申请人：Davidson Alan Hornsby
公开号：US20140163042A1
公开（公告）日：2014-06-12
Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein R
1
is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R
2
is the side chain of a natural or non-natural alpha amino acid; Y is a bond, —C(═O), —S(═O)
2
—, —C(═O)O—, —C(O)NR
3
—, —C(═S)—NR
3
, —C(═NH)NR
3
or —S(═O)
2
NR
3
— wherein R
3
is hydrogen or optionally substituted C
1
-C
6
alkyl; L
1
is a divalent radical of formula -(Alk
1
)
m
(Q)
n
(Alk
2
)
p
- wherein m, n and p are independently 0 or 1, Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X
2
-Q
1
- or -Q
1
-X
2
— wherein X
2
is —O—, S— or NR
A
— wherein R
A
is hydrogen or optionally substituted C
1
-C
3
alkyl, and Q
1
is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, Alk
1
and Alk
2
independently represent optionally substituted divalent C
3
-C
7
cycloalkyl radicals, or optionally substituted straight or branched, C
1
-C
6
alkylene, C
2
-C
6
alkenylene, or C
2
-C
6
alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR
A
—) link wherein R
A
is hydrogen or optionally substituted C
1
-C
3
alkyl; X
1
represents a bond; —C(═O); or —S(═O)
2
—; —NR
4
C(═O)—, —C(═O)NR
4
—, —NR
4
C(═O)NR
5
—, —NR
4
S(═O)
2
—, or —S(═O)
2
NR
4
— wherein R
4
and R
5
are independently hydrogen or optionally substituted C
1
-C
6
alkyl; z is 0 or 1; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R
1
R
2
NH—Y-L
1
-X
1
-[CH
2
]
Z
— and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONIIOII, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.
式(I)的化合物是组蛋白
去乙酰化酶活性
抑制剂，可用于治疗癌症等疾病，其中R1是
羧酸基（-COOH）或可由一个或多个细胞内
羧酸酯酶水解为
羧酸基的酯基；R2是天然或非天然α
氨基酸的侧链；Y是键，-C（=O），-S（=O）2-，-C（=O）O-，-C（=O）NR3-，-C（=S）-NR3，-C（=NH）NR3或-S（=O）2NR3-，其中R3是氢或可选取代的C1-C6烷基；L1是式-(Alk1)m(Q)n(Alk2)p-的二价基团，其中m、n和p独立地为0或1，Q是（i）一个可选取代的二价单环或双环碳环或杂环基团，具有5-13个环成员，或（ii）在m和p均为0的情况下，是式-Q1-X2-或-X2-Q1-的二价基团，其中X2是-O-，-S-或-NRA-，其中RA是氢或可选取代的C1-C3烷基，Q1是可选取代的二价单环或双环碳环或杂环基团，具有5-13个环成员，Alk1和Alk2独立地表示可选取代的二价C3-C7环烷基基团，或可选取代的直链或支链，C1-C6烷基，C2-C6烯基或C2-C6炔基基团，其可以可选地含有或终止于醚（-O-），
硫醚（-S-）或
氨基（-NRA-）链，其中RA是氢或可选取代的C1-C3烷基；X1表示键，-C（=O）或-S（=O）2-；-NR4C（=O）-，-C（=O）NR4-，-NR4C（=O）NR5-，-NR4S（=O）2-或-S（=O）2NR4-，其中R4和R5独立地为氢或可选取代的C1-C6烷基；z为0或1；A表示可选取代的单环、双环或
三环碳环或杂环系统，其中基团R1R2NH-Y-L1-X1-[CH2]Z-和HONHCO-[LINKER]-附着在不同的环原子上；-[Linker]-表示将A中的一个环原子与羟酰胺酸基团CONIIOII连接的二价连接基团，连接基团的长度，从连接到A环原子的末端原子到连接到羟酸胺基团的末端原子，相当于从3-10个碳原子的直链饱和碳氢链的长度。
