JP2003292492A - Thienopyrimidine compound, method for producing the same and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a thienopyrimidine compound having a gonadotrophic hormone-releasing hormone antagonism, and to provide a medicine containing the same. <P>SOLUTION: This compound represented by the formula [R<SP>1</SP>is a 1 to 4C alkyl; R<SP>2</SP>is (1) phenyl which may have a substituent such a amino, a mono 1 to 4C alkylamino, or a di 1 to 4C alkylamino, (2) a heterocyclic group which may have a substituent such a amino, a mono 1 to 4C alkylamino, or a di 1 to 4C alkylamino, or the like; R<SP>3</SP>is H or a 1 to 4C alkyl; R<SP>4</SP>is a 1 to 4C alkyl which may have a 1 to 4C alkoxy-carbonyl, carboxy, a mono 1 to 4C alkylamino, an N-1 to 4C alkyl-N-7 to 10C aralkylamino or the like] or its salt. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to gonadotropin releasing hormone (GnRH).
e)) Thieno [2,3-d] pyrimidine compounds exhibiting antagonism, production method and use thereof.

[0002]

BACKGROUND OF THE INVENTION Secretion of the anterior pituitary gland is achieved by the secretion of peripheral hormones secreted from the target organs of the respective hormones and hormones secreted by the hypothalamus, which is the upper center of the anterior pituitary gland (hereinafter referred to as In the specification, these hormone groups are collectively referred to as hypothalamic hormones). To date, hypothalamic hormones such as thyrotropin-releasing hormone (TRH) or gonadotropin-releasing hormone {GnR
H (Gonadotropin releasing hormone): LH-RH (Luteinizing hormone relea
Also known as sing hormone)]}. It is presumed that these hypothalamic hormones exert their hormonal actions through receptors that are considered to be present in the anterior pituitary gland, and the analysis of receptor genes specific to these, including in humans, is also possible. It is being advanced.
Therefore, a specific and selective antagonist or agonist for these receptors regulates the action of hypothalamic hormone and controls the secretion of anterior pituitary hormone. As a result, prevention or treatment of such an anterior pituitary hormone-dependent disease can be expected. As a compound having a GnRH antagonistic action, a linear peptide that is a derivative of GnRH (Patent Document 1 and Patent Document 2)
), A cyclic hexapeptide derivative (see Patent Document 3), a bicyclic peptide derivative (see Non-Patent Document 1), and the like. Examples of the non-peptidic compound having a GnRH antagonistic action include the compounds described in Patent Documents 4 to 11.

[0003]

[Patent Document 1] US Pat. No. 5,140,009

[Patent Document 2] US Pat. No. 5,171,835

[Patent Document 3] JP-A-61-191698

[Patent Document 4] JP-A-8-295693 (WO 95/28405
Issue)

[Patent Document 5] JP-A-9-169768 (WO 96/24597
Issue)

[Patent Document 6] JP-A-9-169735 (WO 97/14682)
Issue)

[Patent Document 7] JP-A-9-169767 (WO 97/14697
Issue)

[Patent Document 8] Japanese Patent Laid-Open No. 11-315079 (WO 99/33831
Issue)

[Patent Document 9] Japanese Patent Laid-Open No. 2000-219691 (WO 00/00493
Issue)

[Patent Document 10] Japanese Patent Laid-Open No. 2001-278884 (WO 00/567
(Gazette No. 39)

[Patent Document 11] Japanese Patent Laid-Open No. 2002-30087

[Non-Patent Document 1] Journal of Medicinal Chemistry, 36, 32
65-3273, 1993

[0004]

DISCLOSURE OF THE INVENTION Peptide compounds are
Problems remain in many aspects such as oral absorbability, dosage form, dose, drug stability, duration of action, and stability against metabolism. Has excellent therapeutic effect on hormone-dependent cancers such as prostate cancer, endometriosis, precocious puberty,
Moreover, there is a strong demand for a GnRH antagonist having excellent oral absorbability that does not cause a transient pituitary-gonadotropic action (acute action), particularly a non-peptide antagonist.

[0005]

[Means for Solving the Problems] As a result of intensive investigations, the present inventors have found that the 6-position phenyl para-position of the thieno [2,3-d] pyrimidine skeleton is substituted with 3-C _1-4 alkylureido. Formulas with chemical structural characteristics

[Chemical 2] [In the formula, R¹Is C_1-4Alkyl, R²Is (I) (1) amino, (2)
Mono C_1-4Alkylamino, (3) di C_1-4Alkylamino,
(4) -NR^FiveCOR⁶(R^FiveIs a hydrogen atom or C_1-4Alkyl, R⁶Is C
_1-4Alkyl, Mono C_{1- Four}Alkylamino or di-C_1-4A
(Shows ruquilamino), (5) -NR⁷SO₂R⁸(R⁷Is a hydrogen atom
Or C_1-4Alkyl, R⁸Is C_1-4Alkyl, Mono C_1-4Archi
Lumino or di-C_1-4Alkylamino), (6) -CO
NR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Even if it has an alkoxy
Good c_1-4Alkyl or C_3-8Cycloalkyl, R^TenIs water
Elementary atom or C_1-4Alkyl, R⁹And R^TenAre together
To form a ring with the adjacent nitrogen atom.
I), (7) -SO₂NR¹¹R¹²(R¹¹Is a hydrogen atom, C_1-4Arcoki
C which may have shi_1-4Alkyl or C_3-8Cycloa
Rukiru, R¹²Is a hydrogen atom or C_1-4Alkyl, R¹¹
And R¹²Together form a ring with the adjacent nitrogen atom
May be formed), (8) -CO₂R¹³(R¹³Is C_1-4Alkyl
), (9) hydroxyl group, C_1-4Alkoxy, C_1-4Alkyl
-Carbonyloxy, -NR^FiveCOR⁶(R^FiveAnd R⁶Is the same as above
Show meaning), -NR⁷SO₂R⁸(R⁷And R⁸Is the same meaning as above
,)-CONR ⁹R^Ten(R⁹And R^TenHas the same meaning as above
),-SO₂NR¹¹R¹²(R¹¹And R¹²Has the same meaning as above
Or) -CO₂R¹³(R¹³Has the same meaning as above)
May be C_1-4Alkoxy, (10) hydroxyl group, -NR^FiveCOR⁶
(R^FiveAnd R⁶Has the same meaning as above), -NR⁷SO₂R⁸(R⁷
And R⁸Has the same meaning as above), -CONR⁹R^Ten(R⁹And
And R^TenHas the same meaning as above), -SO₂NR¹¹R¹²(R¹¹And
And R¹²Has the same meaning as above), -CO₂R¹³(R¹³Is as above
Have the same meaning) or C_1-4May have alkoxy
I C_1-4Alkyl, (11) halogen atom, (12) hydroxyl group and
And (13) nitro (hereinafter abbreviated as Substituent group A)
Phenyl optionally having 1 to 3 substituents,
(II) 1 to 3 selected from the substituent group A and oxo
Heterocyclic groups optionally having 1 substituent, (III) the substitution
Even if it has 1 to 3 substituents selected from Group A
Good c_3-8Cycloalkyl or (IV) (1) 5- or 8-membered inclusions
Nitrogen heterocyclic group, (2) hydroxyl group and (3) C_1-4From alkoxy
C optionally having 1 to 3 substituents selected_1-4A
Rukiru, R³Is a hydrogen atom or C_1-4Alkyl, R^FourIs (I) (1)
 C_1-4C which may have alkoxy_1-4Alkoxy,
(2) -NR¹⁴COR¹⁵(R¹⁴Is a hydrogen atom or C_1-4Alkyl, R
¹⁵Is C_1-4Alkyl)), (3) -NR¹⁶SO ₂R¹⁷(R¹⁶Is water
Elementary atom or C_1-4Alkyl, R¹⁷Is C_1-4Show alkyl
), (4) -CONR¹⁸R¹⁹(R¹⁸Is a hydrogen atom or C_1-4Archi
Le, R¹⁹Is C_1-4C which may have alkoxy_1-4Al
Indicates a kill, R¹⁸And R¹⁹Are adjacent nitrogen together
May form a ring with atoms), (5) -SO₂NR²⁰R
^{twenty one}(R²⁰Is a hydrogen atom or C_1-4Alkyl, R^{twenty one}Is C_1-4Al
C, which may have Coxi_1-4Alkyl, R²⁰Oh
And R^{twenty one}Together form a ring with the adjacent nitrogen atom
May be formed), (6) (1 ') hydroxy-C_1-4Alkyl,
(2 ') C_1-4Alkoxy-carbonyl, (3 ') mono C_1-4Archi
Le-carbamoyl or (4 ') diC_1-4Alkyl-carbamoy
A 5- to 7-membered nitrogen-containing heterocyclic group which may have a
(7) C_1-4Alkoxy-carbonyl, (8) carboxyl, (9)
Mono C_1-4Alkylamino and (10) N-C_1-4Alkyl-N-C
_7-10Aralkylamino (hereinafter abbreviated as Substituent group B)
C optionally having 1 to 3 substituents selected from
_1-4Alkyl or (II) 1 selected from the above substituent group B
C optionally having 3 substituents_3-8Cycloalk
(However, R²Is mono-substituted with a halogen atom.
R when^FourIs C_1-4C substituted with an alkoxy
_1-4A new compound represented by
Starting with a salt (hereinafter sometimes abbreviated as compound (I))
Compound (I) is based on its unique chemical structure
Unexpectedly excellent GnRH antagonism, especially strong antagonism
It has gonist activity and these compounds are poisonous.
Very low in activity, sufficient as a drug with GnRH antagonism
For the first time, we found that we were satisfied,
The invention has been completed based on the observations.

That is, the present invention is based on the formula [1]

[Chemical 3] [In the formula, R¹Is C_1-4Alkyl, R²Is (I) (1) amino, (2)
Mono C_1-4Alkylamino, (3) di C_1-4Alkylamino,
(4) -NR^FiveCOR⁶(R^FiveIs a hydrogen atom or C_1-4Alkyl, R⁶Is C
_1-4Alkyl, Mono C_1-4Alkylamino or di-C_1-4A
(Shows ruquilamino), (5) -NR⁷SO₂R⁸(R⁷Is a hydrogen atom
Or C_1-4Alkyl, R⁸Is C_1-4Alkyl, Mono C_1-4Archi
Lumino or di-C_1-4Alkylamino), (6) -CO
NR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Even if it has an alkoxy
Good c_1-4Alkyl or C_3-8Cycloalkyl, R^TenIs water
Elementary atom or C_1-4Alkyl, R⁹And R^TenAre together
To form a ring with the adjacent nitrogen atom.
I), (7) -SO₂NR¹¹R¹²(R¹¹Is a hydrogen atom, C_1-4Arcoki
C which may have shi_1-4Alkyl or C_3-8Cycloa
Rukiru, R¹²Is a hydrogen atom or C_1-4Alkyl, R¹¹
And R¹²Together form a ring with the adjacent nitrogen atom
May be formed), (8) -CO₂R¹³(R¹³Is C_1-4Alkyl
), (9) hydroxyl group, C_1-4Alkoxy, C_1-4Alkyl
-Carbonyloxy, -NR^FiveCOR⁶(R^FiveAnd R⁶Is the same as above
Show meaning), -NR⁷SO₂R⁸(R⁷And R⁸Is the same meaning as above
,)-CONR⁹R^Ten(R⁹And R^TenHas the same meaning as above
),-SO₂NR ¹¹R¹²(R¹¹And R¹²Has the same meaning as above
Or) -CO₂R¹³(R¹³Has the same meaning as above)
May be C_1-4Alkoxy, (10) hydroxyl group, -NR^FiveCOR⁶
(R^FiveAnd R⁶Has the same meaning as above), -NR⁷SO₂R⁸(R⁷
And R⁸Has the same meaning as above), -CONR⁹R^Ten(R⁹And
And R^TenHas the same meaning as above), -SO₂NR¹¹R¹²(R¹¹And
And R¹²Has the same meaning as above), -CO₂R¹³(R¹³Is as above
Have the same meaning) or C_1-4May have alkoxy
I C_1-4Alkyl, (11) halogen atom, (12) hydroxyl group and
And (13) nitro (hereinafter abbreviated as Substituent group A)
Phenyl optionally having 1 to 3 substituents,
(II) 1 to 3 selected from the substituent group A and oxo
Heterocyclic group optionally having substituents, (III)
Having 1 to 3 substituents selected from Group A
Moyo C_3-8Cycloalkyl or (IV) (1) 5 to 7 membered
Nitrogen-containing heterocyclic group, (2) hydroxyl group and (3) C_1-4Alkoxy
C optionally having 1 to 3 substituents selected from_1-4
Alkyl, R³Is a hydrogen atom or C_{1 -Four}Alkyl, R^FourIs (I)
(1) C_1-4C which may have alkoxy_1-4Arcoki
Si, (2) -NR¹⁴COR¹⁵(R¹⁴Is a hydrogen atom or C_1-4Archi
Le, R¹⁵Is C_1-4Alkyl)), (3) -NR¹⁶SO₂R¹⁷(R¹⁶
Is a hydrogen atom or C_1-4Alkyl, R¹⁷Is C_1-4Alkyl
Show), (4) -CONR¹⁸R¹⁹(R¹⁸Is a hydrogen atom or C_1-4Al
Kill, R¹⁹Is C_1-4C which may have alkoxy_1-4A
Show Rukiru, R¹⁸And R¹⁹Are together and adjacent
May form a ring with elementary atoms), (5) -SO₂NR²⁰R^{twenty one}
(R²⁰Is a hydrogen atom or C_1-4Alkyl, R^{twenty one}Is C_1-4Arco
C which may have xy_1-4Alkyl, R²⁰And
And R^{twenty one}Together form a ring with the adjacent nitrogen atom
(6) (1 ') hydroxy-C_1-4Alkyl,
(2 ') C_1-4Alkoxy-carbonyl, (3 ') mono C_1-4Archi
Le-carbamoyl or (4 ') diC_1-4Alkyl-carbamoy
A 5- to 7-membered nitrogen-containing heterocyclic group which may have a
(7) C_1-4Alkoxy-carbonyl, (8) carboxyl, (9)
Mono C_1-4Alkylamino and (10) N-C_1-4Alkyl-N-C
_7-10Aralkylamino (hereinafter abbreviated as Substituent group B)
C optionally having 1 to 3 substituents selected from
_1-4Alkyl or (II) 1 selected from the above substituent group B
C optionally having 3 substituents_3-8Cycloalk
(However, R²Is mono-substituted with a halogen atom.
R when^FourIs C_1-4C substituted with an alkoxy
_1-4Not alkyl)] or a compound thereof
Salt, [2] R¹Is C_1-4Alkyl, R²Is (I) (1) amino, (2)
 Mono C_1-4Alkylamino, (3) di C_1-4Alkylami
No, (4) -NR^FiveCOR⁶(R^FiveIs a hydrogen atom or C_1-4Alkyl, R
⁶Is C_1-4Alkyl, Mono C_1-4Alkylamino or di-C
_1-4Alkylamino), (5) -NR⁷SO₂R⁸(R⁷Is hydrogen
Atom or C_1-4Alkyl, R⁸Is C_1-4Alkyl, Mono C_{1 -Four}
Alkylamino or di-C_1-4Alkylamino),
(6) -CONR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Having an alkoxy
May be C_1-4Alkyl or C_3-8Cycloalkyl, R
^TenIs a hydrogen atom or C_1-4Alkyl, R⁹And R^Ten
Together form a ring with the adjacent nitrogen atom
Good), (7) -SO₂NR¹¹R¹²(R¹¹Is a hydrogen atom, C_1-4Al
C, which may have Coxi_1-4Alkyl or C_3-8Shiku
Lower alkyl, R¹²Is a hydrogen atom or C_1-4Show alkyl
Then R¹¹And R¹²Together with the adjacent nitrogen atom
May form a ring), (8) -CO₂R¹³(R¹³Is C_1-4A
), (9) hydroxyl group, C_1-4Alkoxy, C_1-4A
Rukiru-carbonyloxy, -NR^FiveCOR⁶(R^FiveAnd R⁶Is before
Same meaning as above), -NR⁷SO₂R⁸(R⁷And R⁸Is as above
Have the same meaning), -CONR⁹R^Ten(R⁹And R^TenAgree with the above
Justify), -SO₂NR¹¹R¹²(R¹¹And R¹²Agree with the above
Meaning) or -CO₂R¹³(R¹³Means the same as above)
May have C_1-4Alkoxy, (10) hydroxyl group, -NR
^FiveCOR⁶(R^FiveAnd R⁶Has the same meaning as above), -NR⁷SO₂R⁸
(R⁷And R⁸Has the same meaning as above), -CONR⁹R^Ten(R⁹
And R^TenHas the same meaning as above), -SO₂NR¹¹R¹²(R¹¹
And R¹²Has the same meaning as above), -CO₂R¹³(R¹³Is before
Same meaning as above) or C_1-4Has an alkoxy
Moyo C_1-4Alkyl, (11) halogen atom, (12) hydroxyl group
And (13) nitro (hereinafter abbreviated as Substituent group A)
Phenyl optionally having 1 to 3 substituents selected
, (II) 1 selected from the above-mentioned substituent group A and oxo
A heterocyclic group which may have three substituents or (III)
Having 1 to 3 substituents selected from the above-mentioned substituent group A
May be C_3-8Cycloalkyl, R³Is a hydrogen atom or
C_1-4Alkyl, R^FourIs (I) (1) C_1-4Has an alkoxy
May be C_1-4Alkoxy, (2) -NR¹⁴COR¹⁵(R¹⁴Is hydrogen
Child or C_1-4Alkyl, R¹⁵Is C_1-4Represents alkyl),
(3) -NR¹⁶SO₂R¹⁷(R¹⁶Is a hydrogen atom or C_1-4Alkyl, R
¹⁷Is C_1-4Alkyl)), (4) -CONR¹⁸R¹⁹(R¹⁸Is hydrogen
Atom or C_1-4Alkyl, R¹⁹Is C_1-4Have alkoxy
May be C_1-4Alkyl, R¹⁸And R¹⁹Are together
To form a ring with the adjacent nitrogen atom.
I), (5) -SO₂NR²⁰R^{twenty one}(R²⁰Is a hydrogen atom or C_1-4Al
Kill, R^{twenty one}Is C_1-4C which may have alkoxy_1-4A
Show Rukiru, R²⁰And R^{twenty one}Are together and adjacent
May form a ring with elementary atoms), (6) 5 to 7 members
Nitrogen-containing heterocyclic group, (7) C_1-4Alkoxy-carbonyl,
(8) Carboxyl, (9) Mono C_1-4Alkylamino and (1
0) N-C_1-4Alkyl-N-C_{7- Ten}Aralkylamino (below
1 to 3 substituents selected from the group B'group)
May have C_1-4Alkyl or (II) Substituent
It may have 1 to 3 substituents selected from B'group
I C_3-8The compound according to the above [1], which is cycloalkyl,
[3] R¹Is C_1-4Alkyl, R²Is (I) (1) amino, (2) -NHC
OR^{6 '}(R^{6 '}Is C_1-4Alkyl or mono C_1-4Alkylami
No)), (3) -CONR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Arco
C which may have xy_1-4Alkyl or C_3-8Cyclo
Alkyl, R^TenIs a hydrogen atom or C_1-4Alkyl, R
⁹And R^TenTogether form a ring with the adjacent nitrogen atom
May be formed), (4) -CO₂R¹³(R¹³Is C_1-4Alkyl
), (5) hydroxyl group, C_1-4Alkoxy, C_1-4Alkyl
-Carbonyloxy, -NHSO₂R^{8 '}(R^{8 '}Is C_1-4Alkyl
Shown) or -CONR⁹R^Ten(R⁹And R^TenHas the same meaning as above
C) which may have_1-4Alkoxy, (6) hydroxy
Group, -CONR⁹R^Ten(R⁹And R^TenMeans the same as above)
Or C_1-4C which may have alkoxy_1-4Alkyl,
Selected from (7) halogen atom, (8) hydroxyl group and (9) nitro
Phenyl optionally having 1 to 3 substituents,
(II) (1) -CONR⁹R^Ten(R⁹And R^TenHas the same meaning as above
C) which may have_1-4Alkyl, (2) C_1-4Archi
Le-carbonyloxy or -CONR⁹R^Ten(R⁹And R^TenIs
C having the same meaning as above)_{1 -Four}Arcoki
Having a (3) halogen atom, (4) hydroxyl group or (5) oxo
Optionally a 5- to 8-membered nitrogen-containing heterocyclic group, (III) hydroxy
C which may have a group_3-8Cycloalkyl or (I
V) (1) 5- to 7-membered nitrogen-containing heterocyclic group, (2) hydroxyl group and
(3) C_1-41 to 3 substituents selected from alkoxy
You may have C_1-4Alkyl, R³Is a hydrogen atom or C
_1-4Alkyl, R^FourIs (I) (1) C_1-4Has an alkoxy
Moyo C_1-4Alkoxy, (2) -NR¹⁴COR¹⁵(R¹⁴Is a hydrogen atom
Or C_1-4Alkyl, R¹⁵Is C _1-4Indicates alkyl), (3)
-NR¹⁶SO₂R¹⁷(R¹⁶Is a hydrogen atom or C_1-4Alkyl, R^{1 7}
Is C_1-4Alkyl)), (4) -CONR¹⁸R¹⁹(R¹⁸Is hydrogen
Child or C_1-4Alkyl, R¹⁹Is C_1-4Having an alkoxy
May be C_1-4Alkyl, R¹⁸And R¹⁹Together
And form a ring with the adjacent nitrogen atom.
I), (5) (1 ') hydroxy-C_1-4Alkyl, (2 ') C_1-4Al
Coxy-carbonyl or (3 ') mono C_1-4Alkyl-carb
5- to 7-membered nitrogen-containing heterocycle optionally having moyl
Base, (6) C_1-4Alkoxy-carbonyl, (7) carboxy
Le, (8) Mono C_1-4Alkylamino and (9) N-C_1-4Archi
Le-N-C_7-101 to 3 selected from aralkylamino
C which may have a substituent_1-4Alkyl or (II) C_3-8
The compound according to the above [1], which is cycloalkyl, [4]
R¹The compound according to the above [1], wherein is ethyl. [5] R²But
(1) Amino, (2) -NHCOR^{6 '}(R^{6 '}Is C_1-4Alkyl or mo
No C_1-4Alkylamino), (3) -CONR^{9 '}R^Ten'(R^{9 '}
Is a hydrogen atom, C_1-4Alkyl or C_3-8Cycloalkyl,
R^Ten'Is a hydrogen atom or C_1-4Alkyl, R^{9 '}And R
^Ten'Together form a ring with an adjacent nitrogen atom
May be), (4) -CO₂R¹³(R^{1 3}Is C_1-4Show alkyl
), (5) hydroxyl group, C_1-4Alkoxy, C_1-4Alkyl-cal
Bonyloxy or -CONR^{9 '}R^Ten'(R^{9 '}And R^Ten'Is the above
C has the same meaning as_1-4Alkoxy,
(6) Hydroxyl group or -CONR^{9 '}R^Ten'(R^{9 '}And R^Ten'Is as above
C may have the same meaning)_1-4Alkyl, (7)
Selected from halogen atom, (8) hydroxyl group and (9) nitro
It is phenyl which may have 1 to 3 substituents.
The compound described in [1] above, [6] R³Is methyl
[1] described compound, [7] R^FourIs (1) -NR¹⁴COR¹⁵(R¹⁴Is
Hydrogen atom or C_1-4Alkyl, R¹⁵Is C_1-4Show alkyl
), (2) -NR¹⁶SO₂R¹⁷(R¹⁶Is a hydrogen atom or C_1-4Al
Kill, R¹⁷Is C_1-4Alkyl)), (3) -CONR¹⁸R¹⁹(R
¹⁸Is a hydrogen atom or C_1-4Alkyl, R¹⁹Is C _1-4Arcoki
C which may have shi_1-4Alkyl, R¹⁸And R
¹⁹Together form a ring with the adjacent nitrogen atom
(4) 5 to 7-membered nitrogen-containing heterocyclic group, (5) C_1-4
Alkoxy-carbonyl, (6) carboxyl, (7) mono C
_1-4Alkylamino and (8) N-C_1-4Alkyl-N-C_7-10A
Having 1 to 3 substituents selected from aralkylamino
May be C_1-4The compound according to the above [1], which is alkyl
Things, [8] R^FourIs C_1-4C substituted with an alkoxy_1-4Archi
A compound according to the above [1] which is

[9] The compound described in [1] above, wherein R ⁴ is 2-methoxyethyl, [10] R ¹ is ethyl, R ² is (1) amino, (2) -NHCOR ^{6 ′} (R ^{6 ′} is C _{1 -4} alkyl or mono C _1-4 alkylamino), (3) -CONR
^{9 'R 10' (R 9} ' is hydrogen atom, C _1-4 alkyl or C _3-8 cycloalkyl, R ^10' represents a hydrogen atom or C _1-4 alkyl, R ^{9 'and} R ^10' are together May form a ring with an adjacent nitrogen atom), (4) -CO ₂ R ¹³ (R ¹³ is C _1-4
Alkyl), (5) hydroxyl group, C _1-4 alkoxy, C _1-4
Alkyl - carbonyloxy or ^{-CONR 9 'R 10' (R} 9 ' and R ^10' is as defined above) which may have a C
C _1-4 which may have _1-4 alkoxy, (6) hydroxyl group or -CONR ^{9 ′} R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as described above)
Alkyl, (7) halogen atom, (8) hydroxyl group and (9) phenyl optionally having 1 to 3 substituents selected from nitro, R ³ is methyl, R ⁴ is (1) -NR ¹⁴ COR ¹⁵ (R ¹⁴ is a hydrogen atom or a C _{1 -4} alkyl, R ¹⁵ represents a C _1-4 ^{alkyl), (2) -NR 16 SO} 2 R 17 (R 16 is a hydrogen atom or C _1-4 alkyl, R ¹⁷ represents C _1-4 alkyl), (3) -CONR ¹⁸ R ¹⁹ (R
¹⁸ represents a hydrogen atom or C _1-4 alkyl, R ¹⁹ is optionally C _1-4 alkyl optionally having C _1-4 alkoxy, R ¹⁸ and R
¹⁹ may together form a ring with an adjacent nitrogen atom), (4) a 5- to 7-membered nitrogen-containing heterocyclic group, (5) C _1-4
Alkoxy-carbonyl, (6) carboxyl, (7) mono C
_1-4 alkylamino and (8) NC _1-4 alkyl -NC _7-10 wherein also optionally C _1-4 alkyl optionally having 1 to 3 substituents selected from aralkylamino [1] Compound, [11] R ¹ is ethyl, R ² is (1) amino, (2) -NHCOR
^{6 '(R 6'} represents a C _1-4 alkyl or mono C _1-4 ^{alkylamino), (3) -CONR 9 '} R 10' (R 9 ' is hydrogen atom, C _1-4 alkyl or C _{3 -8} cycloalkyl, R ^{10 '} is a hydrogen atom or
C _1-4 alkyl, R ^{9 '} and R ^10' may together form a ring with an adjacent nitrogen atom), (4) -CO
₂ R ¹³ (R ¹³ represents C _1-4 alkyl), (5) hydroxyl group, C _1-4 alkoxy, C _1-4 alkyl-carbonyloxy or —CONR
C _1-4 alkoxy optionally having ^{9 ′} R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as described above), (6) hydroxyl group or —CONR ^{9 ′}
R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as defined above) optionally selected from C _1-4 alkyl, (7) halogen atom, (8) hydroxyl group and (9) nitro. [12] 2- [4-, wherein the phenyl optionally has 1 to 3 substituents, R ³ is methyl, and R ⁴ is 2-methoxyethyl.
(1- (2,6-difluorobenzyl) -6- (4- {[(ethylamino)
Carbonyl] amino} phenyl) -5- {[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidine-3 (2H)- Il) phenyl] -N-
Methylacetamide, 2- [4- (1- (2,6-difluorobenzyl)
-6- (4-{[(ethylamino) carbonyl] amino} phenyl)-
5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-
Dioxo-1,4-dihydrothieno [2,3-d] pyrimidine-3 (2H)
-Yl) phenoxy] -N-ethylacetamide, N- {4- [1- (2,6
-Difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -3- (4-methoxy-3-methylphenyl)-
2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N- {4- [1-
(2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-
({Methyl [2- (2-oxo-1-piperidinyl) ethyl] amino}
Methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,
3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N
-{4- [1- (2,6-Difluorobenzyl) -3- [4- (2-methoxyethoxy) phenyl] -5-({methyl [2- (2-oxo-1-piperidinyl) ethyl] amino } Methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl}
-N'-ethylurea, N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- (4-fluorophenyl ) -2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl}
(Methyl) amino] ethyl} -N-methylsulfonamide, N-
{2-[({1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- [4- (2-methoxyethoxy) phenyl] -2 , 4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl} methyl) (methyl) amino] ethyl} -N-methylsulfonamide, N- [4- ( 1- (2,6-
Difluorobenzyl) -5-{[[2- (2-methoxyethoxy) ethyl] (methyl) amino] methyl} -2,4-dioxo-3phenyl
-1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5] -{[(2-Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) Phenyl] -N'-
Ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5-
{[(2-Ethoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (2-pyridyl) -1,2,3,4-tetrahydrothieno
[2,3-d] Pyrimidin-6-yl) phenyl] -N'-ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl ) Amino] methyl} -2,4-dioxo-3-
(5-methyl-2-pyridyl) -1,2,3,4-tetrahydrothieno
[2,3-d] Pyrimidin-6-yl) phenyl] -N'-ethylurea or N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-
Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo
-3- (6-methyl-2-pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea or salts thereof, [13 ] A prodrug of the compound described in [1] above, [14] A compound comprising the compound described in [1] above or a prodrug thereof, [15] The above [14] which is a gonadotropin-releasing hormone antagonist. [16] The drug according to [14] above, which is a prophylactic / therapeutic agent for sex hormone-dependent diseases, [17] sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, benign prostatic hyperplasia, uterine fibroids, Endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease, infertility, hypersensitivity If benign, enteropathy syndrome or hormone independent and LH-RH sensitive Or a preventive / therapeutic agent for malignant tumor, a reproductive regulator, a contraceptive, an ovulation inducer, or a sex hormone-dependent cancer postoperative recurrence preventive agent [1.
[4] The pharmaceutical composition according to [4], [18] a method for antagonizing gonadotropin-releasing hormone, which comprises administering to a mammal an effective amount of the compound according to [1], [19] gonadotropin-releasing hormone It relates to the use of the compound according to the above [1] for producing an antagonist and the like.

The definition of each substituent in the above formula is shown below.
In the present specification, the term “C _1-4 alkyl” means, for example, linear C _1-4
Alkyl (eg, methyl, ethyl, propyl, butyl, etc.), branched C _3-4 alkyl (eg, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) and the like can be mentioned.

In the present specification, "C _3-8 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include cyclohexyl, cycloheptyl, cyclooctyl and the like.

In the present specification, "mono C _1-4 alkylamino"
Examples of are, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino and the like.

In the present specification, "di C _1-4 alkylamino" means, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, N-ethyl-N-methylamino, N- Methyl-N-propylamino, N-ethyl-N-propylamino and the like can be mentioned.

In the present specification, "NC _1-4 alkyl-NC _7-10 aralkylamino" means, for example, N-benzyl-N-methylamino, N-benzyl-N-ethylamino, N-benzyl-N- Propylamino, N-methyl-N-phenethylamino, N-ethyl-
N-phenethylamino and the like can be mentioned.

In the present specification, "C _1-4 alkoxy" means, for example, linear C _1-4 alkoxy (eg, methoxy, ethoxy,
Propoxy, butoxy, etc.), branched C _3-4 alkoxy (eg, isopropoxy, isobutoxy, sec-butoxy,
tert-butoxy etc.) and the like.

In the present specification, "C _1-4 alkyl-carbonyloxy" means, for example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyl. Oxy, tert-butylcarbonyloxy and the like can be mentioned.

In the present specification, "C _1-4 alkoxy-carbonyl" means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, se.
Examples thereof include c-butoxycarbonyl and tert-butoxycarbonyl.

In the present specification, the "halogen atom" includes, for example, fluorine, chlorine, bromine, iodine and the like.

In the present specification, "hydroxy-C _1-4 alkyl" means, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-
Examples thereof include hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl and the like.

In the present specification, "mono C _1-4 alkyl-carbamoyl" means, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl. And so on.

In the present specification, examples of the “di C _1-4 alkyl-carbamoyl” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, N-ethyl-N-methylcarbamoyl and the like.

In the present specification, "a ring formed by R ⁹ and R ¹⁰ together with an adjacent nitrogen atom", "a ring formed by R ¹¹ and R ¹² together with an adjacent nitrogen atom", Examples of the “ring formed by R ¹⁸ and R ¹⁹ together with the adjacent nitrogen atom” and the “ring formed by R ²⁰ and R ²¹ together with the adjacent nitrogen atom” include, for example, a 5- or 6-membered ring. Examples thereof include nitrogen-containing heterocycles (pyrrolidine, piperidine, morpholine, 2-oxopyrrolidine, 2-oxopiperidine, oxazolidinone, etc.).

In the present specification, the “heterocyclic group” represented by R ² includes an aromatic heterocyclic group or a non-aromatic heterocyclic group.

Examples of the "aromatic heterocyclic group" include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 3,4-oxadiazolyl, flazanil, 1,2,3-
Thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
5- or 6-membered aromatic monocyclic heterocyclic group such as tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and, for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, Benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, Phtharazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenato. Lydinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2-
a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 8- to 12-membered fused aromatic heterocyclic group such as 1,2,4-triazolo [4,3- b ] pyridazinyl (preferably the 5- or 6-membered aromatic monocyclic heterocyclic group described above is a benzene ring) A heterocycle condensed with or a heterocycle in which two identical or different heterocycles of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group are condensed, more preferably a 5- or 6-membered aromatic monocycle described above. A heterocycle in which the formula heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl, benzopyranyl, benzo [ b ] thienyl, etc.) and the like can be mentioned.

Examples of the "non-aromatic heterocyclic group" include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl,
3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group such as piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-hexahydrocyclopenta [ c ] pyrrolyl, homopiperidyl, homopiperazyl, etc., or dihydropyridyl , Dihydropyrimidyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl and the like aromatic monocyclic heterocyclic groups or aromatic condensed heterocycles described above. Examples thereof include non-aromatic heterocyclic groups in which a part or all of the double bonds are saturated. Among them, the “heterocyclic group” represented by R ² is preferably a 5- to 8-membered nitrogen-containing heterocyclic group, and particularly pyridyl, dihydropyrimidyl, piperidyl, pyrrolyl, morpholyl, 3-
Hexahydrocyclopenta [ c ] pyrrolyl, homopiperidyl and the like are preferable.

In the present specification, “5” used in the substituent group B is used.
To 7-membered nitrogen-containing heterocyclic group, for example, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2
-Oxopyrrolidin-1-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1-methylsulfonylpyrrolidin-2-yl,
1-methylsulfonylpyrrolidin-3-yl, 1-methyl-2-oxopyrrolidin-3-yl, 2-oxo-1,3-oxazolidine
-3-yl, oxazolidin-3-yl, thiazolidin-3-yl, isoxazolidin-2-yl, isothiazolidin-2-
2-oxo-1,3-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl, 1,1-dioxoisothiazolidin-2-yl, 2-oxo-1,3-oxazoline -3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidine-3
-Yl, pyrazolidin-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-1-yl , Pyrazol-3-yl, pyrazol-4-yl, 1,2,3-triazol-1-yl, 1,2,5-triazol-
1-yl, tetrazol-1-yl, tetrazol-2-yl,
Tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazole
-3-yl, isoxazol-4-yl, isoxazole
-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, piperidin-1-
Il, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl,
Pyrimidin-4-yl, Pyrimidin-5-yl, Pyridazin-3
-Yl, pyridazin-4-yl, etc., among them,
2-oxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1
-Methylsulfonylpyrrolidin-2-yl, 1,1-dioxoisothiazolidin-2-yl, pyridin-2-yl, pyridine-3
-Yl, pyridin-4-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,2,3-triazol-1-yl, 1,2,5-triazol-1-yl , Tetrazol-1-yl, tetrazol-2-yl, tetrazole-5-
And the like are preferred. Particularly, 1-methylsulfonylpyrrolidin-2-yl, 1,1-dioxo-isothiazolidin-2-yl, 1-methyl-2-oxopyrrolidin-3-yl and the like are preferable.

As R ¹ , linear C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.) is preferable, and ethyl is particularly preferable.

[R]²As (I) (1) amino, (2) -NHCOR^{6 '}
(R^{6 '}Is C_1-4Alkyl or mono C_{1- Four}Alkylamino
Shown), (3) -CONR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Alkoxy
May have C_1-4Alkyl or C_3-8Cycloal
Kill, R^TenIs a hydrogen atom or C _1-4Alkyl, R⁹Oh
And R^TenTogether form a ring with the adjacent nitrogen atom
May be formed), (4) -CO₂R¹³(R¹³Is C_1-4Alkyl
Shown), (5) hydroxyl group, C_{1- Four}Alkoxy, C_1-4Alkyl-
Carbonyloxy, -NHSO₂R^{8 '}(R^{8 '}Is C_1-4Show alkyl
Or) -CONR⁹R^Ten(R⁹And R^TenHas the same meaning as above
C) which may have_1-4Alkoxy, (6) hydroxyl group,
-CONR⁹R^Ten(R⁹And R^TenHas the same meaning as above) or
C_1-4C which may have alkoxy_1-4Alkyl, (7)
Selected from halogen atom, (8) hydroxyl group and (9) nitro
Phenyl optionally having 1 to 3 substituents, (II)
(1) -CONR⁹R^Ten(R⁹And R^TenMeans the same as above)
You may have C_1-4Alkyl, (2) C_1-4Alkyl-cal
Bonyloxy or -CONR⁹R^Ten(R⁹And R^TenIs the same as above
C) which may have meaning)_1-4Alkoxy (3)
Even if it has a rogen atom, (4) hydroxyl group or (5) oxo
A good 5- to 8-membered nitrogen-containing heterocyclic group, (III) C_3-8Cycloa
Rukyl or (IV) (1) 5- to 7-membered nitrogen-containing heterocyclic group,
(2) hydroxyl group and (3) C_1-4No one selected from alkoxy
C optionally having 3 substituents_1-4Alkyl preferred
Good Among them, (1) amino, (2) -NHCOR^{6 '}(R^{6 '}Is C_1-4
Alkyl or mono C_1-4Alkylamino)), (3)-
CONR^{9 '}R^Ten'(R^{9 '}Is a hydrogen atom, C_1-4Alkyl or C_{3- 8}
Cycloalkyl, R^Ten'Is a hydrogen atom or C_1-4Alkyl
Shows, R^{9 '}And R^Ten'Are adjacent nitrogen atoms together
May form a ring with), (4) -CO₂R¹³(R^{1 3}Is C
_1-4Alkyl)), (5) hydroxyl group, C_1-4Alkoxy, C
_1-4Alkyl-carbonyloxy or -CONR^{9 '}R^Ten'(R^{9 '}
And R^Ten'Have the same meaning as described above)
C_1-4Alkoxy, (6) hydroxyl group or -CONR^{9 '}R^Ten'(R^{9 '}Oh
And R^Ten'Has the same meaning as above) C
_1-4Alkyl, (7) halogen atom, (8) hydroxyl group and (9) diamine
It may have 1 to 3 substituents selected from Toro
More preferred is phenyl. Also, C_1-4Have alkyl
Pyridyl which may be present is also preferred.

R ³ is preferably C _1-4 alkyl, and more preferably linear C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.). Especially, methyl is preferable.

Examples of the R ^4, (indicating the R ¹⁴ is a hydrogen atom or C _1-4 alkyl, R ¹⁵ is C _{1 -4} alkyl) (I) (1) -NR 14 COR 15, (2) -NR 16 SO ₂ R ¹⁷ (R ¹⁶ represents a hydrogen atom or C _1-4 alkyl, R ¹⁷ represents C _1-4 alkyl), (3) -CONR ¹⁸ R ¹⁹ (R
¹⁸ represents a hydrogen atom or C _1-4 alkyl, R ¹⁹ is optionally C _1-4 alkyl optionally having C _1-4 alkoxy, R ¹⁸ and R
¹⁹ may together form a ring with an adjacent nitrogen atom), (4) a 5- to 7-membered nitrogen-containing heterocyclic group, (5) C _1-4
Alkoxy-carbonyl, (6) carboxyl, (7) mono C
_1-4 alkylamino and (8) NC _1-4 alkyl-NC _7-10 C _1-4 alkyl optionally having 1 to 3 substituents selected from aralkylamino or (II) C _1- C _1-4 alkyl substituted with ₄ alkoxy (especially 2-methoxyethyl) is preferred.

Among the present compounds, the preferred form is
[1] R ¹ is ethyl, R ² is (1) amino, (2) -NHCOR ^{6 ′} (R ^{6 ′}
_Represents C _1-4 alkyl or mono C _1-4 alkylamino), (3) -CONR ^{9 ′} R ^{10 ′} (R ^{9 ′} is a hydrogen atom, C _1-4 alkyl or C _3-8 cycloalkyl, R ^{10 '} is a hydrogen atom or C _1-4
An alkyl, R ^{9 'and} R ^10' may form a ring together with the adjacent nitrogen atom _{together), (4) -CO 2 R} 13
(R ¹³ represents C _1-4 alkyl), (5) hydroxyl group, C _1-4 alkoxy, C _1-4 alkyl-carbonyloxy or —CONR ^{9 ′}
C _1-4 alkoxy optionally having R ^{10 ′} (R ^{9 ′} and R ^{10 ′} are as defined above), (6) hydroxyl group or —CONR ^{9 ′} R
^{1 ′} selected from C _1-4 alkyl _optionally having ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as described above), (7) halogen atom, (8) hydroxyl group and (9) nitro. To phenyl optionally having 3 substituents, R ³ is methyl, R ⁴ is (1) -NR ¹⁴ CO
R ¹⁵ (R ¹⁴ is a hydrogen atom or a C _{1 -4} alkyl, R ¹⁵ represents a C _1-4 ^{alkyl), (2) -NR 16 SO} 2 R 17 (R 16 is a hydrogen atom or C _1-4 alkyl, R ¹⁷ represents C _1-4 alkyl), (3) -CON
R ¹⁸ R ¹⁹ (R ¹⁸ is a hydrogen atom or C _1-4 alkyl, R ¹⁹ is C _1-4
R represents C _1-4 alkyl which may have alkoxy, R
¹⁸ and R ¹⁹ may together form a ring with an adjacent nitrogen atom), (4) a 5- to 7-membered nitrogen-containing heterocyclic group, (5) C _1-4 alkoxy-carbonyl, (6 ) carboxyl, (7) mono C _1-4 alkylamino and (8) NC _1-4 alkyl -NC _7-10 to 1 is aralkyl amino optionally having three substituents C _1-4 Compounds that are alkyl
(I) or [2] R ¹ is ethyl, R ² is (1) amino, (2) -N
HCOR ^{6 '(R 6'} represents a C _1-4 alkyl or mono C _1-4 ^{alkylamino), (3) -CONR 9 '} R 10' (R 9 ' is hydrogen atom, C _1-4
Alkyl or C _3-8 cycloalkyl, R ^{10 ′} represents a hydrogen atom or C _1-4 alkyl, and R ^{9 ′} and R ^{10 ′} together may form a ring with the adjacent nitrogen atom), (Four)-
CO ₂ R ¹³ (R ¹³ represents C _1-4 alkyl), (5) hydroxyl group, C
_1-4 alkoxy, C _1-4 alkyl-carbonyloxy or
^{-CONR 9 'R 10' (R} 9 ' and R ^10' are as defined above shows a) optionally C _1-4 alkoxy optionally having, (6) hydroxy group or -C
ONR ^{9 ′} R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as described above) _optionally C _1-4 alkyl, (7) halogen atom, (8) hydroxyl group and (9) nitro The compound (I) is phenyl which may have 1 to 3 substituents selected from R ³ , R ³ is methyl, and R ⁴ is 2-methoxyethyl.

More specifically, 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5- {[(2 -Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d]
Pyrimidin-3 (2H) -yl) phenyl] -N-methylacetamide, 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-
Dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenoxy] -N-ethylacetamide, N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl ) (Methyl) amino] methyl} -3- (4-methoxy-3-methylphenyl) -2,4-dioxo
-1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N- {4- [1- (2,6-difluorobenzyl) -3 -(4-fluorophenyl) -5-({methyl [2-
(2-oxo-1-piperidinyl) ethyl] amino} methyl) -2,4
-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N- {4- [1- (2,
6-difluorobenzyl) -3- [4- (2-methoxyethoxy) phenyl] -5-({methyl [2- (2-oxo-1-piperidinyl) ethyl] amino} methyl) -2,4-dioxo- 1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N- {2-[{[1- (2,6-difluorobenzyl)- 6- (4-
{[(Ethylamino) carbonyl] amino} phenyl) -3- (4-
(Fluorophenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} -N-methylsulfonamide, N -{2-[({1- (2,
6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- [4- (2-methoxyethoxy) phenyl] -2,4-dioxo-1,2,3, 4-tetrahydrothieno [2,
3-d] pyrimidin-5-yl} methyl) (methyl) amino] ethyl} -N-methylsulfonamide, N- [4- (1- (2,6-difluorobenzyl) -5-{[[2- (2-Methoxyethoxy) ethyl] (methyl) amino] methyl} -2,4-dioxo-3phenyl-1,2,3,4
-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl ) (Methyl) amino] methyl}-
2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno
[2,3-d] Pyrimidin-6-yl) phenyl] -N'-ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-ethoxyethyl) (methyl ) Amino] methyl} -2,4-dioxo-3-
(2-Pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea, N- [4- (1-
(2,6-difluorobenzyl) -5-{[(2-methoxyethyl)
(Methyl) amino] methyl} -2,4-dioxo-3- (5-methyl-2-
Pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea or N- [4-
(1- (2,6-Difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (6-methyl
-2-Pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea or salts thereof are mentioned as examples of preferred compounds.

The salt of compound (I) is preferably a physiologically acceptable acid addition salt. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.), or organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid). Acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.)
Salt and the like are used. When the compound (I) has an acidic group, an inorganic base (eg, alkali metal salt or alkaline earth metal such as sodium, potassium, calcium, magnesium, ammonia, etc.) or an organic base (eg, trimethylamine, triethylamine) , Pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Physiologically acceptable salts with N, N'-dibenzylethylenediamine).

The compound (I) can be produced, for example, by the following production method 1 and production method 2. The compound in the reaction scheme may form a salt, and examples of the salt include the same as the salt of compound (I). Hereinafter, the compound (I) to the compound (VI) are meant to include those salts. (Production method 1)

[Chemical 4] [In the formula, L represents a leaving group, and other symbols have the same meanings as described above. ]

The "leaving group" represented by L is, for example, a halogen atom or C which may have a halogen atom.
_1-4 alkylsulfonyloxy and the like can be mentioned. Examples of the “C _1-4 alkylsulfonyloxy optionally having a halogen atom” include methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy and the like.

Compound (II) is described in JP-A-2001-278884, W
It can be produced by the method described in O00 / 56739 or a method analogous thereto. For example, compound (I)
Can be produced by reacting compound (II) with a compound represented by R ⁴ -L. The reaction is preferably carried out in the presence of a base. Examples of the "base" include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, or organic bases such as triethylamine, diisopropylethylamine and pyridine. A base is used. Compound (II), in the reaction with the compound represented by R ⁴ -L, amount of the compound represented by R ⁴ -L is about 1 to about 3 moles relative to compound (II) 1 mol . The amount of the base used is approximately 1 to approximately 3 mol with respect to 1 mol of the compound (II). This reaction is generally carried out in a suitable solvent that does not affect the reaction. As the “solvent”,
For example, ethers (eg, diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons Type (eg, chloroform,
Dichloromethane etc.) and the like are used. The reaction temperature is generally about 0 to about 150 ° C, preferably about 50 to about 80 ° C. The reaction time is usually about 1 to about 24 hours.

Compound (II) can also be produced by the following production method.

[Chemical 5] [In the formula, R ^a represents C _1-4 alkyl, R ^b represents C _1-4 alkyl or benzyl, R ^c represents C _1-4 alkyl, and other symbols have the same meanings as described above. The “C _1-4 alkyl” represented by R ^a , R ^b and R ^c is, for example, straight chain C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.), branched C _{3 -4} alkyl (eg, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) and the like.

Compound (III) is described in JP-A-2001-278884,
It can be produced by the method described in WO00 / 56739 or a method analogous thereto. Compound (IV) is a compound
It can be produced by stirring (III) and the compound represented by R ^c -I in a solvent. The amount of the compound represented by R ^c -I is
It is about 1 to about 3 mol per 1 mol of the compound (III). This reaction is generally carried out in a suitable solvent that does not affect the reaction. Examples of the “solvent” include ethers (eg,
Diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc., aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane) Etc.) are used. The reaction temperature is generally about 0 to about 150 ° C, preferably about 50 to about 80 ° C. Reaction time is usually about 1 to about
24 hours.

The compound (II) is converted into the compound (IV) in the presence of a base.
It can be produced by reacting with a compound represented by R ³ —NH ₂ . Examples of the "base" include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, or organic bases such as triethylamine, diisopropylethylamine and pyridine. A base is used. Compound (IV) and the amount of the compound represented by R ³ -NH ₂ in the reaction with the compound represented by R ³ -NH ₂ is about 1 to about 10 moles relative to the compound (IV) 1 mole .
The amount of the base used is about 1 to about 10 per 1 mol of compound (IV).
It is a mole. This reaction is generally carried out in a suitable solvent that does not affect the reaction. Examples of the “solvent” include:
Ethers (eg, diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons ( (Eg, chloroform, dichloromethane, etc.) and the like are used. The reaction temperature is usually
It is about 0 to about 150 ° C, preferably about 80 to about 120 ° C.
The reaction time is usually about 1 to about 6 hours. Compound (I), (II)
And (IV) can be isolated and purified by a separation means known per se, for example, recrystallization, distillation, chromatography and the like.

(Production method 2)

[Chemical 6] [In the formula, R ^d represents a hydrogen atom or C _1-4 alkyl, and R ^e represents C _1-4.
Alkyl and other symbols are as defined above. ] C _1-4 alkyl represented by R ^d and R ^e is, for example, a straight chain
C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.), branched C _3-4 alkyl (eg, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) and the like can be mentioned.

Compound (V) is reacted with a known method, for example, by reacting p-nitrophenylacetone, a cyanoacetic acid ester derivative and sulfur (eg, Chem. Ber., 99, 94-100,
1966), and the resulting 2-amino-4-methyl-5- (4-nitrophenyl) thiophene was prepared according to JP-A-9-169768, WO 96/24.
It can be obtained by applying the method described in Japanese Patent No. 597 or the like or a method analogous thereto.

When R ^d is a hydrogen atom, the compound (V) is reacted with a compound represented by R ² —NH ₂ or a salt thereof in the presence of a condensation reagent to obtain a compound (VI), followed by a ring closure reaction. Attached to
Compound (I) is obtained. Examples of the “condensation reagent” include W
SC (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), diethyl cyanophosphate, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (benzotriazol) -1-yloxy
tripyrrolidinophosphonium hexafluorophosphate: PyB
OP) and the like. The amount of the “condensation reagent” used is about 1 to about 3 mol with respect to 1 mol of the compound (V). This reaction is
It is usually carried out in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (eg, ethanol, methanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons. (Eg, chloroform, dichloromethane, etc.) and the like are used. The reaction temperature is generally about 0 to about 150 ° C, preferably about 0 to about 25 ° C. The reaction time is usually about 1 to
It's about 36 hours. The product can be used as it is in the reaction solution or as a crude product in the next reaction, or can be isolated from the reaction mixture according to a conventional method.

Compound (VI) is subjected to a ring closure reaction in the presence of a base. Examples of the "base" include inorganic bases such as sodium methoxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and thallium hydroxide, or organic bases such as triethylamine and pyridine. A base is used. The amount of the “base” used is approximately 2 mol to approximately 20 mol, preferably approximately 5 mol to approximately 12 mol, with respect to 1 mol of the compound (VI).
This reaction is usually carried out in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (eg, ethanol, methanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons. (Eg, chloroform, dichloromethane, etc.) and the like are used. The reaction temperature is usually about 0 to about 1.
50 ° C., preferably at room temperature (about 15 to about 25 ° C.).
The reaction time is usually about 1 to about 36 hours.

When R ^d is an alkyl group, compound (I) is obtained by activating R ² —NH ₂ and reacting with compound (V). Activation of R ² —NH ₂ can be performed according to a method known per se. For example, the compound R ² —NH ₂ is reacted with the organoaluminum reagent in a suitable solvent that does not adversely influence the reaction. As the “organoaluminum reagent”, for example,
Examples include trimethylaluminum, dimethylaluminum chloride, and the like, or solutions containing these. The amount of the “organoaluminum reagent” used is the amount of the compound R ²
It is about 1 to about 5 mol, preferably about 1 mol, relative to 1 mol of —NH ₂ . As the solvent, for example, halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) are preferable. The reaction temperature is generally about 0 to about 150 ° C., preferably about 0.
~ About 25 ℃. The reaction time is usually about 1 to about 6 hours. By activating the compound R ² —NH ₂ and reacting it with the compound (V), a ring closure reaction is carried out to obtain the compound (I). The amount of the "compound (V)" used is preferably about 1/5 based on the mixture of the compound R ² -NH ₂ and the organoaluminum reagent. This reaction is usually carried out in a suitable solvent that does not adversely influence the reaction. As the solvent, the solvent used when activating the compound R ² —NH ₂ is preferable. The reaction temperature is
Usually, it is about 0 to 150 ° C, preferably about 0 to 25 ° C. The reaction time is usually about 1 to 48 hours.

Compound (I) is isolated by a separation means known per se, for example, recrystallization, distillation, chromatography and the like,
It can be purified. When the compound (I) is obtained in a free form, it can be converted into a desired salt by a method known per se or a method analogous thereto, and conversely, when it is obtained as a salt, a method known per se. Alternatively, it can be converted into the free form or other desired salt by a method similar thereto. The compound (I) may be hydrate or non-hydrate. Examples of the hydrate include monohydrate, sesquihydrate and dihydrate. When the compound (I) is obtained as a mixture of optically active substances, the target is obtained by an optical resolution means known per se (R).
It can be separated into the body or the (S) body. Compound (I) is
It may be used as a prodrug, and as such a prodrug, a compound that is converted into a compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, enzymatically causes oxidation, reduction, hydrolysis, etc. Compound (I)
A compound that changes into a compound (I) by being hydrolyzed by gastric acid or the like. As a prodrug of compound (I), the amino group of compound (I) is acylated,
Alkylated, phosphorylated compound (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxy Carbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (Example, a compound in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); Esterified or amidated compounds (eg, carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl ether Ether, dimethylaminomethyl ester, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,
Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds and the like); and the like. These compounds can be produced from the compound of the present invention by a method known per se. Further, the prodrug of the compound of the present invention is one which is changed to the compound of the present invention under physiological conditions as described in Hirokawa Shoten 1990 "Development of Pharmaceuticals" Volume 7 Molecular Design, pages 163 to 198. May be The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S) and the like.

In each of the above reactions, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group after the reaction, if necessary. Examples of the amino group-protecting group include optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, propionyl, etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl). , Tert-butoxycarbonyl, etc.), phenyloxycarbonyl (eg, benzoxycarbonyl, etc.),
C _7-14 aralkyloxycarbonyl (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl and the like are used. These substituents include halogen atoms (for example, fluorine,
Chlorine, bromine, iodine etc.), C _1-6 alkylcarbonyl (eg acetyl, propionyl, butyryl etc.),
A nitro group or the like is used, and the number of substituents is about 1 to 3. Examples of the carboxyl group-protecting group include optionally substituted C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like.
As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), formyl, nitro group, etc. are used. The number of is about 1 to 3. Examples of the hydroxyl-protecting group include optionally substituted C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-
Butyl, etc.), phenyl, C _7-10 aralkyl (eg,
Benzyl etc., C _1-6 alkylcarbonyl (eg acetyl, propionyl etc.), formyl, phenyloxycarbonyl, C _7-10 aralkyloxycarbonyl (eg benzyloxycarbonyl etc.), pyranyl, furanyl, silyl etc. are used. . As these substituents, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group, etc. are used, and the number of substituents is 1 to There are about four. In addition, as a method for introducing and removing a protecting group, a method known per se or a method analogous thereto (for example, the method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press)) is used, As a removing method, for example, a method of treating with acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

The compound (I) of the present invention and salts thereof (hereinafter referred to as
"Compound of the present invention" may be abbreviated) is an excellent Gn
Has RH antagonism and low toxicity. Moreover, it is excellent in oral absorbability and duration of action, and also excellent in stability and pharmacokinetics. In mammals (eg, humans, monkeys, cows, horses, dogs, cats, rabbits, rats, mice, etc.), GnRH receptor antagonism suppresses gonadotropin secretion and regulates blood sex hormone levels Therefore, it can be safely used for the prophylaxis / treatment of male and female hormone-dependent diseases and the prophylaxis / treatment of diseases caused by excess of these hormones. For example, the compound of the present invention is used for sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), sex hormone-dependent cancer bone metastasis, benign prostatic hyperplasia, uterine fibroids, endometriosis, Uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease (Alzheimer's disease, Alzheimer-type senile dementia) And / or prevention of sex hormone-dependent diseases such as
Useful for treatment. In addition, the compound of the present invention is also useful for regulation of reproduction in males and females (eg, pregnancy regulator, menstrual cycle regulator, etc.). The compound of the present invention can be further used as a contraceptive agent for men and women, and as an ovulation inducer for women. The compound of the present invention can be used for treating infertility by utilizing the rebound effect after withdrawal. It can also be used as a prophylactic / therapeutic agent for benign or malignant tumors that are sex hormone independent and LH-RH sensitive. Further, the compound of the present invention is a preventive / therapeutic agent for irritable bowel syndrome and a preventive agent for postoperative recurrence of sex hormone-dependent cancer (prostatic cancer postoperative recurrence preventive agent, premenopausal and postmenopausal breast cancer or ovarian cancer postoperative recurrence preventive agent). It is also possible to use as a drug, etc., particularly preferably as a preventive agent for recurrence of breast cancer or ovarian cancer after menopause).
Furthermore, the compound of the present invention is useful in the field of animal husbandry for controlling estrus of animals, improving meat quality for meat, and promoting growth of animals. The compound of the present invention is also useful as a spawning promoter for fish.

The compound of the present invention can be used for suppressing the transient increase in blood testosterone concentration (flare phenomenon) which is observed upon administration of GnRH hyperagonist such as leuprorelin acetate. The compounds of the present invention are leuprorelin acetate and gonadorelin.
elin), Buserelin (Buserelin), Triptorelin (T
riptorelin), Goserelin, Nafarelin, Histrelin, Deslorelin, Meterelin, Lecirelin and other GnRH hyperagonists (preferably leuprorelin acetate) Can be used. Further, the compound of the present invention is a steroidal or nonsteroidal antiandrogen or antiestrogen,
Chemotherapeutic agents, peptide-based GnRH antagonists, α-reductase inhibitors, α-receptor inhibitors, aromatase inhibitors, 17β-
It is also effective to use it in combination with at least one of hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents, agents that inhibit the action of cell growth factor or its receptor. .
The "chemotherapeutic agent" is ifosfamide (Ifosfami).
de), Adriamycin, Peplomycin, Cisplatin, Cyclophosphamide, 5-FU, UFT,
Methotrexate, mitomycin C (M
Itomycin C), mitoxantrone and the like. The "peptidic GnRH antagonist" includes cetrorelix, ganirelix (Ga
nirelix), Abarelix and other parenterally administered peptide GnRH antagonists. Examples of the "adrenal androgen production inhibitor" include lyase (C
_17,20- lyase) inhibitors and the like. Examples of the “phosphorase inhibitor” include tyrosine phosphorylase and the like. Examples of the “hormone therapeutic agent” include an anti-estrogen agent, a luteinizing hormone agent (eg, MPA, etc.), an androgen agent, an estrogen agent, an anti-androgen agent and the like.

The "growth factors" may be any substances as long as they are substances that promote the growth of cells, and are usually peptides having a molecular weight of 20,000 or less, which are low due to binding to the receptor. Factors that exert an action depending on the concentration are specifically (1) EGF (epidermal growth fac
tor) or substances having substantially the same activity (eg, EGF, hallegulin (HER2 ligand), etc.), (2)
Insulin or a substance having substantially the same activity as insulin (eg, insulin, IGF (insulin-like growth f
actor) -1, IGF-2, etc.), (3) FGF (fibroblast growt
h factor) or substances having substantially the same activity (eg, aFGF, bFGF, KGF (KeratindcyteGrowth Facto
r), HGF (Hepatocyte Growth Factor), FGF-10, etc.), (4) Other cell growth factors (eg, CSF (colony s
timulating factor), EPO (erythropoietin), IL-2
(Interleukin-2), NGF (nerve growth factor), PDGF
(Platelet-derived growth factor), TGFβ (transfo
rming growth factor β) etc.) and the like. The "receptor for cell growth factor" may be any one as long as it is a receptor capable of binding to the above cell growth factor, and specifically, EGF receptor, hallegulin receptor (HER2) , Insulin receptor-1, insulin receptor
-2, IGF receptor, FGF receptor-1 or FGF receptor-2. Examples of the drug that inhibits the action of the cell growth factor include Herceptin (HER2 receptor antibody). Examples of the drug that inhibits the action of the above cell growth factor or its receptor include herbimycin and PD15.
3035 (Science 265 (5175) p1093, (1994)) and the like.

HER2 inhibitors can also be mentioned as agents that inhibit the action of cell growth factors or their receptors. HER2
As an inhibitor, as long as it is a substance that inhibits the activity of HER2 (eg, phosphorylation activity), an antibody, a low molecular compound (synthetic compound, natural product), antisense, HER2 ligand, heregulin, or part of these structures can be used. It may be modified or altered. It may also be a substance that inhibits HER2 activity by inhibiting HER2 receptor (eg, HER2 receptor antibody). Examples of the low molecular weight compound having a HER2 inhibitory action include compounds described in WO98 / 03505, specifically 1- [3- [4- [2-((E) -2-phenylethenyl) -4. -Oxazolylmethoxy] phenyl] propyl] -1,2,4-triazole and the like. GnRH for benign prostatic hyperplasia
Hyperagonist, anti-androgen, anti-estrogen, peptide GnRH antagonist, α-reductase inhibitor, α-receptor inhibitor, aromatase inhibitor, 17β-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibition Combination use of the compound of the present invention with a drug, a drug such as a phosphorylase inhibitor, and the like can be mentioned.

For prostate cancer, GnRH hyperagonist, anti-androgen agent, anti-estrogen agent, chemotherapeutic agent [eg, ifosfamide, UFT, adriamycin, peplomycin, cisplatin) Etc.], peptide-based GnRH antagonists, aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents [eg, estrogen agents (eg, DSB, EMP Etc.) and anti-androgens (eg CMA
Etc.] and the like], and a compound of the present invention is used in combination with a drug such as a drug that inhibits the action of cell growth factor or its receptor. For breast cancer, GnRH hyperagonists, anti-estrogens, chemotherapeutic agents [eg, cyclophosphamide (Cycl
ophosphamide), 5-FU, UFT, Methotr
exate), Adriamycin, Mitomycin C, Mitoxatron
etc.], peptide-based GnRH antagonists, aromatase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents [eg, anti-estrogen agents (eg,
Tamoxifen, etc.), luteinizing hormone agents (eg, MPA, etc.), androgens agents, estrogen agents, etc.], agents such as agents that inhibit the action of cell growth factors or their receptors, and the compounds of the present invention are used in combination. The administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
Such an administration form includes, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) separately preparing the compound of the present invention and a concomitant drug Simultaneous administration of two types of preparations obtained by the formulation, (3) Two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, with a time lag in the same administration route Administration, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug through different administration routes, (5) separately preparing the compound of the present invention and a concomitant drug Examples of the administration include administration of the two types of pharmaceutical preparations obtained by the above-mentioned preparation with different time lags by different administration routes (for example, administration of the compound of the present invention → concomitant drug in the order or administration in the reverse order).

When the compound of the present invention is used as a preventive and / or therapeutic agent for the above-mentioned diseases or in the field of animal husbandry or fisheries, either oral administration or parenteral administration is possible according to a method known per se. It is usually mixed with a pharmaceutically acceptable carrier and usually orally administered as a solid preparation such as tablets, capsules, granules and powders, or injected intravenously, subcutaneously, intramuscularly, etc. by injection, suppository or sublingually. It is parenterally administered as tablets. It may also be administered sublingually, subcutaneously, intramuscularly, etc. as a sustained-release preparation such as sublingual tablets and microcapsules. The daily dose varies depending on the degree of symptoms; age, sex, body weight, difference in sensitivity of administration subject; timing of administration, interval, properties of pharmaceutical preparation, preparation, type; type of active ingredient, etc. The above-mentioned sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty as long as When used for the treatment of etc., as an oral agent, the active ingredient (the compound of the present invention) is usually added in an amount of about 0.01 to 30 m / kg of mammal.
g, preferably about 0.02-10 mg, more preferably 0.1-10 m
g, most preferably 0.1-5 mg is usually administered in 1 to 4 divided doses per day. When used in the fields of livestock or fisheries, the dose is similar to the above.
About 0.01 to 30 m of active ingredient (the compound of the present invention) per body weight
g, preferably about 0.1-10 mg is usually administered in 1 to 3 divided doses per day. The content of the compound (I) in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight of the total composition.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations , Solubilizer, suspending agent,
It is used as an isotonicity agent, a buffering agent, a soothing agent and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Suitable examples of the above-mentioned excipients include, for example, lactose, sucrose, D-mannitol,
Starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Preferable examples of the suspending agent include, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and other surfactants; for example, polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and other hydrophilic polymers. Preferable examples of the above-mentioned isotonicity agent include sodium chloride,
Examples thereof include glycerin and D-mannitol. Preferable examples of the above buffer include buffers such as phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Suitable examples of the above preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol,
Examples thereof include benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Preferable examples of the above antioxidant include sulfite, ascorbic acid and the like.

The compound of the present invention is added with a suspending agent, a solubilizing agent,
By adding a stabilizer, an isotonizing agent, a preservative and the like, a intravenous, subcutaneous or intramuscular injection can be prepared by a method known per se. At that time, if necessary, a freeze-dried product can be prepared by a method known per se. When the compound of the present invention is administered to, for example, a human, it is safely administered orally or parenterally as a pharmaceutical composition by mixing itself or with an appropriate pharmacologically acceptable carrier, excipient or diluent. can do. Examples of the pharmaceutical composition include oral agents (eg, powders, granules, capsules, tablets), parenteral agents [eg, injections, drip infusions, external preparations (eg, nasal preparations, transdermal preparations, etc.) , Suppositories (eg, rectal suppositories, vaginal suppositories, etc.)]. These preparations can be produced by a method known per se which is generally used in the preparation process.

The compound of the present invention is a dispersant (eg, Tween (Tw
een) 80 (manufactured by Atlas Powder, USA), HCO60 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, benzyl alcohol, etc.), tonicity agent (eg. , Sodium chloride, mannitol, sorbitol, glucose, etc.) into an aqueous injection, or dissolved, suspended or emulsified in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, or propylene glycol to form an oil-based injection, It can be an injection. In order to make an oral preparation, the compound of the present invention can be prepared according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrating agent (eg, starch, calcium carbonate, etc.), a binder (eg, starch). , Gum arabic,
Carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression molded,
Then, if necessary, it may be coated by a method known per se for the purpose of taste masking, enteric coating or sustainability, to give an oral administration preparation. Examples of the coating agent include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (Rohm Corporation). , Germany, methacrylic acid / acrylic acid copolymerization) and pigments (eg red iron oxide, titanium dioxide, etc.) are used. In the case of an enteric-coated preparation, an intermediate phase can be provided between the enteric phase and the drug-containing phase by a method known per se for the purpose of separating both phases.

To prepare an external preparation, the compound of the present invention can be prepared as a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the above solid, the compound of the present invention may be used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative,
Acrylic acid polymer, etc.) is added and mixed to obtain a powdery composition. The above liquid form is an oily or aqueous suspension, which is similar to the case of the injection. In the case of semi-solid form, an aqueous or oily gel or ointment form is preferable. In addition, these are all pH adjusting agents (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), etc. May be added. For example, in the case of a suppository, the compound of the present invention can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the above composition include glycerides of higher fatty acids [eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel, Germany) Etc.] or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. Further, as the aqueous base, for example, polyethylene glycols, propylene glycol, as the aqueous gel base, for example, natural gums, cellulose derivatives,
Examples thereof include vinyl polymers and acrylic acid polymers.

[0054]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto. ¹ H
-NMR spectra are measured with a Varian GEMINI 200 (200 MHz) type spectrometer, JEOL LAMBDA300 (300 MHz) type spectrometer or Bruker AM 500 (500 MHz) type spectrometer using tetramethylsilane as an internal standard. However, all δ values are shown in ppm.
"%" Indicates percent by weight unless otherwise specified. However, the yield shows mol / mol%. Other symbols in the present specification have the following meanings. s: singlet d: doublet t: triplet dt: double triplet m: multiplet br: wide range AIBN: 2,2-azobisisobutyronitrile DMF: N, N-dimethylformamide NBS: N-bromosuccinimide THF: tetrahydrofuran TFA : Trifluoroacetic acid Me: Methyl Et: Ethyl Ph: Phenyl Room temperature is in the range of about 15 to about 25 ° C., but is not particularly limited.

[0055]

Examples Reference Example 1 N-benzyl [1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-
Preparation of 3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] -N, N-dimethylmethanaminium iodo

[Chemical 7] N- (4- {5-{[benzyl (methyl) amino] methyl} -1- (2,6-difluorobenzyl) -3-phenyl-2,4-dioxo-1,2,3,4-
Tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (JP 2001-278884 A, WO00 / 5
6739) (3.33 g, 5 mmol) in DMF (6 ml),
Methyl iodide (0.62 ml, 10 mmol) was added, and the mixture was stirred at 60 ° C for 1 hr and 30 min. After the reaction solution was concentrated, ethyl acetate was added. The precipitate was washed with ethyl acetate and diethyl ether to give the title compound (4.01 g, 99%) as a pale-yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.2 Hz), 2.77
(6H, brs), 3.25-3.30 (2H, m), 4.55 (2H, brs), 4.9-
5.3 (2H, br), 5.3-5.5 (2H, br), 6.2-6.3 (1H, m), 6.
94 (2H, t, J = 8.4 Hz), 7.2-7.6 (14H, m), 7.70 (1
H, d, J = 8.4 Hz), 8.73 (1H, s) .IR (KBr): 1711, 1667, 1537, 1470, 1316, 1225, 1032
cm ^-1 . Elemental analysis Calculated as C ₃₈ H ₃₆ F ₂ IN ₅ O ₃ S ・ 1.5H ₂ O: C, 54.68; H, 4.71; N, 8.39. Found: C, 54.53; H, 4.67; N , 8.25.mp 185-187 ℃. Reference Example 2 Preparation of 3-bromo-N-methylpropanamide

[Chemical 8] 3-Bromopropionic acid (1.52 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml), and oxalyl chloride (0.94 m
(1, 11 mmol) and DMF (2 drops) were added, and the mixture was stirred at room temperature for 1 hr.
The reaction mixture was concentrated under reduced pressure, dissolved in tetrahydrofuran (20 ml), triethylamine (2.08 ml, 15 mmol) and a tetrahydrofuran solution of methylamine (2M) (6 ml, 12 mmol) were added under ice cooling, and the mixture was stirred for 3 hours. . Saturated saline was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (0.78 g, 47%) as a pale-yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 2.75 (2H, t, J = 6.6 Hz), 2.85
(3H, d, J = 4.6 Hz), 3.65 (2H, t, J = 6.6 Hz), 5.4
-5.7 (1H, brm). Reference Example 3 Production of 3-bromo-N, N-dimethylpropanamide

[Chemical 9] Using 3-bromopropionic acid (3.06 g, 20 mmol) and a solution of dimethylamine in tetrahydrofuran (2M) (12 ml, 24 mmol), the same reaction as in Reference Example 2 was performed and the title compound (2.53
g, 70%) was obtained as an orange oil. ¹ H-NMR (CDCl ₃ ) δ: 2.91 (2H, t, J = 7.2 Hz), 2.97
(3H, s), 2.91 (2H, t, J = 7.2 Hz), 3.02 (3H, s), 3.
65 (2H, t, J = 7.2 Hz).

Reference Example 4 Preparation of 3-[(benzyloxy) methyl] -1-methylpyrrolidin-2-one

[Chemical 10] To a solution of diisopropylamine (3.08 ml, 22 mmol) in tetrahydrofuran (50 ml), a hexane solution of n-butyllithium (1.6M) (13.75 ml, 22 mmol) was added dropwise under ice cooling. After stirring at 0 ° C for 30 minutes, the mixture was cooled to -78 ° C, and a solution of 1-methylpyrrolidin-2-one (1.98 g, 20 mmol) in THF (20 ml) was added dropwise. After stirring at -78 ° C for 30 minutes, a solution of benzyl chloromethyl ether (3.76 g, 24 mmol) in THF (30 ml) was added dropwise. After stirring at -78 ° C for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / hexane; 4/1) to give the title compound (4.14 g, 94%)
Was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.95-2.3 (2H, m), 2.6-2.8 (1H,
m), 2.85 (3H, s), 3.25-3.4 (2H, m), 3.6-3.8 (2H,
m), 4.45-4.6 (2H, m), 7.25-7.45 (5H, m). Reference Example 5 Preparation of 3- (hydroxymethyl) -1-methylpyrrolidin-2-one

[Chemical 11] 3-[(benzyloxy) methyl] -1-methylpyrrolidin-2-one (4.14 g, 18.88 mmol) was dissolved in methanol (20 ml), 10% hydrous palladium on carbon (1.04 g) was added, and the mixture was placed under hydrogen atmosphere. The mixture was stirred at room temperature for 2 hours. After the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate / methanol; 10
/ 1) to give the title compound (1.55 g, 64%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.7-1.9 (1H, m), 2.05-2.25 (1H,
m), 2.6-2.8 (1H, m), 2.86 (3H, s), 3.25-3.45 (3H,
m), 3.65-3.95 (2H, m). Reference Example 6 Preparation of 2- (1,1-dioxideisothiazolin-2-yl) ethyl methanesulfonate

[Chemical 12] 2,2 ^'- dissolved iminodiethanol a (1.05 g, 10 mmol) in ethyl acetate (30 ml), under ice-cooling, triethylamine (4.86 m
l, 35 mmol) and methanesulfonyl chloride (2.40 ml, 31
mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. Add baking soda water,
Extracted with ethyl acetate / THF. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The precipitate was washed with diethyl ether to obtain a trimesylate body (2.16 g, 64%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.99 (3H, s), 3.08 (6H, s), 3.66
(4H, t, J = 5.4 Hz), 4.41 (4H, t, J = 5.4 Hz).
N-Butyllithium (4.04 ml,
A hexane solution (1.6 M) of 6.47 mmol) was added dropwise. 2 at room temperature
After stirring for an hour, a hexane solution (1.6 M) of n-butyllithium (4.04 ml, 6.47 mmol) was added, and the mixture was further stirred at room temperature for 2 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate / THF. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / hexane; 4/1) to give the title compound (0.
71 g, 54%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.3-2.5 (2H, m), 3.08 (3H, s),
3.17 (2H, t, J = 7.6 Hz), 3.35-3.5 (4H, m), 4.40
(2H, t, J = 5.2 Hz).

Reference Example 7 2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-4- [N- (2-methoxyethyl) -N-methylaminomethyl] -5- (4 -Aminophenyl) thiophene-3-carboxylic acid ethyl ester production

[Chemical 13] 2- [N- (2,6-Difluorobenzyl) -N-ethoxycarbonyl] amino-4- [N- (2-methoxyethyl) -N-methylaminomethyl] -5- (4-nitrophenyl) thiophene- 3-carboxylic acid ethyl ester (12.43 g) (JP 2001-278884 A,
WO00 / 56739) in ethanol (315 ml) solution, 2N-hydrogen chloride / diethyl ether solution (21 ml) and 50% water-1
Add 0% palladium on carbon (3.73 g) and add 1 under hydrogen atmosphere.
Stir vigorously for hours. The catalyst-free filtrate was neutralized with aqueous sodium hydrogen carbonate, and the solvent was evaporated. The obtained residue is ethyl acetate /
The mixture was partitioned with water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to NH-silica gel (Fuji Silysia Chemical) chromatography to give the title compound (11.44 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.30 (3H, br), 2.05 (3H,
s), 2.39 (2H, t, J = 6.3 Hz), 3.27 (3H, s), 3.32
(3H, t, J = 6.3 Hz), 3.59 (2H, s), 3.78 (2H, s),
4.20 (2H, q, J = 7.1 Hz), 4.10-4.23 (2H, br), 5.00
(2H, s), 6.66 (2H, d, J = 8.6 Hz), 6.84 (2H, t, J
= 8.2 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.15-7.30 (1
H, m). IR (KBr): 1717, 1626, 1609, 1472, 1406, 1300, 1246
cm ⁻¹ . Reference Example 8 2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-4- [N- (2-methoxyethyl) -N-methylaminomethyl] -5- [ Production of 4- (ethylaminocarbonyl) aminophenyl] thiophene-3-carboxylic acid ethyl ester

[Chemical 14] Ethyl isocyanate (2.26 ml) was added to a pyridine (143 ml) solution of the compound of Reference Example 7 (8.05 g) under ice-cooling, and the mixture was gradually warmed to room temperature and stirred for 18 hours. The solvent was evaporated, and the obtained residue was subjected to NH-silica gel (Fuji Silysia Chemical) chromatography to give the title compound (9.25 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.11-1.26 (6H, m), 1.30 (3H, t,
J = 7.1 Hz), 2.02 (3H, s), 2.38 (2H, t, J = 6.3 H
z), 3.26 (3H, s), 3.25-3.35 (4H, m), 3.58 (2H, s),
4.11-4.26 (4H, m), 4.91-5.02 (1H, br), 5.00 (2H,
s), 6.71-6.82 (1H, br), 6.84 (2H, t, J = 7.7 Hz),
7.20-7.39 (5H, m) .IR (KBr): 1721, 1593, 1541, 1472, 1408, 1310, 1231
cm ^-1 .Reference Example 9 2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-4- [N- (2-methoxyethyl) -N-methylaminomethyl] -5- [ Preparation of 4- (ethylaminocarbonyl) aminophenyl] thiophene-3-carboxylic acid

[Chemical 15] To a solution of the compound of Reference Example 8 (19.9 g) in ethanol (472 ml) was added 2N sodium hydroxide solution (78.5 ml), and the mixture was mixed at 60 ° C. for 5 minutes.
Stir for hours. The mixture was returned to room temperature, 1N hydrochloric acid (157 ml) was added, and the solvent was evaporated. The obtained residue was dissolved in ethanol and toluene, and the solvent was distilled off again. Absolute ethanol in the residue
(150 ml) was added and the inorganic matter was filtered off. The filtrate is concentrated to dryness,
The obtained residue was micronized with anhydrous ether and then collected by filtration.
The title compound (18.2 g) was obtained by drying. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2 Hz), 1.18
(3H, t, J = 7.4 Hz), 2.55 (3H, s), 2.90 (2H, br),
3.18-3.39 (2H, m), 3.26 (3H, s), 3.54 (2H, br), 3.
92-4.30 (4H, m), 5.02 (2H, s), 6.82 (2H, t, J = 7.
9 Hz), 6.92-7.10 (2H, m), 7.16-7.28 (1H, m), 7.50-
7.71 (2H, m), 8.92 (1H, s), 9.27 (1H, s) .IR (KBr): 2982, 1715, 1595, 1543, 1472, 1406, 1314
cm ^-1 .

Reference Example 10 2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-4- (N-methylaminomethyl) -5- (4-aminophenyl) thiophene-3-carboxylic Production of acid ethyl ester

[Chemical 16] Subjected to the same reaction as in Reference Example 7, 4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-5- (4 -Nitrophenyl) thiophene-3-carboxylic acid ethyl ester (14.0 g)
1-278884, WO00 / 56739), 2N-hydrogen chloride / diethyl ether solution (22.4 ml) and 50% water content-10% palladium / carbon (4.2 g) to give the title compound (9.65 g) as an oil. Got as. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, br), 1.32 (3H, t, J =
7.0 Hz), 1.78 (1H, s), 2.32 (3H, s), 3.65 (2H,
s), 3.78 (2H, s), 4.17-4.28 (4H, m), 4.95 (2H, s),
6.69 (2H, d, J = 8.6 Hz), 6.83 (2H, t, J = 7.9 H
z), 7.16-7.28 (3H, m). IR (KBr): 2980, 1715, 1626, 1609, 1518, 1472, 140
8, 1298, 1244 cm ^-1 . Reference Example 11 4- [N- (2-ethoxyethyl) -N-methylaminomethyl] -2-
Production of [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-5- (4-aminophenyl) thiophene-3-carboxylic acid ethyl ester

[Chemical 17] 2-Ethoxyethyl chloride (1.02 g), N-ethyldiisopropylamine (2.01 ml) and potassium iodide (1.55 g) were added to a DMF solution (46.8 ml) of the compound of Reference Example 10 (2.36 g) to give 7
The mixture was stirred at 0 ° C for 24 hours. The reaction mixture was partitioned with ethyl acetate / water, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on NH-silica gel (Fuji Silysia Chemical Ltd.) to give the title compound (2.38 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.12-
1.26 (3H, br), 1.30 (3H, t, J = 7.5 Hz), 2.04 (3H,
s), 2.40 (2H, t, J = 6.4 Hz), 3.36 (2H, t, J = 6.4
Hz), 3.41 (2H, q, J = 7.0 Hz), 3.58 (2H, s), 3.78
(2H, s), 4.20 (2H, q, J = 7.0 Hz), 4.10-4.21 (2H.
m), 5.00 (2H, s), 6.66 (2H, d, J = 8.4 Hz), 6.84
(2H, t, J = 7.7 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.1
9-7.31 (1H, m). IR (KBr): 1721, 1626, 1593, 1522, 1472, 1300 cm ^-1 . Reference Example 12 2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl ] Production of amino-4- [N- (2-ethoxyethyl) -N-methylaminomethyl] -5- [4- (ethylaminocarbonyl) aminophenyl] thiophene-3-carboxylic acid ethyl ester

[Chemical 18] Subjected to the same reaction as in Reference Example 8, the compound of Reference Example 11 (2.2
 g), pyridine (38 ml), ethylisocyanate (0.6 ml)
The title compound (1.83 g) was obtained as an oil. ¹ H-NMR (CDCl₃) δ: 1.13 (3H, t, J = 7.5 Hz), 1.14
(3H, t, J = 7.5 Hz), 1.24-1.32 (6H, m), 2.02 (3H,
s), 2.39 (2H, t, J = 6.3 Hz), 3.19-3.28 (2H, m), 3.
30-3.44 (4H, m), 3.57 (2H, s), 4.11-4.24 (4H, m),
4.37 (1H, br), 5.00 (2H, s), 5.20 (1H, br), 6.84 (2
H, t, J = 8.0 Hz), 7.08 (1H, br), 7.19-7.35 (4H,
m). IR (KBr): 1715, 1593, 1539, 1472, 1379, 1308 cm^-1.

Reference Example 13 Ethyl 4-{[benzyl (methyl) amino] methyl} -2-[(2,6-
Difluorobenzyl) (ethoxycarbonyl) amino] -5-
Production of (4-{[(ethylamino) carbonyl] amino} phenyl) thiophene-3-carboxylate

[Chemical 19] Ethyl 5- (4-aminophenyl) -4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] aminothiophene-3-carboxylate Esters (JP 2001-278884 A, WO 00/56739 B) (6.32
g, 10.64 mmol) and the same reaction as in Reference Example 8 was carried out to obtain the title compound (6.57 g, 93%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 1.29
(3H, t, J = 7.2 Hz), 1.09-1.25 (3H, br), 1.89 (3H,
s), 3.20 (2H, s), 3.24-3.37 (2H, m), 3.64 (2H,
s), 4.21 (2H, q, J = 7.2 Hz), 4.12-4.28 (2H, br),
4.88 (1H, br), 5.02 (2H, s), 6.63 (1H, br), 6.78
(2H, t, J = 8.0 Hz), 7.07-7.40 (10H, m). IR (KBr): 3331, 2980, 1721, 1661, 1593, 1541, 147
2, 1406, 1310 cm ^-1 . Reference Example 14 N- (4- {5-{[benzyl (methyl) amino] methyl} -1- (2,6-difluorobenzyl) -3- [4- (2- Methoxyethoxy) phenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]
Production of pyrimidin-6-yl} phenyl) -N'-ethylurea

[Chemical 20] 4- (2-Methoxyethoxy) aniline (8.72 g, 52.1 mmol)
Was dissolved in dichloromethane (60 ml), and under ice-cooling, a hexane solution of dimethylaluminum chloride (0.98M) (48.3 ml,
(47.34 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Further, a dichloromethane (50 ml) solution of the compound of Reference Example 13 (5.25 g, 7.89 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) and recrystallized from ethyl acetate / methanol to give the title compound (4.52 g, 77%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.05
(3H, s), 3.25-3.4 (2H, m), 3.45 (3H, s), 3.56 (2H,
s), 3.7-3.8 (2H, m), 3.89 (2H, s), 4.1-4.2 (2H,
m), 4.6-4.7 (1H, m), 5.35 (2H, s), 6.32 (1H, s), 6.
91 (2H, t, J = 8.2Hz), 7.05 (2H, d, J = 9.0Hz),
7.15-7.3 (3H, m), 7.36 (2H, d, J = 8.6 Hz), 7.68
(2H, d, J = 8.6 Hz) .IR (KBr): 1659, 1514, 1244, 1123, 1063, 1038, 928,
835 cm ⁻¹ .mp 114-116 ° C. Reference Example 15 N- (4- {5-{[benzyl (methyl) amino] methyl} -1- (2,6-difluorobenzyl) -3- (4-fluoro Phenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6
-Yl} phenyl) -N'-ethylurea production

[Chemical 21] Using the compound of Reference Example 13 (333 mg, 0.5 mmol), the same reaction as in Reference Example 14 was carried out to give the title compound (162 mg, 48%).
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.04
(3H, s), 3.30 (2H, dq, J = 5.5, 7.2 Hz), 3.55 (2H,
s), 3.87 (2H, s), 4.81 (1H, t, J = 5.5 Hz), 5.35 (2
H, s), 6.58 (1H, s), 6.91 (2H, t, J = 8.2 Hz), 7.1
5-7.30 (10H, m), 7.37 (2H, d, J = 8.4 Hz), 7.65 (2
H, d, J = 8.8 Hz) .IR (KBr): 3318, 1717, 1672, 1591, 1553, 1472, 131
8, 1236 cm ^-1 .

Reference Example 16 Production of methyl 6- (bromomethyl) nicotinate

[Chemical formula 22] Methyl 6-methylnicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml) and NBS (3.56 g, 20 mmol) and AIBN were added.
(329 mg, 2 mmol) was added. After stirring at 80 ° C for 3 hours, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / hexane; 1/4) to give the title compound (68
2 mg, 28%) was obtained as an orange amorphous. ¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 4.58 (2H, s), 7.53
(1H, d, J = 8.2 Hz), 8.30 (2H, dd, J = 1.8, 8.2 H
z), 9.17 (1H, d, J = 1.8 Hz). Reference Example 17 Ethyl 2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(ethylamino) carbonyl] Amino} phenyl) -4-[(methylamino) methyl] thiophene-3-
Carboxylate production

[Chemical formula 23] The compound of Reference Example 13 (7.47 g, 11.2 mmol) was used to perform the same reaction as in Reference Example 7 to obtain the title compound (3.57 g, 55%) as a yellow powder. Reference Example 18 Ethyl 2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(ethylamino) carbonyl] amino}
Phenyl) -4-{[methyl (pyridin-2-ylmethyl) amino]
Manufacture of methyl} thiophene-3-carboxylate

[Chemical formula 24] Using the compound of Reference Example 17 (3.57 g, 6.21 mmol) and 2-chloromethylpyridine hydrochloride (1.53 g, 9.32 mmol), the same reaction as in Example 4 described below was performed and the title compound (4.68 g, D
MF) was obtained as a yellow oil.

Reference Example 19 2-[(2,6-Difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(ethylamino) carbonyl] amino} phenyl) -4-{[methyl (pyridine- Preparation of 2-ylmethyl) amino] methyl} thiophene-3-carboxylic acid

[Chemical 25] Using the compound of Reference Example 18 (4.68 g, including DMF) and 2N sodium hydroxide (8.75 ml, 17.5 mmol), Reference Example 9
The title compound (2.35 g, 59%, 2 steps)
Was obtained as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.4 (6H, m), 2.36 (3H, s),
3.2-3.4 (2H, m), 3.7-4.3 (6H, m), 5.05 (2H, s), 6.
45 (1H, s), 6.7-7.7 (11H, m), 8.45-8.5 (1H, m). Reference Example 20 Ethyl 2- (1H-tetrazol-1-yl) propanate and ethyl 2- (2H-tetrazole- 2-yl) Propanate production

[Chemical formula 26] Tetrazole (2.80 g, 40 mmol) and ethyl 2-bromopropionate (5.71 ml, 44 mmol) were dissolved in acetonitrile (80 ml), and potassium carbonate (8.29 g, 60 mmol) was added. After stirring at room temperature for 4 days, saturated saline was added, and the mixture was extracted twice with ethyl acetate. Collect the organic layers, dry over magnesium sulfate,
Concentration under reduced pressure gave the title compound (7.08 g, quant.) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.9-2.05 (6H, m), 3.7-3.85 (6H,
m), 5.5-5.6 (1H, m), 5.65-5.75 (1H, m), 8.56 (1H,
s), 8.81 (1H, s). Reference Example 21 2- (1H-tetrazol-1-yl) propan-1-ol (1) and 2- (2H-tetrazol-2-yl) propan-1-ol ( 2)
Manufacturing of

[Chemical 27] Lithium aluminum hydride (2.28 g, 60 mmol) in THF
(60 ml), ethyl 2- (1H-tetrazol-1-yl)
A THF (60 ml) solution of propanate and ethyl 2- (2H-tetrazol-2-yl) propanate (7.08 g, 40 mmol) was added dropwise under ice cooling. After stirring at 0 ° C for 1 hour, water (2.3 m
l), 1N sodium hydroxide (2.3 ml), and water (6.9 ml) were sequentially added dropwise. The insoluble material was removed by filtration through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 1/0 to 20/1) to give the title compound (1-yl compound) (1.74 g, 34%) and the title compound.
(2-yl compound) (1.29 g, 25%) was obtained as a colorless oil. 1-yl (1) ¹ H-NMR (CDCl ₃ ) δ: 1.68 (3H, d, J = 7.0 Hz), 2.4-2.
5 (1H, m), 3.9-4.1 (2H, m), 4.75-4.9 (1H, m), 8.70
(1H, s) .2-yl (2) ¹ H-NMR (CDCl ₃ ) δ: 1.67 (3H, d, J = 7.0 Hz), 2.34
(1H, t, J = 6.6 Hz), 4.0-4.2 (2H, m), 4.95-5.15 (1
H, m), 8.54 (1H, s).

Reference Example 22 Production of ethyl 2- (1H-1,2,3-triazol-1-yl) propanate and ethyl 2- (2H-1,2,3-triazol-2-yl) propanate

[Chemical 28] Reference example 2 using 1,2,3-triazole (1.38 g, 20 mmol) and ethyl 2-bromopropionate (3.90 ml, 30 mmol)
The reaction was performed in the same manner as for 0 to give the title compound (3.43 g, quant., DMF
Was obtained as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.35 (3H, m), 1.85 (1.5H, d,
J = 7.5 Hz), 1.91 (1.5H, d, J = 7.5 Hz), 4.15-4.3
(2H, m), 5.42 (1H, q, J = 7.5 Hz), 5.50 (1H, q, J
= 7.5 Hz), 7.66 (1H, s), 7.74 (1H, s). Reference Example 23 2- (1H-1,2,3-triazol-1-yl) propan-1-ol
(1) and 2- (2H-1,2,3-triazol-2-yl) propane-
Manufacture of 1-alls (2)

[Chemical 29] Hydrogenation with ethyl 2- (1H-1,2,3-triazol-1-yl) propanate and ethyl 2- (2H-1,2,3-triazol-2-yl) propanate (3.43 g, including DMF) Using lithium aluminum (1.14 g, 30 mmol), the same reaction as in Reference Example 21 was carried out to give the title compound (1-yl compound) (1.03 g, 41%) and the title compound (2-yl compound) (0.57 g, 0.57 g, 22%) was obtained as a colorless oil. 1-yl (1) ¹ H-NMR (CDCl ₃ ) δ: 1.61 (3H, d, J = 6.6 Hz), 2.59
(1H, t, J = 6.6 Hz), 4.01 (2H, t, J = 6.2 Hz), 4.6
5-4.85 (1H, m), 7.65 (1H, s), 7.71 (1H, s). 2-yl body (2) ¹ H-NMR (CDCl ₃ ) δ: 1.59 (3H, d, J = 6.6 Hz ), 2.85
(1H, t, J = 6.6 Hz), 4.01 (2H, t, J = 6.6 Hz), 4.7
-4.9 (1H, m), 7.64 (2H, s). Reference Example 24 2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-4- [N- (2-ethoxyethyl) -N-methylaminomethyl] -5- [4- (ethylaminocarbonyl) aminophenyl]
Production of thiophene-3-carboxylic acid

[Chemical 30] Subjected to the same reaction as in Reference Example 9, the compound of Reference Example 12 (10.
The title compound (9.89 g) was obtained from 96 g). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2 Hz), 1.14
(3H, t, J = 7.2 Hz), 1.18 (3H, t, J = 7.4 Hz), 2.5
7 (3H, s), 2.62-3.10 (2H, br), 3.18-3.43 (4H, m),
3.58 (2H, brs), 4.01 (2H, brs), 4.09-4.24 (2H, m),
5.04 (2H, s), 6.81 (2H, t, J = 7.6 Hz), 6.95-7.07
(2H, m), 7.19-7.27 (1H, m), 7.56-7.70 (2H, m), 9.1
2 (1H, s), 9.44 (1H, s). IR (KBr): 1713, 1599, 1539, 1472, 1404, 1312 cm ^-1 .

Example 1 N- {4- [1- (2,6-difluorobenzyl) -5-{[methylamino]]
Methyl} -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N-ethylurea

[Chemical 31] Subjected to the same reaction as in Reference Example 7, N- {4- [5-{[benzyl (methyl) amino] methyl} -1- (2,6-difluorobenzyl) -2,4
-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,
3-d] pyrimidin-6-yl] phenyl} -N-ethylurea (JP 2001-278884, WO 00/56739) (1.12 g) and 2
Normal-hydrogen chloride / diethyl ether solution (0.76 ml) and 50%
Water content-10% Palladium on carbon (336 mg) to give the title compound (791
(mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.3 Hz), 2.34
(3H, s), 3.15-3.29 (2H, m), 3.78 (2H, s), 5.02 (1
H, t, J = 5.4 Hz), 5.36 (2H, s), 6.91 (2H, t, J =
8.1 Hz), 7.10 (1H, s), 7.23-7.37 (8H, m), 7.41-7.6
0 (3H, m). IR (KBr): 2975, 1713, 1669, 1593, 1534, 1472, 131
6, 1236 cm ^-1 . Elemental analysis Calculated as C ₃₀ H ₂₇ N ₅ O ₃ SF ₂ 1.0H ₂ O: C, 60.70; H, 4.92; N, 11.80. Found: C, 61.01; H, 5.03 N, 11.91. Example 2 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) amino] methyl} -2,4-dioxo-3phenyl-1 , 2,3,4
-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 32] The compound of Reference Example 1 (1.60 g, 2 mmol) and 2-methoxyethylamine (0.74 g, 10 mmol) were dissolved in DMF (10 ml), and N, N-
Diisopropylethylamine (0.52 ml, 3 mmol) was added, and the mixture was stirred at 100 ° C for 1 hr. Add sodium bicarbonate water to the reaction mixture,
It was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol / triethylamine; 40/2/1), and recrystallized from dichloromethane / methanol,
The title compound (463 mg, 37%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.2 Hz), 2.71
(2H, t, J = 5.4 Hz), 3.15-3.25 (2H, m), 3.26 (3H,
s), 3.40 (2H, t, J = 5.4 Hz), 3.87 (2H, s), 5.15-
5.25 (1H, m), 5.36 (2H, s), 6.85-6.9 (2H, m), 6.92
(2H, t, J = 8.0 Hz), 7.25-7.6 (10H, m). IR (KBr): 1717, 1667, 1472, 1236, 1034, 733 cm ^-1 . Elemental analysis C ₃₂ H ₃₁ F ₂ N ₅ Calculated as O ₄ S ・ 0.2H ₂ O: C, 61.66; H, 5.08; N, 11.24. Found: C, 61.40; H, 4.98; N, 11.04.mp 221-223 ° C. Example 3 N- [4- (1- (2,6-Difluorobenzyl) -5-{[(2-methoxyethyl) amino] methyl} -2,4-dioxo-3phenyl-1,2,3,4
-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 33] Using the compound of Reference Example 1 (1.60 g, 2 mmol) and 2-ethoxyethylamine (1.78 g, 20 mmol), the same reaction as in Example 2 was carried out to give the title compound (396 mg, 31%) as colorless crystals. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (6H, t, J = 7.0 Hz), 2.65-
2.75 (2H, m), 3.15-3.25 (2H, m), 3.42 (2H, q, J =
7.0 Hz), 3.88 (2H, s), 5.29 (1H, t, J = 5.4 Hz),
5.36 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 6.85-7.0
(2H, m), 7.2-7.35 (6H, m), 7.45-7.6 (3H, m). IR (KBr): 1715, 1669, 1534, 1472, 1236, 1034, 733
cm ^-1 .Elemental analysis Calculated as C ₃₃ H ₃₃ F ₂ N ₅ O ₄ S: C, 62.55; H, 5.25; N, 11.05. Found: C, 62.27; H, 5.16; N, 11.06.mp 211 -213 ° C.

Example 4 Ethyl 3-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbomyl] amino} phenyl) -2,4-dioxo-
Preparation of 3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] propanate

[Chemical 34] The compound of Example 1 (576 mg, 1 mmol) was dissolved in DMF (4 ml), and N, N-diisopropylethylamine (0.52 ml, 1.5 mm)
ol) and ethyl 3-bromopropionate (0.15 ml, 1.2 mmol)
Was added and stirred at 50-60 ° C for 16 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 40/1), and further dichloromethane /
Recrystallization from methanol / diethyl ether gave the title compound (389 mg, 58%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.0 Hz), 1.18
(3H, t, J = 7.0 Hz), 2.13 (3H, s), 2.37 (2H, t, J
= 6.4 Hz), 2.75 (2H, t, J = 6.4 Hz), 3.2-3.4 (2H,
m), 3.78 (2H, s), 4.00 (2H, q, J = 7.0 Hz), 4.7-4.
8 (1H, s), 5.37 (2H, s), 6.36 (1H, s), 6.92 (2H,
t, J = 8.0 Hz), 7.2-7.6 (10H, m) .IR (KBr): 1717, 1669, 1532, 1472, 1236, 1034, 733
cm ^-1 .Elemental analysis Calculated as C ₃₅ H ₃₅ F ₂ N ₅ O ₅ S ・ 0.5H ₂ O: C, 61.39; H, 5.30; N, 10.23. Found: C, 61.09; H, 5.10; N , 9.96. Mp 198-200 ° C. Example 5 Ethyl [{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo -
Preparation of 3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] acetate

[Chemical 35] The compound of Example 1 (1.09 g, 1.8 mmol) and ethyl bromoacetate (0.24 ml, 2.16 mmol) were used to perform the same reaction as in Example 4 to obtain the title compound (0.96 g, 81%) as colorless crystals. It was ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.0 Hz), 1.17
(3H, t, J = 7.2 Hz), 2.25 (3H, s), 3.2-3.4 (2H,
m), 3.37 (2H, s), 3.98 (2H, q, J = 7.0 Hz), 4.03
(2H, s), 4.7-4.8 (1H, m), 5.36 (2H, s), 6.44 (1H,
s), 6.92 (2H, t, J = 8.0 Hz), 7.25-7.55 (10H, m) .IR (KBr): 1713, 1674, 1472, 1460, 1316, 1236, 103
. 6, 789, 735 cm ^-1 elemental analysis _{C 34 H 33 F 2 N 5} O 5 S · 0.2H 2 O Calculated:. C, 61.38; H, 5.06; N, 10.53 Found: C, 61.18; H, 5.16; N, 10.51. Mp 208-209 ° C. Example 6 Ethyl 4-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl ) -2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] butanate

[Chemical 36] Using the compound of Example 1 (2.0 g, 3.47 mmol) and ethyl 4-bromo-n-butyrate (0.60 ml, 4.16 mmol), the same reaction as in Example 4 was carried out to give the title compound (1.82 g, 76%). Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.20
(3H, t, J = 7.2 Hz), 1.55-1.75 (2H, m), 2.07 (3H,
s), 2.18 (3H, t, J = 7.4 Hz), 2.40 (2H, t, J = 7.4
Hz), 3.2-3.4 (2H, m), 3.76 (2H, s), 4.05 (2H, q, J
= 7.2 Hz), 4.7-4.8 (1H, m), 5.37 (2H, s), 6.42 (1
H, s), 6.92 (2H, t, J = 8.2 Hz), 7.25-7.6 (10H,
m) .IR (KBr): 1717, 1667, 1472, 1236, 1032, 735 cm ^-1 . Calculated as elemental analysis C ₃₆ H ₃₇ F ₂ N ₅ O ₅ S: C, 62.69; H, 5.41; N, 10.15. Actual measurement: C; 62.29; H, 5.37; N, 10.15.mp 203-204 ℃.

Example 7 N-{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} -N-methyl-β-alanine production

[Chemical 37] The compound of Example 4 (500 mg, 0.74 mmol) was added to ethanol (20 mg).
(1 ml) and tetrahydrofuran (10 ml), the mixture was dissolved, 1N aqueous sodium hydroxide solution (1 ml, 1 mmol) was added, and the mixture was stirred at room temperature for 16 hr. Under ice-cooling, add 1N hydrochloric acid (1 ml),
The precipitate was washed with water and ethyl acetate, and the title compound (144 mg,
30%) as a brown powder. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.16 (3H, t, J = 7.4 H
z), 2.36 (3H, s), 2.3-2.4 (2H, m), 2.55-2.65 (2H,
m), 3.2-3.3 (2H, m), 4.00 (2H, s), 5.34 (2H, s), 5.
85-5.95 (1H, m), 6.9-7.0 (2H, m), 7.2-7.6 (10H,
m), 8.37 (1H, s) .IR (KBr): 1709, 1667, 1537, 1472, 1316, 1236, 1032
cm ^-1 .Example 8 [{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] acetic acid production

[Chemical 38] Using the compound of Example 5 (0.99 g, 1.5 mmol) and 1N aqueous sodium hydroxide solution (2 ml, 2 mmol), the same reaction as in Example 7 was carried out to give the title compound (598 mg, 60%) as yellow. It was obtained as a powdery crude product and used in the next reaction. Example 9 4-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] butanoic acid

[Chemical Formula 39] Using the compound of Example 6 (1.2 g, 1.74 mmol) and 1N aqueous sodium hydroxide solution (2 ml, 2 mmol), the same reaction as in Example 7 was carried out to give the title compound (1.28 g, quant.) As yellow. Obtained as a powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.0 Hz), 1.45
-1.6 (2H, m), 2.00 (3H, s), 2.0-2.15 (2H, m), 2.2-
2.35 (2H, m), 3.0-3.2 (2H, m), 3.68 (2H, s), 5.30 (2
H, s), 6.3-6.4 (1H, m), 7.05-7.55 (14H, m), 8.86
(1H, s).

Example 10 3-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] -N, N-dimethylpropanamide

[Chemical 40] The compound of Example 7 (300 mg, 0.463 mmol) was dissolved in DMF (5 ml), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (142 mg, 0.741 mmol), 1-hydroxybenzo Triazole (113 mg, 0.741 mmol), N, N-diisopropylethylamine (0.15 ml, 0.833 mmol) and dimethylamine in tetrahydrofuran (2M) (0.46 ml, 0.92
6 mmol) was added. After stirring at room temperature for 18 hours, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After washing the organic layer with saline,
It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 20/1) and recrystallized from dichloromethane / methanol to give the title compound (99 mg, 32
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2 Hz), 2.05
(3H, s), 2.4-2.5 (2H, m), 2.65-2.8 (2H, m), 2.86
(3H, s), 2.87 (3H, s), 3.2-3.35 (2H, m), 3.79 (2H,
s), 5.1-5.25 (1H, m), 5.36 (2H, s), 6.91 (2H, t, J
= 8.0 Hz), 6.85-6.95 (1H, m), 7.1-7.55 (10H, m). IR (KBr): 1709, 1667, 1620, 1532, 1470, 1219, 103
. 6, 793, 739 cm ^-1 elemental analysis _{C 35 H 36 F 2 N 6} O 4 S · 0.5H 2 O Calculated: C, 61.48; H, 5.45 ; N, 12.29 Found:. C; 61.47; H, 5.23; N, 12.18.mp 236-237 ° C. Example 11 3-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] -N, N-diethylpropanamide

[Chemical 41] Compound of Example 7 (50 mg, 0.077 mmol) and diethylamine
(11 mg, 0.154 mmol) was used to carry out the same reaction as in Example 10 to obtain the title compound (7.6 mg, 14%). HPLC (220 nm) Purity 91% (Retention time 2.66 minutes) MS (ESI +, m / e) 703 (M + 1) HPLC was measured under the following conditions. Column: CAPCELLPAKCC18UG120, S-3 μm, 20 × 50 mm Solvent: Solution A (water containing 0.1% trifluoroacetic acid), solution B (acetonitrile containing 0.1% trifluoroacetic acid) Gradient cycle: 0.00 minutes (solution A / solution B = 90) / 10), 4.00
Min (Solution A / B = 5/95), 5.50 minutes (Solution A / B = 5/95), 5.51 minutes (Solution A)
/ B solution = 90/10), 8.00 minutes (A solution / B solution = 90/10) Flow rate: 0.5 ml / min Example 12 N- {4- [1- (2,6-difluorobenzyl) -5- ({Methyl [3-oxo-3- (1-piperidyl) propyl] amino} methyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidi-6-yl] phenyl} -N'-ethylurea

[Chemical 42] The compound of Example 7 (50 mg, 0.077 mmol) and piperidine (13
mg, 0.154 mmol) and the same reaction as in Example 10 was carried out to obtain the title compound (4.0 mg, 7%). HPLC (220 nm) Purity 100% (retention time 2.69 min) MS (ESI +, m / e) 715 (M + 1)

Example 13 N- {4- [1- (2,6-difluorobenzyl) -5-({methyl [3- (4-
Morpholinyl) -3-oxopropyl] amino} methyl) -2,4
-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,
Production of 3-d] pyrimidi-6-yl] phenyl} -N'-ethylurea

[Chemical 43] The compound of Example 7 (50 mg, 0.077 mmol) and morpholine (13
mg, 0.154 mmol) and the same reaction as in Example 10 was carried out to obtain the title compound (17 mg, 31%) as colorless crystals. HPLC (220 nm) Purity 98% (retention time 2.46 min) MS (ESI +, m / e) 717 (M + 1) Example 14 3-[{[1- (2,6-difluorobenzyl) -6- ( 4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} amino] -N- (2-methoxyethyl) -N-methylpropanamide

[Chemical 44] Using the compound of Example 7 (50 mg, 0.077 mmol) and N- (2-methoxyethyl) -N-methylamine (14 mg, 0.154 mmol), the same reaction as in Example 10 was carried out to give the title compound ( 17 m
g, 31%) was obtained. HPLC (220 nm) Purity 97% (retention time 2.54 minutes) MS (ESI +, m / e) 719 (M + 1) Example 15 3-[{[1- (2,6-difluorobenzyl) -6- ( 4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] -N-methylpropanamide

[Chemical formula 45] Using the compound of Example 7 (200 mg, 0.309 mmol) and a solution of methylamine in tetrahydrofuran (2M) (1 ml, 2 mmol), the same reaction as in Example 10 was carried out to give the title compound (8 mg,
4%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 1.84
(3H, s), 2.2-2.3 (2H, m), 2.4-2.5 (5H, m), 3.2-3.4
(2H, m), 3.67 (2H, s), 5.05-5.15 (1H, m), 5.37 (2
H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.6 (10H, m),
8.0-8.1 (1H, m). IR (KBr): 1717, 1669, 1534, 1470, 1236, 1032, 735
cm ^-1 .

Example 16 3-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3-phenyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] -N-isopropylpropanamide

[Chemical formula 46] Using the compound of Example 7 (200 mg, 0.309 mmol) and isopropylamine (0.53 ml, 6.18 mmol), the same reaction as in Example 10 was carried out to obtain the title compound (20 mg, 9%) as colorless crystals. It was ¹ H-NMR (CDCl ₃ ) δ: 0.89 (6H, t, J = 6.6 Hz), 1.16
(3H, t, J = 7.2 Hz), 2.06 (3H, s), 2.15-2.25 (2H,
m), 2.35-2.45 (2H, m), 3.2-3.4 (2H, m), 3.75 (2H,
s), 3.8-4.0 (1H, m), 5.2-5.3 (1H, m), 5.37 (2H,
s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.7 (11H, m). IR (KBr): 1717, 1669, 1532, 1470, 1236, 1034, 731
cm ⁻¹ .mp 213-215 ° C. Example 17 2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4 -Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] -N, N-dimethylacetamide

[Chemical 47] Using the compound of Example 8 (200 mg, 0.316 mmol) and a solution of dimethylamine in tetrahydrofuran (2M) (1 ml, 2 mmol), the same reaction as in Example 10 was carried out to give the title compound (21 mg,
10%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.4 Hz), 2.11
(3H, s), 2.81 (3H, s), 2.89 (3H, s), 3.2-3.35 (4H,
m), 3.93 (2H, s), 5.25-5.35 (1H, m), 5.36 (2H, s),
6.92 (2H, t, J = 8.0 Hz), 7.2-7.6 (10H, m) .IR (KBr): 1719, 1674, 1628, 1534, 1319, 1227, 1030
cm ⁻¹ .mp 208-209 ° C. Example 18 4-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4 -Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-5
-Yl] methyl} (methyl) amino] -N, N-dimethylbutanamide

[Chemical 48] A solution of the compound of Example 9 (300 mg, 0.453 mmol) and dimethylamine in tetrahydrofuran (2M) (0.45 ml, 0.906 mmol)
Was performed in the same manner as in Example 10 to give the title compound
(154 mg, 49%) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4 Hz), 1.6-1.
75 (2H, m), 1.98 (3H, s), 2.15-2.3 (2H, m), 2.3-2.5
(2H, m), 2.84 (3H, s), 2.88 (3H, s), 3.2-3.4 (2H,
m), 3.74 (2H, s), 5.2-5.3 (1H, m), 5.36 (2H, s),
6.91 (2H, t, J = 8.0 Hz), 7.2-7.6 (10H, m). IR (KBr): 1717, 1663, 1626, 1470, 1233, 1030, 741
cm ^-1 .Elemental analysis Calculated as C ₃₆ H ₃₈ F ₂ N ₆ O ₄ S ・ 0.5H ₂ O: C, 61.97; H, 5.63; N, 12.04. Found: C; 61.89; H, 5.63; N , 12.13.mp 191-193 ° C.

Example 19 N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3 -
Production of phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} acetamide

[Chemical 49] Dissolve N-2-hydroxyethylacetamide (516 mg, 5 mmol) in tetrahydrofuran (10 ml) and add triethylamine.
(0.69 ml, 5 mmol) and methanesulfonyl chloride (0.39 m
(1, 5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The aqueous layer was salted out and extracted with ethyl acetate. The organic layers were collected, dried over magnesium sulfate, and concentrated under reduced pressure to give mesylate. The obtained mesylate, the compound of Example 1 (288 mg, 0.5 mmol), N, N-diisopropylethylamine (0.17 ml, 1 mmol) and potassium iodide (0.83 g, 5 mmol) in DMF (4 ml) were added to 50 parts. After stirring at -60 ° C for 3 days, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Eluent: ethyl acetate / methanol; 10/1) and further recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (123 mg, 37%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.53
(3H, s), 1.58 (3H, s), 2.3-2.4 (2H, m), 3.05-3.2 (2
H, m), 3.2-3.4 (2H, m), 3.62 (2H, s), 5.2-5.3 (1H,
m), 5.37 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.15-
7.6 (10H, m). IR (KBr): 1717, 1655, 1535, 1468, 1236, 1032, 735
cm ^-1 .Elemental analysis Calculated as C ₃₄ H ₃₄ F ₂ N ₆ O ₄ S ・ 2.0H ₂ O: C, 58.61; H, 5.50; N, 12.06. Found: C, 58.43; H, 5.21; N , 11.97. Mp 185-186 ° C. Example 20 N- {4- [1- (2,6-difluorobenzyl) -5-({methyl [2- (2-
Oxo-1-pyrrolidinyl) ethyl] amino} methyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical 50] Using the compound of Example 1 (288 mg, 0.5 mmol) and 1- (2-hydroxyethyl) -2-pyrrolidone (0.65 g, 5 mmol), the same reaction as in Example 19 was carried out to give the title compound (85 mg , twenty five %)
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.7-1.
9 (2H, m), 2.12 (3H, s), 2.15-2.3 (2H, m), 2.45-2.
6 (2H, m), 3.15-3.35 (6H, m), 3.76 (2H, s), 5.1-5.2
(1H, m), 5.37 (2H, s), 6.91 (2H, t, J = 8.0 Hz),
7.1-7.55 (10H, m). IR (KBr): 1717, 1667, 1534, 1470, 1236, 1032, 737
cm ^-1 . Elemental analysis Calculated as C ₃₆ H ₃₆ F ₂ N ₆ O ₄ S 1.0H ₂ O: C, 61.35; H, 5.43; N, 11.92. Found: C; 61.11; H, 5.23; N , 11.70. Mp 140-142 ° C. Example 21 N- {4- [1- (2,6-difluorobenzyl) -5-({methyl [2- (2-
Oxo-1-pyrrolidinyl) propyl] amino} methyl) -2,4
-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,
Production of 3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical 51] Using the compound of Example 1 (288 mg, 0.5 mmol) and 1- (3-hydroxypropyl) -2-pyrrolidone (716 mg, 5 mmol),
The reaction was performed in the same manner as in Example 19, and the title compound (205 mg, 59
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.8-2.
0 (2H, m), 2.02 (3H, s), 2.25-2.4 (4H, m), 3.1-3.4
(6H, m), 3.73 (2H, s), 5.2-5.3 (1H, m), 5.36 (2H,
s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.6 (10H, m) .IR (KBr): 1713, 1672, 1532, 1460, 1318, 1238, 103
. 4, 735 cm ^-1 elemental analysis _{C 37 H 38 F 2 N 6} O 4 S · 1.2H 2 O Calculated: C, 61.52; H, 5.64 ; N, 11.63 Found:. C; 61.17; H, 5.25; N, 11.56.mp 193-195 ° C.

Example 22 N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2,4-dioxo-3 -
Preparation of phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} methanesulfonamide

[Chemical 52] The compound of Example 1 (288 mg, 0.5 mmol) and 2-aminoethanol (153 mg, 2.5 mmol) were subjected to the same reaction as in Example 19 to obtain the title compound (267 mg, 77%) as colorless crystals. It was ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.83
(3H, s), 2.45-2.55 (2H, m), 2.54 (3H, s), 3.05-3.15
(2H, m), 3.25-3.35 (2H, m), 3.67 (2H, s), 4.85-4.
9 (1H, m), 5.25-5.35 (1H, brm), 5.36 (2H, s), 6.68
(1H, s), 6.93 (2H, t, J = 8.1 Hz), 7.2-7.6 (10H,
m). IR (KBr): 1717, 1667, 1470, 1316, 1236, 1148, 1032
. cm ^-1 elemental analysis _{C 33 H 34 F 2 N 6} O 5 S 2 · 1.0H 2 O Calculated: C, 55.45; H, 5.08 ; N, 11.76 Found:. C; 55.42; H, 5.14; N, 11.66. Mp 186-188 ° C. Example 23 N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl)- 2,4-dioxo-3-
Preparation of phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} -N-methylmethanesulfonamide

[Chemical 53] Using the compound of Example 1 (2.90 g, 5.04 mmol) and 2-methylaminoethanol (1.88 g, 25 mmol), the same reaction as in Example 19 was carried out to give the title compound (3.04 g, 85%) as colorless crystals. Got as. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.54 (3H, t, J = 6.2 Hz), 2.71 (6H, s), 3.
1-3.2 (2H, m), 3.2-3.4 (2H, m), 3.81 (2H, s), 4.75
-4.85 (1H, m), 5.37 (2H, s), 6.53 (1H, s), 6.92 (2
H, t, J = 8.0 Hz), 7.2-7.6 (10H, m). IR (KBr): 1713, 1674, 1535, 1460, 1325, 1238, 113
. 8, 1036, 976, 789 cm -1 elemental analysis _{C 34 H 36 F 2 N 6} O 5 S 2 Calculated: C, 57.45; H, 5.10 ; N, 11.82 Found:. C; 57.09; H, 5.23; N, 11.59. Mp 216-218 ° C. Example 24 N- {4- [1- (2,6-difluorobenzyl) -5-({methyl [2- (2-
Oxo-1,3-oxazolin-3-yl) ethyl] amino} methyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- [Ill] phenyl} -N'-ethylurea production

[Chemical 54] 2-oxo-1,3-oxazoline (1.74 g, 10 mmol) was added to DMF (15
65% oily sodium hydride (0.40
g, 11 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Further, 1-bromo-2-chloroethane (1.66 ml, 20 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 days. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layers were collected, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a halide. The obtained halide,
DMF solution (4 ml) of the compound of Example 1 (200 mg, 0.347 mmol), N, N-diisopropylethylamine (0.12 ml, 0.694 mmol) and potassium iodide (115 mg, 0.694 mmol) was added at 50-60 ° C.
After stirring for 16 hours, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (41 mg, 17%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4 Hz), 2.09
(3H, s), 2.45-2.6 (2H, m), 3.2-3.45 (6H, m), 3.78
(2H, s), 4.0-4.15 (2H, m), 5.1-5.2 (1H, m), 5.36
(2H, s), 6.92 (2H, t, J = 8.4 Hz), 7.04 (1H, s),
7.2-7.6 (10H, m). IR (KBr): 1717, 1671, 1535, 1468, 1236, 1034, 737
cm ^-1 . Elemental analysis Calculated as C ₃₅ H ₃₄ F ₂ N ₆ O ₅ S 1.0H ₂ O: C, 59.48; H, 5.13; N, 11.89. Found: C, 59.50; H, 4.89; N , 12.02.mp 153-155 ℃.

Example 25 N- {4- [5-{[{2- [benzyl (methyl) amino] ethyl} (methyl) amino] methyl} -1- (2,6-difluorobenzyl) -2,4 -
Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3
Production of -d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical 55] Using the compound of Example 1 (1.15 g, 2 mmol) and N-methyl-N-benzylamine (1.21 g, 10 mmol), the same reaction as in Example 24 was carried out to give the title compound (939 mg, 65%). Was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.08
(3H, s), 2.11 (3H, s), 2.35-2.5 (2H, m), 2.5-2.65
(2H, m), 3.2-3.4 (2H, m), 3.41 (2H, s), 3.81 (2H,
s), 4.65-4.75 (1H, m), 5.35 (2H, s), 6.35-6.45 (1
H, m), 6.91 (2H, t, J = 8.2), 7.2-7.6 (15H, m) .IR (KBr): 1717, 1667, 1532, 1470, 1236, 1032, 735
cm ^-1 .Elemental analysis Calculated as C ₄₀ H ₄₀ F ₂ N ₆ O ₃ S ・ 0.6H ₂ O: C, 65.48; H, 5.66; N, 11.45. Found: C; 65.18; H, 5.58; N , 11.49. Mp 151-153 ° C. Example 26 N- {4- [1- (2,6-difluorobenzyl) -5-({methyl [2- (methylamino) ethyl] amino} methyl) -2, 4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
Production of -6-yl] phenyl} -N'-ethylurea

[Chemical 56] The compound of Example 25 (900 mg, 1.2 mmol) was added to methanol (3
It was dissolved in 0 ml), 1N hydrochloric acid (2.5 ml, 2.5 mmol) and 10% hydrous palladium carbon (300 mg) were added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the palladium carbon was filtered off, the filtrate was neutralized with 1N aqueous sodium hydroxide solution (2.5 ml).
After concentration under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 10/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (453 mg, 49%) as colorless crystals. . ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 2.02
(3H, s), 2.25 (3H, s), 2.4-2.6 (4H, m), 3.2-3.4 (2
H, m), 3.76 (2H, s), 4.9-5.0 (1H, m), 5.36 (2H,
s), 6.65-6.75 (1H, m), 6.92 (2H, t, J = 8.2 Hz),
7.2-7.6 (10H, m). IR (KBr): 1713, 1672, 1534, 1472, 1458, 1316, 123
8, 1034, 789 cm ^-1 . Elemental analysis Calculated as C ₃₃ H ₃₄ F ₂ N ₆ O ₃ S ・ 0.2H ₂ O: C, 62.29; H, 5.45; N, 13.21. Found: C, 62.01; H, 5.43; N, 13.15.mp 192-193 ° C. Example 27 N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino } Phenyl) -2,4-dioxo-3-
Preparation of phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} -N-methylacetamide

[Chemical 57] The compound of Example 26 (200 mg, 0.316 mmol) was added to THF (8 ml).
Was dissolved in water, triethylamine (0.066 ml, 0.474 mmol) and acetic anhydride (0.036 ml, 0.379 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (163 mg, 76%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (1.5H, t, J = 7.2 Hz), 1.16
(1.5H, t, J = 7.2 Hz), 1.94 (1.5H, s), 2.00 (1.5
H, s), 2.13 (1.5H, s), 2.18 (1.5H, s), 2.5-2.6 (2
H, m), 2.75 (1.5H, s), 2.83 (1.5H, s), 3.2-3.4 (4
H, m), 3.78 (1H, s), 3.82 (1H, s), 5.2-5.3 (1H, m),
5.37 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.1-7.2 (1
H, m), 7.2-7.6 (10H, m). IR (KBr): 1713, 1674, 1535, 1460, 1316, 1238, 103
. 6, 787, 735 cm ^-1 elemental analysis _{C 35 H 36 F 2 N 6} O 4 S · 0.8H 2 O Calculated:. C, 61.00; H, 5.50; N, 12.19 Found: C, 60.71; H, 5.20; N, 12.09.mp 180-181 ° C.

Example 28 N- (4- {1- (2,6-difluorobenzyl) -3- [4- (2-methoxyethoxy) phenyl] -5-[(methylamino) methyl] -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
-6-yl} phenyl) -N'-ethylurea production

[Chemical 58] The compound of Reference Example 14 (2.0 g, 2.70 mmol) was added to methanol (5
It was dissolved in 0 ml), 1N hydrochloric acid (6 ml) and 10% hydrous palladium-carbon (0.75 g) were added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After removing the palladium carbon, the filtrate was neutralized with 1N aqueous sodium hydroxide solution (6 ml). After concentration under reduced pressure,
Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The precipitate was washed with diethyl ether and the title compound (1.50
g, 86%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.2 Hz), 2.34
(3H, s), 3.2-3.4 (2H, m), 3.46 (3H, s), 3.7-3.8 (4
H, m), 4.16 (2H, t, J = 4.8 Hz), 4.8-4.9 (1H, m),
5.36 (2H, s), 6.82 (1H, s), 6.91 (2H, t, J = 8.2 H
z), 7.05 (2H, d, J = 9.0 Hz), 7.17 (2H, d, J = 9.0
Hz), 7.25-7.4 (5H, m) .IR (KBr): 1713, 1665, 1472, 1254, 1034, 791 cm ^-1 . Elemental analysis C ₃₃ H ₃₃ F ₂ N ₅ O ₅ S ・ 0.2H ₂ O Calculated as: C, 60.67; H, 5.15; N, 10.72. Found: C, 60.42; H, 5.14; N, 10.67.mp 203-205 ° C. Example 29 N- (4- {1- (2 , 6-Difluorobenzyl) -3- (4-fluorophenyl) -5-[(methylamino) methyl] -2,4-dioxo-1,2,3,
Preparation of 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea

[Chemical 59] Using the compound of Reference Example 15 (2.1 g, 3.07 mmol), the same reaction as in Example 28 was carried out to give the title compound (1.43 g, 78).
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.1-1.2 (3H, m), 2.35 (3H, s),
3.25-3.35 (2H, m), 3.76 (2H, s), 4.7-4.8 (1H, m),
5.36 (2H, s), 6.55-6.6 (1H, m), 6.85-7.0 (2H, m),
7.15-7.45 (10H, m) .IR (KBr): 1721, 1663, 1472, 1238, 1034, 839, 762 c
m ⁻¹ .mp 220-221 ° C. Example 30 3-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylaminocarbonyl) amino] phenyl} -3- (4 -Fluorophenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]
Preparation of Pyrimidin-5-yl) methyl] (methyl) amino} -N-methylpropanamide

[Chemical 60] The compound of Example 29 (200 mg, 0.337 mmol) and 3-bromo-N
-Methylpropanamide (84 mg, 0.506 mmol) was used to carry out the same reaction as in Example 4 to give the title compound (116 mg,
51%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 1.85
(3H, s), 2.2-2.3 (2H, m), 2.35-2.5 (2H, m), 2.45
(2H, d, J = 4.4 Hz), 3.2-3.4 (2H, m), 3.67 (2H,
s), 5.2-5.3 (1H, m), 5.36 (2H, s), 6.92 (2H, t, J
= 8.0 Hz), 7.15-7.5 (9H, m), 8.0-8.1 (1H, m). IR (KBr): 1721, 1667, 1474, 1236, 1036, 837, 762 c
m ^-1 .Elemental analysis Calculated as C ₃₄ H ₃₃ F ₃ N ₆ O ₄ S ・ 0.5H ₂ O: C, 59.38; H, 4.98; N, 12.22. Found: C; 59.39; H, 4.91; N , 12.15.mp 237-239 ℃.

Example 31 3-[({1- (2,6-difluorobenzyl) -6- (4-{[(ethylaminocarbonyl) amino] phenyl} -3- [4- (2-methoxyethoxy) Phenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl} (methyl) amino) -N-methylpropanamide

[Chemical formula 61] The compound of Example 28 (200 mg, 0.308 mmol) and 3-bromo-N
-Methylpropanamide (77 mg, 0.462 mmol) was used to carry out the same reaction as in Example 4 to give the title compound (168 mg,
74%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4 Hz), 1.81
(3H, s), 2.2-2.5 (7H, m), 3.2-3.4 (2H, m), 3.46 (3
H, s), 3.66 (2H, s), 3.77 (2H, t, J = 4.8 Hz), 4.1
6 (2H, t, J = 4.8 Hz), 5.2-5.3 (1H, m), 5.36 (2H,
s), 6.91 (2H, t, J = 8.2 Hz), 7.05 (2H, d, J = 8.8
Hz), 7.1-7.5 (5H, m), 7.41 (2H, d, J = 8.8 Hz), 7.5
9 (1H, s), 8.05-8.15 (1H, m). IR (KBr): 1715, 1667, 1470, 1238, 1032, 764 cm ^-1 . Elemental analysis C ₃₇ H ₄₀ F ₂ N ₆ O ₆ S ・Calculated as 0.5H ₂ O: C, 59.75; H, 5.56; N, 11.30. Found: C; 59.52; H, 5.45; N, 11.26.mp 163-165 ° C. Example 32 3-[{[1 -(2,6-Difluorobenzyl) -6- (4-{[(ethylaminocarbonyl) amino] phenyl} -3- (4-fluorophenyl) -2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d]
Preparation of Pyrimidin-5-yl) methyl] (methyl) amino} -N, N-dimethylpropanamide

[Chemical formula 62] The compound of Example 29 (200 mg, 0.300 mmol) and 3-bromo-N
-Methylpropanamide (77 mg, 0.462 mmol) was used to carry out the same reaction as in Example 4 to give the title compound (50 mg, 24
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2 Hz), 2.05
(3H, s), 2.4-2.5 (2H, m), 2.7-2.8 (2H, m), 2.87 (3
H, s), 2.89 (2H, s), 3.2-3.4 (2H, m), 3.77 (2H,
s), 5.2-5.3 (1H, m), 5.35 (2H, s), 6.91 (2H, t, J
= 8.2 Hz), 7.1-7.45 (9H, m). IR (KBr): 1719, 1669, 1626, 1472, 1236, 1032, 764
. cm ^-1 elemental analysis _{C 35 H 35 F 3 N 6} O 4 S · 0.5H 2 O Calculated: C, 59.90; H, 5.17 ; N, 11.98 Found:. C; 59.60; H, 4.95; N , 11.86. Mp 210-212 ° C. Example 33 N- {4- [1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-({methyl [2- (2-oxo Preparation of -1-piperidinyl) ethyl] amino} methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical formula 63] Using the compound of Example 29 (297 mg, 0.5 mmol) and 1- (2-hydroxyethyl) -2-pyrrolidone (0.65 g, 5 mmol),
The reaction was performed in the same manner as in Example 19, and the title compound (179 mg, 50
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.7-1.
9 (2H, m), 2.12 (3H, s), 2.23 (2H, t, J = 8.0 Hz),
2.5-2.6 (2H, m), 3.15-3.4 (6H, m), 3.75 (2H, s),
5.2-5.3 (1H, m), 5.36 (2H, s), 6.91 (2H, t, J = 8.
2 Hz), 7.1-7.3 (5H, m), 7.39 (2H, d, J = 8.6 Hz),
7.48 (2H, d, J = 8.6 Hz) .IR (KBr): 1721, 1665, 1464, 1236, 1036, 837, 762 c
m ^-1 .Elemental analysis Calculated as C ₃₆ H ₃₅ F ₃ N ₆ O ₄ S ・ 0.5H ₂ O: C, 60.58; H, 5.08; N, 11.77. Found: C; 60.67; H, 4.87; N , 11.83.mp 204-206 ℃.

Example 34 N- {4- [1- (2,6-difluorobenzyl) -3- [4- (2-methoxyethoxy) phenyl] -5-({methyl [2- (2-oxo- 1-piperidinyl) ethyl] amino} methyl) -2,4-dioxo-1,2,3,4-
Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical 64] Using the compound of Example 28 (325 mg, 0.5 mmol) and 1- (2-hydroxyethyl) -2-pyrrolidone (0.65 g, 5 mmol),
The reaction was performed in the same manner as in Example 19, and the title compound (302 mg, 79
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.7-1.
9 (2H, m), 2.12 (3H, s), 2.23 (2H, t, J = 7.8 Hz),
2.5-2.6 (2H, m), 3.15-3.35 (6H, m), 3.46 (3H, s),
3.7-3.8 (4H, m), 4.15 (2H, t, J = 4.8 Hz), 5.15-
5.25 (1H, m), 5.36 (2H, s), 6.90 (2H, t, J = 8.2 H
z), 7.03 (2H, d, J = 9.0 Hz), 7.16 (2H, d, J = 9.0
Hz), 7.25-7.35 (2H, m), 7.39 (2H, d, J = 8.4 Hz),
7.48 (2H, d, J = 4.8 Hz) .IR (KBr): 1717, 1665, 1534, 1470, 1238, 1032 cm ^-1 . Elemental analysis C ₃₉ H ₄₂ F ₂ N ₆ O ₆ S ・ 0.5H ₂ O Calculated as: C, 60.85; H, 5.63; N, 10.92. Found: C; 60.58; H, 5.60; N, 10.80.mp 175-177 ° C. Example 35 N- {4- [1- (2 , 6-Difluorobenzyl) -3- (4-fluorophenyl) -5-({methyl [2- (2-oxo-1,3-oxazolidine-3-
Iyl) methyl] amino} methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl}
-N'-Ethylurea production

[Chemical 65] The compound of Example 29 (200 mg, 0.34 mmol) and 2-oxo-1,
Example 24 using 3-oxazoline (0.87 g, 10 mmol)
The same reaction as in (1) was performed to give the title compound (37 mg, 15%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 2.10
(3H, s), 2.5-2.6 (2H, m), 3.2-3.45 (6H, m), 3.78
(2H, s), 4.0-4.15 (2H, m), 5.0-5.1 (1H, m), 5.36
(2H, s), 6.8-6.9 (1H, m), 6.92 (2H, t, J = 8.2 H
z), 7.1-7.35 (5H, m), 7.40 (2H, d, J = 8.8 Hz), 7.4
8 (2H, d, J = 8.8 Hz). IR (KBr): 1721, 1665, 1472, 1236, 1036, 762 cm ^-1 .mp 193-195 ° C. Example 36 N- {4- [1- ( 2,6-Difluorobenzyl) -3- (4-fluorophenyl) -5-({methyl [(1-methyl-2-oxo-3-pyrrolidinyl) methyl] amino} methyl) -2,4-dioxo-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl}
-N'-Ethylurea production

[Chemical formula 66] The compound of Example 29 (237 mg, 0.4 mmol) and 3- (hydroxymethyl) -1-methylpyrrolidin-2-one (0.52 g, 4 mmol)
Was performed in the same manner as in Example 19 to give the title compound
(88 mg, 31%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4 Hz), 1.7-1.
9 (1H, m), 1.95 (3H, s), 2.0-2.2 (1H, m), 2.4-2.8
(3H, m), 2.79 (3H, s), 3.2-3.4 (4H, m), 3.77 (2H,
s), 5.15-5.25 (1H, m), 5.25-5.45 (2H, m), 6.92 (2
H, t, J = 8.2 Hz), 7.15-7.45 (10H, m). IR (KBr): 1723, 1665, 1474, 1236, 1036, 837, 762 c
m ^-1 .Elemental analysis Calculated as C ₃₆ H ₃₅ F ₃ N ₆ O ₄ S ・ 0.5H ₂ O: C, 60.58; H, 5.08; N, 11.77. Found: C; 60.34; H, 4.99; N , 11.69.mp 233-234 ℃.

Example 37 N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- (4-fluorophenyl ) -2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,
Preparation of 3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} -N-methylsulfonamide

[Chemical formula 67] Using the compound of Example 29 (250 mg, 0.42 mmol) and 2-methylaminoethanol (158 mg, 2.1 mmol), Example 1
The same reaction as in 9 was performed to give the title compound (133 mg, 44%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.13
(3H, s), 2.5-2.6 (2H, m), 2.706 (3H, s), 2.713 (3
H, s), 3.1-3.2 (2H, m), 3.2-3.4 (2H, m), 3.80 (2H, m
s), 4.7-4.8 (1H, m), 5.36 (2H, s), 6.47 (1H, s),
6.92 (2H, t, J = 7.8 Hz), 7.15-7.35 (5H, m), 7.39
(2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.6 Hz). IR (KBr): 1723, 1663, 1474, 1333, 1236, 1144, 103
. 4, 762 cm ^-1 elemental analysis _{C 34 H 35 F 3 N 6} O 5 S 2 Calculated: C, 56.03; H, 4.84 ; N, 11.53 Found:. C; 55.74; H, 4.76; N, 11.46. Mp 228-230 ° C. Example 38 N- {2-[({1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- [4- (2-Methoxyethoxy) phenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl} methyl) (methyl)
Amino] ethyl} -N-methylsulfonamide production

[Chemical 68] Using the compound of Example 28 (250 mg, 0.385 mmol) and 2-methylaminoethanol (158 mg, 2.1 mmol), Example 1
The same reaction as in 9 was performed to give the title compound (218 mg, 72%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.5-2.6 (2H, m), 2.70 (6H, s), 3.1-3.2 (2
H, m), 3.2-3.4 (2H, m), 3.45 (3H, s), 3.7-3.85 (4
H, m), 4.1-4.2 (2H, m), 4.7-4.8 (1H, m), 5.36 (2H,
s), 6.46 (1H, s), 6.91 (2H, t, J = 8.2 Hz), 7.03
(2H, d, J = 9.0 Hz), 7.16 (2H, d, J = 9.0 Hz), 7.2
5-7.35 (1H, m), 7.38 (2H, d, J = 8.6 Hz), 7.48 (2
H, d, J = 8.6Hz) .IR (KBr): 1717, 1663, 1472, 1331, 1238, 1032, 762
. cm ^-1 elemental analysis _{C 37 H 42 F 2 N 6} O 7 S 2 · 0.1H 2 O Calculated: C, 56.49; H, 5.41 ; N, 10.68 Found:. C; 56.21; H, 5.35; N, 10.68.mp 197-199 ° C. Example 39 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5- {[(2-Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-
Preparation of dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenyl] -N, N-dimethylacetamide:

[Chemical 69] The compound of Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-hydroxybenzotriazole (230 m
g), 4-aminophenyl-N, N-dimethylacetamide (268
mg) in DMF solution (7.5 ml) under ice-cooling, N-ethyldiisopropylamine (323 μl) was added, and the mixture was gradually warmed to room temperature.
After stirring for 24 hours, the reaction solution was partitioned with ethyl acetate / water. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was roughly purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.) to obtain a crude amide compound (384
mg) was dissolved in ethanol (24.5 ml), sodium ethoxide (66.5 mg) was added, and the mixture was stirred at room temperature for 3 hr. The precipitated crystals were collected by filtration, washed and dried to give the title compound (117 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.1 Hz), 2.08
(3H, s), 2.57 (2H, t, J = 5.8 Hz), 2.98 (3H, s), 3.
04 (3H, s), 3.22 (3H, s), 3.21-3.34 (2H, m), 3.36
(2H, t, J = 5.8 Hz), 3.78 (4H, s), 5.14 (1H, t, J
= 5.5 Hz), 5.33 (2H, s), 6.90 (2H, t, J = 8.1 Hz),
6.99 (1H, s), 7.23 (2H, d, J = 8.4 Hz), 7.21-7.29
(1H, m), 7.34 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J
= 8.4 Hz), 7.50 (2H, d, J = 8.4 Hz). IR (KBr): 1715, 1671, 1593, 1534, 1464, 1318, 1236
cm ^-1 . Elemental analysis Calculated as C ₃₇ H ₄₀ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 61.06; H, 5.68; N, 11.55. Found: C, 60.94; H, 5.48; N, 11.57.

Example 40 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5- {[(2-methoxyethyl ) (Methyl) amino] methyl} -2,4-dioxo-1,4
Preparation of -dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenyl] -N-ethylacetamide:

[Chemical 70] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-hydroxy A crude amide compound (330 mg) was obtained from benzotriazole (230 mg), 4-aminophenyl-N-ethylacetamide (268 mg), and N-ethyldiisopropylamine (323 μl),
In addition, ethanol (20.5 ml), sodium ethoxide (55
The title compound (268 mg) was obtained. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.09 (3H, t, J = 7.2 Hz),
1.17 (3H, t, J = 7.4Hz), 2.09 (3H, s), 2.59 (2H,
t, J = 5.8 Hz), 3.19-3.33 (4H, m), 3.25 (3H, s),
3.40 (2H, t, J = 5.8 Hz), 3.64 (2H, s), 3.82 (2H,
s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.27
(2H, d, J = 8.4 Hz), 7.24-7.33 (1H, m), 7.40 (2H,
d, J = 8.4 Hz), 7.44 (4H, s) .IR (KBr): 1721, 1667, 1628, 1532, 1470 cm ^-1 . Elemental analysis C ₃₇ H ₄₀ N ₆ O ₅ SF ₂・ 0.25H ₂ O Calculated as: C, 61.44; H, 5.64; N, 11.62. Found: C, 61.49; H, 5.52; N, 11.68. Example 41 2- [4- (1- (2,6-difluorobenzyl) -6- (4- {[(ethylamino) carbonyl] amino} phenyl) -5- {[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-
Preparation of dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenyl] -N-methylacetamide:

[Chemical 71] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-hydroxy Benzotriazole (230 mg), 4-aminophenyl-N-methylacetamide (246 mg), N-ethyldiisopropylamine (323 μl) to obtain a crude amide compound (387 mg), further ethanol (24 ml), sodium ethoxide ( The title compound (264 mg) was obtained using (64 mg). ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.16 (3H, t, J = 7.2 Hz),
2.08 (3H, s), 2.58 (2H, t, J = 5.8 Hz), 2.73 (3H,
s), 3.23-3.30 (2H, m), 3.25 (3H, s), 3.40 (2H, t,
J = 5.8 Hz), 3.65 (2H, s), 3.81 (2H, s), 5.37 (2
H, s), 6.94 (2H, t, J = 8.1 Hz), 7.27 (2H, d, J =
8.4 Hz), 7.27-7.35 (1H, m), 7.40 (2H, d, J = 8.4 H
z), 7.44 (4H, s) .IR (KBr): 1717, 1669, 1593, 1553, 1532, 1470, 131
. 8, 1236 cm ^-1 elemental analysis _{C 36 H 38 N 6 O 5} SF 2 · 0.5H 2 O Calculated:. C, 60.58; H, 5.51; N, 11.77 Found: C, 60.31; H, 5.51 N, 11.88. Example 42 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3 -{4- [2-
Oxo-2- (1-pyrrolidinyl) ethoxy] phenyl} -1,2,3,
Preparation of 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 72] Subjected to the same reaction as in Example 39, the compound (454 mg) obtained in Reference Example 9, diethyl cyanophosphate (152 μl), and 4-aminophenoxypyrrolidinyl acetamide (330 mg) were used as a crude amide compound. (501 mg) and ethanol (29 ml) and sodium ethoxide (80 mg) to give the title compound (331 m
g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (3H, t, J = 7.2 Hz), 1.7
4-1.83 (2H, m), 1.87-1.93 (2H, m), 2.05 (3H, s),
2.47 (2H, t, J = 5.7 Hz), 3.07-3.15 (2H, m), 3.15
(3H, s), 3.28-3.37 (4H, m), 3.49 (2H, t, J = 5.7 H
z), 3.70 (2H, s), 4.77 (2H, s), 5.28 (2H, s), 6.20
(1H, t, J = 5.6 Hz), 6.99 (2H, t, J = 9.0 Hz), 7.10
-7.16 (4H, m), 7.40-7.54 (5H, m), 8.67 (1H, s) .IR (KBr): 1717, 1665, 1595, 1531, 1462, 1300, 1229
cm ^-1 .Elemental analysis Calculated as C ₃₉ H ₄₂ N ₆ O ₆ SF ₂・ 0.5H ₂ O: C, 60.84; H, 5.63; N, 10.92. Found: C, 60.96; H, 5.36; N, 10.74.

Example 43 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl ) (Methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenoxy]
Production of -N-ethylacetamide:

[Chemical formula 73] Subjected to the same reaction as in Example 39, the compound (454 mg) obtained in Reference Example 9, diethyl cyanophosphate (152 μl), and 4-aminophenoxy-N-ethylacetamide (292 mg) were used to give a crude amide compound ( 493 mg) and ethanol (30 ml) and sodium ethoxide (82 mg) were used to give the title compound (356 mg).
Got ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 6.9 Hz), 1.0
7 (3H, t, J = 7.2 Hz), 2.05 (3H, s), 2.48 (2H, t, J
= 6.0 Hz), 3.07-3.23 (4H, m), 3.15 (3H, s), 3.30
(2H, t, J = 6.0 Hz), 3.70 (2H, s), 4.51 (2H, s),
5.28 (2H, s), 6.20 (1H, t, J = 5.4 Hz), 7.04 (2H,
d, J = 8.7 Hz), 7.10-7.17 (4H, m), 7.41-7.54 (5H,
m), 8.16 (1H, t, J = 5.1 Hz), 8.66 (1H, s) .IR (KBr): 1717, 1669, 1595, 1532, 1470, 1314, 1236
cm ^-1 . Elemental analysis Calculated as C ₃₇ H ₄₀ N ₆ O ₆ SF ₂・ 0.5H ₂ O: C, 59.75; H, 5.56; N, 11.30. Found: C, 59.73; H, 5.27; N, 11.17. Example 44 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) (Methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenoxy]
Production of -N-methylacetamide:

[Chemical 74] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-hydroxy A crude amide compound (447 mg) was obtained from benzotriazole (230 mg), 4-aminophenoxy-N-methylacetamide (270 mg) and N-ethyldiisopropylamine (323 μl).
In addition, ethanol (27 ml) and sodium ethoxide (74 m
The title compound (339 mg) was obtained using g). ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.1 Hz), 2.0
5 (3H, s), 2.48 (2H, t, J = 6.0 Hz), 2.68 (3H, d,
J = 1.8 Hz), 3.07-3.15 (2H, m), 3.15 (3H, s), 3.30
(2H, t, J = 6.0 Hz), 3.70 (2H, s), 4.52 (2H, s),
5.28 (2H, s), 6.20 (1H, t, J = 5.6 Hz), 7.05 (2H,
d, J = 8.7 Hz), 7.10-7.18 (4H, m), 7.41-7.54 (5H,
m), 8.10 (1H, q, J = 1.8 Hz), 8.67 (1H, s) .IR (KBr): 1717, 1667, 1595, 1532, 1472, 1298, 1236
. cm ^-1 elemental analysis _{C 36 H 38 N 6 O 6} SF 2 · H 2 O Calculated:. C, 58.53; H, 5.46; N, 11.38 Found: C, 58.56; H, 5.45 ; N, 11.44 Example 45 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) ( Methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenoxy] -N, N-dimethylacetamide:

[Chemical 75] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-hydroxy Benzotriazole (230 mg), 4-aminophenoxy-N-methylacetamide (270 mg), N-ethyldiisopropylamine (323 μl) to crude amide (511 mg)
The title compound (375 mg) was obtained using ethanol (30 ml) and sodium ethoxide (82 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.2 Hz), 2.0
5 (3H, s), 2.48 (2H, t, J = 6.0 Hz), 2.87 (3H, s),
3.03 (3H, s), 3.07-3.14 (2H, m), 3.15 (3H, s), 3.3
1 (2H, t, J = 6.0 Hz), 3.70 (2H, s), 4.86 (2H, s),
5.28 (2H, s), 6.19 (1H, t, J = 5.4 Hz), 6.99 (2H,
d, J = 9.0 Hz), 7.11-7.16 (4H, m), 7.40-7.54 (5H,
m), 8.65 (1H, s) .IR (KBr): 1721, 1669, 1593, 1532, 1470, 1314, 1236
cm ^-1 . Elemental analysis Calculated as C ₃₇ H ₄₀ N ₆ O ₆ SF ₂・ 0.5H ₂ O: C, 59.75; H, 5.56; N, 11.30. Found: C, 59.90; H, 5.79; N, 11.53.

Example 46 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl ) (Methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenoxy] acetamide:

[Chemical 76] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-hydroxy Benzotriazole (230 mg), 4-aminophenoxyacetamide (250 mg), N-ethyldiisopropylamine (323 μl) to obtain a crude amide compound (397 mg), further ethanol (25 ml), sodium ethoxide ( The title compound (298 mg) was obtained using 68 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.2 Hz), 2.0
5 (3H, s), 2.48 (2H, t, J = 6.0 Hz), 3.07-3.15 (2
H, m), 3.15 (3H, s), 3.31 (2H, t, J = 5.7 Hz), 3.7
0 (2H, s), 4.48 (2H, s), 5.29 (2H, s), 6.19 (1H,
t, J = 5.5 Hz), 7.04 (2H, d, J = 9.3 Hz), 7.13 (2
H, t, J = 8.7 Hz), 7.15 (2H, d, J = 9.0 Hz, 7.40-
7.59 (7H, m), 8.66 (1H, s) .IR (KBr): 1715, 1669, 1593, 1539, 1472, 1296, 1236
. cm ^-1 elemental analysis _{C 35 H 36 N 6 O 6} SF 2 · 0.5H 2 O Calculated:. C, 58.73; H, 5.21; N, 11.74 Found: C, 58.98; H, 5.13 ; N, 11.80. Example 47 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) Preparation of (methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl)] benzamide:

[Chemical 77] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (390 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (246 mg), 1-hydroxy Benzotriazole (196 mg), 4-aminobenzamide (174 mg), N-ethyldiisopropylamine (207
The crude amide compound (216 mg) was obtained from
ml) and sodium ethoxide (25 mg) to give the title compound (72 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.1 Hz), 2.0
5 (3H, s), 2.48 (2H, t, J = 6.0 Hz), 3.07-3.16 (2
H, m), 3.15 (3H, s), 3.31 (2H, t, J = 6.0 Hz), 3.7
0 (2H, s), 5.29 (2H, s), 6.19 (1H, t, J = 5.4 Hz),
7.13 (2H, t, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 H
z), 7.43-7.54 (6H, m), 7.97 (2H, d, J = 8.4 Hz), 8.
07 (1H, s), 8.65 (1H, s). IR (KBr): 1717, 1669, 1601, 1532, 1472, 1385, 1319
cm ^-1 . Elemental analysis Calculated as C ₃₄ H ₃₄ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 59.55; H, 5.14; N, 12.26. Found: C, 59.74; H, 5.42; N, 12.55. Example 48 Methyl [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) ( Methyl) amino] methyl} -2,4-dioxo-1,4-
Preparation of dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) benzoate:

[Chemical 78] Subjected to the same reaction as in Example 39, the compound (5.45 g) obtained in Reference Example 9, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (2.59 g), 1-hydroxy A crude amide compound (2.92 g) was obtained from benzotriazole (2.07 g), methyl 4-aminobenzoate (2.04 g) and N-ethyldiisopropylamine (2.91 ml), and further methanol (198 ml) and sodium methoxide (427 mg). The title compound (2.30 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.1 Hz), 2.11
(3H, s), 2.60 (2H, t, J = 5.7 Hz), 3.24 (3H, s), 3.
22-3.32 (2H, m), 3.40 (2H, t, J = 5.7 Hz), 3.80 (2
H, s), 3.93 (3H, s), 4.82 (1H, t, J = 5.9 Hz), 5.3
5 (2H, s), 6.58 (1H, s), 6.92 (2H, t, J = 8.1 Hz),
7.24-7.39 (5H, m), 7.52 (2H, d, J = 8.4 Hz), 8.17
(2H, d, J = 8.4 Hz) .IR (KBr): 2978, 1717, 1674, 1593, 1532, 1464, 1281
. cm ^-1 elemental analysis _{C 35 H 35 N 5 O 6} SF 2 · H 2 O Calculated:. C, 59.23; H, 5.25; N, 9.87 Found: C, 59.38; H, 5.30 ; N, 9.86 .

Example 49 Ethyl [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) (Methyl) amino] methyl} -2,4-dioxo-1,4-
Preparation of dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) benzoate:

[Chemical 79] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (6.05 g), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (2.3 g), 1-hydroxy A crude amide compound (1.76 g) was obtained from benzotriazole (1.84 g), ethyl 4-aminobenzoate (1.98 g) and N-ethyldiisopropylamine (2.07 ml).
74 g), ethanol (49 ml), sodium ethoxide (134 g)
mg) to give the title compound (0.294 g). ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.4 Hz), 1.39
(3H, t, J = 7.1 Hz), 2.11 (3H, s), 2.62 (2H, t, J
= 5.9 Hz), 3.25 (3H, s), 3.24-3.35 (2H, m), 3.41 (2
H, t, J = 5.9 Hz), 3.81 (2H, s), 4.40 (2H, q, J =
7.1 Hz), 4.74 (1H, t, J = 6.0 Hz), 5.36 (2H, s),
6.45 (1H, s), 6.93 (2H, t, J = 8.2 Hz), 7.26-7.39
(5H, m), 7.54 (2H, d, J = 8.4 Hz), 8.18 (2H, d, J
= 8.4 Hz) .IR (KBr): 1713, 1669, 1595, 1535, 1464,
. 1277 cm ^-1 elemental analysis _{C 36 H 37 N 5 O 6} SF 2 · 0.5H 2 O Calculated:. C, 60.49; H, 5.36; N, 9.80 Found: C, 60.69; H, 5.29 ; N Example 50 N- [4- (1- (2,6-difluorobenzyl) -3- (4-hydroxy-3)
-Methylphenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- Production of yl) phenyl] -N'-ethylurea:

[Chemical 80] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (288 mg), 1-
Hydroxybenzotriazole (230 mg), 4-hydroxy
3-Methylaniline ・ hydrogen bromide (306 mg), N-ethyldiisopropylamine (484 μl) to crude amide (230 mg)
The title compound (130 mg) was obtained using methanol (20 ml) and sodium ethoxide (40.2 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.1 Hz), 2.11
(3H, s), 2.60 (2H, t, J = 5.7 Hz), 3.24 (3H, s), 3.
22-3.32 (2H, m), 3.40 (2H, t, J = 5.7 Hz), 3.80 (2
H, s), 3.93 (3H, s), 4.82 (1H, t, J = 5.9 Hz), 5.3
5 (2H, s), 6.58 (1H, s), 6.92 (2H, t, J = 8.1 Hz),
7.24-7.39 (5H, m), 7.52 (2H, d, J = 8.4 Hz), 8.17
(2H, d, J = 8.4 Hz) .IR (KBr): 2978, 1717, 1674, 1593, 1532, 1464, 1281
cm ^-1 . Elemental analysis Calculated as C ₃₄ H ₃₅ N ₅ O ₅ SF ₂ 0.75H ₂ O: C, 60.30; H, 5.43; N, 10.34. Found: C, 60.32; H, 5.53; N, 10.20. Example 51 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -3- [4-methoxy-3- ( Methoxymethyl) phenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 81] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (288 mg), 1-hydroxybenzo Triazole (230 mg), 4-methoxy-3-
A crude amide compound (352 mg) was obtained from methoxymethylaniline (251 mg) and N-ethyldiisopropylamine (323 μl), and further ethanol (22 ml) and sodium ethoxide (59.3 m).
The title compound (230 mg) was obtained using g). ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.0 Hz), 2.12
(3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.25 (3H, s), 3.
21-3.34 (2H, m), 3.41 (3H, s), 3.40 (2H, t, J = 5.7
Hz), 3.83 (5H, s), 4.50 (2H, s), 4.88 (1H, t, J =
5.4 Hz), 5.35 (2H, s), 6.66 (1H, s), 6.89-6.96 (3
H, m), 7.16 (1H, dd, J = 2.4 Hz, 8.7 Hz), 7.24-7.28
(2H, m), 7.35 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J
= 8.4Hz). IR (KBr): 1713, 1671, 1593, 1534, 1464, 1314 cm ^-1 . Elemental analysis C ₃₆ H ₃₉ N ₅ O ₆ SF ₂・ 0.5H ₂ O Calculated value: C, 60.32; H, 5.62; N, 9.77. Found: C, 60.58; H, 5.46; N, 9.86.

Example 52 N- [4- (1- (2,6-difluorobenzyl) -3- [4- (1-hydroxy-1-methylethyl) phenyl] -5-{[(2-methoxyethyl ) (Methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl]
-N'-Ethylurea production

[Chemical formula 82] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (318 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (202 mg), 1-hydroxybenzo Triazole (161 mg), 4- (1-hydroxy-1-methylethyl) aniline (160 mg), N-ethyldiisopropylamine (228 μl) to obtain a crude amide compound (217 mg), further ethanol (12 ml) , Sodium ethoxide
The title compound (46 mg) was obtained using (32.7 mg). Elemental analysis _{C 36 H 39 N 5 O 5} SF 2 · 0.75H 2 O Calculated:. C, 61.31; H, 5.79; N, 9.93 Found:. C, 61.18; H, 5.56; N, 9.88 1 H -NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.58
(6H, s), 1.96 (1H, s), 2.13 (3H, s), 2.62 (2H, t, J
= 5.8 Hz), 3.25 (3H, s), 3.22-3.31 (2H, m), 3.40
(2H, t, J = 5.8 Hz), 3.82 (2H, s), 4.85 (1H, t, J
= 5.4 Hz), 5.36 (2H, s), 6.65 (1H, s), 6.92 (2H, t,
J = 8.1 Hz), 7.24 (2H, dd, J = 8.4Hz), 7.25-7.31
(1H, m), 7.35 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J
= 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz). IR (KBr): 3335, 2975, 1715, 1669, 1593, 1537, 147
0, 1316 cm ^-1 . Example 53 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -3- (6- Methoxy-3-pyridinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 83] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 was used.
Compound (454 mg), diethyl cyanophosphate (164 mg), 5-ami
No-2-methoxypyridine (186 mg), N-ethyldiisopro
Pyramine (2259 μl) was used to obtain the crude amide compound (450 mg).
Ethanol (29.5 ml), sodium ethoxide (80 m
The title compound (265 mg) was obtained using g). ¹ H-NMR (CDCl₃) δ: 1.16 (3H, t, J = 7.2 Hz), 2.11
(3H, s), 2.62 (2H, t, J = 5.6 Hz), 3.25 (3H, s), 3.
23-3.34 (2H, m), 3.41 (2H, t, J = 5.6 Hz), 3.81 (2
H, s), 3.96 (3H, s), 4.86 (1H, t, J = 5.5 Hz), 5.3
5 (2H, s), 6.62 (1H, s), 6.83-6.96 (3H, m), 7.23-7.
31 (1H, m), 7.37 (2H, d, J = 8.4 Hz), 7.47-7.54 (3
H, m), 8.09 (1H, d, J = 2.6 Hz). IR (KBr): 1717, 1672, 1593, 1532, 1464, 1387, 1283
 cm^-1. Elemental analysis C₃₃H₃₄N₆O_Fivescience fiction₂・ 0.25H₂As O Calculated: C, 59.23; H, 5.20; N, 12.56. Found: C, 59.18; H, 5.12; N, 12.48. Example 54 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl
(Cyl) (methyl) amino] methyl} -2,4-dioxo-3- (2-oxy)
So-1,2-dihydro-4-pyrimidinyl) -1,2,3,4-tetrahi
Dorothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-E
Chillurea production:

[Chemical 84] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (164 mg), cytosine (167 mg), N-ethyldiisopropylamine (2259 μl)
The crude amide compound (64 mg) was obtained from
The title compound (24 mg) was obtained using l) and sodium ethoxide (10.5 mg). ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 1.07 (3H, t, J = 7.2 Hz),
2.14 (3H, brs), 2.53 (2H, brs), 3.08-3.13 (2H, m),
3.16 (3H, s), 3.38 (2H, brs), 3.71 (2H, s), 5.29
(2H, s), 6.55 (1H, d, J = 6.6 Hz), 7.14 (2H, t, J
= 8.2 Hz), 7.40-7.60 (5H, m), 8.18 (1H, d, J = 6.6
Hz). IR (KBr): 1717, 1674, 1593, 1537, 1470, 1441, 131
8, 1236 cm ^-1 . Elemental analysis Calculated as C ₃₁ H ₃₁ N ₇ O ₅ SF ₂ 1.75H ₂ O: C, 54.50; H, 5.09; N, 14.35. Found: C, 54.49; H, 5.03 N, 14.60.

Example 55 N- [4- (3-cyclohexyl-1- (2,6-difluorobenzyl)-
5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-
Preparation of dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 85] Subjected to the same reaction as in Example 39, the compound (363 mg) obtained in Reference Example 9, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg), 1-hydroxybenzo Triazole (138 mg), cyclohexylamine (99 mg), N-ethyldiisopropylamine (155
The crude amide compound (354 mg) was obtained from
The title compound (173 mg) was obtained using 0 ml) and sodium methoxide (222 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.4 Hz), 1.21-
1.54 (4H, m), 1.60-1.93 (4H, m), 2.14 (3H, s), 2.3
6-2.60 (2H, m), 2.65 (2H, t, J = 5.8 Hz), 3.23-3.3
7 (2H, m), 3.30 (3H, s), 3.45 (2H, t, J = 5.8 Hz),
3.84 (2H, s), 4.83 (1H, t, J = 6.2 Hz), 4.86-5.00
(1H, m), 5.29 (2H, s), 6.53 (1H, s), 6.90 (2H, t,
J = 8.3 Hz), 7.21-7.28 (1H, m), 7.35 (2H, d, J =
8.4 Hz), 7.51 (2H, d, J = 8.4 Hz). IR (KBr): 1705, 1661, 1593, 1537, 1470, 1314, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₃ H ₃₉ N ₅ O ₄ SF ₂・ 0.5H ₂ O: C, 61.09; H, 6.21; N, 10.79. Found: C, 61.34; H, 6.27; N, 10.97. Example 56 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (1 Preparation of -piperidinyl)-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 86] Subjected to the same reaction as in Example 39, the compound (363 mg) obtained in Reference Example 9, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg), 1-hydroxybenzo Triazole (138 mg), 1-aminopiperidine (100 mg), N-ethyldiisopropylamine (155 μ
The crude amide compound (174 mg) was obtained from
ml) and sodium methoxide (119 mg) to give the title compound (100 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.30-
1.60 (2H, m), 1.62-1.84 (4H, m), 2.14 (3H, s), 2.6
5 (2H, t, J = 5.9 Hz), 3.20-3.33 (4H, m), 3.28 (3
H, s), 3.34-3.42 (2H, m), 3.43 (2H, t, J = 5.9 H
z), 3.84 (2H, s), 4.97 (1H, t, J = 5.5 Hz), 5.30
(2H, s), 6.79 (1H, s), 6.89 (2H, t, J = 8.2 Hz),
7.21-7.32 (1H, m), 7.36 (2H, d, J = 8.4 Hz), 7.51
(2H, d, J = 8.4Hz) .IR (KBr): 1715, 1678, 1593, 1537, 1462, 1314, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₂ H ₃₈ N ₆ O ₄ SF ₂・ 0.5H ₂ O: C, 59.15; H, 6.05; N, 12.93. Found: C, 59.41; H, 5.94; N, 12.91. Example 57 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -3- (4-morpholinyl) -2,
Preparation of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N′-ethylurea:

[Chemical 87] Subjected to the same reaction as in Example 39, the compound (363 mg) obtained in Reference Example 9, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg), 1-hydroxybenzo Triazole (138 mg), 1-aminomorpholine (102 mg), N-ethyldiisopropylamine (155 μ
The crude amide compound (136 mg) was obtained from (1) and further methanol (9 m
l), the title compound using sodium methoxide (97 mg)
(64 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.3 Hz), 2.13
(3H, s), 2.65 (2H, t, J = 5.7 Hz), 3.23-3.60 (4H,
m), 3.29 (3H, s), 3.43 (2H, t, J = 5.7 Hz), 3.45-3.
60 (2H, m), 3.83 (2H, s), 3.80-3.93 (4H, m), 4.89
(1H, t, J = 5.5Hz), 5.30 (2H, s), 6.68 (1H, s), 6.
90 (2H, t, J = 8.1 Hz), 7.22-7.30 (1H, m), 7.37 (2
H, d, J = 8.4 Hz), 7.49 (2H, d, J = 8.4 Hz). IR (KBr): 1715, 1678, 1593, 1532, 1470, 1314, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₁ H ₃₆ N ₆ O ₅ SF ₂ 0.25H ₂ O: C, 57.53; H, 5.68; N, 12.98. Found: C, 57.59; H, 5.82; N, 12.99.

Example 58 N- [4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl}- 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]
Production of Pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 88] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (605 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg), 1-hydroxybenzo Triazole (184 mg), 4-fluoroaniline (134 mg), N-ethyldiisopropylamine (215 μ
The crude amide compound (420 mg) was obtained from
ml) and sodium methoxide (286 mg) to give the title compound (311 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.4 Hz), 2.12
(3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.25 (3H, s), 3.
25-3.34 (2H, m), 3.41 (2H, t, J = 5.8 Hz), 3.81 (2
H, s), 4.78 (1H, brs), 5.35 (2H, s), 6.50 (1H, s),
6.92 (2H, t, J = 8.0 Hz), 7.15-7.34 (5H, m), 7.37
(2H, d, J = 8.4 Hz), 7.64 (2H, d, J = 8.4 Hz) .IR (KBr): 1715, 1674, 1593, 1532, 1470, 1316, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₃ H ₃₂ N ₅ O ₄ SF ₃ 0.25H ₂ O: C, 60.40; H, 4.99; N, 10.67. Found: C, 60.39; H, 4.82; N, 10.58. Example 59 N- [4- (1- (2,6-difluorobenzyl) -3- (2,4-difluorophenyl) -5-{[(2-methoxyethyl) (methyl) amino]
Methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,
Preparation of 3-d] pyrimidin-6-yl) phenyl] -N′-ethylurea:

[Chemical 89] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (400 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (190 mg), 1-hydroxybenzo Triazole (153 mg), 2,4-difluoroaniline (128 mg), N-ethyldiisopropylamine (19
The crude amide compound (246 mg) was obtained from
(16.8 ml) and sodium methoxide (181 mg) were used to obtain the title compound (162 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4 Hz), 2.13
(3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.
24-3.34 (2H, m), 3.41 (2H, t, J = 5.7 Hz), 3.73 (1
H, d, J = 12.3 Hz), 3.89 (1H, d, J = 12.3 Hz), 4.8
6 (1H, t, J = 5.1 Hz), 5.36 (2H, d, J = 3.9 Hz),
6.61 (1H, s), 6.92 (2H, t, J = 8.1 Hz), 6.99 (2H,
d, J = 8.1 Hz), 7.28-7.34 (2H, m), 7.44 (2H, d, J
= 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz) .IR (KBr): 1721, 1682, 1593, 1532, 1470, 1316, 1277
cm ^-1 . Elemental analysis Calcd for C ₃₃ H ₃₁ N ₅ O ₄ SF ₄ : C, 59.18; H, 4.67; N, 10.46. Found: C, 59.12; H, 4.57; N, 10.50. Example 60 N- [4- (1- (2,6-difluorobenzyl) -3- (3,5-difluorophenyl) -5-{[(2-methoxyethyl) (methyl) amino]
Methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,
Preparation of 3-d] pyrimidin-6-yl) phenyl] -N′-ethylurea:

[Chemical 90] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (400 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (190 mg), 1-hydroxybenzo Triazole (153 mg), 3,5-difluoroaniline (128 mg), N-ethyldiisopropylamine (19
The crude amide compound (58 mg) was obtained from
(0.8 ml) and sodium methoxide (43 mg) were used to obtain the title compound (33 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.3 Hz), 2.11
(3H, s), 2.63 (2H, t, J = 5.6 Hz), 3.27 (3H, s), 3.
26-3.35 (2H, m), 3.42 (2H, t, J = 5.6 Hz), 3.80 (2
H, s), 4.68 (1H, t, J = 6.6 Hz), 5.35 (2H, s), 6.3
7 (1H, s), 6.85-6.97 (5H, m), 7.25-7.32 (1H, m), 7.
38 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz). IR (KBr): 1719, 1672, 1640, 1607, 1566, 1472, 1302
. cm ^-1 elemental analysis _{C 33 H 31 N 5 O 4} SF 4 Calculated:. C, 59.18; H, 4.67; N, 10.46 Found: C, 58.93; H, 4.64 ; N, 10.31.

Example 61 4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) (methyl ) Amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) -N-isopropylbenzamide:

[Chemical Formula 91] Isopropylamine (85.1 mg) and N-ethyldiisopropylamine (155 mg) were dissolved in methylene chloride (3 ml) and 1M-dimethylaluminum chloride in hexane was dissolved under ice-cooling.
(1.23 ml) was added and the mixture was stirred for 30 minutes. Furthermore, a dichloromethane solution (3 ml) of the compound of Example 48 (139 mg) was added, the temperature was gradually returned to room temperature, and the mixture was stirred for 19 hours. The reaction mixture was partitioned with chloroform / saturated aqueous sodium hydrogen carbonate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue, which was purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.). The eluate was recrystallized from dichloromethane / methanol to give the title compound (62 mg). ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.17 (3H, t, J = 7.4 Hz),
1.28 (6H, d, J = 6.6Hz), 2.07 (3H, s), 2.57 (2H,
t, J = 5.9 Hz), 3.24 (3H, s), 3.23-3.32 (2H, m), 3.
40 (2H, t, J = 5.9 Hz), 3.81 (2H, s), 4.23-4.30 (1
H, m), 5.37 (2H, s), 6.94 (2H, t, J = 7.8 Hz), 7.2
8-7.34 (1H, m), 7.36 (2H, d, J = 8.7Hz), 7.43 (4H,
s), 7.78 (2H, d, J = 8.7 Hz) .IR (KBr): 1721, 1667, 1597, 1537, 1472, 1323,1238
cm ^-1 .Elemental analysis Calculated as C ₃₇ H ₄₀ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 61.06; H, 5.68; N, 11.55. Found: C, 60.78; H, 5.57; N, 11.50. Example 62 N-Cyclopropyl-4- (1- (2,6-difluorobenzyl) -6-
(4-{[(ethylamino) carbonyl] amino} phenyl) -5-
{[(2-Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidine-3 (2H)-
Il) Preparation of benzamide:

[Chemical Formula 92] Subjected to the same reaction as in Example 61, cyclopropylamine
(83 mg), N-ethyldiisopropylamine (155 mg), 1M-
Dimethylaluminum chloride in hexane (1.23 m
l), using the compound of Example 48 (139 mg) to give the title compound (8
8 mg) was obtained. ¹ H-NMR (CDCl₃+ CD₃OD) δ: 0.61-0.64 (2H, m), 1.17
(3H, t, J = 7.4 Hz), 2.06 (3H, s), 2.56 (2H, t, J
= 5.9 Hz), 2.90-2.94 (1H, m), 3.23 (3H, s), 3.28-
3.33 (2H, m), 3.38 (2H, t, J = 5.9 Hz), 3.79 (2H,
s), 5.35 (2H, s), 6.93 (2H, t, J = 8.1 Hz), 7.27-
7.32 (1H, m), 7.34 (2H, d, J = 8.7 Hz), 7.41-7.45
(4H, m), 7.86 (2H, d, J = 8.7 Hz). IR (KBr): 1717, 1669, 1597, 1532, 1472, 1318, 1236
 cm^-1. Elemental analysis C₃₇H₃₈N₆O_Fivescience fiction₂・ 0.5H₂As O Calculated: C, 61.23; H, 5.42; N, 11.58. Found: C, 60.22; H, 5.30; N, 11.62. Example 63 4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylami
No) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl
(Methyl) amino] methyl} -2,4-dioxo-1,4-dihydride
Rotieno [2,3-d] pyrimidin-3 (2H) -yl) -N-methylben
Zamide production:

[Chemical formula 93] Subjected to the same reaction as in Example 61, 2M-methylamine / tetrahydrofuran solution (0.72 ml), N-ethyldiisopropylamine (155 mg), hexane solution of 1M-dimethylaluminium chloride (1.23 ml), Example 48. Compound (139 m
The title compound (58 mg) was obtained using g). ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.16 (3H, t, J = 7.2 Hz),
2.07 (3H, s), 2.57 (2H, t, J = 5.7 Hz), 2.99 (3H,
d, J = 4.8 Hz), 3.23 (3H, s), 3.24-3.32 (2H, m),
3.39 (2H, t, J = 5.7 Hz), 3.80 (2H, s), 5.36 (2H,
s), 5.54 (1H, t, J = 5.4 Hz), 6.93 (2H, t, J = 8.3
Hz), 7.23 (1H, q, J = 4.8 Hz), 7.30-7.34 (2H, m),
7.35 (2H, d, J = 8.4 Hz), 7.42 (4H, s), 7.89 (2H,
d, J = 8.4 Hz) .IR (KBr): 1717, 1669, 1595, 1552, 1472, 1318, 1236
. cm ^-1 elemental analysis _{C 35 H 36 N 6 O 5} SF 2 · H 2 O Calculated:. C, 59.31; H, 5.40; N, 11.86 Found: C, 59.55; H, 5.30 ; N, 12.06 .

Example 64 4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-methoxyethyl) (methyl ) Amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) -N, N-dimethylbenzamide:

[Chemical 94] Subjected to the same reaction as in Example 61, 2M-dimethylamine / tetrahydrofuran solution (0.72 ml), N-ethyldiisopropylamine (155 mg), hexane solution of 1M-dimethylaluminum chloride (1.23 ml), and in Example 48. Compound (139
The title compound (119 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.2 Hz), 1.90
(3H, s), 2.34 (2H, t, J = 5.8 Hz), 3.10 (6H, s), 3.
16 (2H, t, J = 5.8 Hz), 3.18 (3H, s), 3.26-3.39 (2
H, m), 3.78 (2H, s), 5.35 (2H, s), 5.77 (1H, t, J
= 4.9 Hz), 6.91 (2H, t, J = 8.3 Hz), 7.05 (2H, d, J
= 8.4 Hz), 7.22-7.34 (1H, m), 7.37 (4H, d, J = 8.4
Hz), 7.58 (2H, d, J = 8.4 Hz), 7.91 (1H, s) .IR (KBr): 1717, 1672, 1597, 1537, 1462, 1319, 1231
cm ^-1 .Elemental analysis Calculated as C ₃₆ H ₃₈ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 60.58; H, 5.51; N, 11.77. Found: C, 60.82; H, 5.44; N, 11.85. Example 65 N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -3- (4-methoxy-3-methyl Phenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno
Production of [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical 95] 4-Methoxy-3-methylaniline (959 mg) in methylene chloride
This was dissolved in (11.3 ml), 1M-dimethylaluminum chloride in hexane (5.75 ml) was added under ice cooling, and the mixture was stirred for 30 minutes. Furthermore, a dichloromethane solution (5 ml) of the compound of Reference Example 8 (597 mg) was added, the temperature was gradually returned to room temperature, and the mixture was stirred for 21 hours. The reaction mixture was partitioned with chloroform / saturated aqueous sodium hydrogen carbonate, the organic layer was dried over magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.), The title compound (129 mg) was obtained as a crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.1 Hz), 2.12
(3H, s), 2.21 (3H, s), 2.61 (2H, t, J = 5.9 Hz), 3.
25 (3H, s), 3.21-3.34 (2H, m), 3.40 (2H, t, J = 5.9
Hz), 3.83 (2H + 3H, s), 4.90 (1H, t, J = 6.0 Hz),
5.35 (2H, s), 6.71 (1H, s), 6.91 (2H, t, J = 7.7 H
z), 6.88-7.10 (3H, m), 7.24-7.30 (1H, m), 7.35 (2H,
d, J = 8.4 Hz), 7.52 (2H, d, J = 8.4 Hz) .IR (KBr): 2971, 1713, 1669, 1593, 1532, 1470, 131
. 4, 1256 cm ^-1 elemental analysis _{C 35 H 37 N 5 O 5} SF 2 · 0.5H 2 O Calculated:. C, 61.21; H, 5.58; N, 10.20 Found: C, 61.22; H, 5.60 N, 10.23. Example 66 N- [4- (1- (2,6-difluorobenzyl) -3- (3,5-didimethylphenyl) -5-{[(2-methoxyethyl) (methyl) amino]
Methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,
Preparation of 3-d] pyrimidin-6-yl) phenyl] -N′-ethylurea:

[Chemical 96] Subjected to the same reaction as in Example 65, 3,5-dimethylaniline
(665 mg), a hexane solution of 1 M-dimethylaluminum chloride (5.09 ml), and the compound of Reference Example 8 (526 mg) were used to obtain the title compound (323 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.3 Hz), 2.13
(3H, s), 2.33 (6H, s), 2.63 (2H, t, J = 5.9 Hz), 3.
26 (3H, s), 3.21-3.35 (2H, m), 3.41 (2H, t, J = 5.9
Hz), 3.83 (2H, s), 4.81 (1H, t, J = 4.9 Hz), 5.35
(2H, s), 6.56 (1H, s), 6.88 (2H, s), 6.92 (2H, t,
J = 8.0 Hz), 7.03 (1H, s), 7.22-7.36 (1H, m), 7.35
(2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz). IR (KBr): 2973, 1715, 1672, 1593, 1537, 1470, 131
. 6, 1236 cm ^-1 elemental analysis _{C 35 H 37 N 5 O 4} SF 2 · 0.25H 2 O Calculated:. C, 63.10; H, 5.67; N, 10.51 Found: C, 63.18; H, 5.58 N, 10.53.

Example 67 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-ethoxyethyl) (methyl) amino] methyl} -3- (4-fluorophenyl)- 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 97] Subjected to the same reaction as in Example 65, 4-fluoroaniline (3
06 mg), a hexane solution of 1 M-dimethylaluminum chloride (2.55 ml), and the compound of Reference Example 12 (324 mg) were used to obtain the title compound (105 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 6.9 Hz), 1.16
(3H, t, J = 6.9 Hz), 2.13 (3H, s), 2.63 (2H, t, J
= 6.0 Hz), 3.26-3.35 (2H, m), 3.40 (2H, q, J = 6.9
Hz), 3.45 (2H, t, J = 6.0 Hz), 3.81 (2H, s), 4.78
(1H, t, J = 5.3Hz), 5.35 (2H, s), 6.49 (1H, s), 6.
92 (2H, t, J = 8.1 Hz), 7.15-7.31 (5H, m), 7.36 (2
H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz) .IR (KBr): 1715, 1674, 1593, 1532, 1470, 1236 cm ^-1 . Elemental analysis C ₃₄ H ₃₄ N ₅ Calculated as O ₄ SF ₃ : C, 61.34; H, 5.15; N, 10.52. Found: C, 61.22; H, 5.15; N, 10.61. Example 68 N- [4- (1- (2,6 -Difluorobenzyl) -3- (2,6-difluorophenyl) -5-{[(2-methoxyethyl) (methyl) amino]
Methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,
Preparation of 3-d] pyrimidin-6-yl) phenyl] -N′-ethylurea:

[Chemical 98] Subjected to the same reaction as in Example 65, 2,6-difluoroaniline (674 mg), a hexane solution of 1M-dimethylaluminum chloride (4.84 ml), and the compound of Reference Example 8 (502 mg) were used to give the title compound ( 172 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.4 Hz), 2.16
(3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.
25-3.34 (2H, m), 3.41 (2H, t, J = 5.7 Hz), 3.83 (2
H, s), 4.82 (1H, brs), 5.40 (2H, s), 6.55 (1H, br
s), 6.93 (2H, t, J = 8.1 Hz), 7.05 (2H, t, J = 8.0
Hz), 7.28-7.45 (2H, m), 7.36 (2H, d, J = 8.4 Hz),
7.57 (2H, d, J = 8.4 Hz) .IR (KBr): 2976, 1723, 1682, 1601, 1534, 1472, 131
6, 1238 cm ^-1 . Elemental analysis Calculated as C ₃₃ H ₃₁ N ₅ O ₄ SF ₄・ 0.5H ₂ O: C, 58.40; H, 4.75; N, 10.32. Found: C, 58.15; H, 4.86 N, 10.27. Example 69 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3 -(2,4,
Preparation of 6-trifluorophenyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 99] Subjected to the same reaction as in Example 65, 2,4,6-trifluoroaniline (599 mg), a hexane solution of 1M-dimethylaluminum chloride (3.78 ml), and the compound of Reference Example 8 (391 mg) were used. The title compound (158 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.15
(3H, s), 2.61 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.
23-3.33 (2H, m), 3.41 (2H, t, J = 5.9 Hz), 3.82 (2
H, s), 4.81 (1H, t, J = 5.4 Hz), 5.39 (2H, s), 6.5
4 (1H, s), 6.82 (2H, t, J = 7.8 Hz), 6.93 (2H, t, J
= 8.1 Hz), 7.24-7.34 (1H, m), 7.36 (2H, d, J = 8.8
Hz), 7.56 (2H, d, J = 8.6 Hz). IR (KBr): 2976, 1725, 1684, 1593, 1532, 1470, 131
8, 1236 cm ^-1 . Elemental analysis Calculated as C ₃₃ H ₃₀ N ₅ O ₄ SF ₅・ 0.5H ₂ O: C, 56.89; H, 4.48; N, 10.05. Found: C, 56.92; H, 4.57 N, 10.06.

Example 70 N- {4- [1- (2,6-difluorobenzyl) -3- (3-fluoro-4-)
Methoxyphenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl ] Phenyl} -N'-ethylurea production:

[Chemical 100] Subjected to the same reaction as in Example 65, 4-fluoro-3-methoxyaniline (589 mg), a hexane solution of 1M-dimethylaluminum chloride (3.87 ml), the compound of Reference Example 8 (400 m
The title compound (248 mg) was obtained using g). ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.
27-3.35 (2H, m), 3.41 (2H, t, J = 5.9 Hz), 3.81 (2
H, s), 3.91 (3H, s), 4.77 (1H, t, J = 5.4 Hz), 5.3
4 (2H, s), 6.49 (1H, s), 6.92 (2H, t, J = 8.3 Hz),
7.00-7.08 (3H, m), 7.26-7.33 (1H, m), 7.36 (2H, d,
J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz). IR (KBr): 2976, 1715, 1669, 1593, 1520, 1464, 131
0, 1273 cm ^-1 . Elemental analysis Calculated as C ₃₄ H ₃₄ N ₅ O ₅ SF ₃・ 0.5H ₂ O: C, 59.12; H, 5.12; N, 10.14. Found: C, 59.39; H, 5.15 N, 10.16. Example 71 N- {4- [1- (2,6-difluorobenzyl) -3- (4-fluoro-3-)
Methylphenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno
Production of [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical 101] Using the same reaction as in Example 65, using 3-methyl-4-fluoroaniline (540 mg), a hexane solution of 1M-dimethylaluminum chloride (4.0 ml), and the compound of Reference Example 8 (414 mg), the title compound was obtained. (303 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.4 Hz), 2.13
(3H, s), 2.29 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.
26 (3H, s), 3.26-3.35 (2H, m), 3.41 (2H, t, J = 5.7
Hz), 3.81 (2H, s), 4.74 (1H, t, J = 5.6 Hz), 5.35
(2H, s), 6.44 (1H, s), 6.92 (2H, t, J = 8.3 Hz),
7.02-7.15 (3H, m), 7.26-7.34 (1H, m), 7.36 (2H, d,
J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz). IR (KBr): 2924, 1715, 1669, 1593, 1532, 1470, 131
. 6, 1236 cm ^-1 elemental analysis _{C 34 H 34 N 5 O 4} SF 3 · 0.75H 2 O Calculated:. C, 60.12; H, 5.27; N, 10.31 Found: C, 60.13; H, 5.09 N, 10.51. Example 72 N- {4- [1- (2,6-difluorobenzyl) -3- (3-fluoro-4-)
Methylphenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno
Production of [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical 102] Subjected to the same reaction as in Example 65, 4-methyl-3-fluoroaniline (535 mg), a hexane solution of 1M-dimethylaluminum chloride (3.96 ml), and the compound of Reference Example 8 (410 mg).
To give the title compound (248 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.30 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.
26 (3H, s), 3.26-3.35 (2H, m), 3.41 (2H, t, J = 5.9
Hz), 3.81 (2H, s), 4.75 (1H, t, J = 5.4 Hz), 5.35
(2H, s), 6.47 (1H, s), 6.92 (2H, t, J = 8.4 Hz),
6.95-6.99 (2H, m), 7.26-7.33 (2H, m), 7.36 (2H, d,
J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz). IR (KBr): 2976, 1715, 1669, 1593, 1532, 1470, 131
6, 1236 cm ^-1 . Elemental analysis Calculated as C ₃₄ H ₃₄ N ₅ O ₄ SF ₃・ 0.5H ₂ O: C, 60.52; H, 5.23; N, 10.38. Found: C, 60.79; H, 5.37 N, 10.45.

Example 73 N- [4- (3-cyclopropyl-1- (2,6-difluorobenzyl)-
5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-
Preparation of dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 103] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (242 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzo Triazole (92 mg), cyclopropylamine (38 mg), N-ethyldiisopropylamine (104
The crude amide compound (96 mg) was obtained from (μl) and further methanol (7.
The title compound (58 mg) was obtained using 5 ml) and sodium methoxide (80 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.77-0.89 (2H, m), 1.17 (3H, t,
J = 7.4 Hz), 1.15-1.26 (2H, m), 2.15 (3H, s), 2.6
7 (2H, t, J = 6.1 Hz), 2.73-2.80 (1H, m), 3.24-3.3
8 (2H, m), 3.30 (3H, s), 3.45 (2H, t, J = 6.1 Hz),
3.84 (2H, s), 4.74 (1H, t, J = 5.5 Hz), 5.31 (2H,
s), 6.43 (1H, s), 6.90 (2H, t, J = 8.1 Hz), 7.25-
7.33 (1H, m), 7.35 (2H, d, J = 8.8 Hz), 7.53 (2H,
d, J = 8.8Hz) .IR (KBr): 2975, 1713, 1672, 1593, 1534, 1472, 131
. 6, 1236 cm ^-1 elemental analysis _{C 30 H 33 N 5 O 4} SF 2 Calculated:. C, 60.29; H, 5.57; N, 11.72 Found: C, 60.23; H, 5.38 ; N, 11.84. Example 74 N- [4- (3-cyclopentyl-1- (2,6-difluorobenzyl)-
5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-
Preparation of dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea:

[Chemical 104] Subjected to the same reaction as in Example 39, the compound (242 mg) obtained in Reference Example 9, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzo Triazole (92 mg), cyclopentylamine (56 mg), N-ethyldiisopropylamine (104
The crude amide compound (114 mg) was obtained from
(8.5 ml) and sodium methoxide (91 mg) were used to obtain the title compound (59 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 1.50-
1.69 (2H, m), 1.77-2.05 (4H, m), 2.11 (3H, s), 2.0
7-2.26 (2H, m), 2.65 (2H, t, J = 5.9 Hz), 3.23-3.3
7 (2H, m), 3.30 (3H, s), 3.46 (2H, t, J = 5.9 Hz),
3.84 (2H, s), 4.84 (1H, t, J = 5.5 Hz), 5.31 (2H,
s), 5.38-5.55 (1H, m), 6.56 (1H, s), 6.89 (2H, t,
J = 8.2 Hz), 7.20-7.34 (1H, m), 7.35 (2H, d, J =
8.8 Hz), 7.48 (2H, d, J = 8.8 Hz) .IR (KBr): 1705, 1661, 1593, 1537, 1470, 1316, 1236
cm ^-1 . Elemental analysis C ₃₂ H ₃₇ N ₅ O ₄ SF ₂ Calculated value: C, 61.42; H, 5.96; N, 11.19. Measured value: C, 61.12; H, 5.91; N, 11.12. Example 75 N- [4- (1- (2,6-difluorobenzyl) -3-hexahydrocyclopenta [c] pyrrole-2 (1H) -yl-5-{[(2methoxyethyl) (methyl) aminomethyl] -2,4-dioxo-1,2,3,4 tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl)
Production of -N'-ethylurea:

[Chemical 105] 3-Amino-3-azabicyclo 〔3.3.0〕 octane ・ hydrochloride (6
78 mg) was suspended in dichloromethane (7.6 ml), triethylamine (639 μl) was added, the mixture was stirred for 20 minutes, and then stirred under ice-cooling with a 1M-dimethylaluminum chloride / hexane solution (3.87 ml).
Was added, the mixture was returned to room temperature for 30 minutes and ice-cooled again. Then, a dichloromethane solution (4 ml) of the compound of Reference Example 8 (400 mg) was added, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was partitioned with chloroform / saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was converted to methanol.
(6.3 ml), add sodium methoxide (324 m
g) was added and the mixture was stirred at room temperature for 13 hours. The reaction mixture was partitioned with ethyl acetate / water, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.) and recrystallized from ethyl acetate-diethyl ether to give the title compound (168
(mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.3 Hz), 1.50-
1.92 (6H, m), 2.11 (3H, s), 2.65 (2H, t, J = 6.2 H
z), 2.64-2.78 (2H, brs), 3.16-3.36 (2H, m), 3.28
(3H, s), 3.45 (2H, t, J = 6.2 Hz), 3.41-3.53 (2H,
m), 3.84 (2H, s), 5.03 (1H, t, J = 5.5 Hz), 5.31 (2
H, s), 6.90 (2H, t, J = 8.6 Hz), 6.91 (1H, s), 7.2
1-7.33 (1H, m), 7.37 (2H, d, J = 8.4 Hz), 7.47 (2
H, d, J = 8.4 Hz) .IR (KBr): 1715, 1674, 1593, 1537, 1462, 1314, 1236
. cm ^-1 elemental analysis _{C 34 H 40 N 6 O 4} SF 2 Calculated:. C, 61.24; H, 6.05; N, 12.60 Found: C, 61.08; H, 6.15 ; N, 12.37.

Example 76 N- [4- (3- (1-azepanyl) -1- (2,6-difluorobenzyl) -5-
{[(2-Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
Production of -6-yl) phenyl] -N'-ethylurea:

[Chemical formula 106] Subjected to the same reaction as in Example 75, 1-aminohomopiperidine (470 mg), 1M-dimethylaluminum chloride / hexane solution (3.81 ml), compound of Reference Example 8 (394 mg), sodium methoxide (324 mg). The title compound (232 mg) was obtained from. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.1 Hz), 1.63-
1.85 (8H, m), 2.14 (3H, s), 2.66 (2H, t, J = 5.8 H
z), 3.21-3.36 (6H, m), 3.29 (3H, s), 3.44 (2H, t,
J = 5.8 Hz), 3.84 (2H, s), 4.87 (1H, t, J = 5.5 H
z), 5.32 (2H, s), 6.60 (1H, s), 6.89 (2H, t, J = 8.
3 Hz), 7.21-7.32 (1H, m), 7.35 (2H, d, J = 8.4 Hz),
7.52 (2H, d, J = 8.4 Hz) .IR (KBr): 1719, 1676, 1593, 1534, 1460, 1315, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₃ H ₄₀ N ₆ O ₄ SF ₂ 0.25H ₂ O: C, 60.12; H, 6.19; N, 12.75. Found: C, 60.01; H, 6.12; N, 12.68. Example 77 N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (1 -Pyrrolidinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical formula 107] Subjected to the same reaction as in Example 75, 1-aminopyrrolidine (5
The title compound (230 mg) was obtained from 83 mg), a 1 M dimethylaluminum chloride / hexane solution (4.41 ml), the compound of Reference Example 8 (455 mg) and sodium methoxide (324 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 2.00
(4H, t, J = 6.6 Hz), 2.12 (3H, s), 2.67 (2H, t, J
= 5.9 Hz), 3.26-3.36 (6H, m), 3.28 (3H, s), 3.45 (2
H, t, J = 5.9 Hz), 3.85 (2H, s), 5.08 (1H, brs),
5.32 (2H, s), 6.90 (2H, t, J = 8.0 Hz), 6.84-6.95
(1H, brs), 7.22-7.33 (1H, m), 7.37 (2H, d, J = 8.6
Hz), 7.47 (2H, d, J = 8.6 Hz) .IR (KBr): 1715, 1676, 1593, 1534, 1462, 1316, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₁ H ₃₆ N ₆ O ₄ SF ₂・ 0.5H ₂ O: C, 58.57; H, 5.87; N, 13.22. Found: C, 58.51; H, 5.63; N, 13.06. Example 78 N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (1H Preparation of -pyrrol-1-yl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical 108] Subjected to the same reaction as in Example 75, 1-aminopyrrole (403
mg), a 1M-dimethylaluminum chloride / hexane solution (4.55 ml), and the compound of Reference Example 8 (471 mg) to give the title compound (230 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.3 Hz), 2.11
(3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.24-3.34 (2H,
m), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 (2
H, s), 4.79 (1H, t, J = 5.5 Hz), 5.35 (2H, s), 6.3
4 (2H, t, J = 2.4 Hz), 6.54 (1H, s), 6.72 (1H, t,
J = 2.4 Hz), 6.93 (2H, t, J = 8.2 Hz), 7.24-7.32
(1H, m), 7.38 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J
= 8.4 Hz). IR (KBr): 1734, 1699, 1593, 1530, 1470, 1316, 1236
cm ^-1 . Elemental analysis Calculated as C ₃₁ H ₃₂ N ₆ O ₄ SF ₂ 0.25H ₂ O: C, 59.37; H, 5.22; N, 13.40. Found: C, 59.41; H, 5.09; N, 13.52.

Example 79 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-ethoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- ( Preparation of 1-piperidinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N′-ethylurea:

[Chemical 109] Subjected to the same reaction as in Example 75, 1-aminopiperidine (3
The title compound (130 mg) was obtained from 97 mg), a 1M-dimethylaluminum chloride / hexane solution (3.67 ml), the compound of Reference Example 12 (391 mg) and sodium methoxide (324 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 1.15
(3H, t, J = 7.4 Hz), 1.36-1.57 (2H, m), 1.64-1.84
(4H, m), 2.14 (3H, s), 2.66 (2H, t, J = 6.0Hz), 3.
20-3.50 (10H, m), 3.84 (2H, s), 5.03 (1H, t, J =
5.3 Hz), 5.30 (2H, s), 6.90 (2H, t, J = 8.3 Hz),
6.88 (1H, s), 7.21-7.33 (1H, m), 7.36 (2H, d, J =
8.8 Hz), 7.51 (2H, d, J = 8.8 Hz) .IR (KBr): 1717, 1678, 1593, 1534, 1462, 1315, 1236
cm ^-1 . Elemental analysis C ₃₃ H ₄₀ N ₆ O ₄ SF ₂ Calculated value: C, 60.53; H, 6.16; N, 12.84. Measured value: C, 60.27; H, 6.11; N, 12.80. N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-ethoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3-phenyl-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidine-6
Preparation of -yl) phenyl] -N'-ethylurea:

[Chemical 110] The compound of Example 1 (288 mg), potassium iodide (104 mg),
N-Ethyldiisopropylamine (294 μl) and 2-ethoxyethyl chloride (176 μl) were suspended in DMF (5 ml) at 60 ° C.
Stir for 23 hours. The reaction solution was partitioned with ethyl acetate / water,
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.) and recrystallized from ethyl acetate to give the title compound (196 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 6.9 Hz), 1.12
(3H, t, J = 7.2 Hz), 2.12 (3H, s), 2.62 (2H, t, J
= 5.8 Hz), 3.20-3.29 (2H, m), 3.38 (2H, q, J = 6.9
Hz), 3.44 (2H, t, J = 5.8 Hz), 3.83 (2H, s), 5.00
(1H, t, J = 5.6Hz), 5.35 (2H, s), 6.84 (1H, s), 6.
91 (2H, t, J = 8.1 Hz), 7.25-7.29 (3H, m), 7.35 (2
H, d, J = 8.7 Hz), 7.39-7.53 (5H, m). IR (KBr): 2975, 1715, 1669, 1593, 1539, 1464, 131
8, 1236 cm ^-1 . Calculated as elemental analysis C ₃₄ H ₃₅ N ₅ O ₄ SF ₂ : C, 63.04; H, 5.45; N, 10.81. Found: C, 62.98; H, 5.37; N, 10.68. Example 81 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3-phenyl-1, 2,3,4-Tetrahydrothieno [2,3-d] pyrimidine-6
Preparation of -yl) phenyl] -N'-ethylurea:

[Chemical 111] Subjected to the same reaction as in Example 80, the compound of Example 1 (23.
48 g), potassium iodide (20.31 g), N-ethyldiisopropylamine (21.3 ml), 2-methoxyethyl chloride (14.9
The title compound (18.76 g) was obtained from (3 ml). ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.1 Hz), 2.13
(3H, s), 2.63 (2H, t, J = 5.8 Hz), 3.26 (3H, s), 3.
28 (2H, q, J = 7.1 Hz), 3.41 (2H, t, J = 5.8 Hz),
3.82 (2H, s), 4.72 (1H, t, J = 5.8 Hz), 5.36 (2H,
s), 6.43 (1H, s), 6.92 (2H, t, J = 8.2 Hz), 7.26-
7.51 (5H, m), 7.36 (2H, d, J = 8.8 Hz), 7.56 (2H,
d, J = 8.8 Hz) .IR (KBr): 3333, 1715, 1669, 1593, 1537, 1470, 131
6, 1236 cm ^-1 . Calculated as C ₃₃ H ₃₃ N ₅ O ₄ SF _{2 by} elemental analysis: C, 62.55; H, 5.25; N, 11.05. Found: C, 62.44; H, 5.17; N, 11.00.

Example 82 N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- ( Preparation of 6-oxo-1,6-dihydro-3-pyridinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical 112] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (245 mg), 5-amino-2 (1H) -pyridinone (172 mg), N- A crude amide compound (288 mg) was obtained from ethyldiisopropylamine (259 μl), and further ethanol (19.5 ml) and sodium ethoxide (53 mg).
To give the title compound (206 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.2 Hz), 2.0
6 (3H, s), 2.49 (2H, t, J = 6.0 Hz), 3.07-3.16 (2
H, m), 3.16 (3H, s), 3.32 (2H, t, J = 6.0 Hz), 3.7
1 (2H, s), 5.26 (2H, s), 6.18 (1H, t, J = 5.4 Hz),
6.39 (1H, d, J = 9.6 Hz), 7.12 (2H, t, J = 8.4 H
z), 7.31 (1H, dd, J = 1.2 Hz, 8.4 Hz), 7.44-7.53
(6H, m), 8.64 (1H, s), 11.79 (1H, s). IR (KBr): 1717, 1669, 1626, 1593, 1532, 1462, 1235
cm ^-1 .Elemental analysis Calculated as C ₃₂ H ₃₂ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 58.26; H, 5.04; N, 12.74. Found: C, 58.20; H, 5.13; N, 12.73. Example 83 N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (1 -Methyl-6-oxo-1,6-dihydro-3-pyridinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl}
Production of -N'-ethylurea:

[Chemical 113] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (245 mg), 1-methyl-5-amino-2 (1H) -pyridinone (186 mg) ), N-ethyldiisopropylamine (259 μl) to crude amide (433 mg)
The title compound (283 mg) was obtained using ethanol (29.5 ml) and sodium ethoxide (80 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.11
(3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.26 (3H, s), 3.
27-3.36 (2H, m), 3.42 (2H, t, J = 5.8 Hz), 3.57 (3
H, s), 3.79 (2H, s), 5.01 (1H, brs), 5.32 (2H, s),
6.66 (1H, d, J = 9.6 Hz), 6.93 (2H, t, J = 8.4 H
z), 6.86-6.98 (1H, brs), 7.24-7.32 (2H, m), 7.34-
7.43 (3H, m), 7.49 (2H, d, J = 8.7 Hz) .IR (KBr): 1715, 1674, 1593, 1537, 1470, 1316, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₅ SF ₂・ 0.25H ₂ O: C, 59.23; H, 5.20; N, 12.56. Found: C, 59.21; H, 4.99; N, 12.49. Example 84 N- (4- {1- (2,6-difluorobenzyl) -5-[(methyl {[(2S)-
1- (Methylsulfonyl) pyrrolidinyl] methyl} amino) methyl] -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl}- Production of N'-ethylurea

[Chemical 114] Using the compound of Example 1 (403 mg, 0.7 mmol) and (L) -prolinol (0.35 g, 3.5 mmol), the same reaction as in Example 19 was carried out to give the title compound (325 mg, 63%) as a colorless compound. Obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.4 Hz), 1.7-
1.8 (4H, m), 2.07 (3H, s), 2.2-2.6 (2H, m), 2.73 (3
H, s), 3.15-3.4 (4H, m), 3.65-3.9 (3H, m), 4.7-4.8
(1H, m), 5.37 (2H, s), 6.51 (1H, s), 6.92 (2H, t,
J = 8.2 Hz), 7.2-7.6 (10H, m) .IR (KBr): 1723, 1671, 1472, 1335, 1142, 1030, 735
. cm ^-1 elemental analysis _{C 36 H 38 F 2 N 6} O 5 S 2 · 0.5H 2 O Calculated: C, 57.97; H, 5.27 ; N, 11.27 Found:. C; 57.99; H, 5.03; N, 11.39.mp 189-191 ° C.

Example 85 N- (4- {1- (2,6-difluorobenzyl) -5-[(methyl {[(2R)-
1- (Methylsulfonyl) pyrrolidinyl] methyl} amino) methyl] -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl}- Production of N'-ethylurea

[Chemical 115] Using the compound of Example 1 (403 mg, 0.7 mmol) and (R) -prolinol (0.35 g, 3.5 mmol), the same reaction as in Example 19 was carried out to give the title compound (312 mg, 60%) as colorless Obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.7-1.
8 (4H, m), 2.07 (3H, s), 2.2-2.6 (2H, m), 2.73 (3H,
s), 3.15-3.4 (4H, m), 3.65-3.9 (3H, m), 4.7-4.8
(1H, m), 5.37 (2H, s), 6.50 (1H, s), 6.92 (2H, t,
J = 8.2 Hz), 7.2-7.6 (10H, m). IR (KBr): 1717, 1671, 1470, 1335, 1144, 1030, 735
. cm ^-1 elemental analysis _{C 36 H 38 F 2 N 6} O 5 S 2 · 0.5H 2 O Calculated: C, 57.97; H, 5.27 ; N, 11.27 Found:. C; 58.06; H, 5.28; N, 11.43. Mp 189-190 ° C. Example 86 N- [4- (1- (2,6-difluorobenzyl) -5-{[[2- (1,1-dioxo-2-isothiazolidinyl ) Ethyl] (methyl) amino] methyl} -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'- Production of ethylurea

[Chemical formula 116] A reaction similar to that in Example 4 was performed using the compound of Example 1 (461 mg, 0.8 mmol) and 2- (1,1-dioxideisothiazolin-2-yl) ethyl methanesulfonate (0.71 g, 2.92 mmol). The title compound (552 mg, 85%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.11 (3
H, s), 2.1-2.25 (2H, m), 2.62 (2H, t, J = 6.0 Hz),
2.95-3.1 (4H, m), 3.13 (3H, t, J = 6.8 Hz), 3.2-3.
4 (2H, m), 3.79 (2H, s), 4.8-4.9 (1H, m), 5.37 (2
H, s), 6.59 (1H, s), 6.93 (2H, t, J = 8.2), 7.2-7.6
(10H, m). IR (KBr): 1713, 1674, 1460, 1316, 1236, 1138, 103
. 6, 735 cm ^-1 elemental analysis _{C 35 H 36 F 2 N 6} O 5 S 2 Calculated: C, 58.16; H, 5.02 ; N, 11.63 Found:. C; 57.89; H, 4.98; N, 11.63. Mp 210-211 ° C. Example 87 N- (4- {1- (2,6-difluorobenzyl) -3- (4-fluorophenyll) -5-[(methyl {[(2S) -1 -(Methylsulfonyl) pyrrolidinyl] methyl} amino) methyl] -2,4-dioxo-1,2,3,4-
Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea

[Chemical 117] Using the compound of Example 29 (350 mg, 0.59 mmol), the same reaction as in Example 19 was carried out to give the title compound (216 mg, 48%).
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.7-
1.85 (4H, m), 2.07 (3H, s), 2.2-2.4 (1H, m), 2.5-2.
65 (1H, m), 2.73 (3H, s), 3.2-3.4 (4H, m), 3.65-3.
8 (1H, m), 3.72 (1H, d, J = 12.8 Hz), 3.87 (1H, d,
J = 12.8 Hz), 4.7-4.8 (1H, m), 5.36 (2H, s), 6.54
(1H, s), 6.92 (2H, t, J = 8.0 Hz), 7.1-7.5 (9H,
m). IR (KBr): 1721, 1671, 1472, 1335, 1236, 1144, 1030
. cm ^-1 elemental analysis _{C 36 H 37 F 3 N 6} O 5 S 2 · 1.0H 2 O Calculated:. C, 55.95; H, 5.09; N, 10.87 Found: C, 55.75; H, 4.82 ; N, 10.95.

Example 88 N- (4- {1- (2,6-difluorobenzyl) -3- [4- (2-methoxyethoxy) phenyl] -5-[(methyl {[(2S) -1- (Methylsulfonyl) pyrrolidinyl] methyl} amino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6
-Yl} phenyl) -N'-ethylurea production

[Chemical 118] Using the compound of Example 28 (350 mg, 0.54 mmol), the same reaction as in Example 19 was carried out to give the title compound (158 mg, 36
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.7-
1.85 (4H, m), 2.05 (3H, s), 2.2-2.4 (1H, m), 2.5-2.
6 (1H, m), 3.2-3.4 (4H, m), 3.46 (3H, s), 3.7-3.9
(5H, m), 4.1-4.2 (2H, m), 4.7-4.8 (1H, m), 5.36 (2
H, s), 6.49 (1H, s), 6.91 (2H, t, J = 8.0 Hz), 7.03
(2H, d, J = 9.0 Hz), 7.16 (2H, d, J = 9.0 Hz), 7.2
-7.5 (5H, m). IR (KBr): 1719, 1667, 1470, 1333, 1250, 1144, 103
0, 789 cm ^-1 . Elemental analysis C ₃₉ H ₄₄ F ₂ N ₆ O ₇ S ₂・ 0.5H ₂ O calculated: C, 57.13; H, 5.53; N, 10.25. Found: C, 56.88; H , 5.67; N, 10.00. Example 89 N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo Preparation of -3- (2-pyridinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea:

[Chemical formula 119] Subjected to the same reaction as in Example 39, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (245 mg), 2-aminopyridine (142 mg), N-ethyldiisopropylamine
The crude amide compound (361 mg) was obtained from (259 μl), and the title compound (198 mg) was obtained using ethanol (24.7 ml) and sodium ethoxide (67 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.4 Hz), 2.12
(3H, s), 2.61 (2H, t, J = 5.9 Hz), 3.25 (3H, s), 3.
25-3.31 (2H, m), 3.40 (2H, t, J = 5.9 Hz), 3.80 (2
H, br), 4.87 (1H, t, J = 5.6Hz), 5.20 (2H, br), 6.
90 (1H, s), 6.91 (2H, t, J = 8.1 Hz), 7.25-7.44 (2
H, m), 7.35 (2H, d, J = 8.7 Hz), 7.48 (2H, d, J =
8.7 Hz), 7.91 (1H, dt, J = 1.8 Hz, 8.1 Hz), 8.68-
8.70 (1H, m). IR (KBr): 1717, 1672, 1593, 1532, 1460, 1318, 1236
cm ^-1 .Elemental analysis Calculated as C ₃₂ H ₃₂ N ₆ O ₄ SF ₂・ 0.5H ₂ O: C, 59.71; H, 5.17; N, 13.06. Found: C, 59.95; H, 5.18; N, 12.99. Example 90 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-propoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3-phenyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
Production of -6-yl) phenyl] -N'-ethylurea:

[Chemical 120] The compound of Example 1 (172 mg), potassium iodide (50 mg), N
-Ethyldiisopropylamine (294 μl) and 2-propoxyethyl chloride (111 mg) were suspended in DMF (3 ml), and suspended at 75 ° C for 2
Stir for 4 hours. The reaction mixture was partitioned with ethyl acetate / water, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.) and recrystallized from dichloromethane-methanol to give the title compound (112 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.83 (3H, t, J = 7.3 Hz), 1.13
(3H, t, J = 7.2 Hz), 1.40-1.58 (2H, m), 2.13 (3H,
s), 2.63 (2H, t, J = 6.0 Hz), 3.20-3.33 (4H, m), 3.
44 (2H, t, J = 6.0 Hz), 3.82 (2H, s), 4.93 (1H, t,
J = 5.5 Hz), 5.36 (2H, s), 6.74 (1H, s), 6.92 (2
H, t, J = 8.2 Hz), 7.23-7.37 (5H, m), 7.41-7.54 (5
H, m). IR (KBr): 2965, 1715, 1674, 1593, 1537, 1470, 1318
cm ^-1 .Elemental analysis Calculated as C ₃₅ H ₃₇ N ₅ O ₄ SF ₂・ 0.5H ₂ O: C, 62.67; H, 5.71; N, 10.44. Found: C, 62.96; H, 5.73; N, 10.41.

Example 91 N- {4- [5-{[cyclohexyl (methyl) amino] methyl} -1-
(2,6-difluorobenzyl) -2,4-dioxo-3phenyl-
Production of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical 121] Example 2 Using the compound of Reference Example 1 (0.40 g, 0.5 mmol) and N-methylcyclohexylamine (0.11 g, 1.0 mmol)
The same reaction was carried out to obtain the title compound (150 mg, 45%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, t, J = 7.0 Hz), 2.05
(3H, s), 1.20-1.40 (6H, m), 1.50-1.70 (4H, m), 2.05
-2.15 (1H, m), 3.24 (2H, q, J = 7.0 Hz), 3.82 (2H, m
s), 5.20 (1H, t, J = 5.4 Hz), 5.35 (2H, s), 6.94
(2H, t, J = 8.0Hz), 7.25-7.35 (6H, m), 7.45-7.60
(4H, m). Calculated as elemental analysis C ₃₆ H ₃₇ F ₂ N ₅ O ₃ S: C, 65.73; H, 5.67; N, 10.65. Found: C, 65.98; H, 5.72; N, 10.42. mp 210-212 ° C. Example 92 N- [4- (1- (2,6-difluorobenzyl) -5-{[isopropyl
(Methyl) amino] methyl} -2,4-dioxo-3phenyl-1,2,
Production of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical formula 122] Using the compound of Reference Example 1 (0.40 g, 0.5 mmol) and N-methylisopropylamine (0.07 g, 1.0 mmol), the same reaction as in Example 2 was carried out to give the title compound (130 mg, 41%) as colorless crystals. Got as. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.0 Hz), 1.03
(6H, d, J = 7.0 Hz), 2.60-2.75 (1H, m), 3.254 (2H,
q, J = 7.0 Hz), 3.83 (2H, s), 5.26 (1H, t, J = 5.4
Hz), 5.36 (2H, s), 6.98 (2H, t, J = 8.0 Hz), 7.25
-7.35 (6H, m), 7.45-7.60 (4H, m). Elemental analysis Calculated as C ₃₃ H ₃₃ F ₂ N ₅ O ₃ S: C, 64.16; H, 5.38; N, 11.34. Found: C , 64.32; H, 5.51; N, 11.20.mp 208-210 ° C. Example 93 N- {4- [5-{[cyclopentyl (methyl) amino] methyl} -1-
(2,6-difluorobenzyl) -2,4-dioxo-3phenyl-
Production of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical 123] Example 2 Using the compound of Reference Example 1 (0.40 g, 0.5 mmol) and N-methylcyclopentylamine (0.10 g, 1.0 mmol), Example 2
The same reaction as in (1) was performed to give the title compound (110 mg, 40%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.0 Hz), 1.20-
1.50 (4H, m), 1.50-1.70 (4H, m), 2.10 (3H, S), 2.05-
2.15 (1H, m), 3.26 (2H, q, J = 7.0 Hz), 3.84 (2H,
s), 5.30 (1H, t, J = 5.4 Hz), 5.35 (2H, s), 6.99
(2H, t, J = 8.0 Hz), 7.25-7.35 (6H, m), 7.45-7.60
(4H, m). Elemental analysis Calculated as C ₃₅ H ₃₅ F ₂ N ₅ O ₃ S: C, 65.30; H, 5.48; N, 10.88. Found: C, 65.35; H, 5.28; N, 11.06. mp 210-213 ° C.

Example 94 N- {4- [1- (2,6-difluorobenzyl) -5-({methyl [3-oxo-3- (1-pyrrolidinyl) propyl] amino} methyl) -2,4
-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,
Production of 3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea

[Chemical formula 124] Using the compound of Example 1 (288 mg, 0.5 mmol) and 1- (3-bromopropanoyl) pyrrolidone (0.21 g, 1.0 mmol),
The reaction was performed in the same manner as in Example 19, and the title compound (300 mg, 86
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2), 1.75-1.95
(4H, m), 2.10 (3H, s), 2.60-2.70 (4H, m), 2.90-3.
10 (2H, m), 3.26 (2H, q, J = 7.2 Hz), 3.45-3.65 (2
H, m), 3.82 (2H, s), 5.25 (1H, t, J = 5.4 Hz), 5.3
6 (2H, s), 6.96 (2H, t, J = 8.0), 6.85-6.95 (1H,
m), 7.10-7.55 (10H, m). Elemental analysis Calculated as C ₃₇ H ₃₈ F ₂ N ₆ O ₄ S: C, 63.41; H, 5.47; N, 11.99. Found: C; 63.66; H, 5.22; N, 12.26. Mp 240-244 ° C. Example 95 3-[{[1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -2 , 4-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
Preparation of -5-yl] methyl} (methyl) amino] -N- (2-methoxyethyl) propanamide

[Chemical 125] The compound of Example 1 (288 mg, 0.5 mmol) and 1- (3-bromopropanoyl) -3-methoxyethylamine (0.21 g, 1.0 mmo)
l) was used to carry out the same reaction as in Example 19 to give the title compound.
(300 mg, 85%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2 Hz), 2.10
(3H, s), 2.65-2.75 (4H, m), 3.25 (2H, q, J = 7.2 H
z), 3.30 (3H, s), 3.30-3.37 (2H, m), 3.38-3.50 (2
H, m), 3.80 (2H, s), 5.30 (1H, t, J = 5.4 Hz), 5.3
6 (2H, s), 6.98 (2H, t, J = 8.0 Hz), 6.85-6.95 (1
H, m), 7.10-7.60 (10H, m). Elemental analysis Calculated as C ₃₆ H ₃₈ F ₂ N ₆ O ₅ S: C, 61.35; H, 5.43; N, 11.92. Found: C; 64.60; H, 5.54; N, 11.76.mp 240-244 ° C. Example 96 N- [4- (3- (4-nitrophenyl) -1- (2,6-difluorobenzyl) -5-{[2-methoxy Ethyl (methyl) amino] methyl} -2,4
-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical formula 126] 4-Nitroaniline (2.21 g, 16 mmol) in dichloromethane
(50 ml), hexane solution of dimethyl aluminum chloride (0.98 M) (16.3 ml, 16.0 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Furthermore, the compound of Reference Example 8
(1.21 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue is subjected to silica gel column chromatography (eluent;
Purified by ethyl acetate), the title compound (1.00 g, 92%)
Was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 2.15
(3H, s), 2.64 (2H, t, J = 6.0 Hz), 3.25 (3H, s), 3.
30 (2H, q, J = 7.2 Hz), 3.40 (2H, t, J = 6.0Hz),
3.83 (2H, s), 4.6-4.7 (1H, m), 5.35 (2H, s), 6.34
(1H, s), 6.91 (2H, t, J = 8.2 Hz), 7.25-7.40 (9H,
m).

Example 97 N- [4- (3- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-{[2-methoxyethyl (methyl) amino] methyl} -2, Four
-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 127] The compound of Example 96 (1.00 g) in ethanol (200 ml)
2N-hydrogen chloride / diethyl ether solution (20m
l) and 50% hydrous-10% palladium / carbon (1.00 g) were added, and the mixture was vigorously stirred under a hydrogen atmosphere for 1 hour. The catalyst-free filtrate was neutralized with aqueous sodium hydrogen carbonate, and the solvent was evaporated. The obtained residue was partitioned with ethyl acetate / water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to NH-silica gel (Fuji Silysia Chemical) chromatography and recrystallized from methanol to give the title compound (0.80 g, 62%). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 2.14
(3H, s), 2.64 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.
30 (2H, q, J = 7.2 Hz), 3.41 (2H, t, J = 6.0Hz),
3.77 (2H, s), 3.83 (2H, s), 4.6-4.7 (1H, m), 5.35
(2H, s), 6.3-6.4 (1H, m), 6.76 (2H, d, J = 8.4 Hz),
6.91 (2H, t, J = 8.0 Hz), 7.05 (2H, d, J = 8.4 H
z), 7.2-7.3 (1H, m), 7.35 (2H, d, J = 8.1 Hz), 7.5
6 (2H, d, J = 8.1 Hz). Elemental analysis Calculated as C ₃₃ H ₃₄ F ₂ N ₆ O ₄ S: C, 61.10; H, 5.28; N, 12.95. Found: C; 61.23; H, 5.33; N, 13.06. Mp 205-207 ° C. Example 98 N- [4- (3- (4-acetaminophenyl) -1- (2,6-difluorobenzyl) -5-{[2-methoxyethyl (Methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]
Production of Pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 128] Pyridine (1.00 ml) of the compound of Example 97 (0.10 g)
Acetic anhydride (50 mg) was added dropwise to the solution, and the mixture was stirred at room temperature for 18 hours. After evaporating the solvent under reduced pressure, the obtained residue was partitioned with ethyl acetate / water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by NH-silica gel (Fuji Silysia Chemical Ltd.) chromatography and recrystallized from methanol to give the title compound (0.08 g, 77%). ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.0 Hz), 2.10
(3H, s), 2.17 (3H, s), 2.61 (2H, t, J = 6.0 Hz), 3.
25 (3H, s), 3.30 (2H, q, J = 7.2 Hz), 3.40 (2H, t,
J = 6.0 Hz), 3.81 (2H, s), 5.35 (2H, s), 5.6-5.7
(1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.19 (2H, d, J
= 9.0 Hz), 7.3-7.4 (1H, m), 7.46 (4H, s), 7.72 (2H,
d, J = 8.1 Hz), 8.74 (1H, s). Elemental analysis Calculated as C ₃₅ H ₃₆ F ₂ N ₆ O ₅ S: C, 60.86; H, 5.25; N, 12.17. Found: C; 61.03 H, 5.38; N, 12.02.mp 218-220 ° C. Example 99 N- [4- (3- (4-{(ethylamino) carbonylamino} phenyl) -1- (2,6-difluorobenzyl) -5-{[2-methoxyethyl (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-
Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical formula 129] Pyridine (1.00 ml) of the compound of Example 97 (0.10 g)
Ethyl isotianate (36 mg) was added dropwise to the solution, and the mixture was stirred at room temperature for 18 hours. After evaporating the solvent under reduced pressure, the obtained residue was partitioned with ethyl acetate / water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from methanol to give the title compound (0.06 g, 56%). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.0 Hz), 1.16
(3H, t, J = 7.0 Hz), 2.10 (3H, s), 2.61 (2H, t, J
= 6.0 Hz), 3.25 (3H, s), 3.27 (2H, q, J = 7.2Hz),
3.28 (2H, q, J = 7.2 Hz), 3.40 (2H, t, J = 6.0 H
z), 3.81 (2H, s), 5.34 (2H, s), 5.5-5.6 (1H, m), 5.
6-5.7 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.13 (2H,
d, J = 9.0 Hz), 7.2-7.3 (1H, m), 7.45 (4H, s), 7.
52 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 7.98 (1H, s). Elemental analysis Calculated as C ₃₆ H ₃₉ F ₂ N ₇ O ₅ S: C, 60.07; H, 5.46 N, 13.62. Found: C; 59.94; H, 5.48; N, 13.68.mp 236-239 ° C.

Example 100 3-[({1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- [4- (2-methoxyethoxy) ) Phenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl} methyl) (methyl)
Production of Amino] -N, N-dimethylpropanamide

[Chemical 130] The compound of Example 28 (974 mg, 1.5 mmol) and 3-bromo-N, N
-Dimethylpropanamide (360 mg, 2.0 mmol) was used to carry out the same reaction as in Example 4 to give the title compound (760 mg,
68%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4 Hz), 2.07
(3H, s), 2.17 (3H, s), 2.46 (2H, t, J = 6.0 Hz), 2.
76 (2H, t, J = 6.0 Hz), 2.86 (3H, s), 2.89 (3H,
s), 3.29 (2H, q, J = 7.2 Hz), 3.46 (3H, s), 3.7-3.
8 (4H, m), 4.1-4.2 (2H, m), 4.8-5.2 (1H, br), 5.35
(2H, s), 6.91 (2H, t, J = 8.4 Hz), 7.04 (2H, d, J =
9.0 Hz), 7.18 (2H, d, J = 9.0 Hz), 7.25-7.45 (5H,
m). Elemental analysis Calculated as C ₃₈ H ₄₂ F ₂ N ₆ O ₆ S: C, 60.95; H, 5.65; N, 11.22. Found: C; 61.08; H, 5.54; N, 11.05.mp 215- 218 ° C. Example 101 N- [4- (3- [3,4-bis (2-methoxyethoxy) phenyl] -1-
(2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (
Methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl]-
Production of N'-ethylurea

[Chemical 131] 3,4-bis (2-methoxyethoxy) aniline (3.62 g, 15.
(0 mmol) in dichloromethane (20 ml), and under ice-cooling, a hexane solution of dimethylaluminium chloride (0.98M) (1
(5.3 ml, 15.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour.
Further, the compound of Reference Example 8 (1.21 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) and recrystallized from methanol to give the title compound (0.75 g, 48%).
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.4 Hz), 2.12
(3H, s), 2.62 (2H, t, J = 6.0 Hz), 3.25 (3H, s), 3.
29 (2H, q, J = 7.2 Hz), 3.35-3.45 (8H, s), 3.70-3.
80 (4H, m), 3.82 (2H, s), 4.10-4.20 (4H, m), 4.7-
4.9 (1H, br), 5.34 (2H, s), 6.5-6.7 (1H, br), 6.80
-6.90 (2H, m), 6.94 (2H, t, J = 8.4 Hz), 7.01 (1H,
d, J = 9.0 Hz), 7.26-7.36 (1H, m), 7.35 (2H, d, J
= 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz). Elemental analysis Calculated as C ₃₉ H ₄₅ F ₂ N ₅ O ₈ S ・ 0.5 H ₂ O: C, 59.23; H, 5.86; N, 8.86 Found: C; 59.32; H, 5.89; N, 8.82. Mp 206-208 ° C. Example 102 N- [4- (3- [4- (benzyloxy) phenyl] -1- (2,6-difluoro). Benzyl) -5-{[2-methoxyethyl (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 132] 4-Benzyloxyaniline (3.78 g, 16.0 mmol) was dissolved in dichloromethane (60 ml), and hexane solution of dimethylaluminum chloride (0.98M) (16.4 ml, 16.0 mm) under ice cooling.
ol) was added dropwise and the mixture was stirred at room temperature for 1 hour. Further, the compound of Reference Example 8 (1.21 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from methanol to give the title compound (1.42 g, 96%).
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.14
(3H, s), 2.63 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.
31 (2H, q, J = 7.2 Hz), 3.41 (2H, t, J = 5.7 Hz),
3.82 (2H, s), 4.6-4.7 (1H, m), 5.08 (2H, s), 5.35
(2H, s), 6.3-6.4 (1H, m), 6.91 (2H, t, J = 8.1 Hz),
7.07 (2H, d, J = 6.6 Hz), 7.19 (2H, d, J = 6.6 H
z), 7.26-7.45 (10H, m), 7.57 (2H, d, J = 8.4 Hz). Elemental analysis Calculated as C ₄₀ H ₃₉ F ₂ N ₅ O ₅ S: C, 64.94; H, 5.31; N , 9.47. Found: C; 64.77; H, 5.03; N, 9.38.mp 223-225 ° C.

Example 103 N- [4- (1- (2,6-difluorobenzyl) -3- (4-hydroxyphenyl) -5-{[(-{[2-methoxyethyl (methyl) amino] methyl } -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 133] The compound of Example 102 (1.04 g) in ethanol (20 m
l) solution, 2N-hydrogen chloride / diethyl ether solution (1
ml) and 50% hydrous-10% palladium / carbon (1.00 g),
The mixture was vigorously stirred under a hydrogen atmosphere for 1 hour. The catalyst-free filtrate was neutralized with aqueous sodium hydrogen carbonate, and the deposited precipitate was collected by filtration. The crystals were washed with diethyl ether and dried under reduced pressure to give the title compound (0.88 g, 97%) as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.15
(3H, s), 2.64 (2H, t, J = 5.7 Hz), 3.25 (3H, s), 3.
30 (2H, q, J = 7.2 Hz), 3.42 (2H, t, J = 5.7Hz),
3.80 (2H, s), 4.2-4.3 (1H, m), 5.36 (2H, s), 6.3-
6.4 (1H, m), 6.95 (2H, t, J = 8.1 Hz), 7.10 (2H, d,
J = 6.6 Hz), 7.19 (2H, d, J = 6.6 Hz), 7.25-7.40
(5H, m), 7.58 (2H, d, J = 8.4 Hz). Elemental analysis Calculated as C ₃₃ H ₃₃ F ₂ N ₅ O ₅ S: C, 61.00; H, 5.12; N, 10.78. C; 60.86; H, 5.26; N, 10.62.mp 260-265 ° C. Example 104 N- [4- (1- (2,6-difluorobenzyl) -3- [4- (2-methoxyethoxy) phenyl ] -5-{[(2-Methoxyethyl (methyl) amino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-Ethylurea production

[Chemical 134] A DMF suspension (2 ml) of the compound of Example 103 (0.13 g, 0.2 mmol), bromoethyl methyl ether (70 mg, 0.5 mmol) and cesium carbonate (0.16 g, 0.5 mmol) at 80 ° C.
Stir for hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from methanol to give the title compound (0.12 g, 85%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.14
(3H, s), 2.64 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.
32 (2H, q, J = 7.2 Hz), 3.41 (2H, t, J = 5.7 Hz),
3.45 (3H, s), 3.76 (2H, q, J = 4.5 Hz), 3.83 (2H,
s), 4.15 (2H, q, J = 4.5 Hz), 4.6-4.7 (1H, m), 5.36
(2H, s), 6.2-6.3 (1H, m), 6.92 (2H, t, J = 7.8 H
z), 7.03 (2H, d, J = 6.6 Hz), 7.18 (2H, d, J = 6.6
Hz), 7.26-7.35 (1H, m), 7.36 (2H, d, J = 8.7 Hz),
7.56 (2H, d, J = 8.7 Hz). Elemental analysis Calculated as C ₃₆ H ₃₉ F ₂ N ₅ O ₆ S: C, 61.09; H, 5.55; N, 9.89. Found: C; 61.23; H, 5.62; N, 10.11. Mp 215-218 ° C. Example 105 N- [4- (3- [3,4-bis (2-methoxyethoxy) phenyl] -1-
(2,6-Difluorobenzyl) -5-{[(2-methoxyethyl (methyl) amino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-yl} phenyl) -N'-ethylurea production

[Chemical 135] 3,4-bis (2-methoxyethoxy) aniline (3.62 g, 15.0
mmol) in dichloromethane (60 ml), and under ice-cooling, a hexane solution of dimethylaluminium chloride (0.98M) (15.3M).
(ml, 15.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Further, the compound of Reference Example 8 (1.21 g, 2.0 mmol) was added, and the mixture was stirred at room temperature.
It was stirred for 16 hours. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol) and recrystallized from methanol to give the title compound (0.7
5 g, 48%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.25 (3H, s), 3.
29 (2H, q, J = 7.2 Hz), 3.38-3.44 (4H, m), 3.45 (3
H, s), 3.76 (4H, q, J = 4.5 Hz), 3.82 (2H, s), 4.1
7 (4H, q, J = 4.5 Hz), 4.7-4.8 (1H, m), 5.34 (2H,
s), 6.6-6.7 (1H, m), 6.82-6.85 (2H, m), 6.91 (2H,
t, J = 7.8 Hz), 7.00 (1H, d, J = 6.9 Hz), 7.26-7.3
5 (1H, m), 7.36 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J
= 8.7 Hz). Elemental analysis Calculated as C ₃₉ H ₄₅ F ₂ N ₅ O ₈ S ・ 0.5 H ₂ O: C, 59.23; H, 5.86; N, 8.86. Found: C; 59.32; H, 5.89; N, 8.82.mp 222-225 ℃.

Example 106 N- {2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2 -Methoxyethyl (methyl) amino) methyl] -2,4-dioxo-1,2,3,4-
Preparation of tetrahydrothieno [2,3-d] pyrimidin-3 (2H) -yl} phenoxy) ethyl] methanesulfonamide

[Chemical 136] The compound of Example 103 (0.33 g, 0.5 mmol) and N-mesyl
A DMF suspension (5 ml) of -2-bromoethylamine (0.12 g, 0.6 mmol) and cesium carbonate (0.16 g, 0.5 mmol) was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Eluent: chloroform-methanol) and purified by recrystallization from methanol-ether to give the title compound (0.32 g,
(83%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.14
(3H, s), 2.64 (2H, t, J = 5.7 Hz), 2.96 (3H, s), 3.
32 (2H, q, J = 7.2 Hz), 3.41 (2H, t, J = 5.7 Hz),
3.45 (3H, s), 3.76 (2H, q, J = 4.5 Hz), 3.83 (2H,
s), 4.15 (2H, q, J = 4.5 Hz), 4.6-4.7 (1H, m), 5.35
(2H, s), 6.2-6.3 (1H, m), 6.98 (2H, t, J = 7.8 H
z), 7.03 (2H, d, J = 6.6 Hz), 7.18 (2H, d, J = 6.6
Hz), 7.26-7.34 (1H, m), 7.38 (2H, d, J = 8.7 Hz),
7.58 (2H, d, J = 8.7 Hz). Elemental analysis C ₃₆ H ₄₀ F ₂ N ₆ O ₇ S ₂ Calculated: C, 56.09; H, 5.23; N, 10.90. Found: C; 55.96; H , 5.38; N, 10.83. Mp 232-235 ° C. Example 107 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -5-{[(2-Methoxyethyl (methyl) amino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-3 (2H) -yl} Production of phenoxy) ethyl acetate

[Chemical 137] A DMF suspension (5 ml) of the compound of Example 103 (0.33 g, 0.5 mmol), 2-bromoethyl acetate (0.10 g, 0.6 mmol) and cesium carbonate (0.16 g, 0.5 mmol) was stirred at room temperature for 5 hours. did. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (eluent:
It was purified by chloroform-methanol) and recrystallized from methanol to obtain the title compound (0.35 g, 95%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.09
(3H, s), 2.15 (3H, s), 2.64 (2H, t, J = 5.7 Hz), 3.
32 (2H, q, J = 7.2 Hz), 3.40 (2H, t, J = 5.7 Hz),
3.45 (3H, s), 3.56 (2H, q, J = 4.5 Hz), 3.83 (2H,
s), 4.15 (2H, q, J = 4.5 Hz), 4.6-4.7 (1H, m), 5.36
(2H, s), 6.2-6.3 (1H, m), 6.92 (2H, t, J = 7.8 H
z), 7.03 (2H, d, J = 6.6 Hz), 7.18 (2H, d, J = 6.6
Hz), 7.26-7.35 (1H, m), 7.36 (2H, d, J = 8.7 Hz),
7.56 (2H, d, J = 8.7 Hz). Elemental analysis Calculated as C ₃₇ H ₃₉ F ₂ N ₅ O ₇ S: C, 60.40; H, 5.34; N, 9.52. Found: C; 60.33; H, 5.46; N, 9.43. Mp 212-215 ° C. Example 108 N- [4- (1- (2,6-difluorobenzyl) -3- [4- (2-2,6-difluorobenzylethoxy) phenyl] -5-{[({[2-methoxyethyl (methyl) amino] methyl} -2,4-dioxo-1,2,3,4-
Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 138] The compound of Example 107 (0.25 g) in ethanol (5 ml)
A 1N aqueous potassium hydroxide solution (1.0 ml) was added to the solution, and the mixture was stirred at room temperature for 6 hours. The reaction solution was partitioned between chloroform and water, the organic layer was separated, dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from methanol to give the title compound (0.20 g, 85
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.15
(3H, s), 2.64 (2H, t, J = 5.7 Hz), 3.32 (2H, q, J =
7.2 Hz), 3.42 (2H, t, J = 5.7 Hz), 3.45 (3H, s),
3.55 (2H, q, J = 4.5 Hz), 3.85 (2H, s), 3.95 (2H,
q, J = 4.5 Hz), 4.6-4.7 (1H, m), 5.36 (2H, s), 6.2-
6.3 (1H, m), 6.92 (2H, t, J = 7.8 Hz), 7.06 (2H,
d, J = 6.6 Hz), 7.19 (2H, d, J = 6.6 Hz), 7.25-7.3
5 (1H, m), 7.38 (2H, d, J = 8.7 Hz)), 7.54 (2H, d,
J = 8.7 Hz) .Calculated as elemental analysis C ₃₅ H ₃₇ F ₂ N ₅ O ₆ S: C, 60.59; H, 5.38; N, 10.09. Found: C; 60.65; H, 5.49; N, 10.20. mp 236-238 ℃.

Example 109 N- [4- (1- (2,6-difluorobenzyl) -5-{[[2- (2-methoxyethoxy) ethyl] (methyl) amino] methyl} -2,4- Preparation of dioxo-3phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 139] The compound of Example 1 (575 mg, 1.0 mmol) and 1-bromo-2- (2
-Methoxyethoxy) ethane (0.37 g, 2.0 mmol) was used to carry out the same reaction as in Example 19 to give the title compound (480 mg,
68%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.0 Hz), 2.23
(3H, s), 2.64 (2H, d, J = 4.4 Hz), 3.28 (2H, q, J =
7.2 Hz), 3.75-3.90 (7H, m), 4.84 (1H, t, J = 4.4 H
z), 4.92 (1H, t, J = 4.4 Hz), 5.36 (2H, s), 6.63
(1H, s), 6.92 (2H, t, J = 8.2 Hz), 7.2-7.6 (10H,
m). Elemental analysis Calculated as C ₃₅ H ₃₇ F ₂ N ₅ O ₅ S: C; 62.02; H, 5.50; N, 10.33. Found: C; 62.14; H, 5.36; N, 10.56.mp 228- 231 ° C. Example 110 N- [4- (1- (2,6-difluorobenzyl)-[{2- (2-propoxy) ethyl (methyl) amino} methyl] -2,4-dioxo-3phenyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
-6-yl) phenyl] -N'-ethylurea

[Chemical 140] The compound of Example 1 (575 mg, 1.0 mmol) and 2-isopropyloxyethyl methanesulfonate (0.36 g, 2.0 mmol)
Was performed in the same manner as in Example 19 to give the title compound
(450 mg, 68%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.06 (6H, d, J = 6.2 Hz), 1.15
(3H, t, J = 7.0 Hz), 2.15 (3H, s), 2.63 (2H, t, J
= 5.8 Hz), 3.28 (2H, q, J = 7.2 Hz), 3.43 (2H, t,
J = 5.8 Hz), 3.42-3.54 (1H, m), 3.84 (2H, s), 4.91
4 (1H, t, J = 4.4Hz), 5.36 (2H, s), 6.68 (1H, s),
6.92 (2H, t, J = 8.0 Hz), 7.2-7.6 (10H, m). Calculated as elemental analysis C ₃₅ H ₃₇ F ₂ N ₅ O ₄ S: C, 63.52; H, 5.64; N, 10.58. Found: C; 63.30; H, 5.55; N, 10.48.mp 224-224 ° C. Example 111 N- [4- (1- (2,6-difluorobenzyl) -5-[{[2- (2 -Ethoxy) ethoxy] ethyl (methyl) amino} methyl] -2,4-dioxo-3phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N '-Ethylurea production

[Chemical 141] The compound of Example 1 (575 mg, 1.0 mmol) and 1-bromo-2- (2-
(Ethoxyethoxy) ethane (0.39 g, 2.0 mmol) was used to carry out the same reaction as in Example 19 to give the title compound (400 mg,
56%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 6.0 Hz), 1.15
(3H, t, J = 7.0 Hz), 2.64 (2H, d, J = 4.4 Hz), 3.2
8 (2H, q, J = 7.2 Hz), 3.42 (2H, q, J = 6.0 Hz),
3.75-3.90 (7H, m), 4.84 (1H, t, J = 4.4 Hz), 4.92
(1H, t, J = 4.4 Hz), 5.36 (2H, s), 6.63 (1H, s),
6.92 (2H, t, J = 8.2 Hz), 7.2-7.6 (10H, m). Elemental analysis Calculated as C ₃₆ H ₃₉ F ₂ N ₅ O ₅ S: C, 62.50; H, 5.49; N, 10.12. Found: C; 62.63; H, 5.43; N, 10.22.mp 230-233 ° C.

Example 112 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3-phenyl -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6
Preparation of -yl) phenyl] -N'-ethylurea monohydrochloride:

[Chemical 142] A solution of the compound of Example 81 (2.80 g) in dichloromethane (14
12% methanolic hydrogen chloride (2.65 g) was added to the mixture (ml) under ice-cooling and the mixture was stirred for 15 min, and the solvent was evaporated. The obtained residue was pulverized in dry diethyl ether, and the crystalline powder was collected by filtration and dried to give the title compound (2.92 g). ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.1 Hz), 2.67
(3H, s), 3.10-3.30 (4H, m), 3.22 (3H, s), 3.60 (2
H, s), 4.47 (2H, br), 5.30 (2H, s), 6.45 (1H, t, J
= 5.3 Hz), 6.91 (2H, t, J = 8.1 Hz), 7.09 (2H, d,
J = 8.8 Hz), 7.24-7.58 (5H, m), 7.66 (2H, d, J =
8.8 Hz), 9.44 (1H, s) .IR (KBr): 3303, 1713, 1667, 1593, 1539, 1472, 131
8, 1235 cm ^-1 . Elemental analysis C ₃₃ H ₃₃ N ₅ O ₄ SF ₂・ HCl ・ H ₂ O Calculated value: C, 57.59; H, 5.27; N, 10.18. Actual value: C, 57.66; H, 5.40; N, 10.31.Example 113 N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2-pyridylmethyl) amino) methyl) -2,4-dioxo-3- Phenyl-
Production of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) -N'-ethylurea

[Chemical 143] N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (350 mg, 0.608 mmol) and 2-chloromethylpyridine hydrochloride (199 mg, 1.2 mmol) were used to carry out the same reaction as in Example 4. The title compound (294 mg, 73%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.09
(3H, s), 3.2-3.4 (2H, m), 3.70 (2H, s), 3.98 (2H,
s), 4.75-4.85 (1H, m), 5.35 (2H, s), 6.61 (1H, s),
6.91 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.2-7.6
(12H, m), 8.42 (1H, d, J = 4.4 Hz). IR (KBr): 1715, 1676, 1530, 1458, 1314, 1238, 103
. 6, 735 cm ^-1 elemental analysis _{C 36 H 32 F 2 N 6} O 3 S · 0.5H 2 O Calculated: C, 63.99; H, 4.92 ; N, 12.44 Found:. C; 63.77; H, 5.01; N, 12.53. Mp 203-204 ° C. Example 114 N- [4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-{[methyl (2-pyridyl Methyl) amino] methyl}-
Production of 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) -N'-ethylurea

[Chemical 144] N- (4- {1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-[(methylamino) methyl] -2,4-dioxo-1,2,3,
Using 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (350 mg, 0.590 mmol) and 2-chloromethylpyridine hydrochloride (193 mg, 1.18 mmol), The title compound (292 mg, 7
2%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.09
(3H, s), 3.2-3.4 (2H, m), 3.70 (2H, s), 3.96 (2H,
s), 4.75-4.85 (1H, m), 5.34 (2H, s), 6.63 (1H, s),
6.91 (2H, t, J = 8.2 Hz), 7.0-7.6 (12H, m), 8.43
(1H, d, J = 4.8 Hz) .IR (KBr): 1721, 1667, 1635, 1472, 1236, 1034, 766
cm ^-1 . Calculated as elemental analysis C ₃₆ H ₃₁ F ₃ N ₆ O ₃ S: C, 63.15; H, 4.56; N, 12.27. Found: C; 63.34; H, 4.53; N, 12.47.mp 243 -244 ° C.

Example 115 N- (4- (1- (2,6-difluorobenzyl) -5-((((6- (hydroxymethyl) -2-pyridyl) methyl) (methyl) amino) methyl)
-2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) -N'-ethylurea

[Chemical 145] N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (200 mg, 0.347 mmol) and 6-bromomethyl-2-pyridinemethanol (0.14 g, 0.694 mmol) were used, the same as in Example 4. The reaction was performed to give the title compound (190 mg, 79%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 2.13
(3H, s), 3.2-3.4 (2H, m), 3.71 (2H, s), 3.96 (2H,
s), 4.2-4.4 (1H, br), 4.68 (2H, s), 4.9-5.0 (1H,
m), 5.36 (2H, s), 6.66 (1H, s), 6.92 (2H, t, J =
8.0 Hz), 7.0-7.6 (13H, m) .IR (KBr): 1713, 1674, 1530, 1458, 1314, 1238, 103
. 6, 789, 735 cm ^-1 elemental analysis _{C 37 H 34 F 2 N 6} O 4 S · 1.0H 2 O Calculated: C, 62.17; H, 5.08 ; N, 11.76 Found:. C; 62.19; H, 4.98; N, 11.78.Example 116 Methyl 6-(((((1- (2,6-difluorobenzyl) -6- (4-(((ethylaminocarbonyl) amino) phenyl) -2,4- Dioxo
Preparation of 3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) nicotinate

[Chemical 146] N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (748 mg, 1.3 mmol) and methyl 6- (bromomethyl) nicotinate (0.49 g, 2.13 mmol) were used in the same reaction as in Example 4. The title compound (559 mg, 59%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.09
(3H, s), 3.2-3.4 (2H, m), 3.75 (2H, s), 3.93 (3H,
s), 3.98 (2H, s), 4.65-4.75 (1H, m), 5.35 (2H, s),
6.44 (1H, s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.6
(11H, m), 8.11 (1H, dd, J = 2.2, 8.0 Hz), 9.0-9.05
(1H, m). IR (KBr): 1730, 1715, 1674, 1458, 1314, 1291, 123
8, 1121, 1036, 735 cm ^-1 . Elemental analysis Calculated as C ₃₈ H ₃₄ F ₂ N ₆ O ₅ S: C, 62.97; H, 4.73; N, 11.60. Found: C; 62.71; H, 4.47 N, 11.51. Example 117 6-(((((1- (2,6-difluorobenzyl) -6- (4-((ethylaminocarbonyl) amino) phenyl) -2,4-dioxo-3- Phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
Preparation of (5-yl) methyl) (methyl) amino) methyl) -N-methylnicotinamide

[Chemical 147] Methylamine (2M THF solution) (1.38 ml, 2.76 mmol) in dichloromethane solution (4 ml) was added to ethyl diisopropylamine (0.48 ml, 2.76 mmol) and dimethylaluminum chloride in hexane (0.98 M) (1.69 M) under ice cooling. ml, 1.656 mm
ol) was added dropwise and the mixture was stirred at room temperature for 30 minutes. Methyl 6-
((((1- (2,6-Difluorobenzyl) -6- (4-(((ethylaminocarbonyl) amino) phenyl) -2,4-dioxo-3-phenyl-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidine-5
-Yl) methyl) (methyl) amino) methyl) nicotinate (20
A dichloromethane (14 ml) solution of 0 mg, 0.276 mmol) was added, and the mixture was stirred at room temperature for 2 days. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 40/1) and recrystallized from dichloromethane / methanol to give the title compound (99 mg, 50%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.25
(3H, s), 3.01 (3H, d, t = 4.6 Hz), 3.2-3.4 (2H, m),
3.68 (2H, s), 3.89 (2H, s), 5.05-5.15 (1H, m), 5.3
4 (2H, s), 6.91 (2H, t, J = 7.8), 6.9-7.0 (1H, m),
7.05-7.15 (2H, m), 7.2-7.6 (10H, m), 7.85-7.95 (1
H, m), 8.8-8.85 (1H, m). IR (KBr): 1717, 1671, 1472, 1240, 1032, 735 cm ^-1 . Elemental analysis C ₃₈ H ₃₅ F ₂ N ₇ O ₄ S ・ 0.5H Calculated as ₂ O: C, 62.28; H, 4.95; N, 13.38. Found: C; 62.32; H, 4.77; N, 13.26.

Example 118 Ethyl 6-((((1- (2,6-difluorobenzyl) -6- (4-(((ethylaminocarbonyl) amino) phenyl) -2,4-dioxo
Preparation of -3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) -2-pyridinecarboxylate

[Chemical 148] N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (576 mg, 1 mmol) and ethyl 6-bromomethyl-2-
Using pyridine carbochelate (399 mg, 2.2 mmol),
The reaction was performed in the same manner as in Example 4 to give the title compound (605 mg, 82%)
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.39
(3H, t, J = 7.2 Hz), 2.03 (3H, s), 3.2-3.4 (2H,
m), 3.77 (2H, s), 3.97 (2H, s), 4.42 (2H, q, J = 7.
2 Hz), 4.85-4.95 (1H, m), 5.34 (2H, s), 6.81 (1H,
s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.6 (11H, m), 7.6
7 (1H, t, J = 7.2 Hz), 7.90 (1H, d, J = 7.2 Hz) .IR (KBr): 1717, 1671, 1593, 1532, 1468, 1318, 123
6, 1032, 762 cm ^-1 . Calculated as elemental analysis C ₃₉ H ₃₆ F ₂ N ₆ O ₅ S: C, 63.40; H, 4.91; N, 11.38. Found: C; 63.23; H, 4.90; N Example 119 6-((((1- (2,6-difluorobenzyl) -6- (4-(((ethylaminocarbonyl) amino) phenyl) -2,4-dioxo-3-phenyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
-5-yl) methyl) (methyl) amino) methyl) -N-methyl-2-
Production of pyridinecarboxamide

[Chemical 149] Methylamine (2M THF solution) (2.03 ml, 4.06 mmol) and ethyl 6-(((((1- (2,6-difluorobenzyl) -6- (4-((ethylaminocarbonyl) amino) phenyl)- 2,4-dioxo-3-
Phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) -2-pyridinecarboxylate (300 mg, 0.406 mmol) The same reaction as in Example 117 was performed to give the title compound (191 mg, 65
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.14
(3H, s), 2.95 (3H, d, J = 5.2 Hz), 3.2-3.4 (2H, m),
3.72 (2H, s), 3.97 (2H, s), 4.95-5.0 (1H, m), 5.3
6 (2H, s), 6.84 (1H, s), 6.92 (2H, t, J = 8.2 Hz),
7.25-7.6 (11H, m), 7.66 (1H, t, J = 7.4 Hz), 7.95
(1H, d, J = 7.4 Hz), 8.05-8.15 (1H, m). IR (KBr): 1721, 1661, 1534, 1472, 1236, 1032, 737
cm ^-1 .Elemental analysis Calculated as C ₃₈ H ₃₅ F ₂ N ₇ O ₄ S ・ 1.4H ₂ O: C, 60.93; H, 5.09; N, 13.09. Found: C; 61.24; H, 5.20; N , 12.81. Example 120 N- (4- (1- (2,6-difluorobenzyl) -5-(((2- (1H-imidazol-1-yl) ethyl) (methyl) amino) methyl) -2 , 4-Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 150] N- (4- (1- (2,6 difluorobenzyl) -5-(((2-hydroxyethyl) (methyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2,3, 4-Tetrahydrothieno [2,3-d] pyrimidine-6
-Yl) phenyl) -N'-ethylurea (135 mg, 0.218 mmo
l) was dissolved in tetrahydrofuran (30 ml), triethylamine (0.18 ml, 1.308 mmol) and methanesulfonyl chloride (0.070 ml, 0.872 mmol) were added, and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The aqueous layer was salted out and extracted with ethyl acetate. The organic layers were collected, dried over magnesium sulfate, and concentrated under reduced pressure to give mesylate. Obtained mesylate, imidazole (148 mg, 2.18 mmo
l), potassium carbonate (60 mg, 0.436 mmol) in DMF solution (4 ml)
Was stirred at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 40/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (33 mg, 22%) as colorless crystals. . ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.19
(3H, s), 2.65-2.75 (2H, m), 3.2-3.4 (2H, m), 3.80
(2H, s), 3.85-4.0 (2H, m), 5.25-5.35 (1H, m), 5.37
(2H, s), 6.81 (1H, s), 6.85-7.0 (3H, m), 7.2-7.6
(12H, m).

Example 121 N- (4- (1- (2,6-difluorobenzyl) -5-(((2- (2- (2-hydroxyethyl) -1H-imidazol-1-yl) ethyl)) (Methyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2,3,4-
Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 151] N- (4- (1- (2,6 difluorobenzyl) -5-(((2-hydroxyethyl) (methyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2,3, 4-Tetrahydrothieno [2,3-d] pyrimidine-6
-Yl) phenyl) -N'-ethylurea (135 mg, 0.218 mmo
l) and 2- (2-hydroxyethyl) imidazole (122 mg, 1.0
(9 mmol) was used and the same reaction as in Example 120 was carried out to obtain the title compound (23 mg, 15%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.22
(3H, s), 2.6-2.75 (4H, m), 3.2-3.4 (2H, m), 3.75 (2
H, s), 3.7-3.85 (2H, m), 3.9-4.0 (2H, m), 4.95-5.0
5 (1H, m), 5.37 (2H, s), 6.75 (1H, s), 6.82 (1H,
s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.6 (11H, m). Example 122 2- (4- (1- (2,6-difluorobenzyl) -6- (4- ( ((Ethylaminocarbonyl) amino) phenyl) -5-((methyl (2-pyridylmethyl) amino) methyl) -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidine-3 (2H ) -Yl) phenoxy) -N
-Manufacture of methylacetamide

[Chemical 152] DMF of the compound of Reference Example 19 (319 mg, 0.5 mmol) and 4-aminophenoxy-N-methylacetamide (135 mg, 0.75 mmol)
To the solution (4 ml), add ethyldiisopropylamine (0.14 ml,
0.8 mmol) and diethyl cyanophosphate (0.11 ml, 0.75 mmo
l) was added, and the mixture was stirred at room temperature for 3 days. Aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 20/1) to give an amide. The obtained amide was dissolved in methanol (8 ml) and sodium methoxide was added.
(189 mg, 3.5 mmol) was added. After stirring at room temperature for 2 hours, the mixture was concentrated, 1N hydrochloric acid was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / methanol; 20/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (122 mg, 46%).
Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.09
(3H, s), 2.92 (3H, d, J = 4.8 Hz), 3.2-3.4 (2H, m),
3.70 (2H, s), 3.96 (2H, s), 4.54 (2H, s), 4.8-4.9
(1H, m), 5.34 (2H, s), 6.5-6.7 (2H, m), 6.91 (2H,
t, J = 8.0 Hz), 7.0-7.6 (11H, m), 8.4-8.5 (1H, m) .IR (KBr): 1719, 1669, 1472, 1236, 1032, 764 cm ^-1 . Elemental analysis C ₃₉ Calculated as H ₃₇ F ₂ N ₇ O ₅ S 1.0H ₂ O: C, 60.69; H, 5.09; N, 12.70. Found: C; 60.89; H, 5.00; N, 12.78. (4- (1- (2,6-difluorobenzyl) -6- (4-(((ethylaminocarbonyl) amino) phenyl) -5-((methyl (2-pyridylmethyl) amino) methyl) -2, 4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenyl) -N-
Production of ethylacetamide

[Chemical 153] Using the compound of Reference Example 19 (319 mg, 0.5 mmol) and 4-aminophenoxy-N-methylacetamide (134 mg, 0.75 mmol), the same reaction as in Example 122 was carried out to give the title compound (4
3 mg, 14%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.3 (6H, m), 2.10 (3H, s),
3.2-3.4 (4H, m), 3.64 (2H, s), 3.71 (2H, s), 3.97
(2H, s), 4.75-4.85 (1H, m), 5.34 (2H, s), 5.5-5.6
(1H, m), 6.61 (1H, s), 6.92 (2H, t, J = 8.0 Hz),
7.0-7.5 (10H, m), 7.55 (2H, d, J = 8.2 Hz), 8.4-8.5
(1H, m). IR (KBr): 1713, 1671, 1555, 1470, 1238, 1032, 762
cm ^-1 . Elemental analysis Calculated as C ₄₀ H ₃₉ F ₂ N ₇ O ₄ S 1.0H ₂ O: C, 62.41; H, 5.37; N, 12.74. Found: C; 62.54; H, 5.13; N , 12.84.

Example 124 N- (4- (1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -5-((methyl (2-pyridylmethyl) amino))
Methyl) -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 154] Using the compound of Reference Example 19 (319 mg, 0.5 mmol) and trans-4-aminocyclohexanol (86 mg, 0.75 mmol),
The reaction was performed in the same manner as in Example 122, and the title compound (82 mg,
29%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 1.4-1.
8 (4H, m), 2.0-2.2 (2H, m), 2.13 (3H, s), 2.55-2.7
5 (2H, m), 3.2-3.4 (2H, m), 3.7-3.8 (1H, m), 3.73
(2H, s), 3.99 (2H, s), 4.75-4.85 (1H, m), 4.9-5.05
(1H, m), 5.28 (2H, s), 6.5-6.6 (1H, m), 6.9 (2H,
t, J = 8.8 Hz), 7.0-7.6 (8H, m), 8.4-8.5 (1H, m) .IR (KBr): 1707, 1659, 1472, 1314, 1236, 1067, 103
2, 781 cm ^-1 . Elemental analysis Calculated as C ₃₆ H ₃₈ F ₂ N ₆ O ₄ S ・ 0.6H ₂ O: C, 61.81; H, 5.65; N, 12.01. Found: C; 61.54; H, 5.76; N, 11.92. Example 125 N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (2H-
Tetrazol-2-yl) ethyl) amino) mel) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N '-Ethylurea (1) production

[Chemical 155] N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (1H-
Tetrazol-1-yl) ethyl) amino) mel) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N '-Ethylurea (2) production

[Chemical 156] Potassium carbonate (2.075 g, 15 mmol) was added to a DMF solution (5 ml) of tetrazole (0.70 g, 20 mmol) and 1-bromo-2-chloroethane (1.25 ml, 15 mmol), and the mixture was stirred at room temperature for 16 hours.
Saturated saline was added, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over magnesium sulfate, and concentrated under reduced pressure to give a halide (2.115 g, including DMF). With the obtained halide
N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (576 mg, 1 mmol) was used to carry out the same reaction as in Example 4 to give the title compound 2-yl compound (104 mg, 16%). And 1-yl compound (379 mg, 56%) were obtained as colorless crystals. 2-yl (1) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.24
(3H, s), 3.03 (2H, t, J = 6.3 Hz), 3.3-3.4 (2H, m),
3.77 (2H, s), 4.64 (2H, t, J = 6.3 Hz), 4.75-4.85
(1H, m), 5.37 (2H, s), 6.48 (1H, s), 6.92 (2H, t,
J = 8.0 Hz), 6.85-6.95 (1H, m), 7.15-7.55 (9H,
m), 8.28 (1H, s) .IR (KBr): 1713, 1667, 1470, 1236, 1034, 735 cm ^-1 . Elemental analysis C ₃₃ H ₃₁ F ₂ N ₉ O ₃ S ・ 0.5H ₂ O Value: C, 58.23; H, 4.74; N, 18.52. Found: C; 58.06; H, 4.64; N, 18.33. 1-yl (2) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.04
(3H, s), 2.73 (2H, t, J = 5.4 Hz), 3.25-3.4 (2H,
m), 3.78 (2H, s), 4.43 (2H, t, J = 5.4 Hz), 4.95-
5.05 (1H, m), 5.36 (2H, s), 6.73 (1H, s), 6.90 (2
H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.2-7.6 (9H,
m), 8.54 (1H, s). IR (KBr): 1711, 1667, 1534, 1470, 1236, 1034, 735
cm ^-1 . Elemental analysis Calculated as C ₃₃ H ₃₁ F ₂ N ₉ O ₃ S ・ 0.5H ₂ O: C, 58.23; H, 4.74; N, 18.52. Found: C; 58.16; H, 4.68; N , 18.31. Example 126 N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxyethyl) -5-((methyl (2-pyridylmethyl) amino) methyl)-
Production of 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 157] Example 12 Using the compound of Reference Example 19 (350 mg, 0.55 mmol) and 2-aminoethanol (0.10 ml, 1.65 mmol)
The same reaction as in 2 was performed to give the title compound (23 mg, 7%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.4 Hz), 2.21
(3H, s), 3.2-3.4 (2H, m), 3.77 (2H, s), 3.98 (2H,
s), 3.9-4.1 (2H, m), 4.35-4.45 (2H, m), 4.8-4.9 (1
H, m), 5.25 (2H, s), 6.65-6.7 (1H, m), 6.90 (2H,
t, J = 7.8 Hz), 6.95-7.1 (1H, m), 7.2-7.6 (7H, m),
8.35-8.4 (1H, m).

Example 127 N- (4- (1- (2,6-difluorobenzyl) -3- (3-hydroxypropyl) -5-((methyl (2-pyridylmethyl) amino) methyl)
-2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 158] Example 1 Using the compound of Reference Example 19 (350 mg, 0.55 mmol) and 3-aminopropanol (0.13 ml, 1.65 mmol)
The same reaction as in 22 was performed to give the title compound (15 mg, 4%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 1.85-
2.05 (2H, m), 2.12 (3H, s), 3.25-3.4 (2H, m), 3.5-
3.65 (2H, m), 3.72 (2H, s), 3.98 (2H, s), 4.2-4.3
(2H, m), 4.7-4.8 (1H, m), 5.34 (2H, s), 6.45-6.55
(1H, m), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m),
7.2-7.6 (7H, m), 8.4-8.5 (1H, m) .Example 128 N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5- ( (Methyl (2- (2H-1,2,3-triazol-2-yl)
Ethyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-
Production of ethylurea (1)

[Chemical 159] N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (2- (1H-1,2,3-triazol-1-yl)
Ethyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-
Production of ethylurea (2)

[Chemical 160] N- (4- {1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-[(methylamino) methyl] -2,4-dioxo-1,2,3,
Using 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (594 mg, 1 mmol) and 1,2,3-triazole (0.69 g, 10 mmol), The reaction was performed in the same manner as in Example 125 to obtain the title compound 2-yl compound (97 mg, 14%) and 1-yl compound (381 mg, 56%) as colorless crystals. 2-yl (1) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.22
(3H, s), 2.98 (2H, t, J = 6.4 Hz), 3.25-3.45 (2H,
m), 3.77 (2H, s), 4.44 (2H, t, J = 6.4 Hz), 4.6-4.
7 (1H, m), 5.36 (2H, s), 6.30 (1H, s), 6.93 (2H,
t, J = 8.2 Hz), 7.1-7.5 (11H, m). Elemental analysis Calculated as C ₃₄ H ₃₁ F ₃ N ₈ O ₃ S ・ 0.5H ₂ O: C, 58.53; H, 4.62; N, 16.06 Actual value: C; 58.40; H, 4.51; N, 15.90. 1-yl (2) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.16
(3H, s), 2.82 (2H, t, J = 5.8 Hz), 3.2-3.4 (2H, m),
3.78 (2H, s), 4.40 (2H, t, J = 5.8 Hz), 5.0-5.1
(1H, m), 5.36 (2H, s), 6.88 (1H, s), 6.92 (2H, t,
J = 8.2 Hz), 7.15-7.4 (9H, m), 7.50 (1H, s), 7.55
(1H, s). Elemental analysis Calculated as C ₃₄ H ₃₁ F ₃ N ₈ O ₃ S ・ 0.5H ₂ O: C, 58.53; H, 4.62; N, 16.06. Found: C; 58.34; H, 4.58 N, 15.91. Example 129 N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (2- (2H-tetrazol-2-yl )ethyl)
Amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea (1)

[Chemical 161] N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (2- (1H-tetrazol-1-yl) ethyl))
Amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea (2)

[Chemical 162] N- (4- {1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-[(methylamino) methyl] -2,4-dioxo-1,2,3,
4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (594 mg, 1 mmol) and tetrazole (0.70 g, 10 mmol) were used as in Example 125. The reaction was performed to obtain the title compound 2-yl compound (100 mg, 14%) and 1-yl compound (324 mg, 47%) as colorless crystals. 2-yl (1) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.4 Hz), 2.24
(3H, s), 3.01 (2H, t, J = 6.2 Hz), 3.25-3.45 (2H,
m), 3.77 (2H, s), 4.63 (2H, t, J = 6.2 Hz), 4.7-4.
8 (1H, m), 5.36 (2H, s), 6.42 (1H, s), 6.93 (2H,
t, J = 7.8 Hz), 7.1-7.4 (9H, m), 8.29 (1H, s). Elemental analysis Calculated as C ₃₃ H ₃₀ F ₃ N ₉ O ₃ S ・ 0.5H ₂ O: C, 56.73; H, 4.47; N, 18.04.Actual value: C; 56.99; H, 4.32; N, 17.93. 1-yl (2) ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.4 Hz ), 2.08
(3H, s), 2.65-2.75 (2H, m), 3.25-3.45 (2H, m), 3.77
(2H, s), 4.35-4.45 (2H, m), 4.9-5.0 (1H, m), 5.36
(2H, s), 6.64 (1H, s), 6.91 (2H, t, J = 8.2 Hz),
7.15-7.4 (9H, m), 8.53 (1H, s). Elemental analysis Calculated as C ₃₃ H ₃₀ F ₃ N ₉ O ₃ S: C, 57.47; H, 4.38; N, 18.28. Found: C; 57.20; H, 4.29; N, 18.13.

Example 130 N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (1H-
1,2,3-triazol-1yl) propyl) amino) methyl)-
2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno
Production of [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical formula 163] N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (200 mg, 0.347 mmol) and the compound of Reference Example 23
(0.515 g, 4.05 mmol) was used to perform the same reaction as in Example 19 to obtain the title compound (38 mg, 16%) as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.43
(3H, d, J = 6.2 Hz), 2.03 (3H, s), 2.55-2.8 (1H,
m), 2.85-3.05 (1H, m), 3.2-3.4 (2H, m), 3.65-3.85
(2H, m), 4.7-4.85 (1H, m), 5.05-5.15 (1H, m), 5.37
(2H, s), 6.85-7.0 (3H, m), 7.2-7.6 (12H, m). Example 131 N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluoro Phenyl) -5-((methyl (2- (1H-1,2,3-triazol-1-yl)
Propyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl)-
Production of N'-ethylurea

[Chemical 164] N- (4- {1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-[(methylamino) methyl] -2,4-dioxo-1,2,3,
4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (110 mg, 0.185 mmol) and the compound of Reference Example 23 (0.515 g, 4.05 mmol) were used. 1
The same reaction as in 9 was performed to give the title compound (12 mg, 9%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.2 Hz), 1.43
(3H, d, J = 6.6 Hz), 2.07 (3H, s), 2.5-2.7 (1H,
m), 2.85-3.05 (1H, m), 3.2-3.4 (2H, m), 3.65-3.85
(2H, m), 4.7-4.85 (1H, m), 4.9-5.0 (1H, m), 5.36
(2H, s), 6.68 (1H, s), 6.92 (2H, t, J = 7.8 Hz),
7.1-7.45 (10H, m), 7.52 (1H, s) .Example 132 N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (1H-
Tetrazol-1-yl) propyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 165] N- (4- {1- (2,6-difluorobenzyl) -3-phenyl-5-[(methylamino) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} phenyl) -N'-ethylurea (150 mg, 0.261 mmol) and the compound of Reference Example 21
(0.435 g, 3.385 mmol) was used to perform the same reaction as in Example 19 to obtain the title compound (44 mg, 25%) as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.2 Hz), 1.46
(3H, d, J = 6.6 Hz), 2.45-2.55 (1H, m), 2.85-2.95
(1H, m), 3.25-3.4 (2H, m), 3.59 (1H, d, J = 12.0 H
z), 4.75-4.85 (1H, m), 4.91 (1H, t, J = 5.4 Hz),
5.29 (1H, d, J = 15.7 Hz), 5.43 (1H, d, J = 15.7 H
z), 6.60 (1H, s), 6.90 (2H, t, J = 8.1 Hz), 7.2-7.
6 (10H, m), 8.50 (1H, s).

Example 133 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (2-methoxy-3-) Pyridinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 166] A solution of the compound obtained in Reference Example 9 (560 mg) and 2-methoxy-3-aminopyridine (220 mg) in DMF (8.8 ml) under ice cooling, diethyl cyanophosphate (289 mg), N-ethyldiisopropyl. Amine (336 μl) was added, the temperature was gradually returned to room temperature, the mixture was stirred for 13 hours, and the reaction mixture was partitioned with ethyl acetate / water. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was roughly purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical Ltd.), and the obtained crude amide compound (546 mg) was dissolved in ethanol (29 ml). , 28% -Sodium methoxide in methanol (280 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. After neutralizing with 1N-hydrochloric acid (1.45 ml), the solvent was evaporated and the residue was partitioned with ethyl acetate / water. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel chromatography (Merck; 45 g; developing solution; 4% methanol-containing chloroform → 5% (5% ammonia-containing methanol) -containing chloroform). Title compound
(370 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 58.83; H, 5.24; N, 12.47. Found: C, 59.09; H, 5.22; N, 12.62. ¹ H -NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.1 Hz), 2.12
(3H, s), 2.60 (2H, t, J = 5.7 Hz), 3.22 (3H, s),
3.39 (2H, t, J = 5.7 Hz), 3.71 (1H, d, J = 12.0 H
z), 3.91 (3H, s), 3.92 (1H, d, J = 12.0 Hz), 5.25-
5.46 (3H, m), 6.91 (2H, t, J = 8.0 Hz), 6.98-7.01
(1H, m), 7.22-7.48 (6H, m), 7.56 (1H, d, J = 7.4 H
z), 8.20 (1H, d, J = 5.2 Hz) .IR (KBr): 1715, 1674, 1597, 1537, 1472, 1314 cm ^-1.Example 134 N- (4- (1- (2,6 -Difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinylmethyl) -1,2,3,4-tetrahydrothieno [2, Production of 3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 167] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (303 mg), diethyl cyanophosphate (152 μl), N-
Crude amide compound (180 mg) was obtained from ethyldiisopropylamine (190 μl) and 2-aminomethylpyridine (109 mg), and ethanol (12.5 ml) and 28% -sodium methoxide in methanol (97 mg) were used. The title compound (95 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₄ SF ₂・ 0.5H ₂ O: C, 60.26; H, 5.36; N, 12.78. Found: C, 60.28; H, 5.37; N, 12.60. ¹ H -NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2 Hz), 1.98
(3H, s), 2.53 (2H, t, J = 5.9 Hz), 3.22 (3H, s), 3.
21-3.31 (2H, m), 3.37 (2H, t, J = 5.9 Hz), 3.73 (2
H, s), 5.03 (1H, t, J = 5.4 Hz), 5.12 (2H, s), 5,4
1 (2H, s), 6.90 (2H, t, J = 8.1 Hz), 7.08 (2H, d, J
= 8.4 Hz), 7.20-7.32 (4H, m), 7.42 (1H, d, J = 7.8
Hz), 7.74 (1H, dt, J = 1.8 Hz, 7.8 Hz), 8.33 (1H,
s), 8.51 (1H, d, J = 3.9 Hz) .IR (KBr): 1707, 1667, 1593, 1537, 1472, 1316, 1236
cm ^-1 .Example 135 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- Production of (3-pyridinylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 168] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (303 mg), diethyl cyanophosphate (152 μl), N-
The crude amide compound (205 mg) was obtained from ethyldiisopropylamine (190 μl) and 3-aminomethylpyridine (109 mg), and ethanol (14.4 ml) and 28% sodium methoxide in methanol (111 mg) were used. The title compound (134 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₄ SF ₂・ 0.5H ₂ O: C, 60.26; H, 5.36; N, 12.78. Found: C, 60.32; H, 5.51; N, 12.67. ¹ H -NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.10
(3H, s), 2.63 (2H, t, J = 5.9 Hz), 3.28 (3H, s),
3.25-3.34 (2H, m), 3.44 (2H, t, J = 5.9 Hz), 3.82
(2H, s), 4.92 (1H, t, J = 5.6 Hz), 5.25 (2H, s),
5,32 (2H, s), 6.71 (1H, s), 6.87 (2H, t, J = 8.1 H
z), 7.21-7.29 (2H, m), 7.33 (2H, d, J = 8.7 Hz), 7.
44 (2H, d, J = 8.7 Hz), 7.83 (1H, dt, J = 1.8 Hz,
7.8 Hz), 8.50 (1H, dd, J = 1.8 Hz, 4.8 Hz), 8.76
(1H, d, J = 1.8 Hz) IR (KBr): 1705, 1661, 1593, 1537, 1472, 1318, 1236
cm ^-1 .

Example 136 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- ( Preparation of 4-pyridinylmethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 169] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (303 mg), diethyl cyanophosphate (152 μl), N-
A crude amide compound (189 mg) was obtained from ethyldiisopropylamine (190 μl) and 4-aminomethylpyridine (109 mg), and ethanol (13 ml) and 28% sodium methoxide in methanol (101 mg) were used. The title compound (70 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₄ SF ₂ : C, 61.10; H, 5.28; N, 12.95. Found: C, 61.05; H, 5.32; N, 12.79. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.11
(3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.27 (3H, s), 3.
21-3.34 (2H, m), 3.43 (2H, t, J = 5.7 Hz), 3.82 (2
H, s), 4.88 (1H, t, J = 5.6 Hz), 5.24 (2H, s), 5,3
4 (2H, s), 6.73 (1H, s), 6.89 (2H, t, J = 8.1 Hz),
7.23-7.31 (3H, m), 7.36 (2H, d, J = 8.7 Hz), 7.47
(2H, d, J = 8.7 Hz), 8.53 (2H, dd, J = 1.5 Hz, 4.5
Hz). IR (KBr): 1707, 1667, 1595, 1534, 1472, 1316, 1236
cm ^-1 . Example 137 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-ethoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- Production of (2-pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 170] The compound (7.42 g) obtained in Reference Example 24, diethyl cyanophosphate (6.52 g), and N were subjected to the same reaction as in Example 133.
-Ethyldiisopropylamine (6.46 g), 2-aminopyrimidine (1.90 g) to obtain a crude amide (5.20 g), further using methanol (50 ml), sodium methoxide (4.05 g) to give the title compound (2.05 g ) Was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₄ SF ₂ : C, 61.10; H, 5.28; N, 12.95. Found: C, 60.85; H, 5.42; N, 12.91. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (6H, t, J = 7.1 Hz), 2.11
(3H, s), 2.61 (2H, t, J = 6.0 Hz), 3.20-3.29 (2H,
m), 3.37 (2H, q, J = 7.1 Hz), 3.43 (2H, t, J = 6.0
Hz), 3.77 (2H, brs), 5.13 (1H, t, J = 5.4 Hz), 5.3
7 (2H, brs), 6.90 (2H, t, J = 8.0 Hz), 7.24-7.44
(8H, m), 7.90 (1H, dt, J = 2.1 Hz, 7.8Hz), 8.65-8.
68 (1H, m). IR (KBr): 1717, 1672, 1593, 1532, 1460 cm ^-1 . Example 138 N- (4- (1- (2,6-difluorobenzyl) -3- (5- Fluoro-2-
Pyridinyl) -5-(((2-methoxyethyl) (methyl) amino)
Methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,
Production of 3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 171] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (303 mg), diethyl cyanophosphate (152 μl), N-
A crude amide compound (218 mg) was obtained from ethyldiisopropylamine (190 μl) and 2-amino-5-fluoropyridine (113 mg),
Methanol (15 ml) and 28% -sodium methoxide in methanol (116 mg) were used to give the title compound (159 mg).
Was obtained as a colorless powder. Elemental analysis Calculated as C ₃₂ H ₃₁ N ₆ O ₄ SF ₃ : C, 58.89; H, 4.79; N, 12.88. Found: C, 58.59; H, 4.83; N, 12.71. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2 Hz), 2.11
(3H, s), 2.60 (2H, t, J = 5.9 Hz), 3.24 (3H, s), 3.
23-3.32 (2H, m), 3.40 (2H, t, J = 5.9 Hz), 3.79 (2
H, brs), 4.91 (1H, t, J = 5.6 Hz), 5.28 (2H, brs),
6.76 (1H, s), 6.90 (2H, t, J = 8.1 Hz), 7.24-7.39
(4H, m), 7.50 (2H, d, J = 8.7 Hz), 7.55-7.61 (1H,
m), 8.50 (1H, d, J = 3.0 Hz). IR (KBr): 1715, 1674, 1593, 1532, 1462 cm ^-1 .

Example 139 N- (4- (3- (5-chloro-2-pyridinyl) -1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) Methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 172] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (363 mg), diethyl cyanophosphate (182 μl), N-
A crude amide compound (256 mg) was obtained from ethyldiisopropylamine (228 μl) and 2-amino-5-chloropyridine (155 mg), further ethanol (17.8 ml) and a methanol solution of 28% -sodium methoxide (138 mg). ) Was used to give the title compound (119 mg)
Was obtained as a colorless powder. Elemental analysis Calculated as C ₃₂ H ₃₁ N ₆ O ₄ SClF ₂ 0.75H ₂ O: C, 56.30; H, 4.80; N, 12.31. Found: C, 56.25; H, 4.67; N, 12.13. ¹ H -NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.2 Hz), 2.11
(3H, s), 2.59 (2H, t, J = 5.7 Hz), 3.24 (3H, s), 3.
22-3.31 (2H, m), 3.39 (2H, t, J = 5.7 Hz), 3.77 (2
H, brs), 5.02 (1H, t, J = 5.4 Hz), 5.28 (2H, brs),
6.90 (2H, t, J = 8.3 Hz), 6.91 (1H, s), 7.25-7.37
(4H, m), 7.48 (2H, d, J = 8.7 Hz), 7.83 (1H, dd, J
= 2.7 Hz, 8.4 Hz), 8.59 (1H, d, J = 2.7 Hz). IR (KBr): 2975, 1717, 1674, 1593, 1532, 1456cm ^-1 Example 140 N- (4- (3- (5-Bromo-2-pyridinyl) -1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 173] Subjected to the same reaction as in Example 133, the compound (363 mg) obtained in Reference Example 9, diethyl cyanophosphate (182 μl), and N-
A crude amide compound (230 mg) was obtained from ethyldiisopropylamine (228 μl) and 2-amino-5-bromopyridine (208 mg), further ethanol (15 ml) and 28% -sodium methoxide methanol solution (116 mg). The title compound (84 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₂ H ₃₁ N ₆ O ₄ SBrF ₂ 0.5H ₂ O: C, 53.19; H, 4.46; N, 11.63. Found: C, 53.33; H, 4.53; N, 11.62. ¹ H -NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2 Hz), 2.10
(3H, s), 2.59 (2H, t, J = 5.9 Hz), 3.23 (3H, s), 3.
19-3.28 (2H, m), 3.39 (2H, t, J = 5.9 Hz), 3.77 (2
H, brs), 5.22 (1H, t, J = 5.6 Hz), 5.27 (2H, brs),
6.90 (2H, t, J = 8.1 Hz), 7.18 (1H, s), 7.23-7.34
(1H, m), 7.29 (1H, d, J = 8.4 Hz), 7.35 (2H, d, J
= 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.97 (1H, dd,
J = 2.4Hz, 8.4 Hz), 8.69 (1H, d, J = 2.4 Hz). IR (KBr): 2976, 1717, 1674, 1593, 1532, 1456 cm ^-1 . Example 141 N- [4- ( 1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (5-methyl-2-pyridyl) -1,2 , 3,4-Tetrahydrothieno [2,3-d]
Production of Pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 174] Subjected to the same reaction as in Example 133, the compound (363 mg) obtained in Reference Example 9, diethyl cyanophosphate (182 μl), and N-
A crude amide compound (275 mg) was obtained from ethyldiisopropylamine (228 μl) and 2-amino-5-methylpyridine (130 mg), and further ethanol (19.8 ml) and a 28% -sodium methoxide methanol solution (153 mg). ) Was used to give the title compound (196 mg)
Was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₄ SF ₂ 0.75H ₂ O: C, 59.85; H, 5.40; N, 12.69. Found: C, 59.79; H, 5.20; N, 12.51. ¹ H -NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.1 Hz), 2.09
(3H, s), 2.39 (3H, s), 2.58 (2H, t, J = 5.7 Hz), 3.
22 (3H, s), 3.17-3.26 (2H, m), 3.38 (2H, t, J = 5.7
Hz), 3.67 (1H, brs), 3.85 (1H, brs), 5.09 (1H, br
s), 5.31 (1H, t, J = 5.4 Hz), 5.37 (1H, brs), 6.88
(2H, t, J = 8.1 Hz), 7.22-7.31 (1H, m), 7.28 (1H,
d, J = 8.1 Hz), 7.33 (2H, d, J = 8.7 Hz), 7.38 (2
H, d, J = 8.7 Hz), 7.55 (1H, s), 7.69 (1H, dd, J =
2.4 Hz, 8.1 Hz), 8.46 (1H, d, J = 2.4 Hz). IR (KBr): 2976, 1715, 1669, 1593, 1532, 1462 cm ^-1 .

Example 142 N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- ( 6-methyl-2-pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d]
Production of Pyrimidin-6-yl) phenyl] -N'-ethylurea

[Chemical 175] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (363 mg), diethyl cyanophosphate (182 μl), N-
A crude amide compound (275 mg) was obtained from ethyldiisopropylamine (228 μl) and 2-amino-6-methylpyridine (130 mg), and further ethanol (19.8 ml) and a 28% -sodium methoxide methanol solution (153 mg). ) Was used to give the title compound (195 mg)
Was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₄ SF ₂ H ₂ O: C, 59.45; H, 5.44; N, 12.60. Found: C, 59.41; H, 5.25; N, 12.49. ¹ H- NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 7.2 Hz), 2.08
(3H, s), 2.59 (2H, t, J = 6.0 Hz), 2.61 (3H, s), 3.
23 (3H, s), 3.18-3.27 (2H, m), 3.38 (2H, t, J = 6.0
Hz), 3.62 (1H, d, J = 12.3 Hz), 3.92 (1H, d, J =
12.3 Hz), 4.93 (1H, d, J = 15.6 Hz), 5.17 (1H, t, J
= 5.6 Hz), 5.46 (1H, d, J = 15.6 Hz), 6.89 (2H,
t, J = 8.4 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.26 (1
H, d, J = 7.8 Hz), 7.27-7.38 (5H, m), 7.62 (1H, s),
7.79 (1H, t, J = 7.8 Hz). IR (KBr): 2975, 1715, 1672, 1601, 1532, 1456 cm ^-1 Example 143 N- (4- (1- (2,6-difluorobenzyl) ) -5-(((2-Ethoxyethyl) (methyl) amino) methyl) -3- (2-pyrimidinyl) -2,4
-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 176] The compound (372 mg) obtained in Reference Example 24, diethyl cyanophosphate (228 μl), and N were subjected to the same reaction as in Example 133.
-Ethyldiisopropylamine (310 μl), 2-aminopyrimidine (143 mg) was used to obtain the crude amide compound (87 mg), and methanol (6 ml) and 28% sodium methoxide in methanol (46 mg) were used. The title compound (47 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₂ H ₃₃ N ₇ O ₄ SF ₂ · H ₂ O: C, 57.56; H, 5.28; N, 14.68. Found: C, 57.66; H, 5.26; N, 14.28. ¹ H- NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 6.9 Hz), 1.13
(3H, t, J = 6.9 Hz), 2.16 (3H, s), 2.60 (2H, t, J
= 6.2 Hz), 3.21-3.30 (2H, m), 3.38 (2H, q, J = 6.9
Hz), 3.44 (2H, t, J = 6.2 Hz), 3.79 (2H, s), 5.09
(1H, t, J = 5.6Hz), 5.32 (2H, s), 6.90 (2H, t, J =
8.1 Hz), 6.98 (1H, s), 7.24-7.31 (1H, m), 7.36 (2
H, d, J = 8.7 Hz), 7.41 (1H, t, J = 4.8 Hz), 7.54
(2H, d, J = 8.7 Hz), 8.91 (2H, d, J = 4.8 Hz) .IR (KBr): 2975, 1717, 1674, 1593, 1532, 1472, 1406
cm ^-1 .Example 144 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -3- (3-methoxy-6 -Methyl
-2-Pyridinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 177] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 24 (464 mg), diethyl cyanophosphate (228 μl), N 2
-Ethyldiisopropylamine (310 μl), 2-amino-3-
From methoxy-6-methylpyridine (208 mg) to crude amide (26
5 mg) was obtained, and the title compound (217 mg) was obtained as a colorless powder using methanol (17.5 ml) and a 28% -sodium methoxide methanol solution (135 mg). Elemental analysis _{C 35 H 38 N 6 O 5} SF 2 · 0.5H 2 O Calculated:. C, 59.90; H, 5.60; N, 11.98 Found:. C, 60.11; H, 5.41; N, 12.01 1 H -NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.2 Hz), 1.10
(3H, t, J = 6.9 Hz), 2.15 (3H, s), 2.51 (3H, s),
2.60 (2H, t, J = 6.2 Hz), 3.17-3.26 (2H, m), 3.37
(2H, q, J = 6.9 Hz), 3.42 (2H, t, J = 6.2 Hz), 3.7
8 (5H, s), 5.15 (1H, d, J = 15.9 Hz), 5.20 (1H, t,
J = 5.7 Hz), 5.41 (1H, d, J = 15.9 Hz), 6.88 (2H,
t, J = 8.1 Hz), 7.19-7.33 (6H, m), 7.47 (2H, d, J
= 8.7 Hz). IR (KBr): 2975, 1715, 1672, 1593, 1534, 1470cm ^-1 .

Example 145 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (3-methoxy-6- Methyl
-2-Pyridinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 178] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (227 μl), N-
Ethyldiisopropylamine (310 μl), 2-amino-3-methoxy-6-methylpyridine (208 mg) to crude amide (291
mg), and methanol (19 ml) and 28% -sodium methoxide in methanol (147 mg) to give the title compound.
(138 mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₄ H ₃₆ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 59.38; H, 5.42; N, 12.22. Found: C, 59.24; H, 5.47; N, 11.95. ¹ H -NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.50 (3H, s), 2.58 (2H, t, J = 5.9 Hz), 3.
14-3.23 (2H, m), 3.21 (3H, s), 3.37 (2H, t, J = 5.9
Hz), 3.74 (1H, d, J = 12.3 Hz), 3.78 (3H, s), 3.8
1 (1H, d, J = 12.3 Hz), 5.16 (1H, d, J = 15.6 Hz),
5.41 (1H, d, J = 15.6 Hz), 5.42 (1H, t, J = 5.7 H
z), 6.87 (2H, t, J = 8.0 Hz), 7.19-7.28 (3H, m),
7.32 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz),
7.67 (1H, s). IR (KBr): 2975, 1715, 1669, 1593, 1532, 1470 cm ^-1 . Example 146 N- (4- (1- (2,6-difluorobenzyl) -3- ( 4,6-dimethyl-
2-Pyridinyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6- Production of (yl) phenyl) -N'-ethylurea

[Chemical 179] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (227 μl), N-
Ethyldiisopropylamine (310 μl), 2-amino-4,6-
The crude amide compound (381 mg) was obtained from dimethylpyridine (184 mg), and methanol (26 ml) and 28% -sodium methoxide in methanol (200 mg) were used to give the title compound (182
mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₄ H ₃₆ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 59.38; H, 5.42; N, 12.22. Found: C, 59.24; H, 5.47; N, 11.95. ¹ H -NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.2 Hz), 2.12
(3H, s), 2.50 (3H, s), 2.58 (2H, t, J = 5.9 Hz), 3.
14-3.23 (2H, m), 3.21 (3H, s), 3.37 (2H, t, J = 5.9
Hz), 3.74 (1H, d, J = 12.3 Hz), 3.78 (3H, s), 3.8
1 (1H, d, J = 12.3 Hz), 5.16 (1H, d, J = 15.6 Hz),
5.41 (1H, d, J = 15.6 Hz), 5.42 (1H, t, J = 5.7 H
z), 6.87 (2H, t, J = 8.0 Hz), 7.19-7.28 (3H, m),
7.32 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz),
7.67 (1H, s). IR (KBr): 2975, 1715, 1669, 1593, 1532, 1470 cm ^-1.Example 147 N- (4- (1- (2,6-difluorobenzyl) -3- ( 3-hydroxy-6
-Methyl-2-pyridinyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine Production of -6-yl) phenyl) -N'-ethylurea

[Chemical 180] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (306 mg), 1-hydroxy A crude amide compound (101 mg) was obtained from benzotriazole (288 mg), N-ethyldiisopropylamine (517 μl) and 2-amino-6-methyl-3-hydroxypyridine (187 mg),
Furthermore, the title compound (70 mg) was obtained as a colorless powder using methanol (7 ml) and a 28% -sodium methoxide methanol solution (54 mg). Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₅ SF ₂・ 1.5H ₂ O: C, 57.30; H, 5.39; N, 12.15. Found: C, 57.31; H, 5.45; N, 12.02. ¹ H -NMR (CDCl ₃ + CD ₃ OD) δ: 1.13 (3H, t, J = 7.3 Hz),
2.06 (3H, s), 2.49 (3H, s), 2.63 (2H, t, J = 5.5
Hz), 3.20 (3H, s), 3.24 (2H, q, J = 7.3 Hz), 3.40
(2H, t, J = 5.5 Hz), 3.53 (1H, d, J = 12.4 Hz), 4.
18 (1H, d, J = 12.4 Hz), 5.09 (1H, d, J = 15.8 H
z), 5.30 (1H, d, J = 15.8 Hz), 6.89 (2H, t, J = 8.0
Hz), 7.15 (2H, d, J = 8.4 Hz), 7.15 (1H, d, J =
7.6 Hz), 7.22-7.31 (1H, m), 7.33 (1H, d, J = 7.6 H
z), 7.41 (2H, d, J = 8.4Hz). IR (KBr): 2976, 1715, 1669, 1593, 1537, 1472 cm ^-1 .

Example 148 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -3- (3-hydroxy-6- Methyl-2-pyridinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 181] Subjected to the same reaction as in Example 133, the compound (464 mg) obtained in Reference Example 24, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (306 mg), 1-hydroxybenzo A crude amide compound (98 mg) was obtained from triazole (288 mg), N-ethyldiisopropylamine (517 μl) and 2-amino-6-methyl-3-hydroxypyridine (187 mg),
Further, the title compound (71 mg) was obtained as a colorless powder using methanol (6.7 ml) and a 28% -sodium methoxide methanol solution (52 mg). Elemental analysis Calculated as C ₃₄ H ₃₆ N ₆ O ₅ SF ₂・ 1.5H ₂ O: C, 57.86; H, 5.57; N, 11.91. Found: C, 58.11; H, 5.47; N, 11.72. ¹ H -NMR (CDCl ₃ + CD ₃ OD) δ: 1.08 (3H, t, J = 6.9 Hz),
1.14 (3H, t, J = 7.4Hz), 2.11 (3H, s), 2.49 (3H,
s), 2.69 (2H, t, J = 5.7 Hz), 3.25 (2H, q, J = 6.9)
Hz), 3.36 (2H, q, J = 7.4 Hz), 3.46 (2H, t, J = 5.
7 Hz), 3.58 (1H, d, J = 12.6 Hz), 4.22 (1H, d, J =
12.6 Hz), 5.12 (1H, d, J = 15.4 Hz), 5.29 (1H, d,
J = 15.4 Hz), 6.90 (2H, t, J = 8.0 Hz), 7.15 (2H,
d, J = 8.4 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.22-7.3
3 (1H, m), 7.34 (1H, d, J = 8.0 Hz), 7.43 (2H, d,
J = 8.4 Hz). IR (KBr): 1713, 1669, 1593, 1537, 1472 cm ^-1 . Example 149 N- (4- (1- (2,6-difluorobenzyl) -5-(((2 -Methoxyethyl) (methyl) amino) methyl) -3- (3-methoxy-2-pyridinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-
Production of d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 182] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (285 μl), N-
A crude amide compound (268 mg) was obtained from ethyldiisopropylamine (388 μl) and 2-amino-3-methoxypyridine (233 mg),
Methanol (18.5 ml) and 28% -sodium methoxide in methanol (143 mg) were used to give the title compound (169 m
g) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₅ SF ₂・ 0.5H ₂ O: C, 58.83; H, 5.24; N, 12.47. Found: C, 58.93; H, 5.39; N, 12.29. ¹ H -NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.4 Hz), 2.17
(3H, s), 2.61 (2H, t, J = 5.9 Hz), 3.20-3.30 (2H,
m), 3.25 (3H, s), 3.39 (2H, t, J = 5.9 Hz), 3.81 (2
H, s), 3.83 (3H, s), 4.95 (1H, t, J = 5.5 Hz), 5.2
4 (1H, d, J = 15.8 Hz), 5.39 (1H, d, J = 15.8 Hz),
6.86 (1H, s), 6.90 (2H, t, J = 8.1 Hz), 7.22-7.44
(5H, m), 7.55 (2H, d, J = 8.4 Hz), 8.22-8.25 (1H,
m) .IR (KBr): 1717, 1672, 1593, 1530, 1470 cm ^-1.Example 150 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl ) (Methyl) amino) methyl) -3- (4- (1-methoxy-1-methylethyl) phenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] Production of pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 183] Subjected to the same reaction as in Example 133, the compound (363 mg) obtained in Reference Example 9, diethyl cyanophosphate (136 μl), and N-
Ethyldiisopropylamine (171 μl), 4- (1-methoxy
-1-Methylethyl) aniline (149 mg) to the crude amide (296
mg), and methanol (19 ml) and a 28% -sodium methoxide methanol solution (146 mg) were used to give the title compound (143 mg) as a colorless powder. Elemental analysis _{C 37 H 41 N 5 O 5} SF 2 · 0.5H 2 O Calculated:. C, 62.17; H, 5.92; N, 9.80 Found:. C, 62.41; H, 5.79; N, 9.83 1 H -NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2 Hz), 2.14
(3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.10 (3H, s), 3.
25 (3H, s), 3.24-3.33 (2H, m), 3.40 (2H, t, J = 5.9
Hz), 3.82 (2H, s), 4.78 (1H, t, J = 5.1 Hz), 5.35
(2H, s), 6.51 (1H, s), 6.91 (2H, t, J = 8.0 Hz),
7.23-7.32 (3H, m), 7.35 (2H, d, J = 8.7 Hz), 7.52
(2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz). IR (KBr): 1715, 1672, 1593, 1534, 1470, 1316 cm ^-1 .

Example 151 N- (4- (1- (2,6-difluorobenzyl) -3-isobutyl-5-
(((2-Methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
Production of -6-yl) phenyl) -N'-ethylurea

[Chemical 184] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (228 μl), N-
Crude amide compound (248 mg) was obtained from ethyldiisopropylamine (310 μl) and isobutylamine (117 mg), and methanol (20 ml) and 28% -sodium methoxide methanol solution (154 mg) were added at 50 ° C for 12 hours. The reaction was performed, and the same treatment as described below was performed to obtain the title compound (73 mg) as a colorless powder. Elemental analysis Calculated as C ₃₁ H ₃₇ N ₅ O ₄ SF ₂ : C, 60.67; H, 6.08; N, 11.41. Found: C, 60.28; H, 6.08; N, 11.31. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.9 Hz), 1.18
(3H, t, J = 7.2 Hz), 2.16 (3H, s), 2.15-2.23 (2H,
m), 2.65 (2H, t, J = 5.9 Hz), 3.26-3.35 (2H, m), 3.
29 (3H, s), 3.44 (2H, t, J = 5.9 Hz), 3.85 (2H,
s), 3.91 (2H, d, J = 7.5 Hz), 4.71 (1H, t, J = 5.7
Hz), 5.33 (2H, s), 6.37 (1H, s), 6.89 (2H, t, J =
8.3 Hz), 7.23-7.30 (1H, m), 7.34 (2H, d, J = 8.7 H
z), 7.55 (2H, d, J = 8.7 Hz) .IR (KBr): 2961, 1705, 1661, 1593, 1537, 1472 cm ^-1.Example 152 N- (4- (1- (2,6 -Difluorobenzyl) -3- (2-isopropoxyethyl-5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3
Production of -d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 185] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (228 μl), N-
A crude amide compound (310 mg) was obtained from ethyldiisopropylamine (310 μl) and 2-isopropoxyethylamine (155 mg), and methanol (22 ml) and 28% -sodium methoxide methanol solution (170 mg) were used. Title compound (150
mg) was obtained as a colorless powder. Elemental analysis Calculated as C ₃₂ H ₃₉ N ₅ O ₅ SF ₂・ 0.5H ₂ O: C, 58.88; H, 6.18; N, 10.73. Found: C, 58.98; H, 6.27; N, 10.66. ¹ H -NMR (CDCl ₃ ) δ: 1.11 (6H, d, J = 6.3 Hz), 1.17
(3H, t, J = 7.2 Hz), 2.14 (3H, s), 2.65 (2H, t, J
= 5.7 Hz), 3.26-3.35 (2H, m), 3.29 (3H, s), 3.45 (2
H, t, J = 5.7 Hz), 3.60-3.69 (3H, m), 3.84 (2H,
s), 4.26 (2H, d, J = 5.7 Hz), 4.77 (1H, t, J = 5.7
Hz), 5.30 (2H, s), 6.48 (1H, s), 6.88 (2H, t, J =
8.3 Hz), 7.23-7.30 (1H, m), 7.34 (2H, d, J = 8.7 H
z), 7.51 (2H, d, J = 8.7 Hz). IR (KBr): 2973, 1707, 1663, 1593, 1534, 1472 cm ^-1 Example 153 N- (4- (1- (2,6 -Difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) 3-(1-methyl-1H-imidazol-2-yl) -2,4-dioxo-1,2,3, Production of 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 186] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (228 μl), N-
Ethyldiisopropylamine (586 μl), 2-amino-1-methylimidazole hydrochloride (214 mg) to crude amide (56
mg), and methanol (3.8 ml) and a 28% -sodium methoxide methanol solution (30 mg) were used to obtain the title compound (28 mg) as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, d, J = 7.2 Hz), 2.09
(3H, s), 2.60 (2H, t, J = 5.9 Hz), 3.18-3.27 (2H,
m), 3.25 (3H, s), 3.39 (2H, t, J = 5.9 Hz), 3.56 (1
H, d, J = 12.6 Hz), 3.56 (3H, s), 3.88 (1H, d, J =
12.6 Hz), 4.70 (1H, t, J = 15.6 Hz), 5.31 (1H, t,
J = 5.6 Hz), 5.60 (1H, d, J = 15.6 Hz), 6.90 (2H,
t, J = 8.1 Hz), 7.06 (1H, d, J = 1.5 Hz), 7.16 (1
H, d, J = 1.5 Hz), 7.18 (2H, d, J = 8.7 Hz), 7.24-
7.33 (1H, m), 7.34 (2H, d, J = 8.7 Hz), 8.32 (1H,
s) .IR (KBr): 1726, 1682, 1593, 1531, 1470 cm ^-1 .

Example 154 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) 3-(6-methoxy-3-pyridanyl ) -2,4-Dioxo-1,2,3,4-tetrahydrothieno
Production of [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 187] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 9 (454 mg), diethyl cyanophosphate (285 μl), N-
Ethyldiisopropylamine (388 μl), 3-amino-6-chloropyridazine (243 mg) to obtain a crude amide compound (313 mg),
Methanol (22 ml) and 28% -sodium methoxide in methanol (166 mg) were used to give the title compound (224 mg).
Was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2 Hz), 2.05
(3H, s), 2.58 (2H, t, J = 5.6 Hz), 3.22 (3H, s), 3.
26-3.45 (5H, m), 3.94 (1H, brs), 4.20 (3H, s), 5.09
(1H, brs), 5.30 (1H, brs), 6.01 (1H, t, J = 5.1 H
z), 6.87 (2H, t, J = 8.1 Hz), 6.97 (2H, d, J = 8.7
Hz), 7.25 (1H, d, J = 9.0 Hz), 7.25-7.34 (1H, m),
7.36 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 9.0 H
z), 8.24 (1H, s). IR (KBr): 2975, 1717, 1674, 1593, 1532, 1462 cm ^-1 Example 155 N- (4- (1- (2,6-difluorobenzyl)- 5-(((2-ethoxyethyl) (methyl) amino) methyl) -3- (6-methoxy-3-pyridanyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno
Production of [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 188] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 24 (464 mg), diethyl cyanophosphate (285 μl), N 2
-Ethyldiisopropylamine (388 μl), 3-amino-6-
The crude amide compound (359 mg) was obtained from chloropyridazine (243 mg), and methanol (24 ml) and 28% -sodium methoxide methanol solution (187 mg) were used to give the title compound (257
mg) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 6.9 Hz), 1.17
(3H, t, J = 7.2 Hz), 2.09 (3H, s), 2.62 (2H, t, J
= 5.7 Hz), 3.25-3.50 (7H, m), 3.95 (1H, brs), 4.20
(3H, s), 5.12 (1H, brs), 5.29 (1H, brs), 5.95 (1
H, t, J = 5.1 Hz), 6.87 (2H, t, J = 8.0 Hz), 7.00
(2H, d, J = 8.7 Hz), 7.25 (1H, d, J = 9.3 Hz), 7.2
5-7.32 (1H, m), 7.36 (2H, d, J = 8.7 Hz), 7.58 (2
H, d, J = 9.3 Hz), 8.16 (1H, s) .IR (KBr): 2975, 1717, 1674, 1593, 1532, 1462 cm ^-1.Example 156 N- (4- (1- (2 , 6-Difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3-(3-
Pyridanyl) 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 189] Subjected to the same reaction as in Example 133, the compound (363 mg) obtained in Reference Example 9, diethyl cyanophosphate (182 μl), and N-
Ethyldiisopropylamine (414 μl), 3-aminopyridazine hydrochloride (158 mg) to obtain a crude amide compound (93 mg), further methanol (6.6 ml), 28% -sodium methoxide methanol solution (51 mg) The title compound (45 mg) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.2 Hz), 2.02
(3H, s), 2.54 (2H, t, J = 5.9 Hz), 3.20 (3H, s), 3.
25-3.37 (5H, m), 3.90 (1H, brs), 5.12 (1H, brs), 5.
35 (1H, brs), 6.33 (1H, t, J = 5.1 Hz), 6.87 (2H,
t, J = 8.1 Hz), 6.95 (2H, d, J = 8.7 Hz), 7.25-7.3
4 (1H, m), 7.40 (2H, d, J = 8.7 Hz), 7.78 (1H, dd,
J = 1.8 Hz, 8.4 Hz), 7.83 (1H, dd, J = 4.5 Hz, 8.4
Hz), 8.27 (1H, s), 9.29 (1H, dd, J = 1.8 Hz, 4.5
IR) (KBr): 2973, 1717, 1674, 1593, 1532, 1470 cm ^-1 .

Example 157 N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- ( 3-Pyridanyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 190] The compound (372 mg) obtained in Reference Example 24, diethyl cyanophosphate (182 μl), and N were subjected to the same reaction as in Example 133.
-Ethyldiisopropylamine (414 μl), 3-aminopyridazine hydrochloride (158 mg) to obtain a crude amide compound (93 mg), further methanol (6.5 ml), 28% -sodium methoxide methanol solution (50 mg) The title compound (32 mg) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 6.9 Hz), 1.20
(3H, t, J = 7.3 Hz), 2.03 (3H, s), 2.55 (2H, t, J
= 5.8 Hz), 3.27-3.41 (7H, m), 3.89 (1H, brs), 5.14
(1H, brs), 5.34 (1H, brs), 6.39 (1H, t, J = 5.3 H
z), 6.87 (2H, t, J = 8.1 Hz), 6.95 (2H, d, J = 8.7
Hz), 7.25-7.34 (1H, m), 7.39 (2H, d, J = 8.4 Hz),
7.78 (1H, dd, J = 1.8 Hz, 8.7 Hz), 7.84 (1H, dd, J
= 4.5 Hz, 8.7 Hz), 8.34 (1H, s), 9.29 (1H, dd, J
= 1.8 Hz, 4.5 Hz). IR (KBr): 2973, 1717, 1674, 1593, 1532, 1470 cm ^-1 . Example 158 N- (4- (1- (2,6-difluorobenzyl) -5- (((2-Ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3-
(2-Pyrazinyl) -1,2,3,4-tetrahydrothieno [2,3-d]
Production of pyrimidin-6-yl) phenyl) -N'-ethylurea

[Chemical 191] Subjected to the same reaction as in Example 133, the compound obtained in Reference Example 24 (619 mg), diethyl cyanophosphate (303 μl), N
-Ethyldiisopropylamine (380 μl), 2-aminopyrazine (190 mg) was used to obtain the crude amide compound (357 mg), and then methanol (25 ml) and 28% sodium methoxide in methanol (193 mg) were used. The title compound (170 mg) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 6.9 Hz), 1.15
(3H, t, J = 7.2 Hz), 2.14 (3H, s), 2.62 (2H, t, J
= 6.0 Hz), 3.24-3.33 (2H, m), 3.35-3.46 (4H, m), 3.
80 (2H, s), 4.99 (1H, t, J = 5.1 Hz), 5.33 (2H,
s), 6.83 (1H, s), 6.92 (2H, t, J = 8.3 Hz), 7.28-7.
36 (1H, m), 7.38 (2H, d, J = 8.7 Hz), 7.50 (2H, d,
J = 8.7 Hz), 8.65 (1H, s), 8.66 (1H, d, J = 3.3 H
z), 8.67 (1H, d, J = 3.3 Hz). IR (KBr): 1719, 1676, 1534, 1464cm ^-1 .

Formulation Example 1 Compound of Example 110 (100 mg), lactose (165 m
Tablets are manufactured by a conventional method using g), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg). Formulation Example 2 The compound of Example 110 (5 g) was dissolved in distilled water for injection to make a total volume of 100 ml. This solution is aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 2 ml aliquots into wash-sterilized vials, and freeze-dried by a conventional method to give 100 mg. / Produce lyophilized injections of vials. Formulation Example 3 The compound of Example 112 (100 mg), lactose (165 m
Tablets are manufactured by a conventional method using g), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg). Formulation Example 4 The compound of Example 112 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 2 ml aliquots into wash-sterilized vials, and freeze-dried by a conventional method to give 100 mg. / Produce lyophilized injections of vials.

Formulation Example 5 (1) Compound of Example 110 or 112 5 g (2) Lactose / crystalline cellulose (granules) 330 g (3) D-mannitol 29 g (4) Low-substituted hydroxypropylcellulose 20 g ( 5) Talc 25 g (6) Hydroxypropylcellulose 50 g (7) Aspartame 3 g (8) Dipotassium glycyrrhizinate 3 g (9) Hydroxypropylmethylcellulose 2910 30 g (10) Titanium oxide 3.5 g (11) Yellow trioxide Iron 0.5 g (12) Light anhydrous silicic acid 1 g (1), (3), (4), (5), (6), (7) and (8) are suspended or dissolved in purified water, ( The core particles of 2) are coated to produce fine particles. The fine granules are coated with (9) to (11) to form coated fine granules, which are mixed with (12) to form compound KM05283 fine granules 1%, 500 g
To make. This is divided into 500 mg each.

Test Example 1 (1) Preparation of ¹²⁵ I-leuprorelin 10 μl of 3 × 10 ⁻⁴ M leuprorelin aqueous solution, and 0.01
Transfer 10 μl of mg / ml lactoperoxidase to a tube, add 10 μl of Na ¹²⁵ I solution (37 MBq), and after stirring,
10 μl of 0.001% H ₂ O ₂ was added and reacted at room temperature for 20 minutes. Add 700 μl of 0.05% TFA solution to stop the reaction and reverse phase.
Purified by HPLC. The HPLC conditions are shown below. ¹²⁵ I-
Leuprorelin was eluted at a retention time of 26-27 minutes. Column: TSKgel ODS-80 ^TM (TM indicates a registered trademark. The same applies below.) CTR (4.6 mm × 10 cm) Eluent: Solvent A (0.05% TFA) Solvent B (40% CH ₃ CN-0.05) % TFA) 0 minutes (100% solvent A) -3 minutes (100% solvent A) -7 minutes (50% solvent A)
+ 50% solvent B) -40 minutes (100% solvent B) Elution temperature: room temperature Elution rate: 1 ml / min

(2) Preparation of Anterior Pituitary Membrane Fraction Containing Rat GnRH Receptor The anterior pituitary was extracted from 40 Wistar rats (8-week-old, male) and homogenated buffer {25 mM Tri
s [Tris (hydroxymethyl) aminomethane] -HC
l}, 0.3M saccharose, 1mM EGTA (glycol ether diamine tetraacetic acid), 0.25mM PMSF (phenylmethylsulfonyl fluoride), 10U / ml aprotinin, 1μg / ml pepstatin, 20μg / ml leupeptin, 100μg / ml phosphoramidon, It was washed with 0.03% sodium azide, pH 7.5). The pituitary was suspended in 2 ml of homogenate buffer and homogenized using a Polytron homogenizer. Centrifuge at 700 xg for 15 minutes and collect the supernatant in an ultracentrifuge tube.
Centrifugation was performed at 000 × g for 1 hour to obtain a membrane fraction precipitate. Add 2 ml of assay buffer (25 mM Tris-HCl, 1
mMEDTA (ethylenediaminetetraacetic acid), 0.1% BSA (bovine serum albumin), 0.25mMPMSF, 1 μg / ml pepstatin,
20 μg / ml leupeptin, 100 μg / ml phosphoramidon, 0.03% sodium azide, pH 7.5) were added and suspended, and the mixture was centrifuged at 100,000 × g for 1 hour. The membrane fraction recovered as a precipitate was suspended again in 10 ml of assay buffer, dispensed, stored at -80 ° C, and thawed before use.

(3) CHO containing human GnRH receptor
(Chinese hamster ovary) Preparation of cell membrane fraction Human GnRH receptor-expressing CHO cells (10 ⁹ cells) were suspended in phosphate buffered saline (PBS-EDTA) containing 5 mM EDTA and centrifuged at 100 xg for 5 minutes. . Add homogenate buffer for cells (10 mM NaHCO ₃ , 5 mM EDTA, pH
7.5 ml) was added and homogenized using a Polytron homogenizer. After centrifugation at 400 xg for 15 minutes, the supernatant was collected in an ultracentrifuge tube and centrifuged at 100,000 xg for 1 hour to obtain a membrane fraction precipitate. The precipitate was suspended in 2 ml of assay buffer and centrifuged at 100,000 xg for 1 hour. The membrane fraction recovered as a precipitate was suspended again in 20 ml of assay buffer, dispensed, stored at -80 ° C, and thawed each time before use.

(4) Measurement of ¹²⁵ I-leuprorelin binding inhibition rate The rat and human membrane fractions prepared in (2) and (3) above were diluted with assay buffer to 200 μg / ml, and the tube was prepared. 188 μl each was dispensed. When the rat anterior pituitary membrane fraction was used, 2 μl of 0.1 mM compound dissolved in 60% DMSO (dimethyl sulfoxide) and 38 nM
10 5 μl of ¹²⁵ I-leuprorelin was added at the same time. When the human GnRH receptor-expressing CHO cell membrane fraction was used, 2 μl of 2 mM compound dissolved in 60% DMSO and 38 nM
10 5 μl of ¹²⁵ I-leuprorelin was added at the same time. To determine maximum binding, 2 μl 60% DMSO and 38 nM
A reaction solution to which 10 μl of ¹²⁵ I-leuprorelin was added was prepared. In addition, in order to measure the amount of non-specific binding, 60%
2 μl of 100 μM leuprorelin in DMSO
A reaction solution to which 10 μl of 8 nM ¹²⁵ I-leuprorelin was added was also prepared at the same time. When the rat anterior pituitary membrane fraction was used, it was reacted at 4 ° C for 90 minutes, and human GnRH receptor-expressing C
When the HO cell membrane fraction was used, the reaction was carried out at 25 ° C for 60 minutes. After the reaction, the reaction solution was suction-filtered using a Whatman glass filter (GF-F) treated with polyethyleneimine. After filtration, it remained on the filter paper using a γ-counter
The radioactivity of ¹²⁵ I-leuprorelin was measured. (TB-SB)
/ (TB-NSB) × 100 (SB: radioactivity when compound is added,
(TB: maximum binding radioactivity, NSB: non-specific binding radioactivity) is calculated to determine the binding inhibition rate of each test substance, and the inhibition rate is determined by changing the concentration of the test substance, and 50% binding is determined. The concentration (IC ₅₀ value) of the test substance that inhibits γ was calculated from the Hill plot. The results are shown below. [Table 1] IC ₅₀ value (μM) Test substance Rat Human Compound of Example 110 0.2 <0.0001 Compound of Example 112 0.2 0.0001

[0122]

The compounds of the present invention have excellent gonadotropin-releasing hormone antagonism. Furthermore, it has good oral absorbability and is excellent in stability and pharmacokinetics. It is also low in toxicity and excellent in safety. Therefore, it can be used, for example, as a prophylactic or therapeutic agent for hormone-dependent diseases. Specifically, for example, as a drug, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer,
Pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea syndrome, premenstrual syndrome, multilocular ovary syndrome, polycystic ovary syndrome, acne, bald head Or as a preventive or therapeutic agent for Alzheimer's disease, or a pregnancy regulator (eg, contraceptive, etc.), infertility therapeutic agent, menstrual regulator, prophylactic / therapeutic agent for irritable bowel syndrome,
Effective as a preventive agent for postoperative recurrence of sex hormone-dependent cancer, and in the field of livestock production, it is also effective as a fish spawning promoter in the field of estrus regulation, meat quality improvement for meat, animal growth regulation, and fisheries field. Is.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 35/00 A61P 35/00 43/00 111 43/00 111 (72) Inventor Takenori Takataka Takarazuka, Hyogo Prefecture Ichikayama Satsukidai 6-1-22-302 (72) Inventor Norihiro Miwa 2-12-6 Goryomine-Kendocho, Nishikyo-ku, Kyoto-shi, Kyoto Prefecture 72-6 Inventor Masami Kusaka 1-chome, Higashi-cho, Nishi-ku, Kobe-shi, Hyogo No. 102-301 (72) Inventor Nobuhiro Suzuki 4-16-61 Minoh, Minoh City, Osaka Prefecture F-term (reference) 4C071 AA01 BB01 CC02 CC21 EE12 FF05 GG05 HH08 JJ01 LL01 4C086 AA01 AA02 AA03 CB26 MA01 MA11 NA14 ZA02 ZC12

Claims (19)

[Claims] 1. A formula [Chemical 1] [In the formula, R¹Is C_1-4Alkyl, R²Is (I) (1) amino, (2)
Mono C_1-4Alkylamino, (3) di C_1-4Alkylamino,
(4) -NR^FiveCOR⁶(R^FiveIs a hydrogen atom or C_1-4Alkyl, R⁶Is C
_1-4Alkyl, Mono C_{1- Four}Alkylamino or di-C_1-4A
(Shows ruquilamino), (5) -NR⁷SO₂R⁸(R⁷Is a hydrogen atom
Or C_1-4Alkyl, R⁸Is C_1-4Alkyl, Mono C_1-4Archi
Lumino or di-C_1-4Alkylamino), (6) -CO
NR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Even if it has an alkoxy
Good c_1-4Alkyl or C_3-8Cycloalkyl, R^TenIs water
Elementary atom or C_1-4Alkyl, R⁹And R^TenAre together
To form a ring with the adjacent nitrogen atom.
I), (7) -SO₂NR¹¹R¹²(R¹¹Is a hydrogen atom, C_1-4Arcoki
C which may have shi_1-4Alkyl or C_3-8Cycloa
Rukiru, R¹²Is a hydrogen atom or C_1-4Alkyl, R¹¹
And R¹²Together form a ring with the adjacent nitrogen atom
May be formed), (8) -CO₂R¹³(R¹³Is C_1-4Alkyl
), (9) hydroxyl group, C_1-4Alkoxy, C_1-4Alkyl
-Carbonyloxy, -NR^FiveCOR⁶(R^FiveAnd R⁶Is the same as above
Show meaning), -NR⁷SO₂R⁸(R⁷And R⁸Is the same meaning as above
,)-CONR ⁹R^Ten(R⁹And R^TenHas the same meaning as above
),-SO₂NR¹¹R¹²(R¹¹And R¹²Has the same meaning as above
Or) -CO₂R¹³(R¹³Has the same meaning as above)
May be C_1-4Alkoxy, (10) hydroxyl group, -NR^FiveCOR⁶
(R^FiveAnd R⁶Has the same meaning as above), -NR⁷SO₂R⁸(R⁷
And R⁸Has the same meaning as above), -CONR⁹R^Ten(R⁹And
And R^TenHas the same meaning as above), -SO₂NR¹¹R¹²(R¹¹And
And R¹²Has the same meaning as above), -CO₂R¹³(R¹³Is as above
Have the same meaning) or C_1-4May have alkoxy
I C_1-4Alkyl, (11) halogen atom, (12) hydroxyl group and
And (13) nitro (hereinafter abbreviated as Substituent group A)
Phenyl optionally having 1 to 3 substituents,
(II) 1 to 3 selected from the substituent group A and oxo
Heterocyclic group optionally having substituents, (III)
Having 1 to 3 substituents selected from Group A
Moyo C_3-8Cycloalkyl or (IV) (1) 5 to 7 membered
Nitrogen-containing heterocyclic group, (2) hydroxyl group and (3) C_1-4Alkoxy
C optionally having 1 to 3 substituents selected from_1-4
Alkyl, R³Is a hydrogen atom or C_1-4Alkyl, R^FourIs (I)
(1) C_1-4C which may have alkoxy_1-4Arcoki
Si, (2) -NR¹⁴COR¹⁵(R¹⁴Is a hydrogen atom or C_1-4Archi
Le, R¹⁵Is C_1-4Alkyl)), (3) -NR¹⁶SO ₂R¹⁷(R¹⁶
Is a hydrogen atom or C_1-4Alkyl, R¹⁷Is C_1-4Alkyl
Show), (4) -CONR¹⁸R¹⁹(R¹⁸Is a hydrogen atom or C_1-4Al
Kill, R¹⁹Is C_1-4C which may have alkoxy_1-4A
Show Rukiru, R¹⁸And R¹⁹Are together and adjacent
May form a ring with elementary atoms), (5) -SO₂NR²⁰R^{twenty one}
(R²⁰Is a hydrogen atom or C_1-4Alkyl, R^{twenty one}Is C_1-4Arco
C which may have xy_1-4Alkyl, R²⁰And
And R^{twenty one}Together form a ring with the adjacent nitrogen atom
(6) (1 ') hydroxy-C_1-4Alkyl,
(2 ') C_1-4Alkoxy-carbonyl, (3 ') mono C_1-4Archi
Le-carbamoyl or (4 ') diC_1-4Alkyl-carbamoy
A 5- to 7-membered nitrogen-containing heterocyclic group which may have a
(7) C_1-4Alkoxy-carbonyl, (8) carboxyl, (9)
Mono C_1-4Alkylamino and (10) N-C_1-4Alkyl-N-C
_7-10Aralkylamino (hereinafter abbreviated as Substituent group B)
C optionally having 1 to 3 substituents selected from
_1-4Alkyl or (II) 1 selected from the above substituent group B
C optionally having 3 substituents_3-8Cycloalk
(However, R²Is mono-substituted with a halogen atom.
R when^FourIs C_1-4C substituted with an alkoxy
_1-4Not alkyl)] or a compound thereof
salt. 2. R¹Is C_1-4Alkyl, R²Is (I) (1) amino,
(2) Mono C_1-4Alkylamino, (3) di C_1-4Alkylami
No, (4) -NR^FiveCOR⁶(R^FiveIs a hydrogen atom or C_1-4Alkyl, R
⁶Is C_1-4Alkyl, Mono C_{1- Four}Alkylamino or di-C
_1-4Alkylamino), (5) -NR⁷SO₂R⁸(R⁷Is hydrogen
Atom or C_1-4Alkyl, R⁸Is C_1-4Alkyl, Mono C_1-4
Alkylamino or di-C_1-4Alkylamino),
(6) -CONR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4Having an alkoxy
May be C_1-4Alkyl or C_3-8Cycloalkyl, R
^TenIs a hydrogen atom or C_1-4Alkyl, R⁹And R^Ten
Together form a ring with the adjacent nitrogen atom
Good), (7) -SO₂NR¹¹R¹²(R¹¹Is a hydrogen atom, C_1-4Al
C, which may have Coxi_1-4Alkyl or C_3-8Shiku
Lower alkyl, R¹²Is a hydrogen atom or C_1-4Show alkyl
Then R¹¹And R¹²Together with the adjacent nitrogen atom
May form a ring), (8) -CO₂R¹³(R¹³Is C_1-4A
), (9) hydroxyl group, C_1-4Alkoxy, C_1-4A
Rukiru-carbonyloxy, -NR^FiveCOR⁶(R^FiveAnd R⁶Is before
Same meaning as above), -NR⁷SO₂R⁸(R⁷And R⁸Is as above
Have the same meaning), -CONR⁹R ^Ten(R⁹And R^TenAgree with the above
Justify), -SO₂NR¹¹R¹²(R¹¹And R¹²Agree with the above
Meaning) or -CO₂R¹³(R¹³Means the same as above)
May have C_1-4Alkoxy, (10) hydroxyl group, -NR
^FiveCOR⁶(R^FiveAnd R⁶Has the same meaning as above), -NR⁷SO₂R⁸
(R⁷And R⁸Has the same meaning as above), -CONR⁹R^Ten(R⁹
And R^TenHas the same meaning as above), -SO₂NR¹¹R¹²(R¹¹
And R¹²Has the same meaning as above), -CO₂R¹³(R¹³Is before
Same meaning as above) or C_1-4Has an alkoxy
Moyo C _1-4Alkyl, (11) halogen atom, (12) hydroxyl group
And (13) nitro (hereinafter abbreviated as Substituent group A)
Phenyl optionally having 1 to 3 substituents selected
, (II) 1 selected from the above-mentioned substituent group A and oxo
A heterocyclic group which may have three substituents or (III)
Having 1 to 3 substituents selected from the above-mentioned substituent group A
May be C_3-8Cycloalkyl, R³Is a hydrogen atom or
C_1-4Alkyl, R^FourIs (I) (1) C_1-4Has an alkoxy
May be C_1-4Alkoxy, (2) -NR¹⁴COR¹⁵(R¹⁴Is hydrogen
Child or C_1-4Alkyl, R¹⁵Is C_1-4Represents alkyl),
(3) -NR¹⁶SO ₂R¹⁷(R¹⁶Is a hydrogen atom or C_1-4Alkyl, R
¹⁷Is C_1-4Alkyl)), (4) -CONR¹⁸R¹⁹(R¹⁸Is hydrogen
Atom or C_1-4Alkyl, R¹⁹Is C_1-4Have alkoxy
May be C_1-4Alkyl, R¹⁸And R¹⁹Are together
To form a ring with the adjacent nitrogen atom.
I), (5) -SO₂NR²⁰R^{twenty one}(R²⁰Is a hydrogen atom or C_1-4Al
Kill, R^{twenty one}Is C_1-4C which may have alkoxy_1-4A
Show Rukiru, R²⁰And R^{twenty one}Are together and adjacent
May form a ring with elementary atoms), (6) 5 to 7 members
Nitrogen-containing heterocyclic group, (7) C_1-4Alkoxy-carbonyl,
(8) Carboxyl, (9) Mono C_1-4Alkylamino and (1
0) N-C_1-4Alkyl-N-C_7-10Aralkylamino (below
1 to 3 substituents selected from the group B'group)
May have C_1-4Alkyl or (II) Substituent
It may have 1 to 3 substituents selected from B'group
I C_3-8The compound of claim 1 which is cycloalkyl. 3. R¹Is C_1-4Alkyl, R²Is (I) (1) amino,
(2) -NHCOR^{6 '}(R^{6 '}Is C_1-4Alkyl or mono C_1-4Archi
Lumino)), (3) -CONR⁹R^Ten(R⁹Is a hydrogen atom, C_1-4
C which may have alkoxy_1-4Alkyl or C_3-8
Cycloalkyl, R^TenIs a hydrogen atom or C_1-4Alkyl
Shows, R⁹And R^TenTogether with the adjacent nitrogen atom
May form a ring together), (4) -CO₂R¹³(R¹³Is C_1-4
Alkyl)), (5) hydroxyl group, C_1-4Alkoxy, C_1-4
Alkyl-carbonyloxy, -NHSO₂R^{8 '}(R^{8 '}Is C_1-4A
Show rukill) or -CONR⁹R^Ten(R⁹And R^TenIs as above
C may have the same meaning)_{1 -Four}Alkoxy,
(6) hydroxyl group, -CONR⁹R^Ten(R⁹And R^TenHas the same meaning as above
Show) or C_1-4C which may have alkoxy_1-4A
Rutile, (7) halogen atom, (8) hydroxyl group and (9) nitro
A group which may have 1 to 3 substituents selected from
Phenyl, (II) (1) -CONR⁹R^Ten(R⁹And R^TenAgree with the above
C) which may have_{1 -Four}Alkyl, (2) C_1-4
Alkyl-carbonyloxy or -CONR⁹R^Ten(R⁹and
R^TenHas the same meaning as above) C_1-4A
Lucoxy (3) halogen atom, (4) hydroxyl group or (5) oxo
A 5- to 8-membered nitrogen-containing heterocyclic group optionally having (II
I) C which may have a hydroxyl group_3-8Cycloalkyl
Or (IV) (1) 5- to 7-membered nitrogen-containing heterocyclic group, (2) hydroxyl group or
And (3) C_1-41 to 3 substitutions selected from alkoxy
C which may have a group_1-4Alkyl, R³Is a hydrogen atom
Is C_1-4Alkyl, R^FourIs (I) (1) C_1-4Having an alkoxy
May be C_1-4Alkoxy, (2) -NR¹⁴COR¹⁵(R¹⁴Is hydrogen
Atom or C_1-4Alkyl, R¹⁵Is C_1-4Show alkyl
), (3) -NR¹⁶SO ₂R¹⁷(R¹⁶Is a hydrogen atom or C_1-4Al
Kill, R¹⁷Is C_1-4Alkyl)), (4) -CONR¹⁸R¹⁹(R
¹⁸Is a hydrogen atom or C_1-4Alkyl, R¹⁹Is C_1-4Arcoki
C which may have shi_1-4Alkyl, R¹⁸And R
¹⁹Together form a ring with the adjacent nitrogen atom
May be), (5) (1 ') hydroxy-C_1-4Alkyl, (2 ') C
_1-4Alkoxy-carbonyl or (3 ') mono C_1-4Alkyl
-5- to 7-membered nitrogen-containing, which may have carbamoyl
Heterocyclic group, (6) C_1-4Alkoxy-carbonyl, (7) carbo
Kicil, (8) Mono C_1-4Alkylamino and (9) N-C_1-4A
Rukiru-N-C_7-101 to 3 selected from aralkylamino
C optionally having 4 substituents_1-4Alkyl or (II)
C_3-8The compound of claim 1 which is cycloalkyl. 4. The compound according to claim 1, wherein R ¹ is ethyl. 5. R²Is (1) amino, (2) -NHCOR^{6 '}(R^{6 '}Is C_1-4
Alkyl or mono C_1-4Alkylamino)), (3)-
CONR^{9 '}R^Ten'(R^{9 '}Is a hydrogen atom, C_1-4Alkyl or C_3-8
Cycloalkyl, R^Ten'Is a hydrogen atom or C_1-4Alkyl
Shows, R^{9 '}And R ^Ten'Are adjacent nitrogen atoms together
May form a ring with), (4) -CO₂R^{1 3}(R¹³Is C
_1-4Alkyl)), (5) hydroxyl group, C_1-4Alkoxy, C
_1-4Alkyl-carbonyloxy or -CONR^{9 '}R^Ten'(R^{9 '}
And R^Ten'Have the same meaning as described above)
C_1-4Alkoxy, (6) hydroxyl group or -CONR^{9 '}R^Ten'(R^{9 '}Oh
And R^Ten'Has the same meaning as above) C
_1-4Alkyl, (7) halogen atom, (8) hydroxyl group and (9) diamine
It may have 1 to 3 substituents selected from Toro
The compound according to claim 1, which is phenyl. 6. The compound according to claim 1, wherein R ³ is methyl. 7. R ⁴ is (1) -NR ¹⁴ COR ¹⁵ (R ¹⁴ is a hydrogen atom or
C _1-4 alkyl, R ¹⁵ represents a C _1-4 alkyl), (2) -NR ¹⁶ S
O ₂ R ¹⁷ (R ¹⁶ is a hydrogen atom or C _1-4 alkyl, R ¹⁷ is C _1-4
An ^{alkyl), (3) -CONR 18 R} 19 (R 18 represents a hydrogen atom or C _1-4 alkyl, R ¹⁹ is optionally C _1-4 alkyl optionally having C _1-4 alkoxy, R ¹⁸ and R ¹⁹ may together form a ring with an adjacent nitrogen atom), (4) 5
To 7-membered nitrogen-containing heterocyclic group, (5) C _1-4 alkoxy-carbonyl, (6) carboxyl, (7) mono C _1-4 alkylamino and (8) NC _1-4 alkyl-NC _7-10 C _{1-4 optionally} having 1 to 3 substituents selected from aralkylamino
The compound of claim 1 which is alkyl. 8. A compound of claim 1, wherein R ⁴ is C _1-4 alkyl substituted with C _1-4 alkoxy. 9. The compound according to claim 1, wherein R ⁴ is 2-methoxyethyl. 10. R ¹ is ethyl, R ² is (1) amino, (2) -NHCO
R ^{6 ′} (R ^{6 ′} represents C _1-4 alkyl or mono C _1-4 alkylamino), (3) -CONR ^{9 ′} R ^{10 ′} (R ^{9 ′} is a hydrogen atom, C _1-4 alkyl or C _3-8 cycloalkyl, R ^{10 '} is a hydrogen atom or
C _1-4 alkyl, R ^{9 ′} and R ^{10 ′} may together form a ring with an adjacent nitrogen atom), (4) -CO
₂ R ¹³ (R ¹³ represents a C _1-4 alkyl), (5) a hydroxyl group, C _1-4 alkoxy, C _1-4 alkyl - carbonyloxy or -CONR
C _1-4 alkoxy optionally having ^{9 ′} R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as described above), (6) hydroxyl group or —CONR ^{9 ′}
R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as above) optionally selected from C _1-4 alkyl, (7) halogen atom, (8) hydroxyl group and (9) nitro. Phenyl optionally having 1 to 3 substituents, R ³ is methyl, R ⁴ is (1) -NR ¹⁴ CO
R ¹⁵ (R ¹⁴ represents a hydrogen atom or C _1-4 alkyl, R ¹⁵ represents C _1-4 alkyl), (2) -NR ¹⁶ SO ₂ R ¹⁷ (R ¹⁶ represents a hydrogen atom or C _1-4 alkyl, R ¹⁷ represents C _1-4 alkyl), (3) -CON
R ¹⁸ R ¹⁹ (R ¹⁸ is a hydrogen atom or C _1-4 alkyl, R ¹⁹ is C _1-4
R represents C _1-4 alkyl which may have alkoxy, R
¹⁸ and R ¹⁹ may together form a ring with an adjacent nitrogen atom), (4) a 5- to 7-membered nitrogen-containing heterocyclic group, (5) C _1-4 alkoxy-carbonyl, (6 ) carboxyl, (7) mono C _1-4 alkylamino and (8) NC _1-4 alkyl -NC _7-10 to 1 is aralkyl amino optionally having three substituents C _1-4 Alkyl 1.
The described compound. 11. R ¹ is ethyl, R ² is (1) amino, (2) -NHCO
R ^{6 ′} (R ^{6 ′} represents C _1-4 alkyl or mono C _1-4 alkylamino), (3) -CONR ^{9 ′} R ^{10 ′} (R ^{9 ′} is a hydrogen atom, C _1-4 alkyl or C _3-8 cycloalkyl, R ^{10 '} is a hydrogen atom or
C _1-4 alkyl, R ^{9 ′} and R ^{10 ′} may together form a ring with an adjacent nitrogen atom), (4) -CO
₂ R ¹³ (R ¹³ represents a C _1-4 alkyl), (5) a hydroxyl group, C _1-4 alkoxy, C _1-4 alkyl - carbonyloxy or -CONR
C _1-4 alkoxy optionally having ^{9 ′} R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as described above), (6) hydroxyl group or —CONR ^{9 ′}
R ^{10 ′} (R ^{9 ′} and R ^{10 ′} have the same meanings as defined above) optionally selected from C _1-4 alkyl, (7) halogen atom, (8) hydroxyl group and (9) nitro. The compound according to claim 1, wherein phenyl optionally having 1 to 3 substituents, R ³ is methyl, and R ⁴ is 2-methoxyethyl. 12. 2- [4- (1- (2,6-difluorobenzyl) -6-
(4- {[(ethylamino) carbonyl] amino} phenyl) -5-
{[(2-Methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidine-3 (2H)-
Iyl) phenyl] -N-methylacetamide, 2- [4- (1- (2,6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl]]
Amino} phenyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-1,4-dihydrothieno [2,3-
d] pyrimidin-3 (2H) -yl) phenoxy] -N-ethylacetamide, N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] Methyl} -3- (4-methoxy-3-
Methylphenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N- {4- [1- ( 2,6-Difluorobenzyl) -3- (4-fluorophenyl) -5-({methyl [2- (2-oxo-1-piperidinyl) ethyl] amino} methyl) -2,4-dioxo-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl}-
N'-ethylurea, N- {4- [1- (2,6-difluorobenzyl)-
3- [4- (2-methoxyethoxy) phenyl] -5-({methyl [2- (2
-Oxo-1-piperidinyl) ethyl] amino} methyl) -2,4-
Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-ethylurea, N- {2-[{[1- (2,
6-difluorobenzyl) -6- (4-{[(ethylamino) carbonyl] amino} phenyl) -3- (4-fluorophenyl) -2,4-
Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} -N-methylsulfonamide, N- {2-[({1 -(2,6-difluorobenzyl) -6
-(4-{[(ethylamino) carbonyl] amino} phenyl) -3-
[4- (2-Methoxyethoxy) phenyl] -2,4-dioxo-1,2,
3,4-Tetrahydrothieno [2,3-d] pyrimidin-5-yl} methyl) (methyl) amino] ethyl} -N-methylsulfonamide, N- [4- (1- (2,6-difluorobenzyl ) -5-{[[2- (2-Methoxyethoxy) ethyl] (methyl) amino] methyl} -2,4-
Dioxo-3phenyl-1,2,3,4-tetrahydrothieno [2,3-
d] pyrimidin-6-yl) phenyl] -N'-ethylurea, N-
[4- (1- (2,6-Difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3-phenyl-1,2,3,4 -Tetrahydrothieno [2,3-d] pyrimidine-6-
Iyl) phenyl] -N'-ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-ethoxyethyl) (methyl) amino] methyl} -2,4-dioxo -3- (2-pyridyl) -1,2,3,4-
Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea, N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (Methyl) amino] methyl}-
2,4-Dioxo-3- (5-methyl-2-pyridyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl]-
N'-ethylurea or N- [4- (1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo-3- (6 -Methyl-2-pyridyl) -1,2,3,4-
Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-ethylurea or salts thereof. 13. A prodrug of the compound according to claim 1. 14. A medicine comprising the compound according to claim 1 or a prodrug thereof. 15. The medicine according to claim 14, which is a gonadotropin-releasing hormone antagonist. 16. The medicine according to claim 14, which is a prophylactic / therapeutic agent for sex hormone-dependent diseases. 17. Sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, menstruation. Prevention and treatment of dysplasia, multilocular ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome or hormone-independent, LH-RH-sensitive benign or malignant tumors Agent, reproductive regulator,
15. The pharmaceutical composition according to claim 14, which is a contraceptive agent, an ovulation inducer, or a sex hormone-dependent cancer postoperative recurrence preventive agent. 18. A method for antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound according to claim 1 to a mammal. 19. Use of the compound according to claim 1 for producing a gonadotropin-releasing hormone antagonist.