TWI535705B - 胺基二氫噻衍生物 - Google Patents

胺基二氫噻衍生物 Download PDF

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TWI535705B
TWI535705B TW101124677A TW101124677A TWI535705B TW I535705 B TWI535705 B TW I535705B TW 101124677 A TW101124677 A TW 101124677A TW 101124677 A TW101124677 A TW 101124677A TW I535705 B TWI535705 B TW I535705B
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TW201245159A (en
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小林尚武
上田和生
伊藤尚弘
鈴木慎司
阪口岳
加藤晃
行正顯
堀章洋
郡山雄二
原口英和
安井健
神田泰彥
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鹽野義製藥股份有限公司
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
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  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Description

胺基二氫噻 衍生物
本發明為有關具有類澱粉β產生抑制作用、作為類澱粉β蛋白質之產生、分泌及/或沈著而誘發之疾病之治療劑有用之化合物。
於阿滋海默症患者之腦內廣泛有由稱為類澱粉β蛋白質之約40個胺基酸而成之胜肽蓄積神經細胞外之不溶性之斑點(老人斑)。認為此老人斑使神經細胞死滅而致阿滋海默症發症，阿滋海默症治療劑有類澱粉β蛋白質之分解促進劑、類澱粉β疫苗等之研究。
分泌酶(seretase)為令稱類澱粉β前體蛋白質(APP)之蛋白質於細胞內切斷而生成類澱粉β蛋白質之酵素。職司類澱粉β蛋白質N末端之生成之酵素乃稱BACE1(beta-site APP-cleaving enzyme 1、β分泌酶)，抑制此酵素來抑制類澱粉β蛋白質生成，而認為可當作阿滋海默症治療劑。
於專利文獻1記載與本發明化合物構造類似之化合物，掲示具有NO合成酶抑制活性，對痴呆有效。
於專利文獻2~4、非專利文獻1及非專利文獻2雖記載與本發明構造類似之化合物，但各僅記載作為血壓上昇劑、啡樣鎮痛劑或鎮靜藥等、醫藥品中間體、鎮痛劑有用。
作為BACE-1抑制劑雖知專利文獻5~13等，但皆具有與本發明化合物不同骨架。
[專利文獻1]國際公開第96/014842號小冊[專利文獻2]美國專利第3235551號說明書[專利文獻3]美國專利3227713號說明書[專利文獻4]特開平9-067355號公報[專利文獻5]國際公開第01/187293號小冊[專利文獻6]國際公開第04/014843號小冊[專利文獻7]特開2004-149429號公報[專利文獻8]國際公開第02/96897號小冊[專利文獻9]國際公開第04/043916號小冊[專利文獻10]國際公開第2005/058311號小冊[專利文獻11]國際公開第2005/097767號小冊[專利文獻12]國際公開第2006/041404號小冊[專利文獻13] 國際公開第2006/041405號小冊
[非專利文獻1]Journal of Hetero cyclic Chemistry，14卷，717頁~723頁(1977年)[非專利文獻2]Journal of Organic Chemistry，33卷，8號，3126頁~3132頁(1968年)
提供具有類澱粉β產生抑制作用，尤其BACE1抑制作用，作為由類澱粉β蛋白質之產生、分泌或沈著而誘發之疾病之治療劑有用之化合物。
本發明提供：(a)以如下式(I)： (式中環A為可有取代基之碳環基或可有取代基之雜環基， ，Alk1為低伸烷基或低伸烯基，R0為氫、低烷基或醯基，X為S、O或NR1，R1為氫或低烷基，R2a及R2b各自獨立為氫、羥基、可有取代基之低烷基、可有取代基之低烯基、可有取代基之胺基、可有取代基之甲脒基、可有取代基之醯基、可有取代基之胺甲醯基、可有取代基之胺甲醯羰基、可有取代基之低烷磺醯基、可有取代基之芳磺醯基、可有取代基之碳環基或可有取代基之雜環基，R3a、R3b、R4a及R4b各自獨立為氫、鹵素、羥基、可有取代基之低烷基、可有取代基之低烯基、可有取代基之醯基、羧基、可有取代基之低烷氧羰基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之碳環基或可有取代基之雜環基，n及m各自獨立為0~3之整數，n+m為1~3，各R3a、各R3b、各R4a、各R4b可相異，R5為氫、可有取代基之低烷基、可有取代基之低烯基、可有取代基之低炔基、可有取代基之碳環基或可有取代基之雜環基， 為時，R5與環A共形成(R5a及R5b各自獨立為氫低烷基，s為1~4之整數，各R5a、各R5b可相異)。
但n+m為2，R5為氫，環A為無取代苯基之化合物除外)化合物或其製藥容許鹽或彼等之溶劑合物為有效成分之BACE1抑制劑，(a1)以如下式(I)： (式中環A為可有取代基之碳環基或可有取代基之雜環基 ，Alk1為低伸烷基，R0為氫、低烷基或醯基，X為S、O或NR1，R1為氫或低烷基， R2a及R2b各自獨立為氫、羥基、可有取代基之低烷基、可有取代基之低烯基、可有取代基之胺基、可有取代基之甲脒基、可有取代基之醯基、可有取代基之胺甲醯基、可有取代基之低烷磺醯基、可有取代基之芳磺醯基、可有取代基之碳環基或可有取代基之雜環基、R3a、R3b、R4a及R4b各自獨立為氫、鹵素、羥基、可有取代基之低烷基、可有取代基之低烯基、可有取代基之醯基、羧基、可有取代基之低烷氧羰基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之碳環基或可有取代基之雜環基，n及m各自獨立為0~3之整數，n+m為1~3，各R3a、各R3b、各R4a、各R4b可相異，R5為氫、可有取代基之低烷基、可有取代基之低烯基、可有取代基之低炔基、可有取代基之碳環基或可有取代基之雜環基， 為時，R5與環A共形成(R5a及R5b各自獨立為氫或低烷基，s為1~4之整數，各R5a、各R5b可相異)，但n+m為2，R5為氫，環A為無取代苯基之化合物除外)化合物或其製藥容許鹽或彼等之溶劑合物為有效成分之BACE1抑制劑。
(b)X為S之(a)記載之BACE1抑制劑，(c)n為2，m為0之(a)記載之BACE1抑制劑，(d)E為單鍵之(a)記載之BACE1抑制劑，(e)如下式(I)： (式中各符號與(a)同義，但以下之化合物除外：i)n+m為2，R5為氫，環A為無取代之苯基之化合物，ii)n為2，m為0，R2a為氫，R2b為氫或乙醯基，R5為甲基，環A為苯基或4-甲氧苯基之化合物，iii)n為2，m為0，R2a為氫，R2b為氫或乙醯基，R5為乙基，環A為3,4-二甲氧苯基之化合物，iv)n為2，m為0，R2a為氫，R2b為氫或乙醯基，R5及環A為苯基之化合物，v)n為2，m為0，R2a及R2b為氫，R5及環A一起形成 (式中Me為甲基，各與前述同義)之化合物，vi)n+m為2，R5為氫，環A為由羥基、鹵素、低烷基、低 烷氧基、硝基、胺基、低烷羰胺基、氫硫基、低烷硫基及胺甲醯基選擇之只1~2個取代基取代之苯基、無取代苯基或無取代萘基之化合物)化合物或其製藥容許鹽或彼等之溶劑合物，(f)X為S之(e)記載之化合物或其製藥容許鹽或彼等之溶劑合物。
(g)n為2，m為0之(e)或(f)記載之化合物或其製藥容許鹽或彼等之溶劑合物，(h)R5為可有取代基之低烷基、可有取代基之低烯基、可有取代基之低炔基、可有取代基之碳環基或可有取代基之雜環基之(e)~(g)之任一之化合物或其製藥容許鹽或彼等之溶劑合物、(i)R2a為氫，R2b為氫、可有取代基之低烷基、可有取代基之醯基、可有取代基之低烷磺醯基、可有取代基之甲脒基之(e)~(h)之任一之化合物或其製藥容許鹽或彼等之溶劑合物、(j)NR2aR2b為 ， R6、R7及R8各自獨立為氫、低烷基或醯基，Y為可有取代基之低伸烷基、可有取代基之低伸烯基或可有取代基之低伸炔基，Z為O或S之(e)~(h)之任一之化合物或其製藥容許鹽或彼等之溶劑合物，(k)環A為有取代苯基之(e)~(j)之任一之化合物或其製藥容許鹽或彼等之溶劑合物，(l)環A為 (R9、R10及R11為氫或G、G為鹵素、羥基、氰基、硝基、氫硫基、可有取代基之低烷基、可有取代基之低烷氧基、可有取代基之低烯基、可有取代基之低炔基、可有取代基之醯基、可有取代基之醯氧基、羧基、可有取代基之低烷氧羰基、可有取代基之低烷氧羰氧基、可有取代基之芳氧羰氧基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之胺甲醯氧基、可有取代基之低烷硫基、可有取代基之芳硫基、可有取代基之低烷磺醯基、可有取代基之芳磺醯基、可有取代基之低烷亞磺醯基、可有取代基之芳亞磺醯基、可有取代基之低烷磺醯氧基、可有取代基之芳磺醯氧基、可有取代基之碳環基、可有取代基之碳環氧基、可有取代基之雜環基或可有取代基之雜環氧基、各G可相異)、(e)~(j)之任一之化合物或其製藥容許鹽或彼等之溶劑合物、 (m)G為 ，Q1、Q2及Q3各自獨立為單鍵、可有取代基之低伸烷基或可有取代基之低伸烯基，Q4為可有取代基之低伸烷基或可有取代基之低伸烯基，W1及W2各自獨立為O或S，W3為O、S或NR12，R12為氫、低烷基、羥低烷基、低烷氧低烷基、低烷氧羰低烷基、碳環低烷基或醯基，R14為氫或低烷基，環B為可有取代基之碳環基或可有取代基之雜環基，Alk2為可有取代基之低烷基， p為1或2，有複數之W1、複數之W3、複數之R12存在時，各可獨立相異，(xii)中氧原子對取代基R14可呈順或反之關係之(l)記載之化合物、或其製藥容許鹽或彼等之溶劑合物、(n)環B可有由鹵素、羥基、可有取代基之低烷基、可有取代基之低烷氧基、可有取代基之醯基、可有取代基之胺基、氰基、可有取代基之胺甲醯基、可有取代基之碳環基、可有取代基之碳環氧基或可有取代基之雜環基選擇之1以上基各取代之芳基或雜芳基之(m)記載之化合物、或其製藥容許鹽或彼等之溶劑合物，(o)G為 (式中各與前述同義)之(m)記載之化合物、或其製藥容許鹽或彼等之溶劑合物，(p)R5為C1~C3烷基之(e)~(o)之任一之化合物、或其製藥容許鹽或彼等之溶劑合物，(q)R5為甲基之(e)~(o)之任一之化合物、或其製藥容許鹽或彼等之溶劑合物， (r)R3a及R3b各自獨立為氫、鹵素、羥基、可有取代基之低烷基、可有取代基之低烷氧基或可有取代基之芳基之(e)~(q)之任一之化合物、或其製藥容許鹽或彼等之溶劑合物，(s)R3a及R3b皆氫之(e)~(q)之任一之化合物、或其製藥容許鹽或彼等之溶劑合物，(t)以(e)~(s)之任一之化合物、或其製藥容許鹽或彼等之溶劑合物為有效成分為特徵之醫藥組成物，(u)以(e)~(s)之任一之化合物、或其製藥容許鹽或彼等之溶劑合物為有效成分為特徵之BACE1抑制劑，(v)為類澱粉β產生抑制劑之(a)~(d)或(u)記載之BACE1抑制劑，(w)為由類澱粉β蛋白質之產生、分泌及/或沈著誘發之疾病之治療劑之(a)~(d)、(u)或(v)之任一之BACE1抑制劑，(x)為阿滋海默症治療劑之(a)~(d)、(u)或(v)記載之BACE1抑制劑。
又提供：(y)由類澱粉β蛋白質之產生、分泌或沈著誘發之疾病之治療方法，其特徵為投與上述(a)記載之式(I)化合物或其製藥容許鹽或彼等之溶劑合物，(z)上述(a)記載之式(I)化合物或其製藥容許鹽或彼等之溶劑合物之使用，用以製造由類澱粉β蛋白質之產生、分泌或沈著誘發之疾病之治療之醫藥，(aa)阿滋海默症之治療方法，其特徵為投與上述(a)記載 之式(I)化合物或其製藥容許鹽或彼等之溶劑合物，(ab)上述(a)記載之式(I)化合物或其製藥容許鹽或彼等之溶劑合物之使用，用以製造治療阿滋海默症之醫藥。
本發明之化合物作為由類澱粉β蛋白質之產生、分泌或沈著誘發之疾病(阿滋海默症等)之治療劑有用。
[實施發明之最佳形態]
本說明書中，「鹵素」包含氟、氯、溴及碘。
「鹵低烷基」、「鹵低烷氧基」、「鹵醯基」、「鹵低烷硫基」及「鹵低烷氧羰基」之鹵素部分與上述「鹵素」同樣。
「低烷基」包含碳數1~15，宜碳數1~10，尤宜碳數1~6，更宜碳數1~3之直鏈或分枝狀之烷基，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、新戊基、己基、異己基、正庚基、異庚基、正辛基、異辛基、正壬基及正癸基等。
「碳環低烷基」、「低烷氧基」、「鹵低烷基」、「鹵低烷氧基」、「鹵低烷硫基」、「羥低烷基」、「低烷氧羰基」、「鹵低烷氧羰基」、「低烷氧羰低烷基」、「低烷氧羰氧基」、「低烷胺基」、「低烷羰胺基」、「低烷氧羰胺基」、「低烷氧低烷基」、「低烷胺甲醯基」、「羥低烷胺甲醯基」、「胺低烷基」、「羥亞胺低烷基」、「低烷氧亞胺低烷基」、「低烷硫基」、 「低烷磺醯基」、「低烷胺磺醯基」、「低烷亞磺醯基」、「低烷磺醯氧基」、「低烷氧羰低炔基」、「低烷硫低烷基」、「芳低烷基」、「芳低烷胺基」、「芳低烷氧羰基」、「芳低烷胺甲醯基」、「雜環低烷胺基」及「雜環低烷胺甲醯基」之低烷基部分也與上述「低烷基」同樣。
環A之取代基之「可有取代基之低烷基」可有由取代基群α、羥亞胺基及低烷氧亞胺基而成之群選擇之1以上基取代之低烷基、上述(i)、(ii)、(iv)、(vi)、(viii)、(x)之基(各Q1為可有取代基之低伸烷基)、(iii)、(v)、(vii)、(ix)(各Q2為可有取代基之低伸烷基)、(xii)之基。
其以外之場合中「可有取代基之低烷基」為可有由取代基群α選擇之1以上基取代。
取代基群α乃由鹵素、羥基、低烷氧基、羥低烷氧基、低烷氧低烷氧基、醯基、醯氧基、羧基、低烷氧羰基、胺基、醯胺基、低烷胺基、低烷硫基、胺甲醯基、低烷胺甲醯基、羥低烷胺甲醯基、胺磺醯基、低烷胺磺醯基、低烷亞磺醯基、氰基、硝基、芳基及雜環基而成之群。
尤其Alk2中「可有取代基之低烷基」之取代基以鹵素、羥基、低烷氧基、低烷氧低烷氧基、低烷氧羰基、胺基、醯胺基、低烷胺基及/或低烷硫基等較佳。
環A之取代基之「可有取代基之低烷氧基」可有由上述取代基群α選擇之1以上基取代之低烷氧基、及上述 (iii)(Q1為可有取代基之低伸烷基、Q2為單鍵、W2為O)、(v)(Q1為可有取代基之低伸烷基、Q2為單鍵、W3為O)、(vi)(Q1為單鍵、Q2為可有取代基之低伸烷基、W2為O)或(xi)(Q4為可有取代基之低伸烷基、W2為O)之基。
其以外之場合中「可有取代基之低烷氧基」、「可有取代基之低烷氧羰基」、「可有取代基之低烷氧羰氧基」、「可有取代基之低烷磺醯基」、「可有取代基之低烷亞磺醯基」、「可有取代基之低烷磺醯氧基」及「可有取代基之低烷硫基」之取代基為由上述取代基群α選擇之1以上基。
「低烯基」包含在任意位置有1以上之雙鍵之碳數2~15，宜碳數2~10，尤宜碳數2~6，更宜碳數2~4之直鏈或分枝狀之烯基。具體而言，乙烯基、烯丙基、丙烯基、異丙烯基、丁烯基、異丁烯基、異戊二烯基、丁二烯基、戊烯基、異戊烯基、戊二烯基、己烯基、異己烯基、己二烯基、庚烯基、辛烯基、壬烯基、癸烯基、十一碳烯基、十二碳烯基、十三碳烯基、十四碳烯基、十五碳烯基等。
「低炔基」包含在任意位置有1以上之三鍵之碳數2~10，宜碳數2~8，更宜碳數3~6之直鏈或分枝狀之炔基。具體而言，可為乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基、癸炔基等。這些可更在任意位置有雙鍵。
「低烷氧羰低炔基」之低炔基部分與上述「低炔基」同樣。
環A之取代基之「可有取代基之低烯基」乃指可有由取代基群α選擇之1以上基取代之低烯基、上述(i)、(ii)、(iv)、(vi)、(viii)或(x)(Q1為可有取代基之低伸烯基)之基、(iii)、(v)、(vii)或(ix)(Q2為可有取代基之低伸烯基)之基。
此以外之場合中「可有取代基之低烯基」及「可有取代基之低炔基」之取代基乃指由上述取代基群α選擇之1以上基。
環A之取代基之「可有取代基之胺基」乃指可有由低烷基、醯基、羥基、低烷氧基、低烷氧羰基、碳環基及雜環基而成之群選擇之1以上基取代之胺基及上述(ii)(Q1為單鍵)、(iv)(Q1為單鍵)、(v)(Q2為單鍵、W3為NR12)、(ix)(Q2為單鍵)、(xiii)或(xiv)之基。
環A之取代基之「可有取代基之胺甲醯基」乃指可有由低烷基、醯基、羥基、低烷氧基、低烷氧羰基、碳環基及雜環基而成之群選擇之1以上基取代之胺甲醯基及上述(i)、(viii)(各Q1為單鍵)或(xv)之基。
此以外之場合中「可有取代基之胺基」、「可有取代基之甲脒基」、「可有取代基之胺甲醯基」、「可有取代基之胺甲醯羰基」、及「可有取代基之胺甲醯氧基」之取代基乃指可有由低烷基、醯基、羥基、低烷氧基、低烷氧羰基、碳環基及雜環基等選擇之1~2個基。
「醯基」包含碳數1~10之脂肪族醯基、碳環羰基及雜環羰基。具體而言、甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、特戊醯基、己醯基、丙烯醯基、 丙炔醯基、甲基丙烯醯基、巴豆醯基、苄醯基、環己烷羰基、吡啶羰基、呋喃羰基、噻吩羰基、苯并噻唑羰基、吡羰基、哌啶羰基、硫N-啉基等。
「鹵醯基」、「醯胺基」及「醯氧基」之醯基部分與上述同樣。
「可有取代基之醯基」及「可有取代基之醯氧基」之取代基乃指由取代基群α選擇之1以上基。碳環羰基及雜環羰基之環部分可有由低烷基、取代基群α、及可有由取代基群α選擇之1以上基取代低烷基選擇之1以上基取代。
「碳環基」包含環烷基、環烯基、芳基及非芳香族稠合碳環基等。
「環烷基」包含碳數3~10，宜碳數3~8，尤宜碳數4~8之碳環基，例如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基及環癸基等。
「環烯基」包含在上述環烷基之環中任意位置有1以上雙鍵者，具體而言，環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、環辛烯基及環己二烯基等。
「芳基」包含苯基、萘基、蒽基及菲基等，尤其苯基較佳。
「非芳香族稠合碳環基」包含由上述「環烷基」、「環烯基」及「芳基」選擇之2個以上環狀基稠合之基，具體而言，氫茚基、茚基、四氫萘基及茀基等。
「碳環氧基」、「碳環低烷基」及「碳環低烷基」之碳環部分與「碳環基」同樣。
「芳低烷基」、「芳氧基」、「芳氧羰基」、「芳氧羰氧基」、「芳低烷氧羰基」、「芳硫基」、「芳胺基」、「芳低烷胺基」、「芳磺醯基」、「芳磺醯氧基」、「芳亞磺醯基」、「芳胺磺醯基」、「芳胺甲醯基」及「芳低烷胺甲醯基」之芳基部分與上述「芳基」同樣。
「雜環基」包含環內有1以上由O、S及N任意選擇之雜原子之雜環基，具體而言，吡咯基、咪唑基、吡唑基、吡啶基、嗒基、嘧啶基、吡基、三唑基、三基、四唑基、異唑基、唑基、二唑基、異噻唑基、噻唑基、噻二唑基、呋喃基及噻吩基等5~6員之雜芳基；吲哚基、異吲哚基、吲唑基、吲基、吲哚啉基、異吲哚啉基、喹啉基、異喹啉基、啈啉基、呔基、喹唑啉基、萘啶基、喹喏啉基、嘌呤基、喋啶基、苯并吡喃基、苯并咪唑基、苯并三唑基、苯并異唑基、苯并唑基、苯并二唑基、苯并異噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、異苯并呋喃基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、吡唑并吡啶、三唑并吡啶基、咪唑并噻唑基、吡并嗒基、喹唑啉基、喹啉基、異喹啉基、萘啶基、二氫苯并呋喃基、四氫喹啉基、四氫異喹啉基、二氫苯并基、四氫苯并噻吩基等2環之稠合雜環基；咔唑基、吖啶基、基、啡噻基、啡噻基、啡基、二苯并呋喃基、咪唑并喹啉基等3環之稠合雜環基；二烷基、噻丙環基、丙環基、噻丙環基、吖丁啶基、噻己環基、噻唑啶基、吡咯啶基 、吡咯啉基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉基、哌啶基、哌基、啉基、N-啉基、硫啉基、硫N-啉基、二氫吡啶基、二氫苯并咪唑基、四氫吡啶基、四氫呋喃基、四氫吡喃基、四氫噻唑基、四氫異噻唑基、二氫基、六氫吖庚因基、四氫二吖庚因基等非芳香族雜環基。宜5~6員之雜芳基或非芳香族雜環基。
「雜環氧基」、「雜環硫基」、「雜環羰基」、「雜環胺基」、「雜環羰胺基」、「雜環胺磺醯基」、「雜環磺醯基」、「雜環胺甲醯基」、「雜環氧羰基」、「雜環低烷胺基」及「雜環低烷胺甲醯基」之雜環部分與上述「雜環基」同樣。
環A中「可有取代基之碳環基」及「可有取代基之雜環基」之取代基可為：取代基群α(宜鹵素、羥基、醯基、醯氧基、羧基、低烷氧羰基、胺甲醯基、胺基、低烷胺基、低烷硫基等)、可有由取代基群α選擇之1以上基取代之低烷基(此取代基宜鹵素、羥基、低烷氧基、低烷氧羰基等)、有由取代基群α選擇之1以上基取代之胺低烷基(此取代基為醯基、低烷基及/或低烷氧基等)、羥亞胺低烷基、低烷氧亞胺低烷基、可有由取代基群α選擇之1以上基取代之低烯基(取代低烷氧羰基、鹵素及/或鹵低烷氧羰基等)、可有由取代基群α選擇之1以上基取代之低炔基(取代基宜低烷氧羰基等)、 可有由取代基群α選擇之1以上基取代之一低烷氧基(取代基宜低烷胺甲醯基及/或羥低烷胺甲醯基等)、可有由取代基群α選擇之1以上基取代之低烷硫基、有由取代基群α選擇之1以上基取代之低烷胺基、可有由取代基群α選擇之1以上基取代之低烷磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳低烷氧羰基、有由取代基群α選擇之1以上基取代之醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之環烷基、可有由取代基群α選擇之1以上基取代之低烷亞磺醯基、胺磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳氧基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環氧基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳硫基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環硫基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以 上基取代之芳胺基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環胺基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳低烷胺基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環低烷胺基、可有由取代基群α選擇之1以上基取代之低烷胺磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳胺磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環胺磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環磺醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳胺甲醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環胺甲醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳低烷胺甲醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環低烷胺甲醯基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以 上基取代之芳氧羰基、可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環氧羰基、可有鹵素取代之低伸烷基二氧基、氧基、疊氮基、 (Q1、Q2及Q3各自獨立為單鍵、可有取代基之低伸烷基或可有取代基之低伸烯基，Q4為可有取代基之低伸烷基或可有取代基之低伸烯基，W1及W2各自獨立為O或S，W3為O、S或NR12，R12為氫、低烷基、羥低烷基、低烷氧低烷基、低烷氧羰低烷基、碳環低烷基或醯基， R14為氫或低烷基，環B為可有取代基之碳環基或可有取代基之雜環基，Alk2為可有取代基之低烷基)之基等，可有由這些選擇之1以上基取代。有複數之W1、複數之W3、複數之R12等存在時，各可獨立相異。
(xii)中氧原子可對取代基R14呈順或反之關係。
「有取代苯基」之取代基與上述同樣，宜有由取代基群α及(i)~(xv)之基選擇之1~2個基取代之苯基。
環B中「可有取代基之碳環基」或「可有取代基之雜環基」之取代基可為例如：取代基群α(宜鹵素、羥基、低烷氧基、羧基、低烷氧羰基、醯基、胺基、低烷胺基、醯胺基、胺甲醯基、低烷胺甲醯基、氰基、硝基等)由取代基群α選擇之1以上基取代之低烷基(此取代基宜鹵素、羥基、低烷氧基等)，有由取代基群α選擇之1以上基取代之胺低烷基、羥亞胺低烷基、低烷氧亞胺低烷基，可有由取代基群α選擇之1以上基取代之低烯基，可有由取代基群α選擇之1以上基取代之低炔基，可有由取代基群α選擇之1以上基取代之低烷氧基(取代基宜鹵素、羥基等)，可有由取代基群α選擇之1以上基取代之低烷硫基(取代基宜鹵素)，可有由取代基群α選擇之1以上基取代之低烷胺基(取代基宜胺基)， 可有由取代基群α選擇之1以上基取代之低烷磺醯基，可有由取代基群α及低烷基而成之群選擇之1以上基取代之芳低烷氧羰基，可有由取代基群α選擇之1以上基取代之醯基(取代基宜鹵素)，可有由取代基群α選擇之1以上基取代之低烷磺醯基、胺磺醯基，可有由取代基群α選擇之1以上基取代之低烷胺磺醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之環烷基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環基(取代基宜鹵素、低烷基等)，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳氧基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環氧基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳硫基(取代基宜鹵素、羥基、低烷氧基、醯基等)，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環硫基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以 上基取代之芳胺基(取代基宜鹵素、羥基、低烷氧基、醯基等)，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環胺基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳低烷胺基(取代基宜鹵素、羥基、低烷氧基、醯基等)，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環低烷胺基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳胺磺醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環胺磺醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳磺醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環磺醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳胺甲醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環胺甲醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳低烷胺甲醯基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環低烷胺甲醯基， 可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之芳氧羰基，可有由取代基群α、疊氮基及低烷基而成之群選擇之1以上基取代之雜環氧羰基，可有鹵素取代之低伸烷基二氧基、氧基等，可有由這些選擇之1以上基取代。
上述之場合以外中，「可有取代基之碳環基」、「可有取代基之雜環基」、「可有取代基之碳環氧基」、「可有取代基之芳磺醯基」、「可有取代基之芳氧羰氧基」、「可有取代基之雜環氧基」、「可有取代基之芳亞磺醯基」、「可有取代基之芳磺醯氧基」、「可有取代基之芳硫基」之取代基可為由低烷基及取代基群α而成之群選擇之1以上基。
「雜芳基」包含上述「雜環基」中芳香族環基。
「可有取代基之5~6員之雜芳基」之取代基與上述「環B」中「可有取代基之雜環基」之取代基同樣。宜由低烷基及取代基群α而成之群選擇之1以上基。
「低伸烷基」包含碳數1~10，宜碳數1~6，尤宜碳數1~3之直鏈狀或分枝狀之2價之碳鏈。具體而言，亞甲基、二亞甲基、三亞甲基、四亞甲基、甲基三亞甲基等。
「低伸烷基二氧基」之低伸烷基部分與上述「低伸烷基」同樣。
「低伸烯基」包含在任意位置有雙鍵之直鏈或分枝狀之碳數2~10，宜碳數2~6，尤宜碳數2~4之2價碳鏈。 具體而言，伸乙烯基、伸丙烯基、伸丁烯基、伸丁二烯基、甲基伸丙烯基、伸戊烯基及伸己烯基等。
「低伸炔基」包含在任意之位置有三鍵，更也可有雙鍵之直鏈或分枝狀之碳數2~10，尤宜碳數2~6，尤宜碳數2~4之2價碳鏈。具體而言，伸乙炔基、伸丙炔基、伸丁炔基、伸戊炔基及伸己炔基等。
「可有取代基之低伸烷基」、「可有取代基之低伸烯基」、「可有取代基之低伸炔基」之取代基可為取代基群α，宜鹵素、羥基等。
「各R3a、各R3b、各R4a、各R4b可相異」乃指n為2或3時，2或3個R3a各可相異，2或3個R3b各可相異。同樣m為2或3時，2或3個R4a各可相異，2或3個R4b各可相異。為時，R5與環A共形成形成時，包含如下場合。
(各與前述同義)
宜R5a、R5b皆氫之基。
本說明書中，「溶劑合物」包含例如與有機溶劑之溶劑合物、水合物等。形成水合物時，可與任意數之水分子配位。
化合物(I)包含製藥容許鹽，例如：與鹼金屬(鈉、鉀等)、鹼土金屬(鈣、鎂等)、銨、有機鹼及胺基酸之鹽、或與無機酸(鹽酸、硫酸、硝酸、氫溴酸、磷酸或氫碘酸等)、及有機酸(乙酸、三氟乙酸、檸檬酸、乳酸、酒石酸、草酸、馬來酸、富馬酸、苦杏仁酸、戊二酸、蘋果酸、苯甲酸、酞酸、苯磺酸鹽、對甲苯磺酸、甲磺酸或乙磺酸等)之鹽。尤其鹽酸、磷酸、酒石酸或甲磺酸等較佳。這些鹽可依通常施行之方法形成。
化合物(I)不限定於特定之異構物、包括所有可能之異構物(酮-烯醇異構物、亞胺-烯胺異構物、非對映異構物、光學異構物及回轉異構物等)和消旋體。例如R2a為氫之化合物(I)包含如下互變異構物。
本發明之化合物(I)可仿例如非專利文獻1之方法，或依下述方法製造。
胺基二氫噻環之合成 A法
(式中R2b及R2c之至少一方為氫，R3c及R3d各自獨立為氫、鹵素、羥基、可有取代基之低烷基、可有取代基之低烯基、可有取代基之醯基、羧基、可有取代基之低烷氧羰基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之碳環基或可有取代基之雜環基，其他各符號與前述同義)
第一工程
令市售或公知之方法調製之化合物a於乙醚、四氫呋喃等溶劑或乙醚-四氫呋喃等混合溶劑中，於-100℃~50℃，宜-80℃~0℃加乙烯基氯化鎂、乙烯基溴化鎂、丙烯基溴化鎂等具有與目的化合物對應之取代基之格任亞試藥而反應0.2小時~24小時，宜0.5小時~5小時，得化合物b。
第二工程
於化合物b有甲苯等溶劑之存在下或非存在下，在乙酸、三氟乙酸、氯化氫、硫酸等酸或彼等之混合物中， 加硫脲或N-甲硫基脲、N,N’-二甲硫基脲等具有與目的化合物對應之取代基之取代硫脲，在-20℃~100℃，宜0℃~50℃反應0.5小時~120小時，宜1小時~72小時，得化合物c。
第三工程
於化合物c有甲苯等溶劑之存在下或非存在下加三氟乙酸、甲磺酸、三氟甲磺酸等酸或彼等之混合物，於-20℃~100℃，宜0℃~50℃反應0.5~120小時，宜1小時~72小時，R2b為氫時得(I-2)，R2c為氫時得(I-1)。
胺基二氫噻環之合成 B法
(式中L為鹵素或磺醯氧基等脫離基，其他與前述同義)
第一工程
令依市售或公知之方法調製之化合物d於甲苯、氯仿、四氫呋喃等溶劑中、有水及鹽酸、硫酸等酸之存在下與硫氰酸鈉、硫氰酸銨等硫氰酸鹽於0℃~150℃，宜20℃~100℃反應0.5小時~24小時，宜1小時~12小時，得化合物e。
第二工程
令化合物e於四氫呋喃、甲醇、乙醇、水等溶劑中或乙醇水等混合溶劑中，有磷酸二氫鈉等緩衝劑之存在下或非存在下，加硼氫化鈉等還原劑，於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時，得化合物f。
第三工程
令化合物f在甲苯、二氯甲烷等溶劑之存在下或非存在下，與亞磺醯氯、氧氯化磷、四溴化碳-三苯膦等鹵化劑於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時，或化合物f於甲苯、二氯甲烷等溶劑中，有三乙胺等鹼之存在下與甲磺醯氯、對甲苯磺醯氯等磺醯化劑於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時，得化合物g。
第四工程
令化合物g於甲醇、乙醇、水等溶劑中或甲醇水等混合溶劑中與氨或甲胺等第一胺於-20℃~80℃，宜0℃~40℃反應0.5小時~48小時，宜1小時~24小時，得化合物(I-3)。
胺基二氫噻環之合成 C法
(式中R為氫或羧基之保護基，其他與前述同義)
第一工程
令依市售或公知之方法調製之化合物h與氫化鋰鋁、氫化二異丙基鋁等還原劑於四氫呋喃、乙醚等溶劑中，於-80℃~150℃，宜25℃~100℃反應0.1小時~24小時，宜0.5小時~12小時，得化合物i。
第二工程
令化合物i於甲苯、氯仿、四氫呋喃等溶劑中，有二異丙基乙胺、三乙胺、吡啶、氫氧化鈉等鹼之存在下或非存在下，與異氰酸4-甲氧苄酯、異氰酸第三丁酯等與目的化合物對應之異氰酸酯、或與N,N-二甲硫胺甲醯氯、N,N-二乙基硫胺甲醯氯等與目的化合物對應之硫胺甲醯鹵於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物j。
第三工程
令化合物j於乙腈、甲苯、二氯甲烷等溶劑中，與亞磺醯氯、氧氯化磷、四溴化碳-三苯膦等鹵化劑於-80℃ ~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時，或令化合物j於甲苯、二氯甲烷等溶劑中，有三乙胺等鹼之存在下與甲磺醯氯、對甲苯磺醯氯等磺醯化劑於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時。所得鹵化物、或磺醯基化合物與二異丙基乙胺、碳酸鉀、碳酸氫鈉、氫化鈉、氫氧化鈉等鹼於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物(I-4)。
胺基二氫噻環之合成 D法
胺基噻唑啉環之合成 A法
胺基四氫噻吖庚因環之合成 A法
(式中L為鹵素或磺醯氧基等脫離基，m為1~3之整數，其他與前述同義)
第一工程
令依市售或公知之方法調製之化合物k於二甲基甲磺醯胺、四氫呋喃等溶劑中，加疊氮化鈉等疊氮基化劑，於0℃~200℃，宜40℃~150℃反應0.5小時~24小時，宜1小時~12小時，得化合物l。
第二工程
令化合物l與氫化鋰鋁、氫化二異丁基鋁等還原劑於四氫呋喃、乙醚等溶劑中，於-80℃~150℃，宜25℃~100℃反應0.1小時~24小時，宜0.5小時~12小時，得化合物m。
第三工程
令化合物m於甲苯、氯仿、四氫呋喃等溶劑中，與甲基異氰酸甲酯、異氰酸乙酯等目的化合物對應之異氰酸甲酯或與N,N-二甲硫胺甲醯氯、N,N-二乙基硫胺甲醯氯等目的化合物對應之硫胺甲醯鹵於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物n。
第四工程
令化合物n於乙腈、甲苯、二氯甲烷等溶劑中，與亞磺醯氯、氧氯化磷、四溴化碳-三苯膦等鹵化劑於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時，或令化合物n於甲苯、二氯甲烷等溶劑中，有二異丙基乙胺、三乙胺等鹼之存在下，與甲磺醯氯、對甲苯磺醯氯等磺醯基化劑於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時。令所得鹵化物、或磺酸酯衍生物與碳酸鉀、碳酸氫鈉、氫化鈉、氫氧化鈉等鹼，於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物(I-5)。
胺基二氫噻環之合成 E法
胺基噻唑啉環之合成 B法
胺基四氫噻吖庚因環之合成 B法
(式中R2b及R2c之至少一方為氫，n為1~3之整數，其他各與前述同義)
第一工程
令依市售或公知之方法調製之化合物o，於乙醇、甲醇、四氫呋喃、甲苯等溶劑中，與硫脲或N-甲硫基脲、N,N-二甲硫基脲、N,N’-二甲硫基脲與等目的化合物對應之取代硫脲，於-20℃~200℃，宜0℃~150℃反應0.5小時~200小時，宜1小時~120小時，得化合物p。
第二工程
令化合物p於乙醚、四氫呋喃等溶劑中，或彼等之混合溶劑中，於-100℃~50℃，宜-80℃~30℃，加甲基氯 化鎂、乙基溴化鎂、苄基溴化鎂等與目的化合物對應之格任亞試藥反應0.2小時~24小時，宜0.5小時~5小時，得化合物q。
第三工程
令化合物q有甲苯等溶劑之存在下或非存在下，加三氟乙酸、甲磺酸、三氟甲磺酸等酸或彼等之混合物，於-20℃~100，宜0℃~50℃反應0.5小時~200小時，宜1小時~150小時，得化合物(I-6)(R2c=H)或(I-7)(R2b=H)。
胺基二氫噻環之合成 F法
(式中各與前述同義)
第一工程
令依公知之方法調製之化合物r於乙酸等溶劑中，與氯化銨於0℃~200℃，宜10℃~100℃反應0.1小時~100小時，宜0.5小時~24小時，得化合物s。
第二工程
令化合物s和氫化鋰鋁，氫化二異丁基鋁等還原劑於四氫呋喃、乙醚等溶劑中，於-80℃~150℃，宜0℃~100 ℃反應0.1小時~24小時，宜0.5小時~12小時，得化合物t。
第三工程
令化合物t於甲苯、氯仿、四氫呋喃等溶劑中，有二異丙基乙胺、三乙胺、吡啶、氫氧化鈉等鹼之存在下或非存在下，與異氰酸4-甲氧苄酯、異氰酸第三丁酯等目的化合物對應之異氰酸甲酯或與N,N-二甲硫胺甲醯氯、N,N-二乙基硫胺甲醯氯等與目的化合物對應之胺甲醯鹵在0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物u。
第四工程
令化合物u於乙腈、甲苯、二氯甲烷等溶劑中，與亞磺醯氯、氧氯化磷、四溴化碳-三苯膦等鹵化劑於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時，或令化合物u於甲苯、二氯甲烷等溶劑中，有三乙胺等鹼之存在下，與甲磺醯氯、對甲苯磺醯氯等磺醯基化劑，於-80℃~50℃，宜-20℃~20℃反應0.1小時~24小時，宜0.5小時~12小時。令所得鹵化物、或磺酸酯衍生物，與二異丙基乙胺、碳酸鉀、碳酸氫鈉、氫化鈉、氫氧化鈉等鹼，於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物(I-8)。
胺基二氫環之合成 A法
胺基四氫吖庚因環之合成 A法
(式中各與前述同義)
第一工程
令胺基二氫噻環之合成D法之第三工程(m至n)所得化合物n，於甲醇、乙醇、二甲基甲磺醯胺、四氫呋喃等溶劑中，有二異丙基乙胺、三乙胺、吡啶、氫氧化鈉等鹼之存在下或非存在下，與甲基碘、硫酸二乙酯、苄基溴等烷基化劑，於0℃~200℃，宜40℃~150℃反應0.1小時~48小時，宜0.5小時~24小時，得化合物v。
第二工程
令化合物v於二甲基甲磺醯胺、四氫呋喃、二氯甲烷等溶劑中、二異丙基乙胺、三乙胺、吡啶、氫氧化鈉等鹼之存在下或非存在下，與氧化銀、氧化汞、二氧化錳等金屬氧化物，於0℃~200℃，宜10℃~150℃反應1小時~120小時，宜0.5小時~100小時，得化合物(I-9)。
胺基二氫環之合成 B法
胺基唑啉環之合成
胺基四氫吖庚因環之合成 B法
(式中R15為可有取代基之低烷基(第三丁基、苄基等)，R16為氫或低烷基，n為1~3之整數，其他與前述同義)
第一工程
令依市售或公知之方法調製之化合物w於甲苯、第三丁醇、四氫呋喃等溶劑中，有二異丙基乙胺、三乙胺、吡啶等鹼之存在下，與二苯磷醯疊氮等疊氮基化劑，於0℃~200℃，宜40℃~150℃反應1小時~48小時，宜0.5小時~24小時，得化合物x。
第二工程
令化合物x於甲苯、二甲苯、二甲基甲磺醯胺、四氫呋喃等溶劑中，與第三丁醇、3,4-二甲氧苄醇、4-甲氧苄醇等醇，於0℃~300℃，宜50℃~200℃反應1小時~800小時，宜5小時~500小時，得化合物y。
第三工程
令化合物y於水、甲苯、二氯甲烷、甲醇、1,4-二烷 、乙酸、乙酸乙酯等溶劑之存在下或非存在下，有鹽酸、硫酸、氫溴酸、三氟乙酸等酸之存在下，於0℃~200℃，宜25℃~150℃反應0.1小時~48小時，宜0.5小時~24小時，得化合物z。
第四工程
令化合物z於甲苯、氯仿、四氫呋喃等溶劑中，有二異丙基乙胺、三乙胺、吡啶等鹼之存在下，與甲基異氰酸甲酯、異氰酸乙酯等與目的化合物對應之異氰酸甲酯或與N,N-二甲硫胺甲醯氯、N,N-二乙基硫胺甲醯氯等與目的化合物對應之硫胺甲醯鹵，於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物aa。
第五工程
令化合物aa於甲醇、乙醇、二甲基甲磺醯胺、四氫呋喃等溶劑中，有二異丙基乙胺、三乙胺、吡啶、氫氧化鈉等鹼之存在下或非存在下，與甲基碘、硫酸二乙酯、苄基溴等烷基化劑，於0℃~200℃，宜40℃~150℃反應1小時~48小時，宜0.5小時~24小時，得化合物ab。
第六工程
令化合物ab於二甲基甲磺醯胺、四氫呋喃、二氯甲烷等溶劑中，二異丙基乙胺、三乙胺、吡啶、氫氧化鈉等鹼之存在下，與氧化銀、氧化汞、二氧化錳等金屬氧化物，於0℃~200℃，宜10℃~150℃反應1小時~120小時，宜0.5小時~100小時，得化合物(I-10)。
胺基四氫嘧啶環之合成
(式中各與前述同義)
第一工程
令依公知之方法調製之化合物ac在二甲基甲磺醯胺、甲醇等溶劑中，加疊氮化鈉、疊氮化鋰等疊氮基化劑，於20℃~150℃，宜50℃~100℃反應0.5小時~120小時，宜1小時~72小時，得化合物ad。
第二工程
於氮大氣下，令氫化鋰鋁懸浮於四氫呋喃或乙醚等溶劑，於-80℃~20℃，宜-30℃~0℃加化合物ad溶解於四氫呋喃或乙醚等溶劑之溶液而反應1分~10小時，宜10 分~1小時，或令化合物ad於乙醇、異丙醇、正丁醇等溶劑中，於10℃~110℃，宜50℃~80℃加阮來鎳反應1分~10小時，宜10分~1小時，得化合物ae。
第三工程
令化合物ae於四氫呋喃、二氯甲烷等溶劑中，有乙酸、丙酸等酸之存在下，與氰化硼氫化鈉、三乙醯氧基硼氫化鈉等還原劑於-50℃~100℃，宜0℃~50℃反應0.1小時~48小時，宜0.5小時~24小時，或令化合物ae於四氫呋喃、二甲基甲磺醯胺等溶劑中，1-乙基-3-(3-二甲胺基丙基)碳化二亞胺-N-羥基苯并三唑、羰基二咪唑等脫水縮合劑之存在下，又三乙胺、碳酸鉀等鹼之存在下或非存在下，與甲酸、乙酸等羧酸於-50℃~100℃，宜0℃~50℃反應0.1小時~48小時，宜0.5小時~16小時，得醯胺衍生物。次於氮大氣下，令氫化鋰鋁懸浮於四氫呋喃或乙醚等溶劑，於-50℃~60℃，宜0℃~50℃加上述醯胺衍生物溶解於四氫呋喃或乙醚等溶劑之溶液來反應1分~48小時，宜10分~10小時，得化合物af。
第四工程
令化合物ae或af於乙腈、四氫呋喃、二甲基甲磺醯胺等溶劑中，與3,5-二甲基吡唑-1-羧脒或S-甲硫基脲等於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~24小時，得化合物ag。
第五工程
令化合物ag(R2b及R2c中至少一方為氫)於甲苯等溶劑之存在下或非存在下，加三氟乙酸、甲磺酸、三氟甲磺酸 等酸或彼等之混合物，於-20℃~100℃，宜0℃~50℃反應0.5~120小時宜1小時~72小時，R2b為氫時得(I-2)，R2c為氫時得(I-1)。但R2a、R2b、R2c為具有於第三丁基氧羰基等酸性条件下易分解之構造時，化合物(I-1)、(I-2)中之R2a、R2b、R2c有時可轉換為氫。
胺基噻唑啉環之合成 C法
(式中Hal為鹵素，其他各與前述同義)
第一工程
令依市售或公知之方法調製之化合物ah於甲苯、氯仿、四氫呋喃等溶劑中，或氯仿-水等混合溶劑中，有碘、溴、氯等鹵素與硫氰酸鈉、硫氰酸銨等硫氰酸鹽，必要時有四丁基溴化銨等相間移動觸媒之存在下，於0℃~150℃，宜20℃~100℃反應0.5小時~48小時，宜1小時~24小時，得化合物ai。
第二工程
令化合物ai於甲苯、氯仿、四氫呋喃等溶劑中，加氨或甲胺、二乙胺等具有與目的化合物對應之取代基之胺，於0℃~150℃，宜20℃~100℃反應0.5小時~48小時，宜1小時~24小時，得化合物(I-11)。
醯胺基衍生物-1
(式中R17為可有取代基之低烷基、可有取代基之碳化氫環或可有取代基之雜環基等，其他與前述同義)
令R2b為氫之化合物(I-12)於四氫呋喃、二氯甲烷等溶劑之存在下或非存在下，有吡啶、三乙胺等鹼之存在下或非存在下，與苄醯氯、2-呋喃醯氯、乙酐等具有與目的化合物對應之取代基之醯基化劑，於-80℃~100℃，宜-20℃~40℃反應0.1小時~24小時，宜1小時~12小時，或令化合物(I-12)於二甲基甲磺醯胺、四氫呋喃、二氯甲烷等溶劑中，有二環己基碳化二亞胺，羰基二咪唑等脫水縮合劑之存在下，與胺基酸、羥乙酸等具有與目的化合物對應之取代基之羧酸，於-80℃~100℃，宜-20℃~40℃反應0.1小時~24小時，宜1小時~12小時，得化合物(I-13)及/或(I-14)(R2a為氫之場合)。
胍基衍生物
(式中各與前述同義)
令R2b為氫之化合物(I-12)於乙腈、四氫呋喃、二甲基甲磺醯胺等溶劑中，有三乙胺、碳酸氫鈉等鹼之存在下或非存在下，與3,5-二甲基吡唑-1-羧脒或S-甲基異硫脲等，於0℃~150℃，宜20℃~100℃反應0.5小時~120小時，宜1小時~24小時，得化合物(I-15)。
胺甲醯基衍生物
(式中CONR18R19為可有取代基之胺甲醯基，其他與前述同義)
令作為環A之取代基具有羧基之化合物(I-16)，於二甲基甲磺醯胺、四氫呋喃、二氯甲烷等溶劑中，有二環己基碳化二亞胺、羰基二咪唑、二環己基碳化二亞胺-N-羥基苯并三唑等脫水縮合劑之存在下，與具有與目的化合物對應之取代基之第一胺或第二胺(苯胺、2-胺基吡啶、二甲胺等)，於-80℃~100℃，宜-20℃~40℃反應0.1小時~24小時，宜1小時~12小時，得化合物(I-17)。
醯胺基衍生物-2
(式中NHR20為可有取代基之胺基，NR20COR21為可有取代基之醯胺基、可有取代基之脲基、氧上有取代基之羧胺基，其他各與前述同義)
令具有於環A可有取代基之胺基之化合物(I-18)於四氫呋喃、二氯甲烷等溶劑之存在下或非存在下，於吡啶、三乙胺等鹼之存在下或非存在下，與具有與目的化合物對應之取代基之醯氯類、酸酐、氯碳酸酯類、異氰酸酯類等反應劑(苄醯氯、2-呋喃醯氯、乙酐、氯碳酸苄酯、二碳酸二第三丁酯、異氰酸苯酯等)，於-80℃~100℃，宜-20℃~40℃反應0.1小時~24小時，宜1小時~12小時，或令化合物(I-18)於二甲基甲磺醯胺、四氫呋喃、二氯甲烷等溶劑中、有二環己基碳化二亞胺、羰基二咪唑、二環己基碳化二亞胺-N-羥基苯并三唑等脫水縮合劑之存在下，與苯甲酸、2-吡啶羧酸等具有與目的化合物對應之取代基之羧酸，於-80℃~100℃，宜-20℃~40℃反應0.1小時~24小時，宜1小時~12小時，得化合物(I-19)。
烷胺基衍生物
(式中NHR20為可有取代基之胺基，R22為低烷基)
令於環A具有胺基之化合物(I-18)於二氯甲烷，四氫呋喃 等溶劑中，有乙酸等酸之存在下或非存在下，與苄醛、吡啶-2-甲醛等具有與目的化合物對應之取代基之醛及氰基三氫硼酸鈉、三乙醯氧基硼氫化鈉等還原劑，於-80℃~100℃，宜0℃~40℃反應0.5小時~150小時，宜1小時~24小時，得化合物(I-20)。
取代烷氧基衍生物
(式中R23為可有取代基之低烷基、可有取代基之碳環基或可有取代基之雜環基等，其他與前述同義)
令作為A環之取代基具有羥基之化合物(I-21)，於二甲基甲磺醯胺、四氫呋喃等溶劑中，有碳酸鉀、氫氧化鈉、氫化鈉等鹼之存在下，與苄基氯、甲基碘等與具有與目的化合物對應之取代基之烷基化劑，於-80℃~100℃，宜0℃~40℃反應0.5小時~150小時，宜1小時~24小時，或令化合物(I-18)於二甲基甲磺醯胺、四氫呋喃等溶劑中，有三苯膦-偶氮二羧酸二乙酯等光延反應試藥之存在下，與2-胺基乙醇等醇類，於-80℃~100℃，宜0℃~40℃反應0.5小時~72小時，宜1小時~24小時，得化合物(I-22)。
由於鈀偶合之取代基之導入
(式中Hal為鹵素，G為可有取代基之低烯基、可有取代基之低炔基、可有取代基之低烷氧羰基、可有取代基之碳環基或可有取代基之雜環基等，其他與前述同義)
令作為環A之取代基具有鹵素之化合物(I-23)，於四氫呋喃、二甲基甲磺醯胺、1,2-二甲氧乙烷、甲醇等溶劑中，有三乙胺、碳酸鈉等鹼、乙酸鈀、氯化鈀等鈀觸媒及三苯膦等配位子之存在下，與目的化合物之取代基對應之化合物(苯乙烯、炔丙醇、芳基硼烷酸、一氧化碳等)，於微波之照射下或非照射下，於-80℃~150℃，宜0℃~100℃反應0.5小時~72小時，宜1小時~24小時，得化合物(I-24)。
肟衍生物
(式中R24為氫或可有取代基之低烷基等，R25為氫、可有取代基之低烷基、可有取代基之低烯基或可有取代基之碳環基或可有取代基之雜環基等，其他與前述同義)
令作為環A之取代基具有醯基之化合物(I-25)，於甲醇或乙醇等溶劑中，有乙酸鉀等添加劑之存在下或非存在下，與具有與目的化合物對應之取代基之羥胺類(羥胺、甲氧胺、O-苄基羥胺等)或其鹽，於-80℃~100℃，宜0℃~40℃反應0.5小時~150小時，宜1小時~72小時，得化合物(I-26)。
上述所有工程中，有成為反應之阻礙之取代基(例如羥基、氫硫基、胺基、甲醯基、羰基、羧基等)時，可依Protective Groups in Organic Synthesis,Theodora W Green(John Wiley & Sons)等方法預先保護，而於所望階段去除其保護基。
本發明之化合物(I)中，特以X為S，E為單鍵或亞甲基之以下化合物較佳。
1)式(I’)化合物， (式中t為0或1，其他各符號與上述(a)同義，但以下之化合物除外。
i)n+m為2，R5為氫，環A為無取代之苯基之化合物，ii)n為2，m為0，R2a為氫，R2b為氫或乙醯基，R5為甲基，環A為苯基或4-甲氧苯基之化合物，iii)n為2，m為0，R2a為氫，R2b為氫或乙醯基，R5為乙 基，環A為3,4-二甲氧苯基之化合物，iv)n為2，m為0，R2a為氫，R2b為氫或乙醯基，R5及環A為苯基之化合物，v)n為2，m為0，R2a及R2b為氫，R5及環A一起形成 之化合物，vi)n+m為1或2，R5為氫，環A為由羥基、鹵素、低烷基、低烷氧基、硝基、胺基、低烷羰胺基、氫硫基、低烷硫基、胺甲醯基、低烷胺基、低烷胺甲醯基及低烷氧羰基選擇之只1~2個取代基取代之苯基、無取代苯基或無取代萘基之化合物)。
式(I’)中，以如下化合物較佳。
2)n為1，m為0之化合物(以下稱nm-1之化合物)，3)n為2，m為0之化合物(以下稱nm-2之化合物)，4)n為3，m為0之化合物(以下稱nm-3之化合物)，5)R2a為氫，R2b為氫、可有取代基之低烷基、可有取代基之醯基、可有取代基之低烷磺醯基、可有取代基之甲脒基之化合物(以下稱R2-1之化合物)。
6)R2a為氫，R2b為氫、可有取代基之低烷基或可有取代基之醯基之化合物(以下稱R2-2之化合物)。
7)NR2aR2b為 (各與前述同義)，R6、R7及R8各自獨立為氫、低烷基或醯基，Y為可有取代基之低伸烷基、可有取代基之低伸烯基或可有取代基之低伸炔基，Z為O或S之化合物(以下稱R2-3之化合物)，8)NR2aR2b為NH2之化合物(以下稱R2-4之化合物)，9)環A為有取代苯基或有取代吡啶基之化合物(以下稱A-1之化合物)，10)環A為 (R9、R10及R11為氫或G，G為鹵素、羥基、氰基、硝基、氫硫基、可有取代基之低烷基、可有取代基之低烷氧基、可有取代基之低烯基、可有取代基之低炔基、可有取代基之醯基、可有取代基之醯氧基、羧基、可有取代基之低烷氧羰基、可有取代基之低烷氧羰氧基、可有取代基之芳氧羰氧基、可有 取代基之胺基、可有取代基之胺甲醯基、可有取代基之胺甲醯氧基、可有取代基之低烷硫基、可有取代基之芳硫基、可有取代基之低烷磺醯基、可有取代基之芳磺醯基、可有取代基之低烷亞磺醯基、可有取代基之芳亞磺醯基、可有取代基之低烷磺醯氧基、可有取代基之芳磺醯氧基、可有取代基之胺磺醯基、可有取代基之碳環基、可有取代基之碳環氧基、可有取代基之雜環基或可有取代基之雜環氧基，各G可相異)(以下稱A-2)，11)環A為 (R9及R10各自獨立為氫、鹵素、羥基、可有取代基之低烷基、氰基、硝基、可有取代基之低烷氧基、可有取代基之醯基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之胺甲醯氧基、可有取代基之低烷磺醯基、可有取代基之芳磺醯基、可有取代基之低烷磺醯氧基、可有取代基之芳磺醯氧基、可有取代基之碳環基、可有取代基之碳環氧基、可有取代基之雜環基或可有取代基之雜環氧基、G與上述10)同義)之化合物(以下稱A-3之化合物)， 12)環A為 (R9及R10與11)同義，G與上述10)同義)之化合物(以下稱A-4之化合物)，13)環A、R9及R10為11)所定義之基，G為可有取代基之胺基之化合物(以下稱A-5之化合物)，14)環A、R9及R10為11)所定義之基，G為可有取代基之芳羰胺基或可有取代基之雜環羰胺基之化合物，15)環A、R9及R10為11)所定義之基，G為可有取代基之雜環羰胺基之化合物(以下稱A-6之化合物)，16)環A為11)所定義之基，G為 (Q1、Q2及Q3各自獨立為單鍵、可有取代基之低伸烷基或可有取代基之低伸烯基，Q4為可有取代基之低伸烷基或可有取代基之低伸烯基，W1及W2各自獨立為O或S，W3為O、S或NR12，R12為氫、低烷基、羥低烷基、低烷氧低烷基、低烷氧羰低烷基、碳環低烷基或醯基，R14為氫或低烷基，環B為可有取代基之碳環基或可有取代基之雜環基Alk2為可有取代基之低烷基) ，R9及R10為11)同義之化合物(以下稱A-7之化合物)，17)環A、R9及R10為11)所定義之基，G為16)所定義之基，環B可有鹵素、羥基、可有取代基之低烷基、可有取代基之低烷氧基、可有取代基之醯基、可有取代基之胺基、氰基、可有取代基之胺甲醯基、可有取代基之碳環基、可有取代基之碳環氧基或可有取代基之雜環基選擇之1以上基各取代之芳基或雜芳基，其他符號為16)同義之化合物(以下稱A-8之化合物)，18)環A、R9及R10為11)所定義之基，G為 (式中各符號為16)同義)之化合物(以下稱A-9之化合物)19)環A為 ，G為16)所定義之基，環B為可有取代基之芳基或可有取代基之雜芳基，R9及R10之一為氫，另一為氫、鹵素 、可有取代基之低烷基、氰基、硝基、可有取代基之低烷氧基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之低烷磺醯基、可有取代基之碳環基或可有取代基之雜環基之化合物(以下稱A-10之化合物)，20)環A為 ，G為18)所定義之基，其他符號為19)同義之化合物(以下稱A-11之化合物)，21)環A為 ，G為16)所定義之基，環B為各可有取代基之苯基、5~6員之雜芳基、苯并噻二唑基或苯并噻吩基，R9及R10為19)同義之化合物(以下稱A-12之化合物)，22)環A為 ，G為18)所定義之基，環B為21)同義，R9及R10為19)同義之化合物(以下稱A-13之化合物)，23)環A為 (式中R9為氫、鹵素、可有取代基之低烷基、氰基、硝基、可有取代基之低烷氧基、可有取代基之胺基、可有取代基之胺甲醯基、可有取代基之低烷磺醯基、可有取代基之碳環基或可有取代基之雜環基，環B為21)同義，R12為氫或低烷基)之化合物(以下稱A-14之化合物)，24)R5為氫或C1~C3烷基之化合物(以下稱R5-1之化合物)，25)R5為C1~C3烷基之化合物(以下稱R5-2之化合物)，26)R5為甲基之化合物(以下稱R5-3之化合物)，27)R3a及R3b各自獨立為氫、鹵素、羥基、可有取代基之低烷基、可有取代基之低烷氧基或可有取代基之芳基之化合物(以下稱R3-1之化合物)，28)R3a為氫、鹵素、羥基、可有取代基之低烷基、可有取代基之低烷氧基或可有取代基之芳基，R3b為氫，n為2時，1個R3a為氫，n為3時，1~2個R2a為氫之化合物(以下稱R3-2之化合物)29)R3a及R3b皆氫之化合物(以下稱R3-3之化合物)，式(I’)中、n、m、R2a、R2b、環A、R5、R3a及R3b之組合(nm、R2、A、R5、R3)為如下之化合物。
(nm、R2、A、R5、R3)=(nm-1,R2-1,A-1,R5-1,R3-1),(nm-1,R2-1,A-1,R5-1,R3-2),(nm-1,R2-1,A-1,R5-2,R3-1),(nm-1,R2-1,A-1,R5-2,R3-2),(nm-1,R2-1,A-1,R5-3,R3-1),(nm-1,R2-1,A-1,R5-3,R3-2),(nm-1,R2-1,A-2,R5-1,R3-1),(nm-1,R2-1,A-2,R5-1,R3-2),(nm-1,R2-1,A-2,R5-2,R3-1),(nm-1,R2-1,A-2,R5-2,R3-2),(nm-1,R2-1,A-2,R5-3,R3-1),(nm-1,R2-1,A-2,R5-3,R3-2),(nm-1,R2-1,A-3,R5-1,R3-1),(nm-1,R2-1,A-3,R5-1,R3-2),(nm-1,R2-1,A-3,R5-2,R3-1),(nm-1,R2-1,A-3,R5-2,R3-2),(nm-1,R2-1,A-3,R5-3,R3-1),(nm-1,R2-1,A-3,R5-3,R3-2),(nm-1,R2-1,A-4,R5-1,R3-1),(nm-1,R2-1,A-4,R5-1,R3-2),(nm-1,R2-1,A-4,R5-2,R3-1),(nm-1,R2-1,A-4,R5-2,R3-2),(nm-1,R2-1,A-4,R5-3,R3-1),(nm-1,R2-1,A-4,R5-3,R3-2),(nm-1,R2-1,A-5,R5-1,R3-1),(nm-1,R2-1,A-5,R5-1,R3-2),(nm-1,R2-1,A-5,R5-2,R3-1),(nm-1,R2-1,A-5,R5-2,R3-2),(nm-1,R2-1,A-5,R5-3,R3-1),(nm-1,R2-1,A-5,R5-3,R3-2),(nm-1,R2-1,A-6,R5-1,R3-1),(nm-1,R2-1,A-6,R5-1,R3-2),(nm-1,R2-1,A-6,R5-2,R3-1),(nm-1,R2-1,A-6,R5-2,R3-2),(nm-1,R2-1,A-6,R5-3,R3-1),(nm-1,R2-1,A-6,R5-3,R3-2),(nm-1,R2-1,A-7,R5-1,R3-1),(nm-1,R2-1,A-7,R5-1,R3-2),(nm-1,R2-1,A-7,R5-2,R3-1),(nm-1,R2-1,A-7,R5-2,R3-2),(nm-1,R2-1,A-7,R5-3,R3-1),(nm-1,R2-1,A-7,R5-3,R3-2),(nm-1,R2-1,A-8,R5-1,R3-1),(nm-1,R2-1,A-8,R5-1,R3-2),(nm-1,R2-1,A-8,R5-2,R3-1),(nm-1,R2-1,A-8,R5-2,R3-2),(nm-1,R2-1,A-8,R5-3,R3-1),(nm-1,R2-1,A-8,R5-3,R3- 2),(nm-1,R2-1,A-9,R5-1,R3-1),(nm-1,R2-1,A-9,R5-1,R3-2),(nm-1,R2-1,A-9,R5-2,R3-1),(nm-1,R2-1,A-9,R5-2,R3-2),(nm-1,R2-1,A-9,R5-3,R3-1),(nm-1,R2-1,A-9,R5-3,R3-2),(nm-1,R2-1,A-10,R5-1,R3-1),(nm-1,R2-1,A-10,R5-1,R3-2),(nm-1,R2-1,A-10,R5-2,R3-1),(nm-1,R2-1,A-10,R5-2,R3-2),(nm-1,R2-1,A-10,R5-3,R3-1),(nm-1,R2-1,A-10,R5-3,R3-2),(nm-1,R2-1,A-11,R5-1,R3-1),(nm-1,R2-1,A-11,R5-1,R3-2),(nm-1,R2-1,A-11,R5-2,R3-1),(nm-1,R2-1,A-11,R5-2,R3-2),(nm-1,R2-1,A-11,R5-3,R3-1),(nm-1,R2-1,A-11,R5-3,R3-2),(nm-1,R2-1,A-12,R5-1,R3-1),(nm-1,R2-1,A-12,R5-1,R3-2),(nm-1,R2-1,A-12,R5-2,R3-1),(nm-1,R2-1,A-12,R5-2,R3-2),(nm-1,R2-1,A-12,R5-3,R3-1),(nm-1,R2-1,A-12,R5-3,R3-2),(nm-1,R2-1,A-13,R5-1,R3-1),(nm-1,R2-1,A-13,R5-1,R3-2),(nm-1,R2-1,A-13,R5-2,R3-1),(nm-1,R2-1,A-13,R5-2,R3-2),(nm-1,R2-1,A-13,R5-3,R3-1),(nm-1,R2-1,A-13,R5-3,R3-2),(nm-1,R2-1,A-14,R5-1,R3-1),(nm-1,R2-1,A-14,R5-1,R3-2),(nm-1,R2-1,A-14,R5-2,R3-1),(nm-1,R2-1,A-14,R5-2,R3-2),(nm-1,R2-1,A-14,R5-3,R3-1),(nm-1,R2-1,A-14,R5-3,R3-2),(nm-1,R2-2,A-1,R5-1,R3-1),(nm-1,R2-2,A-1,R5-1,R3-2),(nm-1,R2-2,A-1,R5-2,R3-1),(nm-1,R2-2,A-1,R5-2,R3-2),(nm-1,R2-2,A-1,R5-3,R3-1),(nm-1,R2-2,A-1,R5-3,R3-2),(nm-1,R2-2,A-2,R5-1,R3-1),(nm-1,R2-2,A-2,R5-1,R3-2),(nm-1,R2-2,A-2,R5-2,R3-1),(nm-1,R2-2,A-2,R5-2,R3-2),(nm-1,R2-2,A- 2,R5-3,R3-1),(nm-1,R2-2,A-2,R5-3,R3-2),(nm-1,R2-2,A-3,R5-1,R3-1),(nm-1,R2-2,A-3,R5-1,R3-2),(nm-1,R2-2,A-3,R5-2,R3-1),(nm-1,R2-2,A-3,R5-2,R3-2),(nm-1,R2-2,A-3,R5-3,R3-1),(nm-1,R2-2,A-3,R5-3,R3-2),(nm-1,R2-2,A-4,R5-1,R3-1),(nm-1,R2-2,A-4,R5-1,R3-2),(nm-1,R2-2,A-4,R5-2,R3-1),(nm-1,R2-2,A-4,R5-2,R3-2),(nm-1,R2-2,A-4,R5-3,R3-1),(nm-1,R2-2,A-4,R5-3,R3-2),(nm-1,R2-2,A-5,R5-1,R3-1),(nm-1,R2-2,A-5,R5-1,R3-2),(nm-1,R2-2,A-5,R5-2,R3-1),(nm-1,R2-2,A-5,R5-2,R3-2),(nm-1,R2-2,A-5,R5-3,R3-1),(nm-1,R2-2,A-5,R5-3,R3-2),(nm-1,R2-2,A-6,R5-1,R3-1),(nm-1,R2-2,A-6,R5-1,R3-2),(nm-1,R2-2,A-6,R5-2,R3-1),(nm-1,R2-2,A-6,R5-2,R3-2),(nm-1,R2-2,A-6,R5-3,R3-1),(nm-1,R2-2,A-6,R5-3,R3-2),(nm-1,R2-2,A-7,R5-1,R3-1),(nm-1,R2-2,A-7,R5-1,R3-2),(nm-1,R2-2,A-7,R5-2,R3-1),(nm-1,R2-2,A-7,R5-2,R3-2),(nm-1,R2-2,A-7,R5-3,R3-1),(nm-1,R2-2,A-7,R5-3,R3-2),(nm-1,R2-2,A-8,R5-1,R3-1),(nm-1,R2-2,A-8,R5-1,R3-2),(nm-1,R2-2,A-8,R5-2,R3-1),(nm-1,R2-2,A-8,R5-2,R3-2),(nm-1,R2-2,A-8,R5-3,R3-1),(nm-1,R2-2,A-8,R5-3,R3-2),(nm-1,R2-2,A-9,R5-1,R3-1),(nm-1,R2-2,A-9,R5-1,R3-2),(nm-1,R2-2,A-9,R5-2,R3-1),(nm-1,R2-2,A-9,R5-2,R3-2),(nm-1,R2-2,A-9,R5-3,R3-1),(nm-1,R2-2,A-9,R5-3,R3-2),(nm-1,R2-2,A-10,R5-1,R3-1),(nm-1,R2-2,A-10,R5-1,R3-2),(nm-1,R2-2,A-10,R5-2,R3-1),(nm-1,R2-2,A-10,R5-2,R3-2),(nm-1,R2-2,A-10,R5-3,R3-1),(nm-1,R2-2,A-10,R5-3,R3- 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3,R2-3,A-12,R5-3,R3-2),(nm-3,R2-3,A-13,R5-1,R3-1),(nm-3,R2-3,A-13,R5-1,R3-2),(nm-3,R2-3,A-13,R5-2,R3-1),(nm-3,R2-3,A-13,R5-2,R3-2),(nm-3,R2-3,A-13,R5-3,R3-1),(nm-3,R2-3,A-13,R5-3,R3-2),(nm-3,R2-3,A-14,R5-1,R3-1),(nm-3,R2-3,A-14,R5-1,R3-2),(nm-3,R2-3,A-14,R5-2,R3-1),(nm-3,R2-3,A-14,R5-2,R3-2),(nm-3,R2-3,A-14,R5-3,R3-1),(nm-3,R2-3,A-14,R5-3,R3-2),(nm-3,R2-4,A-1,R5-1,R3-1),(nm-3,R2-4,A-1,R5-1,R3-2),(nm-3,R2-4,A-1,R5-2,R3-1),(nm-3,R2-4,A-1,R5-2,R3-2),(nm-3,R2-4,A-1,R5-3,R3-1),(nm-3,R2-4,A-1,R5-3,R3-2),(nm-3,R2-4,A-2,R5-1,R3-1),(nm-3,R2-4,A-2,R5-1,R3-2),(nm-3,R2-4,A-2,R5-2,R3-1),(nm-3,R2-4,A-2,R5-2,R3-2),(nm-3,R2-4,A-2,R5-3,R3-1),(nm-3,R2-4,A-2,R5-3,R3-2),(nm-3,R2-4,A-3,R5-1,R3-1),(nm-3,R2-4,A-3,R5-1,R3-2),(nm-3,R2-4,A-3,R5-2,R3-1),(nm-3,R2-4,A-3,R5-2,R3-2),(nm-3,R2-4,A-3,R5-3,R3-1),(nm-3,R2-4,A-3,R5-3,R3-2),(nm-3,R2-4,A-4,R5-1,R3-1),(nm-3,R2-4,A-4,R5-1,R3-2),(nm-3,R2-4,A-4,R5-2,R3-1),(nm-3,R2-4,A-4,R5-2,R3-2),(nm-3,R2-4,A-4,R5-3,R3-1),(nm-3,R2-4,A-4,R5-3,R3-2),(nm-3,R2-4,A-5,R5-1,R3-1),(nm-3,R2-4,A-5,R5-1,R3-2),(nm-3,R2-4,A-5,R5-2,R3-1),(nm-3,R2-4,A-5,R5-2,R3-2),(nm-3,R2-4,A-5,R5-3,R3-1),(nm-3,R2-4,A-5,R5-3,R3-2),(nm-3,R2-4,A-6,R5-1,R3-1),(nm-3,R2-4,A-6,R5-1,R3-2),(nm-3,R2-4,A-6,R5-2,R3-1),(nm-3,R2-4,A-6,R5-2,R3-2),(nm-3,R2-4,A-6,R5-3,R3-1),(nm-3,R2-4,A-6,R5- 3,R3-2),(nm-3,R2-4,A-7,R5-1,R3-1),(nm-3,R2-4,A-7,R5-1,R3-2),(nm-3,R2-4,A-7,R5-2,R3-1),(nm-3,R2-4,A-7,R5-2,R3-2),(nm-3,R2-4,A-7,R5-3,R3-1),(nm-3,R2-4,A-7,R5-3,R3-2),(nm-3,R2-4,A-8,R5-1,R3-1),(nm-3,R2-4,A-8,R5-1,R3-2),(nm-3,R2-4,A-8,R5-2,R3-1),(nm-3,R2-4,A-8,R5-2,R3-2),(nm-3,R2-4,A-8,R5-3,R3-1),(nm-3,R2-4,A-8,R5-3,R3-2),(nm-3,R2-4,A-9,R5-1,R3-1),(nm-3,R2-4,A-9,R5-1,R3-2),(nm-3,R2-4,A-9,R5-2,R3-1),(nm-3,R2-4,A-9,R5-2,R3-2),(nm-3,R2-4,A-9,R5-3,R3-1),(nm-3,R2-4,A-9,R5-3,R3-2),(nm-3,R2-4,A-10,R5-1,R3-1),(nm-3,R2-4,A-10,R5-1,R3-2),(nm-3,R2-4,A-10,R5-2,R3-1),(nm-3,R2-4,A-10,R5-2,R3-2),(nm-3,R2-4,A-10,R5-3,R3-1),(nm-3,R2-4,A-10,R5-3,R3-2),(nm-3,R2-4,A-11,R5-1,R3-1),(nm-3,R2-4,A-11,R5-1,R3-2),(nm-3,R2-4,A-11,R5-2,R3-1),(nm-3,R2-4,A-11,R5-2,R3-2),(nm-3,R2-4,A-11,R5-3,R3-1),(nm-3,R2-4,A-11,R5-3,R3-2),(nm-3,R2-4,A-12,R5-1,R3-1),(nm-3,R2-4,A-12,R5-1,R3-2),(nm-3,R2-4,A-12,R5-2,R3-1),(nm-3,R2-4,A-12,R5-2,R3-2),(nm-3,R2-4,A-12,R5-3,R3-1),(nm-3,R2-4,A-12,R5-3,R3-2),(nm-3,R2-4,A-13,R5-1,R3-1),(nm-3,R2-4,A-13,R5-1,R3-2),(nm-3,R2-4,A-13,R5-2,R3-1),(nm-3,R2-4,A-13,R5-2,R3-2),(nm-3,R2-4,A-13,R5-3,R3-1),(nm-3,R2-4,A-13,R5-3,R3-2),(nm-3,R2-4,A-14,R5-1,R3-1),(nm-3,R2-4,A-14,R5-1,R3-2),(nm-3,R2-4,A-14,R5-2,R3-1),(nm-3,R2-4,A-14,R5-2,R3-2),(nm-3,R2-4,A- 14,R5-3,R3-1),(nm-3,R2-4,A-14,R5-3,R3-2),(nm-3,R2-4,A-14,R5-3,R3-3)。
式(I’)中n、m、R2a、R2b、環A、R5、R3a及R3b之組合(nm、R2、A、R5、R3)為上述之任一，E為單鍵之化合物。
本發明之化合物對類澱粉β蛋白質之產生，由分泌或沈著誘發之疾病有用，例如阿滋海默型痴呆(阿滋海默症、阿滋海默型老年痴呆等)、唐氏症、記憶阻礙、prion病(克勞伊登．雅各布(Creutzfeldt-Jacob)病等)、輕度認知阻礙(MCI)、荷蘭型遺傳性類澱粉性腦出血、腦類澱粉血管阻礙、其他變性痴呆、血管性變性混合型痴呆、巴金森病伴隨之痴呆、進行性核上麻痺伴隨之痴呆、皮質基底核變性症伴隨之痴呆、擴散性Lewy小體型阿滋海默病、加齡黄斑變性症、巴金森病、類澱粉血管緊張病等之治療及/或預防、症狀改善有效。
本發明之化合物投與時，可與其他醫藥(例如乙醯基膽鹼酯酶等其他阿滋海默症治療劑等)併用。例如可與鹽酸donepezil、tacrine、galanthamine、rivastigmine、zanapezil、memantine、vinpocetine等抗痴呆藥等併用。
本發明之化合物於人投與時，可以散劑、顆粒劑、錠劑、膠囊劑、丸劑、液劑等經口、或以注射劑、坐劑、經皮吸収劑、吸入劑等非經口投與。又可必要時於本化合物之有效量混合適合其劑型之賦形劑、結合劑、濕潤劑、崩壞劑、滑澤劑等醫藥用添加劑而作成醫藥製劑。
投與量依疾病之狀態、投與途徑、患者之年齡、或體重而異，成人經口投與時，通常0.1μg~1g/日，宜0.01~200mg/日，非經口投與時，通常1μg~10g/日，宜0.1~2g/日。
次以實施例及試驗例詳說明本發明，但本發明不受這些限定。
實施例中，各簡稱之意義如下。
Me 甲基Et 乙基iPr、Pr1 異丙基Ph 苯基Bn 苄基Boc 第三丁氧羰基TBDPS 第三丁基二苯基矽烷基
[實施例1]
化合物588之合成
第一工程
令化合物(1-1)(7.98 g)於氮大氣下溶解於乙醚(330 ml)-四氫呋喃(36 ml)混合溶劑，以乾冰-丙酮浴冷却下加乙烯基氯化鎂之四氫呋喃溶液(1.32 mol/L,44.8 ml)，20分之攪拌而反應液更於冰冷下30分、室溫35分之攪拌後，加飽和氯化銨水溶液，以乙酸乙酯萃取，有機層以飽和氯化銨水溶液、飽和碳酸氫鈉水溶液、飽和食鹽水順序洗淨後，以無水硫酸鎂乾燥，減壓蒸除溶劑。殘渣以中壓以矽膠柱層析精製，得化合物(1-2)(6.00 g)。
1H-NMR(CDCl3)：1.63(3H,s),2.08(1H,br),5.20(1H,dd,J=10.6,1.6 Hz),5.31(1H,dd,J=17.1,1.6Hz),6.09(1H,m),7.46(1H,m),7.52(1H,dd,J=3.4,2.6 Hz),7.80(1H,dd,J=3.9,2.6 Hz),8.06(1H,br)
第二工程
令化合物(1-2)(6.36 g)溶解於乙酸(30 ml)，加硫脲(1.50 g)、1 mol/L鹽酸乙酸溶液(20.7 ml)，於室溫3小時、40℃ 3小時之攪拌後，更於室溫66小時、40℃ 19小時之攪拌後，追加硫脲(0.450 g)、1 mol/L鹽酸乙酸溶液(7.53 ml)，於40℃ 23小時之攪拌後，確認化合物(1-2)消失，減壓蒸除溶劑，殘渣以甲醇/乙醚結晶化，得化合物(1-3)(5.23 g)結晶。又令母液減壓濃縮乾涸，得化合物(1-3)(3.00 g)，固體粗生成物。
1H-NMR(DMSO-d6)：2.09(3H,s),4.10(2H,d,J=7.3 Hz),5.94(1H,t,J=7.7 Hz),7.50(1H,s),7.75(1H,s),7.87(1H,s),9.17(3H,br),11.46(1H,s)
第三工程
令化合物(1-3)(5.23 g)溶解於三氟乙酸(25 ml)，於冰冷下攪拌滴下三氟甲磺酸(2.14 ml)。滴下終了後，反應液昇溫至室溫，3.5小時之攪拌後，確認化合物(1-3)消失，減壓蒸除溶劑。所得殘渣加水及碳酸鈉，以乙酸乙酯萃取。有機層以飽和碳酸氫鈉水溶液洗淨後，以無水硫酸鎂乾燥，減壓下濃縮乾涸，得化合物(1-4)(4.90 g)粗生成物。
1H-NMR(CDCl3)：1.53(3H,s),1.90(1H,m),2.09(1H,m),2.74(1H,m),2.97(1H,m),4.32(2H,br),7.34(1H,t,J=1.6 Hz),7.37(1H,t,J=1.8 Hz),7.86(1H,t,J=1.8 Hz)
第四工程
令化合物(1-4)(4.90 g)氮大氣下溶解於四氫呋喃(30 ml)，冰冷下攪拌加二碳酸二第三丁酯(2.97 g)、三乙胺 (1.89 ml)，2小時之攪拌後，反應液昇溫至室溫，更3小時之攪拌後，加水而以乙酸乙酯萃取。有機層以水洗淨，以無水硫酸鎂乾燥後，減壓蒸除溶劑。所得殘渣由乙酸乙酯/乙醚結晶化，得化合物(1-5)(4.62 g)。
1H-NMR(CDCl3)：1.36(9H,s),1.72(3H,s),2.10(1H,m),2.41(1H,m),2.62(1H,m),2.75(1H,m),7.22(1H,s),7.48(1H,s),8.29(1H,s)
第五工程
令化合物(1-5)(1.00 g)溶解於四氫呋喃(8.7 ml)，加1 mol/L氫氧化鋰水溶液(4.43 ml)，於50℃ 4小時之攪拌後，反應液加水，以乙酸乙酯萃取，有機層以水、飽和食鹽水順序洗淨，以無水硫酸鎂乾燥後，減壓蒸除溶劑。所得殘渣以中壓以矽膠柱層析，得化合物(1-6)(0.668 g)。
1H-NMR(CDCl3)：1.51(9H,s),1.63(3H,s),2.06(1H,m),2.40(1H,m),2.68-2.74(2H,m),3.83(2H,br),6.51(1H,t,J=1.8 Hz),6.72-6.74(2H,m)
第六工程
令化合物(1-6)(20.0 mg)溶解於4 mol/L鹽酸1,4-二烷溶液，16小時之攪拌後，反應液減壓濃縮，所得殘渣由甲醇/乙醚結晶化，得化合物(588)(14.7 mg)。
1H-NMR(DMSO-d6)：1.59(3H,s),2.09-2.76(4H,m),6.44(1H,t,J=1.6 Hz),6.60(1H,t J=1.9 Hz),6.71(1H,t,J=2.0 Hz),10.4(1H,s)
[實施例2]
化合物835之合成
第一工程
令化合物(2-1)(2020 mg)溶解於氯仿(20 ml)，於室溫攪拌下加水(4 ml)，硫氰酸鈉(1470 mg)後，於冰冷滴下硫酸(1.94 ml)。滴下終了後，反應液昇溫至室溫，345分之攪拌後，於60℃攪拌一晚。以TLC確認化合物(2-1)之殘存，反應液冷却至室溫後，順序加硫氰酸鈉(1470 mg)、水(5 ml)、硫酸(1.94 ml)。反應液昇溫至60℃後，攪拌1日。冰冷下加飽和碳酸氫鈉水使反應液為鹼性後，以乙酸乙酯萃取。有機層以飽和食鹽水洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，所得殘渣以以矽膠柱層析，得化合物(2-2)(968 mg)。
1H-NMR(CDCl3,270 MHz)：1.99(3H,s),3.55(1H,d,J=16.1 Hz),3.69(1H,d,J=16.1 Hz),7.12-7.64(8H,m),7.82-7.95(2H,m)
第二工程
令化合物(2-2)(842 mg)溶解於乙醇(8.4 ml)，冰冷攪拌下順序加磷酸二氫鈉(1600 mg)、硼氫化鈉(113.2 mg)之水(2.8 ml)溶液後，於同溫30分之攪拌後，以TLC確認化合物(2-2)消失後，於冰冷下加乙酸乙酯和水，數分之攪拌後，以乙酸乙酯萃取。有機層以水、飽和食鹽水順序洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，得化合物(2-3)(904.8mg)粗生成物。
第三工程
令化合物(2-3)(900 mg)溶解於甲苯(10ml)，於冰冷攪拌下加亞磺醯氯(0.7 ml)之甲苯(5 ml)溶液，於同溫1小時之攪拌後，以TLC確認化合物(2-3)消失後，減壓下使反應液濃縮，得化合物(2-4)(1076.8 mg)粗生成物。
第四工程
令化合物(2-4)(1070 mg)於室溫下溶解於約7mol/L之氨之甲醇溶液(20ml)，於同溫攪拌1日。以TLC確認化合物(2-4)消失後，減壓下使反應液濃縮，得化合物(835)(2633 mg)粗生成物。
[實施例3]
化合物561之合成
第一工程
於冰冷攪拌下、四氫呋喃(30 ml)中令氫化鋰鋁(0.63 g)徐徐添加後，滴下化合物(3-1)(1.94 g)之四氫呋喃(40 ml)溶液。於室溫20分、加熱回流下反應3小時後，冰冷攪拌下令冰徐徐添加，於室溫攪拌一晝夜。反應液過濾後，濾液減壓蒸發，殘渣以矽膠柱層析，得化合物(3-2)(0.90 g)。
1H-NMR(CDCl3)：1.22(3H,s),3.08(1H,d,J=12.5 Hz),3.34(1H,d,J=12.5 Hz),3.85(1H,d,J=11.0 Hz),4.11(1H,d,J=11.0 Hz),7.21-7.25(1H,m),7.34-7.40(2H,m),7.46-7.50(2H,m).
第二工程
令化合物(3-2)(0.90 g)溶解於四氫呋喃(15 ml)，冰冷攪拌下加異氰酸第三丁酯(0.69 g)之四氫呋喃(5 ml)溶液。於室溫攪拌3日後，加水而以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(3-3)(1.33 g)。
1H-NMR(CDCl3)：1.12(9H,s),1.34(3H,s),3.15(1H,br),3.76(1H,d,J=11.2 Hz),3.87(1H,dd,J=14.2,4.6 Hz),4.13(1H,d,J=11.2 Hz),4.23(1H,dd,J=14.2,6.6 Hz),5.18(1H,br),6.01(1H,br),7.23-7.28(1H,m),7.34-7.41(4H,m).
第三工程
令化合物(3-3)(315 mg)溶解於乙腈(3 ml)，冰冷攪拌下，加三苯膦(440 mg)及四氯化碳(520 mg)之乙腈(3 ml)溶液。於室溫攪拌1小時後，冰冷攪拌下，加碳酸鉀(460 mg)，於室溫2日之攪拌後，加水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(3-4)(0.23 g)。
1H-NMR(CDCl3)：1.30(9H,s),1.36(3H,s),3.13(1H,d,J=12.2 Hz),3.24(1H,dd,J=12.2,2.3 Hz),3.51(1H,br),3.53(1H,d,J=15.2 Hz),3.99(1H,dd,J=15.2,2.3 Hz),7.20-7.25(1H,m),7.30-7.36(2H,m),7.39-7.43(2H,m).
第四工程
於化合物(3-4)(0.22 g)加濃鹽酸(4.5 ml)，加熱回流下、2小時之攪拌後，反應液減壓蒸發。殘渣以甲醇/乙醚結晶化，得化合物561(0.16 g)。
1H-NMR(DMSO-d6)：1.33(3H,s),3.33-3.49(2H,m),3.65-3.96(2H,m),7.29(1H,t.J=7.6 Hz),7.40(2H,t.J=7.6 Hz),7.48(2H,t.J=7.6 Hz).
[實施例4]
化合物534之合成
第一工程
令化合物(4-1)(0.72 g)溶解於N,N-二甲基甲磺醯胺(15 ml)，加疊氮化鈉(0.31 g)。於100℃ 13小時之攪拌後，加水，以乙醚萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑，得粗生成之化合物(4-2)(0.71 g)。
第二工程
於化合物(4-2)(0.71 g)之四氫呋喃(10 ml)溶液，冰冷攪拌下，徐徐添加氫化鋰鋁(0.14 g)後，於室溫2小時之攪拌。反應終了後，冰冷攪拌下徐徐添加冰，於室溫18小時之攪拌。反應液過濾後，濾液減壓蒸發，得粗生成之化合物(4-3)(0.89 g)。
第三工程
令化合物(4-3)(0.89 g)溶解於四氫呋喃(10 ml)，冰冷攪拌下加異氰酸第三丁酯(0.56 g)之四氫呋喃(5 ml)溶液。於室溫4小時之攪拌後，加水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(4-4)(0.72 g)。
1H-NMR(CDCl3)：1.39(9H,s),2.08(3H,s),2.09- 2.15(2H,m),3.37-3.44(1H,m),3.80-3.87(1H,m),5.97(1H,br.),6.86(1H,br.),7.28-7.43(5H,m).
第四工程
令化合物(4-4)(120 mg)溶解於乙腈(2 ml)，冰冷攪拌下加三苯膦(170 mg)及四氯化碳(200 mg)之乙腈(1 ml)溶液。於室溫5小時之攪拌後，冰冷攪拌下，加碳酸鉀(177 mg)，於室溫5日之攪拌後，加水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(4-5)(0.06 g)。
1H-NMR(CDCl3)：1.35(9H,s),1.59(3H,s),1.91(1H,ddd,J=13.5,8.8,5.0 Hz),2.06(1H,dt,J=13.5,5.0 Hz),3.00(1H,ddd,J=15.1,8.8,5.0 Hz),3.30(1H,dt,J=15.1,5.0 Hz),7.24-7.38(5H,m).
第五工程
於化合物(4-5)(0.06 g)加濃鹽酸(3 ml)，加熱回流下1小時之攪拌後，反應液減壓蒸發。殘渣以甲醇/水結晶化，得化合物534(0.02 g)。
1H-NMR(DMSO-d6)：1.43(3H,s),1.77(1H,dt.J=8.4,3.4 Hz),2.11(1H,d.J=9.2 Hz),2.48-2.50(1H,m),2.83-2.99(1H,m),6.12(1H,br),6.65(1H,br),7.21-7.24(1H,m),7.31-7.37(4H,m).
[實施例5]
化合物1008之合成
第一工程
令化合物(5-1)(3.00 g)溶解於乙醇(30 ml)，加硫脲(1.13 g)，26小時之加熱回流後，反應液減壓蒸發。殘渣以乙酸乙酯/己烷結晶化，得化合物(5-2)(4.03 g)。
1H-NMR(DMSO-d6)：1.95(2H,quint,J=6.8 Hz),3.13(2H,t,J=6.8 Hz),3.21(2H,t,J=6.8 Hz),3.85(3H,s),7.06(2H,d,J=8.8 Hz),7.95(2H,d,J=8.8 Hz),9.18(4H,br).
第二工程
令化合物(5-2)(1.00 g)溶解於四氫呋喃(25 ml)，加二碳酸二第三丁酯(1.74 g)及三乙胺(0.88 g)，於室溫3小時之攪拌後，加水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(5-3)(1.24 g)。
1H-NMR(CDCl3)：1.50(9H,s),2.07-2.17(2H,m), 2.98(2H,t,J=7.8 Hz),3.09(2H,t,J=6.3 Hz),6.95(2H,d,J=8.9 Hz),7.95(2H,d,J=8.9 Hz).
第三工程
令化合物(5-3)(1.18 g)溶解於四氫呋喃(12 ml)，於乙腈/乾冰浴冷却攪拌下，加0.9mol/L甲基溴化鎂/四氫呋喃溶液(10.1 ml)，1小時之攪拌後，於室溫下攪拌30分。反應後，加冰冷攪拌下飽和氯化銨水溶液，以乙醚萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(5-4)(0.39 g)。
1H-NMR(CDCl3)：1.51(9H,s),1.63(3H,s),1.55-1.65(2H,m),1.87-1.91(2H,m),2.96-3.12(2H,m),6.86(2H,d,J=8.9 Hz),7.36(2H,d,J=8.9 Hz).
第四工程
令化合物(5-4)(0.24 g)溶解於三氟乙酸(6 ml)，於室溫20小時之攪拌後，反應液減壓蒸發。於殘渣加水及飽和碳酸氫鈉水溶液，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物1008(0.06 g)。
1H-NMR(CDCl3)：1.54(3H,s),1.77-1.87(1H,m),1.90-1.97(1H,m),2.20-2.36(2H,m),2.67-2.79(2H,m),3.81(3H,s),5.30(2H,br),6.87(2H,d,J=9.0 Hz),7.33(2H,d,J=9.0 Hz).
[實施例6]
化合物783之合成
第一工程
令化合物(6-1)(0.55 g)溶解於甲醇(7 ml)，於室溫攪拌下，加甲基碘(0.36 g)。室溫18小時之攪拌後，反應液減壓蒸發，得粗生成之化合物(6-2)(0.92g)。
第二工程
令化合物(6-2)(0.92 g)溶解於四氫呋喃(7 ml)，加三乙胺(0.24 g)及氧化銀(1.1 g)。於室溫3日之攪拌後，濾別不溶物，令濾液減壓濃縮後，殘渣以矽膠柱層析，得化合物(6-3)(0.31 g)。
1H-NMR(CDCl3)：1.35(9H,s),1.60(3H,s),1.92(1H,ddd,J=9.2,5.8,3.4 Hz),2.07(1H,dt,J=9.2,3.4 Hz),3.00(1H,ddd,J=9.2,5.8,3.4 Hz),3.30(1H,dt,J=9.2,3.4 Hz),7.24-7.38(5H,m).
第三工程
於化合物(6-3)(0.29 g)加濃鹽酸(3 ml)，加熱回流下1小時之攪拌後，反應液減壓蒸發。於殘渣加水來結晶化，得化合物783(0.13 g)。
1H-NMR(DMSO-d6)：1.44(3H,s),1.78(1H,dt.J=12.4, 4.2 Hz),2.12(1H,d.J=8.9 Hz),2.51-2.52(1H,m),2.96(1H,d.J=4.2 Hz),6.12(1H,br),6.66(1H,br),7.21-7.24(1H,m),7.32-7.37(4H,m).
[實施例7]
化合物69之合成
第一工程
令化合物(7-1)(1.93 g)、二苯磷醯疊氮(1.60 g)、三乙胺(0.59 g)之甲苯(20 ml)溶液於80℃ 3小時之攪拌後，加水，以乙醚萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(7-2)(1.69 g)。
1H-NMR(CDCl3)：1.00(9H,s),1.72(3H,s),2.17-2.22(2H,m),3.49-3.58(1H,m),3.70-3.80(1H,m),7.20-7.42(10H,m),7.58-7.63(5H,m).
第二工程
令化合物(7-2)(1.68 g)溶解於甲苯(9 ml)，加3,4-二甲氧苄醇(0.79 g)，加熱回流8日後，加水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(7-3)(2.09 g)。
1H-NMR(CDCl3)：1.03(9H,s),1.87(3H,s),2.04(2H,m),3.48(1H,m),3.51(1H,m),3.62(3H,s),3.65(3H,s),4.95(1H,d,J=12.2 Hz),5.03(1H,d,J=12.2 Hz),6.80-7.09(3H,m),7.22-7.42(10H,m),7.56-7.64(5H,m).
第三工程
令化合物(7-3)(2.09 g)溶解於1,4-二烷(15 ml)、加4mol/L-鹽酸/1,4-二烷溶液(15 ml)，於室溫下24小時之攪拌後，加水及1mol/L-氫氧化鈉溶液，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(7-4)(0.45 g)。
1H-NMR(CDCl3)：1.57(3H,s),1.07-1.98(2H,m),3.48-3.56(1H,m),3.72-3.86(1H,m),7.23-7.45(15H,m).
第四工程
令化合物(7-4)(0.44 g)溶解於四氫呋喃(15 ml)，加異氰酸第三丁酯(0.41 g)及二異丙基乙胺(0.46 g)。於室溫3日之攪拌後，加水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(7-5)(0.17 g)。
1H-NMR(CDCl3)：1.79(3H,s),1.82-2.20(2H,m),3.71-3.81(2H,m),5.09(1H,br),7.30-7.52(5H,m).
第五工程
令化合物(7-5)(0.17 g)溶解於四氫呋喃(3.4 ml)，於室溫攪拌下，加甲基碘(0.11 g)。於室溫23小時之攪拌後，反應液減壓蒸發，得粗生成之化合物(7-6)(0.28g)。
第六工程
令化合物(7-6)(0.28 g)溶解於四氫呋喃(5 ml)，加三乙胺(74 mg)及氧化銀(0.34 g)。於室溫20小時之攪拌後，濾別不溶物，令濾液減壓濃縮後，殘渣以矽膠柱層析，得化合物(7-7)(0.14 g)。
1H-NMR(CDCl3)：1.36(9H,s),1.49(3H,s),1.96-2.09(2H,m),2.77-3.83(1H,m),4.05-4.10(1H,m),7.19(1H,t,J=7.3 Hz),7.31(2H,t,J=7.3 Hz),7.44(2H,d,J=7.3 Hz).
第七工程
於化合物(7-7)(0.12 g)加濃鹽酸(9ml)，加熱回流下1小時之攪拌後，反應液減壓蒸發。殘渣以甲醇/水結晶化，得化合物69(0.10 g)。
1H-NMR(DMSO-d6)：1.65(3H,s),2.28-2.35(1H,m),2.39-2.44(1H,m),3.97(1H,dt,J=7.8,3.0 Hz),4.53(1H,dt,J=7.8,3.0 Hz),7.32-7.44(5H,m),8.44(2H,br),10.33(1H,s).
[實施例8]
化合物256之合成
第一工程
令化合物(8-1)(4890 mg)溶解於二甲基甲磺醯胺(100 ml)，於室溫攪拌下加疊氮化鈉(5720 mg)，反應液昇溫至80℃而12小時之攪拌後，以TLC確認化合物(8-1)消失，反應液冷却至室溫，加乙醚和水，以乙醚萃取。有機層以飽和食鹽水洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，得化合物(8-2)(4940 mg)之粗生成物。
第二工程
於氮大氣、冰冷下，於氫化鋰鋁(1080 mg)之四氫呋喃(90 ml)懸浮液加化合物(8-2)(4940 mg)之四氫呋喃(15 ml)溶液後，於同溫攪拌30分。以TLC確認化合物(8-2)消失後，冰冷下加1mol/L之氫氧化鈉水溶液而稍攪拌。 濾別生成之凝膠，母液以乙醚萃取。有機層以飽和食鹽水順序洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，得化合物(8-3)(4219.1 mg)之粗生成物。
第三工程
令化合物(8-3)(800 mg)溶解於乙腈(16 ml)，於室溫攪拌下加化合物(8-4)(1840mg)，於同溫13小時之攪拌後，以TLC確認化合物(8-3)消失，減壓下令反應液濃縮，所得殘渣以矽膠柱層析，得化合物(8-5)(1550.7 mg)。
8-5-(Z)：1H-NMR(CDCl3,270 MHz)：1.49(18H,s),2.06(3H,d,J=1.4 Hz),3.91-4.00(2H,m),5.54(1H,td,J=7.1,1,4 Hz),7.12-7.41(5H,m),8.17-8.25(1H,m),11.47(1H,s)
8-5-(E)：1H-NMR(CDCl3,270 MHz)：1.49(9H,s),1.52(9H,s),2.09(3H,d,J=1.5 Hz),4.24(2H,dd,J=6.6,5.3 Hz),5.80(1H,td,J=6.6,1,5 Hz),7.21-7.48(5H,m),8.28-8.38(1H,m),11.51(1H,s)
第四工程
令化合物(8-5)(474.1 mg)於冰冷下溶解於三氟乙酸(4.5 ml)，昇溫為室溫而4小時之攪拌後，以NMR確認化合物(8-5)消失。令反應液注入有浮冰之1mol/L氫氧化鈉水溶液來中和，以乙酸乙酯萃取。有機層以飽和食鹽水洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，得化合物(8-6)(326.4 mg)之粗生成物。
第五工程
令化合物(8-6)(326.4 mg)溶解於1,4-二烷(2.4 ml)， 於室溫攪拌下順序加氫氧化鈉(195 mg)、水(1.2 ml)後，於冰冷下加二碳酸二第三丁酯(0.84 ml)。昇溫為室溫而15小時之攪拌後，以LC-MS確認化合物(8-6)消失。加水後，反應液以乙酸乙酯萃取。有機層以飽和食鹽水洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，所得殘渣以矽膠柱層析，得化合物(8-7)(113.6 mg)。
1H-NMR(CDCl3,400 MHz)：1.46(9H,s),1.51(9H,s),1.64(3H,s),2.06(1H,ddd,J=13.4,11.4,5.0 Hz),2.27(1H,dt,J=13.4,4.6 Hz),3.15(1H,ddd,J=12.9,11.3,4.6 Hz),3.70(1H,dt,J=12.9,4.7 Hz),7.23-7.29(1H,m),7.33-7.38(4H,m)
第六工程
令化合物(8-7)(110 mg)於冰冷下溶解於4mol/L之氯化氫之1,4-二烷溶液(1 ml)，昇溫至室溫後，攪拌2日。以LC-MS確認化合物(8-7)消失後，於室溫下反應液加乙醚和水。分離乙醚層後，令水層減壓濃縮。所得殘渣加甲醇，濾別生成之結晶。減壓蒸除母液之甲醇，得化合物(256)(69 mg)。
1H-NMR(DMSO-d6,400 MHz)：1.57(3H,s),1.87-1.96(1H,m),2.30(1H,dt,J=13.6,3.8 Hz),2.60(1H,td,J=12.0,3.7 Hz),3.25(1H,ddd,J=12.8,8.2,4.4 Hz),6.93(2H,s),7.27-7.44(5H,m),7.94(1H,s),8.63(1H,s)
[實施例9]
化合物24之合成
第一工程
令化合物(9-1)(0.39 g)溶解於氯仿(20 ml)，於室溫攪拌下，加碘(1.53 g)、硫氰酸鉀(1.25 g)、觸媒量之四丁基氯化銨及水(1 ml)，15小時之攪拌而反應後，加10%硫代硫酸鈉水溶液及水，以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(9-2)(0.56 g)。
1H-NMR(CDCl3)：1.95(3H,s),3.62(2H,s),7.30-7.40(4H,m).
第二工程
於化合物(9-2)(0.56 g)之四氫呋喃(10 ml)溶液加第三丁胺(0.24 g)，於室溫18小時之攪拌後，反應液減壓蒸發，殘渣以矽膠柱層析，得化合物(9-3)(190 mg)。
1H-NMR(CDCl3)：1.43(9H,s),1.56(3H,s),3.27(1H,d,J=10.6 Hz),3.36(1H,d,J=10.6 Hz),7.28(2H,d,J=8.2 Hz),7.43(2H,d,J=8.2 Hz).
第三工程
化合物(9-3)(190 mg)加濃鹽酸(3 ml)，於100℃ 7小時之攪拌後，冰冷攪拌下加6mol/L-氫氧化鈉水溶液而中和，以二氯甲烷萃取後，有機層以無水硫酸鈉乾燥，減 壓蒸除溶劑。殘渣以矽膠柱層析後，以二氯甲烷/正己烷結晶化，得化合物24(110 mg)。
1H-NMR(CDCl3)：1.62(3H,s),3.47(1H,d,J=10.6 Hz),3.52(1H,d,J=10.6 Hz),4.59(2H,br),7.29(2H,d,J=8.6 Hz),7.39(2H,d,J=8.6 Hz).
[實施例10]
化合物48之合成
第一工程
令化合物(10-1)(79.6 mg)及(10-2)(120 mg)溶解於二甲基甲磺醯胺(3 ml)，於室溫攪拌下加1-羥基苯并三唑(54.6 mg)及N,N’-二異丙基碳化二亞胺(0.063 ml)後，反應液於室溫一晚攪拌，確認化合物(10-1)消失後，加水，以乙酸乙酯萃取，有機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥，減壓蒸除溶劑。殘渣以柱層析精製，得化合物(10-3)(110.2 mg)，非對映體之混合物。
1H-NMR(CDCl3)：0.78-1.00(6H,m,),1.14(9/2H,s),1.16(9/2H,s)1.52(3/2H,s),1.54(3/2H,s)1.86-2.28 (3H,m),2.56-2.89(2H,m),3.80(3/2H,s),3.81(3/2H,s)4.04-4.14(1H,m),6.80-6.91(2H,m),7.08-7.22(2H,m),7.30-7.51(6H,m),7.61-7.76(4H,m)
第二工程
於氮氣流下，令化合物(10-3)(100 mg)溶解於四氫呋喃(3 ml)，於0℃攪拌下加四丁基氟化銨之1mol/L四氫呋喃溶液(0.18 ml)。反應液於0℃攪拌5分，確認化合物(10-3)消失後，加水，以乙酸乙酯萃取，有機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥，減壓蒸除溶劑。殘渣以柱層析精製，得化合物48(40.7 mg)，非對映體之混合物。
1H-NMR(CDCl3)：0.80-0.90(3H,m,)1.01-1.12(3H,m)1.70(3H,m),2.02-2.31(2H,m)2.39--2.55(1H,m),2.61-2.90(2H,m)3.53-3.70(1H,m)3.81(3H,m),3.96-4.08(1H,m)6.87-6.96(2H,m),7.13-7.22(2H,m)
[實施例11]
化合物707之合成
第一工程
令化合物(11-1)(150 mg)溶解於乙腈(5 ml)，於室溫攪拌下加化合物(11-2)(219.6 mg)，反應液昇溫為60℃而25小時之攪拌後，以TLC確認化合物(11-1)殘存。減壓濃縮反應液，所得殘渣以矽膠柱層析，得化合物(11-3)(211.4 mg)。
1H-NMR(CDCl3,400 MHz)：1.46(9H,s),1.50(9H,s),1.57(3H,s),1.90(1H,ddd,J=13.7,10.0,3.8 Hz)2.11(1H,ddd,J=13.7,6.5,3.7 Hz)2.68-2.76(1H,m),2.86-2.93(1H,m),3.88(3H,s),6.91(1H,t,J=8.6 Hz)6.99-7.03(1H,m),7.06(1H,dd,J=13.0,2.2 Hz),10.14(1H,s),13.93(1H,s)
第二工程
令化合物(11-3)(210 mg)於冰冷下溶解於4mol/L之氯 化氫之1,4-二烷溶液(4 ml)，昇溫至室溫而67小時之攪拌後，以LC-MS確認化合物(11-3)消失，減壓濃縮反應液。所得殘渣以甲醇乙醚結晶化後，濾取結晶，以乙醚洗淨，得化合物(707)(140.2 mg)。
1H-NMR(DMSO-d6,400 MHz)：1.56(3H,s),1.90-2.01(1H,m),2.43-2.62(2H,m),2.95-3.03(1H,m),3.84(3H,s),7.10-7.27(3H,m),7.76(3H,br s),8.26(1H,br s),9.42(1H,s)
[實施例12]
化合物845之合成
第一工程
令化合物(12-1)(50 mg)及哌啶(17.9 mg)溶解於二甲基甲磺醯胺(2 ml)，於室溫攪拌下加O-(7-吖苯并三唑-1-基)-1,1,3,3-四甲基六氟磷酸烏龍(79.8 mg)。反應液於室溫40小時之攪拌後，確認化合物(12-1)消失，加熱減壓蒸除溶劑。殘渣以飽和碳酸氫鈉加水，以乙酸乙酯萃取，有機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥，減壓蒸除溶劑。殘渣以柱層析精製，得化合物845(30.7 mg)。
1H-NMR(CDCl3)：1.60(3H,s),1.51-1.82(6H,m),1.87- 1.98(1H,m),2.09-2.19(1H,m),2.91-2.97(2H,m),3.64-3.68(4H,m),6.73(1H,d,J=4.05 Hz),7.14(1H,d,J=4.05 Hz)
[實施例13]
化合物1262之合成
第一工程
令化合物(13-1)(50.0 mg)於氮大氣下溶解於四氫呋喃(1 ml)，冰冷下加三乙胺(19 μl)、4-溴苄醯氯(30.1 mg)而40分之攪拌後，減壓濃縮反應液，所得殘渣溶解於乙酸乙酯，以飽和碳酸氫鈉水溶液洗淨，以無水硫酸鎂乾燥後，減壓濃縮。濾集析出結晶，得化合物(13-2)(57.2 mg)。
1H-NMR(CDCl3)：1.48(9H,s),1.68(3H,s),2.08(1H,m),2.44(1H,m),2.65(1H,m),2.76(1H,m),7.18(1H,s),7.32(1H,s),7.64(2H,d,J=8.2 Hz),7.78(2H,d,J=8.2 Hz),8.15(1H,s),8.25(1H,br)
第二工程
令化合物(13-2)(62.3 mg)溶解於4mol/L鹽酸1,4-二烷溶液而24小時之攪拌後，減壓濃縮反應液，所得殘渣以甲醇/乙醚結晶化，得化合物(1262)(44.7 mg)。
1H-NMR(DMSO-d6)：1.67(3H,s),2.10(1H,m),2.50- 2.61(3H,m),7.33(1H,s),7.74(1H,s),7.77(2H,d,J=8.6 Hz),7.91(2H,d,J=8.6 Hz),8.08(1H,s),10.6(1H,s)
[實施例14]
化合物753之合成
第一工程
令化合物(14-1)(46 mg)溶解於二氯甲烷(2 ml)，加4-氯苄醛(20 mg)及乙酸(17 mg)，於室溫20分之攪拌後，冰冷攪拌下加三乙醯氧基硼氫化鈉(45 mg)。於室溫14小時之攪拌後，加水而以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(14-2)(52 mg)。
1H-NMR(CDCl3)：1.50(9H,s),1.64(3H,s),2.02-2.10(1H,m),2.40(1H,dt,J=14.0,4.1 Hz),2.62-2.74(2H,m),4.30(2H,s),6.49(1H,ddd,J=,7.8,2.0,0.8 Hz),6.52(1H,t,J=2.0 Hz),6.60(1H,ddd,J=,7.8,2.0,0.8 Hz),7.16(1H,t,J=7.8 Hz),7.18-7.33(4H,m).
第二工程
於化合物(14-2)(52 mg)加4mol/L-鹽酸/1,4-二烷溶液(4 ml)，於室溫下4日之攪拌後，反應液減壓蒸發。殘渣以甲醇/乙醚結晶化，得化合物753(42 mg)。
1H-NMR(DMSO-d6)：1.58(3H,s),2.00(1H,ddd,J=, 14.3,11.3,3.3 Hz),2.49-2.57(2H,m),3.07(1H,dt,J=12.7,3.3 Hz),4.27(2H,s),6.47(1H,d,J=8.2 Hz),6.51-6.53(2H,m),7.08(1H,t,J=8.2 Hz),7.37(4H,s),8.80(2H,br).
[實施例15]
化合物1135之合成
第一工程
於化合物(15-1)(101 mg)、2-丙醇(56 μl)、三苯膦(189 mg)之四氫呋喃(2 ml)溶液，滴下偶氮二羧酸二乙酯之2.2 mol/L甲苯溶液(328 μl)。滴下終了而於室溫1小時之攪拌後，確認化合物(15-1)消失，減壓蒸除溶劑。殘渣以柱層析精製，得化合物(15-2)與氧化三苯膦及伸肼基二羧酸二乙酯之混合物(280 mg)。
第二工程
於5-氯吡啶-2-羧酸(47 mg)之甲苯(1 ml)懸浮液，加二甲基甲磺醯胺(1滴)及亞磺醯氯(91 μl)，於100℃ 1小 時之攪拌後，減壓蒸除溶劑，殘渣溶解於四氫呋喃(1 ml)，於0℃滴下化合物(15-2)之混合物(280 mg)及吡啶(194 μl)之四氫呋喃(0.5 ml)溶液。於室溫攪拌10分，確認化合物(15-2)消失後，加水而以乙酸乙酯萃取。有機層以水洗淨後，減壓蒸除溶劑。所得殘渣以柱層析精製，得化合物(15-3)與伸肼基二羧酸二乙酯之混合物(68 mg)。
第三工程
於化合物(15-3)與伸肼基二羧酸二乙酯之混合物(68 mg)加4mol/L-鹽酸/1，4-二烷溶液(1 ml)，於室溫16小時之攪拌後，確認化合物(44)消失，反應液減壓蒸發。殘渣以2-丙醇/乙醚結晶化，得化合物1135(36 mg)。
1H-NMR(DMSO-d6)：1.30(3H,d,J=6.4 Hz),1.31(3H,d,J=6.4 Hz),1.65(3H,s),2.04-2.11(1H,m),2.50-2.64(2H,m),3.12-3.16(1H,m),4.61(1H,sep,J=6.4 Hz),6.66(1H,t,J=2.0 Hz),7.48(1H,t,J=2.0 Hz),7.60(1H,t,J=2.0 Hz),8.16(1H,dd,J=8.4,0.8 Hz),8.22(1H,dd,J=8.4,2.4 Hz),8.79(1H,dd,J=2.4,0.8 Hz),10.33(1H,s),10.72(1H,s).
[實施例16]
化合物161之合成
第一工程
於氮大氣下，令化合物(16-1)(200 mg)、乙酸鈀(4.7 mg)、三鄰甲苯膦(12.5 mg)溶解於二甲基甲磺醯胺(2 ml)，於室溫攪拌下加正丁胺(0.196 ml)、對氯苯乙烯(0.074 ml)，反應液昇溫為80℃而3小時之攪拌後，以TLC確認化合物(16-1)消失後，冷却至室溫而加飽和氯化銨水溶液。以乙酸乙酯萃取，有機層以水及飽和食鹽水洗淨後，以硫酸鎂乾燥。減壓蒸除溶劑，所得殘渣以矽膠柱層析，得化合物(16-2)(213.1 mg)。
1H-NMR(CDCl3,400 MHz)：1.54(18H,s),1.64(3H,s),1.96(1H,ddd,J=13.7,9.1,4.0 Hz)2.10(1H,ddd,J=13.7,8.1,3.4 Hz)2.86(1H,ddd,J=12.3,9.1,3.4 Hz),3.03(1H,ddd,J=12.3,8.1,4.0Hz),7.08(1H,d,J=16.4 Hz)7.15(1H,d,J=16.4 Hz),7.27-7.40(5H,m)7.44(2H,d,J=8.8 Hz),7.58(1H,s)
第二工程
令化合物(16-2)(213 mg)於冰冷下溶解於4mol/L之氯化氫之1,4-二烷溶液(5 ml)，昇溫至室溫而63小時之 攪拌後，以LC-MS確認化合物(16-2)消失，反應液以乙醚稀釋。濾集析出結晶，以乙醚洗淨，得化合物(161)(108.6 mg)。
1H-NMR(DMSO-d6,400 MHz)：1.69(3H,s),2.08-2.18(1H,m),2.56-2.70(2H,m),3.13-3.20(1H,m),7.23(1H,d,J=8.0 Hz),7.31(1H,d,J=17.0 Hz),7.35(1H,d,J=17.0 Hz),7.45(2H,d,J=8.6 Hz),7.46(1H,t,7.6 Hz),7.59(1H,d,J=2.0 Hz),7.61-7.64(1H,m),7.64(2H,d,J=8.6 Hz),8.53-9.50(2H,br),10.67(1H,br s)
[實施例17]
化合物597之合成
第一工程
令化合物(17-1)(135 mg)、鹽酸甲氧胺(39 mg)、乙酸鉀(27 mg)之甲醇(3 ml)溶液於室溫16小時之攪拌後，加水而以二氯甲烷萃取，有機層以無水硫酸鈉乾燥，減壓蒸除溶劑。殘渣以矽膠柱層析，得化合物(17-2)(110 mg)。
1H-NMR(CDCl3)：1.51(9H,s),1.70(3H,s),2.14(1H,ddd,J=14.4,11.4,3.4 Hz),2.22(3H,s),2.48(1H,m),2.65(1H,dt,J=12.6,11.4 Hz),2.78(1H,ddd,J=12.6, 5.6,3.4 Hz),4.00(3H,s),7.30(1H,d,J=7.8 Hz),7.38(1H,d,J=7.8 Hz),7.54-7.57(2H,m).
第二工程
於化合物(17-2)(110 mg)加4mol/L-鹽酸/1,4-二烷溶液(4.5 ml)，於室溫下4日之攪拌後，反應液減壓蒸發。殘渣以甲醇/乙醚結晶化，得化合物597(65 mg)。
1H-NMR(DMSO-d6)：1.67(3H,s),2.08-2.15(1H,m),2.20(3H,s),2.56-2.64(2H,m),3.14-3.17(1H,m),3.92(3H,s),7.37(1H,d,J=8.0 Hz),7.48(1H,d,J=8.0 Hz),7.56(1H,s),7.62(1H,d,J=8.0 Hz).
仿上合成其他化合物。構造式及物理恆數如下。
表中為為為
上述式(Ia)~(Ih)中、NR2aR2b、R3c、R3d、R5及G之組合(NR2aR2b、R3c、R3d、R5、G)為如下之化合物。
(NHMe,H,H,Me,CONHPh),(NHMe,H,H,Me,CONH-3-pyridyl),(NHMe,H,H,Me,NHCOPh),(NHMe,H,H,Me,NHCO-2-furyl),(NHMe,H,H,Me,NHCONHPh),(NHMe,H,H,Me,NHCOCONHPh),(NHMe,H,H,Et,CONHPh),(NHMe,H,H,Et,CONH-3-pyridyl),(NHMe,H,H,Et,NHCOPh),(NHMe,H,H,Et,NHCO-2-furyl),(NHMe,H,H,Et,NHCONHPh),(NHMe,H,H,Et,NHCOCONHPh),(NHMe,H,H,CH2OH,CONHPh),(NHMe,H,H,CH2OH,CONH-3-pyridyl),(NHMe,H,H,CH2OH,NHCOPh),(NHMe,H,H,CH2OH,NHCO-2-furyl),(NHMe,H,H,CH2OH,NHCONHPh),(NHMe,H,H,CH2OH,NHCOCONHPh),(NHMe,H,Me,Me,CONHPh),(NHMe,H,Me,Me,CONH-3-pyridyl),(NHMe,H,Me,Me,NHCOPh),(NHMe,H,Me,Me,NHCO-2-furyl),(NHMe,H,Me,Me,NHCONHPh),(NHMe,H,Me,Me,NHCOCONHPh),(NHMe,H,Me,Et,CONHPh),(NHMe,H,Me,Et,CONH-3-pyridyl),(NHMe,H,Me,Et,NHCOPh),(NHMe,H,Me,Et,NHCO-2-furyl),(NHMe,H,Me,Et,NHCONHPh),(NHMe,H,Me,Et,NHCOCONHPh),(NHMe,H,Me,CH2OH,CONHPh),(NHMe,H,Me,CH2OH,CONH-3-pyridyl),(NHMe,H,Me,CH2OH,NHCOPh),(NHMe,H,Me,CH2OH,NHCO-2-furyl),(NHMe,H,Me,CH2OH,NHCONHPh),(NHMe,H,Me,CH2OH,NHCOCONHPh),(NHMe,H,Ph,Me,CONHPh),(NHMe,H,Ph,Me,CONH-3-pyridyl),(NHMe,H,Ph,Me,NHCOPh),(NHMe,H,Ph,Me,NHCO-2-furyl),(NHMe,H,Ph,Me,NHCONHPh),(NHMe,H,Ph,Me,NHCOCONHPh),(NHMe,H,Ph,Et, CONHPh),(NHMe,H,Ph,Et,CONH-3-pyridyl),(NHMe,H,Ph,Et,NHCOPh),(NHMe,H,Ph,Et,NHCO-2-furyl),(NHMe,H,Ph,Et,NHCONHPh),(NHMe,H,Ph,Et,NHCOCONHPh),(NHMe,H,Ph,CH2OH,CONHPh),(NHMe,H,Ph,CH2OH,CONH-3-pyridyl),(NHMe,H,Ph,CH2OH,NHCOPh),(NHMe,H,Ph,CH2OH,NHCO-2-furyl),(NHMe,H,Ph,CH2OH,NHCONHPh),(NHMe,H,Ph,CH2OH,NHCOCONHPh),(NHMe,H,OH,Me,CONHPh),(NHMe,H,OH,Me,CONH-3-pyridyl),(NHMe,H,OH,Me,NHCOPh),(NHMe,H,OH,Me,NHCO-2-furyl),(NHMe,H,OH,Me,NHCONHPh),(NHMe,H,OH,Me,NHCOCONHPh),(NHMe,H,OH,Et,CONHPh),(NHMe,H,OH,Et,CONH-3-pyridyl),(NHMe,H,OH,Et,NHCOPh),(NHMe,H,OH,Et,NHCO-2-furyl),(NHMe,H,OH,Et,NHCONHPh),(NHMe,H,OH,Et,NHCOCONHPh),(NHMe,H,OH,CH2OH,CONHPh),(NHMe,H,OH,CH2OH,CONH-3-pyridyl),(NHMe,H,OH,CH2OH,NHCOPh),(NHMe,H,OH,CH2OH,NHCO-2-furyl),(NHMe,H,OH,CH2OH,NHCONHPh),(NHMe,H,OH,CH2OH,NHCOCONHPh),(NHMe,Me,H,Me,CONHPh),(NHMe,Me,H,Me,CONH-3-pyridyl),(NHMe,Me,H,Me,NHCOPh),(NHMe,Me,H,Me,NHCO-2-furyl),(NHMe,Me,H,Me,NHCONHPh),(NHMe,Me,H,Me,NHCOCONHPh),(NHMe,Me,H,Et,CONHPh),(NHMe,Me,H,Et,CONH-3-pyridyl),(NHMe,Me,H,Et,NHCOPh),(NHMe,Me,H,Et,NHCO-2-furyl),(NHMe,Me,H,Et,NHCONHPh),(NHMe,Me,H,Et,NHCOCONHPh),(NHMe,Me,H,CH2OH,CONHPh),(NHMe,Me,H,CH2OH,CONH-3-pyridyl),(NHMe,Me,H,CH2OH,NHCOPh),(NHMe,Me,H,CH2OH,NHCO-2-furyl),(NHMe,Me,H,CH2OH,NHCONHPh),(NHMe,Me,H,CH2OH,NHCOCONHPh),(NHMe,Me,Me,Me,CONHPh),(NHMe,Me,Me,Me,CONH-3-pyridyl),(NHMe,Me,Me,Me,NHCOPh),(NHMe,Me,Me,Me,NHCO-2-furyl),(NHMe,Me,Me,Me,NHCONHPh),(NHMe,Me,Me,Me,NHCOCONHPh),(NHMe,Me,Me,Et,CONHPh),(NHMe,Me,Me,Et,CONH-3-pyridyl),(NHMe,Me,Me,Et,NHCOPh),(NHMe,Me,Me,Et,NHCO-2-furyl),(NHMe,Me,Me,Et,NHCONHPh),(NHMe,Me,Me,Et,NHCOCONHPh),(NHMe,Me,Me,CH2OH,CONHPh),(NHMe,Me,Me,CH2OH,CONH-3-pyridyl),(NHMe,Me,Me,CH2OH,NHCOPh),(NHMe,Me,Me,CH2OH,NHCO-2-furyl),(NHMe,Me,Me,CH2OH,NHCONHPh),(NHMe,Me,Me,CH2OH,NHCOCONHPh),(NHMe,Me,Ph,Me,CONHPh),(NHMe,Me,Ph,Me,CONH-3-pyridyl) ,(NHMe,Me,Ph,Me,NHCOPh),(NHMe,Me,Ph,Me,NHCO-2-furyl),(NHMe,Me,Ph,Me,NHCONHPh),(NHMe,Me,Ph,Me,NHCOCONHPh),(NHMe,Me,Ph,Et,CONHPh),(NHMe,Me,Ph,Et,CONH-3-pyridyl),(NHMe,Me,Ph,Et,NHCOPh),(NHMe,Me,Ph,Et,NHCO-2-furyl),(NHMe,Me,Ph,Et,NHCONHPh),(NHMe,Me,Ph,Et,NHCOCONHPh),(NHMe,Me,Ph,CH2OH,CONHPh),(NHMe,Me,Ph,CH2OH,CONH-3-pyridyl),(NHMe,Me,Ph,CH2OH,NHCOPh),(NHMe,Me,Ph,CH2OH,NHCO-2-furyl),(NHMe,Me,Ph,CH2OH,NHCONHPh),(NHMe,Me,Ph,CH2OH,NHCOCONHPh),(NHMe,Me,OH,Me,CONHPh),(NHMe,Me,OH,Me,CONH-3-pyridyl),(NHMe,Me,OH,Me,NHCOPh),(NHMe,Me,OH,Me,NHCO-2-furyl),(NHMe,Me,OH,Me,NHCONHPh),(NHMe,Me,OH,Me,NHCOCONHPh),(NHMe,Me,OH,Et,CONHPh),(NHMe,Me,OH,Et,CONH-3-pyridyl),(NHMe,Me,OH,Et,NHCOPh),(NHMe,Me,OH,Et,NHCO-2-furyl),(NHMe,Me,OH,Et,NHCONHPh),(NHMe,Me,OH,Et,NHCOCONHPh),(NHMe,Me,OH,CH2OH,CONHPh),(NHMe,Me,OH,CH2OH,CONH-3-pyridyl),(NHMe,Me,OH,CH2OH,NHCOPh),(NHMe,Me,OH,CH2OH,NHCO-2-furyl),(NHMe,Me,OH,CH2OH,NHCONHPh),(NHMe,Me,OH,CH2OH,NHCOCONHPh),(NHMe,Ph,H,Me,CONHPh),(NHMe,Ph,H,Me,CONH-3-pyridyl),(NHMe,Ph,H,Me,NHCOPh),(NHMe,Ph,H,Me,NHCO-2-furyl),(NHMe,Ph,H,Me,NHCONHPh),(NHMe,Ph,H,Me,NHCOCONHPh),(NHMe,Ph,H,Et,CONHPh),(NHMe,Ph,H,Et,CONH-3-pyridyl),(NHMe,Ph,H,Et,NHCOPh),(NHMe,Ph,H,Et,NHCO-2-furyl),(NHMe,Ph,H,Et,NHCONHPh),(NHMe,Ph,H,Et,NHCOCONHPh),(NHMe,Ph,H,CH2OH,CONHPh),(NHMe,Ph,H,CH2OH,CONH-3-pyridyl),(NHMe,Ph,H,CH2OH,NHCOPh),(NHMe,Ph,H,CH2OH,NHCO-2-furyl),(NHMe,Ph,H,CH2OH,NHCONHPh),(NHMe,Ph,H,CH2OH,NHCOCONHPh),(NHMe,Ph,Me,Me,CONHPh),(NHMe,Ph,Me,Me,CONH-3-pyridyl),(NHMe,Ph,Me,Me,NHCOPh),(NHMe,Ph,Me,Me,NHCO-2-furyl),(NHMe,Ph,Me,Me,NHCONHPh),(NHMe,Ph,Me,Me,NHCOCONHPh),(NHMe,Ph,Me,Et,CONHPh),(NHMe,Ph,Me,Et,CONH-3-pyridyl),(NHMe,Ph,Me,Et,NHCOPh),(NHMe,Ph,Me,Et,NHCO-2-furyl),(NHMe,Ph,Me,Et,NHCONHPh),(NHMe,Ph,Me,Et,NHCOCONHPh),(NHMe,Ph,Me,CH2OH,CONHPh),(NHMe,Ph,Me,CH2OH,CONH-3-pyridyl),(NHMe,Ph,Me,CH2OH,NHCOPh),(NHMe, Ph,Me,CH2OH,NHCO-2-furyl),(NHMe,Ph,Me,CH2OH,NHCONHPh),(NHMe,Ph,Me,CH2OH,NHCOCONHPh),(NHMe,Ph,Ph,Me,CONHPh),(NHMe,Ph,Ph,Me,CONH-3-pyridyl),(NHMe,Ph,Ph,Me,NHCOPh),(NHMe,Ph,Ph,Me,NHCO-2-furyl),(NHMe,Ph,Ph,Me,NHCONHPh),(NHMe,Ph,Ph,Me,NHCOCONHPh),(NHMe,Ph,Ph,Et,CONHPh),(NHMe,Ph,Ph,Et,CONH-3-pyridyl),(NHMe,Ph,Ph,Et,NHCOPh),(NHMe,Ph,Ph,Et,NHCO-2-furyl),(NHMe,Ph,Ph,Et,NHCONHPh),(NHMe,Ph,Ph,Et,NHCOCONHPh),(NHMe,Ph,Ph,CH2OH,CONHPh),(NHMe,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHMe,Ph,Ph,CH2OH,NHCOPh),(NHMe,Ph,Ph,CH2OH,NHCO-2-furyl),(NHMe,Ph,Ph,CH2OH,NHCONHPh),(NHMe,Ph,Ph,CH2OH,NHCOCONHPh),(NHMe,Ph,OH,Me,CONHPh),(NHMe,Ph,OH,Me,CONH-3-pyridyl),(NHMe,Ph,OH,Me,NHCOPh),(NHMe,Ph,OH,Me,NHCO-2-furyl),(NHMe,Ph,OH,Me,NHCONHPh),(NHMe,Ph,OH,Me,NHCOCONHPh),(NHMe,Ph,OH,Et,CONHPh),(NHMe,Ph,OH,Et,CONH-3-pyridyl),(NHMe,Ph,OH,Et,NHCOPh),(NHMe,Ph,OH,Et,NHCO-2-furyl),(NHMe,Ph,OH,Et,NHCONHPh),(NHMe,Ph,OH,Et,NHCOCONHPh),(NHMe,Ph,OH,CH2OH,CONHPh),(NHMe,Ph,OH,CH2OH,CONH-3-pyridyl),(NHMe,Ph,OH,CH2OH,NHCOPh),(NHMe,Ph,OH,CH2OH,NHCO-2-furyl),(NHMe,Ph,OH,CH2OH,NHCONHPh),(NHMe,Ph,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,H,Me,CONHPh),(NHCH2CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,H,Me,NHCOPh),(NHCH2CH2OH,H,H,Me,NHCO-2-furyl),(NHCH2CH2OH,H,H,Me,NHCONHPh),(NHCH2CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH2OH,H,H,Et,CONHPh),(NHCH2CH2OH,H,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,H,Et,NHCOPh),(NHCH2CH2OH,H,H,Et,NHCO-2-furyl),(NHCH2CH2OH,H,H,Et,NHCONHPh),(NHCH2CH2OH,H,H,Et,NHCOCONHPh),(NHCH2CH2OH,H,H,CH2OH,CONHPh),(NHCH2CH2OH,H,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,H,CH2OH,NHCOPh),(NHCH2CH2OH,H,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,H,CH2OH,NHCONHPh),(NHCH2CH2OH,H,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Me,Me,CONHPh),(NHCH2CH2OH,H,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,Me,NHCOPh),(NHCH2CH2OH,H,Me,M e,NHCO-2-furyl),(NHCH2CH2OH,H,Me,Me,NHCONHPh),(NHCH2CH2OH,H,Me,Me,NHCOCONHPh),(NHCH2CH2OH,H,Me,Et,CONHPh),(NHCH2CH2OH,H,Me,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,Et,NHCOPh),(NHCH2CH2OH,H,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,H,Me,Et,NHCONHPh),(NHCH2CH2OH,H,Me,Et,NHCOCONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,CH2OH,NHCOPh),(NHCH2CH2OH,H,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,H,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Me,CONHPh),(NHCH2CH2OH,H,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,Me,NHCOPh),(NHCH2CH2OH,H,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,Me,NHCONHPh),(NHCH2CH2OH,H,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Et,CONHPh),(NHCH2CH2OH,H,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,Et,NHCOPh),(NHCH2CH2OH,H,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,Et,NHCONHPh),(NHCH2CH2OH,H,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,OH,Me,CONHPh),(NHCH2CH2OH,H,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,Me,NHCOPh),(NHCH2CH2OH,H,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,H,OH,Me,NHCONHPh),(NHCH2CH2OH,H,OH,Me,NHCOCONHPh),(NHCH2CH2OH,H,OH,Et,CONHPh),(NHCH2CH2OH,H,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,Et,NHCOPh),(NHCH2CH2OH,H,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,H,OH,Et,NHCONHPh),(NHCH2CH2OH,H,OH,Et,NHCOCONHPh),(NHCH2CH2OH,H,OH,CH2OH,CONHPh),(NHCH2CH2OH,H,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,CH2OH,NHCOPh),(NHCH2CH2OH,H,OH,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,H,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,H,Me,CONHPh),(NHCH2CH2OH,Me,H,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,Me,N HCOPh),(NHCH2CH2OH,Me,H,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,H,Me,NHCONHPh),(NHCH2CH2OH,Me,H,Me,NHCOCONHPh),(NHCH2CH2OH,Me,H,Et,CONHPh),(NHCH2CH2OH,Me,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,Et,NHCOPh),(NHCH2CH2OH,Me,H,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,H,Et,NHCONHPh),(NHCH2CH2OH,Me,H,Et,NHCOCONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,CH2OH,NHCOPh),(NHCH2CH2OH,Me,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Me,CONHPh),(NHCH2CH2OH,Me,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,Me,Me,NHCOPh),(NHCH2CH2OH,Me,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,Me,NHCONHPh),(NHCH2CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Et,CONHPh),(NHCH2CH2OH,Me,Me,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,Me,Et,NHCOPh),(NHCH2CH2OH,Me,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,Et,NHCONHPh),(NHCH2CH2OH,Me,Me,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Me,CONHPh),(NHCH2CH2OH,Me,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,Me,NHCOPh),(NHCH2CH2OH,Me,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,Me,NHCONHPh),(NHCH2CH2OH,Me,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Et,CONHPh),(NHCH2CH2OH,Me,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,Et,NHCOPh),(NHCH2CH2OH,Me,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,Et,NHCONHPh),(NHCH2CH2OH,Me,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Me,CO NHPh),(NHCH2CH2OH,Me,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,Me,NHCOPh),(NHCH2CH2OH,Me,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,OH,Me,NHCONHPh),(NHCH2CH2OH,Me,OH,Me,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Et,CONHPh),(NHCH2CH2OH,Me,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,Et,NHCOPh),(NHCH2CH2OH,Me,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,OH,Et,NHCONHPh),(NHCH2CH2OH,Me,OH,Et,NHCOCONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,CH2OH,NHCOPh),(NHCH2CH2OH,Me,OH,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,H,Me,CONHPh),(NHCH2CH2OH,Ph,H,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,Me,NHCOPh),(NHCH2CH2OH,Ph,H,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,Me,NHCONHPh),(NHCH2CH2OH,Ph,H,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,H,Et,CONHPh),(NHCH2CH2OH,Ph,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,Et,NHCOPh),(NHCH2CH2OH,Ph,H,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,Et,NHCONHPh),(NHCH2CH2OH,Ph,H,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,H,CH2OH,CONHPh),(NHCH2CH2OH,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,Me,CONHPh),(NHCH2CH2OH,Ph,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Me,Me,NHCOPh),(NHCH2CH2OH,Ph,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,Me,NHCONHPh),(NHCH2CH2OH,Ph,Me,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,Et,CONHPh),(NHCH2CH2OH,Ph,Me,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Me,Et,NHCOPh),(NHCH2CH2OH,Ph,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,Et,NHCONHPh),(NHCH2CH2OH,Ph,Me,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,CONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Me,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,CH2OH,NHCONHPh),(NHC H2CH2OH,Ph,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,Me,CONHPh),(NHCH2CH2OH,Ph,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,Me,NHCOPh),(NHCH2CH2OH,Ph,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,Me,NHCONHPh),(NHCH2CH2OH,Ph,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,Et,CONHPh),(NHCH2CH2OH,Ph,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,Et,NHCOPh),(NHCH2CH2OH,Ph,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,Et,NHCONHPh),(NHCH2CH2OH,Ph,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,Me,CONHPh),(NHCH2CH2OH,Ph,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,Me,NHCOPh),(NHCH2CH2OH,Ph,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,Me,NHCONHPh),(NHCH2CH2OH,Ph,OH,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,Et,CONHPh),(NHCH2CH2OH,Ph,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,Et,NHCOPh),(NHCH2CH2OH,Ph,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,Et,NHCONHPh),(NHCH2CH2OH,Ph,OH,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,CONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,NHCOCONHPh),(NHCH2CONH2,H,H,Me,CONHPh),(NHCH2CONH2,H,H,Me,CONH-3-pyridyl),(NHCH2CONH2,H,H,Me,NHCOPh),(NHCH2CONH2,H,H,Me,NHCO-2-furyl),(NHCH2CONH2,H,H,Me,NHCONHPh),(NHCH2CONH2,H,H,Me,NHCOCONHPh),(NHCH2CONH2,H,H,Et,CONHPh),(NHCH2CONH2,H,H,Et,CONH-3-pyridyl),(NHCH2CONH2,H,H,Et,NHCOPh),(NHCH2CONH2,H,H,Et,NHCO-2-furyl),(NHCH2CONH2,H,H,Et,NHCONHPh),(NHCH2CONH2,H,H,Et,NHCOCONHPh),(NHCH2CONH2,H,H,CH2OH,CONHPh),(NHCH2CONH2,H,H,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,H,CH2OH,NHCOPh),(NHCH2CONH2,H,H,CH2OH,NHCO-2-f 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dyl),(NHSO2Me,Me,Me,Me,NHCOPh),(NHSO2Me,Me,Me,Me,NHCO-2-furyl),(NHSO2Me,Me,Me,Me,NHCONHPh),(NHSO2Me,Me,Me,Me,NHCOCONHPh),(NHSO2Me,Me,Me,Et,CONHPh),(NHSO2Me,Me,Me,Et,CONH-3-pyridyl),(NHSO2Me,Me,Me,Et,NHCOPh),(NHSO2Me,Me,Me,Et,NHCO-2-furyl),(NHSO2Me,Me,Me,Et,NHCONHPh),(NHSO2Me,Me,Me,Et,NHCOCONHPh),(NHSO2Me,Me,Me,CH2OH,CONHPh),(NHSO2Me,Me,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,Me,CH2OH,NHCOPh),(NHSO2Me,Me,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,Me,CH2OH,NHCONHPh),(NHSO2Me,Me,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Me,Ph,Me,CONHPh),(NHSO2Me,Me,Ph,Me,CONH-3-pyridyl),(NHSO2Me,Me,Ph,Me,NHCOPh),(NHSO2Me,Me,Ph,Me,NHCO-2-furyl),(NHSO2Me,Me,Ph,Me,NHCONHPh),(NHSO2Me,Me,Ph,Me,NHCOCONHPh),(NHSO2Me,Me,Ph,Et,CONHPh),(NHSO2Me,Me,Ph,Et,CONH-3-pyridyl),(NHSO2Me,Me,Ph,Et,NHCOPh),(NHSO2Me,Me,Ph,Et,NHCO-2-furyl),(NHSO2Me,Me,Ph,Et,NHCONHPh),(NHSO2Me,Me,Ph,Et,NHCOCONHPh),(NHSO2Me,Me,Ph,CH2OH,CONHPh),(NHSO2Me,Me,Ph,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,Ph,CH2OH,NHCOPh),(NHSO2Me,Me,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,Ph,CH2OH,NHCONHPh),(NHSO2Me,Me,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Me,OH,Me,CONHPh),(NHSO2Me,Me,OH,Me,CONH-3-pyridyl),(NHSO2Me,Me,OH,Me,NHCOPh),(NHSO2Me,Me,OH,Me,NHCO-2-furyl),(NHSO2Me,Me,OH,Me,NHCONHPh),(NHSO2Me,Me,OH,Me,NHCOCONHPh),(NHSO2Me,Me,OH,Et,CONHPh),(NHSO2Me,Me,OH,Et,CONH-3-pyridyl),(NHSO2Me,Me,OH,Et,NHCOPh),(NHSO2Me,Me,OH,Et,NHCO-2-furyl),(NHSO2Me,Me,OH,Et,NHCONHPh),(NHSO2Me,Me,OH,Et,NHCOCONHPh),(NHSO2Me,Me,OH,CH2OH,CONHPh),(NHSO2Me,Me,OH,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,OH,CH2OH,NHCOPh),(NHSO2Me,Me,OH,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,OH,CH2OH,NHCONHPh),(NHSO2Me,Me,OH,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,H,Me,CONHPh),(NHSO2Me,Ph,H,Me,CONH-3-pyridyl),(NHSO2Me,Ph,H,Me,NHCOPh),(NHSO2Me,Ph,H,Me,NHCO-2-furyl),(NHSO2Me,Ph,H,Me,NHCONHPh),(NHSO2Me,Ph,H,Me,NHCOCONHPh),(NHSO2Me,Ph,H,Et,CONHPh),(NHSO2Me,P h,H,Et,CONH-3-pyridyl),(NHSO2Me,Ph,H,Et,NHCOPh),(NHSO2Me,Ph,H,Et,NHCO-2-furyl),(NHSO2Me,Ph,H,Et,NHCONHPh),(NHSO2Me,Ph,H,Et,NHCOCONHPh),(NHSO2Me,Ph,H,CH2OH,CONHPh),(NHSO2Me,Ph,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,H,CH2OH,NHCOPh),(NHSO2Me,Ph,H,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,H,CH2OH,NHCONHPh),(NHSO2Me,Ph,H,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,Me,Me,CONHPh),(NHSO2Me,Ph,Me,Me,CONH-3-pyridyl),(NHSO2Me,Ph,Me,Me,NHCOPh),(NHSO2Me,Ph,Me,Me,NHCO-2-furyl),(NHSO2Me,Ph,Me,Me,NHCONHPh),(NHSO2Me,Ph,Me,Me,NHCOCONHPh),(NHSO2Me,Ph,Me,Et,CONHPh),(NHSO2Me,Ph,Me,Et,CONH-3-pyridyl),(NHSO2Me,Ph,Me,Et,NHCOPh),(NHSO2Me,Ph,Me,Et,NHCO-2-furyl),(NHSO2Me,Ph,Me,Et,NHCONHPh),(NHSO2Me,Ph,Me,Et,NHCOCONHPh),(NHSO2Me,Ph,Me,CH2OH,CONHPh),(NHSO2Me,Ph,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,Me,CH2OH,NHCOPh),(NHSO2Me,Ph,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,Me,CH2OH,NHCONHPh),(NHSO2Me,Ph,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,Ph,Me,CONHPh),(NHSO2Me,Ph,Ph,Me,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,Me,NHCOPh),(NHSO2Me,Ph,Ph,Me,NHCO-2-furyl),(NHSO2Me,Ph,Ph,Me,NHCONHPh),(NHSO2Me,Ph,Ph,Me,NHCOCONHPh),(NHSO2Me,Ph,Ph,Et,CONHPh),(NHSO2Me,Ph,Ph,Et,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,Et,NHCOPh),(NHSO2Me,Ph,Ph,Et,NHCO-2-furyl),(NHSO2Me,Ph,Ph,Et,NHCONHPh),(NHSO2Me,Ph,Ph,Et,NHCOCONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,CH2OH,NHCOPh),(NHSO2Me,Ph,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,Ph,CH2OH,NHCONHPh),(NHSO2Me,Ph,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,OH,Me,CONHPh),(NHSO2Me,Ph,OH,Me,CONH-3-pyridyl),(NHSO2Me,Ph,OH,Me,NHCOPh),(NHSO2Me,Ph,OH,Me,NHCO-2-furyl),(NHSO2Me,Ph,OH,Me,NHCONHPh),(NHSO2Me,Ph,OH,Me,NHCOCONHPh),(NHSO2Me,Ph,OH,Et,CONHPh),(NHSO2Me,Ph,OH,Et,CONH-3-pyridyl),(NHSO2Me,Ph,OH,Et,NHCOPh),(NHSO2Me,Ph,OH,Et,NHCO-2-furyl),(NHSO2Me,Ph,OH,Et,NHCONHPh),(NHSO2Me,Ph,OH,Et,NHCOCONHPh),(NHSO2Me,Ph,OH,CH2OH,CONHPh),(NHSO2Me,Ph,OH,C H2OH,CONH-3-pyridyl),(NHSO2Me,Ph,OH,CH2OH,NHCOPh),(NHSO2Me,Ph,OH,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,OH,CH2OH,NHCONHPh),(NHSO2Me,Ph,OH,CH2OH,NHCOCONHPh),(NH2,H,H,Me,CONHPh),(NH2,H,H,Me,CONH-3-pyridyl),(NH2,H,H,Me,NHCOPh),(NH2,H,H,Me,NHCO-2-furyl),(NH2,H,H,Me,NHCONHPh),(NH2,H,H,Me,NHCOCONHPh),(NH2,H,H,Et,CONHPh),(NH2,H,H,Et,CONH-3-pyridyl),(NH2,H,H,Et,NHCOPh),(NH2,H,H,Et,NHCO-2-furyl),(NH2,H,H,Et,NHCONHPh),(NH2,H,H,Et,NHCOCONHPh),(NH2,H,H,CH2OH,CONHPh),(NH2,H,H,CH2OH,CONH-3-pyridyl),(NH2,H,H,CH2OH,NHCONHPh),(NH2,H,H,CH2OH,NHCOCONHPh),(NH2,H,Me,Me,CONHPh),(NH2,H,Me,Me,CONH-3-pyridyl),(NH2,H,Me,Me,NHCONHPh),(NH2,H,Me,Me,NHCOCONHPh),(NH2,H,Me,Et,CONHPh),(NH2,H,Me,Et,CONH-3-pyridyl),(NH2,H,Me,Et,NHCOPh),(NH2,H,Me,Et,NHCO-2-furyl),(NH2,H,Me,Et,NHCONHPh),(NH2,H,Me,Et,NHCOCONHPh),(NH2,H,Me,CH2OH,CONHPh),(NH2,H,Me,CH2OH,CONH-3-pyridyl),(NH2,H,Me,CH2OH,NHCONHPh),(NH2,H,Me,CH2OH,NHCOCONHPh),(NH2,H,Ph,Me,CONHPh),(NH2,H,Ph,Me,CONH-3-pyridyl),(NH2,H,Ph,Me,NHCONHPh),(NH2,H,Ph,Me,NHCOCONHPh),(NH2,H,Ph,Et,CONHPh),(NH2,H,Ph,Et,CONH-3-pyridyl),(NH2,H,Ph,Et,NHCOPh),(NH2,H,Ph,Et,NHCO-2-furyl),(NH2,H,Ph,Et,NHCONHPh),(NH2,H,Ph,Et,NHCOCONHPh),(NH2,H,Ph,CH2OH,CONHPh),(NH2,H,Ph,CH2OH,CONH-3-pyridyl),(NH2,H,Ph,CH2OH,NHCONHPh),(NH2,H,Ph,CH2OH,NHCOCONHPh),(NH2,H,OH,Me,CONHPh),(NH2,H,OH,Me,CONH-3-pyridyl),(NH2,H,OH,Me,NHCONHPh),(NH2,H,OH,Me,NHCOCONHPh),(NH2,H,OH,Et,CONHPh),(NH2,H,OH,Et,CONH-3-pyridyl),(NH2,H,OH,Et,NHCOPh),(NH2,H,OH,Et,NHCO-2-furyl),(NH2,H,OH,Et,NHCONHPh),(NH2,H,OH,Et,NHCOCONHPh),(NH2,H,OH,CH2OH,CONHPh),(NH2,H,OH,CH2OH,CONH-3-pyridyl),(NH2,H,OH,CH2OH,NHCONHPh),(NH2,H,OH,CH2OH,NHCOCONHPh),(NH2,Me,H,Me,CONHPh),(NH2,Me,H,Me,CONH-3-pyridyl),(NH2,Me,H,Me,NHCONHPh),(NH2,Me,H,Me,NHCOCONHPh),(NH2,Me,H,Et,CONHPh),(NH2,Me,H,Et,CONH-3-pyridyl),(NH2,Me,H,Et,NHCOPh),(NH2,Me,H,Et,NHCO-2-fury l),(NH2,Me,H,Et,NHCONHPh),(NH2,Me,H,Et,NHCOCONHPh),(NH2,Me,H,CH2OH,CONHPh),(NH2,Me,H,CH2OH,CONH-3-pyridyl),(NH2,Me,H,CH2OH,NHCONHPh),(NH2,Me,H,CH2OH,NHCOCONHPh),(NH2,Me,Me,Me,CONHPh),(NH2,Me,Me,Me,CONH-3-pyridyl),(NH2,Me,Me,Me,NHCONHPh),(NH2,Me,Me,Me,NHCOCONHPh),(NH2,Me,Me,Et,CONHPh),(NH2,Me,Me,Et,CONH-3-pyridyl),(NH2,Me,Me,Et,NHCOPh),(NH2,Me,Me,Et,NHCO-2-furyl),(NH2,Me,Me,Et,NHCONHPh),(NH2,Me,Me,Et,NHCOCONHPh),(NH2,Me,Me,CH2OH,CONHPh),(NH2,Me,Me,CH2OH,CONH-3-pyridyl),(NH2,Me,Me,CH2OH,NHCONHPh),(NH2,Me,Me,CH2OH,NHCOCONHPh),(NH2,Me,Ph,Me,CONHPh),(NH2,Me,Ph,Me,CONH-3-pyridyl),(NH2,Me,Ph,Me,NHCOPh),(NH2,Me,Ph,Me,NHCO-2-furyl),(NH2,Me,Ph,Me,NHCONHPh),(NH2,Me,Ph,Me,NHCOCONHPh),(NH2,Me,Ph,Et,CONHPh),(NH2,Me,Ph,Et,CONH-3-pyridyl),(NH2,Me,Ph,Et,NHCOPh),(NH2,Me,Ph,Et,NHCO-2-furyl),(NH2,Me,Ph,Et,NHCONHPh),(NH2,Me,Ph,Et,NHCOCONHPh),(NH2,Me,Ph,CH2OH,CONHPh),(NH2,Me,Ph,CH2OH,CONH-3-pyridyl),(NH2,Me,Ph,CH2OH,NHCONHPh),(NH2,Me,Ph,CH2OH,NHCOCONHPh),(NH2,Me,OH,Me,CONHPh),(NH2,Me,OH,Me,CONH-3-pyridyl),(NH2,Me,OH,Me,NHCONHPh),(NH2,Me,OH,Me,NHCOCONHPh),(NH2,Me,OH,Et,CONHPh),(NH2,Me,OH,Et,CONH-3-pyridyl),(NH2,Me,OH,Et,NHCOPh),(NH2,Me,OH,Et,NHCO-2-furyl),(NH2,Me,OH,Et,NHCONHPh),(NH2,Me,OH,Et,NHCOCONHPh),(NH2,Me,OH,CH2OH,CONHPh),(NH2,Me,OH,CH2OH,CONH-3-pyridyl),,(NH2,Me,OH,CH2OH,NHCONHPh),(NH2,Me,OH,CH2OH,NHCOCONHPh),(NH2,Ph,H,Me,CONHPh),(NH2,Ph,H,Me,CONH-3-pyridyl),(NH2,Ph,H,Me,NHCONHPh),(NH2,Ph,H,Me,NHCOCONHPh),(NH2,Ph,H,Et,CONHPh),(NH2,Ph,H,Et,CONH-3-pyridyl),(NH2,Ph,H,Et,NHCOPh),(NH2,Ph,H,Et,NHCO-2-furyl),(NH2,Ph,H,Et,NHCONHPh),(NH2,Ph,H,Et,NHCOCONHPh),(NH2,Ph,H,CH2OH,CONHPh),(NH2,Ph,H,CH2OH,CONH-3-pyridyl),(NH2,Ph,H,CH2OH,NHCONHPh),(NH2,Ph,H,CH2OH,NHCOCONHPh),(NH2,Ph,Me,Me,CONHPh),(NH2,Ph,Me,Me,CONH-3-pyridyl),(NH2,Ph,Me,Me,NHCONHPh),(NH2,Ph,Me,Me,NHCOCONHPh),(NH2,Ph,Me,Et,CONHPh),(NH2,Ph,Me,Et,CONH-3-pyridyl),(NH2,Ph,Me,Et, NHCOPh),(NH2,Ph,Me,Et,NHCO-2-furyl),(NH2,Ph,Me,Et,NHCONHPh),(NH2,Ph,Me,Et,NHCOCONHPh),(NH2,Ph,Me,CH2OH,CONHPh),(NH2,Ph,Me,CH2OH,CONH-3-pyridyl),(NH2,Ph,Me,CH2OH,NHCONHPh),(NH2,Ph,Me,CH2OH,NHCOCONHPh),(NH2,Ph,Ph,Me,CONHPh),(NH2,Ph,Ph,Me,CONH-3-pyridyl),(NH2,Ph,Ph,Me,NHCOPh),(NH2,Ph,Ph,Me,NHCO-2-furyl),(NH2,Ph,Ph,Me,NHCONHPh),(NH2,Ph,Ph,Me,NHCOCONHPh),(NH2,Ph,Ph,Et,CONHPh),(NH2,Ph,Ph,Et,CONH-3-pyridyl),(NH2,Ph,Ph,Et,NHCOPh),(NH2,Ph,Ph,Et,NHCO-2-furyl),(NH2,Ph,Ph,Et,NHCONHPh),(NH2,Ph,Ph,Et,NHCOCONHPh),(NH2,Ph,Ph,CH2OH,CONHPh),(NH2,Ph,Ph,CH2OH,CONH-3-pyridyl),(NH2,Ph,Ph,CH2OH,NHCOPh),(NH2,Ph,Ph,CH2OH,NHCO-2-furyl),(NH2,Ph,Ph,CH2OH,NHCONHPh),(NH2,Ph,Ph,CH2OH,NHCOCONHPh),(NH2,Ph,OH,Me,CONHPh),(NH2,Ph,OH,Me,CONH-3-pyridyl),(NH2,Ph,OH,Me,NHCONHPh),(NH2,Ph,OH,Me,NHCOCONHPh),(NH2,Ph,OH,Et,CONHPh),(NH2,Ph,OH,Et,CONH-3-pyridyl),(NH2,Ph,OH,Et,NHCOPh),(NH2,Ph,OH,Et,NHCO-2-furyl),(NH2,Ph,OH,Et,NHCONHPh),(NH2,Ph,OH,Et,NHCOCONHPh),(NH2,Ph,OH,CH2OH,CONHPh),(NH2,Ph,OH,CH2OH,CONH-3-pyridyl),(NH2,Ph,OH,CH2OH,NHCOPh),(NH2,Ph,OH,CH2OH,NHCO-2-furyl),(NH2,Ph,OH,CH2OH,NHCONHPh),(NH2,Ph,OH,CH2OH,NHCOCONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2OH,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOCONHPh),(NHCH2CH (OH)CH2NHMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NH2,H,H,Me,CONHPh),(NHC(O)C(O)NH2,H,H,Me,CONH-3-pyridyl),(NHC(O)C(O)NH2,H,H,Me,NHCOPh),(NHC(O)C(O)NH2,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)NH2,H,H,Me,NHCONHPh),(NHC(O)C(O)NH2,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NHMe,H,H,Me,CONHPh),(NHC(O)C(O)NHMe,H,H,Me,CONH-3-pyridyl),(NHC(O)C(O)NHMe,H,H,Me,NHCOPh),(NHC(O)C(O)NHMe,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)NHMe,H,H,Me,NHCONHPh),(NHC(O)C(O)NHMe,H,H,Me,NHCOCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONH-3-pyridyl),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOCONHPh)。
上述式(Ii)或(Ij)中B、Linker、A、R5之組合(B、Linker、A、R5)為以下之化合物。
(B、Linker、A、R5)=(B1,L1,A1,R51),(B1,L1,A1,R52),(B1,L1,A1,R53),(B1,L1,A1,R54),(B1,L1,A1,R55),(B1,L1,A1,R56),(B1,L1,A2,R51),(B1,L1,A2,R52),(B1,L1,A2,R53),(B1,L1,A2,R54),(B1,L1,A2,R55),(B1,L1,A2,R56),(B1,L1,A3,R51),(B1,L1,A3,R52),(B1,L1,A3,R53),(B1,L1,A3,R54),(B1,L1,A3,R55),(B1,L1,A3,R56),(B1,L1,A4,R51),(B1,L1,A4,R52),(B1,L1,A4,R53),(B1,L1,A4,R54),(B1,L1,A4,R55),(B1,L1,A4,R56),(B1,L1,A5,R51),(B1,L1,A5,R52),(B1,L1,A5,R53),(B1,L1,A5,R54),(B1,L1,A5,R55),(B1,L1,A5,R56),(B1,L2,A1,R51),(B1,L2,A1,R52),(B1,L2,A1,R53),(B1,L2,A1,R54),(B1,L2,A1,R55),(B1,L2,A1,R56),(B1,L2,A2,R51),(B1,L2,A2,R52),(B1,L2,A2,R53),(B1,L2,A2,R54),(B1,L2,A2,R55),(B1,L2,A2,R56),(B1,L2,A3,R51),(B1,L2,A3,R52),(B1,L2,A3,R53),(B1,L2,A3,R54),(B1,L2,A3,R55),(B1,L2,A3,R56),(B1,L2,A4,R51),(B1,L2,A 4,R52),(B1,L2,A4,R53),(B1,L2,A4,R54),(B1,L2,A4,R55),(B1,L2,A4,R56),(B1,L2,A5,R51),(B1,L2,A5,R52),(B1,L2,A5,R53),(B1,L2,A5,R54),(B1,L2,A5,R55),(B1,L2,A5,R56),(B1,L3,A1,R51),(B1,L3,A1,R52),(B1,L3,A1,R53),(B1,L3,A1,R54),(B1,L3,A1,R55),(B1,L3,A1,R56),(B1,L3,A2,R51),(B1,L3,A2,R52),(B1,L3,A2,R53),(B1,L3,A2,R54),(B1,L3,A2,R55),(B1,L3,A2,R56),(B1,L3,A3,R51),(B1,L3,A3,R52),(B1,L3,A3,R53),(B1,L3,A3,R54),(B1,L3,A3,R55),(B1,L3,A3,R56),(B1,L3,A4,R51),(B1,L3,A4,R52),(B1,L3,A4,R53),(B1,L3,A4,R54),(B1,L3,A4,R55),(B1,L3,A4,R56),(B1,L3,A5,R51),(B1,L3,A5,R52),(B1,L3,A5,R53),(B1,L3,A5,R54),(B1,L3,A5,R55),(B1,L3,A5,R56),(B1,L4,A1,R51),(B1,L4,A1,R52),(B1,L4,A1,R53),(B1,L4,A1,R54),(B1,L4,A1,R55),(B1,L4,A1,R56),(B1,L4,A2,R51),(B1,L4,A2,R52),(B1,L4,A2,R53),(B1,L4,A2,R54),(B1,L4,A2,R55),(B1,L4,A2,R56),(B1,L4,A3,R51),(B1,L4,A3,R52),(B1,L4,A3,R53),(B1,L4,A3,R54),(B1,L4,A3,R55),(B1,L4,A3,R56),(B1,L4,A4,R51),(B1,L4,A4,R52),(B1,L4,A4,R53),(B1,L4,A4,R54),(B1,L4,A4,R55),(B1,L4,A4,R56),(B1,L4,A5,R51),(B1,L4,A5,R52),(B1,L4,A5,R53),(B1,L4,A5,R54),(B1,L4,A5,R55),(B1,L4,A5,R56),(B1,L5,A1,R51),(B1,L5,A1,R52),(B1,L5,A1,R53),(B1,L5,A1,R54),(B1,L5,A1,R55),(B1,L5,A1,R56),(B1,L5,A2,R51),(B1,L5,A2,R52),(B1,L5,A2,R53),(B1,L5,A2,R54),(B1,L5,A2,R55),(B1,L5,A2,R56),(B1,L5,A3,R51),(B1,L5,A3,R52),(B1,L5,A3,R53),(B1,L5,A3,R54),(B1,L5,A3,R55),(B1,L5,A3,R56),(B1,L5,A4,R51),(B1,L5,A4,R52),(B1,L5,A4,R53),(B1,L5,A4,R54),(B1,L5,A4,R55),(B1,L5,A4,R56),(B1,L5,A5,R51),(B1,L5,A5,R52),(B1,L5,A5,R53),(B1,L5,A5,R54),(B1,L5,A5,R55),(B1,L5,A5,R56),(B2,L1,A1,R51),(B2,L1,A1,R52),(B2,L1,A1,R53),(B2,L1,A1,R54),(B2,L1,A1,R55),(B2,L1,A1,R56),(B2,L1,A2,R51),(B2,L1,A2,R52),(B2,L1,A2,R53),(B2,L1,A2,R54),(B2,L1,A2,R55),(B2,L1,A2,R56),(B2,L1,A3,R51),(B2,L1,A3,R52),(B2,L1,A3,R53),(B2,L1,A3,R54),(B2,L1,A3,R55),(B2,L1,A3,R56),(B2,L1,A4,R51),(B2,L1,A4,R52),(B2,L1,A4,R53),(B2,L1,A4,R54),(B2,L1,A4,R55),(B2,L1,A4,R56),(B2,L1,A5,R51),(B2,L1,A5,R52),(B2,L1,A5,R53),(B2,L1,A5,R54),(B2,L1,A5,R55),(B2,L1,A5,R56),(B2,L2,A1,R51),(B2,L2,A1,R52),(B2,L2,A1,R53),(B2,L2,A1,R54),(B2,L2,A1,R55),(B2,L2,A1,R56),(B2,L2,A2,R51),(B2,L2,A2,R52),(B2,L2,A2,R53),(B2,L2,A2,R54),(B2,L2,A2,R55),(B2,L2,A2,R56),(B2,L 2,A3,R51),(B2,L2,A3,R52),(B2,L2,A3,R53),(B2,L2,A3,R54),(B2,L2,A3,R55),(B2,L2,A3,R56),(B2,L2,A4,R51),(B2,L2,A4,R52),(B2,L2,A4,R53),(B2,L2,A4,R54),(B2,L2,A4,R55),(B2,L2,A4,R56),(B2,L2,A5,R51),(B2,L2,A5,R52),(B2,L2,A5,R53),(B2,L2,A5,R54),(B2,L2,A5,R55),(B2,L2,A5,R56),(B2,L3,A1,R51),(B2,L3,A1,R52),(B2,L3,A1,R53),(B2,L3,A1,R54),(B2,L3,A1,R55),(B2,L3,A1,R56),(B2,L3,A2,R51),(B2,L3,A2,R52),(B2,L3,A2,R53),(B2,L3,A2,R54),(B2,L3,A2,R55),(B2,L3,A2,R56),(B2,L3,A3,R51),(B2,L3,A3,R52),(B2,L3,A3,R53),(B2,L3,A3,R54),(B2,L3,A3,R55),(B2,L3,A3,R56),(B2,L3,A4,R51),(B2,L3,A4,R52),(B2,L3,A4,R53),(B2,L3,A4,R54),(B2,L3,A4,R55),(B2,L3,A4,R56),(B2,L3,A5,R51),(B2,L3,A5,R52),(B2,L3,A5,R53),(B2,L3,A5,R54),(B2,L3,A5,R55),(B2,L3,A5,R56),(B2,L4,A1,R51),(B2,L4,A1,R52),(B2,L4,A1,R53),(B2,L4,A1,R54),(B2,L4,A1,R55),(B2,L4,A1,R56),(B2,L4,A2,R51),(B2,L4,A2,R52),(B2,L4,A2,R53),(B2,L4,A2,R54),(B2,L4,A2,R55),(B2,L4,A2,R56),(B2,L4,A3,R51),(B2,L4,A3,R52),(B2,L4,A3,R53),(B2,L4,A3,R54),(B2,L4,A3,R55),(B2,L4,A3,R56),(B2,L4,A4,R51),(B2,L4,A4,R52),(B2,L4,A4,R53),(B2,L4,A4,R54),(B2,L4,A4,R55),(B2,L4,A4,R56),(B2,L4,A5,R51),(B2,L4,A5,R52),(B2,L4,A5,R53),(B2,L4,A5,R54),(B2,L4,A5,R55),(B2,L4,A5,R56),(B2,L5,A1,R51),(B2,L5,A1,R52),(B2,L5,A1,R53),(B2,L5,A1,R54),(B2,L5,A1,R55),(B2,L5,A1,R56),(B2,L5,A2,R51),(B2,L5,A2,R52),(B2,L5,A2,R53),(B2,L5,A2,R54),(B2,L5,A2,R55),(B2,L5,A2,R56),(B2,L5,A3,R51),(B2,L5,A3,R52),(B2,L5,A3,R53),(B2,L5,A3,R54),(B2,L5,A3,R55),(B2,L5,A3,R56),(B2,L5,A4,R51),(B2,L5,A4,R52),(B2,L5,A4,R53),(B2,L5,A4,R54),(B2,L5,A4,R55),(B2,L5,A4,R56),(B2,L5,A5,R51),(B2,L5,A5,R52),(B2,L5,A5,R53),(B2,L5,A5,R54),(B2,L5,A5,R55),(B2,L5,A5,R56),(B3,L1,A1,R51),(B3,L1,A1,R52),(B3,L1,A1,R53),(B3,L1,A1,R54),(B3,L1,A1,R55),(B3,L1,A1,R56),(B3,L1,A2,R51),(B3,L1,A2,R52),(B3,L1,A2,R53),(B3,L1,A2,R54),(B3,L1,A2,R55),(B3,L1,A2,R56),(B3,L1,A3,R51),(B3,L1,A3,R52),(B3,L1,A3,R53),(B3,L1,A3,R54),(B3,L1,A3,R55),(B3,L1,A3,R56),(B3,L1,A4,R51),(B3,L1,A4,R52),(B3,L1,A4,R53),(B3,L1,A4,R54),(B3,L1,A4,R55),(B3,L1,A4,R56),(B3,L1,A5,R51),(B3,L1,A5,R52),(B3,L1,A5,R53),(B3,L1,A5,R54),(B3,L1,A5,R55),(B3,L1,A5,R56),(B3,L2,A1,R51),(B3,L2,A1,R52),(B3,L2,A1,R53),(B3,L2,A1,R54),(B3,L2,A1,R55),(B 3,L2,A1,R56),(B3,L2,A2,R51),(B3,L2,A2,R52),(B3,L2,A2,R53),(B3,L2,A2,R54),(B3,L2,A2,R55),(B3,L2,A2,R56),(B3,L2,A3,R51),(B3,L2,A3,R52),(B3,L2,A3,R53),(B3,L2,A3,R54),(B3,L2,A3,R55),(B3,L2,A3,R56),(B3,L2,A4,R51),(B3,L2,A4,R52),(B3,L2,A4,R53),(B3,L2,A4,R54),(B3,L2,A4,R55),(B3,L2,A4,R56),(B3,L2,A5,R51),(B3,L2,A5,R52),(B3,L2,A5,R53),(B3,L2,A5,R54),(B3,L2,A5,R55),(B3,L2,A5,R56),(B3,L3,A1,R51),(B3,L3,A1,R52),(B3,L3,A1,R53),(B3,L3,A1,R54),(B3,L3,A1,R55),(B3,L3,A1,R56),(B3,L3,A2,R51),(B3,L3,A2,R52),(B3,L3,A2,R53),(B3,L3,A2,R54),(B3,L3,A2,R55),(B3,L3,A2,R56),(B3,L3,A3,R51),(B3,L3,A3,R52),(B3,L3,A3,R53),(B3,L3,A3,R54),(B3,L3,A3,R55),(B3,L3,A3,R56),(B3,L3,A4,R51),(B3,L3,A4,R52),(B3,L3,A4,R53),(B3,L3,A4,R54),(B3,L3,A4,R55),(B3,L3,A4,R56),(B3,L3,A5,R51),(B3,L3,A5,R52),(B3,L3,A5,R53),(B3,L3,A5,R54),(B3,L3,A5,R55),(B3,L3,A5,R56),(B3,L4,A1,R51),(B3,L4,A1,R52),(B3,L4,A1,R53),(B3,L4,A1,R54),(B3,L4,A1,R55),(B3,L4,A1,R56),(B3,L4,A2,R51),(B3,L4,A2,R52),(B3,L4,A2,R53),(B3,L4,A2,R54),(B3,L4,A2,R55),(B3,L4,A2,R56),(B3,L4,A3,R51),(B3,L4,A3,R52),(B3,L4,A3,R53),(B3,L4,A3,R54),(B3,L4,A3,R55),(B3,L4,A3,R56),(B3,L4,A4,R51),(B3,L4,A4,R52),(B3,L4,A4,R53),(B3,L4,A4,R54),(B3,L4,A4,R55),(B3,L4,A4,R56),(B3,L4,A5,R51),(B3,L4,A5,R52),(B3,L4,A5,R53),(B3,L4,A5,R54),(B3,L4,A5,R55),(B3,L4,A5,R56),(B3,L5,A1,R51),(B3,L5,A1,R52),(B3,L5,A1,R53),(B3,L5,A1,R54),(B3,L5,A1,R55),(B3,L5,A1,R56),(B3,L5,A2,R51),(B3,L5,A2,R52),(B3,L5,A2,R53),(B3,L5,A2,R54),(B3,L5,A2,R55),(B3,L5,A2,R56),(B3,L5,A3,R51),(B3,L5,A3,R52),(B3,L5,A3,R53),(B3,L5,A3,R54),(B3,L5,A3,R55),(B3,L5,A3,R56),(B3,L5,A4,R51),(B3,L5,A4,R52),(B3,L5,A4,R53),(B3,L5,A4,R54),(B3,L5,A4,R55),(B3,L5,A4,R56),(B3,L5,A5,R51),(B3,L5,A5,R52),(B3,L5,A5,R53),(B3,L5,A5,R54),(B3,L5,A5,R55),(B3,L5,A5,R56),(B4,L1,A1,R51),(B4,L1,A1,R52),(B4,L1,A1,R53),(B4,L1,A1,R54),(B4,L1,A1,R55),(B4,L1,A1,R56),(B4,L1,A2,R51),(B4,L1,A2,R52),(B4,L1,A2,R53),(B4,L1,A2,R54),(B4,L1,A2,R55),(B4,L1,A2,R56),(B4,L1,A3,R51),(B4,L1,A3,R52),(B4,L1,A3,R53),(B4,L1,A3,R54),(B4,L1,A3,R55),(B4,L1,A3,R56),(B4,L1,A4,R51),(B4,L1,A4,R52),(B4,L1,A4,R53),(B4,L1,A4,R54),(B4,L1,A4,R55),(B4,L1,A4,R56),(B4,L1,A5,R51),(B4,L1,A5,R52),(B4,L1,A5,R53),(B4,L1,A5,R54) ,(B4,L1,A5,R55),(B4,L1,A5,R56),(B4,L2,A1,R51),(B4,L2,A1,R52),(B4,L2,A1,R53),(B4,L2,A1,R54),(B4,L2,A1,R55),(B4,L2,A1,R56),(B4,L2,A2,R51),(B4,L2,A2,R52),(B4,L2,A2,R53),(B4,L2,A2,R54),(B4,L2,A2,R55),(B4,L2,A2,R56),(B4,L2,A3,R51),(B4,L2,A3,R52),(B4,L2,A3,R53),(B4,L2,A3,R54),(B4,L2,A3,R55),(B4,L2,A3,R56),(B4,L2,A4,R51),(B4,L2,A4,R52),(B4,L2,A4,R53),(B4,L2,A4,R54),(B4,L2,A4,R55),(B4,L2,A4,R56),(B4,L2,A5,R51),(B4,L2,A5,R52),(B4,L2,A5,R53),(B4,L2,A5,R54),(B4,L2,A5,R55),(B4,L2,A5,R56),(B4,L3,A1,R51),(B4,L3,A1,R52),(B4,L3,A1,R53),(B4,L3,A1,R54),(B4,L3,A1,R55),(B4,L3,A1,R56),(B4,L3,A2,R51),(B4,L3,A2,R52),(B4,L3,A2,R53),(B4,L3,A2,R54),(B4,L3,A2,R55),(B4,L3,A2,R56),(B4,L3,A3,R51),(B4,L3,A3,R52),(B4,L3,A3,R53),(B4,L3,A3,R54),(B4,L3,A3,R55),(B4,L3,A3,R56),(B4,L3,A4,R51),(B4,L3,A4,R52),(B4,L3,A4,R53),(B4,L3,A4,R54),(B4,L3,A4,R55),(B4,L3,A4,R56),(B4,L3,A5,R51),(B4,L3,A5,R52),(B4,L3,A5,R53),(B4,L3,A5,R54),(B4,L3,A5,R55),(B4,L3,A5,R56),(B4,L4,A1,R51),(B4,L4,A1,R52),(B4,L4,A1,R53),(B4,L4,A1,R54),(B4,L4,A1,R55),(B4,L4,A1,R56),(B4,L4,A2,R51),(B4,L4,A2,R52),(B4,L4,A2,R53),(B4,L4,A2,R54),(B4,L4,A2,R55),(B4,L4,A2,R56),(B4,L4,A3,R51),(B4,L4,A3,R52),(B4,L4,A3,R53),(B4,L4,A3,R54),(B4,L4,A3,R55),(B4,L4,A3,R56),(B4,L4,A4,R51),(B4,L4,A4,R52),(B4,L4,A4,R53),(B4,L4,A4,R54),(B4,L4,A4,R55),(B4,L4,A4,R56),(B4,L4,A5,R51),(B4,L4,A5,R52),(B4,L4,A5,R53),(B4,L4,A5,R54),(B4,L4,A5,R55),(B4,L4,A5,R56),(B4,L5,A1,R51),(B4,L5,A1,R52),(B4,L5,A1,R53),(B4,L5,A1,R54),(B4,L5,A1,R55),(B4,L5,A1,R56),(B4,L5,A2,R51),(B4,L5,A2,R52),(B4,L5,A2,R53),(B4,L5,A2,R54),(B4,L5,A2,R55),(B4,L5,A2,R56),(B4,L5,A3,R51),(B4,L5,A3,R52),(B4,L5,A3,R53),(B4,L5,A3,R54),(B4,L5,A3,R55),(B4,L5,A3,R56),(B4,L5,A4,R51),(B4,L5,A4,R52),(B4,L5,A4,R53),(B4,L5,A4,R54),(B4,L5,A4,R55),(B4,L5,A4,R56),(B4,L5,A5,R51),(B4,L5,A5,R52),(B4,L5,A5,R53),(B4,L5,A5,R54),(B4,L5,A5,R55),(B4,L5,A5,R56),(B5,L1,A1,R51),(B5,L1,A1,R52),(B5,L1,A1,R53),(B5,L1,A1,R54),(B5,L1,A1,R55),(B5,L1,A1,R56),(B5,L1,A2,R51),(B5,L1,A2,R52),(B5,L1,A2,R53),(B5,L1,A2,R54),(B5,L1,A2,R55),(B5,L1,A2,R56),(B5,L1,A3,R51),(B5,L1,A3,R52),(B5,L1,A3,R53),(B5,L1,A3,R54),(B5,L1,A3,R55),(B5,L1,A3,R56),(B5,L1,A4,R51),(B5,L1,A4,R52),(B5,L1,A4,R 53),(B5,L1,A4,R54),(B5,L1,A4,R55),(B5,L1,A4,R56),(B5,L1,A5,R51),(B5,L1,A5,R52),(B5,L1,A5,R53),(B5,L1,A5,R54),(B5,L1,A5,R55),(B5,L1,A5,R56),(B5,L2,A1,R51),(B5,L2,A1,R52),(B5,L2,A1,R53),(B5,L2,A1,R54),(B5,L2,A1,R55),(B5,L2,A1,R56),(B5,L2,A2,R51),(B5,L2,A2,R52),(B5,L2,A2,R53),(B5,L2,A2,R54),(B5,L2,A2,R55),(B5,L2,A2,R56),(B5,L2,A3,R51),(B5,L2,A3,R52),(B5,L2,A3,R53),(B5,L2,A3,R54),(B5,L2,A3,R55),(B5,L2,A3,R56),(B5,L2,A4,R51),(B5,L2,A4,R52),(B5,L2,A4,R53),(B5,L2,A4,R54),(B5,L2,A4,R55),(B5,L2,A4,R56),(B5,L2,A5,R51),(B5,L2,A5,R52),(B5,L2,A5,R53),(B5,L2,A5,R54),(B5,L2,A5,R55),(B5,L2,A5,R56),(B5,L3,A1,R51),(B5,L3,A1,R52),(B5,L3,A1,R53),(B5,L3,A1,R54),(B5,L3,A1,R55),(B5,L3,A1,R56),(B5,L3,A2,R51),(B5,L3,A2,R52),(B5,L3,A2,R53),(B5,L3,A2,R54),(B5,L3,A2,R55),(B5,L3,A2,R56),(B5,L3,A3,R51),(B5,L3,A3,R52),(B5,L3,A3,R53),(B5,L3,A3,R54),(B5,L3,A3,R55),(B5,L3,A3,R56),(B5,L3,A4,R51),(B5,L3,A4,R52),(B5,L3,A4,R53),(B5,L3,A4,R54),(B5,L3,A4,R55),(B5,L3,A4,R56),(B5,L3,A5,R51),(B5,L3,A5,R52),(B5,L3,A5,R53),(B5,L3,A5,R54),(B5,L3,A5,R55),(B5,L3,A5,R56),(B5,L4,A1,R51),(B5,L4,A1,R52),(B5,L4,A1,R53),(B5,L4,A1,R54),(B5,L4,A1,R55),(B5,L4,A1,R56),(B5,L4,A2,R51),(B5,L4,A2,R52),(B5,L4,A2,R53),(B5,L4,A2,R54),(B5,L4,A2,R55),(B5,L4,A2,R56),(B5,L4,A3,R51),(B5,L4,A3,R52),(B5,L4,A3,R53),(B5,L4,A3,R54),(B5,L4,A3,R55),(B5,L4,A3,R56),(B5,L4,A4,R51),(B5,L4,A4,R52),(B5,L4,A4,R53),(B5,L4,A4,R54),(B5,L4,A4,R55),(B5,L4,A4,R56),(B5,L4,A5,R51),(B5,L4,A5,R52),(B5,L4,A5,R53),(B5,L4,A5,R54),(B5,L4,A5,R55),(B5,L4,A5,R56),(B5,L5,A1,R51),(B5,L5,A1,R52),(B5,L5,A1,R53),(B5,L5,A1,R54),(B5,L5,A1,R55),(B5,L5,A1,R56),(B5,L5,A2,R51),(B5,L5,A2,R52),(B5,L5,A2,R53),(B5,L5,A2,R54),(B5,L5,A2,R55),(B5,L5,A2,R56),(B5,L5,A3,R51),(B5,L5,A3,R52),(B5,L5,A3,R53),(B5,L5,A3,R54),(B5,L5,A3,R55),(B5,L5,A3,R56),(B5,L5,A4,R51),(B5,L5,A4,R52),(B5,L5,A4,R53),(B5,L5,A4,R54),(B5,L5,A4,R55),(B5,L5,A4,R56),(B5,L5,A5,R51),(B5,L5,A5,R52),(B5,L5,A5,R53),(B5,L5,A5,R54),(B5,L5,A5,R55),(B5,L5,A5,R56)。
試驗例 β分泌酶抑制作用之測定
於96穴半域板(黑色板；共星公司製)之各穴注入48.5μl之基質胜肽(Biotin-XSEVNLDAEFRHDSGC-Eu：X=ε-胺基-正己酸、Eu=銪穴狀化合物)溶液，各添加0.5μl之被檢化合物(N,N’-二甲基甲醛溶液)及1μl之重組人類BACE-1(R&D系統公司製)後，於30℃反應3小時。基質胜肽為於Biotin-XSEVNLDAEFRHDSGC(胜肽研究所製)與穴狀化合物TBPCOOH mono SMP(CIS bio國際公司製)反應來合成。基質胜肽之最終濃度為18 nM，重組人類BACE-1之最終濃度為7.4 nM，反應緩衝液採用乙酸鈉緩衝液(50 mM乙酸鈉pH 5.0、0.008% Triton X-100)。反應終了後，令溶解於磷酸緩衝液(150 mM磷酸氫二鉀-磷酸二氫鉀pH 7.0、0.008% Triton X-100、0.8 M KF)之8.0 μg/ml之Streptavidin-XL665(CIS bio國際公司製)各穴各添加50μl，於30℃靜置1小時。其後，令螢光強度(激發波長320 nm，測定波長620 nm及665 nm)用娃拉克1420多標識計數機(Perkin Elmer生命科學公司製)測定。酶活性由各測定波長之計數率(10000 x計數665/計數620)求出，而算出抑制酶活性50%之用量(IC50)。被檢物質之IC50值如下表170。
以下化合物也仿上試驗，IC50值呈100μM以下。 3,4,6,8,12,17,18,30,31,35,36,38,39,42,43,57,61,67,67,71,77,78,80,85,97,99,105,106,113,114,115,117,120,121,125,128,129,130,134,139,144,154,157,159,164,172,175,178,181,182,186,189,200,200,201,204,207,209,211,214,215,216,228,232,240,241,243,243,243,251,255,259,267,,273,275,278,279,281,282,,293,298,299,300,302, 303,307,314,319,321,322,326,328,330,333,335,339,341,344,345,346,348,352,353,357,358,359,359,359,360,361,363,369,370,373,378,380,383,389,390,393,396,397,402,405,406,409,410,413,415,426,442,443,444,451,452,454,456,463,467,469,472,472,479,480,482,482,483,491,493,497,500,501,502,509,511,515,516,517,527,528,532,542,544,549,550,551,558,560,568,569,575,578,584,586,588,591,600,607,608,611,613,618,620,629,634,634,637,643,646,652,657,661,671,677,681,687,691,708,711,719,720,723,725,728,729,730,732,735,743,746,756,758,761,770,775,781,787,788,790,791,792,796,797,802,803,804,808,809,813,816,819,820,824,833,835,836,847,850,861,865,866,871,876,887,893,894,900,905,906,908,910,919,922,928,932,933,935,936,939,941,943,944,946,947,949,959,966,971,984,986,988,990,1004,1005,1007,1009,1013,1020,1028,1034,1039,1046,1055,1062,1063,1069,1074,1077,1084,1089,1096,1099,1108,1109,1114,1124,1125,1131,1140,1142,1145,1147,1148,1150,1164,1165,1172,1174,1184,1185,1193,1211,1217,1221,1237,1241,1243,1255,1256,1257,1258,1261,1263,1264,1265,1266,1268,1269,1270,1271,1272,1274等。
製劑例1
製造含有以下成分之顆粒劑。
令式(I)化合物和乳糖通過60篩孔之篩。令玉米澱粉通過120篩孔之篩。令這些於V型混合機混合。於混合粉末加HPC-L(低粘度羥丙基纖維素)水溶液而捏合，造粒(擠壓造粒 孔徑0.5~1mm)，施行乾燥工程。所得乾燥顆粒以振動篩(12/60篩孔)篩過，得顆粒劑。
製劑例2
製造含有以下之成分之膠嚢充填用顆粒劑。
令式(I)化合物，乳糖通過60篩孔之篩。令玉米澱粉通過120篩孔之篩。混合這些，而於混合粉末添加HPC-L溶液而捏合、造粒、乾燥。所得乾燥顆粒整粒後，其150mg充填於4號硬明膠膠嚢。
製劑例3
製造含有以下之成分之錠劑。
令式(I)化合物、乳糖、微結晶纖維素、CMC-Na(羧甲基纖維素鈉鹽)通過60篩孔之篩而混合。於混合粉末混合硬脂酸鎂，得製錠用混合粉末。令本混合粉末打錠，得150mg之錠劑。
製劑例4
令以下之成分加溫混合後，滅菌作成注射劑。
[產業上之利用可能性]
本發明之化合物可作為由類澱粉β蛋白質之產生、分泌及/或沈著誘發之疾病之治療劑有用之醫藥。

Claims (15)

  1. 一種下式(I)化合物或其製藥容許鹽， (式中環A為可選擇性經選自群組<A>之1至4個的基取代的苯基或可選擇性經選自群組<A>之1或2個的基取代的雜環基；R2a及R2b各自獨立為氫；或C1-C15烷基；R3a及R3b各自獨立為氫；鹵素；可選擇經選自取代基群α之1至3個的基取代的C1-C15烷基；各R3a及各R3b可獨立相異，R5為可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷基；取代基群α：由鹵素、羥基、C1-C15烷氧基、C1-C15烷氧基C1-C15烷氧基、醯基、羧基、C1-C15烷氧基羰基、胺基、醯基胺基、C1-C15烷基胺基、C1-C15烷硫基、胺甲醯基、C1-C15烷基胺甲醯基、羥基C1-C15烷基胺甲醯基、胺磺醯基、C1-C15烷基胺磺醯基、C1-C15烷基亞磺醯基、氰基、硝基、芳基及雜環基組成之群組；群組<A>為下列所示之基：(A)鹵素，及 (B) 環B為可選擇性經選自群組<I>之1至3個的基取代的苯基或可選擇性經選自群組<I>之1至3個的基取代的雜環基)；其中，群組<I>為下列所表示的群組：(a)取代基群α，(b)可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷基，(c)經選自取代基群α之1或2個的基取代的胺基C1-C15烷基，(f)可選擇性經選自取代基群α之1個的基取代的C2-C15烯基，(g)可選擇性經選自取代基群α之1個的基取代的C2-C10炔基，(h)可選擇性經選自取代基群α之1至4個的基取代的C1-C15烷氧基，(i)可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷硫基，(j)經選自取代基群α之1個的基取代的C1-C15烷基胺基，(k)可選擇性經選自取代基群α之1個的基取代的C1-C15烷基磺醯基， (l)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的芳基C1-C15烷氧基羰基，(m)經選自取代基群α之1個的基取代的醯基，(p)可選擇性經選自取代基群α之1或2個的基取代的C1-C15烷基胺磺醯基，(q)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的C3-C10環烷基，(r)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1或2個的基取代的芳基，(s)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的雜環基，(t)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的芳氧基，(v)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的芳硫基，(z)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的芳基C1-C15烷基胺基，(aa)可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的雜環C1-C15烷基胺基，(al)可選擇性經鹵素取代之C1-C10伸烷二氧基，及(am)側氧基；醯基為C1-C10脂肪族醯基、碳環羰基或雜環羰基，碳環為C3-C10環烷、C3-C10環烯、苯、萘、蒽、菲或非芳香族稠合碳環， 芳基為苯基、萘基、蒽基或菲基，非芳香族稠合碳環基為由選自C3-C10環烷基、C3-C10環烯基、或芳基之2個以上的環狀基所稠合的基，雜環為環內具有1至3個任意選自O、S及N的雜原子之雜環，雜環基為環內具有1至3個任意選自O、S及N的雜原子之雜環基)。
  2. 如申請專利範圍第1項之化合物或其製藥容許鹽，其中R2a為氫原子，且R2b為氫原子。
  3. 如申請專利範圍第1項之化合物或其製藥容許鹽，其中環A為經選自群組<A>之1至4個的基取代的苯基。
  4. 如申請專利範圍第1項之化合物或其製藥容許鹽，其中群組<I>為：(a)取代基群α；(b)可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷基；(h)可選擇性經選自取代基群α之1至4個的基取代的C1-C15烷氧基。
  5. 如申請專利範圍第1項之化合物或其製藥容許鹽，其中環A為 (R9、R10及R11為氫原子或鹵素，G為 其中環B為可選擇性經1至3個選自群組<I>之基取代之苯基或可選擇性經1至3個選自群組<I>之基取代之雜環基)。
  6. 如申請專利範圍第5項之化合物或其製藥容許鹽，其中環B為苯基或雜芳基，其中該苯基或該雜芳基係可選擇性經選自下列基之1至3個的基取代：鹵素、羥基、可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷基；可選擇性經選自取代基群α之1至4個的基取代的C1-C15烷氧基；可選擇性經選自取代基群α之1個的基取代的醯基；胺基；醯基胺基；C1-C15烷基胺基；經選自取代基群α之1個的基取代的C1-C15烷基胺基；可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的芳基C1-C15烷基胺基；可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的雜環C1-C15烷基胺基；氰基；胺甲醯基；C1-C15烷基胺甲醯基；羥基C1-C15烷基胺甲醯基；可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的芳基；可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的碳環氧基；或可選擇性經選自由取代基群α及C1-C15烷基組成之群組之1個的基取代的雜環基；其中雜芳基為吡咯基、咪唑基、吡唑基、吡啶基 、嗒基、嘧啶基、吡基、三唑基、三基、四唑基、異唑基、唑基、二唑基、異噻唑基、噻唑基、噻二唑基、呋喃基、噻吩基、吲哚基、異吲哚基、吲唑基、吲基、異吲哚啉基、喹啉基、異喹啉基、啉基、呔基、喹唑啉基、萘啶基、喹啉基、嘌呤基、喋啶基、苯并咪唑基、苯并三唑基、苯并異唑基、苯并唑基、苯并二唑基、苯并異噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、異苯并呋喃基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、吡唑并吡啶、三唑并吡啶基、咪唑并噻唑基、吡并嗒基、咔唑基、吖啶基、二苯并呋喃基、或咪唑并喹啉基。
  7. 如申請專利範圍第6項之化合物或其製藥容許鹽，其中環B為苯基或雜芳基，其中該苯基或該雜芳基係可選擇性經選自下列基之1至3個的基取代：鹵素、羥基、可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷基；可選擇性經選自取代基群α之1至4個的基取代的C1-C15烷氧基；醯基；胺基；醯基胺基；C1-C15烷基胺基；氰基；胺甲醯基；C1-C15烷基胺甲醯基；芳基；或雜環基。
  8. 如申請專利範圍第1項之化合物或其製藥容許鹽，其中環A為未經取代之苯基。
  9. 如申請專利範圍第1或5項之化合物或其製藥容許鹽， 其中R5為C1-C3烷基。
  10. 如申請專利範圍第1或5項之化合物或其製藥容許鹽，其中R5為甲基。
  11. 如申請專利範圍第1或5項之化合物或其製藥容許鹽，其中R3a及R3b各自獨立為氫原子、或可選擇性經選自取代基群α之1至3個的基取代的C1-C15烷基。
  12. 如申請專利範圍第1或5項之化合物或其製藥容許鹽，其中R3a及R3b皆為氫原子。
  13. 一種類澱粉β蛋白質之產生、分泌及/或沈著所誘發的疾病之治療劑，其特徵為以如申請專利範圍第1至12項中任一項之化合物或其製藥容許鹽為有效成分。
  14. 一種阿滋海默型痴呆之治療、預防及/或症狀改善劑，其特徵為以如申請專利範圍第1至12項中任一項之化合物或其製藥容許鹽為有效成分。
  15. 一種BACE1(β位類澱粉β前體蛋白質裂解酶1，又稱β分泌酶)抑制劑，其係使用如申請專利範圍第1至12項中任一項之化合物或其製藥容許鹽作為有效成分。
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US20090082560A1 (en) 2009-03-26
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