TW486472B

TW486472B - Triazine angiogenesis inhibitors

Info

Publication number: TW486472B
Application number: TW87120449A
Authority: TW
Inventors: Jack Henkin; Donald J Davidson; George S Sheppard; Keith W Woods; Richard W Mccroskey
Original assignee: Abbott Lab
Priority date: 1997-12-12
Filing date: 1998-12-09
Publication date: 2002-05-11
Also published as: AR013802A1; CO4990954A1; ZA9811227B

Abstract

Compounds having formula (I) or pharmaceutically acceptable salts or prodrugs thereof, are useful for treating pathological states which arise from or are exacerbated by angiogenesis. The invention also relates to pharmaceutical compositions comprising these compounds and to methods of inhibiting angiogenesis in mammal.

Description

486472 五、發明說明（1) 技術範圍本發明係關於經取代之三嗪’其可用來治療起因其生成作用，或因其而加劇之病理學狀況，包括這此/人吕之醫藥組合物，以及在哺乳動物中抑制血管 D物法。二力乂忭用的方發明背景血f生成作用，藉此而形成新血管的過程，對於 A 身體活動而言是必要的，包括再生、#育和傷口恢復：鈐然亚不完全瞭解該過程，咸相信其涉及複雜的調節 : 胞（微血管的主要細胞）生長之分子的相互作用。在正常的，況下，這些分子顯然將微血管分布狀況維持在靜止的狀怨（也就是無毛細血管生長的狀況），持續延長的期間，可能持:續數週之久^在一些案例中可持續十年。在需要時疋一在傷口恢復的期間），這些相同的細胞可在5天的期間内經歷迅速的增殖並周轉之（Folkman， J·和Shmg，Y.， The Journal of Bi〇iogical chemistry, 267(16), l〇931-l〇 9 3 45 ( 1 9 9 2 ) , a ^Fokman, J. 1 agsbrun, •，Scie:ce，2 3 5，442 —447 ( 1 98 7 ))。雖…、'血官生成作用在正常的狀況下是受到高度調節的過疋許f疾病（其特徵為血管生成之疾病）受到持續不 =二=之血官生成作用的驅使。另一方面，不受調節之血二、作用可直接弓丨起特定的疾㉟，或使已存在之病理狀况加劇。例如」已姑 — g ^ 、，二日日不眼睛的血管新生作用是瞎眼最常 '原因’亚支配大約二十種眼睛的疾#。在某些現存的 486472 五、發明說明（2) 狀況中，像是關節炎，新形成的微血管侵犯關節並破壞軟骨。在糖尿病中，在視網膜中新形成的微血管侵犯玻璃體、出血並引起瞎眼。固體腫瘤的生長和轉移亦依賴血管· 生成作用（Folkman， J.， cancer Research， 46， 46 7- 473 (1986), Folkman, J., Journal of the National486472 V. Description of the invention (1) Technical scope The present invention relates to a substituted triazine 'which can be used to treat pathological conditions that are caused by its generating effect, or exacerbated by it, including this / human pharmaceutical composition, And the method of inhibiting blood vessel D matter in mammals. BACKGROUND OF THE INVENTION FOR THE USE OF ERLI BACKGROUND OF THE INVENTION The process of blood formation, through which new blood vessels are formed, is necessary for A's physical activity, including regeneration, healing, and wound recovery: Ranya does not fully understand the process Xian believes that it involves complex regulation: the interaction of molecules with the growth of cells (the main cells of microvessels). Under normal conditions, these molecules apparently maintain the microvascular distribution status at a static state (that is, the condition of no capillary growth). For a prolonged period, it may hold: Continued for several weeks ^ In some cases it may be For ten years. When needed, during the period of wound recovery), these same cells can undergo rapid proliferation and turnover within a period of 5 days (Folkman, J. and Shmg, Y., The Journal of Biochemistry chemistry, 267 (16), 10931-1093 45 (199.2), a Fokman, J. 1 agsbrun, •, Scie: ce, 2 3 5, 442-447 (1 98 7)). Although ..., "hematogenetic effects are highly regulated under normal conditions. This disease (characterized by an angiogenic disease) is driven by a continuous hemorrhagic effect. On the other hand, unregulated blood Second, the effect can directly cause specific diseases, or exacerbate existing pathological conditions. For example, "Gu Gu-g ^", the angiogenesis effect of the second day without eyes is the most common 'cause' of blindness. In some existing conditions, such as arthritis, newly formed microvessels invade joints and destroy cartilage. In diabetes, newly formed microvessels in the retina invade the vitreous, bleed and cause blindness. The growth and metastasis of solid tumors also depend on angiogenesis (Folkman, J., cancer Research, 46, 46 7- 473 (1986), Folkman, J., Journal of the National

Cancer Institute. 82，4-6 ( 1 9 8 9 ))。已經顯示，例如腫瘤增加至2毫米以上時，必須獲得它自己的血液供應，而藉著引起新微血管的生長來達成這樣。一旦這些新血管埋入腫瘤中’它們便對腫瘤細胞提供進入循環，並轉移至，如肝臟、肺贜或骨骼之類遠處位置的方法（Weidner，Ν. φ 等人 ’The New England J〇urnal 〇f Madicine， 324(1)， 1-8 (1991))。 w 9 IT有數個血管生成作用的抑制劑在進行發展之中，闬來’口療血|生成的疾病（〇33叩1^1^，〇和}]31'1'：[3，人·！^·， Clin· Oncoi·， 13(3): 765一782， i995)，但是關於這些^合物有一些缺點。例如蘇拉明（Suranun)，是有效的 =官生成抑制劑，但是在抗腫瘤活性所需之劑量下，在人 =引起厭重的全身毒性。諸如類視黃素（ret inoid)、干擾 $和抗雖激素之類的化合物，對於人類使用而言是較安全 $ ’但僅具有微弱的抗-血管生成的效力。艾爾索格蘭丁 =〇 g 1 a d i n e ) ’ 一種抗腫瘤藥物，具有低毒性，卻僅具 U弱的抗—血管生成作用。因此，對於在哺乳動物中可用來/α療血官,生成之疾病的化合物仍有所需求。 I明概述 486472 五、發明說明（3) 在本發明的一個具體實施例中係揭示具有式I之化合物：Cancer Institute. 82, 4-6 (1 9 8 9)). It has been shown, for example, that when a tumor increases above 2 mm, it must obtain its own blood supply, and this is achieved by causing the growth of new microvessels. Once these new blood vessels are embedded in the tumor, they provide tumor cells with access to the circulation and transfer to distant locations such as the liver, lungs, or bones (Weidner, N. φ et al. 'The New England J. Urnal Madicine, 324 (1), 1-8 (1991)). w 9 IT has several inhibitors of angiogenesis in development, and has come to 'oral treatment of blood | produced diseases (〇33 叩 1 ^ 1 ^, 〇 and}) 31'1': [3, human · ^ ·, Clin · Oncoi ·, 13 (3): 765-782, i995), but there are some disadvantages about these compounds. For example, Suranun is effective = an inhibitor of official production, but at the dose required for antitumor activity, it causes systemic toxicity in humans. Compounds such as ret inoid, interference $ and anti-hormones are safer for human use, but have only weak anti-angiogenic efficacy. Elso Grandine = 0 g 1 a d i n e) ’An anti-tumor drug with low toxicity but only U weak anti-angiogenic effect. Therefore, there is still a need for compounds that can be used in mammals to treat hemogenetic, alpha-produced diseases. Brief description of the invention 486472 V. Description of the invention (3) In a specific embodiment of the present invention, the compound having the formula I is disclosed:

或其在藥學上可接受的鹽類或前藥，其中Or a pharmaceutically acceptable salt or prodrug thereof, wherein

Ri、R2、R3和R4分別選自包括氫、q - C2Q燒基和q - C2Q鏈烧醯基；或心和R2與附接於其上的氮原子一起形成環，其分別選自包括嗎啉、六氫吡啶、六氫吡畊和吡咯啶；或 r3和r4與附接於其上的氪原子一起形成環，其分別選自包括嗎啉、六氫咬、六氫哦明1和吼洛咬； A選自包括雜環基、（雜環基）-C2Q -烷基、C3-C1Q環烷基、C6_C15-螺烧基，以及B~~L-Y ; B和Y分別為芳基、C3-C1(}環炫基、C4-C1Q環烯基、雜環基或C6 - q 5 -螺院基； L 為基價鍵、-C (二 W ) -、Q - C2。伸院基、-N R5 -、 -NR6C(X)NR7-、C2-C2。伸快基、C2-C2Q 伸稀基、-0-、 -s(o)t-、-nr6c(x)-、-c(x)nr6-、-nr6so2nr7-、 -NR6S〇2-、-S〇2NR6-，或)-; 為氫、Ci - C2(3院基、C丨-C2Q鏈烧醯基，和Ci - C2()芳烧基； R6和R7分別為氫、G - C2〇烧基和芳基-q - C2Q -烧基；Ri, R2, R3 and R4 are respectively selected from the group consisting of hydrogen, q-C2Q alkyl and q-C2Q alkyl; or oxo and R2 form a ring together with the nitrogen atom attached thereto, and are each selected from the group consisting of Or hexahydropyridine, hexahydropyridine, and pyrrolidine; or r3 and r4 form a ring together with the pyrene atom attached to it, which are selected from the group consisting of morpholine, hexahydrobite, hexahydropyridine 1 and roar Los bite; A is selected from the group consisting of heterocyclyl, (heterocyclyl) -C2Q-alkyl, C3-C1Q cycloalkyl, C6-C15-spiroalkyl, and B ~~ LY; B and Y are aryl and C3, respectively -C1 (} cyclohexyl, C4-C1Q cycloalkenyl, heterocyclyl or C6-q 5 -spiroyl; L is a basic valence bond, -C (di-W)-, Q-C2. -N R5-, -NR6C (X) NR7-, C2-C2. Extended base, C2-C2Q extended base, -0-, -s (o) t-, -nr6c (x)-, -c ( x) nr6-, -nr6so2nr7-, -NR6S〇2-, -S〇2NR6-, or)-; is hydrogen, Ci-C2 (3 courtyard, C 丨 -C2Q chain alkyl, and Ci-C2 ( ) Aromatic alkyl; R6 and R7 are hydrogen, G-C20 alkyl and aryl-q-C2Q-alkyl, respectively;

486472 δ〇· 6· 21 案號87120449 气ύ年月曰修正五、發明說明（4) 1^和1^2為先前之定義； W 為0、S 4( = N_0_R6)； X為0或S ; t 為 0 - 2 ; 顯示每個L以其左端與B附接，並以其右端與Y附接；並在每次出現時，芳基、環烷基、環烯基、雜環基、螺烷基、伸烷基和（雜環基）烷基均可視需要以1 - 3個分別選自包括Ci-Cw烷氧基、匕-(：2{)烷基、胺基、芳基、疊氮基、氰基、鹵素、鹵烷基、雜環基、硝基或R1Q和Rn之取代基來取代之，486472 δ〇 · 6.21 Case No. 87120449 Modification of Qi Qi Year and Year V. Description of Invention (4) 1 ^ and 1 ^ 2 are the previous definitions; W is 0, S 4 (= N_0_R6); X is 0 or S ; t is 0-2; show that each L is attached to B with its left end and Y with its right end; and aryl, cycloalkyl, cycloalkenyl, heterocyclyl, Spiroalkyl, alkylene, and (heterocyclyl) alkyl can be selected from 1 to 3, respectively, including Ci-Cw alkoxy, d-(: 2 {) alkyl, amine, aryl, Azido, cyano, halogen, haloalkyl, heterocyclyl, nitro or substituents of R1Q and Rn,

其中R1()和R 起為 !〈其中A和D分別為氧或 5 ( 0 ) t，且η為2 - 3，其限制條件為當B和Y是未經取代之苯基且L為共價鍵時，h、R2、R3和1?4中至少有一個是氫以外的，且其限制條件為當L為共價鍵且B或Y中有一個是未經取代之 1:7米唾，而另一個是未經取代之苯基時，Ri、R2、R3和84中至少有一個是氫以外的。在本發明的其它具體實施例中，係揭示治療的方法，其包括投予有效量之具有式I的化合物。在本發明另外的具體實施例中，係揭示包括式I化合物的醫藥組合物。本發明之化合物包括但不限於選自包括下列的化合物： 6 - [1 -（二苯曱基）-3-氮雜環丁烷基]- 1，3, 5 -三嗪- 2, 4-二Where R1 () and R start from! <Where A and D are oxygen or 5 (0) t, respectively, and η is 2-3, the limitation is that when B and Y are unsubstituted phenyl and L is co- At the time of valence bond, at least one of h, R2, R3, and 1-4 is other than hydrogen, and the restriction is that when L is a covalent bond and one of B or Y is an unsubstituted 1: 7 meter saliva When the other is an unsubstituted phenyl group, at least one of Ri, R2, R3 and 84 is other than hydrogen. In other specific embodiments of the invention, methods of treatment are disclosed which include administering an effective amount of a compound having Formula I. In another specific embodiment of the invention, a pharmaceutical composition comprising a compound of formula I is disclosed. The compounds of the present invention include, but are not limited to, compounds selected from the group consisting of: 6-[1- (diphenylfluorenyl) -3-azetidinyl]-1, 3, 5-triazine-2, 4- two

II 111II 111

O:\56\56069.ptc 第9頁 2001.06.21.009 486472 五、發明說明（5) 胺， 6-(1-苯基-4-六氫〇比咬基）-1，3，5 -三嗪-2，4 -二胺，反-6-(4 -苯基環己基）-1，3，5 -三嘻-2，4 -二胺， 6-[3-(lH-Dit17各-1-基）苯基]-1，3，5 -三嗦_2，4 -二胺，順/反-6-(3 -苯基環丁基）-1，3, 5 -三嗪-2, 4-二胺， 6-[1，1’ -聯苯基]-2-基-1，3，5 -三嗓-2，4 -二胺， 6-(4’ -硝基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二胺， 6-[4-(4-戊基環己基）苯基]-1，3, 5 -三嗪-2, 4 -二胺， 6-(4-苯氧苯基）-1，3，5-三嗪-2，4-二胺， N -環己基-Ν’ -[4-( 4, 6 -二胺基-1，3.，5 -三嗪-2-基）苯基] 脲’ (4,6-二胺基-1，3,5-三嗪-2-基）苯基曱烯酮， Ν-[4-(4, 6 -二胺基-1，3, 5 -三嗓-2-基）苯基]-Ν’ -苯基脲， 6-(1，4 -二噚-8 -氮雜螺[4, 5]癸-8 -基）-1，3, 5 -三嗪-2, 4-二胺， 6-(4’ -戊基[1，1’ -聯苯基]-4-基）-1，3, 5 -三嗪-2, 4 -二胺， 6-(4’ -（戊氧基）[1，1’ -聯苯基]-4 -基）-1，3，5 -三嗪- 2,4-二胺， 6-(6-甲氧基-2 -苯并噻唑基）-1，3, 5 -三嗪-2, 4 -二胺， 6-(4’ -胺基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二胺， · 6-[4-( 5 -噚唑基）苯基]-1，3, 5 -三嗪-2, 4-二胺，O: \ 56 \ 56069.ptc Page 9 2001.06.21.009 486472 V. Description of the invention (5) Amine, 6- (1-phenyl-4-hexahydro octayl) -1,3,5-triazine -2,4-diamine, trans-6- (4-phenylcyclohexyl) -1,3,5-trihex-2,4-diamine, 6- [3- (lH-Dit17 each-1- Phenyl) phenyl] -1,3,5-trifluorene_2,4-diamine, cis / trans-6- (3-phenylcyclobutyl) -1,3,5-triazine-2, 4 -Diamine, 6- [1,1'-biphenyl] -2-yl-1,3,5-trimethyl-2,4-diamine, 6- (4'-nitro [1,1 ' -Biphenyl] -4 -yl) -1,3,5-triazine-2,4-diamine, 6- [4- (4-pentylcyclohexyl) phenyl] -1,3, 5- Triazine-2, 4-diamine, 6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diamine, N-cyclohexyl-N '-[4- (4 , 6-diamino-1,3., 5-triazin-2-yl) phenyl] urea '(4,6-diamino-1,3,5-triazin-2-yl) phenyl Limonenone, Ν- [4- (4, 6-diamino-1,3,5-trimethyl-2-yl) phenyl] -N'-phenylurea, 6- (1,4-di Hydrazone-8-azaspiro [4,5] dec-8-yl) -1,3,5-triazine-2,4-diamine, 6- (4'-pentyl [1,1'-linked Phenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- (4 '- (Pentyloxy) [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- (6-methoxy-2 -benzothiazole Group) -1,3,5-triazine-2,4-diamine, 6- (4'-amino [1,1'-biphenyl] -4 -yl) -1,3,5-tri Hydrazine-2,4-diamine, 6- [4- (5-oxazolyl) phenyl] -1,3,5-triazine-2,4-diamine,

第10頁 486472 五、發明說明（6) 6-[4-[[5-(三氟曱基）-2 -吡啶基]氧基]苯基]-1，3, 5 -三嗪 -2, 4-二胺， 4’ - (4, 6 -二胺基-1，3, 5 -三嗪-2 -基）[1，1’ -聯苯基]-4-腈， 6-(4’ -曱氧基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二胺， 6-(4,-氟[1，1’ _ 聯苯基]-4-基）-1，3, 5 -三嗪-2, 4-二胺， 1^-[4-(4，6-二胺基-1，3，5*~三嗓-2-基）苯基]苯續1&胺， 6-[ 1-( [ 1，1’ -聯苯基]-4 -基）-4 -六氫吡啶基]-1，3, 5 -三_ _ 2，4 -二胺， N-[4-(4, 6 -二胺基-1，3, 5 -三嗪-2 -基）苯基]-2 -萘磺醯胺， 2，5 -二氯-N-[4-(4，6 -二胺基-1，3，5 -三嗪-2 -基）苯基]苯石黃酸胺’ 6-(1-苯基環己基）-1，3,5-三嗪-2,4-二胺， 6-[1-(4-甲氧苯基）-4-六氫吡啶基]-1，3, 5-三嗪-2, 4 -二胺， 6-[2 - [4-(三就甲基）苯基]-4 -噻唾基]-1，3，5 -三嗪-2，4-二胺， 6-[ 1-(4-曱氧苯基）環己基]-1，3, 5 -三嗪-2, 4 -二胺， 6-[4-(2-噻吩基）苯基]-1，3,5-三嗪-2,4-二胺， 6-[4-(苯基乙炔基）苯基]-1,3，5 -三嗦-2，4 -二胺， 1^，『-（-[1，1’，聯苯基]-4-基-1，3，5_三嗪-2，4-二基）雙 [乙醯胺]，Page 10 486472 V. Description of the invention (6) 6- [4-[[5- (trifluorofluorenyl) -2-pyridyl] oxy] phenyl] -1,3, 5-triazine-2, 4-diamine, 4 '-(4, 6 -diamino-1,3,5-triazin-2 -yl) [1,1' -biphenyl] -4-nitrile, 6- (4 ' -Methoxy [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- (4, -fluoro [1,1'_bi Phenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 1 ^-[4- (4,6-diamino-1,3,5 * ~ triol- 2-yl) phenyl] benzene 1 & amine, 6- [1- ([1,1 '-biphenyl] -4 -yl) -4 -hexahydropyridyl] -1,3, 5 -tri _ 2,4-diamine, N- [4- (4, 6-diamino-1,3,5-triazin-2-yl) phenyl] -2 -naphthalenesulfonamide, 2,5 -Dichloro-N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] benzite xanthate '6- (1-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine, 6- [1- (4-methoxyphenyl) -4-hexahydropyridyl] -1,3,5-triazine-2, 4-diamine, 6- [2- [4- (tri-n-methyl) phenyl] -4-thiasialyl] -1,3,5-triazine-2,4-diamine, 6- [1 -(4-fluorenoxyphenyl) cyclohexyl] -1,3,5-triazine-2,4-diamine, 6- [4- (2-thienyl) Phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (phenylethynyl) phenyl] -1,3,5-trifluorene-2,4-diamine , 1 ^, "-(-[1,1 ', biphenyl] -4-yl-1,3,5-triazine-2,4-diyl) bis [acetamidine],

第11頁 486472 五、發明說明（7) N-(4 -胺基-6-[1，1’ -聯苯基]-4 -基-1，3, 5 -三嗪-2 -基）乙酿胺， N-[4-(4,6 -二胺基-1，3, 5 -三嗪-2 -基）苯基]-卜萘磺醯胺， 6-(4’-疊氮基[1，1’-聯苯基]-4-基）-1，3，5-三嗓-2，4-二胺， 6-[4-(4 -嗎啉磺醯基）苯基]-1，3, 5 -三嗪-2, 4 -二胺， 6-[4-(2 -呋喃基）苯基]-1，3, 5 -三嗪-2, 4-二胺， 1『-[6-(4-苯氧苯基）-1，3,5-三嗪-2,4-二基]雙[乙醯| 胺]， N - [4 -胺基-6-(4-苯氧苯基）-1，3，5 -三嗦-2 -基]乙酸胺， 6-(5 -苯基-2 -呋喃基）-1，3, 5 -三嗪-2, 4 -二胺， 6-(5 -苯基-2 -噻吩基）-1，3, 5 -三嗪-2, 4 -二胺， N，Ν’ - [6-(4 -苯基環己基）-1，3，5 -三嗓-2，4 -二基]雙[乙· 胺]， Ν-[4 -胺基-6-(4-苯基環己基）-1，3,5_三嗪-2 -基]乙醯胺， 6-(4-苯基-1-萘基）-1，3, 5 -三嗪-2, 4 -二胺， 6~~[4-(苯硫基）苯基]-1，3，5-三嗓-2，4-二胺， 6-(2 -喹琳基）-1，3，5 -三嗦-2，4 -二胺， 6-(3-喹啉基）-1，3,5_ 三嗪-2,4-二胺， 6-(苯并[b]噻吩-2-基曱基）-1，3，5 -三嗪-2,4 -二胺， 6-(2,2-二曱基-211-1-苯并哌喃-6-基）-1，3,5-三嗪-2,4-二胺，Page 11 486472 V. Description of the invention (7) N- (4-amino-6- [1,1'-biphenyl] -4-yl-1,3,5-triazin-2-yl) ethyl Styramine, N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -naphthosulfonamide, 6- (4'-azido [ 1,1'-biphenyl] -4-yl) -1,3,5-trimethyl-2,4-diamine, 6- [4- (4-morpholinesulfonyl) phenyl] -1 , 3, 5-triazine-2, 4-diamine, 6- [4- (2-furanyl) phenyl] -1,3, 5-triazine-2, 4-diamine, 1 『-[ 6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diyl] bis [acetamidine | amine], N-[4-amino-6- (4-phenoxy Phenyl) -1,3,5-trisino-2-yl] amine, 6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4-diamine, 6- (5-phenyl-2-thienyl) -1,3,5-triazine-2,4-diamine, N, N '-[6- (4-phenylcyclohexyl) -1,3 , 5 -trimethyl-2,4-diyl] bis [ethyl · amine], Ν- [4-amino-6- (4-phenylcyclohexyl) -1,3,5_triazine-2- Group] Ethylamine, 6- (4-phenyl-1-naphthyl) -1,3,5-triazine-2,4-diamine, 6 ~~ [4- (phenylthio) phenyl] -1,3,5-triad-2,4-diamine, 6- (2-quinolinyl) -1,3,5-triamidine-2, 4-diamine, 6- (3-quinolinyl) -1,3,5-triazine-2,4-diamine, 6- (benzo [b] thien-2-ylfluorenyl) -1,3 , 5-triazine-2,4-diamine, 6- (2,2-difluorenyl-211-1-benzopiperan-6-yl) -1,3,5-triazine-2,4 -Diamine,

第12頁 486472 五、發明說明（8) 6-(1-異喹啉基）-1，3,5-三嗪-2,4-二胺， 6-(2,3 -二氫-1,4 -苯并二氧茚（dioxin)-2 -基）-1，3, 5 -三嗪-2, 4 -二胺， 6-(三環[3· 3· 1· I3.7]癸烷-1-基）-1，3, 5 -三嗪-2, 4-二胺， (+/-)-4-(4，6 -二胺基-1，3，5 -三嗦-2-基苯基苯甲醇， 6-(2,3-二氫-1，4-苯并二氧茚（(11〇\111)-6-基）-1，3,5-三嗓-2，4 -二胺， 6-(1-氮雜二環[2.2.2]辛烧-4-基）-1，3，5-三嗦-2，4-二胺， 6-[4-(苯基亞石黃醯基）苯基]-1,3，5 -三嗪-2，4 -二胺， 6-[4-(苯基磺醯基）苯基]-1，3, 5-三嗪-2, 4-二胺， [4-(4，6 -二胺基-1,3，5 -三嗓-2-基）苯基]苯基曱酮，柄， 6-吡畊基-1，3,5-三嗪-2,4-二胺， 2, 4 -二胺基-6-[ (4 -苯基乙烯基）苯基]-1，3, 5 -三嗪， 2，4 -二胺基-6-[(4-(2 -石肖苯基）乙稀基）苯基]-1，3，5 -三嗪， 6-[1，1，-聯苯基]-4-基^，-二曱基-1，3,5-三嗪-2,4-二胺， 6-[1，1’-聯苯基]-4-基-1曱基-1，3,5-三嗪-2,4-二胺， 6-(二環[2· 2. 1 ]庚-2 -基）-1，3, 5 -三嗪-2, 4 -二胺， 6-[1，1’ -聯苯基]-4 -基-N，Ν’-二乙基-1，3，5 -三嗦-2,4 -二胺， - 6-(2’ -硝基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二Page 12 486472 V. Description of the invention (8) 6- (1-isoquinolinyl) -1,3,5-triazine-2,4-diamine, 6- (2,3-dihydro-1, 4-benzodioxin-2-yl) -1,3,5-triazine-2,4-diamine, 6- (tricyclo [3 · 3 · 1 · I3.7] decane -1-yl) -1,3,5-triazine-2,4-diamine, (+/-)-4- (4,6-diamino-1,3,5-trifluorene-2- Phenylbenzyl alcohol, 6- (2,3-dihydro-1,4-benzodioxindene ((11〇 \ 111) -6-yl) -1,3,5-trimethyl-2,4 -Diamine, 6- (1-azabicyclo [2.2.2] octan-4-yl) -1,3,5-trifluorene-2,4-diamine, 6- [4- (phenyl Sulfinite) phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2 , 4-diamine, [4- (4,6-diamino-1,3,5-triso-2-yl) phenyl] phenylfluorenone, stalk, 6-pyridyl-1,3 , 5-triazine-2,4-diamine, 2, 4-diamino-6-[(4-phenylvinyl) phenyl] -1,3,5-triazine, 2,4-diamine Amino-6-[(4- (2-Shishophenyl) ethenyl) phenyl] -1,3,5-triazine, 6- [1,1, -biphenyl] -4-yl ^,-Difluorenyl-1,3,5-triazine-2,4-diamine, 6- [1,1'-biphenyl] -4-yl-1 曱-1,3,5-triazine-2,4-diamine, 6- (bicyclo [2 · 2.1] heptan-2-yl) -1,3,5-triazine-2, 4-diamine Amine, 6- [1,1'-biphenyl] -4-yl-N, N'-diethyl-1,3,5-trifluorene-2,4-diamine, 6- (2 ' -Nitro [1,1'-biphenyl] -4 -yl) -1,3,5-triazine-2, 4-di

第13頁五、發明說明（9) 胺， 6-(6-曱基-3-吡啶基）-1，3,5-三嗪-2,4-二胺， 6-(6-氯-3 -吡啶基）-1，3, 5 -三嗪-2, 4 -二胺， 6-(5-溴-3-吡啶基）-1，3,5_ 三嗪-2,4-二胺， 6-(2，3 -二氮_2，2，3，3 -四敦-1，4_ 苯并二氧印（dioxin)-6-基）-1，3，5 -三嗪-2, 4 -二胺， 6-[4-（4-氣苯基）甲氧基]苯基]-1，3, 5 -三嗪-2, 4-二胺， 6-[4-(1-六氫1：1比17定石黃驢基）苯基]-1，3，5-三嗓-2，4-二胺， 6-(1-苯甲醯基-4-六氫吡啶基）-1，3,5-三嗪-2,4-二胺' 6-[ 1-（苯甲基）-4 -六氫吡啶基]-1，3, 5 -三嗪-2, 4-二胺， Ν，Ν’ -二乙醯基-6-[4-(苯磺醯基）苯基]-1，3, 5 -三嗪-2, 4-二胺， Ν-乙酸基-6_[4-(苯石黃蕴基）苯基]_1，3，5 -三嚷-2，4-二胺，以及 6-(2 -六氫吡啶-1-基苯基）-1，3, 5 -三嗪-2, 4 -二胺。發明說明名詞定義在本文中使用M鏈烷醯基"一詞時，代表具有1 -2 0個碳原子之烷基基團，經由羰基附接在親代分子基團上。在本文中使用π烷氧基π —詞時，代表具有卜2 0個碳原子之烷基基團，經由氧原子附接在親代分子基團上。在本文中使用"烷基π —詞時，代表具有1 -2 0個碳原子，衍生自直線或·支鏈之飽和烴的單價基團。本發明之烷基基團可以1 - 3個分別選自芳基或雜環基之取代基來取代。Page 13 V. Description of the invention (9) Amine, 6- (6-fluorenyl-3-pyridyl) -1,3,5-triazine-2,4-diamine, 6- (6-chloro-3 -Pyridyl) -1,3,5-triazine-2,4-diamine, 6- (5-bromo-3-pyridyl) -1,3,5-triazine-2,4-diamine, 6 -(2,3 -diaza_2,2,3,3 -tetradun-1,4_ dioxin-6-yl) -1,3,5-triazine-2, 4- Diamine, 6- [4- (4-Gaphenyl) methoxy] phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (1-hexahydro1 : 1 to 17 stilbene) phenyl] -1,3,5-trimethyl-2,4-diamine, 6- (1-benzylidene-4-hexahydropyridyl) -1,3 , 5-triazine-2,4-diamine '6- [1- (benzyl) -4 -hexahydropyridyl] -1,3, 5-triazine-2,4-diamine, Ν, Ν'-diethylfluorenyl-6- [4- (benzenesulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, Ν-acetoxy-6_ [4- (benzene Ruthazine) phenyl] _1,3,5-trifluorene-2,4-diamine, and 6- (2-hexahydropyridin-1-ylphenyl) -1,3,5-triazine-2, 4-diamine. Description of the invention Definition of terms When the term "M-alkanoyl" is used herein, it represents an alkyl group having 1 to 20 carbon atoms and is attached to the parent molecular group via a carbonyl group. When the term πalkoxyπ is used herein, it represents an alkyl group having 20 carbon atoms and is attached to the parent molecular group through an oxygen atom. When the term "alkylπ" is used herein, it represents a monovalent group having 1 to 20 carbon atoms and derived from a straight or branched saturated hydrocarbon. The alkyl group of the present invention may be substituted with 1 to 3 substituents each selected from an aryl group or a heterocyclic group.

第14頁 6472 五、發明說明（ίο) 在本文中使用"伸烧基"一詞時，代表具有1 - 2 0個碳原子，衍生自直線或支鏈之飽和烴的飽和二價基團。本發明之伸烷基可視需要以氧代、硫酮基、卜N-〇-R6)或-0R6來取代。在本文中使用lf伸烯基” 一詞時，代表具有2 - 2 0個碳原子，衍生自直線或支鏈烯的不飽和二價基團。在本文中使用"伸快基” 一詞時，代表具有2 - 2 0個碳原子，衍生自線或支鏈炔的不飽和二價基團。在本文中使用π胺基"一詞時，代表-NH2-。 t 在本文中使用lf芳基"一詞時，代表衍生自一或兩個芳香族環之單-或二環的碳環系統。本發明之芳基可視需要以 1-4個分別選自燒氧基、胺基、胺基、芳基、疊氮基、氰基、鹵素、鹵烧基、雜環基或石肖基之取代基來取代。在本文中使用"芳烷基"一詞時，代表經由烷基基團附接到親代分子基團上的芳基基團。在本文中使用π疊氮基” 一詞時，代表-n3。在本文中使用"氰基"一詞時，代表-C N。在本文中使用π環烷基π —詞時，代表具有3 - 1 0個碳原子，衍生自環狀或二環烴之飽和的單價基團。本發明之環烷基可視需要以1 - 3個分別選自烷基、芳基或雜環基之取代基來取代。在本文中使用"環烯基π —詞時，代表具有4 - 1 0個碳原子，衍生自環.狀或二環烯之不飽和的單價基團。本發明之環烯基可視需要以1 - 3個分別選自烷基、芳基或雜環基之Page 14 6472 5. Description of the invention (ίο) When the term "sender" is used herein, it represents a saturated divalent radical of 1 to 20 carbon atoms derived from a straight or branched chain saturated hydrocarbon. group. The alkylene group of the present invention may optionally be substituted with oxo, thioketo, N-O-R6) or -0R6. The term "lfenenyl" is used herein to represent an unsaturated divalent group having 2 to 20 carbon atoms derived from a linear or branched olefin. The term "quotinyl" is used herein , Represents an unsaturated divalent group having 2 to 20 carbon atoms, derived from a linear or branched alkyne. When the term "piamino" is used herein, it stands for -NH2-. t The term lfaryl " is used herein to mean a mono- or bicyclic carbocyclic ring system derived from one or two aromatic rings. The aryl group of the present invention may optionally have 1-4 substituents selected from the group consisting of alkoxy, amine, amine, aryl, azido, cyano, halogen, halo, heterocyclic, or schottyl, respectively. To replace. When the term " aralkyl " is used herein, it represents an aryl group attached to a parent molecular group through an alkyl group. The term "πazido" is used in this document to represent -n3. The term "cyano" is used in this document to represent -CN. The term "π cycloalkylπ" is used in this document to mean to have 3 to 10 carbon atoms, derived from a saturated monovalent group of a cyclic or bicyclic hydrocarbon. The cycloalkyl group of the present invention may optionally be substituted with 1 to 3 substituents selected from an alkyl group, an aryl group, or a heterocyclic group. The term "cycloalkenyl π" is used herein to represent an unsaturated monovalent group having 4 to 10 carbon atoms derived from a ring-shaped or bicyclic olefin. The cyclic olefin of the present invention The base may be selected from 1 to 3 respectively selected from alkyl, aryl or heterocyclic groups.

第15頁 4.86472 五、發明說明（11) 取代基來取代。在本文中使用H鹵素” 一詞時，代表F、Cl、Br或I。在本文中使用H鹵烷基π —詞時，代表其上附接至少一個鹵素原子的烷基基團。在本文中使用π雜環基"一詞時，代表含有一、二或三個分別選自包括氮、氧和硫之雜原子的4-、5-、6 -或7-員環。4 -和5 -員環具有零到兩個雙鍵，而6 -和7 -員環具有零到三個雙鍵。這些雜環基包括苯并咪唑基、苯并呋喃基、苯并噻唾基、苯并噻吩基、苯并噚峻基、二氫噻吩基、二氫嘲哄基、二氫咲喃基、二氫脈喃基、二嚷σ坐基、咲喃基、高六氫吡啶基、咪唑基、咪唑啉基、咪唑啶基、異噻唑基、異噻唑啶基、異喹啉基、吲哚基、異噚唑基、異噚 σ坐咬基、異噻唾基、嗎啉基、卩萼°坐σ定基、卩萼吐基、六氫D比畊基、六氫吡啶基、哌喃基、吡畊基、吡唑啶基、吡唑琳基、吡唑基、吡啶基、吡咯啶基、吡咯啉基、吡咯基、嗒哄基、ϋ密σ定基、嘴σ定基、嗤啉基、四氫咲喃基、四氫異喹啉基、四氫喹啉基、四氫噻吩基、四唾基、噻二唾基、噻唑啶基、噻唑基、噻吩基、硫代嗎啉基、***基、噚二唑基及其類似物。雜環類亦包括二環、三環和四環的基團，其中係將任何上文提及之雜環，融合至一或兩個分別選自芳基環、環己烷環、環己烯環、環戊烷環、環戊烯環或其他單環之雜環的環上。這些雜環包括苯并咲喃基、苯并噻吩基、D引Π朵基、異喹啉基、喹啉基、四氫喹啉基及其類似物。Page 15 4.86472 V. Description of the invention (11) Substituted by substituents. When the term "H halogen" is used herein, it means F, Cl, Br or I. When the term H haloalkylπ is used herein, it means an alkyl group to which at least one halogen atom is attached. Herein The term π heterocyclyl " is used to represent a 4-, 5-, 6-, or 7-membered ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur, respectively. 4 -and 5-membered rings have zero to two double bonds, while 6- and 7-membered rings have zero to three double bonds. These heterocyclic groups include benzimidazolyl, benzofuranyl, benzothiasilyl, benzene Benzothienyl, benzofluorenyl, dihydrothienyl, dihydrocarbyl, dihydropyranyl, dihydropulsanyl, difluorenyl sigmato, sulfanyl, homohexahydropyridyl, imidazole Base, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolyl, isoquinolinyl, indolyl, isoxazolyl, isoxazolysine, isothiasalyl, morpholinyl, amidine萼 ° stilbyl, stilbyl, hexahydro-D-pyridyl, hexahydropyridyl, piperanyl, pyridyl, pyrazolyl, pyrazoline, pyrazolyl, pyridyl, pyrrolidine Base, pyrrolinyl, Pyryl, daphthyl, dense stilbyl, stilbyl, fluorinyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrothienyl, tetrasialyl, thiodi Salyl, thiazolyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, oxadiazolyl, and the like. Heterocyclics also include bicyclic, tricyclic, and tetracyclic groups, of which Is to fuse any of the above-mentioned heterocycles to one or two heterocycles selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic rings, respectively These heterocycles include benzopyranyl, benzothienyl, D-indolyl, isoquinolyl, quinolyl, tetrahydroquinolyl, and the like.

第16頁 486472 五、發明說明（12) 雜環亦包括下式之化合物 α Ύ* 其中Γ選自-CH2-、-CH20-和-0-，且Γ選自 -c(0)-和-(C(Rn )2)v-，其中R”為氫或具有一至四個碳原子之烷基，且v為1 - 3。這些雜環包括1，3 -苯并間二氧雜環戊烯基、1，4-苯并二噚烷基及其類似物。本發明之雜環類亦可視需要以1 -4個分別選自烷氧基、烷基、胺基、芳基、豐氮基、氰基、鹵素、鹵院基、雜環基、石肖基或R1Q和Rn之Page 16 486472 V. Description of the invention (12) The heterocyclic ring also includes the compound αΎ * where Γ is selected from -CH2-, -CH20- and -0, and Γ is selected from -c (0)-and- (C (Rn) 2) v-, where R "is hydrogen or an alkyl group having one to four carbon atoms, and v is 1 to 3. These heterocyclic rings include 1,3-benzo-dioxopentene Group, 1,4-benzodifluorenyl group and the like. The heterocyclic group of the present invention may optionally be selected from alkoxy group, alkyl group, amine group, aryl group, and nitrogen group with 1 to 4 members as required. , Cyano, halogen, haloalkyl, heterocyclyl, Schottky, or R1Q and Rn

取代基來取代，其中R1Q和Ru —起為 (CH^n 其中A和D 分別為氧或S(0)t，且η為2-3。在本文中使用π (雜環）烷基π —詞時，代表以雜環取代之烷基。本發明之（雜環）烷基可視需要以芳基或雜環基來取代。在本文中使用”經基π —詞時，代表-0 Η。在本文中使用π硝基"一詞時，代表-Ν〇2。在本文中使用"氧代"一詞時，代表（二0)。Substituents for substitution, where R1Q and Ru — start from (CH ^ n where A and D are oxygen or S (0) t, respectively, and η is 2-3. Π (heterocyclic) alkyl π — is used herein When the word is used, it represents an alkyl group substituted with a heterocyclic ring. The (heterocyclic) alkyl group of the present invention may be substituted with an aryl group or a heterocyclic group as required. When the term πnitro is used in this article, it stands for -NO2. When the term "oxo" is used in this article, it stands for (20).

在本文中使用π在藥學上可接受的前藥π —詞時，代表當本發明之化合物可能具有不適當之毒性、刺激性、過敏反應，及其類似者，並具有相當合理之利益/危險比例，且對於其想要之用途和兩性離子形式是有效的時，在正常的醫學判斷的範圍内，其適合用來與人類和低等動物的組織接觸的那些本潑明之化合物的前藥。在本文中使用π前藥"一詞時，代表在活體内可訊速轉變When the term π, a pharmaceutically acceptable prodrug, is used herein, it means that the compounds of the present invention may have inappropriate toxicity, irritant, allergic reactions, and the like, and have a reasonable benefit / danger. Proportions of those compounds that are predominant to be used in contact with tissues of humans and lower animals, within the scope of normal medical judgment, are valid for their intended use and zwitterionic form. When the term π prodrug is used in this article, it means that it can be changed rapidly in vivo.

第17頁 486472 五、發明說明（13) 成上式之親代化合物的化合物，例如藉著在血液中的水解作用。在T· Higuchi 和V· Stella， Prodrugs as Novel Delivery Systems, A.C.S· Symposium Series 之第14冊，以及在Edward Β· Roche編輯，Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press， 1 9 8 7 中提供徹底的討論，將兩者合併於此以作為參考。在本文中使用〃螺烷基"一詞時，代表伸烷基雙（自由）基，其兩端與親代基團的相同碳原子結合，形成螺環基團。本發明之螺烷基可視需要以丨_ 2個分別選自烷基、芳基或雜每的取代基來取代。在本文中使用π硫酮基一詞時，代表（ = s)。在本發明化合物中可能出現不對稱或手性中心。本企圖包括各種立體異構物及其混合別的立Ϊ異構物，從構買得到的含有不對手;= ϊ Π ’以合成方式來製11，或藉著對映體化合物之-合物的製備作用，接著以& & +葙土、版化口物之此製備之。W離的===.已：知的解離方法來體的消旋混合物附接至丰柹字。卩*名為（+ /-)之對映層析法分離所得的非對 1:者再結晶作用或之混合物。在本文中，且接刀離先學對映體 i據在手性碳；^ +闲问> % # 構型，以符號"R"和"S"也 ’、周圍之取代基的在本發明化合物中亦it:的對映體。亦可i出現幾何異構物。本發明企圖Page 17 486472 V. Description of the invention (13) A compound of the parent compound of the above formula, for example, by hydrolysis in blood. In T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series, and in Edward Beta Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1 8 7 Provide a thorough discussion and incorporate both here for reference. When the term "spirospiroalkyl" is used herein, it refers to an alkylidene bis (free) group whose two ends are bonded to the same carbon atom of the parent group to form a spirocyclic group. The spiroalkyl group of the present invention may be optionally substituted with 2 substituents selected from an alkyl group, an aryl group, or a hetero group, respectively. When the term π-thioketo is used in this article, it stands for (= s). Asymmetric or chiral centers may occur in the compounds of the invention. The intention is to include various stereoisomers and their mixed other stereoisomeric isomers, which are obtained from the structure and contain no rivals; = ϊ Π '11 synthetically, or by enantiomeric compounds The preparation effect is followed by & & + soil and plated mouth. W ===. Already: the racemic mixture of the known dissociation method is attached to the font.卩 * The non-pairing 1: obtained by enantiochromatographic separation named (+/-) or recrystallization or a mixture thereof. In this article, the enantiomer i is based on the chiral carbon; ^ + idle question>% # configuration, with the symbols " R " and " S " also ', the surrounding substituents It is also the enantiomer of: in the compounds of the invention. Geometric isomers may also occur. The present invention attempts

11

第頁 486472Page 486472

ί Ϊ ί = Ϊ碳—碳雙鍵周圍之取代基的排列，或是在代基的排列所產生之幾何異構·，及其= ,,ζ" Ί:二:鍵周圍的取代基被命名為ζ或Ε構型，复/ Ζ 一㈣代表在碳—碳雙鍵同側上的取代基，而”Ε„ —ί Ϊ ί = 排列 The arrangement of substituents around the carbon-carbon double bond, or the geometric isomerism produced by the arrangement of the generation group, and its = ,, ζ " Ί: Two: The substituents around the bond are named In the ζ or Ε configuration, the complex / Z-㈣ represents a substituent on the same side of the carbon-carbon double bond, and "Ε„ —

St雙f相反侧上的取代基。在碳環周圍之取代i 士的取減，而”反”-詞代表在環平面反;=:;側 ,、中在％平面之同側和反側兩邊都有配置有取代基f 物之混合物被稱為順/反。％ β 内皮細胞蒋動測定真基本上按照P〇lverin1· P.J·等人，Methods Enzymol， 440 — 4 5 0 ( 1 9 9 1 )的描述來進行内皮細胞移動測定。簡言之，使人類微血管内皮細胞（HMVEC)在含有〇· 1%牛血清白蛋白（BSA)的DMEM (Dulbecc，s Modified EagleSubstituents on the opposite side of St double f. Substitutions around the carbocyclic ring are reduced, and the "anti" -word stands for anti-ring in the ring plane; = :; side, in the same side and the opposite side of the% plane are equipped with substituents f The mixture is called cis / trans. % Β endothelial cell assay was performed Endothelial cell migration assay was basically performed as described by Polverin1 · P.J. et al., Methods Enzymol, 440-4 50 (1 991). Briefly, human microvascular endothelial cells (HMVEC) were cultured in DMEM (Dulbecc, Modified Eagle) containing 0.1% bovine blood albumin (BSA).

Medium)上挨餓過夜。然後利用胰蛋白酶收獲細胞，並以 1 · 5 X 1 06個細胞/毫升之濃度再懸浮於含有〇 · i % BSA的 D Μ E Μ中。將忒細胞加至4 8 -孔經過修改之β 0 y d e n展開室 (Nucleopore Corporation， Cabln John, MD)的底部。集合展展室並倒轉之，並容許細胞在3 了。C下2小時，附接到已經在0 · 1 %明膠中浸泡.過夜並脫水的聚碳酸酯趨化性膜（5 微米孔隙大小）上。然後再倒轉展開室，並在上排室的孔中加入鹼性纖維母細胞生長因子（bFGF)和受試物質（至總體積50微升）；.然後在37 t下培養該裝置4小時。回收該膜’固定並染色（DiffQinck， FiSher Scientific，Medium) starved overnight. Cells were then harvested using trypsin and resuspended in DM E M with 0.1% BSA at a concentration of 1.5 x 106 cells / ml. Plutonium cells were added to the bottom of a 48-well modified β 0 y d e n deployment chamber (Nucleopore Corporation, Cabln John, MD). Assemble the exhibition room and turn it upside down, and allow the cells to stand at 3. At 2 hours at C, it was attached to a polycarbonate chemotactic film (5 micron pore size) that had been soaked in 0.1% gelatin overnight and dehydrated. Then invert the expansion chamber, and add basic fibroblast growth factor (bFGF) and test substance (to a total volume of 50 microliters) to the wells of the upper row; then incubate the device at 37 t for 4 hours. The membrane was recovered and fixed and stained (DiffQinck, FiSher Scientific,

第19頁 48()4/2Page 19 48 () 4/2

Pittsbrugh, PA), 上排室的細胞數目並以每1 0個高倍視或是在混合得自複較之移動抑制百分並計算每10個高倍視野中已經移動至。減去至DMEM + O.U BSA之背景移動，野（4 Ο Ο X)的移動細胞數目來報告數據，數實驗之結果時，以與陽性對照組相比比采報告之。結果顯示在表1中。代表性化合物對bFGF 抑制效力表1 誘發之人類微血管内皮細胞之移動的實例 _處艾爾索格蘭丁 (Irs〇gladine) -(600 nM) — 1 ____^20 (600) —一 3 ____ 100(600) 4 -----62(600) 6 7 ----^95 (600) -^_J00 (600) 8 -30 (600) 9 29 (6Ω0) 10 ____ 29 (600) 12 ---- 36 (600) 486472 五、發明說明（16) 實例抑制％>$_(nM)處 13 53 % (600 nM) 47 65 (600) 48 55 (600) 49 14(600) 50 100(600) 51 100(600) 52 100(600) 53 85 (600) 55 84 (600) 56 30 (600) 58 100 (600) 60 100 (600) 63 79 (500) 65 32 (200) 68 73 (500) 69 39 (500) 74 82 (500) 75 16 (500) 76 33 (500) 77 50 (500) 本發明之化合物，包括但不限於在實例中指定的那些，具有抗-血管生成的活性。像血管生成抑制劑一樣，這類化合物可用來治療原發性和轉移的固體腫瘤，以及乳癌；結腸癌；肺癌；口咽癌；咽下癌；食道癌；胃癌；胰臟癌；肝癌；膽囊癌；膽管癌；小腸癌；泌尿道癌，包括腎 1Pittsbrugh, PA), the number of cells in the upper row of cells and at 10 high magnifications or in the mixture obtained from the comparison of the percent inhibition of movement and calculated that every 10 high magnifications have moved to. After subtracting the background movement to DMEM + O.U. BSA, the number of moving cells in the field (4 00 ×) is used to report the data. When counting the results of the experiment, it is reported in comparison with the positive control group. The results are shown in Table 1. Inhibitory efficacy of representative compounds on bFGF Table 1 Examples of human microvascular endothelial cell-induced migration_Issoladine-(600 nM) — 1 ____ ^ 20 (600) — 3 ____ 100 (600) 4 ----- 62 (600) 6 7 ---- ^ 95 (600)-^ _ J00 (600) 8 -30 (600) 9 29 (6Ω0) 10 ____ 29 (600) 12- -36 (600) 486472 V. Description of the invention (16) Example inhibition%> 13 53% (600 nM) at $ _ (nM) 47 65 (600) 48 55 (600) 49 14 (600) 50 100 ( 600) 51 100 (600) 52 100 (600) 53 85 (600) 55 84 (600) 56 30 (600) 58 100 (600) 60 100 (600) 63 79 (500) 65 32 (200) 68 73 ( 500) 69 39 (500) 74 82 (500) 75 16 (500) 76 33 (500) 77 50 (500) The compounds of the present invention, including but not limited to those specified in the examples, have anti-angiogenic activity . Like angiogenesis inhibitors, these compounds are used to treat primary and metastatic solid tumors, as well as breast cancer; colon cancer; lung cancer; oropharyngeal cancer; pharyngeal cancer; esophagus cancer; gastric cancer; pancreatic cancer; liver cancer; Cancer; bile duct cancer; small intestine cancer; urinary tract cancer, including kidney 1

III 486472 五、發明說明（17) 臟癌、膀胱癌和尿道上皮癌；雌性生殖道的癌症，包括子宮頸癌、子宮癌、卵巢癌、絨毛膜癌和懷孕之滋養層的疾病、雄性生殖道的癌症’包括A列腺癌、精囊癌、睪丸癌和胚細胞腫瘤；内分泌腺的癌症，包括甲狀腺癌、’腎上腺癌和腦下腺癌；皮膚癌，包括血管瘤、黑色素瘤、起因於骨骨各或軟組織之肉瘤，以及卡波西氏（K a ρ 〇 s i ’ s )肉瘤；腦；神經、眼和腦膜的腫瘤，包括星狀細胞瘤、神經膠質瘤、神經膠質母細胞瘤、視網膜胚細胞瘤、神經瘤、神經胚細胞瘤、許旺細胞瘤和腦膜瘤；起因於造血惡性之固體^ 腫瘤，像是白血病，並包括綠色瘤，黴菌病黴菌樣的斑點和腫瘤，以及皮膚的T -細胞淋巴瘤/白血病；淋巴瘤包括霍奇金氏和非霍奇金氏的淋巴瘤；預防自體免疫之疾病，包括風濕性關節炎、免疫和退化性關節炎；眼科疾病，包括糖尿病之視網膜病、早產性視網膜病、角膜移殖之排斥、晶體後的纖維組織增殖、血管新生之青光眼、發紅、起因於黃斑退化和缺氧的視網膜血管新生；眼睛之異常的血管新生狀況；皮膚疾病，包括牛皮癖；血管疾病，包括血管瘤和在動脈粥樣硬化之斑點内的微血管增殖；奥斯勒 -威伯（0 s 1 e r - W e b b e r )病候群；心肌血管生成作用；斑點血管新生作用；毛細血管擴張；血友病之關節；血管纖維瘤；傷口肉芽組織化；其特徵為内皮細胞過度或異常刺激的疾病，包括腸黏連、克隆氏症、動脈粥樣硬化和肥厚的瘢痕（也就是瘢瘤），以及具有血管生成作用的疾病，像是病理性的結果，包括描葡萄瘡症（R 〇 c h e 1 e m i n a 1 i aIII 486472 V. Description of the invention (17) Dirty cancer, bladder cancer and urinary tract epithelial cancer; cancers of the female reproductive tract, including cervical cancer, uterine cancer, ovarian cancer, choriocarcinoma, and trophoblastic diseases of pregnancy 'Cancer' includes column A adenocarcinoma, seminal vesicle cancer, testicular cancer, and blastoma; cancers of the endocrine glands, including thyroid cancer, 'adrenal and subcranial adenocarcinoma; skin cancers, including hemangiomas, melanoma, and bone-causing Sarcoma of bone or soft tissue, and Kaposi's sarcoma; brain; tumors of nerves, eyes, and meninges, including astrocytoma, glioma, glioblastoma, retina Germ cell tumors, neuromas, neuroblastomas, Schwann cell tumors, and meningioma; solid tumors of hematopoietic origin ^ tumors, such as leukemia, and including green tumors, fungal-like spots and tumors, and T-cell lymphoma / leukemia; lymphomas include Hodgkin's and non-Hodgkin's lymphomas; prevention of autoimmune diseases, including rheumatoid arthritis, immunity, and degeneration Arthritis; ophthalmic diseases, including diabetic retinopathy, premature retinopathy, rejection of corneal transplantation, fibrous tissue proliferation after lens, angiogenic glaucoma, redness, retinal angiogenesis due to macular degradation and hypoxia Abnormal angiogenesis of the eye; skin diseases, including psoriasis; vascular diseases, including hemangiomas and microvascular proliferation in atherosclerotic spots; Osler-Webber (0 s 1 er-W ebber) Symptoms; Myocardial angiogenesis; Spotted angiogenesis; Capillary dilation; Hemophilic joints; Hemangiofibroma; Wound granulation organization; Characterized by diseases of excessive or abnormal stimulation of endothelial cells, including intestinal adhesions, Crohn's disease, atherosclerosis, and hypertrophic scars (also known as keloids), as well as angiogenic diseases, such as pathological results, including rosacea (Roche 1 emina 1 ia

第22頁 486472 五、發明說明（18) quintosa) ’ 和〉貝瘍（幽門螺桿菌（Heiic〇bacter pylori)) 。其他的用途是作為生育控制劑，其抑制***和胎盤的建立。本發明之化合物在單獨使用或與放射治療及/或其他以傳統方式投予患者來治療癌症之化學治療一起時，亦可用來預防上述之腫瘤的轉移。例如，在用來治療固體腫瘤時，本發明之化合物可與化學治療劑一起投予，像是α干擾素、COMP (環磷醯胺、常春新鹼、胺曱碟呤和脫气可的松）、鬼臼乙叉苷（etoposide)、mBAC0D(胺曱碟呤、博贫黴素、阿黴素（doxorubicin)、環磷醯胺、長春轫认、木‘ 塞米松）、PR0-MACE/M0PP(脫氩可的松、胺曱碟吟（具务（1 e u c 〇 v i η )解救）、阿黴素、環碟酸胺、紫杉醇、一龙有白乙叉苷/氮芥（mechlorethamine)、常春新鹼、脫g ^ 氧可的和曱基苄肼（procarbazine))、常春新鹼、常春芯私 1匕圏發、‘ 管抑制素（angioinhibins)、TNP-470、戊聚糖容汰a 血小板因子4、血管靜止素（angiostatin) (thalidomide)、SP-PG及其類似物。其他的化學 SU-101、CM-101、特克卡倫（Techgalan)、欧胺呢口定自巧療劑包 % 括烧基化製劑，像是氮芥，包括氮芥、***酸1 $ (melphan)、苯丁酸氮芬、環磷醯胺和依芙斯醯胺 ' (ifosfamide);亞硝基脲，包括雙氣乙基亞確脲 (carmus t i ne )、環己亞石肖S尿（1〇mu s t i n e )、曱環P ^ u氣乙亞硝脲（s e m u s t i n e )和鏈脲黴素（s t r e p t ο z o c i n );於心尹、峻院其酯，包括二曱磺酸丁酯（b u s u 1 f a η );三嗪類，包杠凡土访甲氮咪Page 22 486472 V. Description of the invention (18) quintosa) ′ and> beiyang (HeiicObacter pylori). Other uses are as fertility control agents, which inhibit ovulation and the establishment of placenta. The compounds of the present invention can also be used to prevent the metastasis of the aforementioned tumors when used alone or in combination with radiation therapy and / or other conventional chemotherapy to treat patients with cancer. For example, when used to treat solid tumors, the compounds of the present invention can be administered with chemotherapeutics, such as interferon alpha, COMP (cyclophosphamide, vincristine, aminopterin, and deacortisone ), Podophyllotoxin (etoposide), mBAC0D (aminopterin, bleomycin, doxorubicin, cyclophosphamide, vinorelbine, cemetose), PR0-MACE / M0PP (Descortisol, Ammonium Diazepam (Rescue (1 euc 〇 vi η)), Doxorubicin, Cycloperamide, Paclitaxel, Yilongyou Ethylglycoside / Metalethamine, Changchun Neophylline, deoxycodamine and procarbazine), vinblastine, vinorexin, hairpin, angioinhibins, TNP-470, pentosan-containing platelets Factor 4, angiostatin (thalidomide), SP-PG and its analogs. Other chemistry SU-101, CM-101, Techgalan, Euramine, and self-made therapeutics. Includes burn-based preparations, such as nitrogen mustard, including nitrogen mustard, phenylalanine 1 $ ( melphan), phentermine, cyclophosphamide, and ifosfamide; nitrosourea, including carmus ti ne, cyclohexanite (10mu stine), hydrazone ring Pseudoane nitrosourea (semustine) and streptozotocin (strept zocin); Yu Xinyin, Junyuan's esters, including butyl disulfonate (busu 1 fa η); triazines

第23頁 486472 五、發明說明（19) 胺（dacarbazine);乙烯亞胺類；包括硫化三（環氮丙基）石粦和六曱基三聚氰胺；葉酸類似物，包括胺甲碟呤；^咬類似物，包括5 -氟尿嘧咬、***糖胞脊；σ票呤類似物，包括6 -魏基嘌呤和6 -硫代鳥嘌呤；抗腫瘤之抗生物，包括放線菌素D ;蒽環型藥物，包括阿黴素、博菜黴素、絲ι裂徽素(：和曱烯土黴素（1^1：[11^11^(：丨11);荷爾蒙和荷爾蒙拮抗劑’包括三苯氧胺（tamoxifen)和皮質類固醇以及各式各樣的製劑，包括氣氨鉑（c i s p 1 a t i η )和布雷奎爾 (brequinar)。、叮以衍生自無機或有機酸之在藥學上可接受的鹽類形式，來使用本發明之化合物。”在藥學上可接受的"鹽意指那二在正常的醫學判斷的範圍内，適用於人類和低等動物之組織接觸，而沒有不適當之毒性、刺激性、過敏反應及 f類似者，並具有相當合理之利益/危險比例的鹽類。在藥學上可接受的鹽類是此項技藝中已熟知的。例如，s. M.Page 23 486472 V. Description of the invention (19) Amine (dacarbazine); Ethyleneimines; Including tris (cycloaziridyl) sulfur, hydrazone and hexafluorenyl melamine; Folic acid analogs, including amine methotrexate; ^ Bite Analogs, including 5-fluorouracil bites, arabinospores; sigmoidin analogs, including 6-weisylpurine and 6-thioguanine; antitumor antibiotics, including actinomycin D; anthracycline Type drugs, including doxorubicin, bleomycin, mitomycin (: and pinenemycin (1 ^ 1: [11 ^ 11 ^ (: 丨 11); hormones and hormone antagonists including tamoxifen (Tamoxifen) and corticosteroids and a variety of preparations, including cisplatin (cisp 1 ati η) and brequinar., Pharmaceutically acceptable salts derived from inorganic or organic acids Form, to use the compounds of the present invention. "A pharmaceutically acceptable" salt "means that within the scope of normal medical judgment, it is suitable for human and lower animal tissue contact without undue toxicity, Irritation, allergic reactions and similar, and have a reasonable Benefit / danger ratio salts. Pharmaceutically acceptable salts are well known in the art. For example, s. M.

Berge 等人，在J· Pharmaceutical Sciences， 1977， 66: 1以下，詳細地描述了在藥學上可接受的鹽類。這些鹽類 :就地最後的分離和純化本發明化合物的期間製備，或藉者使自由驗官能與適當的酸反應來單獨製備。代表性的酸加成鹽包括但不限於乙酸鹽、己二酸鹽、藻酸鹽、檸檬酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸 ^彳早酸鹽、樟腦磧酸鹽、一葡萄糖酸鹽、甘油磷酸鹽、，硫酸鹽.、庚酸鹽、己酸鹽、反丁烯二酸鹽、氫氣酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙烷磺酸鹽（羥乙磺酸Berge et al., J. Pharmaceutical Sciences, 1977, 66: 1 and below, describe pharmaceutically acceptable salts in detail. These salts can be prepared separately during the final in-situ isolation and purification of the compounds of the invention, or by reacting freely available functional groups with an appropriate acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyric acid ^ Isotrate, camphor salt, monogluconate, glyceryl phosphate, sulfate., Heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide Acid salt, 2-hydroxyethane sulfonate

第24頁 486472 五、發明說明（20) 鹽）、乳酸鹽、順丁烯二酸鹽、甲烷磺酸鹽、菸鹼酸鹽、 2 -萘磺酸鹽、草酸鹽、帕馬酸鹽、果膠酸鹽、過（二）硫酸鹽、3 -苯基丙酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫代氰酸鹽、磷酸鹽、穀胺酸鹽、碳酸氫鹽、對-曱苯續酸鹽和十一烧酸鹽。再者，可利用諸如低碳數烷基鹵之類的試劑，像是曱基、乙基、丙基和丁基氯、溴和碘；硫酸二烷基酯，像硫酸二曱酯、二乙酯、二丁 g旨和二戊醋；長鏈的_化物，像是癸基、月桂基、肉莖蔻基和硬脂醯基氣、溴和碘；芳烷基鹵，像是苄基和苯q 基溴及其他，將鹼性含氮的基團四級銨化。藉此獲得水或油-可溶或可分散的產物。可用來形成在藥學上可接受之酸加成鹽的酸類之實例，包括諸如氫氣酸、氫溴酸、硫酸和磷酸之類的無機酸，以及諸如乳酸、順丁烯二酸、琥珀酸和擰檬酸之類的有機酸。鹼加成鹽可就地在最後的分離和純化本發明化合物的期間中製備，藉著使含有羧酸之部份與適當之鹼反應，像是在藥學上可接受之金屬陽離子的氫氧化物、碳酸鹽或碳酸氫鹽，或與氨或有機的一級、二級或三級胺反應。在藥學上可接受的鹽類包括但不限於以鹼金屬或鹼土金屬為基礎的陽離子，像是經、鈉、鉀、妈、鎮和铭鹽，及其類似物，以及無毒性的四級銨和胺陽離子，包括銨、四曱銨、四乙銨、曱胺、二曱胺、三曱胺、三乙胺、二乙胺、乙胺及其類似物。·其他可用來形成鹼加成鹽之代表性的有機胺包括乙二胺、乙醇胺、二乙醇胺、六氫吡啶、六氫吡畊及Page 24 486472 V. Description of the invention (20) salt), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, Pectate, per (di) sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, valley Amine salts, bicarbonates, p-benzophenone salts, and undecanoate salts. Furthermore, reagents such as low-carbon alkyl halides can be used, such as fluorenyl, ethyl, propyl, and butyl chloride, bromine, and iodine; dialkyl sulfates, such as diethyl sulfate, diethyl sulfate Esters, dibutyl esters and dipentyl vinegar; long chain compounds such as decyl, lauryl, myristyl and stearyl, bromine and iodine; aralkyl halides such as benzyl and Benzene bromide and others, quaternize the basic nitrogen-containing groups. Thereby a water or oil-soluble or dispersible product is obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrogen acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and lactic acid, maleic acid, succinic acid, and Organic acids like citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting a moiety containing a carboxylic acid with a suitable base, such as a pharmaceutically acceptable hydroxide of a metal cation , Carbonate or bicarbonate, or react with ammonia or organic primary, secondary or tertiary amines. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals, such as sodium, potassium, sodium, potassium, magnesium, and town salts, and the like, and non-toxic quaternary ammonium And amine cations, including ammonium, tetraammonium, tetraethylammonium, ammonium, diamine, triamidine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines that can be used to form alkali addition salts include ethylenediamine, ethanolamine, diethanolamine, hexahydropyridine, hexahydropyridine, and

第25頁 486472 五、發明說明（21) 其類似物。本發明化合物的較佳鹽類包括磷酸鹽、三羥曱基胺基甲烧和乙酸鹽。本發明之化合物可與在藥學上可接受的延遲釋放之基質混合，像是生物可降解之聚合物，形成治療用的組合物。在本文中使用之延遲-釋放的基質，為可由酵素或酸-鹼水解或藉著溶解作用降解之物質，通常是聚合物製成的基質。一旦***體内，藉著酵素和體液作用在該基質上。希望從生物可相容的物質中選出延遲-釋放的基質，像是微脂粒、聚交酯（聚乳酸）、聚乙交酯（羧基乙酸的聚合物）、t 聚交酯共-乙交酯（乳酸與竣基乙酸的共聚物）聚酸酐、聚 (正）酯、多肽、透明質酸、膠原蛋白、硫酸軟骨素、羧酸、脂肪酸、磷脂類、多醣、核酸、多胺基酸、諸如苯丙胺酸、酪胺酸、異亮胺酸之類的胺基酸、聚核苷酸、聚乙烯丙烯、聚乙烯吡咯烷酮和矽酮。較佳之生物可降解的基質為具有聚交酯、聚乙交酯或聚交酯共-乙交酯（乳酸與羧基乙酸的共聚物）之一的基質。本發明之化合物或其組合可與在藥學上可接受的賦形劑或載劑混合，形成治療用的組合物。在藥學上可接受的載劑或賦形劑意指任何類型之無毒性的固體、半固體或液體填料、稀釋劑、包膠材料或調配物輔助劑。該組合物可以非經腸、舌下、腦池内、***内、腹腔内、經直腸、頰部或局部（像是藉著散劑、軟膏、藥水、經皮貼片或離子透入之裝置）的方式投予。在本文中使3 π非經腸的π —詞，意指投藥之模式包括靜Page 25 486472 V. Description of the invention (21) Analogues thereof. Preferred salts of the compounds of the present invention include phosphate, trishydroxymethylaminomethyl, and acetate. The compounds of the present invention can be mixed with a pharmaceutically acceptable delayed release matrix, such as a biodegradable polymer, to form a therapeutic composition. As used herein, a delayed-release matrix is a substance that can be hydrolyzed by enzymes or acid-bases or degraded by dissolution, and is generally a matrix made of a polymer. Once inserted into the body, the substrate acts through enzymes and body fluids. It is desirable to select a delayed-release matrix from biocompatible materials, such as microlipids, polylactide (polylactic acid), polyglycolide (polymer of carboxylic acid), t-polylactide co-glycolide Esters (copolymers of lactic acid and acetic acid) polyanhydrides, poly (n-) esters, peptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, Amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinyl pyrrolidone, and silicone. A preferred biodegradable matrix is a matrix having one of polylactide, polyglycolide, or polylactide co-glycolide (a copolymer of lactic acid and carboxylic acid). The compound of the present invention or a combination thereof may be mixed with a pharmaceutically acceptable excipient or carrier to form a therapeutic composition. A pharmaceutically acceptable carrier or excipient means any type of non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation adjuvant. The composition can be parenteral, sublingual, intracranial, intravaginal, intraperitoneal, rectal, buccal or topical (such as by means of powders, ointments, potions, transdermal patches or iontophoretic devices) Way to administer. In this paper, the term π is used to mean 3 π non-intestinal, meaning that the mode of administration includes static

第26頁 486472 五、發明說明（22) 脈内、肌肉内、腹腔内、胸骨内、皮下和關節内注射和輸液。可供非經腸注射之醫藥組合物包括在藥學上可接受的無菌含水或不含水之溶液、分散體、懸浮液或乳劑，以及在使用之前才在無菌的注射用溶液或分散體中重建的無菌散劑。適當之含水或不含水之載劑、稀釋劑、溶劑或媒劑的實例，包括水、乙醇、多元醇（像是甘油、丙二醇、聚乙二醇及其類似物）、羧曱基纖維素及其適當的混合物，植物油（像是撖欖油）和注射用的有機酯類，如油酸乙酯。例如，可藉著使用塗膜材料，像是卵填脂，在分散體的案i 例中藉著維持所需之顆粒大小，並藉著使用表面活性劑，維持適當的流動性。這些組合物亦可含有佐劑，像是防腐劑、濕潤劑、乳化劑和分散劑。可藉著包含各種抗細菌和抗真菌之製劑來確保沒有微生物的作用，像是對羥基苯曱酸、氣丁醇、酚、山梨酸及其類似物。亦可能想要包含等滲壓的製劑，像是糖類、氣化鈉及其類似物。可藉著包含延遲吸收之製劑，如單硬脂酸鋁和明膠，導致注射用醫藥形式的延長吸收作用。藉著在生物可降解之聚合物中，如聚交酯-聚乙交酯、聚（正酯）和聚（酸酐），形成藥物的微包膠基質，來製造注射用的儲藏形式。依據藥物聚合物之比例和所使用之特定聚合物的性質，可控制藥物釋放的速率。亦可藉著使藥物陷入與身體組織可相容之微脂粒或微乳劑中，來製備備藏之注射用的調配物。可將注射用的調配物滅S ，例如藉著通過保留細国之濾紙來過濾，或藉著以滅菌之固體組合物的形式將滅菌劑併入，在使用之前才Page 26 486472 V. Description of the invention (22) Intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injections and infusions. Pharmaceutical compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and those which are reconstituted in sterile parenteral solutions or dispersions before use. Sterile powder. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethyl cellulose, and Suitable mixtures are vegetable oils (such as olive oil) and organic esters for injection, such as ethyl oleate. For example, by using a coating material, such as egg filling, in the case of the dispersion, by maintaining the required particle size, and by using a surfactant, proper fluidity can be maintained. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Various antibacterial and antifungal preparations can be used to ensure that there is no microbiological effect, such as parabens, gas butanol, phenol, sorbic acid and the like. Formulations containing isotonic pressure, such as sugars, sodium vaporization, and the like, may also be desired. Prolonged absorption of pharmaceutical forms for injection can be caused by formulations containing delayed absorption, such as aluminum monostearate and gelatin. By using biodegradable polymers such as polylactide-polyglycolide, poly (n-ester), and poly (anhydride) to form microencapsulated matrices of drugs, storage forms for injection are manufactured. Depending on the proportion of drug polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Preparations for injection can also be prepared by immersing the drug in microlipids or microemulsions compatible with body tissues. Formulations for injection can be eliminated, for example, by filtering through the retention of fine paper, or by incorporating a sterilizing agent in the form of a sterilized solid composition, before use.

第27頁 486472 五、發明說明（23) 將其溶解或分散於滅菌的水或其他滅菌之注射用的介質中。局部投藥包括對皮膚、黏膜和肺臟與眼睛的表面投藥。局部投藥的組合物，包括吸入用的那些，可以加壓或無加壓之乾粉的形式來製備。在無加壓的粉末組合物中，可使用精細分開之形式的活性成份，與較大尺寸之在藥學上可接受的惰性載劑混合，其包括具有大小，例如直徑高達 1 0 0微米之顆粒。適當之惰性載劑包括諸如乳糖之類的糖類。想要的是，活性成份之顆粒至少有9 5重量％具有在 t 0. 0 1到1 0微米之範圍内的有效顆粒大小。至於對眼睛的局」ί 部投藥，在藥學上可接受之眼科媒劑中來遞送本發明之化合物，使得該組合物與眼睛表面維持接觸充份的時間，足以容許該化合物貫穿角膜和眼睛的内部區域，例如前房、後房、玻璃體、眼前房水、眼後房水、角膜、虹膜/睫狀體、晶狀體、脈絡膜/網膜和鞏膜。在藥學上可接受的眼科媒劑可以是例如眼藥膏、植物油或包膠的材料。另外，亦可將本發明之化合物直接注射到玻璃體和眼前房水中。可將該組合物加壓，並含有壓縮氣體，像是氮氣或液化的氣體推進劑。液化的推進劑介質與全部的組合物確實最丨Β 好是使活性成份不能以任何實質上的程度溶解於其中。力口壓的組合物亦可含有表面活性劑，像是液態或固態之非離子性表面活性劑，或可以是固態的陰離子性表面活性劑。在鈉鹽形式中使用固態之陰離子表面活性劑是較佳的。經直腸或***投藥的組合物，最好是坐劑，可藉著將本Page 27 486472 V. Description of the invention (23) Dissolve or disperse it in sterilized water or other sterilized injection media. Topical administration includes administration to the skin, mucous membranes, and the surface of the lungs and eyes. Compositions for topical administration, including those for inhalation, can be prepared in the form of a dry powder under pressure or without pressure. In non-pressurized powder compositions, the active ingredient can be used in finely divided form, mixed with a larger size of a pharmaceutically acceptable inert carrier, which includes particles having a size, such as up to 100 microns in diameter . Suitable inert carriers include sugars such as lactose. It is desirable that at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of t 0.01 to 10 microns. As for the administration to the eye, the compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle so that the composition maintains sufficient contact with the surface of the eye for a time sufficient to allow the compound to penetrate the cornea and the eye. Internal areas such as anterior chamber, posterior chamber, vitreous body, anterior aqueous humor, posterior aqueous humor, cornea, iris / ciliary body, lens, choroid / omentum, and sclera. A pharmaceutically acceptable ophthalmic vehicle may be, for example, an ophthalmic ointment, a vegetable oil, or an encapsulated material. In addition, the compounds of the present invention can also be injected directly into the vitreous and anterior aqueous humor. The composition may be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and the entire composition are indeed the best. The active ingredient cannot be dissolved in it to any substantial extent. Compressed compositions may also contain surfactants, such as liquid or solid nonionic surfactants, or may be solid anionic surfactants. It is preferred to use solid anionic surfactants in the sodium salt form. Compositions for rectal or vaginal administration, preferably as boluses,

第28頁 486472 五、發明說明（24) 發明化合物與適當之無刺激性的賦形劑或載劑混合來製備之，像是可可油、聚乙二醇或坐劑蠟，其在室溫下為固態，但是在體溫下為液態，並因此在直腸或***腔中融化，而釋放出該活性化合物。本發明之化合物亦可以微脂粒之形式投予。如同在此項技藝中已熟知的，微脂粒通常衍生自礙脂類或其他的脂質物質。藉著在含水介質中分散之單-或多-層水合的液晶來形成微脂粒。可以使用能夠形成微脂粒之任何無毒性、在生理學上可接受並可代謝的脂質。以微脂粒形式的本發明t 組合物，除了本發明化合物以外，還可以含有穩定劑、防腐劑、賦形劑及其類似物。較佳的脂質為天然或合成的石粦脂類和磷脂醯膽鹼（卵磷脂）。形成微脂粒之方法是此項技藝中已熟知的。參見例如P r e s c〇11編輯，M e t h〇d s i η Cell Biology ，第XIV冊，Academic Press， New York, N · Y. ( 1 9 7 6 )，第3 3頁以下，將其合併於此以作為參考。當在上文或其他治療中使用時，可以使用純物質形式之有療效之含量的本發明化合物，或是出現在帶有或不帶有在藥學上可接受之賦形劑之在藥學上可接受的鹽類形式中的這類形式。本發明化合物之"有療效的含量"，意指以合理的利益/危險比例，應用於任何醫學治療時，該化合物的含量足以治療血管生成之疾病（例如限制腫瘤的生長，或減慢或阻斷腫瘤的轉移）。然而，亦明瞭本發明之化合物和組合物每’日使用總量，將由負責照料的臨床醫師在正常醫學判斷的範圍内決定。對於任何特定患者的特別有療Page 28 486472 V. Description of the invention (24) The compound of the invention is prepared by mixing it with an appropriate non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or tinting wax, which is at room temperature. It is solid but liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing the active compound. The compounds of the present invention can also be administered in the form of microfat particles. As is well known in the art, microlipids are often derived from lipid-blocking or other lipid substances. Microlipids are formed by mono- or multi-layered hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming microliposome can be used. The t composition of the present invention in the form of microfat particles may contain a stabilizer, a preservative, an excipient and the like in addition to the compound of the present invention. Preferred lipids are natural or synthetic lithotripsy lipids and phospholipids choline (lecithin). The method for forming liposomes is well known in the art. See, for example, Prescolo 11 editors, Methodesi n Cell Biology, Book XIV, Academic Press, New York, N.Y. (197.6), pages 33 and below, incorporated herein by reference as reference. When used above or in other treatments, a therapeutically effective amount of a compound of the present invention may be used, or it may be pharmaceutically acceptable with or without pharmaceutically acceptable excipients. This form of the accepted salt form. The "effective content" of the compound of the present invention means that when applied to any medical treatment at a reasonable benefit / danger ratio, the content of the compound is sufficient to treat angiogenic diseases (such as limiting tumor growth or slowing down Or block tumor metastasis). However, it is also clear that the total daily usage of the compounds and compositions of the present invention will be determined by the clinician in charge within the scope of normal medical judgment. Special treatment for any particular patient

第29頁 486472 此一，而構成每將明瞭為了發明化合物混是原則上包括劑。本發明化合物之製備五、發明說明（25) 效之劑量含量和該疾病的嚴之特定組合物別和飲食；投物的***速率或同時使用的素。Ϊ列士口， 4匕所需的含量，亦完全是在此部或全身性投之每日總劑量天，而較常見了投藥之目的單一劑量 ’將依據各種重性；所使用 ;患者的年齡樂的時間；投 ;治療的期間藥物，以及在合物一開始之並逐漸增加劑項技藝的範圍予人類或其他，可以是例如的是1至300毫，可將每日的之組合物可含曰劑量。抑制、治療或合的製劑，並任何可用來治因素而定，包括待處理之疾病之特定化合物的活性；所使用、體重、一般的健康狀況、姓藥的途徑；所使用之特定化合 ;與所使用之特定化合物混合醫學技藝中已熟知的類似因劑量低於達到想要之治療效力量直到達到想要的效果為止，内。以單一或分開之劑量，局t 哺乳動物宿主的本發明化合物從0 . 0 1到2 0 0亳克/公斤體重每克/公斤體重。如果希望，為有效劑量分成數個劑量。因有如此的含量，或其幾分之預防血管生成之疾病而可與本不限於上文所列舉的那些，但療或預防血管生成之疾病的製縮寫在計劃說明亞楓，DME為」氫咲喃。和實例中已經使用之縮寫如下：DMSO為二曱二曱氧乙烷，EtOAc為醋酸乙酯，且THF為四P.29 486472 This one, while constituting each will make it clear that the compound of the invention is included in principle. Preparation of the compound of the present invention 5. Description of the invention (25) The effective dosage content and the specific composition and diet of the disease; the excretion rate of the drug or the simultaneously used element. The required amount of Ϊ 列士口, 4 dagger, is also completely the total daily dose of this part or systemically administered, and the single dose for the purpose of administration is more common will be based on various seriousness; used; the patient's The time of age; the time of administration; the drug during the treatment, and gradually increasing the range of dosage skills to humans or others at the beginning of the compound, which can be, for example, 1 to 300 milligrams, which can be a daily composition May contain a daily dose. Inhibitory, therapeutic, or combination preparations, and any factors that can be used to treat it, including the activity of the specific compound of the disease to be treated; the use, weight, general health, route of drug use; the specific combination used; and The particular compound used is well known in the art of medical compounding because the dosage is lower than the amount required to achieve the desired therapeutic effect until the desired effect is achieved. In single or divided doses, the compounds of the invention in mammalian hosts range from 0.01 to 200 g / kg body weight per g / kg body weight. If desired, divide the effective dose into several doses. Because of such content, or its fractional prevention of angiogenic diseases, it is not limited to those listed above, but the abbreviation for treating or preventing angiogenic diseases is described in the plan. Yafeng, DME is "hydrogen" Murmur. The abbreviations that have been used in the examples are as follows: DMSO is dioxoethane, EtOAc is ethyl acetate, and THF is four

^1^ 1

第30頁 486472 五、發明說明（26) 合成方法本發明之化合物和過程，將就有關於下列的合成計劃來更詳細地解釋，其解釋了藉此可製備本發明化合物的方法。計劃1 Η NR3R4-Page 30 486472 V. Description of the invention (26) Synthetic methods The compounds and processes of the present invention will be explained in more detail with regard to the following synthetic plan, which explains the methods by which the compounds of the present invention can be prepared. Plan 1 Η NR3R4-

反應 1: a-co2r +R1R2WReaction 1: a-co2r + R1R2W

NH NH 2B 反應2·· Α<ΝNH NH 2B reaction 2 Α < Ν

NH 如計劃1所示，從酯與雙胍的縮合作用（反應1 )，或從腈與氰基胍的縮合作用（反應2)來製備式I化合物三嗪環。反應2係在極性、高沸點的溶劑中，像是2 -曱氧乙醇，並在諸如氫氧化鉀之類強鹼的存在下進行。反應1係在醇中，最好是曱醇中進行。酯和腈前驅物係賭自商業來源，或使用已知之化學轉化作用來製備。計劃2NH As shown in Scheme 1, the triazine ring of the compound of formula I is prepared from the condensation of an ester with biguanide (Reaction 1), or from the condensation of a nitrile with cyanoguanidine (Reaction 2). Reaction 2 is performed in a polar, high boiling point solvent, such as 2-oxoethanol, and is performed in the presence of a strong base such as potassium hydroxide. Reaction 1 is carried out in an alcohol, preferably methanol. Ester and nitrile precursors are bet on commercial sources or are prepared using known chemical conversions. Plan 2

R3R4NR3R4N

Ri 、 R2 、 R3和為ΗRi, R2, R3 and Η

R3R4N R3和R4為Η ; R2為鐽烷醯基R3R4N R3 and R4 are fluorene; R2 is fluorenylalkyl

第31頁 486472 五、發明說明（27)Page 31 486472 V. Description of the invention (27)

Ri、R2、R3和 R4為 Η 1^和1?3為Η ; R2和iU為鐽烷醯基Ri, R2, R3, and R4 are Η 1 ^ and 1 to 3 are Η; R2 and iU are fluorenylfluorenyl

如計劃2所示，藉著在昇高溫度下，較佳的是8 0 - 9 0 °C，加熱帶有竣酸酐的二胺基三嗓前驅物，完成提供式I化合物之選擇性單醯化作用。或者，亦可藉著在較高的溫度下，較佳為在140-160 °C下，加熱帶有羧酸酐的二胺基三嗪前驅物，以完成2，4 -二酸化作用。計劃3As shown in plan 2, by heating the diamine trisodium precursor with end-anhydride at elevated temperature, preferably 80-90 ° C, the selective monomers of the compound of formula I are completed.化性。 Effect. Alternatively, the 2,4-diacidification can be accomplished by heating the diamine triazine precursor with carboxylic anhydride at a higher temperature, preferably at 140-160 ° C. Plan 3

實例20AExample 20A

R3R4 A為-B-L-Y ; B和Y為可視需要經取代之芳基或雜環基；且L為共價鍵或炔基R3R4 A is -B-L-Y; B and Y are optionally substituted aryl or heterocyclic groups; and L is a covalent bond or an alkynyl group

第32頁 486472 五、發明說明（28)Page 32 486472 V. Description of the Invention (28)

如計劃3所示，使用藉著諸如四價（三苯膦）鈀之類的鈀催化劑催化的過渡金屬-催化之交叉-偶聯反應，將2，4 -二胺基_ 6 -溴芳基-三嗦轉變為式I化合物。此外，藉著在諸如四價（三苯膦）ί巴之類的飽催化劑的存在下，以有機錫試劑，較佳的是六甲基二錫處理，接著與芳基溴進行交叉-偶聯，將實例20Α轉變為2, 4-二胺基-6-(三烷基甲錫烷基）芳基-三嗪，提供另一種製備式I化合物的途徑。在諸如四價（三苯膦）鈀之類的鈀催化劑的存在下，以諸如三甲基 (苯基乙炔基）錫之類的乙炔錫試劑處理實例20A，亦可提供式I化合物。計劃4As shown in Plan 3, 2,4-diamino-6-bromoaryl is catalyzed using a transition metal-catalyzed cross-coupling reaction catalyzed by a palladium catalyst such as tetravalent (triphenylphosphine) palladium. -The conversion of triamidine to a compound of formula I. In addition, by cross-coupling with an aryl bromide by treatment with an organotin reagent, preferably hexamethylditin, in the presence of a saturated catalyst such as tetravalent (triphenylphosphine) palladium The conversion of Example 20A into 2,4-diamino-6- (trialkylstannyl) aryl-triazine provides another way to prepare compounds of formula I. Treatment of Example 20A with a tin acetylene reagent such as trimethyl (phenylethynyl) tin in the presence of a palladium catalyst such as tetravalent (triphenylphosphine) palladium may also provide a compound of formula I. Plan 4

A為-B-L-Y ， B為環己基， Y為可視需要經取代之芳基，且 L為共價鐽A is -B-L-Y, B is cyclohexyl, Y is optionally substituted aryl, and L is covalent 鐽

如計劃4所示，可藉著芳基與環稀腈之弗瑞德-克來福特 (F r i e d e 1 C r a f t s )烧基化作用，接著按照在計劃1中的描述，加工腈中間物，來製備式I化合物。As shown in plan 4, by firing of Friede 1 Crafts of aryl groups and cyclonitrile, and then processing the nitrile intermediate as described in plan 1, A compound of formula I is prepared.

第33頁 486472 五、發明說明（29) 計劃Page 33 486472 V. Description of Invention (29) Plan

严iR Ν^Ν R3JR4N^ Ν人Yan iR Ν ^ Ν R3JR4N ^ Ν person

A a為m，可視需要經取代之雜環基， Y為可視需要經取代之芳基，且 L為共價鐽如計劃5所示，藉著在銅（I I )催化劑的存在下，異3 -哌啶曱酸酯與三芳基鉍試劑的烷基化作用，將六氫吡啶基芳基醋轉變為式I化合物。計劃6A a is m, optionally substituted heterocyclic group, Y is optionally substituted aryl, and L is covalent. As shown in plan 5, by the presence of a copper (II) catalyst, iso3 -Alkylation of piperidine phosphonate with triarylbismuth reagent to convert hexahydropyridylaryl vinegar to a compound of formula I. Plan 6

严1R2 N^N JL A R3R4N^N > -►Yan 1R2 N ^ N JL A R3R4N ^ N > -►

A A為 HY， B為環丁基， Y為芳基，且 L為共價鍵如計劃6所示，藉著將雙-曱苯磺酸鹽與丙二酸酯縮合A A is HY, B is cyclobutyl, Y is aryl, and L is a covalent bond. As shown in Scheme 6, by condensing bis-xylbenzenesulfonate with malonate

第34頁 486472 五、發明說明（30) 建構環烷環，在昇高的溫度下進行單-脫羧基作用一步根據計劃1 (反應1)處理，來製備式I化合物。計劃7 並進 C1Page 34 486472 V. Description of the invention (30) Construction of a naphthene ring and mono-decarboxylation at elevated temperature One step treatment according to plan 1 (reaction 1) to prepare a compound of formula I. Plan 7 goes forward C1

Cl Cl NR3R4 乂〜人。RiR2N^N^A RiR2N^n^A NR3R4 N^N 2N^N^^ArylCl Cl NR3R4 乂 ~ person. RiR2N ^ N ^ A RiR2N ^ n ^ A NR3R4 N ^ N 2N ^ N ^^ Aryl

Suzuki N CouplingSuzuki N Coupling

RlR2N N ClRlR2N N Cl

基環且，雜， -Y或鐽 -L基價基 -B芳共芳為為為為 ABLY 如計劃7所示，在胺基基團上帶有烷基取代基之二胺基三嗪，可利用經過控制並可斷定之方式來製備，隨後從三嗪環中置換氣。首先藉著親核性加成物，如格利雅試劑，將6 -芳基，雜芳基或環烷基取代基導入氰尿醯氯中，或是在例如，藉著利用硼酸之P d -催化的鈴木（S u z u k i )交叉偶聯反應來導入氮之後。本發明之化合物和過程，將就有關於下列的實例來更詳細地解釋，其企圖作為解釋之用，而非對本發明之範圍有所限制。 ’ 實例1 .And a hetero, -Y or 鐽 -L valence group -B aromatic co-aryl is ABLY As shown in Scheme 7, a diaminotriazine having an alkyl substituent on an amine group, It can be prepared in a controlled and deterministic manner, with subsequent replacement of gas from the triazine ring. First introduce 6-aryl, heteroaryl or cycloalkyl substituents into cyanuric chloride by nucleophilic adducts, such as Grignard reagents, or, for example, by using P d- After catalyzing a Suzuki cross-coupling reaction to introduce nitrogen. The compounds and processes of the present invention will be explained in more detail with reference to the following examples, which are intended to be illustrative, and not to limit the scope of the present invention. ’Example 1.

第35頁 486472 9a 6S 21] 案號87120449 年月曰修正五、發明說明（31) 6 - [ 1 -（二苯曱基）-3-氮雜環丁烧基1一1，3，5-三嗪一2，4一二 Μ 將在2 -曱氧乙醇（1 0毫升）中之1 -(聯苯曱基）-3 -氮雜環丁烷腈（500毫克，2.01毫莫耳）、雙氰胺（220毫克，2.62 毫莫耳）和ΚΟΗ (34毫克，0· 6 04毫莫耳）的溶液加熱至迴流 4小時，以水稀釋並冷卻至室溫。以水沖洗沉澱物，並在真空下脫水，得到標題化合物。熔點 1 2 6 - 1 2 8 °C ; MS (DCI/NH3) m/e 3 33 (M + H)+ ； M NMR ( 3 0 0 兆赫茲，DMSO — d6) ά 7· 3 (d， 4Η), 7.2 (t, 4Η), 7.05 (t, 2H), 6.5-6.7 (br s, 4H), 4.35 (s, 1H), 3. 2-3. 3 (m, 3H), 3.1-3.15 (m, 2H); 關於 C19H2GN6 ·0·75Η2Ο 之分析計算值：C, 6 5.9 7; H, 6.26; N， 24.29。實驗值：C, 65.67; H, 5.65; N, 23.84。實例2 6 -（1一苯基一4一六氫口比°定基）一1，3，5 -三嗪一2，4 一二胺Page 35 486472 9a 6S 21] Case No. 87120449 Rev. V. Description of the Invention (31) 6-[1-(Diphenylfluorenyl) -3-azacyclobutanyl 1-1, 3, 5- Triazine-2,4-2M will be 1- (biphenylfluorenyl) -3-azacyclobutanenitrile (500 mg, 2.01 mmol) in 2 -oxoethanol (10 ml), A solution of dicyandiamide (220 mg, 2.62 mmol) and KIOΗ (34 mg, 0.64 mmol) was heated to reflux for 4 hours, diluted with water and cooled to room temperature. The precipitate was washed with water and dehydrated under vacuum to give the title compound. Melting point 1 2 6-1 2 8 ° C; MS (DCI / NH3) m / e 3 33 (M + H) +; M NMR (3 0 0 MHz, DMSO — d6) ά 7 3 (d, 4Η ), 7.2 (t, 4Η), 7.05 (t, 2H), 6.5-6.7 (br s, 4H), 4.35 (s, 1H), 3. 2-3. 3 (m, 3H), 3.1-3.15 ( m, 2H); Analytical calculated values for C19H2GN6 · 0 · 75Η2Ο: C, 6 5.9 7; H, 6.26; N, 24.29. Experimental values: C, 65.67; H, 5.65; N, 23.84. Example 2 6-(1 -phenyl-4-hexahydro port ratio ° aryl)-1,3,5-triazine -2,4 -diamine

實例2 A 在室溫下攪拌在二氯曱烷（100毫升）中之三苯基鉍（5.02 克，11.4毫莫耳）、乙酸銅（1.79克，9.85毫莫耳）和異3-哌啶曱酸乙酯（1 · 5毫升，9 · 7毫莫耳）的溶液1 8小時，以水稀釋並通過矽藻土®過濾。將有機層脫水（MgS04)並濃縮之。藉著閃爍層析法在矽膠上純化殘餘物，以0 - 2 %丙酮/ 二氯曱烷洗脫，得到預定的化合物。Example 2 A Triphenylbismuth (5.02 g, 11.4 mmol), copper acetate (1.79 g, 9.85 mmol) and iso 3-piperidine in dichloromethane (100 ml) were stirred at room temperature. A solution of ethyl acetate (1.5 ml, 9.7 mmol) was diluted for 18 hours, diluted with water and filtered through Celite®. The organic layer was dehydrated (MgS04) and concentrated. The residue was purified on silica gel by scintillation chromatography and eluted with 0-2% acetone / dichloromethane to give the intended compound.

O:\56\56069.ptc 第36頁 2001.06.21.036 486472 五、發明說明（32) MS (DCI/NH3) m/e 234 (M.H)+。O: \ 56 \ 56069.ptc Page 36 2001.06.21.036 486472 V. Description of the invention (32) MS (DCI / NH3) m / e 234 (M.H) +.

實例2B 按照在Inorganic Synthesis，第7冊，第56-58 頁 (1 9 6 3 )中的描述來製備預定的化合物。Example 2B A predetermined compound was prepared as described in Inorganic Synthesis, Volume 7, pages 56-58 (1 963).

實例2 C 6-（1-苯基-4-六氫吡啶基）-1，3, 5 -三嗪-2, 4 -二胺在室溫下攪拌在曱醇（4毫升）中之實例2A (0.464克， 1 · 9 9毫莫耳）和2B ( 0 · 2 1 1克，2 · 0 9毫莫耳）的溶液1 6小時。以曱醇沖洗沉澱物，在真空下脫水，並使其從二氧六, /乙醇中再結晶，得到標題化合物。熔點 2 0 2 - 2 0 4 °C ; MS (DCI/NH3) m/e 271 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 7· 1 9 (t， 2H)， 6· 94 (t， 211)，6·72 (t，1Η)，6.56 (br s，4Η)，4.11 (q，2Η)， 3.77 (m， 2H)， 2.75 (dt， 2H)， 2.41 (m， 1H)， 1.79 (m，2H)。關於CmH18N6. 0. 67H20 之分析計算值：C， 5 9. 5 8 ; H， 6.90; N，27.78。實驗值：C，59.27; H， 6·79; N，25.51。實例3 反-6-(4 -苯基環己基）-1，3, 5 -三嗪-2, 4-二胺Example 2 C 6- (1-phenyl-4-hexahydropyridyl) -1,3,5-triazine-2,4-diamine Example 2A with stirring in methanol (4 ml) at room temperature (0.464 g, 1.99 mmol) and 2B (0.21 1.1 g, 2.09 mmol) solution for 16 hours. The precipitate was washed with methanol, dehydrated under vacuum, and recrystallized from dioxane / ethanol to give the title compound. Melting point 2 02-2 0 4 ° C; MS (DCI / NH3) m / e 271 (M + H) +; 4 NMR (300 MHz, DMS〇-d6) 5 7 · 1 9 (t, 2H), 6.94 (t, 211), 6.72 (t, 1Η), 6.56 (br s, 4Η), 4.11 (q, 2Η), 3.77 (m, 2H), 2.75 (dt, 2H), 2.41 (m, 1H), 1.79 (m, 2H). Analytical calculated values for CmH18N6. 0. 67H20: C, 5 9. 5 8; H, 6.90; N, 27.78. Experimental values: C, 59.27; H, 6.79; N, 25.51. Example 3 trans-6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine

實例3A 4-苯基己烯腈以A 1C 13 (13克，97毫莫耳）分批處理環己烯腈（9毫升， 8 0. 6毫莫耳）和苯（75毫升）的溶液，然後在室溫下攪拌2小Example 3A 4-Phenylhexenenitrile was treated with a solution of cyclohexenenitrile (9 ml, 8 0.6 mmol) and benzene (75 ml) in batches of A 1C 13 (13 g, 97 mmol), Then stir at room temperature for 2 hours

第37頁 486472 五、發明說明（33) 時。將該混合物倒入冰中，並以醋酸乙酯萃取。連續以水和鹽水沖洗該萃取物，脫水（MgS04)並濃縮之。在125 °C下蒸顧該殘餘物（0 · 6毫米采柱），得到標題化合物。 MS (DCI/NH3) m/e 2 0 3 (Μ + ΝΗ4)+ ；實例3 Β 反- 6- (4 -苯基環己基）-1，3，5 -三曉-2，4 -二胺按照實例1來處理實例3 A，得到標題化合物。 MS (DCI/NH3) m/e 2 7 0 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) δ 7· 20-7· 32 (m， 4H)， 7.12-7.18 (m, 1H), 6.57 (br s, 4H), 2.46 (tt, 1H), 2.32 (tt, 1H), 1.80-1.93 (m, 4H), 1.41-1.66 (m, 4H); 關於 C15H19N5 之分析計算值：C， 6 6.8 8; H， 7.11; N， 2 6.0 0。實驗值：C，6 6.8 5; Η, 7·00; N，2 6.0 8。實例4 6-3-( 1 H-吡咯-1-基）苯基]-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理3-(1Η -吡咯-1-基）苄腈，得到標題化合物。熔點 1 64- 1 7 0 °C ; MS (DCI/NH3) m/e 2 5 3 (Μ + Η)τ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-dG) 5 8· 35 (s， 1H)，8· 15 (d， III)， 7·7 (dd， III)， 7.6-7.5 (m， 1H)， 7.3 (t， 3H)， 7. 0-6. 8 (br s, 4H), 6. 3-6. 25 (m, 2H);Page 37 486472 V. Description of the invention (33). The mixture was poured into ice and extracted with ethyl acetate. The extract was washed successively with water and brine, dehydrated (MgS04) and concentrated. The residue was evaporated at 125 ° C (0.6 mm column) to give the title compound. MS (DCI / NH3) m / e 2 0 3 (Μ + ΝΗ4) +; Example 3 Beta trans-6- (4-phenylcyclohexyl) -1,3,5-trixiao-2,4-diamine Example 3 A was treated as in Example 1 to give the title compound. MS (DCI / NH3) m / e 2 7 0 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) δ 7.20-7 · 32 (m, 4H), 7.12-7.18 (m, 1H), 6.57 (br s, 4H), 2.46 (tt, 1H), 2.32 (tt, 1H), 1.80-1.93 (m, 4H), 1.41-1.66 (m, 4H); Analysis on C15H19N5 Calculated: C, 6 6.8 8; H, 7.11; N, 2 6.0 0. Experimental values: C, 6 6.8 5; Η, 7.0; N, 2 6.0 8. Example 4 6-3- (1 H-pyrrole-1-yl) phenyl] -1,3,5-triazine-2, 4-diamine ) Benzonitrile to give the title compound. Melting point 1 64- 1 70 ° C; MS (DCI / NH3) m / e 2 5 3 (Μ + Η) τ; 4 NMR (300 MHz, DMS〇-dG) 5 8.35 (s, 1H), 8.15 (d, III), 7.7 (dd, III), 7.6-7.5 (m, 1H), 7.3 (t, 3H), 7. 0-6. 8 (br s, 4H) , 6. 3-6. 25 (m, 2H);

關於CnH 13 u12 n6 之分析計算值：C， 61. 89; H, 4. 79; N,Analytical calculated values for CnH 13 u12 n6: C, 61. 89; H, 4. 79; N,

ill 1ill 1

III mIII m

ISIS

IIP 第38頁 486472 五、發明說明（34) 33.31。實驗值：C，62.20; H，4.56; N，32.39。實例5 順/反-6-(3 -苯基環丁基）-1，3, 5 -三嗪-2, 4 -二胺按照在J. Am. Chem· Soc. 1985， 107， 7247-7257 中的描述來製備3-苯基環丁烷-1 -羧酸順/反-曱酯的溶液，並按照實例2C來處理，得到標題化合物。溶點 98-102 C ; Μ NMR ( 3 0 0 兆赫茲，DMSO-d6) 5 7· 31 (m，4H)，7. 19 (m， 1H), 6.60 (m, 4H), 3.62 (m, 0.4H), 3.43 (m, 0.4Η)^ 3.18 (m, 0.8H), 2.88 (m, 0.8H), 2.56 (m, 1.2H), 2.38 (m, 2. 4H); 關於C13H15N5 · 0· 5CH3C02CH2CH3 之分析計算值：C，63.14; H，7.71; N，24.54。實驗值：C， 6 2· 75; H， 6.73; N， 24.48。實例6 6-[ 1，1’ -聯苯基]-2 -基-1，3, 5 -三嗪-2, 4-二胺按照實例1來處理[1，1 ’ -聯苯基）-2 -腈，得到標題化合物。 MS (DCI/NH3) m/e 2 64 (M + H)1 ； 41 NMR ( 3 0 0 兆赫茲，DMSO-d6) 3 7· 63-7· 2 (m，5H)， 7· 37-7· 27 (m，4Η)，6. 6 (br s，4Η); 關於C15H13N5 之分析計算值：C， 68·42; H， 4.97;. N， 2 6 · 5 9。實驗值：C，6 7 · 8 5 ; II，4 · 9 4 ; N，2 6 · 5 0。實例7IIP Page 38 486472 V. Description of Invention (34) 33.31. Experimental values: C, 62.20; H, 4.56; N, 32.39. Example 5 Cis / trans-6- (3-phenylcyclobutyl) -1,3,5-triazine-2,4-diamine according to J. Am. Chem · Soc. 1985, 107, 7247-7257 To prepare a solution of 3-phenylcyclobutane-1 -carboxylic acid cis / trans-fluorenate, and work up as in Example 2C to give the title compound. Melting point: 98-102 C; M NMR (300 MHz, DMSO-d6) 5 7.31 (m, 4H), 7.19 (m, 1H), 6.60 (m, 4H), 3.62 (m, 0.4H), 3.43 (m, 0.4Η) ^ 3.18 (m, 0.8H), 2.88 (m, 0.8H), 2.56 (m, 1.2H), 2.38 (m, 2. 4H); About C13H15N5 · 0 · Analytical calculation value for 5CH3C02CH2CH3: C, 63.14; H, 7.71; N, 24.54. Experimental values: C, 6 2.75; H, 6.73; N, 24.48. Example 6 6- [1,1'-biphenyl] -2-yl-1,3,5-triazine-2,4-diamine [1,1'-biphenyl)- 2-Nitrile to give the title compound. MS (DCI / NH3) m / e 2 64 (M + H) 1; 41 NMR (300 MHz, DMSO-d6) 3 7 · 63-7 · 2 (m, 5H), 7. 37-7 · 27 (m, 4Η), 6.6 (br s, 4Η); Analytical calculated values for C15H13N5: C, 68 · 42; H, 4.97 ;. N, 2 6 · 5 9. Experimental values: C, 6 7 · 8 5; II, 4 · 9 4; N, 2 6 · 50. Example 7

第39頁 486472 五、發明說明（35) 6-(4，-石肖基[1，1，-聯苯基]-4-基）-1，3，5-三嗦-2，4 -二胺按照實例1來處理4’ -硝基-[1，1’ -聯苯基]-4-腈，得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 3 0 9 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMSO-d6) δ8·5-8·4 (m， 4H)， 8·1 (d，2H)，7· 95 (d，2H)，6· 85 (br s，4H); 關於C15H12N6 02 之分析計算值：C， 5 8.43; H，3.92; N， 2 7. 42。實驗值：C，58. 46; H，3· 76; N，27· 12。 t 實例8 反- 6- [4-(4 -戊基環己基）苯基]-1，3，5 -三嗦-2，4 -二胺按照實例1來處理4-(反-4-戊基環己基）笮腈，得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 34 0 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMSO —d6) δ 8· 2 (d， 2H)， 7· 3 (d， 2H), 6.75 (bs, 4H), 1.85 (d, 4H), 1.55-1.4 (m, 2H), 1.37-1.2 (m, 10H), 1.1-1.05 (m, 2H), .85 (t5 3H); 關於C2QH29N5 之分析計算值：C， 7 0.7 6; H, 8.61; N, 2 0 · 6 2。實驗值：C，7 0 · 7 1 ; H，8 · 7 3 ; N，2 0 · 6 7。實例9 6 — (4—苯氧苯基）一1，3，5 —三嗪一2，4 —二月安按照實例1來處理4-苯氧基苄腈，得到標題化合物。Page 39 486472 V. Description of the invention (35) 6- (4, -Shi Xiaoji [1,1, -biphenyl] -4-yl) -1,3,5-trifluorene-2,4-diamine according to Example 1 was used to treat 4'-nitro- [1,1'-biphenyl] -4-carbonitrile to give the title compound. Melting point> 2 5 0 ° C; MS (DCI / NH3) m / e 3 0 9 (M + H) +; 4 NMR (3 0 0 MHz, DMSO-d6) δ8 · 5-8 · 4 (m , 4H), 8.1 (d, 2H), 7.95 (d, 2H), 6.85 (br s, 4H); Analytical calculated values for C15H12N6 02: C, 5 8.43; H, 3.92; N , 2 7. 42. Experimental values: C, 58. 46; H, 3.76; N, 27.12. t Example 8 trans-6- [4- (4-pentylcyclohexyl) phenyl] -1,3,5-trifluorene-2,4-diamine 4- (trans-4-pentane) was treated as in Example 1. Cyclohexyl) cyanonitrile to give the title compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 34 0 (M + H) +; 41 NMR (3 0 0 MHz, DMSO — d6) δ 8 · 2 (d, 2H), 7.3 (d, 2H), 6.75 (bs, 4H), 1.85 (d, 4H), 1.55-1.4 (m, 2H), 1.37-1.2 (m, 10H), 1.1-1.05 (m, 2H), .85 (t5 3H); Analytical calculated value for C2QH29N5: C, 7 0.7 6; H, 8.61; N, 2 0 · 62. Experimental values: C, 7 0 · 7 1; H, 8 · 7 3; N, 20 · 67. Example 9 6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diueanzine 4-phenoxybenzonitrile was treated according to Example 1 to obtain the title compound.

第40頁 486472 五、發明說明（36) 炫點 1 9 8 - 2 0 0 C ; MS (DCI/NH3) m/e 28 0 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) δ 8· 3-8· 2 (m，2H)， 7.5-7.4 (m, 2Η), 7.2 (t, 1H), 7.17-7.0 (m, 4H), 6. 9-6. 65 (br s, 4H); 關於 C15H13N50 之分析計算值：C, 64.51; H， 4.69; N, 2 5.0 7。實驗值：C，6 3.84; H，4·67; N，24.9 0。實例1 0 N-環己基-Ν’ -[4-(4, 6 -二胺基-1，3, 5 -三嗪-2-基）苯基]脲Page 40 486472 V. Description of the invention (36) Dazzle point 1 9 8-2 0 0 C; MS (DCI / NH3) m / e 28 0 (M + H) +; 4 NMR (3 0 0 MHz, DMS 〇-d6) δ 8 · 3-8 · 2 (m, 2H), 7.5-7.4 (m, 2Η), 7.2 (t, 1H), 7.17-7.0 (m, 4H), 6. 9-6. 65 (br s, 4H); Analytical calculated values for C15H13N50: C, 64.51; H, 4.69; N, 2 5.0 7. Experimental values: C, 6 3.84; H, 4.67; N, 24.90. Example 1 0 N-Cyclohexyl-N '-[4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] urea

實例1 0 A 按照實例1來處理4-胺基笮腈，得到預定的化合物。 MS (DCI/NH3) m/e 2 0 3 (M + H)+ ；Example 10 A 4-Aminofluorenitrile was treated according to Example 1 to obtain the intended compound. MS (DCI / NH3) m / e 2 0 3 (M + H) +;

實例1 0 B N —環己基一Ν’ 一[4-(4，6 —二月安基一1，3，5 —三d秦一2 -基）苯基]服在室溫下攪拌在二氧六環中之實例10A (1. 0克，4. 9毫莫耳）、異氰酸環己酯（610毫克，4.9毫莫耳）和三乙胺 (0 · 6 8毫升，4 · 9毫莫耳）的混合物過夜。以水沖洗沉澱物，並在真空下脫水，得到標題化合物。 MS (DCI/NH3) m/e 32 8 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMSO-d6) ά 8· 4 (s， 1H)， 8· 23 (t， HI), 8.8-8.75 (m, III), 7.5 5 - 7.4 5 (m, III), 7.25-7.2 (t，1H)，7.0-6.8 (br s，411)，6.0 (d，1H)，3.55-3.4 (m, III), 1.9-1.8 (m, 2H), 1.7-1.6 (m, 2H), 1.59- 1· 5 (m， III)， 1· 2-0· 5 (m， 5H);Example 1 0 BN—Cyclohexyl-N ′-[4- (4,6—Febranyl-1,3,5—Tri-d-Qin-2-yl) phenyl] was stirred at room temperature under dioxin. Examples of Hexacyclic 10A (1.0 g, 4.9 mmol), cyclohexyl isocyanate (610 mg, 4.9 mmol) and triethylamine (0.68 ml, 4.9 mmol) Mol) mixture overnight. The precipitate was washed with water and dehydrated under vacuum to give the title compound. MS (DCI / NH3) m / e 32 8 (M + H) +; 41 NMR (3 0 0 MHz, DMSO-d6) ά 8. 4 (s, 1H), 8. 23 (t, HI), 8.8-8.75 (m, III), 7.5 5-7.4 5 (m, III), 7.25-7.2 (t, 1H), 7.0-6.8 (br s, 411), 6.0 (d, 1H), 3.55-3.4 ( m, III), 1.9-1.8 (m, 2H), 1.7-1.6 (m, 2H), 1.59- 1.5 (m, III), 1.2-2-0 · 5 (m, 5H);

第41頁 486472 五、發明說明（37) 關於C15H21N7〇之分析計算值：C， 5 8.7 0; H, 6.47; N, 2 9.9 5。實驗值：C，58.49; Η，6·59; Ν，29·49。實例11 (4, 6 -二胺基-1，3, 5 -三嗪-2 -基）苯基甲烯酮按照實例1來處理4-氰基二苯酮，得到標題化合物。熔點 > 2 5 0 °C ; Μ NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 4 (d， 2H)， 7· 9 (d， 2H), 7.8 (m, 2H), 7.7 (m, 1H), 7.6 (t, 2H), 6.9 (b r s，4 H ); MS (DCI/NH3) m/e 2 9 2 (M + H)+; 關於C16H13N5〇之分析計算值：C， 6 5.9 7; H， 4.50; N， 24.04。實驗值：C，6 5.74; H，4.32; N，2 3.9 3。實例1 2 N-[4-(4，6 -二胺基-1，3，5 -三嗪-2-基）苯基]-Ν’ -苯基脲按照實例1 0Β來製備實例1 0A，但是以異氰酸苯基酯來取代異氰酸環己酯，得到標題化合物。 4 NMR ( 3 0 0 兆赫茲，DMSO-d6) ά 8. 8 (s， 1H)， 8. 65 (s， 1Η)，8.35 (t，1Η)，7.9 (d，1Η)，7.6-7.5 (m，1Η)， 7.4 9-7.44 (m, 2H), 7.35 (t, 1H), 7.29 (t, 2H), 7.0 (t，1H)，6· 8-6· 7 (br s，4H); 關於C16H15N70 之分析計算值：C， 5 9. 8 0 ; H， 4. 70 ; N， 3 0 · 5 1。實驗值：C，5 9 . 6 1 ; II，4 · 7 2 ; N，2 9 · 9 1。實例1 3 6-(1，4 -二噚-8_ 氮雜螺[4, 5]癸-8 -基）-1，3, 5 -三嗪-2, 4-Page 41 486472 V. Explanation of the invention (37) The calculated value of C15H21N70: C, 5 8.7 0; H, 6.47; N, 2 9.9 5. Experimental values: C, 58.49; Η, 6.59; Ν, 29.49. Example 11 (4,6-diamino-1,3,5-triazin-2-yl) phenylmethenone 4-cyanobenzophenone was treated according to Example 1 to give the title compound. Melting point> 2 50 ° C; M NMR (300 MHz, DMS 0-d6) 58.4 (d, 2H), 7.9 (d, 2H), 7.8 (m, 2H), 7.7 (m, 1H), 7.6 (t, 2H), 6.9 (brs, 4 H); MS (DCI / NH3) m / e 2 9 2 (M + H) +; Analytical calculated value for C16H13N50: C, 6 5.9 7; H, 4.50; N, 24.04. Experimental values: C, 6 5.74; H, 4.32; N, 2 3.9 3. Example 1 2 N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -N'-phenylurea Example 10A was prepared according to Example 10B, However, the substitution of cyclohexyl isocyanate with phenyl isocyanate gave the title compound. 4 NMR (3 0 0 MHz, DMSO-d6) ά 8. 8 (s, 1H), 8. 65 (s, 1Η), 8.35 (t, 1Η), 7.9 (d, 1Η), 7.6-7.5 ( m, 1Η), 7.4 9-7.44 (m, 2H), 7.35 (t, 1H), 7.29 (t, 2H), 7.0 (t, 1H), 6. 8-6 · 7 (br s, 4H); Analytical calculated values for C16H15N70: C, 5 9. 8 0; H, 4. 70; N, 3 0 · 51. Experimental values: C, 5 9. 6 1; II, 4 · 7 2; N, 2 9 · 9 1. Example 1 3 6- (1,4-Dihydrazone-8_ azaspiro [4, 5] dec-8-yl) -1,3,5-triazine-2, 4-

第42頁 486472 五、發明說明（38) 二胺將在二氧六環（10毫升）和乙醇（40毫升）中之2,4 -二胺基 -6 -氯-1,3，5 -三嗓（2克，14毫莫耳）、1，4 -二卩萼-8-氮雜螺 [4· 5]癸烷（3克，21毫莫耳）和KOH (100毫克，1· 8毫莫耳）的混合物加熱至迴流過夜，以水稀釋並過濾·之。以水沖洗沉澱物並在真空下脫水，得到標題化合物。熔點 2 0 9 - 2 1 1 °C ; MS (DCI/NH3) m/e 2 5 3 (M + H)+ ； 4 NMR (300 兆赫茲，DMSO-d6)56.14 (br s， 4H)， 3.90t (s, 4H), 3.75-3.68 (m, 4H), 1.58-1.51 (m, 4H); 關於 C1gH16N6 02 之分析計算值：C，47.61; H， 6.39; N， 33·31。實驗值：C，47·45; H，6·34; N，3 3.24。實例1 4 6-(4’ -戊基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4-二胺按照實例1來處理4’ -戊基[1，1’ -聯苯基]-4-腈，得到標題化合物。熔點 2 4 2 - 2 4 4 °C ; MS (DCI/NH3) m/e 334 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8. 3 (d， 2H)， 8. 75 (d， 2H)， 8.65 (d， 2H)， 7.3 (d， 2H)， 6.75-6.82 (br s， 411)，2.6 (t，2H)，1.6-1.7 (m，2H)，1.3-1.4 (m， 2II), 0.95 (t, 311); 關於C2GH23N5 · 0· 25H20 之分析計算值：C， 71.61; H， 7.09; N，2 0.0 3。實驗值：C，71.80; H，7.00; N，Page 42 486472 V. Description of the invention (38) The diamine will be 2,4-diamino-6-chloro-1,3,5-tris in dioxane (10 ml) and ethanol (40 ml) Larynx (2 g, 14 mmol), 1,4-difluorene-8-azaspiro [4.5] decane (3 g, 21 mmol) and KOH (100 mg, 1.8 mmol) Mol) mixture was heated to reflux overnight, diluted with water and filtered. The precipitate was washed with water and dehydrated under vacuum to give the title compound. Melting point 2 0 9-2 1 1 ° C; MS (DCI / NH3) m / e 2 5 3 (M + H) +; 4 NMR (300 MHz, DMSO-d6) 56.14 (br s, 4H), 3.90 t (s, 4H), 3.75-3.68 (m, 4H), 1.58-1.51 (m, 4H); Analytical calculated values for C1gH16N6 02: C, 47.61; H, 6.39; N, 33 · 31. Experimental values: C, 47 · 45; H, 6.34; N, 3 3.24. Example 1 4 6- (4'-pentyl [1,1'-biphenyl] -4 -yl) -1,3,5-triazine-2,4-diamine 4 '-according to Example 1 Amyl [1,1'-biphenyl] -4-nitrile to give the title compound. Melting point 2 4 2-2 4 4 ° C; MS (DCI / NH3) m / e 334 (M + H) +; 41 NMR (300 MHz, DMS〇-d6) 5 8. 3 (d, 2H ), 8. 75 (d, 2H), 8.65 (d, 2H), 7.3 (d, 2H), 6.75-6.82 (br s, 411), 2.6 (t, 2H), 1.6-1.7 (m, 2H) , 1.3-1.4 (m, 2II), 0.95 (t, 311); Analytical calculated values for C2GH23N5 · 0 · 25H20: C, 71.61; H, 7.09; N, 2 0.0 3. Experimental values: C, 71.80; H, 7.00; N,

第43頁 486472 五、發明說明（39) 2 0.45。實例1 5 6-[4’ -戊氧基[1，1’ -聯苯基1-4 -基「-1，3, 5 -三嗪-2, 4 -二狴按照實例1來處理4’ -(戊氧基）[1，Γ -聯苯基]-4-腈，得到標題化合物。熔點 2 4 6 - 2 4 9 °C ; MS (DCI/NH3) m/e 3 5 0 (M + H)+ ； NMR (300 兆赫茲，DMS〇-d6)(J8.3 (d，2H)，7·75-7·6@ (m，4H)，7.07 (d，2H)，6.85-6.7 (br s，4H)，4.05 (t, 2H), 1.8-1.7 (m, 2H), 1.5-1.3 (m, 4H), 0.9 (t, 3H); 關於C2QH23N50之分析計算值：C， 6 8.7 5; H， 6.63; N， 2 0.04。實驗值：C，68·64; H，6·77; N，19.94。實例1 6 6~(6—曱氧基一2 —苯并噻哇基）—1，3，5 —三嗪—2，4 —二胺按照實例1來處理6-甲氧基-2-聯苯并噻唑腈，得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 2 7 5 (M + H)1 ； !Η NMR ( 3 0 0 兆赫茲，DMS〇-d6) δ 7· 98 (d， 1H)， 7· 71 (d， 1Η), 7.17 (dd, 1H), 7.16 (br s, 211), 6.95 (br s, 2 H )，3 · 8 5 ( s，3 H ); 關於 CnH1QN6OS 之分析計算值：C， 48. 17; H, 3. 67; N,Page 43 486472 V. Description of the invention (39) 2 0.45. Example 1 5 6- [4'-pentyloxy [1,1'-biphenyl1-4-yl "-1,3,5-triazine-2, 4-dihydrazone was treated as in Example 1 4 ' -(Pentyloxy) [1, Γ-biphenyl] -4-nitrile to give the title compound. Melting point 2 4 6-2 4 9 ° C; MS (DCI / NH3) m / e 3 5 0 (M + H) +; NMR (300 MHz, DMS 0-d6) (J8.3 (d, 2H), 7.75-7 · 6 @ (m, 4H), 7.07 (d, 2H), 6.85-6.7 ( br s, 4H), 4.05 (t, 2H), 1.8-1.7 (m, 2H), 1.5-1.3 (m, 4H), 0.9 (t, 3H); Analytical calculation for C2QH23N50: C, 6 8.7 5 H, 6.63; N, 2 0.04. Experimental values: C, 68 · 64; H, 6.77; N, 19.94. Example 1 6 6 ~ (6-fluorenyloxy-2—benzothiacarbyl) — 1,3,5-triazine-2,4-diamine The 6-methoxy-2-bibenzothiazonitrile was treated according to Example 1 to obtain the title compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 2 7 5 (M + H) 1;! Η NMR (300 MHz, DMS0-d6) δ 7.98 (d, 1H), 7.71 (d, 1Η), 7.17 (dd, 1H), 7.16 (br s, 211), 6.95 (br s, 2 H), 3 · 8 5 (s, 3 H); Analytical calculation for CnH1QN6OS: C, 48. 17; H, 3. 67; N,

第44頁 486472 五、發明說明（40) 30.64。實驗值：C，48.07; Η，3.75; N，30.72。實例1 7 6-(4’ -胺基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理4’ -胺基[1，1 ’ -聯苯基]-4-腈，得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 2 7 9 (M + H)+ ； !Η NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 25 (d， 2H)， 7· 65 (d， 2Η), 7.45 (d, 2H), 6.8-6.6 (m, 6H), 5.3 (s, 2H); 關於C15HUN6 之分析計算值：C， 64. 73 ; H, 5. 07; N, 3 0.2 0。實驗值：C，64.34; H，5·18; N，29.91。實例1 8 6 - [ 4 - ( 5 -噚唑基）苯基]-1，3，5 -三嗪-2 , 4 -二胺按照實例1來處理4-(5-卩署唑基）苄腈，得到標題化合物。 MS (DCI/NH3) m/e 2 5 5 (M + H)f ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 55 (s， 1H)， 8· 37 (d， 2H)， 7.9-7.8 (t， 3H)， 6.9-6.7 (br s， 4H); 關於C12H10N6〇之分析計算值：C， 5 6.5 6; II, 3.96; N, 3 3 . 0 5。實驗值：C，5 6 · 4 0 ; II，4 · 0 2 ; N，3 3 . 1 1。實例1 9 6-[4-[「5-(三氟曱基）-2 -吡啶基]氧基]苯基]-1，3, 5 -三嗪 - 2，4 -二月$ ' 按照實例1來處理4-[ [5-(三氟甲基）-2 -吡啶基]氧基]苄Page 44 486472 V. Description of the invention (40) 30.64. Experimental values: C, 48.07; Η, 3.75; N, 30.72. Example 1 7 6- (4'-Amino [1,1'-biphenyl] -4 -yl) -1,3,5-triazine-2,4-diamine Treatment of 4 '-according to Example 1 Amine [1,1'-biphenyl] -4-nitrile to give the title compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 2 7 9 (M + H) +;! NMR (300 MHz, DMS〇-d6) 5 8 · 25 (d, 2H), 7.65 (d, 2Η), 7.45 (d, 2H), 6.8-6.6 (m, 6H), 5.3 (s, 2H); Analytical calculated values for C15HUN6: C, 64. 73; H, 5. 07; N, 3 0.2 0. Experimental values: C, 64.34; H, 5.18; N, 29.91. Example 1 8 6-[4-(5-oxazolyl) phenyl] -1,3,5-triazine-2, 4-diamine Treatment of 4- (5-oxazolyl) benzyl as in Example 1 Nitrile to give the title compound. MS (DCI / NH3) m / e 2 5 5 (M + H) f; 41 NMR (300 MHz, DMS0-d6) 5 8.55 (s, 1H), 8.37 (d, 2H ), 7.9-7.8 (t, 3H), 6.9-6.7 (br s, 4H); Analytical calculated values for C12H10N60: C, 5 6.5 6; II, 3.96; N, 3 3.05. Experimental values: C, 5 6 · 4 0; II, 4 · 0 2; N, 3 3. Example 1 9 6- [4-["5- (Trifluorofluorenyl) -2-pyridyl] oxy] phenyl] -1,3,5-triazine-2,4-February 1 to process 4-[[5- (trifluoromethyl) -2-pyridyl] oxy] benzyl

第45頁 486472 五、發明說明（41) 腈，得到標題化合物。 MS (DCI/NH3) m/e 34 9 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 6 (s，1H)，8· 6-8· 5 (m，3H)，7.4-7.3 (m，3H)，6.9-6,7 (br s，4H); 關於C15HUF3N6〇之分析計算值：C， 51.73; H， 3.18; N， 24. 13。實驗值：C，51· 67; H, 3· 20; N，2 3. 8 3。實例2 0 , 4’ - (4, 6 -二胺基-1，3, 5 -三嗪-2 -基）「1，Γ -聯苯基]-4 -腈實例2 0 A t 按照實例1來處理4-溴苄腈，得到預定的化合物。 MS (DCI/NH3) m/e 26 7 (M + HV。Page 45 486472 V. Description of the invention (41) Nitrile to give the title compound. MS (DCI / NH3) m / e 34 9 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) 5 8 · 6 (s, 1H), 8 6-8 · 5 ( m, 3H), 7.4-7.3 (m, 3H), 6.9-6,7 (br s, 4H); Analytical calculated values for C15HUF3N60: C, 51.73; H, 3.18; N, 24.13. Experimental values: C, 51 · 67; H, 3.20; N, 2 3. 8 3. Example 2 0, 4 '-(4, 6 -diamino-1,3,5-triazin-2-yl) "1, Γ -biphenyl] -4 -nitrile Example 2 0 A t According to Example 1 To treat 4-bromobenzonitrile to give the intended compound. MS (DCI / NH3) m / e 26 7 (M + HV.

，實例2 0 B 將在脫水、脫氣之二曱基乙醯胺（4 5毫升）中之實例2 0 A (0 · 7 6克，2 · 9毫莫耳）和四價（三苯膦）鈀（0 · 1 7克，0 · 1 5毫莫耳）的溶液加熱至1 0 0 °C，以六甲基二錫（1 · 0克，3 · 1毫莫耳）處理，加熱至1 0 0 °C 3小時，以醋酸乙酯處理，連續以1 Μ N a Ο Η和鹽水沖洗，脫水（M g S 04)並濃縮之，得到預定的化合物。 MS (DCI/NH3) m/e 3 5 2 (M + HV。Example 20B Example 20 A (0. 76 g, 2. 9 mmol) and tetravalent (triphenylphosphine) in dehydrated, degassed difluorenylacetamide (45 ml) ) A solution of palladium (0.17 g, 0.15 mmol) was heated to 100 ° C, treated with hexamethylditin (1.0 g, 3.1 mmol), and heated to 100 ° C for 3 hours, treated with ethyl acetate, successively rinsed with 1 M NaCl and brine, dehydrated (MgS04) and concentrated to obtain the predetermined compound. MS (DCI / NH3) m / e 3 5 2 (M + HV.

實例2 0 C 4’ -(4, 6 -二胺基-1，3, 5 -三嗪-2 -基）[1，Γ -聯苯基1-4 -腈將在脫水、脫氣之二曱基乙醯胺（4 5毫升）中之實例2 0 B (0· 95克，2· 7毫莫耳）、4 -溴苄腈（0· 55克，3. 0毫莫耳）和四價（三苯膦）鈀（0.20克，0.17毫莫耳）的溶液加熱至100Example 2 0 C 4 '-(4, 6 -diamino-1,3,5-triazin-2-yl) [1, Γ -biphenyl 1-4 -nitrile will be dehydrated and degassed. Examples in fluorenylacetamide (4.5 ml) 20 B (0.95 g, 2.7 mmol), 4-bromobenzonitrile (0.55 g, 3.0 mmol) and Solution of valence (triphenylphosphine) palladium (0.20 g, 0.17 mmol) to 100

苐46頁 486472 五、發明說明（42) °C 3小時，冷卻至室溫，以醋酸乙酯處理，連續以1 Μ N a〇Η 和鹽水沖洗，脫水（MgS04)並濃縮，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 28 9 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 36 (d， 2H)， 7· 96 (s， 4H)，7. 88 (d，2H)，6· 81 (br s，4H); 關於q 6心2 N6 · 0 · 7 5 H2〇之分析計算值：C， 6 3 · 6 7 ; Η， 4. 51; N，2 7. 84。實驗值：C，64. 0 6 ; H，4· 38 ; N， 27.17。 ^ 實例2 1 6-(4’ -曱氧基「1, 1’ -聯苯基卜4-基）-l, 3, 5 -三嗪-2, 4 -二 m 將在脫水、脫氣之二曱基乙醯胺（4 5毫升）中之實例2 0 A (0.749克，2·8毫莫耳）和四價（三苯膦）鈀（0.15克，0·13 毫莫耳）的溶液加熱至1 0 0 °C，連續以在無水乙醇（1 5毫升）中之4 -曱氧苯基硼酸（0 · 6 4 8克，4 · 3毫莫耳）和飽和的 N a IIC 03 ( 3 0毫升）處理，加熱至1 0 0 °C 3小時，冷卻至室溫，以醋酸乙酯處理，以鹽水沖洗，脫水（MgS04)並濃縮之。使殘餘物從二氧六環/***中再結晶，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 2 94 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 31 (d， 211)，7· 72 (t， 4H)， 7·03 (d， 211)， 6·86 (br s， 4H)， 3.81 (s， 3H);页 Page 46 486472 V. Description of the invention (42) ° C for 3 hours, cooled to room temperature, treated with ethyl acetate, successively washed with 1 M N a0Η and brine, dehydrated (MgS04) and concentrated to obtain the title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 28 9 (M + H) +; 4 NMR (3 0 0 MHz, DMS 0-d6) 5 8 · 36 (d, 2H) , 7.96 (s, 4H), 7.88 (d, 2H), 6.81 (br s, 4H); Analytical calculation for q 6 heart 2 N6 · 0 · 7 5 H2〇: C, 6 3 · 6 7; Η, 4. 51; N, 2 7. 84. Experimental values: C, 64.06; H, 4.38; N, 27.17. ^ Example 2 1 6- (4'-Methoxy "1, 1'-biphenylbut 4-yl) -l, 3, 5-triazine-2, 4-di-m will be dehydrated and degassed Solution of Example 20 A (0.749 g, 2.8 mmol) in tetramethyleneacetamide (4.5 ml) and tetravalent (triphenylphosphine) palladium (0.15 g, 0.13 mmol) Heated to 100 ° C, continuously with 4-oxophenylphenylboronic acid (0.64 g, 4.3 mol) in anhydrous ethanol (15 ml) and saturated Na IIC 03 ( 30 ml), heated to 100 ° C for 3 hours, cooled to room temperature, treated with ethyl acetate, washed with brine, dehydrated (MgS04) and concentrated. The residue was taken from dioxane / ether Recrystallization to give the title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 2 94 (M + H) +; 41 NMR (300 MHz, DMS 0-d6) 5 8 31 (d, 211), 7.72 (t, 4H), 7.03 (d, 211), 6.86 (br s, 4H), 3.81 (s, 3H);

第47頁 486472 五、發明說明（43) 關於C16H15N50.0· 33H20之分析計算值：C，64.21; H， 5.27; N，2 3.4 0。實驗值：C，64.2 6; H，5.35; N， 2 3.43。實例2 2 6 —（4’ 一氟「1， 1’ 一聯苯基]—4 —基）一1，3， 5 -三[1秦一 2，4 -二胺按照實例2 4來處理實例2 0 A和4 -氟苯基硼酸，得到標題化合物。熔點 > 2 6 0。(：； MS (DCI/NH3) m/e 28 2 (M + H)+ ; 1 NMR ( 3 0 0 兆赫茲，DMSO-d6) 5 8· 32 (d，2H)，7· 77 (m 4H), 7.32 (t, 2H), 6. 75 (br s, 4H)；關於C15H12FN5 · 0· 25H20 之分析計算值：C, 6 3.04; H， 4·41; N，24.5 0。實驗值:C，63.41; H，4·49; N， 24.17。實例2 3Page 47 486472 V. Description of the invention (43) The analytical calculated values of C16H15N50.0 · 33H20: C, 64.21; H, 5.27; N, 2 3.4 0. Experimental values: C, 64.2 6; H, 5.35; N, 2 3.43. Example 2 2 6 — (4 ′ monofluoro “1, 1 ′ monobiphenyl] -4-yl) -1,3, 5-tri [1qin-2,4-diamine Example was treated as in Example 24 2 0 A and 4-fluorophenylboronic acid to give the title compound. Melting point> 2 6 0. (:; MS (DCI / NH3) m / e 28 2 (M + H) +; 1 NMR (300 mega Hertz, DMSO-d6) 5 8.32 (d, 2H), 7.77 (m 4H), 7.32 (t, 2H), 6. 75 (br s, 4H); Analysis and calculation of C15H12FN5 · 0 · 25H20 Value: C, 6 3.04; H, 4.41; N, 24.5 0. Experimental values: C, 63.41; H, 4.49; N, 24.17. Example 2 3

Hz! 4-(4，6 -二胺基-1，3，5-三嗪-2 -基）苯基笼石黃違胺將在吡啶（5毫升）中之實例10A ( 5 75毫克，2· 8毫莫耳）和苯項酸氣（5 5 4毫克，3 · 1毫莫耳）的溶液加至熱至迴流4 小時，在室溫下攪拌過夜，以水處理並以醋酸乙酯萃取。以水和鹽水沖洗該萃取物，脫水（MgS04)並濃縮之。使殘餘物從乙醇中再結晶，得到標題化合物。熔點 1 9 7 - 1 9 9 °C ; MS (DCI/NH3) m/e 343 (M + H)+ ; NMR ( 3 0 0 兆赫茲，DMS〇-dG) 510· 20 (br s， 1H)，Hz! Example of 4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl cagedite xanthamine in pyridine (5 ml) 10A (5 75 mg, 2 · 8 mmoles) and benzoic acid gas (55 4 mg, 3.1 mmoles) were heated to reflux for 4 hours, stirred at room temperature overnight, treated with water and extracted with ethyl acetate . The extract was washed with water and brine, dehydrated (MgSO4) and concentrated. The residue was recrystallized from ethanol to give the title compound. Melting point 197-199 ° C; MS (DCI / NH3) m / e 343 (M + H) +; NMR (300 MHz, DMS〇-dG) 510 · 20 (br s, 1H) ,

第48頁 486472 五、發明說明（44) 8.03-8.01 (m, 1H), 7.94-7.91 (m, 1H), 7.80-7.78 (m, 2H), 7.6 0 -7.5 0 (m, 3H), 7.34- 7.2 5 (m, 1H), 7. 22-7. 19 (m, 1H); 關於C15H14N6〇2S. C2H5〇H之分析計算值：C， 5 2.5 6; H， 5.18; N，21.63。實驗值：C，5 2.47;'H，5.24; N， 21.54。實例24 6 - [1~~([1，1’ -聯苯基]-4 -基）-4 -六氫口比咬基]-1，3，5 -三嗦 - 2，4 -二月安 tPage 48 486472 V. Description of the invention (44) 8.03-8.01 (m, 1H), 7.94-7.91 (m, 1H), 7.80-7.78 (m, 2H), 7.6 0 -7.5 0 (m, 3H), 7.34 -7.2 5 (m, 1H), 7. 22-7. 19 (m, 1H); Analytical calculated values for C15H14N6〇2S. C2H50OH: C, 5 2.5 6; H, 5.18; N, 21.63. Experimental values: C, 5 2.47; 'H, 5.24; N, 21.54. Example 24 6-[1 ~~ ([1,1'-Biphenyl] -4 -yl) -4 -Hexahydropyridyl] -1,3,5 -trisene-2,4 -February An t

實例24A 在78°C下以第三-丁基鋰（100毫升在戊烷中之1.7 Μ的溶液，170毫莫耳）處理在THF ( 8 2 0毫升）中之4 -溴聯苯 (19· 16克，82毫莫耳），攪拌8分鐘，以THF (100毫升）中之三氣化鉍（8. 62克，27. 4毫莫耳）處理，再攪拌3小時，以飽和的含水N H4 C 1處理，並以醋酸乙酯萃取。以水和鹽水沖洗萃取物，覆以（M g S 04)脫水並濃縮之。在真空烘箱中將殘餘物脫水，得到預定的化合物。 13C NMR ( 3 0 0 兆赫茲，CDC13) 5 153· 83， 1 4 1. 0 4, 1 4 0. 6 9, 1 3 8. 0 7，129· 21，1 2 8. 7 5，1 2 7. 3 3，127· 07。Example 24A Treatment of 4-bromobiphenyl (19 in THF, 820 ml) with tert-butyllithium (100 ml of a 1.7 M solution in pentane, 170 mmol) at 78 ° C 16 grams, 82 millimoles), stirred for 8 minutes, treated with bismuth trioxide (8.62 grams, 27.4 millimoles) in THF (100 ml), and stirred for 3 hours, with saturated water Treated with N H4 C 1 and extracted with ethyl acetate. The extract was rinsed with water and saline, dried over (M g S 04) and concentrated. The residue was dehydrated in a vacuum oven to obtain a predetermined compound. 13C NMR (300 MHz, CDC13) 5 153 · 83, 1 4 1. 0 4, 1 4 0. 6 9, 1 3 8. 0 7,129 · 21, 1 2 8. 7 5, 1 2 7. 3 3, 127 · 07.

實例2 4 B 6-[ 1-( [1，Γ -聯苯基]-4-基）-4-六氫吡啶基]-1，3, 5 -三嗪 -2，4 -二胺按照實例2 A和2 C來處理實例2 4 A和異3 -哌啶甲酸乙酯，得到標題化合物。Example 2 4 B 6- [1- ([1, Γ -biphenyl] -4-yl) -4-hexahydropyridyl] -1,3, 5-triazine-2,4-diamine 2 A and 2 C were used to treat Example 2 4 A and ethyl 3-piperidinecarboxylic acid to give the title compound.

第49頁 486472 五、發明說明（45) 熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 347 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) (57.58 (m， 2H)， 7·47 (d， 2H)，7.39 (m，2H)，7.23 (m，1H)，6.97 (d，2H)， 6.59 (br s， 4H)， 3·61 (m， 1H)， 1.78 (m， 4H)， 1.58 (m，4H)。實例2 5 N-[4_(4，6 -二胺基-1,3，5 -三嗦-2 -基）苯基]-2 -蔡石黃醯胺按照實例23來處理6-(4 -胺苯基）-1，3, 5 -三嗪-2, 4 -二^ 胺，但是以2 -萘磺醯氯來取代苯磺醯氯，得到標題化合物。熔點 2 3 0 - 2 3 3 °C ; MS (DCI/NH3) m/e 3 9 3 (M + H)f ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) δ10· 55 (s， 1H)， 8· 5 (s， 1H)， 8.2-8.05 (m， 3H)， 8.0 (d， 1H)， 7.9-7.85 (m， 1H)，7.8-7.75 (m，1H)，7.74-7.6 (m，2H)，7.3-7.2 (m, 2H), 6. 9-6. 65 (br s, 4H); 關於Ci9H16N6 02 S· 1.5C4H8 02 之分析計算值：C， 5 7.2 3; H， 5 . 3 7 ; N， 1 6 · 0 2。實驗值：C，5 7 · 1 1 ; H，5 · 3 3 ; N， 16.28。實例2 6 2，5 -二氣-N~[4-(4，6 -二胺基-1，3，5 -三嗓-2 -基）苯基]苯石黃S藍月$ 按照實例2 3來處理實例1 Q A，但是以2，5 -二氯苯磺醯氣Page 49 486472 V. Description of the invention (45) Melting point > 2 60 ° C; MS (DCI / NH3) m / e 347 (M + H) +; 1 NMR (300 MHz, DMS〇-d6 ) (57.58 (m, 2H), 7.47 (d, 2H), 7.39 (m, 2H), 7.23 (m, 1H), 6.97 (d, 2H), 6.59 (br s, 4H), 3.61 (m, 1H), 1.78 (m, 4H), 1.58 (m, 4H). Example 2 5 N- [4_ (4,6-diamino-1,3,5-trifluorene-2-yl) benzene [2-yl] -2-zeolite baicalin was treated according to Example 23 as 6- (4-aminophenyl) -1,3,5-triazine-2,4-di ^ amine, but with 2-naphthalenesulfonyl chloride To replace the benzylsulfonium chloride to give the title compound. Melting point 2 3 0-2 3 3 ° C; MS (DCI / NH3) m / e 3 9 3 (M + H) f; 41 NMR (3 0 0 MHz, DMS〇-d6) δ10 · 55 (s, 1H), 8.5 (s, 1H), 8.2-8.05 (m, 3H), 8.0 (d, 1H), 7.9-7.85 (m, 1H), 7.8- 7.75 (m, 1H), 7.74-7.6 (m, 2H), 7.3-7.2 (m, 2H), 6. 9-6. 65 (br s, 4H); Analysis and calculation of Ci9H16N6 02 S · 1.5C4H8 02 Values: C, 5 7.2 3; H, 5. 3 7; N, 16 · 0 2. Experimental values: C, 5 7 · 1 1; H, 5 · 3 3; N, 16.28. Example 2 6 2, 5-two gas-N ~ [4- (4,6-diamino-1,3,5-trimethyl-2-yl) phenyl] benzene stone yellow S blue month $ Example 1 QA was treated as in Example 2 3, but with 2, 5-Dichlorobenzenesulfonium

第50頁 486472 五、發明說明（46) 來取代苯磺醯氯，得到標題化合物。熔點 2 3 0 - 2 3 3 °C ; MS (DCI/NH3) m/e 411 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMSO —d6) ά 10· 5 (s， 1H)， 8· 05 (m， 3H), 7.7 5- 7.77 (m, 2H), 7.35 (t, 1H), 7.25-7.2 (m, 1H), 6. 8-6. 7 (br s, 4H); 關於(：15}112(：12%〇23.0.5(：113(：}12〇}1之分析計算值：C， 44. 24; H，3.48; N， 19.35。實驗值：C，44.43; H，3.26; N， 19.44。 t 實例2 7 6 - ( 1 -苯基環己基）-1，3，5 -三嗪-2，4 -二胺按照實例1來處理1 -苯基環己烷腈，得到標題化合物。熔點 1 5 3 - 1 5 5 °C ; MS (DCI/NH3) m/e 27 0 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 7· 4-7· 3 (m，2H)，7· 15 (t，2Η)，7.2-7.1 (m，1Η)，6.6-6.5 (br s，4Η)， 2.7-2.6 (m， 2H)， 1.75-1.6 (m， 2H)， 1.6-1.2 (m， 6H); 關於C15H19N5 之分析計算值：C， 6 6.8 9; II, 7.11; N, 2 6 · 0 0。實驗值：C，6 6 · 9 4 ; II，7 · 2 0 ; N，2 6 . 0 4。實例2 8 6 - [ 1-(4-曱氧苯基）—4—六氫比口定基]—1，3，5 —三嗪—2，4 —二胺 ^ 按照實例24A來製備三（4’ -曱氧基[1，1’ -聯苯基]鉍，並Page 50 486472 V. Description of the invention (46) Substitute benzylsulfonium chloride to obtain the title compound. Melting point 2 3 0-2 3 3 ° C; MS (DCI / NH3) m / e 411 (M + H) +; 4 NMR (3 0 0 MHz, DMSO —d6) ά 10 · 5 (s, 1H) , 8.05 (m, 3H), 7.7 5- 7.77 (m, 2H), 7.35 (t, 1H), 7.25-7.2 (m, 1H), 6. 8-6. 7 (br s, 4H); About (: 15) 112 (: 12% 〇23.0.5 (: 113 (:) 1212) 1: Analytical calculation value: C, 44. 24; H, 3.48; N, 19.35. Experimental value: C, 44.43; H, 3.26; N, 19.44. Example 2 7 6-(1-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine Treatment of 1-phenylcyclohexane as in Example 1 Nitrile to give the title compound. Melting point 1 5 3-1 5 5 ° C; MS (DCI / NH3) m / e 27 0 (M + H) +; 41 NMR (300 MHz, DMS 0-d6) 5 7 · 4-7 · 3 (m, 2H), 7.15 (t, 2Η), 7.2-7.1 (m, 1Η), 6.6-6.5 (br s, 4Η), 2.7-2.6 (m, 2H), 1.75-1.6 (m, 2H), 1.6-1.2 (m, 6H); Analytical calculated values for C15H19N5: C, 6 6.8 9; II, 7.11; N, 2 6 · 0 0. Experimental values: C, 6 6 · 9 4; II, 7 · 2 0; N, 2 6. 0 4. Example 2 8 6-[1- (4-fluorenyloxy) -4-hexahydropyridyl] -1, 3, 5 —Triazine—2,4—di Amine ^ Tris (4'-fluorenyl [1,1'-biphenyl] bismuth was prepared according to Example 24A, and

第51頁 486472 五、發明說明（47) 按照實例2A和2C來處理異3-哌啶曱酸乙酯，得到標題化合物。熔點 2 0 4 - 2 0 5 °C ; MS (DCI/NH3) m/e 301 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) (5 6. 92 (d， 2H)， 6· 81 (d， 2H)， 6.58 (m， 4H)， 3.59 (m， 2H)， 2.62 (m， 2H)， 2· 35 (m，1H), 1 · 82 (m，4H)。實例2 9 6-[2-[4-(三 II 曱基）]-4-嚷哇基]-1，3，5-三嗦-2，4-二胺 t 按照實例2 C來處理2 - [ 4 -(三氟曱基）苯基]唾嗤-4 -護酸乙酯和實例2 B，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 3 3 9 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 42 (s， 1H)， 8· 19 (d， 2H)，7. 91 (d，2H)，6· 82 (br s，411); 關於 C13H9F3N6S之分析計算值：C， 46.15; H， 2.68; N， 24.84。實驗值：C，4 5.8 5; H，2.64; N，24·44。實例3 0 6-[ 1-(4-曱氧苯基）環己基1-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理卜（4 -甲氧苯基）環己烷腈，得到標題化合物。熔點 1 5 9 - 1 6 3 °C ; MS (DCI/NH3) m/e 3 0 0 (Μ + Η)1 ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) δ 7· 15 (d， 2H)， 6. 8 (d， i illPage 51 486472 V. Description of the invention (47) Ethyl 3-piperidinate was treated according to Examples 2A and 2C to obtain the title compound. Melting point 2 04-2 5 ° C; MS (DCI / NH3) m / e 301 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) (5 6. 92 (d, 2H), 6.81 (d, 2H), 6.58 (m, 4H), 3.59 (m, 2H), 2.62 (m, 2H), 2.35 (m, 1H), 1.82 (m, 4H) Example 2 9 6- [2- [4- (Tri-II fluorenyl)]-4-fluorenyl] -1,3,5-trifluorene-2,4-diamine t Processed as in Example 2 C 2 -[4- (trifluorofluorenyl) phenyl] sialo-4-ethyl acetate and Example 2 B to give the title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 3 3 9 (M + H) +; 41 NMR (300 MHz, DMS0-d6) 5 8.42 (s, 1H), 8.19 (d, 2H), 7.91 (d, 2H) , 6.82 (br s, 411); Analytical calculated values for C13H9F3N6S: C, 46.15; H, 2.68; N, 24.84. Experimental values: C, 4 5.8 5; H, 2.64; N, 24. 44. Examples 3 0 6- [1- (4-Methoxyphenyl) cyclohexyl 1-1,3,5-triazine-2, 4-diamine was treated as in Example 1 (4-methoxyphenyl) cyclohexyl Alkonitrile to give the title compound. Melting point 159-16 3 ° C; MS (DCI / NH3) m / e 3 0 0 (Μ + Η) 1; 41 NMR (300 MHz, DMS 0-d6 ) δ 7 · 15 (d, 2H), 6. 8 (d, i ill

第52頁 486472 五、發明說明（48) 2H)，6·6 (br s，4H)，3.7 (s, 3H), 2.7-2.6 (m, 2H), 1.7-1.6 (m, 2H), 1. 6-1. 2 (m, 6H); 關於 C16H21N50 之分析計算值：C， 64.19; H, 7.07; N， 2 3.3 9。實驗值：C，64.13; H，7·07; N，2 3.2 5。實例3 1 6-[4-(2 -噻吩基）苯基]-1，3, 5 -三嗪-2, 4-二胺以四價（三苯膦）鈀（1 1 5毫克，0 · 1毫莫耳）處理在脫水、脫氣之二曱乙醯胺（15毫升）中之實例20A (500毫克，1.9 毫莫耳）和2 -三-正-丁基錫噻吩（840毫克，2. 2毫莫耳）的^ 溶液，加熱至100 °C3小時，冷卻，以IN NaOH處理，並以醋酸乙酯萃取。以鹽水沖洗該萃取物，脫水（MgS04)並濃縮之。使殘餘物從乙醇/二氧六環中再結晶，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 2 7 0 (M + H)+ ； Μ NMR ( 3 0 0 兆赫茲，DMSO-dG) 5 8· 31-8· 24 (m，2H)， 7·8-7·72 (m， 2H)， 7.62-7.59 (m， 2H)， 7.2-7.16 (m， 1H)，6.92 (br s, 4H); 關於CuHS之分析計算值：C， 5 7. 9 7; II, 4.11; N, 2 6.0 0。實驗值：C，57·91; II，4.06; N，25·83。實例3 2 6 ~ [ 4 -(苯基乙炔基）苯基]-1，3，5 -三嗦-2，4 -二胺Page 52 486472 V. Description of the invention (48) 2H), 6.6 (br s, 4H), 3.7 (s, 3H), 2.7-2.6 (m, 2H), 1.7-1.6 (m, 2H), 1 6-1. 2 (m, 6H); Analytical calculated values for C16H21N50: C, 64.19; H, 7.07; N, 2 3.3 9. Experimental values: C, 64.13; H, 7.07; N, 2 3.2 5. Example 3 1 6- [4- (2-Thienyl) phenyl] -1,3,5-triazine-2,4-diamine with tetravalent (triphenylphosphine) palladium (1 15 mg, 0 · 1 millimolar) Example 20A (500 mg, 1.9 millimoles) and 2-tri-n-butyltinthiophene (840 mg, 2.2 MM) solution, heated to 100 ° C for 3 hours, cooled, treated with IN NaOH, and extracted with ethyl acetate. The extract was washed with brine, dehydrated (MgS04) and concentrated. The residue was recrystallized from ethanol / dioxane to give the title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 2 7 0 (M + H) +; M NMR (300 MHz, DMSO-dG) 5 8 · 31-8 · 24 ( m, 2H), 7 · 8-7 · 72 (m, 2H), 7.62-7.59 (m, 2H), 7.2-7.16 (m, 1H), 6.92 (br s, 4H); Analysis and calculation of CuHS : C, 5 7. 9 7; II, 4.11; N, 2 6.0 0. Experimental values: C, 57.91; II, 4.06; N, 25.83. Example 3 2 6 ~ [4- (phenylethynyl) phenyl] -1,3,5-trifluorene-2,4-diamine

實例32A 按照實例31來處理4-溴苄腈和三甲基（苯基乙炔基）錫，Example 32A 4-bromobenzonitrile and trimethyl (phenylethynyl) tin were treated according to Example 31,

第53頁 486472 五、發明說明（49) 得到預定的化合物。 MS (DCI/NH3) m/e 221 (Μ + ΝΗ4)+。Page 53 486472 V. Description of the invention (49) A predetermined compound is obtained. MS (DCI / NH3) m / e 221 (Μ + ΝΗ4) +.

實例3 2 B 6-[4-(苯基乙快基）苯基]-1，3，5-三嗦-2，4~~二胺按照實例1來處理4 -(苯基乙炔基）苄腈，得到標題化合物。溶點 248-249 C ; MS (DCI/NH3) m/e 2 8 9 (M-fH)1 ； NMR ( 3 0 0 兆赫兹，DMSO —d6) ά 8. 30 (d, 2H)， 7.67 (d、 2H), 7.61-7.58 (m, 2H), 7.5-7.43 (m, 3H), 6.82 (br s，4H); Η，4.56; N N， 24.0 8 。關於q 7心3 N5之分析計算值：C， 7 1 . 0 6 ; 2 4 · 3 7。實驗值：C，7 0 · 7 9 ; H，4 · 7 3 實例3 3 N，Ν’ -(6-Π，Γ -聯苯基]-4 -基-1，3, 5 -三嗪-2, 4 -二基）雙 [乙酸胺]Example 3 2 B 6- [4- (phenylethynyl) phenyl] -1,3,5-trifluorene-2,4 ~~ diamine Treatment of 4- (phenylethynyl) benzyl according to Example 1 Nitrile to give the title compound. Melting point: 248-249 C; MS (DCI / NH3) m / e 2 8 9 (M-fH) 1; NMR (3 0 0 MHz, DMSO — d6); 8. 30 (d, 2H), 7.67 ( d, 2H), 7.61-7.58 (m, 2H), 7.5-7.43 (m, 3H), 6.82 (br s, 4H); Η, 4.56; NN, 24.0 8. Analytical calculated values for q 7 heart 3 N5: C, 7 1. 0 6; 2 4 · 37. Experimental values: C, 7 0 · 7 9; H, 4 · 7 3 Example 3 3 N, N '-(6-Π, Γ -biphenyl] -4 -yl-1,3,5-triazine- 2, 4 -diyl) bis [amine acetate]

實例3 3 A 按照實例1來處理4-苯基苄腈，得到預定的化合物。 MS (DCI/NH3) m/e 264 (Μ + Η)τ。實例33Β Ν，Ν’ -(6-[1，Γ -聯苯基]-4 -基-1，3, 5 -三嗪-2, 4 -二基）雙 [乙Si胺] 使在乙酸酐（1 0毫升）中之實例3 3 A ( 0 . 2 6克，0 . 9 9毫莫耳）的溶液迴流20小時，並冷卻至室溫。以飽和的NaHC〇qExample 3 3 A 4-phenylbenzonitrile was treated according to Example 1 to obtain the intended compound. MS (DCI / NH3) m / e 264 (M + Η) τ. Example 33B Ν, Ν '-(6- [1, Γ -biphenyl] -4 -yl-1,3,5-triazine-2,4-diyl) bis [ethylSiamine] (10 ml) of a solution of Example 3 A (0.26 g, 0.99 mmol) was refluxed for 20 hours and cooled to room temperature. With saturated NaHC〇q

第54頁 486472 五、發明說明（50) 沖洗沉澱物，並在真空下脫水，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 348 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 1 0· 79 (s， 2H)， 8· 43 (d， 2H)， 7·91 (d， 2H)， 7.79 (d， 2H)， 7·52 (m， 2H)， 7.41 (m, 1H), 2.41 (s, 6H); 關於 C19H17N5 02 之分析計算值：C， 6 5.7 0; H，4.93; N， 20.16。實驗值：C，65·63; H，4.84; N，20.18。實例34 t N-( 4-胺基-6-「1，1’ -聯苯基1-4 -基-1，3, 5三嗪-2 -基）乙醯 m 將在乙酸酐（4毫升）中之實例33A (0.38克，1.4毫莫耳）的溶液加熱至8 0 °C 2 0小時，以醋酸乙酯處理並冷卻至室溫。藉著真空過濾收集沉澱物，以含水的碳酸鈉沖洗，並在真空下脫水，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 3 0 6 (M + H)+ ； NMR ( 3 0 0 兆赫兹，DMS〇-d6) 5 10. 22 (s， 1H)，8. 39 (d，2H)，7.83 (d，211)，7.53 (m，3H)，7.41 (m，2H)， 2.36 ( s, 3II); 關於C17H15N5〇.0. 2CH3C〇2H之分析計算值：C， 6 5.8 6; H， 5 · 0 2 ; N，2 2 . 0 7。實驗值：C，6 5 · 8 2 ; H，4 . 9 7 ; N， 2 2.3 7。實例3 5Page 54 486472 V. Description of the invention (50) The precipitate was washed and dehydrated under vacuum to obtain the title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 348 (M + H) +; 4 NMR (300 MHz, DMS〇-d6) 5 1 0 · 79 (s, 2H) , 8.43 (d, 2H), 7.91 (d, 2H), 7.79 (d, 2H), 7.52 (m, 2H), 7.41 (m, 1H), 2.41 (s, 6H); About Analytical calculated values for C19H17N5 02: C, 6 5.7 0; H, 4.93; N, 20.16. Experimental values: C, 65 · 63; H, 4.84; N, 20.18. Example 34 t N- (4-amino-6- "1,1'-biphenyl1-4-yl-1,3,5triazin-2-yl) acetamidine will be dissolved in acetic anhydride (4 ml ) The solution of Example 33A (0.38 g, 1.4 mmol) was heated to 80 ° C for 20 hours, treated with ethyl acetate and cooled to room temperature. The precipitate was collected by vacuum filtration, and aqueous sodium carbonate was used. Rinse and dehydrate under vacuum to give the title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 3 0 6 (M + H) +; NMR (300 MHz, DMS). -d6) 5 10. 22 (s, 1H), 8. 39 (d, 2H), 7.83 (d, 211), 7.53 (m, 3H), 7.41 (m, 2H), 2.36 (s, 3II); Analytical calculated values for C17H15N50.0.2CH3C〇2H: C, 6 5.8 6; H, 5 · 0 2; N, 2 2. 07. Experimental values: C, 6 5 · 8 2; H, 4. 9 7; N, 2 2.3 7. Example 3 5

第55頁 486472 五、發明說明（51) N-4-(4,6 -二胺基-1，3,5 -三嗪-2 -基）苯基]-1-萘磺醯胺按照實例2 3來處理實例1 0 A，但是以1 -萘磺醯氯取代苯石黃酿氣’得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 3 9 3 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 310. 8 (s， 1H)， 8· 8 (d， 1H)，8.3 (d， 1H)， 8. 2 (d， 1H)， 8. 1 (d，1H)， 8.0 (s，1H)， 7. 83-7. 6 (m， 4H)，7.2 (t ，1H)，7.1 5-7.1 (m，1H)， 6.83-6.7 (m， 4H); 關於 Ci9 H16. N6 02 S · H20 之分析計算值： C， 5 5.5 9; Η, 442; N, 20. 47 。實驗值： c， 5 5.5 7; Η， 4. 42; Ν，20. 52 ° 4 實例3 6 6-(4,-疊氮基[1，1 ’ - 聯苯基]-4 -基） -1 ，3, 5_三嗪- 2, 4-二實例3 6 A 連續以亞硝酸鈉（0 .338 t ， 4. 90 - 毫莫耳）和疊氮化1内 (0. 33 克， 5. 1毫莫耳 )處理在三氟乙酸 (12. 5毫升）中之4’ 胺基[1，1’ -聯苯基]-4 -膳（0.490克，2. 53毫莫耳）的溶液，在室溫下攪拌1 0分鐘，以水處理並以醋酸乙酯萃取。將該萃取物脫水（MgS04)，濃縮得到預定的化合物。 MS (DCI/NH3) m/e 2 3 8 (M + NH,)1 ；Page 55 486472 V. Description of the invention (51) N-4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -1-naphthalenesulfonamide according to Example 2 3 to treat Example 10 A, but substituting 1-naphthalenesulfonyl chloride for benzene stone yellow gas' to give the title compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 3 9 3 (M + H) +; 4 NMR (300 MHz, DMS〇-d6) 310. 8 (s, 1H) , 8.8 (d, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 8. 1 (d, 1H), 8.0 (s, 1H), 7. 83-7. 6 ( m, 4H), 7.2 (t, 1H), 7.1 5-7.1 (m, 1H), 6.83-6.7 (m, 4H); Analysis and calculation of Ci9 H16. N6 02 S · H20: C, 5 5.5 9 ; Η, 442; N, 20. 47. Experimental values: c, 5 5.5 7; pyrene, 4. 42; Ν, 20. 52 ° 4 Example 3 6 6- (4, -azido [1,1 '-biphenyl] -4 -yl)- 1, 3, 5_triazine-2, 4-di Example 3 6 A continuous with sodium nitrite (0.338 t, 4. 90-millimolar) and azide 1 (0.33 g, 5 1 millimolar) solution of 4 'amine [1,1'-biphenyl] -4 -diamine (0.490 g, 2.53 mmol) in trifluoroacetic acid (12.5 ml) , Stirred at room temperature for 10 minutes, treated with water and extracted with ethyl acetate. The extract was dehydrated (MgS04) and concentrated to obtain the intended compound. MS (DCI / NH3) m / e 2 3 8 (M + NH,) 1;

實例3 6 B 6-（4’ -疊氮基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二胺Example 3 6 B 6- (4'-azido [1,1'-biphenyl] -4 -yl) -1,3,5-triazine-2,4-diamine

第56頁 486472 五、發明說明（52) 按照實例1來處理實例3 6 A，得到標題化合物。熔點2 3 (TC (裂解）； MS (DCI/NH3) m/e 3 0 5 (M + H)+ ； 4 NMR (300 兆赫茲，DMSO-d6)58.32 (d， 2H) 7 ^ 4H), 7. 24 (d, 2H), 6. 74 (bds, 4H)； ’ 關於C15 H12 N8 · 0 · 3 3 H2〇之分析計异值：C， 5 8 〇 7 · Η 4·11; N，36.12。實驗值：C，58.15; H，3. 84; n， 3 3.0 9。 · ’ ’ 實例3 7Page 56 486472 V. Description of the invention (52) Example 3 6 A was treated according to Example 1 to obtain the title compound. Melting point 2 3 (TC (cracking); MS (DCI / NH3) m / e 3 0 5 (M + H) +; 4 NMR (300 MHz, DMSO-d6) 58.32 (d, 2H) 7 ^ 4H), 7. 24 (d, 2H), 6. 74 (bds, 4H); 'About the analysis value of C15 H12 N8 · 0 · 3 3 H2〇: C, 5 8 〇7 · Η 4 · 11; N, 36.12. Experimental values: C, 58.15; H, 3. 84; n, 3 3.0 9. · ’’ Example 3 7

6 - [ 4-(4 -嗎啉磺醯基）苯基]-1，3, 5 -三嗪-2, 4 -二胺6-[4- (4-morpholinesulfonamido) phenyl] -1,3, 5-triazine-2, 4-diamine

實例37A 在室溫下攪拌在二氣曱烷（10毫升）中之4—氰基苯磺醯氯 ( 6 0 0毫克，2· 98毫莫耳）、嗎啉（ 3 0 0毫克，3. 44毫莫耳）和〇比^疋（3 5 0祕升’ 3 4 2耄克’ 4 · 3 3宅莫耳）的溶液過夜，以飽和的ΜΗ* C 1處理’並以醋酸乙酯萃取。以水和鹽水沖洗該萃取物，脫水（MgS〇4)並濃縮，得到預定的化合物。 MS (DCI/NH3) m/e 2 7 0 (M + NH4)+。。Example 37A 4-cyanobenzenesulfonyl chloride (600 mg, 2.98 mmol), morpholine (300 mg, 3. 44 millimoles) and 〇疋 ^ 疋 (350 liters' 3 4 2 耄 g '4 · 3 3 moles) overnight, treated with saturated MΗ * C 1' and extracted with ethyl acetate . The extract was washed with water and brine, dehydrated (MgS04) and concentrated to give the intended compound. MS (DCI / NH3) m / e 2 7 0 (M + NH4) +. .

實例37B 4-(2，4 -二胺基-1，3 狴 5 -三嗓-2-基）- j林基）苯確§1Example 37B 4- (2,4-diamino-1,3 狴 5 -trimethyl-2-yl) -jlinyl) benzene1

合物。按照實例1來處理實例3 7 A，得到標題化熔點 > 2 6 0 °C ; MS (DCI/iNH3) -m/e 3 3 7 (M + H)f ； (d， NMR ( 3 0 0 兆赫茲，DMSO —dG) 5 8· 46 U 9τιλ ’ ^ Η )组合。 The compound. Example 3 7 A was processed as in Example 1 to obtain the titled melting point> 2 60 ° C; MS (DCI / iNH3) -m / e 3 3 7 (M + H) f; (d, NMR (3 0 0 Megahertz, DMSO —dG) 5 8 · 46 U 9τιλ '^))

第57頁 486472 五、發明說明（53) 2H)， 6.91 (br s， 4H)， 3.65-3.60 (m， 4H)， 2.94-2.88 (m, 4H); 關於C13H16N6 03 S之分析計算值：C， 46.42; H，4.79; N， 24.98。實驗值：C，46.21; Η，4.69; N，25.24。實例3 8 6-[4-(2 -呋喃基）苯基]-1，3, 5 -三嗪-2, 4 -二胺按照實例31來處理6-(4 -溴苯基）-1，3, 5 -三嗪-2, 4-二胺，但是以2 -三-正-丁基錫呋喃來取代2 -三-正-丁基錫噻吩，得到標題化合物。 t MS (DCI/NH3) m/e 2 54 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 3 (d， 2H)， 7· 8 (d， 3H)，7.05 (d，1H)，6.8-6.7 (br s，4H)，6.65-6.6 (m, 1 H ); 關於C13HnN50 之分析計算值：C， 6 0.3 0; H, 5.57; N, 24.3 0。實驗值：C，5 9.8 3; H，5·44; N，24.8 6。實例3 9 1『-[6-(4-苯氧苯基）-1，3,5-三嗪-2,4-二基]雙[乙醯 m] · 按照實例3 3B來處理實例9，得到標題化合物。熔點 2 4 3 - 2 4 5 °C ; MS (DCI/NH3) m/e 3 6 4 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMSO-d6) ά 10. 74 (s， 2H)， 8· 38 (d，2H)，7·47 (t，2H)，7·24 (t，III)，7·14 (dd， 4H)， 2. 38 (s， 6H);Page 57 486472 V. Description of the invention (53) 2H), 6.91 (br s, 4H), 3.65-3.60 (m, 4H), 2.94-2.88 (m, 4H); Analysis and calculation value of C13H16N6 03 S: C , 46.42; H, 4.79; N, 24.98. Experimental values: C, 46.21; Η, 4.69; N, 25.24. Example 3 8 6- [4- (2-furanyl) phenyl] -1,3,5-triazine-2,4-diamine Treatment of 6- (4-bromophenyl) -1 according to Example 31, 3,5-triazine-2,4-diamine, but replacing 2-tri-n-butyltinthiophene with 2-tri-n-butyltinfuran, gave the title compound. t MS (DCI / NH3) m / e 2 54 (M + H) +; 41 NMR (300 MHz, DMS〇-d6) 5 8 · 3 (d, 2H), 7.8 (d, 3H ), 7.05 (d, 1H), 6.8-6.7 (br s, 4H), 6.65-6.6 (m, 1 H); Analytical calculated values for C13HnN50: C, 6 0.3 0; H, 5.57; N, 24.3 0 . Experimental values: C, 5 9.8 3; H, 5.44; N, 24.8 6. Example 3 9 1 "-[6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diyl] bis [ethane 醯 m] · Example 9 was treated according to Example 3 3B, The title compound was obtained. Melting point 2 4 3-2 4 5 ° C; MS (DCI / NH3) m / e 3 6 4 (M + H) +; 41 NMR (3 0 0 MHz, DMSO-d6) ά 10. 74 (s, 2H), 8.38 (d, 2H), 7.47 (t, 2H), 7.24 (t, III), 7.14 (dd, 4H), 2. 38 (s, 6H);

第58頁 486472 五、發明說明（54) 關於C19H17N5 03 之分析計算值：C， 6 2.8 0; H，4.72; N， 19.27。實驗值：C，62.56; Η，4·82; Ν，19·40。實例4 0 Ν-[4 -胺基-6-(4-苯氧苯基）-1，3, 5 -三嗪-2 -基]乙醯胺按照實例3 4來處理實例9，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 3 2 2 (M + H)1 ； NMR ( 3 0 0 兆赫茲，DMS〇-d6) 510· 21 (s， 1H)， 8· 32 (d，2H)，7.46 (t，2H)，7.37 (bds, 2H)，7.13 (d， 2H)，7.08 (d, 2H)，2· 32 (s，3H); 關於C17H15N5〇2之分析計算值：C， 6 3.54; H， 4.71; N， 21.79。實驗值：C，6 3.2 5; II，4.79; N，21.84。實例4 1 6 -（5 -苯基-2 - 口夫喃基）-1，3，5_三嗦-2，4 -二胺Page 58 486472 V. Explanation of the invention (54) The analytical calculated value of C19H17N5 03: C, 6 2.8 0; H, 4.72; N, 19.27. Experimental values: C, 62.56; Y, 4.82; N, 19.40. Example 4 0 Ν- [4-amino-6- (4-phenoxyphenyl) -1,3,5-triazin-2-yl] acetamidine Example 9 was treated as in Example 34 to give the title compound . Melting point > 2 60 ° C; MS (DCI / NH3) m / e 3 2 2 (M + H) 1; NMR (300 MHz, DMS0-d6) 510 · 21 (s, 1H), 8.32 (d, 2H), 7.46 (t, 2H), 7.37 (bds, 2H), 7.13 (d, 2H), 7.08 (d, 2H), 2.32 (s, 3H); About C17H15N502 Analytical calculated values: C, 6 3.54; H, 4.71; N, 21.79. Experimental values: C, 6 3.2 5; II, 4.79; N, 21.84. Example 4 1 6-(5-Phenyl-2 -Xanthyl) -1,3,5_trifluorene-2,4-diamine

實例4 1 A 按照實例2 1來處理5 -溴-2 -糠酸曱酯和四價（三苯膦）在巴，得到預定的化合物。 MS (DCI/NH3) m/e 2 0 3 (M + H)1 ；Example 4 1 A The 5-bromo-2-furanoic acid phosphonium ester and the tetravalent (triphenylphosphine) at Bar were treated according to Example 21 to obtain the intended compound. MS (DCI / NH3) m / e 2 0 3 (M + H) 1;

實例4 1 B _6-(5 -苯基-2- 〇夫喃基）-1，3，5 -三嗪-2，4 -二胺按照實例2 C來處理實例4 1 A和2 B，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 2 5 4 (M + H)十； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 7· 80 (d，2H)，7· 52-Example 4 1 B 6- (5-phenyl-2-oxanyl) -1,3,5-triazine-2,4-diamine Example 4 1 A and 2 B were treated according to Example 2 C to obtain Title compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 2 5 4 (M + H); 41 NMR (3 0 0 MHz, DMS 0-d6) 5 7.80 (d, 2H ), 7.52-

第59頁 486472 五、發明說明（55) 7.44 (m， 2H)， 7.41-7.37 (m， 1H)， 7.23 (dd， 1H)， 7. 16 (dd, 1H), 6.78 (br s, 4H); 關於 C13HuN50 之分析計算值：C，61.65; H，4.37; N， 27.65。實驗值：C，61·33; H，4.37; N，27.42。實例42 6-(5 -苯基-2 -噻吩基）-1，3, 5 -三嗪-2, 4 -二胺按照實例41 A和4 1B來處理5 -苯基噻吩-2 -羧酸甲酯，得到標題化合物。熔點 > 2 5 0 °C ; t MS (DCI/NH3) m/e 2 7 0 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 7· 80 (d， 1H)， 7.71-7.76 (m，2H)，7.56 (d，1H)，7.31 -7.49 (m， 311)，6· 78 (bds，4H); 關於之分析計算值：C， 5 6.0 9; H， 4 . 3 4 ; N，2 5 · 1 6。實驗值：C，5 6 . 3 5 ; H，4 · 0 1 ; N， 2 5.2 7。實例4 3 N，N’-[6-(4 -苯基環己基）-1,3, 5 -三嗪-2, 4 -二基1雙[乙· 胺] 按照實例3 3 B來處理實例3，得到標題化合物。熔點 2 3 5 - 2 3 6 °C ; MS (DCI/NII3) m/e 3 5 4 (M + II)f ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 6 10. 61 (s， 2H)， 7· 30 (m，4H)，7.18 (m，111)，2.63 (m，1H)，2.56 (m，1H)，Page 59 486472 V. Description of the invention (55) 7.44 (m, 2H), 7.41-7.37 (m, 1H), 7.23 (dd, 1H), 7. 16 (dd, 1H), 6.78 (br s, 4H) ; Analytical calculated values for C13HuN50: C, 61.65; H, 4.37; N, 27.65. Experimental values: C, 61 · 33; H, 4.37; N, 27.42. Example 42 6- (5-phenyl-2-thienyl) -1,3,5-triazine-2,4-diamine Treatment of 5-phenylthiophene-2-carboxylic acid according to Examples 41 A and 4 1B Methyl ester to give the title compound. Melting point> 2 50 ° C; t MS (DCI / NH3) m / e 2 7 0 (M + H) +; 4 NMR (300 MHz, DMS〇-d6) 5 7 · 80 (d, 1H), 7.71-7.76 (m, 2H), 7.56 (d, 1H), 7.31-7.49 (m, 311), 6.78 (bds, 4H); Analytical calculated values: C, 5 6.0 9; H , 4. 3 4; N, 2 5 · 1 6. Experimental values: C, 5 6. 3 5; H, 4 · 0 1; N, 2 5.2 7. Example 4 3 N, N '-[6- (4-phenylcyclohexyl) -1,3, 5-triazine-2, 4-diyl 1 bis [ethyl · amine] Example was treated as in Example 3 3 B 3. The title compound is obtained. Melting point 2 3 5-2 3 6 ° C; MS (DCI / NII3) m / e 3 5 4 (M + II) f; 41 NMR (300 MHz, DMS〇-d6) 6 10. 61 (s , 2H), 7.30 (m, 4H), 7.18 (m, 111), 2.63 (m, 1H), 2.56 (m, 1H),

第60頁 486472 五、發明說明（56) 2.36 (s， 6H)， 1.98 (m， 4H)， 1.63 (m， 4H); 關於C19H23N5 02 · 0· 25H20 之分析計算值：C， 6 3.7 6; H， 6.62; N， 19.57。實驗值：C，6 3.8 3; H，6.52; N， 19.27。實例44 N-[4 -胺基- 6- (4 -苯基環己基）-1，3，5~~三嗓-2 -基]乙酿胺按照實例3 4來處理實例3，得到標題化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 312 (M + H)+ ； 1H)， 7.28 2.25 (s， 3H)， 6. 80; N, 22.74。 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 0· 02 (s (m， 7H)， 2. 54 (m， 1H)， 2.44 (m， 1H)， 1 . 96 (m, 4H), 1.59 (m, 4H); 關於C17H2iN50之分析計算值：C， 6 5. 5 7; H, 22.49。實驗值：C，65.37; H，6 · 8 5 ; N，實例4 5 6-(4-苯基-1-萘基）-l，3，5 -三嗪-2，4 -二胺Page 60 486472 V. Description of the invention (56) 2.36 (s, 6H), 1.98 (m, 4H), 1.63 (m, 4H); Analytical calculated value for C19H23N5 02 · 0 · 25H20: C, 6 3.7 6; H, 6.62; N, 19.57. Experimental values: C, 6 3.8 3; H, 6.52; N, 19.27. Example 44 N- [4-amino-6- (4-phenylcyclohexyl) -1,3,5 ~~ trimethyl-2-yl] ethylamine The Example 3 was treated as in Example 34 to obtain the title compound. . Melting point > 2 60 ° C; MS (DCI / NH3) m / e 312 (M + H) +; 1H), 7.28 2.25 (s, 3H), 6. 80; N, 22.74. 41 NMR (300 MHz, DMS〇-d6) 0.02 (s (m, 7H), 2. 54 (m, 1H), 2.44 (m, 1H), 1. 96 (m, 4H), 1.59 (m, 4H); Analytical calculated values for C17H2iN50: C, 6 5. 5 7; H, 22.49. Experimental values: C, 65.37; H, 6 · 8 5; N, Example 4 5 6- (4- Phenyl-1-naphthyl) -1,3,5-triazine-2,4-diamine

實例4 5 A 在-78 °C下以在二氣曱烷（15毫升）中之BBq (5克，20毫腈（3 · 莫耳）處理在二氣曱烷（15毫升）中之4-曱氧基-1 克，1 9毫莫耳）的溶液，在室溫下攪拌1 8小時，以A 1 C 13 (5克，3 8毫莫耳）處理，在室溫下攪拌1 8小時，以水處理並以醋酸乙酯萃取。以水和鹽水沖洗該萃取物，脫水 (MgS04)並濃縮，之。藉著閃爍層析法在矽膠上純化殘餘物，以3 0 %醋酸乙酯/己烷洗脫，得到預定的化合物。Example 4 5 A was treated with BBq (5 g, 20 mmol nitrile (3 · mole)) in dioxane (15 ml) at -78 ° C 4- A solution of fluorenyl-1 g, 19 mmoles, stirred at room temperature for 18 hours, treated with A 1 C 13 (5 g, 38 mmoles), and stirred at room temperature for 18 hours , Treated with water and extracted with ethyl acetate. The extract was washed with water and brine, dehydrated (MgS04) and concentrated, and then. The residue was purified on silica gel by flash chromatography, eluting with 30% ethyl acetate / hexane, to give the intended compound.

486472 五、發明說明（57) MS (DCI/NH3) m/e 187 (M + NH4)‘。486472 V. Description of the invention (57) MS (DCI / NH3) m / e 187 (M + NH4) '.

實例4 5 B 將在0 °C之二氯曱烷（15毫升）中之實例45A (1· 0克，5· 9 毫莫耳）、三乙胺（1毫升，7. 2毫莫耳）和Ν-苯基-三氟甲烷磺醯胺（2. 1克，5. 9毫莫耳）的溶液，在室溫下攪拌過夜。以醋酸乙酯處理該反應，並以10% HC1、20% ΚΟΗ、水和鹽水連續沖洗，脫水（M g S 04)並濃縮，得到預定的化合物。 MS (DCI/NH3) m/e 319 (M+NHJ+ 。實例4 5 C t 按照實例2 1來處理實例4 5 B和苯基硼酸，得到預定的化合物。 MS (DCI/NH3) m/e 247 (M + NH4)+。Example 4 5 B Example 45A (1.0 g, 5.9 mmol), triethylamine (1 mL, 7.2 mmol) in dichloromethane (15 ml) at 0 ° C And a solution of N-phenyl-trifluoromethanesulfonamide (2.1 g, 5.9 mmol) and stirred at room temperature overnight. The reaction was treated with ethyl acetate and washed successively with 10% HC1, 20% KOH, water and saline, dehydrated (Mg S 04) and concentrated to obtain the intended compound. MS (DCI / NH3) m / e 319 (M + NHJ +. Example 4 5 C t Example 4 5 B and phenylboronic acid were treated as in Example 21 to give the intended compound. MS (DCI / NH3) m / e 247 (M + NH4) +.

實例4 5 D 6-(4 -苯基-1-蔡基）-1，3，5 -三嗦-2，4 -二胺按照實例1來處理實例4 5 C，得到標題化合物。熔點 2 3 9 - 2 4 0 °C ; MS (DCI/NH3) m/e 314 (M + H)1 ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) (5 8· 8 4- 8. 8 0 (m， 1H)， 7.97 (d, 1H), 7.85-7.81 (m, 1H), 7.6 9 -7.48 (m, 8H)， 6· 84 (bds， 4H); 關於 C19H15N5 之分析計算值：C， 72.82; H， 4.82; N， 2 2 · 3 4。實驗值：C，7 2 · 6 8 ; H，4 . 7 7 ; N，2 2 · 3 5。實例4 6 6-[4-(苯硫基）苯基1-1，3, 5 -三嗪-2, 4-二胺Example 4 5 D 6- (4-phenyl-1-Czechyl) -1,3,5-trifluorene-2,4-diamine Example 4 was treated as in Example 1 to obtain the title compound. Melting point 2 3 9-2 4 ° C; MS (DCI / NH3) m / e 314 (M + H) 1; 41 NMR (300 MHz, DMS〇-d6) (5 8 · 8 4- 8 8 0 (m, 1H), 7.97 (d, 1H), 7.85-7.81 (m, 1H), 7.6 9 -7.48 (m, 8H), 6.84 (bds, 4H); Analytical calculated values for C19H15N5 : C, 72.82; H, 4.82; N, 2 2 · 3 4. Experimental values: C, 7 2 · 6 8; H, 4. 7 7; N, 2 2 · 3 5. Example 4 6 6- [4 -(Phenylthio) phenyl 1-1,3,5-triazine-2,4-diamine

第62頁 486472 五、發明說明（58) 實例將在DMF (20毫升）中之4-溴苄腈（1· 〇克，5 5哀^ 苯硫酚（ 644毫克，5· 8毫莫耳）、k2C〇3 (1 9克·笔美耳）、耳）和CuI (1.05克’5. 5毫莫耳）的溶液加熱至毫莫時，以醋酸乙酯處理，並通過矽藻土©過清、 ⑽4小沖洗渡液，脫水（M g S Ο*)並濃縮之。藉著閃燦声析、、義& 膠上純化殘餘物’以5 %酷酸乙§旨/己燒洗脫’1 ^】夕化合物。、、疋的 MS (DCI/NH3) m/e 2 2 9 (M + NH4y。Page 62 486472 V. Description of the invention (58) Example 4-Bromobenzonitrile (1.0 g, 5 5 ^ thiophenol (644 mg, 5.8 mmol) in DMF (20 ml) , K2C〇3 (19 g · Peltier), ear) and CuI (1.05 g '5.5 mmol) were heated to millimol, treated with ethyl acetate, and passed through diatomaceous earth © Rinse and rinse for 4 small rinses, dehydrate (M g S Ο *) and concentrate. The residue was purified by flash chromatography, gelatin & gel ' to elute the compound with 5% ethyl acetate / hexane. MS (DCI / NH3) m / e 2 2 9 (M + NH4y.

實例4 6.B 6 - [ 4 -(苯石荒基）苯基]-1，3 嗓-2 4 -- 〆按照實例1來處理實例46A，得到標題化合物。熔點 2 1 3 - 2 1 5 °C ; MS (DCI/NH3) m/e 2 9 6 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMSO-d6) 68· 19 (d， 2h) 7 〇 — 7·41 (m， 5H)， 7· 32 (d， 2H)， 6. 77 (bds， 4H).·— 關於 Ci5 Hi 3 N5 S 之分析 a十异值：C， 6 0 . 9 9 ; H，4 4 3 . j\j 23.71。實驗值：C，6 0.7 0; H，4.32; N，23 55’。’ 實例4 7 6-(2-嗤啉基）-1，3，5 -三i —二脸按照實例1來處理2 -喹啉腈，得到標題化合物。 MS (DCI/NH3) m/e 23 9 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS0-d6) 5 8· 5 (d， 1H) 8 3 5 〔 1H)， 8.15-8.0 (m， 2H)， 7·9-7·8 (m，，1H)，’775—7 486472 五、發明說明（59) (m, 1H), 7. 1-7.0 (br s, 2H), 7.0-6.9 (br s, 2H); 關於C12H1()N6 之分析計算值：C， 6 0.4 9; H， 4.23; N， 3 5.2 7。實驗值：C，6 0.24; H，3.94; N，35.12。實例4 8 6-(3 -喹啉基）-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理3 -喹啉腈，得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 23 9 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) (5 9· 7 (d， 1H)， 9· 1 (d， 1H)， 8.2-8.1 (m， 2H)， 6.9-6.85 (m， 1H)， 6.8-6.7 (m, 1H), 7.05-6.9 (br s, 4H); 關於 C12H1QN6 之分析計算值：C， 60.49; H，4.23; N， 3 5.2 7。實驗值：C，6 0.32; H，4.06; N，35.54。實例4 9 6-(苯并[b]噻吩-2 -基曱基）-1，3, 5 -三嗉-2, 4 -二胺按照實例1來處理苯并[b ]噻吩-2 -乙腈，得到標題化合物。熔點 2 1 6 - 2 1 8 °C ; MS (DCI/NH3) m/e 2 5 8 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMSO-d6) 5 7· 97-7· 92 (m， 1H)， 7.8 7- 7.8 0 (m，1H)，7.48 (s，1H)，7.4-7.32 (m，2H)， 6. 65 (br s，4H)，3. 90 (s，2H); 關於C12HnN5S之分析計算值：C， 56.01; H， 4.30; N， 27.21。實驗值：C，55·97; H，4.19; N，27.31。Example 4 6.B 6-[4- (Benzoaryl) phenyl] -1,3 -2-2---- Example 46A was treated as in Example 1 to give the title compound. Melting point 2 1 3-2 1 5 ° C; MS (DCI / NH3) m / e 2 9 6 (M + H) +; 41 NMR (3 0 0 MHz, DMSO-d6) 68 · 19 (d, 2h ) 7〇— 7.41 (m, 5H), 7.32 (d, 2H), 6. 77 (bds, 4H). · — About the analysis of Ci5 Hi 3 N5 S a ten different values: C, 6 0 9 9; H, 4 4 3. J \ j 23.71. Experimental values: C, 6 0.7 0; H, 4.32; N, 23 55 '. Example 4 7 6- (2-Phenolinyl) -1,3,5-tri-i-diface Treatment of 2-quinolinonitrile according to Example 1 gave the title compound. MS (DCI / NH3) m / e 23 9 (M + H) +; 41 NMR (3 0 0 MHz, DMS0-d6) 5 8 · 5 (d, 1H) 8 3 5 〔1H), 8.15-8.0 (m, 2H), 7 · 9-7 · 8 (m ,, 1H), '775-7 486472 V. Description of the invention (59) (m, 1H), 7. 1-7.0 (br s, 2H), 7.0-6.9 (br s, 2H); Analytical calculated values for C12H1 () N6: C, 6 0.4 9; H, 4.23; N, 3 5.2 7. Experimental values: C, 6 0.24; H, 3.94; N, 35.12. Example 4 8 6- (3-Quinolinyl) -1,3,5-triazine-2,4-diamine Treatment of 3-quinolinonitrile as in Example 1 gave the title compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 23 9 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) (5 9 · 7 (d, 1H ), 9.1 (d, 1H), 8.2-8.1 (m, 2H), 6.9-6.85 (m, 1H), 6.8-6.7 (m, 1H), 7.05-6.9 (br s, 4H); About C12H1QN6 Analytical calculated values: C, 60.49; H, 4.23; N, 3 5.2 7. Experimental values: C, 6 0.32; H, 4.06; N, 35.54. Example 4 9 6- (Benzo [b] thiophene-2- Sulfenyl) -1,3,5-trifluorene-2,4-diamine The benzo [b] thiophene-2-acetonitrile was treated according to Example 1 to give the title compound. Melting point 2 1 6-2 1 8 ° C ; MS (DCI / NH3) m / e 2 5 8 (M + H) +; 1 NMR (300 MHz, DMSO-d6) 5 7 · 97-7 · 92 (m, 1H), 7.8 7- 7.80 (m, 1H), 7.48 (s, 1H), 7.4-7.32 (m, 2H), 6. 65 (br s, 4H), 3. 90 (s, 2H); Analytical calculated values for C12HnN5S: C, 56.01; H, 4.30; N, 27. 21. Experimental values: C, 55 · 97; H, 4.19; N, 27.31.

第64頁 486472 五、發明說明（60) 實例5 0 6-(2,2-二曱基-211-1-苯并哌喃-6-基）-1，3,5-三嗪-2,4- 二胺按照實例1來處理2，2 -二曱基-2 Η - 1 -苯并哌喃-6 -腈，得到標題化合物。 MS (DCI/NH3) m/e 2 7 0 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 05 (dd， 1H)， 7· 95 (d，1H)，6.9 (d，1H)，6.78 - 6.7 5 (br s，4H)，6.70 (d，1H)，5. 80 (d，1H)，1 · 20 (s，6H); 關於C14H15N50 之分析計算值：C， 6 2. 44; H, 5. 61 ; N, 2 6.0 0。實驗值：C，62.19; H，5.70; N，2 5.54。實例5 1 6-(2，3 -二氫-1，4 -苯并二氧印（dioxin)-2 -基）-1，3，5 -三嗓-2，4 -二胺按照實例1來處理2, 3 -二氫-1，4-苯并二氧茚（dioxin) -2 -腈，得到標題化合物。 MS (DCI/NH3) m/e 24 6 (M + H)+ ； 4 N MR (300 兆赫茲，DM SO-d6 )57.0-6.75 (m， 8H)， 3.5 (t，1 H )，3 . 3 ( d，2 H ); 關於CuHnN5〇2之分析計算值：C， 53.81; H，4.52; N， 28.55。實驗值：C，5 3.8 0; H，4.36; N，2 8.4 0。實例5 2 6-(三環[3.3.1.13.7]癸烧-1-基）-1，3，5-三嗓-2，4-二胺按照實例2C來處理三環[3. 3. 1. I3.7]癸烷-1-羧酸甲酯和Page 64 486472 V. Description of the invention (60) Example 5 0 6- (2,2-Difluorenyl-211-1-benzopiperan-6-yl) -1,3,5-triazine-2, 4-Diamine was treated in accordance with Example 1 to 2,2-difluorenyl-2fluorene-1 -benzopiperan-6-nitrile to give the title compound. MS (DCI / NH3) m / e 2 7 0 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) 5 8 · 05 (dd, 1H), 7. 95 (d, 1H ), 6.9 (d, 1H), 6.78-6.7 5 (br s, 4H), 6.70 (d, 1H), 5. 80 (d, 1H), 1 · 20 (s, 6H); Analysis and calculation of C14H15N50 Value: C, 6 2. 44; H, 5. 61; N, 2 6.0 0. Experimental values: C, 62.19; H, 5.70; N, 2 5.54. Example 5 1 6- (2,3-dihydro-1,4-dioxin-2-yl) -1,3,5-trimethyl-2,4-diamine Treatment of 2, 3 -dihydro-1,4-benzodoxin-2-dinitrile gave the title compound. MS (DCI / NH3) m / e 24 6 (M + H) +; 4 N MR (300 MHz, DM SO-d6) 57.0-6.75 (m, 8H), 3.5 (t, 1 H), 3. 3 (d, 2 H); Analytical calculated value for CuHnN50 2: C, 53.81; H, 4.52; N, 28.55. Experimental values: C, 5 3.80; H, 4.36; N, 2 8.40. Example 5 2 6- (Tricyclic [3.3.1.13.7] decyl-1-yl) -1,3,5-trimethyl-2,4-diamine Tricyclic was treated according to Example 2C [3.3. 1. I3.7] methyl decane-1-carboxylate and

第65頁 486472 五、發明說明（61) 實例2 B，得到標題化合物。熔點 2 6 1 - 2 6 2 ; MS (DCI/NH3) m/e 246 (M + H)+ ； 1 NMR (300 兆赫茲，DMS〇-d6 )56.47 (br s，4H) 1.95 (m， 3H)， 1.9-1.88 (m， 6H)， 1.77-1.60 (m， 6H); 關於 C13Hi9N5 之分析計算值：C， 63.64; H，7.80; N， 2 8.54。實驗值：C，63.48; H，7.66; N，2 8.34。實例5 3 6-(1-異喹啉基）-1，3, 5 -三嗪-2, 4 -二胺 ‘ 按照實例1來處理卜異喹啉腈，得到標題化合物。熔點 > 2 5 (Γ C ; MS (DCI/NH3) m/e 2 3 9 (M + H)+ ； 41 NMR ( 3 0 0 兆赫兹，DMS〇-d6) δ 8. 1 Η )，8 · 0 ( d，1 Η )，7 · 9 ( d，1 Η )， (dt，1Η)，6· 9 (bs，4Η); 關於C12H1QN6 · 0· 3Η20之分析計算值： N，3 5 · 2 7。實驗值：C，5 9 · 5 5 ; Η，實例5 4 2.05- (d 7. 1H)，8. 2 (d， (dt， 1H)， 7. 65 C， 60.49; H, 4.23; 4.35; N, 34.0 3。 (+/-)-4-(4，6 -二胺基~~1，3，5~~ 三嗓~~2 -基苯基苯曱醇將在乙醇（5毫升）中之實例1 1 (1 5 0毫克，0 · 5 1 5毫莫耳）和·氫化鈉（6毫克，0. 1 5毫莫耳）的混合物加熱至迴流3 0 分鐘，然後在室溫下攪拌過夜。以水沖洗沉澱物，並在真空下脫水，得.到標題化合物。熔點 2 1 4 - 2 1 6 °C ;P.65 486472 V. Description of the Invention (61) Example 2 B to give the title compound. Melting point 2 6 1-2 6 2; MS (DCI / NH3) m / e 246 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) 56.47 (br s, 4H) 1.95 (m, 3H ), 1.9-1.88 (m, 6H), 1.77-1.60 (m, 6H); Analytical calculated values for C13Hi9N5: C, 63.64; H, 7.80; N, 2 8.54. Experimental values: C, 63.48; H, 7.66; N, 2 8.34. Example 5 3 6- (1-Isoquinolinyl) -1,3,5-triazine-2,4-diamine ′ The isoquinolinonitrile was treated as in Example 1 to give the title compound. Melting point> 2 5 (Γ C; MS (DCI / NH3) m / e 2 3 9 (M + H) +; 41 NMR (300 MHz, DMS〇-d6) δ 8. 1 1), 8 · 0 (d, 1 Η), 7 · 9 (d, 1 Η), (dt, 1 Η), 6. · 9 (bs, 4 Η); Analytical calculation for C12H1QN6 · 0 · 3 Η 20: N, 3 5 · 2 7. Experimental values: C, 5 9 · 5 5; Η, Example 5 4 2.05- (d 7. 1H), 8. 2 (d, (dt, 1H), 7. 65 C, 60.49; H, 4.23; 4.35; N, 34.0 3. (+/-)-4- (4,6-diamino group ~~ 1,3,5 ~~ Trisodium ~~ 2-phenylphenylbenzyl alcohol will be in ethanol (5 ml) Example 11 A mixture of 1 1 (150 mg, 0.51 5 mmol) and sodium hydride (6 mg, 0.1 15 mmol) was heated to reflux for 30 minutes, and then stirred at room temperature Overnight. The precipitate was washed with water and dehydrated under vacuum to give the title compound. Melting point 2 1 2-2 16 ° C;

11

第66頁 486472 五、發明說明（62) iVIS (DCI/NH3) m/e 2 94 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 2 (d， 2H)， 7· 5 (d， 2H)，7·4 (d，2H)，7.3 (t，2H)，7·2 (m，1H)，6·7 (br s，4H)，6· 0 (d，1H)，5. 75 (d，1H); 關於 C16H15N50 之分析計算值：C， 65.51; H，5.15; N， 2 3.8 7。實驗值：C，65·33; H，4·91; N，2 3.6 5。實例5 5 6 — (2，3—二氮一1，4一苯弁二氧 E卩(dioxin) — 6 —基)一1，3，5 —三嗓-2，4 -二胺按照實例1來處理2，3 -二氫-1，4 -苯并二氧茚（d i ◦ X i η ) -6 -腈，得到標題化合物。熔點 24 1 -244 °C ; MS (DCI/NH3) m/e 24 6 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 8二8· 75 (m， 2H)， 6.95-6.9 (m, 1H), 6.9-6.8 (br s, 4H), 4.25-4.33 (m， 4H); 關於之分析計算值：C， 53· 87 ; H，4. 52 ; N， 2 8.5 6。實驗值：C，5 3.9 3; 11，4.27; N，28.41。實例5 6 6-(1-氮雜二環[2·2·2]辛烧-4 -基）-1，3，5 -三嗪- 2，4 -二胺按照實例1來處理卜氮雜二環[2 · 2 . 2 ]辛烷-4-腈，得到標題化合物。· 熔點 > 2 4 5 °C ;Page 66 486472 V. Description of the invention (62) iVIS (DCI / NH3) m / e 2 94 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) 5 8 2 (d, 2H), 7.5 (d, 2H), 7.4 (d, 2H), 7.3 (t, 2H), 7.2 (m, 1H), 6.7 (br s, 4H), 6.0 (d, 1H), 5.75 (d, 1H); Analytical calculated values for C16H15N50: C, 65.51; H, 5.15; N, 2 3.8 7. Experimental values: C, 65 · 33; H, 4.91; N, 2 3.6 5. Example 5 5 6 — (2,3-Diazine-1,4-diphenyloxine dioxin (dioxin) -6-yl) -1,3,5-trithal-2,4-diamine According to Example 1 Treatment of 2,3-dihydro-1,4-benzodioxindene (di ◦ X i η) -6-nitrile gave the title compound. Melting point 24 1 -244 ° C; MS (DCI / NH3) m / e 24 6 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) 5 8 · 8-2 8.75 (m , 2H), 6.95-6.9 (m, 1H), 6.9-6.8 (br s, 4H), 4.25-4.33 (m, 4H); Analytical calculated values: C, 53 · 87; H, 4.52; N, 2 8.5 6. Experimental values: C, 5 3.9 3; 11, 4.27; N, 28.41. Example 5 6 6- (1-Azabicyclo [2 · 2 · 2] octane-4 -yl) -1,3,5-triazine-2,4-diamine Bicyclo [2.2.2] octane-4-carbonitrile gave the title compound. Melting point > 2 4 5 ° C;

第67頁 486472Page 67 486472

(DCI/NH3) m/e 221 (Μ + Η)+ ; lH NMR ( 3 0 0 兆赫茲，DMS0_d6) 56· 6_6· 5 3*35 2H), 2.9 (t, 5H), 1.7 (t, 5H)； ^ 關於&〇Η16Ν6 之分析計算值：C， 54.53; H， 7.32，· N， 38· 15。實驗值：C，54. 40; H，7, 38; N，38. 25 / 實例5 7 inLiz(苯苯基 ^嗪-2,4—二胺在室溫下攪拌在乙酸（2毫升）中之實例4 9 (丨〇 2毫克，〇 · 3 4笔莫耳）和過硫氫酸鉀製劑© (1 〇 6毫克，〇 · 1 7毫莫耳）的混合物過夜，以飽和的NaHC〇3處理，並以醋酸乙酯萃 :。以水和鹽水沖洗該萃取物，㈤水(MgS〇4)並濃縮。使殘餘物從乙醇中再結晶’得到標題化合物。熔點 2 5 3 - 2 5 5 °C ; MS (DCI/NH3) m/e 312 (M + H)+ ; lH NMR ( 3 0 0 兆赫茲， 2H)， 7·75-7· 72 (m， (br s， 4H); DMSO-d6) 58. 36 (d, 2H), 7. 81 (d 2H)，7· 6"· 52 (m，3H)，6. 82 關於C15H13N5OS · 〇·25Η2〇之分析計算值· c 57 〇3 4·3〇; N，22.17。實驗值：C，57 · ’ 〇 21.81。 5 ? 5 實例三嗪-2, 4- 二 m Chem 按照實例1來處理4-(苯基磺醯基）爷，膳 1 9 8 9， 5 4，4 6 9 1 ) ’件到標題化合物'。(DCI / NH3) m / e 221 (Μ + Η) +; lH NMR (300 MHz, DMS0_d6) 56 · 6_6 · 5 3 * 35 2H), 2.9 (t, 5H), 1.7 (t, 5H ); ^ Analytical calculated value for & 〇616Ν6: C, 54.53; H, 7.32, · N, 38 · 15. Experimental values: C, 54. 40; H, 7, 38; N, 38. 25 / Example 5 7 inLiz (phenylphenyl ^ azin-2,4-diamine was stirred in acetic acid (2 ml) at room temperature The mixture of Example 4 9 (丨 02 mg, 0.34 Molar) and potassium persulfate formulation © (106 mg, 0.1 17 Molar) was overnight, saturated with NaHC03. Work up and extract with ethyl acetate: Rinse the extract with water and brine, rinse with water (MgS04) and concentrate. Recrystallize the residue from ethanol to give the title compound. Melting point 2 5 3-2 5 5 ° C; MS (DCI / NH3) m / e 312 (M + H) +; 1H NMR (300 MHz, 2H), 7.75-7 · 72 (m, (br s, 4H); DMSO -d6) 58. 36 (d, 2H), 7. 81 (d 2H), 7.6 " 52 (m, 3H), 6. 82 Analytical calculated value for C15H13N5OS 〇 · 25Η2〇 · c 57 〇 3 4 · 3〇; N, 22.17. Experimental value: C, 57 · '〇21.81. 5? 5 Example Triazine-2, 4-dim Chem Treatment of 4- (phenylsulfonyl) group according to Example 1 , 1 1 9 8 9, 5, 4, 4 6 9 1) 'Pieces to the title compound'.

486472 五、發明說明（64) 熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 3 2 8 (M + H)+ ； 1 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 41 (d， 2Η)， 8. 08 (d, 2H), 7.96 (d， 2H), 7. 71-7. 60 (m, 3H), 6. 92 (br s, 4H); 關於q 5 3 N5〇2 S . 0 · 2 5 H2〇之分析計算值：C， 5 4. 2 8 ; H， 4.10; N，21.10。實驗值：C，54.2 8; H，3·92; N， 2 0.8 2。實例5 9 4 E/Z-「4-(4，6 -二胺基-1，3, 5 -三嗪-2 -基）苯基1苯基曱酮，486472 V. Description of the invention (64) Melting point > 2 50 ° C; MS (DCI / NH3) m / e 3 2 8 (M + H) +; 1 NMR (300 MHz, DMS〇-d6) 5 8 · 41 (d, 2Η), 8. 08 (d, 2H), 7.96 (d, 2H), 7. 71-7. 60 (m, 3H), 6. 92 (br s, 4H); About Analytical calculation values for q 5 3 N50 2 S. 0. 2 5 H 2 0: C, 5 4. 2 8; H, 4.10; N, 21.10. Experimental values: C, 54.2 8; H, 3.92; N, 2 0.8 2. Example 5 9 4 E / Z- "4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl 1phenylfluorenone,

E 將在1 : 1之乙醇/吡啶（1 0毫升）中之實例1 1 ( 3 0 0毫克， 1. 0 3毫莫耳）和羥胺鹽酸鹽（7 0毫克，1. 0毫莫耳）的混合物加熱至迴流3小時，在室溫下g拌過夜，以水處理並過濾之。以水沖洗沉澱物，並脫水後得到標題化合物。熔點 9 7 - 1 0 7 t：; MS (DCI/NH3) m/e 3 0 7 (M + H)+ ； !H NMR ( 3 0 0 兆赫兹，DMS〇一d6) 5 11. 42 (s， 0. 5H)， 11.41 (s，0 · 5 H)，8. 3 5 (d，1H)，8· 2 (d，1H)，7· 3 - 7· 5 (m， 7H), 6. 8 (br s, 4H); 關於 C16H14N6〇.CH3CH2OH 之分析計算值：C， 61.35; H， 5 . 7 2 ; N，2 3 · 8 4。實驗值：C，6 1 . 6 7 ; II，5 · 2 9 ; N， 2 3.3 7。實例6 0E Example 1 in ethanol / pyridine (10 ml) 1: 1 (300 mg, 1.0 mmol) and hydroxylamine hydrochloride (70 mg, 1.0 mmol) The mixture was heated to reflux for 3 hours, stirred overnight at room temperature, treated with water and filtered. The precipitate was washed with water and dehydrated to give the title compound. Melting point 9 7-1 0 7 t:; MS (DCI / NH3) m / e 3 0 7 (M + H) +;! H NMR (3 0 0 MHz, DMS〇-d6) 5 11. 42 (s , 0. 5H), 11.41 (s, 0 · 5 H), 8. 3 5 (d, 1H), 8. 2 (d, 1H), 7.3-7.5 (m, 7H), 6. 8 (br s, 4H); Analytical calculated values for C16H14N6〇.CH3CH2OH: C, 61.35; H, 5. 7 2; N, 2 3 · 84. Experimental values: C, 6 1. 6 7; II, 5. 2 9; N, 2 3.3 7. Example 6 0

第69頁 486472Page 69 486472

五、發明說明（65) 6 -吡畊基-1，3，5 -三嗅^^二胺按照實例1來處理吡畊腈，得到標題化合物熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 190 (M + H)+ ; 4 NMR (300 兆赫兹，DMS〇-d6)56.9 (br s 2H) (br s， 2H)， 8.75-8.8 (m， 2H)， 9.3 (s， 1H)· 關於C7H7N7之分析計算值：C，44.44; H，3.72. n 51.82。實驗值：C，44.40; H，3.62; N，51 79 實例6 1V. Description of the invention (65) 6-Pyracyl-1,3,5-triol ^^ diamine Treatment of Pycnitrile according to Example 1 to obtain the melting point of the title compound> 2 50 ° C; MS (DCI / NH3) m / e 190 (M + H) +; 4 NMR (300 MHz, DMS 0-d6) 56.9 (br s 2H) (br s, 2H), 8.75-8.8 (m, 2H), 9.3 (s , 1H) · Analysis and calculation of C7H7N7: C, 44.44; H, 3.72. N 51.82. Experimental values: C, 44.40; H, 3.62; N, 51 79 Example 6 1

g_，4 -二胺基-6-[(4 -苯基乙稀基）苯某]—5 —三嗪g_, 4-diamino-6-[(4-phenylethenyl) benzene] -5-triazine

實例6 1 A 在室溫下以六曱基二矽疊氮化鋰（1M在甲苯中，53毫升’ 53¾莫耳）處理在THF (100毫升）中之氣化窄基三苯鳞 (2 2 · 8克’ 5 8毫莫耳）的溶液，加熱至迴流1 5分鐘，冷卻至室溫，以在THF (40毫升）中之4-氰基苯曱醛（7克，53毫莫耳）處理，在室溫下過夜攪拌，以1 〇% HC1酸化並過濾之，以醋酸乙酯萃取濾液，脫水（MgS04)並濃縮之。將殘餘物溶解於熱的醋酸乙酯中，並通過矽膠的塞子過濾，得到預定的化合物。Example 6 1 A Gasified narrow-base triphenyl scale (2 2) was treated with hexafluorenyldisilazide (1M in toluene, 53 ml '53 ¾ mole) in THF (100 ml) at room temperature. · 8 grams of a solution of '58 mol), heated to reflux for 15 minutes, and cooled to room temperature to give 4-cyanobenzaldehyde (7 g, 53 mmol) in THF (40 ml) Work up, stir at room temperature overnight, acidify with 10% HC1 and filter it. Extract the filtrate with ethyl acetate, dehydrate (MgS04) and concentrate. The residue was dissolved in hot ethyl acetate and filtered through a plug of silicone to give the intended compound.

實例6 1 B 按照實例1來處理實例6 1 A，得到標題化合物。熔點 2 1 6 - 2 1 7。(：； MS (DCI/NH3) .m/e 2 9 0 (M + H)+ ； NMR ( 3 0 0 兆赫茲，DMSO-d6) ά 8· 25 (d， 2H)， 7· 75 (d，Example 6 1 B Example 6 1 A was treated according to Example 1 to obtain the title compound. Melting point 2 1 6-2 1 7. (:; MS (DCI / NH3) .m / e 2 9 0 (M + H) +; NMR (3 0 0 MHz, DMSO-d6) ά 8.25 (d, 2H), 7.75 (d ,

第70頁 486472 五、發明說明（66) 2H), 7.65 (d, 2H), 7.2-7.4 (m, 5H), 6.75 (br s, 4H); 關於 C17H15N5 · 0· 5CH3C02CH2CH3 之分析計算值：C，6 8.45; Η，5 · 7 4 ; N，2 1 · Ο 0。實驗值：C，6 8 · 5 Ο ; Η，5 · 4 9 ; N， 21.43。實例6 2 2，4-二胺基-6-[(4-(2-石肖苯基）乙烯基)苯基]1，3，5 -三P秦按照實例6 1 A和6 1 B來處理溴化4-硝窄基三苯鱗，得到標題化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 3 3 5 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 8· 25 (t， 4H)， 7· 9 (d， 2H)， 7·8 (d， 2H)， 7·6 (m， 2H)， 6.8 (br s， 4H); 關於C17Hi4N6 02 之分析計算值：C， 61.07; H，4.22; N， 2 5 · 1 4。實驗值：C，6 0 · 7 8 ; ΙΊ，4 · 1 2 ; N，2 4 · 8 9。實例6 3 6-[1，1’-聯苯基]-4-基-^『-二曱基-1，3,5-三嗪-2,4-二 ΜPage 70 486472 V. Description of the invention (66) 2H), 7.65 (d, 2H), 7.2-7.4 (m, 5H), 6.75 (br s, 4H); Analysis and calculation of C17H15N5 · 0 · 5CH3C02CH2CH3: C , 6 8.45; Η, 5 · 7 4; N, 2 1 · Ο 0. Experimental values: C, 6 8 · 5 Ο; Η, 5 · 4 9; N, 21.43. Example 6 2 2,4-Diamino-6-[(4- (2-Shishophenyl) vinyl) phenyl] 1,3,5-tri-P-phenylene was obtained according to Examples 6 1 A and 6 1 B. Treatment of 4-nitronyl triphenyl scales to give the title compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 3 3 5 (M + H) +; 41 NMR (300 MHz, DMS〇-d6) 5 8.25 (t, 4H ), 7.9 (d, 2H), 7.8 (d, 2H), 7.6 (m, 2H), 6.8 (br s, 4H); Analytical calculated value for C17Hi4N6 02: C, 61.07; H , 4.22; N, 2 5 · 1 4. Experimental values: C, 6 0 · 7 8; 1Ί, 4 · 1 2; N, 2 4 · 8 9. Example 6 3 6- [1,1'-biphenyl] -4-yl-^ "-diamidyl-1,3,5-triazine-2,4-di M

實例6 3 A 2-[1，1’ -聯苯基]-4 -基-4，6 -二氯-1，3，5 -三嗪在0 °C下攪拌苯（90毫升）中之溴化4-苯基-苯基鎂（從在 40毫升***中之4 -溴聯苯（7. 75克，33毫莫耳）和杜林尼 (turnings)鎂（0.83克，35毫莫耳）來製備）和氰尿醯氣 (4. 0 0克，2 1 . 7毫莫耳）的混合物9 0分鐘。將該反應蒸發至Example 6 3 A 2- [1,1'-Biphenyl] -4-yl-4,6-dichloro-1,3,5-triazine was stirred at 0 ° C for bromine in benzene (90 ml) 4-Phenyl-phenylmagnesium (from 4-bromobiphenyl (7.75 g, 33 mmol) in 40 ml of ether) and magnesium magnesium turning (0.83 g, 35 mmol) To prepare) and a mixture of cyanuric tritium (4.0 g, 21.7 mmol) for 90 minutes. The reaction was evaporated to

第71頁 486472 五、發明說明（67) 無水，並在石夕膠上對該殘餘物進行閃燦層析，以5 0 %己烧/ 二氯甲烷洗脫，得到想要的化合物（2. 80克，43%)。 MS (DCI/NH3) m/e 301 (M + H)+ ；Page 71 486472 V. Description of the invention (67) Anhydrous, and the residue was subjected to flash chromatography on Shixi gum, eluting with 50% hexane / dichloromethane, to obtain the desired compound (2. 80 grams, 43%). MS (DCI / NH3) m / e 301 (M + H) +;

實例63B 6-[ 1，1，-聯苯基]-4 -基-N，r -二曱基-1，3, 5 -三嗪-2, 4 -二在周圍溫度下攪拌在四氫呋喃（2 5毫升）中之實例63A (0· 52克，1· 72毫莫耳）和N-曱胺（30毫莫耳）的混合物72小時。減少該反應的體積，並以水稀釋之。收集沉澱物，q 水和***沖洗，並脫水之。藉著逆相HPLC純化，得到想要的化合物。熔點 1 9 8 - 2 0 0 °C ; MS (DCI/NH3) m/e 2 9 2 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) δ 8· 37 (m， 2H)， 7· 74 (m， 4H)，7.51 (m，2H)，7.39 (m，1H)，7.22 (bdm，2H)， 2.82 (m， 6H); 關於C17H17N5 · 0· 25H20 之分析計算值：C， 69.01; H， 5 · 9 6 ; N，2 3 . 6 7。實驗值：C，6 9 · 3 7 ; H，5 · 8 5 ; N， 2 3.6 3。實例64 6-[ 1，1’ -聯苯基]-4 -基-N-曱基-1，3, 5 -三嗪-2, 4 -二胺Example 63B 6- [1,1, -biphenyl] -4-yl-N, r-difluorenyl-1,3,5-triazine-2,4-di, stirred at ambient temperature in tetrahydrofuran (2 5 ml) of a mixture of Example 63A (0.52 g, 1.72 mmol) and N-amidamine (30 mmol) for 72 hours. Reduce the volume of the reaction and dilute it with water. Collect the precipitate, rinse with q water and ether, and dehydrate it. Purification by reverse phase HPLC gave the desired compound. Melting point 198-2 0 ° C; MS (DCI / NH3) m / e 2 9 2 (M + H) +; 41 NMR (300 MHz, DMS〇-d6) δ 8.37 (m , 2H), 7.74 (m, 4H), 7.51 (m, 2H), 7.39 (m, 1H), 7.22 (bdm, 2H), 2.82 (m, 6H); Analysis and calculation of C17H17N5 · 0 · 25H20 Value: C, 69.01; H, 5 · 9 6; N, 2 3. 6 7. Experimental values: C, 6 9 · 3 7; H, 5 · 8 5; N, 2 3.6 3. Example 64 6- [1,1 '-biphenyl] -4 -yl-N-fluorenyl-1,3, 5-triazine-2, 4-diamine

實例6 4 A L嗪-2 -胺聯苯基]-4 -基 4-[1，1’ 聯苯基1-4 -基-6 -氣-1，3, 5 在0 °C下攪拌在40毫升***中之2-[1，1Example 6 4 AL azine-2 -amine biphenyl] -4 -yl 4- [1,1 'biphenyl 1-4 -yl-6 -gas-1,3, 5 was stirred at 0 ° C at 40 2- [1,1 in ml of ether

第72頁 486472 五、發明說明（68) -4,6-二氯-1，3,5-三嗪（實例 63A) ( 0.8 04·克，2.67 毫莫耳）和在四氫咲喃（30毫升）中之濃氫氧化銨（2毫升，30毫莫耳）的混合物6 0分鐘，並在周圍溫度下攪拌2 0分鐘。減少該反應之體積，以水稀釋並收集沉澱物，以水和***沖洗，並脫水之，得到想要的化合物（0 · 0 9 0克，1 2% )。 MS (DCI/NH3) m/e 2 8 2 (M + H)+ ；Page 72 486472 V. Description of the invention (68) -4,6-dichloro-1,3,5-triazine (Example 63A) (0.8 04 · g, 2.67 mmol) and tetrahydrofuran (30 Ml) of a mixture of concentrated ammonium hydroxide (2 ml, 30 mmol) for 60 minutes and stirred at ambient temperature for 20 minutes. The volume of the reaction was reduced, the precipitate was diluted with water and collected, washed with water and ether, and dehydrated to obtain the desired compound (0.090 g, 12%). MS (DCI / NH3) m / e 2 8 2 (M + H) +;

實例64B 6-[ 1，1，-聯笨基]-4-基-N-曱基-1，3, 5 -三嗪-2, 4-二胺在室溫下攪拌在四氫呋喃（9毫升）中之實例64A (0· 0 9 0 ^ 克，0. 32毫莫耳）和N-甲胺（6毫莫耳）24小時。減少該反應之體積，並以水稀釋。收集沉澱物，以水和***沖洗，並將其脫水，得到想要的化合物（0 . 0 6 2克，7 0 % )。熔點 2 3 7 - 2 3 8 t：; MS (DCI/NII3) m/e 278 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMSO-d6) 5 8· 39 (d， 1H)， 8· 32 (d， 1H)，7.77 (m，4H)，7.51 (t，2H)，7.41 (m，1H)， 7.25 (q，1H)，6.79 (bds，2H)，2.79 (d，3H); 關於C16H15N5 . 0· 5C4H8〇2 之分析計算值：C， 6 7.2 7; H， 5.96; N，21.79。實驗值：C，67.20; H，5.71; N， 2 2.0 5。實例6 5 6-(二環[2· 2· 1]庚-2 -基）-1，3，5 -三嗦-2，4 -二胺Example 64B 6- [1,1, -Bibenzyl] -4-yl-N-fluorenyl-1,3,5-triazine-2,4-diamine stirred at room temperature in tetrahydrofuran (9 ml) Example 64A (0.09 g, 0.32 mmol) and N-methylamine (6 mmol) for 24 hours. Reduce the volume of the reaction and dilute with water. The precipitate was collected, washed with water and ether, and dehydrated to obtain the desired compound (0.062 g, 70%). Melting point 2 3 7-2 3 8 t :; MS (DCI / NII3) m / e 278 (M + H) +; 41 NMR (3 0 0 MHz, DMSO-d6) 5 8 · 39 (d, 1H) , 8.32 (d, 1H), 7.77 (m, 4H), 7.51 (t, 2H), 7.41 (m, 1H), 7.25 (q, 1H), 6.79 (bds, 2H), 2.79 (d, 3H ); Analytical calculated values for C16H15N5. 0.5C4H802: C, 6 7.2 7; H, 5.96; N, 21.79. Experimental values: C, 67.20; H, 5.71; N, 2 2.0 5. Example 6 5 6- (Bicyclo [2 · 2 · 1] heptan-2-yl) -1,3,5-trifluorene-2,4-diamine

實例6 5 A 6-(二環[2. 2. Π 庚-2 -烯-5 -基）-1，3, 5 -三嗪-2, 4 -二胺Example 6 5 A 6- (bicyclo [2. 2. Πheptan-2-en-5 -yl) -1,3,5-triazine-2,4-diamine

第73頁 486472 五、發明說明（69) 按照實例1來處理二環[2. 2. 1 ]庚-2 -烯-5 -腈，得到想要的化合物。 MS (DCI/NH3) m/e 2 04 (M + H) +Page 73 486472 V. Description of the invention (69) The bicyclic [2. 2. 1] heptan-2-ene-5 -nitrile was treated according to Example 1 to obtain the desired compound. MS (DCI / NH3) m / e 2 04 (M + H) +

實例6 5 B 1-（二環[2· 2· 1 ]庚-2 -基）-1，3, 5 -三嗪-2, 4-二胺利用氫氣和鈀碳將在曱醇中之實例6 5 Α的溶液還原，過濾並蒸發之，得到想要的化合物。熔點 2 1 6 - 2 1 7 °C ; MS (DCI/NH3) m/e 2 0 6 (M + H)+ ； 4 NMR (300 兆赫茲，DMS0-d6)(56.52 (bds， 4H)， 2.83 ‘ (m, 1H), 2.39 (m, 1H), 2.21 (m, 2H), 2.04 (m, 1H), 1.91 (m, 1H), 1.6-1.2 (m, 5H), 6.52 (m, 1H); 關於C1QH15N5 之分析計算值：C; 58.52，H; 7.37，N; 34.12。實驗值：C; 58·59，H; 7.40，N; 34.00。實例6 6 6-[1，1，一聯苯基]—4 —基一N，N，一二乙基一1，3，5 —三嗪一2，4 —二狴將在脫水、脫氣之二曱基乙醯胺（45毫升）中之2, 4 -二 -N-乙胺基-6 —氯—1，3，5 -三嗪（〇·55克’2.7毫莫耳）和四價 (三苯膦）把（〇 · 1 9克’ 〇 · 1 6毫莫耳）的混合物加熱至1 0 0 ，連續以在無水乙醇（15毫升）中之4-(苯基）苯基硼酸 (Yabroff 等人，Journal 0 f the American Chemical Society ’ 第56 冊，1934，第 1850-1856 頁）（〇·8〇克 ’4.0 毫莫耳）和飽1和的含水碳酸氫納（3 〇毫升）處理’並將°亥反Example 6 Example of 5 B 1- (bicyclo [2 · 2 · 1] heptan-2-yl) -1,3,5-triazine-2,4-diamine using hydrogen and palladium carbon in methanol The 6 A solution was reduced, filtered and evaporated to give the desired compound. Melting point 2 1 6-2 1 7 ° C; MS (DCI / NH3) m / e 2 0 6 (M + H) +; 4 NMR (300 MHz, DMS0-d6) (56.52 (bds, 4H), 2.83 '(m, 1H), 2.39 (m, 1H), 2.21 (m, 2H), 2.04 (m, 1H), 1.91 (m, 1H), 1.6-1.2 (m, 5H), 6.52 (m, 1H) Analytical calculated value for C1QH15N5: C; 58.52, H; 7.37, N; 34.12. Experimental value: C; 58 · 59, H; 7.40, N; 34.00. Example 6 6 6- [1, 1, Biphenyl Methyl] -4 -yl-N, N, diethyl-1,3,5-triazine-2,4-dihydrazone will be in the dehydrated and degassed dimethylacetamide (45 ml) 2,4-di-N-ethylamino-6-chloro-1,3,5-triazine (0.55 g '2.7 mmol) and tetravalent (triphenylphosphine) (0.19 g '〇 · 16 mil) mixture was heated to 100, continuously with 4- (phenyl) phenylboronic acid (Yabroff et al., Journal 0 f the American Chemical Society) in absolute ethanol (15 ml) Volume 56, 1934, pages 1850-1856) (0.80 g '4.0 mmol) and saturated aqueous sodium bicarbonate (30 ml) and treat

486472 五、發明說明（70) 應混合物維持在1 0 0 °C下3天。將該反應混合物冷卻至室溫，並以醋酸乙酯稀釋。以鹽水沖洗有機層，脫水· (MgS04)，濃縮並以真空脫水。使殘餘物從2 : 1之二氧六環 /乙醇中再結晶，得到0 . 1 5克（1 7% )白色固體狀的想要化合物。熔點 1 8 3 - 1 8 4 °C ; MS (DCI/NH3) m/e 3 2 0 (M + H)+ ； W NMR ( 3 0 0 兆赫茲，DMS〇 —d6) 5 8· 36 (m， 2H)， 7· 78 (d， 2H)，7· 73 (d，2H)，7· 49 (m，2H)，7· 38 (m，1H)， ^ 7.28 (m， 2H)， 3.40 (m， 4H)， 1.16 (m， 6H); 關於C19H2iN5 . 0· 2C4H8 02 之分析計算值：C，70.91; H， 6 · 5 5 ; N，8 · 2 8。實驗值：C，7 1 · 2 1 ; H，6 · 5 0 ; N， 21.13。實例6 7 6-(2,-硝基[1，1’ -聯苯基]-4 -基）-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理4-氰基-2’ -硝聯苯基，得到想要的化合物。熔點 > 2 5 0 °C ; 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 6 8. 3 (d， 2H， J二9 Hz)， 8.05 (dd, 1H), 7.8 (m, III), 7.6-7.7 (m, 2H), 7.45 (d，2H)，6· 8 (br s，4H); MS (DCI/NH3) m/e 3 0 9 (M + II)1; 關於C15Hi2N6 02 之分析計算值：C， 5 8.44; H， 3.92; N， 2 7 · 2 6。實驗值：C，5 8 . 4 6 ; H，3 · 9 9 ; N，2 7 · 1 5。486472 V. Description of the invention (70) The mixture should be maintained at 100 ° C for 3 days. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with brine, dehydrated (MgS04), concentrated and dehydrated in vacuo. The residue was recrystallized from 2: 1 dioxane / ethanol to obtain 0.15 g (17%) of the desired compound as a white solid. Melting point 1 8 3-1 8 4 ° C; MS (DCI / NH3) m / e 3 2 0 (M + H) +; W NMR (300 MHz, DMS〇-d6) 5 8 · 36 (m , 2H), 7.78 (d, 2H), 7.73 (d, 2H), 7.49 (m, 2H), 7.38 (m, 1H), ^ 7.28 (m, 2H), 3.40 ( m, 4H), 1.16 (m, 6H); Analytical calculated values for C19H2iN5. 0 · 2C4H8 02: C, 70.91; H, 6 · 5 5; N, 8 · 2 8. Experimental values: C, 7 1 · 2 1; H, 6 · 5 0; N, 21.13. Example 6 7 6- (2, -Nitro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine 4-cyanocyanate was treated as in Example 1. -2'-nitrobiphenyl to give the desired compound. Melting point> 2 50 ° C; 41 NMR (300 MHz, DMS 0-d6) 6 8. 3 (d, 2H, J 2 9 Hz), 8.05 (dd, 1H), 7.8 (m, III ), 7.6-7.7 (m, 2H), 7.45 (d, 2H), 6.8 (br s, 4H); MS (DCI / NH3) m / e 3 0 9 (M + II) 1; About C15Hi2N6 02 Analytical calculated values: C, 5 8.44; H, 3.92; N, 2 7 · 2 6. Experimental values: C, 5 8. 4 6; H, 3 · 9 9; N, 2 7 · 15.

第75頁 486472 五、發明說明（71) 實例6 8 6-(6-曱基-3- D比咬基）-1，3, 5 —三嗪—2, 4 -二胺按照實例1來處理6 -曱基菸鹼醯腈，得到想要的化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 2 0 3 (M + H)+ ； 4 NMR ( 3 0 0 兆赫茲，DMS〇-d6) 5 9· 23 (d， 1H)， 8. 39 (dd，1H，J二 11)，7.38 (d，1H)，6·81 (br s，4H)， 2 · 5 6 ( s，3 H ); 關於C9H1QN6 之分析計算值：C， 53.45; H，4,98; N， 4 1 · 5 5。實驗值：C，5 3 · 4 6 ; H，4 · 9 4 ; N，4 1 · 8 4。實例6 9 6 — (6 —氣—3 — D 比口定基）—1，3，5 —三曉—2，4 —二胺按照實例2 C來處理6 -氯菸鹼酸曱酯和亞胺二碳亞胺基二醯胺（2 B )，得到想要的化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 2 2 3, 2 2 5 (M + H)+ ； NMR ( 3 0 0 兆赫茲，DMS〇-d6) (5 9· 17 (d， 1H)， 8· 46 (dd，1H，J 二 11)，7.62 (d，1H)，6.91 (br s，4H); 關於C8H7C1N6 之分析計算值：C， 43·ί5; H， 3.16; N， 3 7.74。實驗值：C，43·05; H，3.08; N，3 7.5 0。實例7 0 6 - ( 5 - :;臭-3 - 口比口定基）-1，3，5 -三嗦-2，4 -二胺按照實例1來處理5 -溴菸鹼醯腈，得到想要的化合物。Page 75 486472 V. Description of the invention (71) Example 6 8 6- (6-fluorenyl-3-D specific bite group) -1,3,5-triazine-2, 4-diamine was treated as in Example 1. 6-fluorenyl nicotine cyanonitrile to give the desired compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 2 0 3 (M + H) +; 4 NMR (3 0 0 MHz, DMS 0-d6) 5 9 · 23 (d, 1H ), 8. 39 (dd, 1H, J 2: 11), 7.38 (d, 1H), 6.81 (br s, 4H), 2 · 5 6 (s, 3 H); Analytical calculated values for C9H1QN6: C, 53.45; H, 4,98; N, 4 1 · 5 5. Experimental values: C, 5 3 · 4 6; H, 4 · 9 4; N, 4 1 · 8 4. Example 6 9 6 — (6 —Gas — 3 — D Biphenyl) —1,3,5 —Tris —2,4 —Diamine Treatment of 6-chloronicotinate and imine according to Example 2 C Dicarbodiimide (2B) to give the desired compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 2 2 3, 2 2 5 (M + H) +; NMR (300 MHz, DMS〇-d6) (5 9 · 17 (d, 1H), 8.46 (dd, 1H, J 2:11), 7.62 (d, 1H), 6.91 (br s, 4H); Analytical calculated values for C8H7C1N6: C, 43 · ί5; H, 3.16 N, 3 7.74. Experimental values: C, 43.05; H, 3.08; N, 3 7.5 0. Example 7 0 6-(5-:; Odor-3-Mouth fixed base)-1, 3, 5 -Trisamidine-2,4-diamine The 5-bromonicotinic cyanide was treated according to Example 1 to obtain the desired compound.

第76頁 486472 m 案號 87120449 c 年匕月il 修正五、發明說明（72) 熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 267 (M+H)+ ； 1H NMR (300 兆赫兹，DMS0-d6)59.3 (d, 1H), 8.82 (d， 1H, J = 3 赫茲），8· 6 2 - 8. 6 4 (m， 1H)， 6. 8 - 7· 1 (br s, 1H); 關於 C8H7BrN6 之分析計算值：C， 3 5.9 8; H， 2.64; N， 31.47 。實驗值：C， 35.89; H， 2.53; N， 31.22 。實例7 1 6 -（2，3 - 二氫 -2，2，3，3 - 四氣 -1，4- 苯并二曙啡 -6-基）-1，3, 5-三嗦- 2，4-二胺按照實例1來處理6 -氰基-2 ,3 -二氫-2，2，3，3 -四氣-1,4-苯并二噚烷，得到想要的化合物。熔點 1 7 6 - 1 7 9 °C ; MS (DCI/NH3) m/e 2 75 (M + H)+ ； !H NMR (300 兆赫兹，DMSO—d6) 57. 98 (d, 1H), 7.71 (d 1H), 7.17 (dd, 1H), 7.16 (br s, 2H), 6.95 (br s, 2H), 3.85 (s, 3H); 關於CnlFJsOz 之分析計算值：C ; 41 · 65， H ; 2.22, N; 2 2 · 0 8。實驗值：C ; 4 1 · 5 5，H ; 2 · 1 0， N ; 2 2 · 0 9。實例7 2 胺 6 - [4-f(4—氯苯基）曱氧基]苯基1一 1，3，5 -三嗪一 2, 4- 得到想按照實例1來處理4-[ (4 -氯苯基）曱氧基]腈要的化合物。熔點 2 4 6 - 2 4 8 °C ;Page 76 486472 m Case No. 87120449 Year c il il Rev. V. Description of the invention (72) Melting point > 2 60 ° C; MS (DCI / NH3) m / e 267 (M + H) +; 1H NMR ( 300 MHz, DMS0-d6) 59.3 (d, 1H), 8.82 (d, 1H, J = 3 Hz), 8. 6 2-8. 6 4 (m, 1H), 6. 8-7 · 1 ( br s, 1H); Analytical calculated values for C8H7BrN6: C, 3 5.9 8; H, 2.64; N, 31.47. Experimental values: C, 35.89; H, 2.53; N, 31.22. Example 7 1 6-(2,3-dihydro-2,2,3,3-tetrakis-1,4-benzodinoquinone-6-yl) -1,3,5-trifluorene-2, 4-Diamine was treated according to Example 1 to 6-cyano-2,3-dihydro-2,2,3,3-tetragas-1,4-benzodioxane to give the desired compound. Melting point 1 7 6-179 ° C; MS (DCI / NH3) m / e 2 75 (M + H) +;! H NMR (300 MHz, DMSO—d6) 57. 98 (d, 1H), 7.71 (d 1H), 7.17 (dd, 1H), 7.16 (br s, 2H), 6.95 (br s, 2H), 3.85 (s, 3H); Analytical calculated values for CnlFJsOz: C; 41 · 65, H 2.22, N; 2 2 · 0 8. Experimental values: C; 4 1 · 5 5, H; 2 · 1 0, N; 2 2 · 0 9. Example 7 2 Amine 6-[4-f (4-chlorophenyl) fluorenyloxy] phenyl 1 -1,3,5-triazine-2, 4- 4- I want to treat 4- [(4 -Chlorophenyl) fluorenyl] nitrile. Melting point 2 4 6-2 4 8 ° C;

O:\56\56069.ptc 第77頁 2001.06.21.077 486472 五、發明說明（73) MS (DCI/NH3) m/e 342 (M + H)+ ； !H NMR ( 3 0 0 兆赫兹，DMS〇一d6) 6 7. 45 (s, 4H)， 7.25 (d， 2H)，6.9 (d，2H)，6.6 (br s，4H)，5.05 (s，2H)， 3.55 (s, 2H); 關於 C17H16C1N50 之分析計算值：C， 5 9.74; H，4·72; N， 2 0.49。實驗值：C，5 9.64; H，4· 64; N，20·49。實例7 3 6-[4-( 1-六氫吡啶磺醯基）苯基]-1，3, 5 -三嗪-2, 4 -二胺實例7 3 A 暮 1 - [ ( 4 -氰苯基）績酿基]六氫吼σ定在周圍溫度下攪拌在10毫升二氣曱烷中之4 -氰基苯磺醯氣（0 . 5 1克，2. 5毫莫耳）和六氫吡啶（0 . 6 0毫升，5 1 7毫克，6. 04毫莫耳）的混合物過夜。連續以水、5% HC1和鹽水沖洗有機層，脫水（Na2 S04)並濃縮之。可直接使用所得的白色固體（0.61克，96%)不需進一步純化。O: \ 56 \ 56069.ptc Page 77 2001.06.21.077 486472 V. Description of the invention (73) MS (DCI / NH3) m / e 342 (M + H) +;! H NMR (3 0 0 MHz, DMS 〇 a d6) 6 7. 45 (s, 4H), 7.25 (d, 2H), 6.9 (d, 2H), 6.6 (br s, 4H), 5.05 (s, 2H), 3.55 (s, 2H); Analysis and calculation of C17H16C1N50: C, 5 9.74; H, 4.72; N, 2 0.49. Experimental values: C, 5 9.64; H, 4.64; N, 20 · 49. Example 7 3 6- [4- (1-Hexahydropyridylsulfonyl) phenyl] -1,3,5-triazine-2, 4-diamine Example 7 3 A 2-[(4-cyanobenzene (Base) Jijiji] Hexahydrozine σ is fixed at ambient temperature, and 4-cyanobenzenesulfonium (0.51 g, 2.5 mmol) in hexamethylene dioxane is stirred at ambient temperature and hexahydrogen A mixture of pyridine (0.60 ml, 5 17 mg, 6.04 mmol) was overnight. The organic layer was washed successively with water, 5% HC1 and saline, dehydrated (Na2 S04) and concentrated. The resulting white solid (0.61 g, 96%) was used directly without further purification.

實例7 3 B 6-[4-(1-六氫吡啶磺醯基）苯基]-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理實例7 3 A之產物，得到想要的化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 3 3 5 (M + H)f ； 41 NMR ( 3 0 0 兆赫兹，DMS〇一d6) (5 8. 43 (d， 2H)， 7.84 (d， 2H)，6.90 (bds，411)，2.9 0 - 2.9 7 (m，4H)，1.50-1.59 (m, 4H), 1.32- 1.42 (m, 2H); 關於C14Hi8NG02S 之分析計算值：C， 5 0. 2 8 ; H， 5.42; N,Example 7 3 B 6- [4- (1-hexahydropyridylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine The product of Example 7 3 A was treated according to Example 1, The desired compound is obtained. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 3 3 5 (M + H) f; 41 NMR (300 MHz, DMS〇-d6) (5 8. 43 (d, 2H), 7.84 (d, 2H), 6.90 (bds, 411), 2.90-2.9 7 (m, 4H), 1.50-1.59 (m, 4H), 1.32- 1.42 (m, 2H); Analysis of C14Hi8NG02S Calculated: C, 5 0. 2 8; H, 5.42; N,

第78頁 486472 五、發明說明（74) 2 5. 13。實驗值：C， 50· 43; H， 5. 32; N， 25· 12。實例74 6-(1-笨曱醯基-4-六氫吡啶基）-1，3,5-三嗪-2,4-二胺Page 78 486472 V. Description of Invention (74) 2 5. 13. Experimental values: C, 50 · 43; H, 5. 32; N, 25 · 12. Example 74 6- (1-Benzenyl-4-hexahydropyridyl) -1,3,5-triazine-2,4-diamine

實例74 A 1-苯曱醯基-4-六氫吡啶腈在乙醇/冰浴中冷卻在30毫升DMF中之1-苯曱醯基-4-六氫吡啶酮（2 · 0克，9 · 8毫莫耳）、曱苯磺醯基曱月卡（2 · 5克， 1 2 · 8毫莫耳）和乙醇（1 · 0毫升，1 7 · 1亳莫耳）的混合物，以維持該反應溫度< 1 0 °C的速率，加入第三-丁醇鉀。移開木浴，容許在室溫下攪拌該反應過夜。藉著過濾移出固體，以D Μ E沖洗，並蒸發渡液。將殘餘物溶解於E10 A c中，以水和鹽水沖洗，脫水（MgS04)，通過矽膠過濾並濃縮之，得到2 . 1 4克（6 6 % )微黃色的油。Example 74 A 1-Phenylfluorenyl-4-hexahydropyridinonitrile cooled in 30 ml DMF in ethanol / ice bath 1-phenylfluorenyl-4-hexahydropyridone (2.0 g, 9 g 8 millimoles), benzenesulfenylsulfonium card (2.5 grams, 12 · 8 millimoles) and ethanol (1.0 ml, 17 · 1 millimoles) to maintain the At a reaction temperature < 10 ° C, potassium tert-butoxide was added. The wooden bath was removed and the reaction was allowed to stir at room temperature overnight. The solid was removed by filtration, rinsed with D M E, and the eluate was evaporated. The residue was dissolved in E10 A c, rinsed with water and brine, dehydrated (MgS04), filtered through silica gel, and concentrated to give 2.14 g (66%) of a slightly yellow oil.

實例74B 6-(1-苯曱醯基-4 -六氫吡啶基）-1，3, 5 -三嗪-2, 4 -二胺按照實例1來處理實例74 A的產物，得到想要的化合物。熔點 2 4 6 - 2 4 8 °C ; MS (DCI/NH3) m/e 2 9 9 (M + H)* ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-dG) 5 7· 43- 7. 4 9 (m， 3H)， 7·33-7·39 (m， 2H)， 6.58 (bds， 4H)， 4.44-4.52 (bm， III), 3.5 5 - 3.6 7 (bm, 1H), 2.7 9 - 3.2 7 (bm, 2H), 1.5 3 - 1.9 4 (bm, 5II); 關於Ci5H18N60 之分析計算值：C， 6 0. 3 8 ; H， 6· 08 ; N， 2 8 . 1 6。驗值：C，6 0 · 0 9 ; H，6 . 0 2 ; N，2 8 · 2 9。Example 74B 6- (1-phenylfluorenyl-4 -hexahydropyridyl) -1,3,5-triazine-2,4-diamine The product of Example 74 A was treated as in Example 1 to give the desired Compound. Melting point 2 4 6-2 4 8 ° C; MS (DCI / NH3) m / e 2 9 9 (M + H) *; 41 NMR (3 0 0 MHz, DMS〇-dG) 5 7 · 43- 7 4 9 (m, 3H), 7.33-7 · 39 (m, 2H), 6.58 (bds, 4H), 4.44-4.52 (bm, III), 3.5 5-3.6 7 (bm, 1H), 2.7 9-3.2 7 (bm, 2H), 1.5 3-1.9 4 (bm, 5II); Analytical calculated values for Ci5H18N60: C, 6 0. 3 8; H, 6 · 08; N, 2 8. 1 6. Test value: C, 6 0 · 0 9; H, 6. 0 2; N, 2 8 · 2 9.

第79頁 486472 五、發明說明（75) 實例7 5 6 — [ 1 —(苯曱基）—4 -六氫D比咬基ί—1，3, 5 -三嗪-2, 4 -二胺按照實例74Α和74Β來處理Ν-苄基-4-六氫吡啶酮，得到想要的化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 28 5 (M + H)+ ； !Η NMR ( 3 0 0 兆赫茲，DMS〇-d6) d 7· 19-7.32 (m，5H)， 6.50 (bds，4Η)，3.44 (s，2Η)，2.7 8 -2.8 6 (m，2Η)， 2.16-2.28 (m, 1H), 1.90-1.99 (m, 2H), 1.63-1.76 t (m, 4 H ); 關於C15H20N6 · H2〇之分析計算值：C， 59· 58 ; H， 7· 33 ; N， 2 7 · 7 9。實驗值：C，6 0 · 0 6 ; H，7 · 1 9 ; N，2 7 · 9 4。實例7 6 N，N’ -二乙醯基-6-「4-(苯磺醯基）苯基]-1，3, 5 -三嗪-2,4-二月安按照實例33B來處理6-[4-(苯磺醯基）苯基]-1，3, 5 -三嗪 -2, 4-二胺（實例58)，得到想要的化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 412 (M + H)+ ； 41 NMR ( 3 0 0 兆赫茲，DMS〇-d6) d 8·52 (d，2H，J:8 赫茲）， 8· 18 (d， 2H， J = 8 赫茲），8· 01 (m， 2H)， 7· 73 (in，1H)，7· 68 (m，2H)，2. 37 (s，6H); 關於C19II17N5 04 之分析計算值：C，5 5.47; H，4.16; N， 17.02。實驗值：C，5 5.47; II，4.19; N，17.11。Page 79 486472 V. Description of the invention (75) Example 7 5 6 — [1 — (phenylfluorenyl) — 4 -hexahydro D than phenyl — 1, 3, 5 -triazine-2, 4 -diamine Treatment of N-benzyl-4-hexahydropyridone following Examples 74A and 74B gave the desired compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 28 5 (M + H) +;! Η NMR (300 MHz, DMS〇-d6) d 7.19-7.32 (m , 5H), 6.50 (bds, 4Η), 3.44 (s, 2Η), 2.78 -2.8 6 (m, 2Η), 2.16-2.28 (m, 1H), 1.90-1.99 (m, 2H), 1.63-1.76 t (m, 4 H); Analytical calculated values for C15H20N6 · H20: C, 59.58; H, 7.33; N, 2 7 · 79. Experimental values: C, 6 0 · 0 6; H, 7 · 1 9; N, 2 7 · 9 4. Example 7 6 N, N'-diethylfluorenyl-6- "4- (benzenesulfonyl) phenyl] -1,3,5-triazine-2,4-diazulon was treated as in Example 33B. 6 -[4- (benzenesulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (Example 58) to obtain the desired compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 412 (M + H) +; 41 NMR (300 MHz, DMS0-d6) d 8.52 (d, 2H, J: 8 Hz), 8.18 (d , 2H, J = 8 Hz), 8.01 (m, 2H), 7.73 (in, 1H), 7.68 (m, 2H), 2. 37 (s, 6H); Analysis on C19II17N5 04 Calculated: C, 5 5.47; H, 4.16; N, 17.02. Experimental: C, 5 5.47; II, 4.19; N, 17.11.

第80頁 486472 _案號87120449_年月曰修正_ 五、發明說明（78) 實例7 7 Ν，『-乙驢基-6 - [4 -（苯石黃龜基）苯基]-1，3，5 -三嗓-2，4-二胺按照實例34來處理6-[4-(苯磺醯基）苯基]-1，3, 5 -三嗪 -2，4-二胺（實例5 8 )，得到想要的化合物。熔點 > 2 6 0 °C ; MS (DCI/NH3) m/e 3 7 0 (M + H)+ ； 1H NMR ( 3 0 0 兆赫兹，CF3C〇2D) 58.51 (d， 2H), 8.27 (d, 2H) , 8. 06 (d, 2H), 7.78 (t, 1H), 7.68 (t, 2H), 2.56 (s, 3H); 關於 C17 H15 N5 03 · 0 · 5 H2 0 之分析計算值：C， 5 3.9 6; H, 4·26; N， 18.51。實驗值：C， 53·75; H， 3.91; N， 18.83 ^ 實例7 8 6-(2 -六氫吡啶-1-基苯基）-1，3, 5 -三嗪-2,4 -二胺按照實例1來處理2 - ( 1 -六氫吡啶基）腈，得到想要的化合物。熔點 > 2 5 0 °C ; MS (DCI/NH3) m/e 271 (M + H)+ ； lH NMR (300 兆赫兹，DMS0-d6)57.27 (d, 2H), 6.93 (d, 2H), 6.89 (m, 1H), 6.63 (bds, 4H), 3.88 (m, 4H), 1.47 (bdm, 6H); 關於 C14H18N6 之分析計算值：C ; 62· 20， H ; 6 . 7 1 , N ; 3 1 · 0 9。實驗值：C ; 6 1 · 8 8，H ; 6 · 3 6， N ; 3 1. 3 7。Page 80 486472 _Case No. 87120449_ Year and month Amendment _ V. Description of the invention (78) Example 7 7 Ν, "-ethonyl-6-[4-(benzoxanthoyl) phenyl] -1, 3,5-tris-2,4-diamine Treatment of 6- [4- (benzenesulfonyl) phenyl] -1,3,5-triazine-2,4-diamine according to Example 34 (Example 5 8) to obtain the desired compound. Melting point> 2 60 ° C; MS (DCI / NH3) m / e 3 7 0 (M + H) +; 1H NMR (300 MHz, CF3CO2D) 58.51 (d, 2H), 8.27 ( d, 2H), 8. 06 (d, 2H), 7.78 (t, 1H), 7.68 (t, 2H), 2.56 (s, 3H); Analytical calculations for C17 H15 N5 03 · 0 · 5 H2 0 : C, 5 3.9 6; H, 4.26; N, 18.51. Experimental values: C, 53.75; H, 3.91; N, 18.83 ^ Example 7 8 6- (2-Hexahydropyridin-1-ylphenyl) -1,3,5-triazine-2,4-di The amine was treated with 2- (1-hexahydropyridyl) nitrile as in Example 1 to give the desired compound. Melting point> 2 50 ° C; MS (DCI / NH3) m / e 271 (M + H) +; lH NMR (300 MHz, DMS0-d6) 57.27 (d, 2H), 6.93 (d, 2H) , 6.89 (m, 1H), 6.63 (bds, 4H), 3.88 (m, 4H), 1.47 (bdm, 6H); Analytical calculated value for C14H18N6: C; 62 · 20, H; 6. 7 1, N ; 3 1 · 0 9. Experimental values: C; 6 1 · 88, H; 6 · 36, N; 3 1. 37.

O:\56\56069.ptc 第81頁 2000. 08.14. 083O: \ 56 \ 56069.ptc Page 81 2000. 08.14. 083

Claims

48647乏年月 \Z*：ry. >C- j^· -- '‘.咖 —..先 / ._-、 .* 一y < lA 87Ώ0449 ΘΙ年彡月曰修正 'T^if M 1. 一種具有式I之化合物：48647 Years and months \ Z *: ry. &Gt; C- j ^ ·-''. Coffee-- .. first / ._-,. * Y < lA 87Ώ0449 M 1. A compound having formula I:

或其在藥學上可接受的鹽類，其中 Ri、R2、I和h分別選自包括氫和Ci-C6烧醯基； B係選自包括苯基、C4-C6-環烷基、氮雜環丁烷基、六氫吡啶基、噻唑基、呋喃基及噻吩基； Y係選自包括苯基、c3-c6_環烷基、六氫吡啶基、嗎啉基、吡咯基、噚唑基、噻吩基及吡啶基；其中B及Y所定義之基團係經由環内可取代之碳原子或氮原子連接；及其中Y所定義之基團可視需要經1 - 2個分別選自包括烧基、Ci-C6_烧氧基及^-烧基之基團所取代； L係選自包括共價鍵、-C( = 0)-、C「06伸烧基、-N HC(0)NH- 、-0-及S02 ；其中每一L所定義之基團顯示左端與B連接，而右端與 Y連接；所有上述之定義不包括下列之組合： B或Y之一為苯基或吡啶基時，另一者為苯基或吡啶基；Or a pharmaceutically acceptable salt thereof, wherein Ri, R2, I, and h are respectively selected from the group consisting of hydrogen and Ci-C6 alkyl; B is selected from the group consisting of phenyl, C4-C6-cycloalkyl, and aza Cyclobutyl, hexahydropyridyl, thiazolyl, furyl and thienyl; Y is selected from phenyl, c3-c6-cycloalkyl, hexahydropyridyl, morpholinyl, pyrrolyl, oxazolyl , Thienyl, and pyridyl; wherein the groups defined by B and Y are connected via a substitutable carbon or nitrogen atom in the ring; and the groups defined by Y are optionally selected from 1 to 2 groups including Group, Ci-C6-alkoxy group and ^ -alkynyl group; L is selected from the group consisting of covalent bonds, -C (= 0)-, C "06 alkynyl, -N HC (0) NH-, -0-, and S02; each of the groups defined by L shows that the left end is connected to B, and the right end is connected to Y; all the above definitions do not include the following combinations: one of B or Y is phenyl or pyridine Base, the other is phenyl or pyridyl;

O:\56\56069.ptc 第1頁 2002. 03. 07. 084 486472 _案號87120449 ^丨年3>月日修正__ 六、申請專利範圍 B為苯基；Y為環烷基；及L為-0-;及 h、R2、R3及1?4為氫；B為C3-C6-環烷基；Y為苯基；及L 為共價鍵。 2 .根據申請專利範圍第1項之化合物，其中該化合物係選自包括下列之群： 6-[1-（二苯曱基）-3-氮雜環丁烷基]-1，3,5-三嗪 -2，4-二胺， 6-(1-苯基-4 -六氫吡啶基）-1，3, 5-三嗉-2, 4 -二胺，反- 6 -（4-苯基環己基）-1，3，5 -三嗦-2，4 -二胺’ 6-[3-(111-吡咯-1-基）苯基]-1，3,5-三嗪-2,4-二胺，順/反-6-( 3_苯基環丁基）-1，3, 5 -三嗪-2, 4-二胺， 6 - [4 -（4-戊基環己基）苯基]-1，3, 5 -三嗪-2, 4 -二胺， N -環己基-Ν’-[4-（4,6 -二胺基-1，3, 5 -三嗪-2 -基）苯基]脲， 6 - [4-(5-噚唑基）苯基]-1，3, 5 -三嗪-2, 4 -二胺， 6-[ 1-( [1，1’ -二苯基]:4 -基）-4-六氫吡啶基]-1，3, 5-三嗪-2, 4 -二胺， 6-（1-苯基環己基）-1，3,5-三嗪-2,4-二胺， 6- [卜（4-曱氧苯基）-4-六氫吡啶基]-1，3, 5-三嗪 -2，4-二胺， 6 - [2 - [4-（三氟甲基）苯基]-4 -噻唑基]-1，3, 5-三嗪 -2，4-二胺， 6 - [1-(4-曱氧苯基）環己基]-1，3, 5 -三嗪-2 ,4 -二胺， 6-[4_(2-嘻吩基）苯基]-1，3，5-三嗦-2，4-二胺，O: \ 56 \ 56069.ptc Page 1 2002. 03. 07. 084 486472 _ Case No. 87120449 ^ 丨 year 3 > Month and Day Amendment _ 6. The scope of patent application B is phenyl; Y is cycloalkyl; L is -0-; and h, R2, R3, and 1-4 are hydrogen; B is C3-C6-cycloalkyl; Y is phenyl; and L is a covalent bond. 2. The compound according to item 1 of the scope of patent application, wherein the compound is selected from the group consisting of: 6- [1- (diphenylfluorenyl) -3-azetidinyl] -1,3,5 -Triazine-2,4-diamine, 6- (1-phenyl-4 -hexahydropyridyl) -1,3,5-triamidine-2,4-diamine, trans-6- (4- Phenylcyclohexyl) -1,3,5-trifluorene-2,4-diamine '6- [3- (111-pyrrole-1-yl) phenyl] -1,3,5-triazine-2 , 4-diamine, cis / trans-6- (3-phenylcyclobutyl) -1,3,5-triazine-2,4-diamine, 6- [4- (4-pentylcyclohexyl) ) Phenyl] -1,3,5-triazine-2,4-diamine, N-cyclohexyl-N '-[4- (4,6-diamino-1,3,5-triazine- 2-yl) phenyl] urea, 6- [4- (5-oxazolyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- [1- ([1, 1'-diphenyl]: 4-yl) -4-hexahydropyridyl] -1,3,5-triazine-2, 4-diamine, 6- (1-phenylcyclohexyl) -1, 3,5-triazine-2,4-diamine, 6-[[(4- (oxophenyl) -4-hexahydropyridyl]]-1,3,5-triazine-2,4-diamine , 6-[2-[4- (trifluoromethyl) phenyl] -4 -thiazolyl] -1,3,5-triazine-2,4-diamine, 6-[1- (4-fluorene Oxyphenyl) Cyclohexyl] -1,3,5-triazine-2,4-diamine, 6- [4- (2-Hiptenyl) phenyl] -1,3,5-trifluorene-2,4-diamine ,

O:\56\56069.ptc 第2頁 2002. 03. 07. 085 486472 案號 87120449 4丨年彡月曰修正六、申請專利範圍 6-[4-(4-嗎琳磺醯基）苯基]-1，3,5 -三嗪_2,4 -二胺， 6-(5 -苯基-2 -呋喃基）-1，3, 5 -三嗪-2, 4-二胺， 6-(5 -苯基-2 -噻吩基）-1，3, 5 -三嗪-2, 4 -二胺， N，Ν’ - [6-（4_苯基環己基）-1，3, 5 -三嗉-2, 4-二基]雙 [乙醯胺]， Ν-[4-胺基-6-（4-苯基環己基）-1，3,5 -三嗪-2 -基]乙醯胺， (+/-）-4-(4，6-二胺基-1,3, 5-三嗪-2-基α -苯基苯曱醇， 6 - [4-(1-六氫吡啶磺醯基）苯基]-1,3, 5 -三嗪-2, 4-二胺， 6—（1一苯曱醯基一 4 -六氫[I比唆基）一 1，3, 5 -三嗪-2, 4 一二胺， 6 - [；1 -（苯曱基）-4-六氫吡啶基]-1，3, 5 -三嗪-2, 4-二胺，及 6-(2 -六氫吡啶-1-基苯基）-1，3, 5 -三嗪-2, 4 -二胺。 3 . —種用於改善血管生成之疾病的醫藥組合物，包括具式I之有效治療量之化合物 1： R3sfcO: \ 56 \ 56069.ptc Page 2 2002. 03. 07. 085 486472 Case No. 87120449 4 彡 Year of the month and year 6 Amendment of patent application 6- [4- (4-morpholinsulfonyl) phenyl ] -1,3,5-triazine_2,4-diamine, 6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4-diamine, 6- (5-phenyl-2 -thienyl) -1,3,5-triazine-2,4-diamine, N, N '-[6- (4-phenylcyclohexyl) -1,3, 5 -Triamidine-2,4-diyl] bis [acetamido], N- [4-amino-6- (4-phenylcyclohexyl) -1,3,5-triazin-2-yl] Acetylamine, (+/-)-4- (4,6-diamino-1,3,5-triazin-2-yl α-phenylbenzyl alcohol, 6-[4- (1-hexa Hydropyridylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (1-phenylfluorenyl-4-hexahydro [I than fluorenyl) -1,3 , 5-triazine-2, 4-monodiamine, 6-[; 1- (phenylfluorenyl) -4-hexahydropyridyl] -1,3, 5-triazine-2, 4-diamine, and 6- (2-Hexahydropyridin-1-ylphenyl) -1,3,5-triazine-2,4-diamine. 3. A pharmaceutical composition for improving angiogenic diseases, including Effective therapeutic amount of compound I of formula I: R3sfc

FUFU

O:\56\56069.ptc 第3頁 2002. 03. 07. 086 486472 _案號87120449_4丨年士月 S 修正__ 六、申請專利範圍或其在藥學上可接受的鹽類，其中 Ri、R2、R3和1?4分別選自包括氫和C^-Ce烧酸基； B係選自包括苯基、C4-C6-環烷基、氮雜環丁烷基、六氫吡啶基、噻唑基、呋喃基及噻吩基； Y係選自包括苯基、C3_C6-環烷基、六氩吡啶基、嗎啉基、吡咯基、卩f唑基、噻吩基及吡啶基；其中B及Y所定義之基團係經由環内可取代之碳原子或氮原子連接；及其中Y所定義之基團可視需要經1 _ 2個分別選自包括 Ci-Cg-烧基、烧氧基及Ci-C3_鹵烧基之基團所取代， L係選自包括共價鍵、-C( = 0)-、（^-(^伸烧基、 -NHC(0)NH- 、-0- 及S02 ；其中每一 L所定義之基團顯示左端與B連接，而右端與 Y連接；所有上述之定義不包括下列之組合： B或Y之一為苯基或吡啶基時，另一者為苯基或吡啶基； B為苯基；Y為環烷基；及L為-0-;及 h、R2、R3及1?4為氫；B為(：3-(：6-環烷基；Y為苯基；及L 為共價鍵。 4.根據申請專利範圍第3項之醫藥組合物，其中該疾病係選自包括癌症、糖尿病之視網膜病和黃斑退化。 5 .根據申請專利範圍第3項之醫藥組合物，其中化合物係選自包括下列之群：O: \ 56 \ 56069.ptc Page 3 2002. 03. 07. 086 486472 _ Case No. 87120449_4 丨 years and months S amendment__ 6. The scope of the patent application or its pharmaceutically acceptable salts, where Ri, R2, R3 and 1-4 are respectively selected from the group consisting of hydrogen and C ^ -Ce alkyl group; B is selected from the group consisting of phenyl, C4-C6-cycloalkyl, azetidinyl, hexahydropyridyl, and thiazole Y, furanyl, and thienyl; Y is selected from the group consisting of phenyl, C3-C6-cycloalkyl, hexaarginyl, morpholinyl, pyrrolyl, pyrazolyl, thienyl, and pyridyl; The defined group is connected via a substitutable carbon or nitrogen atom in the ring; and the group defined by Y in it may be optionally selected from the group consisting of Ci-Cg-carbyl, alkoxy, and Ci- Substituted by a C3_halohalo group, L is selected from the group consisting of covalent bonds, -C (= 0)-, (^-(^ arsenyl, -NHC (0) NH-, -0-, and S02 Each of the groups defined by L shows that the left end is connected to B and the right end is connected to Y; all the above definitions do not include the following combinations: When one of B or Y is phenyl or pyridyl, the other is benzene Or pyridyl; B is benzene Y is cycloalkyl; and L is -0-; and h, R2, R3, and 1-4 are hydrogen; B is (: 3-(: 6-cycloalkyl; Y is phenyl; and L is Covalent bond. 4. The pharmaceutical composition according to item 3 of the patent application, wherein the disease is selected from the group consisting of cancer, diabetic retinopathy and macular degeneration. 5. The pharmaceutical composition according to item 3 of the patent application, wherein The compound is selected from the group consisting of:

O:\56\56069.ptc 第4頁 2002.03.07.087 486472 案號 87120449 θ ί年彡月曰修正六、申請專利範圍 6-[1 -（二苯曱基）- 3-氮雜環丁烧基]-1，3，5-三曉 -2, 4-二胺， 6-(1-苯基-4 -六氫吡啶基）-1，3, 5 -三嗪-2, 4 -二胺，反-6-(4_苯基環己基）-1，3,5 -三嗪_2, 4 -二胺， 6-[3-(111-吡咯-1-基）苯基]-1，3,5-三嗪-2,4-二胺，順/反-6-(3-苯基環丁基）-1，3, 5 -三嗪-2, 4-二胺， 6-[4-(4-戊基環己基）苯基]-1,3, 5_三嗪-2 ,4 -二胺， N -環己基-Ν’-[4-(4, 6 -二胺基-1，3, 5 -三嗪-2 -基）苯基]脲， 6-[4-(5 -噚唑基）苯基]-1，3, 5 -三嗪-2, 4_二胺， 6-[ 1_( [1，1’ -二苯基]-4-基）-4-六氫吡啶基]-1，3, 5- · 三嗪-2, 4-二胺， 6 -（1-苯基環己基）-1，3,5-三嗪-2,4-二胺， 6-[ 1-(4-曱氧苯基）-4 -六氫吡啶基]-1，3, 5-三嗪 -2, 4-二胺， 6-[2-[4-(三氟曱基）苯基]-4-噻唑基]-1，3,5_三嗪 - 2，4-二胺， 6-[1-(4-曱氧苯基）環己基]-1，3，5-三嘻-2 ,4 -二胺， 6 - [4-(2 -噻吩基）苯基]-1,3, 5 -三嗪-2, 4 -二胺， 6 - [4-(4-嗎啉磺醯基）苯基]-1，3, 5 -三嗪-2, 4_二胺， 6-（5-苯基-2 -呋喃基）-1，3, 5 -三嗪_2, 4 -二胺， 6-（5_苯基-2 -噻吩基）-1，3, 5 -三嗪-2,4 -二胺， N，N’ - [64-苯基環己基）- 1，3, 5 -三嗪-2, 4-二基]雙 [乙醯胺]，O: \ 56 \ 56069.ptc Page 4 2002.03.07.087 486472 Case No. 87120449 θ ί Years, months, and months Amendment VI. Application for Patent Range 6- [1-(Diphenylfluorenyl)-3-azacyclobutanyl ] -1,3,5-trixiao-2,4-diamine, 6- (1-phenyl-4 -hexahydropyridyl) -1,3,5-triazine-2, 4-diamine, Trans-6- (4-phenylcyclohexyl) -1,3,5-triazine_2,4-diamine, 6- [3- (111-pyrrole-1-yl) phenyl] -1,3 , 5-triazine-2,4-diamine, cis / trans-6- (3-phenylcyclobutyl) -1,3,5-triazine-2,4-diamine, 6- [4- (4-pentylcyclohexyl) phenyl] -1,3,5-triazine-2,4-diamine, N-cyclohexyl-N '-[4- (4,6-diamine-1, 3, 5-triazin-2-yl) phenyl] urea, 6- [4- (5-oxazolyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- [1 _ ([1,1'-Diphenyl] -4-yl) -4-hexahydropyridyl] -1,3,5- · triazine-2,4-diamine, 6-(1-benzene Cyclohexyl) -1,3,5-triazine-2,4-diamine, 6- [1- (4-fluorenyloxy) -4 -hexahydropyridyl] -1,3, 5-tri Azine-2, 4-diamine, 6- [2- [4- (trifluorofluorenyl) phenyl] -4-thiazolyl] -1,3,5-triazine-2,4-diamine, 6 -[1- (4-fluorenyloxyphenyl) ring Group] -1,3,5-trihex-2,4-diamine, 6- [4- (2-thienyl) phenyl] -1,3,5-triazine-2, 4-diamine, 6-[4- (4-morpholinesulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (5-phenyl-2 -furyl) -1, 3, 5-triazine_2,4-diamine, 6- (5-phenyl-2-thienyl) -1,3,5-triazine-2,4-diamine, N, N '-[ 64-phenylcyclohexyl) -1,3,5-triazine-2,4-diyl] bis [acetamidine],

O:\56\56069.ptc 第5頁 2002. 03. 07. 088 486472 案號 87120449 叫丨年多修正六、申請專利範圍 N-[4 -胺基-6-(4-苯基環己基）-1，3, 5 -三嗪-2-基]乙醯胺， (+/-）-4-(4, 6 -二胺基-1，3, 5-三嗪-2-基）- α-苯基苯曱醇， 6- [4-U -六氫吡啶磺醯基）苯基]-1,3, 5 -三嗪-2, 4-二胺， 6-（1-苯曱酸基-4一六氫口比。定基）一1，3,5-三_一2,4一二胺， 6-[1一（苯曱基）-4一六氫吼咬基]一1，3,5-三嗪一2,4-二胺，及 6-（2 -六氫吡啶-1-基苯基）-1，3, 5 -三嗪-2, 4_二胺。 6 .根據申請專利範圍第1項之化合物，其中Β為苯基。 7. 根據申請專利範圍第1項之化合物，其中Β為氮雜環丁烧基。 8. 根據申請專利範圍第1項之化合物，其中Β為六氫吡啶基。 9 ·根據申請專利範圍第1項之化合物，其中Β為C4環烷基。 1 0 .根據申請專利範圍第1項之化合物，其中B為C6環烷基。 1 1 .根據申請專利範圍第1項之化合物，其中B為呋喃基。 · 1 2.根據申請專利範圍第1項之化合物，其中B為噻吩基0O: \ 56 \ 56069.ptc Page 5 2002. 03. 07. 088 486472 Case No. 87120449 Called for more than six years 6. Application for patent scope N- [4-amino-6- (4-phenylcyclohexyl) -1,3,5-triazin-2-yl] acetamidine, (+/-)-4- (4,6-diamine-1,3,5-triazin-2-yl) -α -Phenylphenyl fluorenol, 6- [4-U-hexahydropyridinesulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (1-phenylhydrazone -4 Hexahydro ratio. Fixed base) -1,3,5-tri_-2,4-diamine, 6- [1 ((phenylamidino) -4 -hexahydrohydrocarbyl]-1,3 , 5-triazine-2,4-diamine, and 6- (2-hexahydropyridin-1-ylphenyl) -1,3,5-triazine-2,4-diamine. 6. The compound according to item 1 of the scope of patent application, wherein B is phenyl. 7. The compound according to item 1 of the scope of patent application, wherein B is azetidinyl. 8. The compound according to item 1 of the application, wherein B is hexahydropyridyl. 9-The compound according to item 1 of the scope of patent application, wherein B is a C4 cycloalkyl group. 10. The compound according to item 1 of the scope of patent application, wherein B is a C6 cycloalkyl group. 1 1. The compound according to item 1 of the scope of patent application, wherein B is furyl. · 1 2. The compound according to item 1 of the scope of patent application, wherein B is thienyl 0

O:\56\56069.ptc 第6頁 2002.03.07. 089 486472 案號 87120449 4丨年j月曰修正六、申請專利範圍 1 3 .根據申請專利範圍第1項之化合物，其中B為噻唑基。 1 4.根據申請專利範圍第1項之化合物，其中&，R2，R3 及1為氫，B為C6環烷基，Y為苯基及L為共價鍵。O: \ 56 \ 56069.ptc Page 6 2002.03.07. 089 486472 Case No. 87120449 4 / J. Amendment 6 、 Application for Patent Scope 1 3. According to the compound in the scope of application for Item 1 where B is thiazolyl . 1 4. The compound according to item 1 of the scope of patent application, wherein &, R2, R3 and 1 are hydrogen, B is C6 cycloalkyl, Y is phenyl and L is a covalent bond.

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