Histone deacetylases (HDACS) inhibitorsHistone deacetylases (HDACs) inhibitors are disclosed. The HDACs inhibitors possess cytotoxicities to various cancer cell lines. They are useful for treating a tumor associated with deregulation of the activity of histone deacetylases in a subject in need thereof, in one embodiment, the HDACs inhibitors of the invention are useful for treating glioma, breast cancer, colon cancer, targe cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, stomach cancer, liver cancer, ovary adenocarcinoma, pancreas carcinoma, prostate carcinoma, promyiocytic leukemia, chronic myelocytic leukemia, or acute lymphocytic leukemia in a subject in need thereof.A compound of formula i or a pharmaceutically acceptable salt thereof,whereinr is (c)1-c6) alkyl, (c)3-c6) alkenyl, phenyl (c)3-c6) alkenyl, (c)3-c6) cycloalkyl, (c3-c6) cycloalkenyl (c1-c6) alkyl, (c1-c6) alkyl (c)c3-c6) cycloalkyl group, (c)5) heterocycloalkyl group, (c)1-c6) alkyl radical (c)6-c18) aryl, cyclopropyl-c6h5、(c1-c6) alkoxy (c)1-c6) alkyl, halo (c)1-c6) alkyl, halo (c)3-c6) cycloalkyl group, (c)6-c18) aryl, halophenyl, halo (c)1-c6) alkylphenyl, halo (c)1-c6) alkyl radical (c)6-c18) aryl radical (c)1-c6) alkoxy, halo (c)1-c6) alkylphenoxy (c)1-c6) alkyl, halo (c)1-c6) alkyl halogenophenyl, (c)1-c6) alkyl halo (c)1-c6) alkylphenyl, hydroxyphenyl, nitrophenyl (c)1-c6) alkyl, aminophenyl (c)1-c6) alkyl, n- (c)1-c6) alkylamino radical (c)6-c18) aryl radical (c)1-c6) an alkyl group; (c)1-c6) alkylbenzoic acids, hydroxy (c)1-c6) alkyl, hydroxy (c)3-c6) cycloalkyl (c)1-c6) alkyl, hydroxy (c)6-c18) aryl radical (c)1-c6) alkyl, hydroxy (c)1-c6) alkyl radical (c)6-c18) aryl group, (c)1-c6) alkoxy (c)6-c18) aryl group, (c)6-c18) aryl radical (c)1-c6) alkyl, (c)3-c18) heteroaryl (c)1-c6) alkyl, halo (c)6-c18) aryl radical (c)1-c6) alkyl, halo (c)1-c6) alkoxy (c)6-c18) aryl, halo (c)1-c6) alkoxy (c)6-c18) aryl radical (c)1-c6) alkyl, halo (c)1-c6) alkyl radical (c)6-c18) aryl radical (c)1-c6) alkyl, (c)1-c6) alkylamino radical (c)6-c18) aryl radical (c)1-c6) alkyl, morpholinyl (c)1-c6) alkyl, morpholinyl (c)1-c6) alkyl radical (c)6-c18) aryl, morpholinyl (c)1-c6) alkyl radical (c)6-c18) aryl radical (c)1-c6) alkyl, morpholinyl (c)6-c18) aryl radical (c)1-c6) alkyl, piperidinyl (c)1-c6) alkyl, n- (c)1-c6) alkylpiperidinyl, n-di (c)1-c6) alkylpiperidinyl, piperidinyl-n- (c)1-c6) alkoxy (c)6-c18) aryl radical (c)1-c6) alkyl, piperidinyl (c)1-c6) alkyl radical (c)6-c18) aryl radical (c)1-c6) alkyl, pyridine and (c)1-c6) alkyl pyridine, (c)1-c6) alkyl imidazole, hydroxy (c)6-c18) aryl radical (c)1-c6) alkyl, n-dimethyl (c)6-c18) aryl radical (c)1-c6) alkyl, (c)1-c6) alkoxy (c)6-c18) aryl radical (c)1-c6) alkyl, hydroxy (c)1-c6) alkoxy (c)6-c18) aryl radical (c)1-c6) alkyl, methylenedioxyphenyl (c)1-c6) alkyl or (c)6-c18) aryl radical (c)1-c6) an alkoxy group;heterocyclic moietiesoptionally substituted by one or more raor rbor r isaand rbsubstituted, and selected from:andwherein r isaand rbindependently selected from hydrogen, halogen, (c)1-c6) alkyl, (c)6-c18) aryl group, (c)3-c18) heteroaryl, (c)3-c6) cycloalkyl group, (c)1-c6) alkoxy group, (c)1-c6) alkoxy (c)1-c6) alkoxy, aryloxy, hydroxy, -no2、-cn、-cf3and-ch2cf3；moieties are selected from:andwherein r iscis optionally present and is hydrogen, halogen, (c1-c6) alkyl or (c1-c6) alkoxy;y is absent or selected from-ch2–、–cf2-, -cfh-, -ch ═ ch-and-ch2ch2-; andz is-oh, -o-c (═ o) -ch3-o-valine, -o-valine hydrochloride, -o-valine trifluoroacetate or-o-c (═ o) -ch (nh2) -ch (ch)3)2hydrochloride or trifluoroacetate.
히스톤 데아세틸라제(HDAC) 저해제히스톤 데아세틸라제(HDAC) 저해제가 개시되어 있다. HDAC 저해제는 각종 암세포주에 대해서 세포독성을 지닌다. 이러한 저해제는 치료를 필요로 하는 대상체에서 히스톤 데아세틸라제의 활성도의 조절이상과 연관된 종양을 치료하는데 유용하다. 일 실시형태에 있어서, 본 발명의 HDAC 저해제는 치료를 필요로 하는 대상체에서 신경교종, 유방암, 결장암, 대세포 폐암, 폐 선암종, 소세포 폐암, 위암, 간암, 난소 선암종, 췌장 암종, 전립선 암종, 전골수구성 백혈병, 만성 골수성 백혈병, 또는 급성 림프구성 백혈병을 치료하는데 유용하다.하기 화학식 I의 화합물 또는 이의 약제학적으로 허용 가능한 염:[이미지]식 중,R은 (C1-C6)알킬, (C3-C6)알켄일, 페닐(C3-C6)알켄일, (C3-C6)사이클로알킬, (C3-C6)사이클로알켄일(C1-C6)알킬, (C1-C6)알킬(C3-C6)사이클로알킬, (C5)헤테로사이클로알킬, (C1-C6)알킬(C6-C18)아릴, 사이클로프로필-C6H5, (C1-C6)알콕시(C1-C6)알킬, 할로(C1-C6)알킬, 할로(C3-C6)사이클로알킬, (C6-C18)아릴, 할로페닐, 할로(C1-C6)알킬페닐, 할로(C1-C6)알킬(C6-C18)아릴(C1-C6)알콕시, 할로(C1-C6)알킬페녹시(C1-C6)알킬, 할로(C1-C6)알킬할로페닐, (C1-C6)알킬할로(C1-C6)알킬페닐, 하이드록시페닐, 나이트로페닐, 나이트로페닐(C1-C6)알킬, 아미노페닐(C1-C6)알킬, N-(C1-C6)알킬아미노(C6-C18)아릴(C1-C6)알킬; (C1-C6)알킬벤조산, 하이드록실(C1-C6)알킬, 하이드록실(C3-C6)사이클로알킬(C1-C6)알킬, 하이드록실(C6-C18)아릴(C1-C6)알킬, 하이드록실(C1-C6)알킬(C6-C18)아릴, (C1-C6)알콕시(C6-C18)아릴, (C6-C18)아릴(C1-C6)알킬, (C3-C18)헤테로아릴(C1-C6)알킬, 할로(C6-C18)아릴(C1-C6)알킬, 할로(C1-C6)알콕시(C6-C18)아릴, 할로(C1-C6)알콕시(C6-C18)아릴(C1-C6)알킬, 할로(C1-C6)알킬(C6-C18)아릴(C1-C6)알킬, (C1-C6)알킬아미노(C6-C18)아릴(C1-C6)알킬, 몰폴린일(C1-C6)알킬, 몰폴린일(C1-C6)알킬(C6-C18)아릴, 몰폴린일(C1-C6)알킬(C6-C18)아릴(C1-C6)알킬, 몰폴린일(C6-C18)아릴(C1-C6)알킬, 피페리딘일, 피페리딘일(C1-C6)알킬, N-(C1-C6)알킬피페리딘일, N,N-다이(C1-C6)알킬피페리딘일, 피페리딘일-N-(C1-C6)알콕시(C6-C18)아릴(C1-C6)알킬, 피페리딘일(C1-C6)알킬(C6-C18)아릴(C1-C6)알킬, 피리딘, (C1-C6)알킬피리딘, (C1-C6)알킬이미다졸, 하이드록실(C6-C18)아릴(C1-C6)알킬, N,N-다이메틸(C6-C18)아릴(C1-C6)알킬, (C1-C6)알콕시(C6-C18)아릴(C1-C6)알킬, 하이드록실(C1-C6)알콕시(C6-C18)아릴(C1-C6)알킬, 메틸렌다이옥시페닐(C1-C6)알킬 또는 (C6-C18)아릴(C1-C6)알콕시이고;복소환식 모이어티 [이미지]는 선택적으로 하나 이상의 Ra 또는 Rb, 또는 Ra 및 Rb로 치환되고, [이미지]로 이루어진 군으로부터 선택되되,Ra 및 Rb는 독립적으로 수소, 할로겐, (C1-C6)알킬, (C6-C18)아릴, (C3-C18)헤테로아릴, (C3-C6)사이클로알킬, (C1-C6)알콕시, (C1-C6)알콕시(C1-C6)알콕시, 아릴옥시, 하이드록실, -NO2, -CN, -CF3 및 -CH2CF3로 이루어진 군으로부터 선택되고;모이어티 [이미지]는[이미지]로 이루어진 군으로부터 선택되되,Rc는 선택적으로 존재하고 수소, 할로겐, (C1-C6)알킬 또는 (C1-C6)알콕실이고;Y는 존재하지 않거나 또는 -CH2-, -CF2-, -CFH-, -CH=CH- 및 -CH2CH2-로 이루어진 군으로부터 선택되고; 그리고Z는 -OH, -O-C(=O)-CH3, -O-발린, -O-발린 염산염, -O-발린 트라이플루오로아세트산염, 또는 -O-C(=O)-CH(NH2)-CH(CH3)2 하이드로클로라이드 또는 트라이플루오로아세트산염이다.