JP4039574B2 - Thienopyrimidine compounds and uses thereof - Google Patents

Description

  The present invention relates to a thieno [2,3-d] pyrimidine compound exhibiting gonadotropin releasing hormone (GnRH (Gonadotropin releasing hormone)) antagonistic action, a method for producing the same, and use thereof.

The secretion of anterior pituitary hormones is a peripheral hormone secreted from the target organ of each hormone and a secretory promoting or secreting hormone secreted from the hypothalamus that is the upper center of the anterior pituitary gland (hereinafter referred to as `` in this specification, '' These hormone groups are collectively called hypothalamic hormones.) To date, hypothalamic hormones, for example, thyroid stimulating hormone releasing hormone (TRH) or gonadotropin releasing hormone (GnRH (Gonadotropin releasing hormone): also called luteinizing hormone releasing hormone (LH-RH)) } Has been confirmed. These hypothalamic hormones are presumed to exert their hormonal actions via receptors that are thought to be present in the anterior pituitary gland. It is being advanced. Thus, specific and selective antagonists or agonists for these receptors will regulate the action of hypothalamic hormones and control the secretion of anterior pituitary hormones. As a result, prevention or treatment of such an anterior pituitary hormone-dependent disease can be expected.
Examples of compounds having GnRH antagonistic activity include linear peptides (see Patent Document 1 and Patent Document 2), cyclic hexapeptide derivatives (see Patent Document 3), and bicyclic peptide derivatives (Non-Patent Document 1). For example). Examples of the non-peptidic compound having a GnRH antagonistic action include compounds described in Patent Documents 4 to 11.

U.S. Pat.No. 5,140,009 U.S. Pat.No. 5,171,835 JP 61-191698 A Japanese Patent Laid-Open No. 8-295693 (WO 95/28405) Japanese Patent Laid-Open No. 9-169768 (WO 96/24597) JP-A-9-169735 (WO 97/14682) JP-A-9-169767 (WO 97/14697) Japanese Patent Laid-Open No. 11-315079 (WO 99/33831) JP 2000-219691 (WO 00/00493) JP 2001-278884 (WO 00/56739) JP 2002-30087 Journal of Medicinal Chemistry, 36, 3265-3273, 1993

  Peptide compounds still have problems in many aspects such as oral absorption, dosage form, dosage, drug stability, sustained action, and metabolic stability. Oral absorption that has excellent therapeutic effects on hormone-dependent cancers such as prostate cancer, endometriosis, precocious puberty, etc., and does not cause transient pituitary-gonadal stimulating action (acute action) There is a strong demand for GnRH antagonists with excellent properties, particularly non-peptide antagonists.

〔式中、R¹はC_1-4アルキル、R²は(1)(1')水酸基、(2') C_1-4アルコキシ、(3')C_1-4アルコキシ-カルボニル、(4')ジC_1-4アルキル-カルバモイル、(5')5ないし7員の含窒素複素環基、(6')C_1-4アルキル-カルボニルおよび(7')ハロゲンから選ばれる置換基を有していてもよいC_1-6アルキル、(2)(1')水酸基または(2')モノC_1-4アルキル-カルボニルアミノを有していてもよいC_3-8シクロアルキル、(3)(1')ハロゲン、(2')水酸基、(3')C_1-4アルキルおよび(4')C_1-4アルコキシから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基、(4)(1')ハロゲン、(2')C_1-4アルコキシ-C_1-4アルキル、(3')モノC_1-4アルキル-カルバモイル-C_1-4アルキル、(4')C_1-4アルコキシおよび(5')モノC_1-4アルキル-カルバモイル-C_1-4アルコキシから選ばれる置換基を有していてもよいフェニルまたは(5)C_1-4アルコキシ、R³はC_1-4アルキル、R⁴は(1)水素原子、(2)C_1-4アルコキシ、(3)C_6-10アリール、(4)N-C_1-4アルキル-N-C_1-4アルキルスルホニルアミノ、(5)水酸基および(6)(1')オキソ、(2')C_1-4アルキル、(3')ヒドロキシ-C_1-4アルキル、(4')C_1-4アルコキシ-カルボニル、(5')モノC_1-4アルキル-カルバモイルおよび(6')C_1-4アルキルスルホニルから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基、nは1ないし4の整数を示す。（但し、R²が置換基を有していてもよいフェニルのとき、R⁴は(1)オキソ、(2)ヒドロキシ-C_1-4アルキル、(3)C_1-4アルコキシ-カルボニル、(4)モノC_1-4アルキル-カルバモイルおよび(5)C_1-4アルキルスルホニルから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基を示す）〕で表される化合物（以下、化合物(I)と略記することがある。）またはその塩を初めて合成し、化合物(I)がその特異的な化学構造に基づいて、予想外にも優れたGnRH拮抗作用、特に強力なアンタゴニスト活性を有すること、かつ、これらの化合物が毒性も極めて低く、GnRH拮抗作用を有する医薬として十分満足できるものであることを初めて見出し、これらの知見に基づいて本発明を完成した。 As a result of diligent search, the present inventors have found that the phenyl para-position of the 6-position of the thieno [2,3-d] pyrimidine skeleton is substituted with 3-C _1-4 alkoxyureido. Formula with characteristics

Wherein R ¹ is C _1-4 alkyl, R ² is (1) (1 ′) hydroxyl group, (2 ′) C _1-4 alkoxy, (3 ′) C _1-4 alkoxy-carbonyl, (4 ′ ) Di-C _1-4 alkyl-carbamoyl, (5 ′) 5- to 7-membered nitrogen-containing heterocyclic group, (6 ′) C _1-4 alkyl-carbonyl and (7 ′) a substituent selected from halogen _Optionally C _1-6 alkyl, (2) (1 ′) hydroxyl group or (2 ′) C _3-8 cycloalkyl optionally having mono C _1-4 alkyl-carbonylamino, (3) ( 5- to 7-membered nitrogen-containing heterocycle optionally having a substituent selected from 1 ′) halogen, (2 ′) hydroxyl group, (3 ′) C _1-4 alkyl and (4 ′) C _1-4 alkoxy Ring group, (4) (1 ′) halogen, (2 ′) C _1-4 alkoxy-C _1-4 alkyl, (3 ′) mono C _1-4 alkyl-carbamoyl-C _1-4 alkyl, (4 ′ ) C _1-4 alkoxy and (5 ') mono C _1-4 alkyl - carbamoyl -C _1-4 phenyl or an optionally substituted group selected from alkoxy (5) C _1-4 Alkoxy, R ³ is C _1-4 alkyl, R ⁴ is (1) hydrogen atom, (2) C _1-4 alkoxy, (3) C _6-10 aryl, (4) NC _1-4 alkyl -NC _{1- 4} alkylsulfonylamino, (5) hydroxyl group and (6) (1 ′) oxo, (2 ′) C _1-4 alkyl, (3 ′) hydroxy-C _1-4 alkyl, (4 ′) C _1-4 alkoxy A 5- to 7-membered nitrogen-containing heterocyclic group optionally having a substituent selected from -carbonyl, (5 ') mono C _1-4 alkyl-carbamoyl and (6') C _1-4 alkylsulfonyl, n Represents an integer of 1 to 4. (However, when R ² is an optionally substituted phenyl, R ⁴ is (1) oxo, (2) hydroxy-C _1-4 alkyl, (3) C _1-4 alkoxy-carbonyl, ( 4) represents a 5- to 7-membered nitrogen-containing heterocyclic group optionally having a substituent selected from mono-C _1-4 alkyl-carbamoyl and (5) C _1-4 alkylsulfonyl)] A compound (hereinafter sometimes abbreviated as compound (I)) or a salt thereof was synthesized for the first time, and based on its specific chemical structure, compound (I) had unexpectedly superior GnRH antagonistic activity, It was found for the first time that these compounds have a powerful antagonist activity, and these compounds have extremely low toxicity, and are sufficiently satisfactory as pharmaceuticals having a GnRH antagonistic action, and the present invention was completed based on these findings.

〔式中、R¹はC_1-4アルキル、R²は(1)(1')水酸基、(2') C_1-4アルコキシ、(3')C_1-4アルコキシ-カルボニル、(4')ジC_1-4アルキル-カルバモイル、(5')5ないし7員の含窒素複素環基、(6')C_1-4アルキル-カルボニルおよび(7')ハロゲンから選ばれる置換基を有していてもよいC_1-6アルキル、(2)(1')水酸基または(2')モノC_1-4アルキル-カルボニルアミノを有していてもよいC_3-8シクロアルキル、(3)(1')ハロゲン、(2')水酸基、(3')C_1-4アルキルおよび(4')C_1-4アルコキシから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基、(4)(1')ハロゲン、(2')C_1-4アルコキシ-C_1-4アルキル、(3')モノC_1-4アルキル-カルバモイル-C_1-4アルキル、(4')C_1-4アルコキシおよび(5')モノC_1-4アルキル-カルバモイル-C_1-4アルコキシから選ばれる置換基を有していてもよいフェニルまたは(5)C_1-4アルコキシ、R³はC_1-4アルキル、R⁴は(1)水素原子、(2)C_1-4アルコキシ、(3)C_6-10アリール、(4)N-C_1-4アルキル-N-C_1-4アルキルスルホニルアミノ、(5)水酸基および(6)(1')オキソ、(2')C_1-4アルキル、(3')ヒドロキシ-C_1-4アルキル、(4')C_1-4アルコキシ-カルボニル、(5')モノC_1-4アルキル-カルバモイルおよび(6')C_1-4アルキルスルホニルから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基、nは1ないし4の整数を示す。（但し、R²が置換基を有していてもよいフェニルのとき、R⁴は(1)オキソ、(2)ヒドロキシ-C_1-4アルキル、(3)C_1-4アルコキシ-カルボニル、(4)モノC_1-4アルキル-カルバモイルおよび(5)C_1-4アルキルスルホニルから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基を示す）〕で表される化合物またはその塩、
〔２〕R²が(1)(1')水酸基、(2') C_1-4アルコキシ、(3')C_1-4アルコキシ-カルボニル、(4')ジC_1-4アルキル-カルバモイルおよび(5')5ないし7員の含窒素複素環基から選ばれる置換基を有していてもよいC_1-4アルキル、(2)(1')水酸基または(2')モノC_1-4アルキル-カルボニルアミノを有していてもよいC_3-8シクロアルキル、(3)(1')ハロゲン、(2')水酸基、(3')C_1-4アルキルおよび(4')C_1-4アルコキシから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基、(4)(1')ハロゲン、(2')C_1-4アルコキシ-C_1-4アルキル、(3')モノC_1-4アルキル-カルバモイル-C_1-4アルキルおよび(4')モノC_1-4アルキル-カルバモイル-C_1-4アルコキシから選ばれる置換基を有していてもよいフェニルまたは(5)C_1-4アルコキシ、R⁴が(1)C_1-4アルコキシ、(2)C_6-10アリール、(3)N-C_1-4アルキル-N-C_1-4アルキルスルホニルアミノおよび(4)(1')オキソ、(2')ヒドロキシ-C_1-4アルキル、(3')C_1-4アルコキシ-カルボニル、(4')モノC_1-4アルキル-カルバモイルおよび(5')C_1-4アルキルスルホニルから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基である前記〔１〕記載の化合物、
〔３〕R¹がメチルである前記〔１〕記載の化合物、
〔４〕R²が(1)ハロゲン、(2)水酸基、(3)C_1-4アルキルおよび(4)C_1-4アルコキシから選ばれる置換基を有していてもよい5ないし7員の含窒素複素環基である前記〔１〕記載の化合物、
〔５〕R³がメチルである前記〔１〕記載の化合物、
〔６〕R⁴がC_1-4アルコキシである前記〔１〕記載の化合物、
〔７〕nが2である前記〔１〕記載の化合物、
〔８〕R³がメチル、R⁴が水素原子、nが1である前記〔１〕記載の化合物、
〔９〕N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア、N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-エトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア、N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアもしくはN-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシピリジン-3-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアまたはそれらの塩、
〔１０〕N-(4-(5-(((2-メトキシエチル)メチルアミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(4-メトキシフェニル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアもしくはN-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(4-メトキシフェニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアまたはそれらの塩、
〔１１〕前記〔１〕記載の化合物のプロドラッグ、
〔１２〕前記〔１〕記載の化合物またはそのプロドラッグを含有してなる医薬、
〔１３〕性腺刺激ホルモン放出ホルモン拮抗剤である前記〔１２〕記載の医薬、
〔１４〕性ホルモン依存性疾患予防・治療剤である前記〔１２〕記載の医薬、
〔１５〕性ホルモン依存性ガン、性ホルモン依存性ガンの骨転移、前立腺肥大症、子宮筋腫、子宮内膜症、子宮線維腫、思春期早発症、無月経症、月経前症候群、月経困難症、多房性卵巣症候群、多嚢胞性卵巣症候群、ニキビ、禿頭症、アルツハイマー病、不妊症、過敏性腸症候群、ホルモン非依存性でLH-RH感受性である良性もしくは悪性腫瘍またはホットフラッシュの予防・治療剤、生殖調節剤、避妊薬、排卵誘発剤あるいは性ホルモン依存性ガン術後再発予防剤である前記〔１２〕記載の医薬、
〔１６〕哺乳動物に対し、前記〔１〕記載の化合物の有効量を投与することを特徴とする性腺刺激ホルモン放出ホルモン拮抗方法、
〔１７〕性腺刺激ホルモン放出ホルモン拮抗剤を製造するための前記〔１〕記載の化合物の使用、
〔１８〕式

〔式中、R^aは(1)水素原子、(2)(i)ハロゲン、(ii)ニトロ、(iii)シアノ、(iv)アミノ、(v)エステル化またはアミド化されていてもよいカルボキシル基、 (vi)アルキレンジオキシ、(vii)アルキル、(viii)アルコキシ、(ix)アルキルチオ、(x)アルキルスルフィニルおよび(xi)アルキルスルホニルから選ばれる1ないし5個の置換基を有していてもよいアリール基、(3)置換基を有していてもよいシクロアルキル基または(4)置換基を有していてもよい複素環基、R^bは置換基を有していてもよい含窒素複素環基、R^cは置換基を有していてもよいアミノ基、R^dは置換基を有していてもよいアリール基、pは0ないし3の整数、qは0ないし3の整数を示す〕で表される化合物またはその塩等に関する。 That is, the present invention
[1] Formula

Wherein R ¹ is C _1-4 alkyl, R ² is (1) (1 ′) hydroxyl group, (2 ′) C _1-4 alkoxy, (3 ′) C _1-4 alkoxy-carbonyl, (4 ′ ) Di-C _1-4 alkyl-carbamoyl, (5 ′) 5- to 7-membered nitrogen-containing heterocyclic group, (6 ′) C _1-4 alkyl-carbonyl and (7 ′) a substituent selected from halogen _Optionally C _1-6 alkyl, (2) (1 ′) hydroxyl group or (2 ′) C _3-8 cycloalkyl optionally having mono C _1-4 alkyl-carbonylamino, (3) ( 5- to 7-membered nitrogen-containing heterocycle optionally having a substituent selected from 1 ′) halogen, (2 ′) hydroxyl group, (3 ′) C _1-4 alkyl and (4 ′) C _1-4 alkoxy Ring group, (4) (1 ′) halogen, (2 ′) C _1-4 alkoxy-C _1-4 alkyl, (3 ′) mono C _1-4 alkyl-carbamoyl-C _1-4 alkyl, (4 ′ ) C _1-4 alkoxy and (5 ') mono C _1-4 alkyl - carbamoyl -C _1-4 phenyl or an optionally substituted group selected from alkoxy (5) C _1-4 Alkoxy, R ³ is C _1-4 alkyl, R ⁴ is (1) hydrogen atom, (2) C _1-4 alkoxy, (3) C _6-10 aryl, (4) NC _1-4 alkyl -NC _{1- 4} alkylsulfonylamino, (5) hydroxyl group and (6) (1 ′) oxo, (2 ′) C _1-4 alkyl, (3 ′) hydroxy-C _1-4 alkyl, (4 ′) C _1-4 alkoxy A 5- to 7-membered nitrogen-containing heterocyclic group optionally having a substituent selected from -carbonyl, (5 ') mono C _1-4 alkyl-carbamoyl and (6') C _1-4 alkylsulfonyl, n Represents an integer of 1 to 4. (However, when R ² is an optionally substituted phenyl, R ⁴ is (1) oxo, (2) hydroxy-C _1-4 alkyl, (3) C _1-4 alkoxy-carbonyl, ( 4) represents a 5- to 7-membered nitrogen-containing heterocyclic group optionally having a substituent selected from mono-C _1-4 alkyl-carbamoyl and (5) C _1-4 alkylsulfonyl)] A compound or a salt thereof,
[2] R ² is (1) (1 ′) hydroxyl group, (2 ′) C _1-4 alkoxy, (3 ′) C _1-4 alkoxy-carbonyl, (4 ′) diC _1-4 alkyl-carbamoyl and (5 ′) C _1-4 alkyl optionally having a substituent selected from a 5- to 7-membered nitrogen-containing heterocyclic group, (2) (1 ′) hydroxyl group or (2 ′) mono C _1-4 C _3-8 cycloalkyl _optionally having alkyl-carbonylamino, (3) (1 ′) halogen, (2 ′) hydroxyl, (3 ′) C _1-4 alkyl and (4 ′) C _1- 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from ₄ alkoxy, (4) (1 ′) halogen, (2 ′) C _1-4 alkoxy-C _1-4 alkyl, Optionally substituted phenyl selected from (3 ′) mono C _1-4 alkyl-carbamoyl-C _1-4 alkyl and (4 ′) mono C _1-4 alkyl - carbamoyl-C _1-4 alkoxy or (5) C _1-4 alkoxy, R ⁴ is (1) C _1-4 alkoxy, (2) C _6-10 aryl, (3) NC _1-4 alkyl -NC _1-4 Arukirusu Lulphonylamino and (4) (1 ′) oxo, (2 ′) hydroxy-C _1-4 alkyl, (3 ′) C _1-4 alkoxy-carbonyl, (4 ′) mono C _1-4 alkyl-carbamoyl and (5 ') The compound according to the above [1], which is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from C _1-4 alkylsulfonyl,
[3] The compound according to the above [1], wherein R ¹ is methyl,
[4] R ² may have a substituent selected from (1) halogen, (2) hydroxyl group, (3) C _1-4 alkyl and (4) C _1-4 alkoxy The compound of the above-mentioned [1], which is a nitrogen-containing heterocyclic group,
[5] The compound of the above-mentioned [1], wherein R ³ is methyl,
[6] The compound according to the above [1], wherein R ⁴ is C _1-4 alkoxy.
[7] The compound according to the above [1], wherein n is 2.
[8] The compound according to [1], wherein R ³ is methyl, R ⁴ is a hydrogen atom, and n is 1.
[9] N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl ) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea, N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1,2,3,4-tetrahydrothieno [2,3-d] Pyrimidin-6-yl) phenyl) -N'-methoxyurea, N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxy-3 -Pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or N- (4- (1- (2,6-Difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxypyridin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl) phenyl) -N'-methoxyure A or their salts,
[10] N- (4- (5- ( ((2-methoxyethyl) methylamino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4- Dioxo-3- (4-methoxyphenyl) thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or N- (4- (1- (2,6-difluorobenzyl)- 5-((dimethylamino) methyl) -3- (4-methoxyphenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or a salt thereof,
[11] A prodrug of the compound according to [1] above,
[12] A medicament comprising the compound of the above [1] or a prodrug thereof,
[13] The medicament according to [12] above, which is a gonadotropin releasing hormone antagonist,
[14] The medicament according to [12] above, which is a prophylactic / therapeutic agent for sex hormone-dependent diseases,
[15] Sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea , Prevention of multifocal ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, hormone-independent, LH-RH sensitive benign or malignant tumor or hot flash The medicament according to [12] above, which is a therapeutic agent, a reproductive regulator, a contraceptive, an ovulation inducer, or a preventive agent for sex hormone-dependent cancer postoperative recurrence,
[16] A method for antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound according to [1] to a mammal,
[17] Use of the compound of the above-mentioned [1] for producing a gonadotropin releasing hormone antagonist,
[18] Formula

[Wherein, R ^a is (1) a hydrogen atom, (2) (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) an optionally esterified or amidated carboxyl A group having (vi) alkylenedioxy, (vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl. May be an aryl group, (3) an optionally substituted cycloalkyl group, or (4) an optionally substituted heterocyclic group, and R ^b may optionally have a substituent. Nitrogen heterocyclic group, R ^c is an optionally substituted amino group, R ^d is an optionally substituted aryl group, p is an integer of 0 to 3, q is an integer of 0 to 3 Or a salt thereof and the like.

Definitions of terms in this specification are shown below.
“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.).
“C _1-6 alkyl” means, for example, linear C _1-6 alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), branched C _3-6 alkyl (eg, isopropyl, isobutyl, etc.) , Sec-butyl, tert-butyl, isopentyl, etc.).
“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.).
Examples of “C _1-4 alkoxy-carbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
Examples of “diC _1-4 alkyl-carbamoyl” include dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, N-ethyl-N-methylcarbamoyl and the like.

  “5- to 7-membered nitrogen-containing heterocyclic group” means, for example, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazolidine-3-yl, thiazolidin-3-yl, isoxazolidine- 2-yl, isothiazolidine-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-1-yl, pyrazolidin-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, pyrazole- 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, isoxazol-3-yl , Isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole- 5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, morpholine-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, pyridazine-4-yl and the like can be mentioned. Among them, pyrrolidin-1-yl, pyrrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, 1,2,3-triazol-1-yl, 1,2,5-triazol-1-yl , Tetrazol-1-yl, tetrazol-2-yl, pyridin-2-yl, pyridin-4-yl and the like are preferable.

“C _1-4 alkyl-carbonyl” means, for example, methyl-carbonyl, ethyl-carbonyl, propyl-carbonyl, isopropyl-carbonyl, butyl-carbonyl, isobutyl-carbonyl, sec-butyl-carbonyl, tert-butyl-carbonyl, etc. Can be given.
“Halogen” includes fluorine, chlorine, bromine and iodine.
“Mono C _1-4 alkyl-carbonylamino” means, for example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonyl Amino and the like.
Examples of “C _3-8 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
“C _1-4 alkoxy-C _1-4 alkyl” means methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 1-methoxybutyl, 2 -Methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, 1-methoxy-1-methylethyl, 2-methoxy-1-methylethyl, 1-methoxy-1-methylpropyl, 2-methoxy-1-methylpropyl, 3-methoxy-1-methylpropyl, 1- (methoxymethyl) propyl, 1-methoxy-2-methylpropyl, 2-methoxy-2-methylpropyl, 3-methoxy-2-methylpropyl, 2-methoxy-1, Examples thereof include 1-dimethylethyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl and the like.

Examples of “mono C _1-4 alkyl-carbamoyl-C _1-4 alkyl” include methylaminocarbonylmethyl, ethylaminocarbonylmethyl, 2-methylaminocarbonylethyl, 2-ethylaminocarbonylethyl and the like.
Examples of “mono C _1-4 alkyl-carbamoyl-C _1-4 alkoxy” include methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, 2-methylaminocarbonylethoxy, 2-ethylaminocarbonylethoxy and the like.
Examples of “C _6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like.
The "NC _1-4 alkyl -NC _1-4 alkylsulfonylamino", for example, N- methyl -N- methylsulfonylamino, N- ethyl -N- methylsulfonylamino, N- ethylsulfonylamino -N- methylamino, N-ethyl-N-ethylsulfonylamino and the like.
“Hydroxy-C _1-4 alkyl” means, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxy Butyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1-methylethyl, 1-hydroxy-1-methylpropyl, 2-hydroxy-1-methylpropyl, 3- Hydroxy-1-methylpropyl, 1- (hydroxymethyl) propyl, 1-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-2-methylpropyl, 2-hydroxy-1,1- And dimethylethyl.
Examples of the “mono C _1-4 alkyl-carbamoyl” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl and the like.
Examples of “C _1-4 alkylsulfonyl” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.

R ¹ is preferably methyl or ethyl, and particularly preferably methyl.
R ² includes a 5- to 7-membered group optionally having a substituent selected from (1) halogen, (2) hydroxyl group, (3) C _1-4 alkyl, and (4) C _1-4 alkoxy. Nitrogen heterocyclic groups are preferred. Among them, pyridyl (pyridin-2-yl, pyridine) which may have a substituent selected from (1) halogen, (2) hydroxyl group, (3) C _1-4 alkyl, and (4) C _1-4 alkoxy 3-yl, pyridin-4-yl) are preferred, and unsubstituted pyridin-2-yl is particularly preferred.
R ³ is preferably methyl or ethyl, and particularly preferably methyl.
R ⁴ is preferably C _1-4 alkoxy, and particularly preferably methoxy or ethoxy.
As n, 1 or 2 is preferable, and 2 is particularly preferable.
Further, as a combination of R ³ , R ⁴ and n, a combination in which R ³ is methyl, R ⁴ is a hydrogen atom, and n is 1 is also a preferred example.

  As compound (I), N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- ( 2-pyridinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea, N- (4- (1- (2,6- Difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1,2,3,4-tetrahydrothieno [2,3 -d] pyrimidin-6-yl) phenyl) -N'-methoxyurea, N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6- Methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxypyridin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydro Thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-me Toxiurea is a preferred example.

  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, sulphurous acid). And salts with acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. When the compound (I) has an acidic group, an inorganic base (eg, alkali metal salt such as sodium, potassium, calcium, magnesium or alkaline earth metal, ammonia, etc.) or an organic base (eg, trimethylamine, triethylamine) , Pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) and physiologically acceptable salts.

〔式中、Lは脱離基を、その他の記号は前記と同意義を示す。〕 Compound (I) can be produced, for example, by the following production method. The compound in the reaction formula may form a salt, and examples of the salt include the same salts as the salt of compound (I). Compound (I) to Compound (IV) shown in the following reaction formula may form an acceptable salt depending on the reaction conditions.
(Production method 1)

[Wherein L represents a leaving group, and other symbols are as defined above. ]

Examples of the “leaving group” represented by L include a halogen atom, C _1-4 alkylsulfonyloxy which may have a halogen atom, and the like. Examples of the “C _1-4 alkylsulfonyloxy optionally having a halogen atom” include methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy and the like.

Compound (II) can be produced by the method described in JP-A-2001-278884, WO00 / 56739 or a method analogous thereto.
For example, compound (I) can be produced by reacting compound (II) with a compound represented by R ⁴ — (CH ₂ ) _n —L. This 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, thallium hydroxide, and organic bases such as triethylamine, diisopropylethylamine, and pyridine. A base is used.
Compound ^{(II), R 4 - (} CH 2) in the reaction with the compound represented by ^{_{n -L, R 4 - (CH}} 2) amount of the compound represented by _n -L, the compound (II) About 1 to about 3 moles per mole. The amount of the base to be used is about 1 to about 3 mol per 1 mol of compound (II).
This reaction is usually 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 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.

〔式中、R'は水素原子またはC_1-4アルキルを、R''はC_1-4アルキルを、その他の記号は前記と同意義を示す。〕
R'およびR''で表されるC_1-4アルキルとは、例えば直鎖状C_1-4アルキル（例、メチル、エチル、プロピル、ブチルなど）、分枝状C_3-4アルキル（例、イソプロピル、イソブチル、sec-ブチル、tert-ブチルなど）などが挙げられる。 (Production method 2)

[Wherein, R ′ is a hydrogen atom or C _1-4 alkyl, R ″ is C _1-4 alkyl, and other symbols are as defined above. ]
C _1-4 alkyl represented by R ′ and R ″ is, 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.).

  Compound (III) can be obtained by a known method, for example, by reacting p-nitrophenylacetone, a cyanoacetate derivative and sulfur (eg, Chem. Ber., 99, 94-100, 1966, etc.) 2 -Amino-4-methyl-5- (4-nitrophenyl) thiophene can be obtained by subjecting it to the method described in JP-A-9-169768, WO 96/24597 or the like, or a method analogous thereto.

(1) When R ′ is a hydrogen atom, compound (III) is reacted with a compound represented by R ² —NH ₂ or a salt thereof in the presence of a condensation reagent to obtain compound (IV), and then a ring-closing reaction To give compound (I).
Examples of the “condensation reagent” include WSC (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), diethyl cyanophosphate, benzotriazol-1-yloxytri Pyrrolidinophosphonium hexafluorophosphate (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate: PyBOP).
The amount of the “condensation reagent” to be used is about 1 to about 3 mol per 1 mol of compound (III).
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, etc. (Eg, chloroform, dichloromethane, etc.) 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 about 36 hours.
The product can be used in the next reaction as the reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.

Compound (IV) 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, thallium hydroxide, and organic such as triethylamine and pyridine. A base is used.
The amount of the “base” to be used is about 2 mol to about 20 mol, preferably about 5 mol to about 12 mol, per 1 mol of compound (IV).
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, etc. (Eg, chloroform, dichloromethane, etc.) are used.
The reaction temperature is generally about 0 to about 150 ° C, preferably room temperature (about 15 to about 25 ° C). The reaction time is usually about 1 to about 36 hours.

(2) When R ′ is an alkyl group, R ² —NH ₂ is activated and reacted with compound (III) to obtain compound (I).
R ² —NH ₂ can be activated according to a method known per se. For example, the organoaluminum reagent and the compound R ² —NH ₂ are reacted in a suitable solvent that does not adversely influence the reaction.
Examples of the “organoaluminum reagent” include trimethylaluminum, dimethylaluminum chloride and the like, and solutions containing these.
The amount of the “organoaluminum reagent” to be used is about 1 to about 5 mol, preferably about 1 mol, per 1 mol of compound R ² —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 to about 25 ° C. The reaction time is usually about 1 to about 6 hours.
By activating compound R ² —NH ₂ and reacting with compound (III), a ring closure reaction is carried out to obtain compound (I).
The amount of the “compound (III)” used is preferably about 1/5 of the amount 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 generally about 0 to 150 ° C, preferably about 0 to 25 ° C. The reaction time is usually about 1 to 48 hours.
In addition to the above reaction, a known hydrolysis reaction, deprotection reaction, acylation reaction, alkylation reaction, oxidation reaction, cyclization reaction, carbon chain extension reaction, substituent exchange reaction may be carried out individually or in combination, if desired. Compound (I) can also be produced by carrying out in combination.

Compound (I) can be isolated and purified by separation means known per se, such as recrystallization, distillation, chromatography and the like.
When compound (I) is obtained in a free form, it can be converted to the target 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 to a free form or other desired salt by a method equivalent thereto.
Compound (I) may be a hydrate or non-hydrate. Examples of the hydrate include monohydrate, 1.5 hydrate, dihydrate and the like.
When compound (I) is obtained as a mixture of optically active substances, it can be separated into the desired (R) isomer or (S) isomer by optical resolution means known per se.
Compound (I) may be used as a prodrug, and as such a prodrug, a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, A compound that undergoes hydrolysis or the like and changes to compound (I), or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (I). As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl , Dimethylaminomethylcarbonylated compounds, etc.); These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to the compound of the present invention under physiological conditions, as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, pages 163 to 198. It may be.
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 raw material compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protective group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the protecting group for the amino group include optionally substituted C _1-6 alkyl - carbonyl (eg acetyl, propionyl etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg methoxycarbonyl, ethoxy Carbonyl, tert-butoxycarbonyl etc.), phenyloxycarbonyl, C _7-14 aralkyloxycarbonyl (eg benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl etc.), trityl, phthaloyl etc. are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine), C _1-6 alkyl - carbonyl (eg, acetyl, propionyl, butyryl, etc.), nitro groups, etc. are used. Is about 1 to 3.
Examples of the protecting group for the carboxyl 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, halogen atoms (eg, fluorine, chlorine, bromine, iodine), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, butyryl, etc.), formyl, nitro groups, etc. are used. The number is about 1 to 3.
Examples of the protecting group for the hydroxyl 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 alkyl-carbonyl (eg acetyl, propionyl etc.), formyl, phenyloxycarbonyl, C _7-10 aralkyl-oxycarbonyl (eg benzyloxycarbonyl etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl etc. Is used. As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is 1 to 4 About one.
In addition, as a method for introducing and removing a protecting group, a method known per se or a method equivalent thereto (for example, a method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press)) is used. As the removal 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 a salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention”) have an excellent GnRH antagonistic action and are toxic (for example, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity) Toxicity, cardiotoxicity, drug interaction, carcinogenicity) is low. In addition, it is excellent in oral absorption and sustained action, and also in terms of stability and pharmacokinetics. It is also less susceptible to plasma components. In mammals (eg, humans, monkeys, cows, horses, dogs, cats, rabbits, rats, mice, etc.), GnRH receptor antagonism suppresses the secretion of gonadotropins and controls the concentration of sex hormones in the blood Therefore, it can be safely used for the prevention and treatment of male hormone or female hormone dependent diseases and the prevention and treatment of diseases caused by excess of these hormones.
For example, the compound of the present invention is a sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroid, endometriosis, Uterine fibroma, 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 their mixed types) are useful for the prevention and / or treatment of sex hormone-dependent diseases. The compounds of the present invention are also useful for the regulation of reproduction in males and females (eg, pregnancy regulators, menstrual cycle regulators, etc.). The compounds of the present invention can be further used as male and female contraceptives and as female ovulation inducers. The compound of the present invention can be used for treatment of infertility by utilizing the rebound effect after drug withdrawal. It can also be used as a prophylactic / therapeutic agent for benign or malignant tumors that are independent of sex hormones and are LH-RH sensitive. In addition, the compound of the present invention is a prophylactic / therapeutic agent for irritable bowel syndrome and a preventive agent for recurrence after surgery for sex hormone dependent cancer (preventive agent for recurrence after prostate cancer surgery, prevention of recurrence after breast cancer or ovarian cancer before and after menopause). It can also be used as an agent for preventing recurrence of breast cancer or ovarian cancer after surgery, particularly preferably before menopause.
Furthermore, the compound of the present invention is useful for regulating the estrus of animals, improving meat quality for meat, promoting the growth of animals, etc. in the field of livestock. The compounds of the present invention are also useful as fish spawning promoters.

The compound of the present invention can be used to suppress a transient increase in blood testosterone concentration (flare phenomenon) observed during administration of a GnRH superagonist such as leuprorelin acetate. The compounds of the present invention include leuprorelin acetate (Leuprorelin), gonadorelin (Gonadorelin), buserelin (Buserelin), triptorelin (Triptorelin), goserelin (Goserelin), nafarelin (Nafarelin), historelin (Histrelin), deslorelin (Deslorelin), It can be used in combination with GnRH superagonists (preferably leuprorelin acetate) such as Meterelin) and Recirelin.
The compound of the present invention is a steroidal or non-steroidal antiandrogen or antiestrogen, chemotherapeutic agent, peptide GnRH antagonist, α-reductase inhibitor, α-receptor inhibitor, aromatase inhibitor, 17β -It is also effective to use in combination with at least one of hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy agent, cell growth factor or its receptor, etc. is there.
Examples of the “chemotherapeutic agents” include Ifosfamide, Adriamycin, Peplomycin, Cisplatin, Cyclophosphamide, 5-FU, UFT, Methotrexate, Mitomycin C (Mitomycin C), Mitoxantrone and the like.
Examples of the “peptidic GnRH antagonist” include parenteral-administered peptidic GnRH antagonists such as cetrorelix, ganirelix, and abarelix.
Examples of the “adrenal androgen production inhibitor” include a lyase (C _17,20 -lyase) inhibitor and the like.
Examples of the “phosphorase inhibitor” include tyrosine kinase.
Examples of the “hormone therapeutic agent” include antiestrogens, luteinizing hormones (eg, MPA, etc.), androgens, estrogens, antiandrogens and the like.

The “growth factors” may be any substance that promotes cell growth, and is usually a peptide having a molecular weight of 20,000 or less, which acts at a low concentration by binding to a receptor. Specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity (eg, EGF, haregulin (HER2 ligand), etc.), (2) Insulin or a substance having substantially the same activity (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), (3) FGF (fibroblast growth factor) or substantially the same Substances with activity (eg, aFGF, bFGF, KGF (Keratinocyte Growth Factor), HGF (Hepatocyte Growth Factor), FGF-10, etc.), (4) Other cell growth factors (eg, CSF (colony stimulating factor), EPO) (Erythropoietin), IL-2 (interleukin-2), NGF (nerve gro wth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factorβ) and the like.
The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically, EGF receptor, haregulin 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 agent that inhibits the action of the cell growth factor or its receptor include herbimycin, PD153035 (Science 265 (5175) p1093, (1994)) and the like.

In addition, HER2 inhibitors are also included as drugs that inhibit the action of cell growth factors or their receptors. As a HER2 inhibitor, if it is a substance that inhibits HER2 activity (eg, phosphorylation activity), antibody, low molecular weight compound (synthetic compound, natural product), antisense, HER2 ligand, haregulin or their structure Any of partial modification and modification may be used. Further, it may be a substance that inhibits HER2 activity by inhibiting HER2 receptor (eg, HER2 receptor antibody). Examples of the low molecular weight compound having 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.
For benign prostatic hyperplasia, GnRH hyperagonist, antiandrogen, antiestrogen, peptidic GnRH antagonist, α-reductase inhibitor, α-receptor inhibitor, aromatase inhibitor, 17β-hydroxysteroid dehydrogenation The combined use of the compound of the present invention with a drug such as an enzyme inhibitor, an adrenal androgen production inhibitor, or a phosphorylase inhibitor.

For prostate cancer, GnRH superagonist, anti-androgen, anti-estrogen, chemotherapeutic agent (eg, ifosfamide, UFT, adriamycin, peplomycin, cisplatin, etc.), Peptide GnRH antagonist, aromatase inhibitor, 17β-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy agent (eg, estrogen (eg, DSB, EMP, etc.), Anti-androgen agents (eg, CMA, etc.)], combinations of the compounds of the present invention with drugs such as drugs that inhibit the action of cell growth factors or their receptors.
For breast cancer, GnRH superagonists, antiestrogens, chemotherapeutic agents (eg, cyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C) ), Mitoxantrone, etc.], peptide GnRH antagonists, aromatase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents (eg, antiestrogens (eg, Tamoxifen, etc.), A combination of the compound of the present invention and a drug such as a luteinizing hormone agent (eg, MPA, etc.), an androgen agent, an estrogen agent, etc.), a drug that inhibits the action of cell growth factor or its receptor, and the like.
The administration mode 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. Examples of such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations obtained by the same route by the same route of administration, (3) with a time difference in the same route of administration of the two formulations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Formulating the compound of the present invention and the concomitant drug separately Administration of the two types of preparations obtained by the preparation in different administration routes (for example, administration in the order of the compound of the present invention → concomitant drug, or administration in the reverse order).

When the compound of the present invention is used as a prophylactic and / or therapeutic agent for the above diseases, or in the livestock or fisheries field, it can be administered orally or parenterally according to a method known per se. Mixed with pharmaceutically acceptable carriers and usually administered orally as solid preparations such as tablets, capsules, granules, powders, or as injections, suppositories, sublingual tablets, etc. intravenously, subcutaneously, intramuscularly, etc. It is administered parenterally. Alternatively, it may be administered sublingually, subcutaneously, intramuscularly or the like as a sustained release preparation such as a sublingual tablet or a microcapsule. The daily dose varies depending on the degree of symptom; age, sex, weight, sensitivity difference of administration subject; timing of administration, interval, nature of pharmaceutical preparation, preparation, type; type of active ingredient, etc. As long as the above is achieved, 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 When used for the treatment of the above, etc., as an oral agent, the active ingredient (the compound of the present invention) is usually about 0.01 to 30 mg, preferably about 0.02 to 10 mg, more preferably 0.1 to 10 mg per kg body weight of a mammal. Most preferably, 0.1 to 5 mg is usually administered in 1 to 4 divided doses per day.
The dosage for use in the field of livestock or fisheries is also the same as above, but as an oral preparation, about 0.01 to 30 mg, preferably about 0.1 to 10 mg of the active ingredient (the compound of the present invention) per 1 kg body weight of the organism to be administered. In general, administer 1 to 3 times a 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 whole composition.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids It is formulated as an agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. 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, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch 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 solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate and citrate. Preferable examples of the soothing agent include benzyl alcohol. Preferable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite and ascorbic acid.

Suspending agents, solubilizers, stabilizers, tonicity agents, preservatives and the like can be added to the compounds of the present invention to give intravenous, subcutaneous and intramuscular injections by methods known per se. At that time, if necessary, a freeze-dried product can be obtained by a method known per se. When the compound of the present invention is administered to, for example, humans, it can be safely administered orally or parenterally as a pharmaceutical composition by itself or mixed with an appropriate pharmacologically acceptable carrier, excipient or diluent. can do.
Examples of the pharmaceutical composition include oral preparations (eg, powders, granules, capsules, tablets), parenteral preparations (eg, injections, drops, 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 generally used in the preparation process.

The compound of the present invention contains a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, Benzyl alcohol, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), etc. in aqueous injections, or in vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc. Or it can emulsify and shape | mold into an oily injection and can be set as an injection.
In order to obtain an oral preparation, according to a method known per se, the compound of the present invention is treated, for example, with an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate etc.), a binder (eg, starch). , Gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. For enteric or long-lasting purposes, an oral preparation can be obtained by coating by a method known per se. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm) Made in Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengara, titanium dioxide, etc.). In the case of an enteric 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.

In order to obtain an external preparation, the compound of the present invention can be made into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the solid state, the compound of the present invention is used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivatives, acrylic acid) Polymer etc.) and the like are added and mixed to obtain a powdery composition. The liquid form is an oily or aqueous suspension, almost the same as in the case of injections. In the case of a semi-solid form, an aqueous or oily gel or an ointment is preferred. In addition, these are all pH adjusters (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, to make a suppository, the compound of the present invention can be converted 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 composition include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany)) Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

〔式中、R¹¹およびR¹³はC_1-4アルキル、R¹⁴は水素原子またはC_1-4アルコキシ、mは1ないし4の整数を示す。〕で表される化合物（以下、化合物(V)と略記することがある。）またはその塩も、本発明の化合物(I) と同様に優れたGnRH拮抗作用、特に強力なアンタゴニスト活性を有する。
R¹¹およびR¹³で表される「C_1-4アルキル」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル等があげられる。
R¹⁴で表される「C_1-4アルコキシ」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ等があげられる。
R¹¹としては、メチルが好ましい。
R¹³としては、メチルが好ましい。
R¹⁴としては、水素原子またはメトキシが好ましい。
mとしては、1または2が好ましい。 Outside the scope of compound (I),

[Wherein, R ¹¹ and R ¹³ are C _1-4 alkyl, R ¹⁴ is a hydrogen atom or C _1-4 alkoxy, and m is an integer of 1 to 4. ] (Hereinafter sometimes abbreviated as compound (V)) or a salt thereof also has excellent GnRH antagonistic activity, particularly potent antagonist activity, as in the case of compound (I) of the present invention.
Examples of “C _1-4 alkyl” represented by R ¹¹ and R ¹³ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
Examples of “C _1-4 alkoxy” represented by R ¹⁴ include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
R ¹¹ is preferably methyl.
R ¹³ is preferably methyl.
R ¹⁴ is preferably a hydrogen atom or methoxy.
m is preferably 1 or 2.

As the compound (V), specifically, N- (4- (5- ( ((2-methoxyethyl) methylamino) methyl) -1- (2,6-difluorobenzyl) -1,2,3 , 4-Tetrahydro-2,4-dioxo-3- (4-methoxyphenyl) thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (4-methoxyphenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d Pyrimidin-6-yl) phenyl) -N′-methoxyurea or a salt thereof is a preferred example.

  The salt of compound (V) 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, sulphurous acid). And salts with acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. When the compound (V) has an acidic group, an inorganic base (eg, alkali metal salt or alkaline earth metal such as sodium, potassium, calcium, magnesium, etc.) or an organic base (eg, trimethylamine, triethylamine) , Pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) and physiologically acceptable salts.

Compound (V) can be produced, for example, by the method described in JP-A-9-169768 (WO96 / 24597) and JP-A-2001-278884 (WO00 / 56739) and a method analogous thereto. it can.
Compound (V) may be a hydrate or non-hydrate. Examples of the hydrate include monohydrate, 1.5 hydrate, dihydrate and the like.
Compound (V) may be used as a prodrug, and as such a prodrug, a compound that is converted into compound (V) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically oxidized or reduced , A compound that undergoes hydrolysis or the like and changes to compound (V), or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (V) As a prodrug of the compound (V), a compound in which the amino group of the compound (V) is acylated, alkylated or phosphorylated (eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated). , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.) Is mentioned. These compounds can be produced from the compounds of the present invention by methods known per se.
In addition, the prodrug of compound (V) is a compound that changes to the compound of the present invention under physiological conditions as described in Hirokawa Shoten 1990 "Pharmaceutical Development", Volume 7, pages 163 to 198 of molecular design. It may be.
Compound (V) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S) and the like.

〔式中、R^aは(1)水素原子、(2)(i)ハロゲン、(ii)ニトロ、(iii)シアノ、(iv)アミノ、(v)エステル化またはアミド化されていてもよいカルボキシル基、 (vi)アルキレンジオキシ、(vii)アルキル、(viii)アルコキシ、(ix)アルキルチオ、(x)アルキルスルフィニルおよび(xi)アルキルスルホニルから選ばれる1ないし5個の置換基を有していてもよいアリール基、(3)置換基を有していてもよいシクロアルキル基または(4)置換基を有していてもよい複素環基、R^bは置換基を有していてもよい含窒素複素環基、R^cは置換基を有していてもよいアミノ基、R^dは置換基を有していてもよいアリール基、pは0ないし3の整数、qは0ないし3の整数を示す〕で表される化合物（以下、化合物(A)と略記することがある。）またはその塩も、本発明の化合物(I)と同様に優れたGnRH拮抗作用、特に強力なアンタゴニスト活性を有する。 In addition, a formula containing a part of the compound (I) of the present invention

[Wherein, R ^a is (1) a hydrogen atom, (2) (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) carboxylate which may be esterified or amidated. A group having (vi) alkylenedioxy, (vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl. May be an aryl group, (3) an optionally substituted cycloalkyl group, or (4) an optionally substituted heterocyclic group, and R ^b may optionally have a substituent. Nitrogen heterocyclic group, R ^c is an optionally substituted amino group, R ^d is an optionally substituted aryl group, p is an integer of 0 to 3, q is an integer of 0 to 3 The compound represented by the formula (hereinafter sometimes abbreviated as compound (A)) or a salt thereof is also excellent GnRH antagonistic activity as in the case of compound (I) of the present invention. Have particularly potent antagonist activity.

Hereinafter, the definition of each substituent in the compound (A) is shown.
Represented by R ^a `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( `` aryl group '' of `` aryl group optionally having 1 to 5 substituents selected from vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl '' Examples thereof include C <sub>6-14</sub> aryl such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like.
Represented by R <sup>a</sup> `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( As "halogen" in "vii) aryl group optionally having 1 to 5 substituents selected from alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl" Examples thereof include fluorine, chlorine, bromine and iodine.
Represented by R ^a `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( vii) an aryl group optionally having 1 to 5 substituents selected from alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl ” Examples of the “optionally amidated carboxyl group” include carboxyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxy carbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), C _3-6 cycloalkyl Oxy - carbonyl (e.g., cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.), C _6-14 aryloxy - carbonyl (e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxy Carbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl, acenaphthylenyloxycarbonyl, etc.), C _7-10 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.), carbamoyl, N-mono C _1-6 alkyl- Carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentyl Rubamoiru, hexylcarbamoyl, etc.), N- mono- -C _3-6 cycloalkyl - carbamoyl (e.g., cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, etc.), N- mono- -C _6-14 aryl - carbamoyl ( Examples include phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, anthrylcarbamoyl, phenanthrylcarbamoyl, acenaphthylenylcarbamoyl, etc., N-mono-C _7-10 aralkyl-carbamoyl (eg, benzylcarbamoyl etc.), etc. can give.

Represented by R ^a `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( vii) aryl group optionally having 1 to 5 substituents selected from alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl ” "Is, for example, C <sub>1-6</sub> alkylenedioxy (eg, -OCH <sub>2</sub> O-, -O (CH <sub>2</sub> ) <sub>2</sub> O-, -O (CH <sub>2</sub> ) <sub>3</sub> O-, -O (CH <sub>2</sub> ) <sub>4</sub> O -, -O (CH <sub>2</sub> ) <sub>5</sub> O-, -O (CH <sub>2</sub> ) <sub>6</sub> O-).
Represented by R <sup>a</sup> `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( As `` alkyl '' of `` aryl group optionally having 1 to 5 substituents selected from vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl '' Examples thereof include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like.
Represented by R ^a `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( As "alkoxy" in "vii) aryl group optionally having 1 to 5 substituents selected from alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl" Examples thereof include C <sub>1-6</sub> alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like).
Represented by R <sup>a</sup> `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( As `` alkylthio '' in `` aryl group optionally having 1 to 5 substituents selected from vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl '' Examples thereof include C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc.).

Represented by R ^a `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( `` alkylsulfinyl '' of `` aryl group optionally having 1 to 5 substituents selected from vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl '' As, for example, C <sub>1-6</sub> alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc.) Can be given.
Represented by R <sup>a</sup> `` (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) alkylenedioxy, ( `` alkylsulfonyl '' of `` aryl group optionally having 1 to 5 substituents selected from vii) alkyl, (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl '' As, for example, C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.) Can be given.

Examples of the “cycloalkyl group” of the “cycloalkyl group optionally having substituent (s)” represented by R ^a include C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), etc. Is given.
The “heterocyclic group” of the “optionally substituted heterocyclic group” represented by R ^a is, for example, selected from (1) oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom 5-membered cyclic groups containing 1 to 4 heteroatoms (for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3 -Isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- (1,2,4-oxadiazolyl), 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- (1,2, 4-thiadiazolyl), 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- (1,2,3 -Thiadiazolyl), 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimi Dazinyl, dioxotriazinyl, pyrrolidinyl, etc.), (2) 6-membered cyclic groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms (for example, 2 -Pyridyl, 3-pyridyl, 4-pyridyl, N-oxide-2-pyridyl, N-oxide-3-pyridyl, N-oxide-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, N-oxide -2-pyrimidinyl, N-oxide-4-pyrimidinyl, N-oxide-5-pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1 , 4-thiazinyl, 1,3-thiazinyl, 2-pi Razinyl, 3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl, pyrazinyl, N-oxide-3-pyridazinyl, N-oxide-4-pyridazinyl, etc.), (3) oxygen atoms in addition to carbon atoms A bicyclic or tricyclic condensed ring group containing 1 to 4 heteroatoms selected from sulfur atom, nitrogen atom, etc. (eg, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl , Triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, , Chromanyl, benzoxazinyl, phenazini , Phenothiazinyl, phenoxazinyl, etc.) and the like.

The “substituent” of the “cycloalkyl group optionally having substituent (s)” represented by R ^a and the “heterocyclic group optionally having substituent (s)” includes (i) C _1-6 alkyl (Eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (ii) C _2-6 alkenyl (eg, vinyl, allyl, 1-butenyl, 2- Butenyl), (iii) C _2-6 alkynyl (eg, ethynyl, propargyl, 2-butynyl, 5-hexynyl, etc.), (iv) C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) ), (V) C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), (vi) C _7-14 aralkyl (eg, benzyl, phenethyl, etc.), (vii) nitro, (viii) Hydroxy, (ix) mercapto, (x) cyano, (xi) carbamoyl, (xii) carboxyl (Xiii) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxy Carbonyl, etc.), (xiv) sulfo, (xv) halogen (eg, fluorine, chlorine, bromine, iodine), (xvi) C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, optionally having -butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.) pentyloxy, hexyloxy, etc.), (xvii) C _6-10 ants Yloxy (e.g., phenoxy, 1-naphthyloxy, 2-naphthyloxy etc.), (xviii) C _1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec- butylthio, tert- butylthio , Pentylthio, hexylthio, etc.), (xix) C _6-10 arylthio (eg, phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), (xx) C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl) , Isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc.), (xxi) C _6-10 arylsulfinyl (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2- Naphthyl sulfi N), (xxii) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.) ), (Xxiii) C _6-10 arylsulfonyl (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), (xxiv) amino, (xxv) C _1-6 acylamino (eg, formylamino, acetylamino) , Propionylamino, butyrylamino, isobutyrylamino, valerylamino, etc.), (xxvi) mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xxvii) di -C _1-6 alkylamino (e.g., dimethylamino, Jiechirua Bruno, dipropylamino, diisopropylamino, dibutylamino, etc.), (xxviii) C _3-6 cycloalkylamino (e.g., cyclopropylamino, cyclobutyl amino, cyclopentylamino, cyclohexylamino, etc.), (xxix) C _6-10 Arylamino (eg, anilino, 1-naphthylamino, 2-naphthylamino, etc.), (xxx) C _1-6 acyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, etc.), (xxxi) C _{6- 10} aryl-carbonyl (eg, benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl, etc.), (xxxii) C _1-4 alkylenedioxy (eg, —OCH ₂ O—, —O (CH ₂ ) ₂ O—, -O (CH ₂ ) ₃ O-, -O (CH ₂ ) ₄ O-), (xxxiii) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, nitrogen atoms, etc. in addition to carbon atoms5 Or a 6-membered heterocyclic group (eg, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2- Imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- (1,2,4-oxadiazolyl), 5- (1 , 2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- (1,2,4-thiadiazolyl), 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- (1,2,3-thiadiazolyl), 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl, 2-pyridyl, 3-pyridyl, 4-pi Jyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1, 3-thiazinyl, 2-piperazinyl, 3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl, pyrazinyl, etc.), (xxxiv) oxo and (xxxv) thioxo, etc. It may have 1 to 6, preferably 1 to 3.

The “nitrogen-containing heterocyclic group” of the “nitrogen-containing heterocyclic group optionally having substituent (s)” represented by R ^b is, for example, a 5- to 7-membered nitrogen-containing heterocyclic ring (eg, pyrrolidine-1- Yl, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazolidine-3-yl, thiazolidin-3-yl, isoxazolidine-2-yl, isothiazolidin-2-yl, imidazolidin-1-yl, imidazolidine- 2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazole-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, o Sazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl , Thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, piperidin-1-yl, 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, 1,2,3-triazin-4-yl, 1, 2,3-triazin-5-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazine -6-yl, 1,3,5-triazin-2-yl, 1,2,3,4-tetrazin-5-yl, 1,2,3,5-tetrazin-4-yl, azepan-1-yl Azepan-2-yl, 1,2-diazepan-3-yl, 1,2-diazepan-4-yl, 1,2-diazepan-5-yl, 1,3-diazepan-2-yl, 1,3 -Diazepan-4-yl, 1,3-diazepan-5-yl, 1,4-diazepan-2-yl, 1,4-diazepan-3-yl, 1,4-diazepan-5-yl, 1,2 , 3-triazepan-4-yl, 1,2,3-triazepan-5-yl, 1,2,4-triazepan-3-yl, 1,2,4-triazepan-5-yl, etc.) .
As the “substituent” of the “nitrogen-containing heterocyclic group optionally having substituent (s)” represented by R ^b , the “cycloalkyl group optionally having substituent (s)” represented by the above R ^a And the same number and the same as the “substituent” of the “optionally substituted heterocyclic group”.

As the “amino group optionally having substituent (s)” represented by R ^c , for example, the formula —NR ^e R ^f (wherein R ^e is (1) a hydrogen atom, (2) has a substituent) _Optionally substituted C _1-6 alkyl, (3) optionally substituted C _3-6 cycloalkyl, (4) optionally substituted C _6-14 aryl, (5) _Optionally substituted C _7-20 aralkyl, (6) optionally substituted carbamoyl or (7) heterocyclic group, R ^f has a hydrogen atom or a substituent. Or a group represented by C _1-6 alkyl).

Examples of the “C _1-6 alkyl” of the “ _optionally substituted C _1-6 alkyl” represented by R ^e and R ^f include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
Examples of the substituent of the “ _optionally substituted C _1-6 alkyl” represented by ^Re and R ^f include, for example, (1) C _1-6 alkyl (eg, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (2) C _2-6 alkenyl (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, etc.), (3) C _2-6 alkynyl (eg, ethynyl, 1-propynyl, propargyl, etc.), (4) C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) C _5-7 cycloalkenyl ( Eg, cyclopentenyl, cyclohexenyl, etc.), (6) C _7-11 aralkyl (eg, benzyl, α-methylbenzyl, phenethyl, etc.), (7) C _6-14 aryl (eg, phenyl, naphthyl, etc.), ( 8) C _1-6 alkoxy (e.g., methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, etc.), (9) C _6-14 aryloxy (e.g., phenoxy, 1-naphthoxy, 2-naphthoxy, etc.), (10) C _1-6 alkanoyl (Eg, formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), (11) C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl, etc.), (12) C _1-6 alkanoyl Oxy (eg, formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, etc.), (13) C _6-14 aryl-carbonyloxy (eg, benzoyloxy, 1-naphthylcarbonyloxy, 2-naphthylcarbonyloxy, etc.) ), (14) carboxy, (15) C _1-6 alkoxy-carbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxy) Bonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), (16) carbamoyl, (17) N-mono-C _1-4 alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl) , N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), (18) N, N-di-C _1-4 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), (19) cyclic aminocarbonyl (eg 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-pi Peridinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.), (20) halogen (eg, fluorine, chlorine, bromine, iodine), (21) C _1-4 alkyl substituted with 1 to 3 halogens (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), (22) oxo, (23) amidino, (24) Imino, (25) amino, (26) mono- or di-C _1-4 alkylamino (eg methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butyl) Amino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, etc.), (27) in addition to carbon atom and one nitrogen atom, a hetero atom selected from oxygen atom, sulfur atom, nitrogen atom, etc. 3 to 6 membered cyclic aminos (eg aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazo Jiniru, piperidino, morpholino, dihydropyridyl, pyridyl, N- methylpiperazinyl, N- ethylpiperazinyl, etc.), (28) C _1-6 alkanoylamino (e.g., formylamino, acetylamino, trifluoroacetylamino, Propionylamino, butyrylamino, isobutyrylamino, etc.), (29) benzamide, (30) carbamoylamino, (31) (NC _1-4 alkylcarbamoyl) amino (eg, (N-methylcarbamoyl) amino, (N-ethyl) Carbamoyl) amino, (N-propylcarbamoyl) amino, (N-isopropylcarbamoyl) amino, (N-butylcarbamoyl) amino, etc.), (32) (N, N-di-C _1-4 alkylcarbamoyl) amino (eg , (N, N-dimethylcarbamoyl) amino, (N, N-diethylcarbamoyl) amino, (N, N-dipropylcarbamoyl) amino, N, N-dibutylcarbamoyl) amino, etc.), (33) C _1-6 alkylenedioxy _{(e.g., -OCH 2 O-, -O (CH} 2) 2 O-, -O (CH 2) 3 O-, -O (CH ₂ ) ₄ O-, -O (CH ₂ ) ₅ O-, -O (CH ₂ ) ₆ O-), (34) dihydroboryl, (35) hydroxy, (36) epoxy, (37) nitro , (38) cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43) sulfamoyl, (44) NC _1-6 alkylsulfamoyl (eg, N-methylsulfamoyl) Moyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (45) N, N-diC _1-6 alkylsulfamoyl (eg N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), (46) C _1-6 alkylthio (eg, Methylthio, ethylthio, propylthio, isopropylthio, Lucio, sec- butylthio, tert- butylthio, etc.), (47) phenylthio, (48) C _1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl etc.), (49) phenylsulfinyl, ( 50) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like), (51) phenylsulfonyl and the like. It may have 1 to 6, preferably 1 to 3, substituents selected from these at substitutable positions.

Represented by R ^e of "optionally C _3-6 cycloalkyl optionally having substituent (s)" as the "C _3-6 cycloalkyl", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The substituent of the "optionally substituted C _3-6 cycloalkyl" represented by R ^e, "which may have a substituent represented by the R ^e and R ^f _Examples thereof include those similar to the substituent of “C _1-6 alkyl”, and may have 1 to 6, preferably 1 to 3 substituents at substitutable positions.

The C _6-14 aryl "optionally substituted C _6-14 aryl" represented by R ^e, e.g., phenyl, naphthyl, anthracenyl and the like.
The substituent of the "optionally substituted C _6-14 aryl" represented by R ^e, which may have a "substituent represented by the R ^e and R ^f C _Examples thereof include those obtained by removing oxo and epoxy from the substituent of “ _1-6 alkyl”, and may have 1 to 6, preferably 1 to 3 at substitutable positions.

The C _7-20 aralkyl "optionally substituted C _7-20 aralkyl" represented by R ^e, e.g., benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like.
The substituent of the "optionally substituted C _7-20 aralkyl" represented by R ^e, which may have a "substituent represented by the R ^e and R ^f C _Examples thereof are the same as the substituents of “ _1-6 alkyl”, and may have 1 to 6, preferably 1 to 3 at substitutable positions.

Examples of the substituent of "carbamoyl which may have a substituent" represented by R ^e, (1) has may have a substituent group C _1-6 alkyl, (2) substituent C _3-6 cycloalkyl _optionally having (3) C _6-14 aryl _optionally having substituent, (4) C _7-20 aralkyl _optionally having substituent, (5) Hydroxy, (6) optionally substituted C _1-6 alkoxy, (7) optionally substituted C _1-6 alkoxy-carbonyl and the like. Or you may have two.
The “optionally substituted C _1-6 alkyl” as a substituent of the “optionally substituted carbamoyl” represented by R ^e is the above-mentioned R ^e and R ^f Examples thereof are the same as those represented by “C _1-6 alkyl _optionally having substituent (s)”.
Represented by R ^e "which may have a substituent C _3-6 cycloalkyl" as a substituent of "carbamoyl which may have a substituent" it may have a "substituent the optionally C _6-14 aryl "and" optionally substituted C _7-20 aralkyl, "the R ^e represented by" optionally substituted C _3-6 cycloalkyl Examples thereof include the same as “alkyl”, “ _optionally substituted C _6-14 aryl” and “ _optionally substituted C _7-20 aralkyl”.
As the C _1-6 alkoxy in the "optionally substituted C _1-6 alkoxy" as the substituent of "carbamoyl which may have a substituent" represented by R ^e, for example, Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. As the substituent of the "optionally substituted C _1-6 alkoxy", and the substituent of the "optionally substituted C _1-6 alkyl" represented by R ^e The same may be mentioned, and it may have 1 to 6, preferably 1 to 3 at substitutable positions.
The “optionally substituted C _1-6 alkoxy-carbonyl” as the substituent of the “optionally substituted carbamoyl” represented by R ^e is the above-mentioned R ^e And a group in which “optionally substituted C _1-6 alkoxy” as a substituent of “optionally substituted carbamoyl” is bonded to carbonyl.

As the "heterocyclic group" represented by R ^e is, for example, (1) an oxygen atom in addition to carbon atom, a sulfur atom,, 1 to heteroatom selected from nitrogen atom a 5-membered ring containing four (eg 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3 -Pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- ( 1,2,4-oxadiazolyl), 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- (1,2,4-thiadiazolyl), 5- (1,2,4- Thiadiazolyl), 1,3,4-thiadiazolyl, 4- (1,2,3-thiadiazolyl), 5- (1,2,3-thiadiazolyl), 1 , 2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl, etc.), (2) 6-membered cyclic group containing 1 to 4 hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom (for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxide-2- Pyridyl, N-oxide-3-pyridyl, N-oxide-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, N-oxide-2-pyrimidinyl, N-oxide-4-pyrimidinyl, N-oxide- 5-pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl, 3- Piperazinyl, triazinyl, Xisotriazinyl, 3-pyridazinyl, 4-pyridazinyl, pyrazinyl, N-oxide-3-pyridazinyl, N-oxide-4-pyridazinyl, etc.), (3) other than carbon atoms, oxygen atoms, sulfur atoms, nitrogen atoms, etc. A bicyclic or tricyclic fused ring group containing 1 to 4 heteroatoms (for example, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, Benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, Phenothiazinyl, phenoxazinyl, etc.) Can be given.

Examples of the aryl of “optionally substituted aryl” represented by R ^d include C _6-14 aryl such as phenyl, naphthyl, anthracenyl and the like.
^Examples of the substituent of the “optionally substituted aryl” represented by R ^d include (1) (i) hydroxy, (ii) amino, (iii) mono- or di-C _1-6 alkyl Amino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), (iv) C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.) and (v) C _6-14 aryl (eg, phenyl, naphthyl, etc.) _optionally having 1 to 4 substituents selected from halogen (eg, fluorine, chlorine, bromine, iodine), (2) hydroxy, (3 ) Carboxy, (4) nitro, (5) C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), (6) C _1-6 alkyl-carbonyloxy ( E.g. acetoxy, propionyloxy , Butyryloxy, iso-butyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, pentyl carbonyloxy, hexyl carbonyloxy, etc.), (7) C _1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyl Thio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc.) (8) C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl) , Tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc.), (9) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isop Propylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), (10) halogen (eg, fluorine, chlorine, bromine, iodine), (11) formula -NR ^g R ^h (wherein R ^g is (a) a hydrogen atom, (b) an optionally substituted C _1-6 alkyl, (c) an optionally substituted C _3-6 Cycloalkyl, (d) C _6-14 aryl _optionally having substituent, (e) C _7-20 aralkyl _optionally having substituent, (f) (i) having substituent Optionally substituted C _3-6 cycloalkyl, (ii) optionally substituted C _6-14 aryl, (iii) _optionally substituted C _7-20 aralkyl, (iv) 1 or 2 substituents selected from hydroxy, (v) optionally substituted C _1-6 alkoxy and (vi) optionally substituted C _1-6 alkoxy-carbonyl A carbamoyl or (g) heterocyclic group which may have one, R ^h represents a hydrogen atom or a C _1-6 alkyl which may have a substituent, and a group represented by (12) carbon 5-membered cyclic group containing 1 to 4 hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to atoms (for example, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl) , 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5 -Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- (1,2,4-oxadiazolyl), 5- (1,2,4-oxadiazolyl) 1,3,4-oxadiazolyl, 3- (1,2,4-thiadiazolyl), 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- (1,2,3-thiadiazolyl), 5- (1,2,3-thiadiazolyl), 1,2,5- Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl, etc.), (13) oxygen in addition to carbon atoms 6-membered cyclic groups containing 1 to 4 heteroatoms selected from atoms, sulfur atoms, nitrogen atoms, etc. (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxide-2-pyridyl, N-oxide) -3-pyridyl, N-oxide-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, N-oxide-2-pyrimidinyl, N-oxide-4-pyrimidinyl, N-oxide-5-pyrimidinyl, 2 -Thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxy Sasinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl, 3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl, pyrazinyl, N-oxide-3-pyridazinyl, N-oxide -4-pyridazinyl etc.), (14) Bicyclic or tricyclic condensed ring groups containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, nitrogen atoms, etc. in addition to carbon atoms (eg, benzofuryl, Benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl , Purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, Romanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.), (15) C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- Butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), (16) carbamoyl, (17) N-mono-C _1-6 alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N -Propylcarbamoyl, N-isopropylcarbamoyl, etc.), (18) N, N-di-C _1-6 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl) 1 to 6 at the substitutable positions, preferably May have 1 to 3.

Represented by the formula —NR ^g R ^h (wherein R ^g and R ^h are as defined above) as a substituent of “optionally substituted aryl” represented by R ^d The definitions of R ^g and R ^{h in} the group are shown below.
The “optionally substituted C _1-6 alkyl” represented by R ^g and R ^h is the above-mentioned “optionally substituted C represented by R ^e and R ^f ”. _Examples thereof include those similar to “ _1-6 alkyl”.
Represented by R ^g "optionally substituted C _3-6 cycloalkyl", "optionally C _6-14 aryl optionally having substituent (s)", it may have a "substituent good C _7-20 aralkyl "and the" heterocyclic group ", the" optionally substituted C _3-6 cycloalkyl represented by R ^e ', have a "substituent And the same as "C _6-14 aryl", "C _7-20 aralkyl _optionally having substituent (s)" and "heterocyclic group".
^Represented by R ^g `` (i) an optionally substituted C <sub>3-6</sub> cycloalkyl; (ii) an optionally substituted C <sub>6-14</sub> aryl; (iii) a substituent. <sub>Optionally</sub> substituted C <sub>7-20</sub> aralkyl, (iv) hydroxy, (v) optionally substituted C <sub>1-6</sub> alkoxy and (vi) optionally substituted C <sub>1- 6</sub> alkoxy - "optionally substituted C <sub>3-6</sub> cycloalkyl" of the substituents selected from carbonyl 1 or 2 optionally having carbamoyl ", have a" substituent the optionally C <sub>6-14</sub> aryl "and" optionally substituted C <sub>7-20</sub> aralkyl, "the" optionally C <sub>3-6</sub> cycloalkyl optionally having substituent group represented by R <sup>e</sup> ”,“ C <sub>6-14</sub> aryl <sub>optionally</sub> having substituent (s) ”, and“ C <sub>7-20</sub> aralkyl <sub>optionally</sub> having substituent (s) ”.
<sup>Represented</sup> by R <sup>g</sup> `` (i) an optionally substituted C _3-6 cycloalkyl; (ii) an optionally substituted C _6-14 aryl; (iii) a substituent. _Optionally substituted C _7-20 aralkyl, (iv) hydroxy, (v) optionally substituted C _1-6 alkoxy and (vi) optionally substituted C _1- Examples of the “optionally substituted C _1-6 alkoxy” of the “carbamoyl optionally having 1 or 2 substituents selected from ₆ alkoxy-carbonyl” include methoxy, ethoxy, propoxy, Examples thereof include isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. The substituent of the "C _1-6 alkoxy optionally having substituent (s)", the substituent of the "optionally substituted C _1-6 alkyl" represented by R ^e And may have 1 to 6, preferably 1 to 3 at substitutable positions.
^Represented by R ^g `` (i) an optionally substituted C _3-6 cycloalkyl; (ii) an optionally substituted C _6-14 aryl; (iii) a substituent. _Optionally substituted C _7-20 aralkyl, (iv) hydroxy, (v) optionally substituted C _1-6 alkoxy and (vi) optionally substituted C _{1- The “} optionally substituted C _1-6 alkoxy-carbonyl” of “carbamoyl optionally having 1 or 2 substituents selected from ₆ alkoxy-carbonyl” is represented by the above R ^g . And a group in which “optionally substituted C _1-6 alkoxy” as a substituent of “optionally substituted carbamoyl” is bonded to carbonyl.

R ^a includes (i) halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group that may be esterified or amidated, (vi) alkylenedioxy, (vii An aryl group optionally having 1 to 5 substituents selected from alkyl), (viii) alkoxy, (ix) alkylthio, (x) alkylsulfinyl and (xi) alkylsulfonyl is preferable. Mono- or di-substituted phenyl, especially 2,6-difluorophenyl, is preferred.
R ^b is pyrrolidin-1-yl, pyrrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, 1,2,3-triazol-1-yl, 1,2,5-triazole-1 -Yl, tetrazol-1-yl, tetrazol-2-yl, pyridin-2-yl and pyridin-4-yl are preferred, with pyridin-2-yl being particularly preferred.

R ^c has the formula —NR ^{e ′} R ^{f ′} (where R ^{e ′} is (1) an optionally substituted C _1-6 alkyl or (2) C _7-20 aralkyl, R ^{f '} _{Represents a} C _1-6 alkyl). Of these, the formula —N (Me) R ^{e ″} (wherein R ^{e ″} is C _1-6 alkyl or benzyl substituted with C _1-6 alkoxy) is preferable.
R ^d is preferably phenyl optionally having substituent (s), and in particular, the 4-position is represented by the formula —NR ^g R ^h (wherein R ^g and R ^h are as defined above). Preferred is a phenyl group substituted with a group. In particular, the 4-position is represented by the formula —NHR ^{g ′} (wherein R ^{g ′} is (i) an optionally substituted C _3-6 cycloalkyl, (ii) an optionally substituted C _6-14 aryl, (iii) optionally substituted C _7-20 aralkyl, (iv) hydroxy, (v) optionally substituted C _1-6 alkoxy and (vi) substituted And a phenyl group substituted with a group represented by the following formula: (C _1-6 alkoxy-carbonyl optionally having 1 or 2 substituents optionally having a group) A phenyl group substituted at the 4-position with C _1-6 alkoxyamino-carbonylamino (4-methoxyaminocarbonylaminophenyl, 4-ethoxyaminocarbonylaminophenyl, etc.) is preferred.
p is preferably 1. Further, q is preferably 1.

  The salt of compound (A) 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, sulphurous acid). And salts with acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. When the compound (A) has an acidic group, an inorganic base (eg, alkali metal salt such as sodium, potassium, calcium, magnesium or alkaline earth metal, ammonia, etc.) or an organic base (eg, trimethylamine, triethylamine) , Pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) and physiologically acceptable salts.

Compound (A) can be produced, for example, by the method described in JP-A-9-169768 (WO96 / 24597) and JP-A-2001-278884 (WO00 / 56739) and a method analogous thereto. it can.
Compound (A) may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5 hydrate, dihydrate and the like.
When compound (A) is obtained as a mixture of optically active substances, it can be separated into the desired (R) isomer or (S) isomer by optical resolution means known per se.
Compound (A) may be used as a prodrug, and as such a prodrug, a compound that is converted to compound (A) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized or reduced , A compound that undergoes hydrolysis or the like and changes to compound (A), or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (A). As a prodrug of the compound (A), a compound in which the amino group of the compound (A) is acylated, alkylated or phosphorylated (eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (A) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxyl group of compound (A) is esterified or amidated (eg, compound (A)) Carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo 1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, and the like). These compounds can be produced from the compounds of the present invention by methods known per se.
In addition, the prodrug of compound (A) is a compound that changes to the compound of the present invention under physiological conditions as described in Hirokawa Shoten 1990 "Pharmaceutical Development", Volume 7, pages 163 to 198 of molecular design. It may be.
Compound (A) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S) and the like.

Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto.
¹ H-NMR spectrum using tetramethylsilane as internal standard, Varian GEMINI 200 (200 MHz) spectrum meter, JEOL LAMBDA300 (300 MHz) spectrum meter, or Brucker AM 500 (500 MHz) spectrum meter The total δ value is expressed in ppm. “%” Indicates weight percent unless otherwise specified. However, the yield indicates mol / mol%. Other symbols in this 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
TFA: trifluoroacetic acid
THF: tetrahydrofuran
Me: methyl
Et: ethyl
Ph: Phenyl
TBS: tert-butyldimethylsilyl
Ms: Methanesulfonyl Room temperature refers to a range of about 15 to about 25 ° C., but is not particularly limited.
As the lactose, corn starch D-mannitol, low-substituted hydroxypropylcellulose, talc, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, titanium oxide and light anhydrous silicic acid used in the following formulation examples, the 14th revision Japanese Pharmacopoeia A compatible product was used.

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸エチルエステル(3.64 g, 5.47 mmol)のエタノール(100 ml)溶液に、1規定塩酸(8 ml)と50%含水-10%パラジウム／炭素(1.82 g)を加えて、水素雰囲気下 6時間激しく攪拌した。触媒を除いた濾液を1規定水酸化ナトリウム水溶液で中和した後、溶媒を留去した。得られた残渣を酢酸エチル／水で分配し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去して得られた残渣をNH-シリカゲル（富士シリシア化学製）クロマトグラフィーに付し、表題化合物(2.43g, 77%)を黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 1.18 (3H, t, J = 7.0 Hz), 1.33 (3H, t, J = 7.2 Hz), 2.33 (3H, s), 3.65 (2H, s), 3.82 (5H, s), 4.16 (2H, q, J = 7.0 Hz), 4.24(2H, q, J = 7.2 Hz), 4.96 (2H, s), 6.84 (2H, t, J = 7.8 Hz), 7.1-7.35 (3H, m), 7.44 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.63 (1H, s).
参考例２
エチル2-[(2,6-ジフルオロベンジル)(エトキシカルボニル)アミノ]-5-(4-{[(メトキシアミノ)カルボニル]アミノ}フェニル)-4-{[メチル(ピリジン-2-イルメチル)アミノ]メチル}チオフェン-3-カルボキシレートの製造

参考例１の化合物(2.43 g, 4.21 mmol)をDMF(20 ml)に溶解し、N,N-ジイソプロピルエチルアミン(2.93 ml, 16.84 mmol)と2-クロロメチルピリジン塩酸塩(1.04 g, 6.32 mmol)を加え、室温で24時間攪拌した。重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル)により精製し、表題化合物(2.34g, 83%)を黄色粉末として得た。
参考例３
2-[(2,6-ジフルオロベンジル)(エトキシカルボニル)アミノ]-5-(4-{[(メトキシアミノ)カルボニル]アミノ}フェニル)-4-{[メチル(ピリジン-2-イルメチル)アミノ]メチル}チオフェン-3-カルボン酸の製造

参考例２の化合物(2.34 g, 3.5 mmol)のエタノール(40 ml)溶液に2規定水酸化ナトリウム溶液(8.75 ml)を加えて50-60℃で14時間攪拌した。室温に戻して1規定塩酸で中和した後、溶媒を留去した。得られた残渣を酢酸エチルと水で分配し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、表題化合物(2.06 g, 92%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 1.1-1.3 (3H, m), 2.28 (3H, s), 3.7-3.9 (2H, brm), 3.84 (3H, s), 3.91 (3H, s), 4.1-4.3 (2H, m), 5.07 (2H, s), 6.7-6.85 (2H, m), 7.15-7.8 (10H, m), 8.5-8.6 (1H, m).
参考例４
メチル6-(ブロモメチル)ニコチネートの製造

メチル 6-メチルニコチネート(1.05 g, 10 mmol)を酢酸エチル(50 ml)に溶解し、NBS(3.56 g, 20 mmol)とAIBN(329 mg, 2 mmol)を加えた。80℃で3時間攪拌後、重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル／ヘキサン；1／4)により精製し、表題化合物(682 mg, 28%)をオレンジ色アモルファスとして得た。
¹H-NMR(CDCl₃) 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 Hz), 9.17 (1H, d, J = 1.8 Hz). Reference example 1
Ethyl 2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(methoxyamino) carbonyl] amino} phenyl) -4-[(methylamino) methyl] thiophene-3- Carboxylate production

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- To a solution of ethyl 3-carboxylic acid ethyl ester (3.64 g, 5.47 mmol) in ethanol (100 ml), 1N hydrochloric acid (8 ml) and 50% hydrous 10% palladium / carbon (1.82 g) were added, and hydrogen atmosphere Stir vigorously for 6 hours. The filtrate from which the catalyst had been removed was neutralized with 1N aqueous sodium hydroxide solution, and then the solvent was distilled off. The obtained residue was partitioned with ethyl acetate / water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to NH-silica gel (Fuji Silysia Chemical) chromatography to obtain the title compound (2.43 g, 77%) as a yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.33 (3H, t, J = 7.2 Hz), 2.33 (3H, s), 3.65 (2H, s), 3.82 ( 5H, s), 4.16 (2H, q, J = 7.0 Hz), 4.24 (2H, q, J = 7.2 Hz), 4.96 (2H, s), 6.84 (2H, t, J = 7.8 Hz), 7.1- 7.35 (3H, m), 7.44 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.63 (1H, s).
Reference example 2
Ethyl 2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(methoxyamino) carbonyl] amino} phenyl) -4-{[methyl (pyridin-2-ylmethyl) amino ] Methyl} thiophene-3-carboxylate production

The compound of Reference Example 1 (2.43 g, 4.21 mmol) was dissolved in DMF (20 ml), N, N-diisopropylethylamine (2.93 ml, 16.84 mmol) and 2-chloromethylpyridine hydrochloride (1.04 g, 6.32 mmol) And stirred at room temperature for 24 hours. Sodium bicarbonate 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) to give the title compound (2.34 g, 83%) as a yellow powder.
Reference example 3
2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(methoxyamino) carbonyl] amino} phenyl) -4-{[methyl (pyridin-2-ylmethyl) amino] Methyl} thiophene-3-carboxylic acid production

To a solution of the compound of Reference Example 2 (2.34 g, 3.5 mmol) in ethanol (40 ml) was added 2N sodium hydroxide solution (8.75 ml), and the mixture was stirred at 50-60 ° C. for 14 hours. After returning to room temperature and neutralizing with 1N hydrochloric acid, the solvent was distilled off. The obtained residue was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.06 g, 92%) as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 1.1-1.3 (3H, m), 2.28 (3H, s), 3.7-3.9 (2H, brm), 3.84 (3H, s), 3.91 (3H, s), 4.1 -4.3 (2H, m), 5.07 (2H, s), 6.7-6.85 (2H, m), 7.15-7.8 (10H, m), 8.5-8.6 (1H, m).
Reference example 4
Preparation of methyl 6- (bromomethyl) nicotinate

Methyl 6-methylnicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), and NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol) were added. After stirring at 80 ° C. for 3 hours, aqueous sodium bicarbonate 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 (682 mg, 28%) 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 Hz), 9.17 (1H, d, J = 1.8 Hz).

2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニル]アミノ-4-[N-(2-メトキシエチル)-N-メチルアミノメチル]-5-(4-ニトロフェニル)チオフェン-3-カルボン酸エチルエステル(12.43 g)（特開2001-278884号公報、WO00/56739号公報）のエタノール(315 ml)溶液に、2規定-塩化水素／ジエチルエーテル溶液(21 ml)と50%含水-10%パラジウム／炭素(3.73 g)を加えて、水素雰囲気下1時間激しく攪拌した。触媒を除いた濾液を重曹水で中和した後、溶媒を留去した。得られた残渣を酢酸エチル／水で分配し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去して得られた残渣をNH-シリカゲル（富士シリシア化学製）クロマトグラフィーに付し、表題化合物(11.44 g)を油状物として得た。
¹H-NMR (CDCl₃) 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 (1H, m).
IR (KBr): 1717, 1626, 1609, 1472, 1406, 1300, 1246 cm^-1.
参考例６
2-[(2,6-ジフルオロベンジル)(エトキシカルボニル)アミノ]-5-(4-{[(メトキシアミノ)カルボニル]アミノ}フェニル)-4-{[(2-メトキシエチル)(メチル)アミノ]メチル}-3-チオフェンカルボン酸エチルエステルの製造

参考例５の化合物(4.89 g)のジクロロメタン溶液(113 ml)に、氷冷下でN-エチルジイソプロピルアミン(3.06 ml)を加え攪拌した。この反応液に氷冷下でN,N'-カルボニルジイミダゾール(2.82 g)を加え、氷冷下から室温に戻し67時間攪拌した。再度氷冷下に戻し、O-メチルヒドロキシアミン塩酸塩(7.26 g)、N-エチルジイソプロピルアミン(15.6 ml)を加えた。反応液を氷冷下から室温に戻し、19時間攪拌し、クロロホルムと飽和重曹水で分配した。水層をクロロホルムで抽出し、抽出液をあわせて食塩水で洗浄、乾燥(MgSO₄)後、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し淡黄色カラメル状の表題化合物(4.89 g)を得た。
¹H-NMR (CDCl₃) δ: 1.19 (3H, brs), 1.30 (3H, t, J = 6.9 Hz), 2.04 (3H, s), 2.40 (2H, t, J = 6.0 Hz), 3.27 (3H, s), 3.33 (2H, t, J = 6.0 Hz), 3.60 (2H, s), 3.81 (3H, s), 4.13-4.24 (4H, m), 5.00 (2H, s), 6.84 (2H, t, J = 7.8 Hz), 7.19-7.29 (2H, m), 7.36 (2H, d, J = 8.7 Hz), 7.50 (2H, d, J = 8.7 Hz), 7.60 (1H, s).
IR (KBr): 1717, 1590, 1528, 1472, 1408, 1304 cm^-1.
参考例７
2-[(2,6-ジフルオロベンジル)(エトキシカルボニル)アミノ]-5-(4-{[(メトキシアミノ)カルボニル]アミノ}フェニル)-4-{[(2-メトキシエチル)(メチル)アミノ]メチル}-3-チオフェンカルボン酸の製造

参考例６の化合物(4.81 g)のエタノール(114 ml)溶液に2規定水酸化ナトリウム溶液(18.9 ml)を加えて60℃で5時間攪拌した。室温に戻して1規定塩酸(37.8 ml)を加えて溶媒を留去した。得られた残渣をエタノール、トルエンに溶解し再度溶媒を留去した。残渣に無水エタノール(30 ml)を加え無機物を濾去した。濾液を濃縮乾固し、得られた残渣を無水エーテルで微細化後、これを濾取、乾燥することで表題化合物(4.43 g)を得た。
¹H-NMR (CDCl₃) δ: 1.17 (3H, brs), 2.45 (3H, s), 2.81 (2H, brs), 3.28 (3H, s), 3.55 (2H, t, J = 4.8 Hz), 3.82 (3H, s), 3.92 (2H, s), 4.10-4.35 (2H, m), 5.06 (2H, s), 6.82 (2H, t, J = 7.8 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.22-7.35 (1H, m), 7.60 (2H, d, J = 8.4 Hz), 8.00-8.50 (2H, br).
IR (KBr): 1713, 1605, 1528, 1472, 1408 cm^-1.
参考例８
4-(1-ヒドロキシ-1-メチルエチル)アニリン(1)及び4-(1-メトキシ-1-メチルエチル)アニリン(2)の製造

2-メチル-2-(4-ニトロフェニル)-2-プロパノール(2.0 g)のメタノール溶液(55 ml)に5%-白金/炭素(0.3 g)を加え、水素雰囲気下、4時間攪拌した。触媒を濾去し、濾液を濃縮乾固して得られた残留物をアミノプロピルシリカゲル（富士シリシア化学製）のカラムクロマトグラフィー（120 g；展開液；ヘキサン/酢酸エチル：9/1→1/4）で精製することにより4-(1-ヒドロキシ-1-メチルエチル)アニリン(1)(1.0 g)と4-(1-メトキシ-1-メチルエチル)アニリン(2)(0.35 g)が得られた。
4-(1-ヒドロキシ-1-メチルエチル)アニリン(1)
¹H-NMR (CDCl₃) δ: 1.45 (1H, s), 1.55 (6H, s), 3.64 (2H, brs), 6.66 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz).
IR (KBr): 3335, 2975, 1613, 1516, 1256 cm^-1.
4-(1-メトキシ-1-メチルエチル)アニリン(2)
¹H-NMR (CDCl₃) δ: 1.49 (6H, s), 3.03 (3H, s), 3.64 (2H, brs), 6.67 (2H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.7 Hz).
IR (KBr): 2978, 1630, 1613, 1518, 1358, 1264 cm^-1. Reference Example 5
2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -4- [N- (2-methoxyethyl) -N-methylaminomethyl] -5- (4-aminophenyl) thiophene- Production of 3-carboxylic acid ethyl ester

2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonyl] amino-4- [N- (2-methoxyethyl) -N-methylaminomethyl] -5- (4-nitrophenyl) thiophene- Ethanol (315 ml) of 3-carboxylic acid ethyl ester (12.43 g) (JP 2001-278884, WO 00/56739) was added to 2N-hydrogen chloride / diethyl ether solution (21 ml) and 50% Hydrous -10% palladium / carbon (3.73 g) was added, and the mixture was vigorously stirred for 1 hour in a hydrogen atmosphere. After neutralizing the filtrate from which the catalyst had been removed with aqueous sodium bicarbonate, the solvent was distilled off. The obtained residue was partitioned with ethyl acetate / water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting 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 (1H, m).
IR (KBr): 1717, 1626, 1609, 1472, 1406, 1300, 1246 cm ^-1 .
Reference Example 6
2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(methoxyamino) carbonyl] amino} phenyl) -4-{[(2-methoxyethyl) (methyl) amino ] Production of methyl} -3-thiophenecarboxylic acid ethyl ester

To a dichloromethane solution (113 ml) of the compound of Reference Example 5 (4.89 g), N-ethyldiisopropylamine (3.06 ml) was added and stirred under ice cooling. N, N′-carbonyldiimidazole (2.82 g) was added to the reaction mixture under ice cooling, and the mixture was returned to room temperature under ice cooling and stirred for 67 hours. The mixture was returned to ice-cooling again, and O-methylhydroxyamine hydrochloride (7.26 g) and N-ethyldiisopropylamine (15.6 ml) were added. The reaction solution was cooled to room temperature under ice cooling, stirred for 19 hours, and partitioned between chloroform and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform, and the extracts were combined, washed with brine, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (4.89 g) as a pale yellow caramel.
¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, brs), 1.30 (3H, t, J = 6.9 Hz), 2.04 (3H, s), 2.40 (2H, t, J = 6.0 Hz), 3.27 ( 3H, s), 3.33 (2H, t, J = 6.0 Hz), 3.60 (2H, s), 3.81 (3H, s), 4.13-4.24 (4H, m), 5.00 (2H, s), 6.84 (2H , t, J = 7.8 Hz), 7.19-7.29 (2H, m), 7.36 (2H, d, J = 8.7 Hz), 7.50 (2H, d, J = 8.7 Hz), 7.60 (1H, s).
IR (KBr): 1717, 1590, 1528, 1472, 1408, 1304 cm ^-1 .
Reference Example 7
2-[(2,6-difluorobenzyl) (ethoxycarbonyl) amino] -5- (4-{[(methoxyamino) carbonyl] amino} phenyl) -4-{[(2-methoxyethyl) (methyl) amino ] Methyl} -3-thiophenecarboxylic acid production

To a solution of the compound of Reference Example 6 (4.81 g) in ethanol (114 ml) was added 2N sodium hydroxide solution (18.9 ml), and the mixture was stirred at 60 ° C. for 5 hours. After returning to room temperature, 1N hydrochloric acid (37.8 ml) was added and the solvent was distilled off. The obtained residue was dissolved in ethanol and toluene, and the solvent was distilled off again. To the residue was added anhydrous ethanol (30 ml) and the inorganic substance was removed by filtration. The filtrate was concentrated to dryness, and the resulting residue was refined with anhydrous ether, and then collected by filtration and dried to obtain the title compound (4.43 g).
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, brs), 2.45 (3H, s), 2.81 (2H, brs), 3.28 (3H, s), 3.55 (2H, t, J = 4.8 Hz), 3.82 (3H, s), 3.92 (2H, s), 4.10-4.35 (2H, m), 5.06 (2H, s), 6.82 (2H, t, J = 7.8 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.22-7.35 (1H, m), 7.60 (2H, d, J = 8.4 Hz), 8.00-8.50 (2H, br).
IR (KBr): 1713, 1605, 1528, 1472, 1408 cm ^-1 .
Reference Example 8
Production of 4- (1-hydroxy-1-methylethyl) aniline (1) and 4- (1-methoxy-1-methylethyl) aniline (2)

To a methanol solution (55 ml) of 2-methyl-2- (4-nitrophenyl) -2-propanol (2.0 g) was added 5% -platinum / carbon (0.3 g), and the mixture was stirred under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the residue obtained by concentrating the filtrate to dryness was subjected to column chromatography on aminopropyl silica gel (Fuji Silysia Chemical) (120 g; developing solution; hexane / ethyl acetate: 9/1 → 1 / Purification in 4) yields 4- (1-hydroxy-1-methylethyl) aniline (1) (1.0 g) and 4- (1-methoxy-1-methylethyl) aniline (2) (0.35 g). It was.
4- (1-hydroxy-1-methylethyl) aniline (1)
¹ H-NMR (CDCl ₃ ) δ: 1.45 (1H, s), 1.55 (6H, s), 3.64 (2H, brs), 6.66 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz).
IR (KBr): 3335, 2975, 1613, 1516, 1256 cm ^-1 .
4- (1-Methoxy-1-methylethyl) aniline (2)
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 3.03 (3H, s), 3.64 (2H, brs), 6.67 (2H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.7 Hz).
IR (KBr): 2978, 1630, 1613, 1518, 1358, 1264 cm ^-1 .

6-メチル-2-ニトロ-3-ヒドロキシピリジン(4.63 g)のDMF溶液(120 ml)に炭酸カリウム(4.15 g)とヨウ化メチル(2.80 ml)を加えて、室温で14時間攪拌した。反応液を酢酸エチル/水で分配し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下、溶媒留去後の残渣を酢酸エチル/ヘキサンで再結晶し、表題化合物(3.94 g)を針状晶として得た。
¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 3.95 (3H, s), 7.37 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.8 Hz).
IR (KBr): 1541, 1489, 1381, 1308, 1289 cm^-1.
参考例１０
2-アミノ-3-メトキシ-6-メチルピリジンの製造

3-メトキシ-6-メチル-2-ニトロピリジン(3.85 g)のエタノール溶液(91.6 ml)に50%含水-10%-パラジウム/炭素(0.96 g)を加え、水素雰囲気下、2時間攪拌した。触媒を濾去し、濾液を濃縮乾固して得られた残留物を酢酸エチル/ヘキサンで再結晶し、表題化合物(2.89 g)を得た。
¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 3.81 (3H, s), 4.61 (2H, s), 6.44 (1H, d, J = 8.4 Hz), 6.81 (1H, d, J = 8.4 Hz).
IR (KBr): 1624, 1576, 1480, 1439, 1258 cm^-1.
参考例１１
2-アミノ-3-ヒドロキシ-6-メチルピリジンの製造

参考例１０と同様の反応に付し、6-メチル-2-ニトロ-3-ヒドロキシピリジン(4.63 g)から表題化合物(2.81 g)を結晶性粉末として得た。
¹H-NMR (DMSO-d₆) δ: 2.14 (3H, s), 5.29 (2H, s), 6.20 (1H, d, J = 7.5 Hz), 6.70 (1H, d, J = 7.5 Hz), 9.09 (1H, s).
参考例１２
3-メトキシ-2-ニトロピリジンの製造

参考例９と同様の反応に付し、2-ニトロ-3-ヒドロキシピリジン(7.0 g)、炭酸カリウム(6.91 g)、ヨウ化メチル(4.67 ml)から表題化合物(7.5 g)を結晶性粉末として得た。
¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.54-7.56 (2H, m), 8.09-8.12 (1H, m).
IR (KBr): 1601, 1537, 1530, 1422, 1364, 1275 cm^-1.
参考例１３
2-アミノ-3-メトキシピリジンの製造

参考例１０と同様の反応に付し、3-メトキシ-2-ニトロピリジン(7.5 g)から表題化合物(5.42 g)を結晶性粉末として得た。
¹H-NMR (CDCl₃) δ: 3.84 (3H, s), 4.65 (2H, brs), 6.62 (1H, d, J = 5.0 Hz, 7.6 Hz), 6.90 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.66 (1H, dd, J = 1.4 Hz, 5,0 Hz).
IR (KBr): 3443, 3142, 1634, 1601, 1570, 1483, 1460, 1441 cm^-1. Reference Example 9
Production of 3-methoxy-6-methyl-2-nitropyridine

To a DMF solution (120 ml) of 6-methyl-2-nitro-3-hydroxypyridine (4.63 g) were added potassium carbonate (4.15 g) and methyl iodide (2.80 ml), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was partitioned with ethyl acetate / water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue after evaporation of the solvent under reduced pressure was recrystallized from ethyl acetate / hexane to give the title compound (3.94 g) as needle crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 3.95 (3H, s), 7.37 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.8 Hz).
IR (KBr): 1541, 1489, 1381, 1308, 1289 cm ^-1 .
Reference Example 10
Preparation of 2-amino-3-methoxy-6-methylpyridine

To an ethanol solution (91.6 ml) of 3-methoxy-6-methyl-2-nitropyridine (3.85 g) was added 50% water-containing 10% -palladium / carbon (0.96 g), and the mixture was stirred under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, the filtrate was concentrated to dryness, and the resulting residue was recrystallized from ethyl acetate / hexane to give the title compound (2.89 g).
¹ H-NMR (CDCl ₃ ) δ: 2.32 (3H, s), 3.81 (3H, s), 4.61 (2H, s), 6.44 (1H, d, J = 8.4 Hz), 6.81 (1H, d, J = 8.4 Hz).
IR (KBr): 1624, 1576, 1480, 1439, 1258 cm ^-1 .
Reference Example 11
Preparation of 2-amino-3-hydroxy-6-methylpyridine

The title compound (2.81 g) was obtained as a crystalline powder from 6-methyl-2-nitro-3-hydroxypyridine (4.63 g) by the same reaction as in Reference Example 10.
¹ H-NMR (DMSO-d ₆ ) δ: 2.14 (3H, s), 5.29 (2H, s), 6.20 (1H, d, J = 7.5 Hz), 6.70 (1H, d, J = 7.5 Hz), 9.09 (1H, s).
Reference Example 12
Production of 3-methoxy-2-nitropyridine

The same reaction as in Reference Example 9 was carried out, and the title compound (7.5 g) was obtained as a crystalline powder from 2-nitro-3-hydroxypyridine (7.0 g), potassium carbonate (6.91 g), and methyl iodide (4.67 ml). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.54-7.56 (2H, m), 8.09-8.12 (1H, m).
IR (KBr): 1601, 1537, 1530, 1422, 1364, 1275 cm ^-1 .
Reference Example 13
Production of 2-amino-3-methoxypyridine

The reaction was conducted in the same manner as in Reference Example 10 to give the title compound (5.42 g) as a crystalline powder from 3-methoxy-2-nitropyridine (7.5 g).
¹ H-NMR (CDCl ₃ ) δ: 3.84 (3H, s), 4.65 (2H, brs), 6.62 (1H, d, J = 5.0 Hz, 7.6 Hz), 6.90 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.66 (1H, dd, J = 1.4 Hz, 5,0 Hz).
IR (KBr): 3443, 3142, 1634, 1601, 1570, 1483, 1460, 1441 cm ^-1 .

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸 (2.40 g, 3.76 mmol)と2-アミノピリジン(1.06 g, 11.28 mmol) のDMF溶液(20 ml)にエチルジイソプロピルアミン(1.05 ml, 6.02 mmol)とシアノリン酸ジエチル(0.86 ml, 5.64 mmol)を加え、室温で3日間攪拌した。重曹水を加え、酢酸エチルで抽出し、有機層を食塩水で洗浄した。硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル)により精製し、アミドを得た。得られたアミドをメタノール(40 ml)に溶解し、ナトリウムメトキシド(2.03 mg, 37.6 mmol)を加えた。室温で5時間攪拌後、濃縮し、1規定塩酸を加えて中和し、酢酸エチルで抽出した。有機層を食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー(溶出液；酢酸エチル)により精製し、表題化合物(1.59 g, 63%)を淡黄色アモルファスとして得た。
¹H-NMR(CDCl₃) δ: 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.89 (2H, s), 5.34 (2H, brs), 6.91 (2H, t, J = 8.0 Hz), 7.1-7.45 (9H, m), 7.56 (2H, d, J = 8.8 Hz), 7.65 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.91 (1H, dt, J = 2.0, 7.7 Hz), 8.7-8.75 (1H, m).
元素分析 C₃₅H₃₀F₂N₆O₄S₂として
計算値: C, 62.86; H, 4.52; N, 12.57.
実測値: C, 62.72; H, 4.31; N, 12.40.
mp 179-182℃.
参考例１４
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチルアミノ)メチル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例１の化合物(1.59 g, 2.38 mmol)のエタノール(40 ml)溶液に、1規定塩酸(7 ml)と50%含水-10%パラジウム／炭素(0.63 g)を加えて、水素雰囲気下 20時間激しく攪拌した。触媒を除いた濾液を1規定水酸化ナトリウム水溶液で中和した後、溶媒を留去した。得られた残渣を酢酸エチル／水で分配し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去して得られた粉末をジエチルエーテルで洗浄し、表題化合物 (980 mg, 71%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.34 (3H, s), 3.78 (2H, s), 3.82 (2H, s), 5.38 (2H, brs), 6.92 (2H, t, J = 8.2 Hz), 7.2-7.8 (9H, m), 7.92 (1H, dt, J = 1.8 Hz, 7.6 Hz), 8.72 (1H, d, J = 4.8 Hz).
実施例２
N-{2-[{[1-(2,6-ジフルオロベンジル)-6-(4-{[(メトキシアミノ)カルボニル]アミノ}フェニル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-5-イル]メチル}(メチル)アミノ]エチル}-N-メチルスルホンアミドの製造

2-(メチルアミノ)エタノール(0.14 g, 1.903 mmol)をTHF(10 ml)に溶解し、トリエチルアミン(0.58 ml, 4.15 mmol)とメタンスルホニルクロリド(0.27 ml, 3.46 mmol)を加え、室温で1時間攪拌した。重曹水を加え、酢酸エチルで抽出した。水層を塩析後、酢酸エチルで抽出した。有機層を集め、硫酸マグネシウムで乾燥後、減圧濃縮し、メシレートを得た。得られたメシレート、参考例１４の化合物(200 mg, 0.346 mmol)、N,N-ジイソプロピルエチルアミン(0.12 ml, 0.692 mmol)とよう化カリウム(230 mg, 1.38 mmol)のDMF溶液(8 ml)を50-60℃で16時間攪拌後、重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル／メタノール；80／1)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物 (115 mg, 47%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.11 (3H, s), 2.45-2.6 (2H, m), 2.70 (3H, s), 2.75 (3H, s), 3.1-3.25 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.6 (7H, m), 7.65 (1H, s), 7.85-7.95 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1715, 1669, 1530, 1462, 1333, 1146, 1032, 781 cm^-1.
元素分析 C₃₂H₃₃F₂N₇O₆S₂・0.3H₂Oとして
計算値: C, 53.44; H, 4.71; N, 13.63.
実測値: C, 53.76; H, 4.75; N, 13.21.
mp 185-187℃. Example 1
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -2,4-dioxo-3- (2-pyridinyl) -1,2,3, 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- Ethyldiisopropylamine (1.05 ml, 6.02 mmol) and diethyl cyanophosphate (0.86 ml, 5.64) were added to a DMF solution (20 ml) of 3-carboxylic acid (2.40 g, 3.76 mmol) and 2-aminopyridine (1.06 g, 11.28 mmol). mmol) was added and stirred at room temperature for 3 days. An aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate, and the organic layer was washed with brine. After drying over magnesium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to obtain an amide. The obtained amide was dissolved in methanol (40 ml), and sodium methoxide (2.03 mg, 37.6 mmol) was added. The mixture was stirred at room temperature for 5 hours, concentrated, neutralized with 1N hydrochloric acid, and 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 NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate) to obtain the title compound (1.59 g, 63%) as a pale yellow amorphous.
¹ H-NMR (CDCl ₃ ) δ: 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.89 (2H, s), 5.34 (2H, brs), 6.91 (2H, t , J = 8.0 Hz), 7.1-7.45 (9H, m), 7.56 (2H, d, J = 8.8 Hz), 7.65 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.91 (1H , dt, J = 2.0, 7.7 Hz), 8.7-8.75 (1H, m).
Elemental analysis _{C 35 H 30 F 2 N 6} O 4 S 2 Calculated: C, 62.86; H, 4.52 ; N, 12.57.
Found: C, 62.72; H, 4.31; N, 12.40.
mp 179-182 ° C.
Reference Example 14
N- (4- (1- (2,6-difluorobenzyl) -5-((methylamino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1,2,3,4-tetrahydro Preparation of thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

To a solution of the compound of Example 1 (1.59 g, 2.38 mmol) in ethanol (40 ml), 1N hydrochloric acid (7 ml) and 50% water-containing 10% palladium / carbon (0.63 g) are added, and hydrogen atmosphere is added. Stir vigorously for hours. The filtrate from which the catalyst had been removed was neutralized with 1N aqueous sodium hydroxide solution, and then the solvent was distilled off. The obtained residue was partitioned with ethyl acetate / water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting powder was washed with diethyl ether to give the title compound (980 mg, 71%) as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.78 (2H, s), 3.82 (2H, s), 5.38 (2H, brs), 6.92 (2H, t, J = 8.2 Hz), 7.2-7.8 (9H, m), 7.92 (1H, dt, J = 1.8 Hz, 7.6 Hz), 8.72 (1H, d, J = 4.8 Hz).
Example 2
N- {2-[{[1- (2,6-difluorobenzyl) -6- (4-{[(methoxyamino) carbonyl] amino} phenyl) -2,4-dioxo-3- (2-pyridinyl) Preparation of -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl] methyl} (methyl) amino] ethyl} -N-methylsulfonamide

2- (Methylamino) ethanol (0.14 g, 1.903 mmol) is dissolved in THF (10 ml), triethylamine (0.58 ml, 4.15 mmol) and methanesulfonyl chloride (0.27 ml, 3.46 mmol) are added, and the mixture is stirred at room temperature for 1 hour. Stir. Sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate. The aqueous layer was salted out and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to obtain mesylate. The obtained mesylate, the compound of Reference Example 14 (200 mg, 0.346 mmol), N, N-diisopropylethylamine (0.12 ml, 0.692 mmol) and potassium iodide (230 mg, 1.38 mmol) in DMF (8 ml) were added. After stirring 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; 80/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (115 mg, 47%) as pale yellow crystals. It was.
¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.45-2.6 (2H, m), 2.70 (3H, s), 2.75 (3H, s), 3.1-3.25 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.6 (7H, m), 7.65 ( 1H, s), 7.85-7.95 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1715, 1669, 1530, 1462, 1333, 1146, 1032, 781 cm ^-1 .
Elemental analysis Calculated as C ₃₂ H ₃₃ F ₂ N ₇ O ₆ S ₂ 0.3H ₂ O: C, 53.44; H, 4.71; N, 13.63.
Found: C, 53.76; H, 4.75; N, 13.21.
mp 185-187 ° C.

参考例１４の化合物(200 mg, 0.346 mmol)と1-(2-ヒドロキシエチル)-2-ピロリドン(0.25 g, 1.903 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (97 mg, 41%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.7-1.85 (2H, m), 2.17 (3H, s), 2.15-2.3 (2H, m), 2.5-2.6 (2H, m), 3.15 (2H, t, J = 7.0 Hz), 3.2-3.4 (2H, m), 3.76 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J = 8.4 Hz), 7.16 (1H, s), 7.2-7.7 (8H, m), 7.85-7.95 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1715, 1672, 1526, 1464, 1329, 1032, 783 cm^-1.
元素分析 C₃₄H₃₃F₂N₇O₅S・0.5H₂Oとして
計算値: C, 58.44; H, 4.90; N, 14.03.
実測値: C, 58.75; H, 4.98; N, 13.71.
mp 199-201℃.
実施例４
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-ピリジニルメチル)アミノ)メチル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１４の化合物(150 mg, 0.259 mmol)をDMF(4 ml)に溶解し、N,N-ジイソプロピルエチルアミン(0.20 ml, 1.14 mmol)と2-クロロメチルピリジン塩酸塩(85 mg, 0.518 mmol)を加え、室温で1時間攪拌した。重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル／メタノール；40／1)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物 (70 mg, 40%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.10 (3H, s), 3.70 (2H, s), 3.82 (3H, s), 3.96 (3H, s), 5.34 (2H, brs), 6.85-7.7 (14H, m), 7.85-7.95 (1H, m), 8.4-8.5 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1717, 1672, 1526, 1464, 1331, 1236, 1036, 772 cm^-1.
元素分析 C₃₄H₂₉F₂N₇O₄S・0.3H₂Oとして
計算値: C, 62.36; H, 4.58; N, 12.47.
実測値: C; 62.22; H, 4.32; N, 12.57.
mp 165-167℃.
実施例５
N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシエチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(1.28 g, 2 mmol)と2-アミノエタノール(183 mg, 3 mmol)のDMF溶液(12 ml)に、エチルジイソプロピルアミン(0.56 ml, 3.2 mmol)とシアノリン酸ジエチル(0.46 ml, 3 mmol)を加え、室温で3日間攪拌した。重曹水を加え、酢酸エチルで抽出し、有機層を食塩水で洗浄した。硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー(溶出液；酢酸エチル／メタノール；80／1)により精製し、アミドを得た。得られたアミドをメタノール(20 ml)に溶解し、ナトリウムメトキシド(589 mg, 10.9 mmol)を加えた。50-60℃で3時間攪拌後、濃縮し、1規定塩酸を加えて中和し、酢酸エチルで抽出した。有機層を食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物 (511 mg, 74%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.04 (3H, s), 2.5-2.65 (1H, m), 3.58 (2H, s), 3.83 (3H, s), 3.91 (2H, s), 3.9-4.0 (2H, m), 4.37 (2H, t, J = 5.0 Hz), 5.34 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.4 (7H, m), 7.54 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.6-7.7(1H, m).
IR (KBr): 1711, 1649, 1535, 1470, 1323, 1236, 1028, 785 cm^-1.
元素分析 C₃₂H₃₁F₂N₅O₅S・0.5H₂Oとして
計算値: C, 59.62; H, 5.00; N, 10.86.
実測値: C, 59.75; H, 4.81; N, 10.93. Example 3
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (2-oxo-1-pyrrolidinyl) ethyl) amino) methyl) -2,4-dioxo-3- ( 2-Pyridinyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 14 (200 mg, 0.346 mmol) and 1- (2-hydroxyethyl) -2-pyrrolidone (0.25 g, 1.903 mmol), the title compound (97 mg , 41%) was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.7-1.85 (2H, m), 2.17 (3H, s), 2.15-2.3 (2H, m), 2.5-2.6 (2H, m), 3.15 (2H, t, J = 7.0 Hz), 3.2-3.4 (2H, m), 3.76 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J = 8.4 Hz), 7.16 ( 1H, s), 7.2-7.7 (8H, m), 7.85-7.95 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1715, 1672, 1526, 1464, 1329, 1032, 783 cm ^-1 .
Elemental analysis Calculated as C ₃₄ H ₃₃ F ₂ N ₇ O ₅ S0.5H ₂ O: C, 58.44; H, 4.90; N, 14.03.
Found: C, 58.75; H, 4.98; N, 13.71.
mp 199-201 ° C.
Example 4
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound of Reference Example 14 (150 mg, 0.259 mmol) was dissolved in DMF (4 ml), N, N-diisopropylethylamine (0.20 ml, 1.14 mmol) and 2-chloromethylpyridine hydrochloride (85 mg, 0.518 mmol) And stirred at room temperature for 1 hour. Sodium bicarbonate 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 (70 mg, 40%) as pale yellow crystals. It was.
¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, s), 3.70 (2H, s), 3.82 (3H, s), 3.96 (3H, s), 5.34 (2H, brs), 6.85-7.7 (14H , m), 7.85-7.95 (1H, m), 8.4-8.5 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1717, 1672, 1526, 1464, 1331, 1236, 1036, 772 cm ^-1 .
Elemental analysis Calculated as C ₃₄ H ₂₉ F ₂ N ₇ O ₄ S ・ 0.3H ₂ O: C, 62.36; H, 4.58; N, 12.47.
Found: C; 62.22; H, 4.32; N, 12.57.
mp 165-167 ° C.
Example 5
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (2-hydroxyethyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- To a DMF solution (12 ml) of 3-carboxylic acid (1.28 g, 2 mmol) and 2-aminoethanol (183 mg, 3 mmol), ethyl diisopropylamine (0.56 ml, 3.2 mmol) and diethyl cyanophosphate (0.46 ml, 3 mmol) was added and stirred at room temperature for 3 days. An aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate, and the organic layer was washed with brine. After drying over magnesium sulfate and concentrating under reduced pressure, the residue was purified by NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate / methanol; 80/1) to obtain an amide. The obtained amide was dissolved in methanol (20 ml), and sodium methoxide (589 mg, 10.9 mmol) was added. The mixture was stirred at 50-60 ° C for 3 hours, concentrated, neutralized with 1N hydrochloric acid, and 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 (511 mg, 74%) as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.04 (3H, s), 2.5-2.65 (1H, m), 3.58 (2H, s), 3.83 (3H, s), 3.91 (2H, s), 3.9-4.0 (2H, m), 4.37 (2H, t, J = 5.0 Hz), 5.34 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.4 (7H, m), 7.54 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.6-7.7 (1H, m).
IR (KBr): 1711, 1649, 1535, 1470, 1323, 1236, 1028, 785 cm ^-1 .
Elemental analysis Calculated as C ₃₂ H ₃₁ F ₂ N ₅ O ₅ S ・ 0.5H ₂ O: C, 59.62; H, 5.00; N, 10.86.
Found: C, 59.75; H, 4.81; N, 10.93.

N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-2,4-ジオキソ-3-(2-(1H-1,2,3-トリアゾール-1-イル)エチル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(2)

実施例５の化合物(450 mg, 0.708 mmol)を用いて実施例２と同様の反応を行い、メシレートを得た。得られたメシレート、1,2,3-トリアゾール(148 mg, 2.12 mmol)と炭酸カリウム(294 mg, 2.12 mmol)のDMF溶液(8 ml)を室温で18時間、さらに50-60℃で3時間攪拌後、重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル)により精製し、表題化合物2-イル体(243 mg, 50%)を白色アモルファスとして得、一方、ジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物1-イル体(177 mg, 36%)を無色結晶として得た。
2-イル体(1)
¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 3.51 (2H, s), 3.82 (3H, s), 3.86 (2H, s), 4.57 (2H, t, J = 6.2 Hz), 4.81 (2H, t, J = 6.2 Hz), 5.28 (2H, s), 6.91 (2H, t, J = 8.4 Hz), 7.15-7.35 (6H, m), 7.46 (2H, s), 7.53 (2H, d, J = 8.6 Hz), 7.62 (1H, s), 7.70 (2H, t, J = 8.6 Hz), 7.75 (1H, s).
IR (KBr): 1705, 1663, 1530, 1472, 1323, 1034, 786 cm^-1.
1-イル体(2)
¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 3.52 (2H, s), 3.82 (3H, s), 3.85 (2H, s), 4.58 (2H, t, J = 6.4 Hz), 4.78 (2H, t, J = 6.4 Hz), 5.30 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, s), 7.15-7.4(7H, m), 7.54 (2H, d, J = 8.8 Hz), 7.55-7.65 (2H, m), 7.67 (2H, d, J = 8.8 Hz).
IR (KBr): 1709, 1659, 1526, 1472, 1319, 1028, 799 cm^-1.
元素分析 C₃₄H₃₂F₂N₈O₄S・0.8H₂Oとして
計算値: C, 58.24; H, 4.83; N, 15.98.
実測値: C, 58.48; H, 4.89; N, 15.65.
実施例７
N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-2,4-ジオキソ-3-(2-(2H-テトラゾール-2-イル)エチル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(1)

N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-2,4-ジオキソ-3-(2-(1H-テトラゾール-1-イル)エチル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(2)

実施例５の化合物(636 mg, 1 mmol)とテトラゾール(210 mg, 3 mmol) を用いて実施例６と同様の反応を行い、表題化合物2-イル体(234 mg, 34%)を白色アモルファスとして得、一方、ジエチルエーテルから粉末化し、表題化合物1-イル体(34 mg, 5%)を淡黄色結晶として得た。
2-イル体(1)
¹H-NMR(CDCl₃) δ: 2.02 (3H, s), 3.51 (2H, s), 3.83 (5H, s), 4.6-4.7 (2H, m), 5.0-5.1 (2H, m), 5.28 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, s), 7.2-7.75 (11H, m), 8.38 (1H, s).
IR (KBr): 1705, 1663, 1530, 1472, 1323, 1236, 1032, 777 cm^-1.
1-イル体(2)
¹H-NMR(CDCl₃) δ: 2.01 (3H, s), 3.51 (2H, s), 3.83 (3H, s), 3.8-4.0 (2H, m), 4.6-4.7 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.65-6.75 (1H, m), 6.85-7.0 (2H, m), 7.1-7.7 (11H, m), 8.68 (1H, s).
実施例８
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシエチル)-5-(((2-メトキシエチル)( メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(1.21 g, 2 mmol)と2-アミノエタノール(0.18 ml, 3 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (302 mg, 25%)を淡黄色アモルファスとして得た。
¹H-NMR(CDCl₃) δ: 2.11 (3H, s), 2.65 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.46 (2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.9-4.0 (2H, m), 4.35 (2H, t, J = 5.2 Hz), 5.34 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.14 (1H, s), 7.2-7.35 (1H, m), 7.5-7.65 (5H, m). Example 6
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -2,4-dioxo-3- (2- (2H-1,2,3- Preparation of triazol-2-yl) ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (1)

N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -2,4-dioxo-3- (2- (1H-1,2,3- Triazol-1-yl) ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (2)

The same reaction as in Example 2 was performed using the compound of Example 5 (450 mg, 0.708 mmol) to obtain mesylate. DMF solution (8 ml) of the obtained mesylate, 1,2,3-triazole (148 mg, 2.12 mmol) and potassium carbonate (294 mg, 2.12 mmol) at room temperature for 18 hours and further at 50-60 ° C for 3 hours After stirring, aqueous sodium bicarbonate 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) to give the title compound 2-yl compound (243 mg, 50%) as a white amorphous substance, while being recrystallized from dichloromethane / methanol / diethyl ether. Compound 1-yl compound (177 mg, 36%) was obtained as colorless crystals.
2-Ile body (1)
¹ H-NMR (CDCl ₃ ) δ: 2.04 (3H, s), 3.51 (2H, s), 3.82 (3H, s), 3.86 (2H, s), 4.57 (2H, t, J = 6.2 Hz), 4.81 (2H, t, J = 6.2 Hz), 5.28 (2H, s), 6.91 (2H, t, J = 8.4 Hz), 7.15-7.35 (6H, m), 7.46 (2H, s), 7.53 (2H , d, J = 8.6 Hz), 7.62 (1H, s), 7.70 (2H, t, J = 8.6 Hz), 7.75 (1H, s).
IR (KBr): 1705, 1663, 1530, 1472, 1323, 1034, 786 cm ^-1 .
1-il body (2)
¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 3.52 (2H, s), 3.82 (3H, s), 3.85 (2H, s), 4.58 (2H, t, J = 6.4 Hz), 4.78 (2H, t, J = 6.4 Hz), 5.30 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, s), 7.15-7.4 (7H, m), 7.54 (2H , d, J = 8.8 Hz), 7.55-7.65 (2H, m), 7.67 (2H, d, J = 8.8 Hz).
IR (KBr): 1709, 1659, 1526, 1472, 1319, 1028, 799 cm ^-1 .
Elemental analysis Calculated as C ₃₄ H ₃₂ F ₂ N ₈ O ₄ S0.8H ₂ O: C, 58.24; H, 4.83; N, 15.98.
Found: C, 58.48; H, 4.89; N, 15.65.
Example 7
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -2,4-dioxo-3- (2- (2H-tetrazol-2-yl) Preparation of ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (1)

N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -2,4-dioxo-3- (2- (1H-tetrazol-1-yl) Preparation of ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (2)

The same reaction as in Example 6 was carried out using the compound of Example 5 (636 mg, 1 mmol) and tetrazole (210 mg, 3 mmol) to give the title compound 2-yl compound (234 mg, 34%) as a white amorphous product. On the other hand, it was triturated from diethyl ether to give the title compound 1-yl compound (34 mg, 5%) as pale yellow crystals.
2-Ile body (1)
¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 3.51 (2H, s), 3.83 (5H, s), 4.6-4.7 (2H, m), 5.0-5.1 (2H, m), 5.28 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, s), 7.2-7.75 (11H, m), 8.38 (1H, s).
IR (KBr): 1705, 1663, 1530, 1472, 1323, 1236, 1032, 777 cm ^-1 .
1-il body (2)
¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 3.51 (2H, s), 3.83 (3H, s), 3.8-4.0 (2H, m), 4.6-4.7 (2H, m), 4.8 -4.9 (2H, m), 5.30 (2H, s), 6.65-6.75 (1H, m), 6.85-7.0 (2H, m), 7.1-7.7 (11H, m), 8.68 (1H, s).
Example 8
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxyethyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- The same reaction as in Example 5 was carried out using 3-carboxylic acid (1.21 g, 2 mmol) and 2-aminoethanol (0.18 ml, 3 mmol) to give the title compound (302 mg, 25%) as a pale yellow amorphous product. Got as.
¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.65 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.46 (2H, t, J = 5.8 Hz), 3.82 ( 5H, s), 3.9-4.0 (2H, m), 4.35 (2H, t, J = 5.2 Hz), 5.34 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.14 (1H, s ), 7.2-7.35 (1H, m), 7.5-7.65 (5H, m).

N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(2-(1H-テトラゾール-1-イル)エチル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(2)

実施例８の化合物 (250 mg, 0.414 mmol)とテトラゾール(145 mg, 2.07 mmol)を用いて実施例６と同様の反応を行い、表題化合物2-イル体(66 mg, 24%)と1-イル体(27 mg, 10%)を白色アモルファスとして得た。
2-イル体(1)
¹H-NMR(CDCl₃) δ: 2.10 (3H, brs), 2.55-2.65 (2H, m), 3.31 (3H, s), 3.4-3.5 (2H, m), 3.76 (2H, s), 3.82 (3H, s), 4.62 (2H, t, J = 5.8 Hz), 5.02 (2H, t, J = 5.8 Hz), 5.27 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.25-7.4 (1H, m), 7.5-7.65 (5H, m), 8.43 (1H, s).
1-イル体(2)
¹H-NMR(CDCl₃) δ: 2.07 (3H, s), 2.55-2.65 (2H, m), 3.30 (3H, s), 3.4-3.5 (2H, m), 3.74 (2H, s), 3.82 (3H, s), 4.55-4.65 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.93 (2H, t, J = 7.8 Hz), 7.10 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m), 8.69 (1H, s).
実施例１０
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(2-(2H-1,2,3-トリアゾール-2-イル)エチル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例６の化合物（1-イル体）(200 mg, 0.291 mmol)を用いて参考例１４と同様の反応を行い、脱ベンジル体(0.11 g, 63%) を白色粉末として得た。得られた脱ベンジル体(0.11 g, 0.184mmol)と2-(クロロメチル)メチルエーテル(0.10 ml, 1.104 mmol)を用いて実施例４と同様の反応を行い、表題化合物 (35 mg, 29%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.11 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.31 (3H, s), 3.44 (2H, t, J = 5.8 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.55 (2H, t, J = 5.6 Hz), 4.79 (2H, t, J = 5.6 Hz), 5.27 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.10 (1H, s), 7.2-7.4 (2H, m), 7.51 (2H, s), 7.45-7.65 (4H, m).
元素分析 C₃₀H₃₂F₂N₈O₅Sとして
計算値: C, 55.04; H, 4.93; N, 17.12.
実測値: C, 55.02; H, 4.85; N, 16.83.
参考例１５
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチルアミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

5-(N-ベンジル-N-メチルアミノメチル)-1-(2,6-ジフルオロベンジル)-6-[4-(3-メトキシウレイド)フェニル]-3-フェニルチエノ[2,3-d]ピリミジン-2,4(1H, 3H)-ジオン(6.68 g, 10 mmol)を用い、参考例１４と同様の反応を行い表題化合物 (5.52 g, 96%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.35 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.25-7.7 (12H, m). Example 9
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2- (2H-tetrazole -2-yl) ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (1)

N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2- (1H-tetrazole 1-yl) ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (2)

The same reaction as in Example 6 was performed using the compound of Example 8 (250 mg, 0.414 mmol) and tetrazole (145 mg, 2.07 mmol) to give the title compound 2-yl compound (66 mg, 24%) and 1- Ill form (27 mg, 10%) was obtained as white amorphous.
2-Ile body (1)
¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, brs), 2.55-2.65 (2H, m), 3.31 (3H, s), 3.4-3.5 (2H, m), 3.76 (2H, s), 3.82 (3H, s), 4.62 (2H, t, J = 5.8 Hz), 5.02 (2H, t, J = 5.8 Hz), 5.27 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.25-7.4 (1H, m), 7.5-7.65 (5H, m), 8.43 (1H, s).
1-il body (2)
¹ H-NMR (CDCl ₃ ) δ: 2.07 (3H, s), 2.55-2.65 (2H, m), 3.30 (3H, s), 3.4-3.5 (2H, m), 3.74 (2H, s), 3.82 (3H, s), 4.55-4.65 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.93 (2H, t, J = 7.8 Hz), 7.10 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m), 8.69 (1H, s).
Example 10
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2- (2H-1 , 2,3-Triazol-2-yl) ethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 14 was carried out using the compound of Example 6 (1-yl form) (200 mg, 0.291 mmol) to obtain a debenzylated form (0.11 g, 63%) as a white powder. Using the obtained debenzylated form (0.11 g, 0.184 mmol) and 2- (chloromethyl) methyl ether (0.10 ml, 1.104 mmol), the same reaction as in Example 4 was performed to give the title compound (35 mg, 29% ) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.31 (3H, s), 3.44 (2H, t, J = 5.8 Hz), 3.78 ( 2H, s), 3.82 (3H, s), 4.55 (2H, t, J = 5.6 Hz), 4.79 (2H, t, J = 5.6 Hz), 5.27 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.10 (1H, s), 7.2-7.4 (2H, m), 7.51 (2H, s), 7.45-7.65 (4H, m).
Elemental analysis Calculated as C ₃₀ H ₃₂ F ₂ N ₈ O ₅ S: C, 55.04; H, 4.93; N, 17.12.
Found: C, 55.02; H, 4.85; N, 16.83.
Reference Example 15
N- (4- (1- (2,6-difluorobenzyl) -5-((methylamino) methyl) -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2, Preparation of 3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] Pyrimidine-2,4 (1H, 3H) -dione (6.68 g, 10 mmol) was used for the same reaction as in Reference Example 14 to obtain the title compound (5.52 g, 96%) as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.25-7.7 (12H, m).

N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-(1H-1,2,3-トリアゾール-1-イル)エチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(2)

1,2,3-トリアゾール(0.46 g, 6.67 mmol)、1-ブロモ-2-クロロエタン(0.83 ml, 10 mmol)の DMF溶液(5 ml)に炭酸カリウム(1.33 g, 10 mmol)を加え、室温で1時間、さらに50-60℃で3時間攪拌した。飽和食塩水を加え、酢酸エチルで2回抽出した。有機層を集め、硫酸マグネシウムで乾燥後、減圧濃縮し、ハライドを得た。
参考例１５の化合物(700 mg, 1.21 mmol)をDMF(12 ml)に溶解し、N,N-ジイソプロピルエチルアミン(1.16 ml, 6.67 mmol)と上記で得られたハライドを加え、50-60℃で16時間攪拌した。重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー(溶出液；酢酸エチル)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物2-イル体(140 mg, 17%)と1-イル体(332 mg, 41%)を無色結晶として得た。
2-イル体(1)
¹H-NMR(CDCl₃) δ: 2.23 (3H, s), 3.00 (2H, t, J = 6.3 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.45 (2H, t, J = 6.3 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.11 (1H, s), 7.2-7.6 (12H, m).
IR (KBr): 1715, 1671, 1530, 1470, 1331, 1236, 1032, 822, 735 cm^-1.
元素分析 C₃₃H₃₀F₂N₈O₄S・0.3H₂Oとして
計算値: C, 58.45; H, 4.55; N, 16.52.
実測値: C, 58.75; H, 4.27; N, 16.20.
mp 166-168℃.
1-イル体(2)
¹H-NMR(CDCl₃) δ: 2.14 (3H, s), 2.82 (2H, t, J = 6.0 Hz), 3.80 (2H, s), 3.82 (3H, s), 4.39 (2H, t, J = 6.0 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.63 (1H, s).
IR (KBr): 1719, 1672, 1526, 1470, 1236, 1231, 1028, 824, 733 cm^-1.
元素分析 C₃₃H₃₀F₂N₈O₄S・0.4H₂Oとして
計算値: C, 58.30; H, 4.57; N, 16.48.
実測値: C, 58.53; H, 4.50; N, 16.29.
mp 194-196℃. Example 11
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (2H-1,2,3-triazol-2-yl) ethyl) amino) methyl) -2,4 -Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (1)

N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (1H-1,2,3-triazol-1-yl) ethyl) amino) methyl) -2,4 -Dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (2)

Potassium carbonate (1.33 g, 10 mmol) was added to a DMF solution (5 ml) of 1,2,3-triazole (0.46 g, 6.67 mmol) and 1-bromo-2-chloroethane (0.83 ml, 10 mmol) at room temperature. The mixture was further stirred at 50-60 ° C. for 3 hours. Saturated brine was added, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a halide.
The compound of Reference Example 15 (700 mg, 1.21 mmol) was dissolved in DMF (12 ml), N, N-diisopropylethylamine (1.16 ml, 6.67 mmol) and the halide obtained above were added, and 50-60 ° C was added. Stir for 16 hours. Sodium bicarbonate 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 NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound 2-yl compound (140 mg, 17%) The 1-yl compound (332 mg, 41%) was obtained as colorless crystals.
2-Ile body (1)
¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 3.00 (2H, t, J = 6.3 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.45 (2H, t, J = 6.3 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.11 (1H, s), 7.2-7.6 (12H, m).
IR (KBr): 1715, 1671, 1530, 1470, 1331, 1236, 1032, 822, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₃ H ₃₀ F ₂ N ₈ O ₄ S ・ 0.3H ₂ O: C, 58.45; H, 4.55; N, 16.52.
Found: C, 58.75; H, 4.27; N, 16.20.
mp 166-168 ° C.
1-il body (2)
¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.82 (2H, t, J = 6.0 Hz), 3.80 (2H, s), 3.82 (3H, s), 4.39 (2H, t, J = 6.0 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.63 (1H, s).
IR (KBr): 1719, 1672, 1526, 1470, 1236, 1231, 1028, 824, 733 cm ^-1 .
Elemental analysis Calculated as C ₃₃ H ₃₀ F ₂ N ₈ O ₄ S0.4H ₂ O: C, 58.30; H, 4.57; N, 16.48.
Found: C, 58.53; H, 4.50; N, 16.29.
mp 194-196 ° C.

参考例１５の化合物(350 mg, 0.606 mmol)と2-(2-ヒドロキシエチル)ピリジン(0.45 g, 3.64 mmol)を用いて実施例２と同様の反応を行い、表題化合物 (233 mg, 56%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.20 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.60 (1H, s), 8.43 (1H, d, J = 4.0 Hz).
IR (KBr): 1717, 1667, 1530, 1470, 1331, 1236, 1030, 735 cm^-1.
元素分析 C₃₆H₃₂F₂N₆O₄Sとして
計算値: C, 63.33; H, 4.72; N, 12.31.
実測値: C, 63.17; H, 4.56; N, 12.31.
mp 159-160℃.
実施例１３
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-(4-ピリジニル) エチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１５の化合物(350 mg, 0.606 mmol)と4-(2-ヒドロキシエチル)ピリジン塩酸塩(0.58 g, 3.64 mmol)を用いて実施例２と同様の反応を行い、表題化合物 (166 mg, 40%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.18 (3H, s), 2.68 (4H, s), 3.83 (5H, s), 5.37 (2H, s), 6.85-7.0 (5H, m), 7.16 (1H, s), 7.2-7.65 (10H, m), 8.35-8.4 (2H, m).
IR (KBr): 1715, 1667, 1532, 1470, 735 cm^-1.
元素分析 C₃₆H₃₂F₂N₆O₄S・0.1H₂Oとして
計算値: C, 63.16; H, 4.74; N, 12.28.
実測値: C, 62.91; H, 4.68; N, 12.26.
mp 194-196℃. Example 12
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (2-pyridinyl) ethyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction of Example 2 was carried out using the compound of Reference Example 15 (350 mg, 0.606 mmol) and 2- (2-hydroxyethyl) pyridine (0.45 g, 3.64 mmol), and the title compound (233 mg, 56% ) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.60 (1H, s), 8.43 (1H, d, J = 4.0 Hz).
IR (KBr): 1717, 1667, 1530, 1470, 1331, 1236, 1030, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₆ H ₃₂ F ₂ N ₆ O ₄ S: C, 63.33; H, 4.72; N, 12.31.
Found: C, 63.17; H, 4.56; N, 12.31.
mp 159-160 ° C.
Example 13
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (4-pyridinyl) ethyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (350 mg, 0.606 mmol) and 4- (2-hydroxyethyl) pyridine hydrochloride (0.58 g, 3.64 mmol), the same reaction as in Example 2 was carried out, and the title compound (166 mg, 40%) was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 2.68 (4H, s), 3.83 (5H, s), 5.37 (2H, s), 6.85-7.0 (5H, m), 7.16 (1H , s), 7.2-7.65 (10H, m), 8.35-8.4 (2H, m).
IR (KBr): 1715, 1667, 1532, 1470, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₆ H ₃₂ F ₂ N ₆ O ₄ S ・ 0.1H ₂ O: C, 63.16; H, 4.74; N, 12.28.
Found: C, 62.91; H, 4.68; N, 12.26.
mp 194-196 ° C.

参考例１５の化合物(350 mg, 0.606 mmol)と2-クロロメチルピリジン塩酸塩(149 mg, 0.908 mmol)を用いて実施例４と同様の反応を行い、表題化合物 (297 mg, 73%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.15 (1H, s), 7.2-7.35 (4H, m), 7.4-7.65 (9H, m), 8.4-8.5 (1H, m).
IR (KBr): 1715, 1667, 1532, 1472, 735 cm^-1.
元素分析 C₃₅H₃₀F₂N₆O₄S・0.5H₂Oとして
計算値: C, 62.03; H, 4.61; N, 12.40.
実測値: C, 62.13; H, 4.59; N, 12.47.
mp 181-182℃.
参考例１６
N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-2,4-ジオキソ-3-(4-フルオロフェニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(2.87 g, 4.49 mmol)と4-フルオロアニリン(0.64 ml, 6.735 mmol) を用いて、実施例５と同様の反応を行い、表題化合物(2.71 g, 88%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.05 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.89 (2H, s), 5.36 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.1-7.35 (11H, m), 7.56 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J = 8.4 Hz).
元素分析 C₃₆H₃₀F₃N₅O₄S・0.5H₂Oとして
計算値: C, 62.24; H, 4.50; N, 10.08.
実測値: C, 62.43; H, 4.21; N, 9.84.
参考例１７
N-(4-(1-(2,6-ジフルオロベンジル)-3-(4-フルオロフェニル)-5-((メチルアミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１６の化合物(2.50 g, 3.65 mmol)を用い、参考例１４と同様の反応を行い表題化合物 (1.85 g, 85%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.37 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-7.0 (1H, brs), 7.15-7.35 (6H, m), 7.42 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.63 (1H, s). Example 14
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2,3,4- Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Example 4 was carried out using the compound of Reference Example 15 (350 mg, 0.606 mmol) and 2-chloromethylpyridine hydrochloride (149 mg, 0.908 mmol) to give the title compound (297 mg, 73%). Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.92 (2H, t , J = 8.2 Hz), 7.0-7.1 (1H, m), 7.15 (1H, s), 7.2-7.35 (4H, m), 7.4-7.65 (9H, m), 8.4-8.5 (1H, m).
IR (KBr): 1715, 1667, 1532, 1472, 735 cm ^-1 .
Elemental analysis _{C 35 H 30 F 2 N 6} O 4 S · 0.5H 2 O Calculated: C, 62.03; H, 4.61 ; N, 12.40.
Found: C, 62.13; H, 4.59; N, 12.47.
mp 181-182 ° C.
Reference Example 16
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -2,4-dioxo-3- (4-fluorophenyl) -1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- The same reaction as in Example 5 was carried out using 3-carboxylic acid (2.87 g, 4.49 mmol) and 4-fluoroaniline (0.64 ml, 6.735 mmol) to give the title compound (2.71 g, 88%) as a pale yellow powder. Got as.
¹ H-NMR (CDCl ₃ ) δ: 2.05 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.89 (2H, s), 5.36 (2H, s), 6.93 (2H, t , J = 8.0 Hz), 7.1-7.35 (11H, m), 7.56 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J = 8.4 Hz).
Elemental analysis Calculated as C ₃₆ H ₃₀ F ₃ N ₅ O ₄ S0.5H ₂ O: C, 62.24; H, 4.50; N, 10.08.
Found: C, 62.43; H, 4.21; N, 9.84.
Reference Example 17
N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methylamino) methyl) -2,4-dioxo-1,2,3,4- Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 16 (2.50 g, 3.65 mmol), the same reaction as in Reference Example 14 was performed to obtain the title compound (1.85 g, 85%) as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 2.37 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-7.0 (1H, brs), 7.15-7.35 (6H, m), 7.42 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.63 (1H, s).

参考例１７の化合物(150 mg, 0.25 mmol)と2-クロロメチルピリジン塩酸塩(85 mg, 0.52 mmol)を用いて実施例４と同様の反応を行い、表題化合物 (105 mg, 61%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 5.35 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.0-7.7 (14H, m), 8.4-8.5 (1H, m).
IR (KBr): 1723, 1665, 1532, 1510, 1474, 1236, 1032, 761 cm^-1.
元素分析 C₃₅H₂₉F₃N₆O₄S・0.7H₂Oとして
計算値: C, 60.11; H, 4.38; N, 12.02.
実測値: C, 59.76; H, 4.03; N, 11.71.
mp 183-185℃.
実施例１６
N-(4-(1-(2,6-ジフルオロベンジル)-3-(4-フルオロフェニル)-5-((メチル(2-(2-ピリジニル)エチル) アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１７の化合物(150 mg, 0.25 mmol)と2-(2-ヒドロキシエチル)ピリジン(0.19 g, 1.512 mmol)を用いて実施例２と同様の反応を行い、表題化合物 (100 mg, 57%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.19 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.36 (2H, s), 6.9-7.55 (13H, m), 7.60 (1H, s), 8.4-8.45 (1H, m).
IR (KBr): 1723, 1665, 1534, 1510, 1474, 1464, 1238, 1034, 762 cm^-1.
元素分析 C₃₆H₃₁F₃N₆O₄S・0.5H₂Oとして
計算値: C, 60.92; H, 4.54; N, 11.84.
実測値: C, 61.12; H, 4.63; N, 11.78.
mp 185-187℃.
実施例１７
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-(2-ピリジニル)エチル)アミノ)メチル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１４の化合物(150 mg, 0.259 mmol)と2-(2-ヒドロキシエチル)ピリジン(0.18 g, 1.425 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (83 mg, 47%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.21 (3H, s), 2.8-2.9 (4H, m), 3.82 (5H, s), 5.34 (2H, brs), 6.85-7.75 (13H, m), 7.60 (1H, s), 7.85-7.95 (1H, m), 8.4-8.5 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1715, 1671, 1530, 1458, 1329, 1032, 781 cm^-1.
mp 194-196℃. Example 15
N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2,4-dioxo-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 17 (150 mg, 0.25 mmol) and 2-chloromethylpyridine hydrochloride (85 mg, 0.52 mmol), the same reaction as in Example 4 was carried out to give the title compound (105 mg, 61%). Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 5.35 (2H, s), 6.93 (2H, t , J = 8.2 Hz), 7.0-7.7 (14H, m), 8.4-8.5 (1H, m).
IR (KBr): 1723, 1665, 1532, 1510, 1474, 1236, 1032, 761 cm ^-1 .
Elemental analysis Calculated as C ₃₅ H ₂₉ F ₃ N ₆ O ₄ S0.7H ₂ O: C, 60.11; H, 4.38; N, 12.02.
Found: C, 59.76; H, 4.03; N, 11.71.
mp 183-185 ° C.
Example 16
N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (2- (2-pyridinyl) ethyl) amino) methyl) -2,4- Preparation of dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction of Example 2 was carried out using the compound of Reference Example 17 (150 mg, 0.25 mmol) and 2- (2-hydroxyethyl) pyridine (0.19 g, 1.512 mmol), and the title compound (100 mg, 57% ) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.36 (2H, s), 6.9-7.55 (13H, m), 7.60 (1H , s), 8.4-8.45 (1H, m).
IR (KBr): 1723, 1665, 1534, 1510, 1474, 1464, 1238, 1034, 762 cm ^-1 .
Elemental analysis Calculated as C ₃₆ H ₃₁ F ₃ N ₆ O ₄ S0.5H ₂ O: C, 60.92; H, 4.54; N, 11.84.
Found: C, 61.12; H, 4.63; N, 11.78.
mp 185-187 ° C.
Example 17
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (2-pyridinyl) ethyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 14 (150 mg, 0.259 mmol) and 2- (2-hydroxyethyl) pyridine (0.18 g, 1.425 mmol), the title compound (83 mg, 47% ) Was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.8-2.9 (4H, m), 3.82 (5H, s), 5.34 (2H, brs), 6.85-7.75 (13H, m), 7.60 (1H, s), 7.85-7.95 (1H, m), 8.4-8.5 (1H, m), 8.65-8.75 (1H, m).
IR (KBr): 1715, 1671, 1530, 1458, 1329, 1032, 781 cm ^-1 .
mp 194-196 ° C.

参考例１５の化合物(150 mg, 0.26 mmol)と3-クロロメチルピリジン塩酸塩(85 mg, 0.52 mmol)を用いて、実施例４と同様の反応を行い表題化合物 (117 mg, 67%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.04 (3H, s), 3.58 (2H, s), 3.83 (3H, s), 3.92 (2H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.05-7.7 (14H, m), 8.35-8.45 (2H, m).
IR (KBr): 1713, 1669, 1532, 1464, 1329, 1238, 1032, 787 cm^-1.
元素分析 C₃₅H₃₀F₂N₆O₄S・0.3H₂Oとして
計算値: C, 62.36; H, 4.58; N, 12.47.
実測値: C, 62.22; H, 4.32; N, 12.57.
mp 184-185℃.
実施例１９
N-(4-(1-(2,6-ジフルオロベンジル)-5-((((6-(ヒドロキシメチル)-2-ピリジニル)メチル)(メチル) アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１５の化合物(150 mg, 0.26 mmol)と6-ブロモメチル-2-ピリジンメタノール(105 mg, 0.52 mmol)を用いて、実施例４と同様の反応を行い表題化合物 (115 mg, 63%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.13 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 4.05-4.1 (1H, m), 4.65-4.75 (2H, m), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 6.9-7.05 (1H, m), 7.1-7.2 (2H, m), 7.2-7.7 (12H, m).
IR (KBr): 1713, 1669, 1534, 1472, 1032, 789, 735 cm^-1.
元素分析 C₃₆H₃₂F₂N₆O₅S・1.1H₂Oとして
計算値: C, 60.17; H, 4.80; N, 11.70.
実測値: C, 60.02; H, 4.70; N, 11.53.
実施例２０
メチル 6-((((1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-5-イル)メチル)(メチル)アミノ)メチル)ニコチナートの製造

参考例１５の化合物(280 mg, 0.485 mmol)とメチル6-(ブロモメチル)ニコチネート(0.19 g, 0.825 mmol)を用いて、実施例４と同様の反応を行い表題化合物 (267mg, 76%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.09 (3H, s), 3.76 (2H, s), 3.83 (3H, s), 3.93 (3H, s), 3.99 (2H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.26 (1H, s), 7.2-7.6 (11H, m), 7.64 (1H, s), 8.05-8.15 (1H, m), 9.0-9.05 (1H, s).
IR (KBr): 1732, 1715, 1669, 1526, 1470, 1296, 1032, 789, 735 cm^-1.
元素分析 C₃₇H₃₂F₂N₆O₆Sとして
計算値: C, 61.15; H, 4.44; N, 11.56.
実測値: C, 60.96; H, 4.47; N, 11.52. Example 18
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (3-pyridinylmethyl) amino) methyl) -2,4-dioxo-3-phenyl-1,2,3,4- Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (150 mg, 0.26 mmol) and 3-chloromethylpyridine hydrochloride (85 mg, 0.52 mmol), the same reaction as in Example 4 was carried out to give the title compound (117 mg, 67%). Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.04 (3H, s), 3.58 (2H, s), 3.83 (3H, s), 3.92 (2H, s), 5.37 (2H, s), 6.92 (2H, t , J = 8.2 Hz), 7.05-7.7 (14H, m), 8.35-8.45 (2H, m).
IR (KBr): 1713, 1669, 1532, 1464, 1329, 1238, 1032, 787 cm ^-1 .
Elemental analysis _{C 35 H 30 F 2 N 6} O 4 S · 0.3H 2 O Calculated: C, 62.36; H, 4.58 ; N, 12.47.
Found: C, 62.22; H, 4.32; N, 12.57.
mp 184-185 ° C.
Example 19
N- (4- (1- (2,6-difluorobenzyl) -5-((((6- (hydroxymethyl) -2-pyridinyl) methyl) (methyl) amino) methyl) -2,4-dioxo- Preparation of 3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (150 mg, 0.26 mmol) and 6-bromomethyl-2-pyridinemethanol (105 mg, 0.52 mmol), the same reaction as in Example 4 was performed to give the title compound (115 mg, 63%) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 4.05-4.1 (1H, m), 4.65-4.75 (2H, m), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 6.9-7.05 (1H, m), 7.1-7.2 (2H, m), 7.2-7.7 (12H, m ).
IR (KBr): 1713, 1669, 1534, 1472, 1032, 789, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₆ H ₃₂ F ₂ N ₆ O ₅ S1.1H ₂ O: C, 60.17; H, 4.80; N, 11.70.
Found: C, 60.02; H, 4.70; N, 11.53.
Example 20
Methyl 6-((((1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -2,4-dioxo-3-phenyl-1,2, 3,4-Tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) nicotinate

Using the compound of Reference Example 15 (280 mg, 0.485 mmol) and methyl 6- (bromomethyl) nicotinate (0.19 g, 0.825 mmol), the same reaction as in Example 4 was carried out to give the title compound (267 mg, 76%) as colorless Obtained as crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.09 (3H, s), 3.76 (2H, s), 3.83 (3H, s), 3.93 (3H, s), 3.99 (2H, s), 5.35 (2H, s ), 6.92 (2H, t, J = 8.2 Hz), 7.26 (1H, s), 7.2-7.6 (11H, m), 7.64 (1H, s), 8.05-8.15 (1H, m), 9.0-9.05 ( 1H, s).
IR (KBr): 1732, 1715, 1669, 1526, 1470, 1296, 1032, 789, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₇ H ₃₂ F ₂ N ₆ O ₆ S: C, 61.15; H, 4.44; N, 11.56.
Found: C, 60.96; H, 4.47; N, 11.52.

メチルアミン(2M THF 溶液)(1.38 ml, 2.76 mmol)のジクロロメタン溶液(4 ml)に、氷冷下、エチルジイソプロピルアミン(0.48 ml, 2.76 mmol)とジメチルアルミニウムクロリドのヘキサン溶液(0.98 M, 1.69 ml, 1.656 mmol)を滴下し、室温で30分間攪拌した。さらに実施例２０の化合物(200 mg, 0.275mmol)のジクロロメタン(14 ml)溶液を加え、室温で2日間攪拌した。重曹水を加え、クロロホルムで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー(溶出液；酢酸エチル／メタノール ；40／1)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物 (68mg, 34%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.21(3H, s), 3.00 (3H, d, J = 4.6 Hz), 3.74 (2H, s), 3.84 (3H, s), 3.92 (2H, s), 5.36 (2H, s), 6.5-6.65 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.15-7.6 (12H, m), 7.71 (1H, s), 7.9-8.0 (1H, m), 8.80-8.85 (1H, m).
IR (KBr): 1713, 1665, 1534, 1470, 1327, 1032, 735 cm^-1.
元素分析 C₃₇H₃₃F₂N₇O₅S・1.6H₂Oとして
計算値: C, 58.89; H, 4.84; N, 12.99.
実測値: C, 59.12; H, 5.06; N, 12.66.
実施例２２
エチル 6-((((1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-5-イル)メチル)(メチル)アミノ)メチル)-2-ピリジンカルボキシレートの製造

参考例１５の化合物(578 mg, 1 mmol)とエチル6-ヒドロキシメチル-2-ピリジンカルボキシレート (797 mg, 4.4 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (590 mg, 80%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.40 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.79 (2H, s), 3.83 (3H, s), 4.01(2H, s), 4.43 (2H, q, J = 7.2 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.15 (1H, s), 7.2-7.7 (13H, m), 7.88 (1H, d, J = 7.4 Hz).
IR (KBr): 1717, 1667, 1530, 1464, 1310, 1236, 1032, 747 cm^-1.
元素分析 C₃₈H₃₄F₂N₆O₆Sとして
計算値: C, 61.61; H, 4.63; N, 11.34.
実測値: C, 61.39; H, 4.65; N, 11.17.
実施例２３
6-((((1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-2,4-ジオキソ-3-フェニル-1,2,3,4テトラヒドロチエノ[2,3-d]ピリミジン-5-イル) メチル)(メチル)アミノ)メチル)-N-メチル-2-ピリジンカルボキサミドの製造

実施例２２の化合物(300 mg, 0.413 mmol)とメチルアミンのTHF溶液(2M, 2.07 ml, 4.13 mmol)を用いて、実施例２１と同様の反応を行い表題化合物 (158 mg, 53%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.13 (3H, s), 2.95 (3H, d, J = 5.2 Hz), 3.74 (2H, s), 3.84 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.15-7.7 (13H, m), 7.9-8.1 (3H, m).
IR (KBr): 1719, 1663, 1534, 1472, 1331, 1032, 737 cm^-1.
元素分析 C₃₇H₃₃F₂N₇O₅S・1.0H₂Oとして
計算値: C, 59.75; H, 4.74; N, 13.18.
実測値: C, 59.60; H, 4.77; N, 13.12. Example 21
6-((((1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -2,4-dioxo-3-phenyl-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) -N-methylnicotinamide

To a solution of methylamine (2M in THF) (1.38 ml, 2.76 mmol) in dichloromethane (4 ml), ice-cooled ethyldiisopropylamine (0.48 ml, 2.76 mmol) and dimethylaluminum chloride in hexane (0.98 M, 1.69 ml) , 1.656 mmol) was added dropwise and stirred at room temperature for 30 minutes. Further, a solution of the compound of Example 20 (200 mg, 0.275 mmol) in dichloromethane (14 ml) was added, and the mixture was stirred at room temperature for 2 days. Sodium bicarbonate water 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 NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate / methanol; 40/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound (68 mg, 34% ) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.00 (3H, d, J = 4.6 Hz), 3.74 (2H, s), 3.84 (3H, s), 3.92 (2H, s), 5.36 (2H, s), 6.5-6.65 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.15-7.6 (12H, m), 7.71 (1H, s), 7.9-8.0 (1H, m), 8.80-8.85 (1H, m).
IR (KBr): 1713, 1665, 1534, 1470, 1327, 1032, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₇ H ₃₃ F ₂ N ₇ O ₅ S1.6H ₂ O: C, 58.89; H, 4.84; N, 12.99.
Found: C, 59.12; H, 5.06; N, 12.66.
Example 22
Ethyl 6-((((1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -2,4-dioxo-3-phenyl-1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) -2-pyridinecarboxylate

Using the compound of Reference Example 15 (578 mg, 1 mmol) and ethyl 6-hydroxymethyl-2-pyridinecarboxylate (797 mg, 4.4 mmol), the title compound (590 mg, 80%) was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.79 (2H, s), 3.83 (3H, s), 4.01 (2H, s), 4.43 (2H, q, J = 7.2 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.15 (1H, s), 7.2-7.7 (13H, m), 7.88 (1H , d, J = 7.4 Hz).
IR (KBr): 1717, 1667, 1530, 1464, 1310, 1236, 1032, 747 cm ^-1 .
Elemental analysis Calculated as C ₃₈ H ₃₄ F ₂ N ₆ O ₆ S: C, 61.61; H, 4.63; N, 11.34.
Found: C, 61.39; H, 4.65; N, 11.17.
Example 23
6-((((1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -2,4-dioxo-3-phenyl-1,2,3 , 4 Tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) methyl) -N-methyl-2-pyridinecarboxamide

Using the compound of Example 22 (300 mg, 0.413 mmol) and methylamine in THF (2M, 2.07 ml, 4.13 mmol), the same reaction as in Example 21 was carried out to give the title compound (158 mg, 53%). Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.95 (3H, d, J = 5.2 Hz), 3.74 (2H, s), 3.84 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.15-7.7 (13H, m), 7.9-8.1 (3H, m).
IR (KBr): 1719, 1663, 1534, 1472, 1331, 1032, 737 cm ^-1 .
Elemental analysis Calculated as C ₃₇ H ₃₃ F ₂ N ₇ O ₅ S1.0H ₂ O: C, 59.75; H, 4.74; N, 13.18.
Found: C, 59.60; H, 4.77; N, 13.12.

参考例１５の化合物(289 mg, 0.5 mmol)をDMF(30 ml)に溶解し、エチルジイソプロピルアミン(0.44 ml, 2.5 mmol)と1-ブロモ-2-クロロエタン(0.17 ml, 2.5 mmol)を加え、50-60℃で１時間攪拌した。重曹水を加え、酢酸エチルで抽出した。有機層を集め、硫酸マグネシウムで乾燥後、減圧濃縮し、ハライドを得た。得られたハライド、イミダゾール(177 mg, 2.6 mmol)、炭酸カリウム(72 mg, 0.52 mmol)のDMF溶液(4 ml)を室温で18時間、さらに50-60℃で１時間攪拌後、水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー(溶出液；酢酸エチル／メタノール；80／1から20／1)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物(40 mg, 23%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.17 (3H, s), 2.6-2.8 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.78 (1H, s), 6.85-7.0 (3H, m), 7.2-7.6 (12H, m), 7.71 (1H, s).
実施例２５
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-(2-(2-ヒドロキシエチル)-1H-イミダゾール-1-イル)エチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１５の化合物(289 mg, 0.5 mmol)と2-(2-ヒドロキシエチル)イミダゾール(292 mg, 2.6 mmol) を用いて、実施例２４ と同様の反応を行い表題化合物 (19 mg, 10%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.9-2.1 (2H, m), 2.16 (3H, s), 2.6-2.8 (4H, m), 3.78 (2H, s), 3.83 (2H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.70 (1H, s), 6.80 (1H, s), 6.94 (2H, t, J = 8.0 Hz), 7.2-7.6 (11H, m), 7.73 (1H, s).
実施例２６
2-(4-(1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-5-((メチル(2-ピリジニルメチル)アミノ)メチル)-2,4-ジオキソ-1,4-ジヒドロチエノ[2,3-d]ピリミジン-3(2H)-イル)フェノキシ)-N-メチルアセタミドの製造

参考例３の化合物 (320 mg, 0.5 mmol) と4-アミノフェノキシ-N-メチルアセタミド(135 mg, 0.75 mmol)を用いて、実施例５と同様の反応を行い表題化合物 (192 mg, 51%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.09 (3H, s), 2.93 (3H, d, J = 4.8 Hz), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 4.55 (2H, s), 5.35 (2H, s), 6.55-6.65 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.0-7.65 (14H, m), 8.44 (1H, d, J = 6.0 Hz).
IR (KBr): 1721, 1669, 1532, 1472, 1236, 1032, 764 cm^-1.
元素分析 C₃₈H₃₅F₂N₇O₆S・0.5H₂Oとして
計算値: C, 59.68; H, 4.74; N, 12.82.
実測値: C, 59.51; H, 4.66; N, 12.68. Example 24
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-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound of Reference Example 15 (289 mg, 0.5 mmol) was dissolved in DMF (30 ml), ethyldiisopropylamine (0.44 ml, 2.5 mmol) and 1-bromo-2-chloroethane (0.17 ml, 2.5 mmol) were added, The mixture was stirred at 50-60 ° C for 1 hour. Sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a halide. The resulting halide, imidazole (177 mg, 2.6 mmol), potassium carbonate (72 mg, 0.52 mmol) in DMF (4 ml) was stirred at room temperature for 18 hours and further at 50-60 ° C for 1 hour, and then water was added. And 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 NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate / methanol; 80/1 to 20/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound ( 40 mg, 23%) was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.6-2.8 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.78 (1H, s), 6.85-7.0 (3H, m), 7.2-7.6 (12H, m), 7.71 (1H, s).
Example 25
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-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (289 mg, 0.5 mmol) and 2- (2-hydroxyethyl) imidazole (292 mg, 2.6 mmol), the title compound (19 mg, 10% ) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.9-2.1 (2H, m), 2.16 (3H, s), 2.6-2.8 (4H, m), 3.78 (2H, s), 3.83 (2H, s), 3.9 -4.0 (2H, m), 5.38 (2H, s), 6.70 (1H, s), 6.80 (1H, s), 6.94 (2H, t, J = 8.0 Hz), 7.2-7.6 (11H, m), 7.73 (1H, s).
Example 26
2- (4- (1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -5-((methyl (2-pyridinylmethyl) amino) methyl)- Preparation of 2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenoxy) -N-methylacetamide

Using the compound of Reference Example 3 (320 mg, 0.5 mmol) and 4-aminophenoxy-N-methylacetamide (135 mg, 0.75 mmol), the same reaction as in Example 5 was carried out to give the title compound (192 mg, 51%) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.09 (3H, s), 2.93 (3H, d, J = 4.8 Hz), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 4.55 (2H, s), 5.35 (2H, s), 6.55-6.65 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.0-7.65 (14H, m), 8.44 (1H, d, J = 6.0 Hz).
IR (KBr): 1721, 1669, 1532, 1472, 1236, 1032, 764 cm ^-1 .
Elemental analysis Calculated as C ₃₈ H ₃₅ F ₂ N ₇ O ₆ S0.5H ₂ O: C, 59.68; H, 4.74; N, 12.82.
Found: C, 59.51; H, 4.66; N, 12.68.

参考例３の化合物 (320 mg, 0.5 mmol) と4-アミノフェニル-N-エチルアセタミド(134 mg, 0.75 mmol)を用いて、実施例５と同様の反応を行い表題化合物 (145 mg, 38%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.10 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.2-3.4 (2H, m), 3.64 (2H, s), 3.72 (2H, s), 3.83 (3H, s), 3.98 (2H, s), 5.36 (2H, s), 5.45-5.55 (1H, m), 6.93 (2H, t, J = 8.0 Hz), 7.0-7.1 (1H, m), 7.16 (1H, s), 7.25-7.7 (12H, m), 8.44 (1H, d, J = 4.0 Hz).
IR (KBr): 1721, 1672, 1534, 1470, 1032, 762 cm^-1.
元素分析 C₃₉H₃₇F₂N₇O₅S・0.5H₂Oとして
計算値: C, 61.41; H, 5.02; N, 12.85.
実測値: C, 61.44; H, 4.90; N, 12.75.
実施例２８
メチル3-(1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-5-((メチル(2-ピリジニルメチル)アミノ)メチル)-2,4-ジオキソ-1,4-ジヒドロチエノ[2,3-d]ピリミジン-3(2H)-イル)プロパナートの製造

参考例３の化合物(320 mg, 0.5 mmol) とβ-アラニンメチルエステル(115 mg, 0.75 mmol)を用いて、実施例５と同様の反応を行い表題化合物 (255 mg, 75%)を淡黄色アモルファスとして得た。
¹H-NMR(CDCl₃) δ: 2.10 (3H, s), 2.65-2.8 (2H, m), 3.68 (3H, s), 3.72 (2H, s),3.83 (3H, s), 3.98 (2H, s), 4.3-4.5 (2H, m), 5.31 (2H, s), 6.91 (2H, t, J = 7.6 Hz), 7.0-7.4 (5H, m), 7.45-7.65 (5H, m), 8.4-8.5 (1H, m).
実施例２９
3-(1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-5-((メチル(2-ピリジニルメチル)アミノ)メチル)-2,4-ジオキソ-1,4-ジヒドロチエノ[2,3-d]ピリミジン-3(2H)-イル)-N,N-ジメチルプロパンアミドの製造

実施例２８の化合物(300 mg, 0.413 mmol)とジメチルアミンのTHF溶液(2M)(1.63 ml, 3.26 mmol)を用いて、実施例２１と同様の反応を行い表題化合物 (73 mg, 33%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.09 (3H, s), 2.75 (3H, d, J = 7.8 Hz), 2.94 (3H, s), 3.02 (3H, s), 3.73 (2H, s), 3.83 (3H, s), 4.07 (2H, s), 4.40 (2H, t, J = 7.8 Hz), 5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.35 (5H, m), 7.5-7.65 (5H, m), 8.45 (1H, d, J = 4.0 Hz).
IR (KBr): 1703, 1659, 1530, 1472, 1321, 1034, 779 cm^-1.
元素分析 C₃₄H₃₅F₂N₇O₅S・1.0H₂Oとして
計算値: C, 57.54; H, 5.25; N, 13.81.
実測値: C, 57.56; H, 5.05; N, 13.59. Example 27
2- (4- (1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -5-((methyl (2-pyridinylmethyl) amino) methyl)- Preparation of 2,4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) phenyl) -N-ethylacetamide

Using the compound of Reference Example 3 (320 mg, 0.5 mmol) and 4-aminophenyl-N-ethylacetamide (134 mg, 0.75 mmol), the same reaction as in Example 5 was performed to give the title compound (145 mg, 38%) Was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.2-3.4 (2H, m), 3.64 (2H, s), 3.72 (2H, s ), 3.83 (3H, s), 3.98 (2H, s), 5.36 (2H, s), 5.45-5.55 (1H, m), 6.93 (2H, t, J = 8.0 Hz), 7.0-7.1 (1H, m), 7.16 (1H, s), 7.25-7.7 (12H, m), 8.44 (1H, d, J = 4.0 Hz).
IR (KBr): 1721, 1672, 1534, 1470, 1032, 762 cm ^-1 .
Elemental analysis _{C 39 H 37 F 2 N 7} O 5 S · 0.5H 2 O Calculated: C, 61.41; H, 5.02 ; N, 12.85.
Found: C, 61.44; H, 4.90; N, 12.75.
Example 28
Methyl 3- (1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2, Preparation of 4-dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) propanate

Using the compound of Reference Example 3 (320 mg, 0.5 mmol) and β-alanine methyl ester (115 mg, 0.75 mmol), the same reaction as in Example 5 was carried out to give the title compound (255 mg, 75%) as pale yellow Obtained as amorphous.
¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, s), 2.65-2.8 (2H, m), 3.68 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.98 (2H , s), 4.3-4.5 (2H, m), 5.31 (2H, s), 6.91 (2H, t, J = 7.6 Hz), 7.0-7.4 (5H, m), 7.45-7.65 (5H, m), 8.4-8.5 (1H, m).
Example 29
3- (1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2,4 Of 2-Dioxo-1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) -N, N-dimethylpropanamide

Using the compound of Example 28 (300 mg, 0.413 mmol) and dimethylamine in THF (2M) (1.63 ml, 3.26 mmol), the same reaction as in Example 21 was carried out to give the title compound (73 mg, 33%) Was obtained as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 2.09 (3H, s), 2.75 (3H, d, J = 7.8 Hz), 2.94 (3H, s), 3.02 (3H, s), 3.73 (2H, s), 3.83 (3H, s), 4.07 (2H, s), 4.40 (2H, t, J = 7.8 Hz), 5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.35 (5H , m), 7.5-7.65 (5H, m), 8.45 (1H, d, J = 4.0 Hz).
IR (KBr): 1703, 1659, 1530, 1472, 1321, 1034, 779 cm ^-1 .
Elemental analysis Calculated as C ₃₄ H ₃₅ F ₂ N ₇ O ₅ S ・ 1.0H ₂ O: C, 57.54; H, 5.25; N, 13.81.
Found: C, 57.56; H, 5.05; N, 13.59.

実施例２８の化合物(320 mg, 0.5 mmol) と4-アミノシクロヘキサノール(86 mg, 0.75 mmol)を用いて、実施例５と同様の反応を行い表題化合物 (154 mg, 45%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.4-1.8 (4H, m), 2.0-2.1 (2H, m), 2.12 (3H, s), 2.55-2.75 (2H, m), 3.73 (2H, s), 3.7-3.8 (1H, m), 3.82 (3H, s), 3.98 (2H, s), 4.9-5.1 (1H, brm), 5.29 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.4 (7H, m), 7.45-7.65 (5H, m), 8.45 (1H, d, J = 4.8 Hz).
IR (KBr): 1705, 1659, 1530, 1470, 1312, 1236, 1069, 1034, 783 cm^-1.
元素分析 C₃₅H₃₆F₂N₆O₅S・1.5H₂Oとして
計算値: C, 58.57; H, 5.48; N, 11.71.
実測値: C, 58.65; H, 5.35; N, 11.64.
実施例３１
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-(2H-テトラゾール-2-イル)エチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(1)

N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-(1H-テトラゾール-1-イル)エチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造(2)

テトラゾール(0.70 g, 10 mmol)、1-ブロモ-2-クロロエタン(1.25 ml, 15 mmol)の DMF溶液(5 ml)に炭酸カリウム(2.075 g, 15 mmol)を加え、室温で16時間攪拌した。飽和食塩水を加え、酢酸エチルで2回抽出した。有機層を集め、硫酸マグネシウムで乾燥後、減圧濃縮し、ハライド(4.23 g, DMFを含む)を得た。
参考例１５の化合物(578 mg, 1 mmol)をDMF(10 ml)に溶解し、N,N-ジイソプロピルエチルアミン(1.16 ml, 6.67 mmol)と上記で得られたハライドを加え、60-70℃で16時間攪拌した。重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；酢酸エチル／ヘキサン；9／1)により精製し、さらにジクロロメタン／メタノール／ジエチルエーテルから再結晶し、表題化合物2-イル体(80 mg, 12%)と1-イル体(38 mg, 57%)を無色結晶として得た。
2-イル体(1)
¹H-NMR(CDCl₃) δ: 2.25 (3H, s), 3.04 (2H, t, J = 6.2 Hz), 3.78 (2H, s), 3.83 (3H, s), 4.66 (2H, t, J = 6.2 Hz), 5.38 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.16 (1H, s), 7.2-7.6 (10H, m), 7.64 (1H, s), 8.30 (1H, s).
IR (KBr): 1713, 1669, 1530, 1470, 1325, 1032, 735 cm^-1.
元素分析 C₃₂H₂₉F₂N₉O₄S・0.5H₂Oとして
計算値: C, 56.30; H, 4.43; N, 18.46.
実測値: C, 56.18; H, 4.42; N, 18.19.
1-イル体(2)
¹H-NMR(CDCl₃) δ: 2.02 (3H, s), 2.7-2.8 (2H, m), 3.78 (2H, s), 3.83 (3H, s), 4.4-4.5 (2H, m), 5.38 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.17 (1H, s), 7.25-7.65 (10H, m), 7.66 (1H, s).
IR (KBr): 1713, 1669, 1530, 1470, 1327, 1236, 1032, 735 cm^-1.
元素分析 C₃₂H₂₉F₂N₉O₄S・0.5H₂Oとして
計算値: C, 56.30; H, 4.43; N, 18.46.
実測値: C, 56.54; H,4.30; N, 18.27.
実施例３２
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシエチル)-5-((メチル(2-ピリジニルメチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例３の化合物 (410 mg, 0.64 mmol) と2-アミノエタノール(0.06 ml, 0.96 mmol)を用いて、実施例５と同様の反応を行い表題化合物 (76 mg, 19%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.22 (3H, s), 3.3-3.5 (1H, br), 3.78 (2H, s), 3.83 (3H, s), 3.9-4.05 (2H, m), 3.99 (2H, s), 4.35-4.4 (2H, m), 5.27 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 6.9-7.1 (1H, m), 7.15 (1H, s), 7.2-7.65 (8H, m), 8.35-8.4 (1H, m).
IR (KBr): 1709, 1649, 1470, 1323, 1030, 787 cm^-1.
元素分析 C₃₁H₃₀F₂N₆O₅S・0.5H₂Oとして
計算値: C, 57.67; H, 4.84; N, 13.02.
実測値: C, 57.77; H, 4.90; N, 12.82. Example 30
N- (4- (1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2,4-dioxo-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Example 28 (320 mg, 0.5 mmol) and 4-aminocyclohexanol (86 mg, 0.75 mmol), the same reaction as in Example 5 was carried out to give the title compound (154 mg, 45%) as colorless crystals. Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.4-1.8 (4H, m), 2.0-2.1 (2H, m), 2.12 (3H, s), 2.55-2.75 (2H, m), 3.73 (2H, s) , 3.7-3.8 (1H, m), 3.82 (3H, s), 3.98 (2H, s), 4.9-5.1 (1H, brm), 5.29 (2H, s), 6.91 (2H, t, J = 8.2 Hz ), 7.0-7.4 (7H, m), 7.45-7.65 (5H, m), 8.45 (1H, d, J = 4.8 Hz).
IR (KBr): 1705, 1659, 1530, 1470, 1312, 1236, 1069, 1034, 783 cm ^-1 .
Elemental analysis Calculated as C ₃₅ H ₃₆ F ₂ N ₆ O ₅ S1.5H ₂ O: C, 58.57; H, 5.48; N, 11.71.
Found: C, 58.65; H, 5.35; N, 11.64.
Example 31
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (2H-tetrazol-2-yl) ethyl) amino) methyl) -2,4-dioxo-3-phenyl -1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (1)

N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (2- (1H-tetrazol-1-yl) ethyl) amino) methyl) -2,4-dioxo-3-phenyl -1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (2)

Potassium carbonate (2.075 g, 15 mmol) was added to a DMF solution (5 ml) of tetrazole (0.70 g, 10 mmol) and 1-bromo-2-chloroethane (1.25 ml, 15 mmol), and the mixture was stirred at room temperature for 16 hours. Saturated brine was added, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a halide (4.23 g, containing DMF).
The compound of Reference Example 15 (578 mg, 1 mmol) was dissolved in DMF (10 ml), N, N-diisopropylethylamine (1.16 ml, 6.67 mmol) and the halide obtained above were added, and the mixture was heated at 60-70 ° C. Stir for 16 hours. Sodium bicarbonate 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 / hexane; 9/1) and recrystallized from dichloromethane / methanol / diethyl ether to give the title compound 2-yl compound (80 mg, 12%) and 1 -The yl form (38 mg, 57%) was obtained as colorless crystals.
2-Ile body (1)
¹ H-NMR (CDCl ₃ ) δ: 2.25 (3H, s), 3.04 (2H, t, J = 6.2 Hz), 3.78 (2H, s), 3.83 (3H, s), 4.66 (2H, t, J = 6.2 Hz), 5.38 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.16 (1H, s), 7.2-7.6 (10H, m), 7.64 (1H, s), 8.30 (1H , s).
IR (KBr): 1713, 1669, 1530, 1470, 1325, 1032, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₂ H ₂₉ F ₂ N ₉ O ₄ S ・ 0.5H ₂ O: C, 56.30; H, 4.43; N, 18.46.
Found: C, 56.18; H, 4.42; N, 18.19.
1-il body (2)
¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 2.7-2.8 (2H, m), 3.78 (2H, s), 3.83 (3H, s), 4.4-4.5 (2H, m), 5.38 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.17 (1H, s), 7.25-7.65 (10H, m), 7.66 (1H, s).
IR (KBr): 1713, 1669, 1530, 1470, 1327, 1236, 1032, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₂ H ₂₉ F ₂ N ₉ O ₄ S ・ 0.5H ₂ O: C, 56.30; H, 4.43; N, 18.46.
Found: C, 56.54; H, 4.30; N, 18.27.
Example 32
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxyethyl) -5-((methyl (2-pyridinylmethyl) amino) methyl) -2,4-dioxo-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 3 (410 mg, 0.64 mmol) and 2-aminoethanol (0.06 ml, 0.96 mmol), the same reaction as in Example 5 was carried out to give the title compound (76 mg, 19%) as colorless crystals. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.3-3.5 (1H, br), 3.78 (2H, s), 3.83 (3H, s), 3.9-4.05 (2H, m), 3.99 (2H, s), 4.35-4.4 (2H, m), 5.27 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 6.9-7.1 (1H, m), 7.15 (1H, s), 7.2-7.65 (8H, m), 8.35-8.4 (1H, m).
IR (KBr): 1709, 1649, 1470, 1323, 1030, 787 cm ^-1 .
Elemental analysis Calculated as C ₃₁ H ₃₀ F ₂ N ₆ O ₅ S0.5H ₂ O: C, 57.67; H, 4.84; N, 13.02.
Found: C, 57.77; H, 4.90; N, 12.82.

参考例１５の化合物 (404 mg, 0.7 mmol) と1-(3-ヒドロキシプロピル)-2-ピロリドン(0.55 g, 3.85 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (322 mg, 66%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.5-1.7 (2H, m), 1.8-2.0 (2H, m), 2.05 (3H, s), 2.25-2.45 (4H, m), 3.15 (2H, t, J = 7.8 Hz), 3.23 (2H, t, J = 7.2 Hz), 3.76 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.15 (1H, s), 7.2-7.6 (10H, m), 7.67 (1H, s).
IR (KBr): 1715, 1671, 1532, 1470, 1327, 1032, 735 cm^-1.
元素分析 C₃₆H₃₆F₂N₆O₅S・1.0H₂Oとして
計算値: C, 59.99; H, 5.31; N, 11.66.
実測値: C, 60.21; H, 5.18; N, 11.74.
mp 128-129℃
実施例３４
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(2-(2-オキソ-1-ピロリジニル)エチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１５の化合物 (404 mg, 0.7 mmol) と1-(3-ヒドロキシエチル)-2-ピロリドン(0.50 g, 3.85 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (290 mg, 60%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.7-1.85 (2H, m), 2.14 (3H, s), 2.21 (2H, t, J = 8.1 Hz), 2.54 (2H, t, J = 6.2 Hz), 3.19 (2H, t, J = 7.0 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77 (2H, s), 3.83 (3H, s), 5.38 (2H, s), 6.93 (2H, t, J = 8.1 Hz), 7.18 (1H, s), 7.25-7.7 (11H, m).
IR (KBr): 1715, 1672, 1530, 1470, 1323, 1238, 1032, 735 cm^-1.
元素分析 C₃₅H₃₄F₂N₆O₅S・0.5H₂Oとして
計算値: C, 60.25; H, 5.06; N, 12.04.
実測値: C, 60.29; H, 5.04; N, 12.13.
mp 134-136℃
実施例３５
N-(4-(1-(2,6-ジフルオロベンジル)-3-(4-フルオロフェニル)-5-((メチル(2-(2-オキソ-1-ピロリジニル)エチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d] ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１７の化合物 (350 mg, 0.588 mmol) と1-(3-ヒドロキシエチル)-2-ピロリドン(0.50 g, 3.85 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (283 mg, 68%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.7-1.9 (2H, m), 2.15 (3H, s), 2.15-2.3 (2H, m), 2.52 (2H, t, J = 6.2 Hz), 3.20 (2H, t, J = 6.8 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.35 (6H, m), 7.5-7.65 (4H, m), 7.64 (1H, s).
IR (KBr): 1723, 1667, 1532, 1472, 1236, 1034, 837, 762 cm^-1.
元素分析 C₃₅H₃₃F₃N₆O₅S・0.5H₂Oとして
計算値: C, 58.73; H, 4.79; N, 11.74.
実測値: C, 58.99; H, 4.98; N, 11.92.
mp 198-200℃ Example 33
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (3- (2-oxo-1-pyrrolidinyl) propyl) amino) methyl) -2,4-dioxo-3-phenyl -1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (404 mg, 0.7 mmol) and 1- (3-hydroxypropyl) -2-pyrrolidone (0.55 g, 3.85 mmol), the same reaction as in Example 2 was performed to give the title compound (322 mg , 66%) as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.5-1.7 (2H, m), 1.8-2.0 (2H, m), 2.05 (3H, s), 2.25-2.45 (4H, m), 3.15 (2H, t, J = 7.8 Hz), 3.23 (2H, t, J = 7.2 Hz), 3.76 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.0 Hz) , 7.15 (1H, s), 7.2-7.6 (10H, m), 7.67 (1H, s).
IR (KBr): 1715, 1671, 1532, 1470, 1327, 1032, 735 cm ^-1 .
Elemental analysis Calculated as C ₃₆ H ₃₆ F ₂ N ₆ O ₅ S ・ 1.0H ₂ O: C, 59.99; H, 5.31; N, 11.66.
Found: C, 60.21; H, 5.18; N, 11.74.
mp 128-129 ℃
Example 34
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-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (404 mg, 0.7 mmol) and 1- (3-hydroxyethyl) -2-pyrrolidone (0.50 g, 3.85 mmol), the same reaction as in Example 2 was carried out to give the title compound (290 mg , 60%) was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.7-1.85 (2H, m), 2.14 (3H, s), 2.21 (2H, t, J = 8.1 Hz), 2.54 (2H, t, J = 6.2 Hz), 3.19 (2H, t, J = 7.0 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77 (2H, s), 3.83 (3H, s), 5.38 (2H, s), 6.93 (2H, t , J = 8.1 Hz), 7.18 (1H, s), 7.25-7.7 (11H, m).
IR (KBr): 1715, 1672, 1530, 1470, 1323, 1238, 1032, 735 cm ^-1 .
Elemental analysis _{C 35 H 34 F 2 N 6} O 5 S · 0.5H 2 O Calculated: C, 60.25; H, 5.06 ; N, 12.04.
Found: C, 60.29; H, 5.04; N, 12.13.
mp 134-136 ℃
Example 35
N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (2- (2-oxo-1-pyrrolidinyl) ethyl) amino) methyl)- Preparation of 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 17 (350 mg, 0.588 mmol) and 1- (3-hydroxyethyl) -2-pyrrolidone (0.50 g, 3.85 mmol), the same reaction as in Example 2 was carried out to give the title compound (283 mg , 68%) as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.7-1.9 (2H, m), 2.15 (3H, s), 2.15-2.3 (2H, m), 2.52 (2H, t, J = 6.2 Hz), 3.20 (2H , t, J = 6.8 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.35 (6H, m), 7.5-7.65 (4H, m), 7.64 (1H, s).
IR (KBr): 1723, 1667, 1532, 1472, 1236, 1034, 837, 762 cm ^-1 .
Elemental analysis _{C 35 H 33 F 3 N 6} O 5 S · 0.5H 2 O Calculated: C, 58.73; H, 4.79 ; N, 11.74.
Found: C, 58.99; H, 4.98; N, 11.92.
mp 198-200 ℃

参考例１７の化合物 (350 mg, 0.588 mmol) と2-メチルアミノエタノール(0.29 g, 3.85 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (263 mg, 61%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.13 (3H, s), 2.55 (2H, t, J = 6.4 Hz), 2.70 (3H, s), 2.71 (3H, s), 3.15 (2H, t, J = 6.4 Hz), 3.81 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.7 (11H, m).
IR (KBr): 1725, 1663, 1534, 1474, 1331, 1236, 1142, 1034, 793 cm^-1.
元素分析 C₃₃H₃₃F₃N₆O₆S₂として
計算値: C, 54.24; H, 4.55; N, 11.50.
実測値: C, 54.10; H, 4.45; N, 11.36.
mp 218-220℃
実施例３７
N-(4-(1-(2,6-ジフルオロベンジル)-5-((メチル(((2S)-1-(メチルスルホニル)-2-ピロリジニル)メチル)アミノ)メチル)-2,4-ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d] ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１５の化合物 (404 mg, 0.7 mmol) と(L)-2-ヒドロキシメチルピロリジン(0.39 g, 3.85 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (262mg, 51%)を無色結晶として得た。
¹H-NMR (CDCl₃) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.7 (11H, m).
IR (KBr): 1713, 1667, 1528, 1470, 1333, 1148, 1030, 785 cm^-1.
元素分析 C₃₅H₃₆F₂N₆O₆S₂として
計算値: C, 56.90; H, 4.91; N, 11.37.
実測値: C, 56.55; H, 4.87; N, 11.23.
mp 195-197℃
実施例３８
N-(4-(1-(2,6-ジフルオロベンジル)-3-(4-フルオロフェニル)-5-((メチル(((2S)-1-(メチルスルホニル)-2-ピロリジニル)メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d] ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１７の化合物 (400 mg, 0.672 mmol) と(L)-2-ヒドロキシメチルピロリジン(0.39 g, 3.85 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (222 mg, 44%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.7-1.85 (4H, m), 2.09 (3H, s), 2.25-2.35 (1H, m), 2.55-2.65 (1H, m), 2.71 (3H, s), 3.15-3.3 (2H, m), 3.65-3.7 (2H, m), 3.74 (1H, d, J = 12.0 Hz), 3.83 (3H, s), 3.87 (1H, d, J = 12.0 Hz), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.1-7.35 (5H, m), 7.49 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.62 (1H, s).
IR (KBr): 1715, 1667, 1530, 1470, 1333, 1236, 1152, 1032, 795 cm^-1.
元素分析 C₃₅H₃₅F₃N₆O₆S₂として
計算値: C, 55.55; H, 4.66; N, 11.10.
実測値: C, 55.42; H, 4.45; N, 11.01.
mp 202-204℃ Example 36
N- (2-(((1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -2,4- Preparation of dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) ethyl) -N-methylmethanesulfonamide

The same reaction as in Example 2 was carried out using the compound of Reference Example 17 (350 mg, 0.588 mmol) and 2-methylaminoethanol (0.29 g, 3.85 mmol) to give the title compound (263 mg, 61%) as pale yellow Obtained as crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.55 (2H, t, J = 6.4 Hz), 2.70 (3H, s), 2.71 (3H, s), 3.15 (2H, t, J = 6.4 Hz), 3.81 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.7 (11H, m).
IR (KBr): 1725, 1663, 1534, 1474, 1331, 1236, 1142, 1034, 793 cm ^-1 .
Elemental analysis Calculated as C ₃₃ H ₃₃ F ₃ N ₆ O ₆ S ₂ : C, 54.24; H, 4.55; N, 11.50.
Found: C, 54.10; H, 4.45; N, 11.36.
mp 218-220 ℃
Example 37
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (((2S) -1- (methylsulfonyl) -2-pyrrolidinyl) methyl) amino) methyl) -2,4- Preparation of dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (404 mg, 0.7 mmol) and (L) -2-hydroxymethylpyrrolidine (0.39 g, 3.85 mmol), the same reaction as in Example 2 was performed to give the title compound (262 mg, 51%) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65 (1H, m), 2.72 (3H, s) , 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s ), 7.2-7.7 (11H, m).
IR (KBr): 1713, 1667, 1528, 1470, 1333, 1148, 1030, 785 cm ^-1 .
Elemental analysis _{C 35 H 36 F 2 N 6} O 6 S 2 Calculated: C, 56.90; H, 4.91 ; N, 11.37.
Found: C, 56.55; H, 4.87; N, 11.23.
mp 195-197 ℃
Example 38
N- (4- (1- (2,6-difluorobenzyl) -3- (4-fluorophenyl) -5-((methyl (((2S) -1- (methylsulfonyl) -2-pyrrolidinyl) methyl) Amino) methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 17 (400 mg, 0.672 mmol) and (L) -2-hydroxymethylpyrrolidine (0.39 g, 3.85 mmol), the title compound (222 mg, 44% ) Was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.7-1.85 (4H, m), 2.09 (3H, s), 2.25-2.35 (1H, m), 2.55-2.65 (1H, m), 2.71 (3H, s) , 3.15-3.3 (2H, m), 3.65-3.7 (2H, m), 3.74 (1H, d, J = 12.0 Hz), 3.83 (3H, s), 3.87 (1H, d, J = 12.0 Hz), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.1-7.35 (5H, m), 7.49 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.62 (1H, s).
IR (KBr): 1715, 1667, 1530, 1470, 1333, 1236, 1152, 1032, 795 cm ^-1 .
Elemental analysis _{C 35 H 35 F 3 N 6} O 6 S 2 Calculated: C, 55.55; H, 4.66 ; N, 11.10.
Found: C, 55.42; H, 4.45; N, 11.01.
mp 202-204 ℃

参考例１５の化合物 (188 mg, 0.325 mmol) と(R)-2-ヒドロキシメチルピロリジン(0.14 g, 1.38 mmol)を用いて、実施例２と同様の反応を行い表題化合物 (136 mg, 57%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.7 (11H, m).
IR (KBr): 1713, 1665, 1530, 1470, 1333, 1148, 1030, 785 cm^-1.
元素分析 C₃₅H₃₆F₂N₆O₆S₂・0.5H₂Oとして
計算値: C, 56.21; H, 4.99; N, 11.24.
実測値: C, 56.29; H, 4.79; N, 11.11.
mp 208-210℃
実施例４０
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(2-ピリジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例７で得られた化合物(607 mg)、2-アミノピリジン(142 mg)のDMF(10 ml)溶液に氷冷下、シアノりん酸ジエチル(245 mg)、N−エチルジイソプロピルアミン(284 μl)を加え、徐々に室温に戻して13時間攪拌後、反応液を酢酸エチル/水で分配した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去して得られた残渣をアミノプロピルシリカゲル（富士シリシア化学製）のクロマトグラフィーで粗精製し、得られた粗アミド体(350 mg)をエタノール(25.5 ml)に溶解し、28%-ナトリウムメトキシドのメタノール溶液(196 mg)を加えて室温15時間攪拌した。1規定-塩酸(1 ml)で中和後、溶媒を留去し、残渣を酢酸エチル/水で分配した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去して得られた残渣をアミノプロピルシリカゲル（富士シリシア化学製）のクロマトグラフィー（45 g；展開液；酢酸エチル/ヘキサン：7/3→酢酸エチル）で精製し、THF-エタノールで再結晶することにより表題化合物(210 mg)を無色結晶として得た。
元素分析 C₃₁H₃₀N₆O₅SF₂として
計算値：C, 58.48; H, 4.75; N, 13.20.
実測値：C, 58.46; H, 4.68; N, 12.93.
¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 (3H, s), 3.81 (2H, brs), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.24-7.40 (4H, m), 7.53 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.65 (1H, s), 7.88 (1H, dt, J = 1.5 Hz, 7.8 Hz), 8.67-8.69 (1H, m).
IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm^-1. Example 39
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (((2R) -1- (methylsulfonyl) -2-pyrrolidinyl) methyl) amino) methyl) -2,4- Preparation of dioxo-3-phenyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 15 (188 mg, 0.325 mmol) and (R) -2-hydroxymethylpyrrolidine (0.14 g, 1.38 mmol), the title compound (136 mg, 57% ) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65 (1H, m), 2.72 (3H, s) , 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s ), 7.2-7.7 (11H, m).
IR (KBr): 1713, 1665, 1530, 1470, 1333, 1148, 1030, 785 cm ^-1 .
Elemental analysis Calculated as C ₃₅ H ₃₆ F ₂ N ₆ O ₆ S ₂ 0.5H ₂ O: C, 56.21; H, 4.99; N, 11.24.
Found: C, 56.29; H, 4.79; N, 11.11.
mp 208-210 ℃
Example 40
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

To a solution of the compound obtained in Reference Example 7 (607 mg) and 2-aminopyridine (142 mg) in DMF (10 ml) was added ice-cooled diethyl cyanophosphate (245 mg), N-ethyldiisopropylamine (284 μl). The mixture was gradually warmed to room temperature and 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 residue obtained by distilling off the solvent under reduced pressure was roughly purified by chromatography on aminopropyl silica gel (Fuji Silysia Chemical), and the resulting crude amide (350 mg) was dissolved in ethanol (25.5 ml). Then, a methanol solution (196 mg) of 28% -sodium methoxide was added and stirred at room temperature for 15 hours. After neutralization with 1N-hydrochloric acid (1 ml), the solvent was distilled off, 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 residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on aminopropyl silica gel (manufactured by Fuji Silysia Chemical) (45 g; developing solution; ethyl acetate / hexane: 7/3 → ethyl acetate). -Recrystallization from ethanol gave the title compound (210 mg) as colorless crystals.
Elemental analysis Calculated as C ₃₁ H ₃₀ N ₆ O ₅ SF ₂ : C, 58.48; H, 4.75; N, 13.20.
Found: C, 58.46; H, 4.68; N, 12.93.
¹ H-NMR (CDCl ₃ ) δ: 2.15 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 ( 3H, s), 3.81 (2H, brs), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.24-7.40 (4H, m), 7.53 (2H, d, J = 8.4 Hz ), 7.62 (2H, d, J = 8.4 Hz), 7.65 (1H, s), 7.88 (1H, dt, J = 1.5 Hz, 7.8 Hz), 8.67-8.69 (1H, m).
IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm ^-1 .

参考例１４の化合物(251 mg)のDMF溶液(4.3 ml)に2-エトキシエチルクロリド(141 mg)、N−エチルジイソプロピルアミン(245 μl)、ヨウ化カリウム(107 mg)を加えて60℃で24時間攪拌した。反応液を酢酸エチル/水で分配し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後の残渣をアミノプロピルシリカゲル（富士シリシア化学製）のクロマトグラフィー（45 g；展開液；酢酸エチル/ヘキサン：3/2→4/1）で精製し、酢酸エチルで再結晶することにより表題化合物(62 mg)を無色結晶として得た。
元素分析 C₃₂H₃₂N₆O₅SF₂・0.1AcOEtとして
計算値：C, 59.01; H, 5.01; N, 12.74.
実測値：C, 59.11; H, 5.13; N, 12.55.
¹H-NMR (CDCl₃) δ: 1.13 (3H, t, J = 6.9 Hz), 2.15 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.39 (2H, q, J = 6.9 Hz), 3.44 (2H, t, J = 6.2 Hz), 3.80 (2H, brs), 3.81 (3H, s), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.19 (1H, s), 7.27-7.32 (1H, m), 7.35-7.41 (2H, m), 7.53 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.64 (2H, d, J = 8.4 Hz), 7.88 (1H, dt, J = 1.2 Hz, 7.5 Hz), 8.68 (1H, dt, J = 0.9 Hz, 4.8 Hz).
IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm^-1.
実施例４２
N-(4-(1-(2,6-ジフルオロベンジル)-3-(5-フルオロ-2-ピリジニル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(304 mg)、シアノりん酸ジエチル(153 μl)、2-アミノ-5-フルオロピリジン(113 mg)、N-エチルジイソプロピルアミン(190 μl)から粗アミド体(270 mg)を得、さらにメタノール(19 ml)、28%-ナトリウムメトキシドのメタノール溶液(146 mg)を用いて表題化合物(113 mg)を得た。
元素分析 C₃₁H₂₉N₆O₅SF₃として
計算値：C, 56.87; H, 4.46; N, 12.84.
実測値：C, 56.69; H, 4.57; N, 12.83.
¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 (2H, brs), 3.82 (3H, s), 5.33 (2H, brs), 6.92 (2H, t, J = 8.3 Hz), 7.19 (1H, s), 7.28-7.38 (2H, m), 7.52-7.63 (6H, m), 8.51 (1H, d, J = 3.0 Hz).
IR (KBr): 1715, 1674, 1586, 1530, 1462 cm^-1.
実施例４３
N-(4-(3-(5-ブロモ-2-ピリジニル)-1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(304 mg)、シアノりん酸ジエチル(153 μl)、2-アミノ-5-ブロモピリジン(173 mg)、N-エチルジイソプロピルアミン(190 μl)から粗アミド体(228 mg)を得、さらにメタノール(14.5 ml)、28％-ナトリウムメトキシドのメタノール溶液(112 mg)を用いて表題化合物(113 mg)を得た。
元素分析 C₃₁H₂₉N₆O₅SBrF₂・0.5H₂Oとして
計算値：C, 51.39; H, 4.17; N, 11.60.
実測値：C, 51.68; H, 4.25; N, 11.53.
¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.78 (2H, brs), 3.80 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.1 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.27-7.33 (1H, m), 7.37 (1H, s), 7.54 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.64 (1H, s), 7.98 (1H, dd, J = 2.7 Hz, 8.4 Hz), 8.72 (1H, d, J = 2.7 Hz).
IR (KBr): 2938, 1717, 1674, 1590, 1456 cm^-1. Example 41
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

To a DMF solution (4.3 ml) of the compound of Reference Example 14 (251 mg), 2-ethoxyethyl chloride (141 mg), N-ethyldiisopropylamine (245 μl) and potassium iodide (107 mg) were added, and the mixture was added at 60 ° C. Stir for 24 hours. The reaction mixture was partitioned with ethyl acetate / water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue after evaporation of the solvent is purified by chromatography on aminopropyl silica gel (Fuji Silysia Chemical) (45 g; developing solution; ethyl acetate / hexane: 3/2 → 4/1) and recrystallized with ethyl acetate. Gave the title compound (62 mg) as colorless crystals.
Elemental analysis Calculated as C ₃₂ H ₃₂ N ₆ O ₅ SF ₂ .0.1AcOEt: C, 59.01; H, 5.01; N, 12.74.
Found: C, 59.11; H, 5.13; N, 12.55.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 6.9 Hz), 2.15 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.39 (2H, q, J = 6.9 Hz), 3.44 (2H, t, J = 6.2 Hz), 3.80 (2H, brs), 3.81 (3H, s), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.19 ( 1H, s), 7.27-7.32 (1H, m), 7.35-7.41 (2H, m), 7.53 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.64 (2H, d, J = 8.4 Hz), 7.88 (1H, dt, J = 1.2 Hz, 7.5 Hz), 8.68 (1H, dt, J = 0.9 Hz, 4.8 Hz).
IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm ^-1 .
Example 42
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 [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (304 mg), diethyl cyanophosphate (153 μl), 2-amino-5-fluoropyridine (113 mg), N-ethyldiisopropyl The crude amide (270 mg) was obtained from the amine (190 μl), and the title compound (113 mg) was obtained using methanol (19 ml) and a methanol solution of 28% -sodium methoxide (146 mg).
Elemental analysis Calculated as C ₃₁ H ₂₉ N ₆ O ₅ SF ₃ : C, 56.87; H, 4.46; N, 12.84.
Found: C, 56.69; H, 4.57; N, 12.83.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 ( 2H, brs), 3.82 (3H, s), 5.33 (2H, brs), 6.92 (2H, t, J = 8.3 Hz), 7.19 (1H, s), 7.28-7.38 (2H, m), 7.52-7.63 (6H, m), 8.51 (1H, d, J = 3.0 Hz).
IR (KBr): 1715, 1674, 1586, 1530, 1462 cm ^-1 .
Example 43
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-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (304 mg), diethyl cyanophosphate (153 μl), 2-amino-5-bromopyridine (173 mg), N-ethyldiisopropyl The crude amide (228 mg) was obtained from the amine (190 μl), and the title compound (113 mg) was obtained using methanol (14.5 ml) and 28% -sodium methoxide in methanol (112 mg).
Elemental analysis Calculated as C ₃₁ H ₂₉ N ₆ O ₅ SBrF ₂ · 0.5H ₂ O: C, 51.39; H, 4.17; N, 11.60.
Found: C, 51.68; H, 4.25; N, 11.53.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.78 ( 2H, brs), 3.80 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.1 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.27-7.33 (1H, m ), 7.37 (1H, s), 7.54 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.64 (1H, s), 7.98 (1H, dd, J = 2.7 Hz) , 8.4 Hz), 8.72 (1H, d, J = 2.7 Hz).
IR (KBr): 2938, 1717, 1674, 1590, 1456 cm ^-1 .

実施例４０と同様の反応に付し、参考例７で得られた化合物(304 mg)、シアノりん酸ジエチル(153 μl)、2-アミノ-5-メチルピリジン(109 mg)、N-エチルジイソプロピルアミン(190 μl)から粗アミド体(188 mg)を得、さらにメタノール(13.5 ml)、28%-ナトリウムメトキシドのメタノール溶液(103 mg)を用いて表題化合物(122 mg)を得た。
元素分析 C₃₂H₃₂N₆O₅SF₂・0.5H₂Oとして
計算値：C, 58.26; H, 5.04; N, 12.74.
実測値：C, 58.55; H, 5.14; N, 12.67.
¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.77 (2H, brs), 3.80 (3H, s), 5.26 (1H, brs), 5.38 (1H, brs), 6.91 (2H, t, J = 8.3 Hz), 7.23-7.34 (2H, m), 7.42 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.62 (2H, d, J = 8.7 Hz), 7.66 (1H, s), 7.66-7.69 (1H, m), 8.48 (1H, d, J = 2.4 Hz).
IR (KBr): 2938, 1717, 1675, 1586, 1530, 1462 cm^-1.
実施例４５
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(6-メチル-2-ピリジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(423 mg)、シアノりん酸ジエチル(212 μl)、2-アミノ-6-メチルピリジン(151 mg)、N-エチルジイソプロピルアミン(265 μl)から粗アミド体(242 mg)を得、さらにメタノール(17 ml)、28%-ナトリウムメトキシドのメタノール溶液(131 mg)を用いて表題化合物(145mg)を得た。
元素分析 C₃₂H₃₂N₆O₅SF₂・0.5H₂Oとして
計算値：C, 58.26; H, 5.04; N, 12.74.
実測値：C, 58.39; H, 4.86; N, 12.79.
¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.60 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.66-3.94 (2H, m), 3.81 (3H, s), 5.15 (1H, d, J = 15.3 Hz), 5.48 (1H, d, J = 15.3 Hz), 6.91 (2H, t, J = 8.1 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.25 (1H, s), 7.26-7.35 (1H, m), 7.53 (2H, d, J = 8.7 Hz), 7.63 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.64 (2H, d, J = 8.7 Hz), 7.76 (1H, t, J = 7.8 Hz).
IR (KBr): 2936, 1715, 1672, 1603, 1530, 1472 cm^-1.
実施例４６
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(3-メトキシ-6-メチル-2-ピリジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(227 μl)、2-アミノ-3-メトキシ-6-メチルピリジン(208 mg)、N−エチルジイソプロピルアミン(310 μl)から粗アミド体(130 mg)を得、さらにメタノール(8.5 ml)、28%-ナトリウムメトキシドのメタノール溶液(66 mg)を用いて表題化合物(107 mg)を得た。
元素分析 C₃₃H₃₄N₆O₆SF₂・0.5H₂Oとして
計算値：C, 57.47; H, 5.11; N, 12.18.
実測値：C, 57.54; H, 5.03; N, 12.26.
¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.51 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.40 (2H, t, J = 5.9 Hz), 3.77 (1H, d, J = 12.3 Hz), 3.77 (3H, s), 3.79 (3H, s), 3.86 (1H, d, J = 12.3 Hz), 5.24 (1H, d, J = 15.6 Hz), 5.40 (1H, d, J = 15.6 Hz), 6.90 (2H, t, J = 8.1 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.23-7.34 (1H, m), 7.27 (1H, d, J = 8.4 Hz), 7.51 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.65 (1H, s), 7.69 (1H, s).
IR (KBr): 2938, 1715, 1674, 1589, 1532, 1470 cm^-1. Example 44
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (5-methyl-2-pyridinyl) -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (304 mg), diethyl cyanophosphate (153 μl), 2-amino-5-methylpyridine (109 mg), N-ethyldiisopropyl The crude amide (188 mg) was obtained from the amine (190 μl), and the title compound (122 mg) was obtained using methanol (13.5 ml) and a 28% -sodium methoxide methanol solution (103 mg).
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, 58.55; H, 5.14; N, 12.67.
¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.77 (2H, brs), 3.80 (3H, s), 5.26 (1H, brs), 5.38 (1H, brs), 6.91 (2H, t, J = 8.3 Hz), 7.23-7.34 (2H , m), 7.42 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.62 (2H, d, J = 8.7 Hz), 7.66 (1H, s), 7.66-7.69 (1H, m) , 8.48 (1H, d, J = 2.4 Hz).
IR (KBr): 2938, 1717, 1675, 1586, 1530, 1462 cm ^-1 .
Example 45
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (6-methyl-2-pyridinyl) -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (423 mg), diethyl cyanophosphate (212 μl), 2-amino-6-methylpyridine (151 mg), N-ethyldiisopropyl The crude amide compound (242 mg) was obtained from the amine (265 μl), and the title compound (145 mg) was obtained using methanol (17 ml) and a methanol solution of 28% -sodium methoxide (131 mg).
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, 58.39; H, 4.86; N, 12.79.
¹ H-NMR (CDCl ₃ ) δ: 2.15 (3H, s), 2.60 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.66-3.94 (2H, m), 3.81 (3H, s), 5.15 (1H, d, J = 15.3 Hz), 5.48 (1H, d, J = 15.3 Hz), 6.91 (2H, t , J = 8.1 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.25 (1H, s), 7.26-7.35 (1H, m), 7.53 (2H , d, J = 8.7 Hz), 7.63 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.64 (2H, d, J = 8.7 Hz), 7.76 (1H, t, J = 7.8 Hz ).
IR (KBr): 2936, 1715, 1672, 1603, 1530, 1472 cm ^-1 .
Example 46
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'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (227 μl), 2-amino-3-methoxy-6-methylpyridine (208 mg), A crude amide (130 mg) was obtained from N-ethyldiisopropylamine (310 μl), and further the title compound (107 mg) was obtained using methanol (8.5 ml) and 28% -sodium methoxide in methanol (66 mg). Obtained.
Elemental analysis _{C 33 H 34 N 6 O 6} SF 2 · 0.5H 2 O Calculated: C, 57.47; H, 5.11 ; N, 12.18.
Found: C, 57.54; H, 5.03; N, 12.26.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.51 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.40 (2H, t, J = 5.9 Hz), 3.77 (1H, d, J = 12.3 Hz), 3.77 (3H, s), 3.79 (3H, s), 3.86 (1H, d, J = 12.3 Hz), 5.24 (1H, d, J = 15.6 Hz), 5.40 (1H, d, J = 15.6 Hz), 6.90 (2H, t, J = 8.1 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.23-7.34 (1H, m), 7.27 (1H, d, J = 8.4 Hz), 7.51 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.65 (1H, s), 7.69 (1H, s).
IR (KBr): 2938, 1715, 1674, 1589, 1532, 1470 cm ^-1 .

参考例７で得られた化合物(455 mg)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド・ハイドロクロリド(306 mg)、1-ヒドロキシベンゾトリアゾール(288 mg)、2-アミノ-3-ヒドロキシ-6-メチルピリジン(187mg)、N-エチルジイソプロピルアミン(517 μl)から粗アミド体(163 mg)を得、さらにメタノール(11 ml)、28%-ナトリウムメトキシドのメタノール溶液(85 mg)を用いて表題化合物(127 mg)を得た。
元素分析 C₃₃H₃₄N₆O₆SF₂・H₂Oとして
計算値：C, 56.13; H, 5.01; N,12.27.
実測値：C, 56.03; H, 5.21; N,12.05.
¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.48 (3H, s), 2.51-2.59 (2H, m), 3.20 (3H, s), 3.30-3.46 (4H, m), 3.60 (1H, d, J = 12.3 Hz), 3.79 (3H, s), 4.05 (1H, d, J = 12.3 Hz), 5.21 (1H, d, J = 15.6 Hz), 5.31 (1H, d, J = 15.6 Hz), 6.88 (2H, t, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.21-7.31 (2H, m), 7.43-7.51 (4H, m), 7.69 (1H, s).
IR (KBr): 2936, 1715, 1669, 1591, 1530, 1472 cm^-1.
実施例４８
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(3-メトキシ-2-ピリジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)- N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(285 μl)、2-アミノ-3-メトキシピリジン(233 mg)、N−エチルジイソプロピルアミン(388 μl)から粗アミド体(226 mg)を得、さらにメタノール(15.5 ml)、28%-ナトリウムメトキシドのメタノール溶液(120 mg)を用いて表題化合物(115 mg)を得た。
元素分析 C₃₂H₃₂N₆O₆SF₂・0.5H₂Oとして
計算値：C, 56.88; H, 4.92; N, 12.44.
実測値：C, 56.88; H, 4.96; N, 12.31.
¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.28 (3H, s), 3.41 (2H, t, J = 6.2 Hz), 3.78 (1H, d, J = 12.3 Hz), 3.82 (3H, s), 3.84 (3H, s), 3.88 (1H, d, J = 12.3 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.1 Hz), 7.17 (1H, s), 7.23-7.39 (3H, m), 7.54 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.69 (2H, d, J = 8.8 Hz), 8.23-8.27 (1H, m).
IR (KBr): 1717, 1674, 1590, 1530, 1470 cm^-1.
実施例４９
N-(4-(1-(2,6-ジフルオロベンジル)-3-(4-(1-ヒドロキシ-1-メチルエチル)フェニル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(1.22 g)、シアノりん酸ジエチル(456 μl)、4-(1-ヒドロキシ-1-メチルエチル)アニリン(454 mg)、N-エチルジイソプロピルアミン(569 μl)から粗アミド体(1.12 g)を得、さらにエタノール(60 ml)、28%-ナトリウムメトキシドのメタノール溶液(579 mg)を用いて表題化合物(849 mg)を得た。
元素分析 C₃₅H₃₇N₅O₆SF₂・0.5H₂Oとして
計算値：C, 59.82; H, 5.45; N, 9.97.
実測値：C, 60.09; H, 5.40; N, 10.06.
¹H-NMR (CDCl₃) δ: 1.60 (6H, s), 1.79 (1H, s), 2.14 (3H, s), 2.63 (2H, t, J = 5.9 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.82 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20-7.34 (4H, m), 7.53 (2H, d, J = 8.7 Hz), 7.60-7.63 (5H, m).
IR (KBr): 1713, 1669, 1590, 1532, 1470 cm^-1. Example 47
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] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound obtained in Reference Example 7 (455 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (306 mg), 1-hydroxybenzotriazole (288 mg), 2-amino- Crude amide (163 mg) was obtained from 3-hydroxy-6-methylpyridine (187 mg) and N-ethyldiisopropylamine (517 μl), and methanol (11 ml), 28% -sodium methoxide in methanol solution (85 mg) was used to give the title compound (127 mg).
Elemental analysis Calculated as C ₃₃ H ₃₄ N ₆ O ₆ SF ₂ .H ₂ O: C, 56.13; H, 5.01; N, 12.27.
Found: C, 56.03; H, 5.21; N, 12.05.
¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.48 (3H, s), 2.51-2.59 (2H, m), 3.20 (3H, s), 3.30-3.46 (4H, m), 3.60 (1H, d, J = 12.3 Hz), 3.79 (3H, s), 4.05 (1H, d, J = 12.3 Hz), 5.21 (1H, d, J = 15.6 Hz), 5.31 (1H, d, J = 15.6 Hz), 6.88 (2H, t, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.21-7.31 (2H, m), 7.43-7.51 (4H, m), 7.69 (1H, s).
IR (KBr): 2936, 1715, 1669, 1591, 1530, 1472 cm ^-1 .
Example 48
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-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (285 μl), 2-amino-3-methoxypyridine (233 mg), N-ethyldiisopropyl The crude amide compound (226 mg) was obtained from the amine (388 μl), and the title compound (115 mg) was obtained using methanol (15.5 ml) and 28% -sodium methoxide in methanol (120 mg).
Elemental analysis Calculated as C ₃₂ H ₃₂ N ₆ O ₆ SF ₂ .0.5H ₂ O: C, 56.88; H, 4.92; N, 12.44.
Found: C, 56.88; H, 4.96; N, 12.31.
¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.28 (3H, s), 3.41 (2H, t, J = 6.2 Hz), 3.78 ( 1H, d, J = 12.3 Hz), 3.82 (3H, s), 3.84 (3H, s), 3.88 (1H, d, J = 12.3 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.1 Hz), 7.17 (1H, s), 7.23-7.39 (3H, m), 7.54 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.69 (2H, d, J = 8.8 Hz ), 8.23-8.27 (1H, m).
IR (KBr): 1717, 1674, 1590, 1530, 1470 cm ^-1 .
Example 49
N- (4- (1- (2,6-difluorobenzyl) -3- (4- (1-hydroxy-1-methylethyl) phenyl) -5-(((2-methoxyethyl) (methyl) amino) Preparation of methyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, and the compound (1.22 g) obtained in Reference Example 7, diethyl cyanophosphate (456 μl), 4- (1-hydroxy-1-methylethyl) aniline (454 mg) The crude amide (1.12 g) was obtained from N-ethyldiisopropylamine (569 μl), and the title compound (849 mg) was obtained using ethanol (60 ml) and 28% -sodium methoxide in methanol (579 mg). Got.
Elemental analysis Calculated as C ₃₅ H ₃₇ N ₅ O ₆ SF ₂ .0.5H ₂ O: C, 59.82; H, 5.45; N, 9.97.
Found: C, 60.09; H, 5.40; N, 10.06.
¹ H-NMR (CDCl ₃ ) δ: 1.60 (6H, s), 1.79 (1H, s), 2.14 (3H, s), 2.63 (2H, t, J = 5.9 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.82 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20-7.34 (4H , m), 7.53 (2H, d, J = 8.7 Hz), 7.60-7.63 (5H, m).
IR (KBr): 1713, 1669, 1590, 1532, 1470 cm ^-1 .

実施例４０と同様の反応に付し、4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(470 mg)、シアノりん酸ジエチル(167 μl)、4-(1-ヒドロキシ-1-メチルエチル)アニリン(166 mg)、N-エチルジイソプロピルアミン(209 μl)から粗アミド体(422 mg)を得、さらにエタノール(25.5 ml)、ナトリウムエトキシド(70 mg)を用いて表題化合物(303 mg)を得た。
元素分析 C₃₉H₃₇N₅O₅SF₂として
計算値：C, 64.54; H, 5.14; N, 9.65.
実測値：C, 64.46; H, 5.05; N, 9.70.
¹H-NMR (CDCl₃) δ: 1.62 (6H, s), 1.77 (1H, s), 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.90 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.14-7.38 (9H, m), 7.55 (2H, d, J = 9.0 Hz), 7.62 (1H, s), 7.64 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.4 Hz).
IR (KBr): 1713, 1669, 1590, 1530, 1470 cm^-1.
実施例５１
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(4-(1-メトキシ-1-メチルエチル)フェニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(364 mg)、シアノりん酸ジエチル(136 μl)、4-(1-メトキシ-1-メチルエチル)アニリン(149 mg)、N-エチルジイソプロピルアミン(171 μl)から粗アミド体(292 mg)を得、さらにエタノール(19 ml)、28%-ナトリウムメトキシドのメタノール溶液(146 mg)を用いて表題化合物(146 mg)を得た。
元素分析 C₃₆H₃₉N₅O₆SF₂として
計算値：C, 61.09; H, 5.55; N, 9.89.
実測値：C, 60.97; H, 5.54; N, 9.92.
¹H-NMR (CDCl₃) δ: 1.55 (6H, s), 2.15 (3H, s), 2.64 (2H, t, J = 5.9 Hz), 3.11 (3H, s), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.83 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.16 (1H, s), 7.24-7.36 (4H, m), 7.51-7.63 (6H, m).
IR (KBr): 1715, 1674, 1590, 1532, 1464, 1327 cm^-1.
実施例５２
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(1-メチル-1H-イミダゾール-2-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(228 μl)、2-アミノ-1-メチル-1H-イミダゾール・塩酸塩(214 mg)、N-エチルジイソプロピルアミン(586 μl)から粗アミド体(48 mg)を得、さらにメタノール(3.3 ml)、28%-ナトリウムメトキシドのメタノール溶液(25 mg)を用いて表題化合物(17 mg)を得た。
¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.61 (2H, dt, J = 1.8 Hz, 6.90 Hz), 3.27 (3H, s), 3.40 (2H, dt, J = 1.8 Hz, 6.0 Hz), 3.53 (3H, s), 3.75 (1H, d, J = 12.3 Hz), 3.80 (3H, s), 3.81 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 15.9 Hz), 5.57 (1H, d, J = 15.9 Hz), 6.91 (2H, t, J = 8.1 Hz), 6.99 (1H, d, J = 1.5 Hz), 7.14 (1H, d, J = 1.5 Hz), 7.28 (1H, s), 7.25-7.34 (1H, m), 7.53 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.70 (1H, s).
IR (KBr): 1725, 1682, 1590, 1530, 1470 cm^-1． Example 50
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (4- (1-hydroxy-1-methylethyl) phenyl) -2, Preparation of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction was carried out in the same manner as in Example 40, and 4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4 -(3-Methoxyureido) phenyl] thiophene-3-carboxylic acid (470 mg), diethyl cyanophosphate (167 μl), 4- (1-hydroxy-1-methylethyl) aniline (166 mg), N-ethyl The crude amide (422 mg) was obtained from diisopropylamine (209 μl), and the title compound (303 mg) was obtained using ethanol (25.5 ml) and sodium ethoxide (70 mg).
Elemental analysis _{C 39 H 37 N 5 O 5} SF 2 Calculated: C, 64.54; H, 5.14 ; N, 9.65.
Found: C, 64.46; H, 5.05; N, 9.70.
¹ H-NMR (CDCl ₃ ) δ: 1.62 (6H, s), 1.77 (1H, s), 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.90 (2H, s ), 5.36 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.14-7.38 (9H, m), 7.55 (2H, d, J = 9.0 Hz), 7.62 (1H, s), 7.64 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.4 Hz).
IR (KBr): 1713, 1669, 1590, 1530, 1470 cm ^-1 .
Example 51
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (4- (1-methoxy-1-methylethyl) Preparation of phenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (364 mg), diethyl cyanophosphate (136 μl), 4- (1-methoxy-1-methylethyl) aniline (149 mg) The crude amide compound (292 mg) was obtained from N-ethyldiisopropylamine (171 μl), and further the title compound (146 mg) using ethanol (19 ml) and 28% -sodium methoxide in methanol (146 mg). Got.
Elemental analysis Calculated as C ₃₆ H ₃₉ N ₅ O ₆ SF ₂ : C, 61.09; H, 5.55; N, 9.89.
Found: C, 60.97; H, 5.54; N, 9.92.
_{^{1 H-NMR (CDCl 3)}} δ: 1.55 (6H, s), 2.15 (3H, s), 2.64 (2H, t, J = 5.9 Hz), 3.11 (3H, s), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.83 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.16 (1H, s ), 7.24-7.36 (4H, m), 7.51-7.63 (6H, m).
IR (KBr): 1715, 1674, 1590, 1532, 1464, 1327 cm ^-1 .
Example 52
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (1-methyl-1H-imidazol-2-yl) -2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228 μl), 2-amino-1-methyl-1H-imidazole hydrochloride (214 mg) ), N-ethyldiisopropylamine (586 μl) to give a crude amide (48 mg), and further using methanol (3.3 ml) and 28% -sodium methoxide in methanol (25 mg) to give the title compound (17 mg )
¹ H-NMR (CDCl ₃ ) δ: 2.15 (3H, s), 2.61 (2H, dt, J = 1.8 Hz, 6.90 Hz), 3.27 (3H, s), 3.40 (2H, dt, J = 1.8 Hz, 6.0 Hz), 3.53 (3H, s), 3.75 (1H, d, J = 12.3 Hz), 3.80 (3H, s), 3.81 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 15.9 Hz), 5.57 (1H, d, J = 15.9 Hz), 6.91 (2H, t, J = 8.1 Hz), 6.99 (1H, d, J = 1.5 Hz), 7.14 (1H, d, J = 1.5 Hz) ), 7.28 (1H, s), 7.25-7.34 (1H, m), 7.53 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.70 (1H, s).
IR (KBr): 1725, 1682, 1590, 1530, 1470 cm ^-1 .

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(228 μl)、イソアミルアミン(139 mg)、N-エチルジイソプロピルアミン(310 μl)から粗アミド体(102 mg)を得、さらにメタノール(7 ml)、28%-ナトリウムメトキシドのメタノール溶液(55 mg)を用いて55℃で20時間攪拌し、以下同様の処理をすることにより表題化合物(80 mg)を得た。
元素分析 C₃₁H₃₇N₅O₅SF₂として
計算値：C, 59.13; H, 5.92; N, 11.12.
実測値：C, 58.97; H, 5.99; N, 10.90.
¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J = 6.3 Hz), 1.52-1.58 (2H, m), 1.64-1.71 (1H, m), 2.14 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.85 (2H, s), 4.04-4.09 (2H, m), 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.17 (1H, s), 7.24-7.35 (1H, m), 7.51 (2H, d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (1H, s).
IR (KBr): 2959, 1705, 1659, 1590, 1531, 1472 cm^-1.
実施例５４
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-メトキシエチル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(228 μl)、2-メトキシエチルアミン(120 mg)、N-エチルジイソプロピルアミン(310 μl)から粗アミド体(266 mg)を得、さらにメタノール(19.6 ml)、28%-ナトリウムメトキシドのメタノール溶液(152 mg)を用いて表題化合物(140 mg)を得た。
元素分析 C₂₉H₃₃N₅O₆SF₂として
計算値：C, 56.39; H, 5.39; N, 11.34.
実測値：C, 56.40; H, 5.35; N, 11.15.
¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.65 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.36 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.66 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.30 (2H, t, J = 5.9 Hz), 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.15 (1H, s), 7.24-7.34 (1H, m), 7.51 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz), 7.60 (1H, m).
IR (KBr): 2936, 1705, 1663, 1590, 1532, 1472 cm^-1.
実施例５５
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-エトキシエチル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(228 μl)、2-エトキシエチルアミン(143 mg)、N-エチルジイソプロピルアミン(310 μl)から粗アミド体(259 mg)を得、さらにメタノール(18.7 ml)、28%-ナトリウムメトキシドのメタノール溶液(144 mg)を用いて表題化合物(193 mg)を得た。
元素分析 C₃₀H₃₅N₅O₆SF₂として
計算値：C, 57.04; H, 5.58; N, 11.09.
実測値：C, 57.01; H, 5.66; N, 10.93.
¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J = 6.9 Hz), 2.14 (3H, s), 2.66 (2H, t, J = 6.0 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 6.0 Hz), 3.54 (2H, q, J = 6.9 Hz), 3.69 (2H, t, J = 6.0 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.29 (2H, t, J = 6.0 Hz), 5.32 (2H, s), 6.89 (2H, t, J = 8.1 Hz), 7.17 (1H, s), 7.23-7.34 (1H, m), 7.52 (2H, d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (1H, m).
IR (KBr): 2975, 1705, 1663, 1590, 1532, 1472 cm^-1. Example 53
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (3-methylbutyl) -2,4-dioxo-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction was conducted in the same manner as in Example 40. From the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228 μl), isoamylamine (139 mg) and N-ethyldiisopropylamine (310 μl). Crude amide (102 mg) was obtained, and further stirred with methanol (7 ml) and 28% -sodium methoxide in methanol (55 mg) at 55 ° C. for 20 hours. Compound (80 mg) was obtained.
Elemental analysis Calculated as C ₃₁ H ₃₇ N ₅ O ₅ SF ₂ : C, 59.13; H, 5.92; N, 11.12.
Found: C, 58.97; H, 5.99; N, 10.90.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.3 Hz), 1.52-1.58 (2H, m), 1.64-1.71 (1H, m), 2.14 (3H, s), 2.66 (2H , t, J = 5.9 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.85 (2H, s), 4.04-4.09 (2H, m) , 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.17 (1H, s), 7.24-7.35 (1H, m), 7.51 (2H, d, J = 8.7 Hz), 7.57 ( 2H, d, J = 8.7 Hz), 7.60 (1H, s).
IR (KBr): 2959, 1705, 1659, 1590, 1531, 1472 cm ^-1 .
Example 54
N- (4- (1- (2,6-difluorobenzyl) -3- (2-methoxyethyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction was carried out in the same manner as in Example 40, and the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228 μl), 2-methoxyethylamine (120 mg), N-ethyldiisopropylamine (310 μl ) To give a crude amide (266 mg), and further methanol (19.6 ml) and 28% -sodium methoxide in methanol (152 mg) to give the title compound (140 mg).
Elemental analysis Calculated as C ₂₉ H ₃₃ N ₅ O ₆ SF ₂ : C, 56.39; H, 5.39; N, 11.34.
Found: C, 56.40; H, 5.35; N, 11.15.
¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.65 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.36 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.66 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.30 (2H, t, J = 5.9 Hz), 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.15 (1H, s), 7.24-7.34 (1H, m), 7.51 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz) ), 7.60 (1H, m).
IR (KBr): 2936, 1705, 1663, 1590, 1532, 1472 cm ^-1 .
Example 55
N- (4- (1- (2,6-difluorobenzyl) -3- (2-ethoxyethyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228 μl), 2-ethoxyethylamine (143 mg), N-ethyldiisopropylamine (310 μl). ) To give a crude amide (259 mg), and further methanol (18.7 ml) and 28% -sodium methoxide in methanol (144 mg) to give the title compound (193 mg).
Elemental analysis _{C 30 H 35 N 5 O 6} SF 2 Calculated: C, 57.04; H, 5.58 ; N, 11.09.
Found: C, 57.01; H, 5.66; N, 10.93.
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 6.9 Hz), 2.14 (3H, s), 2.66 (2H, t, J = 6.0 Hz), 3.30 (3H, s), 3.45 ( 2H, t, J = 6.0 Hz), 3.54 (2H, q, J = 6.9 Hz), 3.69 (2H, t, J = 6.0 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.29 ( 2H, t, J = 6.0 Hz), 5.32 (2H, s), 6.89 (2H, t, J = 8.1 Hz), 7.17 (1H, s), 7.23-7.34 (1H, m), 7.52 (2H, d , J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (1H, m).
IR (KBr): 2975, 1705, 1663, 1590, 1532, 1472 cm ^-1 .

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(228 μl)、イソプロピルアミン(95 mg)、N-エチルジイソプロピルアミン(310 μl)から粗アミド体(306 mg)を得、さらにメタノール(23.2 ml)、28%-ナトリウムメトキシドのメタノール溶液(179 mg)を用いて60℃で17時間攪拌し、以下同様の処理をすることにより表題化合物(192 mg)を得た。
元素分析 C₂₉H₃₃N₅O₅SF₂として
計算値：C, 57.89; H, 5.53; N, 11.64.
実測値：C, 57.98; H, 5.49; N, 11.72.
¹H-NMR (CDCl₃) δ: 1.52 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.46 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.31 (2H, s), 5.34 (1H, m), 6.90 (2H, t, J = 8.1 Hz), 7.16 (1H, s), 7.24-7.35 (1H, m), 7.52 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.60 (1H, m).
IR (KBr): 2973, 1703, 1659, 1590, 1534, 1472 cm^-1.
実施例５７
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(455 mg)、シアノりん酸ジエチル(285 μl)、3-アミノ-6-クロロピリダジン(243 mg)、N-エチルジイソプロピルアミン(388 μl)から粗アミド体(207 mg)を得、さらにメタノール(14.2 ml)、28%-ナトリウムメトキシドのメタノール溶液(109 mg)を用いて表題化合物(132 mg)を得た。
¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.74 (2H, brs), 3.82 (3H, s), 4.18 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.3 Hz), 7.12 (1H, d, J = 9.3 Hz), 7.24 (1H, s), 7.29-7.35 (1H, m), 7.41 (2H, d, J = 9.3 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.66 (1H, s).
IR (KBr): 2936, 1717, 1674, 1591, 1530, 1460 cm^-1.
実施例５８
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(3-ピリダジニル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(364 mg)、シアノりん酸ジエチル(182 μl)、3-アミノピリダジン・塩酸塩(158 mg)、N-エチルジイソプロピルアミン(414 μl)から粗アミド体(55 mg)を得、さらにメタノール(4 ml)、28%-ナトリウムメトキシドのメタノール溶液(30 mg)を用いて表題化合物(15mg)を得た。
¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 2.61 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.39 (2H, t, J = 5.7 Hz), 3.78 (2H, brs), 3.82 (3H, s), 5.34 (2H, brs), 6.93 (2H, t, J = 8.1 Hz), 7.26 (1H, s), 7.29-7.37 (1H, m), 7.53-7.61 (5H, m), 7.67 (1H, s), 7.69 (1H, dd, J = 4.8 Hz, 8.4 Hz), 9.28 (1H, dd, J = 1.8 Hz, 4.8 Hz).
IR (KBr): 2936, 1717, 1674, 1590, 1530, 1470 cm^-1. Example 56
N- (4- (1- (2,6-difluorobenzyl) -3-isopropyl-5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction was conducted in the same manner as in Example 40, from the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228 μl), isopropylamine (95 mg), N-ethyldiisopropylamine (310 μl). Crude amide (306 mg) was obtained, and further stirred with methanol (23.2 ml) and 28% -sodium methoxide in methanol (179 mg) at 60 ° C. for 17 hours. Compound (192 mg) was obtained.
Elemental analysis Calculated as C ₂₉ H ₃₃ N ₅ O ₅ SF ₂ : C, 57.89; H, 5.53; N, 11.64.
Found: C, 57.98; H, 5.49; N, 11.72.
¹ H-NMR (CDCl ₃ ) δ: 1.52 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.46 ( 2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.31 (2H, s), 5.34 (1H, m), 6.90 (2H, t, J = 8.1 Hz), 7.16 (1H, s), 7.24-7.35 (1H, m), 7.52 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.60 (1H, m).
IR (KBr): 2973, 1703, 1659, 1590, 1534, 1472 cm ^-1 .
Example 57
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (455 mg), diethyl cyanophosphate (285 μl), 3-amino-6-chloropyridazine (243 mg), N-ethyldiisopropyl The crude amide (207 mg) was obtained from the amine (388 μl), and the title compound (132 mg) was obtained using methanol (14.2 ml) and a methanol solution of 28% -sodium methoxide (109 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.74 ( 2H, brs), 3.82 (3H, s), 4.18 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.3 Hz), 7.12 (1H, d, J = 9.3 Hz), 7.24 (1H, s), 7.29-7.35 (1H, m), 7.41 (2H, d, J = 9.3 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J = 8.7 Hz) ), 7.66 (1H, s).
IR (KBr): 2936, 1717, 1674, 1591, 1530, 1460 cm ^-1 .
Example 58
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (3-pyridazinyl) -1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction was conducted in the same manner as in Example 40, but the compound (364 mg) obtained in Reference Example 7, diethyl cyanophosphate (182 μl), 3-aminopyridazine hydrochloride (158 mg), N-ethyldiisopropylamine The crude amide (55 mg) was obtained from (414 μl), and the title compound (15 mg) was obtained using methanol (4 ml) and methanol solution of 28% -sodium methoxide (30 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.12 (3H, s), 2.61 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.39 (2H, t, J = 5.7 Hz), 3.78 ( 2H, brs), 3.82 (3H, s), 5.34 (2H, brs), 6.93 (2H, t, J = 8.1 Hz), 7.26 (1H, s), 7.29-7.37 (1H, m), 7.53-7.61 (5H, m), 7.67 (1H, s), 7.69 (1H, dd, J = 4.8 Hz, 8.4 Hz), 9.28 (1H, dd, J = 1.8 Hz, 4.8 Hz).
IR (KBr): 2936, 1717, 1674, 1590, 1530, 1470 cm ^-1 .

実施例４０と同様の反応に付し、参考例７で得られた化合物(607 mg)、シアノりん酸ジエチル(304 μl)、O-メチルヒドロキシルアミン・塩酸塩(334 mg)、N−エチルジイソプロピルアミン(1.04 ml)から得られた粗成績体をアミノプロピルシリカゲル（富士シリシア化学）カラムクロマトグラフィーで精製することにより、表題化合物(283 mg)を得た。
¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.68 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.47 (2H, t, J = 6.0 Hz), 3.82 (3H, s), 3.83 (2H, s), 4.06 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20 (1H, s), 7.29-7.35 (1H, m), 7.55 (4H, s), 7.63 (1H, s).
IR (KBr): 1725, 1684, 1590, 1530, 1472 cm^-1.
実施例６０
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-メチル-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例４０と同様の反応に付し、参考例７で得られた化合物(607 mg)、シアノりん酸ジエチル(304 μl)、メチルアミン・塩酸塩(270 mg)、N-エチルジイソプロピルアミン(1.04 ml)から粗アミド体(133 mg)を得、さらにメタノール(9.1 ml)、28%-ナトリウムメトキシドのメタノール溶液(70 mg)を用いて60℃で17時間攪拌し、以下同様の処理をすることにより表題化合物(83 mg)を得た。
¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.45 (3H, s), 3.48 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.3 Hz), 7.17 (1H, s), 7.25-7.35 (1H, m), 7.55 (4H, s), 7.62 (1H, s).
IR (KBr): 1705, 1661, 1590, 1532, 1472 cm^-1. Example 59
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3-methoxy-2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound was subjected to the same reaction as in Example 40, the compound obtained in Reference Example 7 (607 mg), diethyl cyanophosphate (304 μl), O-methylhydroxylamine hydrochloride (334 mg), N-ethyldiisopropyl The crude product obtained from the amine (1.04 ml) was purified by aminopropyl silica gel (Fuji Silysia Chemical) column chromatography to obtain the title compound (283 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.68 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.47 (2H, t, J = 6.0 Hz), 3.82 ( 3H, s), 3.83 (2H, s), 4.06 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20 (1H, s), 7.29-7.35 (1H m), 7.55 (4H, s), 7.63 (1H, s).
IR (KBr): 1725, 1684, 1590, 1530, 1472 cm ^-1 .
Example 60
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3-methyl-2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction was conducted in the same manner as in Example 40. The compound obtained in Reference Example 7 (607 mg), diethyl cyanophosphate (304 μl), methylamine hydrochloride (270 mg), N-ethyldiisopropylamine (1.04 The crude amide compound (133 mg) is obtained from (ml), and further stirred with methanol (9.1 ml) and 28% -sodium methoxide in methanol (70 mg) at 60 ° C. for 17 hours, and the same treatment is performed hereinafter. This gave the title compound (83 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.45 (3H, s), 3.48 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.3 Hz), 7.17 (1H, s), 7.25-7.35 (1H m), 7.55 (4H, s), 7.62 (1H, s).
IR (KBr): 1705, 1661, 1590, 1532, 1472 cm ^-1 .

ドライアイス-アセトン浴で冷却したN-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-フェニルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(7.7 g, 11.53 mmol) のTHF (200 ml)溶液にクロロぎ酸α-クロロエチル (1.7 ml, 11.64 mmol)を加え、室温まで昇温し2時間撹拌した。反応混合液を飽和重曹水で希釈し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィー(溶出液；酢酸エチル/クロロホルム；1/4から1/3)により精製し、さらにクロロホルム/ジエチルエーテルから再結晶し、表題化合物(5.66 g, 84 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 3.83 (3H, s), 4.84 (2H, s), 5.27 (2H, s), 5.37 (2H, s), 6.92 (2H, t, J= 7.8 Hz), 7.23-7.35 (4H, m), 7.41-7.66 (8H, m).
参考例１９
N-(4-(5-クロロメチル-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(4-メトキシフェニル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-(N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ)-5-(4-(3-メトキシウレイド)フェニル)チオフェン-3-カルボン酸(5.0 g, 7.83 mmol)とp-アニシジン(1.93 g, 15.65 mmol)を用い、実施例５と同様の反応を行い、N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(4-メトキシフェニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(3.39 g, 62 %)を白色固体として得た。この化合物(80 mg, 0.11 mmol)を用い、参考例１８と同様の反応を行い、表題化合物 (50 mg, 74 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 3.81 (3H, s), 3.83 (3H, s), 4.83 (2H, s), 5.35 (2H, s), 6.92 (2H, t, J= 8.1 Hz), 7.00 (2H, d, J= 10.2 Hz), 7.18-7.35 (3H, m), 7.48-7.65 (5H, m).
参考例２０
N-(4-(5-クロロメチル-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(4-ヒドロキシシクロヘキシル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-(N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ)-5-(4-(3-メトキシウレイド)フェニル)チオフェン-3-カルボン酸(10.0 g, 15.65 mmol)と4-アミノシクロヘキサノール(3.61 g, 31.30 mmol)を用い、実施例５と同様の反応を行いN-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(4-ヒドロキシシクロヘキシル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(5.20 g, 48 %)を白色固体として得た。この化合物(500 mg, 0.72 mmol)を用い、参考例１８と同様の反応を行い、表題化合物(180 mg, 41%)を白色固体として得た。
¹H NMR (CDCl₃) δ 1.41-1.55 (2H, m), 1.71 (2H, d, J= 11.7 Hz), 2.07 (2H, d, J= 12.4 Hz), 2.63 (2H, q, J= 11.1 Hz), 3.70-3.82 (4H, m), 4.84 (2H, s), 4.90-5.06 (1H, m), 5.29 (2H, s), 6.91 (2H, t, J= 8.1 Hz), 7.13 (1H, s), 7.25-7.33 (1H, m), 7.47 (2H, d, J= 8.4 Hz), 7.58 (2H, d, J= 9.0 Hz), 7.63 (1H, s). Reference Example 18
N- (4- (5-Chloromethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno [2,3-d] pyrimidine Preparation of -6-yl) phenyl) -N'-methoxyurea

N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2, cooled in a dry ice-acetone bath, 4-Dioxo-3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (7.7 g, 11.53 mmol) in THF (200 ml) in α-chloroethyl chloroformate (1.7 ml, 11.64 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent; ethyl acetate / chloroform; 1/4 to 1/3) and recrystallized from chloroform / diethyl ether to give the title compound (5.66 g, 84%) as white crystals. It was.
¹ H NMR (CDCl ₃ ) δ 3.83 (3H, s), 4.84 (2H, s), 5.27 (2H, s), 5.37 (2H, s), 6.92 (2H, t, J = 7.8 Hz), 7.23- 7.35 (4H, m), 7.41-7.66 (8H, m).
Reference Example 19
N- (4- (5-chloromethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3- (4-methoxyphenyl) thieno [2, Preparation of 3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- (N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ) -5- (4- (3-methoxyureido) phenyl) thiophene The same reaction as in Example 5 was performed using 3-carboxylic acid (5.0 g, 7.83 mmol) and p-anisidine (1.93 g, 15.65 mmol), and N- (4- (5-((benzyl (methyl) amino) ) Methyl) -1- (2,6-difluorobenzyl) -3- (4-methoxyphenyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 -Yl) phenyl ) -N'-methoxyurea (3.39 g, 62%) was obtained as a white solid. Using this compound (80 mg, 0.11 mmol), the same reaction as in Reference Example 18 was performed to obtain the title compound (50 mg, 74%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 3.81 (3H, s), 3.83 (3H, s), 4.83 (2H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.1 Hz), 7.00 ( 2H, d, J = 10.2 Hz), 7.18-7.35 (3H, m), 7.48-7.65 (5H, m).
Reference Example 20
N- (4- (5-chloromethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3- (4-hydroxycyclohexyl) thieno [2, Preparation of 3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- (N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ) -5- (4- (3-methoxyureido) phenyl) thiophene Using 3-carboxylic acid (10.0 g, 15.65 mmol) and 4-aminocyclohexanol (3.61 g, 31.30 mmol), the same reaction as in Example 5 was performed, and N- (4- (5-((benzyl (methyl)) Amino) methyl) -1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine- 6-yl) phenyl ) -N′-methoxyurea (5.20 g, 48%) was obtained as a white solid. Using this compound (500 mg, 0.72 mmol), the same reaction as in Reference Example 18 was performed to obtain the title compound (180 mg, 41%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.41-1.55 (2H, m), 1.71 (2H, d, J = 11.7 Hz), 2.07 (2H, d, J = 12.4 Hz), 2.63 (2H, q, J = 11.1 Hz), 3.70-3.82 (4H, m), 4.84 (2H, s), 4.90-5.06 (1H, m), 5.29 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.13 (1H , s), 7.25-7.33 (1H, m), 7.47 (2H, d, J = 8.4 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.63 (1H, s).

4-(N-ベンジル-N-メチルアミノメチル)-2-(N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ)-5-(4-(3-メトキシウレイド)フェニル)チオフェン-3-カルボン酸(10.0 g, 15.65 mmol)と2-アミノ-5-フルオロピリジン(3.51 g, 31.30 mmol)を用い、実施例５と同様の反応を行いN-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(5-フルオロピリジン-2-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(3.39 g, 32 %)を白色固体として得た。この化合物(1.0 g, 1.46 mmol)を用い、参考例１８と同様の反応を行い、表題化合物 (560 mg, 64%)を白色固体として得た。
¹H NMR (CDCl₃) δ 3.83 (1H, s), 4.79 (2H, br), 5.34 (2H, br), 6.93 (2H, t, J= 8.0 Hz), 7.14 (1H, s), 7.29-7.40 (2H, m), 7.50-7.65 (5H, m), 8.51 (1H, d, J= 3.0 Hz).
参考例２２
N-(4- (5-クロロメチル-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(ピリジン-2-イル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例1の化合物(500 mg, 0.75 mmol)を参考例１８と同様の反応を行い、表題化合物 (270 mg, 62 %)を白色固体として得た。
¹H NMR (DMDO-d₆) δ 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13 (2H, t, J= 8.3 Hz), 7.41-7.54 (4H, m), 7.78 (2H, d, J= 8.4 Hz), 8.01 (1H, t, J= 8.0 Hz), 8.30 (1H, s), 8.59-8.61 (1H, m), 9.14 (1H, s), 9.66 (1H, s)
参考例２３
N-(4-(1-(2,6-ジフルオロベンジル)-3-(4-ヒドロキシシクロヘキシル)-5-(メチルアミノ)メチル-1,2,3,4-テトラヒドロ-2,4-ジオキソ-チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例２０で得られたN-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(4-ヒドロキシシクロヘキシル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(5.20 g, 48 %)を参考例１４と同様の反応を行い、表題化合物(5.20 g, 48 %)を白色粉末として得た。
¹H NMR (DMDO-d₆) δ 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13 (2H, t, J= 8.3 Hz), 7.41-7.54 (4H, m), 7.78 (2H, d, J= 8.4 Hz), 8.01 (1H, t, J= 8.0 Hz), 8.30 (1H, s), 8.59-8.61 (1H, m), 9.14 (1H, s), 9.66 (1H, s) Reference Example 21
N- (4- (5-chloromethyl-1- (2,6-difluorobenzyl) -3- (5-fluoropyridin-2-yl) -1,2,3,4-tetrahydro-2,4-dioxothieno Preparation of [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- (N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ) -5- (4- (3-methoxyureido) phenyl) thiophene- Using 3-carboxylic acid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine (3.51 g, 31.30 mmol), the same reaction as in Example 5 was performed, and N- (4- (5-((benzyl (Methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (5-fluoropyridin-2-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2 , 3-d] pyrimidin-6-yl) phenyl ) -N′-methoxyurea (3.39 g, 32%) was obtained as a white solid. Using this compound (1.0 g, 1.46 mmol), the same reaction as in Reference Example 18 was performed to obtain the title compound (560 mg, 64%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 3.83 (1H, s), 4.79 (2H, br), 5.34 (2H, br), 6.93 (2H, t, J = 8.0 Hz), 7.14 (1H, s), 7.29- 7.40 (2H, m), 7.50-7.65 (5H, m), 8.51 (1H, d, J = 3.0 Hz).
Reference Example 22
N- (4- (5-Chloromethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3- (pyridin-2-yl) thieno [2 , 3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The compound of Example 1 (500 mg, 0.75 mmol) was subjected to the same reaction as in Reference Example 18 to obtain the title compound (270 mg, 62%) as a white solid.
¹ H NMR (DMDO-d ₆ ) δ 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13 (2H, t, J = 8.3 Hz), 7.41-7.54 (4H , m), 7.78 (2H, d, J = 8.4 Hz), 8.01 (1H, t, J = 8.0 Hz), 8.30 (1H, s), 8.59-8.61 (1H, m), 9.14 (1H, s) , 9.66 (1H, s)
Reference Example 23
N- (4- (1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -5- (methylamino) methyl-1,2,3,4-tetrahydro-2,4-dioxo- Preparation of thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -2,4- obtained in Reference Example 20 Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl ) -N′-methoxyurea (5.20 g, 48%) was reacted in the same manner as in Reference Example 14. The title compound (5.20 g, 48%) was obtained as a white powder.
¹ H NMR (DMDO-d ₆ ) δ 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13 (2H, t, J = 8.3 Hz), 7.41-7.54 (4H , m), 7.78 (2H, d, J = 8.4 Hz), 8.01 (1H, t, J = 8.0 Hz), 8.30 (1H, s), 8.59-8.61 (1H, m), 9.14 (1H, s) , 9.66 (1H, s)

メトキシアセトン(2.92 g, 33.14 mmol)とメチルアミンの2.0 M THF溶液(100 ml, 200.0 mmol)、酢酸(0.5 ml)のTHF(100 ml)溶液を氷冷下30分撹拌し、その後トリアセトキシ水素化ほう素ナトリウム(14.05 g, 66.28 mmol)を加え、室温で4日間撹拌した。反応混合物に飽和重曹水(100 ml)と酢酸エチル(100 ml)とベンジルオキシカルボニルクロライド(8.48 g, 49.71 mmol)を順次加え、室温で5時間撹拌した。反応混合物を飽和重曹水と酢酸エチルで分配し、酢酸エチル層を飽和食塩水で洗浄、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルクロマトグラフィー(溶出液：酢酸エチル/ヘキサン：6/1から4/1)により精製し、無色液体(4.24 g, 54 %)を得た。
この液体(0.94 g, 3.96 mmol)と10 %パラジウム炭素(94 mg)のエタノール(10 ml)混合液を水素雰囲気下、室温で2時間撹拌した後、ろ過し、ろ液を減圧下濃縮して表題化合物(220 mg, 54 %)を淡黄色液体として得た。
¹H NMR (CDCl₃) δ 1.15 (3H, d, J= 6.6 Hz), 2.50 (3H, s), 2.90-2.99 (1H, m), 3.29-3.44 (5H, m).
参考例２５
N-(4- (5-メチルアミノメチル-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(4-メトキシフェニル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア塩酸塩の製造

参考例１９で合成したN-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(4-メトキシフェニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(2.0 g, 2.87 mmol)と10%パラジウム炭素(200 mg)と1N塩酸(3 ml)のエタノール(40 ml)混合液を水素雰囲気下、室温で72時間撹拌した。反応混合物をろ過し、ろ液を濃縮乾固し、表題化合物 (1.77 g, 96 %)を白色粉末として得た。
¹H NMR (CDCl₃) δ 2.73 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 4.00-4.18 (2H, br), 5.35 (2H, s), 5.37 (2H, s), 6.90-7.08 (4H, m), 7.20-7.38 (5H, m), 7.61 (4H, s), 7.77 (1H, s), 7.95 (1H, s).
参考例２６
N-(4-(5-(((1R)-1-フェニルエチル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-フェニルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１８の化合物 (100 mg, 0.17 mmol) と(R)-(+)-N-α-ジメチルベンジルアミン (28 mg,0.21 mmol)、N-エチルジイソプロピルアミン (29 mg, 0.22 mmol)のDMF (200 ml)溶液を室温で24時間撹拌した。反応混合液を飽和重曹水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィー(溶出液；酢酸エチル/クロロホルム；2/3からクロロホルム/メタノール；20/1)により精製し、さらにクロロホルム/ジエチルエーテルから再結晶し、表題化合物 (58 mg, 50 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.25 (3H, d, J= 6.6 Hz), 1.89 (3H, s), 3.82 (3H, s), 3.82-3.87 (1H, m), 3.91 (2H, d, J= 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.3 Hz), 7.14-7.30 (9H, m), 7.43-7.61 (8H, m).
mp 192-193 ℃. Reference Example 24
Production of N- (2-methoxy-1-methylethyl) -N-methylamine

A solution of methoxyacetone (2.92 g, 33.14 mmol) and methylamine in 2.0 M THF (100 ml, 200.0 mmol) and acetic acid (0.5 ml) in THF (100 ml) was stirred for 30 minutes under ice-cooling, and then triacetoxyhydrogen Sodium borohydride (14.05 g, 66.28 mmol) was added, and the mixture was stirred at room temperature for 4 days. Saturated aqueous sodium hydrogen carbonate (100 ml), ethyl acetate (100 ml) and benzyloxycarbonyl chloride (8.48 g, 49.71 mmol) were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane: 6/1 to 4/1) to obtain a colorless liquid (4.24 g, 54%).
A mixture of this liquid (0.94 g, 3.96 mmol) and 10% palladium on carbon (94 mg) in ethanol (10 ml) was stirred in a hydrogen atmosphere at room temperature for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. The title compound (220 mg, 54%) was obtained as a pale yellow liquid.
¹ H NMR (CDCl ₃ ) δ 1.15 (3H, d, J = 6.6 Hz), 2.50 (3H, s), 2.90-2.99 (1H, m), 3.29-3.44 (5H, m).
Reference Example 25
N- (4- (5-Methylaminomethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3- (4-methoxyphenyl) thieno [2 , 3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea hydrochloride

N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (4-methoxyphenyl) -2,4-dioxo synthesized in Reference Example 19 -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl ) -N'-methoxyurea (2.0 g, 2.87 mmol) with 10% palladium on carbon (200 mg) and 1N A mixture of hydrochloric acid (3 ml) in ethanol (40 ml) was stirred under a hydrogen atmosphere at room temperature for 72 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (1.77 g, 96%) as a white powder.
¹ H NMR (CDCl ₃ ) δ 2.73 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 4.00-4.18 (2H, br), 5.35 (2H, s), 5.37 (2H, s ), 6.90-7.08 (4H, m), 7.20-7.38 (5H, m), 7.61 (4H, s), 7.77 (1H, s), 7.95 (1H, s).
Reference Example 26
N- (4- (5-(((1R) -1-phenylethyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4 -Dioxo-3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

DMF of the compound of Reference Example 18 (100 mg, 0.17 mmol) and (R)-(+)-N-α-dimethylbenzylamine (28 mg, 0.21 mmol), N-ethyldiisopropylamine (29 mg, 0.22 mmol) The (200 ml) solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent; ethyl acetate / chloroform; 2/3 to chloroform / methanol; 20/1) and recrystallized from chloroform / diethyl ether to give the title compound (58 mg, 50%). Obtained as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.25 (3H, d, J = 6.6 Hz), 1.89 (3H, s), 3.82 (3H, s), 3.82-3.87 (1H, m), 3.91 (2H, d, J = 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J = 8.3 Hz), 7.14-7.30 (9H, m), 7.43-7.61 (8H, m).
mp 192-193 ° C.

参考例１８の化合物(100 mg, 0.17 mmol)と(S)-(-)-N-α-ジメチルベンジルアミン(28 mg,0.21 mmol)を用いて参考例２６と同様の反応を行い、表題化合物 (61 mg, 53 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.25 (3H, d, J= 6.6 Hz), 1.89 (3H, s), 3.82 (3H, s), 3.82-3.90 (1H, m), 3.91 (2H, d, J= 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.0 Hz), 7.19-7.30 (9H, m), 7.43-7.61 (8H, m).
mp 191-192 ℃.
参考例２８
N-(4-(5-(((1R)-1-フェニルエチルアミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-フェニルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１８の化合物 (100 mg, 0.17 mmol) と(R)-(+)-1-フェニルエチルアミン (25 mg, 0.21 mmol)を用いて参考例２６と同様の反応を行い、表題化合物 (56 mg, 49 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.32 (3H, d, J= 6.6 Hz), 3.59 (1H, d, J= 12.0 Hz), 3.65-3.82 (5H, m), 5.25-5.46 (2H, AB), 6.90 (2H, t, J= 8.1 Hz), 7.11-7.59 (13H, m).
元素分析 C₃₆H₃₁F₂N₅O₄S・0.2H₂Oとして
計算値: C, 64.41; H, 4.71; N, 10.43.
実測値: C, 64.29; H, 4.64; N, 10.46.
mp 180-182 ℃.
参考例２９
N-(4-(5-(((1S)-1-フェニルエチルアミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-フェニルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１８の化合物(100 mg, 0.17 mmol)と(S)-(-)-1-フェニルエチルアミン (25 mg,0.21 mmol)を用いて参考例２６と同様の反応を行い、表題化合物 (56 mg, 49 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.31 (3H, d, J= 6.6 Hz), 3.58 (1H, d, J= 12.3 Hz), 3.72-3.82 (5H, m), 5.24-5.46 (2H, AB), 6.90 (2H, t, J= 8.1 Hz), 7.12 (1H, s), 7.16-7.37 (8H, m), 7.43-7.56 (4H, m).
元素分析 C₃₆H₃₁F₂N₅O₄Sとして
計算値: C, 64.76; H, 4.68; N, 10.49.
実測値: C, 64.46; H, 4.57; N, 10.60.
mp 182-185 ℃. Reference Example 27
N- (4- (5- ((methyl ((1S) -1-phenylethyl ) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4 -Dioxo-3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 18 (100 mg, 0.17 mmol) and (S)-(−)-N-α-dimethylbenzylamine (28 mg, 0.21 mmol), the same reaction as in Reference Example 26 was performed, and the title compound (61 mg, 53%) was obtained as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.25 (3H, d, J = 6.6 Hz), 1.89 (3H, s), 3.82 (3H, s), 3.82-3.90 (1H, m), 3.91 (2H, d, J = 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.19-7.30 (9H, m), 7.43-7.61 (8H, m).
mp 191-192 ° C.
Reference Example 28
N- (4- (5-(((1R) -1-phenylethylamino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo- Preparation of 3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 18 (100 mg, 0.17 mmol) and (R)-(+)-1-phenylethylamine (25 mg, 0.21 mmol), the same reaction as in Reference Example 26 was performed, and the title compound (56 mg , 49%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.32 (3H, d, J = 6.6 Hz), 3.59 (1H, d, J = 12.0 Hz), 3.65-3.82 (5H, m), 5.25-5.46 (2H, AB), 6.90 (2H, t, J = 8.1 Hz), 7.11-7.59 (13H, m).
Elemental analysis Calculated as C ₃₆ H ₃₁ F ₂ N ₅ O ₄ S ・ 0.2H ₂ O: C, 64.41; H, 4.71; N, 10.43.
Found: C, 64.29; H, 4.64; N, 10.46.
mp 180-182 ° C.
Reference Example 29
N- (4- (5-(((1S) -1-phenylethylamino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo- Preparation of 3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 18 (100 mg, 0.17 mmol) and (S)-(-)-1-phenylethylamine (25 mg, 0.21 mmol), the same reaction as in Reference Example 26 was performed, and the title compound (56 mg , 49%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.31 (3H, d, J = 6.6 Hz), 3.58 (1H, d, J = 12.3 Hz), 3.72-3.82 (5H, m), 5.24-5.46 (2H, AB), 6.90 (2H, t, J = 8.1 Hz), 7.12 (1H, s), 7.16-7.37 (8H, m), 7.43-7.56 (4H, m).
Elemental analysis Calculated as C ₃₆ H ₃₁ F ₂ N ₅ O ₄ S: C, 64.76; H, 4.68; N, 10.49.
Found: C, 64.46; H, 4.57; N, 10.60.
mp 182-185 ° C.

1-フェニル-1-プロパノール(1.0 g, 7.34 mmol)とN-エチルジイソプロピルアミン(1.42 g, 11.01 mmol)のジクロロメタン(10 ml)溶液に氷冷下、塩化メタンスルホニル(690 μl, 8.81 mmol)を加え、室温で5時間撹拌した。反応混合物を飽和重曹水で希釈し、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、溶媒を留去した。残渣をシリカゲルクロマトグラフィー(溶出液：酢酸エチル/ヘキサン：5/1)で精製し、1-クロロ-1-フェニルプロパン(610 mg, 54 %)を淡黄色液体として得た。
参考例15の化合物 (100 mg, 0.17 mmol)と、この 1-クロロ-1-フェニルプロパン(32 mg, 0.21 mmol)を用いて参考例２６と同様の反応を行い、表題化合物 (45 mg, 38 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 0.67 (3H, t, J= 7.2 Hz), 1.63-1.91 (5H, m), 3.52-3.57 (1H, m), 3.73-3.93 (5H, m), 3.91 (2H, d, J= 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.1 Hz), 7.08-7.34 (8H, m), 7.41-7.55 (8H, m), 7.64 (1H, s).
mp 171-172 ℃.
参考例３１
メチル (((1-(2,6-ジフルオロベンジル)-6-(4-(((メトキシアミノ)カルボニル)アミノ)フェニル)-2,4ジオキソ-3-フェニル-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-5-イル)メチル)(メチル)アミノ)(フェニル)酢酸の製造

参考例１５の化合物(150 mg, 0.17 mmol)とα-ブロモフェニル酢酸メチル(71 mg, 0.31 mmol)を用いて実施例２０と同様の反応を行い、表題化合物 (73 mg, 39 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 2.08 (3H, s), 3.54 (32H, s), 3.79 (3H, s), 3.89-4.20 (2H, AB), 4.67 (1H, s), 5.35 (2H, brs), 6.92 (2H, t, J= 8.2 Hz), 7.22-7.37 (6H, m), 7.44-7.56 (7H, m) 7.71 (2H, d, J= 8.0 Hz).
元素分析 C₃₈H₃₃F₂N₅O₆Sとして
計算値: C, 62.89; H, 4.58; N, 9.65.
実測値: C, 62.70; H, 4.61; N, 9.78.
mp 147-149 ℃.
参考例３２
N-(4-(1-(2,6-ジフルオロベンジル)-5-((2-メトキシ-1-フェニルエチル(メチル)アミノ)メチル)- 1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-フェニルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

メチルフェネチルエーテル(1.0 g, 7.34 mmol)とNBS(1.96 g, 11.01 mmol)、AIBN(240 mg, 1.47 mmol)の四塩化炭素(30 ml)溶液を2時間加熱還流した。冷却後、反応混合物を飽和重曹水で希釈し、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下濃縮し、粗2-メトキシ-1-フェニルブロモエタン(1.33 g, 84 %)を茶色液体として得た。
参考例１５の化合物 (200 mg, 0.34 mmol)と上記粗ブロマイド(50 mg)を用いて実施例１４と同様の反応を行い、表題化合物 (42 mg, 18 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.97 (3H, s), 3.24 (3H, s), 3.55-3.61 (1H, m), 3.80 (3H, s), 3.86-3.96 (3H, m), 4.67 (1H, s), 5.36 (2H, s), 6.91 (2H, t, J= 8.1 Hz), 7.14-7.31 (8H, m), 7.33-7.56 (8H, m), 7.63 (1H, s).
元素分析 C₃₈H₃₅F₂N₅O₅S・0.2H₂Oとして
計算値: C, 63.80; H, 4.99; N, 9.79.
実測値: C, 63.64; H, 4.95; N, 9.89.
mp 169-172 ℃. Reference Example 30
N- (4- (5- ( (Methyl (1-phenylpropyl ) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3 -Phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Methanesulfonyl chloride (690 μl, 8.81 mmol) was added to a solution of 1-phenyl-1-propanol (1.0 g, 7.34 mmol) and N-ethyldiisopropylamine (1.42 g, 11.01 mmol) in dichloromethane (10 ml) under ice-cooling. The mixture was further stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane: 5/1) to give 1-chloro-1-phenylpropane (610 mg, 54%) as a pale yellow liquid.
Using the compound of Reference Example 15 (100 mg, 0.17 mmol) and this 1-chloro-1-phenylpropane (32 mg, 0.21 mmol), the same reaction as in Reference Example 26 was performed, and the title compound (45 mg, 38 %) Was obtained as white crystals.
¹ H NMR (CDCl ₃ ) δ 0.67 (3H, t, J = 7.2 Hz), 1.63-1.91 (5H, m), 3.52-3.57 (1H, m), 3.73-3.93 (5H, m), 3.91 (2H , d, J = 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.08-7.34 (8H, m), 7.41-7.55 (8H, m), 7.64 (1H, s).
mp 171-172 ° C.
Reference Example 31
Methyl (((1- (2,6-difluorobenzyl) -6- (4-(((methoxyamino) carbonyl) amino) phenyl) -2,4dioxo-3-phenyl-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) methyl) (methyl) amino) (phenyl) acetic acid

The same reaction as in Example 20 was carried out using the compound of Reference Example 15 (150 mg, 0.17 mmol) and methyl α-bromophenylacetate (71 mg, 0.31 mmol) to give the title compound (73 mg, 39%) as white Obtained as crystals.
¹ H NMR (CDCl ₃ ) δ 2.08 (3H, s), 3.54 (32H, s), 3.79 (3H, s), 3.89-4.20 (2H, AB), 4.67 (1H, s), 5.35 (2H, brs ), 6.92 (2H, t, J = 8.2 Hz), 7.22-7.37 (6H, m), 7.44-7.56 (7H, m) 7.71 (2H, d, J = 8.0 Hz).
Elemental analysis Calculated as C ₃₈ H ₃₃ F ₂ N ₅ O ₆ S: C, 62.89; H, 4.58; N, 9.65.
Found: C, 62.70; H, 4.61; N, 9.78.
mp 147-149 ° C.
Reference Example 32
N- (4- (1- (2,6-difluorobenzyl) -5-((2-methoxy-1-phenylethyl (methyl) amino) methyl) -1,2,3,4-tetrahydro-2,4 -Dioxo-3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

A solution of methyl phenethyl ether (1.0 g, 7.34 mmol), NBS (1.96 g, 11.01 mmol) and AIBN (240 mg, 1.47 mmol) in carbon tetrachloride (30 ml) was heated to reflux for 2 hours. After cooling, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 2-methoxy-1-phenylbromoethane (1.33 g, 84%) as a brown liquid.
The same reaction as in Example 14 was carried out using the compound of Reference Example 15 (200 mg, 0.34 mmol) and the above crude bromide (50 mg) to obtain the title compound (42 mg, 18%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.97 (3H, s), 3.24 (3H, s), 3.55-3.61 (1H, m), 3.80 (3H, s), 3.86-3.96 (3H, m), 4.67 (1H , s), 5.36 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.14-7.31 (8H, m), 7.33-7.56 (8H, m), 7.63 (1H, s).
Elemental analysis Calculated as C ₃₈ H ₃₅ F ₂ N ₅ O ₅ S ・ 0.2H ₂ O: C, 63.80; H, 4.99; N, 9.79.
Found: C, 63.64; H, 4.95; N, 9.89.
mp 169-172 ° C.

2-エチルピリジン(10.0 g, 93.34 mmol)とN-ブロモこはく酸イミド(17.44 g, 98.00 mmol)、アゾビスイソブチロ二トリル(1.53 g, 9.33 mmol)の四塩化炭素(300 ml)溶液を90℃で1時間撹拌した。冷却後、反応混合物をろ過し、ろ液を飽和重曹水、飽和食塩水で洗浄し硫酸マグネシウムで乾燥後、濃縮した。残渣をシリカゲルクロマトグラフィーで精製し、ブロマイド(15.68g, 90%)を淡黄色液体として得た。
参考例１５の化合物(160 mg, 0.26 mmol)と上記ブロマイド(62 mg, 0.33 mmol)を用いて実施例１４と同様の反応を行い、表題化合物(133 mg, 75 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.30 (3H, d, J= 6.9 Hz), 1.92 (3H, s), 3.80 (3H, s), 4.00 (2H, s), 4.04 (1H, q, J= 6.6 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.0 Hz), 7.02-7.06 (1H, m), 7.24-7.30 (4H, m), 7.40-7.54 (8H, m), 7.65 (1H, s), 8.44 (1H, d, J= 5.7 Hz).
mp 146-148 ℃.
表題化合物(40 mg)をヘキサン/2-プロパノール=3/2を移動相とするCHIRALPAK AD(50 mmI.D.×500 mmL)を用いたHPLC分取により光学分割し、CHIRALPAK AD(4.6 mmI.D.×250 mmL)を用いた分析において保持時間25分(99.9% ee)と29分(99.0% ee)の光学活性体をそれぞれ19mgと19mgを白色粉末として得た。
参考例３４
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシ-1-メチルエチル)メチルアミノ)メチル)- 1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-フェニルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１８の化合物 (100 mg, 0.17 mmol) と参考例２４の化合物(21 mg,0.21 mmol)を用いて参考例２６と同様の反応を行い、表題化合物(24 mg, 21 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 0.90 (3H, d, J= 6.3 Hz), 2.04 (3H, s),3.06-3.16 (2H, m), 3.26 (3H, s), 3.40-3.46 (1H, m), 3.51-3.98 (4H, m), 5.35 (2H, s), 6.90 (2H, t, J= 8.4 Hz), 7.09 (1H, s), 7.25-7.32 (5H, m), 7.39-7.60 (6H, m).
元素分析 C₃₃H₃₃F₂N₅O₅S・0.3H₂Oとして
計算値: C, 60.50; H, 5.17; N, 10.69.
実測値: C, 60.28; H, 5.21; N, 10.53.
mp 154-155 ℃.
表題化合物 (48 mg)をヘキサン/2-プロパノール=65/35を移動相とするCHIRALPAK AD(50 mmI.D.×500 mmL)を用いたHPLC分取により光学分割し、CHIRALPAK OD(4.6 mmI.D.×250 mmL)を用いた分析において保持時間49分(99.0 % ee)と54分(99.0% ee)の光学活性体をそれぞれ22 mgと21 mgを白色粉末として得た。
参考例３５
N-(4- (1-(2,6-ジフルオロベンジル)-5-((メチル(1-ピリジン-2-イルエチル)アミノ)メチル)- 1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(ピリジン-2-イル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例１４の化合物(100 mg, 0.17 mmol)を用いて参考例３３と同様の反応を行い、表題化合物(31 mg, 27 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.30 (3H, d, J= 6.9 Hz), 1.92 (3H, s), 3.80 (3H, s), 3.98-4.10 (3H, m), 5.33 (2H, brs), 6.90 (2H, t, J= 8.1 Hz), 7.01-7.06 (1H, m), 7.23-7.42 (5H, m), 7.49-7.56 (4H, m) 7.65 (1H, s), 7.90 (1H, t, J= 7.8 Hz), 8.44 (1H, d, J= 3.9 Hz), 8.68 (1H, d, J= 5.7 Hz).
mp 143-144 ℃.
表題化合物(20 mg)をヘキサン/2-プロパノール=1/1を移動相とするCHIRALPAK AD(50 mmI.D.×500 mmL)を用いたHPLC分取により光学分割し、CHIRALPAK AD(4.6 mmI.D.×250 mmL)を用いた分析において保持時間23分(99.9% ee)と28分(99.2% ee)の光学活性体をそれぞれ10mgと11mgを無色油状物として得た。 Reference Example 33
N- (4- (1- (2,6-difluorobenzyl) -5- ( (methyl (1-pyridin-2-ylethyl) amino) methyl) -1,2,3,4-tetrahydro-2,4- Preparation of dioxo-3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

A solution of 2-ethylpyridine (10.0 g, 93.34 mmol), N-bromosuccinimide (17.44 g, 98.00 mmol) and azobisisobutyronitryl (1.53 g, 9.33 mmol) in carbon tetrachloride (300 ml) Stir at 90 ° C. for 1 hour. After cooling, the reaction mixture was filtered, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography to obtain bromide (15.68 g, 90%) as a pale yellow liquid.
The same reaction as in Example 14 was carried out using the compound of Reference Example 15 (160 mg, 0.26 mmol) and the above bromide (62 mg, 0.33 mmol) to obtain the title compound (133 mg, 75%) as white crystals. .
¹ H NMR (CDCl ₃ ) δ 1.30 (3H, d, J = 6.9 Hz), 1.92 (3H, s), 3.80 (3H, s), 4.00 (2H, s), 4.04 (1H, q, J = 6.6 Hz), 5.35 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.02-7.06 (1H, m), 7.24-7.30 (4H, m), 7.40-7.54 (8H, m), 7.65 (1H, s), 8.44 (1H, d, J = 5.7 Hz).
mp 146-148 ° C.
The title compound (40 mg) was optically resolved by HPLC fractionation using CHIRALPAK AD (50 mmI.D. × 500 mmL) with hexane / 2-propanol = 3/2 as the mobile phase, and CHIRALPAK AD (4.6 mmI. In the analysis using D. × 250 mmL), 19 mg and 19 mg of optically active substances having a retention time of 25 minutes (99.9% ee) and 29 minutes (99.0% ee) were obtained as white powder, respectively.
Reference Example 34
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxy-1-methylethyl) methylamino) methyl) -1,2,3,4-tetrahydro-2,4 -Dioxo-3-phenylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 26 was carried out using the compound of Reference Example 18 (100 mg, 0.17 mmol) and the compound of Reference Example 24 (21 mg, 0.21 mmol) to give the title compound (24 mg, 21%) as white crystals Got as.
¹ H NMR (CDCl ₃ ) δ 0.90 (3H, d, J = 6.3 Hz), 2.04 (3H, s), 3.06-3.16 (2H, m), 3.26 (3H, s), 3.40-3.46 (1H, m ), 3.51-3.98 (4H, m), 5.35 (2H, s), 6.90 (2H, t, J = 8.4 Hz), 7.09 (1H, s), 7.25-7.32 (5H, m), 7.39-7.60 ( 6H, m).
Elemental analysis Calculated as C ₃₃ H ₃₃ F ₂ N ₅ O ₅ S ・ 0.3H ₂ O: C, 60.50; H, 5.17; N, 10.69.
Found: C, 60.28; H, 5.21; N, 10.53.
mp 154-155 ° C.
The title compound (48 mg) was optically resolved by HPLC fractionation using CHIRALPAK AD (50 mmI.D. × 500 mmL) with hexane / 2-propanol = 65/35 as the mobile phase, and CHIRALPAK OD (4.6 mmI. In the analysis using D. × 250 mmL), 22 mg and 21 mg of optically active substances having retention times of 49 minutes (99.0% ee) and 54 minutes (99.0% ee) were obtained as white powder, respectively.
Reference Example 35
N- (4- (1- (2,6-difluorobenzyl) -5-((methyl (1-pyridin-2-ylethyl) amino) methyl) -1,2,3,4-tetrahydro-2,4- Preparation of dioxo-3- (pyridin-2-yl) thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 33 was carried out using the compound of Reference Example 14 (100 mg, 0.17 mmol) to give the title compound (31 mg, 27%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.30 (3H, d, J = 6.9 Hz), 1.92 (3H, s), 3.80 (3H, s), 3.98-4.10 (3H, m), 5.33 (2H, brs), 6.90 (2H, t, J = 8.1 Hz), 7.01-7.06 (1H, m), 7.23-7.42 (5H, m), 7.49-7.56 (4H, m) 7.65 (1H, s), 7.90 (1H, t , J = 7.8 Hz), 8.44 (1H, d, J = 3.9 Hz), 8.68 (1H, d, J = 5.7 Hz).
mp 143-144 ° C.
The title compound (20 mg) was optically resolved by HPLC fractionation using CHIRALPAK AD (50 mmI.D. × 500 mmL) with hexane / 2-propanol = 1/1 as the mobile phase, and CHIRALPAK AD (4.6 mmI. In the analysis using D. × 250 mmL), 10 mg and 11 mg of optically active substances having retention times of 23 minutes (99.9% ee) and 28 minutes (99.2% ee) were obtained as colorless oils, respectively.

参考例２３の化合物(100 mg, 0.17 mmol)を用いて参考例３３と同様の反応を行い、表題化合物(17 mg, 14 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.35 (3H, d, J= 6.9 Hz), 1.43-1.54 (2H, m), 1.91 (3H, s), 2.09 (2H, d, J= 12.3 Hz), 2.65 (2H, q, J= 12.8 Hz), 3.73-3.81 (4H, m), 3.98-4.13 (3H, m), 4.60 (1H, t, J= 12.0 Hz), 5.28 (2H, brs), 6.88 (2H, t, J= 8.1 Hz), 6.89-7.08 (1H, m), 7.22-7.31 (3H, m), 7.40-7.54 (4H, m) 7.62 (1H, s), 8.45 (1H, d, J= 4.89 Hz).
mp 144-145 ℃.
参考例３７
N-(4-(5-(((1R)-1-フェニルエチルアミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(4-ヒドロキシシクロヘキシル)-1,2,3,4-テトラヒドロ-2,4-ジオキソチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例２０の化合物(180 mg, 0.30 mmol)を用いて参考例２６と同様の反応を行い、表題化合物(77 mg, 37 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.30 (3H, d, J= 6.6 Hz), 1.43-1.57 (2H, m), 1.71 (2H, d, J= 9.9 Hz), 1.88 (3H, s), 2.04-2.15 (2H, m), 2.62-2.71 (2H, m), 3.70-3.93 (7H, m), 4.90-5.10 (1H, m), 5.28 (2H, s), 6.89 (2H, t, J= 8.1 Hz), 7.11-7.30 (8H, m), 7.51 (3H, s), 7.60 (1H, s).
元素分析 C₃₇H₃₉F₂N₅O₅S・1.5H₂Oとして
計算値: C, 60.81; H, 5.79; N, 9.58.
実測値: C, 60.77; H, 5.72; N, 9.41.
mp 137-138 ℃.
参考例３８
N-(4-(5-((メチル((1R)-1-フェニルエチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-ピリジン-2-イルチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例２２の化合物 (270 mg, 0.46 mmol)を用いて参考例２６と同様の反応を行い、表題化合物 (178mg, 57 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.27 (3H, d, J= 6.8 Hz), 1.91 (3H, s), 2.04-2.15 (2H, m), 2.62-2.71 (2H, m), 3.75-4.00 (4H, m), 5.30 (2H, brs), 6.91 (2H, t, J= 8.1 Hz), 7.13-7.42 (10H, m), 7.54 (2H, d, J= 8.6 Hz), 7.61 (2H, d, J= 8.5 Hz), 7.91 (1H, t, J= 7.7 Hz), 8.70 (1H, d, J= 4.8 Hz).
元素分析 C₃₆H₃₂F₂N₆O₄S・0.5H₂Oとして
計算値: C, 62.51; H, 4.81; N, 12.15.
実測値: C, 62.34; H, 4.71; N, 12.12.
mp 168-170 ℃. Reference Example 36
N- (4- (1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -5-(( methyl ( 1-pyridin-2-ylethyl) amino) methyl) -1,2,3 , 4-Tetrahydro-2,4-dioxothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 33 was performed using the compound of Reference Example 23 (100 mg, 0.17 mmol) to obtain the title compound (17 mg, 14%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.35 (3H, d, J = 6.9 Hz), 1.43-1.54 (2H, m), 1.91 (3H, s), 2.09 (2H, d, J = 12.3 Hz), 2.65 ( 2H, q, J = 12.8 Hz), 3.73-3.81 (4H, m), 3.98-4.13 (3H, m), 4.60 (1H, t, J = 12.0 Hz), 5.28 (2H, brs), 6.88 (2H , t, J = 8.1 Hz), 6.89-7.08 (1H, m), 7.22-7.31 (3H, m), 7.40-7.54 (4H, m) 7.62 (1H, s), 8.45 (1H, d, J = 4.89 Hz).
mp 144-145 ° C.
Reference Example 37
N- (4- (5-(((1R) -1-phenylethylamino) methyl) -1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -1,2,3,4 -Tetrahydro-2,4-dioxothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 26 was carried out using the compound of Reference Example 20 (180 mg, 0.30 mmol) to obtain the title compound (77 mg, 37%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.30 (3H, d, J = 6.6 Hz), 1.43-1.57 (2H, m), 1.71 (2H, d, J = 9.9 Hz), 1.88 (3H, s), 2.04- 2.15 (2H, m), 2.62-2.71 (2H, m), 3.70-3.93 (7H, m), 4.90-5.10 (1H, m), 5.28 (2H, s), 6.89 (2H, t, J = 8.1 Hz), 7.11-7.30 (8H, m), 7.51 (3H, s), 7.60 (1H, s).
Elemental analysis Calculated as C ₃₇ H ₃₉ F ₂ N ₅ O ₅ S ・ 1.5H ₂ O: C, 60.81; H, 5.79; N, 9.58.
Found: C, 60.77; H, 5.72; N, 9.41.
mp 137-138 ° C.
Reference Example 38
N- (4- (5-(( methyl ( (1R) -1-phenylethyl) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4 -Dioxo-3-pyridin-2-ylthieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 26 was carried out using the compound of Reference Example 22 (270 mg, 0.46 mmol), and the title compound (178 mg, 57%) was obtained as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.27 (3H, d, J = 6.8 Hz), 1.91 (3H, s), 2.04-2.15 (2H, m), 2.62-2.71 (2H, m), 3.75-4.00 (4H , m), 5.30 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.13-7.42 (10H, m), 7.54 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.91 (1H, t, J = 7.7 Hz), 8.70 (1H, d, J = 4.8 Hz).
Elemental analysis Calculated as C ₃₆ H ₃₂ F ₂ N ₆ O ₄ S0.5H ₂ O: C, 62.51; H, 4.81; N, 12.15.
Found: C, 62.34; H, 4.71; N, 12.12.
mp 168-170 ° C.

参考例２１の化合物(280 mg, 0.46 mmol)を用いて参考例２６と同様の反応を行い、表題化合物(187mg, 58 %)を白色結晶として得た。
¹H NMR (CDCl₃) δ 1.27 (3H, d, J= 6.6 Hz), 1.90 (3H, s), 3.78-3.99 (5H, m), 5.33 (2H, brs), 6.91 (2H, t, J= 8.1 Hz), 7.12-7.38 (9H, m), 7.51-7.63 (5H, m), 8.52 (1H, d, J= 3.0 Hz).
元素分析 C₃₆H₃₁F₃N₆O₄S・0.2H₂Oとして
計算値: C, 61.39; H, 4.49; N, 11.93.
実測値: C, 61.22; H, 4.56; N, 11.96.
mp 128-130 ℃.
参考例４０
N-(4-(5-(((2-メトキシエチル)メチルアミノ)メチル)-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(4-メトキシフェニル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例２５の化合物(800 mg, 1.24 mmol)と2-ブロモエチルエチルエーテル(207 mg, 1.49mmol)を用いて実施例４と同様の反応を行い、表題化合物(407mg, 58 %)を白色固体として得た。
¹H NMR (CDCl₃) δ 2.13 (3H, s), 2.64 (2H, t, J= 5.7 Hz), 3.27(3H, s), 3.41 (2H, t, J= 5.6 Hz), 3.82 (3H, s), 3.84 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J= 8.1 Hz), 7.01 (2H, d, J= 8.7 Hz), 7.11 81H, s), 7.19 (2H, d, J= 8.7 Hz), 7.26-7.33 (3H, m), 7.53-7.70 (5H, m).
mp 181-184℃
参考例４１
1-アミノ-2-メチル-2-プロパノールの製造

水素化リチウムアルミニウム(2.85g, 75mmol)のジエチルエーテル(120ml)懸濁液に氷冷下、アセトンシアノヒドリン(4.73g, 50mmol)のジエチルエーテル(30ml)溶液を滴下した。反応液を室温で4時間攪拌後、水(2.85ml)、1N水酸化ナトリウム水溶液(2.85ml)、次いで水(8.55ml)を滴下した。不溶物をろ去後、ろ液を濃縮し、表題化合物(1.32g, 30%)を無色油状物として得た。
¹H-NMR(CDCl₃) δ: 1.17 (6H, s), 2.60 (2H, s). Reference Example 39
N- (4- (5-(( methyl ( (1R) -1-phenylethyl ) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4 -Dioxo-3- (5-fluoropyridin-2-yl) thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction of Reference Example 26 was carried out using the compound of Reference Example 21 (280 mg, 0.46 mmol) to give the title compound (187 mg, 58%) as white crystals.
¹ H NMR (CDCl ₃ ) δ 1.27 (3H, d, J = 6.6 Hz), 1.90 (3H, s), 3.78-3.99 (5H, m), 5.33 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.12-7.38 (9H, m), 7.51-7.63 (5H, m), 8.52 (1H, d, J = 3.0 Hz).
Elemental analysis Calculated as C ₃₆ H ₃₁ F ₃ N ₆ O ₄ S0.2H ₂ O: C, 61.39; H, 4.49; N, 11.93.
Found: C, 61.22; H, 4.56; N, 11.96.
mp 128-130 ° C.
Reference Example 40
N- (4- (5-(( ( 2-methoxyethyl) methylamino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3 -(4-Methoxyphenyl) thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Example 4 was carried out using the compound of Reference Example 25 (800 mg, 1.24 mmol) and 2-bromoethyl ethyl ether (207 mg, 1.49 mmol) to give the title compound (407 mg, 58%) as a white solid Got as.
¹ H NMR (CDCl ₃ ) δ 2.13 (3H, s), 2.64 (2H, t, J = 5.7 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.6 Hz), 3.82 (3H, s), 3.84 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.1 Hz), 7.01 (2H, d, J = 8.7 Hz), 7.11 81H, s), 7.19 (2H , d, J = 8.7 Hz), 7.26-7.33 (3H, m), 7.53-7.70 (5H, m).
mp 181-184 ℃
Reference Example 41
Production of 1-amino-2-methyl-2-propanol

A solution of acetone cyanohydrin (4.73 g, 50 mmol) in diethyl ether (30 ml) was added dropwise to a suspension of lithium aluminum hydride (2.85 g, 75 mmol) in diethyl ether (120 ml) under ice cooling. After the reaction solution was stirred at room temperature for 4 hours, water (2.85 ml), 1N aqueous sodium hydroxide solution (2.85 ml) and then water (8.55 ml) were added dropwise. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (1.32 g, 30%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.17 (6H, s), 2.60 (2H, s).

3-{[tert-ブチル(ジメチル)シリル]オキシ}-2,2-ジメチルプロパン-1-オール(Regstry No. 117932-70-4)(2.18 g, 10 mmol)のTHF(30 ml)溶液に氷冷下、トリエチルアミン(1.67 ml, 12 mmol)とメタンスルホニルクロリド(0.85 ml, 11 mmol)を加えた。反応液を室温で30分攪拌後、重曹水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、無水硫酸マグネシウムで乾燥、減圧濃縮し、表題化合物(2.98g, quant.)を無色油状物として得た。
¹H-NMR(CDCl₃) δ: 0.04 (6H, s), 0.89 (9H, s), 0.93 (6H, s), 2.98 (3H, s), 3.34 (9H, s), 4.00 (2H, s).
参考例４３
2-(3-{[tert-ブチル(ジメチル)シリル]オキシ}-2,2-ジメチルプロピル)-1H-イソインドール-1,3(2H)-ジオンの製造

参考例４２の化合物(2.96 g, 10 mmol)のDMF(10 ml)溶液に、フタルイミドカリウム(1.85 g, 10 mmol)を加えた。反応液を140℃で30時間攪拌後、水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、無水硫酸マグネシウムで乾燥、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル/ヘキサン=1/10）で精製し、表題化合物(2.79 g, 80%)を淡黄色油状物として得た。
¹H-NMR(CDCl₃) δ: 0.01 (6H, s), 0.87 (9H, s), 0.93 (6H, s), 3.39 (2H, s), 3.61 (2H, s), 7.65-7.75 (2H, m), 7.8-7.9 (2H, m).
参考例４４
3-アミノ-2,2-ジメチルプロパン-1-オール塩酸塩の製造

参考例４３の化合物(1.395 g, 4.0 mmol)、濃塩酸(10 ml)、酢酸(7 ml)と水(10 ml)の混合液を24時間還流した。反応液を濃縮し、水を加えた。析出するフタル酸をろ去し、ろ液を濃縮した。残渣を酢酸エチルで再結晶し、表題化合物(257.2 mg, 46%)を淡紫色結晶として得た。
¹H-NMR(CDCl₃+CD₃OD) δ: 2.91 (2H, brs), 3.38 (6H, brs), 3.52 (2H, brs). Reference Example 42
Preparation of tert-butyl (3-ethoxy-2,2-dimethylpropoxy) dimethylsilane

3-{[tert-Butyl (dimethyl) silyl] oxy} -2,2-dimethylpropan-1-ol (Regstry No. 117932-70-4) (2.18 g, 10 mmol) in a THF (30 ml) solution Under ice-cooling, triethylamine (1.67 ml, 12 mmol) and methanesulfonyl chloride (0.85 ml, 11 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.98 g, quant.) As a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.89 (9H, s), 0.93 (6H, s), 2.98 (3H, s), 3.34 (9H, s), 4.00 (2H, s ).
Reference Example 43
Preparation of 2- (3-{[tert-butyl (dimethyl) silyl] oxy} -2,2-dimethylpropyl) -1H-isoindole-1,3 (2H) -dione

To a solution of the compound of Reference Example 42 (2.96 g, 10 mmol) in DMF (10 ml), potassium phthalimide (1.85 g, 10 mmol) was added. The reaction mixture was stirred at 140 ° C. for 30 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate / hexane = 1/10) to give the title compound (2.79 g, 80%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.01 (6H, s), 0.87 (9H, s), 0.93 (6H, s), 3.39 (2H, s), 3.61 (2H, s), 7.65-7.75 (2H , m), 7.8-7.9 (2H, m).
Reference Example 44
Production of 3-amino-2,2-dimethylpropan-1-ol hydrochloride

A mixture of the compound of Reference Example 43 (1.395 g, 4.0 mmol), concentrated hydrochloric acid (10 ml), acetic acid (7 ml) and water (10 ml) was refluxed for 24 hours. The reaction mixture was concentrated and water was added. The precipitated phthalic acid was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to give the title compound (257.2 mg, 46%) as pale purple crystals.
¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.91 (2H, brs), 3.38 (6H, brs), 3.52 (2H, brs).

水素化リチウムアルミニウム(9.34 g, 246 mmol)のTHF(150 ml)溶液に氷冷下、ジメチルシクロプロパン-1,1-ジカルボキシレート(25.95 g, 164.1 mmol)のTHF(150 ml)溶液を滴下した。0℃で2時間攪拌後、水(9.5 ml)、15%NaOH水溶液(9.5 ml)、次いで、水(30 ml)をゆっくりと加えた。不溶物をろ去し、ろ液を濃縮し、シクロプロパン-1,1-ジメチルメタノールを無色油状物として得た。
上記油状物の1,2-ジメトキシエタン(150 ml)溶液に水素化ナトリウム(60% oil, 6.56 g, 164 mmol)を加え、室温で1時間攪拌した。反応液にtert-ブチルクロロジメチルシラン(24.7 g, 164 mmol)の1,2-ジメトキシエタン(100 ml)溶液を滴下し、室温で一晩攪拌を続けた。反応液を水に注ぎ、酢酸エチルで2回抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル/ヘキサン=1/15-1/9）で精製し、表題化合物(28.19g, 79%)を無色油状物として得た。
¹H-NMR(CDCl₃) δ: 0.07 (6H, s), 0.45-0.54 (4H, m), 0.91 (9H, s), 2.35 (1H, brs), 3.56 (2H, s), 3.61 (2H, s).
IR(neat) 3361, 2953, 2856, 1466, 1254, 1088, 1030, 837, 777cm^-1.
参考例４６
tert-ブチル{[1-(エトキシメチル)シクロプロピル]メトキシ}ジメチルシランの製造

参考例４５の化合物(4.33 g, 20 mmol) を用いて、参考例４２と同様の反応を行い、表題化合物 (5.71 g, 97%)を無色油状物として得た。
¹H-NMR(CDCl₃) δ: 0.05 (6H, s), 0.55-0.65 (4H, m), 0.89 (9H, s), 3.01 (3H, s), 3.52 (2H, s), 4.17 (2H, s).
参考例４７
2-{[1-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)シクロプロピル]メチル}-1H-イソインドール-1,3(2H)-ジオンの製造

参考例４６の化合物(5.71 g, 19.39 mmol) を用いて、参考例４３と同様の反応を行い、表題化合物 (5.02 g, 75%)を無色油状物として得た。
¹H-NMR(CDCl₃) δ: -0.07 (6H, s), 0.45-0.55 (2H, m), 0.65-0.75 (2H, m), 0.79 (9H, s), 3.53 (2H, s), 3.74 (2H, s), 7.65-7.75 (2H, m), 7.80-7.90 (2H, m). Reference Example 45
Preparation of [1-({[tert-butyl (dimethyl) silyl] oxy} methyl) cyclopropyl] methanol

A solution of dimethylcyclopropane-1,1-dicarboxylate (25.95 g, 164.1 mmol) in THF (150 ml) was added dropwise to a solution of lithium aluminum hydride (9.34 g, 246 mmol) in THF (150 ml) under ice-cooling. did. After stirring at 0 ° C. for 2 hours, water (9.5 ml), 15% aqueous NaOH solution (9.5 ml), and then water (30 ml) were slowly added. The insoluble material was removed by filtration, and the filtrate was concentrated to give cyclopropane-1,1-dimethylmethanol as a colorless oil.
Sodium hydride (60% oil, 6.56 g, 164 mmol) was added to a solution of the above oil in 1,2-dimethoxyethane (150 ml), and the mixture was stirred at room temperature for 1 hour. A solution of tert-butylchlorodimethylsilane (24.7 g, 164 mmol) in 1,2-dimethoxyethane (100 ml) was added dropwise to the reaction solution, and stirring was continued overnight at room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. 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 = 1 / 15-1 / 9) to give the title compound (28.19 g, 79%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.07 (6H, s), 0.45-0.54 (4H, m), 0.91 (9H, s), 2.35 (1H, brs), 3.56 (2H, s), 3.61 (2H , s).
IR (neat) 3361, 2953, 2856, 1466, 1254, 1088, 1030, 837, 777cm ^-1 .
Reference Example 46
Preparation of tert-butyl {[1- (ethoxymethyl) cyclopropyl] methoxy} dimethylsilane

Using the compound of Reference Example 45 (4.33 g, 20 mmol), the reaction was carried out in the same manner as in Reference Example 42 to obtain the title compound (5.71 g, 97%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.05 (6H, s), 0.55-0.65 (4H, m), 0.89 (9H, s), 3.01 (3H, s), 3.52 (2H, s), 4.17 (2H , s).
Reference Example 47
2-{[1-({[tert-Butyl (dimethyl) silyl] oxy} methyl) cyclopropyl] methyl} -1H-isoindole-1,3 (2H) -dione

Using the compound of Reference Example 46 (5.71 g, 19.39 mmol), the same reaction as in Reference Example 43 was performed to obtain the title compound (5.02 g, 75%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: -0.07 (6H, s), 0.45-0.55 (2H, m), 0.65-0.75 (2H, m), 0.79 (9H, s), 3.53 (2H, s), 3.74 (2H, s), 7.65-7.75 (2H, m), 7.80-7.90 (2H, m).

参考例４７の化合物(2.0g, 5.79mmol) のエタノール(20ml)溶液にヒドラジン1水和物(0.42ml, 8.68mmol)を加え、2時間還流した。不溶物をろ去し、ろ液を濃縮した。残渣を酢酸エチルと1N-水酸化ナトリウム水溶液で分配し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥、濃縮し、表題化合物 (1.15 g, 92%)を淡黄色油状物として得た。
¹H-NMR(CDCl₃) δ: 0.0-0.1 (6H, m), 0.3-0.4 (4H, m), 0.85 (9H, s), 2.61 (2H, s), 3.49 (2H, s).
参考例４９
N-(4- (5-クロロメチル-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(6-メトキシ-3-ピリジニル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(6-メトキシ-3-ピリジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(49.3 mg, 0.074 mmol)を用いて、参考例１８と同様の反応を行い、表題化合物 (44.1mg, quant.)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 3.83 (3H, s), 3.97 (3H, s), 4.83 (2H, s), 5.37 (2H, s), 6.87 (1H, d, J = 9.0 Hz), 6.94 (2H, t, J = 8.4 Hz), 7.13 (1H, s), 7.25-7.35 (1H, m), 7.5-7.6 (3H, m), 7.52 (2H, d, J = 9.0 Hz), 7.66 (1H, s), 8.1-8.15 (1H, m).
参考例５０
N-(4- (5-クロロメチル-1-(2,6-ジフルオロベンジル)-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-(6-メトキシ-3-ピリダジニル)チエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレア(1.34g, 2mmol)を用いて、参考例１８と同様の反応を行い、表題化合物 (888.5 mg, 71%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 3.83 (3H, s), 4.19 (3H, s), 4.7-4.9 (2H, brm), 5.3-5.45 (2H, m), 6.93 (2H, t, J = 8.0 Hz), 7.14 (1H, d, J = 9.0 Hz), 7.16 (1H, s), 7.2-7.4 (1H, m), 7.42(1H, d, J = 9.0 Hz), 7.52(2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.69 (1H, s). Reference Example 48
Preparation of 1- [1-({[tert-butyl (dimethyl) silyl] oxy} methyl) cyclopropyl] methanamine

Hydrazine monohydrate (0.42 ml, 8.68 mmol) was added to a solution of the compound of Reference Example 47 (2.0 g, 5.79 mmol) in ethanol (20 ml) and refluxed for 2 hours. Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the title compound (1.15 g, 92%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.0-0.1 (6H, m), 0.3-0.4 (4H, m), 0.85 (9H, s), 2.61 (2H, s), 3.49 (2H, s).
Reference Example 49
N- (4- (5-chloromethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3- (6-methoxy-3-pyridinyl) thieno Preparation of [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

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-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (49.3 mg, 0.074 mmol) as in Reference Example 18 The title compound (44.1 mg, quant.) Was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H, s), 3.97 (3H, s), 4.83 (2H, s), 5.37 (2H, s), 6.87 (1H, d, J = 9.0 Hz), 6.94 (2H, t, J = 8.4 Hz), 7.13 (1H, s), 7.25-7.35 (1H, m), 7.5-7.6 (3H, m), 7.52 (2H, d, J = 9.0 Hz), 7.66 (1H, s), 8.1-8.15 (1H, m).
Reference Example 50
N- (4- (5-chloromethyl-1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4-dioxo-3- (6-methoxy-3-pyridazinyl) thieno Preparation of [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea (1.34 g, 2 mmol) and similar to Reference Example 18 The reaction was performed to give the title compound (888.5 mg, 71%) as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H, s), 4.19 (3H, s), 4.7-4.9 (2H, brm), 5.3-5.45 (2H, m), 6.93 (2H, t, J = 8.0 Hz), 7.14 (1H, d, J = 9.0 Hz), 7.16 (1H, s), 7.2-7.4 (1H, m), 7.42 (1H, d, J = 9.0 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.69 (1H, s).

後述の実施例６９の化合物(1.75g, 2.54 mmol)を用いて、参考例１４と同様の反応を行い、表題化合物 (1.60g, quant.)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.4-1.9 (3H, m), 2.0-2.2 (2H, m), 2.40 (3H, s), 2.5-2.75 (2H, m), 3.77 (2H, s), 3.7-3.85 (1H, m), 3.82 (3H, s), 4.9-5.1 (1H, m), 5.30 (2H, s), 6.90 (2H, t, J = 8.0 Hz), 7.2-7.35 (2H, m), 7.38 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.61 (1H, s).
参考例５２
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシプロピル)-5-((メチルアミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

後述の実施例７２の化合物(360 mg, 0.554 mmol)を用いて、参考例１４と同様の反応を行い、表題化合物 (281 mg, 91%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 1.29 (3H, d, J = 6.0 Hz), 2.39 (3H, s), 3.80 (2H, s), 3.82 (3H, s), 4.1-4.25 (3H, m), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.25-7.35 (2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.63 (1H, s).
参考例５３
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシ-2-メチルプロピル)-5-((メチルアミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

後述の実施例７３の化合物(310 mg, 0.467 mmol)を用いて、参考例１４と同様の反応を行い、表題化合物 (241 mg, 90%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 1.28 (6H, s), 2.38 (3H, s), 3.80 (2H, s), 3.82 (3H, s), 3.88 (1H, brs), 4.26 (2H, s), 5.37 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.25-7.35 (2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.63 (1H, s). Reference Example 51
N- (4- (1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -5-((methylamino) methyl) -2,4-dioxo-1,2,3,4- Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 14 was carried out using the compound of Example 69 (1.75 g, 2.54 mmol) described later to give the title compound (1.60 g, quant.) As colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.4-1.9 (3H, m), 2.0-2.2 (2H, m), 2.40 (3H, s), 2.5-2.75 (2H, m), 3.77 (2H, s) , 3.7-3.85 (1H, m), 3.82 (3H, s), 4.9-5.1 (1H, m), 5.30 (2H, s), 6.90 (2H, t, J = 8.0 Hz), 7.2-7.35 (2H , m), 7.38 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.61 (1H, s).
Reference Example 52
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxypropyl) -5-((methylamino) methyl) -2,4-dioxo-1,2,3,4- Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 14 was performed using the compound of Example 72 (360 mg, 0.554 mmol) described later to obtain the title compound (281 mg, 91%) as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 6.0 Hz), 2.39 (3H, s), 3.80 (2H, s), 3.82 (3H, s), 4.1-4.25 (3H, m ), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.25-7.35 (2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.63 (1H, s).
Reference Example 53
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxy-2-methylpropyl) -5-((methylamino) methyl) -2,4-dioxo-1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 14 was performed using the compound of Example 73 (310 mg, 0.467 mmol) described later to obtain the title compound (241 mg, 90%) as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, s), 2.38 (3H, s), 3.80 (2H, s), 3.82 (3H, s), 3.88 (1H, brs), 4.26 (2H, s ), 5.37 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.25-7.35 (2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.63 (1H, s).

後述の実施例７７の化合物(320 mg, 0.457 mmol)を用いて、参考例１４と同様の反応を行い、表題化合物 (138 mg, 50%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.34 (3H, s), 3.77 (2H, s), 3.82 (3H, s), 4.19 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.14 (1H, t, J = 9.2 Hz), 7.25-7.5 (5H, m), 7.57 (2H, d, J = 8.6 Hz), 7.64 (1H, s).
参考例５５
N-{4-[1-(2,6-ジフルオロベンジル)-5-[(ジメチルアミノ)メチル]-3-(4-メトキシフェニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル]フェニル}-N'-メトキシウレアの製造

参考例１９の化合物(130 mg, 0.192 mmol)とジメチルアミンのTHF溶液(0.96 ml, 1.92 mmol)を用いて、参考例２６と同様の反応を行い、表題化合物 (43.4 mg, 36%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.14 (6H, s), 3.70 (2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J = 7.8 Hz), 7.01 (1H, d, J = 8.7 Hz), 7.1-7.35 (4H, m), 7.51 (2H, d, J = 8.7 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.63 (1H, s).
参考例５６
N-{4-[1-(2,6-ジフルオロベンジル)-3-(6-メトキシピリダジン-3-イル)-2,4-ジオキソ-5-(ピロリジン-1-イルメチル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル]フェニル}-N'-メトキシウレアの製造

参考例５０の化合物(110 mg, 0.175 mmol)とピロリジン(124 mg, 1.75 mmol)を用いて、参考例２６と同様の反応を行い、表題化合物 (68.1 mg, 60%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.5-1.7 (4H, m), 2.35-2.5 (4H, m), 3.82 (3H, s), 3.89 (2H, brs), 4.18 (3H, s), 5.34 (2H, brs), 6.92 (2H, t, J = 8.8 Hz), 7.12 (2H, d, J = 9.2 Hz), 7.2-7.35 (2H, m), 7.41 (1H, d, J = 9.2 Hz), 7.5-7.6 (3H, m), 7.64 (1H, s). Reference Example 54
N- (4- (1- (2,6-difluorobenzyl) -3- (6-methoxy-3-pyridazinyl) -5-((methylamino) methyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Reference Example 14 was performed using the compound of Example 77 (320 mg, 0.457 mmol) described later to obtain the title compound (138 mg, 50%) as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.77 (2H, s), 3.82 (3H, s), 4.19 (3H, s), 5.35 (2H, s), 6.92 (2H, t , J = 8.0 Hz), 7.14 (1H, t, J = 9.2 Hz), 7.25-7.5 (5H, m), 7.57 (2H, d, J = 8.6 Hz), 7.64 (1H, s).
Reference Example 55
N- {4- [1- (2,6-difluorobenzyl) -5-[(dimethylamino) methyl] -3- (4-methoxyphenyl) -2,4-dioxo-1,2,3,4- Preparation of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

Using the compound of Reference Example 19 (130 mg, 0.192 mmol) and dimethylamine in THF (0.96 ml, 1.92 mmol), the same reaction as in Reference Example 26 was carried out to give the title compound (43.4 mg, 36%) colorless. Obtained as crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.14 (6H, s), 3.70 (2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t , J = 7.8 Hz), 7.01 (1H, d, J = 8.7 Hz), 7.1-7.35 (4H, m), 7.51 (2H, d, J = 8.7 Hz), 7.56 (2H, d, J = 8.7 Hz) ), 7.63 (1H, s).
Reference Example 56
N- {4- [1- (2,6-difluorobenzyl) -3- (6-methoxypyridazin-3-yl) -2,4-dioxo-5- (pyrrolidin-1-ylmethyl) -1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

The same reaction as in Reference Example 26 was carried out using the compound of Reference Example 50 (110 mg, 0.175 mmol) and pyrrolidine (124 mg, 1.75 mmol) to give the title compound (68.1 mg, 60%) as colorless crystals. .
¹ H-NMR (CDCl ₃ ) δ: 1.5-1.7 (4H, m), 2.35-2.5 (4H, m), 3.82 (3H, s), 3.89 (2H, brs), 4.18 (3H, s), 5.34 (2H, brs), 6.92 (2H, t, J = 8.8 Hz), 7.12 (2H, d, J = 9.2 Hz), 7.2-7.35 (2H, m), 7.41 (1H, d, J = 9.2 Hz) , 7.5-7.6 (3H, m), 7.64 (1H, s).

参考例５０の化合物(110 mg, 0.175 mmol)とモルホリン(152 mg, 1.75 mmol)を用いて、参考例２６と同様の反応を行い、表題化合物 (78.0 mg, 67%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.35-2.5 (4H, m), 3.5-3.65 (4H, m), 3.76 (2H, s), 3.83 (3H, s), 4.19 (3H, s), 5.35 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (1H, m), 7.40 (1H, d, J = 9.0 Hz), 7.5-7.7 (5H, m).
参考例５８
N-(4-(5-((ベンジル(2-メトキシエチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例５０の化合物(120 mg, 0.191 mmol)とN-ベンジル-N-(2-メトキシエチル)アミン(316 mg, 1.91 mmol)を用いて、参考例２６と同様の反応を行い、表題化合物 (105.1 mg, 74%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.67 (2H, t, J = 6.2 Hz), 3.18 (3H, s), 3.34 (2H, t, J = 6.2 Hz), 3.65 (2H, s), 3.83 (3H, s), 4.03 (2H, s), 4.20 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.25 (6H, m), 7.25-7.35 (2H, m), 7.40 (1H, d, J = 9.0 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.64 (1H, s), 7.75 (2H, d, J = 8.7 Hz).
元素分析 C₃₇H₃₅F₂N₇O₆S・1.0H₂Oとして
計算値: C, 58.34; H, 4.90; N, 12.87.
実測値: C, 58.51; H, 4.58; N, 12.56.
参考例５９
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)アミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例５８の化合物(400 mg, 0.538 mmol)を用いて、参考例１４と同様の反応を行い、表題化合物 (215.9 mg, 61%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.72 (2H, t, J = 5.6 Hz), 3.28 (3H, s), 3.40 (2H, t, J = 5.6 Hz), 3.82(3H, s), 3.86 (2H, s), 4.19 (3H, s), 5.35 (2H, brs), 6.92 (2H, t, J = 8.4 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.25-7.35 (1H, m), 7.39 (2H, d, J = 9.0 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.64 (1H, s).
元素分析 C₃₀H₂₉F₂N₇O₆S・0.5H₂Oとして
計算値: C, 54.38; H, 4.56; N, 14.80.
実測値: C, 54.62; H, 4.39; N, 14.62. Reference Example 57
N- {4- [1- (2,6-difluorobenzyl) -3- (6-methoxypyridazin-3-yl) -5- (morpholin-4-ylmethyl) -2,4-dioxo-1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

Using the compound of Reference Example 50 (110 mg, 0.175 mmol) and morpholine (152 mg, 1.75 mmol), the same reaction as in Reference Example 26 was performed to obtain the title compound (78.0 mg, 67%) as colorless crystals. .
¹ H-NMR (CDCl ₃ ) δ: 2.35-2.5 (4H, m), 3.5-3.65 (4H, m), 3.76 (2H, s), 3.83 (3H, s), 4.19 (3H, s), 5.35 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (1H, m), 7.40 (1H, d, J = 9.0 Hz), 7.5- 7.7 (5H, m).
Reference Example 58
N- (4- (5-((benzyl (2-methoxyethyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo -1,2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 50 (120 mg, 0.191 mmol) and N-benzyl-N- (2-methoxyethyl) amine (316 mg, 1.91 mmol), the same reaction as in Reference Example 26 was performed, and the title compound ( 105.1 mg, 74%) was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 2.67 (2H, t, J = 6.2 Hz), 3.18 (3H, s), 3.34 (2H, t, J = 6.2 Hz), 3.65 (2H, s), 3.83 ( 3H, s), 4.03 (2H, s), 4.20 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.25 (6H, m), 7.25-7.35 (2H, m), 7.40 (1H, d, J = 9.0 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.64 (1H, s), 7.75 (2H, d, J = 8.7 Hz).
Elemental analysis Calculated as C ₃₇ H ₃₅ F ₂ N ₇ O ₆ S1.0H ₂ O: C, 58.34; H, 4.90; N, 12.87.
Found: C, 58.51; H, 4.58; N, 12.56.
Reference Example 59
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) amino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 58 (400 mg, 0.538 mmol), the same reaction as in Reference Example 14 was performed to obtain the title compound (215.9 mg, 61%) as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.72 (2H, t, J = 5.6 Hz), 3.28 (3H, s), 3.40 (2H, t, J = 5.6 Hz), 3.82 (3H, s), 3.86 ( 2H, s), 4.19 (3H, s), 5.35 (2H, brs), 6.92 (2H, t, J = 8.4 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.25-7.35 (1H, m ), 7.39 (2H, d, J = 9.0 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.64 (1H, s).
Elemental analysis _{C 30 H 29 F 2 N 7} O 6 S · 0.5H 2 O Calculated: C, 54.38; H, 4.56 ; N, 14.80.
Found: C, 54.62; H, 4.39; N, 14.62.

参考例７の化合物(1.82 g, 3 mmol)と1-アミノ-2-プロパノール(0.45 g, 6 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (1.11 g, 60%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 1.27 (3H, d, J = 5.6 Hz), 2.12 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 2.9-3.05 (1H, m), 3.30 (3H, s), 3.45 (2H, d, J = 5.8 Hz), 3.82 (5H, s), 4.05-4.25 (1H, m), 4.18 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.4 (1H, m), 7.5-7.6 (3H, m), 7.63 (1H, s).
元素分析 C₂₉H₃₃F₂N₅O₆S・0.7H₂Oとして
計算値: C, 55.26; H, 5.50; N, 11.11.
実測値: C, 55.42; H, 5.52; N, 10.75.
実施例６２
N-(4-(1-(2,6-ジフルオロベンジル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-3-(2-オキソプロピル)-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

オキサリルクロリド(0.20 g, 1.58 mmol)のジクロロメタン溶液(2 ml)に-78℃冷却下、ジメチルスルホキシド(163 mg, 2.09 mmol)のジクロロメタン溶液(2 ml)を滴下した。10分間攪拌後、実施例６１の化合物(308 mg, 0.5 mmol)のジクロロメタン溶液(2ml)を滴下した。さらに30分間攪拌後、トリエチルアミン(0.40 ml, 2.88 mmol)を滴下し、0℃で2時間攪拌を続けた。0℃で塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー（溶出液；酢酸エチル）で精製し、得られた粉末をジイソプロピルエーテルとヘキサンで洗浄し、表題化合物 (40.7 mg, 13%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.13 (3H, s), 2.27 (3H, s), 2.55-2.65 (2H, m), 3.29 (3H, s), 3.4-3.5 (2H, m), 3.82 (5H, s), 4.88 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.2-7.35 (1H, m), 7.5-7.65 (4H, m).
実施例６３
N-(4-(1-(2,6-ジフルオロベンジル)-3-(3,3-ジメチル-2-オキソブチル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例７の化合物(303 mg, 0.5 mmol)と3,3-ジメチル-2-オキソブチルアミン塩酸塩（米国特許第6,096,688号）(152mg, 1 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (195.7 mg, 60%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.30 (9H, s), 2.12 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.29 (3H, s), 3.44 (2H, d, J = 5.8 Hz), 3.80 (2H, s), 3.82 (3H, s), 5.04 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H,s), 7.2-7.3 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
元素分析 C₃₂H₃₇F₂N₅O₆Sとして
計算値: C, 58.43; H, 5.67; N, 10.65.
実測値: C, 58.15; H, 5.71; N, 10.42. Example 61
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxypropyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 7 (1.82 g, 3 mmol) and 1-amino-2-propanol (0.45 g, 6 mmol), the same reaction as in Example 5 was carried out, and the title compound (1.11 g, 60%) Was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, d, J = 5.6 Hz), 2.12 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 2.9-3.05 (1H, m), 3.30 (3H, s), 3.45 (2H, d, J = 5.8 Hz), 3.82 (5H, s), 4.05-4.25 (1H, m), 4.18 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.4 (1H, m), 7.5-7.6 (3H, m), 7.63 (1H, s).
Elemental analysis Calculated as C ₂₉ H ₃₃ F ₂ N ₅ O ₆ S0.7H ₂ O: C, 55.26; H, 5.50; N, 11.11.
Found: C, 55.42; H, 5.52; N, 10.75.
Example 62
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-oxopropyl)- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Dichloromethane solution (2 ml) of dimethyl sulfoxide (163 mg, 2.09 mmol) was added dropwise to a dichloromethane solution (2 ml) of oxalyl chloride (0.20 g, 1.58 mmol) while cooling at -78 ° C. After stirring for 10 minutes, a dichloromethane solution (2 ml) of the compound of Example 61 (308 mg, 0.5 mmol) was added dropwise. After further stirring for 30 minutes, triethylamine (0.40 ml, 2.88 mmol) was added dropwise, and stirring was continued at 0 ° C for 2 hours. Aqueous ammonium chloride solution was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate), and the resulting powder was washed with diisopropyl ether and hexane to give the title compound (40.7 mg, 13%) as a pale yellow Obtained as a powder.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.27 (3H, s), 2.55-2.65 (2H, m), 3.29 (3H, s), 3.4-3.5 (2H, m), 3.82 (5H, s), 4.88 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.2-7.35 (1H, m), 7.5-7.65 (4H, m).
Example 63
N- (4- (1- (2,6-difluorobenzyl) -3- (3,3-dimethyl-2-oxobutyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2 , 4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 7 (303 mg, 0.5 mmol) and 3,3-dimethyl-2-oxobutylamine hydrochloride (US Pat. No. 6,096,688) (152 mg, 1 mmol), the same reaction as in Example 5 was carried out. The title compound (195.7 mg, 60%) was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s), 2.12 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.29 (3H, s), 3.44 (2H, d, J = 5.8 Hz), 3.80 (2H, s), 3.82 (3H, s), 5.04 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H, s ), 7.2-7.3 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
Elemental analysis Calculated as C ₃₂ H ₃₇ F ₂ N ₅ O ₆ S: C, 58.43; H, 5.67; N, 10.65.
Found: C, 58.15; H, 5.71; N, 10.42.

参考例７の化合物(303 mg, 0.5 mmol)と2,2,2-トリフルオロエチルアミン(99 mg, 1 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (52.9 mg, 16%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.12 (3H, s), 2.65 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.45 (2H, d, J = 6.0 Hz), 3.82 (5H, s), 4.75-4.85 (2H, m), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H,s), 7.2-7.35 (1H, m), 7.55-7.6 (4H, m), 7.62 (1H, s).
元素分析 C₂₈H₂₈F₅N₅O₅S・1.0H₂Oとして
計算値: C, 50.98; H, 4.58; N, 10.62.
実測値: C, 51.14; H, 4.44; N, 10.34.
実施例６５
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシ-3,3-ジメチルブチル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

実施例６３の化合物(120 mg, 0.182 mmol)のメタノール(6 ml)とTHF(4 ml)混液に氷冷下、水素化ホウ素ナトリウム(6.9 mg, 0.182 mmol)を加えた。反応液を室温で1.5時間攪拌した後、減圧濃縮した。残渣を水と酢酸エチルで分配し、有機層を抽出した。食塩水で洗浄後、無水硫酸マグネシウムで乾燥、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー（溶出液；酢酸エチル）で精製し、さらに酢酸エチルとジエチルエーテルから再結晶し、表題化合物 (81.1 mg, 68%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.04 (9H, s), 2.12 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 2.96 (1H, d, J = 6.0 Hz), 3.31 (3H, s), 3.46 (2H, d, J = 6.0 Hz), 3.5-3.6 (1H, m), 3.82 (3H, s), 3.75-3.9 (2H, m), 4.05-4.2 (1H, m), 4.3-4.45 (1H, m), 5.25-5.45(2H, m), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H,s), 7.2-7.35 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
元素分析 C₃₂H₃₉F₂N₅O₆S・0.2H₂Oとして
計算値: C, 57.94; H, 5.99; N, 10.56.
実測値: C, 57.89; H, 5.91; N, 10.43.
実施例６６
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシ-2-メチルプロピル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例７の化合物(303 mg, 0.5 mmol)と参考例４１の化合物(89 mg, 1 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (133.9 mg, 42%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.28 (6H, s), 2.3 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.99 (1H, s), 4.25 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.12 (1H,s), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
元素分析 C₃₀H₃₅F₂N₅O₆S・0.1H₂Oとして
計算値: C, 56.88; H, 5.60; N, 11.06.
実測値: C, 56.65; H, 5.54; N, 10.85. Example 64
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2,2,2- Preparation of (trifluoroethyl) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 7 (303 mg, 0.5 mmol) and 2,2,2-trifluoroethylamine (99 mg, 1 mmol), the same reaction as in Example 5 was carried out, and the title compound (52.9 mg, 16 %) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.12 (3H, s), 2.65 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.45 (2H, d, J = 6.0 Hz), 3.82 ( 5H, s), 4.75-4.85 (2H, m), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.35 (1H, m), 7.55 -7.6 (4H, m), 7.62 (1H, s).
Elemental analysis _{C 28 H 28 F 5 N 5} O 5 S · 1.0H 2 O Calculated: C, 50.98; H, 4.58 ; N, 10.62.
Found: C, 51.14; H, 4.44; N, 10.34.
Example 65
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxy-3,3-dimethylbutyl) -5-(((2-methoxyethyl) (methyl) amino) methyl)- 2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Sodium borohydride (6.9 mg, 0.182 mmol) was added to a mixture of the compound of Example 63 (120 mg, 0.182 mmol) in methanol (6 ml) and THF (4 ml) under ice cooling. The reaction solution was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was extracted. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate) and recrystallized from ethyl acetate and diethyl ether to give the title compound (81.1 mg, 68%) as colorless crystals. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 2.12 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 2.96 (1H, d, J = 6.0 Hz), 3.31 ( 3H, s), 3.46 (2H, d, J = 6.0 Hz), 3.5-3.6 (1H, m), 3.82 (3H, s), 3.75-3.9 (2H, m), 4.05-4.2 (1H, m) , 4.3-4.45 (1H, m), 5.25-5.45 (2H, m), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.35 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
Elemental analysis Calculated as C ₃₂ H ₃₉ F ₂ N ₅ O ₆ S0.2H ₂ O: C, 57.94; H, 5.99; N, 10.56.
Found: C, 57.89; H, 5.91; N, 10.43.
Example 66
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxy-2-methylpropyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2, Preparation of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 7 (303 mg, 0.5 mmol) and the compound of Reference Example 41 (89 mg, 1 mmol), the same reaction as in Example 5 was carried out, and the title compound (133.9 mg, 42%) was colorless. Obtained as crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, s), 2.3 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.99 (1H, s), 4.25 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.12 (1H, s ), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
Elemental analysis Calculated as C ₃₀ H ₃₅ F ₂ N ₅ O ₆ S 0.1H ₂ O: C, 56.88; H, 5.60; N, 11.06.
Found: C, 56.65; H, 5.54; N, 10.85.

参考例７の化合物(303 mg, 0.5 mmol)と参考例４４の化合物(140 mg, 1 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (36.8 mg, 11%)を淡黄色結晶として得た。
¹H-NMR(CDCl₃) δ: 0.96 (6H, s), 2.13 (3H, s), 2.64 (2H, t, J = 6.2 Hz), 3.13(2H, s), 3.30(3H, s), 3.45 (2H, t, J = 6.2 Hz), 3.82 (5H, s), 3.95-4.15(2H, brm), 5.1-5.5 (2H, br), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H,s), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
HPLC (220 nm) 純度90 % (保持時間1.83分)
MS (ESI+, m/e) 646 (M+1)
実施例６８
N-(4-(1-(2,6-ジフルオロベンジル)-3-((1-(ヒドロキシメチル)シクロプロピル)メチル)-5-(((2-メトキシエチル)(メチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例７の化合物(606 mg, 1 mmol)と参考例４７の化合物(431 mg, 2 mmol) を用いて、実施例５と同様の反応を行い、チエノピリミジン環化体 (549.3 mg, 72%)を得た。上記環化体をTHF(10 ml)に溶解させ、テトラブチルアンモニウムフルオリドの1MTHF溶液(1.7 ml, 1.7 mmol)を加え、室温で20時間攪拌した。反応液を水と酢酸エチルで分配し、有機層を抽出した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー（溶出液；酢酸エチル）で精製し、さらに酢酸エチルとジエチルエーテルから再結晶し、表題化合物 (196.1 mg, 43%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 0.46 (2H, t, J = 5.4 Hz), 0.85 (2H, t, J = 5.4 Hz), 2.11 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 3.25(2H, s), 3.31(3H, s), 3.46 (2H, t, J = 6.0 Hz), 3.82 (5H, s), 3.95-4.15(1H, br), 4.14 (2H, s), 5.37 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.12 (1H,s), 7.2-7.4 (1H, m), 7.54 (4H, s), 7.61 (1H, s).
元素分析 C₃₁H₃₅F₂N₅O₆Sとして
計算値: C, 57.84; H, 5.48; N, 10.88.
実測値: C, 57.63; H, 5.46; N, 10.86.
実施例６９
N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(4-ヒドロキシシクロヘキシル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(3.19g, 5 mmol)とtrans-4-アミノシクロヘキサノール(1.44g, 12.5 mmol) を用いて、実施例５と同様の反応を行い、表題化合物 (1.80g, 52%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.35-1.65 (3H, m), 1.65-1.8 (2H, m), 2.07 (3H, s), 2.5-2.8 (2H, m), 3.58 (2H, s), 3.7-3.9 (1H, m), 3.82 (3H, s), 3.91(2H, s), 4.9-5.1 (1H, m), 5.29 (2H, s), 6.90 (2H, t, J = 7.8 Hz), 7.13 (1H,s), 7.15-7.35 (6H, m), 7.53 (2H, d, J = 8.6 Hz), 7.61 (1H, s), 7.66 (2H, d, J = 8.6 Hz).
元素分析 C₃₆H₃₇F₂N₅O₆S・0.5H₂Oとして
計算値: C, 61.09; H, 5.55; N, 9.89.
実測値: C, 61.41; H, 5.65; N, 9.56. Example 67
N- [4- (1- (2,6-difluorobenzyl) -3- (3-hydroxy-2,2-dimethylpropyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl}- Preparation of 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-methoxyurea

Using the compound of Reference Example 7 (303 mg, 0.5 mmol) and the compound of Reference Example 44 (140 mg, 1 mmol), the same reaction as in Example 5 was carried out, and the title compound (36.8 mg, 11%) was palely prepared. Obtained as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, s), 2.13 (3H, s), 2.64 (2H, t, J = 6.2 Hz), 3.13 (2H, s), 3.30 (3H, s), 3.45 (2H, t, J = 6.2 Hz), 3.82 (5H, s), 3.95-4.15 (2H, brm), 5.1-5.5 (2H, br), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).
HPLC (220 nm) purity 90% (retention time 1.83 min)
MS (ESI +, m / e) 646 (M + 1)
Example 68
N- (4- (1- (2,6-difluorobenzyl) -3-((1- (hydroxymethyl) cyclopropyl) methyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 7 (606 mg, 1 mmol) and the compound of Reference Example 47 (431 mg, 2 mmol), the same reaction as in Example 5 was performed, and the thienopyrimidine cyclized product (549.3 mg, 72% ) The cyclized product was dissolved in THF (10 ml), a 1MTHF solution (1.7 ml, 1.7 mmol) of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent; ethyl acetate) and recrystallized from ethyl acetate and diethyl ether to give the title compound (196.1 mg, 43%) as colorless crystals. It was.
¹ H-NMR (CDCl ₃ ) δ: 0.46 (2H, t, J = 5.4 Hz), 0.85 (2H, t, J = 5.4 Hz), 2.11 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 3.25 (2H, s), 3.31 (3H, s), 3.46 (2H, t, J = 6.0 Hz), 3.82 (5H, s), 3.95-4.15 (1H, br), 4.14 (2H, s ), 5.37 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.54 (4H, s), 7.61 (1H, s) .
Elemental analysis Calculated as C ₃₁ H ₃₅ F ₂ N ₅ O ₆ S: C, 57.84; H, 5.48; N, 10.88.
Found: C, 57.63; H, 5.46; N, 10.86.
Example 69
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- The same reaction as in Example 5 was carried out using 3-carboxylic acid (3.19 g, 5 mmol) and trans-4-aminocyclohexanol (1.44 g, 12.5 mmol) to give the title compound (1.80 g, 52%). Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.35-1.65 (3H, m), 1.65-1.8 (2H, m), 2.07 (3H, s), 2.5-2.8 (2H, m), 3.58 (2H, s) , 3.7-3.9 (1H, m), 3.82 (3H, s), 3.91 (2H, s), 4.9-5.1 (1H, m), 5.29 (2H, s), 6.90 (2H, t, J = 7.8 Hz ), 7.13 (1H, s), 7.15-7.35 (6H, m), 7.53 (2H, d, J = 8.6 Hz), 7.61 (1H, s), 7.66 (2H, d, J = 8.6 Hz).
Elemental analysis Calculated as C ₃₆ H ₃₇ F ₂ N ₅ O ₆ S0.5H ₂ O: C, 61.09; H, 5.55; N, 9.89.
Found: C, 61.41; H, 5.65; N, 9.56.

参考例５１の化合物(300 mg, 0.5 mmol)と2-ブロモエチルメチルエーテル(0.69 g, 5 mmol)を用いて、実施例４と同様の反応を行い、表題化合物 (75.1 mg, 23%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.2-1.6 (3H, m), 1.6-1.8 (2H, m), 2.0-2.1 (2H, m), 2.14 (3H, s), 2.5-2.75 (4H, m), 3.31 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.65-3.85 (3H, m), 3.82 (3H, s), 4.9-5.05 (1H, br), 5.30 (2H, s), 6.90 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.25-7.4 (1H, m), 7.5-7.6 (4H, m), 7.60 (1H, s).
元素分析 C₃₂H₃₇F₂N₅O₆S・0.5H₂Oとして
計算値: C, 57.65; H, 5.74; N, 10.50.
実測値: C, 57.54; H, 5.75; N, 10.64.
実施例７１
N-{4-[1-(2,6-ジフルオロベンジル)-5-{[(2-メトキシエチル)(メチル)アミノ]メチル}-3-(6-メチルピリダジン-3-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル]フェニル}-N'-メトキシウレアの製造

参考例７の化合物(303mg, 0.5 mmol)と3-アミノ-6-メチルピリダジン(136 mg, 1.25 mmol)を用いて、実施例５と同様の反応を行い、表題化合物 (48.3 mg, 15%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.13 (3H, s), 2.61 (2H, t, J = 5.8 Hz), 2.79 (3H, s), 3.26 (3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.75-3.85 (2H, m), 3.82 (3H, s), 5.25-5.45 (2H, brm), 6.92 (2H, t, J = 8.2 Hz), 7.18 (1H, s), 7.2-7.7 (8H, m).
実施例７２
N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシプロピル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(639 mg, 1 mmol)と1-アミノ-2-プロパノール(0.19g, 2.5mmol)を用いて、実施例５と同様の反応を行い、表題化合物 (409.7 mg, 63%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.30 (3H, d, J = 6.0 Hz), 2.06 (3H, s), 2.90 (1H, d, J = 5.2 Hz), 3.57 (2H, s), 3.82 (3H, s), 3.91 (2H, s), 4.1-4.25 (1H, m), 4.20 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.16 (1H, s), 7.2-7.4 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.8 Hz).
元素分析 C₃₃H₃₃F₂N₅O₅Sとして
計算値: C, 61.00; H, 5.12; N, 10.78.
実測値: C, 60.82; H, 5.21; N, 10.68. Example 70
N- [4- (1- (2,6-difluorobenzyl) -3- (4-hydroxycyclohexyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-methoxyurea

Using the compound of Reference Example 51 (300 mg, 0.5 mmol) and 2-bromoethyl methyl ether (0.69 g, 5 mmol), the same reaction as in Example 4 was carried out, and the title compound (75.1 mg, 23%) was obtained. Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.2-1.6 (3H, m), 1.6-1.8 (2H, m), 2.0-2.1 (2H, m), 2.14 (3H, s), 2.5-2.75 (4H, m), 3.31 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.65-3.85 (3H, m), 3.82 (3H, s), 4.9-5.05 (1H, br), 5.30 (2H , s), 6.90 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.25-7.4 (1H, m), 7.5-7.6 (4H, m), 7.60 (1H, s).
Elemental analysis Calculated as C ₃₂ H ₃₇ F ₂ N ₅ O ₆ S0.5H ₂ O: C, 57.65; H, 5.74; N, 10.50.
Found: C, 57.54; H, 5.75; N, 10.64.
Example 71
N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -3- (6-methylpyridazin-3-yl) -2, Preparation of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

Using the compound of Reference Example 7 (303 mg, 0.5 mmol) and 3-amino-6-methylpyridazine (136 mg, 1.25 mmol), the same reaction as in Example 5 was carried out, and the title compound (48.3 mg, 15%) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.61 (2H, t, J = 5.8 Hz), 2.79 (3H, s), 3.26 (3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.75-3.85 (2H, m), 3.82 (3H, s), 5.25-5.45 (2H, brm), 6.92 (2H, t, J = 8.2 Hz), 7.18 (1H, s), 7.2 -7.7 (8H, m).
Example 72
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (2-hydroxypropyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- The same reaction as in Example 5 was performed using 3-carboxylic acid (639 mg, 1 mmol) and 1-amino-2-propanol (0.19 g, 2.5 mmol) to give the title compound (409.7 mg, 63%). Obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 6.0 Hz), 2.06 (3H, s), 2.90 (1H, d, J = 5.2 Hz), 3.57 (2H, s), 3.82 ( 3H, s), 3.91 (2H, s), 4.1-4.25 (1H, m), 4.20 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.16 (1H , s), 7.2-7.4 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.8 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.
Found: C, 60.82; H, 5.21; N, 10.68.

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(639 mg, 1 mmol)と参考例４１の化合物(0.22 g, 2.5mmol)を用いて、実施例５と同様の反応を行い、表題化合物 (360.9 mg, 54%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.29 (6H, s), 2.06 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.91 (2H, s), 3.96 (1H, s), 4.28 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.35 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.8 Hz).
元素分析 C₃₄H₃₅F₂N₅O₅Sとして
計算値: C, 61.53; H, 5.32; N, 10.55.
実測値: C, 61.30; H, 5.32; N, 10.32.
実施例７４
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシプロピル)-5-((メチル(2-(2-ピリジニル)エチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例５２の化合物(260 mg, 0.465 mmol)と2-(2-ヒドロキシエチル)ピリジン(400 mg, 1.63mmol)を用いて、実施例２と同様の反応を行い、表題化合物 (195.9 mg, 63%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.28 (3H, d, J = 5.8 Hz), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.0-3.1 (1H, m), 3.82 (5H, s), 4.1-4.2 (1H, m), 4.17 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 (1H, s), 7.2-7.4 (1H, m), 7.4-7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J = 5.0 Hz).
元素分析 C₃₃H₃₄F₂N₆O₅S・0.2H₂Oとして
計算値: C, 59.31; H, 5.19; N, 12.57.
実測値: C, 59.24; H, 5.29; N, 12.32.
実施例７５
N-(4-(1-(2,6-ジフルオロベンジル)-3-(2-ヒドロキシ-2-メチルプロピル)-5-((メチル(2-(2-ピリジニル)エチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例５３の化合物(220 mg, 0.384 mmol)と2-(2-ヒドロキシエチル)ピリジン(800 mg, 3.25 mmol)を用いて、実施例２と同様の反応を行い、表題化合物 (138.2 mg, 53%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.26 (6H, s), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.82 (5H, s), 3.99 (1H, s), 4.24 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.1 (2H, m), 7.13 (1H, s), 7.2-7.35 (1H, m), 7.45-7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J = 4.0 Hz).
元素分析 C₃₄H₃₆F₂N₆O₅S・0.1H₂Oとして
計算値: C, 59.85; H, 5.38; N, 12.32.
実測値: C, 59.81; H, 5.45; N, 12.03. Example 73
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (2-hydroxy-2-methylpropyl) -2,4-dioxo-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- The same reaction as in Example 5 was carried out using 3-carboxylic acid (639 mg, 1 mmol) and the compound of Reference Example 41 (0.22 g, 2.5 mmol) to give the title compound (360.9 mg, 54%) as colorless crystals. Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, s), 2.06 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.91 (2H, s), 3.96 (1H, s ), 4.28 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.35 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.8 Hz).
Elemental analysis Calculated as C ₃₄ H ₃₅ F ₂ N ₅ O ₅ S: C, 61.53; H, 5.32; N, 10.55.
Found: C, 61.30; H, 5.32; N, 10.32.
Example 74
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxypropyl) -5-((methyl (2- (2-pyridinyl) ethyl) amino) methyl) -2,4- Preparation of dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 52 (260 mg, 0.465 mmol) and 2- (2-hydroxyethyl) pyridine (400 mg, 1.63 mmol), the same reaction as in Example 2 was carried out, and the title compound (195.9 mg, 63 %) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J = 5.8 Hz), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.0-3.1 (1H, m), 3.82 (5H , s), 4.1-4.2 (1H, m), 4.17 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 ( 1H, s), 7.2-7.4 (1H, m), 7.4-7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J = 5.0 Hz).
Elemental analysis _{C 33 H 34 F 2 N 6} O 5 S · 0.2H 2 O Calculated: C, 59.31; H, 5.19 ; N, 12.57.
Found: C, 59.24; H, 5.29; N, 12.32.
Example 75
N- (4- (1- (2,6-difluorobenzyl) -3- (2-hydroxy-2-methylpropyl) -5-((methyl (2- (2-pyridinyl) ethyl) amino) methyl)- 2,4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 53 (220 mg, 0.384 mmol) and 2- (2-hydroxyethyl) pyridine (800 mg, 3.25 mmol), the same reaction as in Example 2 was carried out, and the title compound (138.2 mg, 53 %) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, s), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.82 (5H, s), 3.99 (1H, s), 4.24 (2H , s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.1 (2H, m), 7.13 (1H, s), 7.2-7.35 (1H, m), 7.45- 7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J = 4.0 Hz).
Elemental analysis Calculated as C ₃₄ H ₃₆ F ₂ N ₆ O ₅ S ・ 0.1H ₂ O: C, 59.85; H, 5.38; N, 12.32.
Found: C, 59.81; H, 5.45; N, 12.03.

参考例７の化合物(303 mg, 0.5 mmol)とアミノピラジン(119 mg, 1.25mmol)を用いて、実施例５と同様の反応を行い、表題化合物(35.2 mg, 11%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 6.0 Hz), 3.79 (2H, s), 3.83 (1H, s), 5.36 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m), 8.65-8.7 (3H, m).
元素分析 C₃₀H₂₉F₂N₇O₅S・0.1H₂Oとして
計算値: C, 56.35; H, 4.60; N, 15.33.
実測値: C, 56.20; H, 4.52; N, 15.16.
実施例７７
N-(4-(5-((ベンジル(メチル)アミノ)メチル)-1-(2,6-ジフルオロベンジル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

4-(N-ベンジル-N-メチルアミノメチル)-2-[N-(2,6-ジフルオロベンジル)-N-エトキシカルボニルアミノ]-5-[4-(3-メトキシウレイド)フェニル]チオフェン-3-カルボン酸(1.28 g, 2 mmol)と6-クロロ-3-アミノピリダジン(648 mg, 5 mmol)を用いて、実施例５と同様の反応を行い、表題化合物(0.36 g, 26%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.06 (3H, s), 3.55 (2H, s), 3.83 (3H, s), 3.87 (2H, s), 4.19 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.45 (9H, m), 7.55 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J = 8.4 Hz).
実施例７８
N-(4-(1-(2,6-ジフルオロベンジル)-3-(6-メトキシ-3-ピリダジニル)-5-((メチル(2-(2-ピリジニル)エチル)アミノ)メチル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例５４の化合物(135 mg, 0.221 mmol)と2-(2-ヒドロキシエチル)ピリジン(272 mg, 2.21 mmol)を用いて、実施例２と同様の反応を行い、表題化合物(79.6 mg, 50%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.20 (3H, s), 2.7-2.9 (4H, m), 3.78 (2H, s), 3.82 (3H, s), 4.19 (3H, s), 5.34 (2H, s), 6.85-7.2 (5H, m), 7.25-7.45 (2H, m), 7.45-7.7 (7H, m), 8.42 (1H, d, J = 4.0 Hz).
元素分析 C₃₅H₃₂F₂N₈O₅S・1.0H₂Oとして
計算値: C, 57.37; H, 4.68; N, 15.29.
実測値: C, 57.29; H, 4.60; N, 15.15. Example 76
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyrazinyl) -1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The same reaction as in Example 5 was carried out using the compound of Reference Example 7 (303 mg, 0.5 mmol) and aminopyrazine (119 mg, 1.25 mmol) to give the title compound (35.2 mg, 11%) as colorless crystals. It was.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.62 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 6.0 Hz), 3.79 ( 2H, s), 3.83 (1H, s), 5.36 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m), 8.65-8.7 (3H, m).
Elemental analysis Calculated as C ₃₀ H ₂₉ F ₂ N ₇ O ₅ S ・ 0.1H ₂ O: C, 56.35; H, 4.60; N, 15.33.
Found: C, 56.20; H, 4.52; N, 15.16.
Example 77
N- (4- (5-((benzyl (methyl) amino) methyl) -1- (2,6-difluorobenzyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1, Preparation of 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

4- (N-benzyl-N-methylaminomethyl) -2- [N- (2,6-difluorobenzyl) -N-ethoxycarbonylamino ] -5- [4- (3-methoxyureido) phenyl] thiophene- The same reaction as in Example 5 was performed using 3-carboxylic acid (1.28 g, 2 mmol) and 6-chloro-3-aminopyridazine (648 mg, 5 mmol), and the title compound (0.36 g, 26%) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H, s), 3.55 (2H, s), 3.83 (3H, s), 3.87 (2H, s), 4.19 (3H, s), 5.35 (2H, s ), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.45 (9H, m), 7.55 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J = (8.4 Hz).
Example 78
N- (4- (1- (2,6-difluorobenzyl) -3- (6-methoxy-3-pyridazinyl) -5-((methyl (2- (2-pyridinyl) ethyl) amino) methyl) -2 , 4-Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 54 (135 mg, 0.221 mmol) and 2- (2-hydroxyethyl) pyridine (272 mg, 2.21 mmol), the same reaction as in Example 2 was carried out, and the title compound (79.6 mg, 50 %) Was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.7-2.9 (4H, m), 3.78 (2H, s), 3.82 (3H, s), 4.19 (3H, s), 5.34 (2H , s), 6.85-7.2 (5H, m), 7.25-7.45 (2H, m), 7.45-7.7 (7H, m), 8.42 (1H, d, J = 4.0 Hz).
Elemental analysis _{C 35 H 32 F 2 N 8} O 5 S · 1.0H 2 O Calculated: C, 57.37; H, 4.68 ; N, 15.29.
Found: C, 57.29; H, 4.60; N, 15.15.

参考例２５の化合物 (800 mg, 1.24 mmol)と2-(2-ヒドロキシエチル)ピリジン(300 mg, 1.49 mmol)を用いて実施例２と同様の反応を行い、表題化合物 (407 mg, 58 %)を白色固体として得た。
¹H NMR (CDCl₃) δ2.20 (3H, s), 2.86 (4H, m), 3.82-3.84 (8H,m), 5.36 (2H, s), 6.92 (2H, t, J= 8.3 Hz), 7.00-7.06 (4H, m), 7.14-7.33 (4H, m), 7.46-7.51 (5H, m), 7.61 (1H, s), 8.42 (1H, d, J= 5.7 Hz).
元素分析 C₃₇H₃₄F₂N₆O₅S・0.7H₂Oとして
計算値: C, 61.26; H, 4.92; N, 11.59.
実測値: C, 61.06; H, 4.86; N, 11.52.
実施例８０
N-[4-(1-(2,6-ジフルオロベンジル)-3-(6-ヒドロキシピリダジン-3-イル)-5-{[(2-メトキシエチル)(メチル)アミノ]メチル}-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル]-N'-メトキシウレアの製造

実施例５７の化合物(1.34 g, 2 mmol)のTHF(30 ml)溶液に、4N HClの酢酸溶液(2 ml, 8 mmol)を加え、室温で20時間、50℃で10時間、さらに60℃で3時間攪拌した。反応液を重曹水と酢酸エチルで分配し、有機層を抽出した。水層を塩析し、酢酸エチルから抽出した。有機層を集め、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をNH-シリカゲル（富士シリシア化学製）カラムクロマトグラフィー（溶出液；酢酸エチル/メタノール=8/1）で精製し、ジイソプロピルエーテルを加え粉末化後、ろ取、ジイソプロピルエーテルで洗浄し、表題化合物 (539 mg, 41%)を淡黄色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.12 (3H, s), 2.63 (2H, t, J = 5.8 Hz), 3.28 (3H, s), 3.43 (2H, t, J = 5.8 Hz), 3.79 (2H, s), 3.83 (3H, s), 5.35 (2H, s), 6.94 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.2-7.4 (3H, m), 7.5-7.65 (4H, m), 7.63 (1H, s), 10.5-10.6 (1H, brs).
元素分析 C₃₀H₂₉F₂N₇O₆S・2.0H₂Oとして
計算値: C, 52.24; H, 4.82; N, 14.22.
実測値: C, 52.24; H, 4.57; N, 14.06.
実施例８１
N-{4-[1-(2,6-ジフルオロベンジル)-5-{[(2-ヒドロキシエチル)(メチル)アミノ]メチル}-3-(6-メトキシピリダジン-3-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル]フェニル}-N'-メトキシウレアの製造

参考例５４の化合物(305 mg, 0.5 mmol)と2-ブロモエタノール(0.62 g, 5 mmol)を用いて、実施例４と同様の反応を行い、表題化合物 (145.7 mg, 45%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.98 (3H, s), 2.45-2.5 (2H, m), 2.9-3.2 (1H, m), 3.5-3.55 (2H, m), 3.65-3.85 (2H, brm), 3.82 (3H, s), 4.18 (3H, s), 5.34 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.11 (1H, d, J = 9.0 Hz), 7.18 (1H, s), 7.25-7.35 (1H, m), 7.35-7.45 (3H, m), 7.57 (2H, d, J = 8.7 Hz), 7.66 (1H, s).
元素分析 C₃₀H₂₉F₂N₇O₆S・0.6H₂Oとして
計算値: C, 54.23; H, 4.58; N, 14.76.
実測値: C, 53.98; H, 4.61; N, 14.72. Example 79
N- (4- (5-(( methyl ( 2-pyridin-2-ylethyl) amino) methyl) -1- (2,6-difluorobenzyl) -1,2,3,4-tetrahydro-2,4- Dioxo-3- (4-methoxyphenyl) thieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

The reaction of Example 2 was carried out using the compound of Reference Example 25 (800 mg, 1.24 mmol) and 2- (2-hydroxyethyl) pyridine (300 mg, 1.49 mmol), and the title compound (407 mg, 58% ) Was obtained as a white solid.
¹ H NMR (CDCl ₃ ) δ2.20 (3H, s), 2.86 (4H, m), 3.82-3.84 (8H, m), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz) , 7.00-7.06 (4H, m), 7.14-7.33 (4H, m), 7.46-7.51 (5H, m), 7.61 (1H, s), 8.42 (1H, d, J = 5.7 Hz).
Elemental analysis Calculated as C ₃₇ H ₃₄ F ₂ N ₆ O ₅ S0.7H ₂ O: C, 61.26; H, 4.92; N, 11.59.
Found: C, 61.06; H, 4.86; N, 11.52.
Example 80
N- [4- (1- (2,6-difluorobenzyl) -3- (6-hydroxypyridazin-3-yl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} -2, Preparation of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl] -N'-methoxyurea

To a solution of the compound of Example 57 (1.34 g, 2 mmol) in THF (30 ml) was added 4N HCl in acetic acid (2 ml, 8 mmol), 20 hours at room temperature, 10 hours at 50 ° C., and 60 ° C. For 3 hours. The reaction solution was partitioned between aqueous sodium bicarbonate and ethyl acetate, and the organic layer was extracted. The aqueous layer was salted out and extracted from ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by NH-silica gel (Fuji Silysia Chemical) column chromatography (eluent: ethyl acetate / methanol = 8/1), powdered with diisopropyl ether, filtered, washed with diisopropyl ether, and the title compound (539 mg, 41%) was obtained as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 2.12 (3H, s), 2.63 (2H, t, J = 5.8 Hz), 3.28 (3H, s), 3.43 (2H, t, J = 5.8 Hz), 3.79 ( 2H, s), 3.83 (3H, s), 5.35 (2H, s), 6.94 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.2-7.4 (3H, m), 7.5 -7.65 (4H, m), 7.63 (1H, s), 10.5-10.6 (1H, brs).
Elemental analysis _{C 30 H 29 F 2 N 7} O 6 S · 2.0H 2 O Calculated: C, 52.24; H, 4.82 ; N, 14.22.
Found: C, 52.24; H, 4.57; N, 14.06.
Example 81
N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-hydroxyethyl) (methyl) amino] methyl} -3- (6-methoxypyridazin-3-yl) -2, Preparation of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

Using the compound of Reference Example 54 (305 mg, 0.5 mmol) and 2-bromoethanol (0.62 g, 5 mmol), the same reaction as in Example 4 was carried out to give the title compound (145.7 mg, 45%) as colorless crystals. Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, s), 2.45-2.5 (2H, m), 2.9-3.2 (1H, m), 3.5-3.55 (2H, m), 3.65-3.85 (2H, brm), 3.82 (3H, s), 4.18 (3H, s), 5.34 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.11 (1H, d, J = 9.0 Hz), 7.18 ( 1H, s), 7.25-7.35 (1H, m), 7.35-7.45 (3H, m), 7.57 (2H, d, J = 8.7 Hz), 7.66 (1H, s).
Elemental analysis _{C 30 H 29 F 2 N 7} O 6 S · 0.6H 2 O Calculated: C, 54.23; H, 4.58 ; N, 14.76.
Found: C, 53.98; H, 4.61; N, 14.72.

参考例２５の化合物(123 mg, 0.191 mmol)と2-ブロモエタノール(239 mg, 1.91 mmol)を用いて、実施例4と同様の反応を行い、表題化合物 (47.1 mg, 39%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 1.99 (3H, s), 2.45-2.55 (2H, m), 3.5-3.6 (2H, m), 3.79 (2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.1-7.3 (4H, m), 7.39 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.64 (1H, s).
実施例８３
N-(4-(1-(2,6-ジフルオロベンジル)-5-((ジメチルアミノ)メチル)-3-(6-メトキシ-3-ピリダジニル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル)フェニル)-N'-メトキシウレアの製造

参考例５４の化合物(100 mg, 0.164 mmol)とよう化メチル(0.010 ml, 0.164mmol)を用いて、実施例４と同様の反応を行い、表題化合物 (17.3 mg, 17%)を無色結晶として得た。
¹H-NMR(CDCl₃) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s).
実施例８４
N-{4-[1-(2,6-ジフルオロベンジル)-5-[(ジメチルアミノ)メチル]-3-(6-メトキシピリジン-3-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロチエノ[2,3-d]ピリミジン-6-イル]フェニル}-N'-メトキシウレアの製造

参考例４９の化合物(41.1 mg, 0.067 mmol)とジメチルアミンのTHF溶液(0.67 ml, 1.34 mmol)を用いて、参考例２６と同様の反応を行い、表題化合物 (18.4 mg, 44%)を白色粉末として得た。
¹H-NMR(CDCl₃) δ: 2.13 (6H, s), 3.68 (2H, s), 3.83 (3H, s), 3.96 (3H, s), 5.36 (2H, s), 6.8-7.0 (3H, m), 7.13 (1H, s), 7.2-7.4 (1H, m), 7.45-7.65 (6H, m), 8.10 (1H, d, J = 2.6 Hz). Example 82
N- {4- [1- (2,6-difluorobenzyl) -5-{[(2-hydroxyethyl) (methyl) amino] methyl} -3- (4-methoxyphenyl) -2,4-dioxo- Preparation of 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

Using the compound of Reference Example 25 (123 mg, 0.191 mmol) and 2-bromoethanol (239 mg, 1.91 mmol), the same reaction as in Example 4 was carried out to give the title compound (47.1 mg, 39%) as colorless crystals Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.99 (3H, s), 2.45-2.55 (2H, m), 3.5-3.6 (2H, m), 3.79 (2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.1-7.3 (4H, m), 7.39 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.64 (1H, s).
Example 83
N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea

Using the compound of Reference Example 54 (100 mg, 0.164 mmol) and methyl iodide (0.010 ml, 0.164 mmol), the same reaction as in Example 4 was carried out to give the title compound (17.3 mg, 17%) as colorless crystals. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H , t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s).
Example 84
N- {4- [1- (2,6-difluorobenzyl) -5-[(dimethylamino) methyl] -3- (6-methoxypyridin-3-yl) -2,4-dioxo-1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N'-methoxyurea

Using the compound of Reference Example 49 (41.1 mg, 0.067 mmol) and a THF solution of dimethylamine (0.67 ml, 1.34 mmol), the same reaction as in Reference Example 26 was performed, and the title compound (18.4 mg, 44%) was converted to white. Obtained as a powder.
¹ H-NMR (CDCl ₃ ) δ: 2.13 (6H, s), 3.68 (2H, s), 3.83 (3H, s), 3.96 (3H, s), 5.36 (2H, s), 6.8-7.0 (3H , m), 7.13 (1H, s), 7.2-7.4 (1H, m), 7.45-7.65 (6H, m), 8.10 (1H, d, J = 2.6 Hz).

Formulation Example 1
Tablets are produced in a conventional manner using the compound of Example 40 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg).
Formulation Example 2
The compound of Example 40 (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 (manufactured by Sumitomo Electric Industries, Ltd. or Sartorius Co., Ltd.), dispensed in 2 ml aliquots into washed and sterilized vials, lyophilized by conventional methods, and 100 mg / Vial freeze-dried injection is prepared.
Formulation Example 3
Tablets are produced in a conventional manner using the compound of Example 41 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg).
Formulation Example 4
The compound of Example 41 (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 (manufactured by Sumitomo Electric Industries, Ltd. or Sartorius Co., Ltd.), dispensed in 2 ml aliquots into washed and sterilized vials, lyophilized by conventional methods, and 100 mg / Vial freeze-dried injection is prepared.

Formulation Example 5
(1) 5 g of the compound of Example 40 or 41
(2) Lactose / crystalline cellulose (grain) 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) Hydroxypropyl methylcellulose 2910 30 g
(10) Titanium oxide 3.5 g
(11) Yellow iron sesquioxide 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, coated on the core particles of (2), and fine particles are coated. Make it. (9) to (11) are coated on this elementary fine grain to form a coated fine grain, and mixed with (12) to produce compound KM05283 fine grain 1%, 500 g. Package 500 mg of this.

Test example 1
(1) Preparation of ¹²⁵ I-leuprorelin
Take 10 μl of 3 × 10 ⁻⁴ M leuprorelin aqueous solution and 10 μl of 0.01 mg / ml lactoperoxidase in a tube, add 10 μl (37 MBq) of Na ¹²⁵ I solution, and after stirring, 0.001% H ₂ O ₂ 10 μl was added and allowed to react at room temperature for 20 minutes. The reaction was stopped by adding 700 μl of 0.05% TFA solution and purified by reverse phase HPLC. The HPLC conditions are shown below. ¹²⁵ I-leuprorelin was eluted with a retention time of 26-27 minutes.
Column: TSKgel ODS-80 ^TM (TM is a registered trademark. The same shall apply hereinafter.)
CTR (4.6 mm x 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) CHO containing monkey GnRH receptor (Chinese Hamster Ovary) suspension to the cell membrane fraction prepared monkey GnRH receptor-expressing CHO cells (10 ⁹⁾ in phosphate buffered saline supplemented with 5 mM EDTA (PBS-EDTA) And centrifuged at 100 × g for 5 minutes. 10 ml of cell homogenate buffer (10 mM NaHCO ₃ , 5 mM EDTA, pH 7.5) was added to the cell pellet and homogenized using a Polytron homogenizer. Centrifugation was performed at 400 × g for 15 minutes, and the supernatant was taken up in an ultracentrifuge tube and centrifuged at 100,000 × g for 1 hour to obtain a precipitate of a membrane fraction. This precipitate was suspended in 2 ml of assay buffer and centrifuged at 100,000 × g 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 before use.

(3) suspended in CHO (Chinese hamster ovary) cell membrane fraction prepared human GnRH receptor-expressing CHO cells (10 ⁹⁾ in phosphate buffered saline supplemented with 5 mM EDTA (PBS-EDTA) containing human GnRH receptor And centrifuged at 100 × g for 5 minutes. 10 ml of cell homogenate buffer (10 mM NaHCO ₃ , 5 mM EDTA, pH 7.5) was added to the cell pellet and homogenized using a Polytron homogenizer. Centrifugation was performed at 400 × g for 15 minutes, and the supernatant was taken up in an ultracentrifuge tube and centrifuged at 100,000 × g for 1 hour to obtain a precipitate of a membrane fraction. This precipitate was suspended in 2 ml of assay buffer and centrifuged at 100,000 × g 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 before use.

(4) Measurement of ¹²⁵ I-leuprorelin binding inhibition rate The monkey and human membrane fractions prepared in (2) and (3) above were diluted with assay buffer to 200 μg / ml, and 188 μl in a tube. Dispensed one by one. When the monkey GnRH receptor-expressing CHO cell membrane fraction was used, 2 μl of 20 mM compound dissolved in 60% DMSO (dimethyl sulfoxide) and 10 μl of 38 nM ¹²⁵ I-leuprorelin were added simultaneously. When the human GnRH receptor-expressing CHO cell membrane fraction was used, 2 μl of 2 mM compound dissolved in 60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin were added simultaneously. In order to measure the maximum amount of binding, a reaction solution was prepared by adding 2 μl of 60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin. In order to measure the amount of non-specific binding, a reaction solution containing 2 μl of 100 μM leuprorelin dissolved in 60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin was also prepared at the same time.
Monkey and human GnRH receptor-expressing CHO cell membrane fractions were reacted at 25 ° C. for 60 minutes. After the reaction, the reaction solution was subjected to suction filtration using a Whatman glass filter (GF-F) treated with polyethyleneimine. After filtration, the radioactivity of ¹²⁵ I-leuprorelin remaining on the filter paper was measured using a γ-counter.
Calculate (TB-SB) / (TB-NSB) x 100 (SB: radioactivity when compound is added, TB: maximum binding radioactivity, NSB: non-specific binding radioactivity) The binding inhibition rate was determined, the inhibition rate was determined by changing the concentration of the test substance, and the concentration of the test substance that inhibited 50% binding (IC ₅₀ value) was calculated from the Hill plot. The results are shown below.
[Table 1]

IC ₅₀ value (μM)
Test substance Monkey Human
Compound of Example 40 0.009 0.0002
Compound of Example 41 0.003 0.0001

  The compound of the present invention has an excellent gonadotropin releasing hormone antagonistic action. Furthermore, it has good oral absorption 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 preventive or therapeutic agent for hormone-dependent diseases. Specifically, for example, sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty , Amenorrhea syndrome, premenstrual syndrome, multilocular ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease, etc., or pregnancy regulators (eg, contraceptives), infertility It is effective as a therapeutic agent, a menstrual regulator, a preventive / therapeutic agent for irritable bowel syndrome, and a preventive agent for recurrence after sex hormone-dependent cancer surgery. Further, in the animal husbandry field, it controls the estrus of animals and improves the meat quality for meat. It is also effective as a spawning promoter for fish in the field of animal growth regulation and fisheries.

Claims (6)

N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea,
N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea,
N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea
And N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxypyridin-3-yl) -2,4-dioxo-1,2 , 3,4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea
Or a salt thereof . N- (4- (1- (2,6-difluorobenzyl) -5-(((2-methoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea or a salt thereof. N- (4- (1- (2,6-difluorobenzyl) -5-(((2-ethoxyethyl) (methyl) amino) methyl) -2,4-dioxo-3- (2-pyridinyl) -1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N′-methoxyurea or a salt thereof. N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or a salt thereof. N- (4- (1- (2,6-difluorobenzyl) -5-((dimethylamino) methyl) -3- (6-methoxypyridin-3-yl) -2,4-dioxo-1,2, The compound according to claim 1, which is 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl) phenyl) -N'-methoxyurea or a salt thereof. A medicament comprising the compound according to claim 1 or a salt thereof .