U.S. patent application number 17/397752 was filed with the patent office on 2022-03-03 for activators of class i histone deacetylases (hdacs) and uses thereof.
This patent application is currently assigned to Massachusetts Institute of Technology. The applicant listed for this patent is The General Hospital Corporation d/b/a Massachusetts General Hospital, The General Hospital Corporation d/b/a Massachusetts General Hospital, Massachusetts Institute of Technology. Invention is credited to Stephen J. Haggarty, Ling Pan, Debasis Patnaik, Li-Huei Tsai.
Application Number | 20220064151 17/397752 |
Document ID | / |
Family ID | 1000005898835 |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220064151 |
Kind Code |
A1 |
Tsai; Li-Huei ; et
al. |
March 3, 2022 |
ACTIVATORS OF CLASS I HISTONE DEACETYLASES (HDACS) AND USES
THEREOF
Abstract
The present invention provides compounds of Formulae (A), (B),
(C), and (D), pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof,
pharmaceutical compositions thereof, and kits thereof. The present
invention further provides methods of using the compounds to treat
or prevent neurological disorders, including Alzheimer's disease,
Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral
sclerosis), traumatic brain injury, ischemic brain injury, stroke,
frontal temporal dementia, Pick's disease, corticobasal
degeneration, supra cerebral palsy, prion diseases (e.g.,
Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome,
Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal
cerebellar ataxia, spinal muscular dystrophy, ataxia
telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner
syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one
aspect, the methods include administering to a subject in need of
treatment for a neurological disorder a therapeutically effective
amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a
compound of Formula (A), (B), (C), or (D). ##STR00001##
Inventors: |
Tsai; Li-Huei; (Cambridge,
MA) ; Pan; Ling; (Charlestown, MA) ; Haggarty;
Stephen J.; (Gloucester, MA) ; Patnaik; Debasis;
(Weymouth, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Massachusetts Institute of Technology
The General Hospital Corporation d/b/a Massachusetts General
Hospital |
Cambridge
Boston |
MA
MA |
US
US |
|
|
Assignee: |
Massachusetts Institute of
Technology
Cambridge
MA
The General Hospital Corporation d/b/a Massachusetts General
Hospital
Boston
MA
|
Family ID: |
1000005898835 |
Appl. No.: |
17/397752 |
Filed: |
August 9, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16231324 |
Dec 21, 2018 |
11084803 |
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17397752 |
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14834587 |
Aug 25, 2015 |
10167277 |
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16231324 |
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13554670 |
Jul 20, 2012 |
9115053 |
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14834587 |
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61510885 |
Jul 22, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 219/28 20130101;
C07D 487/04 20130101; C07D 307/40 20130101; C07D 405/12 20130101;
C07D 409/12 20130101; C07D 411/12 20130101; C07C 217/58 20130101;
C07D 307/52 20130101 |
International
Class: |
C07D 405/12 20060101
C07D405/12; C07D 307/52 20060101 C07D307/52; C07D 411/12 20060101
C07D411/12; C07D 307/40 20060101 C07D307/40; C07C 217/58 20060101
C07C217/58; C07D 487/04 20060101 C07D487/04; C07C 219/28 20060101
C07C219/28; C07D 409/12 20060101 C07D409/12 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] This invention was made with Government support under Grant
No. AG035711 awarded by the National Institutes of Health. The
Government has certain rights in the invention.
Claims
1. A compound of Formula (A): ##STR00060## or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof,
wherein each instance of X.sup.A1, X.sup.A2, and X.sup.A3 is
independently oxygen or sulfur; each instance of R.sup.A1 and
R.sup.A2 is independently hydrogen, a nitrogen protecting group, or
C.sub.1-6 alkyl; Ar is optionally substituted aryl or optionally
substituted heteroaryl; each instance of R.sup.A3 and R.sup.A4 is
independently selected from the group consisting of halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.A3a,
--N(R.sup.A3b).sub.2, --SR.sup.A3a, --C(.dbd.O)R.sup.A3a,
--C(.dbd.O)OR.sup.A3a, --C(.dbd.O)SR.sup.A3a,
--C(.dbd.O)N(R.sup.A3b).sub.2, --OC(.dbd.O)R.sup.A3a,
--OC(.dbd.O)OR.sup.A3a, --OC(.dbd.O)SR.sup.A3a,
--OC(.dbd.O)N(R.sup.A3b).sub.2, --NR.sup.A3bC(.dbd.O)R.sup.A3b,
--NR.sup.A3bC(.dbd.O)OR.sup.A3a, --NR.sup.A3bC(.dbd.O)SR.sup.A3a,
--NR.sup.A3bC(.dbd.O)N(R.sup.A3b).sub.2, --SC(.dbd.O)R.sup.A3a,
--SC(.dbd.O)OR.sup.A3a, --SC(.dbd.O)SR.sup.A3a,
--SC(.dbd.O)N(R.sup.A3b).sub.2, --C(.dbd.NR.sup.A3b)R.sup.A3a,
--C(.dbd.NR.sup.A3b)OR.sup.A3a, --C(.dbd.NR.sup.A3b)SR.sup.A3a,
--C(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--OC(.dbd.NR.sup.A3b)R.sup.A3a, --OC(.dbd.NR.sup.A3b)OR.sup.A3a,
--OC(.dbd.NR.sup.A3b)SR.sup.A3a,
--OC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--NR.sup.A3bC(.dbd.NR.sup.A3b)R.sup.A3b,
--NR.sup.A3bC(.dbd.NR.sup.A3b)OR.sup.A3a,
--NR.sup.A3bC(.dbd.NR.sup.A3b)SR.sup.A3a,
--NR.sup.A3bC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--SC(.dbd.NR.sup.A3b)R.sup.A3a, --SC(.dbd.NR.sup.A3b)OR.sup.A3a,
--SC(.dbd.NR.sup.A3b)SR.sup.A3a,
--SC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2, --C(.dbd.S)R.sup.A3a,
--C(.dbd.S)OR.sup.A3a, --C(.dbd.S)SR.sup.A3a,
--C(.dbd.S)N(R.sup.A3b).sub.2, --OC(.dbd.S)R.sup.A3a,
--OC(.dbd.S)OR.sup.A3a, --OC(.dbd.S)SR.sup.A3a,
--OC(.dbd.S)N(R.sup.A3b).sub.2, --NR.sup.A3bC(.dbd.S)R.sup.A3b,
--NR.sup.A3bC(.dbd.S)OR.sup.A3a, --NR.sup.A3bC(.dbd.S)SR.sup.A3a,
--NR.sup.A3bC(.dbd.S)N(R.sup.A3b).sub.2, --SC(.dbd.S)R.sup.A3a,
--SC(.dbd.S)OR.sup.A3a, --SC(.dbd.S)SR.sup.A3a,
--SC(.dbd.S)N(R.sup.A3b).sub.2, --S(.dbd.O)R.sup.A3a,
--SO.sub.2R.sup.A3a, --NR.sup.A3bSO.sub.2R.sup.A3a,
--SO.sub.2N(R.sup.A3b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.A3a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.A3b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.A3b groups are joined to
form an optionally substituted heterocyclic ring; m is 0, 1, 2, 3,
or 4; and n is 0, 1, 2, or 3.
2. The compound of claim 1, wherein the compound of Formula (A) is
not of the formula: ##STR00061##
3. The compound of claim 1, wherein X.sup.A1 is oxygen; and
X.sup.A2 is sulfur.
4. The compound of claim 1, wherein X.sup.A3 is oxygen.
5. The compound of claim 1, wherein R.sup.A1 and R.sup.A2 are
hydrogen.
6. The compound of claim 1, wherein X.sup.A1 and X.sup.A3 are
oxygen; X.sup.A2 is sulfur; and R.sup.A1 and R.sup.A2 are
hydrogen.
7. The compound of claim 1, wherein Ar is optionally substituted
aryl.
8. The compound of claim 7, wherein the compound is of formula:
##STR00062## and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, wherein
each instance of R.sup.AI is independently selected from the group
consisting of halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.AIa, --N(R.sup.AIb).sub.2, --SR.sup.AIa,
--C(.dbd.O)R.sup.AIa, --C(.dbd.O)OR.sup.AIa, --C(.dbd.O)SR.sup.AIa,
--C(.dbd.O)N(R.sup.AIb).sub.2, --OC(.dbd.O)R.sup.AIa,
--OC(.dbd.O)OR.sup.AIa, --OC(.dbd.O)SR.sup.AIa,
--OC(.dbd.O)N(R.sup.AIb).sub.2, --NR.sup.AIbC(.dbd.O)R.sup.AIb,
--NR.sup.AIbC(.dbd.O)OR.sup.AIa, --NR.sup.AIbC(.dbd.O)SR.sup.AIa,
--NR.sup.AIbC(.dbd.O)N(R.sup.AIb).sub.2, --SC(.dbd.O)R.sup.AIa,
--SC(.dbd.O)OR.sup.AIa, --SC(.dbd.O)SR.sup.AIa,
--SC(.dbd.O)N(R.sup.AIb).sub.2, --C(.dbd.NR.sup.AIb)R.sup.AIa,
--C(.dbd.NR.sup.AIb)OR.sup.AIa, --C(.dbd.NR.sup.AIb)SR.sup.AIa,
--C(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2,
--OC(.dbd.NR.sup.AIb)R.sup.AIa, --OC(.dbd.NR.sup.AIb)OR.sup.AIa,
--OC(.dbd.NR.sup.AIb)SR.sup.AIa,
--OC(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2,
--NR.sup.AIbC(.dbd.NR.sup.AIb)R.sup.AIb,
--NR.sup.AIbC(.dbd.NR.sup.AIb)OR.sup.AIa,
--NR.sup.AIbC(.dbd.NR.sup.AIb)SR.sup.AIa,
--NR.sup.AIbC(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2,
--SC(.dbd.NR.sup.AIb)R.sup.AIa, --SC(.dbd.NR.sup.AIb)OR.sup.AIa,
--SC(.dbd.NR.sup.AIb)SR.sup.AIa,
--SC(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2, --C(.dbd.S)R.sup.AIa,
--C(.dbd.S)OR.sup.AIa, --C(.dbd.S)SR.sup.AIa,
--C(.dbd.S)N(R.sup.AIb).sub.2, --OC(.dbd.S)R.sup.AIa,
--OC(.dbd.S)OR.sup.AIa, --OC(.dbd.S)SR.sup.AIa,
--OC(.dbd.S)N(R.sup.AIb).sub.2, --NR.sup.AIbC(.dbd.S)R.sup.AIb,
--NR.sup.AIbC(.dbd.S)OR.sup.AIa, --NR.sup.AIbC(.dbd.S)SR.sup.AIa,
--NR.sup.AIbC(.dbd.S)N(R.sup.AIb).sub.2, --SC(.dbd.S)R.sup.AIa,
--SC(.dbd.S)OR.sup.AIa, --SC(.dbd.S)SR.sup.AIa,
--SC(.dbd.S)N(R.sup.AIb).sub.2, --S(.dbd.O)R.sup.AIa,
--SO.sub.2R.sup.AIa, --NR.sup.AIbSO.sub.2R.sup.AIa,
--SO.sub.2N(R.sup.AIb).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.Ala is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, or each occurrence of R.sup.AIb is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.AIb groups are joined to
form a heterocyclic ring; and j is 0, 1, 2, 3, 4, or 5.
9. The compound of claim 8, wherein the compound is of formula:
##STR00063##
10. The compound of claim 9, wherein the compound is of formula:
##STR00064##
11. The compound of claim 1, wherein Ar is optionally substituted
heteroaryl.
12. The compound of claim 11, wherein the compound is of formula:
##STR00065## and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, wherein
each instance of R.sup.AII is independently selected from the group
consisting of halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.AIIa, --N(R.sup.AIIb).sub.2, --SR.sup.AIIa,
--C(.dbd.O)R.sup.AIIa, --C(.dbd.O)OR.sup.AIIa,
--C(.dbd.O)SR.sup.AIIa, --C(.dbd.O)N(R.sup.AIIb).sub.2,
--OC(.dbd.O)R.sup.AIIa, --OC(.dbd.O)OR.sup.AIIa,
--OC(.dbd.O)SR.sup.AIIa, --OC(.dbd.O)N(R.sup.AIIb).sub.2,
--NR.sup.AIIbC(.dbd.O)R.sup.AIIb,
--NR.sup.AIIbC(.dbd.O)OR.sup.AIIa,
--NR.sup.AIIbC(.dbd.O)SR.sup.AIIa,
--NR.sup.AIbC(.dbd.O)N(R.sup.AIIb).sub.2, --SC(.dbd.O)R.sup.AIIa,
--SC(.dbd.O)OR.sup.AIIa, --SC(.dbd.O)SR.sup.AIa,
--SC(.dbd.O)N(R.sup.AIIb).sub.2, --C(.dbd.NR.sup.AIIb)R.sup.AIIa,
--C(.dbd.NR.sup.AIIb)OR.sup.AIIa, --C(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--C(.dbd.NR.sup.AIIb)N(R.sup.AIIb).sub.2,
--OC(.dbd.NR.sup.AIIb)R.sup.AIIa,
--OC(.dbd.NR.sup.AIIb)OR.sup.AIIa,
--OC(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--OC(.dbd.NR.sup.AIIb)N(R.sup.AIIb).sub.2,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)R.sup.AIIb,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)OR.sup.AIIa,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)N(R.sup.AIIb).sub.2,
--SC(.dbd.NR.sup.AIIb)R.sup.AIIa,
--SC(.dbd.NR.sup.AIIb)OR.sup.AIIa,
--SC(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--SC(.dbd.NR.sup.AIIb)N(R.sup.AIIb).sub.2, --C(.dbd.S)R.sup.AIIa,
--C(.dbd.S)OR.sup.AIIa, --C(.dbd.S)SR.sup.AIIa,
--C(.dbd.S)N(R.sup.AIIb).sub.2, --OC(.dbd.S)R.sup.AIIa,
--OC(.dbd.S)OR.sup.AIIa, --OC(.dbd.S)SR.sup.AIa,
--OC(.dbd.S)N(R.sup.AIIb).sub.2, --NR.sup.AIIbC(.dbd.S)R.sup.AIIb,
--NR.sup.AIIbC(.dbd.S)OR.sup.AIIa,
--NR.sup.AIIbC(.dbd.S)SR.sup.AIIa,
--NR.sup.AIIbC(.dbd.S)N(R.sup.AIIb).sub.2, --SC(.dbd.S)R.sup.AIIa,
--SC(.dbd.S)OR.sup.AIIa, --SC(.dbd.S)SR.sup.AIa,
--SC(.dbd.S)N(R.sup.AIIb).sub.2, --S(.dbd.O)R.sup.AIIa,
--SO.sub.2R.sup.AIIa, --NR.sup.AIIbSO.sub.2R.sup.AIIa,
--SO.sub.2N(R.sup.AIIb).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.AIIa is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, and each occurrence of R.sup.AIIb is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.AIIb groups are joined to
form a heterocyclic ring; and k is 0, 1, 2, or 3.
13. The compound of claim 12, wherein the compound is of formula:
##STR00066##
14-46. (canceled)
47. A compound of Formula (D): ##STR00067## or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof,
wherein each instance of X.sup.D1 is independently oxygen, sulfur,
--NR.sup.D1a, or C(R.sup.D1b).sub.2, wherein R.sup.D1a is hydrogen
or C.sub.1-6 alkyl, and each occurrence of R.sup.D1b is hydrogen,
halogen, or C.sub.1-6 alkyl, or two R.sup.D1b groups are joined to
form an optionally substituted carbocyclic or heterocyclic ring; s
is 0, 1, 2, 3, 4, 5, or 6; each instance of R.sup.D1 and R.sup.D2
is independently hydrogen, an oxygen protecting group, C.sub.1-6
alkyl, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2b).sub.2,
--S(.dbd.O)R.sup.D2a, or --S(.dbd.O).sub.2R.sup.D2a wherein each
occurrence of R.sup.D2a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.D2b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.D2b groups are joined to
form an optionally substituted heterocyclic ring; each instance of
R.sup.D3 and R.sup.D4 is independently selected from the group
consisting of halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.D4a, --N(R.sup.D4b).sub.2, --SR.sup.D4a,
--C(.dbd.O)R.sup.D4a, --C(.dbd.O)OR.sup.D4a, --C(.dbd.O)SR.sup.D4a,
--C(.dbd.O)N(R.sup.D4b).sub.2, --OC(.dbd.O)R.sup.D4a,
--OC(.dbd.O)OR.sup.D4a, --OC(.dbd.O)SR.sup.D4a,
--OC(.dbd.O)N(R.sup.D4b).sub.2, --NR.sup.D4bC(.dbd.O)R.sup.D4b,
--NR.sup.D4bC(.dbd.O)OR.sup.D4a, --NR.sup.D4bC(.dbd.O)SR.sup.D4a,
--NR.sup.D4bC(.dbd.O)N(R.sup.D4b).sub.2, --SC(.dbd.O)R.sup.D4a,
--SC(.dbd.O)OR.sup.D4a, --SC(.dbd.O)SR.sup.D4a,
--SC(.dbd.O)N(R.sup.D4b).sub.2, --C(.dbd.NR.sup.D4b)R.sup.D4a,
--C(.dbd.NR.sup.D4b)OR.sup.D4a, --C(.dbd.NR.sup.D4b)SR.sup.D4a,
--C(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--OC(.dbd.NR.sup.D4b)R.sup.D4a, --OC(.dbd.NR.sup.D4b)OR.sup.D4a,
--OC(.dbd.NR.sup.D4b)SR.sup.D4a,
--OC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--NR.sup.D4bC(.dbd.NR.sup.D4b)R.sup.D4b,
--NR.sup.D4bC(.dbd.NR.sup.D4b)OR.sup.D4a,
--NR.sup.D4bC(.dbd.NR.sup.D4b)SR.sup.D4a,
--NR.sup.D4bC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--SC(.dbd.NR.sup.D4b)R.sup.D4aa, --SC(.dbd.NR.sup.D4b)OR.sup.D4a,
--SC(.dbd.NR.sup.D4b)SR.sup.D4a,
--SC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2, --C(.dbd.S)R.sup.D4a,
--C(.dbd.S)OR.sup.D4a, --C(.dbd.S)SR.sup.D4a,
--C(.dbd.S)N(R.sup.D4b).sub.2, --OC(.dbd.S)R.sup.D4a,
--OC(.dbd.S)OR.sup.D4a, --OC(.dbd.S)SR.sup.D4a,
--OC(.dbd.S)N(R.sup.D4b).sub.2, --NR.sup.D4bC(.dbd.S)R.sup.D4b,
--NR.sup.D4bC(.dbd.S)OR.sup.D4a, --NR.sup.D4bC(.dbd.S)SR.sup.D4a,
--NR.sup.D4bC(.dbd.S)N(R.sup.D4b).sub.2, --SC(.dbd.S)R.sup.D4a,
--SC(.dbd.S)OR.sup.D4a, --SC(.dbd.S)SR.sup.D4a,
--SC(.dbd.S)N(R.sup.D4b).sub.2, --S(.dbd.O)R.sup.D4a,
--SO.sub.2R.sup.D4a, --NR.sup.D4bSO.sub.2R.sup.D4a,
--SO.sub.2N(R.sup.D4b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.D4a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.D4b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.D4b groups are joined to
form an optionally substituted heterocyclic ring; t is 0, 1, 2, or
3; and u is 0, 1, 2, 3, 4 or 5.
48-57. (canceled)
58. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, and optionally a pharmaceutically
acceptable excipient.
59. (canceled)
60. A method for treating a neurological disorder in a subject in
need thereof, the method comprising administering to the subject a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
61-121. (canceled)
122. A method for treating a neurological disorder in a subject in
need thereof, the method comprising administering to the subject a
therapeutically effective amount of a compound of Formula (B):
##STR00068## or a pharmaceutically acceptable salt, solvate,
hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, or prodrug thereof, wherein each
instance of X.sup.B1, X.sup.B3, and X.sup.B4 is independently
oxygen, sulfur, --NR.sup.B4a, or C(R.sup.B4b).sub.2, wherein
R.sup.B4a is hydrogen, a nitrogen protecting group, or C.sub.1-6
alkyl, and each occurrence of R.sup.B4b is hydrogen, halogen, or
C.sub.1-6 alkyl, or two R.sup.B4b groups are joined to form an
optionally substituted carbocyclic or heterocyclic ring; X.sup.B2
is nitrogen or CR.sup.B2a, wherein R.sup.B2a is hydrogen, halogen,
or C.sub.1-6 alkyl; each instance of R.sup.B1 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.B1a, --N(R.sup.B1b).sub.2,
--SR.sup.B1a, --C(.dbd.O)R.sup.B1a, --C(.dbd.O)OR.sup.B1a,
--C(.dbd.O)SR.sup.B1a, --C(.dbd.O)N(R.sup.B1b).sub.2,
--OC(.dbd.O)R.sup.B1a, --OC(.dbd.O)OR.sup.B1a,
--OC(.dbd.O)SR.sup.B1a, --OC(.dbd.O)N(R.sup.B1b).sub.2,
--NR.sup.B1bC(.dbd.O)R.sup.B1b, --NR.sup.B1bC(.dbd.O)OR.sup.B1a,
--NR.sup.B1bC(.dbd.O)SR.sup.B1a,
--NR.sup.B1bC(.dbd.O)N(R.sup.B1b).sub.2, --SC(.dbd.O)R.sup.B1a,
--SC(.dbd.O)OR.sup.B1a, --SC(.dbd.O)SR.sup.B1a,
--SC(.dbd.O)N(R.sup.B1b).sub.2, --C(.dbd.NR.sup.B1b)R.sup.B1a,
--C(.dbd.NR.sup.B1b)OR.sup.B1a, --C(.dbd.NR.sup.B1b)SR.sup.B1a,
--C(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--OC(.dbd.NR.sup.B1b)R.sup.B1a, --OC(.dbd.NR.sup.B1b)OR.sup.B1a,
--OC(.dbd.NR.sup.B1b)SR.sup.B1a,
--OC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--NR.sup.B1bC(.dbd.NR.sup.B1b)R.sup.B1b,
--NR.sup.B1bC(.dbd.NR.sup.B1b)OR.sup.B1a,
--NR.sup.B1bC(.dbd.NR.sup.B1b)SR.sup.B1a,
--NR.sup.B1bC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--SC(.dbd.NR.sup.B1b)R.sup.B1a, --SC(.dbd.NR.sup.B1b)OR.sup.B1a,
--SC(.dbd.NR.sup.B1b)SR.sup.B1a,
--SC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2, --C(.dbd.S)R.sup.B1a,
--C(.dbd.S)OR.sup.B1a, --C(.dbd.S)SR.sup.B1a,
--C(.dbd.S)N(R.sup.B1b).sub.2, --OC(.dbd.S)R.sup.B1a,
--OC(.dbd.S)OR.sup.B1a, --OC(.dbd.S)SR.sup.B1a,
--OC(.dbd.S)N(R.sup.B1b).sub.2, --NR.sup.B1bC(.dbd.S)R.sup.B1b,
--NR.sup.B1bC(.dbd.S)OR.sup.B1a, --NR.sup.B1bC(.dbd.S)SR.sup.B1a,
--NR.sup.B1bC(.dbd.S)N(R.sup.B1b).sub.2, --SC(.dbd.S)R.sup.B1a,
--SC(.dbd.S)OR.sup.B1a, --SC(.dbd.S)SR.sup.B1a,
--SC(.dbd.S)N(R.sup.B1b).sub.2, --S(.dbd.O)R.sup.B1a,
--SO.sub.2R.sup.B1a, --NR.sup.B1bSO.sub.2R.sup.B1a,
--SO.sub.2N(R.sup.B1b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.B1a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.B1b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.B1b groups are joined to
form an optionally substituted heterocyclic ring; each instance of
R.sup.B2, R.sup.B3, R.sup.B4, and R.sup.B5 is independently
hydrogen, halogen, or C.sub.1-6 alkyl; R.sup.B6 is hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.B6a,
--N(R.sup.B6b).sub.2, or --SR.sup.B6a, wherein each occurrence of
R.sup.B6a is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, and each occurrence of R.sup.B6b is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.B6b groups are joined to
form an optionally substituted heterocyclic ring; and p is 0, 1, 2,
3, or 4.
123. A pharmaceutical composition comprising a compound of claim
47, or a pharmaceutically acceptable salt, solvate, hydrate,
polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, and optionally a pharmaceutically
acceptable excipient.
124. A method for treating a neurological disorder in a subject in
need thereof, the method comprising administering to the subject a
therapeutically effective amount of a compound of claim 47, or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
Description
RELATED APPLICATIONS
[0001] The present application is a division of and claims priority
under 35 U.S.C. .sctn. 120 to U.S. patent application U.S. Ser. No.
16/231,324, filed Dec. 21, 2018, which is a division of and claims
priority under 35 U.S.C. .sctn. 120 to U.S. patent application U.S.
Ser. No. 14/834,587, filed Aug. 25, 2015, which is a division of
and claims priority under 35 U.S.C. .sctn. 120 to U.S. patent
application U.S. Ser. No. 13/554,670, filed Jul. 20, 2012, which
claims priority under 35 U.S.C. .sctn. 119(e) to U.S. provisional
application, U.S. Ser. No. 61/510,885, filed Jul. 22, 2011, each of
which is incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The field of the invention pertains to activators of class I
histone deacetylases and their uses in the treatment of
neurological disorders.
BACKGROUND OF THE INVENTION
[0004] In a variety of neurodegenerative disorders such as ischemia
and Alzheimer's disease (Hayashi et al., Neuropathol. Appl.
Neurobiol. (2000) 26:390-97; Rashidian et al., Biochim. Biophys.
Acta. (2007) 1772:484-93; Vincent et al., J. Cell. Biol. (1996)
132:413-25.; Yang et al., J. Neurosci. (2001) 21:2661-68), neurons
engage in aberrant cell cycle activities, expressing cell cycle
markers such as Ki-67 and PCNA, and undergoing a limited extent of
DNA replication (Yang et al., J. Neurosci. (2001) 21:2661-68). This
behavior is remarkable considering that neurons have terminally
differentiated during development and remain quiescent for decades
prior to the onset of these events. While the underlying mechanisms
are poorly understood, multiple lines of evidence suggest that
these activities play an early and contributory role in neuronal
death (Andorfer et al., J. Neurosci. (2005) 25:5446-54; Busser et
al., J. Neurosci. (1998) 18:2801-07; Herrup et al., Development.
(1995) 121:2385-95; Nguyen et al., Cell Death Differ. (2002)
9:1294-306.). For example, overexpression of cell cycle
activity-inducing proteins such as SV40 large T antigen, c-myc,
c-Myb, or E2F-1 causes neuronal death in vitro and in vivo
(al-Ubaidi et al., Proc. Natl. Acad. Sci. USA (1992) 89:1194-98.;
Konishi et al., J. Neurosci. (2003) 23:1649-58; Liu et al., Neuron.
(2001) 32:425-38; McShea et al., Biochim. Biophys. Acta. (2007)
1772:467-72), while pharmacological inhibitors of CDKs or other
cell cycle components can exert neuroprotective effects
(Padmanabhan et al., J. Neurosci. (1999) 19:8747-56).
[0005] DNA damage may also be involved in multiple conditions
involving neuronal death (Adamec et al., Brain Res. (1999)
849:67-77; Ferrante et al., J. Neurochem. (1997) 69:2064-74;
Hayashi et al., Brain Res. (1999) 832:159-63; Kruman et al.,
Neuron. (2004) 41:549-61; Robison et al., J. Neurol. Sci. (1984)
64:11-20). For example, oxidative damage to neuronal DNA has been
observed in rodent models of ischemia (Hayashi et al., Brain Res.
(1999) 832:159-63). Accumulation of reactive oxygen species results
in DNA damage, cell cycle activity, and neurodegeneration in mutant
mice with disrupted apoptosis-inducing factor (AIF) (Klein et al.,
Nature (2002) 419:367-74). In addition, congenital syndromes with
DNA repair gene mutations, such as ataxia telangiectasia and
Werner's syndrome, display a progressive neurodegeneration
phenotype, demonstrating the importance of maintaining DNA
integrity in the adult brain (Rolig et al., Trends Neurosci. (2000)
23:417-24). Importantly, DNA damage is involved in the aging of the
human brain (Lu et al., Nature (2004) 429:883-91), which suggests
that DNA damage may play a role in age-dependent neurological
disorders as well.
[0006] Nucleosomes, the primary scaffold of chromatin folding, are
dynamic macromolecular structures, influencing the conformation of
chromatin in solution. The nucleosome core is made up of the
histone proteins, H2A, H2B, H3 and H4. Histone acetylation causes
nucleosomes and nucleosomal arrangements to behave with altered
biophysical properties. The balance between the activities of
histone acetyl transferases (HAT) and histone deacetylases (HDAC)
determines the level of histone acetylation. Acetylated histones
cause relaxation of chromatin and activation of gene transcription,
whereas deacetylated chromatin generally is transcriptionally
inactive.
[0007] HDACs have been grouped in four classes depending on
sequence identity, domain organization, and function: Class I:
HDAC1 (histone deacetylase 1), HDAC2, HDAC3, HDAC8; Class II:
HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10; Class III: SIRT1, SIRT2,
SIRT3, SIRT4, SIRT5, SIRT6, SIRT7; and Class IV: HDAC11. Within
Class I, HDAC1, HDAC2 and HDAC8 are primarily found in the nucleus
while HDAC3 and Class II HDACs can shuttle between the nucleus and
the cytoplasm. Class III HDACs (the sirtuins), couple the removal
of the acetyl group of the histone to NAD hydrolysis, thereby
coupling the deacetylation reaction to the energy status of the
cell.
[0008] A need remains for new compounds and treatment options that
result in the protection of cells, including neuronal cells to DNA
damage. The suppression of DNA damage in neuronal cells is an
important mechanism for suppressing neuronal cell death and
provides an opportunity for the treatment or prevention of various
neurological disorders.
SUMMARY OF THE INVENTION
[0009] The present invention provides inventive compounds of the
Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, and prodrugs
thereof, pharmaceutical compositions thereof, and kits thereof. The
present invention further provides methods of using the inventive
compounds, pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, pharmaceutical
compositions thereof, and kits thereof, to study activation of
class I histone deacetylase (HDAC) and as therapeutics, e.g., for
the treatment of neurological disorders, such as Alzheimer's
disease, Parkinson's disease, Huntington's disease, ALS
(amyotrophic lateral sclerosis), traumatic brain injury, ischemic
brain injury, stroke, frontal temporal dementia, Pick's disease,
corticobasal degeneration, supra cerebral palsy, prion diseases
(e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker
syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C,
spinal cerebellar ataxia, spinal muscular dystrophy, ataxia
telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner
syndrome, xeroderma pigmentosaum, and Bloom syndrome.
[0010] In one aspect, the invention provides compounds of Formula
(A):
##STR00002##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0011] each instance of X.sup.A1, X.sup.A2, and X.sup.A3 is
independently oxygen or sulfur;
[0012] each instance of R.sup.A1 and R.sup.A2 is independently
hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl;
[0013] Ar is optionally substituted aryl or optionally substituted
heteroaryl;
[0014] each instance of R.sup.A3 and R.sup.A4 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.A3a, --N(R.sup.A3b).sub.2,
--SR.sup.A3a, --C(.dbd.O)R.sup.A3a, --C(.dbd.O)OR.sup.A3a,
--C(.dbd.O)SR.sup.A3a, --C(.dbd.O)N(R.sup.A3b).sub.2,
--OC(.dbd.O)R.sup.A3a, --OC(.dbd.O)OR.sup.A3a,
--OC(.dbd.O)SR.sup.A3a, --OC(.dbd.O)N(R.sup.A3b).sub.2,
--NR.sup.A3bC(.dbd.O)R.sup.A3b, --NR.sup.A3bC(.dbd.O)OR.sup.A3a,
--NR.sup.A3bC(.dbd.O)SR.sup.A3a,
--NR.sup.A3bC(.dbd.O)N(R.sup.A3b).sub.2, --SC(.dbd.O)R.sup.A3a,
--SC(.dbd.O)OR.sup.A3a, --SC(.dbd.O)SR.sup.A3a,
--SC(.dbd.O)N(R.sup.A3b).sub.2, --C(.dbd.NR.sup.A3b)R.sup.A3a,
--C(.dbd.NR.sup.A3b)OR.sup.A3a, --C(.dbd.NR.sup.A3b)SR.sup.A3a,
--C(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--OC(.dbd.NR.sup.A3b)R.sup.A3a, --OC(.dbd.NR.sup.A3b)OR.sup.A3a,
--OC(.dbd.NR.sup.A3b)SR.sup.A3a,
--OC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--NR.sup.A3bC(.dbd.NR.sup.A3b)R.sup.A3b,
--NR.sup.A3bC(.dbd.NR.sup.A3b)OR.sup.A3a,
--NR.sup.A3bC(.dbd.NR.sup.A3b)SR.sup.A3a,
--NR.sup.A3bC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--SC(.dbd.NR.sup.A3b)R.sup.A3a, --SC(.dbd.NR.sup.A3b)OR.sup.A3a,
--SC(.dbd.NR.sup.A3b)SR.sup.A3a,
--SC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2, --C(.dbd.S)R.sup.A3a,
--C(.dbd.S)OR.sup.A3a, --C(.dbd.S)SR.sup.A3a,
--C(.dbd.S)N(R.sup.A3b).sub.2, --OC(.dbd.S)R.sup.A3a,
--OC(.dbd.S)OR.sup.A3a, --OC(.dbd.S)SR.sup.A3a,
--OC(.dbd.S)N(R.sup.A3b).sub.2, --NR.sup.A3bC(.dbd.S)R.sup.A3b,
--NR.sup.A3bC(.dbd.S)OR.sup.A3a, --NR.sup.A3bC(.dbd.S)SR.sup.A3a,
--NR.sup.A3bC(.dbd.S)N(R.sup.A3b).sub.2, --SC(.dbd.S)R.sup.A3a,
--SC(.dbd.S)OR.sup.A3a, --SC(.dbd.S)SR.sup.A3a,
--SC(.dbd.S)N(R.sup.A3b).sub.2, --S(.dbd.O)R.sup.A3a,
--SO.sub.2R.sup.A3a, --NR.sup.A3bSO.sub.2R.sup.A3a,
--SO.sub.2N(R.sup.A3b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.A3a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.A3b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.A3b groups are joined to
form an optionally substituted heterocyclic ring;
[0015] m is 0, 1, 2, 3, or 4; and
[0016] n is 0, 1, 2, or 3.
[0017] In another aspect, the invention provides compounds of
Formula (B):
##STR00003##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0018] each instance of X.sup.B1, X.sup.B3, and X.sup.B4 is
independently oxygen, sulfur, --NR.sup.B4a, or C(R.sup.B4b).sub.2,
wherein R.sup.B4a is hydrogen, a nitrogen protecting group, or
C.sub.1-6 alkyl, and each occurrence of R.sup.B4b is hydrogen,
halogen, or C.sub.1-6 alkyl, or two R.sup.B4b groups are joined to
form an optionally substituted carbocyclic or heterocyclic
ring;
[0019] X.sup.B2 is nitrogen or CR.sup.B2a, wherein R.sup.B2a is
hydrogen, halogen, or C.sub.1-6 alkyl;
[0020] each instance of R.sup.B1 is independently selected from the
group consisting of halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.B1a, --N(R.sup.B1b).sub.2, --SR.sup.B1a,
--C(.dbd.O)R.sup.B1a, --C(.dbd.O)OR.sup.B1a, --C(.dbd.O)SR.sup.B1a,
--C(.dbd.O)N(R.sup.B1b).sub.2, --OC(.dbd.O)R.sup.B1a,
--OC(.dbd.O)OR.sup.B1a, --OC(.dbd.O)SR.sup.B1a,
--OC(.dbd.O)N(R.sup.B1b).sub.2, --NR.sup.B1bC(.dbd.O)R.sup.B1b,
--NR.sup.B1bC(.dbd.O)OR.sup.B1a, --NR.sup.B1bC(.dbd.O)SR.sup.B1a
NR.sup.B1bC(.dbd.O)N(R.sup.B1b).sub.2, --SC(.dbd.O)R.sup.B1a,
--SC(.dbd.O)OR.sup.B1a, --SC(.dbd.O)SR.sup.B1a,
--SC(.dbd.O)N(R.sup.B1b).sub.2, --C(.dbd.NR.sup.B1b)R.sup.B1a,
--C(.dbd.NR.sup.B1b)OR.sup.B1a, --C(.dbd.NR.sup.B1b)SR.sup.B1a,
--C(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--OC(.dbd.NR.sup.B1b)R.sup.B1a, --OC(.dbd.NR.sup.B1b)OR.sup.B1a,
--OC(.dbd.NR.sup.B1b)SR.sup.B1a,
--OC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--NR.sup.B1bC(.dbd.NR.sup.B1b)R.sup.B1b,
--NR.sup.B1bC(.dbd.NR.sup.B1b)OR.sup.B1a,
--NR.sup.B1bC(.dbd.NR.sup.B1b)SR.sup.B1a,
--NR.sup.B1bC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--SC(.dbd.NR.sup.B1b)R.sup.B1a, --SC(.dbd.NR.sup.B1b)OR.sup.B1a,
--SC(.dbd.NR.sup.B1b)SR.sup.B1a,
--SC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2, --C(.dbd.S)R.sup.B1a,
--C(.dbd.S)OR.sup.B1a, --C(.dbd.S)SR.sup.B1a,
--C(.dbd.S)N(R.sup.B1b).sub.2, --OC(.dbd.S)R.sup.B1a,
--OC(.dbd.S)OR.sup.B1a, --OC(.dbd.S)SR.sup.B1a,
--OC(.dbd.S)N(R.sup.B1b).sub.2, --NR.sup.B1bC(.dbd.S)R.sup.B1b,
--NR.sup.B1bC(.dbd.S)OR.sup.B1a, --NR.sup.B1bC(.dbd.S)SR.sup.B1a,
--NR.sup.B1bC(.dbd.S)N(R.sup.B1b).sub.2, --SC(.dbd.S)R.sup.B1a,
--SC(.dbd.S)OR.sup.B1a, --SC(.dbd.S)SR.sup.B1a,
--SC(.dbd.S)N(R.sup.B1b).sub.2, --S(.dbd.O)R.sup.B1a,
--SO.sub.2R.sup.B1a, --NR.sup.B1bSO.sub.2R.sup.B1a,
--SO.sub.2N(R.sup.B1b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.B1a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.B1b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.B1b groups are joined to
form an optionally substituted heterocyclic ring;
[0021] each instance of R.sup.B2, R.sup.B3, R.sup.B4, and R.sup.B5
is independently hydrogen, halogen, or C.sub.1-6 alkyl;
[0022] R.sup.B6 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.B6a, --N(R.sup.B6b).sub.2, or --SR.sup.B6a
wherein each occurrence of R.sup.B6a is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, and each occurrence of
R.sup.B6b is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or a nitrogen protecting group, or two R.sup.B6b groups
are joined to form an optionally substituted heterocyclic ring;
[0023] p is 0, 1, 2, 3, or 4.
[0024] In yet another aspect, the invention provides compounds of
Formula (C):
##STR00004##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0025] X.sup.C1 is oxygen, sulfur, or NR.sup.C1a, wherein R.sup.C1a
is hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl;
[0026] each instance of X.sup.C2, X.sup.C3, and X.sup.C4 is
independently nitrogen or CR.sup.C4a, wherein R.sup.C4a is
hydrogen, halogen, or C.sub.1-6 alkyl;
[0027] L is a bond; cyclic or acyclic, substituted or unsubstituted
alkylene; cyclic or acyclic, substituted or unsubstituted
alkenylene; cyclic or acyclic, substituted or unsubstituted
alkynylene; cyclic or acyclic, substituted or unsubstituted
heteroalkylene; cyclic or acyclic, substituted or unsubstituted
heteroalkenylene; cyclic or acyclic, substituted or unsubstituted
heteroalkynylene; substituted or unsubstituted arylene; or
substituted or unsubstituted heteroarylene;
[0028] each instance of R.sup.C1 and R.sup.C2 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.C2a, --N(R.sup.C2b).sub.2,
--SR.sup.C2a, --C(.dbd.O)R.sup.C2a, --C(.dbd.O)OR.sup.C2a,
--C(.dbd.O)SR.sup.C2a, --C(.dbd.O)N(R.sup.C2b).sub.2,
--OC(.dbd.O)R.sup.C2a, --OC(.dbd.O)OR.sup.C2a,
--OC(.dbd.O)SR.sup.C2a, --OC(.dbd.O)N(R.sup.C2b).sub.2,
--NR.sup.C2bC(.dbd.O)R.sup.C2b, --NR.sup.C2bC(.dbd.O)OR.sup.C2a,
--NR.sup.C2bC(.dbd.O)SR.sup.C2a,
--NR.sup.C2bC(.dbd.O)N(R.sup.C2b).sub.2, --SC(.dbd.O)R.sup.C2a,
--SC(.dbd.O)OR.sup.C2a, --SC(.dbd.O)SR.sup.C2a,
--SC(.dbd.O)N(R.sup.C2b).sub.2, --C(.dbd.NR.sup.C2b)R.sup.C2a,
--C(.dbd.NR.sup.C2b)OR.sup.C2a, --C(.dbd.NR.sup.C2b)SR.sup.C2a,
--C(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2,
--OC(.dbd.NR.sup.C2b)R.sup.C2a, --OC(.dbd.NR.sup.C2b)OR.sup.C2a,
--OC(.dbd.NR.sup.C2b)SR.sup.C2a,
--OC(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2,
--NR.sup.C2bC(.dbd.NR.sup.C2b)R.sup.C2b,
--NR.sup.C2bC(.dbd.NR.sup.C2b)OR.sup.C2a,
--NR.sup.C2bC(.dbd.NR.sup.C2b)SR.sup.C2a,
--NR.sup.C2bC(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2,
--SC(.dbd.NR.sup.C2b)R.sup.C2a, --SC(.dbd.NR.sup.C2b)OR.sup.C2a,
--SC(.dbd.NR.sup.C2b)SR.sup.C2a,
--SC(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2, --C(.dbd.S)R.sup.C2a,
--C(.dbd.S)OR.sup.C2a, --C(.dbd.S)SR.sup.C2a,
--C(.dbd.S)N(R.sup.C2b).sub.2, --OC(.dbd.S)R.sup.C2a,
--OC(.dbd.S)OR.sup.C2a, --OC(.dbd.S)SR.sup.C2a,
--OC(.dbd.S)N(R.sup.C2b).sub.2, --NR.sup.C2bC(.dbd.S)R.sup.C2b,
--NR.sup.C2bC(.dbd.S)OR.sup.C2a, --NR.sup.C2bC(.dbd.S)SR.sup.C2a,
--NR.sup.C2bC(.dbd.S)N(R.sup.C2b).sub.2, --SC(.dbd.S)R.sup.C2a,
--SC(.dbd.S)OR.sup.C2a, --SC(.dbd.S)SR.sup.C2a,
--SC(.dbd.S)N(R.sup.C2b).sub.2, --S(.dbd.O)R.sup.C2a,
--SO.sub.2R.sup.C2a, --NR.sup.C2bSO.sub.2R.sup.C2a,
--SO.sub.2N(R.sup.C2b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.C2a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.C2b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.C2b groups are joined to
form an optionally substituted heterocyclic ring;
[0029] q is 0, 1, 2, 3, or 4; and
[0030] r is 0, 1, 2, 3, 4, or 5.
[0031] In yet another aspect, the invention provides compounds of
Formula (D):
##STR00005##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0032] each instance of X.sup.D1 is independently oxygen, sulfur,
--NR.sup.D1a, or C(R.sup.D1b).sub.2, wherein R.sup.D1a is hydrogen
or C.sub.1-6 alkyl, and each occurrence of R.sup.D1b is hydrogen,
halogen, or C.sub.1-6 alkyl, or two R.sup.D1b groups are joined to
form an optionally substituted carbocyclic or heterocyclic
ring;
[0033] s is 0, 1, 2, 3, 4, 5, or 6;
[0034] each instance of R.sup.D1 and R.sup.D2 is independently
hydrogen, an oxygen protecting group, C.sub.1-6 alkyl,
--C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a, --C(.dbd.O)SR.sup.D2a,
--C(.dbd.O)N(R.sup.D2b).sub.2, --S(.dbd.O)R.sup.D2a, or
--S(.dbd.O).sub.2R.sup.D2a, wherein each occurrence of R.sup.D2a is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl,
and each occurrence of R.sup.D2b is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, or a nitrogen protecting group,
or two R.sup.D2b groups are joined to form an optionally
substituted heterocyclic ring;
[0035] each instance of R.sup.D3 and R.sup.D4 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.D4a, --N(R.sup.D4b).sub.2,
--SR.sup.D4a, --C(.dbd.O)R.sup.D4a, --C(.dbd.O)OR.sup.D4a,
--C(.dbd.O)SR.sup.D4a, --C(.dbd.O)N(R.sup.D4b).sub.2,
--OC(.dbd.O)R.sup.D4a, --OC(.dbd.O)OR.sup.D4a,
--OC(.dbd.O)SR.sup.D4a, --OC(.dbd.O)N(R.sup.D4b).sub.2,
--NR.sup.D4bC(.dbd.O)R.sup.D4b, --NR.sup.D4bC(.dbd.O)OR.sup.D4a,
--NR.sup.D4bC(.dbd.O)SR.sup.D4a,
--NR.sup.D4bC(.dbd.O)N(R.sup.D4b).sub.2, --SC(.dbd.O)R.sup.D4a,
--SC(.dbd.O)OR.sup.D4a, --SC(.dbd.O)SR.sup.D4a,
--SC(.dbd.O)N(R.sup.D4b).sub.2, --C(.dbd.NR.sup.D4b)R.sup.D4a,
--C(.dbd.NR.sup.D4b)OR.sup.D4a, --C(.dbd.NR.sup.D4b)SR.sup.D4a,
--C(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--OC(.dbd.NR.sup.D4b)R.sup.D4a, --OC(.dbd.NR.sup.D4b)OR.sup.D4a,
--OC(.dbd.NR.sup.D4b)SR.sup.D4a,
--OC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--NR.sup.D4bC(.dbd.NR.sup.D4b)R.sup.D4b,
--NR.sup.D4bC(.dbd.NR.sup.D4b)OR.sup.D4a,
--NR.sup.D4bC(.dbd.NR.sup.D4b)SR.sup.D4a,
--NR.sup.D4bC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--SC(.dbd.NR.sup.D4b)R.sup.D4a, --SC(.dbd.NR.sup.D4b)OR.sup.D4a,
--SC(.dbd.NR.sup.D4b)SR.sup.D4a,
--SC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2, --C(.dbd.S)R.sup.D4a,
--C(.dbd.S)OR.sup.D4a, --C(.dbd.S)SR.sup.D4a,
--C(.dbd.S)N(R.sup.D4b).sub.2, --OC(.dbd.S)R.sup.D4a,
--OC(.dbd.S)OR.sup.D4a, --OC(.dbd.S)SR.sup.D4a,
--OC(.dbd.S)N(R.sup.D4b).sub.2, --NR.sup.D4bC(.dbd.S)R.sup.D4b,
--NR.sup.D4bC(.dbd.S)OR.sup.D4a, --NR.sup.D4bC(.dbd.S)SR.sup.D4a,
--NR.sup.D4bC(.dbd.S)N(R.sup.D4b).sub.2, --SC(.dbd.S)R.sup.D4a,
--SC(.dbd.S)OR.sup.D4a, --SC(.dbd.S)SR.sup.D4a,
--SC(.dbd.S)N(R.sup.D4b).sub.2, --S(.dbd.O)R.sup.D4a,
--SO.sub.2R.sup.D4a, --NR.sup.D4bSO.sub.2R.sup.D4a,
--SO.sub.2N(R.sup.D4b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.D4a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.D4b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.D4b groups are joined to
form an optionally substituted heterocyclic ring;
[0036] t is 0, 1, 2, or 3; and
[0037] u is 0, 1, 2, 3, 4 or 5.
[0038] In still another aspect, provided are pharmaceutical
compositions comprising a compound of any of the Formulae (A), (B),
(C), and (D), and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, and
optionally a pharmaceutically acceptable excipient.
[0039] In still another aspect, the invention provides methods and
compositions for the suppression of DNA damage in neuronal
cells.
[0040] In still another aspect, the invention provides methods and
compositions for the treatment of neurological disorders. In
certain embodiments, the method comprises administering to a
subject in need of treatment for a neurological disorder a
therapeutically effective amount of a class I HDAC (histone
deacetylase) activator to treat the neurological disorder. In some
embodiments, the neurological disorder is Alzheimer's disease,
Parkinson's disease, Huntington's disease, ALS (Amyotrophic lateral
sclerosis), traumatic brain injury, or ischemic brain injury. In
some embodiments, the class I HDAC activator is selected from the
group of compounds consisting of:
##STR00006##
and compounds of the Formulae (A), (B), (C), and (D), and
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, and prodrugs thereof, or pharmaceutical compositions
thereof.
[0041] In another aspect, the invention provides kits for treating
a neurological disorder comprising a first container comprising a
class I HDAC activator selected from the group of compounds
consisting of DAC-001, DAC-002, DAC-003, DAC-009, DAC-012, and
compounds of the Formulae (A), (B), (C), and (D), and
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, and prodrugs thereof, or pharmaceutical compositions
thereof.
[0042] This Application refers to various issued patent, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference.
[0043] Each of the limitations of the invention can encompass
various embodiments of the invention. It is, therefore, anticipated
that each of the limitations of the invention involving any one
element or combinations of elements can be included in each aspect
of the invention. This invention is not limited in its application
to the details of construction and the arrangement of components
set forth in the following description or illustrated in the
drawings. The invention is capable of other embodiments and of
being practiced or of being carried out in various ways. Also, the
phraseology and terminology used herein is for the purpose of
description and should not be regarded as limiting. The use of the
terms "including", "comprising", "having", "containing",
"involving", and variations thereof herein is meant to encompass
the items listed thereafter and equivalents thereof as well as
additional items.
Definitions
[0044] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0045] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The invention additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0046] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0047] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
10 carbon atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl
group has 1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some
embodiments, an alkyl group has 1 to 8 carbon atoms ("C.sub.1-8
alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon
atoms ("C.sub.1-7 alkyl"). In some embodiments, an alkyl group has
1 to 6 carbon atoms ("C.sub.1-6 alkyl"). In some embodiments, an
alkyl group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has
1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents. In certain
embodiments, the alkyl group is unsubstituted C.sub.1-10 alkyl
(e.g., --CH.sub.3). In certain embodiments, the alkyl group is
substituted C.sub.1-10 alkyl.
[0048] "Perhaloalkyl" is a substituted alkyl group as defined
herein wherein all of the hydrogen atoms are independently replaced
by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some
embodiments, the alkyl moiety has 1 to 8 carbon atoms ("C.sub.1-8
perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 6
carbon atoms ("C.sub.1-6 perhaloalkyl"). In some embodiments, the
alkyl moiety has 1 to 4 carbon atoms ("C.sub.1-4 perhaloalkyl"). In
some embodiments, the alkyl moiety has 1 to 3 carbon atoms
("C.sub.1-3 perhaloalkyl"). In some embodiments, the alkyl moiety
has 1 to 2 carbon atoms ("C.sub.1-2 perhaloalkyl"). In some
embodiments, all of the hydrogen atoms are replaced with fluoro. In
some embodiments, all of the hydrogen atoms are replaced with
chloro. Examples of perhaloalkyl groups include --CF.sub.3,
--CF.sub.2CF.sub.3, --CF.sub.2CF.sub.2CF.sub.3, --CCl.sub.3,
--CFCl.sub.2, --CF.sub.2Cl, and the like.
[0049] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds, and no triple bonds ("C.sub.2-20
alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon
atoms ("C.sub.2-10 alkenyl"). In some embodiments, an alkenyl group
has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In some embodiments,
an alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In
some embodiments, an alkenyl group has 2 to 7 carbon atoms
("C.sub.2-7 alkenyl"). In some embodiments, an alkenyl group has 2
to 6 carbon atoms ("C.sub.2-6 alkenyl"). In some embodiments, an
alkenyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkenyl"). In
some embodiments, an alkenyl group has 2 to 4 carbon atoms
("C.sub.2-4 alkenyl"). In some embodiments, an alkenyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkenyl"). In some embodiments, an
alkenyl group has 2 carbon atoms ("C.sub.2 alkenyl"). The one or
more carbon-carbon double bonds can be internal (such as in
2-butenyl) or terminal (such as in 1-butenyl). Examples of
C.sub.2-4 alkenyl groups include ethenyl (C.sub.2), 1-propenyl
(C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4), 2-butenyl
(C.sub.4), butadienyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkenyl groups as well as pentenyl (C.sub.5), pentadienyl
(C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of
alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkenyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl") with one or more substituents. In certain
embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl.
In certain embodiments, the alkenyl group is substituted C.sub.2-10
alkenyl.
[0050] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds, and optionally one or more double
bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group
has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some
embodiments, an alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9
alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon
atoms ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group
has 2 to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments,
an alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents. In certain embodiments, the alkynyl group is
unsubstituted C.sub.2-10 alkynyl. In certain embodiments, the
alkynyl group is substituted C.sub.2-10 alkynyl.
[0051] The term "heteroalkyl," as used herein, refers to an alkyl
moiety, as defined herein, which contains one or more oxygen,
sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of
carbon atoms.
[0052] The term "heteroalkenyl," as used herein, refers to an
alkenyl moiety, as defined herein, which contains one or more
oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in
place of carbon atoms.
[0053] The term "heteroalkynyl," as used herein, refers to an
alkynyl moiety, as defined herein, which contains one or more
oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in
place of carbon atoms.
[0054] "Carbocyclyl" or "carbocyclic" refers to a radical of a
non-aromatic cyclic hydrocarbon group having from 3 to 10 ring
carbon atoms ("C.sub.3-10 carbocyclyl") and zero heteroatoms in the
non-aromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), bicyclo(2.2.1)heptanyl (C.sub.7),
bicyclo(2.2.2)octanyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl
(C.sub.10), spiro(4.5)decanyl (C.sub.10), and the like. As the
foregoing examples illustrate, in certain embodiments, the
carbocyclyl group is either monocyclic ("monocyclic carbocyclyl")
or contain a fused, bridged or spiro ring system such as a bicyclic
system ("bicyclic carbocyclyl") and can be saturated or can be
partially unsaturated. "Carbocyclyl" also includes ring systems
wherein the carbocyclyl ring, as defined above, is fused with one
or more aryl or heteroaryl groups wherein the point of attachment
is on the carbocyclyl ring, and in such instances, the number of
carbons continue to designate the number of carbons in the
carbocyclic ring system. Unless otherwise specified, each instance
of a carbocyclyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted
(a "substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is unsubstituted
C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-10 carbocyclyl.
[0055] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0056] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered non-aromatic ring system having ring carbon atoms
and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("3-10 membered heterocyclyl"). In
heterocyclyl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclyl group can either be monocyclic ("monocyclic
heterocyclyl") or a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic heterocyclyl"), and can be saturated or
can be partially unsaturated. Heterocyclyl bicyclic ring systems
can include one or more heteroatoms in one or both rings.
"Heterocyclyl" also includes ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more carbocyclyl
groups wherein the point of attachment is either on the carbocyclyl
or heterocyclyl ring, or ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclyl ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclyl ring system. Unless otherwise specified, each instance
of heterocyclyl is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a
"substituted heterocyclyl") with one or more substituents. In
certain embodiments, the heterocyclyl group is unsubstituted 3-10
membered heterocyclyl. In certain embodiments, the heterocyclyl
group is substituted 3-10 membered heterocyclyl.
[0057] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-8 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In
some embodiments, the 5-6 membered heterocyclyl has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0058] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl, and
thiorenyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary
6-membered heterocyclyl groups containing two heteroatoms include,
without limitation, triazinanyl. Exemplary 7-membered heterocyclyl
groups containing one heteroatom include, without limitation,
azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl
groups containing one heteroatom include, without limitation,
azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered
heterocyclyl groups fused to a C.sub.6 aryl ring (also referred to
herein as a 5,6-bicyclic heterocyclic ring) include, without
limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary
6-membered heterocyclyl groups fused to an aryl ring (also referred
to herein as a 6,6-bicyclic heterocyclic ring) include, without
limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the
like.
[0059] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 n electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Unless otherwise
specified, each instance of an aryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
aryl") or substituted (a "substituted aryl") with one or more
substituents. In certain embodiments, the aryl group is
unsubstituted C.sub.6-14 aryl. In certain embodiments, the aryl
group is substituted C.sub.6-14 aryl.
[0060] "Aralkyl" is a subset of alkyl and aryl, as defined herein,
and refers to an alkyl group substituted with an optionally
substituted aryl group.
[0061] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 n electrons shared in a cyclic array) having ring carbon atoms
and 1-4 ring heteroatoms provided in the aromatic ring system,
wherein each heteroatom is independently selected from nitrogen,
oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl
groups that contain one or more nitrogen atoms, the point of
attachment can be a carbon or nitrogen atom, as valency permits.
Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocyclyl or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. "Heteroaryl"
also includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more aryl groups wherein the point of
attachment is either on the aryl or heteroaryl ring, and in such
instances, the number of ring members designates the number of ring
members in the fused (aryl/heteroaryl) ring system. Bicyclic
heteroaryl groups wherein one ring does not contain a heteroatom
(e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of
attachment can be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0062] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has one ring
heteroatom selected from nitrogen, oxygen, and sulfur. Unless
otherwise specified, each instance of a heteroaryl group is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted heteroaryl") or substituted (a "substituted
heteroaryl") with one or more substituents. In certain embodiments,
the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In
certain embodiments, the heteroaryl group is substituted 5-14
membered heteroaryl.
[0063] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl, and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl, and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0064] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as
defined herein, and refers to an alkyl group substituted with an
optionally substituted heteroaryl group.
[0065] "Partially unsaturated" refers to a group that includes at
least one double or triple bond. The term "partially unsaturated"
is intended to encompass rings having multiple sites of
unsaturation, but is not intended to include aromatic groups (e.g.,
aryl or heteroaryl groups) as herein defined. Likewise, "saturated"
refers to a group that does not contain a double or triple bond,
i.e., the group contains all single bonds.
[0066] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, which are divalent
bridging groups are further referred to using the suffix -ene,
e.g., alkylene, alkenylene, alkynylene, carbocyclylene,
heteroalkylene, heteroalkenylene, heteroalkynylene,
heterocyclylene, arylene, and heteroarylene.
[0067] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, are optionally
substituted (e.g., "substituted" or "unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted"
carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or "unsubstituted" aryl, or "substituted" or
"unsubstituted" heteroaryl group). In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that at least one hydrogen present on a group (e.g., a carbon
or nitrogen atom) is replaced with a permissible substituent, e.g.,
a substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that result in
the formation of a stable compound. The present invention
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this invention, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety.
[0068] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3, --OSi(R.sup.aa).sub.3,
--C(.dbd.S)N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa, --SC(.dbd.O)SR.sup.aa,
--OC(.dbd.O)SR.sup.aa, --SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc),
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups;
[0069] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.aa;
[0070] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0071] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0072] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0073] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O).sub.2R.sup.ee, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups, or two geminal R.sup.dd substituents can be joined
to form .dbd.O or .dbd.S;
[0074] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0075] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.ff groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0076] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3, --C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg
substituents can be joined to form O or .dbd.S; wherein X is a
counterion.
[0077] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electronic neutrality. Exemplary counterions
include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-),
NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-, H.sub.2PO.sub.4.sup.-,
HSO.sub.4.sup.-, sulfonate ions (e.g., methansulfonate,
trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate,
10-camphor sulfonate, naphthalene-2-sulfonate,
naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic
acid-2-sulfonate, and the like), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like).
[0078] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0079] A "leaving group" is an art-understood term referring to a
molecular fragment that departs with a pair of electrons in
heterolytic bond cleavage, wherein the molecular fragment is an
anion or neutral molecule. See, for example, Smith, March's
Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving
groups include, but are not limited to, halogen (e.g., chloro,
bromo, iodo), activated hydroxyl groups (e.g.,
--OC(.dbd.O)SR.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--OC(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --OS(.dbd.O)R.sup.aa,
--OSO.sub.2R.sup.aa, --OP(R.sup.cc).sub.2, --OP(R.sup.aa).sub.3,
--OP(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --OP(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --OP(.dbd.O)(NR.sup.bb).sub.2 wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein), substituted thiol groups (e.g.,
--SR.sup.aa, for example, as a molecular fragment departing from of
a compound of the formula R.sup.aaS--SR.sup.aa), substituted
nitrogen groups (e.g., --NR.sup.bb, for example, as a molecular
fragment departing from of a compound of formula
Br--N(R.sup.bb).sub.2, Cl--N(R.sup.bb).sub.2,
I--N(R.sup.bb).sub.2.sup.b, and F--N(R.sup.bb).sub.2), --CN, and
--N.sub.2.
[0080] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary nitrogen atoms. Exemplary nitrogen atom substitutents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups attached to a nitrogen atom are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc
and R.sup.dd are as defined above.
[0081] In certain embodiments, the substituent present on a
nitrogen atom is a nitrogen protecting group (also referred to as
an amino protecting group). Nitrogen protecting groups include, but
are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.a,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g., aralkyl,
heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as
defined herein. Nitrogen protecting groups are well known in the
art and include those described in detail in Protecting Groups in
Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd
edition, John Wiley & Sons, 1999, incorporated herein by
reference.
[0082] Amide nitrogen protecting groups (e.g., --C(.dbd.O)R.sup.aa)
include, but are not limited to, formamide, acetamide,
chloroacetamide, trichloroacetamide, trifluoroacetamide,
phenylacetamide, 3-phenylpropanamide, picolinamide,
3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,
p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,
acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide, and
o-(benzoyloxymethyl)benzamide.
[0083] Carbamate nitrogen protecting groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-(9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl))methyl
carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl
carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl
carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate,
benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
(2-(1,3-dithianyl))methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0084] Sulfonamide nitrogen protecting groups (e.g.,
--S(.dbd.O).sub.2R.sup.aa) include, but are not limited to,
p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,
-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), (3-trimethylsilylethanesulfonamide (SES),
9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0085] Other nitrogen protecting groups include, but are not
limited to, phenothiazinyl-(10)-acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-(2-(trimethylsilyl)ethoxy)methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-((4-methoxyphenyl)diphenylmethyl)amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-((2-pyridyl)mesityl)methyleneamine,
N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-(phenyl(pentaacylchromium- or tungsten)acyl)amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys).
[0086] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to as a hydroxyl
protecting group). Oxygen protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.aa).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Oxygen protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0087] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM),
t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM),
benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),
(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM),
t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl,
2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),
tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,
tetrahydrothiopyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide,
1-((2-chloro-4-methyl)phenyl)-4-methoxypiperidin-4-yl (CTMP),
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl
carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl
p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl
p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate,
alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,
4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, .alpha.-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0088] In certain embodiments, the substituent present on a sulfur
atom is a sulfur protecting group (also referred to as a thiol
protecting group). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.aa).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Sulfur protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0089] An "isomer" includes any and all geometric isomers and
stereoisomers. For example, "isomers" include cis- and
trans-isomers, E- and Z-isomers, R- and S-enantiomers,
diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof,
and other mixtures thereof, as falling within the scope of the
invention.
[0090] "Tautomer" includes two or more interconvertable compounds
resulting from at least one formal migration of a hydrogen atom and
at least one change in valency (e.g., a single bond to a double
bond, a triple bond to a double bond, or vice versa). The exact
ratio of the tautomers depends on several factors, including
temperature, solvent, and pH. Tautomerizations (i.e., the reaction
providing a tautomeric pair) may be catalyzed by acid or base.
Exemplary tautomerizations include keto-to-enol; amide-to-imide;
lactam-to-lactim; enamine-to-imine; and enamine-to-(a different)
enamine tautomerizations.
[0091] These and other exemplary substituents are described in more
detail in the Detailed Description, Examples, and claims. The
invention is not intended to be limited in any manner by the above
exemplary listing of substituents.
Other Definitions
[0092] The term "animal," as used herein, refers to humans as well
as non-human animals, including, e.g., mammals, birds, reptiles,
amphibians, and fish. Preferably, the non-human animal is a mammal
(e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat,
a primate, or a pig). A non-human animal may be a transgenic
animal.
[0093] "Salt" or "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al. describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, and perchloric acid, or with
organic acids such as acetic acid, oxalic acid, maleic acid,
tartaric acid, citric acid, succinic acid, or malonic acid, or by
using other methods used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium, and N+(C.sub.1-4alkyl).sub.4 salts.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
quaternary salts.
[0094] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g., infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or other non-human animals, for example
mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys);
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs), birds (e.g., commercially relevant birds
such as chickens, ducks, geese, and/or turkeys), reptiles,
amphibians, and fish. In certain embodiments, the non-human animal
is a mammal. The non-human animal may be a male or female and at
any stage of development. A non-human animal may be a transgenic
animal.
[0095] "Treat," "treating," and "treatment" contemplate an action
that occurs while a subject is suffering from a condition which
reduces the severity of the condition or retards or slows the
progression of the condition ("therapeutic treatment"), and also
contemplates an action that occurs before a subject begins to
suffer from the condition and which inhibits or reduces the
severity of the condition ("prophylactic treatment").
[0096] An "effective amount" of a compound refers to an amount
sufficient to elicit the desired biological response, i.e.,
treating the condition. As will be appreciated by those of ordinary
skill in this art, the effective amount of a compound of the
invention may vary depending on such factors as the desired
biological endpoint, the pharmacokinetics of the compound, the
condition being treated, the mode of administration, and the age
and health of the subject. An effective amount encompasses
therapeutic and prophylactic treatment.
[0097] A "therapeutically effective amount" of a compound is an
amount sufficient to provide a therapeutic benefit in the treatment
of a condition or to delay or minimize one or more symptoms
associated with the condition. A therapeutically effective amount
of a compound means an amount of a therapeutic agent, alone or in
combination with other therapies, which provides a therapeutic
benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces or avoids symptoms or causes of
the condition, or enhances the therapeutic efficacy of another
therapeutic agent.
[0098] A "prophylactically effective amount" of a compound is an
amount sufficient to prevent a condition, or one or more symptoms
associated with the condition or prevent its recurrence. A
prophylactically effective amount of a compound means an amount of
a therapeutic agent, alone or in combination with other agents,
which provides a prophylactic benefit in the prevention of the
condition. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0099] A "pharmaceutically acceptable excipient" is an excipient
that is non-toxic to recipients at the dosages and concentrations
employed, and is compatible with other ingredients of the
formulation. Pharmaceutically acceptable excipients include any and
all solvents, diluents, or other liquid vehicles, dispersions,
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants,
and the like, as suited to the particular dosage form desired.
General considerations in formulation and/or manufacture of
pharmaceutical compositions agents can be found, for example, in
Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.
Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The
Science and Practice of Pharmacy, 21st Edition (Lippincott Williams
& Wilkins, 2005).
[0100] A "small molecule" is a low molecular weight organic
compound which is not a polymer. The term small molecule,
especially within the field of pharmacology, is usually restricted
to a molecule that also binds with high affinity to a biopolymer
such as protein, polysaccharide, or nucleic acid and in addition
alters the activity or function of the biopolymer. The upper limit
for a small molecule's molecular weight is about 800 Daltons which
allows for the possibility to rapidly diffuse across cell membranes
so that they can reach intracellular sites of action.
[0101] A "protein" or "peptide" comprises a polymer of amino acid
residues linked together by peptide bonds. The term, as used
herein, refers to proteins, polypeptides, and peptide of any size,
structure, or function. Typically, a protein will be at least three
amino acids long. A protein may refer to an individual protein or a
collection of proteins. Inventive proteins preferably contain only
natural amino acids, although non-natural amino acids (i.e.,
compounds that do not occur in nature but that can be incorporated
into a polypeptide chain) and/or amino acid analogs as are known in
the art may alternatively be employed. Also, one or more of the
amino acids in an inventive protein may be modified, for example,
by the addition of a chemical entity such as a carbohydrate group,
a hydroxyl group, a phosphate group, a farnesyl group, an
isofarnesyl group, a fatty acid group, a linker for conjugation,
functionalization, or other modification, etc. A protein may also
be a single molecule or may be a multi-molecular complex. A protein
may be just a fragment of a naturally occurring protein or peptide.
A protein may be naturally occurring, recombinant, or synthetic, or
any combination of these.
[0102] "Histones" are highly alkaline proteins found in eukaryotic
cell nuclei that package and order the DNA into structural units
called nucleosomes. They are the chief protein components of
chromatin, acting as spools around which DNA winds, and play a role
in gene regulation.
[0103] "Histone deacetylases" (HDACs) are a class of enzymes that
remove acetyl groups from an F--N-acetyl lysine amino acid on a
histone. DNA is wrapped around histones, and DNA expression is
regulated by acetylation and deacetylation.
[0104] "Class I histone deacetylase" or "class I HDAC" is a
subclass of HDACs.
[0105] "HDAC1" or "histone deacetylase 1" is a subclass of class I
HDACs.
[0106] A "DAC" refers to a compound that activates class I HDACs'
enzymatic function.
BRIEF DESCRIPTION OF THE DRAWINGS
[0107] FIG. 1 shows an overview of small molecule modulators of
class I HDACs and relevance to response to DNA damage, DNA repair,
and neuroprotection. HDAC1, HDAC2, HDAC3, and HDAC8 are
zinc-dependent hydrolases that remove acetyl groups from the
.epsilon.-amino group of lysine side chains. Class I HDACs have
also been found to have other enzymatic activities, including
esterase activity.
[0108] FIGS. 2A to 2B show HDAC1 microfluidics assay control data
of 7,080 negative control samples (DMSO) (FIG. 2A) and 580
ginkgetin positive controls (50 .mu.M) (FIG. 2B).
[0109] FIGS. 3A to 3B include HDAC1 microfluidics high-throughput
screening data. FIG. 3A depicts a primary microfluidic fluorescence
reader trace for ginkgetin (positive control; for its structure,
see FIG. 6A) showing increased conversion of the peptidic substrate
FAM-TSRHKacKL to the deacetylated product FAM-TSRHKKL (illustrated
with arrows). FIG. 3B depicts a primary microfluidic fluorescence
reader trace for DAC-001, showing increased conversion of the
peptidic substrate FAM-TSRHKacKL to the deacetylated product
FAM-TSRHKKL (illustrated with arrows).
[0110] FIG. 4 shows that DAC compounds reduce histone acetylation.
DAC compounds were added to HEK293T cells for 20 h. Vehicle was
DMSO. Histones were acid-extracted and analyzed by Western blot for
Ac-H3K56, Ac-H4K12, Ac-H3K14 and Ac-H2B. Histone 3 was used as the
loading control.
[0111] FIGS. 5A to 5C show that DAC compounds protect cells from
stress-induced cell death. FIG. 5A shows that DAC compounds protect
cells against oxidative stress. 10 .mu.M DAC-003 can significantly
protect cells from oxidative insults (*p<0.05, compound versus
vehicle treatment, student's t-test). FIG. 5B shows that DAC
compounds protect cells from DNA damage-induced stress. Cells were
treated with etoposide, a topoisomerase II inhibitor, to generate
DNA double strand breaks (DSB). It was found that DAC-001, DAC-002,
DAC-003, DAC-009, and DAC-012 significantly protect cells from
DSB-induced cell death (***p<0.001, compound versus vehicle
treatment, student's t-test). FIG. 5C shows that DAC compounds have
minimal effects on cell proliferation and survival at their working
concentration (5 .mu.M for DAC-001 and DAC-003; 10 .mu.M for the
others).
[0112] FIGS. 6A to 6C show the twenty-one (21) hit structures from
the high throughput HDAC1 activator screen.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0113] The present invention provides compounds that activate Class
I histone deacetlyases (HDACs), and pharmaceutical compositions
thereof, for the treatment of human disease. The present invention
further provides methods of using the compounds described herein,
e.g., as biological probes to study the activation of HDACs, and as
therapeutics, e.g., in the treatment of neurological disorders,
such as Alzheimer's disease, Parkinson's disease, Huntington's
disease, ALS (Amyotrophic lateral sclerosis), traumatic brain
injury, ischemic brain injury, stroke, frontal temporal dementia,
Pick's disease, corticobasal degeneration, supra cerebral palsy,
prion diseases (e.g., Creutzfeldt-Jakob disease,
Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia,
and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal
muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis,
Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, or
Bloom syndrome.
Compounds
[0114] 47,144 compounds were screened for hit compounds, which
enhance the enzymatic activity of class I HDAC, especially, HDAC1.
Of the hit compounds, multiple common structural frameworks were
identified, suggesting the existence of a defined
structure-activity-relationship for HDAC1 activation.
[0115] The compounds depicted below and herein may be prepared by
conventional chemical transformations (including protecting group
methodologies), e.g., those described in R. Larock, Comprehensive
Organic Transformations, VCH Publishers (1989); T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed.,
John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and
Fieser's Reagents for Organic Synthesis, John Wiley and Sons
(1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic
Synthesis, John Wiley and Sons (1995) and subsequent editions
thereof. The compounds can also be synthesized in manners similar
to those described with necessary modifications as recognized by
those skilled in the art.
[0116] In one aspect, provided is a compound of Formula (A):
##STR00007##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0117] each instance of X.sup.A1, X.sup.A2, and X.sup.A3 is
independently oxygen or sulfur;
[0118] each instance of R.sup.A1 and R.sup.A2 is independently
hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl;
[0119] Ar is optionally substituted aryl or optionally substituted
heteroaryl;
[0120] each instance of R.sup.A3 and R.sup.A4 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.A3a, --N(R.sup.A3b).sub.2,
--SR.sup.A3a, --C(.dbd.O)R.sup.A3a, --C(.dbd.O)OR.sup.A3a,
--C(.dbd.O)SR.sup.A3a, --C(.dbd.O)N(R.sup.A3b).sub.2,
--OC(.dbd.O)R.sup.A3a, --OC(.dbd.O)OR.sup.A3a,
--OC(.dbd.O)SR.sup.A3a, --OC(.dbd.O)N(R.sup.A3b).sub.2,
--NR.sup.A3bC(.dbd.O)R.sup.A3b, --NR.sup.A3bC(.dbd.O)OR.sup.A3a,
--NR.sup.A3bC(.dbd.O)SR.sup.A3a,
--NR.sup.A3bC(.dbd.O)N(R.sup.A3b).sub.2, --SC(.dbd.O)R.sup.A3a,
--SC(.dbd.O)OR.sup.A3a, --SC(.dbd.O)SR.sup.A3a,
--SC(.dbd.O)N(R.sup.A3b).sub.2, --C(.dbd.NR.sup.A3b)R.sup.A3a,
--C(.dbd.NR.sup.A3b)OR.sup.A3a, --C(.dbd.NR.sup.A3b)SR.sup.A3a,
--C(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--OC(.dbd.NR.sup.A3b)R.sup.A3a, --OC(.dbd.NR.sup.A3b)OR.sup.A3a,
--OC(.dbd.NR.sup.A3b)SR.sup.A3a,
--OC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--NR.sup.A3bC(.dbd.NR.sup.A3b)R.sup.A3b,
--NR.sup.A3bC(.dbd.NR.sup.A3b)OR.sup.A3a,
--NR.sup.A3bC(.dbd.NR.sup.A3b)SR.sup.A3a,
--NR.sup.A3bC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2,
--SC(.dbd.NR.sup.A3b)R.sup.A3a, --SC(.dbd.NR.sup.A3b)OR.sup.A3a,
--SC(.dbd.NR.sup.A3b)SR.sup.A3a,
--SC(.dbd.NR.sup.A3b)N(R.sup.A3b).sub.2, --C(.dbd.S)R.sup.A3a,
--C(.dbd.S)OR.sup.A3a, --C(.dbd.S)SR.sup.A3a,
--C(.dbd.S)N(R.sup.A3b).sub.2, --OC(.dbd.S)R.sup.A3a,
--OC(.dbd.S)OR.sup.A3a, --OC(.dbd.S)SR.sup.A3a,
--OC(.dbd.S)N(R.sup.A3b).sub.2, --NR.sup.A3bC(.dbd.S)R.sup.A3b,
--NR.sup.A3bC(.dbd.S)OR.sup.A3a, --NR.sup.A3bC(.dbd.S)SR.sup.A3a,
--NR.sup.A3bC(.dbd.S)N(R.sup.A3b).sub.2, --SC(.dbd.S)R.sup.A3a,
--SC(.dbd.S)OR.sup.A3a, --SC(.dbd.S)SR.sup.A3a,
--SC(.dbd.S)N(R.sup.A3b).sub.2, --S(.dbd.O)R.sup.A3a,
--SO.sub.2R.sup.A3a, --NR.sup.A3bSO.sub.2R.sup.A3a,
--SO.sub.2N(R.sup.A3b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.A3a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.A3b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.A3b groups are joined to
form an optionally substituted heterocyclic ring;
[0121] m is 0, 1, 2, 3, or 4; and
[0122] n is 0, 1, 2, or 3.
[0123] In certain embodiments, X.sup.A1, X.sup.A2, and X.sup.A3 are
oxygen. In certain embodiments, X.sup.A1 and X.sup.A2 are oxygen,
and X.sup.A3 is sulfur. In certain embodiments, X.sup.A1 and
X.sup.A3 are oxygen, and X.sup.A2 is sulfur. In certain
embodiments, X.sup.A2 and X.sup.A3 are oxygen, and X.sup.A1 is
sulfur. In certain embodiments, X.sup.A1 and X.sup.A2 are sulfur,
and X.sup.A3 is oxygen. In certain embodiments, X.sup.A1 and
X.sup.A3 are sulfur, and X.sup.A2 is oxygen. In certain
embodiments, X.sup.A2 and X.sup.A3 are sulfur, and X.sup.A1 is
oxygen. In certain embodiments, X.sup.A1, X.sup.A2, and X.sup.A3
are sulfur.
[0124] In certain embodiments, R.sup.A1 is hydrogen. In certain
embodiments, R.sup.A1 is a nitrogen protecting group. In certain
embodiments, R.sup.A1 is C.sub.1-6 alkyl. In certain embodiments,
R.sup.A1 is methyl.
[0125] In certain embodiments, R.sup.A2 is hydrogen. In certain
embodiments, R.sup.A2 is a nitrogen protecting group. In certain
embodiments, R.sup.A2 is C.sub.1-6 alkyl. In certain embodiments,
R.sup.A2 is methyl.
[0126] In certain embodiments, R.sup.A1 and R.sup.A2 are both
hydrogen.
[0127] In certain embodiments, X.sup.A1 and X.sup.A3 are oxygen,
X.sup.A2 is sulfur, and R.sup.A1 and R.sup.A2 are hydrogen.
[0128] In certain embodiments, Ar is aryl. In certain embodiments,
Ar is substituted aryl. In certain embodiments, Ar is heteroaryl.
In certain embodiments, Ar is substituted heteroaryl.
[0129] In certain embodiments, each instance of R.sup.A3 is
independently optionally substituted alkyl. In certain embodiments,
each instance of R.sup.A3 is independently optionally substituted
C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.A3
is independently optionally substituted methyl. In certain
embodiments, each instance of R.sup.A3 is independently methyl.
[0130] In certain embodiments, each instance of R.sup.A4 is
independently optionally substituted alkyl. In certain embodiments,
each instance of R.sup.A4 is independently optionally substituted
C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.A4
is independently optionally substituted methyl. In certain
embodiments, each instance of R.sup.A4 is independently optionally
substituted hydroxyl-substituted alkyl. In certain embodiments,
each instance of R.sup.A4 is independently optionally substituted
hydroxyl-substituted C.sub.1-6 alkyl. In certain embodiments, each
instance of R.sup.A4 is independently substituted hydroxymethyl. In
certain embodiments, each instance of R.sup.A4 is independently
hydroxymethyl.
[0131] In certain embodiments, m is 0. In certain embodiments, m is
1. In certain embodiments, m is 2. In certain embodiments, m is 3.
In certain embodiments, m is 4.
[0132] In certain embodiments, X.sup.A1 and X.sup.A3 are oxygen,
X.sup.A2 is sulfur, R.sup.A1 and R.sup.A2 are hydrogen, and m is
0.
[0133] In certain embodiments, n is 0. In certain embodiments, n is
1. In certain embodiments, n is 2. In certain embodiments, n is
3.
[0134] In certain embodiments, wherein Ar is optionally substituted
phenyl, provided is a compound of Formula (A-I):
##STR00008##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0135] X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3,
R.sup.A4, m, and n are as defined herein;
[0136] each instance of R.sup.A1 is independently selected from the
group consisting of halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.AIa, --N(R.sup.AIbm).sub.2, --SR.sup.AIa,
--C(.dbd.O)R.sup.AIa, --C(.dbd.O)OR.sup.AIa, --C(.dbd.O)SR.sup.AIa,
--C(.dbd.O)N(R.sup.AIb).sub.2, --OC(.dbd.O)R.sup.AIa,
--OC(.dbd.O)OR.sup.AIa, --OC(.dbd.O)SR.sup.AIa,
--OC(.dbd.O)N(R.sup.AIb).sub.2, --NR.sup.AIbC(.dbd.O)R.sup.AIb,
--NR.sup.AIbC(.dbd.O)OR.sup.AIa, --NR.sup.AIbC(.dbd.O)SR.sup.AIa,
--NR.sup.AIbC(.dbd.O)N(R.sup.AIb).sub.2, --SC(.dbd.O)R.sup.AIa,
--SC(.dbd.O)OR.sup.AIa, --SC(.dbd.O)SR.sup.AIa,
--SC(.dbd.O)N(R.sup.AIb).sub.2, --C(.dbd.NR.sup.AIb)R.sup.AIa,
--C(.dbd.NR.sup.AIb)OR.sup.AIa, --C(.dbd.NR.sup.AIb)SR.sup.AIa,
--C(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2,
--OC(.dbd.NR.sup.AIb)R.sup.AIa, --OC(.dbd.NR.sup.AIb)OR.sup.AIa,
--OC(.dbd.NR.sup.AIb)SR.sup.AIa,
--OC(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2,
--NR.sup.AIbC(.dbd.NR.sup.AIb)R.sup.AIb,
--NR.sup.AIbC(.dbd.NR.sup.AIb)OR.sup.AIa,
--NR.sup.AIbC(.dbd.NR.sup.AIb)SR.sup.AIa,
--NR.sup.AIbC(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2,
--SC(.dbd.NR.sup.AIb)R.sup.AIa, --SC(.dbd.NR.sup.AIb)OR.sup.AIa,
--SC(.dbd.NR.sup.AIb)SR.sup.AIa,
--SC(.dbd.NR.sup.AIb)N(R.sup.AIb).sub.2, --C(.dbd.S)R.sup.AIa,
--C(.dbd.S)OR.sup.AIa, --C(.dbd.S)SR.sup.AIa,
--C(.dbd.S)N(R.sup.AIb).sub.2, --OC(.dbd.S)R.sup.AIa,
--OC(.dbd.S)OR.sup.AIa, --OC(.dbd.S)SR.sup.AIa,
--OC(.dbd.S)N(R.sup.AIb).sub.2, --NR.sup.AIbC(.dbd.S)R.sup.AIb,
--NR.sup.AIbC(.dbd.S)OR.sup.AIa, --NR.sup.AIbC(.dbd.S)SR.sup.AIa,
--NR.sup.AIbC(.dbd.S)N(R.sup.AIb).sub.2, --SC(.dbd.S)R.sup.AIa,
--SC(.dbd.S)OR.sup.AIa, --SC(.dbd.S)SR.sup.AIa,
--SC(.dbd.S)N(R.sup.AIb).sub.2, --S(.dbd.O)R.sup.Ala,
--SO.sub.2R.sup.AIa, --NR.sup.AIbSO.sub.2R.sup.AIa,
--SO.sub.2N(R.sup.AIb).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.AIa is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, or each occurrence of R.sup.AIb is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.AIb groups are joined to
form a heterocyclic ring; and
[0137] j is 0, 1, 2, 3, 4, or 5.
[0138] In certain embodiments of Formula (A-I), j is 0. In certain
embodiments, j is 1. In certain embodiments, j is 2. In certain
embodiments, j is 3. In certain embodiments, j is 4. In certain
embodiments, j is 5.
[0139] In certain embodiments, provided is a compound of any of the
formulae:
##STR00009##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.A1,
X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4,
R.sup.AI, m, and n are as defined herein.
[0140] In certain embodiments, provided is a compound of any of the
formulae:
##STR00010##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein wherein
R.sup.A3, R.sup.A4, R.sup.AI, m, and n are as defined herein.
[0141] In certain embodiments, R.sup.AI is C.sub.1-6 alkyl. In
certain embodiments, R.sup.AI is methyl. In certain embodiments,
R.sup.AI is ethyl. In certain embodiments, R.sup.AI is propyl. In
certain embodiments, R.sup.AI is butyl.
[0142] In certain embodiments, provided is a compound of any of the
formulae:
##STR00011##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.A1
X.sup.A2, X.sup.A3, Ar, R.sup.A1, R.sup.A2, and R.sup.A4 are as
defined herein.
[0143] In certain embodiments, provided is a compound of any of the
formulae:
##STR00012##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.A1,
X.sup.A2, X.sup.A3, Ar, R.sup.A1, R.sup.A2, and R.sup.A3 are as
defined herein.
[0144] In certain embodiments, wherein Ar is a optionally
substituted thiophenyl, provided is a compound of Formula
(A-VI):
##STR00013##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0145] X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3,
R.sup.A4, m, and n are as defined herein;
[0146] each instance of R.sup.AII is independently selected from
the group consisting of halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.AIIa, --N(R.sup.AIIb).sub.2, --SR.sup.AIIa,
--C(.dbd.O)R.sup.AIIa, --C(.dbd.O)OR.sup.AIIa,
--C(.dbd.O)SR.sup.AIIa, --C(.dbd.O)N(R.sup.AIIb).sub.2,
--OC(.dbd.O)R.sup.AIIa, --OC(.dbd.O)OR.sup.AIIa,
--OC(.dbd.O)SR.sup.AIIa, --OC(.dbd.O)N(R.sup.AIIb).sub.2,
--NR.sup.AIIbC(.dbd.O)R.sup.AIIb,
--NR.sup.AIIbC(.dbd.O)OR.sup.AIIa,
--NR.sup.AIIbC(.dbd.O)SR.sup.AIIa,
--NR.sup.AIIbC(.dbd.O)N(R.sup.AIIb).sub.2, --SC(.dbd.O)R.sup.AIIa,
--SC(.dbd.O)OR.sup.AIIa, --SC(.dbd.O)SR.sup.AIIa,
--SC(.dbd.O)N(R.sup.AIIb).sub.2, --C(.dbd.NR.sup.AIIb)R.sup.AIIa,
--C(.dbd.NR.sup.AIIb)OR.sup.AIIa, --C(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--C(.dbd.NR.sup.AIIb)N(R.sup.AIb).sub.2,
--OC(.dbd.NR.sup.AIIb)R.sup.AIIa,
--OC(.dbd.NR.sup.AIIb)OR.sup.AIIa,
--OC(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--OC(.dbd.NR.sup.AIIb)N(R.sup.AIb).sub.2,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)R.sup.AIIb,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)OR.sup.AIIa,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--NR.sup.AIIbC(.dbd.NR.sup.AIIb)N(R.sup.AIIb).sub.2,
--SC(.dbd.NR.sup.AIIb)R.sup.AIIa,
--SC(.dbd.NR.sup.AIIb)OR.sup.AIIa,
--SC(.dbd.NR.sup.AIIb)SR.sup.AIIa,
--SC(.dbd.NR.sup.AIIb)N(R.sup.AIIb).sub.2, --C(.dbd.S)R.sup.AIIa,
--C(.dbd.S)OR.sup.AIIa, --C(.dbd.S)SR.sup.AIIa,
--C(.dbd.S)N(R.sup.AIIb).sub.2, --OC(.dbd.S)R.sup.AIIa,
--OC(.dbd.S)OR.sup.AIIa, --OC(.dbd.S)SR.sup.AIIa
OC(.dbd.S)N(R.sup.AIIb).sub.2, --NR.sup.AIIbC(.dbd.S)R.sup.AIb,
--NR.sup.AIbC(.dbd.S)OR.sup.AIIa,
--NR.sup.AIIbC(.dbd.S)SR.sup.AIIa,
--NR.sup.AIIbC(.dbd.S)N(R.sup.AIb).sub.2, --SC(.dbd.S)R.sup.AIIa,
--SC(.dbd.S)OR.sup.AIIa, --SC(.dbd.S)SR.sup.AIIa,
--SC(.dbd.S)N(R.sup.AIIb).sub.2, --S(.dbd.O)R.sup.AIIa,
--SO.sub.2R.sup.AIIa, --NR.sup.AIIbSO.sub.2R.sup.AIIa,
--SO.sub.2N(R.sup.AIIb).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.AIIa is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, and each occurrence of R.sup.AIb is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.AIIb groups are joined to
form a heterocyclic ring; and
[0147] k is 0, 1, 2, or 3.
[0148] In certain embodiments of Formula (A-VI), k is 0. In certain
embodiments, k is 1. In certain embodiments, k is 2. In certain
embodiments, k is 3.
[0149] In certain embodiments of Formula (A-VI), wherein k is 1,
provided is a compound of any of the formulae:
##STR00014##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.A1,
X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4,
R.sup.AII, m, and n are as defined herein.
[0150] In certain embodiments of Formula (A-VI), wherein n is 1,
provided is a compound of any of the formulae:
##STR00015##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.A1,
X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4,
R.sup.AII, k, and m are as defined herein.
[0151] In certain embodiments of Formula (A-VI), provided is a
compound of any of the formulae:
##STR00016##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.A1,
X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.AII, k, and
m are as defined herein.
[0152] In certain embodiments, provided is a compound of any of the
formulae:
##STR00017##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.A3,
R.sup.AII, k, and m are as defined herein.
[0153] In a certain embodiment, the compound of Formula (A) is not
of the formula:
##STR00018##
or a pharmaceutically acceptable salt thereof.
[0154] Another hit from the library was identified with a
structural framework as shown in Formula (B):
##STR00019##
Therefore, in certain embodiments, provided is a compound of
Formula (B), and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, wherein
[0155] each instance of X.sup.B1, X.sup.B3, and X.sup.B4 is
independently oxygen, sulfur, --NR.sup.B4a, or C(R.sup.B4b).sub.2,
wherein R.sup.B4a is hydrogen, a nitrogen protecting group, or
C.sub.1-6 alkyl, and each occurrence of R.sup.B4b is hydrogen,
halogen, or C.sub.1-6 alkyl, or two R.sup.B4b groups are joined to
form an optionally substituted carbocyclic or heterocyclic
ring;
[0156] X.sup.B2 is nitrogen or CR.sup.B2a, wherein R.sup.B2a is
hydrogen, halogen, or C.sub.1-6 alkyl;
[0157] each instance of R.sup.B1 is independently selected from the
group consisting of halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.B1a, --N(R.sup.B1b).sub.2, --SR.sup.B1a,
--C(.dbd.O)R.sup.B1a, --C(.dbd.O)OR.sup.B1a, --C(.dbd.O)SR.sup.B1a,
--C(.dbd.O)N(R.sup.B1b).sub.2, --OC(.dbd.O)R.sup.B1a,
--OC(.dbd.O)OR.sup.B1a, --OC(.dbd.O)SR.sup.B1a,
--OC(.dbd.O)N(R.sup.B1b).sub.2, --NR.sup.B1bC(.dbd.O)R.sup.B1b,
--NR.sup.B1bC(.dbd.O)OR.sup.B1a, --NR.sup.B1bC(.dbd.O)SR.sup.B1a
NR.sup.B1bC(.dbd.O)N(R.sup.B1b).sub.2, --SC(.dbd.O)R.sup.B1a,
--SC(.dbd.O)OR.sup.B1a, --SC(.dbd.O)SR.sup.B1a,
--SC(.dbd.O)N(R.sup.B1b).sub.2, --C(.dbd.NR.sup.B1b)R.sup.B1a,
--C(.dbd.NR.sup.B1b)OR.sup.B1a, --C(.dbd.NR.sup.B1b)SR.sup.B1a,
--C(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--OC(.dbd.NR.sup.B1b)R.sup.B1a, --OC(.dbd.NR.sup.B1b)OR.sup.B1a,
--OC(.dbd.NR.sup.B1b)SR.sup.B1a,
--OC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--NR.sup.B1bC(.dbd.NR.sup.B1b)R.sup.B1b,
--NR.sup.B1bC(.dbd.NR.sup.B1b)OR.sup.B1a,
--NR.sup.B1bC(.dbd.NR.sup.B1b)SR.sup.B1a,
--NR.sup.B1bC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2,
--SC(.dbd.NR.sup.B1b)R.sup.B1a, --SC(.dbd.NR.sup.B1b)OR.sup.B1a,
--SC(.dbd.NR.sup.B1b)SR.sup.B1a,
--SC(.dbd.NR.sup.B1b)N(R.sup.B1b).sub.2, --C(.dbd.S)R.sup.B1a,
--C(.dbd.S)OR.sup.B1a, --C(.dbd.S)SR.sup.B1a,
--C(.dbd.S)N(R.sup.B1b).sub.2, --OC(.dbd.S)R.sup.B1a,
--OC(.dbd.S)OR.sup.B1a, --OC(.dbd.S)SR.sup.B1a,
--OC(.dbd.S)N(R.sup.B1b).sub.2, --NR.sup.B1bC(.dbd.S)R.sup.B1b,
--NR.sup.B1bC(.dbd.S)OR.sup.B1a, --NR.sup.B1bC(.dbd.S)SR.sup.B1a,
--NR.sup.B1bC(.dbd.S)N(R.sup.B1b).sub.2, --SC(.dbd.S)R.sup.B1a,
--SC(.dbd.S)OR.sup.B1a, --SC(.dbd.S)SR.sup.B1a,
--SC(.dbd.S)N(R.sup.B1b).sub.2, --S(.dbd.O)R.sup.B1a,
--SO.sub.2R.sup.B1a, --NR.sup.B1bSO.sub.2R.sup.B1a,
--SO.sub.2N(R.sup.B1b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.B1a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.B1b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.B1b groups are joined to
form an optionally substituted heterocyclic ring;
[0158] each instance of R.sup.B2, R.sup.B3, R.sup.B4, and R.sup.B5
is independently hydrogen, halogen, or C.sub.1-6 alkyl;
[0159] R.sup.B6 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.B6a, --N(R.sup.B6b).sub.2, or --SR.sup.B6a
wherein each occurrence of R.sup.B6a is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, and each occurrence of
R.sup.B6b is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or a nitrogen protecting group, or two R.sup.B6b groups
are joined to form an optionally substituted heterocyclic ring;
[0160] p is 0, 1, 2, 3, or 4.
[0161] In certain embodiments, X.sup.B1 is oxygen. In certain
embodiments, X.sup.B1 is sulfur. In certain embodiments, X.sup.B1
is NR.sup.B4a, wherein NR.sup.B4a is as defined herein. In certain
embodiments, X.sup.B1 is NH. In certain embodiments, X.sup.B1 is
C(R.sup.B4b).sub.2, wherein R.sup.B4b is defined herein.
[0162] In certain embodiments, X.sup.B2 is nitrogen. In certain
embodiments, X.sup.B2 is CR.sup.B2a, wherein R.sup.B2a is as
defined herein.
[0163] In certain embodiments, X.sup.B3 is oxygen. In certain
embodiments, X.sup.B3 is sulfur. In certain embodiments, X.sup.B3
is NR.sup.B4a, wherein NR.sup.B4a is as defined herein. In certain
embodiments, X.sup.B3 is NH. In certain embodiments, X.sup.B3 is
C(R.sup.B4b).sub.2, wherein R.sup.B4b is defined herein.
[0164] In certain embodiments, X.sup.B4 is oxygen. In certain
embodiments, X.sup.B4 is sulfur. In certain embodiments, X.sup.B4
is NR.sup.B4a, wherein NR.sup.B4a is as defined herein. In certain
embodiments, X.sup.B4 is NH. In certain embodiments, X.sup.B4 is
C(R.sup.B4b).sub.2, wherein R.sup.B4b is defined herein.
[0165] In certain embodiments, X.sup.B1 is NH, and X.sup.B2 is
nitrogen.
[0166] In certain embodiments, one or more R.sup.B1 is
independently selected from the group consisting of halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl. In certain embodiments, one or
more R.sup.B1 is independently halogen. In certain embodiments, one
or more R.sup.B1 is independently C.sub.1-6 alkyl.
[0167] In certain embodiments, R.sup.B2 is hydrogen. In certain
embodiments, R.sup.B2 is halogen. In certain embodiments, R.sup.B2
is fluorine. In certain embodiments, R.sup.B2 is chlorine. In
certain embodiments, R.sup.B2 is bromine. In certain embodiments,
R.sup.B2 is iodine. In certain embodiments, R.sup.B2 is C.sub.1-6
alkyl. In certain embodiments, R.sup.B2 is methyl. In certain
embodiments, R.sup.B2 is ethyl. In certain embodiments, R.sup.B2 is
propyl. In certain embodiments, R.sup.B2 is butyl.
[0168] In certain embodiments, R.sup.B3 is hydrogen. In certain
embodiments, R.sup.B3 is halogen. In certain embodiments, R.sup.B3
is fluorine. In certain embodiments, R.sup.B3 is chlorine. In
certain embodiments, R.sup.B3 is bromine. In certain embodiments,
R.sup.B3 is iodine. In certain embodiments, R.sup.B3 is C.sub.1-6
alkyl. In certain embodiments, R.sup.B3 is methyl. In certain
embodiments, R.sup.B3 is ethyl. In certain embodiments, R.sup.B3 is
propyl. In certain embodiments, R.sup.B3 is butyl.
[0169] In certain embodiments, R.sup.B4 is hydrogen. In certain
embodiments, R.sup.B4 is halogen. In certain embodiments, R.sup.B4
is fluorine. In certain embodiments, R.sup.B4 is chlorine. In
certain embodiments, R.sup.B4 is bromine. In certain embodiments,
R.sup.B4 is iodine. In certain embodiments, R.sup.B4 is C.sub.1-6
alkyl. In certain embodiments, R.sup.B4 is methyl. In certain
embodiments, R.sup.B4 is ethyl. In certain embodiments, R.sup.B4 is
propyl. In certain embodiments, R.sup.B4 is butyl.
[0170] In certain embodiments, R.sup.B5 is hydrogen. In certain
embodiments, R.sup.B5 is halogen. In certain embodiments, R.sup.B5
is fluorine. In certain embodiments, R.sup.B5 is chlorine. In
certain embodiments, R.sup.B5 is bromine. In certain embodiments,
R.sup.B5 is iodine. In certain embodiments, R.sup.B5 is C.sub.1-6
alkyl. In certain embodiments, R.sup.B5 is methyl. In certain
embodiments, R.sup.B5 is ethyl. In certain embodiments, R.sup.B5 is
propyl. In certain embodiments, R.sup.B5 is butyl.
[0171] In certain embodiments, R.sup.B6 is hydrogen. In certain
embodiments, R.sup.B6 is optionally substituted alkyl. In certain
embodiments, R.sup.B6 is optionally substituted C.sub.1-6 alkyl. In
certain embodiments, R.sup.B6 is methyl. In certain embodiments,
R.sup.B6 is ethyl. In certain embodiments, R.sup.B6 is propyl. In
certain embodiments, R.sup.B6 is butyl. In certain embodiments,
R.sup.B6 is pentyl. In certain embodiments, R.sup.B6 is hexyl.
[0172] In certain embodiments, p is 0. In certain embodiments, p is
1. In certain embodiments, p is 2. In certain embodiments, p is 3.
In certain embodiments, p is 4.
[0173] In certain embodiments of Formula (B), wherein p is 1,
provided is a compound of any one of the formulae:
##STR00020##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.B1,
X.sup.B2, X.sup.B3, X.sup.B4, R.sup.B1, R.sup.B2, R.sup.B3,
R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.
[0174] In certain embodiments, provided is a compound of Formula
(B-II):
##STR00021##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.B3,
X.sup.B4, R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are
as defined herein.
[0175] In certain embodiments, provided is a compound of Formula
(B-III):
##STR00022##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.B4,
R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined
herein.
[0176] In certain embodiments, provided is a compound of Formula
(B-IV):
##STR00023##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.B3,
R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined
herein.
[0177] In certain embodiments, provided is a compound of Formula
(B-V):
##STR00024##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.B2,
R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined
herein.
[0178] In certain embodiments, provided is a compound of Formula
(B-VI):
##STR00025##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.B4,
R.sup.B5 and R.sup.B6 are as defined herein.
[0179] In certain embodiments, provided is a compound of Formula
(B-VII):
##STR00026##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.B6 is as
defined herein.
[0180] In certain embodiments, provided is a compound of Formula
(B-VIII):
##STR00027##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.B3,
X.sup.B4, R.sup.B2, R.sup.B3, R.sup.B4, and R.sup.B5 are as defined
herein.
[0181] In certain embodiments, provided is a compound of Formula
(B-IX):
##STR00028##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.B1,
X.sup.B2, X.sup.B3, R.sup.B1, R.sup.B4, and R.sup.B5 are as defined
herein.
[0182] In a certain embodiment, the compound of Formula (B) is not
of the formula:
##STR00029##
or a pharmaceutically acceptable salt thereof.
[0183] Another hit from the library was identified with a
structural framework as shown in Formula (C):
##STR00030##
Therefore, in certain embodiments, provided is a compound of
Formula (C), and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, wherein
[0184] X.sup.C1 is oxygen, sulfur, or NR.sup.C1a, wherein R.sup.C1a
is hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl;
[0185] each instance of X.sup.C2, X.sup.C3, and X.sup.C4 is
independently nitrogen or CR.sup.C4a, wherein R.sup.C4a is
hydrogen, halogen, or C.sub.1-6 alkyl;
[0186] L is a bond; cyclic or acyclic, substituted or unsubstituted
alkylene; cyclic or acyclic, substituted or unsubstituted
alkenylene; cyclic or acyclic, substituted or unsubstituted
alkynylene; cyclic or acyclic, substituted or unsubstituted
heteroalkylene; cyclic or acyclic, substituted or unsubstituted
heteroalkenylene; cyclic or acyclic, substituted or unsubstituted
heteroalkynylene; substituted or unsubstituted arylene; or
substituted or unsubstituted heteroarylenelene;
[0187] each instance of R.sup.C1 and R.sup.C2 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.C2a, --N(R.sup.C2b).sub.2,
--SR.sup.C2a, --C(.dbd.O)R.sup.C2a, --C(.dbd.O)OR.sup.C2a,
--C(.dbd.O)SR.sup.C2a, --C(.dbd.O)N(R.sup.C2b).sub.2,
--OC(.dbd.O)R.sup.C2a, --OC(.dbd.O)OR.sup.C2a,
--OC(.dbd.O)SR.sup.C2a, --OC(.dbd.O)N(R.sup.C2b).sub.2,
--NR.sup.C2bC(.dbd.O)R.sup.C2b, --NR.sup.C2bC(.dbd.O)OR.sup.C2a,
--NR.sup.C2bC(.dbd.O)SR.sup.C2a,
--NR.sup.C2bC(.dbd.O)N(R.sup.C2b).sub.2, --SC(.dbd.O)R.sup.C2a,
--SC(.dbd.O)OR.sup.C2a, --SC(.dbd.O)SR.sup.C2a,
--SC(.dbd.O)N(R.sup.C2b).sub.2, --C(.dbd.NR.sup.C2b)R.sup.C2a,
--C(.dbd.NR.sup.C2b)OR.sup.C2a, --C(.dbd.NR.sup.C2b)SR.sup.C2a,
--C(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2,
--OC(.dbd.NR.sup.C2b)R.sup.C2a, --OC(.dbd.NR.sup.C2b)OR.sup.C2a,
--OC(.dbd.NR.sup.C2b)SR.sup.C2a,
--OC(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2,
--NR.sup.C2bC(.dbd.NR.sup.C2b)R.sup.C2b,
--NR.sup.C2bC(.dbd.NR.sup.C2b)OR.sup.C2a,
--NR.sup.C2bC(.dbd.NR.sup.C2b)SR.sup.C2a,
--NR.sup.C2bC(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2,
--SC(.dbd.NR.sup.C2b)R.sup.C2a, --SC(.dbd.NR.sup.C2b)OR.sup.C2a,
--SC(.dbd.NR.sup.C2b)SR.sup.C2a,
--SC(.dbd.NR.sup.C2b)N(R.sup.C2b).sub.2, --C(.dbd.S)R.sup.C2a,
--C(.dbd.S)OR.sup.C2a, --C(.dbd.S)SR.sup.C2a,
--C(.dbd.S)N(R.sup.C2b).sub.2, --OC(.dbd.S)R.sup.C2a,
--OC(.dbd.S)OR.sup.C2a, --OC(.dbd.S)SR.sup.C2a,
--OC(.dbd.S)N(R.sup.C2b).sub.2, --NR.sup.C2bC(.dbd.S)R.sup.C2b,
--NR.sup.C2bC(.dbd.S)OR.sup.C2a, --NR.sup.C2bC(.dbd.S)SR.sup.C2a,
--NR.sup.C2bC(.dbd.S)N(R.sup.C2b).sub.2, --SC(.dbd.S)R.sup.C2a,
--SC(.dbd.S)OR.sup.C2a, --SC(.dbd.S)SR.sup.C2a,
--SC(.dbd.S)N(R.sup.C2b).sub.2, --S(.dbd.O)R.sup.C2a,
--SO.sub.2R.sup.C2a, --NR.sup.C2bSO.sub.2R.sup.C2a,
--SO.sub.2N(R.sup.C2b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.C2a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.C2b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.C2b groups are joined to
form an optionally substituted heterocyclic ring;
[0188] q is 0, 1, 2, 3, or 4;
[0189] r is 0, 1, 2, 3, 4, or 5, and
[0190] In certain embodiments, X.sup.C1 is NR.sup.C1a, wherein
R.sup.C1a is hydrogen, a nitrogen protecting group, or C.sub.1-6
alkyl. In certain embodiments, X.sup.C1 is NH. In certain
embodiments, X.sup.C1 is oxygen. In certain embodiments, X.sup.C1
is sulfur.
[0191] In certain embodiments, X.sup.C2 is nitrogen. In certain
embodiments, X.sup.C2 is CR.sup.C4a. In certain embodiments,
X.sup.C3 is nitrogen. In certain embodiments, X.sup.C3 is
CR.sup.C4a. In certain embodiments, X.sup.C4 is nitrogen. In
certain embodiments, X.sup.C4 is CR.sup.C4a. In any of the above
described embodiments, each instance of R.sup.C4a is independently
nitrogen or CR.sup.C4a, wherein R.sup.C4a is hydrogen, halogen, or
C.sub.1-6 alkyl.
[0192] In certain embodiments, L is a bond. In certain embodiments,
L is cyclic or acyclic, substituted or unsubstituted alkylene. In
certain embodiments, L is cyclic or acyclic, substituted or
unsubstituted alkenylene. In certain embodiments, L is cyclic or
acyclic, substituted or unsubstituted alkynylene. In certain
embodiments, L is cyclic or acyclic, substituted or unsubstituted
heteroalkylene. In certain embodiments, L is cyclic or acyclic,
substituted or unsubstituted heteroalkenylene. In certain
embodiments, L is cyclic or acyclic, substituted or unsubstituted
heteroalkynylene. In certain embodiments, L is substituted or
unsubstituted arylene. In certain embodiments, L is substituted or
unsubstituted heteroarylene.
[0193] In certain embodiments, wherein L is substituted or
unsubstituted heteroalkenylene, L comprises at least 5 atoms which
are not hydrogen. In certain embodiments, wherein L is substituted
or unsubstituted heteroalkenylene, L comprises at least 4 atoms
which are not hydrogen. In certain embodiments, wherein L is
substituted or unsubstituted heteroalkenylene, L comprises at least
3 atoms which are not hydrogen. In certain embodiments, wherein L
is substituted or unsubstituted heteroalkenylene, L comprises at
least 2 atoms which are not hydrogen.
[0194] In certain embodiments, each instance of R.sup.C1 is
independently selected from the group consisting of halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
and optionally substituted heteroaryl. In certain embodiments, at
least one R.sup.C1 is C.sub.1-6 alkyl. In certain embodiments, at
least one R.sup.C1 is methyl. In certain embodiments, at least one
R.sup.C1 is ethyl. In certain embodiments, at least one R.sup.C1 is
propyl. In certain embodiments, at least one R.sup.C1 is butyl.
[0195] In certain embodiments, q is 0. In certain embodiments, q is
1. In certain embodiments, q is 2. In certain embodiments, q is 3.
In certain embodiments, q is 4.
[0196] In certain embodiments, r is 0. In certain embodiments, r is
1. In certain embodiments, r is 2. In certain embodiments, r is 3.
In certain embodiments, r is 4. In certain embodiments, r is 5.
[0197] In certain embodiments, X.sup.C1, X.sup.C2, X.sup.C3, and
X.sup.C4 are nitrogen.
[0198] In certain embodiments, provided is a compound of Formula
(C-I):
##STR00031##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0199] X.sup.C1, X.sup.C2, X.sup.C3, X.sup.C4, R.sup.C1, R.sup.C2,
q, and r are as defined herein;
[0200] X.sup.C5 is oxygen, sulfur, --NR.sup.C5a, or
C(R.sup.C5b).sub.2, wherein R.sup.C5a is hydrogen or C.sub.1-6
alkyl, and each occurrence of R.sup.C5b is hydrogen, halogen, or
C.sub.1-6 alkyl, or two R.sup.C5b groups are joined to form an
optionally substituted carbocyclic or heterocyclic ring; and
[0201] each instance of X.sup.C6 and X.sup.C7 is independently
nitrogen or CR.sup.C7a, wherein R.sup.C7a is hydrogen, halogen, or
C.sub.1-6 alkyl.
[0202] In certain embodiments of Formula (C-I), or a
pharmaceutically acceptable salt thereof, X.sup.C5 is NH. In
certain embodiments of Formula (C-I), or a pharmaceutically
acceptable salt thereof, X.sup.C5 is NR.sup.C5a, wherein R.sup.C5a
is as defined herein.
[0203] In certain embodiments of Formula (C-I), or a
pharmaceutically acceptable salt thereof, X.sup.C6 is nitrogen.
[0204] In certain embodiments of Formula (C-I), or a
pharmaceutically acceptable salt thereof, X.sup.C7 is CH. In
certain embodiments of Formula (C-I), or a pharmaceutically
acceptable salt thereof, X.sup.C7 is C(R.sup.C5b).sub.2, wherein
R.sup.C5b is as defined herein.
[0205] In certain embodiments of Formula (C-I), provided is a
compound of Formula (C-II):
##STR00032##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein X.sup.C1,
X.sup.C2, X.sup.C3, X.sup.C4, R.sup.C1, R.sup.C2, q, and r are as
defined herein.
[0206] In certain embodiments, provided is a compound of Formula
(C-III):
##STR00033##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1,
R.sup.C2, q, and r are as defined herein.
[0207] In certain embodiments of Formula (C-III), wherein q is 1,
provided is a compound of any of the formulae:
##STR00034##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1,
R.sup.C2, and r are as defined herein.
[0208] In certain embodiments of the formulae (C-III-a), (C-III-b),
(C-III-c), and (C-III-d), or a pharmaceutically acceptable salt
thereof, wherein R.sup.C2 and r are as defined herein, R.sup.C1 is
C.sub.1-6 alkyl. In certain embodiments of the formulae (C-III-a),
(C-III-b), (C-III-c), and (C-III-d), or a pharmaceutically
acceptable salt thereof, wherein R.sup.C2 and r are as defined
herein, R.sup.C1 is methyl. In certain embodiments of the formulae
(C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a
pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r
are as defined herein, R.sup.C1 is ethyl. In certain embodiments of
the formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a
pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r
are as defined herein, R.sup.C1 propyl. In certain embodiments of
the formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a
pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r
are as defined herein, R.sup.C1 is butyl.
[0209] In certain embodiments, provided is a compound of Formula
(C-IV):
##STR00035##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C2 and r
are as defined herein.
[0210] In certain embodiments, provided is a compound of Formula
(C-V):
##STR00036##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0211] each instance of R.sup.C3 and R.sup.C4 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.C4a, --N(R.sup.C4b).sub.2,
--SR.sup.C4a, --C(.dbd.O)R.sup.C4a, --C(.dbd.O)OR.sup.C4a,
--C(.dbd.O)SR.sup.C4a, --C(.dbd.O)N(R.sup.C4b).sub.2,
--OC(.dbd.O)R.sup.C4a, --OC(.dbd.O)OR.sup.C4a,
--OC(.dbd.O)SR.sup.C4a, --OC(.dbd.O)N(R.sup.C4b).sub.2,
--NR.sup.C4bC(.dbd.O)R.sup.C4b, --NR.sup.C4bC(.dbd.O)OR.sup.C4a,
--NR.sup.C4bC(.dbd.O)SR.sup.C4a,
--NR.sup.C4bC(.dbd.O)N(R.sup.C4b).sub.2, --SC(.dbd.O)R.sup.C4a,
--SC(.dbd.O)OR.sup.C4a, --SC(.dbd.O)SR.sup.C4a,
--SC(.dbd.O)N(R.sup.C4b).sub.2, --C(.dbd.NR.sup.C4b)R.sup.C4a,
--C(.dbd.NR.sup.C4b)OR.sup.C4a, --C(.dbd.NR.sup.C4b)SR.sup.C4a,
--C(.dbd.NR.sup.C4b)N(R.sup.C4b).sub.2,
--OC(.dbd.NR.sup.C4b)R.sup.C4a, --OC(.dbd.NR.sup.C4b)OR.sup.C4a,
--OC(.dbd.NR.sup.C4b)SR.sup.C4a,
--OC(.dbd.NR.sup.C4b)N(R.sup.C4b).sub.2,
--NR.sup.C4bC(.dbd.NR.sup.C4b)R.sup.C4b,
--NR.sup.C4bC(.dbd.NR.sup.C4b)OR.sup.C4a,
--NR.sup.C4bC(.dbd.NR.sup.C4b)SR.sup.C4a,
--NR.sup.C4bC(.dbd.NR.sup.C4b)N(R.sup.C4b).sub.2,
--SC(.dbd.NR.sup.C4b)R.sup.C4a, --SC(.dbd.NR.sup.C4b)OR.sup.C4a,
--SC(.dbd.NR.sup.C4b)SR.sup.C4a,
--SC(.dbd.NR.sup.C4b)N(R.sup.C4b).sub.2, --C(.dbd.S)R.sup.C4a,
--C(.dbd.S)OR.sup.C4a, --C(.dbd.S)SR.sup.C4a,
--C(.dbd.S)N(R.sup.C4b).sub.2, --OC(.dbd.S)R.sup.C4a,
--OC(.dbd.S)OR.sup.C4a, --OC(.dbd.S)SR.sup.C4a,
--OC(.dbd.S)N(R.sup.C4b).sub.2, --NR.sup.C4bC(.dbd.S)R.sup.C4b,
--NR.sup.C4bC(.dbd.S)OR.sup.C4a, --NR.sup.C4bC(.dbd.S)SR.sup.C4a,
--NR.sup.C4bC(.dbd.S)N(R.sup.C4b).sub.2, --SC(.dbd.S)R.sup.C4a,
--SC(.dbd.S)OR.sup.C4a, --SC(.dbd.S)SR.sup.C4a,
--SC(.dbd.S)N(R.sup.C4b).sub.2, --S(.dbd.O)R.sup.C4a,
--SO.sub.2R.sup.C4a, --NR.sup.C4bSO.sub.2R.sup.C4a,
--SO.sub.2N(R.sup.C4b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.C4a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.C4b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.C4b groups are joined to
form an optionally substituted heterocyclic ring; and
[0212] v is 0, 1, 2, or 3.
[0213] In certain embodiments, v is 0. In certain embodiments, v is
1. In certain embodiments, v is 2. In certain embodiments, v is
3.
[0214] In certain embodiments of Formula (C-V), wherein v is 1,
provided is a compound of any of the formulae:
##STR00037##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1,
R.sup.C2, R.sup.C3, R.sup.C4, and q are as defined herein.
[0215] In certain embodiments of the formulae (C-V-a), (C-V-b), and
(C-V-c), or a pharmaceutically acceptable salt thereof, R.sup.C2,
R.sup.C3, or R.sup.C4 is hydroxyl, --OR.sup.C2a,
--N(R.sup.C2b).sub.2, or --SR.sup.C2a, wherein R.sup.C1, q,
R.sup.C2a, and R.sup.C2b are as defined herein. In certain
embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), or a
pharmaceutically acceptable salt thereof, R.sup.C2 and R.sup.C3 are
independently hydroxyl, --OR.sup.C2a, --N(R.sup.C2b).sub.2, or
--SR.sup.C2a, wherein R.sup.C1, R.sup.C4, q, R.sup.C2a, and
R.sup.C2b are as defined herein. In certain embodiments of the
formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceutically
acceptable salt thereof, R.sup.C2 and R.sup.C4 are independently
hydroxyl, --OR.sup.C2a, --N(R.sup.C2b).sub.2, or --SR.sup.C2a,
wherein R.sup.C1, R.sup.C3, q, R.sup.C2a, and R.sup.C2b are as
defined herein. In certain embodiments of the formulae (C-V-a),
(C-V-b), and (C-V-c), or a pharmaceutically acceptable salt
thereof, R.sup.C3 and R.sup.C4 are independently hydroxyl,
--OR.sup.C2a, --N(R.sup.C2b).sub.2, or --SR.sup.C2a, wherein
R.sup.C1, R.sup.C2, q, R.sup.C2a, and R.sup.C2b are as defined
herein. In certain embodiments of the formulae (C-V-a), (C-V-b),
and (C-V-c), or a pharmaceutically acceptable salt thereof,
R.sup.C2, R.sup.C3, and R.sup.C4 are independently hydroxyl,
--OR.sup.C2a, --N(R.sup.C2b).sub.2, or --SR.sup.C2a, wherein
R.sup.C1, q, R.sup.C2a, and R.sup.C2b are as defined herein.
[0216] In certain embodiments of Formula (C-V), provided is a
compound of Formula (C-VI):
##STR00038##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1,
R.sup.C3, R.sup.C4, and q are as defined herein.
[0217] In certain embodiments of Formula (C-VI), or a
pharmaceutically acceptable salt thereof, R.sup.C3 is hydroxyl,
--OR.sup.C4a, --N(R.sup.C4b).sub.2, or --SR.sup.C4a, wherein
R.sup.C1, R.sup.C4, q, R.sup.C4a, and R.sup.C4b are as defined
herein. In certain embodiments of Formula (C-VI), or a
pharmaceutically acceptable salt thereof, R.sup.C4 is hydroxyl,
--OR.sup.C4a, --N(R.sup.C4b).sub.2, or --SR.sup.C4a, wherein
R.sup.C1, R.sup.C3 q, R.sup.C4a and R.sup.C4b are as defined
herein. In certain embodiments of Formula (C-VI), or a
pharmaceutically acceptable salt thereof, R.sup.C3 and R.sup.C4 are
independently hydroxyl, --OR.sup.C4a, --N(R.sup.C4b).sub.2 or
--SR.sup.C4a, wherein R.sup.C1, q, R.sup.C4a, and R.sup.C4b are as
defined herein. In certain embodiments of Formula (C-VI), R.sup.C3
and R.sup.C4 are both hydroxyl, --OR.sup.C4a, --N(R.sup.C4b).sub.2,
or --SR.sup.C4a, wherein R.sup.C1, q, R.sup.C4a, and R.sup.C4b are
as defined herein.
[0218] In certain embodiments of Formula (C-V), provided is a
compound of Formula (C-VII):
##STR00039##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1,
R.sup.C2, q, and v are as defined herein.
[0219] In certain embodiments of Formula (C-V), provided is a
compound of Formula (C-VIII):
##STR00040##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1 and q
are as defined herein.
[0220] In certain embodiments of Formula (C-VIII), or a
pharmaceutically acceptable salt thereof, each instance of R.sup.C1
is C.sub.1-6 alkyl. In certain embodiments of Formula (C-VIII), or
a pharmaceutically acceptable salt thereof, each instance of
R.sup.C1 is methyl. In certain embodiments of Formula (C-VIII), or
a pharmaceutically acceptable salt thereof, each instance of
R.sup.C1 is ethyl. In certain embodiments of Formula (C-VIII), or a
pharmaceutically acceptable salt thereof, each instance of R.sup.C1
is propyl. In certain embodiments of Formula (C-VIII), or a
pharmaceutically acceptable salt thereof, each instance of R.sup.C1
is butyl.
[0221] In certain embodiments of Formula (C-VIII), wherein q is 1,
provided is a compound of any of the formulae:
##STR00041##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.C1 is as
defined herein.
[0222] In certain embodiments, the compound of Formula (C) is not
of the formula:
##STR00042##
or a pharmaceutically acceptable salt thereof.
[0223] Another hit from the library was identified with a
structural framework as shown in Formula (D):
##STR00043##
Therefore, in certain embodiments, provided is a compound of
Formula (D), and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, wherein
[0224] each instance of X.sup.D1 is independently oxygen, sulfur,
--NR.sup.D1a, or C(R.sup.D1b).sub.2, wherein R.sup.D1a is hydrogen
or C.sub.1-6 alkyl, and each occurrence of R.sup.D1b is hydrogen,
halogen, or C.sub.1-6 alkyl, or two R.sup.D1b groups are joined to
form an optionally substituted carbocyclic or heterocyclic
ring;
[0225] s is 0, 1, 2, 3, 4, 5, or 6;
[0226] each instance of R.sup.D1 and R.sup.D2 is independently
hydrogen, an oxygen protecting group, C.sub.1-6 alkyl,
--C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a, --C(.dbd.O)SR.sup.D2a,
--C(.dbd.O)N(R.sup.D2b).sub.2, --S(.dbd.O)R.sup.D2a, or
--S(.dbd.O).sub.2R.sup.D2a, wherein each occurrence of R.sup.D2a is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl,
and each occurrence of R.sup.D2b is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, or a nitrogen protecting group,
or two R.sup.D2b groups are joined to form an optionally
substituted heterocyclic ring;
[0227] each instance of R.sup.D3 and R.sup.D4 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.D4a, --N(R.sup.D4b).sub.2,
--SR.sup.D4a, --C(.dbd.O)R.sup.D4a, --C(.dbd.O)OR.sup.D4a,
--C(.dbd.O)SR.sup.D4a, --C(.dbd.O)N(R.sup.D4b).sub.2,
--OC(.dbd.O)R.sup.D4a, --OC(.dbd.O)OR.sup.D4a,
--OC(.dbd.O)SR.sup.D4a, --OC(.dbd.O)N(R.sup.D4b).sub.2,
--NR.sup.D4bC(.dbd.O)R.sup.D4b, --NR.sup.D4bC(.dbd.O)OR.sup.D4a,
--NR.sup.D4bC(.dbd.O)SR.sup.D4a,
--NR.sup.D4bC(.dbd.O)N(R.sup.D4b).sub.2, --SC(.dbd.O)R.sup.D4a,
--SC(.dbd.O)OR.sup.D4a, --SC(.dbd.O)SR.sup.D4a,
--SC(.dbd.O)N(R.sup.D4b).sub.2, --C(.dbd.NR.sup.D4b)R.sup.D4a,
--C(.dbd.NR.sup.D4b)OR.sup.D4a, --C(.dbd.NR.sup.D4b)SR.sup.D4a,
--C(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--OC(.dbd.NR.sup.D4b)R.sup.D4a, --OC(.dbd.NR.sup.D4b)OR.sup.D4a,
--OC(.dbd.NR.sup.D4b)SR.sup.D4a,
--OC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--NR.sup.D4bC(.dbd.NR.sup.D4b)R.sup.D4b,
--NR.sup.D4bC(.dbd.NR.sup.D4b)OR.sup.D4a,
--NR.sup.D4bC(.dbd.NR.sup.D4b)SR.sup.D4a,
--NR.sup.D4bC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2,
--SC(.dbd.NR.sup.D4b)R.sup.D4a, --SC(.dbd.NR.sup.D4b)OR.sup.D4a,
--SC(.dbd.NR.sup.D4b)SR.sup.D4a,
--SC(.dbd.NR.sup.D4b)N(R.sup.D4b).sub.2, --C(.dbd.S)R.sup.D4a,
--C(.dbd.S)OR.sup.D4a, --C(.dbd.S)SR.sup.D4a,
--C(.dbd.S)N(R.sup.D4b).sub.2, --OC(.dbd.S)R.sup.D4a,
--OC(.dbd.S)OR.sup.D4a, --OC(.dbd.S)SR.sup.D4a,
--OC(.dbd.S)N(R.sup.D4b).sub.2, --NR.sup.D4bC(.dbd.S)R.sup.D4b,
--NR.sup.D4bC(.dbd.S)OR.sup.D4a, --NR.sup.D4bC(.dbd.S)SR.sup.D4a,
--NR.sup.D4bC(.dbd.S)N(R.sup.D4b).sub.2, --SC(.dbd.S)R.sup.D4a,
--SC(.dbd.S)OR.sup.D4a, --SC(.dbd.S)SR.sup.D4a,
--SC(.dbd.S)N(R.sup.D4b).sub.2, --S(.dbd.O)R.sup.D4a,
--SO.sub.2R.sup.D4a, --NR.sup.D4bSO.sub.2R.sup.D4a,
--SO.sub.2N(R.sup.D4b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.D4a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.D4b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.D4b groups are joined to
form an optionally substituted heterocyclic ring;
[0228] t is 0, 1, 2, or 3; and
[0229] u is 0, 1, 2, 3, 4 or 5.
[0230] In certain embodiments, s is 0. In certain embodiments, s is
1. In certain embodiments, s is 2. In certain embodiments, s is 3.
In certain embodiments, s is 4. In certain embodiments, s is 5. In
certain embodiments, s is 6.
[0231] In certain embodiments of Formula (D), wherein s is 2,
provided is a compound of Formula (D-I):
##STR00044##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D1,
R.sup.D2, R.sup.D3, R.sup.D4, R.sup.D1a, t, and u are as defined
herein.
[0232] In certain embodiments of Formula (D-I), provided is a
compound of Formula (D-II):
##STR00045##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D1,
R.sup.D2, R.sup.D3, R.sup.D4, t, and u are as defined herein.
[0233] In certain embodiments of Formula (D-II), or a
pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2, or
both is C.sub.1-6 alkyl. In certain embodiments of Formula (D-II),
or a pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2,
or both is methyl. In certain embodiments of Formula (D-II), or a
pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2, or
both is ethyl. In certain embodiments of Formula (D-II), or a
pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2, or
both is propyl. In certain embodiments of Formula (D-II), or a
pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2, or
both is butyl.
[0234] In certain embodiments of Formula (D-II), wherein t is 1,
provided is a compound of any of the formulae:
##STR00046##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D1,
R.sup.D2, R.sup.D3, R.sup.D4, and u are as defined herein.
[0235] In certain embodiments of Formula (D-II), provided is a
compound of Formula (D-III):
##STR00047##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D3,
R.sup.D4, t, and u are as defined herein.
[0236] In certain embodiments of Formula (D-III), wherein t is 1,
provided is a compound of any of the formulae:
##STR00048##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D3,
R.sup.D4, and u are as defined herein.
[0237] In certain embodiments of Formula (D), provided is a
compound of Formula (D-III):
##STR00049##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein
[0238] R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, and t are as defined
herein;
[0239] each instance of R.sup.D5 and R.sup.D6 is independently
selected from the group consisting of halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.D6a, --N(R.sup.D6b).sub.2,
--SR.sup.D6a, --C(.dbd.O)R.sup.D6a, --C(.dbd.O)OR.sup.D6a,
--C(.dbd.O)SR.sup.D6a, --C(.dbd.O)N(R.sup.D6b).sub.2,
--OC(.dbd.O)R.sup.D6a, --OC(.dbd.O)OR.sup.D6a,
--OC(.dbd.O)SR.sup.D6a, --OC(.dbd.O)N(R.sup.D6b).sub.2,
--NR.sup.D6bC(.dbd.O)R.sup.D6b, --NR.sup.D6bC(.dbd.O)OR.sup.D6a,
--NR.sup.D6bC(.dbd.O)SR.sup.D6a,
--NR.sup.D6bC(.dbd.O)N(R.sup.D6b).sub.2, --SC(.dbd.O)R.sup.D6a,
--SC(.dbd.O)OR.sup.D6a, --SC(.dbd.O)SR.sup.D6a,
--SC(.dbd.O)N(R.sup.D6b).sub.2, --C(.dbd.NR.sup.D6b)R.sup.D6a,
--C(.dbd.NR.sup.D6b)OR.sup.D6a, --C(.dbd.NR.sup.D6b)SR.sup.D6a,
--C(.dbd.NR.sup.D6b)N(R.sup.D6b).sub.2,
--OC(.dbd.NR.sup.D6b)R.sup.D6a, --OC(.dbd.NR.sup.D6b)OR.sup.D6a,
--OC(.dbd.NR.sup.D6b)SR.sup.D6a,
--OC(.dbd.NR.sup.D6b)N(R.sup.D6b).sub.2,
--NR.sup.D6bC(.dbd.NR.sup.D6b)R.sup.D6b,
--NR.sup.D6bC(.dbd.NR.sup.D6b)OR.sup.D6a,
--NR.sup.D6bC(.dbd.NR.sup.D6b)SR.sup.D6a,
--NR.sup.D6bC(.dbd.NR.sup.D6b)N(R.sup.D6b).sub.2,
--SC(.dbd.NR.sup.D6b)R.sup.D6a, --SC(.dbd.NR.sup.D6b)OR.sup.D6a,
--SC(.dbd.NR.sup.D6b)SR.sup.D6a,
--SC(.dbd.NR.sup.D6b)N(R.sup.D6b).sub.2, --C(.dbd.S)R.sup.D6a,
--C(.dbd.S)OR.sup.D6a, --C(.dbd.S)SR.sup.D6a,
--C(.dbd.S)N(R.sup.D6b).sub.2, --OC(.dbd.S)R.sup.D6a,
--OC(.dbd.S)OR.sup.D6a, --OC(.dbd.S)SR.sup.D6a,
--OC(.dbd.S)N(R.sup.D6b).sub.2, --NR.sup.D6bC(.dbd.S)R.sup.D6b,
--NR.sup.D6bC(.dbd.S)OR.sup.D6a, --NR.sup.D6bC(.dbd.S)SR.sup.D6a,
--NR.sup.D6bC(.dbd.S)N(R.sup.D6b).sub.2, --SC(.dbd.S)R.sup.D6a,
--SC(.dbd.S)OR.sup.D6a, --SC(.dbd.S)SR.sup.D6a,
--SC(.dbd.S)N(R.sup.D6b).sub.2, --S(.dbd.O)R.sup.D6a,
SO.sub.2R.sup.D6a, --NR.sup.D6bSO.sub.2R.sup.D6a,
--SO.sub.2N(R.sup.D6b).sub.2, --CN, --SCN, and --NO.sub.2, wherein
each occurrence of R.sup.D6a is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, and each occurrence of R.sup.D6b
is independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group, or two R.sup.D6b groups are joined to
form an optionally substituted heterocyclic ring; and
[0240] w is 0, 1, 2, or 3.
[0241] In certain embodiments of Formula (D-IV), wherein w is 1,
provided is a compound of any of the formulae:
##STR00050##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D1,
R.sup.D2, R.sup.D3, R.sup.D4, R.sup.D5, R.sup.D6, and t are as
defined herein.
[0242] In certain embodiments of Formula (D-IV), or a
pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or
both are C.sub.1-6 alkyl. In certain embodiments of Formula (D-IV),
or a pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6,
or both are methyl. In certain embodiments of Formula (D-IV), or a
pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or
both are ethyl. In certain embodiments of Formula (D-IV), or a
pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or
both are propyl. In certain embodiments of Formula (D-IV), or a
pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or
both are butyl.
[0243] In certain embodiments, provided is a compound of Formula
(D-V):
##STR00051##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D1,
R.sup.D2, R.sup.D3, R.sup.D4, t and w are as defined herein.
[0244] In certain embodiments of Formula (D-V), and
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, and prodrugs thereof, wherein w is 1, provided is a
compound of any of the formulae:
##STR00052##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D1,
R.sup.D2, R.sup.D3, R.sup.D4, and t are as defined herein.
[0245] In certain embodiments, provided is a compound of Formula
(D-VI):
##STR00053##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.D3,
R.sup.D4, t, and w are as defined herein.
[0246] In certain embodiments, the compound of Formula (D) is not
of the formula:
##STR00054##
or a pharmaceutically acceptable salt thereof.
Pharmaceutical Compositions, Kits, and Administration
[0247] The present invention provides pharmaceutical compositions
comprising a compound of the present invention, e.g., a compound of
any one of the Formulae (A), (B), (C), and (D), and
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, and prodrugs thereof, as described herein, and a
pharmaceutically acceptable excipient. In certain embodiments, the
compound of the present invention or a pharmaceutically acceptable
salt thereof is provided in an effective amount in the
pharmaceutical composition. In certain embodiments, the effective
amount is a therapeutically effective amount. In certain
embodiments, the effective amount is a prophylactically effective
amount.
[0248] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound of
the present invention (the "active ingredient") into association
with a carrier and/or one or more other accessory ingredients, and
then, if necessary and/or desirable, shaping and/or packaging the
product into a desired single- or multi-dose unit.
[0249] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is a discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0250] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0251] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutical compositions include inert
diluents, dispersing and/or granulating agents, surface active
agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering agents, lubricating agents, and/or oils.
Excipients such as cocoa butter and suppository waxes, coloring
agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present in the composition.
[0252] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
and mixtures thereof.
[0253] Exemplary granulating and/or dispersing agents include
potato starch, corn starch, tapioca starch, sodium starch
glycolate, clays, alginic acid, guar gum, citrus pulp, agar,
bentonite, cellulose and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and
mixtures thereof.
[0254] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g. acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g. stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g. carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene
sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween
60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan
monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan
tristearate (Span 65), glyceryl monooleate, sorbitan monooleate
(Span 80)), polyoxyethylene esters (e.g. polyoxyethylene
monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,
polyethoxylated castor oil, polyoxymethylene stearate, and
Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid
esters (e.g. Cremophor.TM.), polyoxyethylene ethers, (e.g.
polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone),
diethylene glycol monolaurate, triethanolamine oleate, sodium
oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate,
sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and/or mixtures thereof.
[0255] Exemplary binding agents include starch (e.g. cornstarch and
starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose,
dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and
synthetic gums (e.g. acacia, sodium alginate, extract of Irish
moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and
larch arabogalactan), alginates, polyethylene oxide, polyethylene
glycol, inorganic calcium salts, silicic acid, polymethacrylates,
waxes, water, alcohol, and/or mixtures thereof.
[0256] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives.
[0257] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[0258] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, dipotassium edetate, and the like),
citric acid and salts and hydrates thereof (e.g., citric acid
monohydrate), fumaric acid and salts and hydrates thereof, malic
acid and salts and hydrates thereof, phosphoric acid and salts and
hydrates thereof, and tartaric acid and salts and hydrates thereof.
Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[0259] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, and sorbic acid.
[0260] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0261] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, and phytic acid.
[0262] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115,
Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments,
the preservative is an anti-oxidant. In other embodiments, the
preservative is a chelating agent.
[0263] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, and
mixtures thereof.
[0264] Exemplary lubricating agents include magnesium stearate,
calcium stearate, stearic acid, silica, talc, malt, glyceryl
behanate, hydrogenated vegetable oils, polyethylene glycol, sodium
benzoate, sodium acetate, sodium chloride, leucine, magnesium
lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[0265] Exemplary natural oils include almond, apricot kernel,
avocado, babassu, bergamot, black current seed, borage, cade,
camomile, canola, caraway, carnauba, castor, cinnamon, cocoa
butter, coconut, cod liver, coffee, corn, cotton seed, emu,
eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd,
grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui
nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary synthetic oils include, but are not
limited to, butyl stearate, caprylic triglyceride, capric
triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,
silicone oil, and mixtures thereof.
[0266] Liquid dosage forms for oral and parenteral administration
include pharmaceutically acceptable emulsions, microemulsions,
solutions, suspensions, syrups and elixirs. In addition to the
active ingredients, the liquid dosage forms may comprise inert
diluents commonly used in the art such as, for example, water or
other solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ,
olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions
can include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents. In
certain embodiments for parenteral administration, the conjugates
of the invention are mixed with solubilizing agents such as
Cremophor.TM., alcohols, oils, modified oils, glycols,
polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0267] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0268] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0269] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This can be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0270] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or
a suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active ingredient.
[0271] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may comprise buffering agents.
[0272] Solid compositions of a similar type can be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally comprise opacifying agents and can be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes. Solid compositions of a
similar type can be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polethylene glycols and the like.
[0273] The active ingredient can be in micro-encapsulated form with
one or more excipients as noted above. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active ingredient can be admixed with at least one inert diluent
such as sucrose, lactose or starch. Such dosage forms may comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may comprise
buffering agents. They may optionally comprise opacifying agents
and can be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0274] Dosage forms for topical and/or transdermal administration
of a compound of this invention may include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants and/or
patches. Generally, the active ingredient is admixed under sterile
conditions with a pharmaceutically acceptable carrier and/or any
needed preservatives and/or buffers as can be required.
Additionally, the present invention contemplates the use of
transdermal patches, which often have the added advantage of
providing controlled delivery of an active ingredient to the body.
Such dosage forms can be prepared, for example, by dissolving
and/or dispensing the active ingredient in the proper medium.
Alternatively or additionally, the rate can be controlled by either
providing a rate controlling membrane and/or by dispersing the
active ingredient in a polymer matrix and/or gel.
[0275] Suitable devices for use in delivering intradermal
pharmaceutical compositions described herein include short needle
devices such as those described in U.S. Pat. Nos. 4,886,499;
5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496;
and 5,417,662. Intradermal compositions can be administered by
devices which limit the effective penetration length of a needle
into the skin, such as those described in PCT publication WO
99/34850 and functional equivalents thereof. Jet injection devices
which deliver liquid vaccines to the dermis via a liquid jet
injector and/or via a needle which pierces the stratum corneum and
produces a jet which reaches the dermis are suitable. Jet injection
devices are described, for example, in U.S. Pat. Nos. 5,480,381;
5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;
5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;
5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460;
and PCT publications WO 97/37705 and WO 97/13537. Ballistic
powder/particle delivery devices which use compressed gas to
accelerate vaccine in powder form through the outer layers of the
skin to the dermis are suitable. Alternatively or additionally,
conventional syringes can be used in the classical mantoux method
of intradermal administration.
[0276] Formulations suitable for topical administration include,
but are not limited to, liquid and/or semi liquid preparations such
as liniments, lotions, oil in water and/or water in oil emulsions
such as creams, ointments and/or pastes, and/or solutions and/or
suspensions. Topically-administrable formulations may, for example,
comprise from about 1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient can be as high
as the solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0277] A pharmaceutical composition of the invention can be
prepared, packaged, and/or sold in a formulation suitable for
pulmonary administration via the buccal cavity. Such a formulation
may comprise dry particles which comprise the active ingredient and
which have a diameter in the range from about 0.5 to about 7
nanometers or from about 1 to about 6 nanometers. Such compositions
are conveniently in the form of dry powders for administration
using a device comprising a dry powder reservoir to which a stream
of propellant can be directed to disperse the powder and/or using a
self propelling solvent/powder dispensing container such as a
device comprising the active ingredient dissolved and/or suspended
in a low-boiling propellant in a sealed container. Such powders
comprise particles wherein at least 98% of the particles by weight
have a diameter greater than 0.5 nanometers and at least 95% of the
particles by number have a diameter less than 7 nanometers.
Alternatively, at least 95% of the particles by weight have a
diameter greater than 1 nanometer and at least 90% of the particles
by number have a diameter less than 6 nanometers. Dry powder
compositions may include a solid fine powder diluent such as sugar
and are conveniently provided in a unit dose form.
[0278] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally the propellant may constitute 50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to
20% (w/w) of the composition. The propellant may further comprise
additional ingredients such as a liquid non-ionic and/or solid
anionic surfactant and/or a solid diluent (which may have a
particle size of the same order as particles comprising the active
ingredient).
[0279] Pharmaceutical compositions of the invention formulated for
pulmonary delivery may provide the active ingredient in the form of
droplets of a solution and/or suspension. Such formulations can be
prepared, packaged, and/or sold as aqueous and/or dilute alcoholic
solutions and/or suspensions, optionally sterile, comprising the
active ingredient, and may conveniently be administered using any
nebulization and/or atomization device. Such formulations may
further comprise one or more additional ingredients including, but
not limited to, a flavoring agent such as saccharin sodium, a
volatile oil, a buffering agent, a surface active agent, and/or a
preservative such as methylhydroxybenzoate. The droplets provided
by this route of administration may have an average diameter in the
range from about 0.1 to about 200 nanometers.
[0280] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a pharmaceutical
composition of the invention. Another formulation suitable for
intranasal administration is a coarse powder comprising the active
ingredient and having an average particle from about 0.2 to 500
micrometers. Such a formulation is administered by rapid inhalation
through the nasal passage from a container of the powder held close
to the nares.
[0281] Formulations for nasal administration may, for example,
comprise from about as little as 0.1% (w/w) and as much as 100%
(w/w) of the active ingredient, and may comprise one or more of the
additional ingredients described herein. A pharmaceutical
composition of the invention can be prepared, packaged, and/or sold
in a formulation for buccal administration. Such formulations may,
for example, be in the form of tablets and/or lozenges made using
conventional methods, and may contain, for example, 0.1 to 20%
(w/w) active ingredient, the balance comprising an orally
dissolvable and/or degradable composition and, optionally, one or
more of the additional ingredients described herein. Alternately,
formulations for buccal administration may comprise a powder and/or
an aerosolized and/or atomized solution and/or suspension
comprising the active ingredient. Such powdered, aerosolized,
and/or aerosolized formulations, when dispersed, may have an
average particle and/or droplet size in the range from about 0.1 to
about 200 nanometers, and may further comprise one or more of the
additional ingredients described herein.
[0282] A pharmaceutical composition of the invention can be
prepared, packaged, and/or sold in a formulation for ophthalmic
administration. Such formulations may, for example, be in the form
of eye drops including, for example, a 0.1/1.0% (w/w) solution
and/or suspension of the active ingredient in an aqueous or oily
liquid carrier. Such drops may further comprise buffering agents,
salts, and/or one or more other of the additional ingredients
described herein. Other opthalmically-administrable formulations
which are useful include those which comprise the active ingredient
in microcrystalline form and/or in a liposomal preparation. Ear
drops and/or eye drops are contemplated as being within the scope
of this invention.
[0283] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0284] Compounds provided herein are typically formulated in dosage
unit form for ease of administration and uniformity of dosage. It
will be understood, however, that the total daily usage of the
compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
subject or organism will depend upon a variety of factors including
the disease, disorder, or condition being treated and the severity
of the disorder; the activity of the specific active ingredient
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the subject; the time of
administration, route of administration, and rate of excretion of
the specific active ingredient employed; the duration of the
treatment; drugs used in combination or coincidental with the
specific active ingredient employed; and like factors well known in
the medical arts.
[0285] The compounds and compositions provided herein can be
administered by any route, including enteral (e.g., oral),
parenteral, intravenous, intramuscular, intra-arterial,
intramedullary, intrathecal, subcutaneous, intraventricular,
transdermal, interdermal, rectal, intravaginal, intraperitoneal,
topical (as by powders, ointments, creams, and/or drops), mucosal,
nasal, bucal, sublingual; by intratracheal instillation, bronchial
instillation, and/or inhalation; and/or as an oral spray, nasal
spray, and/or aerosol. Specifically contemplated routes are oral
administration, intravenous administration (e.g., systemic
intravenous injection), regional administration via blood and/or
lymph supply, and/or direct administration to an affected site. In
general the most appropriate route of administration will depend
upon a variety of factors including the nature of the agent (e.g.,
its stability in the environment of the gastrointestinal tract),
and/or the condition of the subject (e.g., whether the subject is
able to tolerate oral administration).
[0286] The exact amount of a compound required to achieve an
effective amount will vary from subject to subject, depending, for
example, on species, age, and general condition of a subject,
severity of the side effects or disorder, identity of the
particular compound(s), mode of administration, and the like. The
desired dosage can be delivered three times a day, two times a day,
once a day, every other day, every third day, every week, every two
weeks, every three weeks, or every four weeks. In certain
embodiments, the desired dosage can be delivered using multiple
administrations (e.g., two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, or more
administrations).
[0287] In certain embodiments, an effective amount of a compound
for administration one or more times a day to a 70 kg adult human
may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to
about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to
about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to
about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100
mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg,
of a compound per unit dosage form.
[0288] In certain embodiments, the compounds of the invention may
be at dosage levels sufficient to deliver from about 0.001 mg/kg to
about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,
preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from
about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about
10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more
preferably from about 1 mg/kg to about 25 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0289] It will be appreciated that dose ranges as described herein
provide guidance for the administration of provided pharmaceutical
compositions to an adult. The amount to be administered to, for
example, a child or an adolescent can be determined by a medical
practitioner or person skilled in the art and can be lower or the
same as that administered to an adult.
[0290] It will be also appreciated that a compound or composition,
as described herein, can be administered in combination with one or
more additional therapeutically active agents. The compounds or
compositions can be administered in combination with additional
therapeutically active agents that improve their bioavailability,
reduce and/or modify their metabolism, inhibit their excretion,
and/or modify their distribution within the body. It will also be
appreciated that the therapy employed may achieve a desired effect
for the same disorder, and/or it may achieve different effects.
[0291] The compound or composition can be administered concurrently
with, prior to, or subsequent to, one or more additional
therapeutically active agents. In general, each agent will be
administered at a dose and/or on a time schedule determined for
that agent. In will further be appreciated that the additional
therapeutically active agent utilized in this combination can be
administered together in a single composition or administered
separately in different compositions. The particular combination to
employ in a regimen will take into account compatibility of the
inventive compound with the additional therapeutically active agent
and/or the desired therapeutic effect to be achieved. In general,
it is expected that additional therapeutically active agents
utilized in combination be utilized at levels that do not exceed
the levels at which they are utilized individually. In some
embodiments, the levels utilized in combination will be lower than
those utilized individually.
[0292] Exemplary additional therapeutically active agents include,
but are not limited to, anti-cancer agents, anti-diabetic agents,
anti-inflammatory agents, immunosuppressant agents, and a
pain-relieving agent. Therapeutically active agents include small
organic molecules such as drug compounds (e.g., compounds approved
by the U.S. Food and Drug Administration as provided in the Code of
Federal Regulations (CFR)), peptides, proteins, carbohydrates,
monosaccharides, oligosaccharides, polysaccharides, nucleoproteins,
mucoproteins, lipoproteins, synthetic polypeptides or proteins,
small molecules linked to proteins, glycoproteins, steroids,
nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones,
vitamins, and cells.
[0293] Also encompassed by the invention are kits (e.g.,
pharmaceutical packs). The kits provided may comprise an inventive
pharmaceutical composition or compound and a container (e.g., a
vial, ampule, bottle, syringe, and/or dispenser package, or other
suitable container). In some embodiments, provided kits may
optionally further include a second container comprising a
pharmaceutical excipient for dilution or suspension of an inventive
pharmaceutical composition or compound. In some embodiments, the
inventive pharmaceutical composition or compound provided in the
container and the second container are combined to form one unit
dosage form.
[0294] Thus, in one aspect, provided is a pharmaceutical
composition comprising a compound of any one of the Formulae (A),
(B), (C), and (D), and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, and a
pharmaceutically acceptable excipient. In certain embodiments,
provided is a composition described herein, wherein the compound or
pharmaceutically acceptable salt thereof is provided in an
effective amount.
[0295] In another aspect, provided is a kit for treating or
preventing a neurological disorder comprising:
[0296] a first container comprising an HDAC (histone deacetylase)
activator; and
[0297] instructions for administering the HDAC activator to a
subject to treat a neurological disorder. In certain embodiments,
the HDAC activator is a class I HDAC activator. In certain
embodiments, the class I HDAC activator is an HDAC1 (histone
deacetylase 1) activator.
[0298] In certain embodiments, provided is a kit for treating a
neurological disorder comprising:
[0299] a first container comprising the compound of Formula
(DAC-001):
##STR00055##
and
[0300] instructions for administering the compound of Formula
(DAC-001) to a subject to treat a neurological disorder.
[0301] In certain embodiments, provided is a kit for treating a
neurological disorder comprising:
[0302] a first container comprising the compound of Formula
(DAC-002):
##STR00056##
and
[0303] instructions for administering the compound of Formula
(DAC-002) to a subject to treat a neurological disorder.
[0304] In certain embodiments, provided is a kit for treating a
neurological disorder comprising:
[0305] a first container comprising the compound of Formula
(DAC-009):
##STR00057##
or a pharmaceutically acceptable salt thereof; and
[0306] instructions for administering the compound of Formula
(DAC-009) to a subject to treat a neurological disorder.
[0307] In certain embodiments, provided is a kit for treating a
neurological disorder comprising:
[0308] a first container comprising the compound of Formula
(DAC-003):
##STR00058##
or a pharmaceutically acceptable salt thereof; and
[0309] instructions for administering the compound of Formula
(DAC-003) to a subject to treat a neurological disorder.
[0310] In certain embodiments, provided is a kit for treating a
neurological disorder comprising:
[0311] a first container comprising the compound of Formula
(DAC-012):
##STR00059##
or a pharmaceutically acceptable salt thereof; and
[0312] instructions for administering the compound of Formula
(DAC-012) to a subject to treat a neurological disorder.
[0313] In certain embodiments, provided is a kit for treating a
neurological disorder comprising:
[0314] a first container comprising a compound selected from the
group of compounds consisting of the compounds of the Formulae (A),
(B), (C), and (D), or a pharmaceutically acceptable salt thereof;
and
[0315] instructions for administering the compound selected in the
previous step to a subject to treat a neurological disorder.
Methods of Treatment
[0316] In one aspect, the invention provides methods and
compositions for the treatment or prevention of neurological
disorders. In some embodiments, neurological disorders are treated
by decreasing the amount of DNA damage within the neuronal cell. In
some embodiments, neurological disorders are treated by increasing
HDAC activity within the neuronal cell. In some embodiments,
neurological disorders are treated by decreasing histone acetyl
transferase activity within the neuronal cell. In some embodiments,
neurological disorders are treated by increasing the activity of
class I histone deacetylases. In some embodiments, neurological
disorders are treated by increasing the activity of class I HDAC.
In some embodiments, neurological disorders are treated by
increasing the activity of HDAC1. In some embodiments, neurological
disorders are treated by increasing the activity of HDAC2. In some
embodiments, neurological disorders are treated by increasing the
activity of HDAC3. In some embodiments, neurological disorders are
treated by increasing the activity of HDAC8.
[0317] Regulating histone acetylation is an integral aspect of
chromatin modulation and gene regulation that plays a critical role
in many biological processes including cell proliferation and
differentiation (Roth et al., Annu. Rev. Biochem. (2001)
70:81-120). Recent reports have detailed the importance of histone
acetylation in CNS functions such as neuronal differentiation,
memory formation, drug addiction, and depression (Citrome,
Psychopharmacol. Bull. (2003) 37 Suppl. 2:74-88; Johannessen et
al., CNS Drug Rev. (2003) 9:199-216; Tsankova et al., Nature
Neuroscience (2006) 9:519-525). Histone deacetylases remove acetyl
groups from histones, resulting in increased chromatin compaction
and decreased accessibility to DNA for interacting molecules such
as transcription factors (Cerna et al., Curr. Top. Dev. Biol.
(2006) 73:173-204).
[0318] Of the HDACs, HDAC1 was the first protein identified to have
histone-directed deacetylase activity (Taunton et al., Science
(1996) 272:408-411; Vidal et al., Mol. Cell Biol. (1991)
11:6317-6327). HDAC1 plays important roles in regulating the cell
cycle and is required in the transcriptional repression of cell
cycle genes such as p21/WAF, E2F-1, and cyclins A and E (Brehm et
al., Nature (1998) 391:597-601; Iavarone et al., Mol. Cell Biol.
(1999) 19:916-922; Lagger et al., Embo. J. (2002) 21:2672-2681;
Rayman et al., Genes Dev. (2002) 16:933-947; Stadler et al., Dev.
Dyn. (2005) 233:883-889; Stiegler et al., Cancer Res. (1998)
58:5049-5052). The association of HDAC1 with promotor regions of
specific genes is linked to their transcriptional repression (Brehm
et al., Nature (1998) 391:597-601; Gui et al., Proc. Natl. Acad.
Sci. USA (2004) 101:1241-1246; Iavarone et al., Mol. Cell Biol.
(1999) 19:916-922; Rayman et al., Genes Dev. (2002)
16:933-947).
[0319] It has been found that agents that increase HDAC1 activity
are neuroprotective (PCT Patent Application Publication No. WO
2010/011318). Those agents may serve for the treatment of
neurological disorders, including Alzheimer's disease, Parkinson's
disease, Huntington's disease, amyotrophic lateral sclerosis (ALS),
ischemic brain damage, traumatic brain injury, stroke, frontal
temporal dementia, Pick's disease, corticobasal degeneration, supra
cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease,
Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia,
and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal
muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis,
Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and
Bloom syndrome.
[0320] Nucleosomes, the primary scaffold of chromatin folding, are
dynamic macromolecular structures, influencing chromatin solution
conformations. The nucleosome core is made up of histone proteins,
H2A, H2B, H3, and H4. Histone acetylation causes nucleosomes and
nucleosomal arrangements to behave with altered biophysical
properties. The balance between activities of histone acetyl
transferases (HAT) and histone deacetylases determines the level of
histone acetylation. Acetylated histones cause relaxation of
chromatin and activation of gene transcription, whereas
deacetylated chromatin generally is transcriptionally inactive.
[0321] In some embodiments, neurological disorders are treated by
decreasing histone acetylation by the administration of histone
acetylase activators. In some embodiments, neurological disorders
are treated by decreasing histone acetylation by methods other than
increasing HDAC activity. Methods for decreasing histone
acetylation, by a method other than a classic HDAC activator
include, but are not limited to, the administration of nucleic acid
molecule inhibitors such as antisense and RNAi molecules which
reduce the expression of histone acetyl transferases and the
administration of histone acetyl transferase inhibitors. Histone
acetyl transferase inhibitors are known in the art (Eliseeva et
al., Mol. Cancer Ther. (2007) 6:2391-98). The invention embraces
methods that regulate the function of any protein involved with
histone modification, function and regulation.
[0322] In some embodiments, neurological disorders are treated by
protecting cells from DNA damage by increasing the histone
deacetylation activity within the cell. Protection from DNA damage
includes both a decrease in the current level of DNA damage
accumulated within the cell, or a decrease in the rate of DNA
damage acquired by the cell, including DNA damage acquired during
exposure of the cell to DNA damaging events, such as exposure to
DNA damaging agents, including radiation, and events that lead to
increased oxidative stress. Increased deacetylase activity can
protect against any form of DNA damage, including base
modifications, DNA single strand breaks, and DNA double strand
breaks. DNA double strand breaks are potentially the most damaging
to the cell, and other forms of DNA damage can be turned into DNA
double strand breaks by the action of DNA repair enzymes and other
cellular processes. DNA damage, including DNA double strand breaks,
can accumulate in both actively dividing and non-dividing cells. In
actively dividing cells, DNA double strand breaks may inhibit the
replication machinery, while in both actively dividing and
non-dividing cells the transcription machinery may be inhibited by
DNA double strand breaks. In addition, DNA double strand breaks may
initiate potentially damaging recombination events. Thus, increased
deacetylase activity may be protective in any cell type, including
dividing and non-dividing cells. In some embodiments, increased
deacetylase activity is protective in neuronal cells. In some
embodiments, increased deacetylase activity is induced in cells
that are susceptible to acquiring DNA damage, or cells that will be
subjected to a DNA damage inducing event. For instance, histone
deacetylase activity may be increased in cells or tissue in a
subject that need to be protected when a DNA damaging agent is
administered throughout the body (for instance, during
chemotherapy). In some embodiments, neuroprotection is provided by
increasing the histone deacetylation activity within a neuronal
cell. In some embodiments, neuroprotection is provided by
decreasing the histone acetyl transferase activity within a
neuronal cell.
[0323] The invention embraces any method of increasing deacetylase
activity. In some embodiments, deacetylase activity is increased by
increasing the activity of class I HDAC. In some embodiments,
deacetylase activity is increased by increasing the activity of
HDAC1. In some embodiments, deacetylase activity is increased by
increasing the activity of HDAC2. In some embodiments, deacetylase
activity is increased by increasing the activity of HDAC3. In some
embodiments, deacetylase activity is increased by increasing the
activity of HDAC8. In some embodiments, deacetylase activity is
increased by adding an HDAC activator to the cell. In some
embodiments, the HDAC activator is a class I HDAC activator. In
some embodiments, the HDAC activator is an HDAC1 activator. In some
embodiments, the HDAC activator is an HDAC2 activator. In some
embodiments, the HDAC activator is an HDAC3 activator. In some
embodiments, the HDAC activator is an HDAC8 activator. In some
embodiments, HDAC activity is increased by increasing the
expression level of one or more HDACs. In some embodiments, HDAC
activity is increased by selectively increasing the expression
level of one or more HDACs relative to one or more HDACs. In some
embodiments, HDAC activity is increased by selectively increasing
the expression level of one or more HDACs by 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,
20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,
33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,
46%, 47%, 48%, 49%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%,
or 90% to 100% relative to one or more HDACs. In some embodiments,
HDAC activity is increased by selectively increasing the expression
level of one or more HDACs by 100% to 200%, 200% to 300%, 300% to
500%, 500% to 1000%, 1000% to 10000%, or 10000% to 100000% relative
to one or more other HDACs. In some embodiments, the expression
level is increased by increasing the level and/or activity of
transcription factors that act on a specific gene encoding a
histone deacetylase. In some embodiments, the activity is increased
by decreasing the activity of repressor elements. In some
embodiments, deacetylase activity within a cell or subject is
increased by administering histone deacetylase protein to the cell
or subject. In some embodiments, the activity is increased by
inactivating or sequestering an agent that acts as an inhibitor on
a HDAC suppressor pathway.
[0324] An "HDAC activator" as defined herein is any compound that
results in an increase in the level of HDAC activity. Any increase
in enzymatic function of an HDAC is embraced by the invention. In
some embodiments, the activity increase of HDAC is an increase in
HDAC deacetylase activity. In some embodiments, the activity
increase of HDAC is an increase in HDAC esterase activity. HDAC
activity corresponds to the level of histone deacetylase activity
of the HDAC. One of ordinary skill in the art can select suitable
compounds on the basis of the known structures of histone
deacetylases. Examples of such compounds are peptides, nucleic
acids expressing such peptides, small molecules, etc., each of
which can be naturally occurring molecules, synthetic molecules,
and/or FDA approved molecules, that specifically react with the
histone deacetylase and increase its activity.
[0325] In certain embodiments, the HDAC activator is a naturally
occurring compound or a compound that has been synthesized, or a
pharmaceutically acceptable salt thereof, such as a compound of the
Formula (DAC-001), (DAC-002), (DAC-003), (DAC-009), or (DAC-012),
or pharmaceutically acceptable salt thereof.
[0326] In certain embodiments, the HDAC activator is a compound of
Formula (A), (B), (C), or (D), or pharmaceutically acceptable salt
thereof.
[0327] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of the
compound of Formula (DAC-001), or a pharmaceutically acceptable
salt thereof.
[0328] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of the
compound of Formula (DAC-002), or a pharmaceutically acceptable
salt thereof.
[0329] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of the
compound of Formula (DAC-009), or a pharmaceutically acceptable
salt thereof.
[0330] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of the
compound of Formula (DAC-003), or a pharmaceutically acceptable
salt thereof.
[0331] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of the
compound of Formula (DAC-012), or a pharmaceutically acceptable
salt thereof.
[0332] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of a
compound of Formula (A), or a pharmaceutically acceptable salt
thereof.
[0333] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of a
compound of Formula (B), or a pharmaceutically acceptable salt
thereof.
[0334] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of a
compound of Formula (C), or a pharmaceutically acceptable salt
thereof.
[0335] In certain embodiments, provided is a method for treating or
preventing a neurological disorder in a subject, the method
comprising administering to a subject in need of treatment for a
neurological disorder a therapeutically effective amount of a
compound of Formula (D), or a pharmaceutically acceptable salt
thereof.
[0336] In certain embodiments, the neurological disorder being
treated or prevented is Alzheimer's disease.
[0337] In certain embodiments, the neurological disorder being
treated or prevented is Parkinson's disease.
[0338] In certain embodiments, the neurological disorder being
treated or prevented is Huntington's disease.
[0339] In certain embodiments, the neurological disorder being
treated or prevented is ALS (amyotrophic lateral sclerosis).
[0340] In certain embodiments, the neurological disorder being
treated or prevented is traumatic brain injury.
[0341] In certain embodiments, the neurological disorder being
treated or prevented is ischemic brain injury.
[0342] In certain embodiments, the neurological disorder being
treated or prevented is stroke.
[0343] In certain embodiments, the neurological disorder being
treated or prevented is frontal temporal dementia.
[0344] In certain embodiments, the neurological disorder being
treated or prevented is Pick's disease.
[0345] In certain embodiments, the neurological disorder being
treated or prevented is corticobasal degeneration.
[0346] In certain embodiments, the neurological disorder being
treated or prevented is supra cerebral palsy.
[0347] In certain embodiments, the neurological disorder being
treated or prevented is prion diseases (e.g., Creutzfeldt-Jakob
disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial
Insomnia, and Kuru).
[0348] In certain embodiments, the neurological disorder being
treated or prevented is Nieman Pick type C.
[0349] In certain embodiments, the neurological disorder being
treated or prevented is spinal cerebellar ataxia.
[0350] In certain embodiments, the neurological disorder being
treated or prevented is spinal muscular dystrophy.
[0351] In certain embodiments, the neurological disorder being
treated or prevented is ataxia telangiectasia.
[0352] In certain embodiments, the neurological disorder being
treated or prevented is hippocampal sclerosis.
[0353] In certain embodiments, the neurological disorder being
treated or prevented is Cockayne syndrome.
[0354] In certain embodiments, the neurological disorder being
treated or prevented is Werner syndrome.
[0355] In certain embodiments, the neurological disorder being
treated or prevented is xeroderma pigmentosaum.
[0356] In certain embodiments, the neurological disorder being
treated or prevented is Bloom syndrome.
EXAMPLES
[0357] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
Example 1. Recombinant HDAC1 Expression, Purification, and
Proteomic Analysis
[0358] Recombinant, full-length human HDAC1 (GenBank Accession No.
NM_004964) with a C-terminal FLAG tag was produced by BPS
Biosciences (San Diego, Calif.) using large-scale insect cell
protein expression and purification in order to support a
large-scale high-throughput screen (HTS).
[0359] To determine the quality of the protein preparation, and to
confirm the existence of only HDAC1 as the only deacetylase in the
preparation, NanoLC-MS/MS peptide sequencing technology was carried
out by ProtTech, Inc (Norristown, Pa.). In brief, each protein gel
band was destained, cleaned, and digested in-gel with sequencing
grade modified trypsin obtained from Promega (Madison, Wis.). All
other chemicals used in proteolytic digestion and HPLC were
obtained from Sigma (St. Louis, Mo.). The resulting peptide mixture
was analyzed using a LC-MS/MS system Thermo (Palo Alto, Calif.), in
which a high pressure liquid chromatography (HPLC) with a 75
micrometer inner diameter reverse phase C.sub.18 column was on-line
coupled with a Quadrupole ion trap mass spectrometer. The mass
spectrometric data acquired were used to search the most recent
non-redundant protein database (downloaded from NCBI) with
ProtTech's proprietary software suite.
[0360] For the two principle bands in the preparation isolated
after SDS-PAGE, the first was identified as histone deacetylase 1
(HDAC1) with multiple peptides with a minor fraction of peptides
from chaperonin TCP-1.beta.4 that contains t-complex polypeptide 1
(TCP-1) beta subunit 4 (P4) from the Sf9 cells. The second
predominant band was identified as heat shock cognate protein 70
(HSC70) from the Sf9 cells with a minor fraction of HDAC1.
Interestingly, HSC70 has been reported to have ATPase function,
which is common to many chromatin-remodeling complexes, and HSC70
has been shown to interact with Tau protein, a protein implicated
in the pathology of Alzheimer's disease and other neurodegenerative
disorders. An "ATPase" is an enzyme that uses ATP, i.e., adenosine
triphosphate, as an energy source. In the case of TCP-1.beta.4,
these findings are of potential interest because, for HDAC3, a
similar class I HDAC, the assembly of the SMRT-HDAC3 co-repressor
complex requires the TCP-1 ring complex (Guenther et al., Genes
Dev. (2002) 16:3130-35). It is thus possible that the regulation of
HDAC1 conformation by TCP-1 ring complex is important for its
deacetylase activity, which will be taken into consideration when
the mechanisms of action of hits identified in the HTS are
analyzed.
Example 2. Primary HDAC1 High-Throughput Screen
[0361] Using the microfluidics-based HDAC1 assay developed by
Nanosyn (Durham, N.C.) at total of 47,144 compounds from a diverse,
drug-like library were tested for their ability to enhance the
deacetylase activity of recombinant HDAC1. Compounds were tested
with a reaction time of 6 h with compounds tested at a single
concentration (10 .mu.M) in duplicate. As a positive control, the
biflavonoid gingketin was chosen.
High-Throughput Screen Information
[0362] 47,144 compounds were tested for their effect on the
enzymatic activity of HDAC1. Compounds were tested in duplicate at
10 .mu.M nominal final concentration in 384-well plate format. The
reference activator compound, ginkgetin (50 .mu.M), was included in
duplicates in each HTS plate as a positive control condition. 24
negative control samples (DMSO only) were included in each plate to
provide for the 0% activation baseline.
Screening Results
[0363] Within each HTS plate, the effect of individual compounds on
the enzymatic activity of HDAC1 was calculated as % change in the
conversion of the peptide substrate relative to the average
substrate conversion value calculated across the 24 negative
control samples.
[0364] A compounds was considered active if its effect (calculated
as average of two duplicates) on the enzymatic activity of HDAC1 is
above the 66 standard deviations value of the assay, which is the
commonly accepted statistical significance threshold for active
compounds in HTS.
[0365] HDAC1 microfluidics assay control data of 7,080 negative
control samples (DMSO) and 580 ginkgetin positive control samples
(50 .mu.M) are shown in FIG. 2A and FIG. 2B, respectively.
[0366] FIGS. 3A to 3B include HDAC1 HTS data. FIG. 3A depicts a
primary microfluidic fluorescence reader trace for ginkgetin
(positive control) showing increased conversion of the peptidic
substrate FAM-TSRHKacKL to the deacetylated product FAM-TSRHKKL
(illustrated with arrows). FIG. 3B depicts a primary microfluidic
fluorescence reader trace for DAC-001, showing increased conversion
of the peptidic substrate FAM-TSRHKacKL to the deacetylated product
FAM-TSRHKKL (illustrated with arrows).
[0367] HTS results are summarized in Table 1. A total of 21 hits,
including DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012, were
identified by the HTS, the structures of which were determined
using HPLC/UV/MS/ELSD analysis. Analysis of the structures of the
hit compounds revealed multiple common structural frameworks
suggesting the existence of a defined
structure-activity-relationship for HDAC1 activation. All confirmed
hits were re-ordered from commercial sources for further testing.
Percent activation data are included in Table 2 for ginkgetin,
DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012.
TABLE-US-00001 TABLE 1 Summary of data obtained from high-thoughput
screening Total number of compounds screened 47,144 6.sigma. value
of the assay 15.5% activation Positive control Name ginkgetin Total
number of measurements 580 Average effect 26% activation (standard
deviation: 4%) Measurements above 6.sigma. 571 (98.5% of total
number of measurements) Measurements below 6.sigma. 9 (1.5% of
total number of measurements) Estimated probability that a
potentially active compound has <0.00023 not been detected in at
least one of the two replica samples Total number of active
compounds 21 (0.044% of total number of compounds screened)
TABLE-US-00002 TABLE 2 Activation of HDAC1 by certain compounds in
high-thoughput screening Percent activation (%) Compound ID
Replicate 1 Replicate 2 Average ginkgetin 25.6 .+-. 4.7 DAC-001
122.6 138.4 130.5 DAC-002 52.7 56.6 54.7 DAC-003 24.2 24.9 24.6
DAC-009 15.1 22.2 18.7 DAC-012 17.5 17.9 17.7
Example 3. Secondary HDAC1 High-Throughput Screen
[0368] Based upon the results of the HDAC1 activator screen
performed, a total of 21 compounds (for structures, see FIGS. 6A to
6C) were initially selected as hits due to their ability to enhance
the deacetylase activity of recombinant HDAC1. Those hits,
designated as "DACs" (deacetylase activating compounds), were
measured using a microfluidics-based assay with an acetylated
peptidic substrate (FAM-TSRHKacKL) over a reaction time of 6 h. The
21 HTS hits plus two controls: ginkgetin (an activator) and TSA
(trichostatin A, an inhibitor; for its structure, see FIG. 6A) were
retested in an 8-point dose response ranging from 50 .mu.M to 0.02
.mu.M. The positive control (ginkgetin) again demonstrated
dose-dependent activation of HDAC1 (maximal effect of 20% and
plateau at 10 .mu.M), HDAC2 (AC.sub.50=28 M, maximal effect 165%)
and HDAC3 (maximal effect 20% at 100 .mu.M). TSA demonstrated dose
dependent inhibition of all HDAC isoforms as expected. Compounds
were considered as confirmed hits if their AC.sub.50 curve showed
dose-dependent activation of the HDAC1 activity in
microfluidics-based assay. The two most active HTS hits, compounds
DAC-001 and DAC-002 demonstrated activation of up to 287% and 221%
with AC.sub.50 values of 4.05 .mu.M and 8.31 .mu.M, respectively.
These data, included in Table 3, demonstrate the successful
discovery of compounds that activate the deacetylase activity of
HDAC1 in vitro.
TABLE-US-00003 TABLE 3 Activation of HDAC1 by certain comopunds in
a microfluidics-based assay with an acetylated peptidic substrate
(FAM-TSRHKacKL) Average activation Maximum activation % during HTS
% during dose response Compound ID (10 .mu.M) (50 .mu.M maximum)
Ginkgetin 25.6 23 Trichostatin A 0 0 DAC-001 130.5 287 DAC-002 54.7
221 DAC-003 24.6 34 DAC-009 18.7 12 DAC-012 17.7 26
[0369] Microfluidics-based deacetylase assays were also performed
using recombinant HDAC2, HDAC3, and HDAC8 to determine the
selectivity of the compounds. Many of the confirmed compounds also
activated HDAC2 isoform to a similar or even greater extent. Some
compounds activated HDAC3 and inhibited the HDAC8 isoform.
Example 4. Characterization of HDAC1 Activators in Cellular Models
of Neurodegeneration
[0370] Next, what was tested was whether a treatment of HDAC1
activators can increase HDAC1 enzymatic activity in cultured cells.
Human HEK293T cells were treated with compounds at different
concentrations (10 .mu.M or 50 .mu.M) for 20 h. Histone proteins
were extracted, and Western blotting was used to analyze the
acetylation of certain histone lysine residues known to be HDAC1
targets. Treatment with some compounds, such as DAC-001, DAC-002,
DAC-003, and DAC-009, reduced the levels of Ac-H3K56, Ac-H3K14,
Ac-H4K12 and Ac-H2B, indicating those compounds' ability to
activate HDAC1 in cultured cells (FIG. 4).
[0371] HT-22 cells, a hippocampal neuron derived cell line, were
used to model neurodegeneration. Two types of insults were used.
Glutamate treatment induced oxidative stress by depleting
glutathione. Etoposide, a topoisomerase II inhibitor, stressed
cells through DNA damage. These two types of stresses have been
documented in neurodegenerative diseases.
[0372] HT-22 cells were treated with compounds for 3 h prior to the
addition of 2.5 mM glutamate. Cell viability was measured by
CellTiter-Glo assays (Promega) (FIG. 5A). DAC-003 can significantly
protect cells from oxidative stress (p<0.05, student's t-test).
DAC-012 also showed a trend of protection.
[0373] Similarly, HT-22 cells were pre-incubated with compounds (5
.mu.M for DAC-001 and DAC-003; 10 .mu.M for others) for 3 h. Then,
2 .mu.M etoposide was added to the culture medium. Cell viability
was measured 72 h later (FIG. 5B). Of the DAC compounds tested,
DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012 showed significant
protection (p<0.001, student's t-test) against DNA damage
stress. This result is consistent with previous findings that HDAC1
is directly involved in DNA damage repair, and that over-expression
of HDAC1 is able to protect neurons from DNA damage.
[0374] Additionally, the safety of these compounds was tested in
HT-22 cells (FIG. 5C). Cell survival was measured 72 h after
compound treatment. Most compounds showed minimum effects (less
than 10%) upon cell survival. This data also indicate that DAC
compounds are less likely to affect cell proliferation.
[0375] The neuroprotection potential of the candidate compounds
were also tested using a neuronal excitoxicity model. DIV14
cortical neurons were treated with the compounds for 20 h. 50 .mu.M
glutamate was added to the culture 1 h before processing the
samples for immunocytochemistry. MAP2 staining for the neuronal
dendrites demonstrated that treatment with some of the compounds
was able to protect neurons from excitotoxicity, as evidenced by
their retention of dendrites. Ginkgetin was used as a positive
control. Of the DAC compounds tested, DAC-002 and DAC-003 showed a
trend of protection, while DAC-001 showed significant protection
(p<0.01, student's t-test).
* * * * *