Novel molecules that selectively inhibit histone deacetylase 6 relative to histone deacetylase
Abstract
This invention provides a compound having the structure: wherein R 1 is H, halogen, —NR 5 R 6 , —NR 5 —C(═0)-R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl; wherein X is Cl, Br, or F; R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Q is —Ar 1 —Z— or —Z—Ar 1 —Z—, wherein Ar 1 is aryl or heteroaryl; and each occurrence of Z is independently present or absent, and when present is —O—, —S—, —CH 2 —, —C(O)—, —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH—, —NHC(═O)CH 2 C(═O)—, —N(OH)—, —CH 2 CH 2 — or —NHC(═O)CH═CH—; and R 4 is alkyl, —OR 11 or —NH—OR 11 , wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and when Q is —Ar 1 —Z—, Z is absent, Ar 1 is phenyl, R 2 and R 3 are H, n=1, and R 4 is —NHOH, then R 1 is other than carbazole, tetrahydro-β-carboline, tetrahydro-γ-carboline, —C(═O)—NR 5 R 6 and —NR 5 —C(═0)-R 6 , wherein one of R 5 or R 6 is quinline and the other of R 5 or R 6 is H; or a pharmaceutically acceptable salt thereof.
Claims
exact text as granted — not AI-modified1 - 35 . (canceled)
36 . A compound having the structure:
wherein
R 1 is —NR 5 —C(═0)-R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is
R 6 is
wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O) NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Q is —Ar 1 —Z— or —Z—Ar 1 —Z—,
wherein Ar 1 is
wherein X is a Cl, Br, or F; and
each occurrence of Z is present or absent, and when present is —O—, —S—, —CH 2 —, —C(O)—, —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH—, —NHC(═O)CH 2 C(═O)—, —N(OH)—, —CH 2 CH 2 — or —NHC(═O)CH═CH—; and
R 4 is —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl,
or a pharmaceutically acceptable salt thereof.
37 . The compound of claim 36 having the structure:
wherein
R 1 is —NR 5 —C(═0)-R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is
R 6 is
wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Q is —Ar 1 —Z— or —Z—Ar 1 —Z—,
wherein Ar 1 is
wherein X is a Cl, Br, or F; and
each occurrence of Z is present or absent, and when present is —O—, —S—, —CH 2 —, —C(O)—, —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH—, —NHC(═O)CH 2 C(═O)—, —N(OH)—, —CH 2 CH 2 — or —NHC(═O)CH═CH—; and
R 4 is —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and
wherein at least one Z is present,
or a pharmaceutically acceptable salt thereof.
38 . The compound of claim 37 having the structure:
wherein
R 1 is —NR 5 —C(═0)-R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is
R 6 is
wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ar 1 is
wherein X is a Cl, Br, or F;
Z is —O—, —S—, —CH 2 —, —C(O)—, —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH— or —NHC(═O)CH═CH—; and
R 4 is —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl,
or a pharmaceutically acceptable salt thereof.
39 . The compound of claim 37 ,
wherein m=1; R 2 is H or CH 3 ; and R 3 is H, CH 3 , Cl, Br, F, or CF 3 ,
or a pharmaceutically acceptable salt thereof.
40 . The compound of claim 37 ,
wherein R 4 is —NH—OR 11 ,
wherein R 11 is H or CH 3 ,
or a pharmaceutically acceptable salt thereof.
41 . The compound of claim 37 ,
wherein R 5 is
and
R 6 is
or a pharmaceutically acceptable salt thereof.
42 . The compound of claim 37 having the structure:
or a pharmaceutically acceptable salt thereof.
43 . A pharmaceutical composition comprising the compound of claim 37 and a pharmaceutically acceptable carrier.
44 . A method of inhibiting the activity of a histone deactylase in a cell, the method comprising contacting the histone deacetylase with the compound of claim 37 so as to inhibit the activity of the histone deacetylase; or of increasing accumulation of acetylated alpha tubulin in a cell, the method comprising contacting the cell with the compound of claim 37 so as to increase the accumulation of acetylated alpha-tubulin in the cell.
45 . The compound of claim 36 having the structure:
wherein
R 1 is —NR 5 —C(═0)-R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is
R 6 is
wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Q is —Ar 1 —Z— or —Z—Ar 1 —Z—,
wherein Ar 1 is
wherein X is a Cl, Br, or F; and
each occurrence of Z absent; and
R 4 is —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl,
or a pharmaceutically acceptable salt thereof.
46 . The compound of claim 45 having the structure:
wherein
R 1 is —NR 5 —C(═0)-R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is
R 6 is
wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ar 1 is
wherein X is a Cl, Br, or F;
Z absent; and
R 4 is —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl,
or a pharmaceutically acceptable salt thereof.
47 . The compound of claim 45 ,
wherein m=1; R 2 is H or CH 3 ; and R 3 is H, CH 3 , Cl, Br, F, or CF 3 ,
or a pharmaceutically acceptable salt thereof.
48 . The compound of claim 45 ,
wherein R 4 is —NH—OR 11 ,
wherein R 11 is H or CH 3 ,
or a pharmaceutically acceptable salt thereof.
49 . The compound of claim 45 ,
wherein R 5 is
and
R 6 is
or a pharmaceutically acceptable salt thereof.
50 . A pharmaceutical composition comprising the compound of claim 45 and a pharmaceutically acceptable carrier.
51 . A method of inhibiting the activity of a histone deactylase in a cell, the method comprising contacting the histone deacetylase with the compound of claim 45 so as to inhibit the activity of the histone deacetylase; or of increasing accumulation of acetylated alpha tubulin in a cell, the method comprising contacting the cell with the compound of claim 45 so as to increase the accumulation of acetylated alpha-tubulin in the cell.
52 . A compound having the structure:
or a pharmaceutically acceptable salt thereof.
53 . A pharmaceutical composition comprising the compound of claim 52 and a pharmaceutically acceptable carrier.
54 . A method of inhibiting the activity of a histone deactylase in a cell, the method comprising contacting the histone deacetylase with the compound of claim 52 so as to inhibit the activity of the histone deacetylase; or of increasing accumulation of acetylated alpha tubulin in a cell, the method comprising contacting the cell with the compound of claim 52 so as to increase the accumulation of acetylated alpha-tubulin in the cell.Cited by (0)
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