U.S. patent application number 15/496883 was filed with the patent office on 2017-10-12 for methods and compositions for treating beta-thalassemia and sickle cell disease.
This patent application is currently assigned to Academia Sinica. The applicant listed for this patent is Academia Sinica. Invention is credited to Yu-Chi Chou, Che-Kun James Shen, Tsann-Long Su.
Application Number | 20170290820 15/496883 |
Document ID | / |
Family ID | 51844107 |
Filed Date | 2017-10-12 |
United States Patent
Application |
20170290820 |
Kind Code |
A1 |
Shen; Che-Kun James ; et
al. |
October 12, 2017 |
METHODS AND COMPOSITIONS FOR TREATING BETA-THALASSEMIA AND SICKLE
CELL DISEASE
Abstract
Compounds, pharmaceutical compositions, and methods for treating
anemia .beta.-thalassemia anemia or sickle cell anemia.
Inventors: |
Shen; Che-Kun James;
(Taipei, TW) ; Chou; Yu-Chi; (Taipei, TW) ;
Su; Tsann-Long; (Taipei, TW) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Academia Sinica |
Taipei |
|
TW |
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|
Assignee: |
Academia Sinica
Taipei
TW
|
Family ID: |
51844107 |
Appl. No.: |
15/496883 |
Filed: |
April 25, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14787885 |
Oct 29, 2015 |
9662324 |
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PCT/US2014/036369 |
May 1, 2014 |
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15496883 |
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61818058 |
May 1, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 2333/805 20130101;
A61K 45/06 20130101; A61P 7/06 20180101; G01N 33/5044 20130101;
C07D 221/14 20130101; A61K 9/0053 20130101; G01N 2800/52 20130101;
A61K 31/473 20130101; A61K 31/473 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/473 20060101
A61K031/473; G01N 33/50 20060101 G01N033/50; A61K 9/00 20060101
A61K009/00; A61K 45/06 20060101 A61K045/06 |
Claims
1.-27. (canceled)
28. A compound of the formula selected from the group consisting
of: Formula (VI), Formula (VII), and Formula (VIII): ##STR00106##
or a pharmaceutically acceptable salt thereof, wherein: R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are each
independently selected from the group consisting of hydrogen,
optionally substituted alkyl, --N(R.sup.B).sub.2, and
--N(R.sup.A)C(O)R.sup.A; provided that in Formula (VI), R.sup.10 is
optionally substituted alkyl, --N(R.sup.B).sub.2, or
--N(R.sup.A)C(O)R.sup.A. R.sup.14 is hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, or optionally
substituted alkynyl; each instance of R.sup.A is independently
selected from the group consisting of hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, and optionally
substituted alkynyl; and each instance of R.sup.B is independently
selected from the group consisting of hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, and optionally
substituted alkynyl;
29. The compound of claim 28, wherein the compound is selected from
the group consisting of Formula (VI-a), (VII-a), and (VIII-a):
##STR00107## in which each of R.sup.10, R.sup.11, and R.sup.14 is
as defined in claim 28.
30. The compound of claim 29, wherein R.sup.14 is optionally
substituted alkyl.
31. The compound of claim 30, wherein R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein: n is 1, 2, 3, 4, or
5; and R.sup.B is independently optionally substituted C.sub.1-6
alkyl.
32. The compound of claim 31, wherein R.sup.14 is
--(CH.sub.2).sub.2N(CH.sub.3).sub.2.
33. The compound of claim 29, wherein R.sup.10 is
--N(R.sup.B).sub.2 or --N(R.sup.A)C(O)R.sup.A, wherein: R.sup.A is
independently hydrogen or optionally substituted alkyl; and R.sup.B
is independently hydrogen or optionally substituted alkyl.
34. The compound of claim 33, wherein (i) each R.sup.B is methyl or
hydrogen, or (ii) one instance of R.sup.B is optionally substituted
C.sub.1-C.sub.5 alkyl and the other instance of R.sup.B is
hydrogen.
35. The compound of claim 33, wherein one instance of R.sup.A is
optionally substituted alkyl and the other instance of R.sup.A is
hydrogen.
36. The compound of claim 29, wherein R.sup.11 is hydrogen.
37. The compound of claim 29, wherein the compound is selected from
the group consisting of the compounds of the formula: ##STR00108##
or a pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition comprising a compound of claim 28,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
39. A method of inducing .gamma. globin production, comprising:
contacting a cell with an effective amount of a compound of claim
28.
40. The method of claim 39, wherein the contacting step is
performed by administering an effective amount of the compound of
Formula (VI), Formula (VII), or Formula (VIII), or a
pharmaceutically acceptable salt thereof to a subject in need
thereof.
41. The method of claim 40, wherein the subject is a human patient
who suffers from or is suspected of having anemia.
42. The method of claim 41, wherein the anemia is
.beta.-thalassemia or sickle cell anemia.
43. The method of claim 40, wherein the compound is administered
orally.
44. The method of claim 40, wherein the pharmaceutical composition
is administered in combination with an additional therapeutic
agent.
45. A method of treating anemia, comprising: administering to a
subject in need thereof an effective amount of a compound of claim
28.
46. The method of claim 45, wherein the subject is a human patient
who suffers from or is suspected of having .beta.-thalassemia or
sickle cell anemia.
Description
RELATED APPLICATIONS
[0001] This application is a division of and claims priority under
35 U.S.C. .sctn.120 to U.S. application Ser. No. 14/787,885, filed
Oct. 29, 2015, which is a national stage filing under 35 U.S.C.
.sctn.371 of International Application PCT/US2014/036369 entitled
"METHODS AND COMPOSITIONS FOR TREATING BETA-THALASSEMIA AND SICKLE
CELL DISEASE" filed May 1, 2014, which claims the benefit of U.S.
provisional application No. 61/818,058, filed May 1, 2013, the
entire disclosure of each of which is incorporated by reference
herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] The human hemoglobin molecule consists of a protein
heterotetramer (two .alpha.-like globin chains and two .beta.-like
globin chains) and four non-protein heme groups. The .alpha.-like
and .beta.-like globin gene clusters are located on different
chromosomes, and expression of the different globin genes within
the two gene clusters are under temporal control during
development. Genetic defects, such as deletions or mutations,
inside these globin gene loci result in abnormal synthesis of
hemoglobins and consequently lead to hemoglobinopathies. Weatherall
D J, Nat Rev Genet. 2001; 2(4):245-255.
[0003] .beta.-thalassemia and sickle cell disease are the two most
common hemoglobinopathies, which together affect approximately 4.5%
of populations worldwide. Patrinos et al., Hemoglobin. 2008;
32(1-2):229-236. .beta.-thalassemia is the result of either a
deletion or mutation within the .beta.-like globin gene cluster,
diminishing the synthesis of adult .beta. globin chain. Severe
deficiency or absence of the .beta. globin chain leads to
imbalanced expression of the adult .alpha. globin chain and the
overloaded .alpha. globin chain in turn precipitates and damages
the red cell membrane, ultimately inducing rapid apoptosis of the
erythrocytes during early erythroblast development (also termed
.beta.-thalassemia major or Cooley's anemia). Individuals with
.beta.-thalassemia major become profoundly anemic within 6 to 9
months after birth, the time when the hemoglobin switch is
completed from HbF (.alpha.2/.gamma.2) to HbA
(.alpha.2/.beta.2).
[0004] Sickle cell disease is caused by a point mutation at the
sixth position of the .beta. globin chain (from Glu to Val).
Patients with sickle cell disease are characterized by the
existence of sickle hemoglobin HbS (.alpha.2/.beta..sup.s2). The
mutated adult .beta. globin chain promotes the polymerization of
HbS at low oxygen condition, which distorts the red blood cells
into the characteristic sickle shape. Schechter A N, Blood. 2008;
112(10):3927-3938.
[0005] The illness of sickle cell disease is primarily caused by
hemolysis, since the misshaped sickle cells are destroyed inside
the spleen within 10-20 days. With high risk of early death, life
expectancy of patients with the sickle cell disease is reported to
be shortened to an average of 42-48 years. Impairing the generation
of normal adult hemoglobin, both .beta.-thalassemia major and
sickle cell disease patients require regular blood transfusion to
replenish functional HbA for survival. However, constant
transfusions are accompanied by a high cost (exceeding 1 billion US
dollars per year in the US alone) and a high risk of iron
overloading which often leads to death.
[0006] In both .beta.-thalassemia and sickle cell disease, the
elevated expression of HbF has been reported to be helpful in
improving the clinical symptoms of the underlying diseases. In
.beta.-thalassemia major patients, elevation of the fetal .gamma.
globin chain synthesis balances the excess .alpha. globin chains by
formation of HbF, thus modulating the severe anemia in patients.
Natta et al., J Clin Invest. 1974; 54(2):433-438.
[0007] Moreover, the increase of the .gamma. globin chain can also
prevent the formation of HbS, and the existence of HbF directly
inhibits the polymerization of HbS in the sickle cell patients.
Noguchi et al., N Engl J Med. 1988; 318(2):96-99.
[0008] Thus, pharmacological induction of HbF in patients with
hemoglobinopathies is a potentially useful therapeutic strategy. To
date, several chemotherapeutic agents, such as trichostatin A
(histone deacetylase inhibitor), apicidin (histone deacetylase
inhibitor), 5'-aza-cytidine (DNA methyltransferase inhibitor),
hydroxyurea (ribonucleotide reductase inhibitor), butyrate and
other short-chain fatty acids, have been demonstrated to stimulate
fetal hemoglobin production. Ley et al., Annu Rev Med. 1985;
36:485-498; Humphries et al., J Clin Invest. 1985; 75(2):547-557;
Olivieri et al., Hum Mol Genet. 1998; 7(10):1655-1658; McCaffrey et
al., Blood. 1997; 90(5):2075-2083; Witt et al., Blood. 2003;
101(5):2001-2007; and Constantoulakis et al., Blood. 1989;
74(6):1963-1971.
[0009] However, most of these HbF inducers show variable efficacies
from individual to individual, low specificity in globin gene
induction, and high toxicity with irreversible apoptosis. Among
these drugs, hydroxyurea is the first US FDA-approved medicine for
the curing of hemoglobinopathies disease. Unfortunately,
approximately 25% of the recipients are poor or non-responders to
hydroxyurea treatment. Moreover, potential side effects of
myelosuppression and reproductive toxicity exist, leading to
therapeutic concerns for the usage of hydroxyurea in patients.
Grigg A., Intern Med J. 2007; 37(3):190-192; Kinney et al., Blood.
1999; 94(5):1550-1554; Steinberg et al., Blood. 1997;
89(3):1078-1088; and Atweh et al., Hematol Oncol Clin North Am.
2010; 24(6): 1131-1144.
[0010] In view of this, compounds that induce expression of
endogenous embryonic/fetal globin chains for the treatment of
.beta.-thalassemia major and sickle cell diseases are of great
clinical interest.
SUMMARY OF THE INVENTION
[0011] The present disclosure is based on the unexpected discovery
of novel compounds that possess the activity of inducing the
expression of endogenous embryonic/fetal globin (e.g., .gamma.
globin) in erythrycoytes. Accordingly, the present disclosure
provides compositions and methods for the treatment of anemia such
as .beta.-thalassemia or sickle cell disease through at least the
induction of the globin gene expression in erythrycoytes. The
methods described herein comprise the administration of a
pharmaceutical composition to a subject comprising a
therapeutically effective amount of a compound of the present
disclosure effective to treat, delay or prevent the adverse effects
of .beta.-thalassemia or sickle cell disease. In certain
embodiments, a therapeutically effective amount of a compound
described herein is effective for inducing the expression of
embryonic/fetal globin genes.
[0012] In some embodiments, pharmaceutical compositions of
compounds for the treatment of .beta.-thalassemia or sickle cell
disease through induction of endogenous embryonic/fetal globin
chains are provided. Provided compositions comprise an effective
amount of a compound as described herein, and a pharmaceutically
acceptable excipient. In other embodiments, compounds possessing
the property of inducing expression of endogenous embryonic/fetal
globin chains in erythroid cells may be present in a mammalian
host, or in culture as an in vitro model.
[0013] One aspect of the present disclosure is a compound
represented by Formula A:
##STR00001##
or a pharmaceutically acceptable salt, solvate, or hydrate
thereof.
[0014] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6a, and R.sup.6b
are each independently selected from the group consisting of
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted heterocyclyl, optionally substituted heteroaryl,
optionally substituted aryl, --OR.sup.A, --OC(O)R.sup.A,
--SR.sup.A, --N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B.
[0015] R.sup.5 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, or optionally substituted aryl.
[0016] R.sup.7a and R.sup.7b are each independently selected from
the group consisting of hydrogen, oxygen, hydroxyl, --OR, and
--OC(.dbd.O)R wherein the symbol represents a double bond when
R.sup.7a and R.sup.7b is oxygen atom or a single bond when R.sup.7a
and R.sup.7b is a hydrogen, hydroxyl, --OR, or --OC(.dbd.O)R. R is
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl.
[0017] Each instance of R.sup.A is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl.
[0018] Each instance of R.sup.B is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl, or two R.sup.B are
taken together with the intervening atoms to form a
heterocycle.
[0019] In some embodiments, the present disclosure provides a
compound of Formula (I-a):
##STR00002##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6a, and
R.sup.6b are as defined herein. In another aspect, provided herein
is a pharmaceutical composition comprising a compound of Formula
(I-a) and a pharmaceutically acceptable carrier or diluent.
[0020] In other embodiments, the present disclosure provides a
compound of Formula (V-a):
##STR00003##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, and R.sup.16 are as defined herein. Also
provided herein is a pharmaceutical composition comprising a
compound of Formula (V-a) and a pharmaceutically acceptable carrier
or diluent.
[0021] Another aspect of the present disclosure provides a
pharmaceutical composition, which comprises one or more of the
compounds disclosed herein (e.g., one or more of compounds of
Formula A, (I-a), (II), (III), (III-a), (III-b), (VI), (V-a), (VI),
(VI-a), (VII), (VII-a), (VIII), (VIII-a), (IX), (IX-a), (X), (X-a),
(XI), and/or (XI-a)) and a pharmaceutically acceptable carrier.
[0022] Further, the present disclosure provides a method of
treating a subject with .beta.-thalassemia or sickle cell anemia.
The method comprises administering an effective amount of a
pharmaceutical composition to the subject in need thereof, wherein
the composition comprises a compound disclosed herein (e.g., a
compound of Formula A, (I-a), (II), (III), (III-a), (III-b), (VI),
(V-a), (VI), (VI-a), (VII), (VII-a), (VIII), (VIII-a), (IX),
(IX-a), (X), (X-a), (XI), and/or (XI-a))) or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
[0023] In another aspect, the present disclosure provides methods
of inducing .gamma. globin comprising contacting a cell with a
compound or composition provided herein. In certain embodiments,
the contacting step is performed in vitro. In other embodiments,
the contacting step is performed in vivo. In certain embodiments,
the present disclosure provides a method of treating
.beta.-thalassemia comprising administering an effective amount of
a compound or composition provided herein to a patient in need
thereof. In other embodiments, the present disclosure provides a
method of treating sickle cell anemia comprising administering an
effective amount of a compound or composition provided herein to a
patient in need thereof.
[0024] Also within the scope of the present disclosure are
pharmaceutical compositions for use in treating .beta.-thalassemia
or sickle cell anemia, the composition comprising one or more of
the compounds described herein and a pharmaceutically acceptable
carrier, as well as uses of such compounds or compositions in
manufacturing a medicament for use in treating the anemia.
[0025] Further, the present disclosure provides a method for
assessing responsiveness of a subject (e.g., a human patient) to a
hydroxyurea. The method comprises (i) providing a sample derived
from the subject, the sample comprising adult erythroid cells,
which are treated by the hydroxyurea, (ii) measuring the expression
level of a hemoglobin gene in the erythroid cells, and identifying
the subject as being responsive to the hydroxyurea if the
expression level of the hemoglobin in the adult erythorid cells is
elevated as compared to adult erythroid cells not treated by the
hydroxyurea, and identifying the subject as being not responsive to
the hydroxyurea if the expression level of the hemoglobin in the
adult erythorid cells is unchanged or reduced as compared to adult
erythroid cells not treated by the hydroxyurea. In some examples,
the hemoglobin gene is a fetal hemoglobin (HbF) gene. In other
examples, the hydroxyurea is administered to the subject. A subject
identified as being inresponsive to the hydroxyurea may be treated
by a different anti-anemia therapeutic agent, such as the compounds
disclosed herein.
[0026] The details of one or more embodiments of the disclosure are
set forth in the description below. Other features or advantages of
the present disclosure will be apparent from the following drawings
and detailed description of several embodiments, and also from the
appended claims.
Definitions
[0027] 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.+-.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.
[0028] 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, NY, 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 present disclosure additionally encompasses compounds
described herein as individual isomers substantially free of other
isomers, and alternatively, as mixtures of various isomers.
[0029] 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" 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.
[0030] As used herein, a "hydrocarbon chain" refers to a
substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl
group. A hydrocarbon chain includes at least one chain, each node
("carbon unit") of which including at least one carbon atom between
the two radicals of the hydrocarbon chain. For example, hydrocarbon
chain --C.sup.AH(C.sup.BH.sub.2C.sup.CH.sub.3)-- includes only one
carbon unit C.sup.A. The term "C.sub.x hydrocarbon chain," wherein
x is a positive integer, refers to a hydrocarbon chain that
includes x number of carbon unit(s) between the two radicals of the
hydrocarbon chain. If there is more than one possible value of x,
the smallest possible value of x is used for the definition of the
hydrocarbon chain. For example, --CH(C.sub.2H.sub.5)-- is a C.sub.1
hydrocarbon chain, and
##STR00004##
is a C.sub.3 hydrocarbon chain. When a range of values is used,
e.g., a C.sub.1-6hydrocarbon chain, the meaning of the range is as
described herein. A hydrocarbon chain may be saturated (e.g.,
--(CH.sub.2).sub.4--). A hydrocarbon chain may also be unsaturated
and include one or more C.dbd.C and/or C.ident.C bonds anywhere in
the hydrocarbon chain. For instance,
--CH.dbd.CH--(CH.sub.2).sub.2--, --CH.sub.2--C.ident.C--CH.sub.2--,
and --C.ident.C--CH.dbd.CH-- are all examples of a unsubstituted
and unsaturated hydrocarbon chain. In certain embodiments, the
hydrocarbon chain is unsubstituted (e.g., --(CH.sub.2).sub.4--). In
certain embodiments, the hydrocarbon chain is substituted (e.g.,
--CH(C.sub.2H.sub.5)-- and --CF.sub.2--). Any two substituents on
the hydrocarbon chain may be joined to form an optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl
ring. For instance,
##STR00005##
are all examples of a hydrocarbon chain. In contrast, in certain
embodiments
##STR00006##
are not within the scope of the hydrocarbon chains described
herein.
[0031] "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 s
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), iso-propyl
(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.
[0032] "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.
[0033] "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.
[0034] "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 carbocyclic ring, as defined above, is fused toone or
more aryl or heteroaryl groups wherein the point of attachment is
on the carbocyclic 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.
[0035] 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.
[0036] "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 certain
embodiments, the heteroatom is independently selected from
nitrogen, sulfur, and oxygen. 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 partially unsaturated.
Heterocyclyl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heterocyclyl" also includes ring
systems wherein the heterocyclic ring, as defined above, is fused
with one or more carbocyclyl groups wherein the point of attachment
is either on the carbocyclyl or heterocyclic ring, or ring systems
wherein the heterocyclic ring, as defined above, is fused with one
or more aryl or heteroaryl groups, wherein the point of attachment
is on the heterocyclic ring, and in such instances, the number of
ring members continue to designate the number of ring members in
the heterocyclic 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.
[0037] 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. In some embodiments, the 5-6 membered
heterocyclyl is further substituted with another heterocyclic ring,
which is optionally substituted
[0038] 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,
dihydrobenzothienyl, 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. Exemplary 5-6 membered heterocyclyl which is further
substituted with another heterocyclic ring, which is optionally
substituted include, without limitation,
4-piperidinopiperidine.
[0039] "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 it electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms 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.
[0040] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10.pi. 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).
[0041] 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 1 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.
[0042] 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.
[0043] 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,
heterocyclylene, arylene, and heteroarylene.
[0044] As used herein, the term "optionally substituted" refers to
a substituted or unsubstituted moiety.
[0045] 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 results in
the formation of a stable compound. The present disclosure
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this disclosure, 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.
[0046] 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;
[0047] 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.cc;
[0048] 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;
[0049] each instance of R.sup.bb is, independently, 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;
[0050] each instance of R.sup.cc is, independently, 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;
[0051] 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;
[0052] 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;
[0053] each instance of R.sup.ff is, independently, selected from
the group consisting of 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
[0054] 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, 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 .dbd.O or .dbd.S; wherein
X.sup.- is a counterion.
[0055] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electrostaticneutrality. 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).
[0056] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0057] "Acyl" as used herein refers to a moiety selected from the
group consisting of --C(.dbd.O)R.sup.aa, --CHO, --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,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, and --C(.dbd.S)SR.sup.aa, wherein R.sup.aa
and R.sup.bb are as defined herein.
[0058] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary nitrogen atoms. Exemplary nitrogen atom substituents
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.
[0059] 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.aa,
--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 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.
[0060] For example, nitrogen protecting groups such as amide 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.
[0061] Nitrogen protecting groups such as carbamate 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.
[0062] Nitrogen protecting groups such as sulfonamide 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), .beta.-trimethylsilylethanesulfonamide
(SES), 9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0063] 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).
[0064] 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.cc).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 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.
[0065] 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)phenylmethyl,
tri(ryl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl, M),
2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)metlinoyloxyphenyl)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, t-butyl
carbonate (BOC), 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, o-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0066] 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.cc).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 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.
[0067] These and other exemplary substituents are described in more
detail in the Detailed Description, Figures, Examples, and Claims.
The disclosure is not intended to be limited in any manner by the
above exemplary listing of substituents.
[0068] As used throughout, "modulation" is meant to refer to an
increase or a decrease in the indicated phenomenon (e.g.,
modulation of a biological activity refers to an increase in a
biological activity or a decrease in a biological activity).
[0069] As used herein, the terms "treatment," "treating," and the
like, refer to obtaining a desired pharmacologic and/or physiologic
effect. The effect may be prophylactic in terms of completely or
partially preventing a disease or condition, or symptom thereof,
and/or may be therapeutic in terms of a partial or complete cure
for a condition and/or adverse affect attributable to the
condition. "Treatment," as used herein, covers any treatment of a
disease or condition in a mammal, particularly in a human, and
includes: (a) reducing the risk for developing the condition from
occurring in a subject which may be predisposed to the condition
but has not yet been diagnosed as having it; (b) inhibiting the
development of the condition; and/or (c) relieving the condition,
i.e., causing its regression.
[0070] An "effective amount" is an amount sufficient to effect
beneficial or desired results. An effective amount can be
administered in one or more administrations. An effective amount
corresponds with the quantity required to provide a desired average
local concentration of a particular biologic agent, in accordance
with its known efficacy, for the intended period of therapy. A dose
may be determined by those skilled in the art by conducting
preliminary animal studies and generating a dose response curve, as
is known in the art. Maximum concentration in the dose response
curve would be determined by the solubility of the compound in the
solution and by toxicity to the animal model, as known in the
art.
[0071] The effective amount further corresponds with the quantity
required to provide a desired average local concentration of the
particular biologic agent, in accordance with its efficacy for the
intended period of time. Due allowance can be made for losses due
to circulatory fluctuation due to physical activity, for example,
from ten to ninety percent loss allowance could be made depending
upon the individual patient and their routines.
[0072] The terms "individual," "subject," "host," and "patient,"
used interchangeably herein, refer to a mammal, including, but not
limited to, humans, murines, simians, felines, canines, equines,
bovines, mammalian farm animals, mammalian sport animals, and
mammalian pets. Human subjects are of particular interest.
[0073] As used herein, the terms "determining", "assessing",
"assaying", "measuring" and "detecting" refer to both quantitative
and qualitative determinations and as such, the term "determining"
is used interchangeably herein with "assaying," "measuring," and
the like. Where a quantitative determination is intended, the
phrase "determining an amount" and the like is used. Where either a
qualitative or quantitative determination is intended, the phrase
"determining a level of proliferation" or "detecting proliferation"
is used.
[0074] Definitions of specific functional groups and chemical terms
are described in more detail below. For purposes of this
disclosure, the chemical elements are identified in accordance with
the Periodic Table of the Elements, CAS version, Handbook of
Chemistry and Physics, 75th 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
"Organic Chemistry," Thomas Sorrell, University Science Books,
Sausalito: 1999, the entire contents of which are incorporated
herein by reference.
[0075] Certain compounds of the present disclosure may exist in
particular geometric or stereoisomeric forms. The present
disclosure contemplates all such compounds, including cis- and
trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,
(L)-isomers, the racemic mixtures thereof, and other mixtures
thereof, as falling within the scope of the disclosure. Additional
asymmetric carbon atoms may be present in a substituent such as an
alkyl group. All such isomers, as well as mixtures thereof, are
intended to be included in this disclosure.
[0076] Isomeric mixtures containing any of a variety of isomer
ratios may be utilized in accordance with the present disclosure.
For example, where only two isomers are combined, mixtures
containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3,
98:2, 99:1, or 100:0 isomer ratios are all contemplated by the
present disclosure. Those of ordinary skill in the art will readily
appreciate that analogous ratios are contemplated for more complex
isomer mixtures.
[0077] If, for instance, a particular enantiomer of a compound of
the present disclosure is desired, it may be prepared by asymmetric
synthesis, or by derivation with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts are formed with an appropriate
optically-active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0078] The terms "heteroaryl" is given its ordinary meaning in the
art and refers to aryl groups comprising at least one heteroatom as
a ring atom. A "heteroaryl" is a stable heterocyclic or
polyheterocyclic unsaturated moiety having preferably 3-14 carbon
atoms, each of which may be substituted or unsubstituted.
Substituents include, but are not limited to, any of the previously
mentioned substitutents, i.e., the substituents recited for
aliphatic moieties, or for other moieties as disclosed herein,
resulting in the formation of a stable compound. In some cases, a
heteroaryl is a cyclic aromatic radical having from five to ten
ring atoms of which one ring atom is selected from S, O, and N;
zero, one, or two ring atoms are additional heteroatoms
independently selected from S, O, and N; and the remaining ring
atoms are carbon, the radical being joined to the rest of the
molecule via any of the ring atoms, such as, for example, pyridyl,
pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,
furanyl, quinolinyl, isoquinolinyl, and the like.
[0079] It will also be appreciated that aryl and heteroaryl
moieties, as defined herein may be attached via an alkyl or
heteroalkyl moiety and thus also include -(alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, and
-(heteroalkyl)heteroaryl moieties. Thus, as used herein, the
phrases "aryl or heteroaryl moieties" and "aryl, heteroaryl,
-(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, and
-(heteroalkyl)heteroaryl" are interchangeable. Substituents
include, but are not limited to, any of the previously mentioned
substituents, i.e., the substituents recited for aliphatic
moieties, or for other moieties as disclosed herein, resulting in
the formation of a stable compound.
[0080] It will be appreciated that aryl and heteroaryl groups
(including bicyclic aryl groups) can be unsubstituted or
substituted, wherein substitution includes replacement of one or
more of the hydrogen atoms thereon independently with any one or
more of the following moieties including, but not limited to:
aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;
heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2F; --CHF.sub.2; --CH.sub.2CF.sub.3; --CHCl.sub.2;
--CH.sub.2OH; --CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O)R.sub.x;
--S(O).sub.2R.sub.x; --NR.sub.x(CO)R.sub.x wherein each occurrence
of R.sub.x independently includes, but is not limited to,
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic,
heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,
heteroalkylaryl or heteroalkylheteroaryl, wherein any of the
aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or
alkylheteroaryl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, saturated or
unsaturated, and wherein any of the aromatic, heteroaromatic, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Additionally, it will be appreciated, that any two adjacent groups
taken together may represent a 4, 5, 6, or 7-membered substituted
or unsubstituted alicyclic or heterocyclic moiety. Additional
examples of generally applicable substituents are illustrated by
the specific embodiments described herein.
[0081] The term "heterocycle" is given its ordinary meaning in the
art and refers to refer to cyclic groups containing at least one
heteroatom as a ring atom, in some cases, 1 to 3 heteroatoms as
ring atoms, with the remainder of the ring atoms being carbon
atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen,
phosphorus, and the like. In some cases, the heterocycle may be 3-
to 10-membered ring structures or 3- to 7-membered rings, whose
ring structures include one to four heteroatoms.
[0082] The term "heterocycle" may include heteroaryl groups,
saturated heterocycles (e.g., cycloheteroalkyl) groups, or
combinations thereof. The heterocycle may be a saturated molecule,
or may comprise one or more double bonds. In some cases, the
heterocycle is a nitrogen heterocycle, wherein at least one ring
comprises at least one nitrogen ring atom. The heterocycles may be
fused to other rings to form a polycylic heterocycle. The
heterocycle may also be fused to a spirocyclic group. In some
cases, the heterocycle may be attached to a compound via a nitrogen
or a carbon atom in the ring. The heterocycle may be substituted
with another heterocycle.
[0083] Heterocycles include, for example, thiophene,
benzothiophene, thianthrene, furan, tetrahydrofuran, pyran,
isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole,
dihydropyrrole, pyrrolidine, imidazole, pyrazole, pyrazine,
isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline, triazole,
tetrazole, oxazole, isoxazole, thiazole, isothiazole,
phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
oxolane, thiolane, oxazole, oxazine, piperidine, homopiperidine
(hexamnethyleneimine), piperazine (e.g., N-methyl piperazine),
morpholine, lactones, lactams such as azetidinones and
pyrrolidinones, sultams, sultones, other saturated and/or
unsaturated derivatives thereof, and the like. The heterocyclic
ring can be optionally substituted at one or more positions with
such substituents as described herein. In some cases, the
heterocycle is substituted with another heterocycle (e.g.,
4-piperidinopiperidine or the like). In some cases, the heterocycle
may be bonded to a compound via a heteroatom ring atom (e.g.,
nitrogen). In some cases, the heterocycle may be bonded to a
compound via a carbon ring atom. In some cases, the heterocycle is
pyridine, imidazole, pyrazine, pyrimidine, pyridazine, acridine,
acridin-9-amine, bipyridine, naphthyridine, quinoline,
benzoquinoline, benzoisoquinoline, phenanthridine-1,9-diamine, or
the like.
[0084] The term "amino," as used herein, refers to a primary
(--NH.sub.2), secondary (--NHR.sub.x), tertiary
(--NR.sub.xR.sub.y), or quaternary (--N.sup.+R.sub.xR.sub.yR.sub.z)
amine, where R.sub.x, R.sub.y and R.sub.z are independently an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, or
heteroaryl moiety, as defined herein. Examples of amino groups
include, but are not limited to, methylamino, dimethylamino,
ethylamino, diethylamino, methylethylamino, iso-propylamino,
piperidino, trimethylamino, and propylamino.
[0085] The term "alkyne" is given its ordinary meaning in the art
and refers to branched or unbranched unsaturated hydrocarbon groups
containing at least one triple bond. Non-limiting examples of
alkynes include acetylene, propyne, 1-butyne, 2-butyne, and the
like. The alkyne group may be substituted and/or have one or more
hydrogen atoms replaced with a functional group, such as a
hydroxyl, halogen, alkoxy, and/or aryl group.
[0086] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used
herein refers to an alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom or through a
sulfur atom. In certain embodiments, the alkyl group contains 1-20
aliphatic carbon atoms. In certain other embodiments, the alkyl
group contains 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the
disclosure contain 1-8 aliphatic carbon atoms. In still other
embodiments, the alkyl group contains 1-6 aliphatic carbon atoms.
In yet other embodiments, the alkyl group contains 1-4 aliphatic
carbon atoms. Examples of alkoxy, include but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy,
neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not
limited to, methylthio, ethylthio, propylthio, isopropylthio,
n-butylthio, and the like.
[0087] The term "aryloxy" refers to the group, --O-aryl. The term
"acyloxy" refers to the group, --O-acyl.
[0088] The term "alkoxyalkyl" refers to an alkyl group substituted
with at least one alkoxy group (e.g., one, two, three, or more,
alkoxy groups). For example, an alkoxyalkyl group may be
--(C.sub.1-6-alkyl)-O--(C.sub.1-6-alkyl), optionally substituted.
In some cases, the alkoxyalkyl group may be optionally substituted
with another alkyoxyalkyl group (e.g.,
--(C.sub.1-6-alkyl)-O--(C.sub.1-6-alkyl)-O--(C.sub.1-6-alkyl),
optionally substituted.
[0089] As used herein, "haloalkyl" is a substituted alkyl group as
defined herein wherein one or more of the hydrogen atoms are
independently replaced by a halogen, e.g., fluoro, bromo, chloro,
or iodo. "Perhaloalkyl" is a subset of haloalkyl, and refers to an
alkyl group wherein all of the hydrogen atoms are independently
replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In
some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms
("C.sub.1-8 haloalkyl"). In some embodiments, the haloalkyl moiety
has 1 to 6 carbon atoms ("C.sub.1-6 haloalkyl"). In some
embodiments, the haloalkyl moiety has 1 to 4 carbon atoms
("C.sub.1-4 haloalkyl"). In some embodiments, the haloalkyl moiety
has 1 to 3 carbon atoms ("C.sub.1-3 haloalkyl"). In some
embodiments, the haloalkyl moiety has 1 to 2 carbon atoms
("C.sub.1-2 haloalkyl"). In some embodiments, all of the haloalkyl
hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl
group. In some embodiments, all of the haloalkyl hydrogen atoms are
replaced with chloro to provide a "perchloroalkyl" group. Examples
of haloalkyl 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. When there is a position on the
compounds that can be substituted with alkyl, the compounds can be
substituted at that position with a haloalkyl in certain
embodiments.
[0090] It will be appreciated that the above groups and/or
compounds, as described herein, may be optionally substituted with
any number of substituents or functional moieties. That is, any of
the above groups may be optionally substituted. As used herein, the
term "substituted" is contemplated to include all permissible
substituents of organic compounds, "permissible" being in the
context of the chemical rules of valence known to those of ordinary
skill in the art. In general, the term "substituted" whether
preceded by the term "optionally" or not, and substituents
contained in formulas of this disclosure, refer to the replacement
of hydrogen radicals in a given structure with the radical of a
specified substituent. When more than one position in any given
structure may be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at every position. It will be understood that
"substituted" also includes that the substitution results in a
stable compound, e.g., which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
etc. In some cases, "substituted" may generally refer to
replacement of a hydrogen with a substituent as described herein.
However, "substituted," as used herein, does not encompass
replacement and/or alteration of a key functional group by which a
molecule is identified, e.g., such that the "substituted"
functional group becomes, through substitution, a different
functional group. For example, a "substituted phenyl group" must
still comprise the phenyl moiety and cannot be modified by
substitution, in this definition, to become, e.g., a pyridine ring.
In a broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
herein. The permissible substituents can be one or more and the
same or different for appropriate organic compounds. For purposes
of this disclosure, the heteroatoms such as nitrogen may have
hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valencies of
the heteroatoms. Furthermore, this disclosure is not intended to be
limited in any manner by the permissible substituents of organic
compounds. Combinations of substituents and variables envisioned by
this disclosure are preferably those that result in the formation
of stable compounds useful for the formation of an imaging agent or
an imaging agent precursor. The term "stable," as used herein,
preferably refers to compounds which possess stability sufficient
to allow manufacture and which maintain the integrity of the
compound for a sufficient period of time to be detected and
preferably for a sufficient period of time to be useful for the
purposes detailed herein.
[0091] Examples of substituents include, but are not limited to,
halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
heterocyclyl, aromatic or heteroaromatic moieties, --CF.sub.3,
--CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl,
heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino,
halide, alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido,
acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl,
alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl,
-carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl,
alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano,
alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like.
[0092] Any of the compounds described herein may be in a variety of
forms, such as, but not limited to, salts, solvates, hydrates,
tautomers, and isomers.
[0093] The term "pharmaceutically acceptable salt" as used herein
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, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this
disclosure 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.sup.+(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,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counter ions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0094] In certain embodiments, the compound is in the form of a
hydrate or solvate. The term "hydrate" as used herein refers to a
compound non-covalently associated with one or more molecules of
water. Likewise, the term "solvate" refers to a compound
non-covalently associated with one or more molecules of an organic
solvent.
[0095] In certain embodiments, the compound described herein may
exist in various tautomeric forms. The term "tautomer" as used
herein 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 single 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.
[0096] In certain embodiments, the compounds described herein may
exist in various isomeric forms. The term "isomer" as used herein
includes any and all geometric isomers and stereoisomers (e.g.,
enantiomers, diasteromers, etc.). For example, "isomer" includes
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
disclosure. For instance, an isomer/enantiomer may, in some
embodiments, be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically-enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound of the present disclosure is made
up of at least about 90% by weight of a preferred enantiomer. In
other embodiments the compound is made up of at least about 95%,
98%, or 99% by weight of a preferred enantiomer. Preferred
enantiomers may be isolated from racemic mixtures by any method
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts or prepared by asymmetric syntheses. See, for
example, Jacques, et al., Enantiomers, Racemates and Resolutions
(Wiley Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving
Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, Ind. 1972).
[0097] The present disclosure provides the endogenous
embryonic/fetal globin chain inducers in a variety of formulations
for therapeutic administration. In one aspect, the agents are
formulated into pharmaceutical compositions by combination with
appropriate, pharmaceutically acceptable carriers or diluents, and
are formulated into preparations in solid, semi-solid, liquid or
gaseous forms, such as tablets, capsules, powders, granules,
ointments, solutions, suppositories, injections, inhalants, gels,
microspheres, and aerosols. As such, administration is achieved in
various ways. In some formulations, the inducers are systemic after
administration; in others, the inhibitor is localized by virtue of
the formulation, such as the use of an implant that acts to retain
the active dose at the site of implantation.
[0098] Before the present disclosure is further described, it is to
be understood that this disclosure is not limited to particular
embodiments described, as such may, of course, vary. It is also to
be understood that the terminology used herein is for the purpose
of describing particular embodiments only, and is not intended to
be limiting, since the scope of the present disclosure will be
limited only by the appended claims.
[0099] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within the disclosure.
The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges, and are also
encompassed within the present disclosure, subject to any
specifically excluded limit in the stated range. Where the stated
range includes one or both of the limits, ranges excluding either
or both of those included limits are also included in the
disclosure.
[0100] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present disclosure, the preferred methods and materials are now
described. All publications mentioned hereunder are incorporated
herein by reference. Unless mentioned otherwise, the techniques
employed herein are standard methodologies well known to one of
ordinary skill in the art.
[0101] It must be noted that as used herein and in the appended
claims, the singular forms "a," "and," and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a biomarker" includes a plurality of such
biomarkers and reference to "the sample" includes reference to one
or more samples and equivalents thereof known to those skilled in
the art, and so forth. It is further noted that the claims may be
drafted to exclude any optional element. As such, this statement is
intended to serve as antecedent basis for use of such exclusive
terminology as "solely," "only" and the like in connection with the
recitation of claim elements, or use of a "negative" limitation.
Moreover any positively recited element of the disclosure provides
basis for a negative limitation to exclude that element from the
claims.
[0102] All publications and patents cited in this specification are
herein incorporated by reference as if each individual publication
or patent were specifically and individually indicated to be
incorporated by reference and are incorporated herein by reference
to disclose and describe the methods and/or materials in connection
with which the publications are cited. The citation of any
publication is for its disclosure prior to the filing date and
should not be construed as an admission that the present disclosure
is not entitled to antedate such publication by virtue of prior
disclosure. Further, the dates of publication provided may be
different from the actual publication dates which may need to be
independently confirmed.
[0103] Other objects, features and advantages of the present
disclosure will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and specific examples, while indicating preferred
embodiments of the disclosure, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the disclosure will become apparent to those skilled in
the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0104] FIG. 1 shows the structures of S51021, naphthalimides, and
SS-2394.
[0105] FIG. 2 shows the structures of five subgroups of
N-substituted 1,8-naphthalimide derivatives. The naphthalimide
derivatives were prepared by the condensation of naphthalic
anhydride derivatives with substituted aniline (A1-A14),
dimethylaminopropylamine/dimethylethylene diamine (B1-B4), alkly
amine (C1-C5), or ethyl 4-aminobutyrate (D1). The amino-substituted
naphthalimide derivatives (E1-E3) were prepared by the reduction of
the nitro-substituted naphthalimide compounds A2, B2, and B3 by
catalytic hydrogenation.
[0106] FIGS. 3A-3F are a series of graphs showing the dosage
effects of six naphthalimide derivatives, Compounds A2, Compound
B1, Compound B4, Compound E1, Compound E2, and Compound E3,
respectively, in mediating the .gamma. globin gene induction and
cell proliferation in primary human erythroid cells. Six
naphthalimide derivatives with identical pharmacophore were
selected to estimate their .gamma. globin gene inducing abilities
in primary human erythroid cells. After 3 days of compounds
treatment, the total mRNA was extracted and the relative induction
fold of the .gamma. globin gene was analyzed by quantitative
RT-PCR. The cell proliferation rate was examined by AlamarBlue
reagent. Data are presented as the relative expression level in
mean.+-.SEM, N=8.
[0107] FIGS. 4A-4D are graphs showing the expression profiles of
the .gamma. globin gene and HbF-related regulators after compounds
treatment in the primary human erthroid cells. The primary human
erythroid cells were treated with HU (145.9 .mu.M), NaB (221.6
.mu.M), S51021 (21.8 .mu.M) or SS-2394 (2.3 .mu.M) at their
IC.sub.50 for 3 days. FIG. 4A shows that the total RNA was
extracted, and the expression profiles of .gamma. globin, NF-E4,
BCL11A, and c-Myb were analyzed by relative quantitative RT-PCR.
Data are presented as the relative expression level in mean.+-.SEM,
N=8. FIG. 4B shows a graph and two panels. Upper panel: For
detection of the induction level of .gamma. globin, fifty microgram
of total cell lysate was analyzed by western blot analysis using
antibody against .gamma. globin, or .beta.-actin. Lower panel: The
signal intensity was quantified by an image-analyzing software. The
intensity of .gamma. globin expression levels of mock control was
set as 1. Data are shown as the mean.+-.SEM, N=5. FIG. 4C shows a
graph and two panels. Upper panel: For detection of the expression
level of BCL11A, thirty microgram of total protein was separated by
SDS-PAGE electrophoresis, transferred to PVDF membrane, and
immunobloted with antibody against BCL11A and .beta.-actin. Lower
panel: The signal was quantified by an image-analyzing software.
The intensity of the mock control BCL11A levels were set as 1. Data
are shown as the mean.+-.SEM, N=5. FIG. 4D is a graph showing that
the HU-nonresponding primary human erythroid cells were treated
with HU (145.9 .mu.M), NaB (221.6 .mu.M), S51021 (21.8 .mu.M) or
SS-2394 (2.3 .mu.M) for 3 days. Total RNA was extracted, and the
expression level of .gamma. globin gene was analyzed by relative
quantitative RT-PCR. Data are shown as the mean.+-.SEM, N=3.
[0108] FIG. 5 is a graph showing the phosphorylation status of p38
in primary erythroid cells treating with HU, NaB, S51021, or
SS-2394. Upper panel: For detection of the phosphorylation status
of p38, twenty microgram of total cell lysate extracted from the
primary human erythroid cells treated with HU (145.9 .mu.M), NaB
(221.6 .mu.M), S51021 (21.8 .mu.M) or SS-2394 (2.3 .mu.M) was
analyzed by Western blot analysis using antibody against p-p38 or
p38. Lower panel: The signal intensity was quantified by an
image-analyzing software. The intensity of p-p38 levels of mock
control cells was set as 1. Data are shown as the mean.+-.SEM,
N=5.
[0109] FIG. 6 is a graph showing the acetylation status of histone
H4 in primary erythroid cells treating with HU, NaB, S51021 or
SS-2394. Upper pnel: To examine the acetylation pattern of histone
H4, the primary human erythroid cells were treated with HU (145.9
.mu.M), NaB (221.6 .mu.M), S51021 (21.8 .mu.M) or SS-2394 (2.3
.mu.M) at their IC.sub.50 for 3 days. Total histones were extracted
by histone extraction buffer. Thirty microgram of histone extract
was used for western blot analysis and immunobloted with antibody
against histone H4 or acetylated histone H4. Lower panel: The
signal intensity was quantified by an image-analyzing software. The
intensity of mock control was set as 1. Data are shown as the
mean.+-.SEM, N=4.
[0110] FIG. 7 shows two exemplary synthetic schemes, Scheme 1 and
Scheme 2, for synthesing the compounds described herein.
[0111] FIG. 8 shows the effect of .gamma. globin-induction and
cytotoxicity against primary erythroid cells by the representative
analogues of 2,3-dihydro-1H-benzo[de]isoquinoline.
DETAILED DESCRIPTION OF THE INVENTION
[0112] The present disclosure stems, in part, from the unexpected
discovery that a number of small molecules were found to induce
.gamma. globin gene expression. The compounds identified herein are
useful for treatment of .beta.-thalassemia or sickle cell disease
through induction of endogenous embryonic/fetal globin chains.
Accordingly, disclosed herein are compounds capable of inducing
.gamma. globin gene expression and uses thereof in treating anemia
such as .beta.-thalassemia or sickle cell disease.
Compounds Capable of Inducing .gamma. Globin Gene Expression
[0113] In one embodiment, the compound is represented by structural
formula A, I, I-a, II, III, IV, III-a, III-b, (V-a), (VI), (VI-a),
(VII), (VII-a), (VIII), (VIII-a), (IX), (IX-a), (X), (X-a), (XI),
and/or (XI-a) wherein the values for the variables are as defined
herein.
[0114] Compounds of interest include naphthalimides, e.g.,
compounds that include a naphthalimide scaffold substituted with
one or more substituents, which are non-hydrogen. The naphthalimide
scaffold of Formula (I) may be substituted at any position 1, 2, 3,
4, 5, 6, and/or 7 shown below.
##STR00007##
[0115] In certain embodiments, positions 3 and 4 of the
naphthalimide scaffold are substituted. In certain embodiments,
position 3 of the naphthalimide scaffold is substituted. In certain
embodiments, positions 3, 4, and 7 of the naphthalimide scaffold
are substituted. In certain embodiments, positions 3 and 7 of the
naphthalimide scaffold are substituted.
[0116] In certain embodiments, a substituent may contribute to
optical isomerism and/or stereo isomerism of a compound. The
compound(s) of the present disclosure provided herein include the
neutral form, salts, solvates, hydrates, and prodrug forms of a
compound. All such forms are embraced by the present disclosure.
Thus the compounds described herein include salts, solvates,
hydrates, prodrug, and isomer forms thereof, including the
pharmaceutically acceptable salts, solvates, hydrates, prodrugs,
and isomers thereof. In certain embodiments, a compound may be a
metabolized into a pharmaceutically active derivative.
[0117] In certain embodiments, the present disclosure employs a
compound of Formula (I-a):
##STR00008##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein:
[0118] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6a, and R.sup.6b
are each independently selected from the group consisting of
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted heterocyclyl, optionally substituted heteroaryl,
optionally substituted aryl, --OR.sup.A, --OC(O)R.sup.A,
--SR.sup.A, --N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B;
[0119] R.sup.5 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, or optionally substituted aryl;
[0120] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl;
[0121] each instance of R.sup.B is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl, or two R.sup.B are
taken together with the intervening atoms to form a
heterocycle.
[0122] In some embodiments of Formula I-a, R.sup.6a and R.sup.6b
are each hydrogen. In certain embodiments, the present disclosure
employs a compound of Formula (II):
##STR00009##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
described herein.
[0123] As described generally above, R.sup.1 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.1 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.1 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, heteroaryl,
--SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain embodiments,
R.sup.1 is selected from the group consisting of --OH, --Cl, --Br,
--F, optionally substituted C.sub.1-6 alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, --OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, heteroaryl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.1 is selected from the group consisting
of --H, --OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.1 is hydrogen. In some embodiments,
R.sup.1 is C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is
--C(O)OR.sup.A. In certain embodiments, R.sup.1 is --CO.sub.2H. In
certain embodiments, R.sup.1 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.1 is halogen. In certain embodiments, R.sup.1 is
fluoro. In certain embodiments, R.sup.1 is chloro. In certain
embodiments, R.sup.1 is bromo. In certain embodiments, R.sup.1 is
iodo. In some embodiments, R.sup.1 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.1 is --NH.sub.2. In some embodiments, R.sup.1 is
--NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is
--NHCH.sub.3. In certain embodiments, R.sup.1 is --NO.sub.2. In
some embodiments, R.sup.1 is optionally substituted naphthyl.
[0124] As described generally above, R.sup.2 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.2 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.2 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.2 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.2 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.2 is hydrogen. In some embodiments,
R.sup.2 is C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is
--C(O)OR.sup.A. In certain embodiments, R.sup.2 is --CO.sub.2H. In
certain embodiments, R.sup.2 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.2 is halogen. In certain embodiments, R.sup.2 is
fluoro. In certain embodiments, R.sup.2 is chloro. In certain
embodiments, R.sup.2 is bromo. In certain embodiments, R.sup.2 is
iodo. In some embodiments, R.sup.2 is --NH.sub.2. In some
embodiments, R.sup.2 is --N(R.sup.B).sub.2. In some embodiments,
R.sup.2 is --NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.2
is --NHCH.sub.3. In certain embodiments, R.sup.2 is --NO.sub.2. In
some embodiments, R.sup.2 is optionally substituted naphthyl.
[0125] As described generally above, R.sup.3 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.3 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.3 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.3 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.3 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.3 is hydrogen. In some embodiments,
R.sup.3 is C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is
--C(O)OR.sup.A. In certain embodiments, R.sup.3 is --CO.sub.2H. In
certain embodiments, R.sup.3 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.3 is
fluoro. In certain embodiments, R.sup.3 is chloro. In certain
embodiments, R.sup.3 is bromo. In certain embodiments, R.sup.3 is
iodo. In some embodiments, R.sup.3 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.3 is --NH.sub.2. In some embodiments, R.sup.3 is
--NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is
--NHCH.sub.3. In certain embodiments, R.sup.3 is --NO.sub.2. In
some embodiments, R.sup.3 is optionally substituted naphthyl.
[0126] As described generally above, R.sup.4 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.4 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.4 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.4 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.4 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.4 is hydrogen. In some embodiments,
R.sup.4 is C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is
--C(O)OR.sup.A. In certain embodiments, R.sup.4 is --CO.sub.2H. In
certain embodiments, R.sup.4 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.4 is halogen. In certain embodiments, R.sup.4 is
fluoro. In certain embodiments, R.sup.4 is chloro. In certain
embodiments, R.sup.4 is bromo. In certain embodiments, R.sup.4 is
iodo. In some embodiments, R.sup.4 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.4 is --NH--C.sub.1-6 alkyl. In certain
embodiments, R.sup.4 is --NHCH.sub.3. In certain embodiments,
R.sup.4 is --NO.sub.2. In some embodiments, R.sup.4 is optionally
substituted naphthyl.
[0127] As described generally above, R.sup.5 is hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, or optionally
substituted aryl. In certain embodiments, R.sup.5 is hydrogen. In
some embodiments, R.sup.5 is optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl or optionally substituted aryl.
In certain embodiments, R.sup.5 is optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.5 is substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.5 is unsubstituted C.sub.1-6
alkyl. In certain embodiments, R.sup.5 is methyl, ethyl, propyl,
butyl, pentyl, or hexyl. In certain embodiments, R.sup.5 is
isopropyl, isobutyl, or isoamyl. In certain embodiments, R.sup.5 is
isobutyl. In certain embodiments, R.sup.5 is tert-butyl. In certain
embodiments, R.sup.5 is --(CH.sub.2).sub.n--N(R.sup.B).sub.2,
wherein n is 1, 2, 3, 4, 5, or 6. In certain embodiments, n is 1.
In certain embodiments, n is 2. In certain embodiments, n is 3. In
certain embodiments, n is 4. In certain embodiments, n is 5. In
certain embodiments, n is 6. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--NHR.sup.B. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is optionally
substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is unsubstituted
C.sub.1-6 alkyl. In certain embodiment, R.sup.5 is
--(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is substituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--N(CH.sub.3)R.sup.B, wherein each R.sup.B is
independently optionally substituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.5 is --(CH.sub.2).sub.n--N(CH.sub.3)R.sup.B,
wherein each R.sup.B is independently unsubstituted C.sub.1-6
alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--N(CH.sub.3).sub.2. In certain embodiments,
R.sup.5 is --(CH.sub.2).sub.n--N(CH.sub.2CH.sub.3)R.sup.B, wherein
each R.sup.B is independently optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--N(CH.sub.2CH.sub.3)R.sup.B, wherein each
R.sup.B is independently unsubstituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.5 is --(CH.sub.2).sub.n--N(R.sup.B).sub.2,
wherein each R.sup.B is independently selected from the group
consisting of methyl, ethyl, isopropyl, isobutyl, isoamyl, and
benzyl. In some embodiments, R.sup.5 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein each R.sup.B is the
same. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, 5,
or 6, and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle with at least 1-4
heteroatoms. In certain embodiments, the heterocycle is a 3-8
membered ring. In certain embodiments, the heterocycle formed is In
certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, or
5, and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle. In some embodiments,
R.sup.5 is --(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein each
R.sup.B is different. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.n--NH.sub.2. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.s--CO.sub.2R.sup.A, wherein s is 1, 2, 3, 4, 5, or
6. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.s--CO.sub.2H. In some embodiments, s is 1. In some
embodiments, s is 2. In some embodiments, s is 3. In some
embodiments, s is 4. In some embodiments, s is 5. In some
embodiments, s is 6. In certain embodiments, R.sup.5 is
--CH.sub.2--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.5 is
--C(O)O-methyl. In certain embodiments, R.sup.5 is --C(O)O-ethyl.
In certain embodiments, R.sup.5 is --C(O)O-propyl,
--OC(O)-isopropyl, --C(O)O-isobutyl, or --OC(O)-isoamyl. In certain
embodiments, R.sup.5 is --(CH.sub.2).sub.2--CO.sub.2R.sup.A,
wherein R.sup.A is hydrogen or optionally substituted alkyl. In
certain embodiments, R.sup.5 is
--(CH.sub.2).sub.3--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.4--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.5--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.6--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.5 is
--(CH.sub.2).sub.s--CO.sub.2NR.sup.A.sub.3, wherein R.sup.A is
hydrogen or optionally substituted alkyl, and s is 1 to 5.
[0128] In certain embodiments, R.sup.5 is optionally substituted
aryl. In some embodiments, R.sup.5 is of the following
structure:
##STR00010##
wherein:
[0129] each instance of R.sup.7 is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B;
[0130] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl;
[0131] each instance of R.sup.B is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl, or two R.sup.B are
taken together with the intervening atoms to form a heterocycle;
and
[0132] n is 0, 1, 2, 3, 4 or 5.
[0133] As generally defined herein, n is 0, 1, 2, 3, 4, or 5. In
certain embodiments, n is 0 and R.sup.5 is phenyl. In certain
embodiments, n is 1 and R.sup.5 is of the formula
##STR00011##
In certain embodiments, n is 1 and R.sup.5 is of the formula
##STR00012##
In certain embodiments, n is 1 and R.sup.5 is of the formula
##STR00013##
In certain embodiments, n is 2 and R.sup.5 is of the formula
##STR00014##
In certain embodiments, n is 2 and R.sup.5 is of the formula
##STR00015##
In certain embodiments, n is 2 and R.sup.5 is of the formula
##STR00016##
In certain embodiments, n is 2 and R.sup.5 is of the formula
##STR00017##
In certain embodiments, In certain embodiments, n is 2 and R.sup.5
is of the formula
##STR00018##
In certain embodiments, In certain embodiments, n is 2 and R.sup.5
is of the formula
##STR00019##
In certain embodiments, n is 3 and R.sup.5 is of the formula
##STR00020##
In certain embodiments, n is 3 and R.sup.5 is of the formula
##STR00021##
In certain embodiments, n is 3 and R.sup.5 is of the formula
##STR00022##
In certain embodiments, n is 3 and R.sup.5 is of the formula
##STR00023##
In certain embodiments, n is 3 and R.sup.5 is of the formula
##STR00024##
In certain embodiments, n is 4 and R.sup.5 is of the formula
##STR00025##
In certain embodiments, n is 4 and R.sup.5 is of the formula
##STR00026##
In certain embodiments, n is 4 and R.sup.5 is of the formula
##STR00027##
In certain embodiments, n is 5 and R.sup.5 is of the formula
##STR00028##
[0134] In certain embodiments, R.sup.7 is hydrogen. In some
embodiments, R.sup.7 is halo. In certain embodiments, R.sup.7 is
fluoro. In certain embodiments, R.sup.7 is chloro. In certain
embodiments, R.sup.7 is bromo. In certain embodiments, R.sup.7 is
iodo. In some embodiments, R.sup.7 is optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl or optionally substituted aryl.
In certain embodiments, R.sup.7 is optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.7 is substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.7 is substituted methyl,
ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments,
R.sup.7 is CH.sub.2F. In certain embodiments, R.sup.7 is CHF.sub.2.
In certain embodiments, R.sup.7 is CF.sub.3. In certain
embodiments, R.sup.7 is --(CH.sub.2).sub.s--CO.sub.2R.sup.A,
wherein s is 1, 2, 3, 4, 5, or 6. In certain embodiments, R.sup.7
is --(CH.sub.2).sub.s--CO.sub.2H. In some embodiments, s is 1. In
some embodiments, s is 2. In some embodiments, s is 3. In some
embodiments, s is 4. In some embodiments, s is 5. In some
embodiments, s is 6. In certain embodiments, R.sup.7 is
--CH.sub.2--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--C(O)O-methyl. In certain embodiments, R.sup.7 is --C(O)O-ethyl.
In certain embodiments, R.sup.7 is --C(O)O-propyl,
--OC(O)-isopropyl, --C(O)O-isobutyl, or --OC(O)-isoamyl. In certain
embodiments, R.sup.7 is --(CH.sub.2).sub.2--CO.sub.2R.sup.A,
wherein R.sup.A is hydrogen or optionally substituted alkyl. In
certain embodiments, R.sup.7 is
--(CH.sub.2).sub.3--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--(CH.sub.2).sub.4--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--(CH.sub.2).sub.5--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--(CH.sub.2).sub.6--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl.
[0135] In certain embodiments, R.sup.7 is unsubstituted C.sub.1-6
alkyl. In certain embodiments, R.sup.7 is methyl, ethyl, propyl,
butyl, pentyl, or hexyl. In certain embodiments, R.sup.7 is
isopropyl, isobutyl, or isoamyl. In certain embodiments, R.sup.7 is
isobutyl. In certain embodiments, R.sup.7 is tert-butyl.
[0136] In certain embodiments, R.sup.7 is --OR.sup.A. In certain
embodiments, R.sup.7 is --OH. In certain embodiments, R.sup.7 is
--OR.sup.A, wherein R.sup.A is optionally substituted alkyl. In
certain embodiments, R.sup.7 is --O-methyl. In certain embodiments,
R.sup.7 is --O-ethyl. In certain embodiments, R.sup.7 is
--O-propyl, --O-isopropyl, --O-isobutyl, or --O-isoamyl.
[0137] In certain embodiments, R.sup.7 is --N(R.sup.B).sub.2,
wherein each R.sup.B is independently selected from the group
consisting of methyl, ethyl, isopropyl, isobutyl, isoamyl, and
benzyl. In some embodiments, R.sup.7 is --N(R.sup.B).sub.2, wherein
each R.sup.B is the same. In some embodiments, R.sup.7 is
--N(R.sup.B).sub.2, wherein each R.sup.B is different. In certain
embodiments, R.sup.7 is --NH.sub.2.
[0138] In certain embodiments, R.sup.7 is --CO.sub.2R.sup.A. In
certain embodiments, R.sup.7 is --CO.sub.2H. In certain
embodiments, R.sup.7 is --CO.sub.2R.sup.A, wherein R.sup.A is
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--C(O)O-methyl. In certain embodiments, R.sup.7 is --C(O)O-ethyl.
In certain embodiments, R.sup.7 is --C(O)O-propyl,
--OC(O)-isopropyl, --C(O)O-isobutyl, or --OC(O)-isoamyl.
[0139] In some embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are hydrogen. In certain embodiments, R.sup.1
and R.sup.4 are hydrogen. In certain embodiments, R.sup.3 and
R.sup.4 are hydrogen. In certain embodiments, R.sup.1 and R.sup.2
are hydrogen. In certain embodiments, R.sup.1 and R.sup.3 are
hydrogen. In certain embodiments, R.sup.2 and R.sup.4 are hydrogen.
In some embodiments, at least two of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are each hydrogen, and R.sup.5 is hydrogen. In some
embodiments, R.sup.1, R.sup.3, and R.sup.4 are hydrogen. In some
embodiments, R.sup.1, R.sup.2, and R.sup.3 are hydrogen. In some
embodiments, R.sup.2, R.sup.3, and R.sup.4 are hydrogen.
[0140] In some embodiments, the compound provided herein is of
Formula (III) or (IV):
##STR00029##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are as defined
herein. In certain embodiments, R.sup.2 and R.sup.3 are taken
together with their intervening atoms to form an optionally
substituted carbocycle or heterocycle.
[0141] In certain embodiments, the compound provided herein is of
Formula (III-a) or (III-b):
##STR00030##
[0142] or a pharmaceutically acceptable salt, solvate, or hydrate
thereof, wherein R.sup.1, R.sup.2, and R.sup.5 are as defined
herein. In certain embodiments, a compound of the present
disclosure is selected from the group consisting of the compounds
listed in Tables 1a and 1b.
[0143] Compounds of interest also include
2,3-dihydro-1H-benzo[de]isoquinoline analogues, e.g., compounds
that include a 2,3-dihydro-1H-benzo[de]isoquinoline scaffold
substituted with one or more substituents which are non-hydrogen.
The 2,3-dihydro-1H-benzo[de]isoquinoline scaffold of Formula (V)
may be substituted at any position 1, 2, 3, 4, 5, 6, 7, 8 and/or
9:
##STR00031##
[0144] In certain embodiments, positions 3, 7, 8, and/or 9 of the
Formula (V) scaffold are substituted as described herein. In
certain embodiments, only positions 3 and 7 of the Formula (V)
scaffold are substituted as described herein. In certain
embodiments, positions 7, 8, and/or 9 of the Formula (V) scaffold
are substituted as described herein. In certain embodiments,
positions 7 and 8 of the Formula (V) scaffold are substituted as
described herein. In certain embodiments, positions 7 and 9 of the
Formula (V) scaffold are substituted as described herein. In
certain embodiments, positions 7 of the Formula (V) scaffold are
substituted as described herein. In certain embodiments, positions
3, 4, 7, 8, and/or 9 of the Formula (V) scaffold are substituted as
described herein. In certain embodiments, positions 4, 7, 8, and 9
of the Formula (V) scaffold are substituted as described herein. In
certain embodiments, positions 4 and 7 of the Formula (V) scaffold
are substituted as described herein. The remaining positions of the
foregoing embodiments are substituted with hydrogen.
TABLE-US-00001 TABLE 1a Exemplary Compounds of Formula I-a. BO
.gamma. globin num- IC.sub.50 induction Reference Yield ID ber
Structure (.mu.M) (at IC.sub.50) MF MW MP (.degree. C.) MP
(.degree. C.) (%) A1 BO- 2388 ##STR00032## >100 ND
C.sub.18H.sub.11NO.sub.2 273.3 218-220 202 (16) 70.7 A2 BO- 2375
##STR00033## 0.3 1.1 C.sub.18H.sub.10N.sub.2O.sub.4 318.3 >280
280-282 (17) 92.7 A3 BO- 2376 ##STR00034## 5.2 ND
C.sub.18H.sub.8Cl.sub.2N.sub.2O.sub.4 387.2 >280 85.2 A4 BO-
2377 ##STR00035## 21 ND C.sub.19H.sub.12N.sub.2O.sub.5 348.3
>280 92.2 A5 BO- 2378 ##STR00036## 6.7 ND
C.sub.22H.sub.12N.sub.2O.sub.6 404.4 254.5-256 38 A6 BO- 2379
##STR00037## >100 ND C.sub.18H.sub.10ClNO.sub.2 307.7 263-265.5
231-233 (18) 22.4 A7 BO- 2380 ##STR00038## >100 ND
C.sub.19H.sub.12ClNO.sub.3 337.8 >280 37 A8 BO- 2381
##STR00039## >100 ND C.sub.19H.sub.9ClF.sub.3NO.sub.2 375.7
278-279 17.3 A9 BO- 2382 ##STR00040## >100 ND
C.sub.18H.sub.9BrClNO.sub.2 386.6 >280 13.2 A10 BO- 2383
##STR00041## >100 ND C.sub.18H.sub.9Cl.sub.2NO.sub.2 342.2
273-275 12.1 A11 BO- 2384 ##STR00042## >100 ND
C.sub.18H.sub.8BrClFNO.sub.2 404.6 >280 49.2 A12 BO- 2384
##STR00043## >100 ND C.sub.18H.sub.9ClFNO.sub.2 325.7 274-276
40.5 A13 BO- 2386 ##STR00044## >100 ND
C.sub.18H.sub.9BrClNO.sub.2 386.6 >280 66.3 A14 BO- 2387
##STR00045## >100 ND C.sub.18H.sub.8Cl.sub.3NO.sub.2 376.6
>280 >300 (18) 15.9 B1 BO- 2393 ##STR00046## 10.7 4.1
C.sub.16H.sub.17ClN.sub.2O.sub.2 304.8 >280 296-298 (20) 84.5 B2
BO- 2390 ##STR00047## 2.6 ND C.sub.16H.sub.15N.sub.3O.sub.4 313.3
131-133 106-109 (20) 65.7 B3 BO- 2391 ##STR00048## 2.3 ND
C.sub.17H.sub.17N.sub.3O.sub.4 327.3 108-110 106-109 (21) 42 B4 BO-
2392 ##STR00049## 5 3.3 C.sub.16H.sub.16Cl.sub.2N.sub.2O.sub.2
339.2 >280 293-295 (22) 81.5 C1 BO- 2400 ##STR00050## >100 ND
C.sub.14H.sub.11NO.sub.2 225.2 171-172.5 158 (18) 37.3 C2 BO- 2396
##STR00051## >100 ND C.sub.13H.sub.8N.sub.2O.sub.4 256.2
209-212.5 208-209 (18) 51.1 C3 BO- 2397 ##STR00052## >100 ND
C.sub.14H.sub.10N.sub.2O.sub.4 270.2 191-192.5 187.5-188.5 (18)
34.1 C4 BO- 2398 ##STR00053## >100 ND C.sub.13H.sub.8ClNO.sub.2
245.7 186-188 171-173 (18) 32.6 C5 BO- 2399 ##STR00054## >100 ND
C.sub.14H.sub.10ClNO.sub.2 259.7 167-170 165-166 (18) 33.7 D1 BO-
2401 ##STR00055## 6.3 ND C.sub.18H.sub.16N.sub.2O.sub.6 356.3
115-116 97 E1 BO- 2389 ##STR00056## 2.2 1.3
C.sub.18H.sub.12N.sub.2O.sub.2 288.3 276-278 302-304 (23) 56.4 E2
(SS- 2394) BO- 2394 ##STR00057## 2.3 4
C.sub.16H.sub.18ClN.sub.3O.sub.2 319.8 >280 184-185 (20) 77.3 E3
BO- 2395 ##STR00058## 11.2 2.7 C.sub.17H.sub.20ClN.sub.3O.sub.2
333.8 >280 184-185 (21) 42.8
TABLE-US-00002 TABLE 1b Additional Exemplary Compounds of Formula
I-a. BO number Structure BO-2562 ##STR00059## BO-2559 ##STR00060##
BO-2561 ##STR00061##
[0145] In certain embodiments, a substituent may contribute to
optical isomerism and/or stereo isomerism of a compound. The
compound(s) of the present disclosure provided herein include the
neutral form, salts, solvates, hydrates, and prodrug forms of a
compound. All such forms are embraced by the present disclosure.
Thus the compounds described herein include salts, solvates,
hydrates, prodrug, and isomer forms thereof, including the
pharmaceutically acceptable salts, solvates, hydrates, prodrugs,
and isomers thereof. In certain embodiments, a compound may be a
metabolized into a pharmaceutically active derivative.
[0146] In certain embodiments, the present disclosure employs a
compound of Formula (V-a):
##STR00062##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein:
[0147] R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13
are each independently selected from the group consisting of
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted heterocyclyl, optionally substituted heteroaryl,
optionally substituted aryl, --OR.sup.A, --OC(O)R.sup.A,
--SR.sup.A, --N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B;
[0148] R.sup.14 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, or optionally substituted aryl;
[0149] R.sup.15 and R.sup.16 are each independently selected from
the group consisting of hydrogen, oxygen, hydroxyl, --OR, and
--OC(O)R, wherein both R.sup.15 and R.sup.16 are not oxygen
connected via a double bond, wherein R is optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, and optionally substituted aryl;
[0150] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl; and
[0151] each instance of R.sup.B is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl, or two R.sup.B are
taken together with the intervening atoms to form a
heterocycle.
[0152] In some embodiments, R.sup.10 is --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.A is independently hydrogen or optionally
substituted alkyl. In some embodiments, R.sup.A is independently
hydrogen, methyl or ethyl. In some embodiments, R.sup.B is
independently hydrogen or optionally substituted alkyl. In some
embodiments, R.sup.B is independently hydrogen, methyl or ethyl. In
some embodiments, each R.sup.B is hydrogen. In some embodiments,
each R.sup.B is methyl. In some embodiments, R.sup.10 is hydrogen,
--NH.sub.2, --NHC(O)CH.sub.3, --NHC(O)OR.sup.A, --NHR.sup.B,
--NR.sup.B.sub.2, wherein R.sup.B can be C.sub.1-C.sub.5 alkyl. In
some embodiments, R.sup.10 is hydrogen, --NHC(O)CH.sub.3,
--NHC(O)O(CH.sub.3), --N(CH.sub.3).sub.2, --NH.sub.2, or
--NHCH.sub.2CH.sub.3. In some embodiments, R.sup.10 is hydrogen and
R.sup.8, R.sup.9, R.sup.11, R.sup.12, and R.sup.13 are each
independently H or the groups recited for R.sup.10.
[0153] In some embodiments, R.sup.11 is --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.A is independently hydrogen or optionally
substituted alkyl. In some embodiments, R.sup.A is independently
hydrogen, methyl or ethyl. In some embodiments, R.sup.B is
independently hydrogen or optionally substituted alkyl. In some
embodiments, R.sup.B is independently hydrogen, methyl or ethyl. In
some embodiments, each R.sup.B is hydrogen. In some embodiments,
each R.sup.B is methyl. In some embodiments, R.sup.11 is hydrogen,
--NH.sub.2, --NHC(O)CH.sub.3, --N(R.sup.A)C(O)OR.sup.B,
--NHR.sup.B, --NR.sup.B.sub.2, wherein R.sup.B can be
C.sub.1-C.sub.5 alkyl. In some embodiments, R.sup.11 is hydrogen,
--NHC(O)CH.sub.3, --NHC(O)O(CH.sub.3), --N(CH.sub.3).sub.2,
--NH.sub.2, or --NHCH.sub.2CH.sub.3. In some embodiments, R.sup.11
is hydrogen and R.sup.8, R.sup.9, R.sup.11, R.sup.12, and R.sup.13
are each independently H or the groups recited for R.sup.11.
[0154] In certain embodiments, R.sup.14 is hydrogen. In some
embodiments, R.sup.14 is an optionally substituted alkyl. In
certain embodiments, R.sup.14 is an optionally substituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is a substituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is a
unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is
a substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In
certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, 5,
or 6, and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle with at least 1-4
heteroatoms. In certain embodiments, the heterocycle is a 3-8
membered ring. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, or
5, and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle. In certain embodiments, n
is 1. In certain embodiments, n is 2. In certain embodiments, n is
3. In certain embodiments, n is 4. In certain embodiments, n is 5.
In certain embodiments, n is 6. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 2. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.n--NHR.sup.B, wherein
R.sup.B is optionally substituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.n--NHR.sup.B, wherein
R.sup.B is unsubstituted C.sub.1-6 alkyl. In certain embodiment,
R.sup.14 is --(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is
substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(CH.sub.3)R.sup.B, wherein each R.sup.B is
independently optionally substituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.n--N(CH.sub.3)R.sup.B,
wherein each R.sup.B is independently unsubstituted C.sub.1-6
alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(CH.sub.3).sub.2. In certain embodiments,
R.sup.14 is --(CH.sub.2).sub.n--N(CH.sub.2CH.sub.3)R.sup.B, wherein
each R.sup.B is independently optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(CH.sub.2CH.sub.3)R.sup.B, wherein each
R.sup.B is independently unsubstituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.n--N(R.sup.B).sub.2,
wherein each R.sup.B is independently selected from the group
consisting of methyl, ethyl, isopropyl, isobutyl, isoamyl, and
benzyl. In some embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein each R.sup.B is the
same. In some embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein each R.sup.B is
different. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--NH.sub.2. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.2N(CH.sub.3).sub.2. In certain embodiments,
R.sup.14 comprises a carboxylic acid or tetra-ammonium moiety. In
certain embodiments, R.sup.14 is --(CH.sub.2).sub.n--COOH or
--(CH.sub.2).sub.n--COONR.sup.C.sub.3 or, wherein n is 1, 2, 3, 4,
5, or 6 and R.sup.C is an optionally substituted C.sub.1-6 alkyl,
wherein the optional substituent is a hydroxyl. In certain
embodiments, R.sup.C is --(CH.sub.2).sub.2OH, --(CH.sub.2).sub.2OH,
--(CH.sub.2).sub.3OH, --(CH.sub.2).sub.4OH,
--(CH.sub.2).sub.5OH.
[0155] As described generally above, R.sup.8 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.8 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.8 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.8 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.8 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.8 is hydrogen. In some embodiments,
R.sup.8 is C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is
--C(O)OR.sup.A. In certain embodiments, R.sup.8 is --CO.sub.2H. In
certain embodiments, R.sup.8 is --C(O)N(R.sup.B).sub.2 or
--N(R.sup.A)C(O)R.sup.A. In some embodiments, R.sup.8 is halogen.
In certain embodiments, R.sup.8 is fluoro. In certain embodiments,
R.sup.8 is chloro. In certain embodiments, R.sup.8 is bromo. In
certain embodiments, R.sup.8 is iodo. In some embodiments, R.sup.8
is --NH.sub.2. In some embodiments, R.sup.8 is --N(R.sup.B).sub.2.
In some embodiments, R.sup.8 is --NH--C.sub.1-6 alkyl. In certain
embodiments, R.sup.8 is --NHCH.sub.3. In certain embodiments,
R.sup.8 is --NO.sub.2. In some embodiments, R.sup.8 is optionally
substituted naphthyl.
[0156] As described generally above, R.sup.9 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.9 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.9 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.9 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.9 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.9 is hydrogen. In some embodiments,
R.sup.9 is C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is
--C(O)OR.sup.A. In certain embodiments, R.sup.9 is --CO.sub.2H. In
certain embodiments, R.sup.9 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.9 is halogen. In certain embodiments, R.sup.9 is
fluoro. In certain embodiments, R.sup.9 is chloro. In certain
embodiments, R.sup.9 is bromo. In certain embodiments, R.sup.9 is
iodo. In some embodiments, R.sup.9 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.9 is --NH.sub.2. In some embodiments, R.sup.9 is
--NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is
--NHCH.sub.3. In certain embodiments, R.sup.9 is --NO.sub.2. In
some embodiments, R.sup.9 is optionally substituted naphthyl.
[0157] As described generally above, R.sup.10 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.10 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.10 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.10 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.10 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.10 is hydrogen. In some embodiments,
R.sup.10 is C.sub.1-6 alkyl. In certain embodiments, R.sup.10 is
--C(O)OR.sup.A. In certain embodiments, R.sup.10 is --CO.sub.2H. In
certain embodiments, R.sup.10 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A--. In some
embodiments, R.sup.10 is halogen. In certain embodiments, R.sup.10
is fluoro. In certain embodiments, R.sup.10 is chloro. In certain
embodiments, R.sup.10 is bromo. In certain embodiments, R.sup.10 is
iodo. In some embodiments, R.sup.10 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.10 is --NH.sub.2. In some embodiments, R.sup.10
is --NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.10 is
--NHCH.sub.3. In certain embodiments, R.sup.10 is --NO.sub.2. In
some embodiments, R.sup.10 is optionally substituted naphthyl. In
some embodiments, R.sup.10 is --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.A is independently hydrogen or optionally
substituted alkyl. In some embodiments, R.sup.A is independently
hydrogen, methyl or ethyl. In some embodiments, R.sup.B is
independently hydrogen or optionally substituted alkyl. In some
embodiments, R.sup.B is independently hydrogen, methyl or ethyl. In
some embodiments, each R.sup.B is hydrogen. In some embodiments,
each R.sup.B is methyl. In some embodiments, R.sup.10 is hydrogen,
--NH.sub.2, --NHC(O)CH.sub.3, --NHC(O)O(R.sup.A), --NHR.sup.B,
--NR.sup.B.sub.2, wherein R.sup.B can be C.sub.1-C.sub.5 alkyl. In
some embodiments, R.sup.10 is hydrogen, --NHC(O)CH.sub.3,
--NHC(O)O(CH.sub.3), --N(CH.sub.3).sub.2, --NH.sub.2, or
--NHCH.sub.2CH.sub.3.
[0158] As described generally above, R.sup.11 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.11 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.11 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.11 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.11 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.11 is hydrogen. In some embodiments,
R.sup.11 is C.sub.1-6 alkyl. In certain embodiments, R.sup.11 is
--C(O)OR.sup.A. In certain embodiments, R.sup.11 is --CO.sub.2H. In
certain embodiments, R.sup.11 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.11 is halogen. In certain embodiments, R.sup.11
is fluoro. In certain embodiments, R.sup.11 is chloro. In certain
embodiments, R.sup.11 is bromo. In certain embodiments, R.sup.11 is
iodo. In some embodiments, R.sup.11 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.11 is --NH.sub.2. In some embodiments, R.sup.11
is --NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.11 is
--NHCH.sub.3. In certain embodiments, R.sup.11 is --NO.sub.2. In
some embodiments, R.sup.11 is optionally substituted naphthyl. In
some embodiments, R.sup.11 is --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.A is independently hydrogen or optionally
substituted alkyl. In some embodiments, R.sup.A is independently
hydrogen, methyl or ethyl. In some embodiments, R.sup.B is
independently hydrogen or optionally substituted alkyl. In some
embodiments, R.sup.B is independently hydrogen, methyl or ethyl. In
some embodiments, each R.sup.B is hydrogen. In some embodiments,
each R.sup.B is methyl. In some embodiments, R.sup.11 is hydrogen,
--NH.sub.2, --NHC(O)CH.sub.3, --NHC(O)O(R.sup.A), --NHR.sup.B,
--NR.sup.B.sub.2, wherein R.sup.B can be C.sub.1-C.sub.5 alkyl. In
some embodiments, R.sup.11 is hydrogen, --NHC(O)CH.sub.3,
--NHC(O)O(CH.sub.3), --N(CH.sub.3).sub.2, --NH.sub.2, or
--NHCH.sub.2CH.sub.3.
[0159] As described generally above, R.sup.12 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.12 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.12 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.12 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.12 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.12 is hydrogen. In some embodiments,
R.sup.12 is C.sub.1-6 alkyl. In certain embodiments, R.sup.12 is
--C(O)OR.sup.A. In certain embodiments, R.sup.12 is --CO.sub.2H. In
certain embodiments, R.sup.12 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.12 is halogen. In certain embodiments, R.sup.12
is fluoro. In certain embodiments, R.sup.12 is chloro. In certain
embodiments, R.sup.12 is bromo. In certain embodiments, R.sup.12 is
iodo. In some embodiments, R.sup.12 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.12 is --NH.sub.2. In some embodiments, R.sup.12
is --NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.12 is
--NHCH.sub.3. In certain embodiments, R.sup.12 is --NO.sub.2. In
some embodiments, R.sup.12 is optionally substituted naphthyl.
[0160] As described generally above, R.sup.13 is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2, --C(O)R.sup.A,
--C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.13 is selected from the group consisting of
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, optionally
substituted aryl, --OR.sup.A, --OC(O)R.sup.A, --SR.sup.A,
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B. In certain
embodiments, R.sup.13 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, optionally substituted C.sub.1-6 alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, --OR.sup.A, --NO.sub.2,
--N(R.sup.B).sub.2, --C(O)CH.sub.3, --CO.sub.2H, --C(O)OR.sup.A,
--C(O)N(R.sup.B).sub.2, --CN, heterocyclyl, --SO.sub.2-alkyl, and
--SO.sub.2-aryl. In certain embodiments, R.sup.13 is selected from
the group consisting of --OH, --Cl, --Br, --F, optionally
substituted C.sub.1-6 alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
--OR.sup.A, --NO.sub.2, --N(R.sup.B).sub.2, --C(O)CH.sub.3,
--CO.sub.2H, --C(O)OR.sup.A, --C(O)N(R.sup.B).sub.2, --CN,
heterocyclyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In certain
embodiments, R.sup.13 is selected from the group consisting of --H,
--OH, --Cl, --Br, --F, methyl, ethyl, methoxy, ethoxy,
--C.ident.C-aryl, phenyl, naphthyl, --NO.sub.2, --NH--C.sub.1-6
alkyl, --C(O)CH.sub.3, --CO.sub.2H, --CO.sub.2Et, --CONH-aryl,
--CN, N-morpholinyl, --SO.sub.2-alkyl, and --SO.sub.2-aryl. In
certain embodiments, R.sup.13 is hydrogen. In some embodiments,
R.sup.13 is C.sub.1-6 alkyl. In certain embodiments, R.sup.13 is
--C(O)OR.sup.A. In certain embodiments, R.sup.13 is --CO.sub.2H. In
certain embodiments, R.sup.13 is --C(O)N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A or --N(R.sup.A)C(O)OR.sup.A. In some
embodiments, R.sup.13 is halogen. In certain embodiments, R.sup.13
is fluoro. In certain embodiments, R.sup.13 is chloro. In certain
embodiments, R.sup.13 is bromo. In certain embodiments, R.sup.13 is
iodo. In some embodiments, R.sup.13 is --N(R.sup.B).sub.2. In some
embodiments, R.sup.13 is --NH.sub.2. In some embodiments, R.sup.13
is --NH--C.sub.1-6 alkyl. In certain embodiments, R.sup.13 is
--NHCH.sub.3. In certain embodiments, R.sup.13 is --NO.sub.2. In
some embodiments, R.sup.13 is optionally substituted naphthyl.
[0161] As described generally above, R.sup.14 is hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, or optionally
substituted aryl. In certain embodiments, R.sup.14 is hydrogen. In
some embodiments, R.sup.14 is optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl or optionally substituted aryl.
In certain embodiments, R.sup.14 is optionally substituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is substituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is unsubstituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is methyl, ethyl,
propyl, butyl, pentyl, or hexyl. In certain embodiments, R.sup.14
is isopropyl, isobutyl, or isoamyl. In certain embodiments,
R.sup.14 is isobutyl. In certain embodiments, R.sup.14 is
tert-butyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, 5,
or 6 and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle with at least 1-4
heteroatoms. In certain embodiments, the heterocycle is a 3-8
membered ring. In certain embodiments, the heterocycle formed is In
certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, or
5, and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle. In certain embodiments, n
is 1. In certain embodiments, n is 2. In certain embodiments, n is
3. In certain embodiments, n is 4. In certain embodiments, n is 5.
In certain embodiments, n is 6. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--NHR.sup.B. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is optionally
substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is unsubstituted
C.sub.1-6 alkyl. In certain embodiment, R.sup.14 is
--(CH.sub.2).sub.n--NHR.sup.B, wherein R.sup.B is substituted
C.sub.1-6 alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(CH.sub.3)R.sup.B, wherein each R.sup.B is
independently optionally substituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.n--N(CH.sub.3)R.sup.B,
wherein each R.sup.B is independently unsubstituted C.sub.1-6
alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(CH.sub.3).sub.2. In certain embodiments,
R.sup.14 is --(CH.sub.2).sub.n--N(CH.sub.2CH.sub.3)R.sup.B, wherein
each R.sup.B is independently optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(CH.sub.2CH.sub.3)R.sup.B, wherein each
R.sup.B is independently unsubstituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.n--N(R.sup.B).sub.2,
wherein each R.sup.B is independently selected from the group
consisting of methyl, ethyl, isopropyl, isobutyl, isoamyl, and
benzyl. In some embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein each R.sup.B is the
same. In some embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein each R.sup.B is
different. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--NH.sub.2. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.2N(CH.sub.3).sub.2. In certain embodiments,
R.sup.14 comprises a carboxylic acid or tetra-ammonium moiety. In
certain embodiments, R.sup.14 is
--(CH.sub.2).sub.s--CO.sub.2R.sup.A, wherein s is 1, 2, 3, 4, 5, or
6. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.s--CO.sub.2H. In some embodiments, s is 1. In some
embodiments, s is 2. In some embodiments, s is 3. In some
embodiments, s is 4. In some embodiments, s is 5. In some
embodiments, s is 6. In certain embodiments, R.sup.14 is
--CH.sub.2--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.14 is
--CH.sub.2--CO.sub.2NR.sup.c.sub.3, wherein R.sup.C is an
optionally substituted C.sub.1-6 alkyl, wherein the optional
substituent is a hydroxyl. In certain embodiments, R.sup.C is
--(CH.sub.2).sub.2OH, --(CH.sub.2).sub.2OH, --(CH.sub.2).sub.3OH,
--(CH.sub.2).sub.4OH, --(CH.sub.2).sub.5OH. In certain embodiments,
R.sup.14 is --C(O)O-methyl. In certain embodiments, R.sup.14 is
--C(O)O-ethyl. In certain embodiments, R.sup.14 is --C(O)O-propyl,
--OC(O)-isopropyl, --C(O)O-isobutyl, or --OC(O)-isoamyl. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.2--CO.sub.2R.sup.A,
wherein R.sup.A is hydrogen or optionally substituted alkyl. In
certain embodiments, R.sup.14 is
--(CH.sub.2).sub.3--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.4--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.5--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.6--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl.
[0162] In certain embodiments, R.sup.14 is optionally substituted
aryl. In some embodiments, R.sup.14 is of the following
structure:
##STR00063##
wherein:
[0163] each instance of R.sup.7 is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, optionally substituted aryl, --OR.sup.A,
--OC(O)R.sup.A, --SR.sup.A, --N(R.sup.B).sub.2,
--N(R.sup.A)C(O)R.sup.A, --C(O)N(R.sup.B).sub.2, --CN, --NO.sub.2,
--C(O)R.sup.A, --C(O)OR.sup.A, --S(O)R.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2N(R.sup.B).sub.2, and --NHSO.sub.2R.sup.B;
[0164] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl;
[0165] each instance of R.sup.B is independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, and optionally substituted aryl, or two R.sup.B are
taken together with the intervening atoms to form a heterocycle;
and
[0166] n is 0, 1, 2, 3, 4 or 5.
[0167] As generally defined herein, n is 0, 1, 2, 3, 4, or 5. In
certain embodiments, n is 0 and R.sup.14 is phenyl. In certain
embodiments, n is 1 and R.sup.14 is of the formula
##STR00064##
In certain embodiments, n is 1 and R.sup.14 is of the formula.
##STR00065##
In certain embodiments, n is 1 and R.sup.14 is of the formula
##STR00066##
certain embodiments, n is 2 and R.sup.14 is of the formula
##STR00067##
In certain embodiments, n is 2 and R.sup.14 is of the formula
##STR00068##
In certain embodiments, n is 2 and R.sup.14 is of the formula
##STR00069##
In certain embodiments, n is 2 and R.sup.14 is of the formula
##STR00070##
In certain embodiments, In certain embodiments, n is 2 and R.sup.14
is of the formula
##STR00071##
In certain embodiments, In certain embodiments, n is 2 and R.sup.14
is of the formula
##STR00072##
In certain embodiments, n is 3 and R.sup.14 is of the formula
##STR00073##
In certain embodiments, n is 3 and R.sup.14 is of the formula
##STR00074##
In certain embodiments, n is 3 and R.sup.14 is of the formula
##STR00075##
In certain embodiments, n is 3 and R.sup.14 is of the formula
##STR00076##
In certain embodiments, n is 3 and R.sup.14 is of the formula
##STR00077##
In certain embodiments, n is 4 and R.sup.14 is of the formula
##STR00078##
In certain embodiments, n is 4 and R.sup.14 is of the formula
##STR00079##
In certain embodiments, n is 4 and R.sup.14 is of the formula
##STR00080##
In certain embodiments, n is 5 and R.sup.14 is of the formula
##STR00081##
[0168] In certain embodiments, R.sup.7 is hydrogen. In some
embodiments, R.sup.7 is halo. In certain embodiments, R.sup.7 is
fluoro. In certain embodiments, R.sup.7 is chloro. In certain
embodiments, R.sup.7 is bromo. In certain embodiments, R.sup.7 is
iodo. In some embodiments, R.sup.7 is optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted heterocyclyl or optionally substituted aryl.
In certain embodiments, R.sup.7 is optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.7 is substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.7 is substituted methyl,
ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments,
R.sup.7 is CH.sub.2F. In certain embodiments, R.sup.7 is CHF.sub.2.
In certain embodiments, R.sup.7 is CF.sub.3. In certain
embodiments, R.sup.7 is --(CH.sub.2).sub.s--CO.sub.2R.sup.A,
wherein s is 1, 2, 3, 4, 5, or 6. In certain embodiments, R.sup.7
is --(CH.sub.2).sub.s--CO.sub.2H. In some embodiments, s is 1. In
some embodiments, s is 2. In some embodiments, s is 3. In some
embodiments, s is 4. In some embodiments, s is 5. In some
embodiments, s is 6. In certain embodiments, R.sup.7 is
--CH.sub.2--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--C(O)O-methyl. In certain embodiments, R.sup.7 is --C(O)O-ethyl.
In certain embodiments, R.sup.7 is --C(O)O-propyl,
--OC(O)-isopropyl, --C(O)O-isobutyl, or --OC(O)-isoamyl. In certain
embodiments, R.sup.7 is --(CH.sub.2).sub.2--CO.sub.2R.sup.A,
wherein R.sup.A is hydrogen or optionally substituted alkyl. In
certain embodiments, R.sup.7 is
--(CH.sub.2).sub.3--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--(CH.sub.2).sub.4--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--(CH.sub.2).sub.5--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--(CH.sub.2).sub.6--CO.sub.2R.sup.A, wherein R.sup.A is hydrogen or
optionally substituted alkyl.
[0169] In certain embodiments, R.sup.7 is unsubstituted C.sub.1-6
alkyl. In certain embodiments, R.sup.7 is methyl, ethyl, propyl,
butyl, pentyl, or hexyl. In certain embodiments, R.sup.7 is
isopropyl, isobutyl, or isoamyl. In certain embodiments, R.sup.7 is
isobutyl. In certain embodiments, R.sup.7 is tert-butyl.
[0170] In certain embodiments, R.sup.7 is --OR.sup.A. In certain
embodiments, R.sup.7 is --OH. In certain embodiments, R.sup.7 is
--OR.sup.A, wherein R.sup.A is optionally substituted alkyl. In
certain embodiments, R.sup.7 is --O-methyl. In certain embodiments,
R.sup.7 is --O-ethyl. In certain embodiments, R.sup.7 is
--O-propyl, --O-isopropyl, --O-isobutyl, or --O-isoamyl.
[0171] In certain embodiments, R.sup.7 is --N(R.sup.B).sub.2,
wherein each R.sup.B is independently selected from the group
consisting of methyl, ethyl, isopropyl, isobutyl, isoamyl, and
benzyl. In some embodiments, R.sup.7 is --N(R.sup.B).sub.2, wherein
each R.sup.B is the same. In some embodiments, R.sup.7 is
--N(R.sup.B).sub.2, wherein each R.sup.B is different. In certain
embodiments, R.sup.7 is --NH.sub.2.
[0172] In certain embodiments, R.sup.7 is --CO.sub.2R.sup.A. In
certain embodiments, R.sup.7 is --CO.sub.2H. In certain
embodiments, R.sup.7 is --CO.sub.2R.sup.A, wherein R.sup.A is
optionally substituted alkyl. In certain embodiments, R.sup.7 is
--C(O)O-methyl. In certain embodiments, R.sup.7 is --C(O)O-ethyl.
In certain embodiments, R.sup.7 is --C(O)O-propyl,
--OC(O)-isopropyl, --C(O)O-isobutyl, or --OC(O)-isoamyl.
[0173] In some embodiments, at least two of R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are hydrogen. In certain
embodiments, R.sup.8, R.sup.9, R.sup.12, and R.sup.13 are hydrogen.
In certain embodiments, R.sup.12, and R.sup.13 are are hydrogen. In
certain embodiments, R.sup.8, R.sup.9, R.sup.10 are hydrogen. In
certain embodiments, R.sup.8, R.sup.9, and R.sup.11 are hydrogen.
In certain embodiments, R.sup.10 and R.sup.12 are hydrogen. In some
embodiments, at least two of R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, and R.sup.13 are each hydrogen, and R.sup.14 is hydrogen.
In some embodiments, R.sup.8, R.sup.9, R.sup.11, R.sup.12, and
R.sup.13 are hydrogen.
[0174] In some embodiments of Formula (V-a), R.sup.15 and R.sup.16
are each hydrogen. In certain embodiments, the present disclosure
employs a compound of Formula (VI):
##STR00082##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
and R.sup.14 are as described herein for Formula (V-a).
[0175] In some embodiments of Formula (VI), R.sup.8, R.sup.9,
R.sup.11, R.sup.12, and R.sup.13 are each hydrogen. In certain
embodiments, the present disclosure employs a compound of Formula
(VI-a):
##STR00083##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.10 and R.sup.14 are as described herein for Formula
(V-a). In some examples, R.sup.10 and R.sup.14, independently, are
hydrogen, optionally substituted C.sub.1-6 alkyl, --NR.sup.B.sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A or hydroxyl.
[0176] In some embodiments of Formula (V-a), R.sup.15 is hydroxyl
and R.sup.16 is oxygen connected via a double bond. In certain
embodiments, the present disclosure employs a compound of Formula
(VII):
##STR00084##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
and R.sup.14 are as described herein for Formula (V-a).
[0177] In some embodiments of Formula (VII), R.sup.8, R.sup.9,
R.sup.11, R.sup.12, and R.sup.13 are each hydrogen. In some
embodiments, R.sup.8, R.sup.9, R.sup.10, R.sup.12, and R.sup.13 are
each hydrogen. In some embodiments, R.sup.8, R.sup.9, R.sup.12, and
R.sup.13 are each hydrogen. In certain embodiments, the present
disclosure employs a compound of Formula (VII-a):
##STR00085##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.10, R.sup.11, and R.sup.14 are as described herein
for Formula (V-a). In some examples, R.sup.10, R.sup.11, and
R.sup.14 independently, are hydrogen, optionally substituted
C.sub.1-6 alkyl, --NR.sup.B.sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A or hydroxyl.
[0178] In some embodiments of Formula (V-a), R.sup.15 is hydrogen
and R.sup.16 is oxygen connected via a double bond. In certain
embodiments, the present disclosure employs a compound of Formula
(VIII):
##STR00086##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14 are as described herein for Formula (V-a).
[0179] In some embodiments of Formula (VIII), R.sup.8, R.sup.9,
R.sup.11, R.sup.12, R.sup.13 are each hydrogen. In some
embodiments, R.sup.8, R.sup.9, R.sup.10, R.sup.12, R.sup.13, and
R.sup.15 are each hydrogen. In some embodiments, R.sup.8, R.sup.9,
R.sup.12, R.sup.13, and R.sup.15 are each hydrogen. In certain
embodiments, the present disclosure employs a compound of Formula
(VIII-a):
##STR00087##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.10, R.sup.11, and R.sup.14 are as described herein
for Formula (V-a). In some examples, R.sup.10, R.sup.11, and
R.sup.14 independently, are hydrogen, optionally substituted
C.sub.1-6 alkyl, --NR.sup.B.sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A or hydroxyl.
[0180] In some embodiments of Formula (V-a), R.sup.15 is hydrogen
and R.sup.16 is hydroxyl. In certain embodiments, the present
disclosure employs a compound of Formula (IX):
##STR00088##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13
and R.sup.14 are as described herein for Formula (V-a).
[0181] In some embodiments of Formula (IX), R.sup.8, R.sup.9,
R.sup.12, R.sup.13, and R.sup.15 are each hydrogen. In some
embodiments of Formula (IX), R.sup.8, R.sup.9, R.sup.10, R.sup.12,
R.sup.13, and R.sup.15 are each hydrogen. In some embodiments of
Formula (IX), R.sup.8, R.sup.9, R.sup.11, R.sup.12, R.sup.13, and
R.sup.15 are each hydrogen. In certain embodiments, the present
disclosure employs a compound of Formula (IX-a):
##STR00089##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.10, R.sup.11, and R.sup.14 are as described herein
for Formula (V-a). In some examples, R.sup.10, R.sup.11, and
R.sup.14 independently, are hydrogen, optionally substituted
C.sub.1-6 alkyl, --NR.sup.B.sub.2, --N(R.sup.A)C(O)R.sup.A,
--N(R.sup.A)C(O)OR.sup.A or hydroxyl.
[0182] In some embodiments of Formula (V-a), R.sup.15 and R.sup.16
are each hydroxyl. In certain embodiments, the present disclosure
employs a compound of Formula (X):
##STR00090##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13
and R.sup.14 are as described herein for Formula (V-a).
[0183] In some embodiments, R.sup.8, R.sup.9, R.sup.11, R.sup.12,
and R.sup.13 of Formula (X) are each hydrogen. In certain
embodiments, the present disclosure employs a compound of Formula
(X):
##STR00091##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.10 and R.sup.14 are as described herein for Formula
(V-a). In some examples, R.sup.10 and R.sup.14, independently, are
hydrogen, optionally substituted C.sub.1-6 alkyl, --NR.sup.B.sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A or hydroxyl.
[0184] In some embodiments of Formula (V-a), R.sup.15 and R.sup.16
are each hydrogen. In certain embodiments, the present disclosure
employs a compound of Formula (XI):
##STR00092##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
and R.sup.14 are as described herein for Formula (V-a).
[0185] In some embodiments, R.sup.8, R.sup.9, R.sup.11, R.sup.12,
and R.sup.13 of Formula (XI) are each hydrogen. In certain
embodiments, the present disclosure employs a compound of Formula
(XI-a):
##STR00093##
or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
wherein R.sup.10 and R.sup.14 are as described herein for Formula
(V-a). In some examples, R.sup.10 and R.sup.14, independently, are
hydrogen, optionally substituted C.sub.1-6 alkyl, --NR.sup.B.sub.2,
--N(R.sup.A)C(O)R.sup.A, --N(R.sup.A)C(O)OR.sup.A or hydroxyl.
[0186] In some embodiments of the present disclosure is a compound
represented by formula (V-a), (VI), (VI-a), (VII), (VII-a), (VIII),
(VIII-a), (IX), (IX-a), (X), (X-a), (XI), and/or (XI-a) or a
pharmaceutically acceptable salt thereof, wherein R.sup.10 is
--N(R.sup.B).sub.2, --N(R.sup.A)C(O)R.sup.A, or
--N(R.sup.A)C(O)OR.sup.A and R.sup.14 is an optionally substituted
alkyl. In some embodiments, R.sup.A is independently hydrogen or
optionally substituted alkyl. In some embodiments, R.sup.A is
independently hydrogen, methyl or ethyl. In some embodiments,
R.sup.B is independently hydrogen or optionally substituted alkyl.
In some embodiments, R.sup.B is independently hydrogen, methyl or
ethyl. In some embodiments, each R.sup.B is hydrogen. In some
embodiments, each R.sup.B is methyl. In some embodiments, R.sup.10
is hydrogen, --NH.sub.2, --NHC(O)CH.sub.3, --NHC(O)OR.sup.A,
--NHR.sup.B, --NR.sup.B.sub.2, wherein R.sup.B can be
C.sub.1-C.sub.5 alkyl. In some embodiments, R.sup.10 is hydrogen,
--NHC(O)CH.sub.3, --NHC(O)O(CH.sub.3), --N(CH.sub.3).sub.2,
--NH.sub.2, or --NHCH.sub.2CH.sub.3. In some embodiments, R.sup.14
is an optionally substituted alkyl. In certain embodiments,
R.sup.14 is an optionally substituted methyl, ethyl, propyl, butyl,
pentyl, or hexyl. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 1, 2, 3, 4, 5,
or 6 and wherein R.sup.B is independently optionally substituted
C.sub.1-6 alkyl or two R.sup.B are taken together with the
intervening atoms to form a heterocycle with at least 1-4
heteroatoms. In certain embodiments, the heterocycle is a 3-8
membered ring. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--N(R.sup.B).sub.2, wherein n is 2. In certain
embodiments, R.sup.14 is --(CH.sub.2).sub.2NH.sub.2. In certain
embodiments, R.sup.14 comprises a carboxylic acid or tetra-ammonium
moiety. In certain embodiments, R.sup.14 is
--(CH.sub.2).sub.n--COOH or --(CH.sub.2).sub.n--COONR.sup.C.sub.3
or, wherein n is 1, 2, 3, 4, 5, or 6 and R.sup.C is an optionally
substituted C.sub.1-6 alkyl, wherein the optional substituent is a
hydroxyl. In certain embodiments, R.sup.C is --(CH.sub.2).sub.2OH,
--(CH.sub.2).sub.2OH, --(CH.sub.2).sub.3OH, --(CH.sub.2).sub.4OH,
--(CH.sub.2).sub.5OH.
[0187] In certain embodiments, exemplary compounds of the present
disclosure is one of the compounds provided below or analogues
thereof:
##STR00094##
[0188] In some embodiments, a compound of the present disclosure is
1H-benzo[de]isoquinoline-1,3(2H)-dione or analogues thereof as
represented by formula A, I-a, II, III, IV, III-a, or III-b. In
some embodiments, a compound of the present disclosure is
2,3-dihydro-1H-benzo[de]isoquinoline-1-one or analogues thereof as
represented by formula V-a, VIII, or VIII-a. In some embodiments, a
compound of the present disclosure is
2,3-dihydro-1H-benzo[de]isoquinoline or analogues thereof as
represented by formula V-a, XI, or XI-a. In some embodiments, a
compound of the present disclosure is
2,3-dihydro-1H-benzo[de]isoquinoline-1,3-diol or analogues thereof
as represented by formula V, X, or X-a. In some embodiments, a
compound of the present disclosure is
2,3-dihydro-1H-benzo[de]isoquinolin-1-ol or analogues thereof as
represented by formula V, IX, or IX-a. In some embodiments, a
compound of the present disclosure is
3-hydroxy-2,3-dihydro-1H-benzo[de]isoquinoline-1-one or analogues
thereof as represented by formula V, VII, or VII-a.
[0189] In an alternative embodiment, a compound of the present
disclosure is depicted by a compound in Table 2 or a
pharmaceutically acceptable salt, solvate, or hydrate thereof.
TABLE-US-00003 TABLE 2 Structures of Examplary Compounds BO number
Structure BO-2566 ##STR00095## BO-2563 ##STR00096## BO-2560
##STR00097## BO-2565 ##STR00098## BO-2477 ##STR00099## BO-2476
##STR00100## BO-2478 ##STR00101##
Pharmaceutical Compositions
[0190] Pharmaceutical compositions of the present disclosure and
for use in accordance with the present disclosure may include a
pharmaceutically acceptable excipient or carrier. As used herein,
the term "pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" means a non-toxic, inert solid, semi-solid or
liquid filler, diluent, encapsulating material or formulation
auxiliary of any type. Remington's Pharmaceutical Sciences,
Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa.,
1980) discloses various excipients used in formulating
pharmaceutical compositions and known techniques for the
preparation thereof. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose, and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose, and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil;
glycols such as propylene glycol; esters such as ethyl oleate and
ethyl laurate; agar; detergents such as Tween 80; buffering agents
such as magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol; and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator. The pharmaceutical compositions
of this present disclosure can be administered to humans and/or to
animals, orally, rectally, parenterally, intracisternally,
intravaginally, intranasally, intraperitoneally, topically (as by
powders, creams, ointments, or drops), bucally, or as an oral or
nasal spray.
[0191] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups, and elixirs. In addition to the active
ingredients (i.e., microparticles, nanoparticles, liposomes,
micelles, polynucleotide/lipid complexes), the liquid dosage forms
may contain 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 (in
particular, 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 also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0192] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also 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 may 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. In certain
embodiments, the particles are suspended in a carrier fluid
comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v)
Tween 80.
[0193] The injectable formulations can be sterilized, for example,
by filtration through a bacteria-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.
[0194] 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 may be accomplished by the use of a
liquid suspension or crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution that, 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. Injectable depot forms
are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide. Depending
upon the ratio of drug to polymer and the nature of the particular
polymer employed, the rate of drug release can be controlled.
Examples of other biodegradable polymers include poly(orthoesters)
and poly(anhydrides). Depot injectable formulations are also
prepared by entrapping the drug in liposomes or microemulsions
which are compatible with body tissues.
[0195] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
particles 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
particles.
[0196] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the particles are 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-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 also comprise buffering agents.
[0197] Solid compositions of a similar type may also 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.
[0198] 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 contain
opacifying agents and can also 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.
[0199] Solid compositions of a similar type may also 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.
[0200] Dosage forms for topical or transdermal administration of an
inventive pharmaceutical composition include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants, or
patches. The particles are admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
disclosure.
[0201] In certain embodiments, the pharmaceutically acceptable
topical formulations of the present disclosure comprise at least a
compound described herein and a penetration enhancing agent. The
choice of topical formulation will depend or several factors,
including the condition to be treated, the physicochemical
characteristics of the inventive compound and other excipients
present, their stability in the formulation, available
manufacturing equipment, and costs constraints. As used herein the
term "penetration enhancing agent" means an agent capable of
transporting a pharmacologically active compound through the
stratum coreum and into the epidermis or dermis, preferably, with
little or no systemic absorption. A wide variety of compounds have
been evaluated as to their effectiveness in enhancing the rate of
penetration of drugs through the skin. See, for example,
Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E.
(eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the
use and testing of various skin penetration enhancers, and
Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation
Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh
T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc.,
Buffalo Grove, Ill. (1997). In certain exemplary embodiments,
penetration agents for use with the present disclosure include, but
are not limited to, triglycerides (e.g., soybean oil), aloe
compositions (e.g., aloe-vera gel), ethyl alcohol, isopropyl
alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene
glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid
esters (e.g., isopropyl myristate, methyl laurate, glycerol
monooleate, and propylene glycol monooleate), and N-methyl
pyrrolidone.
[0202] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the microparticles or
nanoparticles in a proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
can be controlled by either providing a rate controlling membrane
or by dispersing the particles in a polymer matrix or gel.
[0203] In certain embodiments, the compositions may be in the form
of ointments, pastes, creams, lotions, gels, powders, solutions,
sprays, inhalants. or patches. In certain exemplary embodiments,
formulations of the compositions according to the present
disclosure are creams, which may further contain saturated or
unsaturated fatty acids such as stearic acid, palmitic acid, oleic
acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid
being particularly preferred. Creams of the present disclosure may
also contain a non-ionic surfactant, for example,
polyoxy-40-stearate. In certain embodiments, the active component
is admixed under sterile conditions with a pharmaceutically
acceptable excipient and any needed preservatives or buffers as may
be required. Ophthalmic formulations, eardrops, and eye drops are
also contemplated as being within the scope of this disclosure.
Additionally, the present disclosure contemplates the use of
transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
are made by dissolving or dispensing the compound in the proper
medium. As discussed above, penetration enhancing agents can also
be used to increase the flux of the compound across the skin. The
rate can be controlled by either providing a rate controlling
membrane or by dispersing the compound in a polymer matrix (e.g.,
PLGA) or gel.
[0204] The ointments, pastes, creams, and gels may contain
excipients such as animal and vegetable fats, oils, waxes,
paraffins, starch, tragacanth, cellulose derivatives, polyethylene
glycols, silicones, bentonites, silicic acid, talc, and zinc oxide,
or mixtures thereof.
[0205] Powders and sprays can contain excipients such as lactose,
talc, silicic acid, aluminum hydroxide, calcium silicates, and
polyamide powder, or mixtures of these substances. Sprays can
additionally contain customary propellants such as
chlorofluorohydrocarbons.
[0206] It will also be appreciated that the compounds and
pharmaceutical compositions of the present disclosure can be
formulated and employed in combination therapies, that is, the
compounds and pharmaceutical compositions can be formulated with or
administered concurrently with, prior to, or subsequent to, one or
more other desired therapeutics or medical procedures. The
particular combination of therapies (therapeutics or procedures) to
employ in a combination regimen will take into account
compatibility of the desired therapeutics and/or procedures and the
desired therapeutic effect to be achieved. It will also be
appreciated that the therapies employed may achieve a desired
effect for the same disorder (for example, a provided compound may
be administered concurrently with another agent effective against
.beta.-thalassemia or sickle cell disease), or they may achieve
different effects (e.g., control of any adverse effects).
[0207] It will also be appreciated that certain of the compounds of
present disclosure can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present disclosure, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or a prodrug or
other adduct or derivative of a compound described herein which
upon administration to a patient in need is capable of providing,
directly or indirectly, a compound as otherwise described herein,
or a metabolite or residue thereof.
Methods of Treatment
[0208] The present disclosure provides compounds that induce
.gamma. globin and can produce beneficial therapeutic effects. In
certain embodiments, compounds and compositions described herein
are used to treat hemoglobinopathies such as sickle cell anemia or
.beta.-thalassemia. In certain embodiments, a provided compound or
composition is used to treat sickle cell anemia. In certain other
embodiments, a provided compound or composition is used to treat
.beta.-thalassemia.
[0209] Without being bound by theory, the compounds (non-HDACi
compounds) described herein can stimulate .gamma. globin expression
via regulating both the p38/MAPK signaling pathway and globin gene
regulators. As shown in the Examples below, several compounds
described herein exhibited better gamma globin-inducing
capabilities than hydroxyurea, including higher gamma globin level
and superior therapeutic effect (IC.sub.50/EC). Most importantly,
those compounds are able to induce .gamma. globin gene expression
in both hydroxyurea-responsive cells and hydroxyurea-resistant
cells.
[0210] In one aspect, the present disclosure provides methods
comprising the compounds described herein, e.g., compounds of
Formula A, I, I-a, II, III, IV, III-a, III-b, V-a, VI, VII, VIII,
IX, X or XI, or compositions thereof for stimulating .gamma. globin
expression comprising: contacting a subject with a compound or a
composition described herein under conditions suitable to induce
.gamma. globin expression in the subject.
[0211] In certain embodiments, the present disclosure provides a
method of inducing .gamma. globin comprising: contacting a cell
with an effective amount of a compound of Formula A, I, I-a, II,
III, IV, III-a, III-b, V-a, VI, VII, VIII, IX, X or XI. In certain
embodiments, the present disclosure provides a method of inducing
.gamma. globin comprising: administering to a subject an effective
amount of a compound of Formula A, I, I-a, II, III, IV, III-a,
III-b, V-a, VI, VII, VIII, IX, X or XI.
[0212] In certain embodiments, the present disclosure provides a
method of treating 3-thalassemia or sickle cell anemia, the method
comprising: administering an effective amount of one or more of the
provided compounds or composition to a patient suffering from,
suspected of having, or at risk for .beta.-thalassemia or sickle
cell anemia.
[0213] In certain embodiments, a provided compound or composition
is administered orally. In certain embodiments, a provided compound
or composition is administered parenterally. In certain
embodiments, a provided compound or composition is administered in
combination with an additional therapeutic agent.
[0214] The compounds of the present disclosure are preferably
formulated in dosage unit form for ease of administration and
uniformity of dosage. The expression "dosage unit form" as used
herein refers to a physically discrete unit of therapeutic agent
appropriate for the patient to be treated. It will be understood,
however, that the total daily usage of the compounds and
compositions of the present disclosure will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient or organism will depend upon a variety of factors including
the disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex,
and diet of the subject; the time of administration, mute of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts (see, for example, Goodman
and Gilman's The Pharmacological Basis of Therapeutics, Tenth
Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Bill
Press, 155-173, 2001, which is incorporated herein by reference in
its entirety).
Methods of Assessing Responsiveness to Hydroxyurea
[0215] Hydroxyurea, also known as hydroxycarbamide, is an
antineoplastic drug for treating proliferative disorders. It is
also used in treating sickle cell disease (SCD). Since a SCD
patient's responsiveness to hydroxyurea depends on the expression
level of HbF induced by hydroxyurea, the responsiveness of RBC can
be used to predict one's responsiveness to hydroxyurea.
[0216] To assess whether a patient is responsive to hydroxyurea, a
biological sample (e.g., a blood sample) containing RBCs can be
collected from the patient and the expression level of a hemoglobin
gene, such as a HbF gene, in the RBCs can be measured using a
routine method (e.g., real-time PCR). If the expression level of
the hemoglobin gene is elevated after treatment of hydroxyurea,
this indicates that the patient is responsive to the treatment. On
the other hand, if the expression level of the hemoglobin gene is
unchanged or decreased, this indicates that the patient might not
be responsive to hydroxyurea treatment. The RBCs can be treated by
hydroxyurea in vitro. Alternatively, the blood sample can be
obtained from a patient who is subject to hydroxyurea
treatment.
[0217] A subject identified by the method described herein as
inresponsive to a hydroxyurea treatment can be subjected to a
different treatment, such as a non-hydroxyurea conventional
treatment or using any of the compounds disclosed herein.
[0218] Without further elaboration, it is believed that one skilled
in the art can, based on the above description, utilize the present
disclosure to its fullest extent. The following specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever. All publications cited herein are incorporated by
reference for the purposes or subject matter referenced herein.
Examples
Example 1: Effect of Exemplary Compounds in Inducing HbF
[0219] A dual fluorescence reporter assay system was established to
screen for the potential HbF-inducing agents. Taking advantage of
fluoresence signal detected by fluorometer, these chemical
compounds could be surveyed quickly to determine those that can
switch-on the fetal .gamma. globin promoter. Application of this
dual fluoresence reporter system has successfully led to
identification of several heterocyclic compounds with common core
structure (benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one) and
with higher efficacies/specificities in the induction of the
embryonic/fetal globin chains. These chemical compounds may be
developed into a new generation of therapeutical drugs for the cure
of hemoglobinopathies including sickle cell disease and
P-thalassemia (e.g., 3-thalassemia major).
Materials and Methods
[0220] Chemistry. General Information.
[0221] All commercial chemicals and solvents were reagent grade and
were used without further purification. Melting points were
determined in open capillaries on a Fargo melting point apparatus
and are uncorrected. Thin-layer chromatography was performed on
silica gel G60 F254 (Merck) with short-wavelength UV light for
visualization. High resolution mass spectra were recorded on a
Waters HDMS G1 instrument with ESI+, centroid mode, the samples
were dissolved in MeOH. High-performance liquid chromatography was
performed on Hitachi L-1230 instrument: column: Kinetex 2.6.mu.
HILIC (150.times.4.6 mm). Compounds were detected by UV at 260 nm.
The mobile phase was MeCN/THF (80:20 v/v) with flow rate of 1
mL/min. The purity of all tested compounds was .gtoreq.98% based on
analytical HPLC. 1H NMR spectra was recorded on Bruker AVANCE 600
DRX and/or 400 MHz, Bruker Top-Spin spectrometers in the solvents
indicated. The Proton chemical shifts were reported in parts per
million (.delta. ppm) relative to (CH.sub.3).sub.4Si and coupling
constants (J) in Hertz (Hz) and s, d, t, m, br s, refer to singlet,
doublet, triplet, multiplet, broad respectively.
[0222] Chemical Synthesis.
[0223] The synthetic route of preparing exemplified compounds is
shown in Schemes 1 and 2. A mixture of naphthalic anhydride and
various amines in a molar ratio of 1:10 [such as aniline,
dimethylaminopropylamine, dimethylethylene diamine or ethyl
4-aminobutyrate)] in toluene in the presence of acetic acid was
heated at reflux. After completion of the reaction, the solvent was
evaporated under reduced pressure to dryness. The solid residue was
dissolved in ethyl acetate, washed with water, and dried over
Na.sub.2SO.sub.4. The solvent was removed by evaporation in vacuo.
The amino substituted derivatives were synthesized from the
corresponding nitro substituted derivatives by catalytic
hydrogenation (5% Pd/C, H.sub.2) at 35 psi. The product was
purified by recrystallization with EtOH or by column
chromatography.
Compounds
N-Phenyl-1,8-naphthalimide (A1)
[0224] Compound A1 was obtained from 1,8-naphthalic anhydride (1.2
g, 6 mmol) in aniline (50 ml) through general procedure to yield
1.16 g (70.7%), mp 218-220.degree. C. (Lit.sup.16 202.degree. C.)
(Jaubert et al., Berichte der deutschen chemischen Gesellschaft.
1895; 28(1):360-364), ESI-HRMS calcd for C.sub.18H.sub.11NO.sub.2
m/z 296.0687 (M+Na), found 296.0692 (M+Na). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.57 (t, J=7.16 Hz, 4H, naphthylic-H) 7.97 (t, J=7.69
Hz, 2H, naphthylic-H) 7.60 (t, J=7.13 Hz, 2H, benzene-H) 7.53 (t,
J=7.66 Hz, 1H, benzene-H) 7.45 (d, J=7.27 Hz, 2H, benzene-H).
N-Phenyl-4-nitro-1,8-naphthalimide (A2)
[0225] Compound A2 was obtained from 4-nitro-1,8-naphthalic
anhydride (2.43 g, 10 mmol) in toluene (50 ml) and aniline (9.1 ml,
100 mmol) through general procedure to yield 2.775 g (92.7%), mp
>280.degree. C. (Lit.sup.17 280-282.degree. C.) (Mitsuo et al.,
Journal of Synthetic Organic Chemistry, Japan. 1956;
14(9):558-564), FAB-HRMS calcd for C.sub.18H.sub.10N.sub.2O.sub.4
m/z 319.0719 (M+H), found 319.0715 (M+H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.83 (d, J=8.55 Hz, 1H, naphthylic-H) 8.71 (d, J=7.27
Hz, 1H, naphthylic-H) 8.69 (d, J=8.04 Hz, 1H, naphthylic-H) 8.66
(d, J=7.42 Hz, 1H, naphthylic-H) 8.2 (t, J=7.43 Hz, 1H,
naphthylic-H) 7.61 (t, J=7.23 Hz, 2H, benzene-H) 7.55 (t, J=6.89
Hz, 1H, benzene-H) 7.48 (d, J=7.27 Hz, 2H, benzene-H).
N-(3,4-Dichloro-phenyl)-4-nitro-1,8-naphthalimide (A3)
[0226] Compound A3 was obtained from of 4-nitro-1,8-naphthalic
anhydride (2.43 g, 10 mmol) and 3,4-dichloroaniline (16 g, 100
mmol) through general procedure to yield 3.3 g (85.2%), mp
>280.degree. C., FAB-HRMS calcd for
C.sub.18H.sub.8Cl.sub.2N.sub.2O.sub.4 m/z 386.9939 (M+H), found
386.993 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.79 (d, J=8.33
Hz, 1H, naphthylic-H) 8.67 (d, J=6.62 Hz, 1H, naphthylic-H) 8.64
(d, J=8.12 Hz, 1H, naphthylic-H) 8.6 (d, J=7.91 Hz, 1H,
naphthylic-H) 8.15 (t, J=8.65 Hz, 1H, naphthylic-H) 7.86 (d, J=8.55
Hz, 1H, benzene-H) 7.83 (s, 1H, benzene-H) 7.5 (d, J=8.65 Hz, 1H,
benzene-H).
N-(3-Methoxy-phenyl)-4-nitro-1,8-naphthalimide (A4)
[0227] Compound A4 was obtained from 4-nitro-1,8-naphthalic
anhydride (2.43 g, 10 mmol) and m-anisidine (11.2 ml, 100 mmol)
through general procedure to yield 3.21 g (92.2%), mp
>280.degree. C., FAB-HRMS calcd for
C.sub.19H.sub.12N.sub.2O.sub.5 m/z 349.0824 (M+H), found 349.0832
(M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.83 (d, J=8.76 Hz, 1H,
naphthylic-H) 8.71 (d, J=7.27 Hz, 1H, naphthylic-H) 8.69 (d, J=7.48
Hz, 1H, naphthylic-H) 8.65 (d, J=7.48 Hz, 1H, naphthylic-H) 8.2 (t,
J=8.16 Hz, 1H, naphthylic-H) 7.51 (t, J=8.01 Hz, 1H, benzene-H)
7.12 (m, 2H, benzene-H) 7.05 (d, J=8.15 Hz, 1H, benzene-H) 3.85 (s,
3H, OCH.sub.3).
N-(4-Butyric acid-phenyl)-4-nitro-1,8-naphthalimide (A5)
[0228] Compound A5 was obtained from 4-nitro-1,8-naphthalic
anhydride (486.4 g, 2 mmol) and 4-(4-amino-phenyl)butyric acid
(358.5 mg, 20 mmol) through general procedure to yield 877.5 mg
(95.1%), mp 254.5-256.degree. C., ESI-HRMS calcd for
C.sub.22H.sub.12N.sub.2O.sub.6 m/z 427.0906 (M+Na), found 427.0898
(M+Na). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.82 (d, J=8.41 Hz, 1H,
naphthylic-H) 8.7 (d, J=7.27 Hz, 1H, naphthylic-H) 8.68 (d, J=8.14
Hz, 1H, naphthylic-H) 8.64 (d, J=7.76 Hz, 1H, naphthylic-H) 8.19
(t, J=8.03 Hz, 1H, naphthylic-H) 7.42 (d, J=8.03 Hz, 2H, benzene-H)
7.38 (d, J=8.41 Hz, 2H, benzene-H) 2.75 (t, J=7.84 Hz, 2H,
CH.sub.2CH.sub.2CH.sub.2COOH) 2.35 (t, J=7.46 Hz, 2H,
CH.sub.2CH.sub.2CH.sub.2COOH) 1.94 (quin, J=7.55 Hz, 2H,
CH.sub.2CH.sub.2CH.sub.2COOH).
N-Phenyl-4-chloro-1,8-naphthalimide (A6)
[0229] Compound A6 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and aniline (1.8 ml, 20 mmol) through
general procedure to yield 137.9 mg (22.4%), mp 263-265.5.degree.
C. (Lit.sup.18 231-233.degree. C.) (Takaaki et al., Fungicidal
Compositions; 1973), FAB-HRMS calcd for C.sub.18H.sub.10ClNO.sub.2
m/z 308.0478 (M+H), found 308.048 (M+H). 1H NMR (500 MHz,
DMSO-d.sub.6) 8.75 (d, J=7.7 Hz, 1H, naphthylic-H) 8.67 (d, J=6.6
Hz, 1H, naphthylic-H) 8.52 (d, J=7.9 Hz, 1H, naphthylic-H) 8.16 (d,
J=7.9 Hz, 1H, naphthylic-H) 8.12 (t, J=7.5 Hz, 1H, naphthylic-H)
7.60 (t, J=7.18 Hz, 2H, benzene-H) 7.53 (t, J=6.89 Hz, 2H,
benzene-H) 7.46 (d, J=7.46 Hz, 2H, benzene-H).
N-(3-Methoxy-phenyl)-4-chloro-1,8-naphthalimide (A7)
[0230] Compound A7 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and m-anisidine (2.3 ml, 20 mmol)
through general procedure to yield 250 mg (37%), mp >280.degree.
C., FAB-HRMS calcd for C.sub.19H.sub.12ClNO.sub.3 m/z 338.0584
(M+H), found 338.0576 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
8.67 (d, J=8.72 Hz, 1H, naphthylic-H) 8.6 (d, J=6.47 Hz, 1H,
naphthylic-H) 8.45 (d, J=7.9 Hz, 1H, naphthylic-H) 8.08 (d, J=7.9
Hz, 1H, naphthylic-H) 8.05 (t, J=8.71 Hz, 1H, naphthylic-H) 7.43
(t, J=8.01 Hz, 1H, benzene-H) 7.04 (d, J=8.09 Hz, 1H, benzene-H)
7.02 (s, J=7.46 Hz, 1H, benzene-H) 6.96 (d, J=8.72 Hz, 1H,
benzene-H) 3.78 (s, 3H, OCH.sub.3).
N-(3-Trifluoromethyl-phenyl)-4-chloro-1,8-naphthalimide (A8)
[0231] Compound A8 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 3-aminobenzotrifluoride (2.5 ml, 20
mmol) through general procedure to yield 130.2 mg (17.3%), mp
278-279.degree. C., FAB-HRMS calcd for
C.sub.19H.sub.9ClF.sub.3NO.sub.2 m/z 376.0352 (M+H), found 376.0345
(M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.7 (d, J=8.5 Hz, 1H,
naphthylic-H) 8.62 (d, J=6.61 Hz, 1H, naphthylic-H) 8.47 (d, J=7.9
Hz, 1H, naphthylic-H) 8.11 (d, J=7.9 Hz, 1H, naphthylic-H) 8.07 (t,
J=7.8 Hz, 1H, naphthylic-H) 7.9 (s, 1H, benzene-H) 7.87 (d, J=7.7
Hz, 1H, benzene-H) 7.8 (d, J=7.78 Hz, 1H, benzene-H) 7.77 (t,
J=5.83 Hz, 1H, benzene-H).
N-(3-Bromo-phenyl)-4-chloro-1,8-naphthalimide (A9)
[0232] Compound A9 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 3-bromoaniline (2.2 ml, 20 mmol)
through general procedure to yield 102.2 mg (13.2%), mp
>280.degree. C., FAB-HRMS calcd for C.sub.18H.sub.9BrClNO.sub.2
m/z 385.9583 (M+H), found 385.9577 (M+H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.7 (d, J=8.33 Hz, 1H, naphthylic-H) 8.61 (d, J=7.27
Hz, 1H, naphthylic-H) 8.46 (d, J=7.91 Hz, 1H, naphthylic-H) 8.1 (d,
J=7.91 Hz, 1H, naphthylic-H) 8.07 (t, J=7.91 Hz, 1H, naphthylic-H)
7.72 (br s, 1H, benzene-H) 7.7 (d, J=8.12 Hz, 1H, benzene-H) 7.51
(t, J=7.8 Hz, 1H, benzene-H) 7.46 (d, J=7.09 Hz, 1H,
benzene-H).
N-(3-Chloro-phenyl)-4-chloro-1,8-naphthalimide (A10)
[0233] Compound A10 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 3-chloroaniline (2.13 ml, 20 mmol)
through general procedure to yield 82.8 mg (12.1%), mp
273-275.degree. C., FAB-HRMS calcd for
C.sub.18H.sub.9Cl.sub.2NO.sub.2 m/z 342.0089 (M+H), found 342.0098
(M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.7 (d, J=8.55 Hz, 1H,
naphthylic-H) 8.62 (d, J=7.27 Hz, 1H, naphthylic-H) 8.47 (d, J=7.91
Hz, 1H, naphthylic-H) 8.1 (d, J=7.91 Hz, 1H, naphthylic-H) 8.07 (t,
J=7.91 Hz, 1H, naphthylic-H) 7.58 (m, 3H, benzene-H) 7.41 (d,
J=5.94 Hz, 1H, benzene-H). Papenfuhs et al., United Kingdom:
Hoechst Aktiengesellschaft (Frankfurt am Main, DE); 1977.
N-(3-Bromo-4-fluoro-phenyl)-4-chloro-1,8-naphthalimide (A11)
[0234] Compound A11 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 3-bromo-4-fluroaniline (3.8 g, 20
mmol) through general procedure to yield 398 mg (49.2%), mp
>280.degree. C., FAB-HRMS calcd for C.sub.18H.sub.8BrClFNO.sub.2
m/z 403.9489 (M+H), found 403.949 (M+H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.69 (d, J=8.76 Hz, 1H, naphthylic-H) 8.61 (d, J=7.29
Hz, 1H, naphthylic-H) 8.46 (d, J=7.91 Hz, 1H, naphthylic-H) 8.1 (d,
J=7.91 Hz, 1H, naphthylic-H) 8.07 (t, J=7.65 Hz, 1H, naphthylic-H)
7.87 (dd, J=6.3, 2.24 Hz, 1H, benzene-H) 7.54 (m, 2H,
benzene-H)
N-(4-Fluoro-phenyl)-4-chloro-1,8-naphthalimide (A12)
[0235] Compound A12 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 4-fluroaniline (1.9 ml, 20 mmol)
through general procedure to yield 264 mg (40.5%), mp
274-276.degree. C., FAB-HRMS calcd for C.sub.18H.sub.9ClFNO.sub.2
m/z 326.0384 (M+H), found 326.0391 (M+H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.69 (d, J=8.56 Hz, 1H, naphthylic-H) 8.61 (d, J=7.34
Hz, 1H, naphthylic-H) 8.46 (d, J=7.91 Hz, 1H, naphthylic-H) 8.1 (d,
J=7.91 Hz, 1H, naphthylic-H) 8.06 (t, J=8.79 Hz, 1H, naphthylic-H)
7.46 (m, 2H, benzene-H) 7.37 (m, 2H, benzene-H)
N-(4-Bromo-phenyl)-4-chloro-1,8-naphthalimide (A13)
[0236] Compound A13 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 4-bromoaniline (3.4 g, 20 mmol)
through general procedure to yield 513 mg (66.3%), mp
>280.degree. C., FAB-HRMS calcd for C.sub.18H.sub.9BrClNO.sub.2
m/z 385.9583 (M+H), found 385.9587 (M+H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.69 (d, J=7.38 Hz, 1H, naphthylic-H) 8.61 (d, J=7.95
Hz, 1H, naphthylic-H) 8.46 (d, J=7.91 Hz, 1H, naphthylic-H) 8.1 (d,
J=7.91 Hz, 1H, naphthylic-H) 8.06 (t, J=8.42 Hz, 1H, naphthylic-H)
7.74 (d, J=8.52 Hz, 2H, benzene-H) 7.39 (d, J=8.51 Hz, 2H,
benzene-H).sup.19
N-(3,4-Dichloro-phenyl)-4-chloro-1,8-naphthalimide (A14)
[0237] Compound A14 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and 3,4-dichloroaniline (3.24 g, 20
mmol) through general procedure to yield 123 mg (15.9%), mp
>280.degree. C. (Lit.sup.18 >300.degree. C.), FAB-HRMS calcd
for C.sub.18H.sub.8Cl.sub.3NO.sub.2 m/z 375.9699 (M+H), found
375.9697 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.7 (d, J=8.33
Hz, 1H, naphthylic-H) 8.62 (d, J=6.62 Hz, 1H, naphthylic-H) 8.47
(d, J=7.91 Hz, 1H, naphthylic-H) 8.11 (d, J=7.91 Hz, 1H,
naphthylic-H) 8.07 (t, J=7.91 Hz, 1H, naphthylic-H) 7.85 (s, 1H,
benzene-H) 7.82 (m, 1H, benzene-H) 7.48 (d, J=8.12 Hz, 1H,
benzene-H).
N-(2-Dimethylamino-ethyl)-1,8-naphthalimide hydrochloride (B1)
[0238] Compound B1 was obtained from 1,8-naphthalic anhydride (1 g,
5.05 mmol) and N,N-dimethylethylene diamine (5.5 ml, 50 mmol)
through general procedure and form water soluble salt with 1.75 M
HCl/EtOAc (2.9 ml, 5.1 mmol) to yield 1.3 g (84.5%), mp
>280.degree. C. (Lit.sup.20 296-298.degree. C.), ESI-HRMS calcd
for C.sub.16H.sub.17ClN.sub.2O.sub.2 m/z 303.09 (M-H), found
303.0906 (M-H). .sup.1H NMR (500 MHz, Methanol-d4) 9.61 (br s, 1H,
HCl) 8.53 (d, J=7.13, 2H, naphthylic-H) 8.51 (d, J=7.47 Hz, 2H,
naphthylic-H) 7.91 (t, J=7.47 Hz, 2H, naphthylic-H) 4.41 (t, J=5.98
Hz, 2H, ethylene-CH.sub.2) 3.45 (t, J=5.98 Hz, 2H,
ethylene-CH.sub.2) 3.03 (s, 6H, N(CH.sub.3).sub.2).
N-(2-Dimethylamino-ethyl)-4-nitro-1,8-naphthalimide (B2)
[0239] Compound B2 was obtained from 4-nitro-1,8-naphthalic
anhydride (1 g, 4.11 mmol) and N,N-dimethylethylene diamine (4.37
ml, 40 mmol) through general procedure to yield 843.6 mg (65.7%),
mp 131-133.degree. C. (Lit.sup.20 106-109.degree. C.), ESI-HRMS
calcd for C.sub.16H.sub.15N.sub.3O.sub.4 m/z 314.1141 (M+H), found
314.1148 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.72 (d, J=8.55
Hz, 1H, naphthylic-H) 8.64 (d, J=7.27 Hz, 1H, naphthylic-H) 8.62
(d, J=8.12 Hz, 1H, naphthylic-H) 8.56 (d, J=8.12 Hz, 1H,
naphthylic-H) 8.1 (t, J=8.01 Hz, 1H, naphthylic-H) 4.16 (t, J=6.95
Hz, 2H, ethylene-CH.sub.2) 2.53 (m, 2H, ethylene-CH.sub.2) 2.38 (s,
6H, N(CH.sub.3).sub.2).
N-(3-Dimethylamino-propyl)-4-nitro-1,8-naphthalimide (B3)
[0240] Compound B3 was obtained from 4-nitro-1,8-naphthalic
anhydride (1 g, 4.11 mmol) and 3-dimethylaminopropylamine (4.4 ml,
40 mmol) through general procedure to yield 564 mg (42.0%), mp
108-110.degree. C. (Lit.sup.21 106-109.degree. C.), ESI-HRMS calcd
for C.sub.17H.sub.17N.sub.3O.sub.4 m/z 328.1297 (M+H), found
328.1299 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.71 (d, J=8.55
Hz, 1H, naphthylic-H) 8.64 (d, J=7.27 Hz, 1H, naphthylic-H) 8.61
(d, J=7.91 Hz, 1H, naphthylic-H) 8.55 (d, J=7.91 Hz, 1H,
naphthylic-H) 8.1 (t, J=7.91 Hz, 1H, naphthylic-H) 4.08 (t, J=7.25
Hz, 2H, propylene-CH.sub.2) 2.31 (t, J=6.95 Hz, 2H,
propylene-CH.sub.2) 2.12 (s, 6H, N(CH.sub.3).sub.2) 1.78 (quin,
J=7.27 Hz, 2H, propylene-CH.sub.2).
N-(2-dimethylamino-ethyl)-4-chloro-1,8-naphthalimide hydrochloride
(B4)
[0241] Compound B4 was obtained from 4-chloro-1,8-naphthalic
anhydride (1 g, 4.3 mmol) and N,N-dimethylethylene diamine (4.37
ml, 40 mmol) through general procedure and form water soluble salt
with 1.75 M HCl/EtOAc (2.6 ml, 4.5 mmol) to yield 1.16 g (81.5%),
mp >280.degree. C. (Lit.sup.22 293-295.degree. C.), ESI-HRMS
calcd for C.sub.16H.sub.16Cl.sub.2N.sub.2O.sub.2 m/z 332.1166
(M-H), found 332.1157 (M-H). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
9.76 (br s, 1H, HCl) 8.66 (d, J=8.55 Hz, 1H, naphthylic-H) 8.62 (d,
J=7.27 Hz, 1H, naphthylic-H) 8.47 (d, J=7.91 Hz, 1H, naphthylic-H)
8.09 (d, J=7.91 Hz, 1H, naphthylic-H) 8.05 (t, J=7.52 Hz, 1H,
naphthylic-H) 4.4 (t, J=5.98 Hz, 2H, ethylene-CH.sub.2) 3.44 (t,
J=5.88 Hz, 2H, ethylene-CH.sub.2) 2.88 (s, 6H,
N(CH.sub.3).sub.2).
N-Ethyl-1,8-naphthalimide (C1)
[0242] Compound C1 was obtained from 1,8-naphthalic anhydride
(396.4 mg, 2 mmol) and ethylamine (12.9, 20 mmol) through general
procedure to yield 168 mg (37.3%), mp 171-172.5.degree. C.
(Lit.sup.18 158.degree. C.), FAB-HRMS calcd for
C.sub.14H.sub.11NO.sub.2 m/z 226.0868 (M+H), found 226.0868 (M+H).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.57 (d, J=7.99 Hz, 2H,
naphthylic-H) 8.53 (d, J=8.67 Hz, 2H, naphthylic-H) 7.94 (t, J=7.69
Hz, 2H, naphthylic-H) 4.16 (q, J=7.05 Hz, 2H, CH.sub.2CH.sub.3)
1.28 (t, J=7.05 Hz, 3H, CH.sub.2CH.sub.3).
N-Methyl-4-nitro-1,8-naphthalimide (C2)
[0243] Compound C2 was obtained from 4-nitro-1,8-naphthalic
anhydride (2.43 g, 10 mmol) and methylamine (77 g, 100 mmol)
through general procedure to yield 1.31 g (51.1%), mp
209-212.5.degree. C. (Lit.sup.18 208-209.degree. C.), FAB-HRMS
calcd for C.sub.13H.sub.8N.sub.2O.sub.4 m/z 257.0562 (M+H), found
257.0563 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.7 (d, J=8.22
Hz, 1H, naphthylic-H) 8.62 (m, 2H, naphthylic-H) 8.56 (m, 1H,
naphthylic-H) 8.09 (t, J=8.22 Hz, 1H, naphthylic-H) 3.41 (s, 3H,
CH.sub.3).
N-Ethyl-4-nitro-1,8-naphthalimide (C3)
[0244] Compound C3 was obtained from 4-nitro-1,8-naphthalic
anhydride (2.43 g, 10 mmol) and ethylamine (64.4 g, 40 mmol)
through general procedure to yield 922.6 mg (34.1%), mp
191-192.5.degree. C. (Lit.sup.18 187.5-188.5.degree. C.), FAB-HRMS
calcd for C.sub.14H.sub.10N.sub.2O.sub.4 m/z 271.0719 (M+H), found
271.0722 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.71 (d, J=9.0
Hz, 1H, naphthylic-H) 8.63 (m, 2H, naphthylic-H) 8.56 (m, 1H,
naphthylic-H) 8.09 (t, J=7.63 Hz, 1H, naphthylic-H) 4.09 (q, J=7.04
Hz, 2H, CH.sub.2CH.sub.3) 1.24 (t, J=7.04 Hz, 3H,
CH.sub.2CH.sub.3).
N-Methyl-4-chloro-1,8-naphthalimide (C4)
[0245] Compound C4 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and methylamine (15.5 g, 200 mmol)
through general procedure to yield 160 mg (32.6%), mp
186-188.degree. C. (Lit.sup.18 171-173.degree. C.) (Takaaki et al.,
Fungicidal Compositions; 1973), FAB-HRMS calcd for
C.sub.13H.sub.8ClNO.sub.2 m/z 246.032 (M+H), found 246.0318 (M+H).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.62 (d, J=8.69 Hz, 1H,
naphthylic-H) 8.60 (d, J=7.48 Hz, 1H, naphthylic-H) 8.45 (d, J=7.69
Hz, 1H, naphthylic-H) 8.06 (d, J=7.91 Hz, 1H, naphthylic-H) 8.02
(t, J=7.91 Hz, 1H, naphthylic-H) 3.4 (s, 3H, CH.sub.3).
N-Ethyl-4-chloro-1,8-naphthalimide (C5)
[0246] Compound C5 was obtained from 4-chloro-1,8-naphthalic
anhydride (465 mg, 2 mmol) and ethylamine (12.9 g, 200 mmol)
through general procedure to yield 170 mg (32.7%), mp
167-170.degree. C. (Lit.sup.18 165-166.degree. C.) (Takaaki et al.,
Fungicidal Compositions; 1973), FAB-HRMS calcd for
C.sub.14H.sub.10ClNO.sub.2 m/z 260.0478 (M+H), found 260.0484
(M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.61 (t, J=7.91 Hz, 2H,
naphthylic-H) 8.45 (d, J=7.91 Hz, 1H, naphthylic-H) 8.05 (d, J=7.91
Hz, 1H, naphthylic-H) 8.02 (t, J=7.49 Hz, 1H, naphthylic-H) 4.08
(q, J=7.05 Hz, 2H, CH.sub.2CH.sub.3) 1.22 (t, J=7.05 Hz, 3H,
CH.sub.2CH.sub.3).
N-(Butyric acid ethyl ester)-4-nitro-1,8-naphthalimide (D1)
[0247] Compound D1 was obtained from ethyl 4-aminobutyrate
hydrochloride (8.4 g, 50 mmol) and 4-nitro-1,8-naphthalic anhydride
(1.22 g, 5 mmol) through general procedure to yield 1.65 g (97.0%),
mp 115-116.degree. C., FAB-HRMS calcd for
C.sub.18H.sub.16N.sub.2O.sub.6 m/z 357.1087 (M+H), found 357.1091
(M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.72 (d, J=8.55 Hz, 1H,
naphthylic-H) 8.64 (d, J=7.27 Hz, 1H, naphthylic-H) 8.62 (d, J=8.12
Hz, 1H, naphthylic-H) 8.56 (d, J=7.91 Hz, 1H, naphthylic-H) 8.1 (t,
J=8.01 Hz, 1H, naphthylic-H) 4.11 (t, J=6.84 Hz, 2H,
CH.sub.2CH.sub.2CH.sub.2COOCH.sub.2CH.sub.3) 3.97 (q, J=7.05 Hz,
2H, CH.sub.2CH.sub.2CH.sub.2COOCH.sub.2CH.sub.3) 2.41 (t, J=7.37
Hz, 2H, CH.sub.2CH.sub.2CH.sub.2COOCH.sub.2CH.sub.3) 1.94 (quin,
J=7.11 Hz, 2H, CH.sub.2CH.sub.2CH.sub.2COOCH.sub.2CH.sub.3) 1.12
(t, J=7.05 Hz, 3H, CH.sub.2CH.sub.2CH.sub.2COOCH.sub.2CH.sub.3)
N-Phenyl-4-amino-1,8-naphthalimide (E1)
[0248] Compound E1 was obtained from N-phenyl-4-nitro-naphthalimide
(1.27 g, 4 mmol) through general procedure to yield 583 mg (56.4%),
mp 276-278.degree. C. (Lit.sup.23 302-304.degree. C.) (Mitsuo et
al., Journal of Synthetic Organic Chemistry, Japan. 1956;
14(8):504-508), ESI-HRMS calcd for C.sub.18H.sub.12N.sub.2O.sub.2
m/z 287.0821 (M-H), found 287.0816 (M-H). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) 8.66 (d, J=7.69 Hz, 1H, naphthylic-H) 8.43 (d, J=6.62
Hz, 1H, naphthylic-H) 8.19 (d, J=8.33 Hz, 1H, naphthylic-H) 7.69
(t, J=8.58 Hz, 1H, naphthylic-H) 7.5 (m, 4H, benzene-H, amino-H)
7.43 (t, J=7.8 Hz, 1H, benzene-H) 7.3 (d, J=6.95 Hz, 2H, benzene-H)
6.88 (d, J=8.33 Hz, 1H, naphthylic-H).
N-(2-dimethylamino-ethyl)-4-amino-1,8-naphthalimide hydrochloride
(E2)
[0249] Compound E2 was obtained from
N-(2-dimethylamino-ethyl)-4-nitro-1,8-naphthalimide (200 mg, 0.64
mmol) through general procedure and form water soluble salt with
1.75 M HCl/EtOAc (0.37 ml, 0.65 mmol) to yield 174.2 mg (77.3%), mp
>280.degree. C. (Lit.sup.20 184-185.degree. C.) (Norton et al.,
Anticancer Drugs. 2008; 19(1):23-36), ESI-HRMS calcd for
C.sub.16H.sub.18ClN.sub.3O.sub.2 m/z 318.1009 (M-H), found 318.1003
(M-H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.3 (br s, 1H, HCl) 8.66
(d, J=8.72 Hz, 1H, naphthylic-H) 8.46 (d, J=6.79 Hz, 1H,
naphthylic-H) 8.22 (d, J=8.55 Hz, 1H, naphthylic-H) 7.68 (t, J=8.73
Hz, 1H, naphthylic-H) 7.56 (br s, 2H, exchangeable, amino-H) 6.87
(d, J=8.33 Hz, 1H, naphthylic-H) 4.35 (t, J=5.88 Hz, 2H,
ethylene-CH.sub.2) 3.42 (in H.sub.2O, show in methanol-d4,
ethylene-CH.sub.2) 2.89 (br s, 6H, N(CH.sub.3).sub.2). Norton et
al., Anticancer Drugs. 2008; 19(1):23-36.
N-(3-dimethylamino-propyl)-4-amino-1,8-naphthalimide hydrochloride
(E3)
[0250] Compound E3 was obtained from
N-(3-dimethylamino-propyl)-4-nitro-naphthalimide (250 mg, 0.76
mmol) through general procedure and form water soluble salt with
1.75 M HCl/EtOAc (0.45 ml, 0.8 mmol), to yield 120 mg (42.8%), mp
>280.degree. C. (Lit.sup.21 184-185.degree. C.) (Stevenson et
al., J Med Chem. 1984; 27(12):1677-1682), ESI-HRMS calcd for
C.sub.17H.sub.20ClN.sub.3O.sub.2 m/z 303.09 (M-Cl), found 303.0903
(M-Cl). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.75 (br s, 1H, HCl)
8.65 (d, J=8.79 Hz, 1H, naphthylic-H) 8.44 (d, J=8.79 Hz, 1H,
naphthylic-H) 8.21 (d, J=8.33 Hz, 1H, naphthylic-H) 7.67 (t, J=8.79
Hz, 1H, naphthylic-H) 7.51 (br s, 2H, exchangeable, amino-H) 6.86
(d, J=8.55 Hz, 1H, naphthylic-H) 4.08 (t, J=6.62 Hz, 2H,
propylene-CH.sub.2) 3.11 (t, J=7.82 Hz, 2H, propylene-CH.sub.2)
2.73 (s, 6H, N(CH.sub.3).sub.2) 2.02 (m, 2H,
propylene-CH.sub.2).
[0251] The Primary Erythroid Cell Culture.
[0252] The peripheral blood samples were purchased from the Taipei
Blood Center. The concentrated blood was diluted 1:5 (V/V) with PBS
and gentle layer on Ficoll-Hypaque (d=1.007 g/ml) (Ge-Healthcare).
After centrifugation at 400 g for 20 minutes, the cells in the
inter-phase region were collected. The collected cells were washed
with PBS and centrifuged at low speed for three times. The remained
mononuclear cells were expanded in Phase I medium containing
1.times.SFEM (StemSpan), 100 ng/ml SCF, 20 ng/ml IL-3, 20 ng/ml
IL-6, and 100 ng/ml Fit3-L at 37.degree. C. incubator with 5%
CO.sub.2 for 7 days. The expanded mononuclear cells were then
differentiated in Phase II medium which contains 1.times.SFEM
(StemSpan), 20 ng/ml SCF, 5 ng/ml IL-3, 1 U/ml EPO for another 7
days. The resulted differentiated erythroid cells were treated with
indicated compounds of different dosages with the seeding density
of 5.times.10.sup.5 cells/ml for another 3 days.
[0253] Quantitative RT-PCR.
[0254] After 3 days of drug-treatment, the total RNA was extracted
by RNA Spin mini kit (Ge-Healthcare) and reverse-transcription was
performed by using superscript II (Invitrogen) followed the
manufactors instruction. Quantitative PCR was performed on
LightCycler with using STBR green master mix followed the
manufactors instruction (Roche). The absolute quantitative RT-PCR
was calculated by the standard curve with supplying a known copy
number of plasmids. The relative quantitative RT-PCR was normalized
to the expression levels of the .beta.-actin and compared to the
mock control.
[0255] Cell Viability Assay.
[0256] The cell viability was detected by using AlamarBlue reagent
(Invitrogen). After 3 days, the drug-tested cells were transferred
into 96-well plate, added with 1/10 volume of AlamarBlue reagent,
and then incubate at 37.degree. C. overnight. The cell viability
was calculated by a fluorescence reader (Ex 530-560 nm, Em 590
nm).
[0257] Western Blot Analysis.
[0258] After 3 days of compound treatment, total protein or histone
of the drug-treated cells was extracted. Histone was extracted by
histone extraction buffer (10 mM HEPES, 1.5 mM MgCl.sub.2, 10 mM
KCl, 0.5 mM DTT, 1.5 mM PMSF and 0.2 N HCl) at 4.degree. C.
overnight then centrifuged at 13,000 rpm for 5 minutes and
collected the supernatant. Thirty microgram of histone extracts
were separated in 15% SDS-PAGE and blotted onto PVDF membrane.
After blocking with 5% non-fat milk in TBST, the membrane was then
incubated with primary antibody against total histone H4 or total
acetyl histone H4 at 4.degree. C. overnight. Total protein was
extracted by modified RIPA (50 mM Tris-HCl pH7.8, 150 mM NaCl, 1%
NP-40, 0.5% sodium deoxycholate, 0.1% SDS, 1 mM EGTA, 5 mM EDTA, 10
mM NaF, 1 mM NaV.sub.3O.sub.4 and 1.times. complete, EDTA-free
Protease Inhibitor Cocktail). Thirty microgram of total protein
extracts were separate by 10% SDS-PAGE and blotted onto PVDF
membrane. After blocking with 5% non-fat milk in TBST, the membrane
was incubated with primary antibody against BCL11A, p38, p-p38,
.gamma.-globin or .beta.-actin at 4.degree. C. overnight. After
incubating with horseradish peroxidase-conjugated secondary
antibodies and washing the blot, the signals of indicated proteins
were visualized by using ECL (PerKinElmer) following the
manufactor's protocol.
[0259] Statistical Analysis.
[0260] The data are presented as the mean plus or minus standard
error of the mean (SEM) for at least 3 experiments. Statistical
analysis of the raw data was performed by the 2-tailed t test. The
Student t test was used to measure differences in samples. A
probability of less than 0.05 (P<0.05) was considered
significant. (*: P<0.05, **: P<0.01, ***: P<0.001)
Results
N-Substituted 1,8-Naphthalimide Derivatives are Potential
HbF-Inducing Agents.
[0261] To search for new agents, which are capable of inducing the
expression of .gamma. globin, a series of naphthalimide derivatives
with various substituent(s) on the naphthalene ring and the
heterocyclic N-atom (A1-A14, B1-B4, C1-C5, D1, and E1-E3, FIG. 2)
were synthesized. These derivatives were subjected to evaluating
the .gamma. globin induction abilities in differentiated peripheral
blood mononuclear cells (PBMCs). The PBMCs isolated from the
peripheral blood of donors were expanded and differentiated for a
total of 14 days in a two-phase liquid culture. The resulted
primary erythoid cells were then treated with different dosages of
naphthalimide derivatives individually for another 3 days. The
expression levels of the endogenous .gamma. globin gene were
estimated by relative quantitative RT-PCR and the proliferation
rates of these cells were examined by AlamarBlue cell viability
assay. Among these naphthalimide derivatives, compounds A2, B1, B4,
E1, E2, and E3 were found to have potent .gamma. globin-inducing
effect; 2-4.5-folds induction of the .gamma. globin gene expression
in the compounds-treated cells (FIG. 3).
[0262] The proliferation rates of these cells displayed reverse
relationships with the concentrations of these compounds. To
compare the HbF-inducing capability of these compounds, the
induction folds of .gamma. globin gene at concentrations of their
IC.sub.50 (the half maximal inhibitory concentration) were
examined. The IC.sub.50 values indicate that the concentrations of
the individual compound at which the cell (primary human erythroid
cells) proliferation rate is reduced by 50%. As shown in Table 3,
compounds B1, B4, E2, and E3 significantly elevated the expression
levels of .gamma. globin mRNA up to 4.1-, 3.3-, 4.0-, and 2.7-folds
at concentrations of their IC.sub.50, respectively (Table 3),
While, compounds A2 and E1 displayed only minor .gamma.
globin-inducing potentials with only 1.1- and 1.3-folds of the
.gamma. globin gene induction at concentrations of their IC.sub.50,
respectively.
TABLE-US-00004 TABLE 3 Comparison of IC.sub.50, solubility, and
.gamma. globin gene inducing abilities of .gamma. globin-inducing
compounds. EC (.mu.M) induction .gamma. globin induction Compound
ID DMSO H.sub.2O IC.sub.50(.mu.M) of HU IC.sub.50(2.3 fold)
IC.sub.50/EC (IC.sub.50) S51021 10 mM 21.8 2.3 9.5 2.97 A1 10 mM
2.3 7.8 0.3 1.3 B1 >100 mM 10.7 4.7 2.3 4.1 B4 >100 mM 5.0
2.2 2.3 3.3 E1 10 mM 0.3 2.9 0.1 1.1 E2 (SS-2394) >100 mM 2.3
0.8 2.9 4.0 E3 >100 mM 11.2 7.4 1.5 2.7 HU >100 mM 145.9
145.9 1 2.3 NaB >500 mM 221.6 ND ND 1.3
[0263] The primary human erythorid cells were treated with parental
compound, NaB, HU, or synthesized naphthalimide derivatives (A1,
B1, B4, E, E2, or E3) individually. The values of IC.sub.50 (the
half mximal inhibitory concentration), EC (effective
concentration), and the ratio of IC.sub.50 to EC (IC.sub.50/EC)
were calculated, which were used to compare the advantages of these
g globin-inducing compounds to hydroxyurea and each other. The g
globin induction fold of each compound at its IC.sub.50 was also
shown. ND: non-detectable.
Comparisons of the Therapeutic Potentials Among Naphthalimide
Derivatives, S51021, NaB, and HU
[0264] In order to evaluate the therapeutic potentials of
naphthalimide derivatives A2, B1, B4, E1, E2, and E3 in comparison
with the parental S51021 as well as other HbF inducers (e.g., NaB
and HU), the effective concentration (EC) of each compound was
investigated first. The EC values are defined as the concentrations
of compounds that induce the .gamma. globin gene expression by
2.3-folds, the fold of the .gamma. globin gene induction by HU at
the concentration of IC.sub.50. The ratio of IC.sub.50 to EC
(IC.sub.50/EC) is used to determine whether the compound tested has
superior therapeutic effect than that of HU (the ratio IC.sub.50/EC
of HU was set as 1). Although compounds A2 and E1 can activate the
.gamma. globin gene expression, their therapeutic potentials were
lower than that of HU. In contrast, compounds B1, B4, E2 and E3
exhibit better therapeutic potentials than HU. Of these agents,
compound E2 (SS-2394) has the highest IC.sub.50/EC ratio
(IC.sub.50/EC=2.79) and relatively higher .gamma. globin induction
folds (4.0-folds) at the concentration of IC.sub.50 (Table I).
Although none of naphthalimide derivatives showed better
IC.sub.50/EC value than that of S51021, compounds B1, B4, and E2
indeed displayed higher .gamma. globin induction folds than that of
S51021 at the concentrations of their IC.sub.50. It should be noted
that compounds B1, B4, E2, and E3 were synthesized as hydrochloride
salts and have greatly improved water-solubility (Table 3).
The HbF-Inducing Agents Specifically Induce the Embryonic/Fetal
Globin Genes Expression.
[0265] To evaluate the specificity of S51021, SS-2394, HU, and NaB
in mediating globin genes activation, the amounts of individual
P3-liked globin mRNAs were measured by absolute quantitative
RT-PCR. As shown in Table 4, the proportions of the embryonic E
globin and the fetal .gamma. globin mRNAs were both significantly
increased by the tested compounds. On the other hand, the
proportions of the .beta. globin mRNA were notably reduced after
drug-treatment. Among them, the SS-2394 is the most effective fetal
globin inducer; increasing the proportion of the fetal .gamma.
globin from 7.9% to 11.6% in the drug-treated primary human adult
erythroid cells, whereas the proportion of the adult .beta. globin
mRNA was reduced from 88.8% to 82.3% (Table 4).
TABLE-US-00005 TABLE 4 The expression levels of each .beta.-like
globin chains in the primary human erythroid cells .epsilon. globin
.gamma. globin .beta. globin .delta. globin Mock 0.0 .+-. 0.0% 7.9
.+-. 0.8% 88.8 .+-. 1.0% 3.3 .+-. 0.2% HU 0.1 .+-. 0.0% 11.2 .+-.
1.1% 84.2 .+-. 1.3% 4.5 .+-. 0.2% NaB 0.1 .+-. 0.0% 10.8 .+-. 1.0%
87.4 .+-. 1.0% 1.8 .+-. 0.1% S51021 0.1 .+-. 0.0% 10.6 .+-. 1.2%
85.6 .+-. 1.2% 3.7 .+-. 0.2% SS-2394 0.5 .+-. 0.1% 11.6 .+-. 1.0%
82.3 .+-. 1.1% 5.5 .+-. 0.4%
[0266] The primary human erythroid cells were treated with HU
(145.9 .mu.M), NaB (221.6 .mu.M), S51021 (21.8 .mu.M) or SS2394
(2.3 .mu.M) for 3 days, and the expression levels of each globin
mRNA were estimated by absolute quantitative RT-PCR analysis. The
proportions of individual 3-like globin chains among the total
3-like globin mRNA are shown. Data are presented as the
mean.+-.SEM, N=3.
Expression Levels of Transcription Activator and Repressor are
Modulated by the HbF-Inducing Compounds
[0267] It has been reported that several transcriptional factors,
such as NF-E4, c-Myb, and BCL11A, are involved in the regulation of
the .gamma. globin gene expression. Zhou et al., Mol Cell Biol.
2000; 20(20):7662-7672; Jiang et al., Blood. 2006; 108(3):
1077-1083; and Sankaran et al., Science. 2008; 322(5909):1839-1842.
NF-E4 was reported to form transcription activation complex, stage
selector protein (SSP), which recruited to the .gamma. globin
promoter and switched on the .gamma. globin gene expression in the
primary human adult erythorid cells. Zhou et al., Mol Cell Biol.
2000; 20(20):7662-7672. c-Myb was showed to involve in
erythropoiesis and its overexpression in K562 cells inhibited the
.gamma.-globin gene expression..sup.25 More recently, BCL11A was
identified to be a developmental stage-specific repressor for
controlling the .gamma. globin gene expression. Sankaran et al.,
Science. 2008; 322(5909):1839-1842. The expression level of
full-length BCL11A was increased in parallel with globin switching,
suggesting that BCL11A represses the .gamma. globin gene expression
in the adult erythroid cells. To clarify the regulatory factors
involved in modulating .gamma. globin gene expression in the
drug-treated primary human adult erythroid cells, the mRNA levels
of the .gamma. globin as well as these transcription factors in
response to compounds treatment were determined by the relative
quantitative RT-PCR (FIG. 4A). The expression levels of the .gamma.
globin mRNA were significantly up-regulated to 1.9-3.7-folds in the
cells treated with S51021, SS-2394, or HU, but not NaB (FIG.
4A).
[0268] The elevation of protein expression levels of the .gamma.
globin chain were further confirmed in the primary human adult
erythroid cells treated with S51021 and SS-2394 (FIG. 4B). The
expression levels of NF-E4 were increased to 2.4- and 3.4-folds in
the cells treated with S51021 and SS-2394, respectively, but
decreased to 0.6 fold in the cells treated with either HU or NaB
(FIG. 4A). The expression level of c-Myb mRNA was reduced only in
the cells treated with S51021 (FIG. 4A). The expression levels of
BCL11A mRNA were significantly reduced to 0.8-, 0.6-, and 0.6-folds
by S51021, SS-2394, and NaB, respectively (FIG. 4A). A significant
reduction of BCL11A protein was also revealed in the primary human
adult erythroid cells treated with S51021, SS-2394, or NaB (FIG.
4C). Taken together, these data suggest that the modulations of
certain transcription factors, such as NF-E4, c-Myb, and BCL11A,
may cooperatively contribute to the .gamma. globin gene induction
by the tested compounds. Furthermore, both S51021 and SS-2394 can
efficiently induce the re-activation of .gamma. globin gene in the
primary human adult erythroid cells, which were not responded upon
HU treatment, indicating that S51021 and SS-2394 activate the
.gamma. globin gene expression through a distinct mechanism from
that of HU (FIG. 4D).
p38 Signaling Pathway is Involved in the .gamma. Globin Gene
Activation Triggered by the HbF-Inducing Agents.
[0269] In addition to these transcription factors, the activation
of p38 MAPK signaling pathway was also suggested to mediate the
fetal .gamma. globin gene expression in response to NaB or TSA
treatment. Ramakrishnan et al., Blood Cells Mol Dis; 47(1): 12-22;
and Pace et al., Exp Hematol. 2003; 31(11):1089-1096. To verify
whether the p38 MAPK signaling pathway is involved in the
activation of the .gamma. globin expression by the tested
compounds, the phosphorylation status of p38 in these drug-treated
erythroid cells was examined by Western blot analysis. Our data
showed that all the tested compounds (S51021, SS-2394, HU, and NaB)
significantly increased the phosphorylation levels of p38 in
parallel with the elevated .gamma. globin protein (FIG. 5),
suggesting that the activation of p38 MAPK signaling pathway may,
at least in part, contribute to the re-activation of the .gamma.
globin gene expression by these HbF-inducing compounds.
S51021 and SS-2394 are not Histone Deacetylase Inhibitors.
[0270] Several HDACi, such as NaB, apicidin, and TSA, have been
reported to function as HbF-inducing agents. General believes that
the hyper-acetylation of histone by HDACi treatments would
contribute to the activation of the .gamma. globin gene expression.
To realize whether the epigenetic modification of histone H4 is
manipulated by S51021 or SS-2394 treatment, primary human adult
erythroid cells were treated with S51021, SS-2394, HU, or NaB for 3
days, and the acetylation status of cellular histone H4 was then
analyzed (FIG. 6). Our data showed that the global acetylation
status of histone H4 (total acH4) was significantly enhanced in the
NaB-treated primary erythroid cells. In the contrast, the amounts
of global acetylated histone H4 were not dramatically alternated by
S51021, SS-2394 and HU. It indicates that the S51021, SS-2394, and
HU are not histone deacetylase inhibitors.
DISCUSSION
Underlying Mechanisms Involved in Reactivation of the .gamma.
Globin Gene Expression Mediated by S51021 and SS-2394
[0271] Unlike NaB or TSA, S51021 and SS-2394 are not histone
deacetylase inhibitors, which did not modulate the global
acetylation statues of histone H4 (FIG. 6). Furthermore, it was
found that both S51021 and SS-2394 could efficiently re-activate
the expression of .gamma. globin gene even in these primary
erythroid cells which were not responded to HU (FIG. 4D). All these
data demonstrate that the S51021 and SS-2394 belong to a novel
class of HbF-inducing agents, which are functional different from
these of previous identified compounds including NaB, HU, and TSA.
Although the detail mechanisms involved in the .gamma. globin gene
induction have not yet been completely clarified, our current
studies provide insight into understanding of the underlying
mechanism that involves in the re-activation of the .gamma. globin
gene expression mediated by S51021 or SS-2394. In the primary human
adult erythroid cells, S51021 and SS-2394 treatment significantly
down-regulated the expression levels of transcription repressor
BCL11A. On the other hand, the expression level of transcription
activator NF-E4 was significantly up-regulated by S51021 and
SS-2394 treatment (FIG. 4). In addition to these transcription
mediators (BCL11A and NF-E4), our data also showed that the
phosphorylation level of the p38 was significantly increased by
S51021 and SS-2394 (FIG. 5). Moreover, the pre-treatment of p38
MAPK inhibitor SB203580 efficiently abolished the elevation of
.gamma. globin gene expression triggered by S51021 and SS-2394
(data not shown). Taken together, it is demonstrated here that
re-activation of the .gamma. globin gene expression mediated by
S51021 or SS-2394 is a complicated process, in which the
modulations of transcription regulators (BCL11A and NF-E4) as well
as p38 signaling participate in the regulatory program.
Cell Stress Response Involves in the Elevation of the .gamma.
Globin Gene Expression Mediated by HbF-Induing Agents.
[0272] Previous studies have demonstrated that 1,8-naphthalimides,
such as amonafide, function as DNA intercalators and topoisomerase
II (topo II) inhibitors in clinical development for the treatment
of cancers including acute myeloid leukemia and prostate carcinoma.
Norton et al., Anticancer Drugs. 2008; 19(1):23-36; and Allen et
al., Expert Opinion on Investigational Drugs. 2011; 20(7):995-1003.
The newly identified compounds, B1, B4, E2, and E3, which induce
HbF, were previous found to exert their anti-cancer ability due to
inhibition of topo II (DNA intercalator). Norton et al., Anticancer
Drugs. 2008; 19(1):23-36; Stevenson et al., J Med Chem. 1984;
27(12):1677-1682; and Zee-Cheng et al., J Med Chem. 1985;
28(9):1216-1222. Considering the fact that cell growth inhibition
and DNA intercalating cause cell stress response, it raises the
possibility that cell stress response signaling may contribute to
the elevation of .gamma. globin gene expression. Indeed, several
cell stress response-inducing agents, such as HU, thalidomide, TSA,
and anisomycin, have been reported to activate the .gamma. globin
gene expression. Pace B et al., Exp Hematol. 2003;
31(11):1089-1096; Mabaera R et al, Exp Hematol. 2008;
36(9):1057-1072; Aerbajinai et al., Blood. 2007; 110(8):2864-2871;
and Cokic V P., Journal of Clinical Investigation. 2003;
111(2):231-239. It also demonstrated that most of these cell stress
response-inducing agents also inhibit cell proliferation and
activate the p38 MAPK signaling pathway..sup.31 As shown in FIG. 5,
both S51021 and SS-2394 inhibited cell growth and elevated the
phosphorylation status of p38 MAPK at the concentrations of their
IC.sub.50, suggesting that the cell stress response may be involved
in the .gamma. globin gene re-activation mediated by S51021 and
SS-2394. However, the correlations between cell stress response and
modulations of transcription regulators mediated by compound
treatment need to be further investigated.
SS-2394 is a Lead Compound for Further Developing Novel
HbF-Inducing Agent.
[0273] A a series of naphthalimide derivatives were synthesized for
evaluating their HbF-inducing abilities. These agents were
identified via lead optimization by structural modification of
S51021. Of these derivatives, SS-2394 was found to have significant
effect on increasing elevation of the .gamma. globin mRNA. Although
SS-2394 displayed lower IC.sub.50/EC ratio than that of S51021,
several lines of evidence suggest that SS-2394 is a better lead
compound for further drug development as an effective agent for
treating P-thalassemia and sickle cell disease; First, SS-2394
shows higher .gamma. globin gene induction fold at the
concentration of its IC.sub.50 than that of S51021, suggesting that
SS-2394 is a more efficient HbF-inducing agent than S51021 or
others (FIG. 4A). Second, SS-2394 contains a symmetric
pharmacophore which can be easily synthesized and purified. Third,
this agent has greatly improved water-solubility and
bioavailability and is more proper for new drug development (Table
I). Fourth, SS-2394 displays higher HbF-inducing specificity than
other compounds as demonstrated by the observation of the highest
proportion of the .gamma. globin mRNA (Table II). In sum, SS-2394,
which is not a histone deacetylase inhibitor, was identified as a
lead compound for further developing novel agents for treating
hemoglobinopathies such as 3-thalassemia and sickle cell
disease.
Example 2: Exemplary Compounds for Treating .beta.-Thalassemia and
Sickle-Cell Disease
[0274] SS-2394 shows higher water-solubility than that of the
parental compound S51021 but SS-2394 has much higher cytotoxicity
than that of S51021 as evident by comparison of their IC.sub.50. To
optimize the biological activity and reduce the cytotoxicity of
SS-2394 by structural modification, the core structure of
naphthalimide (I) was modified by alternating the carbonyl function
of benzo[de]isoquinoline-1,3(2H)-dione; reducing the carbonyl
function to hydroxyl derivatives (II), which can be further
converted into dehydroxylated derivatives III and IV (Scheme 1).
During biological evaluation of SS-2394, it was observed that the
C6-amino function in SS-2394 was unstable and can be deaminated or
converted into the corresponding C6-hydroxy derivatives. Therefore,
various substituent R to the C6 of benzo[de]isoquinolin ring were
introduced. The substituent R can be H, NH.sub.2, NHCOCH.sub.3,
NHR', NR'.sub.2; wherein R' can be a C1 to C5 alkyl group. The new
compounds bear a N,N-dimethylaminoethyl hydrophilic side chain,
which can form acid salts with various inorganic acids or organic
acids. Thus, the compounds are water soluble compounds and are
suitable for biological application.
##STR00102##
General Methods
[0275] Several representative analogues which have been synthesized
are provided in Table 2. The synthetic routes of these derivatives
are displayed in Schemes 2, 3 and 4. See also Daffy et al.,
Chemistry--A European Journal, 1998, 4, 1810-1815; Cheng; Journal
of Medicinal Chemistry, 1985, 28, 1216-1222; and Lucatello et al.,
Bioorganic and Medicinal Chemistry, 2007, 15, 555-562.
[0276] Briefly, compound SS-2394 (1) was treated with acetic
acid/acetic anhydride to give the N-acetyl derivatives (2,
BO-2559), which was converted into
2,3-dihydro-1H-benzo[de]isoquinoline 3 (BO-2566) (Scheme 2).
Treatment of 3 with HCl in EtOH gave the
6-amino-2,3-dihydro-1H-benzo[de]isoquinoline (4, BO-2560).
##STR00103##
[0277] To prevent the hydrolysis of C6-NH.sub.2 function, a
NMe.sub.2 function was introduced to the C6 position of
2,3-dihydro-1H-benzo[de]isoquinoline-1,3(2H)-dione. Thus, compound
6-NMe.sub.2 substituted derivative BO-2561 (6, Scheme 3) was
synthesized from C6-Cl derivative 5 by treating with dimethylamine
in DMF in the presence of KOH. Under such reaction conditions, we
also obtained C6-OH derivative (7, BO-2562) as the by-product. By
following a similar procedure, compound 6 (BO-2561) was converted
into 6-NH.sub.2-2,3-dihydro-1H-benzo[de]isoquinoline (8, BO-2563).
The C6-NEt derivatives (9, BO-2564) was also synthesized by
treating compound 5 with ethylamine. Similarly, compound 9 was
further converted into the corresponding benzo[de]isoquinoline (10,
BO-2565).
##STR00104##
[0278] Compound lacking one or two carbonyl function(s) were
synthesized for evaluating their biological activity. As shown in
Scheme 4, dione 11 was treated with NaBH.sub.4 in ethanol to give
mono-hydroxy derivative 12 (BO-2476), which was further converted
into mono-carbonyl derivative 13 (BO-2477). Similarly, dione 11 was
converted into the corresponding benzo[de]isoquinoline 14
(BO-2563).
##STR00105##
Compounds
N-(2-(2-(Dimethylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoli-
n-6-yl)acetamide (2, BO-2559)
[0279] Daffy et al., Chemistry--A European Journal, 1998, 4,
1810-1815. A suspension of known
6-amino-2-(2-(dimethylamino)-ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dion-
e (1, 640 mg, 2 mmol) in a mixture of acetic acid (24 mL) and
acetic anhydride (3 mL) was refluxed for 45 min. Methanol was added
to destroy excess acetic anhydride and then co-evaporated with
methanol several times to dryness. The yellow product was collected
by filtration to give the desired product
N-(2-(2-(dimethylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-benzo-[de]isoquino-
lin-6-yl)acetamide (2, BO-2559),.sup.1 590 mg (90%); mp.
278-279.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.30 (3H, s,
CH.sub.3), 2.87 (6H, s, N(CH.sub.3).sub.2), 3.41 (2H, t, J=5.9 Hz,
CH.sub.2), 4.38 (2H, t, J=5.9 Hz CH.sub.2), 7.91 (1H, t, J=8.5 Hz,
ArH), 8.34 (1H, d, J=8.2 Hz, ArH), 8.50 (1H, d, J=8.2 Hz, ArH),
8.55 (1H, d, J=6.6 Hz, ArH), 8.79 (1H, d, J=8.6 Hz, ArH), 10.52
(1H, br, NH). HRMS [ES.sup.+]: calcd for
C.sub.18H.sub.19N.sub.3O.sub.3, 325.3618 [M+H].sup.+, found
326.1500.
2-(2-(Dimethylamino)ethyl)-2,3-dihydro-1H-benzo[de]isoquinolin-6-amine
(4, BO-2560)
[0280] LiAlH.sub.4 (20 mg, 3 mmol) was added portionwise to a
stirring suspension of AlCl.sub.3 (85 mg, 0.62 mmol) in dry THF (10
mL) in an ice-water bath under Argon and stirred for 10 min.
N-(2-(2-(dimethylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinol-
in-6-yl)acetamide (2, 163 mg, 0.5 mmol) was added portionwise to
the above suspension. The reaction mixture was stirred at room
temperature for 20 min and then heated to 40.degree. C. for 1 hr.
The reaction mixture was poured into ice-water and the solid was
removed by filtration through a pad of Celite. The filtrates were
evaporated to dryness under reduced pressure and the residue was
dissolved in ethanol (50 mL) and then HCl.sub.(conc) (0.5 mL) and
then evaporated to dryness. The solid product was recrystallized
from ethanol to give
2-(2-(dimethylamino)ethyl)-2,3-dihydro-1H-benzo[de]isoquinolin-6-amine
(4, BO-2560), 101 mg (78%); mp. 253-254.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.86 (6H, s, N(CH.sub.3).sub.2), 3.70 (4H,
s, 2.times.CH.sub.2), 4.65-4.97 (4H, s, 2.times.CH.sub.2), 6.65
(1H, d, J=7.8 Hz, ArH), 7.28 (1H, d, J=7.8 Hz, ArH), 7.42 (1H, d,
J=7.1 Hz, ArH), 7.49 (1H, t, J=7.8 Hz, ArH), 8.22 (1H, d, J=8.3 Hz,
ArH), 10.83 (2H, br, NH.sub.2). HRMS [ES.sup.+]: calcd for
C.sub.16H.sub.21N.sub.3, 255.3580 [M+H].sup.+, found 256.1814.
2-(2-(dimethylamino)ethyl)-6-hydroxy-H-benzo[de]isoquinoline-1,3(2H)-dione
(6, BO-2562).sup.2 and
6-(dimethylamino)-2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1,3-
(2H)-dione (7, BO-2561)
[0281] A solution of
6-chloro-2-(2-(dimethylamino)ethyl)-1H-benzo-[de]isoquinoline-1,3(2H)-dio-
ne (5, 1.5 g, 5 mmol) and KOH (1.12 g, 20 mmol) in 10 mL of DMF was
heated at reflux for 45 min. The solvent was then evaporated in
vacuo to dryness. The residue was chromotographered on a silica gel
column (4.times.20 cm) using CHCl.sub.3:MeOH (100:2 v/v) as the
eluent. The first main product eluated was collected to give
6-(dimethylamino)-2-(2-(dimethyl-amino)ethyl)-1H-benzo[de]isoquinoline-1,-
3(2H)-dione (7, BO-2561), 795 mg (50%), mp. 198-199.degree. C.
.sup.1H NMR (DMSO-d.sub.6) .delta. 2.89 (6H, s, N(CH.sub.3).sub.2),
3.12 (6H, s, N(CH.sub.3).sub.2), 3.44 (2H, t, J=5.9 Hz, CH.sub.2),
4.38 (2H, t, J=5.9 Hz, CH.sub.2), 7.24 (1H, d, J=7.8 Hz, ArH), 7.79
(1H, t, J=7.9 Hz, ArH), 8.37 (1H, d, J=8.4 Hz, ArH), 8.50 (1H, d,
J=7.2 Hz, ArH), 8.56 (1H, d, J=8.4 Hz, ArH). HRMS [ES.sup.+]: calcd
for C.sub.18H.sub.21N.sub.3O.sub.2, 311.3782 [M+H].sup.+, found
312.1061).
[0282] The second product eluated was collected to give
2-(2-(dimethylamino)ethyl)-6-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dio-
ne (6) (Daffy et al., Chemistry--A European Journal, 1998, 4,
1810-1815) 160 mg (11%); mp. 202-204.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.38 (6H, s, N(CH.sub.3).sub.2), 2.71 (2H,
t, J=8.3 Hz, CH.sub.2), 4.19 (2H, t, J=8.3 Hz, CH.sub.2), 6.77 (1H,
d, J=8.5 Hz, ArH), 7.56 (1H, t, J=7.7 Hz, ArH), 8.18 (1H, d, J=8.5
Hz, ArH), 8.37 (1H, d, J=7.2 Hz, ArH), 8.48 (1H, d, J=8.1 Hz, ArH).
HRMS [ES.sup.+]: calcd for C.sub.16H.sub.16N.sub.2O.sub.3, 284.3098
[M+H].sup.+, found 285.1240.
2-(2-(Dimethylamino)ethyl)-N,N-dimethyl-2,3-dihydro-1H-benzo[de]isoquinoli-
n-6-amine (8, BO-2563)
[0283] LiAlH.sub.4 (20 mg, 3 mmol) was added portionwise to a
stirring suspension of AlCl.sub.3 (85 mg, 0.62 mmol) in 10 mL of
THF in an ice-water bath under Argon for 10 min.
6-(dimethylamino)-2-(2-(dimethylamino)ethyl)-1H-benzo[de]-isoquinoline-1,-
3(2H)-dione (7, 311 mg, 1 mmol) was added portionwise. The reaction
mixture was allowed to stir at room temperature and then heated to
40.degree. C. for 1 h. The reaction mixture was poured into
ice-water and filtered through a pad of Celite. The filtrate were
evaporated to dryness under reduced pressure. The solid product was
recrystallized from EtOH to give
2-(2-(dimethylamino)ethyl)-N,N-dimethyl-2,3-dihydro-1H-benzo[de]isoq-
uinolin-6-amine (8, BO-2563), 184 mg (65%), mp. 251-252.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 2.89 (6H, s, N(CH.sub.3).sub.2),
2.95 (6H, s, N(CH.sub.3).sub.2), 3.94 (4H, S, 2.times.CH.sub.2),
4.71 (2H, S, CH.sub.2), 4.76 (2H, S, CH.sub.2), 7.36 (1H, d, J=7.2
Hz, ArH), 7.46 (1H, d, J=7.8 Hz, ArH), 7.52 (1H, d, J=7.2 Hz, ArH),
7.66 (1H, t, J=7.8 Hz, ArH), 8.19 (1H, d, J=8.5 Hz, ArH). HRMS
[ES.sup.+]: cald for C.sub.18H.sub.25N.sub.3, 283.4112 [M+H].sup.+,
found 284.2129.
2-(2-(Dimethylamino)ethyl)-6-(ethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-
-dione (9, BO-2564)
[0284] A solution of
6-chloro-2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dion-
e (1.8 g, 6 mmol), and KOH (1.68 g, 30 mmol) in 4 mL of
N,N-diethylformamide was refluxed for 2 hr. The solvent was
evaporated to dryness. The residue was chromotographer on silica
gel (6.times.20 cm) using CHCl.sub.3:methanol 100:4 as eluant to
give syrup product
2-(2-(dimethylamino)ethyl)-6-(ethylamino)-1H-benzo[de]isoquinoline-1,3(2H-
)-dione (9, BO-2564), 313 mg (10%); mp. 253-4.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta.1.30 (3H, t, J=7.1 Hz, CH.sub.2CH.sub.3),
2.20 (6H, s, N(CH.sub.3).sub.2), 2.48. (2H, t, J=6.9 Hz, CH.sub.2),
3.42 (2H, q, J=7.1 Hz, CH.sub.2CH.sub.3) 4.13 (2H, t, J=6.9 Hz,
CH.sub.2), 6.79 (1H, d, J=8.5 Hz, ArH), 7.68 (1H, t, J=7.9 Hz,
ArH), 7.74 (1H, br, NH), 8.28 (1H, d, J=8.5 Hz, ArH), 8.42 (1H, d,
J=9.0 Hz, ArH), 8.44 (1H, d, J=7.3 Hz, ArH), 8.69 (1H, d, J=8.5 Hz,
ArH). HRMS [ES.sup.+]: calcd for C.sub.18H.sub.21N.sub.3O.sub.2,
311.3782 [M+H].sup.+, found 312.1814.
2-(2-(dimethylamino)ethyl)-N-ethyl-2,3-dihydro-1H-benzo[de]isoquinolin-6-a-
mine (10, BO-2565)
[0285] A suspension of AlCl.sub.3 (85 mg, 0.62 mmol) in 10 mL of
THF was added portionwise LiAlH.sub.4 (20 mg, 3 mmol) at ice-water
bath under Argon for 10 min.
2-(2-(dimethylamino)ethyl)-6-(ethylamino)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (170 mg, 0.5 mmol) was added portionwise at ice-water.
It was stirred at room temperature and then heated to 40.degree. C.
for 1 hr. The reaction mixture was poured into ice-water. The solid
was removed by a pad of Celite. The filtrates were evaporated to
dryness. The product was recrystallized from EtOH/HCl to give
2-(2-(dimethyl-amino)ethyl)-N-ethyl-2,3-dihydro-1H-benzo[de]isoquinolin-6-
-amine, 38 mg (24%), mp. 239-240.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta.1.30 (3H, t, J=7.0 Hz, CH.sub.2CH.sub.3),
2.87 (6H, s, N(CH.sub.3).sub.2), 3.27 (2H, q, J=7.0 Hz,
CH.sub.2CH.sub.3), 3.69 (4H, brs, 2.times.CH.sub.2), 4.87 (4H, brs,
2.times.CH.sub.2), 6.61 (1H, d, J=7.3 Hz, ArH), 7.29 (1H, d, J=7.7
Hz, ArH), 7.49 (1H, br, NH), 7.62 (1H, t, J=7.7 Hz, ArH), 7.98 (1H,
d, J=8.2 Hz, ArH), 8.20 (1H, d, J=8.4 Hz, ArH). HRMS [ES.sup.+]:
calcd for C.sub.18H.sub.25N.sub.3, 283.4112 [M+H].sup.+, found
284.3225.
2-(2-(Dimethylamino)ethyl)-3-hydroxy-2,3-dihydro-1H-benzo[de]isoquinolin-1-
-one (12, BO-2476)
[0286] NaBH.sub.4 (0.37 g, 10 mmol) was added portionwise to a
solution of
2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
(11, 0.27 g, 1 mmol) in EtOH/Water (20 mL, v/v:10/1). The mixture
was stirred overnight at room temperature. After the completion of
the reaction, the reaction mixture was evaporated under reduced
pressure to dryness. The solid residue was triturated with water
and extracted with CH.sub.2Cl.sub.2 (100 mL.times.3). The combined
organic extracts were dried over Na.sub.2SO.sub.4 and evaporated to
dryness and the solid was recrystallized from
Haxen/CH.sub.2Cl.sub.2 to afford the desired product
2-(2-(dimethylamino)ethyl)-3-hydroxy-2,3-dihydro-1H-benzo[de]isoquinolin--
1-one (12, BO-2476), 0.24 g (89%); mp. 129-130.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.26 (6H, s, N-Me.sub.2), 2.48-2.45 (1H,
m, CH), 2.72-2.68 (1H, m, CH), 3.71-3.65 (1H, m, CH), 3.97-3.92
(1H, m, CH), 6.15 (1H, s, CH--OH), 7.71-7.64 (3H, m, ArH), 7.78
(1H, s, CH--OH, exchangeable), 8.03 (1H, d, J=7.1 Hz, ArH), 8.19
(1H, d, J=8.2 Hz, ArH), 8.24 1H, d, J=7.1 Hz, ArH). HRMS
[ES.sup.+]: cald for C.sub.16H.sub.18N.sub.2O.sub.2, 270.3262
[M+H].sup.+, found 271.2231.
2-(2-(Dimethylamino)ethyl)-2,3-dihydro-1H-benzo[de]isoquinolin-1-one
(13, BO-2477)
[0287] To a solution of
2-(2-(dimethylamino)ethyl)-3-hydroxy-2,3-dihydro-1H-benzo[de]isoquinolin--
1-one (12, 0.27 g, 1 mmol) in CH.sub.2Cl.sub.2 (10 mL) were added
triethylsilane (0.48 mL, 3 mmol) and TFA (4 mL). The reaction
mixture was stirred overnight at room temperature. After the
completion of, solvent was evaporated under reduced pressure to
dryness and the residue was triturated with saturated NaHCO.sub.3
solution and then extracted with CH.sub.2Cl.sub.2. The combined
organic extracts were dried over Na.sub.2SO.sub.4 and evaporated to
dryness. The solid residue was recrystallized from
Haxen/CH.sub.2Cl.sub.2 to
2-(2-(dimethylamino)ethyl)-2,3-dihydro-1H-benzo[de]isoquinolin-1-one
(13, BO-2477), 0.22 g, 86%; mp. 253-254.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.86 (6H, s, N-Me.sub.2), 3.48-3.45 (2H, m,
CH.sub.2), 4.02-3.99 (2H, m, CH.sub.2), 5.14 (2H, s, CH.sub.2),
7.48 (1H, d, J=7.0 Hz, ArH), 7.66-7.59 (2H, m, ArH), 7.91 (1H, d,
J=8.2 Hz, ArH), 8.16-8.12 (2H, m, ArH). HRMS [ES.sup.+]: cald for
C.sub.16H.sub.18N.sub.2O, 254.3269 [M+H].sup.+, found 255.1169.
2-(1H-Benzo[de]isoquinolin-2(3H)-yl)-N,N-dimethylethan-1-amine (14,
BO-2478)
[0288] Lucatello et al., Bioorganic and Medicinal Chemistry, 2007,
15, 555-562. To suspension of AlCl.sub.3 (0.17 g, 1.25 mmol) in
anhydrous THF was added LiAlH.sub.4 (0.24 g, 6 mmol) followed by
slow addition of
2-(2-(dimethyl-amino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
(11, 0.27 g, 1 mmol) at 0.degree. C. The mixture was then refluxed
for 3 h, cooled to 0.degree. C. and then poured into ice/THF
cautiously. The solid separated was collected by filtration and the
filtrate was extracted with CH.sub.2Cl.sub.2. The organic layer was
separated and dried over anhydrous Na.sub.2SO.sub.4 and evaporated
to dryness afforded the final product. The final product was then
converted in to HCl salt by treating with EA/HCl to give
2-(1H-benzo[de]isoquinolin-2(3H)-yl)-N,N-dimethylethan-1-amine (14,
BO-2478), 0.215 g (78%); mp. 208-209.degree. C.; .sup.1H NMR
(CDCl.sub.3-d.sub.6) .delta. 2.28 (6H, s, N--(CH.sub.3).sub.2),
2.62-2.58 (2H, m, CH.sub.2), 2.78-2.75 (2H, m, CH.sub.2), 4.02 (2H,
s, CH.sub.2), 7.19 (2H, d, J=8.6 Hz, ArH), 7.41-7.36 (2H, m, ArH),
7.68 (2H, d, J=10.3 Hz, ArH). HRMS [ES.sup.+]: cald for
C.sub.16H.sub.21N.sub.2Cl, 276.8043 [M+H].sup.+, found
277.7241.
Biological Activity
[0289] All the newly synthesized compounds were evaluated for their
.gamma. globin-inducing abilities. FIG. 8 shows the effect of
.gamma. globin-induction and cytotoxicity against primary erythroid
cells by the representative analogues of
2,3-dihydro-1H-benzo[de]isoquinoline (line 1: mock control; line 2:
hydroxyurea (HU); line 3: sodium butyrate (NaB); line 4: SS-2394;
line 5: S51021; line 6: BO-2562; line 7: BO-2561; line 8: BO-2559;
line 9: BO-2566; line 10: BO-2563, line 11: BO-2560; line 12:
BO-2565; line 13; BO-2477; line 14: BO-2476; line 15: BO-2478. The
tested concentrations of each compound and the survival rates of
the primary erythroid cells after 2 days of compound treatment are
listed at the bottom of the graph.
[0290] As shown in FIG. 8, the newly synthesized compounds BO-2559,
BO-2560, BO-2561, BO-2476 and BO-2477 showed significant .gamma.
globin-inducing abilities, of which the expression levels of
.gamma. globin gene were up-regulated by 2.1-6.9 folds in primary
erythroid cells. All these newly identified .gamma. globin-inducing
compounds have reduced cytotoxicities with IC.sub.50 ranging from 5
to 40 .mu.M against primary erythroid cells. Among the compounds
tested, compound BO-2477 was shown to have the highest .gamma.
globin-inducing activity with relatively lower cytotoxicity.
* * * * *