BENZODIAZEPINE AND BENZOPIPERAZINE ANALOG INHIBITORS OF HISTONE DEACETYLASEThis invention relates to compounds for the inhibition of histone deacetylase More particularly, the invention provides for compounds of formula (I): wherein A, B, D, E, X1, X2, X3, X4 and n are as defined in the specification A method of inhibiting histone deacetylase in a cell, the method comprising contacting the cell with a compound of formula (I), in an amount sufficient to inhibit histone deacetylase, is also disclosed.A compound of the formula (I): and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof,wherein n is 0 or 1 ;X1, X2, X3 and X4 are independently selected from the group consisting of CH, C-Z and N, wherein no more than two of X1, X2 X3 and X4 are N and no more than one of X1, X2, X3 and X4 are C-Z;X5-X6 is C=C; orX1, X2, X3 and X4 are absent, X5 is a covalent bond and X6 is independently selected from the group consisting of CH2 and CH(Z), with the provisio that an N, O or S(O)0.! in Z is separated from the CH of X6 by at least two carbon atoms;Z is independently selected from the group consisting of halo, -CF3, -NO2, -CN, -(C0-C6)alkyl- OR1, -(C0-C6)alkyl-N(R1)2, -(CrC6)alkyl, -N(R1)-C(O)-(CrC6)alkyl, -N(R1)-S(O)2-(Cr C6)alkyl, -O-(C2-C6)alkyl-N(R1)(R1), -S-R1, -(C0-C6)alkyl-C(O)-OR1 , -N(R1)-C(O)-CF3, - N(R1)-(C2-C6)alkyl-N(R1)(R1), -(C0-C7)alkyl-W, -(C2-C7)alkenyl-W, -(C2-C7)alkynyl-W, -(C0- C5)alkyl-CH=CH-W, -C(O)-(C1-C7)alkyl-W, -(Co-C3)alkyl-N(R1)-C(0)-(C1-C6)alkyl-W, -(C0- C3)alkyl-N(R1)-C(S)-(C1-C6)alkyl-W, -C(O)-N(R1 )-(C1-C6)alkyl-W, -(Co-C3)alkyl-N(R1)-(Cr C6)alkyl-W, -(Co-C3)alkyl-N(R1)-C(0)-N(R1)-(CrC6)alkyl-W, -(C0-C3)alkyl-N(R1)-C(O)-O- (CrCeOalkyl-W, -S(O)2-N(R1)-(C1-C6)alkyl-W, -(Co-C3)alkyl-N(R1)-S(0)2-(CrC6)alkyl-W, - C(O)-N(R1)2, -(C0-C3)alkyl-O-C(O)-N(R1)-(C1-C6)alkyl-W, -(C0-C3)alkyl-O-(C1-C6)alkyl-W, - (C0-C3)alkyl-S-(C1-C6)alkyl-W, -N(R1)-C(O)-OR1, -S(O)2-N(R1)2, -N(R1)-S(O)2R1, -(C0- C7)alkyl-aryl-W, -(C0-C7)alkyl-heteroaryl-W, -(Co-C3)alkyl-0-(Co-C3)alkyl-aryl, -(C0- C3)alkyl-O-(C0-C3)alkyl-heteroaryl, -aryl, -(Ci-C6)alkylaryl-, -heteroaryl, -(C1- C6)alkylheteroaryl-, -(C1-C8)heteroalkyl, -(C3-C6)cycloalkyl, -(C3-C6)heterocycloalkyl, -(C0- C3)alkyl-N(R1)-(Co-C3)alkyl-aryl-(CH=CH)o-rW, -(C0-C3)alkyl-O-(C0-C3)alkyl-aryl-(CH=CHK1-W, -(Co-C3)alkyl-S-(Co-C3)alkyl-aryl-(CH=CH)o-1-W, -(C0-C3)alkyl-N(R1)C(O)- 0-(C0-C3)alkyl-aryl-(CH=CH)o.rW, -(C0-C3)alkyl-O-C(O)N(R1)-(C0-C3)alkyl-aryl-(CH=CHK1-W, -(C0-C3)alkyl-S(0)2N(R1)-(Co-C3)alkyl-aryl-(CH=CH)o-1-W, -(CQ-C3)alkyl- N(R1)S(0)2-(Co-C3)alkyl-aryl-(CH=CH)o-1-W, -(C0-C3)alkyl-C(O)N(R1)-(C0-C3)alkyl-aryl- (CH=CH)0-I-W, -(Co-C3)alkyl-N(R1)C(0)-(Co-C3)alkyl-aryl-(CH=CH)o.1-W, -(C0-C3)alkyl- N(R1)C(0)N(R1)-(C0-C3)alkyl-aryl-(CH=CH)o-i-W, -(C0-C3)alkyl-(CH=CH)-(C0-C3)alkyl- -(C0-C3)alkyl-N(R1)-(Co-C3)alkyl-heteroaryl-(CH=CH)o.i-W, -(C0- C3)alkyl-0-(Co-C3)alkyl-heteroaryl-(CH=CH)o-rW, -(C0-C3)alkyl-S-(C0-C3)alkyl-heteroaryl- (CH=CH)0-I-W, -(Co-C3)alkyl-N(R1)C(0)-0-(C0-C3)alkyl-heteroaryl-(CH=CH)o-i-W, -(C0- C3)alkyl-OC(0)N(R1)-(C0-C3)alkyl-heteroaryl-(CH=CH)o.1-W, -(C0-C3)alkyl-S(0)2N(R1)-(Co- C3)alkyl-heteroaryl-(CH=CH)o-rWI -(C0-C3)alkyl-N(R1)S(O)2-(C0-C3)alkyl-heteroaryl-(CH=CH)0-I-W, -(CQ-C3)alkyl-C(0)N(R1)-(Co-C3)alkyl-heteroaryl-(CH=CH)0.1-W, -(C0- C3)alkyl-N(R1)C(O)-(C0-C3)alkyl-heteroaryl-(CH=CH)0.1-W, -(C0-C3)alkyl-N(R1)C(O)N(R1)- (Co-C3)alkyl-heteroaryl-(CH=CH)0-1-W and -(Co-C3)alkyl-(CH=CH)-(C0-C3)alkyl-heteroaryl- (CH=CH)0-I-W, -(C0-C5)alkyl-C ≡C-W, -(C0-C3)alkyl-O-(C0-C3)alkyl-aryl-(C aC)0-1-W, -(C0- C3)alkyl-S-(C0-C3)alkyl-aryl-(C ≡C)0.rW, -(C0-C3)alkyl-N(R1)C(O)-O-(C0-C3)alkyl-aryl-(C 3C)0-1-W, -(C0-C3)alkyl-0-C(0)N(R1)-(Co-C3)alkyl-aryl-(C ≡C)O-rW, -(C0-C3)alkyl- S(O)2N(R1)-(C0-C3)alkyl-aryl-(C ^:)0.l-W, -(Co-C3)alkyl-N(R1)S(0)2-(C0-C3)alkyl-aryl-(C^)0-1-W, -(C0-C3)alkyl-C(O)N(R1)-(C0-C3)alkyl-aryl-(C ^)o.rW, -(C0-C3)alkyl- N(R1)C(O)-(C0-C3)alkyl-aryl-(C -(Co-C3)alkyl-N(R1)C(0)N(R1)-(C0-C3)alkyl-aryl- (C ≡C)0-i-W, -(C0-C3)alkyl-(C ^)-(C0-C3)alkyl-aryl-(CH=CH)0.1-W, -(C0-C3)alkyl-(CH=CH)- (C0-C3)alkyl-aryl-(C SC)0-1-W, -(C0-C3)alkyl-(C -C)-(C0-C3)alkyl-aryl-(C C)o,-W, -(C0- C3)alkyl-N(R1HC0-C3)alkyl-heteroary!-(C ^V1-W, -(C0-C3)alkyl-O-(C0-C3)alkyl- heteroaryl-(C ^)0-I-W, -(Co-C3)alkyl-S-(Co-C3)alkyl-heteroaryl-(C ≡C)0-i-W, -(C0-C3)alkyl- N(R1 )C(O)-O-(C0-C3)alkyl-heteroaryl-(C ^)0-1-W, -(C0-C3)alkyl-OC(O)N(R1)-(C0-C3)alkyl- heteroaryl-(C ^)0-1-W, -(C0-C3)alkyl-S(O)2N(R1)-(C0-C3)alkyl-heteroaryl-(C 3CV1-W, -(C0- C3)alkyl-N(R1)S(O)2-(C0-C3)alkyl-heteroaryl-(C ^)0-1-W, -(C0-C3)alkyl-C(O)N(R1)-(C0- C3)alkyl-heteroaryl-(C ^)0-1-W1 -(C0-C3)alkyl-N(R1)C(O)-(C0-C3)alkyl-heteroaryl-(C ≡C)0.1- W, -(C0-C3)alkyl-N(R1)C(O)N(R1)-(C0-C3)alkyl-heteroaryl-(C M:)0.1-W, -(C0-C3)alkyl-(C ^)- (C0-C3)alkyl-heteroaryl-(CH=CH)o-rW, -(C0-C3)alkyl-(CH=CH)-(C0-C3)alkyl-heteroaryl- (C ^)0-1-W, -(C0-C3)alkyl-(C 3C)-(C0-C3)alkyl-heteroaryl-(C ^)0.rW, (C0-C3)alkyl-C(O)- N(R1)-(CrC6)alkyl-W, (C0-C3)alkyl-C(S)-N(R1)-(C1-C6)alkyl-W, -(C0-C3)alkyl-N(R1)-C(O)- (CrC6)alkyl-C(O)-aryl, -(C0-C3)alkyl-N(R1)-C(O)-(C1-C6)alkyl-C(O)-heteroaryl, -(C0- C3)alkyl-N(Ri J-C(O)-(C1 -C6)alkyl-C(O)-N(Ri )-aryl, and -(C0-C3)alkyl-N(R1 J-C(O)-(C1- C6)alkyl-C(O)-N(Ri)-heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocyclyl moieties of the above-mentioned Z is optionally substituted with one or more substituents selected from the group consisting of oxo, -OH, -CN, -(Ci-C6)alkyl, -(C1- C6)alkoxy, -NO2, -N(R1)2, halo, -SH, ...
히스톤 탈아세틸 효소의 벤조디아제핀 및 벤조피페라진 유도체 억제제본 발명은 히스톤 탈아세틸 효소 억제를 위한 화합물에 관한 것이다. 보다 구체적으로 본 발명은 아래의 화학식(I)을 가진 화합물을 제공한다:  여기서 A, B, D, E, X1, X2, X3, X4 및 n은 명세서에 정의한 바와 같다. 세포 내에서 히스톤 탈아세틸화를 억제하는 방법은 히스톤 탈아세틸화를 억제하는데 충분한 양의 화학식(I)의 화합물과 세포를 접촉하는 것을 포함한다.아래의 화학식(I)의 화합물 또는 그것의 N-산화물, 수화물, 용매화물, 약학적으로 허용가능한 염, 전구 약물 또는 복합체:  여기서 n은 0 또는 1이고; X1, X2, X3 및 X4는 독립적으로 CH, C-Z 및 N으로 구성되는 군으로부터 선택되며, 여기서 X1, X2, X3 및 X4 중 둘 이하가 N이고 X1, X2, X3 및 X4 중 하나 이하가 C-Z이며; X5-X6는 C=C이거나; X1, X2, X3 및 X4는 부재이며, X5는 공유 결합이고 X6은 독립적으로 CH2 및 CH(Z)로 구성되는 군으로부터 선택되며, 다만, Z에서 N, O 또는 S(O)0-1는 적어도 두 개의 탄소 원자에 의해 X6의 CH로부터 분리되고; Z는 독립적으로 할로, -CF3, -NO2, -CN, -(C0-C6)알킬-OR1, -(C0-C6)알킬-N(R1)2, -(C1-C6)알킬, -N(R1)-C(O)-(C1-C6)알킬, -N(R1)-S(O)2-(C1-C6)알킬, -O-(C2-C6)알킬-N(R1)(R1), -S-R1, -(C0-C6)알킬-C(O)-OR1, -N(R1)-C(O)-CF3, -N(R1)-(C2-C6)알킬-N(R1)(R1), -(C0-C7)알킬-W, -(C2-C7)알케닐-W, -(C2-C7)알키닐-W, -(C0-C5)알킬-CH=CH-W, -C(O)-(C1-C7)알킬-W, -(C0-C3)알킬-N(R1)-C(O)-(C1-C6)알킬-W, -(C0-C3)알킬-N(R1)-C(S)-(C1-C6)알킬-W, -C(O)-N(R1)-(C1-C6)알킬-W, -(C0-C3)알킬-N(R1)-(C1-C6)알킬-W, -(C0-C3)알킬-N(R1)-C(O)-N(R1)-(C1-C6)알킬-W, -(C0-C3)알킬-N(R1)-C(O)-O-(C1-C6)알킬-W, -S(O)2-N(R1)-(C1-C6)알킬-W, -(C0-C3)알킬-N(R1)-S(O)2-(C1-C6)알킬-W, -C(O)-N(R1)2, -(C0-C3)알킬-O-C(O)-N(R1)-(C1-C6)알킬-W, -(C0-C3)알킬-O-(C1-C6)알킬-W, -(C0-C3)알킬-S-(C1-C6)알킬-W, -N(R1)-C(O)-OR1, -S(O)2-N(R1)2, -N(R1)-S(O)2R1, -(C0-C7)알킬-아릴-W, -(C0-C7)알킬-헤테로아릴-W, -(C0-C3)알킬-O-(C0-C3)알킬-아릴, -(C0-C3)알킬-O-(C0-C3)알킬-헤테로아릴, -아릴, -(C1-C6)알킬아릴-, -헤테로아릴, -(C1-C6)알킬헤테로아릴-, -(C1-C8)헤테로알킬, -(C3-C6)사이클로알킬, -(C3-C6)헤테로사이클로알킬, -(C0-C3)알킬-N(R1)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-O-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-S-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)C(O)-O-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-O-C(O)N(R1)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-S(O)2N(R1)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)S(O)2-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-C(O)N(R1)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)C(O)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)C(O)N(R1)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-(CH=CH)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-O-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-S-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)C(O)-O-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-OC(O)N(R1)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-S(O)2N(R1)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)S(O)2-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-C(O)N(R1)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)C(O)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-N(R1)C(O)N(R1)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W 및 -(C0-C3)알킬-(CH=CH)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C5)알킬-C≡C-W, -(C0-C3)알킬-O-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-S-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)C(O)-O-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-O-C(O)N(R1)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-S(O)2N(R1)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)S(O)2-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-C(O)N(R1)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)C(O)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)C(O)N(R1)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-(C≡C)-(C0-C3)알킬-아릴-(CH=CH)0-1-W, -(C0-C3)알킬-(CH=CH)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-(C≡C)-(C0-C3)알킬-아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-O-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-S-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)C(O)-O-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-OC(O)N(R1)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-S(O)2N(R1)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)S(O)2-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-C(O)N(R1)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)C(O)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-N(R1)C(O)N(R1)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-(C≡C)-(C0-C3)알킬-헤테로아릴-(CH=CH)0-1-W, -(C0-C3)알킬-(CH=CH)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, -(C0-C3)알킬-(C≡C)-(C0-C3)알킬-헤테로아릴-(C≡C)0-1-W, (C0-C3)알킬-C(O)-N(R1)-(C1-C6)알킬-W, (C0-C3)알킬-C(S)-N(R1)-(C1-C6)알킬-W, -(C0-C3)알킬-N(R1)-C(O)-(C1-C6)알킬-C(O)-아릴, -(C0-C3)알킬-N(R1)-C(O)-(C1-C6)알킬-C(O)-헤테로아릴, -(C0-C3)알킬-N(R1)-C(O)-(C1-C6)알킬-C(O)-N(R1)-아릴 및 -(C0-C3)알킬-N(R1)-C(O)-(C1-C6)알킬-C(O)-N(R1)-헤테로아릴로 구성되는 군으로부터 선택되며, 여기서 각각의 앞에서 언급된 Z의 아릴, 헤테로아릴, 사이클로알킬 및 헤테로사이클릴 부분은 옥소, -OH, -CN, -(C1-C6)알킬, -(C1-C6)알콕시, -NO2, -N(R1)2, 할로, -SH, 모노- 에서 퍼-할로겐화된 -(C1-C6)알킬, 및 -(C2-C4)알킬-N(R1)2로 구성되는 군으로부터 선택되는 하나 이상의 치환체로 치환되거나 치환되지 않고, 여기서 두 개의 R1기는 이들이 결합된 질소 원자와 함께 헤테로사이클릴기를 형성하거나 형성하지 않으며; R1은 독립적으로 -H, -(C1-C6)알킬, -(C1-C6)헤테로알킬, -(C3-C6)사이클로알킬, 헤테로사이클릴, -(C0-C6)알킬-아릴, -(C0-C6)알킬-헤테로아릴 및 -(C2-C4)알킬-N(R1)2로 구성되는 군으로부터 선택되고, 여기서 상기 -(C3-C6)사이클로알킬, 헤테로사이클릴, -(C0-C6)알킬-아릴 및 -(C0-C6)알킬-헤테로아릴의 각각의 아릴, 헤테로아릴, 사이클로알킬 및 헤테로사이클릴 부분은 옥소, -OH, -CN, -(C1-C6)알킬, -(C1-C6)알콕시, -NO2, -N(R1)2, 할로, 아릴, 헤테로아릴, 모노- 에서 퍼-할로겐화된-(C1-C6)알킬 및 -(C2-C4)알킬-N(R1)2로 구성되는 군으로부터 선택되는 하나 이상의 치환체로 치환되거나 치환되지 않으며, 여기서 두 개의 R1기는 이들이 결합된 질소 원자와 함께 헤테로사이클릴기를 형성하거나 형성하지 않고; W는 -C(O)-NH-OH, -C(O)-C1-C4 알킬, -C(O)-N(R1)2, -(C1-C6)알킬-N(OH)-C(O)H-, -(C1-C6)알킬-SR1, -(C1-C6)알킬-S-C(O)-(C1-C4)알킬, -C(O)-OR1, , -C(O)-(C1-C4)알킬-SH, -C(O)-(C1-C4)알킬-S-C(O)R1, -C(O)-(C1-C4)알킬-S-헤테로아릴, -(C1-C6)알킬-NH-C(O)-(C1-C6)알킬-할로, -(C1-C6)알킬-NH-C(O)-(C1-C6)알킬-SH, -(C1-C6)알킬-NH-C(O)-(C1-C6)알킬-SC(O)R1, -C(O)-NH-(C2-C6)알킬-SH, -C(O)-N(R1)-(C0-C6)알킬-SR1, -C(O)-사이클로알킬, -C(O)-헤테로사이클릴, -C(O)-N(R1)-아릴-Q, -C(O)-N(R1)-헤테로아릴-Q, -C(O)-아릴, -C(O)-헤테로아릴 및 -C(O)-(C1-C6)알킬로 구성되는 군으로부터 선택되며, 여기서 알킬은 할로, 모노- ...