U.S. patent application number 17/690323 was filed with the patent office on 2022-09-01 for 5-bromo-indirubins.
The applicant listed for this patent is City of Hope, National and Kapodistrian University of Athens. Invention is credited to Nicolas GABORIAUD-KOLAR, David HORNE, Richard JOVE, Marina KRITSANIDA, Sangkil NAM, Alexios Leandros SKALTSOUNIS, Jun XIE.
Application Number | 20220274964 17/690323 |
Document ID | / |
Family ID | 1000006320526 |
Filed Date | 2022-09-01 |
United States Patent
Application |
20220274964 |
Kind Code |
A1 |
JOVE; Richard ; et
al. |
September 1, 2022 |
5-BROMO-INDIRUBINS
Abstract
Disclosed herein inter alia are compositions and methods for
treating cancer using 5-Br-indirubin derivatives.
Inventors: |
JOVE; Richard; (Pasadena,
CA) ; NAM; Sangkil; (Tujunga, CA) ; HORNE;
David; (Altadena, CA) ; XIE; Jun; (Duarte,
CA) ; SKALTSOUNIS; Alexios Leandros; (Athens, GR)
; KRITSANIDA; Marina; (Athens, GR) ;
GABORIAUD-KOLAR; Nicolas; (Athens, GR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
City of Hope
National and Kapodistrian University of Athens |
Duarte
Athens |
CA |
US
GR |
|
|
Family ID: |
1000006320526 |
Appl. No.: |
17/690323 |
Filed: |
March 9, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16790611 |
Feb 13, 2020 |
11306072 |
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17690323 |
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15898151 |
Feb 15, 2018 |
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16790611 |
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14850579 |
Sep 10, 2015 |
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15898151 |
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PCT/US2014/028730 |
Mar 14, 2014 |
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14850579 |
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61783290 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/496 20130101;
A61K 45/06 20130101; C07D 401/14 20130101; A61K 31/4439 20130101;
C07D 209/40 20130101; C07D 209/48 20130101; C07D 401/04 20130101;
C07D 403/14 20130101; A61K 31/404 20130101 |
International
Class: |
C07D 403/14 20060101
C07D403/14; C07D 401/04 20060101 C07D401/04; C07D 209/40 20060101
C07D209/40; C07D 209/48 20060101 C07D209/48; A61K 45/06 20060101
A61K045/06; A61K 31/404 20060101 A61K031/404; A61K 31/4439 20060101
A61K031/4439; A61K 31/496 20060101 A61K031/496; C07D 401/14
20060101 C07D401/14 |
Claims
1. A compound, or pharmaceutically acceptable salt thereof, having
the formula: ##STR00026## wherein L is an unsubstituted alkylene;
R.sup.1 is --NR.sup.2R.sup.3; R.sup.2 and R.sup.3 are joined
together to forma substituted or unsubstituted heterocycloalkyl or
substituted or unsubstituted heteroaryl; R.sup.5 and R.sup.6 are
independently hydrogen.
2.-5. (canceled)
6. The compound of claim 1, wherein L is unsubstituted C.sub.2
alkylene.
7.-17. (canceled)
18. The compound of claim 1, wherein R.sup.2 and R.sup.3 are joined
together to form a substituted or unsubstituted C.sub.5-C.sub.7
heterocycloalkyl.
19. The compound of claim 18, wherein R.sup.2 and R.sup.3 are
joined together to form a substituted C.sub.5-C.sub.7
heterocycloalkyl.
20. The compound of claim 19, wherein R.sup.2 and R.sup.3 are
joined together to form an R.sup.23-substituted C.sub.5-C.sub.7
heterocycloalkyl, wherein R.sup.23 is independently a substituted
or unsubstituted alkyl or substituted or unsubstituted
heteroalkyl.
21. The compound of claim 20, wherein R.sup.23 is independently a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl or substituted
or unsubstituted 2 to 8 membered heteroalkyl.
22. The compound of claim 16, wherein R.sup.2 and R.sup.3 are
joined together to form a substituted or unsubstituted
pyrrolidinyl.
23. The compound of claim 16, wherein R.sup.2 and R.sup.3 are
joined together to form a substituted or unsubstituted
piperazinyl.
24. The compound of claim 1 comprising a protonated nitrogen cation
or a plurality of protonated nitrogen cations.
25. (canceled)
26. (canceled)
27. The compound of claim 1 having formula: ##STR00027##
##STR00028## including pharmaceutical salts thereof.
28. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of claim 1.
29. The compound of claim 1 for use in treating cancer in a subject
in need thereof.
30. The compound of claim 29, wherein said compound is administered
in an effective amount to said subject.
31. The compound of claim 29, wherein said compound is in a
pharmaceutical composition comprising a pharmaceutically acceptable
excipient.
32. The compound of claim 29, wherein said cancer is lung cancer,
breast cancer, ovarian cancer, leukemia, lymphoma, melanoma,
pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain
cancer, cervical cancer, colon cancer, esophageal cancer, gastric
cancer, liver cancer, head and neck cancer, kidney cancer, myeloma,
thyroid cancer, or prostate cancer.
33. The compound of claim 29, wherein said compound is
co-administered with an effective amount of an anti-cancer
agent.
34. A method of modulating a kinase, a JAK, JAK2, TYK2, Src, c-Src,
ABL1, ABL1 T315I, an Aurora kinase, Aurora A, GSK-3.beta., a CDK, a
STAT, or STAT3, said method comprising contacting the protein with
the compound of claim 1.
35. The method of claim 34, wherein the compound is in a
pharmaceutical composition comprising a pharmaceutically acceptable
excipient.
36. A method of modulating a Janus kinase, said method comprising
contacting said Janus kinase with the compound of claim 1.
37. The method of claim 36, wherein the compound is in a
pharmaceutical composition comprising a pharmaceutically acceptable
excipient.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/790,611, filed Feb. 13, 2020, which is a continuation of
U.S. application Ser. No. 15/898,151 filed Feb. 15, 2018, now
abandoned, which is a continuation of U.S. application Ser. No.
14/850,579, filed Sep. 10, 2015, now abandoned, which is a
continuation of International Appl. No. PCT/US2014/028730, filed
Mar. 14, 2014, which claims the benefit of U.S. Provisional
Application No. 61/783,290, filed Mar. 14, 2013, the content of
each of which is incorporated by reference herein in its entirety
and for all purposes.
BACKGROUND OF THE INVENTION
[0002] Cancer is a significant cause of death worldwide. In 2008,
cancer accounted for an estimated 13% of worldwide deaths. Lung,
prostate, and colorectal cancer are the most common forms of cancer
in men and accounted for 40% of all cancers in men in 2008. Breast,
colorectal, and cervical cancers made up more than 40% of all
cancers in women in the same year. Overall, lung cancer is the most
common cancer. Protein kinases are involved in many signal
transduction and other cellular processes. Dysregulation of kinase
activity has been found to be associated with many forms of cancer.
Disclosed herein are, inter alia, indirubin derivatives capable of
modulating different kinases or single kinases that provide
solutions to these and other problems in the art.
BRIEF SUMMARY OF THE INVENTION
[0003] Provided herein, inter alia, are compounds, or
pharmaceutically acceptable salt thereof, having the formula:
##STR00001##
[0004] In the compound of formula (I), L is a bond or substituted
or unsubstituted alkylene. R.sup.1 is hydrogen, halogen,
--CX.sup.1.sub.3, --OCX.sup.1.sub.3, --CN, --OH, --NH.sub.2,
--COOH, --C(O)OR.sup.4, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, --NR.sup.2R.sup.3, --OR.sup.4, --SR.sup.4,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.1 is
independently a halogen. R.sup.2 and R.sup.3 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. R.sup.2 and
R.sup.3 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.4 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. R.sup.5 and R.sup.6 are independently
hydrogen, halogen, --CX.sup.2.sub.3, --OCX.sup.2.sub.3, --CN, --OH,
--NH.sub.2, --COOH, --C(O)OR.sup.9, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, NR.sup.7R.sup.8, --OR.sup.9, --SR.sup.9, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
or substituted or unsubstituted heteroaryl. X.sup.2 is
independently a halogen. R.sup.7 and R.sup.8 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl, wherein R.sup.7
and R.sup.8 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.9 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl.
[0005] Also provided herein are pharmaceutical compositions
including a pharmaceutically acceptable excipient and a compound,
or pharmaceutically acceptable salt thereof, as described herein
(e.g. a compound of formula (I) or formula (II), including
embodiments thereof).
[0006] In another aspect is provided a method of treating cancer by
administering an effective amount of a compound, or
pharmaceutically acceptable salt thereof, as described herein,
including embodiments thereof.
[0007] In another aspect is provided a method of modulating the
level, activity, or function of a protein associated with a
disease. The method includes contacting the protein with an
effective amount of a compound, or pharmaceutically acceptable salt
thereof, as described herein, including embodiments thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1. Structures of 5-bromoindirubin-3'-oxime derivatives
(5BIODs).
[0009] FIGS. 2A-2G. Effects of 5BIODs on viabilities of human
cancer cells; MTS assays were performed for cell viability; human
A549 non-small cell lung cancer (FIG. 2A), MDA-MB-231 and
MDA-MB-468 breast cancer (FIG. 2B), A2058 melanoma (FIG. 2C), DU145
prostate cancer (FIG. 2D), SKOV3 ovarian cancer (FIG. 2E), T315I
Abl mutant KCL-22 CML (FIG. 2F) and MIA-PaCa2 pancreatic cancer
(FIG. 2G) cells were seeded in 96-well plates (5000/well for solid
tumor cell lines and 10000 cells/well for CML cell line), incubated
overnight at 37.degree. C. in 5% (v/v) CO.sub.2 and exposed to
5BIODs at 1 .mu.M or 10 .mu.M concentration for 48 h; DMSO was used
as the vehicle control; cell viability was determined by
tetrazolium conversion to its formazan dye and absorbance was
measured at 490 nm using an automated ELISA plate reader; each
experiment was performed in quadruplicate. Histogram ordering: FIG.
2B depicts MDA-MB-231 (black) and MDA-MB-468 (gray), in order left
to right; FIG. 2C: 1 .mu.M (gray); 10 .mu.M (black), in order left
to right; FIG. 2D: 1 .mu.M (gray); 10 .mu.M (black), in order left
to right;
[0010] FIG. 3. Compound 1276 and 1289 reduce viabilities of SKOV3
ovarian cancer cells; MTS assays were performed for cell viability
as described in FIGS. 2A-2G; IC.sub.50 values were determined; each
experiment was performed in quadruplicate. Histogram ordering (left
to right): 1276 (black); 1289 (gray).
[0011] FIGS. 4A-4C. Effects of compound 1289 and 810 on viabilities
of ovarian and pancreatic cancer cells; (FIG. 4A). Structures of
compound 1289 (5-bromoindirubin-3'-oxime derivative) and compound
810 (6-bromoindirubin-3'-oxime derivative). As described in FIG. 3,
IC.sub.50 values were determined using MTS assays in SKOV3 ovarian
(FIG. 4B) and pancreatic (FIG. 4C) cancer cells; each experiment
was performed in quadruplicate. Histogram ordering (left to right):
FIG. 4B: #810 (dark gray); #1289 (light gray).
[0012] FIG. 5. Kinase profiling in vitro for compounds #1276 and
#1289.
[0013] FIG. 6. Structures of 5-bromoindirubin-3'-oxime derivatives
(5BIODs).
[0014] FIGS. 7A-7B. Effects of compounds described herein on
viabilities of human cancer cells: FIG. 7A) effect on A2058
melanoma cells; FIG. 7B) effect on DU145 prostate cancer cells.
Histogram ordering (left to right); 0.25 .mu.M, 1 .mu.M,
respectively.
[0015] FIGS. 8A-8D: Efficacy of compounds 1281. FIG. 8A: tumor
volume over time in days of treatment; FIG. 8B: histogram of tumor
weight for vehicle (left bin) and IRD1281 (right bin)); FIG. 8C:
tumor volume over time in days of treatment; FIG. 8D: histogram of
tumor weight for vehicle (left bin) and IRD1289 (right bin)) on
A549 lung cancer SQ xenografts. Conditions: NSG mice, female;
Vehicle group: 10; Treatment group: 10; Oral administration at 25
mg/kg, twice/day. Legend: FIG. 8A: vehicle (diamonds); IRD 1281:
squares); FIG. 8C: vehicle (diamonds); IRD 1289 (squares).
DETAILED DESCRIPTION OF THE INVENTION
[0016] The abbreviations used herein have their conventional
meaning within the chemical and biological arts. The chemical
structures and formulae set forth herein are constructed according
to the standard rules of chemical valency known in the chemical
arts.
[0017] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents that would result
from writing the structure from right to left, e.g., --CH.sub.2O--
is equivalent to --OCH.sub.2--.
[0018] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight (i.e.,
unbranched) or branched carbon chain (or carbon), or combination
thereof, which may be fully saturated, mono- or polyunsaturated and
can include mono-, di- and multivalent radicals, having the number
of carbon atoms designated (i.e., C.sub.1-C.sub.10 means one to ten
carbons). Alkyl is an uncyclized chain. Examples of saturated
hydrocarbon radicals include, but are not limited to, groups such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,
sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds. Examples of unsaturated alkyl groups include, but are
not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An
alkoxy is an alkyl attached to the remainder of the molecule via an
oxygen linker (--O--).
[0019] The term "alkylene," by itself or as part of another
substituent, means, unless otherwise stated, a divalent radical
derived from an alkyl, as exemplified, but not limited by,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having eight or fewer
carbon atoms. The term "alkenylene," by itself or as part of
another substituent, means, unless otherwise stated, a divalent
radical derived from an alkene.
[0020] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or combinations thereof, including at least one
carbon atom and at least one heteroatom selected from the group
consisting of O, N, P, Si, and S, and wherein the nitrogen and
sulfur atoms may optionally be oxidized, and the nitrogen
heteroatom may optionally be quaternized. The heteroatom(s) O, N,
P, S, B, As, and Si may be placed at any interior position of the
heteroalkyl group or at the position at which the alkyl group is
attached to the remainder of the molecule. Heteroalkyl is an
uncyclized chain. Examples include, but are not limited to:
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3,
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3, --O--CH.sub.3,
--O--CH.sub.2--CH.sub.3, and --CN. Up to two or three heteroatoms
may be consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3
and --CH.sub.2--O--Si(CH.sub.3).sub.3.
[0021] Similarly, the term "heteroalkylene," by itself or as part
of another substituent, means, unless otherwise stated, a divalent
radical derived from heteroalkyl, as exemplified, but not limited
by, --CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents both --C(O).sub.2R'-- and
--R'C(O).sub.2--. As described above, heteroalkyl groups, as used
herein, include those groups that are attached to the remainder of
the molecule through a heteroatom, such as --C(O)R', --C(O)NR',
--NR'R'', --OR', --SR', and/or --SO.sub.2R'. Where "heteroalkyl" is
recited, followed by recitations of specific heteroalkyl groups,
such as --NR'R'' or the like, it will be understood that the terms
heteroalkyl and --NR'R'' are not redundant or mutually exclusive.
Rather, the specific heteroalkyl groups are recited to add clarity.
Thus, the term "heteroalkyl" should not be interpreted herein as
excluding specific heteroalkyl groups, such as --NR'R'' or the
like.
[0022] The terms "cycloalkyl" and "heterocycloalkyl," by themselves
or in combination with other terms, mean, unless otherwise stated,
cyclic versions of "alkyl" and "heteroalkyl," respectively.
Cycloalkyl and heteroalkyl are not aromatic. Additionally, for
heterocycloalkyl, a heteroatom can occupy the position at which the
heterocycle is attached to the remainder of the molecule. Examples
of cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,
3-cyclohexenyl, cycloheptyl, and the like. Examples of
heterocycloalkyl include, but are not limited to,
1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,
1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a
"heterocycloalkylene," alone or as part of another substituent,
means a divalent radical derived from a cycloalkyl and
heterocycloalkyl, respectively.
[0023] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" includes, but is
not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0024] The term "acyl" means, unless otherwise stated, --C(O)R
where R is a substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0025] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, hydrocarbon substituent, which can be a
single ring or multiple rings (preferably from 1 to 3 rings) that
are fused together (i.e., a fused ring aryl) or linked covalently.
A fused ring aryl refers to multiple rings fused together wherein
at least one of the fused rings is an aryl ring. The term
"heteroaryl" refers to aryl groups (or rings) that contain at least
one heteroatom such as N, O, or S, wherein the nitrogen and sulfur
atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized. Thus, the term "heteroaryl" includes fused
ring heteroaryl groups (i.e., multiple rings fused together wherein
at least one of the fused rings is a heteroaromatic ring). A
5,6-fused ring heteroarylene refers to two rings fused together,
wherein one ring has 5 members and the other ring has 6 members,
and wherein at least one ring is a heteroaryl ring. Likewise, a
6,6-fused ring heteroarylene refers to two rings fused together,
wherein one ring has 6 members and the other ring has 6 members,
and wherein at least one ring is a heteroaryl ring. A 6,5-fused
ring heteroarylene refers to two rings fused together, wherein one
ring has 6 members and the other ring has 5 members, and wherein at
least one ring is a heteroaryl ring. A heteroaryl group can be
attached to the remainder of the molecule through a carbon or
heteroatom. Non-limiting examples of aryl and heteroaryl groups
include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,
pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,
purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl and heteroaryl ring
systems are selected from the group of acceptable substituents
described below. An "arylene" and a "heteroarylene," alone or as
part of another substituent, mean a divalent radical derived from
an aryl and heteroaryl, respectively. A heteroaryl group
substituent may be a --O-- bonded to a ring heteroatom
nitrogen.
[0026] A "fused ring aryl-heterocycloalkyl" is an aryl fused to a
heterocycloalkyl. A "fused ring heteroaryl-heterocycloalkyl" is a
heteroaryl fused to a heterocycloalkyl. A "fused ring
heterocycloalkyl-cycloalkyl" is a heterocycloalkyl fused to a
cycloalkyl. A "fused ring heterocycloalkyl-heterocycloalkyl" is a
heterocycloalkyl fused to another heterocycloalkyl. Fused ring
aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl,
fused ring heterocycloalkyl-cycloalkyl, or fused ring
heterocycloalkyl-heterocycloalkyl may each independently be
unsubstituted or substituted with one or more of the substituents
described herein. Fused ring aryl-heterocycloalkyl, fused ring
heteroaryl-heterocycloalkyl, fused ring
heterocycloalkyl-cycloalkyl, or fused ring
heterocycloalkyl-heterocycloalkyl may each independently be named
according to the size of each of the fused rings. Thus, for
example, 6,5 aryl-heterocycloalkyl fused ring describes a 6
membered aryl moiety fused to a 5 membered heterocycloalkyl.
Spirocyclic rings are two or more rings wherein adjacent rings are
attached through a single atom. The individual rings within
spirocyclic rings may be identical or different. Individual rings
in spirocyclic rings may be substituted or unsubstituted and may
have different substituents from other individual rings within a
set of spirocyclic rings. Possible substituents for individual
rings within spirocyclic rings are the possible substituents for
the same ring when not part of spirocyclic rings (e.g. substituents
for cycloalkyl or heterocycloalkyl rings). Spirocyclic rings may be
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted
heterocycloalkylene and individual rings within a spirocyclic ring
group may be any of the immediately previous list, including having
all rings of one type (e.g. all rings being substituted
heterocycloalkylene wherein each ring may be the same or different
substituted heterocycloalkylene). When referring to a spirocyclic
ring system, heterocyclic spirocyclic rings means a spirocyclic
rings wherein at least one ring is a heterocyclic ring and wherein
each ring may be a different ring. When referring to a spirocyclic
ring system, substituted spirocyclic rings means that at least one
ring is substituted and each substituent may optionally be
different.
[0027] The term "oxo," as used herein, means an oxygen that is
double bonded to a carbon atom.
[0028] The term "thio," as used herein, means a sulfur that is
single bonded to carbon or to another sulfur.
[0029] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl," and "heteroaryl") includes both substituted and
unsubstituted forms of the indicated radical. Preferred
substituents for each type of radical are provided below.
[0030] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one
or more of a variety of groups selected from, but not limited to,
--OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR'''',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --NR'NR''R''', --ONR'R'',
--NR'C(O)NR''NR'''R'''', --CN, --NO.sub.2, --NR'SO.sub.2R'',
--NR'C(O)R'', --NR'C(O)OR'', --NR'OR'', in a number ranging from
zero to (2m'+1), where m' is the total number of carbon atoms in
such radical. R, R', R'', R''', and R'''' each preferably
independently refer to hydrogen, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl (e.g., aryl substituted with 1-3 halogens), substituted or
unsubstituted heteroaryl, substituted or unsubstituted alkyl,
alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound
of the invention includes more than one R group, for example, each
of the R groups is independently selected as are each R', R'',
R''', and R'''' group when more than one of these groups is
present. When R' and R'' are attached to the same nitrogen atom,
they can be combined with the nitrogen atom to form a 4-, 5-, 6-,
or 7-membered ring. For example, --NR'R'' includes, but is not
limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above
discussion of substituents, one of skill in the art will understand
that the term "alkyl" is meant to include groups including carbon
atoms bound to groups other than hydrogen groups, such as haloalkyl
(e.g., --CF.sub.3 and --CH.sub.2CF.sub.3) and acyl (e.g.,
--C(O)CH.sub.3, --C(O)CF.sub.3, --C(O)CH.sub.2OCH.sub.3, and the
like).
[0031] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are varied and are
selected from, for example: --OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR'''',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --NR'NR''R''', --ONR'R'',
--NR'C(O)NR''NR'''R'''', --CN, --NO.sub.2, --R', --N.sub.3,
--CH(Ph).sub.2, fluoro(C.sub.1-C.sub.4)alkoxy, and
fluoro(C.sub.1-C.sub.4)alkyl, --NR'SO.sub.2R'', --NR'C(O)R'',
--NR'C(O)OR'', --NR'OR'', in a number ranging from zero to the
total number of open valences on the aromatic ring system; and
where R', R'', R''', and R'''' are preferably independently
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. When a compound of the
invention includes more than one R group, for example, each of the
R groups is independently selected as are each R', R'', R''', and
R'''' groups when more than one of these groups is present.
[0032] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl,
aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or
heteroarylene) may be depicted as substituents on the ring rather
than on a specific atom of a ring (commonly referred to as a
floating substituent). In such a case, the substituent may be
attached to any of the ring atoms (obeying the rules of chemical
valency) and in the case of fused rings or spirocyclic rings, a
substituent depicted as associated with one member of the fused
rings or spirocyclic rings (a floating substituent on a single
ring), may be a substituent on any of the fused rings or
spirocyclic rings (a floating substituent on multiple rings). When
a substituent is attached to a ring, but not a specific atom (a
floating substituent), and a subscript for the substituent is an
integer greater than one, the multiple substituents may be on the
same atom, same ring, different atoms, different fused rings,
different spirocyclic rings, and each substituent may optionally be
different. Where a point of attachment of a ring to the remainder
of a molecule is not limited to a single atom (a floating
substituent), the attachment point may be any atom of the ring and
in the case of a fused ring or spirocyclic ring, any atom of any of
the fused rings or spirocyclic rings while obeying the rules of
chemical valency. Where a ring, fused rings, or spirocyclic rings
contain one or more ring heteroatoms and the ring, fused rings, or
spirocyclic rings are shown with one more floating substituents
(including, but not limited to, points of attachment to the
remainder of the molecule), the floating substituents may be bonded
to the heteroatoms. Where the ring heteroatoms are shown bound to
one or more hydrogens (e.g. a ring nitrogen with two bonds to ring
atoms and a third bond to a hydrogen) in the structure or formula
with the floating substituent, when the heteroatom is bonded to the
floating substituent, the substituent will be understood to replace
the hydrogen, while obeying the rules of chemical valency.
[0033] Two or more substituents may optionally be joined to form
aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such
so-called ring-forming substituents are typically, though not
necessarily, found attached to a cyclic base structure. In one
embodiment, the ring-forming substituents are attached to adjacent
members of the base structure. For example, two ring-forming
substituents attached to adjacent members of a cyclic base
structure create a fused ring structure. In another embodiment, the
ring-forming substituents are attached to a single member of the
base structure. For example, two ring-forming substituents attached
to a single member of a cyclic base structure create a spirocyclic
structure. In yet another embodiment, the ring-forming substituents
are attached to non-adjacent members of the base structure.
[0034] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally form a ring of the formula
-T-C(O)--(CRR').sub.q-U-, wherein T and U are independently --NR--,
--O--, --CRR'--, or a single bond, and q is an integer of from 0 to
3. Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula -A-(CH.sub.2).sub.r-B-, wherein A and B
are independently --CRR'--, --O--, --NR--, --S--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2NR'--, or a single bond, and r is an
integer of from 1 to 4. One of the single bonds of the new ring so
formed may optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula --(CRR'), --X'--(C''R''R''').sub.d--,
where s and d are independently integers of from 0 to 3, and X' is
--O--, --NR'--, --S--, --S(O)--, --S(O).sub.2--, or
--S(O).sub.2NR'--. The substituents R, R', R'', and R''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0035] As used herein, the terms "heteroatom" or "ring heteroatom"
are meant to include, oxygen (O), nitrogen (N), sulfur (S),
phosphorus (P), Boron (B), Arsenic (As), and silicon (Si).
[0036] A "substituent group," as used herein, means a group
selected from the following moieties: [0037] (A) oxo, halogen,
--CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H,
--SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2,
--NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH,
--OCF.sub.3, --OCHF.sub.2, unsubstituted alkyl, unsubstituted
heteroalkyl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0038] (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
and heteroaryl, substituted with at least one substituent selected
from: [0039] (i) oxo, halogen, --CF.sub.3, --CN, --OH, --NH.sub.2,
--COOH, --CONH.sub.2, --NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H,
--SO.sub.4H, --SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2,
--NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H,
--NHC(O)OH, --NHOH, --OCF.sub.3, --OCHF.sub.2, unsubstituted alkyl,
unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0040] (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
and heteroaryl, substituted with at least one substituent selected
from: [0041] (a) oxo, halogen, --CF.sub.3, --CN, --OH, --NH.sub.2,
--COOH, --CONH.sub.2, --NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H,
--SO.sub.4H, --SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2,
--NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H,
--NHC(O)OH, --NHOH, --OCF.sub.3, --OCHF.sub.2, unsubstituted alkyl,
unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0042] (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl, substituted with at least one substituent selected
from: oxo, halogen, --CF.sub.3, --CN, --OH, --NH.sub.2, --COOH,
--CONH.sub.2, --NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H,
--SO.sub.4H, --SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2,
--NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H,
--NHC(O)OH, --NHOH, --OCF.sub.3, --OCHF.sub.2, unsubstituted alkyl,
unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, unsubstituted aryl, and unsubstituted
heteroaryl.
[0043] A "size-limited substituent" or "size-limited substituent
group," as used herein, means a group selected from all of the
substituents described above for a "substituent group," wherein
each substituted or unsubstituted alkyl is a substituted or
unsubstituted C.sub.1-C.sub.20 alkyl, each substituted or
unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20
membered heteroalkyl, each substituted or unsubstituted cycloalkyl
is a substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, and
each substituted or unsubstituted heterocycloalkyl is a substituted
or unsubstituted 3 to 8 membered heterocycloalkyl.
[0044] A "lower substituent" or"lower substituent group," as used
herein, means a group selected from all of the substituents
described above for a "substituent group," wherein each substituted
or unsubstituted alkyl is a substituted or unsubstituted
C.sub.1-C.sub.8 alkyl, each substituted or unsubstituted
heteroalkyl is a substituted or unsubstituted 2 to 8 membered
heteroalkyl, each substituted or unsubstituted cycloalkyl is a
substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, and each
substituted or unsubstituted heterocycloalkyl is a substituted or
unsubstituted 3 to 7 membered heterocycloalkyl.
[0045] In some embodiments, each substituted group described in the
compounds herein is substituted with at least one substituent
group. More specifically, in some embodiments, each substituted
alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, substituted heteroaryl,
substituted alkylene, substituted heteroalkylene, substituted
cycloalkylene, substituted heterocycloalkylene, substituted
arylene, and/or substituted heteroarylene described in the
compounds herein are substituted with at least one substituent
group. In other embodiments, at least one or all of these groups
are substituted with at least one size-limited substituent group.
In other embodiments, at least one or all of these groups are
substituted with at least one lower substituent group.
[0046] In other embodiments of the compounds herein, each
substituted or unsubstituted alkyl may be a substituted or
unsubstituted C.sub.1-C.sub.2 alkyl, each substituted or
unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20
membered heteroalkyl, each substituted or unsubstituted cycloalkyl
is a substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl,
and/or each substituted or unsubstituted heterocycloalkyl is a
substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In
some embodiments of the compounds herein, each substituted or
unsubstituted alkylene is a substituted or unsubstituted
C.sub.1-C.sub.20 alkylene, each substituted or unsubstituted
heteroalkylene is a substituted or unsubstituted 2 to 20 membered
heteroalkylene, each substituted or unsubstituted cycloalkylene is
a substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene,
and/or each substituted or unsubstituted heterocycloalkylene is a
substituted or unsubstituted 3 to 8 membered
heterocycloalkylene.
[0047] In some embodiments, each substituted or unsubstituted alkyl
is a substituted or unsubstituted C.sub.1-C.sub.8 alkyl, each
substituted or unsubstituted heteroalkyl is a substituted or
unsubstituted 2 to 8 membered heteroalkyl, each substituted or
unsubstituted cycloalkyl is a substituted or unsubstituted
C.sub.3-C.sub.7 cycloalkyl, and/or each substituted or
unsubstituted heterocycloalkyl is a substituted or unsubstituted 3
to 7 membered heterocycloalkyl. In some embodiments, each
substituted or unsubstituted alkylene is a substituted or
unsubstituted C.sub.1-C.sub.8 alkylene, each substituted or
unsubstituted heteroalkylene is a substituted or unsubstituted 2 to
8 membered heteroalkylene, each substituted or unsubstituted
cycloalkylene is a substituted or unsubstituted C.sub.3-C.sub.7
cycloalkylene, and/or each substituted or unsubstituted
heterocycloalkylene is a substituted or unsubstituted 3 to 7
membered heterocycloalkylene.
[0048] Certain compounds of the present invention possess
asymmetric carbon atoms (optical or chiral centers) or double
bonds; the enantiomers, racemates, diastereomers, tautomers,
geometric isomers, stereoisomeric forms that may be defined, in
terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or
(L)- for amino acids, and individual isomers are encompassed within
the scope of the present invention. The compounds of the present
invention do not include those which are known in art to be too
unstable to synthesize and/or isolate. The present invention is
meant to include compounds in racemic and optically pure forms.
Optically active (R)- and (S)-, or (D)- and (L)-isomers may be
prepared using chiral synthons or chiral reagents, or resolved
using conventional techniques. When the compounds described herein
contain olefinic bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers.
[0049] As used herein, the term "isomers" refers to compounds
having the same number and kind of atoms, and hence the same
molecular weight, but differing in respect to the structural
arrangement or configuration of the atoms.
[0050] The term "tautomer," as used herein, refers to one of two or
more structural isomers which exist in equilibrium and which are
readily converted from one isomeric form to another.
[0051] It will be apparent to one skilled in the art that certain
compounds of this invention may exist in tautomeric forms, all such
tautomeric forms of the compounds being within the scope of the
invention.
[0052] Unless otherwise stated, structures depicted herein are also
meant to include all stereochemical forms of the structure; i.e.,
the R and S configurations for each asymmetric center. Therefore,
single stereochemical isomers as well as enantiomeric and
diastereomeric mixtures of the present compounds, generally
recognized as stable by those skilled in the art, are within the
scope of the invention.
[0053] Unless otherwise stated, structures depicted herein are also
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of a hydrogen by
a deuterium or tritium, or the replacement of a carbon by .sup.13C-
or .sup.14C-enriched carbon are within the scope of this
invention.
[0054] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes atone or more of the atoms
that constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I), or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are encompassed within the scope of the
present invention.
[0055] The symbol "" denotes the point of attachment of a chemical
moiety to the remainder of a molecule or chemical formula.
[0056] The terms "a" or "an," as used in herein means one or more.
In addition, the phrase "substituted with a[n]," as used herein,
means the specified group may be substituted with one or more of
any or all of the named substituents. For example, where a group,
such as an alkyl or heteroaryl group, is "substituted with an
unsubstituted C.sub.1-C.sub.20 alkyl, or unsubstituted 2 to 20
membered heteroalkyl," the group may contain one or more
unsubstituted C.sub.1-C.sub.20 alkyls, and/or one or more
unsubstituted 2 to 20 membered heteroalkyls.
[0057] Moreover, where a moiety is substituted with an R
substituent, the group may be referred to as "R-substituted." Where
a moiety is R-substituted, the moiety is substituted with at least
one R substituent and each R substituent is optionally different.
Where a particular R group is present in the description of a
chemical genus (such as Formula (I)), a Roman alphabetic symbol may
be used to distinguish each appearance of that particular R group.
For example, where multiple R.sup.13 substituents are present, each
R.sup.13 substituent may be distinguished as R.sup.13A, R.sup.13B,
R.sup.13C, R.sup.13D, etc., wherein each of R.sup.13A, R.sup.13B,
R.sup.13C, R.sup.13D, etc. is defined within the scope of the
definition of R.sup.13 and optionally differently.
[0058] Description of compounds of the present invention is limited
by principles of chemical bonding known to those skilled in the
art. Accordingly, where a group may be substituted by one or more
of a number of substituents, such substitutions are selected so as
to comply with principles of chemical bonding and to give compounds
which are not inherently unstable and/or would be known to one of
ordinary skill in the art as likely to be unstable under ambient
conditions, such as aqueous, neutral, and several known
physiological conditions. For example, a heterocycloalkyl or
heteroaryl is attached to the remainder of the molecule via a ring
heteroatom in compliance with principles of chemical bonding known
to those skilled in the art thereby avoiding inherently unstable
compounds.
[0059] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds that are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino, or magnesium salt, or
a similar salt. When compounds of the present invention contain
relatively basic functionalities, acid addition salts can be
obtained by contacting the neutral form of such compounds with a
sufficient amount of the desired acid, either neat or in a suitable
inert solvent. Examples of pharmaceutically acceptable acid
addition salts include those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogen phosphoric,
sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
the like, as well as the salts derived from relatively nontoxic
organic acids like acetic, propionic, isobutyric, maleic, malonic,
benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds
of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
[0060] Thus, the compounds of the present invention may exist as
salts, such as with pharmaceutically acceptable acids. The present
invention includes such salts. Examples of such salts include
hydrochlorides, hydrobromides, sulfates, methanesulfonates,
nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g.,
(+)-tartrates, (-)-tartrates, or mixtures thereof including racemic
mixtures), succinates, benzoates, and salts with amino acids such
as glutamic acid. These salts may be prepared by methods known to
those skilled in the art.
[0061] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt form sin
certain physical properties, such as solubility in polar
solvents.
[0062] In addition to salt forms, the present invention provides
compounds, which are in a prodrug form. Prodrugs of the compounds
described herein include those compounds that readily undergo
chemical changes under physiological conditions to provide the
compounds of the present invention. Additionally, prodrugs can be
converted to the compounds of the present invention by chemical or
biochemical methods in an ex vivo environment. For example,
prodrugs can be slowly converted to the compounds of the present
invention when placed in a transdermal patch reservoir with a
suitable enzyme or chemical reagent.
[0063] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms. In general, all physical
forms are equivalent for the uses contemplated by the present
invention and are intended to be within the scope of the present
invention.
[0064] As used herein, the term "salt" refers to acid or base salts
of the compounds used in the methods of the present invention.
Illustrative examples of acceptable salts are mineral acid
(hydrochloric acid, hydrobromic acid, phosphoric acid, and the
like) salts, organic acid (acetic acid, propionic acid, glutamic
acid, citric acid and the like) salts, quaternary ammonium (methyl
iodide, ethyl iodide, and the like) salts.
[0065] The terms "treating", or "treatment" refers to any indicia
of success in the treatment or amelioration of an injury, disease,
pathology or condition, including any objective or subjective
parameter such as abatement; remission; diminishing of symptoms or
making the injury, pathology or condition more tolerable to the
patient; slowing in the rate of degeneration or decline; making the
final point of degeneration less debilitating; improving a
patient's physical or mental well-being. The treatment or
amelioration of symptoms can be based on objective or subjective
parameters; including the results of a physical examination,
neuropsychiatric exams, and/or a psychiatric evaluation. The term
"treating" and conjugations thereof, include prevention of an
injury, pathology, condition, or disease.
[0066] An "effective amount" is an amount sufficient to accomplish
a stated purpose (e.g. achieve the effect for which it is
administered, treat a disease, reduce enzyme activity, reduce one
or more symptoms of a disease or condition, reduce the level of a
kinase activity in a cell (e.g. JAK2, Src, STAT3, ABL1, T351 mutant
ABL1, TYK2, Aurora A, cyclin dependent kinase, or GSK-3.beta.). An
example of an "effective amount" is an amount sufficient to
contribute to the treatment, prevention, or reduction of a symptom
or symptoms of a disease, which could also be referred to as a
"therapeutically effective amount." A "reduction" of a symptom or
symptoms (and grammatical equivalents of this phrase) means
decreasing of the severity or frequency of the symptom(s), or
elimination of the symptom(s). The exact amounts will depend on the
purpose of the treatment, and will be ascertainable by one skilled
in the art using known techniques (see, e.g., Lieberman,
Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art,
Science and Technology of Pharmaceutical Compounding (1999);
Pickar, Dosage Calculations (1999); and Remington: The Science and
Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott,
Williams & Wilkins).
[0067] "Control" or "control experiment" is used in accordance with
its plain ordinary meaning and refers to an experiment in which the
subjects or reagents of the experiment are treated as in a parallel
experiment except for omission of a procedure, reagent, or variable
of the experiment. In some instances, the control is used as a
standard of comparison in evaluating experimental effects.
[0068] "Contacting" is used in accordance with its plain ordinary
meaning and refers to the process of allowing at least two distinct
species (e.g. chemical compounds including biomolecules, or cells)
to become sufficiently proximal to react, interact or physically
touch. It should be appreciated, however, that the resulting
reaction product can be produced directly from a reaction between
the added reagents or from an intermediate from one or more of the
added reagents which can be produced in the reaction mixture.
[0069] The term "contacting" may include allowing two species to
react, interact, or physically touch, wherein the two species may
be a compound as described herein and a protein or enzyme (e.g.
JAK, JAK2, TYK2, c-Src, ABL1, T315I mutant ABL1, Aurora A,
GSK-3.beta., CDK). In embodiments contacting includes allowing a
compound described herein to interact with a protein or enzyme that
is involved in a signaling pathway (e.g. STAT3 pathway).
[0070] As defined herein, the term "inhibition", "inhibit",
"inhibiting" and the like in reference to a protein-inhibitor
interaction means negatively affecting (e.g. decreasing) the
activity or function of the protein (e.g. decreasing the
phosphorylation of another protein by a kinase) relative to the
activity or function of the protein (e.g. kinase) in the absence of
the inhibitor (e.g. kinase inhibitor or kinase inhibitor compound).
In embodiments inhibition refers to reduction of a disease or
symptoms of disease. In embodiments, inhibition refers to a
reduction in the activity of a signal transduction pathway or
signaling pathway (e.g. reduction of a pathway involving JAK, JAK2,
TYK2, c-Src, ABL1, T315I mutant ABL1, Aurora A, GSK-3.beta., CDK,
STAT, or STAT3). Thus, inhibition includes, at least in part,
partially or totally blocking stimulation, decreasing, preventing,
or delaying activation, or inactivating, desensitizing, or
down-regulating signal transduction or enzymatic activity or the
amount of a protein (e.g. JAK, JAK2, TYK2, c-Src, ABL1, T315I
mutant ABL1, Aurora A, GSK-3.beta., CDK, STAT, or STAT3). In
embodiments, JAK, JAK2, TYK2, c-Src, ABL1, T315I mutant ABL1,
Aurora A, GSK-3.beta., CDK, STAT, or STAT3 is a human protein.
[0071] The term "modulator" refers to a composition that increases
or decreases the level of a target molecule or the function of a
target molecule (e.g. a target may be a kinase (e.g. a JAK, JAK2,
TYK2, c-Src, ABL1, T315I mutant ABL1, Aurora A, GSK-3s, CDK) and
the function may be to phosphorylate a molecule or the target may
be a kinase (e.g. a JAK, JAK2, TYK2, c-Src, ABL1, T315I mutant
ABL1, Aurora A, GSK-3.beta., CDK) and the function may be the
function of a downstream signaling pathway including a STAT or
STAT3). In embodiments, a kinase modulator is a compound that
reduces the activity of a kinase in a cell. A kinase modulator may
reduce the activity of one kinase but cause an increase in enzyme
activity of another kinase that results in a reduction or increase,
respectively, of cell growth and proliferation. In embodiments, a
kinase disease modulator is a compound that reduces the severity of
one or more symptoms of a disease associated with the kinase (e.g.
cancer).
[0072] "Patient" or "subject in need thereof" refers to a living
organism suffering from or prone to a disease or condition that can
be treated by administration of a compound or pharmaceutical
composition, as provided herein. Non-limiting examples include
humans, other mammals, bovines, rats, mice, dogs, monkeys, goat,
sheep, cows, deer, and other non-mammalian animals. In embodiments,
a patient is human.
[0073] "Disease" or "condition" refer to a state of being or health
status of a patient or subject capable of being treated with a
compound, pharmaceutical composition, or method provided herein. In
embodiments, the disease is a disease related to (e.g. caused by)
an activated or overactive kinase or aberrant kinase activity as
described herein. In embodiments, the disease is a disease related
to (e.g. characterized by) an inhibited kinase or reduced kinase
activity (e.g. cancer with decreased level of a JAK, JAK2, TYK2,
c-Src, ABL1, T315I mutant ABL1, Aurora A, GSK-3.beta., or CDK
activity or decreased signal transduction activity in pathways
involving a JAK, JAK2, TYK2, c-Src, ABL1, T315I mutant ABL1, Aurora
A, GSK-3.beta., CDK, a STAT, or STAT3). Examples of diseases,
disorders, or conditions include, but are not limited to, cancer,
lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma,
melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer,
brain cancer, cervical cancer, colon cancer, esophageal cancer,
gastric cancer, liver cancer, head and neck cancer, kidney cancer,
myeloma, thyroid cancer, prostate cancer, metastatic cancer, or
carcinoma. In some instances, "disease" or "condition" refers to
cancer. In some further instances, "cancer" refers to human cancers
and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias,
melanomas, etc., including solid and lymphoid cancers, kidney,
breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach,
brain, head and neck, skin, uterine, testicular, glioma, esophagus,
liver cancer, including hepatocarcinoma, lymphoma, including
B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g.,
Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's
lymphoma, leukemia (including AML, ALL, and CML), and/or multiple
myeloma.
[0074] As used herein, the term "cancer" refers to all types of
cancer, neoplasm or malignant tumors found in mammals, including
leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that
may be treated with a compound, pharmaceutical composition, or
method provided herein include lymphoma, sarcoma, bladder cancer,
bone cancer, brain tumor, cervical cancer, colon cancer, esophageal
cancer, gastric cancer, head and neck cancer, kidney cancer,
myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer
(e.g. ER positive, ER negative, chemotherapy resistant, herceptin
resistant, HER2 positive, doxorubicin resistant, tamoxifen
resistant, ductal carcinoma, lobular carcinoma, primary,
metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g.
hepatocellular carcinoma), lung cancer (e.g. non-small cell lung
carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell
lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma),
glioblastoma multiforme, glioma, or melanoma. Additional examples
include, cancer of the thyroid, endocrine system, brain, breast,
cervix, colon, head & neck, liver, kidney, lung, non-small cell
lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or
Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma,
multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme,
ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary
macroglobulinemia, primary brain tumors, cancer, malignant
pancreatic insulanoma, malignant carcinoid, urinary bladder cancer,
premalignant skin lesions, testicular cancer, lymphomas, thyroid
cancer, neuroblastoma, esophageal cancer, genitourinary tract
cancer, malignant hypercalcemia, endometrial cancer, adrenal
cortical cancer, neoplasms of the endocrine or exocrine pancreas,
medullary thyroid cancer, medullary thyroid carcinoma, melanoma,
colorectal cancer, papillary thyroid cancer, hepatocellular
carcinoma, Paget's Disease of the Nipple, Phyllodes Tumors, Lobular
Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate
cells, cancer of the hepatic stellate cells, or prostate
cancer.
[0075] The term "leukemia" refers broadly to progressive, malignant
diseases of the blood-forming organs and is generally characterized
by a distorted proliferation and development of leukocytes and
their precursors in the blood and bone marrow. Leukemia is
generally clinically classified on the basis of (1) the duration
and character of the disease-acute or chronic; (2) the type of cell
involved; myeloid (myelogenous), lymphoid (lymphogenous), or
monocytic; and (3) the increase or non-increase in the number
abnormal cells in the blood-leukemic or aleukemic (subleukemic).
Exemplary leukemias that may be treated with a compound,
pharmaceutical composition, or method provided herein include, for
example, acute nonlymphocytic leukemia, chronic lymphocytic
leukemia, acute granulocytic leukemia, chronic granulocytic
leukemia, acute promyelocytic leukemia, adult T-cell leukemia,
aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia,
blast cell leukemia, bovine leukemia, chronic myelocytic leukemia,
leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross'
leukemia, hairy-cell leukemia, hemoblastic leukemia,
hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,
acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,
lymphoblastic leukemia, lymphocytic leukemia, lymphogenous
leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell
leukemia, megakaryocytic leukemia, micromyeloblastic leukemia,
monocytic leukemia, myeloblastic leukemia, myelocytic leukemia,
myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli
leukemia, plasma cell leukemia, multiple myeloma, plasmacytic
leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's
leukemia, stem cell leukemia, subleukemic leukemia, or
undifferentiated cell leukemia.
[0076] The term "sarcoma" generally refers to a tumor which is made
up of a substance like the embryonic connective tissue and is
generally composed of closely packed cells embedded in a fibrillar
or homogeneous substance. Sarcomas that may be treated with a
compound, pharmaceutical composition, or method provided herein
include a chondrosarcoma, fibrosarcoma, lymphosarcoma,
melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma,
adipose sarcoma, liposarcoma, alveolar soft part sarcoma,
ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio
carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial
sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma,
fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma,
Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic
sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic
sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer
cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma
sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,
serocystic sarcoma, synovial sarcoma, or telangiectaltic
sarcoma.
[0077] The term "melanoma" is taken to mean a tumor arising from
the melanocytic system of the skin and other organs. Melanomas that
may be treated with a compound, pharmaceutical composition, or
method provided herein include, for example, acral-lentiginous
melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's
melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma,
lentigo maligna melanoma, malignant melanoma, nodular melanoma,
subungal melanoma, or superficial spreading melanoma.
[0078] The term "carcinoma" refers to a malignant new growth made
up of epithelial cells tending to infiltrate the surrounding
tissues and give rise to metastases. Exemplary carcinomas that may
be treated with a compound, pharmaceutical composition, or method
provided herein include, for example, medullary thyroid carcinoma,
familial medullary thyroid carcinoma, acinar carcinoma, acinous
carcinoma, adenocystic carcinoma, adenoid cystic carcinoma,
carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar
carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma
basocellulare, basaloid carcinoma, basosquamous cell carcinoma,
bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic
carcinoma, cerebriform carcinoma, cholangiocellular carcinoma,
chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus
carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma
cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct
carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma,
encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale
adenoides, exophytic carcinoma, carcinoma exulcere, carcinoma
fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell
carcinoma, carcinoma gigantocellulare, glandular carcinoma,
granulosa cell carcinoma, hair-matrix carcinoma, hematoid
carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,
hyaline carcinoma, hypernephroid carcinoma, infantile embryonal
carcinoma, carcinoma in situ, intraepidermal carcinoma,
intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell
carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma
lenticulare, lipomatous carcinoma, lobular carcinoma,
lymphoepithelial carcinoma, carcinoma medullare, medullary
carcinoma, melanotic carcinoma, carcinoma molle, mucinous
carcinoma, carcinoma muciparum, carcinomamucocellulare,
mucoepidermoidcarcinoma, carcinomamucosum, mucous carcinoma,
carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell
carcinoma, carcinoma ossificans, osteoid carcinoma, papillary
carcinoma, periportal carcinoma, preinvasive carcinoma, prickle
cell carcinoma, pultaceous carcinoma, renal cell carcinoma of
kidney, reserve cell carcinoma, carcinoma sarcomatodes,
schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti,
signet-ring cell carcinoma, carcinoma simplex, small-cell
carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle
cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous
cell carcinoma, string carcinoma, carcinoma telangiectaticum,
carcinoma telangiectodes, transitional cell carcinoma, carcinoma
tuberosum, tubular carcinoma, tuberous carcinoma, verrucous
carcinoma, or carcinoma villosum.
[0079] The term "associated" or "associated with" in the context of
a substance or substance activity or function associated with a
disease (e.g. a protein associated disease, a cancer associated
with aberrant kinase activity) means that the disease (e.g. cancer)
is caused by (in whole or in part), or a symptom of the disease is
caused by (in whole or in-part) the substance or substance activity
or function. For example, a cancer associated with aberrant kinase
activity or function may be a cancer that results (entirely or
partially) or is otherwise characterized by aberrant kinase
activity or function (e.g. enzyme activity, protein-protein
interaction, signaling pathway) or a cancer wherein a particular
symptom of the disease is caused (entirely or partially) by
aberrant kinase activity or function. As used herein, what is
described as being associated with a disease, if a causative agent,
could be a target for treatment of the disease. For example, a
cancer associated with aberrant kinase activity or function or a
kinase associated cancer, may be treated with a kinase modulator or
kinase inhibitor, in the instance where increased kinase activity
or function (e.g. signaling pathway activity) causes the
cancer.
[0080] The term "signaling pathway" as used herein refers to a
series of interactions between cellular and optionally
extra-cellular components (e.g. proteins, nucleic acids, small
molecules, ions, lipids) that conveys a change in one component to
one or more other components, which in turn may convey a change to
additional components, which is optionally propogated to other
signaling pathway components. For example, binding of a kinase with
a compound as described herein may result in a change in one or
more protein-protein interactions of the kinase, resulting in
changes in cell growth, proliferation, or survival.
[0081] "Pharmaceutically acceptable excipient" and
"pharmaceutically acceptable carrier" refer to a substance that
aids the administration of an active agent to and absorption by a
subject and can be included in the compositions of the present
invention without causing a significant adverse toxicological
effect on the patient. Non-limiting examples of pharmaceutically
acceptable excipients include water, NaCl, normal saline solutions,
lactated Ringer's, normal sucrose, normal glucose, binders,
fillers, disintegrants, lubricants, coatings, sweeteners, flavors,
salt solutions (such as Ringer's solution), alcohols, oils,
gelatins, carbohydrates such as lactose, amylose or starch, fatty
acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and
colors, and the like. Such preparations can be sterilized and, if
desired, mixed with auxiliary agents such as lubricants,
preservatives, stabilizers, wetting agents, emulsifiers, salts for
influencing osmotic pressure, buffers, coloring, and/or aromatic
substances and the like that do not deleteriously react with the
compounds of the invention. One of skill in the art will recognize
that other pharmaceutical excipients are useful in the present
invention.
[0082] The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as a
carrier providing a capsule in which the active component with or
without other carriers, is surrounded by a carrier, which is thus
in association with it. Similarly, cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges
can be used as solid dosage forms suitable for oral
administration.
[0083] As used herein, the term "administering" means oral
administration, administration as a suppository, topical contact,
intravenous, parenteral, intraperitoneal, intramuscular,
intralesional, intrathecal, intranasal or subcutaneous
administration, or the implantation of a slow-release device, e.g.,
a mini-osmotic pump, to a subject. Administration is by any route,
including parenteral and transmucosal (e.g., buccal, sublingual,
palatal, gingival, nasal, vaginal, rectal, or transdermal).
Parenteral administration includes, e.g., intravenous,
intramuscular, intra-arteriole, intradermal, subcutaneous,
intraperitoneal, intraventricular, and intracranial. Other modes of
delivery include, but are not limited to, the use of liposomal
formulations, intravenous infusion, transdermal patches, etc.
[0084] By "co-administer" it is meant that a composition described
herein is administered at the same time, just prior to, or just
after the administration of one or more additional therapies, for
example cancer therapies such as chemotherapy, hormonal therapy,
radiotherapy, or immunotherapy. The compound of the invention can
be administered alone or can be coadministered to the patient.
Coadministration is meant to include simultaneous or sequential
administration of the compound individually or in combination (more
than one compound or agent). Thus, the preparations can also be
combined, when desired, with other active substances (e.g. to
reduce metabolic degradation).
[0085] The compounds described herein can be used in combination
with one another, with other active agents known to be useful in
treating a disease associated with cells expressing a particular
kinase as described herein, or with adjunctive agents that may not
be effective al one, but may contribute to the efficacy of the
active agent.
[0086] In embodiments, co-administration includes administering one
active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours
of a second active agent. Co-administration includes administering
two active agents simultaneously, approximately simultaneously
(e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other),
or sequentially in any order. In embodiments, co-administration can
be accomplished by co-formulation, i.e., preparing a single
pharmaceutical composition including both active agents. In other
embodiments, the active agents can be formulated separately. In
embodiments, the active and/or adjunctive agents may be linked or
conjugated to one another.
[0087] The compositions of the present invention can be delivered
transdermally, by a topical route, formulated as applicator sticks,
solutions, suspensions, emulsions, gels, creams, ointments, pastes,
jellies, paints, powders, and aerosols. Oral preparations include
tablets, pills, powder, dragees, capsules, liquids, lozenges,
cachets, gels, syrups, slurries, suspensions, etc., suitable for
ingestion by the patient. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. Liquid form preparations include solutions, suspensions,
and emulsions, for example, water or water/propylene glycol
solutions. The compositions of the present invention may
additionally include components to provide sustained release and/or
comfort. Such components include high molecular weight, anionic
mucomimetic polymers, gelling polysaccharides and finely-divided
drug carrier substrates. These components are discussed in greater
detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and
4,861,760. The entire contents of these patents are incorporated
herein by reference in their entirety for all purposes.
[0088] The compositions of the present invention can also be
delivered as microspheres for slow release in the body. For
example, microsphees can be administered via intradermal injection
of drug-containing microspheres, which slowly release
subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,
1995; as biodegradable and injectable gel formulations (see, e.g.,
Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral
administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,
1997). In embodiments, the formulations of the compositions of the
present invention can be delivered by the use of liposomes which
fuse with the cellular mem brane or are endocytosed, i.e., by
employing receptor ligands attached to the liposome, that bind to
surface membrane protein receptors of the cell resulting in
endocytosis. By using liposomes, particularly where the liposome
surface carries receptor ligands specific for target cells, or are
otherwise preferentially directed to a specific organ, one can
focus the delivery of the compositions of the present invention
into the target cells in vivo. (See, e.g., Al-Muhammed, J.
Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.
6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587,
1989).
[0089] Pharmaceutical compositions provided by the present
invention include compositions wherein the active ingredient (e.g.
compounds described herein, including embodiments thereof) is
contained in a therapeutically effective amount, i.e., in an amount
effective to achieve its intended purpose. The actual amount
effective for a particular application will depend, inter alia, on
the condition being treated. When administered in methods to treat
a disease, such compositions will contain an amount of active
ingredient effective to achieve the desired result, e.g.,
modulating the activity of a target molecule such as a kinase
described herein, and/or reducing, eliminating, or slowing the
progression of disease symptoms (e.g. cancer growth or metastasis).
Determination of a therapeutically effective amount of a compound
of the invention is well within the capabilities of those skilled
in the art, especially in light of the detailed disclosure
herein.
[0090] The dosage and frequency (single or multiple doses)
administered to a mammal can vary depending upon a variety of
factors, for example, whether the mammal suffers from another
disease, and its route of administration; size, age, sex, health,
body weight, body mass index, and diet of the recipient; nature and
extent of symptoms of the disease being treated (e.g. cancer, lung
cancer, breast cancer, ovarian cancer, leukemia, melanoma,
pancreatic cancer, or prostate cancer), kind of concurrent
treatment, complications from the disease being treated or other
health-related problems. Other therapeutic regimens or agents can
be used in conjunction with the methods and compounds of
Applicants' invention. Adjustment and manipulation of established
dosages (e.g., frequency and duration) are well within the ability
of those skilled in the art.
[0091] For any compound described herein, the therapeutically
effective amount can be initially determined from cell culture
assays. Target concentrations will be those concentrations of
active compound(s) that are capable of achieving the methods
described herein, as measured using the methods described herein or
known in the art.
[0092] As is well known in the art, therapeutically effective
amounts for use in humans can also be determined from animal
models. For example, a dose for humans can be formulated to achieve
a concentration that has been found to be effective in animals. The
dosage in humans can be adjusted by monitoring compounds
effectiveness and adjusting the dosage upwards or downwards, as
described above. Adjusting the dose to achieve maximal efficacy in
humans based on the methods described above and other methods is
well within the capabilities of the ordinarily skilled artisan.
[0093] Dosages may be varied depending upon the requirements of the
patient and the compound being employed. The dose administered to a
patient, in the context of the present invention should be
sufficient to effect a beneficial therapeutic response in the
patient overtime. The size of the dose also will be determined by
the existence, nature, and extent of any adverse side-effects.
Determination of the proper dosage fora particular situation is
within the skill of the practitioner. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
increments until the optimum effect under circumstances is
reached.
[0094] Dosage amounts and intervals can be adjusted individually to
provide levels of the administered compound effective for the
particular clinical indication being treated. This will provide a
therapeutic regimen that is commensurate with the severity of the
individual's disease state.
[0095] Utilizing the teachings provided herein, an effective
prophylactic or therapeutic treatment regimen can be planned that
does not cause substantial toxicity and yet is effective to treat
the clinical symptoms demonstrated by the particular patient. This
planning should involve the careful choice of active compound by
considering factors such as compound potency, relative
bioavailability, patient body weight, presence and severity of
adverse side effects, preferred mode of administration and the
toxicity profile of the selected agent.
[0096] "Anti-cancer agent" is used in accordance with its plain
ordinary meaning and refers to a composition (e.g. compound, drug,
antagonist, inhibitor, modulator) having antineoplastic properties
or the ability to inhibit the growth or proliferation of cells. In
some embodiments, an anti-cancer agent is a chemotherapeutic agent.
In embodiments, an anti-cancer agent is an agent identified herein
having utility in methods of treating cancer. In embodiments, an
anti-cancer agent is an agent approved by the FDA or similar
regulatory agency of a country other than the USA, for treating
cancer. Examples of anti-cancer agents include, but are not limited
to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518,
CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib,
GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059,
TAK-733, PD318026, AS703026, BAY 869766), alkylating agents (e.g.,
cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,
mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen
mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,
meiphalan), ethylenimine and methylmelamines (e.g.,
hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),
nitrosoureas (e.g., carmustine, lomusitne, semustine,
streptozocin), triazenes (decarbazine)), anti-metabolites (e.g.,
5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine,
pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),
purine analogs (e.g., mercaptopurine, thioguanine, pentostatin),
etc.), plant alkaloids (e.g., vincristine, vinblastine,
vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel,
etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,
amsacrine, etoposide (VP16), etoposide phosphate, teniposide,
etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,
daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,
mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.
cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g.,
mitoxantrone), substituted urea (e.g., hydroxyurea), methyl
hydrazine derivative (e.g., procarbazine), adrenocortical
suppressant (e.g., mitotane, aminoglutethimide),
epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,
daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,
L-asparaginase), inhibitors of mitogen-activated protein kinase
signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142266,
SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk
inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol,
genasense, polyphenol E, Chlorofusin, all trans-retinoic acid
(ATRA), bryostatin, tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all
trans retinoic acid, doxorubicin, vincristine, etoposide,
gemcitabine, imatinib (Gleevec.RTM.), geldanamycin,
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352,
20-epi-1, 25 dihydroxyvitaminD3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonistD; antagonist
G; antarelix; anti-dorsalizingmorphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine, betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinyIspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustineanalogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrinB; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; p entostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B 1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;
sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; zinostatin stimalamer,
Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar
sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; imofosine; interleukin Il (including
recombinant interleukin II, or r1L.sub.2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1; interferon alfa-n3;
interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine;
mechlorethaminehydrochloride; megestrol acetate; melengestrol
acetate; melphalan; menogaril; mercaptopurine; methotrexate;
methotrexate sodium; metoprine; meturedepa; mitindomide;
mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin;
mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid;
nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;
peliomycin; pentamustine; peplomycin sulfate; perfosfamide;
pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin;
plomestane; porfimer sodium; porfiromycin; prednimustine;
procarbazine hydrochloride; puromycin; puromycin hydrochloride;
pyrazofurin; riboprine; rogletimide; safingol; safingol
hydrochloride; semustine; simtrazene; sparfosate sodium;
sparsomycin; spirogermanium hydrochloride; spiromustine;
spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;
tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone
acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
zinostatin; zorubicin hydrochloride, agents that arrest cells in
the G2-M phases and/or modulate the formation or stability of
microtubules, (e.g. Taxol.TM. (i.e. paclitaxel), Taxotere.TM.,
compounds comprising the taxane skeleton, Erbulozole (i.e.
R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128), Mivobulin
isethionate (i.e. as C1-980), Vincristine, NSC-639829,
Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e.
E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C),
Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3,
Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7,
Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e.
LU-103793 and NSC-D-669356), Epothilones (e.g. Epothilone A,
Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA),
Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothiloneB),
EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A
N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e.
BMS-310705), 21-hydroxyepothilone D (i.e. DesoxyepothiloneF and
dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663),
Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577),
LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559
(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358
(Daiichi), FR-182877 (Fujisawa, i.e. WS-9265B), GS-164 (Takeda),
GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651
(BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e.
AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062,
AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,
Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), T-138067
(Tularik, i.e. T-67, TL-138067 and TI-138067), COBRA-1 (Parker
Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State
University), H16 (Kansas State University), Oncocidin A1 (i.e.
BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide
B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker
Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai
School of Medicine, i.e. MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
i.e. MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e.
NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine),
A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781
(Aventis), Eleutherobins (such as Desmethyleleutherobin,
Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),
Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),
D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350
(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),
Diozostatin, (
-)-Phenylahistin (i.e. NSCL-96F037), D-62638 (Asta Medica), D-62636
(Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862),
A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase
inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as
goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone),
progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin
(BCG), levamisole, interleukin-2, alpha-interferon, etc.),
monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52,
anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins
(e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate,
anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate,
etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody
conjugated to .sup.111In .sup.90Y, .sup.131I, etc.), triptolide,
homoharringtonine, dactinomycin, doxorubicin, epirubicin,
topotecan, itraconazole, vindesine, cerivastatin, vincristine,
deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine,
5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,
gefitinib, EGFR inhibitors, epidermal growth factor receptor
(EGFR)-targeted therapy or therapeutic (e.g. gefitinib
(Iressa.TM.), erlotinib (Tarceva.TM.), cetuximab (Erbitux.TM.),
lapatinib (Tykerb.TM.), panitumumab (Vectibix.TM.), vandetanib
(Caprelsa.TM.), afatinib/BIBW2992, C1-1033/canertinib,
neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543,
ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl
erlotinib, AZD8931, AEE726, pelitinib/EKB-569, CUDC-101, WZ8040,
WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib,
imatinib, sunitinib, dasatinib, or the like.
[0097] "Chemotherapeutic" or "chemotherapeutic agent" is used in
accordance with its plain ordinary meaning and refers to a chemical
composition or compound having antineoplastic properties or the
ability to inhibit the growth or proliferation of cells.
[0098] Additionally, the compounds described herein can be
co-administered with conventional immunotherapeutic agents
including, but not limited to, immunostimulants (e.g., Bacillus
Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon,
etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2,
anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies),
immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin
conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin
conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20
monoclonal antibody conjugated to "In, 90-, Y or 13'I, etc.).
[0099] In a further embodiment, the compounds described herein can
be co-administered with conventional radiotherapeutic agents
including, but not limited to, radionuclides such as .sup.47Sc,
.sup.64Cu, .sup.67Cu, .sup.89Sr, .sup.86Y, .sup.87Y, .sup.90Y,
.sup.105Rh, .sup.111Ag, .sup.111In, .sup.117mSn, .sup.149Pm,
.sup.153Sm, .sup.166Ho, .sup.177Lu, .sup.186Re, .sup.126Re,
.sup.211At, and .sup.212Bi, optionally conjugated to antibodies
directed against tumor antigens.
I. Compositions
[0100] Provided herein are compounds, or pharmaceutically
acceptable salt thereof, having the formula:
##STR00002##
[0101] In the compound of formula (I), L is a bond, substituted or
unsubstituted alkylene, or substituted or unsubstituted
heteroalkylene. R.sup.1 is hydrogen, halogen, --CX.sup.1.sub.3,
--OCX.sup.1.sub.3, --CN, --OH, --NH.sub.2, --COOH, --C(O)OR.sup.4,
--CONH.sub.2, --NO.sub.2, --SH, --NHNH.sub.2, --NR.sup.2R.sup.3,
--OR.sup.4, --SR.sup.4, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. X.sup.1 is independently a halogen.
R.sup.2 and R.sup.3 are independently substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or R.sup.2 and R.sup.3 are optionally
joined together to form a substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted heteroaryl.
R.sup.4 is substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl.
R.sup.5 and R.sup.6 are independently hydrogen, halogen,
--CX.sup.2.sub.3, --OCX.sup.2.sub.3, --CN, --OH, --NH.sub.2,
--COOH, --C(O)OR.sup.9, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, --NR.sup.7R.sup.8, --OR.sup.9, --SR.sup.9,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.2 is
independently a halogen. R.sup.7 and R.sup.8 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl, or R.sup.7 and
R.sup.8 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.9 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl.
[0102] Provided herein are compounds, or pharmaceutically
acceptable salt thereof, having the formula:
##STR00003##
[0103] In the compound of formula (I), L is a bond or substituted
or unsubstituted alkylene. R.sup.1 is hydrogen, halogen,
--CX.sup.1.sub.3, --OCX.sup.1.sub.3, --CN, --OH, --NH.sub.2,
--COOH, --C(O)OR.sup.4, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, --NR.sup.2R.sup.3, --OR.sup.4, --SR.sup.4,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.1 is
independently a halogen. R.sup.2 and R.sup.3 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, or R.sup.2 and
R.sup.3 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.4 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. R.sup.5 and R.sup.6 are independently
hydrogen, halogen, --CX.sup.2.sub.3, --OCX.sup.2.sub.3, --CN, --OH,
--NH.sub.2, --COOH, --C(O)OR.sup.9, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, --NR.sup.7R.sup.8, --OR.sup.9, --SR.sup.9,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.2 is
independently a halogen. R.sup.7 and R.sup.8 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl, or R.sup.7 and
R.sup.8 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.9 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl.
[0104] In embodiments, L is substituted or unsubstituted alkylene.
L may be unsubstituted alkylene. L may be unsubstituted
C.sub.1-C.sub.8 alkylene. L may be unsubstituted C.sub.1-C.sub.4
alkylene. L may be unsubstituted C.sub.2 alkylene. L may be
unsubstituted methylene. In embodiments, Lisa bond. In embodiments,
L is independently a bond or R.sup.47-substituted or unsubstituted
alkylene.
[0105] R.sup.47 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.48-substituted or unsubstituted alkyl,
R.sup.48-substituted or unsubstituted heteroalkyl,
R.sup.48-substituted or unsubstituted cycloalkyl,
R.sup.48-substituted or unsubstituted heterocycloalkyl,
R.sup.48-substituted or unsubstituted aryl, or R.sup.48-substituted
or unsubstituted heteroaryl.
[0106] R.sup.48 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.49-substituted or unsubstituted alkyl,
R.sup.49-substituted or unsubstituted heteroalkyl,
R.sup.49-substituted or unsubstituted cycloalkyl,
R.sup.49-substituted or unsubstituted heterocycloalkyl,
R.sup.49-substituted or unsubstituted aryl, or R.sup.49-substituted
or unsubstituted heteroaryl.
[0107] In embodiments, R.sup.1 is halogen, --CX.sup.13,
--OCX.sup.13, --CN, --OH, --NH.sub.2, --COOH, --C(O)OR.sup.4,
--CONH.sub.2, --NO.sub.2, --SH, --NHNH.sub.2, --NR.sup.2R.sup.3,
--OR.sup.4, --SR.sup.4, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. In embodiments, X.sup.1 is
independently --F. In embodiments, X.sup.1 is independently --Cl.
In embodiments, X.sup.1 is independently --I. In embodiments,
X.sup.1 is independently --Br. In embodiments, R.sup.1 is
--NR.sup.2R.sup.3. In embodiments, R.sup.1 is substituted alkyl.
R.sup.1 may be substituted C.sub.1-C.sub.8 alkyl. In embodiments,
R.sup.1 is substituted C.sub.1-C.sub.4 alkyl. R.sup.1 may be
substituted ethyl. In embodiments, R.sup.1 is a substituted methyl.
In embodiments, R.sup.1 is not hydrogen.
[0108] In embodiments, R.sup.1 is independently hydrogen, halogen,
--CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --NHNH.sub.2, --OCF.sub.3, --OCHF.sub.2,
R.sup.20-substituted or unsubstituted alkyl, R.sup.20-substituted
or unsubstituted heteroalkyl, R.sup.20-substituted or unsubstituted
cycloalkyl, R.sup.20-substituted or unsubstituted heterocycloalkyl,
R.sup.20-substituted or unsubstituted aryl, or R.sup.20-substituted
or unsubstituted heteroaryl.
[0109] In embodiments, R.sup.1 is independently halogen,
--CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --NHNH.sub.2, --OCF.sub.3, --OCHF.sub.2,
R.sup.L0-substituted or unsubstituted alkyl, R.sup.20-substituted
or unsubstituted heteroalkyl, R.sup.20-substituted or unsubstituted
cycloalkyl, R.sup.20-substituted or unsubstituted heterocycloalkyl,
R.sup.20-substituted or unsubstituted aryl, or R.sup.20-substituted
or unsubstituted heteroaryl.
[0110] R.sup.20 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.21-substituted or unsubstituted alkyl,
R.sup.21-substituted or unsubstituted heteroalkyl,
R.sup.21-substituted or unsubstituted cycloalkyl,
R.sup.21-substituted or unsubstituted heterocycloalkyl,
R.sup.21-substituted or unsubstituted aryl, or R.sup.21-substituted
or unsubstituted heteroaryl.
[0111] R.sup.21-- is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.22-substituted or unsubstituted alkyl,
R.sup.22-substituted or unsubstituted heteroalkyl,
R.sup.22-substituted or unsubstituted cycloalkyl,
R.sup.22-substituted or unsubstituted heterocycloalkyl,
R.sup.22-substituted or unsubstituted aryl, or R.sup.22-substituted
or unsubstituted heteroaryl.
[0112] In embodiments, R.sup.2 is independently substituted or
unsubstituted alkyl. R.sup.2 may independently be substituted or
unsubstituted C.sub.1-C.sub.8 alkyl. R.sup.2 may independently be
substituted C.sub.1-C.sub.8 alkyl. R.sup.2 may independently be
unsubstituted C.sub.1-C.sub.8 alkyl. R.sup.2 may independently be
substituted or unsubstituted C.sub.1-C.sub.4 alkyl. R.sup.2 may
independently be substituted C.sub.1-C.sub.4 alkyl. R.sup.2 may
independently be unsubstituted C.sub.1-C.sub.4 alkyl. R.sup.2 may
independently be --OH substituted or unsubstituted C.sub.1-C.sub.4
alkyl. R.sup.2 may independently be substituted or unsubstituted
methyl. R.sup.2 may independently be substituted or unsubstituted
ethyl. R.sup.2 may independently be substituted or unsubstituted
propyl. In embodiments, R.sup.2 is independently
R.sup.23-substituted or unsubstituted alkyl, R.sup.23-substituted
or unsubstituted heteroalkyl, R.sup.23-substituted or unsubstituted
cycloalkyl, R.sup.23-substituted or unsubstituted heterocycloalkyl,
R.sup.23-substituted or unsubstituted aryl, or R.sup.23-substituted
or unsubstituted heteroaryl.
[0113] In embodiments, R.sup.2 is substituted or unsubstituted
C.sub.1-C.sub.20 alkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted C.sub.1-C.sub.20 alkyl. R.sup.2 may be substituted or
unsubstituted C.sub.1-C.sub.10 alkyl. R.sup.2 may be
R.sup.23-substituted or unsubstituted C.sub.1-C.sub.10 alkyl.
R.sup.2 may be substituted or unsubstituted C.sub.1-C.sub.8 alkyl.
R.sup.2 may be R.sup.23-substituted or unsubstituted
C.sub.1-C.sub.8 alkyl. R.sup.2 may be substituted or unsubstituted
C.sub.1-C.sub.5 alkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted C.sub.1-C.sub.8 alkyl.
[0114] In embodiments, R.sup.2 is substituted or unsubstituted 2 to
20 membered heteroalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 2 to 20 membered heteroalkyl. R.sup.2 may be
substituted or unsubstituted 2 to 10 membered heteroalkyl. R.sup.2
may be R.sup.23-substituted or unsubstituted 2 to 10 membered
heteroalkyl. R.sup.2 may be substituted or unsubstituted 2 to 8
membered heteroalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 2 to 8 membered heteroalkyl. R.sup.2 may be
substituted or unsubstituted 2 to 6 membered heteroalkyl. R.sup.2
may be R.sup.23-substituted or unsubstituted 2 to 6 membered
heteroalkyl.
[0115] In embodiments, R.sup.2 is substituted or unsubstituted 3 to
20 membered cycloalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 3 to 20 membered cycloalkyl. R.sup.2 may be
substituted or unsubstituted 3 to 10 membered cycloalkyl. R.sup.2
may be R.sup.23-substituted or unsubstituted 3 to 10 membered
cycloalkyl. R.sup.2 may be substituted or unsubstituted 3 to 8
membered cycloalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 3 to 8 membered cycloalkyl. R.sup.2 may be
substituted or unsubstituted 3 to 6 membered cycloalkyl. R.sup.2
may be R.sup.23-substituted or unsubstituted 3 to 6 membered
cycloalkyl. R.sup.2 may be substituted or unsubstituted 5 membered
cycloalkyl. R.sup.2 may be R.sup.23-substituted or unsubstituted 5
membered cycloalkyl. R.sup.2 may be substituted or unsubstituted 6
membered cycloalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 6 membered cycloalkyl.
[0116] In embodiments, R.sup.2 is substituted or unsubstituted 3 to
20 membered heterocycloalkyl. R.sup.2 may be R.sup.23-substituted
or unsubstituted 3 to 20 membered heterocycloalkyl. R.sup.2 may be
substituted or unsubstituted 3 to 10 membered heterocycloalkyl.
R.sup.2 may be R.sup.23-substituted or unsubstituted 3 to 10
membered heterocycloalkyl. R.sup.2 may be substituted or
unsubstituted 3 to 8 membered heterocycloalkyl. R.sup.2 may be
R.sup.23-substituted or unsubstituted 3 to 8 membered
heterocycloalkyl. R.sup.2 may be substituted or unsubstituted 3 to
6 membered heterocycloalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 3 to 6 membered heterocycloalkyl. R.sup.2 may be
substituted or unsubstituted 5 membered heterocycloalkyl. R.sup.2
may be R.sup.23-substituted or unsubstituted 5 membered
heterocycloalkyl. R.sup.2 may be substituted or unsubstituted 6
membered heterocycloalkyl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 6 membered heterocycloalkyl.
[0117] In embodiments, R.sup.2 is substituted or unsubstituted 5 to
10 membered aryl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 5 to 10 membered aryl. R.sup.2 may be substituted or
unsubstituted 5 to 8 membered aryl. R.sup.2 may be
R.sup.23-substituted or unsubstituted 5 to 8 membered aryl. R.sup.2
may be substituted or unsubstituted 6 membered aryl. R.sup.2 may be
R.sup.23-substituted or unsubstituted 6 membered aryl.
[0118] In embodiments, R.sup.2 is substituted or unsubstituted 5 to
10 membered heteroaryl. R.sup.2 may be R.sup.23-substituted or
unsubstituted 5 to 10 membered heteroaryl. R.sup.2 may be
substituted or unsubstituted 5 to 8 membered heteroaryl. R.sup.2
may be R.sup.23-substituted or unsubstituted 5 to 8 membered
heteroaryl. R.sup.2 may be substituted or unsubstituted 6 membered
heteroaryl. R.sup.2 may be R.sup.23-substituted or unsubstituted 6
membered heteroaryl.
[0119] R.sup.23 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.24-substituted or unsubstituted alkyl,
R.sup.24-substituted or unsubstituted heteroalkyl,
R.sup.24-substituted or unsubstituted cycloalkyl,
R.sup.24-substituted or unsubstituted heterocycloalkyl,
R.sup.24-substituted or unsubstituted aryl, or R.sup.24-substituted
or unsubstituted heteroaryl. R.sup.23 may independently be --OH.
R.sup.23 may independently be unsubstituted methyl. R.sup.23 may
independently be R.sup.24-substituted or unsubstituted heteroalkyl.
R.sup.23 may independently be R.sup.24-substituted or unsubstituted
alkyl. R.sup.23 may independently be R.sup.24-substituted or
unsubstituted C.sub.1-C.sub.4 alkyl.
[0120] R.sup.24 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.25-substituted or unsubstituted alkyl,
R.sup.25-substituted or unsubstituted heteroalkyl,
R.sup.25-substituted or unsubstituted cycloalkyl,
R.sup.25-substituted or unsubstituted heterocycloalkyl,
R.sup.25-substituted or unsubstituted aryl, or R.sup.25-substituted
or unsubstituted heteroaryl. R.sup.24 may independently be
--OH.
[0121] In embodiments, R.sup.3 is independently substituted or
unsubstituted alkyl. R.sup.3 may independently be substituted or
unsubstituted C.sub.1-C.sub.8 alkyl. R.sup.3 may independently be
substituted C.sub.1-C.sub.8 alkyl. R.sup.3 may independently be
unsubstituted C.sub.1-C.sub.8 alkyl. R.sup.3 may independently be
substituted or unsubstituted C.sub.1-C.sub.4 alkyl. R.sup.3 may
independently be substituted C.sub.1-C.sub.4 alkyl. R.sup.3 may
independently be unsubstituted C.sub.1-C.sub.4 alkyl. R.sup.3 may
independently be --OH substituted or unsubstituted C.sub.1-C.sub.4
alkyl. R.sup.3 may independently be substituted or unsubstituted
methyl. R.sup.3 may independently be substituted or unsubstituted
ethyl. R.sup.3 may independently be substituted or unsubstituted
propyl. In embodiments, R.sup.3 is independently
R.sup.26-substituted or unsubstituted alkyl, R.sup.26-substituted
or unsubstituted heteroalkyl, R.sup.26-substituted or unsubstituted
cycloalkyl, R.sup.26-substituted or unsubstituted heterocycloalkyl,
R.sup.26-substituted or unsubstituted aryl, or R.sup.26-substituted
or unsubstituted heteroaryl.
[0122] In embodiments, R.sup.3 is substituted or unsubstituted
C.sub.1-C.sub.20 alkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted C.sub.1-C.sub.20 alkyl. R.sup.3 may be substituted or
unsubstituted C.sub.1-C.sub.10 alkyl. R.sup.3 may be
R.sup.26-substituted or unsubstituted C.sub.1-C.sub.10 alkyl.
R.sup.3 may be substituted or unsubstituted C.sub.1-C.sub.8 alkyl.
R.sup.3 may be R.sup.26-substituted or unsubstituted
C.sub.1-C.sub.8 alkyl. R.sup.3 may be substituted or unsubstituted
C.sub.1-C.sub.8 alkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted C.sub.1-C.sub.8 alkyl.
[0123] In embodiments, R.sup.3 is substituted or unsubstituted 2 to
20 membered heteroalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 2 to 20 membered heteroalkyl. R.sup.3 may be
substituted or unsubstituted 2 to 10 membered heteroalkyl. R.sup.3
may be R.sup.26-substituted or unsubstituted 2 to 10 membered
heteroalkyl. R.sup.3 may be substituted or unsubstituted 2 to 8
membered heteroalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 2 to 8 membered heteroalkyl. R.sup.3 may be
substituted or unsubstituted 2 to 6 membered heteroalkyl. R.sup.3
may be R.sup.26-substituted or unsubstituted 2 to 6 membered
heteroalkyl.
[0124] In embodiments, R.sup.3 is substituted or unsubstituted 3 to
20 membered cycloalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 3 to 20 membered cycloalkyl. R.sup.3 may be
substituted or unsubstituted 3 to 10 membered cycloalkyl. R.sup.3
may be R.sup.26-substituted or unsubstituted 3 to 10 membered
cycloalkyl. R.sup.3 may be substituted or un substituted 3 to 8
membered cycloalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 3 to 8 membered cycloalkyl. R.sup.3 may be
substituted or unsubstituted 3 to 6 membered cycloalkyl. R.sup.3
may be R.sup.26-substituted or unsubstituted 3 to 6 membered
cycloalkyl. R.sup.3 may be substituted or unsubstituted 5 membered
cycloalkyl. R.sup.3 may be R.sup.26-substituted or unsubstituted 5
membered cycloalkyl. R.sup.3 may be substituted or unsubstituted 6
membered cycloalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 6 membered cycloalkyl.
[0125] In embodiments, R.sup.3 is substituted or unsubstituted 3 to
20 membered heterocycloalkyl. R.sup.3 may be R.sup.26-substituted
or unsubstituted 3 to 20 membered heterocycloalkyl. R.sup.3 may be
substituted or unsubstituted 3 to 10 membered heterocycloalkyl.
R.sup.3 may be R.sup.26-substituted or unsubstituted 3 to 10
membered heterocycloalkyl. R.sup.3 may be substituted or
unsubstituted 3 to 8 membered heterocycloalkyl. R.sup.3 may be
R.sup.26-substituted or unsubstituted 3 to 8 membered
heterocycloalkyl. R.sup.3 may be substituted or unsubstituted 3 to
6 membered heterocycloalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 3 to 6 membered heterocycloalkyl. R.sup.3 may be
substituted or unsubstituted 5 membered heterocycloalkyl. R.sup.3
may be R.sup.26-substituted or unsubstituted 5 membered
heterocycloalkyl. R.sup.3 may be substituted or unsubstituted 6
membered heterocycloalkyl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 6 membered heterocycloalkyl.
[0126] In embodiments, R.sup.3 is substituted or unsubstituted 5 to
10 membered aryl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 5 to 10 membered aryl. R.sup.3 may be substituted or
unsubstituted 5 to 8 membered aryl. R.sup.3 may be
R.sup.26-substituted or unsubstituted 5 to 8 membered aryl. R.sup.3
may be substituted or unsubstituted 6 membered aryl. R.sup.3 may be
R.sup.26-substituted or unsubstituted 6 membered aryl.
[0127] In embodiments, R.sup.3 is substituted or unsubstituted 5 to
10 membered heteroaryl. R.sup.3 may be R.sup.26-substituted or
unsubstituted 5 to 10 membered heteroaryl. R.sup.3 may be
substituted or unsubstituted 5 to 8 membered heteroaryl. R.sup.3
may be R.sup.26-substituted or unsubstituted 5 to 8 membered
heteroaryl. R.sup.3 may be substituted or unsubstituted 6 membered
heteroaryl. R.sup.3 may be R.sup.26-substituted or unsubstituted 6
membered heteroaryl.
[0128] R.sup.26 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.27-substituted or unsubstituted alkyl,
R.sup.27-substituted or unsubstituted heteroalkyl,
R.sup.27-substituted or unsubstituted cycloalkyl,
R.sup.27-substituted or unsubstituted heterocycloalkyl,
R.sup.27-substituted or unsubstituted aryl, or R.sup.27-substituted
or unsubstituted heteroaryl. R.sup.26 may independently be --OH.
R.sup.26 may independently be unsubstituted methyl. R.sup.23 may
independently be R.sup.24-substituted or unsubstituted heteroalkyl.
R.sup.26 may independently be R.sup.27-substituted or unsubstituted
alkyl. R.sup.26 may independently be R.sup.27-substituted or
unsubstituted C.sub.1-C.sub.4 alkyl.
[0129] R.sup.27 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.28-substituted or unsubstituted alkyl,
R.sup.28-substituted or unsubstituted heteroalkyl,
R.sup.28-substituted or unsubstituted cycloalkyl,
R.sup.28-substituted or unsubstituted heterocycloalkyl,
R.sup.28-substituted or unsubstituted aryl, or R.sub.28-substituted
or unsubstituted heteroaryl. R.sup.27 may independently be
--OH.
[0130] In embodiments, R.sup.2 and R.sup.3 are joined together to
form a substituted or unsubstituted heterocycloalkyl or substituted
or unsubstituted heteroaryl. R.sup.2 and R.sup.3 may be joined
together to form a substituted or unsubstituted heterocycloalkyl.
R.sup.2 and R.sup.3 may be joined together to form a substituted or
unsubstituted 3 to 8 membered heterocycloalkyl. R.sup.2 and R.sup.3
may be joined together to form a substituted 3 to 8 membered
heterocycloalkyl. R.sup.2 and R.sup.3 may be joined together to
form a substituted or unsubstituted 5 to 7 membered
heterocycloalkyl. R.sup.2 and R.sup.3 may be joined together to
form a substituted 5 to 7 membered heterocycloalkyl. R.sup.2 and
R.sup.3 may be joined together to form a substituted or
unsubstituted 4 membered heterocycloalkyl. R.sup.2 and R.sup.3 may
be joined together to form a substituted or unsubstituted 5
membered heterocycloalkyl. R.sup.2 and R.sup.3 may be joined
together to form a substituted or unsubstituted 6 membered
heterocycloalkyl.
[0131] R.sup.2 and R.sup.3 may be joined together to form a
R.sup.23-substituted or unsubstituted heterocycloalkyl. R.sup.2 and
R.sup.3 may be joined together to form a R.sup.23-substituted or
unsubstituted 5 to 7 membered heterocycloalkyl. R.sup.2 and R.sup.3
may be joined together to forma R.sup.23-substituted or
unsubstituted 4 membered heterocycloalkyl. R.sup.2 and R.sup.3 may
be joined together to form an R.sup.23-substituted or unsubstituted
5 to 7 membered heterocycloalkyl, wherein R.sup.23 is independently
a substituted or unsubstituted alkyl or substituted or
unsubstituted heteroalkyl. R.sup.2 and R.sup.3 may be joined
together to form an R.sup.23-substituted 5 to 7 membered
heterocycloalkyl, wherein R.sup.23 is independently a substituted
or unsubstituted C.sub.1-C.sub.8 alkyl or substituted or
unsubstituted 2 to 8 membered heteroalkyl.
[0132] In embodiments, R.sup.2 and R.sup.3 are joined together to
forma substituted or unsubstituted pyrrolidinyl. In embodiments,
R.sup.2 and R.sup.3 are joined together to form a substituted or
unsubstituted piperazinyl. In embodiments, R.sup.2 and R.sup.3 are
joined together to form a R.sup.23-substituted or unsubstituted
pyrrolidinyl. In embodiments, R.sup.2 and R.sup.3 are joined
together to form a R.sup.23-substituted or unsubstituted
piperazinyl. R.sup.23 is as described herein, including embodiments
thereof In embodiments, R.sup.2 and R.sup.3 are joined together to
form a R.sup.24-substituted or unsubstituted phthalimidyl.
[0133] In embodiments, R.sup.4 is independently
R.sup.29-substituted or unsubstituted alkyl, R.sup.29-substituted
or unsubstituted heteroalkyl, R.sup.29-substituted or unsubstituted
cycloalkyl, R.sup.29-substituted or unsubstituted heterocycloalkyl,
R.sup.29-substituted or unsubstituted aryl, or R.sup.29-substituted
or unsubstituted heteroaryl.
[0134] R.sup.29 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.30-substituted or unsubstituted alkyl,
Rao_substituted or unsubstituted heteroalkyl, R.sup.30-substituted
or unsubstituted cycloalkyl, R.sup.20-substituted or unsubstituted
heterocycloalkyl, R.sup.30-substituted or unsubstituted aryl, or
R.sup.31-substituted or unsubstituted heteroaryl.
[0135] R.sup.30 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.31-substituted or unsubstituted alkyl,
R.sup.31-substituted or unsubstituted heteroalkyl,
R.sup.31-substituted or unsubstituted cycloalkyl,
R.sup.2'-substituted or unsubstituted heterocycloalkyl,
R.sup.31-substituted or unsubstituted aryl, or R.sup.31-substituted
or unsubstituted heteroaryl.
[0136] R.sup.5 may independently be halogen, --CX.sup.23,
--OCX.sup.23, --CN, --OH, --NH.sub.2, --COOH, --C(O)OR.sup.9,
--CONH.sub.2, --NO.sub.2, --SH, --NHNH.sub.2, --NR.sup.7R.sup.8,
--OR.sup.9, --SR.sup.9, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. In embodiments, R.sup.5 is
independently --F. In embodiments, R.sup.5 is independently --Cl.
In embodiments, R.sup.5 is independently --I. In embodiments,
R.sup.5 is independently --Br. In embodiments, X.sup.2 is
independently --F. In embodiments, X.sup.2 is independently --Cl.
In embodiments, X.sup.2 is independently I. In embodiments, X.sup.2
is independently --Br. In embodiments, R.sup.5 is
--NR.sup.7R.sup.8.
[0137] In embodiments, R.sup.5 is --C(O)OCH.sub.3. In embodiments,
R.sup.5 is --OCH.sub.3. In embodiments, R.sup.5 is
--OCH(CH.sub.3).sub.2. In embodiments, R.sup.5 is --CN. In
embodiments, R.sup.5 is --NO.sub.2. In embodiments, R.sup.5 is
--NH.sub.2. In embodiments, R.sup.5 is halogen. In embodiments,
R.sup.5 is independently hydrogen. In embodiments, R.sup.5 is
independently unsubstituted methyl. In embodiments, R.sup.5 is
independently --OCF.sub.3. In embodiments, R.sup.5 is independently
--NHAc. In embodiments, R.sup.5 is independently --OH. In
embodiments, R.sup.5 is unsubstituted alkyl. R.sup.5 may be
unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.5 is
unsubstituted C.sub.1-C.sub.4 alkyl. R.sup.5 may be unsubstituted
ethyl. In embodiments, R.sup.5 is an unsubstituted methyl. In
embodiments, R.sup.5 is independently hydrogen, halogen,
--CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --NHNH.sub.2, --OCF.sub.3, --OCHF.sub.2,
R.sup.32-substituted or unsubstituted alkyl, R.sup.32-substituted
or unsubstituted heteroalkyl, R.sup.32-substituted or unsubstituted
cycloalkyl, R.sup.32-substituted or unsubstituted heterocycloalkyl,
R.sup.32-substituted or unsubstituted aryl, or R.sup.32-substituted
or unsubstituted heteroaryl. In embodiments, R.sup.5 is
independently halogen, --CF.sub.3, --CN, --OH, --NH.sub.2, --COOH,
--CONH.sub.2, --NO.sub.2, --SH, --NHNH.sub.2, --OCF.sub.3,
--OCHF.sub.2, R.sup.32-substituted or unsubstituted alkyl,
R.sup.32-substituted or unsubstituted heteroalkyl,
R.sup.32-substituted or unsubstituted cycloalkyl,
R.sup.32-substituted or unsubstituted heterocycloalkyl,
R.sup.32-substituted or unsubstituted aryl, or R.sup.32-substituted
or unsubstituted heteroaryl. In embodiments R.sup.5 is not
hydrogen.
[0138] Each R.sup.32 is independently oxo, halogen, --CF.sub.3,
--CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.23-substituted or unsubstituted alkyl,
R.sup.33-substituted or unsubstituted heteroalkyl,
R.sup.33-substituted or unsubstituted cycloalkyl,
R.sup.33-substituted or unsubstituted heterocycloalkyl,
R.sup.33-substituted or unsubstituted aryl, or R.sup.33-substituted
or unsubstituted heteroaryl.
[0139] Each R.sup.33 is independently oxo, halogen, --CF.sub.3,
--CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.34-substituted or unsubstituted alkyl,
R.sup.34-substituted or unsubstituted heteroalkyl,
R.sup.34-substituted or unsubstituted cycloalkyl,
R.sup.34-substituted or unsubstituted heterocycloalkyl,
R.sup.34-substituted or unsubstituted aryl, or R.sup.34-substituted
or unsubstituted heteroaryl.
[0140] R.sup.6 may independently be halogen, --CX.sup.23,
--OCX.sup.23, --CN, --OH, --NH.sub.2, --COOH, --C(O)OR.sup.9,
--CONH.sub.2, --NO.sub.2, --SH, --NHNH.sub.2, --NR.sup.7R.sup.8,
--OR.sup.9, --SR.sup.9, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. In embodiments, R.sup.6 is
independently --F. In embodiments, R.sup.6 is independently --Cl.
In embodiments, R.sup.6 is independently --I. In embodiments,
R.sup.6 is independently --Br. In embodiments, X.sup.2 is
independently --F. In embodiments, X.sup.2 is independently --Cl.
In embodiments, X.sup.2 is independently I. In embodiments, X.sup.2
is independently --Br. In embodiments, R.sup.6 is
--NR.sup.7R.sup.8.
[0141] In embodiments, R.sup.6 is --C(O)OCH.sub.3. In embodiments,
R.sup.6 is --OCH.sub.3. In embodiments, R.sup.6 is
--OCH(CH.sub.3).sub.2. In embodiments, R.sup.6 is --CN. In
embodiments, R.sup.6 is --NO.sub.2. In embodiments, R.sup.6 is
--NH.sub.2. In embodiments, R.sup.6 is halogen. In embodiments,
R.sup.6 is independently hydrogen. In embodiments, R.sup.6 is
independently unsubstituted methyl. In embodiments, R.sup.6 is
independently --OCF.sub.3. In embodiments, R.sup.6 is independently
--NHAc. In embodiments, R.sup.6 is independently --OH. In
embodiments, R.sup.6 is unsubstituted alkyl. R.sup.6 may be
unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.6 is
unsubstituted C.sub.1-C.sub.4 alkyl. R.sup.6 may be unsubstituted
ethyl. In embodiments, R.sup.6 is an unsubstituted methyl. In
embodiments, R.sup.6 is independently hydrogen, halogen,
--CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --NHNH.sub.2, --OCF.sub.3, --OCHF.sub.2,
R.sup.3-substituted or unsubstituted alkyl, R.sup.35-substituted or
unsubstituted heteroalkyl, R.sup.5-substituted or unsubstituted
cycloalkyl, R.sup.31-substituted or unsubstituted heterocycloalkyl,
R.sup.35-substituted or unsubstituted aryl, or R.sup.35-substituted
or unsubstituted heteroaryl. In embodiments, R.sup.6 is
independently halogen, --CF.sub.3, --CN, --OH, --NH.sub.2, --COOH,
--CONH.sub.2, --NO.sub.2, --SH, --NHNH.sub.2, --OCF.sub.3,
--OCHF.sub.2, R.sup.35-substituted or unsubstituted alkyl,
R.sup.5-substituted or unsubstituted heteroalkyl,
R.sup.35-substituted or unsubstituted cycloalkyl,
R.sup.31-substituted or unsubstituted heterocycloalkyl,
R.sup.35-substituted or unsubstituted aryl, or R.sup.5-substituted
or unsubstituted heteroaryl. In embodiments, R.sup.5 and R.sup.6
are independently hydrogen. In embodiments, R.sup.6 is not
hydrogen.
[0142] Each R.sup.35 is independently oxo, halogen, --CF.sub.3,
--CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.36-substituted or unsubstituted alkyl,
R.sup.36-substituted or unsubstituted heteroalkyl,
R.sup.36-substituted or unsubstituted cycloalkyl,
R.sup.36-substituted or unsubstituted heterocycloalkyl,
R.sup.36-substituted or unsubstituted aryl, or R.sup.36-substituted
or unsubstituted heteroaryl.
[0143] Each R.sup.36 is independently oxo, halogen, --CF.sub.3,
--CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.37-substituted or unsubstituted alkyl,
R.sup.37-substituted or unsubstituted heteroalkyl,
R.sup.37-substituted or unsubstituted cycloalkyl,
R.sup.37-substituted or unsubstituted heterocycloalkyl,
R.sup.37-substituted or unsubstituted aryl, or R.sup.37-substituted
or unsubstituted heteroaryl.
[0144] In embodiments, R.sup.7 is independently hydrogen, oxo,
halogen, --CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sup.2,
--NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H,
--SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2,
--NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH,
--OCF.sub.3, --OCHF.sub.2, R.sup.38-substituted or unsubstituted
alkyl, R.sup.38-substituted or unsubstituted heteroalkyl,
R.sup.38-substituted or unsubstituted cycloalkyl,
R.sup.38-substituted or unsubstituted heterocycloalkyl,
R.sup.38-substituted or unsubstituted aryl, or R.sup.38-substituted
or unsubstituted heteroaryl.
[0145] R.sup.38 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, --S(O).sub.2CHCH.sub.2, --NHS(O).sub.2CHCH.sub.2,
R.sup.39-substituted or unsubstituted alkyl, R.sup.39-substituted
or unsubstituted heteroalkyl, R.sup.39-substituted or unsubstituted
cycloalkyl, R.sup.39-substituted or unsubstituted heterocycloalkyl,
R.sup.39-substituted or unsubstituted aryl, or R.sup.39-substituted
or unsubstituted heteroaryl. R.sup.38 may independently be --OH.
R.sup.38 may independently be unsubstituted methyl. R.sup.38 may
independently be R.sup.39-substituted or unsubstituted heteroalkyl.
R.sup.38 may independently be R.sup.39-substituted or unsubstituted
alkyl. R.sup.38 may independently be R.sup.39-substituted or
unsubstituted C.sub.1-C.sub.4 alkyl.
[0146] R.sup.39 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, --S(O).sub.2CHCH.sub.2, --NHS(O).sub.2CHCH.sub.2,
R.sup.40-substituted or unsubstituted alkyl, R.sup.40-substituted
or unsubstituted heteroalkyl, R.sup.40-substituted or unsubstituted
cycloalkyl, R.sup.40-substituted or unsubstituted heterocycloalkyl,
R.sup.40-substituted or unsubstituted aryl, or R.sup.40-substituted
or unsubstituted heteroaryl.
[0147] In embodiments, R.sup.8 is independently hydrogen, oxo,
halogen, --CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H,
--SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2,
--NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH,
--OCF.sub.3, --OCHF.sub.2, R.sup.41-substituted or unsubstituted
alkyl, R.sup.41-substituted or unsubstituted heteroalkyl,
R.sup.41-substituted or unsubstituted cycloalkyl,
R.sup.41-substituted or unsubstituted heterocycloalkyl,
R.sup.41-substituted or unsubstituted aryl, or R.sup.41-substituted
or unsubstituted heteroaryl.
[0148] R.sup.41-- is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, --S(O).sub.2CHCH.sub.2, --NHS(O).sub.2CHCH.sub.2,
R.sup.42-substituted or unsubstituted alkyl, R.sup.42-substituted
or unsubstituted heteroalkyl, R.sup.42-substituted or unsubstituted
cycloalkyl, R.sup.42-substituted or unsubstituted heterocycloalkyl,
R.sup.42-substituted or unsubstituted aryl, or R.sup.42-substituted
or unsubstituted heteroaryl.
[0149] R.sup.42 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, --S(O)2CHCH.sub.2, --NHS(O).sub.2CHCH.sub.2,
R.sup.43-substituted or unsubstituted alkyl, R.sup.43-substituted
or unsubstituted heteroalkyl, R.sup.43-substituted or unsubstituted
cycloalkyl, R.sup.43-substituted or unsubstituted heterocycloalkyl,
R.sup.43-substituted or unsubstituted aryl, or R.sup.43-substituted
or unsubstituted heteroaryl.
[0150] In embodiments, R.sup.7 and R.sup.8 are joined together to
form a substituted or unsubstituted heterocycloalkyl or substituted
or unsubstituted heteroaryl. R.sup.7 and R.sup.8 may be joined
together to form a substituted or unsubstituted heterocycloalkyl.
R.sup.7 and R.sup.8 may be joined together to form a substituted or
unsubstituted 3 to 8 membered heterocycloalkyl. R.sup.7 and R.sup.8
may be joined together to form a substituted 3 to 8 membered
heterocycloalkyl. R.sup.7 and R.sup.8 may be joined together to
form a substituted or unsubstituted 5 to 7 membered
heterocycloalkyl. R.sup.7 and R.sup.8 may be joined together to
form a substituted 5 to 7 membered heterocycloalkyl. R.sup.7 and
R.sup.8 may be joined together to form an R.sup.38-substituted 5 to
7 membered heterocycloalkyl, wherein R.sup.38 is as described
herein above. R.sup.7 and R.sup.8 may be joined together to form an
R.sup.38-substituted 5 to 7 membered heterocycloalkyl, wherein
R.sup.38 is independently a substituted or unsubstituted alkyl or
substituted or unsubstituted heteroalkyl. R.sup.7 and R.sup.8 may
be joined together to form an R.sup.38-substituted 5 to 7 membered
heterocycloalkyl, wherein R.sup.38 is independently a substituted
or unsubstituted C.sub.1-C.sub.8 alkyl or substituted or
unsubstituted 2 to 8 membered heteroalkyl. R.sup.7 and R.sup.8 may
be joined together to form a substituted or unsubstituted
pyrrolidinyl. R.sup.7 and R.sup.8 may be joined together to form a
substituted or unsubstituted piperazinyl.
[0151] In embodiments, R.sup.9 is independently hydrogen, oxo,
halogen, --CF.sub.3, --CN, --OH, --NH.sub.2, --COOH, --CONH.sub.2,
--NO.sub.2, --SH, --SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H,
--SO.sub.2NH.sub.2, --NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2,
--NHC(O)NH.sub.2, --NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH,
--OCF.sub.3, --OCHF.sub.2, R.sup.44-substituted or unsubstituted
alkyl, R.sup.44-substituted or unsubstituted heteroalkyl,
R.sup.44-substituted or unsubstituted cycloalkyl,
R.sup.44-substituted or unsubstituted heterocycloalkyl,
R.sup.44-substituted or unsubstituted aryl, or R.sup.44-substituted
or unsubstituted heteroaryl.
[0152] R.sup.44 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.45-substituted or unsubstituted alkyl,
R.sup.45-substituted or unsubstituted heteroalkyl,
R.sup.45-substituted or unsubstituted cycloalkyl,
R.sup.45-substituted or unsubstituted heterocycloalkyl,
R.sup.45-substituted or unsubstituted aryl, or R.sup.45-substituted
or unsubstituted heteroaryl.
[0153] R.sup.45 is independently oxo, halogen, --CF.sub.3, --CN,
--OH, --NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH,
--SO.sub.2Cl, --SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2,
--NHNH.sub.2, --ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2,
--NHSO.sub.2H, --NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3,
--OCHF.sub.2, R.sup.6-substituted or unsubstituted alkyl,
R.sup.6-substituted or unsubstituted heteroalkyl,
R.sup.6-substituted or unsubstituted cycloalkyl,
R.sup.46-substituted or unsubstituted heterocycloalkyl,
R.sup.6-substituted or unsubstituted aryl, or R.sup.6-substituted
or unsubstituted heteroaryl.
[0154] Each R.sup.22, R.sup.25, R.sup.28, R.sup.31, R.sup.34,
R.sup.37, R.sup.40, R.sup.43, R.sup.46, and R.sup.49 is
independently hydrogen, oxo, halogen, --CF.sub.3, --CN, --OH,
--NH.sub.2, --COOH, --CONH.sub.2, --NO.sub.2, --SH, --SO.sub.2Cl,
--SO.sub.3H, --SO.sub.4H, --SO.sub.2NH.sub.2, --NHNH.sub.2,
--ONH.sub.2, --NHC(O)NHNH.sub.2, --NHC(O)NH.sub.2, --NHSO.sub.2H,
--NHC(O)H, --NHC(O)OH, --NHOH, --OCF.sub.3, --OCHF.sub.2,
unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or
unsubstituted heteroaryl.
[0155] In embodiments, the compound of formula (I) is a compound of
formula (II):
##STR00004##
[0156] The compounds, or pharmaceutically acceptable salts thereof,
provided herein, may include a protonated nitrogen cation. The
compounds, or pharmaceutically acceptable salts thereof, provided
herein, may include a plurality of protonated nitrogen cations.
[0157] In embodiments, the compound of formula (I) has the
formula:
##STR00005## ##STR00006## ##STR00007##
including pharmaceutically acceptable salts thereof.
[0158] In embodiments, the compound of formula (I) has the
formula:
##STR00008## ##STR00009## ##STR00010##
including pharmaceutically acceptable salts thereof
[0159] In embodiments, the compound has the formula 1276, or a
pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1277, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula 1278, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1279, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula 1280, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1281, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula 1282, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1283, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula 1284, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1285, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula 1286, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1287, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula 1288, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula 1289. In embodiments, the compound has the
formula 1501. In embodiments, the compound has the formula 1501p.
In embodiments, the compound has the formula 1502. In embodiments,
the compound has the formula 1502p. In embodiments, the compound
has the formula XNH5, or a pharmaceutically acceptable salt
thereof. In embodiments, the compound has the formula XNH6, or a
pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula XNH6p, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula XNH7, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula XNH7p, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula XNH9, or
a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula XNH9p, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula XNH10,
or a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula XNH10p, or a pharmaceutically acceptable
salt thereof. In embodiments, the compound has the formula XNH12,
or a pharmaceutically acceptable salt thereof. In embodiments, the
compound has the formula XNH12p, or a pharmaceutically acceptable
salt thereof.
[0160] In embodiments, a compound, or pharmaceutically acceptable
salts thereof, as described herein may include multiple instances
of R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.9, R.sup.20
to R.sup.49, X.sup.1, X.sup.2, and/or other variables. In such
embodiments, each variable may optional be different and be
appropriately labeled to distinguish each group for greater
clarity. For example, where each R.sup.2, R.sup.3, R.sup.4,
R.sup.7, R.sup.8, R.sup.9, R.sup.20 to R.sup.49, X.sup.1, or
X.sup.2, is different, they may be referred to, for example, as
R.sup.2.1, R.sup.2.2, R.sup.2.3, R.sup.2.4, R.sup.2.5, R.sup.2.6,
R.sup.2.7, R.sup.2.8, R.sup.2.9, R.sup.2.10, R.sup.2.11,
R.sup.2.12, R.sup.2.13, R.sup.2.14, R.sup.2.15, R.sup.2.16,
R.sup.2.17, R.sup.2.18, R.sup.2.19, R.sup.2.20, R.sup.2.21,
R.sup.2.22, R.sup.2.23, R.sup.2.24, R.sup.2.25, R.sup.2.26,
R.sup.2.27, R.sup.2.28, R.sup.2.29, R.sup.2.30, R.sup.2.31,
R.sup.2.32, R.sup.2.33, R.sup.2.34, R.sup.235, R.sup.2.36,
R.sup.2.37, R.sup.2.38, R.sup.2.39, R.sup.2.40, R.sup.2.41,
R.sup.2.42, R.sup.3.1, R.sup.3.2, R.sup.3.3, R.sup.3.4, R.sup.3.5,
R.sup.3.6, R.sup.3.7, R.sup.3.8, R.sup.3.9, R.sup.3.10, R.sup.3.11,
R.sup.3.12, R.sup.3.13, R.sup.3.14, R.sup.3.15, R.sup.3.16,
R.sup.3.17, R.sup.3.18, R.sup.3.19, R.sup.3.20, R.sup.3.21,
R.sup.3.22, R.sup.3.23, R.sup.3.24, R.sup.3.25, R.sup.3.26,
R.sup.3.27, R.sup.3.28, R.sup.3.29, R.sup.3.30, R.sup.3.31,
R.sup.3.32, R.sup.3.33, R.sup.3.34, R.sup.3.35, R.sup.3.36,
R.sup.3.37, R.sup.3.38, R.sup.3.39, R.sup.3.40, R.sup.3.41,
R.sup.3.42, R.sup.4.1, R.sup.4.2, R.sup.4.3, R.sup.4.4, R.sup.4.5,
R.sup.4.6, R.sup.4.7, R.sup.4.8, R.sup.4.9, R.sup.4.10, R.sup.4.11,
R.sup.4.12, R.sup.4.13, R.sup.4.14, R.sup.4.15, R.sup.4.16,
R.sup.4.17, R.sup.4.18, R.sup.4.19, R.sup.4.20, R.sup.4.21,
R.sup.4.22, R.sup.4.23, R.sup.4.24, R.sup.4.25, R.sup.4.26,
R.sup.4.27, R.sup.4.28, R.sup.4.29, R.sup.4.30, R.sup.4.31,
R.sup.4.32, R.sup.4.33, R.sup.4.34, R.sup.4.35, R.sup.4.36,
R.sup.4.37, R.sup.4.38, R.sup.4.39, R.sup.4.40, R.sup.4.41,
R.sup.4.42, R.sup.7.1, R.sup.7.2, R.sup.7.3, R.sup.7.4, R.sup.7.5,
R.sup.7.6, R.sup.7.7, R.sup.7.8, R.sup.7.9, R.sup.7.10, R.sup.7.11,
R.sup.7.12, R.sup.7.13, R.sup.7.14, R.sup.7.15, R.sup.7.16,
R.sup.7.17, R.sup.7.18, R.sup.7.19, R.sup.7.20, R.sup.7.21,
R.sup.7.22, R.sup.7.23, R.sup.7.24, R.sup.7.25, R.sup.7.26,
R.sup.7.27, R.sup.1.28, R.sup.7.29, R.sup.7.30, R.sup.7.31,
R.sup.7.32, R.sup.7.33, R.sup.7.34, R.sup.7.35, R.sup.7.36,
R.sup.7.37, R.sup.7.38, R.sup.7.39, R.sup.7.40, R.sup.7.41,
R.sup.7.42, R.sup.8.1, R.sup.8.2, R.sup.8.3, R.sup.8.4, R.sup.8.5,
R.sup.8.6, R.sup.8.7, R.sup.8.8, R.sup.8.9, R.sup.8.10, R.sup.8.11,
R.sup.8.12, R.sup.8.13, R.sup.8.14, R.sup.8.15, R.sup.8.16,
R.sup.8.17, R.sup.8.18, R.sup.8.19, R.sup.8.20, R.sup.8.21,
R.sup.8.22, R.sup.8.23, R.sup.8.24, R.sup.8.25, R.sup.8.26,
R.sup.8.27, R.sup.8.28, R.sup.8.29, R.sup.8.30, R.sup.8.31,
R.sup.8.32, R.sup.8.33, R.sup.8.34, R.sup.8.35, R.sup.8.36,
R.sup.8.37, R.sup.8.38, R.sup.8.39, R.sup.8.40, R.sup.8.41,
R.sup.8.42, R.sup.9.1, R.sup.9.2, R.sup.9.3, R.sup.9.4, R.sup.9.5,
R.sup.9.6, R.sup.9.7, R.sup.9.8, R.sup.9.9, R.sup.9.10, R.sup.9.11,
R.sup.9.12, R.sup.9.13, R.sup.9.14, R.sup.9.15, R.sup.9.16,
R.sup.9.17, R.sup.9.18, R.sup.9.19, R.sup.9.20, R.sup.9.21,
R.sup.9.22, R.sup.9.23, R.sup.9.24, R.sup.9.25, R.sup.9.26,
R.sup.9.27, R.sup.9.28, R.sup.9.29, R.sup.9.30, R.sup.9.31,
R.sup.9.32, R.sup.9.33, R.sup.9.34, R.sup.9.35, R.sup.9.36,
R.sup.9.37, R.sup.9.38, R.sup.9.39, R.sup.9.40, R.sup.9.41,
R.sup.9.42, R.sup.20.1 to R.sup.49.1, R.sup.20.2 to R.sup.49.2,
R.sup.20.3 to R.sup.49.3, R.sup.20.4 to R.sup.49.4, R.sup.20.5 to
R.sup.49.5, R.sup.20.6 to R.sup.49.6, R.sup.20.7 to R.sup.49.7,
R.sup.20.8 to R.sup.49.8, R.sup.20.9 to R.sup.49.9, R.sup.20.10 to
R.sup.49.10, R.sup.20.11 to R.sup.49.11, R.sup.20.12 to
R.sup.49.12, R.sup.20.13 to R.sup.49.13, R.sup.20.14 to
R.sup.49.14, R.sup.20.15 to R.sup.49.15, R.sup.20.16 to
R.sup.49.16, R.sup.20.17 to R.sup.49.17, R.sup.20.18 to
R.sup.49.18, R.sup.20.19 to R.sup.49.19, R.sup.20.20 to
R.sup.49.20, R.sup.20.21 to R.sup.49.21, R.sup.20.22 to
R.sup.49.22, R.sup.20.23 to R.sup.49.23, R.sup.20.24 to
R.sup.49.24, R.sup.20.25 to R.sup.49.25, R.sup.20.26 to
R.sup.49.26, R.sup.20.27 to R.sup.49.27, R.sup.20.28 to
R.sup.49.28, R.sup.20.29 to R.sup.49.29, R.sup.20.30 to
R.sup.49.30, R.sup.20.31 to R.sup.49.31, R.sup.20.32 to
R.sup.49.32, R.sup.20.33 to R.sup.49.33, R.sup.20.34 to
R.sup.49.34, R.sup.20.35 to R.sup.49.35, R.sup.20.36 to
R.sup.49.36, R.sup.20.37 to R.sup.49.37, R.sup.20.38 to
R.sup.49.38, R.sup.20.39 to R.sup.49.39, R.sup.20.40 to
R.sup.49.40, R.sup.20.41 to R.sup.49.41, R.sup.20.42 to
R.sup.49.42, X.sup.1.1, X.sup.1.2, X.sup.1.3, X.sup.1.4, X.sup.1.5,
X.sup.1.6, X.sup.1.7, X.sup.1.8, X.sup.1.9, X.sup.1.10, X.sup.1.11,
X.sup.1.12, X.sup.1.13, X.sup.1.14, X.sup.1.15, X.sup.1.16,
X.sup.1.17, X.sup.1.18, X.sup.1.19, X.sup.1.20, X.sup.1.21,
X.sup.1.22, X.sup.1.23, X.sup.1.24, X.sup.1.25, X.sup.1.26,
X.sup.1.27, X.sup.1.28, X.sup.1.29, X.sup.1.30, X.sup.1.31,
X.sup.1.32, X.sup.1.33, X.sup.1.34, X.sup.1.35, X.sup.1.36,
X.sup.1.37, X.sup.1.38, X.sup.1.39, X.sup.1.40, X.sup.1.41,
X.sup.1.42, X.sup.2.1, X.sup.2.2, X.sup.2.3, X.sup.2.4, X.sup.2.5,
X.sup.2.6, X.sup.2.7, X.sup.2.8, X.sup.2.9, X.sup.2.10, X.sup.2.11,
X.sup.2.12, X.sup.2.13, X.sup.2.14, X.sup.2.15, X.sup.2.16,
X.sup.2.17, X.sup.2.18, X.sup.2.19, X.sup.2.20, X.sup.2.21,
X.sup.2.22, X.sup.2.23, X.sup.2.24, X.sup.2.25, X.sup.2.26,
X.sup.2.27, X.sup.2.28, X.sup.2.29, X.sup.2.30, X.sup.2.31,
X.sup.2.32, X.sup.2.33, X.sup.2.34, X.sup.2.35, X.sup.2.36,
X.sup.2.37, X.sup.2.38, X.sup.2.39, X.sup.2.40, X.sup.2.41,
X.sup.2.42, respectively, wherein the definition of R.sup.2 is
assumed by R.sup.2.1, R.sup.2.2, R.sup.2.3, R.sup.2.4, R.sup.2.5,
R.sup.2.6, R.sup.2.7, R.sup.2.8, R.sup.2.9, R.sup.2.10, R.sup.2.11,
R.sup.2.12, R.sup.2.13, R.sup.2.14, R.sup.2.15, R.sup.2.16,
R.sup.2.17, R.sup.2.18, R.sup.2.19, R.sup.2.20, R.sup.2.21,
R.sup.2.22, R.sup.2.23, R.sup.2.24, R.sup.2.25, R.sup.2.26,
R.sup.2.27, R.sup.2.28, R.sup.2.29, R.sup.2.30, R.sup.2.31,
R.sup.2.32, R.sup.2.33, R.sup.2.34, R.sup.2.35, R.sup.2.36,
R.sup.2.37, R.sup.2.38, R.sup.2.39, R.sup.2.40, R.sup.2.41,
R.sup.2.42, the definition of R.sup.3 is assumed by R.sup.3.1,
R.sup.3.2, R.sup.3.3, R.sup.3.4, R.sup.3.5, R.sup.3.6, R.sup.3.7,
R.sup.3.8, R.sup.3.9, R.sup.3.10, R.sup.3.11, R.sup.3.12,
R.sup.3.13, R.sup.3.14, R.sup.3.15, R.sup.3.16, R.sup.3.17,
R.sup.3.18, R.sup.3.19, R.sup.3.20, R.sup.3.21, R.sup.3.22,
R.sup.3.23, R.sup.3.24, R.sup.3.25, R.sup.3.26, R.sup.3.27,
R.sup.3.28, R.sup.3.29, R.sup.3.30, R.sup.3.31, R.sup.3.32,
R.sup.3.33, R.sup.3.34, R.sup.3.35, R.sup.3.36, R.sup.3.37,
R.sup.3.38, R.sup.3.39, R.sup.3.40, R.sup.3.41, R.sup.3.42, the,
definition of R.sup.4 is assumed by R.sup.4.1, R.sup.4.2,
R.sup.4.3, R.sup.4.4, R.sup.4.5, R.sup.4.6, R.sup.4.7, R.sup.4.8,
R.sup.4.9, R.sup.4.10, R.sup.4.11, R.sup.4.12, R.sup.4.13,
R.sup.4.14, R.sup.4.15, R.sup.4.16, R.sup.4.17, R.sup.4.18,
R.sup.4.19, R.sup.4.20, R.sup.4.21, R.sup.4.22, R.sup.4.23,
R.sup.4.24, R.sup.4.25, R.sup.4.26, R.sup.4.27, R.sup.4.28,
R.sup.4.29, R.sup.4.30, R.sup.4.31, R.sup.4.32, R.sup.4.33,
R.sup.4.34, R.sup.4.35, R.sup.4.36, R.sup.4.37, R.sup.4.38,
R.sup.4.39, R.sup.4.40, R.sup.4.41, R.sup.4.42, the definition of
R.sup.7 is assumed by R.sup.7.1, R.sup.7.2, R.sup.7.3, R.sup.7.4,
R.sup.7.5, R.sup.7.6, R.sup.7.7, R.sup.7.8, R.sup.7.9, R.sup.7.10,
R.sup.7.11, R.sup.7.12, R.sup.7.13, R.sup.7.14, R.sup.7.15,
R.sup.7.16, R.sup.7.17, R.sup.7.18, R.sup.7.19, R.sup.7.20,
R.sup.7.21, R.sup.7.22, R.sup.7.23, R.sup.7.24, R.sup.7.25,
R.sup.7.26, R.sup.7.27, R.sup.7.28, R.sup.7.29, R.sup.7.30,
R.sup.7.31, R.sup.7.32, R.sup.7.33, R.sup.7.34, R.sup.7.35,
R.sup.7.36, R.sup.7.37, R.sup.7.38, R.sup.7.39, R.sup.7.40,
R.sup.7.41, R.sup.7.42, the definition of R.sup.8 is assumed by
R.sup.8.1, R.sup.8.2, R.sup.8.3, R.sup.8.4, R.sup.8.5, R.sup.8.6,
R.sup.8.7, R.sup.8.8, R.sup.8.9, R.sup.8.10, R.sup.8.11,
R.sup.8.12, R.sup.8.13, R.sup.8.14, R.sup.8.15, R.sup.8.16,
R.sup.8.17, R.sup.8.18, R.sup.8.19, R.sup.8.20, R.sup.8.21,
R.sup.8.22, R.sup.8.23, R.sup.8.24, R.sup.8.25, R.sup.8.26,
R.sup.8.27, R.sup.8.28, R.sup.8.29, R.sup.8.30, R.sup.8.31,
R.sup.8.32, R.sup.8.33, R.sup.8.34, R.sup.8.35, R.sup.8.36,
R.sup.8.37, R.sup.8.38, R.sup.8.39, R.sup.8.40, R.sup.8.41,
R.sup.8.42, the definition of R.sup.9 is assumed by R.sup.9.1,
R.sup.9.2, R.sup.9.3, R.sup.9.4, R.sup.9.5, R.sup.9.6, R.sup.9.7,
R.sup.9.8, R.sup.9.9, R.sup.9.10, R.sup.9.11, R.sup.9.12,
R.sup.9.13, R.sup.9.14, R.sup.9.15, R.sup.9.16, R.sup.9.17,
R.sup.9.18, R.sup.9.19, R.sup.9.20, R.sup.9.21, R.sup.9.22,
R.sup.9.23, R.sup.9.24, R.sup.9.25, R.sup.9.26, R.sup.9.27,
R.sup.9.28, R.sup.9.29, R.sup.9.30, R.sup.9.31, R.sup.9.32,
R.sup.9.33, R.sup.9.34, R.sup.9.35, R.sup.9.36, R.sup.9.37,
R.sup.9.38, R.sup.9.39, R.sup.9.40, R.sup.9.41, R.sup.9.42, the,
definitions of R.sup.20 to R.sup.49 are assumed by R.sup.20.1 to
R.sup.49.1, R.sup.20.2 to R.sup.49.2, R.sup.20.3 to R.sup.49.3,
R.sup.20.4 to R.sup.49.4, R.sup.20.5 to R.sup.49.5, R.sup.20.6 to
R.sup.49.6, R.sup.20.7 to R.sup.49.7, R.sup.20.8 to R.sup.49.8,
R.sup.20.9 to R.sup.49.9, R.sup.20.10 to R.sup.49.10, R.sup.20.11
to R.sup.49.11, R.sup.20.12 to R.sup.49.12, R.sup.20.13 to
R.sup.49.13, R.sup.20.14 to R.sup.49.14, R.sup.20.15 to
R.sup.49.15, R.sup.20.16 to R.sup.49.16, R.sup.20.17 to
R.sup.49.17, R.sup.20.18 to R.sup.49.18, R.sup.20.19 to
R.sup.49.19, R.sup.20.20 to R.sup.49.20, R.sup.20.21 to
R.sup.49.21, R.sup.20.22 to R.sup.49.22, R.sup.20.23 to
R.sup.49.23, R.sup.20.24 to R.sup.49.24, R.sup.20.25 to
R.sup.49.25, R.sup.20.26 to R.sup.49.26, R.sup.20.27 to
R.sup.49.27, R.sup.20.28 to R.sup.49.28, R.sup.20.29 to
R.sup.49.29, R.sup.20.30 to R.sup.49.30, R.sup.20.31 to
R.sup.49.31, R.sup.20.32 to R.sup.49.32, R.sup.20.33 to
R.sup.49.33, R.sup.20.34 to R.sup.49.34, R.sup.20.35 to
R.sup.49.35, R.sup.20.36 to R.sup.49.36, R.sup.20.37 to
R.sup.49.37, R.sup.20.38 to R.sup.49.38, R.sup.20.39 to
R.sup.49.39, R.sup.20.40 to R.sup.49.40, R.sup.20.41 to
R.sup.49.41, R.sup.20.42 to R.sup.49.42, the definition of X.sup.1
is assumed by X.sup.1.1, X.sup.1.2, X.sup.1.3, X.sup.1.4,
X.sup.1.5, X.sup.1.6, X.sup.1.7, X.sup.1.8, X.sup.1.9, X.sup.1.10,
X.sup.1.11, X.sup.1.12, X.sup.1.13, X.sup.1.14, X.sup.1.15,
X.sup.1.16, X.sup.1.17, X.sup.1.18, X.sup.1.19, X.sup.1.20,
X.sup.1.21, X.sup.1.22, X.sup.1.23, X.sup.1.24, X.sup.1.25,
X.sup.1.26, X.sup.1.27, X.sup.1.28, X.sup.1.29, X.sup.1.30,
X.sup.1.31, X.sup.1.32, X.sup.1.33, X.sup.1.34, X.sup.1.35,
X.sup.1.36, X.sup.1.37, X.sup.1.38, X.sup.1.39, X.sup.1.40,
X.sup.1.41, X.sup.1.42, the definition of X.sup.2 is assumed by
X.sup.2.1, X.sup.2.2, X.sup.2.3, X.sup.2.4, X.sup.2.5, X.sup.2.6,
X.sup.2.7, X.sup.2.8, X.sup.2.9, X.sup.2.10, X.sup.2.11,
X.sup.2.12, X.sup.2.13, X.sup.2.14, X.sup.2.15, X.sup.2.16,
X.sup.2.17, X.sup.2.18, X.sup.2.19, X.sup.2.20, X.sup.2.21,
X.sup.2.22, X.sup.2.23, X.sup.2.24, X.sup.2.25, X.sup.2.26,
X.sup.2.27, X.sup.2.28, X.sup.2.29, X.sup.2.30, X.sup.2.31,
X.sup.2.32, X.sup.2.33, X.sup.2.34, X.sup.2.35, X.sup.2.36,
X.sup.2.37, X.sup.2.38, X.sup.2.39, X.sup.2.40, X.sup.2.41,
X.sup.2.42.
[0161] The variables used within a definition of R.sup.2, R.sup.3,
R.sup.4, R.sup.7, R.sup.8, R.sup.9, R.sup.20 to R.sup.49, X.sup.2
and/or other variables that appear at multiple instances and are
different may similarly be appropriately labeled to distinguish
each group for greater clarity.
[0162] Further provided herein is a pharmaceutical composition
including a pharmaceutically acceptable excipient and a compound,
or pharmaceutically acceptable salt thereof, as described herein
(e.g. a compound of formula (I) or (II), including embodiments
thereof). In embodiments, the pharmaceutical composition includes a
compound, or pharmaceutically acceptable salt thereof, as described
herein (e.g. a compound of formula (I) or (II), including
embodiments thereof) in a therapeutically effective amount. In
embodiments, the pharmaceutical composition includes a second agent
(e.g. therapeutic agent). In embodiments, the pharmaceutical
composition includes a second agent (e.g. therapeutic agent) in a
therapeutically effective amount. In embodiments, the second agent
(e.g. therapeutic agent) is an anti-cancer agent. In embodiments,
the second agent (e.g. therapeutic agent) is a chemotherapeutic
agent.
II. Methods of Treatment
[0163] Also provided herein is a method of treating cancer in a
subject in need thereof by administering an effective amount of a
compound, or pharmaceutically acceptable salt thereof, as described
herein, including embodiments thereof, to the subject. The compound
may be administered as described herein, including embodiments,
thereof. The method may include co-administering an effective
amount of an anti-cancer agent as described herein. In embodiments,
the anti-cancer agent is a chemotherapeutic agent.
[0164] The cancer may be, for example, lung cancer, breast cancer,
ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer,
sarcoma, bladder cancer, bone cancer, brain cancer, cervical
cancer, colon cancer, esophageal cancer, gastric cancer, liver
cancer, head and neck cancer, kidney cancer, myeloma, thyroid
cancer, or prostate cancer. The method of treating cancer may be a
method of treating lung cancer. The method of treating cancer may
be a method of treating breast cancer. The method of treating
cancer may be a method of treating ovarian cancer. The method of
treating cancer may be a method of treating lymphoma. The method of
treating cancer may be a method of treating pancreatic cancer. The
method of treating cancer may be a method of treating melanoma. The
method of treating cancer may be a method of treating prostate
cancer. The method of treating cancer may be a method of treating
sarcoma. The method of treating cancer may be a method of treating
bladder cancer. The method of treating cancer may be a method of
treating bone cancer. The method of treating cancer may be a method
of treating brain cancer. The method of treating cancer may be a
method of treating cervical cancer. The method of treating cancer
may be a method of treating colon cancer. The method of treating
cancer may be a method of treating esophageal cancer. The method of
treating cancer may be a method of treating gastric cancer. The
method of treating cancer may be a method of treating liver cancer.
The method of treating cancer may be a method of treating head and
neck cancer. The method of treating cancer may be a method of
treating kidney cancer. The method of treating cancer may be a
method of treating myeloma. The method of treating cancer may be a
method of treating multiple myeloma. The method of treating cancer
may be a method of treating thyroid cancer. In embodiments, the
compounds set forth herein are provided as pharmaceutical
compositions including the compound and a pharmaceutically
acceptable excipient.
[0165] Also provided herein are methods of modulating the level,
activity, or function of a protein associated with a disease (e.g.
cancer). The method includes contacting the protein with an
effective amount of a compound, or pharmaceutically acceptable salt
thereof, as described herein, including embodiments thereof.
[0166] In embodiments, the method of modulation includes
administering an effective amount of a compound, or
pharmaceutically acceptable salt thereof, as described herein
including embodiments thereof. In embodiments, the protein is
selected from the group consisting of a JAK, JAK2, TYK2, c-Src,
ABL1, T315I mutant ABL1, Aurora A, GSK-3.beta., CDK, a STAT, and
STAT3. The protein may be a JAK. The protein may be Src. The
protein may be GSK-3.beta.. The protein may be a CDK. The protein
may be STAT3. In embodiments, the method of modulation includes
modulating different proteins (e.g. kinases). In embodiments, the
method of modulation includes modulating two, three, four, five, or
six proteins (e.g. kinases).
[0167] The method may include modulating the level (e.g. amount) of
a protein associated with a disease (e.g. cancer). The method may
include modulating the activity of a protein associated with a
disease (e.g. cancer). The method may include modulating function
of a protein associated with a disease (e.g. cancer). In
embodiments, modulating is inhibiting and the compound, or
pharmaceutically acceptable salt thereof, as described herein
(including embodiments) is an inhibitor. In embodiments, the
compounds set forth herein are provided as pharmaceutical
compositions including the compound and a pharmaceutically
acceptable excipient.
III. Embodiments
[0168] Embodiment P1 A compound, or pharmaceutically acceptable
salt thereof, having the formula:
##STR00011##
L is a bond or substituted or unsubstituted alkylene. R.sup.1 is
hydrogen, halogen, --CX.sup.1.sub.3, --OCX.sup.1.sub.3, --CN, --OH,
--NH.sub.2, --C(O)OH, --C(O)OR.sup.4, --CONH.sub.2, --NO.sub.2,
--SH, --NHNH.sub.2, --NR.sup.2R.sup.3, --OR.sup.4, --SR.sup.4,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.1 is
independently a halogen. R.sup.2 and R.sup.3 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl, wherein R.sup.2
and R.sup.3 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.4 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. R.sup.5 and R.sup.6 are independently
hydrogen, halogen, --CX.sup.2.sub.3, --OCX.sup.2.sub.3, --CN, --OH,
--NH.sub.2, --C(O)OH, --C(O)OR.sup.9, --CONH.sub.2, --NO.sub.2,
--SH, --NHNH.sub.2, --NR.sup.7R.sup.8, --OR.sup.9, --SR.sup.9,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.2 is
independently a halogen. R.sup.7 and R.sup.8 are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl, wherein R.sup.7
and R.sup.8 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. and R.sup.9 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl.
[0169] Embodiment P2 The compound of embodiment 1, wherein R.sup.3
and R.sup.6 are hydrogen.
[0170] Embodiment P3 The compound of any one of embodiments 1 to 2,
wherein L is unsubstituted alkylene.
[0171] Embodiment P4 The compound of any one of embodiments 1 to 3,
wherein L is unsubstituted C.sub.1-C.sub.8 alkylene.
[0172] Embodiment P5 The compound of any one of embodiments 1 to 4,
wherein L is unsubstituted C.sub.1-C.sub.4 alkylene.
[0173] Embodiment P6 The compound of any one of embodiments 2 to 5,
wherein L is unsubstituted C.sub.2 alkylene.
[0174] Embodiment P7 The compound of embodiment 1, wherein L is a
bond.
[0175] Embodiment P8 The compound of any one of embodiments 1 to 7,
wherein R.sup.1 is halogen, --CX.sub.3, --OCX.sub.3, --CN, --OH,
--NH.sub.2, --C(O)OH, --C(O)OR.sup.4, --CONH.sub.2, --NO.sub.2,
--SH, --NHNH.sub.2, --NR.sup.2R.sup.3, --OR.sup.4, --SR.sup.4,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl.
[0176] Embodiment P9 The compound of any one of embodiments 1 to 8,
wherein R.sup.1 is --NR.sup.2R.sup.3.
[0177] Embodiment P10 The compound of any one of embodiments 1 to
9, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
or substituted or unsubstituted heteroaryl.
[0178] Embodiment P11 The compound of any one of embodiments 1 to
10, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted alkyl.
[0179] Embodiment P12 The compound of any one of embodiments 1 to
11, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted C.sub.1-C.sub.8 alkyl.
[0180] Embodiment P13 The compound of any one of embodiments 11 to
12, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted C.sub.1-C.sub.4 alkyl.
[0181] Embodiment P14 The compound of anyone of embodiments 1 to
13, wherein R.sup.2 and R.sup.3 are independently --OH substituted
or unsubstituted C.sub.1-C.sub.4 alkyl.
[0182] Embodiment P15 The compound of anyone of embodiments 1 to
15, wherein R.sup.2 and R.sup.3 are independently unsubstituted
C.sub.1-C.sub.4 alkyl.
[0183] Embodiment P16 The compound of anyone of embodiments 1 to 9,
wherein R.sup.2 and R.sup.3 are joined together to form a
substituted or unsubstituted heterocycloalkyl or substituted or
unsubstituted heteroaryl.
[0184] Embodiment P17 The compound of embodiment 16, wherein
R.sup.2 and R.sup.3 are joined together to form a substituted or
unsubstituted heterocycloalkyl.
[0185] Embodiment P18 The compound of any one of embodiments 16 to
17, wherein R.sup.2 and R.sup.3 are joined together to form a
substituted or unsubstituted C.sub.5-C.sub.7 heterocycloalkyl.
[0186] Embodiment P19 The compound of any one of embodiments 16 to
19, wherein R.sup.2 and R.sup.3 are joined together to form a
substituted C.sub.5-C.sub.7 heterocycloalkyl.
[0187] Embodiment P20 The compound of any one of embodiments 16 to
19, wherein R.sup.2 and R.sup.3 are joined together to form an
R.sup.23-substituted C.sub.5-C.sub.7 heterocycloalkyl, wherein
R.sup.23 is independently a substituted or unsubstituted alkyl or
substituted or unsubstituted heteroalkyl.
[0188] Embodiment P21 The compound of embodiment 20, wherein
R.sup.23 is independently a substituted or unsubstituted
C.sub.1-C.sub.5 alkyl or substituted or unsubstituted 2 to 8
membered heteroalkyl.
[0189] Embodiment P22 The compound of any one of embodiments 16 to
18, wherein R.sup.2 and Ware joined together to form a substituted
or unsubstituted pyrrolidinyl.
[0190] Embodiment P23 The compound of any one of embodiments 16 to
18, wherein R.sup.2 and R.sup.3 are joined together to form a
substituted or unsubstituted piperazinyl.
[0191] Embodiment P24 The compound of any one of embodiments 1 to
23 comprising a protonated nitrogen cation.
[0192] Embodiment P25 The compound of anyone of embodiments 1 to 24
comprising a plurality of protonated nitrogen cations.
[0193] Embodiment P26 A pharmaceutical composition comprising a
pharmaceutically acceptable excipient and a compound of any one of
embodiments 1 to 25.
[0194] Embodiment P27 A method of treating cancer in a subject in
need thereof, the method comprising administering an effective
amount of a compound of any one of embodiments 1 to 25.
[0195] Embodiment P28 The method of embodiment 27, wherein the
compound is in a pharmaceutical composition comprising a
pharmaceutically acceptable excipient.
[0196] Embodiment P29 The method of any one of embodiments 27 to
28, wherein the cancer is lung cancer, breast cancer, ovarian
cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma,
bladder cancer, bone cancer, brain cancer, cervical cancer, colon
cancer, esophageal cancer, gastric cancer, liver cancer, head and
neck cancer, kidney cancer, myeloma, thyroid cancer, or prostate
cancer.
[0197] Embodiment P30 The method of any one of embodiments 27 to
29, comprising co-administering an effective amount of an
anti-cancer agent.
[0198] Embodiment P31 A method of modulating a kinase, a JAK, JAK2,
TYK2, Src, c-Src, ABL1, ABL1 T315I, an Aurora kinase, Aurora A,
GSK-3.beta., a CDK, a STAT, or STAT3, the method comprising
contacting the protein with the compound of any one of embodiments
1 to 25.
[0199] Embodiment P32 The method of embodiment 31, wherein the
compound is in a pharmaceutical composition comprising a
pharmaceutically acceptable excipient.
[0200] Embodiment P33 A method of modulating a Janus kinase, the
method comprising contacting the Janus kinase with the compound of
any one of embodiments 1 to 25.
[0201] Embodiment P34 The method of embodiment 33, wherein the
compound is in a pharmaceutical composition comprising a
pharmaceutically acceptable excipient.
[0202] Embodiment 1 A compound, or pharmaceutically acceptable salt
thereof, having the formula:
##STR00012##
Wherein L is a bond or substituted or unsubstituted alkylene.
R.sup.1 is hydrogen, halogen, --CX.sup.1.sub.3, --OCX.sup.1.sub.3,
--CN, --OH, --NH.sub.2, --COOH, --C(O)OR.sup.4, --CONH.sub.2,
--NO.sub.2, --SH, NHNH.sub.2, --NR.sup.2R.sup.3, --OR.sup.4,
--SR.sup.4, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl.
X.sup.1 is independently a halogen. R.sup.2 and R.sup.3 are
independently substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl,
wherein R.sup.2 and R.sup.3 are optionally joined together to form
a substituted or unsubstituted heterocycloalkyl or substituted or
unsubstituted heteroaryl. R.sup.4 is substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. R.sup.5 and R.sup.6 are independently
hydrogen, halogen, --CX.sup.2.sub.3, --OCX.sup.2.sub.3, --CN, --OH,
--NH.sub.2, --COOH, --C(O)OR.sup.9, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, --NR.sup.7R.sup.8, --OR.sup.9, --SR.sup.9,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl. X.sup.2 is
independently a halogen. R.sup.7 and le are independently
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted heteroaryl, wherein R.sup.7
and R.sup.8 are optionally joined together to form a substituted or
unsubstituted heterocycloalkyl or substituted or unsubstituted
heteroaryl. R.sup.9 is substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl.
[0203] Embodiment 2 The compound of embodiment 1, wherein R.sup.5
and R.sup.6 are hydrogen.
[0204] Embodiment 3 The compound of any one of embodiments 1 to 2,
wherein L is unsubstituted alkylene.
[0205] Embodiment 4 The compound of any one of embodiments 1 to 3,
wherein Lis unsubstituted C.sub.1-C.sub.8 alkylene.
[0206] Embodiment 5 The compound of any one of embodiments 1 to 4,
wherein L is unsubstituted C.sub.1-C.sub.4 alkylene.
[0207] Embodiment 6 The compound of any one of embodiments 1 to 5,
wherein L is unsubstituted C.sub.2 alkylene.
[0208] Embodiment 7 The compound of embodiments 1 to 6, wherein L
is a bond.
[0209] Embodiment 8 The compound of any one of embodiments 1 to 7,
wherein R.sup.1 is halogen, --CX.sub.3, --OCX.sub.3, --CN, --OH,
--NH.sub.2, --COOH, --C(O)OR.sup.4, --CONH.sub.2, --NO.sub.2, --SH,
--NHNH.sub.2, --NR.sup.2R.sup.3, --OR.sup.4, --SR.sup.4 substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
or substituted or unsubstituted heteroaryl.
[0210] Embodiment 9 The compound of any one of embodiments 1 to 8,
wherein R.sup.1 is --NR.sup.2R.sup.3.
[0211] Embodiment 10 The compound of any one of embodiments 1 to 9,
wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
or substituted or unsubstituted heteroaryl.
[0212] Embodiment 11 The compound of any one of embodiments 1 to
10, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted alkyl.
[0213] Embodiment 12 The compound of any one of embodiments 1 to
11, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted C.sub.1-C.sub.8 alkyl.
[0214] Embodiment 13 The compound of any one of embodiments 1 to
12, wherein R.sup.2 and R.sup.3 are independently substituted or
unsubstituted C.sub.1-C.sub.4 alkyl.
[0215] Embodiment 14 The compound of any one of embodiments 1 to
13, wherein R.sup.2 and R.sup.3 are independently --OH substituted
or unsubstituted C.sub.1-C.sub.4 alkyl.
[0216] Embodiment 15 The compound of any one of embodiments 1 to
14, wherein R.sup.2 and R.sup.3 are independently unsubstituted
C.sub.1-C.sub.4 alkyl.
[0217] Embodiment 16 The compound of any one of embodiments 1 to
15, wherein R.sup.2 and R.sup.3 are joined together to form a
substituted or unsubstituted heterocycloalkyl or substituted or
unsubstituted heteroaryl.
[0218] Embodiment 17 The compound of embodiments 1 to 16, wherein
R.sup.2 and R.sup.3 are joined together to form a substituted or
unsubstituted heterocycloalkyl.
[0219] Embodiment 18 The compound of embodiments 1 to 17, wherein
R.sup.2 and R.sup.3 are joined together to form a substituted or
unsubstituted C.sub.5-C.sub.7 heterocycloalkyl.
[0220] Embodiment 19 The compound of any one of embodiments 1 to
16, wherein R.sup.2 and R.sup.3 are joined together to form a
substituted C.sub.5-C.sub.7 heterocycloalkyl.
[0221] Embodiment 20 The compound of any one of embodiments 1 to
16, wherein R.sup.2 and R.sup.3 are joined together to form an
R.sup.23-substituted C.sub.5-C.sub.7 heterocycloalkyl, wherein
R.sup.23 is independently a substituted or unsubstituted alkyl or
substituted or unsubstituted heteroalkyl.
[0222] Embodiment 21 The compound of embodiment 20, wherein
R.sup.23 is independently a substituted or unsubstituted
C.sub.1-C.sub.8 alkyl or substituted or unsubstituted 2 to 8
membered heteroalkyl.
[0223] Embodiment 22 The compound of embodiments 1 to 16, wherein
R.sup.2 and R.sup.3 are joined together to form a substituted or
unsubstituted pyrolidinyl.
[0224] Embodiment 23 The compound of embodiments 1 to 16, wherein
R.sup.2 and R.sup.3 are joined together to form a substituted or
unsubstituted piperazinyl.
[0225] Embodiment 24 The compound of embodiments 1 to 23 comprising
a protonated nitrogen cation.
[0226] Embodiment 25 The compound of embodiments 1 to 24 comprising
a plurality of protonated nitrogen cations.
[0227] Embodiment 26 The compound of embodiment 1 having
formula:
##STR00013## ##STR00014## ##STR00015##
including pharmaceutical salts thereof
[0228] Embodiment 27 The compound of embodiments 1 having
formula:
##STR00016## ##STR00017## ##STR00018##
including pharmaceutical salts thereof.
[0229] Embodiment 28 A pharmaceutical composition comprising a
pharmaceutically acceptable excipient and a compound of embodiments
1 to 27.
[0230] Embodiment 29 The compound of embodiments 1 to 28 for use in
treating cancer in a subject in need thereof
[0231] Embodiment 30 The compound of embodiment 29, wherein the
compound is administered in an effective amount to the subject.
[0232] Embodiment 31 The compound of embodiments 29 to 30, wherein
the compound is in a pharmaceutical composition comprising a
pharmaceutically acceptable excipient.
[0233] Embodiment 32 The compound of embodiments 29 to 31, wherein
the cancer is lung cancer, breast cancer, ovarian cancer, leukemia,
lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer,
bone cancer, brain cancer, cervical cancer, colon cancer,
esophageal cancer, gastric cancer, liver cancer, head and neck
cancer, kidney cancer, myeloma, thyroid cancer, or prostate
cancer.
[0234] Embodiment 33 The compound of embodiments 29 to 32, wherein
the compound is co-administered with an effective amount of an
anti-cancer agent.
[0235] Embodiment 34 A method of modulating a kinase, a JAK, JAK2,
TYK2, Src, c-Src, ABL1, ABL1 T315I, an Aurora kinase, Aurora A,
GSK-3.beta., a CDK, a STAT, or STAT3, the method comprising
contacting the protein with the compound embodiments 1 to 28.
[0236] Embodiment 35 The method of embodiment 34, wherein the
compound is in a pharmaceutical composition comprising a
pharmaceutically acceptable excipient.
[0237] Embodiment 36 A method of modulating a Janus kinase, the
method comprising contacting the Janus kinase with the compound
embodiments 1 to 28.
[0238] Embodiment 37 The method of embodiment 36, wherein the
compound is in a pharmaceutical composition comprising a
pharmaceutically acceptable excipient.
IV. Examples
[0239] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
Example 1
TABLE-US-00001 [0240] TABLE 1 Determination of IC5o values of
5BIODs using solid and blood tumor cells. MTS assays were performed
for cell viability as described for FIGS. 2A-2G. Each experiment
was performed in quadruplicate. IC.sub.50 values (.mu.M) of 5-bromo
indirubins against cancer cells. T3151 Alb Comp. A549 MDA-MB-231
SKOV3 A2058 DU145 PaCa2 mutant ID lung breast ovarian melanoma
prostate pancreatic KCL-22 CML 1276 0.47 0.30 0.41 0.36 0.42 1.2
0.30 1277 *ND ND ND 1.9 0.77 ND ND 1278 0.60 0.71 0.75 1.7 0.78 2.5
0.5 1279 ND ND ND 2.2 2.0 ND ND 1280 0.84 0.66 1.34 1.6 0.66 0.96
0.86 1281 0.40 0.37 0.75 1.8 0.66 0.44 0.58 1282 0.50 0.78 0.77 ND
0.91 1 ND 1283 ND ND ND ND 2.1 ND ND 1284 0.44 1.0 1.36 ND ND ND ND
1285 ND ND ND ND ND ND ND 1286 0.93 1.36 1.84 ND ND ND ND 1287 ND
ND ND ND ND ND ND 1226 ND ND ND ND 3.0 ND ND 1289 0.38 0.40 0.46
1.1 0.69 0.46 0.6 1501 ND ND ND 0.88 0.32 ND ND 1502 ND ND ND 1.7
1.5 ND ND *ND: not determined
Example 2
TABLE-US-00002 [0241] TABLE 2 5BIODs inhibit activities of Src and
Janus kinases (JAKs) in vitro. IC.sub.50 values (nM) against kinase
activities in vitro using recombinant proteins Kinase 1276 1277
1278 1279 1281 1226 1289 ABL1 1020 4770 392 1440 2500 432 71.4 ABL1
6580 >10000 1550 5550 7080 1480 214 (T315I) AuroraA 954 3310 122
301 2050 366 143 c-Src 34.3 95.4 12.1 69.6 19.7 18.2 3.7 JAK2 526
1250 104 410 264.0 274 47.6 TYK2 31.6 146 27 62.7 21.0 138 20.1
[0242] The kinase assays were performed with recombinant proteins.
Briefly, proteins, freshly prepared substrates and .sup.33P-ATP
(specific activity 0.01 .mu.Ci/.mu.l final) were mixed in reaction
buffer (20 mM HEPES pH 7.5, 10 mM MgCl.sub.2, 1 mM EGTA, 0.02%
Brij35, 0.02 mg/ml BSA, 0.1 mM Na.sub.3VO.sub.4, 2 mM DTT) in the
presence of DMSO as control or 5BIODs. The mixtures were reacted
for 120 min at room temperature. Samples were transferred onto P81
ion exchange paper and filters were extensively washed with 0.75%
phosphoric acid. The radioactivities were monitored.
Example 3
[0243] General Procedure for the Preparation of
5-bromo-indirubin
[0244] Commercially available 5-bromo-isatin (1 eq.) and
3-acetoxyindole (0.8 eq.) were dissolved in methanol in presence of
sodium carbonate. The mixture was stirred for about 3.5 h. After
addition of methanolic water (1/1) the precipitate was filtered,
washed with water and dried to afford the 5-bromoindirubin with
.about.80% yield.
[0245] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 11.12
(2H, s, N--H, N'--H), 8.94 (1H, s, H-4), 7.66 (1H, d, J=7.5 Hz,
H-4'), 7.60 (1H, t, J=7.5 Hz, H-6'), 7.45 (2H, m, H-6, 7'), 7.05
(1H, t, J=7.5 Hz, H-5'), 6.86 (1H, d, J=8.3 Hz, H-7). MS (m/z,
ESI+): m/z: 341, 343 (M+H)+.
[0246] General Procedure for the Preparation of
5-bromo-3'-oxim-indirubin
[0247] 5-bromoindirubin (1 eq) is then dissolved in pyridine in
presence of an excess of hydroxylamine hydrochloride (10 eq) and
refluxed for 1 h 30. Addition of water after cooling, filtration
and washings with water afforded the 5-bromo-3'-oxim-indirubin
(5-BIO) in quantitative yield.
[0248] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 13.71
(1H, brs, NOH), 11.85 (1H, s, N'--H), 10.84 (1H, s, N--H), 8.76
(1H, brs, H-4), 8.24 (1H, d, J=7.7 Hz, H-4'), 7.42 (2H, m, H-6',
7'), 7.26 (1H, m, H-6), 7.06 (1H, t, J=7.7 Hz, H-5'), 6.84 (1H, d,
J=8.2 Hz, H-7). MS (m/z, ESI+): 356, 358 (M+H)+.
[0249] General Procedure for the Preparation of
5-bromoindirubin-3'-(O-bromoethyl)oxime
[0250] To a solution of 5-BIO (1 eq) in DMF were added
triethylamine and dibromoethane (2 eq). The reaction is stirred for
24 h at room temperature. Then water is added and the precipitate
was filtered and washed with water to afford the
5-bromoindirubin-3'-(O-bromoethyl)-oxime.
[0251] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 11.72
(0H, s, N'--H), 10.94 (1H, s, N--H), 8.80 (1H, d, J=1.9 Hz, H-4),
8.21 (1H, d, J=7.5 Hz, H-4'), 7.47 (2H, m, H-6', 7'), 7.32 (1H, dd,
J=8.0, 1.9 Hz, H-6), 7.08 (1H, m, H-5'), 6.87 (1H, d, J=8.0 Hz,
H-7), 4.89 (2H, t, J=5.6 Hz, H-1''), 4.03 (2H, t, J=5.6 Hz, H-2'').
MS (m/z, ESI+): 463, 465, 467 (M+H)+.
[0252] General Procedure for the Preparation of the
5-bromoindirubin-3'-(O-ethylamine)oxime
[0253] 5-bromoindirubin-3'-(O-bromoethyl)oxime was dissolved in
anhydrous DMF. An excess of the appropriate amine (diethylamine,
piperazine, N-methylpiperazine, 3-methylamine-1,2-propanediol,
1-(2-hydroxyethyl)piperazine and
1-[2-(2-hydroxyethoxy)-ethyl]piperazine) was added and the mixture
was heated at 90.degree. C. in CEM Single-Mode microwave (100 W)
for about 40 min. Water was added, the precipitate filtered and
washed with water and cyclohexane affording the corresponding
derivatives in 80-90% yield.
##STR00019##
[0254] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 11.75
(1H, s, N'--H), 10.92 (1H, s, N--H), 8.86 (1H, d, J=2.0 Hz, H-4),
8.16 (1H, d, J=7.6 Hz, H-4'), 7.46 (2H, m, H-6', 7'), 7.30 (1H, d,
J=8.2 Hz, H-6), 7.07 (1H, m, H-5'), 6.86 (1H, d, J=8.2 Hz, H-7),
4.70 (2H, t, J=5.8 Hz, H-1''), 3.04 (2H, t, J=5.8 Hz, H-2''), 2.60
(4H, m, H-2''', 5'''), 1.68 (4H, m, H-3''', 4'''). MS (m/z, ESI+):
453, 455 (M+H)+.
##STR00020##
[0255] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 11.73
(1H, s, N'--H), 10.90 (1H, s, N--H), 8.88 (1H, d, J=2.0 Hz, H-4),
8.14 (1H, d, J=7.6 Hz, H-4'), 7.45 (2H, m, H-6', 7'), 7.30 (1H, d,
J=8.2 Hz, H-6), 7.07 (1H, m, H-5'), 6.86 (1H, d, J=8.2 Hz, H-7),
4.70 (2H, t, J=5.8 Hz, H-1''), 2.85 (2H, t, J=5.8 Hz, H-2''), 2.69
(4H, m, H-2''', 5'''), 2.49 (4H, m, H-3''', 4'''). MS (m/z, ESI+):
453, 455 (M+H)+.
[0256] General Procedure for the Preparation of the
5-bromoindirubin-3'-(O-ethylamine)oxime salt
[0257] Each amino derivative was then dissolved in anhydrous THE
and a 2 M HCl-Et.sub.2O solution is added dropwise until no more
precipitation is observed affording the corresponding chloride
salt.
##STR00021##
[0258] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 11.75
(1H, s, N'--H), 10.97 (1H, s, N--H), 9.92 (1H, brs, H-1'''), 8.79
(1H, d, J=2.0 Hz, H4), 8.24 (1H, dd, J=7.8, 0.8 Hz, H4'), 7.49 (2H,
m, H-6', 7'), 7.33 (1H, dd, J=8.0, 2.0 Hz, H-6), 7.09 (1H, m,
H-5'), 6.88 (1H, d, J=8.0 Hz, H-7), 4.91 (2H, m, H-1''), 3.86 (2H,
m, H-2''), 3.67 (2H, m, H-2'''a, 5'''a), 3.16 (2H, m, 2'''b,
5'''b), 2.03 (2H, m, H-3'''a, 4'''a), 1.86 (2H, m, H-3'''b,
4'''b).
##STR00022##
[0259] .sup.1H NMR (DMSO-d6, 400 MHz, .delta. ppm, J in Hz): 11.82
(1H, s, N'--H), 11.05 (1H, s, N--H), 9.32 (2H, br, H-1''', 4'''),
8.79 (1H, d, J=2.0 Hz, H-4), 8.25 (1H, d, J=7.5 Hz, H-4'), 7.48
(2H, m, H-6', 7'), 7.35 (1H, dd, J=8.0, 2.0 Hz, H-6), 7.06 (1H,
ddd, J=7.5, 4.1, 1.4 Hz, H-5'), 6.89 (1H, d, J=8.0 Hz, H-7), 4.98
(2H, m, H-1''), 3.70 (2H, m, H-2''), 3.50 (8H, overlapped, H-2',
3', 5', 6').
##STR00023##
[0260] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.72 (b, 1H),
10.88 (b, 1H), 8.78 (s, 1H), 8.38 (d, J=4.8 Hz, 1H), 8.13 (d, J=7.4
Hz, 1H), 7.58-7.36 (m, 4H), 7.27 (d, J=2.0, 8.2 Hz, 1H), 7.20-7.10
(m, 1H), 7.10-7.01 (m, 1H), 6.83 (d, J=8.2 Hz, 1H), 4.72 (t, J=5.8
Hz, 2H), 3.80-3.70 (m, 2H), 3.10-2.96 (m, 2H), 2.35 (s, 3H);
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 170.9, 151.8, 149.1,
145.8, 145.4, 138.0, 136.7, 133.5, 128.8, 128.6, 125.7, 124.9,
123.0, 122.5, 122.3, 116.6, 112.9, 112.6, 111.0, 99.3, 75.1, 63.8,
55.9, 42.9; HRMS C.sub.25H.sub.22BrN.sub.5O.sub.2 [M+H].sup.+
calc'd 504.1030, found. 504.1039.
##STR00024##
[0261] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.72 (b, 1H),
10.89 (b, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.15 (d, J=7.4 Hz, 1H),
7.48-7.40 (m, 2H), 7.28 (dd, J=2.0, 8.2 Hz, 1H), 7.09-7.00 (m, 1H),
6.84 (d, J=8.2 Hz, 1H), 4.69 (t, J=5.8 Hz, 2H), 3.40-3.30 (m, 4H),
2.87 (t, J=5.6 Hz, 2H), 2.85-2.70 (m, 3H), 2.70-2.60 (m, 2H),
2.10-2.00 (m, 1H), 1.72 (t, J=10.2 Hz, 1H), 0.87 (d, J=6.2 Hz, 3H);
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 170.9, 151.8, 145.8,
145.4, 138.0, 133.4, 128.7, 128.7, 125.7, 124.9, 122.3, 116.6,
112.9, 112.6, 111.0, 99.2, 74.9, 61.6, 57.3, 53.9, 50.6, 45.7,
19.9; HRMS C.sub.23H.sub.24BrN.sub.5O.sub.2 [M+H].sup.+ calc'd
482.1186, found. 482.1183.
##STR00025##
[0262] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.73 (b, 1H),
10.89 (b, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H),
7.48-7.40 (m, 2H), 7.28 (dd, J=2.0, 8.2 Hz, 1H), 7.09-7.01 (m, 1H),
6.84 (d, J=8.2 Hz, 1H), 4.67 (t, J=5.6 Hz, 2H), 4.34 (t, J=5.2 Hz,
1H), 3.46 (dd, J=6.2, 11.8 Hz, 1H), 2.99 (1, J=5.8 Hz, 2H), 2.54
(t, J=6.2 Hz, 2H), 2.3 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 170.9, 151.8, 145.8, 145.4, 138.0, 133.4, 128.8, 128.6,
125.7, 124.9, 122.4, 116.6, 112.9, 112.5, 111.0, 99.2, 75.4, 60.2,
59.5, 56.5, 43.3; HRMS C.sub.21H.sub.21BrN.sub.4O.sub.3.
[M+H].sup.+ calc'd 457.0870, found. 457.0863.
Example 4
[0263] Kinase profiling in vitro for 1276 and 1289. See FIG. 5. The
kinase assays were performed with recombinant proteins. Briefly,
proteins, freshly prepared substrates and .sup.33P-ATP (specific
activity 0.01 .mu.Ci/.mu.l final) were mixed in reaction buffer (20
mM HEPES pH 7.5, 10 mM MgCl.sub.2, 1 mM EGTA, 0.02% Brij35, 0.02
mg/ml BSA, 0.1 mM Na.sub.3VO.sub.4, 2 mM DTT) in the presence of
DMSO as control, 1276 or 1289. The mixtures were reacted for 120
min at room temperature. Samples were transferred onto P81 ion
exchange paper and filters were extensively washed with 0.75%
phosphoric acid. The radioactivities were monitored. IC.sub.50
values were determined using GraphPad Prism software.
[0264] MTS assays were performed for cell viability. See FIGS.
7A-7B. Human A2058 melanoma (FIG. 7A) and DU145 prostate cancer
(FIG. 7B) cancer cells (5000/well) were seeded in 96-well plates,
incubated overnight at 37.degree. C. in 5% (v/v) CO.sub.2 and
exposed to XNHs at 0.25 .mu.M or 1 .mu.M concentration for 48 h.
DMSO was used as the vehicle control. Cell viability was determined
by tetrazolium conversion to its formazan dye and absorbance was
measured at 490 nm using an automated ELISA plate reader and each
experiment was performed in quadruplicate.
[0265] Human A549 non-small cell lung cancer cells
(5.times.10.sup.6) were resuspended in serum-free RPMI1640 medium
and subcutaneously injected into the flank of 5-6 weeks old
NOD/SCID/IL-2rg(ko)(NSG) female mouse. See FIGS. 8A-8D. When
palpable tumor sizes reached at approximately 70 mm.sup.3, mice
were divided into two groups (vehicle=10, treatment=10). Then, 1281
(left panel) or 1289 (right panel) was administered with oral
administration injection at 25 mg/kg with vehicle (10% DMSO+30%
Solutol+60% Saline), twice daily for 31 days. Tumor volumes were
calculated by the formula 1/2a.times.b.sup.2, where a is the long
diameter, and b is the short diameter. Tumor volumes correlate with
tumor weights. The statistical significance of group differences
was analyzed using a Student's t-test with the two-tailed
distribution. P values less than 0.05 were considered statistically
significant.
* * * * *