TW200908964A

TW200908964A - Use of HDAC inhibitors for the treatment of gastrointestinal cancers

Info

Publication number: TW200908964A
Application number: TW097116351A
Authority: TW
Inventors: Peter Wisdom Atadja
Original assignee: Novartis Ag
Priority date: 2007-05-04
Filing date: 2008-05-02
Publication date: 2009-03-01
Also published as: CL2008001269A1; MX2009011692A; CN101674825A; RU2009144842A; ZA200906739B; TN2009000427A1; EP2142190A1; CA2683554A1; IL201318A0; KR20100016171A; WO2008137630A1; MA31356B1; AU2008247603A1; BRPI0811112A2; JP2010526149A

Abstract

The present invention relates to the use of an HDAC inhibitor for the preparation of a medicament for the treatment of gastrointestinal cancers; a method of treating a warm-blooded animal, especially a human, having gastrointestinal cancer, comprising administering to said animal a therapeutically effective amount of an HDAC inhibitor, especially a compound of formula (I) as defined herein; and to a pharmaceutical composition and a commercial package.

Description

200908964 九、發明說明：【發明所屬之技術領域】本發明關於HDAC抑制劑用於製備供治瘃深貝腸癌之藥劑；一種治療患有胃勝癌的溫血動物之方法，尤其β 類’包括對該動物投與治療有效量之HDAC抑制劑，2為本文定義化學式（I)之化合物；本發明關於醫藥組合物及商業包裝。 σ 【先前技術】感染胃腸癌的病人類存活機率普遍偏低。標準化療法並非總是有效。因此’有必要研究出新的治療方法。【發明内容】用於此處之術語"胃腸癌"包括但不限於肝細胞癌 (hepatocellular carcinoma)及/或胰腺癌 0 本文定義之化學式⑴之化學物為組蛋白脫乙酿基酶抑制劑（HDAC抑制劑）。組蛋白之可逆乙醯化作用為基因表現之主要調節劑，其通過改變轉錄因子通往〇1^八之通道起作用。正常細胞中，組蛋白脫乙醯基酶（HDA)和組蛋白乙醯基轉移酶一起控制組蛋白乙醯化的量以維持平衡。hda之抑制引起高乙醯化組蛋白積聚，這將導致大量細胞反應。如今，令人驚奇地發現：HDAC抑制劑，尤其本文定義之化學式⑴之化合物，可直接抑制胃腸癌（如肝細胞癌及/ 或胰腺癌）增生。因此，本發明關於HDAC抑制劑用於製備供治療胃腸癌之藥劑。 130311 .doc 200908964 【實施方式】 HDAC抑制劑化合物在本發明之組合中，具有特別用處之HDAC抑制劑化合物為化學式（I)之羥肟酸化合物：200908964 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to an agent for the preparation of a deep-sucking intestinal cancer for the treatment of sputum, and a method for treating a warm-blooded animal having a gastric cancer, especially a beta-type This includes administering to the animal a therapeutically effective amount of a HDAC inhibitor, 2 being a compound of formula (I) as defined herein; and the present invention relating to pharmaceutical compositions and commercial packaging. σ [Prior Art] The survival rate of patients infected with gastrointestinal cancer is generally low. Standardized therapies are not always effective. Therefore, it is necessary to develop new treatment methods. SUMMARY OF THE INVENTION The term "gastrointestinal cancer" as used herein includes, but is not limited to, hepatocellular carcinoma and/or pancreatic cancer. The chemical of formula (1) as defined herein is histone deacetylase inhibition. Agent (HDAC inhibitor). The reversible acetylation of histones is a major regulator of gene expression by altering the transcription factor to the channel of 〇1^8. In normal cells, histone deacetylase (HDA) and histone acetyltransferase together control the amount of histone acetylation to maintain equilibrium. Inhibition of hda causes high acetylated histone accumulation, which results in a large number of cellular responses. Nowadays, it has been surprisingly found that HDAC inhibitors, especially the compounds of formula (1) as defined herein, directly inhibit the proliferation of gastrointestinal cancers such as hepatocellular carcinoma and/or pancreatic cancer. Accordingly, the present invention relates to HDAC inhibitors for the preparation of a medicament for the treatment of gastrointestinal cancer. 130311 .doc 200908964 [Embodiment] HDAC inhibitor compound In the combination of the present invention, the HDAC inhibitor compound having a special use is a hydroxamic acid compound of the formula (I):

Ri為Η ;鹵素；或直鏈CrC6烷基，尤其為甲基、乙基或正丙基，其中甲基、乙基或正丙基取代基為未經取代或經一個或多個如下對烷基所描述之取代基取代； R2選自Η ; CVCm烷基’較佳為Cl_C6烷基，如甲基、乙基或-CH2CH2-OH; (：4-(：9環烷基；c4-C9雜環烷基； C4_C9雜ί衣烧基烧基，環烧基烧基，如環丙基甲基； ^基；雜方基’芳基燒基’如苯曱基；雜芳基烧基，如吡啶基甲基；-(CH2)nC(0)R6 ; -(CH2)n〇c(〇)R6 ;胺基醯基；HON-qcO-Ci^Cd)-芳基-烷基_ ;及 •(CH2)nR7 ; R3和R4可相同或不同且各獨立為H、CrC：6烷基、醯基或醯胺基，或 R3和R4與其相連的碳原子一起表示c=〇、c=S戈 C=NRs，或 R2和其相連的乳原子以及R·3和其相連的碳原子，可形成 130311.doc 200908964 cvc9雜環燒基，雜芳I，多雜芳基，非芳族的多雜環’或芳基和非芳基多雜環的混合； R5選自η，Cl_c6烷基；C4_C9環院基；C4_C9雜環烷基；酿基；芳基；雜芳基；芳基烧基，如苯甲基；雜芳基院基如°比°定基甲基；多環芳香烴；多環非芳香烴；混合含芳基和非芳基多環；聚雜芳基；非芳香多雜環；或現合芳基和料基多雜環； η、m n2和n3可相同或不同且獨立地選自0到6之間，當Ri is hydrazine; halogen; or a linear CrC6 alkyl group, especially methyl, ethyl or n-propyl, wherein the methyl, ethyl or n-propyl substituent is unsubstituted or via one or more of the following paraffins Substituted by a substituent as described; R2 is selected from fluorene; CVCm alkyl' is preferably a C1-C6 alkyl group such as methyl, ethyl or -CH2CH2-OH; (: 4-(:9-cycloalkyl; c4-C9) Heterocycloalkyl; C4_C9 heterobromoalkyl, cycloalkyl, such as cyclopropylmethyl; ^; heteroaryl 'arylalkyl', such as phenylhydrazine; heteroarylalkyl, Such as pyridylmethyl; -(CH2)nC(0)R6; -(CH2)n〇c(〇)R6; amine fluorenyl; HON-qcO-Ci^Cd)-aryl-alkyl-; • (CH2)nR7; R3 and R4 may be the same or different and each independently H, CrC: 6 alkyl, fluorenyl or decylamino, or R3 and R4 together with the carbon atom to which they are attached represent c=〇, c=S Ge C=NRs, or R2 and its attached milk atom and R·3 and its attached carbon atom, can form 130311.doc 200908964 cvc9 heterocycloalkyl, heteroaryl I, polyheteroaryl, non-aromatic a mixture of a heterocyclic ring or an aryl group and a non-aryl polyheterocyclic ring; R5 is selected from the group consisting of η, Cl_c6 alkyl; C4_C9 ring-based; C4_C 9 heterocycloalkyl; aryl; aryl; heteroaryl; arylalkyl, such as benzyl; heteroaryl group, such as ° methyl group; polycyclic aromatic hydrocarbon; polycyclic non-aromatic hydrocarbon; Mixed aryl-containing and non-aryl polycyclic; polyheteroaryl; non-aromatic polyheterocyclic; or aryl and polyheterocyclic; η, m n2 and n3 may be the same or different and independently selected from 0 Between 6 and when

ηι為1到6時’各碳原子可以視情況且獨立地經R3及/或 R4取代； x和γ可相同或不同且獨立地選自H; i素；㈣烷基’如 CH3和 cf3 ; N〇2 ; c⑼Ri ; 〇R9 ; SR9 ; CN ; 及NRi〇Rn ; 心選自Η ; Cl-C6烧基；CrC9環烧基；C4_C9雜環烷基；環烧基烧基，如環丙基甲基；芳基；雜芳基；芳基& 基，如苯甲基和2-苯基乙浠基；雜芳基燒基，如吼咬基甲基；or12 ;和 nr13r14 ; 、S02r17、NR13R14 和 R7 選自〇Rl5、SR] 5 NR12SO2R6 ; R山自 Η，〇r15，nR13ri4 ; Ci C6燒基；〔4 ^環烧基；G-C9雜環烷基；芳基；雜芳基；芳基烷基，如苯甲基，雜芳基烧基，如吼π定基甲基； R9選自c〗-c4烷基，如ch3和Cf3 ; c(〇)_烷基，如 C(0)CH3 ;及 C(0)CF3 ; 130311.doc 200908964When ηι is from 1 to 6, 'each carbon atom may be optionally substituted with R 3 and/or R 4 ; x and γ may be the same or different and independently selected from H; i; (iv) alkyl ' such as CH 3 and cf 3 ; N〇2; c(9)Ri; 〇R9; SR9; CN; and NRi〇Rn; heart selected from Η; Cl-C6 alkyl; CrC9 cycloalkyl; C4_C9 heterocycloalkyl; cycloalkyl group, such as cyclopropyl Methyl; aryl; heteroaryl; aryl & base, such as benzyl and 2-phenylethenyl; heteroarylalkyl, such as thiomethyl; or12; and nr13r14; , S02r17, NR13R14 and R7 are selected from the group consisting of 〇Rl5, SR] 5 NR12SO2R6; R: 山r15, nR13ri4; Ci C6 alkyl; [4^cycloalkyl; G-C9 heterocycloalkyl; aryl; heteroaryl; Arylalkyl, such as benzyl, heteroarylalkyl, such as 吼π-decylmethyl; R9 is selected from c-c4 alkyl, such as ch3 and Cf3; c(〇)-alkyl, such as C(0 )CH3 ; and C(0)CF3 ; 130311.doc 200908964

Rio和R〗】為相同的或不同且獨立地選自只 ' 1:1 ’ G-C4烧基和 -c(o)-烷基； R12選自Η ; C〗-C6烷基；C4-C9環烷基；c 雜％烧基；Rio and R are the same or different and independently selected from only '1:1' G-C4 alkyl and -c(o)-alkyl; R12 is selected from Η; C--C6 alkyl; C4- C9 cycloalkyl; c hetero-% alkyl;

C4-C9雜環炫基烧基；芳基；混A m σ π基和非芳基多環；雜芳基；芳基院基，如苯甲基. 不Τ丞，及雜芳基烷基，如吡啶基甲基； R13和R14可相同或不同且獨立地遠自Η. ρ & « 1烷基；C4- ㈣基n雜芳基；芳基院基，如苯甲基；雜芳基烧基，如吼咬基甲基；胺基酿基，或 R13和R"與相連的氮原子一起形成C4_C.環院基，雜芳基，多雜芳基，非芳香多雜環或混合芳基和非芳基多雜環； C4_C9雜環烷基，雜芳基烷基和C4-C9 heterocyclic ketone alkyl; aryl; mixed A m σ π group and non-aryl polycyclic ring; heteroaryl; aryl group, such as benzyl. unbranched, and heteroarylalkyl , such as pyridylmethyl; R13 and R14 may be the same or different and independently from Η. ρ & « 1 alkyl; C4- (tetra) n-aryl; aryl group, such as benzyl; a base group such as a benzyl group; an amine group, or R13 and R" together with a nitrogen atom to be bonded to form a C4_C. ring-based, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or a mixture Aryl and non-aryl polyheterocycles; C4_C9 heterocycloalkyl, heteroarylalkyl and

Ris選自Η，CVC6烷基，c4-C9環烷基，芳基’雜芳基，芳基烷基， (CH2)mZR12 ;Ris is selected from the group consisting of hydrazine, CVC6 alkyl, c4-C9 cycloalkyl, aryl 'heteroaryl, arylalkyl, (CH2)mZR12;

Rl6選自Cl-C6院基；C4_C9環烧基；c4_c9雜環烧基；芳基；雜芳基；多雜芳基；芳㈣基；雜芳基烧基和 (CH2)mZR12 ; R〗7選自Cl_C6烷基；c4-c9環烷基 , 签,万基；多環芳香、烴；雜芳基；芳基烷基；雜芳基烷基; 多雜芳基和NR13R14 ; m是選自〇到6之間的整數；和 z選自〇，NR13 ; S ;和 s(o)， 130311.doc 200908964 或其醫藥可接受之鹽類。 ”未經取代"之適當含義指無取代基或僅有氫之取代基。鹵素取代基選自氟基、氣基、漠基和峨基，較佳為氣基或氯基。烷基取代基包括直鏈和支鏈c^c：6烷基，除非另作說明。適當直鍵和支鏈C^-C6烧基之例子包括甲基、乙基、正丙基、2-丙基、正丁基、第二丁基、第三丁基等等。除非另作說明’焼基取代基包括未經取代之院基及可經如下一個或多個適宜取代基取代之烷基：包括不飽和鍵，亦即有一個或多個C-C雙鍵和C-C三鍵；醯基；環烧基；幽素；氧基烧基；烧基胺基；胺基烧基；酿基胺基；及 OR!5，如烷氧基。烷基之較佳取代基包括鹵素、經基、烧氧基、氧基烧基、烧基胺基和胺基烧基。環烧基取代基包括C3_C9環烧基，如環丙基、環丁基、 %戍基和ί衣己基專專，除非另作說明。除非另作說明，環烧基取代基包括未經取代之環院基及可經如下一個或多個適宜取代基取代之環烷基：包括CrC6烷基、鹵素、經基、胺基院基、乳基烧基、烧基胺基和5，如烧氧基。環烧基之較佳取代基包括南素、羥基、烧氧基、氧基烧基、烷基胺基和胺基烷基。上述討論之烷基和環烷基取代基也適用於其他取代基之烧基部分’如（不限於）烷氧基、烷基胺、烷基酮、芳基烧基、雜芳基炫•基、烧基確醯基和烧基酯取代基等等。雜環烷基取代基包括3到9-員脂肪環，如4到7_員脂肪 130311.doc 200908964 環，其包含1到3個選自氮、硫和氧的雜原？。適當雜環烧基取代基之例子包括吡咯烷基、四氫呋喃基、四氫噻吩基 (tetrahydrothiofuranyl)、哌啶基、嗒嗪基、四氫吡喃基、嗎啉-4-基（morphilino)、1，3-二氮雜環庚烷、丨，4•二氮雜環庚烷（l，4-diaZapane)、1，4_氧雜氮雜環庚和1’4 -氧雜硫雜環庚烧（1，4-〇xathiapane)。除非另作規明，環為未經取代或在碳原子上經如下一個或多個適當之取代基取代：包括C^-C：6烷基；CU-C9環烷基；芳基；雜芳基；芳基烷基，如苯甲基；雜芳基烷基，如吡啶基甲基；鹵素’胺基，烧基胺基和〇R]5 ’如烧氧基^除非另作說明，氮雜原子為未經取代或經Η ; 烷基；芳基烷基，如苯甲基；雜芳基烷基’如吡啶基甲基；醯基；胺基醯基；烷基項酿基和方基續酿基取代。環烧基烷基取代基包括化學式_(CH2)n5-環烷基的化合物’其中n5介於1到6之數。適當的烷基環烷基取代基包括環戊基甲基、環戊基乙基、環己基甲基等等。該類取代基為未經取代’或於烷基部分或者於環烷基部分經適當取代基取代’包括如上述對烷基和環烷基所列之取代基。芳基取代基包括未經取代的苯基及經如下一個或多個適當的取代基取代之苯基：包括（^-(：6烷基；環烷基烷基，如環丙基曱基；OC(O)烷基；氧基烷基；鹵素；硝基；胺基；烷基胺基；胺基烷基；烷基酮；腈；羧烷基；烷基確酿基，胺基確酿基；芳基績醯基和5 ’如烧氧基。較佳取代基包括C^-Ce烧基；環烧基，如環丙基甲基；院氧 130311.doc -10- 200908964 基；氧基烷基；_素；硝基；胺基；烷基胺基；胺基烷基’烧基綱；腈；羧烷基；烷基磺醯基；芳基磺醯基和胺基磺醯基。適宜芳基例子包括Ci_C4烷基苯基、Ci_C4烷氧基苯基、三氟甲基苯基、甲氧基苯基、羥乙基苯基、二甲胺基苯基、胺基丙基苯基、羰乙氧基苯基、甲磺醯基苯基和曱苯磺醯基苯基。芳族多環包括萘基和經如下一個或多個適當取代基取代的萘基·包括C】-C6烷基；烷基環烷基，如環丙基甲基；氧基烷基，齒素；硝基；胺基；烷基胺基；胺基烷基；烷基酮；腈；羧烷基；烷基磺醯基；芳基磺醯基；胺基磺醯基和OR〗5，如烷氧基。雜芳基取代基包括含5到7_員芳族環的化合物，其中芳族環包含一個或多個雜原子，如選自氮、氧和硫的1到4個雜原子。典型的雜芳基取代基包括呋喃基、噻吩基、。比各°比°坐、二°坐、嗟°坐、〇惡。坐、吼。定、嘴咬、異。惡。坐基、吡嗪等等。除非另作說明，雜芳基取代基為未經取代或於碳原子上經一個或多個如下適當取代基取代：包括烷基，如上描述之院基取代基，和其他雜芳基取代基。氮原子為未、里取代或由如取代；尤其有用的Ν取代基包括Η、匸广 C4燒基、醯基、胺基醯基和磺醯基。芳基烧基取代基包括如下化學式之基團：_(CH2)n5•芳基 ’ -(CH2)n5-丨_(CH-芳基 HCH2)n5-芳基或 _(CH2)n5 iCH(芳基）（芳基），其中芳基和心定義如上。該類芳基烷基取代基 L括笨曱基、2-苯基乙基' 苯基乙基、甲苯基_3_丙基、 130311.doc 200908964 2-苯基丙基、二苯基甲基、2_二苯基乙基、5,5_二甲基_3_ 苯基戊基等等。芳基烷基取代基為未經取代或於烷基部分或芳基部分或於烧基部分和芳基部分，經如上所述對炫基和芳基所述之取代基取代。雜芳基烷基取代基包括式_(CH2)n5_雜芳基之基，其中雜芳基和n5定義如上，且橋聯基與該雜芳基部分的碳原子或氮原子連接，如2-、3-或4-«比啶基甲基、咪唑基曱基、喹啉基乙基和吡咯基丁基。雜芳基取代基為未經取代或經如上述對雜芳基和烷基所述之取代基取代。胺基醯基取代基包括如式_c(〇)_(CH2)n_c(H)(NRl3U· (CH2)n Rs之基，其中n、R5為如上所述。適當的胺基醯基取代基包括天然胺基酸和非天然胺基酸，比如甘氨醯基，D·色氛醯基，L_賴氨醯基，DjL•高絲氧酸酿基，4-胺基丁醯基和士_3_胺基_4_己烯醯基。非芳香多環取代基包括雙環和三環稠環㈣，其中各環可為4到9-員原子且各環包含零個、一個或多個雙鍵及/或三鍵。非芳香多環之適當例子包括十氫化萘”v氫節、全氫化苯並環庚烯和全氫化苯並*甘菊環。該取代基為未經取代或如上所述對環烷基所述之取代基取代。混合芳基和非芳基多環取代基包括雙環和三環稍環體系，其中各環可為4到9_員且至少一個為芳族。混合芳基和非方基多環的適當例子包括亞曱二氧苯基；雙亞甲二氧 =基I，2,3,4-四氫化萘、二苯並環庚烷、二氫蒽和9H_ 苟。該取代基為未經取代或經硝基取代或經如上對環烧基 13031 l.doc -12· 200908964 所述之取代。Rl6 is selected from the group consisting of Cl-C6; C4_C9 cycloalkyl; c4_c9 heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; aryl(tetra)yl; heteroarylalkyl and (CH2)mZR12; Selected from Cl_C6 alkyl; c4-c9 cycloalkyl, benzyl, polycyclic aromatic, hydrocarbon; heteroaryl; arylalkyl; heteroarylalkyl; polyheteroaryl and NR13R14; m is selected from 〇 to an integer between 6; and z is selected from 〇, NR13; S; and s(o), 130311.doc 200908964 or a pharmaceutically acceptable salt thereof. The meaning of "unsubstituted" means an unsubstituted or hydrogen-only substituent. The halogen substituent is selected from the group consisting of a fluorine group, a gas group, a molybdenum group and a mercapto group, preferably a gas group or a chlorine group. The base includes straight-chain and branched c^c:6 alkyl groups, unless otherwise specified. Examples of suitable straight-chain and branched C--C6 alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-Butyl, t-butyl, tert-butyl, etc. Unless otherwise specified, the fluorenyl substituent includes an unsubstituted ortho group and an alkyl group which may be substituted with one or more suitable substituents as follows: a saturated bond, that is, one or more CC double bonds and CC triple bonds; anthracenyl; cycloalkyl; spectrin; oxyalkyl; an alkyl group; an amine group; a aryl group; Preferred groups for the alkyl group include a halogen, a trans group, an alkoxy group, an oxyalkyl group, an alkyl group, and an amine group. The cycloalkyl substituent includes a C3_C9 cycloalkyl group. , such as cyclopropyl, cyclobutyl, % fluorenyl and hexyl, unless otherwise stated. Unless otherwise specified, the cycloalkyl substituent includes an unsubstituted ring and can be A cycloalkyl group substituted with one or more suitable substituents: including CrC6 alkyl, halogen, thiol, amine aryl, arylalkyl, alkylamino and 5, such as alkoxy. Preferred substituents include sulfhydryl, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. The alkyl and cycloalkyl substituents discussed above are also suitable for the alkyl moiety of other substituents. 'As (not limited to) alkoxy, alkylamine, alkyl ketone, arylalkyl, heteroaryl, decyl and alkyl ester substituents, etc. Heterocycloalkyl substituent Including a 3 to 9-membered fat ring, such as a 4 to 7-member fat 130311.doc 200908964 ring, which contains 1 to 3 heterogenes selected from nitrogen, sulfur, and oxygen. Examples of suitable heterocyclic alkyl substituents include Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, pyridazinyl, tetrahydropyranyl, morphilino, 1,3-diazepane,丨, 4•diazepine (1,4-diaZapane), 1,4-oxazepine and 1'4-oxathiazepine (1,4-〇xathiapane). another It is stated that the ring is unsubstituted or substituted on the carbon atom by one or more of the following suitable substituents: including C^-C:6 alkyl; CU-C9 cycloalkyl; aryl; heteroaryl; An alkyl group such as a benzyl group; a heteroarylalkyl group such as pyridylmethyl; a halogen 'amino group, an alkylamino group and a fluorene R'5' such as an alkoxy group; unless otherwise specified, the nitrogen hetero atom is Unsubstituted or fluorene; alkyl; arylalkyl, such as benzyl; heteroarylalkyl, such as pyridylmethyl; fluorenyl; amine fluorenyl; alkyl aryl and aryl Substituted. The cycloalkylalkyl substituent includes a compound of the formula _(CH2)n5-cycloalkyl, wherein n5 is between 1 and 6. Suitable alkylcycloalkyl substituents include cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and the like. Such substituents are unsubstituted or substituted with an alkyl moiety or with a suitable substituent at the cycloalkyl moiety and include the substituents listed above for the alkyl and cycloalkyl groups. The aryl substituent includes an unsubstituted phenyl group and a phenyl group substituted with one or more suitable substituents including: (^-(:6 alkyl; cycloalkylalkyl, such as cyclopropyl fluorenyl; OC(O)alkyl; oxyalkyl; halogen; nitro; amine; alkylamino; aminoalkyl; alkyl ketone; nitrile; carboxyalkyl; alkyl aryl, amine a aryl group and a 5' group such as an alkoxy group. Preferred substituents include a C^-Ce alkyl group; a cycloalkyl group such as a cyclopropylmethyl group; a hospital oxygen 130311.doc -10-200908964 base; Alkyl; _ nitrite; nitro; amine; alkyl amine; aminoalkyl 'alkyl group; nitrile; carboxyalkyl; alkyl sulfonyl; aryl sulfonyl and amine sulfonyl Examples of suitable aryl groups include Ci_C4 alkylphenyl, Ci_C4 alkoxyphenyl, trifluoromethylphenyl, methoxyphenyl, hydroxyethylphenyl, dimethylaminophenyl, aminopropylbenzene a base, a carbonyl ethoxyphenyl group, a methanesulfonyl phenyl group, and a pyrenyl sulfonyl phenyl group. The aromatic polycyclic ring includes a naphthyl group and a naphthyl group substituted with one or more suitable substituents as follows. C6 alkyl; alkylcycloalkyl, such as cyclopropyl Oxyalkyl, acne; nitro; amine; alkylamino; aminoalkyl; alkyl ketone; nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl; Sulfhydryl and OR 5, such as alkoxy. Heteroaryl substituents include compounds containing 5 to 7 membered aromatic rings, wherein the aromatic ring contains one or more heteroatoms, such as selected from the group consisting of nitrogen, oxygen, and 1 to 4 heteroatoms of sulfur. Typical heteroaryl substituents include furyl, thienyl, sitting at a ratio of °°, sitting at 2°, sitting at 嗟°, disgusting. Sitting, licking, mouth biting Heteroyl, pyrazine, etc. Unless otherwise stated, a heteroaryl substituent is unsubstituted or substituted on a carbon atom with one or more suitable substituents including alkyl groups, as described above. Tertiary substituents, and other heteroaryl substituents. The nitrogen atom is unsubstituted or substituted by, for example; particularly useful oxime substituents include fluorene, fluorene, fluorenyl, fluorenyl, sulfhydryl and sulfonium. The arylalkyl substituent includes a group of the formula: _(CH2)n5•aryl '-(CH2)n5-丨_(CH-aryl HCH2)n5-aryl or _(CH2)n5 iCH (fang (aryl), wherein the aryl group and the core are as defined above. The arylalkyl substituent L of this type includes alum, 2-phenylethyl 'phenylethyl, tolyl-3-propyl, 130311. Doc 200908964 2-phenylpropyl, diphenylmethyl, 2-diphenylethyl, 5,5-dimethyl-3-ylphenylyl, etc. The arylalkyl substituent is unsubstituted or The alkyl moiety or the aryl moiety or the alkyl moiety and the aryl moiety are substituted with a substituent as described above for the leukoyl group and the aryl group. The heteroarylalkyl substituent includes the formula _(CH2)n5_ a heteroaryl group wherein the heteroaryl group and n5 are as defined above, and the bridging group is bonded to a carbon or nitrogen atom of the heteroaryl moiety, such as 2-, 3- or 4-«pyridylmethyl, imidazole Base group, quinolylethyl and pyrrolylbutyl. The heteroaryl substituent is unsubstituted or substituted with a substituent as described above for the heteroaryl group and the alkyl group. The amino mercapto substituent includes a group of the formula _c(〇)_(CH2)n_c(H)(NRl3U·(CH2)n Rs, wherein n, R5 are as described above. Suitable amino thiol substituents Including natural amino acids and unnatural amino acids, such as glycosaminoglycans, D·chromanthyl, L_lysine, DjL•hyperoxylate, 4-aminobutyryl and _3_ Amino- 4-hexene fluorenyl. Non-aromatic polycyclic substituents include bicyclic and tricyclic fused rings (tetra) wherein each ring may be a 4 to 9-membered atom and each ring contains zero, one or more double bonds and / or triple bond. Suitable examples of non-aromatic polycyclic rings include decalin "v hydrogen", perhydrobenzoxephenene and perhydrobenzo-3-oxaphthalene rings. The substituents are unsubstituted or as described above for naphthenes Substituted substituents. Mixed aryl and non-aryl polycyclic substituents include bicyclic and tricyclic, slightly ring systems wherein each ring may be 4 to 9 members and at least one is aromatic. Mixed aryl and non Suitable examples of the square polycyclic ring include anthracene dioxyphenyl; bismethylenedioxy=yl I,2,3,4-tetrahydronaphthalene, dibenzocycloheptane, indoline and 9H-oxime. Unsubstituted or Group or substituted by a group as described above for cycloalkyl burn 13031 l.doc -12 · 200908964 replace it.

多雜芳基取代基包括雙環和三環稠環體系，其中各環可獨立為5到6-員且含一個或多個雜原子，如選自氧、氮或硫中的1、2、3或4個雜原子，使得該稠環體系為芳族。多雜芳基環體系的適當例子包括喹啉、異喹啉、吡啶並吼嗪、吡咯並吡啶、呋喃並吡啶、吲哚、苯並呋喃、苯並硫呋喃、笨並吲哚、苯並噁唑、吡略並啥琳等等。除非另作說明，多雜芳基取代基為未經取代或於碳原子上經如下一個或多個適當的取代基取代：包括烷基，如上所述之烷基取代基和式·Ο-ΚΗΚΗβΗγΗΒχΟΗ2))】-#之取代基。氮原子為未經取代或經如Ru取代，尤其可用的Ν取代基包括 Η、CrC4烷基、醯基、胺基醢基和磺醯基。非芳香多雜環取代基包括雙環和三環稠環體系，其中各環可為4到9-員且含一個或多個雜原子，如選自氧、氮或硫中的1、2、3或4個雜原子且含零個或一個或多個c_c雙鍵或二鍵。非芳香多雜環類的適當例子包括己糖醇、順_ 全氫化·環庚[bptb録’十氫·苯並[f][M]氧氮雜卓基， 2,8 一氧雜雙環[3,3,〇]辛烷，六氫_隹吩並[3,2七嗟吩全氮料並[3,2帅比略，全氫萘唆，全氫-m-二環戊[㈣比喃。除非另作說明’非芳香多雜環取代基為未經取代或於碳原子上經如下-個或多個取代基取代：包括烧基，如上所述之烧基取代基。氮原子為未經取代或經如取代，尤其可用的N取代基包括H' Ci_C4院基、醯基、胺基醯基和磺醯基。 130311.doc •13· 200908964 混合芳基和非芳基多雜環類取代基包括雙環和三環稠環體系，各環可為4到9-員、含一個或多個選自氧、氮或硫中的雜原並至少一個環為芳族。適當的混合芳基和非芳基多雜環類的例子包括2,3_二氫吲哚、四氫喹琳、5，11_ 二氫·10H_ 二苯[b，e][1，4]二氮雜卓、5h_ 二苯並 [b，e][l，4]二氮雜卓、丨一-二氫。比咯並[341)][1，5]苯並二氮雜卓、1，5-二氫-吼啶並[2,3-b][l，4]二氮雜卓酮、 1，2,3,4’6，11-六氫_苯並[15]吡啶並[2,34][1，4]二氮雜卓_5_ 酮。除非另作說明，混合芳基和非芳基多雜環類取代基為未經取代或於碳原子上經如下一個或多個適當的取代基取代.包括-N-OH，=Ν-ΟΗ，烷基及如上所述之烷基取代基。氮原子為未經取代或經如3取代；尤其可用的Ν取代基包括Η、C^-C：4烷基、醯基、胺基醯基和磺醯基。胺基取代基包括一級、二級和三級胺和鹽形式的四級錢。胺基取代基的例子包括單-和二-烷基胺基、單-和二_ 芳基胺基、單-和二-芳基烷基胺基、芳基-芳基烷基胺基、烷基-芳基胺基、烷基-芳基烷基胺基等等。磺醯取代基包括烷基磺醯基和芳基磺醯基，如甲烷磺醯基、苯磺醯基和曱苯磺醯基等等。醯基取代基包括式-c(o)-w，-oc(o)-w，-C(0)-0-W威 -C(0)NR13R14之基，其中冒為尺16、Η或環烷基烷基。醯基胺基取代基包括式-N(R12)C(0)-W、-hKRyCCO)-0-W和-N(R12)C(0)-NH0H之基且R12、W定義如上。 R2取代基HON-CCCO-CHsCd)-芳基-烷基-為下式之基： 130311.doc •14· 200908964Polyheteroaryl substituents include bicyclic and tricyclic fused ring systems wherein each ring may independently be 5 to 6-membered and contain one or more heteroatoms, such as 1, 2, 3 selected from oxygen, nitrogen or sulfur. Or 4 heteroatoms such that the fused ring system is aromatic. Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyridazine, pyrrolopyridine, furopyridinium, indole, benzofuran, benzothiofuran, stupid and benzoxazole Oxazole, pyridine and 啥琳. Unless otherwise specified, a polyheteroaryl substituent is unsubstituted or substituted on a carbon atom with one or more suitable substituents including an alkyl group, an alkyl substituent as described above, and a formula of Ο-ΚΗΚΗβΚΗΚΗγΗ2 ))]-# substituent. The nitrogen atom is unsubstituted or substituted by Ru, and particularly useful hydrazine substituents include hydrazine, CrC4 alkyl, fluorenyl, amino fluorenyl and sulfonyl. Non-aromatic polyheterocyclic substituents include bicyclic and tricyclic fused ring systems wherein each ring can be 4 to 9-membered and contain one or more heteroatoms, such as 1, 2, 3 selected from oxygen, nitrogen or sulfur. Or 4 heteroatoms and containing zero or one or more c_c double or double bonds. Suitable examples of non-aromatic polyheterocycles include hexitol, cis-perhydrogenated cyclohepta [bptb-labeled 'decahydro-benzo[f][M]oxazepine, 2,8-oxabicyclo[ 3,3,〇]octane, hexahydro-隹并 [3,2 嗟全全全全 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ Nor. Unless otherwise specified, a non-aromatic polyheterocyclic substituent is unsubstituted or substituted on a carbon atom with one or more substituents including an alkyl group, an alkyl group as described above. The nitrogen atom is unsubstituted or substituted, and particularly useful N substituents include H' Ci_C4, fluorenyl, sulfhydryl and sulfonyl. 130311.doc •13· 200908964 Mixed aryl and non-aryl polyheterocyclic substituents include bicyclic and tricyclic fused ring systems, each ring may be 4 to 9-membered, containing one or more selected from oxygen, nitrogen or The impurities in the sulfur and at least one ring are aromatic. Examples of suitable mixed aryl and non-aryl polyheterocycles include 2,3-dihydroindole, tetrahydroquinoline, 5,11-dihydro-10H-diphenyl [b,e][1,4] Aza-based, 5h-dibenzo[b,e][l,4]diazepine, indole-dihydrogen.咯和[341)][1,5]benzodiazepine, 1,5-dihydro-acridino[2,3-b][l,4]diazepine, 1,2 , 3,4'6,11-hexahydro-benzo[15]pyrido[2,34][1,4]diazepine-5-one. Unless otherwise specified, the mixed aryl and non-aryl polyheterocyclic substituents are unsubstituted or substituted on the carbon atom with one or more suitable substituents as follows. Includes -N-OH, =Ν-ΟΗ, An alkyl group and an alkyl substituent as described above. The nitrogen atom is unsubstituted or substituted with 3; particularly useful hydrazine substituents include hydrazine, C^-C:4 alkyl, fluorenyl, amino fluorenyl and sulfonyl. Amino substituents include the first, second and third amines and the fourth grade in the form of a salt. Examples of the amino substituent include mono- and di-alkylamino groups, mono- and di-arylamino groups, mono- and di-arylalkylamino groups, aryl-arylalkylamino groups, and alkane Alkyl-arylamino group, alkyl-arylalkylamino group and the like. The sulfonium substituent includes an alkylsulfonyl group and an arylsulfonyl group such as a methanesulfonyl group, a benzenesulfonyl group, an anthracenesulfonyl group and the like. The thiol substituent includes a group of the formula -c(o)-w, -oc(o)-w, -C(0)-0-W-C(0)NR13R14, wherein the rule is 16, a ring or a ring Alkylalkyl. The mercaptoamino substituent includes a group of the formula -N(R12)C(0)-W, -hKRyCCO)-0-W and -N(R12)C(0)-NHOH and R12, W are as defined above. The R2 substituent HON-CCCO-CHsCd)-aryl-alkyl- is the group of the following formula: 130311.doc •14· 200908964

車父佳之各取代基包括如下： R!SH、鹵素或直鏈C1-C4烧基； R2選自Η、CVC6烷基、C4_C9環烷基、c4_c9雜環烷基、環烧基烧基、芳基、雜芳基、芳基燒基、雜芳基烧基、-(CH2)nC(0)R6、胺基醢基和 _(CH2)nR7;The substituents of the car father include the following: R!SH, halogen or linear C1-C4 alkyl; R2 is selected from fluorene, CVC6 alkyl, C4_C9 cycloalkyl, c4_c9 heterocycloalkyl, cycloalkyl, aryl Base, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2)nC(0)R6, aminoguanidino and _(CH2)nR7;

&和R4可相同或不同且獨立地選自H和〇：1〇6烷基’或 R3和R4與其相連的碳原子一起形成c=〇、c=s或 C=NR8 ; R5選自Η，cvc6烷基，烷基，C4_C9雜環烷基，芳基，雜芳基，芳基烷基，雜芳基烷基，芳族多環，非芳族多環，混合芳基和非芳基雜環，多雜芳基，非芳香多雜環，混合芳基和非芳基多雜環； ni、h和ns可相同或不同且獨立地選自〇到6之間當m 為1到6日寸，各奴原子為未經取代或經及/或R4取代； X和Y可相同或不同且獨立地選自Η，鹵素，Cl-C4烷基，CF3 ’ N〇2 ’ C(0)R! ’ 〇r9，Sr9，CN和 nr】〇r"; R6選自H ’ C1_C6烧基’ c4-c9環院基，c4_c9雜環院基，烷基環烷基，芳基，雜芳基，芳基烷基，雜芳基烷基，〇Rl2和 NR13R14 ; R7 選自 or15 ’ sr15 ’ s(o)Rl6，s〇2Ri7，NRi3Ri4 和 130311.doc 200908964 nr12so2r6 ; R8選自 Η ; OR15 ’ NR13R14 ’ Ci_C6烧基，c4_c9環烷基， CU-C：9雜環烷基，芳基，芳基烷基及雜芳基烷基； R9選自C1-C4烧基和C(O)-院基； R1〇和Rh可相同或不同且獨立地選自H、Cl-C4烧基和 -c(0)-烷基； R】2選自Η，（VC6烧基，c4-c9環烷基，C4-C9雜環烷基，芳基，雜芳基’芳基烷基和雜芳基烷基； R13和R14可相同或不同且獨立地選自H，CrCe院基，C4-C9環院基’ C4-C9雜環烧基，芳基，雜芳基，芳基院基，雜芳基烧基和胺基醯基；And R4 may be the same or different and independently selected from H and 〇: 1〇6 alkyl' or R3 and R4 together with the carbon atom to which they are attached form c=〇, c=s or C=NR8; R5 is selected from Η , cvc6 alkyl, alkyl, C4_C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycyclic, non-aromatic polycyclic, mixed aryl and non-aryl Heterocyclic, polyheteroaryl, non-aromatic polyheterocyclic, mixed aryl and non-aryl polyheterocyclic; ni, h and ns may be the same or different and independently selected from 〇 to 6 when m is from 1 to 6 Days, each slave atom is unsubstituted or substituted with and/or R4; X and Y may be the same or different and independently selected from hydrazine, halogen, Cl-C4 alkyl, CF3 'N〇2 'C(0) R! ' 〇r9,Sr9,CN and nr】〇r"; R6 is selected from H 'C1_C6 alkyl' c4-c9 ring, c4_c9 heterocyclic, alkylcycloalkyl, aryl, heteroaryl , arylalkyl, heteroarylalkyl, 〇Rl2 and NR13R14; R7 is selected from or15 'sr15 's(o)Rl6, s〇2Ri7, NRi3Ri4 and 130311.doc 200908964 nr12so2r6; R8 is selected from Η; OR15 'NR13R14 ' Ci_C6 alkyl, c4_c9 cycloalkyl, CU-C: 9 heterocycloalkane R, aryl, arylalkyl and heteroarylalkyl; R9 is selected from C1-C4 alkyl and C(O)-homo; R1〇 and Rh may be the same or different and independently selected from H, Cl- C4 alkyl and -c(0)-alkyl; R]2 is selected from fluorene, (VC6 alkyl, c4-c9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl 'arylalkane And heteroarylalkyl; R13 and R14 may be the same or different and independently selected from H, CrCe, C4-C9 ring-based 'C4-C9 heterocycloalkyl, aryl, heteroaryl, aryl a hospital base, a heteroaryl alkyl group and an amine sulfhydryl group;

Ri5選自Η，CVC6烷基，c4-c9環烷基，c4-c9雜環烷基，芳基，雜芳基’芳基烷基，雜芳基烷基和 (CH2)mZR12 ； R16選自CVC6烧基；C4-C9環烧基；C4-C9雜環烧基；芳基；雜芳基；芳基烷基；雜芳基烷基和（CH2：)mZR12 ; Ri7選***基，C4-C9環烧基；C4-C9雜環烧基；芳基；雜芳基芳基烷基，雜芳基烷基和NR13r14 ; m是選自0到6之間的整數；和 Z選自 0、NR13、S和 S(O); 或其醫藥可接受之鹽類。可用化學式（I)之化合物，包括化合物中R,、X、γ、和尺4各自為Η，包括化合物中112和1I3之一為〇，另一個為1 者，尤其R2是Η或-CH2-CH2-OH者。 130311.doc -16- 200908964 種適當異經肟酸化合物種類為化學式（1&)者Ri5 is selected from the group consisting of hydrazine, CVC6 alkyl, c4-c9 cycloalkyl, c4-c9 heterocycloalkyl, aryl, heteroaryl 'arylalkyl, heteroarylalkyl and (CH2)mZR12; R16 is selected from CVC6 alkyl; C4-C9 cycloalkyl; C4-C9 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl and (CH2:)mZR12; Ri7 selected from alkyl, C4 -C9 cycloalkyl; C4-C9 heterocycloalkyl; aryl; heteroarylarylalkyl, heteroarylalkyl and NR13r14; m is an integer selected from 0 to 6; and Z is selected from 0. , NR13, S and S(O); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) may be used, including R, X, γ, and 4 in the compounds, each of which is Η, including one of 112 and 1I3 in the compound, and the other one, especially R2 is Η or -CH2- CH2-OH. 130311.doc -16- 200908964 The appropriate isophthalic acid compound species are chemical formula (1&)

(la) 其中 n4為0到3 ;(la) where n4 is 0 to 3;

R2選自Η、CVC6烷基、C4-C9環烷基、C4_C9雜環烷基、環烷基烷基、芳基、雜芳基、芳基烷基、雜芳基烷基、-(CH2)nC(0)R6、胺基醯基和_(cH2)nR7 ; R·5為雜务基，雜芳基烧基，如定基甲基；芳香多環，非芳香多環；混合芳基和非芳基雜環；多雜芳基或混合芳基和非芳基多雜環類；或其醫藥可接受之鹽類。另一種適當異經將酸化合物種類為化學式（Ia)者. 〇R2 is selected from the group consisting of hydrazine, CVC6 alkyl, C4-C9 cycloalkyl, C4_C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2) nC(0)R6, amino fluorenyl and _(cH2)nR7; R·5 is a hydroxy group, a heteroaryl group such as a benzyl group; an aromatic polycyclic ring, a non-aromatic polycyclic ring; a mixed aryl group and a non- An aryl heterocycle; a polyheteroaryl or a mixed aryl and a non-aryl polyheterocycle; or a pharmaceutically acceptable salt thereof. Another suitable heterogeneous type of acid compound is the chemical formula (Ia).

其中 114為〇到3 ; R2選自Η、Cl-c6烧基、C4_C9環燒基、C4_C9雜環烧基、環烧基烷基、芳基、雜芳基、芳基烧基、雜芳基烧基、-(CH2)nC(〇)R6、胺基醯基和 R'5為芳基；芳基烷基；芳香多環；基；和非芳基多環，尤其芳基， -(CH2)nR7 ；非芳香多環和混合芳如對_氟笨基、對-氣 I30311.doc 17 200908964 苯基、對-0-CrC4烷基苯基，如對_甲氧基苯基和對_ CrC4烷基苯基；及芳基烷基，如苯甲基，鄰·、間-戋對-氟苯甲基，鄰_、間-或對-氯笨甲基，鄰_、間·或對-單、二-或三-〇_C丨_C4烷基苯甲基，如鄰_、間-或對-甲氧基苯甲基，間_，對-二乙氧基苯甲基，鄰，間，對-二甲氧基苯甲基和鄰_、間_或對-單、二-或三 CU烧基本基，如對-甲基，m，m_二乙基苯基；或其醫藥可接受之鹽類。Wherein 114 is 〇 to 3; R2 is selected from the group consisting of ruthenium, Cl-c6 alkyl, C4_C9 cycloalkyl, C4_C9 heterocycloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroaryl An alkyl group, -(CH2)nC(〇)R6, an amino fluorenyl group and R'5 are an aryl group; an arylalkyl group; an aromatic polycyclic ring; a base; and a non-aryl polycyclic ring, especially an aryl group, -(CH2 nR7; non-aromatic polycyclic and mixed aromatic such as p-fluorophenyl, p-gas I30311.doc 17 200908964 phenyl, p--0-CrC4 alkylphenyl, such as p-methoxyphenyl and p-CrC4 Alkylphenyl; and arylalkyl, such as benzyl, o-, m-fluorenyl-fluorobenzyl, o-, m- or p-chloromethyl, o-, m- or p- Mono-, di- or tri-anthracene-C丨_C4 alkylbenzyl, such as o-, m- or p-methoxybenzyl, m-, p-diethoxybenzyl, o-, , p-dimethoxybenzyl and o-, m- or p-mono, di- or tri- CU base, such as p-methyl, m, m-diethylphenyl; or its pharmaceutical Acceptable salts.

另一種有用之化合物種類為式（Ib)之化合物：Another useful compound is a compound of formula (Ib):

Ο R’2選自Η ; CVC6烷基；c4 -(^環烷基；環烷基烷基，如裱丙基甲基；（CH2)2_4〇R21，其中r21為H、甲基、乙基、丙基和異丙基；且Ο R'2 is selected from Η; CVC6 alkyl; c4-(^cycloalkyl; cycloalkylalkyl, such as fluorenylmethyl; (CH2)2_4〇R21, wherein r21 is H, methyl, ethyl , propyl and isopropyl;

Rs為未經取代的1H _吲哚-3-基、苯並呋喃_3_基或喹啉_ 3-基，或經取代的1H爿哚基，比如 3-基或5-曱氧基_1H-吲哚·3“基，苯並呋喃_3_基或喹琳-3 -基；或其醫藥可接受之鹽類。另一有用之異羥肟酸化合物種類為化學式（lc)者： 130311.doc -18- 200908964Rs is unsubstituted 1H-indol-3-yl, benzofuran-3-yl or quinoline-3-yl, or substituted 1H fluorenyl, such as 3-yl or 5-decyloxy 1H-吲哚·3 "yl, benzofuran-3-yl or quinolin-3-yl; or a pharmaceutically acceptable salt thereof. Another useful hydroxamic acid compound of the formula (lc): 130311.doc -18- 200908964

包含Z1的環為芳香族或不飽和，或非芳香族，該非芳族環可為飽和乙1马 Ο、s 或 N-R2〇 ;The ring containing Z1 is aromatic or unsaturated, or non-aromatic, and the non-aromatic ring may be saturated B1, s or N-R2;

Ri8 為 Η;鹵素；r 卞Cl_C6燒基(甲基、乙基、第三丁基）. A環烧基；芳基，如未經取代之苯基或經4_och 或4-CF3取代之苯基；或雜芳基，如η喃基，2_輕基或2-、3 -或4 -β比π定基； R2〇為η，cvc6烷基；Cl_C6烷基_C3_C9環烷基，如環丙基曱基；芳基；雜芳基；芳基烧基，如笨甲基；雜芳基烷基，如吡啶基曱基；醯基，如乙醯基，丙醯基及笨甲醯基；或磺醯基，如曱基磺酿基，乙基磺醯基，苯磺醯和曱苯磺醯基；八】為1、2或3個取代基，其各自為H; c,-c6烷基； -〇r19 ;鹵素；烷基胺基；胺基烷基；鹵素；或雜芳基烧基，如0比0定基曱基Ri8 is hydrazine; halogen; r 卞Cl_C6 alkyl (methyl, ethyl, tert-butyl). A cycloalkyl; aryl, such as unsubstituted phenyl or phenyl substituted by 4_och or 4-CF3 Or a heteroaryl group such as η 基, 2 _ light or 2-, 3- or 4-β than π; R 2 〇 is η, cvc 6 alkyl; Cl_C 6 alkyl _C 3 _ C 9 cycloalkyl, such as cyclopropyl a fluorenyl group; an aryl group; a heteroaryl group; an aryl group, such as a methyl group; a heteroarylalkyl group, such as a pyridyl group; a fluorenyl group, such as an ethyl group, a propyl group, and a benzoyl group; Or a sulfonyl group, such as a mercaptosulfonic acid group, an ethylsulfonyl group, a benzenesulfonyl sulfonate, and an anthranilyl group; VIII] is 1, 2 or 3 substituents each of which is H; c, -c6 alkane Base; - 〇r19; halogen; alkylamino; aminoalkyl; halogen; or heteroaryl alkyl, such as 0 to 0-based fluorenyl

Rl9選自Η ; Ci-C6炫基；C4-C9環烧基；C4-C9雜環烧基；芳基；雜芳基；芳基烷基’如苯甲基；雜芳基烷基’ 如吡啶基曱基和-(CH2CH=CH(CH3)(CH2))1-3H ; R2選自Η、CVC6炫基、C4-C9環烧基、C4-C9雜環烧基、 130311.doc -19- 200908964 %烷基烷基、芳基、雜芳基、芳基烷基、雜芳基烷基、-(CH2)nC(0)R6、胺基酿基和 _(cH2)nR7 ; v為0、1或2 ; P為0到3 ;和 q為1到5且r為0 ;或 q為0且r為1到5 ; 或其醫藥可接受之鹽類。其他可變取代基定義如上。Rl9 is selected from the group consisting of hydrazine; Ci-C6 leukoxyl; C4-C9 cycloalkyl; C4-C9 heterocycloalkyl; aryl; heteroaryl; arylalkyl 'such as benzyl; heteroarylalkyl' Pyridyl fluorenyl and -(CH2CH=CH(CH3)(CH2))1-3H; R2 is selected from the group consisting of fluorene, CVC6 leuntyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, 130311.doc -19 - 200908964 % alkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2)nC(0)R6, amine aryl and _(cH2)nR7; v is 0 , 1 or 2; P is 0 to 3; and q is 1 to 5 and r is 0; or q is 0 and r is 1 to 5; or a pharmaceutically acceptable salt thereof. Other variable substituents are as defined above.

尤其有用化學式（Ic)的化合物為其中&為Η或 -(CH2)pCH2OH，其中到3者，尤其為其中〜為时；如其中R】為Η且X和Y各自為H，且其中…到山為〇,或 q為0且r為1到3者，尤其其中21為叫2〇者。在該類化合物中較佳R2為Η或-CH^CH^OH且q和r總和較好為丄。另種有用之異羥肟酸化合物種類為化學式（Id)者：Particularly useful compounds of formula (Ic) are those wherein & is Η or -(CH2)pCH2OH, wherein up to 3, especially wherein 〜 is 0; such as where R is Η and X and Y are each H, and wherein... To the mountain is 〇, or q is 0 and r is 1 to 3, especially 21 of them are called 2 。. Preferably, in such a compound, R2 is hydrazine or -CH^CH^OH and the sum of q and r is preferably hydrazine. Another useful type of hydroxamic acid compound is the chemical formula (Id):

ZA〇、s或 N-R2〇 ;ZA〇, s or N-R2〇;

Ri8為Η ’鹵素’ Ci_C6烧基（甲基、乙基和第三丁基）； C3_C7環烷基；芳基，如未經取代的苯基或經4-OCH 或者4-CF3取代之苯基；或者雜芳基； Κ·20為 Η，C!-C6 院基 c^c：6烷基-cvC9環烷基，如環丙 130311.doc •20·Ri8 is Η 'halogen' Ci_C6 alkyl (methyl, ethyl and tert-butyl); C3_C7 cycloalkyl; aryl, such as unsubstituted phenyl or phenyl substituted by 4-OCH or 4-CF3 Or heteroaryl; Κ·20 is Η, C!-C6 院基^^:6-alkyl-cvC9 cycloalkyl, such as cyclopropene 130311.doc •20·

200908964 基甲基；芳基；雜芳基；芳基烷基，如苯甲基；雜芳基烷基，如》比咬基甲基；醯基，如乙醯基，丙醯基和苯甲醯基；或磺醯基，如甲基磺醯基，乙基磺醯基，苯磺醯基，甲苯磺醯基；八,為1、2或者3個取代基’各獨立為H、c丨-c6烷基、 -ORl 9 或 ώ 素，200908964 methyl group; aryl; heteroaryl; arylalkyl, such as benzyl; heteroarylalkyl, such as "biterylmethyl"; fluorenyl, such as ethyl, propyl, benzo Sulfhydryl; or sulfonyl, such as methylsulfonyl, ethylsulfonyl, phenylsulfonyl, toluenesulfonyl; VIII, 1, 2 or 3 substituents, each independently H, c丨-c6 alkyl, -ORl 9 or halogen,

Ri9選自Η，CVC6烧基；C4-C9環烧基；c4-C9雜環统基；芳基，雜芳基，芳基烷基，如苯甲基；及雜芳基烷基，如0比。定基甲基； P為0到3 ;且 q為1到5且r為0 ;或 q為0且r為1到5 ; 或其醫藥可接受之鹽類。其他可變取代基定義如上。尤其有用化學式（Id)的化合物為其中化為11或 _(CH2)pCH2〇H’其中口為1到3者，尤其其中R,為Η者；如其中R】為Η且ΧίσΥ各自為Η，且其中…到山為^ 為0且…到3者。該等化合物中，更好或领2媽_ OH且q與r總和為1。本發明更進而有關化學式（le)之化合物：Ri9 is selected from the group consisting of hydrazine, CVC6 alkyl; C4-C9 cycloalkyl; c4-C9 heterocyclic; aryl, heteroaryl, arylalkyl, such as benzyl; and heteroarylalkyl, such as 0 ratio. Alkylmethyl; P is 0 to 3; and q is 1 to 5 and r is 0; or q is 0 and r is 1 to 5; or a pharmaceutically acceptable salt thereof. Other variable substituents are as defined above. Particularly useful compounds of formula (Id) are those wherein 11 or _(CH2)pCH2〇H' wherein the mouth is 1 to 3, especially wherein R is a ruthenium; such as where R is Η and ΧίσΥ is Η, And among them... to the mountain is ^ is 0 and ... to 3. Among these compounds, it is better or to lead 2 mom _ OH and the sum of q and r is 1. The invention further relates to compounds of formula (le):

Ο RΟ R

130311.doc 21 200908964 或其醫藥可接受之鹽類》其他可變取代基定義如上。尤其有用化學式（ie)之化合物為其中〜奸、氣基、氣基、溴基、CVC4烷基、經取代之Ci_C4烷基、C3_C7環烷基、未經取代之苯基、於對位經取代之苯基，或雜芳基，如0比咬環。土另一群有用化學式（Ie)之化合物為其中汉2為以_130311.doc 21 200908964 or a pharmaceutically acceptable salt thereof. Other variable substituents are as defined above. Particularly useful compounds of the formula (ie) are those in which the thiophene, the gas group, the gas group, the bromo group, the CVC4 alkyl group, the substituted Ci_C4 alkyl group, the C3_C7 cycloalkyl group, the unsubstituted phenyl group, are substituted in the para position. A phenyl group, or a heteroaryl group, such as 0 is a bite ring. Another group of compounds of the formula (Ie) are those in which Han 2 is

(CH2)pCH2〇H，其中…到3者，尤其是其中心為时；如其中R,為Η且X和Y各自為H，且其中_到山為〇,或其中q為0且4 i到3者。在該等化合物巾，&較好為㈣ -CH2-CH2-OH且總和較好為i。該等化合物中更好p 為1且R3和R4較好Η。另一群有用化學式（Ie)之化合物為其、甲基、土第一丁 s _氣甲基、環己基、苯基、4_甲氧基苯基、4-三氟甲基苯基、2“夫喃基和2_嗔吩基，或2_、％或心吡啶基’ #中2-呋喃基、2_噻吩基和2_、3_或4_吡啶基為未經取代或京如上述對雜芳基環所述之取代基取代；^為 Η或-(CH2)pCH2OH，其中到3者；尤其其中〜糾且又矛Y各自為Η’且其中到3Xi^〇，或其中q為〇且『為^ 到3者。在該等化合物中，更好r^h或_ch2_ch”〇h且q 與r總和較好為1。化學式（Ie)之化合物中或C〗_C6烷基，尤其是Η者為如上所述化學式（Ie)之化合物每一亞屬之重要成分。 1^經基-3-[4-[[(2-經乙基）[2_(出_11引11朵_3_基）乙基]_胺基] 甲基]苯基]·2Ε-2·丙烯醯胺，N_經基_3_[4_[[[2_(iH_t朵_3_ 1303Il.doc •22- 200908964 基）乙基]-胺基]甲基]苯基]_2E_2_丙烯醯胺和N_羥基_3_[4_ [[[2-(2-甲基-1H-吲哚_3_基）_乙基]_胺基]甲基]苯基]_2Ε_2_ 丙烯醯胺或其醫藥可接受之鹽類為化學式（Ie)之重要化合物。本發明更進而有關化學式（T f)的化合物：(CH2)pCH2〇H, where ... to 3, especially where the center is time; such as where R is Η and X and Y are each H, and wherein _ to the mountain is 〇, or where q is 0 and 4 i To 3 people. In the compound towels, & is preferably (tetra)-CH2-CH2-OH and the sum is preferably i. More preferably, in these compounds, p is 1 and R3 and R4 are preferably ruthenium. Another group of compounds of the formula (Ie) are methyl, dimethyl s-methyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2" And the 2-furanyl group, or the 2-furyl group, the 2-thiol group, and the 2-, 3- or 4-pyridyl group are unsubstituted or homologous as described above. Substituted by a substituent as described in the aryl ring; ^ is hydrazine or -(CH2)pCH2OH, wherein it is up to 3; in particular, wherein ??? and lance Y are each Η' and wherein 3Xi^〇, or wherein q is 〇 "It is ^ to 3. Among these compounds, better r^h or _ch2_ch" 〇h and the sum of q and r is preferably 1. The compound of the formula (Ie) or the C-C6 alkyl group, especially the latter, is an important component of each subgenus of the compound of the formula (Ie) as described above. 1^, benzyl-3-[4-[[(2-ethyl)][2_(out_11#11__3_yl)ethyl]-amino]methyl]phenyl]·2Ε-2 - acrylamide, N_transcarbyl_3_[4_[[[2_(iH_t _3_1303Il.doc •22-200908964 yl)ethyl]-amino]methyl]phenyl]_2E_2_ acrylamide and N_hydroxy_3_[4_[[[2-(2-methyl-1H-吲哚_3_yl))-ethyl]-amino]methyl]phenyl]_2Ε_2_ acrylamide or its pharmaceutically acceptable The salts are important compounds of the formula (Ie). The invention further relates to compounds of formula (Tf):

Π RΠ R

有用化學式（If)之化合物包括其中1為1^或 -(CH2)pCH2OH’其中卩為！到3者，尤其其中〜為时；如其中RAH且X和Y各自為H，且其中q為蜊3且犷為〇，或其中q為〇且r為1到3者。在該等化合物中，更好]^為11或_ CH2-CH2-〇H且q和r總和較好為i。 Ο N-經基-3-[4-[[[2·(苯並吱喃·3_基）_乙基]胺基]甲基]苯基]·2Ε·2-丙烯醯胺或其醫藥可接受之鹽類為化學式之重要化合物。如上所述化合物經常以醫藥可接受鹽類之形式使用。適當地，醫藥可接受鹽類之形式包括醫藥可接受性驗加成鹽及酸加成鹽，如金屬鹽如鹼金屬鹽和鹼土金屬鹽，銨鹽，有機胺加成鹽及胺基酸加成鹽及續酸鹽。 ^ 機酸加成鹽，如鹽酸鹽，硫酸鹽和較鹽；及有== 130311.doc -23· 200908964 鹽，如烧基續酸鹽，芳基績酸鹽，醋酸鹽，順丁稀_西众鹽，反丁烯二酸鹽’酒石酸鹽，檸檬酸鹽和乳酸鹽。金屬鹽的例子為鹼金屬鹽，如鋰鹽、鈉鹽和鉀鹽；驗土金屬鹽’如鎂鹽和鈣鹽’鋁鹽和辞鹽。銨鹽的例子為錢睡和四甲銨鹽。有機胺加成鹽的例子為與嗎啉和哌D定的鹽。@ λ 酸加成鹽的例子為與甘氨酸、苯基丙氨酸、谷氨酸和賴氣酸的鹽。續酸鹽包括甲磺酸鹽、甲苯磺酸鹽酯和笨績酸鹽0A compound of the formula (If) includes 1 wherein 1 is or -(CH2)pCH2OH' wherein 卩 is! To 3, especially where ~ is a time; such as where RAH and X and Y are each H, and wherein q is 蜊3 and 犷 is 〇, or q is 〇 and r is 1 to 3. Among these compounds, more preferably, it is 11 or _CH2-CH2-〇H and the sum of q and r is preferably i. Ο N-carbyl-3-[4-[[[2((benzofuran-3-yl))ethyl]amino]methyl]phenyl]·2Ε·2-propenylamine or its medicine Acceptable salts are important compounds of the formula. The compounds as described above are often used in the form of pharmaceutically acceptable salts. Suitably, the pharmaceutically acceptable salt forms include pharmaceutically acceptable test addition salts and acid addition salts such as metal salts such as alkali metal and alkaline earth metal salts, ammonium salts, organic amine addition salts and amino acid additions. Salt and hydrochloride. ^ organic acid addition salts, such as hydrochloride, sulfate and salt; and == 130311.doc -23· 200908964 salt, such as alkylate, aryl acid salt, acetate, butadiene _ Xizhong salt, fumarate' tartrate, citrate and lactate. Examples of the metal salt are alkali metal salts such as lithium salt, sodium salt and potassium salt; soil test metal salts such as magnesium salt and calcium salt 'aluminum salt and salt. Examples of ammonium salts are money sleep and tetramethylammonium salts. Examples of organic amine addition salts are the salts with morpholine and piperazine D. Examples of the @λ acid addition salt are salts with glycine, phenylalanine, glutamic acid and lysine. The hydrochloride salt includes methanesulfonate, tosylate and stupid acid.

02/22577。WO 02/22577範圍内之兩種較佳化合物為.02/22577. Two preferred compounds within the scope of WO 02/22577 are.

Ν-羥基-3-[4-[(2-羥乙基）{2_(1η_吲哚_3基甲基]苯基]-2Ε-2-丙稀醯胺或其醫藥可接受 -3-基）乙基]_胺基] 接受之鹽類；和Ν-Hydroxy-3-[4-[(2-hydroxyethyl){2_(1η_吲哚_3ylmethyl]phenyl]-2Ε-2-propanylamine or its pharmaceutically acceptable-3- (ethyl)-amino] accepting salts; and

• Ν-羥基-344-^2-(2-甲基 _1Η-吲哚 _ 基]苯基]-2Ε-2-丙烯醯胺，或其醫藥本發明尤其關於HDAC抑制劑用於'专基）-乙基]-胺基]甲劑之用途。或其醫藥可接受之鹽類。劑用於製備供治療胃腸癌藥之鹽類。 130311.doc -24· 200908964 用於本發明之HDAC抑制劑在如上所述分析中較好展現介於50 nM和2500 nM之間，更好介於250 nM和2〇〇〇 nMi 間’且最好介於5〇〇 nM和1 250 nM之間之IC50值。此外’本發明有關一種治療胃腸癌之方法，尤其肝細胞癌或騰腺癌’該方法包括對有需要之溫血動物（特別是人類）投與治療上有效量之HDAC抑制劑，較好對有需要之溫血動物（特別是人類）投與治療上有效量之如上所述化學式 ⑴之化合物具有至少一個成鹽基之此化合物之鹽類。• Ν-hydroxy-344-^2-(2-methyl-1Η-吲哚-yl]phenyl]-2Ε-2-propenylamine, or a pharmaceutical thereof, particularly for HDAC inhibitors Use of -ethyl]-amino]-agent. Or a pharmaceutically acceptable salt thereof. The agent is used to prepare a salt for treating a gastrointestinal cancer drug. 130311.doc -24· 200908964 The HDAC inhibitors useful in the present invention preferably exhibit between 50 nM and 2500 nM, more preferably between 250 nM and 2〇〇〇nMi, and most Good IC50 value between 5〇〇nM and 1 250 nM. Furthermore, the invention relates to a method for treating gastrointestinal cancer, in particular hepatocellular carcinoma or adenocarcinoma. The method comprises administering a therapeutically effective amount of a HDAC inhibitor to a warm-blooded animal (especially a human) in need thereof, preferably A warm-blooded animal (especially a human) in need thereof is administered a therapeutically effective amount of a salt of the compound having at least one salt-forming group of the compound of the above formula (1).

使用於此之術語”治療”，包括對患有胃腸癌或者處於該癌症前期病人之治療，該治療將延緩病人疾病進展。本發明提供一種治療胃腸癌之方法，尤其肝細胞癌或胰腺癌’該方法包括對有需要之溫血動物投與抗胃腸癌(尤其肝細胞癌或胰腺癌）有效量之量的HDAC抑制劑。熟悉該項技術者完全能夠選出相關試驗模式，用以證明上述和後文提到的抑制HDAC活性之化合物之抗胃腸癌之有利效果。抑制HDAC活性之該化合物的藥理學活性可以藉由適當臨床研究藉由後文所述實例得以證明。本發明也提供本文定義之化學式⑴之化合物組合本發明用卩製備#治療淋巴組織增生:病途。之用途以及之藥劑之用實施例實施例1 單層細胞生長抑制分析之比色计分析。黃色四β坐 MTT係用於測定細胞繁殖速度 1303ll.doc -25- 200908964The term "treatment" as used herein, includes treatment of a patient suffering from or suffering from gastrointestinal cancer, which will delay the progression of the patient's disease. The invention provides a method for treating gastrointestinal cancer, in particular hepatocellular carcinoma or pancreatic cancer. The method comprises administering an effective amount of an HDAC inhibitor to an anti-gastrointestinal cancer (especially hepatocellular carcinoma or pancreatic cancer) in a warm-blooded animal in need thereof. . Those skilled in the art are well able to select relevant test modes to demonstrate the beneficial effects of the compounds described above and below for inhibiting HDAC activity against gastrointestinal cancer. The pharmacological activity of the compound which inhibits HDAC activity can be demonstrated by an appropriate clinical study by the examples described hereinafter. The invention also provides a compound of formula (1) as defined herein. Combination of the invention for the treatment of lymphoid tissue hyperplasia: pathogenesis. Uses and Medicaments Examples Example 1 Colorimetric analysis of monolayer cell growth inhibition assay. Yellow four beta sitting MTT system for measuring cell proliferation rate 1303ll.doc -25- 200908964

鏽 MTT (3-(4,5-二甲基嗟嗤-2)-2 5--笑其 ππ I A ;，本基四唑鑌溴鹽）藉由新陳代謝活性細胞而還原，部分藉脫氫酶之作用，產生如 NADH和NADPH的還原物。藉由分光光度分析法溶解並定量所產生之細胞内紫色甲臜卜所產生訊號與細胞數量成正比。詳細描述MTT分析，使用於多孔組織培養器皿中之6點或9點藥物滴定而進行，但靠外幾組維持為空的。細胞分別以介於1 03和104 cell/ml之間的濃度懸浮於完全培養基中，再加入到每孔中。接著添加適宜培養基（2〇〇 μΐ)。 24小時後，10 μΐ MTS溶液添加至一個平板以計算化合物添加時的活性（TQ)。該平板在37。〇下培育4小時，使用Rust MTT (3-(4,5-dimethylindole-2)-2 5--laughing ππ IA;, the base tetrazolium bromide) is reduced by metabolically active cells, partially dehydrogenase The effect is to produce a reducing substance such as NADH and NADPH. The signal produced by the spectrophotometric method for dissolving and quantifying the intracellular purple formazan is proportional to the number of cells. A detailed description of the MTT assay was performed using a 6 or 9 point drug titration in a multi-well tissue culture vessel, but was left empty by several groups. The cells were suspended in a complete medium at a concentration between 1 03 and 104 cells/ml, respectively, and added to each well. Then add the appropriate medium (2 μ μΐ). After 24 hours, 10 μM of MTS solution was added to one plate to calculate the activity (TQ) when the compound was added. The plate is at 37. Breeding for 4 hours, use

Softmax程式在 Molecular Devices Thermomax(波長 490 nm) 上測量光密度。TG平板作為試驗開始時最初活性之一個參考。接種24小時後開始添加化合物，該相同時間作為丁〇測定。在一個96深孔平板中，平板邊緣最高濃度下，對先前測定之ICso值化合物進行4倍、2倍、1倍、0.5倍、0.25件和0.125倍之連續稀釋。每份稀釋液添加相同三份且完全培養基添加至不含細胞靠外留空的幾組。該化合物單獨或與化合物III(LBH5 89)—起添加至平板中。該平板自接種後於37°C下培育72小時。添加MTS溶液（如其在T()平板之方式），4小時後讀數。為便於分析資料，僅培養基（基準）時的平均值從各個試驗孔所得值中扣除；且對每一化合物稀釋而言’三次重複值取平均。使用下列公式計算生長百分比。 If X>T。，生長％=i〇〇x((x_T〇)/(GC_T〇)) 130311.doc •26- 200908964The Softmax program measures the optical density on a Molecular Devices Thermomax (wavelength 490 nm). The TG plate was used as a reference for the initial activity at the start of the experiment. Compounds were added 24 hours after the inoculation, and the same time was measured as Ding. Serial dilutions of 4, 2, 1, 0.5, 0.25, and 0.125 times the previously determined ICso value compounds were performed at a maximum concentration of the edge of the plate in a 96 deep well plate. The same three portions were added to each dilution and the complete medium was added to groups that were free of empty cells. This compound is added to the plate alone or in combination with Compound III (LBH5 89). The plate was incubated at 37 ° C for 72 hours after inoculation. The MTS solution was added (as it was in the T() plate) and read after 4 hours. For ease of analysis, the median (baseline) average was subtracted from the values obtained for each well and the 'three replicates' averaged for each compound dilution. Use the following formula to calculate the percentage of growth. If X>T. , growth %=i〇〇x((x_T〇)/(GC_T〇)) 130311.doc •26- 200908964

IfX<T〇，生長％=10〇x(X-T〇)/T〇 T0=TG平均值-基準 GC =未處理細胞平均值（三重複值平均）-基準 x=化合物處理細胞平均值（三重複值平均）-基準計算抑制細胞生長達到50%所需之LBH589濃度IC50和降低細胞數量（殺滅細胞）至原始接種量50%之LBH589濃度 LD50。該”生長％"對化合物濃度作圖，且利用Microsoft Excel之使用者自定義樣條函數用於計算IC50和LD50。IfX<T〇, growth%=10〇x(XT〇)/T〇T0=TG average-reference GC=unprocessed cell mean (three-fold value average)-reference x=compound treated cell average (three replicates) Value averaging) - The baseline calculates the LBH589 concentration IC50 and the reduced cell number (killing cells) required to achieve 50% cell growth to 50% of the original inoculum LBH589 concentration LD50. The "growth %" was plotted against compound concentration and was calculated using the user-defined spline function of Microsoft Excel for IC50 and LD50.

在大模板之36個結腸癌細胞株中，LBH589之防增生和細胞毒效應描述於下表：（**Cellline=細胞株）Among the 36 colon cancer cell lines of the large template, the antiproliferative and cytotoxic effects of LBH589 are described in the following table: (**Cellline=cell line)

L NVP-LBH589 Cell Line IC50(nM) LD50 (nM) SW620 0,79 1.70 SW480 1.48 6.90 SW403 2.03 9.84 SW837 0.66 11.46 SW48 1.29 13.09 KM20L2 14.62 16.95 C〇I〇201 15.12 20.14 3.54 25.92 SNU-C1 4.51 26.07 SW1116 2,28 26,93 ΗΤ115 3.49 31.02 Τ84 2.16 32.82 C〇I〇205 14.68 33.52 Colo741 9.22 33.73 SW948 5.06 34.92 WiDr 4.39 41.86 Colo678 5.60 45.52 CaCo2 13.84 45.55 MDST8 4.87 48.44 HCT116 7.11 51.72 LOVO 4.37 52.01 HT29 2.83 70.23 HCT8 4.94 77,70 C〇l〇320 6.50 82.90 LS174T 16.77 87.41 HCC2998 29,67 154.87 LS1034 76.70 227.83 C2Bbe-1 27.46 243.12 DLD-1 61.40 296.27 HT55 8.21 334.52 C170 62.29 382.03 C〇I〇320DM 29.48 1103.37 RKO 5.57 2346.13 C〇I〇206F 10.13 >10000 C〇I〇320HSR 13.82 >10000 HCT116Bax-/- 1.73 >10000 -27- 130311.doc 200908964 結腸癌細胞株用DMSO載體對照組或不同濃度的LBH589 進行處理3天。細胞增生之測量時間為細胞鋪板培養當天和第三日之後處理。如上述計算IC50和LD50值。如IC50 值之低奈莫耳當量濃度所顯示，LBH589顯示對檢測的所有36個結腸癌細胞株具有有效的防增生效果。LBH589對大多數以LD50< 1 μΜ (n=3 1)測試之結腸癌細胞株亦顯示具有有效細胞毒性效應。實例2 對雌性無胸腺裸鼠實施皮下注射HCT116結腸癌細胞株。當腫瘤達到120 mm3之平均腫瘤體積時，老鼠隨機分成每組8隻。每週5次並持續3週給老鼠靜脈（iv)注射5 mg/kg、10 mg/kg或20 mg/kg的 LBH5 89或每週一次並持續 3 週靜脈注射75 mg/kg的5-說尿σ比咬。實驗動物每週用卡鉗進行測量腫瘤體積。經處理動物相對於對照動物腫瘤體積之百分比變化來計算化合物活性（％T/C)。研究結束時的最終腫瘤體積相對於開始腫瘤量之百分比變化來計算復原百分比。5 mg/kg或10 mg/kg的LBH589處理可抑制HCT116腫瘤生長的百分比分別為17%和6%(%T/C)。20 mg/kg的 LBH589處理導致8%的腫瘤復原。結果描述於圖1。實例3 對雌性無胸腺裸鼠實施皮下注射C〇1〇205結腸癌細胞株。當腫瘤達到220 mm3之平均腫瘤體積時，老鼠隨機分成每組1 0隻。每週一、週三和週五並持續3週給老鼠靜脈注射30 mg/kg的LBH589或每週一次並持續3週給老鼠靜脈 130311.doc -28- 200908964 注射75 mg/kg的5-氟尿吡啶，或兩種藥劑的組合。就腫瘤生長抑制（圖2 A)而言’處理動物相對於對照動物腫瘤體積之百分比變化來計算化合物活性（％T/C)。研究結束時最終腫瘤體積相對於開始腫瘤體積之百分比變化計算復原百分比。就腫瘤生長延遲（圖2B)而言，化合物活性通過在平均計算時間到研究結束點（TTE)之間腫瘤體積之百分比變化計算，其中預先確定腫瘤體積為1〇00 mm3。對於載體、 LBH、5-FU和組合處理，平均TTE分別為39」天、32 9 天、44.5天和57，1天《以LBH589或5-FU處理引起腫瘤生長抑制（TGI)和腫瘤生長延遲（TGD)。更重要地，組合處理極大提高了 TGI和TGD。結果闡明於圖2。實例4 胰腺癌細胞株用DMSO載體對照組或不同濃度的LBH589 進行處理3天。細胞增生之測量時間為細胞鋪板培養當天和第三日之後處理。如上述計算IC5〇和LD50值。如IC5〇值之低奈莫耳當量濃度所顯示，LBH589顯示對檢測的所有12個騰腺癌細胞株具有有效防增生效果。lbh5 89亦以 LD50<1 μΜ (n=l〇)顯示對大多數測試之胰腺癌細胞株具有強的細胞毒性效應。在12個胰腺癌細胞株中，LBH589之防增生和細胞毒效應描述於下表2 : (**Cell line=細胞株） 130311.doc -29- 200908964 NVP-L BH589 Cell Lines IC50 [nM] LD50 [nM] MiaPaCa2 14.1 59.5 BxPC3 15.9 104.8 Hs766T 14.1 119.9 SU.86.86 51 170.4 Panel 18.9 175.4 Capanl 55.6 191.5 Panc3.27 38.5 276.8 Panel 0.05 31.8 282.4 AsPC1 25.1 372.4 Panc2.03 22.4 599.5 HPAC 122.7 2051.6 Panc4.03 20.3 >10000 . 在細胞增生分析中，19個胰腺癌細胞株單獨進行分析。細胞株用DMSO載體對照組或不同濃度的LBH5 89進行處理 f、 6天。與表2所示結果一致，如IC50值之低奈莫耳當量濃度所顯示，LBH589對檢測的所有19個胰腺癌細胞株具有有效防增生效果。LBH589亦以LD50<1 μΜ顯示對19個胰腺癌細胞系中的1 8個具有有效細胞毒性效應。結果描述於圖 3 ° 【圖式簡單說明】圖1說明在HCT116異種移植物模式下，LBH589處理抑制腫瘤生長。〇圖2說明在C〇1〇205結腸癌異種移植物模式下，LBH589 和5-氟尿嘧啶之結合處理提高對腫瘤生長的抑制和腫瘤生 ' 長的延遲。圖3說明在19個胰腺癌細胞株中，LBH589具有防增生和細胞毒效應。 130311.doc -30·L NVP-LBH589 Cell Line IC50(nM) LD50 (nM) SW620 0,79 1.70 SW480 1.48 6.90 SW403 2.03 9.84 SW837 0.66 11.46 SW48 1.29 13.09 KM20L2 14.62 16.95 C〇I〇201 15.12 20.14 3.54 25.92 SNU-C1 4.51 26.07 SW1116 2 , 28 26,93 ΗΤ115 3.49 31.02 Τ84 2.16 32.82 C〇I〇205 14.68 33.52 Colo741 9.22 33.73 SW948 5.06 34.92 WiDr 4.39 41.86 Colo678 5.60 45.52 CaCo2 13.84 45.55 MDST8 4.87 48.44 HCT116 7.11 51.72 LOVO 4.37 52.01 HT29 2.83 70.23 HCT8 4.94 77,70 C〇l〇320 6.50 82.90 LS174T 16.77 87.41 HCC2998 29,67 154.87 LS1034 76.70 227.83 C2Bbe-1 27.46 243.12 DLD-1 61.40 296.27 HT55 8.21 334.52 C170 62.29 382.03 C〇I〇320DM 29.48 1103.37 RKO 5.57 2346.13 C〇I〇206F 10.13 >10000 C〇I〇320HSR 13.82 >10000 HCT116Bax-/- 1.73 >10000 -27- 130311.doc 200908964 Colon cancer cell lines were treated with DMSO vehicle control group or different concentrations of LBH589 for 3 days. The measurement time of cell proliferation was treated on the day of cell plating and after the third day. The IC50 and LD50 values were calculated as described above. As shown by the low IC50 value of the Nemo-equivalent concentration, LBH589 showed an effective anti-proliferative effect on all 36 colon cancer cell lines tested. LBH589 also showed potent cytotoxic effects on most colon cancer cell lines tested with LD50 < 1 μΜ (n=3 1). Example 2 Female athymic nude mice were subcutaneously injected with HCT116 colon cancer cell lines. When the tumor reached an average tumor volume of 120 mm3, the mice were randomly divided into 8 groups. Five times a week for 3 weeks, rats were given intravenous (iv) 5 mg/kg, 10 mg/kg or 20 mg/kg LBH5 89 or once a week for 3 weeks intravenous injection of 75 mg/kg 5-negative σ is more than a bite. Experimental animals were measured weekly for caliper volume using a caliper. Compound activity (%T/C) was calculated as a percentage change in tumor volume of treated animals relative to control animals. The percentage of recovery was calculated as the percentage change in the final tumor volume at the end of the study relative to the amount of tumor onset. The percentage of LBH589 treated at 5 mg/kg or 10 mg/kg inhibited HCT116 tumor growth by 17% and 6% (%T/C), respectively. Treatment with LBH589 at 20 mg/kg resulted in 8% tumor restitution. The results are depicted in Figure 1. Example 3 A female athymic nude mouse was subcutaneously injected with a C〇1〇205 colon cancer cell line. When the tumor reached an average tumor volume of 220 mm3, the mice were randomly divided into 10 groups per group. Rats were given intravenous injection of 30 mg/kg LBH589 once a week, Wednesday and Friday for 3 weeks or once a week for 3 weeks. Rats were given 130311.doc -28- 200908964 75 mg/kg 5-fluorouridine , or a combination of two agents. Compound activity (%T/C) was calculated as a percentage change in tumor volume of treated animals relative to control animals in terms of tumor growth inhibition (Fig. 2A). At the end of the study, the percent recovery of the final tumor volume relative to the starting tumor volume was calculated as a percentage of recovery. For tumor growth delay (Fig. 2B), compound activity was calculated as a percentage change in tumor volume between the mean calculation time and the end of study (TTE), where the tumor volume was predetermined to be 1 00 mm3. For vehicle, LBH, 5-FU, and combination treatments, mean TTE was 39" days, 32 9 days, 44.5 days, and 57, 1 days. Treatment with LBH589 or 5-FU caused tumor growth inhibition (TGI) and tumor growth delay (TGD). More importantly, the combined processing greatly enhances TGI and TGD. The results are illustrated in Figure 2. Example 4 Pancreatic cancer cell lines were treated with DMSO vehicle control or different concentrations of LBH589 for 3 days. The measurement time of cell proliferation was treated on the day of cell plating and after the third day. The IC5〇 and LD50 values were calculated as described above. As shown by the low concentration of IC5〇, the LBH589 showed an effective anti-proliferative effect on all 12 adenocarcinoma cell lines tested. Lbh5 89 also showed strong cytotoxic effects on most of the tested pancreatic cancer cell lines with LD50 < 1 μΜ (n = l〇). Among the 12 pancreatic cancer cell lines, the antiproliferative and cytotoxic effects of LBH589 are described in Table 2 below: (**Cell line=cell line) 130311.doc -29- 200908964 NVP-L BH589 Cell Lines IC50 [nM] LD50 [nM] MiaPaCa2 14.1 59.5 BxPC3 15.9 104.8 Hs766T 14.1 119.9 SU.86.86 51 170.4 Panel 18.9 175.4 Capanl 55.6 191.5 Panc3.27 38.5 276.8 Panel 0.05 31.8 282.4 AsPC1 25.1 372.4 Panc2.03 22.4 599.5 HPAC 122.7 2051.6 Panc4.03 20.3 >10000 In the cell proliferation assay, 19 pancreatic cancer cell lines were analyzed separately. The cell lines were treated with DMSO vehicle control group or different concentrations of LBH5 89 for f, 6 days. Consistent with the results shown in Table 2, LBH589 has an effective antiproliferative effect on all 19 pancreatic cancer cell lines tested, as indicated by the low IC50 value of the IC50 value. LBH589 also showed an effective cytotoxic effect on 18 of 19 pancreatic cancer cell lines with LD50 < 1 μΜ. The results are depicted in Figure 3 ° [Simplified Schematic] Figure 1 illustrates that LBH589 treatment inhibits tumor growth in HCT116 xenograft mode. 〇 Figure 2 illustrates that in the C〇1〇205 colon cancer xenograft mode, the combined treatment of LBH589 and 5-fluorouracil increased tumor growth inhibition and tumor growth delay. Figure 3 shows that LBH589 has antiproliferative and cytotoxic effects in 19 pancreatic cancer cell lines. 130311.doc -30·

Claims

200908964 十、申請專利範圍： 1. 2. 用於製備供胃腸癌治療藥劑之用途。其中該HDAC抑制劑為化學式⑴之化 H0\200908964 X. Patent application scope: 1. 2. For the preparation of therapeutic agents for gastrointestinal cancer. Wherein the HDAC inhibitor is chemical formula (1) H0\

一種HDAC抑制劑如請求項1之用途合物：其中齒素；或直鍵Ci_C6烧基，尤其為甲基、乙基或正丙基’其中甲基、乙基及正丙基取代基為未經取代或經一個或多個如下對烷基所述之取代基取代； R2係選自Η，Ci-Ci0烷基，較佳為Ci-C6烷基，如甲基、乙基或-CH2CH2-〇H; c4-c9環烷基；c4_c9雜環烷基；〇4_(：9雜環烷基烷基；環烷基烷基，如環丙基甲基，芳基，雜芳基；芳基烧基，如苯甲基；雜芳基烷基，如。比啶基曱基；_(CH2)nc(0)R6 ; -(CH2)n〇C(〇)R6 ;胺基醯基；HON-C^CO-CIKd)- 芳基-烷基-;及_(CH2)nR7 ; R3和R4為相同或不同且各獨立為H、c〗-c6烷基、醯基或酿基胺基》或 R·3和&與其相連的碳原子一起形成c=〇、C=S或 c=nr8，或 R2和其相連的氮原子且r3和其相連的碳原子，可形成 130311.doc 200908964 CVC9雜環烷基，雜芳基，多雜方基’非芳族的多雜環’或混合之芳基與非芳基多雜環； R5係選自Η ; CVC6烷基；r r 丞匕<9環烷基；C4-C9雜環烷基；醯基；芳基；雜芳基 ^ 土方基烷基，如苯甲基；雜芳基烧基，如吼η定甚甲A . A T基，多環芳香烴；多環非芳香烴；混合之芳基與㈣基多環；多雜芳基；非芳香多雜環；及混合之芳基與非芳基多雜環； …可相同或不同且獨立地選自，當η]An HDAC inhibitor as claimed in claim 1 wherein: dentin; or a direct bond Ci_C6 alkyl, especially methyl, ethyl or n-propyl' wherein the methyl, ethyl and n-propyl substituents are Substituted or substituted by one or more substituents as described for the alkyl group; R2 is selected from the group consisting of hydrazine, Ci-Ci0 alkyl, preferably Ci-C6 alkyl, such as methyl, ethyl or -CH2CH2- 〇H; c4-c9 cycloalkyl; c4_c9 heterocycloalkyl; 〇4_(:9 heterocycloalkylalkyl; cycloalkylalkyl, such as cyclopropylmethyl, aryl, heteroaryl; aryl An alkyl group; such as a benzyl group; a heteroarylalkyl group such as a pyridyl fluorenyl group; _(CH2) nc(0)R6; -(CH2)n〇C(〇)R6; an amine fluorenyl group; -C^CO-CIKd)-aryl-alkyl-; and _(CH2)nR7; R3 and R4 are the same or different and each independently H, c--------- 6-alkyl, fluorenyl or arylamino group Or R.3 and & together with the carbon atom to which they are attached form c=〇, C=S or c=nr8, or R2 and its associated nitrogen atom and r3 and its associated carbon atom may form 130311.doc 200908964 CVC9 Heterocycloalkyl, heteroaryl, polyheteroaryl 'non-aromatic polyheterocycle' or mixed aromatic And non-aryl polyheterocyclic ring; R5 is selected from fluorene; CVC6 alkyl; rr 丞匕 <9 cycloalkyl; C4-C9 heterocycloalkyl; fluorenyl; aryl; heteroaryl a group such as a benzyl group; a heteroaryl group such as 吼η定甲甲 A. AT group, a polycyclic aromatic hydrocarbon; a polycyclic non-aromatic hydrocarbon; a mixed aryl group and a (tetra)-based polycyclic ring; a polyheteroaryl group; Non-aromatic polyheterocycle; and mixed aryl and non-aryl polyheterocycle; ... may be the same or different and independently selected from η]

為1到6時’各碳原子可視情況且獨立經R3及/或R4取代； X和Y可相同或不同且獨立地選自H;南素；⑽烧基，如 CH3 和 cf3 ; N〇2 ; c(〇)Ri ; 〇R9 ; SR9 ; CN ； ANR10RU ; R6選自H ; Cl-C6烧基；C4_C9環垸基；a%雜環烧基；環烷基烷基，如環丙基甲基；芳基；雜芳基；芳基烷基，如苯曱基和2_苯基乙烯基；雜芳基烷基，如吡啶基甲基；〇r12 ;及NR13Ri4 ; R7係選自 or15，sr15，s(o)r16，so2Rl7，皿13尺14和 NR12SO2R6 » Rs係選自 Η，〇R15 ; NR13R14 ; CVC6燒基；C4_C9環烧基，CU-C9雜環烷基；芳基；雜芳基；芳基烷基，如苯曱基；及雜芳基烧基，如吼咬基甲基； R9係選自CrCU烷基，如CH3和CF3 ; c(0)-烷基，如 C(0)CH3 ;及 c(0)CF3 ; 130311.doc 200908964 R1〇和Rii為相同或不同且獨立地選自Η ; CVC4烧基和 -C(O)-烷基； R12係選自Η ; CVC6烷基；〇4-<：9環烷基；c4-C9雜環烷基；CfC9雜環烷基烷基；芳基；混合之芳基和非芳基多環；雜芳基；芳基烷基，如苯曱基；及雜芳基烧基，如。比啶基曱基； Ru和R〗4可相同或不同且獨立地選自H; C】_C6烷基； q-C9環烷基；C4_C9雜環烷基；芳基；雜芳基；芳1 to 6 'each carbon atom may be optionally substituted by R3 and/or R4; X and Y may be the same or different and independently selected from H; south; (10) alkyl, such as CH3 and cf3; N〇2 ; c(〇)Ri ; 〇R9 ; SR9 ; CN ; ANR10RU ; R6 is selected from H ; Cl-C6 alkyl; C4_C9 cycloalkyl; a% heterocycloalkyl; cycloalkylalkyl, such as cyclopropyl Aryl; heteroaryl; arylalkyl, such as phenylhydrazino and 2-phenylvinyl; heteroarylalkyl, such as pyridylmethyl; 〇r12; and NR13Ri4; R7 is selected from or15, Sr15,s(o)r16,so2Rl7, dish 13 ft 14 and NR12SO2R6 » Rs is selected from Η, 〇R15; NR13R14; CVC6 alkyl; C4_C9 cycloalkyl, CU-C9 heterocycloalkyl; aryl; An arylalkyl group, such as a phenyl fluorenyl group; and a heteroarylalkyl group, such as a carbyl methyl group; R9 is selected from the group consisting of CrCU alkyl groups, such as CH3 and CF3; c(0)-alkyl, such as C ( 0) CH3; and c(0)CF3; 130311.doc 200908964 R1〇 and Rii are the same or different and independently selected from Η; CVC4 alkyl and -C(O)-alkyl; R12 is selected from Η; CVC6 Alkyl; 〇4-<:9-cycloalkyl; c4-C9 heterocycloalkyl; CfC9 heterocycloalkylalkyl; aryl; The aryl and non-aryl polyheterocycle ring; heteroaryl; arylalkyl, such as benzyl Yue group; an aryl group and heteroaryl group burning, such as.比曱曱 ;; Ru and R 4 may be the same or different and independently selected from H; C]-C6 alkyl; q-C9 cycloalkyl; C4_C9 heterocycloalkyl; aryl; heteroaryl;

基烷基，如苯甲基；雜芳基烷基，如吡啶基曱基；胺基酿基，或 Rn和R"與相連的氮原子—起形成c4_c_環烧基、雜芳基、多雜芳基、非芳香多雜環或混合之芳基與非芳基多雜環； R15係選^ Η ’ CVC6烧基；c4_C9環烧基；C4_c9雜環烧 ^芳基，雜芳基；芳基烷基；雜芳基烷基和 (CH2)mZR12 ; R1 6係選自C 1 - C &炫其· p p斑基，C4.C9環烷基；c4-c9雜環烷基；方基，雜芳基.客独朴w 土 ’多雜方基；芳基烷基；雜芳基烷基和（CH2)mZR12 ; Ri7係選自CVCfi烷其.r 。几基’ C4-c9環烷基；c4-C9雜環烷基；芳基；多環芳香炉.雜4甘如货4 ’雜方基；芳基烷基；雜芳基烷基；多雜芳基和NR13R14; m係選自0到6之間的整數；和 Z選自〇; NR13; s;和8(〇)， 130311.doc 200908964 或其醫藥可接受之鹽類。 3·如請求項2之用途，其中該化學式（I)之化合物為具有以下化學式（III)之N_羥基-3-[4-[[[2-(2-甲基-lH-η引嗓_3•基）· 乙基]-胺基]甲基]苯基]-2五-2_丙烯醯胺：An alkyl group, such as a benzyl group; a heteroarylalkyl group, such as a pyridyl fluorenyl group; an amine aryl group, or Rn and R" with a linked nitrogen atom to form a c4_c_cycloalkyl group, a heteroaryl group, a heteroaryl group, a non-aromatic polyheterocyclic ring or a mixed aryl group and a non-aryl polyheterocyclic ring; R15 is selected from the group consisting of CVC6 alkyl; C4_C9 cycloalkyl; C4_c9 heterocyclic aryl, heteroaryl; Alkyl; heteroarylalkyl and (CH2)mZR12; R1 6 is selected from the group consisting of C 1 - C & H. pp plaque, C4. C9 cycloalkyl; c4-c9 heterocycloalkyl; , heteroaryl. 客独朴 w soil 'polyheteroaryl; arylalkyl; heteroarylalkyl and (CH2) mZR12; Ri7 is selected from CVCfi alkane.r. Alkyl 'C4-c9 cycloalkyl; c4-C9 heterocycloalkyl; aryl; polycyclic aromatic furnace. hetero 4 ganru 4 'heteroaryl; arylalkyl; heteroarylalkyl; The aryl group and NR13R14; m is selected from an integer between 0 and 6; and Z is selected from the group consisting of ruthenium; NR13; s; and 8 (〇), 130311.doc 200908964 or a pharmaceutically acceptable salt thereof. 3. The use according to claim 2, wherein the compound of the formula (I) is N-hydroxy-3-[4-[[[2-(2-methyl-lH-η)] having the following formula (III) _3•基)·Ethyl]-amino]methyl]phenyl]-2penta-2-propenylamine:

或其醫藥可接受之鹽類。 4. 如請求項⑴中任一項之用途，其中該胃腸癌為肝細胞癌（hepat〇ceiiuiar carcin〇ma)或胰腺癌。 5. 如清求項！至3中任一項之用途，其中該溫血動物為人 (ΠΙ)，Or a pharmaceutically acceptable salt thereof. 4. The use according to any one of the preceding claims, wherein the gastrointestinal cancer is hepatocarcinoma (hepatocyte) or pancreatic cancer. 5. If you want to clear the item! The use of any one of the three, wherein the warm-blooded animal is a human (ΠΙ),

類。 6. -種治療胃腸癌之方法，其包括對需要之溫血動物投與治療有效量之HDAC抑制劑。 7·如π求項6之方法包括對溫血動物投與治療有效量之化學式（I)之化合物：class. 6. A method of treating gastrointestinal cancer comprising administering a therapeutically effective amount of a HDAC inhibitor to a warm-blooded animal in need thereof. 7. The method of π, wherein the method comprises the administration of a therapeutically effective amount of a compound of formula (I) to a warm-blooded animal:

(I) Ri為Η;鹵素；或直鏈已 1 燒基’尤其為曱基、乙基或正丙基，其中甲基、乙美$ I及正丙基取代基為未經取代 130311.doc 200908964 或經一個或多個如下述對烷基所述之取代基取代；係選自Η ; CVCw烷基，較佳為烷基，如甲基、乙基或-CH2CH2-OH; c4-c9環烷基；c4-c9雜環烷基；C4_(：9雜環烷基烷基；環烷基烷基，如環丙基甲基；芳基；雜芳基；芳基烷基，如苯甲基；雜芳基烷基，如吡啶基曱基；_(CH2)nc(0)R6 ; -(CH2)nOC(0)R6 ;胺基醯基；HON-CCC^-CHtCd)- 芳基-烷基-;及-(CH2：)nR7 ;(I) Ri is hydrazine; halogen; or a straight-chain aryl group, especially fluorenyl, ethyl or n-propyl, wherein the methyl, ethyl amide and I-propyl substituents are unsubstituted 130311.doc 200908964 or substituted by one or more substituents as described below for an alkyl group; selected from hydrazine; CVCw alkyl, preferably alkyl such as methyl, ethyl or -CH2CH2-OH; c4-c9 ring Alkyl; c4-c9 heterocycloalkyl; C4_(:9 heterocycloalkylalkyl; cycloalkylalkyl, such as cyclopropylmethyl; aryl; heteroaryl; arylalkyl, such as benzoyl Heteroarylalkyl group, such as pyridyl fluorenyl; _(CH2) nc(0)R6; -(CH2)nOC(0)R6; amine fluorenyl; HON-CCC^-CHtCd)-aryl- Alkyl-; and -(CH2:)nR7;

R3和I可相同或不同且各獨立為H、Ci_C6烷基、醯基或酿基胺基，或 I和I與其相連的碳原子一起形成c=〇、c=s或 C=NR8，或 R2和其相連的氮原子且I和其相連的碳原子，可形成 C4_c9雜環烧基，雜芳基’多雜芳基，非芳族的多雜環，及混合之芳基與非芳基多雜環； R5係選自Η ; Cl-C6烷基；。夂環烷基；C4_C9雜環烷基；醯基；芳基·’雜芳基；芳基烷基，如苯曱基；雜芳基燒基，如吡啶基甲基.之，土 τ丞’多環芳香烴；多環非芳香煙；混合之芳基與非芳基多環；多雜芳基；非芳香多雜環；或混合之芳基與非芳基多雜環； η、ηι、η2和以可相同或不同且獨立選自〇到6之間，當&為1到6時，各碳原子可視情況且獨立地經1及/ 或R4取代； X和Y可相同或不同且獨立地選自H; 鹵素 Ci-C^ 烷 I30311.doc 200908964 基，如 CH3 和 CF3 ; N〇2 ; C(0)R! ； or9 ; sr9 ; CN ;及 NR,〇Rn ； R6選自H，C1-C6烧基，C4-C9環院基；C4-C9雜環烧基；環烷基烷基，如環丙基曱基；芳基；雜芳基；芳基院基，如苯曱基和2-苯基乙稀基；及雜芳基烧基’如吡啶基曱基；OR12 ;和NR13R14 ; R7係選自 or15，sr15，s(o)r16，so2r17，nr13r14* NR12S02R6 ; R8係選自 H ; OR15 ; NR13R14 ; CVC6烷基；c4-c9環烷基；C4_C9雜環烷基；芳基；雜芳基；芳基烷基，如苯曱基；雜芳基烧基，如。比。定基曱基； R9係選自C1-C4烧基’如CH3和CF3 ; C(〇)-院基，如 c(o)ch3 ;及 c(o)cf3 ; Rio和R11為相同或不同且獨立地選自Η ; C1-C4院基和_ c(o)-烷基； Rl2係選自Η，Ci-C6烧基，C4-C9環烧基；C4-C9雜環院基，C4-C9雜環烧基院基；芳基；混合之芳基和非芳基多環；雜芳基；芳基烷基，如苯曱基；雜芳基院基，如吡啶基曱基； R〗3和R〗4可相同或不同且獨立地選自Η ; c广c6烧基. CU-C9環烷基；CU-C9雜環烷基；芳基；雜芳基；芳基烧基，如笨曱基，雜芳基烧基，如。比咬基曱基；胺基醯基，或 Rn和Ru與相連的氮原子一起形成C4_C9雜環烷基、雜 130311.doc 200908964 芳基、多雜芳基、非料多雜環或混合之芳基多雜環； Ri5係選自Η，Ci-C6烧基；C4-c产p其·「p 4 烷基，c4-c9雜環烷基；芳基；雜芳基；芳基貌基；雜芳基貌基和 (CH2)mZR12 ; R16係選自CVC6烷基；〇4-(：9環烷其.Γ r M s 9衣沉基，CVC9雜環烷基；芳基；雜芳基；多雜芳基.笔 ’方基烷基’雜芳基烷基和（CHzUZRu ; Ru係4自C,-C6烷基；c4_c9環烷基；C4_c9雜環烷基；芳基；多環芳香烴·’雜芳基；芳基院基；雜芳基院基；多雜芳基和nr13r14 ; m係選自〇到6之間的整數；和 Z選自 0 ; NR13 ; S ;和 S(O)，或其醫藥可接受之鹽類。 8·如請求項6之方法，苴中該仆輿斗WT、，、T忑化學式⑴之化合物為具有化 C / 學式（m)之Ν_經基-3_[4_[[[2_(2_甲基_出_。引。朵_3_基）_乙基]-胺基]甲基]苯基]-2β-2-丙烯醯胺：〇R3 and I may be the same or different and each independently is H, Ci_C6 alkyl, fluorenyl or arylamino, or I and I together with the carbon atom to which they are attached form c=〇, c=s or C=NR8, or R2 And the nitrogen atom to which it is attached and I and the carbon atom to which it is attached may form a C4_c9 heterocyclic alkyl group, a heteroaryl 'heteroaryl group, a non-aromatic polyheterocyclic ring, and a mixed aryl group and a non-aryl group. Heterocyclic ring; R5 is selected from the group consisting of hydrazine; Cl-C6 alkyl;夂cycloalkyl; C4_C9 heterocycloalkyl; fluorenyl; aryl · 'heteroaryl; arylalkyl, such as phenyl fluorenyl; heteroaryl alkyl, such as pyridylmethyl. Polycyclic aromatic hydrocarbon; polycyclic non-aromatic smoke; mixed aryl and non-aryl polycyclic; polyheteroaryl; non-aromatic polyheterocycle; or mixed aryl and non-aryl polyheterocycle; η, ηι, Η2 and may be the same or different and independently selected from 〇 to 6, when & 1 to 6, each carbon atom may be optionally substituted with 1 and/or R4; X and Y may be the same or different and Independently selected from H; halogen Ci-C^ alkane I30311.doc 200908964 base, such as CH3 and CF3; N〇2; C(0)R!; or9; sr9; CN; and NR, 〇Rn; R6 is selected from H , C1-C6 alkyl, C4-C9 ring-based; C4-C9 heterocycloalkyl; cycloalkylalkyl, such as cyclopropyl fluorenyl; aryl; heteroaryl; aryl-based, such as phenylhydrazine And 2-phenylethenyl; and heteroarylalkyl such as pyridyl fluorenyl; OR12; and NR13R14; R7 is selected from or15, sr15, s(o)r16, so2r17, nr13r14* NR12S02R6; Selected from H; OR15; NR13R14; CVC6 alkyl; c4-c9 ring Group; C4_C9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, such as benzyl group Yue; burn heteroaryl group, such as. ratio. R9 is selected from C1-C4 alkyl groups such as CH3 and CF3; C(〇)-hospital groups such as c(o)ch3; and c(o)cf3; Rio and R11 are the same or different and independent Is selected from the group consisting of Η; C1-C4, and _c(o)-alkyl; Rl2 is selected from the group consisting of ruthenium, Ci-C6 alkyl, C4-C9 cycloalkyl; C4-C9 heterocyclic, C4-C9 a heterocyclic alkyl group; an aryl group; a mixed aryl group and a non-aryl polycyclic ring; a heteroaryl group; an arylalkyl group such as a benzoinyl group; a heteroaryl group such as a pyridyl fluorenyl group; And R 4 may be the same or different and independently selected from fluorene; c-C6 alkyl. CU-C9 cycloalkyl; CU-C9 heterocycloalkyl; aryl; heteroaryl; aryl alkyl, such as stupid Sulfhydryl, heteroaryl alkyl, such as. More than a thiol group; an amine fluorenyl group, or Rn and Ru together with a nitrogen atom to be bonded to form a C4_C9 heterocycloalkyl group, a hybrid 130311.doc 200908964 aryl, polyheteroaryl, non-heterocyclic or mixed aromatic a heteropolycyclic ring; the Ri5 is selected from the group consisting of hydrazine, a Ci-C6 alkyl group; the C4-c is a p-alkyl group, a c4-c9 heterocycloalkyl group; an aryl group; a heteroaryl group; an aryl group; Heteroaryl-based and (CH2)mZR12; R16 is selected from CVC6 alkyl; 〇4-(:9-cycloalkane.Γ r M s 9 sulphonyl, CVC9 heterocycloalkyl; aryl; heteroaryl Polyheteroaryl. pen 'arylalkyl' heteroarylalkyl and (CHzUZRu; Ru 4 from C, -C6 alkyl; c4_c9 cycloalkyl; C4_c9 heterocycloalkyl; aryl; polycyclic aromatic Hydrocarbon·'heteroaryl; aryl-based; heteroaryl-based; polyheteroaryl and nr13r14; m-line selected from an integer between 〇 and 6; and Z selected from 0; NR13; S; O), or a pharmaceutically acceptable salt thereof. 8. According to the method of claim 6, the compound of the formula (1) of the servant WT, , and T忑 is a chemical C / (m) Meridyl-3_[4_[[[2_(2_methyl_出_.引.朵_3_基)_ethyl]-Amino] Yl] phenyl] -2β-2- acrylamide: square

、 (III) 或其醫藥可接收之鹽類。 .ΟΗ 女明求項6之方法，其中該胃腸癌為肝癌或姨腺癌 10.如請求項6之方法，其中該溫血動物為人類。 1303 丨丨.doc, (III) or a salt acceptable for its use in medicine. The method of claim 6, wherein the gastrointestinal cancer is liver cancer or salivary gland cancer. 10. The method of claim 6, wherein the warm-blooded animal is a human. 1303 丨丨.doc