 8.37 (s, 1H), 9.40 (d, J = 6.1Hz, 1H) MS spectrum (FAB, m / z) 683 (M⁺+1) (B) ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [6-methyl-4,5,6,7-tetra
Hydrothieno [3,2-c] pyridin-2-yl] -4
-Oxo-4H-quinolizin-3-carboxylate
p-toluenesulfonic acid salt Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-7-fluoro-9-methyl-8-
[6-Methyl-5-trityl-4,5,6,7-tetra
Hydrothieno [3,2-c] pyridin-2-yl] -4
-Oxo-4H-quinolizin-3-carboxylate
Except that 0.71 g (1.04 mmol) was used,
Reaction was carried out in the same manner as in 1 (b) to give 0.56 g of the title compound.
Obtained as a yellow solid. (88% yield) NMR spectrum (CDCl_Three, Δ): 0.76-0.80 (m, 2
H), 1.03-1.09 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.67 (d, J =
(6.6Hz, 3H) 2.31-2.35 (m, 1H), 2.34 (s, 3H), 2.90 (s, 3
H), 3.05-3.23 (m, 2H), 3.68-3.75 (m, 1H), 3.45-3.56 (m,
1H), 3.78-3.91 (m, 1H), 4.40 (d, J = 13.5Hz, 1H), 4.43 (q,
J = 7.1Hz, 2H), 4.55 (d, J = 13.5Hz, 1H), 6.90 (s, 1H), 7.15
(d, J = 7.8Hz, 2H), 7.62 (d, J = 7.8Hz, 2H), 8.40 (s, 1H),
  9.41 (d, J = 6.3Hz, 1H) MS spectrum (CI, m / z) 441 (M⁺+1) (C) 1-cyclopropyl-7-fluoro-9-methyl
-8- [6-methyl-4,5,6,7-tetrahydrothio
Eno [3,2-c] pyridin-2-yl] -4-oxo
-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-7-fluoro-9-
Methyl-8- [6-methyl-4,5,6,7-tetrahi
Dorothieno [3,2-c] pyridin-2-yl] -4-
Oxo-4H-quinolidine-3-carboxylate p
-0.56 g of toluenesulfonate (0.92 mmol
Reaction was carried out in the same manner as in Example 1 (c), except that l) was used.
This gave 0.29 g of the title compound as an orange solid. (Income
Rate 77%) Melting point: 265-267 ° C NMR spectrum (DMSO-d₆, Δ): 0.72-0.80
(m, 2H), 1.03-1.12 (m, 2H), 1.19 (d, J = 6.3Hz, 3H), 2.48
-2.96 (m, 3H), 2.96 (s, 3H), 3.10-3.20 (m, 1H overlapped
 with H2O), 3.83 (d, J = 14.0Hz, 1H), 3.91 (d, J = 14.0Hz,
 1H), 7.16 (s, 1H), 8.24 (s, 1H), 9.30 (d, J = 5.9Hz, 1H) MS spectrum (CI, m / z) 413 (M⁺+1) IR spectrum (KBr, ν_maxcm^-1) 3418, 1666,
1465 (Example 7)1-cyclopropyl-7-fluoro-9-methyl-8-
[5-methyl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid (Exemplary Compound No. 1-4
31) 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 5-methyl-6-
Trityl-4,5,6,7-tetrahydrothieno [2,
3-c] pyridine (2.08 g, 5.25 mmol)
Ethyl 8-chloro-1-cyclopropyl-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Ethyl 8-chloro-1-cyclopropyl
Ropyl-7-fluoro-9-methyl-4-oxo-4H
0.60 g of quinolidine-3-carboxylate (1.
85 mmol), but reacted in the same manner as in Example 1.
This gave 0.35 g of the title compound as a yellow solid.
(Yield 46%) Melting point: 255 ℃ (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.00-1.14
(m, 2H), 1.41-1.50 (m, 2H), 1.74 (d, J = 6.6Hz, 3H), 2.59-
2.77 (m, 1H), 3.00-3.41 (m, 2H), 3.30 (s.3H), 3.95-4.10
(m, 1H), 4.79-4.90 (m, 2H), 7.28 (s, 1H), 8.76 (s, 1H),
9.39 (brs, 1H) MS spectrum (CI, m / z) 413 (M⁺+1) IR spectrum (KBr, ν_maxcm^-1) 3406, 1668,
 1460 (Example 8)1-cyclopropyl-8- [7-hydroxy-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl] -9-methyl-4-oxo-4H-quinolizi
-3-carboxylic acid (Exemplary Compound No. 1-403) (A) Ethyl 1-cyclopropyl-8- [7- (meth
(Xymethoxy) -5-trityl-4,5,6,7-tet
Lahydrothieno [3,2-c] pyridin-2-yl]-
9-methyl-4-oxo-4H-quinolizin-3-cal
Boxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 7- (methoxymethine)
Toxy) -5-trityl-4,5,6,7-tetrahydride
2.00 g of rothieno [3,2-c] pyridine (4.53
mmol), except that the reaction was conducted in the same manner as in Example 1 (a).
This gave 0.59 g of the title compound as an orange solid.
(63% yield) NMR spectrum (CDCl_Three, Δ): 0.71-0.74 (m, 2
H), 0.99-1.03 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 2.28
-2.38 (m, 1H), 2.52-2.62 (m, 1H), 2.95-3.05 (m, 4
H), 3.18-3.26 (m, 1H), 3.51 (s, 2H), 3.66-3.75 (m,
 1H), 4.42 (q, J = 7.2Hz, 2H), 4.82 (s, 2H), 4.97-5.0
1 (m, 1H), 6.91 (s, 1H), 7.13-7.62 (m, 16H), 8.39
(s, 1H), 9.36 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 711 (M⁺+1) (B) 1-cyclopropyl-8- [7- (methoxymeth
Xy) -4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -9-methyl-4-oxo
-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-8- [7- (methoxymethoxy)
-5-trityl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -9-methyl-4
-Oxo-4H-quinolizin-3-carboxylate
Except that 0.59 g (0.82 mmol) was used,
The reaction was carried out in the same manner as in 1 (b) to give ethyl 1-cyclopro
Pill-8- [7- (methoxymethoxy) -4,5,6
7-tetrahydrothieno [3,2-c] pyridine-2-
Yl] -9-methyl-4-oxo-4H-quinolidine-
3-carboxylate p-toluenesulfonate
And then ethyl 1-cyclopropyl-9-methyl-
4-oxo-8- [4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -4H-quinoli
Gin-3-carboxylate p-toluenesulfonic acid
Instead of the salt, ethyl 1-cyclopropyl-8- [7
-(Methoxymethoxy) -4,5,6,7-tetrahydride
Rothieno [3,2-c] pyridin-2-yl] -9-me
Tyl-4-oxo-4H-quinolidine-3-carboxylic acid
Other than using p-toluenesulfonate sylate,
The reaction was carried out in the same manner as in Example 1 (c) to give the title compound 0.29.
g were obtained as an orange solid. (81% yield) Melting point: 100-103 ° C NMR spectrum (CDCl_Three, Δ): 0.79-0.85 (m, 2
H), 1.07-1.14 (m, 2H), 2.33-2.43 (m, 1H), 3.06 (s,
 3H), 3.18 (dd, J = 13.8 and 3.6Hz, 1H), 3.37 (dd, J = 1
3.8 and 3.6Hz, 1H), 3.49 (s, 3H), 3.92 (d, J = 16.5H
z, 1H), 4.06 (d, J = 16.5Hz, 1H), 4.73 (t, J = 3.6Hz,
1H), 4.84 (s, 2H), 7.04 (s, 1H), 7.35 (d, J = 7.5Hz,
 1H), 8.58 (s, 1H), 9.29 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 441 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3410, 17
33, 1660, 1465 (C) 1-cyclopropyl-8- [7-hydroxy-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid 1-cyclopropyl-8- [7- (methoxymethoxy)
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl] -9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid 0.10 g (0.23 m
mol) was dissolved in 10 ml of methylene chloride, and
2 ml of fluoroacetic acid were added. After stirring at room temperature for 24 hours,
The solvent was distilled off from the obtained reaction solution under reduced pressure. Get
1N hydrochloric acid was added to the resulting residue to form a homogeneous solution, and then 1N water was added.
An aqueous sodium oxide solution was added to adjust the pH to neutral. Raw
The formed precipitate was collected by filtration, washed with water, and 0.09 g of the title compound
Was obtained as an orange solid. (96% yield) Melting point: 153-158 ° C NMR spectrum (CDCl_Three, Δ): 0.79-0.85 (m, 2
H), 1.07-1.13 (m, 2H), 2.33-2.43 (m, 1H), 3.16-3.3
4 (m, 2H), 3.90-4.09 (m, 2H), 4.78-4.84 (m, 1H),
7.03 (s, 1H), 7.34 (d, J = 7.5Hz, 1H), 8.59 (s, 1H),
 9.30 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 397 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3397,171
8,1635,1437 (Example 9)1-cyclopropyl-8- [5,6-dihydro-4H-
Thieno [2,3-c] pyrrol-2-yl] -9-methyl
Ru-4-oxo-4H-quinolidine-3-carboxylic acid
Hydrochloride (Hydrochloride of Exemplified Compound No. 1-829) (A) Ethyl 1-cyclopropyl-9-methyl-4-
Oxo-8- [5-trityl-5,6-dihydro-4H
-Thieno [2,3-c] pyrrol-2-yl] -4H-
Quinolidine-3-carboxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 5-trityl-
5,6-dihydro-4H-thieno [2,3-c] pillow
Except that 0.74 g (6.81 mmol) was used.
The reaction was carried out in the same manner as in Example 1 (a) to give 0.42 g of the title compound.
Was obtained as an orange solid. (80% yield) NMR spectrum (CDCl_Three, Δ): 0.69-0.75 (m, 2
H), 0.98-1.04 (m, 2H), 1.42 (t, J = 7.2Hz, 3H), 2.26
-2.36 (m, 1H), 2.93 (s, 3H), 4.04 (s, 2H), 4.19 (s,
 2H), 4.42 (q, J = 7.2Hz, 2H), 6.87 (s, 1H), 7.08
(d, J = 7.5Hz, 1H), 7.15-7.62 (m, 15H), 8.37 (s, 1
H), 9.33 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 637 (M⁺+1) (B) 1-cyclopropyl-9-methyl-4-oxo-
8- [5-trityl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4H-quinolizi
-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-9-methyl-4-oxo-8-
[5-Trityl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4H-quinolizi
0.43 g (0.65 mmol)
Reaction was carried out in the same manner as in Example 1 (c), except that l) was used.
This gave 0.33 g of the title compound as a yellow solid. (Income
83%) NMR spectrum (CDCl_Three, Δ): 0.76-
0.82 (m, 2H), 1.05-1.12 (m, 2H), 2.35-2.45 (m, 1
H), 3.00 (s, 3H), 4.04-4.06 (m, 2H), 4.20-4.22 (m,
2H), 6.91 (d, J = 6.9Hz, 1H), 7.15-7.65 (m, 16H), 8.5
5 (s, 1H), 9.24 (d, J = 6.9Hz, 1H), 14.00 (brs, 1H) (C) 1-cyclopropyl-8- [5,6-dihydro-
4H-thieno [2,3-c] pyrrol-2-yl] -9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Acid hydrochloride 1-cyclopropyl-9-methyl-4-oxo-8-
[5-Trityl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4H-quinolizi
0.32 g (0.53 mmol) of 1-3-carboxylic acid
Dissolve in 15 ml of methylene chloride, and cool with saturated hydrogen chloride under ice-cooling.
5 ml of a methylene chloride solution were added. After stirring for 1.5 hours,
The generated precipitate was collected by filtration. The obtained filtered material is diethyl
Wash with ether and add 0.20 g of the title compound as a tan solid
As obtained. (96% yield) Melting point: 215-220 ° C (decomposition) NMR spectrum (CD_ThreeOD, δ): 0.78-0.84 (m, 2
H), 1.11-1.17 (m, 2H), 2.47-2.57 (m, 1H), 3.11 (s,
 3H), 4.59 (s, 2H), 4.75 (s, 2H), 7.41 (s, 1H), 7.5
4 (d, J = 7.5Hz, 1H), 8.46 (s, 1H), 9.35 (d, J = 7.5H
z, 1H) MS spectrum (CI, m / z) 367 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3408, 28
76, 2698, 1719, 1635, 1431 (Example 10)1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-8- [4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
-3-carboxylic acid (Exemplified Compound No. 1-91) 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 5-trityl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Using 1.41 g (3.72 mmol) of lysine, ethyl
  8-chloro-1-cyclopropyl-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylate
Instead, ethyl 8-chloro-1-cyclopropyl-7
-Fluoro-9-methyl-4-oxo-4H-quinolidine
0.48 g (1.48 mmol) of -3-carboxylate
The reaction was carried out in the same manner as in Example 1 except that l) was used.
0.19 g of the compound was obtained as a reddish brown solid. (Yield 32
%) Melting point: 168-174 ° C NMR spectrum (CDCl_Three, Δ): 0.77-0.78 (m, 2
H), 1.03-1.14 (m, 2H), 2.23-2.33 (m, 1H), 2.81-2.8
6 (m, 2H), 3.03 (s, 3H), 3.14-3.17 (m, 2H), 4.00
(s, 2H), 6.94 (s, 1H), 8.52 (s, 1H), 9.31 (d, J = 5.
(9Hz, 1H) MS spectrum (CI, m / z) 399 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3428, 17
34, 1664, 1465 (Example 11)1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-8- [4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl] -4H-quinolizi
-3-carboxylic acid (Exemplary Compound No. 1-423) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-8- [6-trityl-4,5,
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -4H-quinolidine-3-carboxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 6-trityl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Using 1.50 g of lysine, ethyl 8-chloro-1-cy
Clopropyl-9-methyl-4-oxo-4H-quinoli
Instead of gin-3-carboxylate, ethyl 8-
Chloro-1-cyclopropyl-7-fluoro-9-methyl
Ru-4-oxo-4H-quinolidine-3-carboxyle
In the same manner as in Example 1 (a) except that 0.60 g of
Reaction yielded 0.85 g of the title compound as an orange solid.
Was. (69% yield) NMR spectrum (CDCl_Three, Δ): 0.73-0.79 (m, 2
H), 1.01-1.10 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 2.30-2.40
(m, 1H), 2.60-2.68 (m, 2H), 2.85-2.95 (m, 5H), 3.58-3.
65 (m, 2H), 4.44 (q, J = 7.1Hz, 2H), 6.93 (s, 1H), 7.16-7.
59 (m, 15H), 8.37 (s, 1H), 9.40 (d, J = 6.3Hz, 1H) MS spectrum (CI, m / z) 669 (M⁺+1) (B) ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-8- [4,5,6,7-tetra
Hydrothieno [2,3-c] pyridin-2-yl] -4
H-quinolidine-3-carboxylate p-toluene
Sulfonate Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-8- [6-trityl-4,5,6,7-tetra
Hydrothieno [2,3-c] pyridin-2-yl] -4
Using 0.85 g of H-quinolidine-3-carboxylate
The reaction was carried out in the same manner as in Example 1 (b),
0.57 g of the compound was obtained as a yellow solid. (75% yield)
NMR spectrum (CDCl_Three, Δ): 0.75-0.81 (m, 2
H), 1.03-1.10 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 2.30-2.38
(m, 3H), 2.91 (s, 3H), 3.05-3.11 (m, 2H), 3.59-3.63 (m,
2H), 4.43 (q, J = 7.1 Hz, 2H), 4.57 (m, 2H), 6.92 (s, 1H),
7.17 (d, J = 8.5Hz, 2H), 7.66 (d, J = 8.5Hz, 2H), 8.39 (s, 1
H), 9.40 (d, J = 6.1Hz, 1H) (C) 1-cyclopropyl-7-fluoro-9-methyl
-4-oxo-8- [4,5,6,7-tetrahydrothi
Eno [2,3-c] pyridin-2-yl] -4H-quino
Lysine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-7-fluoro-9-
Methyl-4-oxo-8- [4,5,6,7-tetrahi
Dorothieno [2,3-c] pyridin-2-yl] -4H
-Quinolidine-3-carboxylate p-toluene
Example 1 (c) except that 0.57 g of sulfonate was used
In the same manner, 0.35 g of the title compound was converted into a yellow solid.
I got it. (Yield 92%) Melting point: 256-257 ℃ NMR spectrum (DMSOd₆, Δ): 0.72-0.77 (m, 2
H), 1.02-1.08 (m, 2H), 2.45-2.55 (m, 1H), 2.61-2.65 (m,
2H), 2.93-2.99 (m, 5H), 3.94-3.96 (m, 2H), 7.15 (s, 1
H), 8.19 (s, 1H), 9.26 (d, J = 6.1Hz, 1H) MS spectrum (CI, m / z) 399 (M⁺+1) I
R spectrum (KBr, ν_max  cm^-1): 3460, 166
8, 1641,1347 (Example 12)1-cyclopropyl-9-methyl-8- [4-methyl-
5,6-dihydro-4H-thieno [2,3-c] pillow
Ru-2-yl] -4-oxo-4H-quinolizin-3-
carboxylic acid (Exemplary Compound No. 1-1065) (A) Ethyl 1-cyclopropyl-9-methyl-8-
[4-Methyl-5-trityl-5,6-dihydro-4H
-Thieno [2,3-c] pyrrol-2-yl] -4-o
Xo-4H-quinolidine-3-carboxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 4-methyl-5-
Trityl-5,6-dihydro-4H-thieno [2,3-
c] 0.88 g (2.30 mmol) of pyrrole was used.
Otherwise, reacting in the same manner as in Example 1 (a) to give the title compound
0.46 g was obtained as an orange solid. (70% yield) NMR spectrum (CDCl_Three, Δ): 0.69-0.75 (m, 2
H), 0.98-1.05 (m, 2H), 1.39-1.47 (m, 6H), 2.26-2.3
6 (m, 1H), 2.82 (s, 3H), 4.09 (d, J = 16.5Hz, 1H),
4.37-4.46 (m, 3H), 4.58 (d, J = 16.5Hz, 1H), 6.53
(s, 1H), 6.98 (d, J = 7.5Hz, 1H), 7.08-7.60 (m, 15H),
 8.36 (s, 1H), 9.30 (d, J = 7.5Hz, 1H) MS spectrum
(CI, m / z) 651 (M⁺+1) (B) 1-cyclopropyl-9-methyl-8- [4-me
Cyl-5,6-dihydro-4H-thieno [2,3-c]
Pyrrole-2-yl] -4-oxo-4H-quinolizine
-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-9-methyl-8-
[4-Methyl-5-trityl-5,6-dihydro-4H
-Thieno [2,3-c] pyrrol-2-yl] -4-o
Xo-4H-quinolidine-3-carboxylate 0.3
Example 1 except that 2 g (0.88 mmol) was used.
By reacting in the same manner as in (c), 1-cyclopropyl-9-
Methyl-8- [4-methyl-5-trityl-5,6-di
Hydro-4H-thieno [2,3-c] pyrrole-2-i
4-oxo-4H-quinolidine-3-carboxylic acid
To obtain 1-cyclopropyl-9-methyl-4-oxo-
8- [5-trityl-5,6-dihydro-4H-thieno
[2,3-c] pyrrol-2-yl] -4H-quinolizi
1-cyclopropyl-
9-methyl-8- [4-methyl-5-trityl-5,6
-Dihydro-4H-thieno [2,3-c] pyrrole-2
-Yl] -4-oxo-4H-quinolizin-3-carbo
The reaction was carried out in the same manner as in Example 9 (c), except that the acid was used.
This gave 0.16 g of the hydrochloride of the title compound. The obtained hydrochloride was washed with 1N aqueous sodium hydroxide.
After dissolving in the solution, 1N hydrochloric acid was added to adjust the pH to neutral.
The resulting precipitate was collected by filtration, washed with water, and washed with the title compound 0.14.
g were obtained as an orange-brown solid. (38% yield) Melting point: 170-175 ° C (decomposition) NMR spectrum (CDCl_Three+ DMSO-d₆, Δ):
0.79-0.85 (m, 2H), 1.09-1.16 (m, 2H), 1.49 (d, J =
6.3Hz, 3H), 2.53-2.63 (m, 1H), 3.09 (s, 3H), 4.28-
4.44 (m, 2H), 4.50-4.60 (m, 1H), 7.10 (s, 1H), 7.4
0 (d, J = 7.5Hz, 1H), 8.54 (s, 1H), 9.30 (d, J = 7.5Hz,
 1H) MS spectrum (CI, m / z) 381 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3441, 16
46, 1468 (Example 13)1-cyclopropyl-9-difluoromethoxy-4-o
Xo-8- [4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -4H-quinolizi
-3-carboxylic acid (Exemplified Compound No. 1-59) (A) Ethyl 1-cyclopropyl-9-difluorome
Toxy-4-oxo-8- [5-trityl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl] -4H-quinolidine-3-carboxylate
Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
Instead of ethyl 8-chloro-1-cyclopropyl
Ru-9-difluoromethoxy-4-oxo-4H-quino
0.35 g of lysine-3-carboxylate (0.90 m
mol)).
This gave 0.63 g of the title compound as an orange solid.
(99% yield) NMR spectrum (CDCl_Three, Δ): 0.66-0.72 (m, 2
H), 0.99-1.1.07 (m, 2H), 1.42 (t, J = 7.2Hz, 3H), 2.3
6-2.46 (m, 1H), 2.62-2.72 (m, 2H), 3.05-3.11 (m, 2
H), 3.45-3.51 (m, 2H), 4.42 (q, J = 7.2Hz, 2H), 6.36
 (t, J = 75.0Hz, 1H), 7.16-7.58 (m, 17H), 8.28 (s, 1
H), 9.28 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 703 (M⁺+1) (B) ethyl 1-cyclopropyl-9-difluorome
Toxic-4-oxo-8- [4,5,6,7-tetrahi
Dorothieno [3,2-c] pyridin-2-yl] -4H
-Quinolidine-3-carboxylate p-toluene
Sulfonate Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-9-difluoromethoxy-4-o
Oxo-8- [5-trityl-4,5,6,7-tetrahi
Dorothieno [3,2-c] pyridin-2-yl] -4H
-Quinolidine-3-carboxylate 0.62 (0.8
Except that 9 mmol) was used in the same manner as in Example 1 (b).
In response, 0.54 g of the title compound was obtained as an orange solid.
Was. (95% yield) NMR spectrum (CDCl_Three, Δ): 0.67-0.73 (m, 2
H), 1.02-1.08 (m, 2H), 1.41 (t, J = 7.2Hz, 3H), 2.30
 (s, 3H), 2.33-2.43 (m, 1H), 3.15-3.22 (m, 2H), 3.6
1-3.67 (m, 2H), 4.41 (q, J = 7.2Hz, 2H), 4.44-4.50
(m, 2H), 6.34 (t, J = 75.0Hz, 1H), 7.12 (d, J = 8.1Hz,
2H), 7.27 (d, J = 8.1Hz, 1H), 7.64 (d, J = 8.1Hz, 2H),
 8.25 (s, 1H), 9.26 (d, J = 8.1Hz, 1H), 9.60 (brs, 2
H) MS spectrum (CI, m / z) 461 (M⁺+1) (C) 1-cyclopropyl-9-difluoromethoxy-
4-oxo-8- [4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -4H-quinoli
Gin-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-9-difluorometh
Xy-4-oxo-8- [4,5,6,7-tetrahydrido
Rothieno [3,2-c] pyridin-2-yl] -4H-
Quinolidine-3-carboxylate p-toluenesul
Others using 0.54 g (0.85 mmol) of fonate
Is reacted in the same manner as in Example 1 (c) to give the title compound
0.30 g was obtained as an orange solid. (Yield 82%) Melting point: 230-238 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 0.92-1.02
(m, 2H), 1.35-1.45 (m, 2H), 2.76-2.86 (m, 1H), 3.4
6-3.54 (m, 2H), 3.88-3.96 (m, 2H), 4.69 (s, 2H), 6.
66 (t, J = 72.0Hz, 1H), 7.92 (s, 1H), 8.22 (d, J = 7.5
Hz, 1H), 8.62 (s, 1H), 9.36 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 433 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3433, 16
57, 1450 (Example 14)1-cyclopropyl-8- [5,6-dihydro-4H-
Thieno [2,3-c] pyrrol-2-yl] -7-fur
Oro-9-methyl-4-oxo-4H-quinolidine-3
-Carboxylic acid (Exemplary Compound No. 1-909) (A) Ethyl 8- [5- (t-butoxycarbonyl)
-5,6-dihydro-4H-thieno [2,3-c] pyro
2-yl] -1-cyclopropyl-7-fluoro
-9-methyl-4-oxo-4H-quinolizin-3-ca
Ruboxylate 5-trityl-4,5,6,7-tetrahydrothieno
Instead of [3,2-c] pyridine, 5- (t-butoxy)
(Cicarbonyl) -5,6-dihydro-4H-thieno
1.10 g of [2,3-c] pyrrole (4.88 mmol)
The reaction was carried out in the same manner as in Example 1 (a) except that l) was used.
This gave 0.15 g of the title compound as an orange solid. (Income
13%) NMR spectrum (CDCl_Three, Δ): 0.76-0.82 (m, 2
H), 1.03-1.10 (m, 2H), 1.44 (t, J = 7.2Hz, 3H), 1.54
 (s, 9H), 2.28-2.38 (m, 1H), 2.96 (s, 3H), 4.43 (q,
 J = 7.2Hz, 2H), 4.56-4.80 (m, 4H), 6.95, 7.00 (each
 s, J = 4.8Hz, total 1H rotamer), 8.40 (s, 1H), 9.42
(d, J = 5.7Hz, 1H) MS spectrum (CI, m / z) 513 (M⁺+1) (B) ethyl 1-cyclopropyl-8- [5,6-di
Hydro-4H-thieno [2,3-c] pyrrole-2-i
Ru] -7-Fluoro-9-methyl-4-oxo-4H-
Quinolidine-3-carboxylate Ethyl 8- [5- (t-butoxycarbonyl) -5,
6-dihydro-4H-thieno [2,3-c] pyrrole-
2-yl] -1-cyclopropyl-7-fluoro-9-
Methyl-4-oxo-4H-quinolidine-3-carboxy
0.15 g (0.30 mmol) of sylate in methyl chloride
Trifluoroacetic acid 1.5m under ice-cooling.
After adding l, the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the obtained reaction solution was washed with saturated carbon
Neutralize with aqueous sodium hydrogen oxyate and methylene chloride three times
Extracted. The obtained organic phase is washed with a saturated aqueous sodium chloride solution.
And dried over anhydrous sodium sulfate, and the solvent is distilled off.
Thus, 78 mg of the title compound was obtained as a brown solid. (yield
62%) NMR spectrum (CDCl_Three, Δ): 0.75-0.81 (m, 2
H), 1.02-1.09 (m, 2H), 1.44 (d, J = 7.2Hz, 1H), 2.29
-2.39 (m, 1H), 2.98 (s, 3H), 4.20 (d, J = 2.7Hz, 2
H), 4.34 (d, J = 2.7Hz, 2H), 4.43 (q, J = 7.2Hz, 2H),
6.96 (s, 1H), 8.39 (s, 1H), 9.42 (d, J = 6.3Hz, 1H) (C) 1-cyclopropyl-8- [5,6-dihydro-
4H-thieno [2,3-c] pyrrol-2-yl] -7
-Fluoro-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-8- [5,6-dihi
Dro-4H-thieno [2,3-c] pyrrole-2-a
Ru] -7-Fluoro-9-methyl-4-oxo-4H-
78 mg of quinolidine-3-carboxylate (0.19
mmol), except that the reaction was conducted in the same manner as in Example 1 (c).
This gave 8 mg of the title compound as an orange solid. (Income
Rate 11%) Melting point: 193-197 ° C (decomposition) NMR spectrum (CDCl_Three, Δ): 0.83-0.90 (m, 2
H), 1.07-1.16 (m, 2H), 2.33-2.43 (m, 1H), 3.04 (s,
 3H), 4.24-4.28 (m, 2H), 4.39-4.43 (m, 2H), 7.01
(s, 1H), 8.58 (s, 1H), 9.33 (d, J = 6.0Hz, 1H) MS spectrum (FAB +, m / z) 385 (M⁺+
1) IR spectrum (KBr, ν_max  cm^-1): 3437, 17
30, 1666, 1431 (Example 15)1-cyclopropyl-8- [6-hydroxymethyl-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid (Exemplary Compound No. 1-323) (A) Ethyl 1-cyclopropyl-8- [6- (meth
(Methoxymethoxymethyl) -5-trityl-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridine-2-i
] -9-methyl-4-oxo-4H-quinolidine-3
-Carboxylate Under an argon atmosphere, 6- (methoxymethoxymethyl)-
5-trityl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridine 2.00 g (4.49 mol)
Is dissolved in 45 ml of tetrahydrofuran, and butyllithium is dissolved.
3.5ml (1.6M hexane solution)
mol) was added dropwise at -70 ° C or lower over 5 minutes. 1
After stirring for 2 hours, 2-isopropoxy-4,4,5,5-
1.4 ml of tramethyl-1,3,2-dioxaborolane
(6.86 mmol) was added dropwise over 5 minutes,
After the temperature was gradually raised, the mixture was stirred for 1 hour. After the completion of the reaction, the obtained reaction solution was added to acetic acid solution.
Butyl and a saturated aqueous solution of ammonium chloride.
Extraction three times. The obtained organic phase is dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue
Silica gel column chromatography gave 6-
(Methoxymethoxymethyl) -2- (4,4,5,5-
Tetramethyl-1,3,2-dioxaborolan-2-i
) -5-trityl-4,5,6,7-tetrahydrothio
1.28 g of eno [3,2-c] pyridine was converted to a white solid.
I got it. Under argon atmosphere, the obtained 6- (methoxy
Cymethoxymethyl) -2- (4,4,5,5-tetrame
Tyl-1,3,2-dioxaborolan-2-yl) -5
-Trityl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridine 1.00 g (1.71 mmol)
1), ethyl 8-chloro-1-cyclopropyl-9-
Methyl-4-oxo-4H-quinolidine-3-carboxy
0.47 g (1.54 mmol) of sylate and tetrakis
(Triphenylphosphine) palladium (0) 0.07
g with toluene 14ml, ethanol 6ml and 2M charcoal
3 ml of an aqueous solution of sodium citrate are sequentially added, and at 80 ° C. for 2 hours
The mixture was stirred while heating. After the completion of the reaction, the obtained reaction solution was cooled to room temperature.
After returning, ethyl acetate and water were added, and ethyl acetate was added three times.
Extracted. The obtained organic phase is washed with a saturated aqueous sodium chloride solution.
And dried over anhydrous sodium sulfate.
Was distilled off. The obtained residue is subjected to silica gel column chromatography.
Chromatography (elution solvent: hexane / ethyl acetate = 3 /
Subject to 2) to give 1.08 g of the title compound as an orange solid
Obtained. (Yield 97%) NMR spectrum (CDCl_Three, Δ): 0.70-0.75 (m, 2
H), 0.98-1.05 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 2.29
-2.39 (m, 1H), 2.41-2.46 (m, 1H), 2.86-2.94 (m, 1
H), 2.98 (s, 3H), 3.08-3.18 (m, 2H), 3.19 (s, 3H),
3.46-3.54 (m, 1H), 3.90-3.98 (m, 1H), 4.19-4.35
(m, 3H), 4.42 (q, J = 7.2Hz, 2H), 6.91 (s, 1H), 7.14
-7.58 (m, 16H), 8.38 (s, 1H), 9.35 (d, J = 7.5Hz, 1
H) (B) 1-cyclopropyl-8- [6- (methoxymeth
Xymethyl) -4,5,6,7-tetrahydrothieno
[3,2-c] pyridin-2-yl] -9-methyl-4
-Oxo-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-8- [6- (methoxymethoxymeth
Tyl) -5-trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -9-methyl
Ru-4-oxo-4H-quinolidine-3-carboxyle
Except that 1.08 g (1.49 mmol) was used.
The reaction was carried out in the same manner as in Example 1 (b) to give ethyl 1-cyclo.
Propyl-8- [6- (methoxymethoxymethyl)-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -9-methyl-4-oxo-4H-
Quinolidine-3-carboxylate p-toluenesul
To give ethyl 1-cyclopropyl-9-methyl
-4-oxo-8- [4,5,6,7-tetrahydrothi
Eno [3,2-c] pyridin-2-yl] -4H-quino
Lysine-3-carboxylate p-toluenesulfone
Instead of the acid salt, ethyl 1-cyclopropyl-8-
[6- (methoxymethoxymethyl) -4,5,6,7-
Tetrahydrothieno [3,2-c] pyridine-2-i
] -9-methyl-4-oxo-4H-quinolidine-3
Using carboxylate p-toluenesulfonate
Otherwise, the reaction was carried out in the same manner as in Example 1 (c) to give the title compound.
0.25 g of product was obtained as an orange solid. (38% yield) Melting point: 172-174 ° C NMR spectrum (CDCl_Three, Δ): 0.77-0.84 (m, 2
H), 1.06-1.14 (m, 2H), 2.35-2.45 (m, 1H), 2.65-2.9
1 (m, 2H), 3.06 (s, 3H), 3.21-3.31 (m, 1H), 3.42
(s, 3H), 3.58-3.64 (m, 1H), 3.76 (dd, J = 9.9 and 3.9
Hz, 1H), 4.03 (d, J = 15.1Hz, 1H), 4.10 (d, J = 15.1H
z, 1H), 4.70 (s, 2H), 7.05 (s, 1H), 7.35 (d, J = 7.5
Hz, 1H), 8.56 (d, J = 1.2Hz, 1H), 9.28 (d, J = 7.5Hz,
1H) (C) 1-cyclopropyl-8- [6-hydroxymethyl
-4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl] -9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid 1-cyclopropyl-8- [7- (methoxymethoxy)
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl] -9-methyl-4-oxo-4H
-Instead of quinolidine-3-carboxylic acid, 1-cyclo
Propyl-8- [6- (methoxymethoxymethyl)-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -9-methyl-4-oxo-4H-
Other than using 0.15 g of quinolidine-3-carboxylic acid,
The reaction was carried out in the same manner as in Example 8 (c) to give the title compound 0.1
3 g were obtained as an orange solid. (Yield 92%) Melting point: 133-136 ° C NMR spectrum (CDCl_Three, Δ): 0.78-0.84 (m, 2
H), 1.07-1.12 (m, 2H), 2.35-2.45 (m, 1H), 2.60-2.7
2 (m, 1H), 2.84-2.92 (m, 1H), 3.06 (s, 3H), 3.14-
3.22 (m, 1H), 3.59-3.66 (m, 1H), 3.83-3.88 (m, 1
H), 3.97-4.14 (m, 2H), 7.05 (s, 1H), 7.35 (d, J = 7.5
Hz, 1H), 8.57 (s, 1H), 9.28 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z) 411 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3372, 16
48, 1463 (Example 16)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methyl-4-oxo-4H-quinolizin-3-ca
Rubonic acid (Exemplary Compound No. 1-583) (a) Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Noridine-3-carboxylate Under an argon atmosphere, 4-tritylamino-4,5,6,
6.51 g of 7-tetrahydrobenzo [b] thiophene
(16.5 mmol) in 150 ml of tetrahydrofuran
Dissolved in s-butyllithium (1.0 M cyclohexyl)
Sun-hexane solution) 37 ml (37.0 mmol)
At -70 ° C or lower, the solution was added dropwise over 15 minutes. Stir for 1 hour
Then, at the same temperature, 2-isopropoxy-4,4,5,5-
Tetramethyl-1,3,2-dioxaborolane 12.2
ml (60 mmol) over 10 minutes.
Then, the mixture was stirred at the same temperature for 1 hour. After the completion of the reaction, the obtained reaction solution was mixed with acetic acid.
Butyl and a saturated aqueous solution of ammonium chloride.
Extracted. The obtained organic phase is washed with saturated aqueous sodium chloride.
After washing with a solution, dry over anhydrous sodium sulfate and dissolve under reduced pressure.
The solvent was distilled off to obtain 11.02 g of a boric acid compound as a white solid.
I got it. Under an argon atmosphere, the obtained boric acid compound
5.33 g (1.71 mmol), ethyl 8-chloro
-1-cyclopropyl-9-methyl-4-oxo-4H
-1.23 g of quinolidine-3-carboxylate (4.
02 mmol) and tetrakis (triphenylphosphine)
N) 0.25 g of palladium (0) and 56 m of toluene
1, ethanol 24ml and 2M sodium carbonate aqueous solution
4 ml was sequentially added, and the mixture was heated and stirred at 80 ° C. for 3 hours. After the completion of the reaction, the obtained reaction solution was brought to room temperature.
After returning, ethyl acetate and water were added, and ethyl acetate was added three times.
Extracted. The obtained organic phase is washed with a saturated aqueous sodium chloride solution.
After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure.
Distilled off. Hexane / ethyl acetate mixed solution in the obtained residue
The liquid was added. The resulting precipitate is collected by filtration, and hexane / acetic acid
After washing with an ethyl mixed solution, 2.58 g of the title compound was added.
Obtained as an orange solid. (96% yield) NMR spectrum (CDCl_Three, Δ): 0.73-0.79 (m, 2
H), 1.02-1.09 (m, 2H), 1.22-1.30 (m, 2H), 1.43 (t,
 J = 7.1Hz, 3H), 1.65-1.75 (m, 1H), 2.03-2.17 (m, 1
H), 2.30-2.40 (m, 1H), 2.65-2.88 (m, 2H), 2.94 (s,
 3H), 3.82-3.86 (m, 1H), 4.43 (q, J = 7.1Hz, 2H), 6.4
3 (s, 1H), 7.06 (d, J = 7.5Hz, 1H), 7.18-7.63 (m, 15
H), 8.38 (s, 1H), 9.35 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z): 665 (M⁺+1) (B) Ethyl 8- [4-amino-4,5,6,7-te
Trahydrobenzo [b] thiophen-2-yl] -1-
Cyclopropyl-9-methyl-4-oxo-4H-quino
Lysine-3-carboxylate hydrochloride Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
2.53 g of noridine-3-carboxylate (3.80 g
mmol) in 150 ml of tetrahydrofuran,
Under ice-cooling, saturated hydrogen chloride tetrahydrofuran solution 30 ml
Was added and stirred at room temperature for 4 hours. The generated precipitate is filtered.
After washing with diethyl ether, the title compound 1.
71 g were obtained as an orange solid. (Yield 98%) NMR spectrum (CD_ThreeOD, δ): 0.70-0.73 (m, 2
H), 1.07-1.12 (m, 2H), 1.39 (t, J = 7.1Hz, 3H), 1.95
-2.50 (m, 5H), 2.94-3.00 (m, 2H), 3.05 (s, 3H), 4.3
6 (q, J = 7.1Hz, 2H), 4.50-4.53 (m, 1H), 7.35 (d, J =
7.8Hz, 1H), 7.47 (s, 1H), 8.40 (s, 1H), 9.32 (d, J =
(7.8Hz, 1H) MS spectrum (CI, m / z): 423 (M⁺+1) (C) 8- [4-amino-4,5,6,7-tetrahydrid
Robenzo [b] thiophen-2-yl] -1-cycloprop
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid Ethyl 8- [4-amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
1.70 g of -3-carboxylate hydrochloride (3.69
mmol) in 50 ml of tetrahydrofuran, and 1
9.0 ml of N sodium hydroxide aqueous solution (9.0 mm
l) and 15 ml of ethanol were added. Stir for 10 hours
Thereafter, 25 ml of water was added to the obtained reaction solution,
After partially distilling off tetrahydrofuran and ethanol,
The insoluble material was removed by filtration. 1N hydrochloric acid was added to the obtained filtrate, and p
H was adjusted to neutral. The generated precipitate is collected by filtration and washed with water.
This gave 1.34 g of the title compound as an orange solid. (Income
Rate 92%) Melting point: 143-148 ° C NMR spectrum (CDCl_Three, Δ): 0.77-0.83 (m, 2
H), 1.06-1.11 (m, 2H), 1.60-2.20 (m, 4H), 2.35-2.4
5 (m, 1H), 2.78-2.94 (m, 2H), 3.08 (s, 3H), 4.00-
4.04 (m, 1H), 7.35 (s, 1H), 7.37 (d, J = 7.5Hz, 1H),
8.56 (s, 1H), 9.27 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z): 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3371, 16
47, 1462 (Example 17)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-7-Fluoro-9-methyl-4-oxo-4H-quino
Lysine-3-carboxylic acid (Exemplified Compound No. 1-663) Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
Instead of ethyl 8-chloro-1-cyclopropyl
Ru-7-fluoro-9-methyl-4-oxo-4H-ki
1.50 g of noridine-3-carboxylate (4.6 m
mol), and reacted in the same manner as in Example 16.
This gave 0.56 g of the title compound as an orange solid. (Income
30%) Melting point: 238-240 ° C NMR spectrum (DMSO-d₆, Δ): 0.73-0.80
(m, 2H), 1.04-1.11 (m, 2H), 1.45-2.08 (m, 4H), 2.40-
2.64 (m, 1H), 2.76-2.84 (m, 2H), 2.97 (s, 3H), 3.85-3.91
(m, 1H), 7.43 (s, 1H), 8.24 (s, 1H), 9.30-9.45 (m, 1H) MS spectrum (CI, m / z) 413 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 146
5,1663,3424 (Example 18)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-Difluoromethoxy-4-oxo 4H-quinoli
Gin-3-carboxylic acid (Exemplary Compound No. 1-631) Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
Instead of ethyl 8-chloro-1-cyclopropyl
Ru-9-difluoromethoxy-4-oxo-4H-quino
Others using 0.50 g of lysine-3-carboxylate
Was reacted in the same manner as in Example 16 to give the title compound 76m
g were obtained as an orange solid. (12%) Melting point: 174-175 ° C NMR spectrum (DMSO-d₆, Δ): 0.67-0.70
(m, 2H), 0.98-1.03 (m, 2H), 1.48-1.62 (m, 1H), 1.70-
1.85 (m, 1H), 1.90-2.07 (m, 2H), 2.33-2.42 (m, 1H), 2.29
-2.36 (m, 2H), 3.89-3.92 (m, 1H), 7.02 (t, J = 23.2Hz, 1
H), 7.93 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 8.14 (s, 1H), 9.
19 (d, J = 7.8Hz, 1H) MS spectrum (CI, m / z) 447 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 145
9,1639,3410 (Example 19)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methoxy-4-oxo-4H-quinolidine-3-
carboxylic acid (Exemplary Compound No. 1-623) Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
Instead of ethyl 8-chloro-1-cyclopropyl
Le-9-methoxy-4-oxo-4H-quinolidine-3
Example 1 except that 0.50 g of carboxylate was used
Reaction was carried out in the same manner as in 6 to give 48 mg of the title compound as an orange solid
As obtained. (Yield 7%) Melting point: 223-224 ° C NMR spectrum (DMSO-d₆, Δ): 0.70-0.75
(m, 2H), 0.98-1.03 (m, 2H), 1.45-1.56 (m, 1H), 1.67-
1.82 (m, 1H), 1.90-2.06 (m, 2H), 2.59-2.70 (m, 1H), 2.75
-2.82 (m, 2H), 3.77 (s, 3H), 3.78-3.89 (m, 1H), 7.96 (d,
J = 8.1Hz, 1H), 8.01 (s, 1H), 8.08 (s, 1H), 9.10 (d, J = 7.5H
z, 1H) MS spectrum (CI, m / z) 411 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 146
3,1644,3375 (Example 20)8- [7-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methyl-4-oxo-4H-quinolizin-3-ca
Rubonic acid (Exemplary Compound No. 1-815) 4-tritylamino-4,5,6,7-tetrahydrobe
7-tritylamino in place of benzo [b] thiophene
-4,5,6,7-tetrahydrobenzo [b] thiophene
Except that 1.50 g (3.80 mmol) was used.
The reaction was conducted in the same manner as in Example 16 to obtain 0.15 g of the title compound.
Obtained as a colored solid. (Yield 29%) Melting point: 214-216 ° C NMR spectrum (DMSO-d₆, Δ): 0.69-0.74
(m, 2H), 1.04-1.10 (m, 2H), 1.46-1.57 (m, 1H), 1.63-
1.79 (m, 1H), 1.89-2.09 (m, 2H), 2.44-2.64 (m, 3H),
3.04 (s, 3H), 3.91-3.96 (m, 1H), 7.34 (s, 1H), 7.63 (d, J =
7.6Hz, 1H), 8.23 (s, 1H), 9.22 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z): 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 143
7,1644 (Example 21)1-cyclopropyl-8- [7-methoxy-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl] -9-methyl-4-oxo-4H-quinolizi
-3-carboxylic acid (Exemplary Compound No. 1-411) (A) Ethyl 1-cyclopropyl-8- [7-methoxy
C-5-trityl-4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -9-methyl-
4-oxo-4H-quinolidine-3-carboxylate Under an argon atmosphere, 7-methoxy-5-trityl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridi
0.89 g (2.16 mmol) of tetrahydrofuran
Dissolved in 25 ml of butyllithium (1.6 M
3.2 ml (5.12 mmol) of sun solution) at -70 ° C
Below, it dripped over 5 minutes. Stir at the same temperature for 1.5 hours
After stirring, 0.5 ml of trimethyl borate (4.46 mmol
l) was added dropwise over 5 minutes, and the mixture was stirred at the same temperature for 1 hour. After the completion of the reaction, water was added to the obtained reaction solution.
After adding 1N hydrochloric acid to adjust the pH to neutral,
Extracted three times with ethyl acid. The organic phase obtained is saturated sodium chloride
After washing with thorium aqueous solution, dry with anhydrous sodium sulfate
The solvent was distilled off under reduced pressure, and 1.17 g of the boric acid compound was whitened.
Obtained as a colored solid. Under an argon atmosphere, the obtained borated compound
Product, ethyl 8-chloro-1-cyclopropyl-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Rate 0.25 g (0.83 mmol) and tetrakis
(Triphenylphosphine) palladium (0) 0.05
g with toluene 14ml, ethanol 6ml and 2M charcoal
1 ml of aqueous sodium acid solution was added in sequence, and the mixture was added at 80 ° C for 1 hour.
The mixture was stirred while heating. After the completion of the reaction, the obtained reaction solution was cooled to room temperature.
After returning, ethyl acetate and water were added, and ethyl acetate was added three times.
Extracted. The obtained organic phase is washed with a saturated aqueous sodium chloride solution.
And dried over anhydrous sodium sulfate.
Distilled off. The obtained residue is subjected to silica gel column chromatography.
Raffy (eluent: hexane / ethyl acetate = 2 / 1-1)
/ 1) to give 0.56 g of the title compound as an orange solid
Almost quantitatively. The NMR spectrum (CDCl_Three, Δ): 0.7
0-0.75 (m, 2H), 0.98-1.04 (m, 2H), 1.42 (t, J = 7.1H
z, 3H), 2.28-2.38 (m, 1H), 2.54-2.64 (m, 1H), 2.91
-3.01 (m, 4H), 3.20-3.28 (m, 1H), 3.54 (s, 3H), 3.6
0-3.69 (m, 1H), 4.42 (q, J = 7.1Hz, 2H), 4.58 (m, 1
H), 6.90 (s, 1H), 7.10-7.62 (m, 16H), 8.39 (s, 1
H), 9.35 (d, J = 7.5Hz, 1H) (B) ethyl 1-cyclopropyl-8- [7-methoxy
C-4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl] -9-methyl-4-oxo-
4H-quinolidine-3-carboxylate p-tolue
Sulfonic acid salt Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-8- [7-methoxy-5-triti
-4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl] -9-methyl-4-oxo-
0.56 g of 4H-quinolidine-3-carboxylate
(0.83 mmol), except that Example 1 (b) was used.
In the same manner, 0.33 g of the title compound was converted into an orange solid.
I got it. (Yield 65%) NMR spectrum (CDCl_Three, Δ): 0.73-0.78 (m, 2
H), 1.02-1.08 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 2.28
-2.38 (m, 4H), 2.94 (s, 3H), 3.48 (s, 3H), 3.70 (s,
 2H), 4.38-4.60 (m, 4H), 4.72 (s, 1H), 7.00-7.17
(m, 4H), 7.70 (d, J = 7.8Hz, 1H), 8.42 (s, 1H), 9.34
(d, J = 7.0Hz, 1H) MS spectrum (CI, m / z): 439 (M⁺+1) (C) 1-cyclopropyl-9-methyl-8- [7-me
Toxi-4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4-oxo-4H-quino
Lysine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4,5,6,7-tetrahydrothieno [3,2
-C] pyridin-2-yl] -4H-quinolizin-3-
Carboxylates Instead of p-Toluenesulfonate
In addition, ethyl 1-cyclopropyl-8- [7-methoxy
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl] -9-methyl-4-oxo-4H
-Quinolidine-3-carboxylate p-toluene
Others using 0.33 g (0.54 mmol) of sulfonate
Is reacted in the same manner as in Example 1 (c) to give the title compound
0.20 g was obtained as an orange solid. (Yield 90%) Melting point: 92-100 ° C NMR spectrum (CDCl_Three, Δ): 0.79-0.85 (m, 2
H), 1.07-1.14 (m, 2H), 2.35-2.45 (m, 1H), 3.06 (s,
 3H), 3.11 (dd, J = 13.5 and 3.4Hz, 1H), 3.40 (dd, J = 1
3.5 and 3.3Hz, 1H), 3.55 (s, 3H), 3.91 (d, J = 16.4H
z, 1H), 4.04 (d, J = 16.4Hz, 1H), 4.32 (m, 1H), 7.04
 (s, 1H), 7.35 (d, J = 7.5Hz, 1H), 8.58 (s, 1H), 9.2
9 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z): 411 (M⁺+1) IR spectrum (KBr, ν_maxcm^-1): 3421,165
2, 1463 (Example 22)8- [4-amino-4,5,6,7-tetrahydrothier
No [2,3-c] pyridin-2-yl] -1-cycloprop
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid (Exemplary compound number 1-443) (A) Ethyl 1-cyclopropyl-9-methyl-8-
[6-Trityl-4-tritylamino-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-2-i
4-oxo-4H-quinolidine-3-carboxy
rate 6-trityl-4-tritylamino under an argon atmosphere
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridine (1.41 g, 2.21 mmol)
It was dissolved in 40 ml of lofuran, and s-butyllithium (1.
0M cyclohexane-hexane solution) 5.1 ml
(5.1 mmol) at -70 ° C or lower over 5 minutes
I gave it. After stirring at the same temperature for 1 hour, trimethyl borate was added.
65 ml (5.80 mmol) was added dropwise over 5 minutes,
The mixture was stirred at the same temperature for 1 hour. After the completion of the reaction, water was added to the obtained reaction solution.
After adding 1N hydrochloric acid to adjust the pH to neutral,
Extracted three times with ethyl acid. The organic phase obtained is saturated sodium chloride
After washing with thorium aqueous solution, dry with anhydrous sodium sulfate
The solvent was distilled off under reduced pressure, and 1.81 g of the boric acid compound was whitened.
Obtained as a colored solid. Under an argon atmosphere, the obtained borated compound
Product, ethyl 8-chloro-1-cyclopropyl-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Rate 0.33 g (1.09 mmol) and tetrakis
(Triphenylphosphine) palladium (0) 0.08
g with toluene 14ml, ethanol 6ml and 2M charcoal
2 ml of an aqueous solution of sodium citrate is added sequentially, and the mixture is
The mixture was stirred while heating. After the completion of the reaction, the obtained reaction solution was cooled to room temperature.
After returning, ethyl acetate and water were added, and ethyl acetate was added three times.
Extracted. The obtained organic phase is washed with a saturated aqueous sodium chloride solution.
And dried over anhydrous sodium sulfate.
Distilled off. The obtained residue is subjected to silica gel column chromatography.
Raffy (elution solvent: hexane / ethyl acetate = 3 / 2-
1/1) to give 0.95 g of the title compound as an orange solid
I got it. (96% yield) MS spectrum (FAB +, m / z): 908 (M⁺+
1) (B) ethyl [4-amino-4,5,6,7-tetra
Hydrothieno [2,3-c] pyridin-2-yl] -1
-Cyclopropyl-9-methyl-8-4-oxo-4H
-Quinolidine-3-carboxylate dihydrochloride Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-9-methyl-8- [6-trityl
-4-Tritylamino-4,5,6,7-tetrahydro
Thieno [2,3-c] pyridin-2-yl] -4-oxo
So-4H-quinolidine-3-carboxylate 0.95
Example 16 except that g (1.05 mmol) was used.
The reaction was carried out in the same manner as in (b) to give 0.54 g of the title compound in orange.
Obtained almost quantitatively as a colored solid. MS spectrum (CI, m / z): 424
(M⁺+1) (C) 8- [4-amino-4,5,6,7-tetrahydrid
Rothieno [2,3-c] pyridin-2-yl] -1-si
Clopropyl-9-methyl-4-oxo-4H-quinoli
Gin-3-carboxylic acid Ethyl 8- [4-amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-Carboxylate Instead of hydrochloride, ethyl
[4-amino-4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl] -1-cyclopro
Pill-9-methyl-8-4-oxo-4H-quinolidine
-3-carboxylate dihydrochloride 0.54 g (1.0
Except that 5 mmol) was used.
Reaction gave 0.25 g of the title compound as an orange solid.
Was. (60% yield) Melting point: 185-195 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.04-1.09
(m, 2H), 1.43-1.49 (m, 2H), 2.63-2.73 (m, 1H), 3.3
3 (s, 3H), 4.24 (dd, J = 15.3 and 5.1Hz, 1H), 4.64 (d,
 J = 13.9Hz, 1H), 4.87 (d, J = 16.6Hz, 1H), 5.04 (d, J
= 16.3Hz, 1H), 5.44 (d, J = 3.7Hz, 1H), 7.87 (s, 1H),
7.97 (d, J = 7.5Hz, 1H), 8.77 (s, 1H), 9.41 (d, J = 7.
(5Hz, 1H) MS spectrum (CI, m / z): 396 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3397, 16
48, 1464 (Example 23)8- [4-amino-6-methyl-4,5,6,7-tet
Lahydrothieno [2,3-c] pyridin-2-yl]-
1-cyclopropyl-9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid (Exemplary Compound No. 1-124
3) (A) Ethyl 1-cyclopropyl-9-methyl-8-
[6-Methyl-4-tritylamino-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridine-2-i
4-oxo-4H-quinolidine-3-carboxy
rate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
6-methyl-4-tritylamino-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine 0.85
Example 22 except that g (2.08 mmol) was used.
Reaction was carried out in the same manner as in (a), and 0.70 g of the title compound was placed in orange.
Obtained almost quantitatively as a colored solid. MS spectrum (CI, m / z): 680
(M⁺+1) (B) ethyl 8- [4-amino-6-methyl-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
N-2-yl] -1-cyclopropyl-9-methyl-4
-Oxo-4H-quinolizin-3-carboxylate
Dihydrochloride Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Instead of Norridine-3-carboxylate, ethyl
1-cyclopropyl-9-methyl-8- [6-methyl-
4-tritylamino-4,5,6,7-tetrahydrothio
Eno [2,3-c] pyridin-2-yl] -4-oxo
0.70 g of -4H-quinolidine-3-carboxylate
Example 16 (b) except that (1.02 mmol) was used.
And react with 0.57 g of the title compound in an orange solid.
Was obtained almost quantitatively. NMR spectrum (CD_ThreeOD, δ): 0.69-0.75 (m, 2
H), 1.07-1.12 (m, 2H), 1.40 (t, J = 7.1Hz, 1H), 2.40-
2.50 (m, 1H), 3.03 (s, 3H), 3.20 (s, 3H), 3.75-4.1
0 (m, 2H), 4.37 (q, J = 7.1Hz, 2H), 4.57-4.82 (m, 2
H), 5.03-5.09 (m, 2H), 7.34 (d, J = 7.5Hz, 1H), 7.64
 (s, 1H), 8.41 (s, 1H), 9.29 (d, J = 7.5Hz, 1H) (C) 8- [4-amino-6-methyl-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-2-i
1] -cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid Ethyl 8- [4-amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-Carboxylate Instead of hydrochloride, ethyl
8- [4-amino-6-methyl-4,5,6,7-tet
Lahydrothieno [2,3-c] pyridin-2-yl]-
1-cyclopropyl-9-methyl-4-oxo-4H-
Quinolizin-3-carboxylate dihydrochloride 0.54
Example 16 except that g (1.05 mmol) was used.
The reaction was carried out in the same manner as in (c) to give 0.32 g of the title compound in orange.
Obtained as a colored solid. (80% yield) Melting point: 140-145 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.04-1.09
(m, 2H), 1.43-1.48 (m, 2H), 2.63-2.73 (m, 1H), 3.3
2 (s, 3H), 3.46 (s, 3H), 4.18 (dd, J = 14.9 and 4.9H
z, 1H), 4.59 (d, J = 14.9Hz, 1H), 4.69 (d, J = 16.1Hz,
 1H), 5.17 (d, J = 15.6Hz, 1H), 5.47 (d, J = 4.6Hz, 1
H), 7.88 (s, 1H), 7.97 (d, J = 7.5Hz, 1H), 8.78 (s, 1H)
1H), 9.41 (d, J = 7.5Hz, 1H) MS spectrum (CI, m / z): 410 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3366, 16
53, 1462 (Example 24)8- [4-amino-7,7-dimethyl-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-2-i
Ru] -1-cyclopropyl-7-fluoro-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid (Example
Compound No. 1-1287) (A) ethyl 8- [4- (t-butoxycarbonyla)
Mino) -6- (t-butoxycarbonyl) -7,7-di
Methyl-4,5,6,7-tetrahydrothieno [2,3
-C] pyridin-2-yl] -1-cyclopropyl-7
-Fluoro-9-methyl-4-oxo-4H-quinolidine
N-3-carboxylate Under an argon atmosphere, 4- (t-butoxycarbonylamino)
No) -6- (t-butoxycarbonyl) -7,7-dim
Cyl-4,5,6,7-tetrahydrothieno [2,3-
c] 0.98 g (2.56 mmol) of pyridine
Dissolve in 40 ml of hydrofuran and add s-butyllithium
(1.0 M cyclohexane in hexane) 7.7 m
1 (7.7 mmol) at -70 ° C or lower over 5 minutes
It was dropped. After stirring at the same temperature for 30 minutes, trimethyl borate
0.86 ml (7.7 mmol) is added dropwise over 5 minutes
Then, the mixture was stirred at the same temperature for 30 minutes. After the completion of the reaction, water, vinegar was added to the obtained reaction solution.
Ethyl acetate and a saturated aqueous solution of ammonium chloride.
Extracted three times with chill. The obtained organic phase is saturated with sodium chloride.
After washing with an aqueous solution of
The solvent was distilled off under pressure, and 1.12 g of a boric acid compound was added to a pale yellow foam.
Obtained as a solid. Under an argon atmosphere, the obtained boric acid compound
And 34 ml of a mixed solvent of toluene / ethanol = 7/3
1.7 ml of 2M sodium carbonate aqueous solution
The air was sufficiently degassed by bubbling. More ethyl
  8-chloro-1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
0.55 g (1.70 mmol) of xylate and tetrakis
S (triphenylphosphine) palladium (0) 0.2
6 g, and the mixture was heated and stirred at 80 ° C. for 3 hours. After the completion of the reaction, the obtained reaction solution was cooled to room temperature.
After returning, ethyl acetate and saturated aqueous sodium chloride solution were added.
In addition, the mixture was extracted twice with ethyl acetate. No organic phase obtained
The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. Profit
The residue obtained is separated by silica gel column chromatography (solvent).
Solvent: chloroform / ethyl acetate = 50/1)
This gave 0.93 g of the title compound as an orange solid. (Income
Rate 82%) NMR spectrum (CDCl_Three, Δ): 0.75-0.81 (m, 2
H), 1.03-1.10 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.
48 (s, 9H), 1.52 (s, 9H), 1.78 (s, 3H), 1.99 (s, 3
H), 2.25-2.40 (m, 1H), 2.95 (s, 3H), 3.50-3.60 (m,
1H), 4.05-4.15 (m, 1H), 4.44 (q, J = 7.1Hz, 2H), 4.70
-4.80 (m, 1H), 4.85-4.95 (m, 1H), 7.04 (s, 1H),
8.39 (s, 1H), 9.41 (d, J = 5.9Hz, 1H) MS spectrum (CI, m / z): 670 (M⁺+1) (B) 8- [4- (t-butoxycarbonylamino)-
6- (t-butoxycarbonyl) -7,7-dimethyl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl] -1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
carboxylic acid Ethyl 8- [4- (t-butoxycarbonylamino)
-6- (t-butoxycarbonyl) -7,7-dimethyl
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridin-2-yl] -1-cyclopropyl-7-fur
Oro-9-methyl-4-oxo-4H-quinolidine-3
To 0.92 g (1.37 mmol) of carboxylate
20 ml of tetrahydrofuran, 1N aqueous sodium hydroxide
Add 5 ml of the solution and 5 ml of ethanol, and add 4 hours
Stirred. After completion of the reaction, 1N hydrochloric acid was added to the obtained reaction solution.
To pH 5 with ethyl acetate and saturated ammonium chloride.
And an aqueous solution, and separated. The obtained organic phase is sulfuric anhydride
After drying over magnesium acid, the solvent was distilled off under reduced pressure to give the title.
0.96 g of the compound was obtained almost quantitatively as an orange foam.
Was. The NMR spectrum (CDCl_Three, Δ): 0.8
0-0.88 (m, 2H), 1.09-1.15 (m, 2H), 1.47 (s, 9H),
1.52 (s, 9H), 1.79 (s, 3H), 2.00 (s, 3H), 2.30-2.45
 (m, 1H), 3.02 (s, 3H), 3.50-3.60 (m, 1H), 4.05-4.1
7 (m, 1H), 4.70-4.90 (m, 1H), 4.91-4.94 (m, 1H), 7.
10 (s, 1H),, 8.58 (s, 1H), 9.32 (d, J = 5.9Hz, 1H),
 13.88 (brs, 1H) MS spectrum (CI, m / z): 642 (M⁺+1) (C) 8- [4-amino-7,7-dimethyl-4,5,
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -1-cyclopropyl-7-fluoro-9-
Methyl-4-oxo-4H-quinolidine-3-carboxyl
acid Under a nitrogen atmosphere, 8- [4- (t-butoxycarbonyl)
Mino) -6- (t-butoxycarbonyl) -7,7-di
Methyl-4,5,6,7-tetrahydrothieno [2,3
-C] pyridin-2-yl] -1-cyclopropyl-7
-Fluoro-9-methyl-4-oxo-4H-quinolidine
To 0.94 g (1.46 mmol) of -3-carboxylic acid
60 ml of methylene chloride is added, and hydrogen chloride gas is added under ice cooling.
After blowing, the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the pressure was reduced from the obtained reaction solution.
The solvent was evaporated under reduced pressure to obtain the dihydrochloride of the title compound. Get
10 ml of water was added to the obtained dihydrochloride, and 1N sodium hydroxide was added.
After adjusting the pH to 12 with an aqueous solution of
Neutralized with N hydrochloric acid. The precipitate formed is collected by filtration, washed with water
This gave 0.40 g of the title compound as an orange solid. (Yield 6
2%) Melting point: 166-168 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.05-1.15
(m, 2H), 1.43-1.47 (m, 2H), 2.04 (s, 3H), 2.16 (s,
 3H), 2.60-2.70 (m, 1H), 3.29 (s, 3H), 4.39 (dd, J = 1
5.4 and 5.1Hz, 1H), 4.45-4.57 (m, 1H), 5.44-5.46 (m, 1
H), 7.72 (s, 1H), 8.80 (s, 1H), 9.42 (d, J = 4.6Hz,
1H) MS spectrum (CI, m / z): 442 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3420, 16
64, 1466 (Example 25)8- [7,7-dimethyl-4-methylamino-4,5
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -1-cyclopropyl-7-fluoro-9-
Methyl-4-oxo-4H-quinolidine-3-carboxyl
acid (Exemplified Compound No. 1-1301) (A) Ethyl 8- [4-[(t-butoxycarboni
Ru) (methyl) amino] -6- (t-butoxycarboni
) -7,7-dimethyl-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridin-2-yl] -1-si
Clopropyl-7-fluoro-9-methyl-4-oxo
-4H-quinolidine-3-carboxylate 4- (t-butoxycarbonylamino) -6- (t-bu
Toxylcarbonyl) -7,7-dimethyl-4,5,6
Instead of 7-tetrahydrothieno [2,3-c] pyridine
4-[(t-butoxycarbonyl) (methyl) amino
No] -6- (t-butoxycarbonyl) -7,7-dim
Cyl-4,5,6,7-tetrahydrothieno [2,3-
c] Pyridine 0.79 g (1.99 mmol) was used.
Otherwise, reacting in the same manner as in Example 24 (a),
This gave 0.63 g of an orange foam. (69% yield) NMR spectrum (CDCl_Three, Δ): 0.75-0.81 (m, 2
H), 1.03-1.10 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.
50 (s, 9H), 1.51 (s, 9H), 1.80 (brs, 3H), 1.96 (br
s, 3H), 2.25-2.40 (m, 1H), 2.74 (brs, 3H), 2.96 (s,
 3H), 3.60-4.00 (m, 2H), 4.43 (q, J = 7.1Hz, 2H), 5.
00-5.40 (m, 2H), 6.91 (s, 1H), 8.39 (s, 1H), 9.41
(d, J = 6.1Hz, 1H) MS spectrum (CI, m / z): 684 (M⁺+1) (B) 8- [4-[(t-butoxycarbonyl) (meth
Ru) amino] -6- (t-butoxycarbonyl) -7,
7-dimethyl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl] -1-cyclopro
Pill-7-fluoro-9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid Ethyl 8- [4- (t-butoxycarbonylamino)
-6- (t-butoxycarbonyl) -7,7-dimethyl
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridin-2-yl] -1-cyclopropyl-7-fur
Oro-9-methyl-4-oxo-4H-quinolidine-3
-Ethyl 8- [4-[(t
-Butoxycarbonyl) (methyl) amino] -6- (t
-Butoxycarbonyl) -7,7-dimethyl-4,5,
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -1-cyclopropyl-7-fluoro-9-
Methyl-4-oxo-4H-quinolidine-3-carboxy
0.605 g (0.884 mmol) of sylate was used.
Otherwise, reacting in the same manner as in Example 24 (b),
0.487 g of the product as an orange solid. (Yield 84%) NMR spectrum (CDCl_Three, Δ): 0.80-0.90 (m, 2
H), 1.09-1.16 (m, 2H), 1.51 (s, 9H), 1.52 (s, 9
H), 1.83 (brs, 3H), 1.97 (brs, 3H), 2.34-2.44 (m, 1
H), 2.75 (brs, 3H), 3.03 (s, 3H), 3.65-4.00 (m, 2
H), 5.00-5.40 (m, 2H), 6.90 (s, 1H), 8.59 (s, 1
H), 9.34 (d, J = 4.4Hz, 1H), 13.88 (s, 1H) MS spectrum (CI, m / z): 656 (M⁺+1) (C) 8- [7,7-dimethyl-4-methylamino-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl] -1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
carboxylic acid 8- [4- (t-butoxycarbonylamino) -6
(T-butoxycarbonyl) -7,7-dimethyl-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
N-2-yl] -1-cyclopropyl-7-fluoro-
9-methyl-4-oxo-4H-quinolizin-3-cal
8- [4-[(t-butoxycarbonyl) instead of boric acid
Ru) (methyl) amino] -6- (t-butoxycarboni
) -7,7-dimethyl-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridin-2-yl] -1-si
Clopropyl-7-fluoro-9-methyl-4-oxo
0.485 g of -4H-quinolidine-3-carboxylic acid
Example 24 (c) except that (0.74 mmol) was used.
To give 0.22 g of the title compound as an orange solid
I got it. (Yield 65%) Melting point: 223-225 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.05-1.15
(m, 2H), 1.41-1.47 (m, 2H), 2.04 (s, 3H), 2.16 (s,
 3H), 2.60-2.70 (m, 1H), 3.24 (s, 3H), 3.29 (s, 3H),
 4.39 (dd, J = 15.6 and 5.1Hz, 1H), 4.46-4.54 (m, 1H), 5.
20-5.24 (m, 1H), 7.68 (s, 1H),, 8.80 (s, 1H), 9.4
2 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z): 456 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3422, 16
64, 1467 (Example 26)1-cyclopropyl-7-fluoro-9-methyl-8-
[Spiro [4-amino-4,5,6,7-tetrahydro
Thieno [2,3-c] pyridine-4,1′-cyclopro
Pan] -2-yl] -4-oxo-4H-quinolidine-
3-carboxylic acid (Exemplary Compound No. 1-1315) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [spiro [4- (t-butoxycarbonyl)
Ru) amino-6- (t-butoxycarbonyl) -4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
-7,1'-Cyclopropane] -2-yl] -4-o
Xo-4H-quinolidine-3-carboxylate 4- (t-butoxycarbonylamino) -6- (t-bu
Toxylcarbonyl) -7,7-dimethyl-4,5,6
Instead of 7-tetrahydrothieno [2,3-c] pyridine
Spiro [4- (t-butoxycarbonyl) amino-
6- (t-butoxycarbonyl) -4,5,6,7-te
Trahydrothieno [2,3-c] pyridine-7,1'-
Cyclopropane] (1.0 g, 2.6 mmol) was used.
Otherwise, reacting in the same manner as in Example 24 (a),
0.36 g of the product was obtained as an orange foam. (Yield 21%) MS spectrum (CI, m / z): 668 (M⁺+1) (B) 1-cyclopropyl-7-fluoro-9-methyl
-8- [spiro [4- (t-butoxycarbonyl) amido]
No-6- (t-butoxycarbonyl) -4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-7,
1'-cyclopropane] -2-yl] -4-oxo-4
H-quinolidine-3-carboxylic acid Ethyl 8- [4- (t-butoxycarbonylamino)
-6- (t-butoxycarbonyl) -7,7-dimethyl
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridin-2-yl] -1-cyclopropyl-7-fur
Oro-9-methyl-4-oxo-4H-quinolidine-3
-Ethyl 1-cyclopropyl in place of carboxylate
Ru-7-fluoro-9-methyl-8- [spiro [4-
(T-butoxycarbonyl) amino-6- (t-butoxy
(Cicarbonyl) -4,5,6,7-tetrahydrothieno
[2,3-c] pyridine-7,1'-cyclopropane]
-2-yl] -4-oxo-4H-quinolizin-3-ca
Using 0.36 g (0.54 mmol) of ruboxylate
Otherwise, the reaction was carried out in the same manner as in Example 24 (b) to give the title.
0.37 g of the compound was obtained almost quantitatively as an orange solid. The NMR spectrum (CDCl_Three, Δ): 0.7
5-1.30 (m, 8H), 1.49 (s, 9H), 1.52 (s, 9H), 2.35-
2.40 (m, 1H), 2.94 (s, 3H), 3.65-3.70 (m, 1H), 4.1
5-4.20 (m, 1H), 4.91 (brs 1H), 5.18 (brs, 1H), 7.2
6 (s, 1H), 8.57 (s, 1H), 9.30 (d, J = 5.9Hz, 1H) MS spectrum (CI, m / z): 640 (M⁺+1) (C) 1-cyclopropyl-7-fluoro-9-methyl
-8- [spiro [4-amino-4,5,6,7-tetra
Hydrothieno [2,3-c] pyridine-7,1'-cycl
Lopropane] -2-yl] -4-oxo-4H-quinoli
Gin-3-carboxylic acid 1-cyclopropyl-7-fluoro-9-methyl-8-
[Spiro [4- (t-butoxycarbonyl) amino-6
-(T-butoxycarbonyl) -4,5,6,7-tetra
Lahydrothieno [2,3-c] pyridine-7,1'-cy
Clopropane] -2-yl] -4-oxo-4H-quino
0.17 g of lysine-3-carboxylic acid (0.27 mmol
l) in 20% trifluoroacetic acid in methylene chloride 2.6
It was dissolved in 5 ml and stirred at room temperature for 2 hours. After completion of the reaction, the obtained reaction solution was depressurized.
After distilling off the solvent, 5 ml of water and further 1N sodium hydroxide were added.
After adjusting the pH to 12 by adding an aqueous solution of lithium, p with 1N hydrochloric acid.
H was adjusted to 6.2. The precipitated solid is collected by filtration and titled
119 mg of the compound was obtained almost quantitatively as an orange solid. Mp 152-154 ° C NMR spectrum (CF_ThreeCOOD, δ): 1.05-1.09
(m, 2H), 1.35-2.30 (m, 6H), 2.60-2.70 (m, 1H), 3.2
8 (s, 3H), 4.33-4.39 (m, 1H), 4.74 (d, J = 14.6Hz, 1
H), 5.49 (m, 1H), 7.73 (s, 1H), 8.79 (s, 1H), 9.40
 (d, J = 4.6Hz, 1H) MS spectrum (FAB, m / z): 440 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3422, 16
63, 1468 (Example 27)8- [4-amino-5,6,7,8-tetrahydro-4
H-thieno [2,3-d] azepin-2-yl] -1-
Cyclopropyl-7-fluoro-9-methyl-4-oxo
So-4H-quinolidine-3-carboxylic acid (Example compound number
No. 1-1477) 4- (t-butoxycarbonylamino) -6- (t-bu
Toxylcarbonyl) -7,7-dimethyl-4,5,6
Instead of 7-tetrahydrothieno [2,3-c] pyridine
4-t-butoxycarbonylamino-6-trityl
-5,6,7,8-tetrahydro-4H-thieno [2,
Using 0.64 g (1.3 mmol) of 3-d] azepine
Otherwise, reacting in the same manner as in Example 24 to give the title compound 3
7 mg was obtained as an orange foam. (Yield 7%) Melting point: 162 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.05-1.10
(m, 2H), 1.43-1.47 (m, 2H), 2.60-2.70 (m, 1H), 3.2
8, 3.31 (each s, rotamer, 3H), 3.50-4.35 (m, 5H),
4.50-4.65 (m, 1H), 5.60 (brs, 1H), 7.54, 7.62 (eac
h s, rotamer, 1H), 8.77, 8.78 (each s, rotamer, 1
H), 9.39 (d, J = 4.9Hz, 1H) MS spectrum (CI, m / z): 428 (M⁺) IR spectrum (KBr, ν_max  cm^-1): 3362, 16
56, 1465 (Example 28)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-4-oxo-4H-quinolidine-3-carboxylic acid (Example
Compound No. 1-575) (A) Ethyl 1-cyclopropyl-4-oxo-8-
[4-Tritylamino-4,5,6,7-tetrahydro
Benzo [b] thiophen-2-yl] -4H-quinolizi
N-3-carboxylate Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
Ethyl 8-chloro-1-cyclopropyl
-4-oxo-4H-quinolidine-3-carboxyle
0.27 g (0.93 mmol) of 4-tri
Tylamino-4,5,6,7-tetrahydrobenzo
[B] 4-t-butoxycarbony instead of thiophene
Ruamino-4,5,6,7-tetrahydrobenzo [b]
Except for using thiophene, the reaction was performed in the same manner as in Example 16 (a).
In response, 0.45 g of the title compound were obtained as an orange foam.
Was. (96% yield) NMR spectrum (CDCl_Three, Δ): 0.66-0.73 (m, 2
H), 1.03-1.09 (m, 2H), 1.28 (t, J = 7.1Hz, 3H), 1.56
 (s, 9H), 1.75-2.12 (m, 4H), 2.80-2.86 (m, 2H), 2.8
3 (q, J = 5.3Hz, 2H), 4.82 (brs, 2H), 7.35 (dd, J = 7.
6 and 2.2Hz, 1H), 7.51 (s, 1H), 8.19 (brs, 1H), 8.2
5 (s, 1H), 9.40 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 509 (M⁺+1) (B) 8- [4-amino-4,5,6,7-tetrahydride
Robenzo [b] thiophen-2-yl] -1-cycloprop
Ropyr-4-oxo-4H-quinolidine-3-carboxyl
acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-9-methyl-4-oxo-8- [4
-T-butoxycarbonylamino-4,5,6,7-te
Trahydrobenzo [b] thiophen-2-yl] -4H
-Quinolidine-3-carboxylate 0.45 g (0.
Example 16 (b) and Example
The title compound (86m) was reacted in the same manner as in Example 16 (c).
g was obtained as a red solid. (26% yield) Melting point: 167-171 ° C NMR spectrum (CD_ThreeCOOD, δ): 0.99 (brs,
2H), 1.34-1.58 (m, 2H), 2.10-2.50 (m, 4H), 3.00-3.
20 (m, 2H), 4.93 (m, 1H), 8.12 (s, 1H), 8.22 (d, J
= 8.1Hz, 1H), 8.50 (s, 1H), 8.94 (s, 1H), 8.22 (d, J = 7.
6Hz, 1H), 8.50 (s, 1H), 8.94 (s, 1H), 9.39 (d, J = 7.
6Hz, 1H) MS spectrum (CI, m / z): 381
(M⁺+1) (Example 29)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -9-chloro-1-cy
Clopropyl-4-oxo-4H-quinolidine-3-ca
Rubonic acid (Exemplified Compound No. 1-647) (A) Ethyl 8- [4-t-butoxycarbonylamido
No-4,5,6,7-tetrahydrobenzo [b] thiof
[En-2-yl] -9-chloro-1-cyclopropyl-
4-oxo-4H-quinolidine-3-carboxylate Ethyl 8-chloro-1-cyclopropyl-4-oxo
Instead of -4H-quinolidine-3-carboxylate
Ethyl 1-cyclopropyl-8,9-dichloro-4-
Oxo-4H-quinolidine-3-carboxylate
Example 28 except that 27 g (0.83 mmol) was used.
The reaction was carried out in the same manner as in (a) to give 0.26 g of the title compound in orange.
Obtained as a colored foam. (58% yield) NMR spectrum (CDCl_Three, Δ): 0.72-0.76 (m, 2
H), 1.01-1.06 (m, 2H), 1.24 (s, 9H), 1.43 (t, J =
(7.3Hz, 3H), 1.75-2.35 (m, 4H), 2.55-2.60 (m, 1H),
2.35-2.45 (m, 2H), 4.42 (q, J = 7.1Hz, 2H), 4.75-4.9
5 (m, 2H), 7.25 (overlapped with CDCl_Three, 1H) 7.63
(s, 1H), 8.46 (s, 1H), 9.33 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z): 543 (M⁺+1) (B) 8- [4-amino-4,5,6,7-tetrahydride
Lobenzo [b] thiophen-2-yl] -9-chloro-
1-cyclopropyl-4-oxo-4H-quinolidine-
3-carboxylic acid Ethyl 8- [4-t-butoxycarbonylamino-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -1-cyclopropyl-4-oxo-4H
Ethyl instead of quinolidine-3-carboxylate
  1- [4-t-butoxycarbonylamino-4,5
6,7-tetrahydrobenzo [b] thiophen-2-i
] -9-chloro-cyclopropyl-4-oxo-8-
0.26 g of 4H-quinolidine-3-carboxylate
Example 28 (b) except that (0.48 mmol) was used.
To give 19 mg of the title compound as an orange solid.
I got it. (10% yield) Melting point: 234 ~ 237 ℃ NMR spectrum (CD_ThreeCOOD, δ): 0.98-1.02
(m, 2H), 1.38-1.42 (m, 2H), 2.25-2.50 (m, 4H), 2.8
5-2.97 (m, 1H), 3.00-3.25 (m, 2H), 4.95 (m, 1H), 8.1
8 (d, J = 7.8Hz, 1H), 8.22 (s, 1H), 8.82 (s, 1H), 9.
36 (d, J = 7.8Hz, 1H) MS spectrum (FAB, m / z): 415 (M⁺+
1) IR spectrum (KBr, ν_max  cm^-1): 3408, 16
53, 1451 (Example 30)8- [4-amino-5,6-dihydro-4H-thieno
[2,3-b] thiopyran-2-yl] -1-cyclopro
Pill-9-methyl-4-oxo-4H-quinolidine-3
-Carboxylic acid (Exemplified Compound No. 1-1397) (A) ethyl 8- [4- (t-butoxycarbonyla)
Mino) -5,6-dihydro-4H-thieno [2,3-
b] thiopyran-2-yl] -1-cyclopropyl-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Xylate 4-tritylamino-4,5,6,7-tetrahydrobe
4- (t-butoxyca) instead of benzo [b] thiophene
Rubonylamino) -5,6-dihydro-4H-thieno
0.99 g of [2,3-b] thiopyran (3.6 mmol
Reaction was carried out in the same manner as in Example 16 (a), except that l) was used.
This gave 0.78 g of the title compound as an orange foam.
(Yield 85%) NMR spectrum (CDCl_Three, Δ): 0.72-0.76 (m, 2
H), 1.02-1.05 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 1.48
 (s, 9H), 2.26-2.38 (m, 3H), 2.99 (s, 3H), 3.11-3.1
5 (m, 2H), 4.45 (q, J = 7.2Hz, 2H), 4.84 (m, 1H), 4.
95 (brs, 1H), 7.11 (d, J = 7.6Hz, 1H), 7.21 (s, 1H),
8.39 (s, 1H), 9.34 (d, J = 7.8Hz, 1H) MS spectrum (CI, m / z): 541 (M⁺+1) (B) 8- (4-amino-5,6-dihydro-4H-thio
Eno [2,3-b] thiopyran-2-yl) -1-cycl
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 8 instead of Norizin-3-carboxylate
-[4- (t-butoxycarbonylamino) -5,6-
Dihydro-4H-thieno [2,3-b] thiopyran-2
-Yl] -1-cyclopropyl-9-methyl-4-oxo
So-4H-quinolidine-3-carboxylate 0.78
Example 16 except that g (0.88 mmol) was used.
The reaction was carried out in the same manner as in (b) and Example 16 (c) to give the title
0.44 g of the compound was obtained as a red solid. (Yield 76
%) Melting point: 210-214 ° C NMR spectrum (CD_ThreeCOOD, δ): 1.01-1.05
(m, 2H), 1.42-1.48 (m, 2H), 2.55-2.65 (m, 3H), 2.7
5-2.80 (m, 2H), 3.25-3.50 (m, 5H), 5.08 (m, 1H), 7.
80 (s, 1H), 8.00 (d, J = 7.6Hz, 1H), 8.67 (s, 1H),
9.32 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z): 413 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3383, 16
34, 1462 (Example 31)8- [4-amino-4,7-dihydro-5H-thieno
[2,3-c] thiopyran-2-yl] -1-cyclopro
Pill-9-methyl-4-oxo-4H-quinolidine-3
-Carboxylic acid (Exemplary Compound No. 1-1419) (A) ethyl 8- [4- (t-butoxycarbonyla)
Mino) -4,7-dihydro-5H-thieno [2,3-
c] thiopyran-2-yl] -1-cyclopropyl-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Xylate 4-tritylamino-4,5,6,7-tetrahydrobe
4- (t-butoxyca) instead of benzo [b] thiophene
Rubonylamino) -4,7-dihydro-5H-thieno
1.15 g of [2,3-c] thiopyran (4.2 mmol
Reaction was carried out in the same manner as in Example 16 (a), except that l) was used.
This gave 0.23 g of the title compound as an orange foam.
(Yield 22%) NMR spectrum (CDCl_Three, Δ): 0.72-0.76 (m, 2
H), 1.02-1.05 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 1.4
7 (s, 9H), 2.92-2.98 (m, 4H), 3.17 (m, 1H), 3.69
(d, J = 16.6Hz, 1H), 3.98 (d, J = 16.6Hz, 1H), 4.42
(q, J = 7.2Hz, 2H), 5.03 (m, 1H), 5.30 (d, J = 8.8Hz, 1
H), 7.11 (d, J = 7.6Hz, 1H), 7.23 (s, 1H), 8.40 (s,
1H), 9.36 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 541 (M⁺+1) (B) 8- [4-amino-4,7-dihydro-5H-thio
Eno [2,3-c] thiopyran-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 8 instead of Norizin-3-carboxylate
-[4- (t-butoxycarbonylamino) -4,7-
Dihydro-5H-thieno [2,3-c] thiopyran-2
-Yl] -1-cyclopropyl-9-methyl-4-oxo
SO-4H-quinolidine-3-carboxylate 0.23
Example 16 except that g (0.43 mmol) was used.
The reaction was carried out in the same manner as in (b) and Example 16 (c) to give the title
107 mg of the compound were obtained as an ocher solid. (Yield 86
%) Melting point: 217-219 ° C NMR spectrum (CD_ThreeCOOD, δ): 1.03-1.06
(m, 2H), 1.43-1.46 (m, 2H), 2.55-2.65 (m, 3H), 2.6
0-2.72 (m, 1H), 3.35-3.40 (m, 4H), 3.49 (dd, J = 15.
1 and 2.4Hz, 1H), 3.88 (d, J = 17.3Hz, 1H), 4.31 (d,
J = 17.6Hz, 1H), 5.11 (s, 1H), 7.70 (s, 1H), 8.01 (d,
 J = 7.6Hz, 1H), 8.73 (s, 1H), 9.38 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z): 413 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3417, 16
51, 1461 (Example 32)8- [4-amino-4,7-dihydro-
5H-thieno [2,3-c] pyran-2-yl] -1-si
Clopropyl-9-methyl-4-oxo-4H-quinoli
Gin-3-carboxylic acid(Exemplified Compound No. 1-1447) (A) ethyl 8- [4- (t-butoxycarbonyla)
Mino) -4,7-dihydro-5H-thieno [2,3-
c] thiopyran-2-yl] -1-cyclopropyl-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Xylate 4-tritylamino-4,5,6,7-tetrahydrobe
4- (t-butoxyca) instead of benzo [b] thiophene
Rubonylamino) -4,7-dihydro-5H-thieno
0.43 g (1.7 mmol) of [2,3-c] pyran
The reaction was carried out in the same manner as in Example 16 (a), except that
0.53 g of the title compound were obtained as an ocher solid. (Yield 3
0%) NMR spectrum (CDCl_Three, Δ): 0.72-0.78 (m, 2
H), 1.02-1.08 (m, 2H),, 1.43 (t, J = 7.1Hz, 3H), 1.
47 (s, 9H), 2.35-2.40 (m, 1H), 2.99 (s, 3H), 3.92
 (dd, J = 14.6 and 3.4Hz, 1H), 4.08 (m, 1H), 4.43 (q,
 J = 7.1Hz, 2H), 4.77 (d, J = 14.1Hz, 1H), 4.93 (d, J = 1
5.1Hz, 1H), 5.09 (d, J = 8.8Hz, 1H), 5.30 (d, J = 8.8H
z, 1H), 7.13 (d, J = 7.6Hz, 1H), 7.26 (s, overlapped
 with CDCl_Three, 1H), 8.41 (s, 1H), 9.37 (d, J = 7.6Hz,
1H) (B) 8- [4-amino-4,7-dihydro-5H-thio
Eno [2,3-c] pyran-2-yl] -1-cyclopro
Pyr-9-methyl-4-oxo-4H-quinolidine-3
-Carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 8 instead of Norizin-3-carboxylate
-[4- (t-butoxycarbonylamino) -4,7-
Dihydro-5H-thieno [2,3-c] pyran-2-i
1] -cyclopropyl-9-methyl-4-oxo-
0.53 g of 4H-quinolidine-3-carboxylate
(16 mmol) in Example 16 (b) except that (1.0 mmol) was used.
And reacting in the same manner as in Example 16 (c) to give the title compound
0.11 g was obtained as an orange solid. (Yield 28%) Melting point: 125-129 ° C NMR spectrum (CD_ThreeCOOD, δ): 1.03-1.06
(m, 2H), 1.43-1.46 (m, 2H), 2.55-2.65 (m, 3H), 2.6
4-2.71 (m, 1H), 3.35 (s, 3H), 4.28 (d, J = 13.4Hz, 1
H), 4.78 (d, J = 13.4Hz, 1H), 4.93 (s, 1H), 5.17 (d,
 J = 16.1Hz, 1H), 5.36 (d, J = 15.9Hz, 1H), 7.76 (s, 1
H), 8.01 (d, J = 7.3Hz, 1H), 8.74 (s, 1H), 9.39 (d,
(J = 7.4Hz, 1H) MS spectrum (CI, m / z): 396 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3398, 16
35, 1437 (Example 33)1-cyclopropyl-9-methyl-8- [4-methyla
Mino-4,7-dihydro-5H-thieno [2,3-c]
Thiopyran-2-yl] -4-oxo-4H-quinolizi
-3-carboxylic acid (Exemplified Compound No. 1-1433) (A) Ethyl 1-cyclopropyl-9-methyl-8-
[4- [methyl (trityl) amino] -4,7-dihydride
B-5H-thieno [2,3-c] thiopyran-2-yl]
-4-oxo-4H-quinolidine-3-carboxyle
G 4-tritylamino-4,5,6,7-tetrahydrobe
4- [methyl (triti) instead of benzo [b] thiophene
Ru) amino] -4,7-dihydro-5H-thieno [2,3
-C] using 1.14 g (2.7 mmol) of thiopyran
Otherwise, the reaction was carried out in the same manner as in Example 16 (a) to give the title.
0.70 g of the compound was obtained as an orange solid. (37% yield) NMR spectrum (CDCl_Three, Δ): 0.81-0.85 (m, 2
H), 1.06-1.13 (m, 3H), 1.45 (t, J = 7.1Hz, 3H), 2.15
-2.22 (m, 1H), 2.25 (s, 3H), 2.45-2.50 (m, 1H), 3.1
7 (s, 3H), 3.56 (d, J = 16.6Hz, 1H), 4.01 (d, J = 16.4
Hz, 1H), 4.45 (q, J = 7.1Hz, 2H), 7.25-7.60 (m, 16H),
 8.02 (s, 1H), 8.45 (s, 1H), 9.45 (d, J = 7.3Hz, 1H) MS spectrum (FAB, m / z): 697 (M⁺+
1) (B) 1-cyclopropyl-9-methyl-8- [4-me
Tylamino-4,7-dihydro-5H-thieno [2,3
-C] thiopyran-2-yl] -4-oxo-4H-ki
Noridine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-9-methyl-8- [4- [methyl
(Trityl) amino] -4,7-dihydro-5H-thie
No [2,3-c] thiopyran-2-yl] -4-oxo-
0.70 g of 4H-quinolidine-3-carboxylate
(B) in Example 1 except that (1.0 mmol) was used.
The reaction was carried out in the same manner as in Example 1 (c) to give the title compound 0.2
5 g were obtained as an orange solid. (Yield 59%) Melting point: 105-109 ° C NMR spectrum (CD_ThreeCOOD, δ): 1.03-1.06
(m, 2H), 1.43-1.46 (m, 2H), 2.65-2.70 (m, 1H), 3.1
2 (s, 1H), 3.35-3.50 (m, 5H), 3.91 (d, J = 17.3Hz, 1
H), 4.31 (d, J = 17.3Hz, 1H), 4.85 (s, 1H), 7.67
(s, 1H), 8.01 (d, J = 7.6Hz, 1H), 8.73 (s, 1H), 9.39
(d, J = 7.Hz, 1H) MS spectrum (CI, m / z): 427 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3433, 17
30, 1435 (Example 34)(+)-8- [4-Amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid ((+)-Form of Exemplified Compound No. 1-583) 4-tritylamino-4,5,6,7-tetrahydrobe
(-)-4- (t-Bu) instead of benzo [b] thiophene
Toxicarbonyl) amino-4,5,6,7-tetrahi
Drobenzo [b] thiophene (Reference Example 87, 2nd Pea
k) Except that 0.51 g (2.00 mmol) was used,
By reacting in the same manner as in Example 16, 0.32 g of the title compound was obtained.
Obtained as a yellow solid. (80% yield) Melting point: 144-148 ° C NMR spectrum (CF_ThreeCOOD, δ): 1.02-1.05
(m, 2H), 1.42-1.47 (m, 2H), 2.20-2.46 (m, 4H), 2.6
3-2.73 (m, 1H), 3.02-3.36 (m, 5H), .4.91-4.94 (m,
1H), 7.75 (s, 1H), 8.04 (d, J = 7.6Hz, 1H), 8.69 (s,
 1H), 9.35 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z) 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3397, 16
44, 1459 [α]_D ²⁰ = +6.59 (c = 0.52, TFA) (Example 35)(-)-8- [4-amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid ((-) Form of Exemplified Compound No. 1-583) 4-tritylamino-4,5,6,7-tetrahydrobe
(+)-4- (t-Bu) instead of benzo [b] thiophene
Toxicarbonyl) amino-4,5,6,7-tetrahi
Drobenzo [b] thiophene (Reference Example 89, 1st Pea
k) Except that 0.52 g (2.00 mmol) was used,
By reacting in the same manner as in Example 16, 0.32 g of the title compound was obtained.
Obtained as a yellow solid. (Yield 45%) Melting point: 146-148 ° C NMR spectrum (CF_ThreeCOOD, δ): 1.03-1.07
(m, 2H), 1.42-1.47 (m, 2H), 2.63-2.73 (m, 1H), 3.3
0 (s, 3H), 4.26 (dd, J = 14.9 and 5.1Hz, 1H), 4.66-4.7
4 (m, 2H), 4.90 (d, J = 16.1Hz, 1H), 5.60-5.62 (m, 1
H), 7.46 (s, 1H), 7.95 (d, J = 7.3Hz, 1H), 8.79 (s,
1H), 9.42 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z) 396 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3362, 16
52, 1463 [α]_D ²⁰ = -7.40 (C = 0.50, TFA) (Example 36)8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methyl-4-oxo-4H-quinolizin-3-ca
Rubonic acid methanesulfonate (Exemplary Compound No. 1-583
Methanesulfonate) 8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methyl-4-oxo-4H-quinolizin-3-ca
300 mg (0.727 mmol) of rubonic acid in ethanol
Suspended in 10 ml of water, and prepared in advance in a 70 ° C warm bath.
Ethanol solution of methanesulfonic acid
Acid 305.6 mg / ethanol 25 ml) 5.73 m
1 (0.727 mmol) was added and dissolved. Allow to cool
The resulting solid was collected by filtration, and 330 mg of the title compound was obtained as a yellow solid.
Obtained as a body. (Yield 92%) Melting point: 260-263 ° C NMR spectrum (DMSO-d₆, Δ): 0.72-0.76
(m, 2H), 1.00-1.15 (m, 2H), 1.60-1.90 (m, 2H), 2.
00-2.15 (m, 2H), 2.31 (s, 3H), 2.45-2.55 (m, 1H),
2.78-2.94 (m, 2H), 3.05 (s, 3H), 4.45-4.50 (m, 1H),
 7.57 (d, J = 7.3Hz, 1H), 7.68 (s, 1H), 8.28 (s, 1H),
 9.28 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3435, 17
26, 1631 (Example 37)(+)-8- [4-Amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3-carboxylic acid methanesulfonate (Example compound number
No. 1-583 (+) methanesulfonate) 8- [4-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methyl-4-oxo-4H-quinolizin-3-ca
(+)-8- [4-amino-4,
5,6,7-tetrahydrobenzo [b] thiophene-2
-Yl] -1-cyclopropyl-9-methyl-4-oxo
Using 150 mg of so-4H-quinolidine-3-carboxylic acid
Otherwise, reacting in the same manner as in Example 36 to give the title compound
150 mg was obtained as an orange solid. (Yield 85%) Melting point: 253-255 ° C NMR spectrum (DMSO-d₆, Δ): 0.72-0.76
(m, 2H), 1.00-1.15 (m, 2H), 1.60-1.90 (m, 2H), 2.
00-2.15 (m, 2H), 2.31 (s, 3H), 2.45-2.55 (m, 1H),
2.78-2.94 (m, 2H), 3.05 (s, 3H), 4.45-4.50 (m, 1H),
 7.57 (d, J = 7.3Hz, 1H), 7.68 (s, 1H), 8.28 (s, 1H),
 9.28 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3443, 16
94, 1636 [α]_D ²⁰ = +78.2 (C = 0.42, DMSO) (Example 38)8- [7-amino-4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -1-cyclopropyl
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid (Exemplified Compound No. 1-361) (A) Ethyl 1-cyclopropyl-9-methyl-4-
Oxo-8- [5-trityl-7-tritylamino-
4,5,6,7-tetrahydrothieno [3,2-c] pi
Lysin-2-yl] -4H-quinolizin-3-carboxy
Sylate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
5-trityl-7-tritylamino-4,5,6,7-
1.33 g of tetrahydrothieno [3,2-c] pyridine
Example 22 (a) except that (2.08 mmol) was used.
In the same manner as described above to give 1.01 g of the title compound as a yellow-orange solid
Obtained almost quantitatively as a body. MS spectrum (FAB +, m / z): 9
08 (M⁺+1) (B) 8- [7-amino-4,5,6,7-tetrahydrid
Rothieno [3,2-c] pyridin-2-yl] -1-cy
Clopropyl-9-methyl-4-oxo-4H-quinoli
Gin-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-9-methyl-4-oxo-8- [5
-Trityl-7-tritylamino-4,5,6,7-te
Trahydrothieno [3,2-c] pyridin-2-yl]
-4H-quinolidine-3-carboxylate 1.01 g
(1.03 mmol), and the others were as in Example 16 (b).
And reacting in the same manner as in Example 16 (c) to give the title compound
0.14 g was obtained as an orange solid. (Yield 35%) Melting point: 142-147 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.02-1.05
(m, 2H), 1.42-1.47 (m, 2H), 2.20-2.46 (m, 4H), 2.6
3-2.73 (m, 1H), 3.02-3.36 (m, 5H), 4.91-4.94, (m,
1H), 7.75 (s, 1H), 8.04 (d, J = 7.6Hz, 1H), 8.69 (s,
 1H), 9.35 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z) 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3408, 16
42, 1460 (Example 39)1-cyclopropyl-9-methyl-8- [4-methyla
Mino-4,5,6,7-tetrahydrobenzo [b] thio
Phen-2-yl] -4-oxo-4H-quinolidine-
3-carboxylic acid (Exemplified Compound No. 1-753) 7-methoxy-5-trityl-4,5,6,7-tetra
4- instead of hydrothieno [3,2-c] pyridine
(Methyl) (trityl) amino-4,5,6,7-tet
1.66 g of lahydrobenzo [b] thiophene (4.06
Example 21 (a), Example 1 except that
The reaction was carried out in the same manner as in (b) and Example 1 (c) to give the title.
0.31 g of the compound was obtained as a yellow-orange solid. (Yield 18
%) Melting point: 205-207 ° C NMR spectrum (CF_ThreeCOOD, δ): 1.03-1.06
(m, 2H), 1.42-1.47 (m, 2H), 2.20-2.40 (m, 4H), 2.6
3-2.73 (m, 1H), 3.08-3.15 (m, 5H), 3.35 (s, 3H), 4.
73-4.75 (s, 1H), 7.72 (s, 1H), 8.03 (d, J = 7.6Hz,
1H), 8.69 (s, 1H), 9.36 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z) 409 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3468, 34
14, 1667, 1464 (Example 40)1-cyclopropyl-8- [4-cyclo
Propylamino-4,5,6,7-tetrahydrobenzo
[B] thiophen-2-yl] -9-methyl-4-oxo
So-4H-quinolidine-3-carboxylic acid(Example compound number
No.1-745) (A) Ethyl 1-cyclopropyl-8- [4-cyclo
Propylamino-4,5,6,7-tetrahydrobenzo
[B] thiophen-2-yl] -9-methyl-4-oxo
So-4H-quinolidine-3-carboxylate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
4-cyclopropylamino-4,5,6,7-tetrahi
0.60 g of drobenzo [b] thiophene (3.08 mm
ol) except that the reaction was carried out in the same manner as in Example 22 (a).
This gave 0.26 g of the title compound as an orange oil.
(54% yield) MS spectrum (CI, m / z) 463 (M⁺+1) (B) 1-cyclopropyl-8- [4-cyclopropyl
Amino-4,5,6,7-tetrahydrobenzo [b] thi
Offen-2-yl] -9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid Ethyl 8- [4-amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3- Ethyl 1 instead of carboxylate hydrochloride
-Cyclopropyl-8- [4-cyclopropylamino-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -9-methyl-4-oxo-4H-quinolyl
0.26 g of gin-3-carboxylate (0.55 mm
ol) was used in the same manner as in Example 16 (c), except that
This gave 0.18 g of the title compound as an orange oil.
(75% yield) Melting point: 189-192 ° C NMR spectrum (CF_ThreeCOOD, δ): 1.03-1.23
(m, 8H), 2.20-2.68 (m, 5H), 3.00-3.21 (m, 3H), 3.3
4 (s, 3H), 4.90-4.92 (m, 1H), 7.70 (s, 1H), 8.02
(d, J = 7.8Hz, 1H), 8.69 (s, 1H), 9.35 (d, J = 7.8Hz,
1H) MS spectrum (CI, m / z) 435 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3425, 17
16, 1436 (Example 41)8- [4-amino-5-methyl-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl] -1-cy
Clopropyl-9-methyl-4-oxo-4H-quinoli
Gin-3-carboxylic acid (Exemplary Compound No. 1-1383) 4-tritylamino-4,5,6,7-tetrahydrobe
4-tritylamino in place of benzo [b] thiophene
-5-methyl-4,5,6,7-tetrahydrobenzo
[B] Example 16 except that 1.61 g of thiophene was used.
To give 0.21 g of the title compound as a yellow-orange solid.
Obtained as a body. (Yield 39%) Melting point: 220-223 ° C NMR spectrum (CF_ThreeCOOD, δ): 0.95-1.12
(m, 2H), 1.18-1.50 (m, 5H), 1.91-2.73 (m, 4H), 3.
06-3.17 (m, 2H), 3.35 (s, 3H), 4.56,4.81 (each d, J
= 4.1 3.9Hz, total 1H diastereomer), 7.70,7.74 (eac
h s, total 1H diastereomer), 8.02 (d, J = 7.3Hz, 1
H), 8.69 (s, 1H), 9.36 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 409 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3414, 16
34, 1463 (Example 42)8- [4-aminomethyl-4,5,6,7-tetrahydride
Robenzo [b] thiophen-2-yl] -1-cycloprop
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid (Exemplary Compound No. 1-457) 4-tritylamino-4,5,6,7-tetrahydrobe
4-tritylamino in place of benzo [b] thiophene
Methyl-4,5,6,7-tetrahydrobenzo [b] thi
Same as Example 16 except that 1.42 g of offense was used.
Reaction yielded 0.11 g of the title compound as a yellow solid.
Was. (11% yield) Melting point: 217-220 ° C NMR spectrum (CF_ThreeCOOD, δ): 0.85-1.12
(m, 2H), 1.27-1.55 (m, 2H), 1.84-2.32 (m, 4H), 2.5
9-2.74 (m, 1H), 2.97-3.08 (m, 2H), 3.28-3.82 (m, 6
H), 7.58 (s, 1H), 8.08 (d, J = 7.3Hz, 1H), 8.65 (s,
1H), 9.32 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 409 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3423, 16
53, 1465 (Example 43)1-cyclopropyl-8- [4-hydroxy-4,5,
6,7-tetrahydrobenzo [b] thiophen-2-i
Ru] -9-Methyl-4-oxo-4H-quinolidine-3
-Carboxylic acid (Exemplified Compound No. 1-785) (A) Ethyl 1-cyclopropyl-8- [4-methoxy
Cymethoxy-4,5,6,7-tetrahydrobenzo
[B] thiophen-2-yl] -9-methyl-4-oxo
So-4H-quinolidine-3-carboxylate 4-tritylamino-4,5,6,7-tetrahydrobe
4-methoxymethoxy instead of benzo [b] thiophene
C-4,5,6,7-tetrahydrobenzo [b] thiof
Same as Example 16 (a) except that 0.95 g of ene was used
To give the title compound almost quantitatively as an orange foam.
I got it. The NMR spectrum (CDCl_Three, Δ): 0.7
2-0.78 (m, 2H), 1.00-1.07 (m, 2H), 1.43 (t, J = 7.1H
z, 3H), 1.87-2.16 (m, 4H), 2.30-2.40 (m, 1H), 2.72
-3.02 (m, 5H), 3.46 (s, 3H), 4.43 (q, J = 7.1Hz, 2
H), 4.72-4.86 (m, 3H), 7.14-7.19 (m, 2H), 8.39 (s,
1H), 9.37 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z): 468 (M⁺+1) (B) ethyl 1-cyclopropyl-8- [4-hydro
Xy-4,5,6,7-tetrahydrobenzo [b] thio
Phen-2-yl] -9-methyl-4-oxo-4H-
Quinolidine-3-carboxylate Ethyl 1-cyclopropyl-8- [4-methoxymethoate
Xy-4,5,6,7-tetrahydrobenzo [b] thio
Phen-2-yl] -9-methyl-4-oxo-4H-
0.50 g of quinolidine-3-carboxylate was added to methyl chloride.
Dissolve in 30 ml of styrene and add trifluoroacetic acid 3 under ice cooling.
Then, the mixture was stirred for 6 hours. After completion of the reaction, the obtained reaction solution was
The solvent was distilled off to obtain a residue. The resulting residue is methylated chloride.
Dissolved in 100 ml of saturated sodium bicarbonate solution
After washing with the liquid, the liquid was separated. The obtained organic phase is dried over anhydrous magnesium sulfate.
After drying with cesium, the solvent was distilled off under reduced pressure. Got
The residue is purified by silica gel column chromatography (elution
Medium: chloroform / methanol = 50/1)
0.18 g of the title compound was obtained as an orange oil. (yield
43%) NMR spectrum (CDCl_Three, Δ): 0.71-0.77 (m, 2
H), 1.01-1.07 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 1.85
-1.96 (m, 2H), 2.03-2.12 (m, 2H), 2.31-2.40 (m, 1
H), 2.74-3.02 (m, 5H), 4.43 (q, J = 7.2Hz, 2H), 4.81
-4.89 (m, 1H), 7.16 (d, J = 7.6Hz, 1H), 7.28 (s, 1H),
 8.39 (s, 1H), 9.36 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z): 424 (M⁺+1) (C) 1-cyclopropyl-8- [4-hydroxy-
4,5,6,7-tetrahydrobenzo [b] thiophene
-2-yl] -9-methyl-4-oxo-4H-quinolyl
Gin-3-carboxylic acid Ethyl 8- [4-amino-4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl] -1-cyclo
Propyl-9-methyl-4-oxo-4H-quinolidine
-3- Ethyl 1 instead of carboxylate hydrochloride
-Cyclopropyl-8- [4-hydroxy-4,5,
6,7-tetrahydrobenzo [b] thiophen-2-i
] -9-methyl-4-oxo-4H-quinolidine-3
Example 1 except that 0.18 g of carboxylate was used
Reaction was carried out in the same manner as in 6 (c) to give 75 mg of the title compound as an orange
Obtained as a colored solid. (44% yield) Melting point: 226-229 ° C NMR spectrum (DMSO-d₆, Δ): 0.63-0.81
(m, 2H), 0.98-1.16 (m, 2H), 1.60-2.07 (m, 4H), 2.4
0-2.60 (m, 1H), 2.69-2.91 (m, 2H), 3.04 (s, 3H), 4.
58-4.70 (m, 1H), 5.15-5.34 (m, 1H), 7.52 (s, 1H), 7.
60 (d, J = 7.3Hz, 1H), 8.23 (s, 1H), 9.22 (d, J = 7.3H
z, 1H) MS spectrum (CI, m / z): 396 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3426, 17
11, 1428 (Example 44)8- [4-amino-5,6-dihydro-4H-cyclope
[B] thiophen-2-yl] -1-cyclopropyl
Ru-9-methyl-4-oxo-4H-quinolidine-3-
carboxylic acid (Exemplified Compound No. 1-1155) 4-tritylamino-4,5,6,7-tetrahydrobe
4- (t-butyl thiophene) instead of benzo [b] thiophene
Xycarbonyl) amino-5,6-dihydro-4H-cy
Except for using 1.0 g of clopenta [b] thiophene,
By reacting in the same manner as in Example 16, 0.13 g of the title compound was obtained.
Obtained as a yellow solid. (Yield 29%) Melting point: 162-165 ° C NMR spectrum (CF_ThreeCOOD, δ): 0.95-1.10
(m, 2H), 1.36-1.99 (m, 2H), 2.62-2.39 (m, 2H), 3.1
7-3.53 (m, 6H), 5.15-5.18 (m, 1H), 7.68 (s, 1H), 8.
04 (d, J = 7.6Hz, 1H), 8.70 (s, 1H), 9.37 (d, J = 7.6H
z, 1H) MS spectrum (CI, m / z): 381 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3385, 16
51, 1463 (Example 45)8- [4-amino-6-methyl-4,5,6,7-tet
Lahydrothieno [2,3-c] pyridin-2-yl]-
1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylic acid (Example compound
Article number 1-1251) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [6-methyl-4-tritylamino-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl] -4-oxo-4H-quinolidine-
3-carboxylate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
6-methyl-4-tritylamino-4,5,6,7-te
1.12 g of trahydrothieno [2,3-c] pyridine
(2.73 mmol) and ethyl 8-chloro-1
-Cyclopropyl-9-methyl-4-oxo-4H-ki
8-chloro instead of noridine-3-carboxylate
-1-cyclopropyl-7-fluoro-9-methyl-4
-Oxo-4H-quinolizin-3-carboxylate
Except that 0.35 g (1.08 mmol) was used,
Reaction was carried out in the same manner as in 22 (a) to give 0.66 g of the title compound.
Was obtained as a yellow solid. (Yield 87%) MS spectrum (CI, m / z) 698 (M⁺+1) (B) 8- [4-amino-6-methyl-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine-2-i
1] -cyclopropyl-7-fluoro-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-7-fluoro-9-methyl-8-
[6-Methyl-4-tritylamino-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridine-2-i
4-oxo-4H-quinolidine-3-carboxy
Apart from using 0.65 g (0.93 mmol) of the rate,
The reaction was carried out in the same manner as in Example 16 (b) and Example 16 (c).
This gave 0.35 g of the title compound as an orange solid.
(88% yield) Melting point: 145-148 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.06-1.10
(m, 2H), 1.43-1.47 (m, 2H), 2.61-2.71 (m, 1H), 3.2
7 (s, 3H), 3.47 (s, 3H), 4.19 (dd, J = 14.6 and 4.6H
z, 1H), 4.60 (d, J = 14.4Hz, 1H), 4.70 (d, J = 16.1Hz,
 1H), 5.19 (d, J = 16.3Hz, 1H), 5.47-5.49 (m, 1H) 7.7
4 (s, 1H), 8.79 (s, 1H), 9.40 (d, J = 4.6Hz, 1H) MS spectrum (CI, m / z) 428 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3402, 16
59, 1463 (Example 46)8- [7-amino-5-methyl-4,5,6,7-tet
Lahydrothieno [3,2-c] pyridin-2-yl]-
1-cyclopropyl-9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid (Exemplified Compound No. 1-1361) (A) Ethyl 1-cyclopropyl-9-methyl-8-
[5-methyl-7-tritylamino-4,5,6,7-
Tetrahydrothieno [3,2-c] pyridine-2-i
4-oxo-4H-quinolidine-3-carboxy
rate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
5-methyl-7-tritylamino-4,5,6,7-te
1.12 g of trahydrothieno [3,2-c] pyridine
Example 22 (a) except that (2.73 mmol) was used.
And react 0.66 g of the title compound with an orange solid.
As obtained. (Yield 77%) MS spectrum (CI, m / z) 680 (M⁺+1) (B) 8- [7-amino-5-methyl-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridine-2-i
1] -cyclopropyl-9-methyl-4-oxo-
4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-9-methyl-8- [5-methyl-7
-Tritylamino-4,5,6,7-tetrahydrothier
No [3,2-c] pyridin-2-yl] -4-oxo-
0.60 g of 4H-quinolidine-3-carboxylate
Example 16 (b) except that (0.88 mmol) was used.
And reacting in the same manner as in Example 16 (c) to give the title compound
0.22 g was obtained as an orange solid. (60% yield) Melting point: 220 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.03-1.07
(m, 2H), 1.43-1.47 (m, 2H), 2.63-2.73 (m, 1H), 3.2
7 (s, 3H), 3.44 (s, 3H), 4.21 (dd, J = 14.2 and 4.6H
z, 1H), 4.52 (d, J = 15.3Hz, 1H), 4.62 (d, J = 14.1Hz,
 1H), 5.03 (d, J = 15.3Hz, 1H), 5.63-5.65 (m, 1H), 7.
44 (s, 1H), 7.95 (d, J = 7.6Hz, 1H), 8.79 (s, 1H),
9.42 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z) 410 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3375, 17
14, 1461 (Example 47)8- [4-amino-7-methyl-4,5,6,7-tet
Lahydrobenzo [b] thiophen-2-yl] -1-cy
Clopropyl-9-methyl-4-oxo-4H-quinoli
Gin-3-carboxylic acid (Exemplified Compound No. 1-543) (A) Ethyl 8- [4- (t-butoxycarbonyl)
Amino-7-methyl-4,5,6,7-tetrahydrobe
Nzo [b] thiophen-2-yl] -1-cyclopropyl
Ru-9-methyl-4-oxo-4H-quinolidine-3-
Carboxylate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
4- (t-butoxycarbonyl) amino-7-methyl-
4,5,6,7-tetrahydrobenzo [b] thiophene
Except that 0.68 g (2.50 mmol) was used,
Reaction was carried out in the same manner as in 22 (a) to give the title compound (0.54 g)
Was obtained almost quantitatively as an orange solid. MS spectrum (CI, m / z) 537
(M⁺+1) (B) 8- [4-amino-7-methyl-4,5,6,7
-Tetrahydrobenzo [b] thiophen-2-yl]-
1-cyclopropyl-9-methyl-4-oxo-4H-
Quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-8- [4- (t-butoxycarboni
Le) amino-7-methyl-4,5,6,7-tetrahydride
Lobenzo [b] thiophen-2-yl] -9-methyl-
4-oxo-4H-quinolidine-3-carboxylate
Except that 0.54 g (1.00 mmol) was used,
The reaction was carried out in the same manner as in Example 16 (b) and Example 16 (c).
0.17 g of the title compound was obtained as an orange solid. (Yield 4
1%) Melting point: 144-147 ° C NMR spectrum (CF_ThreeCOOD, δ): 1.03-1.07
(m, 2H), 1.42-2.68 (m, 10H), 3.20-3.37 (m, 4H), 4.9
0-4.95 (m, 1H), 7.73 7.76 (each s, total 1H, diast
ereomer), 8.05 (d, J = 7.6Hz, 1H), 8.69 (s, 1H), 9.4
2 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z) 409 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3400, 16
52, 1463 (Example 48)8- [5-amino-4,5,6,7-tetrahydroben
Zo [b] thiophen-2-yl] -1-cyclopropyl
-9-methyl-4-oxo-4H-quinolizin-3-ca
Rubonic acid (Exemplified Compound No. 1-793) (A) Ethyl 8- [5- (t-butoxycarbonyl)
Amino-4,5,6,7-tetrahydrobenzo [b] thi
Offen-2-yl] -1-cyclopropyl-9-methyl
Ru-4-oxo-4H-quinolidine-3-carboxyle
To 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
5- (t-butoxycarbonyl) amino-4,5,6
0.76 g of 7-tetrahydrobenzo [b] thiophene
Example 22 (a) except that (3.00 mmol) was used.
In the same manner as above to give 0.45 g of the title compound as an orange foam
Obtained as a product. (Yield 77%) MS spectrum (CI, m / z) 523 (M⁺+1) (B) 8- [5-amino-4,5,6,7-tetrahydrid
Robenzo [b] thiophen-2-yl] -1-cycloprop
Ropyl-9-methyl-4-oxo-4H-quinolidine-
3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 8 instead of Norizin-3-carboxylate
-[5- (t-butoxycarbonyl) amino-4,5,
6,7-tetrahydrobenzo [b] thiophen-2-i
1] -cyclopropyl-9-methyl-4-oxo-
0.43 g of 4H-quinolidine-3-carboxylate
Example 16 (b) except that (0.85 mmol) was used.
And reacting in the same manner as in Example 16 (c) to give the title compound
0.28 g was obtained as a yellow solid. (Yield 82%) Melting point: 221-224 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 0.99-1.05
(m, 2H), 1.40-1.47 (m, 2H), 2.28-2.60 (m, 2H), 2.6
3-2.72 (m, 1H), 3.06-3.45 (m, 7H), 4.07-4.13 (m, 1
H), 7.43 (s, 1H), 8.06 (d, J = 7.6Hz, 1H), 8.66 (s,
1H), 9.33 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z) 395 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3453, 16
55, 1462 (Example 49)8- [4-amino-4,5,6,7-tetrahydrothier
No [2,3-c] pyridin-2-yl] -1-cycloprop
Ropyl-7-fluoro-9-methyl-4-oxo-4H
-Quinolidine-3-carboxylic acid (Exemplary Compound No. 1-45
1) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-8- [6-trityl-4-tri
Tylamino-4,5,6,7-tetrahydrothieno
[2,3-c] pyridin-2-yl] -4H-quinolizi
N-3-carboxylate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
6-trityl-4-tritylamino-4,5,6,7-
2.02 g of tetrahydrothieno [2,3-c] pyridine
(3.16 mmol) using ethyl 8-chloro-1
-Cyclopropyl-9-methyl-4-oxo-4H-ki
Ethyl 8 instead of Norizin-3-carboxylate
-Chloro-1-cyclopropyl-7-fluoro-9-me
Tyl-4-oxo-4H-quinolidine-3-carboxy
Other than using 0.56 g (1.72 mmol) of the rate,
The reaction was carried out in the same manner as in Example 22 (a) to give the title compound 0.1.
60 g were obtained as an orange solid. (38% yield) NMR spectrum (CDCl_Three, Δ): 0.78-0.83 (m, 2
H), 1.04-1.10 (m, 2H), 1.35-1.46 (m, 4H), 2.31-2.4
1 (m, 1H), 2.45-2.55 (m, 1H), 2.96 (s, 3H), 3.03-
3.13 (m, 1H), 3.78-3.88 (m, 1H), 4.40-4.48 (m, 3
H), 6.91 (brs, 1H), 7.12-7.52 (m, 31H), 8.39 (s, 1
H), 9.43 (d, J = 6.1Hz, 1H) (B) 8- [4-amino-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridin-2-yl] -1-si
Clopropyl-7-fluoro-9-methyl-4-oxo
-4H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [4-Tritylamino-4,5,6,7-tetra
Hydrobenzo [b] thiophen-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-7-fluoro-9-methyl-4-o
Xo-8- [6-trityl-4-tritylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
-2-yl] -4H-quinolizin-3-carboxyle
Except that 0.56 g (0.65 mmol) was used.
The reaction was carried out in the same manner as in Example 16 (b) and Example 16 (c).
This gave 0.14 g of the title compound as an orange solid. (Income
Rate 52%) Melting point: 190-210 ° C (decomposition) NMR spectrum (CF_ThreeCOOD, δ): 1.07-1.10
(m, 2H), 1.43-1.47 (m, 2H), 2.61-2.71 (m, 1H), 3.2
7 (s, 3H), 4.22-4.28 (m, 1H), 4.65 (d, J = 15.1Hz, 1
H), 4.88 (d, J = 16.1Hz, 1H), 5.05 (d, J = 16.1Hz, 1H),
 5.45-5.46 (m, 1H) 7.72 (s, 1H), 8.79 (s, 1H), 9.40
 (d, J = 4.4Hz, 1H) MS spectrum (CI, m / z) 414 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3325, 16
64, 1465 (Example 50)1-cyclopropyl-9-methyl-8- [4-methyla
Mino-4,5,6,7-tetrahydrobenzo [b] fura
N-2-yl] -4-oxo-4H-quinolizin-3-
Carboxylic acid hydrochloride (Hydrochloride of Exemplified Compound No. 1-1499) (A) Ethyl 8- [4- (t-butoxycarbonyl)
(Methyl) amino-4,5,6,7-tetrahydroben
Zo [b] furan-2-yl] -1-cyclopropyl-9
-Methyl-4-oxo-4H-quinolidine-3-carbo
Xylate 6-trityl-4-tritylamino-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
4- (t-butoxycarbonyl) (methyl) amino-
4,5,6,7-tetrahydrobenzo [b] furan
Example 22 except that 54 g (2.15 mmol) was used.
The same reaction as in (a) was carried out, and 0.46 g of the title compound was added to orange
Obtained as a colored solid. (88% yield) MS spectrum (CI, m / z) 521 (M⁺+1) (B) 8- [4- (t-butoxycarbonyl) (meth
Le) amino-4,5,6,7-tetrahydrobenzo
[B] Furan-2-yl] -1-cyclopropyl-9-
Methyl-4-oxo-4H-quinolidine-3-carboxyl
acid Ethyl 8- [4- (t-butoxycarbonyl) (methyl
Le) amino-4,5,6,7-tetrahydrobenzo
[B] Furan-2-yl] -1-cyclopropyl-9-
Methyl-4-oxo-4H-quinolidine-3-carboxy
0.46 g (0.88 mmol) of sylate
Lofran 10ml, 1N sodium hydroxide aqueous solution 2ml
And 4 ml of ethanol were added and reacted at room temperature for 7 hours. After completion of the reaction, 1N hydrochloric acid was added to the obtained reaction solution.
To adjust the pH to 6, and add ethyl acetate and saturated sodium chloride.
An aqueous solution of lithium was added to separate the layers. No organic phase obtained
The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure.
0.44 g of the title compound was obtained almost quantitatively as an orange foam.
Was. MS spectrum (CI, m / z) 493
(M⁺+1) (C) 1-cyclopropyl-9-methyl-8- [4-me
Tylamino-4,5,6,7-tetrahydrobenzo
[B] Furan-2-yl] -4-oxo-4H-quinoli
Gin-3-carboxylic acid hydrochloride 8- [4- (t-butoxycarbonyl) (methyl) amido
No-4,5,6,7-tetrahydrobenzo [b] furan
-2-yl] -1-cyclopropyl-9-methyl-4-
0.44 g of oxo-4H-quinolidine-3-carboxylic acid
(0.88 mmol) in 15 ml of tetrahydrofuran
Dissolve and cool with ice-cooled, saturated hydrogen chloride tetrahydrofuran solution
15 ml were added. A precipitate formed after stirring for 3.5 hours
Was collected by filtration. The obtained filtrate is washed with tetrahydrofuran.
Washing afforded 0.33 g of the title compound as an orange solid.
(Yield 87%) Melting point: 275-280 ° C (decomposition) NMR spectrum (DMSO-d₆, Δ): 0.68-0.732
(m, 2H), 1.04-1.11 (m, 2H), 1.90-2.10 (m, 4H), 2.4
6-2.54 (m, 1H), 2.66 (s, 3H), 2.78-2.82 (m, 2H),
3.05 (s, 3H), 4.33-4.35 (m, 1H), 7.59 (s, 1H), 7.
83 (d, J = 7.6Hz, 1H), 8.25 (s, 1H), 9.27 (d, J = 7.3H
z, 1H) MS spectrum (CI, m / z) 393 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3421, 26
84, 1715, 1437 (Example 51)8- [4-amino-6-methyl-7-oxo-4,5,
6,7-tetrahydrothieno [2,3-c] pyridine-
2-yl] -1-cyclopropyl-7-fluoro-9-
Methyl-4-oxo-4H-quinolidine-3-carboxyl
acid (Exemplified Compound No. 1-1265) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8- [6-methyl-7-oxo-4-triti
Ruamino-4,5,6,7-tetrahydrothieno [2,
3-c] pyridin-2-yl] -4-oxo-4H-ki
Noridine-3-carboxylate Under an argon atmosphere, 6-methyl-7-oxo-4-tri
Tylamino-4,5,6,7-tetrahydrothieno
0.87 g of [2,3-c] pyridine (2.05 mmol
l) is dissolved in 20 ml of tetrahydrofuran, and lithium
Diisopropylamide mono (tetrahydrofuran)
(1.5 M cyclohexane solution) 5.0 ml (7.5
mmol) was added dropwise at -70 ° C or lower over 5 minutes.
After stirring at the same temperature for 40 minutes, trimethyl borate 1.00 m
1 (8.9 mmol) was added dropwise over 5 minutes.
For 20 minutes. After the completion of the reaction, water was added to the obtained reaction solution.
And extracted three times with ethyl acetate. The organic phase obtained is anhydrous
After drying over sodium sulfate, the solvent is distilled off under reduced pressure, and boric acid
1.33 g of compound was obtained as a green-brown solid. Under an argon atmosphere, the obtained borated compound
Product, ethyl 8-chloro-1-cyclopropyl-7-fur
Fluoro-9-methyl-4-oxo-4H-quinolidine-
0.33 g (1.00 mmol) of 3-carboxylate
And tetrakis (triphenylphosphine) palladium
(0) 0.12 g, toluene 14 ml, ethanol 6
ml and 2M aqueous sodium carbonate solution in order of 1 ml.
The mixture was heated and stirred at 0 ° C. for 1.5 hours. After completion of the reaction, the obtained reaction solution was cooled to room temperature.
After returning, ethyl acetate and water were added, and ethyl acetate was added three times.
Extracted. The obtained organic phase is washed with a saturated aqueous sodium chloride solution.
And dried over anhydrous sodium sulfate.
Evaporation gave a residue. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: chloroform / acetic acid
Chill = 20/1) to give 0.29 g of the title compound as an orange
Obtained as a colored solid. (40% yield) NMR spectrum (CDCl_Three, Δ): 0.78-0.84 (m, 2
H), 1.05-1.10 (m, 2H), 2.51-2.57 (m, 1H), 1.43 (t,
 J = 5.1, 3H), 2.31-2.41 (m, 1H), 2.50-2.82 (m, 2H),
2.84 (s, 3H), 2.97 (s, 3H), 4.00-4.10 (m, 1H), 4.44
 (q, J = 5.1Hz, 2H), 6.93 (s, 1H), 7.16-7.64 (m, 15
H), 8.42 (s, 1H), 9.45 (d, J = 6.0Hz, 1H) (B) 8- [4-amino-6-methyl-7-oxo-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysin-2-yl] -1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
carboxylic acid Ethyl 1-cyclopropyl-9-methyl-4-oxo
-8- [5-Trityl-4,5,6,7-tetrahydro
Thieno [3,2-c] pyridin-2-yl] -4H-ki
Ethyl 1 instead of Norizin-3-carboxylate
-Cyclopropyl-7-fluoro-9-methyl-8-
[6-Methyl-7-oxo-4-tritylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
N-2-yl] -4-oxo-4H-quinolizin-3-
Use 0.73 g (1.56 mmol) of carboxylate
Other than the above, the same as in Example 1 (b) and Example 1 (c)
Reaction yielded 0.17 g of the title compound as a yellow solid.
Was. (Yield 25%) Melting point: 160 ° C (decomposition) NMR spectrum (DMSO-d₆, Δ): 0.76-0.81
(m, 2H), 1.05-1.11 (m, 2H), 2.51-2.57 (m, 1H), 2.9
5 (s, 3H), 3.01 (s, 3H), 3.46 (dd, J = 12.5 and 8.5H
z, 1H), 3.67 (dd, J = 12.5 and 5.9Hz, 1H), 4.21 (dd,
J = 8.5 and 5.9Hz, 1H), 7.47 (s, 1H), 8.29 (s, 1H) 9.3
5 (d, J = 5.6Hz, 1H) MS spectrum (CI, m / z) 442 (M⁺+1) (Example 52)(+)-1-cyclopropyl-7-fluoro-9-methyl
-8-[(1R) -1-methylisoindoline-5-i
4-oxo-4H-quinolidine-3-carboxylic acid
(R form of Exemplified Compound No. 2-97) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8-[(1R) -1-methyl-2-trityl
Isoindoline-5-yl] -4-oxo-4H-quino
Lysine-3-carboxylate Under an argon atmosphere, (1R) -5-bromo-1-methyl
9.6 g of 2-tritylisoindoline in tetrahydro
Dissolved in 50 ml of furan, butyllithium (1.6M
(Hexane solution) 15.5 ml at -70 ° C or lower for 5 minutes
And dropped. After dropping, stirring at the same temperature for 60 minutes, 2-
Isopropoxy-4,4,5,5-tetramethyl-1,
5.0 ml of 3,2-dioxaborolane is dropped over 5 minutes
I gave it. After stirring at the same temperature for 15 minutes, raise the temperature to 0 ° C,
For 15 minutes. After the completion of the reaction, the resulting reaction solution was added with water 80
and 180 ml of chloroform were added and separated into two phases.
Was. The obtained organic phase was dried over anhydrous sodium sulfate.
Thereafter, the solvent was distilled off under reduced pressure. The residue obtained is silica gel
Chromatography (elution solvent: hexane / ethyl acetate
= 9/1) to obtain 8.1 g of a borane compound. In an argon atmosphere, the above-mentioned borane compound,
Ethyl 8-chloro-1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
2.8 g of carboxylate and tetrakis (triphenyl
0.62 g of phosphine) palladium (0) and toluene
50 ml, ethanol 20 ml and 2M aqueous sodium carbonate
Suspended in a mixed solution with 8.8 ml of the solution,
The mixture was stirred while heating. After the completion of the reaction, the obtained reaction solution was allowed to cool,
Add 150 ml of water and 150 ml of ethyl acetate and separate.
Was. The obtained organic phase was dried over anhydrous sodium sulfate.
Thereafter, the solvent was distilled off under reduced pressure. The residue obtained is silica gel
Chromatography (elution solvent: hexane / ethyl acetate
= 2/1) to give 4.8 g of the title compound as a yellow oil
Obtained as a product. (83% yield) NMR spectrum (CDCl_Three, Δ): 0.73-0.79 (m, 2
H), 0.99-1.10 (m, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.50 (d, J
= 6.8Hz, 3H), 2.32-2.40 (m, 4H), 4.13 (d, J = 16.6Hz, 1H),
4.43 (q, J = 7.1Hz, 2H), 4.55-4.62 (m, 2H), 6.56 (s, 1H),
6.80-6.87 (m, 2H), 7.04-7.59 (m, 15H), 8.31 (s, 1H), 9.4
0 (d, J = 5.9Hz, 1H) (B) ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-8-[(1R) -1-methylisoindoline
-5-yl] -4-oxo-4H-quinolizin-3-ca
Ruboxylate Ethyl 1-cyclopropyl-7-fluoro-9-methyl
Ru-8-[(1R) -1-methyl-2-tritylisoyi
Ndolin-5-yl] -4-oxo-4H-quinolizine
4.8 g of -3-carboxylate in tetrahydrofuran
Dissolved in 30 ml and p-toluenesulfonic acid 1.48 g
Was added and the mixture was stirred at room temperature for 14 hours. After the completion of the reaction, the pressure was reduced from the obtained reaction solution.
Under the solvent was distilled off. The obtained residue is purified by silica gel chromatography.
Chromatography (elution solvent: chloroform / methanol =
9/1) to give 2.3 g of the title compound as a yellow oil.
I got it. (Yield 77%) NMR spectrum (CDCl_Three, Δ): 0.77-0.82 (m, 2
H), 1.01-1.07 (m, 2H), 1.44 (t, J = 7.2Hz, 3H), 1.52 (d, J =
6.3Hz, 3H), 2.30-2.40 (m, 1H), 2.80 (s, 3H), 4.23-4.36
(m, 2H), 4.44 (q, J = 7.2Hz, 2H), 4.51-4.57 (m, 2H), 7.17-
7.36 (m, 3H), 8.39 (s, 1H), 9.47 (d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 421 (M⁺+1) (C) (+)-1-cyclopropyl-7-fluoro-9-
Methyl-8-[(1R) -1-methylisoindoline-
5-yl] -4-oxo-4H-quinolizin-3-cal
Boric acid Ethyl 1-cyclopropyl-7-fluoro-9-methyl
Ru-8-[(1R) -1-methylisoindoline-5
Yl] -4-oxo-4H-quinolidine-3-carboxy
2.3 g of sylate is dissolved in 30 ml of ethanol, and 1N
5.5 ml of sodium hydroxide aqueous solution was added for 15 hours
Stirred. After the completion of the reaction, the resultant reaction solution was decompressed.
Below, ethanol was distilled off. 1N until neutral to residue
Hydrochloric acid was added and the resulting precipitate was collected by filtration to give the title compound.
1.74 g were obtained as a yellow solid. (79% yield) Melting point: 300 ° C or higher NMR spectrum (DMSO-d₆, Δ): 0.76-0.80
(m, 2H), 1.01-1.07 (m, 2H), 1.38 (d, J = 6.6Hz, 3H), 2.43-
2.59 (m, 1H), 2.79 (s, 3H), 4.05-4.22 (m, 2H), 4.32-4.45
(m, 1H), 7.29 (d, J = 7.8,1H), 7.34 (s, 1H), 7.44 (d, J = 7.
8,1H), 8.23 (s, 1H), 9.34 (d, J = 5.9Hz, 1H) MS spectrum (CI, m / z) 393 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3381,168
1,1467,1336 [α]_D ²⁰ = + 15.9 (C = 0.25, TFA) (Example 53)1-cyclopropyl-7-fluoro-8- (isoindo
Phosphorus-5-yl) -9-methyl-4-oxo-4H-ki
Noridine-3-carboxylic acid (Exemplified Compound No. 2-11) (A) Ethyl 1-cyclopropyl-7-fluoro-9
-Methyl-4-oxo-8- (2-tritylisoindo
Phosphorus-5-yl) -4H-quinolizin-3-carboxy
rate Under an argon atmosphere, 5-bromo-2-tritylisoin
1.20 g (2.72 mmol) of drin in tetrahydro
Dissolved in 100 ml of furan, butyllithium (1.54
M hexane solution) 1.86 ml (2.86 mmol)
At -70 ° C or lower over 5 minutes, and at the same temperature for 15 minutes.
Stirred for minutes. 0.74 ml of tributyltin chloride
(2.73 mmol) was added dropwise over 5 minutes.
Stirred for 20 minutes. After completion of the reaction, 2 ml of water was added to the obtained reaction solution.
And the mixture is returned to room temperature, and the solvent is distilled off under reduced pressure.
To. Add 30 ml of water and extract with 60 ml of hexane.
Was. The obtained organic phase is dried over anhydrous magnesium sulfate.
Then, the solvent was distilled off, and 2.80 g of a tin compound was added as a slightly yellow oil.
Obtained as a product. In an argon atmosphere, the above-mentioned tin compound,
Cyl 8-chloro-1-cyclopropyl-7-fluoro
-9-methyl-4-oxo-4H-quinolizin-3-ca
0.40 g (1.24 mmol) of ruboxylate
(Triphenylphosphine) palladium (II) dichloride
Dissolve 0.07 g of lid in 30 ml of toluene, and
Heated to reflux. After the completion of the reaction, the obtained reaction solution was decompressed.
Under the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: chloroform / methano
To 1/0 to 99/1) to give the title compound 0.5
1 g was obtained as a yellow solid. (64% yield) NMR spectrum (CDCl_Three, Δ): 0.75-0.78 (m, 2
H), 1.00-1.03 (m, 2H), 1.43 (t, J = 7.2Hz, 3H), 2.27-
2.37 (m, 1H), 2.75 (s, 3H), 4.02 (s, 4H), 4.43 (q, J =
7.3Hz, 2H), 7.02-7.63 (m, 18H), 8.37 (s, 1H), 9.43
(d, J = 5.4Hz, 1H) (B) 1-cyclopropyl-7-fluoro-8- (iso
Indolin-5-yl) -9-methyl-4-oxo-4
H-quinolidine-3-carboxylic acid Ethyl 1-cyclopropyl-7-fluoro-9-methyl
Ru-4-oxo-8- (2-tritylisoindoline-
5-yl) -4H-quinolidine-3-carboxylate
0.50 g (0.77 mmol) in tetrahydrofuran
Dissolved in 20 ml, p-toluenesulfonic acid-hydrate
Add 0.45 g (2.37 mmol) and leave room for 21 hours
Leave in the warm. After the completion of the reaction, the pressure was reduced from the obtained reaction solution.
Under the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: chloroform / methano
= 20/1-chloroform / methanol / triethyl
Luamine = 17/2 / 0.5) to give a yellow solid.
Was. The obtained yellow solid was washed with tetrahydrofuran 2
Dissolved in 5ml, 1m sodium hydroxide aqueous solution 2.0m
1 (2.0 mmol) and stirred at room temperature for 18 hours.
Was. The pH was adjusted to neutral with 1N hydrochloric acid, and the resulting precipitate was filtered.
I took it. After washing the obtained precipitate with water,
And 82 mg of the title compound was obtained as a yellow solid.
(Yield 28%) Melting point: 285 ° C or higher NMR spectrum (DMSO-d₆, Δ): 0.76-0.80
(m, 2H), 1.03-1.07 (m, 2H), 2.47-2.53 (m.1H overlapped
with solvent), 2.79 (s, 3H), 4.15 (s, 4H), 7.27 (d, J =
7.8Hz, 1H), 7.36 (s, 1H), 7.48 (d, J = 7.8Hz, 1H), 8.23
(s, 1H), 9.34 (d, J = 6.4Hz, 1H) MS spectrum (CI, m / z) 379 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3433,166
6,1466,1441 (Example 54)8- (5-amino-5,6,7,8-tetrahydronaph
Taren-1-yl) -1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid (Example
Compound No. 2-527) (1R) -5-bromo-1-methyl-2-trityliso
5-bromo-1-tritylamino instead of indoline
2.5 g of -1,2,3,4-tetrahydronaphthalene
Ethyl 8-chloro-1-cyclopropyl-7-fluoro
B-9-Methyl-4-oxo-4H-quinolidine-3-
Ethyl 8-chloro-1- instead of carboxylate
Cyclopropyl-9-methyl-4-oxo-4H-quino
0.50 g of lysine-3-carboxylate (1.64 m
mol), and reacted in the same manner as in Example 52.
This gave 0.30 g of the title compound as a yellow solid. (Income
Rate 47%) Melting point: 155-158 ° C NMR spectrum (DMSO-d₆, Δ): 0.76-0.80
(m, 2H), 1.00-1.08 (m, 2H), 1.58-2.57 (m, 7H), 2.68,2.
71 (each s, total 3H rotamer) 、 3.95-4.02 (m, 1H) 、 7.06
(d, J = 7.6Hz, 1H), 7.32-7.42 (m, 2H), 7.64 (d, J = 8.3Hz, 1
H), 8.27 (s, 1H), 9.33-9.35 (m, 1H) MS spectrum (CI, m / z) 389 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 2935, 165
3, 1464 (Example 55)8- (8-amino-5,6,7,8-tetrahydronaph
Taren-2-yl) -1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid (Example
Compound No. 2-457) (1R) -5-bromo-1-methyl-2-trityliso
7-bromo-1-tritylamino instead of indoline
1.6 g of -1,2,3,4-tetrahydronaphthalene
Used, ethyl 8-chloro-1-cyclopropyl-7-
Fluoro-9-methyl-4-oxo-4H-quinolidine
Ethyl 8-chloro in place of -3-carboxylate
-1-cyclopropyl-9-methyl-4-oxo-4H
Using 0.40 g of quinolidine-3-carboxylate
Otherwise, reacting in the same manner as in Example 52 to give the title compound
0.34 g was obtained as a yellow solid. (81% yield) Melting point: 144-146 ° C NMR spectrum (DMSO-d₆, Δ): 0.77-0.81
(m, 2H), 1.03-1.09 (m, 2H), 1.56-1.80 (m, 2H), 1.89-
2.03 (m, 2H), 2.46-2.57 (m, 1H), 2.74-2.94 (m, 5H), 3.88
-3.96 (m, 1H), 7.23-7.31 (m, 2H), 7.54 (d, J = 7.6Hz, 1H),
8.23 (s, 1H), 9.32 (d, J = 7.3Hz, 1H) MS spectrum (CI, m / z) 389 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 2944, 165
3, 1461 (Example 56)8- [5-amino-5,6,7,8-tetrahydronaph
Taren-2-yl] -1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxylic acid (Example
Compound No. 2-445) (1R) -5-bromo-1-methyl-2-trityliso
Instead of indoline, 2-bromo-5- (t-butylthio)
(Xycarbonyl) amino-5,6,7,8-tetrahydrido
Using 0.78 g of lonaphthalene, ethyl 8-chloro-
1-cyclopropyl-7-fluoro-9-methyl-4-
Oxo-4H-quinolidine-3-carboxylate
Instead, ethyl 8-chloro-1-cyclopropyl-9-
Methyl-4-oxo-4H-quinolidine-3-carboxy
Same as Example 52 except that 0.36 g of sylate was used
Reaction yielded 0.14 g of the title compound as a yellow solid.
Was. (Yield 29%) Melting point: 255 ° C (decomposition) NMR spectrum (DMSO-d₆, Δ): 0.73-0.84
(m, 2H), 1.01-1.12 (m, 2H), 1.69-2.13 (m, 4H), 2.4
6-2.58 (m, 1H), 2.70-2.96 (m, 5H), 4.24-4.33 (m, 1
H), 7.33 (s, 1H), 7.41 (d, J = 7.7Hz, 1H), 7.53 (d,
J = 7.6Hz, 1H), 7.70 (d, J = 7.7Hz, 1H), 8.27 (s, 1H),
 9.27 (d, J = 7.6Hz, 1H) MS spectrum (CI, m / z): 389 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 3407, 16
36, 1440 (Reference example) (Reference Example 1)2- (4-chloro-3-methyl-2-pyridyl) cyclo
Propyl acetonitrile Lithium in 10 ml of tetrahydrofuran under nitrogen atmosphere
Diisopropylamide (1.5M cyclohexane solution)
4.3 ml (6.45 mmol) is added and -70 ° C or less
0.5 g of cyclopropylacetonitrile (6.16 m
mol) in 3 ml of tetrahydrofuran and added dropwise
did. After the addition, the mixture was stirred for 20 minutes, and at the same temperature,
0.5 g of chloro-3-methylpyridine (3.09 mmol)
3 ml of a tetrahydrofuran solution in which
After that, the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, a saturated ammonium chloride solution was added to the reaction solution.
An aqueous solution of ammonium was added, and the mixture was extracted three times with ethyl acetate. Get
The organic phase was washed with a saturated aqueous solution of sodium chloride and then dried.
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. Profit
The residue obtained is subjected to silica gel chromatography (elution
Medium: hexane / ethyl acetate = 4/1)
0.20 g of the compound was obtained as a colorless oil. (Yield 31
%) NMR spectrum (CDCl_Three, Δ): 0.46-0.80 (m, 4H)
 , 1.47-1.56 (m, 1H), 2.46 (s, 3H), 3.85 (d, J = 7.8Hz, 1H)
 , 7.30 (d, J = 5.3Hz, 1H), 8.36 (d, J = 5.3Hz, 1H) MS spectrum (CI, m / z) 207 (M⁺+1) (Reference Example 2)Ethyl 2- (4-chloro-3-methyl-2-pyridi
Le) Cyclopropyl acetate Saturate hydrogen chloride gas in 15 ml of absolute ethanol under ice-cooling
To give 2- (4-chloro-3-methyl-2-pyridyl)
0.90 g of cyclopropylacetonitrile (4.35 m
mol) was dissolved in 5 ml of ethanol and added dropwise.
It was left overnight in the warehouse. After completion of the reaction, 1 m of water was added to the obtained reaction solution.
After stirring at room temperature for 1 hour, the mixture was poured into ice water under ice cooling.
And adjusted to neutral with 40% aqueous sodium hydroxide solution.
Extracted three times with loroform. The obtained organic phase is sulfuric anhydride
Dry over magnesium and evaporate the solvent under reduced pressure to give the title
0.89 g of the compound was obtained as a yellow oil. (Yield 81
%) NMR spectrum (CDCl_Three, Δ): 0.12-0.18 (m, 1
H), 0.35-0.42 (m, 1H), 0.49-0.59 (m, 1H), 0.70-0.76
(m, 1H), 1.20 (t, J = 7.1Hz, 3H), 1.64-1.70 (m, 1H), 2.38
(s, 3H), 3.31 (d, J = 9.5Hz, 1H), 4.16 (q, J = 7.1Hz, 2H)
 , 7.21 (d, J = 5.1Hz, 1H), 8.33 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 254 (M⁺+1) (Reference Example 3)2- (4-chloro-3-methyl-2-pyridyl) -2-
Cyclopropylethanol Ethyl 2- (4-chloro-3-methyl-2-pyridi
Le) cyclopropyl acetate 0.89 g (3.51 m
mol) is dissolved in 50 ml of tetrahydrofuran and cooled with ice.
Below, 0.15 g of lithium aluminum hydride (3.95 g)
mmol) was added in portions and stirred for 30 minutes. After the completion of the reaction, the obtained reaction solution was added with saturated sulfuric acid.
Add a small amount of aqueous sodium acid solution and filter off the generated insolubles
did. After washing the residue with ethyl acetate, the resulting organic phase
Was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
To give 0.87 g of the title compound almost as a yellow oil.
Obtained quantitatively. The NMR spectrum (CDCl_Three, Δ): 0.2
1-0.28 (m, 2H), 0.42-0.66 (m, 2H), 1.20-1.32 (m, 1H),
2.37 (s, 3H), 2.56-2.62 (m, 1H), 3.99-4.09 (m, 3H), 7.21
(d, J = 5.1Hz, 1H), 8.27 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 212 (M⁺+1) (Reference Example 4)2- (4-chloro-3-methyl-2-pyridyl) cyclo
Propyl acetaldehyde Under a nitrogen atmosphere, 3.3 ml of dimethyl sulfoxide (4
6.6 mmol) was dissolved in 50 ml of methylene chloride.
Oxalyl chloride 2.0 ml (23.2 m
mol) in methylene chloride and added dropwise over 15 minutes
did. After stirring for 30 minutes, 2- (4-chloro-3-methyl
-2-pyridyl) -2-cyclopropylethanol4.
12 g (19.4 mmol) dissolved in methylene chloride
15 ml of the solution was added dropwise over 5 minutes. After stirring for 30 minutes
13.4 ml (180 mmol) of triethylamine in 1
It was dropped over 5 minutes. After completion of the reaction, the obtained reaction solution was gradually raised.
Warm, add 20 ml of water at around -10 ° C, and add methylene chloride.
Extracted three times. The obtained organic phase is washed with saturated aqueous sodium chloride.
After washing with a solution, drying over anhydrous sodium sulfate was performed under reduced pressure.
The solvent was distilled off to give 4.12 g of the title compound as a yellow oil.
Almost quantitatively. The NMR spectrum (CDCl_Three, Δ): 0.2
4-0.28 (m, 1H), 0.29-0.36 (m, 1H), 0.55-0.62 (m, 1H),
0.71-0.76 (m, 1H), 1.52-1.58 (m, 1H), 2.35 (s, 3H), 3.24
(dd, J = 10.2 and 2.4Hz, 1H), 7.23 (d, J = 5.1Hz, 1H), 8.
34 (d, J = 5.1Hz, 1H), 9.89 (d, J = 2.4Hz, 1H) MS spectrum (CI, m / z) 210 (M⁺+1) (Reference Example 5)Ethyl 8-chloro-1-cyclopropyl-9-methyl
-4-oxo-4H-quinolidine-3-carboxyle
G 2- (4-chloro-3-methyl-2-pyridyl) cyclo
4.12 g of propylacetaldehyde (19.6 mmol
l) was dissolved in 50 ml of ethanol, and 2.3 ml of acetic acid was dissolved.
(40.2 mmol), 2.3 ml of piperidine (23.
2 mmol) and 8.9 ml of diethyl malonate (117 m
mol) and heated at 80 ° C for 8 hours under nitrogen atmosphere
did. After the completion of the reaction, the pressure of the obtained reaction solution was reduced.
Under the solvent was distilled off. Diethyl ether is added to the obtained residue.
, And then sonicated to precipitate solids,
Was filtered. The solvent was distilled off from the obtained filtrate under reduced pressure, and
Under high vacuum, excess diethyl malonate was distilled off,
8.11 g of a red-brown oil was obtained. Xy
After heating and refluxing for 6.5 hours, the mixture was placed under reduced pressure.
The solvent was distilled off. The resulting residue is purified by silica gel column chromatography.
Chromatography (elution solvent: hexane / ethyl acetate = 4
/ 1-1 / 1) to give 3.53 g of the title compound in yellow
Obtained as a solid. (Yield 59%) NMR spectrum (CDCl_Three, Δ): 0.71-0.77 (m, 2
H), 1.02-1.08 (m, 2H), 1.42 (t, J = 7.1Hz, 3H), 2.26-2.3
5 (m, 1H), 3.01 (s, 3H), 4.42 (q, J = 7.1Hz, 2H), 7.10 (d,
J = 7.8Hz, 1H), 8.40 (s, 1H), 9.33 (d, J = 7.8Hz, 1H) MS spectrum (CI, m / z) 306 (M⁺+1) (Reference Example 6)2,4-dichloro-3-hydroxypyridine Under a nitrogen atmosphere, 2,4-dichloropyridine 0.50 g
(3.38 mmol) in 25 ml of tetrahydrofuran
Dissolve and add lithium diisopropylamide (1.5M
2.7 ml (4.05 mmol)
It was added dropwise at -70 ° C. After stirring at the same temperature for 30 minutes,
0.50 ml (4.46 mmol) of trimethyl acid at the same temperature
And the mixture was stirred at the same temperature for 30 minutes. After the completion of the reaction, acetic acid was added to the obtained reaction solution in an amount of 0.1%.
5 ml was added, and the temperature was gradually raised to 0 ° C. Under ice cooling, 30
5% aqueous hydrogen peroxide solution and 2N aqueous sodium hydroxide solution 5
and stirred at room temperature overnight. After completion of the reaction, the obtained reaction solution was washed with a saturated salt.
Into an aqueous solution of ammonium chloride and adjust the pH with 1N hydrochloric acid.
It was adjusted to 4.8 and extracted three times with ethyl acetate. Got
After washing the organic phase with a saturated aqueous sodium chloride solution,
Dry over magnesium and evaporate the solvent under reduced pressure to give the title
0.34 g of the compound was obtained as a pale yellow solid. (Yield 61
%) NMR spectrum (CDCl_Three, Δ): 6.13 (brs, 1H),
7.27 (d, J = 5.4Hz, 1H), 7.91 (d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 164 (M⁺+1) (Reference Example 7)2,4-dichloro-3-methoxypyridine 0.3 g of 2,4-dichloro-3-hydroxypyridine
(1.83 mmol) in N, N-dimethylformamide
Dissolved in 5 ml, and potassium carbonate 0.51 g (3.69 m
mol) and 0.17 ml of methyl iodide (1.83 mmol)
l) and stirred at room temperature for 1 hour. After the reaction was completed, toluene was added to the obtained reaction solution.
And water, and extracted twice with toluene. Obtained
The organic phase was washed with water and saturated aqueous sodium chloride in that order,
Dry over sodium sulfate and evaporate the solvent under reduced pressure.
0.24 g of the title compound was obtained as a pale yellow solid. (yield
74%) NMR spectrum (CDCl_Three, Δ): 3.95 (s, 3H), 7.2
9 (d, J = 5.1Hz, 1H), 8.07 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 178 (M⁺+1) (Reference Example 8)2- (4-chloro-3-methoxy-2-pyridyl) cyclo
Lopropylacetonitrile Instead of 2,4-dichloro-3-methylpyridine,
0.55 g of 2,4-dichloro-3-methoxypyridine
(3.09 mmol), except that Reference Example 1 was used.
Reaction to give 0.15 g of the title compound as a colorless oil
Obtained. (Yield 22%) NMR spectrum (CDCl_Three, Δ): 0.43-0.81 (m, 4H)
 , 1.58-1.51 (m, 1H), 3.79 (d, J = 8.3Hz, 1H), 4.00 (s, 3
H), 7.33 (d, J = 5.4Hz, 1H), 8.28 (d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 223 (M⁺+1) (Reference Example 9)Ethyl 2- (4-chloro-3-methoxy-2-pyridi
Le) Cyclopropyl acetate 2- (4-chloro-3-methyl-2-pyridyl) cyclo
Instead of propylacetonitrile, 2- (4-chloro
-3-methoxy-2-pyridyl) cyclopropylaceto
In addition to using 5.25 g (23.6 mmol) of nitrile
Is reacted in the same manner as in Reference Example 2 and then subjected to silica gel chromatography.
Chromatography (elution solvent: hexane / ethyl acetate = 7 /
3) to give 4.70 g of the title compound as a colorless oil
I got it. (74% yield) NMR spectrum (CDCl_Three, Δ): 0.18-0.24 (m, 1
H), 0.38-0.53 (m, 2H), 0.71-0.80 (m, 1H), 1.21 (t, J =
7.3Hz, 3H), 1.54-1.66 (m, 1H), 3.37 (d, J = 10.0Hz, 1H),
3.89 (s, 3H), 4.13-4.23 (m, 2H), 7.26 (d, J = 5.1Hz, 1
H), 8.27 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 270 (M⁺+1) (Reference Example 10)2- (4-chloro-3-methoxy-2-pyridyl) -2
-Cyclopropylethanol Ethyl 2- (4-chloro-3-methyl-2-pyridi
E) Ethyl 2 instead of cyclopropyl acetate
-(4-chloro-3-methoxy-2-pyridyl) cyclo
4.66 g (17.3 mmol) of propyl acetate
The reaction was carried out in the same manner as in Reference Example 3, except that silica gel was used.
Chromatography (elution solvent: hexane / ethyl acetate
= 1/1) to give 2.94 g of the title compound as a white solid
As obtained. (75% yield) NMR spectrum (CDCl_Three, Δ): 0.26-0.45 (m, 3
H), 0.60-0.67 (m, 1H), 1.19-1.31 (m, 1H), 2.56-2.62
(m, 1H), 3.60 (brs, 1H), 3.84 (s, 3H), 3.97-4.10 (m, 2H),
 7.24 (d, J = 5.1Hz, 1H), 8.22 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 228 (M⁺+1) (Reference Example 11)2- (4-chloro-3-methoxy-2-pyridyl) cyclo
Lopropylacetaldehyde 2- (4-chloro-3-methyl-2-pyridyl) -2-
Instead of cyclopropylethanol, 2- (4-chloro
B-3-Methoxy-2-pyridyl) -2-cyclopropyl
2.94 g (12.9 mmol) of ethanol
Was reacted in the same manner as in Reference Example 4 to give the title compound 3.17.
g was obtained almost quantitatively as an orange oil. The NMR spectrum (CDCl_Three, Δ): 0.2
7-0.35 (m, 1H), 0.41-0.60 (m, 2H), 0.74-0.83 (m, 1H),
1.50-1.57 (m, 1H), 3.25 (dd, J = 10.0 and 2.2Hz, 1H) 3.89
(s, 3H), 7.27 (d, J = 5.1Hz, 1H), 8.28 (d, J = 5.1Hz, 1H),
 9.92 (d, J = 2.2Hz, 1H) MS spectrum (CI, m / z) 226 (M⁺+1) (Reference Example 12)Ethyl 8-chloro-1-cyclopropyl-9-methoxy
C-4-oxo-4H-quinolidine-3-carboxyle
To 2- (4-chloro-3-methyl-2-pyridyl) cyclo
Instead of propylacetaldehyde, 2- (4-chloro
B-3-Methoxy-2-pyridyl) cyclopropylacet
Others using 3.17 g (14.0 mmol) of toaldehyde
Was reacted in the same manner as in Reference Example 5 to give the title compound 1.93.
g were obtained as a yellow solid. (Yield 43%) NMR spectrum (CDCl_Three, Δ): 0.72-0.77 (m, 2
H), 0.97-1.03 (m, 2H), 1.42 (t, J = 7.1Hz, 3H), 2.48-2.5
1 (m, 1H), 3.97 (s, 3H), 4.42 (q, J = 7.1Hz, 2H), 7.11 (d,
J = 7.8Hz, 1H), 8.26 (s, 1H), 9.26 (d, J = 7.8Hz, 1H) MS spectrum (CI, m / z) 322 (M⁺+1) (Reference Example 13)2,4-dichloro-3-difluoromethoxypyridine 2,4-dichloro-3-hydroxypyridine 14.4 g
(88.1 mmol) are suspended in 150 ml of toluene.
Butylammonium bromide (14.2 g, 44.0 mm
ol) and 125 ml of 35% aqueous sodium hydroxide solution.
added. Chlorodifluoromethyl
130 g of tongue is blown in three times.
100 ml of ren and 50 ml of water were added. 4 hours at room temperature
Stirred. After the completion of the reaction, 200 ml of water was added to the obtained reaction solution.
ml, and the insolubles were filtered and extracted three times with toluene.
The obtained organic phase is washed with a saturated aqueous solution of sodium chloride,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
Was. The obtained residue is subjected to silica gel chromatography (solvent chromatography).
Solvent: hexane / ethyl acetate = 4/1)
16.0 g of the title compound were obtained as a red-brown oil. (yield
85%) NMR spectrum (CDCl_Three, Δ): 6.64 (t, J = 73.2H
z, 1H), 7.39 (d, J = 5.1Hz, 1H), 8.22 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 214 (M⁺+1) (Reference Example 14)2- (4-chloro-3-difluoromethoxy-2-pyri
Jill) cyclopropylacetonitrile Instead of 2,4-dichloro-3-methylpyridine,
2,4-dichloro-3-difluoromethoxypyridine 1
Reference Example 1 except that 6.0 g (74.6 mmol) was used.
To give the title compound and 2- (2-chloro-
3-difluoromethoxy-4-pyridyl) cyclopropyl
1: 5 (NMR proton ratio) mixing with luacetonitrile
10.5 g of the product were obtained as a yellow oil. (Yield 9% (pure
Minute)) MS spectrum (CI, m / z) 259 (M⁺+1) (Reference Example 15)Ethyl 2- (4-chloro-3-difluoromethoxy-
2-pyridyl) cyclopropyl acetate 2- (4-chloro-3-methyl-2-pyridyl) cyclo
Instead of propylacetonitrile, 2- (4-chloro
-3-Difluoromethoxy-2-pyridyl) cyclopro
Pyracetonitrile and 2- (2-chloro-3-difluoro)
(Romethoxy-4-pyridyl) cyclopropylacetonit
A 1: 5 (NMR proton ratio) mixture with ril was added to 10.5
After reacting in the same manner as in Reference Example 2 except that
Gel chromatography (elution solvent: hexane / acetic acid
Chill = 4/1) to give the title compound and ethyl 2-
(2-chloro-3-difluoromethoxy-4-pyridi
1) with cyclopropyl acetate (NMR
10.7 g of the mixture was obtained as a pale yellow oil.
(Yield 53% (pure content)) MS spectrum (CI, m / z) 306 (M⁺+1) (Reference Example 16)2- (4-chloro-3-difluoromethoxy-2-pyri
Jil) -2-cyclopropylacetaldehyde Ethyl 2- (4-chloro-3-methyl-2-pyridi
E) Ethyl 2 instead of cyclopropyl acetate
-(4-chloro-3-difluoromethoxy-2-pyridi
Le) cyclopropyl acetate and ethyl 2- (2-k
Rolo-3-difluoromethoxy-4-pyridyl) cyclo
1: 9 (NMR proton ratio) mixture with propyl acetate
The reaction was conducted in the same manner as in Reference Example 3 except that 10.7 g of the compound was used.
To obtain a mixture of alcohols.
(Rolo-3-methyl-2-pyridyl) -2-cyclopropyl
Mixture of alcohols obtained in place of ethanol
The reaction was carried out in the same manner as in Reference Example 4 except that
And 2- (4-chloro-3-difluoromethoxy-2-
1: 9 with pyridyl) cyclopropylacetaldehyde
(NMR proton ratio) 9.8 g of the mixture was almost quantitatively
Obtained as a colored oil. MS spectrum (CI, m / z) 262
(M⁺+1) (Reference Example 17)Ethyl 8-chloro-1-cyclopropyl-9-difur
Oromethoxy-4-oxo-4H-quinolidine-3-ca
Ruboxylate 2- (4-chloro-3-methyl-2-pyridyl) cyclo
Instead of propylacetaldehyde, 2- (4-chloro
B-3-Difluoromethoxy-2-pyridyl) cyclop
Ropylacetaldehyde and 2- (2-chloro-3-dif)
Fluoromethoxy-4-pyridyl) cyclopropylacetate
8. 1: 9 (NMR proton ratio) mixture with aldehyde
After reacting in the same manner as in Reference Example 5 except for using 2 g,
Ricagel column chromatography (elution solvent: hexa
/ Ethyl acetate = 2/1 to 1/1) to give the title compound
0.35 g of the product was obtained as a yellow solid. (Yield 28% (pure
Minute)) NMR spectrum (CDCl_Three, Δ): 0.66-0.72 (m, 2
H), 1.01-1.07 (m, 2H), 1.42 (t, J = 7.1Hz, 3H), 2.36-2.41
(m.1H), 4.42 (t, J = 7.1Hz, 2H), 6.68 (t, J = 74.2Hz, 1H),
7.08 (d, J = 8.1Hz, 1H), 8.35 (s, 1H), 9.31 (d, J = 8.0Hz, 1H
H) MS spectrum (CI, m / z) 358 (M⁺+1) (Reference Example 18)4,5,6,7-tetrahydrothieno [2,3-c] pi
Lysine hydrochloride 10.0 g of 2- (3-thienyl) ethylamine (78.
7 mmol), 7.4 g of 37% formaldehyde aqueous solution
Was added under stirring at room temperature and stirred for 40 minutes. After the completion of the reaction, the obtained reaction solution was washed with diethyl ether.
Extracted with ether. The obtained organic phase is dried over anhydrous sodium sulfate.
After drying with lithium, the solvent was distilled off under reduced pressure to obtain an imine compound.
Was. The obtained imine form was converted to N, N-dimethylform.
5. Dissolve in 10 ml of muamide and dry hydrogen chloride while stirring
7 g of an N, N-dimethylformamide solution 50
The mixture was added dropwise to the mixture at room temperature. 1 hour at room temperature, then 80 ° C
After heating and stirring for 1 hour, the mixture was cooled with ice water to cause crystallization.
The resulting precipitate is collected by filtration, and hexane and diethyl ether
8.65 g of the title compound was washed with a white solid
As obtained. (62% yield) NMR spectrum (DMSO-d₆, Δ): 2.82-2.95
(m, 2H), 3.23-3.36 (m, 2H), 4.30 (brs, 2H), 6.92
(d, J = 5.1Hz, 1H), 7.48 (d, J = 5.1Hz, 1H), 9.91 (brs,
 2H) MS spectrum (CI, m / z) 140 (M⁺+1) (Reference Example 19)6-trityl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
Salting to 8.65 g (49.3 mmol) of lysine hydrochloride
Add 100 ml of methylene and then triethylamine 1
5 ml was added dropwise at room temperature. Thereafter, trityl chloride 13.
74 g (49.3 mmol) dissolved in methylene chloride
After dripping 60 ml of the liquid at room temperature, the mixture was stirred at room temperature for 6 hours.
Was. After the completion of the reaction, 200 ml of water was added to the obtained reaction solution.
ml was added and the organic phase was separated. The obtained organic phase is sulfuric anhydride
The extract was dried over sodium acid and the solvent was distilled off under reduced pressure. Get
The residue was purified by silica gel column chromatography (elution
Medium: toluene), and then crystallized with hexane.
14.1 g of the title compound were obtained as a white solid. (Yield 75
%) Melting point: 186-188 ° C NMR spectrum (CDCl_Three, Δ): 2.56 (brs, 2H),
2.70-2.96 (m, 2H), 3.51 (brs, 2H), 6.78 (d, J = 5.0H
z, 1H), 7.04 (d, J = 5.0Hz, 1H), 7.12-7.60 (m, 15H) MS spectrum (CI, m / z) 382 (M⁺+1) (Reference Example 20)3- (2-nitro-1-propenyl) thiophene 5.0 g of 3-thiophenaldehyde (44.6 mmol)
l) and 1.0 g (13.0 mmol) of ammonium acetate
Is added to 30 ml of nitroethane, and the mixture is added at 90 ° C. for 2 hours 30.
The mixture was heated and stirred for minutes. After the completion of the reaction, the obtained reaction solution was allowed to cool, and
Ricagel column chromatography (elution solvent: toluene)
To give 6.36 g of the title compound as a tan solid.
Was. (Yield 84%) MS spectrum (CI, m / z) 170 (M⁺+1) (Reference Example 21)α-methyl-3-thiophenethanamine 3- (2-nitro-1-propenyl) thiophene 6.3
6 g was dissolved in 50 ml of tetrahydrofuran, and hydrogenated.
Dissolve 3.76 g (100 mmol) of aluminum
In 150 ml of tetrahydrofuran solution
While maintaining the temperature at ℃ 60 ° C., the solution was added dropwise little by little. After dropping,
Stirred at room temperature for 4 hours. After the completion of the reaction, the obtained reaction solution was placed in an ice bath.
After adding water, the insolubles were filtered. Tet the filtrate obtained
Diluted with lahydrofuran and saturated aqueous sodium chloride
Wash, dry over anhydrous sodium sulfate and evaporate the solvent under reduced pressure.
Evaporation gave 3.59 g of the title compound as a brown oil.
Was. (57% yield) NMR spectrum (CDCl_Three, Δ): 1.11 (d, J = 6.3Hz
 3H), 2.50-2.66 (m, 2H), 3.11-3.22 (m, 1H), 6.77-7.
02 (m, 2H), 7.24-7.28 (m, 1H) MS spectrum (CI, m / z) 142 (M⁺+1) (Reference Example 22)5-methyl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridine hydrochloride 3.59 g of α-methyl-3-thiophenethanamine
(25.4 mmol) in 37% formaldehyde aqueous solution
2.40 g (29.4 mmol) was added and the mixture was allowed to stand at room temperature for 1 hour.
Stirred. After the completion of the reaction, the resulting reaction solution was added with diethyl ether.
100 ml of toluene was added and the organic phase was separated. Get
The organic phase was dried over anhydrous magnesium sulfate, and
The solvent was distilled off to obtain 3.92 g of an imine compound. The obtained imine compound was converted into N, N-dimethylform.
Dissolve in 10 ml of muamide, dry hydrogen chloride 2.15 g
(58.90 mmol) dissolved in N, N-dimethylphos
30 ml of Lumamide solution was dropped at room temperature and stirred for 1 hour.
Was. The mixture was further heated and stirred at 80 ° C. for 1 hour. After the completion of the reaction, the resulting reaction solution was allowed to cool,
After the precipitate was collected by filtration and washed with acetone, the title compound 1.
46 g were obtained as a light brown solid. (30% yield) NMR spectrum (CD_ThreeOD, δ): 1.50 (d, J = 6.6H
z, 3H), 2.67-2.81 (m, 1H), 3.05-3.16 (m, 1H), 3.59-
3.73 (m, 1H), 4.47 (s, 2H), 6.89 (d, J = 5.1Hz, 1H),
 7.40 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 154 (M⁺+1) (Reference Example 23)5-methyl-6-trityl-4,5,6,7-tetrahi
Dorothieno [2,3-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 5-methyl-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine hydrochloride
The reaction was carried out in the same manner as in Reference Example 19, except that 1.46 g was used.
Thus, 2.08 g of the title compound was obtained as a pale yellow oil.
(Yield 68%) NMR spectrum (CDCl_Three, Δ): 0.20 (d, J = 6.3H
z, 3H), 2.67 (d, J = 15.3Hz, 1H), 3.12-3.22 (m, 1H),
 3.46 (d, J = 15.6Hz, 1H), 3.76-3.89 (m, 1H), 4.23 (d,
 J = 15.3Hz, 1H), 6.75 (d, J = 5.1Hz, 1H), 7.05 (d, J =
5.1Hz, 1H), 7.08-7.58 (m, 15H) MS spectrum (CI, m / z) 396 (M⁺+1) (Reference Example 24)4-methyl-4,5,6,7-tetrahydrothieno
[3,2-c] pyridine 5.90 g of 2- (2-thienyl) ethanol (46.0)
mmol) is dissolved in 50 ml of chloroform.
Under heating and stirring, a solution of 6.0 g of thionyl chloride in chloroform
30 ml was added dropwise over 60 minutes. 2 hours at 70 ° C
The mixture was stirred while heating. After the completion of the reaction, the obtained reaction solution was depressurized.
Under the solvent was distilled off. The residue obtained is acetonitrile 2
Dissolve in 5 ml and slowly add 10 ml of tin tetrachloride
Thereafter, the mixture was heated under reflux for 20 hours. After completion of the reaction, the obtained reaction solution was allowed to cool,
Make alkaline with diluted ammonia water and extract with methylene chloride
did. The obtained organic phase is dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain an imine compound. 30 ml of ethanol was added to the obtained imine compound.
Add 2.27 g of sodium borohydride at room temperature
After the addition, the mixture was heated under reflux for 8 hours. After completion of the reaction, the obtained reaction solution was allowed to cool,
50 ml of water was added, and the mixture was partially concentrated under reduced pressure.
Extracted. Dry the resulting organic phase over anhydrous sodium sulfate
Dry and evaporate the solvent under reduced pressure to give 4.13 g of the title compound.
Was obtained as a brown oil. (58% yield) NMR spectrum (CDCl_Three, Δ): 1.38 (d, J = 6.6H
z, 3H), 2.64-2.88 (m, 2H), 2.90-3.08 (m, 2H), 3.23-
3.36 (m, 1H), 6.80 (d, J = 5.1Hz, 1H), 7.05 (d, J =
(5.1Hz, 1H) MS spectrum (CI, m / z) 154 (M⁺+1) (Reference Example 25)4-methyl-5-trityl-4,5,6,7-tetrahi
Dorothieno [3,2-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
4-methyl-4,5,6,7 instead of lysine hydrochloride
-Tetrahydrothieno [3,2-c] pyridine 4.13
The reaction was carried out in the same manner as in Reference Example 19 except that g was used.
8.27 g of compound were obtained as a pale yellow solid. (Yield 77
%) Melting point: 162-165 ° C NMR spectrum (CDCl_Three, Δ): 1.21 (d, J = 6.6H
z, 3H), 1.63-1.77 (m, 1H), 2.05-2.16 (m, 1H), 3.33
-3.55 (m, 2H), 4.42-4.53 (m, 1H), 6.54 (d, J = 5.1Hz,
 1H), 6.90 (d, J = 5.1Hz, 1H), 7.05-7.48 (m, 15H) MS spectrum (CI, m / z) 396 (M⁺+1) (Reference Example 26)6-methyl-5-trityl-4,5,6,7-tetrahi
Dorothieno [3,2-c] pyridine Instead of 3-thiophenaldehyde, 2-thiophene
Same as Reference Example 20 except that aldehyde was used as a starting material
To give 2- (2-nitro-1-propenyl) thio.
Offen was obtained followed by 3- (2-nitro-1-propeni)
2) Instead of thiophene, 2- (2-nitro-1-prop)
The same as in Reference Example 21 except that lopenyl) thiophene was used.
React to form α-methyl-2-thiophenethanamine
To obtain α-methyl-3-thiophenethanamine
Alternatively, α-methyl-2-thiophenethanamine is
The reaction was carried out in the same manner as in Reference Example 22 except for using
-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridine hydrochloride was obtained and finally 4,5,6,7-tetra
Instead of hydrothieno [2,3-c] pyridine hydrochloride
6-methyl-4,5,6,7-tetrahydrothieno
Reference Example 1 except that [3,2-c] pyridine hydrochloride was used.
The reaction was carried out in the same manner as in Example 9 to give 2.15 g of the title compound in pale yellow.
Obtained as a solid. (Yield 28%) Melting point: 137-140 ° C NMR spectrum (CDCl_Three, Δ): 0.16 (d, J = 6.3H
z, 3H), 2.41 (d, J = 15.4Hz, 1H), 3.23-3.44 (m, 2H),
 3.83-3.94 (m, 1H), 4.11 (d, J = 14.6Hz, 1H), 6.67
(d, J = 5.1Hz, 1H), 7.02 (d, J = 5.1Hz, 1H), 7.09-7.61
 (m, 15H) MS spectrum (CI, m / z) 396 (M⁺+1) (Reference Example 27)7-methyl-4,5,6,7-tetrahydrothieno
[2,3-c] pyridine 5.93 g of 2- (3-thienyl) ethylamine (46.
69 mmol) and 7.15 g (70.0 mm) of acetic anhydride.
ol) at room temperature in small portions and stir for 1 hour.
50 ml of ene was added, and the solvent was distilled off under reduced pressure.
8.55 g of a mid was obtained. The obtained acetamide was added with toluene 20
ml and 21.7 ml of phosphorus oxychloride and add for 2 hours.
The mixture was heated under reflux and the solvent was distilled off under reduced pressure. The obtained residue is charcoal
Neutralized with aqueous potassium acid solution and extracted with chloroform
Was. The organic phase obtained is dried over anhydrous sodium sulfate and reduced.
The solvent was distilled off under pressure to obtain the imine compound as a black-brown oily substance.
Was. [0317] 30 ml of ethanol was added to the obtained imine compound.
Add 3.53 g of sodium borohydride slightly at room temperature
Were added one by one. After heating and refluxing for another 4 hours,
Then, add 60 ml of water and 180 ml of ethyl acetate and add
The phases were separated. The obtained organic phase is dried over anhydrous sodium sulfate.
After drying under reduced pressure, the solvent was distilled off under reduced pressure to give the title compound.
6.81 g were obtained as a brown oil. (37% yield) NMR spectrum (CDCl_Three, Δ): 1.44 (d, J = 6.6H
z, 3H), 2.61-2.69 (m, 2H), 2.93-3.03 (m, 1H), 3.27-
3.35 (m, 1H), 4.08-4.19 (m, 1H) 6.77 (d, J = 5.1Hz, 1
H), 7.10 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 154 (M⁺+1) (Reference Example 28)7-methyl-6-trityl-4,5,6,7-tetrahi
Dorothieno [2,3-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
7-methyl-4,5,6,7 instead of lysine hydrochloride
-Tetrahydrothieno [2,3-c] pyridine 6.81
The reaction was carried out in the same manner as in Reference Example 19 except that g was used.
4.21 g of the compound was obtained as a white solid. (Yield 23
%) Melting point: 155-157 ° C NMR spectrum (CDCl_Three, Δ): 1.35 (d, J = 6.8H
z, 3H), 1.45-1.66 (m, 1H), 1.92-2.03 (m, 1H), 3.33
-3.52 (m, 2H), 4.55-4.64 (m, 1H), 6.32 (d, J = 5.1Hz,
 1H), 6.89 (d, J = 5.1Hz, 1H), 7.06-7.50 (m, 15H) MS spectrum (CI, m / z) 396 (M⁺+1) (Reference Example 29)4-hydroxy-6-trityl-4,5,6,7-tet
Lahydrothieno [2,3-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
In place of lysine hydrochloride, JP-A-51-48692
4-hydroxy-4,5,5 synthesized according to the description in the report
6,7-tetrahydrothieno [2,3-c] pyridine salt
Except that 19.1 g (100 mmol) of acid salt was used.
The reaction was carried out in the same manner as in Example 19 to give 10.2 g of the title compound as a pale
Obtained as a red-yellow solid. (26% yield) NMR spectrum (CDCl_Three, Δ): 2.03 (brs, 1H),
 2.50-2.66 (m, 1H), 2.70-2.84 (m, 1H), 3.30 (d, J = 1
4.7Hz, 1H), 3.66 (d, J = 14.7Hz, 1H), 4.83 (brs, 1H),
 7.04 (d, J = 5.1Hz, 1H), 7.17 (d, J = 5.1Hz, 1H), 7.2
2-7.61 (m, 15H) MS spectrum (CI, m / z) 398 (M⁺+1) (Reference Example 30)4- (methoxymethoxy) -6-trityl-4,5
6,7-tetrahydrothieno [2,3-c] pyridine 4-hydroxy-6-trityl-4,5,6,7-tet
5.46 g of lahydrothieno [2,3-c] pyridine (1
(3.7 mmol) with 50 ml of tetrahydrofuran.
And N-ethyldiisopropylamine (3.55) under ice-cooling.
g (27.5 mmol) was added dropwise, followed by chloromethyi.
1.88 g (23.4 mmol) of methyl ether
Dissolve in 7 ml of trahydrofuran and add dropwise over 30 minutes
did. After completion of the reaction, the obtained reaction solution was allowed to stand at room temperature.
After stirring for 8 hours, 100 ml of water and 150 ml of ethyl acetate were added.
Was added and the organic phase was separated. The obtained organic phase is dried over anhydrous sodium sulfate.
After drying with thorium, the solvent was distilled off under reduced pressure. Get
The residue was purified by silica gel column chromatography (elution
Solvent: toluene), and 1.37 g of the title compound was pale yellow
Obtained as a colored oil. (23% yield) NMR spectrum (CDCl_Three, Δ): 2.23-2.40 (m, 1
H), 2.94-3.11 (m, 1H), 3.66 (d, J = 14.1Hz, 1H), 3.47
 (s, 3H), 3.82 (d, J = 14.1Hz, 1H), 4.78 (brs, 3H),
6.99 (d, J = 5.1Hz, 1H), 7.09 (d, J = 5.1Hz, 1H), 7.14
-7.67 (m, 15H) MS spectrum (CI, m / z) 442
(M⁺+1) (Reference Example 31)7-hydroxy-5-trityl-4,5,6,7-tet
Lahydrothieno [3,2-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
In place of lysine hydrochloride, JP-A-51-48692
7-Hydroxy-4,5,5 synthesized according to the description of the report
Of 6,7-tetrahydrothieno [3,2-c] pyridine
Except for using 13.7 g (71.3 mmol) of hydrochloride,
The reaction was carried out in the same manner as in Reference Example 19 to give the title compound 20.3.
g were obtained as a reddish brown solid. (Yield 72%) NMR spectrum (CDCl_Three, Δ): 2.24 (brs, 1H),
 2.56-2.89 (m, 2H), 3.20 (d, J = 14.4Hz, 1H), 3.54
(d, J = 14.4Hz, 1H), 4.95 (brs, 1H), 6.64 (d, J = 5.1H
z, 1H), 7.09-7.61 (m, 16H) MS spectrum (CI, m / z) 398 (M⁺+1) (Reference Example 32)7- (methoxymethoxy) -5-trityl-4,5
6,7-tetrahydrothieno [3,2-c] pyridine 4-hydroxy-6-trityl-4,5,6,7-tet
Instead of lahydrothieno [2,3-c] pyridine, 7
-Hydroxy-5-trityl-4,5,6,7-tetra
6.78 g of hydrothieno [3,2-c] pyridine (1
7.1 mmol), but the reaction was performed in the same manner as in Reference Example 30.
In response, 4.32 g of the title compound was obtained as a pale yellow solid.
Was. (57% yield) Melting point: 67-68 ° C NMR spectrum (CDCl_Three, Δ): 2.36-2.50 (m, 1
H), 2.89-3.17 (m, 2H), 3.46 (s, 3H), 3.67 (d, J = 1
4.1Hz, 1H), 4.78 (s, 2H), 4.86-4.92 (m, 1H), 6.64
(d, J = 5.1Hz, 1H), 7.09-7.66 (m, 16H) MS spectrum (CI, m / z) 442 (M⁺+1) (Reference Example 33)Ethyl 5-tosyl-5,6-dihydro-4H-thieno
[2,3-c] pyrrole-2-carboxylate 8.80 g of 60% sodium hydride was added to N, N-dimethyl
Add p-toluene to a solution dissolved in 100 ml of formamide.
18.8 g of N, N-dimethylform
The solution dissolved in 100 ml of amide was cooled for 20 minutes under ice cooling.
The solution was dropped. After stirring for 1 hour, ethyl 4,5-bis (c)
25. Loromethyl) thiophene-2-carboxylate
4 g of N, N-dimethylformamide solution 30
0 ml was dropped at the same temperature over 10 minutes, and then 2 hours
Stirred. After the completion of the reaction, water was added to the obtained reaction solution.
And extracted three times with toluene. The organic phase obtained is combined with water and
After sequentially washing with a saturated aqueous solution of sodium chloride, sulfuric anhydride
After drying over sodium, the solvent was distilled off under reduced pressure.
Sopropyl ether was added, and the mixture was heated and stirred. Generated precipitate
The product was collected by filtration, washed with diisopropyl ether, and
14.1 g of the title compound were obtained as a pale brown solid. (Yield 4
0%) NMR spectrum (CDCl_Three, Δ): 1.43 (t, J = 7.2H
z, 3H), 2.42 (s, 3H), 4.31 (q, J = 7.2Hz, 2H), 4.49
(t, J = 3.0Hz, 2H), 4.64 (t, J = 3.0Hz, 2H), 7.33 (d,
J = 8.1Hz, 2H), 7.45 (s, 1H), 7.76 (d, J = 8.1Hz, 2H) MS spectrum (CI, m / z) 352 (M⁺+1) (Reference Example 34)5-tosyl-5,6-dihydro-4H-thieno [2,3
-C] pyrrole-2-carboxylic acid Ethyl 5-tosyl-5,6-dihydro-4H-thieno
[2,3-c] pyrrole-2-carboxylate13.
7 g (40 mmol) is dissolved in 200 ml of ethanol
200 ml of 1N aqueous sodium hydroxide solution
Then, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, concentrated hydrochloric acid was added to the obtained reaction solution.
It was neutralized. The resulting precipitate is collected by filtration, washed with water,
17.9 g of the compound was obtained almost quantitatively as a brown solid. The NMR spectrum (CDCl_Three+ DMSO-
d₆, Δ): δ 2.43 (s, 3H), 4.45-4.49 (m, 2H), 4.6
0-4.64 (m, 2H), 7.35 (d, J = 8.4Hz, 2H), 7.40 (s, 1
H), 7.74 (d, J = 8.4Hz, 2H) MS spectrum (CI, m / z) 324 (M⁺+1) (Reference Example 35)5-tosyl-5,6-dihydro-4H-thieno [2,3
-C] pyrrole 5-tosyl-5,6-dihydro-4H-thieno [2,3
-C] pyrrole-2-carboxylic acid 325 mg (1.0 m
mol) to cuprous oxide (42 mg, 0.29 mmol),
81 mg (0.5 mmol) of 2,2'-dipyridyl,
Add 1 ml of norin and 2 ml of xylene, and add nitrogen
The mixture was stirred at 150 to 165 ° C for 2 hours. After the completion of the reaction, the resulting reaction solution was decompressed.
Under the solvent was distilled off. Ethyl acetate was added to the obtained residue.
Then, insolubles were filtered. The obtained filtrate is 1N hydrochloric acid, water,
Saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride
Wash sequentially with aqueous solution, dry over anhydrous sodium sulfate, reduce
The solvent was distilled off under pressure, and 89 mg of the title compound was converted into a brown solid.
I got it. (30% yield) NMR spectrum (CDCl_Three, Δ): 2.41 (s, 3H),
4.48-4.51 (m, 2H), 4.61-4.64 (m, 2H), 6.76 (d, J =
5.1Hz, 1H), 7.23 (d, J = 5.1Hz, 1H), 7.31 (d, J = 8.1H
z, 1H), 7.76 (d, J = 8.1Hz, 1H) MS spectrum (CI, m / z) 280 (M⁺+1) (Reference Example 36)5- (t-butoxycarbonyl) -5,6-dihydro-
4H-thieno [2,3-c] pyrrole 5-tosyl-5,6-dihydro-4H-thieno [2,3
-C] pyrrole (3.0 g, 10.7 mmol)
And 30 g of a hydrogen bromide-acetic acid solution (110 m).
and heated and stirred at 40-50 ° C for 10 hours. After the completion of the reaction, the obtained reaction solution was decompressed.
The solvent was distilled off under reduced pressure, and water was added to the obtained residue.
Was washed three times with a rub. 1N sodium hydroxide is added to the obtained aqueous phase.
After adjusting the pH to alkaline, add chloroform.
Extracted by the system. The obtained organic phase is dried over anhydrous sodium sulfate.
After drying, the solvent was distilled off under reduced pressure to obtain a brown oil. The obtained oil was washed with 1N sodium hydroxide
Dissolve in 20 ml of aqueous solution and di-t-butyl dicarbonate 3.2
After adding g (14.7 mmol), the mixture was stirred for 2 hours. After completion of the reaction, the obtained reaction solution was washed with acetic acid.
Extracted with chill. After washing the obtained organic phase with water,
The extract was dried over sodium acid and the solvent was distilled off under reduced pressure. Get
The residue was purified by silica gel column chromatography (elution).
Solvent: hexane / ethyl acetate = 9/1 to 8/1)
This gave 1.12 g of the title compound as a slightly yellow oil.
(Yield 46%) NMR spectrum (CDCl_Three, Δ): 1.51 (s, 9H),
4.47-4.54 (m, 2H), 4.60-4.68 (m, 2H), 6,82, 6.87
(each d, J = 4.8Hz, total 1H rotamer), 7.27 (d, J = 4.
(8Hz, 1H) MS spectrum (CI, m / z) 226 (M⁺+1) (Reference Example 37)2,2-dimethyl-N- [1- (3-thienyl) ethyl
Le] propanamide To 50 ml of a 10% aqueous sodium hydroxide solution, add 1- (3-
7.12 g (56 mmol) of thienyl) ethylamine
added. Next, 8.3 ml of pivaloyl chloride was added at room temperature.
, And the mixture is stirred at room temperature for another 2 hours.
Was. After the completion of the reaction, the obtained reaction solution was diluted with acetic acid.
Extracted with chill. The organic phase obtained is saturated sodium chloride
After washing with an aqueous solution, dry over anhydrous sodium sulfate and reduce
The solvent was distilled off under pressure. Crystallize the obtained residue with hexane
This gave 7.48 g of the title compound as a pale brown solid.
(63% yield) NMR spectrum (CDCl_Three, Δ): 1.20 (s, 9H),
1.50 (d, 3H), 5.15-5.26 (m, 1H), 5.77 (brs, 1H),
7.01 (dd, J = 5.1 and 4.9Hz, 1H), 7.09-7.12 (m, 1H), 7.
28 (dd, J = 5.1 and 2.9Hz, 1H) MS spectrum (CI, m / z) 212 (M⁺+1) (Reference Example 38)3- [1- (2,2-dimethylpropanoylamino) d
[Tyl] thiophene-2-carboxylic acid 2,2-dimethyl-N- [1- (3-thienyl) ethyl
5.0 g of propanamide in tetrahydrofuran 50
dissolved in butyllithium (1.
33 ml of a 5M hexane solution was added dropwise. 2:00 after dropping
After stirring for a while, the temperature was raised to -30 ° C. dry ice
About 10 g was added at a time, and the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, the obtained reaction solution was added to acetic acid solution.
Add 100 ml of chill and 100 ml of water, and add sodium hydroxide.
After adjusting the pH of the aqueous phase to 9.5 with an aqueous solution of
separated. 100 ml of chloroform was added to the obtained aqueous phase.
Then, the pH was adjusted to 3 with concentrated hydrochloric acid, and the organic phase was separated.
The obtained organic phase is dried over anhydrous magnesium sulfate and reduced.
The solvent was distilled off under pressure to give 5.72 g of the title compound in pale yellow.
Obtained as a solid. (Yield 95%) NMR spectrum (CDCl_Three, Δ): 1.19 (s, 9H),
1.49 (d, J = 7.1Hz, 3H), 5.50-5.62 (m, 1H), 7.06
(d, J = 5.1Hz, 1H), 7.36 (d, J = 8.1Hz, 1H), 7.49 (d, J =
5.1Hz, 1H), MS spectrum (CI, m / z) 256 (M⁺+1) (Reference Example 39)N- [1- (2-hydroxymethyl-3-thienyl) e
Tyl] -2,2-dimethylpropanamide 3- [1- (2,2-dimethylpropanoylamino) d
5.72 g of [tyl] thiophene-2-carboxylic acid
Methanesulfonic acid 4.31 g
Was added and heated under reflux for 2 hours. After concentration under reduced pressure,
And chloroform were added, and the organic phase was separated. No organic phase
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
Was. 100 ml of ethanol was added to the obtained residue,
Under ice cooling, 1.69 g of sodium borohydride and calcium chloride
After adding 2.49 g of sodium, the mixture was stirred for 4 hours under ice cooling.
Was. After completion of the reaction, 1N hydrochloric acid was added to the obtained reaction solution.
After dropping 100 ml, 100 ml of chloroform was added.
The organic phase was separated. The obtained organic phase is dried over anhydrous sulfuric acid.
Dry over ganesium and evaporate the solvent under reduced pressure to give the title
4.55 g of the compound was obtained as a pale red yellow solid. (Yield 8
4%) NMR spectrum (CDCl_Three, Δ): 1.13 (s, 9H),
1.49 (d, J = 6.8Hz, 3H), 4.53 (d, 13.2Hz 1H), 5.02
(d, J = 13.2Hz, 1H), 5.14-5.24 (m, 1H), 6.01 (brs, 1
H), 6.91 (d, J = 5.4Hz, 1H) 7.18 (d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 224 (M⁺+ 1-1
8) (Reference Example 40)5- (2,2-dimethylpropanoyl) -4-methyl-
5,6-dihydro-4H-thieno [2,3-c] pyrrole N- [1- (2-hydroxymethyl-3-thienyl) e
Tyl] -2,2-dimethylpropanamide 4.53 g
(18.7 mmol) dissolved in 50 ml of methylene chloride
Then, 4 ml of triethylamine was added. Under ice water cooling, salt
After dropping 2.37 g of methanesulfonyl bromide,
Stirred for hours. After completion of the reaction, water and
Roloform was added and the organic phase was separated. The resulting organic
The phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.
I left. The obtained residue was added to 50 ml of tetrahydrofuran.
Dissolve and add 1.98 g of sodium t-butoxide under ice-cooling
Was added and stirred for 3 hours. After completion of the reaction, water and
Loroform was added and the organic phase was separated. Organic phase obtained
Was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
did. The obtained residue is subjected to silica gel column chromatography.
(Elution solvent: toluene / ethyl acetate = 9/1)
This gave 2.17 g of the title compound as a pale brown oil.
(Yield 52%) NMR spectrum (CDCl_Three, Δ): 1.32 (s, 9H),
1.44 (d, J = 6.3Hz, 3H), 4.90 (dd, J = 12.9 and 3.3Hz, 1
H), 4.96 (d, J = 12.9Hz, 1H), 5.25-5.34 (m, 1H), 6.
83 (d, J = 4.9Hz, 1H) 7.27 (d, J = 4.9Hz, 1H) MS spectrum (CI, m / z) 224 (M⁺+1) (Reference Example 41)4-methyl-5-trityl-5,6-dihydro-4H-
Thieno [2,3-c] pyrrole 4-methyl-5- (2,2-dimethylpropanoyl)-
5,6-dihydro-4H-thieno [2,3-c] pyrrole
30 ml of 6N hydrochloric acid was added to 2.16 g (9.7 mmol).
After heating under reflux for 5 hours, the solvent was distilled off under reduced pressure. Get
50 ml of methylene chloride and triethylamine
2.93 g and the mixture was stirred at room temperature. Then tritium chloride
2.70 g was added in three portions, and the mixture was further stirred at room temperature for 2 hours.
Stirred. After the completion of the reaction, water and
Loroform was added and the organic phase was separated. Organic phase obtained
Was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Was. The obtained residue is subjected to silica gel column chromatography.
(Elution solvent: hexane / ethyl acetate = 19/1)
Thus, 0.88 g of the title compound was obtained as a pale red-white solid.
(Yield 24%) Melting point: 143-146 ° C NMR spectrum (CDCl_Three, Δ): 1.33 (s, 3H),
3.95 (d, J = 15.6Hz, 1H), 4.30-4.39 (m, 1H), 4.48
(d, J = 15.6Hz, 1H), 6.33 (d, J = 6.3Hz, 1H), 6.88
(d, J = 6.3Hz, 1H) 7.03-7.58 (m, 15H) MS spectrum (CI, m / z) 382 (M⁺+1) (Reference Example 42)5- (2,2-dimethylpropanoyl) -5,6-dihi
Dro-4H-thieno [2,3-c] pyrrole Instead of 1- (3-thienyl) ethylamine,
9.55 g (88.4 mmol) of enylmethylamine
Except for using, the reaction was carried out in the same manner as in Reference Example 37 to give 2,2-
Dimethyl-N- [1- (3-thienyl) methyl] propa
To give 2,2-dimethyl-N- [1- (3
-Thienyl) ethyl] propanamide,
2-dimethyl-N- [1- (3-thienyl) methyl] p
The reaction was carried out in the same manner as in Reference Example 38 except that lopanamide was used.
To give 3- [1- (2,2-dimethylpropanoylamino)
No) methyl] thiophene-2-carboxylic acid, and 3
-[1- (2,2-dimethylpropanoylamino) ethyl
3- [1-] instead of [l] thiophene-2-carboxylic acid.
(2,2-dimethylpropanoylamino) methyl] thio
Same as Reference Example 39 except that phen-2-carboxylic acid was used.
And react with N- [1- (2-hydroxymethyl-
3-thienyl) methyl] -2,2-dimethylpropana
And finally N- [1- (2-hydroxymethyl-
3-thienyl) ethyl] -2,2-dimethylpropana
N- [1- (2-hydroxymethyl-
3-thienyl) methyl] -2,2-dimethylpropana
The reaction was carried out in the same manner as in Reference Example 40 except that the amide was used.
3.08 g of the title compound were obtained as a tan solid. (yield
17%) NMR spectrum (CDCl_Three, Δ): 1.34 (s, 9H),
4.58-5.05 (m, 4H), 6.88 (d, J = 4.9Hz, 1H), 7.29 (d,
 J = 4.9Hz, 1H) MS spectrum (CI, m / z) 210 (M⁺+1) (Reference Example 43)5-trityl-5,6-dihydro-4H-thieno [2,
3-c] pyrrole 5- (2,2-dimethylpropanoyl) -5,6-dihi
Doro-4H-thieno [2,3-c] pyrrole 1.0 g
(4.8 mmol), add 15 ml of 4N hydrochloric acid, and
Heated to reflux. The solvent was distilled off under reduced pressure to obtain a black oily substance.
Was. The oil obtained was dissolved in 10 ml of methylene chloride.
Dissolve, 1.5 ml of triethylamine and trityl chloride
After stirring for 1 hour, water was added and methyl chloride was added.
Extracted with styrene. The obtained organic phase is dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue
Silica gel column chromatography (elution solvent: Heki
Sun / ethyl acetate = 20/1 to 15/1)
0.86 g of the title compound was obtained as a white solid. (Yield 49
%) NMR spectrum (CDCl_Three, Δ): 3.93-3.97 (m, 2
H), 4.05-4.09 (m, 2H), 6.66 (d, J = 4.8Hz, 1H), 7.08
 (d, J = 4.8Hz, 1H), 7.13-7.60 (m, 15H) MS spectrum (CI, m / z) 368 (M⁺+1) (Reference Example 44)2- (4-chloro-3-methyl-2-pyridyl) cyclo
Propyl acetaldehyde 200 ml of tetrahydrofuran under a nitrogen atmosphere and ice cooling
To lithium diisopropylamide (1.5M cyclohex
Sun solution) and described in US5789591
N- (2-cyclopropylethylide) synthesized by the method of
N) 50 g (300 mmol) of cyclohexylamine
40 ml of the dissolved tetrahydrofuran solution was added dropwise.
After the addition was completed, the reaction solution was stirred at room temperature for 1 hour. 2,4
-Dichloro-3-methylpyridine (24.3 g)
Dissolve in 40 ml of drofuran and add dropwise at room temperature.
After completion, the mixture was stirred for 2.5 hours. After the completion of the reaction, the resultant reaction solution was cooled with ice.
1 liter of 1M acetic acid aqueous solution
Toluene was added, stirred vigorously and the organic phase was separated. Get
Water, saturated aqueous sodium bicarbonate and
After washing sequentially with saturated aqueous sodium chloride solution, anhydrous magnesium sulfate
After drying with cesium, the solvent was distilled off under reduced pressure. Got
Silica gel chromatography of the residue (elution solvent:
Sun / ethyl acetate = 4/1) to give the title compound 2
6.2 g were obtained as a yellow oil. Yield (83%) NMR spectrum (CDCl_Three, Δ): 0.24-0.28 (m, 1H)
 , 0.29-0.36 (m, 1H), 0.55-0.62 (m, 1H), 0.71-0.76 (m,
1H), 1.52-1.58 (m, 1H), 2.35 (s, 3H), 3.24 (dd, J = 10.2
And 2.4Hz, 1H), 7.23 (d, J = 5.1Hz, 1H), 8.34 (d, J = 5.1
Hz, 1H), 9.89 (d, J = 2.4Hz, 1H) (Reference Example 45)4-azido-6-methyl-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridine 4-hydroxy-6-methyl-4,5,6,7-tetra
5.10 g of hydrothieno [2,3-c] pyridine (30
mmol) was dissolved in 30 ml of toluene, and the solution was cooled under ice-cooling.
9.90 g (36 mmol) of diphenylphosphoryl chloride,
Then, 1,8-diazabicyclo [4.3.0] -7-c
5.90 g (39 mmol) of ndecene was added, and the mixture was added at room temperature for 3 hours.
Stirred for hours. After completion of the reaction, toluene was added to the obtained reaction solution.
Then, ethyl acetate and water were added, and the organic phase was separated. Get
The dried organic phase was dried over anhydrous sodium sulfate,
Under the solvent was distilled off. The obtained residue is
Chromatography (elution solvent: hexane / ethyl acetate
= 4/1 to 6/4) to give 3.18 g of the title compound.
Was obtained as a pale yellow oil. (55% yield) MS spectrum (CI, m / z) 195 (M⁺+1) IR spectrum (liquid film method, ν_max  cm^-1): 2108 (Reference Example 46)4-amino-6-methyl-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridine 1.96 g of lithium aluminum hydride (24.6 mm
ol), add 50 ml of tetrahydrofuran and stir at room temperature
Below, 4-azido-6-methyl-4,5,6,7-tetra
6.75 g of hydrothieno [2,3-c] pyridine (3
4.8 mmol) dissolved in tetrahydrofuran 30 m
The solution was added dropwise over 1 hour. Then at 80 ° C
Stirred for 2.5 hours. After the completion of the reaction, the obtained reaction solution was added with water 2.
0 ml, 15% aqueous sodium hydroxide 2.0 ml, water
4.0 ml and 100 ml of ethyl acetate were added to produce
The precipitate was removed by filtration. From the obtained filtrate, the solvent was removed under reduced pressure.
Evaporation gave 4.25 g of the title compound as a pale brown solid.
Was. (Yield 73%) NMR spectrum (CDCl_Three, Δ): 2.66 (dd, J = 12.
0 and 3.9Hz, 1H), 2.93 (dd, J = 12.0 and 3.9Hz, 1H),
3.42 (d, J = 15.0Hz, 1H), 3.47 (s, 3H), 3.83 (d, J = 1
5.0Hz, 1H), 4.32-4.36 (m, 1H), 7.00 (d, J = 5.1Hz, 1
H), 7.12 (d, J = 5.1Hz, 1H) (Reference Example 47)6-methyl-4-tritylamino-4,5,6,7-te
Trahydrothieno [2,3-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 4-amino-6-methyl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Except for using 5.20 g (30.9 mmol) of lysine,
The reaction was conducted in the same manner as in Reference Example 19 to give 9.52 g of the title compound.
Was obtained as a white solid. (75% yield) Melting point: 156-157 ° C NMR spectrum (CDCl_Three, Δ): 1.46 (dd, J = 11.
7 and 4.4Hz, 1H), 1.71 (dd, J = 11.7 and 3.4Hz, 1H),
2.11 (s, 3H), 3.25 (d, J = 14.6Hz, 1H), 3.69 (d, J = 1
4.6Hz, 1H), 3.72-3.78 (m, 1H), 6.98 (d, J = 5.1Hz, 1
H), 7.10 (d, J = 5.1Hz, 1H), 7.16-7.66 (m, 15H) MS spectrum (CI, m / z) 411 (M⁺+1) (Reference Example 48)4-azido-6-trityl-4,5,6,7-tetrahi
Dorothieno [2,3-c] pyridine 4-hydroxy-6-methyl-4,5,6,7-tetra
Instead of hydrothieno [2,3-c] pyridine, 4-
Hydroxy-6-trityl-4,5,6,7-tetrahi
12.0 g of Dorothieno [2,3-c] pyridine was used
Otherwise, reacting in the same manner as in Reference Example 45, to give the title compound 6.
95 g was obtained as a white solid. (55% yield) IR spectrum (KBr, ν_max  cm^-1): 2102 (Reference Example 49)4-amino-6-trityl-4,5,6,7-tetrahi
Dorothieno [2,3-c] pyridine 4-azido-6-methyl-4,5,6,7-tetrahydride
Instead of rothieno [2,3-c] pyridine, 4-azi
Do-6-trityl-4,5,6,7-tetrahydrothier
No, except that 8.68 g of [2,3-c] pyridine was used.
The reaction was conducted in the same manner as in Example 46 to give 10.52 g of the title compound.
Was obtained almost quantitatively as a reddish brown oil. MS spectrum (CI, m / z) 397
(M⁺+1) (Reference Example 50)6-trityl-4-tritylamino-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridine 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 4-amino-6-trityl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
Except for using 10.52 g of lysine, the same as in Reference Example 19
Reaction yielded 7.27 g of the title compound as a white solid.
Was. (75% yield) Melting point: 202-206 ° C (decomposition) MS spectrum (CI, m / z) 639 (M⁺+1) (Reference Example 51)(2,2-dimethoxyethyl) (1-methyl-1- (2
-Thienyl) ethyl) amine α, α-dimethyl-2-thiophenemethanamine 3.6
5 g (25.8 mmol) dissolved in 60 ml of toluene
Glyoxal 1,1-dimethyl acetal (4
12.0 g (5% t-butyl methyl ether solution)
(1.8 mmol) and 20 g of anhydrous magnesium sulfate.
After stirring, the mixture was stirred at room temperature for 3.5 hours. Filter insolubles to reduce
The solvent was distilled off under pressure. Toluene was added to the obtained residue.
After azeotropic distillation under reduced pressure, ethanol was added to the resulting residue.
Of sodium borohydride.
95 g (51.5 mmol) was added and the mixture was heated under reflux for 1 hour.
Thereafter, 1.0 g of sodium borohydride was further added and stirred overnight.
Stirred. After the completion of the reaction, the pressure was reduced from the obtained reaction solution.
Under the solvent was distilled off. Water and ethyl acetate were added to the obtained residue.
Add saturated sodium bicarbonate and extract three times with ethyl acetate.
Issued. Dry the resulting organic phase over anhydrous magnesium sulfate
Thereafter, the solvent was distilled off under reduced pressure to give 4.77 g of the title compound in yellow.
Obtained as a colored oil. (81% yield) NMR spectrum (CDCl_Three, Δ): 1.53 (s, 6H),
2.58 (d, J = 5.6Hz, 2H), 3.32 (s, 6H) 4.41 (t, J = 5.6
Hz, 1H), 6.86 (dd, J = 3.7 and 1.2Hz, 1H), 6.91 (dd,
J = 5.1 and 3.4Hz, 1H), 7.17 (dd, J = 5.1 and 1.2Hz, 1H), MS spectrum (CI, m / z) 230 (M⁺+1) (Reference Example 52)4-hydroxy-7,7-dimethyl-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridine (2,2-dimethoxyethyl) (1-methyl-1- (2
-Thienyl) ethyl) amine 4.77 g (20.8 mm
ol), add 75 ml of 8N hydrochloric acid and stir at room temperature for 4.5 hours
did. After completion of the reaction, toluene was added to the obtained reaction solution.
Was added, and the mixture was separated. Sodium carbonate was added to the obtained aqueous phase.
And neutralize, and then add 1N aqueous sodium hydroxide solution.
The pH was adjusted to 12 and extracted three times with chloroform. Profit
The organic phase was dried over anhydrous magnesium sulfate and
The solvent was distilled off under reduced pressure to give 2.97 g of the title compound as a yellow solid.
I got it. (78% yield) NMR spectrum (CDCl_Three, Δ): 1.43 (s, 3H),
1.53 (s, 3H), 3.10 (dd, J = 14.2 and 3.2Hz, 1H), 3.22
 (dd, J = 14.2 and 2.9Hz, 1H) 4.56 (dd, J = 3.2 and 2.9Hz,
1H), 6.96 (d, J = 5.1Hz, 1H), 7.15 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 184 (M⁺+1) (Reference Example 53)4-azido-7,7-dimethyl-4,5,6,7-tet
Lahydrothieno [2,3-c] pyridine 4-hydroxy-7,7-dimethyl-4,5,6,7-
2.85 g of tetrahydrothieno [2,3-c] pyridine
(15.6 mmol) was dissolved in 30 ml of toluene.
5.69 g of diphenylphosphoryl diide (20.7 mmol
l) and add 1,8-diazabicyclo
3.10 ml of [5.4.0] -7-undecene (20.7
mmol) was added slowly and stirred at room temperature for 3 hours. After completion of the reaction, the obtained reaction solution was added with ethyl acetate.
Water, saturated aqueous sodium bicarbonate solution,
And the organic phase were separated. The obtained aqueous phase is twice with ethyl acetate
Extracted. Combine the obtained extract with the separated organic phase
After washing with saturated aqueous sodium bicarbonate, anhydrous magnesium sulfate
After drying with cesium, the solvent was distilled off under reduced pressure. Got
The residue is purified by silica gel column chromatography (elution
Medium: chloroform / ethyl acetate = 9/1)
3.09 g of the title compound were obtained as a yellow oil. (Yield 9
5%) NMR spectrum (CDCl_Three, Δ): 1.44 (s, 3H),
 1.53 (s, 3H), 3.14 (dd, J = 14.2 and 2.9Hz, 1H), 3.
25 (dd, J = 14.2 and 3.4Hz, 1H) 4.33 (dd, J = 3.4 and 2.9H
z, 1H), 6.93 (d, J = 5.4Hz, 1H), 7.20 (d, J = 5.4Hz, 1H
 ) MS spectrum (CI, m / z) 209 (M⁺+1) (Reference Example 54)4- (t-butoxycarbonylamino) -6- (t-bu
Toxylcarbonyl) -7,7-dimethyl-4,5,6
7-tetrahydrothieno [2,3-c] pyridine 100 ml of tetrahydrofuran in an argon gas atmosphere
0.85g of lithium aluminum hydride (22.4m
mol) was added little by little and suspended. The temperature inside the bath
4-azido-7,7-dimethyl so as not to exceed 20 ° C
-4,5,6,7-tetrahydrothieno [2,3-c]
Pyridine (3.09 g, 14.8 mmol)
After dissolving in 20 ml of lofuran and dropping, it is 2 hours at room
Stirred. After the completion of the reaction, the obtained reaction solution was added under ice cooling.
0.85 ml of water, 15% aqueous sodium hydroxide solution
0.85 ml and 2.55 ml of water were added sequentially. occured
The insoluble matter is removed by filtration with Celite 545 (trade name), and the insoluble matter is removed.
Washed with ethyl acetate. The obtained filtrate and the obtained washing liquid
The solvent was distilled off from the combined solution under reduced pressure to obtain
1N hydrochloric acid and hexane were added to the residue, and the mixture was separated.
Was extracted three times with 1N hydrochloric acid. 15% water is added to the obtained extract phase.
After adjusting the pH to 12 using an aqueous sodium oxide solution,
Extracted three times with loform. The obtained extracted phase is dried over anhydrous sodium sulfate.
After drying with thorium, the solvent was distilled off under reduced pressure. Got
The residue was dissolved in 100 ml of methylene chloride and triethyl alcohol was added.
2.82 g of min and 3.04 g of di-t-butyl dicarbonate
After the addition, the mixture was reacted at room temperature for 1 hour. After the completion of the reaction, water and chloroform were added to the obtained reaction solution.
Add chloroform and saturated aqueous sodium bicarbonate solution,
Liquid. The resulting aqueous phase was extracted twice with chloroform.
The dried organic phase was dried over anhydrous sodium sulfate,
Under the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: toluene / ethyl acetate = 7
/ 3) to give 1.03 g of the title compound as a white solid
Obtained. (18% yield) NMR spectrum (CDCl_Three, Δ): 1.47 (s, 9H),
1.50 (s, 9H), 1.71 (s, 3H), 1.92 (s, 3H), 3.30-
3.50 (m, 1H), 4.00-4.18 (m, 1H) 4.60-4.80 (m, 1H),
6.87 (d, J = 5.1Hz, 1H), 7.15 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 383 (M⁺+1) (Reference Example 55)4-[(t-butoxycarbonyl) (methyl) amino]-
6- (t-butoxycarbonyl) -7,7-dimethyl-
4,5,6,7-tetrahydrothieno [2,3-c] pi
lysine Under an argon gas atmosphere, 4- (t-butoxycarbonyl)
Amino) -6- (t-butoxycarbonyl) -7,7-
Dimethyl-4,5,6,7-tetrahydrothieno [2,
3-c] pyridine 1.17 g in tetrahydrofuran 40
dissolve in -ml and sec-butyllithium at -70 ° C or less
(1.0 M hexane-cyclohexane solution) 3.0 m
1 was added dropwise. After stirring at the same temperature for 30 minutes, methyl iodide is added.
0.65 g (4.57 mmol) was added dropwise. Same temperature
After stirring for 30 minutes at room temperature, the temperature was raised to room temperature. After completion of the reaction, the obtained reaction solution was added with ethyl acetate.
And water and a saturated aqueous solution of sodium chloride.
Was. The obtained aqueous phase was extracted once with ethyl acetate to obtain
The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
Distilled off. The obtained residue is purified by silica gel column chromatography.
(Eluent: hexane / ethyl acetate = 19/1)
To give 0.80 g of the title compound as a colorless candy.
Was. (Yield 66%) NMR spectrum (CDCl_Three, Δ): 1.49 (s, 9H),
1.50 (s, 9H), 1.70-1.80 (br, 3H), 1.85-1.95 (br, 3
H), 2.60-2.75 (br, 3H), 3.50-4.10 (m, 2H), 4.85-5.1
5 (m, 1H) 5.20-5.30 (m, 1H), 6.72 (d, J = 5.4Hz, 1H),
7.17 (d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 397 (M⁺+1) (Reference Example 56)4- (methyl) (trityl) amino-4,5,6,7-
Tetrahydrobenzo [b] thiophene Under an argon gas atmosphere, 4-keto-4,5,6,7-te
1.52 g of trahydrothianaphthene (10.0 mmo
l) was dissolved in 15 ml of ethanol, and
Hydrochloride 1.35 g (20.0 mmol), triethyl
2.79 ml (20 mmol) of amine, teloisopro
Add 5.9 ml (20.0 mmol) of poxy titanium
Stirred at room temperature overnight. Borohydride is added to the obtained reaction solution.
0.57 g (15 mmol) of sodium was added, and
Stirred overnight at warm. After completion of the reaction, the obtained reaction solution was
Pour into 30 ml of Monia water and add chloroform to make it insoluble
The material was removed by filtration. Extract the obtained aqueous phase twice with chloroform.
did. Dry the resulting organic phase over anhydrous magnesium sulfate
The solvent was distilled off under reduced pressure, and the residue obtained was silica gel.
Column chromatography (elution solvent: chloroform / meta)
(Nol = 50/1) to give 1.40 g of the methylamine compound
Obtained as a yellow oil. The obtained methylamine derivative 1.4
0 g was dissolved in 50 ml of methylene chloride, and triturated at room temperature.
3.5 ml (24.9 mmol) of ethylamine were added,
Further, 3.5 g (12.6 mmol) of trityl chloride was slightly added.
After the addition, the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, toluene was added to the obtained reaction solution.
And water were added, and the mixture was separated. The organic phase obtained is washed with water and saturated salts
Wash sequentially with aqueous sodium chloride solution and dry with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue
Silica gel column chromatography (elution solvent: hexane
/ Ethyl acetate = 19/1) to give the title compound 2.72
g was obtained as a white solid. (Yield 66%) NMR spectrum (CDCl_Three, Δ): 0.40-0.50 (m, 1
H), 0.80-1.00 (m, 1H) 1.43-1.65 (m, 2H), 2.15 (s,
3H), 2.60-2.64 (m, 2H), 4.34-4.39 (m, 1H) 7.12-7.78
 (m, 17H) MS spectrum (CI, m / z) 410 (M⁺+1) (Reference Example 57)4-cyclopropylamino-4,5,6,7-tetrahi
Drobenzo [b] thiophene Under an argon gas atmosphere, 4-keto-4,5,6,7-te
2.28 g of trahydrothianaphthene (15.0 mmo
l) was dissolved in 30 ml of toluene, and cyclopropylamide was dissolved.
After adding 3.45 g (60.0 mmol) of
Dissolve 1.0 ml of titanium tetrachloride in 10 ml of toluene
And added dropwise over 15 minutes. Stirred at room temperature for 2.5 hours
Thereafter, toluene and ice water were added. The resulting insoluble material is
545 (trade name), and the filtrate was separated. Obtained
The organic phase was dried over anhydrous magnesium sulfate and dissolved under reduced pressure.
The solvent was distilled off to obtain 3.21 g of an imine compound as a yellow oily substance.
Was. 80 ml of ethanol was added to the obtained imine compound, and hydrogen was added.
0.70 g (18.5 mmol) of sodium borohydride
In addition, the mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, the resultant reaction solution was depressurized.
Under the solvent was distilled off. Water and chloroform are added to the obtained residue.
And extracted three times with chloroform. The resulting organic
The phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.
I left. The obtained residue is purified by silica gel column chromatography.
-(Eluent: chloroform / methanol = 1/0 to 1
9/1) to give 2.72 g of the title compound as a pale yellow oil
As obtained. (95% yield) NMR spectrum (CDCl_Three, Δ): 0.33-0.51 (m, 4
H), 1.79-2.00 (m, 4H) 2.20-2.30 (m, 2H), 2.70-2.80
 (m, 2H), 3.84-3.88 (m, 1H), 6.95 (d, J = 5.1Hz, 1H)
7.03 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 192 (M⁺+1) (Reference Example 58)5- (t-butoxycarbonylamino) -4,5,6,7
-Tetrahydrobenzo [b] thiophene 4,5,6,7-tetrahydro under argon gas atmosphere
Benzo [b] thiophene-5-carboxylic acid 3.06 g (1
(6.8 mmol) to diphenylphosphoryl azide 5.5
5 g (20.2 mmol) and t-butanol 100 ml
And 4.7 ml (33.4 mmol) of triethylamine
Was added and the mixture was heated under reflux for 24 hours. After the completion of the reaction, the obtained reaction solution was added with ethyl acetate.
And a saturated aqueous solution of sodium bicarbonate.
Was. The obtained aqueous phase is extracted twice with ethyl acetate, and the extract is extracted.
Obtained. The mixed solution of the obtained extract and the organic phase
After washing with aqueous sodium solution, dry over anhydrous sodium sulfate
Then, the solvent was distilled off under reduced pressure. The residue obtained is silica
Gel column chromatography (elution solvent: hexane / acetic acid)
Ethyl = 9/1) and then recrystallized from hexane
Thus, 3.04 g of the title compound was obtained as needle-like white crystals.
(Yield 71%) NMR spectrum (CDCl_Three, Δ): 1.45 (s, 9H),
1.81-1.92 (m, 1H) 2.02-2.09 (m, 1H), 2.49 (dd, J = 1
5.6 and 7.1Hz, 1H), 2.89 (t, J = 6.3Hz, 2H), 2.99 (d, J =
15.9 and 5.1Hz, 1H), 3.95-4.05 (m, 1H), 4.60-4.62
(m, 1H), 6.72 (d, J = 5.1Hz, 1H), 7.08 (d, J = 5.1Hz,
1H) MS spectrum (CI, m / z) 198 (M⁺+1) (Reference Example 59)2- (3,4-dichloro-2-pyridyl) cyclopropyl
Luacetaldehyde 2,2 instead of 2,4-dichloro-3-methylpyridine
1.37 g of 3,4-trichloropyridine (7.50 mm
ol), and reacted in the same manner as in Reference Example 44,
0.77 g of the title compound was obtained as a yellow oil. (yield
45%) MS spectrum (CI, m / z) 230 (M⁺+1) (Reference Example 60)Ethyl 1-cyclopropyl-8,9-dichloro-4-
Oxo-4H-quinolidine-3-carboxylate 2- (4-chloro-3-methyl-2-pyridyl) cyclo
Instead of propylacetaldehyde, 2- (3,4-
Dichloro-2-pyridyl) cyclopropylacetoalde
After reacting in the same manner as in Reference Example 5 using
Gel column chromatography (elution solvent: hexane /
Ethyl acetate = 7/3) to give 0.27 g of the title compound
Was obtained as a yellow solid. (Yield 25%) NMR spectrum (CDCl_Three, Δ): 0.70-0.78 (m, 2
H), 1.04-1.10 (m, 2H), 1.42 (t, J = 7.1Hz, 3H), 2.50-2.55
(m.1H), 4.42 (t, J = 7.1Hz, 2H), 7.13 (d, J = 8.1Hz, 1H), 8.
46 (s, 1H), 9.33 (d, J = 7.8Hz, 1H) MS spectrum (CI, m / z) 326 (M⁺+1) (Reference Example 61)2- (4-chloro-2-pyridyl) cyclopropyl ace
Toaldehyde 2,2 instead of 2,4-dichloro-3-methylpyridine
1.11 g (7.50 mmol) of 4-dichloropyridine
The reaction was carried out in the same manner as in Reference Example 44 except that
1.10 g of the compound were obtained as a yellow oil. (Yield 75
%) MS spectrum (CI, m / z) 196 (M⁺+1) (Reference Example 62)Ethyl 8-chloro-1-cyclopropyl-4-oxo
-4H-quinolidine-3-carboxylate 2- (4-chloro-3-methyl-2-pyridyl) cyclo
Instead of propylacetaldehyde, 2- (4-chloro
B-2-Pyridyl) cyclopropylacetaldehyde
And reacted in the same manner as in Reference Example 5;
Ram chromatography (elution solvent: hexane / acetic acid
(Chill = 7/3) to give 0.27 g of the title compound as yellow
Obtained as a solid. (16% yield) NMR spectrum (CDCl_Three, Δ): 0.66-0.71 (m, 2
H), 1.03-1.10 (m, 2H), 1.42 (t, J = 7.1Hz, 3H), 1.86-2.05
(m.1H), 4.42 (t, J = 7.1Hz, 2H), 7.14 (dd, J = 2.2 and 7.6H
z, 1H), 8.14 (dd, J = 2.2 and 0.7Hz, 1H) 8.31 (s, 1H), 9.
38 (dd, J = 0.7 and 7.6Hz, 1H) MS spectrum (CI, m / z) 292 (M⁺+1) (Reference Example 63)4-amino-4,7-dihydro-5H-thieno [2,3
-C] thiopyran 7H-thieno [2,3-c] thiopyran-4-one
2 g (7.1 mmol) and 0.8 of methoxyamine hydrochloride
8 g, ethanol 20 ml and 1N sodium hydroxide
Dissolve in a mixed solution with 10.7 ml of an aqueous solution, and at 90 ° C
The mixture was heated and stirred for 2 hours. After stirring, 100 ml of water was added.
Then, the mixture was extracted with 100 ml of ethyl acetate. Organic phase obtained
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
Was. The resulting residue was dissolved in 20 ml of diglyme,
1.6 ml of dimethyl-sulfide complex, and 100
The mixture was heated and stirred at ℃ for 2 hours. After standing to cool, 10% potassium hydroxide
50ml aqueous solution and further heated at 90 ° C for 1 hour
Stirred. After completion of the reaction, the obtained reaction solution was allowed to cool.
Then, 100 ml of toluene was added thereto to carry out liquid separation. The obtained tor
The ene phase was extracted three times with 10 ml of 1N hydrochloric acid. Water obtained
PH was adjusted to 12 by adding 10% aqueous potassium hydroxide solution to the phase.
After that, extraction was performed three times with 10 ml of toluene. Obtained
After drying the organic phase over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
Separation gave 0.99 g of the title compound as a pale red oil.
Was. (81% yield) NMR spectrum (CDCl_Three, Δ): 2.75 (dd, J = 13.
4 and 4.0Hz, 1H), 3.10 (dd, J = 13.4 and 3.5Hz, 1H), 3.6
8 (d, J = 16.1Hz, 1H), 3.86 (d, J = 16.1Hz, 1H), 4.09,
 (t, J = 4.15Hz, 1H), 6.99 (d, J = 5.1Hz, 1H), 7.10
(d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 17
2 (M⁺+1) (Reference Example 64)4- (t-butoxycarbonylamino) -4,7-dihi
Dro-5H-thieno [2,3-c] thiopyran 4-amino-4,7-dihydro-5H-thieno [2,3
-C] thiopyran 0.99 g (6.4 mmol)
Dissolved in 20 ml of methylene, 2.0 g of triethylamine
And 1.7 g (7.2 mmol) of di-t-butyl dicarbonate
Was added and stirred at room temperature for 2 hours. After completion of the reaction, the obtained reaction solution was depressurized.
Under the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: hexane / ethyl acetate
= 9/1) to give 1.15 g of the title compound as a pale yellow oil
Obtained as a solid. (Yield 66%) NMR spectrum (CDCl_Three, Δ): 1.46 (s, 9H),
2.89 (dd, J = 13.6 and 3.4Hz, 1H), 3.09 (dd, J = 13.6 and
And 3.4Hz, 1H), 4.95-4.99 (m, 1H), 5,17-5.20 (m, 1H),
6.98 (d, J = 5.4Hz, 1H), 7.10 (d, J = 3.7Hz, 1H) MS spectrum (CI, m / z) 216 (M⁺-55) (Reference Example 65)4-methylamino-4,7-dihydro-5H-thieno
[2,3-c] thiopyran 7H-thieno [2,3-c] thiopyran-4-one
6 g (9.4 mmol) of ethanol 40 ml, triet
1.9 g of tylamine, 1.26 g of methylamine hydrochloride
(18 mmol), tetraisopropoxy titanium 5.4
g (18 mmol) was added at room temperature and stirred for 5 hours.
After stirring, 0.4 g of sodium borohydride (11 mmo
l) was added, and the mixture was further stirred at room temperature for 40 minutes. After the reaction was completed, 4N salt was added to the obtained reaction solution.
200 ml of acid was added and washed with 200 ml of toluene.
The obtained aqueous phase was adjusted to pH 1 with a 1N aqueous sodium hydroxide solution.
After adjusting to 2, extraction was performed with 50 ml of toluene × 3 times. Get
The organic phase was dried over anhydrous sodium sulfate and dissolved under reduced pressure.
The solvent was distilled off to give 1.60 g of the title compound as a black oil.
Obtained. (Yield 92%) NMR spectrum (CDCl_Three, Δ): 2.49 (s, 3H),
2.95 (s, 2H), 3.64 (d, J = 6.1Hz, 1H), 3.67 (s, 1H),
3.92 (d, J = 6.1Hz, 1H), 6.97 (d, J = 4.9Hz, 1H), 7.09
 (d, J = 5.4Hz, 1H) MS spectrum (CI, m / z) 186 (M⁺+1) (Reference Example 66)4- (methyl) (trityl) amino-4,7-dihydro
-5H-thieno [2,3-c] thiopyran 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 4-methylamino-4,7-
Dihydro-5H-thieno [2,3-c] thiopyran
Same as Reference Example 19 except that 6 g (8.6 mmol) was used.
To give 1.14 g of the title compound as a light brown solid.
I got it. (Yield 31%) NMR spectrum (CDCl_Three, Δ): 1.06 (dd J = 12.7
And 3.3Hz, 1H), 2.13 (dd, J = 12.9 and 10.3Hz, 1H),
2.19 (s, 3H), 3.49 (d, J = 15.6Hz, 1H), 3.95 (dd, J =
16.6 and 2.2Hz, 1H), 4.62 (d, J = 10.0Hz, 1H), 7.14-7.
30 (m, 10H), 7.56-7.59 (m, 6H), 7.80 (d, J = 5.1Hz,
1H) MS spectrum (CI, m / z) 428 (M⁺+1) (Reference Example 67)4-amino-5,6-dihydro-4H-thieno [2,3
-B] thiopyran Replacement for 7H-thieno [2,3-c] thiopyran-4-one
Instead, 5,6-dihydrothieno [2,3-b] thiopyra
In addition to using 2.0 g (11.7 mmol) of n-4-one
Was reacted in the same manner as in Reference Example 63 to give the title compound 1.4
5 g were obtained as a pale yellow oil. (Yield 72%) MS spectrum (CI, m / z) 172 (M⁺+1) (Reference Example 68)4- (t-butoxycarbonylamino) -5,6-dihi
Dro-4H-thieno [2,3-b] thiopyran 4-amino-5,6-dihydro-4H-thieno [2,3
-B] chlorination of 1.45 g (9.4 mmol) of thiopyran
Dissolved in 30 ml of methylene, 3.0 g of triethylamine
And 2.5 g (11 mmol) of di-t-butyl dicarbonate
And stirred at room temperature for 2 hours. After completion of the reaction, the obtained reaction solution was depressurized.
Under the solvent was distilled off. The obtained residue is applied to a silica gel column.
Chromatography (elution solvent: hexane / ethyl acetate
= 9/1) to give 0.99 g of the title compound as a white solid
As obtained. (Yield 39%) NMR spectrum (CDCl_Three, Δ): 1.46 (s, 9H),
2.12-2.33 (m, 2H), 2.98-3.10 (m, 2H), 4.76 (brs, 1
H), 4.87 (brs, 1H), 6.94 (d, J = 5.4Hz, 1H), 7.03
(d, J = 5.4Hz, 1H) MS spectrum (EI, m / z) 271 (M⁺) (Reference Example 69)6-trityl-5,6,7,8-tetrahydro-4H-
Thieno [2,3-d] azepin-4-ol 5,6,7,8-tetrahydro-4H-thieno [2,3
-D] azepin-4-ol 1.32 g (7.8 mmol
l) was dissolved in 30 ml of methylene chloride and triethylamide was dissolved.
3.3 g and trityl chloride 2.3 g (8.2 mmol)
And stirred at room temperature for 1 hour. After the completion of the reaction, the obtained reaction solution was depressurized.
Under the solvent was distilled off. 50 ml of water was added to the obtained residue.
And extracted with 100 ml of ethyl acetate. Organic phase obtained
Was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
did. Silica treated with triethylamine
Gel column chromatography (elution solvent: hexane /
Ethyl acetate = 4/1 to 2/1) to give the title compound
2.9 g were obtained as a colorless solid. (Yield 90%) NMR spectrum (CDCl_Three, Δ): 2.35-2.45 (m, 1
H), 2.60-2.90 (m, 3H), 3.02 (dd, J = 13.9 and 7.8Hz, 1
H), 3.17 (dd, J = 13.9 and 8.4Hz, 1H), 4.94 (t, J = 7.8Hz,
 1H), 6.89-6.94 (m, 2H), 7.13-7.58 (m, 15H) MS spectrum (CI, m / z) 412 (M⁺+1) (Reference Example 70)4-amino-6-trityl-5,6,7,8-tetrahi
Dro-4H-thieno [2,3-d] azepine 6-trityl-5,6,7,8-tetrahydro-4H-
2.9 g of thieno [2,3-d] azepin-4-ol
(7.1 mmol) was dissolved in 20 ml of toluene.
2.33 g (8.5 mmol) of diphenylphosphoryl bromide
, And cooled on ice to give 1,8-diazabicyclo [5.
4.0] -7-undecene 1.27 ml (8.5 mmo
l) and stirred under ice-cooling for 1 hour and further at room temperature overnight.
Was. After completion of the reaction, 50 parts of water was added to the obtained reaction solution.
Then, the mixture was extracted with 100 ml of ethyl acetate. Obtained
The organic phase was dried over anhydrous magnesium sulfate and dissolved under reduced pressure.
The medium was distilled off. The residue obtained is treated with triethylamine.
Silica gel column chromatography (elution solvent:
(Xan / ethyl acetate = 9/1) to give the azide form and
And 6-trityl-6H-7,8-dihydro-thieno
[2,3-d] azepine (dehydrated product of raw alcohol)
It was obtained in a ratio of 1.3: 3 (from NMR). The obtained pale yellow
Dissolve the oil in 150 ml of tetrahydrofuran
While warm, 0.8 g of lithium aluminum hydride was added. After the completion of the reaction, the obtained reaction solution was added with water (0.1%).
8 ml, 15% aqueous sodium hydroxide solution 0.8 ml and
2.4 ml of water was sequentially added, and the mixture was stirred at room temperature.
I left. The solvent was distilled off under reduced pressure from the obtained liquid phase to give the title
Compound and 6-trityl-6H-7,8-dihydro
2.3 g of a mixture of thieno [2,3-d] azepines
Obtained as a yellow oil. MS spectrum (CI, m / z) 393 (M⁺-17) (Reference Example 71)4-t-butoxycarbonylamino-6-trityl-
5,6,7,8-tetrahydro-4H-thieno [2,3
-D] azepine 4-amino-5,6-dihydro-4H-thieno [2,3
-B] Instead of thiopyran, 6-triti as an impurity
Ru-6H-7,8-dihydro-thieno [2,3-d] a
4-amino-6-trityl-5,6,7, including zepin
8-tetrahydro-4H-thieno [2,3-d] azepi
The reaction was carried out in the same manner as in Reference Example 69, except that
0.64 g of the compound was obtained as a pale yellow oil. (Yield 1
8%: 6-trityl-5,6,7,8-tetrahydro-
4H-thieno [2,3-d] azepin-4-ol
R) NMR spectrum (CDCl_Three, Δ): 1.46 (s, 9H),
2.1-2.3 (m, 1H), 2.4-2.5 (m, 1H), 2.94-3.20 (m, 4
H), 5.05-5.10 (m, 1H), 5.37-5.41 (m, 1H), 6.86 (s,
2H), 7.26-7.55 (m, 15H) (Reference Example 72)(3-bromothiophen-2-yl) methoxyacetic acid (3-bromothiophen-2-yl) methanol 12.
3 g (64 mmol) in 300 ml of tetrahydrofuran
Dissolved in water at room temperature in a water bath (60%)
3.1 g were added. The reaction solution is cooled on ice and
13.8 g of ethyl bromoacetate dissolved in 30 ml of run
(83 mmol) was added dropwise over 10 minutes. At the same temperature
After stirring for another 15 minutes, return to room temperature and leave overnight
Was. After the completion of the reaction, the obtained reaction solution was diluted with 100 parts of water.
and 100 ml of saturated aqueous sodium chloride solution.
Then, the solvent was distilled off under reduced pressure, and 19.9 g of the ester compound was browned.
Obtained as an oil. The obtained ester form was treated with ethanol 1
And dissolved in sodium hydroxide 3.1 g (78 m
mol) dissolved in 40 ml of water and added at room temperature for 30 minutes.
Stirred. After the completion of the reaction, the pressure was reduced from the obtained reaction solution.
Under the solvent was distilled off. 1N sodium hydroxide was added to the obtained residue.
50 ml of an aqueous solution of sodium hydroxide and washed with 50 ml of toluene.
Was. The resulting aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid,
Extracted three times with 60 ml of rum. The obtained organic phase is dried
The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
The title compound (16.8 g) was obtained almost quantitatively as a brown oil.
Was. NMR spectrum (CDCl_Three, Δ): 4.18 (s, 2H),
4.81 (s, 2H), 6.98 (d, J = 5.1Hz, 1H), 7.34 (d, J = 5.4
(Hz, 1H) (Reference Example 73)2-[(3-bromothiophen-2-yl) methoxy]
-N-methoxy-N-methyl-acetamide (3-bromothiophen-2-yl) methoxyacetic acid 1
6.8 g (64 mmol) of diethyl ether 100m
29.5 g of thionyl chloride (0.25 mmol
l) was added and the mixture was heated under reflux for 1.5 hours. Remove the solvent under reduced pressure
The residue obtained by distillation is distilled off in 100 m
l. 12.2 g of methoxymethylamine hydrochloride
(125 mmol) and 25 g of triethylamine (250
mmol) in 200 ml of methylene chloride.
Of tetrahydrofuran solution over 20 minutes under ice-cooling
I gave it. After the dropwise addition, the temperature was returned to room temperature, and the mixture was separated. The resulting organic
The phases are combined with 100 ml of water and 100 aqueous saturated sodium chloride solution.
Washed sequentially with ml. The resulting organic phase is dried over anhydrous magnesium sulfate.
After drying over sodium, the solvent was distilled off under reduced pressure. Obtained residue
The residue is subjected to silica gel column chromatography (elution solvent:
Hexane / ethyl acetate = 2/1) to give the title compound
16.2 g were obtained as a colorless solid. (86% yield) NMR spectrum (CDCl_Three, Δ): 3.20 (s, 3H),
3.67 (s, 3H), 4.33 (s, 2H), 4.83 (s, 2H), 6.96 (d,
J = 5.4Hz, 1H), 7.31 (d, J = 5.1Hz, 1H) MS spectrum (CI, m / z) 293 (M⁺+1) (Reference Example 73)7H-thieno [2,3-c] pyran-4-one Under a nitrogen atmosphere, 2-[(3-bromothiophen-2-i
M)]-N-methoxy-N-methyl-acetoa
4.7 g (16 mmol) of amide in diethyl ether 16
0 ml, butyllithium
20 ml of (1.6 M hexane solution) was added dropwise. Dripping
Thereafter, the mixture was stirred at the same temperature for 15 minutes, and then heated to room temperature. After the completion of the reaction, the obtained reaction solution was diluted with 20 m of water.
1 and separated. The obtained organic phase was removed under reduced pressure using a solvent.
Was distilled off. The obtained residue is subjected to silica gel column chromatography.
Chromatography (elution solvent: hexane / ethyl acetate = 9 /
According to 1), 0.48 g of the title compound was obtained as a colorless solid.
Obtained. (Yield 19%) NMR spectrum (CDCl_Three, Δ): 4.27 (s, 2H),
5.02 (s, 2H), 7.21 (d, J = 4.9Hz, 1H), 7.45 (d, J = 5.1
(Hz, 1H) MS spectrum (CI, m / z) 155 (M⁺+1) (Reference Example 74)4,7-dihydro-5H-thieno [2,3-c] pyran
-4-ol 7H-thieno [2,3-c] pyran-4-one 0.48
g (3.1 mmol) in 30 ml of methanol,
60 mg (1.5 mmol) of sodium borohydride
The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the obtained reaction solution was depressurized.
Under the solvent was distilled off. Add saturated ammonium chloride to the resulting residue.
50 ml aqueous solution and extract with 50 ml of ethyl acetate
did. Dry the resulting organic phase over anhydrous magnesium sulfate
Thereafter, the solvent was distilled off under reduced pressure to give 0.50 g of the title compound in a pale color.
Obtained almost quantitatively as a yellow oil. NMR spectrum (CDCl_Three, Δ): 2.12-2.15 (m, 1
H), 3.81 (dd, J = 12.0 and 2.0Hz, 1H), 4.08 (dd, J = 12.
0 and 2.4Hz, 1H), 4.57 (brs, 1H), 4.71 (d, J = 14.9Hz,
 1H), 4.90 (d, J = 14.6Hz, 1H), 7.08 (d, J = 4.9Hz, 1
H), 7.23 (d, J = 5.1Hz, 1H) MS spectrum (EI, m / z) 156 (M⁺) (Reference Example 75)4-azido-4,7-dihydro-5H-thieno [2,3
-C] pyran 4-hydroxy-7,7-dimethyl-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
4,7-dihydro-5H-thieno [2,3-c] pyran
Others using 0.50 g (3.2 mmol) of -4-ol
Was reacted in the same manner as in Reference Example 53 to give the title compound 0.4
3 g were obtained as a colorless oil. (74% yield) NMR spectrum (CDCl_Three, Δ): 3.89 (dd, J = 12.
5 and 3.6Hz, 1H), 4.16-4.20 (m, 2H), 4.76 (d, J = 14.9
Hz, 1H), 4.95 (d, J = 15.Hz, 1H), 7.05 (d, J = 5.1Hz,
1H), 7.27 (d, J = 5.1Hz, 1H) MS spectrum (EI, m / z) 181 (M⁺) (Reference Example 76)4- (t-butoxycarbonylamino) -4,7-dihi
Dro-5H-thieno [2,3-c] pyran 4-azido-7,7-dimethyl-4,5,6,7-tet
4- instead of lahydrothieno [2,3-c] pyridine
Azido-4,7-dihydro-5H-thieno [2,3-
c] Others using 0.43 g (2.4 mmol) of pyrane
Was reacted in the same manner as in Reference Example 54 to give the title compound 0.5
6 g were obtained as a colorless oil. (Yield 92%) NMR spectrum (CDCl_Three, Δ): 1.46 (s, 9H),
3.83 (dd, J = 11.8 and 3.0Hz, 1H), 4.04 (d, J = 11.8Hz,
 1H), 4.69-4.75 (m, 2H), 4.85 (d, J = 14.9Hz, 1H),
4.96-5.00 (m, 1H), 7.01 (d, J = 5.1Hz, 1H), 7.18 (d,
 (J = 5.1Hz, 1H) (Reference Example 77)1-thiophen-2-yl-cyclopropylamine 1-thiophen-2-yl-cyclopropanecarboxylic acid
6.86 g (40.8 mmol), triethylamine
Dissolve 6.3 ml in 50 ml of acetone and cool to 0 ° C or less.
After that, 3.5 ml of ethyl chloroformate was added to acetone 15
The resulting solution was added dropwise over 30 minutes. 20 minutes at the same temperature
After stirring, 5.3 g of sodium azide was added to 15 ml of water.
, And added dropwise at -5 to 0 ° C over 25 minutes. Same temperature
After stirring for 30 minutes, add 150 ml of water and
Extraction was performed four times with 50 ml each. The obtained organic phase is sulfuric anhydride
After drying with magnesium, heat and stir at 80 ° C for 30 minutes.
Then, the mixture was heated and refluxed for another 1 hour. After the completion of the reaction, the resultant reaction solution was decompressed.
Under reduced pressure, the solvent was distilled off, and 60 ml of 8N hydrochloric acid was added.
Stirring was performed at night. The obtained reaction solution is treated with sodium hydroxide.
After adjusting the pH to 12 with an aqueous solution, chloroform 100 ml
And extracted three times. The obtained organic phase is dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the title compound 2.4 was obtained.
7 g were obtained as a brown oil. (44% yield) NMR spectrum (CDCl_Three, Δ): 1.01-1.05 (m, 2
H), 1.12-1.17 (m, 2H), 2.00 (s, 2H), 6.79 (dd, J = 3.
6 and 1.2Hz, 1H), 6.90 (dd, J = 5.1 and 3.4Hz, 1H), 6.7
9 (dd, J = 5.1 and 1.2Hz, 1H) MS spectrum (CI, m / z) 140 (M⁺+1) (Reference Example 78)t-butyl (1-thiophen-2-yl-cyclopro
Pill) carbamate 4-amino-5,6-dihydro-4H-thieno [2,3
-B] Instead of thiopyran, 1-thiophen-2-i
7.47 g of le-cyclopropylamine (53.7 mmol
Except for using l), the reaction was carried out in the same manner as in Reference Example 69,
13.71 g of the title compound were obtained almost quantitatively as a colorless solid.
Was. NMR spectrum (CDCl_Three, Δ): 1.23-1.32 (m, 4
H), 1.44 (s, 9H), 6.82 (dd, J = 3.7 and 1.2Hz, 1H), 6.
88 (dd, J = 4.9 and 3.7Hz, 1H), 7.08 (dd, J = 5.1 and 1.
(2Hz, 1H) MS spectrum (EI, m / z) 184 (M⁺-56) (Reference Example 79)Methyl (t-butoxycarbonyl) (1-thiophene
-2-yl-cyclopropyl) aminoacetate Under a nitrogen atmosphere, t-butyl (1-thiophene-2-i
1.0 g of le-cyclopropyl) carbamate (14.2
mmol) in 40 ml of tetrahydrofuran,
At 70 ° C or lower, butyllithium (1.6M hexane solution)
2.6 ml). Stir for 1 hour at the same temperature after dropping
And add 0.6 ml of methyl bromoacetate, and raise to room temperature.
After warming, it was stirred for another 2 hours. After the reaction was completed,
40 ml of hexane was added to the reaction solution, and 30 ml of water and saturated water were added.
After washing with 30 ml of aqueous sodium chloride solution, the layers are separated.
Was. The obtained organic phase is dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue obtained is silica gel
Ram chromatography (elution solvent: hexane / acetic acid
Chill = 95/5) to give 0.84 g of the title compound
Obtained as a colored solid. (70% yield) NMR spectrum (CDCl_Three, Δ): 0.93-1.56 (m, 1
3H), 3.68 (s, 3H), 3.97, 4.02 (each s, 2H, rotame
r), 6.81-6.88 (m, 2H), 7.10-7.14 (m, 1H) MS spectrum (EI, m / z) 255 (M⁺-56) (Reference Example 80)t-butyl (2-hydroxyethyl) (1-thiophene
N-2-yl-cyclopropyl) carbamate Under a nitrogen atmosphere, methyl (t-butoxycarbonyl)
(1-thiophen-2-yl-cyclopropyl) amino
19.2 g (44 mmol) of acetate in tetrahydro
Dissolved in 300 ml of furan, lithium aluminum hydride
1.68 g (44 mmol) was added little by little to the suspension.
And stirred at room temperature for 30 minutes. After the completion of the reaction, the obtained reaction solution was added under ice-cooling.
1.7 ml of water, 15% aqueous sodium hydroxide
After sequentially adding 1.7 ml and 5 ml of water, insoluble materials were removed by filtration.
And washed with ethyl acetate. With the washed ethyl acetate solution
The solvent was distilled off from the combined solution with the filtrate under reduced pressure. Get
The residue was purified by silica gel column chromatography (elution).
Solvent: hexane / ethyl acetate = 4/1 to 2/1)
This gave 9.2 g of the title compound as a pale yellow oil.
(Yield 73%) NMR spectrum (CDCl_Three, Δ): 1.20-1.50 (m, 1
3H), 1.68 (s, 1H), 3.51-3.55 (m, 2H), 3.68-3.73
(m, 2H), 6.82-6.94 (m, 2H), 7.12-7.15 (m, 1H) MS
Spectrum (EI, m / z) 227 (M⁺-56) (Reference Example 81)t-butyl (2-oxoethyl) (1-thiophene-
2-yl-cyclopropyl) carbamate 2- (4-chloro-3-methyl-2-pyridyl) -2-
T-butyl (2) instead of cyclopropylethanol
-Hydroxyethyl) (1-thiophen-2-yl-cy
Chloropropyl) carbamate 9.2 g (33 mmol)
The reaction was carried out in the same manner as in Reference Example 4 except that
7.2 g of the product were obtained as a pale yellow oil. (78% yield) NMR spectrum (CDCl_Three, Δ): 1.25-1.5 (m, 13
H), 3.95, 3.99 (each s, 2H, rotamer), 6.81-6.92
(m, 2H), 7.05-7.12 (m, 1H), 9.41, 9.45 (eachs, 1H,
 rotamer) MS spectrum (EI, m / z) 225 (M⁺-56) (Reference Example 82)Spiro [4-hydroxy-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridine-7,1′-cyclopropyl
Lopin] (2,2-dimethoxyethyl) (1-methyl-1- (2
T-butyl instead of -thienyl) ethyl) amine
(2-oxoethyl) (1-thiophen-2-yl-cy
7.1 g of (clopropyl) carbamate (25.3 mmol
Except for using l), the reaction was carried out in the same manner as in Reference Example 52,
4.63 g of the title compound as a pale brown oil almost quantitatively
Obtained. The NMR spectrum (CDCl_Three, Δ): 0.7
8-1.33 (m, 4H), 2.27 (brs, 2H), 3.13 (dd, J = 13.9 and
3.2Hz, 1H), 3.20 (dd, J = 13.9 and 2.7Hz, 1H), 4.65 (d
d, J = 3.2 and 2.6Hz, 1H), 6.98 (d, J = 5.1Hz, 1H), 7.0
4 (d, J = 5.1Hz, 1H) MS spectrum (EI, m / z) 181 (M⁺) (Reference Example 83)Spiro [4-azido-4,5,6,7-tetrahydrothio
Eno [2,3-c] pyridine-7,1′-cyclopropa
N] 4-hydroxy-7,7-dimethyl-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
Spiro [4-hydroxy-4,5,6,7-tetrahydride
Rothieno [2,3-c] pyridine-7,1'-cycloprop
Ropan] using 4.43 g (24.4 mmol)
Was reacted in the same manner as in Reference Example 53 to give the title compound 7.4.
7 g were obtained almost quantitatively as a colorless oil. NMR spectrum (CDCl_Three, Δ): 0.80-0.92 (m, 1
H), 1.08-1.34 (m, 3H), 2.12 (brs, 1H), 3.20 (d, J =
3.2Hz, 2H), 4.49 (t, J = 3.2Hz, 1H), 6.97 (d, J =
5.1Hz, 1H), 7.08 (d, J = 5.1Hz, 1H) MS spectrum (EI, m / z) 206 (M⁺) (Reference Example 84)Spiro [6- (t-butoxycarbonyl) -4- (t-
Butoxycarbonylamino) -4,5,6,7-tetra
Hydrothieno [2,3-c] pyridine-7,1'-cycl
Lopropane] 4-azido-7,7-dimethyl-4,5,6,7-tet
Spin instead of lahydrothieno [2,3-c] pyridine
B [4-azido-4,5,6,7-tetrahydrothieno
[2,3-c] pyridine-7,1'-cyclopropane]
The reaction was carried out in the same manner as in Reference Example 54 except that
4.01 g of the compound was obtained as a colorless oil. (Yield 43
%) MS spectrum (CI, m / z) 381 (M⁺+1) (Reference Example 85)4-hydroxy-4,5,6,7-tetrahydrobenzo
[B] Thiophene (optically active substance 2nd peak) 0.23 g (2.4 mmol) of trimethyl borate
Dissolve in 20 ml of lahydrofuran and add (S) -diphenyl
0.51 g (2.0 mmol) of prolinol was added, and the
The mixture was stirred for 1 hour under warm conditions. Borane-dimethyl sulfide complex
2.3 ml (1.2 mmol) of the body was added, and the foaming stopped
After that, the mixture was cooled to -40 ° C. 4-keto-4,5,6,7
3.0 g of tetrahydrothianaphthene (2.0 mmo
l) was dissolved in 20 ml of tetrahydrofuran,
After dropping at 0 to -30 ° C over 15 minutes, 1 hour
Then, the temperature was gradually raised to -5 ° C. Saturated sodium bicarbonate
The aqueous solution was added little by little with stirring, and the mixture was further stirred for 1 hour. After the completion of the reaction, the obtained reaction solution was
Extraction with 30 ml. The obtained organic phase is saturated with sodium chloride.
After washing with 30 ml of aqueous solution of lithium, anhydrous magnesium sulfate
The solvent was distilled off under reduced pressure. The residue obtained
To silica gel column chromatography (elution solvent:
Xan / ethyl acetate = 17/3 to 4/1)
2.9 g of the title compound were obtained almost quantitatively as a colorless solid. NMR spectrum (CDCl_Three, Δ): 1.77-2.07 (m, 4
H), 2.65-2.97 (m, 2H), 4.74-4.76 (m, 1H), 7.01 (d,
J = 5.4Hz, 1H), 7.12 (q, J = 5.4Hz, 2H) Retention time 13.1 minutes Optical purity 94.1% ee Analysis conditions Column: Chiralcel OJ-R φ4.
6 x 150 mm (Daicel Chemical Industries) Column temperature: 40 ° C Detection wavelength: 254 nm Eluent: water / acetonitrile = 8/2 Flow rate: 1.0 ml / min (Reference Example 86)4-azido-4,5,6,7-tetrahydrobenzo
[B] Thiophene (optically active substance 2nd peak) 4-hydroxy-7,7-dimethyl-4,5,6,7-
Instead of tetrahydrothieno [2,3-c] pyridine
4-Hydroxy-4,5,6,7 obtained in Reference Example 85
-Tetrahydrobenzo [b] thiophene (optically active substance)
2.9 g (19 mmol) of 2nd peak) was used.
Except for this, the reaction was carried out in the same manner as in Reference Example 53 to give the title compound 3.
2 g were obtained as a colorless oil. (95% yield) NMR spectrum (CDCl_Three, Δ): 1.80-2.05 (m, 4
H), 2.68-2.92 (m, 2H), 4.51-4.52 (m, 1H), 6.98 (d,
J = 5.4Hz, 1H), 7.12 (q, J = 5.4Hz, 2H) Mass spectrum (EI, m / z): 179 (M⁺) Retention time 43 minutes Optical purity 92.4% ee Analysis conditions Column: Daicel AD-RH φ4.6 × 150m
m (Daicel Chemical Industries) Column temperature: 25 ° C Detection wavelength: 254 nm Eluent: 20 mM phosphate buffer (pH 8) / acetoni
Toril = 6/4 Flow rate: 1.0 ml / min (Reference Example 87)(-)-4- (t-butoxycarbonylamino) -4,
5,6,7-tetrahydrobenzo [b] thiophene (light
Biologically active substance 2nd peak) 4-azido-7,7-dimethyl-4,5,6,7-tet
Reference instead of Lahydrothieno [2,3-c] pyridine
4-azido-4,5,6,7-tetra obtained in Example 86
Hydrobenzo [b] thiophene (optically active substance 2nd
peak) 3.2 g (17.9 mmol)
Was reacted in the same manner as in Reference Example 54 to give the title compound 2.8.
g (89% ee optical purity) was obtained as a colorless solid. Get
The colorless solid was recrystallized from pentane
To obtain 1.12 g of the title compound (optical purity 97.
6% ee) was obtained as colorless rods. (26% yield) [α]_D ²⁰ = -68.3 (C = 0.55, CH_TwoCl_Two) Retention time 10.5 minutes Optical purity 97.6% ee Analysis conditions Column: Daicel AD-RH φ4.6 × 150m
m (Daicel Chemical Industries) Column temperature: 25 ° C Detection wavelength: 254 nm Eluent: 20 mM phosphate buffer (pH 8) / acetoni
Toril = 1/1 Flow rate: 1.0 ml / min (Reference Example 88)4-hydroxy-4,5,6,7-tetrahydrobenzo
[B] Thiophene (optically active substance 1st peak) (R) -dife instead of S-diphenylprolinol
Except for using nilprolinol, the same procedure as in Reference Example 85 was repeated.
In response, 4-keto-4,5,6,7-tetrahydrothi
The title compound 5.96 was obtained from anaphthene (4.0 mmol).
g was obtained as a white solid. (95% yield) NMR spectrum (CDCl_Three, Δ): 1.77-2.07 (m, 4
H), 2.65-2.87 (m, 2H), 4.74-4.76 (m, 1H), 7.01 (d,
J = 5.4Hz, 1H), 7.12 (q, J = 5.4Hz, 2H) Retention time 11.5 minutes Optical purity 94.0% ee Analysis conditions Column: Chiralcel OJ-R 4.6
× 150mm (Daicel Chemical Industries) Column temperature: 40 ° C Detection wavelength: 254 nm Eluent: water / acetonitrile = 8/2 Flow rate: 1.0 ml / min (Reference Example 89)(+)-4- (t-butoxycarbonylamino) -4,
5,6,7-tetrahydrobenzo [b] thiophene (light
Activator 1st peak) 4-hydroxy-4,5,6,7-tetrahydrobenzo
[B] of thiophene (optically active substance 2nd peak)
Alternatively, the 4-hydroxy-4, obtained in Reference Example 88,
5,6,7-tetrahydrobenzo [b] thiophene (light
5.96 g (38.6 mm)
ol), except that Reference Example 86 and Reference Example 87 were used.
To 0.89 g of the title compound (97% optical purity).
ee) was obtained as colorless rods. (10% yield) [α]_D ²⁰ = + 69.0 (C = 0.55, CH_TwoCl_Two) Retention time 9.02 minutes Optical purity 97.0% ee Analysis conditions Column: Daicel AD-RH φ4.6 × 150m
m (Daicel Chemical Industries) Column temperature: 25 ° C Detection wavelength: 254 nm Eluent: 20 mM phosphate buffer (pH 8) / acetoni
Toril = 1/1 Flow rate: 1.0 ml / min (Reference Example 90)(2-thiophen-2-yl-propyl) methanesulfo
Nate 2-thiophen-2-ylpropan-1-ol 3.0
g (21 mmol) and 6.6 g of triethylamine
Dissolve in 150 ml of methylene
3.2 g of honyl was added, and the mixture was stirred at the same temperature for 15 minutes. After completion of the reaction, the obtained reaction solution was washed with saturated carbonic acid.
After washing three times with 20 ml of aqueous sodium hydrogen solution, anhydrous
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
(Elution solvent: hexane / ethyl acetate = 2/1)
Quantified 4.76 g of the title compound as a brown oil.
I got it. MS spectrum (CI, m / z) 221 (M⁺+1) (Reference Example 91)2- (2-thiophen-2-yl-propyl) malonic acid 4.5 g of diethyl malonate was added to N, N-dimethylforma.
Dissolved in 120 ml of sodium hydroxide
3.21 g were added little by little. 2-thiophene-2
-Yl-propyl methanesulfonate 4.76 g (2
1 mmol) in N, N-dimethylformamide 20 ml
, And added dropwise, and then heated and stirred at 120 ° C for 2.5 hours
did. After the completion of the reaction, 50 m of water was added to the obtained reaction solution.
and 50 ml of a saturated aqueous sodium chloride solution.
The mixture was extracted three times with 100 ml of hexane. Organic phase obtained
Was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
I left. The obtained residue is subjected to silica gel column chromatography.
Fee (elution solvent: hexane / ethyl acetate = 1 / 0-9
/ 1) to give 5.0 g of the ester compound as a pale yellow oil.
I got it. (Yield 74%)
And 38 g of 10% aqueous sodium hydroxide solution
In addition, the mixture was heated and stirred at 80 ° C. for 1 hour. After the completion of the reaction, the resultant reaction solution was depressurized.
The solvent was distilled off, and 50 ml of water was added to the obtained residue.
Thereafter, the resultant was washed with 30 ml of diethyl ether. Water obtained
After the pH of the phase was adjusted to 1 with concentrated hydrochloric acid, it was added with 30 ml of toluene.
Extracted twice. The solvent is distilled off from the obtained organic phase under reduced pressure.
This gave 3.1 g of the title compound as a yellow oil. (Income
MS spectrum (CI, m / z) 229 (M
⁺+1) (Reference Example 92)7-methyl-6,7-dihydro-5H-benzo [b] thi
Offen-4-one 2- (2-thiophen-2-yl-propyl) malonic acid
Dissolve 0.52 g (2.2 mmol) in 30 ml of 8N hydrochloric acid.
The mixture was heated and refluxed for 15 hours. After the completion of the reaction, the obtained reaction solution was diluted with toluene.
Extraction twice with 30 ml. The obtained organic phase is
The extract was dried over magnesium acid, and the solvent was distilled off under reduced pressure. Profit
The residue obtained is separated by silica gel column chromatography (solvent).
Solvent: hexane / ethyl acetate = 9/1 to 8/2)
This gave 0.14 g of the title compound as a colorless oil.
(Yield 39%) MS spectrum (CI, m / z) 167 (M⁺+1) (Reference Example 93)4-amino-7-methyl-6,7-dihydro-5H-be
Nzo [b] thiophene Replacement for 7H-thieno [2,3-c] thiopyran-4-one
7-methyl-6,7-dihydro-5H-benzo
[B] thiophen-4-one 0.57 g (3.4 mmol
Except for using l), the reaction was carried out in the same manner as in Reference Example 63,
0.44 g of the title compound was obtained as a pale red oil. (Yield 7
7%) MS spectrum (CI, m / z) 168 (M⁺+1) (Reference Example 94)4- (t-butoxycarbonylamino) -7-methyl-
6,7-dihydro-5H-benzo [b] thiophene 4-amino-4,7-dihydro-5H-thieno [2,3
-C] 4-amino-7-methyl- in place of thiopyran
6,7-dihydro-5H-benzo [b] thiophene
Reference Example 64 except that 44 g (2.6 mmol) was used.
Reaction was carried out in the same manner to give the title compound (0.68 mg, colorless oil).
Was obtained almost quantitatively. MS spectrum (EI, m / z) 267 (M⁺) (Reference Example 95)4- (t-butoxycarbonyl) (methyl) amino-
4,5,6,7-tetrahydrobenzo [b] furan 4-keto-4,5,6,7-tetrahydrothianaphthene
6,7-dihydro-4 (5H) -benzofura
Using 4.10 g (30 mmol) of nonyl, trityl chloride
Except that 7 ml of di-t-butyl dicarbonate was used instead of
Reaction was conducted in the same manner as in Reference Example 56, and 3.66 g of the title compound was obtained.
Was obtained as a pale yellow oil. (Yield 49%) NMR spectrum (CDCl_Three, Δ): 1.46 (s, 9H),
1.58-2.04 (m, 4H), 2.50-2.60 (m, 5H), 5.00-5.30
(m, 1H), 6.17 (s, 1H), 7.25 (s, 1H) (Reference Example 96)6-methyl-7-oxo-4-tritylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridi
N 6-methyl-4-tritylamino-4,5,6,7-te
2.03 g of trahydrothieno [2,3-c] pyridine
(4.94 mmol) was dissolved in 70 ml of acetone.
4.50 g (28.5 mmol) of potassium manganate
In addition, the mixture was heated and stirred at 40 ° C. for 1 hour. After the completion of the reaction, the obtained reaction solution was added with ethyl acetate.
And water and sodium sulfite to remove insolubles through Celite.
It was filtered off with 545 (trade name). The obtained filtrate is separated,
The aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were combined.
The phase is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure
did. Diisopropyl ether was added to the obtained residue,
Heated and sonicated at 50 ° C. The generated precipitate is filtered.
And washed with diisopropyl ether to give the title compound.
1.89 g of the product were obtained as a white solid. (Yield 82%) NMR spectrum (CDCl_Three, Δ): 2.32 (dd, J = 12.7
And 5.4Hz, 1H), 2.67 (dd, J = 12.9 and 4.2Hz, 1H), 2.77
 (s, 3H), 3.93-3.96 (m, 1H), 6.99 (d, J = 5.1Hz, 1
H), 7.20-7.35 (m, 9H), 7.46 (d, J = 5.1Hz, 1H), 7.56
-7.60 (m, 6H) MS spectrum (CI, m / z) 425 (M⁺+1) IR spectrum (KBr, ν_max  cm^-1): 1643 (Reference Example 97)4-tritylamino-5-methyl-4,5,6,7-te
Trahydrobenzo [b] thiophene 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 4-amino-5-methyl-
4,5,6,7-tetrahydrobenzo [b] thiophene
The reaction was carried out in the same manner as in Reference Example 19, except that 0.67 g was used.
Thus, 1.61 g of the title compound was obtained as a colorless oil.
(Yield 98%) MS spectrum (CI, m / z): 410 (M⁺+1) (Reference Example 98)4-tritylaminomethyl-4,5,6,7-tetrahi
Drobenzo [b] thiophene 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 4-aminomethyl-4,5,
1.8 g of 6,7-tetrahydrobenzo [b] thiophene
The reaction was carried out in the same manner as in Reference Example 19 except that
3.1 g of the compound were obtained as a white foam. (70% yield) NMR spectrum (CDCl_Three, Δ): 1.59-2.08 (m, 4
H), 2.22 (dd, J = 11.5 and 7.8Hz, 1H), 2.53 (dd, J = 1
1.7 and 4.6Hz, 1H), 2.69-2.90 (m, 3H), 6.60 (d, J = 5.
2Hz, 1H), 6.95 (d, J = 5.2Hz, 1H), 7.09-7.60 (m, 15
H) MS spectrum (CI, m / z): 410 (M⁺+1) (Reference Example 99)4-methoxymethoxy-4,5,6,7-tetrahydro
Benzo [b] thiophene 4-hydroxy-6-trityl-4,5,6,7-tet
Instead of lahydrothieno [2,3-c] pyridine, 4
-Hydroxy-4,5,6,7-tetrahydrobenzo
[B] Reference Example 30 was used except that 2.0 g of thiophene was used.
Similarly, 2.4 g of the title compound was converted into a colorless oil.
I got it. (93% yield) NMR spectrum (CDCl_Three, Δ): 1.78-2.12 (m, 4
H), 2.65-2.93 (m, 2H), 3.44 (s, 3H), 4.69 (t, J = 4.
4Hz, 1H), 4.78 (dd, J = 18.6 and 7.1Hz, 2H), 6.96 (d,
J = 5.3Hz, 1H), 7.08 (d, J = 5.3Hz, 1H) (Reference Example 100)4- (t-butyloxycarbonyl) amino-5,6-
Dihydro-4H-cyclopenta [b] thiophene Replacement for 7H-thieno [2,3-c] thiopyran-4-one
Instead, 5,6-dihydro-cyclopenta [b] thiof
Reference Example 63 and Reference Example 63 except that 1.66 g of ene-4-one were used.
And the reaction was carried out in the same manner as in Reference Example 64 to give the title compound 2.89.
g were obtained as a pale yellow oil. (Yield 97%) NMR spectrum (CDCl_Three, Δ): 1.47 (s, 9H),
2.17-2.29 (m, 1H), 2.78-3.05 (m, 3H), 4.63-4.77
(m, 1H), 5.00-5.11 (m, 1H), 6.89 (d, J = 5.0Hz, 1H),
7.18 (d, J = 5.0Hz, 1H) MS spectrum (CI, m / z): 240 (M⁺+1) (Reference Example 101)4-tritylamino-4,5,6,7-tetrahydrobe
Nzo [b] thiophene 4,5,6,7-tetrahydrothieno [2,3-c] pi
Instead of lysine hydrochloride, 4-amino-4,5,6,7
Using 0.92 g of tetrahydrobenzo [b] thiophene
Other than that, the reaction was carried out in the same manner as in Reference Example 19 to give the title compound.
Was obtained almost quantitatively as a colorless oil. The NMR spectrum (CDCl_Three, Δ): 1.0
3-1.14 (m, 1H), 1.22-1.33 (m, 1H), 1.50-1.65 (m, 1
H), 1.86-2.07 (m, 1H), 2.55-2.83 (m, 2H), 3.72 (t,
 J = 5.2Hz, 1H), 6.50 (d, J = 5.1Hz, 1H), 6.95 (d, J =
5.1Hz, 1H), 7.16-7.64 (m, 15H) MS spectrum (CI, m / z): 396 (M⁺+1) (Reference Example 102)5-bromo-1-tritylamino-1,2,3,4-te
Trahydronaphthalene In Gazzetta Chimica Italiana, 118, p369-374 (1988)
Therefore, 6.2 g of 5-bromo-1-tetralone synthesized was used.
(27.6 mmol) in 50 ml of ethanol,
29 ml of a 1N aqueous sodium hydroxide solution
And 2.4 g (28.7 mmol) of hydrochloric acid
Then, the mixture was stirred at room temperature, and then heated and stirred at 80 ° C. for 13 hours.
After the reaction is completed, ethanol is depressurized from the obtained reaction solution.
Under reduced pressure, 50 ml of water and chloroform were added to the obtained residue.
100 ml were added. The obtained chloroform phase is dried
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
(Eluent: hexane / ethyl acetate = 19/1 to 9 /
6.1 g of the oxime compound as a yellow-green oily substance
Obtained. (87%) 6.1 g of the obtained oxime compound (24.
0 mmol) in 30 ml of tetrahydrofuran,
Borane-tetrahydrofuran complex at 0 ° C under nitrogen atmosphere
(1.0 mol / l tetrahydrofuran solution) 25 m
1 was added dropwise. After the dropwise addition, the mixture was heated and stirred at 80 ° C. for 15 hours,
Thereafter, add 100 ml of diglyme, and further at 120 ° C.
The mixture was heated and stirred for 10 hours. After completion of the reaction, 10% water was added to the obtained reaction solution.
Add 100 ml of potassium oxide aqueous solution, and at 120 ° C for 1 hour
After heating and stirring for a while, allow to cool and add 100 ml of methylene chloride.
Was. The obtained organic phase was separated and 1N with 100 ml of 2N hydrochloric acid.
Extraction was performed once with 100 ml of 4N hydrochloric acid. Water obtained
Combine the phases, add potassium hydroxide and adjust to alkaline.
After that, 100 ml of methylene chloride was added. Separate the organic phase
And dried over anhydrous magnesium sulfate.
Evaporation gave 4.2 g of the amine compound as a pale yellow oil.
(78% yield) 4.2 g (18.6 mmol) of the obtained amine compound was salified.
Dissolve in 20 ml of methylene and 2.8 g of triethylamine
(27.7 mmol) and 5.2 g of trityl chloride (18.
6 mmol) and stirred at room temperature for 5 hours. After the completion of the reaction, 50 m of water was added to the obtained reaction solution.
l and 50 ml of chloroform were added. Separate the organic phase
Dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure.
And the resulting residue is purified by silica gel column chromatography.
-(Elution solvent: hexane / ethyl acetate = 9/1)
Thus, 7.8 g of the title compound was obtained as a white solid. (yield
90%) NMR spectrum (CDCl_Three, Δ): 0.88-0.97 (m, 1
H), 1.21-1.33 (m, 1H), 1.52-1.59 (m, 1H), 1.96-2.11
 (m, 1H), 2.45-2.56 (m, 1H), 2.83-2.91 (m, 1H), 3.5
8-3.61 (m, 1H), 6.91-7.02 (m, 2H), 7.16-7.63 (m, 1
6H) MS spectrum (CI, m / z) 469 (M⁺+1) (Reference Example 103)7-bromo-1-tritylamino-1,2,3,4-te
Trahydronaphthalene In Gazzetta Chimica Italiana, 118, p369-374 (1988)
Therefore, 3.5 g of the synthesized 7-bromo-1-tetralone was used.
(15.6 mmol), except that Reference Example 19 was used
To give 3.9 g of the title compound as a pale yellow oil.
I got it. (Yield 53%) NMR spectrum (CDCl_Three, Δ): 0.88-1.01 (m, 1
H), 1.20-1.28 (m, 1H), 1.50-1.62 (m, 1H), 1.85-1.98
 (m, 1H), 2.43-2.55 (m, 1H), 2.63-2.74 (m, 1H), 3.5
5-3.62 (bs, 1H), 6.90 (d, J = 8.1Hz, 1H), 7.10-7.63
(m, 17H) MS spectrum (CI, m / z) 469 (M⁺+1) (Reference Example 104)6-bromo-1- (t-butyloxycarbonyl) amido
No-1,2,3,4-tetrahydronaphthalene Instead of 5-bromo-1-tetralone, 6-bromo-
Using 1.16 g of 1-tetralone, replacing trityl chloride
Other than using 0.69 g of di-t-butyl dicarbonate,
The reaction was conducted in the same manner as in Example 102 to give the title compound (0.78 g).
Was obtained as a pale yellow oil. (Yield 48%) NMR spectrum (DMSO-d₆, Δ): 1.42 (s, 9
H), 1.60-1.72 (m, 2H), 1.78-1.92 (m, 2H), 2.64-2.7
3 (m, 2H), 4.54-4.63 (m, 1H), 7.12 (d, J = 8.3Hz, 1
H), 7.28 (s, 1H), 7.32 (d, J = 8.3Hz, 1H) MS spectrum (CI, m / z): 327 (M⁺+1) (Formulation example) (Formulation Example 1) (Hard capsule) Each standard bipartite hard gelatin capsule contains 100 mg
Compound of Example 1 in powder form, 150 mg lactose, 50 mg
 Cellulose and 6 mg magnesium stearate
By filling, produce unit capsules, after washing,
dry. (Formulation Example 2) (Soft capsule) Digestible oils such as soybean oil, cottonseed oil or olive oil
A mixture of the compound of Example 2 was prepared and placed
Pump into the gelatin with an exchange pump to get 100 mg of the active ingredient.
The resulting soft capsule is obtained, washed and dried. (Formulation Example 3) (Tablet) In a conventional manner, 100 mg of the compound of Example 3 and 0.2 mg of
Loidal silicon dioxide, 5 mg magnesium stearate
275 mg microcrystalline cellulose, 11 mg starch and
And 98.8 mg of lactose. [0371] If desired, a coating is applied. (Formulation Example 4) (Injection) 1.5% by weight of the compound of Example 4 is added to 10% by volume of propylene
Stir in glycol and then make up to volume with water for injection
And then sterilized for manufacture. (Formulation Example 5) (Suspension) In 5 ml, 100 mg of the finely divided compound of Example 5, 100 m
g of sodium carboxy group methylcellulose, 5 mg
Sodium benzoate, 1.0 g sorbitol solution (Japan
Manufactured to contain 0.025 ml of vanillin
I do. (Formulation Example 6) (Cream) 40% white petrolatum, 3% microcrystalline wax,
10% lanolin, 5% span 20, 0.3% tween 20
100mg fines in 5g cream consisting of 41.7% water
By mixing the compound of Example 6
You. (Formulation Example 7) (Cream) Compound of Example 7 (2 parts by weight), 1,2-propanediol
(5 parts by weight), glycerol stearate (5 parts by weight)
Parts), whale wax (5 parts by weight), isopropyl myristate
(10 parts by weight) and a mixture of polysorbate (4 parts by weight)
Warm, cool and then, with stirring, water (69 parts by weight)
To produce a cream. (Formulation Example 8) (Solution for application) The compound of Example 8 (1 part by weight) was
To 300 parts (99 parts by weight) to produce a coating solution. (Formulation Example 9) (Ointment) Compound of Example 9 (2 parts by weight), polyethylene glyco-
400 (40 parts by weight), polyethylene glycol 1500 (58
Parts by weight) and dissolve it under heating, then cool to produce an ointment
I do. (Test example) Measurement of antibacterial activity Antibacterial activity is measured by agar plate dilution method,
The minimum inhibitory concentration (MIC) was determined by the following method. That is, the test compound was accurately weighed and 1) sterilized.
2) Dissolve in 50% acetone aqueous solution
3) To a small amount of dimethyl sulfoxide
After dissolution, 3% by weight of sodium hydroxide
After addition, the test compound is diluted with sterile distilled water.
A final concentration of 1280 μg / ml solution was prepared. 2 with sterile distilled water
Perform 15-fold dilutions (0.078 μg / ml for the final step), and
The diluent was dispensed into petri dishes at 1 ml each. Muel for each Petri dish
Add 9 ml of ler-Hinton agar and mix to form an agar plate.
Was. On the other hand, the test bacteria were incubated at 37 ° C in Mueller Hinton Broth.
The overnight culture was used. Culture solution diluted 100 times with physiological saline
And place one loopful on the agar plate containing the test drug.
I smeared the line. Inhibits bacterial growth after culturing at 37 ° C for 18 hours
The minimum density to perform was visually determined. The results are shown in Table 3. [0374] [Table 3] The compounds of Examples 1 to 56 of the present invention were obtained from Staphylococcus a
The development of ureus 209P was inhibited at very low concentrations. The medicament containing the compound of the present invention is excellent
Has antibacterial activity and high safety. [0376] The drug of the present invention has excellent antibacterial activity and high safety.
It has totality and is useful as an antibacterial agent.

Continuation of front page    (72) Inventor Naohisa Masuda             Sankyo Co., Ltd. 1-258 Hiromachi, Shinagawa-ku, Tokyo             In the formula company (72) Inventor Yoshiaki Kuroki             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. (72) Inventor Teruhiko Inoue             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. (72) Inventor Makoto Okudo             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. (72) Inventor Toshihide Iwata             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. (72) Koji Kokubo, inventor             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. (72) Inventor Gen Mizuno             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. (72) Inventor Masahiko Hagiwara             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd. F term (reference) 4C065 AA03 BB09 CC01 DD01 EE02                       HH08 JJ04 KK07 PP18                 4C072 MM08 UU01                 4C086 AA01 AA02 CB18 CB26 MA01                       MA04 NA14 ZB35

Claims (1)

[Claim 1] A compound represented by the general formula (I): [Wherein, R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group substituted by one or more halogen atoms,
C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkyl with one or more substituted C ₃ -C ₇ cycloalkyl group, C ₃ -C ₇ cycloalkyl group that is substituted one or more halogen atoms And the same or different substituents selected from an aryl group, a heteroaryl group, or a halogen atom and an amino group.
R ² represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C ₁ -C ₆ alkyl group, or a C 1 or 2 or more substituted with a halogen atom. C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, or C ₁ substituted with 1 or 2 or more halogen atoms
-C ₆ alkoxy group, R ³ represents a hydrogen atom or a halogen atom, (provided that the phenyl ring and the cyclic group G of formula (b) in groups in the following R ⁵
When the group formed by and is an isoindoline ring, R ³ is limited to a halogen atom. ) R ⁴ represents a hydrogen atom, a halogen atom, a nitro group, an amino group or a C ₁ -C ₆ alkyl group, and R ⁵ has the general formula (a): Wherein cyclic group A represents a heteroaryl ring, and cyclic group G has 5 to 8 carbon atoms which may optionally replace a carbon atom with a nitrogen, oxygen or sulfur atom. Represents a cycloalkene ring or a cycloalkane ring having 5 to 8 carbon atoms, wherein R ^{6a to} R ^6c are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, C _1- substituted by one or more halogen atoms
Represents a C ₄ alkyl group or a C ₁ -C ₄ alkoxy group substituted by one or more halogen atoms; R ^{7a to} R ^7d are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a nitro group , A cyano group, a hydroxyimino group, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkyl group substituted by one or more halogen atoms, one or more substituted by halogen atoms Done C ₁
A —C ₄ alkoxy group, a hydroxy C ₁ -C ₄ alkyl group,
C ₁ -C ₄ alkyloxyimino group, amino group, C ₁ -C ₄
An amino group substituted with one or more same or different substituents selected from alkyl and C ₃ -C ₇ cycloalkyl, a C ₁ -C ₄ alkyl group substituted with amino, a C ₁ -C ₄
Together with a C ₁ -C ₄ alkyl group, an oxo group, or a bonding carbon atom substituted by an amino group substituted by one or more same or different substituents selected from alkyl and C ₃ -C ₇ cycloalkyl It represents a group to form a C ₃ -C ₅ cycloalkane ring. ) Or general formula (b) (Wherein the cyclic group G represents a ring as defined above, provided that the condensed ring formed by the phenyl ring and the cyclic group G is a tetrahydroisoquinoline ring)
^{6a to} R ^6c and R ^{7a to} R ^7d have the same meaning as described above. ). Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.