U.S. patent application number 17/217599 was filed with the patent office on 2021-08-05 for small molecule ire1-alpha inhibitors.
The applicant listed for this patent is Cornell University. Invention is credited to Sarah Elizabeth Bettigole, Juan Rodrigo Cubillos-Ruiz, Laurie H. Glimcher, Joseph P. Vacca.
Application Number | 20210238167 17/217599 |
Document ID | / |
Family ID | 1000005519915 |
Filed Date | 2021-08-05 |
United States Patent
Application |
20210238167 |
Kind Code |
A1 |
Glimcher; Laurie H. ; et
al. |
August 5, 2021 |
SMALL MOLECULE IRE1-ALPHA INHIBITORS
Abstract
Described herein are IRE1.alpha. inhibitors, compositions
containing such inhibitors, and methods of treatment that include
administration of such compounds. Exemplary compounds are provided
throughout the application.
Inventors: |
Glimcher; Laurie H.;
(Boston, MA) ; Bettigole; Sarah Elizabeth; (New
York, NY) ; Cubillos-Ruiz; Juan Rodrigo; (New York,
NY) ; Vacca; Joseph P.; (Telford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cornell University |
Ithaca |
NY |
US |
|
|
Family ID: |
1000005519915 |
Appl. No.: |
17/217599 |
Filed: |
March 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16116065 |
Aug 29, 2018 |
10988461 |
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17217599 |
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15449547 |
Mar 3, 2017 |
10125123 |
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16116065 |
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62303951 |
Mar 4, 2016 |
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62303236 |
Mar 3, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61K 31/498 20130101; A61K 31/542 20130101; A61K 31/536 20130101;
A61K 31/496 20130101; C07D 487/04 20130101; A61K 31/517 20130101;
C07D 403/10 20130101; C07D 413/04 20130101; C07D 403/04 20130101;
C07D 401/14 20130101; A61K 31/5025 20130101; A61K 31/55 20130101;
A61K 31/4406 20130101; A61K 31/4188 20130101; A61K 31/4439
20130101; A61K 31/4162 20130101; A61K 31/444 20130101; C07D 407/14
20130101; A61K 31/423 20130101; C07D 401/10 20130101; A61K 31/429
20130101; A61K 31/497 20130101; A61K 31/4725 20130101; C07D 409/14
20130101; A61K 31/4709 20130101; A61K 31/506 20130101; C07D 413/14
20130101; C07D 403/14 20130101; A61K 31/5377 20130101; C07D 401/04
20130101; A61K 31/437 20130101; A61K 31/519 20130101; A61K 31/4155
20130101; A61K 31/4985 20130101; A61K 31/541 20130101 |
International
Class: |
C07D 403/14 20060101
C07D403/14; C07D 401/10 20060101 C07D401/10; C07D 403/10 20060101
C07D403/10; C07D 409/14 20060101 C07D409/14; C07D 487/04 20060101
C07D487/04; C07D 401/04 20060101 C07D401/04; C07D 401/14 20060101
C07D401/14; C07D 403/04 20060101 C07D403/04; C07D 407/14 20060101
C07D407/14; C07D 413/04 20060101 C07D413/04; C07D 413/14 20060101
C07D413/14; C07D 471/04 20060101 C07D471/04; A61K 31/429 20060101
A61K031/429; A61K 31/496 20060101 A61K031/496; A61K 31/497 20060101
A61K031/497; A61K 31/4985 20060101 A61K031/4985; A61K 31/5025
20060101 A61K031/5025; A61K 31/506 20060101 A61K031/506; A61K
31/5377 20060101 A61K031/5377; A61K 31/541 20060101 A61K031/541;
A61K 31/542 20060101 A61K031/542; A61K 31/4155 20060101
A61K031/4155; A61K 31/4162 20060101 A61K031/4162; A61K 31/4188
20060101 A61K031/4188; A61K 31/423 20060101 A61K031/423; A61K
31/437 20060101 A61K031/437; A61K 31/4406 20060101 A61K031/4406;
A61K 31/4439 20060101 A61K031/4439; A61K 31/444 20060101
A61K031/444; A61K 31/4709 20060101 A61K031/4709; A61K 31/4725
20060101 A61K031/4725; A61K 31/498 20060101 A61K031/498; A61K
31/517 20060101 A61K031/517; A61K 31/519 20060101 A61K031/519; A61K
31/536 20060101 A61K031/536; A61K 31/55 20060101 A61K031/55 |
Claims
1. (canceled)
2. A method of treating cancer comprising: administering to a
subject in need thereof a therapeutically effective amount of a
compound of formula Ia: ##STR00138## wherein, A.sub.1 is N, CH, or
CR.sub.1; A.sub.2 is N, CH, or CR.sub.1; A.sub.3 is N, CH, or
CR.sub.t; A.sub.4 is N, CH, or CR.sub.1; A.sub.5 is N, CH, or
CR.sub.1; A.sub.6 is N, CH, or CR.sub.1; A.sub.7 is N, CH, or
CR.sub.1; v is an integer of 0-2; each R.sub.1 is NH.sub.2 or OH;
provided that the number of R.sub.1 on the A ring does not exceed
4; B is selected from: ##STR00139## each R.sub.2 is independently
selected from H and optionally substituted C.sub.1-C.sub.4 alkyl;
X.sub.1 and X.sub.2 are each independently CH.sub.2 or NH; with the
provision that X.sub.1 and X.sub.2 are not each CH.sub.2; R.sub.3
is selected from H, halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl; D is
a heterocyclyl ring containing at least one N atom; and each
R.sub.4 is selected from H, optionally substituted C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.1-C.sub.4 alkoxy, (optionally
substituted C.sub.1-C.sub.4 alkylene)-OH, hydroxy, optionally
substituted aryl, and optionally substituted benzyl; or a
pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein A.sub.1 is CH or CR.sub.1;
A.sub.2 is N; A.sub.3 is CH or CR.sub.1; A.sub.4 is N, CH, or
CR.sub.1; A.sub.5 is CH or CR.sub.1; A.sub.6 is CH or CR.sub.1; and
A.sub.7 is CH or CR.sub.1.
4. The method of claim 2, wherein B is ##STR00140## and each
R.sub.2 is independently H or methyl.
5. The method of claim 2, wherein R.sub.3 is selected from H, halo,
and CF.sub.3.
6. The method of claim 2, wherein D is selected from:
##STR00141##
7. The method of claim 2, wherein v is 1; and R.sub.4 is selected
from H, optionally substituted C.sub.1-C.sub.4 alkyl, (optionally
substituted C.sub.1-C.sub.4 alkylene)-OH, hydroxy, optionally
substituted aryl, and optionally substituted benzyl.
8. The method of claim 2, wherein the compound is ##STR00142##
##STR00143## ##STR00144## ##STR00145## ##STR00146##
9. The method of claim 2, wherein the compound is ##STR00147##
10. The method of claim 2, wherein the compound is ##STR00148##
11. The method of claim 2, wherein the compound is a compound of
formula Ib: ##STR00149##
12. The method of claim 2, wherein the compound is a compound of
formula Ic: ##STR00150##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/116,065, filed Aug. 29, 2018, which is a
continuation of U.S. patent application Ser. No. 15/449,547, filed
Mar. 3, 2017, which claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Patent Application Ser. No. 62/303,951,
filed Mar. 4, 2016, and of U.S. Provisional Patent Application Ser.
No. 62/303,236, filed Mar. 3, 2016, the disclosures of both of
which are incorporated herein in their entirety by reference.
BACKGROUND
[0002] Aggressive tumors have evolved strategies that enable them
to thrive under constant adverse conditions. Cancer cells respond
to hypoxia, nutrient starvation, oxidative stress, and high
metabolic demand by adjusting their protein folding capacity via
the endoplasmic reticulum (ER) stress response pathway. Cancer
patients would benefit from the development of new strategies and
therapeutics.
SUMMARY
[0003] Described herein are IRE1.alpha. inhibitors, compositions
containing such inhibitors, and methods of treatment that include
administration of such compounds.
[0004] The inventors have discovered that XBP1 can promote tumor
progression by confounding the development of protective antitumor
immunity in the ovarian cancer tumor microenvironment. Without
XBP1, tumor resident dendritic cells fail to accumulate
intracellular lipids, which normally disrupt effective antigen
cross-presentation. This pathological lipid accumulation is
fundamentally driven by reactive oxygen species-mediated lipid
peroxidation, which directly destabilizes protein-folding
chaperones within the endoplasmic reticulum to induce a state of ER
stress and XBP1 activation. Additionally, the inventors have found
that IRE1.alpha.-mediated XBP1 signaling is involved in myeloid
cell production of immunosuppressive prostaglandins such as
prostaglandin E2 (PGE2).
[0005] These findings have led to the development of novel
small-molecule IRE1.alpha. inhibitors with the ability to induce
two parallel and mutually reinforcing anti-tumor mechanisms, namely
the direct inhibition of tumor growth and the simultaneous
induction of robust anti-tumor immunity. Such a compound is highly
desirable, as no effective, targeted therapies currently exist for
either TNBC or ovarian cancer.
[0006] Described herein are novel IRE1.alpha. kinase inhibitors
that exhibit such immune-modulatory properties and/or that
allosterically block IRE1alpha endoribonuclease function. The
identified direct IRE1.alpha. inhibitors have unique chemical
structures, unique binding mechanisms, inhibitory activity, and
off-target effects.
[0007] One aspect of the invention is a compound of formula I:
##STR00001##
[0008] wherein: [0009] A and B are separately each a heterocyclyl
ring or a phenyl group, where the A ring has x R.sub.1
substituents; [0010] C is phenyl or pyridinyl; [0011] D is
heterocyclyl ring; [0012] linkage.sub.1 is a single bond between A
and B; [0013] linkage.sub.2 is a C.sub.1-C.sub.3 alkylamido,
amidoalkyl, amino, urea, alkylurea, or ureaalkyl with a first and
second terminal atom; [0014] y is an integer of 0-3, and when y is
0, the linkage between the rings is a single bond; [0015] x is an
integer of 0-4; [0016] v is an integer of 0-2; [0017] R.sub.1
substituents on the A ring are selected from amino, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted ether,
optionally substituted C.sub.1-C.sub.4 alkoxy, oxy, hydroxy,
--NH--SO.sub.2-phenyl-(R.sub.5), and cyano; [0018] R.sub.2
substituents on the B ring are selected from amino, and optionally
substituted C.sub.1-C.sub.4 alkyl; [0019] R.sub.3 substituents on
the C ring are selected from halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl; and
[0020] R.sub.4 substituents on the D ring are selected from
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, (optionally substituted
C.sub.1-C.sub.4 alkylene)-OH, hydroxy, optionally substituted aryl,
optionally substituted benzyl, and optionally substituted
benzaldehyde; [0021] R.sub.5 is halo; or [0022] a pharmaceutically
acceptable salt thereof.
[0023] Another aspect of the invention is compound selected from
any of the compounds in Tables 1-4, the Examples or a
pharmaceutically acceptable salt thereof.
[0024] Another aspect of the invention is a composition that
includes a carrier and any of the compounds of formula I,
pharmaceutically acceptable salts thereof, or any combination of
such compounds.
[0025] Another aspect of the invention is a composition that
includes a carrier and any of the compounds in the Examples,
pharmaceutically acceptable salts thereof, or any combination
thereof.
[0026] Another aspect of the invention is a method that includes
administering one or more of such compositions to a mammal. For
example, the mammal can be in need of administration of the
composition. Such a mammal can, for example, have cancer, a
neurodegenerative disease, inflammation, a metabolic disorder,
liver dysfunction, brain ischemia, heart ischemia, or an autoimmune
disease such as systemic lupus erythematosus. In some cases, the
mammal has triple negative breast cancer or ovarian cancer.
[0027] The compositions and methods described herein can include
one or more agents such as vitamin E, an antioxidant, and/or
hydralazine. Such agents can sequester lipid peroxidation
byproducts, and can be effective treatments for controlling ER
stress responses and sustained IRE1.alpha./XBP1 signaling in
tumor-associated dendritic cells exposed, for example, to ovarian
cancer-derived ascites.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1A is the structure of vitamin E (VitE).
[0029] FIG. 1B is the structure of hydralazine (Hlz), a
representative member of lipid peroxidation-sequestering
hydrazines.
[0030] FIG. 1C is RT-qPCR analyses of markers of ER stress after
culturing purified tumor-resident DCs in the absence (grey bars) or
presence (green bars) of 25% cell-free ovarian cancer ascites
supernatants for 18 hours. Data are normalized to Actb expression
in each sample.
[0031] FIG. 1D is flow cytometry analysis of lipid accumulation in
mouse bone marrow-derived dendritic cells exposed to the indicated
treatments, measured by BODIPY 493/503 staining intensity. Both raw
data and quantified geometric mean fluorescence intensity (MFI) are
shown.
[0032] FIG. 2A is a cartoon of a cleavable RNA probe and
IRE1.alpha.-dependent hairpin cleavage site. In FIG. 2A, the
quenching dye is released, fluorescence is emitted.
[0033] FIG. 2B is a cartoon of a point mutation (G.fwdarw.C) in the
hairpin that abrogates IRE1.alpha. activity against RNA probe,
controlling for contamination by non-specific RNAses. In FIG. 2B,
the quenching dye is retained, and no fluorescence is emitted.
[0034] FIG. 3 is the structure of an IRE1.alpha. inhibitor
identified by computational screening and confirmed by human
IRE1.alpha. FRET assay (commercially available from
InterBioScreen).
DETAILED DESCRIPTION
[0035] The invention relates to compounds that can modulate the
activity of IRE1.alpha.. IRE1.alpha. is a type I transmembrane
protein with dual enzymatic activities, including an N-terminal
domain that projects into the luminal side of the endoplasmic
reticulum (IRE1-LD) and a serine/threonine kinase domain plus a
C-terminal ribonuclease (RNase) domain located on the cytosolic
side of the protein.
[0036] The compounds of the invention include any of the compounds
described herein, in the Examples, the figures, and Tables 1-4.
Embodiments of the invention include but are not limited to one or
more compounds of formula I:
##STR00002##
[0037] wherein: [0038] A and B are separately each a heterocyclyl
ring or a phenyl group, where the A ring has x R.sub.1
substituents; [0039] C is phenyl or pyridinyl; [0040] D is
heterocyclyl ring; [0041] linkage.sub.1 is a single bond between A
and B; [0042] linkage.sub.2 is a C.sub.1-C.sub.3 alkylamido,
amidoalkyl, amino, urea, alkylurea, or ureaalkyl with a first and
second terminal atom; [0043] y is an integer of 0-3, and when y is
0, the linkage between the rings is a single bond; [0044] x is an
integer of 0-4; [0045] v is an integer of 0-2; [0046] R.sub.1
substituents on the A ring are selected from amino, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted ether,
optionally substituted C.sub.1-C.sub.4 alkoxy, oxy, hydroxy,
--NH--SO.sub.2-phenyl-(R.sub.5), and cyano; [0047] R.sub.2
substituents on the B ring are selected from amino, and optionally
substituted C.sub.1-C.sub.4 alkyl; [0048] R.sub.3 substituents on
the C ring are selected from halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl; and
[0049] R.sub.4 substituents on the D ring are selected from
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, (optionally substituted
C.sub.1-C.sub.4 alkylene)-OH, hydroxy, optionally substituted aryl,
optionally substituted benzyl, and optionally substituted
benzaldehyde; [0050] R.sub.5 is halo; or [0051] a pharmaceutically
acceptable salt thereof.
[0052] All structures encompassed within a claim are "chemically
feasible", by which is meant that the structure depicted by any
combination or subcombination of optional substituents meant to be
recited by the claim is physically capable of existence with at
least some stability as can be determined by the laws of structural
chemistry and by experimentation. Structures that are not
chemically feasible are not within a claimed set of compounds.
[0053] When a substituent is specified to be an atom or atoms of
specified identity, "or a bond", a configuration is referred to
when the substituent is "a bond" that the groups that are
immediately adjacent to the specified substituent are directly
connected to each other by a chemically feasible bonding
configuration.
[0054] In general, "optionally substituted" and "substituent"
refers to an organic group as defined herein in which one or more
bonds to a hydrogen atom contained therein are optionally replaced
by one or more bonds to a non-hydrogen atom such as, but not
limited to, a halogen (i.e., "halo" selected from F, Cl, Br, and
I); an oxygen atom in groups such as hydroxyl groups, alkoxy
groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups,
carboxyl groups including carboxylic acids, carboxylates, and
carboxylate esters; a sulfur atom in groups such as thiol groups,
alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups,
sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups
such as amines, hydroxylamines, nitriles, nitro groups. N-oxides,
hydrazides, azides, and enamines; and other heteroatoms in various
other groups. Non-limiting examples of substituents that can be
bonded to a substituted carbon (or other) atom include F, Cl, Br,
I, OR', OC(O)N(R').sub.2, CN, CF.sub.3, OCF.sub.3, R', O, S, C(O),
S(O), methylenedioxy, ethylenedioxy, N(R').sub.2, SR', SOR',
SO.sub.2R', SO.sub.2N(R').sub.2, SO.sub.3R', C(O)R', C(O)C(O)R',
C(O)CH.sub.2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R').sub.2,
OC(O)N(R').sub.2, C(S)N(R').sub.2, (CH.sub.2).sub.0-2NHC(O)R',
(CH.sub.2).sub.0-2N(R')N(R').sub.2, N(R')N(R')C(O)R',
N(R')N(R')C(O)OR', N(R')N(R')CON(R').sub.2, N(R')SO.sub.2R',
N(R')SO.sub.2N(R').sub.2, N(R')C(O)OR', N(R')C(O)R'. N(R')C(S)R',
N(R')C(O)N(R').sub.2, N(R')C(S)N(R').sub.2, N(COR')COR', N(OR')R',
C(.dbd.NH)N(R').sub.2, C(O)N(OR')R', or C(.dbd.NOR')R' wherein R'
can be hydrogen or a carbon-based moiety, and wherein the
carbon-based moiety can itself be further substituted. In some
cases the R' group is a hydrogen, C.sub.1-C.sub.6 alkyl, or
phenyl.
[0055] In many of the compounds described herein, the optional
substituents are selected from amino, C.sub.1-C.sub.3 alkyl, ether,
alkoxy, oxy, CF.sub.3, and cyano C.sub.1-C.sub.3 alkoxy, benzyl,
and benzaldehyde. The ether and alkoxy groups can have 1-6 carbon
atoms.
[0056] Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and
cycloalkenyl groups as well as other substituted groups also
include groups in which one or more bonds to a hydrogen atom are
replaced by one or more bonds, including double or triple bonds, to
a carbon atom, or to a heteroatom such as, but not limited to,
oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane,
and urea groups; and nitrogen in imines, hydroxyimines, oximes,
hydrazones, amidines, guanidines, and nitriles.
[0057] Substituted ring groups such as substituted aryl,
heterocyclyl and heteroaryl groups also include rings and fused
ring systems in which a bond to a hydrogen atom is replaced with a
bond to a carbon atom. Therefore, substituted aryl, heterocyclyl
and heteroaryl groups can also be substituted with alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, and alkynyl groups as defined herein,
which can themselves be further substituted.
[0058] The term "heteroatoms" as used herein refers to non-carbon
and non-hydrogen atoms, capable of forming covalent bonds with
carbon, and is not otherwise limited. Typical heteroatoms are N, O,
and S. When sulfur (S) is referred to, it is understood that the
sulfur can be in any of the oxidation states in which it is found,
thus including sulfoxides (R--S(O)--R') and sulfones
(R--S(O).sub.2--R'), unless the oxidation state is specified; thus,
the term "sulfone" encompasses only the sulfone form of sulfur; the
term "sulfide" encompasses only the sulfide (R--S--R') form of
sulfur. When the phrases such as "heteroatoms selected from the
group consisting of O, NH, NR' and S," or "[variable] is O, S . . .
" are used, they are understood to encompass all of the sulfide,
sulfoxide and sulfone oxidation states of sulfur.
[0059] Alkyl groups include straight chain and branched alkyl
groups and cycloalkyl groups having from 1 to about 20 carbon
atoms, and typically from 1 to 12 carbons or, in some embodiments,
from 1 to 8 carbon atoms. Examples of straight chain alkyl groups
include those with from 1 to 8 carbon atoms such as methyl, ethyl,
n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
Examples of branched alkyl groups include, but are not limited to,
isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and
2,2-dimethylpropyl groups. Representative substituted alkyl groups
can be substituted one or more times with any of the groups listed
above, for example, amino, hydroxy, cyano, carboxy, nitro, thio,
alkoxy, and halogen groups.
[0060] An "alkylene" group refers to a divalent alkyl radical. Any
of the above mentioned monovalent alkyl groups may be an alkylene
by abstraction of a second hydrogen atom from the alkyl. In some
embodiments, an alkylene is a C.sub.1-C.sub.6alkylene. In some
embodiments, an alkylene is a C.sub.1-C.sub.3alkylene. Examples of
alkylene groups include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like.
[0061] Cycloalkyl groups are alkyl groups forming a ring structure,
which can be substituted or unsubstituted. Examples of cycloalkyl
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In
some embodiments, the cycloalkyl group has 3 to 8 ring members,
whereas in other embodiments the number of ring carbon atoms range
from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include
polycyclic cycloalkyl groups such as, but not limited to,
norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl
groups, and fused rings such as, but not limited to, decalinyl, and
the like. Cycloalkyl groups also include rings that are substituted
with straight or branched chain alkyl groups as defined above.
Representative substituted cycloalkyl groups can be
mono-substituted or substituted more than once, such as, but not
limited to, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl
groups or mono-, di- or tri-substituted norbornyl or cycloheptyl
groups, which can be substituted with, for example, amino, hydroxy,
cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
[0062] The terms "carbocyclic" and "carbocycle" denote a ring
structure wherein the atoms of the ring are carbon. In some
embodiments, the carbocycle has 3 to 8 ring members, whereas in
other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
Unless specifically indicated to the contrary, the carbocyclic ring
can be substituted with as many as N substituents wherein N is the
size of the carbocyclic ring with for example, amino, hydroxy,
cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
[0063] (Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are
alkyl groups as defined above in which a hydrogen or carbon bond of
the alkyl group is replaced with a bond to a cycloalkyl group as
defined above.
[0064] Alkenyl groups include straight and branched chain and
cyclic alkyl groups as defined above, except that at least one
double bond exists between two carbon atoms. Thus, alkenyl groups
have from 2 to about 20 carbon atoms, and typically from 2 to 12
carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples
include, but are not limited to --CH.dbd.CH(CH.sub.3),
--CH.dbd.C(CH.sub.3).sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH(CH.sub.3). --C(CH.sub.2CH.sub.3).dbd.CH.sub.2,
vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,
pentadienyl, and hexadienyl among others.
[0065] The term "cycloalkenyl" alone or in combination denotes a
cyclic alkenyl group wherein at least one double bond is present in
the ring structure. Cycloalkenyl groups include cycloalkyl groups
having at least one double bond between two adjacent carbon atoms.
Thus for example, cycloalkenyl groups include but are not limited
to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
[0066] (Cycloalkenyl)alkyl groups are alkyl groups as defined above
in which a hydrogen or carbon bond of the alkyl group is replaced
with a bond to a cycloalkenyl group as defined above.
[0067] Alkynyl groups include straight and branched chain alkyl
groups, except that at least one triple bond exists between two
carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon
atoms, and typically from 2 to 12 carbons or, in some embodiments,
from 2 to 8 carbon atoms. Examples include, but are not limited to
--C.ident.CH, --C.ident.C(CH.sub.3), --C.ident.C(CH.sub.2CH.sub.3),
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3), and
--CH.sub.2C.ident.C(CH.sub.2CH.sub.3), among others.
[0068] Aryl groups are cyclic aromatic hydrocarbons that do not
contain heteroatoms. Thus aryl groups include, but are not limited
to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,
phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,
biphenylenyl, anthracenyl, and naphthyl groups. In some
embodiments, aryl groups contain 6-14 carbons in the ring portions
of the groups. The phrase "aryl groups" includes groups containing
fused rings, such as fused aromatic-aliphatic ring systems (e.g.,
indanyl, tetrahydronaphthyl, and the like), and also includes
substituted aryl groups that have other groups, including but not
limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro,
thio, or alkoxy groups, bonded to one of the ring atoms.
Representative substituted aryl groups can be mono-substituted or
substituted more than once, such as, but not limited to, 2-, 3-,
4-, 5-, or 6-substituted phenyl or naphthyl groups, which can be
substituted with groups including but not limited to those listed
above.
[0069] Aralkyl groups are alkyl groups as defined above in which a
hydrogen or carbon bond of an alkyl group is replaced with a bond
to an aryl group as defined above. Representative aralkyl groups
include benzyl and phenylethyl groups and fused
(cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. The aryl
moiety or the alkyl moiety or both are optionally substituted with
other groups, including but not limited to alkyl, halo, amino,
hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups. Aralkenyl
group are alkenyl groups as defined above in which a hydrogen or
carbon bond of an alkyl group is replaced with a bond to an aryl
group as defined above.
[0070] Heterocyclyl groups include aromatic and non-aromatic ring
compounds containing 3 or more ring members, of which one or more
is a heteroatom such as, but not limited to, N, O. S, or P.
Heteroaryl and heterocyclicalkyl groups are included in the
definition of heterocyclyl. In some embodiments, heterocyclyl
groups include 3 to 20 ring members, whereas other such groups have
3 to 15 ring members. At least one ring contains a heteroatom, but
every ring in a polycyclic system need not contain a heteroatom.
For example, a dioxolanyl ring and a benzdioxolanyl ring system
(methylenedioxyphenyl ring system) are both heterocyclyl groups
within the meaning herein. A heterocyclyl group designated as a
C.sub.2-heterocyclyl can be a 5-ring with two carbon atoms and
three heteroatoms, a 6-ring with two carbon atoms and four
heteroatoms and so forth. Likewise a C-heterocyclyl can be a 5-ring
with one heteroatom, a 6-ring with two heteroatoms, and so forth.
The number of carbon atoms plus the number of heteroatoms sums up
to equal the total number of ring atoms. In some cases, the
heterocyclyl is a single ring. In other cases, the heterocyclyl is
a fusion of two or three rings. The phrase "heterocyclyl group"
includes fused ring species including those having fused aromatic
and non-aromatic groups. The phrase also includes polycyclic ring
systems containing a heteroatom such as, but not limited to,
quinuclidyl and also includes heterocyclyl groups that have
substituents, including but not limited to alkyl, halo, amino,
hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to
one of the ring members. A heterocyclyl group as defined herein can
be a heteroaryl group or a partially or completely saturated cyclic
group including at least one ring heteroatom. Heterocyclyl groups
include, but are not limited to, pyrrolidinyl, furanyl,
tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl,
morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,
benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl,
azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
quinoxalinyl, and quinazolinyl groups. Heterocyclyl groups can be
substituted. Representative substituted heterocyclyl groups can be
mono-substituted or substituted more than once, including but not
limited to, rings containing at least one heteroatom which are
mono, di, tri, tetra, penta, hexa, or higher-substituted with
substituents such as those listed above, including but not limited
to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, and
alkoxy groups.
[0071] Heteroaryl groups are aromatic ring compounds containing 5
or more ring members, of which, one or more is a heteroatom such
as, but not limited to, N, O, and S. A heteroaryl group designated
as a C.sub.2-heteroaryl can be a 5-ring with two carbon atoms and
three heteroatoms, a 6-ring with two carbon atoms and four
heteroatoms and so forth. Likewise a C.sub.4-heteroaryl can be a
5-ring with one heteroatom, a 6-ring with two heteroatoms, and so
forth. The number of carbon atoms plus the number of heteroatoms
sums up to equal the total number of ring atoms. Heteroaryl groups
include, but are not limited to, groups such as pyrrolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,
pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl,
azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The
terms "heteroaryl" and "heteroaryl groups" include fused ring
compounds such as wherein at least one ring, but not necessarily
all rings, are aromatic, including tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. The term
also includes heteroaryl groups that have other groups bonded to
one of the ring members, including but not limited to alkyl, halo,
amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups.
Representative substituted heteroaryl groups can be substituted one
or more times with groups such as those listed above.
[0072] Additional examples of aryl and heteroaryl groups include
but are not limited to phenyl, biphenyl, indenyl, naphthyl
(1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,
N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl,
3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,
3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl,
fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,
pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl
(1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl
(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,
1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl
(2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl,
pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl
(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl,
8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl,
3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl,
6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl
(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),
4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),
6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl),
benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,
4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl,
7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl,
(2-(2,3-dihydro-benzo[b]thiophenyl),
3-(2,3-dihydro-benzo[b]thiophenyl),
4-(2,3-dihydro-benzo[b]thiophenyl),
5-(2,3-dihydro-benzo[b]thiophenyl),
6-(2,3-dihydro-benzo[b]thiophenyl),
7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,
3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole
(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,
7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,
4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl,
7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl,
2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl,
2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl,
6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl,
2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine
(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,
5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,
5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine
(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
[0073] Heterocyclylalkyl groups are cyclic alkyl groups as defined
above in which a hydrogen or carbon bond of an alkyl group is
replaced with a bond to a heterocyclyl group as defined above.
Representative heterocyclyl alkyl groups include, but are not
limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-2-yl
methyl (.alpha.-picolyl), pyridine-3-yl methyl (.beta.-picolyl),
pyridine-4-yl methyl (.gamma.-picolyl), tetrahydrofuran-2-yl ethyl,
and indol-2-yl propyl. Heterocyclylalkyl groups can be substituted
on the heterocyclyl moiety, the alkyl moiety, or both.
[0074] Heteroarylalkyl groups are alkyl groups as defined above in
which a hydrogen or carbon bond of an alkyl group is replaced with
a bond to a heteroaryl group as defined above. Heteroarylalkyl
groups can be substituted on the heteroaryl moiety, the alkyl
moiety, or both.
[0075] By a "ring system" or "ring," as the term is used herein, is
meant a moiety comprising one, two, three or more rings, which can
be substituted with non-ring groups or with other ring systems, or
both, which can be fully saturated, partially unsaturated, fully
unsaturated, or aromatic, and when the ring system includes more
than a single ring, the rings can be fused, bridging, or
spirocyclic. By "spirocyclic" is meant the class of structures
wherein two rings are fused at a single tetrahedral carbon atom, as
is well known in the art.
[0076] A "monocyclic, bicyclic or polycyclic, aromatic or partially
aromatic ring" as the term is used herein refers to a ring system
including an unsaturated ring possessing 4n+2 .mu.l electrons, or a
partially reduced (hydrogenated) form thereof. The aromatic or
partially aromatic ring can include additional fused, bridged, or
spiro rings that are not themselves aromatic or partially aromatic.
For example, naphthalene and tetrahydronaphthalene are both a
"monocyclic, bicyclic or polycyclic, aromatic or partially aromatic
ring" within the meaning herein. Also, for example, a
benzo-[2.2.2]-bicyclooctane is also a "monocyclic, bicyclic or
polycyclic, aromatic or partially aromatic ring" within the meaning
herein, containing a phenyl ring fused to a bridged bicyclic
system. A fully saturated ring has no double bonds therein, and is
carbocyclic or heterocyclic depending on the presence of
heteroatoms within the meaning herein.
[0077] The term "alkoxy" refers to an oxygen atom connected to an
alkyl group, including a cycloalkyl group, as are defined above.
Examples of linear alkoxy groups include but are not limited to
methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, and
the like. Examples of branched alkoxy include but are not limited
to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy,
and the like. Examples of cyclic alkoxy include but are not limited
to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,
and the like.
[0078] The terms "aryloxy" and "arylalkoxy" refer to, respectively,
an aryl group bonded to an oxygen atom and an aralkyl group bonded
to the oxygen atom at the alkyl moiety. Examples include but are
not limited to phenoxy, naphthyloxy, and benzyloxy.
[0079] An "acyl" group as the term is used herein refers to a group
containing a carbonyl moiety wherein the group is bonded via the
carbonyl carbon atom. The carbonyl carbon atom is also bonded to
another carbon atom, which can be part of an alkyl, aryl, aralkyl
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl group or the like. In the special case
wherein the carbonyl carbon atom is bonded to a hydrogen, the group
is a "formyl" group, an acyl group as the term is defined herein.
An acyl group can include 0 to about 12-20 additional carbon atoms
bonded to the carbonyl group. An acyl group can include double or
triple bonds within the meaning herein. An acryloyl group is an
example of an acyl group. An acyl group can also include
heteroatoms within the meaning here. A nicotinoyl group
(pyridyl-3-carbonyl) group is an example of an acyl group within
the meaning herein. Other examples include acetyl, benzoyl,
phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the
like. When the group containing the carbon atom that is bonded to
the carbonyl carbon atom contains a halogen, the group is termed a
"haloacyl" group. An example is a trifluoroacetyl group.
[0080] The term "amine" or "amino" includes primary, secondary, and
tertiary amines having, e.g., the formula N(group).sub.3 wherein
each group can independently be H or non-H, such as alkyl, aryl,
and the like. Amines include but are not limited to R--NH.sub.2,
for example, alkylamines, arylamines, alkylarylamines; R.sub.4NH
wherein each R is independently selected, such as dialkylamines,
diarylamines, aralkylamines, heterocyclylamines and the like; and
R.sub.5N wherein each R is independently selected, such as
trialkylamines, dialkylarylamines, alkyldiarylamines,
triarylamines, and the like. The term "amine" also includes
ammonium ions as used herein.
[0081] An "amino" group is a substituent of the form --NH.sub.2,
--NHR, --N(R).sub.2, --N(R).sub.3.sup.+, wherein each R is
independently selected, and protonated forms of each. Accordingly,
any compound substituted with an amino group can be viewed as an
amine.
[0082] An "ammonium" ion includes the unsubstituted ammonium ion
NH.sub.4, but unless otherwise specified, it also includes any
protonated or quaternarized forms of amines. Thus,
trimethylammonium hydrochloride and tetramethylammonium chloride
are both ammonium ions, and amines, within the meaning herein.
[0083] The term "amide" (or "amido") includes C- and N-amide
groups, i.e., --C(O)N(R).sub.2, and --NRC(O)R-- groups,
respectively. Amide groups therefore include but are not limited to
carbamoyl groups (--C(O)NH.sub.2) and formamide groups (--NHC(O)H).
A "carboxamido" group is a group of the formula C(O)N(R).sub.2,
wherein R can be H, alkyl, aryl, etc.
[0084] The term "urethane" (or "carbamyl") includes N- and
O-urethane groups, i.e., --NRC(O)OR and --OC(O)N(R).sub.2 groups,
respectively.
[0085] The term "sulfonamide" (or "sulfonamido") includes S- and
N-sulfonamide groups, i.e., --SO.sub.2NR.sub.2 and --NRSO.sub.2R
groups, respectively. Sulfonamide groups therefore include but are
not limited to sulfamoyl groups (--SO.sub.2NH.sub.2).
[0086] The term "amidine" or "amidino" includes groups of the
formula --C(NR)N(R).sub.2. Typically, an amidino group is
--C(NH)NH.sub.2.
[0087] The term "guanidine" or "guanidino" includes groups of the
formula --NRC(NR)N(R).sub.2. Typically, a guanidino group is
--NHC(NH)NH.sub.2.
[0088] "Halo," "halogen," and "halide" include fluorine, chlorine,
bromine and iodine.
[0089] The terms "comprising," "including," "having," "composed
of," are open-ended terms as used herein, and do not preclude the
existence of additional elements or components. In a claim element,
use of the forms "comprising," "including," "having," or "composed
of" means that whatever element is comprised, had, included, or
composes is not necessarily the only element encompassed by the
subject of the clause that contains that word.
[0090] A "salt" as is well known in the art includes an organic
compound such as a carboxylic acid, a sulfonic acid, or an amine,
in ionic form, in combination with a counterion. For example, acids
in their anionic form can form salts with cations such as metal
cations, for example sodium, potassium, and the like; with ammonium
salts such as NH.sub.4.sup.+ or the cations of various amines,
including tetraalkyl ammonium salts such as tetramethylammonium, or
other cations such as trimethylsulfonium, and the like. A
"pharmaceutically acceptable" or "pharmacologically acceptable"
salt is a salt formed from an ion that has been approved for human
consumption and is generally non-toxic, such as a chloride salt or
a sodium salt. A "zwitterion" is an internal salt such as can be
formed in a molecule that has at least two ionizable groups, one
forming an anion and the other a cation, which serve to balance
each other. For example, amino acids such as glycine can exist in a
zwitterionic form. A "zwitterion" is a salt within the meaning
herein. The compounds of the present invention may take the form of
salts. The term "salts" embraces addition salts of free acids or
free bases which are compounds of the invention. Salts can be
"pharmaceutically-acceptable salts." The term
"pharmaceutically-acceptable salt" refers to salts which possess
toxicity profiles within a range that affords utility in
pharmaceutical applications. Pharmaceutically unacceptable salts
may nonetheless possess properties such as high crystallinity,
which have utility in the practice of the present invention, such
as for example utility in process of synthesis, purification or
formulation of compounds of the invention.
[0091] Suitable pharmaceutically-acceptable acid addition salts may
be prepared from an inorganic acid or from an organic acid.
Examples of inorganic acids include hydrochloric, hydrobromic,
hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, examples of which include
formic, acetic, propionic, succinic, glycolic, gluconic, lactic,
malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,
pyruvic, aspartic, glutamic, benzoic, anthranilic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
trifluoromethanesulfonic, 2-hydroxyethanesulfonic,
p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,
alginic, .beta.-hydroxybutyric, salicylic, galactaric and
galacturonic acid. Examples of pharmaceutically unacceptable acid
addition salts include, for example, perchlorates and
tetrafluoroborates.
[0092] Suitable pharmaceutically acceptable base addition salts of
compounds of the invention include, for example, metallic salts
including alkali metal, alkaline earth metal and transition metal
salts such as, for example, calcium, magnesium, potassium, sodium
and zinc salts. Pharmaceutically acceptable base addition salts
also include organic salts made from basic amines such as, for
example, N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. Examples of pharmaceutically unacceptable base addition
salts include lithium salts and cyanate salts. Although
pharmaceutically unacceptable salts are not generally useful as
medicaments, such salts may be useful, for example as intermediates
in the synthesis of Formula I compounds, for example in their
purification by recrystallization. All of these salts may be
prepared by conventional means from the corresponding compound
according to Formula I by reacting, for example, the appropriate
acid or base with the compound according to Formula I. The term
"pharmaceutically acceptable salts" refers to nontoxic inorganic or
organic acid and/or base addition salts, see, for example. Lit et
al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33,
201-217, incorporated by reference herein.
[0093] A "hydrate" is a compound that exists in a composition with
water molecules. The composition can include water in
stoichiometric quantities, such as a monohydrate or a dihydrate, or
can include water in random amounts. As the term is used herein a
"hydrate" refers to a solid form, i.e., a compound in water
solution, while it may be hydrated, is not a hydrate as the term is
used herein.
[0094] A "solvate" is a similar composition except that a solvent
other that water replaces the water. For example, methanol or
ethanol can form an "alcoholate", which can again be stoichiometric
or non-stoichiometric. As the term is used herein a "solvate"
refers to a solid form, i.e., a compound in solution in a solvent,
while it may be solvated, is not a solvate as the term is used
herein.
[0095] A "prodrug" as is well known in the art is a substance that
can be administered to a patient where the substance is converted
in vivo by the action of biochemicals within a mammal's body (e.g.,
in a patient's body), such as enzymes, to the active pharmaceutical
ingredient. Examples of prodrugs include esters of carboxylic acid
groups, which can be hydrolyzed by endogenous esterases as are
found in the bloodstream of humans and other mammals.
[0096] In addition, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush group.
For example, if X is described as selected from the group
consisting of bromine, chlorine, and iodine, claims for X being
bromine and claims for X being bromine and chlorine are fully
described. Moreover, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any combination of individual members or subgroups of members of
Markush groups. Thus, for example, if X is described as selected
from the group consisting of bromine, chlorine, and iodine, and Y
is described as selected from the group consisting of methyl,
ethyl, and propyl, claims for X being bromine and Y being methyl
are fully described.
[0097] In various embodiments, the compound or set of compounds,
either per se or as are used in practice of embodiments of the
inventive methods, can be any one of any of the combinations and/or
sub-combinations of the various embodiments recited.
[0098] Provisos may apply to any of the disclosed categories or
embodiments wherein any one or more of the other above disclosed
embodiments or species may be excluded from such categories or
embodiments.
Compounds
[0099] The compounds of the invention include any of those
described herein, including compounds shown in the Examples. In
some instances, the compounds are embraced by formula I:
##STR00003##
[0100] wherein: [0101] A and B are separately each a heterocyclyl
ring or a phenyl group, where the A ring has x R.sub.1
substituents; [0102] C is phenyl or pyridinyl; [0103] D is
heterocyclyl ring; [0104] linkage.sub.1 is a single bond between A
and B; [0105] linkage.sub.2 is a C.sub.1-C.sub.3 alkylamido,
amidoalkyl, amino, urea, alkylurea, or ureaalkyl with a first and
second terminal atom; [0106] y is an integer of 0-3, and when y is
0, the linkage between the rings is a single bond; [0107] x is an
integer of 0-4; [0108] v is an integer of 0-2; [0109] R.sub.1
substituents on the A ring are selected from amino, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted ether,
optionally substituted C.sub.1-C.sub.4 alkoxy, oxy, hydroxy,
--NH--SO.sub.2-phenyl-(R.sub.5), and cyano; [0110] R.sub.2
substituents on the B ring are selected from amino, and optionally
substituted C.sub.1-C.sub.4 alkyl; [0111] R.sub.3 substituents on
the C ring are selected from halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl; and
[0112] R.sub.4 substituents on the D ring are selected from
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, (optionally substituted
C.sub.1-C.sub.4 alkylene)-OH, hydroxy, optionally substituted aryl,
optionally substituted benzyl, and optionally substituted
benzaldehyde; [0113] R.sub.5 is halo; or [0114] a pharmaceutically
acceptable salt thereof.
[0115] In some cases, the A ring is heterocyclyl ring. In some
cases, the A ring is a heterocyclyl that is a single non-fused
ring. In other cases, the A ring is a heterocyclyl that is a fusion
of two or three rings. In other cases, the A ring is a heterocyclyl
that is a fusion of two rings. In some cases, the A ring of the
compounds described herein is heteroaromatic. In some embodiments,
the A ring is a single non-fused 5-membered heteroaryl. In some
embodiments, the A ring is a single non-fused 6-membered
heteroaryl. In some embodiments, the A ring is pyridinyl,
pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, the A
ring is pyridinyl. In some cases, the A ring is a heteroaryl that
is a fusion of two rings. Examples of A rings include indazole,
imadazopyridine, imadazopyrazine, imadazopyridazine,
pyrrolopyridine, hexahydrothienopyrimidine, imidazole, pyrazole,
pyrazine, pyridine, pyrimidine, phenylpyrimidinamine, quinolinyl,
isoquinolinyl, tetrahydroquinolinyl, and quinazolinyl. In some
embodiments, the A ring is isoquinolinyl. In some embodiments, the
A ring is quinazolinyl. For example, the A ring can be selected
from any of the following:
##STR00004##
In some instances, the A ring is
##STR00005##
In some instances, the A ring is
##STR00006##
In some instances, the A ring is
##STR00007##
[0116] In some embodiments, the R.sub.1 substituents on the A ring
are selected from amino, optionally substituted C.sub.1-C.sub.4
alkyl, and hydroxy. In some embodiments, the R.sub.1 substituents
on the A ring can, for example, be selected from amino and
optionally substituted C.sub.1-C.sub.3 alkyl. In some cases, the
R.sub.1 substituents on the A ring are selected from --NH.sub.2 and
--CH.sub.3. In addition, in some cases x=0, but in other cases x=1.
In some cases, x=2. In some cases, x=3. For example, x can in some
cases be 0, 1, or 2 when the A ring is a fusion of two rings. In
other cases, x=1 or 2 when the A ring is a single, nonfused
ring.
[0117] The B ring can be a single, non-fused ring. In some
embodiments, the B ring is single, non-fused 5-membered ring. In
some embodiments, the B ring is pyrazolyl, imidazolyl, or
triazolyl. In some cases, the B ring is pyrazolyl. Alternatively,
the B ring can be a fusion of two rings. In some embodiments, the B
ring is indazolyl or benzoxazolyl. For example, the B ring can be
selected from any of the following:
##STR00008##
In some cases, the B ring is
##STR00009##
In some cases, the B ring is
##STR00010##
In some cases, the B ring is
##STR00011##
In some embodiments, R.sub.2 substituents on the B ring are
optionally substituted C.sub.1-C.sub.4 alkyl. In some embodiments,
R.sub.2 substituents on the B ring are --CH.sub.3.
[0118] In some cases the C ring can be a phenyl group, and in other
cases, a pyridinyl group. In some instances, the C ring is phenyl.
In some embodiments, the R.sub.3 substituents on the C ring are
selected from halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl. In
some embodiments, the R.sub.3 substituent is halo. In some
embodiments, the R.sub.3 substituent is CF.sub.3. In some
embodiments, the R.sub.3 substituent is optionally substituted
C.sub.1-C.sub.4 alkyl. In some embodiments, the R.sub.3 substituent
is optionally substituted heteroaryl.
[0119] The linkage.sub.2 group can, for example, be selected from
any of the following:
##STR00012##
wherein a hydrogen atom on Ring B is replaced by the first terminal
atom of linkage.sub.2 and a hydrogen atom on Ring C is replaced by
the second terminal atom of linkage.sub.2. In some cases,
linkage.sub.2 is
##STR00013##
In some cases, linkage.sub.2 is
##STR00014##
[0120] In some embodiments, D ring is a heterocyclyl ring
containing at least one N atom. In some embodiments, the D ring is
piperidinyl, piperazinyl, or morpholinyl. The D ring can, for
example, be selected from any of the following:
##STR00015##
In some embodiments, Ring D is
##STR00016##
[0121] In some embodiments, the R.sub.4 substituents on the D ring
are optionally substituted C.sub.1-C.sub.4 alkyl. The R.sub.4
substituents on the D ring can in some cases be selected from
CH.sub.3. CH.sub.3CHCH.sub.3. CH.sub.3CH(CH.sub.2)CH.sub.3, and
CH.sub.3CH.sub.2CH.sub.3OH. In some cases, R.sub.4 is CH.sub.3. In
some embodiments, R.sub.4 is optionally substituted C.sub.1-C.sub.4
alkoxy. In some embodiments, R.sub.4 is (optionally substituted
C.sub.1-C.sub.4 alkylene)-OH. In some embodiments, R.sub.4 is
(optionally substituted C.sub.1 alkylene)-OH. In some embodiments,
R.sub.4 is (optionally substituted C.sub.2 alkylene)-OH. In some
embodiments, R.sub.4 is (optionally substituted C.sub.3
alkylene)-OH. In some embodiments, R is (optionally substituted
C.sub.4 alkylene)-OH. In some embodiments, R.sub.4 is hydroxyl. In
some embodiments, R.sub.4 is optionally substituted aryl. In some
embodiments, R.sub.4 is phenyl. In some embodiments, R.sub.4 is
optionally substituted benzyl. In some embodiments, v is 1. In some
embodiments, v is 2. In some embodiments, y is 1. In some
embodiments, y is 2. In some embodiments, y is 3.
[0122] In some instances, the compounds are embraced by formula
Ia:
##STR00017##
[0123] wherein, [0124] A.sub.1 is N, CH, or CR.sub.1; A.sub.2 is N,
CH, or CR.sub.1; A.sub.3 is N. CH, or CR.sub.1; A.sub.4 is N, CH,
or CR.sub.1; A.sub.5 is N, CH, or CR.sub.1; A.sub.6 is N, CH, or
CR.sub.1; A.sub.7 is N CH, or CR.sub.1; [0125] v is an integer of
0-2; [0126] Each R.sub.1 is NH.sub.2 or OH; provided that the
number of R.sub.1 on the A ring does not exceed 4; [0127] B is
selected from:
[0127] ##STR00018## [0128] each R.sub.2 is independently selected
from H and optionally substituted C.sub.1-C.sub.4 alkyl; [0129]
X.sub.1 and X.sub.2 are each independently CH.sub.2 or NH; with the
provision that X.sub.1 and X.sub.2 are not each CH.sub.2; [0130]
R.sub.3 is selected from H, halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl;
[0131] D is heterocyclyl ring containing at least one N atom;
[0132] each R.sub.4 is selected from H, optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4
alkoxy, (optionally substituted C.sub.1-C.sub.4 alkylene)-OH,
hydroxy, optionally substituted aryl, and optionally substituted
benzyl; or [0133] a pharmaceutically acceptable salt thereof.
[0134] In some embodiments, A.sub.1 is CH or CR.sub.1; A.sub.2 is
N; A.sub.3 is CH or CR.sub.1; A.sub.4 is N, CH, or CR.sub.1; As is
CH or CR.sub.1; A.sub.6 is CH or CR.sub.1; and A.sub.7 is CH or
CR.sub.1. In some embodiments, A.sub.1 is CH or CR.sub.1; A.sub.2
is N; A.sub.3 is CH or CR.sub.1; A.sub.4 is N; A.sub.5 is CH or
CR.sub.1; A.sub.6 is CH or CR.sub.1; and A.sub.7 is CH or CR.sub.1.
In some embodiments. A.sub.1 is CH or CR.sub.1; A.sub.2 is N;
A.sub.3 is CH or CR.sub.1; A.sub.4 is CH or CR.sub.1; A.sub.5 is CH
or CR.sub.1; A.sub.6 is CH or CR.sub.1; and A.sub.7 is CH or
CR.sub.1. In some embodiments, A, is CH; A.sub.2 is N; A.sub.3 is
CR.sub.1; A.sub.4 is N; A.sub.5 is CH; A.sub.6 is CH; and A.sub.7
is CH. In some embodiments, A.sub.1 is CH; A.sub.2 is N; A.sub.3 is
CR.sub.1; A.sub.4 is CR.sub.1; A.sub.5 is CH; A.sub.6 is CH; and
A.sub.7 is CH.
[0135] In some embodiments, A.sub.1 is CH or CR.sub.1; A.sub.2 is
N; A.sub.3 is CH or CR.sub.1; A.sub.4 is N; A.sub.5 is CH; A.sub.6
is CH; and A.sub.7 is CH. In some embodiments, A.sub.1 is CH or
CR.sub.1; A.sub.2 is N; A.sub.3 is CH or CR.sub.1; A.sub.4 is CH or
CR.sub.1; A.sub.5 is CH; A.sub.6 is CH; and A.sub.7 is CH.
[0136] In some embodiments, A.sub.1 is N. In some embodiments,
A.sub.1 is CH. In some embodiments, A.sub.1 is CR.sub.1, and
R.sub.1 is OH. In some embodiments, A.sub.1 is CR.sub.1, and
R.sub.1 is NH.sub.2. In some embodiments, A.sub.2 is N. In some
embodiments, A.sub.2 is CH. In some embodiments, A.sub.2 is
CR.sub.1, and R.sub.1 is OH. In some embodiments, A.sub.2 is
CR.sub.1, and R.sub.1 is NH.sub.2. In some embodiments, A.sub.3 is
N. In some embodiments, A.sub.3 is CH. In some embodiments, A.sub.3
is CR.sub.1, and R.sub.1 is OH. In some embodiments, A.sub.3 is
CR.sub.1, and R.sub.1 is NH.sub.2. In some embodiments, A.sub.4 is
N. In some embodiments, A.sub.4 is CH. In some embodiments, A.sub.4
is CR.sub.1, and R.sub.1 is OH. In some embodiments, A.sub.4 is
CR.sub.1, and R.sub.1 is NH.sub.2. In some embodiments, A.sub.5 is
N. In some embodiments, A.sub.5 is CH. In some embodiments, A.sub.5
is CR.sub.1, and R.sub.1 is OH. In some embodiments, A.sub.5 is
CR.sub.1, and R.sub.1 is NH.sub.2. In some embodiments, A.sub.6 is
N. In some embodiments, A.sub.6 is CH. In some embodiments, A.sub.6
is CR.sub.1, and R.sub.1 is OH. In some embodiments, A.sub.6 is
CR.sub.1, and R.sub.1 is NH.sub.2. In some embodiments, A.sub.7 is
N. In some embodiments, A.sub.7 is CH. In some embodiments, A.sub.7
is CR.sub.1, and R.sub.1 is OH. In some embodiments. A.sub.7 is
CR.sub.1, and R.sub.1 is NH.sub.2.
[0137] In some embodiments, B is
##STR00019##
In some embodiments, B is
##STR00020##
In some embodiments, B is
##STR00021##
In some embodiments, each R.sub.2 is H. In some embodiments, each
R.sub.2 is optionally substituted C.sub.1-C.sub.4 alkyl. In some
embodiments, each R.sub.2 is methyl.
[0138] In some embodiments, X.sub.1 and X.sub.2 are each NH. In
some embodiments, X.sub.1 is CH.sub.2 and X.sub.2 is NH. In some
embodiments, X.sub.1 is NH and X.sub.2 is CH.sub.2. In some
embodiments, R.sub.3 is H. In some embodiments, R.sub.3 is halo. In
some embodiments, R.sub.3 is CF.sub.3. In some embodiments, R.sub.3
is optionally substituted C.sub.1-C.sub.4 alkyl. In some
embodiments, R.sub.3 is optionally substituted heteroaryl.
[0139] In some embodiments, D is selected from:
##STR00022##
In some embodiments, D is
##STR00023##
In some embodiments, D is
##STR00024##
In some embodiments, D is
##STR00025##
In some embodiments, D is
##STR00026##
In some embodiments, D is
##STR00027##
In some embodiments, v is 0. In some embodiments, v is 1. In some
embodiments, R.sub.4 is H. In some embodiments, R.sub.4 is
optionally substituted C.sub.1-C.sub.4 alkyl. In some embodiments,
R.sub.4 is Me, Et, or i-Pr. In some embodiments, R.sub.4 is
optionally substituted C.sub.1-C.sub.4 alkylene)-OH. In some
embodiments, R.sub.4 is optionally substituted C.sub.1alkylene)-OH.
In some embodiments, R.sub.4 is optionally substituted
C.sub.2alkylene)-OH. In some embodiments, R.sub.4 is optionally
substituted C.sub.3 alkylene)-OH. In some embodiments, R.sub.4 is
optionally substituted C.sub.4 alkylene)-OH. In some embodiments,
R.sub.4 is hydroxyl. In some embodiments, R.sub.4 is optionally
substituted aryl. In some embodiments, R.sub.4 is phenyl. In some
embodiments, R.sub.4 is optionally substituted benzyl. In some
embodiments, v is 2. In some embodiments, at least one R.sub.4 is
H. In some embodiments, at least one R.sub.4 is optionally
substituted C.sub.1-C.sub.4 alkyl. In some embodiments, at least
one R.sub.4 is Me, Et, or i-Pr. In some embodiments, at least one
R.sub.4 is optionally substituted C.sub.1-C.sub.4 alkylene)-OH. In
some embodiments, at least one R.sub.4 is hydroxyl. In some
embodiments, at least one R.sub.4 is optionally substituted aryl.
In some embodiments, at least one R.sub.4 is optionally substituted
benzyl.
[0140] In some instances, the compounds are embraced by formula
Ib:
##STR00028##
[0141] In some instances, the compounds are embraced by formula
Ic:
##STR00029##
[0142] In some instances, the compounds are embraced by formula
Id:
##STR00030##
[0143] In some instances, the compounds are embraced by formula
Ie:
##STR00031##
[0144] In some instances, the compounds are the compounds as shown
in Tables 1, 2, 3, and 4.
TABLE-US-00001 TABLE 1 Compound No. Structure Name 1 ##STR00032##
1-(1-methyl-6-(pyridin-3-yl)-1H- indazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 2
##STR00033## 1-(5-(benzo[d]isoxazol-6-yl)-1-
methyl-1H-pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 3 ##STR00034##
1-(5-(benzo[d]isoxazol-5-yl)-1- methyl-1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 4
##STR00035## 1-(5-(imidazo[1,2-a]pyridin-7-yl)-
1-methyl-1H-pyrazol-3-yl)-3-(4- ((4-methylpiperazin-1-yl)methyl)-
3-(trifluoromethyl)phenyl)urea 5 ##STR00036##
1-(5-(imidazo[1,2-a]pyridin-8-yl)- 1-methyl-1H-pyrazol-3-yl)-3-(4-
((4-methylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)pheny)urea 6
##STR00037## 1-(1-methyl-5-(quinoxalin-5-yl)-
1H-pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 7 ##STR00038##
1-(4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)-3-(5- (pyridin-3-yl)-1H-pyrazol-3- yl)urea
8 ##STR00039## 1-(5-(2-(difluoromethyl)-4-oxo-
3,4-dihydroquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 9
##STR00040## 1-(6-(2-aminopyrimidin-5-yl)-1-
methyl-1H-indazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 10 ##STR00041##
1-6-(5-aminopyrazin-2-yl)-1- methyl-1H-indazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 11
##STR00042## 1-(6-(2-aminopyrimidin-5-yl)-1H-
indazol-3-yl)-3-(4-(4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 12 ##STR00043##
1-(1-methyl-5-(1-methyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-
pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 13 ##STR00044##
1-(4-(piperazin-1-ylmethyl)-3- (trifluoromethyl)phenyl)-3-(2-
(pyridin-3-yl)benzo[d]oxazol-5- yl)urea 14 ##STR00045##
1-(4-((4-benzylpiperazin-1- yl)methyl)-3-
(trilfuoromethyl)phenyl)-3-(2- (pyridin-3-yl)benzo[d]oxazol-5-
yl)urea 15 ##STR00046## 1-(4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)-3-(2- (pyridin-3-yl)benzo[d]oxazol-5-
yl)urea 16 ##STR00047## 1-(4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)-3-(2- (pyrazolo[1,5-a]pyridin-3-
yl)benzo[d]oxazol-5-yl)urea 17 ##STR00048##
1-(6-methyl-2-(pyrazolo[1,5- a]pyridin-3-yl)benzo[d]oxazol-5-
yl)-3-(4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)urea 18 ##STR00049##
1-(4-methyl-2-(pyrazolo[1,5- a]pyridin-3-yl)benzo[d]oxazol-5-
yl)-3-(4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)urea 19 ##STR00050##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-(3-(2-(4-
methylpiperazin-1- yl)ethyl)phenyl)urea 20 ##STR00051##
N-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-(1H-pyrazol-
1-yl)benzamide 21 ##STR00052## 1-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-3-(2-(1-methyl- 1H-pyrazol-4-yl)-4-((4-
methylpiperazin-1- yl)methyl)phenyl)urea
TABLE-US-00002 TABLE 2 Compound No. Structure Name 22 ##STR00053##
1-(1-methyl-5-(quinazolin-6-yl)- 1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 23
##STR00054## 1-(5-(2-hydroxyquinolin-7-yl)-1-
methyl-1H-pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trithoromethyl)phenyl)urea 24 ##STR00055##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 25
##STR00056## 1-(1-methyl-5-(quinolin-3-yl)-1H-
pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 26 ##STR00057##
1-(5-(3-aminoisoquinolin-7-yl)-1- methyl-1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 27
##STR00058## 1-(5-(2-amino-4- hydroxyquinazolin-6-yl)-1-
methyl-1H-pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 28 ##STR00059##
1-(5-(4-aminoquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 29
##STR00060## 1-(5-(2,4-diaminoquinazolin-6-
yl)-1-methyl-1H-pyrazol-3-yl)-3- (4-((4-methylpiperazin-1-
yl)methyl)-3- (trifluoromethyl)phenyl)urea 30 ##STR00061##
1-(5-(2-aminoquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 31
##STR00062## 2-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-N-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)acetamide 32 ##STR00063##
2-(5-(3-aminoisoquinolin-7-yl)-1- methyl-1H-pyrazol-3-yl)-N-(4-
((4-methylpiperazin-1-yl)methyl)- 3-
(trifluoromethyl)phenyl)acetamide 33 ##STR00064##
2-(5-(2-aminoquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-N-(4-
((4-methylpiperazin-1-yl)methyl)- 3-
(trifluoromethyl)phenyl)acetamide 34 ##STR00065##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-1,2,4-triazol-3-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 35
##STR00066## 1-(4-((4-ethylpiperizin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)-3-(5- (isoquinolin-7-yl)-1-methyl-1H-
pyrazol-3-yl)urea 36 ##STR00067## 1-(4-((4-(2-
hydroxyethyl)piperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)-3-(5- (isoquinolin-7-yl)-1-methyl-1H-
pyrazol-3-yl)urea 37 ##STR00068## 1-(4-((4-isopropylpiperazin-1-
yl)methyl)-3- (trifluoromethyl)phenyl)-3-(5-
(isoquinolin-7-yl)-1-methyl-1H- pyrazol-3-yl)urea 38 ##STR00069##
1-(4-(azepan-1-ylmethyl)-3- (trifluoromethyl)phenyl)-3-(5-
(isoquinolin-7-yl)-1-methyl-1H- pyrazol-3-yl)urea 39 ##STR00070##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-(4-
(morpholinomethyl)-3- (trifluoromethyl)phenyl)urea 40 ##STR00071##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-(4-((4-
phenylpiperidin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 41
##STR00072## 1-(4-((4-hydroxypiperidin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)-3-(5- (isoquinolin-7-yl)-1-methyl-1H-
pyrazol-3-yl)urea 42 ##STR00073## 1-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-3-(4-(piperidin- 1-ylmethyl)-3-
(trifluoromethyl)phenyl)urea 43 ##STR00074##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-(4-((2-
methylpiperidin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 44
##STR00075## 1-(3-bromo-4-((4- methylpiperazin-1-
yl)methyl)phenyl)-3-(5- (isoquinolin-7-yl)-1-methyl-1H-
pyrazol-3-yl)urea 45 ##STR00076## 1-(5-(2-aminoquinazolin-6-yl)-1-
methyl-1H-1,2,4-triazol-3-yl)-3- 4-((4-methylpiperazin-1-
yl)methyl)-3- (trifluoromethyl)phenyl)urea 46 ##STR00077##
1-(5-(isoquinolin-7-yl)-4-methyl- 4H-imidazol-2-yl)-3-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea 47
##STR00078## 1-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-3-(4-((4- methylpiperazin-1- yl)methyl)phenyl)urea
48 ##STR00079## 1-(5-(3-aminoisoquinolin-7-yl)-1-
methyl-1H-pyrazol-3-yl)-3-(4-((1- methylpiperidin-4-yl)methyl)-3-
(trifluoromethyl)phenyl)urea 49 ##STR00080##
2-(5-(2-aminoquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)-N-(4-
((1-methylpiperidin-4-yl)methyl)- 3-
(trifluoromethyl)phenyl)acetamide 50 ##STR00081##
1-(5-(3-aminoisoquinolin-7-yl)- 1,4-dimethyl-1H-imidazol-2-yl)-
3-(4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)urea 51 ##STR00082##
N-(5-(3-aminoisoquinolin-7-yl)-1- methyl-1H-pyrazol-3-yl)-2-(4-((4-
methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)acetamide
52 ##STR00083## 1-(5-(3-aminoisoquinolin-7-yl)-
1H-pyrazol-3-yl)-3-(4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)urea
TABLE-US-00003 TABLE 3 Compound No. Structure Name 53 ##STR00084##
1-(1-methyl-5-(4-(quinoxalin-5- yl)phenyl)-1H-pyrazol-3-yl)-3-(4-
((4-methylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)phenyl)urea 54
##STR00085## 1-(5-(4-(imidazo[1,2-a]pyridin-8-
yl)phenyl)-1-methyl-1H-pyrazol- 3-yl)-3-(4-((4-methylpiperazin-1-
yl)methyl)-3- (trifluoromethyl)phenyl)urea 55 ##STR00086##
1-(5-(4-(6-aminopyridin-3- yl)phenyl)-1H-pyrazol-3-yl)-3-(4-
((4-methylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)phenyl)urea 56
##STR00087## 1-phenyl-3-(2-(pyridin-3- yl)benzo[d]oxazol-5-yl)urea
57 ##STR00088## 1-(2-(pyridin-3- yl)benzo[d]oxazol-5-yl)-3-(3-
(trifluoromethyl)phenyl)urea 58 ##STR00089##
3-phenyl-N-(2-(pyridin-3- yl)benzo[d]oxazol-5- yl)propiolamide 59
##STR00090## (1S,2R)-2-phenyl-N-(2-(pyridin- 3-yl)benzo[d]oxazol-5-
yl)cyclopropane-1-carboxamide 60 ##STR00091##
(Z)-3-phenyl-N-(2-(pyridin-3- yl)benzo[d]oxazol-5- yl)acrylamide 61
##STR00092## N-(5-(3-aminoisoquinolin-7-yl)-1-
methyl-1H-pyrazol-3-yl)-4-((4- methylpiperazin-1-yl)methyl)-1-
naphthamide 62 ##STR00093## 1-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-3-(3-methyl-3,4- dihydro-2H-benzo[e][1,3]oxazin-
7-yl)urea 63 ##STR00094## 1-benzyl.-3-(5-(isoquinolin-7-yl)-
1-methyl-1H-pyrazol-3-yl)urea 64 ##STR00095##
1-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-phenylurea 65
##STR00096## 1-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-3-(2- methoxyphenyl)urea 66 ##STR00097##
N-(5-(3-aminoisoquinolin-7-yl)-1- methyl-1H-pyrazol-3-
yl)benzenesulfonamide 67 ##STR00098##
N-(5-(3-aminoisoquinolin-7-yl)-1- methyl-1H-pyrazol-3- yl)benzamide
68 ##STR00099## 1-(5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)-3-(2- (methylthio)phenyl)urea 69 ##STR00100##
1-(2-fluorophenyl)-3-(5- (isoquinolin-7-yl)-1-methyl-1H-
pyrazol-3-yl)urea 70 ##STR00101## 4-(3-(5-(isoquinolin-7-yl)-1-
methyl-1H-pyrazol-3-yl)ureido)- N-methylbenzenesulfonamide 71
##STR00102## 1-(5-(3-aminoisoquinolin-7-yl)-1-
methyl-1H-pyrazol-3-yl)-3-(4-((1- methylpiperidin-4-
ylidene)methyl)-3- (trifluoromethyl)phenyl)urea 72 ##STR00103##
N-(5-(isoquinolin-7-yl)-1-methyl- 1H-pyrazol-3-yl)-3-
(trithoromethyl)benzenesulfonamide 73 ##STR00104##
3-((5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)amino)-4-((4-((4- methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)phenyl)amino) cyclobut-3-ene-1,2-dione 74
##STR00105## 3-((5-(isoquinolin-7-yl)-1-methyl-
1H-pyrazol-3-yl)amino)-4-((4-((4- methylpiperazin-1-
yl)methyl)phenyl)amino)cyclobut- 3-ene-1,2-dione 75 ##STR00106##
3-((5-(2-aminoquinazolin-6-yl)-1- methyl-1H-pyrazol-3-yl)amino)-4-
((4-((4-methylpiperazin-1- yl)methyl)-3-
(trifluoromethyl)phenyl)amino) cyclobut-3-ene-1,2-dione 76
##STR00107## 3-((5-(2-aminoquinazolin-6-yl)-1-
methyl-1H-pyrazol-3-yl)amino)-4- (cyclopentylamino)cyclobut-3-
ene-1,2-dione
TABLE-US-00004 TABLE 4 Compound No. Structure 77 ##STR00108## 78
##STR00109## 79 ##STR00110## 80 ##STR00111## 81 ##STR00112## 82
##STR00113## 83 ##STR00114## 84 ##STR00115## 85 ##STR00116## 86
##STR00117## 87 ##STR00118## 88 ##STR00119## 89 ##STR00120## 90
##STR00121## 91 ##STR00122## 92 ##STR00123## 93 ##STR00124## 94
##STR00125## 95 ##STR00126## 96 ##STR00127## 97 ##STR00128## 98
##STR00129## 99 ##STR00130##
[0145] More specifically, the inventive compound can be any of the
specific examples shown herein as exemplary compounds of the
invention.
Methods of Use
[0146] XBP1 is believed to sustain dendritic cell immunosuppressive
activity within the tumor microenvironment by directly upregulating
enzymes involved in triglyceride biosynthesis (Cubillos-Ruiz et
al., Cell 161(7): 1527-38 (2015)). XBP1, also known as X-box
binding protein 1, is a transcription factor that regulates the
expression of genes involved in the proper functioning of the
immune system and in the cellular stress response. It is believed
that IRE1.alpha.-mediated XBP1 activation is fueled by the
induction of reactive oxygen species and subsequent formation of
peroxidized lipids.
[0147] The most conserved arm of the endoplasmic reticulum (ER)
stress response is the dual enzyme, IRE1.alpha.. Activated during
periods of ER stress, the IRE1.alpha. endoribonuclease domain
excises a short nucleotide fragment from Xhp1 mRNA to generate the
functional transcription factor, XBP1. This potent, multitasking
protein promotes cell survival by upregulating expression of a
broad range of critical genes involved in protein folding and
quality control. XBP1 drives the pathogenesis of triple negative
breast cancer (TNBC) by promoting tumor cell survival and
metastatic capacity under hypoxic conditions. Silencing of XBP1 in
TNBC leads to suppression of tumor initiation, progression, and
recurrence.
[0148] Unexpectedly, the inventors have identified a second
mechanism by which XBP1 promotes tumor progression: by confounding
the development of protective antitumor immunity in the ovarian
cancer tumor microenvironment. Without XBP1, tumor resident
dendritic cells failed to accumulate intracellular lipids, which
normally disrupt effective antigen cross-presentation. This
pathological lipid accumulation is fundamentally driven by reactive
oxygen species-mediated lipid peroxidation, which directly
destabilizes protein-folding chaperones within the endoplasmic
reticulum to induce a state of ER stress and XBP1 activation.
Additionally, it is believed that IRE1.alpha.-mediated XBP1
signaling is also critical for myeloid cell production of
immunosuppressive prostaglandins such as prostaglandin E2
(PGE2).
[0149] Novel small-molecule IRE1.alpha. inhibitors with the ability
to induce two parallel and mutually reinforcing anti-tumor
mechanisms, namely the direct inhibition of tumor growth and the
simultaneous induction of robust anti-tumor immunity are highly
desirable, as no effective, targeted therapies currently exist for
either TNBC or ovarian cancer. The compositions and methods
described herein are novel IRE1.alpha. kinase inhibitors that
exhibit immune-modulatory properties. No currently existing
compounds possess activity in the presence of human or mouse
ovarian cancer ascites, a critical requirement for IRE1.alpha.
inhibitor usage clinically.
[0150] Novel direct and indirect small molecule IRE1.alpha.
inhibitors can prevent lipid accumulation in myeloid cells exposed
to ovarian cancer-derived ascites supernatants. Furthermore, the
identified direct IRE1.alpha. inhibitors have unique chemical
structures compared to currently available compounds, and therefore
can have unique binding mechanisms, inhibitory activity, and
off-target effects. Additionally, the inventors have demonstrated
that these compounds block myeloid cell immunosuppression mediated
by tumor-associated factors. The invention also includes novel uses
for vitamin E and hydralazine derivatives, which indirectly prevent
IRE1.alpha. activation and thereby suppress cancer cell-induced
lipid accumulation in myeloid dendritic cells.
[0151] The IRE1.alpha.-XBP1 pathway is therefore involved in a
variety of pathological conditions, including neurodegenerative
diseases, inflammation, metabolic disorders, liver dysfunction,
brain ischemia, heart ischemia, autoimmune diseases, and cancer.
Hence, modulation of this pathway provides therapeutic methods
useful for treatment of such diseases. The identified small
molecule compounds can, for example, be employed as therapeutic
compounds that enhance dendritic cell and T cell anti-tumor
activity in mammals. For example, the compounds disclosed herein
can be used to treat murine and human ovarian cancers.
[0152] Hence, a method is described herein that includes
administering any of the compounds or the composition described
herein. The mammal can be in need of administration of the
composition. For example, the mammal can have cancer, a
neurodegenerative disease, inflammation, a metabolic disorder,
liver dysfunction, brain ischemia, heart ischemia, or an autoimmune
disease. In some cases, the mammal has triple negative breast
cancer or ovarian cancer.
Compositions and Combination Treatments
[0153] The IRE1.alpha. inhibitor compounds, their pharmaceutically
acceptable salts or hydrolyzable esters of the present invention
may be combined with a pharmaceutically acceptable carrier to
provide pharmaceutical compositions useful for treating the
biological conditions or disorders noted herein in mammalian
species, and more preferably, in humans. The particular carrier
employed in these pharmaceutical compositions may vary depending
upon the type of administration desired (e.g. intravenous, oral,
topical, suppository, or parenteral).
[0154] In preparing the compositions in oral liquid dosage forms
(e.g. suspensions, elixirs and solutions), typical pharmaceutical
media, such as water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like can be employed.
Similarly, when preparing oral solid dosage forms (e.g. powders,
tablets and capsules), carriers such as starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like can be employed.
[0155] Another aspect of an embodiment of the invention provides
compositions of the compounds of the invention, alone or in
combination with another IRE1.alpha. inhibitor or another type of
therapeutic agent, or both. For example, the compositions and
methods described herein can include one or more agents such as
vitamin E, an antioxidant, and/or hydralazine. Such agents can
sequester lipid peroxidation byproducts, and can be effective
treatments for controlling ER stress responses and sustained
IRE1.alpha./XBP1 signaling in tumor-associated dendritic cells
exposed, for example, to ovarian cancer-derived ascites.
[0156] As set forth herein, compounds of the invention include
stereoisomers, tautomers, solvates, hydrates, salts including
pharmaceutically acceptable salts, and mixtures thereof.
Compositions containing a compound of the invention can be prepared
by conventional techniques, e.g. as described in Remington: The
Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by
reference herein. The compositions can appear in conventional
forms, for example capsules, tablets, aerosols, solutions,
suspensions or topical applications.
[0157] Typical compositions include one or more compounds of the
invention and a pharmaceutically acceptable excipient which can be
a carrier or a diluent. For example, the active compound wall
usually be mixed with a earner, or diluted by a carrier, or
enclosed within a, carrier which can be in the form of an ampoule,
capsule, sachet, paper, or other container. When the active
compound is mixed with a carrier, or when the carrier serves as a
diluent, it can be solid, semi-solid, or liquid material that acts
as a vehicle, excipient, or medium for the active compound. The
active compound can be adsorbed on a granular solid carrier, for
example contained in a sachet. Some examples of suitable carriers
are water, salt solutions, alcohols, polyethylene glycols, poly
hydroxy ethoxy fated castor oil, peanut oil, olive oil, gelatin,
lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,
cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar,
pectin, acacia, stearic acid or lower alkyl ethers of cellulose,
silicic acid, fatty acids, fatty acid amines, fatty acid
monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
Similarly, the carrier or diluent can include any sustained release
material known in the art, such as glyceryl monostearate or
glyceryl distearate, alone or mixed with a wax.
[0158] The formulations can be mixed with auxiliary agents which do
not deleteriously react with the active compounds. Such additives
can include wetting agents, emulsifying and suspending agents, salt
for influencing osmotic pressure, buffers and/or coloring
substances preserving agents, sweetening agents or flavoring
agents. The compositions can also be sterilized if desired.
[0159] The route of administration can be any route which
effectively transports the active compound of the invention which
inhibits the activity of the IRE1.alpha. to the appropriate or
desired site of action, such as oral, nasal, pulmonary, buccal,
subdermal, intradermal, transdermal or parenteral, e.g., rectal,
depot, subcutaneous, intravenous, intraurethral, intramuscular,
intranasal, ophthalmic solution or an ointment, the oral route
being preferred.
[0160] For parenteral administration, the carrier will typically
comprise sterile water, although other ingredients that aid
solubility or serve as preservatives can also be included.
Furthermore, injectable suspensions can also be prepared, in which
case appropriate liquid carriers, suspending agents and the like
can be employed.
[0161] For topical administration, the compounds of the present
invention can be formulated using bland, moisturizing bases such as
ointments or creams.
[0162] If a solid carrier is used for oral administration, the
preparation can be tableted, placed in a hard gelatin capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. If a liquid carrier is used, the preparation can be in the
form of a syrup, emulsion, soft gelatin capsule or sterile
injectable liquid such as an aqueous or non-aqueous liquid
suspension or solution.
[0163] Injectable dosage forms generally include aqueous
suspensions or oil suspensions which can be prepared using a
suitable dispersant or wetting agent and a suspending agent
Injectable forms can be in solution phase or in the form of a
suspension, which is prepared with a, solvent or diluent.
Acceptable solvents or vehicles include sterilized water, Ringer's
solution, or an isotonic aqueous saline solution. Alternatively,
sterile oils can be employed as solvents or suspending agents.
Preferably, the oil or fatty acid is non-volatile, including
natural or synthetic oils, fatty acids, mono-, di- or
tri-glycerides.
[0164] For injection, the formulation can also be a powder suitable
for reconstitution with an appropriate solution as described above.
Examples of these include, but are not limited to, freeze dried,
rotary dried or spray dried powders, amorphous powders, granules,
precipitates, or particulates. For injection, the formulations can
optionally contain stabilizers, pH modifiers, surfactants,
bioavailability modifiers and combinations of these. The compounds
can be formulated for parenteral administration by injection such
as by bolus injection or continuous infusion. A unit dosage form
for injection can be in ampoules or in multi-dose containers.
[0165] The formulations of the invention can be designed to provide
quick, sustained, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in
the art. Thus, the formulations can also be formulated for
controlled release or for slow release.
[0166] Compositions contemplated by the present invention can
include, for example, micelles or liposomes, or some other
encapsulated form, or can be administered in an extended release
form to provide a prolonged storage and/or delivery effect.
Therefore, the formulations can be compressed into pellets or
cylinders and implanted intramuscularly or subcutaneously as depot
injections. Such implants can employ known inert materials such as
silicones and biodegradable polymers, e.g.,
polylactide-polyglycolide. Examples of other biodegradable polymers
include poly(orthoesters) and poly (anhydrides).
[0167] For nasal administration, the preparation can contain a
compound of the invention which inhibits the enzymatic activity of
the focal adhesion kinase, dissolved or suspended in a liquid
carrier, preferably an aqueous earner, for aerosol application. The
carrier can contain additives such as solubilizing agents, e.g.,
propylene glycol, surfactants, absorption enhancers such as
lecithin (phosphatidylcholine) or cyclodextrin, or preservatives
such as parabens.
[0168] For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
[0169] Tablets, dragees, or capsules having talc and/or a
carbohydrate carrier or binder or the like are particularly
suitable for oral application. Preferable carriers for tablets,
dragees, or capsules include lactose, corn starch, and/or potato
starch. A syrup or elixir can be used in cases where a sweetened
vehicle can be employed.
[0170] A typical tablet that can be prepared by conventional
tableting techniques can contain:
TABLE-US-00005 Core: Active compound (as free compound or salt
thereof) 250 mg Colloidal silicon dioxide (Aerosil) .RTM. 1.5 mg
Cellulose, microcryst. (Avicel) .RTM. 70 mg Modified cellulose gum
(Ac-Di-Sol) .RTM. 7.5 mg Magnesium stearate Ad. Coating: HPMC
approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg *Acylated
monoglyceride used as plasticizer for film coating.
[0171] A typical capsule for oral administration contains compounds
of the invention (250 mg), lactose (75 mg) and magnesium stearate
(15 mg). The mixture is passed through a 60 mesh sieve and packed
into a No. 1 gelatin capsule. A typical injectable preparation is
produced by aseptically placing 250 mg of compounds of the
invention into a, vial, aseptically freeze-drying and sealing. For
use, the contents of the vial are mixed with 2 mL of sterile
physiological saline, to produce an injectable preparation.
[0172] The compounds of the invention can be administered to a
human in need of such treatment, prevention, elimination,
alleviation or amelioration of a malcondition that is mediated
through the action of IRE1.alpha., for example, cancer,
neurodegenerative diseases, inflammation, metabolic disorders,
liver dysfunction, brain ischemia, or heart ischemia.
[0173] The pharmaceutical compositions and compounds of the present
invention can generally be administered in the form of a dosage
unit (e.g. tablet, capsule, etc.) in an amount from about 1 ng/kg
of body weight to about 0.5 g/kg of body weight, or from about
1.mu./kg of body weight to about 500 mg/kg of body weight, or from
about 1.mu./kg of body weight to about 250 mg/kg of body weight,
most preferably from about 20.mu./kg of body weight to about 100
mg/kg of body weight. Those skilled in the art will recognize that
the particular quantity of pharmaceutical composition and/or
compounds of the present invention administered to an individual
will depend upon a number of factors including, without limitation,
the biological effect desired, the condition of the individual and
the individual's tolerance for the compound.
[0174] The compounds of the invention are effective over a wide
dosage range. For example, in the treatment of adult humans,
dosages from about 0.05 to about 5000 mg, preferably from about 1
to about 2000 mg, and more preferably between about 2 and about
2000 mg per day can be used. A typical dosage is about 10 mg to
about 1000 mg per day. In choosing a regimen for patients it can
frequently be necessary to begin with a higher dosage and when the
condition is under control to reduce the dosage. The exact dosage
will depend upon the activity of the compound, mode of
administration, on the therapy desired, form in which administered,
the subject to be treated and the body weight of the subject to be
treated, and the preference and experience of the physician or
veterinarian in charge. IRE1.alpha. inhibitor bioactivity of the
compounds of the invention can be determined by use of an in vitro
assay system which measures the activity of IRE lot, which can be
expressed as EC.sub.50 or IC.sub.50 values, as are well known in
the art inhibitors of the invention can be determined by the method
described in the Examples.
[0175] Generally, the compounds of the invention are dispensed in
unit dosage form including from about 0.05 mg to about 1000 mg of
active ingredient together with a pharmaceutically acceptable
carrier per unit dosage.
[0176] Usually, dosage forms suitable for oral, nasal, pulmonal or
transdermal administration include from about 125 .mu.g to about
1250 mg, preferably from about 250 .mu.g to about 500 mg, and more
preferably from about 2.5 mg to about 250 mg, of the compounds
admixed with a pharmaceutically acceptable carrier or diluent.
[0177] Dosage forms can be administered daily, or more than once a
day, such as twice or thrice daily. Alternatively dosage forms can
be administered less frequently than daily, such as every other
day, or weekly, if found to be advisable by a prescribing
physician.
[0178] An embodiment of the invention also encompasses prodrugs of
a compound of the invention which on administration undergo
chemical conversion by metabolic or other physiological processes
before becoming active pharmacological substances. Conversion by
metabolic or other physiological processes includes without
limitation enzymatic (e.g., specific enzymatically catalyzed) and
non-enzymatic (e.g., general or specific acid or base induced)
chemical transformation of the prodrug into the active
pharmacological substance. In general, such prodrugs will be
functional derivatives of a compound of the invention which are
readily convertible in vivo into a compound of the invention.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
[0179] In another embodiment, there are provided methods of making
a composition of a compound described herein including formulating
a, compound of the invention with a pharmaceutically acceptable
carrier or diluent. In some embodiments, the pharmaceutically
acceptable earner or diluent is suitable for oral administration.
In some such embodiments, the methods can further include the step
of formulating the composition into a tablet or capsule. In other
embodiments, the pharmaceutically acceptable carrier or diluent is
suitable for parenteral administration. In some such embodiments,
the methods further include the step of lyophilizing the
composition to form a lyophilized preparation.
[0180] The compounds of the invention can be used therapeutically
in combination with i) one or more other IRE1.alpha. inhibitors
and/or ii) one or more other types of protein kinase inhibitors
and/or one or more other types of therapeutic agents which can be
administered orally in the same dosage form, in a separate oral
dosage form (e.g., sequentially or non-sequentially) or by
injection together or separately (e.g., sequentially or
non-sequentially).
[0181] Accordingly, in another embodiment the invention provides
combinations, comprising:
[0182] a) a compound of the invention as described herein; and
[0183] b) one or more compounds comprising: [0184] i) other
compounds of the present invention, [0185] ii) other agents or
medicaments adapted for treatment of a disease or malcondition for
which inhibition of IRE1.alpha. Is medically indicated, for
example, vitamin E, an antioxidant, hydralazine, or any combination
thereof. Such compounds, agents or medicaments can be medically
indicated for treatment of cancers such as TNRC or ovarian cancer,
neurodegenerative diseases, inflammation, metabolic disorders,
liver dysfunction, autoimmune diseases, brain ischemia, or heart
ischemia.
[0186] Combinations of the invention include mixtures of compounds
from (a) and (b) in a single formulation and compounds from (a) and
(b) as separate formulations. Some combinations of the invention
can be packaged as separate formulations in a kit. In some
embodiments, two or more compounds from (b) are formulated together
while a compound of the invention is formulated separately.
[0187] The dosages and formulations for the other agents to be
employed, where applicable, will be as set out in the latest
edition of the Physicians' Desk Reference, incorporated herein by
reference.
[0188] The Examples illustrate some of experimental work performed
in the development of the invention.
Example 1: Vitamin E and Hydrazine
Suppress Lipid Accumulation in Myeloid Dendritic Cells
[0189] Consistently, both vitamin E and hydralazine suppressed
pathological intracellular lipid accumulation in myeloid dendritic
cells exposed to ovarian cancer ascites supernatants (FIG. 1).
Based on the strong evidence linking aberrant lipid accumulation
myeloid cell immunosuppression, these agents can be used to restore
the function of antigen presenting cells in the tumor
microenvironment.
Example 2: FRET Assay
[0190] In addition to the indirect inhibitors vitamin E and
hydralazine, the compositions and methods described herein can
include one or more direct, small molecule IRE1.alpha.
inhibitors.
[0191] IRE1.alpha. is a dual enzyme, containing a kinase and
endoribonuclease domain. Phosphorylation of the kinase domain
during times of ER stress leads to activation of the
endoribonuclease domain and subsequent Xbp1 splicing, indicating
that small molecules designed to block either the kinase domain or
the endoribonuclease domain are feasible inhibitory strategies.
[0192] To evaluate potential small molecule IRE1 inhibitors, a
Forster resonance energy transfer (FRET)-based small molecule IRE1
screening system was used. In brief, a small XBP1-mimetic RNA
hairpin containing sequence features required for
IRE1.alpha.-mediated splicing has been synthesized with the
fluorophore 6FAM attached to the 5' end and the quenching dye Black
Hole Quencher 1 (BHQ1) attached to the 3' end. When the hairpin is
intact, 6FAM fluorescence is completely absorbed by BHQ1; however,
IRE1.alpha.-mediated cleavage of the RNA hairpin leads to an
increase in the fluorescence signal. The inventors also
incorporated a point mutant version of this same RNA hairpin that
is resistant to IRE1.alpha.-mediated cleavage to control for
non-specific RNAse contamination (FIG. 2).
Example 3: Potent IRE1.alpha. Inhibitors Identified by FRET
Assay
[0193] Approximately 170 compounds were obtained and evaluated
using the FRET assay, and at least one active compound was
identified from this screen (IC50: 26 .mu.M, FIG. 3). Compound
activity was evaluated at the biotechnology company Cyclofluidic
guided entirely by the inventors.
Example 4: Computational Screening
[0194] After establishing the FRET system, computational models of
IRE1.alpha. based on published crystal structures were used to dock
over 7 million compounds commercially available from the company
eMolecules. Docking was performed using the Schrodinger software
suite.
[0195] The cytoplasmic domain of human IRE1.alpha. (approximately
residues 465-977) has been crystallized five separate times (PDBs
4PL3, 4U6R, 4PL4, 4PL5, and 3P23) in different states of
phosphorylation and activation, as well as with both
endoribonuclease inhibitors and kinase Inhibitors (Sanches et al.,
Nature Communications 5:4202 (2014); Harrington et ah, ACS Med Chem
Letters 6:68-72 (2015); All et al., The EMBO J 30:894-905 (2011)).
These studies and others (see, e.g., Wang et al., Nature Chem Biol
8:982-9 (2012)) provide substantial evidence that IRE1.alpha.
kinase inhibitors can either inhibit or activate the IRE1.alpha.
endoribonuclease domain depending on their binding mode.
[0196] Type I kinase inhibitors that lock the IRE1.alpha. kinase
domain into a "DFG-out" conformation block endoribonuclease
activity, while inhibitors that lock the kinase domain into a
"DFG-in" conformation trigger mRNA splicing despite abrogating
autophosphorylation.
[0197] All known endoribonuclease inhibitors bind to a shallow
pocket in a highly solvent exposed manner at the IRE1.alpha.
C-terminus, and make too few key binding contacts to effectively
model computationally.
[0198] At the time this project was initiated, the only kinase
inhibitor co-crystallized with IRE1.alpha. enforced a Type I,
DFG-in configuration (PDB 4U6R). To generate a model of IRE1.alpha.
in the target Type II, DFG-out configuration, the inventors
computationally grafted the DFG loop from the crystal structure of
the SRC kinase bound to the type II inhibitor
1-(4-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phen-
yl)-3-(3-(trifluoromethyl)phenyl)urea onto the 4U6R IRE1 crystal
structure, as this compound also inhibits the IRE1.alpha. kinase
and endoribonuclease domains. After grafting the SRC DFG-loop onto
the IRE1.alpha. crystal structure, the SRC inhibitor was docked
into the hybrid model for quality control.
[0199] The SRC inhibitor exhibited a good docking score using
unconstrained rigid receptor docking, as its urea group made
hydrogen bonds with both a serine residue N-terminal to the DFG
loop and a lysine-aspartate salt bridge in the kinase active site.
With the initial model validated, the set of all compounds
commercially available from the company eMolecules (over 7 million
in sum) was used as the screening collection. From the full list of
7 million compounds, only urea and amide-containing structures were
computationally docked (.about.800,000 compounds), as these motifs
form key hydrogen bond interactions with kinase DFG loops. Top
scoring compounds were clustered by structural similarity and
filtered for those with desirable properties, and the top scoring
compounds from each of 49 clusters were ordered and tested by FRET
assay.
[0200] Initial results indicated that one of the 49 compounds
exhibited some activity against IRE1. The structure-activity
relationships of an additional 62 compounds were examined. However,
secondary screening after FRET assay optimization, performed at the
CRO Cyclofluidic, revealed that none of these 111 compounds exerted
any activity. Cyclofluidic had published a small set of
approximately 50 compounds (5) from their internal work on
derivatives of the BCR-ABL kinase inhibitor Ponatinib, and the
inventors also screened these published compounds for IRE1.alpha.
inhibitory activity.
[0201] While optimizing the first compound series, new crystal
structures of IRE1.alpha. in complex with Type II, DFG-out-inducing
kinase inhibitors became available (Concha et al., Molecular
Pharmacol 88:1011-2 (2015)), which was used to develop a second
model of IRE1.alpha..
[0202] First, the ponatinib-like compounds were docked into this
new model, allowing some structural flexibility, to control for
model quality. Subsequently, a second computational screen was
performed with the updated model, and compounds for follow up were
selected as follows:
[0203] 1. Docked into the ponatinib-like compound induced
structure.
[0204] 2. H-bond with hinge NH
[0205] 3. Strained compounds removed
[0206] 4. Any compound with similarity to any of the known
compounds tested thus far removed
[0207] 5. Clustering
[0208] 6. Selecting the highest docking score per cluster
[0209] The top 63 compounds based on this strategy were then
tested, and only one compound showed weak activity by FRET assay
(FIG. 3).
Example 5: Design of Additional Compounds
[0210] New small molecule compounds were designed to inhibit the
human IRE1.alpha. kinase domain. Multiple variants of the original
compound series were designed and ranked by computational docking
score using the software LiveDesign. High scoring compounds were
synthesized and evaluated biochemically by the IRE1.alpha. FRET
assay.
Example 6: In Vitro FRET Assay Protocol
[0211] In vitro FRET assay was performed to evaluate the ability of
select compounds to inhibit IRE1, the results of which are
summarized in the following table.
[0212] To perform the in vitro FRET assay, 1.times. complete assay
buffer (CAB; 1M DTT, 50 mM sodium citrate pH 7.15, 1 mM magnesium
acetate, 0.02% Tween 20) was used to dilute SignalChem IRE1.alpha.
protein to a final concentration of 2 nM. Selected compounds were
serially diluted with DMSO in a non-binding black 384-well plate
for a total of 15 .mu.l in each well, 2 .mu.l of the serially
diluted compound or DMSO control were then added to new wells
containing 98 .mu.l of 1.times.CAB, for a total volume of 100
.mu.l, 10 .mu.l of which were then transferred to wells of a new
plate, 5 .mu.l of the diluted IRE1.alpha. was then added to each
well, 5 .mu.l of a 400 mM XBP1 RNA probe was then added to each
well. Fluorescence was then read over 30 minutes in kinetic mode
(485/515 nm). Two RNA probes were used, XBP1 wildtype
(CAUGUCCGCAGCACAUG; SEQ ID NO: 1) which is able to be spliced by
active IRE1.alpha. or XBP1 mutant (CAUGUCCCCAGCACAUG; SEQ ID NO: 2)
which is unable to be spliced. Each probe contained a 5' 6-FAM
modification and a 3' IOWA Black FQ modification.
[0213] A second FRET assay was performed to assess ATP-mediated
inhibition. In this case, compounds and IRE1.alpha. were prepared
and combined as discussed above, with the addition of ATP up to 1
mM final concentration. This mixture was incubated at room
temperature for 60 minutes and then 5 .mu.l of 400 nM XBP1 wildtype
or mutant RNA probe was added. Plates were then read over 30
minutes in kinetic mode (485/515 nm).
TABLE-US-00006 Compound Mean EC.sub.50 Ref. No, (nM) 76 C 75 A 74 A
21 C 73 A 57 A 51; Formic Acid B 50; HCl B 72 C 49; TFA D 48; TFA B
71; TFA B 20 D 19 D 47 D 70 D 69 D 68 D 46; TFA A 45; TFA B 67; TFA
D 66; TFA D 65 D 64 D 63 D 62 D 44 B 43 D 42 D 41 D 40 D 39 D 38 D
37 A 36 A 35 A 61 D 34; TFA B 33; TFA B 32; TFA D 31; TFA B 18; TFA
D 17; TFA D 16; TFA A 15; HCl D 14 C 13 D 60 B 59 B 58; HCl D 57 B
56 D 30 D 30 A 12 B 11 B 10 B 9 A 8 A 29 A 28 A 27 A 26; TFA A 55 B
7 B 54 A 53 D 6 D 25 B 24; TFA A 5 D 4 D 3 D 23 B 2 B 22 A 1 A
Note: Biochemical assay Mean EC.sub.50 data are designated within
the following ranges: A: .ltoreq.5000 nM B: >5000 nM to
.ltoreq.50000 nM C: >50000 nM to .ltoreq.100000 nM D: >100000
nM
REFERENCES
[0214] 1. Wang, L., et al., Divergent allosteric control of the
IRE1 alpha endoribonuclease using kinase inhibitors. Nat Chem Biol,
2012, 8(12): p. 982-9. [0215] 2. Harrington, P. E., et al.,
Unfolded Protein Response in Cancer: IRE1alpha Inhibition by
Selective Kinase Ligands Does Not Impair Tumor Cell Viability: ACS
Med Chem Lett, 2015, 6(1): p, 68-72. [0216] 3. Concha, N. O., et
al., Long-Range Inhibitor-Induced Conformational Regulation of
Human IRE1alpha Endoribonuclease Activity. Mol Pharmacol, 2015.
88(6): p. 1011-23. [0217] 4. Mendez, A. S., et al., Endoplasmic
reticulum stress-independent activation of unfolded protein
response kinases by a small molecule ATP-mimic. Elife, 2015. 4.
[0218] 5. Cross, B. C., et al., The molecular basis for selective
inhibition of unconventional mRNA splicing by an IRE1-binding small
molecule. Proc Natl Acad Sci USA, 2012. 109(15): p. E869-78. [0219]
6. Tang, C. H., et al., Inhibition of ER stress-associated
IRE-1/XBP-1 pathway reduces leukemic cell survival. J Clin Invest,
2014. 124(6): p. 2585-98. [0220] 7. Volkmann, K., et al., Potent
and selective inhibitors of the inositol-requiring enzyme I
endoribonuclease. J Biol Chem, 2011. 286(14): p. 12743-55. [0221]
8. Papandreou, I., et al., Identification of an Ire1alpha,
endonuclease specific inhibitor with cytotoxic activity against
human multiple myeloma. Blood, 2011. 117(4): p. 1311-4. [0222] 9.
Mirmura, N., et al., Blockade of XBP1 splicing by inhibition of
IRE1alpha is a promising therapeutic option in multiple myeloma.
Blood, 2012. 119(24): p. 5772-81. [0223] 10. Cubillos-Ruiz, J. R.,
et al., ER Stress Sensor XBP1 Controls Anti-tumor Immunity by
Disrupting Dendritic Cell Homeostasis. Cell, 2015. 161(7): p.
1527-38, [0224] 11. Desai, B., et al., Rapid discovery of a novel
series of Abl kinase inhibitors by application of an integrated
microfluidic synthesis and screening platform. J Med Client, 2013.
56(7): p. 3033-47. [0225] 12. Sanches M, Duffy N M, Talukdar M,
Thevakumaran N, Chiovitti D, Canny M D, et al. Structure and
mechanism of action of the hydroxy-aryl-aldehyde class of IRE1
endoribonuclease inhibitors. Nature communications, 2014; 5:4202.
[0226] 13. Harrington P E, Biswas K, Malwitz D, Tasker A S, Mohr C,
Andrews K L, et al. Unfolded Protein Response in Cancer: IRE1alpha
Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell
Viability. ACS medicinal chemistry letters, 2015; 6:68-72. [0227]
14. Ali M M, Bagratuni T, Davenport E L, Nowak P R,
Silva-Santisteban M C, Hardcastle A, et al. Structure of the Ire1
autophosphorylation complex and implications far the unfolded
protein response. The EMBO journal, 2011; 30:894 905. [0228] 15.
Wang L, Perera B G, Hari S B, Bbhatarai B, Backes B. J, Seeliger M
A, et al. Divergent allosteric control of the IRE1alpha
endoribonuclease using kinase inhibitors. Nature chemical biology,
2012; 8:982-9. [0229] 16. Desai B, Dixon K, Farrant E, Feng Q,
Gibson K R, van Hoorn W P, et al. Rapid discovery of a novel series
of Abl kinase inhibitors by application of an integrated
microfluidic synthesis and screening platform. Journal of medicinal
chemistry, 2013; 56:3033-47. [0230] 17. Concha N O, Smallwood A,
Bonnette W, Totoritis R, Zhang G, Federowicz K, et al. Long-Range
Inhibitor-Induced Conformational Regulation of Human IRE1alpha
Endoribonuclease Activity. Molecular pharmacology. 2015;
88:1011-23.
[0231] All patents and publications referenced herein are hereby
specifically incorporated by reference to the same extent as if it
had been incorporated by reference in its entirety individually or
set forth herein in its entirety. Applicants reserve the right to
physically incorporate into this specification any and all
materials and information from any such cited patents or
publications.
Additional Embodiments
[0232] The following exemplary embodiments are provided, the
numbering of which is not to be construed as designating levels of
importance:
[0233] Embodiment 1 provides a compound of formula I:
##STR00131##
[0234] wherein: [0235] A and B are separately each a heterocyclyl
ring or a phenyl group, where the A ring has x R.sub.1
substituents; [0236] C is phenyl or pyridinyl; [0237] D is
heterocyclyl ring; [0238] linkage.sub.1 is a single bond between A
and B; [0239] linkage.sub.2 is a C.sub.1-C.sub.3 alkylamido,
amidoalkyl, amino, urea, alkylurea, or ureaalkyl with a first and
second terminal atom; [0240] y is an integer of 0-3, and when y is
0, the linkage between the rings is a single bond; [0241] x is an
integer of 0-4; [0242] v is an integer of 0-2; [0243] R.sub.1
substituents on the A ring are selected from amino, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted ether,
optionally substituted C.sub.1-C.sub.4 alkoxy, oxy, hydroxy,
--NH--SO.sub.2-phenyl-(R.sub.5), and cyano; [0244] R.sub.2
substituents on the B ring are selected from amino, and optionally
substituted C.sub.1-C.sub.4 alkyl; [0245] R.sub.3 substituents on
the C ring are selected from halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally substituted heteroaryl; and
[0246] R.sub.4 substituents on the D ring are selected from
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, (optionally substituted
C.sub.1-C.sub.3 alkylene)-OH, hydroxy, optionally substituted aryl,
optionally substituted benzyl, and optionally substituted
benzaldehyde; [0247] R.sub.5 is halo; or a pharmaceutically
acceptable salt thereof.
[0248] Embodiment 2 provides the compound of embodiment 1, where
the A ring is heteroaromatic.
[0249] Embodiment 3 provides a, compound of any one of embodiments
1 or 2, where the A ring is a fusion of two rings.
[0250] Embodiment 4 provides a compound of any one of embodiments
1-3, where the A ring is indazole, imadazopyridine,
imadazopyrazine, imadazopyridazine, pyrrolopyridine,
hexaliydrothienopyrimidine, imidazole, pyrazole, pyrazine,
pyridine, pyrimidine, phenylpyrimidinamine, quinoiinyl,
isoquinolinyl, tetrahydroquinolinyl, and quinazolinyl.
[0251] Embodiment 5 provides a compound of any one of embodiments
1-4, where the A ring is selected from:
##STR00132##
[0252] Embodiment 6 provides a compound of any one of embodiments
1-5, where the B ring is a single, non-fused ring.
[0253] Embodiment 7 provides a compound of embodiment 6, where the
B ring is B ring is pyrazolyl, imidazoiyl, or triazolyl.
[0254] Embodiment 8 provides a compound of any one of embodiments
1-5, where the B ring is a fusion of two rings.
[0255] Embodiment 9 provides a compound of any one of embodiments
1-8, where the B ring is selected from:
##STR00133##
[0256] Embodiment 10 provides a compound of any one of embodiments
1-9, wherein the C ring is phenyl.
[0257] Embodiment 11 provides a compound of any one of embodiments
1-10, wherein the linkage.sub.2 is selected from:
##STR00134## [0258] wherein a hydrogen atom on Ring B replaced by
the first terminal atom of linkage.sub.2 and a hydrogen atom on
Ring C is replaced by the second terminal atom of
linkage.sub.2.
[0259] Embodiment 12 provides a compound of any one of embodiments
1-11, wherein the D ring is a heterocyclyl ring containing at least
one N atom.
[0260] Embodiment 13 provides a compound of embodiment 12, wherein
the D ring is piperidinyl, piperazinyl, or morpholinyl.
[0261] Embodiment 14 provides a compound of any one of embodiments
1-11, wherein D ring is selected from
##STR00135##
[0262] Embodiment 15 provides a compound of any one of embodiments
1-14, where the R.sub.1 substituents on the A ring are selected
from amino and C.sub.1-C.sub.3 alkyl.
[0263] Embodiment 16 provides a compound of any one of embodiments
1-15, where the R.sub.1 substituents on the A ring are selected
from --NH.sub.2 and CH.sub.3.
[0264] Embodiment 17 provides a compound of any one of embodiments
1-14, with x=0.
[0265] Embodiment 18 provides a compound of any one of embodiments
1-16, with x=1.
[0266] Embodiment 19 provides a compound of any one of embodiments
1-16, with x=2.
[0267] Embodiment 20 provides a compound of any one of embodiments
1-19, with x=0, 1 or 2 when the A ring is a fusion of two
rings.
[0268] Embodiment 21 provides a compound of any one of embodiments
1-16, with x=1 or 2 when the A ring is a single, nonfused ring.
[0269] Embodiment 22 provides a compound of any one of embodiments
1-21, wherein the R.sub.3 substituent on the C ring is
CF.sub.3.
[0270] Embodiment 23 provides a compound of any one of embodiments
1-22, wherein the R.sub.4 substituents on the D ring are selected
from CH.sub.3, CH.sub.3CHCH.sub.3, CH.sub.3CH(CH.sub.2)CH.sub.3,
and CH.sub.3CH.sub.2CH.sub.3OH.
[0271] Embodiment 24 provides a compound of formula Ia:
##STR00136##
[0272] wherein, [0273] A.sub.1 is N, CH, or CR.sub.1; A.sub.2 is N,
CH, or CR.sub.1; A.sub.3 is N, CH, or CR.sub.t; A.sub.4 is N, CH,
or CR.sub.1; A.sub.5 is N, CH, or CR.sub.1; A.sub.6 is N, CH, or
CR.sub.1; A.sub.7 is N CH, or CR.sub.1; [0274] v is an integer of
0-2; [0275] Each R.sub.1 is NH.sub.2 or OH; provided that the
number of R.sub.1 on the A ring does not exceed 4; [0276] B is
selected from:
[0276] ##STR00137## [0277] each R.sub.2 is independently selected
from H and optionally substituted C.sub.1-C.sub.4 alkyl; [0278]
X.sub.1 and X.sub.2 are each independently CH.sub.2 or NH; with the
provision that X.sub.1 and X.sub.2 are not each CH.sub.2; [0279]
R.sub.3 is selected from H, halo, CF.sub.3, optionally substituted
C.sub.1-C.sub.4 alkyl, and optionally-substituted heteroaryl;
[0280] D is heterocyclyl ring containing at least one N atom; and
[0281] each R.sub.4 is selected from H, optionally substituted
C.sub.1-C.sub.1 alkyl, optionally substituted C.sub.1-C.sub.4
alkoxy, (optionally substituted C.sub.1-C.sub.4 alkylene)-OH,
hydroxy, optionally substituted aryl, and optionally substituted
benzyl; or [0282] a pharmaceutically acceptable salt thereof.
[0283] Embodiment 25 provides a compound selected from any of the
compounds in Tables 1-4, the Examples, or pharmaceutically
acceptable salts thereof.
[0284] Embodiment 26 provides a compound of any one of embodiments
1-25, pharmaceutically acceptable salts thereof, or any combination
of such compounds or salts.
[0285] Embodiment 27 provides a compound of embodiment 26, further
comprising vitamin E, an antioxidant, hydralazine, or any
combination thereof.
[0286] Embodiment 28 provides a method comprising administering the
composition of any one of embodiments 26 or 27 to a mammal.
[0287] Embodiment 29 provides a method of embodiment 28, wherein
the mammal is in need of administration of the composition.
[0288] Embodiment 29 provides a method of any one of embodiments 28
or 29, wherein the mammal has cancer, a neurodegenerative disease,
inflammation, a metabolic disorder, liver dysfunction, an
autoimmune disease, brain ischemia, or heart ischemia.
[0289] Embodiment 29 provides a method of any one of embodiments
28-30, wherein the mammal has triple negative breast cancer or
ovarian cancer.
[0290] Embodiment 30 provides a compound of any one of embodiments
1-25 for use in treating cancer.
[0291] Embodiment 31 provides a use of a compound of any one of
embodiments 1-25 in treating cancer.
[0292] The specific compositions and methods described herein are
representative, exemplary and not intended as limitations on the
scope of the invention. Other objects, aspects, and embodiments
will occur to those skilled in the art upon consideration of this
specification, and are encompassed within the spirit of the
invention as defined by the scope of the claims. It will be readily
apparent to one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without
departing from the scope and spirit of the invention. The terms and
expressions that have been employed are used as terms of
description and not of limitation, and there is no intent in the
use of such terms and expressions to exclude any equivalent of the
features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention as claimed. Thus, it will be understood that
although the present invention has been specifically disclosed by
embodiments and optional features, modification and variation of
the concepts herein disclosed may be resorted to by those skilled
in the art, and that such modifications and variations are
considered to be within the scope of this invention as defined by
the appended claims and statements of the invention.
[0293] The invention illustratively described herein may be
practiced in the absence of any element or elements, or limitation
or limitations, which is not specifically disclosed herein as
essential. The methods and processes illustratively described
herein may be practiced in differing orders of steps, and the
methods and processes are not necessarily restricted to the orders
of steps indicated herein or in the claims.
[0294] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include plural reference unless the
context clearly dictates otherwise. Thus, for example, a reference
to "a compound" or "a catalyst" or "a ligand" includes a plurality
of such compounds, catalysts or ligands, and so forth. In this
document, the term "or" is used to refer to a nonexclusive or, such
that "A or B" includes "A but not B," "B but not A," and "A and B,"
unless otherwise indicated.
[0295] Under no circumstances may the patent be interpreted to be
limited to the specific examples or embodiments or methods
specifically disclosed herein. Under no circumstances may the
patent be interpreted to be limited by any statement made by any
Examiner or any other official or employee of the Patent and
Trademark Office unless such statement is specifically and without
qualification or reservation expressly adopted in a responsive
waiting by Applicants.
[0296] The invention has been described broadly and genetically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
invention. This includes the generic description of the invention
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein. In addition, where features or
aspects of the invention are described in terms of Markush groups,
those skilled in the art will recognize that the invention is also
thereby described in terms of any individual member or subgroup of
members of the Markush group.
[0297] The Abstract is provided to comply with 37 C.F.R. .sctn.
1.72(b) to allow the reader to quickly ascertain the nature and
gist of the technical disclosure. The Abstract is submitted with
the understanding that it will not be used to interpret or limit
the scope or meaning of the claims.
[0298] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
Sequence CWU 1
1
2117RNAArtificial SequenceA synthetic probe 1cauguccgca gcacaug
17217RNAArtificial SequenceA synthetic probe 2caugucccca gcacaug
17
* * * * *