US2021009519A1PendingUtilityA1
Histone deacetylase inhibitors
Est. expiryJul 2, 2035(~8.9 yrs left)· nominal 20-yr term from priority
A61K 31/44A61P 25/28A61P 31/00C07D 451/04A61P 25/30C07D 207/14C07D 451/06C07D 223/12C07D 211/58C07D 205/04C07D 207/12C07D 223/08A61K 31/55A61K 31/40A61P 25/02C07D 211/46A61K 31/4409A61P 25/00A61P 29/00C07D 451/02C07D 211/54A61P 35/00A61P 43/00A61K 31/46A61P 25/14A61P 21/00
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Claims
Abstract
Provided herein are compounds and methods for inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof
wherein
ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom or a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom;
Z is O, NR 3 , S, SO, or SO 2 ;
R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C(O)C 1-6 alkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or C 0-3 alkylene-C 2-5 cycloheteroalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl);
R 2 is H, F, Cl, or CH 3 ;
R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and
R 4 is H or C 1-3 alkyl.
2 . The compound of claim 1 , wherein ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom or a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom; Z is O, NR 3 , S, or SO 2 ; R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 0-3 alkylene-C 3-7 cycloalkyl; R 2 is H, F, Cl, or CH 3 ; R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and R 4 is H or C 1-3 alkyl.
3 . The compound of claim 1 or 2 , wherein ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one nitrogen ring atom.
4 . The compound of claim 1 or 2 , wherein ring A is a 4-7 membered heterocycloalkyl ring containing one nitrogen ring atom.
5 . The compound of any one of claims 1 to 4 , wherein Z is O or NR 3 .
6 . The compound of any one of claims 1 to 4 , wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C(O)C 1-6 alkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or C 0-3 alkylene-C 2-5 heterocycloalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
7 . The compound of any one of claims 1 to 4 , wherein R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or C 0-3 alkylene-C 2-5 heterocycloalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
8 . The compound of claim 7 , wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or C 0-3 alkylene-C 2-5 heterocycloalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
9 . The compound of claim 7 , wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 0-3 alkylene-C 3-10 cycloalkyl.
10 . The compound of claim 7 , wherein R 1 is H.
11 . The compound of claim 7 , wherein R 1 is a C 1-6 alkyl.
12 . The compound of claim 7 , wherein R 1 is methyl, isopropyl, sec-butyl, or CH 2 C(CH 3 ) 3 .
13 . The compound of claim 7 , wherein R 1 is isopropyl, sec-butyl, or CH 2 C(CH 3 ) 3 .
14 . The compound of claim 7 , wherein R 1 is C 1-6 hydroxyalkyl.
15 . The compound of claim 7 , wherein R 1 is
16 . The compound of claim 7 , wherein R 1 is C 3-10 cycloalkyl or C 1-3 alkylene-C 3-10 cycloalkyl.
17 . The compound of claim 7 , wherein R 1 is C 3-10 cycloalkyl or CH 2 alkylene-C 3-10 cycloalkyl.
18 . The compound of claim 7 , wherein R 1 is C 3-6 cycloalkyl or C 1-3 alkylene-C 3-6 cycloalkyl.
19 . The compound of claim 7 , wherein R 1 is C 3-6 cycloalkyl or CH 2 C 3-6 cycloalkyl.
20 . The compound of claim 7 , wherein R 1 is C 3-6 cycloalkyl.
21 . The compound of claim 7 , wherein R 1 is CH 2 C 3-6 cycloalkyl.
22 . The compound of any one of claims 16 to 22 , wherein the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclohexyl.
23 . The compound of claim 22 , wherein the cycloalkyl group is cyclopropyl.
24 . The compound of claim 7 , wherein R 1 is C 0-3 alkylene-C 10 cycloalkyl.
25 . The compound of claim 24 , wherein R 1 is C 10 cycloalkyl or C 1-3 alkylene-C 10 cycloalkyl.
26 . The compound of claim 25 , wherein R 1 is C 10 cycloalkyl or CH 2 —C 10 cycloalkyl.
27 . The compound of claim 26 , wherein R 1 is adamantanyl or CH 2 -adamantanyl.
28 . The compound of claim 27 , wherein R 1 is CH 2 -adamantanyl.
29 . The compound of claim 7 , wherein R 1 is cyclopropyl, cyclobutyl, cyclohexyl, adamantanyl, CH 2 cyclopropyl, (1-methylcyclopropyl)methyl, CH 2 cyclobutyl, CH 2 cyclohexyl or CH 2 -adamantanyl.
30 . The compound of claim 7 , wherein R 1 is cyclopropyl, cyclobutyl, or cyclohexyl.
31 . The compound of claim 7 , wherein R 1 is cyclopropyl.
32 . The compound of claim 7 , wherein R 1 is CH 2 cyclopropyl, (1-methylcyclopropyl)methyl, CH 2 cyclobutyl, CH 2 cyclohexyl, or CH 2 -adamantanyl.
33 . The compound of claim 7 , wherein R 1 is cyclopropyl, CH 2 cyclopropyl, (1-methylcyclopropyl)methyl, CH 2 cyclohexyl or CH 2 -adamantanyl.
34 . The compound of claim 7 , wherein R 1 is C 0-3 alkylene-C 2-5 heterocycloalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
35 . The compound of claim 7 , wherein R 1 is C 2-5 heterocycloalkyl or C 1-3 alkylene-C 2-5 heterocycloalkyl, with each heterocycloalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
36 . The compound of claim 7 , wherein R 1 is C 2-5 heterocycloalkyl or CH 2 —C 2-5 heterocycloalkyl, with each heterocycloalkyl having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
37 . The compound of any one of claims 34 to 36 , wherein the C 2-5 heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.
38 . The compound of claim 37 , wherein the C 2-5 heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
39 . The compound of claim 37 , wherein the C 2-5 heterocycloalkyl is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
40 . The compound of claim 37 , wherein the C 2-5 heterocycloalkyl is oxetanyl.
41 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II), or a pharmaceutically acceptable salt thereof
wherein
ring A is selected from the group consisting of:
Z is O, NR 3 , S, SO, or SO 2 ;
R 1 is selected from the group consisting of
R 2 is H, F, Cl, or CH 3 ;
R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and
R 4 is H or C 1-3 alkyl.
42 . The compound of claim 41 , wherein Z is O, NR 3 , S, or SO 2 ; and R 1 is selected from the group consisting of H, CH 3 , C(O)CH 3 ,
43 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IIa), or a pharmaceutically acceptable salt thereof:
wherein ring A is selected from the group consisting of
Z is O, NR 3 , S, SO, or SO 2 ; R 1 is selected from the group consisting of H, CH 3 , C(O)CH 3 ,
and R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl.
44 . The compound of any one of claims 1 to 43 , wherein Z is S, SO, or SO 2 .
45 . The compound of claim 44 , wherein Z is S.
46 . The compound of claim 44 , wherein Z is SO.
47 . The compound of claim 44 , wherein Z is SO 2 .
48 . The compound of any one of claims 1 to 43 , wherein Z is O or NR 3 .
49 . The compound of claim 48 , wherein Z is O.
50 . The compound of claim 48 , wherein Z is NR 3 .
51 . The compound of claim 48 or 50 , wherein R 3 is H, C 1-6 alkyl, or C 0-3 alkylene-C 3-7 cycloalkyl.
52 . The compound of claim 51 , wherein R 3 is H, C 1-6 alkyl, or C 3-7 cycloalkyl.
53 . The compound of claim 51 , wherein R 3 is H, C 1-6 alkyl, or C 1-3 alkylene-C 3-7 cycloalkyl.
54 . The compound of claim 51 , wherein R 3 is H, C 1-6 alkyl, or C 3-6 cycloalkyl.
55 . The compound of claim 51 , wherein R 3 is H, C 1-6 alkyl, or C 1-3 alkylene-C 3-6 cycloalkyl.
56 . The compound of claim 51 , wherein R 3 is H.
57 . The compound of claim 51 , wherein R 3 is C 1-6 alkyl.
58 . The compound of claim 51 , wherein R 3 is methyl, ethyl, or propyl.
59 . The compound of claim 51 , wherein R 3 is methyl or ethyl.
60 . The compound of claim 51 , wherein R 3 is methyl.
61 . The compound of claim 51 , wherein R 3 is C 3-7 cycloalkyl or C 1-3 alkylene-C 3-7 cycloalkyl.
62 . The compound of claim 51 , wherein R 3 is C 3-6 cycloalkyl or CH 2 C 3-6 cycloalkyl.
63 . The compound of claim 61 or 62 , wherein the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclohexyl.
64 . The compound of claim 63 , wherein the cycloalkyl group is cyclopropyl.
65 . The compound of claim 51 , wherein R 3 is H, methyl, ethyl, or CH 2 cyclopropyl.
66 . The compound of claim 51 , wherein R 3 is H, methyl, or CH 2 cyclopropyl.
67 . The compound of claim 48 or 50 , wherein R 3 is C(O)C 1-6 alkyl.
68 . The compound of claim 67 , wherein R 3 is C(O)methyl, C(O)ethyl, or C(O)propyl.
69 . The compound of claim 48 or 50 , wherein R 3 is C(O)C 0-3 alkylene-C 3-7 cycloalkyl.
70 . The compound of claim 69 , wherein R 3 is C(O)CH 2 —C 3-7 cycloalkyl or C(O)C 3-7 cycloalkyl.
71 . The compound of claim 69 or 70 , wherein the C 3-7 cycloalkyl is cyclopropyl.
72 . The compound of any one of claims 1 to 71 , wherein ring A is selected from the group consisting of
73 . The compound of claim 72 , wherein ring A is
74 . The compound of claim 72 , wherein ring A is
75 . The compound of any one of claims 1 to 71 , wherein ring A is
76 . The compound of claim 72 , wherein ring A is
77 . The compound of claim 72 , wherein ring A is
78 . The compound of claim 72 , wherein ring A is
79 . The compound of claim 72 , wherein ring A is
80 . The compound of claim 72 , wherein ring A is
81 . The compound of claim 72 , wherein ring A is
82 . The compound of claim 72 , wherein ring A is
83 . The compound of claim 75 , wherein ring A is
84 . The compound of any one of claims 1 to 83 , wherein R 2 is H.
85 . The compound of any one of claims 1 to 83 , wherein R 2 is F.
86 . The compound of any one of claims 1 to 83 , wherein R 2 is Cl.
87 . The compound of any one of claims 1 to 83 , wherein R 2 is CH 3 .
88 . The compound of any one of claims 1 to 87 , wherein R 4 is H.
89 . The compound of any one of claims 1 to 87 , wherein R 4 is C 1-3 alkyl.
90 . The compound of claim 89 , wherein R 4 is methyl.
91 . The compound of any one of claims 1 to 90 , wherein R 1 is selected from the group consisting of
92 . The compound of claim 1 , wherein ring A is selected from the group consisting of
Z is O or NR 3 ; and R 1 is selected from the group consisting of
93 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III), or a pharmaceutically acceptable salt thereof
wherein Z is O, NR 3 , S, SO, or SO 2 ; R 1 is selected from the group consisting of
R 2 is H, F, Cl, or CH 3 ; R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and R 4 is H or C 1-3 alkyl.
94 . The compound of claim 93 , wherein Z is O, NR 3 , S, or SO 2 ; and R 1 is selected from the group consisting of
95 . A compound having a structure selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
96 . A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
97 . A pharmaceutical composition comprising the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
98 . A method of selectively inhibiting HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 .
99 . A method of selectively inhibiting HDAC1 or HDAC2 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 .
100 . A method of selectively inhibiting HDAC1, HDAC2, and HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 .
101 . A method of treating a disease or disorder mediated by HDAC1 or HDAC2 in a subject in need thereof, the method comprising administering an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 , to the subject.
102 . A method of treating a disease or disorder mediated by HDAC3 in a subject in need thereof, the method comprising administering an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 , to the subject.
103 . A method of treating a disease or disorder mediated by HDAC1, HDAC2, and HDAC3 in a subject in need thereof, the method comprising administering an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 , to the subject.
104 . A method of treating a neurological disorder such as Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular atrophy, and Alzheimer's disease; a cancer; an inflammatory disease; a memory impairment condition, frontotemporal dementia, or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 .
105 . A method of treating Friedreich's ataxia in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 .
106 . A method of treating an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 96 , or pharmaceutically acceptable salt thereof, or the composition of claim 97 .
107 . The method of any one of claims 98 to 106 , wherein the compound is a compound as claimed in claim 95 or 96 , or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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