TW200413356A

TW200413356A - Benzofuran compounds

Info

Publication number: TW200413356A
Application number: TW92129917A
Authority: TW
Inventors: Masahiro Sakaitani; Kazunao Masubuchi; Masami Kohchi; Ikumi Hyoudoh; Kohsuke Asoh; Miyuki Asai
Original assignee: Chugai Pharmaceutical Co Ltd
Priority date: 2002-10-28
Filing date: 2003-10-28
Publication date: 2004-08-01
Also published as: WO2004037816A1; AU2003274759A1

Abstract

This invention relates to novel benzofuran compounds of the formula [I], wherein R1 and R2 are as defined in the claims and description, as well as pharmaceutically acceptable salts or solvates thereof, and to pharmaceutical compositions comprising such compounds and to processes for their preparation. The compounds have antitumor activity and are useful for the treatment of cancer.

Description

200413356 (1) 玖、發明說明【發明所屬之技術領域】 *本發明係關於具有抗腫瘤活性之新穎的苯並呋喃化合物，含這些化合物之醫藥組成物，這些化合物在醫療中的用途以及這些化合物之製法。【先前技術】200413356 (1) 发明 Description of the invention [Technical field to which the invention belongs] * The present invention relates to novel benzofuran compounds having antitumor activity, pharmaceutical compositions containing these compounds, the use of these compounds in medicine, and these compounds System of law. [Prior art]

FT酶抑制劑作爲癌症化療藥劑之價値是經由觀察到拉司癌基因之蛋白質產物是細胞膜結合及生物功能法呢基化所需而開始，實際上，許多FT酶抑制劑在多種人類腫瘤細胞系已經顯示生長抑制作用，而且最近其中部份已經在癌症病人展現臨床功效。The value of FT enzyme inhibitors as cancer chemotherapeutics begins by observing that the protein product of ras oncogene is required for cell membrane binding and biological functional farnesylation. In fact, many FT enzyme inhibitors are used in a variety of human tumor cell lines. Growth inhibitory effects have been shown, and recently some of them have shown clinical efficacy in cancer patients.

有趣的是，FT酶抑制劑將阻滯拉司功能之原先假設經由最近的硏究已經證明是無效，現在普遍認爲FT酶抑制劑之生物效應及臨床功效一定是因爲抑制其他蛋白質之法呢基化（Review: Karp J. E·， et al， CurrentInterestingly, the original hypothesis that FT enzyme inhibitors will block the function of ras enzymes has been proven ineffective through recent research. It is now generally believed that the biological effects and clinical efficacy of FT enzyme inhibitors must be due to the inhibition of other proteins Basicization (Review: Karp J. E., et al, Current

Opinion in Oncology， 2001， 13， 470—476) o 經證實約20種小的鍵結細胞膜的GTP結合蛋白質例如 H— Ras、K—Ras、N— Ras、RhoB、RhoE、lamin A、 limin B、Rap 2、HDJ- 2、CENP- E、CENP— F、PxF、 cGMP磷酸二酯酶、磷酸化酶a、磷酸化酶B、酪胺酸磷酸酶、輔導蛋白、視紫貿激酶具有法呢基，且經報導其中許多可作爲分子開關用於調節細胞週期、生長、增生、分化及/或脫隨作用（Review: T am an o i F. et al ， -5- (2) 200413356Opinion in Oncology, 2001, 13, 470-476) o About 20 small GTP-binding proteins such as H-Ras, K-Ras, N-Ras, RhoB, RhoE, lamin A, limin B, Rap 2, HDJ- 2, CENP- E, CENP- F, PxF, cGMP phosphodiesterase, phosphorylase a, phosphorylase B, tyrosine phosphatase, counseling protein, and rhodokinase have farnesyl And it has been reported that many of them can be used as molecular switches to regulate cell cycle, growth, proliferation, differentiation and / or disassociation (Review: Tam an oi F. et al, -5- (2) 200413356

Journal of Cellular Biochemistry 5 200 1， 64 — 70 )。在腫瘤細胞中，部份這些蛋白質之結構性活化作用導致其惡性生長性質’相反地在正常細胞中，此開關機制視經高度調節且發現這些蛋白質主要是結合在其不活化的 GDP結合狀態。 FT酶將含CAAX的蛋白質法呢基化（C. Cys ; a，一種脂肪族胺基酸；X、Ser、Met、Cys、Gin或Ala )，本案發明者在人類基因中鑑定出約400種肽在其C-端有 CAAX四肽序列，且現在使用DNA排列及蛋白質解離（ proteomics )技術在動物模式中硏究哪一種肽在生物效應及功效之間有相關性。【發明內容】Journal of Cellular Biochemistry 5 200 1, 64 — 70). In tumor cells, the structural activation of some of these proteins leads to their malignant growth properties. Conversely, in normal cells, this switch mechanism is highly regulated and it is found that these proteins are mainly bound in their inactive GDP-bound state. FT enzymes farnesylated CAAX-containing proteins (C. Cys; a, an aliphatic amino acid; X, Ser, Met, Cys, Gin, or Ala). The inventors of this case identified about 400 species in human genes The peptide has a CAAX tetrapeptide sequence at its C-terminus, and now uses DNA alignment and proteomics technology to investigate in animal models which peptides have a correlation between biological effects and efficacy. [Summary of the Invention]

本發明之目的是提供更有效的化合物，在哺乳動物中經由抑制法呢基-蛋白質轉移酶（FT酶）用於治療不正常的細胞生長包括癌症，具體地說，本發明係關於式（I )之新穎的苯並呋喃化合物，The object of the present invention is to provide more effective compounds for treating abnormal cell growth including cancer in mammals via the inhibition of farnesyl-protein transferase (FT enzyme). In particular, the present invention relates to formula (I ) A novel benzofuran compound,

mm

Ri R2 其中： R1是一 N 0 2 ; - C N ;或吡啶一 3 —基； R2是氫；鹵基；視需要經各相同或不同的1至3個 -6- (3) (3)200413356 鹵基'一 CN或直鏈或支鏈（Cl—C4)—烷氧基取代之苯基’吼Π定一 3—基；或苯並〔1，3〕二氧茂一 5 —基，及其藥學上可接受的鹽類及溶劑化物。本發明之另一個目的是提供含這些化合物之醫藥組成物’這些化合物在醫療上的用途，特別是治療癌症。本發明之再另一個目的是提供製備這些化合物之方法〇除非另外說明，下列定義是陳述用於說明及定義在本發明文中使用的許多名詞之意義及範圍。名詞”鹵基”係指氟、氯、溴及碘。名詞”烷氧基”係指—Ο — R基，其中R是烷基，一種最多含4個碳原子之直鏈或支鏈烴基，例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基及第三丁氧基。在本發明中，”經取代”係指取代作用可發生在一或多個位置，且除非另外說明，取代基是獨立地選自指定的選擇範圍。 “藥學上可接受的鹽類”係指傳統的酸加成鹽或鹼加成鹽，其保留式（I )化合物之生物效應及性質，且從合適的無毒有機或無機酸或有機或無機鹼形成，樣本酸加成鹽包括衍生自無機酸例如氫氯酸、氫溴酸、氫碘酸、硫酸、胺基磺酸、磷酸及硝酸，及衍生自有機酸例如對甲苯磺酸、水楊酸、甲磺酸 '草酸、琥珀酸、檸檬酸、蘋果酸、乳酸、富馬酸等，樣本鹼加成鹽包括衍生自鉀、鈉、銨及四 (4) (4)200413356 級氫氧化銨例如四甲基氫氧化銨，名詞，’藥學上可接受的鹽類”包括式（Ο化合物之前驅藥。 “藥學上可接受的”例如藥學上可接受的載劑、賦形劑、前驅藥等，係指藥學上可接受且實質上無毒於用藥特定化合物之病人。 “藥學活性代謝物”係指式（I )化合物之藥學上可接受且有效的代謝產物。名詞”前驅藥”係指式（I )化合物其在生理情形下可以轉化或水解成任何式（I)化合物或式（I)化合物之藥學上可接受的鹽類，前驅藥在用藥至病人時可以是無活性，但是在活體內可以轉化成活性的式（I)化合物。式I化合物也可以溶劑化，例如水解化，溶劑化作用可以在製造過程中進行，或發生在例如最初無水的式I化合物之親水性質（水合化）之結果，名詞藥學上可接受的鹽類也包括生理上可接受的溶劑化物。本發明係關於式（I )之新穎的苯並呋喃化合物’及其藥學上可接受的鹽類、前驅藥及溶劑化物。【實施方式】進行本發明之最佳模式本發明係關於式（I)之苯並呋喃化合物’ -8- (5) (5)200413356Ri R2 where: R1 is a N 0 2; -CN; or pyridin 3-yl; R2 is hydrogen; halo; if necessary, 1 to 3 of the same or different -6-(3) (3) 200413356 Halo'-CN or straight-chain or branched (Cl-C4) -alkoxy-substituted phenyl'- 3-diyl group; or benzo [1,3] dioxo- 5-yl, and Pharmaceutically acceptable salts and solvates. Another object of the present invention is to provide a pharmaceutical composition containing these compounds ' These compounds are used medically, especially for treating cancer. Yet another object of the present invention is to provide a method for preparing these compounds. Unless otherwise stated, the following definitions are set forth to illustrate and define the meaning and scope of many terms used in the present invention. The term "halo" refers to fluorine, chlorine, bromine and iodine. The term "alkoxy" refers to a -0-R group, where R is an alkyl group, a straight or branched chain hydrocarbon group containing up to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso Propoxy, n-butoxy, isobutoxy, second butoxy and third butoxy. In the present invention, "substituted" means that the substitution can occur at one or more positions, and unless otherwise specified, the substituents are independently selected from the specified selection range. "Pharmaceutically acceptable salts" refer to traditional acid addition salts or base addition salts, which retain the biological effects and properties of compounds of formula (I), and are derived from suitable non-toxic organic or inorganic acids or organic or inorganic bases Formation, sample acid addition salts include derivatives derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid, and derived from organic acids such as p-toluenesulfonic acid, salicylic acid , Methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. The sample base addition salts include derived from potassium, sodium, ammonium and tetra (4) (4) 200413356 grade ammonium hydroxide such as Tetramethylammonium hydroxide, noun, 'pharmaceutically acceptable salts' includes compounds that are pre-drugs of the formula (0). "Pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, etc. , Refers to a patient that is pharmaceutically acceptable and substantially non-toxic to a particular compound. "Pharmaceutically active metabolites" refers to pharmaceutically acceptable and effective metabolites of a compound of formula (I). The term "prodrug" refers to the formula (I) Compounds in physiological It can be transformed or hydrolyzed into any compound of formula (I) or a pharmaceutically acceptable salt of compound of formula (I). The prodrug may be inactive when administered to a patient, but it can be converted into an active formula in vivo. (I) Compounds. The compounds of the formula I can also be solvated, such as hydrolyzed. The solvation can be carried out during the manufacturing process, or can occur, for example, as a result of the hydrophilic nature (hydration) of the initially anhydrous compound of the formula I. Acceptable salts also include physiologically acceptable solvates. The present invention relates to novel benzofuran compounds of formula (I) and their pharmaceutically acceptable salts, prodrugs, and solvates. Best Mode for Carrying Out the Invention The present invention relates to a benzofuran compound of the formula (I) '-8- (5) (5) 200413356

其中= R1 是一 N〇2; — CN;或 D比 n定—3- 基； R2是氫；鹵基；視需要經各相同或不同的1至3個鹵基、—CN或直鏈或支鏈（CpCd -烷氧基取代之苯基；吼卩定—3 —基；或苯並〔1，3〕二氧茂一 5-基；及其藥學上可接受的鹽類或溶劑化物。在一個較佳的具體實施例中，本發明包括式（I )之苯並咲喃化合物’其中R2是氫、鹵基、苯基、視需要經各相同或不同的1至3個鹵基、一 cn、甲氧基或乙氧基取代之苯基、吡啶一 3-基、或苯並〔丨，3〕二氧茂一5〜基。特別較佳的化合物是式（I )化合物，其中R2是苯基、視需要經各相同或不同的1至3個氟、溴、一 Cn、甲氧基或乙氧基取代之苯基、吡啶一 3—基、或苯並〔1，3 〕二氧茂一 5—基。再更佳的化合物是式（I )化合物，其中r2是3〜氣苯基、4 —氟苯基、3，4一二氟苯基、3，5一二氟苯基、3 一氯苯基、3 -氰基苯基、3 —甲氧基苯基或3_乙氧基苯基。在一個更佳的具體實施例中，本發明包括式（i )化 -9· (6) (6)200413356 合物，其中 R1是_N〇2; — CN;或D比0定一3—基；且 R2是鹵基、苯基、3—氯苯基、3—氯苯基、3—甲氧基苯基、3 -乙氧基苯基、3 —氰基苯基、吡啶一 3 -基、或苯並〔1，3〕二氧茂一 5-基。在另一個較佳的具體實施例中，本發明包括式（I ) 化合物，其中 R1 是一N02 ;且 R2是氫；鹵基；視需要經各相同或不同的1至3個鹵基、—CN或直鏈或支鏈（C!— C4)—烷氧基取代之苯基；吡啶—3 —基；或苯並〔1，3〕二氧茂—5 —基。根據本發明之較佳化合物如下·_ a ) 4一〔胺基—（3 —甲基—3H —咪唑一 4 —基）— (5 —硝基一 7—苯基一苯並咲喃一 2—基）一甲基〕—苯甲腈； b ) 4 一〔胺基—〔7— (3 —甲氧基—苯基）—5 — 硝基—苯並呋喃一 2-基〕一（3 —甲基一 3H —咪唑一 4 — 基）一甲基〕一苯甲腈； c ) 4—〔胺基—（7 —苯並〔1，3〕二氧茂一 5 —基 —5 —硝基一苯並呋喃一 2 —基）—（3 —甲基一 3H —咪唑 —4 一基）一甲基〕一苯甲腈； d ) 4 一〔胺基—〔7- （3 -氟—苯基）_5 —硝基 —苯並呋喃一2 —基〕一（3 -甲基一 3H -咪唑一 4 —基）一甲基〕一苯甲腈； -10- (7) (7)200413356 e) 4一〔胺基一〔7-（3-氰基一苯基）一 5-硝基一苯並呋喃一2—基〕—（3 —甲基—3H —咪唑—4 —基）一甲基〕一苯甲腈； f) 4—〔胺基—〔7— (3 -乙氧基一苯基）—5 —硝基一苯並呋喃一 2-基〕—（3 -甲基—3H —咪唑一 4 —基 )—甲基〕一苯甲腈； g ) 4 —〔胺基—〔7 - （ 3 —氯一苯基）—5 —硝基 —苯並呋喃—2 —基〕—（3 —甲基一 3H —咪唑一 4 —基） —甲基〕一苯甲腈； h ) 4—〔胺基一〔7 - （4 —氟—苯基）一 5 -硝基一苯並呋喃一 2—基〕一（3 —甲基—3H —咪唑一 4一基） —甲基〕一苯甲腈； i ) 4—〔胺基—〔7— (3，5 —二氟一苯基）—5 — 硝基一苯並呋喃—2 —基〕一（3 —甲基一 3H —咪唑—4 一基）_甲基〕一苯甲腈； j ) 4—〔胺基—〔7— (3，4 —二氟—苯基）—5- 硝基一苯並呋喃—2—基〕—（3 —甲基—3H —咪唑—4 — 基）一甲基〕一苯甲腈； k ) 4一〔胺基—（3 -甲基—3H —咪唑—4 —基）— (5—硝基一7—吡啶_3—基一苯並呋喃一 2 —基）一甲基〕一苯甲腈；及 1) 4一〔胺基一（3 -甲基—3H —咪唑一4 —基）— (5—硝基一苯並呋喃一 2 —基）一甲基〕一苯甲腈。在另一個較佳的具體實施例中，本發明包括式（I) -11 - (8) 200413356 化合物，其中 R1是—CN ;且 R2是氫；鹵基；視需要經各相同或不同的1至3個鹵基、—CN或直鏈或支鏈（CpC^)—烷氧基取代之苯基；吼卩定一 3 —基；或苯並〔1，3〕二氧茂—5 —基。根據本發明之較佳苯並呋喃化合物如下： a ) 2—〔胺基一（4 —氰基一苯基）—（3 —甲基—Where = R1 is a No2; —CN; or D is more than n—3-; R2 is hydrogen; halo; if necessary, 1 to 3 halo, —CN or straight chain or — Branched (CpCd-alkoxy-substituted phenyl; hydrazidine-3-yl; or benzo [1,3] dioxocene-5-yl; and pharmaceutically acceptable salts or solvates thereof. In a preferred embodiment, the present invention includes a benzopyran compound of the formula (I) wherein R2 is hydrogen, halo, phenyl, and optionally 1 to 3 halo groups, each cn, methoxy or ethoxy substituted phenyl, pyridin-3-yl, or benzo [丨, 3] dioxocene-5 ~ yl. Particularly preferred compounds are compounds of formula (I), where R2 is Phenyl, optionally substituted with 1 to 3 fluorine, bromine, mono-Cn, methoxy, or ethoxy groups, pyridine-3-yl, or benzo [1,3] dioxy A further 5-yl group. Even more preferred compounds are compounds of formula (I), in which r2 is 3 to 3-phenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3 monochlorophenyl, 3-cyanophenyl , 3-methoxyphenyl or 3-ethoxyphenyl. In a more preferred embodiment, the present invention includes a compound of formula (i)-9 (6) (6) 200413356, wherein R1 Is _N〇2; —CN; or D is 0 to a 3-group; and R2 is halo, phenyl, 3-chlorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3- Ethoxyphenyl, 3-cyanophenyl, pyridin-3-yl, or benzo [1,3] dioxocene-5-yl. In another preferred embodiment, the present invention includes the formula ( I) a compound in which R1 is a NO2; and R2 is hydrogen; a halo group; if necessary, the same or different 1 to 3 halo groups, —CN or a straight or branched chain (C! —C4) —alkoxy Phenyl substituted with phenyl; pyridin-3-yl; or benzo [1,3] dioxo-5-yl. Preferred compounds according to the present invention are as follows: —3H —imidazol — 4-yl) — (5-nitro-7-phenyl-benzopyran-2-yl) -methyl] —benzonitrile; b) 4— [amino group— [7 — (3-methoxy-phenyl) -5 —nitro-benzofuran-2-yl]-(3-methyl 3H-imidazol-4-yl) monomethyl] -benzonitrile; c) 4- [amino- (7-benzo [1,3] dioxocene-5-yl-5-nitro-benzofuran -2 -yl)-(3-methyl- 3H-imidazole-4 -yl) -methyl] -benzonitrile; d) 4-[amino- [7- (3-fluoro-phenyl) _5 — Nitro-benzofuran 2-yl]-(3-methyl- 3H-imidazole-4-yl) monomethyl] -benzonitrile; -10- (7) (7) 200413356 e) 4-one [ Amino- [7- (3-cyano-phenyl) -5-nitro-benzofuran-2-yl]-(3-methyl-3H-imidazol-4-yl) -methyl] -benzene Nitrile; f) 4- [Amino- [7- (3-ethoxy-phenyl) -5-nitro-benzofuran- 2-yl]-(3-methyl-3H-imidazole-4 —Yl) —methyl] monobenzonitrile; g) 4 — [amino— [7-(3-chloro-phenyl) -5—nitro-benzofuran-2-yl] — (3-methyl -3H-imidazole-4-yl) -methyl] -benzonitrile; h) 4- [amino- [7-(4-fluoro-phenyl)-5-nitro Benzofuran-2-yl]-(3-methyl-3H-imidazole-4-yl) -methyl] -benzonitrile; i) 4- [amino- [7- (3,5-difluoro (Monophenyl) -5—nitro-benzofuran-2-yl]-(3-methyl-1HH-imidazol-4-yl) -methyl] -benzonitrile; j) 4— [amino group— [7- (3,4-difluoro-phenyl) -5-nitro-benzofuran-2-yl]-(3-methyl-3H-imidazole-4-yl) -methyl] -benzoyl Nitrile; k) 4- [amino- (3-methyl-3H-imidazol-4-yl)-(5-nitro-7-pyridin-3-yl-benzofuran-2-yl) -methyl ] Benzonitrile; and 1) 4- [amino- (3-methyl-3H-imidazol-4-yl)-(5-nitro-benzofuran 2-yl) -methyl] -benzene Nitrile. In another preferred embodiment, the present invention includes compounds of formula (I) -11-(8) 200413356, wherein R1 is -CN; and R2 is hydrogen; halo; To 3 halo, -CN or linear or branched (CpC ^)-alkoxy substituted phenyl; hydrazone a 3-yl; or benzo [1,3] dioxo-5-yl . The preferred benzofuran compounds according to the present invention are as follows: a) 2- [Amino- (4-cyano-phenyl)-(3-methyl-

3H—咪唑一 4 —基）—甲基〕一 7—苯基一苯並呋喃—5 -甲腈； b ) 2— 〔胺基一（4一氰基—苯基）一（3 —甲基一 3H—咪唑—4 —基）一甲基〕一 7— (3 —甲氧基一苯基） —苯並咲喃一 5 —甲腈； c ) 2— 〔胺基—（4 —氰基一苯基）一（3 —甲基一 3H—咪唑一 4 一基）—甲基〕—7 —苯並〔1，3〕二氧茂一 5 —基—苯並呋喃一 5 —甲腈；3H-imidazole-4-yl) -methyl] -7-phenyl-benzofuran-5-carbonitrile; b) 2- [amino- (4-cyano-phenyl)-(3-methyl -3H-imidazol-4-yl) monomethyl] -7- (3-methoxy-phenyl) -benzopyran-5-carbonitrile; c) 2- [amino group- (4-cyano (Monophenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl] -7-benzo [1,3] dioxocene-5-yl-benzofuran-5-carbonitrile;

d ) 2—〔胺基一（4_氰基一苯基）一（3_甲基— 3H—咪唑一 4一基）一甲基〕一 7—（3 -氟一苯基）—苯並呋喃一 5 —甲腈； e ) 2_ 〔胺基一（4 一氰基一苯基）一（3 —甲基一 3H —味Π坐一4 一基）一甲基〕—7—（3-氯基—苯基）— 苯並呋喃一 5 —甲腈； f) 2-〔胺基_ (4 —氰基一苯基）—（3 —甲基一 3H —咪唑一 4 —基）—甲基〕-7 —（3 -氯—苯基）—苯並呋喃—5 -甲腈；及 -12- (9) (9)200413356 g) 2— 〔胺基一（4 一氰基一苯基）一（3_甲基一 3H —咪唑一4 一基）一甲基〕一 7-吡啶一 3 一基一苯並呋喃一5 —甲腈。在另一^個較佳的具體貫施例中，本發明包括式（I) 化合物，其中 R 1是吡啶一 3 —基；且 R2是氫；鹵基；視需要經各相同或不同的1至3個鹵基、—CN或直鏈或支鏈（Cp C4) 一院氧基取代之苯基；批啶一 3 —基；或苯並〔1，3〕二氧茂一 5—基。根據本發明之較佳苯並呋喃化合物如下： a) 4—〔胺基—〔7-（3-氟一苯基）一 5 — D比卩定一 3 —基一苯並呋喃—2—基〕一（3 —甲基—3H—咪唑一 4 一基）一甲基〕一苯甲腈； b ) 4一〔胺基—（3—甲基一3H —咪唑一 4 —基）一 (7 —苯基—5 — D比[J定一 3—基一苯並咲喃一 2-基）一甲基〕一苯甲腈； c ) 4一〔胺基一〔7—（3 -甲氧基一苯基）一5 —吡 U定一 3 —基一苯並咲喃_2—基〕—（3 —甲基一 3H —咪哗一 4—基）一甲基〕一苯甲腈； d ) 4一〔胺基—（7 —苯並〔1，3〕二氧茂—5 —基 —5 —吡啶—3 —基一苯並呋喃—2 —基）一（3 —甲基— 3H —咪唑一 4 —基）一甲基〕一苯甲腈； e ) 4一〔胺基一〔7-（3-氰基一苯基）—5_D比D定一 3 —基—苯並咲喃一 2-基〕一（3 —甲基一 3H—味13坐一 (10) (10)200413356 4 一基）一甲基〕一苯甲腈； f) 4—〔胺基—〔7— (3 —氯一苯基）_5 — D比π定— 3 —基—苯並咲喃—2 —基〕—（3 —甲基一 3H —咪Π坐—4 一基）一甲基〕—苯甲腈；及 g) 4 - 〔胺基一（5，7 -二吡啶—3 —基—苯並呋喃一 2—基）一（3 —甲基—3H —咪1¾ 一 4 —基）—甲基〕 —苯甲腈。式（I )之苯並呋喃化合物對於多種腫瘤細胞系顯示強烈的抗腫瘤活性，此抗腫瘤活性顯示式（I )化合物及其藥學上可接受的鹽類可作爲抗腫瘤藥劑使用。在另一個具體實施例中，本發明係關於含式（I )之苯並呋喃化合物及藥學上可接受的載劑之醫藥組成物。在另一個具體實施例中，本發明係關於含式（I)之苯並呋喃化合物及化療藥劑之醫藥組成物。根據本發明之醫藥組成物較宜用於治療細胞增生障礙，較宜是癌症，且更宜是結腸直腸癌、肺癌、乳癌、前列腺癌及血癌。式（I)之苯並呋喃化合物是活性對抗多種細胞系包括結腸直腸癌、肺癌、乳癌、前列腺癌及血癌。在另一個具體實施例中，本發明包括式（I)之苯並呋喃化合物用於製備藥劑之用途，尤其是用於製備藥劑供治療細胞增生障礙。更宜根據本發明之用途是用於製備藥劑供治療癌症且最宜是結腸直腸癌、肺癌、乳癌、前列腺癌及血癌。 -14- (11) (11)200413356 對於臨床用途，式（I )之苯並呋喃化合物、其鹽類形式等，可單獨用藥，但是通常是視需要的特定用途及目的，經由混合賦形劑、黏著劑、潤滑劑、分解劑、塗料、乳化劑、懸浮劑、溶劑、安定劑、強化吸收劑及/或軟膏基質，調製成醫藥混合物用藥，此混合物可經由口服、注射、直腸或局部用藥使用。更詳細地說，根據先前所述，含式（I )化合物或其前驅藥之藥劑也是本發明之一個目的，以及生產此藥劑之方法，該方法包括混合一或多種式（I )化合物，且視需要選用一或多種其他有醫療價値的物質成爲用藥形式。本發明也關於在包括人類之哺乳動物中用於抑制不正常細胞生長之醫藥組成物，其含一定量可以有效地抑制法呢基一蛋白質轉移酶（FT酶）之根據上述式（I)之苯並呋喃化合物、或其藥學上可接受的鹽類、前驅藥或溶劑化物，及藥學上可接受的載劑。根據本發明之醫藥組成物含有效醫療量根據上述式（ I)之苯並呋喃化合物、或其藥學上可接受的鹽類、前驅藥或溶劑化物，及藥學上可接受的載劑，且視需要含化療藥劑，在一個具體實施例中，該化療藥劑是選自包括有絲分裂抑制劑、烷基化劑、抗代謝劑、嵌入性抗生素、生長因子抑制劑、細胞週期抑制劑、酶、異構酶抑制劑、生物回應調節劑、抗-荷爾蒙及抗-雄激素。根據本發明之醫藥組成物含一定量式（I)之苯並呋喃衍生物、此化合物之藥學上可接受的鹽類、前驅藥或溶 -15- (12) (12)200413356 劑化物’可以有效地抑制法呢基-蛋白質轉移酶，可用於治療哺乳動物之障礙，例如肺癌、N S C L C (非小細胞肺癌）、骨癌、胰臟癌、皮膚癌、頭及頸癌、皮膚或眼內黑色素癌、子宮癌、卵巢癌、直腸癌、肛門區域之癌症、胃癌、結腸癌、乳癌、女性腫瘤（例如子宮肉瘤、輸卵管之癌症、子宮內膜之癌症、子宮頸之癌症、陰道之癌症或女陰之癌症）、Hodgkin氏症、食管之癌症、小腸之癌症、內分泌系統之癌症（例如甲狀腺、甲狀旁腺或腎上腺之癌症）、軟性組織之癌症、尿道之癌症、陰莖之癌症、前列腺癌、慢性或急性血癌、孩童之固體腫瘤、淋巴細胞淋巴癌、膀胱之癌症、腎臟或輸尿管之癌症（例如腎臟細胞癌、腎盂之癌症）、兒科、惡性腫瘤、中樞神經系統之腫瘤 (例如主要CN S淋巴癌、脊髓腫瘤、腦幹神經膠質瘤或垂體腺瘤）、Barrerr氏食道（惡化前徵候群）、腫瘤性皮膚疾病、牛皮癬、蕈狀肉牙腫、良性前列腺肥大、人類乳頭狀瘤病毒（HPV )及再狹窄。更具體地說，根據本發明之醫藥組成物可用於治療結腸直腸癌、肺癌、乳癌、前列腺癌及血癌。該醫藥組成物可以口服用藥，例如以片劑、包衣片劑、糖衣片、硬或軟明膠膠囊劑、溶液、乳液或懸浮液之形式，也可進行直腸用藥，例如使用栓劑；局部或經皮用藥 ’例如使用軟膏、乳膏、膠體或溶液；或不經腸道用藥，例如使用注射溶液。對於片劑、包衣片劑、糖衣片或硬明膠膠囊劑之製備 -16 - (13) (13)200413356 ，本發明化合物可以與藥學上惰性的無機或有機賦形劑混合，用於片劑、糖衣片或硬明膠膠囊劑之合適賦形劑實例包括乳糖、玉米澱粉或其衍生物、滑石或硬脂酸或其鹽類〇使用於軟明膠膠囊劑之合適賦形劑包括例如植物油' 蠟、脂肪、半固體或液體多元醇類等，根據活性成份之本質，軟明膠膠囊劑可以實際上完全不需要賦形劑。對於溶液及漿劑之製備，可以使用的賦形劑包括例如水、多元醇類、蔗糖、反轉糖及葡萄糖。對於注射溶液，可以使用的賦形劑包括例如水、醇類、多元醇類、甘油、及植物油。對於栓劑、及局部或經皮應用，可以使用的賦形劑包括例如天然或硬化油類、蠟、脂肪及半固體或液體多元醇類。該醫藥組成物也可含防腐劑、溶解劑、安定劑、淫化劑、乳化劑、甜化劑、染劑、改變滲透壓之鹽類、緩衝劑、塗覆劑或抗氧化劑，其也可含其他有價値的醫療藥劑。總而言之，口服用藥之醫藥調製物可以是粒劑、片劑、糖衣片劑、膠囊劑、九劑、懸浮液或乳液，不經腸道注射例如靜脈內、肌肉內或皮下之醫藥調製物可以使用無菌水溶液之形式，其可含其他物質例如鹽類或葡萄糖使溶液等滲化，該抗腫瘤藥劑也可在栓劑或陰道栓劑之形式使用 ’或在洗劑、溶液、乳液、軟膏或撲粉之形式局部使用。當經由口服或不經腸道途徑用藥時，式（I )之苯並 -17- (14) (14)200413356 呋喃化合物之每日劑量是從5至2，000毫克/平方米，據此片劑或膠囊劑可含從5毫克至1，000毫克之活性化合物供單獨用藥或視需要每次二或多份，在任何情形下，實際的劑量是決定於特定病人之體重及回應。本發明也關於治療細胞增生障礙之方法，包括將有效醫療量式（I)之苯並呋喃化合物用藥至對其有需要之病人，具體地說，本發明係關於治療癌症之方法，更確定地說，是治療結腸直腸癌、肺癌、乳癌、前列腺癌及血癌。本發明也關於在包括人類之哺乳動物中抑制不正常細胞生長包括癌症之方法，其包括將可有效地抑制法呢基-蛋白質轉移酶（FT酶）的量之根據上述定義式（I)之苯並呋喃化合物或其藥學上可接受的鹽類、前驅藥或溶劑化物用藥至該哺乳動物。本發明也關於在包括人類之哺乳動物中抑制不正常細胞生長包括癌症之方法，其包括將可有效地抑制不正常細胞生長的量之根據上述定義式（I)之苯並呋喃化合物或其藥學上可接受的鹽類、前驅藥或溶劑化物用藥至該哺乳動物。本發明也關於在包括人類之哺乳動物中抑制不正常細胞生長包括癌症之方法，其包括將結合化療藥劑之有效量根據上述定義式（I)之苯並呋喃化合物或其藥學上可接受的鹽類、前驅藥或溶劑化物用藥至該哺乳動物，在一個具體實施例中，該化療藥劑是選自包括有絲分裂抑制劑、烷基化劑、抗代謝劑、嵌入性抗生素、生長因子抑制劑、 -18- (15) (15)200413356 細胞週期抑制劑、酶、異構酶抑制劑、生物回應調節劑、抗一荷爾蒙及抗-雄激素。本發明還關於在包括人類之哺乳動物中抑制不正常細胞生長包括癌症之方法，其包括將結合放射性治療之有效量根據上述定義式（I)之苯並呋喃化合物或其藥學上可接受的鹽類、前驅藥或溶劑化物用藥至該哺乳動物，其中該式（I )之苯並呋喃化合物、鹽、前驅藥或溶劑化物之量是結合放射性治療，可在哺乳動物中有效地抑制不正常細胞生長，放射性治療之技術已知於此項技藝，且這些技術可以在本文揭示的組合醫療中使用，本發明化合物在此組合醫療中的用藥可根據本文之揭示決定。式（I)之苯並呋喃化合物可使不正常細胞更敏化於放射線治療’供殺死及/或抑制此細胞生長之目的，據此，本發明還關於在哺乳動物中敏化不正常細胞供放射線治療之方法’其包括將一定量式（I)之苯並咲喃化合物或其藥學上可接受的鹽類、前驅藥或溶劑化物用藥至該哺乳動物，該量可以有效地敏化不正常細胞供放射線治療，在此方法中的化合物、鹽、前驅藥或溶劑化物之量，可以根據本文揭示探查此化合物有效量之方法決定。本發明式（I )之苯並呋喃化合物可經由下列方法製造：一種用於製造式〔I〕之苯並呋喃化合物之方法， -19- (16 200413356d) 2- [Amino- (4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -7- (3-fluoro-phenyl) -benzo Furan-5-carbonitrile; e) 2_ [Amino- (4-cyano-phenyl)-(3-methyl-3H-amidine, 4-4-yl) -methyl] -7- (3- Chloro-phenyl) -benzofuran-5-carbonitrile; f) 2- [amino_ (4-cyano-phenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl Group] -7- (3-chloro-phenyl) -benzofuran-5-carbonitrile; and -12- (9) (9) 200413356 g) 2- [aminomono (4-cyanomonophenyl )-(3-methyl- 3H-imidazole- 4-yl) -methyl]-7-pyridine- 3 -yl-benzofuran- 5 -carbonitrile. In another preferred embodiment, the present invention includes a compound of formula (I), wherein R 1 is pyridin-3-yl; and R 2 is hydrogen; halo; To 3 halo, —CN or straight or branched (Cp C4) monooxy substituted phenyl; pyridin 3-yl; or benzo [1,3] dioxo-5—yl. The preferred benzofuran compounds according to the present invention are as follows: a) 4- [Amino- [7- (3-fluoro-phenyl) -5-D than pyridine- 3-yl-benzofuran-2-yl ]-(3-methyl-3H-imidazol-4-yl) -methyl] -benzonitrile; b) 4- [amino- (3-methyl-3H-imidazol 4-yl)-(7 —Phenyl-5 — D ratio [J fixed a 3-yl-benzopyran- 2-yl) -methyl] -benzonitrile; c) 4- [amino- [7- (3-methoxy A phenyl group) a 5-pyridine group, a 3-yl group, a benzopyran-2-yl group, a 3-methyl group, a 3H-imido group, a 4-methyl group, a methyl group, and a benzonitrile group; d) 4- [Amino- (7-benzo [1,3] dioxo-5-yl-5-pyridine-3-yl-benzofuran-2-yl)-(3-methyl-3H —Imidazole—4-yl) -methyl] —benzonitrile; e) 4— [amino— [7- (3-cyano-phenyl) —5—D than D—A—3-yl—benzopyran -2-yl]-(3-methyl- 3H-taste 13- (1)-(10) (10) 200413356 4 1-yl) -methyl] -benzonitrile; f) 4- [amino- [7 — (3-chloro-phenyl) _5 —D ratio π- 3 —yl-benzopyran-2-yl] — (3-methyl- 3H —imidyl-4-4-yl) -methyl] —Benzonitrile; and g) 4-[aminomono (5,7-dipyridine-3-yl-benzofuran-2-yl)-(3-methyl-3H-imid 1¾-4-yl) —Methyl] —benzonitrile. The benzofuran compound of the formula (I) shows strong antitumor activity against various tumor cell lines. This antitumor activity shows that the compound of the formula (I) and its pharmaceutically acceptable salts can be used as antitumor agents. In another embodiment, the present invention relates to a pharmaceutical composition comprising a benzofuran compound of formula (I) and a pharmaceutically acceptable carrier. In another embodiment, the present invention relates to a pharmaceutical composition containing a benzofuran compound of formula (I) and a chemotherapeutic agent. The pharmaceutical composition according to the present invention is more suitable for treating a cell proliferative disorder, more preferably cancer, and more preferably colorectal cancer, lung cancer, breast cancer, prostate cancer, and blood cancer. Benzofuran compounds of formula (I) are active against a variety of cell lines including colorectal, lung, breast, prostate and blood cancers. In another specific embodiment, the invention includes the use of a benzofuran compound of formula (I) for the preparation of a medicament, especially for the preparation of a medicament for the treatment of a cell proliferative disorder. More preferably the use according to the invention is for the preparation of a medicament for the treatment of cancer and most preferably colorectal, lung, breast, prostate and blood cancers. -14- (11) (11) 200413356 For clinical use, the benzofuran compound of formula (I), its salt form, etc. can be used alone, but it is usually a specific use and purpose as needed, via mixed excipients , Adhesives, lubricants, disintegrating agents, coatings, emulsifiers, suspending agents, solvents, stabilizers, fortifying absorbers and / or ointment bases, formulated into pharmaceutical mixtures, which can be administered orally, by injection, rectal or topically use. In more detail, according to the foregoing, a medicament containing a compound of formula (I) or a prodrug thereof is also an object of the present invention, and a method for producing the medicament, which method comprises mixing one or more compounds of formula (I), and Select one or more other medically valuable substances as the medication form as needed. The present invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in mammals including humans, which contains a certain amount according to the above formula (I) that can effectively inhibit farnesyl-protein transferase (FT enzyme). Benzofuran compounds, or pharmaceutically acceptable salts, prodrugs or solvates thereof, and pharmaceutically acceptable carriers. The pharmaceutical composition according to the present invention contains an effective medical amount of the benzofuran compound according to the above formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, and A chemotherapeutic agent is required. In a specific embodiment, the chemotherapeutic agent is selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, an embedded antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, an isomer Enzyme inhibitors, biological response modifiers, anti-hormones and anti-androgens. The pharmaceutical composition according to the present invention contains a certain amount of a benzofuran derivative of the formula (I), a pharmaceutically acceptable salt of the compound, a prodrug, or a soluble -15- (12) (12) 200413356 formulation. Effectively inhibits farnesyl-protein transferase and can be used to treat mammalian disorders such as lung cancer, NSCLC (non-small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanin Cancer, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal area, stomach cancer, colon cancer, breast cancer, female tumors (such as uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer or female Cancer of the yin), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (such as cancer of the thyroid, parathyroid or adrenal glands), cancer of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer , Chronic or acute blood cancer, solid tumors in children, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter (e.g. renal cell carcinoma, renal pelvis Cancer), pediatrics, malignant tumors, tumors of the central nervous system (such as major CNS lymphoma, spinal tumors, brain stem gliomas or pituitary adenomas), Barrerr's esophagus (pre-deterioration syndrome), neoplastic skin diseases , Psoriasis, mycosis, benign prostatic hypertrophy, human papilloma virus (HPV), and restenosis. More specifically, the pharmaceutical composition according to the present invention can be used to treat colorectal cancer, lung cancer, breast cancer, prostate cancer, and blood cancer. The medicinal composition can be administered orally, such as in the form of tablets, coated tablets, sugar-coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions, and can also be administered rectally, such as using suppositories; topically or via Dermal medications' such as the use of ointments, creams, colloids or solutions; or parenteral medications such as the use of injectable solutions. For the preparation of tablets, coated tablets, sugar-coated tablets or hard gelatin capsules -16-(13) (13) 200413356, the compounds of the present invention can be mixed with pharmaceutically inert inorganic or organic excipients for use in tablets Examples of suitable excipients for sugar-coated tablets or hard gelatin capsules include lactose, corn starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes , Fat, semi-solid or liquid polyols, etc., depending on the nature of the active ingredient, soft gelatin capsules may practically not require excipients at all. For the preparation of solutions and slurries, excipients which can be used include, for example, water, polyols, sucrose, invert sugar and glucose. For injectable solutions, excipients that can be used include, for example, water, alcohols, polyols, glycerol, and vegetable oils. For suppositories, and topical or transdermal applications, excipients that can be used include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols. The pharmaceutical composition may also contain preservatives, solubilizers, stabilizers, ecstatics, emulsifiers, sweeteners, dyes, osmotic pressure-changing salts, buffers, coating agents, or antioxidants. Contains other valuable medical medicaments. All in all, pharmaceutical preparations for oral administration can be granules, tablets, sugar-coated tablets, capsules, nine doses, suspensions or emulsions. Parenteral injections such as intravenous, intramuscular or subcutaneous pharmaceutical preparations can be used In the form of a sterile aqueous solution, which may contain other substances such as salts or glucose to make the solution isotonic, the antitumor agent can also be used as a suppository or vaginal suppository 'or in the form of a lotion, solution, emulsion, ointment or dusting powder. For local use. When administered orally or parenterally, the daily dose of benzo-17- (14) (14) 200413356 of the formula (I) is from 5 to 2,000 mg / m2, according to this tablet Dosages or capsules may contain from 5 mg to 1,000 mg of the active compound for single use or two or more servings as needed. In any case, the actual dose depends on the weight and response of the particular patient. The present invention also relates to a method for treating a cell proliferation disorder, comprising administering an effective medical amount of a benzofuran compound of formula (I) to a patient in need thereof. Specifically, the present invention relates to a method for treating cancer. It is said to treat colorectal cancer, lung cancer, breast cancer, prostate cancer and blood cancer. The present invention also relates to a method for inhibiting abnormal cell growth, including cancer, in mammals including humans, which comprises reducing the amount of farnesyl-protein transferase (FT enzyme) effective according to the above-defined formula (I) A benzofuran compound or a pharmaceutically acceptable salt, prodrug or solvate thereof is administered to the mammal. The present invention also relates to a method for inhibiting abnormal cell growth, including cancer, in mammals including humans, which comprises adding a benzofuran compound of formula (I) according to the above definition to an amount effective to inhibit abnormal cell growth, or a medicament thereof An acceptable salt, prodrug or solvate is administered to the mammal. The present invention also relates to a method for inhibiting abnormal cell growth, including cancer, in mammals including humans, which comprises combining an effective amount of a chemotherapeutic agent with a benzofuran compound of formula (I) according to the above definition, or a pharmaceutically acceptable salt thereof Class, prodrug or solvate to the mammal. In a specific embodiment, the chemotherapeutic agent is selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, an embedded antibiotic, a growth factor inhibitor,- 18- (15) (15) 200413356 Cell cycle inhibitors, enzymes, isomerase inhibitors, biological response regulators, anti-hormones and anti-androgens. The present invention also relates to a method for inhibiting abnormal cell growth, including cancer, in mammals including humans, which comprises combining an effective amount of a benzofuran compound of formula (I) or a pharmaceutically acceptable salt thereof according to the above definition with radiotherapy Drugs, prodrugs or solvates to the mammal, wherein the amount of the benzofuran compound, salt, prodrug or solvate of formula (I) is combined with radiotherapy, which can effectively inhibit abnormal cells in mammals Techniques for growth and radiation therapy are known in the art, and these techniques can be used in the combination medicine disclosed herein. The use of the compound of the present invention in this combination medicine can be determined according to the disclosure herein. The benzofuran compound of formula (I) can make abnormal cells more sensitized to radiation therapy for the purpose of killing and / or inhibiting the growth of the cells. Accordingly, the present invention also relates to sensitizing abnormal cells in mammals. Method for radiation therapy ', which comprises administering to the mammal a certain amount of a benzopyran compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof, which amount can effectively sensitize the Normal cells are used for radiation treatment, and the amount of compound, salt, prodrug or solvate in this method can be determined according to the method disclosed herein to explore the effective amount of this compound. The benzofuran compound of formula (I) of the present invention can be prepared by the following method: A method for producing a benzofuran compound of formula [I], -19- (16 200413356

其中R1及R2是相同於上述之定義，其包括用酸性化合物將式〔VII〕化合物4 一〔 2 —甲基一 2-丙亞磺醯胺一苯並呋喃一 2 —基一（3-甲基—3H 一咪唑一 4一基）一甲基〕一苯甲腈之2 —甲基一 2 —丙亞磺醯基解離，Wherein R1 and R2 are the same as the above definitions, and include the use of an acidic compound to form a compound of the formula [VII] 4-[2-methyl-2-propanesulfenamidine-benzofuran-2-yl-(3-methyl -3H-imidazole-4-yl) -methyl] -benzonitrile dissociation of 2-methyl-2 2-propenylsulfinyl,

R1 [VII] 其中R1及R2是相同於上述之定義。另外，本發明包括用於製造式〔VII〕化合物4 一〔 2 甲基一 2 —丙亞磺釀胺一苯並咲喃一 2 —基一（3 —甲基 3H —咪唑一 4一基）一甲基〕一苯甲腈之方法，R1 [VII] wherein R1 and R2 are the same as defined above. In addition, the present invention includes a compound for formula [VII] for preparing 4- [2-methyl-2-propanesulfenamide-benzopyran- 2-yl- (3-methyl 3H-imidazole 4-diyl) Monomethyl] -benzonitrile method,

ri [vii] 其中R1及R2是相同於上述之定義，其包括用式〔VIII〕化合物1 一甲基一 2 -三乙基矽烷基—1H —咪唑—5 —鋰， -20- [VIII] (17) 200413356ri [vii] wherein R1 and R2 are the same as defined above, which includes the use of a compound of the formula [VIII] 1-methyl-2-triethylsilyl-1H—imidazole-5—lithium, -20- [VIII] (17) 200413356

烷基化式〔v〕化合物2 —甲基一丙烷一 2 -亞磺酸苯並呋喃—2—基一（4 一氰基一苯基）—亞甲醯胺，Alkylating a compound of formula [v] 2-methyl monopropane 2- 2-sulfinyl benzofuran-2-yl- (4-cyano-phenyl) -methylenesulfonamide,

[V][V]

其中R1及R2是相同於上述之定義。本發明之另一個目的是製造式〔V〕化合物2-甲基一丙院一 2 -亞磺酸苯並咲喃一 2-基一（4 一氰基—苯基 )一亞甲醯胺之方法，Where R1 and R2 are the same as defined above. Another object of the present invention is to produce a compound of the formula [V], 2-methyl-one-propanone- 2-sulfinyl benzopyran- 2-yl- (4-cyano-phenyl) -methyleneamine method,

其中R1及R2是相同於上述之定義，其包括將式〔II〕化合物4一（苯並呋喃一 2-羰基） —苯甲腈，Wherein R1 and R2 are the same as the above definitions, and include the compound of formula [II] 4- (benzofuran-2-carbonyl) -benzonitrile,

其中R1及R2是相同於上述之定義， -21 - (18) 200413356 與2—甲基—2 —丙亞磺醯胺〔VI〕，〇Where R1 and R2 are the same as the above definitions, -21-(18) 200413356 and 2-methyl-2-propanesulfenamide [VI], 〇

II >[^S、NH2 [VI] 在路易士酸性脫水劑存在下縮合。本發明還關於製造式〔II〕化合物4一（苯並咲喃- 2 一羰基）一苯甲腈之方法， 0II > [^ S, NH2 [VI] Condensation in the presence of a Lewis acid dehydrating agent. The present invention also relates to a method for producing a compound of formula [II] 4- (benzobenzo- 2 -carbonyl) -benzonitrile, 0

其中R1及R2是相同於上述之定義，其包括將式〔III〕化合物2 -羥基苯甲醛，Wherein R1 and R2 are the same as the above definitions, and include the compound 2-hydroxybenzaldehyde of formula [III],

其中R1及R2是相同於上述之定義，與式〔IV〕之4 —氰基苯甲醯甲基鹵，Where R1 and R2 are the same as defined above, and 4-cyanobenzyl methyl halide of formula [IV],

其中X是鹵基，在鹼性化合物存在下縮合。下列實例說明製備本發明化合物之較佳方法，其不能用於限制本發明之範圍。除非另外說明’化合物之物理數據是記錄成碳原子對 -22· (19) (19)200413356 掌中心之非對掌異構物之混合物。除非另外說明，各化合物在LCMS之滯留時間是使用下列方法記錄。情形A : 管柱：Inertsil ODS — 3/4.0x33 毫米（GL Science Inc. ) 移動相：〇.〇5%TFA —水：〇.〇5%TFA -乙腈流速：1 . 〇毫升/分鐘梯度：10% MeCN在 0分鐘—95% MeCN在 4分鐘 —95% MeCN 在 5.5 分鐘—10% MeCN 在 6.0 分鐘情形B : 管柱·· Wakopak® Combi ODS/4.0x50 毫米（WakoWhere X is a halogen group and is condensed in the presence of a basic compound. The following examples illustrate preferred methods for preparing the compounds of the present invention and should not be used to limit the scope of the invention. Unless stated otherwise, the physical data of the compound is recorded as a mixture of non-palladium isomers at the center of the carbon atom pair -22 · (19) (19) 200413356. Unless otherwise stated, the retention time of each compound in LCMS was recorded using the following method. Case A: Column: Inertsil ODS-3 / 4.0x33 mm (GL Science Inc.) Mobile phase: 0.05% TFA-Water: 0.05% TFA-Acetonitrile flow rate: 1.0 ml / min Gradient: 10% MeCN at 0 minutes—95% MeCN at 4 minutes—95% MeCN at 5.5 minutes—10% MeCN at 6.0 minutes Case B: Columns · Wakopak® Combi ODS / 4.0x50 mm (Wako

Inc .) 移動相：〇.〇5%TFA —水：0.05%TFA —乙腈流速：4.0毫升/分鐘梯度：10% MeCN在0分鐘—95% MeCN在3.5分鐘 — 10% MeCN 在 4·5 分鐘—10% MeCN 在 5.0 分鐘必要的起始物質及部份中間物在部份情形下可得自商業化供應，或根據文獻方法製備。在下列圖示及說明中，”Me”代表甲基且”Et”代表乙基，因此例如”HOEt”係指乙醇，且”THF”係指四氫呋喃， ” DCM”係指二氯甲烷，”DMSO”係指二甲亞碩，”DMF”係 (20) (20)200413356 指N，N — 一甲基甲醯胺，Et〇Ac係指醋酸乙酯，MeCN 係指乙腈，LDA係指二異丙基氨化鋰，WSCI係指丨—（3 一二甲胺基丙基）一 3 一乙基—碳化二亞胺鹽酸鹽， ’’DIEA’’係指N—乙基二異丙基胺，H0Bt係指N—羥基苯並二卩坐單水合物，TFA係指三氟醋酸，DMAP係指4 —二甲胺基吡啶’ ”HMT”係指六亞甲基四胺，且Pd ( pph3 ) * 係指肆（三苯基膦）一鈀（〇 )。實例方法1 製備 4一〔胺基一（3-甲基—3H—咪唑一 4 一基）一 (5—硝基一苯並呋喃一 2-基）一甲基〕一苯甲腈衍生物一系列的 4一〔胺基一（3 -甲基一 3H —咪唑—4一基 )一（5—硝基一苯並咲喃一 2 —基）一甲基〕一苯甲腈衍生物9可根據圖示1所示製備。根據文獻方法，在迴流的乙腈中，在碳酸鉀存在下，偶合商業化供應的對硝基苯甲醯甲基溴1及商業化供應的 3-溴一 5 -硝基一水楊醛2，在高產量下導致酮基一苯並呋喃 3 ( Stille， J· R.， Ward， J. A.， Leffelman， C.， and Sullivan， K· A.， Tetrahedron Letters， 1 996， 3 7 ( 5 2 ) ， 93 5 3 - 93 5 6 ) 0 根據文獻方法，經由原鈦酸四乙酯仲介的縮合酮基一苯並呋喃3與商業化供應的（R ) -或（s ) 一亞磺醯胺 4，製備亞硫醯亞胺 5 (Lin， G·’ Cogan， D.A·’ -24- (21) (21)200413356Inc.) Mobile phase: 0.05% TFA-water: 0.05% TFA-acetonitrile flow rate: 4.0 ml / min gradient: 10% MeCN at 0 minutes-95% MeCN at 3.5 minutes-10% MeCN at 4.5 minutes —10% MeCN The starting material and some intermediates necessary in 5.0 minutes may in some cases be obtained from commercial supplies or prepared according to literature methods. In the following illustrations and descriptions, "Me" represents methyl and "Et" represents ethyl, so for example "HOEt" means ethanol, and "THF" means tetrahydrofuran, "DCM" means dichloromethane, and "DMSO" "Refers to Dimethoate," DMF "refers to (20) (20) 200413356 refers to N, N-monomethylformamide, Et〇Ac refers to ethyl acetate, MeCN refers to acetonitrile, and LDA refers to diiso Lithium propylamide, WSCI means 丨-(3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, "DIEA" means N-ethyldiisopropyl Amine, H0Bt means N-hydroxybenzodifluorene monomonohydrate, TFA means trifluoroacetic acid, DMAP means 4-dimethylaminopyridine '"HMT" means hexamethylenetetramine, and Pd ( pph3) * refers to (triphenylphosphine) -palladium (〇). Example Method 1 Preparation of 4-A [amino- (3-methyl-3H-imidazole-4 4-yl)-(5-nitro-benzofuran 2-yl) -methyl] -benzonitrile derivative- Series of 4- [Amino- (3-methyl-3H-imidazole-4-yl)-(5-nitro-benzobenzofuran-2-yl) -methyl] -benzonitrile derivative 9 may Prepared as shown in Figure 1. According to the literature method, in refluxing acetonitrile in the presence of potassium carbonate, the commercially available p-nitrobenzidine methyl bromide 1 and the commercially available 3-bromo-5 -nitromonosalicylic aldehyde 2 were coupled, Keto-benzofuran 3 (Still, J.R., Ward, JA, Leffelman, C., and Sullivan, K. A., Tetrahedron Letters, 1 996, 3 7 (5 2), 93 5 3-93 5 6) 0 According to the literature method, condensed keto-benzofuran 3 via tetraethyl orthotitanate and commercially available (R)-or (s) monosulfinamide 4, Preparation of sulfinimine 5 (Lin, G · 'Cogan, DA ·' -24- (21) (21) 200413356

Owens， T. D·， Tang， Τ· P.， and Ellman , J· A·， J. O r g. Chem. 1 999， 64， 1 27 8 — 1 2 84 ) 〇在一78 °C之四氫呋喃中經i〇分鐘，用根據carpenter 氏方法（Carpenter， A. J.， and Chadwick， D. J.， Tetrahedron， 1 986’ 42， 2 3 5 8 )製備之 2—三甲矽烷基一 5—鋰一 N—甲基咪唑6達成亞硫醯亞胺5之烷基化〇在Suzuki反應情形中，在催化量的鈀複合物存在下，經由與芳基硼酸或芳基硼酸酯之交叉-偶合反應，將多種芳基取代基加入關鍵中間物亞磺醯胺7，得到二芳基化合物 8，隨後在酸性情形下去除保護第三丁基亞硫醯基，得到所要的4一〔胺基一（3-甲基一3H—咪唑—4一基）一（5_硝基—苯並呋喃一 2—基）—甲基〕一苯甲腈衍生物9。圖示1 一製備5-硝基一苯並呋喃Owens, T.D., Tang, T.P., and Ellman, J.A., J. Org. Chem. 1 999, 64, 1 27 8 — 1 2 84) 〇 at 78 ° C Tetrahydrofuran was used for 10 minutes to prepare 2-trimethylsilyl-5-lithium-N-methyl according to Carpenter's method (Carpenter, AJ, and Chadwick, DJ, Tetrahedron, 1 986 '42, 2 3 5 8). Imidazole 6 achieves alkylation of thionylimine 5. In the case of the Suzuki reaction, in the presence of a catalytic amount of a palladium complex, a variety of aromatic compounds are reacted through a cross-coupling reaction with an aryl boronic acid or an aryl boronate Add the key intermediate sulfinyl sulfinamide 7 to obtain the diaryl compound 8 and then remove the protection of the third butyl thiosulfinyl group under the acidic condition to obtain the desired 4-a [amino- (3-methyl -3H-imidazole-4-yl)-(5-nitro-benzofuran-2-yl) -methyl] -benzonitrile derivative 9. Figure 1-Preparation of 5-nitro-benzofuran

-25- (22) (22)200413356-25- (22) (22) 200413356

方法2 製備4—〔胺基一（3 -甲基一 3H—咪唑_4 一基）一 (5—氰基一苯並呋喃一 2—基）—甲基〕一苯甲腈衍生物一系列的 4一〔胺基一（3 —甲基一 3H -咪唑一 4 一基 )一（5 -氛基一苯並咲喃—2—基）一甲基〕一苯甲睛衍生物16可根據圖示2所示製備，根據文獻方法（Suzuki ， Y. e t a 1. C h e m . P h ar m . Bull. 1 9 8 3， 31， 1751 — 1753)，製備 3 —甲酿基—4 —經基—苯甲睛10’在室溫下的乙醇中，經由用溴處理，達成將3 —甲醯基一 4一羥基一苯甲腈1 0溴化，得到3 —溴一 5 -甲醯基一 4 一羥基 —苯甲睛1 1。 -26- (23) (23)200413356 在迴流的乙腈中，在碳酸鉀存在下，偶合商業化供應的對硝基苯甲醯甲基溴1及3—溴一 5—甲醯基一 4一羥基一苯甲腈11，在高產量下導致酮基一苯並呋喃12。經由原鈦酸四乙酯仲介的縮合酮基-苯並呋喃1 2與亞磺醯胺4，製備亞硫醯亞胺1 3。在一 78 °C之四氫呋喃中經1〇分鐘，用 2—三甲矽烷基一 5-鋰一 N-甲基咪唑6達成亞硫醯亞胺13之烷基化，得到關鍵中間物亞磺醯胺1 4。在Suzuki反應情形中，在催化量的鈀複合物存在下，經由與芳基硼酸或芳基硼酸酯之交叉-偶合反應，將多種芳基取代基加入關鍵中間物亞磺醯胺1 4，得到二芳基化合物1 5，隨後在酸性情形下去除保護第三丁基亞硫醯基，得到所要的4-〔胺基一（3 —甲基一 3H—咪唑一 4一基）一（5-氰基—苯並呋喃—2-基）一甲基〕一苯甲腈衍生物1 6。圖示2-製備5-氰基-苯並呋喃衍生物 •27- (24) (24)200413356Method 2 Preparation of a series of 4- [amino- (3-methyl-3H-imidazole-4-yl)-(5-cyano-benzofuran-2-yl) -methyl] -benzonitrile derivatives 4- [amino- (3-methyl- 3H-imidazole-4-yl)-(5-amino-benzobenzo-2-yl) -methyl] -benzonitrile derivative 16 can be based on The preparation is shown in Figure 2. According to the literature method (Suzuki, Y. eta 1. C hem. Pharm. Bull. 1 9 8 3, 31, 1751 — 1753), 3 —methyl alcohol — 4 — Methyl-benzoyl 10 'in ethanol at room temperature through bromine treatment to achieve 3-bromomethyl-4-hydroxy-benzonitrile 10 bromination to obtain 3-bromo-5-methylmethyl One 4 one hydroxy-benzoin 1 1. -26- (23) (23) 200413356 In refluxing acetonitrile in the presence of potassium carbonate, coupled with commercially available p-nitrobenzylmethyl bromide 1 and 3-bromo-5methylformyl-4 1 Hydroxyl-benzonitrile 11 leads to keto-benzofuran 12 at high yields. Keto-benzofuran 12 and sulfenamide 4 are condensed via tetraethyl orthotitanate to prepare sulfinimine 13. Alkylation of thionylimine 13 with 2-trimethylsilyl-5-lithium-N-methylimidazole 6 in tetrahydrofuran at 78 ° C for 10 minutes to obtain the key intermediate sulfenimide 1 4. In the case of the Suzuki reaction, in the presence of a catalytic amount of a palladium complex, via a cross-coupling reaction with an arylboronic acid or an arylboronic acid ester, a variety of aryl substituents are added to the key intermediate, sulfenimidine 14, Diaryl compound 15 is obtained, and the protected third butyl sulfinyl group is removed under acidic conditions to obtain the desired 4- [amino group (3-methyl- 3H-imidazole-4-yl)-(5 -Cyano-benzofuran-2-yl) monomethyl] -benzonitrile derivative 16. Figure 2-Preparation of 5-cyano-benzofuran derivatives • 27- (24) (24) 200413356

方法3 製備4一〔胺基—（3 -甲基—3H -咪唑一 4 —基）一 (5 — Π比π定一 3 —基一苯並咲喃一 2 —基）一甲基〕一苯甲腈衍生物一系列的4一〔胺基一（3 —甲基—3H —咪唑一 4 —基 )一（5 — Π比D定一 3 —基—苯並咲喃一 2-基）一甲基〕一苯甲腈衍生物2 3可根據圖示3所示製備，根據文獻方法 -28- (25) (25)200413356 (Johnson ， Roy Α· ’ Nidy ， Eldon G. ， Aiken ，Method 3 Preparation of 4-A [Amino- (3-methyl-3H-imidazole-4-yl)-(5- Π ratio π-a 3-yl-benzopyran-2-yl) -methyl]- Benzonitrile derivatives a series of 4- (amino- (3-methyl-3H-imidazole-4-yl)-(5- Π ratio D-fixed 3-yl-benzopyran- 2-yl) Monomethyl] -benzonitrile derivative 23 can be prepared as shown in Figure 3, according to the literature method -28- (25) (25) 200413356 (Johnson, Roy Α 'Nidy, Eldon G., Aiken,

James W. ， Crittenden ’ Norman J. ， Gorman，James W., Crittenden ’Norman J., Gorman,

Robert R.， J· Med. Chem· ’ ( 1 9 8 6 ) ， 29， 1461- 1468)，製備2 —羥基—5 —吡啶—3 —基—苯甲醛，在室溫下的D C Μ與甲醇之混合溶液中’經由用苄基三甲基三溴化銨處理，達成將2 一羥基一 5 -吡啶一 3 -基一苯甲醛溴化’得到 3 —溴一2 —羥基一5 —吡啶一3 —基一苯甲醛 18° 在迴流的乙腈中，在碳酸鉀存在下，偶合對氰基苯甲醯甲基溴1及3 —溴一 2 —經基—5 — D比π定一 3 —基—苯甲醒18，在高產量下導致酮基-苯並咲喃19，經由原欽酸四乙酯仲介的縮合酮基-苯並呋喃19與亞磺醯胺，製備亞硫醯亞胺20，用2 —三甲矽烷基一 5 —鋰一 Ν—甲基咪 _ 6達成亞硫醯亞胺2 〇之烷基化，得到關鍵中間物亞磺醯胺2 1。在Suzuki反應情形中，在催化量的鈀複合物存在下 ’經由與芳基硼酸或芳基硼酸酯之交叉一偶合反應，將多種芳基取代基加入關鍵中間物亞磺醯胺2 1，得到二芳基化合物I 22 ’隨後在酸性情形下去除保護第三丁基亞硫醯基’得到所要的4一〔胺基一（3 —甲基—3H —咪唑一 4一基）一（5 —吡啶一 3 -基—苯並呋喃一 2 —基）_甲基〕一苯甲睛衍生物2 3。圖不3〜製備5— ( 5-吡啶—3-基）苯並呋喃衍生物 -29- (26) 200413356Robert R., J. Med. Chem. (1 9 8 6), 29, 1461-1468), prepared 2-hydroxy-5-pyridin-3-yl-benzaldehyde, DC M and methanol at room temperature In the mixed solution, through treatment with benzyltrimethylammonium bromide, bromination of 2-hydroxy-1,5-pyridine-3, yl-benzaldehyde was achieved to obtain 3-bromo-1, 2-hydroxy-1, 5-pyridine-1 3-Methyl-benzaldehyde 18 ° In refluxing acetonitrile, in the presence of potassium carbonate, couple p-cyanobenzylmethyl bromide 1 and 3-bromo-2 — via the group —5 — D ratio π set 3 — -Benzoxine 18, which leads to keto-benzopyran 19 at high yields, and condensed keto-benzofuran 19 and sulfenimide via tetraethyl orthoacetate to prepare sulfenimine 20. The alkylation of thionylimine 20 with 2-trimethylsilyl-5-lithium-N-methylimidium-6 was achieved to obtain the key intermediate sulfinylamine 2 1. In the case of the Suzuki reaction, in the presence of a catalytic amount of a palladium complex, 'via a cross-coupling reaction with an aryl boronic acid or an aryl boronic acid ester, a variety of aryl substituents are added to the key intermediate sulfinamide 2 1, The diaryl compound I 22 'is subsequently removed to protect the third butylthiosulfenyl group under acidic conditions' to give the desired 4-amino [(amino- (3-methyl-3H-imidazole-4-yl)-(5 —Pyridine-3—yl—benzofuran-2-yl) -methyl] -benzonitrile derivative 23. Figure 3 ~ Preparation of 5- (5-pyridin-3-yl) benzofuran derivative -29- (26) 200413356

Κ2〇〇3 ch3cn 60°CΚ2〇〇3 ch3cn 60 ° C

下列提供的實例是爲了幫助進一步了解本發明，特定材料使用的物種及情形是爲了進一步說明本發明，而不是限制其合理的範圍。部份式（I)之苯並呋喃化合物沒有實驗測定其絕對的立體化學組態，在這些情形中，先分離的立體化學異構物形式稱爲”A”且後者稱爲”B”，沒有進一步確認實際的立 -30- (27)200413356 體化學組態。The following examples are provided to help further understand the present invention. The species and conditions of specific materials are used to further illustrate the present invention, but not to limit its reasonable scope. Some of the benzofuran compounds of formula (I) have not been experimentally determined for their absolute stereochemical configuration. In these cases, the stereoisomeric form that was separated first is called "A" and the latter is called "B". Further confirm the actual Li-30-30 (27) 200413356 chemical configuration.

-31 - (28)200413356 表1 : 實例 R1 R2 1 -N〇2 一苯基 2 -N〇2 —3—甲氧基苯基 3 -N〇2 —苯並〔1，3〕二氧茂—5-基 4 -N〇2 一 3 -氟苯基 5 -N〇2 —3 —氰基苯基 6 -N〇2 —3 —乙氧基苯基 7 -N02 —3 -氯苯基 8 -N〇2 一 4一氟苯基 9 -N〇2 一 3，5-一氟苯基 10 -N〇2 —3，4—二氟苯基 11 -N〇2 —吼D定—3 —基 12 -N〇2 一氫 13 -CN —苯基 14 -CN 一 3—甲氧基苯基 15 -CN —苯並〔1，3〕二氧茂一5—基 16 -CN 一 3 _氟苯基 17 -CN 一 3—氰基苯基 18 -CN 一 3 —氯苯基 19 -CN —吼陡—3 —基 20 —吼D定一 3 -基一 3 —氟苯基 2 1 —吼啶一3 —基一苯基 22 —□比症一3 —基 —3 —甲氧基苯基 23 一吡啶一 3 —基 —苯並〔1，3〕二氧茂一 5—基 24 一吼陡一 3 —基一 3 —氰基苯基 25 一批口定—3 —基一 3 —氯苯基 26 一吡啶—3 —基 —0比口定一 3 -基 (29) (29)200413356 製備 4一〔胺基一（3 —甲基—3H-咪唑—4 一基）一（5 一硝基一苯並呋喃一 2—基）一甲基〕一苯甲腈化合物實例1 製備 4—〔胺基一（3 —甲基—3H—咪唑—4 —基）— (5 —硝基一 7—苯基一苯並呋喃—2-基）—甲基〕—苯甲腈 1 — a ) 製備4 一（7 —溴一 5 —硝基一苯並呋喃—2 — 羰基）一苯甲腈3 在 3 —溴—2 —羥基—5 —硝基—苯甲醛（15.0克， 61.0毫莫耳）於CH3CN ( 3 00毫升）之溶液中加入4 — 氰基一苯甲醯甲基溴（14.3克，64.0毫莫耳）及K2C03 (10.1克，73.2毫莫耳），將渾濁的混合物在迴流下加熱4小時，使混合物冷卻至室溫並過濾收集沈澱物，然後將沈澱物用H20及Me OH淸洗，將殘留物在真空中乾燥，得到1 2.5克之4 一（ 7 —溴—5 —硝基—苯並呋喃一 2 -羰基）一苯甲腈淡黃色固體。 LCMS (情形 B ) 、m/z 〔 M + Η〕+、滯留時間分鐘 » ^-NMRCCDCh) d8.68(lH^ J = 2.0Hz) ，8.64 (1H，d，J = 2.0Hz ) ，8.28 ( 2H，dd，J = 2.0，6.6Hz)， 7.9 1 ( 2H，dd，J = 2.0，6.6Hz ) ，7.86 ( 1H，s)。 1— b) 製備2 —甲基一丙烷一 2_亞磺酸（7—溴一5 -33- (30) (30)200413356 —硝基—苯並D夫喃一 2 —基）—（4 —氰基—苯基）一亞甲醯胺5 在4一（7 —溴一 5 -硝基一苯並咲喃一 2-鑛基）一苯甲腈（1 1 ·〇克，23.2毫莫耳）於THF ( 200毫升）之渾濁溶液中加入（R) -或（S) - 2 -甲基一 2 -丙院亞磺醯胺（3.0 9克，2 5 . 5毫莫耳）及原鈦酸四乙酯（丨〇 . 7 克，4 6 · 4毫莫耳），在迴流下加熱1 0小時後，使混合物冷卻至室溫並倒入飽和的NaCl ( 100毫升），將所得的混合物在矽藻土上過濾並用 Ac OEt淸洗，將有機層分離，用鹽水淸洗，經由Na2S04乾燥，過濾並在真空濃縮，在矽膠上將殘留物經由矽膠管柱層析法（流洗液： CH2C12—10% MeOH 於 CH2C12 )純化，得到 7.70 克 2 -甲基一丙烷一 2 —亞磺酸（7 -溴一 5 —硝基—苯並呋喃一 2 -基）一（4一氰基一苯基）—亞甲醯胺橙色固體。 LCMS (情形 B) 、m/z474〔M + H〕+，476〔M + H〕+ 、滯留時間 3·98 分鐘；4 — NMR(CDC13) d8.52 — 8.55 (2H，m) ，7·78 - 7.82 (3H，m) ，7.68(2H，m)， 1 ·40 ( 9H，s )。 1— c) 製備2—甲基—丙烷一 2 —亞磺酸〔（7—溴 —5 —硝基—苯並呋喃—基）—（4 一硝基一苯基）— (3 —甲基一3H —咪唑一 4 —基）—甲基〕一醯胺7 將在己烷中的正丁基鋰（1.58莫耳濃度，10·1毫升，16.0毫莫耳）添加至Ν —甲基咪唑（1.28毫升，16.0 (31) (31)200413356 毫莫耳）於THF (50毫升）在—78 t：之溶液中，攪拌 30分鐘後，將三乙基矽烷基氯（2.69毫升，16.00毫莫耳 )添加至反應混合物，使混合物溫熱至室溫後冷卻至- 7 8 °C，再度加入在己烷中的正丁基鋰（丨.5 8莫耳濃度，1 〇. 1 毫升，1 6 · 0毫莫耳），使反應混合物溫熱至—2 〇 °C後冷卻至一 78 °C ’將製備的混合物添加至2 —甲基—丙烷一 2 — 亞石Η酸（7-漠一 5-硝基一苯並D夫喃—2-基）一（4 —氰基一苯基）—亞甲醯胺（5.0克，10.5毫莫耳）於THF 在一 78°C之溶液中，攪拌10分鐘後，加入飽和的NH2C1 ，將反應混合物用 AcOEt萃取，將合倂的有機層經由 Na2S04乾燥並在真空蒸發，在砂膠上將殘留物經由砂膠管柱層析法（流洗液：AcOEt — 1 0% MeOH於 AcOEt )純化，得到3 · 64克2 —甲基一丙烷_ 2 -亞磺酸〔（7 —溴— 5 —硝基一苯並呋喃一 2-基）—（4 一硝基一苯基）一（3 一甲基一3H —咪唑一 4 —基）一甲基〕一醯胺橙色固體。 LCMS (情形 B) 、m/z556〔M + H〕+，558〔M + H〕+ 、滯留時間2.8 2分鐘； NMR (CDC13) d8.44 ( 1H’ d，J = 2.2Hz) ，8.39 (1H，d，J = 2.2Hz ) ，7.75 ( 2H，dd，J = 2 · 0，6 · 4 H z )， 7.64 ( 2H，dd，J = 2.0，6.4Hz ) ，7.54 ( 1H，s ) ，7.28 ( lH，s) ，7.27(1H，s) ，6.95(1H，s) ，4.70(1H，s )，3.15 ( 3H，s) ，1.36 ( 9H，s)。 1 - d ) 製備2 —甲基一丙院一 2—亞擴酸〔（4 一氰 -35- (32) (32)200413356 基一苯基）_ (3 —甲基〜3H —咪唑一 4 —基）一（5-硝基一 7—苯基—苯並咲喃一 2-基）一甲基〕一醯胺8 將2 —甲基一丙院一 2 —亞磺酸〔（7 —溴一 5 —硝基一苯並呋喃—2-基）—（4 一硝基一苯基）—（3 —甲基一 3H —咪唑—4 —基）—甲基〕—醯胺（1.95克，3.50毫莫耳）、2 —苯基一〔1’ 3，2〕二哼硼烷（1.70克，10.5 鼋莫耳）、肆（三苯基膦）一鈀（〇) (1.21克，1.05 毫莫耳）及磷酸三鉀（2.23克，10.5毫莫耳）於THF ( φ 5 〇毫升）·之溶液在迴流下加熱4小時，將反應混合物用 Ac OEt稀釋並將鈀過濾去除，將過濾液用鹽水淸洗，經由 Na2S〇4乾燥並在真空蒸發，在矽膠上將殘留物經由砂膠管柱層析法（流洗液：AcOEt —5% MeOH於AcOEt — 1 0%-31-(28) 200413356 Table 1: Example R1 R2 1 -N〇2 monophenyl 2-N〇2 -3-methoxyphenyl 3 -N〇2 -benzo [1,3] dioxo —5-yl 4 —N0 2 —3-fluorophenyl 5 —N 2 —3 —cyanophenyl 6 —N 2 —3 —ethoxyphenyl 7 —N02 — 3 —chlorophenyl 8 -N〇2-4 monofluorophenyl 9-No 2-3, 5- monofluorophenyl 10-No 2-3, 4-difluorophenyl 11-No 2-H D-3- Group 12 -N〇2 monohydro 13 -CN -phenyl 14 -CN -3-methoxyphenyl 15 -CN -benzo [1,3] dioxo- 5-yl 16 -CN -3 _fluorobenzene Group 17 -CN -3 -cyanophenyl 18 -CN -3 -chlorophenyl 19 -CN -Hou steep -3 -Base 20 -Hou D D 3 -yl -3 -Fluorophenyl 2 1 -Houidine -3 -yl-phenyl 22-bispyridine 3 -yl -3 -methoxyphenyl 23 -pyridine -3 -yl -benzo [1,3] dioxo-5 -yl 24 3 -yl- 3 -cyanophenyl 25 batches of 3 -yl -3 -chlorophenyl 26 -pyridine-3 -yl-0 than 3 -yl (29) (29) 200413356 Preparation 4 A 3-methyl-3H-imidazole-4 monoyl)-(5-mononitro-benzofuran 2-yl) -methyl] -benzonitrile compound Example 1 Preparation of 4- [amino- (3-methyl -3H-imidazol-4-yl)-(5-nitro-7-phenyl-benzofuran-2-yl) -methyl] -benzonitrile 1-a) Preparation of 4- (7-bromo- 5-Nitro-benzofuran-2—carbonyl) -benzonitrile 3 in 3-bromo-2-hydroxy-5—nitro-benzaldehyde (15.0 g, 61.0 mmol) in CH3CN (300 ml) To the solution was added 4-cyano-monobenzoylmethyl bromide (14.3 g, 64.0 mmol) and K2C03 (10.1 g, 73.2 mmol), and the turbid mixture was heated under reflux for 4 hours to cool the mixture. The precipitate was collected at room temperature and filtered. The precipitate was washed with H20 and Me OH, and the residue was dried in vacuo to obtain 1 2.5 g of 4-a (7-bromo-5-nitro-benzofuran-2. -Carbonyl) -benzonitrile as a pale yellow solid. LCMS (case B), m / z [M + Η] +, residence time minutes »^ -NMRCCDCh) d8.68 (lH ^ J = 2.0Hz), 8.64 (1H, d, J = 2.0Hz), 8.28 ( 2H, dd, J = 2.0, 6.6 Hz), 7.9 1 (2H, dd, J = 2.0, 6.6 Hz), 7.86 (1H, s). 1- b) Preparation of 2-methyl-propane- 2-sulfinic acid (7-bromo- 5 -33- (30) (30) 200413356 -nitro-benzo-D-furan- 2 -yl)-(4 —Cyano-phenyl) -methyleneamine 5 in 4- (7-bromo-5-nitro-benzopyran-2-mine) -benzonitrile (11.10 g, 23.2 mmol Ear) To a turbid solution of THF (200 ml) was added (R)-or (S)-2 -methyl-2 -propanylsulfenamide (3.0 9 g, 25.5 mmol) and the original Tetraethyl titanate (0.7 g, 46.4 mmol) was heated under reflux for 10 hours. The mixture was cooled to room temperature and poured into saturated NaCl (100 ml). The mixture was filtered over diatomaceous earth and washed with Ac OEt. The organic layer was separated, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was passed through silica gel column chromatography on silica gel (flow washing solution). : CH2C12-10% MeOH in CH2C12) was purified to obtain 7.70 g of 2-methyl monopropane-2-sulfinic acid (7-bromo-5-nitro-benzofuran 2-yl)-(4-cyano Monophenyl) —methyleneamine orange solid . LCMS (case B), m / z474 [M + H] +, 476 [M + H] +, residence time 3.98 minutes; 4 — NMR (CDC13) d8.52 — 8.55 (2H, m), 7 · 78-7.82 (3H, m), 7.68 (2H, m), 1.40 (9H, s). 1- c) Preparation of 2-methyl-propane- 2 -sulfinic acid [(7-bromo-5 -nitro-benzofuran-yl)-(4-nitro-phenyl)-(3-methyl -3H-imidazole-4-yl) -methyl] monofluorenamine 7 Add n-butyllithium (1.58 mole concentration, 10.1 ml, 16.0 mmol) in hexane to N-methylimidazole (1.28 ml, 16.0 (31) (31) 200413356 mmol) in THF (50 ml) in a solution of -78 t: After stirring for 30 minutes, the triethylsilyl chloride (2.69 ml, 16.00 mmol) Ear) was added to the reaction mixture, the mixture was allowed to warm to room temperature, and then cooled to-7 8 ° C, and n-butyllithium in hexane (1.58 Molar concentration, 10.1 ml, 1 6.0 mmol), the reaction mixture was allowed to warm to -20 ° C and then cooled to -78 ° C. 'The prepared mixture was added to 2-methyl-propane-2-sulfite (7- Mo 5-Nitro-benzo-Danfuran-2-yl)-(4-cyano-phenyl) -methylenefluoride (5.0 g, 10.5 mmol) in THF at a temperature of 78 ° C After stirring for 10 minutes, add saturated NH2C 1. The reaction mixture was extracted with AcOEt. The combined organic layer was dried over Na2S04 and evaporated in vacuo. The residue was passed through a silica gel column chromatography on a sand gel (eluent: AcOEt — 10% MeOH in AcOEt). ) Purified to give 3.64 g of 2-methylmonopropane 2-sulfinic acid [(7-bromo-5-nitro-benzofuran 2-yl)-(4-nitro-phenyl)- (3-Methyl- 3H-imidazole-4-yl) -methyl] -amidine orange solid. LCMS (case B), m / z556 [M + H] +, 558 [M + H] +, retention time 2.82 minutes; NMR (CDC13) d8.44 (1H 'd, J = 2.2Hz), 8.39 ( 1H, d, J = 2.2Hz), 7.75 (2H, dd, J = 2 · 0, 6 · 4 H z), 7.64 (2H, dd, J = 2.0, 6.4Hz), 7.54 (1H, s), 7.28 (lH, s), 7.27 (1H, s), 6.95 (1H, s), 4.70 (1H, s), 3.15 (3H, s), 1.36 (9H, s). 1-d) Preparation of 2-methyl-a-propanone- 2-subarylene acid [(4-cyano-35- (32) (32) 200413356 yl-phenyl) _ (3-methyl ~ 3H-imidazole-1 4 -Yl)-(5-nitro-7-phenyl-benzopyran- 2-yl) -methyl] -pyridylamine 8 2-methyl-propanone- 2-sulfinic acid [(7 — Bromo-5-nitro-benzofuran-2-yl)-(4-nitronitrophenyl)-(3-methyl-3H-imidazol-4-yl) -methyl] -fluorenamine (1.95 g , 3.50 millimolar), 2-phenyl- [1 '3,2] dihumorane (1.70 g, 10.5 mol), tris (triphenylphosphine) -palladium (〇) (1.21 g, 1.05 MM) and tripotassium phosphate (2.23 g, 10.5 mM) in THF (φ50 ml). The solution was heated under reflux for 4 hours. The reaction mixture was diluted with Ac OEt and palladium was filtered off. The solution was rinsed with brine, dried over Na2S04 and evaporated in vacuo. The residue was passed through silica gel column chromatography on silica gel (flow washing solution: AcOEt —5% MeOH in AcOEt — 10%).

Me0H於AcOEt )純化，得到1.38克2 —甲基一丙烷一2 —亞磺酸〔（4 —氰基—苯基）—（3 —甲基一 3H—咪唑一 4 一基）一（5 一硝基—7 —苯基一苯並咲喃一 2-基）一甲基〕〜醯胺淡黃色無定形粉末。 · LCMS (情形 B ) 、m/z5 5 4〔 M + H〕+，滯留時間 3.17 分鐘； h-NMRCCDCh) d8.46(lH，d，J = 2.3Hz) ，8.37 (1 Η，d，J = 2.3Hz ) ，7·72 ( 2H，dd，J = 2.〇 ’ 6·6Ηζ ) ’ 7·62 - 7·66 ( 2H，m ) ，7 · 5 9 ( 2 Η，d d，J = 2 · 〇，8 · 8 Η ζ ) ，7.53(ih，s) ，7.43-7.51 (3H，m) ，7.29(1H’s )，6.9〇(ih，s) ，4.64(1H，s) ，3.14(3H，s) ’ 1 .3 1 ( 9H，s )。 -36- (33) (33)200413356 1 一 e) 製備4—〔胺基一（3 —甲基—3H —咪唑一 4 一基）一（5 —硝基—7 —苯基—苯並D夫喃—2—基）一甲基〕一苯甲腈在2 —甲基—丙烷一 2—亞磺酸〔（4一氰基—苯基） —(3 —甲基一3H-味哗—4 —基）一（5 —硝基—7 -苯基一苯並呋喃—2 —基）—甲基〕—醯胺（50毫克，0.09 毫莫耳）於THF-甲醇（3毫升，1毫升）在〇°C之溶液中加入在AcOEt溶液中的4莫耳濃度HC1 ( 1毫升），將反應混合物在室溫攪拌1小時，將反應用1莫耳濃度 NaOH水溶液（5毫升）淬火，並將所得的混合物用 AcOEt萃取，將有機層分離，用鹽水淸洗，經由Na2S04 乾燥並在真空蒸發，在矽膠上將殘留物經由矽膠管柱層析法（流洗液：AcOEt —5% MeOH 於 AcOEt—1 0% MeOH 於 AcOEt )純化，得到40毫克4—〔胺基—（3 —甲基—3H —味Π坐—4 一基）—（5 —硝基一 7-苯基—苯並咲喃—2 — 基）一甲基〕一苯甲腈淡黃色固體。 LCMS (情形 B ) 、m/z451〔 M + H〕+，滯留時間 3·02 分鐘； lU - NMR ( CD3〇D ) d8.50 ( 1H，d，J=1 ·9Ηζ )， 8.36(lH，d，J = 1.9Hz) ，7.76—7.80 (4H，m) ，7·63 —7·65 ( 3H，m) ，7.41— 7·51 ( 1H，m) ，6.88 ( 1H，s )，6.57 ( 1H，s ) ，3.41 ( 3H，s )。 -37- (34) (34)200413356 實例2 4一〔胺基一〔7— （3 —甲氧基一苯基）一 5-硝基— 苯並呋喃一 2—基〕一（3 -甲基—3H-咪唑—4 一基）— 甲基〕一苯甲腈類似於實例1 一 d )及1 一 e )揭示的方法，2 -甲基一丙烷一 2 -亞磺酸〔（7 -溴一 5 -硝基—苯並呋喃一 2 —基 )一（4 —氰基—苯基）—（3 —甲基一 3H —咪唑—4 —基 )一甲基〕一醯胺與 2 - （3 —甲氧基—苯基）—〔1，3 ，2〕二哼硼烷之 Suzuki偶合反應，隨後用氫氯酸（在 AcOEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) 、m/z48 0〔 M + H〕+，滯留時間 3· 1 1 分鐘； NMR ( CD30D) d8.50 ( 1H，d，J = 2.4Hz)， 8.35 ( 1H，d，J = 2.4Hz ) ，7.79 ( 2H，d，J = 8.8Hz )， 7.6 3 — 7.6 5 ( 4H，m ) ，7.40 ( 1H，dd，J = 7.6，7.6Hz ) ，7.31— 7.33(2H，m) ，6.98-7.01 (lH，m) ，6.91( lH，s) ，6.61(lH，s) ，3.78(3H，s) ，3.43(3H，s 、° 實例3 4一〔胺基—（7 —苯並〔1，3〕二氧茂一 5 —基—5 — 硝基—苯並呋喃—2 —基）一（3 —甲基—3H—咪唑一4 一基）一甲基〕一苯甲腈 -38- (35) (35)200413356 類似於實例1 一 d )及1 一 e )揭示的方法，2 —甲基一丙烷一 2-亞磺酸〔（7-溴—5-硝基一苯並呋喃一 2-基 )一（4 —氰基一苯基）一（3 —甲基一 3H—咪唑一 4 —基 )一甲基〕一醯胺與 5- 〔1，3，2〕二哼硼烷一 2 —基— 苯並〔1，3〕二氧茂之Suzuki偶合反應，隨後用氫氯酸 (在Ac OEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B) 、m/z494〔M + H〕+，滯留時間 2.99 分鐘； NMR (CDC13) d8.35 ( 1H，d，J = 2.3Hz) ，8.31 (1H，d，J = 2.3Hz ) ，7.75 ( 2H，d，J = 8.6Hz ) ，7.59 ( 2H，d，J = 8.6Hz ) ，7.78 ( 1H，s) ，7.24 ( 1H，dd， J = 2.0，8.3Hz) ，7.22 ( 1H，d，J = 2.0Hz ) ，6.93 ( 1H，d ，J = 8.3Hz ) ，6.65 ( 1H，s) ，6.57 ( 1H，s) ，6.05 ( 2H，s ) ，3.4 1 ( 3H，s )。實例4 4一〔胺基一〔7— (3-氟一苯基）一 5-硝基—苯並呋喃一 2_基〕一（3 —甲基—3H —咪唑一 4 一基）一甲基〕一苯甲腈類似於實例1 一 d )及1 一 e )揭示的方法，2 —甲基— 丙烷一 2—亞磺酸〔（7-溴一 5-硝基一苯並呋喃一 2-基 )一（4 一氰基—苯基）一（3 —甲基—3H —咪唑一4 —基 )一甲基〕一醯胺與2— (3 —氟—苯基）一〔1，3，2〕 -39- (36) 200413356 二噚硼烷之 Suzuki偶合反應，隨後用氫氯酸（在 AcOEt 中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末 LCMS (情形 B ) 、m/z46 8〔 M + H〕+，滯留時間 3.03 分鐘；iH-NMRCCDgOD) d8.56 ( 1H，d，J = 2.0Hz)， 8.42 ( 1H，d，J = 2.0Hz ) ，7.80 ( 2H，d，J = 8.8Hz )，Me0H was purified on AcOEt) to obtain 1.38 g of 2-methyl-propane-2-sulfinic acid [(4-cyano-phenyl)-(3-methyl- 3H-imidazole-4-yl)-(5- Nitro-7-phenyl-benzo-pyran- 2-yl) -methyl] ~ fluoramine is a light yellow amorphous powder. LCMS (case B), m / z5 5 4 [M + H] +, residence time 3.17 minutes; h-NMRCCDCh) d8.46 (lH, d, J = 2.3Hz), 8.37 (1 Η, d, J = 2.3Hz), 7.72 (2H, dd, J = 2.〇'6 · 6Ηζ) '7.62-7.66 (2H, m), 7 · 5 9 (2Η, dd, J = 2 · 〇, 8 · 8 Η ζ), 7.53 (ih, s), 7.43-7.51 (3H, m), 7.29 (1H's), 6.90 (ih, s), 4.64 (1H, s), 3.14 (3H, s) '1.3 .1 (9H, s). -36- (33) (33) 200413356 1-e) Preparation of 4- [Amine- (3-methyl-3H-imidazole-4-yl)-(5-nitro-7-phenyl-benzoD -Furan-2-yl) monomethyl] -benzonitrile in 2-methyl-propane-2-sulfinic acid [(4-cyano-phenyl) — (3-methyl-3H-weibo — 4-yl) mono (5-nitro-7-phenyl-benzofuran-2-yl) -methyl] -fluorenamine (50 mg, 0.09 mmol) in THF-methanol (3 ml, 1 ml ) 4 mol HC1 (1 ml) in AcOEt solution was added to the solution at 0 ° C, the reaction mixture was stirred at room temperature for 1 hour, the reaction was quenched with a 1 mol NaOH aqueous solution (5 ml), and The resulting mixture was extracted with AcOEt, the organic layer was separated, washed with brine, dried over Na2S04 and evaporated in vacuo. The residue was passed through a silica gel column chromatography on silica gel (eluent: AcOEt —5% MeOH in AcOEt—10% MeOH in AcOEt) was purified to give 40 mg of 4- [amino group— (3-methyl-3H—taste Π—4-mono) — (5-nitro-7-phenyl-benzo). Murmur—2 —Yl) -methyl] -benzonitrile as a pale yellow solid. LCMS (case B), m / z451 [M + H] +, residence time 3.02 minutes; lU-NMR (CD3〇D) d8.50 (1H, d, J = 1 · 9Ηζ), 8.36 (lH, d, J = 1.9 Hz), 7.76-7.80 (4H, m), 7.63-7.65 (3H, m), 7.41-7.51 (1H, m), 6.88 (1H, s), 6.57 ( 1H, s), 3.41 (3H, s). -37- (34) (34) 200413356 Example 2 4- [Amino- [7- (3-methoxy-phenyl) -5-nitro-benzofuran- 2-yl]-(3-methyl -3H-imidazole-4 monoyl) -methyl] -benzonitrile is similar to the method disclosed in Examples 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7- Bromo-5 -nitro-benzofuran-2-yl)-(4-cyano-phenyl)-(3-methyl- 3H-imidazol-4-yl) -methyl] -ammoniumamine and 2- (3-Methoxy-phenyl)-[1,3,2] Suzuki coupling reaction of dihumorane, followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder. LCMS (case B), m / z48 0 [M + H] +, retention time 3.1 1 minutes; NMR (CD30D) d8.50 (1H, d, J = 2.4Hz), 8.35 (1H, d, J = 2.4Hz), 7.79 (2H, d, J = 8.8Hz), 7.6 3 — 7.6 5 (4H, m), 7.40 (1H, dd, J = 7.6, 7.6Hz), 7.31— 7.33 (2H, m) , 6.98-7.01 (lH, m), 6.91 (lH, s), 6.61 (lH, s), 3.78 (3H, s), 3.43 (3H, s, °) Example 3 4— [Amino- (7-benzene Benzo [1,3] dioxocene-5 -yl-5 -nitro-benzofuran-2-yl)-(3-methyl-3H-imidazole-4 4-yl) -methyl] -benzonitrile- 38- (35) (35) 200413356 Similar to the methods disclosed in Examples 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5-nitro-benzo) Furan 2-yl)-(4-cyano-phenyl)-(3-methyl- 3H-imidazol 4-yl) -methyl] -amidine and 5- [1,3,2] dihum Suzuki coupling reaction of borane-2-yl-benzo [1,3] dioxocene followed by treatment with hydrochloric acid (4 molar solution in Ac OEt) to give the title compound Colored powder. LCMS (case B), m / z494 [M + H] +, retention time 2.99 minutes; NMR (CDC13) d8.35 (1H, d, J = 2.3Hz), 8.31 (1H, d, J = 2.3Hz) , 7.75 (2H, d, J = 8.6Hz), 7.59 (2H, d, J = 8.6Hz), 7.78 (1H, s), 7.24 (1H, dd, J = 2.0, 8.3Hz), 7.22 (1H, d, J = 2.0 Hz), 6.93 (1H, d, J = 8.3 Hz), 6.65 (1H, s), 6.57 (1H, s), 6.05 (2H, s), 3.4 1 (3H, s). Example 4 4- [Amino- [7- (3-fluoro-phenyl) -5-nitro-benzofuran- 2-yl]-(3-methyl-3H-imidazole-4-yl) -methyl Group] -benzonitrile is similar to the method disclosed in Example 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5-nitro-benzofuran-2) -Yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -ammoniumamine and 2- (3-fluoro-phenyl)-[1, 3, 2] -39- (36) 200413356 Suzuki coupling reaction of diborane, followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to obtain the title compound as a colorless powder LCMS (Case B), m / z46 8 〔M + H〕 +, retention time 3.03 minutes; iH-NMRCCDgOD) d8.56 (1H, d, J = 2.0Hz), 8.42 (1H, d, J = 2.0Hz), 7.80 (2H, d, J = 8.8Hz),

7.62- 7.65 (4H，m) ，7.50— 7.56 (2H，m) ^ 7.20 ( 1H7.62- 7.65 (4H, m), 7.50— 7.56 (2H, m) ^ 7.20 (1H

，ddd，J = 2.0，8.3，8.3Hz) ，6.94(1 H，s) ，6.58(1H ，s ) ，3.48 ( 3H，s )。實例5 4一〔胺基一〔7— (3 —氰基一苯基）一 5 —硝基一苯並呋喃一2 —基〕—（3 —甲基—3H —咪唑—4 —基）—甲基〕一苯甲腈類似於實例1 一 d )及1 一 e )揭示的方法，2 —甲基一丙烷一 2 -亞磺酸〔（7 —溴—5 —硝基一苯並呋喃—2 -基 )—(4 —氰基一苯基）一（3 -甲基—3H—咪唑一4 一基 )—甲基〕一醯胺與 3—〔1，3，2〕二哼硼烷一2 —基— 苯甲腈之Suzuki偶合反應，隨後用氫氯酸（在AcOEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) 、：m/z4 7 5〔 M + H〕+，滯留時間 2.90 分鐘； j-NMR ( CD30D) d8.60 ( 1H，d，J = 2.0Hz)， 8.46 ( 1H，d，J = 2.0Hz ) ，8.12 ( 2H，d，J = 7.8Hz )， -40- (37) (37)200413356, Ddd, J = 2.0, 8.3, 8.3 Hz), 6.94 (1 H, s), 6.58 (1 H, s), 3.48 (3H, s). Example 5 4- [Amine- [7- (3-cyano-phenyl) -5-nitro-benzofuran 2-yl]-(3-methyl-3H-imidazole-4-yl)- Methyl] -benzonitrile is similar to the method disclosed in Example 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5-nitro-benzofuran- 2 -yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] monomethylamine and 3- [1,3,2] dihumorane A 2-yl-benzonitrile Suzuki coupling reaction followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder. LCMS (case B), m / z 4 7 5 [M + H] +, retention time 2.90 minutes; j-NMR (CD30D) d8.60 (1H, d, J = 2.0Hz), 8.46 (1H, d, J = 2.0Hz), 8.12 (2H, d, J = 7.8Hz), -40- (37) (37) 200413356

7.80— 7.83 ( 3H，m) ，7·64— 7.72 (4H，m) ，6.99(1H ，s) ，6.55(lH，s) ，3.41(3H，s)。實例6 4一〔胺基—〔7—（3—乙氧一苯基）—5—硝基—苯並呋喃一 2 —基〕—（3 —甲基一 3H —咪唑一 4一基）—甲基〕一苯甲腈類似於實例1 一 d )及1 — e )揭示的方法，2 -甲基— 丙烷一 2—亞磺酸〔（7-溴一 5-硝基一苯並呋喃一 2-基 )—(4 一氰基一苯基）一（3 -甲基一 3H —咪唑一 4一基 )—甲基〕一醯胺與 2— (3 —乙氧基—苯基）一〔1，3 ，2〕二噚硼烷之Suzuki偶合反應，隨後用氫氯酸（在 AcOEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) 、m/z494〔 M + H〕+，滯留時間 3 . 1 0 分鐘； - NMR ( CD3〇D ) d8.5 1 ( 1H，d，J = 2.3Hz )， 8.36 ( 1H，d，J = 2.3Hz ) ，7.79 ( 2H，d，J = 8.6Hz )， 7.62-7.66 (3H，m) ，7·30— 7·43 (3H，m) ，6.96 — 7.00(lH，m) ，6.92(lH，s) ，6.60(lH，s) ^ 4.00 (2H，q，J = 6.9Hz ) ，3.42 ( 3H，s )。實例7 4一〔胺基一〔7— (3-氯一苯基）—5 -硝基一苯並 -41 - (38) (38)200413356 呋喃_2—基〕一（3 —甲基一3H —咪唑一 4 —基）—甲基〕一苯甲腈類似於實例1 一 d )及1 — e )揭示的方法，2 —甲基一丙院一 2-亞擴酸〔（7-溴—5 -硝基一苯並咲喃一 2-基 )_ (4 —氰基—苯基）一（3 —甲基—3H —咪唑—4 一基 )—甲基〕一醯胺與2— (3 -氯—苯基）—〔1，3，2〕二哼硼烷之 Suzuki偶合反應，隨後用氫氯酸（在 AcOEt 中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末〇 LCMS (情形 B ) 、m/z484〔 M + H〕+，滯留時間 3.15 分鐘； lH ~ NMR ( CD3〇D ) d8.57 ( 1H，d，J = 2.3Hz )， 8.40 ( 1H，d，J = 2.3Hz ) ，7.8 1 ( 2H，d，J = 8.9Hz )， 7·70— 7·76 (2H，m) ，7.62—7.67 (3H，m) ，7.43 — 7.53 ( 2H，m) ，7.00 ( 1H，s) ，6 · 5 9 ( 1 H，b r s )， 3.42 ( 3H，s )。實例8 4一〔胺基一〔7— (4 —氟一苯基）—5 -硝基—苯並呋喃一 2-基〕—（3 —甲基一 3H—咪唑一 4 —基）一甲基〕一苯甲腈類似於實例1 — d )及1 一 e )揭示的方法，2 —甲基一丙烷一 2 -亞磺酸〔（7 -溴一 5 -硝基一苯並呋喃一 2 —基 )一（4 —氰基—苯基）一（3 —甲基一 3H —咪唑一 4 一基 (39) (39)200413356 )一甲基〕—醯胺與2— (4 —氟—苯基）一〔1，3，2〕二噚硼烷之 Suzuki偶合反應，隨後用氫氯酸（在AcOEt 中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末〇 LCMS (情形 B ) 、m/z46 8〔 M + H〕+，滯留時間 3.06 分鐘； lH - NMR ( CD3OD ) d8.5 1 ( 1H，d，J = 2.5Hz )， 8.36 ( 1H，d，J = 2.5Hz ) ，7.7 9 — 7 · 8 4 ( 4 H，m ) ，7 · 6 2 -7.70 ( 3H，m) ，7.24 ( 2H，dd，J = 8.79，8.79Hz )， 6.87(lH，s) ，6.57(lH，brs) ，3.43(3H，s)。實例9 4—〔胺基一〔7-（3，5 —二氟—苯基）—5 —硝基 —苯並呋喃—2-基〕—（3 —甲基一 3H—咪唑一 4一基）一甲基〕一苯甲腈類似於貫例1 一 d)及1 一 e)揭不的方法，2—甲基一丙烷一 2 —亞磺酸〔（7-溴一 5-硝基一苯並呋喃一 2-基 )—(4 一氰基—苯基）一（3 -甲基一 3H—咪哩一4 一基 )—甲基〕—醯胺與2—（3，5—二氟一苯基）—〔1，3 ，2〕二哼硼烷之Suzuki偶合反應，隨後用氫氯酸（在 Ac OEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) ' m/z4 8 6〔 M + H〕+，滯留時間 3.13 (40) (40)200413356 lH - NMR ( CD3〇D ) d8.59 ( 1H，d，J = 2.5Hz )， 8.43 ( 1H，d，J = 2.5Hz ) ，7.79 ( 2H，d，J = 8.8Hz )， 7.6 3 - 7.6 6 ( 3 H，m ) ，7 · 4 0 — 7.4 2 ( 2 H，m ) ，7.04 — 7.08 ( 1H，m) ，6.97 ( 1H，s) ，6·57 ( 1H，brs )， 3.4 1 ( 3H，s )。實例1 〇 4—〔胺基—〔7— (3，4 一二氟—苯基）—5 —硝基 —苯並D夫喃一 2 —基〕—（3 -甲基一3H-味D坐—4 —基）一甲基〕一苯甲腈類似於實例1 — d )及1 — e )揭示的方法，2 —甲基一丙烷—2 -亞磺酸〔（7 —溴一 5 —硝基—苯並呋喃—2 —基 )一（4 一氰基—苯基）—（3 —甲基一 3H —咪唑一 4一基 )—甲基〕一醯胺與 2— (3，4 一二氟—苯基）一〔1，3 ，2〕二鳄硼烷之 Suzuki偶合反應，隨後用氫氯酸（在 AcOEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) 、m/z4 8 6〔 M + H〕+，滯留時間 3.0 1 9分鐘； 1 Η 一 NMR (CD3OD) d8.57 ( 1H，d ，J = -2.4Uz )， 39 ( 1 Η ，d， J = 2.4Hz ) ，7.80 ( 2H，d ，J = = 8.8Hz )， 73 ( 1 Η ，ddd ，J=2.0 ， 7 .3，1 1 · 7Hz) ， 7 .62 -7.65 ( 4H m ) ，7 .41 ( 1H ， ddd ， J=8.79 ，{ 179，1 0.7Hz ) ，6.91 1 Η， s ) ，6.5 7 ( 1H，br s ) ，3 . 43 (3H， s ) 0 -44- (41) (41)200413356 實例Η 4一〔胺基—（3 —甲基一 3H-咪唑-4—基）一（5 —硝基一 7 — Dtt陡一 3 —基一苯並口夫喃一 2 -基）—甲基〕一苯甲腈類似於實例1 一 d )及1 一 e )揭示的方法，2 —甲基一丙烷一 2-亞磺酸〔（7-溴一 5-硝基一苯並呋喃一 2-基 )_ (4 一氰基一苯基）一（3 —甲基—3H —咪唑—4 一基 )—甲基〕—醯胺與吡啶—3 —硼酸之Suzuki偶合反應，隨後用氫氯酸（在AcOEt中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) 、m/z45 1〔 M + H〕+，滯留時間 2.27 分鐘； - NMR ( CD3〇D ) d8.99 ( 1H，d，J=1 .6Hz )， 8.58 - 8.61 ( 2H，m) ，8·45 ( 1H，d，J = 2.0Hz ) ，8.267.80— 7.83 (3H, m), 7.64— 7.72 (4H, m), 6.99 (1H, s), 6.55 (lH, s), 3.41 (3H, s). Example 6 4- [Amino- [7- (3-ethoxy-phenyl) -5-nitro-benzofuran 2-yl]-(3-methyl- 3H-imidazole-4-yl)- Methyl] -benzonitrile is similar to the method disclosed in Example 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5-nitro-benzofuran- 2-yl)-(4-cyano-phenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl] -amidine and 2- (3-ethoxy-phenyl)- [1,3,2] The Suzuki coupling reaction of diborane, followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder. LCMS (case B), m / z494 [M + H] +, retention time 3.10 minutes;-NMR (CD3〇D) d8.5 1 (1H, d, J = 2.3Hz), 8.36 (1H, d, J = 2.3Hz), 7.79 (2H, d, J = 8.6Hz), 7.62-7.66 (3H, m), 7.30-7.43 (3H, m), 6.96-7.00 (lH, m) , 6.92 (lH, s), 6.60 (lH, s) ^ 4.00 (2H, q, J = 6.9 Hz), 3.42 (3H, s). Example 7 4- [Amino- [7- (3-chloro-phenyl) -5-nitro-benzo-41- (38) (38) 200413356 furan_2-yl]-(3-methyl- 3H-imidazol-4-yl) -methyl] -benzonitrile is similar to the method disclosed in Example 1-d) and 1-e), 2-methyl-propanone-2-subarylene acid [(7-bromo —5 -Nitromonobenzopyran-2-yl) _ (4-cyano-phenyl)-(3-methyl-3H-imidazole-4 mono) -methyl] monofluorene and 2- (3-Chloro-phenyl)-[1,3,2] Suzuki coupling reaction of dihumorane, followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder. LCMS (case B), m / z484 [M + H] +, retention time 3.15 minutes; lH ~ NMR (CD3〇D) d8.57 (1H, d, J = 2.3Hz), 8.40 (1H, d, J = 2.3Hz), 7.81 (2H, d, J = 8.9Hz), 7.70— 7.76 (2H, m), 7.62—7.67 (3H, m), 7.43 — 7.53 (2H, m), 7.00 (1H, s), 6 · 5 9 (1 H, brs), 3.42 (3H, s). Example 8 4- [Amino- [7- (4-fluoro-phenyl) -5-nitro-benzofuran 2-yl]-(3-methyl-3H-imidazole-4-yl) -methyl Phenyl] -benzonitrile is similar to the method disclosed in Examples 1-d) and 1-e), 2-methyl-propane-2 -sulfinic acid [(7-bromo-5 -nitro-benzofuran-2 -Yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl (39) (39) 200413356) -methyl] -amidamine and 2- (4-fluoro- Phenyl) mono [1,3,2] diborane in Suzuki coupling reaction, followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder, LCMS (Case B) , M / z46 8 〔M + H〕 +, retention time 3.06 minutes; lH-NMR (CD3OD) d8.5 1 (1H, d, J = 2.5Hz), 8.36 (1H, d, J = 2.5Hz), 7.7 9 — 7 · 8 4 (4 H, m), 7 · 6 2-7.70 (3H, m), 7.24 (2H, dd, J = 8.79, 8.79 Hz), 6.87 (lH, s), 6.57 (lH , Brs), 3.43 (3H, s). Example 9 4- [Amino- [7- (3,5-difluoro-phenyl) -5-nitro-benzofuran-2-yl]-(3-methyl- 3H-imidazole-4-yl ) Monomethyl] -benzonitrile is similar to the methods described in Examples 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5nitro-1 Benzofuran-2-yl)-(4-cyano-phenyl)-(3-methyl- 3H-imido-4 4-yl) -methyl] -amidamine and 2- (3,5-di Fluoro-phenyl)-[1,3,2] dihumorane in a Suzuki coupling reaction, followed by treatment with hydrochloric acid (4 molar solution in Ac OEt) to give the title compound as a colorless powder. LCMS (case B) 'm / z4 8 6 〔M + H〕 +, retention time 3.13 (40) (40) 200413356 lH-NMR (CD3〇D) d8.59 (1H, d, J = 2.5Hz), 8.43 (1H, d, J = 2.5Hz), 7.79 (2H, d, J = 8.8Hz), 7.6 3-7.6 6 (3 H, m), 7 · 4 0 — 7.4 2 (2 H, m), 7.04 — 7.08 (1H, m), 6.97 (1H, s), 6.57 (1H, brs), 3.4 1 (3H, s). Example 1 04- [Amino- [7- (3,4-difluoro-phenyl) -5-nitro-benzo-Danfuran-2-yl]-(3-methyl-3H-odor D Sit-4-yl) monomethyl] -benzonitrile is similar to the method disclosed in Examples 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5 — Nitro-benzofuran-2-yl)-(4-monocyano-phenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl] -amidine and 2- (3,4 A Suzuki coupling reaction of mono-difluoro-phenyl)-[1,3,2] diacoborane, followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder. LCMS (case B), m / z4 8 6 [M + H] +, retention time 3.0 19 minutes; 1 Η NMR (CD3OD) d8.57 (1H, d, J = -2.4Uz), 39 (1 Η, d, J = 2.4Hz), 7.80 (2H, d, J = = 8.8Hz), 73 (1 Η, ddd, J = 2.0, 7.3, 1 1 · 7Hz), 7.62 -7.65 ( 4H m), 7.41 (1H, ddd, J = 8.79, {179, 1 0.7Hz), 6.91 1 Η, s), 6.57 (1H, br s), 3. 43 (3H, s) 0- 44- (41) (41) 200413356 Example Η 4- [Amino- (3-methyl- 3H-imidazol-4-yl)-(5-nitro-7-Dtt steep-3-yl-benzo Carbofuran-2-yl) -methyl] -benzonitrile is similar to the method disclosed in Examples 1-d) and 1-e), 2-methyl-propane-2-sulfinic acid [(7-bromo-5) -Nitro-benzofuran-2-yl) _ (4-monocyanophenyl)-(3-methyl-3H-imidazole-4 mono) -methyl] -fluorenamine and pyridine-3 -boronic acid The Suzuki coupling reaction was followed by treatment with hydrochloric acid (4 molar solution in AcOEt) to give the title compound as a colorless powder. LCMS (case B), m / z45 1 [M + H] +, retention time 2.27 minutes;-NMR (CD3〇D) d8.99 (1H, d, J = 1.6Hz), 8.58-8.61 (2H, m), 8.45 (1H, d, J = 2.0Hz), 8.26

—8.29 ( 1H，m) ，7.8 1 ( 2H，d，J = 6.4Hz ) ，7.65 ( 2H ，d，J = 6.4Hz) ，7.57-7.60 (2H，m) ，6.92(lH，s) ，6.57 ( 1H，s ) ，3.46 ( 3H，s )。實例1 2 4—〔胺基—（3 —甲基一3H —咪唑_4 —基）—（5 一硝基一苯並咲喃一 2 —基）一甲基〕一苯甲腈類似於實例1 一 d )及1 一 e )揭示的方法，使用2 -羥基—5 -硝基—苯甲醛代替3 -溴一 2 —羥基一 5 -硝基 -45 - (42) 200413356 一苯甲醛，2 —甲基一丙烷一 2—亞磺酸〔（5 -硝基一苯並咲喃—2—基）—（4 —氨基—苯基）一（3 —甲基—3H —咪唑—4—基）—甲基〕—醯胺與苯基硼酸之Suzuki偶合反應，隨後用氫氯酸（在Ac OEt中的4莫耳濃度溶液 )處理，得到標題化合物之無色粉末。 EI — MS : m/z3 7 3〔 Μ〕+，--8.29 (1H, m), 7.81 (2H, d, J = 6.4Hz), 7.65 (2H, d, J = 6.4Hz), 7.57-7.60 (2H, m), 6.92 (lH, s), 6.57 (1H, s), 3.46 (3H, s). Example 1 2 4— [Amino group— (3-methyl-3H—imidazol-4-yl group) — (5-nitro-benzobenzofuran-2-yl) -methyl] -benzonitrile is similar to the example 1-d) and 1-e), using 2-hydroxy-5 -nitro-benzaldehyde instead of 3-bromo-2 -hydroxy-5 -nitro-45-(42) 200413356 monobenzaldehyde, 2 —Methyl monopropane 2-sulfinic acid [(5-nitro-benzobenzo-2-yl) — (4-amino-phenyl) — (3-methyl-3H —imidazole — 4-yl ) -Methyl] -amidamine and Suzuki coupling reaction of phenylboronic acid, followed by treatment with hydrochloric acid (4 molar solution in Ac OEt) to give the title compound as a colorless powder. EI — MS: m / z3 7 3 〔Μ〕 +,

NMR ( CDC13) d8.37 ( 1Η，br— s) ，8.18 ( 1 H ，d，J = 9. 1 Hz ) ，7.65 ( 2H，d，J = 8.9Hz ) ，7.47—7.52 (3H，m) ，7.39(lH，s) ，6.55(lH，s) ，6.38(1H ，s ) ，3.37 ( 3H，s ) ，2·40 ( 2H，brs )。製備2— 〔胺基—（4一氰基一苯基）一（3 —甲基— 3H—咪唑一 4 一基）—甲基〕一苯並呋喃一 5 -甲腈化合物實例1 3NMR (CDC13) d8.37 (1Η, br— s), 8.18 (1H, d, J = 9.1 Hz), 7.65 (2H, d, J = 8.9Hz), 7.47-7.52 (3H, m) , 7.39 (lH, s), 6.55 (lH, s), 6.38 (1H, s), 3.37 (3H, s), 2.40 (2H, brs). Preparation 2- [Amino- (4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -benzofuran-5-carbonitrile compound Example 1 3

製備2— 〔胺基—（4 —氰基一苯基）—（3 —甲基一 3 Η —味哗一4 —基）一甲基〕一 7—苯基一苯並咲喃—5 — 甲腈 13 — a) 製備3 —溴一5 —甲醯基一4一羥基一苯甲腈 11 在 3 —甲醯基—4 —羥基一苯甲腈（6.65克，45.2毫莫耳）〔Suzuki， Y. et a 1. C h e m . P h arm. Bull. 1 9 8 3， 31， 1751— 1753〕於 EtOH (200毫升）之溶液中，在 -46- (43) (43)200413356 室溫下逐滴加入溴（7毫升，1 3 6.6毫莫耳）歷時1 5分鐘，將所得的混合物在室溫攪拌3 0分鐘，將溶劑蒸發，得到3 —溴一 5 —甲醯基一4 一羥基—苯甲腈（粗，1 0.2克），其不再純化而用於下一個步驟。Preparation 2— [Amine— (4-cyano-phenyl) — (3-methyl-1, 3-fluorene — odor-4—yl] —methyl] —7—phenyl—benzobenzo—5 — Nitrile 13 — a) Preparation of 3-bromo-5 —methylfluorenyl-4 4-hydroxy-benzonitrile 11 in 3-methylfluorenyl-4 —hydroxymonobenzonitrile (6.65 g, 45.2 mmol) [Suzuki Y. et a 1. C hem. Ph arm. Bull. 1 9 8 3, 31, 1751— 1753] in EtOH (200 ml) solution at -46- (43) (43) 200413356 room temperature Bromine (7 ml, 1 3 6.6 mmol) was added dropwise over a period of 15 minutes. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give 3-bromo-1, 5-methylamyl-4 1 Hydroxy-benzonitrile (crude, 10.2 g), which was used in the next step without further purification.

El - MS ： m/z22 5 ( M+ ) ，227 (M + 2) ，】H-NMR( CDCl3)dl2.08(lH，s) ，9.90(lH，s) ，8.05(lH，d ，J = 2Hz ) ，7·9 1 ( 1 H，d，J = 2Hz )。 13 — b) 製備7-溴—2— (4—氰基一苯甲醯基）苯並呋喃一 5 —甲腈將粗的 3 —溴—5 —甲醯基一4 —羥基—苯甲腈（10.2 克）添加至4一氰基苯甲醯甲基溴（11.7克，49.6毫莫耳 )及 K2C03 ( 7.5 克，54.3 毫莫耳）於 CH3CN ( 2 5 0 毫升）之溶液，將混合物在迴流下攪拌3 0分鐘，然後在真空將溶劑蒸發，將殘留物用Ac OEt及H20淸洗，然後用 Me 0H淸洗，得到13.8克之7 —溴—2— ( 4 —氰基一苯甲醯基）苯並呋喃- 5-甲腈淡棕色粉末。El-MS: m / z22 5 (M +), 227 (M + 2), H-NMR (CDCl3) dl2.08 (lH, s), 9.90 (lH, s), 8.05 (lH, d, J = 2Hz), 7.9 1 (1 H, d, J = 2Hz). 13 — b) Preparation of 7-bromo-2- (4-cyano-benzylidene) benzofuran-5—carbonitrile. The crude 3—bromo-5—methylfluorenyl-4—hydroxy-benzonitrile. (10.2 g) was added to a solution of 4-monocyanobenzylmethyl bromide (11.7 g, 49.6 mmol) and K2C03 (7.5 g, 54.3 mmol) in CH3CN (250 ml). Stir at reflux for 30 minutes, then evaporate the solvent in vacuo, wash the residue with Ac OEt and H20, and then wash with Me 0H to obtain 13.8 g of 7-bromo-2- (4-cyano-benzidine). Group) Benzofuran-5-carbonitrile light brown powder.

El— MS:m/z350(M+) ，352(M + 2) ^ 1 U - NMR (El— MS: m / z350 (M +), 352 (M + 2) ^ 1 U-NMR (

CDC13 ) d8.26 ( 2H，dt，1^8.5Hz > J2 = 2Hz ) ，8.09 ( 1H ，d，J=lHz) ，7.96(lH，d，J=lHz) ，7.89(2H，dt，了！ = 8.51^，】2 = 21^) ，7.76(lH，s)。 13 - c ) 製備2 —甲基一丙烷—2-亞磺酸（7—溴— 5 —氰基一苯並呋喃—2—基）—（4 —氰基一苯基）亞甲 -47 - (44) (44)200413356 醯胺在 7-溴一 2— （4 一氰基一苯甲醯基）苯並呋喃一 5 一甲腈（13.5克，38.5毫莫耳）於無水THF (500毫升 )之溶液中，在室溫下加入 Ti(〇Et) 4 (23.8毫升， 1 1 5 · 8毫莫耳），然後在混合物中加入2 —甲基一 2 —丙烷亞磺醯胺（5.13克，42.3毫莫耳），並將混合物在迴流下攪拌8小時，冷卻至室溫後，將混合物倒入等體積之鹽水中並快速攪拌，將所得的懸浮液經由矽藻土過濾，並將濾餅用AcOEt淸洗，將過濾液用AcOEt ( χ2 )萃取，將有機層合倂，用鹽水淸洗，經由Na2S04乾燥並在真空蒸發，在矽膠上將殘留物經由管柱層析法（流洗液： CH2C12 —在DCM之5% MeOH)純化，得到7.5克之2 — 甲基一丙院一 2-亞磺酸（7 —溴—5—氰基一苯並D夫喃—2 一基）—（4 —氰基一苯基）亞甲醯胺黃色無定形粉末。 LCMS (情形 B ) m/z454〔 M + H〕+，滯留時間 3.84 分鐘； ]H - NMR ( CDC13 ) d7.93 ( 1H，br— s) ，7.88-7·87 ( 1H，m) ，7 · 7 8 ( 2 Η，d，J = 8 · 5 Η z ) ，7.65 — 7.62 (2H，m ) ，7.08 ( 1H，br — s )。 13 - d ) 製備2 —甲基一丙烷一 2—亞磺酸〔（7-溴一 5—氰基一苯並咲喃一 2-基）—（4 一氰基一苯基）一 (3 —甲基一3H —咪唑一 4 —基）一甲基〕一醯胺將在己烷中的正丁基鋰（1.57莫耳濃度，11.6毫升 -48- (45) (45)200413356 ，18.2毫莫耳）添加至N—甲基咪唑（ι·45毫升，18.2 毫莫耳）於THF ( 30毫升）在—781：之溶液中，攪拌 3〇分鐘後，將三乙基矽烷基氯（3.1毫升，18.5毫莫耳）添加至反應混合物，使混合物溫熱至室溫後冷卻至—7 8 °C ，再度加入在己烷中的正丁基鋰（1.57莫耳濃度，11.6 毫升’ 1 8 · 2毫莫耳），使反應混合物溫熱至—2 〇。(：後冷卻至一7 8 °C，將所得的混合物添加至2 -甲基—丙烷—2 — 亞磺酸（7—溴一 5-氰基一苯並咲喃一 2〜基）—（4 —氰基一苯基）一亞甲醯胺（5.5克，12.1毫莫耳）於THF (1 1 5毫升）在—7 8 °C之溶液中，攪拌1 5分鐘後，加入飽和的NH2C1，將反應混合物用 AcOEt ( χ2 )萃取，將有機層合倂，用鹽水淸洗，經由Na2 S 04乾燥並在真空蒸發，在矽膠上將殘留物經由矽膠管柱層析法（流洗液：在 DCM中的2% MeOH —在DCM中的5% MeOH)純化，得到3.62克2—甲基一丙烷一 2 —亞磺酸〔（7—溴一 5—氰基一苯並咲喃—2—基）—（4 —氰基一苯基）—（3 -甲基一 3H—咪Π坐一 4 一基）—甲基〕—醯胺無色固體。 LCMS (情形 B ) m/z5 3 6〔 M + H〕+，滯留時間 2.78 分鐘； !Η— NMR ( CDC13) d7.85 ( 1H，d，J = 1.5Hz) ，7·74 (2H，dt，Ji = 8.5Hz，J2 = 2Hz ) ，7.73 ( 1H，s) ，7.63 ( 2H，dt，JjUz，J2 = 2Hz ) ，7.54 ( 1H，s) ，7.19 ( 1H，s) ，6.94 ( 1 H，d，J = 1 ·5Ηζ ) ，4.65 ( 1H，s)， 3.15(3H，s) ，1.35( 9H，s)。 -49 - (46) (46)200413356 13 — e) 製備2 —甲基一丙烷一 2 —亞磺酸〔（4 —氰基一苯基）一（5 -氰基一 7-苯基一苯並呋喃一 2-基） —(3 —甲基一 3H —咪唑一 4一基）一甲基〕一醯胺將2—甲基—丙烷—2 —亞磺酸〔（7-溴—5 —氰基 —本並D夫喃一2 -基）一（4 一氰基—苯基）一（3 —甲基 —3H—咪唑一 4_基）—甲基〕—醯胺（800毫克，1.49 毫莫耳）、2 —苯基—〔1，3，2〕二吗硼院（0.67毫升， 4.47毫莫耳）、肆（三苯基膦）—鈀（〇) (345毫克， 0·30毫莫耳）及磷酸三鉀（1.27毫克，5.98毫莫耳）於 D M F ( 2 4毫升）之溶液在1 0 0 °C加熱1小時，將反應混合物用 AcOEt稀釋並將鈀過濾去除，將過濾液用 AcOEt 萃取，將有機層合倂，用鹽水淸洗，經由Na2S04乾燥並在真空蒸發，在矽膠上將殘留物經由矽膠管柱層析法（流洗液：在DCM中的1% MeOH —在DCM中的1〇% Me〇H) 純化’得到714晕;克2 —甲基一丙垸一 2 -亞磺酸〔（4 — 氰基一苯基）一（5 —氰基一 7-苯基一苯並咲喃〜2 一基 )—(3 -甲基一3H—咪唑一4 —基）一甲基〕一醯胺無色粉末。 LCMS (情形 B ) m/Z5 3 4〔 M + H〕+，滯留時間 3 〇1 分鐘； !H— NMR ( CDC13) d7.86 ( 1H，d，J=i.5Hz) ，7 71 (2H，d，J = 8.5Hz ) ，7.67 ( 1H，d，J=1.5Hz) ，7.57 ( 2H，d，J = 8.5Hz ) ，7.5 8 - 7.5 3 ( 3 H，m ) , 7.46— 7 42 (47) 200413356 (3H，m ) ，7.20 ( 1H，s ) ，6.87 ( 1H，br— s) ，4.68 (lH，s) ，3.13(3H，s) ，1.30(9H，s)。 13— O 製備2-〔胺基—（4 —氰基一苯基）一（3 一甲基一 3H —咪唑一4 —基）—甲基〕—7 -苯基〜苯並呋喃一 5 —甲腈CDC13) d8.26 (2H, dt, 1 ^ 8.5Hz > J2 = 2Hz), 8.09 (1H, d, J = lHz), 7.96 (lH, d, J = lHz), 7.89 (2H, dt, ! = 8.51 ^,] 2 = 21 ^), 7.76 (lH, s). 13-c) Preparation of 2-methyl monopropane-2-sulfinic acid (7-bromo-5 -cyano-benzofuran-2-yl)-(4-cyano-phenyl) methylene-47- (44) (44) 200413356 Amidine in 7-bromo-2- (4-cyano-benzylhydrazino) benzofuran-5-carbonitrile (13.5 g, 38.5 mmol) in anhydrous THF (500 ml ) Solution, Ti (〇Et) 4 (23.8 ml, 1 15 · 8 mmol) was added at room temperature, and then 2-methyl-2-propanesulfenimide (5.13 g) was added to the mixture. , 42.3 millimoles), and the mixture was stirred under reflux for 8 hours. After cooling to room temperature, the mixture was poured into an equal volume of saline and quickly stirred. The resulting suspension was filtered through celite, and filtered The cake was washed with AcOEt, the filtrate was extracted with AcOEt (χ2), the organic layer was washed, washed with brine, dried over Na2S04 and evaporated in vacuo, and the residue was passed through a silica gel column chromatography (flow washing Liquid: CH2C12—purified in 5% MeOH in DCM) to give 7.5 g of 2-methyl-propanone-2-sulfinic acid (7-bromo-5-cyano-benzo-Danfuran-2-yl) - (4 - cyano-phenyl) methylene Amides yellow amorphous powder. LCMS (Case B) m / z454 [M + H] +, retention time 3.84 minutes;] H-NMR (CDC13) d7.93 (1H, br-s), 7.88-7 · 87 (1H, m), 7 · 7 8 (2 Η, d, J = 8 · 5 Η z), 7.65 — 7.62 (2H, m), 7.08 (1H, br — s). 13-d) Preparation of 2-methyl monopropane-2-sulfinic acid [(7-bromo-5-cyano-benzopyran-2-yl)-(4-cyano-phenyl)-(3 —Methyl-3H—imidazol-4-yl) -methyl] -ammonium amine will be n-butyllithium in hexane (1.57 mole concentration, 11.6 ml-48- (45) (45) 200413356, 18.2 milliliter Mol) was added to a solution of N-methylimidazole (45 ml, 18.2 mmol) in THF (30 ml) in -781 :, and after stirring for 30 minutes, triethylsilyl chloride (3.1 Ml, 18.5 millimoles) was added to the reaction mixture, the mixture was allowed to warm to room temperature and then cooled to -7 8 ° C, and n-butyllithium in hexane (1.57 mole concentration, 11.6 ml '1 8 · 2 mmol), and the reaction mixture was allowed to warm to -200. (: After cooling to -78 ° C, the resulting mixture is added to 2-methyl-propane-2-sulfinic acid (7-bromo-5-cyano-benzopyran-2 ~ yl)-( 4-Cyanomonophenyl) methylenesulfonamide (5.5 g, 12.1 mmol) in THF (115 ml) at -78 ° C, stirred for 15 minutes, then added saturated NH2C1 The reaction mixture was extracted with AcOEt (χ2), the organic layer was combined, washed with brine, dried over Na2S04 and evaporated in vacuo. The residue was passed through a silica gel column chromatography on silica gel (fluid washing solution: 2% MeOH in DCM—5% MeOH in DCM) was purified to give 3.62 g of 2-methylmonopropane-2-sulfinic acid [(7-bromo-5-cyano-benzopyran-2] —Yl) — (4-cyano-phenyl) — (3-methyl-3H-imidyl-4-methyl) -methyl] -amidine colorless solid. LCMS (Case B) m / z5 3 6 〔M + H〕 +, retention time 2.78 minutes;! Η— NMR (CDC13) d7.85 (1H, d, J = 1.5Hz), 7.74 (2H, dt, Ji = 8.5Hz, J2 = 2Hz) , 7.73 (1H, s), 7.63 (2H, dt, JjUz, J2 = 2Hz) 7.54 (1H, s), 7.19 (1H, s), 6.94 (1 H, d, J = 1.5 Ηζ), 4.65 (1H, s), 3.15 (3H, s), 1.35 (9H, s).- 49-(46) (46) 200413356 13 — e) Preparation of 2-methyl monopropane 2-sulfinic acid [(4-cyano-phenyl)-(5-cyano-7-phenyl-benzo) Furan 2-yl) — (3-methyl- 3H —imidazole-4-yl) -methyl] -ammonium amine 2-methyl-propane-2 —sulfinic acid [(7-bromo-5 —cyanine -Benzyl-D-Franan-2-yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazol-4-yl) -methyl] -amidamine (800 mg, 1.49 mmol Moore), 2-Phenyl- [1,3,2] Dimorph Boron (0.67 ml, 4.47 mmol), Tris (triphenylphosphine) -Pd (0) (345 mg, 0.30 mmol) Mol) and tripotassium phosphate (1.27 mg, 5.98 mmol) in DMF (24 ml) were heated at 100 ° C for 1 hour. The reaction mixture was diluted with AcOEt and palladium was removed by filtration. The filtrate was filtered. Extract with AcOEt, combine the organic layers, rinse with brine, dry over Na2S04 and evaporate in vacuo, Purify the residue on silica gel by silica gel column chromatography (flow wash: 1% MeOH in DCM-10% MeOH in DCM) to obtain 714 halo; g 2-methyl-propane Fluorene-2 2-sulfinic acid [(4-cyano-phenyl)-(5-cyano-7-phenyl-benzopyran ~ 2-yl)-(3-methyl-3H-imidazole-4 —Methyl) monomethyl] monofluorene colorless powder. LCMS (Case B) m / Z5 3 4 〔M + H〕 +, retention time 301 minutes;! H— NMR (CDC13) d7.86 (1H, d, J = i.5Hz), 7 71 (2H , D, J = 8.5Hz), 7.67 (1H, d, J = 1.5Hz), 7.57 (2H, d, J = 8.5Hz), 7.5 8-7.5 3 (3 H, m), 7.46— 7 42 ( 47) 200413356 (3H, m), 7.20 (1H, s), 6.87 (1H, br-s), 4.68 (lH, s), 3.13 (3H, s), 1.30 (9H, s). 13-O Preparation of 2- [Amino- (4-cyano-phenyl)-(3-methyl- 3H-imidazol-4-yl) -methyl] -7-phenyl ~ benzofuran-5— Nitrile

在2—甲基一丙院一 2-亞磺酸〔（4 —氰基一苯基） —(5 —氰基一 7—苯基—苯並呋喃—2-基）一（3〜甲基 —3H —咪唑一4 —基）—甲基〕一醯胺（687毫克，k28 毫莫耳）於THF ( 10毫升）之溶液中，在室溫下加入在二噚烷中的4莫耳濃度HC1溶液（5毫升），在室溫攪拌1小時後，將反應混合物在〇°C用飽和的NaHC03淬火並用 AcOEt ( x2 )萃取，將有機層合倂並用鹽水淸洗，經由Na2S04乾燥並在真空蒸發，將殘留物經由MPLC 〔 CPO— HS— 221— Si - 10 KUSAN0， 22x300 毫米〕（流In 2-methyl-propanone-2-sulfinic acid [(4-cyano-phenyl)-(5-cyano-7-phenyl-benzofuran-2-yl)-(3 ~ methyl —3H —Imidazol-4-yl) -methyl] monofluorenamine (687 mg, k28 mmol) in THF (10 ml), added at 4 mol in dioxane at room temperature HC1 solution (5 ml), after stirring at room temperature for 1 hour, the reaction mixture was quenched with saturated NaHC03 at 0 ° C and extracted with AcOEt (x2). The organic layer was combined and washed with brine, dried over Na2S04 and under vacuum Evaporate and pass the residue through MPLC [CPO— HS— 221— Si-10 KUSAN0, 22x300 mm] (flow

洗液：在DCM中的2.5% MeOH)純化，得到477毫克2 一〔胺基一（4 一氰基一苯基）一（3 —甲基一 3H —咪唑 —4 一基）一甲基〕一 7-苯基一苯並咲喃一 5 —甲臆無色粉末。 LCMS (情形 B ) m/z43 0〔 M + H〕+，滯留時間 2.90 分鐘； NMR(CDCh) d7.81 ( 1H，d，J=1.5Hz) ，7.73Washing solution: 2.5% MeOH in DCM) to obtain 477 mg of 2-a [amino- (4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] A 7-phenyl-benzopyran-5-formamidine colorless powder. LCMS (case B) m / z43 0 〔M + H〕 +, retention time 2.90 minutes; NMR (CDCh) d7.81 (1H, d, J = 1.5Hz), 7.73

-7.68 ( 4H，m ) ，7.67 ( 1H，d，J= 1 .5Hz ) ，7.55 ( 2H ，dt，Ji = 8.5Hz，J2 = 2Hz ) ，7 · 5 1 - 7 · 4 3 ( 4 H，m ) ，6.66 -51 - (48) (48)200413356 (lH，d，J=lHz) ，6.44(lH，s) ，3.39(3H，s)， 2.46(2H，br— s)。實例1 4 製備2—〔胺基—（4 一氰基—苯基）—（3 -甲基— 3 Η —味嗤一 4 一基）一甲基〕—7 — (3 —甲氧基—苯基）一苯並呋喃一 5 —甲腈類似於實例1 3 — e及1 3 — f揭示的方法，2 —甲基一丙烷一2 -亞磺酸〔（7 -溴—5 —氰基一苯並呋喃一 2 —基 )一（4 —氰基一苯基）一（3 —甲基—3H —咪唑一4 一基 )—甲基〕—醯胺與2 — （3 —甲氧基苯基）—〔1，3，2 〕二Df硼烷之Suzuki偶合反應，隨後用氫氯酸（在1，4 -二Df烷中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z460〔 M + H〕+，滯留時間 2.94 分鐘；】H— NMR ( CDC13) d7.81 ( 1H，d，J=1.5Hz) ，7·73 (1H，dt，J! = 8.5Hz ^ J2 = 2Hz ) ，7.44 ( 2H，br— d， J=lHz ) ，7.40 ( 1H，t，J = 8Hz ) ，7.26 ( 1H，dt，-7.68 (4H, m), 7.67 (1H, d, J = 1.5 Hz), 7.55 (2H, dt, Ji = 8.5Hz, J2 = 2Hz), 7 · 5 1-7 · 4 3 (4 H, m), 6.66 -51-(48) (48) 200413356 (lH, d, J = lHz), 6.44 (lH, s), 3.39 (3H, s), 2.46 (2H, br-s). Example 1 4 Preparation of 2- [Amino- (4-monocyano-phenyl)-(3-methyl-3 hydrazone —Miso-4 4-yl) monomethyl] -7— (3—methoxy— Phenyl) monobenzofuran-5-carbonitrile is similar to the method disclosed in Examples 13-e and 13-f, 2-methyl-propane-2-sulfinic acid [(7-bromo-5-cyano Monobenzofuran 2-yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4 4-yl) -methyl] -amidamine and 2- (3-methoxy Phenyl) — [1,3,2] diDf borane by Suzuki coupling reaction, followed by treatment with hydrochloric acid (4 mol concentration solution in 1,4-diDf alkane) to give the title compound as a colorless powder . LCMS (case B): m / z460 〔M + H〕 +, residence time 2.94 minutes; H-NMR (CDC13) d7.81 (1H, d, J = 1.5Hz), 7.73 (1H, dt, J! = 8.5Hz ^ J2 = 2Hz), 7.44 (2H, br — d, J = lHz), 7.40 (1H, t, J = 8Hz), 7.26 (1H, dt,

Ji = 8Hz，J 2 = 2 H z ) ，7.21 ( 1H，br— t，J = 2 H z ) ，6.98 ( 1 H，ddd，J! = 8Hz，J2 = 2Hz，J3 = 1Hz ) ，6.67 ( 1H，d， J=1 Hz ) ，6.46(lH，s) ，3.83(3H，s) ，3.39(3H，s )，2·45 ( 2H，br— s )。 -52- (49) (49)200413356 實例1 5 製備2-〔胺基—（4 —氰基一苯基）一（3 -甲基一 3H —咪唑一 4 —基）一甲基〕一7_苯並〔1，3〕二氧茂一 5—基一苯並呋喃一 5-甲腈類似於實例1 3 — e及1 3 - f揭示的方法，2 —甲基— 丙烷一 2-亞磺酸〔（7-溴一 5 —氰基—苯並呋喃一 2 —基 )—(4 一氰基一苯基）一（3 —甲基—3H—咪唑一4 —基 )—甲基〕一醯胺與5—〔1，3，2〕二哼硼烷一2 —基一苯並〔1，3〕二鸣烷之Suzuki偶合反應，隨後用氫氯酸 (在1，4 一二噚烷中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形B ): m / z 4 7 4 [ M + H〕+ ，滯留時間2. 87 分鐘 - NMR ( CDCls ) d7.77 ( 1H ， d ， J =1 . 5 Η z ) ，7. 73 (2H，dt， J! = 9Hz，J2 = 2Hz )， 7.65 ( 1H ，d，J = 1 ·5Ηζ ) ，7. 56 ( 2H，dt，Ji = 9Hz ^ J2 = 2Hz ) ，7. 44 ( 1 H ，b r - -d ，J= 1 Hz ) ，7.17 ( 1H，，d d，J 1 = :8Hz，J2 = 2Hz )， 7.13 ( 1H， d，J = 2Hz ) ，6.92 (1H，d ，J=8Hz) ，6.63 (1H > ，d ，J= 1 Hz ) ，6.47 ( 1H ，s ) ，6 • 05 ( 1H，丨 d，J = 1 Hz ) 6.04 (1 H ，d，J=1Hz ) ，3.39 ( 3H，s ) ，2.47 ( 2H， br -s ) 0 實例 16 製備 2 —〔胺基一 (4一氰基一苯基） -(3- •甲基 — -53- (50) (50)200413356 3H—咪唑—4—基）一甲基〕一 7— （3 —氟—苯基）一苯並呋喃一5 —甲腈類似於實例1 3 - e及1 3 — f揭示的方法，2 —甲基— 丙烷一 2 -亞磺酸〔（7 —溴一 5-氰基一苯並呋喃—2 —基 )一（4 —氯基—苯基）—（3 -甲基一 3H —味哗—4 一基 )—甲基〕—醯胺與2— (3 -氟苯基）—〔1，3，2〕二哼硼烷之Suzuki偶合反應，隨後用氫氯酸（在1，4 —二口f烷中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z44 8〔 M + H〕+，滯留時間 2.92 分鐘， ^-NMRCCDCh) d7.85(lH» J=1.5Hz) ，7.73 (2H，d，J = 8.5Hz) ，7.72 ( 1H，d，J=1 .5Hz ) ，7.56 ( 2H，d，J = 8.5Hz ) ，7.4 8 — 7.4 5 ( 3 H，m ) ，7.40 - 7.32 (1H，m) ，7.20 — 7. 1 1 ( 1 H，m ) ，6.62 ( 1H，d， J= 1 Hz ) ，6.50(lH，s) ，3.39(3H，s) ，2·48(2Η， b r — s ) o 實例1 7 製備2—〔胺基一（4 —氰基一苯基）一（3—甲基一 3H —味D坐一4 —基）一甲基〕—7— （3 —氨基—苯基）— 苯並呋喃一 5—甲腈類似於實例1 3 — e及1 3 - f揭示的方法，2 —甲基— 丙烷一 2 —亞磺酸〔（7-溴一 5 —氰基一苯並呋喃一 2-基 -54- (51) 200413356 )—(4 一氰基一苯基）—（3 —甲基一 3H-咪唑一 4 一基 )—甲基〕—醯胺與2-（3—氰基苯基）一〔1，3，2〕二哼硼烷之Suzuki偶合反應，隨後用氫氯酸（在1’4一二哼烷中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z45 5〔 M + H〕+，滯留時間 2.76Ji = 8Hz, J 2 = 2 H z), 7.21 (1H, br— t, J = 2 H z), 6.98 (1 H, ddd, J! = 8 Hz, J2 = 2 Hz, J3 = 1 Hz), 6.67 ( 1H, d, J = 1 Hz), 6.46 (lH, s), 3.83 (3H, s), 3.39 (3H, s), 2.45 (2H, br-s). -52- (49) (49) 200413356 Example 1 5 Preparation of 2- [Amino- (4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -7 _Benzo [1,3] dioxocene-5-yl-benzofuran-5-carbonitrile is similar to the method disclosed in Examples 13-e and 13-f, 2-methyl-propane-2-sulfenic acid Acid [(7-Bromo-5-cyano-benzofuran-2-yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl]- Suzuki coupling reaction of amidamine with 5- [1,3,2] dihumorane-2-yl-benzo [1,3] dioxane, followed by hydrochloric acid (in 1,4-dioxane 4 Molar concentration solution in) to give the title compound as a colorless powder. LCMS (Case B): m / z 4 7 4 [M + H] +, retention time 2. 87 minutes-NMR (CDCls) d7.77 (1H, d, J = 1.5 Η z), 7.73 (2H, dt, J! = 9Hz, J2 = 2Hz), 7.65 (1H, d, J = 1 · 5Ηζ), 7.56 (2H, dt, Ji = 9Hz ^ J2 = 2Hz), 7.44 (1 H, br--d, J = 1 Hz), 7.17 (1H ,, dd, J1 =: 8Hz, J2 = 2Hz), 7.13 (1H, d, J = 2Hz), 6.92 (1H, d, J = 8Hz), 6.63 (1H >, d, J = 1 Hz), 6.47 (1H, s), 6 • 05 (1H, 丨 d, J = 1 Hz) 6.04 (1 H, d, J = 1Hz), 3.39 (3H, s), 2.47 (2H, br -s) 0 Example 16 Preparation of 2— [Amino- (4-Cyano-phenyl)-(3- • methyl—-53- (50) (50 200413356 3H-imidazol-4-yl) monomethyl] -7- (3-fluoro-phenyl) -benzofuran-5-carbonitrile is similar to the method disclosed in Examples 1 3-e and 1 3-f, 2-methyl-propane-2-sulfinic acid [(7-bromo-5-cyano-benzofuran-2-yl)-(4-chloro-phenyl)-(3-methyl-3H — Taste of Wow—4 One Group) -methyl] -amidamine and 2- (3-fluorophenyl)-[1,3,2] dihumorane in a Suzuki coupling reaction, followed by hydrochloric acid (in the 1,4-two-port f 4 molar solution in hexane) to give the title compound as a colorless powder. LCMS (case B): m / z44 8 〔M + H〕 +, retention time 2.92 minutes, ^ -NMRCCDCh) d7.85 (lH »J = 1.5Hz), 7.73 (2H, d, J = 8.5Hz), 7.72 (1H, d, J = 1 .5Hz), 7.56 (2H, d, J = 8.5Hz), 7.48 — 7.4 5 (3 H, m), 7.40-7.32 (1H, m), 7.20 — 7. 1 1 (1 H, m), 6.62 (1H, d, J = 1 Hz), 6.50 (lH, s), 3.39 (3H, s), 2.48 (2Η, br — s) o Example 1 7 Preparation 2- [Amino- (4-cyano-phenyl)-(3-methyl-3H-taste-d-4-yl) -methyl] -7- (3-amino-phenyl) -benzo Furan 5-carbonitrile is similar to the method disclosed in Examples 13-e and 1 3-f, 2-methyl-propane-2-sulfinic acid [(7-bromo-5-cyano-benzofuran-2] -Yl-54- (51) 200413356)-(4-monocyano-phenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl] -amidine and 2- (3-cyano Phenyl)-[1,3,2] Suzuki coupling reaction of dihumorane and subsequent treatment with hydrochloric acid (4 mol concentration solution in 1'4-dihumane) to give the title compound as a colorless End. LCMS (Case B): m / z45 5 〔M + H〕 +, residence time 2.76

分鐘 ’^H—NMR ( CDC13) d7.98 ( 1H，br-s) ，7.92 ( 1H，dt，J1 = 8Hz，J2=1Hz ) ，7.89 ( 1H，d，J=lHz )， 7.76(2H，d，J = 8Hz) ，7.74(lH，d，J = 8Hz) ，7.72( 1H，d，J-l Hz ) ，7.63 ( 1H，d，J = 8Hz ) ，7.56 ( 2H，d ，J = 8Hz) ，7.46 ( 1H，s) ，6.58 ( 1H，d，J=lHz )， 6.54 ( 1H ^ s ) ，3.40(3H，s) ，2.48(2H，br-s)。實例1 8 製備2 —〔胺基一（4 一氰基—苯基）一（3 —甲基一 3H —咪唑一4 —基）一甲基〕—7— (3 -氯—苯基）一苯並呋喃一 5—甲腈類似於實例1 3 — e及1 3 - f揭示的方法，2 —甲基一丙;1：兀一 2 -亞搞酸〔（7 —溴—5 —氰基—苯並咲喃一 2 —基 )—(4 一氰基—苯基）一（3 -甲基一 3H-咪唑一 4 —基 )—甲基〕—醯胺與2-（3 -氯苯基）一〔1，3，2〕二口琴硼烷之Suzuki偶合反應，隨後用氫氯酸（在i，4 -二口f烷中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 -55- (52) 200413356 LCMS (情形 B ) : m/z464〔 M + H〕+，滯留時間分鐘， NMR ( CDC13) d7.85 ( 1H，d，J=1.5Hz)， (2H，dt，JH^Hz，J2 = 2Hz) ，7.71 ( 1H，d，J=1 )，7.64 ( 1H，m) ，7.58 ( 1H，m) ，7.56 ( 2H， J = 8.5Hz ) ，7.43 ( 2H，m) ，7.42 ( 1H，d，J = lHz 6.63 ( 1H，d，J=1 Hz ) ，6.56 ( 1H，s) ，3.3 8 ( 3H，，2.47 ( 2H，br— s )。實例1 9 製備2—〔胺基—（4 一氰基一苯基）一（3-甲 3 Η —味口坐一 4 —基）一甲基〕一7 — 〇比D定一 3 —基一苯喃一 5 —甲腈類似於實例1 3 — e及1 3 - f揭示的方法，2 —甲丙烷—2 -亞磺酸〔（7-溴一 5 —氰基一苯並呋喃一 2 )一（4 —氰基一苯基）—（3 —甲基一3H —咪唑—4 )—甲基〕一醯胺與3—〔1，3，2〕二鳄硼烷—2 — 吡啶之Suzuki偶合反應，隨後用氫氯酸（在1，4 — 烷中的4莫耳濃度溶液）處理，得到標題化合物之無末。 LCMS (情形 B ) ·· m/z43 1〔 M + H〕+，滯留時間分鐘，】Η— NMR(CD3OD) d8.96(lH，d，J=1.6Hz 8.59 ( 1H，dd，J = 1 · 6，4 · 8 Hz ) ，8 · 2 5 ( 1 H，d dd，J ，2.0，8.0Hz) ，8.08 ( 1 H，d，J = 1.4 H z ) ，7.94 ( 3.05 7.74 • 5Hz d ，基一並呋基一 —基 -基基一二口咢色粉 2.16 )， [ = 2.0 1H， -56- (53) (53)200413356 d，1 = 1.4 Η z ) ，7.81 ( 2H，d ’ J == 8.8 H z ) ’ 7.5 5 — 7.65 ( 4H，m) ，6.84(1H，s) ，6.55(1H，s) ，3.43(3H，s 、〇製備 4一〔胺基—（5 — DtfcH定一 3 -基—苯並咲喃—2 —基）一（3 一甲基—3H —咪唑一 4 —基）一甲基〕一苯甲腈化合物實例20 製備 4—〔胺基—〔7-（3 -氟一苯基）—5 -吡啶一 3 —基—苯並呋喃—2-基〕一（3 —甲基—3H —咪唑一 4 一基）一甲基〕一本甲膳 20 — a) 製備 3 —溴一 2-經基—5 — D比π定—3 —基— 苯甲醛在2 —經基—5 — D比卩定—3 —基一本甲酵（20.0克， 1 00毫莫耳）於 DCM/MeOH ( 5 0 0/2 0 0毫升）之溶液中，在室溫下加入苄基三甲基三溴化銨（39.1克，100毫莫耳），在室溫攪拌2小時後，將混合物用水淬火，將混合物用DCM ( χ2 )萃取，將有機層合倂，經由MgS04乾燥，過濾並在真空蒸發，得到25.0克3-溴—2 -羥基一 5 一吡啶一 3—基一苯甲醛淡黃色固體（粗）。 LCMS (情形 B ) : m/z2 7 8〔 M + H〕+，滯留時間 2.54 分鐘，Min '^ H-NMR (CDC13) d7.98 (1H, br-s), 7.92 (1H, dt, J1 = 8Hz, J2 = 1Hz), 7.89 (1H, d, J = 1Hz), 7.76 (2H, d, J = 8Hz), 7.74 (lH, d, J = 8Hz), 7.72 (1H, d, Jl Hz), 7.63 (1H, d, J = 8Hz), 7.56 (2H, d, J = 8Hz), 7.46 (1H, s), 6.58 (1H, d, J = lHz), 6.54 (1H ^ s), 3.40 (3H, s), 2.48 (2H, br-s). Example 1 8 Preparation of 2- [amino- (4-cyano-phenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl] -7- (3-chloro-phenyl)- Benzofuran-5-carbonitrile is similar to the method disclosed in Examples 13-e and 13-f, 2-methyl-propane; 1: 2-methyl-acid [(7-bromo-5-cyano —Benzopyran-2-yl) — (4-cyano-phenyl)-(3-methyl- 3H-imidazol-4-yl) -methyl] -fluorenamine and 2- (3-chlorobenzene Base) Suzuki coupling reaction of [1,3,2] di harmonica borane, followed by treatment with hydrochloric acid (4 mol concentration solution in i, 4-dihalo fane) to obtain a colorless powder of the title compound . -55- (52) 200413356 LCMS (case B): m / z464 〔M + H〕 +, residence time minutes, NMR (CDC13) d7.85 (1H, d, J = 1.5Hz), (2H, dt, JH ^ Hz, J2 = 2Hz), 7.71 (1H, d, J = 1), 7.64 (1H, m), 7.58 (1H, m), 7.56 (2H, J = 8.5Hz), 7.43 (2H, m) , 7.42 (1H, d, J = lHz 6.63 (1H, d, J = 1 Hz), 6.56 (1H, s), 3.3 8 (3H,, 2.47 (2H, br— s). Example 1 9 Preparation 2— [Amine- (4-cyano-phenyl)-(3-methyl3, fluorene-taste, 4-methyl) -methyl]-7-〇 than D fixed a 3-yl-benzoan-5- Nitrile is similar to the method disclosed in Examples 13-e and 13-f. 2-methylpropane-2-sulfinic acid [(7-bromo-5-cyano-benzofuran-2)-(4-cyano -Phenyl-phenyl)-(3-methyl- 3H-imidazole-4) -methyl] monofluorenamine and Suzuki coupling reaction of 3- [1,3,2] diaguaborane-2-pyridine, followed by Treatment with hydrochloric acid (4 mol concentration solution in 1,4-alkane) gave the title compound without residue. LCMS (Case B) ·· m / z43 1 [M + H] +, retention Minutes,] Η—NMR (CD3OD) d8.96 (lH, d, J = 1.6Hz 8.59 (1H, dd, J = 1 · 6, 4 · 8 Hz), 8 · 2 5 (1 H, d dd , J, 2.0, 8.0 Hz), 8.08 (1 H, d, J = 1.4 Hz), 7.94 (3.05 7.74 • 5Hz d, base-furfuryl-based-based-two-portion toner 2.16) , [= 2.0 1H, -56- (53) (53) 200413356 d, 1 = 1.4 Η z), 7.81 (2H, d 'J == 8.8 H z)' 7.5 5 — 7.65 (4H, m), 6.84 (1H, s), 6.55 (1H, s), 3.43 (3H, s, 0) Preparation of 4- [Amino- (5-DtfcH-a 3-yl-benzopyran-2-yl)-(3 a Methyl-3H-imidazol-4-yl) monomethyl] -benzonitrile compound Example 20 Preparation of 4- [amino group- [7- (3-fluoro-phenyl) -5-pyridine-3-yl-benzene Benzofuran-2-yl]-(3-methyl-3H-imidazol-4-yl) -methyl] -benzyl 20-a) Preparation of 3-bromo-2-yl- 5 -D ratio —3 —based —benzaldehyde at 2 —based —5 —D ratio than —3 —based-formaldehyde (20.0 g, 100 mmol) in DCM / MeOH (50 0/2 0 0 ml To the solution, benzyltrimethylammonium tribromide (39.1 g, 100 mmol) was added at room temperature, and after stirring at room temperature for 2 hours, the mixture was quenched with water, and the mixture was extracted with DCM (χ2). The organic layer was combined, dried over MgS04, filtered and evaporated in vacuo to give 25.0 g of 3-bromo-2-hydroxy-5pyridine-3-yl-benzaldehyde as a pale yellow solid (crude). LCMS (Case B): m / z2 7 8 〔M + H〕 +, retention time 2.54 minutes,

】H— NMR(CDC13) dll.65 (s’ 1 Η ) ，9.96(s，1H -57- (54) (54)200413356 )，8.83 ( d，J=1.7Hz，1 H ) ，8.64 ( dd，J=1.7，4.8Hz ，1 H ) ，8.03 ( d，J = 2.3Hz，1 H ) ，7.86 ( ddd，1=1.1， 2.3，7.9Hz，1 H ) ，7.76 ( d，J = 2.3Hz，1 H ) ，7.4 1 ( dd ，J = 4.8，7.9Hz，1H )。 2〇— b) 製備 4 一（7 —溴一5 —吼啶一3 —基一苯並呋喃—2 —羰基）—苯甲腈將3 —溴一2 —羥基—5 —吡啶—3-基一苯甲醛（12.0 克，43.1毫莫耳）添加至4一氰基苯甲醯甲基溴（10.6克，47.4毫莫耳）及 K2C03 (59·6克，431毫莫耳）於 CHsCN ( 200毫升）之溶液，將混合物在6(TC之氬氣壓下攪拌1小時，在真空將溶劑蒸發，將殘留物用H20及 MeOH淸洗，得到6.5克之4— (7-漠—5 — D比π定一 3 —基一苯並呋喃一 2-羰基）一苯甲腈淡棕色粉末。 LCMS (情形 B ) : m/z403〔 M + H〕+，滯留時間 2.90 分鐘， NMR(DMSO) d8.96(d，J = 2.3Hz，1H) ，8.62 (dd，J=1 ·6，4·6Ηζ，1H ) ，8. 1 0 — 8 · 2 3 ( m，7 Η )， 7.97 ( s ^ 1 H ) ，7.53 ( dd ^ J = 4.6，7.9Hz，1 H )。 20- c ) 製備2—甲基一丙烷—2 —亞磺酸（7—溴一 5—吡啶—3 —基一苯並呋喃一 2-基）一（4 —氰基一苯基 )亞甲醯胺在 4— (7 —漠—5 -吼0定一 3 —基一苯並咲喃—2_羯 -58- (55) (55)200413356 基）一苯甲腈（6.5克，16.4毫莫耳）於THF (200毫升 )之溶液中，在室溫下加入Ti ( OEt ) 4 ( 1 1 · 1毫升， 54.1毫莫耳）及2-甲基一 2 —丙烷亞磺醯胺（2.2克， 1 8.0毫莫耳），將混合物在迴流下攪拌4小時，使反應混合物冷卻至室溫後，加入鹽水並快速攪拌，將所得的懸浮液經由矽藻土過濾，並將濾餅用EtOAc淸洗，將過濾液分配，將水層用EtOAc ( x2 )萃取，將有機層合倂，經由MgS04乾燥並在真空蒸發，在矽膠上將殘留物經由管柱層析法（流洗液：CH2C12 —在DCM之5% MeOH )純化 ’侍到3.8克之2 _甲基一丙院一 2 —亞礦酸（7 —漠一 5 — 口比陡一 3 -基一苯並D夫喃一 2-基）—（4 一氰基一苯基）亞甲醯胺橙色無定形粉末。 LCMS (情形 B) m/z5 06〔 M+〕，5 08〔 M + 2〕，滯留時間3.0 0分鐘； NMR(CDC13) d8.84(d，J=1.7Hz，1H) ，8·64 (dd，J=1 ·7，4.8Hz，1Η ) ，7 · 8 7 ( d d d，J = 1 · 7，2.6， 7·9Ηζ，1H) ，7.74 — 7.8 3 ( m，7H ) ，7.41 ( d d，J = 4 · 8 ，7·9Ηζ，1H ) ，1 .40 ( s，9H )。 2〇- d) 製備2—甲基一丙烷一 2-亞磺酸〔（7—溴 —5—吡啶—3 —基一苯並呋喃一 2 —基）一（4 —氰基一苯基）一（3 —甲基一 3H —咪唑一 4 一基）_甲基〕一醯胺 2 1 將在己烷中的正丁基鋰（1.57莫耳濃度，7.4毫升， -59- (56) (56)200413356 1 1.6毫莫耳）添加至N—甲基咪唑（0.84毫升，1〇·5毫莫耳）於THF ( 18毫升）在—78 °C之溶液中，攪拌15 分鐘後，將三乙基矽烷基氯（1.9毫升，11.6毫莫耳）添加至反應混合物，使混合物溫熱至室溫後冷卻至- 7 8 °C，再度加入在己烷中的正丁基鋰（1.57莫耳濃度，6.7毫升，10.5毫莫耳），使反應混合物溫熱至一 20°C後冷卻至-7 8 °C，將所得的混合物添加至2 -甲基一丙烷一 2 -亞磺酸（7-漠—5 — Dthn定—3-基一苯並D夫喃一 2 —基）—（4 一氰基一苯基）亞甲醯胺（3.8克，7.50毫莫耳）於THF (7 0毫升）在一 7 8 °C之溶液中，攪拌1 5分鐘後，加入飽和的NH3C1，將反應混合物用EtOAc (x2)萃取，將有機層合倂，用鹽水淸洗，經由Mg S04乾燥並在真空蒸發，在矽膠上將殘留物經由矽膠管柱層析法（流洗液： DCM —在DCM中的5% MeOH)純化，得到3·8克2 —甲基一丙院—2 -亞磺酸〔（7 —溴—5 —批D定一 3-基一苯並口夫喃一 2-基）—（4 —氨基一苯基）—（3 -甲基—3Η — 咪唑一 4一基）一甲基〕一醯胺黃色無定形粉末。 LCMS (情形 B)m/z588〔M+〕，590〔M + 2〕，滯留時間2.3 9分鐘； NMR(CDC13) d8.81 (d，J = 2.3Hz，1H) ，8·62 (dd，J=1 .7，4.6Hz，1H ) ，7.84 ( ddd，J=1.7，2.3， 7·9Ηζ，1 H ) ，7.72— 7.76 (m，2H) ，7.64— 7.67 (m， 4H ) ，7·54 ( s，1H ) ，7.39 ( dd，J = 4.6，7.9Hz，1H ) ，7.03(s，lH) ，6.97(s，lH) ，4.63(s，lH) ^ 3.22 -60- (57) 200413356 (s，3H ) ，1 .3 5 ( s，9H )。 20 — e) 製備2—甲基一丙院一 2—亞磺酸〔（4一氰基一苯基）—〔7— (3 -藥—苯基）一 5 — D比卩定一 3 —基— 苯並咲喃—2 —基〕—（3 -甲基一 3H —味π坐—4 —基）一甲基〕一醯胺] H-NMR (CDC13) dll.65 (s' 1 Η), 9.96 (s, 1H -57- (54) (54) 200413356), 8.83 (d, J = 1.7Hz, 1 H), 8.64 (dd , J = 1.7, 4.8 Hz, 1 H), 8.03 (d, J = 2.3 Hz, 1 H), 7.86 (ddd, 1 = 1.1, 2.3, 7.9 Hz, 1 H), 7.76 (d, J = 2.3 Hz , 1 H), 7.4 1 (dd, J = 4.8, 7.9 Hz, 1H). 2〇— b) Preparation of 4- (7-bromo-5—anhydropyridine-3—yl-benzofuran-2-carbonyl) —benzonitrile, 3-bromo-2—hydroxy-5—pyridine-3-yl Monobenzaldehyde (12.0 g, 43.1 mmol) was added to 4-cyanobenzyl methyl bromide (10.6 g, 47.4 mmol) and K2C03 (59.6 g, 431 mmol) in CHsCN (200 Ml) solution, the mixture was stirred at 6 (TC argon pressure for 1 hour, the solvent was evaporated in vacuo, the residue was washed with H20 and MeOH to obtain 6.5 g of 4- (7-amo-5-D ratio π A light brown powder of 3-yl-benzofuran-2-carbonyl) -benzonitrile. LCMS (Case B): m / z403 〔M + H〕 +, retention time 2.90 minutes, NMR (DMSO) d8.96 (d, J = 2.3Hz, 1H), 8.62 (dd, J = 1 · 6, 4 · 6Ηζ, 1H), 8. 1 0 — 8 · 2 3 (m, 7 Η), 7.97 (s ^ 1 H ), 7.53 (dd ^ J = 4.6, 7.9Hz, 1H). 20-c) Preparation of 2-methyl-propane-2-sulfinic acid (7-bromo-5-pyridin-3-yl-benzofuran) 2- (2-yl)-(4-cyano-phenyl) methylenesulfonamide in 4- (7- -Benzo-pyrano-2--2-fluorene-58- (55) (55) 200413356 based) solution of benzonitrile (6.5 g, 16.4 mmol) in THF (200 ml), added at room temperature Ti (OEt) 4 (1 1.1 ml, 54.1 mmol) and 2-methyl-2-propanesulfenamidine (2.2 g, 1 8.0 mmol), and the mixture was stirred at reflux for 4 hours, After the reaction mixture was allowed to cool to room temperature, brine was added and quickly stirred, the resulting suspension was filtered through celite, and the filter cake was washed with EtOAc, the filtrate was partitioned, and the aqueous layer was extracted with EtOAc (x2), The organic layer was combined, dried over MgS04 and evaporated in vacuo, and the residue was purified on silica gel by column chromatography (flow wash: CH2C12-5% MeOH in DCM) to '3.8 g of 2-methyl Yifuyuan-1 2—Sulfuric acid (7—Mo-5—Mouth steeper—3—Base—Benzobenzofuran—2 —) — (4—Cyano—phenyl) Methylenepyramine orange without Setting powder. LCMS (Case B) m / z5 06 [M +], 5 08 [M + 2], retention time 3.00 minutes; NMR (CDC13) d8.84 (d, J = 1.7Hz, 1H), 8.64 (dd , J = 1 · 7, 4.8Hz, 1Η), 7 · 8 7 (ddd, J = 1 · 7, 2.6, 7 · 9Ηζ, 1H), 7.74 — 7.8 3 (m, 7H), 7.41 (dd, J = 4 · 8, 7 · 9Ηζ, 1H), 1.40 (s, 9H). 2〇- d) Preparation of 2-methyl monopropane 2-sulfinic acid [(7-bromo-5-pyridin-3-yl-benzofuran 2-yl)-(4-cyano-phenyl) Mono (3-methyl-3H-imidazole-4 mono) -methyl] monofluorenamine 2 1 n-Butyl lithium (1.57 mole concentration, 7.4 ml, -59- (56) ( 56) 200413356 1 1.6 mmol) was added to a solution of N-methylimidazole (0.84 ml, 10.5 mmol) in THF (18 ml) at -78 ° C, and after stirring for 15 minutes, Ethylsilyl chloride (1.9 ml, 11.6 mmol) was added to the reaction mixture, the mixture was allowed to warm to room temperature and then cooled to-7 8 ° C, and n-butyllithium (1.57 moles) in hexane was added again. Concentration, 6.7 ml, 10.5 mmol), the reaction mixture was warmed to a temperature of 20 ° C and then cooled to -7 ° C, and the resulting mixture was added to 2-methyl-propane-2-sulfinic acid (7 -Mo-5 — Dthn-D 3-n-benzobenzofuran-2-yl) — (4-cyano-phenyl) methyleneimide (3.8 g, 7.50 mmol) in THF (7 0 Ml) in a solution at 78 ° C, stirring for 15 minutes After 22 minutes, saturated NH3C1 was added and the reaction mixture was extracted with EtOAc (x2). The organic layer was combined, washed with brine, dried over Mg S04 and evaporated in vacuo. The residue was passed through a silica gel column chromatography on silica gel. (Flow washing solution: DCM—5% MeOH in DCM) to obtain 3.8 g of 2-methyl-propane-2-sulfinic acid [(7-bromo-5—batch D fixed a 3- Amino-benzoxan-2-yl)-(4-amino-phenyl)-(3-methyl-3'-imidazole-4-yl) -methyl] -amidamine yellow amorphous powder. LCMS (case B) m / z588 [M +], 590 [M + 2], retention time 2.39 minutes; NMR (CDC13) d8.81 (d, J = 2.3Hz, 1H), 8.62 (dd, J = 1.7, 4.6Hz, 1H), 7.84 (ddd, J = 1.7, 2.3, 7.9 7ζ, 1H), 7.72-7.76 (m, 2H), 7.64-7.67 (m, 4H), 7.54 (s, 1H), 7.39 (dd, J = 4.6, 7.9 Hz, 1H), 7.03 (s, lH), 6.97 (s, lH), 4.63 (s, lH) ^ 3.22 -60- (57) 200413356 ( s, 3H), 1.3 5 (s, 9H). 20 — e) Preparation of 2-methyl-propanone-2-sulfinic acid [(4-Cyano-phenyl) — [7— (3-Drug-phenyl) —5—D ratio than Ding—3— -Benzo-pyran-2-yl]-(3-methyl-3H-taste π-4-yl) monomethyl] monofluorenamine

將 2 —甲基—丙烷一 2 —亞磺酸〔（7 —溴一 5 —吡啶一 3 —基一苯並呋喃—2 —基）一（4 一氰基—苯基）—（3 —甲基一 3H —咪唑一4_基）—甲基〕一醯胺（1.5克， 2.55 毫莫耳）、2-（3 - 氟—苯基）—〔1，3，2〕二鸣硼烷（1.3克，7.65毫莫耳）、肆（三苯基膦）一鈀（〇 ) (589毫克，0.51毫莫耳）及磷酸三鉀（1.6克，7.65Add 2-methyl-propane-2-sulfinic acid [(7-bromo-5-pyridine-3-yl-benzofuran-2-yl)-(4-cyano-phenyl)-(3-methyl -3H-imidazol-4-yl) -methyl] monofluorenylamine (1.5 g, 2.55 mmol), 2- (3-fluoro-phenyl)-[1,3,2] diborane ( 1.3 grams, 7.65 millimoles), tris (triphenylphosphine) -palladium (〇) (589 mg, 0.51 millimoles) and tripotassium phosphate (1.6 grams, 7.65

毫莫耳）於DMF ( 20毫升）之溶液在l〇〇°C加熱2小時，將反應混合物用 EtOAc稀釋並將鈀過濾去除，將過濾液分配在EtOAc及H20，將水層用EtOAc ( χ2 )萃取，將有機層合倂，經由Mg S04乾燥並在真空蒸發，在矽膠上將殘留物經由矽膠管柱層析法（流洗液：DCM—在 DCM中的5% Me 0H)純化，得到1.1克2—甲基一丙烷 —2 —亞擴酸〔（4 —氰基一苯基）—〔7—（3 —氟一苯基 )一 5— D比Π定一 3 —基一苯並咲喃一 2—基〕—（3—甲基— 3H 一咪唑一 4 —基）一甲基〕一醯胺淡黃色粉末。 LCMS (情形 B ) m/z604〔 M + H〕+，滯留時間 2.54 分鐘； ]H - NMR ( CDCls ) d8.88(d，J = 2.0Hz，1Η ) ，8.63 -61 - (58) (58)200413356 (dd ’ J=1.7 ^ 4·9Ηζ，1H ) ，7.92 ( dt ^ J = 2.0，8.2Hz， 1H)，7.37 — 7.25 (m’llH)，7.17 (s，lH)，7.10( ddt，J=1.3，2.5，8.2Hz，lH) ，6.93(s，lH) ,4.67( s，lH) ，3.18(s，3H) ，1.31(s，9H)。 20— f) 製備4一〔胺基—〔7-（3-氟—苯基）一 5 —吡啶一 3 —基—苯並呋喃—2 —基〕一（3 —甲基—3H 一咪唑一 4一基）一甲基〕一苯甲腈在2-甲基一丙烷—2 —亞磺酸〔（4 —氰基—苯基）一〔7—（3 —氟一苯基）—5—吡啶—基一苯並呋喃— 2—基〕一（3 —甲基一 3H —咪唑一 4一基）—甲基〕一醯胺（1.1克，1.82毫莫耳）於THF ( 15毫升）之溶液中 ’在室溫下加入在EtOAc中的4莫耳濃度HC1溶液（7 毫升），將混合物在室溫攪拌1 5小時，將反應混合物用飽和的NaHC03淬火並用EtOAc ( χ2 )萃取，將有機層合倂，經由 M g S 0 4乾燥並在真空蒸發，將殘留物經由矽膠管柱層析法（流洗液：在D C Μ中的3 % M e Ο Η )純化，得到 810毫克4—〔胺基一〔7— （3 —氟—苯基）一5 — 吡啶一 3-基—苯並呋喃—2-基〕—（3 —甲基一 3Η —咪唑一 4 一基）一甲基〕一苯甲腈無色粉末。 LCMS (情形 B ) m/z5 00〔 Μ + Η〕+，滯留時間 2.46 分鐘； - NMR ( CDCls ) d8.89(dd，J=1.0，2·6Ηζ，1Η ) ，8.62 ( dd ’ J=1 .7，4·9Ηζ，1Η ) ，7.92 ( dt ’ J = 2.2 ’ (59) 200413356 8.6Hz ，1 Η ) ，7.69 -7, .74 ( m，3H ) ，7· 54 - 7.64 (m， 4H )， 7.38 —7.50 ( m ， 4H ) ，7.11 ( ddt ，J = 1 · 0， 2.6， 8.6Hz ，1 Η ) ，6·68 (d ，J = 1 • 0Hz，1 H )， 6.49 ( s， 1H ) ，3.42 (s， 3Η ) ，2 • 49 (b r s ，：l H )。實例2 1A solution of mM) in DMF (20 mL) was heated at 100 ° C for 2 hours. The reaction mixture was diluted with EtOAc and the palladium was filtered off. The filtrate was partitioned between EtOAc and H20, and the aqueous layer was washed with EtOAc (χ2 ) Extraction, the organic layer was combined, dried over Mg S04 and evaporated in vacuo, and the residue was purified on a silica gel by silica gel column chromatography (flow washing solution: DCM—5% Me 0H in DCM) to obtain 1.1 g of 2-methyl-propane-2-ene sulfite [(4-cyano-phenyl)-[7- (3-fluoro-phenyl) -5-D Amino-2-yl]-(3-methyl-3H-imidazol-4-yl) -methyl] -pyramine is a light yellow powder. LCMS (case B) m / z604 〔M + H〕 +, retention time 2.54 minutes;] H-NMR (CDCls) d8.88 (d, J = 2.0Hz, 1 ，), 8.63 -61-(58) (58 ) 200413356 (dd 'J = 1.7 ^ 4.9Ηζ, 1H), 7.92 (dt ^ J = 2.0, 8.2Hz, 1H), 7.37 — 7.25 (m'llH), 7.17 (s, lH), 7.10 (ddt, J = 1.3, 2.5, 8.2 Hz, 1H), 6.93 (s, 1H), 4.67 (s, 1H), 3.18 (s, 3H), 1.31 (s, 9H). 20- f) Preparation of 4- [amino- [7- (3-fluoro-phenyl) -5-pyridine-3-yl-benzofuran-2-yl]-(3-methyl-3H-imidazole- 4- (1-yl) -methyl] -benzonitrile in 2-methyl-propane-2-sulfinic acid [(4-cyano-phenyl)-[7- (3-fluoro-phenyl) -5— Pyridine-yl-benzofuran-2-yl]-(3-methyl- 3H-imidazole-4-yl) -methyl] -amidine (1.1 g, 1.82 mmol) in THF (15 ml) To the solution 'was added a 4 molar HC1 solution (7 ml) in EtOAc at room temperature, the mixture was stirred at room temperature for 15 hours, the reaction mixture was quenched with saturated NaHC03 and extracted with EtOAc (χ2). The organic Laminated amidine, dried over M g S 0 4 and evaporated in vacuo, and the residue was purified by silica gel column chromatography (fluid washing solution: 3% M e 0 Η in DC M) to obtain 810 mg of 4- [Amino- [7- (3-fluoro-phenyl) -5-pyridine-3-yl-benzofuran-2-yl]-(3-methyl-1,3,6-imidazole-4, 1-yl) -methyl Monobenzonitrile Powder. LCMS (case B) m / z50 00 [M + Η] +, retention time 2.46 minutes;-NMR (CDCls) d8.89 (dd, J = 1.0, 2 · 6Ηζ, 1Η), 8.62 (dd 'J = 1 .7, 4 · 9Ηζ, 1Η), 7.92 (dt 'J = 2.2' (59) 200413356 8.6Hz, 1 Η), 7.69 -7, .74 (m, 3H), 7.54-7.64 (m, 4H ), 7.38 —7.50 (m, 4H), 7.11 (ddt, J = 1 · 0, 2.6, 8.6Hz, 1 Η), 6.68 (d, J = 1 • 0Hz, 1 H), 6.49 (s, 1H), 3.42 (s, 3Η), 2 • 49 (brs ,: lH). Example 2 1

製備 4—〔胺基—（3 —甲基一 3H -味哗一 4 —基）— (7 —苯基一 5 — D比U定—3 —基一苯並D夫喃—2 —基）—甲基〕一苯甲腈類似於實例2 0 — e及2 0 — f揭示的方法，2 —甲基― 丙烷一2 —亞磺酸〔（7 -溴一 5 -吡啶一 3 —基—苯並呋喃一 2—基）一（4 一氰基一苯基）一（3 —甲基—3H —咪唑一 4 —基）—甲基〕—釀胺與 2-苯基—1，3，2 — 一砸烷之Suzuki偶合反應，隨後用氫氯酸（在EtOAc中的4 莫耳濃度溶液）處理，得到標題化合物之無色粉末。Preparation 4- [Amino- (3-methyl- 3H-weiwa-4-yl)-(7-phenyl-5-D than U-Ding-3-yl-benzo-Danfuran-2-yl) —Methyl] monobenzonitrile is similar to the method disclosed in Examples 2 0 — e and 2 0 — f, 2-methyl-propane-2—sulfinic acid [(7-bromo-5—pyridine—3-yl— Benzofuran- 2-yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -vinylamine and 2-phenyl-1,3, 2-Suzuki coupling reaction of 1-methane, followed by treatment with hydrochloric acid (4 molar solution in EtOAc) to give the title compound as a colorless powder.

LCMS (情形 B ) : m/z48 2〔 M + H〕+，滯留時間 2.63 分鐘，NMR(CD30D) d8.87(d，J = 2.3Hz，1H)， 8.52 ( d，J = 4.8Hz，1 H ) ，8.17 ( d，J = 8.0Hz，1H )， 7.73— 7.84 (m，6H) ，7.62—7.65 (m，3H) ，7.53(dd ，J = 4.8，8.0Hz，1H) ，7.35-7.48 (m，3H) ，6.76(s ，：IH ) ，6.58 ( s，1H ) ，3.42 ( s，3H )。實例2 2 製備4一〔胺基一〔7— (3 —甲氧基一苯基）一5 — -63- (60) 200413356 吡啶一3 —基一苯並呋喃—2—基〕一（3 —甲基—3H—咪唑一 4 一基）一甲基〕—苯甲腈類似於實例2 0 — e及2 0 — f揭示的方法，2 —甲基一丙院一 2 —亞礦酸〔（7-漠一 5 - D比D定一 3 -基一苯並咲喃 —2 —基）—（4 —氰基一苯基）一（3 —甲基—3H—咪唑一 4 一基）一甲基〕一醯胺與2- （3 -甲氧基—苯基）一LCMS (Case B): m / z48 2 〔M + H〕 +, retention time 2.63 minutes, NMR (CD30D) d8.87 (d, J = 2.3Hz, 1H), 8.52 (d, J = 4.8Hz, 1 H), 8.17 (d, J = 8.0Hz, 1H), 7.73-7.84 (m, 6H), 7.62-7.65 (m, 3H), 7.53 (dd, J = 4.8, 8.0Hz, 1H), 7.35-7.48 (m, 3H), 6.76 (s ,: IH), 6.58 (s, 1H), 3.42 (s, 3H). Example 2 2 Preparation of 4- [Amino- [7- (3-methoxy-phenyl)-5--63- (60) 200413356 Pyridine- 3-yl-benzofuran-2-yl]-(3 —Methyl—3H—imidazole—4-yl) —methyl] —benzonitrile is similar to the method disclosed in Examples 2 0 — e and 2 0 — f, 2 —methyl 1-propanone — 2 —sulfite [ (7-Mo-5-D than D-A-1 3-yl-benzopyran-2-yl)-(4-cyano-phenyl)-(3-methyl-3H-imidazole-4 4-yl) Monomethyl] monomethylamine and 2- (3-methoxy-phenyl)-

〔1，3，2〕—二哼硼烷之Suzuki偶合反應，隨後用氫氯酸（在EtO Ac中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z512〔 M + H〕+，滯留時間 2.43 分鐘， 4 一 NMR(CDC13) d8.89(d，J = 2.0Hz，1H) ，8.62 (dd，J=1.7，4·9Ηζ，1 Η ) ，7.92 ( dt，J = 2.0，8.6Hz， 1 H ) ，7.72 ( dd，J = 2.0，6.6Hz.2H ) ，7.66 ( dd，J = 2.0 ，4.5Hz，2H ) ，7.58 ( dd，J = 2.0，6·6Ηζ，2H ) ，7.31[1, 3, 2]-Suzuki coupling reaction of dihumorane, followed by treatment with hydrochloric acid (4 mol concentration solution in EtO Ac) to obtain a colorless powder of the title compound. LCMS (case B): m / z512 〔M + H〕 +, retention time 2.43 minutes, 4-NMR (CDC13) d8.89 (d, J = 2.0Hz, 1H), 8.62 (dd, J = 1.7, 4 · 9Ηζ, 1 Η), 7.92 (dt, J = 2.0, 8.6Hz, 1H), 7.72 (dd, J = 2.0, 6.6Hz. 2H), 7.66 (dd, J = 2.0, 4.5Hz, 2H), 7.58 (dd, J = 2.0, 6 · 6Ηζ, 2H), 7.31

—7.44 ( m，5H ) ，6.96 ( ddd，J = 1.7，2·6，7·6Ηζ，1 H )，6.72(d，J = 1.0Hz，lH) ，6.45(s，lH) ^ 3.83 ( s ，3H) ，3.42(s，3H) ，2.45(brs，2H)。實例23 製備4一〔胺基—（7-苯並〔1，3〕一氧茂一 5-基 —5 —吼啶一 3 —基一苯並呋喃_2_基）一（3 —甲基一 3H —咪唑一 4 —基）一甲基〕一苯甲腈類似於實例2 0 — e及2 0 — f揭示的方法，2 —甲基— -64 - (61) (61)200413356 丙烷一 2 -亞磺酸〔（7 -溴—5 —吡啶一 3 —基—苯並呋喃 —2—基）一（4 一氨基一苯基）—（3 —甲基—3H —味口坐一 4 一基）一甲基〕一酸胺與5-〔1，3，2〕— 一^啤棚院 —2 —基一苯並〔1，3〕一鸣之Suzuki偶合反應，隨後用氫氯酸（在EtO Ac中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z5 2 6〔 M + H〕+，滯留時間 2.4 1 分鐘， ]H - NMR ( CD3〇D ) d8.85(s，1H) ，8.52(d， J = 4.9Hz，lH) ，8.16(d，J = 6.4Hz，lH) ，7.78— 7.80 ( m，3H ) ，7.6 3 - 7.66 ( m，4H ) ，7.53 ( dd，J = 4.9， 7.8Hz，1 H ) ，7.31 (d，J = 7.8Hz，1 H ) ，7.25(s，1H ) ，6.91 (d，J = 7.8Hz，1 H ) ，6.77 ( s ^ 1 H ) ，6.57(s， 1 H ) ，6.00 ( s，2H ) ，3.48 ( s，3H ) 〇實例2 4 製備4一〔胺基一〔7- （3 -氰基一苯基）一5 —吡 D定一 3 一基一苯並咲喃一 2 —基〕—（3 —甲基—3 Η —味口坐一 4 一基）一甲基〕一苯甲腈類似於實例2 0 — e及2 0 — f揭示的方法，2 —甲基一丙烷一 2-亞磺酸〔（7 —溴—5 —吡啶一 3 -基—苯並呋喃一 2 —基）—（4 一氰基一苯基）_ (3 —甲基一 3H —咪唑 _4 一基）—甲基〕一醯胺與2— （3 -氰基苯基）一〔1 ，3，2〕—二哼硼烷之Suzuki偶合反應，隨後用氫氯酸 -65- (62) (62)200413356 (在EtOAc中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z5 07〔 M + H〕+，滯留時間 2.43 分鐘， - NMR ( CD3〇D ) d8.91 ( d，J = 2.0Hz，1H )， 8.54 ( dd，J=1 .5 ，4.9Hz， 1H ) ， 8 · 21 ( d t，J = 1 .5， 7. 8Hz， 1 Η )， 8.15 一 8· 1 7 ( m， 2H )， 7.9 5 (d， J = 2.0Hz 1H ) ，7 • 82 — 7.84 ( m，3Η ) 7.76 ( 〔dt， J=1 .5 ，7‘lHz 1H ) 7.64 -7.69 (m，4 Η ) ，7, .55 ( d d， J = 4.9， 8. 8Hz， 1 Η )， 6.87 ( s，1 Η ) ，6. ,55 ( s，1 H )， 3.43 ( s 3H ) ο 實例2 5 製備4_〔胺基一〔7-（3 -氯一苯基）—5-吡啶一 3 —基—苯並呋喃—2 —基〕一（3 —甲基一 3H —咪唑一 4 一基）一甲基〕一苯甲腈類似於實例20 - e及20 — f揭示的方法，2 —甲基一丙烷—2 -亞磺酸〔（7 —溴一 5—吡啶一 3 —基—苯並呋喃一 2—基）一（4 一氰基一苯基）一（3 —甲基—3H —咪唑一 4 —基）一甲基〕—醯胺與2— (3 —氯苯基）一〔1，3 ，2〕—二鸣硼烷之Suzuki偶合反應，隨後用氫氯酸（在 EtO Ac中的4莫耳濃度溶液）處理，得到標題化合物之無色粉末。 LCMS (情形 B ) : m/z516〔 M + H〕+，滯留時間 2.59 (63) 200413356 分鐘， NMR(CDC13) d8.87(d，J = 2.6Hz，1H)， (dd，J=1 .7，5.0Hz，1 H ) ，7.92 ( ddd，J=1 .7，2 8.9Hz，1 H ) ，7.69— 7.75 (m，4H ) ，7.6 3 - 7.6 7 (—7.44 (m, 5H), 6.96 (ddd, J = 1.7, 2 · 6, 7 · 6Ηζ, 1 H), 6.72 (d, J = 1.0Hz, lH), 6.45 (s, lH) ^ 3.83 (s 3H), 3.42 (s, 3H), 2.45 (brs, 2H). Example 23 Preparation of 4- [Amino- (7-benzo [1,3] -oxocene-5-yl-5-yl-pyridine-3-yl-benzofuran_2-yl)-(3-methyl- 3H-imidazol-4-yl) monomethyl] -benzonitrile is similar to the method disclosed in Examples 20-e and 20-f, 2-methyl- -64-(61) (61) 200413356 propane-2 -Sulfinic acid [(7-bromo-5 -pyridine-3 -yl-benzofuran-2-yl)-(4 -amino -phenyl)-(3 -methyl -3H-taste mouth sitting one 4 one Base) monomethyl] monoacid amine and 5- [1,3,2]-[1,3,2] -yl beer benzo-2 -yl-benzo [1,3] Yiming Suzuki coupling reaction, followed by hydrochloric acid ( 4 Molar solution in EtO Ac) to give the title compound as a colorless powder. LCMS (case B): m / z5 2 6 〔M + H〕 +, retention time 2.4 1 minute,] H-NMR (CD3〇D) d8.85 (s, 1H), 8.52 (d, J = 4.9Hz , LH), 8.16 (d, J = 6.4Hz, lH), 7.78-7.80 (m, 3H), 7.6 3-7.66 (m, 4H), 7.53 (dd, J = 4.9, 7.8Hz, 1H), 7.31 (d, J = 7.8Hz, 1 H), 7.25 (s, 1H), 6.91 (d, J = 7.8Hz, 1 H), 6.77 (s ^ 1 H), 6.57 (s, 1 H), 6.00 (s, 2H), 3.48 (s, 3H). Example 2 4 Preparation of 4- [amino- [7- (3-cyano-phenyl) -5-pyridine D- 3-yl-benzopyran -2 -yl]-(3 -methyl-3 Η-taste mouth seat-4-1 -yl) -methyl]-benzonitrile is similar to the method disclosed in Example 2 0-e and 2 0-f, 2- -Propane- 2-sulfinic acid [(7-bromo-5 -pyridine-3-yl-benzofuran-2 -yl)-(4 -cyano-phenyl)-(3-methyl-3H- Suzuki coupling reaction of imidazole-4 mono-methyl) -methylamine with 2- (3-cyanophenyl)-[1,3,2] -dihumorane, followed by hydrochloric acid-65- (62) (62) 200413356 (4 molar solution in EtOAc) to give the title compound as a colorless powder. LCMS (case B): m / z5 07 〔M + H〕 +, retention time 2.43 minutes,-NMR (CD3〇D) d8.91 (d, J = 2.0Hz, 1H), 8.54 (dd, J = 1 .5, 4.9Hz, 1H), 8 · 21 (dt, J = 1.5, 7.8 Hz, 1 Η), 8.15-8.17 (m, 2H), 7.9 5 (d, J = 2.0Hz 1H), 7 • 82 — 7.84 (m, 3Η) 7.76 (〔dt, J = 1 .5, 7'lHz 1H) 7.64 -7.69 (m, 4 Η), 7, .55 (dd, J = 4.9, 8. 8Hz, 1 Η), 6.87 (s, 1 Η), 6., 55 (s, 1 H), 3.43 (s 3H) ο Example 2 5 Preparation of 4_ [amino group 7- (3-chloro- Phenyl) -5-pyridine- 3-yl-benzofuran-2-yl]-(3-methyl- 3H-imidazole-4 4-yl) -methyl] -benzonitrile is similar to Example 20-e and The method disclosed by 20-f, 2-methyl-propane-2-sulfinic acid [(7-bromo-5-pyridine-3-yl-benzofuran-2-yl)-(4-cyano-phenyl Suzuki coupling reaction of) (3-methyl-3H-imidazol-4-yl) -methyl] -amidamine with 2- (3-chlorophenyl)-[1,3,2] -dibisborane Followed by treatment with hydrochloric acid (4 molar concentration in solution EtO Ac) to afford the title compound as a colorless powder. LCMS (case B): m / z516 〔M + H〕 +, retention time 2.59 (63) 200413356 minutes, NMR (CDC13) d8.87 (d, J = 2.6Hz, 1H), (dd, J = 1. 7, 5.0Hz, 1 H), 7.92 (ddd, J = 1.7, 2 8.9Hz, 1 H), 7.69— 7.75 (m, 4H), 7.6 3-7.6 7 (

1 H ) ，7·57— 7.62 (m，3H) ，7·37— 7.45 (m，4H 6.69 (d，J=1.0Hz，1 H ) ，6.53 (s，1 H ) ，3.4 1 ( s )，2.48 ( brs，1 H )。實例2 6 製備 4一〔胺基一（5，7 —二一吡啶—3 —基— 呋喃一 2 —基）_ (3 -甲基—3H —咪唑一 4 —基）— 〕一苯甲腈類似於實例2 0 - e及2 0 — f揭示的方法，2 —甲丙烷_2 -亞磺酸〔（7 —溴一 5 —吡啶—3 —基—苯並 —2 —基）一（4 —氰基一苯基）一（3 —甲基—3H — —4 —基）—甲基〕一醯胺與 3—〔1，3，2〕—二噚 —2 —基—吡啶之 Suzuki偶合反應，隨後用氫氯酸 EtOAc中的4莫耳濃度溶液）處理，得到標題化合物色粉末。 LCMS (情形 B ) : m/z4 8 3〔 M + H〕+，滯留時間分鐘， JH— NMR ( CD30D) d9.04 ( d，J = 1.5Hz，1H 8.91 (d，J=1.5Hz，1 H ) ，8.54— 8.57 (m，2H )， (ddd，J=1.5，2.4，8.8Hz，1 H ) ，8.2 1 ( ddd，J= 11 H), 7.57— 7.62 (m, 3H), 7.37— 7.45 (m, 4H 6.69 (d, J = 1.0Hz, 1 H), 6.53 (s, 1 H), 3.4 1 (s) , 2.48 (brs, 1 H). Example 2 6 Preparation of 4-a [amino- (5,7-di-pyridine-3-yl-furan-2-yl) _ (3-methyl-3H-imidazole-4) —Base) —] Monobenzonitrile is similar to the method disclosed in Examples 20-e and 20-f, 2-methylpropane_2-sulfinic acid [(7-bromo-5-pyridine-3-yl-benzene And 2- (2-yl)-(4-cyano-phenyl)-(3-methyl-3H-4 -yl) -methyl] monofluorenamine and 3- [1,3,2] -difluorene Suzuki coupling reaction of -2-yl-pyridine, followed by treatment with 4 molar solution in hydrochloric acid EtOAc) to give the title compound as a color powder. LCMS (case B): m / z4 8 3 〔M + H〕 +, residence time minutes, JH— NMR (CD30D) d9.04 (d, J = 1.5Hz, 1H 8.91 (d, J = 1.5Hz, 1 H), 8.54— 8.57 (m, 2H), (ddd, J = 1.5, 2.4, 8.8 Hz, 1 H), 8.2 1 (ddd, J = 1

8.63 • 6， m ， )，，3H 苯並甲基基一呋喃咪唑硼烷 (在之並 j \\\ 1.93 )， 8.32 • 5 ， -67- (64) (64)200413356 2·4，7·3Ηζ，1H ) ，7 · 9 5 ( d，J = 2 · 0 Η ζ，1 Η ) ，7·85 ( d ，J=1.5Hz，1 Η ) ，7.82 ( d，J = 8.8Hz，2Η ) ，7.65 ( d，8.63 • 6, m,), 3H benzomethyl-furfurimidazole borane (incorporated j \\\ 1.93), 8.32 • 5, -67- (64) (64) 200413356 2 · 4, 7 · 3Ηζ, 1H), 7 · 9 5 (d, J = 2 · 0 Η ζ, 1 Η), 7.85 (d, J = 1.5Hz, 1 Η), 7.82 (d, J = 8.8Hz, 2Η ), 7.65 (d,

J = 8.8Hz，2H ) ，7.64 — 7.67 ( m，1 H ) ，7.5 4 - 7.5 9 ( m ，2H) ，6.81(s，lH) ，6.56(s，lH) ，3.44(s，3H 實例2 7 用於抑制法呢基-蛋白質轉移酶及搌牛兒基德牛兒基一蛋白質轉移酶之試管內測試法實質上根據揭示的方法（Methods Enzymol. 1995 V ο 1. 2 5 0 pp3— 12 Bacterial expression and purification of human protein prenyltransferases using epitope — tagged， translationally coupled systems. Omer ， Charles A. Diehl， Ronald E. and Krai， Astrid M.)，除了使用 pT7 — 7 ( Comb Chem High Throughput Screen. 1 9 9 9 Vo 1. 5 pp279 — 8 7 Application of homogeneous time — resolvedJ = 8.8 Hz, 2H), 7.64 — 7.67 (m, 1 H), 7.5 4-7.5 9 (m, 2H), 6.81 (s, lH), 6.56 (s, lH), 3.44 (s, 3H) Example 2 7 In-tube test methods for inhibiting farnesyl-protein transferase and geranyl-geranyl-protein transferase are essentially based on the methods disclosed (Methods Enzymol. 1995 V ο 1. 2 5 0 pp3-12 Bacterial expression and purification of human protein prenyltransferases using epitope — tagged, translationally coupled systems. Omer, Charles A. Diehl, Ronald E. and Krai, Astrid M.), except for using pT7 — 7 (Comb Chem High Throughput Screen. 1 9 9 9 Vo 1. 5 pp279 — 8 7 Application of homogeneous time — resolved

fluorescence (HTRFTM ) to monitor poly ubiquitination of wild — type p 5 3 Y abuk i ， Nfluorescence (HTRFTM) to monitor poly ubiquitination of wild — type p 5 3 Y abuk i, N

Watanabe， S.， Kudoh， T.， Nihira， Si.， and Miyamato， C .)，將人類法呢基一蛋白質轉移_ α及石次單元共同表達在大腸桿菌 BL21 CodonPlus ( DE3 ) RIL (Stratagene)，經由在含75毫莫耳濃度NaCl、50 微莫耳濃度ZnCl2、5毫莫耳濃度二硫蘚糖醇、0.5毫莫耳濃度4 -（脒基苯基）甲磺醯基氟及蛋白酶抑制劑合劑片 -68- (65) (65)200413356 劑（完全無 Mini EDTA，Roche Diagnostics)的 5 毫莫耳濃度磷酸鈉緩衝液（pH 7.2 )中超音波化，將培養的細胞分裂，在將粗萃取物在40，000 X g離心30分鐘，經由三次管柱層析法，使用 DEAE S ephacel ( Amer sham Pharmacia Biotech ) 、 HiTrapQ 管柱 ( Amer shamWatanabe, S., Kudoh, T., Nihira, Si., And Miyamato, C.), co-expressed human farnesyl-protein transfer alpha and stone subunits in E. coli BL21 CodonPlus (DE3) RIL (Stratagene) Inhibited by 75 mmol NaCl, 50 μmol ZnCl2, 5 mol Mosses dithiofusitol, 0.5 mol Moss concentration 4-(fluorenylphenyl) methanesulfonyl fluoride and protease inhibition Mixture Tablets-68- (65) (65) 200413356 (5 mM Molecule Sodium Phosphate Buffer (pH 7.2) completely without Mini EDTA, Roche Diagnostics) was ultrasonicated, and the cultured cells were divided. The extract was centrifuged at 40,000 X g for 30 minutes and passed through three column chromatography using DEAE S ephacel (Amer sham Pharmacia Biotech), HiTrapQ column (Amer sham

Pharmacia Biotech ) 及 Phenyl Sepharose High Performance 管柱(Amersham Pharmacia Biotech ) ，從上淸液純化人類法呢基-蛋白質轉移酶。使用 pGEX4T - 1 ( Amersham Pharmacia Biotech) 將人類法呢基一蛋白質轉移酶α及/3次單元共同表達在大腸桿菌 BL2 1 CodonPlus ( DE3 ) RIL，經由在含 1% Triton X - 100的磷酸鹽緩衝化鹽水中超音波化，將培養的細胞分裂，在4°C將粗萃取物在40，000 X g離心30分鐘，經由三次管柱層析法，使用 DEAE Sephacel ( Amersham Pharmacia Biotech ) 、 HiTrapQ 管柱(Pharmacia Biotech) and Phenyl Sepharose High Performance columns (Amersham Pharmacia Biotech) to purify human farnesyl-protein transferase from the supernatant. Co-expression of human farnesyl-protein transferase α and / 3 subunits in E.coli BL2 1 CodonPlus (DE3) RIL using pGEX4T-1 (Amersham Pharmacia Biotech), via phosphate buffered saline containing 1% Triton X-100 Ultrasonicated in saline, the cultured cells were divided, and the crude extract was centrifuged at 40,000 X g for 30 minutes at 4 ° C. After three column chromatography, DEAE Sephacel (Amersham Pharmacia Biotech), HiTrapQ column was used. (

Amersham Pharmacia Biotech )及 Phenyl Sepharose High Performance 管柱（Amersham Pharmacia Biotech)，從上淸液純化椐牛兒基椐牛兒基-蛋白質轉移酶，將含牴牛兒基据牛兒基一蛋白質轉移酶的部份集中並經由含20%甘油之50毫莫耳濃度Tris - Cl pH 7.5透析。在大腸桿菌JM 109中使用pT7— 7病媒作爲N —端六 —組織胺酸—標記的蛋白質，表達全長度人類Κ 一 Ras4B G12V ( GenBank登記編號：m5496 8對野生型），將培養液懸浮在含6莫耳濃度呱呢啶氫氯化物、1 0毫莫耳濃 -69- (66) (66)200413356 度Tris — Cl pH8.0、1毫莫耳濃度MgCl2之緩衝液內，在 4 °C將混合物在4 0，0 0 0 X g離心1 5分鐘’將上淸液施加至Ni — NTA —管柱（QIAGEN)並將6莫耳濃度呱呢啶氫氯化物換成8莫耳濃度脲，除了緩衝液含1毫莫耳濃度 M g C 12以外，經由管柱手冊中建議的P Η梯度流洗K — Ras4B，將含Κ 一 Ras的部份集中並經由梯度透析及最後從10毫莫耳濃度Tris— C1 ρΗ8·5及1毫莫耳濃度MgCl2 去除脲。經由過濾法，從再重組的人類K— Ras4B蛋白質之〔 3 Η〕法呢基化評估法呢基轉移酶活性，5 0微升反應混合物含50毫莫耳濃度Tris - Cl ( PH7.5 ) 、5毫莫耳濃度二硫蘚糖醇、0.3微莫耳濃度 ZnCl2、10毫莫耳濃度 MgCl2 v 60毫微莫耳濃度〔1 一 3H〕一焦磷酸法呢酯（ 60nCi， Muromachi Yakuhin Kogyo) 、86 毫微莫耳濃度 K- Ras及0.4微克人類法呢基一蛋白質轉移酶，將測試化合物溶解在二甲亞硕（DMSO )並在最終濃度小於1%之 DM SO下添加至反應混合物，在96槽平板中經由加入〔1 一 3 Η〕—焦磷酸法呢酯開啓反應，在3 0 °C培養60分鐘後，經由加入50微升10% TCA使反應停止，將混合物轉移至 Multiscreen 平板（MAFBN0B50， Millipore)，各槽中先加入1 〇〇微升乙醇，然後將平板過濾並用乙醇淸洗三次，在各槽中加入 30 微升液體閃爍劑 OptiPhase ‘SuperMix’ （Wallac)並在 MicroBeta 閃燦計數器（ Wall ac )測量放射活性，與對照阻比較，計算法呢基轉移 -70- (67) 200413356 酶活性得到50%抑制的濃度之IC5 〇値。經由相同方法但是反應含50毫莫耳濃度Tris — Cl ( pH7.5 ) 、5毫莫耳濃度二硫蘚糖醇、0.5微莫耳濃度Amersham Pharmacia Biotech) and Phenyl Sepharose High Performance columns (Amersham Pharmacia Biotech). Purified geranyl-geranyl-protein transferase from the supernatant. Partially concentrated and dialyzed against 50 mM Tris-Cl pH 7.5 with 20% glycerol. The pT7-7 vector was used as the N-terminal hexa-histidine-labeled protein in E. coli JM 109 to express full-length human K-Ras4B G12V (GenBank accession number: m5496 8-pair wild type), and the culture solution was suspended. In a buffer solution containing 6 moles of linalidine hydrochloride, 10 mmoles of 69- (66) (66) 200413356 degrees Tris — Cl pH 8.0, and 1 mmole of MgCl 2 in a buffer solution, Centrifuge the mixture at 40,000 x g for 15 minutes at ° C. 'Apply the supernatant to a Ni — NTA — column (QIAGEN) and replace the 6 mol tarimidine hydrochloride with 8 mol. Concentrated urea, in addition to the buffer containing 1 millimolar concentration of M g C 12, was washed with K-Ras4B through the PΗ gradient flow recommended in the column manual. The fraction containing K-Ras was concentrated and subjected to gradient dialysis and finally from Tris—C1 ρΗ8.5 · 10 at 10 mmoles and MgCl2 at 1 mmoles to remove urea. 50 μl of the reaction mixture containing Tris-Cl (PH7.5) at a concentration of 50 millimolars was evaluated from the [3Η] farnesylation of re-recombined human K-Ras4B protein by filtration. , 5 millimolar concentration of dithiofusitol, 0.3 micromolar concentration of ZnCl2, 10 millimolar concentration of MgCl2 v 60 nanomolar concentration [1-3H] -farnesyl pyrophosphate (60nCi, Muromachi Yakuhin Kogyo) , 86 nanomolar concentration of K-Ras and 0.4 micrograms of human farnesyl-protein transferase, dissolve the test compound in Dimethoate (DMSO) and add it to the reaction mixture at a final concentration of less than 1% DM SO, The reaction was started in a 96-well plate by adding [1 to 3 Η] -farnesyl pyrophosphate. After incubation at 30 ° C for 60 minutes, the reaction was stopped by adding 50 μl of 10% TCA, and the mixture was transferred to a Multiscreen plate. (MAFBN0B50, Millipore), add 1000 microliters of ethanol to each tank, then filter the plate and wash with ethanol three times, add 30 microliters of liquid scintillator OptiPhase 'SuperMix' (Wallac) to each tank and flash in MicroBeta Can Counter ac) Measure the radioactivity, and calculate the farnesyl transfer -70- (67) 200413356 at a concentration of 50% inhibition of IC50 compared with the control resistance. After the same method but the reaction contains 50 millimolar Tris — Cl (pH 7.5), 5 millimolar dithithiol, 0.5 micromol

ZnCl2、10毫莫耳濃度MgCl2、5毫微莫耳濃度ATP、1 .2 毫微莫耳濃度〔1 一 3H〕-焦磷酸德牛兒基德牛兒酯（ 3μ(Γί， Muromachi Yakuhin Kogyo ) 、86 毫微莫耳濃度 K 一 Ras及7微克人類椐牛兒基牴牛兒基-蛋白質轉移酶，評估搌牛兒基据牛兒基-蛋白質轉移酶活性。表2ZnCl2, 10 nanomolar concentration MgCl2, 5 nanomolar concentration ATP, 1.2 nanomolar concentration [1-3H] -de-geranyl pyrophosphate (3μ (Γ), Muromachi Yakuhin Kogyo) , 86 nanomolar concentration K-Ras and 7 micrograms of human geranyl-geranyl-protein transferase to evaluate geranyl-based geranyl-protein transferase activity. Table 2

在K- Ras存在下的人類法呢基一蛋白質轉移酶之抑制作用實例 IC5〇 (毫微莫耳濃度） 1 4.5 2 2.4 3 1 .9 4 1 .6 13 1 .0 14 1 .2 16 1 . 1 18 0.9 20 1.0 21 2.5 2 2 1.1 -71 - (68) 200413356 實例2 8 細胞生長的抑制作用之試管內測試法抗增生活性測試法進行如下，將腫瘤細胞之單一懸浮液培養至序列稀釋的96 -槽微量測試平板內，然後在3 7 °C將模板在5% C02中培養4天（2 - 3 X 1 03細胞/槽），經由使用 WST— 8 ( Dojindo， Japan )測量單層中的細胞生長程度，計算產生5 0% 0D的對照組生長之藥劑濃度作爲藥劑對抗腫瘤細胞之1C 5〇値。表3Example of inhibitory effect of human farnesyl-protein transferase in the presence of K-Ras IC50 (nanomolar concentration) 1 4.5 2 2.4 3 1 .9 4 1 .6 13 1 .0 14 1 .2 16 1 1 18 0.9 20 1.0 21 2.5 2 2 1.1 -71-(68) 200413356 Example 2 8 In vitro test method for inhibition of cell growth The anti-proliferative test method was performed as follows, a single suspension of tumor cells was cultured to serial dilution 96-well microtest plate, and then incubate the template in 5% C02 for 4 days (2-3 X 103 cells / well) at 37 ° C, and measure the monolayer by using WST-8 (Dojindo, Japan) The degree of cell growth in the medium was calculated as the concentration of the agent that produced 50% 0D in the control group as 1C 50% of the agent against tumor cells. table 3

對抗人類腫瘤細胞系QG56之試管內抗腫瘤活性實例 IC5〇 (毫微莫耳濃度） 1 5.9 2 1 . 1 3 0.6 4 2 1.0 13 9.6 14 0.1 16 2.0 18 1.2 20 1.3 2 1 7.7 22 0.3 因此本發明化合物具有醫療活性，產生固體腫瘤之退化或 -72- (69) (69)200413356 減輕。實例2 9 下列調製物舉例說明根據本發明合適全身或局部用藥至溫血動物之給藥單元形式之典型醫藥調製物。在這些實例中使用的”活性成份”（A · I ·)係指式（！ )及（2 )化合物、其藥學上可接受的酸或鹼加成鹽類或立體化學異構物形式。實例2 9 - 1 口服溶液將9克4一經基苯甲酸甲醋及1克4一經基苯甲酸丙酯溶解在1升沸騰純化的水中，在3升此溶液中先溶解 10克2，3—二羥基丁二酸及隨後20克A.I.，將後者溶液與剩下的前者溶液混合並在其中加入1 2升1，2，3 -丙三醇及3升山梨糖醇7 0 %溶液，將40克糖精鈉溶解在0.5 升水中並加入2毫升木莓及2毫升醋栗精，將後者溶液與前者混合，加入水直到體積是20升，得到每茶匙（5毫升）含5毫克A.I.之口服溶液，將所得的溶液塡入合適的容器內。實例2 9 — 2 . 膠囊劑調製物將2 0克A. I .、6克硫酸月桂酯鈉、5 6克澱粉、5 6克 -73- (70) (70)200413356 乳糖、0.8克膠質二氧化矽及1.2克硬脂酸鎂在一起激烈攪拌，將所得的混合物隨後塡入1 〇〇〇個合適的硬化明膠膠囊內，各含20毫克A.I.。實例29 — 3 包膜片劑調製物將100克A.I.、5 70克乳糖及200克殿粉混合均勻且隨後用5克硫酸十二烷酯鈉及丨〇克聚乙烯基吡咯酮在約 2 00毫升水中的溶液溼化，將溼粉末混合物過篩，乾燥並再度過篩，然後加入100克微晶纖維素及15克氫化植物油，將整體混合均勻並壓製成片劑，得到1 0，0 0 0個片劑，各含10毫克A.I.。在1 〇克甲基纖維素於75毫升變性乙醇的溶液中加入 5克乙基纖維素於150毫升DCM之溶液，然後在其中加入75毫升DCM及2.5毫升1，2，3 —丙三醇，將1〇克聚乙二醇熔化並溶解在75毫升DCM，將後者溶液添加至前者後在其中加入2.5克十八烷酸鎂、5克聚乙烯基吡咯酮及3 0毫升濃縮色素懸浮液，並將整體均勻化，在包覆裝置中用如此所得的混合物包覆片劑核心。實例29 - 4 注射溶液/乳液製劑將1.8克4 —羥基苯甲酸甲酯及0.2克4一羥基苯甲酸丙酯溶解在約0.5升用於注射之沸騰純化的水中’冷卻 -74- (71) (71)200413356 至約5 0 °C，在攪拌下在其中加入4克乳酸、0.0 5克丙二醇及4克A . I ·，使溶液冷卻至室溫並補充用於注射的水直到體積是1升，得到含4毫克/毫升A.I.之溶液，經由過清、將溶液殺囷並續入無菌的容器內。實例29- 5 栓劑將3克A.I.溶解在3克2，3-二羥基丁二酸於25毫升聚乙二醇4 0 0之溶液中，將1 2克表面活性劑及3 0 0克甘油三酯熔化在一起，將後者混合物與前者溶液混合均勻，將如此所得的混合物倒入溫度是3 7 - 3 8 °C之模具內形成100個栓劑。Example of in vitro antitumor activity against human tumor cell line QG56 IC50 (nanomolar concentration) 1 5.9 2 1.. 1 3 0.6 4 2 1.0 13 9.6 14 0.1 16 2.0 18 1.2 20 1.3 2 1 7.7 22 0.3 The compound of the invention is medically active, produces solid tumors that degenerate or is reduced by -72- (69) (69) 200413356. Example 2 9 The following formulations exemplify typical pharmaceutical formulations in the form of dosing units suitable for systemic or topical application to warm-blooded animals according to the present invention. The "active ingredient" (A · I ·) used in these examples refers to the compounds of formulae (!) And (2), their pharmaceutically acceptable acid or base addition salts or stereochemically isomeric forms. Example 2 9-1 Oral Solution Dissolve 9 g of 4-methyl-benzoate and 1 g of 4-propyl-benzoate in 1 liter of boiling purified water. In 3 liter of this solution, firstly dissolve 10 g of 2, 3-— Dihydroxysuccinic acid and then 20 g of AI, mix the latter solution with the remaining former solution and add 12 liters of 1,2,3-glycerol and 3 liters of sorbitol 70% solution. Dissolve saccharin sodium in 0.5 liters of water and add 2 ml of raspberry and 2 ml of gooseberry essence. Mix the latter solution with the former, add water until the volume is 20 liters, and obtain an oral solution containing 5 mg of AI per teaspoon (5 ml). Put the resulting solution into a suitable container. Example 2 9-2. Capsule preparation 20 grams of A.I., 6 grams of sodium lauryl sulfate, 56 grams of starch, 56 grams of -73- (70) (70) 200413356 lactose, 0.8 grams of gum The silica and 1.2 grams of magnesium stearate were stirred vigorously together, and the resulting mixture was then poured into 1,000 suitable hardened gelatin capsules, each containing 20 mg of AI. Example 29 — 3 Coated Tablet Formulation 100 g of AI, 5 70 g of lactose, and 200 g of powder were mixed and then 5 g of sodium dodecyl sulfate and 5 g of polyvinylpyrrolidone were used at about 200 The solution in milliliter of water was humidified, the wet powder mixture was sieved, dried and sieved again, then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added, and the whole was mixed uniformly and compressed into tablets to obtain 10.0 0 tablets, each containing 10 mg of AI. To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose in 150 ml of DCM, and then 75 ml of DCM and 2.5 ml of 1,2,3-glycerol were added thereto. 10 g of polyethylene glycol was melted and dissolved in 75 ml of DCM, and the latter solution was added to the former and 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated pigment suspension were added thereto. The whole is homogenized, and the tablet core is coated with the thus-obtained mixture in a coating device. Example 29-4 Injection Solution / Emulsion Formulation 1.8 grams of methyl 4-hydroxybenzoate and 0.2 grams of propyl 4-hydroxybenzoate were dissolved in about 0.5 liters of boiling purified water for injection. 'Cool-74- (71) (71) 200413356 to about 50 ° C, add 4 grams of lactic acid, 0.05 grams of propylene glycol, and 4 grams of A. I · while stirring, allow the solution to cool to room temperature and replenish water for injection until the volume is 1 Liter, to obtain a solution containing 4 mg / ml AI, pass through the solution, kill the solution and continue into a sterile container. Example 29-5 Suppository 3 g of AI was dissolved in 3 g of 2,3-dihydroxysuccinic acid in 25 ml of polyethylene glycol 400 solution, 12 g of surfactant and 300 g of triglyceride The esters are melted together, the latter mixture and the former solution are mixed uniformly, and the thus obtained mixture is poured into a mold having a temperature of 37-38 ° C to form 100 suppositories.

•75-• 75-

Claims

(1) (1) 200413356 Patent application scope 1 · A benzofuran compound of the formula [I],

Wherein · R1 is —N02; —CN; or pyridin-3-yl; R2 is hydrogen; halo; if necessary, 1 to 3 halo, —CN or straight or branched (G— C4) —Alkoxy substituted phenyl; pyridin-3-yl; or benzo [1,3] dioxocene-5-yl; and pharmaceutically acceptable salts and solvates thereof. 2. The benzofuran compound according to item 1 of the scope of the patent application, wherein R2 is hydrogen, halo, phenyl, substituted by 1 to 3 halo, each CN, methoxy or ethoxy, which are the same or different Phenyl, pyridinyl 3-yl, or benzo [1,3] dioxo-5-yl. 3. A benzofuran compound according to item 2 of the application, wherein R2 is a phenyl group, a phenyl group substituted with 1 to 3 fluorine, bromine, monoCN, methoxy or ethoxy groups which are each the same or different, Pyridine-3-yl, or benzo [1,3] dioxo-5-yl. 4. The benzofuran compound according to item 3 of the scope of the patent application, wherein R2 is 3-fluorophenyl, 4-monofluorophenyl, 3,4-difluorophenyl, 3,5-monofluorophenyl, 3- Chlorophenyl, 3-cyanophenyl, 3-methoxyphenyl or 3-ethoxyphenyl. -76- (2) (2) 200413356 5. For example, the benzofuran compound of item 1 in the scope of patent application, wherein R2 is halo, phenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxy Phenyl, 3-ethoxyphenyl, 3-cyanophenyl, pyridin-3-yl, or benzo [1,3] dioxo-5-yl. 6. The benzofuran compound according to item 1 of the application, wherein R1 is nitro. 7. The benzofuran compound according to item 6 of the scope of application, which is selected from the group consisting of: a) 4- [amino- (3-methyl-3H-imidazole-4-yl)-(5-nitro- 7-phenyl-benzofuran 2-yl) -methyl] -benzonitrile; b) 4- [amino_ [7- (3-methoxy-phenyl) -5-nitro-benzene Benzofuran-2-yl]-(3-methyl-3H-imidazol-4-yl) -methyl] -benzonitrile; c) 4- [amino- (7-benzo [1,3] di Oxocene-5-yl-5-nitro-benzofuran-2-yl)-(3-methyl-3H-imidazol-4-yl) -methyl] -benzonitrile; d) 4-[amino — [7- (3-fluoromonophenyl) -5-nitro-benzofuran-2-yl] — (3-methyl-3H-imidazol-4-yl) monomethyl] -benzonitrile; e) 4- [Amino- [7- (3-cyano-phenyl) -5-nitro-benzofuran-2-yl]-(3-methyl-3H-imidazole-4-yl) — Methyl] -benzonitrile; f) 4- [amino- [7- (3-ethoxy-phenyl) -5-nitro-77- (3) (3) 2 00413356 phenyl-benzofuran-2-yl]-(3-methyl-3H-imidazol-4-yl) -methyl] -benzonitrile; g) 4- [amino- (3-methyl-3H —Imidazole— 4-yl)-(5-nitro-benzobenzo-2-yl) -methyl] -benzonitrile; h) 4- [amino- [7— (3-chloro-phenyl ) —5 -nitro-benzofuran-2-yl]-(3-methyl- 3H-imidazol-4-yl) -methyl] -benzonitrile; i) 4— [amino- [7- (4-fluoro-phenyl) -5-nitro-benzofuran-2-yl]-(3-methyl-3H-imidazol-4-yl) -methyl] -benzonitrile; j) 4- [Amine— [7— (3,5-difluoro-phenyl) -5—nitro-benzofuran_2-yl] — (3-methyl- 3H-imidazole-4-yl) -methyl ] -Benzonitrile; k) 4- [Amino- [7- (3,4-difluoro-phenyl) -5-nitro-benzofuran-2-yl]-(3-methyl-3H -Imidazole-4-yl) monomethyl] -benzonitrile; l) 4- [aminomono (3-methyl-3H-imidazole-4-yl) — (5-nitro-7-pyridine-3-yl-benzofuran 2-yl) -methyl] -benzonitrile. 8. The benzofuran compound according to item 1 of the application, wherein R1 is cyano. 9. The benzofuran compound according to item 8 of the scope of application, which is selected from the group consisting of: a) 2-[amino group-(4-cyano-phenyl)-(3-methyl-78- (4 ) (4) 200413356 3 Η Blizzard 4-4-yl) monomethyl] -7-phenyl-benzopyran-5-carbonitrile; b) 2- [amino- (4-cyano-phenyl) )-(3-methyl-3H-imidazol-4-yl) -methyl] -7- (3-methoxy-phenyl) -benzofuran-5-carbonitrile; c) 2- [amino Mono (4-cyano-phenyl)-(3-methyl-3H-imidazol-4-yl) -methyl] -7-benzo [1,3] dioxo- 5-yl-benzofuran— 5 -carbonitrile; d) 2-[amino- (4-cyano-phenyl)-(3-methyl- 3H-imidazole-4-yl) -methyl]-7- (3-fluoro-benzene Group) -benzofuran-5-carbonitrile; e) 2— [amino- (4-cyano-phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -7 — (3-cyano-phenyl) -benzofuran-5-carbonitrile; f) 2- [amino- (4-monocyano -Phenyl)-(3-methyl-3H-imidazole-4-yl) -methyl] -7- (3-chloro-phenyl) -benzofuran-5-carbonitrile; and g) 2- [Amine- (4-Cyano-phenyl) — (3-Methyl- 3H—taste-D-A-4—Methyl] —Methyl] -7-Au-D 5—Nitrile. 10. The benzofuran compound according to item 1 of the scope of the patent application, wherein R 1 is a cyclohex-3-yl group. 1 1. The benzofuran compound according to item 10 of the scope of patent application, which is selected from the group consisting of: -79- (5) (5) 200413356 a) 4- [amino- (3-methyl-3H-imidazole) -4-yl)-(7 -phenyl-5 -pyridin-3-yl-benzofuran-2-yl) methyl] -benzonitrile; b) 4-[amino group-[7-(3- Methoxy-phenyl)-5-pyridine-3-yl-benzofuran-2-yl]-(3-methyl-3H-imidazole-4-yl) -methyl] -benzonitrile; c) 4- [Amino- (7-benzo [1,3] dioxocene-5-yl-5-yl-1,5-pyridine-3-yl-benzofuran-2-yl)-(3-methyl- 3H-imidazole -4-yl) -methyl] -benzonitrile; d) 4- [amino- [7- (3-chloro-phenyl) -5-D than B-A-3 -yl-benzofuran_2 -Yl]-(3-methyl-3H-imidazole-4 4-yl) _methyl] -benzonitrile; e) 4- [amino- [7- (3-cyano-phenyl)-5- D ratio is π-3 -yl-benzopyran- 2-yl]-(3-methyl-3H-t D-4-yl) -methyl Monobenzonitrile; f) 4-a [amino- [7- (3-chloro-phenyl) -5-D than B-a-3—yl-benzopyran- 2-yl] — (3-methyl -3H-taste D 4-a-yl) -methyl] -benzonitrile; g) 4- [amino- (5 '7-bis-D than D-D- 3 -yl-benzofuran-2 —Base) — (3-Methyl-3H-imidazole-4-yl) -methyl] -benzonitrile; 1 2. — A pharmaceutical composition containing any of the items in the scope of claims 1 to 11 A benzofuran compound of formula (I), and a pharmaceutically acceptable carrier. -80- (6) (6) 200413356 1 3. The pharmaceutical composition according to item 12 of the patent application scope, which further contains a chemical agent. 14 · The compound according to any one of claims 1 to 11 in the scope of patent application, which is used as a medicament. 15. The use of a benzofuran compound according to any one of claims 1 to 11 of the scope of application for a patent, which is used for the preparation of a medicament. 16. The application according to item 15 of the scope of patent application, for the preparation of a medicament for the treatment of a cell proliferative disorder. 17 · The application according to item 16 of the scope of patent application, wherein the cell proliferation disorder is cancer. 18. The application according to item 17 of the scope of patent application, wherein the cancer is colorectal cancer, lung cancer, breast cancer, prostate cancer and blood cancer. 19 · A method for treating a cell proliferation disorder, comprising administering an effective medical amount of a benzofuran compound as defined in any one of claims 1 to 11 to a patient in need thereof. 20. The method according to claim 19, wherein the cell proliferation disorder is cancer. 2 1. The method of claim 20, wherein the cancer is colorectal cancer, lung cancer, breast cancer, prostate cancer, and blood cancer. 22 · —a method for preparing a benzofuran compound of the formula [I],

-81-(7) 200413356 wherein R 1 and R 2 are the same as defined in the scope of the patent application, which includes the definition of the compound of the formula [VII] with an acidic compound 4-[2 -methyl-2 -propanesulfenamide Dissociation of monobenzofuran 2-yl-1 (3-methyl-3H, 1-D, 4-4-yl), 1-methyl] -benzonitrile,

R1 [VII] R2

Among them, R1 and R2 are the same as the definition of item 1 in the scope of patent application.

23.—A compound of the formula [VII] for use in the method as claimed in item 22 of the scope of the patent application 4— [2-Methyl-2-propanesulfenamido-benzopyran-2-yl— (3-methyl-3H-imidazo-4-yl) -methyl] -benzonitrile method,

R2 R1 [VII] wherein R 1 and R 2 are the same as defined in the first scope of the patent application, which includes the use of a compound of formula [VIII] 1-methyl- 2 -triethylsilyl-1H-imidazole-5 -lithium , -82- [VIII] (8) 200413356

Compounds of the formula [V] 2-methyl-propanone- 2-sulfinic acid benzofuran- 2-yl- (4-cyano-phenyl) -methyleneamine,

Among them, R 1 and R 2 are the same as the definition of item 1 in the scope of the patent application. 24.-a kind of compound of formula [V] used in the method of the scope of patent application in the scope of patent application. —A method for benzosulfanyl sulfanyl-2-yl- (4-cyano-phenyl) -methyleneamine,

R2 Ri [V] where R1 and R2 are the same as those defined in the scope of the first patent application, which includes the compound of formula [II] 4- (benzofuran-2-carbonyl) -benzonitrile, -83- 200413356

Ri ρΩ where R1 and R2 are the same as the definition of item 1 in the scope of patent application and 2-methyl-2-propanesulfenamide [VI], > | ^ S, NH2 [VI] acid dehydration in Louis Condensation in the presence of an agent. 25. A method for preparing a compound 4- (benzofuran-2-carbonyl) -benzonitrile of the formula [II] used in the method as claimed in item 24 of the scope of patent application,

Wherein R 1 and R 2 are the same as those defined in item 1 of the scope of patent application, which includes the compound of formula [III] 2-hydroxybenzaldehyde,

Among them, R 1 and R 2 are the same as the definitions in item 1 of the scope of the patent application. -84- (10) 200413356 and 4-cyanobenzoylmethyl halide of formula [IV], 0

[IV] where X is a halogen group, and is condensed in the presence of a basic compound. 2 6. —A novel compound, a novel medicinal composition, a preparation method and a method for preparing the above-mentioned substance and the application of the compound are substantially disclosed in this document. -85- 200413356 指定, designated representative map: (1), designated representative map in this case For: None (two), the component representative symbols of this representative diagram are simply explained: None

捌. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: Formula (I)