TW483896B - Condensed-ring thiophene derivatives, their production and use - Google Patents

Abstract

A condensed-ring thiophene derivative is effectives as a prophylactic or therapeutic agent for the prevention or treatment of several hormone dependent diseases, for example, a sex hormone dependent cancer (e.g. prostatic cancer, cancer of uterine cervix, breast cancer, pituitary adenoma), benign prostatic hypertrophy, myeloma of the uterus, endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, polycystic ovary syndrome and acne vulgaris; is effective as a fertility controlling agent in both sexes (e.g. a pregnancy controlling agent and a menstrual cycle controlling agent); can be used as a contraceptive of male or female, as an ovulation-inducing agent of female; can be used as an infertility treating agent by using a rebound effect owing to a stoppage of administration thereof; is useful as modulating estrous cycles in animals in the field of animal husbandry, as an agent for improving the quality of edible meat or promoting the growth of animals; and is useful as an agent of spawning promotion in fish.

Description

483896 經濟部中央標準局員工消费合作社印製 A7 B7五、發明説明（3 ) [發明之領域] 本發明偽有關新穎之縮合環《吩衍生物及其塩。本發 明又有關製造此吩并嘧啶衍生物及其塩之方法，及含此 I*吩并嘧啶衍生物之醫藥組成物。 [發明之背景] 垂體前葉激素之分泌，受個別激素所屬標的器官所分 泌之周遴激素（peripheral hormones)控制，及受垂體前 葉上部中心器官之迁腦下部所分泌之促進或抑制激素（於 本文，此等激素總稱“丘腦下部激素”）所控制。目前階 段，丘腦下部激素己證實有九種激素存在，包含例如促甲 狀腺激素（TRH)或***釋出激素{GnRH:有時稱作 LH-RH(促黃體激素釋出激素）}(參見，Seirigaku 2, M. Iriku 及 K. Toyama 缠輯，Bunkohdo 出版，610 〜618 頁， 1986年）。此等丘腦下部激素被假定藉咸認為存於垂體前 葉（參見，同前）之受體來顯示其作用，且對此等激素（包 含人類者）有專一性之受體基因己展開觀察研究（受髏Kiso To Rinsho, Η· Inura等编輯，Asakura Shoten出販，297 〜304頁，1993年）。於是，對此等受體有專一性及選擇性 作用之拮抗劑或激動劑，會控制丘腦下部激素之作用及控 制垂體前葉激素之分泌。結果，期望以此等拮抗劑及激動 劑用作垂體前葉激素依賴性疾病之預防及治療劑。 亮替林（Leuprorelin)乙酸塩[Fujino等著，生物及生 物物理研究通訊（Biological and Biophysical R e s e a r c h C ο b u n i c a t i ο n s )，6 0 卷，0 0 · 4 0 6 · 4 1 3 頁· 1 9 7 4 (請先閱讀背.δ之注意事項再填寫本頁) *裝· 訂 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 3 483896 經濟部中央樣率局員工消費合作杜印製 A7 B7五、發明説明（4 ) 年；Oliver，R.T.D.等著，英國癌症雜誌（British Journal of Cancers), 59卷，823頁，1989年，及 Toguchi等著，國際醫學研究雜誌（Journal of Interational Medical Research) , 18卷，35〜41 頁], 其為強效之***釋出激素之衍生物，乃丘腦下部激 素之一，（後文有時簡稱為GnRH)[Schally A.V.等著，生 物化學雜誌（Journal of Biological Chemistry), 246卷 ,7230〜7236頁，1971年；及Burgus, R.等著，美國國 家科學院院報（Proceeding of Natural Academic Science, USA), 69卷，2 78 〜2 82 頁，1 9 72年]，多重劑量 給藥後，可降低垂體***之釋出生産，此導致精囊 及卵巢對***之反應性降低，而制約睪酮及*** 之分泌。因此，亮普林乙酸塩已知對此等激素依賴性癌症 如***癌，顯示抗腫瘤活性，且廣用於臨床領域。亮普 林乙酸塩亦廣用於臨床方面如子宮内膜異位及早熟思春期 之治療劑。亮普林乙酸塩之高度抗腫瘤活性，被假定是由 於與天然GnRH比較之對蛋白酶更高之抗性，且由於對 GnRH受體之高度親和力，而降低受體數目，引起GnRH過敏 化作用。然而，如同亮普林乙酸塩對GnRH受髖為超瀲動劑 •已知在第一次給藥後，由於垂體-***之作用（急 性作用），隨著血清中睪酮濃度之增加，會立即短暫惡化 病情。由於上述情況，需要具有實質上如上述相同之治療 效果，但不會引起如上述短暫之垂體-促性脒瀲素作用（急 性作用）之GnRH拮抗蕖。有許多化合物具有此GnRH拮抗活 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X：Z97公釐） 4 483896 A7 B7 五、發明説明（5 ) 性之化合物，包含例如GnRH衍生物，如直鍵胜肽（美國專 利5140009, 5171835),環狀六胜肽衍生物[JPA S61( 1986)-191698]或二環胜肽衍生物[翳藥化學雜誌（ Journal of Medicinal Chemistry) , 36卷，3265〜 3273頁，1993年]。然而，此等化合物均為胜肽，具有許 多問題，包含例如劑型，藥劑安定性，作用持久性，及代 謝安定性。為解決此等問題，極為企盼口服式GnRH拮抗劑 ，特別是非胜肽類。但是，目前尚未有非胜肽GnRH拮抗藥 之報告。 本發明之目的乃提供具有優異之***釋出激素 拮抗活性之新穎化合物，及優異之***釋出激素拮 抗劑。 [發明之概述] 因此，本發明提供： (1) 一種式（I)之新穎BS吩并嘧啶衍生物： (請先閱讀背面之注意事項再填寫本頁) -裝· 、11 0 丨-(CH2)r、 經濟部中夬標準局員工消費合作社印製 ,ΛΛ483896 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (3) [Field of Invention] The present invention pseudo-relates to the novel condensed ring "Phenyl derivatives and their hydrazones." The present invention also relates to a method for producing the phenopyrimidine derivative and its hydrazone, and a pharmaceutical composition containing the I * phenopyrimidine derivative. [Background of the Invention] The secretion of anterior pituitary hormones is controlled by peripheral hormones secreted by the target organ to which the individual hormone belongs, and by the promoting or inhibiting hormones secreted by the lower part of the brain from the central organ in the upper part of the anterior pituitary gland (in this article) These hormones are collectively called "lower thalamus hormones"). At this stage, nine hormones have been identified in the hypothalamus hormones, including, for example, thyroid stimulating hormone (TRH) or gonadotropin releasing hormone {GnRH: sometimes called LH-RH (luteinizing hormone releasing hormone)} (see , Seirigaku 2, M. Iriku and K. Toyama, Bunkohdo, 610-618 pages, 1986). These hypothalamic hormones have been hypothesized to show their effects through receptors believed to exist in the anterior pituitary gland (see, ibid.), And observational studies have been conducted on specific receptor genes for these hormones (including humans) ( Edited by Kiso To Rinsho, Η · Inura and others, published by Asakura Shoten, pp. 297-304, 1993). Therefore, antagonists or agonists that have specific and selective effects on these receptors will control the action of hormones in the hypothalamus and the secretion of hormones in the anterior pituitary. As a result, these antagonists and agonists are expected to be used as preventive and therapeutic agents for anterior pituitary hormone-dependent diseases. Leuprorelin Acetyl Acetate [Fujino et al., Biological and Biophysical R esearch C ο bunicati ο ns], Volume 60, 0 0 · 4 0 6 · 4 1 3 pages · 1 9 7 4 (Please read the precautions of .δ before filling out this page) * The size of the paper is bound to the Chinese National Standard (CNS) Α4 specification (210X 297 mm) 3 483896 The staff sample cooperation of the Central Sample Rate Bureau of the Ministry of Economic Affairs Du printed A7 B7 V. Invention Description (4) years; Oliver, RTD, etc., British Journal of Cancers, Volume 59, 823 pages, 1989, and Toguchi et al., Journal of International Medical Research (Journal of Interational Medical Research), Vol. 18, pages 35 to 41], which is a derivative of a potent gonadotropin-releasing hormone, and is one of the hormones in the hypothalamus (hereinafter sometimes referred to as GnRH) [Schally AV, etc. Author, Journal of Biological Chemistry, Vol. 246, pages 7230-7236, 1971; and Burgus, R. et al., Proceeding of Natural Academic Science, USA, Vol. 69, 2 78 ~ 2 82, 1972], after multiple dose administration, it can reduce the release of pituitary gonadotropin, which leads to a decrease in the responsiveness of seminal vesicles and ovaries to gonadotropins, and restricts the secretion of testosterone and estrogen. . Therefore, leupulin gadolinium acetate is known to show antitumor activity against such hormone-dependent cancers such as prostate cancer, and is widely used in the clinical field. Leuprolium acetate is also widely used in clinical applications such as endometriosis and precocious puberty. The high antitumor activity of leupulin gadolinium acetate is assumed to be due to the higher resistance to proteases compared to natural GnRH, and due to the high affinity for GnRH receptors, the number of receptors is reduced, causing GnRH allergic effects. However, as levulinin acetate is a hyperkinetic agent for GnRH affected hips • It is known that after the first administration, due to the action of pituitary-gonadotropin (acute effect), as the concentration of fluorenone in the serum increases, Will immediately worsen the condition. Because of the above, it is necessary to have GnRH antagonistic scabs that have substantially the same therapeutic effect as described above, but do not cause the transient pituitary-gonadotropin effect (acute effect) as described above. There are many compounds with this GnRH antagonist activity (please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X: Z97 mm) 4 483896 A7 B7 V. Description of the invention (5 ) Compounds, including, for example, GnRH derivatives, such as straight-chain peptides (US patents 5140009, 5171835), cyclic hexapeptide derivatives [JPA S61 (1986) -191698] or bicyclic peptide derivatives [peony Journal of Medicinal Chemistry, Vol. 36, pp. 3265 ~ 3273, 1993]. However, these compounds are all peptides and have many problems including, for example, dosage form, pharmaceutical stability, persistence of action, and metabolic stability. To solve these problems, oral GnRH antagonists, especially non-peptides, are highly desired. However, there are no reports of non-peptide GnRH antagonists. The object of the present invention is to provide a novel compound having excellent gonadotropin-releasing hormone antagonistic activity and an excellent gonadotropin-releasing hormone antagonist. [Summary of the Invention] Therefore, the present invention provides: (1) a novel BS phenopyrimidine derivative of the formula (I): (Please read the precautions on the back before filling out this page) CH2) r Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs, ΛΛ

VJ (i) 其中R1為氫，烷基或下式之基： Q- (CH2)P- 其中Q為（1)可被1或多個下列取代基取代之芳基；（ i)豳素，（ii)硝基，（iii)«基，（U)胺基，U)任意取代 之羧基，Ui)伸烷二氣基及（vii)式- A-R5之基，其中A為 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 5 483896 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（6 ) 化學鍵或間隔基及R 5為烷基，（2 )任意取代之環烷基或（3 ) 任意取代之雜環基，及P為0至3之整數； R2為氫，可被烷氯基取代之烷基，任意取代之芳基， 任意取代之芳烷基或任意取代之環烷基； R3為任意取代之胺基；r為0至3之整數；及 R 4為任意取代之芳基； 或其塩； (2) 如上述（1)之化合物，其中A所示之間隔基為- O-或-S-(0)m-,其中m為0至2之整數； (3) 如上述（1)之化合物，其中R1為下式之基： Q- (CH2) P- 其中Q為可被1或多個下列取代基取代之芳基：（i)鹵 素及（ii)式-A-R5之基，其中A為-0-或-S(0)m-,其 中m為0至2之整數及R5為烷基；及p為0至3之整 數； (4) 如上述（1)之化合物，其中R2為（1)可被烷氣基取代之 烷基，（2)可被1或多個下列取代基取代之芳基：（i) 胺基，（ii)醯基，（iii)胺甲醯基，（丨v)羧基，U)硝 基，（vi)羥基，（vii)可被烷氣基取代之烷氣基， (viii)鹵素及（ίχ)式- S(0)n-R6之基，其中η為0至 2之整數及R6為烷基，（3)可被豳素取代之芳烷基或（ 4)琛烷基； (5) 如上述（4)之化合物，其中R2為（1)可被烷氣基取代之 烷基，（2 )可經1或多偏下列取代基取代之芳基：（i ) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂 i 6 483896 A7 B7五、發明説明（7 ) 羥基，（ii)可被烷氣基取代之烷氧基，（iii)鹵素及 (iv)式-S(0)n-R6之基，其中η為0至2之整數及R6 為烷基，（3)芳烷基或（4)環烷基； (6) 如上述（4)之化合物，其中R2為可被1或多個下列取 代基取代之芳基：（1)可被烷氯基取代之烷氯基，（2) 鹵素及（3)式-S(0)n-R6之基，其中η為0至2之整數 及R6為烷基； (7) 如上述（1)之化合物，其中R3為下式之任意取代胺基： R22,-(CH2)w (請先閱讀背面之注意事項再填寫本頁)VJ (i) where R1 is hydrogen, alkyl or a group of the formula: Q- (CH2) P- where Q is (1) an aryl group which may be substituted with 1 or more of the following substituents; (i) halogen, (Ii) Nitro, (iii) «, U, amine, U) optionally substituted carboxyl, Ui) alkylene and (vii) formula-A-R5, where A is the paper standard Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 5 483896 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (6) Chemical bond or spacer and R 5 is alkyl, (2) Optionally substituted cycloalkyl or (3) optionally substituted heterocyclyl, and P is an integer from 0 to 3; R2 is hydrogen, an alkyl group which may be substituted by an alkylchloro group, an optionally substituted aryl group, an optionally substituted aromatic group An alkyl group or an optionally substituted cycloalkyl group; R3 is an optionally substituted amine group; r is an integer from 0 to 3; and R4 is an optionally substituted aryl group; or 塩; or (2) a compound as described in (1) above Where the spacer shown by A is -O- or -S- (0) m-, where m is an integer from 0 to 2; (3) The compound as described in (1) above, wherein R1 is a base of the formula: Q- (CH2) P- where Q is 1 or more of Substituted aryl: (i) halogen and (ii) a radical of the formula -A-R5, where A is -0- or -S (0) m-, where m is an integer from 0 to 2 and R5 is an alkane And p is an integer from 0 to 3; (4) A compound as described in (1) above, wherein R2 is (1) an alkyl group which may be substituted by an alkanoyl group, and (2) may be substituted by one or more of the following substituents Substituted aryl groups: (i) amine, (ii) fluorenyl, (iii) carbamoyl, (丨 v) carboxyl, U) nitro, (vi) hydroxyl, (vii) may be substituted by alkane Alkane group, (viii) halogen and (ίχ)-S (0) n-R6 group, wherein η is an integer of 0 to 2 and R6 is alkyl group, (3) arane which may be substituted by halogen Or (4) chenalkyl; (5) The compound as described in (4) above, wherein R2 is (1) an alkyl group which may be substituted by an alkanoyl group, (2) may be substituted by 1 or more of the following substituents Aromatic: (i) This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) Order i 6 483896 A7 B7 V. Description of the invention (7 ) A hydroxyl group, (ii) an alkoxy group which may be substituted by an alkanoyl group, (iii) a halogen and (iv) a group of the formula -S (0) n-R6, where η is An integer of 0 to 2 and R6 is an alkyl group, (3) an aralkyl group or (4) a cycloalkyl group; (6) a compound as described in (4) above, wherein R2 is a group which may be substituted by 1 or more of the following substituents Aryl: (1) an alkylchloro group which may be substituted by an alkylchloro group, (2) a halogen and (3) a group of formula -S (0) n-R6, where η is an integer of 0 to 2 and R6 is an alkyl group (7) As the compound of (1) above, in which R3 is an optionally substituted amino group of the following formula: R22,-(CH2) w (Please read the precautions on the back before filling this page)

經濟部中央櫟準局員工消費合作社印製 R23 其中R22’為（1)可被1或多個下列取代基取代之芳基： (i)胺基，（ii)醛基，（iii)胺甲醛基，（iv)羧基，（ v)硝基，（vi)羥基，UU)可被烷氣基取代之烷氧基， (viii)鹵素，Πχ)烷基及U)式- S(0)n-R6之基，其中 η為0至2之整數及R6為烷基，（2)可被1或多個下 列取代基取代之雜環基：（i)胺基，Ui)醯基，Uii) 胺甲醛基，（iv)羧基，U)硝基，Ui)羥基，（vii)烷 氣基，Uiii)齒素，（ix)烷基及（X)式- S(0)n-R6之基 ，其中η為0至2之整數及R 6為烷基，（3)可被豳素 取代之芳烷基，（4)下式之基： R24 \ / N- (CH2)X- 本紙張尺度逋用中國國家標準（CNS ) A4規格（210X 297公釐） 7 483896 R 2 3 ··， 其中R22”’為（1)可被烷硫基取代芳基，（2)雜環基，（ 3)下式之基： R24， A7 B7 五、發明説明（8 ) 其中R24為氫，烷基或芳基，R25為氫或烷基，及R24及 R25可形成含相鄰氮原子之可任意被取代之5至7員 環狀胺基，及X為0至3之整數，或（5)可被烷硫基 取代之烷基，w為0至3之整數；及R23,為氫或烷基R23 printed by the Consumers 'Cooperative of the Central Oakland Bureau of the Ministry of Economic Affairs, where R22' is (1) an aryl group which may be substituted with 1 or more of the following substituents: (i) amine group, (ii) aldehyde group, (iii) amine formaldehyde (Iv) carboxyl, (v) nitro, (vi) hydroxyl, UU) alkoxy which may be substituted by alkanoyl, (viii) halogen, Πχ) alkyl and U) formula-S (0) n -A group of R6, wherein η is an integer of 0 to 2 and R6 is an alkyl group, (2) a heterocyclic group which may be substituted by 1 or more of the following substituents: (i) an amino group, Ui) a fluorenyl group, Uii) Amine formyl, (iv) carboxyl, U) nitro, Ui) hydroxyl, (vii) alkanoyl, Uiii) dentin, (ix) alkyl and (X) groups of formula-S (0) n-R6 , Where η is an integer from 0 to 2 and R 6 is an alkyl group, (3) an aralkyl group which may be substituted by halogen, and (4) a group of the formula: R24 \ / N- (CH2) X- Paper size Use Chinese National Standard (CNS) A4 (210X 297 mm) 7 483896 R 2 3 ··, where R22 "'is (1) an aryl group which may be substituted by an alkylthio group, (2) a heterocyclic group, (3 ) The base of the formula: R24, A7 B7 V. Description of the invention (8) where R24 is hydrogen, alkyl or aryl, R25 is hydrogen or alkyl, and R24 and R25 may be Forms an optionally substituted 5- to 7-membered cyclic amine group containing adjacent nitrogen atoms, and X is an integer of 0 to 3, or (5) an alkyl group which may be substituted by an alkylthio group, and w is 0 to 3 An integer; and R23 is hydrogen or alkyl

I (8)如上述（1)之化合物，其中R3為下式之任意取代胺基： R 2 2 ”( C Η 2 ) w (請先閱讀背面之注意事項再填寫本頁) 經濟部中央橾準局員工消費合作社印製 其中R24’為氫或烷基，R2『為氫或烷基，及R24’及 ϋ25’可形成含鄰接氮原子之5至7員琛狀胺基，或（ 4)可被烷硫基取代之烷基，w為0至3之整數；及 R 2 3 ” ’為氳或烷基； (9) 如上述（1)之化合物，其中R4為可被1或多個下列取 代基取代之芳基：（1)任恚取代之胺基，（2)醯基，（3) 任意取代之胺甲醯基，（4)羧基，（5)硝基，（6)羥基， (7 )任意取代之烷氣基及（8 )任意取代之烯基； (10) 如上述（1)之化合物，其中R4為可被1或多個下列取 代基取代之芳基：（1 )下式之基：I (8) The compound as described in (1) above, in which R3 is an optionally substituted amino group of the following formula: R 2 2 ”(C Η 2) w (Please read the notes on the back before filling this page) Central Ministry of Economic Affairs 橾Printed by the quasi-station employee consumer cooperative where R24 'is hydrogen or alkyl, R2' is hydrogen or alkyl, and R24 'and ϋ25' can form 5 to 7 member amine-like amine groups containing adjacent nitrogen atoms, or (4) Alkyl which may be substituted by alkylthio, w is an integer from 0 to 3; and R 2 3 ″ ′ is 氲 or alkyl; (9) The compound as described in (1) above, wherein R 4 is a compound which may be substituted by 1 or more Aryl substituted with the following substituents: (1) any amine substituted amine, (2) fluorenyl, (3) optionally substituted carbamoyl, (4) carboxyl, (5) nitro, (6) hydroxyl (7) optionally substituted alkanyl and (8) optionally substituted alkenyl; (10) The compound as described in (1) above, wherein R4 is an aryl group which may be substituted with 1 or more of the following substituents: (1 The base of the formula:

本紙張尺度適用中國國家標準（CNS ) Α4規格（210 Χ 297公釐） 8 483896 A7 B7 五、發明説明（ 其中R1 〃為（i)氫，（ii)烷基，（iii)任意取代之烷氧 基，（iv)任意取代之醯基或U)式- S(0)-n-R6之基， 其中η為0至2之整數，及R6為烷基及 ’為氫或烷 基；（2)醯基，（3)胺甲醯基，（4)Ν-單-或二-烷基胺 甲醛基，（5)硝基，（6)可再被一或多値烷氣基，烷醯 基，氣代基，羥基，環烷基及鹵素取代之烷氯基，（7 )可再被烷氣羰基或烷羰基取代之烯基及（8)烯氧基； (11)如上述（1)之化合物，其中R4為可被1或多値下列取 代基取代之芳基：（1)下式之基： (請先閲讀背面之注意事項 % 項再填· 裝-- :寫本頁) 訂 經濟部中央櫟隼局貝工消費合作社印裝 R 12- 其中R11"為（i)氫，（ii)烷基，（iii)可被鹵素或烷氣 基取代之烷氧基，（iv)甲醛基，U)可被鹵素或烷氣 基取代之烷醸基，（vi)苯甲醯基或式-S(0)n-R6之基， 其中η為0至2之整數及R6為烷基，及R12”為氫或烷 基，（2)可被烷氣基，烷醯基或琛烷基取代之烷氣基， (3)Ν-單或二-烷基胺甲醛基，（4)硝基，（5)可被烷氣 羰基或烷羰基取代之烯基或（6)烯氣基； (12)如上述（1)之化合物，你2,4(1Η,3Η)_二氣代- 6- (4 -甲 氣苯基）-3-苯基-1-(2-氰-6-氟苯甲基苯甲基 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 9 483896 A7 B7五、發明説明（10 ) -付-甲胺基甲基）1*吩并[2,3-(^]嘧啶或其塩； (13) 如上述（1)之化合物，偽2,4-(1Η,3Η) -二氣代-1-(2, 6-二氣苯甲基）-6-(4-丙醯胺基苯基）-5-(N-苯甲基-N -甲胺甲基）-3-(3-甲氣苯基盼并[2,3-d]嘧啶或其 塩； (14) 如上述（1)之化合物，偽2,4-(1Η,3Η) -二氣代-1-(2, 6 -二氟苯甲基）-6-(4 -異丁醯胺基苯基）-5-(N -苯甲基 -N-甲胺甲基）-3-(3-甲氯苯基）BS吩并[2,3-d]嘧啶或 其塩； (15) —種製造式（I)化合物或其塩之方法： (請先閱讀背面之注意事項再填寫本頁) 0This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 483896 A7 B7 V. Description of the invention (where R1 〃 is (i) hydrogen, (ii) alkyl, (iii) optionally substituted alkane Oxy, (iv) optionally substituted fluorenyl or U) a radical of the formula -S (0) -n-R6, where η is an integer from 0 to 2, and R6 is alkyl and 'is hydrogen or alkyl; 2) fluorenyl, (3) carbamoyl, (4) N-mono- or di-alkylamine formaldehyde, (5) nitro, (6) may be further substituted by one or more fluorenyl alkyl, alkane Fluorenyl, oxo, hydroxy, cycloalkyl and halogen-substituted alkylchloro, (7) alkenyl and (8) alkenyl which may be further substituted with alkoxycarbonyl or alkylcarbonyl; (11) as described above ( 1) A compound in which R4 is an aryl group which may be substituted by 1 or more of the following substituents: (1) a group of the following formula: (Please read the notes on the back of the item and fill in and install-: write this page ) Order R 12 printed by the Shell Quarry Consumer Cooperative of the Central Quercus Bureau of the Ministry of Economic Affairs, where R11 is (i) hydrogen, (ii) alkyl, (iii) alkoxy which may be substituted by halogen or alkanoyl, (iv ) Formaldehyde, U) an alkanoyl group which may be substituted by a halogen or alkane group, vi) benzamidine or a radical of the formula -S (0) n-R6, where η is an integer of 0 to 2 and R6 is an alkyl group, and R12 "is hydrogen or an alkyl group, and (2) may be an alkane group , Alkyl groups substituted by alkanoyl or alkynyl, (3) N-mono- or di-alkylamine formaldehyde groups, (4) nitro, (5) alkenyl groups which may be substituted by alkane carbonyl or alkylcarbonyl Or (6) alkenyl group; (12) As the compound of (1) above, your 2,4 (1Η, 3Η) _digaso-6- (4-methylphenyl) -3-phenyl-1 -(2-cyano-6-fluorobenzylbenzyl) This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 9 483896 A7 B7 V. Description of the invention (10) -P-methylaminomethyl ) 1 * pheno [2,3-(^] pyrimidine or its hydrazone; (13) As the compound of (1) above, pseudo 2,4- (1Η, 3Η) -digaso-1- (2, 6 -Digas benzyl) -6- (4-propanamidophenyl) -5- (N-benzyl-N -methylaminomethyl) -3- (3-methylaminophenyl) [ 2,3-d] pyrimidine or its pyrene; (14) The compound as described in (1) above, pseudo 2,4- (1Η, 3Η) -digaso-1- (2, 6-difluorobenzyl) -6- (4-Isobutylamidophenyl) -5- (N-benzyl-N-methylaminemethyl) -3- (3-methylchlorophenyl) BS benzo [2,3- d) pyrimidine Salt thereof; (15) - A method of fabricating a compound of formula (I) or Salt of: (Read precautions to fill out the back of the page) 0

(工: (其中R1, R2, R3, R4及r如前述定義）；該方法包括 使下式之化合物或其塩： 0 經濟部中央標隼局員工消费合作社印製(Work: (where R1, R2, R3, R4 and r are as defined above); this method includes making the compound of the formula or its 塩:

(II) (其中R1, R2, R4及r如前述定義， 下式之化合物或其塩反應： R3H (其中R3如前述定義）； 為離去基）；與 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 10 483896 A7 B7 五、發明説明（U ) (16) —種翳藥組成物，包括上述（1)定義之化合物及其載 劑，賦形劑或稀釋劑； (17) 如上述（16)之組成物，係***釋出激素拮抗劑 組成物， (18) 如上述（16)之組成物，偽用以預防或治療性激素依賴 性疾病之組成物； (19) 一種於哺乳類中拮抗***釋出激素之方法，包 括對患有***釋出激素衍生性障礙之哺乳類投 與有效量之上述（1)定義之化合物； (20) 如上述（19)之方法，其中***釋出激素衍生性 障礙俱性激素依賴性疾病； (21) 如上述（1)之化合物，偽用於B藥用途者； (22) —種上述（1)定義之化合物之用途，偽用以製造可拮 抗患有***釋出激素衍生性障礙之哺乳類之促 性腺激素釋出激素之***釋出激素拮抗組成物 t 經濟部中央標準局員工消费合作社印製 (請先閱讀背面之注意事項再填寫本頁) (23) 如上述（22)之用途，其中***釋出激素衍生性 障礙偽性激素依賴性疾病。 本化合物之核2,4(111,3(〇-二氣代1*吩井[2,3-(^]嘧淀 偽如下所示：(II) (where R1, R2, R4 and r are as defined above, and the compound of the following formula or its hydrazone reaction: R3H (where R3 is as defined above) is a leaving group); Chinese national standard (CNS) applies to this paper standard ) A4 specification (210X 297 mm) 10 483896 A7 B7 V. Description of the invention (U) (16) — a kind of peony composition, including the compound as defined in (1) above and its carrier, excipient or diluent; (17) The composition as described in (16) above is a gonadotropin-releasing hormone antagonist composition, (18) The composition as described in (16) above is a composition for the purpose of preventing or treating sex hormone-dependent diseases; (19) A method for antagonizing gonadotropin-releasing hormones in mammals, comprising administering an effective amount of a compound defined in (1) above to mammals suffering from gonadotropin-releasing hormone-derived disorders; (20) as described above The method of (19), wherein the gonadotropin-releasing hormone-derived disorder is a sex hormone-dependent disease; (21) The compound as described in (1) above, which is pseudo-used for the use of B medicine; (22)-one of the above (1) The use of a compound as defined for the manufacture of a substance that antagonizes Gonadotropin-releasing hormone-derived disorders of mammalian gonadotropin-releasing hormone-gonadotropin-releasing hormone antagonist composition t Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) (23) The use as described in (22) above, wherein the gonadotropin-releasing hormone-derived disorder is a pseudohormone-dependent disease. The nucleus of this compound 2,4 (111,3 (〇- 二 气 代 1 * phenwell [2,3-(^] pyrimidine) is as follows:

本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 2W公釐） 11 4^3896 經濟部中央標隼局員工消費合作社印製 明説 明發 五 示 所 提 可 基 烷 之 中 基 丙 異 基 3 至 11 有 具 以 中 基 烷 之 代 取 基 氣 烷 被 可 之 示 所 2 R 及 基 烷例二磺或 及 之及第 個基環1¾基 如 基 丙 基 乙 基 甲 如 /(\ 基 烷 其 ο \1/ 基 己 基 戊 基 丁 三 第 基 丁 二 第This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 2W mm) 11 4 ^ 3896 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and printed instructions issued by the five instructions 3 to 11 are substituted with a middle alkyl group instead of a basic alkyl group. 2 R and an alkyl group such as disulfone or and a first radical ring 1¾ group such as propylpropylethylmethyl such as / (\ group Alkanes ο \ 1 / Hexylpentylbutane

或 基 芳 之 示 所 Q 單 如 例 及 提 可 苯 含以 包中 6 基 佳 較 基 烷 之 子 原 基 芳 之 中 基 芳 代 取 意 任 之 示 所 4 R 及 例 實 佳 較 其 ο 基 殘 烴 族 芳 環 多 合 縮 或 (請先閲讀背面之注意事 如 基 芳 萘 其 ο 等 基 苊 基 菲 基 憩 基 萘 基 佳 更 基 萘 個 多 或 含 包 例 實 1 基 為代 數取 基之 代上 取基 之芳 上 示 基所 4 芳R 及 個 3 至 IX 為 好 較 基 甲 如 /(\ 基 烷 —0 -項再填 裝-- 寫本頁) 異 基 丁 正 基 丙 基 丙 正 基 乙 基 代 取 基 羰 氣 烷 或 基 羰 烷 被 可 基 烷 該 如 基 烯 基 丙 烯 基 烯 乙 如 /V 基 烯 被 可 其 \—/ 基 個 多 或 或 基 0 基 炔 丙 基 炔 乙 如 /V 基 炔 基 基 己 基 戊 之 代 取 意 任 基 烯 丁 烯 訂 代 取 基 羰 氣 烷 基 炔 基 炔 己 4) C3-7環烷基（如環丙基，琛丁基，環戊基，琛己基），（ 5) (:^4芳基（如苯基，萘基），其可被1或多個下列基取 代：（i)鹵素，（ii)烷基，（iii)可再被烷氣基取代之烷氣 基，（iv)硝基，（V)氰基，Ui)式-S(0)rt-R6之基，其中η 為0至2之整數及R6示烷基或胺基，Uii)胺基，（viii) 醯基，（ix)胺甲醛基，（X)羧基及（xi)羥基，（6)雜琛基例 如具有1至4個選自氮原子，氣原子及硫原子之雜原子之 5 -至9 -員芳族雜環基（如呋喃基，α吩基，吡咯基，as唑基，眯唑基，吡唑基，吡啶基），或具有1至4傾蘧自氪 本紙張尺度適用中國國家標準（CNS ) Α4規格（2丨0Χ297公釐） ~ 483896 A 7 B7 五、發明説明（13 ) 原子，氣原子及硫原子之雜原子之5 -至9 -員非芳族雜環基 (如環氧乙烷基，吖丁啶基，氯雜環丁烷基，硫雜環丁烷 基，吡咯啶基，四氫呋喃基，四氫理吩基，六氫吡啶基， 四氫€喃基，皭啉基，硫嗎啉基，六氫吡阱基），該等雜 環基可被1或多個下列基取代：（i)鹵素，（ii)烷基，（Or Jifang's shown Q single example and Tikeben contains 6 groups in the package is better than the alkyl group of the original aryl aromatic middle group aromatic substitution of any shown 4 R and examples are better than its ο residual hydrocarbon family Aromatic ring polycondensation or (please read the notes on the back side such as aryl aryl naphthalene and ο, etc., such as fluorenyl phenanthryl, naphthyl, and more quinyl naphthalene). Taking the aromatic base of the base as shown above, 4 aryl R and 3 to IX are better than base methyl such as / (\ alkane — 0-item and refill-write this page) Substitute carbonyl alkane or carbonyl alkane by coke alkane such as alkenyl propenyl ethene such as / V alkene by coke — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — —, — of the formula of / V Substitute alkynylhexylpentyl for any alkene butenyl substituted alkynylalkynylalkynyl hexadecyl 4) C3-7 cycloalkyl (such as cyclopropyl, henyl, cyclopentyl, chen Hexyl), (5) (: ^ 4 aryl (such as phenyl, naphthyl), which can be 1 or more The following groups are substituted: (i) halogen, (ii) alkyl, (iii) alkanoyl which may be further substituted with alkanoyl, (iv) nitro, (V) cyano, Ui) formula -S (0) a group of rt-R6, wherein η is an integer of 0 to 2 and R6 represents an alkyl group or an amine group, Uii) an amine group, (viii) a fluorenyl group, (ix) an amine formaldehyde group, (X) a carboxyl group, and (xi) a hydroxyl group (6) Hexenyl has, for example, a 5- to 9-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, gas, and sulfur atoms (such as furyl, αphenyl, and pyrrolyl, as azolyl, oxazolyl, pyrazolyl, pyridyl), or with 1 to 4 tilts. The size of this paper is applicable to Chinese National Standards (CNS) A4 specifications (2 丨 0 × 297 mm) ~ 483896 A 7 B7 5 5. Description of the invention (13) 5- to 9-membered non-aromatic heterocyclic groups of heteroatoms of atoms, gas atoms and sulfur atoms (such as ethylene oxide, azetidinyl, chlorocyclobutane, sulfur heterocycles) Butyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrophenenyl, hexahydropyridyl, tetrahydro € anyl, fluorenyl, thiomorpholinyl, hexahydropyridyl), and these heterocyclic groups may be Substituted with 1 or more of: (i) halogen, ( ii) alkyl, (

Hi)胺基，（iv)醯基，（v)胺甲醯基， i)羧基，（vii)硝 基，Uiii)羥基，（ix)烷氣基及（X)式-S(0)n-R6之基，其 中η為0至2之整數及R6為烷基，（7)Cn3芳烷基（如苯 甲基，苯乙基，二苯甲基），其可被1或多個鹵素所取代， (8)任意取代之胺基如下式之基： (請先閱讀背面之注意事項再填寫本頁) 其中 示氫；烷基如可被羥基取代之Ci-6烷基；可 經濟部中央樣準局員工消費合作杜印製 被1或多個鹵素或烷氧基取代之醯基（如Cu烷羰基，甲 醛基；芳羰基）；如下述之任意取代之烷氣基；可被一或 多個羥基取代之C3-7環烷基；式- S(0)n-R6之基，其中η 為0至2之整數及R6為烷基；及R12示氫或Ct-6烷基，（9) 下式之基： 2 4Hi) amine, (iv) fluorenyl, (v) carbamoyl, i) carboxyl, (vii) nitro, Uiii) hydroxyl, (ix) alkane and (X) formula -S (0) n -A base of R6, wherein η is an integer of 0 to 2 and R6 is an alkyl group, (7) a Cn3 aralkyl group (such as benzyl, phenethyl, diphenylmethyl), which may be substituted by 1 or more halogens Substituted, (8) Any substituted amine group has the following formula: (Please read the precautions on the back before filling this page) where hydrogen is shown; the alkyl group is a Ci-6 alkyl group which can be substituted by a hydroxyl group; Ministry of Economic Affairs Consumption cooperation between employees of the Central Bureau of Prototype and Du Printing of fluorenyl groups substituted with 1 or more halogen or alkoxy groups (such as Cu alkylcarbonyl, formaldehyde, arylcarbonyl); any substituted alkane groups as described below; Or a hydroxy-substituted C3-7 cycloalkyl group; a group of formula -S (0) n-R6, wherein η is an integer of 0 to 2 and R6 is an alkyl group; and R12 represents hydrogen or a Ct-6 alkyl group, (9) The base of the formula: 2 4

N- (CH2)X 其中R24為氫，烷基或芳基，R25為氫或烷基及R24與 23可形成含相鄰«原子之任意取代之5至7員琛狀胺基， 本紙張尺度適用中國國家標準（CNS ) A4規格（2HTX 297公釐） 13 483896 經濟部中央標準局員工消费合作社印製 A7 B7五、發明説明（14 ) 及X為0至3之整數，（10)脒基，（11)醯基（如Ci-8烷醯 基如甲醯基，乙醯基，丙醯基，丁醯基，辛醯基；Ci-8烷 氧羰基如甲氣羰基，乙氣羰基，丙氯羰基，丁氯羰基； 芳羰基如苯甲醯基；Cs-^芳烷羰基如苯甲羰基； C7- i 2芳烷氣羰基如苯甲氯羰基），其可任意被1或多値取 代基（如鹵素，烷硫基，烷氧基，氯代基，羥基）所取代， (12)任意取代之胺甲醯基如胺甲酷基，N -單取代之胺甲醯 基（如7烷基）胺甲醯基如甲基胺甲醯基，乙基胺甲 醛基，丙基胺甲醯基，異丙基胺甲醛基}, Ν,Ν -二取代之 胺甲醯基[如Ν,Ν-二（Ct-6烷基）胺甲醯基如二甲基胺甲醯 基，二乙基胺甲醛基，N-乙基-N-甲基胺甲醛基，N-丙基-N -甲基胺甲醛基}, (13)胺磺醛基，（14)N -單取代胺磺醯 基（如KCi-s烷基）胺磺醯基如甲基胺磺醛基，乙基胺磺 醯基，丙基胺磺醛基}, (15)N,N -二取代胺磺醛基{如1»1- 二（Ci-6烷基）胺磺醛基如二甲基胺磺酵基，二乙基胺磺醛 基}, (16)羧基，（17)(^-3烷氣羰基（如甲氣羰基，乙氣羰 基，丙氧羰基），（18)羥基，（19)任意取代之烷氣基如 Ci-6烷氣基（如甲氣基，乙氧基，丙氣基，異丙氣基，丁 氧基，異丁氣基，第二丁氣基，第三丁氣基，戊氣基，己 氧基），其可具有1或多個取代基（如上述之Ci-6烷醯基， Cl-3烷基，鹵素，Ci-3烷硫基，Ci-3烷氣基，氣代基，羥 基，如上述之C3-7璨烷基），（20)C2-4烯氣基（乙烯氣基， 烯丙氣基），（21)C3-7琛烷氣基（如環丙氣基，環戊氣基， 環己氣基），（22)〇7-13芳烷氣基（如苯甲氣基，二苯甲氣 (請先閱讀背面之注意事項再填寫本頁) I# 項再填. 裝· 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 14 483896 A7 B7 五、發明説明（15 ) 基），（23)C6-i4芳氧基（如苯氯基，萘氣基），（24)巯基， (25)C7-i3芳烷硫基（如苯甲硫基，二苯甲硫基），（26) C6-14芳硫基（如苯硫基，萘硫基），（27)式-S(0)n-R6之基 ，其中η為0至2之整數及R6為烷基（如甲硫基，乙硫基， 丙硫基，甲亞磺醯基，乙亞磺醯基，丙亞磺醯基，甲磺醯 基，乙磺醯基，丙磺醯基），（28)Ct-3伸烷二氯基（如亞甲 二氧基，伸乙二氣基，伸丙二氣基），（29)磺基，（30)氰 基，（31)11氮基，（32)硝基，（33)亞硝基，（34)鹵素（如 氣，氛，溴，碘）等。 R1及R2之Q所示之任意取代之環烷基中之環烷基，可 提及例如（：3-10環烷基及（：3-10雙環烷基。其較佳實例包含 環丙基，環丁基，環戊基，環己基，環庚基，環辛基，雙 環[2,2,1]庚基，雙環[2,2,2]辛基，雙環[3,2,1]辛基， 雙環[3,2,1]壬基，雙環[4,2·1]壬基，雙環[4,3,1]癸基 。其中以環戊基及環己基較佳。其可具有如上述對R2及 R4所示芳基之取代基之定義相同的取代基。取代基較佳實 例為烷基，烷氧基或鹵素。 經濟部中央橾隼局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) R1之Q所示之任意取代之雜琛基中之雜琛基，可提及 例如具有1至4個遴自氣原子，硫原子及氮原子之雜原子 之5 -至13 -員芳族雜琛基；或飽和或不飽和非芳族雜琛基 0 芳族雜琛基之實例，包含芳族單琛雜琛基（如，呋喃 基，β吩基，吡咯基，唑基，異垮唑基，0；唑基，異1« 唑基，眯唑基，吡唑基，1,2,3 -吗二唑基，1,2,4-1?二唑 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 15 483896 經濟部中央櫺準局員工消費合作社印製 A7 B7 五、發明説明（16 ) 基，1,3,4 -吗二唑基，呋阽基，1,2,3-α二唑基，1,2,4-瞧二唑基，1,3,4-!*二唑基，1,2,3-***基，1,2,4-*** 基，四唑基，吡啶基，嗒畊基，嘧啶基，吡畊基，三畊基 ),芳族縮合環雜環基（如，苯并呋喃基，異苯并呋喃基， 苯并[b ]«吩基，吲睬基，異吲睬基，1 Η - e?丨唑基，苯并咪 唑基，苯并枵唑基，1,2 -苯并異垮唑基，苯并α唑基，1, 2-苯并異I*唑基，1Η-苯并***基，〇f啉基，異〇f啉基， 曄啉基，時唑啉基，時垮啉基，呔I#基，萘啶基，瞟昤基 ,喋啶基，咔唑基，α-咔啉基，>9-咔啉基，咔啉基， 吖啶基，啡垮姘基，啡〇*阱基，啡胼基，啡垮I*基，I*嗯 基，啡啶基，啡啉基，吲畊基，吡咯并[1 , 2 - b ]嗒畊基， 吡唑并[1,5-a]吡啶基，眯唑并[1,2-a]吡啶基，眯唑并[ 1.5-a]吡啶基，眯唑并[l,2-b]B§姘基，咪唑并[1,2-a]嗒 畊基，1,2,4 -***并[4,3-a]吡啶基，1,2,4 -***并[4,3, b]嗒畊基}。非芳族雜琛基之實例，包含環氣丁烷基，吖 丁畊基，氣雜環丁烷基，硫雜環丁烷基，吡咯啶基，四氫 呋喃基，四氫α吩基，六氫吡啶基，四氫吡喃基，皭啉基 ，硫嗎啉基，六氫吡畊基。其中，以呋喃基，α吩基，α 唑基，眯唑基，吡唑基，吡啶基，嘧啶基，苯并呋喃基， 吲睬基及of啉基較佳。 雜琛基可具有1個或多個取代基，較宜1至3個取代 基。此取代基之定義如同R2及R4所示任意經取代之芳基處 所述。取代基較佳實例為鹵素，烷基，烷硫基或烷氧基。 作為Q所示芳基之取代基之鹵素，可提及及氟，氛， 本紙張尺度適用中國國家標準（CNS ) Α4規格（2丨0 X 29*7公釐） ---------^裝-- (請先閲讀背面之注意事項再填寫本頁)N- (CH2) X where R24 is hydrogen, alkyl or aryl, R25 is hydrogen or alkyl, and R24 and 23 can form a 5 to 7 member amine-like amine group with adjacent «atoms, size of this paper Applicable to China National Standard (CNS) A4 specification (2HTX 297 mm) 13 483896 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (14) and X are integers from 0 to 3, (10) base (11) fluorenyl (such as Ci-8 alkylfluorenyl such as methylsulfonyl, ethylfluorenyl, propylfluorenyl, butylfluorenyl, octylfluorenyl; Ci-8 alkoxycarbonyl groups such as methylcarbonyl, ethylcarbonyl, propylchlorocarbonyl, Butylchlorocarbonyl; arylcarbonyl such as benzamidine; Cs- ^ aralkylcarbonyl such as benzylcarbonyl; C7-i 2 aralkyl gas carbonyl such as benzylchlorocarbonyl), which may be optionally substituted with 1 or more fluorene substituents (such as Halogen, alkylthio, alkoxy, chloro, hydroxy), (12) optionally substituted carbamoyl groups such as carbamoyl, N-monosubstituted carbamoyl groups (such as 7 alkyl) Carbamoyl groups such as methylcarbamoyl, ethylaminocarbamoyl, propylaminocarbamoyl, isopropylaminocarbamoyl}, Ν, Ν -disubstituted carbamoyl [eg Ν, Ν- Di (Ct-6 alkyl Carboxamidine groups such as dimethylaminocarbamyl, diethylaminocarbamyl, N-ethyl-N-methylaminocarbamyl, N-propyl-N-methylaminocarbamyl}, (13) Amine sulfonyl, (14) N-monosubstituted amine sulfonyl (such as KCi-s alkyl) amine sulfonyl such as methyl amine sulfonyl, ethyl amine sulfonyl, propyl amine sulfonyl} , (15) N, N -disubstituted amine sulfonyl group {such as 1 »1-bis (Ci-6 alkyl) amine sulfonyl group such as dimethylamine sulfonyl group, diethylamine sulfonyl group}, (16) Carboxyl, (17) (^ -3 alkane carbonyl (such as methyl carbonyl, ethyl carbonyl, propoxycarbonyl), (18) hydroxyl, (19) optionally substituted alkane such as Ci-6 alkane (Such as methylamino, ethoxy, propanyl, isopropyl, butoxy, isobutanyl, second butanyl, third butanyl, pentyl, hexyloxy), It may have 1 or more substituents (such as the Ci-6 alkyl group, Cl-3 alkyl group, halogen, Ci-3 alkylthio group, Ci-3 alkanoyl group, oxo group, hydroxyl group, as described above) (C3-7 alkyl), (20) C2-4 alkenyl (ethylene, allyl), (21) C3-7 alkenyl (such as cyclopropyl, cyclopentyl) Ring ), (22) 〇7-13 Arane gas group (such as benzyl group, dibenzoyl group (please read the precautions on the back before filling out this page) I # then fill. China National Standard (CNS) A4 specification (210X 297 mm) 14 483896 A7 B7 V. Description of the invention (15) group, (23) C6-i4 aryloxy group (such as benzyl group, naphthyl group), (24 ) Mercapto, (25) C7-i3 aralkylthio (such as benzylthio, dibenzothio), (26) C6-14 arylthio (such as phenylthio, naphthylthio), (27) A group of formula -S (0) n-R6, wherein η is an integer of 0 to 2 and R6 is an alkyl group (such as methylthio, ethylthio, propylthio, methylsulfinyl, and ethylsulfinyl) , Propanesulfenyl, mesylsulfenyl, ethylsulfenyl, propanesulfonyl), (28) Ct-3 alkanedichloro (such as methylenedioxy, ethanedioxy, propylene (Two gas groups), (29) sulfo, (30) cyano, (31) 11 nitrogen, (32) nitro, (33) nitroso, (34) halogen (such as gas, atmosphere, bromine, iodine )Wait. As the cycloalkyl group in the optionally substituted cycloalkyl group represented by Q of R1 and R2, for example, (: 3-10 cycloalkyl group and (: 3-10 bicycloalkyl group). Preferred examples thereof include cyclopropyl group. , Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2,2,1] heptyl, bicyclo [2,2,2] octyl, bicyclo [3,2,1] Octyl, bicyclic [3,2,1] nonyl, bicyclic [4,2 · 1] nonyl, bicyclic [4,3,1] decyl. Among them, cyclopentyl and cyclohexyl are preferred. It may have Substituents with the same definition as above for the substituents of aryl groups shown by R2 and R4. Preferred examples of the substituents are alkyl, alkoxy or halogen. Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs (Please read first Note on the back, please fill in this page again.) Among the heterocyclic radicals of the optionally substituted heterocyclic radicals indicated by Q of R1, mention may be made of, for example, heteroatoms having 1 to 4 heteroatoms derived from gas, sulfur and nitrogen. 5- to 13-membered aromatic heterobenzyl; or saturated or unsaturated non-aromatic heterobenzyl. 0 Examples of aromatic heterobenzyl, including aromatic monobenzyl (e.g., furanyl, β phenyl, Pyrrolyl, oxazolyl, isodozolyl, 0; oxazolyl, iso1 «azole Base, oxazolyl, pyrazolyl, 1,2,3-morphadiazole, 1,2,4-1? Diazolyl This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 15 483896 Printed by A7 B7 of the Consumer Cooperatives of the Central Bureau of Quasi-Staff of the Ministry of Economic Affairs 5. Description of the invention (16), 1,3,4-morphadiazole, furyl, 1,2,3-αdiazolyl, 2,4-oxadiazolyl, 1,3,4-! * Diazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, dagen Group, pyrimidinyl, pyrenyl, triphenyl), aromatic condensed ring heterocyclyl (eg, benzofuranyl, isobenzofuranyl, benzo [b] «phenyl, indanyl, isoindole Fluorenyl, 1 Η-e? 丨 azolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisocarbazolyl, benzoαazolyl, 1, 2-benzisoI * azole Group, 1 fluorenyl-benzotriazolyl group, ocfolinyl group, iso ocfolinyl group, fluorenyl group, oxazolinyl group, chloridolinyl group, fluorene I # group, naphthyridinyl group, fluorenyl group, pyridinium Group, carbazolyl group, α-carbolinyl group, > 9-carbolinyl group, carbolinyl group, acridinyl group, phenanthryl group, phenoxy group, phenanthryl group, morphino I * group, I * Humyl, morphinyl, morpholinyl, ind Phenyl, pyrrolo [1, 2-b] Tharyl, pyrazolo [1,5-a] pyridyl, oxazo [1,2-a] pyridyl, oxazo [1.5-a] Pyridyl, oxazolo [l, 2-b] B§fluorenyl, imidazolo [1,2-a] dalophenyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4 -triazolo [4,3, b] daponyl}. Examples of non-aromatic heterobenzyl groups include cyclobutane, azetino, acyclobutanyl, thioheterocycle Butyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroαphenyl, hexahydropyridyl, tetrahydropyranyl, fluorenyl, thiomorpholinyl, hexahydropyridyl. Among them, furyl, αphenyl, αoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, benzofuryl, indyl, and ofolinyl are preferred. The heterozenyl group may have one or more substituents, preferably 1 to 3 substituents. The definition of this substituent is as described for any substituted aryl group represented by R2 and R4. Preferred examples of the substituent are halogen, alkyl, alkylthio or alkoxy. As the halogen of the substituent of the aryl group shown in Q, fluorine and atmosphere can be mentioned. This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 0 X 29 * 7 mm) ------- -^ 装-(Please read the notes on the back before filling this page)

、1T 16 483896 經濟部中央橾準局員工消费合作社印製 A7 B7五、發明説明（17 ) 溴，碘。 Q所示芳基之任意經取代羧基之取代基，可述及例如 ，烷基，環烷基，芳基，芳烷基及雜環基，定義悉如上述 及後述。 作為Q所示芳基之取代基之低级伸烷二氣基，述及例 如，Ci-6伸烷二氧基。伸烷二氧基實例包含亞甲二氣基， 伸乙二氣基，伸丙二氣基，2,2 -二甲基亞甲二氯基。 符號“ A ”所示之間隔基，述及例如，C : - 4伸烷基（如 ，亞甲基，伸乙基），C2-6伸烯基（如，伸乙烯基，伸丁二 烯基）；式-(CH2)cNR26之基，式中c為0至3及R26為氫， Ci-6烷基（如，甲基，乙基，丁基）；式-C0-之基；式-CONR27 -之基，式中R27為氫，Ci-s烷基（烷基實例如上述） ,C3-7環烷基（環烷基之實例如上述），芳基（芳基之 實例如上述），雜環基（雜環基之實例如上述）；式-S(0)m-之基，式中η為0至2之整數；-0 -;式-N R 2 7 S ( 0 ) z -之基 ，式中Ζ為0至2之整數及R27如上述定義。 可為R2所示烷基之取代基之烷氣基可提及Ci-6烷氣基 Ο R2所示任意取代之芳烷基中之芳烷基，可提及例如芳 基-烷基。芳基如前述定義。烷基之實例包含Ci-6烷基如 甲基，乙基，丙基，丁基，戊基，己基。R2所示芳烷基上 之取代基與R2及R4所示芳基可具有之取代基定義相同。 R3所示之任意取代胺基，可述及例如（1)下式之基： (請先閱讀背面之注意事 I# ，項再填 裝-- 寫本頁) 訂 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 17 483896 A7 B7 五、發明説明（18 2 2-1T 16 483896 Printed by the Consumers' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (17) Bromine and iodine. The substituent of any substituted carboxyl group of the aryl group represented by Q may be, for example, alkyl, cycloalkyl, aryl, aralkyl, and heterocyclic group, and the definitions are as described above and later. As the lower alkylene dioxy group as a substituent of the aryl group represented by Q, for example, Ci-6 alkylene dioxy group is mentioned. Examples of butanedioxy include methylenedioxo, ethylenedioxo, propylenedioxo, and 2,2-dimethylmethylenedichloro. The spacer shown by the symbol "A" refers to, for example, C: -4 alkylene (e.g., methylene, ethylene), C2-6 alkylene (e.g., vinylene, butadiene) A group of the formula-(CH2) cNR26, where c is 0 to 3 and R26 is hydrogen, a Ci-6 alkyl group (eg, methyl, ethyl, butyl); a group of the formula -C0-; -CONR27-, where R27 is hydrogen, Ci-s alkyl (examples of alkyl are as above), C3-7 cycloalkyl (examples of cycloalkyl are as above), aryl (examples of aryl are as above) ), Heterocyclyl (examples of heterocyclyl are as described above); radicals of formula -S (0) m-, where η is an integer from 0 to 2; -0-; formula -NR 2 7 S (0) z The base of-, where Z is an integer of 0 to 2 and R27 is as defined above. As the alkanoyl group which may be a substituent of the alkyl group represented by R2, Ci-6 alkanoyl group may be mentioned. Among the optionally substituted aralkyl groups shown by R2, aralkyl group may be mentioned, for example, aryl-alkyl group. Aryl is as defined above. Examples of the alkyl group include Ci-6 alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, and hexyl. The substituent on the aralkyl group represented by R2 is the same as the substituent which the aryl group represented by R2 and R4 may have. The arbitrary substituted amine group shown by R3 can be mentioned, for example, (1) the following formula: (Please read the note on the back I #, then fill in the items-write this page) The paper size is applicable to Chinese national standards (CNS) Α4 specification (210X297 mm) 17 483896 A7 B7 V. Description of the invention (18 2 2-

(CH2) W R2代 中取 其經 意 任 基 烷 環 基 烷 為(CH2) W R2 is taken from its arbitrary alkane cycloalkane as

數 整 之 3 至 ο 為 W 可之 基代 等取 該意 且任 基或 環氫 雜為 或23 基R 芳 ， 環 基 烷 中 3 2 R 及 2 2 R 述 上 ο 基 胺 四 基 甲 亞 六 \—/ 2 ✓fv 或 基 烷 上 基 芳 示 所 4 R 及 2 R 述 上 與 基 代 取 之 上 基 環 雜 及 基 芳 Λ 基 烷 具 基 代 取 之 義及 定述 在可 基 隔 間 佳 較 之 示 所 A 中 基 代 取 之 上 〇 基 義芳 定之 同 Q 相中 有R1 或 數 整 之 2 至 ο 為 m 中 其 式 及 述 可 例 實 佳 較 之 基 1 R 述 上 其 基 之 (請先閱讀背面之注意事項再填寫本頁) 義 定 述 前 如 P 及 Q 中 例 實 佳 ， 較素 之齒 基被 R1可 述示 上Qf 中 其 基 硝 ㈡式 T或 式 ， 或基 氫胺 及 ， 述基 可気 基 之 其 如 有 具 P 及 基 芳 之 代 取 所 \1/ 基 烷 示 5 R 及- S- 或- ο I 示 A 中 義 定 述 上 式 及 提 可 例 實 佳 3 之 基 R 述 上 其 基 之 經濟部中央橾隼局員工消費合作社印裝 基 芳 之 代 取 基 列 下 個 多 或 - 被 可 為 Q 中 為 A 中 其 基 之 或 式 之 2 至 ο 為 0 中 其 ο 數 整 之 3 至 ο 為 P 及 基 烷 為 5 R 及 數 整The integer of 3 to ο is W. The radical can be taken as above, and the radical or heterocyclic ring is 23 or R aryl. The 3 2 R and 2 2 R in the cycloalkane are as described above. Six \ — / 2 ✓fv or aryl on the alkane shows 4 R and 2 R as described above and taken from the basic ring hetero and aryl Λ alkane has the meaning of the substituted and defined in the base The comparison of the bases in the above shows that the radicals in A are replaced by 0. The radicals in the same Q phase have R1 or integers 2 to ο are m. The formula and description in the example are better than the base 1 R. The base is described above. (Please read the precautions on the back before filling this page) The definitions before P and Q are good. The basic tooth base R1 can be shown in the Qf formula T or formula in Qf. Hydrogen amines, and the above-mentioned groups may be substituted with P and aryl groups. / 1 / alkylalkane shows 5 R and -S- or-ο I shows A in the above definition and the examples are good. The base of 3 R The base of the central government bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Consumer Cooperative printed on behalf of Jifang Column in the multi-yl or - Q may be for A or in which the group of Formula 2 to the number ο ο is the integer of 0 to 3 alkoxy groups and ο a P and an integer of 5 R

式 或 素 鹵 被 可 及 提 可 例 實 佳 § 又 之 基 R 之 代 取 所 vly 基 烷 為 ε 5 R 及- S- 或- ο- 為 " A 中 式 及 提 可 例 實 佳 特 之 基 基 甲- 基 芳 中 其 基 之 ο 數 整 之 3 至 ο 為 P 及 基 芳 之 代 取 素 鹵 被 可 為 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 18 其 483896 經濟部中央樣隼局員工消费合作社印製 A7 B7五、發明説明（19 ) R2基之較佳實例，可提及（1)可被烷氯基取代之烷基， (2)可被1或多個下列基取代之芳基：（i)胺基，（ii)醯基， (iii)胺甲醯基，（iv)羧基，（v)硝基，（vi)羥基，（vii) 可被烷氧基取代之烷氣基，（viii)鹵素及（ix)式 -S(0)n-R6之基，其中η為0至2之整數及R6為烷基，（3) 可被鹵素取代之芳烷基或（4)環烷基。 R2基之更佳實例，可提及（1)可被Ci-3烷氣基取代之 0-6烷基，（2)可被1或多値下列基取代之Cs-m芳基：胺 基，醯基，胺甲醛基，羧基，硝基，羥基，Ci-3烷氣基， 磺基，鹵素及式-S(0)n-R6之基，其中η為0至2之整數 及R6為Cl-3烷基，或（3)C3-l〇環烷基。 R2基之又更佳實例，可提及（1)可被烷氣基取伐之烷 基，（2)可被1或多個下列基取代之芳基：（i)羥基，（ii) 可被烷氯基取代之烷氣基，（iii)鹵素及（iv)式-S(0)n-R6 之基，其中ri為0至2之整數及R6為烷基，（3)芳烷基或（ 4)環烷基。 R2基之更佳實例，可提及（1)可被Ct-3烷氣基取代之 Ci-6烷基，（2)可被1或多個Ci-3烷氣基及式-S(0)n-R6基 (其中η為0至2之整數及R6為Ci-3烷基）取代之C6-14芳 基，或（3) C3- 1〇琛烷基。 R2基之最佳實例，可提及可被1或多個下列基取代之 芳基：（1)可被烷氣基取代之烷氣基，（2)鹵素及（3)式 -S(0)n-R5之基，其中rt為0至2之整數及R5為烷基。 上述R3基之較佳實例，可提及六亞甲基四胺基或下式 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 19 483896 A7 B7 五、發明説明（2 0 之經取代胺基：The formula or elementary halogen is best available and can be exemplified. § The substitution of the base R is vly alkane as ε 5 R and -S- or-ο- is the base of "A Chinese formula and best practice. Base A-Base 3 in base ο integers from 3 to ο are P and base substitutes for halogens can be applied to Chinese paper standard (CNS) A4 size (210X297 mm) for paper size 18 its 483896 Ministry of Economic Affairs A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Samples 5. Description of the invention (19) A good example of the R2 group can be mentioned (1) an alkyl group which can be substituted by an alkyl chloride group, (2) can be substituted by 1 or more Aryl substituted with: (i) amine, (ii) fluorenyl, (iii) carbamoyl, (iv) carboxyl, (v) nitro, (vi) hydroxyl, (vii) may be alkoxy Alkyl substituted alkanoyl, (viii) halogen and (ix) a radical of the formula -S (0) n-R6, where η is an integer of 0 to 2 and R6 is an alkyl group, and (3) aromatic may be substituted by halogen Alkyl or (4) cycloalkyl. As a better example of the R2 group, mention may be made of (1) a 0-6 alkyl group which may be substituted by a Ci-3 alkanoyl group, and (2) a Cs-m aryl group which may be substituted by 1 or more of the following groups: amine group , Fluorenyl, aminoformyl, carboxyl, nitro, hydroxyl, Ci-3 alkanoyl, sulfo, halogen and a group of the formula -S (0) n-R6, where η is an integer from 0 to 2 and R6 is Cl-3 alkyl, or (3) C3-10 cycloalkyl. As a more preferable example of the R2 group, mention may be made of (1) an alkyl group which can be removed by an alkane group, (2) an aryl group which may be substituted by 1 or more of the following groups: (i) a hydroxyl group, (ii) a An alkane group substituted with an alkyl chloride group, (iii) a halogen and (iv) a group of the formula -S (0) n-R6, where ri is an integer of 0 to 2 and R6 is an alkyl group, and (3) an aralkyl group Or (4) cycloalkyl. For a better example of the R2 group, mention may be made of (1) a Ci-6 alkyl group which may be substituted with a Ct-3 alkyl group, (2) a Ci-3 alkyl group which may be substituted with one or more Ci-3 groups, and the formula -S (0 ) a C6-14 aryl group substituted with an n-R6 group (where n is an integer of 0 to 2 and R6 is a Ci-3 alkyl group), or (3) a C3-10 alkyl group. As the best example of the R2 group, an aryl group which may be substituted by 1 or more of the following groups may be mentioned: (1) an alkane group which may be substituted by an alkane group, (2) a halogen and (3) a formula -S (0 ) a group of n-R5, wherein rt is an integer of 0 to 2 and R5 is an alkyl group. The preferred examples of the above R3 group can be mentioned hexamethylenetetramine group or the following formula (please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 Mm) 19 483896 A7 B7 V. Description of the invention (2 0 substituted amino groups:

(CH2) W R23 · 其中R22’為（1)可被1或多個下列取代基取代之芳基： U)胺基，（ii)醯基，（iii)胺甲醯基，（iv)羧基，（V)硝 基，（Vi)羥基，Uii)可被烷氣基取代之烷氯基，Uiii) 鹵素，（i X )烷基或（X )式-S ( 0 ) η - I? 6之基，其中η為0至2 之整數及R6為烷基，（2)可被1或多値下列取代基取代之 雜環基：（i)胺基，（ii)醯基，（iii)胺甲醛基，（iv)羧基， (v)硝基，（vi)羥基，（vii)烷氣基，（viii)鹵素，（ix)烷 (請先閱讀背面之注意事項 Φ, ▼項再填 裝-- 寫本頁) 基或（X)式-S(0)n-R6之基，其中η為0至2之整數及 烷基，（3)可被鹵素取代之芳烷基，（4)下式之基： 為 訂 2 4(CH2) W R23 · wherein R22 'is (1) an aryl group which may be substituted with 1 or more of the following substituents: U) amine group, (ii) fluorenyl group, (iii) carbamoyl group, (iv) carboxyl group , (V) nitro, (Vi) hydroxyl, Uii) alkylchloro which may be substituted by alkanoyl, Uiii) halogen, (i X) alkyl or (X) formula -S (0) η-I? 6 Group, wherein η is an integer of 0 to 2 and R6 is an alkyl group, (2) a heterocyclic group which may be substituted by 1 or more of the following substituents: (i) an amino group, (ii) a fluorenyl group, (iii) Amine formaldehyde, (iv) carboxyl, (v) nitro, (vi) hydroxyl, (vii) alkanoyl, (viii) halogen, (ix) alkane (Please read the notes on the back Φ, ▼, then fill in (Write-write this page) group or (X) -S (0) n-R6 group, where η is an integer of 0 to 2 and alkyl group, (3) aralkyl group which may be substituted by halogen, (4 ) The base of the formula: for order 2 4

N- (CH2)X k 2 5 經濟部中央標隼局員工消費合作社印製 其中R24為氫，烷基或芳基，R25為氫或烷基，及R24 及R25可形成含相鄰氮原子之可任意被取代之5至7員環 狀胺基，及X為0至3之整數，或（5)可被烷硫基取代之 烷基，w為0至3之整數；及R23,為氫或烷基。 上述R3基之更佳實例，可提及六亞甲基四胺基或下式 之基： 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 20 483896 A7 B7 五、發明説明（2 1 ) R23，- (其中R22”示（1)烷基，（2)可被1或多個鹵素，硝基， 烷基及式- S(0)n-R6基（式中ri為0至2之整數及R6為烷基 或胺基）取代之苯基，（3)可被1或多艏鹵素及烷基取代之 雜環基，或（4)H-烷基胺甲醛基，W為0至3之整數； R 2 3 ”示氫或烷基）。 上述R3基之更佳實例，可提及下式之經取代胺基： 2 2 (CH2) 2 3 其中R22”’為（1)可被烷硫基取代之芳基，（2)雜環基， (3)下式之基： P 2 4 · —-------IP欲裝-- (請先閱讀背面之注意事項再填寫本頁) -Φ it 經濟部中央樣準局員工消費合作社印製 R25， 其中R2^為氫或烷基，R25f為氫或烷基，及R21及 R2『可形成含鄰接氡原子之5至7員琛狀胺基，或（4)可 被烷硫基取代之烷基，w為0至3之整數·，及R 2 3 ” ’為氬 或烷基 上述R3基之較佳實例，可提及下式之基 本紙張尺度適用中國國家標準（CNS ) A4規格（210X：Z97公釐） 21 483896 A7 B7 五、發明説明（22 ) R22 · - (CH2) w \N- (CH2) X k 2 5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs where R24 is hydrogen, alkyl or aryl, R25 is hydrogen or alkyl, and R24 and R25 can form adjacent nitrogen atoms. 5 to 7 membered cyclic amine groups which may be optionally substituted, and X is an integer of 0 to 3, or (5) an alkyl group which may be substituted by an alkylthio group, w is an integer of 0 to 3, and R23 is hydrogen Or alkyl. For a better example of the above R3 group, mention may be made of a hexamethylenetetramine group or a group of the following formula: The paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 20 483896 A7 B7 V. Description of the invention (2 1) R23,-(wherein R22 "represents (1) alkyl, (2) may be substituted by 1 or more halogen, nitro, alkyl and -S (0) n-R6 groups (where ri is An integer of 0 to 2 and R6 is an alkyl or amino group) substituted phenyl group, (3) a heterocyclic group which may be substituted with 1 or more halogen and alkyl group, or (4) H-alkylamine formaldehyde group, W is an integer from 0 to 3; R 2 3 ″ represents hydrogen or alkyl). For a better example of the above R3 group, a substituted amine group of the following formula may be mentioned: 2 2 (CH2) 2 3 where R22 "′ is (1) an aryl group which may be substituted by an alkylthio group, (2) a heterocyclic group (3) The basis of the following formula: P 2 4 · ----------- IP to install-(Please read the precautions on the back before filling out this page)-Φ it Staff consumption of the Central Procurement Bureau of the Ministry of Economic Affairs The cooperative prints R25, where R2 ^ is hydrogen or alkyl, R25f is hydrogen or alkyl, and R21 and R2 "may form a 5 to 7 member amine-like amine group with adjacent fluorene atoms, or (4) may be alkylsulfur A substituted alkyl group, w is an integer from 0 to 3, and R 2 3 ″ is a preferred example of the above R 3 group, argon or an alkyl group. The basic paper size of the following formula is applicable to the Chinese National Standard (CNS) A4 specifications (210X: Z97 mm) 21 483896 A7 B7 V. Description of the invention (22) R22 ·-(CH2) w \

N / R23 f (其中R22’為苯基或吡啶基，該等基為未經取代或經 式-S ( 0 ) η - R 6之基（其中η為0至2之整數及R 6為烷基）取 代，w為0至3之整數；R23’為氩或烷基）。 R4基之較佳實例，可提及可被1或多値下列取代基取 代之芳基：（1)任意取代之胺基，（2)醯基，（3)任意取代之 胺甲醯基，（4)羧基，（5)硝基，（6)羥基，（7)任意取代之 烷氯基及（8 )任意取代之烯基。 上述R4基之更佳實例，可提及可被1或多個下列取代 基取代之芳基：（1)下式之基： (請先閱讀背面之注意事項再填寫本頁)N / R23 f (where R22 'is phenyl or pyridyl, these groups are unsubstituted or via the formula -S (0) η-R 6 (where η is an integer from 0 to 2 and R 6 is an alkane Group), w is an integer from 0 to 3; R23 'is argon or alkyl). Preferable examples of the R4 group may include an aryl group which may be substituted with 1 or more of the following substituents: (1) optionally substituted amine group, (2) fluorenyl group, (3) optionally substituted carbamoyl group, (4) carboxyl, (5) nitro, (6) hydroxyl, (7) optionally substituted alkylchloro and (8) optionally substituted alkenyl. For a better example of the above R4 group, mention may be made of an aryl group which may be substituted by 1 or more of the following substituents: (1) a base of the formula: (Please read the precautions on the back before filling this page)

R12， 經濟部中央樣準局員工消费合作社印製 Ν / 其中R11’為U)氫，（ii)烷基，（iii)任意取代之烷氣 基，（i v )任意取代之醛基或（v )式-S ( 0 ) η - R 6之基，其中η 為0至2之整數，及R6為烷基及R12’為氫或烷基；（2)醛 基，（3)胺甲醯基，（4)Ν-單或二-烷基胺甲醛基，（5)硝基 ,(6)可被一或多個烷氣基，烷醛基，氣代基，羥基，琛 烷基及鹵素取代之烷氣基，（7)可被烷氧羰基或烷羰基取 代之烯基及（8)烯氣基。 上述R4基之又更佳實例，可提及可被1或多個下列取 代基取代之芳基：（1)下式之基： 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） 22 483896 A7 B7 五、發明説明（2 3 ) 其中 ’為（i)氫，（ii)烷基，（iii)可被鹵素或烷氧 基取代之烷氯基，（iv)甲醯基，U)可被鹵素或烷氣基取 代之烷醯基，（vi)苯甲醛基或式-S(0)n-R6之基，其中η為 0至2之整數及R6為烷基，及R12”為氫或烷基，（2)可被烷 氧基，烷醯基或環烷基取代之烷氯基，（3)Ν -單式二-烷基 胺甲醛基，（4)硝基，（5)可被烷氣羰基或烷羰基取代之烯 基或（6)烯氣基。 上述任意取代之芳基R4中芳基之更佳實例可提及苯基 。R4所示芳基上之取代基較佳實例可提及胺基，醛基，胺 甲醯基，單取代之烷基胺甲醛基，羧基，硝基，羥基，R12, printed by the Consumer Cooperatives of the Central Bureau of Prospecting, Ministry of Economic Affairs / where R11 'is U) hydrogen, (ii) alkyl, (iii) optionally substituted alkane, (iv) optionally substituted aldehyde, or (v ) A group of formula -S (0) η-R 6 where η is an integer from 0 to 2 and R 6 is an alkyl group and R 12 ′ is hydrogen or an alkyl group; (2) an aldehyde group, (3) a carbamoyl group (4) N-mono- or di-alkylamine formaldehyde, (5) nitro, (6) can be substituted by one or more alkanoyl, alkanoyl, oxo, hydroxy, alkynyl and halogen Substituted alkanoyl, (7) alkenyl and (8) alkenyl which may be substituted by alkoxycarbonyl or alkcarbonyl. As a more preferred example of the above R4 group, mention may be made of aryl groups which may be substituted by 1 or more of the following substituents: (1) a base of the following formula: This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297) (Mm) 22 483896 A7 B7 V. Description of the invention (2 3) where 'is (i) hydrogen, (ii) alkyl, (iii) alkylchloro which may be substituted by halogen or alkoxy, (iv) formamidine Group, U) an alkylfluorenyl group which may be substituted by a halogen or an alkanoyl group, (vi) a benzaldehyde group or a group of the formula -S (0) n-R6, wherein η is an integer of 0 to 2 and R6 is an alkyl group, And R12 "is hydrogen or an alkyl group, (2) an alkylchloro group which may be substituted by an alkoxy group, an alkylamino group or a cycloalkyl group, (3) N -mono-di-alkylamine formaldehyde group, (4) nitrate (5) Alkenyl or (6) Alkenyl which may be substituted by alkoxycarbonyl or alkcarbonyl. For a better example of the aryl group in the optionally substituted aryl group R4 mentioned above, mention may be made of phenyl group. Aryl group shown by R4 Preferred examples of the substituents mentioned may include amine, aldehyde, carbamoyl, monosubstituted alkylamine formaldehyde, carboxyl, nitro, hydroxyl,

可被CCan be C

烷氧基取代之C 烷氣基，下式之基： (請先閲讀背面之注意事項再填寫本頁) 經濟部中央橾準局員工消費合作社印製 R32 (其中烷基；可被烷氣基取代之Ci-3烷 氣基；或甲醯基；R32示氫或Ct-6烷基），或可被烷氣羰基 或烷羰基取代之C2-4烯基。 R4基之任意取代之芳基中芳基之更佳實例可提及苯基 。R4所示芳基上之取代基更實例可提及胺基；醯基；N -取 代之烷基胺甲醯基；硝基；可被Cl-3烷氣基取代之Ci-3院 氣基；下式之基： 本紙張尺度適用中國國家標準（CNS ) A4規格（210X29*7公釐） 23 483896 A7 B7 五、發明説明（24 )Alkoxy-substituted C-alkane radicals, radicals of the following formula: (Please read the notes on the back before filling out this page) Printed by R32 (of which alkyl groups; can be alkane-based) Substituted Ci-3 alkylamino; or methylamino; R32 represents hydrogen or Ct-6 alkyl), or C2-4 alkenyl which may be substituted by alkylcarbonyl or alkylcarbonyl. Preferable examples of the aryl group in the optionally substituted aryl group of the R4 group include a phenyl group. For more examples of the substituents on the aryl group shown by R4, mention may be made of amine groups; fluorenyl groups; N-substituted alkylaminomethylamino groups; nitro groups; Ci-3 alkyl groups which may be substituted by Cl-3 alkylamino groups The basis of the following formula: This paper size applies to the Chinese National Standard (CNS) A4 specification (210X29 * 7mm) 23 483896 A7 B7 V. Description of the invention (24)

(其中烷基，可被Ci-3烷氣基取代之Ci-3醯 基；可被Ch4醯基取代之Cu烷氣基；苯甲醯基；或甲醯 基；R34示氫或Ci-6烷基），可被Ci-3烷氣羰基或Ci-3烷羰 基取代之C2-4嫌基。 上述各基中，取代基之數目較好為1至3, r較好為 1, P較好為1及v較好為1。 含氮原子之5至7員環狀胺基，可提及吡咯啶基，吡 咯啉基，吡咯基，吡唑啶基，吡唑啉基，吡唑基，眯唑啶 基，咪唑啉基，眯唑基，1,2,3-三胼基，1,2,3-***啶基 ,1,2,3·***基，1,2,3,4 -四唑基，六氫吡啶基，六氫吡 姘基，六亞甲基胺基，垮唑啶基，嗎啉基，1*唑啶基或硫 嗎啉基。更佳之環狀胺基，可提及吡咯啶基，吡唑啉基， 吡唑基，六簠吡啶基，六氫吡胼基，嗎啉基及硫嗎啉基。 經濟部中央標準局員工消費合作社印製 -------φ—^-- (請先閱讀背面之注意事項再填寫本頁) 訂 該琛狀胺基可經取代。取代基之實例包含Ci-6烷基， C6-M芳基，C7-l0芳烷基，二苯甲基，Cl-6烷羰基， C6-14芳羰基，Ci-6烷氧羰基。較佳之取代基可提及Ci-6 烷基，較好為C 1 -3烷基。 上述定義中較佳之烷基，可提及例如Ci-10烷基。烷 基之實例包含甲基，乙基，丙基，異丙基，丁基，異丁基 ，第二丁基，第三丁基，戊基，異戊基，新戊基及己基。 其中以具有1至6籲磺原子之烷基更佳，且以具有至3 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 2 4 483896 經濟部中央標隼局員工消費合作社印製 A 7 B7五、發明説明（25 ) 個碩原子之烷基又更佳。 至於醯基，可提及Ck0醯基且醯基之實例例如上述 之烷醯基，芳羰基，芳烷羰基及芳烷氯羰基。 上述定義中較佳之醯基及烷醯基，可提及烷基-羰基， 且烷基如前述定義。 上述定義中較佳之烷氣基，可提及(：卜6烷氣基，且烷 氣基之實例包含甲氣基，乙氧基，丙氧基，異丙氣基，丁 氧基，異丁氣基，第二丁氣基，第三丁氣基，戊氯基，異 戊氣基，新戊氣基，己氣基。其中以具有1至3個碩原子 之烷氣基較佳。 上述定義中較佳之烯基，可提及C2-4烯基。烯基之實 例包含乙烯基，烯丙基，1-丁烯基，2-丁烯基。 上述定義中較佳之芳基，可提及芳基。芳基之 實例包含苯基，萘基。 上述定義中較佳之芳烷基，可提及C7-10芳烷基。芳 烷基之實例包含苯甲基，苯乙基。 鹵素可提及氣、氛、溴、碘。 本發明化合物（I)可易於依本身已知之方法製造，例 如下列製造方法或其類似方法。 1 .方法A 依 Κ· Gewald, Ε· Schinke及 H. Bttcher,化學報告（ C h e m · B e r · ) , , 94-100 頁（1966年）所述之方法•使 具有活性亞甲基之合宜酮或K(i),與氰乙酸酯衍生物及 硫相反應，而轉化成2-胺基β吩衍生物（ii)。詳言之，使 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS〉A4規格（210 X 297公釐） 25 483896 A/ B7 五、發明説明（26) 用酮（R3’关Η)時，使之與氣乙酸酯衍生物，於乙酸及乙酸 鞍之存在下，於合宜之溶劑（如，甲苯）中回流加熱，獲得 亞烷氰乙酸酯衍生物，然後，於硫及鹼之存在下於合宜溶 劑（如，乙醇）中，加熱獲得2 -胺基α吩衍生物（ii)。又則 ，使用醛（R3’关H)時，於合宜溶劑（如，二甲基甲醯胺）中 ，於氰乙酸酯衍生物，硫及鹺之存在下，加熱獲得2 -胺基 α吩衍生物（i丨）。 0(i)(Wherein the alkyl group is a Ci-3 fluorenyl group which may be substituted by a Ci-3 alkanoyl group; the Cu alkynyl group which may be substituted by a Ch4 fluorenyl group; a benzyl fluorenyl group; or a methyl fluorenyl group; R34 represents hydrogen or Ci-6 Alkyl), a C2-4 alkyl group which may be substituted by Ci-3 alkoxycarbonyl or Ci-3 alkoxycarbonyl. Among the above-mentioned groups, the number of substituents is preferably 1 to 3, r is preferably 1, P is preferably 1 and v is preferably 1. 5 to 7-membered cyclic amino groups containing nitrogen atoms, mentioning pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolyl, pyrazolinyl, pyrazolyl, oxazolyl, imidazolinyl, Oxazolyl, 1,2,3-triamyl, 1,2,3-triazolyl, 1,2,3 · triazolyl, 1,2,3,4-tetrazolyl, hexahydropyridine , Hexahydropyridinyl, hexamethyleneamino, oxazolidinyl, morpholinyl, 1 * azolidyl or thiomorpholinyl. More preferred cyclic amino groups include pyrrolidinyl, pyrazolinyl, pyrazolyl, hexapyridyl, hexahydropyridyl, morpholinyl and thiomorpholinyl. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ------- φ-^-(Please read the notes on the back before filling out this page) Order The amine-like amine group can be replaced. Examples of the substituent include a Ci-6 alkyl group, a C6-M aryl group, a C7-10 aralkyl group, a benzyl group, a Cl-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, and a Ci-6 alkoxycarbonyl group. As a preferred substituent, a Ci-6 alkyl group may be mentioned, and a C 1 -3 alkyl group is more preferable. As the preferred alkyl group in the above definition, there may be mentioned, for example, Ci-10 alkyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, neopentyl and hexyl. Among them, an alkyl group having 1 to 6 sulfur atoms is more preferred, and to 3 paper sizes, the Chinese National Standard (CNS) A4 specification (210X297 mm) is applicable. 2 4 483896 Printed by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs Preparation of A 7 B 7 V. Description of the invention (25) The alkyl group with a large atom is even better. As for the fluorenyl group, there may be mentioned a C00 fluorenyl group and examples of the fluorenyl group such as the above-mentioned alkanoyl group, arylcarbonyl group, aralkylcarbonyl group, and aralkylchlorocarbonyl group. As the preferable fluorenyl group and alkyl fluorenyl group in the above definition, an alkyl-carbonyl group can be mentioned, and the alkyl group is as defined above. As the preferred alkane group in the above definition, mention may be made of: (6) alkane group, and examples of the alkane group include methyl group, ethoxy group, propoxy group, isopropyl group, butoxy group, isobutyl group Gas group, second butanyl group, third butanyl group, pentyl chloride group, isoamyl group, neopentyl group, hexyl group. Among them, an alkane group having 1 to 3 large atoms is preferred. As the preferred alkenyl group in the definition, mention may be made of C2-4 alkenyl. Examples of the alkenyl group include vinyl, allyl, 1-butenyl, 2-butenyl. The preferred aryl group in the above definition may be And aryl groups. Examples of aryl groups include phenyl and naphthyl. Preferred aralkyl groups in the above definitions include C7-10 aralkyl. Examples of aralkyl groups include benzyl and phenethyl. Halogen may Mention is made of gas, atmosphere, bromine, and iodine. The compound (I) of the present invention can be easily produced by a method known per se, for example, the following production method or the like. 1. Method A according to K. Gewald, E. Schinke, and H. Bttcher , Chemical Report (C hem · Ber ·),, Method described on pages 94-100 (1966) • Use of methylene ketone or K (i) with active methylene, and cyanoacetic acid The derivative reacts with the sulfur phase to be converted into a 2-amino β-pheno derivative (ii). In detail, (Please read the precautions on the back before filling this page) The paper size applies to Chinese national standards (CNS> A4 specification (210 X 297 mm) 25 483896 A / B7 V. Description of the invention (26) When using ketone (R3 'off), it should be mixed with acetic acid derivative in the presence of acetic acid and saddle acetate. Heating under reflux in a suitable solvent (eg, toluene) to obtain an alkylene cyanoacetate derivative, and then heating in a suitable solvent (eg, ethanol) in the presence of sulfur and a base to obtain 2-aminoαphene Derivative (ii). In addition, when using an aldehyde (R3 'off H), heat in a suitable solvent (eg, dimethylformamide) in the presence of a cyanoacetate derivative, sulfur, and amidine. A 2-aminoaminophene derivative (i 丨) is obtained. 0 (i)

(Rr -Η) (請先閲讀背面之注意事項再填寫本頁) 經濟部中央橾隼局員工消費合作社印製 以方法Α所述方法製得之2 -胺基®盼衍生物（ii)或其 塩與異氣酸酯衍生物反應。異氛酸酯衍生物例如式R2-NCO 所示之衍生物（其中R2如前述定義）。化合物（Π)或其塩與 異氣酸酯衍生物之反應，可在不影響反應之溶劑（如四氫 呋喃，吡啶，二垮烷，苯，二氮甲烷，1,2 -二氯乙烷，甲 苯，二甲苯）中，在約1 5至約1 3 0 1C之溫度範圍進行。相對 於1當量化合物（Π),異氰酸酯衍生物之用董約1至5當 置，較好約1.1至2.5當量。反應時間自數小時至數天，較 好約1 5分鐘至約2天。 2 .方法B : 使胺[例如式R2-HH2所示之化合物（式中，R2之定義如 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐） 26 483896 A7 B7 五、發明説明（27) 上述）]進行加成反應至異氰酸酯衍生物上，該異氰酸酯衍 生物乃使2-胺基吩衍生物（Π)或其塩，與光氣或其同類 化合物[例如，二光氣，如，雙（三氛甲基）碩酸塩，三光 氣，如，三氛甲基氛甲酸酯]反應而製得。化合物（Π)或 其塩與光氣或其同類化合物之反應，偽於不影響反應之溶 劑（例如，二枵烷，四氫呋喃，苯，甲苯，二甲苯，1,2-二氛乙烷，氛仿）中，於約40至120t：之溫度下，進行之。 光氣或其同類化合物，使用約0.5至2當量，宜約0.9至 1.1當量。反應時間由數分鐘至數天，宜約15分鐘至約2 天。胺之加成反應，於不影鬱反應之溶劑（如，吡啶，四 氫呋喃，二n等烷，苯，二氛甲烷，1,2 -二氛乙烷，甲苯， 二甲苯）中，在約15至130C溫度範圍内進行。胺使用約 1至5當量，宜約1.1至3當量。反應時間為數分鐘至數 天，宜約15分鐘至約2天。 經濟部中央樣準局員工消費合作杜印製 所得之化合物（xv)或其塩，以齡處理，使之閉環反應 ，而製得I*吩并[2,3-d]喃啶衍生物（XVI)。此閉環反應於 不影饗反應之溶劑中進行。溶劑例如醇類，如甲醇，乙醇 或丙醇，及醚類，如二垮烷或四氫呋喃。至於鹼使用例如 ,鹸金屬烷氯化物，如，甲氣納，乙氣納或異丙氣鈉，及 齡金屬氫化物，如，氫化鈉。齡之用量，為每1當量化合 物（XV),使用1至5當量，宜約1.5至3當量。反應溫度 為約10C至所用溶劑之沸點，宜約25C至所用溶劑之沸點 。反應時間為數分鐘至數天，宜約10分鐘至2天。 化合物（XVI)及鹵化芳烷基衍生，於酴（例如，有機鹼 27 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 483896 A7 B7 五、發明説明（28 ) ,如吡啶或三乙胺）之存在下，於不影響反應之溶劑（例如 ,醯胺類，如二甲基甲醯胺或二甲基乙醯胺）中，於約10 至loot： ϋ拌製得2,4 -二氯代α吩并[2,3-d]嘧啶衍生物（ Ila)。接著，此化合物（Ila)與N -溴丁二醯亞胺（NBS),於 不影響反·之溶劑（例，鹵化烴類，如四氣化磺或氛仿）中 ，在a ,cc 偶氮雙異丁腈之存在下攪拌製得化合物（II) 。再則，此化合物（II)與多種胺類，於鹼之存在下，於不 影響反應之溶劑（例如，醯胺類，如二甲基甲醯胺或二甲 基乙醯胺；腈類，例如乙腈；醇類，例如乙醇）中，約10 至lOOt溫度下攪拌0.5至8小時而製得化合物（I)。需要 的話，此化合物（I)以合宜之酸（如，塩酸或草酸）製成對 應之塩。 前述製法示於下列反應圖1 : --------裝— (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央樣隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 28 483896 A7 B7 五、發明説明（2 9 反應圖1 个 个 3 ΟίϋΜ 上 M OCJN 0 -3C00 :cix(Rr -Η) (Please read the precautions on the back before filling out this page) Printed by the Consumer Affairs Cooperative of the Central Government Bureau of the Ministry of Economic Affairs of 2-Amine-derived derivatives (ii) or Its hydrazone reacts with isonic acid ester derivatives. An isocyanate derivative is, for example, a derivative represented by the formula R2-NCO (where R2 is as defined above). The reaction of the compound (Π) or its hydrazone with an isonic acid ester derivative can be carried out in a solvent that does not affect the reaction (such as tetrahydrofuran, pyridine, dipentane, benzene, diazomethane, 1,2-dichloroethane, toluene , Xylene) in a temperature range of about 15 to about 13 0 1C. The use of the isocyanate derivative is about 1 to 5 equivalents, preferably about 1.1 to 2.5 equivalents, with respect to 1 equivalent of the compound (Π). The reaction time is from several hours to several days, preferably from about 15 minutes to about 2 days. 2. Method B: Make amines [for example, compounds represented by formula R2-HH2 (wherein, the definition of R2 is the same as the paper standard applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 26 483896 A7 B7 (Explanation of the invention (27) above)] The addition reaction is performed on the isocyanate derivative, which is a 2-aminopheno derivative (Π) or its hydrazone, and phosgene or its similar compound [for example, two Phosgene, such as bis (triammonium methyl) terbium sulfonate, triphosgene, such as triammonium methylammonium formate] is prepared by reaction. The reaction of the compound (Π) or its hydrazone with phosgene or a similar compound is pseudo-solvent which does not affect the reaction (for example, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dioxane, ethane Imitation), at a temperature of about 40 to 120 t :. Phosgene or similar compounds are used in an amount of about 0.5 to 2 equivalents, preferably about 0.9 to 1.1 equivalents. The reaction time is from several minutes to several days, preferably about 15 minutes to about 2 days. Addition of amines in solvents that do not affect the reaction (eg, pyridine, tetrahydrofuran, di-n-alkanes, benzene, dioxane, 1,2-dioxane, toluene, xylene), at about 15 Temperature range to 130C. The amine is used in an amount of about 1 to 5 equivalents, preferably about 1.1 to 3 equivalents. The reaction time is several minutes to several days, preferably about 15 minutes to about 2 days. The compound (xv) or its hydrazone obtained by the printing and printing of employees of the Central Bureau of Prototype of the Ministry of Economic Affairs was treated with age to make it undergo a closed-loop reaction, and an I * pheno [2,3-d] pyrimidine derivative ( XVI). This ring closure reaction is performed in a solvent which does not affect the reaction. Solvents are, for example, alcohols, such as methanol, ethanol or propanol, and ethers, such as dioxane or tetrahydrofuran. As the base, for example, sulfonium metal alkane chlorides, such as sodium gas, sodium gas, or sodium isopropoxide, and age metal hydrides, such as sodium hydride. The dosage for age is 1 to 5 equivalents, preferably about 1.5 to 3 equivalents per 1 quantified compound (XV). The reaction temperature is about 10C to the boiling point of the solvent used, preferably about 25C to the boiling point of the solvent used. The reaction time is several minutes to several days, preferably about 10 minutes to 2 days. Derivatives of compounds (XVI) and halogenated aralkyl groups, such as organic base 27 (please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) 483896 A7 B7 V. Description of the invention (28), such as pyridine or triethylamine, in the presence of a solvent that does not affect the reaction (for example, amidines such as dimethylformamide or dimethylacetamide) ), At about 10 to loot: 2,4 -dichloroαpheno [2,3-d] pyrimidine derivative (Ila) was prepared by mixing. Next, this compound (Ila) and N-bromosuccinimide (NBS), in a solvent that does not affect the reaction (for example, halogenated hydrocarbons, such as tetrakis Compound (II) is prepared by stirring in the presence of azobisisobutyronitrile. Furthermore, the compound (II) and various amines are in a solvent that does not affect the reaction in the presence of a base (for example, amidines such as dimethylformamide or dimethylacetamide; nitriles, For example, acetonitrile; alcohols such as ethanol), and the compound (I) is prepared by stirring at a temperature of about 10 to 100 t for 0.5 to 8 hours. If necessary, the compound (I) is prepared with a suitable acid (for example, osmic acid or oxalic acid). The aforesaid manufacturing method is shown in the following reaction chart 1: -------- install— (please read the notes on the back before filling out this page) Order printed by the Central Government Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, and the paper size is applicable to China Standard (CNS) A4 specification (210X297 mm) 28 483896 A7 B7 V. Description of the invention (2 9 reaction diagrams 1 3 3 ΟίϋΜ on M OCJN 0 -3C00: cix

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(Η) 離 示 X Ο 義 定 之 同 相 述 前 與 有 具 基 別 個 中 麵 應 反 述 上 基 去 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 29 483896 A7 B7 五、發明説明（30) X所示之離去基，述及例如，可經親核性試劑例如具 有帶負電荷之雜原子（如氯原子，硫原子及氮原子）之烴殘 基取代之基。更待定言之，例如鹵素（如碘，溴，氛），烷 醯氣基（如，乙醯氯基），烷磺醯氣基（如甲磺醯氧基）及烷 基-芳磺醯氯基（如，對-甲苯磺醯氧基）。 3 .方法C : 經濟部中夬標隼局員工消費合作社印製 可使用任何本身習知之方法，例如依循由化合物（Π) 製造化合物（Ila)之製程，取代上述反應圖1中由化合物（ ii)製成化合物（Ila)之製法。亦卽，化合物（ii)溶劑不影 響反應之適宜溶劑（如甲醇、乙醇）中，添加2N氫氧化鈉， 混合物在室溫至加熱（至約100t：)下反應1至12小時。所 得其中-C 0 0 E t轉化成-C 0 0 Η之化合物溶於適宜溶劑如二垮 烷中，並於溶液中添加等量三光氣且混合物在80至1501C 之溫度下攪拌反應1至1 0小時。所得1 -羥基鸣畊化合物以 類似於前述化合物（XVI)反應成化合物（Ila)之方法處理。 因而所得在1 -位置導入R 1基之垮畊化合物溶劑適宜溶劑如 二氛甲烷中，於溶液中添加等置至略過量之胺如銨，烷胺 ,芳胺等，且混合物在室溫至加熱（至lOOt：)下攪拌反應 1至12小時。接箸，於反應混合物中再添加三光氣及三乙 胺作為驗，混合物在約100C下回流反應1至6小時，得 式（I I a )化合物。 4 .其他方法： 化合物（I)上之取代基可藉本身已知之習知方法轉化 成其他取代基。該方法實例如下。 30 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X29?公釐） 483896 經濟部中央樣隼局貝工消費合作社印製 A7 B7 五、發明説明（31) (i )硝基取代基，可轉化成胺基；使起始化合物溶於適宜 溶劑如乙醇、甲醇，及（a)於溶液中添加ffi -碩且混合 物在氫氣及室溫下反應1至12小時，或（b)於溶液中 添加鐵粉及塩酸且反應在室溫反應1至12小時。 (Π)胺基可轉化成醯化胺基；使起始化合物溶於適宜溶劑 如四氫呋喃、二甲基亞碾，於溶液中添加磺酸鉀、吡 啶及三乙胺作為鹼，及酸酐或醯鹵，混合物在室溫攪 拌反應1至1 0小時。 (iii) 由胺基化合物（具有胺基之化合物）轉化成烯胺基化 合物。例如起始化合物溶於適宜溶劑如乙酸、二甲基 甲醯胺、二氛甲烷、四氫呋喃、二垮烷、乙腈，於溶 液中添加重氮化劑如亞硝酸納、亞硝酸異戊酯，於混 合物添加把催化劑如雙（二苯亞甲基丙酮）把及1至過 量當量之烯基衍生物，且混合物在室溫至加熱（801C) 下攪拌1至1 2小時。 (iv) 碩原子可導入胺基中，例如於適宜溶劑如乙酸、二甲 基甲醯胺、二氛甲烷、四氫呋喃、二垮烷中之起始化 合物中添加丙烯酸衍生物或環氣乙烷衍生物如過氧化 物化合物，混合物在0至80CII拌6至24小時。 (v) 硫原子導至化合物中之胺基，例如於適宜溶劑如吡啶 、二甲基甲醛胺、二氰甲烷、四氳呋喃、***、二垮 烷中之起始化合物中添加硫化合物之鹵化物。混合物 在0至8010攪拌6至24小時。 (vi) 取代基甲睡基可轉化成甲基；起始化合物溶於適宜溶 31 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 483896 經濟部中央櫺隼局員工消費合作社印装 A7 B7五、發明説明（32 ) 劑如四氫呋喃中，並於混合物中添加有機硼烷衍生物 如二甲硫醚硼烷，且混合物在室溫至回流加熱下反應 數小時，如1至3小時。 (vii) 由甲氣衍生物可製備三乙氧甲氧基（actonyloxy)衍 生物；起始物溶劑適宜溶劑如二氛甲烷中，於溶液中 添加1至過量當量之路易士酸如氛化鋁，及硫醇化合 物或硫醚化合物（如二甲硫醚），且混合物在冰冷却至 室溫下反應1至1 0小時，接著所得羥基衍生物溶於適 宜溶劑如二甲基甲醯胺中，於溶液中添加鹼如氫氣化 鈉或碩酸鉀及烷鹵化物，混合物在室溫反應1至12小 時。 (viii) 甲氣基可改變成異丙氯基；起始物溶於適宜溶劑如 二氣甲烷中，於溶液中添加1至過量當量之路易士酸 如氛化鋁，及硫醇化合物或硫醚化合物（如二甲硫醚） ，且混合物在室溫至冰冷却下反應1至10小時。 (ix) 可導入胺欺基；具有鹵素原子之起始化合物溶於適宜 溶劑如二甲氣乙烷中，於溶液中添加芳基硼酸衍生物 ，鹼（如碩酸鈉），耙化合物（如肆（三苯膝）把（0)作為 催化劑，且混合物回流1至6小時。 (X)烷硫基化合物可轉化成烷亞磺醯化合物或烷磺醯化合 物；偽藉由使起始化合物與氣化劑（如間-氱過苯甲酸 )在適當溶劑（如二氯甲烷）中，於冰冷却至加熱下反 應而得。當更瀲烈加熱或以過量氣化劑處理時，可得 烷磺睡基化合物。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 32 483896 經濟部中夬樣隼局員工消费合作社印製 A7 B7五、發明説明（33 ) 上述獲得之本發明化合物（I)之塩，宜為生理學上可 接受之酸加成塩。此塩之實例，包含與無機酸（如塩酸， 氫溴酸，硝酸，硫酸及磷酸）形成之塩，或與有機酸（如甲 酸，乙酸，三氟乙酸，反丁烯二酸，草酸，酒石酸，順丁 烯二酸，檸樣酸，丁二酸，蘋果酸，甲磺酸，苯磺酸，及 對-甲苯磺酸）形成之塩。再則，本發明之化合物（I)具有 酸基，如- COOH,此化合物（I)可與無機鹼（如鹼金屬或鹼 土金屬，如鈉，鉀，鈣及鎂；氨）形成塩，或與有機鹼（如 三甲胺，三乙胺，吡啶，甲基吡啶，乙醇胺，二乙醇胺， 三乙醇胺，二環己胺及Μ,ίΤ -二苯甲基伸乙二胺）形成塩。 上述製得之本發明之化合物（I)或其塩，可依傳統之 分離方式，例如再結晶，蒸餾及層析，予以單離及純化。 若製得之化合物（I)為游離型式，可依本身之傳統方式或 類似方法，予以轉化成其塩。反之，若為塩型式，可轉化 成其游離型或成任何其他塩。 若本發明之化合物（I)或其塩為光學活性化合物，則 可依一般之光學解析法，分離成d -化合物及1-化合物。 由於本發明之化合物（I)具有GnRH拮抗活性且毒性低 黴，因此可安全用於哺乳動物（如，人，猴，牛，馬，狗， 貓，兔，老鼠及小鼠等），由GnRH受體拮抗作用制約促性 腺激素之分泌，以治療雄性激素或雌性瀲素依賴性疾病， 以及治療由此等激素遇度分泌引起之疾病。詳言之，本發 明之化合物有效用作用以預防或治療數種激素依顗性疾病 ，例如，性激素依糴性«症（如，***癌，子宮頸癌， (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 33 483896 經濟部中央標準局員工消費合作社印製 A 7 B7五、發明説明（3〇 乳癌，垂體腺癌），良性***肥大，子宮肌瘤，子宮内 膜異位，早熟思春期，停經，經前激候，多囊性卵黛激候 群及尋常痤瘡之預防或治療劑。此外，本發明之化合物亦 有效用作兩性之生育控制劑（如，妊娠控制劑及月經週期 控制劑）。本發明之化合物又可用作雄性或雌性之避孕藥， 及雌性之***ί發劑。本發明之化合物可由於停止給藥之 回躍作用而用作***治療劑。再則，本發明之化合物在畜 牧業領域有用作諝節動作春情週期，及用作食用肉品之品 質改良劑，或動物成長促進劑。此外，本發明之化合物可 用作魚類産卵促進劑。雖然，本發明之化合物可單獨使用 ，亦可與類固醇或非類固醇抗産雄劑併用。本發明之化合 物可用以制約因給予GnRH超拮抗劑，如亮普林乙酸塩而産 生之血漿中睪酮濃度之上昇。本發明之化合物可與癌症化 學治療劑合併給藥。治療***癌時，化學治療劑之實例 ,包含埃弗醒胺（Ifosfamide), UFT,阿霉素（Adriamycin ),派普勒素（Peplomycin),順氛氣 ifi(Cisplatin)等。治 療乳癌時，化學治療劑之實例，包含琛弗醯胺（ Cyclophohamide), 5-FU, UFT,氣甲喋脸（Methotrexate) ,阿霉素（Adriamycin)綠裂徽素C(Mitomycin C)，綠山純 (Mitoxantrone)# 〇 本發明化合物（I)經由皮下或口服投蕖顯示充分之 GnRH活性，其經由口服投藥可穩定地吸收且長時間顯現 GnRH活性。 若本發明之化合物，在畜牧業或餐殖業領域，用作上 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 34 483896 A7 B7 五、發明説明（35 ) 述疾病之預防及治療劑，可依本身己知之方式，經口或非 經口給藥。本發明之化合物與醫藥上可接受之載劑混合， 通常以固體製劑如錠劑，膠囊劑，粒劑或粉劑而經口給予 ,或呈靜脈，皮下或肌内注射劑而非經口給予，或成栓劑 或舌下給藥錠劑。再則，呈缓釋劑如舌下給藥錠劑或徹膠 囊，經舌下，皮下或肌内給藥。本化合物（I)之日用劑量 依患病程度；欲給藥者之年齡，性別，體重及敏感度差異 ;給藥之時間及間隔，醫藥製劑之性質，劑型及種類；有 效成分之種類等而變化。雖然沒有特別限制，但通常哺乳 類動物每1公斤體重，給予約0.01至10 m g,宜約0.02至 2mg,更宜約0.01至lmg,通常每日給藥1次，或分成2至 4次給藥。若於畜牧業或養殖業領域，日劑量類似上述情 況而不同，每1公斤體重個體動物或魚，約0.01至5mg, 宜約0.002至2nig,每日1次或2至3次。 經濟部中夬標準局貝工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 上述醫藥上可接受之載劑，使用習知各種有機或無機 載劑，於固體組成物中以賦形劑，潤滑劑，黏合劑及崩解 劑等併入，及於液體組成物則以溶劑，增溶劑，懸浮劑， 等張劑，缓衝劑及缓痛劑併入。而且，依需要，亦可使用 添加劑，例如，保存劑，抗氣化劑，著色劑及甜味劑。 上述賦形劑之較宜實例包含乳糖，蔗糖，D -甘露糖醇 ,澱粉，結晶纖維素及更具揮發性之二氣化矽。上述澗滑 劑較宜之實例包含硬脂酸鎂，硬脂酸鈣，滑石及膠龌氣化 矽。上述黏合劑較宜之實例包含結晶纖維素，蔗糖，D -甘 露糖酵，期精，羥丙基纖維素，羥甲基鐵維素及聚乙烯啦 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X29?公釐） 35 483896 A7 B7 五、發明説明（36)咯酮。上述崩解劑較宜之實例包含澱粉，羧甲基纖維素 。 乙 乙 納聚聚 粉 ，含 澱醇包 基二例 甲丙實 羧 ，之 及醇宜 鈉乙較 素 ，劑 維水溶 纖用增 基射述 甲注上 羧含 〇 聯包油 交例米 , 實 玉 鈣之及 素宜油 維較麻 纖劑芝 基溶 ， 甲述醇 羧上二 參 述醇 上乙 , 。三 醇鈉基 乙酸脂 , 樣 硬 酯檸 , 甲及如 苯鈉例 酸酸 ， 甲碩劑 苯 ，性 , 胺活 醇醇面 糖乙表 露 三 含 甘 ，包 D-醇例 , 固 實 醇膽之 二 ，宜 丙烷較 ,甲劑 醇基浮 二胺懸 胺銨 烷 苄 化 氛 脂 酸 卵 酸 丙 基 胺 基Λ… 桂 月 鈉 酸 硫 基 桂 月 物 合 聚 性 水 親 及 酯 油 甘0 脂 i 7 0 單 及 銨 烷 乙 甲 苯 化 氛 甲 納 素 維 纖 基 甲 羧 酮 咯 oth 烯 乙 聚 醇 烯 乙 聚 如 例 素 維 m 基 丙 羥 及 素 維0 基 乙 羥 素 維 纖 基 甲 羥 素 維 纖 基 醇 ， 糖塩 露酸 甘磷 - D » 及如 油例 甘 ， ， 液 鈉溶 化衝 氛缓 含含 包 包 例例 實實 之之 宜宜 較 較 劑劑 張衝 等缓 述述 上上 含 包 例 實 之 宜 較 劑 痛 缓 述 上 ο 塩 酸 檬 檸 及 塩 酸 磺 塩 酸 乙 氛化 , 氯 酯抗 酸述 甲上 苯 。 基酸 羥梨 對山 含及 包酸 例乙 實氫 之脱 宜 ， 較醇 劑乙 存苯 保 ， 述醇 上甲 。 苯 醇 ， 甲 醇 苯丁 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作杜印製 酸 血0 抗 及 塩 I 酸 ί 硫物 亞 合 含化 包之 例明 實發 之本 宜於 較 0 中 劑 溶 增 劑 浮 懸 如 例 入 加 混本 使依 法可 方 ， 之話 知的 己要 身霈 本 〇 依劑 , 射 後注 然 内 , 肌 劑或 存下 保皮 及 ， 劑脈 張靜 等成 , 配 劑調 定物 安合 劑 製 乾 凍 成 製 劑 射 注 等 此 將 法 方 之 知 已 身 如 劑 服 Π 為 例 實 之 物),劑 成劑裂 組錠皮 蕖及經 醫劑 述囊劑 上膠製 # 劑滴 劑 射 注 劑劑 粉用 釋外 稀 ， , 剤 如射 /(\ 注 滴 黏 粒 等 劑 * 軟 資 軟 腸 直 • 道 如陰 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 36 483896 經濟部中央標準局員工消費合作社印製 Λ7 B7 五、發明説明（37) 軟資，等）等。 此等翳藥組成物可依一般製備K藥組成物所用本身已 知之方法製造。 本發明之化合物（I)或其塩可製成注射劑。可與分散 劑[如，Tween 80(美國，Atlas 粉廠），HCO 80(日本， Nikko藥品公司），聚乙二醇，羧甲基纖維素，藻酸鈉，等 ],保存劑（如，對羥苯甲酸甲酯，對羥苯甲酸丙酯，苯甲 醇，等），等張劑（如，氛化鈉，甘露耱醇，山梨糖醇，葡 萄糖，等）等，製成水溶液型注射劑，或藉溶解，懸浮或 乳化於植物油（如，橄欖油，芝麻油，棉仔油，玉米油，等），丙二醇等，製成油性注射劑。 製備口服醫藥組成物時，使本發明化合物（1)或其塩 ,與例如填充劑（如，乳糖，蔗糖，澱糖，等），崩解劑（ 如，澱粉，磺酸鈣，等），黏合劑（如，澱粉，***膠， 羧甲基纖維素，聚乙烯吡咯酮，羥丙基纖維素，等），或 潤滑劑（如，滑石、硬脂酸鎂、聚乙二醇6000,等）等，壓 縮模製之。若霈要，依本身已知之方法，以矯味，腸衣或 長效性物質包覆組成物。包覆劑之實例為羥丙基甲基纖維 素，乙基纖維素，羥甲基纖維素，羥丙基纖維素，聚氣乙 二醇，Tween 80,普魯尼（pluronic)F68,乙酸酞酸酷纖 維素，羥丙基甲基纖維素酞酸酯，羥甲基纖維素乙酸丁二 酸酯，E ii d r a g i U甲基丙烯酸與丙烯酸之共聚物；R 〇 h m製 造，徳國），氣化鐵紅等。依本身已知之方法，可於腸衣 靥及核心層之間，予以再包覆一靥。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 37 483896 經濟部中央櫺隼局員工消費合作社印製 A7 B7 五、發明説明（38 ) 製備外用組成物時，使本發明之化合物（I)本身或其 塩，依本身已知之方法，製成外用之固體，半固體或液體 劑。例如，依下述製成固體製劑。於是，以本發明之化合 物本身，或添加及/或混合瑱充劑（如，乙二醇，甘露糖醇 ，澱粉，微晶織維素，等），增稠劑（如，天然膠，纖維素 衍生物，丙烯酸聚合物，等）等後，製成粉末組成物。關 於液體組成物，可以類似注射劑之方式製成油性或水性懸 浮液。半固體組成物之例中，較宜為水性或油性凝膠或軟 音。各可與pH調節劑（如，硪酸，磷酸，檸檬酸，塩酸， 氫氣化納，等），防腐劑（如，對-羥苯甲酸酯，氛丁醇， 氛化苄烷銨，等）等化合。 製造軟蕾時，例如，本發明之化合物（I)或其塩可製 成油性或水性固體，半固體或液體軟音。上述組成物所用 油基物料之實例，為高级脂肪酸甘油酯[如，可可脂， Witepsols(Dynaniite-Nobel製造），等]，中级脂肪酸甘油 酯[如，Miglyols(Dynamite-Hobel 製造），等]及植物油（ 如，芝麻油，大豆油，棉仔油，等）等。水基物料之實例 為聚乙二醇及丙二醇，且水性凝膠之基料實例為天然膠， 纖維素衍生物，乙烯基聚合物，丙烯酸聚合物，等。 准行太發明：>麝佯榭式 Η由下述參考例及實施例詳述本發明，但不應由此限 制本發明之範圍。 M-NMR 譜以 Varian GEMINI 200(200ΜΗζ)型光譜儀， JEOL LAMBDA 300(300 MHz)型光磨儀或 Brucker AM 500( 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） —--------•裝-- (請先閱讀背面之注意事項再填寫本頁) 訂 38 483896 A7 B7 五、發明説明（39) 500MHZ)型光譜儀，用四甲基矽烷作内標準，测定之。所 有數據值以P P m表示。 本說明書所用之符號，意義如下： s:單峯，d:雙峯，t:銮峯，dt:雙峯#峯，ίο:多 峯，br:寬 袞者例1 2-胺基-5-苯基I*吩-3-羧酸乙酯之製造 於氣乙酸乙酯（6.1g, SOmniol),硫（1.61g, 50mmol), 三乙胺（3.5ml, 25ηιαιο1)及二甲基甲醛胺（10ml)之混合物 中，於45t：攪拌下以20分鐘滴加入苯基乙醛（50%故酸二 乙酯溶液；12.05g, 50nmol)。此混合物於45P攪拌9小 時，反應混合物予以濃縮。所得殘物以乙酸乙酯萃取。所 得萃取物以氛化鈉水溶液洗滌，然後使之脱水（MsS〇4), 接著減壓蒸餾去除溶劑。殘物進行矽膠靥析，接著自*** -己烷中再結晶，獲得淡黃色片晶（5.55g, 45%), ιπ·ρ·: 124.5-125,5t：(文獻參考值 123-1241C )。(Η) Before showing the same meaning of X 〇, there should be a base in the middle and the base should be reversed. The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 29 483896 A7 B7 V. Invention Note that the leaving group represented by (30) X refers to, for example, a group which may be substituted with a nucleophile such as a hydrocarbon residue having a negatively charged hetero atom (such as a chlorine atom, a sulfur atom, and a nitrogen atom). To be more specific, for example, halogens (such as iodine, bromine, and ammonium), alkylsulfonyl (eg, ethylsulfonyl), alkylsulfonyl (eg, methylsulfonyloxy), and alkyl-arylsulfonyl chloride (Eg, p-toluenesulfonyloxy). 3. Method C: Printed by the Consumers' Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. It can use any method known per se, such as following the process of manufacturing compound (Ila) from compound (Π) instead of the above reaction shown in Figure 1 by compound (ii ) Production method of compound (Ila). In addition, the solvent of compound (ii) does not affect a suitable solvent (such as methanol, ethanol), 2N sodium hydroxide is added, and the mixture is reacted at room temperature to heating (to about 100t :) for 1 to 12 hours. The obtained compound in which -C 0 0 E t is converted into -C 0 0 Η is dissolved in a suitable solvent such as dipentane, and an equal amount of triphosgene is added to the solution, and the mixture is stirred for reaction at a temperature of 80 to 1501C for 1 to 1 0 hours. The obtained 1-hydroxynatamine compound is treated in a manner similar to the reaction of the aforementioned compound (XVI) to the compound (Ila). Therefore, a suitable solvent for introducing the R 1 group at the 1-position is obtained as a suitable solvent such as dichloromethane, and an amine such as ammonium, alkylamine, aromatic amine, etc. is added to the solution in a slight excess, and the mixture is at room temperature to The reaction was stirred with heating (to 100 t :) for 1 to 12 hours. Then, triphosgene and triethylamine are added to the reaction mixture as a test, and the mixture is reacted at about 100 C under reflux for 1 to 6 hours to obtain a compound of formula (I I a). 4. Other methods: The substituents on compound (I) can be converted into other substituents by conventional methods known per se. An example of this method is as follows. 30 (Please read the precautions on the back before filling this page) This paper size is applicable to the Chinese National Standard (CNS) A4 size (210X29? Mm) 483896 Printed by the Central Sample Industry Bureau of the Ministry of Economy, Shellfish Consumer Cooperative, A7 B7 V. Invention Explanation (31) (i) Nitro substituents can be converted into amine groups; the starting compounds are dissolved in a suitable solvent such as ethanol, methanol, and (a) ffi-is added to the solution and the mixture is under hydrogen and room temperature The reaction is performed for 1 to 12 hours, or (b) iron powder and osmic acid are added to the solution and the reaction is performed at room temperature for 1 to 12 hours. (Π) The amine group can be converted into a halogenated amine group; the starting compound is dissolved in a suitable solvent such as tetrahydrofuran, dimethylimine, and potassium sulfonate, pyridine and triethylamine are added to the solution as a base, and the acid anhydride or hydrazone Halogen, the mixture was stirred at room temperature for 1 to 10 hours. (iii) Conversion of amine compounds (compounds with amine groups) to enamine compounds. For example, the starting compound is dissolved in a suitable solvent such as acetic acid, dimethylformamide, dihydromethane, tetrahydrofuran, dipentane, and acetonitrile, and a diazotizing agent such as sodium nitrite and isoamyl nitrite is added to the solution. The mixture is added with a catalyst such as bis (diphenylmethyleneacetone) and 1 to excess equivalents of the alkenyl derivative, and the mixture is stirred at room temperature to heat (801C) for 1 to 12 hours. (iv) Master atoms can be introduced into the amine group, for example, by adding acrylic acid derivatives or cycloethane ethane to the starting compounds in a suitable solvent such as acetic acid, dimethylformamide, dihydromethane, tetrahydrofuran, and dipentane. Such as a peroxide compound, the mixture is stirred at 0 to 80CII for 6 to 24 hours. (v) Sulfur atoms leading to amine groups in compounds, for example, halogenation of sulfur compounds by addition of starting compounds in suitable solvents such as pyridine, dimethylformamide, dicyanomethane, tetramethylenefuran, diethyl ether, and dipentane Thing. The mixture is stirred at 0 to 8010 for 6 to 24 hours. (vi) Substituted methysyl can be converted into methyl; the starting compound is soluble in 31. This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) (Please read the notes on the back before filling (This page) 483896 A7 B7 printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs. 5. Description of the invention (32) in a reagent such as tetrahydrofuran, and an organic borane derivative such as dimethyl sulfide borane added to the mixture. Reaction at room temperature to reflux for several hours, such as 1 to 3 hours. (vii) A triethoxymethoxy derivative can be prepared from a methyl derivative; a suitable solvent for the starting material is a suitable solvent such as methylene chloride, and 1 to an excess equivalent of a Lewis acid such as aluminized aluminum is added to the solution. And a thiol compound or a thioether compound (such as dimethyl sulfide), and the mixture is reacted for 1 to 10 hours under ice-cooling to room temperature, and then the obtained hydroxy derivative is dissolved in a suitable solvent such as dimethylformamide To the solution, add a base such as sodium hydride or potassium sulfonate and an alkane halide, and the mixture reacts at room temperature for 1 to 12 hours. (viii) The methyl group can be changed to isopropyl chloride; the starting material is dissolved in a suitable solvent such as methane, and 1 to excess equivalents of a Lewis acid such as aluminized aluminum, and a thiol compound or sulfur are added to the solution. Ether compound (such as dimethyl sulfide), and the mixture is reacted at room temperature to ice cooling for 1 to 10 hours. (ix) An amine group can be introduced; a starting compound having a halogen atom is dissolved in a suitable solvent such as dimethyl ethane, and an arylboronic acid derivative, a base (such as sodium sulfonate), and a rake compound (such as (Triphenylsene) uses (0) as a catalyst, and the mixture is refluxed for 1 to 6 hours. (X) Alkylthio compounds can be converted into alkanesulfinyl compounds or alkanesulfonium compounds; Gasification agent (such as m-fluorene perbenzoic acid) in an appropriate solvent (such as dichloromethane), obtained by reaction under ice cooling to heat. When more intense heating or treatment with excess gasification agent, alkane Sulfur-based compounds. (Please read the notes on the back before filling this page.) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm). Preparation of A7 B7 V. Description of the invention (33) The hydrazone of the compound (I) of the present invention obtained above is preferably a physiologically acceptable acid addition hydrazone. Examples of this hydrazone include inorganic acids (such as hydrazone, hydrogen bromide). Acid, nitric acid, sulfuric acid and phosphoric acid), With organic acids (such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and -Toluenesulfonic acid). Furthermore, the compound (I) of the present invention has an acid group such as -COOH, and the compound (I) can be used with an inorganic base such as an alkali metal or an alkaline earth metal such as sodium, potassium, calcium And magnesium; ammonia) to form amidine, or with organic bases (such as trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and M, ίΤ-diphenylmethyl ethylene) Diamine) to form hydrazone. The compound (I) of the present invention or its hydrazone obtained as described above can be isolated and purified by conventional separation methods, such as recrystallization, distillation, and chromatography. If the compound (I ) Is a free form, which can be converted into its hydrazone according to its own traditional method or a similar method. Conversely, if it is a 塩 form, it can be transformed into its free form or into any other hydrazone. If the compound (I) of the present invention or塩 is an optically active compound. It is separated into d-compound and 1-compound. Since the compound (I) of the present invention has GnRH antagonistic activity and low toxicity, it can be safely used in mammals (eg, human, monkey, cow, horse, dog, cat, rabbit , Mice, mice, etc.), GnRH receptor antagonism restricts the secretion of gonadotropins to treat androgen- or estrogen-dependent diseases, and to treat diseases caused by the secretion of these hormones. Specifically, The compounds of the present invention are effective for preventing or treating several hormone-dependent diseases, such as sex hormone-dependent diseases (such as prostate cancer, cervical cancer, (please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) 33 483896 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Description of the invention (30 breast cancer, pituitary adenocarcinoma), benign prostate Hypertrophy, uterine fibroids, endometriosis, precocious puberty, menopause, premenstrual arousal, polycystic egg daisy syndrome and preventive or therapeutic agents for acne vulgaris. In addition, the compounds of the present invention are also effective as fertility control agents for both sexes (e.g., pregnancy control agents and menstrual cycle control agents). The compounds of the present invention are also useful as contraceptives for males and females, and ovulation agents for females. The compound of the present invention can be used as a therapeutic agent for infertility due to the rebound effect of stopping administration. Furthermore, the compounds of the present invention are used in the field of animal husbandry as spring festival cycle for slugs, as a quality improver for edible meat, or as an animal growth promoter. In addition, the compounds of the present invention can be used as fish spawning promoters. Although the compounds of the present invention can be used alone, they can also be used in combination with steroid or non-steroidal anti-androgens. The compounds of the present invention can be used to limit the increase in the concentration of fluorenone in the plasma produced by the administration of a GnRH super-antagonist, such as leuprolide acetate. The compound of the present invention can be administered in combination with a cancer chemical therapeutic agent. Examples of chemotherapeutic agents for treating prostate cancer include Ifosfamide, UFT, Adriamycin, Peplomycin, Cisplatin, and the like. In the treatment of breast cancer, examples of chemotherapeutics include Cyclophohamide, 5-FU, UFT, Methotrexate, Adriamycin, Mitomycin C, and green Mountain pure (Mitoxantrone) # 〇 The compound (I) of the present invention shows sufficient GnRH activity through subcutaneous or oral administration, which can be stably absorbed through oral administration and exhibit GnRH activity for a long time. If the compound of the present invention is used in the field of animal husbandry or food industry (please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 34 483896 A7 B7 V. Description of the Invention (35) The preventive and therapeutic agents for the diseases mentioned above can be administered orally or parenterally in a manner known per se. The compound of the present invention is mixed with a pharmaceutically acceptable carrier and is usually administered orally as a solid preparation such as a lozenge, capsule, granule or powder, or as an intravenous, subcutaneous or intramuscular injection instead of orally, or Suppositories or lozenges are administered sublingually. Further, it is given as a slow-release agent such as a lozenge or a capsule administered sublingually, and administered sublingually, subcutaneously, or intramuscularly. The daily dose of the compound (I) depends on the degree of illness; differences in age, sex, weight and sensitivity of the person to be administered; the time and interval of administration, the nature, dosage form and type of the pharmaceutical preparation; types of active ingredients, etc. And change. Although not particularly limited, mammals usually give about 0.01 to 10 mg, preferably about 0.02 to 2 mg, more preferably about 0.01 to 1 mg, per 1 kg of body weight, usually administered once a day, or divided into two to four times. In the field of animal husbandry or aquaculture, the daily dose is similar to the above, and it is about 0.01 to 5 mg, preferably about 0.002 to 2 nig, or 1 to 2 or 3 times per 1 kg of individual animal or fish. Printed by Shelley Consumer Cooperative of China Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). The above pharmaceutically acceptable carriers use a variety of organic or inorganic carriers, and are used in solid compositions. Excipients, lubricants, binders, and disintegrating agents are incorporated, and liquid compositions are incorporated with solvents, solubilizers, suspending agents, isotonic agents, buffering agents, and analgesics. Moreover, additives such as a preservative, an anti-gasification agent, a colorant, and a sweetener may be used as needed. Preferred examples of the above excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and more volatile silicon dioxide. Preferred examples of the above slip agents include magnesium stearate, calcium stearate, talc, and rubber siliconized gas. Preferred examples of the above-mentioned binders include crystalline cellulose, sucrose, D-mannose, periodin, hydroxypropylcellulose, hydroxymethyl fervidin, and polyethylene. This paper is compliant with Chinese National Standards (CNS) A4 Specifications (210 X29? Mm) 35 483896 A7 B7 V. Description of the invention (36) Pyrone. Preferred examples of the above disintegrants include starch, carboxymethyl cellulose. Ethyl naphthalene polymer powder, containing two examples of methyl propyl carboxylate, and sodium acetoacetate, and alcohol sodium acetin, the agent for water-soluble fiber, using a base to increase the injection of carboxyl, containing 0 oil, rice, Sapphire calcium and Suyi oil are more soluble than hemp fiber agent Zhizhi. Sodium triol acetate, stearic acid-like lemon, formic acid and sodium benzene, for example, acid acid, methyl benzene, benzene, sex, amine active alcohol, sugar, sugar, B, three sugar-containing, including D-alcohol, solid cholesterol Second, it is better to use propane, a methyl alcohol, floating diamine, suspending ammonium alkane, benzylated fatty acid, phosphoamino acid, propyl ... Fatty i 7 0 Mono- and ammonium ethane ethyl toluinated carbamate carboxymethyl ketone ketoethene Polyvinyl alcohol ene oligomers such as exemplified vitamin m propyl hydroxy and sulfonyl 0 hydroxyethoxylated vinyl cellulose Hydroxyl resveratrol, glyphosate glycoside-D »and other examples such as oil, sweet, liquid sodium dissolve, slowly contain the package, and the case should be compared with the agent Zhang Chong, etc. The above description contains the appropriate examples of pain and pain relief. Ο citric acid lemon and osmic acid sulfoacetic acid acetylated, chloroester anti-acid methanophenone. The base acid hydroxypear is not suitable for the removal of ethyl hydrogen containing mountain and acid-containing cases. Phenyl alcohol, methanol phentermine (please read the precautions on the back before filling out this page) The consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs Du printed acid blood 0 Anti- and acid I Sulfur compounds The actual hair is better than 0 medium solubilizers. For example, it is advisable to add the mixture so that it can be done according to the law. If you know it, you must copy it. Depend on the injection, after injection, intramuscular or save Preservation of skin, and preparation of Zhangmai Jingjing, preparation of formulations, preparations, mixtures, dry-freeze preparations, injection of injections, etc.The knowledge of the French method has already been shown in the dosage form, and the tablets are divided into tablets.皮 蕖 和 经 药剂 解囊 剂 上 胶制 # Drips Drops Injectable powder is used to release thinner,, 如 射 / (\ 滴滴 泥 粒 等 剂 * Soft and soft intestines straight • Dao Ru Yin Ben The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 36 483896 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 B7 V. Description of the invention (37) Soft assets, etc.). These peony compositions can be produced according to a method known per se for the preparation of a K drug composition. The compound (I) or its hydrazone of the present invention can be prepared as an injection. Can be used with dispersants [such as Tween 80 (Atlas Powder Factory, USA), HCO 80 (Japan, Nikko Pharmaceuticals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.], preservatives (such as, Methyl paraben, propyl paraben, benzyl alcohol, etc.), isotonicity agents (such as sodium flammable sodium, mannitol, sorbitol, glucose, etc.), etc., made into aqueous injections, Or it can be made into oily injection by dissolving, suspending or emulsifying in vegetable oil (such as olive oil, sesame oil, cotton seed oil, corn oil, etc.), propylene glycol, etc. When preparing an oral pharmaceutical composition, the compound (1) of the present invention or a hydrazone thereof is combined with, for example, a bulking agent (eg, lactose, sucrose, syrup, etc.), a disintegrant (eg, starch, calcium sulfonate, etc.), Binders (eg, starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.), or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) ) Etc., compression molding. If desired, the composition is coated with a flavoring, casing or long-acting substance according to a method known per se. Examples of coating agents are hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, Tween 80, pluronic F68, acetate phthalic acid Cool cellulose, hydroxypropyl methylcellulose phthalate, hydroxymethyl cellulose acetate succinate, E ii dragi U copolymer of methacrylic acid and acrylic acid; manufactured by Rohm, Japan), gasification Iron red and so on. According to a method known per se, it is possible to coat the casing between the casing and the core layer. (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 37 483896 Printed by the Consumer Affairs Cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (38) In preparing the composition for external use, the compound (I) of the present invention or the compound thereof is made into a solid, semi-solid or liquid agent for external use according to a method known per se. For example, a solid preparation is prepared as follows. Therefore, the compound of the present invention itself, or added and / or mixed with fillers (eg, ethylene glycol, mannitol, starch, microcrystalline vitamins, etc.), thickeners (eg, natural rubber, fiber Pigment derivatives, acrylic polymers, etc.), etc., into powder compositions. The liquid composition can be made into an oily or aqueous suspension similar to an injection. Examples of the semi-solid composition are preferably an aqueous or oily gel or soft sound. Each can be combined with a pH adjuster (e.g., osmic acid, phosphoric acid, citric acid, osmic acid, sodium hydroxide, etc.), a preservative (e.g., para-hydroxybenzoate, phenbutanol, benzoated ammonium, etc.) ) And so on. In the production of soft buds, for example, the compound (I) of the present invention or its hydrazone can produce an oily or aqueous solid, semi-solid or liquid soft sound. Examples of the oil-based materials used in the above composition are higher fatty acid glycerides [e.g., cocoa butter, Witepsols (manufactured by Dynaniite-Nobel), etc.], intermediate fatty acid glycerides [e.g., Miglyols (manufactured by Dynamite-Hobel), etc.] and Vegetable oils (eg, sesame oil, soybean oil, cotton seed oil, etc.), etc. Examples of the water-based materials are polyethylene glycol and propylene glycol, and examples of the water-based gel are natural rubber, cellulose derivatives, vinyl polymers, acrylic polymers, and the like. The quasi-invention: > The musk type is described in detail by the following reference examples and examples, but the scope of the invention should not be limited thereby. The M-NMR spectrum is based on a Varian GEMINI 200 (200MHz) spectrometer, a JEOL LAMBDA 300 (300 MHz) type light mill or a Bruker AM 500 (this paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) --- ------ • Installation-- (Please read the precautions on the back before filling this page) Order 38 483896 A7 B7 V. Description of the invention (39) 500MHZ) spectrometer, using tetramethylsilane as internal standard, measurement Of it. All data values are expressed as P P m. The meanings of the symbols used in this specification are as follows: s: singlet, d: doublet, t: krypton, dt: doublet #peak, ί: multimodal, br: wide band Example 1 2-amino-5- Production of phenyl I * phen-3-carboxylic acid ethyl ester in ethyl acetate (6.1g, SOmniol), sulfur (1.61g, 50mmol), triethylamine (3.5ml, 25ηιαιο1), and dimethylformamide ( 10 ml) of the mixture, at 45 t: phenyl acetaldehyde (50% diethyl acetate solution; 12.05 g, 50 nmol) was added dropwise over 20 minutes with stirring. The mixture was stirred at 45P for 9 hours, and the reaction mixture was concentrated. The obtained residue was extracted with ethyl acetate. The obtained extract was washed with an aqueous sodium hydroxide solution and then dehydrated (MsSO), and then the solvent was distilled off under reduced pressure. The residue was decanted with silica gel, and then recrystallized from ether-hexane to obtain pale yellow platelets (5.55g, 45%), ιπ · ρ ·: 124.5-125, 5t: (literature reference value 123-1241C).

元素分析：C13H13NO2S 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) C ( % ) H ( ^ ) Ν ( ^ ) 計算值：63.13; 5.30; 5.66 實測值：6 2 · 9 9 ; 5 · 0 5 ; 5 · 6 3 1H-NMR ( 2 0 0 MHz , CDCl3)5 ： 1.37 ( 3 Η ,t , J = 7 . 1 Ηz ), 4.30(2H,d,J=7.1Hz), 5.97(2H,br), 7·17-7·46(6Η,β) IRUBr): 3 448, 3 320, 1 6 67, 1 590，1 5 49CH-1 金者例2 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 39 經濟部中央樣隼局員工消费合作社印製 483896 A7 B7 五、發明説明（40) 2-胺基-4-甲基- 5-(4-甲氯苯基）堪吩-3-羧酸乙酯之製造 4-甲氣苯基丙酮（16.5g, O.lOmol),氰乙酸乙酯（ 1 2 · 2 g , 0 · 1 0 m ο 1 ),乙酸銨（1 · 5 5 g， 2 0 m m ο 1 ),乙酸（ 4.6ml, 80mmol)及苯（20ml)之混合物，經回流加熱24小時 ，同時用丁斯達克（Dean and Stark)裝置移除反應混合物 中産生之水。經冷却後，反應混合物予以減壓濃縮。殘物 於二氛甲烷及碩酸氫鈉水溶液間分配。有機層以氣化鈉水 溶液洗滌，然後使之脱水（MgS〇4),接著減壓蒸餾去除溶 劑。於殘物之乙醇（30ml)溶液中，加人硫（3.21g, O.lOmol)及二乙胺（10.41ml, O.lOmol)。混合物於 50-60 t：攪拌2小時，然後濃縮之，濃縮物以乙酸乙酯萃取。所 得萃取物以氛化鈉水溶液洗滌，使之脱水（MgS〇4),接著 減壓蒸餾去除溶劑。殘物進行矽膠層析，自***-己烷中 結晶之，獲得淡黃色片晶（1 1 · 5 g , 4 0 % ) , πι · p · 7 9 - 8 0 °C。Elemental analysis: C13H13NO2S Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) C (%) H (^) Ν (^) Calculated value: 63.13; 5.30; 5.66 Measured value: 6 2 · 9 9; 5 · 0 5; 5 · 6 3 1H-NMR (200 MHz, CDCl3) 5: 1.37 (3 Η, t, J = 7. 1 Ηz), 4.30 (2H, d, J = 7.1Hz), 5.97 (2H, br), 7.17-7 · 46 (6Η, β) IRUBr): 3 448, 3 320, 1 6 67, 1 590, 1 5 49CH-1 Gold Example 2 Paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 39 Printed by the Consumer Cooperatives of the Central Bureau of Samples, Ministry of Economic Affairs 483896 A7 B7 V. Description of the invention (40) -(4-methylchlorophenyl) kanphen-3-carboxylic acid ethyl ester 4-methylphenylacetone (16.5g, 0.1mol), ethyl cyanoacetate (1 2 · 2 g, 0 · 1 0 m ο 1), a mixture of ammonium acetate (1.55 g, 20 mm ο 1), acetic acid (4.6ml, 80mmol) and benzene (20ml), heated under reflux for 24 hours, while using Ding Stark ( Dean and Stark) device removes water produced in the reaction mixture. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous sodium bisulfate solution. The organic layer was washed with a gasified sodium water solution, and then dehydrated (MgSO4), followed by distillation under reduced pressure to remove the solvent. To a solution of the residue in ethanol (30 ml), human sulfur (3.21 g, 0.1 mol) and diethylamine (10.41 ml, 0.1 mol) were added. The mixture was stirred at 50-60 t: 2 hours, then concentrated, and the concentrate was extracted with ethyl acetate. The obtained extract was washed with an aqueous sodium hydroxide solution and dehydrated (MgS04), and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and crystallized from ether-hexane to obtain pale yellow platelets (11.5 g, 40%), π · p · 79-80 ° C.

元素分析：Cl5Hl7N〇3S C (% ) Η ( % ) Ν ( % ) S ( % ) 計算值：61.83; 5.88; 4.81; 11.01 實測值：6 1 · 8 1 ; 5 · 7 5 ; 4 . 7 4 ; 1 0 · 8 2 1 H -HMR ( 2 0 0 MHz , CDC la) δ ： 1.37 (3H, t , J=7. 1Hz), 2.28(3H,s), 3.83(3H,s), 4.31(2H,q,J=7.1Hz), 6.05(2H,brs), 6.91(2H，d,J=8.8Hz), 7.27(2H,d，J= 8 . 8Hz) IRUBr): 3426, 3328， 1651， 1586, 1550, 1505, 1 48 5c·- 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） I--------^裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 40 483896 A7 _B7五、發明説明（41 ) FAB-MS m/z： 291(M") 參者例3 使用多種丙酮衍生物代替4 -甲氧苯基丙酮，依參考 2所述之實質相同方式，製得表1所示之化合物。 表1 ^C00C2H: R4 \s/-'nh2 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消费合作杜印製 參考例3 化合物 R3， R4 産率 (% ) m . p . (t：) 1 甲基 苯基 40 6 4-65 2 甲基 2-甲氣苯基 12 70-71 3 甲基 溴 兹者例4 2-胺基-4-甲基- 5-(4-硝基苯基）〇*吩-3-羧酸乙酯之製 本質上依參考例1之相_程序，使用4 -硝苯基丙0 35.0g, 195ran〇l)取代4-甲氣苯基丙酮，及使用氰乙酸 酯（2 3 g · 1 9 · 5 b ο 1 ),乙酸銨（3 · 1 g , 4 Ο α b ο 1 )，乙酸（ 9 · 1 1 , 1 5 9 鼸 ο 1 ),硫（5 · 0 g , 1 6 0 n ο 1 )及二乙胺（1 6 ·( 造M乙 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 41 483896 經濟部中央樣準局員工消費合作社印製 A7 B7 五、發明説明（42 ) 160mmol),製得無色結晶之標的化合物（22.2g, 52%), 1^.168-170¾ (自***-己烷再結晶）。Elemental analysis: Cl5Hl7N03S C (%) Η (%) Ν (%) S (%) Calculated: 61.83; 5.88; 4.81; 11.01 Found: 6 1 · 8 1; 5 · 7 5; 4. 7 4 ; 1 0 · 8 2 1 H -HMR (2000 MHz, CDC la) δ: 1.37 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 3.83 (3H, s), 4.31 ( 2H, q, J = 7.1Hz), 6.05 (2H, brs), 6.91 (2H, d, J = 8.8Hz), 7.27 (2H, d, J = 8.8Hz) IRUBr): 3426, 3328, 1651, 1586, 1550, 1505, 1 48 5c ·-1 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) I -------- ^ Package-- (Please read the Note: Please fill in this page again.) Order 40 483896 A7 _B7 V. Description of the invention (41) FAB-MS m / z: 291 (M ") Reference Example 3 Use a variety of acetone derivatives instead of 4-methoxyphenylacetone. Substantially the same manner as described in 2 was used to obtain the compounds shown in Table 1. Table 1 ^ C00C2H: R4 \ s /-'nh2 (Please read the precautions on the back before filling this page) Employees of the Central Bureau of Standards of the Ministry of Economic Affairs, Consumer Consumption Du printed Reference Example 3 Compound R3, R4 Yield (%) m p. (t :) 1 Methylphenyl 40 6 4-65 2 Methyl 2-methylphenyl 12 70-71 3 Examples of methyl bromide 4 2-Amino-4-methyl-5- ( 4-Nitrophenyl) O * phen-3-carboxylic acid ethyl ester was prepared essentially in accordance with the procedure of Reference Example 1, using 4-nitrophenylpropanyl (35.0g, 195ranol) instead of 4-methyl gas. Phenylacetone and cyanoacetate (2 3 g · 1 9 · 5 b ο 1), ammonium acetate (3 · 1 g, 4 〇 α b ο 1), acetic acid (9 · 1 1, 1 5 9鼸 ο 1), sulfur (5.0 · 0 g, 16 0 n ο 1) and diethylamine (1 6 · (M2 paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 41 483896 A7 B7 was printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. 5. Description of the invention (42) 160mmol), the target compound (22.2g, 52%) was obtained as colorless crystals, 1 ^ .168-170¾ (from ether-hexane re-crystallize).

元素分析：C14H14N2O4S C ( % ) Η ( % ) Η ( % ) 計算值：54·89; 4.61； 9.14 實測值：5 4 · 8 3 ; 4 · 9 0 ; 9.09 1H-NMR(200MHz, CDCla)^ ： 1.39(3H,t,J=7.1Hz). 2,40(3H,s), 4.34(2H,q,J=7.1Hz), 6.27(2H,brs), 7.48(2H,d,J=8.7Hz), 8.23(2H,d,J=8.7Hz)。 IRUBr): 3446, 3324， 1667， 1580, 1545, 1506, 1491, 1 47 5 , 1 4 1 0 , 1 3 3 2 cm- 1 〇 兹者例5 2,4(1H,3H)_二氯代-5-甲基-6-(4 -甲氣苯基）《盼并[2,3-d]嘧啶-3-乙酸乙酯之製造 於含參考例1製得化合物（5.00g, 17.20mmol)之溶液 中添加異氰酸基乙酸乙酯（2.90ml, 25.80mmol)。混合物 在45t!攪拌6小時，接著減壓濃縮。濃縮液溶於乙醇（ 6ml)中，於其中添加乙醇鈉{自乙醇（30ml)及鈉（0.79g, 34.30ramol)所製備}。混合物在室溫攪拌24小時，於其中 添加2N HCl(18ml, 36βπιο1)。減壓下蒸除乙醇並使殘留物 進行過濾，以水-乙酵洗滌並於減®乾燥，接著自乙酵再 結晶，得白色針晶（5.70g, 89%), a.p.l64-165t：。Elemental analysis: C14H14N2O4S C (%) Η (%) Η (%) Calculated: 54 · 89; 4.61; 9.14 Found: 5 4 · 8 3; 4 · 9 0; 9.09 1H-NMR (200MHz, CDCla) ^ : 1.39 (3H, t, J = 7.1Hz). 2,40 (3H, s), 4.34 (2H, q, J = 7.1Hz), 6.27 (2H, brs), 7.48 (2H, d, J = 8.7 Hz), 8.23 (2H, d, J = 8.7Hz). IRUBr): 3446, 3324, 1667, 1580, 1545, 1506, 1491, 1 47 5, 1 4 1 0, 1 3 3 2 cm- 1 〇 Example 5 2,4 (1H, 3H) _dichloro Preparation of 5-methyl-6- (4-methylphenyl) acetic acid [2,3-d] pyrimidine-3-ethyl acetate, compound containing Reference Example 1 (5.00 g, 17.20 mmol) To the solution was added ethyl isocyanate (2.90 ml, 25.80 mmol). The mixture was stirred at 45t! For 6 hours, and then concentrated under reduced pressure. The concentrated solution was dissolved in ethanol (6 ml), and sodium ethoxide {prepared from ethanol (30 ml) and sodium (0.79 g, 34.30 ramol)} was added thereto. The mixture was stirred at room temperature for 24 hours, and 2N HCl (18 ml, 36 βπο1) was added thereto. The ethanol was distilled off under reduced pressure, and the residue was filtered, washed with water-acetic acid, and dried with acetic acid, and then recrystallized from acetic acid to obtain white needles (5.70 g, 89%), a.p.l64-165t :.

元素分析：C 1 8H 1 8N2O5S C ( % ) Η ( ^ ) Ν ( ^ ) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） ---------^裝-- (請先閲讀背面之注意事項再填寫本f ) 訂 -1% 42 483896 A7 B7 五、發明説明（43 ) 計算值：5 7 , 7 4 ; 4.85； 7.48 實測值：5 7 · 7 8 ; 5.03； 7.45 ^-NMR ( 2 0 0 MHz, CDCl3)5 ： 1 . 3 0 ( 3 Η , t , J = 7 . 2 Η z ), 2.45(3H,s), 3.85(3H,s), 4.26(2H,q,J=7.2Hz), 4.78(2H,s), 6.95(2H,d,J=8.8Hz), 7.31(2H,d,J=8.8Hz) ,10 . 58 (1H , s) 〇 IR(KBr)： 2914, 1742, 1713, 1655, 1605, 1568, 1528, 1499cm-1 〇 兹者例6 使用參考例2, 3或4製得之化合物作為起始物，依 據參考例5所述方法製得表2所列化合物。 表 2 iMmi ϋϋ .^m mu m- flm mi mi an (請先閲讀背面之注意事項再填寫本頁) 訂Elemental analysis: C 1 8H 1 8N2O5S C (%) Η (^) Ν (^) This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) --------- ^ pack- -(Please read the notes on the back before filling in this f) Order -1% 42 483896 A7 B7 V. Description of the invention (43) Calculated value: 5 7, 7 4; 4.85; 7.48 Measured value: 5 7 · 7 8; 5.03; 7.45 ^ -NMR (200 MHz, CDCl3) 5: 1.30 (3 Η, t, J = 7. 2 Ηz), 2.45 (3H, s), 3.85 (3H, s), 4.26 (2H, q, J = 7.2Hz), 4.78 (2H, s), 6.95 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 10.58 (1H, s) 〇IR (KBr): 2914, 1742, 1713, 1655, 1605, 1568, 1528, 1499cm-1 〇 Example 6 Use the compound prepared in Reference Example 2, 3 or 4 as the starting material, according to the reference example 5 The compounds listed in Table 2 were prepared by the methods described. Table 2 iMmi ϋϋ. ^ M mu m- flm mi mi an (Please read the precautions on the back before filling this page) Order

經濟部中央標隼局員工消費合作社印装 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 43 483896 五、發明説明（44 ) 經濟部中央標隼局貝工消費合作社印製 參考例6 化合物编號 R2 R4 産率 (% ) m. p. (V) 1 (乙氯羰基）甲基 苯基 85 119-120 2 甲基 4-甲氧苯基 84 273-276 3 苯基 4-甲氣苯基 85 >300 4 苯基 4-硝苯基 84 >300 5 苯甲基 4-甲氣苯基 92 241-242 6 4-甲氧苯基 4-甲氧苯基 99 >300 7 環己基 4-甲氣苯基 84 275-276 8 2-甲氣苯基 4-甲氧苯基 81 257-258 9 3-甲氣苯基 4-甲氣苯基 93 >300 10 2-氣苯基 4-甲氧苯基 95 285-286 11 3-氛苯基 4-甲氣苯基 97 >300 12 4-氛苯基 [甲氧苯基 95 >300 13 3-甲氣苯基 溴 100 245-247 14 3-異丙氣苯基 溴 15 3-異丙氧苯基 4-甲氣苯基 16 3-甲氣基甲氣苯基 4-硝苯基 86 263-267 (請先閱讀背面之注意事項再填寫本頁) _裝- 訂 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X 297公釐） 44 483896 A7 B7 五、發明説明（45 ) 參 考 例 7 2 , 4 ( 1 Η ,3H) 二 :氧0 6- (4 -硝苯基）-5 -甲基α吩并[2, 3-d] 嘧 啶 - 3 -乙酸乙酯之製造 於 參 考 例 6製 得 之 化 合物1 ( 2 . 20g , 6 .39m mol) 中 添加 濃 硫 酸 (1 2m 1) 〇在 冰 冷 却 下，於 混 合物中 滴加 含硝 酸 m ( 5 5 0 m 6 .47m mol) 之 濃 硫 酸溶液 % 接著在 冰冷 却下 攪 拌1 小 時 〇 反 應 混 合物 倒 入 冰 水中， 以 乙酸乙 酯萃 取。 萃 取液 以 氛 化 m 水 溶 液洗 滌 並 脱 水（MgS〇4 ),接著減壓蒸除溶劑， 殘 留 物 於 矽 膠 上層 析 $ 得 黃色固 髏 (1 · 30g ,52 % ), 接著 白 乙 酸 乙 酯 -己院中再結晶得黃色結晶。m .P .= 2 7 7 - 2 8 0 t： 〇 元 素 分 析 ： C 1 ?H 1 5 N3 〇6 S， ► 0 . 4H2 0 C (% ) Η ( % ) N ( % ) 計 算 值 51 .48 ； 4 . 01 10.59 實 測 值 ： 51 .64 ； 3 . 79 ； 10.61 (請先閱讀背面之注意事項再填寫本頁) 「裝· 經濟部中央標準局貝工消费合作社印製 1H-NMR ( 2 0 0 MHz, CDCl3)5 ： 1.33(3 Η ,t,J = 7.2 Ηz ), 2.56(3H,s), 4.28(2H,q,J=7,2Hz), 4.79(2H,s), 7.57(2H,d，J=8.8Hz), 8.30(2H，d,J=8.8Hz), ,10. 30 (1H , s) 〇 IRUBr) : 1 7 48 , 1 7 1 9，1 66 3 , 1 5 2 2 , 1 46 0 cm· 1 〇 &老例8 2,4(1H,3H) -二氧代-卜（2 -氣苯甲基）-6-(4 -硝苯基）-5 -甲 基吩并[2,3-d]哺啶-3-乙酸乙酯·· 於含參考例7製得之化合物（700ag, 1.80··〇1)之二 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 45 483896 A7 B7 五、發明説明（46 ) 甲基甲醯胺（lOnil)溶液中，添加碩酸鉀（372rag, 2.70π»ιησ1 )，碘化鉀（299mg, 1.80minol)及 2 -氣苯甲基氛（0.43ml, 3.60inmol),混合物在室溫攪拌2小時，濃縮反應混合物 且濃縮液分配於乙酸乙酯及氱化鈉水溶液之間，水層以乙 酸乙酯萃取。合併之萃取液以氣化鈉水溶液洗滌，然後脱 水（MgS〇4),接著減壓蒸除溶劑。殘留物在矽膠上層析， 得白色粉末（500ng, 56%)。ιη·ρ·155-158υ。 元素分析：C24H2〇N3〇6SF*0.5H2〇 C ( % ) Η ( % ) Ν ( % ) 計算值：56·91; 4.18； 8.30 實測值：5 6 · 7 4 ; 3.84； 8.25 1 H-NMR ( 2 0 0 MHz , CDCls)^ ： 1 . 32 ( 3 Η , t , J = 7 . 2 Ηz), 3.84(3H,s), 4.27(2H,q,J=7.2Hz), 4.84(2H,s), 5.30(2H,s), 7.06-7.33(4H,m), 7.54(2H,d,J=8.9Hz), 7 · 27 (2H , d，J = 8·9Hz) 〇 IR UBr) : 1 7 48 , 1 7 1 1 , 1 6 7 3 , 1 5 2 0 , 1 4 9 1 c m - 1 〇 (請先閲讀背面之注意事項再填寫本頁) 例 老 參 經濟部中央樣準局員工消費合作社印製 例 考 參 依 始 起 物 合 化 之 得 製 6 例 考 參 自 法 方 述 所 物 合 化 列 所 3 表 備 製 表Printed on the paper of the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 43 483896 V. Description of the invention (44) Printed by the Shell's Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics Preparation Reference Example 6 Compound No. R2 R4 Yield (%) mp (V) 1 (Ethylchlorocarbonyl) methylphenyl 85 119-120 2 Methyl 4-methoxyphenyl 84 273-276 3 Phenyl 4- Methoxyphenyl 85 > 300 4 phenyl 4-nitrophenyl 84 > 300 5 benzyl 4-methylphenyl 92 241-242 6 4-methoxyphenyl 4-methoxyphenyl 99 > 300 7 Cyclohexyl 4-methylphenyl 84 275-276 8 2-methylphenyl 4-methoxyphenyl 81 257-258 9 3-methylphenyl 4-methylphenyl 93 > 300 10 2 -Phenylphenyl 4-methoxyphenyl 95 285-286 11 3-phenylphenyl 4-methylphenyl 97 > 300 12 4-phenylphenyl [methoxyphenyl 95 > 300 13 3-methylphenyl Phenyl bromide 100 245-247 14 3-isopropylphenyl bromide 15 3-isopropyloxyphenyl 4-methylaminophenyl 16 3-methylaminomethylphenyl 4-nitrophenyl 86 263-267 ( (Please read the notes on the back before filling out this page) _Package-Book size for China House standard 隼 (CNS) A4 specification (210X 297 mm) 44 483896 A7 B7 V. Description of the invention (45) Reference example 7 2, 4 (1 Η, 3H) 2: oxygen 0 6- (4-nitrophenyl) -5 -Methyl αpheno [2, 3-d] pyrimidine-3 -ethyl acetate production Compound 1 (2.20 g, 6.39 m mol) prepared in Reference Example 6 was added with concentrated sulfuric acid (12 m 1) 〇 Concentrated sulfuric acid solution containing nitric acid m (550 m 6.47 m mol) was added dropwise to the mixture under ice cooling, followed by stirring for 1 hour under ice cooling. The reaction mixture was poured into ice water and extracted with ethyl acetate. . The extract was washed with dehydrated m aqueous solution and dehydrated (MgS04), then the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel to obtain a yellow solid cross (1.30g, 52%), followed by white ethyl acetate- Recrystallized in the courtyard to obtain yellow crystals. m .P. = 2 7 7-2 8 0 t: 〇 Elemental analysis: C 1? H 1 5 N3 〇6 S, ► 0.4 H2 0 C (%) Η (%) N (%) Calculated 51. 48 ； 4. 01 10.59 Measured value: 51.64 ； 3. 79 ； 10.61 (Please read the precautions on the back before filling out this page) “Installation · Printed by the Central Bureau of Standards, Ministry of Economic Affairs, 1G-NMR (2 0 0 MHz, CDCl3) 5: 1.33 (3 Η, t, J = 7.2 Ηz), 2.56 (3H, s), 4.28 (2H, q, J = 7,2Hz), 4.79 (2H, s), 7.57 ( 2H, d, J = 8.8Hz), 8.30 (2H, d, J = 8.8Hz),, 10.30 (1H, s) 〇IRUBr): 1 7 48, 1 7 1 9, 1 66 3, 1 5 2 2, 1 46 0 cm · 1 〇 & Old example 8 2,4 (1H, 3H) -dioxo-bu (2-Gaphenyl) -6- (4-Nitrophenyl) -5- Methylpheno [2,3-d] pyridine-3-ethyl acetate ·· Two of the compounds (700ag, 1.80 ·· 〇1) containing the compound prepared in Reference Example 7 are applicable to Chinese paper standards (CNS) ) A4 specification (210 × 297 mm) 45 483896 A7 B7 V. Description of the invention (46) Methylformamide (lOnil) solution, potassium potassium sulphate (372rag, 2.70π »ιησ1), potassium iodide (299mg, 1.80minol) And 2-Qi Methyl ether (0.43ml, 3.60inmol), the mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated and the concentrated solution was partitioned between ethyl acetate and aqueous sodium trioxide solution, and the aqueous layer was extracted with ethyl acetate. The combined extracts It was washed with an aqueous solution of vaporized sodium, then dehydrated (MgS04), and then the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to obtain a white powder (500ng, 56%). Ι · ρ · 155-158υ. Elemental analysis : C24H2ON3〇6SF * 0.5H2OC (%) Η (%) N (%) Calculated: 56 · 91; 4.18; 8.30 Found: 5 6 · 7 4; 3.84; 8.25 1 H-NMR (2 0 0 MHz, CDCls) ^: 1. 32 (3 Η, t, J = 7. 2 Ηz), 3.84 (3H, s), 4.27 (2H, q, J = 7.2Hz), 4.84 (2H, s) , 5.30 (2H, s), 7.06-7.33 (4H, m), 7.54 (2H, d, J = 8.9Hz), 7 · 27 (2H, d, J = 8.9Hz) 〇IR UBr): 1 7 48, 1 7 1 1, 1 6 7 3, 1 5 2 0, 1 4 9 1 cm-1 〇 (Please read the precautions on the back before filling this page) Example: Employees' Cooperatives of the Central Sample Bureau of the Ministry of Economic Affairs 6 examples of printed references are obtained from the beginning of the synthesis of materials. Tabulate

CH 4nn c ^ 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X 297公釐） 46 483896 經濟部中央標準局員工消費合作社印製 五、發明説明（47 ) 花1杨编號 R2 Rl4,R15 R4 簡 m. P. (t：) 1 (乙氣羰基）甲基 2-氣 4-甲氣苯基 87 127-128 2 甲基 2-甲氯基 4-甲氧苯基 92 174-175 3 甲基 2-氣 4-甲氧苯基 97 179-180 4 苯基 2-甲氯基 4-甲氧笨基 93 240-241 5 苯基 2-氣 4-甲氣苯基 96 252-253 6 苯基 2， 4-硝苯基 87 294-295 7 苯基 3-氣 4-甲氣苯基 88 215-217 8 苯基 4-氣 4-甲氣苯基 66 209-212 9 苯基 2,4-二氣 4-甲氣苯基 73 227-228 10 苯基 2,6-二氟 4-甲氣苯基 87 291-292 11 苯基 2-氯，6-氟 4-甲氧苯基 91 287-288 12 苯基 2-甲硫基 4-甲氯苯基 81 239-240 13 苯甲基 2-氣 4-甲氣苯基 86 124-126 14 苯甲基 2,6-二氣 4-甲氧苯基 82 161-163 15 甲氣苯基 2-氣 4-甲氯苯基 87 270-272 16 4-甲氣苯基 2,6-二氣 4-甲氯苯基 83 >300 17 環己基 2-氣 4-甲氯苯基 79 172-173 18 環己基 2,6-二氣 4-甲氣苯基 73 207-208 19 苯基 2,6-二氣 4-硝苯基 93 280-282 20 2-甲氯苯基 2-氣 4-甲氣苯基 84 195-198 21 2-甲氯苯基 2,6-二氣 4-甲氣苯基 86 205-208 22 3-甲氧苯基 2-氣 [甲氣苯基 89 241-242 23 3-甲氣苯基 2,6-二氣 4-甲氣苯基 85 253-255 24 2-氛苯基 2-氟 4-甲氣苯基 91 220*221 25 2-氣苯基 2,6-二氣 4-甲氧苯基 83 178-182 26 3-氛苯基 2-氣 4-甲氧苯基 90 247-248 27 3-氣苯基 2,6-二氣 4-甲氧苯基 93 278-279 28 4-氛苯基 2-氣 4-甲氯苯基 79 269-270 29 4-氛苯基 2,6-二氣 4-甲氯苯基 91 >300 30 3-甲氣苯基 2,6-二氣 溴 89 261-262 31 3-異丙氧苯基 2,6-二氣 溴 32 3-異丙氣苯基 2,6-二氟 甲氣苯基 I--------裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 47 經濟部中央樣準局員工消費合作社印製 483896 A 7 B7 五、發明説明（48 ) 參者例10 5-溴甲基-2,4-(1Η,3Η)-二氯代-1-(2-氟苯甲基）-6-(4-硝 苯基盼并[2,3-d]嘧啶-3-乙酸乙酯之製造 參考例8製得之化合（0.300g, 0.603minol), N -溴丁 二醯亞胺（0.107g, 0.603mmol), α,α’-偶氮雙異丁腈（ 10mg, 0.60mmol)及四氛化磺（15ml)之混合物回流2小時 。冷却後，自反應混合物濾除所得不溶物且濾液以氣仿稀 釋。有機層以氣化鈉水溶液洗滌並脱水（MgS〇4),接著減 壓蒸除溶劑。殘留物自乙酸乙酯中再結晶，得無色針晶（CH 4nn c ^ This paper size applies to Chinese National Standards (CNS) M specifications (210X 297 mm) 46 483896 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (47) Hua 1 Yang No. R2 Rl4, R15 R4 m. P. (t :) 1 (ethane carbonyl) methyl 2-air 4-methylphenyl 87 127-128 2 methyl 2-methylchloro 4-methoxyphenyl 92 174-175 3 Methyl 2-methyl 4-methoxyphenyl 97 179-180 4 Phenyl 2-methylchloro 4-methoxybenzyl 93 240-241 5 Phenyl 2-methyl 4-methoxyphenyl 96 252-253 6 Phenyl 2,4-nitrophenyl 87 294-295 7 phenyl 3-gas 4-methylphenyl 88 88 215-217 8 phenyl 4-gas 4-methylphenyl 66 209-212 9 phenyl 2, 4-digas 4-methylphenyl 73 73 227-228 10 phenyl 2,6-difluoro 4-methylphenyl 87 291-292 11 phenyl 2-chloro, 6-fluoro 4-methoxyphenyl 91 287-288 12 phenyl 2-methylthio 4-methylchlorophenyl 81 239-240 13 benzyl 2-methyl 4-methylphenyl 86 124-126 14 benzyl 2,6-diphenyl 4- Methoxyphenyl 82 161-163 15 Methoxyphenyl 2-gas 4-methylchlorophenyl 87 270-272 16 4-Methoxyphenyl 2,6-digas 4-methylchlorophenyl 83 > 300 17 Cyclohexyl 2-gas 4- Methylchlorophenyl 79 172-173 18 Cyclohexyl 2,6-digas 4-methylphenyl 73 73 207-208 19 Phenyl 2,6-digas 4-nitrophenyl 93 280-282 20 2-methyl chloride Phenyl 2-gas 4-methylphenylphenyl 84 195-198 21 2-methylchlorophenyl 2,6-digas 4-methylphenyl 86 86 205-208 22 3-methoxyphenyl 2-methyl [methyl Phenyl 89 241-242 23 3-methylphenyl 2,6-dimethyl 4-methylphenyl 85 253-255 24 2-phenylphenyl 2-fluoro 4-methylphenyl 91 220 * 221 25 2-Phenyl 2,6-digas 4-methoxyphenyl 83 178-182 26 3-Phenyl 2-gas 4-methoxyphenyl 90 247-248 27 3-Phenyl 2,6-phenyl Dimethoxy 4-methoxyphenyl 93 278-279 28 4-phenanthrene 2-gas 4-methylchlorophenyl 79 269-270 29 4-diphenyl 2,6-dichloro 4-methylchlorophenyl 91 > 300 30 3-methanephenyl 2,6-difluorobromo 89 261-262 31 3-isopropoxyphenyl 2,6-digas brom 32 32 isopropylphenyl 2,6-difluoro Methylphenyl I ------ Pack-(Please read the notes on the back before filling this page) The size of the paper is applicable to China National Standard (CNS) A4 (210X 297 mm) 47 Economy Printed by the Employees' Cooperatives of the Central Provincial Bureau of Standards, Ministry of Foreign Affairs 483896 A 7 B7 V. Description of Invention (48) Participant Example 10 5-Bromomethyl-2,4- (1Η, 3Η) -dichloro-1- (2-fluorobenzyl) -6- (4-nitrophenylpano [2 , 3-d] Pyrimidine-3-ethyl acetate production The compound obtained in Reference Example 8 (0.300g, 0.603minol), N-bromosuccinimide (0.107g, 0.603mmol), α, α'- A mixture of azobisisobutyronitrile (10mg, 0.60mmol) and tetramethanesulfonate (15ml) was refluxed for 2 hours. After cooling, the resulting insoluble matter was filtered off from the reaction mixture and the filtrate was diluted with aerosol. The organic layer was washed with an aqueous solution of vaporized sodium and dehydrated (MgS04), and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give colorless needles (

0 . 28 4 g , 82%), m. p , 1 6 5 - 1 6 7 t： 〇 元素分析：C24Hi9N3〇6SBrF C ( % ) Η ( % ) Η ( ^ ) 計算值：50.01; 3.^2； 7.29 實测值：4 9 · 8 7 ; 3.27； 7.23 1 H-NMR ( 2 0 0 MHz , CDCl3)5 ： 1.31 ( 3 Η , t , J = 7.1 Ηz), 4.26(2H,q,J=7.1Hz), 4.78(2H,s), 4.86(2H,s), 5-30(2H,s), 7.07-7.37(4H,m), 7.75(2H,d,J=8.8Hz), 8.33(2H,d,J=8.8Hz)。 IRUBr): 1713, 1673, 1524, 1477cm-1。 兹老例1 1 自參考例9製得之化合物起始，依參考例10之相同方 法製得表4所列化合物。化合物30至33係以實例18之方法 自參考例9之化合物30或31而裂得。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 >< 297公釐） --------裝-- (請先閱讀背面之注意事項再填寫本頁)0. 28 4 g, 82%), m.p, 16 5-16 7 t: 〇Elemental analysis: C24Hi9N3〇6SBrF C (%) Η (%) Η (^) Calculated value: 50.01; 3. ^ 2; 7.29 found: 4 9 · 8 7; 3.27; 7.23 1 H-NMR (2 0 MHz, CDCl3) 5: 1.31 (3 Η, t, J = 7.1 Ηz), 4.26 (2H, q, J = 7.1Hz), 4.78 (2H, s), 4.86 (2H, s), 5-30 (2H, s), 7.07-7.37 (4H, m), 7.75 (2H, d, J = 8.8Hz), 8.33 (2H, d, J = 8.8Hz). IRUBr): 1713, 1673, 1524, 1477cm-1. The old example 11 starts from the compound prepared in reference example 9 and the compounds listed in table 4 are prepared in the same manner as in reference example 10. Compounds 30 to 33 were cleaved from Compound 30 or 31 of Reference Example 9 by the method of Example 18. This paper size applies the Chinese National Standard (CNS) Α4 specification (210 > < 297 mm) -------- install-(Please read the precautions on the back before filling this page)

，1T 48 483896, 1T 48 483896

AA

7 B 五、發明説明（49 ) 表 4 07 B V. Description of the invention (49) Table 4 0

人， --------—— (請先閲讀背面之注意事項再填寫本頁) 訂 I 戶 參考例11 化合物编號 R2 R14，R15 R4， 産率 {%) m.P. (1C) 1 (乙氯羰基）甲基 2-氣 甲氧基 70 152-153 2 甲基 2-甲氯基 甲氣基 63 173Ί76 3 甲基 2-氟 甲氯基 82 175-177 4 苯基 2-甲氧基 甲氣基 93 240-241 5 苯基 2-氣 甲氧基 86 230-233 6 苯基 2-氣 硝基 86 224-225 7 苯基 3-氣 甲氧基 84 215-216 8 苯基 4-氟 甲氯基 84 232-233 9 苯基 2,4·二氣 甲氣基 84 230-231 10 苯基 2,6-二氣 甲氧基 87 250-252 11 苯基 2-氛，6-氣 甲氣基 86 255-257 12 苯基 2-甲硫基 甲氧基 90 212-214 13 苯甲基 2-氣 甲氣基 83 132-134 14 苯甲基 2,6-二氣 甲氣基 89 154-155 15 4-甲氣苯基 2-氟 甲氣基 88 226-228 16 4-甲氣苯基 2,6-二氟 甲氣基 80 249-251 17 琛己基 2-氟 甲氧基 86 149-151 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）49 經濟部中央樣準局員工消費合作社印製 Γ 483896 五、發明説明（5〇 ) 經濟部中央標準局員工消費合作社印裂 參考例11 化合物编號 R2 R14,R15 R4， 産率 ⑷ m. p. (V) 18 環己基 2,6-二氣 甲氣基 77 192-194 19 苯基 2,6-二氟 硝基 94 228-229 20 2-甲氣苯基 2-氣 甲氣基 77 180-181 21 2-甲氯苯基 2,6-二氣 甲氣基 79 212-214 22 3-甲氣苯基 2-氟 甲氣基 82 234-235 23 3-甲氣苯基 2,6-二氣 甲氧基 88 225-256 24 2-氛苯基 2-氟 甲氣基 85 175-178 25 2-氣苯基 2,6-二氣 甲氣基 88 191-193 26 3-氛苯基 2-氟 甲氣基 81 243-246 27 3-氛苯基 2,6-二氟 甲氧基 92 270-273 28 4-氛苯基 2-氣 甲氣基 84 271-274 29 4-氣苯基 2,6-二氣 甲氣基 78 265-268 30 3-甲氧苯基 2,6-二氣 丙胺羰基 31 3-甲氣苯基 2,6-二氣 異丙胺玻基 32 3-異丙氣苯基 2·6-二氣 丙胺羰基 33 3-異丙氣苯基 2,6-二氣 異丙胺羰基 34 3-異丙氣苯基 2,6-二氣 甲氧基 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）50 經濟部中央標準局負工消费合作社印製 483896 A7 B7 五、發明説明（5 1 ) 參者例12 5-(N-苯甲基-N-甲胺基甲基）-2,4(1Η,3Η)-二氣代-1-(2-氣苯甲基）-6-(4-硝苯基盼并[2,3-d]嘧啶-3-乙酸乙酯 塩酸塩之製造 在冰冷却下，於含參考例1 0製得之化合物（(K 2 7 0 g , 0.47mmol)之二甲基甲醯胺（10ml)溶液中，添加乙基二異 丙基胺（0.12ml, 0.710rainol)及苯甲基甲基胺（0.07ral, 0.56min〇l)。混合物在室溫攪拌20小時。濃縮反應混合物 且濃縮液分配於乙酸乙酯及飽和碩酸氫納水溶液之間，水 層以乙酸乙酯萃取，合併有機層並脱水（MgS〇4),接著減 壓蒸除溶劑。殘留物在矽膠上層析，得無色油（〇.297g, 10 0%)。在冰冷却下，在含此油之乙酸乙酯溶液中，添加 氛化氫於***之1N溶液，混合物在同溫攪拌10分鐘。反應 混合物於減壓下濃縮，且濃縮液自乙酸乙酯-***中結晶 而得白色結晶之對應塩酸塩（〇 . 〇 4 8 g )。 m . P . 1 2 0 - 1 2 8 ^People, --------—— (Please read the precautions on the back before filling this page) Subscriber Reference Example 11 Compound No. R2 R14, R15 R4, Yield {%) mP (1C) 1 (Ethylchlorocarbonyl) methyl 2-aminomethoxy 70 152-153 2 methyl 2-methylchloromethylamino 63 173Ί76 3 methyl 2-fluoromethylchloro 82 175-177 4 phenyl 2-methoxy Methylmethylamino 93 240-241 5 Phenyl 2-aminomethoxy 86 230-233 6 Phenyl 2-aminonitro 86 224-225 7 Phenyl 3-aminomethoxy 84 215-216 8 Phenyl4 -Fluoromethylchloro 84 232-233 9 Phenyl 2,4 · dicarbamoyl 84 230-231 10 Phenyl 2,6-digasmethoxy 87 250-252 11 Phenyl 2-ammonium, 6- Carboxymethyl 86 255-257 12 Phenyl 2-methylthiomethoxy 90 212-214 13 Benzyl 2-carbamoyl 83 132-134 14 Benzyl 2,6-dichloromethyl 89 154-155 15 4-methylaminophenyl 2-fluoromethylamino 88 226-228 16 4-methylaminophenyl 2,6-difluoromethylamino 80 249-251 17 hexanyl 2-fluoromethoxy 86 149-151 This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 49 Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs Preparation Γ 483896 V. Description of the invention (50) Reference example 11 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Compound No. R2 R14, R15 R4, yield ⑷ mp (V) 18 cyclohexyl 2,6-digas Gasoline 77 192-194 19 Phenyl 2,6-difluoronitro 94 228-229 20 2-Methophenyl 2-methanemethyl 77 180-181 21 2-Methylchlorophenyl 2,6-di Carbomethyl 79 212-214 22 3-methylphenyl 2-fluoromethyl 82 82 234-235 23 3-methylphenyl 2,6-dimethylmethoxy 88 225-256 24 2-benzylbenzene 2-fluoromethylamino 85 175-178 25 2-aminophenyl 2,6-dimethylamino 88 191-193 26 3-aminophenyl 2-fluoromethylamino 81 243-246 27 3-amino Phenyl 2,6-difluoromethoxy 92 270-273 28 4-Hydroxyphenyl 2-carbamoyl 84 271-274 29 4-Phenyl 2,6-difluoromethyl 78 78 265-268 30 3-methoxyphenyl 2,6-diaminopropylamine carbonyl 31 3-methylaminophenyl 2,6-diaminoisopropylamine glass 32 3-isopropylphenyl 2,6-diaminopropylamine carbonyl 33 3 -Isopropylphenyl 2,6-diisopropylaminecarbonyl 34 3-Isopropylphenyl 2,6-dimethoxy (Please read the notes on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 50 Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives 483896 A7 B7 V. Description of the Invention (5 1) Participant Example 12 5- (N- Benzyl-N-methylaminomethyl) -2,4 (1Η, 3Η) -digaso-1- (2-gasbenzyl) -6- (4-nitrophenylpano [2, 3-d] Production of pyrimidine-3-ethylacetic acid hydrazone Under ice-cooling, dimethylformamide (10 ml) containing the compound ((K 2 70 g, 0.47 mmol) obtained in Reference Example 10) To the solution, ethyldiisopropylamine (0.12ml, 0.710rainol) and benzylmethylamine (0.07ral, 0.56min) were added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and the concentrated solution was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenarsenate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dehydrated (MgS04), and then the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give a colorless oil (0.297 g, 100%). Under ice-cooling, to a solution of this oil in ethyl acetate, a 1N solution of hydrogenated ether in ether was added, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was crystallized from ethyl acetate-diethyl ether to give the corresponding hydrazone (0.048 g) as white crystals. m. P. 1 2 0-1 2 8 ^

元素分析·· C32H29N4O6SF· HC1· H2O C (% ) Η ) Ν ( % ) 計 算 值 ·· 57 .27 ； 4 .81 ； 8， 35 實 測 值 57 • 23 ； 4 .55 ； 8 . 42 IR (KBr )·· 1711, 1 6 6 5 , 1522 ,1 4 9 3 c m " 1 〇 灸 考 例 13 3- 異 丁 基 -2 • 4- (1H, 3Η)- 二 氧 代- 5-甲基-6 Λ 盼 并 [2 • 3 -d ]哺 啶 之製 造 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） —-------^裝-- (請先閱讀背面之注意事項再填寫本頁) 訂 483896 A7 B7 五、發明説明（52 ) 異戊酸（1.15ml, 10·03αιπιο1),二苯磷醯叠®化物（ 2.83g, 10·30ππιο1),三乙胺（1.45ml, 10·30ιηιηο1)及苯（ 1 5 πι 1 )之混合物回流加熱1 . 5小時，以釋出異氡酸異丁酯。 於所得混合物中添加參考例2製得之化合物（2 . 0 0 g , 6.85mmol)及苯（5ml)且混合物回流加熱4天。反應混合物 分配於乙酸乙酯及氛化鈉水溶液之間，水層以乙酸乙酯萃 取且合併之萃取液以氛化納水溶液洗滌並以MgS〇4脱水， 並於減壓下移除溶劑。殘留物於矽膠上層析得白色粉末（ 2 . 6 4 g , 9 9 % )。所得脲衍生物溶於乙醇（3 0 m 1 )中，於該溶 液中添加28%甲醇鈉（3.93g, 20.37mm〇l),混合物在室溫 攪拌16小時，添加1H塩酸（22ml, 22πιπι〇1)。減壓下蒸除乙 醇溶劑，過濾所得殘留物，以水-乙醇洗滌，於減壓下乾 燥，且接著自乙醇中結晶，得白色針晶（1 · 6U , 70 % )。 m*p.215-216t： 〇Elemental analysis · C32H29N4O6SF · HC1 · H2O C (%))) Ν (%) Calculated value · 57.27; 4.81; 8, 35 Found 57 · 23; 4.55; 8.42 IR (KBr ) ·· 1711, 1 6 6 5, 1522, 1 4 9 3 cm " 1 moxibustion examination example 13 3-isobutyl-2 • 4- (1H, 3Η) -dioxo- 5-methyl- 6 Λ PAN [2 • 3 -d] Manufacturing of hydrazine This paper is sized to the Chinese National Standard (CNS) A4 (210X 297 mm) —------- ^ installed-(Please read the back first Please pay attention to this page and fill in this page) Order 483896 A7 B7 V. Description of the invention (52) Isovaleric acid (1.15ml, 10.03αιπιο1), diphenylphosphonium sulfide compound (2.83g, 10.30ππιο1), triethylamine (1.45ml, 10 · 30ιηιηο1) and benzene (15 πι 1) were heated at reflux for 1.5 hours to release isobutyl isocyanate. To the obtained mixture, the compound (2.0 g, 6.85 mmol) and benzene (5 ml) obtained in Reference Example 2 were added, and the mixture was heated under reflux for 4 days. The reaction mixture was partitioned between ethyl acetate and an aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed with an aqueous sodium hydroxide solution and dehydrated with MgS04, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel to give a white powder (2.64 g, 99%). The obtained urea derivative was dissolved in ethanol (30 m 1), 28% sodium methoxide (3.93 g, 20.37 mm) was added to the solution, the mixture was stirred at room temperature for 16 hours, and 1H acetic acid (22 ml, 22 μm) was added. 1). The ethanol solvent was distilled off under reduced pressure, and the resulting residue was filtered, washed with water-ethanol, dried under reduced pressure, and then crystallized from ethanol to obtain white needles (1.6 U, 70%). m * p.215-216t: 〇

元素分析：Cl8H20N2〇3S C ( % ) Η ( % ) Ν ( % ) 計算值：62.77; 5.85； 8.13 經濟部中央樣準局貝工消费合作社印製 (請先閲讀背面之注意事項再填寫本頁) 實測值：6 2 · 7 5 ; 5.82; 8.04 ( 3 0 0 MHz, CDCia)^ ： 0 . 96 ( 6 Η , d , J = 6 . 8 Ηz), 2-20(lH,sept,J = 6.8Hz), 2.50(3H,s), 3.85-3.87(5H,in) ,6·96(2H,d，J = 8 · 8Hz) , 7·33 (2H，d,J = 8 · 8Hz), 9·50 (1H , s) 〇 IRUBr): 1711, 1657, 1537, 1499, 1458c·!-1。 &者例1 4 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 52 483896 經濟部中央樣隼局員工消費合作杜印製 五、發明説明（5 3 ) 使用參考例2或4製得之化合物作為起始物，依據參 考例1 3所述方法製得表5所列化合物。 a 參考例1 4 化合物编號 R2 R4 · 産率 (% ) m . p . (V ) 1 甲氣乙基 甲氧基 95 131-233 2 3,5-二甲氯苯基 甲氧基 87 >300 3 3, 5-二甲氣苯基 硝 基 85 >300 參者例15 2-胺基-4-甲基- 5-(4-甲氣苯基）《吩-3-羧酸之製造 於參考例2所得化合物（3.0g, 10.3ιππιο1)之乙醇溶液 (60ml)中添加2N氫氣化納（20.0ml, 40.Ommol)且混合物回 流加熱1 . 5小時。冷却後，於反應混合物中添加2 N塩酸（ 2 0 . 0 m I , 4 0 . 0 in m ο 1 )以使溶液中和，且溶液以乙酸乙酯萃 取，有機層以氯化納水溶液洗滌，接著以MsS〇4脱水。減 壓蒸除溶劑，且殘留物以***-己烷洗滌，得淡黄色粉末（ 2·2g, 91^ )〇 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事 4 項再填· 裝— 寫本頁) 訂 ••線 53 483896 A7 B7 五、發明説明（54 ) m.P.1 42-145t： ^H-HMR(200MHz, DMS〇-d6)5 ： 2.22(3H,s), 3.79(3H,s), 6.98(2H,d,J=8.8Hz), 7.25(lH,d,J=8.8Hz), 7.39(2H,s)Elemental analysis: Cl8H20N2〇3S C (%) Η (%) Ν (%) Calculated value: 62.77; 5.85; 8.13 Printed by Shelley Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) ) Measured value: 6 2 · 7 5; 5.82; 8.04 (300 MHz, CDCia) ^: 0.96 (6 Η, d, J = 6.8 Ηz), 2-20 (lH, sept, J = 6.8Hz), 2.50 (3H, s), 3.85-3.87 (5H, in), 6.96 (2H, d, J = 8 · 8Hz), 7.33 (2H, d, J = 8 · 8Hz), 9.50 (1H, s) (IRUBr): 1711, 1657, 1537, 1499, 1458c ·! -1. & Example 1 4 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 52 483896 Printed by the staff of the Central Bureau of Procurement, Ministry of Economic Affairs. 5. Description of the invention (5 3) Reference example 2 Or the compound prepared in 4 is used as a starting material, and the compounds listed in Table 5 are prepared according to the method described in Reference Example 13. a Reference Example 1 4 Compound No. R2 R4 · Yield (%) m. p. (V) 1 Methyethylmethoxy 95 131-233 2 3,5-dimethylchlorophenylmethoxy 87 > 300 3 3,5-Dimethylphenylphenyl 85 > 300 Reference Example 15 2-Amino-4-methyl-5- (4-methylphenyl) 2N sodium hydrogen hydride (20.0 ml, 40.0 mmol) was added to an ethanol solution (60 ml) of the compound (3.0 g, 10.3 μπιο 1) obtained in Reference Example 2 and the mixture was heated at reflux for 1.5 hours. After cooling, 2 N osmic acid (20.0 m I, 40.0 in m ο 1) was added to the reaction mixture to neutralize the solution, and the solution was extracted with ethyl acetate, and the organic layer was washed with an aqueous sodium chloride solution. , Followed by dehydration with MsS04. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether-hexane to obtain a light yellow powder (2.2 g, 91 ^). This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read first Note on the back 4 items are refilled and installed — write this page) Order • • Line 53 483896 A7 B7 V. Description of the invention (54) mP1 42-145t: ^ H-HMR (200MHz, DMS〇-d6) 5: 2.22 (3H, s), 3.79 (3H, s), 6.98 (2H, d, J = 8.8Hz), 7.25 (lH, d, J = 8.8Hz), 7.39 (2H, s)

O IR(KBr)： 3 4 7 0, 1 6 4 7, 1 5 7 6, 1 5 0 8, 1 4 7 5 cm^ 1 〇 袞者例1 6 2,4(1H)_二氣代- 6- (4 -甲氣苯基）-5 -甲基B*吩并[2,3-d] 枵畊之製造 於參考例15所得化合物（6.00g, 22.8mniol)之二B等烷 溶液（l〇ml)中添加三光氣（6.76g, 22.8mmol),且混合物' 在100t：攪拌4小時。反應後，濃縮反應溶液，接箸過濾 殘留物並以***洗滌，得淡黃色粉末（596g, 90%)。 m.p.209-210t： xH-HMR ( 2 0 0 MHz , DMS〇-d6)5 ： 2.36(3H,s), 3.82(3H,s), 7.06(2H,d，J=8.8Hz), 7.41(lH，d,J=8.8Hz), 10.50(lH,s )〇 IR(KBr)： 1 7 7 9, 1 7 0 9, 1 5 3 3, 1 49 7 cm~ 1 〇 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 袞老例17 2,4(1H)_二氧代-1-(2-氣苯甲基）-6-(4-甲氣苯基）-5-甲 基α吩并[2,3-d]垮畊之製造 於參考例1 6製得之化合物（4 . 8 0 g , 1 6 . 5 9 m Β» ο 1 )之二甲 基甲醯胺（30ml)溶液中，添加磺酸鉀（3.43g, 24·88ηηο1) ,碘化鉀（2.75g, 16.59mnol)及 2 -氣苯甲基氛（2.96ml, 24.88mi»ol),且混合物在室溫»拌2小時。囊縮反應混合 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 54 483896 經濟部中央樣隼局員工消费合作社印装 A7 B7五、發明説明（5 5 ) 物，殘留物分配於乙酸乙酯與氛化鈉水溶液之間。水層以 乙酸乙酯萃取，合併萃取液並以氛化鈉水溶液洗滌及以 M g S 0 4脱水，及於減壓下蒸除溶劑。所得殘留物以矽膠管 柱層析純化而得白色結晶（4.87g, 74%)。 m.p. 162-163^ ! H-NMR ( 2 0 0 MHz , CDCla)^ ： 2.43(3H,s), 3.84(3H,s), 5.21(2H，s), 6.95(2H,d,J=8.8Hz), 7.05-7.44(6H,m)。 IR(KBr) 1769, 1719, 1562, 1531, 1493〇 FAB-MS m/z ： 3 9 8 · 1 (MH” 〇 兹者例1 8 2,4(1H)_二氣代-1-(2,6 -二氣苯甲基）-6-(4 -甲氣苯基） -5 -甲基《吩并[2,3-d] B等肼之製造 本質上依參考例17所述之相同程序，使用2,6 -二氣苯 甲基氛（1.18g, 7.26mniol)取代2 -氣苯甲基氛，自參考例 17所得化合物（2.0(^,6.911^〇1),5嚴酸鉀（0.958, 6.91mmol)及碘化鉀（1.15g, 6.91mmol),製得無色結晶之 標的化合物（2 · 3 4 s , 8 2 % )。 m.P.189-19010 (自乙酸乙酯-己烷中再結晶）。 1H-HMR(300MHz> CDCla)^ ： 2.42(3H,s), 3-84(3H,s), 5.27(2H,s), 6·90-δ·9δ(4Η,η), 7·24-7·36(3Η,ιη)。 I R ( K B r ) : 1 7 7 5，1 7 3 1 , 1 5 2 3 , 1 4 6 8 c η - 1。 &老例1 9 2,4-(1131〇-二氣代卜（2-«苯甲基）-6-(4-甲氧苯基）-3-(3 -甲氣丙基）-5 -甲基β吩并[2,3-d]嘧啶之製造 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標隼（CNS〉A4規格（210 X 297公釐〉 55 483896 A7 B7 五、發明説明（56 ) 於冰冷却下，於參考例1 7所得化合物之二氣甲烷（ 12ml)溶液中，添加3 -甲氣丙基胺（0.17ml, 1.67minol)且 混合物在室溫攪拌1小時。藉濃縮該反應混合物而得之殘 留物分配於二氛甲烷及氛化鈉水溶液之間，水層以二氣甲 烷萃取，合併萃取液，萃取液以氮化鈉水溶液洗滌及以 MgS〇4乾燥，接著蒸除溶劑。所得殘留物藉矽膠管柱層析 而純化，得白色粉末（5 2 4 in g , 7 8 % )。所得胺衍生物溶於 四氫呋喃（20ml)中，並於此溶液中添加三光氣（351rag, l. 18mmol)及三乙胺（0.15ral, 2.37mmol),且混合物加熱 攪拌1.5小時。冷却後，反應混合物以乙酸乙酯萃取，有 機層以氮化鈉水溶液洗滌及以MsS〇4脱水，且於減壓下蒸 除溶劑。由此所得之殘留物藉矽膠層析純化，乾燥後以乙 酸乙酯-己烷進行再結晶，得白色片晶（3 9 8 m g , 7 2 % )。O IR (KBr): 3 4 7 0, 1 6 4 7, 1 5 7 6, 1 5 0 8, 1 4 7 5 cm ^ 1 〇 Example of the case 1 6 2, 4 (1H) _ 二 气 代- 6- (4-methylaminophenyl) -5 -methyl B * pheno [2,3-d] Phenol's bis-B alkane solution (6.00 g, 22.8 mniol) obtained in Reference Example 15 ( 10 ml) was added triphosgene (6.76 g, 22.8 mmol), and the mixture was stirred at 100 t: 4 hours. After the reaction, the reaction solution was concentrated, and the residue was filtered and washed with diethyl ether to obtain a pale yellow powder (596 g, 90%). mp209-210t: xH-HMR (200 MHz, DMS〇-d6) 5: 2.36 (3H, s), 3.82 (3H, s), 7.06 (2H, d, J = 8.8Hz), 7.41 (lH ， D, J = 8.8Hz), 10.50 (lH, s) 〇IR (KBr): 1 7 7 9, 1 7 0 9, 1 5 3 3, 1 49 7 cm ~ 1 〇 Staff consumption of the Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative (please read the precautions on the back before filling in this page) 衮 Old example 17 2,4 (1H) _dioxo-1- (2-gasbenzyl) -6- (4-methylgasbenzene Group) -5-methylαpheno [2,3-d], which is produced in Reference Example 16 (4.80 g, 16.65 m Β »ο 1) bis To a solution of methylformamidine (30ml), potassium sulfonate (3.43g, 24 · 88ηηο1), potassium iodide (2.75g, 16.59mnol), and 2-gas benzyl atmosphere (2.96ml, 24.88mi »ol) were added, And the mixture was stirred at room temperature »for 2 hours. Shrinking reaction mixture This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 54 483896 Printed by A7 B7, Consumer Cooperatives of the Central Provincial Bureau of Economic Affairs, Ministry of Economic Affairs, A7 B7, and residues are distributed in Between ethyl acetate and aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate, and the extracts were combined and washed with an aqueous sodium hydroxide solution and dehydrated with M g S 0 4, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain white crystals (4.87 g, 74%). mp 162-163 ^! H-NMR (2 0 0 MHz, CDCla) ^: 2.43 (3H, s), 3.84 (3H, s), 5.21 (2H, s), 6.95 (2H, d, J = 8.8Hz ), 7.05-7.44 (6H, m). IR (KBr) 1769, 1719, 1562, 1531, 1493〇 FAB-MS m / z: 3 9 8 · 1 (MH ”〇 Example 1 8 2,4 (1H) _two gas generation-1- (2 The production of hydrazine such as 6,6-digas benzyl) -6- (4-methylphenyl) -5-methyl "pheno [2,3-d] B is essentially the same as described in Reference Example 17 Procedure, using 2,6-diphenylbenzyl (1.18g, 7.26mniol) instead of 2-benzyl, from the compound obtained in Reference Example 17 (2.0 (^, 6.911 ^ 〇1), 5 potassium potassium acid (0.958, 6.91 mmol) and potassium iodide (1.15 g, 6.91 mmol) to prepare the target compound (2.34 s, 8 2%) as colorless crystals. MP189-19010 (recrystallized from ethyl acetate-hexane) ). 1H-HMR (300MHz > CDCla) ^: 2.42 (3H, s), 3-84 (3H, s), 5.27 (2H, s), 6.90-δ · 9δ (4Η, η), 7 · 24-7 · 36 (3Η, ιη). IR (KB r): 1 7 7 5, 1 7 3 1, 1 5 2 3, 1 4 6 8 c η-1. & Old example 1 9 2, 4 -(1131〇-difluorotetramethyl (2- «benzyl) -6- (4-methoxyphenyl) -3- (3-methylaminopropyl) -5-methylβpheno [2, 3-d] Manufacture of pyrimidine (please read the precautions on the back before filling this page) This paper size is applicable to Chinese national standard (CNS> A4 specification (210 X 297 Li> 55 483896 A7 B7 V. Description of the invention (56) Under ice cooling, to a solution of the compound obtained in Reference Example 17 in digas methane (12 ml), 3-methylpropylpropylamine (0.17 ml, 1.67 minol) was added and The mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture was partitioned between dichloromethane and aqueous sodium hydroxide solution, the aqueous layer was extracted with digas methane, the extracts were combined, and the extracts were aqueous sodium nitride solution. It was washed and dried with MgSO4, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain a white powder (54 in g, 78%). The obtained amine derivative was dissolved in tetrahydrofuran (20 ml). In this solution, triphosgene (351rag, 1.18mmol) and triethylamine (0.15ral, 2.37mmol) were added to this solution, and the mixture was stirred with heating for 1.5 hours. After cooling, the reaction mixture was extracted with ethyl acetate, and the organic layer was The aqueous solution was washed with sodium nitride and dehydrated with MsSO4, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel chromatography, dried and recrystallized from ethyl acetate-hexane to obtain white flakes. (398 mg, 72%).

m. ρ· 113-115TCm. ρ 113-115TC

元素分析：C25H25N2O4SF C ( % ) Η ( % ) Ν ( % ) 計算值：64.09; 5.38； 5.98 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 實測值：6 3 . 8 9 ; 5.39； 5.92 1 H-NMR ( 3 0 0 MHz , CDCla) δ ： 2.00(2H,quint,J = 6.7Hz), 2.50(3H,s), 3.34(3H,s), 3.50(2H,t,J=6.7Hz), 3.83 (3H,s), 4.18(2H,t,J=6.7Hz), 5.26(2H,s), 6.93(2H,d,J=8.8Hz), 7.07-7.12(2H,m), 7.24-7.29 (4H · m) 〇 IRUBr): 1700, 1659, 1473c 通-1。 本紙張尺度適用中國國家標準（CNS ) A4規格（2i〇X20公釐） 56 483896 7 Β 經濟部中央標隼局員工消費合作社印製 五、發明説明（5 7 ) 參者例20 使用參考例13製得之化合物作為起始物，依據參考例 15所述方法，製備表6所列化合物。 表 6 0Elemental analysis: C25H25N2O4SF C (%) Η (%) Ν (%) Calculated: 64.09; 5.38; 5.98 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Measured values: 6 3. 8 9; 5.39; 5.92 1 H-NMR (300 MHz, CDCla) δ: 2.00 (2H, quint, J = 6.7Hz), 2.50 (3H, s), 3.34 (3H, s), 3.50 (2H, t, J = 6.7Hz), 3.83 (3H, s), 4.18 (2H, t, J = 6.7Hz), 5.26 (2H, s), 6.93 (2H, d, J = 8.8Hz), 7.07 -7.12 (2H, m), 7.24-7.29 (4H · m) (IRUBr): 1700, 1659, 1473c through -1. This paper size is in accordance with Chinese National Standard (CNS) A4 (2i0x20mm) 56 483896 7 Β Printed by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs 5. Description of the invention (5 7) Participant example 20 Use reference example 13 The obtained compound was used as a starting material, and the compounds listed in Table 6 were prepared according to the method described in Reference Example 15. Table 6 0

參考例20 化合物编號 R 1 4，R 1 5 R2 産率 (^ ) m · Ρ · (V ) 1 2，6-二氟 甲氣丙基 76 173-174 2 2 , 6-二氣 甲硫苯基 39 243-245 袞者例21 2,4(1H，3H) -二氣代-3-苯基-5-甲基-6-U -甲氣苯基吩并[ 2, 3-d]嘧啶之製造 於參考例4所得化合物（5 · 0 0 g , 1 6 . 3 2 m «I ο 1 )之吡啶（ 30ml)溶液中添加異氰酸苯酯（2.66ml, 24,48mm〇l)。混合 物在45t：»拌6小時，反應混合物於減®濃縮得殘留物， 殘留物溶於乙酵（6ml)中，於該溶液中添加28%甲醇鈉（ 7.86%, 40.80ι·ο1),混合物在室溫攪拌2小時·於所得 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐〉 ---------—I (請先閱讀背面之注意事項再填寫本頁) 訂 57 經濟部中央標隼局員工消费合作社印製 483896 A7 B7 五、發明説明（5 8 ) 物中添加2N塩酸（25ml, 50αι«ιο1),及於減壓下蒸除乙醇溶 劑。因而所得殘留物進行過濾，以水-乙醇洗滌，減壓乾 燥，及以乙醇再結晶，得黃色粉末（6.09g, 98%)。 P. > 3 0 0 ^ 元素分析·· Cl9Hl3N3〇4S*0.3H2〇 C ( % ) Η ( % ) Η ( % ) 計算值：59.30; 3.56； 10.92 實測值：5 9 · 5 6 ; 3.52； 10.93 HMRUOOMHz, DMS0-de)5 : 2.50(3H,s), 7·31-7·46 (5H,m), 7.78(2H,d,J=8.8Hz), 8.32(2H,d,J=8.8Hz), 12 . 50 (1H , s) 〇 RUBr): 1715, 1657, 1593, 1510cm-1。 參老例22 2,4(1H,3H)-二氧代-5-甲基- 3-(3-甲氣苯基）-6-(4 -甲氣 苯基）β盼并[2,3-d]嘧啶之製造 依參考例21所述相同程序，使用異《酸3 -甲氣苯酯（ l. 57ml, 12.Ommol)取代異気酸苯酯，自參考例4所得化 合物（3.06s, lO.OOMmnol)及 28% 甲酵納（4.82g, 25.00mmol),製得無色結晶之標的化合物（3.15g, 77%) ΟReference Example 20 Compound No. R 1 4, R 1 5 R2 Yield (^) m · ρ · (V) 1 2,6-difluoromethylpropane 76 173-174 2 2, 6-digas methylsulfide Phenyl 39 243-245 Example 21 of 2,4 (1H, 3H) -Digaso-3-phenyl-5-methyl-6-U -methylphenylpheno [2, 3-d] Pyrimidine was produced in a solution of the compound (5.00 g, 16.2.32 m «I ο 1) in pyridine (30 ml) obtained in Reference Example 4 with phenyl isocyanate (2.66 ml, 24, 48 mm). . The mixture was stirred at 45t for 6 hours. The reaction mixture was concentrated in minus ® to obtain a residue. The residue was dissolved in acetic acid (6ml), and 28% sodium methoxide (7.86%, 40.80ι · ο1) was added to the solution. The mixture Stir at room temperature for 2 hours. Applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) at the paper size obtained. ---------— I (Please read the precautions on the back before filling this page. ) Order 57 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 483896 A7 B7 5. In the description of the invention (5 8), 2N acetic acid (25ml, 50αι «ιο1) was added, and the ethanol solvent was distilled off under reduced pressure. The residue was filtered, washed with water-ethanol, dried under reduced pressure, and recrystallized from ethanol to obtain a yellow powder (6.09 g, 98%). P. > 3 0 0 ^ Elemental analysis · Cl9Hl3N3O4S * 0.3H2 〇C (%) Η (%) Η (%) Calculated: 59.30; 3.56; 10.92 Found: 5 9 · 5 6; 3.52; 10.93 HMRUOOMHz, DMS0-de) 5: 2.50 (3H, s), 7 · 31-7 · 46 (5H, m), 7.78 (2H, d, J = 8.8Hz), 8.32 (2H, d, J = 8.8Hz), 12.50 (1H, s) 〇RUBr): 1715, 1657 , 1593, 1510cm-1. See old example 22 2,4 (1H, 3H) -Dioxo-5-methyl- 3- (3-methylphenyl) -6- (4-methylphenyl) βpan [2,3 -d] Pyrimidine was produced according to the same procedure as described in Reference Example 21, using isopropyl 3-methylphenoxylate (1.57 ml, 12.0 mmol) instead of phenyl isocyanate, and the compound obtained from Reference Example 4 (3.06s , lO.OOMmnol) and 28% formazan (4.82g, 25.00mmol) to prepare the target compound as colorless crystals (3.15g, 77%) 〇

m. P . > 3 0 0 1Cm. P. > 3 0 0 1C

元素分析·· C2〇Hl5H3〇5S C ( ^ ) Η ( % ) N ( ^ ) 計算值·· 5 8 · 6 7 ; 3.69； 10-26 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） --------^裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 •破 58 經濟部中央標準局員工消费合作社印製 483896 A7 B7 五、發明説明（5 9 ) 實測值：5 8 · 7 6; 3.67； 10.32 1H-NMR ( 3 0 0 MHz, CDC 1 3) δ ： 2 · 50(3 Η , s ) · 3 · 78 ( 3 Η , s), 6.78(lH,d,J = 8.1Hz), 6.92 (1Η , s) , 7.00(lH,d,J = 8.1Hz) ,7.38(lH,t,J = 8.1Hz) , 7.77 (1 Η , d , J = 8 . 7Ηζ), 8.31(2H,d，J=8.7Hz), 12.48(lH,s)〇 ΙΜΚΒ「）： 1 7 1 7, 1 6 6 1, 1 5 9 3, 1 5 1 0, 1 4 29 cm-1。 參者例23 2·4(1Η,3Η)-二氧代-1-(2,6-二氣苯甲基）-5 -甲基- 3- (3-甲基亞磺醛苯基）-6-(4 -甲氣苯基）《吩并[2,3-d]嘧啶之 製造 在冰冷却下，於含參考例2 0所得化合物2 (表6 )( 200mg, 0.37minol)之二氛甲烷（20ml)溶液中添加、-氛過 苯甲酸（129mg, 0.37mnol),混合物攪拌30分鐘，反應混 合物分配於二氛甲烷與氯化鈉水溶液之間，水層以二氛甲 烷萃取，合併之萃取液以氛化鈉水溶液脱水及以MgS〇4脱 水，及於減壓下蒸除溶劑，因而所得之殘留物以矽膠管柱 層析，得白色粉末（183mg, 89%)。Elemental analysis ·· C2〇Hl5H3〇5S C (^) Η (%) N (^) Calculated value · 5 8 · 6 7; 3.69; 10-26 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 (Mm) -------- ^ equipment-(Please read the notes on the back before filling out this page) Order • Break 58 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 483896 A7 B7 V. Description of the invention ( 5 9) Found: 5 8 · 7 6; 3.67; 10.32 1H-NMR (300 MHz, CDC 1 3) δ: 2 · 50 (3 Η, s) · 3 · 78 (3 Η, s), 6.78 (lH, d, J = 8.1Hz), 6.92 (1Η, s), 7.00 (lH, d, J = 8.1Hz), 7.38 (lH, t, J = 8.1Hz), 7.77 (1 Η, d, J = 8. 7Ηζ), 8.31 (2H, d, J = 8.7Hz), 12.48 (lH, s) 〇ΙΜΚΒ ″): 1 7 1 7, 1 6 6 1, 1 5 9 3, 1 5 1 0, 1 4 29 cm-1. Example 23 2 · 4 (1Η, 3Η) -dioxo-1- (2,6-digas benzyl) -5 -methyl-3- (3-methyl Production of sulfinaldehyde phenyl) -6- (4-methylphenyl) pheno [2,3-d] pyrimidine Under ice cooling, the compound 2 (Table 6) obtained in Reference Example 20 (200 mg, 0.37minol) added in dichloromethane (20ml) solution, -dibenzoperbenzoic acid (129mg, 0.37mnol ), The mixture was stirred for 30 minutes, the reaction mixture was partitioned between dichloromethane and sodium chloride aqueous solution, the aqueous layer was extracted with dichloromethane, the combined extracts were dehydrated with aqueous sodium hydroxide solution and dehydrated with MgS04, and The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain a white powder (183 mg, 89%).

m,p.267-268TC lH-NMR(300MHz, CDCl3)5 ： 2.46(3H,s), 2,79(3H/s), 3.85(3H,s), 5,35(2H,s), 6·90-6·97(4Η，ιη), 7 . 33~7 . 72 (7H , η) 〇 I R U B r ) : 1 7 1 7，1 6 6 7 , 1 6 2 8 , 1 5 6 2 · 1 5 3 3 c m * 1 〇 FAB-MS in/z ： 5 5 3 . 1 (MH^) 〇 金者例24 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） --------·裝-- (請先閱讀背面之注意事項再填寫本頁) ,ιτ 59 483896 A7 B7 五、發明説明（60 ) (請先閲讀背面之注意事項再填寫本頁) 2,4(1H,3H)-二氯代-卜（2,6-二氟苯甲基）-5 -甲基-3- (3, 甲基磺醯苯基）-6-(4 -甲氧苯基）ι*吩并[2,3-d]嘧啶之製 造 本質上依參考例23所述之相同程序，再使用間-氛過 苯甲酸（62mg, 0.18miB〇l),自參考例23所得化合物（ 100mg,0.18mmol),製得無色結晶之標的化合物（98mg, 9 5 % ) 〇m, p.267-268TC lH-NMR (300MHz, CDCl3) 5: 2.46 (3H, s), 2,79 (3H / s), 3.85 (3H, s), 5,35 (2H, s), 6 · 90-6 · 97 (4Η, ιη), 7.33 ~ 7.72 (7H, η) 〇IRUB r): 1 7 1 7, 1 6 6 7, 1 6 2 8, 1 5 6 2 · 1 5 3 3 cm * 1 〇FAB-MS in / z: 5 5 3. 1 (MH ^) 〇 Gold case 24 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ----- --- · Installation-(Please read the precautions on the back before filling out this page), ιτ 59 483896 A7 B7 V. Description of the invention (60) (Please read the precautions on the back before filling out this page) 2,4 ( 1H, 3H) -dichloro-bu (2,6-difluorobenzyl) -5 -methyl-3- (3, methylsulfonylphenyl) -6- (4-methoxyphenyl) The production of phen * [2,3-d] pyrimidine was essentially the same as described in Reference Example 23, followed by the use of m-aeroperbenzoic acid (62 mg, 0.18 miB0l), the compound obtained from Reference Example 23 ( 100 mg, 0.18 mmol) to prepare the target compound as colorless crystals (98 mg, 95%).

m.p.256-257lC UMRHOOMHz, CDCl3)5 : 2.46(3H,s), 3.10(3H,s), 3.85(3H,s), 5.36(2H,s), 6.90-6.97(4H,m), 7 · 29-8 · 01 (7H , m) 〇 IR(KBr)： 1 7 1 9, 1 6 6 5, 1 5 3 1, 1 47 3 cm - 1 〇 FAB-MS m/z ： 5 6 9. 1 (MH") 〇 參者例25 使用依參考例13, 14， 21或22之方法製得之化合物作 為起始物，依據參考例17所述方法製得表7所列化合物。 表 7 經濟部中央標準局員工消費合作杜印製mp256-257lC UMRHOOMHz, CDCl3) 5: 2.46 (3H, s), 3.10 (3H, s), 3.85 (3H, s), 5.36 (2H, s), 6.90-6.97 (4H, m), 7 · 29 -8 · 01 (7H, m) 〇IR (KBr): 1 7 1 9, 1 6 6 5, 1 5 3 1, 1 47 3 cm-1 〇 FAB-MS m / z: 5 6 9. 1 ( MH ") ○ Participant Example 25 The compounds listed in Table 7 were prepared according to the method described in Reference Example 17 using the compounds prepared according to the methods of Reference Examples 13, 14, 21 or 22 as starting materials. Table 7 Duplicate printing of employee cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐） 60 483896 經濟部中央櫟隼局員工消费合作社印製 五、發明説明（βι ) 參考例25 化合物编號 R2 R 1 4 ^ 1 5 R4， 産率 (% ) m. Ρ. (V) 1 異丁基 2-氣 甲氣基 80 136-138 2 異丁基 2,6-二氣 甲氧基 73 121-122 3 甲氯乙基 2-氣 甲氧基 74 102-104 4 甲氧乙基 2,6-二氣 甲氯基 86 152-153 5 3,5-二甲氯苯基 2-氣 甲氯基 76 250-252 6 3,5-二甲氯苯基 2,6-二氟 甲氣基 90 270-272 7 3,5-二甲氧苯基 2,6-二氣 硝基 95 257-258 8 苯基 2,6-二氣 硝基 93 280-282 9 3-甲氯苯基 2,6-二氣 硝基 84 231-234 10 3-異丙氧苯基 2,6-二氟 硝基 11 3-甲氣甲氱苯基 2,6-二氧 硝基 88 209-210 ---------·裝— (請先閲讀背面之注意事項再填寫本頁)This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 60 483896 Printed by the Consumer Cooperative of the Central Quercus Bureau of the Ministry of Economic Affairs 5. Description of Invention (βι) Reference Example 25 Compound No. R2 R 1 4 ^ 1 5 R4, Yield (%) m. P. (V) 1 isobutyl 2-carbamoyl 80 136-138 2 isobutyl 2,6-dimethoxymethoxy 73 121-122 3 methyl Chloroethyl 2-aminomethoxy 74 102-104 4 methoxyethyl 2,6-diaminomethylchloro 86 152-153 5 3,5-dimethylchlorophenyl 2-aminomethylchloro 76 250- 252 6 3,5-Dichlorochlorophenyl 2,6-difluoromethylamino 90 270-272 7 3,5-dimethoxyphenyl 2,6-difluoronitro 95 257-258 8 phenyl 2 1,6-Difluoronitro 93 280-282 9 3-methylchlorophenyl 2,6-difluoronitro 84 231-234 10 3-isopropyloxyphenyl 2,6-difluoronitro 11 3-methyl Pyroformyl 2,6-dioxonitro 88 209-210 --------- · pack— (Please read the precautions on the back before filling this page)

，1T 4 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 61 483896 A7 B7 五、發明説明（62 ) 參者例26 2 , 4 (1 Η , 3 Η )-二氣代-1 - ( 2 -氣苯甲基）-5 -溴甲基-6 - ( 4 -甲 氣苯基）-3-(3 -甲氯丙基）0：盼并[2,3-d]嘧啶之製造 參考例19所得化合物（270mg, 0.576πιιαο1), N -溴丁二 醯亞胺（103mg, 0.576mmol), a,ct’偶氮雙異丁腈（10mg, 0.058mmol)及四氛化磺（10ml)之混合物予以加熱回流，冷 却後，濾除不溶物，濾液以氛仿稀釋。有機層以氣化鈉水 溶液洗滌並以M g S 0 4脱水，接著於減壓下蒸除溶劑，所得 殘留物以乙酸乙酯再結晶，得無色粉末（2 9 4 m g , 9 3 % )。 x H-NHR ( 3 0 0 MHz , CDCla) δ ： 2.01(2H,quint,J = 6.7Hz), 3.33(3H,s), 3.50(2H,t,J=6.7Hz), 3.85(3H,s), 4.21( 2H，t，J=6.7Hz)· 4.81(2H,s), 5.27(2H,s), 6.98(2H,d,J=8.8Hz), 7.09-7.34(4H,m), 7.49(2H,d,J=8.8Hz)〇 IRUBr)·· 1713, 1661, 1628，154 1 cm·1。 FAB-MS m/z : 5 48· 1 (MH + ) 〇 兹者例27 經濟部中央標準局員工消費合作杜印製 (請先閱讀背面之注意事項再填寫本頁) 使用參考例19, 20, 23, 24或25中製得之化合物作為 起始物，依參考例26所述方法製得表8所列化合物。 表 8 0， 1T 4 This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 61 483896 A7 B7 V. Description of the invention (62) Participant example 26 2, 4 (1 Η, 3 Η)-two-generation -1-(2 -Phenylbenzyl) -5 -bromomethyl-6-(4 -methylphenyl) -3- (3-methylchloropropyl) 0: PAN [2,3-d] Preparation of pyrimidine The compound obtained in Reference Example 19 (270mg, 0.576πιιαο1), N-bromosuccinimide (103mg, 0.576mmol), a, ct'azobisisobutyronitrile (10mg, 0.058mmol) and tetraammonium The mixture of sulphur (10 ml) was heated to reflux. After cooling, the insoluble matter was filtered off, and the filtrate was diluted with chloroform. The organic layer was washed with a gasified sodium water solution and dehydrated with M g S 0 4, and then the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate to obtain a colorless powder (294 mg, 93%). x H-NHR (300 MHz, CDCla) δ: 2.01 (2H, quint, J = 6.7Hz), 3.33 (3H, s), 3.50 (2H, t, J = 6.7Hz), 3.85 (3H, s ), 4.21 (2H, t, J = 6.7Hz) · 4.81 (2H, s), 5.27 (2H, s), 6.98 (2H, d, J = 8.8Hz), 7.09-7.34 (4H, m), 7.49 (2H, d, J = 8.8 Hz) IRUBr) · 1713, 1661, 1628, 1541 cm · 1. FAB-MS m / z: 5 48 · 1 (MH +) 〇 Example 27 Printed by the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Reference examples 19, 20 The compounds listed in 23, 24, or 25 were used as starting materials, and the compounds listed in Table 8 were prepared according to the method described in Reference Example 26. Table 8 0

本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0'〆297公釐） 62 483896This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 0'〆297mm) 62 483896

7 7 A B 經濟部中央樣隼局員工消費合作社印製 五、發明説明（63 ) 參考例27 化合物编號 R2 Rl4,R15 R4· 産率 m. p. (C) 1 甲氧丙基 2,6-二氣 甲氣基 77 166-167 2 3-甲基颈苯基 2,6-二氣 甲氣基 90 228-230 3 3-甲基亞磺醯苯基 2,6-二氣 甲氣基 85 272-273 4 3-甲基磺醯苯基 2,6-二氣 甲氣基 100 261-263 5 異丁基 2-氣 甲氣基 79 125-127 6 異丁基 2,6-二氣 甲氧基 88 155-157 7 甲氣乙基 2-氣 甲氣基 87 152-153 8 甲氯乙基 2,6-二氣 甲氣基 88 150-151 9 3,5-二甲氧苯基 2-氣 甲氯基 76 234-238 10 3,5-二甲氯苯基 2,6-二氣 甲氣基 86 251-253 11 3,5-二甲氣苯基 2,6-二氣 硝基 91 245-247 12 苯基 2,6-二氣 硝基 94 228-229 13 3-甲氣苯基 2,6-二氣 硝基 91 253-254 14 3-異丙氣苯基 2,6-二氟 硝基 15 3-甲氣甲氧苯基 2,6-二氣 硝基 97 207-209 --------^裝— (請先閱讀背面之注意事項再填寫本頁) 訂 4 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 63 483896 A7 B7 五、發明説明（64 ) 曹例1 2 , 4 ( 1 Η ,3H) -二 :氣代- 6 - (4 -甲氣苯基）-3-苯基 -1-(2- 氣苯 甲 基 )- 5- (N-苯甲 丨基- Ν - 甲 胺 基甲 基）Β*吩并[2 ,3-d]嘧啶塩 酸 塩 之 製 造 在 冰 冷却 下 9 於 含 參 考 例11 所得 化合物5 (0.150 g， 0 . 3 1 0 π mo 1)之 二 甲 基 甲 m 胺 (10m 1)之 溶液中， 添加乙基二 異 丙 胺 (0 .08m 1， 0 .460 m m ο 1 )及甲基苯甲胺（0 • 0 5 πι 1 , 0 . 3 7 0 m mo 1)〇 在 室 溫 攪 拌 2 小時 後， 濃縮反應混合物。殘 留 物 分 配 於乙 酸 乙 酯 及 飽 和 磺酸 氫鈉 水溶液之間。水層以 乙 酸 乙 酯 萃取 $ 合 併 之 有 機 層以 MgSO 4脫水， 減壓下 蒸除 溶 劑 f 且 殘留 物 於 矽 膠 上 層 析， 得無 色油（0 · 1 59g , 97 % ) 〇 在 冰 冷 却下 9 於 含 此 油 之 乙酸 乙酯 (4 in 1 )溶 液中添 加含 於 乙 醚 中 1 N塩 酸 溶 液 (0 .3 m 1 )。於冰冷却下懺 拌10分 鐘， 減 m 下 濃 縮反 應 混 合 物 〇 殘 留物 自乙 酸乙酯- ***中 結晶， 得 白 色 結 晶之 標 的 塩 酸 塩 (0 .144 g ) 〇 m . P . 140- 1431C 元 素 分 析 C35H 3〇 N 3 ：0 3 丨SF ♦ HC 1 · Η 2 0 C ( % ) Η ( ’、％ ) N (% ) 計 算 值 ·· 65.05； 5 · 14 ; 6 • 50 實 测 值 ： 65.1 4 ； 5 · 03 6 • 37 經濟部中央櫟準局員工消費合作杜印製 (請先閱讀背面之注意事項再填寫本頁) IRUBr)1711· 1665, 1543, 1477cm-1。 實例2 自參考例11所得化合物起始，以實例1所述方法裂備 表9所得化合物。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 64 4838967 7 AB Printed by the Consumer Cooperatives of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 5. Description of the Invention (63) Reference Example 27 Compound No. R2 Rl4, R15 R4 · Yield mp (C) 1 Methoxypropyl 2,6-digas Methanoyl 77 166-167 2 3-methyl-neckyl 2,6-diaminomethylamino 90 228-230 3 3-methylsulfenylphenyl 2,6-dimethylamino 85 272- 273 4 3-Methylsulfonylphenyl 2,6-dicarbamoyl 100 261-263 5 Isobutyl 2-carbamoyl 79 125-127 6 Isobutyl 2,6-dimethoxymethoxy 88 155-157 7 Methyethyl 2-ketomethyl 87 152-153 8 Mechloroethyl 2,6-dimethanoyl 88 150-151 9 3,5-Dimethoxyphenyl 2-ketone Methyl chloride 76 234-238 10 3,5-Dichlorochlorophenyl 2,6-difluoromethylamino 86 251-253 11 3,5-Dimethylphenyl 2,6-difluoronitro 91 245 -247 12 Phenyl 2,6-difluoronitro 94 228-229 13 3-Methylphenyl 2,6-difluoronitro 91 253-254 14 3-Isopropylphenyl 2,6-difluoro Nitro 15 3-Methoxymethoxyphenyl 2,6-Digas Nitro 97 207-209 -------- ^ pack— (Please read the notes on the back before filling this page) Order 4 Paper size applies to Chinese national standards (CN S) A4 specification (210X297 mm) 63 483896 A7 B7 V. Description of the invention (64) Cao Example 1 2, 4 (1 Η, 3H) -II: Gasoline-6-(4 -methylphenyl) -3 -Phenyl-1- (2-aminobenzyl)-5- (N-benzyl-N-methylaminomethyl) B * pheno [2,3-d] pyrimidinepyridine To a solution containing compound 5 (0.150 g, 0.3 1 0 π mo 1) in dimethylmethylamine (10m 1) under ice cooling, ethyl diisopropylamine (0.08m 1) was added under ice cooling. , 0.460 mm ο 1) and methyl benzylamine (0 • 0 5 μm 1, 0.3 7 m mo 1). After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogen sulfonate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dehydrated with MgSO 4, the solvent f was distilled off under reduced pressure, and the residue was chromatographed on silica gel to obtain a colorless oil (0.159 g, 97%). Under ice-cooling 9 To a solution of this oil in ethyl acetate (4 in 1) was added a 1 N osmic acid solution (0.3 m 1) in ether. Stir for 10 minutes under ice cooling and concentrate the reaction mixture under reduced temperature. The residue is crystallized from ethyl acetate-diethyl ether to give the target osmium osmium acid (0.144 g) as white crystals. M. P. 140-1431C elemental analysis C35H 3〇N 3 ： 0 3 丨 SF HC 1 · Η 2 C (%) Η (',%) N (%) Calculated value · 65.05; 5 · 14; 6 • 50 Measured value: 65.1 4; 5 · 03 6 · 37 Printed by the Consumer Affairs Cooperation Department of the Central Oakland Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) IRUBr) 1711 · 1665, 1543, 1477cm-1 Example 2 Starting from the compound obtained in Reference Example 11, the compound obtained in Table 9 was prepared by the method described in Example 1. This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 64 483896

A B 五、發明説明（6 5 ) 表 9A B V. Description of the invention (6 5) Table 9

經濟部中央橾準局員工消費合作社印製 實例2 化合物编號 R2 R14,R15 R4， R 産率 %) m.p. (V) 1 甲基 2-甲氯基 甲氧基 苯基 46 119-122 2 甲基 2_氣 甲氣基 苯基 97 128-131 3 苯基 2-甲氣基 甲氯基 苯基 95 97-105 4 苯基 2-氣 硝基 苯基 100 140-143 5 苯基 3-氣 甲氣基 苯基 97 152-156 6 苯基 4-氣 甲氧基 苯基 100 165-170 7 苯基 2,4-二氟 甲氣基 苯基 77 155-160 8 苯基 2,6-二氣 甲氧基 苯基 100 160-162 9 苯基 2-氛,6-氟 甲氧基 苯基 98 150-155 10 苯基 2-甲硫基 甲氣基 苯基 76 152-158 11 苯甲基 2-氣 甲氯基 苯基 89 128-134 12 苯甲基 2,6-二氣 甲氣基 苯基 100 123-127 13 4-甲氧苯基 2-氣 甲氯基 苯基 93 150-155 14 4-甲氯苯基 2,6-二氣 甲氣基 苯基 84 153-157 15 琛己基 2-氣 甲氣基 苯基 93 144-150 16 琛己基 2,6-二氣 甲氯基 苯基 97 145-150 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）防 (請先閲讀背面之注意事項再填寫本頁) 483896 五、發明説明（66 ) 經濟部中央樣隼局員工消費合作社印裝 實例2 化合物编號 R2 Rl4,R15 R4， R 産率 .¾) m.p. (V) 17 苯基 2,6-二氣 硝基 苯基 93 155-160 18 2-甲氯苯基 2-氣 甲氯基 苯基 93 152-153 19 2-甲氧苯基 2,6-二氣 甲氣基 苯基 100 148-150 20 3-甲氧苯基 2-氣 甲氯基 苯基 92 155-158 21 3-甲氣苯基 2,6-二氣 甲氯基 苯基 91 160-163 22 2-氛苯基 2-氣 甲氣基 苯基 97 147-152 23 2-氛苯基 2,6-二氣 甲氯基 苯基 98 150-155 24 3-氛苯基 2-氣 甲氧基 苯基 100 148-153 25 3-氣苯基 2,6-二氣 甲氣基 苯基 100 152-157 26 4-氣苯基 2-氣 丨甲氣基 苯基 91 161-164 27 4-氛苯基 2,6-二氣 甲氯基 苯基 86 145-146 28 3-甲氰苯基 2,6-二氟 丙胺羰基 苯基 29 3-甲氰苯基 2,6-二氟 異丙胺羰基 苯基 30 3-異丙氣苯基 2,6-二氣 丙胺羰基 苯基 31 3-異丙氯苯基 2,6-二氣 異丙胺羰基 苯基 32 3-甲氧苯基 2,6-二氟 甲氯基 苯基 91 160-163 33 3-異丙氣苯基 2,6-二氣 甲氣基 苯基 34 3-甲氯苯基 2,6-二氣 甲氣基 2-甲硫苯基 35 3-甲氯苯基 2,6-二氟 甲氣基 2-吡啶基 36 苯基 2,6-二氣 甲氣基 2-甲硫苯基 37 苯基 2,6-二氣 甲気基 2-吡啶基 38 苯基 2,6-二氣 甲氣基 二甲胺甲基 39 苯基 2,6-二氣 甲氧基 二乙胺甲基 40 苯基 2,6-二氣 甲氯基 Htt略啶基甲基 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 66 483896 經濟部中央橾準局員工消费合作社印裝 A7 B7五、發明説明U7 ) 奮例3 6-(4-胺苯基）-2,4-(1Η,3Η)_二氣代-1-(2-氣苯甲基）-3- 苯基-5-(1甲基-1苯甲胺基甲基）1*吩并[2,3-(1]嘧啶之 製造 實例2所得化合物4 ( 0 . 1 5 g , 0 . 2 4 7 m m ο 1 )溶於乙醇（ 15ml),於其中添加10%把-碩（15mg)。混合物於1大氣壓 之氫氣中在室溫氫化8小時。反應混合物以矽藻土過濾並 於減壓下濃縮該濾液。濃縮物於矽膠上層析，得黃色不定 形晶體（0.046g, 32%)。 ! H-NMR ( 3 0 0 MHz , CDC Is) δ ·· 2 . 05 (3H , s) , 3 . 57 (2H , s), 3.81(2H,br,s), 3.89(2H,s), 5.29(2H,s), 6.69(2H,d,J=8.7Hz), 7.05-7.56(16H,s)〇 FAB-MS m/z ： 5 7 7 (MH” 〇 啻例4 6-(胺苯基）-2,4-(lH,3H) -二氯代-卜（2,6 -二氣苯甲基） -5-(N -甲基-N-苯甲胺基甲基）-3-苯基《吩并[2,3-d]嘧啶 之製造 自實例2製得之化合物编17起始，依實例3所述方法 製得不定形結晶之標的化合物（6 5 % )。 1H-NMR(300MHz, CDCla)^ ： 2-05(3H,s)f 3-56(2H,s), 3,81(2H,br,s)· 3.88(2H,s), 5.36(2H,s), 6.71(2H,d,J=8.7Hz), 6.91(2H,t,J=8.7Hz). 7.21-7.53 (13H,m) 〇 奮例5 (請先閱讀背面之注意事 4 項再填. 裝— 寫本頁) 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 67 483896 A7 B7 五、發明説明（6 8 ) 6-(4-乙醯胺基苯基）-2,4-(1Η,3Η)-二氣代-1-(2-氣苯甲 基）-5-(N -甲基-N-苯甲胺基甲基）-3-苯基〇S吩并[2,3-d] 嘧啶之製造 實例3之所得化合物（0 . 6 3 g , 0 . 11 m m ο 1 )溶於無水吡 啶（5ml),於其中添加乙酸酐（0.01ml, O.llmmol)。混合 物在室溫掇拌2小時，反應混合物於減壓下濃縮，濃縮物 分配於二氛甲烷（3 0 m 1 )及飽和氛化鈉水溶液（1 0 in 1 )之間。 水層再以二氛甲烷（30ml)萃取，合併之有機層以硫酸鎂脱 水，於減壓下濃縮，濃縮液於矽膠上層析，得無色固體（ O.Olg, 15¾ )〇 1 H-NMR ( 3 0 0 MHz , CDCIg)^ ： 2.06(3H,s), 2.19(3H,s), 3.57(2H,s), 3.90(2H,s), 5.30(2H,s), 7.04-7,57(16H,s), 7.70(2H,d，J=8.4Hz)〇 奮例6 使用實例3所得化合物作為起始物，本質上依實例5 所述之相同程序，製得下列化合物。 编號1 : 2,4(2H,3H)_二氧代-1-(2 -氣苯甲基）-5-(N -甲基 經濟部中央櫟準局貝工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) -N-苯甲胺基甲基）-3-苯基-6-(4-丙醯胺基苯基） 瘭吩并[2,3-(^]嘧啶塩酸塩（産率：86%,111^· 172-1751C ) 〇 编號 2 : 2,4(2H,3H) -二氣代-1-(2 -氰苯甲基）-6-(4 -異丁 醯胺基苯基）-5-(N-甲基-N-苯甲胺基甲基）-3-苯 基》*吩并[2,3-<1]嘧啶塩酸塩（産率：77%,1!1.9· 1 8 5 - 1 8 8 1C ) 〇 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 68 483896 A7 B7 五、發明説明（6 9 ) 编號3 : 2,4(2H,3H)_二氯代-1-(2 -氣苯甲基）-6-(4 -甲氯 乙醯胺基苯基）-5-(N -甲基苯甲胺基甲基）-3-苯基噬吩并[2,3-d]嘧啶塩酸塩（産率：88%, a. p . 1 5 7 - 1 6 2 ¾ ) 〇 奮例7 2,4(1H,3H)-二氯代-1-(2 -氟苯甲基）-5-(N-苯甲基-N-甲 胺基甲基）-6-(4-甲氧苯基）-3-(3-甲氧丙基）〇*吩并[2,3-d]嘧啶之製造 於含參考例26所得化合物（284mg, 0.159αιιηο1)之二甲 基甲醯胺（1〇1111)溶液中，添加乙基二異丙胺（0.14〇1111, 0.780mraol)及甲基苯甲胺（0.080ml, 0.620mmol)。混合物 在室溫攪拌2小時，濃縮反應混合物且所得殘留分配於乙 酸乙酯與飽和碩酸氫鈉之間，水層以乙酸乙酯萃取，萃取 液與有機層合併，以MgS〇4乾燥，減壓下蒸除溶劑，所得 殘留物以矽謬管柱層析法純化，得無色油狀物質（280mg, 經濟部中央標準局員工消費合作社印製 9 2%)。油狀物質溶於乙酸乙酯（4 m 1 ),並在冰冷却下於該 溶液中添加於***中之1 N塩酸溶液（0 . 3 m 1 ),混合物於冰 冷却下攪拌，且反應混合物於減壓下濃縮，殘留物以乙酸 乙酯-***結晶，得白色結晶之標的化合物塩酸塩（ 220iog;) Ο m.p.95-100t： 元素分析：C35H34N3O4SF· 1.0HC1· 0·5Η2〇 C ( % ) Η ( % ) Ν ( ^ ) 計算值：62·60; 5.73； 6.64 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 69 483896 A 7 B7 五、發明説明（70 ) 實測值：6 2 · 7 3 ; 5.67； 6.56 IR(KBr)： 1 7 0 2, 1 6 5 7, 1 5 6 2, 1 5 4 3, 1 4 8 9 cm~ 1 〇 奮例8 自參考例2 7製得之化合物起始，依賓例7所述方法製 備表1 0所列化合物。藉由使化合物2 1水解製得化合物2 2及 藉由使化合物22與烷基鹵在齡存在下反應而製得化合物19 及2 0 〇 表 10 (請先閱讀背面之注意事 1·. •項再填. 裝-- 窝本瓦) 訂 經濟部中央橾隼局員工消費合作社印製Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs Example 2 Compound No. R2 R14, R15 R4, R Yield%) mp (V) 1 Methyl 2-methylchloromethoxyphenyl 46 119-122 2 A 2-Phenylmethylaminophenyl 97 128-131 3 phenyl 2-methylaminomethylchlorophenyl 95 97-105 4 phenyl 2-nitronitrophenyl 100 140-143 5 phenyl 3-amino Methoxyphenyl 97 152-156 6 Phenyl 4-aminomethoxyphenyl 100 165-170 7 Phenyl 2,4-difluoromethylaminophenyl 77 155-160 8 Phenyl 2,6-di Gasomethoxyphenyl 100 160-162 9 Phenyl 2-atom, 6-fluoromethoxyphenyl 98 150-155 10 Phenyl 2-methylthiomethylaminophenyl 76 152-158 11 Benzyl 2-Aminomethylchlorophenyl 89 128-134 12 benzyl 2,6-diaminomethylphenyl 100 100 123-127 13 4-methoxyphenyl 2-aminomethylchlorophenyl 93 150-155 14 4-methylchlorophenyl 2,6-difluoromethylphenyl 84 153-157 15 Benzohexyl 2-aminomethylphenyl 93 144-150 16 Benzohexyl 2,6-dimethylmethylchlorobenzene Base 97 145-150 This paper size is applicable to China National Standard (CNS) A4 size (210X 297 mm). (Please read the back first Please pay attention to this page and fill in this page again) 483896 V. Description of the invention (66) Example of printing by the Consumer Cooperative of the Central Bureau of Samples of the Ministry of Economic Affairs 2 Compound No. R2 Rl4, R15 R4, R Yield. ¾) mp (V) 17 Benzene Phenyl 2,6-diaminonitrophenyl 93 155-160 18 2-methylchlorophenyl 2-aminomethylchlorophenyl 93 152-153 19 2-methoxyphenyl 2,6-dimethylamino Phenyl 100 148-150 20 3-methoxyphenyl 2-aminomethylchlorophenyl 92 155-158 21 3-methoxyphenyl 2,6-difluoromethylchlorophenyl 91 160-163 22 2- 2-phenyl-2-aminomethylphenyl 97 147-152 23 2-diphenyl-2,6-dichloromethylphenyl 98 150-155 24 3-diphenyl 2-aminomethoxyphenyl 100 148-153 25 3-Gaphtyl 2,6-digasmylphenyl 100 152-157 26 4-Gaphthyl 2-gasmethanephenyl 91 161-164 27 4-Hydroxyphenyl 2,6-difluoromethylchlorophenyl 86 145-146 28 3-methylcyanophenyl 2,6-difluoropropylamine carbonylphenyl 29 3-methylcyanophenyl 2,6-difluoroisopropylamine carbonylphenyl 30 3-isopropylphenyl 2,6-difluoropropylamine carbonylphenyl 31 3-isopropylchlorophenyl 2,6-diisopropylamine carbonylphenyl 32 3- Oxyphenyl 2,6-difluoromethylchlorophenyl 91 160-163 33 3-isopropylphenyl 2,6-difluoromethylphenyl 34 3-methylchlorophenyl 2,6-diphenyl Methylamino 2-methylthiophenyl 35 3-methylchlorophenyl 2,6-difluoromethylamino 2-pyridyl 36 phenyl 2,6-difluoromethylamino 2-methylthiophenyl 37 phenyl 2,6-Difluoromethanemethyl 2-pyridyl 38 phenyl 2,6-difluoromethylamino dimethylamine methyl 39 phenyl 2,6-difluoromethoxydiethylamine methyl 40 phenyl 2,6-Difluoromethylchloro Htt slightly pyridylmethyl (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 66 483896 Ministry of Economic Affairs A7 B7 printed by the Consumers' Cooperative of the Central Central Quasi-Bureau Bureau 5. Description of the invention U7) Example 3 6- (4-aminophenyl) -2,4- (1Η, 3Η) _ 二 气 代 -1- (2- 气Benzyl) -3-phenyl-5- (1methyl-1benzylaminomethyl) 1 * Compound obtained from Production Example 2 of benzo [2,3- (1) pyrimidine 4 (0.1 5 g, 0.247 mm (1)) was dissolved in ethanol (15ml), and 10% suoshuo (15mg) was added to it. The mixture was hydrogenated under 1 atmosphere of hydrogen at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The concentrate was chromatographed on silica gel to give yellow amorphous crystals (0.046 g, 32%). ! H-NMR (300 MHz, CDC Is) δ · 2.05 (3H, s), 3.57 (2H, s), 3.81 (2H, br, s), 3.89 (2H, s), 5.29 (2H, s), 6.69 (2H, d, J = 8.7Hz), 7.05-7.56 (16H, s). FAB-MS m / z: 5 7 7 (MH ”〇 Example 4 6- (amine benzene ) -2,4- (lH, 3H) -dichloro-bu (2,6-diphenylbenzyl) -5- (N -methyl-N-benzylaminomethyl) -3- The production of phenyl "pheno [2,3-d] pyrimidine was started from Compound No. 17 obtained in Example 2 and the target compound (65%) was obtained as an amorphous crystal according to the method described in Example 3. 1H-NMR (300MHz, CDCla) ^: 2-05 (3H, s) f 3-56 (2H, s), 3,81 (2H, br, s) 3.88 (2H, s), 5.36 (2H, s), 6.71 (2H, d, J = 8.7Hz), 6.91 (2H, t, J = 8.7Hz). 7.21-7.53 (13H, m) 〇Example 5 (Please read the 4 notes on the back before filling.) — Write this page) The size of the paper used for the edition is in accordance with the Chinese National Standard (CNS) A4 (210X 297 mm) 67 483896 A7 B7 V. Description of the invention (6 8) 6- (4-Ethylaminophenyl) -2 , 4- (1Η, 3Η) -dioxo-1- (2-gasbenzyl) -5- (N -methyl-N-benzylaminomethyl) -3-phenyl [2,3-d] The compound obtained in Production Example 3 of pyrimidine (0.63 g, 0 11 mm ο 1) dissolved in anhydrous pyridine (5ml), acetic anhydride (0.01ml, 0.11mmol) was added thereto. The mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the concentrate was partitioned into two Between methane (30 m 1) and saturated aqueous sodium hydroxide solution (10 in 1). The aqueous layer was extracted with dimethane (30 ml), and the combined organic layers were dehydrated with magnesium sulfate, and concentrated under reduced pressure. The concentrated solution was chromatographed on silica gel to obtain a colorless solid (O.Olg, 15¾). 0 H-NMR (300 MHz, CDCIg) ^: 2.06 (3H, s), 2.19 (3H, s), 3.57 (2H , s), 3.90 (2H, s), 5.30 (2H, s), 7.04-7,57 (16H, s), 7.70 (2H, d, J = 8.4Hz) Example 6 The compound obtained in Example 3 was used as Starting materials were essentially prepared according to the same procedure as described in Example 5 to prepare the following compounds. No. 1: 2,4 (2H, 3H) _dioxo-1- (2-Gaphenylmethyl) -5- (N-methyl Read the notes on the back and fill in this page) -N-benzylaminomethyl) -3-phenyl-6- (4-propanamidophenyl) Pyeno [2,3-(^] pyrimidine Europium osmate (yield: 86%, 111 ^ · 172-1751C) 〇 No. 2: 2,4 (2H, 3H) -digaso-1- (2-cyanobenzyl) -6- (4- Isobutylammonylphenyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenyl "* pheno [2,3- < 1] pyrimidinepyridine (yield ： 77%, 1! 1.9 · 1 8 5-1 8 8 1C) 〇 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 68 483896 A7 B7 V. Description of invention (6 9) No. 3: 2,4 (2H, 3H) _dichloro-1- (2-gasbenzyl) -6- (4-methylchloroacetamidophenyl) -5- (N-methylbenzene Methylaminomethyl) -3-phenylphano [2,3-d] pyrimidinepyridinate (yield: 88%, a.p. 1 5 7-1 6 2 ¾) 〇 Example 7 2, 4 (1H, 3H) -dichloro-1- (2-fluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methoxyphenyl) -3- (3-methoxypropyl) 〇 * benzo [2,3-d] pyrimidine Manufactured in a solution of dimethylformamide (101111) containing the compound (284mg, 0.159αιιο1) obtained in Reference Example 26, and ethyldiisopropylamine (0.1401111, 0.780mraol) and methylbenzylamine ( 0.080 ml, 0.620 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the resulting residue was partitioned between ethyl acetate and saturated sodium bisulfate. The aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer. It was dried over MgS04, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a colorless oily substance (280 mg, printed by the Consumer Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs, 9 2%). Oil The substance was dissolved in ethyl acetate (4 m 1), and a 1 N acetic acid solution (0.3 m 1) in diethyl ether was added to the solution under ice cooling. The mixture was stirred under ice cooling, and the reaction mixture was reduced under reduced pressure. It was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diethyl ether to obtain the target compound of white crystals, osmium osmium acid (220iog;) 〇 mp95-100t: elemental analysis: C35H34N3O4SF · 1.0HC1 · 0.5 · 2ΗC (%) ) Ν (^) Calculated: 62 · 60; 5.73; 6.64 copies Zhang scale is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) 69 483896 A 7 B7 V. Description of the invention (70) Measured value: 6 2 · 7 3 5.67; 6.56 IR (KBr): 1 7 0 2, 1 6 5 7, 1 5 6 2, 1 5 4 3, 1 4 8 9 cm ~ 1 〇Example 8 Since the compound prepared in Reference Example 27 Initially, the compounds listed in Table 10 were prepared according to the method described in Example 7. Compound 2 2 is prepared by hydrolyzing compound 21 and compounds 19 and 20 are prepared by reacting compound 22 with an alkyl halide in the presence of age. Table 10 (Please read the note 1 on the back first .. • Fill in the items again. Pack-Wobenwa) Order printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS ) Μ規格（210X：Z97公釐） 483896 經濟部令夬揉準局員工消費合作杜印製 五、發明説明（71 ) 實例8 化合物编號 R2 R14,Rl5 R4· R 産率 ⑷ m.p. (Ό) 1 甲氯丙基 2,6-二氣 甲氯基 苯基 69 95-100 2 3-甲硫苯基 2,6-二氣 甲氧基 苯基 94 139-144 3 3-甲基亞磺醒苯基 2,6-二氣 甲氣基 苯基 93 153-156 4 3-甲基磺醯苯基 2,6-二氣 甲氯基 苯基 98 155-159 5 異丁基 2-氣 甲氯基 苯基 100 150-153 6 異丁基 2,6-二氣 甲氣基 苯基 98 165-167 7 甲氣乙基 2-氣 甲氧基 苯基 95 154-156 8 甲氣乙基 2,6-二氟 甲氯基 苯基 91 126-130 9 3,5-二甲氧苯基 2,氣 甲氧基 苯基 90 140-145 10 3,5-二甲氧苯基 2,6-二氣 甲氧基 苯基 91 146-148 11 3,5-二甲氣苯基 2,6-二氟 硝基 苯基 97 142-146 12 苯基 2,6-二氣 硝基 苯基 93 152-153 13 3-甲氣苯基 2,6-二氟 硝基 苯基 82 142-144 14 3-異丙氣苯基 2,6-二氣 硝基 苯基 70 不定形 (80-90) 15 3-異丙氣苯基 2,6-二氣 硝基 2-硫甲基苯基 16 3-異丙氣苯基 2,6-二氣 硝基 2-吡啶基 17 3-甲氣苯基 2,6-二氣 硝基 2-硫甲基苯基 18 3-甲氧苯基 2,6-二氟 硝基 2-吡啶基 19 3-乙氣苯基 2,6-二氟 硝基 苯基 93 171-176 20 3-丙氯苯基 2,6-二氣 硝基 苯基 86 149-151 21 3-甲氣甲氣苯基 2,6-二氣 硝基 苯基 86 110-120 22 3-涇苯基 2· 6-二氣 硝基 苯基 86 207-209 23 3-甲氧苯基 2,6-二氣 硝基 二乙胺基甲基 24 3-甲氧苯基 2,6-二氟 硝基 三甲基胺基甲基 25 3-甲氣苯基 2,6-二氣 硝基 1-吡啶啶基甲基 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X： 297公釐） 71 483896 A7 B7 五、發明説明（72 ) 奮例9 6-U-胺苯基），2,4(1H,3H)_二氯代-1-(2,6-二氣苯甲基） -5-(N-苯甲基-N-甲胺基甲基）-3-(3 -甲氧苯基）〇*吩井 [2,3-d]嘧啶塩酸塩之製造 在冰冷却下，於含實例8製得之化合物1 3之甲酸（ 200ml)溶液中，添加50 % )钯-磺粉末（0.90g),且混合物 於室溫及氫氣中攪拌2小時。使反應混合物濃縮且殘留物 分配於二氛甲烷與飽和磺酸氫鈉之間，水層以二氣甲烷萃 取且萃取液與有機層合併，混合物以MgS〇4脱水並於減壓 下蒸除溶劑。殘留物藉矽膠管柱層析法純化，得無色粉末 (5.13g, 60%)。所得化合物（lOOmg)溶於乙酸乙酯（4ml) 中，並在冰冷却下於該溶液中添加於***中之氣化氫1 Ν溶 液（0.3ml)且混合物於冰冷却下攪拌10分鐘。反應混合物 於減壓下濃縮且殘留物自乙酸乙酯-***中結晶，得白色 結晶之標的化合物之塩酸塩（95nig)。 in. P . 1 6 2 - 1 6 5 Ό 經濟部中央標準局貝工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 元素分析：C35H30N4O3SF· 2.0HC1· 1·ΟΗ2〇 Ζ{% ) Η ( % ) Ν ( % ) 計算值：58.74; 4.79； 7.83 實測值：5 8 · 4 4 ; 4.72； 7.66 IR (KBr) ： 1 7 1 5 , 1 6 5 9 , 1 5 3 7, 1 4 7 3 cm~ 1 〇 奮例10 由實例8所得之化合物起始，依實例9之方法製得表 1 1所列化合物。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 72 483896 五、發明説明（7 3 ) 表 11The size of this paper applies Chinese National Standard (CNS) M specifications (210X: Z97 mm) 483896 Orders from the Ministry of Economic Affairs of the Bureau of Consumption and Co-operation of Employees Du Printing 5. Description of the Invention (71) Example 8 Compound No. R2 R14, Rl5 R4 R yield ⑷ mp (Ό) 1 methylchloropropyl 2,6-difluoromethylchlorophenyl 69 95-100 2 3-methylthiophenyl 2,6-dimethoxymethoxyphenyl 94 139- 144 3 3-methylsulfinyl phenyl 2,6-dichloromethylphenyl 93 153-156 4 3-methylsulfonyl phenyl 2,6-dichloromethylphenyl 98 155-159 5 Isobutyl 2-aminomethylchlorophenyl 100 150-153 6 Isobutyl 2,6-difluoromethylamino phenyl 98 165-167 7 Methyethyl 2-aminomethoxyphenyl 95 154 -156 8 Methyethyl 2,6-difluoromethylchlorophenyl 91 126-130 9 3,5-dimethoxyphenyl 2, 90methoxy phenyl 90 140-145 10 3,5-di Methoxyphenyl 2,6-dimethoxymethoxyphenyl 91 146-148 11 3,5-Dimethoxyphenyl 2,6-difluoronitrophenyl 97 142-146 12 Phenyl 2,6- Dinitronitrophenyl 93 152-153 13 3-methylphenyl 2,6-difluoronitrophenyl 82 142-144 14 3-isopropylphenyl 2,6-dinitronitrobenzene 70 Amorphous (80-90) 15 3-isopropylphenyl 2,6-difluoronitro 2-thiomethylphenyl 16 3-isopropylphenyl 2,6-difluoronitro 2-pyridine Group 17 3-methoxyphenyl 2,6-difluoronitro 2-thiomethylphenyl 18 3-methoxyphenyl 2,6-difluoronitro 2-pyridyl 19 3-ethoxyphenyl 2 1,6-Difluoronitrophenyl 93 171-176 20 3-Prochlorochlorophenyl 2,6-Difluoronitrophenyl 86 149-151 21 3-Methylchlorophenyl 2,6-dinitronitro Phenyl phenyl 86 110-120 22 3-Hydroxyphenyl 2. 6-dinitronitrophenyl 86 207-209 23 3-methoxyphenyl 2,6-difluoronitrodiethylaminomethyl 24 3 -Methoxyphenyl 2,6-difluoronitrotrimethylaminomethyl 25 3-methoxyphenyl 2,6-difluoronitro 1-pyridinylmethyl (please read the precautions on the back first) (Fill in this page again) This paper size is in accordance with Chinese National Standard (CNS) A4 (210X: 297 mm) 71 483896 A7 B7 V. Description of the invention (72) Fen example 9 6-U-aminophenyl), 2,4 (1H, 3H) _dichloro-1- (2,6-digasbenzyl) -5- (N-benzyl-N-methylaminomethyl) -3- (3-methoxybenzene Group) 〇 * phen well [2,3-d] pyrimidine hydrazone is manufactured in Under cooling, to obtain the compound containing the carboxylic acid prepared in Example 8 of 13 (200ml) was added 50%) palladium - sulfo powder (0.90 g), and the mixture was stirred at room temperature for 2 hours and hydrogen gas. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated sodium hydrogen sulfonate. The aqueous layer was extracted with methane and the extract was combined with the organic layer. The mixture was dehydrated with MgS04 and the solvent was evaporated under reduced pressure. . The residue was purified by silica gel column chromatography to obtain a colorless powder (5.13 g, 60%). The obtained compound (100 mg) was dissolved in ethyl acetate (4 ml), and a solution of hydrogenated 1N in diethyl ether (0.3 ml) in ether was added to the solution under ice cooling, and the mixture was stirred under ice cooling for 10 minutes. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethyl acetate-diethyl ether to give the target compound (95 nig) as white crystals. in. P. 1 6 2-1 6 5 印 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Elemental analysis: C35H30N4O3SF · 2.0HC1 · 1 · ΟΗ2〇Z { %) Η (%) Ν (%) Calculated: 58.74; 4.79; 7.83 Found: 5 8 · 4 4; 4.72; 7.66 IR (KBr): 1 7 1 5, 1 6 5 9, 1 5 3 7, 1 4 7 3 cm ~ 10 Example 10 Starting from the compound obtained in Example 8, the compounds listed in Table 11 were prepared according to the method of Example 9. This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 72 483896 V. Description of Invention (7 3) Table 11

經濟部中央橾準局員工消費合作社印製 實例10 化合物编號 R2 R14,R15 R 産率 ⑷ Q1.P. (V) 1 3,5-二甲氧苯基 2,、6-二氣 苯基 69 95-100 2 苯基 2,6-二氣 苯基 94 139-144 3 3-異丙氯苯基 2,6-二氣 苯基 77 138-140 4 3-異丙氯苯基 2,6-二氣 甲硫苯基 5 3-異丙氧苯基 2,6-二氣 2-吡啶基 6 3-甲氧苯基 2,6-二氣 2-甲硫苯基 7 3-甲氣苯基 2,6-二氣 2-吡啶基 8 3-乙氧苯基 2,6-二氣 苯基 67 169-172 9 3-丙氯苯基 2,6-二氣 苯基 73 115-120 10 3-甲氧苯基 2,6-二氣 二乙胺甲基 11 3-甲氣苯基 2·6-二氟 二甲胺甲基 12 3-甲氣苯基 2·6-二氣 1-吡咯啶基甲基 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 73 :裝-- (請先閲讀背面之注意事項再填寫本頁) 483896 A7 B7 五、發明説明（7 4 ) 曹例1 1 2,4(113^〇-二氣代-1-(2,6-二氣苯甲基）-5-(«-苯甲基 -N-甲胺基甲基）-6-(4-甲醯胺基苯基）-3-苯基噬吩并[ 2, 3-d]嘧啶之製造 在冰冷却下將甲酸（0 . 5 πι 1 , 1 3 · 3 m π» ο 1 )添加至乙酸酐（ l.Onil, 10.6mniol)中，混合物在5〇1〇攪拌1小時，得甲酸 -乙酸酐。在冰冷却下，於含實例10所得化合物2 ( 2 0 0 mg , 0.34mmol)之四氫呋喃（10ml)溶液中添加該甲酸-乙酸酐（ 0 3 m 1 )且混合物襯拌3 0分鐘。混合物攪拌1小時，於減壓 下濃縮反應混合物，殘留物藉矽膠管柱層析法純化，得無 色固體物質之標的化合物（125nig)。 m· p . 1 9 4 - 1 9 6 t： 一裝-- (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumers Cooperative of the Central Bureau of Quasi-Staff of the Ministry of Economic Affairs 10 Compound No. R2 R14, R15 R Yield ⑷ Q1.P. 69 95-100 2 phenyl 2,6-difluorophenyl 94 139-144 3 3-isochlorochlorophenyl 2,6-difluorophenyl 77 138-140 4 3-isochlorochlorophenyl 2,6 -Digasmethylthiophenyl 5 3-isopropoxyphenyl 2,6-digas 2-pyridyl 6 3-methoxyphenyl 2,6-digas 2-methylthiophenyl 7 3-methylbenzene 2,6-Dioxoyl 2-pyridyl 8 3-ethoxyphenyl 2,6-dioxophenyl 67 169-172 9 3-propylchlorophenyl 2,6-dioxophenyl 73 115-120 10 3-methoxyphenyl 2,6-difluorodiethylamine methyl 11 3-methoxyphenyl 2,6-difluorodimethylamine methyl 12 3-methoxyphenyl 2,6-digas 1 Pyrrolidylmethyl This paper is sized for the Chinese National Standard (CNS) A4 (210X297 mm) 73: Packing-(Please read the precautions on the back before filling this page) 483896 A7 B7 V. Description of the invention (7 4)曹 例 1 1 2,4 (113 ^ 〇-digaso-1- (2,6-digas benzyl) -5-(«-benzyl-N-methylaminomethyl) -6- (4-formamidophenyl) -3-phenylphanobenzo [ Production of 2, 3-d] pyrimidine Under ice cooling, formic acid (0.5 μm 1, 1 3 · 3 m π »ο 1) was added to acetic anhydride (l.Onil, 10.6mniol), and the mixture was at 501. 〇 Stir for 1 hour to obtain formic acid-acetic anhydride. Under ice cooling, add the formic acid-acetic anhydride (0 3 m 1) to a solution containing compound 2 (200 mg, 0.34 mmol) obtained in Example 10 in a tetrahydrofuran (10 ml) solution. And the mixture was stirred for 30 minutes. The mixture was stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (125nig) as a colorless solid substance. M · p. 1 9 4 -1 9 6 t: one pack-(Please read the notes on the back before filling this page)

-1T 經濟部中央標準局員工消費合作社印製 元素分析：C35H3〇H4〇3SF2*0.5H2〇 C ( % ) Η ( % ) Ν ( % ) 計 算值： 66.55； 4 . 63 ； 8.87 實 測值： 66,74； 4 . 56 ； 8.88 1 Η -HHR ( 3 0 0 ΜΗ ζ , CDC 1 3 ) 5 : 3 · 57 (2H » s ) > 3.90( 2H , s) · 5 . 37 (2Η , s ), 6 . 90-7 • 30 (12Η , m )，7 · 34-7 • 79 (6H ,m ), 8 . 42 (1Η , S ) 〇 IR (K B r )： 171 5 , 1 6 6 5 , 1531 , 1 46 7 c m ~ 1 〇 實 例12 自實 例9 或 10所 得化合物起始， 依實 例11所 述方法製 得 表12所 列化 合 物。 7 4 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 483896-1T Analysis of printed elements of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: C35H3〇H4〇3SF2 * 0.5H2〇C (%) Η (%) Ν (%) Calculated value: 66.55; 4.63; 8.87 Found: 66 , 74; 4. 56; 8.88 1 Η -HHR (300 ΜΗ ζ, CDC 1 3) 5: 3 · 57 (2H »s) > 3.90 (2H, s) · 5. 37 (2Η, s) , 6.90-7 • 30 (12Η, m), 7.34-7 • 79 (6H, m), 8. 42 (1Η, S) 〇IR (KB r): 171 5, 1 6 6 5, 1531, 1 46 7 cm ~ 10 Example 12 Starting from the compound obtained in Example 9 or 10, the compounds listed in Table 12 were prepared according to the method described in Example 11. 7 4 This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) 483896

A B 五、發明説明（75 ) 表 12厂R CH-CH:'rr CH〇-NH"^A B V. Description of the invention (75) Table 12 Plant R CH-CH: 'rr CH〇-NH " ^

經濟部中央標準局員工消費合作社印製 實例12 化合物编號 R2 R14,R15 R 産率 m. p. (1C) 1 3,5-二甲氣苯基 2,6-二氣 苯基 55 239-243 2 3-甲氣苯基 2,6-二氣 苯基 56 213-215 3 3-異丙氣苯基 2,6_ 二氣 苯基 4 3-異丙氧苯基 2,6-二氣 2-甲硫苯基 5 3-異丙氣苯基 2,6-二氣 2-吡啶基 6 3-甲氧苯基 2,6-二氣 2-甲硫苯基 7 3-甲氧苯基 2,6-二氣 2-吡啶基 • (請先閱讀背面之注意事項再填寫本頁) d 項再填- 裝· 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）75 483896 經濟部中央標準局員工消费合作社印製 A7 B7 五、發明説明（76 ) 奮例13 2,4(111,3叼-二氯代-1-(2,6-二氣苯甲基）-5-(1^苯甲基 -N -甲胺基甲基）-6-(4-甲胺基苯基）-3 - (3 -甲氣苯基）〇*吩 并 [2 ,3 -d ]嘧啶塩酸塩之製 造 在 冰 冷却下， 於 含實例1 2所得化合物2 (7 3 0 m g , 1 . 12 mm 〇1)之四氫呋喃（30m 1 )溶液中添 加二 甲硫醚硼烷（ 0 . 28 ml 2 8 m m ο 1 ), 且混合 物回流加熱 2小 時。添加塩酸（ pH <2 )接著回流加熱1 小時 後， 所得物 予以 濃縮且殘留物 分 配 於 二 氮甲烷及 飽 和碩酸氫 鈉之間。 水層以二氛甲烷萃 取 9 萃 取 液與有機 層 合併， 混 合物以Μ g S 0 4 脱水並於減壓 下 蒸 除 溶 劑。殘留 物 以矽膠管 柱層析法純化，得無色粉末 (6 10 mg 9 8 5 % ) 〇 在 ¢1 c冷却 下， 於含此 所得 化合物之乙酸 乙 酯 (4 m 1 )溶液中， 添加於 ***中之氛 化氫 1 N 溶液（0 · 3 πι 1 ) $ 且 混 合 物於冰冷 却 下攪拌10分鐘。在減壓下濃縮反應混 合 物 所 得 之殘留物 進 行結晶， 得白色結晶之標的化合物之 塩 酸 塩 (9 5 m g )。 ID . P . 155- 1601C 元 素 分 析 * C 3 5 Η 3 〇 N4 0 3 S F 2 • 2 • 0HC 1 · 0 . 5 A cOEt · 3 . 0 Η 2〇 C ( r〇 ) Η ( % ) Ν (为 計 算 值 56.36； 5 . 47 ； 6 . 9 1 實 測 值 ·· 56.08； 5 . 22 ； 6.86 IR (KBr .): :1 715, 1663, 1 6 0 7 , 1 5 4 3 , 1475 -1 cm 1 〇 奮例1 4 2, 4(1H,3H)-二氱代-1-(2,6-二氣苯甲基）-6-(4-丙 K 按基 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 7 6 ^-- (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消费合作社印製 483896 A7 B7 五、發明説明（7 7 ) 苯基）-5-(N-苯甲基-N-甲胺基甲基）-3-(3 -甲氯苯基®吩 并[2, 3-d]嘧啶塩酸塩之製法 在冰冷却下，於含實例9所得化合物（2 5 0 m g， 0.33mraol)之二氛甲烷（10ml)溶液中添加三乙胺（0.053rag, ,0.38mmol)及丙醯氛（0.0 33ml, 0.33maiol)，且混合物攪 拌1小時。反應混合物分配於二氛甲烷及飽和碩酸氫鈉之 間，水層以二氛甲烷萃取，使萃取液合併，合併之萃取液 以氣化鈉水溶液洗滌並以M g S 0 4脱水，及於減壓下蒸除溶 劑。殘留物藉矽膠管柱層析法純化，得無色油狀物質（ 220mg, 82%)。在冰冷却下，於含所得醯基衍生物之乙酸 乙酯（4 m 1 )溶液中，添加於***中之1 N塩酸溶液（0 · 3 οι 1 )， 且混合物在冰冷却下攪拌10分鐘。於減®下濃縮反應混合 物，使殘留物結晶化得白色結晶之標的化合物之塩酸塩（ 2 1 3 m g ) 〇Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 12 Compound No. R2 R14, R15 R Yield mp (1C) 1 3,5-Dimethylphenyl 2,6-diphenylphenyl 55 239-243 2 3 -Methanephenyl 2,6-diaminophenyl 56 213-215 3 3-isopropylphenyl 2,6_ diaminophenyl 4 3-isopropyloxyphenyl 2,6-dimethyl 2-sulfan Phenyl 5 3-isopropylphenyl 2,6-digas 2-pyridyl 6 3-methoxyphenyl 2,6-digas 2-methylthiophenyl 7 3-methoxyphenyl 2,6- Digas 2-pyridyl • (Please read the notes on the back before filling out this page) Item d is refilled-Binding · The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 75 483896 Central Ministry of Economic Affairs Printed by A7 B7, Consumer Cooperatives of the Bureau of Standards V. Description of the Invention (76) Example 13 2,4 (111,3 叼 -dichloro-1- (2,6-digas benzyl) -5- (1 ^ Benzyl-N-methylaminomethyl) -6- (4-methylaminophenyl) -3-(3-methylphenyl) o * pheno [2,3-d] pyrimidinesulfonate Manufactured under ice cooling, and added to a tetrahydrofuran (30m 1) solution containing Compound 2 (7 30 mg, 1.12 mm 〇1) obtained in Example 12 Methyl sulfide borane (0. 28 ml 2 8 mm ο 1), and the mixture was heated under reflux for 2 hours. After adding osmic acid (pH < 2) followed by heating under reflux for 1 hour, the resultant was concentrated and the residue was partitioned into diazonium Methane and saturated sodium bisulfate. The aqueous layer was extracted with dichloromethane. 9 The extract was combined with the organic layer. The mixture was dehydrated with MgSO 4 and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. Purified by method to obtain a colorless powder (6 10 mg 9 8 5%) 〇 Under ¢ 1 c cooling, in a solution of the obtained compound in ethyl acetate (4 m 1), add 1N of hydrogenated ether in ether The solution (0 · 3 πι 1) was added and the mixture was stirred under ice-cooling for 10 minutes. The residue obtained by concentrating the reaction mixture under reduced pressure was crystallized to obtain the target compound of white crystals (9 5 mg). ID. P 155- 1601C Elemental Analysis * C 3 5 Η 3 〇N4 0 3 SF 2 • 2 • 0HC 1 · 0.5 A cOEt · 3. 0 Η 2〇C (r〇) Η (%) Ν (calculated value) 56.36; 5.47 6.9 Measured 56.08; 5.22; 6.86 IR (KBr.):: 1 715, 1663, 1 6 0 7, 1 5 4 3, 1475 -1 cm 1 〇Example 1 4 2, 4 (1H, 3H) -Dioxo-1- (2,6-digas benzyl) -6- (4-propyl K Applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) according to basic paper size ) 7 6 ^-(Please read the notes on the back before filling out this page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 483896 A7 B7 V. Description of the invention (7 7) Phenyl) -5- (N- Preparation of benzyl-N-methylaminomethyl) -3- (3-methylchlorophenyl® benzo [2, 3-d] pyrimidinepyridinium sulfonium acid, under ice cooling, containing the compound obtained in Example 9 (2 5 0 mg, 0.33 mraol) of dichloromethane (10 ml) was added with triethylamine (0.053rag, 0.38 mmol) and propane (0.0 33 ml, 0.33 maiol), and the mixture was stirred for 1 hour. The reaction mixture was partitioned between methane and saturated sodium bisulfate. The aqueous layer was extracted with methane and the extracts were combined. The combined extracts were washed with a gasified sodium aqueous solution and dehydrated with M g S 0 4. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless oily substance (220mg, 82%). To a solution of the ethyl acetate (4 m 1) containing the obtained fluorenyl derivative under ice cooling, a 1 N acetic acid solution (0 · 3 οι 1) in diethyl ether was added, and the mixture was stirred under ice cooling for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized to obtain white crystals of the target compound (2,13 mg).

m.p . 2 1 8 - 22 4 TC IR(KBr)： 1 7 1 3, 1 6 6 5, 1 6 0 1, 1 5 43, 1 4 7 5 c in ^ 1 〇 奮例15 自實例9或1 0所得之化合物起始，依實例1 4之方法製 備表1 3所列之化合物。 表 13mp. 2 1 8-22 4 TC IR (KBr): 1 7 1 3, 1 6 6 5, 1 6 0 1, 1 5 43, 1 4 7 5 c in ^ 1 〇 Example 15 from Example 9 or 1 Starting from the compounds obtained in 0, the compounds listed in Table 13 were prepared according to the method of Example 14. Table 13

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ¾-- (請先閱讀背面之注意事項再填寫本頁) 訂 4 77 483896 經濟部中央橾隼局員工消费合作社印製 五、發明説明（78 ) 實例15 化合物编號 R2 R4’ R 産率 (%) πι.ρ. (X) 1 3-甲氧苯基 異丁醯胺基 苯基 85 170-173 2 苯基 異丁醯胺基 苯基 67 185-190 3 3,5-二甲氯苯基 丙醯胺基 苯基 82 218-224 4 3,5-二甲氣苯基 異丁醯胺基 苯基 76 240-245 5 3-甲氣苯基 田甚 丙醯胺基 苯基 84 138-143 6 3-甲氣苯基 甲基-Ν -異丁醯胺基 苯基 91 146-152 7 苯基 丙醯胺基 苯基 78 197-202 8 苯基 丁醯胺基 苯基 76 169-170 9 苯基 苯甲醯胺基 苯基 81 167-169 10 3-甲氣苯基 丙m胺基 苯基 83 170-175 11 3-異丙氣苯基 異丁醯胺基 苯基 12 3-異丙氯苯基 異丁醯胺基 2-甲硫苯基 13 3-異内氧苯基 異丁 m胺基 2-吡啶基 14 3-甲氧苯基 異丁醯胺基 3-甲硫苯基 15 3-甲氧苯基 異丁醯胺基 2-吡啶基 16 3-異丙氯苯基 丙醯胺基 苯基 94 179-181 17 3-乙氣苯基 丙醯胺基 苯基 67 164-168 18 3-丙氣苯基 丙m胺基 苯基 87 165-170 19 3-甲氧苯基 乙磺醯胺基 苯基 20 3-甲氧苯基 三氟乙醯胺基 苯基 21 3-甲氯苯基 異丁醯胺基 二乙胺甲基 22 3-甲氣苯基 異丁醯胺基 二甲胺甲基 23 3-甲氣苯基 異丁醯胺基 卜吡咯啶甲基 -裝— (請先閱讀背面之注意事項再填寫本頁)This paper size applies to China National Standard (CNS) A4 (210X297 mm) ¾-(Please read the precautions on the back before filling out this page) Order 4 77 483896 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs Description of the Invention (78) Example 15 Compound No. R2 R4 'R Yield (%) π.ρ. (X) 1 3-methoxyphenylisobutylamidinophenyl 85 170-173 2 phenylisobutylamidine Aminophenyl 67 185-190 3 3,5-Dichlorochlorophenylpropanylaminophenyl 82 218-224 4 3,5-Dimethylphenylphenyl isobutylamidinophenyl 76 240-245 5 3-methylaminophenyl ciprofenaminophenyl 84 138-143 6 3-methylaminophenyl-N-isobutylamidophenyl 91 91-146-152 7 phenylpropylaminophenyl 78 197-202 8 Phenylbutanylaminophenyl 76 169-170 9 Phenylbenzylaminophenyl 81 167-169 10 3-Methylphenylpropylaminoamino 83 83-175 11 3 -Isopropylphenyl isobutylamidinophenyl 12 3-isochlorophenyl isobutylamidino 2-methylthiophenyl 13 3-isoendophenyl isobutyl mamino 2-pyridyl 14 3-methoxyphenylisobutylamido 3-methylthiophenyl 15 3-methyl Oxyphenyl isobutylamidino 2-pyridyl 16 3-isochlorochloropropionamidinophenyl 94 179-181 17 3-ethoxyphenylpropylamidinophenyl 67 164-168 18 3- Propane phenylpropylamine amino phenyl 87 165-170 19 3-methoxyphenyl ethylsulfonamidophenyl 20 3-methoxyphenyl trifluoroacetamidophenyl 21 3-methylchlorophenyl Isobutylamidodiethylamine methyl 22 3-methylphenyl isobutylamidodimethylamine 23 23 3-methylphenyl isobutylamidopyrrolidine methyl-pack — (please first (Read the notes on the back and fill out this page)

，1T 本紙張尺度適用中國國家標準（CNS ) Μ規格（210 X 297公釐） 78 483896 A7 B7 五、發明説明（79 ) 奮例1 6 本質上依實例1 4所述相同程序，使用實例9或1 0所得 化合物及使用三氣乙酸酐取代丙醯氛，得三氣乙醯胺基衍 生物。在適宜鹸（如碩酸鉀）存在下，於不影響反應之溶劑 (如二甲基甲醯胺）中，於該衍生物中添加鹵基衍生物（如 丙基溴異丙基溴），混合物.在室溫攪拌1至6小時。於反 應混合物中添加2 N氫氣化鈉水溶液供水解1至2小時，得 表1 4所列化合物。 表 14， 1T This paper size applies the Chinese National Standard (CNS) M specification (210 X 297 mm) 78 483896 A7 B7 V. Description of the invention (79) Example 1 6 In essence, the same procedure as described in Example 1 4 is used, using Example 9 Alternatively, the compound obtained by 10 and triacetic acid anhydride is used instead of propane, to obtain trigas acetamido derivative. Add a halogenated derivative (such as propyl bromoisopropyl bromide) to the derivative in a solvent that does not affect the reaction (such as dimethylformamide) in the presence of a suitable hafnium (such as potassium sulfonate), Mixture. Stir at room temperature for 1 to 6 hours. To the reaction mixture was added a 2 N aqueous sodium hydrogen solution for hydrolysis for 1 to 2 hours to obtain the compounds listed in Table 14. Table 14

;裝-- (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央樣隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS〉A4規格（210 X297公釐） 79 483896 A7 B7 五、發明説明（8〇 ) 經濟部中央標準局員工消費合作社印製 實例16 化合物编號 R2 R4 · R 1 3 -甲氣苯基 丙胺基 苯基 2 3-甲氯苯基 異丙胺基 声基 3 3 -異丙、氧苯基 丙胺基 苯基 4 3 -異丙氯苯基 異丙胺基 苯基 5 3-異丙氣絮基 丙胺基 2-甲硫苯基 6 3-異丙氯苯基 丙胺基 2 -啦啶基 7 3-異丙氯苯基 異丙胺基 2-甲硫苯基 8 3 -異丙氯苯基 異丙胺基 2 -吼啶基 9 3-甲氯苯基 乙胺基 苯基 10 3-異丙氣苯基 乙胺基 苯基 11 3-甲氣苯基 異丙胺基 2-甲硫苯基 12 3-甲氯苯基 異丙胺基 2 - €啶基 13 3 -甲氣苯基 丙胺基 2 -甲硫苯基 14 3-甲氣苯基 丙胺基 2-吡啶基 15 3-甲氣苯基 丙胺基 二乙胺甲基 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 80 483896 A7 B7 五、發明説明（8 1 ) 曹例1 7 使用實例9或1 〇所得化合物作為起始物，$ ^ ® $ & 合物與異戊腈、乙烯基化合物及把化合物（如肆三苯薛®， 二苯亞甲基丙酮粑）於乙酸中在室溫或加熱下樓伴1至6 小時而反應，製得表1 5所列化合物。 請 先 閲 面; Install-(Please read the precautions on the back before filling this page) Order the paper printed by the Central Consumer Samples Cooperative of the Ministry of Economic Affairs. The paper size applies to Chinese national standards (CNS> A4 (210 X297 mm) 79 483896 A7 B7 V. Description of the invention (80) Example printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 16 Compound No. R2 R4 · R 1 3 -methylphenylpropylaminophenyl 2-methylchlorophenylisopropylamine 3 3 -isopropyl, oxyphenylpropylaminophenyl 4 3 -isochlorochloroisopropylaminophenyl 5 3 -isopropylcarbamoyl 2-methylthiophenyl 6 3-isopropylchlorobenzene Propylamino 2 -laridinyl 7 3-isochlorochloroisopropylamino 2-methylthiophenyl 8 3 -isopropylchlorophenyl isopropylamino 2 -carolinyl 9 3-methylchlorophenylethylamine Phenylphenyl 10 3-isopropylphenylethylaminophenyl 11 3-methylphenylphenylisopropylamine 2-methylthiophenyl 12 3-methylchlorophenylisopropylamine 2-€ pyridyl 13 3- Methylphenylalanyl 2-methylthiophenyl 14 3-methylphenylalanyl 2-pyridyl 15 3-methylphenylalanyldiethylamine methyl (Please read the notes on the back first (Fill in this page again.) This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 80 483896 A7 B7 V. Description of the invention (8 1) Cao Example 1 7 Use the compound obtained in Example 9 or 10 as the starting point Compounds, $ ^ ® $ & compounds with isovaleronitrile, vinyl compounds, and compounds (such as Tribenzyl®, diphenylmethyleneacetone) in acetic acid at room temperature or heated downstairs with 1 to 6 hours of reaction to obtain the compounds listed in Table 15. Please read

經 濟 部 中 央 樣 準 % 貝 X 消 費 合 作 杜 印 製 實例17 化合物编號 R2 R4， R 1 3-甲氧苯基 乙氯羰基乙烯基 苯基 2 3-甲氧苯基 乙氧羰基乙烯基 2-甲硫苯基 3 3-甲氯苯基 乙氣羰基乙烯基 2-啦症基 4 3-甲氯苯基 丙醯基乙烯基 苯基 5 3-甲氣苯基 丙醯基乙烯基 2-甲硫苯基 6 3-甲氣苯基 丙醯基乙烯基 2-flit啶基 7 3-異丙氣苯基 乙氧羰基乙烯基 苯基 8 3-異丙氣苯基 丙醯基乙烯基 苯基 9 3-異丙氣苯基 乙氣羰基乙烯基 2-甲硫苯基 10 3-異丙氣苯基 乙氣羰基乙烯基 2 - Bit淀基 11 3-異丙氣苯基 丙醯基乙烯基 2 -甲硫基苯基 12 3-異丙氯苯基 丙醯基乙烯基 2-吡啶基 13 3-甲氣苯基 丙醯基乙烯基 二甲胺基甲基 14 3-甲氯苯基 丙醛基乙烯基 卜吡咯啶基甲基 15 3-甲氧苯基 丙醯基乙烯基 二乙胺基甲基 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 訂 t 81 483896 A7 __B7 五、發明説明（82 ) 窨例18 於含參考例9所得之化合物3 0或3 1、少量芳基硼酸衍 生物、2M 5戾酸鈉水溶液及1,2 -二甲氣乙烷之混合物中，添 加催化量之肆（三苯膝）把（0 ),且因而所得之混合物回流 攪拌2小時。於所得化合物中，依據參考例26及實例1所 述方法導入N -甲基苯甲胺基，而得表1 6所列化合物。 表 16 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消资合作社印製 實例1 3 化合物编號 R2 R4 · 1 3 -甲\<苯基 丙胺羰基 2 3-異丙氧苯基 \ 丙胺羰基 3 \ 3 -甲氣苯基 異丙胺羰基 4 3-異丙氣苯基 異丙胺羰基 5 3 -甲氧苯基 乙胺羰基 6 3-甲氧苯基 N -甲基-N -丙胺羰基Central sample of the Ministry of Economic Affairs% Beijing X Consumption Cooperation Du printed example 17 Compound No. R2 R4, R 1 3-methoxyphenylethylchlorocarbonylvinylphenyl 2- 3-methoxyphenylethoxycarbonylvinyl2- Methylthiophenyl 3 3-methylchlorophenyl ethyl carbonylvinyl 2-lazyl 4 3-methylchlorophenylpropanylvinylphenyl 5 3-methylchlorophenylpropanylvinyl 2-methyl Thiophenyl 6 3-methylphenylphenylpropenylvinyl 2-flitpyridyl7 3-isopropylphenylphenylethoxycarbonylvinylphenyl 8 3-isopropylphenylpropionylvinylphenyl 9 3-Isopropylphenylethylcarbonylcarbonylvinyl 2-methylthiophenyl 10 3-Isopropylphenylethylcarbonylcarbonylvinyl 2-Bit Lake 11-Isopropylphenylphenylpropylvinyl 2-methylthiophenyl 12 3-isochlorochloropropionylvinyl 2-pyridyl 13 3-methylphenylpropionylvinyldimethylaminomethyl 14 3-methylchlorophenylpropyl Aldol vinyl pyrrolidinyl methyl 15 3-methoxyphenylpropanyl vinyl diethylamino methyl This paper is dimensioned to Chinese National Standard (CNS) A4 (210X297 mm) Order t 81 483896 A7 __B7 V. Description of the invention (82) Example 18 In a mixture containing the compound 30 or 31 obtained in Reference Example 9, a small amount of an arylboronic acid derivative, a 2M aqueous solution of sodium phosphonium 5 and a mixture of 1,2-dimethylethane. , A catalytic amount of triphenylene (triphenyl knee) was added (0), and the resulting mixture was then stirred under reflux for 2 hours. Among the obtained compounds, N-methylbenzylamino groups were introduced according to the methods described in Reference Example 26 and Example 1 to obtain the compounds listed in Table 16. Table 16 (Please read the notes on the back before filling this page) Example printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 1 3 Compound No. R2 R4 · 1 3 -methyl \ < phenylpropylamine carbonyl 2 3-iso Propoxyphenyl \ propylamine carbonyl 3 \ 3-methoxyphenyl isopropylamine carbonyl 4 3-isopropylphenyl isopropylamine carbonyl 5 3 -methoxyphenylethylamine carbonyl 6 3-methoxyphenyl N-methyl -N -propylamine carbonyl

本紙浪尺度適用中國國家標準（CNS ) A4規格（210X；297公釐） 82 483896The paper scale is applicable to China National Standard (CNS) A4 (210X; 297 mm) 82 483896

7 B7 B

五、發明説明（83 在冰冷却下，於含實例2所得化合物之二氛甲烷中， 添加3當量二甲硫醚及3當量氮化鋁。此混合物攪拌1至 4小時而得R 4酚衍生物。因而所得化合物與少量烷基_ ( 如氯丙酮）及鹼（如磺酸鉀）於二甲基甲醯胺中混合，得表 1 7所列化合物。 表 17 (請先閲讀背面之注意事項再填寫本頁) -裝· 經濟部中央標準局員工消費合作社印製 實 例19 R2 R 4， R 化 合物编號 1 苯 基 丙 m 氧 基 苯 基 2 苯 基 丙 酮 氣 基 2- 甲 硫 苯 基 3 苯 基 丙 m 氧 基 2- 吡 啶 基 4 苯 基 丙 酮 氯 基 二 乙 胺 甲 基 5 苯 基 丙 酮 m 基 二 甲 胺 甲 基 6 苯 基 丙 _ 氣 基 1 - 吡 咯 淀 基甲基 7 苯 基 烯 丙 氯 基 苯 基 8 苯 基 丙 氣 基 苯 基 9 苯 基 異 丁 氣 基 苯 基 10 苯 基 環 丙 基 甲氣基 苯 基 11 苯 基 烯 丙 氣 基 二 乙 胺 甲 基 12 苯 基 丙 氧 基 二 乙 胺 甲 基 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 83 訂 483896 A7 B7 五、發明説明（84 ) 奮例20 使用實例4製得之化合物（1 0 0 m g ),乳糖（1 6 5 in g ),玉 米澱粉（5 m g ),聚乙烯醇（4 m g )及硬脂酸鎂（1 in g ),依一般 方法製備錠劑。 窨例2 1 實例4製得化合物（5 g )溶於注射用蒸餾水，使總量成 100ml。此溶液經0.22// m濾膜（住友電子工業株式会社， 或Zartolius Inc.製造）無菌過減，各取2ml分装入無菌小 瓶，接著冷凍乾燥，製備凍乾注射溶液l〇〇mg/小瓶。 奮例22 實例1 5製得之化合物1 (1 0 0 m g ),乳糖（1 6 5 m g ),玉米 澱粉（25mg),聚乙烯醇（4mg)及硬脂酸鎂（ling), K —般方 法製備錠劑。 奮例23 實例1 5製得之化合物1 (5 d溶於注射用蒸餾水，使總 量成100ml。此溶液經0.22/im濾膜（住友電子工業株式会 (請先閱讀背面之注意事項再填寫本I) 裝V. Explanation of the invention (83) Under ice cooling, 3 equivalents of dimethyl sulfide and 3 equivalents of aluminum nitride were added to the dichloromethane containing the compound obtained in Example 2. The mixture was stirred for 1 to 4 hours to obtain an R 4 phenol derivative. Therefore, the obtained compound is mixed with a small amount of alkyl (such as chloroacetone) and a base (such as potassium sulfonate) in dimethylformamide to obtain the compounds listed in Table 17. Table 17 (Please read the precautions on the back first (Fill in this page again)-Example of printing by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 19 R2 R 4, R Compound No. 1 Phenylpropanyl oxyphenyl 2 Phenylacetone 2-methylthiophenyl 3 Phenylpropanyloxy 2-pyridyl 4 Phenylacetone chlorodiethylamine methyl 5 Phenylacetone myl dimethylamine methyl 6 Phenylpropanyl 1-pyrrolidylmethyl 7 phenylene Prochlorochlorophenyl 8 Phenylpropanylphenyl 9 Phenylisobutanylphenyl 10 Phenylcyclopropylmethylaminophenyl 11 Phenylallyldiethylaminemethyl 12 Phenylpropoxy Diethylamine methyl This paper applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 83 Order 483896 A7 B7 V. Description of the invention (84) Fen Example 20 Compound (100 mg) prepared using Example 4 Lactose (165 in g), corn starch (5 mg), polyvinyl alcohol (4 mg), and magnesium stearate (1 in g) were prepared according to the usual methods. Example 2 1 Example 4 Compounds (5 g) was dissolved in distilled water for injection to make a total of 100 ml. This solution was over-sterilized through a 0.22 // m filter (manufactured by Sumitomo Electronics Industries, Ltd., or Zartolius Inc.), and 2 ml each was filled into sterile vials. And then freeze-drying to prepare a lyophilized injection solution 100 mg / vial. Fen Example 22 Compound 1 (100 mg) prepared in Example 15 of Example 15, lactose (165 mg), corn starch (25 mg), poly Vinyl alcohol (4 mg) and magnesium stearate (ling), K—prepared lozenges. Example 23 Compound 15 prepared in Example 15 (5 d) was dissolved in distilled water for injection to make a total of 100 ml. This solution Filtered through 0.22 / im (Sumitomo Electronics Industrial Co., Ltd. (Please read the precautions on the back before filling in this I).

、1T 經濟部中央標準局員工消費合作杜印製 社， 或 乙a r t ο 1 i U S In c . 製 造 )無薗過濾， 各取2m 1 分装 入無 菌小 瓶 $ 接 著 冷 凍 乾 燥 $ 製 得凍乾注射 溶液1 0 0 m g /小 瓶。 蓄例 24 ⑴ 實 施 例 4 製 得 之 化 合 物 或實例1 5製 得之化合 物1 5 g (2) 乳 糖 ♦ 結 晶 纖 維 素 (顆粒） 3 3 0 g (3) D- 甘 露 糖 醇 29g (4) 低 取 代 之 羥 丙 基 纖 維 素 20g (5) 石 25g 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 。4 8 4 483896 A7 B7五、發明説明（85 ) (6 )羥丙基纖維素 5 0 g (7) 阿斯1 巴甜（Aspartame) 3 g (8) 甘草亭二鉀（Dipotassium glycyrrhetinate) 3 g (9) 羥丙基甲基纖維素2910 3 0 g (1 0 )氯化鈦 3 . 5 g (11)黃色倍半氧化鐵（iron sesquioxide) 0 . 5 g (1 2 )輕矽酸酐 1 g 經濟部中央樣隼局員工消费合作杜印製 於精純水中，懸浮或溶解（1) , (3), (4), (5), (7) 及（8 )。 （ 2 )之核心粒以懸浮液或溶液包覆，以製備原料細 粒，以（9)-(11)包覆，製備包覆之細粒，與（12)相混合， 獲得含有1 %實例4製得之化合物或實例1 5製得之化合物 1之細粒500g。所得細粒各取500mg包装之。 丁業寵用 本發明之®吩并嘧啶衍生物（I)可有效作為預防或治 療數種激素依賴性疾病之預防或治療劑，該等激素依賴性 疾病例如性激素依賴性癌症（如，***癌，子宮頸癌， 乳癌，垂體腺瘤），良性***肥大，子宮肌瘤，子宮内 膜組織異位，早熟思春期，閉經，經前激候群，多囊性卵 m激候群及尋常痤瘡；可有效作為兩性生育控制劑（如， 妊娠控制劑及月經週期控制劑）；可用作男性或女性之避 孕藥，用作女性***誘導劑；可用作由於停止給藥而有回 躍作用之***治療劑；在畜牧業領域，用作調節動物之動 情週期，食用肉品之品質改良劑或動物成長促進劑；用作 魚類産卵促進劑。 (請先閱讀背面之注意事項再填寫本頁) 項再填· 裝- 訂 曛 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 85, 1T Consumer Cooperative Cooperative, Central Standards Bureau, Ministry of Economic Affairs, Du Yinsha, or Yi art ο 1 i US In c.) Without filter, take 2m 1 each into sterile vials $ and then freeze dry $ to obtain lyophilized injections Solution 100 mg / vial. Storage Example 24 化合物 Compound prepared in Example 4 or compound prepared in Example 15 15 g (2) Lactose ♦ crystalline cellulose (particles) 3 3 0 g (3) D-mannitol 29g (4) low 20g of substituted hydroxypropyl cellulose (5) 25g of stone This paper size applies to China National Standard (CNS) A4 specification (210X297 mm). 4 8 4 483896 A7 B7 V. Description of the invention (85) (6) Hydroxypropyl cellulose 50 g (7) Aspartame 3 g (8) Dipotassium glycyrrhetinate 3 g (9) Hydroxypropyl methylcellulose 2910 3 0 g (1 0) titanium chloride 3.5 g (11) yellow iron sesquioxide 0.5 g (1 2) light silicic anhydride 1 g Consumption cooperation of employees of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs is printed in pure water, suspended or dissolved (1), (3), (4), (5), (7) and (8). (2) The core particles are coated with a suspension or solution to prepare raw material fine particles, coated with (9)-(11) to prepare coated fine particles, and mixed with (12) to obtain an example containing 1% 500 g of compound obtained in 4 or compound 1 obtained in Example 15. Each of the obtained fine particles was packed in 500 mg. Ding Yechuang uses the phenacopyrimidine derivative (I) of the present invention as an effective preventive or therapeutic agent for the prevention or treatment of several hormone-dependent diseases such as sex hormone-dependent cancers (eg, prostate cancer, Cervical cancer, breast cancer, pituitary adenoma), benign prostatic hypertrophy, uterine fibroids, endometrial ectopic, precocious puberty, amenorrhea, premenstrual stress group, polycystic egg m group syndrome and acne vulgaris; can Effective as an bisexual birth control agent (eg, pregnancy control agent and menstrual cycle control agent); as a contraceptive for men or women; as an ovulation inducer for women; Pregnancy treatment; in the field of animal husbandry, used to regulate the estrous cycle of animals, quality improvers of edible meat or animal growth promoters; used as fish spawning promoters. (Please read the precautions on the reverse side before filling out this page) Refilling items · Packing-曛 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 85

Claims (1)

483896 H3 經濟部中央標準局員工福利委員會印製 附件二m綠#'Mpir，^c;v.fe^^^^ltf:#rr®4^ ，483896 H3 Printed by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs Annex II m green # 'Mpir ， ^ c; v.fe ^^^^ ltf: # rr®4 ^, 公居·· 8 4 103400A01號專利申請案 申請專利範圍修正本 (88年10月28日） .一種下式之化合物： (I) 其中R 1為下式之基： Q-(CH2)p- 其中Q為可經1或2個選自Ci-6烷基、鹵素、Ct-6烷氧 基及Ct-4烷硫基之取代基所取代之苯基；p為1至3之整 數； R2為可經Cl-6烷氧基、苄基、C5-7環烷基或苯基 取代之Ci-6烷基，該苯基又可經1或2個選自Ci-6烷氧 基、鹵素、Cl-6综硫基、Cl-6燒亞碌醢基、Cl-6烧碌 醯基及羥基之取代基取代； R3為H-(Ci-4烷基）-N-(甲硫基苄基）胺基或N-( Ci-4烷基）-N -(二乙胺基乙基）胺基； R4為可經1或2個選自Ct-6烷氧基、硝基、鹵素、 Ci-6烷基胺羰基、胺基、d-5烷醯胺基及甲醸胺基之 取代基取代之苯基；及 r為1至3之整數； 或其塩。 2.如申請專利範圍第1項之化合物，係2,4(1H,3H)_二氧 本紙張尺度適用中國國家標準（C N S ) A4規格（210 X 297公爱) 483896 _H3_ 代- 6- (4-甲氧苯基）-3 -苯基-1-(2 -氯-6-氟苯甲基）-5-(N-苯甲基-N-甲胺基甲基）《吩并[2,3-d]嘧啶或其塩。 3. 如申請專利範圍第1項之化合物，係2,4(1H,3H) -二氧 代-1-(2,6 -二氟苯甲基）-6-(4 -丙醯胺基苯基）-5-(N-苯甲基-N-甲胺甲基）-3-(3-甲氧苯基）ί«吩并[2, 3-d] 嗤喃或其塩。 4. 如申讅專利範圍第1項之化合物，係2,4(1H,3H) -二氧 代-1-(2,6 -二氟苯甲基）-6-(4 -異丁炔胺基苯基）-5-(N -苯甲基-N-甲胺甲基）-3-(3-甲氧苯基）(*吩并[2, 3-d] 嘧啶或其塩。 5. —種製造式（I)化合物或其塩之方法： 8、(CH2)r\Residence ·· 8 4 103400A01 Patent Application Amendment to Patent Scope (October 28, 88). A compound of the formula: (I) where R 1 is the base of the formula: Q- (CH2) p- Where Q is a phenyl group which may be substituted by 1 or 2 substituents selected from Ci-6 alkyl, halogen, Ct-6 alkoxy and Ct-4 alkylthio; p is an integer from 1 to 3; R2 It is a Ci-6 alkyl group which can be substituted by Cl-6 alkoxy group, benzyl group, C5-7 cycloalkyl group or phenyl group, and the phenyl group can be further selected from Ci-6 alkoxy group and halogen , Cl-6 isothiol, Cl-6 alkylene, Cl-6 alkyl and hydroxyl substituents; R3 is H- (Ci-4 alkyl) -N- (methylthiobenzyl Group) amino group or N- (Ci-4 alkyl) -N- (diethylaminoethyl) amino group; R4 can be selected from 1 or 2 selected from Ct-6 alkoxy, nitro, halogen, Ci-6 alkylamine carbonyl, amine, d-5 alkylamino and methylamido substituted phenyl; and r is an integer from 1 to 3; or 塩. 2. If the compound in the first item of the patent application scope is 2,4 (1H, 3H) _dioxin, the paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 public love) 483896 _H3_ Generation-6- ( 4-methoxyphenyl) -3 -phenyl-1- (2-chloro-6-fluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) "benzo [2 , 3-d] pyrimidine or its hydrazone. 3. If the compound in the first item of the patent application scope is 2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -6- (4-propanamidobenzene Phenyl) -5- (N-benzyl-N-methylaminemethyl) -3- (3-methoxyphenyl) fluoreno [2, 3-d] sulfan or its hydrazone. 4. For example, the compound in item 1 of the patent scope is 2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -6- (4-isobutynylamine Phenyl) -5- (N-benzyl-N-methylaminemethyl) -3- (3-methoxyphenyl) (* pheno [2, 3-d] pyrimidine or its hydrazone. 5. —A method for manufacturing a compound of formula (I) or its hydrazone: (CH2) r \ 基 之 式 下 為 1 R 中 其 基 烷 氧 烷 經濟部中央標準局員工福利委員會印製 張 紙 本 整 之 3 T至 1 1 c i 為 > P 素 ； 鹵基 、 苯 之 代 -6取 C 所 自基 選代 個取 經硫 可烷 為--4 IX Q C 中 其 及 ·， 基數 之 代 取 經 可 為 素 鹵 % 基 基 苄 % 基 氧 烷 基 苯 或 基 烷 環 自 、 選基 醯 磺 亞 經烷 可-6 又C1 基 、 笨基 該硫 , 烷 基 T 烷C1 個 2 或 氧磺 烷烷 或 基 胺 基 苄 基 硫 甲 /V ·> | 代T 取 } i基 基烷 代t 取卜 之(C 基N-羥為 及R3 基 醯 國 國 中 用 適 恥 4 A \]/ 5 N C /—ν' 準 一他 29 2 483896 ___H3_ Ci-4烷基）-N-(二乙胺基乙基）胺基； R4為可經1或2個選自Ci-6烷氧基、硝基、鹵素、 Ci-6烷基胺羰基、胺基、Ci-5烷醯胺基及甲醯胺基之 取代基取代之苯基；及 f為1至3之整數； 該方法包括使下式之化合物或其塩：X-(CHz)r VThe basic formula is 1 R. Its basic alkoxyalkane is printed by the Employees Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs. The whole paper is printed from 3 T to 1 1 ci is >P; halogen and benzene are substituted by -6. C The selected radicals can be replaced by thiocoxane as -4 IX QC. · The substitution of the base number can be plain halogen%, benzyl%, oxyalkylbenzene, or alkane ring. Alkyl-6 is C1 group, benzyl sulfide, alkyl T alkane C1 2 or oxane alkane or amine benzylthiomethane / V · > | Substitute T to take} i-based alkyl t Take the (C-based N-hydroxyl group and R3-based group in China, 4 A \] / 5 NC / —ν 'quasi-one 29 2 483896 ___H3_ Ci-4 alkyl) -N- (diethylamine Ethyl) amine group; R4 may be selected from Ci-6 alkoxy, nitro, halogen, Ci-6 alkylaminocarbonyl, amine, Ci-5 alkylamino, and formamidine Phenyl substituted with an amino group; and f is an integer from 1 to 3; the method includes making a compound of the formula or VII: X- (CHz) r V I R1' 中 其 2 R 基 去 離 為 X 義 定 逑 前 如 Γ 及 與 應 反 塩 其 或 物 合 化 之 式 下 ο \—/ 義 定 述 前 如 3 R 中 其 申或 括劑 包形 , 賦 物 ， 成劑 組載 藥其 翳及 之物 劑合 抗化 拮之 素義 激定 出項 釋 1 素第 腺圍 性範 促利 種專 1 請 6 劑 釋 稀 療 治 或 防 預 % 用 係 物 成 組 之 項 6 第 圍 範 利 專 讅 Ψ 如 經濟部中央標準局員工福利委員會印製 物 成 組 之 病 疾 性 賴 依 素 激 性 本紙張尺度適用中國國家標準（CNS)A4規格（210X297公营) 3In I R1 ', the 2 R group is removed as X before the definition, such as Γ, and the combination with the reaction should be the following formula. The drug group, the drug group, the drug combination, and the combination of anti-antagonism, the meaning of the hormone, and the determinant of the release of the first 1 peri-glandular facilitation of special breeds 1 please 6 doses of thinning treatment or prevention Grouped item 6: Fan Li Zhuan, such as printed by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economics, grouped by disease, relied on agitation, this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public) ) 3