U.S. patent application number 15/580224 was filed with the patent office on 2018-06-14 for methods and compositions for the prevention and treatment of hearing loss.
The applicant listed for this patent is St. Jude Children's Research Hospital. Invention is credited to Taosheng Chen, Jie Fang, Asli Goktug, R. Kiplin Guy, Jaeki Min, Tai Teitz, Jian Zuo.
Application Number | 20180161340 15/580224 |
Document ID | / |
Family ID | 57546475 |
Filed Date | 2018-06-14 |
United States Patent
Application |
20180161340 |
Kind Code |
A1 |
Zuo; Jian ; et al. |
June 14, 2018 |
METHODS AND COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF
HEARING LOSS
Abstract
In one aspect, pharmaceutical compositions comprising a CDK2
inhibitor and one or more of at least one agent known to treat a
hearing impairment and at least one agent known to prevent a
hearing impairment, and methods of treating and/or preventing
hearing impairments or disorders using the compositions are
disclosed. This abstract is intended as a scanning tool for
purposes of searching in the particular art and is not intended to
be limiting of the present invention.
Inventors: |
Zuo; Jian; (Memphis, TN)
; Teitz; Tai; (Memphis, TN) ; Fang; Jie;
(Memphis, TN) ; Goktug; Asli; (Memphis, TN)
; Chen; Taosheng; (Germantown, TN) ; Min;
Jaeki; (Memphis, TN) ; Guy; R. Kiplin;
(Memphis, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
St. Jude Children's Research Hospital |
Memphis |
TN |
US |
|
|
Family ID: |
57546475 |
Appl. No.: |
15/580224 |
Filed: |
June 20, 2016 |
PCT Filed: |
June 20, 2016 |
PCT NO: |
PCT/US16/38384 |
371 Date: |
December 6, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62181755 |
Jun 18, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/454 20130101;
A61K 31/52 20130101; A61K 31/55 20130101; A61K 31/506 20130101;
A61K 31/404 20130101; A61P 27/16 20180101 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/52 20060101 A61K031/52; A61K 31/404 20060101
A61K031/404; A61K 31/506 20060101 A61K031/506; A61K 31/454 20060101
A61K031/454; A61P 27/16 20060101 A61P027/16 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with U.S. Government support under
grant numbers N000140911014, N000141210191, N000141210775, and
N000141612315 awarded by the Office of Naval Research (ONR), and
grant numbers DC006471, DC013879, DC015010, and CA21765 awarded by
the National Institute of Health (NIH). The U.S. government has
certain rights in the invention.
Claims
1. A method of treating hearing impairment, the method comprising
administering to a subject diagnosed with a need for treatment of
hearing impairment a therapeutically effective amount of a
cyclin-dependent kinase 2 (CDK2) inhibitor, or a pharmaceutically
acceptable salt thereof.
2. The method of claim 1, wherein the CDK2 inhibitor is selected
from a paullone derivative, a purine derivative, and a
3-(2-phenylhydrazono)indolin-2-one derivative, or a
pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein the CDK2 inhibitor is selected
from: ##STR00100## or a pharmaceutically acceptable salt
thereof.
4. The method of claim 2, wherein the CDK2 inhibitor is selected
from: ##STR00101## or a pharmaceutically acceptable salt
thereof.
5. The method of claim 1, wherein the CDK2 inhibitor is
administered in an amount of from about 0.001 .mu.M to about
1.0.times.10.sup.4 .mu.M at least once every three weeks.
6. The method of claim 1, wherein the hearing impairment is
drug-induced.
7. The method of claim 6, wherein the drug is a chemotherapeutic
agent.
8. The method of claim 6, wherein the drug is an antibiotic.
9. The method of claim 9, wherein the antibiotic is selected from
daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D,
bleomycin, mitomycin-C, amikacin, apramycin, arbekacin, astromicin,
bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B,
isepamicin, kanamycin, neomycin, netilmicin, paromomycin,
rhodostreptomycin, ribostamycin, sisomicin, spectinomycin,
streptomycin, tobramycin, and verdamicin, or a pharmaceutically
acceptable salt thereof.
10. A pharmaceutical composition comprising a CDK2 inhibitor,
wherein the CDK2 inhibitor is not a paullone derivative, or a
pharmaceutically acceptable salt thereof; and one or more of: a) at
least one agent known to treat hearing impairment, or a
pharmaceutically acceptable salt thereof; and b) at least one agent
known to prevent hearing impairment, or a pharmaceutically
acceptable salt thereof; and a pharmaceutically acceptable
carrier.
11. The composition of claim 10, wherein the CDK2 inhibitor has a
structure represented by a formula: ##STR00102## wherein each of
R.sup.5a and R.sup.5b is independently selected from hydrogen,
C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein each of R.sup.5a and
R.sup.5b is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl; wherein q, when
present, is an integer selected from 1, 2, 3, and 4; wherein
R.sup.8, when present, is selected from hydrogen, --OH, --SH,
--NH.sub.2, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and
C1-C4 dialkylamino; wherein R.sup.6 is selected from halogen,
OR.sup.9, and NR.sup.10aR.sup.10b; wherein R.sup.9, when present,
is selected from C1-C8 alkyl, (CH.sub.2).sub.pCy.sup.1, and
(CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when present, is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein p, when present, is an integer selected
from 0, 1, 2, and 3; wherein Cy.sup.1, when present, is selected
from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted
with 0, 1, 2, or 3 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl; wherein Ar.sup.1, when present, is
selected from aryl and heteroaryl and substituted with 0, 1, 2, or
3 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein each of R.sup.10a and R.sup.10b, when
present, is independently selected from C1-C8 alkyl, Cy.sup.2,
Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2
and substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein r, when present, is an integer selected
from 0, 1, 2, and 3; wherein Cy.sup.2, when present, is selected
from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted
with 0, 1, 2, or 3 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl; wherein Ar.sup.2, when present, is
selected from aryl and heteroaryl and substituted with 0, 1, 2, or
3 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; and wherein R.sup.7, when present, is selected
from hydrogen and C1-C8 alkyl, or a pharmaceutically acceptable
salt thereof.
12. The composition of claim 10, wherein the CDK2 inhibitor has a
structure represented by a formula: ##STR00103## or a
pharmaceutically acceptable salt thereof.
13. The composition of claim 10, wherein the 3 CDK2 inhibitor has a
structure represented by a formula: ##STR00104## wherein each of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15; wherein each occurrence of R.sup.15, when
present, is independently selected from hydrogen, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --NH.sub.2, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2; wherein each of R.sup.12 and R.sup.13 is
independently selected from hydrogen and C1-C4 alkyl; wherein each
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16; and wherein each
occurrence of R.sup.16, when present, is independently selected
from hydrogen, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--NH.sub.2, --NH(CH.sub.3), and --N(CH.sub.3).sub.2, or a
pharmaceutically acceptable salt thereof.
14. The composition of claim 10, wherein the CDK2 inhibitor has a
structure represented by a formula: ##STR00105## or a
pharmaceutically acceptable salt thereof.
15. The composition of claim 10, wherein the CDK2 inhibitor has a
structure represented by a formula: ##STR00106## wherein R.sup.20
is selected from --SO.sub.2R.sup.20a, --OH, NH.sub.2, substituted
amide, C1-C4 alkyl carbonyl, C1-C4 monoalkylamino, C1-C4
dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1,
or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;
wherein each of R.sup.21, R.sup.23, and R.sup.25 is independently
selected from hydrogen, halogen, --OH, NH.sub.2, C1-C4
monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is
independently substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl; and wherein each of R.sup.22 and R.sup.24
is independently selected from hydrogen and C1-C8 alkyl and is
independently substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl, or a pharmaceutically acceptable salt
thereof.
16. The composition of claim 10, wherein the CDK2 inhibitor has a
structure represented by a formula: ##STR00107## wherein each
occurrence of X is independently a halogen; wherein each of
R.sup.30, R.sup.31, R.sup.32, and R.sup.33 is independently
selected from hydrogen and C1-C8 alkyl and is independently
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; and wherein R.sup.34 is selected from --OH,
NH.sub.2, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8
alkyl and is substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl, or a pharmaceutically acceptable salt
thereof.
17. The composition of claim 10, wherein the CDK2 inhibitor is
selected from: ##STR00108## or a pharmaceutically acceptable salt
thereof.
18. The composition of claim 10, wherein the CDK2 inhibitor is
selected from: ##STR00109## or a pharmaceutically acceptable salt
thereof.
19. The composition of claim 10, wherein the pharmaceutical
composition is used to treat hearing impairment.
20. The composition of claim 10, wherein the pharmaceutical
composition is used to prevent hearing impairment.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This Application claims the benefit of U.S. Provisional
Application No. 62/181,755, filed on Jun. 18, 2015, which is
incorporated herein by reference in its entirety.
BACKGROUND
[0003] Noise-induced hearing loss (NIHL) is the most common
sensorineural hearing impairment. The World Health Organization
recently reported that more than a billion teens and young adults
worldwide are at risk of NIHL caused by loud music
(http://www.cnn.com/2015/03/06/health/hearing-loss-loud-music/index.html)-
. Acute or chronic acoustic overexposure has put more than 40
million U.S. workers at risk of permanent hearing loss (Kopke et
al. (2007) Hear. Res. 226: 114-125). NIHL is also prevalent in
military settings, costing more than $2 billion per year in
veterans (VA) compensation.
[0004] Noise trauma results in two types of hearing loss, depending
on intensity and duration: permanent or temporary threshold shift
(PTS or TTS). Persons can recover from TTS within 24-48 hrs,
whereas PTS is irreversible. Mechanistically, acoustic overexposure
causes hearing loss through overproduction of reactive oxygen
species (ROS), mitochondrial injury, lipid peroxidation,
glutathione (GSH) depletion, reperfusion injury, excessive
glutamate release, and/or loss of hair cells and neurons through
programmed cell death (PCD, apoptosis) and inflammatory pathways
(Kopke et al. (2007) Hear. Res. 226: 114-125). Many of these
cellular pathways overlap with those involved in hearing loss
caused by cisplatin chemotherapy, antibiotics, and age (Mukherjea
et al. (2011) Expert Opin. Drug Discov. 6: 491-505; Schacht et al.
(2012) Anat. Rec. (Hoboken) 295: 1837-1850; Vu et al. (2013) PLoS
One 8: e54794. However, it is not known which pathways, established
or novel, are key to the prevention of NIHL and other forms of
ototoxicity, such as cisplatin-induced or chemotherapy-induced
hearing loss, antibiotic-induced hearing loss, and age-related
hearing loss.
[0005] Cisplatin is known to exhibit toxic effects on hair cells of
the inner ear. Indeed, high frequency hearing loss (>8 kHZ) has
been reported to be as high as 90% in children undergoing cisplatin
therapy (Allen et al. (1998) Otolaryngol Head Neck Surg 118:
584-588). Other clinically important and commonly used drugs also
have documented ototoxic effects, including loop diuretics
(Greenberg (2000) Am. J. Med. Sci. 319:10-24), antimalarial
sesquiterpene lactone endoperoxides (e.g., artemesinins) (Toovey
and Jamieson (2004) Trans. R. Soc. Trop. Med. Hyg. 98: 261-267),
antimalarial quinines (Claessen et al. (1998) Trop. Med. Int.
Health 3: 482-489), salicylates (Matz (1990) Ann. Otol. Rhinol.
Laryngol. Suppl. 148: 39-41), and interferon polypeptides (Formann
et al. (2004) Am. J. Gastroenterol. 99: 873-877).
[0006] Moreover, ototoxicity to the vestibular system, which
includes the vestibule and semicircular canal, manifests as balance
and orientation-related disorders. These disorders include, but are
not limited to, induced or spontaneous vertigo, dysequilibrium,
increased susceptibility to motion sickness, nausea, vomiting,
ataxia, labyrinthitis, oscillopsia, nystagmus, syncope,
lightheadedness, dizziness, increased falling, difficulty walking
at night, Meniere's disease, and difficulty in visual tracking and
processing.
[0007] Extensive research in recent years has sought to identify
small molecules that can protect against hearing loss. Those tested
can be classified into three different groups based on their main
cellular function: 1) antioxidants and ROS scavengers, 2)
anti-inflammatory drugs, and 3) apoptosis inhibitors. Many
candidate compounds are currently in pre-clinical and clinical
trials; most are related to antioxidants, vitamins, and glutathione
metabolism, although their effectiveness remains unclear.
[0008] Despite the promising protective effects of N-acetylcysteine
(NAC) in preclinical and clinical safety studies, it has shown no
protection against NIHL in several clinical trials (Kopke et al.
(2007) Hear. Res. 226: 114-125; Tieu and Campbell (2013)
Otolaryngology 3:130). D-methionine has shown protective effects
against NIHL but remains to be tested in clinical trials (Muller
and Barr-Gillespie (2015) Nat. Rev. Drug Discov. 14: 346-365; Oishi
and Schacht (2011) Expert Opin. Emerg. Drugs 16: 235-245).
Similarly, Ebelsen (SPI-1005), a seleno-organic compound with
antioxidant activity through glutathione peroxidase-like action,
has been tested against TTS in noise-induced excitotoxicity studies
but remains unproven in clinical trials (See "Sound Pharmaceuticals
Inc. successfully completes its first Phase 2 clinical trial with
SPI-1005" (Nov. 5, 2013); Lynch and Kil (2005) Drug Discov. Today
10: 1291-1298). To date, no drugs are FDA-approved for protection
against NIHL and traumatic brain injury (TBI)-associated hearing
loss. Thus, there remains a need for compositions and methods of
preventing and treating hearing loss.
SUMMARY
[0009] In accordance with the purpose(s) of the invention, as
embodied and broadly described herein, the invention, in one
aspect, relates to compositions and methods for use in the
prevention and treatment of a hearing impairment.
[0010] Disclosed are methods of treating hearing impairment, the
methods comprising administering to a subject diagnosed with a need
for treatment of hearing impairment a therapeutically effective
amount of a cyclin-dependent kinase 2 (CDK2) inhibitor, or a
pharmaceutically acceptable salt thereof.
[0011] Also disclosed are methods of preventing hearing impairment,
the methods comprising administering to a subject a CDK2 inhibitor
in an amount of from about 0.001 .mu.M to about 1.0.times.10.sup.4
.mu.M at least once every three weeks, or a pharmaceutically
acceptable salt thereof.
[0012] Also disclosed are pharmaceutical compositions comprising a
CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; and
one or more of: (a) at least one agent known to treat hearing
impairment, or a pharmaceutically acceptable salt thereof, and (b)
at least one agent known to prevent hearing impairment, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0013] Also disclosed are pharmaceutical compositions comprising a
CDK2 inhibitor, wherein the CDK2 inhibitor is not a paullone
derivative, or a pharmaceutically acceptable salt thereof; and one
or more of: at least one agent known to treat hearing impairment,
or a pharmaceutically acceptable salt thereof, and at least one
agent known to prevent hearing impairment, or a pharmaceutically
acceptable salt thereof; and a pharmaceutically acceptable
carrier.
[0014] Also disclosed are methods for making compounds and for
making compounds for use in pharmaceutical compositions. Also
disclosed are the products of said methods.
[0015] Also disclosed are methods of preparing a pharmaceutical
composition, the method comprising the step of combining a CDK2
inhibitor, or a pharmaceutically acceptable salt thereof; and one
or more of: (a) at least one agent known to treat hearing
impairment, or a pharmaceutically acceptable salt thereof; (b) at
least one agent known to prevent hearing impairment, or a
pharmaceutically acceptable salt thereof, wherein at least one is
present in an effective amount; and a pharmaceutically acceptable
carrier.
[0016] Also disclosed are kits comprising a CDK2 inhibitor, or a
pharmaceutically acceptable salt thereof; and one or more of: (a)
at least one agent known to treat a hearing impairment; (b) at
least one agent known to prevent a hearing impairment; (c) at least
one antibiotic agent; (d) at least one chemotherapeutic agent; (e)
instructions for treating a hearing impairment; and (f)
instructions for preventing a hearing impairment.
[0017] Also disclosed are kits comprising a compound selected
from:
##STR00001##
or a pharmaceutically acceptable salt thereof; and one or more of:
(a) at least one agent known to treat a hearing impairment; (b) at
least one agent known to prevent a hearing impairment; (c) at least
one antibiotic agent; (d) at least one chemotherapeutic agent; (e)
instructions for treating a hearing impairment; and (f)
instructions for preventing a hearing impairment.
[0018] While aspects of the present invention can be described and
claimed in a particular statutory class, such as the system
statutory class, this is for convenience only and one of skill in
the art will understand that each aspect of the present invention
can be described and claimed in any statutory class. Unless
otherwise expressly stated, it is in no way intended that any
method or aspect set forth herein be construed as requiring that
its steps be performed in a specific order. Accordingly, where a
method claim does not specifically state in the claims or
descriptions that the steps are to be limited to a specific order,
it is no way intended that an order be inferred, in any respect.
This holds for any possible non-express basis for interpretation,
including matters of logic with respect to arrangement of steps or
operational flow, plain meaning derived from grammatical
organization or punctuation, or the number or type of aspects
described in the specification.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The accompanying figures, which are incorporated in and
constitute a part of this specification, illustrate several aspects
and together with the description serve to explain the principles
of the invention.
[0020] FIG. 1 shows a representative plot illustrating the percent
activity of the bioactive compounds in a cell-based high-throughput
screen.
[0021] FIG. 2a-e show representative dose response curves of
kenpaullone (compound 4) (FIG. 2a), Olomoucine II (compound 9)
(FIG. 2b), CDK2 inhibitor II (compound 12) (FIG. 2c), compound 3
(FIG. 2d), and compound 1 (FIG. 2e), determined using the
Caspase-/37 Glo assay and the Promega Cell Titer Glo assay
(CTG).
[0022] FIG. 3A-G show representative data illustrating that
compounds 4 (FIG. 3A-E), 9 (olomoucine II or compound 9, FIG. 3F),
and 12 (CDK2 inhibitor II or compound 12, FIG. 3G) protect against
cisplatin-induced hair cell loss in cochlear explants.
[0023] FIG. 4A-E show representative data illustrating that
compound 4 protects against cisplatin-induced hair cell loss in
zebrafish lateral lines in vivo.
[0024] FIG. 5 shows kenpaullone protects against cisplatin-induced
hair cell loss in vivo in mouse. Panel 5a shows experimental
diagram. Either ear of the same FVB wild-type mouse at P28 was
trans-tympanically injected (in a volume of 5 .mu.L) with compound
(Kenpaullone 250 .mu.M in 0.5% DMSO) or 0.5% DMSO only, in a
double-blinded manner. Two hours later, the mice were treated
intraperitoneally (IP) with cisplatin 30 mg/kg body weight, which
was expected to damage OHCs equally in both ears. Panel 5b
demonstrates that kenpaullone (Ken) significantly reduces cisplatin
(Cis)-induced ABR hearing threshold shifts relative to DMSO control
at 16 kHz and 32 kHz 14 days post transtympanic injection. Panel 5c
shows representative images double stained with phalloidin and
myosin 7a which is a hair cell specific marker in the cochlea and
illustrates that kenpaullone protects against cisplatin-induced
hair cell loss at 32 kHz region 14 days post transtympanic
injection. Panel 5d demonstrates kenpaullone significantly
increases outer hair cell (OHC) survival in all 11 mice at the 32
kHz region.
[0025] FIG. 6 shows kenpaullone protects against noise-induced
hearing loss. Panel 6a is an experimental design in which adult FVB
mice at P28 were exposed to noise (8-16 kHz at 100 dB SPL for 2
hours). Immediately afterward, kenpaullone (250 .mu.M in 0.5% DMSO)
or 0.5% DMSO was delivered (via trans-tympanic injection) to either
ear of the same mouse. ABR thresholds were recorded prior, 7 days,
or 14 days post noise exposure. Cochlear histology was examined at
14 days. Panel 6b shows that, in a total of 19 mice, kenpaullone
significantly protects noise-induced hearing loss at 8 kHz and 16
kHz 14 days post noise damage. Panel 6c also shows that wave 1
amplitudes of ABRs at 16 kHz displayed significant differences
between the kenpaullone and DMSO control ears. Panel 6d shows
representative images of triple staining with phalloidin, Tuj1 and
myosin 7a in the organ of Corti. There are no hair cell loss and no
detectable spiral ganglion neuron fiber differences at the 16 kHz
region. Panel 6e comparison of the ctbp2 puncta staining and
qualification in control (Ctrl) without any treatment, noise damage
with DMSO transtympanic injection (DMSO+Noise) and noise damage
with kenpaullone transtympanic injection (Ken+Noise). Kenpaullone
significantly protects ctbp2 puncta loss comparing with DMSO
sample. Inner hair cells (IHCs) are traced by dash line in Panel 6e
top figure.
[0026] FIG. 7 shows kenpaullone inhibits CDK2 kinase activity in
vitro. Increasing doses of kenpaullone were tested with Cdk2
immunoprecipitated from HEI--OC cells without (panel 7a) or with
(panel 7b) cisplatin treatment and the kinase activity was
quantified as the level of phosphorylation of the substrate histone
H1. Three (N=3) independent experiments were used for calculation
of IC.sub.50.
[0027] FIG. 8 shows germline CDK2 knockout (KO) cochlear explants
confer resistance to cisplatin treatment and kenpaullone
administration phenocopies CDK2 knockout resistance to cisplatin
ototoxicity. Panels 8a-c show middle turn organs of Corti with
actin staining (phalloidin-Alexa Flour 568) in WT and CDK2 KO
cochleae without any treatment (Media, panel 8a), with 50 .mu.M
cisplatin treatment (panel 8b) and with 50 .mu.M cisplatin and 5
.mu.M kenpaullone (Panel 8c). Outer hair cell (OHCs) numbers of
actin-positive cells per 160 .mu.m of the middle turn cochleae were
counted (panel 8d) and data are mean.+-.s.e.m. Numbers of explants
tested in each condition are indicated in the bars. *** P<0.001
by one-way ANOVA with Bonferroni's multiple comparison test.
[0028] FIG. 9 shows testing of kenpaullone toxicity in vivo in
adult FVB mice (.about.P28). FVB mice at P28 were administrated
kenpaullone at various concentrations (310 .mu.M, 155 .mu.M and
77.5 .mu.M) by transtympanic injection. Basel turn organs of Corti
24 hours post kenpaullone treatments as visualized by DAPI and
Parvalbumin show that kenpaullone is toxic at 310 .mu.M but not at
lower doses. Arrows label lost outer hair cells. Two independent
mice were tested for each dose.
[0029] FIG. 10 shows the lack of toxicity of kenpaullone (at 250
.mu.M by transtymapnic injection) in vivo. Panel 10a shows no
significant ABR threshold shifts 7 days, 14 days, 28 days, 56 days
and 84 days post kenpaullone or DMSO transtympanic injection at 16
kHz. Panel 10b demonstrates there are no detectable ABR threshold
shifts 84 days post kenpaullone or DMSO transtympanic injection at
8 kHz, 16 kHz and 32 kHz. Panel 10c indicates kenpaullone treatment
does not affect the length of the cochlea. Panel 10d visualizes
organs of Corti 84 days post kenpaullone (Ken) treatment in vivo
and demonstrates that kenpaullone lacks ototoxicity at 250 .mu.M
after 84 days in vivo.
[0030] FIG. 11 addresses interference with cisplatin's killing
function in tumors. Four neurosphere lines derived from mouse
medulloblastoma (MB) and two human neuroblastoma (NB) cell lines
were tested. HEI--OC1 cell line was tested as controls. Viability
assay (Cell Titer Glo) was used 48 hours post treatment of the
cells with or without cisplatin (23 .mu.M, IC.sub.90.+-.10 for all
7 cell lines) and each tested compound (conc. of
3.times.IC.sub.50). * and ** indicated p<0.05 and 0.01
respectively.
[0031] Additional advantages of the invention will be set forth in
part in the description which follows, and in part will be obvious
from the description, or can be learned by practice of the
invention. The advantages of the invention will be realized and
attained by means of the elements and combinations particularly
pointed out in the appended claims. It is to be understood that
both the foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive of the invention, as claimed.
DETAILED DESCRIPTION
[0032] The present invention can be understood more readily by
reference to the following detailed description of the invention
and the Examples included therein.
[0033] Before the present compounds, compositions, articles,
systems, devices, and/or methods are disclosed and described, it is
to be understood that they are not limited to specific synthetic
methods unless otherwise specified, or to particular reagents
unless otherwise specified, as such may, of course, vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular aspects only and is not intended
to be limiting. Although any methods and materials similar or
equivalent to those described herein can be used in the practice or
testing of the present invention, example methods and materials are
now described.
[0034] While aspects of the present invention can be described and
claimed in a particular statutory class, such as the system
statutory class, this is for convenience only and one of skill in
the art will understand that each aspect of the present invention
can be described and claimed in any statutory class. Unless
otherwise expressly stated, it is in no way intended that any
method or aspect set forth herein be construed as requiring that
its steps be performed in a specific order. Accordingly, where a
method claim does not specifically state in the claims or
descriptions that the steps are to be limited to a specific order,
it is no way intended that an order be inferred, in any respect.
This holds for any possible non-express basis for interpretation,
including matters of logic with respect to arrangement of steps or
operational flow, plain meaning derived from grammatical
organization or punctuation, or the number or type of aspects
described in the specification.
[0035] Throughout this application, various publications are
referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which this pertains. The references disclosed are also individually
and specifically incorporated by reference herein for the material
contained in them that is discussed in the sentence in which the
reference is relied upon. Nothing herein is to be construed as an
admission that the present invention is not entitled to antedate
such publication by virtue of prior invention. Further, the dates
of publication provided herein may be different from the actual
publication dates, which can require independent confirmation.
A. DEFINITIONS
[0036] As used in the specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a functional group," "an alkyl," or "a residue"
includes mixtures of two or more such functional groups, alkyls, or
residues, and the like.
[0037] As used in the specification and in the claims, the term
"comprising" can include the aspects "consisting of" and
"consisting essentially of."
[0038] Ranges can be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another aspect includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another aspect. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint. It is
also understood that there are a number of values disclosed herein,
and that each value is also herein disclosed as "about" that
particular value in addition to the value itself. For example, if
the value "10" is disclosed, then "about 10" is also disclosed. It
is also understood that each unit between two particular units are
also disclosed. For example, if 10 and 15 are disclosed, then 11,
12, 13, and 14 are also disclosed.
[0039] As used herein, the terms "about" and "at or about" mean
that the amount or value in question can be the value designated
some other value approximately or about the same. It is generally
understood, as used herein, that it is the nominal value indicated
.+-.10% variation unless otherwise indicated or inferred. The term
is intended to convey that similar values promote equivalent
results or effects recited in the claims. That is, it is understood
that amounts, sizes, formulations, parameters, and other quantities
and characteristics are not and need not be exact, but can be
approximate and/or larger or smaller, as desired, reflecting
tolerances, conversion factors, rounding off, measurement error and
the like, and other factors known to those of skill in the art. In
general, an amount, size, formulation, parameter or other quantity
or characteristic is "about" or "approximate" whether or not
expressly stated to be such. It is understood that where "about" is
used before a quantitative value, the parameter also includes the
specific quantitative value itself, unless specifically stated
otherwise.
[0040] References in the specification and concluding claims to
parts by weight of a particular element or component in a
composition denotes the weight relationship between the element or
component and any other elements or components in the composition
or article for which a part by weight is expressed. Thus, in a
compound containing 2 parts by weight of component X and 5 parts by
weight component Y, X and Y are present at a weight ratio of 2:5,
and are present in such ratio regardless of whether additional
components are contained in the compound.
[0041] A weight percent (wt. %) of a component, unless specifically
stated to the contrary, is based on the total weight of the
formulation or composition in which the component is included.
[0042] As used herein, the terms "optional" or "optionally" means
that the subsequently described event or circumstance can or cannot
occur, and that the description includes instances where said event
or circumstance occurs and instances where it does not.
[0043] As used herein, the term "subject" can be a vertebrate, such
as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the
subject of the herein disclosed methods can be a human, non-human
primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig
or rodent. The term does not denote a particular age or sex. Thus,
adult and newborn subjects, as well as fetuses, whether male or
female, are intended to be covered. In one aspect, the subject is a
mammal. A patient refers to a subject afflicted with a disease or
disorder. The term "patient" includes human and veterinary
subjects.
[0044] As used herein, the term "treatment" refers to the medical
management of a patient with the intent to cure, ameliorate,
stabilize, or prevent a disease, pathological condition, or
disorder. This term includes active treatment, that is, treatment
directed specifically toward the improvement of a disease,
pathological condition, or disorder, and also includes causal
treatment, that is, treatment directed toward removal of the cause
of the associated disease, pathological condition, or disorder. In
addition, this term includes palliative treatment, that is,
treatment designed for the relief of symptoms rather than the
curing of the disease, pathological condition, or disorder;
preventative treatment, that is, treatment directed to minimizing
or partially or completely inhibiting the development of the
associated disease, pathological condition, or disorder; and
supportive treatment, that is, treatment employed to supplement
another specific therapy directed toward the improvement of the
associated disease, pathological condition, or disorder. In various
aspects, the term covers any treatment of a subject, including a
mammal (e.g., a human), and includes: (i) preventing the disease
from occurring in a subject that can be predisposed to the disease
but has not yet been diagnosed as having it; (ii) inhibiting the
disease, i.e., arresting its development; or (iii) relieving the
disease, i.e., causing regression of the disease. In one aspect,
the subject is a mammal such as a primate, and, in a further
aspect, the subject is a human. The term "subject" also includes
domesticated animals (e.g., cats, dogs, etc.), livestock (e.g.,
cattle, horses, pigs, sheep, goats, etc.), and laboratory animals
(e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
[0045] As used herein, the term "prevent" or "preventing" refers to
precluding, averting, obviating, forestalling, stopping, or
hindering something from happening, especially by advance action.
It is understood that where reduce, inhibit or prevent are used
herein, unless specifically indicated otherwise, the use of the
other two words is also expressly disclosed.
[0046] As used herein, the term "diagnosed" means having been
subjected to a physical examination by a person of skill, for
example, a physician, and found to have a condition that can be
diagnosed or treated by the compounds, compositions, or methods
disclosed herein.
[0047] As used herein, the terms "administering" and
"administration" refer to any method of providing a pharmaceutical
preparation to a subject. Such methods are well known to those
skilled in the art and include, but are not limited to, oral
administration, transdermal administration, administration by
inhalation, nasal administration, topical administration,
intravaginal administration, ophthalmic administration, intraaural
administration, intracerebral administration, rectal
administration, sublingual administration, buccal administration,
and parenteral administration, including injectable such as
intravenous administration, intra-arterial administration,
intramuscular administration, and subcutaneous administration.
Administration can be continuous or intermittent. In various
aspects, a preparation can be administered therapeutically; that
is, administered to treat an existing disease or condition. In
further various aspects, a preparation can be administered
prophylactically; that is, administered for prevention of a disease
or condition.
[0048] As used herein, the terms "effective amount" and "amount
effective" refer to an amount that is sufficient to achieve the
desired result or to have an effect on an undesired condition. For
example, a "therapeutically effective amount" refers to an amount
that is sufficient to achieve the desired therapeutic result or to
have an effect on undesired symptoms, but is generally insufficient
to cause adverse side effects. The specific therapeutically
effective dose level for any particular patient will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the specific composition employed; the
age, body weight, general health, sex and diet of the patient; the
time of administration; the route of administration; the rate of
excretion of the specific compound employed; the duration of the
treatment; drugs used in combination or coincidental with the
specific compound employed and like factors well known in the
medical arts. For example, it is well within the skill of the art
to start doses of a compound at levels lower than those required to
achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved. If desired, the
effective daily dose can be divided into multiple doses for
purposes of administration. Consequently, single dose compositions
can contain such amounts or submultiples thereof to make up the
daily dose. The dosage can be adjusted by the individual physician
in the event of any contraindications. Dosage can vary, and can be
administered in one or more dose administrations daily, for one or
several days. Guidance can be found in the literature for
appropriate dosages for given classes of pharmaceutical products.
In further various aspects, a preparation can be administered in a
"prophylactically effective amount"; that is, an amount effective
for prevention of a disease or condition.
[0049] As used herein, "dosage form" means a pharmacologically
active material in a medium, carrier, vehicle, or device suitable
for administration to a subject. A dosage forms can comprise
inventive a disclosed compound, a product of a disclosed method of
making, or a salt, solvate, or polymorph thereof, in combination
with a pharmaceutically acceptable excipient, such as a
preservative, buffer, saline, or phosphate buffered saline. Dosage
forms can be made using conventional pharmaceutical manufacturing
and compounding techniques. Dosage forms can comprise inorganic or
organic buffers (e.g., sodium or potassium salts of phosphate,
carbonate, acetate, or citrate) and pH adjustment agents (e.g.,
hydrochloric acid, sodium or potassium hydroxide, salts of citrate
or acetate, amino acids and their salts) antioxidants (e.g.,
ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate
20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium
desoxycholate), solution and/or cryo/lyo stabilizers (e.g.,
sucrose, lactose, mannitol, trehalose), osmotic adjustment agents
(e.g., salts or sugars), antibacterial agents (e.g., benzoic acid,
phenol, gentamicin), antifoaming agents (e.g.,
polydimethylsilozone), preservatives (e.g., thimerosal,
2-phenoxyethanol, EDTA), polymeric stabilizers and
viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer
488, carboxymethylcellulose) and co-solvents (e.g., glycerol,
polyethylene glycol, ethanol). A dosage form formulated for
injectable use can have a disclosed compound, a product of a
disclosed method of making, or a salt, solvate, or polymorph
thereof, suspended in sterile saline solution for injection
together with a preservative.
[0050] As used herein, "kit" means a collection of at least two
components constituting the kit. Together, the components
constitute a functional unit for a given purpose. Individual member
components may be physically packaged together or separately. For
example, a kit comprising an instruction for using the kit may or
may not physically include the instruction with other individual
member components. Instead, the instruction can be supplied as a
separate member component, either in a paper form or an electronic
form which may be supplied on computer readable memory device or
downloaded from an internet website, or as recorded
presentation.
[0051] As used herein, "instruction(s)" means documents describing
relevant materials or methodologies pertaining to a kit. These
materials may include any combination of the following: background
information, list of components and their availability information
(purchase information, etc.), brief or detailed protocols for using
the kit, trouble-shooting, references, technical support, and any
other related documents. Instructions can be supplied with the kit
or as a separate member component, either as a paper form or an
electronic form which may be supplied on computer readable memory
device or downloaded from an internet website, or as recorded
presentation. Instructions can comprise one or multiple documents,
and are meant to include future updates.
[0052] As used herein, the term "CDK2 Inhibitor" refers to a small
molecule chemical compound that binds to CDK2 protein isolated from
cochlear cells and cochlear explants, inhibits CDK2 kinase or other
activities with IC.sub.50 of <10 .mu.M, and thus prevents
cisplatin-induced hair cell loss with IC.sub.50 of <10 .mu.M.
See FIGS. 3, 7, and 8.
[0053] As used herein, the term "therapeutic agent" includes any
synthetic or naturally occurring biologically active compound or
composition of matter which, when administered to an organism
(human or nonhuman animal), induces a desired pharmacologic,
immunogenic, and/or physiologic effect by local and/or systemic
action. The term therefore encompasses those compounds or chemicals
traditionally regarded as drugs, vaccines, and biopharmaceuticals
including molecules such as proteins, peptides, hormones, nucleic
acids, gene constructs and the like. Examples of therapeutic agents
are described in well-known literature references such as the Merck
Index (14.sup.th edition), the Physicians' Desk Reference
(64.sup.th edition), and The Pharmacological Basis of Therapeutics
(12.sup.th edition), and they include, without limitation,
medicaments; vitamins; mineral supplements; substances used for the
treatment, prevention, diagnosis, cure or mitigation of a disease
or illness; substances that affect the structure or function of the
body, or pro-drugs, which become biologically active or more active
after they have been placed in a physiological environment. For
example, the term "therapeutic agent" includes compounds or
compositions for use in all of the major therapeutic areas
including, but not limited to, adjuvants; anti-infectives such as
antibiotics and antiviral agents; analgesics and analgesic
combinations, anorexics, anti-inflammatory agents, anti-epileptics,
local and general anesthetics, hypnotics, sedatives, antipsychotic
agents, neuroleptic agents, antidepressants, anxiolytics,
antagonists, neuron blocking agents, anticholinergic and
cholinomimetic agents, antimuscarinic and muscarinic agents,
antiadrenergics, antiarrhythmics, antihypertensive agents,
hormones, and nutrients, antiarthritics, antiasthmatic agents,
anticonvulsants, antihistamines, antinauseants, antineoplastics,
antipruritics, antipyretics; antispasmodics, cardiovascular
preparations (including calcium channel blockers, beta-blockers,
beta-agonists and antiarrythmics), antihypertensives, diuretics,
vasodilators; central nervous system stimulants; cough and cold
preparations; decongestants; diagnostics; hormones; bone growth
stimulants and bone resorption inhibitors; immunosuppressives;
muscle relaxants; psychostimulants; sedatives; tranquilizers;
proteins, peptides, and fragments thereof (whether naturally
occurring, chemically synthesized or recombinantly produced); and
nucleic acid molecules (polymeric forms of two or more nucleotides,
either ribonucleotides (RNA) or deoxyribonucleotides (DNA)
including both double- and single-stranded molecules, gene
constructs, expression vectors, antisense molecules and the like),
small molecules (e.g., doxorubicin) and other biologically active
macromolecules such as, for example, proteins and enzymes. The
agent may be a biologically active agent used in medical, including
veterinary, applications and in agriculture, such as with plants,
as well as other areas. The term "therapeutic agent" also includes
without limitation, medicaments; vitamins; mineral supplements;
substances used for the treatment, prevention, diagnosis, cure or
mitigation of disease or illness; or substances which affect the
structure or function of the body; or pro-drugs, which become
biologically active or more active after they have been placed in a
predetermined physiological environment.
[0054] The term "pharmaceutically acceptable" describes a material
that is not biologically or otherwise undesirable, i.e., without
causing an unacceptable level of undesirable biological effects or
interacting in a deleterious manner.
[0055] As used herein, the term "derivative" refers to a compound
having a structure derived from the structure of a parent compound
(e.g., a compound disclosed herein) and whose structure is
sufficiently similar to those disclosed herein and based upon that
similarity, would be expected by one skilled in the art to exhibit
the same or similar activities and utilities as the claimed
compounds, or to induce, as a precursor, the same or similar
activities and utilities as the claimed compounds. Exemplary
derivatives include salts, esters, amides, salts of esters or
amides, and N-oxides of a parent compound.
[0056] As used herein, the term "pharmaceutically acceptable
carrier" refers to sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, as well as sterile powders
for reconstitution into sterile injectable solutions or dispersions
just prior to use. Examples of suitable aqueous and nonaqueous
carriers, diluents, solvents or vehicles include water, ethanol,
polyols (such as glycerol, propylene glycol, polyethylene glycol
and the like), carboxymethylcellulose and suitable mixtures
thereof, vegetable oils (such as olive oil) and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions and by the use of surfactants. These compositions can
also contain adjuvants such as preservatives, wetting agents,
emulsifying agents and dispersing agents. Prevention of the action
of microorganisms can be ensured by the inclusion of various
antibacterial and antifungal agents such as paraben, chlorobutanol,
phenol, sorbic acid and the like. It can also be desirable to
include isotonic agents such as sugars, sodium chloride and the
like. Prolonged absorption of the injectable pharmaceutical form
can be brought about by the inclusion of agents, such as aluminum
monostearate and gelatin, which delay absorption. Injectable depot
forms are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide,
poly(orthoesters) and poly(anhydrides). Depending upon the ratio of
drug to polymer and the nature of the particular polymer employed,
the rate of drug release can be controlled. Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions which are compatible with body tissues. The
injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved or dispersed in sterile water or other sterile
injectable media just prior to use. Suitable inert carriers can
include sugars such as lactose. Desirably, at least 95% by weight
of the particles of the active ingredient have an effective
particle size in the range of 0.01 to 10 micrometers.
[0057] The term "hearing impairment" as used herein refers to a
neurologic disorder, oto-neurological in nature, typically
sensorineural, but including composite loss (both sensorineural and
conductive loss), preferably either a sensory or a neural (8.sup.th
nerve related) hearing lost, and most preferably a sensory loss
(cochlear related), in which the patient will display, complain of,
or is diagnosed to have a hearing loss. Conductive hearing loss is
typically related to the external or middle ear. These impairments
of interest to the present invention are those associated with hair
cell damage. Less preferably such impairments can occur along with
conductive hearing loss damage or damage, loss, or degeneration of
a neuron of the auditory system. Hair cells are epithelial cells
possessing fine projections and located in the maculae and the
organ of Corti.
[0058] Examples of hearing impairments and situations in which such
hearing impairments can occur encompassed by the term "hearing
impairment," as used herein, include sensory hearing loss due to
end-organ lesions, e.g., acoustic trauma, viral endolymphatic
labyrinthitis, and Meniere's disease. The impairment can also be a
neural hearing loss due to events including cerebellopontine angle
tumors of the 8.sup.th nerve. Hearing impairments include tinnitus,
this is a perception of sound in the absence of an acoustic
stimulus, and may be intermittent or continuous, wherein there is a
diagnosed sensorineural loss. Hearing loss may be due to bacterial
or viral infection of the 8.sup.th nerve ganglia, such as in herpes
zoster oticus, purulent labyrinthitis arising from acute otitis
media, purulent meningitis, chronic otitis media, sudden deafness
including that of viral origin, e.g., viral endolymphatic
labyrinthitis caused by viruses including mumps, measles,
influenza, chickenpox, mononucleosis, and adenoviruses. The hearing
loss can be congenital, such as that caused by rubella, anoxia
during birth, bleeding into the inner ear due to trauma during
delivery, ototoxic drugs administered to the mother,
erythroblastosis fetalis, and hereditary conditions including
Waardenburg's syndrome and Hurler's syndrome. The hearing loss can
be noise-induced, generally due to a noise greater than 85 decibels
(db) SPL (sound pressure level) that damages the inner ear. Hearing
loss includes presbycusis, which is a sensorineural hearing loss
occurring as a normal part of aging, fractures of the temporal bone
extending into the middle ear and rupturing the tympanic membrane
and possibly the ossicular chain, fractures affecting the cochlea,
and acoustic neurinoma, which are tumors generally of Shwann cell
origin that arise from either the auditory or vestibular divisions
of the 8.sup.th nerve. In various aspects, the hearing loss is
caused by an ototoxic drug that affects the auditory portion of the
inner ear, particularly the organ of Corti. The hearing loss may be
due to chemotherapy or to cisplatin. The hearing loss can be
related to a vestibular disorder including vertigo, dysequilibrium,
increased susceptibility to motion sickness, nausea, vomiting,
ataxia, labyrinthitis, oscillopsia, nystagmus, syncope,
lightheadedness, dizziness, increased falling, difficulty walking
at night, Meniere's disease, and difficulty in visual tracking and
processing. Incorporated herein by reference are Chapters 196, 197,
198, and 199 of The Merck Index, 14.sup.th Edition (1982), Merck
Sharp & Dome Research Laboratories, N.J. and related chapters
in the most recent edition, relating to description and diagnosis
of hearing impairments.
[0059] Tests are known and available for diagnosing hearing
impairments. Neuro-otological, neuro-ophthalmological, neurological
examinations, and electra-oculography can be used (Wennmo et al.,
Acta Otolaryngol 1982, 94, 507). Sensitive and specific measures
are available to identify patients with auditory impairments. For
example, tuning fork tests can be used to differentiate a
conductive from a sensorineural hearing loss and determine whether
the loss is unilateral. An audiometer is used to quantitate hearing
loss, measured in decibels. With this device the hearing for each
ear is measured, typically from 125 to 8000 Hz, and plotted as an
audiogram. Speech audiometry can also be performed. The speech
recognition threshold, the intensity at which speed is recognized
as a meaningful symbol, can be determined at various speech
frequencies. Speech or phoneme discrimination can also be
determined and used as an indicator of sensorineural hearing loss
since analysis of speech sounds relies upon the inner ear and
8.sup.th nerve. Tympanometry can be used to diagnose conductive
hearing loss and aid in the diagnosis of those patients with
sensorineural hearing loss. Electrocochleography, measuring the
cochlear microphonic response and action potential of the 8.sup.th
nerve, and evoked response audiometry, measuring evoked response
from the brainstem and auditory cortex, to acoustic stimuli can be
used in patients, particularly infants and children or patients
with sensorineural hearing loss of obscure etiology. Auditory
brainstem responses (ABRs) or distortion products otoacoustic
emissions (DPOAEs) are most commonly used audiometry methods. These
tests serve a diagnostic function as well as a clinical function in
assessing response to therapy.
[0060] A residue of a chemical species, as used in the
specification and concluding claims, refers to the moiety that is
the resulting product of the chemical species in a particular
reaction scheme or subsequent formulation or chemical product,
regardless of whether the moiety is actually obtained from the
chemical species. Thus, an ethylene glycol residue in a polyester
refers to one or more --OCH.sub.2CH.sub.2O-- units in the
polyester, regardless of whether ethylene glycol was used to
prepare the polyester. Similarly, a sebacic acid residue in a
polyester refers to one or more --CO(CH.sub.2).sub.8CO-- moieties
in the polyester, regardless of whether the residue is obtained by
reacting sebacic acid or an ester thereof to obtain the
polyester.
[0061] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic, and
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
below. The permissible substituents can be one or more and the same
or different for appropriate organic compounds. For purposes of
this disclosure, the heteroatoms, such as nitrogen, can have
hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. This disclosure is not intended to be limited in
any manner by the permissible substituents of organic compounds.
Also, the terms "substitution" or "substituted with" include the
implicit proviso that such substitution is in accordance with
permitted valence of the substituted atom and the substituent, and
that the substitution results in a stable compound, e.g., a
compound that does not spontaneously undergo transformation such as
by rearrangement, cyclization, elimination, etc. It is also
contemplated that, in certain aspects, unless expressly indicated
to the contrary, individual substituents can be further optionally
substituted (i.e., further substituted or unsubstituted).
[0062] In defining various terms, "A.sup.1," "A.sup.2," "A.sup.3,"
and "A.sup.4" are used herein as generic symbols to represent
various specific substituents. These symbols can be any
substituent, not limited to those disclosed herein, and when they
are defined to be certain substituents in one instance, they can,
in another instance, be defined as some other substituents.
[0063] The term "aliphatic" or "aliphatic group," as used herein,
denotes a hydrocarbon moiety that may be straight-chain (i.e.,
unbranched), branched, or cyclic (including fused, bridging, and
spirofused polycyclic) and may be completely saturated or may
contain one or more units of unsaturation, but which is not
aromatic. Unless otherwise specified, aliphatic groups contain 1-20
carbon atoms. Aliphatic groups include, but are not limited to,
linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids
thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl.
[0064] The term "alkyl" as used herein is a branched or unbranched
saturated hydrocarbon group of 1 to 24 carbon atoms, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl,
t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl,
octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl,
tetracosyl, and the like. The alkyl group can be cyclic or acyclic.
The alkyl group can be branched or unbranched. The alkyl group can
also be substituted or unsubstituted. For example, the alkyl group
can be substituted with one or more groups including, but not
limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide,
hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A
"lower alkyl" group is an alkyl group containing from one to six
(e.g., from one to four) carbon atoms. The term alkyl group can
also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5
alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10
alkyl, and the like up to and including a C1-C24 alkyl.
[0065] Throughout the specification "alkyl" is generally used to
refer to both unsubstituted alkyl groups and substituted alkyl
groups; however, substituted alkyl groups are also specifically
referred to herein by identifying the specific substituent(s) on
the alkyl group. For example, the term "halogenated alkyl" or
"haloalkyl" specifically refers to an alkyl group that is
substituted with one or more halide, e.g., fluorine, chlorine,
bromine, or iodine. Alternatively, the term "monohaloalkyl"
specifically refers to an alkyl group that is substituted with a
single halide, e.g. fluorine, chlorine, bromine, or iodine. The
term "polyhaloalkyl" specifically refers to an alkyl group that is
independently substituted with two or more halides, i.e. each
halide substituent need not be the same halide as another halide
substituent, nor do the multiple instances of a halide substituent
need to be on the same carbon. The term "alkoxyalkyl" specifically
refers to an alkyl group that is substituted with one or more
alkoxy groups, as described below. The term "aminoalkyl"
specifically refers to an alkyl group that is substituted with one
or more amino groups. The term "hydroxyalkyl" specifically refers
to an alkyl group that is substituted with one or more hydroxy
groups. When "alkyl" is used in one instance and a specific term
such as "hydroxyalkyl" is used in another, it is not meant to imply
that the term "alkyl" does not also refer to specific terms such as
"hydroxyalkyl" and the like.
[0066] This practice is also used for other groups described
herein. That is, while a term such as "cycloalkyl" refers to both
unsubstituted and substituted cycloalkyl moieties, the substituted
moieties can, in addition, be specifically identified herein; for
example, a particular substituted cycloalkyl can be referred to as,
e.g., an "alkylcycloalkyl." Similarly, a substituted alkoxy can be
specifically referred to as, e.g., a "halogenated alkoxy," a
particular substituted alkenyl can be, e.g., an "alkenylalcohol,"
and the like. Again, the practice of using a general term, such as
"cycloalkyl," and a specific term, such as "alkylcycloalkyl," is
not meant to imply that the general term does not also include the
specific term.
[0067] The term "cycloalkyl" as used herein is a non-aromatic
carbon-based ring composed of at least three carbon atoms. Examples
of cycloalkyl groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The
term "heterocycloalkyl" is a type of cycloalkyl group as defined
above, and is included within the meaning of the term "cycloalkyl,"
where at least one of the carbon atoms of the ring is replaced with
a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,
or phosphorus. The cycloalkyl group and heterocycloalkyl group can
be substituted or unsubstituted. The cycloalkyl group and
heterocycloalkyl group can be substituted with one or more groups
including, but not limited to, alkyl, cycloalkyl, alkoxy, amino,
ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as
described herein.
[0068] The term "polyalkylene group" as used herein is a group
having two or more CH.sub.2 groups linked to one another. The
polyalkylene group can be represented by the formula
--(CH.sub.2).sub.a--, where "a" is an integer of from 2 to 500.
[0069] The terms "alkoxy" and "alkoxyl" as used herein to refer to
an alkyl or cycloalkyl group bonded through an ether linkage; that
is, an "alkoxy" group can be defined as --OA.sup.1 where A.sup.1 is
alkyl or cycloalkyl as defined above. "Alkoxy" also includes
polymers of alkoxy groups as just described; that is, an alkoxy can
be a polyether such as --OA.sup.1--A.sup.2 or
--OA.sup.1--(OA.sup.2).sub.a--OA.sup.3, where "a" is an integer of
from 1 to 200 and A.sup.1, A.sup.2, and A.sup.3 are alkyl and/or
cycloalkyl groups.
[0070] The term "alkenyl" as used herein is a hydrocarbon group of
from 2 to 24 carbon atoms with a structural formula containing at
least one carbon-carbon double bond. Asymmetric structures such as
(A.sup.1A.sup.2)C.dbd.C(A.sup.3A.sup.4) are intended to include
both the E and Z isomers. This can be presumed in structural
formulae herein wherein an asymmetric alkene is present, or it can
be explicitly indicated by the bond symbol C.dbd.C. The alkenyl
group can be substituted with one or more groups including, but not
limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino,
carboxylic acid, ester, ether, halide, hydroxy, ketone, azide,
nitro, silyl, sulfo-oxo, or thiol, as described herein.
[0071] The term "cycloalkenyl" as used herein is a non-aromatic
carbon-based ring composed of at least three carbon atoms and
containing at least one carbon-carbon double bound, i.e., C.dbd.C.
Examples of cycloalkenyl groups include, but are not limited to,
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,
cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term
"heterocycloalkenyl" is a type of cycloalkenyl group as defined
above, and is included within the meaning of the term
"cycloalkenyl," where at least one of the carbon atoms of the ring
is replaced with a heteroatom such as, but not limited to,
nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and
heterocycloalkenyl group can be substituted or unsubstituted. The
cycloalkenyl group and heterocycloalkenyl group can be substituted
with one or more groups including, but not limited to, alkyl,
cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,
aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,
halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol
as described herein.
[0072] The term "alkynyl" as used herein is a hydrocarbon group of
2 to 24 carbon atoms with a structural formula containing at least
one carbon-carbon triple bond. The alkynyl group can be
unsubstituted or substituted with one or more groups including, but
not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino,
carboxylic acid, ester, ether, halide, hydroxy, ketone, azide,
nitro, silyl, sulfo-oxo, or thiol, as described herein.
[0073] The term "cycloalkynyl" as used herein is a non-aromatic
carbon-based ring composed of at least seven carbon atoms and
containing at least one carbon-carbon triple bound. Examples of
cycloalkynyl groups include, but are not limited to, cycloheptynyl,
cyclooctynyl, cyclononynyl, and the like. The term
"heterocycloalkynyl" is a type of cycloalkenyl group as defined
above, and is included within the meaning of the term
"cycloalkynyl," where at least one of the carbon atoms of the ring
is replaced with a heteroatom such as, but not limited to,
nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and
heterocycloalkynyl group can be substituted or unsubstituted. The
cycloalkynyl group and heterocycloalkynyl group can be substituted
with one or more groups including, but not limited to, alkyl,
cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,
aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,
halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol
as described herein.
[0074] The term "aromatic group" as used herein refers to a ring
structure having cyclic clouds of delocalized .pi. electrons above
and below the plane of the molecule, where the .pi. clouds contain
(4n+2) .pi. electrons. A further discussion of aromaticity is found
in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter
13, entitled "Aromaticity," pages 477-497, incorporated herein by
reference. The term "aromatic group" is inclusive of both aryl and
heteroaryl groups.
[0075] The term "aryl" as used herein is a group that contains any
carbon-based aromatic group including, but not limited to, benzene,
naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl
group can be substituted or unsubstituted. The aryl group can be
substituted with one or more groups including, but not limited to,
alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,
cycloalkynyl, aryl, heteroaryl, aldehyde, --NH.sub.2, carboxylic
acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl,
sulfo-oxo, or thiol as described herein. The term "biaryl" is a
specific type of aryl group and is included in the definition of
"aryl." In addition, the aryl group can be a single ring structure
or comprise multiple ring structures that are either fused ring
structures or attached via one or more bridging groups such as a
carbon-carbon bond. For example, biaryl can be two aryl groups that
are bound together via a fused ring structure, as in naphthalene,
or are attached via one or more carbon-carbon bonds, as in
biphenyl.
[0076] The term "aldehyde" as used herein is represented by the
formula --C(O)H. Throughout this specification "C(O)" is a short
hand notation for a carbonyl group, i.e., C.dbd.O.
[0077] The terms "amine" or "amino" as used herein are represented
by the formula --NA.sup.1A.sup.2, where A.sup.1 and A.sup.2 can be,
independently, hydrogen or alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as
described herein. A specific example of amino is --NH.sub.2.
[0078] The term "alkylamino" as used herein is represented by the
formula --NH(-alkyl) where alkyl is a described herein.
Representative examples include, but are not limited to,
methylamino group, ethylamino group, propylamino group,
isopropylamino group, butylamino group, isobutylamino group,
(sec-butyl)amino group, (tert-butyl)amino group, pentylamino group,
isopentylamino group, (tert-pentyl)amino group, hexylamino group,
and the like.
[0079] The term "dialkylamino" as used herein is represented by the
formula --N(-alkyl).sub.2 where alkyl is a described herein.
Representative examples include, but are not limited to,
dimethylamino group, diethylamino group, dipropylamino group,
diisopropylamino group, dibutylamino group, diisobutylamino group,
di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino
group, diisopentylamino group, di(tert-pentyl)amino group,
dihexylamino group, N-ethyl-N-methylamino group,
N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the
like.
[0080] The term "carboxylic acid" as used herein is represented by
the formula --C(O)OH.
[0081] The term "ester" as used herein is represented by the
formula --OC(O)A.sup.1 or --C(O)OA.sup.1, where A.sup.1 can be
alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,
aryl, or heteroaryl group as described herein. The term "polyester"
as used herein is represented by the formula
--(A.sup.1O(O)C-A.sup.2-C(O)O).sub.a-- or
(A.sup.1O(O)C-A.sup.2--OC(O)).sub.a--, where A.sup.1 and A.sup.2
can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein
and "a" is an integer from 1 to 500. "Polyester" is as the term
used to describe a group that is produced by the reaction between a
compound having at least two carboxylic acid groups with a compound
having at least two hydroxyl groups.
[0082] The term "ether" as used herein is represented by the
formula A.sup.1OA.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
The term "polyether" as used herein is represented by the formula
-(A.sup.1O-A.sup.2O).sub.a--, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein
and "a" is an integer of from 1 to 500. Examples of polyether
groups include polyethylene oxide, polypropylene oxide, and
polybutylene oxide.
[0083] The terms "halo," "halogen," or "halide," as used herein can
be used interchangeably and refer to F, Cl, Br, or I.
[0084] The terms "pseudohalide," "pseudohalogen," or "pseudohalo,"
as used herein can be used interchangeably and refer to functional
groups that behave substantially similar to halides. Such
functional groups include, by way of example, cyano, thiocyanato,
azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and
perfluoroalkoxy groups.
[0085] The term "heteroalkyl," as used herein refers to an alkyl
group containing at least one heteroatom. Suitable heteroatoms
include, but are not limited to, O, N, Si, P and S, wherein the
nitrogen, phosphorous and sulfur atoms are optionally oxidized, and
the nitrogen heteroatom is optionally quaternized. Heteroalkyls can
be substituted as defined above for alkyl groups.
[0086] The term "heteroaryl," as used herein refers to an aromatic
group that has at least one heteroatom incorporated within the ring
of the aromatic group. Examples of heteroatoms include, but are not
limited to, nitrogen, oxygen, sulfur, and phosphorus, where
N-oxides, sulfur oxides, and dioxides are permissible heteroatom
substitutions. The heteroaryl group can be substituted or
unsubstituted. The heteroaryl group can be substituted with one or
more groups including, but not limited to, alkyl, cycloalkyl,
alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or
thiol as described herein. Heteroaryl groups can be monocyclic, or
alternatively fused ring systems. Heteroaryl groups include, but
are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl,
thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,
isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl,
isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl,
pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl,
indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and
pyrazolopyrimidinyl. Further not limiting examples of heteroaryl
groups include, but are not limited to, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo
[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl,
indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,
benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and
pyrido[2,3-b]pyrazinyl.
[0087] The terms "heterocycle" or "heterocyclyl," as used herein
can be used interchangeably and refer to single and multi-cyclic
aromatic or non-aromatic ring systems in which at least one of the
ring members is other than carbon. Thus, the term is inclusive of,
but not limited to, "heterocycloalkyl", "heteroaryl", "bicyclic
heterocycle" and "polycyclic heterocycle." Heterocycle includes
pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole,
isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole,
including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole,
thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and
1,3,4-thiadiazole, triazole, including, 1,2,3-triazole,
1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and
1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including
1,2,4-triazine and 1,3,5-triazine, tetrazine, including
1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,
azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.
The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3
heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6
heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9
heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the
like up to and including a C2-C18 heterocyclyl. For example, a C2
heterocyclyl comprises a group which has two carbon atoms and at
least one heteroatom, including, but not limited to, aziridinyl,
diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
Alternatively, for example, a C5 heterocyclyl comprises a group
which has five carbon atoms and at least one heteroatom, including,
but not limited to, piperidinyl, tetrahydropyranyl,
tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is
understood that a heterocyclyl group may be bound either through a
heteroatom in the ring, where chemically possible, or one of
carbons comprising the heterocyclyl ring.
[0088] The term "bicyclic heterocycle" or "bicyclic heterocyclyl,"
as used herein refers to a ring system in which at least one of the
ring members is other than carbon. Bicyclic heterocyclyl
encompasses ring systems wherein an aromatic ring is fused with
another aromatic ring, or wherein an aromatic ring is fused with a
non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems
wherein a benzene ring is fused to a 5- or a 6-membered ring
containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is
fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring
heteroatoms. Bicyclic heterocyclic groups include, but are not
limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,
benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,
2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,
1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and
1H-pyrazolo[3,2-b]pyridin-3-yl.
[0089] The term "heterocycloalkyl" as used herein refers to an
aliphatic, partially unsaturated or fully saturated, 3- to
14-membered ring system, including single rings of 3 to 8 atoms and
bi- and tricyclic ring systems. The heterocycloalkyl ring-systems
include one to four heteroatoms independently selected from oxygen,
nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom
optionally can be oxidized and a nitrogen heteroatom optionally can
be substituted. Representative heterocycloalkyl groups include, but
are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,
isothiazolidinyl, and tetrahydrofuryl.
[0090] The term "hydroxyl" or "hydroxyl" as used herein is
represented by the formula --OH.
[0091] The term "ketone" as used herein is represented by the
formula A.sup.1C(O)A.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group as described
herein.
[0092] The term "azide" or "azido" as used herein is represented by
the formula --N.sub.3.
[0093] The term "nitro" as used herein is represented by the
formula --NO.sub.2.
[0094] The term "nitrile" or "cyano" as used herein is represented
by the formula --CN.
[0095] The term "silyl" as used herein is represented by the
formula --SiA.sup.1A.sup.2A.sup.3, where A.sup.1, A.sup.2, and
A.sup.3 can be, independently, hydrogen or an alkyl, cycloalkyl,
alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or
heteroaryl group as described herein.
[0096] The term "sulfo-oxo" as used herein is represented by the
formulas --S(O)A.sup.1, --S(O).sub.2A.sup.1, --OS(O).sub.2A.sup.1,
or --OS(O).sub.2OA.sup.1, where A.sup.1 can be hydrogen or an
alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,
aryl, or heteroaryl group as described herein. Throughout this
specification "S(O)" is a short hand notation for S.dbd.O. The term
"sulfonyl" is used herein to refer to the sulfo-oxo group
represented by the formula --S(O).sub.2A.sup.1, where A.sup.1 can
be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group as described
herein. The term "sulfone" as used herein is represented by the
formula A.sup.1S(O).sub.2A.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group as described
herein. The term "sulfoxide" as used herein is represented by the
formula A.sup.1S(O)A.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkynyl, aryl, or heteroaryl group as described
herein.
[0097] The term "thiol" as used herein is represented by the
formula --SH.
[0098] "R.sup.1," "R.sup.2," "R.sup.3," "R.sup.n," where n is an
integer, as used herein can, independently, possess one or more of
the groups listed above. For example, if R.sup.1 is a straight
chain alkyl group, one of the hydrogen atoms of the alkyl group can
optionally be substituted with a hydroxyl group, an alkoxy group,
an alkyl group, a halide, and the like. Depending upon the groups
that are selected, a first group can be incorporated within second
group or, alternatively, the first group can be pendant (i.e.,
attached) to the second group. For example, with the phrase "an
alkyl group comprising an amino group," the amino group can be
incorporated within the backbone of the alkyl group. Alternatively,
the amino group can be attached to the backbone of the alkyl group.
The nature of the group(s) that is (are) selected will determine if
the first group is embedded or attached to the second group.
[0099] As described herein, compounds of the invention may contain
"optionally substituted" moieties. In general, the term
"substituted," whether preceded by the term "optionally" or not,
means that one or more hydrogen of the designated moiety are
replaced with a suitable substituent. Unless otherwise indicated,
an "optionally substituted" group may have a suitable substituent
at each substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at every position. Combinations
of substituents envisioned by this invention are preferably those
that result in the formation of stable or chemically feasible
compounds. In is also contemplated that, in certain aspects, unless
expressly indicated to the contrary, individual substituents can be
further optionally substituted (i.e., further substituted or
unsubstituted).
[0100] The term "stable," as used herein, refers to compounds that
are not substantially altered when subjected to conditions to allow
for their production, detection, and, in certain aspects, their
recovery, purification, and use for one or more of the purposes
disclosed herein.
[0101] Suitable monovalent substituents on a substitutable carbon
atom of an "optionally substituted" group are independently
halogen; --(CH.sub.2).sub.0-4R.sup.o; --(CH.sub.2).sub.0-4OR.sup.o;
--O(CH.sub.2).sub.0-4R.sup.o, --O--(CH.sub.2).sub.0-4C(O)OR.sup.o;
--(CH.sub.2).sub.0-4CH(OR.sup.o.sub.2;
--(CH.sub.2).sub.0-4SR.sup.o; --(CH.sub.2).sub.0-4Ph, which may be
substituted with R.sup.o; --(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph
which may be substituted with R.sup.o; --CH.dbd.CHPh, which may be
substituted with R.sup.o;
--(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1-pyridyl which may be
substituted with R.sup.o; --NO.sub.2; --CN; --N.sub.3;
--(CH.sub.2).sub.0-4N(R.sup.o).sub.2;
--(CH.sub.2).sub.0-4N(R.sup.o)C(O)R.sup.o; --N(R.sup.o)C(S)R.sup.o;
--(CH.sub.2).sub.0-4N(R.sup.o)C(O)NR.sup.o.sub.2;
--N(R.sup.o)C(S)NR.sup.o.sub.2;
--(CH.sub.2).sub.0-4N(R.sup.o)C(O)OR.sup.o;
--N(R.sup.o)N(R.sup.o)C(O)R.sup.o;
--N(R.sup.o)N(R.sup.o)C(O)NR.sup.o.sub.2;
--N(R.sup.o)N(R.sup.o)C(O)OR.sup.o;
--(CH.sub.2).sub.0-4C(O)R.sup.o; --C(S)R.sup.o;
(CH.sub.2).sub.0-4C(O)OR.sup.o; --(CH.sub.2).sub.0-4C(O)SR.sup.o;
--(CH.sub.2).sub.0-4C(O)OSiR.sup.o.sub.3;
--(CH.sub.2).sub.0-4OC(O)R.sup.o; --OC(O)(CH.sub.2).sub.0-4SR--,
SC(S)SR.sup.o; --(CH.sub.2).sub.0-4SC(O)R.sup.o;
--(CH.sub.2).sub.0-4C(O)NR.sup.o.sub.2; --C(S)NR.sup.o.sub.2;
--C(S)SR.sup.o; --(CH.sub.2).sub.0-4OC(O)NR.sup.o.sub.2;
--C(O)N(OR.sup.o)R.sup.o; --C(O)C(O)R.sup.o;
--C(O)CH.sub.2C(O)R.sup.o; --C(NOR.sup.o)R.sup.o;
--(CH.sub.2).sub.0-4SSR.sup.o;
--(CH.sub.2).sub.0-4S(O).sub.2R.sup.o;
--(CH.sub.2).sub.0-4S(O).sub.2OR.sup.o;
--(CH.sub.2).sub.0-4OS(O).sub.2R.sup.o; --S(O).sub.2NR.sup.o.sub.2;
--(CH.sub.2).sub.0-4S(O)R.sup.o;
--N(R.sup.o)S(O).sub.2NR.sup.o.sub.2;
--N(R.sup.o)S(O).sub.2R.sup.o; --N(OR.sup.o)R.sup.o;
--C(NH)NR.sup.o.sub.2; --P(O).sub.2R.sup.o; --P(O)R.sup.o.sub.2;
--OP(O)R.sup.o.sub.2; --OP(O)(OR.sup.o).sub.2; SiR.sup.o.sub.3;
--(C.sub.1-4 straight or branched)alkylene)O--N(R.sup.o).sub.2; or
--(C.sub.1-4 straight or branched)alkylene)C(O)O--N(R.sup.o).sub.2,
wherein each R.sup.o may be substituted as defined below and is
independently hydrogen, C.sub.1-C.sub.6 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, --CH.sub.2-(5-6 membered heteroaryl ring),
or a 5-6-membered saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or, notwithstanding the definition above, two
independent occurrences of R.sup.o, taken together with their
intervening atom(s), form a 3-12-membered saturated, partially
unsaturated, or aryl mono or bicyclic ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, which may
be substituted as defined below.
[0102] Suitable monovalent substituents on R.sup.o (or the ring
formed by taking two independent occurrences of R.sup.o together
with their intervening atoms), are independently halogen,
--(CH.sub.2).sub.0-2R.sup. , -(haloR.sup. ),
--(CH.sub.2).sub.0-2OH, --(CH.sub.2).sub.0-2OR.sup. ,
--(CH.sub.2).sub.0-2CH(OR.sup. ).sub.2; --O(haloR.sup. ), --CN,
--N.sub.3, --(CH.sub.2).sub.0-2C(O)R.sup. ,
--(CH.sub.2).sub.0-2C(O)OH, --(CH.sub.2).sub.0-2C(O)OR.sup. ,
--(CH.sub.2).sub.0-2SR.sup. , --(CH.sub.2).sub.0-2SH,
--(CH.sub.2).sub.0-2NH.sub.2, --(CH.sub.2).sub.0-2NHR.sup. ,
--(CH.sub.2).sub.0-2NR.sup. .sub.2, --NO.sub.2, --SiR.sup. .sub.3,
--OSiR.sup. .sub.3, --C(O)SR.sup. --(C.sub.1-4 straight or branched
alkylene)C(O)OR.sup. , or SSR.sup. wherein each R.sup. is
unsubstituted or where preceded by "halo" is substituted only with
one or more halogens, and is independently selected from C.sub.1-4
aliphatic, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5-6membered
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Suitable divalent substituents on a saturated carbon atom
of R.sup.o include .dbd.O and .dbd.S.
[0103] Suitable divalent substituents on a saturated carbon atom of
an "optionally substituted" group include the following: .dbd.O,
.dbd.S, .dbd.NNR*.sub.2, .dbd.NNHC(O)R*, .dbd.NNHC(O)OR*,
.dbd.NNHS(O).sub.2R*, .dbd.NR*, .dbd.NOR*,
--O(C(R*.sub.2)).sub.2-3O--, or --S(C(R*.sub.2)).sub.2-3S--,
wherein each independent occurrence of R* is selected from
hydrogen, C.sub.1-6 aliphatic which may be substituted as defined
below, or an unsubstituted 5-6membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Suitable divalent
substituents that are bound to vicinal substitutable carbons of an
"optionally substituted" group include: --O(CR*.sub.2).sub.2-3O--,
wherein each independent occurrence of R* is selected from
hydrogen, C.sub.1-6 aliphatic which may be substituted as defined
below, or an unsubstituted 5-6membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0104] Suitable substituents on the aliphatic group of R* include
halogen, R.sup. , -(haloR.sup. ), --OH, OR.sup. , --O(haloR.sup. ),
--CN, --C(O)OH, --C(O)OR.sup. , --NH.sub.2, --NHR.sup. , --NR.sup.
.sub.2, or --NO.sub.2, wherein each R.sup. is unsubstituted or
where preceded by "halo" is substituted only with one or more
halogens, and is independently C.sub.1-4 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, or a 5-6membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0105] Suitable substituents on a substitutable nitrogen of an
"optionally substituted" group include --R.sup..dagger.,
--NR.sup..dagger..sub.2, --C(O)R.sup..dagger.,
--C(O)OR.sup..dagger., --C(O)C(O)R.sup..dagger.,
--C(O)CH.sub.2C(O)R.sup..dagger., --S(O).sub.2R.sup..dagger.,
--S(O).sub.2NR.sup..dagger..sub.2, --C(S)NR.sup..dagger..sub.2,
--C(NH)NR.sup..dagger..sub.2, or
--N(R.sup..dagger.)S(O).sub.2R.sup..dagger.; wherein each
R.sup..dagger. is independently hydrogen, C.sub.1-6 aliphatic which
may be substituted as defined below, unsubstituted --OPh, or an
unsubstituted 5-6membered saturated, partially unsaturated, or aryl
ring having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or, notwithstanding the definition above, two
independent occurrences of R.sup..dagger., taken together with
their intervening atom(s) form an unsubstituted 3-12membered
saturated, partially unsaturated, or aryl mono or bicyclic ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0106] Suitable substituents on the aliphatic group of
R.sup..dagger. are independently halogen, --R.sup. , -(haloR.sup.
), --OH, OR.sup. , --O(haloR.sup. ), --CN, --C(O)OH, --C(O)OR.sup.
, --NH.sub.2, --NHR.sup. , --NR.sup. .sub.2, or --NO.sub.2, wherein
each R.sup. is unsubstituted or where preceded by "halo" is
substituted only with one or more halogens, and is independently
C.sub.1-4 aliphatic, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a
5-6membered saturated, partially unsaturated, or aryl ring having
0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0107] The term "leaving group" refers to an atom (or a group of
atoms) with electron withdrawing ability that can be displaced as a
stable species, taking with it the bonding electrons. Examples of
suitable leaving groups include halides and sulfonate esters,
including, but not limited to, triflate, mesylate, tosylate, and
brosylate.
[0108] The terms "hydrolysable group" and "hydrolysable moiety"
refer to a functional group capable of undergoing hydrolysis, e.g.,
under basic or acidic conditions. Examples of hydrolysable residues
include, without limitation, acid halides, activated carboxylic
acids, and various protecting groups known in the art (see, for
example, "Protective Groups in Organic Synthesis," T. W. Greene, P.
G. M. Wuts, Wiley-Interscience, 1999).
[0109] The term "organic residue" defines a carbon containing
residue, i.e., a residue comprising at least one carbon atom, and
includes but is not limited to the carbon-containing groups,
residues, or radicals defined hereinabove. Organic residues can
contain various heteroatoms, or be bonded to another molecule
through a heteroatom, including oxygen, nitrogen, sulfur,
phosphorus, or the like. Examples of organic residues include but
are not limited alkyl or substituted alkyls, alkoxy or substituted
alkoxy, mono or di-substituted amino, amide groups, etc. Organic
residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,
carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6
carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an
organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon
atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon
atoms, or 2 to 4 carbon atoms.
[0110] A very close synonym of the term "residue" is the term
"radical," which as used in the specification and concluding
claims, refers to a fragment, group, or substructure of a molecule
described herein, regardless of how the molecule is prepared. For
example, a 2,4-thiazolidinedione radical in a particular compound
has the structure:
##STR00002##
regardless of whether thiazolidinedione is used to prepare the
compound. In some embodiments the radical (for example an alkyl)
can be further modified (i.e., substituted alkyl) by having bonded
thereto one or more "substituent radicals." The number of atoms in
a given radical is not critical to the present invention unless it
is indicated to the contrary elsewhere herein.
[0111] "Organic radicals," as the term is defined and used herein,
contain one or more carbon atoms. An organic radical can have, for
example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms,
1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a
further aspect, an organic radical can have 2-26 carbon atoms, 2-18
carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon
atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen
bound to at least some of the carbon atoms of the organic radical.
One example, of an organic radical that comprises no inorganic
atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some
embodiments, an organic radical can contain 1-10 inorganic
heteroatoms bound thereto or therein, including halogens, oxygen,
sulfur, nitrogen, phosphorus, and the like. Examples of organic
radicals include but are not limited to an alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino,
di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,
substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl,
thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl,
haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or
substituted heterocyclic radicals, wherein the terms are defined
elsewhere herein. A few non-limiting examples of organic radicals
that include heteroatoms include alkoxy radicals, trifluoromethoxy
radicals, acetoxy radicals, dimethylamino radicals and the
like.
[0112] "Inorganic radicals," as the term is defined and used
herein, contain no carbon atoms and therefore comprise only atoms
other than carbon. Inorganic radicals comprise bonded combinations
of atoms selected from hydrogen, nitrogen, oxygen, silicon,
phosphorus, sulfur, selenium, and halogens such as fluorine,
chlorine, bromine, and iodine, which can be present individually or
bonded together in their chemically stable combinations. Inorganic
radicals have 10 or fewer, or preferably one to six or one to four
inorganic atoms as listed above bonded together. Examples of
inorganic radicals include, but not limited to, amino, hydroxy,
halogens, nitro, thiol, sulfate, phosphate, and like commonly known
inorganic radicals. The inorganic radicals do not have bonded
therein the metallic elements of the periodic table (such as the
alkali metals, alkaline earth metals, transition metals, lanthanide
metals, or actinide metals), although such metal ions can sometimes
serve as a pharmaceutically acceptable cation for anionic inorganic
radicals such as a sulfate, phosphate, or like anionic inorganic
radical. Inorganic radicals do not comprise metalloids elements
such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or
tellurium, or the noble gas elements, unless otherwise specifically
indicated elsewhere herein.
[0113] Compounds described herein can contain one or more double
bonds and, thus, potentially give rise to cis/trans (E/Z) isomers,
as well as other conformational isomers. Unless stated to the
contrary, the invention includes all such possible isomers, as well
as mixtures of such isomers.
[0114] Unless stated to the contrary, a formula with chemical bonds
shown only as solid lines and not as wedges or dashed lines
contemplates each possible isomer, e.g., each enantiomer and
diastereomer, and a mixture of isomers, such as a racemic or
scalemic mixture. Compounds described herein can contain one or
more asymmetric centers and, thus, potentially give rise to
diastereomers and optical isomers. Unless stated to the contrary,
the present invention includes all such possible diastereomers as
well as their racemic mixtures, their substantially pure resolved
enantiomers, all possible geometric isomers, and pharmaceutically
acceptable salts thereof. Mixtures of stereoisomers, as well as
isolated specific stereoisomers, are also included. During the
course of the synthetic procedures used to prepare such compounds,
or in using racemization or epimerization procedures known to those
skilled in the art, the products of such procedures can be a
mixture of stereoisomers.
[0115] Many organic compounds exist in optically active forms
having the ability to rotate the plane of plane-polarized light. In
describing an optically active compound, the prefixes D and L or R
and S are used to denote the absolute configuration of the molecule
about its chiral center(s). The prefixes d and l or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light
by the compound, with (-) or meaning that the compound is
levorotatory. A compound prefixed with (+) or d is dextrorotatory.
For a given chemical structure, these compounds, called
stereoisomers, are identical except that they are
non-superimposable mirror images of one another. A specific
stereoisomer can also be referred to as an enantiomer, and a
mixture of such isomers is often called an enantiomeric mixture. A
50:50 mixture of enantiomers is referred to as a racemic mixture.
Many of the compounds described herein can have one or more chiral
centers and therefore can exist in different enantiomeric forms. If
desired, a chiral carbon can be designated with an asterisk (*).
When bonds to the chiral carbon are depicted as straight lines in
the disclosed formulas, it is understood that both the (R) and (S)
configurations of the chiral carbon, and hence both enantiomers and
mixtures thereof, are embraced within the formula. As is used in
the art, when it is desired to specify the absolute configuration
about a chiral carbon, one of the bonds to the chiral carbon can be
depicted as a wedge (bonds to atoms above the plane) and the other
can be depicted as a series or wedge of short parallel lines is
(bonds to atoms below the plane). The Cahn-Ingold-Prelog system can
be used to assign the (R) or (S) configuration to a chiral
carbon.
[0116] Compounds described herein comprise atoms in both their
natural isotopic abundance and in non-natural abundance. The
disclosed compounds can be isotopically-labeled or
isotopically-substituted compounds identical to those described,
but for the fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass
or mass number typically found in nature. Examples of isotopes that
can be incorporated into compounds of the invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
fluorine and chlorine, such as .sup.2 H, .sup.3 H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S, .sup.18F and
.sup.36Cl, respectively. Compounds further comprise prodrugs
thereof, and pharmaceutically acceptable salts of said compounds or
of said prodrugs which contain the aforementioned isotopes and/or
other isotopes of other atoms are within the scope of this
invention. Certain isotopically-labeled compounds of the present
invention, for example those into which radioactive isotopes such
as .sup.3 H and .sup.14 C are incorporated, are useful in drug
and/or substrate tissue distribution assays. Tritiated, i.e.,
.sup.3 H, and carbon-14, i.e., .sup.14 C, isotopes are particularly
preferred for their ease of preparation and detectability. Further,
substitution with heavier isotopes such as deuterium, i.e., .sup.2
H, can afford certain therapeutic advantages resulting from greater
metabolic stability, for example increased in vivo half-life or
reduced dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labeled compounds of the present
invention and prodrugs thereof can generally be prepared by
carrying out the procedures below, by substituting a readily
available isotopically labeled reagent for a non- isotopically
labeled reagent.
[0117] The compounds described in the invention can be present as a
solvate. In some cases, the solvent used to prepare the solvate is
an aqueous solution, and the solvate is then often referred to as a
hydrate. The compounds can be present as a hydrate, which can be
obtained, for example, by crystallization from a solvent or from
aqueous solution. In this connection, one, two, three or any
arbitrary number of solvent or water molecules can combine with the
compounds according to the invention to form solvates and hydrates.
Unless stated to the contrary, the invention includes all such
possible solvates.
[0118] The term "co-crystal" means a physical association of two or
more molecules which owe their stability through non-covalent
interaction. One or more components of this molecular complex
provide a stable framework in the crystalline lattice. In certain
instances, the guest molecules are incorporated in the crystalline
lattice as anhydrates or solvates, see e.g. "Crystal Engineering of
the Composition of Pharmaceutical Phases. Do Pharmaceutical
Co-crystals Represent a New Path to Improved Medicines?"
Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896,
2004. Examples of co-crystals include p-toluenesulfonic acid and
benzenesulfonic acid.
[0119] It is also appreciated that certain compounds described
herein can be present as an equilibrium of tautomers. For example,
ketones with an .alpha.-hydrogen can exist in an equilibrium of the
keto form and the enol form.
##STR00003##
[0120] Likewise, amides with an N-hydrogen can exist in an
equilibrium of the amide form and the imidic acid form. As another
example, pyrazoles can exist in two tautomeric forms,
N.sup.1-unsubstituted, 3-A.sup.3 and M-unsubstituted, 5-A.sup.3 as
shown below.
##STR00004##
Unless stated to the contrary, the invention includes all such
possible tautomers.
[0121] It is known that chemical substances form solids which are
present in different states of order which are termed polymorphic
forms or modifications. The different modifications of a
polymorphic substance can differ greatly in their physical
properties. The compounds according to the invention can be present
in different polymorphic forms, with it being possible for
particular modifications to be metastable. Unless stated to the
contrary, the invention includes all such possible polymorphic
forms.
[0122] In some aspects, a structure of a compound can be
represented by a formula:
##STR00005##
which is understood to be equivalent to a formula:
##STR00006##
wherein n is typically an integer. That is, R.sup.n is understood
to represent five independent substituents, R.sup.n(a), R.sup.n(b),
R.sup.n(c), R.sup.n(d), R.sup.n(e). By "independent substituents,"
it is meant that each R substituent can be independently defined.
For example, if in one instance R.sup.n(a) halogen, then R.sup.n(b)
is not necessarily halogen in that instance.
[0123] Certain materials, compounds, compositions, and components
disclosed herein can be obtained commercially or readily
synthesized using techniques generally known to those of skill in
the art. For example, the starting materials and reagents used in
preparing the disclosed compounds and compositions are either
available from commercial suppliers such as Aldrich Chemical Co.,
(Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher
Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are
prepared by methods known to those skilled in the art following
procedures set forth in references such as Fieser and Fieser's
Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,
1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and
supplemental volumes (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989).
[0124] Unless otherwise expressly stated, it is in no way intended
that any method set forth herein be construed as requiring that its
steps be performed in a specific order. Accordingly, where a method
claim does not actually recite an order to be followed by its steps
or it is not otherwise specifically stated in the claims or
descriptions that the steps are to be limited to a specific order,
it is no way intended that an order be inferred, in any respect.
This holds for any possible non-express basis for interpretation,
including: matters of logic with respect to arrangement of steps or
operational flow; plain meaning derived from grammatical
organization or punctuation; and the number or type of embodiments
described in the specification.
[0125] Disclosed are the components to be used to prepare the
compositions of the invention as well as the compositions
themselves to be used within the methods disclosed herein. These
and other materials are disclosed herein, and it is understood that
when combinations, subsets, interactions, groups, etc. of these
materials are disclosed that while specific reference of each
various individual and collective combinations and permutation of
these compounds cannot be explicitly disclosed, each is
specifically contemplated and described herein. For example, if a
particular compound is disclosed and discussed and a number of
modifications that can be made to a number of molecules including
the compounds are discussed, specifically contemplated is each and
every combination and permutation of the compound and the
modifications that are possible unless specifically indicated to
the contrary. Thus, if a class of molecules A, B, and C are
disclosed as well as a class of molecules D, E, and F and an
example of a combination molecule, A-D is disclosed, then even if
each is not individually recited each is individually and
collectively contemplated meaning combinations, A-E, A-F, B-D, B-E,
B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any
subset or combination of these is also disclosed. Thus, for
example, the sub-group of A-E, B-F, and C-E would be considered
disclosed. This concept applies to all aspects of this application
including, but not limited to, steps in methods of making and using
the compositions of the invention. Thus, if there are a variety of
additional steps that can be performed it is understood that each
of these additional steps can be performed with any specific
embodiment or combination of embodiments of the methods of the
invention.
[0126] It is understood that the compositions disclosed herein have
certain functions. Disclosed herein are certain structural
requirements for performing the disclosed functions, and it is
understood that there are a variety of structures that can perform
the same function that are related to the disclosed structures, and
that these structures will typically achieve the same result.
B. COMPOUNDS
[0127] In one aspect, disclosed are compounds useful in treating or
preventing hearing disorders. In a further aspect, the disclosed
compounds exhibit inhibition of CDK2. In a still further aspect,
the disclosed compounds exhibit antagonism of CDK2.
[0128] In one aspect, the compounds of the invention are useful in
the treatment or prevention of hearing disorders associated with
CDK2 dysfunction and other diseases in which CDK2s are involved, as
further described herein.
[0129] It is contemplated that each disclosed derivative can be
optionally further substituted. It is also contemplated that any
one or more derivative can be optionally omitted from the
invention. It is understood that a disclosed compound can be
provided by the disclosed methods. It is also understood that the
disclosed compounds can be employed in the disclosed methods of
using.
[0130] 1. Paullone Derivatives
[0131] In various aspects, the compound is a paullone derivative,
or a pharmaceutically acceptable solvate, salt, or polymorph
thereof. Paullones are a family of benzazepinones characterized by
a core framework represented by a structure:
##STR00007##
[0132] Paullones constitute a well-established class of
cyclin-dependent kinase (CDK) inhibitors. CDK's are a family of
serine/threonine protein kinases known to play a central role in
the normal growth and life cycle of eukaryotic cells. Inhibitors of
CDK could potentially serve as pharmacological agents to treat
diseases of proliferation such as cancer, psoriasis, and restenosis
(Sharma, V. M., et al. (2008) Indian J. of Biochem. &
Biophysics 45, 416; Leost, M., et al. (2000) Eur. J. Biochem. 267,
5983-5994).
[0133] Paullone derivatives have been previously described in, for
example, US 2003/0181439 A1; U.S. Pat. No. 7,232,814 B2; Kunick,
C., et al. (2005) ChemBioChem 6, 541-549; Zaharevitz, D., et al.
(1999) Cancer Res. 59, 2566-2569; Leost, M., et al. (2000) Eur. J.
Biochem. 267, 5983-5994; WO 2006/117212 A2; WO 2009/010298 A2;
Sharma, V. M., et al. (2008) Indian J. of Biochem. & Biophysics
45, 416; Pies, T. (2003) Dissertation, Hamburg University, Hamburg,
GER, which are herein incorporated by reference.
[0134] In one aspect, disclosed are paullone derivatives having a
structure represented by a formula:
##STR00008##
wherein R.sup.1 is selected from hydrogen, halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, --(S.dbd.O)R.sup.3, --SO.sub.2R.sup.3,
C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6
alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl,
C1-C6 monoalkylamino, and C1-C6 dialkylamino; wherein R.sup.3, when
present, is selected from hydrogen, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --NH.sub.2, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2; wherein R.sup.2 is selected from hydrogen,
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, --(S.dbd.O)R.sup.4,
--SO.sub.2R.sup.4, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6
polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl,
C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino;
and wherein R.sup.4, when present, is selected from hydrogen,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3, --NH.sub.2,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2, or a pharmaceutically
acceptable salt thereof.
[0135] In a further aspect, the paullone derivative has a structure
represented by a formula selected from:
##STR00009##
or a pharmaceutically acceptable salt thereof.
[0136] In a further aspect, the paullone derivative has a structure
represented by a formula selected from:
##STR00010##
or a pharmaceutically acceptable salt thereof.
[0137] In a further aspect, the paullone derivative has a structure
represented by a formula:
##STR00011##
or a pharmaceutically acceptable salt thereof.
[0138] In a further aspect, the paullone derivative has a structure
represented by a formula selected from:
##STR00012##
or a pharmaceutically acceptable salt thereof.
[0139] In a further aspect, the paullone derivative has a structure
represented by a formula:
##STR00013##
or a pharmaceutically acceptable salt thereof.
[0140] In a further aspect, the paullone derivative has a structure
represented by a formula:
##STR00014##
or a pharmaceutically acceptable salt thereof.
[0141] a. R.sup.1 Groups
[0142] In one aspect, R.sup.1 is selected from hydrogen, halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, --(S.dbd.O)R.sup.3,
--SO.sub.2R.sup.3, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6
polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl,
C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
In a further aspect, R.sup.1 is selected from hydrogen, halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, --(S.dbd.O)R.sup.3,
--SO.sub.2R.sup.3, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3
polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl,
C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3
dialkylamino.
[0143] In a further aspect, R.sup.1 is selected from hydrogen,
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C6 alkyl, C1-C6
monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl,
C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and
C1-C6 dialkylamino. In a still further aspect, R.sup.1 is selected
from hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C3
alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy,
C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3
monoalkylamino, and C1-C3 dialkylamino. In yet a further aspect,
R.sup.1 is selected from hydrogen, --F, --Cl, --Br, --OH, --CN,
--NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0144] In a further aspect, R.sup.1 is selected from hydrogen,
halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl,
C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6
hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino. In a
still further aspect, R.sup.1 is selected from hydrogen, halogen,
C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3
alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl,
C1-C3 monoalkylamino, and C1-C3 dialkylamino. In yet a further
aspect, R.sup.1 is selected from hydrogen, --F, --Cl, --Br,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0145] In a further aspect, R.sup.1 is selected from hydrogen,
C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl. In a still further
aspect, R.sup.1 is selected from hydrogen, C1-C3 monohaloalkyl, and
C1-C3 polyhaloalkyl. In yet a further aspect, R.sup.1 is selected
from hydrogen, --CClH.sub.2, --CCl.sub.2H, --CCl.sub.3,
--CFH.sub.2, --CF.sub.2H, and --CF.sub.3. In an even further
aspect, R.sup.1 is selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3.
[0146] In a further aspect, R.sup.1 is selected from hydrogen and
C1-C6 alkyl. In a still further aspect, R.sup.1 is selected from
hydrogen, methyl, ethyl, iso-propyl, n-propyl, tert-butyl,
sec-butyl, iso-butyl, and n-butyl. In yet a further aspect, R.sup.1
is selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
In an even further aspect, R.sup.1 is selected from hydrogen,
methyl, and ethyl. In a still further aspect, R.sup.1 is selected
from hydrogen and methyl. In yet a further aspect, R.sup.1 is
selected from hydrogen and ethyl. In an even further aspect,
R.sup.1 is hydrogen. In a still further aspect, R.sup.1 is methyl.
In yet a further aspect, R.sup.1 is ethyl.
[0147] In a further aspect, R.sup.1 is selected from hydrogen and
halogen. In a still further aspect, R.sup.1 is selected from
hydrogen, --F, --Cl, and --Br. In yet a further aspect, R.sup.1 is
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.1 is selected from hydrogen and --F. In a still further
aspect, R.sup.1 is selected from hydrogen and --Cl.
[0148] In a further aspect, R.sup.1 is halogen. In a still further
aspect, R.sup.1 is selected from --F, --Cl, and --Br. In yet a
further aspect, R.sup.1 is selected from --F and --Cl. In an even
further aspect, R.sup.1 is --Br. In a still further aspect, R.sup.1
is --Cl. In yet a further aspect, R.sup.1 is --F.
[0149] b. R.sup.2 Groups
[0150] In one aspect, R.sup.2 is selected from hydrogen, halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, --(S.dbd.O)R.sup.4,
--SO.sub.2R.sup.4, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6
alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl,
C1-C6 monoalkylamino, and C1-C6 dialkylamino. In a further aspect,
R.sup.2 is selected from hydrogen, halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, --(S.dbd.O)R.sup.4, --SO.sub.2R.sup.4, C1-C3
monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl,
C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and
C1-C3 dialkylamino.
[0151] In a further aspect, R.sup.2 is selected from hydrogen,
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C6 alkyl, C1-C6
monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl,
C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and
C1-C6 dialkylamino. In a still further aspect, R.sup.2 is selected
from hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C3
alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy,
C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3
monoalkylamino, and C1-C3 dialkylamino. In yet a further aspect,
R.sup.2 is selected from hydrogen, --F, --Cl, --Br, --OH, --CN,
--NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0152] In a further aspect, R.sup.2 is selected from hydrogen,
halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl,
C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6
hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino. In a
still further aspect, R.sup.2 is selected from hydrogen, halogen,
C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3
alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl,
C1-C3 monoalkylamino, and C1-C3 dialkylamino. In yet a further
aspect, R.sup.2 is selected from hydrogen, --F, --Cl, --Br,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0153] In a further aspect, R.sup.2 is selected from hydrogen,
C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl. In a still further
aspect, R.sup.2 is selected from hydrogen, C1-C3 monohaloalkyl, and
C1-C3 polyhaloalkyl. In yet a further aspect, R.sup.2 is selected
from hydrogen, --CClH.sub.2, --CCl.sub.2H, --CCl.sub.3,--CFH.sub.2,
--CF.sub.2H, and --CF.sub.3. In an even further aspect, R.sup.2 is
selected from hydrogen, --CFH.sub.2, --CF.sub.2H, and
--CF.sub.3.
[0154] In a further aspect, R.sup.2 is selected from hydrogen and
C1-C6 alkyl. In a still further aspect, R.sup.2 is selected from
hydrogen, methyl, ethyl, iso-propyl, n-propyl, tert-butyl,
sec-butyl, iso-butyl, and n-butyl. In yet a further aspect, R.sup.2
is selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
In an even further aspect, R.sup.2 is selected from hydrogen,
methyl, and ethyl. In a still further aspect, R.sup.2 is selected
from hydrogen and methyl. In yet a further aspect, R.sup.2 is
selected from hydrogen and ethyl. In an even further aspect,
R.sup.2 is hydrogen. In a still further aspect, R.sup.2 is methyl.
In yet a further aspect, R.sup.2 is ethyl.
[0155] In a further aspect, R.sup.2 is selected from hydrogen and
halogen. In a still further aspect, R.sup.2 is selected from
hydrogen, --F, --Cl, and --Br. In yet a further aspect, R.sup.2 is
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.2 is selected from hydrogen and --F. In a still further
aspect, R.sup.2 is selected from hydrogen and --Cl.
[0156] In a further aspect, R.sup.2 is halogen. In a still further
aspect, R.sup.2 is selected from --F, --Cl, and --Br. In yet a
further aspect, R.sup.2 is selected from --F and --Cl. In an even
further aspect, R.sup.2 is --Br. In a still further aspect, R.sup.2
is --Cl. In yet a further aspect, R.sup.2 is --F.
[0157] c. R.sup.3 Groups
[0158] In one aspect, R.sup.3, when present, is selected from
hydrogen, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--NH.sub.2, --NH(CH.sub.3), and --N(CH.sub.3).sub.2. In a further
aspect, R.sup.3, when present, is selected from hydrogen,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --NH.sub.2, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2. In a still further aspect, R.sup.3, when
present, is selected from hydrogen, --CH.sub.3, --CFH.sub.2,
--NH.sub.2, and --NH(CH.sub.3). In yet a further aspect, R.sup.3,
when present, is selected from hydrogen, --CH.sub.3, and
--NH.sub.2. In an even further aspect, R.sup.3, when present, is
selected from hydrogen and --CH.sub.3. In a still further aspect,
R.sup.3, when present, is selected from hydrogen and --NH.sub.2. In
yet a further aspect, R.sup.3, when present, is hydrogen.
[0159] d. R.sup.4 Groups
[0160] In one aspect, R.sup.4, when present, is selected from
hydrogen, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--NH.sub.2, --NH(CH.sub.3), and --N(CH.sub.3).sub.2. In a further
aspect, R.sup.4, when present, is selected from hydrogen,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --NH.sub.2, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2. In a still further aspect, R.sup.4, when
present, is selected from hydrogen, --CH.sub.3, --CFH.sub.2,
--NH.sub.2, and --NH(CH.sub.3). In yet a further aspect, R.sup.4,
when present, is selected from hydrogen, --CH.sub.3, and
--NH.sub.2. In an even further aspect, R.sup.4, when present, is
selected from hydrogen and --CH.sub.3. In a still further aspect,
R.sup.4, when present, is selected from hydrogen and --NH.sub.2. In
yet a further aspect, R.sup.4, when present, is hydrogen.
[0161] 2. Purine Derivatives
[0162] In one aspect, disclosed are purine derivatives having a
structure represented by a formula:
##STR00015##
wherein each of R.sup.5a and R.sup.5b is independently selected
from hydrogen, C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein each of R.sup.5a and
R.sup.5b is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl; wherein q, when
present, is an integer selected from 1, 2, 3, and 4; wherein
R.sup.8, when present, is selected from hydrogen, --OH, --SH,
--NH.sub.2, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and
C1-C4 dialkylamino; wherein R.sup.6 is selected from halogen,
OR.sup.9, and NR.sup.10aR.sup.10b ; wherein R.sup.9, when present,
is selected from C1-C8 alkyl, (CH.sub.2).sub.pCy.sup.1, and
(CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when present, is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein p, when present, is an integer selected
from 0, 1, 2, and 3; wherein Cy.sup.1, when present, is selected
from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted
with 0, 1, 2, or 3 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl; wherein Ar.sup.1, when present, is
selected from aryl and heteroaryl and substituted with 0, 1, 2, or
3 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein each of R.sup.10a and R.sup.10b, when
present, is independently selected from C1-C8 alkyl, Cy.sup.2,
Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2
and substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein r, when present, is an integer selected
from 0, 1, 2, and 3; wherein Cy.sup.2, when present, is selected
from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted
with 0, 1, 2, or 3 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl; wherein Ar.sup.2, when present, is
selected from aryl and heteroaryl and substituted with 0, 1, 2, or
3 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; and wherein R.sup.7, when present, is selected
from hydrogen and C1-C8 alkyl, or a pharmaceutically acceptable
salt thereof.
[0163] In one aspect, q, when present, is an integer selected from
1, 2, 3, and 4. In a further aspect, q, when present, is an integer
selected from 1, 2, and 3. In a still further aspect, q, when
present, is an integer selected from 2, 3, and 4. In yet a further
aspect, q, when present, is an integer selected from 1, 2, and 4.
In an even further aspect, q, when present, is an integer selected
from 1, 3, and 4. In a still further aspect, q, when present, is an
integer selected from 1 and 2. In yet a further aspect, q, when
present, is an integer selected from 1 and 3. In an even further
aspect, q, when present, is an integer selected from 1 and 4. In a
still further aspect, q, when present, is an integer selected from
2 and 3. In yet a further aspect, q, when present, is an integer
selected from 2 and 4. In an even further aspect, q, when present,
is an integer selected from 3 and 4. In a still further aspect, q,
when present, is 1. In yet a further aspect, q, when present, is 2.
In an even further aspect, q, when present, is 3. In a still
further aspect, q, when present, is 4.
[0164] In one aspect, p, when present, is an integer selected from
0, 1, 2, and 3. In a further aspect, p, when present, is an integer
selected from 0, 1, and 2. In a still further aspect, p, when
present, is an integer selected from 0, 1, and 3. In yet a further
aspect, p, when present, is an integer selected from 0, 2, and 3.
In an even further aspect, p, when present, is an integer selected
from 1, 2, and 3. In a still further aspect, p, when present, is an
integer selected from 0 and 1. In yet a further aspect, p, when
present, is an integer selected from 0 and 2. In an even further
aspect, p, when present, is an integer selected from 0 and 3. In a
still further aspect, p, when present, is an integer selected from
1 and 2. In yet a further aspect, p, when present, is an integer
selected from 1 and 3. In an even further aspect, p, when present,
is an integer selected from 2 and 3. In a still further aspect, p,
when present, is 0. In yet a further aspect, p, when present, is 1.
In an even further aspect, p, when present, is 2. In a still
further aspect, p, when present, is 3.
[0165] In one aspect, r, when present, is an integer selected from
0, 1, 2, and 3. In a further aspect, r, when present, is an integer
selected from 0, 1, and 2. In a still further aspect, r, when
present, is an integer selected from 0, 1, and 3. In yet a further
aspect, r, when present, is an integer selected from 0, 2, and 3.
In an even further aspect, r, when present, is an integer selected
from 1, 2, and 3. In a still further aspect, r, when present, is an
integer selected from 0 and 1. In yet a further aspect, r, when
present, is an integer selected from 0 and 2. In an even further
aspect, r, when present, is an integer selected from 0 and 3. In a
still further aspect, r, when present, is an integer selected from
1 and 2. In yet a further aspect, r, when present, is an integer
selected from 1 and 3. In an even further aspect, r, when present,
is an integer selected from 2 and 3. In a still further aspect, r,
when present, is 0. In yet a further aspect, r, when present, is 1.
In an even further aspect, r, when present, is 2. In a still
further aspect, r, when present, is 3.
[0166] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00016##
or a pharmaceutically acceptable salt thereof.
[0167] In a further aspect, the purine derivative has a structure
represented by a formula:
##STR00017##
or a pharmaceutically acceptable salt thereof.
[0168] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00018##
or a pharmaceutically acceptable salt thereof.
[0169] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00019##
or a pharmaceutically acceptable salt thereof.
[0170] In a further aspect, the purine derivative has a structure
represented by a formula:
##STR00020##
or a pharmaceutically acceptable salt thereof.
[0171] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00021##
or a pharmaceutically acceptable salt thereof.
[0172] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00022##
or a pharmaceutically acceptable salt thereof.
[0173] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00023##
or a pharmaceutically acceptable salt thereof.
[0174] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00024##
or a pharmaceutically acceptable salt thereof.
[0175] In a further aspect, the purine derivative has a structure
represented by a formula selected from:
##STR00025##
or a pharmaceutically acceptable salt thereof.
[0176] In a further aspect, the purine derivative has a structure
represented by a formula:
##STR00026##
or a pharmaceutically acceptable salt thereof.
[0177] a. R.sup.5A and R.sup.5B Groups
[0178] In one aspect, each of R.sup.5a and R.sup.5b is
independently selected from hydrogen, C1-C8 alkyl,
(CH.sub.2).sub.qR.sup.8, and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein each of R.sup.5a and R.sup.5b is independently substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a further aspect, each of R.sup.5a and
R.sup.5b is independently selected from hydrogen, C1-C4 alkyl,
(CH.sub.2).sub.qR.sup.8, and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein each of R.sup.5a and R.sup.5b is independently substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0179] In a further aspect, each of R.sup.5a and R.sup.5b is
independently selected from hydrogen, C1-C8 alkyl,
(CH.sub.2).sub.qR.sup.8, and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein each of R.sup.5a and R.sup.5b is independently substituted
with 1 or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, each of R.sup.5a and R.sup.5b is
independently selected from hydrogen, C1-C8 alkyl,
(CH.sub.2).sub.qR.sup.8, and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein each of R.sup.5a and R.sup.5b is independently substituted
with 0 or 1 group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, each of R.sup.5a and R.sup.5b is independently selected
from hydrogen, C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein each of R.sup.5a and
R.sup.5b is independently monosubstituted with a group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, each of
R.sup.5a and R.sup.5b is independently selected from hydrogen,
C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein each of R.sup.5a and
R.sup.5b is unsubstituted.
[0180] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is selected from C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein R.sup.5b is substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is selected from C1-C4 alkyl,
(CH.sub.2).sub.qR.sup.8, and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein R.sup.5b is substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl.
[0181] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is selected from C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein R.sup.5b is substituted
with 1 or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is selected from C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein R.sup.5b is substituted
with 0 or 1 group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.5a, when present, is hydrogen and R.sup.5b is
selected from C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein R.sup.5b is
monosubstituted with a group selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is selected from C1-C8 alkyl, (CH.sub.2).sub.qR.sup.8, and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein R.sup.5b is
unsubstituted.
[0182] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is selected from (CH.sub.2).sub.qR.sup.8 and
C.dbd.O(CH.sub.2).sub.qR.sup.8 and wherein R.sup.5b is substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is selected from
(CH.sub.2).sub.qR.sup.8 and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein R.sup.5b is substituted with 1 or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is selected from
(CH.sub.2).sub.qR.sup.8 and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein R.sup.5b is substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In an even further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is selected from
(CH.sub.2).sub.qR.sup.8 and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein R.sup.5b is monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is selected from
(CH.sub.2).sub.qR.sup.8 and C.dbd.O(CH.sub.2).sub.qR.sup.8 and
wherein R.sup.5b is unsubstituted.
[0183] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is C1-C8 alkyl substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.5a, when present, is hydrogen and R.sup.5b is C1-C4
alkyl substituted with 0, 1, or 2 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is selected from methyl, ethyl,
n-propyl, and iso-propyl and wherein R.sup.5b is substituted with
0, 1, or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is selected from methyl and ethyl and wherein R.sup.5b is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is ethyl substituted with 0, 1,
or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In yet a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is methyl substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl.
[0184] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is C1-C8 alkyl substituted with 1 or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.5a, when present, is hydrogen and R.sup.5b is C1-C8
alkyl substituted with 0 or 1 group selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In yet a further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is C1-C8 alkyl monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, R.sup.5a, when present, is hydrogen and R.sup.5b is
unsubstituted C1-C8 alkyl.
[0185] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is C1-C8 alkyl substituted with 1 or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,
C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylaminomethyl. In a still further
aspect, R.sup.5a, when present, is hydrogen and R.sup.5b is C1-C8
alkyl substituted with 0 or 1 group selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl. In yet a further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is C1-C8 alkyl monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,
C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylaminomethyl.
[0186] In a further aspect, R.sup.5a, when present, is hydrogen and
R.sup.5b is n-propyl monosubstituted with a C1-C4 hydroxyalkyl
group. In a still further aspect, R.sup.5a, when present, is
hydrogen and R.sup.5b is n-propyl monosubstituted with a C1-C2
hydroxyalkyl group. In yet a further aspect, R.sup.5a, when
present, is hydrogen and R.sup.5b is n-propyl monosubstituted with
a CH.sub.2OH group.
[0187] b. R.sup.6 Groups
[0188] In one aspect, R.sup.6 is selected from halogen, OR.sup.9,
and NR.sup.10aR.sup.10b. In a further aspect, R.sup.2 is selected
from OR.sup.9 and NR.sup.10aR.sup.10b. In a still further aspect,
R.sup.2 is selected from halogen and OR.sup.9. In a yet further
aspect, R.sup.2 is selected from halogen and NR.sup.10aR.sup.10b.
In an even further aspect, R.sup.2 is halogen. In a still further
aspect, R.sup.2 is OR.sup.9. In a yet further aspect, R.sup.2 is
NR.sup.10aR.sup.10b.
[0189] c. R.sup.7 Groups
[0190] In one aspect, R.sup.7, when present, is selected from
hydrogen and C1-C8 alkyl. In a further aspect, R.sup.7, when
present, is selected from hydrogen and C1-C4 alkyl. In a still
further aspect, R.sup.7, when present, is hydrogen.
[0191] In a further aspect, R.sup.7, when present, is selected from
hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, and tert-butyl. In a still further aspect, R.sup.7, when
present, is selected from hydrogen, methyl, ethyl, n-propyl, and
iso-propyl. In yet a further aspect, R.sup.7, when present, is
selected from hydrogen, methyl, and ethyl. In an even further
aspect, R.sup.7, when present, is selected from hydrogen and
methyl. In a still further aspect, R.sup.7, when present, is
selected from hydrogen and ethyl.
[0192] In a further aspect, R.sup.7, when present, is selected from
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
and tert-butyl. In a still further aspect, R.sup.7, when present,
is selected from methyl, ethyl, n-propyl, and iso-propyl. In yet a
further aspect, R.sup.7, when present, is selected from methyl, and
ethyl. In an even further aspect, R.sup.7, when present, is methyl.
In a still further aspect, R.sup.7, when present, is ethyl. In yet
a further aspect, R.sup.7, when present, is n-propyl. In an even
further aspect, R.sup.7, when present, is iso-propyl.
[0193] d. R.sup.8 Groups
[0194] In one aspect, R.sup.8, when present, is selected from
hydrogen, --OH, --SH, --NH.sub.2, C1-C4 alkoxy, C1-C4 thioalkoxy,
C1-C4 alkylamino, and C1-C4 dialkylamino. In a further aspect,
R.sup.8, when present, is selected from hydrogen, --OH, --SH,
--NH.sub.2, C1-C4 alkoxy, C1-C2 thioalkoxy, C1-C2 alkylamino, and
C1-C2 dialkylamino. In a still further aspect, R.sup.8, when
present, is hydrogen.
[0195] In a further aspect, R.sup.8, when present, is selected from
hydrogen, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and
C1-C4 dialkylamino. In a still further aspect, R.sup.8, when
present, is selected from hydrogen, C1-C2 alkoxy, C1-C2 thioalkoxy,
C1-C2 alkylamino, and C1-C2 dialkylamino.
[0196] In a further aspect, R.sup.8, when present, is selected from
hydrogen, --OH, --SH, and --NH.sub.2. In a still further aspect,
R.sup.8, when present, is selected from hydrogen, --OH, and --SH.
In yet a further aspect, R.sup.8, when present, is selected from
hydrogen, --OH and --NH.sub.2. In an even further aspect, R.sup.8,
when present, is selected from hydrogen and --OH. In a still
further aspect, R.sup.8, when present, is selected from hydrogen
and --SH. In yet a further aspect, R.sup.8, when present, is
selected from hydrogen and --NH.sub.2.
[0197] e. R.sup.9 Groups
[0198] In one aspect, R.sup.9, when present, is selected from C1-C8
alkyl, (CH.sub.2).sub.pCy.sup.1, and (CH.sub.2).sub.pAr.sup.1 and
wherein R.sup.9, when present, is substituted with 0, 1, or 2
groups independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a further aspect,
R.sup.9, when present, is selected from C1-C4 alkyl,
(CH.sub.2).sub.pCy.sup.1, and (CH.sub.2).sub.pAr.sup.1 and wherein
R.sup.9, when present, is substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl.
[0199] In a further aspect, R.sup.9, when present, is selected from
C1-C8 alkyl, (CH.sub.2).sub.pCy.sup.1, and (CH.sub.2).sub.pAr.sup.1
and wherein R.sup.9, when present, is substituted with 1 or 2
groups independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.9, when present, is selected from C1-C8 alkyl,
(CH.sub.2).sub.pCy.sup.1, and (CH.sub.2).sub.pAr.sup.1 and wherein
R.sup.9, when present, is substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.9, when
present, is selected from C1-C8 alkyl, (CH.sub.2).sub.pCy.sup.1,
and (CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when present, is
monosubstituted with a group selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, R.sup.9, when present, is selected from
C1-C8 alkyl, (CH.sub.2).sub.pCy.sup.1, and (CH.sub.2).sub.pAr.sup.1
and wherein R.sup.9, when present, is unsubstituted.
[0200] In a further aspect, R.sup.9, when present, is selected from
(CH.sub.2).sub.pCy.sup.1 and (CH.sub.2).sub.pAr.sup.1 and wherein
R.sup.9, when present, is substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.9, when present, is selected from
(CH.sub.2).sub.pCy.sup.1 and (CH.sub.2).sub.pAr.sup.1 and wherein
R.sup.9, when present, is substituted with 1 or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.9, when present, is selected from
(CH.sub.2).sub.pCy.sup.1 and (CH.sub.2).sub.pAr.sup.1 and wherein
R.sup.9, when present, is substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, R.sup.9, when
present, is selected from (CH.sub.2).sub.pCy.sup.1 and
(CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when present, is
monosubstituted with a group selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.9, when present, is selected from
(CH.sub.2).sub.pCy.sup.1 and (CH.sub.2).sub.pAr.sup.1 and wherein
R.sup.9, when present, is unsubstituted.
[0201] In a further aspect, R.sup.9, when present, is
(CH.sub.2).sub.pCy.sup.1 and wherein R.sup.9, when present, is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pCy.sup.1 and wherein R.sup.9, when
present, is substituted with 1 or 2 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pCy.sup.1 and wherein R.sup.9, when
present, is substituted with 0 or 1 group selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In an even further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pCy.sup.1 and wherein R.sup.9, when
present, is substituted with a group selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pCy.sup.1 and wherein R.sup.9, when
present, is unsubstituted.
[0202] In a further aspect, R.sup.9, when present, is
(CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when present, is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when
present, is substituted with 1 or 2 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when
present, is substituted with 0 or 1 group selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In an even further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when
present, is substituted with a group selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.9, when
present, is (CH.sub.2).sub.pAr.sup.1 and wherein R.sup.9, when
present, is unsubstituted.
[0203] In a further aspect, R.sup.9, when present, is C1-C8 alkyl
and wherein R.sup.9, when present, is substituted with 0, 1, or 2
groups independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.9, when present, is C1-C8 alkyl and wherein R.sup.9,
when present, is substituted with 1 or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.9, when
present, is C1-C8 alkyl and wherein R.sup.9, when present, is
substituted with 0 or 1 group selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, R.sup.9, when present, is C1-C8 alkyl
and wherein R.sup.9, when present, is substituted with a group
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, R.sup.9, when
present, is C1-C8 alkyl and wherein R.sup.9, when present, is
unsubstituted.
[0204] In a further aspect, R.sup.9, when present, is C1-C8 alkyl.
In a still further aspect, R.sup.9, when present, is selected from
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
and tert-butyl. In yet a further aspect, R.sup.9, when present, is
selected from methyl, ethyl, n-propyl, and iso-propyl. In an even
further aspect, R.sup.9, when present, is selected from methyl and
ethyl. In a still further aspect, R.sup.9, when present, is ethyl.
In yet a further aspect, R.sup.9, when present, is methyl.
[0205] f. R.sup.10A and R.sup.10B Groups
[0206] In one aspect, each of R.sup.10a and R.sup.10b, when
present, is independently selected from C1-C8 alkyl, Cy.sup.2,
Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2
and wherein each of R.sup.10a and R.sup.10b is independently
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a further aspect, each of R.sup.10a and
R.sup.10b, when present, is independently selected from C1-C4
alkyl, Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein each of R.sup.10a and
R.sup.10b is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl.
[0207] In a further aspect, each of R.sup.10a and R.sup.10b, when
present, is independently selected from C1-C8 alkyl, Cy.sup.2,
Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2
and wherein each of R.sup.10a and R.sup.10b is independently
substituted with 1 or 2 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, each of R.sup.10a
and R.sup.10b, when present, is independently selected from C1-C8
alkyl, Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein each of R.sup.10a and
R.sup.10b is independently substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, each of
R.sup.10a and R.sup.10b, when present, is independently selected
from C1-C8 alkyl, Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein each of R.sup.10a and
R.sup.10b is independently monosubstituted with a group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, each of
R.sup.10a and R.sup.10b, when present, is independently selected
from C1-C8 alkyl, Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein each of R.sup.10a and
R.sup.10b is unsubstituted.
[0208] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is selected from C1-C8 alkyl,
Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is substituted with
0, 1, or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is selected from C1-C4 alkyl, Cy.sup.2,
Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2
and wherein R.sup.10b is substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl.
[0209] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is selected from C1-C8 alkyl,
Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is substituted with
1 or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is selected from C1-C8 alkyl, Cy.sup.2,
Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2
and wherein R.sup.10b is substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is selected from
C1-C8 alkyl, Cy.sup.2, Ar.sup.2, (CH.sub.2).sub.rCy.sup.2, and
(CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is selected from C1-C8 alkyl, Cy.sup.2, Ar.sup.2,
(CH.sub.2).sub.rCy.sup.2, and (CH.sub.2).sub.rAr.sup.2 and wherein
R.sup.10b is unsubstituted.
[0210] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is C1-C8 alkyl and substituted with 0,
1, or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is C1-C4 alkyl and substituted with 0, 1,
or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In yet a further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is selected from methyl, ethyl, n-propyl,
and iso-propyl and substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, R.sup.10a,
when present, is hydrogen and R.sup.10b, when present, is selected
from methyl and ethyl and substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is ethyl substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is methyl
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0211] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is C1-C8 alkyl and substituted with 1
or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is C1-C8 alkyl and substituted with 0 or 1
group selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is C1-C8 alkyl and monosubstituted with a group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, R.sup.10a,
when present, is hydrogen and R.sup.10b, when present, is
unsubstituted C1-C8 alkyl.
[0212] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is selected from Cy.sup.2 and
(CH.sub.2).sub.rCy.sup.2 and wherein R.sup.10b is substituted with
0, 1, or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is selected from Cy.sup.2 and
(CH.sub.2).sub.rCy.sup.2 and wherein R.sup.10b is substituted with
1 or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In yet a further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b when present, is selected from Cy.sup.2 and
(CH.sub.2).sub.rCy.sup.2 and wherein R.sup.10b is substituted with
0 or 1 group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is selected from Cy.sup.2 and (CH.sub.2).sub.rCy.sup.2 and
wherein R.sup.10b is monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is selected from
Cy.sup.2 and (CH.sub.2).sub.rCy.sup.2 and wherein R.sup.10b is
unsubstituted.
[0213] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is Cy.sup.2 and substituted with 0, 1,
or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is Cy.sup.2 and substituted with 1 or 2
groups independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is Cy.sup.2 and substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, R.sup.10a,
when present, is hydrogen and R.sup.10b, when present, is Cy.sup.2
and monosubstituted with a group selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is unsubstituted Cy.sup.2.
[0214] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is (CH.sub.2).sub.rCy.sup.2 and
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
(CH.sub.2).sub.rCy.sup.2 and substituted with 1 or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is (CH.sub.2).sub.rCy.sup.2 and substituted with 0 or 1
group selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is (CH.sub.2).sub.rCy.sup.2 and monosubstituted with a
group selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is unsubstituted (CH.sub.2).sub.rCy.sup.2.
[0215] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is CH.sub.2Cy.sup.2 and substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
CH.sub.2Cy.sup.2 and substituted with 1 or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
CH.sub.2Cy.sup.2 and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In an even further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
CH.sub.2Cy.sup.2 and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is unsubstituted
CH.sub.2Cy.sup.2.
[0216] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is selected from Ar.sup.2 and
(CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is substituted with
0, 1, or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is selected from Ar.sup.2 and
(CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is substituted with
1 or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In yet a further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b when present, is selected from Ar.sup.2 and
(CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is substituted with
0 or 1 group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is selected from Ar.sup.2 and (CH.sub.2).sub.rAr.sup.2 and
wherein R.sup.10b is monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is selected from
Ar.sup.2 and (CH.sub.2).sub.rAr.sup.2 and wherein R.sup.10b is
unsubstituted.
[0217] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is Ar.sup.2 and substituted with 0, 1,
or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is Ar.sup.2 and substituted with 1 or 2
groups independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is Ar.sup.2 and substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, R.sup.10a,
when present, is hydrogen and R.sup.10b, when present, is Ar.sup.2
and monosubstituted with a group selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, R.sup.10a, when present, is hydrogen and
R.sup.10b, when present, is unsubstituted Ar.sup.2.
[0218] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is (CH.sub.2).sub.rAr.sup.2 and
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
(CH.sub.2).sub.rAr.sup.2 and substituted with 1 or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is (CH.sub.2).sub.rAr.sup.2 and substituted with 0 or 1
group selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is (CH.sub.2).sub.rAr.sup.2 and monosubstituted with a
group selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, R.sup.10a, when present, is hydrogen and R.sup.10b, when
present, is unsubstituted (CH.sub.2).sub.rAr.sup.2.
[0219] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is (CH.sub.2)Ar.sup.2 and substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
(CH.sub.2)Ar.sup.2 and substituted with 1 or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
(CH.sub.2)Ar.sup.2 and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In an even further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is
(CH.sub.2)Ar.sup.2 and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, R.sup.10a, when
present, is hydrogen and R.sup.10b, when present, is unsubstituted
(CH.sub.2)Ar.sup.2.
[0220] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is (CH.sub.2)Ar.sup.2 and substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, and --NH.sub.2. In a still further aspect,
R.sup.ma, when present, is hydrogen and R.sup.10b, when present, is
(CH.sub.2)Ar.sup.2 and substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, and --NH.sub.2. In yet a
further aspect, R.sup.10a, when present, is hydrogen and R.sup.10b,
when present, is (CH.sub.2)Ar.sup.2 and substituted with 0, 1, or 2
groups independently selected from --OH and --NH.sub.2. In an even
further aspect, R.sup.10a, when present, is hydrogen and R.sup.10b,
when present, is (CH.sub.2)Ar.sup.2 and substituted with 0, 1, or 2
OH groups. In a still further aspect, R.sup.10a, when present, is
hydrogen and R.sup.10b, when present, is (CH.sub.2)Ar.sup.2 and
substituted with 0, 1, or 2 --NH.sub.2 groups.
[0221] In a further aspect, R.sup.10a, when present, is hydrogen
and R.sup.10b, when present, is (CH.sub.2)Ar.sup.2 monosubstituted
with an --OH group.
[0222] g. Cy.sup.1 Groups
[0223] In one aspect, Cy.sup.1, when present, is selected from
C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0,
1, 2, or 3 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a further aspect, Cy.sup.1, when present, is
selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylaminomethyl.
[0224] In a further aspect, Cy.sup.1, when present, is selected
from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, Cy.sup.1, when
present, is selected from C3-C6 cycloalkyl and C3-C6
heterocycloalkyl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Cy.sup.1, when
present, is selected from C3-C6 cycloalkyl and C3-C6
heterocycloalkyl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Cy.sup.1, when
present, is selected from C3-C6 cycloalkyl and C3-C6
heterocycloalkyl and unsubstituted.
[0225] In a further aspect, Cy.sup.1, when present, is C3-C6
cycloalkyl and substituted with 0, 1, 2, or 3 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Cy.sup.1, when present, is C3-C6 cycloalkyl and substituted
with 0, 1, 2, or 3 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylaminomethyl.
[0226] In a further aspect, Cy.sup.1, when present, is C3-C6
cycloalkyl and substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Cy.sup.1, when present, is C3-C6 cycloalkyl and substituted
with 0 or 1 group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In yet a further aspect, Cy.sup.1, when present, is C3-C6
cycloalkyl and monosubstituted with a group selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Cy.sup.1, when
present, is unsubstituted C3-C6 cycloalkyl.
[0227] In a further aspect, Cy.sup.1, when present, is C3-C6
heterocycloalkyl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, Cy.sup.1, when present, is C3-C6
heterocycloalkyl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0228] In a further aspect, Cy.sup.1, when present, is C3-C6
heterocycloalkyl and substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, Cy.sup.1, when present, is C3-C6
heterocycloalkyl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Cy.sup.1, when
present, is C3-C6 heterocycloalkyl and monosubstituted with a group
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further
aspect, Cy.sup.1, when present, is unsubstituted C3-C6
heterocycloalkyl.
[0229] h. Cy.sup.2 Groups
[0230] In one aspect, Cy.sup.2, when present, is selected from
C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0,
1, 2, or 3 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a further aspect, Cy.sup.2, when present, is
selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylaminomethyl.
[0231] In a further aspect, Cy.sup.2, when present, is selected
from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted
with 0, 1, or 2 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl. In a still further aspect, Cy.sup.2, when
present, is selected from C3-C6 cycloalkyl and C3-C6
heterocycloalkyl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Cy.sup.2, when
present, is selected from C3-C6 cycloalkyl and C3-C6
heterocycloalkyl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Cy.sup.2, when
present, is selected from C3-C6 cycloalkyl and C3-C6
heterocycloalkyl and unsubstituted.
[0232] In a further aspect, Cy.sup.2, when present, is C3-C6
cycloalkyl and substituted with 0, 1, 2, or 3 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Cy.sup.2, when present, is C3-C6 cycloalkyl and substituted
with 0, 1, 2, or 3 groups independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylaminomethyl.
[0233] In a further aspect, Cy.sup.2, when present, is C3-C6
cycloalkyl and substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Cy.sup.2, when present, is C3-C6 cycloalkyl and substituted
with 0 or 1 group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In yet a further aspect, Cy.sup.2, when present, is C3-C6
cycloalkyl and monosubstituted with a group selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Cy.sup.2, when
present, is unsubstituted C3-C6 cycloalkyl.
[0234] In a further aspect, Cy.sup.2, when present, is C3-C6
heterocycloalkyl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, Cy.sup.2, when present, is C3-C6
heterocycloalkyl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0235] In a further aspect, Cy.sup.2, when present, is C3-C6
heterocycloalkyl and substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, Cy.sup.2, when present, is C3-C6
heterocycloalkyl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl.
[0236] In yet a further aspect, Cy.sup.2, when present, is C3-C6
heterocycloalkyl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Cy.sup.2, when
present, is unsubstituted C3-C6 heterocycloalkyl.
[0237] i. Ar.sup.1 Groups
[0238] In one aspect, Ar.sup.1, when present, is selected from aryl
and heteroaryl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a further aspect, Ar.sup.1, when present, is selected from aryl
and heteroaryl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0239] In a further aspect, Ar.sup.1, when present, is selected
from aryl and heteroaryl and substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, Ar.sup.1, when present, is selected from
aryl and heteroaryl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Ar.sup.1, when
present, is selected from aryl and heteroaryl and monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, Ar.sup.1, when present, is selected from
aryl and heteroaryl and unsubstituted.
[0240] In a further aspect, Ar.sup.1, when present, is aryl and
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.1, when
present, is aryl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0241] In a further aspect, Ar.sup.1, when present, is aryl and
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.1, when
present, is aryl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Ar.sup.1, when
present, is aryl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Ar.sup.1, when
present, is unsubstituted aryl.
[0242] In a further aspect, Ar.sup.1, when present, is phenyl and
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.1, when
present, is phenyl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0243] In a further aspect, Ar.sup.1, when present, is phenyl and
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.1, when
present, is phenyl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Ar.sup.1, when
present, is phenyl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Ar.sup.1, when
present, is unsubstituted phenyl.
[0244] In a further aspect, Ar.sup.1, when present, is heteroaryl
and substituted with 0, 1, 2, or 3 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Ar.sup.1, when present, is heteroaryl and substituted with
0, 1, 2, or 3 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0245] In a further aspect, Ar.sup.1, when present, is heteroaryl
and substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.1, when
present, is heteroaryl and substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, Ar.sup.1, when present, is heteroaryl and monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, Ar.sup.1, when present, is unsubstituted
heteroaryl.
[0246] In a further aspect, Ar.sup.1, when present, is pyridinyl
and substituted with 0, 1, 2, or 3 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Ar.sup.1, when present, is pyridinyl and substituted with
0, 1, 2, or 3 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0247] In a further aspect, Ar.sup.1, when present, is pyridinyl
and substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.1, when
present, is pyridinyl and substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, Ar.sup.1, when present, is pyridinyl and monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, Ar.sup.1, when present, is unsubstituted
pyridinyl.
[0248] j. Ar.sup.2 Groups
[0249] In one aspect, Ar.sup.2, when present, is selected from aryl
and heteroaryl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a further aspect, Ar.sup.2, when present, is selected from aryl
and heteroaryl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0250] In a further aspect, Ar.sup.2, when present, is selected
from aryl and heteroaryl and substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In a still further aspect, Ar.sup.2, when present, is selected from
aryl and heteroaryl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Ar.sup.2, when
present, is selected from aryl and heteroaryl and monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, Ar.sup.2, when present, is selected from
aryl and heteroaryl and unsubstituted.
[0251] In a further aspect, Ar.sup.2, when present, is aryl and
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.2, when
present, is aryl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0252] In a further aspect, Ar.sup.2, when present, is aryl and
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.2, when
present, is aryl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Ar.sup.2, when
present, is aryl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Ar.sup.2, when
present, is unsubstituted aryl.
[0253] In a further aspect, Ar.sup.2, when present, is phenyl and
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.2, when
present, is phenyl and substituted with 0, 1, 2, or 3 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0254] In a further aspect, Ar.sup.2, when present, is phenyl and
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.2, when
present, is phenyl and substituted with 0 or 1 group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In yet a further aspect, Ar.sup.2, when
present, is phenyl and monosubstituted with a group selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In an even further aspect, Ar.sup.e, when
present, is unsubstituted phenyl.
[0255] In a further aspect, Ar.sup.2, when present, is heteroaryl
and substituted with 0, 1, 2, or 3 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Ar.sup.2, when present, is heteroaryl and substituted with
0, 1, 2, or 3 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0256] In a further aspect, Ar.sup.2, when present, is heteroaryl
and substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.2, when
present, is heteroaryl and substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, Ar.sup.2, when present, is heteroaryl and monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, Ar.sup.2, when present, is unsubstituted
heteroaryl.
[0257] In a further aspect, Ar.sup.2, when present, is pyridinyl
and substituted with 0, 1, 2, or 3 groups independently selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further
aspect, Ar.sup.2, when present, is pyridinyl and substituted with
0, 1, 2, or 3 groups independently selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylaminomethyl.
[0258] In a further aspect, Ar.sup.2, when present, is pyridinyl
and substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl. In a still further aspect, Ar.sup.2, when
present, is pyridinyl and substituted with 0 or 1 group selected
from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further
aspect, Ar.sup.2, when present, is pyridinyl and monosubstituted
with a group selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
In an even further aspect, Ar.sup.e, when present, is unsubstituted
pyridinyl.
[0259] 3. 3-(2-phenylhydrazono)indolin-2-one Derivatives
[0260] In one aspect, disclosed are
3-(2-phenylhydrazono)indolin-2-one derivatives having a structure
represented by a formula:
##STR00027##
wherein each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15; wherein each occurrence
of R.sup.15, when present, is independently selected from hydrogen,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3, --NH.sub.2,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2; wherein each of R.sup.12
and R.sup.13 is independently selected from hydrogen and C1-C4
alkyl; wherein each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, halogen,
--OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4
dialkylamino, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16; and
wherein each occurrence of R.sup.16, when present, is independently
selected from hydrogen, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --NH.sub.2, --NH(CH.sub.3), and --N(CH.sub.3).sub.2, or
a pharmaceutically acceptable salt thereof.
[0261] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00028##
or a pharmaceutically acceptable salt thereof.
[0262] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00029##
or a pharmaceutically acceptable salt thereof.
[0263] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00030##
or a pharmaceutically acceptable salt thereof.
[0264] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00031##
or a pharmaceutically acceptable salt thereof.
[0265] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00032##
or a pharmaceutically acceptable salt thereof.
[0266] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00033##
or a pharmaceutically acceptable salt thereof.
[0267] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00034## ##STR00035##
or a pharmaceutically acceptable salt thereof.
[0268] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula selected
from:
##STR00036##
or a pharmaceutically acceptable salt thereof.
[0269] In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one
derivative has a structure represented by a formula:
##STR00037##
or a pharmaceutically acceptable salt thereof.
[0270] a. R.sup.11A, R.sup.11B, R.sup.11C, and R.sup.11D Groups
[0271] In one aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen, halogen, --OH,
--SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4
dialkylamino, --SO.sub.2R.sup.15, and --CO.sub.2R.sup.15. In a
further aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen, halogen, --OH,
--SH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2
dialkylamino, --SO.sub.2R.sup.15, and --CO.sub.2R.sup.15. In yet a
further aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d is hydrogen.
[0272] In a further aspect, each of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylamino. In a still further aspect, each of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, --F, --Cl, --Br, --OH, --CN,
--NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0273] In a further aspect, each of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen, halogen, C1-C2
alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,
C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, --F, --Cl, --Br, --CH.sub.3,
--CFH.sub.2, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0274] In a further aspect, each of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further
aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, C1-C2 monohaloalkyl, and
C1-C2 polyhaloalkyl. In yet a further aspect, each of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is independently is selected
from hydrogen, --CFH.sub.2, --CF.sub.2H, and --CF.sub.3.
[0275] In a further aspect, each of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen
and C1-C4 alkyl. In a still further aspect, each of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a further
aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, methyl, and ethyl. In an even
further aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen and methyl. In a
still further aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen and ethyl.
[0276] In a further aspect, each of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen
and halogen. In a still further aspect, each of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, --F, --Cl, and --Br. In yet a further aspect, each of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from hydrogen, --F, and --Cl. In an even further aspect,
each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen and --F. In a still further
aspect, each of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen and --Cl.
[0277] In a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, R.sup.11a is
hydrogen and each of R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0278] In a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
R.sup.11a is hydrogen and each of R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen, halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylamino. In yet a further aspect, R.sup.11a is hydrogen and
each of R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from hydrogen, --F, --Cl, --Br, --OH, --CN, --NO.sub.2,
--NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0279] In a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
In yet a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0280] In a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a still
further aspect, R.sup.11a is hydrogen and each of R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a further
aspect, R.sup.11a is hydrogen and each of R.sup.11b, R.sup.11c, and
R.sup.11d is independently is selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3.
[0281] In a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen and C1-C4 alkyl. In a still further aspect, R.sup.11a is
hydrogen and each of R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, methyl, ethyl, iso-propyl,
and n-propyl. In yet a further aspect, R.sup.11a is hydrogen and
each of R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from hydrogen, methyl, and ethyl. In an even further
aspect, R.sup.11a is hydrogen and each of R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen and methyl. In a
still further aspect, R.sup.11a is hydrogen and each of R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen
and ethyl.
[0282] In a further aspect, R.sup.11a is hydrogen and each of
R.sup.11b, R.sup.11c, and R.sup.11d is independently selected from
hydrogen and halogen. In a still further aspect, R.sup.11a is
hydrogen and each of R.sup.11b, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, --F, --Cl, and --Br. In yet a
further aspect, R.sup.11a is hydrogen and each of R.sup.11b,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
--F, and --Cl. In an even further aspect, R.sup.11a is hydrogen and
each of R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from hydrogen and --F. In a still further aspect,
R.sup.11a is hydrogen and each of R.sup.11b, R.sup.11c, and
R.sup.11d is independently selected from hydrogen and --Cl.
[0283] In a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, C1-C4 dialkylamino, SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, R.sup.11b is
hydrogen and each of R.sup.11a, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0284] In a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
R.sup.11b is hydrogen and each of R.sup.11a, R.sup.11c, and
R.sup.11d is independently selected from hydrogen, halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylamino. In yet a further aspect, R.sup.11b is hydrogen and
each of R.sup.11a, R.sup.11c, and R.sup.11d is independently
selected from hydrogen, --F, --Cl, --Br, --OH, --CN, --NO.sub.2,
--NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0285] In a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
In yet a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0286] In a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a still
further aspect, R.sup.11b is hydrogen and each of R.sup.11a,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a further
aspect, R.sup.11b is hydrogen and each of R.sup.11a, R.sup.11c, and
R.sup.11d is independently is selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3.
[0287] In a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen and C1-C4 alkyl. In a still further aspect, R.sup.11b is
hydrogen and each of R.sup.11a, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, methyl, ethyl, iso-propyl,
and n-propyl. In yet a further aspect, R.sup.11b is hydrogen and
each of R.sup.11a, R.sup.11c, and R.sup.11d is independently
selected from hydrogen, methyl, and ethyl. In an even further
aspect, R.sup.11b is hydrogen and each of R.sup.11a, R.sup.11c, and
R.sup.11d is independently selected from hydrogen and methyl. In a
still further aspect, R.sup.11b is hydrogen and each of R.sup.11a,
R.sup.11c, and R.sup.11d is independently selected from hydrogen
and ethyl.
[0288] In a further aspect, R.sup.11b is hydrogen and each of
R.sup.11a, R.sup.11c, and R.sup.11d is independently selected from
hydrogen and halogen. In a still further aspect, R.sup.11b is
hydrogen and each of R.sup.11a, R.sup.11c, and R.sup.11d is
independently selected from hydrogen, --F, --Cl, and --Br. In yet a
further aspect, R.sup.11b is hydrogen and each of R.sup.11a,
R.sup.11c, and R.sup.11d is independently selected from hydrogen,
--F, and --Cl. In an even further aspect, R.sup.11b is hydrogen and
each of R.sup.11a, R.sup.11c, and R.sup.11d is independently
selected from hydrogen and --F. In a still further aspect,
R.sup.11b is hydrogen and each of R.sup.11a, R.sup.11c, and
R.sup.11d is independently selected from hydrogen and --Cl.
[0289] In a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, R.sup.11c is
hydrogen and each of R.sup.11a, R.sup.11b, and R.sup.11d is
independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0290] In a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
R.sup.11c is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11d is independently selected from hydrogen, halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylamino. In yet a further aspect, R.sup.11c is hydrogen and
each of R.sup.11a, R.sup.11b, and R.sup.11d is independently
selected from hydrogen, --F, --Cl, --Br, --OH, --CN, NO.sub.2,
--NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0291] In a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
In yet a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen, --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0292] In a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a still
further aspect, R.sup.11c is hydrogen and each of R.sup.11a,
R.sup.11b, and R.sup.11d is independently selected from hydrogen,
C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a further
aspect, R.sup.11c is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11d is independently is selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3.
[0293] In a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen and C1-C4 alkyl. In a still further aspect, R.sup.11c is
hydrogen and each of R.sup.11a, R.sup.11b, and R.sup.11d is
independently selected from hydrogen, methyl, ethyl, iso-propyl,
and n-propyl. In yet a further aspect, R.sup.11c is hydrogen and
each of R.sup.11a, R.sup.11b, and R.sup.11d is independently
selected from hydrogen, methyl, and ethyl. In an even further
aspect, R.sup.11c is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11d is independently selected from hydrogen and methyl. In a
still further aspect, R.sup.11c is hydrogen and each of R.sup.11a,
R.sup.11b, and R.sup.11d is independently selected from hydrogen
and ethyl.
[0294] In a further aspect, R.sup.11c is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11d is independently selected from
hydrogen and halogen. In a still further aspect, R.sup.11c is
hydrogen and each of R.sup.11a, R.sup.11b, and R.sup.11d is
independently selected from hydrogen, --F, --Cl, and --Br. In yet a
further aspect, R.sup.11c is hydrogen and each of R.sup.11a,
R.sup.11b, and R.sup.11d is independently selected from hydrogen,
--F, and --Cl. In an even further aspect, R.sup.11c is hydrogen and
each of R.sup.11a, R.sup.11b, and R.sup.11d is independently
selected from hydrogen and --F. In a still further aspect,
R.sup.11c is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11d is independently selected from hydrogen and --Cl.
[0295] In a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c is independently selected from
hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, R.sup.11d is
hydrogen and each of R.sup.11a, R.sup.11b, and R.sup.11c is
independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0296] In a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
R.sup.11d is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11c is independently selected from hydrogen, halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl,
C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2
aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylamino. In yet a further aspect, R.sup.11d is hydrogen and
each of R.sup.11a, R.sup.11b, and R.sup.11c is independently
selected from hydrogen, --F, --Cl, --Br, --OH, --CN, --NO.sub.2,
--NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0297] In a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c independently selected from
hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c is independently selected from
hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
In yet a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c is independently selected from
hydrogen, --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0298] In a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c independently selected from
hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a still
further aspect, R.sup.11a is hydrogen and each of R.sup.11a,
R.sup.11b, and R.sup.11c is independently selected from hydrogen,
C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a further
aspect, R.sup.11d is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11c is independently is selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3.
[0299] In a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c independently selected from
hydrogen and C1-C4 alkyl. In a still further aspect, R.sup.11d is
hydrogen and each of R.sup.11a, R.sup.11b, and R.sup.11c is
independently selected from hydrogen, methyl, ethyl, iso-propyl,
and n-propyl. In yet a further aspect, R.sup.11d is hydrogen and
each of R.sup.11a, R.sup.11b, and R.sup.11c is independently
selected from hydrogen, methyl, and ethyl. In an even further
aspect, R.sup.11d is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11c is independently selected from hydrogen and methyl. In a
still further aspect, R.sup.11d is hydrogen and each of R.sup.11a,
R.sup.11b, and R.sup.11c is independently selected from hydrogen
and ethyl.
[0300] In a further aspect, R.sup.11d is hydrogen and each of
R.sup.11a, R.sup.11b, and R.sup.11c independently selected from
hydrogen and halogen. In a still further aspect, R.sup.11d is
hydrogen and each of R.sup.11a, R.sup.11b, and R.sup.11c is
independently selected from hydrogen, --F, --Cl, and --Br. In yet a
further aspect, R.sup.11d is hydrogen and each of R.sup.11a,
R.sup.11b, and R.sup.11c is independently selected from hydrogen,
--F, and --Cl. In an even further aspect, R.sup.11d is hydrogen and
each of R.sup.11a, R.sup.11b, and R.sup.11c is independently
selected from hydrogen and --F. In a still further aspect,
R.sup.11d is hydrogen and each of R.sup.11a, R.sup.11b, and
R.sup.11c is independently selected from hydrogen and --Cl.
[0301] In a further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from halogen,
--OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4
dialkylamino, --SO.sub.2R.sup.15, and --CO.sub.2R.sup.15. In a
still further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are independently selected from halogen, --OH, --SH,
--CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0302] In a further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylamino.
[0303] In a still further aspect, two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and two of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from --F, --Cl, --Br, --OH, --CN, --NO.sub.2, --NH.sub.2,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0304] In a further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from halogen,
C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4
alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a still further
aspect, two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
hydrogen and two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d
are independently selected from halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and two of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is independently
selected from --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0305] In a further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from C1-C4
monohaloalkyl and C1-C4 polyhaloalkyl. In a still further aspect,
two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen
and two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
independently selected from C1-C2 monohaloalkyl and C1-C2
polyhaloalkyl. In yet a further aspect, two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and two of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are independently
selected from --CFH.sub.2, --CF.sub.2H, and --CF.sub.3.
[0306] In a further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from C1-C4
alkyl. In a still further aspect, two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are independently selected from
methyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect,
two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen
and two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
independently selected from methyl and ethyl. In an even further
aspect, two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
hydrogen and two of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d
are methyl. In a still further aspect, two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are ethyl.
[0307] In a further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from halogen.
In a still further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are independently selected from --F, --Cl,
and --Br. In yet a further aspect, two of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are independently selected from
--F and --Cl. In an even further aspect, two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and two of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are --F. In a still
further aspect, two of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and two of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are --Cl. In yet a further aspect, two of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and two of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are --Br.
[0308] In a further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from halogen, --OH,
--SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4
dialkylamino, --SO.sub.2R.sup.15, and --CO.sub.2R.sup.15. In a
still further aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d is selected from halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0309] In a further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from halogen, --OH,
--CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylamino. In a still further aspect, three of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and one of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, three of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and one of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is selected from
--F, --Cl, --Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3,
--CFH.sub.2, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0310] In a further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from halogen, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
three of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
hydrogen and one of R.sup.11a, R.sup.11b, R11c, and R.sup.11d is
selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
In yet a further aspect, three of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d are hydrogen and one of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d is selected from --F, --Cl, --Br,
--CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0311] In a further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from C1-C4
monohaloalkyl and C1-C4 polyhaloalkyl. In a still further aspect,
three of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d
is selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl. In
yet a further aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d is selected from --CFH.sub.2, --CF.sub.2H, and
--CF.sub.3.
[0312] In a further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from C1-C4 alkyl.
In a still further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from methyl, ethyl,
iso-propyl, and n-propyl. In yet a further aspect, three of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and one
of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is selected from
methyl and ethyl. In an even further aspect, three of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d are hydrogen and one of
R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d is methyl. In a
still further aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d is ethyl.
[0313] In a further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is selected from halogen. In a
still further aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d is selected from --F, --Cl, and --Br. In yet a
further aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and
R.sup.11d are hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c,
and R.sup.11d is selected from --F and --Cl. In an even further
aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d
is --F. In a still further aspect, three of R.sup.11a, R.sup.11b,
R.sup.11c, and R.sup.11d are hydrogen and one of R.sup.11a,
R.sup.11b, R.sup.11c, and R.sup.11d is --Cl. In yet a further
aspect, three of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are
hydrogen and one of R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d
is --Br.
[0314] b. R.sup.12 and R.sup.13 Groups
[0315] In one aspect, each of R.sup.12 and R.sup.13 is
independently selected from hydrogen and C1-C4 alkyl. In a further
aspect, each of R.sup.12 and R.sup.13 is hydrogen.
[0316] In a further aspect, each of R.sup.12 and R.sup.13 is
independently selected from hydrogen, methyl, ethyl, n-propyl, and
iso-propyl. In a still further aspect, each of R.sup.12 and
R.sup.13 is independently selected from hydrogen, methyl, and
ethyl. In yet a further aspect, each of R.sup.12 and R.sup.13 is
independently selected from hydrogen and ethyl. In an even further
aspect, each of R.sup.12 and R.sup.13 is independently selected
from hydrogen and methyl.
[0317] In a further aspect, R.sup.12 is hydrogen and R.sup.13 is
C1-C4 alkyl. In a still further aspect, R.sup.12 is hydrogen and
R.sup.13 is selected from methyl, ethyl, n-propyl, and iso-propyl.
In yet a further aspect, R.sup.12 is hydrogen and R.sup.13 is
selected from methyl and ethyl. In an even further aspect, R.sup.12
is hydrogen and R.sup.13 is ethyl. In a still further aspect,
R.sup.12 is hydrogen and R.sup.13 is methyl.
[0318] In a further aspect, R.sup.13 is hydrogen and R.sup.12 is
C1-C4 alkyl. In a still further aspect, R.sup.13 is hydrogen and
R.sup.12 is selected from methyl, ethyl, n-propyl, and iso-propyl.
In yet a further aspect, R.sup.13 is hydrogen and R.sup.12 is
selected from methyl and ethyl. In an even further aspect, R.sup.13
is hydrogen and R.sup.12 is ethyl. In a still further aspect,
R.sup.13 is hydrogen and R.sup.12 is methyl.
[0319] c. R.sup.14A, R.sup.14B, R.sup.14C, R.sup.14D, and R.sup.14E
Groups
[0320] In one aspect, each of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen,
halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 alkyl,
C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4
alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,
C1-C4 dialkylamino, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In
a still further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen,
halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2
alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,
C1-C2 dialkylamino, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
[0321] In a further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
is independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2
dialkylamino.
[0322] In a further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d and R.sup.14e is independently selected from hydrogen,
halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet
a further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen,
--F, --Cl, --Br, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0323] In a further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a still
further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, C1-C2
monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a further aspect,
each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d and R.sup.14e is
independently is selected from hydrogen, --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0324] In a further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen and C1-C4 alkyl. In a still further aspect, each of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, methyl, ethyl, iso-propyl,
and n-propyl. In yet a further aspect, each of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, methyl, and ethyl. In an even further
aspect, each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is independently selected from hydrogen and methyl. In a
still further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen
and ethyl.
[0325] In a further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen and halogen. In a still further aspect, each of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --F, --Cl, and --Br. In yet a further
aspect, each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is independently selected from hydrogen, --F, and --Cl.
In an even further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen
and --F. In a still further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen and --Cl.
[0326] In a further aspect, each of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is independently selected from hydrogen, --OH, --SH,
--NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In yet a
further aspect, each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In an even further
aspect, each of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is independently selected from hydrogen and
--SO.sub.2R.sup.16. In a still further aspect, each of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and --CO.sub.2R.sup.16.
[0327] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In a still further aspect, R.sup.14a is
hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
is independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
[0328] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, R.sup.14a is hydrogen and each of R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
--Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0329] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylamino. In a still further aspect, R.sup.14a is hydrogen and
each of R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, R.sup.14a is hydrogen
and each of R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, --F, --Cl, --Br, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2.
[0330] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4
polyhaloalkyl. In a still further aspect, R.sup.14a is hydrogen and
each of R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, C1-C2 monohaloalkyl, and
C1-C2 polyhaloalkyl. In yet a further aspect, R.sup.14a is hydrogen
and each of R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently is selected from hydrogen, --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0331] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and C1-C4 alkyl. In a still further aspect,
R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, methyl,
ethyl, iso-propyl, and n-propyl. In yet a further aspect, R.sup.14a
is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is independently selected from hydrogen, methyl, and
ethyl. In an even further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and methyl. In a still further aspect,
R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen and
ethyl.
[0332] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and halogen. In a still further aspect,
R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
and --Br. In yet a further aspect, R.sup.14a is hydrogen and each
of R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen and --F. In a
still further aspect, R.sup.14a is hydrogen and each of R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen and --Cl.
[0333] In a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen,
--OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In yet a further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In an even further aspect, R.sup.14a is hydrogen and each of
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and --SO.sub.2R.sup.16. In a still further
aspect, R.sup.14a is hydrogen and each of R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen
and --CO.sub.2R.sup.16.
[0334] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In a still further aspect, R.sup.14b is
hydrogen and each of R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e
is independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
[0335] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, R.sup.14b is hydrogen and each of R.sup.14a,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
R.sup.14b is hydrogen and each of R.sup.14a, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
--Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0336] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylamino. In a still further aspect, R.sup.14b is hydrogen and
each of R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, R.sup.14b is hydrogen
and each of R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, --F, --Cl, --Br, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2.
[0337] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4
polyhaloalkyl. In a still further aspect, R.sup.14b is hydrogen and
each of R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, C1-C2 monohaloalkyl, and
C1-C2 polyhaloalkyl. In yet a further aspect, R.sup.14b is hydrogen
and each of R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is
independently is selected from hydrogen, --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0338] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and C1-C4 alkyl. In a still further aspect,
R.sup.14b is hydrogen and each of R.sup.14a, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, methyl,
ethyl, iso-propyl, and n-propyl. In yet a further aspect, R.sup.14b
is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is independently selected from hydrogen, methyl, and
ethyl. In an even further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and methyl. In a still further aspect,
R.sup.14b is hydrogen and each of R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen and
ethyl.
[0339] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and halogen. In a still further aspect,
R.sup.14b is hydrogen and each of R.sup.14a, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
and --Br. In yet a further aspect, R.sup.14b is hydrogen and each
of R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.14b is hydrogen and each of R.sup.14a, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from hydrogen and --F. In a
still further aspect, R.sup.14b is hydrogen and each of R.sup.14a,
R.sup.14c, R.sup.14d, and R.sup.14e is independently selected from
hydrogen and --Cl.
[0340] In a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, R.sup.14b is hydrogen and each of R.sup.14a, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen,
--OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In yet a further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In an even further aspect, R.sup.14b is hydrogen and each of
R.sup.14a, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and --SO.sub.2R.sup.16. In a still further
aspect, R.sup.14b is hydrogen and each of R.sup.14a, R.sup.14c,
R.sup.14d, and R.sup.14e is independently selected from hydrogen
and --CO.sub.2R.sup.16.
[0341] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In a still further aspect, R.sup.14c is
hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e
is independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
[0342] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, R.sup.14c is hydrogen and each of R.sup.14a,
R.sup.14b, R.sup.14d, and R.sup.14e is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
--Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0343] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C I -C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylamino. In a still further aspect, R.sup.14c is hydrogen and
each of R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, R.sup.14c is hydrogen
and each of R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, --F, --Cl, --Br, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2.
[0344] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4
polyhaloalkyl. In a still further aspect, R.sup.14c is hydrogen and
each of R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is
independently selected from hydrogen, C1-C2 monohaloalkyl, and
C1-C2 polyhaloalkyl. In yet a further aspect, R.sup.14c is hydrogen
and each of R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is
independently is selected from hydrogen, --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0345] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and C1-C4 alkyl. In a still further aspect,
R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, methyl,
ethyl, iso-propyl, and n-propyl. In yet a further aspect, R.sup.14c
is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d, and
R.sup.14e is independently selected from hydrogen, methyl, and
ethyl. In an even further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and methyl. In a still further aspect,
R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d,
and R.sup.14e is independently selected from hydrogen and
ethyl.
[0346] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and halogen. In a still further aspect,
R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
and --Br. In yet a further aspect, R.sup.14c is hydrogen and each
of R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14d,
and R.sup.14e is independently selected from hydrogen and --F. In a
still further aspect, R.sup.14c is hydrogen and each of R.sup.14a,
R.sup.14b, R.sup.14d, and R.sup.14e is independently selected from
hydrogen and --Cl.
[0347] In a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b,
R.sup.14d, and R.sup.14e is independently selected from hydrogen,
--OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In yet a further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In an even further aspect, R.sup.14c is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14d, and R.sup.14e is independently
selected from hydrogen and --SO.sub.2R.sup.16. In a still further
aspect, R.sup.14c is hydrogen and each of R.sup.14a, R.sup.14b,
R.sup.14d, and R.sup.14e is independently selected from hydrogen
and --CO.sub.2R.sup.16.
[0348] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In a still further aspect, R.sup.14d is
hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e
is independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
[0349] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, R.sup.14d is hydrogen and each of R.sup.14a,
R.sup.14b, R.sup.14c, and R.sup.14e is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
R.sup.14d is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
--Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0350] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylamino. In a still further aspect, R.sup.14d is hydrogen and
each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is
independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, R.sup.14d is hydrogen
and each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is
independently selected from hydrogen, --F, --Cl, --Br, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2.
[0351] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4
polyhaloalkyl. In a still further aspect, R.sup.14d is hydrogen and
each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is
independently selected from hydrogen, C1-C2 monohaloalkyl, and
C1-C2 polyhaloalkyl. In yet a further aspect, R.sup.14d is hydrogen
and each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is
independently is selected from hydrogen, --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0352] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen and C1-C4 alkyl. In a still further aspect,
R.sup.14d is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14e is independently selected from hydrogen, methyl,
ethyl, iso-propyl, and n-propyl. In yet a further aspect, R.sup.14d
is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c, and
R.sup.14e is independently selected from hydrogen, methyl, and
ethyl. In an even further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14c, and R.sup.14e is independently selected from
hydrogen and methyl. In a still further aspect, R.sup.14d is
hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e
is independently selected from hydrogen and ethyl.
[0353] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen and halogen. In a still further aspect,
R.sup.14d is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14e is independently selected from hydrogen, --F, --Cl,
and --Br. In yet a further aspect, R.sup.14d is hydrogen and each
of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.14d is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14e is independently selected from hydrogen and --F. In a
still further aspect, R.sup.14d is hydrogen and each of R.sup.14a,
R.sup.14b, R.sup.14c, and R.sup.14e is independently selected from
hydrogen and --Cl.
[0354] In a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, R.sup.14d is hydrogen and each of R.sup.14a, R.sup.14b,
R.sup.14c, and R.sup.14e is independently selected from hydrogen,
--OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In yet a further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In an even further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen and --SO.sub.2R.sup.16.
[0355] In a still further aspect, R.sup.14d is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14e is independently
selected from hydrogen and --CO.sub.2R.sup.16.
[0356] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In a still further aspect, R.sup.14e is
hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d
is independently selected from hydrogen, halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
[0357] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, R.sup.14e is hydrogen and each of R.sup.14a,
R.sup.14b, R.sup.14c, and R.sup.14d is independently selected from
hydrogen, halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl,
C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2
cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14d is independently selected from hydrogen, --F, --Cl,
--Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0358] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylamino. In a still further aspect, R.sup.14e is hydrogen and
each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is
independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino.
[0359] In yet a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0360] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4
polyhaloalkyl. In a still further aspect, R.sup.14e is hydrogen and
each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is
independently selected from hydrogen, C1-C2 monohaloalkyl, and
C1-C2 polyhaloalkyl. In yet a further aspect, R.sup.14e is hydrogen
and each of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is
independently is selected from hydrogen, --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0361] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen and C1-C4 alkyl. In a still further aspect,
R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14d is independently selected from hydrogen, methyl,
ethyl, iso-propyl, and n-propyl. In yet a further aspect, R.sup.14e
is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c, and
R.sup.14d is independently selected from hydrogen, methyl, and
ethyl. In an even further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen and methyl. In a still further aspect,
R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14d is independently selected from hydrogen and
ethyl.
[0362] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen and halogen. In a still further aspect,
R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14d is independently selected from hydrogen, --F, --Cl,
and --Br. In yet a further aspect, R.sup.14e is hydrogen and each
of R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, --F, and --Cl. In an even further aspect,
R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b, R.sup.14c,
and R.sup.14d is independently selected from hydrogen and --F. In a
still further aspect, R.sup.14e is hydrogen and each of R.sup.14a,
R.sup.14b, R.sup.14c, and R.sup.14d is independently selected from
hydrogen and --Cl.
[0363] In a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b,
R.sup.14c, and R.sup.14d is independently selected from hydrogen,
--OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In yet a further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16.
In an even further aspect, R.sup.14e is hydrogen and each of
R.sup.14a, R.sup.14b, R.sup.14c, and R.sup.14d is independently
selected from hydrogen and --SO.sub.2R.sup.16. In a still further
aspect, R.sup.14e is hydrogen and each of R.sup.14a, R.sup.14b,
R.sup.14c, and R.sup.14d is independently selected from hydrogen
and --CO.sub.2R.sup.16.
[0364] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
is independently selected from halogen, --OH, --SH, --CN,
--NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino,
--SO.sub.2R.sup.15, and --CO.sub.2R.sup.15.
[0365] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14eare independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are hydrogen and three of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are independently selected from halogen,
--OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
is independently selected from --F, --Cl, --Br, --OH, --CN,
--NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0366] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,
C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
In yet a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is independently
selected from --F, --Cl, --Br, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0367] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl. In a
still further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl. In yet a
further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are hydrogen and three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are independently selected from
--CFH.sub.2, --CF.sub.2H, and --CF.sub.3.
[0368] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from C1-C4 alkyl. In a still further aspect, two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are independently selected from methyl, ethyl,
iso-propyl, and n-propyl. In yet a further aspect, two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are independently selected from methyl and ethyl. In
an even further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are methyl. In a
still further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are ethyl.
[0369] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from halogen. In a still further aspect, two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are independently selected from --F, --Cl, and --Br. In yet a
further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are hydrogen and three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are independently selected from
--F and --Cl. In an even further aspect, two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are --F. In a still further aspect, two of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and three of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are --Cl.
In yet a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are --Br.
[0370] In a further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from hydrogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are independently selected from
hydrogen, --OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In yet a further aspect, two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are independently selected from hydrogen, --SO.sub.2R.sup.16, and
--CO.sub.2R.sup.16. In an even further aspect, two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are independently selected from hydrogen and --SO.sub.2R.sup.16. In
a still further aspect, two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from hydrogen and --CO.sub.2R.sup.16.
[0371] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from halogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl,
C1-C2 monoalkylamino, C1-C2 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15.
[0372] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a
still further aspect, three of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C2
alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,
C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2
monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect,
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is independently selected from --F, --Cl, --Br, --OH,
--CN, --NO.sub.2, --NH.sub.2, --CH.sub.3, --CFH.sub.2, --CF.sub.2H,
--CF.sub.3, --OCH.sub.3, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2.
[0373] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from halogen, C1-C4 alkyl, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylamino. In a still further aspect, three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from halogen, C1-C2 alkyl, C1-C2
monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,
C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and
C1-C2 dialkylamino. In yet a further aspect, three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
independently selected from --F, --Cl, --Br, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2.
[0374] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from C1-C4 monohaloalkyl and C1-C4
polyhaloalkyl. In a still further aspect, three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from C1-C2 monohaloalkyl and C1-C2
polyhaloalkyl. In yet a further aspect, three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from --CFH.sub.2, --CF.sub.2H, and
--CF.sub.3.
[0375] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from C1-C4 alkyl. In a still further aspect,
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are selected from methyl, ethyl, iso-propyl, and
n-propyl. In yet a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from methyl and ethyl. In an even further
aspect, three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are methyl. In a still further aspect,
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are ethyl.
[0376] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from halogen. In a still further aspect,
three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are independently selected from --F, --Cl, and --Br.
In yet a further aspect, three of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from --F and --Cl. In an even further aspect, three of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are --F. In a still further aspect, three of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
--Cl. In yet a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
--Br.
[0377] In a further aspect, three of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and two of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
independently selected from hydrogen, --OH, --SH, --CN, --NO.sub.2,
--NH.sub.2, --SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still
further aspect, three of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and two of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are independently
selected from hydrogen, --OH, --SH, --NH.sub.2, --SO.sub.2R.sup.16,
and --CO.sub.2R.sup.16. In yet a further aspect, three of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are independently selected from hydrogen,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In an even further
aspect, three of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are independently selected from hydrogen
and --SO.sub.2R.sup.16. In a still further aspect, three of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and two of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are independently selected from hydrogen and
--CO.sub.2R.sup.16.
[0378] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
C1-C4 monoalkylamino, C1-C4 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15. In a still further aspect, four of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from halogen, --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2
polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl,
C1-C2 monoalkylamino, C1-C2 dialkylamino, --SO.sub.2R.sup.15, and
--CO.sub.2R.sup.15.
[0379] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4
alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,
four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e
are hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e is selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet
a further aspect, four of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and one of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is selected from
--F, --Cl, --Br, --OH, --CN, --NO.sub.2, --NH.sub.2, --CH.sub.3,
--CFH.sub.2, --CF.sub.2H, --CF.sub.3, --OCH.sub.3, --NH(CH.sub.3),
and --N(CH.sub.3).sub.2.
[0380] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
In a still further aspect, four of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and one of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is selected from
halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,
C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2
hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet
a further aspect, four of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and one of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is selected from
--F, --Cl, --Br, --CH.sub.3, --CFH.sub.2, --CF.sub.2H, --CF.sub.3,
--OCH.sub.3, --NH(CH.sub.3), and --N(CH.sub.3).sub.2.
[0381] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl. In a
still further aspect, four of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and one of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is selected from
C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl. In yet a further
aspect, four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is selected from --CFH.sub.2, --CF.sub.2H,
and --CF.sub.3.
[0382] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from C1-C4 alkyl. In a still further aspect, four of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is selected from methyl, ethyl, iso-propyl, and n-propyl.
In yet a further aspect, four of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e are hydrogen and one of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is selected from
methyl and ethyl. In an even further aspect, four of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
methyl. In a still further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
ethyl.
[0383] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from halogen. In a still further aspect, four of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is selected from --F, --Cl, and --Br. In yet a further
aspect, four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is selected from --F and --Cl. In an even
further aspect, four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d,
and R.sup.14e are hydrogen and one of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e is --F. In a still further
aspect, four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is --Cl. In yet a further aspect, four of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are
hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e is --Br.
[0384] In a further aspect, four of R.sup.14a, R.sup.14b,
R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one of
R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
selected from --OH, --SH, --CN, --NO.sub.2, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In a still further
aspect, four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is selected from --OH, --SH, --NH.sub.2,
--SO.sub.2R.sup.16, and --CO.sub.2R.sup.16. In yet a further
aspect, four of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are hydrogen and one of R.sup.14a, R.sup.14b, R.sup.14c,
R.sup.14d, and R.sup.14e is selected from --SO.sub.2R.sup.16 and
--CO.sub.2R.sup.16. In an even further aspect, four of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
--SO.sub.2R.sup.16. In a still further aspect, four of R.sup.14a,
R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e are hydrogen and one
of R.sup.14a, R.sup.14b, R.sup.14c, R.sup.14d, and R.sup.14e is
--CO.sub.2R.sup.16.
[0385] d. R.sup.15 Groups
[0386] In one aspect, each occurrence of R.sup.15, when present, is
independently selected from hydrogen, --CH.sub.3, --CFH.sub.2,
--CF.sub.3, --NH.sub.2, --NH(CH.sub.3), and --N(CH.sub.3).sub.2. In
a further aspect, each occurrence of R.sup.15, when present, is
hydrogen.
[0387] In a further aspect, each occurrence of R.sup.15, when
present, is independently selected from hydrogen and --CH.sub.3. In
a still further aspect, each occurrence of R.sup.15, when present,
is --CH.sub.3.
[0388] In a further aspect, each occurrence of R.sup.15, when
present, is independently selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3. In a still further aspect, each
occurrence of R.sup.15, when present, is independently selected
from hydrogen, --CFH.sub.2, and --CF.sub.2H. In yet a further
aspect, each occurrence of R.sup.15, when present, is independently
selected from hydrogen and --CFH.sub.2. In an even further aspect,
each occurrence of R.sup.15, when present, is --CF.sub.3. In a
still further aspect, each occurrence of R.sup.15, when present, is
--CF.sub.2H. In yet a further aspect, each occurrence of R.sup.15,
when present, is --CFH.sub.2.
[0389] In a further aspect, each occurrence of R.sup.15, when
present, is independently selected from hydrogen, --NH.sub.2,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2. In a still further aspect,
each occurrence of R.sup.15, when present, is independently
selected from hydrogen, --NH.sub.2, and --NH(CH.sub.3). In yet a
further aspect, each occurrence of R.sup.15, when present, is
independently selected from hydrogen and --NH.sub.2. In an even
further aspect, each occurrence of R.sup.15, when present, is
--N(CH.sub.3).sub.2. In a still further aspect, each occurrence of
R.sup.15, when present, is --NH(CH.sub.3). In yet a further aspect,
each occurrence of R.sup.15, when present, is --NH.sub.2.
[0390] e. R.sup.16 Groups
[0391] In one aspect, each occurrence of R.sup.16, when present, is
independently selected from hydrogen, --CH.sub.3, --CFH.sub.2,
--CF.sub.2H, --CF.sub.3, --NH.sub.2, --NH(CH.sub.3), and
--N(CH.sub.3).sub.2. In a further aspect, each occurrence of
R.sup.16, when present, is hydrogen.
[0392] In a further aspect, each occurrence of R.sup.16, when
present, is independently selected from hydrogen and --CH.sub.3. In
a still further aspect, each occurrence of R.sup.16, when present,
is --CH.sub.3.
[0393] In a further aspect, each occurrence of R.sup.16, when
present, is independently selected from hydrogen, --CFH.sub.2,
--CF.sub.2H, and --CF.sub.3. In a still further aspect, each
occurrence of R.sup.16, when present, is independently selected
from hydrogen, --CFH.sub.2, and --CF.sub.2H. In yet a further
aspect, each occurrence of R.sup.16, when present, is independently
selected from hydrogen and --CFH.sub.2. In an even further aspect,
each occurrence of R.sup.16, when present, is --CF.sub.3. In a
still further aspect, each occurrence of R.sup.16, when present, is
--CF.sub.2H. In yet a further aspect, each occurrence of R.sup.16,
when present, is --CFH.sub.2.
[0394] In a further aspect, each occurrence of R.sup.16, when
present, is independently selected from hydrogen, --NH.sub.2,
--NH(CH.sub.3), and --N(CH.sub.3).sub.2. In a still further aspect,
each occurrence of R.sup.16, when present, is independently
selected from hydrogen, --NH.sub.2, and --NH(CH.sub.3). In yet a
further aspect, each occurrence of R.sup.16, when present, is
independently selected from hydrogen and --NH.sub.2. In an even
further aspect, each occurrence of R.sup.16, when present, is
--N(CH.sub.3).sub.2. In a still further aspect, each occurrence of
R.sup.16, when present, is --NH(CH.sub.3). In yet a further aspect,
each occurrence of R.sup.16, when present, is --NH.sub.2.
[0395] 4. Other CDK2 Inhibitors
[0396] In one aspect, disclosed are CDK2 inhibitors having a
structure represented by a formula:
##STR00038##
wherein R.sup.20 is selected from --SO.sub.2R.sup.20a, --OH,
NH.sub.2, substituted amide, C1-C4 alkyl carbonyl, C1-C4
monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein each of R.sup.21, R.sup.23, and
R.sup.25 is independently selected from hydrogen, halogen, --OH,
NH.sub.2, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8
alkyl and is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein each of
R.sup.22 and R.sup.24 is independently selected from hydrogen and
C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl, or a pharmaceutically
acceptable salt thereof.
[0397] For example, a CDK2 inhibitor can have a structure
represented by a formula:
##STR00039##
wherein R.sup.20a is selected from --OH, NH.sub.2, C1-C4
monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl; wherein each of R.sup.21, R.sup.23, and
R.sup.25 is independently selected from hydrogen, halogen, --OH,
NH.sub.2, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8
alkyl and is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein each of
R.sup.22 and R.sup.24 is independently selected from hydrogen and
C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl, or a pharmaceutically
acceptable salt thereof.
[0398] In one aspect, a CDK2 inhibitor is provided as a compound
having the formula:
##STR00040##
[0399] This compound is a potent inhibitor of CDK1/2/9 with IC50 of
16 nM/6 nM/20 nM. This compound has high oral bioavailability,
F=91%.
[0400] a. R.sup.20 Groups
[0401] In one aspect, each occurrence of R.sup.20, when present, is
selected from --OH, NH.sub.2, C1-C4 monoalkylamino (e.g.,
methylamino, ethylamino, propylamino, or butylamino), C1-C4
dialkylaminomethyl (e.g., dimethylamino, methylethylamino,
methylpropylamino, methylbutylamino, diethylamino,
ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino,
or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl
can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
[0402] In a further aspect, each occurrence of R.sup.20a can be
selected from --OH, NH.sub.2, C1-C4 monoalkylamino, C1-C4
dialkylaminomethyl, and C1-C8 alkyl.
[0403] In a further aspect, each occurrence of R.sup.20 and
R.sup.20a can be substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO2, --NH2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl.
[0404] b. R.sup.21 Groups
[0405] In one aspect, each occurrence of R.sup.21, when present, is
selected from hydrogen, halogen (e.g., fluoride, chloride, bromide,
or iodide), --OH, NH.sub.2, C1-C4 monoalkylamino (e.g.,
methylamino, ethylamino, propylamino, or butylamino), C1-C4
dialkylaminomethyl (e.g., dimethylamino, methylethylamino,
methylpropylamino, methylbutylamino, diethylamino,
ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino,
or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl
can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
[0406] In a further aspect, each occurrence of R.sup.21 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0407] c. R.sup.22 Groups
[0408] In one aspect, each occurrence of R.sup.22, when present, is
selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,
C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or
C1-C2 alkyl.
[0409] In a further aspect, each occurrence of R.sup.22 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0410] d. R.sup.23 Groups
[0411] In one aspect, each occurrence of R.sup.23, when present, is
selected from hydrogen, halogen (e.g., fluoride, chloride, bromide,
or iodide), --OH, NH.sub.2, C1-C4 monoalkylamino (e.g.,
methylamino, ethylamino, propylamino, or butylamino), C1-C4
dialkylaminomethyl (e.g., dimethylamino, methylethylamino,
methylpropylamino, methylbutylamino, diethylamino,
ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino,
or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl
can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
[0412] In a further aspect, each occurrence of R.sup.23 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0413] e. R.sup.24 Groups
[0414] In one aspect, each occurrence of R.sup.24, when present, is
selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,
C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or
C1-C2 alkyl.
[0415] In a further aspect, each occurrence of R.sup.24 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0416] f. R.sup.25 Groups
[0417] In one aspect, each occurrence of R.sup.25, when present, is
selected from hydrogen, halogen (e.g., fluoride, chloride, bromide,
or iodide), --OH, NH.sub.2, C1-C4 monoalkylamino (e.g.,
methylamino, ethylamino, propylamino, or butylamino), C1-C4
dialkylaminomethyl (e.g., dimethylamino, methylethylamino,
methylpropylamino, methylbutylamino, diethylamino,
ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino,
or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl
can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
[0418] In a further aspect, each occurrence of R.sup.25 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0419] In one aspect, disclosed are CDK2 inhibitors having a
structure represented by a formula:
##STR00041##
wherein each occurrence of R.sup.30 is independently selected from
substituted phenyl, C1-C8 alkyl, carbocyclic, substituted
cyclohexyl, piperidine wherein each of R.sup.31, R.sup.32, and
R.sup.33 is independently selected from hydrogen and C1-C8 alkyl
and is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein R.sup.34
is selected from hydroxy alkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted benzyl or a pharmaceutically
acceptable salt thereof.
[0420] In a further aspect, disclosed are CDK2 inhibitors having a
structure represented by a formula:
##STR00042##
wherein each occurrence of X is independently a halogen (e.g.,
fluoride, chloride, bromide, or iodide), wherein each of R.sup.30,
R.sup.31, R.sup.32, and R.sup.33 is independently selected from
hydrogen and C1-C8 alkyl and is independently substituted with 0,
1, or 2 groups independently selected from halogen, --OH, --CN,
--NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;
and wherein R.sup.34 is selected from --OH, NH.sub.2, C1-C4
monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO.sub.2, --NH.sub.2, C1-C4 monohaloalkyl,
C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4
aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl, or a pharmaceutically acceptable salt
thereof.
[0421] In one aspect, a CDK2 inhibitor is provided as a compound
having the formula:
##STR00043##
[0422] This compound is a multi-CDK inhibitor for CDK1, 2, 4, 6 and
9 with IC50 of 10-210 nM. In certain aspects, this compound can
have a low oral bioavailability (<1%). This compound is a potent
cell cycle inhibitor and can be useful for the treatment of chronic
lymphocytic leukemia and for the treatment of mantle cell
lymphoma.
[0423] g. R.sup.30 Groups
[0424] In one aspect, each occurrence of R.sup.30, when present, is
selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,
C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or
C1-C2 alkyl.
[0425] In a further aspect, each occurrence of R.sup.30 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0426] h. R.sup.31 Groups
[0427] In one aspect, each occurrence of R.sup.31, when present, is
selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,
C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or
C1-C2 alkyl.
[0428] In a further aspect, each occurrence of R.sup.31 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0429] i. R.sup.32 Groups
[0430] In one aspect, each occurrence of R.sup.32, when present, is
selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,
C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or
C1-C2 alkyl.
[0431] In a further aspect, each occurrence of R.sup.32 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0432] j. R.sup.33 Groups
[0433] In one aspect, each occurrence of R.sup.33, when present, is
selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,
C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or
C1-C2 alkyl.
[0434] In a further aspect, each occurrence of R.sup.33 can be
substituted with 0, 1, or 2 groups independently selected from
halogen, --OH, --CN, --NO2, --NH2, C1-C4 monohaloalkyl, C1-C4
polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4
dialkylaminomethyl.
[0435] k. R.sup.34 Groups
[0436] In one aspect, each occurrence of R.sup.30 is independently
selected from substituted phenyl, C1-C8 alkyl, carbocyclic,
substituted cyclohexyl, piperidine wherein each of R.sup.31,
R.sup.32, and R.sup.33 is independently selected from hydrogen and
C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups
independently selected from halogen, --OH, --CN, --NO.sub.2,
--NH.sub.2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,
C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein R.sup.34
is selected from hydroxy alkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted benzyl or a pharmaceutically
acceptable salt thereof.
[0437] In a further aspect, each occurrence of R.sup.34a, when
present, is selected from --OH, NH.sub.2, C1-C4 monoalkylamino
(e.g., methylamino, ethylamino, propylamino, or butylamino), C1-C4
dialkylaminomethyl (e.g., dimethylamino, methylethylamino,
methylpropylamino, methylbutylamino, diethylamino,
ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino,
or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl
can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
[0438] In a further aspect, each occurrence of R.sup.34 and
R.sup.34a can be substituted with 0, 1, or 2 groups independently
selected from halogen, --OH, --CN, --NO2, --NH2, C1-C4
monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and
C1-C4 dialkylaminomethyl.
TABLE-US-00001 HEI- Explant OC1 Cisplatin Explant Therapeutic
Compound IC50 IC50 Cisplatin Index (Scaffold (nM) (nM) LD50 (nM)
LD50/IC50 SJZuo-4 Kenpaullone (Paullone) ##STR00044## 2100 150
>30,000 >200 SJZuo-19 AZD5438 (Pyrimidine) ##STR00045## ~25
<1,000 <40 SJZuo-20 AT7519 (Pyrazole) ##STR00046## 380 ~25
<1,000 <40 SJZuo-12 CDK2 inhibitor II (Indole) ##STR00047##
500 1,000 >12,000 12 SJZuo-9 Olomoucine II (Purine) ##STR00048##
800 3,000 >33,000 11
[0439] 5. Example Compounds
[0440] In one aspect, a compound can be present as one or more of
the following structures:
##STR00049## ##STR00050## ##STR00051##
or a pharmaceutically acceptable salt thereof.
[0441] In one aspect, a compound can be present as one or more of
the following structures:
##STR00052##
[0442] In one aspect, a compound can be present as one or more of
the following structures:
##STR00053##
or a pharmaceutically acceptable salt thereof.
C. METHODS OF MAKING A COMPOUND
[0443] The compounds of this invention can be prepared by employing
reactions as shown in the following schemes, in addition to other
standard manipulations that are known in the literature,
exemplified in the experimental sections or clear to one skilled in
the art. For clarity, examples having a single substituent are
shown where multiple substituents are allowed under the definitions
disclosed herein.
[0444] Reactions used to generate the compounds of this invention
are prepared by employing reactions as shown in the following
Reaction Schemes, as described and exemplified below. In certain
specific examples, the disclosed compounds can be prepared by Route
I and Route II, as described and exemplified below. The following
examples are provided so that the invention might be more fully
understood, are illustrative only, and should not be construed as
limiting.
[0445] 1. Route I
[0446] In one aspect, paullone derivatives can be prepared as shown
below.
##STR00054##
[0447] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00055##
[0448] In one aspect, compounds of type 1.3, and similar compounds,
can be prepared according to reaction Scheme 1B above. Thus,
compounds of type 1.6 can be prepared by a cyclization reaction
(e.g., Fischer indole reaction) of an appropriate hydrazine, e.g.,
1.4 as shown above, with an appropriate benzazepine, e.g., 1.5 as
shown above. Appropriate hydrazines and appropriate benzazepines
are commercially available or prepared by methods known to one
skilled in the art. The cyclization reaction is carried out in the
presence of an appropriate base, e.g., sodium acetate, in an
appropriate protic solvent, e.g., acetic acid, at an appropriate
temperature, e.g., 70.degree. C., for an appropriate period of
time, e.g., 1 hour. As can be appreciated by one skilled in the
art, the above reaction provides an example of a generalized
approach wherein compounds similar in structure to the specific
reactants above (compounds similar to compounds of type 1.1 and
1.2), can be substituted in the reaction to provide paullone
derivatives similar to Formula 1.3.
[0449] It is contemplated that each disclosed method can further
comprise additional steps, manipulations, and/or components. It is
also contemplated that any one or more step, manipulation, and/or
component can be optionally omitted from the invention. It is
understood that a disclosed method can be used to provide the
disclosed compounds. It is also understood that the products of the
disclosed methods can be employed in the disclosed methods of
using.
[0450] 2. Route II
[0451] In one aspect, purine derivatives can be prepared as shown
below.
##STR00056##
[0452] Compounds are represented in generic form, wherein X is a
halogen, and other substituents are as noted in compound
descriptions elsewhere herein. A more specific example is set forth
below.
##STR00057##
[0453] In one aspect, compounds of type 2.7, and similar compounds,
can be prepared according to reaction Scheme 2B above. Thus,
compounds of type 2.9 can be prepared by a substitution reaction of
an appropriate aryl halide, e.g., 2.7 as shown above. Appropriate
aryl halides are commercially available or prepared by methods
known to one skilled in the art. The substitution reaction is
carried out in the presence of an appropriate amine, e.g., 2.8 as
shown above, in an appropriate solvent, e.g., ethanol. Compounds of
type 2.11 can be prepared an alkylation reaction of an appropriate
amine, e.g., 2.9 as shown above. The alkylation reaction is carried
out in the presence of an appropriate alkyl halide, e.g., 2.10, and
an appropriate base, e.g., potassium carbonate, in an appropriate
solvent, e.g., dimethylsulfoxide. Compounds of type 2.13 can be
prepared by a substitution reaction of an appropriate aryl halide,
e.g., 2.11 as shown above. The substitution reaction is carried out
in the presence of an appropriate amine, e.g., 2.12 as shown above,
in an appropriate solvent, e.g., ethanol. As can be appreciated by
one skilled in the art, the above reaction provides an example of a
generalized approach wherein compounds similar in structure to the
specific reactants above (compounds similar to compounds of type
2.1, 2.2, 2.3, 2.4, 2.5, and 2.6), can be substituted in the
reaction to provide purine derivatives similar to Formula 2.7.
[0454] It is contemplated that each disclosed method can further
comprise additional steps, manipulations, and/or components. It is
also contemplated that any one or more step, manipulation, and/or
component can be optionally omitted from the invention. It is
understood that a disclosed method can be used to provide the
disclosed compounds. It is also understood that the products of the
disclosed methods can be employed in the disclosed methods of
using.
[0455] 3. Route III
[0456] In one aspect, purine derivatives can be prepared as shown
below.
##STR00058##
[0457] Compounds are represented in generic form, wherein each of
X.sup.1 and X.sup.2 are independently halogen, and where
substituents are as noted in compound descriptions elsewhere
herein. A more specific example is set forth below.
##STR00059##
[0458] In one aspect, compounds of type 3.5, and similar compounds,
can be prepared according to reaction Scheme 3B above. Thus,
compounds of type 3.8 can be prepared by a displacement reaction of
an appropriate guanine derivative, e.g., 3.6 as shown above.
Appropriate guanine derivatives are commercially available or
prepared by methods known to one skilled in the art. The
displacement reaction is carried out in the presence of an
appropriate acetate, e.g., 3.7 as shown above, and an appropriate
base, e.g., 1,8-diazobicyclo[5.4.0] undec-7-ene (DBU), in an
appropriate solvent, e.g., acetonitrile, at an appropriate
temperature, e.g., 0.degree. C., for an appropriate period of time,
e.g., thirty minutes. Compounds of type 3.10 can be prepared by an
alkylation reaction of an appropriate amine, e.g., 3.8 as shown
above. The alkylation reaction is carried out in the presence of an
appropriate alkyl halide, e.g., 3.9 as shown above, and an
appropriate base, e.g., potassium carbonate, in an appropriate
solvent, e.g., dimethylsulfoxide. As can be appreciated by one
skilled in the art, the above reaction provides an example of a
generalized approach wherein compounds similar in structure to the
specific reactants above (compounds similar to compounds of type
3.1, 3.2, 3.3, and 3.4), can be substituted in the reaction to
provide para-substituted arenes similar to Formula 3.5.
[0459] It is contemplated that each disclosed method can further
comprise additional steps, manipulations, and/or components. It is
also contemplated that any one or more step, manipulation, and/or
component can be optionally omitted from the invention. It is
understood that a disclosed method can be used to provide the
disclosed compounds. It is also understood that the products of the
disclosed methods can be employed in the disclosed methods of
using.
[0460] 4. Route IV
[0461] In one aspect, purine derivatives can be prepared as shown
below.
##STR00060##
[0462] Compounds are represented in generic form, where
substituents are as noted in compound descriptions elsewhere
herein. A more specific example is set forth below.
##STR00061##
[0463] In one aspect, compounds of type 4.9, and similar compounds,
can be prepared according to reaction Scheme 4B above. Thus,
compounds of type 4.1 can be prepared by protection of an
appropriate purine derivative, e.g., 3.6 as shown above.
Appropriate purine derivatives are commercially available or
prepared by methods known to one skilled in the art. The protection
is carried out in the presence of an appropriate protecting group,
e.g., di-tert-butyldicarbonate as shown above, and an appropriate
catalytic base, e.g., DMAP as shown above, in an appropriate
solvent, e.g., dimethylsulfoxide, at an appropriate temperature,
e.g., 0.degree. C. The reaction is then warmed to an appropriate
temperature, e.g., room temperature, over a period of time
sufficient to allow the reaction to proceed, e.g., 2 hours.
Compounds of type 4.2 can be prepared by protection of an
appropriate amine, e.g., 4.1 as shown above. The protection is
carried out in the presence of an appropriate base, e.g., sodium
hydride, in an appropriate solvent, e.g., tetrahydrofuran.
Compounds of type 4.11 can be prepared by a displacement reaction
of an appropriate amine, e.g., 4.2 as shown above. The displacement
reaction is carried out in the presence of an appropriate alcohol,
e.g., 4.10 as shown above, and an appropriate nucleophile, e.g.,
triphenylphosphine, followed by the addition of an appropriate
azodicarboxylate, e.g., diisopropyl azodicarboxylate. Compounds of
type 4.13 can be prepared by a displacement reaction of an
appropriate amine, e.g., 4.11 as shown above. The displacement
reaction is carried out in the presence of an appropriate alcohol,
e.g., 4.12 as shown above, and an appropriate nucleophile, e.g.,
triphenylphosphine, followed by the addition of an appropriate
azodicarboxylate, e.g., diisopropyl azodicarboxylate. Compounds of
type 4.15 can be prepared by a displacement reaction of an
appropriate halide, e.g., 4.13 as shown above. The displacement
reaction is carried out in the presence of an appropriate alcohol,
e.g., 4.14 as shown above, and an appropriate nucleophile, e.g.,
triphenylphosphine, followed by the addition of an appropriate
azodicarboxylate, e.g., diisopropyl azodicarboxylate. Compounds of
type 4.16 can be prepared by deprotection of an appropriate amine,
e.g., 4.15 as shown above. The deprotection is carried out in the
presence of an appropriate acid, e.g., trifluoroacetic acid. As can
be appreciated by one skilled in the art, the above reaction
provides an example of a generalized approach wherein compounds
similar in structure to the specific reactants above (compounds
similar to compounds of type 3.6, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6,
4.7, and 4.8), can be substituted in the reaction to provide purine
derivatives similar to Formula 4.9.
[0464] It is contemplated that each disclosed method can further
comprise additional steps, manipulations, and/or components. It is
also contemplated that any one or more step, manipulation, and/or
component can be optionally omitted from the invention. It is
understood that a disclosed method can be used to provide the
disclosed compounds. It is also understood that the products of the
disclosed methods can be employed in the disclosed methods of
using.
[0465] 5. Route V
[0466] In one aspect, 3-(2-phenylhydrazono)indolin-2-one
derivatives can be prepared as shown below.
##STR00062##
[0467] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00063##
[0468] In one aspect, compounds of type 5.3, and similar compounds,
can be prepared according to reaction Scheme 5B above. Thus,
compounds of type 5.6 can be prepared by a hydrolysis reaction of
an appropriate hydrazone, e.g., 5.4 as shown above. Appropriate
hydrazones are commercially available or prepared by methods known
to one skilled in the art. The hydrolysis reaction is carried out
in the presence of an appropriate hydrazine, e.g., 5.5 as shown
above, which are commercially available or prepared by methods
known to one skilled in the art, in an appropriate solvent, e.g.,
ethanol, at an appropriate temperature, e.g., refluxing conditions,
for an appropriate period of time, e.g., 16 hours. As can be
appreciated by one skilled in the art, the above reaction provides
an example of a generalized approach wherein compounds similar in
structure to the specific reactants above (compounds similar to
compounds of type 5.1 and 5.2), can be substituted in the reaction
to provide 3-(2-phenylhydrazono)indolin-2-one derivatives similar
to Formula 5.3.
[0469] It is contemplated that each disclosed method can further
comprise additional steps, manipulations, and/or components. It is
also contemplated that any one or more step, manipulation, and/or
component can be optionally omitted from the invention. It is
understood that a disclosed method can be used to provide the
disclosed compounds. It is also understood that the products of the
disclosed methods can be employed in the disclosed methods of
using.
[0470] 6. Route VI
[0471] In one aspect,
4-(1H-imidazol-5-yl)-N-(phenyl)pyrimidin-2-amine derivatives can be
prepared as shown below.
##STR00064##
[0472] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00065##
[0473] In one aspect, compounds of type 6.3, and similar compounds,
can be prepared according to reaction Scheme 6B above. Thus,
compounds of type 6.6 can be prepared by a coupling reaction
between appropriate aryl halide and amino pyrimidines, e.g., 6.4
and 6.5 respectively as shown above. Appropriate aryl halides are
commercially available or prepared by methods known to one skilled
in the art. The coupling reaction is carried out in the presence of
an appropriate imidazoly pyrimidines, e.g., 6.5 as shown above,
which are commercially available or prepared by methods known to
one skilled in the art, in an appropriate solvent, e.g., dioxane,
at an appropriate temperature, e.g., refluxing conditions, for an
appropriate period of time, e.g., 16 hours. As can be appreciated
by one skilled in the art, the above reaction provides an example
of a generalized approach wherein compounds similar in structure to
the specific reactants above (compounds similar to compounds of
type 6.1 and 6.2), can be substituted in the reaction to provide
4-(1H-imidazol-5-yl)-N-(phenyl)pyrimidin-2-amine derivatives
similar to Formula 6.3.
##STR00066##
[0474] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00067##
D. PHARMACEUTICAL COMPOSITIONS
[0475] In one aspect, disclosed are pharmaceutical compositions
comprising a CDK2 inhibitor, or a pharmaceutically acceptable salt
thereof; and one or more of: (a) at least one agent known to treat
hearing impairment, or a pharmaceutically acceptable salt thereof;
and (b) at least one agent known to prevent hearing impairment, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
[0476] In one aspect, disclosed are pharmaceutical compositions
comprising a compound selected from:
##STR00068##
or a pharmaceutically acceptable salt thereof; and one or more of:
at least one agent known to treat hearing impairment, or a
pharmaceutically acceptable salt thereof; at least one agent known
to prevent hearing impairment, or a pharmaceutically acceptable
salt thereof; wherein at least one is present in an effective
amount; and a pharmaceutically acceptable carrier.
[0477] In one aspect, disclosed are pharmaceutical compositions
comprising a compound selected from:
##STR00069##
or a pharmaceutically acceptable salt thereof; and one or more of:
(a) at least one agent known to treat hearing impairment, or a
pharmaceutically acceptable salt thereof; and (b) at least one
agent known to prevent hearing impairment, or a pharmaceutically
acceptable salt thereof; and a pharmaceutically acceptable
carrier.
[0478] In various aspects, the compounds and compositions of the
invention can be administered in pharmaceutical compositions, which
are formulated according to the intended method of administration.
The compounds and compositions described herein can be formulated
in a conventional manner using one or more physiologically
acceptable carriers or excipients. For example, a pharmaceutical
composition can be formulated for local or systemic administration,
e.g., administration by drops or injection into the ear,
insufflation (such as into the ear), intravenous, topical, or oral
administration.
[0479] The nature of the pharmaceutical compositions for
administration is dependent on the mode of administration and can
readily be determined by one of ordinary skill in the art. In
various aspects, the pharmaceutical composition is sterile or
sterilizable. The therapeutic compositions featured in the
invention can contain carriers or excipients, many of which are
known to skilled artisans. Excipients that can be used include
buffers (for example, citrate buffer, phosphate buffer, acetate
buffer, and bicarbonate buffer), amino acids, urea, alcohols,
ascorbic acid, phospholipids, polypeptides (for example, serum
albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol,
water, and glycerol. The nucleic acids, polypeptides, small
molecules, and other modulatory compounds featured in the invention
can be administered by any standard route of administration. For
example, administration can be parenteral, intravenous,
subcutaneous, or oral. A modulatory compound can be formulated in
various ways, according to the corresponding route of
administration. For example, liquid solutions can be made for
administration by drops into the ear, for injection, or for
ingestion; gels or powders can be made for ingestion or topical
application. Methods for making such formulations are well known
and can be found in, for example, Remington's Pharmaceutical
Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa.
1990.
[0480] In various aspects, the disclosed pharmaceutical
compositions comprise the disclosed compounds (including
pharmaceutically acceptable salt(s) thereof) as an active
ingredient, a pharmaceutically acceptable carrier, and, optionally,
other therapeutic ingredients or adjuvants. The instant
compositions include those suitable for oral, rectal, topical, and
parenteral (including subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route in any given case
will depend on the particular host, and nature and severity of the
conditions for which the active ingredient is being administered.
The pharmaceutical compositions can be conveniently presented in
unit dosage form and prepared by any of the methods well known in
the art of pharmacy.
[0481] In various aspects, the pharmaceutical compositions of this
invention can include a pharmaceutically acceptable carrier and a
compound or a pharmaceutically acceptable salt of the compounds of
the invention. The compounds of the invention, or pharmaceutically
acceptable salts thereof, can also be included in pharmaceutical
compositions in combination with one or more other therapeutically
active compounds.
[0482] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0483] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media can be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like can be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like can be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets can be coated by standard aqueous or nonaqueous
techniques
[0484] A tablet containing the composition of this invention can be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets can be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets can be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent.
[0485] The pharmaceutical compositions of the present invention
comprise a compound of the invention (or pharmaceutically
acceptable salts thereof) as an active ingredient, a
pharmaceutically acceptable carrier, and optionally one or more
additional therapeutic agents or adjuvants. The instant
compositions include compositions suitable for oral, rectal,
topical, and parenteral (including subcutaneous, intramuscular, and
intravenous) administration, although the most suitable route in
any given case will depend on the particular host, and nature and
severity of the conditions for which the active ingredient is being
administered. The pharmaceutical compositions can be conveniently
presented in unit dosage form and prepared by any of the methods
well known in the art of pharmacy.
[0486] Pharmaceutical compositions of the present invention
suitable for parenteral administration can be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0487] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g., glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0488] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, dusting powder, mouth washes,
gargles, and the like. Further, the compositions can be in a form
suitable for use in transdermal devices. These formulations can be
prepared, utilizing a compound of the invention, or
pharmaceutically acceptable salts thereof, via conventional
processing methods. As an example, a cream or ointment is prepared
by mixing hydrophilic material and water, together with about 5 wt
% to about 10 wt % of the compound, to produce a cream or ointment
having a desired consistency.
[0489] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories can be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
molds.
[0490] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above can include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound of the
invention, and/or pharmaceutically acceptable salts thereof, can
also be prepared in powder or liquid concentrate form.
[0491] In a further aspect, the CDK2 inhibitor is selected from a
paullone derivative, a purine derivative, and a
3-(2-phenylhydrazono)indolin-2-one derivative, or a
pharmaceutically acceptable salt thereof. In a still further
aspect, the CDK2 inhibitor is selected from:
##STR00070##
or a pharmaceutically acceptable salt thereof.
[0492] In a further aspect, an effective amount is a
therapeutically effective amount. In a still further aspect, an
effective amount is a prophylactically effective amount.
[0493] In a further aspect, the pharmaceutical composition is
administered to a mammal. In a still further aspect, the mammal is
a human. In an even further aspect, the human is a patient.
[0494] In a further aspect, the agent known to treat hearing
impairment is selected from an antiepileptic drug blocking T-type
calcium channels; an anticonvulsant; a synthetic glucocorticoid; a
loop diuretic; an anti-oxidant; a proton pump inhibitor; a PDES
inhibitor; and a mGluR7 inhibitor. In a still further aspect, the
agent known to treat a hearing impairment is selected from
trimethadione; mibefrabil; ethosuximide;
3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-pip-
eridin-4-ylmethyl]-benzamide (TTA-P2); NNC 55-0396; ML 218;
nilvadipine; valproic acid; oxcarbazepine; phenobarbital;
phenytoin; zonisamide; nicardipine; chlordiazepoxide; sipatrigine;
halothane; octanol; pimozide; penfluridol; fluspirilene;
thioridazine; clozapine; haloperidol; tetramethrin; tetrandrine;
amiodarone; bepridil; cinnarizine; flunarizine; amiloride;
anandamide; dexamethasone; methylprednisolone;
N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-ox-
o-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide;
2-phenyl-1,2-benzisoselenazol-3-one (ebselen); sodium thiosulfate;
D-methionine; furosemide; N-acetyl-L-cysteine; vitamin A; vitamin
C; vitamin E; vigabatrin; omeprazole; lansoprazole; pantoprazole;
rabeprazole; esomerprazole; pariprazole; leminoprazole;
3,3'-diindolylmethane; vardenafil; sildenafil; tadalafil; udenafil;
dasantafil; avanafil; SLx2101; LAS34179;
N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride;
R(+)-N-propargyl-1-aminoindan; and L-carnitine.
[0495] In a further aspect, the chemotherapeutic agent is selected
from a platinum-based agent. In a still further aspect, the
platinum-based agent is selected from carboplatin, cisplatin,
transplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin,
transplatin, and triplatin. In yet a further aspect, the
platinum-based agent is cisplatin.
[0496] In a further aspect, the ototoxic agent is selected from one
or more of an antibiotic, a loop diuretic, an antimetabilite, and a
salicyclate. In a still further aspect, the antibiotic agent is
selected from one or more of daunorubicin, doxorubicin, epirubicin,
idarubicin, actinomycin-D, bleomycin, and mitomycin-C, or a
pharmaceutically acceptable salt thereof. In yet a further aspect,
the antibiotic agent is an aminoglycoside. In an even further
aspect, the aminoglycoside is selected from one or more of
amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin,
framycetin, gentamicin, hygromycin B, isepamicin, kanamycin,
neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin,
sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin,
or a pharmaceutically acceptable salt thereof.
[0497] In a further aspect, the loop diuretic is selected from one
or more of furosemide; ethacrynic acid; or bumetanide, or a
pharmaceutically acceptable salt thereof.
[0498] In a further aspect, the antimetabilite is selected one or
more of an anti-folate, a fluoropyridimidine, a deoxynucleoside
analogue, and a thiopurine. In a still further aspect, the
antimetabolite is selected from one or more of methotrexate,
pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine,
decitabine, 5-azacytidine, fludarabine, nelarabine, cladribine,
clofarabine, pentostatin, thioguanine, and mercaptopurine, or a
pharmaceutically acceptable salt thereof.
[0499] In a further aspect, the salicylate is selected from one or
more of salicylic acid, methyl salicylate, and trolamine
salicylate, or pharmaceutically acceptable salts thereof.
[0500] In a further aspect, the agent known to prevent hearing
impairment is selected from one or more of fish oil, an omega-3
fatty acid, magnesium, folic acid, vitamin A, vitamin C, vitamin E,
rebamipide, alpha-lipoic acid, N-acetylcysteine (NAC), Elselen,
D-methionine, magnesium, ABC magnesium (vitamins A, B, and C, plus
magnesium).
[0501] Molecular hydrogen (hydrogen-rich water), dexamethasone,
Acuval, CoQ10, L-arginine, Ginko biloba, coenzyme Q10, Z-VAD-fmk,
thymidylate kinase (TMK, AM111), retinoic acid, calcium,
calcineurin inhibitors, or a pharmaceutically acceptable salt
thereof.
[0502] In a further aspect, the pharmaceutical composition is used
to treat hearing impairment.
[0503] In a further aspect, the pharmaceutical composition is used
to prevent a hearing impairment.
[0504] It is understood that the disclosed compositions can be
prepared from the disclosed compounds. It is also understood that
the disclosed compositions can be employed in the disclosed methods
of using.
E. METHODS OF PREPARING A COMPOSITION
[0505] In one aspect, disclosed are methods of preparing a
pharmaceutical composition, the method comprising the step of
combining a CDK2 inhibitor, or a pharmaceutically acceptable salt
thereof and one or more of: (a) at least one agent known to treat
hearing impairment, or a pharmaceutically acceptable salt thereof
(b) at least one agent known to prevent hearing impairment, or a
pharmaceutically acceptable salt thereof wherein at least one is
present in an effective amount; and a pharmaceutically acceptable
carrier. In a further aspect, the effective amount is a
prophylactically effective amount. In a still further aspect, the
effective amount is a therapeutically effective amount.
[0506] In one aspect, disclosed are methods of preparing a
pharmaceutical composition, the method comprising the step of
combining a compound selected from:
##STR00071##
or a pharmaceutically acceptable salt thereof; and one or more of:
at least one agent known to treat hearing impairment, or a
pharmaceutically acceptable salt thereof; at least one agent known
to prevent hearing impairment, or a pharmaceutically acceptable
salt thereof; wherein at least one is present in an effective
amount; and a pharmaceutically acceptable carrier.
[0507] In one aspect, disclosed are methods of preparing a
pharmaceutical composition, the method comprising the step of
combining a compound selected from:
##STR00072##
or a pharmaceutically acceptable salt thereof; and one or more of:
(a) at least one agent known to treat hearing impairment, or a
pharmaceutically acceptable salt thereof; (b) at least one agent
known to prevent hearing impairment, or a pharmaceutically
acceptable salt thereof; wherein at least one is present in an
effective amount; and a pharmaceutically acceptable carrier.
[0508] In a further aspect, the CDK2 inhibitor is selected from a
paullone derivative, a purine derivative, and a
3-(2-phenylhydrazono)indolin-2-one derivative, or a
pharmaceutically acceptable salt thereof. In a still further
aspect, the CDK2 inhibitor is selected from:
##STR00073##
or a pharmaceutically acceptable salt thereof.
[0509] In a further aspect, an effective amount is a
therapeutically effective amount. In a still further aspect, an
effective amount is a prophylactically effective amount.
[0510] In a further aspect, combining is co-formulation of the CDK2
inhibitor, the agent known to treat hearing impairment and/or the
agent known to prevent hearing impairment with the pharmaceutically
acceptable carrier. In a still further aspect, co-formulation is an
oral solid dosage form comprising the CDK2 inhibitor, the agent
known to treat hearing impairment, and/or the agent known to
prevent hearing impairment, and the pharmaceutically acceptable
carrier. In yet a further aspect, the solid dosage form is a
tablet. In an even further aspect, the solid dosage dorm is a
capsule.
[0511] In a further aspect, co-formulation is an inhaled dosage
form comprising the CDK2 inhibitor, the agent known to treat
hearing impairment, and/or the agent known to prevent hearing
impairment, and the pharmaceutically acceptable carrier.
[0512] In a further aspect, co-formulation is an injectable dosage
form comprising the CDK2 inhibitor, the agent known to treat
hearing impairment, and/or the agent known to prevent hearing
impairment, and the pharmaceutically acceptable carrier.
[0513] In a further aspect, the pharmaceutical composition is used
to treat hearing impairment. In a further aspect, the
pharmaceutical composition is used to prevent hearing
impairment.
F. METHODS OF TREATING HEARING IMPAIRMENT
[0514] In one aspect, disclosed are methods of treating hearing
impairment comprising administering to a subject diagnosed with a
need for treatment of hearing impairment a therapeutically
effective amount of a cyclin-dependent kinase 2 (CDK2) inhibitor,
or a pharmaceutically acceptable salt thereof.
[0515] In one aspect, disclosed are methods of treating hearing
impairment, the method comprising administering to a subject
diagnosed with a need for treatment of hearing impairment a
therapeutically effective amount of a compound selected from:
##STR00074##
or a pharmaceutically acceptable salt thereof.
[0516] In one aspect, disclosed are methods of treating hearing
impairment, the method comprising administering to a subject
diagnosed with a need for treatment of hearing impairment a
therapeutically effective amount of a compound selected from:
##STR00075##
or a pharmaceutically acceptable salt thereof.
[0517] In various aspects, the compounds and compositions disclosed
herein are useful for treating, preventing, ameliorating,
controlling or reducing the risk of a variety of hearing
impairments and disorders, including hearing loss, deafness,
tinnitus, ringing, Presbyacusis, auditory neuropathy, acoustic
trauma, acoustic neuroma, Pendred syndrome, Usher syndrome,
Wardenburg syndrome, non-syndromic sensorineural deafness, otitis
media, otosclerosis, Meniere's disease, ototoxicity, labyrinthitis,
as well as hearing impairments caused by infection (i.e., measles,
mumps, or meningitis), medicines such as antibiotics, and some
cancer treatments (i.e., chemotherapy and radiation therapy).
[0518] Noise-induced hearing loss (NIHL) caused by intense or
constant noise exposure is irreversible, resulting in a permanent
disability to military personnel. NIHL is the No. 1 diagnosis among
U.S. soldiers who served in Afghanistan
(http://issuu.com/hearinghealthmagazine/docs/hearinghealthwinter2010issuu-
rev3). Of 1,250 Marine Commandos who served in Afghanistan, 69%
suffered hearing loss due to the intense noise of combat. Hearing
impairment significantly affects performance (Consideration of
Hazardous Noise in the Acquisition of Selected Major Department of
the Navy Weapon Systems and Platforms N2010-0038, 22 June 2010).
Given the importance of auditory acuity in perceiving commands and
sensing enemy activity, it is clear that even mild loss of hearing
increases the risk to soldiers. While hearing aids and cochlear
implants are helpful devices in the civilian and non-combatant
community, they are not an appropriate remedy in a combat setting.
When hearing loss restricts continued military service, forces
suffer loss of personnel, often including the most effective and
experienced officers and non-commissioned officers (NCOs). Finally,
even the best available protection cannot prevent NIHL. As a
result, 2.3 million veterans now receive disability compensation
and treatment that exceeds $2 billion annually (Annual Benefits
Report Fiscal Year 2012, U.S. Dept. Veterans Affairs). Among
veterans who suffer from NIHL, difficulty in communicating with
clinicians and family impedes reintegration into society and
exacerbates depression and anxiety. A preventive solution would
cost-effectively and significantly improve the effectiveness of
military personnel and the quality of life of veterans.
[0519] Traumatic brain injury (TBI) and blast-associated injury
occur most frequently in military situations where blast exposure
cannot be predicted, trauma intensity exceeds the effectiveness of
protective devices, or protective devices are not available. TBI is
often accompanied by a diverse range of disruption or damage to the
auditory sensory system, which is highly vulnerable to blast
injury. Extreme physical blast force can cause damage of various
types to the peripheral auditory system, including rupture of the
tympanic membrane (TM, eardrum), fracture of the middle ear bones,
dislocation of sensory hair cells from the basilar membrane, and
loss of spiral ganglia that innervate hair cells. In human studies
of blast injury, approximately 17-29% of cases involve severe TM
rupture, while 33-78% involve moderate to severe sensorineural
hearing loss (hair cell and ganglion loss). Therefore, TBI and
blast injury are a common, although extreme, cause of hearing
loss.
[0520] In various aspects, the disclosed compounds can be used in
combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of hearing
impairments and disorders for which disclosed compounds or the
other drugs can have utility, where the combination of the drugs
together are safer or more effective than either drug alone. Such
other drug(s) can be administered, by a route and in an amount
commonly used therefor, contemporaneously or sequentially with a
compound of the present invention. When a compound of the present
invention is used contemporaneously with one or more other drugs, a
pharmaceutical composition in unit dosage form containing such
other drugs and a disclosed compound is preferred. However, the
combination therapy can also include therapies in which a disclosed
compound and one or more other drugs are administered on different
overlapping schedules. It is also contemplated that when used in
combination with one or more other active ingredients, the
disclosed compounds and the other active ingredients can be used in
lower doses than when each is used singly. Accordingly, the
pharmaceutical compositions include those that contain one or more
other active ingredients, in addition to a compound of the present
invention.
[0521] Where appropriate, following treatment, the subject (e.g.,
human or other animal) can be tested for an improvement in hearing
or in other symptoms related to hearing disorders. Methods for
measuring hearing are well-known and include pure tone audiometry,
air conduction, and bone conduction tests. These exams measure the
limits of loudness (intensity) and pitch (frequency) that a human
can hear. Hearing tests in humans include behavioral observation
audiometry (for infants to seven months), visual reinforcement
orientation audiometry (for children 7 months to 3 years) and play
audiometry for children older than 3 years. Oto-acoustic emission
testing can be used to test the functioning of the cochlear hair
cells, and electro-cochleography provides information about the
functioning of the cochlea and the first part of the nerve pathway
to the brain. In various aspects, treatment can be continued with
or without modification or can be stopped.
[0522] In a further aspect, the CDK2 inhibitor is selected from a
paullone derivative, a purine derivative, and a
3-(2-phenylhydrazono)indolin-2-one derivative, or a
pharmaceutically acceptable salt thereof. In a still further
aspect, the CDK2 inhibitor is selected from:
##STR00076##
or a pharmaceutically acceptable salt thereof.
[0523] In a further aspect, the subject is a mammal. In a still
further aspect, the mammal is human.
[0524] In a further aspect, the subject has been diagnosed with a
need for treatment of a hearing impairment prior to the
administering step. In a still further aspect, the subject is at
risk for developing a hearing impairment prior to the administering
step.
[0525] In a further aspect, the CDK2 inhibitor is administered
locally. In a still further aspect, the CDK2 inhibitor is
administered systemically. In yet a further aspect, the CDK2
inhibitor is administered locally to the inner ear of the subject.
In an even further aspect, the CDK2 inhibitor is administered via
injection into one or more of the scala tympani, cochlear duct,
scala vestibule of the cochlea, into the auditory nerve trunk in
the internal auditory meatus, or into the middle ear space across
the transtympanic membrane/ear drum.
[0526] In a further aspect, the CDK2 inhibitor is administered in
an amount of from about 0.001 .mu.M to about 1.0.times.10.sup.4
.mu.M. In a still further aspect, the CDK2 inhibitor is
administered in an amount of from about 0.001 .mu.M to about
1.0.times.10.sup.2 .mu.M. In yet a further aspect, the CDK2
inhibitor is administered in an amount of from about 0.001 .mu.M to
about 10 .mu.M. In an even further aspect, the CDK2 inhibitor is
administered in an amount of from about 0.01 .mu.M to about
1.0.times.10.sup.4 .mu.M. In a still further aspect, the CDK2
inhibitor is administered in an amount of from about 0.1 .mu.M to
about 1.0.times.10.sup.4 .mu.M. In yet a further aspect, the CDK2
inhibitor is administered in an amount of from about 1.0 .mu.M to
about 1.0.times.10.sup.4 .mu.M.
[0527] In a further aspect, the CDK2 inhibitor is administered
locally. In a still further aspect, the CDK2 inhibitor is
administered systemically.
[0528] In a further aspect, the CDK2 inhibitor is administered at
least once every three weeks. In a still further aspect, the CDK2
inhibitor is administered at least once every week. In yet a
further aspect, the CDK2 inhibitor is administered at least once
every 24 h. In an even further aspect, the CDK2 inhibitor is
administered at least once every four hours. In a still further
aspect, the CDK2 inhibitor is administered at least once every one
hour.
[0529] In a further aspect, the CDK2 inhibitor is administered in
an amount of from about 0.001 .mu.M to about 1.0.times.10.sup.4
.mu.M at least once every three weeks.
[0530] In a further aspect, the hearing impairment is
noise-induced. In a still further aspect, the noise-induced hearing
loss is temporary. In yet a further aspect, the noise-induced
hearing loss is permanent.
[0531] In a further aspect, the hearing impairment is drug-induced.
In a still further aspect, the drug is a chemotherapeutic agent. In
yet a further aspect, the chemotherapeutic agent is platinum-based.
In an even further aspect, the platinum-based chemotherapeutic
agent is selected from carboplatin, cisplatin, transplatin,
nedaplatin, oxaliplatin, picoplatin, satraplatin, transplatin, and
triplatin, or a pharmaceutically acceptable salt thereof. In a
still further aspect, the platinum-based chemotherapeutic agent is
cisplatin, or a pharmaceutically acceptable salt thereof. In yet a
further aspect, the drug is an antibiotic. In an even further
aspect, the antibiotic is selected from daunorubicin, doxorubicin,
epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C,
amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin,
framycetin, gentamicin, hygromycin B, isepamicin, kanamycin,
neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin,
sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin,
or a pharmaceutically acceptable salt thereof.
[0532] In a further aspect, the hearing impairment is
age-related.
[0533] In a further aspect, the hearing impairment is related to a
balance or orientation-related disorder. Examples of balance
disorders include, but are not limited to, induced or spontaneous
vertigo, dysequilibrium, increased susceptibility to motion
sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia,
nystagmus, syncope, lightheadedness, dizziness, increased falling,
difficulty walking at night, Meniere's disease, and difficulty in
visual tracking and processing.
[0534] In a further aspect, the subject has been diagnosed with a
need for prevention of hearing impairment prior to the
administering step.
[0535] In a further aspect, the method further comprises
identifying a subject at risk for developing a hearing impairment
prior to the administering step.
G. METHODS OF PREVENTING HEARING IMPAIRMENT
[0536] In one aspect, disclosed are methods of preventing hearing
impairment, the method comprising administering to a subject a CDK2
inhibitor in an amount of from about 0.001 .mu.M to about
1.0.times.10.sup.4 .mu.M at least once every three weeks, or a
pharmaceutically acceptable salt thereof.
[0537] In one aspect, disclosed are methods of preventing hearing
impairment, the method comprising administering to a subject a
compound selected from:
##STR00077##
or a pharmaceutically acceptable salt thereof, in an amount of from
about 0.001 .mu.M to about 1.0.times.10.sup.4 .mu.M at least once
every three weeks.
[0538] In one aspect, disclosed are method of preventing hearing
impairment, the method comprising administering to a subject a
compound selected from:
##STR00078##
or a pharmaceutically acceptable salt thereof, in an amount of from
about 0.001 .mu.M to about 1.0.times.10.sup.4 at least once every
three weeks.
[0539] Examples of hearing impairment include, but are not limited
to, hearing loss, deafness, tinnitus, ringing, Presbyacusis,
auditory neuropathy, acoustic trauma, acoustic neuroma, Pendred
syndrome, Usher syndrome, Wardenburg syndrome, non-syndromic
sensorineural deafness, otitis media, otosclerosis, Meniere's
disease, ototoxicity, labyrinthitis, as well as hearing impairments
caused by infection (i.e., measles, mumps, or meningitis),
medicines such as antibiotics, and some cancer treatments (i.e.,
chemotherapy and radiation therapy).
[0540] More than one billion teens and young adults worldwide are
at risk of hearing loss from exposure to loud music, as recently
reported by the World Health Organization
(http://www.cnn.com/2015/03/06/health/hearing-loss-loud-music/index.html)-
. Many other noise exposures, including occupational settings and
consumer-operated devices, also cause NIHL, which is among the most
common physical complaints and which detracts significantly from
the ability to converse, communicate, and participate in everyday
life (thus reducing general quality of life of the individual and
the family). Acute or chronic acoustic overexposure has put more
than 40 million US workers at risk of permanent hearing loss (Kopke
et al., 2007).
[0541] Biological protection of hearing is more promising than
currently available mechanical protective devices. Hearing aids are
frequently problematic because of their high cost and their many
technical issues. Ideally, service men and women could take
protective drugs before entering high-risk or high-noise settings
and would then be protected from noise injury with no effect on
performance. To date, there are no FDA-approved drugs for
protection against noise- and TBI-associated hearing loss.
[0542] In a further aspect, the CDK2 inhibitor is selected from a
paullone derivative, a purine derivative, and a
3-(2-phenylhydrazono)indolin-2-one derivative, or a
pharmaceutically acceptable salt thereof. In a still further
aspect, the CDK2 inhibitor is selected from:
##STR00079##
or a pharmaceutically acceptable salt thereof.
[0543] In a further aspect, the subject is a mammal. In a still
further aspect, the mammal is human.
[0544] In a further aspect, the CDK2 inhibitor is administered
locally. In a still further aspect, the CDK2 inhibitor is
administered systemically. In yet a further aspect, the CDK2
inhibitor is administered locally to the inner ear of the subject.
In an even further aspect, the CDK2 inhibitor is administered via
injection into one or more of the scala tympani, cochlear duct,
scala vestibule of the cochlea, into the auditory nerve trunk in
the internal auditory meatus, or into the middle ear space across
the transtympanic membrane/ear drum.
[0545] In a further aspect, the hearing impairment is
noise-induced. In a still further aspect, the noise-induced hearing
loss is temporary. In yet a further aspect, the noise-induced
hearing loss is permanent.
[0546] In a further aspect, the hearing impairment is drug-induced.
In a still further aspect, the drug is a chemotherapeutic agent. In
yet a further aspect, the chemotherapeutic agent is platinum-based.
In an even further aspect, the platinum-based chemotherapeutic
agent is selected from carboplatin, cisplatin, transplatin,
nedaplatin, oxaliplatin, picoplatin, satraplatin, transplatin, and
triplatin, or a pharmaceutically acceptable salt thereof. In a
still further aspect, the platinum-based chemotherapeutic agent is
cisplatin, or a pharmaceutically acceptable salt thereof. In yet a
further aspect, the drug is an antibiotic. In an even further
aspect, the antibiotic is selected from daunorubicin, doxorubicin,
epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C,
amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin,
framycetin, gentamicin, hygromycin B, isepamicin, kanamycin,
neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin,
sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin,
or a pharmaceutically acceptable salt thereof.
[0547] In a further aspect, the hearing impairment is
age-related.
[0548] In a further aspect, the hearing impairment is related to a
balance or orientation-related disorder. Examples of balance
disorders include, but are not limited to, induced or spontaneous
vertigo, dysequilibrium, increased susceptibility to motion
sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia,
nystagmus, syncope, lightheadedness, dizziness, increased falling,
difficulty walking at night, Meniere's disease, and difficulty in
visual tracking and processing.
H. METHODS OF USING THE COMPOSITIONS
[0549] The compounds and compositions are further useful in methods
for the prevention, treatment, control, amelioration, or reduction
of risk of the hearing impairments and disorders noted herein. The
compounds and compositions are further useful in a method for the
prevention, treatment, control, amelioration, or reduction of risk
of the aforementioned hearing impairments and disorders in
combination with other agents.
[0550] Also provided are methods of using of a disclosed
composition or medicament. In one aspect, the method of use is
directed to the treatment of a disorder. In a further aspect, the
disclosed compounds can be used as single agents or in combination
with one or more other drugs in the treatment, prevention, control,
amelioration, or reduction of risk of the aforementioned diseases,
disorders and conditions for which the compound or the other drugs
have utility, where the combination of drugs together are safer or
more effective than either drug alone. The other drug(s) can be
administered by a route and in an amount commonly used therefore,
contemporaneously or sequentially with a disclosed compound. When a
disclosed compound is used contemporaneously with one or more other
drugs, a pharmaceutical composition in unit dosage form containing
such drugs and the disclosed compound is preferred. However, the
combination therapy can also be administered on overlapping
schedules. It is also envisioned that the combination of one or
more active ingredients and a disclosed compound can be more
efficacious than either as a single agent.
[0551] The pharmaceutical compositions and methods of the present
invention can further comprise other therapeutically active
compounds as noted herein which are usually applied in the
treatment of the above mentioned pathological conditions.
[0552] 1. Manufacture of a Medicament
[0553] In one aspect, the invention relates to a medicament
comprising a CDK2 inhibitor, or a pharmaceutically acceptable salt
thereof and one or more of at least one agent known to treat a
hearing impairment, or a pharmaceutically acceptable salt thereof,
and at least one agent known to prevent a hearing impairment, or a
pharmaceutically acceptable salt thereof.
[0554] In various aspects, the invention relates methods for the
manufacture of a medicament for treating and/or preventing hearing
impairment comprising combining one or more disclosed compounds,
products, or compositions or a pharmaceutically acceptable salt
thereof, with a pharmaceutically acceptable carrier. It is
understood that the disclosed methods can be performed with the
disclosed compounds, products, and pharmaceutical compositions. It
is also understood that the disclosed methods can be employed in
connection with the disclosed methods of using.
[0555] 2. Use of Compounds and Compositions
[0556] Also provided are the uses of the disclosed compounds and
compositions. Thus, in one aspect, the invention relates to the
uses of a CDK2 inhibitor, or a pharmaceutically acceptable salt
thereof and one or more of at least one agent known to treat a
hearing impairment, or a pharmaceutically acceptable salt thereof,
and at least one agent known to prevent a hearing impairment, or a
pharmaceutically acceptable salt thereof.
[0557] In a further aspect, the invention relates to the use of a
CDK2 inhibitor, or a pharmaceutically acceptable salt thereof in
the manufacture of a medicament for the treatment of a hearing
impairment or disorder.
[0558] In a further aspect, the use relates to a process for
preparing a pharmaceutical composition comprising a therapeutically
effective amount of a CDK2 inhibitor, or a pharmaceutically
acceptable salt thereof, and one or more of at least one agent
known to treat a hearing impairment, or a pharmaceutically
acceptable salt thereof, and at least one agent known to prevent a
hearing impairment, or a pharmaceutically acceptable salt thereof,
for use as a medicament.
[0559] In a further aspect, the use relates to a process for
preparing a pharmaceutical composition comprising a therapeutically
effective amount of a CDK2 inhibitor, or a pharmaceutically
acceptable salt thereof, and one or more of at least one agent
known to treat a hearing impairment, or a pharmaceutically
acceptable salt thereof, and at least one agent known to prevent a
hearing impairment, or a pharmaceutically acceptable salt thereof,
wherein a pharmaceutically acceptable carrier is intimately mixed
with a therapeutically effective amount of the CDK2 inhibitor, the
at least one agent known to treat a hearing impairment, or the at
least one agent known to prevent a hearing impairment.
[0560] In various aspects, the use relates to the treatment of a
hearing impairment or disorder in a vertebrate animal. In a further
aspect, the use relates to the treatment of a hearing impairment or
disorder in a human subject.
[0561] In a further aspect, the use is the treatment of a hearing
impairment or disorder. In a still further aspect, the use is the
treatment of a hearing impairment. In yet a further aspect, the use
is the treatment of a hearing disorder.
[0562] It is understood that the disclosed uses can be employed in
connection with the disclosed compounds, methods, compositions, and
kits. In a further aspect, the invention relates to the use of a
disclosed compound or composition of a medicament for the treatment
of a hearing impairment or disorder in a mammal.
[0563] In a further aspect, the invention relates to the use of a
disclosed compound or composition in the manufacture of a
medicament for the treatment of a hearing impairment or disorder
selected from hearing loss, deafness, tinnitus, ringing,
Presbyacusis, auditory neuropathy, acoustic trauma, acoustic
neuroma, Pendred syndrome, Usher syndrome, Wardenburg syndrome,
non-syndromic sensorineural deafness, otitis media, otosclerosis,
Meniere's disease, ototoxicity, labyrinthitis, as well as hearing
impairments caused by infection (i.e., measles, mumps, or
meningitis), medicines such as antibiotics, and some cancer
treatments (i.e., chemotherapy and radiation therapy).
[0564] In a further aspect, the invention relates to the use of a
disclosed compound or composition in the manufacture of a
medicament for the treatment of a hearing impairment or
disorder.
[0565] In a further aspect, the invention relates to the use of a
disclosed compound or composition in the treatment of hair cell
loss and any disorder that arises as a consequence of cell loss in
the ear, such as hearing impairments (e.g., because of trauma or
prolonged exposure to loud noises), deafness (e.g., because of a
genetic or congenital defect), and vestibular disorders (e.g.,
including bilateral and unilateral vestibular dysfunction), for
example, by promoting differentiation (e.g., complete or partial
differentiation) of one or more cells into one or more cells
capable of functioning as sensory cells of the ear, e.g., hair
cells. Subjects benefiting from such treatment include those at
risk of hair cell loss and/or a patient with hair cell loss. For
example, a subject having or at risk for developing a hearing loss
can hear less well than the average subject (e.g., an average human
being), or less well than a subject before experiencing the hearing
loss. For example, hearing can be diminished by at least 5%, 10%,
30%, 50% or more.
[0566] In various aspects, the methods described herein can be used
to generate hair cell growth in the ear and/or to increase the
number of hair cells in the ear (e.g., in the inner, middle, and/or
outer ear). In this respect, an effective amount of a stimulatory
agent and an inhibitory agent described herein is an amount that
increases the number of hair cells in the ear by about 2-, 3-, 4-,
6-, 8-, or 10-fold, or more, as compared to the number of hair
cells before treatment. This new hair cell growth can effectively
restore or establish at least a partial improvement in the
subject's ability to hear. For example, administration of a
stimulatory agent and an inhibitory agent of this invention can
improve hearing loss by about 5, 10, 15, 20, 40, 60, 80, 100% or
more.
[0567] In various aspects, the agents and methods described herein
can be used prophylactically, such as to prevent, reduce, or delay
progression of hearing loss, deafness, or other auditory disorders
associated with loss of inner ear function.
[0568] 3. Kits
[0569] In one aspect, disclosed are kits comprising a CDK2
inhibitor, or a pharmaceutically acceptable salt thereof; and one
or more of: (a) at least one agent known to treat a hearing
impairment; (b) at least one agent known to prevent a hearing
impairment; (c) at least one antibiotic agent; (d) at least one
chemotherapeutic agent; (e) instructions for treating a hearing
impairment; and (f) instructions for preventing a hearing
impairment.
[0570] In one aspect, disclosed are kits comprising a compound
selected from:
##STR00080##
or a pharmaceutically acceptable salt thereof; and one or more of:
at least one agent known to treat a hearing impairment; at least
one agent known to prevent a hearing impairment; at least one
antibiotic agent; at least one chemotherapeutic agent; instructions
for treating a hearing impairment; and instructions for preventing
a hearing impairment.
[0571] In one aspect, disclosed are kits comprising a compound
selected from:
##STR00081##
or a pharmaceutically acceptable salt thereof; and one or more of:
(a) at least one agent known to treat a hearing impairment; (b) at
least one agent known to prevent a hearing impairment; (c) at least
one antibiotic agent; (d) at least one chemotherapeutic agent; (e)
instructions for treating a hearing impairment; and (f)
instructions for preventing a hearing impairment.
[0572] In various aspects, the agents and pharmaceutical
compositions described herein can be provided in a kit. The kit can
also include combinations of the agents and pharmaceutical
compositions described herein.
[0573] In various aspects, the informational material can be
descriptive, instructional, marketing or other material that
relates to the methods described herein and/or to the use of the
agents for the methods described herein. For example, the
informational material may relate to the use of the agents herein
to treat a subject who has, or who is at risk for developing, a
hearing impairment. The kits can also include paraphernalia for
administering the agents of this invention to a cell (in culture or
in vivo) and/or for administering a cell to a patient.
[0574] In various aspects, the informational material can include
instructions for administering the pharmaceutical composition
and/or cell(s) in a suitable manner to treat a human, e.g., in a
suitable dose, dosage form, or mode of administration (e.g., a
dose, dosage form, or mode of administration described herein). In
a further aspect, the informational material can include
instructions to administer the pharmaceutical composition to a
suitable subject, e.g., a human having, or at risk for developing,
a hearing impairment.
[0575] In various aspects, the composition of the kit can include
other ingredients, such as a solvent or buffer, a stabilizer, a
preservative, a fragrance or other cosmetic ingredient. In such
aspects, the kit can include instructions for admixing the agent
and the other ingredients, or for using one or more compounds
together with the other ingredients.
[0576] In a further aspect, the CDK2 inhibitor and the at least one
agent known to treat a hearing impairment are co-formulated. In a
still further aspect, the CDK2 inhibitor and the at least one agent
known to treat a hearing impairment are co-packaged.
[0577] In a further aspect, the agent known to treat a hearing
impairment is selected from an antiepileptic drug blocking T-type
calcium channels; an anticonvulsant; a synthetic glucocorticoid; a
loop diuretic; an anti-oxidant; a proton pump inhibitor; a PDES
inhibitor; and a mGluR7 inhibitor. In a still further aspect, the
agent known to treat a hearing impairment is selected from
trimethadione; mibefrabil; ethosuximide;
3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-pip-
eridin-4-ylmethyl]-benzamide (TTA-P2); NNC 55-0396; ML 218;
nilvadipine; valproic acid; oxcarbazepine; phenobarbital;
phenytoin; zonisamide; nicardipine; chlordiazepoxide; sipatrigine;
halothane; octanol; pimozide; penfluridol; fluspirilene;
thioridazine; clozapine; haloperidol; tetramethrin; tetrandrine;
amiodarone; bepridil; cinnarizine; flunarizine; amiloride;
anandamide; dexamethasone; methylprednisolone;
N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-ox-
o-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide;
2-phenyl-1,2-benzisoselenazol-3-one (ebselen); sodium thiosulfate;
D-methionine; furosemide; N-acetyl-L-cysteine; vitamins A; vitamin
C; vitamin E; vigabatrin; omeprazole; lansoprazole; pantoprazole;
rabeprazole; esomerprazole; pariprazole; leminoprazole;
3,3'-diindolylmethane; vardenafil; sildenafil; tadalafil; udenafil;
dasantafil; avanafil; SLx2101; LAS34179;
N,N-dibenzhydrylethane-1,2-diamine dihydrochloride;
R(+)-N-propargyl-1-aminoindan; and L-carnitine.
[0578] In a further aspect, the CDK2 inhibitor and the at least one
agent known to prevent a hearing impairment are co-formulated. In a
still further aspect, the CDK2 inhibitor and the at least one agent
known to prevent a hearing impairment are co-packaged.
[0579] In a further aspect, the CDK2 inhibitor and the at least one
antibiotic agent are co-formulated. In a still further aspect, the
CDK2 inhibitor and the at least one antibiotic agent are
co-packaged.
[0580] In a further aspect, the CDK2 inhibitor and the at least one
chemotherapeutic agent are co-formulated. In a still further
aspect, the CDK2 inhibitor and the at least one chemotherapeutic
agent are co-packaged.
[0581] In a further aspect, the chemotherapeutic agent is a
platinum-based agent. In a still further aspect, the platinum-based
agent is selected from carboplatin, cisplatin, transplatin,
nedaplatin, oxaliplatin, picoplatin, satraplatin, transplatin, and
triplatin. In yet a further aspect, the platinum-based agent is
cisplatin.
[0582] In a further aspect, the kit further comprises a plurality
of dosage forms, the plurality comprising one or more doses;
wherein each dose comprises an effective amount of a CDK2 inhibitor
and the at least one agent known to treat a hearing impairment. In
a still further aspect, the effective amount is a therapeutically
effective amount. In yet a further aspect, the effective amount is
a prophylactically effective amount. In an even further aspect,
each dose of the CDK2 inhibitor and the agent known to treat a
hearing impairment are co-packaged. In a still further aspect, each
dose of the CDK2 inhibitor and the agent known to treat a hearing
impairment are co-formulated.
[0583] In a further aspect, the kit further comprises a plurality
of dosage forms, the plurality comprising one or more doses;
wherein each dose comprises an effective amount of a CDK2 inhibitor
and the at least one agent known to prevent a hearing impairment.
In a still further aspect, the effective amount is a
therapeutically effective amount. In yet a further aspect, the
effective amount is a prophylactically effective amount. In an even
further aspect, each dose of the CDK2 inhibitor and the agent known
to prevent a hearing impairment are co-packaged. In a still further
aspect, each dose of the CDK2 inhibitor and the agent known to
prevent a hearing impairment are co-formulated.
[0584] In a further aspect, the kit further comprises a plurality
of dosage forms, the plurality comprising one or more doses;
wherein each dose comprises an effective amount of a CDK2 inhibitor
and the at least one antibiotic agent. In a still further aspect,
the effective amount is a therapeutically effective amount. In yet
a further aspect, the effective amount is a prophylactically
effective amount. In an even further aspect, each dose of the CDK2
inhibitor and the antibiotic agent are co-packaged. In a still
further aspect, each dose of the CDK2 inhibitor and the antibiotic
agent are co-formulated.
[0585] In a further aspect, the kit further comprises a plurality
of dosage forms, the plurality comprising one or more doses;
wherein each dose comprises an effective amount of a CDK2 inhibitor
and the at least one chemotherapeutic agent. In a still further
aspect, the effective amount is a therapeutically effective amount.
In yet a further aspect, the effective amount is a prophylactically
effective amount. In an even further aspect, each dose of the CDK2
inhibitor and the chemotherapeutic agent are co-packaged. In a
still further aspect, each dose of the CDK2 inhibitor and the
chemotherapeutic agent are co-formulated.
[0586] In a further aspect, the dosage forms are formulated for
topical administration. In a still further aspect, the dosage forms
are formulated for injection into the luminae of the cochlea, the
auditory nerve trunk in the internal auditory meatus, the scala
tympani, or the middle ear space across the transtympanic
membrane/ear drum; or, if present, into a cochlear implant.
[0587] In a further aspect, the CDK2 inhibitor is formulated for
topical administration; and the agent known to treat a hearing
impairment is formulated for injection into the luminae of the
cochlea, the auditory nerve trunk in the internal auditory meatus,
the scala tympani, or the middle ear space across the transtympanic
membrane/ear drum; or, if present, into a cochlear implant. In a
still further aspect, the CDK2 inhibitor is formulated for
injection into the luminae of the cochlea, the auditory nerve trunk
in the internal auditory meatus, the scala tympani, or the middle
ear space across the transtympanic membrane/ear drum; or, if
present, into a cochlear implant; and the agent known to treat a
hearing impairment is formulated for topical administration.
[0588] In a further aspect, the CDK2 inhibitor is formulated for
topical administration; and the agent known to prevent a hearing
impairment is formulated for injection into the luminae of the
cochlea, the auditory nerve trunk in the internal auditory meatus,
the scala tympani, or the middle ear space across the transtympanic
membrane/ear drum; or, if present, into a cochlear implant. In a
still further aspect, the CDK2 inhibitor is formulated for
injection into the luminae of the cochlea, the auditory nerve trunk
in the internal auditory meatus, the scala tympani, or the middle
ear space across the transtympanic membrane/ear drum; or, if
present, into a cochlear implant; and the agent known to prevent a
hearing impairment is formulated for topical administration.
[0589] In a further aspect, the CDK2 inhibitor is formulated for
intravenous administration and the chemotherapeutic agent is
formulated for oral administration. In a still further aspect, the
CDK2 inhibitor is formulated for oral administration and the
chemotherapeutic agent is formulated for intravenous
administration. In yet a further aspect, the CDK2 inhibitor is
formulated for intravenous administration and the antibiotic agent
is formulated for oral administration. In an even further aspect,
the CDK2 inhibitor is formulated for oral administration and the
antibiotic agent is formulated for intravenous administration.
[0590] 4. Subjects
[0591] In various aspects, the subject of the herein disclosed
methods is a vertebrate, e.g., a mammal. Thus, the subject of the
herein disclosed methods can be a human, non-human primate, horse,
pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The
term does not denote a particular age or sex. Thus, adult and
newborn subjects, as well as fetuses, whether male or female, are
intended to be covered. A patient refers to a subject afflicted
with a disease or disorder. The term "patient" includes human and
veterinary subjects.
[0592] In some aspects of the disclosed methods, the subject has
been diagnosed with a need for treatment prior to the administering
step. In some aspects of the disclosed method, the subject has been
diagnosed with a hearing impairment or disorder prior to the
administering step. In some aspects of the disclosed methods, the
subject has been identified with a need for treatment prior to the
administering step. In one aspect, a subject can be treated
prophylactically with a compound or composition disclosed herein,
as discussed herein elsewhere.
[0593] a. Dosage
[0594] Toxicity and therapeutic efficacy of the agents and
pharmaceutical compositions described herein can be determined by
standard pharmaceutical procedures, using either cells in culture
or experimental animals to determine the LD.sub.50 (the dose lethal
to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
can be expressed as the ratio LD.sub.50/ED.sub.50. Polypeptides or
other compounds that exhibit large therapeutic indices are
preferred.
[0595] Data obtained from cell culture assays and further animal
studies can be used in formulating a range of dosage for use in
humans. The dosage of such compounds lies preferably within a range
of circulating concentrations that include the ED.sub.50 with
little or no toxicity, and with little or no adverse effect on a
human's ability to hear. The dosage may vary within this range
depending upon the dosage form employed and the route of
administration utilized. For any agents used in the methods
described herein, the therapeutically effective dose can be
estimated initially from cell culture assays. A dose can be
formulated in animal models to achieve a circulating plasma
concentration range that includes the IC.sub.50 (that is, the
concentration of the test compound which achieves a half-maximal
inhibition of symptoms) as determined in cell culture. Such
information can be used to more accurately determine useful doses
in humans. Exemplary dosage amounts of a differentiation agent are
at least from about 0.01 to 3000 mg per day, e.g., at least about
0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200,
500, 1000, 2000, or 3000 mg per kg per day, or more.
[0596] The formulations and routes of administration can be
tailored to the disease or disorder being treated, and for the
specific human being treated. For example, a subject can receive a
dose of the agent once or twice or more daily for one week, one
month, six months, one year, or more. The treatment can continue
indefinitely, such as throughout the lifetime of the human.
Treatment can be administered at regular or irregular intervals
(once every other day or twice per week), and the dosage and timing
of the administration can be adjusted throughout the course of the
treatment. The dosage can remain constant over the course of the
treatment regimen, or it can be decreased or increased over the
course of the treatment.
[0597] In various aspects, the dosage facilitates an intended
purpose for both prophylaxis and treatment without undesirable side
effects, such as toxicity, irritation or allergic response.
Although individual needs may vary, the determination of optimal
ranges for effective amounts of formulations is within the skill of
the art. Human doses can readily be extrapolated from animal
studies (Katocs et al., (1990) Chapter 27 in Remington's
Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing
Co., Easton, Pa.). In general, the dosage required to provide an
effective amount of a formulation, which can be adjusted by one
skilled in the art, will vary depending on several factors,
including the age, health, physical condition, weight, type and
extent of the disease or disorder of the recipient, frequency of
treatment, the nature of concurrent therapy, if required, and the
nature and scope of the desired effect(s) (Nies et al., (1996)
Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York,
N.Y.).
[0598] b. Routes of Administration
[0599] Also provided are routes of administering the disclosed
compounds and compositions. The compounds and compositions of the
present invention can be administered by direct therapy using
systemic administration and/or local administration. In various
aspects, the route of administration can be determined by a
patient's health care provider or clinician, for example following
an evaluation of the patient. In various aspects, an individual
patient's therapy may be customized, e.g., the type of agent used,
the routes of administration, and the frequency of administration
can be personalized. Alternatively, therapy may be performed using
a standard course of treatment, e.g., using pre-selected agents and
pre-selected routes of administration and frequency of
administration.
[0600] Systemic routes of administration can include, but are not
limited to, parenteral routes of administration, e.g., intravenous
injection, intramuscular injection, and intraperitoneal injection;
enteral routes of administration e.g., administration by the oral
route, lozenges, compressed tablets, pills, tablets, capsules,
drops (e.g., ear drops), syrups, suspensions and emulsions; rectal
administration, e.g., a rectal suppository or enema; a vaginal
suppository; a urethral suppository; transdermal routes of
administration; and inhalation (e.g., nasal sprays).
[0601] In various aspects, the compounds and compositions described
herein can be administered to a patient, e.g., a patient identified
as being in need of treatment for hair cell loss, using a local
route of administration. Such local routes of administration
include administering the agents described herein into the ear of a
patient and/or the inner ear of a patient, for example, by
injection and/or using a pump or placing a gelfoam for constant
release of compounds into the inner ear.
[0602] In various aspects, a pharmaceutical composition can be
injected into the ear (e.g., auricular administration), such as
into the luminae of the cochlea (e.g., the Scala media, Sc
vestibulae, and Sc tympani), e.g., using a syringe, e.g., a
single-dose syringe. For example, the compounds and compositions
described herein can be administered by intratympanic injection
(e.g., into the middle ear), and/or injections into the outer,
middle, and/or inner ear. Such methods are routinely used in the
art, for example, for the administration of steroids and
antibiotics into human ears. Injection can be, for example, through
the round window of the ear or through the cochlear capsule. Other
inner ear administration methods are known in the art (see, e.g.,
Salt and Plontke, Drug Discovery Today 2005, 10, 1299).
[0603] In various aspects, the pharmaceutical composition can be
administered in situ, via a catheter or pump. A catheter or pump
can, for example, direct a pharmaceutical composition into the
cochlear luminae or the round window of the ear and/or the lumen of
the colon. Exemplary drug delivery apparatus and methods suitable
for administering one or more of the compounds described herein
into an ear, e.g., a human ear, are described in US 2006/0030837
and U.S. Pat. No. 7,206,639. In a further aspect, a catheter or
pump can be positioned, e.g., in the ear (e.g., the outer, middle,
and/or inner ear) of a patient during a surgical procedure. In a
still further aspect, a catheter or pump can be positioned, e.g.,
in the ear (e.g., the outer, middle, and/or inner ear) of a patient
without the need for a surgical procedure.
[0604] In various aspects, one or more of the compounds and
compositions described herein can be administered in combination
with a mechanical device such as a cochlear implant or a hearing
aid, which is worn in the outer ear. An exemplary cochlear implant
that is suitable for use with the present invention is described in
US 2007/0093878.
[0605] In various aspects, the modes of administration described
above may be combined in any order.
[0606] In various aspects, the compounds and compositions described
herein can be administered via cell therapy, wherein cells are
contacted ex vivo with the combination of agents described herein
to promote complete or partial differentiation of the cells to or
toward a mature cell type of the inner ear (e.g., a hair cell) in
vitro. Cells resulting from such methods can then be transplanted
or implanted into a patient in need of such treatment.
[0607] In various aspects, suitable cells can be derived from a
mammal, such as a human, mouse, rat, pig, sheep, goat, or non-human
primate. For example, stem cells have been identified and isolated
from the mouse utricular macula (Li, H., et al. (2003) Nature
Medicine 9, 1293-1299). The cells can also be obtained from a
patient to whom they will subsequently be re-administered.
[0608] In various aspects, suitable cells (e.g., a stem cell,
progenitor cell, and/or support cell) may be isolated from the
inner ear of an animal. Specifically, suitable cells can be
obtained from the cochlear organ of Corti, the modiolus (center) of
the cochlea, the spiral ganglion of the cochlea, the vestibular
sensory epithelia of the saccular macula, the utricular macula, or
the cristae of the semicircular canals. The stem cell, progenitor
cell, and/or supporting cells can also be obtained, however, from
other tissues such as bone marrow, blood, skin, or an eye. The
cells employed can be obtained from a single source (e.g., the ear
or a structure or tissue within the ear) or a combination of
sources (e.g., the ear and one or more peripheral tissues (e.g.,
bone marrow, blood, skin, or an eye).
I. EXAMPLES
[0609] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the compounds, compositions, articles, devices
and/or methods claimed herein are made and evaluated, and are
intended to be purely exemplary of the invention and are not
intended to limit the scope of what the inventors regard as their
invention. Efforts have been made to ensure accuracy with respect
to numbers (e.g., amounts, temperature, etc.), but some errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, temperature is in .degree. C. or is at
ambient temperature, and pressure is at or near atmospheric.
[0610] The Examples are provided herein to illustrate the
invention, and should not be construed as limiting the invention in
any way. Examples are provided herein to illustrate the invention
and should not be construed as limiting the invention in any
way.
[0611] 1. Primary Screen of a Bioactive Library for Reduction of
Cisplatin-Induced Apoptosis in the HEI--OC1 Cell Line
[0612] Caspase-3 activation is an important downstream molecular
event known to occur in the majority of cellular pathways leading
to apoptosis, including apoptosis of inner ear cells. Previous work
has shown that inhibition of caspases, for example, by zVAD-fmk, an
irreversible general caspase inhibitor, confers robust protection
against cisplatin-induced cell death (Liu et al. (1998) Neuroreport
9: 2609-2614). For this screen, caspase-3 cleavage was chosen as
the endpoint indicating cisplatin-induced cell death, as it allowed
the inhibition of cell death to be monitored at the level of any
intracellular molecular target upstream of caspase-3 cleavage in
the cell line. Pifithrin-.alpha. was also chosen as a reference
compound for the screen, as it provided good protection against
cisplatin ototoxicity by inhibiting caspase-3 cleavage with an
IC.sub.50 of 17 .mu.M. Pifithrin-.alpha., a small molecule that
inhibits p53, was shown to suppress the expression of p53,
caspase-3, and caspase-1 in mouse cochlear explants (Zhang et al.
(2003) Neuroscience 120: 191-205). Pifithrin-.alpha. has previously
been shown to confer reasonable protection from cisplatin-induced
cell death in cell lines and, importantly, in mouse cochlear
explants at concentrations of 20-100 .mu.M (Zhang et al. (2003)
Neuroscience 120: 191-205), although at these doses it was reported
to damage the hair cell stereocillia.
[0613] To measure cell death induced by cisplatin in cochlear hair
cells, the HEI--OC1 immortalized inner ear cell line isolated
originally from P7 organs of Corti of the Immortomouse (Kalinec et
al. (2003) Adiol. Neurootol. 8: 177-189) was used. This cell line
has been shown to serve as a good model of inner ear cells (Kim et
al. (2010) J. Neurosci. 30: 3933-3946), and it was independently
confirmed by qRT-PCR that the cells used in this screen express the
hair cell markers Myo6 and Myo7a.
[0614] This screen is also described in Teitz, T., Goktug, A. N.,
Chen, T., Zuo, J., 2016. Development of cell-based high throughput
chemical screens for protection against cisplatin-induced
ototoxicity In: Sokolowski, B., (Ed.), Auditory and Vestibular
Research, Methods and Protocols, Second Edition. Humana Press. pp
419-430. doi: 10.1007/978-1-4939-3615-1_22.
[0615] Before starting the automated high-throughput screen (HTS)
accomplished with the help of robots in 384-well plates, assay
conditions were optimized on the bench, including the cell number
plated (1600 cells per well), cisplatin concentration (50 .mu.M,
based on the dose-response curve), incubation time (22 hrs at
33.degree. C., 10% CO.sub.2), and concentration of the reference
compound, pifithrin-.alpha.. The Promega Caspase-3/7 Glo assay,
which allows measurement of light emitted as the result of caspase
cleavage and is suitable for HTS, was used. The linearity of the
Caspase-3/7 Glo assay was validated and it was verified that 0.5%
DMSO had no effect on cell death kinetics. The Caspase-3/7 Glo
assay was then tested for reproducibility on the St. Jude robot
systems. By using a pintool, test compounds were added to the
screen to a final concentration of 8 .mu.M, and cisplatin solution
was added immediately to each well to a final concentration of 50
.mu.M. Cells were incubated with the test compounds and cisplatin
for 22 hrs at 33.degree. C., 10% CO.sub.2 with the medium as
previously described (Kalinec et al. (2003) Adiol. Neurootol. 8:
177-189); no .gamma.-interferon was added. The 384-well plates were
shaken and spun after compound addition to enhance assay
reproducibility.
[0616] The assay positive control, pifithrin-.alpha., induced 50%
reduction of caspase-3/7 activity at 17 .mu.M (IC.sub.50) and full
reduction at 34 .mu.M. Pifithrin-.alpha. was added to each of the
34 plates as a screening quality control. FIG. 1 shows the percent
activity of caspase-3/7 in screening of the 4,359 unique bioactive
compounds, including >844 FDA approved drugs. Cisplatin-induced
caspase-3/7 activity was reduced by 60% or more by 177 compounds,
which were further analyzed for dose response and toxicity.
[0617] Referring to FIG. 1, a screen of a bioactive compound
library, including 4,359 unique compounds and 844 FDA-approved
drugs, was conducted. The cell-based screen average z' was 0.75,
signal window was 12, and signal fold was 4.9. Cells treated with
50 .mu.M cisplatin were assigned 100% caspase-3/7 activity. Cells
not treated with cisplatin (grown in media only) were assigned 0%
caspase-3/7 activity. 177 compounds were found to decrease
cisplatin-induced caspase-3/7 activity by 60% or more (see black
line and below).
[0618] 2. Dose-Response and Toxicity of the Top Hits from the
Primary Screen
[0619] The Caspase-3/7 Glo assay was used as described above to
test the 177 top hit compounds for protection against
cisplatin-induced cell death. Ten serial 1:3 dilutions (40 .mu.M to
40 nM) of each compound were tested in triplicate in the presence
of 50 .mu.M cisplatin. To measure the viability of the HEI--OC1
cells treated with these compounds alone, the compounds were added
to the cells without cisplatin at the same final concentrations of
40 .mu.M to 40 nM. Cell viability was assayed in triplicate by
using the Promega Cell Titer Glo assay (CTG), which quantifies the
ATP released from live cells and is suitable for HTS. Cells grown
in media only, without compounds, under identical conditions served
as positive control for 100% viability. Cells treated with a 100%
lethal concentration of staurosporine for 22 hours were controls
for 0% viability. The results of the caspase-3/7 assay and the CTG
viability assay are shown for three known compounds
(pifithrin-.alpha., zVAD-fmk, and Ebselen, shown in Teitz et al.,
2016, Auditory and Vestibular Research, Methods and Protocols,
Second Edition. Humana Press. pp 419-430) and five representative
compounds (3, 4, 1, 12, and 9) in FIG. 2a-e. Each plate contained
wells for the reference compound pifithrin-.alpha.. One of the top
hits was zVAD-fmk, an irreversible, potent general caspase
inhibitor predicted to appear in this screen. zVAD-fmk has been
shown to inhibit cisplatin-induced cell death in the mouse cochlea
with high potency (IC.sub.50=0.2 .mu.M) (Atar and Avraham (2010)
Neuroscience 168: 851-857; Liu et al. (1998) Neuroreport 9:
2609-2614). However, this compound is unlikely to be the best
choice for therapeutic use in vivo. Another interesting hit from
the screen was Ebselen, which is currently being tested for
protection against noise-induced hearing loss in a clinical Phase 2
trial (www.soundpharmaceuticals.com). Ebselen showed low potency in
protection against cisplatin and was toxic at the concentration
that inhibited caspase-3/7.
[0620] Referring to FIG. 2a-e, dose response curves were generated
after 22 hr culture in HEI--OC1 cells. Shown are Caspase-3/7 Glo
assay (cisplatin-induced cell death; compound+cisplatin) and Cell
Titer Glo (CTG) assay (cell viability; compound only) data for
compounds 4, 9, 12, 3, and 1 (FIG. 2a-e, respectively). The
Caspase-3/7 IC.sub.50 activity is indicated for each compound.
[0621] Table 1 lists the top 18 compound hits in the screen in
terms of high potency and low toxicity. Their drug status for other
diseases and corresponding mechanism of action are listed in Table
2. The top ten compounds were further evaluated by a viability
assay (Cell Titer Glo, Promega) in medulloblastoma neurosphere cell
lines and neuroblastoma cell lines to test whether they inhibit the
ability of cisplatin to kill the tumor cells. The majority had no
antagonistic effect on cisplatin's antitumor activity (data not
shown) and are therefore safe to use systemically together with
cisplatin during chemotherapy to protect against cisplatin-induced
hearing loss.
TABLE-US-00002 TABLE 1 HEI- HEI- OC1 OC1 Cmpd. IC.sub.50 LD.sub.50
No. Cmpd. Name Chemical Structure (.mu.M) (.mu.M) 1 Leflunomide
##STR00082## 3.0 >40 2 Olsalazine sodium ##STR00083## 6.2 >40
3 Pelitinib ##STR00084## 0.6 >40 4 Kenpaullone ##STR00085## 2.1
>40 5 Antimycin A ##STR00086## 0.04 >10 6 Cyanocobalamin
(vitamin B12) ##STR00087## 4.2 >40 7 EHT1864 ##STR00088## 2.0
>20 8 Lanatoside C ##STR00089## 7.6 >40 9 Olomoucine II
##STR00090## 0.8 >40 10 2- Mercaptobenzothi- azole ##STR00091##
7.0 >10 11 Patulin ##STR00092## 0.7 >10 12 CDK2 inhibitor II
##STR00093## 0.5 >40 13 D- Ribofuranosylben- zimidazole
##STR00094## 4.0 >40 14 GSK JS 84326- 047A1 ##STR00095## 1.3
>10 15 Roche (R002830409- 001) ##STR00096## 0.1 >10 16 GSK
(AN100368- 079A1) ##STR00097## 0.8 >40 17 GSK (U18675/6/1)
##STR00098## 2.1 >40 18 GSK (U11667/23/1) ##STR00099## 3.4
>40
TABLE-US-00003 TABLE 2 Drug Status Cmpd. For Other No. Diseases
Mechanism of Action in Other Diseases 1 FDA approved Prodrug:
pyrimidine synthesis inhibitor for for the rheumatoid arthritis,
inhibitor of JNK, inhib- treatment itor of TNF-dependent NF-kB
activation, of active inhibitor of Cox-2, inhibitor of tyrosine
rheumatoid kinase phosphorylation, inhibitor of DHODH arthritis (de
novo pyrimidine synthesis). 2 FDA approved Derivative of
salicylate: 5-aminosalicyclic acid prodrug used in inflammatory
bowel disease, ulcerative colitis, anti-inflammatory and
anti-apoptotic regulation. 3 IND phase Irreversible inhibitor of
epidermal growth factor receptor. 4 In vivo, Inhibitor of
CDK1/cyclin B (IC.sub.50 = 400 nM), Rodent CDK2/cyclin A (IC.sub.50
= 680 nM), CDK5/p25 (IC.sub.50 = 850 nM), GSK-3.beta. (IC.sub.50 =
230 nM), and HCK (MAP4K4) kinases (reduction of
HGK-Tak1-Mkk4-JNK-c-Jun cell death signaling cascade) 5 In vivo,
Antibiotic, inhibitor of mitochondrial electron Rodent transport
and inducer of apoptosis, toxin 6 FDA General methyl metabolism,
methyl donor for approved L-methionine synthesis 7 In vivo,
Inhibitor of Rac family of GTPases and blocks Rodent activation by
direct binding to Rac1, Rac1b, Rac2, and Rac3 8 IND Phase Cardiac
glycoside, inhibitor of Na.sup.+/K.sup.+-ATPase 9 In vitro
Inhibitor of CDKs 2, 5, 7, and 9; inhibitor and substrate of ABCB1
and ABCG2 transporters 10 In vivo, Toxin, multiple mechanisms
Rodent 11 In vivo, Mycotoxin, antibiotic Rodent 12 In vitro
ATP-competitive, selective inhibitor of CDK2 (IC.sub.50 = 60 nM) 13
In vitro Inhibitor of CDKs 7 and 9, RNA synthesis 14 -- Potent and
selective CNS penetrant furan-based inhibitor of B-Raf kinase 15 --
Potent oxindole inhibitor of CDK2 16 -- Potent and selective
inhibitor of GSK3 17 -- Heterocyclic inhibitor of GSK3 18 --
Oxindole-based inhibitor of CDK2
[0622] 3. Protection Against Cisplatin-Induced Hair Cell Loss in
Cochlear Explants
[0623] The top 13 compounds were texted ex vivo in neonatal (P3)
mouse cochlear explants. P3 wild-type mouse cochleae were dissected
and cultured with the aid of matrigel as previously described
(Driver and Kelley (2010) Curr. Protoc. Neurosci. Chapter 4, Unit 4
34: 31-10). After one day of culture, cisplatin (50 .mu.M) with or
without compounds were added to growth media and incubated for 24
hrs at 37.degree. C. 50 .mu.M cisplatin was chosen because the
explant assay consistently showed death at 40% of outer hair cells
(OHCs) in the mouse cochlea at this concentration after 24 hrs
co-incubation (FIG. 3A-G). It is known that OHCs are the first
cells to be damaged ex vivo and in vivo by cisplatin and noise,
while inner hair cells (IHCs) are injured at higher concentrations
of cisplatin or higher levels of noise (Oishi and Schacht (2011)
Expert Opin. Emerg. Drugs 16: 235-245; Zhang et al. (2003)
Neuroscience 120: 191-205). Cochleae were fixed with 4%
paraformaldehyde (PFA) and stained against actin with
Phalloidin-Alexa Fluor 568 to determine hair cells' viability,
which was also assayed by 4',6-diamidino-2-phenylindole (DAPI)
staining, FM1-43 dye uptake, and immunohistochemistry with known
hair cell markers (Parvalbumin and Myo7a). Cochleae were imaged by
confocal microscopy, two 160 .mu.m regions from middle turns were
photographed, and the number of intact hair cells was counted.
Three to twelve cochleae were tested under each condition.
[0624] Referring to FIG. 3A-D, compound 4 protects against
cisplatin-induced hair cell loss in mouse cochlear explants.
Confocal images of whole mount cochlear explants that have been
treated with media (FIG. 3A), cisplatin (FIG. 3B), compound 4 (FIG.
3C), or cisplatin and compound 4 (FIG. 3C) for 24 hrs are shown.
Phalloidin labels the hair cells.
[0625] Referring to FIG. 3E-G, outer hair cell survival (%) when
treated with various doses (.mu.M) of compounds 4 (FIG. 3E), 9
(FIG. 3F), or 12 (FIG. 3G), and/or cisplatin (CIS) are shown. The
number of cochlear explants analyzed is indicated in each bar.
***P<0.001 using one-way ANOVA test followed by Bonferroni
comparison.
[0626] Ten of these compounds protected the cochlear explants at
>2 concentrations, as measured by hair cell viability after 24
hr cisplatin co-treatment. Four compounds (1, 4, 9, and 12) showed
excellent protection (100% OHC survival), with IC.sub.50 values of
0.1 to 25 .mu.M (FIG. 3 shows compound 4; Table 3). The remaining
compounds (2, 3, 5-7, and 13) protected 31-76% of the OHCs against
cisplatin (Table 3).
TABLE-US-00004 TABLE 3 Cmpd. Mouse Explant Mouse Explant No.
IC.sub.50 (.mu.M) LD.sub.50 (.mu.M) 1 ~25 >50 2 ~30 (For 50%)
>30 3 ~6 (For 50%) <13 4 ~0.15 >30 5 ~1.8 (For 31%) <4
6 ~21 (For 53%) >21 7 ~10 (For 58%) <20 8 >12-76 9 ~2.0
>33 10 >49 11 >3-9 12 ~2.0 >12 13 ~8.0 (For 76%)
[0627] 4. Protection Against Cisplatin-Induced Hair Cell Loss in
Zebrafish Lateral Lines In Vivo
[0628] The top ten compounds as determined by the mouse cochlear
explants were further tested in the lateral line neuromasts of
5-days post-fertilization (dpf) zebrafish larvae in vivo. Hair
cells in the zebrafish lateral line are considered homologous to
sensory hair cells in the mammalian inner ear and have similar
responses to ototoxic drugs (Ou et al. (2007) Hear. Res. 233:
46-53). Zebrafish are well established in vivo system to test
cisplatin damage, as the hair cells are easily accessible to drugs
(Coffin et al. (2013) Apoptosis 18: 393-408; Vlasits et al. (2012)
Hear. Res. 294: 153-165). The experiments were performed with 5-dpf
larval zebrafish of the *AB wild-type strain. Dose-response studies
were performed to find the cisplatin concentration at which most of
the hair cells in each neuromast were killed in the absence of a
protective compound and at the same DMSO concentration (<0.2%).
It was determined that 5 .mu.M cisplatin killed 91% of the hair
cells without addition of protective compounds in zebrafish treated
for 20 hrs (FIG. 4A-E, see the data point of 9% survival with "5.0
CIS"). Next, the cisplatin protection effect of the top ten
compounds as determined by the experiments herein above was tested.
As positive controls in these experiments, Paroxetine and Benzamil
were used at concentrations previously shown to confer cisplatin
protection in zebrafish (Vlasits et al. (2012) Hear. Res. 294:
153-165; FIG. 4A-E).
[0629] Referring to FIG. 4A-D, compound 4 protects against
cisplatin-induced hair cell loss in zebrafish lateral lines in
vivo. Lateral line neuromasts (white dots) in the zebrafish head
were visualized by staining with 0.005% DASPEI vital dye after
treatment with medium (FIG. 4A), cisplatin (FIG. 4B), compound 4
and Benzamil (FIG. 4C), or compound 4 and cisplatin (FIG. 4D).
Benzamil and Paroxetine are compounds known to protect against
cisplatin-induced hair cell loss in zebrafish (Vlasits et al.
(2012) Hear. Res. 294: 153-165).
[0630] Referring to FIG. 4E, hair cell survival (%) at various
doses (.mu.M) of compound 4 and cisplatin are shown. The number of
zebrafish tested in each condition was 3-13. Standard errors are
shown for each condition. ***P<0.001 using one-way ANOVA
followed by Bonferroni comparison. ND: not detected.
[0631] Experiments were performed in 24-well plates with 5 fish per
well in volumes of 1-2 mL. Fish were incubated with 5 .mu.M and
stained with 0.005% DASPEI vital dye for 15 minutes. After two
washes with egg water, fish were visualized in an epiflourescence
microscope. Ten specific neuromasts in each fish were scored based
on their intensity, in a scale from 0 (no labeling) to 2 (high
intensity), as described previously (Owens et al. (2009) Hear. Res.
253: 32-41). Results were plotted as percent survival of hair cells
in the cisplatin-treated fish relative to the untreated fish (FIG.
4A-E).
[0632] Of the ten compounds tested, only compound 4 showed
significant protection of zebrafish neuromasts against
cisplatin-induced hair cell loss (FIG. 4A-E; Table 4). Without
wishing to be bound by theory, these results suggest that most of
these compounds protect through molecular mechanisms that are
specific and unique to mammalian cells. This observation is
consistent with recent work that shows that only a fraction of the
compounds that protect zebrafish neuromasts from aminoglycosides
and cisplatin also protect mammalian cochlear cells from these
drugs (Ou et al. (2007) Hear. Res. 233: 46-53; Ou et al. (2010)
Drug Discov. Today 15: 265-271; Vlasits et al. (2012) Hear. Res.
294: 153-165).
TABLE-US-00005 TABLE 4 Cmpd. Zebrafish IC.sub.50 Zebrafish
LD.sub.50 No. (.mu.M) (.mu.M) 1 No >5.0 2 No >30 3 No <27
4 ~30 <90 5 No <0.6 7 No <1.0 8 No >50 9 No >50 12
No >50 13 No >75
[0633] 5. Protection Against Cisplatin-Induced Hair Cell Loss and
Hearing Loss in Adult Mice Treated Locally via Transtympanic
Injection
[0634] Compound 4 was tested for protection against
cisplatin-induced hair cell loss in vivo in adult mice (FIG. 5)
after transtympanic injection. Either ear of the same FVB P28
wild-type mouse was trans-tympanically injected (in a volume of 5
.mu.L) with compound 4 (250 .mu.M in 0.5% DMSO) or 0.5% DMSO only,
in a double-blinded manner. Two hours later, the mice were treated
intraperitoneally (IP) with cisplatin 30 mg/kg body weight, which
was expected to damage OHCs equally in both ears (FIG. 5A). At 14
days post-cisplatin treatment, cochlear hair cells were analyzed by
phalloidin staining. As expected, many OHCs at basal turns were
lost in DMSO-treated ears; however, these OHCs were significantly
protected in Compound 4 treated ears (paired t-tests, one-tailed or
two-tailed) (FIG. 5C-D). Without wishing to be bound by theory,
these results indicate that locally delivered compound 4 protects
against cisplatin-induced hair cell loss in vivo.
[0635] Referring to FIG. 5C-D, compound 4 protects against
cisplatin-induced hair cell loss in adult mice by local delivery in
vivo. Either compound 4 (250 .mu.M) or DMSO was delivered to either
ear of the same mouse for 2 hrs; cisplatin was injected via i.p.
and cochleae were fixed after 24 hrs and analyzed (FIG. 5C).
Confocal images of basal turn cochleae with phalloidin staining are
shown for DMSO, compound 4, and cisplatin+compound 4 (FIG. 5C).
[0636] Referring to FIG. 5D, outer hair cell survival (%) in eleven
mice is shown. Each line links two cochleae of each mouse. Using
paired t-test, two-tailed: p=0.0028. Despite variations between
animals, compound 4 significantly protects cisplatin-induced hair
cell loss in these conditions. Referring to FIG. 5B, Compound 4 was
tested for protection against cisplatin-induced hearing loss in
vivo in adult mice after transtympanic injection (TT), similar to
the procedures described in FIG. 5A and FIG. 6A, followed by
intraponeal injection of cisplatin (30 mg/kg) in 2 hrs. Hearing
tests (ABR) were performed 7 and 14 days post treatment. Referring
to FIG. 5B, hearing loss as measured by ABR threshold shift (dB
SPL) is significantly reduced at 16 and 32 kHz in compound 4
treated ears compared to DMSO control ears in 11 mice. (*:
p<0.05, paired t-tests, two-sided).
[0637] 6. Protection Against Noise-Induced Hearing Loss in Adult
Mice Treated Locally Via Transtympanic Injection
[0638] To confirm that compound 4 protects against noise-induced
hearing loss in vivo, another set of experiments was performed
(FIG. 6A). First, auditory brainstem response (ABR) thresholds were
recorded at P28 in adult FVB wild-type mice and exposed to 100 dB
SPL 8-16 kHz octave band noise for 2 hrs. A few minutes afterward,
compound 4 (250 .mu.M in 0.5% DMSO) or 0.5% DMSO only was injected
(5 .mu.L, trans-tympanically) in either ear of the same mouse.
Next, ABR thresholds were recorded 7 and 14 days post-exposure and
cochlear morphology was analyzed after the day-14 ABR measurement
(FIG. 6A). The entire experiment was performed in a double-blinded
manner.
[0639] Referring to FIG. 6A, an experimental design in which adult
FVB mice at P28 were exposed to noise or TBI. Immediately
afterward, compound 4 (250 .mu.M) or DMSO was delivered (via
trans-tympanic injection) to either ear of the same mouse. ABR and
DPOAE thresholds were recorded prior, 7 days, or 14 days post noise
exposure. Cochlear histology was examined at 14 days.
[0640] Referring to FIG. 6A, a double-blinded design for compound
versus DMSO injection to either ear of the same mouse is shown.
[0641] The results in a total of 19-20 mice indicated that compound
4 significantly protects adult mice from NIHL 7 days after exposure
to 8 kHz and 14 days after exposure 8 kHz and 16 kHz of noise (FIG.
6B and FIG. 6C). The mice had a mean of 12 dB of hearing protection
at these frequencies. Moreover, significant differences were
detected in a multiple regression longitudinal modeling with time
points (pre-, D7 and D14) and frequencies (8, 16 and 32 kHz) as
explanatory factors (p<0.01, t test of regression coefficients)
(not shown). The wave 1 amplitudes of ABR at 16 kHz were also
increased in compound 4 injected ears relative to DMSO-injected
ears (FIG. 6C). Without wishing to be bound by theory, these
results suggest that compound 4 protects in vivo against NIHL when
delivered locally.
[0642] Referring to FIG. 6B, the ABR threshold shift at
post-exposure day 14 (D14) in DMSO and compound 4 treated ears in
19 mice is shown. Error bars: S.E. **p<0.01;*p<0.05, paired
t-test, two-tailed.
[0643] Box plots of the intra-mouse ABR threshold difference
between the two treated ears (ABR.sub.4 ABR.sub.Dmso) of each mouse
is shown at pre- and post-exposure day 7 (D7) and 14 (D14) in 20,
20, and 19 mice, respectively, at 8, 16, and 32 kHz. Significant
differences were observed at 8 kHz at D7 and D14 and at 16 kHz at
D14. **p<0.01 (paired t-test). Additionally, significant
differences were detected in multiple regression longitudinal
modeling with time points (pre-, D7, and D14) and frequencies (8,
16, and 32 kHz) as explanatory factors (p<0.01, t-test of
regression coefficients).
[0644] 7. Effect of Compound 4 on Cisplatin Anti-Tumor Activity
[0645] Compound 4 did not interfere with cisplatin anti-tumor
activity in three tumor cell lines (two mouse medulloblastoma
neurosphere cell lines and one human neuroblastoma cell line)
although it did so to certain extent in three other tumor cell
lines (two medulloblastoma neurosphere cell lines and one human
neuroblastoma cell line) (Morfouace, M. et al. Cancer cell 25,
516-529, 2014). FIG. 11 provides strong evidence that our compound
4 is more suitable for local delivery while compounds 7 and 12
exhibited no interference in all tumor cell lines (except one for
Compound 7) and therefore were better suitable for both systemic
and local delivery.
J. PROPHETIC EXAMPLES
[0646] 1. Protection Against Cisplatin Ototoxicity Ex Vivo in
Neonatal Mouse Cochlear Explant Culture
[0647] The ability of the top 18 compound hits to protect against
cisplatin ototoxicity will be measured in wild-type mouse cochleae
harvested from P3 mice and grown in medium for 1-4 days at
37.degree. C. The explants will be isolated and grown with the aid
of matrigel (Driver and Kelley (2010) Curr. Protoc. Neurosci.
Chapter 4, Unit 4 34: 31-10). Cisplatin solution will be added in a
final concentration of 50 .mu.M, 1 day after cochleae are placed in
medium. For every compound tested, hair cell death will be compared
under four conditions: growth medium only, 50 .mu.M cisplatin only,
test compound only, and test compound with 50 .mu.M cisplatin. Each
compound will be tested at least three concentrations (IC.sub.10,
IC.sub.50, and IC.sub.90) based on the dose responses in the HEI-
OC1 cell experiments. In addition, each compound's toxicity will be
tested at three or more concentrations (1.times.IC.sub.90,
5.times.IC.sub.90, and 25.times.IC.sub.90). Each compound's
IC.sub.50 (potency of protection) and LD.sub.50 (toxicity) will be
estimated in explants.
[0648] After immunostaining with phalloidin, both outer and inner
hair cells in the cultured cochleae will be counted after each
treatment by confocal microscopy. Co-immunostaining with Myo7a will
further confirm that the phalloidin+cells are viable hair cells.
The live hair cells will be enumerated in two separate 160 .mu.m
long areas in the cochlear apical, middle, and basal regions,
respectively.
[0649] Two-sample two-sided t test will be applied to compare the
percentage of surviving cells between cells treated by
Cisplatin-only (control) vs. cisplatin-plus-compound at a given
concentration. Five cochleae will be tested at each concentration
of each compound, to adjust for the variability in ex-vivo explant
cultures. zVAD-fmk and pifithrin-.alpha. will be used as positive
control at concentrations reported to confer cisplatin protection
in mouse cochlear explants (Atar and Avraham (2010) Neuroscience
168: 851-857; Liu et al. (1998) Neuroreport 9: 2609-2614; Zhang et
al. (2003) Neuroscience 120: 191-205).
[0650] 2. Protection Against Noise- and Blast Injury-Induced
Hearing Loss In Vivo in Adult Mouse Models
[0651] The protective effects of the top 4 compounds, administered
locally (transtympanic injection into the middle ear), will be
tested against NIHL and blast injury-induced hearing loss in adult
mouse models. The local delivery route was chosen for several
reasons. First, it is frequently used in mammalian hearing studies,
as it offers minimal invasiveness and simple procedures. In fact,
drugs are commonly administered via this route by pediatricians and
ENT doctors to patients of diverse ages (Banerjee and Parnes (2005)
Otol. Neurotol. 26: 878-881; Dodson et al. (2004) Ear Nose Throat
83: 394-398; McCall et al. (2010) Ear Hear. 31: 156-165; Muller and
Barr-Gillespie (2015) Nat. Rev. Drug Discov. 14: 346-365; Rauch
(2004) Otolaryngol. Clin. North Am. 37: 1061-1074). If the
compounds work well in murine models when delivered in this manner,
they can be directly tested for prevention of cisplatin-associated
hearing loss in patients undergoing cisplatin chemotherapy in
clinical trials. Second, transtympanic delivery allows the
compounds to diffuse easily across the round window membrane into
the endolymphatic fluid (Borkholder (2008) Curr. Opin. Otolaryngol.
Head Neck Surg. 16: 472-477; Mizutari et al. (2013) Neuron 77:
58-69; Swan et al. (2008) Adv. Drug Deliv. Rev. 60: 1583-1599;
Tamura et al. (2005) Laryngoscope 115: 2000-2005), such that their
potency and toxicity can be directly tested in vivo with little
concern about the blood-labyrinth barrier (BLB). In the future oral
and other routes may be considered for further characterization of
in vivo properties of these compounds (e.g., solubility,
permeability, pharmacokinetics/pharmacodynamics (PK/PD), and
absorption, distribution, metabolism, excretion, and toxicology
(ADMET)).
[0652] The compounds to test in this manner will be chosen on the
basis of the following considerations: (1) they exhibit potent
IC.sub.50 values and minimal toxicity (i.e., high
LD.sub.50/IC.sub.50 values, preferably >50-100 .mu.M); (2) they
target several different biological targets/pathways; and (3) they
can be delivered via other routes (e.g., oral).
[0653] For tests of noise injury, wild-type FVB mice will be used
at age P28, when hearing has matured but long before significant
age-related hearing loss (Kermany et al. (2006) Hear Res. 220:
76-86; Maison et al. (2002) J. Neurosci. 22: 10838-10846; Maison et
al. (2007) J. Neurophysiol. 97: 2930-2936; Zheng et al. (1999)
Hearing Research 130: 94-107). The standard noise exposure
protocols (94, 100, 106, 116, and 120 dB sound pressure level (SPL)
ocaave-band 8-16 kHz noise for 2 hrs) have previously been tested
in various transgenic mouse strains from the FVB background (Maison
et al. (2002) J. Neurosci. 22: 10838-10846; Maison et al. (2007) J.
Neurophysiol. 97: 2930-2936). These noise injury protocols led to
hearing loss (ABR) (see FIG. 6A-D) similar to those previously
reported in CBA/CaJ mice (Wang et al. (2002) J. Assoc. Res.
Otolaryngol. 3: 248-268).
[0654] Repeated impulses at 135-155 dB SPL can effectively
recapitulate the effects of blast injury in adult mouse cochleae.
Previous studies of blast injuries in animal models have
demonstrated that 50-160 repeated impulses at 147-160 dB SPL impose
physiological and morphological damage to the cochleae of
chinchilla, sheep and pigs similar to 3-4 impulses of 14 psi blasts
(194 peak dB SPL) in rats (Choi et al. (2008) Free Radic. Biol.
Med. 44: 1772-1784; Hamernik et al. (1987) J. Acoust. Soc. Am. 81:
1118-1129; Henselman et al. (1994) Hear. Res. 78: 1-10; Kopke et
al. (2005) Acta Otolaryngol. 125: 235-243; Roberto et al. (1989)
Ann. Otol. Rhinol. Laryngol. Suppl. 140: 23-34). More
interestingly, 3-4 impulses of 14 psi blasts caused 43% OHC loss
and 30-40 dB ABR threshold elevation in rats 21 days post- blast,
damage that resembles that caused by 6 hrs of continuous exposure
to 105 dB SPL octave-band noise centered at 4 kHz in chinchillas
(Choi et al. (2008) Free Radic. Biol. Med. 44: 1772-1784; Ewert et
al. (2012) Hear. Res. 285: 29-39; Kopke et al. (2005) Acta
Otolaryngol. 125: 235-243). Based on these results, a range of
135-155 dB SPL octave-band 8-16 kHz noise impulses of 10-ms
duration were chosen, which can be repeated 100 times at 1-s
intervals in mouse models to mimic traumatic blast injury (Choi et
al. (2008) Free Radic. Biol. Med. 44: 1772-1784; Ewert et al.
(2012) Hear. Res. 285: 29-39; Henselman et al. (1994) Hear. Res.
78: 1-10; McFadden et al. (2000) J. Acoust. Soc. Am. 107:
2162-2168).
[0655] FIG. 6A depicts the experimental design. Mice exposed to
noise or blast exposure will be immediately treated with the
individual compounds in one ear and vehicle control (0.5% DMSO) in
the other ear. DMSO or compound will be delivered locally at the
highest feasible dose (which should be much higher than the
IC.sub.50 in cochlear explants but not toxic by itself in vivo) by
trans-tympanic injection into the adult mouse middle ear at
.about.5 .mu.L per ear. The ABR and Distortion Products Otoacoustic
Emissions (DPOAE) will be measured pre-noise exposure or TBI and at
1 and 2 weeks post-injection. After hearing tests by ABR and DPOAE,
the mice will be cardiac-perfused for fixation and harvesting of
the cochleae. The cochleae will be analyzed by using both
whole-mount preparations and sections, and immunofluorescence will
be used to detect HC/SC markers (i.e., phalloidin, Myo7a, Prestin,
and Sox2, etc.) and synaptic markers (Ctbp2, GluR2/3 and Tuj1) (Liu
et al. (2014) PLoS One 9: e89377).
[0656] The entire procedure will be double-blinded: one person will
encode DMSO or compound while the other person will randomly inject
the left and right ears of the same mouse, and the person who
records ABR and DPOAE will not know which ear was injected with
compound until the entire experiment is completed.
[0657] a. ABR/DPOAE Measurements in Adult Mice
[0658] ABR measurements have been previously described in detail
(Dallos et al. (2008) Neuron 58: 333-339; Gao et al. (2007) Mol.
Cell Biol. 27: 4500-4512; Liberman et al. (2002) Nature 419:
300-304; Liu et al. (2014) PLoS One 9: e89377; Wu et al. (2004)
Brain Res. Mol. Brain Res. 126: 30-37; Yamashita et al. (2012) PLoS
One 7: e45453). Briefly, mice will be anesthetized by
intraperitoneal injection of Avertin (0.5 mg/kg body weight) and
placed on an electric heating pad to maintain body temperature,
using a homeothermic blanket system (Harvard Apparatus Ltd). Mice
that die or show signs of middle-ear dysfunction during the course
of the experiment will be excluded from analysis. All recordings
will be conducted in a sound booth (Industrial Acoustic Company).
For acoustic stimulation and measurements two speakers (f1 and f2;
EC1) and a microphone (ER-10B, Etymotic Research, Elk Grove
Village, Ill.) are connected to a short flexible coupler tube with
a tapered plastic tip that is inserted into the external auditory
meatus. The microphone will be calibrated in situ, with the coupler
in the measuring position. At frequencies higher than 22 kHz, the
frequency responses of the measurement microphone (ER10B+) are
lower than those of a reference microphone (ACO-7017; ACO Pacific,
Inc., Belmont, Calif.). Therefore, DPOAE 2f1-f2 responses will be
recorded at a frequency f1 range of 5454-18180 Hz, using the TDT
BioSig III system (TDT). Signal duration is 83.88 ms, with a
repetition rate of 11.92/s. The f1 and f2 responses are passed
separately through an RX6 MultiFunction Processor (TDT) for
digital/analog conversion to PAS programmable attenuators. Stimulus
intensity will be reduced from 90 to 0 dB in 5 dB steps to
establish thresholds and will be digitally sampled at 200 kHz and
averaged from 100 discrete spectra. The signals are delivered
through ED1 speaker drivers that feed into the EC1 electrostatic
speakers coupled to the ear canal. The resulting ear canal sound
pressure will be recorded with an ER10B+low noise microphone (gain
Ox) and probe (Etymotic) housed in the same coupler as the f1 and
f2 speakers. The output of the ER10B+ amplifier is routed directly
to an RX6 MultiFunction Processor (TDT) for analog/digital
conversion for sampling at 200 kHz. Fast-Fourier transforms (FFT)
of averaged responses will be generated by using TDT BioSigRP
software on the resultant waveform (TDT). Noise floors will be
determined by averaging the sound levels of 10 frequency bins above
and below the 2f1-f2 frequency bin. No instrumental distortion
products have been observed in evaluation of ears postmortem.
[0659] b. Noise Injury in Adult Mice
[0660] Mice will be placed individually in a cage within a
custom-made acrylic chamber in which no two sides are parallel. The
sound stimulus will be produced by an RZ6 processor (Tucker-Davis
Technologies, Gainesville Fla.), filtered (Frequency Devices, Inc.,
Haverhill, Mass.), amplified (Crown XTi 1000 amplifier; Crown,
Elkhart, Ind.), and delivered to the acrylic chamber via a speaker
horn (JBL, Northridge, Calif.). The sound pressure level will be
measured through a 1/4-inch freefield microphone (ACO Pacific,
Belmont, Calif.) and calibrated to a 124 dB pistonphone (Bruel and
Kjaer, Denmark). Prior to experimental noise exposure, four
quadrants of the chamber will be sampled with the 1/4-inch
microphone to ensure that sound pressure varies by <0.5 dB
across the measured positions.
[0661] C. Trans-Tympanic Injection of Adult Mice
[0662] Mice will be anesthetized by intraperitoneal (i.p.)
injection of Avertin or ketamine and xylazine. Body temperature is
maintained on a heating pad during the surgical procedure.
Lubricant eye ointment is applied to prevent corneal ulcers, as the
blinking reflex disappears during surgery. The tympanic membrane is
visualized with a surgical stereomicroscope. Using a 33-gauge
cannula, 5 .mu.L of compound or DMSO in PBS is gently injected
through the tympanic membrane, followed by surgical
stereomicroscopic confirmation that the solution is in the middle
ear cavity. Mice are then placed in the cage on the heating pad for
an additional 30 minutes. After surgery, all mice are allowed to
recover on a heating pad before being returned to the animal
housing facility.
K. REFERENCES
[0663] Abaamrane, L., Raffin, F., Gal, M., Avan, P., and Sendowski,
I. (2009). Long-term administration of magnesium after acoustic
trauma caused by gunshot noise in guinea pigs. Hear Res 247,
137-145.
[0664] Abaamrane, L., Raffin, F., Schmerber, S., and Sendowski, I.
(2011). Intracochlear perfusion of leupeptin and z-VAD-FMK:
influence of antiapoptotic agents on gunshot-induced hearing loss.
Eur Arch Otorhinolaryngol 268, 987-993.
[0665] Atar, O., and Avraham, K.B. (2010). Anti-apoptotic factor
z-Val-Ala-Asp-fluoromethylketone promotes the survival of cochlear
hair cells in a mouse model for human deafness. Neuroscience 168,
851-857.
[0666] Attias, J., Weisz, G., Almog, S., Shahar, A., Wiener, M.,
Joachims, Z., Netzer, A., Ising, H., Rebentisch, E., and Guenther,
T. (1994). Oral magnesium intake reduces permanent hearing loss
induced by noise exposure. Am J Otolaryngol 15, 26-32.
[0667] Banerjee, A., and Parnes, L. S. (2005). Intratympanic
corticosteroids for sudden idiopathic sensorineural hearing loss.
Otol Neurotol 26, 878-881.
[0668] Borkholder, D. A. (2008). State-of-the-art mechanisms of
intracochlear drug delivery. Curr Opin Otolaryngol Head Neck Surg
16, 472-477.
[0669] Campbell, K., Claussen, A., Meech, R., Verhulst, S., Fox,
D., and Hughes, L. (2011). D-methionine (D-met) significantly
rescues noise-induced hearing loss: timing studies. Hear Res 282,
138-144.
[0670] Campbell, K. C., Meech, R. P., Klemens, J. J., Gerberi, M.
T., Dyrstad, S. S., Larsen, D. L., Mitchell, D. L., El-Azizi, M.,
Verhulst, S. J., and Hughes, L. F. (2007). Prevention of noise- and
drug-induced hearing loss with D-methionine. Hear Res 226,
92-103.
[0671] Cascella, V., Giordano, P., Hatzopoulos, S., Petruccelli,
J., Prosser, S., Simoni, E., Astolfi, L., Fetoni, A. R.,
Skarzynski, H., and Martini, A. (2012). A new oral otoprotective
agent. Part 1: Electrophysiology data from protection against
noise-induced hearing loss. Med Sci Monit 18, BR1-8.
[0672] Chai, R., Kuo, B., Wang, T., Liaw, E. J., Xia, A., Jan, T.
A., Liu, Z., Taketo, M. M., Oghalai, J. S., Nusse, R., et al.
(2012). Wnt signaling induces proliferation of sensory precursors
in the postnatal mouse cochlea. Proc Natl Acad Sci USA 109,
8167-8172.
[0673] Cheng, P. W., Liu, S. H., Young, Y. H., Hsu, C. J., and
Lin-Shiau, S. Y. (2008). Protection from noise-induced temporary
threshold shift by D-methionine is associated with preservation of
ATPase activities. Ear Hear 29, 65-75.
[0674] Choi, C. H., Chen, K., Vasquez-Weldon, A., Jackson, R. L.,
Floyd, R. A., and Kopke, R. D. (2008). Effectiveness of 4-hydroxy
phenyl N-tert-butylnitrone (4--OHPBN) alone and in combination with
other antioxidant drugs in the treatment of acute acoustic trauma
in chinchilla. Free Radic Biol Med 44, 1772-1784.
[0675] Coffin, A. B., Williamson, K. L., Mamiya, A., Raible, D. W.,
and Rubel, E. W. (2013). Profiling drug-induced cell death pathways
in the zebrafish lateral line. Apoptosis 18, 393-408.
[0676] Dallos, P., Wu, X., Cheatham, M.A., Gao, J., Zheng, J.,
Anderson, C. T., Jia, S., Wang, X., Cheng, W. H., Sengupta, S., et
al. (2008). Prestin-based outer hair cell motility is necessary for
mammalian cochlear amplification. Neuron 58, 333-339.
[0677] Dodson, K. M., Woodson, E., and Sismanis, A. (2004).
Intratympanic steroid perfusion for the treatment of Meniere's
disease: a retrospective study. Ear Nose Throat J 83, 394-398.
[0678] Driver, E. C., and Kelley, M. W. (2010). Transfection of
mouse cochlear explants by electroporation. Curr Protoc Neurosci
Chapter 4, Unit 4 34 31-10.
[0679] Du, X., Ewert, D. L., Cheng, W., West, M. B., Lu, J., Li,
W., Floyd, R. A., and Kopke, R. D. (2013). Effects of antioxidant
treatment on blast-induced brain injury. PLoS One 8, e80138.
[0680] Ewert, D. L., Lu, J., Li, W., Du, X., Floyd, R., and Kopke,
R. (2012). Antioxidant treatment reduces blast- induced cochlear
damage and hearing loss. Hear Res 285, 29-39.
[0681] Fang, J., Zhang, W. C., Yamashita, T., Gao, J., Zhu, M. S.,
and Zuo, J. (2012). Outer hair cell-specific prestin- CreERT2
knockin mouse lines. Genesis 50, 124-131.
[0682] Forge, A., and Van De Water, T. R. (2008). Protection and
repair of inner ear sensory cells. In Hair cell regeneration,
repair, and protection, R. J. Salvi, A. N. Popper, and R. R. Fay,
eds (New York: Springer Science), pp. 199-256.
[0683] Gao, J., Maison, S.F., Wu, X., Hirose, K., Jones, S. M.,
Bayazitov, I., Tian, Y., Mittleman, G., Matthews, D. B.,
Zakharenko, S. S., et al. (2007). Orphan glutamate receptor deltal
subunit required for high- frequency hearing. Mol Cell Biol 27,
4500-4512.
[0684] Giono, L. E., and Manfredi, J. J. (2007). Mdm2 is required
for inhibition of Cdk2 activity by p21, thereby contributing to
p53-dependent cell cycle arrest. Mol Cell Biol 27, 4166-4178.
[0685] Hamernik, R. P., Patterson, J. H., and Salvi, R. J. (1987).
The effect of impulse intensity and the number of impulses on
hearing and cochlear pathology in the chinchilla. J Acoust Soc Am
81, 1118-1129.
[0686] Henselman, L. W., Henderson, D., Subramaniam, M., and
Sallustio, V. (1994). The effect of `conditioning` exposures on
hearing loss from impulse noise. Hear Res 78, 1-10.
[0687] Huang, H., Regan, K. M., Lou, Z., Chen, J., and Tindall, D.
J. (2006). CDK2-dependent phosphorylation of FOXO1 as an apoptotic
response to DNA damage. Science 314, 294-297.
[0688] Ising, H., Handrock, M., Gunther, T., Fischer, R., and
Dombrowski, M. (1982). Increased noise trauma in guinea pigs
through magnesium deficiency. Arch Otorhinolaryngol 236,
139-146.
[0689] Joachims, Z., Babisch, W., Ising, H., Gunther, T., and
Handrock, M. (1983). Dependence of noise-induced hearing loss upon
perilymph magnesium concentration. J Acoust Soc Am 74, 104-108.
[0690] Joachims, Z., Netzer, A., Ising, H., Rebentisch, E., Attias,
J., Weisz, G., and Gunther, T. (1993). Oral magnesium
supplementation as prophylaxis for noise-induced hearing loss:
results of a double blind field study. Schriftenr Ver Wasser Boden
Lufthyg 88, 503-516.
[0691] Kalinec, G. M., Webster, P., Lim, D. J., and Kalinec, F.
(2003). A cochlear cell line as an in vitro system for drug
ototoxicity screening. Audiol Neurootol 8, 177-189.
[0692] Kermany, M. H., Parker, L. L., Guo, Y. K., Miller, D.,
Swanson, D. J., Yoo, T. J., Goldowitz, D., and Zuo, J. (2006).
Identification of 17 hearing impaired mouse strains in the TMGC
ENU-mutagenesis screen. Hear Res 220, 76-86.
[0693] Kim, H. J., Lee, J. H., Kim, S. J., Oh, G. S., Moon, H. D.,
Kwon, K. B., Park, C., Park, B. H., Lee, H. K., Chung, S. Y., et
al. (2010). Roles of NADPH oxidases in cisplatin-induced reactive
oxygen species generation and ototoxicity. J Neurosci 30,
3933-3946.
[0694] Kim, S. J., Lim, J. Y., Lee, J. N., Choe, S. K., Kim, Y. I.,
Song, S. R., Cho, M., So, H. S., and Park, R. (2014). Activation of
beta-catenin by inhibitors of glycogen synthase kinase-3
ameliorates cisplatin-induced cytotoxicity and pro-inflammatory
cytokine expression in HEI--OC1 cells. Toxicology 320, 74-82.
[0695] Kopke, R., Bielefeld, E., Liu, J., Zheng, J., Jackson, R.,
Henderson, D., and Coleman, J. K. (2005). Prevention of impulse
noise-induced hearing loss with antioxidants. Acta Otolaryngol 125,
235-243.
[0696] Kopke, R. D., Jackson, R. L., Coleman, J. K., Liu, J.,
Bielefeld, E. C., and Balough, B. J. (2007). NAC for noise: from
the bench top to the clinic. Hear Res 226, 114-125.
[0697] Latchoumycandane, C., Goh, C. W., Ong, M. M., and
Boelsterli, U. A. (2007). Mitochondrial protection by the JNK
inhibitor leflunomide rescues mice from acetaminophen-induced liver
injury. Hepatology 45, 412-421.
[0698] Le Prell, C. G., Dolan, D. F., Bennett, D. C., and Boxer, P.
A. (2011a). Nutrient plasma levels achieved during treatment that
reduces noise-induced hearing loss. Transl Res 158, 54-70.
[0699] Le Prell, C. G., Gagnon, P. M., Bennett, D. C., and
Ohlemiller, K. K. (2011b). Nutrient-enhanced diet reduces
noise-induced damage to the inner ear and hearing loss. Transl Res
158, 38-53.
[0700] Le Prell, C. G., Hughes, L. F., and Miller, J. M. (2007a).
Free radical scavengers vitamins A, C, and E plus magnesium reduce
noise trauma. Free Radic Biol Med 42, 1454-1463.
[0701] Le Prell, C. G., Yamashita, D., Minami, S. B., Yamasoba, T.,
and Miller, J. M. (2007b). Mechanisms of noise- induced hearing
loss indicate multiple methods of prevention. Hear Res 226,
22-43.
[0702] Li, E. K., Tam, L. S., and Tomlinson, B. (2004). Leflunomide
in the treatment of rheumatoid arthritis. Clin Ther 26,
447-459.
[0703] Li, J., Liu, H., Yao, X., Liu, M., Hu, Z., and Fan, B.
(2007). Structure-activity relationship study of oxindole- based
inhibitors of cyclin-dependent kinases based on least-squares
support vector machines. Anal Chim Acta 581, 333-342.
[0704] Liberman, M. C., Gao, J., He, D. Z., Wu, X., Jia, S., and
Zuo, J. (2002). Prestin is required for electromotility of the
outer hair cell and for the cochlear amplifier. Nature 419,
300-304.
[0705] Lin, Y., Kashio, A., Sakamoto, T., Suzukawa, K., Kakigi, A.,
and Yamasoba, T. (2011). Hydrogen in drinking water attenuates
noise-induced hearing loss in guinea pigs. Neurosci Lett 487,
12-16.
[0706] Liu, W., Staecker, H., Stupak, H., Malgrange, B., Lefebvre,
P., and Van De Water, T. R. (1998). Caspase inhibitors prevent
cisplatin-induced apoptosis of auditory sensory cells. Neuroreport
9, 2609-2614.
[0707] Liu, Z., Fang, J., Dearman, J., Zhang, L., and Zuo, J.
(2014). In vivo generation of immature inner hair cells in neonatal
mouse cochleae by ectopic Atohl expression. PLoS One 9, e89377.
[0708] Luk, K. C., Simcox, M. E., Schutt, A., Rowan, K., Thompson,
T., Chen, Y., Kammlott, U., DePinto, W., Dunten, P., and
Dermatakis, A. (2004). A new series of potent oxindole inhibitors
of CDK2. Bioorg Med Chem Lett 14, 913-917.
[0709] Lynch, E. D., Gu, R., Pierce, C., and Kil, J. (2004).
Ebselen-mediated protection from single and repeated noise exposure
in rat. Laryngoscope 114, 333-337.
[0710] Lynch, E. D., and Kil, J. (2005). Compounds for the
prevention and treatment of noise-induced hearing loss. Drug Discov
Today 10, 1291-1298.
[0711] Maison, S. F., Luebke, A. E., Liberman, M. C., and Zuo, J.
(2002). Efferent protection from acoustic injury is mediated via
alpha9 nicotinic acetylcholine receptors on outer hair cells. J
Neurosci 22, 10838-10846.
[0712] Maison, S. F., Parker, L. L., Young, L., Adelman, J. P.,
Zuo, J., and Liberman, M. C. (2007). Overexpression of SK2 channels
enhances efferent suppression of cochlear responses without
enhancing noise resistance. J Neurophysiol 97, 2930-2936.
[0713] Marazita, M. C., Ogara, M. F., Sonzogni, S. V., Marti, M.,
Dusetti, N. J., Pignataro, O. P., and Canepa, E. T. (2012). CDK2
and PKA mediated-sequential phosphorylation is critical for
p19INK4d function in the DNA damage response. PLoS One 7,
e35638.
[0714] McCall, A. A., Swan, E. E., Borenstein, J. T., Sewell, W.F.,
Kujawa, S. G., and McKenna, M. J. (2010). Drug delivery for
treatment of inner ear disease: current state of knowledge. Ear
Hear 31, 156-165.
[0715] McFadden, S. L., Zheng, X. Y., and Ding, D. L. (2000).
Conditioning-induced protection from impulse noise in female and
male chinchillas. J Acoust Soc Am 107, 2162-2168.
[0716] Meltser, I., Tahera, Y., and Canlon, B. (2010). Differential
activation of mitogen-activated protein kinases and brain-derived
neurotrophic factor after temporary or permanent damage to a
sensory system. Neuroscience 165, 1439-1446.
[0717] Mizutari, K., Fujioka, M., Hosoya, M., Bramhall, N., Okano,
H. J., Okano, H., and Edge, A. S. (2013). Notch inhibition induces
cochlear hair cell regeneration and recovery of hearing after
acoustic trauma. Neuron 77, 58-69.
[0718] Mukherjea, D., Rybak, L. P., Sheehan, K. E., Kaur, T.,
Ramkumar, V., Jajoo, S., and Sheth, S. (2011). The design and
screening of drugs to prevent acquired sensorineural hearing loss.
Expert Opin Drug Discov 6, 491-505.
[0719] Muller, U., and Barr-Gillespie, P. G. (2015). New treatment
options for hearing loss. Nat Rev Drug Discov. Oishi, N., and
Schacht, J. (2011). Emerging treatments for noise-induced hearing
loss. Expert Opin Emerg Drugs 16, 235-245.
[0720] Ou, H. C., Raible, D. W., and Rubel, E. W. (2007).
Cisplatin-induced hair cell loss in zebrafish (Danio rerio) lateral
line. Hear Res 233, 46-53.
[0721] Ou, H. C., Santos, F., Raible, D. W., Simon, J. A., and
Rubel, E. W. (2010). Drug screening for hearing loss: using the
zebrafish lateral line to screen for drugs that prevent and cause
hearing loss. Drug Discov Today 15, 265-271.
[0722] Owens, K. N., Coffin, A. B., Hong, L. S., Bennett, K. O.,
Rubel, E. W., and Raible, D. W. (2009). Response of mechanosensory
hair cells of the zebrafish lateral line to aminoglycosides reveals
distinct cell death pathways. Hear Res 253, 32-41.
[0723] Pourbakht, A., and Yamasoba, T. (2003). Ebselen attenuates
cochlear damage caused by acoustic trauma. Hear Res 181,
100-108.
[0724] Price, P. M., Yu, F., Kaldis, P., Aleem, E., Nowak, G.,
Safirstein, R. L., and Megyesi, J. (2006). Dependence of
cisplatin-induced cell death in vitro and in vivo on
cyclin-dependent kinase 2. J Am Soc Nephrol 17, 2434-2442.
[0725] Rauch, S. D. (2004). Intratympanic steroids for
sensorineural hearing loss. Otolaryngol Clin North Am 37,
1061-1074.
[0726] Roberto, M., Hamernik, R. P., and Turrentine, G. A. (1989).
Damage of the auditory system associated with acute blast trauma.
Ann Otol Rhinol Laryngol Suppl 140, 23-34.
[0727] Rohrmeier, C., Koemm, N., Babilas, P., Prahs, P., Strutz,
J., and Buettner, R. (2013). Sudden sensorineural hearing loss:
systemic steroid therapy and the risk of glucocorticoid-induced
hyperglycemia. Eur Arch Otorhinolaryngol 270, 1255-1261.
[0728] Rybak, L. P., and Ramkumar, V. (2007). Ototoxicity. Kidney
Int 72, 931-935.
[0729] Samson, J., Wiktorek-Smagur, A., Politanski, P., Rajkowska,
E., Pawlaczyk-Luszczynska, M., Dudarewicz, A., Sha, S. H., Schacht,
J., and Sliwinska-Kowalska, M. (2008). Noise-induced time-dependent
changes in oxidative stress in the mouse cochlea and attenuation by
D-methionine. Neuroscience 152, 146-150.
[0730] Satyanarayana, A., and Kaldis, P. (2009). A dual role of
Cdk2 in DNA damage response. Cell Div 4, 9.
[0731] Schacht, J., Talaska, A. E., and Rybak, L. P. (2012).
Cisplatin and aminoglycoside antibiotics: hearing loss and its
prevention. Anat Rec (Hoboken) 295, 1837-1850.
[0732] Shelat, A. A., and Guy, R. K. (2007). Scaffold composition
and biological relevance of screening libraries. Nat Chem Biol 3,
442-446.
[0733] Shim, H. J., Kang, H. H., Ahn, J. H., and Chung, J. W.
(2009). Retinoic acid applied after noise exposure can recover the
noise-induced hearing loss in mice. Acta Otolaryngol 129,
233-238.
[0734] Shutes, A., Onesto, C., Picard, V., Leblond, B.,
Schweighoffer, F., and Der, C. J. (2007). Specificity and mechanism
of action of EHT 1864, a novel small molecule inhibitor of Rac
family small GTPases. J Biol Chem 282, 35666-35678.
[0735] Suckfuell, M., Canis, M., Strieth, S., Scherer, H., and
Haisch, A. (2007). Intratympanic treatment of acute acoustic trauma
with a cell-permeable JNK ligand: a prospective randomized phase
I/II study. Acta Otolaryngol 127, 938-942.
[0736] Swan, E. E., Mescher, M. J., Sewell, W. F., Tao, S. L., and
Borenstein, J. T. (2008). Inner ear drug delivery for auditory
applications. Adv Drug Deliv Rev 60, 1583-1599.
[0737] Tamura, T., Kita, T., Nakagawa, T., Endo, T., Kim, T. S.,
Ishihara, T., Mizushima, Y., Higaki, M., and Ito, J. (2005). Drug
delivery to the cochlea using PLGA nanoparticles. Laryngoscope 115,
2000-2005.
[0738] Thomas Dickey, D., Muldoon, L. L., Kraemer, D. F., and
Neuwelt, E. A. (2004). Protection against cisplatin- induced
ototoxicity by N-acetylcysteine in a rat model. Hear Res 193,
25-30.
[0739] Thorne, C. A., Wichaidit, C., Coster, A. D., Posner, B. A.,
Wu, L. F., and Altschuler, S. J. (2015). GSK-3 modulates cellular
responses to a broad spectrum of kinase inhibitors. Nat Chem Biol
11, 58-63.
[0740] Tieu, C., and Campbell, K. C. (2013). Current pharmacologic
otoprotective agents in or approaching clinical trials: how they
elucidate mechanisms of noise-induced hearing loss. Otolaryngology
3, 130.
[0741] Uemaetomari, I., Tabuchi, K., Hoshino, T., and Hara, A.
(2005). Protective effect of calcineurin inhibitors on acoustic
injury of the cochlea. Hear Res 209, 86-90.
[0742] Vlasits, A. L., Simon, J. A., Raible, D. W., Rubel, E. W.,
and Owens, K. N. (2012). Screen of FDA-approved drug library
reveals compounds that protect hair cells from aminoglycosides and
cisplatin. Hear Res 294, 153-165.
[0743] Vu, A. A., Nadaraja, G. S., Huth, M. E., Luk, L., Kim, J.,
Chai, R., Ricci, A. J., and Cheng, A. G. (2013). Integrity and
regeneration of mechanotransduction machinery regulate
aminoglycoside entry and sensory cell death. PLoS One 8,
e54794.
[0744] Wang, B., Liu, Y., Chi, F., Zhang, Y., Yang, M., and Zhu, X.
(2013). Dexamethasone suppresses cochlear Hes1 expression after
noise exposure. Acta Otolaryngol 133, 233-238.
[0745] Wang, Y., Hirose, K., and Liberman, M. C. (2002). Dynamics
of noise-induced cellular injury and repair in the mouse cochlea. J
Assoc Res Otolaryngol 3, 248-268.
[0746] Wu, X., Gao, J., Guo, Y., and Zuo, J. (2004). Hearing
threshold elevation precedes hair-cell loss in prestin knockout
mice. Brain Res Mol Brain Res 126, 30-37.
[0747] Yamashita, T., Fang, J., Gao, J., Yu, Y., Lagarde, M. M.,
and Zuo, J. (2012). Normal hearing sensitivity at low- to-middle
frequencies with 34% prestin-charge density. PLoS One 7,
e45453.
[0748] Yamasoba, T., Pourbakht, A., Sakamoto, T., and Suzuki, M.
(2005). Ebselen prevents noise-induced excitotoxicity and temporary
threshold shift. Neurosci Lett 380, 234-238.
[0749] Yang, H., Gan, J., Xie, X., Deng, M., Feng, L., Chen, X.,
Gao, Z., and Gan, L. (2010). Gfil-Cre knock-in mouse line: A tool
for inner ear hair cell-specific gene deletion. Genesis 48,
400-406.
[0750] Yang, Y. M., Gupta, S. K., Kim, K. J., Powers, B. E.,
Cerqueira, A., Wainger, B. J., Ngo, H. D., Rosowski, K. A., Schein,
P. A., Ackeifi, C. A., et al. (2013). A small molecule screen in
stem-cell-derived motor neurons identifies a kinase inhibitor as a
candidate therapeutic for ALS. Cell Stem Cell 12, 713-726.
[0751] Zaharevitz, D. W., Gussio, R., Leost, M., Senderowicz, A.
M., Lahusen, T., Kunick, C., Meijer, L., and Sausville, E. A.
(1999). Discovery and initial characterization of the paullones, a
novel class of small- molecule inhibitors of cyclin-dependent
kinases. Cancer Res 59, 2566-2569.
[0752] Zhang, M., Liu, W., Ding, D., and Salvi, R. (2003).
Pifithrin-alpha suppresses p53 and protects cochlear and vestibular
hair cells from cisplatin-induced apoptosis. Neuroscience 120,
191-205.
[0753] Zheng, Q. Y., Johnson, K. R., and Erway, L. C. (1999).
Assessment of hearing in 80 inbred strains of mice by ABR threshold
analyses. Hearing Research 130, 94-107.
[0754] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
embodiments of the invention will be apparent to those skilled in
the art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the invention being indicated by the following
claims.
* * * * *
References