U.S. patent application number 13/171652 was filed with the patent office on 2012-08-02 for modulators of muscarinic receptors.
This patent application is currently assigned to Vertex Pharmaceuticals Incorporated. Invention is credited to Robert Davies, Jingwang Xu.
Application Number | 20120196857 13/171652 |
Document ID | / |
Family ID | 38459571 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120196857 |
Kind Code |
A9 |
Davies; Robert ; et
al. |
August 2, 2012 |
Modulators of Muscarinic Receptors
Abstract
The present invention relates to modulators of muscarinic
receptors. The present invention also provides compositions
comprising such modulators, and methods therewith for treating
muscarinic receptor mediated diseases.
Inventors: |
Davies; Robert; (Watertown,
MA) ; Xu; Jingwang; (Framingham, MA) |
Assignee: |
Vertex Pharmaceuticals
Incorporated
Cambridge
MA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20120004226 A1 |
January 5, 2012 |
|
|
Family ID: |
38459571 |
Appl. No.: |
13/171652 |
Filed: |
June 29, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11709662 |
Feb 22, 2007 |
8003660 |
|
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13171652 |
|
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60775813 |
Feb 22, 2006 |
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Current U.S.
Class: |
514/235.5 ;
514/278 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
29/00 20180101; A61K 31/4545 20130101; A61P 17/02 20180101; C07D
221/20 20130101; A61K 31/55 20130101; A61P 43/00 20180101; C07D
417/12 20130101; A61P 27/06 20180101; A61P 25/28 20180101; A61P
25/00 20180101; A61P 25/02 20180101; A61P 25/14 20180101; A61P
25/04 20180101; A61P 25/16 20180101; A61P 27/02 20180101; A61K
31/438 20130101; C07D 405/12 20130101; A61P 1/14 20180101; A61P
9/00 20180101; C07D 401/12 20130101; A61P 3/04 20180101; A61K
31/444 20130101; A61P 25/24 20180101; A61P 11/06 20180101; A61P
25/18 20180101 |
Class at
Publication: |
514/235.5 ;
514/278 |
International
Class: |
A61K 31/438 20060101
A61K031/438; A61P 25/00 20060101 A61P025/00; A61P 3/04 20060101
A61P003/04; A61P 25/28 20060101 A61P025/28; A61P 27/02 20060101
A61P027/02; A61P 25/16 20060101 A61P025/16; A61P 11/06 20060101
A61P011/06; A61P 17/02 20060101 A61P017/02; A61P 29/00 20060101
A61P029/00; A61K 31/5377 20060101 A61K031/5377; A61P 25/18 20060101
A61P025/18 |
Claims
1-59. (canceled)
60. A method of modulating the activity of a muscarinic receptor
comprising the step of contacting said receptor with a compound of
formula Ie: ##STR00318## or a pharmaceutically acceptable salt
thereof, wherein: R.sub.1 is a branched or straight C.sub.1-12
aliphatic optionally substituted with 1-3 of R.sup.A, wherein up to
3 carbon units of R.sub.1 are optionally and independently replaced
by --CONR.sup.F--, --O--, --NR.sup.FCO--, or --S--; Each R.sup.A is
halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3; Each
R.sup.F is hydrogen, or a branched or straight C.sub.1-8 aliphatic
group optionally substituted with 1-3 of R.sup.A; R.sub.2a is
--Z.sup.BR.sub.5, wherein each Z.sup.B is independently a bond or
an optionally substituted branched or straight C.sub.1-4 aliphatic
chain wherein up to two carbon units of Z.sup.B are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; Each R.sub.5
is independently R.sup.B, halo, --OH, --CN, or --OCF.sub.3; Each
R.sup.B is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, an optionally substituted heteroaryl,
or R.sub.2a and R.sub.3 together with the atoms to which they are
attached form a 5-7 membered partially unsaturated optionally
substituted cyclic group optionally having 1-2 heteroatoms
independently selected from N, O, and S; Each R.sub.2b is hydrogen,
fluoro or methyl; or R.sub.2a and one R.sub.2b together with the
atoms to which they are attached form a 5-7 membered partially
unsaturated optionally substituted cyclic group optionally having
1-2 heteroatoms independently selected from N, O, and S, wherein
R.sub.2b is attached to a carbon atom vicinal to the carbon atom to
which R.sub.2a is attached on the fused phenyl of formula I, or Two
of R.sub.2b together with the atoms to which they are attached form
a 5-7 membered partially unsaturated optionally substituted cyclic
group optionally having 1-2 heteroatoms independently selected from
N, O, and S, wherein each R.sub.2b is attached to a vicinal carbon
atom on the fused phenyl of formula Ie; one of R.sub.3 and R'.sub.3
is hydrogen and the other of R.sub.3 and R'.sub.3 is independently
--Z.sup.CR.sub.6, wherein each Z.sup.C is independently an
optionally substituted branched or straight C.sub.1-4 aliphatic
chain wherein up to two carbon units of Z.sup.C are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.C--,
--CONR.sup.CNR.sup.C--, --CO.sub.2--, --OCO--,
--NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--SO--, --SO.sub.2--, --SO.sub.2NR.sup.C--, --NR.sup.CSO.sub.2--,
or --NR.sup.CSO.sub.2NR.sup.C--; Each R.sub.6 is independently
R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3;
Each R.sup.C is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group; an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl having 1-3 heteroatoms; R.sub.4 and R'.sub.4 are each
independently hydrogen or fluoro; m is 2, p is 2; n is 0-2; and q
is 0-3;
61. The method of claim 60, wherein R.sub.1 is a straight
C.sub.1-10 alkyl, straight C.sub.2-10 alkenyl, straight C.sub.2-10
alkynyl, branched C.sub.3-12 alkyl, branched C.sub.3-12 alkenyl, or
branched C.sub.3-12 alkynyl, each of which is optionally
substituted with 1-3 of R.sup.A; and each R.sup.A is independently
halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3.
62. The method of claim 60, wherein R.sub.1 is an optionally
substituted straight or branched C.sub.1-12 aliphatic wherein 1-2
of the carbon units have been optionally replaced with --S--.
63. The method of claim 60, wherein R.sub.1 is one selected from:
##STR00319## ##STR00320## ##STR00321## ##STR00322##
64. The method of claim 60, wherein q is 0 and R.sub.2a is
hydrogen.
65. The method of claim 60, wherein one of R.sub.3 and R'.sub.3 is
a branched or straight optionally substituted C.sub.1-4 aliphatic
wherein up to two carbon units of R.sub.3 or R'.sub.3 are
optionally and independently replaced by --C(O)--, --CONH--, or
--S(O).sub.2--, and the remaining R.sub.3 or R'.sub.3 is
hydrogen.
66. The method of claim 65, wherein one of R.sub.3 and R'.sub.3 is
straight optionally substituted C.sub.2-4 aliphatic wherein a first
carbon unit is optionally and independently replaced by
--CONH--.
67. The method of claim 66, wherein one of R.sub.3 and R'.sub.3 is
an optionally substituted (methylcarbonyl)amino, and the remaining
R.sub.3 or R'.sub.3 is hydrogen.
68. The method of claim 60, wherein R.sub.3 or R'.sub.3 is
independently selected from: ##STR00323## ##STR00324## ##STR00325##
##STR00326## ##STR00327## ##STR00328## ##STR00329##
##STR00330##
69. A method of modulating the activity of a muscarinic receptor
comprising the step of contacting said receptor with a compound
selected from the group consisting of: ##STR00331## ##STR00332##
##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337##
##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342##
##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347##
##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352##
##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357##
##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362##
##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367##
##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372##
##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377##
##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382##
##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387##
##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392##
##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397##
##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402##
##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407##
##STR00408## ##STR00409## ##STR00410## ##STR00411## ##STR00412##
##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417##
##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422##
##STR00423##
70. A method of modulating the activity of a muscarinic receptor
comprising the step of contacting said receptor with a compound
selected from the group consisting of: ##STR00424## ##STR00425##
##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430##
##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435##
##STR00436## ##STR00437## ##STR00438## ##STR00439##
71. A method of treating or reducing the severity of a muscarinic
receptor mediated disease in a mammal, comprising the step of
administering to said mammal a compound as described in claim
60.
72. The method according to claim 71, wherein said muscarinic
receptor is M.sub.4.
73. The method according to claim 71, wherein said muscarinic
receptor is M.sub.1.
74. A method of treating or reducing the severity of a disease in a
patient, wherein said disease is selected from CNS derived
pathologies including cognitive disorders, Attention Deficit
Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease,
various dementias such as vascular dementia, psychosis associated
with CNS disorders including schizophrenia, mania, bipolar
disorders, pain conditions including acute and chronic syndromes,
Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's
Syndrome, Downs Syndrome, Pick disease, clinical depression,
Parkinson's disease, peripheral disorders such as reduction of
intra ocular pressure in Glaucoma and treatment of dry eyes and dry
mouth including Sjogren's Syndrome, bradhycardia, gastric acid
secretion, asthma, GI disturbances, and wound healing, wherein said
method comprises the step of contacting said patient with a
compound as described in claim 60.
Description
CLAIM OF PRIORITY
[0001] This application is a divisional application which claims
priority under 35 U.S.C. .sctn.121 to U.S. application Ser. No.
11/709,662, filed on Feb. 22, 2007, which claims priority to U.S.
Provisional Application Ser. No. 60/775,813, filed on Feb. 22,
2006. Both applications are hereby incorporated by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to modulators of muscarinic
receptors. The present invention also provides compositions
comprising such modulators, and methods therewith for treating
muscarinic receptor mediated diseases.
BACKGROUND OF THE INVENTION
[0003] The neurotransmitter acetylcholine binds to two types of
cholinergic receptors: the ionotropic family of nicotinic receptors
and the metabotropic family of muscarinic receptors. Muscarinic
receptors belong to the large superfamily of plasma membrane-bound
G protein coupled receptors (GPCRs). To date, five subtypes of
muscarinic receptors (M.sub.1-M.sub.5) have been cloned and
sequenced from a variety of species, and show a remarkably high
degree of homology across species and receptor subtype. These
M.sub.1-M.sub.5 muscarinic receptors are predominantly expressed
within the parasympathetic nervous system which exerts excitatory
and inhibitory control over the central and peripheral tissues and
participate in a number of physiologic functions, including heart
rate, arousal, cognition, sensory processing, and motor
control.
[0004] Muscarinic agonists such as muscarine and pilocarpine, and
antagonists, such as atropine have been known for over a century,
but little progress has been made in the discovery of receptor
subtype-selective compounds, thereby making it difficult to assign
specific functions to the individual receptors. See, e.g., DeLapp,
N. et al., "Therapeutic Opportunities for Muscarinic Receptors in
the Central Nervous System," J. Med. Chem., 43(23), pp. 4333-4353
(2000); Hulme, E. C. et al., "Muscarinic Receptor Subtypes," Ann.
Rev. Pharmacol. Toxicol., 30, pp. 633-673 (1990); Caulfield, M. P.
et al., "Muscarinic Receptors--Characterization, Coupling, and
Function," Pharmacol. Ther., 58, pp. 319-379 (1993); Caulfield, M.
P. et al., International Union of Pharmacology. XVII.
Classification of Muscarinic Acetylcholine Receptors," Pharmacol.
Rev., 50, pp. 279-290 (1998), the disclosures of which are
incorporated herein by reference.
[0005] The Muscarinic family of receptors is the target of a large
number of pharmacological agents used for various diseases,
including leading drugs for COPD, asthma, urinary incontinence,
glaucoma, Alzheimer's (AchE inhibitors). Despite the large
therapeutic value of this family, cholinergic drugs are limited by
the lack of selectivity of these agents, with significant
activation of the parasympathetic autonomous system and elevated
incidence of adverse effects. The molecular cloning of the
muscarinic receptors and the identification of the physiological
role of specific isoforms using knock-out mice, has recently
delineated novel opportunities for selective muscarinic ligands,
and has helped to define the selectivity profile that is required
for enhanced efficacy and reduced side effects.
[0006] There is a need for modulators of muscarinic receptors
M.sub.1-M.sub.5. There is also a need for methods for treating
muscarinic receptor-mediated diseases.
[0007] There is also a need for modulators of muscarinic receptors
that are selective as to subtypes M.sub.1-M.sub.5.
SUMMARY OF THE INVENTION
[0008] The present invention provides methods of modulating the
activity of a muscarinic receptor (e.g., M.sub.1, M.sub.2, M.sub.3,
M.sub.4, M.sub.5, or combinations thereof) using compounds of
formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2a, R.sub.2bR.sub.3, R'.sub.3, R.sub.4, R'.sub.4, n, m, p,
and q are described below.
[0009] Another aspect of the present invention provides methods of
treating or reducing the severity of a muscarinic receptor mediated
disease in a mammal, comprising the step of administering to said
mammal a compound as described above. In several embodiments, the
muscarinic receptor is M.sub.4. In others, the muscarinic receptor
is M.sub.1.
[0010] Another aspect of the present invention provides methods of
treating or reducing the severity of a disease in a patient,
wherein said disease is selected from CNS derived pathologies
including cognitive disorders, Attention Deficit Hyperactivity
Disorder (ADHD), obesity, Alzheimer's disease, various dementias
such as vascular dementia, psychosis associated with CNS disorders
including schizophrenia, mania, bipolar disorders, pain conditions
including acute and chronic syndromes, Huntington's Chorea,
Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs
Syndrome, Pick disease, clinical depression, Parkinson's disease,
peripheral disorders such as reduction of intra ocular pressure in
Glaucoma and treatment of dry eyes and dry mouth including
Sjogren's Syndrome, bradhycardia, gastric acid secretion, asthma,
GI disturbances, and wound healing, wherein said method comprises
the step of contacting said patient with a compound as described
above.
[0011] Another aspect of the present invention provides
pharmaceutical compositions comprising a compound described above
and a pharmaceutical carrier.
DETAILED DESCRIPTION
I. Definitions
[0012] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed.
Additionally, general principles of organic chemistry are described
in "Organic Chemistry", Thomas Sorrell, University Science Books,
Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed.,
Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York:
2001, the entire contents of which are hereby incorporated by
reference.
[0013] The term "muscarinic receptor," without a prefix specifying
the receptor subtype, refers to one or more of the five receptor
subtypes M.sub.1-M.sub.5.
[0014] The term "modulating" as used herein means increasing or
decreasing, e.g. activity, by a measurable amount. Compounds that
modulate muscarinic activity by increasing the activity of the
muscarinic receptors are called agonists. Compounds that modulate
muscarinic activity by decreasing the activity of the muscarinic
receptors are called antagonists. An agonist interacts with a
muscarinic receptor to increase the ability of the receptor to
transduce an intracellular signal in response to endogenous ligand
binding. An antagonist interacts with a muscarinic receptor and
competes with the endogenous ligand(s) or substrate(s) for binding
site(s) on the receptor to decrease the ability of the receptor to
transduce an intracellular signal in response to endogenous ligand
binding.
[0015] The phrase "treating or reducing the severity of a
muscarinic receptor mediated disease" refers both to treatments for
diseases that are directly caused by muscarinic activities and
alleviation of symptoms of diseases not directly caused by
muscarinic activities. Examples of diseases whose symptoms may be
affected by muscarinic activity include, but are not limited to,
CNS derived pathologies including cognitive disorders, Attention
Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's
disease, various dementias such as vascular dementia, psychosis
including schizophrenia, mania, bipolar disorders, pain conditions
including acute and chronic syndromes, Huntington's Chorea,
Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs
Syndrome, Pick disease, clinical depression, Parkinson's disease,
peripheral disorders such as `reduction of intra ocular pressure in
Glaucoma and treatment of dry eyes and dry mouth including
Sjogren's Syndrome, bradhycardia, gastric acid secretion, asthma,
GI disturbances and wound healing.
[0016] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention.
[0017] As used herein the term "aliphatic" encompasses the terms
alkyl, alkenyl, alkynyl, each of which being optionally substituted
as set forth below.
[0018] As used herein, an "alkyl" group refers to a saturated
aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4)
carbon atoms. An alkyl group can be straight or branched. Examples
of alkyl groups include, but are not limited to, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be
substituted (i.e., optionally substituted) with one or more
substituents such as halo; cycloaliphatic [e.g., cycloalkyl or
cycloalkenyl]; heterocycloaliphatic [e.g., heterocycloalkyl or
heterocycloalkenyl]; aryl; heteroaryl; alkoxy; aroyl; heteroaroyl;
acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or
(heterocycloaliphatic)carbonyl]; nitro; cyano; amido [e.g.,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
arylaminocarbonyl, or heteroarylaminocarbonyl]; amino [e.g.,
aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino];
sulfonyl [e.g., aliphatic-S(O).sub.2--]; sulfinyl; sulfanyl;
sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo; carboxy;
carbamoyl; cycloaliphaticoxy; heterocycloaliphaticoxy; aryloxy;
heteroaryloxy; aralkyloxy; heteroarylalkoxy; alkoxycarbonyl;
alkylcarbonyloxy; or hydroxy. Without limitation, some examples of
substituted alkyls include carboxyalkyl (such as HOOC-alkyl,
alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl); cyanoalkyl;
hydroxyalkyl; alkoxyalkyl; acylalkyl; aralkyl; (alkoxyaryl)alkyl;
(sulfonylamino)alkyl (such as alkyl-S(O).sub.2-aminoalkyl);
aminoalkyl; amidoalkyl; (cycloaliphatic)alkyl; or haloalkyl.
[0019] As used herein, an "alkenyl" group refers to an aliphatic
carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and
at least one double bond. Like an alkyl group, an alkenyl group can
be straight or branched. Examples of an alkenyl group include, but
are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An
alkenyl group can be optionally substituted with one or more
substituents such as halo; cycloaliphatic [e.g., cycloalkyl or
cycloalkenyl]; heterocycloaliphatic [e.g., heterocycloalkyl or
heterocycloalkenyl]; aryl; heteroaryl; alkoxy; aroyl; heteroaroyl;
acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or
(heterocycloaliphatic)carbonyl]; nitro; cyano; amido [e.g.,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
arylaminocarbonyl, or heteroarylaminocarbonyl]; amino [e.g.,
aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or
aliphaticsulfonylamino]; sulfonyl [e.g., alkyl-S(O).sub.2--,
cycloaliphatic-S(O).sub.2--, or aryl-S(O).sub.2--]; sulfinyl;
sulfanyl; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo;
carboxy; carbamoyl; cycloaliphaticoxy; heterocycloaliphaticoxy;
aryloxy; heteroaryloxy; aralkyloxy; heteroaralkoxy; alkoxycarbonyl;
alkylcarbonyloxy; or hydroxy. Without limitation, some examples of
substituted alkenyls include cyanoalkenyl, alkoxyalkenyl,
acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
(sulfonylamino)alkenyl (such as (alkyl-S(O).sub.2-aminoalkenyl),
aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or
haloalkenyl.
[0020] As used herein, an "alkynyl" group refers to an aliphatic
carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and
has at least one triple bond. An alkynyl group can be straight or
branched. Examples of an alkynyl group include, but are not limited
to, propargyl and butynyl. An alkynyl group can be optionally
substituted with one or more substituents such as aroyl;
heteroaroyl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy;
heteroaryloxy; aralkyloxy; nitro; carboxy; cyano; halo; hydroxy;
sulfo; mercapto; sulfanyl [e.g., aliphatic-S-- or
cycloaliphatic-S--]; sulfinyl [e.g., aliphatic-S(O)-- or
cycloaliphatic-S(O)--]; sulfonyl [e.g., aliphatic-S(O).sub.2--,
aliphaticamino-S(O).sub.2--, or cycloaliphatic-S(O).sub.2--]; amido
[e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,
heteroarylcarbonylamino or heteroarylaminocarbonyl]; urea;
thiourea; sulfamoyl; sulfamide; alkoxycarbonyl; alkylcarbonyloxy;
cycloaliphatic; heterocycloaliphatic; aryl; heteroaryl; acyl [e.g.,
(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl]; amino
[e.g., aliphaticamino]; sulfoxy; oxo; carbamoyl;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; or
(heteroaryl)alkoxy.
[0021] As used herein, an "amido" encompasses both "aminocarbonyl"
and "carbonylamino". These terms when used alone or in connection
with another group refers to an amido group such as
--N(R.sup.X)--C(O)--R.sup.Y or --C(O)--N(R.sup.X).sub.2, when used
terminally, and --C(O)--N(R.sup.X)-- or --N(R.sup.X)--C(O)-- when
used internally, wherein R.sup.X and R.sup.Y are defined below.
Examples of amido groups include alkylamido (such as
alkylcarbonylamino or alkylaminocarbonyl),
(heterocycloaliphatic)amido, (heteroaralkyl)amido,
(heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido,
aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
[0022] As used herein, an "amino" group refers to --NR.sup.XR.sup.Y
wherein each of R.sup.X and R.sup.Y is independently hydrogen,
alkyl, cycloaliphatic, (cycloaliphatic)aliphatic, aryl,
araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic,
heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl,
(aliphatic)carbonyl, (cycloaliphatic)carbonyl,
((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,
(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or
(heteroaraliphatic)carbonyl, each of which being defined herein and
being optionally substituted. Examples of amino groups include
alkylamino, dialkylamino, or arylamino. When the term "amino" is
not the terminal group (e.g., alkylcarbonylamino), it is
represented by --NR.sup.X--. R.sup.X has the same meaning as
defined above.
[0023] As used herein, an "aryl" group used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers
to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl,
naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic
(e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl,
anthracenyl) ring systems in which the monocyclic ring system is
aromatic or at least one of the rings in a bicyclic or tricyclic
ring system is aromatic. The bicyclic and tricyclic groups include
benzofused 2-3 membered carbocyclic rings. For example, a
benzofused group includes phenyl fused with two or more C.sub.4-8
carbocyclic moieties. An aryl is optionally substituted with one or
more substituents including aliphatic [e.g., alkyl, alkenyl, or
alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl;
heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy;
aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy;
aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring
of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido;
acyl [e.g., aliphaticcarbonyl, (cycloaliphatic)carbonyl,
((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g.,
aliphatic-S(O).sub.2-- or amino-S(O).sub.2--]; sulfinyl [e.g.,
aliphatic-S(O)-- or cycloaliphatic-S(O)--]; sulfanyl [e.g.,
aliphatic-S--]; cyano; halo; hydroxy; mercapto; sulfoxy; urea;
thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an
aryl can be unsubstituted.
[0024] Non-limiting examples of substituted aryls include haloaryl
[e.g., mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl];
(carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl
[e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl,
(alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and
(((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];
(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (amino
sulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,
((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl;
(nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl;
((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl;
(cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl;
alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl;
p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or
(m-(heterocycloaliphatic)-o-(alkyl))aryl.
[0025] As used herein, an "araliphatic" such as an "aralkyl" group
refers to an aliphatic group (e.g., a C.sub.1-4 alkyl group) that
is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl"
are defined herein. An example of an araliphatic such as an aralkyl
group is benzyl.
[0026] As used herein, an "aralkyl" group refers to an alkyl group
(e.g., a C.sub.1-4 alkyl group) that is substituted with an aryl
group. Both "alkyl" and "aryl" have been defined above. An example
of an aralkyl group is benzyl. An aralkyl is optionally substituted
with one or more substituents such as aliphatic [e.g., alkyl,
alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or
haloalkyl such as trifluoromethyl]; cycloaliphatic [e.g.,
cycloalkyl or cycloalkenyl]; (cycloalkyl)alkyl; heterocycloalkyl;
(heterocycloalkyl)alkyl; aryl; heteroaryl; alkoxy; cycloalkyloxy;
heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy;
heteroaralkyloxy; aroyl; heteroaroyl; nitro; carboxy;
alkoxycarbonyl; alkylcarbonyloxy; amido [e.g., aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or
heteroaralkylcarbonylamino]; cyano; halo; hydroxy; acyl; mercapto;
alkylsulfanyl; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo;
or carbamoyl.
[0027] As used herein, a "bicyclic ring system" includes 8-12
(e.g., 9, 10, or 11) membered structures that form two rings,
wherein the two rings have at least one atom in common (e.g., 2
atoms in common). Bicyclic ring systems include bicycloaliphatics
(e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics,
bicyclic aryls, and bicyclic heteroaryls.
[0028] As used herein, a "cycloaliphatic" group encompasses a
"cycloalkyl" group and a "cycloalkenyl" group, each of which being
optionally substituted as set forth below.
[0029] As used herein, a "cycloalkyl" group refers to a saturated
carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10
(e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl,
bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,
bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl,
azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.
[0030] A "cycloalkenyl" group, as used herein, refers to a
non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms
having one or more double bonds. Examples of cycloalkenyl groups
include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl,
cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl,
cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.
[0031] A cycloalkyl or cycloalkenyl group can be optionally
substituted with one or more substituents such as aliphatic [e.g.,
alkyl, alkenyl, or alkynyl]; cycloaliphatic;
(cycloaliphatic)aliphatic; heterocycloaliphatic;
(heterocycloaliphatic) aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;
heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;
heteroaroyl; amino; amido [e.g., (aliphatic)carbonylamino,
(cycloaliphatic)carbonylamino,
((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,
((heterocycloaliphatic)aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino];
nitro; carboxy [e.g., HOOC--, alkoxycarbonyl, or alkylcarbonyloxy];
acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl]; cyano; halo; hydroxy; mercapto;
sulfonyl [e.g., alkyl-S(O).sub.2-- and aryl-S(O).sub.2--]; sulfinyl
[e.g., alkyl-S(O)--]; sulfanyl [e.g., alkyl-S--]; sulfoxy; urea;
thiourea; sulfamoyl; sulfamide; oxo; or carbamoyl.
[0032] As used herein, the term "heterocycloaliphatic" encompasses
a heterocycloalkyl group and a heterocycloalkenyl group, each of
which being optionally substituted as set forth below.
[0033] As used herein, a "heterocycloalkyl" group refers to a 3-10
membered mono- or bicyclic (fused or bridged) (e.g., 5- to
10-membered mono- or bicyclic) saturated ring structure, in which
one or more of the ring atoms is a heteroatom (e.g., N, O, S, or
combinations thereof). Examples of a heterocycloalkyl group include
piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl,
1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl,
isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl,
octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl,
octahydropyrindinyl, decahydroquinolinyl,
octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,
1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and
2,6-dioxa-tricyclo[3.3.1.0.sup.3,7]nonyl. A monocyclic
heterocycloalkyl group can be fused with a phenyl moiety such as
tetrahydroisoquinoline to produce a heteroaryl group.
[0034] A "heterocycloalkenyl" group, as used herein, refers to a
mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic)
non-aromatic ring structure having one or more double bonds, and
wherein one or more of the ring atoms is a heteroatom (e.g., N, O,
or S).
[0035] Monocyclic and bicycloheteroaliphatics are numbered
according to standard chemical nomenclature.
[0036] A heterocycloalkyl or heterocycloalkenyl group can be
optionally substituted with one or more substituents such as
aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;
(cycloaliphatic)aliphatic; heterocycloaliphatic;
(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;
heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;
heteroaroyl; amino; amido [e.g., (aliphatic)carbonylamino,
(cycloaliphatic)carbonylamino, ((cycloaliphatic)
aliphatic)carbonylamino, (aryl)carbonylamino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,
((heterocycloaliphatic) aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino];
nitro; carboxy [e.g., HOOC--, alkoxycarbonyl, or alkylcarbonyloxy];
acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl]; nitro; cyano; halo; hydroxy;
mercapto; sulfonyl [e.g., alkylsulfonyl or arylsulfonyl]; sulfinyl
[e.g., alkylsulfinyl]; sulfanyl [e.g., alkylsulfanyl]; sulfoxy;
urea; thiourea; sulfamoyl; sulfamide; oxo; or carbamoyl.
[0037] A "heteroaryl" group, as used herein, refers to a
monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring
atoms wherein one or more of the ring atoms is a heteroatom (e.g.,
N, O, S, or combinations thereof) and in which the monocyclic ring
system is aromatic or at least one of the rings in the bicyclic or
tricyclic ring systems is aromatic. A heteroaryl group includes a
benzofused ring system having 2 to 3 rings. For example, a
benzofused group includes benzo fused with one or two 4 to 8
membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of
heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,
thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,
isoquinolinyl, benzthiazolyl, xanthene, thioxanthene,
phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,
puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl,
quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl,
benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[0038] Without limitation, monocyclic heteroaryls include furyl,
thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl,
2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl,
pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered
according to standard chemical nomenclature.
[0039] Without limitation, bicyclic heteroaryls include indolizyl,
indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl,
isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl,
benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl,
isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl,
1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered
according to standard chemical nomenclature.
[0040] A heteroaryl is optionally substituted with one or more
substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl];
cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic;
(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;
heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;
heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or
heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy;
amido; acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl;
((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g.,
aliphatic-S(O).sub.2-- or amino-S(O).sub.2--]; sulfinyl [e.g.,
aliphatic-S(O)--]; sulfanyl [e.g., aliphatic-S--]; nitro; cyano;
halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl;
sulfamide; or carbamoyl. Alternatively, a heteroaryl can be
unsubstituted.
[0041] Non-limiting examples of substituted heteroaryls include
(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];
(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];
cyanoheteroaryl; aminoheteroaryl [e.g.,
((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl];
(amido)heteroaryl [e.g., aminocarbonylheteroaryl,
((alkylcarbonyl)amino)heteroaryl,
((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
(((heteroaryl)amino)carbonyl)heteroaryl,
((heterocycloaliphatic)carbonyl)heteroaryl, and
((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;
(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,
(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,
(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;
(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;
((carboxy)alkyl)heteroaryl; [((dialkyl)amino)alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;
(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;
((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;
(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl];
(alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g.,
trihaloalkylheteroaryl].
[0042] A "heteroaraliphatic" (such as a heteroaralkyl group) as
used herein, refers to an aliphatic group (e.g., a C.sub.1-4 alkyl
group) that is substituted with a heteroaryl group. "Aliphatic,"
"alkyl," and "heteroaryl" have been defined above.
[0043] A "heteroaralkyl" group, as used herein, refers to an alkyl
group (e.g., a C.sub.1-4 alkyl group) that is substituted with a
heteroaryl group. Both "alkyl" and "heteroaryl" have been defined
above. A heteroaralkyl is optionally substituted with one or more
substituents such as alkyl (e.g., carboxyalkyl, hydroxyalkyl, and
haloalkyl such as trifluoromethyl); alkenyl; alkynyl; cycloalkyl;
(cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl;
heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy;
heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl;
nitro; carboxy; alkoxycarbonyl; alkylcarbonyloxy; aminocarbonyl;
alkylcarbonylamino; cycloalkylcarbonylamino;
(cycloalkylalkyl)carbonylamino; arylcarbonylamino;
aralkylcarbonylamino; (heterocycloalkyl)carbonylamino;
(heterocycloalkylalkyl)carbonylamino; heteroarylcarbonylamino;
heteroaralkylcarbonylamino; cyano; halo; hydroxy; acyl; mercapto;
alkylsulfanyl; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo;
or carbamoyl.
[0044] As used herein, an "acyl" group refers to a formyl group or
Rx--C(O)-- (such as -alkyl-C(O)--, also referred to as
"alkylcarbonyl") where Rx and "alkyl" have been defined previously.
Acetyl and pivaloyl are examples of acyl groups.
[0045] As used herein, an "aroyl" or "heteroaroyl" refers to an
aryl-C(O)-- or a heteroaryl-C(O)--. The aryl and heteroaryl portion
of the aroyl or heteroaroyl is optionally substituted as previously
defined.
[0046] As used herein, an "alkoxy" group refers to an alkyl-O--
group where "alkyl" has been defined previously.
[0047] As used herein, a "carbamoyl" group refers to a group having
the structure --O--CO--NR.sup.XR.sup.Y or
--NR.sup.X--CO--O--R.sup.Z wherein R.sup.X and R.sup.Y have been
defined above and R.sup.Z can be aliphatic, aryl, araliphatic,
heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[0048] As used herein, a "carboxy" group refers to --COOH,
--COOR.sup.X, --OC(O)H, --OC(O)R.sup.X when used as a terminal
group; or --OC(O)-- or --C(O)O-- when used as an internal
group.
[0049] As used herein, a "haloaliphatic" group refers to an
aliphatic group substituted with 1-3 halogen. For instance, the
term haloalkyl includes the group --CF.sub.3.
[0050] As used herein, a "mercapto" group refers to --SH.
[0051] As used herein, a "sulfo" group refers to --SO.sub.3H or
--SO.sub.3R.sup.X when used terminally or --S(O).sub.3-- when used
internally.
[0052] As used herein, a "sulfamide" group refers to the structure
--NR.sup.X--S(O).sub.2--NR.sup.YR.sup.Z when used terminally and
--NR.sup.X--S(O).sub.2--NR.sup.Y-- when used internally, wherein
R.sup.X, R.sup.Y, and R.sup.Z have been defined above.
[0053] As used herein, a "sulfamoyl" group refers to the structure
--S(O).sub.2--NR.sup.XR.sup.Y or --NR.sup.X--S(O).sub.2--R.sup.Z
when used terminally; or --S(O).sub.2--NR.sup.X-- or
--NR.sup.X--S(O).sub.2-- when used internally, wherein R.sup.X,
R.sup.Y, and R.sup.Z are defined above.
[0054] As used herein a "sulfanyl" group refers to --S--R.sup.X
when used terminally and --S-- when used internally, wherein
R.sup.X has been defined above. Examples of sulfanyls include
aliphatic-S--, cycloaliphatic-S--, aryl-S--, or the like.
[0055] As used herein a "sulfinyl" group refers to --S(O)--R.sup.X
when used terminally and --S(O)--when used internally, wherein
R.sup.X has been defined above. Exemplary sulfinyl groups include
aliphatic-S(O)--, aryl-S(O)--, (cycloaliphatic(aliphatic))-S(O)--,
cycloalkyl-S(O)--, heterocycloaliphatic-S(O)--, heteroaryl-S(O)--,
or the like.
[0056] As used herein, a "sulfonyl" group refers to
--S(O).sub.2--R.sup.X when used terminally and --S(O).sub.2-- when
used internally, wherein R.sup.X has been defined above. Exemplary
sulfonyl groups include aliphatic-S(O).sub.2--, aryl-S(O).sub.2--,
(cycloaliphatic(aliphatic))-S(O).sub.2--,
cycloaliphatic-S(O).sub.2--, heterocycloaliphatic-S(O).sub.2--,
heteroaryl-S(O).sub.2--,
(cycloaliphatic(amido(aliphatic)))-S(O).sub.2-- or the like.
[0057] As used herein, a "sulfoxy" group refers to --O--SO--R.sup.X
or --SO--O--R.sup.X, when used terminally and --O--S(O)-- or
--S(O)--O-- when used internally, where R.sup.X has been defined
above.
[0058] As used herein, a "halogen" or "halo" group refers to
fluorine, chlorine, bromine or iodine.
[0059] As used herein, an "alkoxycarbonyl," which is encompassed by
the term carboxy, used alone or in connection with another group
refers to a group such as alkyl-O--C(O)--.
[0060] As used herein, an "alkoxyalkyl" refers to an alkyl group
such as alkyl-O-alkyl-, wherein alkyl has been defined above.
[0061] As used herein, a "carbonyl" refer to --C(O)--.
[0062] As used herein, an "oxo" refers to .dbd.O.
[0063] As used herein, an "aminoalkyl" refers to the structure
(R.sup.X).sub.2N-alkyl-.
[0064] As used herein, a "cyanoalkyl" refers to the structure
(NC)-alkyl-.
[0065] As used herein, a "urea" group refers to the structure
--NR.sup.X--CO--NR.sup.YR.sup.Z and a "thiourea" group refers to
the structure --NR.sup.X--CS--NR.sup.YR.sup.Z when used terminally
and --NR.sup.X--CO--NR.sup.Y-- or --NR.sup.X--CS--NR.sup.Y-- when
used internally, wherein R.sup.X, R.sup.Y, and R.sup.Z have been
defined above.
[0066] As used herein, a "guanidino" group refers to the structure
--N.dbd.C(N(R.sup.XR.sup.Y))N(R.sup.XR.sup.Y) wherein R.sup.X and
R.sup.Y have been defined above.
[0067] As used herein, the term "amidino" group refers to the
structure --C.dbd.(NR.sup.X)N(R.sup.XR.sup.Y) wherein R.sup.X and
R.sup.Y have been defined above.
[0068] In general, the term "vicinal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to adjacent carbon atoms.
[0069] In general, the term "geminal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to the same carbon atom.
[0070] The terms "terminally" and "internally" refer to the
location of a group within a substituent. A group is terminal when
the group is present at the end of the substituent not further
bonded to the rest of the chemical structure. Carboxyalkyl, i.e.,
R.sup.XO(O)C-alkyl is an example of a carboxy group used
terminally. A group is internal when the group is present in the
middle of a substituent to at the end of the substituent bound to
the rest of the chemical structure. Alkylcarboxy (e.g.,
alkyl-C(O)O-- or alkyl-OC(O)--) and alkylcarboxyaryl (e.g.,
alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy
groups used internally.
[0071] As used herein, the term "amidino" group refers to the
structure --C.dbd.(NR.sup.X)N(R.sup.XR.sup.Y) wherein R.sup.X and
R.sup.Y have been defined above.
[0072] As used herein, a "bridged bicyclic ring system" refers to a
bicyclic heterocyclicalipahtic ring system or bicyclic
cycloaliphatic ring system in which the rings are bridged. Examples
of bridged bicyclic ring systems include, but are not limited to,
adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,
bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl,
2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl,
3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
A bridged bicyclic ring system can be optionally substituted with
one or more substituents such as alkyl (including carboxyalkyl,
hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl,
alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0073] As used herein, "cyclic group" or "cyclic moiety" include
mono-, bi-, and tri-cyclic ring systems including cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, each of which has been
previously defined.
[0074] As used herein, an "aliphatic chain" refers to a branched or
straight aliphatic group (e.g., alkyl groups, alkenyl groups, or
alkynyl groups). A straight aliphatic chain has the structure
--[CH.sub.2].sub.v--, where v is 1-6. A branched aliphatic chain is
a straight aliphatic chain that is substituted with one or more
aliphatic groups. A branched aliphatic chain has the structure
--[CHQ].sub.v- where Q is hydrogen or an aliphatic group; however,
Q shall be an aliphatic group in at least one instance. The term
aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl
chains, where alkyl, alkenyl, and alkynyl are defined above.
[0075] The phrase "optionally substituted" is used interchangeably
with the phrase "substituted or unsubstituted." As described
herein, compounds of the invention can optionally be substituted
with one or more substituents, such as are illustrated generally
above, or as exemplified by particular classes, subclasses, and
species of the invention. As described herein, the variables
R.sub.1, R.sub.2a, R.sub.2b, R.sub.3, R'.sub.3, R.sub.4, R'.sub.4,
and other variables contained therein formulae I encompass specific
groups, such as alkyl and aryl. Unless otherwise noted, each of the
specific groups for the variables R.sub.1, R.sub.2a, R.sub.2b,
R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, and other variables contained
therein can be optionally substituted with one or more substituents
described herein. Each substituent of a specific group is further
optionally substituted with one to three of halo, cyano, oxoalkoxy,
hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, an
alkyl group can be substituted with alkylsulfanyl and the
alkylsulfanyl can be optionally substituted with one to three of
halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and
alkyl. As an additional example, the cycloalkyl portion of a
(cycloalkyl)carbonylamino can be optionally substituted with one to
three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
When two alkoxy groups are bound to the same atom or adjacent
atoms, the two alkoxy groups can form a ring together with the
atom(s) to which they are bound.
[0076] In general, the term "substituted," whether preceded by the
term "optionally" or not, refers to the replacement of hydrogen
radicals in a given structure with the radical of a specified
substituent. Specific substituents are described above in the
definitions and below in the description of compounds and examples
thereof. Unless otherwise indicated, an optionally substituted
group can have a substituent at each substitutable position of the
group, and when more than one position in any given structure can
be substituted with more than one substituent selected from a
specified group, the substituent can be either the same or
different at every position. A ring substituent, such as a
heterocycloalkyl, can be bound to another ring, such as a
cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings
share one common atom. As one of ordinary skill in the art will
recognize, combinations of substituents envisioned by this
invention are those combinations that result in the formation of
stable or chemically feasible compounds.
[0077] The phrase "stable or chemically feasible," as used herein,
refers to compounds that are not substantially altered when
subjected to conditions to allow for their production, detection,
and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a
stable compound or chemically feasible compound is one that is not
substantially altered when kept at a temperature of 40.degree. C.
or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0078] As used herein, an effective amount is defined as the amount
required to confer a therapeutic effect on the treated patient, and
is typically determined based on age, surface area, weight, and
condition of the patient. The interrelationship of dosages for
animals and humans (based on milligrams per meter squared of body
surface) is described by Freireich, et al., Cancer Chemother. Rep.,
50: 219 (1966). Body surface area may be approximately determined
from height and weight of the patient. See, e.g., Scientific
Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). As used
herein, "patient" refers to a mammal, including a human.
[0079] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
II. Compounds
[0080] A. Generic Compounds
[0081] The present invention provides methods of modulating
activity of a muscarinic receptor comprising the step of contacting
said receptor with a compound of formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof.
[0082] R.sub.1 is a branched or straight C.sub.1-12 aliphatic
optionally substituted with 1-3 of R.sup.A, wherein up to 3 carbon
units of R.sub.1 are optionally and independently replaced by
--CO--, --CS--, --CONR.sup.F--, --CONR.sup.FNR.sup.F--,
--CO.sub.2--, --OCO--, --NR.sup.FCO.sub.2--, --O--,
--NR.sup.FCONR.sup.F--, --OCONR.sup.F--, --NR.sup.FNR.sup.F--,
--NR.sup.FCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.F--,
--S(O).sub.2NR.sup.F--, --NR.sup.FSO.sub.2--, or
--NR.sup.FS(O).sub.2NR.sup.F. Each R.sup.A is independently halo,
--OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3. Each R.sup.F is
independently hydrogen, or a branched or straight C.sub.1-8
aliphatic group optionally substituted with 1-3 of R.sup.A.
[0083] R.sub.2a is --Z.sup.BR.sub.5, wherein each Z.sup.B is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.B are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--,
--OCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.B--, --S(O).sub.2NR.sup.B--,
--NR.sup.BS(O).sub.2--, or --NR.sup.BS(O).sub.2NR.sup.B--. Each
R.sub.5 is independently R.sup.B, halo, --OH, --CN, or --OCF.sub.3.
Each R.sup.B is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl.
[0084] Alternatively, R.sub.2a and R.sub.3 together with the atoms
to which they are attached form a 5-7 membered partially
unsaturated optionally substituted cyclic group optionally having
1-2 heteroatoms independently selected from N, O and S.
[0085] Each R.sub.2b is independently --Z.sup.ER.sub.8, wherein
each Z.sup.E is independently a bond or an optionally substituted
branched or straight C.sub.1-4 aliphatic chain wherein up to two
carbon units of Z.sup.E are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.G--, --CONR.sup.GNR.sup.G--,
--CO.sub.2--, --OCO--, --NR.sup.GCO.sub.2--, --O--,
--NR.sup.GCONR.sup.G--, --OCONR.sup.G--, --NR.sup.GNR.sup.G--,
--NR.sup.GCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.G--,
--S(O).sub.2NR.sup.G--, --NR.sup.GS(O).sub.2--, or
--NR.sup.GS(O).sub.2NR.sup.G--. Each R.sub.8 is independently
R.sup.G, halo, --OH, --CN, or --OCF.sub.3. Each R.sup.G is
independently hydrogen, an optionally substituted C.sub.1-8
aliphatic group, an optionally substituted cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally
substituted aryl, or an optionally substituted heteroaryl.
[0086] Alternatively, R.sub.2a and one R.sub.2b together with the
atoms to which they are attached form a 5-7 membered partially
unsaturated optionally substituted cyclic group optionally having
1-2 heteroatoms independently selected from N, O, and S, wherein
R.sub.2b is attached to a carbon atom vicinal to the carbon atom to
which R.sub.2a is attached on the fused phenyl of formula I; or two
of R.sub.2b together with the atoms to which they are attached form
a 5-7 membered partially unsaturated optionally substituted cyclic
group optionally containing 1-2 heteroatoms independently selected
from N, O, and S, wherein each R.sub.2b is attached to a vicinal
carbon atom on the fused phenyl of formula I.
[0087] R.sub.3 and R'.sub.3 together form an oxo group, or each is
independently --Z.sup.CR.sub.6, wherein each Z.sup.C is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.C are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--,
--OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.C--, --S(O).sub.2NR.sup.C--,
--NR.sup.CS(O).sub.2--, or --NR.sup.CS(O).sub.2NR.sup.C--. Each
R.sub.6 is independently R.sup.C, halo, --OH, --NH.sub.2,
--NO.sub.2, --CN, or --OCF.sub.3. Each R.sup.C is independently
hydrogen, an optionally substituted C.sub.1-8 aliphatic group; an
optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0088] Alternatively, R.sub.3 and R.sub.4 together with the atoms
to which they are attached form a 5-6 membered optionally
substituted cycloaliphatic or a 5-6 membered optionally substituted
heterocycloaliphatic.
[0089] R.sub.4 and R'.sub.4 together form an oxo group, or each is
independently --Z.sup.DR.sub.7, wherein each Z.sup.D is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.D are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.D--, --CONR.sup.DNR.sup.D--, --CO.sub.2--,
--OCO--, --NR.sup.DCO.sub.2--, --O--, --NR.sup.DCONR.sup.D--,
--OCONR.sup.D--, --NR.sup.DNR.sup.D--, --NR.sup.DCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.D--, --S(O).sub.2NR.sup.D--,
--NR.sup.DS(O).sub.2--, or --NR.sup.DS(O).sub.2NR.sup.D--. Each
R.sub.7 is independently R.sup.D, halo, --OH, --NH.sub.2,
--NO.sub.2, --CN, or --OCF.sub.3. Each R.sup.D is independently
hydrogen, an optionally substituted C.sub.1-8 aliphatic group; an
optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0090] m is 0-3, p is 0-3, and m+p is 3, 4, 5, or 6.
[0091] n is 0-2.
[0092] q is 0-3.
[0093] B. Specific Compounds
[0094] 1. Substituent R.sub.1:
[0095] R.sub.1 is a branched or straight C.sub.1-12 aliphatic
optionally substituted with 1-3 of R.sup.A, wherein up to 3 carbon
units of R.sub.1 are optionally and independently replaced by
--CO--, --CS--, --CONR.sup.F--, --CONR.sup.FNR.sup.F--,
--CO.sub.2--, --OCO--, --NR.sup.FCO.sub.2--, --O--,
--NR.sup.FCONR.sup.F--, --OCONR.sup.F--, --NR.sup.FNR.sup.F--,
--NR.sup.FCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.F--,
--S(O).sub.2NR.sup.F--, --NR.sup.FS(O).sub.2--, or
--NR.sup.FS(O).sub.2NR.sup.F--; each R.sup.A is halo, --OH,
--NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3; each R.sup.F is
hydrogen, or a branched or straight C.sub.1-8 aliphatic group
optionally substituted with 1-3 of R.sup.A.
[0096] In several embodiments, R.sub.1 is an optionally substituted
straight or branched C.sub.1-12 aliphatic, wherein up to 3 carbon
units of R.sub.1 are optionally and independently replaced with
--C(O)--, --S(O).sub.2--, --S--, --O--, or combinations
thereof.
[0097] In several embodiments, R.sub.1 is an optionally substituted
straight C.sub.1-10 aliphatic. For example, R.sub.1 is a straight
C.sub.1-10 alkyl, a straight C.sub.2-10 alkenyl, or a straight
C.sub.2-10 alkynyl, each of which is optionally substituted with
1-3 of halo, hydroxy, cyano, or combinations thereof. In several
examples, R.sub.1 is a straight C.sub.1-10 alkyl, a straight
C.sub.2-10 alkenyl, or a straight C.sub.2-10 alkynyl, each of which
is unsubstituted. In alternative examples, R.sub.1 is a straight
C.sub.1-10 alkyl that is optionally substituted with 1-3 of halo or
cyano. In additional examples, R.sub.1 is a C.sub.2-10 alkenyl
having 1-2 C--C double bonds that is optionally substituted with
1-3 of halo, hydroxy, cyano, or combinations thereof. In additional
examples, R.sub.1 is an optionally substituted C.sub.2-10
alkynyl.
[0098] In several examples, R.sub.1 is an optionally substituted
branched C.sub.3-12 aliphatic. For example, R.sub.1 is a branched
C.sub.3-12 alkyl, a branched C.sub.3-12 alkenyl, or a branched
C.sub.3-12 alkynyl, each of which is optionally substituted with
1-3 of halo, hydroxy, cyano, or combinations thereof. In several
examples, R.sub.1 is a branched C.sub.3-10 alkyl, a branched
C.sub.3-10 alkenyl, or a branched C.sub.3-10 alkynyl, each of which
is unsubstituted. In alternative examples, R.sub.1 is an alkyl that
is optionally substituted with 1-3 of halo or cyano. In additional
examples, R.sub.1 is an alkenyl having 1-2 C--C double bonds and is
optionally substituted. In additional examples, R.sub.1 is an
optionally substituted branched C.sub.2-12 alkynyl.
[0099] In several embodiments, R.sub.1 is a straight C.sub.1-10
aliphatic or a branched C.sub.3-12 aliphatic, each of which is
optionally substituted with 1-3 of halo, hydroxy, cyano, or
combinations thereof.
[0100] In several embodiments, up to 2 carbon units of R.sub.1 are
optionally and independently replaced with --C(O)--,
--S(O).sub.2--, --S--, --O--, --NR.sup.F--, or combinations
thereof.
[0101] In several embodiments, R.sub.1 is a straight C.sub.1-10
alkyl, straight C.sub.2-10 alkenyl, straight C.sub.2-10 alkynyl,
branched C.sub.3-12 alkyl, branched C.sub.3-12 alkenyl, or branched
C.sub.3-12 alkynyl, each of which is optionally substituted with
1-3 of R.sup.A.
[0102] In several embodiments, R.sub.1 is a straight C.sub.2-10
alkenyl having 1-2 C--C double bonds or a branched C.sub.3-12
alkenyl having 1-2 C--C double bonds, each of which is optionally
substituted.
[0103] In several embodiments, R.sub.1 is an optionally substituted
straight or branched C.sub.1-12 aliphatic wherein 1-2 of the carbon
units have been optionally replaced with --S-- or --S(O).sub.2--.
In other embodiments, R.sub.1 is an optionally substituted straight
or branched aliphatic wherein 1-2 of the carbon units have been
optionally replaced with --S--. In several embodiments, R.sub.1 is
aliphatic-S(O).sub.2-aliphatic or aliphatic-S-aliphatic, each of
which is optionally substituted with 1-3 of halo, hydroxy, cyano,
nitro, alkoxy, or combinations thereof. For example, R.sub.1 is an
(alkylsulfonyl)alkyl or (alkylsulfanyl)alkyl, each of which is
optionally substituted.
[0104] In several embodiments, R.sub.1 is an optionally substituted
straight or branched C.sub.1-12 aliphatic wherein 1-2 of the carbon
units have been optionally replaced with --C(O)--, --O--, or
--CO.sub.2--. In several embodiments, R.sub.1 is an optionally
substituted straight or branched C.sub.1-12 aliphatic wherein one
carbon unit has been replaced with --C(O)--, and another carbon
unit has been replaced by --O--. In several embodiments, R.sub.1 is
an acyl [e.g., (aliphatic)carbonyl],
(aliphatic(carbonyl))aliphatic, (aliphaticoxy(carbonyl))aliphatic,
or carboxy [e.g. (aliphaticoxy)carbonyl], each of which is
optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, or
combinations thereof.
[0105] In several embodiments, R.sub.1 is one selected from:
##STR00003## ##STR00004## ##STR00005## ##STR00006##
[0106] 2. Substituents R.sub.2a and R.sub.2b:
[0107] R.sub.2a is --Z.sup.BR.sub.5, wherein each Z.sup.B is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.B are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--,
--OCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--S(O)--, --S(O).sub.2--, --NO--, --S(O).sub.2NR.sup.B--,
--NR.sup.BS(O).sub.2--, or --NR.sup.BS(O).sub.2NR.sup.B--. Each
R.sub.5 is independently R.sup.B, halo, --OH, --CN, or --OCF.sub.3.
Each R.sup.B is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl. Alternatively, R.sub.2a and R.sub.3 together with the
atoms to which they are attached form a 5-7 membered partially
unsaturated optionally substituted cyclic group optionally
containing 1-2 heteroatoms independently selected from N, O, and S.
Each R.sub.2b is independently --Z.sup.ER.sub.8, wherein each
Z.sup.E is independently a bond or an optionally substituted
branched or straight C.sub.1-4 aliphatic chain wherein up to two
carbon units of Z.sup.E are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.G--, --CONR.sup.GNR.sup.G--,
--CO.sub.2--, --OCO--, --NR.sup.GCO.sub.2--, --O--,
--NR.sup.GCONR.sup.G--, --OCONR.sup.G--, --NR.sup.GNR.sup.G--,
--NR.sup.GCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.G--,
--S(O).sub.2NR.sup.G--, --NR.sup.GS(O).sub.2--, or
--NR.sup.GS(O).sub.2NR.sup.G--. Each R.sub.8 is independently
R.sup.G, halo, --OH, --CN, or --OCF.sub.3. Each R.sup.G is
independently hydrogen, an optionally substituted C.sub.1-8
aliphatic group, an optionally substituted cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally
substituted aryl, or an optionally substituted heteroaryl.
[0108] Alternatively, R.sub.2a and one R.sub.2b together with the
atoms to which they are attached form an 5-7 membered partially
unsaturated optionally substituted cyclic group optionally having
1-2 heteroatoms independently selected from N, O, and S, wherein
R.sub.2b is attached to a carbon atom vicinal to the carbon atom to
which R.sub.2a is attached on the fused phenyl of formula I.
[0109] Alternatively, two of R.sub.2b together with the atoms to
which they are attached form an 5-7 membered partially unsaturated
optionally substituted cyclic group optionally having 1-2
heteroatoms independently selected from N, O, and S, wherein each
R.sub.2b is attached to a vicinal carbon atom on the fused phenyl
of formula I.
[0110] In several embodiments, R.sub.2a or R.sub.2b is hydrogen.
For example, in some embodiments, q is 0 and R.sub.2a is
hydrogen.
[0111] In several embodiments, when q is 1, 2, or 3, R.sub.2b is
attached to the core structure of formula I at the 6 position, 7
position, 8 position, or combinations thereof. For example,
R.sub.2b is attached at the 6 or 7 position, or combinations
thereof.
[0112] In several embodiments, R.sub.2a or R.sub.2b is an
optionally substituted amino. For example, R.sub.2a or R.sub.2b is
an (aliphatic)amino, (cycloaliphatic)amino, or combinations
thereof, each of which is optionally substituted.
[0113] In several embodiments, R.sub.2a or R.sub.2b is an
optionally substituted amido. For example, R.sub.2a or R.sub.2b is
an (alkyl(carbonyl))amino, (cycloalkyl(carbonyl))amino,
(alkyl(amino))carbonyl, (cycloalkyl(amino))carbonyl, or combination
thereof, each of which is optionally substituted.
[0114] In several embodiments, R.sub.2a or R.sub.2b is an
optionally substituted (alkyl(amino))carbonyl, an optionally
substituted (aliphatic)carbonyl, or an optionally substituted
(alkoxy)carbonyl. For example, R.sub.2a or R.sub.2b is a
(methyl(amino))carbonyl, (ethyl(amino))carbonyl,
(propyl(amino))carbonyl, or combinations thereof, each of which is
optionally substituted. In other examples, R.sub.2a or R.sub.2b is
a (methoxy)carbonyl, (ethoxy)carbonyl, (propoxy)carbonyl,
(butoxy)carbonyl, or combinations thereof, each of which is
optionally substituted. Additional examples of R.sub.2a or R.sub.2b
include (methyl)carbonyl, (ethyl)carbonyl, (propyl)carbonyl,
(butyl)carbonyl, or combinations thereof, each of which is
optionally substituted.
[0115] In several embodiments, q is 2 and two of R.sub.2b taken
together with the carbon atoms to which they are attached form a
5-7 membered partially unsaturated optionally substituted cyclic
group optionally having 1-2 heteroatoms independently selected from
N, O, and S, wherein each R.sub.2b is attached to the phenyl of
formula I on a carbon atom adjacent to the carbon atom substituted
with the other R.sub.2b. For example, two of R.sub.2b and the atoms
to which they are attached and the phenyl of formula I form an
optionally substituted benzo[d][1,3]dioxolyl.
[0116] In several embodiments, q is 0; and R.sub.2a and R.sub.3
taken together with the atoms to which they are attached form a 5-7
membered partially unsaturated optionally substituted
heterocycloaliphatic. For example, R.sub.2a and R.sub.3 taken
together with the atoms to which they are attached form optionally
substituted 1H-pyrrol-2(5H)-onyl. In other examples, R.sub.2a and
R.sub.3 taken together with the atoms to which they are attached
form a 1H-pyrrol-2(5H)-onyl that is optionally substituted with 1-2
oxo groups.
[0117] In several embodiments, q is 1 or 2, and each R.sub.2b is
independently halo, or methoxy.
[0118] In several embodiments, R.sub.2a or R.sub.2b is halo,
hydrogen, or methoxy. Other embodiments include 2 R.sub.2b groups
(i.e., q=2), wherein each is methoxy.
[0119] 3. Substituents R.sub.3 and R'.sub.3:
[0120] R.sub.3 and R'.sub.3 together form an oxo group, or each is
independently --Z.sup.CR.sub.6, wherein each Z.sup.C is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.C are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--,
--OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.C--, --S(O).sub.2NR.sup.C--,
--NR.sup.CS(O).sub.2--, or --NR.sup.CS(O).sub.2NR.sup.C--; each
R.sub.6 is independently R.sup.C, halo, --OH, --NH.sub.2,
--NO.sub.2, --CN, or --OCF.sub.3; each R.sup.C is independently
hydrogen, an optionally substituted C.sub.1-8 aliphatic group; an
optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl; or R.sub.3 and R.sub.4 together
with the atoms to which they are attached form a 5-7 membered
optionally substituted cycloaliphatic or a 5-7 membered optionally
substituted heterocycloaliphatic.
[0121] In several embodiments, one of R.sub.3 and R'.sub.3 is
independently an optionally substituted branched or straight
C.sub.1-4 aliphatic wherein up to two carbon units of R.sub.3 or
R'.sub.3 is optionally and independently replaced by --C(O)--,
--NH--, --S(O).sub.2--, or combinations thereof; and the remaining
R.sub.3 or R'.sub.3 is hydrogen. In several embodiments, one of
R.sub.3 and R'.sub.3 are straight optionally substituted C.sub.2-4
aliphatic groups wherein a first carbon unit is optionally and
independently replaced by --NH--, and a second carbon unit is
optionally and independently replaced by --C(O)--; and the
remaining R.sub.3 or R'.sub.3 is hydrogen. In another embodiment,
one of R.sub.3 and R'.sub.3 is optionally substituted
(methylcarbonyl)amino and the remaining R.sub.3 or R'.sub.3 is
hydrogen. In other embodiments, each of R.sub.3 and R'.sub.3 is
independently hydrogen or a methylcarbonylamino,
N,N-dimethylaminocarbonylamino, ethylcarbonylamino,
pyrrolidine-2,5-dion-1-yl, piperidin-2-one-1-yl,
methylaminocarbonyl, N,N-dimethylaminocarbonyl, aminocarbonyl,
cyano, or methoxycarbonylamino, each of which is optionally
substituted.
[0122] In several embodiments, one of R.sub.3 and R'.sub.3 is an
optionally substituted heterocycloaliphatic, and the remaining
R.sub.3 or R'.sub.3 is hydrogen. In several examples, one of
R.sub.3 and R'.sub.3 is an optionally substituted 5-7 membered
heterocycloaliphatic having 1-2 heteroatoms independently selected
from N, O, and S, and the remaining R.sub.3 or R'.sub.3 is
hydrogen. In other examples, one of R.sub.3 and R'.sub.3 is a 5-7
membered heterocycloaliphatic group optionally substituted with 1-3
of halo, hydroxy, cyano, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, aliphatic, alkoxy, oxo, or combinations
thereof; and the remaining R.sub.3 or R'.sub.3 is hydrogen. In
several examples, one of R.sub.3 and R'.sub.3 is an optionally
substituted 5-7 membered heterocycloaliphatic optionally
substituted with 1-2 oxo groups, and the remaining R.sub.3 or
R'.sub.3 is hydrogen. For example, one of R.sub.3 and R'.sub.3 is
pyrrolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrazolidinyl,
tetrahydropyranyl, thiomorpholinyl, morpholinyl, piperidinyl,
piperazinyl, 1,4-dioxanyl, or 1,4-dithianyl, each of which is
optionally substituted with 1-3 of halo, hydroxy, cyano, aryl,
heteroaryl, cycloaliphatic, heterocycloaliphatic, aliphatic,
alkoxy, oxo, or combinations thereof; and the remaining R.sub.3 or
R'.sub.3 is hydrogen.
[0123] In several embodiments, R.sub.3 and R'.sub.3 are each
independently hydrogen or halo.
[0124] In several embodiments, R.sub.3 and R'.sub.3 are
independently --Z.sup.CR.sub.6, wherein each Z.sup.C is a
independently a bond or an optionally substituted straight
C.sub.1-4 aliphatic chain wherein up to two carbon units of Z.sup.C
are optionally and independently replaced by --CO--, or --NH--.
R.sub.6 is an optionally substituted cycloaliphatic or hydrogen.
For example, R.sub.6 is cyclopropyl, cyclobutyl, cyclopentyl,
cycloheptyl, or cyclohexyl, each of which is optionally
substituted.
[0125] In several embodiments, R.sub.3 and R.sub.4 together with
the atoms to which they are attached form a 5-6 membered optionally
substituted heterocycloaliphatic. For example, R.sub.3 and R.sub.4
taken together with the atoms to which they are attached form an
optionally substituted 5-6 membered heterocycloaliphatic having 1-2
heteroatoms selected from N, O, and S. In other examples, R.sub.3
and R.sub.4 taken together with the atoms to which they are
attached form an optionally substituted 5-6 membered
heterocycloaliphatic that is optionally substituted with 1-2 oxo
groups. For example, R.sub.3 and R.sub.4 together form
pyrrolidin-2-onyl, imidazolidin-2-onyl, or oxazolidin-2-onyl, each
of which is optionally substituted.
[0126] In several embodiments, R.sub.3 and R'.sub.3 together with
the carbon atom to which they are attached form an oxo group, or
R.sub.3 and R'.sub.3 are each independently selected from
hydrogen,
##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012## ##STR00013## ##STR00014##
[0127] 4. Substituents R.sub.4 and R'.sub.4:
[0128] R.sub.4 and R'.sub.4 together form an oxo group, or each is
--Z.sup.DR.sub.7, wherein each Z.sup.D is independently a bond or
an optionally substituted branched or straight C.sub.1-4 aliphatic
chain wherein up to two carbon units of Z.sup.D are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.D--,
--CONR.sup.DNR.sup.D--, --CO.sub.2--, --OCO--,
--NR.sup.DCO.sub.2--, --O--, --NR.sup.DCONR.sup.D--,
--OCONR.sup.D--, --NR.sup.DNR.sup.D--, --NR.sup.DCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.D--, --S(O).sub.2NR.sup.D--,
--NR.sup.DS(O).sub.2--, or --NR.sup.DS(O).sub.2NR.sup.D--; each
R.sub.7 is R.sup.D, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or
--OCF.sub.3; and each R.sup.D is independently hydrogen, an
optionally substituted C.sub.1-8 aliphatic group; an optionally
substituted cycloaliphatic, an optionally substited
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0129] In several embodiments, R.sub.4 and R'.sub.4 are each
independently hydrogen.
[0130] In several embodiments, R.sub.4 and R'.sub.4 are each
independently optionally substituted C.sub.1-4 aliphatic. For
example, R.sub.4 and R'.sub.4 are each independently hydrogen
methyl, ethyl, propyl, or butyl, each of which is optionally
substituted.
[0131] In several embodiments, R.sub.4 and R'.sub.4 are both
hydrogen. In other embodiments, R.sub.4 and R'.sub.4 are both
fluoro.
[0132] 5. Variables n, m, p, and q:
[0133] m and p are each independently 0-3; however, m+p is 3, 4, 5,
or 6.
[0134] In several embodiments, m and p are both 2.
[0135] Each n is 0-2.
[0136] Each q is 0-3.
[0137] In several embodiments, m and p are each 0, 1, or 2. In
other embodiments, n is 0 or 1. In several embodiments, q is 0, 1,
2, 3, or 4.
[0138] B. Sub-Generic Compounds
[0139] Another aspect of the present invention provides compounds
of formula Ia:
##STR00015##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2a, R.sub.2b, R.sub.4, R'.sub.4, m, n, p, and q are defined
in formula I.
[0140] R'.sub.3 is --Z.sup.FR.sub.10, wherein each Z.sup.F is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.F are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.E--, --CONR.sup.ENR.sup.E--CO.sub.2--, --OCO--,
--NR.sup.ECO.sub.2--, --O--, --NR.sup.ECONR.sup.E--,
--OCONR.sup.E--, --NR.sup.ENR.sup.E--, --NR.sup.ECO--, --S--,
--S(O)--, --S(O).sub.2--, --S(O).sub.2NR.sup.E--,
--NR.sup.ES(O).sub.2--, or --NR.sup.ES(O).sub.2NR.sup.E--. Each
R.sub.10 is independently R.sup.E, halo, --OH, --NH.sub.2,
--NO.sub.2, --CN, or --OCF.sub.3. Each R.sup.E is independently an
optionally substituted C.sub.1-8 aliphatic group; an optionally
substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0141] R.sub.3 is independently --Z.sup.CR.sub.6, wherein each
Z.sup.C is independently a bond or an optionally substituted
branched or straight C.sub.1-4 aliphatic chain wherein up to two
carbon units of Z.sup.C are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--,
--CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--,
--NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--,
--NR.sup.CCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.C--,
--S(O).sub.2NR.sup.C--, --NR.sup.CS(O).sub.2--, or
--NR.sup.CS(O).sub.2NR.sup.C--; each R.sub.6 is independently
R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3;
each R.sup.C is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group; an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl.
[0142] Another aspect of the present invention provides compounds
of formula Ib:
##STR00016##
or a pharmaceutically acceptable salt thereof, wherein R.sub.2a,
R.sub.2b, R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, m, n, p, and q are
defined in formula I.
[0143] R.sub.1 is a branched or straight C.sub.1-12 aliphatic
optionally substituted with 1-3 of R.sup.A, wherein up to 2 carbon
units of R.sub.1 are optionally and independently replaced by
--CS--, --CONR.sup.F--, --CONR.sup.FNR.sup.F--, --CO.sub.2--,
--OCO--, --NR.sup.FCO.sub.2--, --O--, NR.sup.FCONR.sup.F--,
--OCONR.sup.F--, --NR.sup.FNR.sup.F--, --NR.sup.FCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.F--, --S(O).sub.2NR.sup.F--,
--NR.sup.FS(O).sub.2--, or --NR.sup.FS(O).sub.2NR.sup.F--. Each
R.sup.A is halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or
--OCF.sub.3. R.sup.F has been defined in formula I.
[0144] Another aspect of the present invention provides compounds
of formula Ic:
##STR00017##
or a pharmaceutically acceptable salt thereof, wherein R.sub.2a,
R.sub.2b, R.sub.4, R'.sub.4, m, n, p, and q are defined in formula
I.
[0145] R.sub.1 is a branched or straight C.sub.1-12 aliphatic
optionally substituted with 1-3 of R.sup.A, wherein up to 2 carbon
units of R.sub.1 are optionally and independently replaced by
--CS--, --CONR.sup.F--, --CONR.sup.FNR.sup.F--, --CO.sub.2--,
--OCO--, --NR.sup.FCO.sub.2--, --O--, --NR.sup.FCONR.sup.F--,
--OCONR.sup.F--, --NR.sup.FNR.sup.F--, --NR.sup.FCO--, S--,
--S(O)--, --S(O).sub.2--, --NR.sup.F--, --S(O).sub.2NR.sup.F--,
--NR.sup.FS(O).sub.2--, or --NR.sup.FS(O).sub.2NR.sup.F--; and each
R.sup.A is halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or
--OCF.sub.3. R.sup.F has been defined in formula I.
[0146] R.sub.3 is independently --Z.sup.CR.sub.6, wherein each
Z.sup.C is independently a bond or an optionally substituted
branched or straight C.sub.1-4 aliphatic chain wherein up to two
carbon units of Z.sup.C are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--,
--CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--,
--NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--,
--NR.sup.CCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.C--,
--S(O).sub.2NR.sup.C--, --NR.sup.CS(O).sub.2--, or
--NR.sup.CS(O).sub.2NR.sup.C--; each R.sub.6 is independently
R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3;
each R.sup.C is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group; an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl.
[0147] R'.sub.3 is --Z.sup.CR.sub.6, wherein each Z.sup.C is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.C are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--,
--OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.C--, --S(O).sub.2NR.sup.C--,
--NR.sup.CS(O).sub.2--, or --NR.sup.CS(O).sub.2NR.sup.C--, or
R.sub.3 and R'.sub.3 together form an oxo group. Each R.sup.C is
independently an optionally substituted C.sub.1-8 aliphatic group;
an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0148] Alternatively, R.sub.3 and R'.sub.3 together form an oxo
group.
[0149] Another aspect of the present invention provides compounds
of formula Id:
##STR00018##
or a pharmaceutically acceptable salt thereof, wherein R.sub.2a,
R.sub.2b, R.sub.4, R'.sub.4, m, n, p, and q are defined above.
[0150] R.sub.1 is a branched or straight C.sub.1-12 aliphatic
optionally substituted with 1-3 of R.sup.A, wherein up to 2 carbon
units of R.sub.1 are optionally and independently replaced by
--CS--, --CONR.sup.F--, --CONR.sup.FNR.sup.F--, --CO.sub.2--,
--OCO--, --NR.sup.FCO.sub.2--, --O--, --NR.sup.FCONR.sup.F--,
--OCONR.sup.F--, --NR.sup.FNR.sup.F--, --NR.sup.FCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.F--, --S(O).sub.2NR.sup.F--,
--NR.sup.FS(O).sub.2--, or --NR.sup.FS(O).sub.2NR.sup.F--; each
R.sup.A is halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or
--OCF.sub.3; and R.sup.F has been defined in formula I.
[0151] R.sub.3 is independently --Z.sup.CR.sub.6, wherein each
Z.sup.C is independently a bond or an optionally substituted
branched or straight C.sub.1-4 aliphatic chain wherein up to two
carbon units of Z.sup.C are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--,
--CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--,
--NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--,
--NR.sup.CCO--, --S--, --S(O)--, --S(O).sub.2--, --NR.sup.C--,
--S(O).sub.2NR.sup.C--, --NR.sup.CS(O).sub.2--, or
--NR.sup.CS(O).sub.2NR.sup.C--; each R.sub.6 is independently
R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3;
each R.sup.C is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group; an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl.
[0152] R'.sub.3 is --Z.sup.CR.sub.6, wherein each Z.sup.C is
independently a bond or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.C are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--,
--OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.C--, --S(O).sub.2NR.sup.C--,
--NR.sup.CS(O).sub.2--, or --NR.sup.CS(O).sub.2NR.sup.C--. Each
R.sup.C is independently an optionally substituted C.sub.1-8
aliphatic group; an optionally substituted cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally
substituted aryl, or an optionally substituted heteroaryl.
[0153] Alternatively, R.sub.3 and R.sub.4 together with the atoms
to which they are attached form a 5-6 membered optionally
substituted heterocycloaliphatic.
[0154] Another aspect of the present invention provides compounds
of formula Ie:
##STR00019##
or a pharmaceutically acceptable salt thereof, wherein R.sub.2a,
R.sub.2b, R.sub.4, R'.sub.4, m, n, p, and q are define in formula
I.
[0155] R.sub.1 is a branched or straight C.sub.1-12 aliphatic
optionally substituted with 1-3 of R.sup.A, wherein up to 2 carbon
units of R.sub.1 are optionally and independently replaced by
--CS--, --CONR.sup.F--, --CONR.sup.FNR.sup.F--, --CO.sub.2--,
--OCO--, --NR.sup.FCO.sub.2--, --O--, --NR.sup.FCONR.sup.F--,
--OCONR.sup.F--, --NR.sup.FNR.sup.F--, --NR.sup.FCO--, --S--,
--S(O)--, --S(O).sub.2--, --NR.sup.F--, --S(O).sub.2NR.sup.F--,
--NR.sup.FS(O).sub.2--, or --NR.sup.FS(O).sub.2NR.sup.F--. Each
R.sup.A is halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or
--OCF.sub.3. R.sup.F has been defined in formula I.
[0156] Each R.sub.3 and R'.sub.3 is independently --Z.sup.CR.sub.6,
wherein each Z.sup.C is independently a bond or an optionally
substituted branched or straight C.sub.1-4 aliphatic chain wherein
up to two carbon units of Z.sup.C are optionally and independently
replaced by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--,
--CO.sub.2--, --OCO--, --NR.sup.C--, --NR.sup.CCO.sub.2--, --O--,
--NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--,
--NR.sup.CCO--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR.sup.C--, --NR.sup.CS(O).sub.2--, or
--NR.sup.CS(O).sub.2NR.sup.C--. Each R.sub.6 is independently
R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3.
Each R.sup.C is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group; an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl.
[0157] Alternatively, R.sub.3 and R.sub.4 together with the atoms
to which they are attached form a 5-6 membered optionally
substituted heterocycloaliphatic.
[0158] Alternatively, R.sub.3 and R'.sub.3 together form an oxo
group.
[0159] Provided that when R.sub.1 is --CH.sub.3 or hydrogen,
neither R.sub.3 nor R'.sub.3 are
1-(2,3-dichlorophenyl)tetrazol-5-yl-amino.
[0160] C. Exemplary Compounds
[0161] Exemplary compounds of the present invention include, but
are not limited to, those illustrated in Table 1 below.
TABLE-US-00001 TABLE 1 Exemplary compounds of formulae I, Ia, Ib,
Ic, Id, and Ie. 1 ##STR00020## 2 ##STR00021## 3 ##STR00022## 4
##STR00023## 5 ##STR00024## 6 ##STR00025## 7 ##STR00026## 8
##STR00027## 9 ##STR00028## 10 ##STR00029## 11 ##STR00030## 12
##STR00031## 13 ##STR00032## 14 ##STR00033## 15 ##STR00034## 16
##STR00035## 17 ##STR00036## 18 ##STR00037## 19 ##STR00038## 20
##STR00039## 21 ##STR00040## 22 ##STR00041## 23 ##STR00042## 24
##STR00043## 25 ##STR00044## 26 ##STR00045## 27 ##STR00046## 28
##STR00047## 29 ##STR00048## 30 ##STR00049## 31 ##STR00050## 32
##STR00051## 33 ##STR00052## 34 ##STR00053## 35 ##STR00054## 36
##STR00055## 37 ##STR00056## 38 ##STR00057## 39 ##STR00058## 40
##STR00059## 41 ##STR00060## 42 ##STR00061## 43 ##STR00062## 44
##STR00063## 45 ##STR00064## 46 ##STR00065## 47 ##STR00066## 48
##STR00067## 49 ##STR00068## 50 ##STR00069## 51 ##STR00070## 52
##STR00071## 53 ##STR00072## 54 ##STR00073## 55 ##STR00074## 56
##STR00075## 57 ##STR00076## 58 ##STR00077## 59 ##STR00078## 60
##STR00079## 61 ##STR00080## 62
##STR00081## 63 ##STR00082## 64 ##STR00083## 65 ##STR00084## 66
##STR00085## 67 ##STR00086## 68 ##STR00087## 69 ##STR00088## 70
##STR00089## 71 ##STR00090## 72 ##STR00091## 73 ##STR00092## 74
##STR00093## 75 ##STR00094## 76 ##STR00095## 77 ##STR00096## 78
##STR00097## 79 ##STR00098## 80 ##STR00099## 81 ##STR00100## 82
##STR00101## 83 ##STR00102## 84 ##STR00103## 85 ##STR00104## 86
##STR00105## 87 ##STR00106## 88 ##STR00107## 89 ##STR00108## 90
##STR00109## 91 ##STR00110## 92 ##STR00111## 93 ##STR00112## 94
##STR00113## 95 ##STR00114## 96 ##STR00115## 97 ##STR00116## 98
##STR00117## 99 ##STR00118## 100 ##STR00119## 101 ##STR00120## 102
##STR00121## 103 ##STR00122## 104 ##STR00123## 105 ##STR00124## 106
##STR00125## 107 ##STR00126## 108 ##STR00127## 109 ##STR00128## 110
##STR00129## 111 ##STR00130## 112 ##STR00131## 113 ##STR00132## 114
##STR00133## 115 ##STR00134## 116 ##STR00135## 117 ##STR00136## 118
##STR00137## 119 ##STR00138## 120 ##STR00139## 121 ##STR00140## 122
##STR00141## 123 ##STR00142## 124 ##STR00143## 125
##STR00144## 126 ##STR00145## 127 ##STR00146## 128 ##STR00147## 129
##STR00148## 130 ##STR00149## 131 ##STR00150## 132 ##STR00151## 133
##STR00152## 134 ##STR00153## 135 ##STR00154## 136 ##STR00155## 137
##STR00156## 138 ##STR00157## 139 ##STR00158## 140 ##STR00159## 141
##STR00160## 142 ##STR00161## 143 ##STR00162## 144 ##STR00163## 145
##STR00164## 146 ##STR00165## 147 ##STR00166## 148 ##STR00167## 149
##STR00168## 150 ##STR00169## 151 ##STR00170## 152 ##STR00171## 153
##STR00172## 154 ##STR00173## 155 ##STR00174## 156 ##STR00175## 157
##STR00176## 158 ##STR00177## 159 ##STR00178## 160 ##STR00179## 161
##STR00180## 162 ##STR00181## 163 ##STR00182## 164 ##STR00183## 165
##STR00184## 166 ##STR00185## 167 ##STR00186## 168 ##STR00187## 169
##STR00188## 170 ##STR00189## 171 ##STR00190## 172 ##STR00191## 173
##STR00192## 174 ##STR00193## 175 ##STR00194## 176 ##STR00195## 177
##STR00196## 178 ##STR00197## 179 ##STR00198## 180 ##STR00199## 181
##STR00200## 182 ##STR00201## 183 ##STR00202## 184 ##STR00203## 185
##STR00204## 186 ##STR00205## 187 ##STR00206##
188 ##STR00207## 189 ##STR00208## 190 ##STR00209## 191 ##STR00210##
192 ##STR00211## 193 ##STR00212## 194 ##STR00213## 195 ##STR00214##
196 ##STR00215## 197 ##STR00216## 198 ##STR00217## 199 ##STR00218##
200 ##STR00219## 201 ##STR00220## 202 ##STR00221## 203 ##STR00222##
204 ##STR00223## 205 ##STR00224## 206 ##STR00225## 207 ##STR00226##
208 ##STR00227## 209 ##STR00228## 210 ##STR00229## 211 ##STR00230##
212 ##STR00231## 213 ##STR00232## 214 ##STR00233## 215 ##STR00234##
216 ##STR00235## 217 ##STR00236## 218 ##STR00237## 219 ##STR00238##
220 ##STR00239## 221 ##STR00240## 222 ##STR00241## 223 ##STR00242##
224 ##STR00243## 225 ##STR00244## 226 ##STR00245## 227 ##STR00246##
228 ##STR00247## 229 ##STR00248## 230 ##STR00249## 231 ##STR00250##
232 ##STR00251## 233 ##STR00252## 234 ##STR00253## 235 ##STR00254##
236 ##STR00255## 237 ##STR00256## 238 ##STR00257## 239 ##STR00258##
241 ##STR00259## 242 ##STR00260## 243 ##STR00261## 244 ##STR00262##
245 ##STR00263## 246 ##STR00264## 247 ##STR00265## 248 ##STR00266##
249 ##STR00267## 250 ##STR00268## 251 ##STR00269##
252 ##STR00270## 253 ##STR00271## 254 ##STR00272## 255 ##STR00273##
256 ##STR00274## 257 ##STR00275## 258 ##STR00276## 259 ##STR00277##
260 ##STR00278## 261 ##STR00279## 262 ##STR00280## 263 ##STR00281##
264 ##STR00282## 267 ##STR00283## 269 ##STR00284## 271 ##STR00285##
272 ##STR00286## 273 ##STR00287## 275 ##STR00288## 276 ##STR00289##
277 ##STR00290## 279 ##STR00291## 280 ##STR00292## 282 ##STR00293##
287 ##STR00294## 288 ##STR00295## 289 ##STR00296## 290 ##STR00297##
291 ##STR00298## 292 ##STR00299## 293 ##STR00300## 294 ##STR00301##
295 ##STR00302## 297 ##STR00303## 298 ##STR00304## 299 ##STR00305##
300 ##STR00306## 301 ##STR00307## 302 ##STR00308##
III. Synthetic Schemes
[0162] The compounds of formulae (I, Ia, Ib, Ic, Id, and Ie) may be
readily synthesized from commercially available or known starting
materials by known methods. Exemplary synthetic routes to produce
compounds of formulae (I, Ia, Ib, Ic, Id, and Ie) are provided
below in Schemes 1-3 below. In the following generic schemes, for
simplicity a single formula is used wherein n is 1, p and m are
both 2, and R.sub.4 and R'.sub.4 are both H. However, the generic
schemes are not limiting and can be applied to preparation of other
compounds having different variables.
[0163] Scheme 1 below depicts general conditions for the synthesis
of compounds of formula I.
##STR00309##
[0164] Referring to Scheme 1 the spirotetralone 1a is reacted with
an optically active amine O*--NH.sub.2 (step a) in the presence of
a catalyst such as, for example, boron trifluoride etherate to
provide the imine 1b as described in WO 2004/089307, hereby
incorporated by reference. Suitable O*--NH.sub.2 compounds are
those wherein O* is an optically active amine protecting group,
such as R or S (1-phenylethyl)amine, which may be subsequently
removed. Reduction of the imine (step b) with, for example, sodium
borohydride, provides the optically active amine 1c wherein *
represents an optically active carbon. Removal of O* in (step c)
can be achieved using know methods, for example, when O* is
(1-phenylethyl)amine, hydrogenation in the presence of a palladium
catalyst provides the amino compound 1d. Acylation of 1d using
known methods (step d) provides acylamino compounds of formula 1e.
Removal of the protecting group PG in 1e (step e) using known
methods provides compounds of formula 1f. Compounds of formula 1f
can be further modified to include R.sub.1 functionalities.
[0165] In some embodiments, wherein R.sup.C represents a
cycloaliphatic, lactam ring intermediates of formula 2e may be
prepared as shown in Scheme 2.
##STR00310##
[0166] Referring to Scheme 2, the alkylated spiroamine compound of
formula 2c is prepared from 2a and the aldehyde ester 2b, where E
is a C.sub.1-4 aliphatic, by known reductive amination procedures
such as reaction in the presence of sodium cyanoborohydride and
acetic acid. In some instances, compounds of formula 2c may
spontaneously cyclize to the lactam 2d. In other instances, the
lactam 2d may be formed from 2c by heating in an inert solvent
(e.g., toluene, NMP, or mixtures thereof) optionally in the
presence of a catalyst such as, for example, potassium acetate.
Removal of the protecting group from 2d provides the intermediates
2e.
[0167] Scheme 3 is another depiction of general conditions for the
synthesis of compounds of formula I where R.sub.3 and R'.sub.3 are
both hydrogen.
##STR00311##
[0168] Referring to Scheme 3, the R.sub.1-substituted
3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] compound (3b) is
prepared from the unsubstituted
3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] compound (3a)
using known alkylation procedures.
[0169] Further elaboration of intermediates 1f and 2e may be
achieved using known methods and as illustrated in the
examples.
IV. Formulations, Administrations, and Uses
[0170] A. Pharmaceutically Acceptable Compositions
[0171] The present invention includes within its scope
pharmaceutically acceptable prodrugs of the compounds of the
present invention. A "pharmaceutically acceptable prodrug" means
any pharmaceutically acceptable salt, ester, salt of an ester, or
other derivative of a compound of the present invention which, upon
administration to a recipient, is capable of providing (directly or
indirectly) a compound of this invention or an active metabolite or
residue thereof. Preferred prodrugs are those that increase the
bioavailability of the compounds of this invention when such
compounds are administered to a mammal or which enhance delivery of
the parent compound to a biological compartment relative to the
parent species.
[0172] The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0173] Pharmaceutically acceptable salts of the compounds of this
invention include those derived from pharmaceutically acceptable
inorganic and organic acids and bases. Examples of suitable acid
salts include acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycerophosphate, glycolate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate, succinate,
sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other
acids, such as oxalic, while not in themselves pharmaceutically
acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
[0174] Salts derived from appropriate bases include alkali metal
(e.g., sodium and potassium), alkaline earth metal (e.g.,
magnesium), ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization.
[0175] The compositions of the present invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, infrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously. Sterile injectable forms of the
compositions of this invention may be aqueous or oleaginous
suspension. These suspensions may be formulated according to
techniques known in the art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium.
[0176] For this purpose, any bland fixed oil may be employed
including synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0177] The pharmaceutically acceptable compositions of this
invention may be orally administered in any orally acceptable
dosage form including, but not limited to, capsules, tablets,
aqueous suspensions or solutions. In the case of tablets for oral
use, carriers commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful diluents
include lactose and dried cornstarch. When aqueous suspensions are
required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents may also be added.
[0178] Alternatively, the pharmaceutically acceptable compositions
of this invention may be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0179] The pharmaceutically acceptable compositions of this
invention may also be administered topically, especially when the
target of treatment includes areas or organs readily accessible by
topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0180] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0181] For topical applications, the pharmaceutically acceptable
compositions may be formulated in a suitable ointment containing
the active component suspended or dissolved in one or more
carriers. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutically acceptable compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0182] For ophthalmic use, the pharmaceutically acceptable
compositions may be formulated as micronized suspensions in
isotonic, pH adjusted sterile saline, or, preferably, as solutions
in isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutically acceptable compositions may
be formulated in an ointment such as petrolatum.
[0183] The pharmaceutically acceptable compositions of this
invention may also be administered by nasal aerosol or inhalation.
Such compositions are prepared according to techniques well-known
in the art of pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing
agents.
[0184] Most preferably, the pharmaceutically acceptable
compositions of this invention are formulated for oral
administration.
[0185] The amount of the compounds of the present invention that
may be combined with the carrier materials to produce a composition
in a single dosage form will vary depending upon the host treated,
the particular mode of administration. Preferably, the compositions
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of the modulator can be administered to a patient
receiving these compositions.
[0186] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of a compound of the
present invention in the composition will also depend upon the
particular compound in the composition.
[0187] Depending upon the particular condition, or disease, to be
treated or prevented, additional therapeutic agents, which are
normally administered to treat or prevent that condition, may also
be present in the compositions of this invention. As used herein,
additional therapeutic agents that are normally administered to
treat or prevent a particular disease, or condition, are known as
"appropriate for the disease, or condition, being treated."
[0188] According to a preferred embodiment, the compounds of
formulae (I, Ia, Ib, Ic, Id, and Ie) are selective modulators of
M.sub.1, M.sub.2 and M.sub.4. More preferably, the compounds of
formulae (I, Ia, Ib, Ic, Id, and Ie) are selective modulators of
M.sub.1 and/or M.sub.4. Yet more preferably, certain compounds of
formulae (I, Ia, Ib, Ic, Id, and Ie) are selective modulators of
M.sub.1. Or, preferably, certain compounds of formulae (I, Ia, Ib,
Ic, Id, and Ie) are selective modulators of M.sub.4.
[0189] Applicants believe that the ability of the compounds of the
present invention to modulate the activity of muscarinic receptors
is derived from the affinity of these compounds to the muscarinic
receptors. Such affinity, applicants believe, activates a
muscarinic receptor (i.e., an agonist) or inhibits the activity of
a muscarinic receptor.
[0190] The term "selective" as used herein means a measurably
greater ability to modulate one muscarinic receptor subtype when
compared to the other muscarinic receptor subtypes. E.g., the term
"selective M.sub.4 agonist" means a compound that has a measurably
greater ability to act as an M.sub.4 agonist when compared to that
compound's agonist activity with the other muscarinic receptor
subtype(s).
[0191] According to an alternative embodiment, the present
invention provides a method of treating a muscarinic receptor
mediated disease in a mammal, such as a human, including the step
of administering to said mammal a composition comprising a compound
of formulae (I, Ia, Ib, Ic, Id, and Ie), or an embodiment thereof
as set forth herein.
[0192] According to another embodiment, the present invention
provides a method of treating a disease mediated by a muscarinic
receptor including the step of administering to said mammal a
composition comprising a compound of formulae (I, Ia, Ib, Ic, Id,
and Ie), or other embodiments thereof as set forth above.
Preferably, said disease is mediated by M.sub.1, or said disease is
mediated by M.sub.4.
[0193] According to yet another embodiment, the present invention
provides a method of treating or reducing the severity of a disease
in a patient, wherein said disease is selected from CNS derived
pathologies including cognitive disorders, Attention Deficit
Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease,
various dementias such as vascular dementia, psychosis including
schizophrenia, mania, bipolar disorders, pain conditions including
acute and chronic syndromes, Huntington's Chorea, Friederich's
ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick
disease, clinical depression, sudden infant death syndrome,
Parkinson's disease, peripheral disorders such as reduction of
intra ocular pressure in Glaucoma and treatment of dry eyes and dry
mouth including Sjogren's Syndrome, wherein said method comprises
the step of contacting said patient with a compound according to
the present invention.
[0194] According to an alternative embodiment, the present
invention provides a method of treating or reducing the severity of
a disease in a patient, wherein said disease is selected from pain,
psychosis (including schizophrenia, hallucinations, and delusions),
Alzheimer's disease, Parkinson's disease, glaucoma, bradhycardia,
gastric acid secretion, asthma, or GI disturbances.
[0195] According to a preferred embodiment, the present invention
is useful for treating or reducing the severity of psychosis,
Alzheimer's disease, pain, or Parkinson's disease. All references
cited within this document are incorporated herein by
reference.
IV. Preparations and Examples
[0196] In order that the invention described therein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
[0197] .sup.1H-NMR spectra were recorded at 500 MHz using a Bruker
AMX 500 instrument. Mass spectroscopy samples were analyzed on a
MicroMass ZQ or Quattro II mass spectrometer operated in single MS
mode with electrospray ionization. Samples were introduced into the
mass spectrometer using chromatography, using Zorbax SB C18 column,
3.0.times.150 mm. Flow rate: 1.0 mL/minute. Detection: 254 &
214 nm. Mobile phase for all mass spectroscopy analysis consisted
of acetonitrile-water mixtures with 0.2% formic acid as a modifier
using 10-90% acetonitrile and water gradient. As used herein, the
term "R.sub.t" refers to the HPLC retention time, in minutes,
associated with the compound. HPLC purification refers to C-18
reverse phase using Gilson instrument, YMC combiprep ProC 18
column, 20.times.100 mm. Flow rate is 20 ml/minute. Mobile phase
consisted of water with 0.1% TFA and acetonitrile with 0.1% TFA.
Running time is 10 minutes.
Preparation A: Synthesis of tert-butyl
4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-carboxylate
##STR00312##
[0199] 1'-Methyl-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]
(A1) was prepared from commercially available
4-(3-phenylpropyl)pyridine as previously described. (Eberehard
Reimann, Johann Speckbacher, Hermann Lotter, Arch Pharm.
(Weinheim), 320 (1987), 385-393. Graham L. Patrick, J. Chem. Soc.
Perkin Trans 1, (1995) 1273-1279).
[0200] To a solution of the N-methylpiperidine (A1) (37 g, 172
mmol) in 1,2-dichloroethane (250 ml) was added 1-chloroethyl
chloroformate (20.7 ml, 190 mmol) at 0.degree. C. The solution
turned to a solid. After 0.5 hours at room temperature, the
reaction mixture was heated under reflux for 15 hours. After
concentration, the residue was dissolved in methanol (250 ml) and
heated at 50.degree. C. for 2 hours. The mixture was cooled to room
temperature, the precipitate was filtered and washed with ether to
produce 3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] HCl salt
(A2). The filtrate was concentrated, suspended in ether, filtered,
and the solid washed with MeOH and ether to give additional
3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] HCl salt (A2).
LC-MS: m/e=202.1 (M+H). R.sub.1=1.61 min. .sup.1H-NMR (500 MHz,
CDCl.sub.3): 9.74 (s, 2H), 7.58 (d, J=7.9, 1H), 7.22 (t, J=7.8,
1H), 7.14 (t, J=7.9, 1H), 7.08 (d, J=8.0, 1H), 3.47 (d, J=12.4,
2H), 3.22-3.18 (m, 2H), 2.88 (t, J=4.9, 2H), 2.81 (t, J=6.2, H),
2.60 (td, 2H), 1.93-1.89 (m, 2H), 1.83-1.77 (m, 2H).
[0201] A solution of the piperidine salt (A2) (2.2 g, 9.2 mmol) in
dichloromethane (100 ml) was treated with Et.sub.3N (4 ml, 28.9
mmol) and di-tert-butyldicarbonate (2.5 g, 11.4 mmol) at room
temperature for 2 hours. The reaction mixture was washed with
dilute aqueous HCl, and the organic phase was washed with aqueous
sodium bicarbonate, dried (Na.sub.2SO.sub.4), and concentrated to
give tert-butyl
3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-carboxylate
(A3) as a white solid. LC-MS: m/e=246.0 (M+H-tBu). R.sub.t=4.16
min. .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.27 (d, J=7.9, 1H), 7.10
(td, J=7.4, 1.6, 1H), 7.05 (td, J=7.3, 1.3, 1H), 7.00 (d, J=7.6,
1H), 3.93 (br.d, J=13.3, 2H), 2.92 (td, J=13.2, 2.8, 2H), 2.71 (t,
J=6.3, H), 1.90 (td, J=13.4, 5.0, 2 H), 1.82-1.80 (m, 2H),
1.72-1.67 (m, 2H), 1.49-1.46 (m, 2H), 1.42 (s, 9H).
[0202] To a solution of the Boc-piperidine (602 mg, 2 mmol) in
acetonitrile (10 ml) was added potassium permanganate (KMnO.sub.4,
950 mg, 6 mmol). The reaction mixture was stirred at 70.degree. C.
for 15 hours, filtered through Celite, and the filter cake was
washed with dichloromethane. The filtrate and washings were
concentrated and the residue was dissolved in acetonitrile (10 ml)
and reacted with KMnO.sub.4 (950 mg, 6 mmol) at 70.degree. C. for
another 24 hours. After filtration, washing and concentrating, the
residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/CH.sub.3CN: 1:0 to 9:1) to provide tert-butyl
4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-carboxylate
(A4). LC-MS: m/e=260.0 (M+H-tBu). R.sub.t=3.46 min. .sup.1H-NMR
(500 MHz, CDCl.sub.3): 8.07 (dd, J=1.5, 7.8, 1H), 7.60-7.57 (td,
J=7.9, 1.2, 1H), 7.50 (d, J=7.9, 1H), 7.36 (t, J=7.6, 1.0, 1H),
4.10 (br.d, J=13.2, 2H), 3.08 (t, J=13.8, 2H), 2.71 (t, J=6.7, 2H),
2.27 (t, J=6.9, 2H), 2.05 (td, J=13.4, 4.7, 2H), 1.73 (br.d,
J=13.2, 2H), 1.52 (s, 9H).
Preparation B: Synthesis of
(S)--N-(3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-4-yl)acetamide
##STR00313##
[0204] A solution of tert-butyl
4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-carboxylate
(A4) (5.0 g, 15.8 mmol), (S)-1-phenylethanamine (3.0 ml, 23.8 mmol)
and boron trifluoride dimethyl etherate (0.5 ml, 5 mmol) in dry
toluene (150 ml) was heated at 140.degree. C. under a Dean-Stark
trap for 24 hours. The solvent was distilled and the residue was
cooled with an ice bath, dissolved in ethyl acetate, washed with
saturated NaHCO.sub.3, and water. The organic phase was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give (S)-tert-butyl
4-(1-phenylethylimino)-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]--
1'-carboxylate (B1) as a gum. LC-MS analysis of the crude indicated
that there is trace of starting material (A4). LC-MS: m/e=419.37
(M+H). R.sub.t=2.24 min.
[0205] At -78.degree. C., NaBH.sub.4 (760 mg, 20 mmol) was added to
a solution of the imine (B1) (7.82 g, 20 mmol) in methanol (100
ml). The reaction mixture was allowed to warm to 0.degree. C. over
2-3 hours then treated with saturated NaHCO.sub.3 (ca. 100 ml),
concentrated under reduced pressure at <30.degree. C. to remove
the solvent. The residue was extracted with ethyl acetate. The
organic phase was washed with water, dried over Na.sub.2SO.sub.4
and concentrated to give (S)-tert-butyl
4-((S)-1-phenylethylamino)-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidi-
ne]-1'-carboxylate (B2) as a solid. LC-MS: m/e=421.32 (M+H).
R.sub.t=2.20 min.
[0206] A suspension of the crude protected amine (B2) (7.55, 17.9
mmol), ammonium formate (10 g, 158 mmol) and 10% Pd/C (2.0 g) in
methanol (150 ml) was stirred under N.sub.2 for 24 hours. The
reaction mixture was filtered through Celite and the filtrate was
concentrated. The residue was dissolved in ethyl acetate, washed
with saturated NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, and
concentrated to give (S)-tert-butyl
4-amino-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-carboxylate
(B3) as a syrup. LC-MS: m/e=317.21 (M+H), 244.2 (M+H-Me.sub.3CO).
R.sub.t=1.81 min.
[0207] At -78.degree. C., acetyl chloride (1 ml, 12 mmol) was added
to a solution of the amine (B3) (3.2 g, 10 mmol) in dry
acetonitrile (100 ml) followed by the dropswise addition of
triethylamine. The reaction mixture was warmed to room temperature,
stirred for 1 hour then concentrated. The residue was dissolved in
ethyl acetate. The solution was washed with saturated NaHCO.sub.3
and brine, dried and concentrated. The crude product was further
purified by silica gel chromatography (CH.sub.2Cl.sub.2/CH.sub.3CN
9:1 to 7:3) to give (S)-tert-butyl
4-acetamido-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-carboxyl-
ate (B4). LC-MS: m/e=359.3 (M+H), 303.3 (M+H-Me.sub.3CO).
R.sub.t=2.94 min. .sup.1H-NMR (500 MHz, DMSO-d.sub.6): 8.17 (d,
1H), 7.36 (d, 1H), 7.22 (ddd, 1H), 7.14 (m, 2H), 4.95 (m, 1H), 3.86
(m, 2H), 2.97 (m, 2H), 2.01 (m, 1H), 1.85 (s, 3H), 1.80 (m, 4H),
1.61 (m 2H), 1.48 (d, 1H), 1.42 (s, 9H).
[0208] Similarly, the enantiomer of (B4), compound (B6) or its
racemate, Racemic (B6), was also synthesized applying the same
synthetic route but replacing (S)-1-phenylethanamine with
(R)-1-phenylethanamine or racemic mixture of
1-phenylethanamine.
[0209] The enantiomeric purity was confirmed using analytical
chiral HPLC (CHIRALPAK AD column 250.times.4.6 mm, 1.5 mL/min, 7%
2-propanol/hexane, 15 minute run time). For Racemic (B6), there are
two peaks at 12.18 min and 12.57 min, corresponding to (B4) and
(B6), respectively. The enantiomeric purity was determined greater
than 90% for both (B4) and (B6).
[0210] At 0.degree. C., a solution of (B4) (2.2 g, 6.1 mmol) in
dichloromethane (20 ml) was treated with TFA (10 ml) for 1 hour,
concentrated, co-evaporated with acetonitrile and dissolved in
dichloromethane. The resulting solution was washed with a mixture
of brine (ca. 100 ml) and 6N NaOH (3 ml), dried over
Na.sub.2SO.sub.4 and concentrated to give
(S)--N-(3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-4-yl)acetamide
(B5) as a white solid. LC-MS: m/e=258.9 (M+H). R.sub.t=0.96 min.
The crude was used directly for further reactions.
Preparation C: Synthesis of
(S)-1-(3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-4-yl)pyrrolidin--
2-one
##STR00314##
[0212] A solution of the amine (B3) (480 mg, 1.24 mmol) and methyl
3-formylpropanoate (232 mg, 2.00 mmol) in dichloromethane (5 ml)
was stirred at room temperature for 1.5 hours. Then methanol (2
ml), sodium cyanoborohydride (200 mg, 3.10 mmol), and acetic acid
(0.1 ml) were added, and the mixture was kept overnight. The
reaction mixture was diluted with dichloromethane (ca. 100 ml),
washed with a mixture of saturated sodium bicarbonate (2 ml), 6N
sodium hydroxide (2 ml) and brine (ca. 50 ml). The organic phase
was separated, dried over Na.sub.2SO.sub.4 and concentrated to give
a crude mixture of (S)-tert-butyl
4-(4-methoxy-4-oxobutylamino)-3,4-dihydro-2H-spiro[naphthalene-1,4'-piper-
idine]-1'-carboxylate (C1) and (8)-tert-butyl
4-(2-oxopyrrolidin-1-yl)-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine-
]-1'-carboxylate (C2) in 1.6:1 ratio based on analytical HPLC.
LC-MS: m/e=417.36 (M.sub.(S)-7+H), R.sub.t=2.00 min; m/e=385.30
(M.sub.(S)-8+H), R.sub.t=3.25 min.
[0213] A solution of the above crude mixture (700 mg) in methanol
(20 ml) was heated together with potassium acetate (1.2 g) at
50.degree. C. for 4 hours. The analytical HPLC data indicated that
there was little conversion of (C1) to (C2). The solvent was
evaporated and the residue was suspended in toluene (50 ml) and
1-methyl-2-pyrrolidinone (NMP) (3 ml) and heated at 120.degree. C.
for 5 days. The mixture was concentrated, and the residue was
suspended in ethyl acetate. The solution was washed with saturated
sodium bicarbonate, dried and evaporated. The residue was passed
through silica gel column to give a crude mixture of (C1) and (C2)
with a ratio of 2:1.
[0214] A solution of the mixture of (C1) and (C2) (530 mg) in
dichloromethane (10 ml) was treated with TFA (5 ml) at 0.degree. C.
for 2 hours. The reaction mixture was concentrated. The residue was
co-evaporated with acetonitrile, dissolved in dichloromethane (ca.
100 ml), washed with a mixture of brine (ca. 20 ml) and 6N sodium
hydroxide (2 ml). The organic phase was dried over sodium sulfate
and concentrated to give a crude product (C3), which was further
purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH 9:1)
to give (S)-9 as oil. LC-MS: m/e=285.22 (M+H). R.sub.t=1.31 min.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): 8.58 (br. s, 1H), 8.35 (br. s,
1H), 7.40 (d, 1H), 7.30 (t, 1H), 7.20 (t, 1H), 6.93 (d, 1H), 5.14
(dd, 1H), 3.25-3.05 (m, 5H), 2.87 (td, 1H), 2.40-2.29 (m, 4H),
1.98-1.85 (m, 4H), 1.80 (t, 1H), 1.74 (m, 1H), 1.63 (t, 1H), 1.58
(d, 1H).
Method 1: Coupling with Aldehydes
Example 1
Synthesis of
(S)--N-(1'-(3,3-dimethylbutyl)-3,4-dihydro-2H-spiro[naphthalene-1,4'-pipe-
ridine]-4-yl)acetamide (Compound No. 190)
##STR00315##
[0216] A solution of 3,3-dimethylbutyraldehyde (13 mg, 0.13 mmol)
and the spiro-piperidine (B5) (25 mg, 0.10 mmol) in dry
dichloromethane (2 ml) was stirred at room temperature for 30 min,
cooled with ice-bath, and treated with sodium triacetoxyborohydride
(44 mg, 0.2 mml), followed by acetic acid (1 drop) and methanol (1
ml). The reaction mixture was stirred for another 5 hours and
concentrated under a stream of nitrogen. The residue was dissolved
in methanol (1 ml) and purified by reverse phase HPLC to give the
title compound no. 17 as a TFA salt. LC-MS: m/e=343.30 (M+H).
R.sub.t=1.63 min. .sup.1H-NMR (500 MHz, DMSO-d.sub.6): 9.28 (br.s,
1H), 8.18 (d, 1H), 7.35 (d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.16
(d, 1H), 4.92 (m, 1H), 3.45 (m, 2H), 3.14 (m, 4H), 2.19 (m, 2H),
2.05 (m, 1H), 1.87 (s, 3H), 1.82 (m, 2H), 1.73 (d, 1H), 1.60 (m,
3H), 0.93 (m, 9H).
Method 2: Coupling with Ketones
Example 2
Synthesis of
(S)--N-(1'-(pentan-3-yl)-3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine-
]-4-yl)acetamide (Compound No. 61)
##STR00316##
[0218] A solution of the piperidine (B5) (20 mg, 0.077 mmol) and
3-pentanone (27 mg, 0.31 mmol) in dichloromethane (2 ml) was
stirred in a vial for 90 minutes and treated with titanium (IV)
isopropoxide (60 .mu.l, 0.21 mmol) for 24 hours. To the reaction
mixture was added sodium borohydride (10 mg, 0.27 mmol) and stirred
for 5 hours, then treated with methanol (1 ml) and acetic acid (1
drop) for 1 hour. The solvents were evaporated and the residue was
dissolved in methanol (1 ml) and acidified with TFA and purified by
HPLC to give the title compound no. 56. LC-MS: m/e=329.28 (M+H).
R.sub.t=1.42 min. .sup.1H-NMR (500 MHz, DMSO-d.sub.6): 8.65 (br.s,
1H), 8.18 (d, 1H), 7.42 (d, 1H), 7.31 (t, 1H), 7.20 (t, 1H), 7.16
(d, 1H), 4.92 (m, 1H), 3.45 (m, 1H), 3.35 (m, 1H), 3.28-3.17 (m,
2H), 3.10 (m, 1H), 2.28 (m, 2H), 2.05 (m, 1H), 1.86 (s, 3H), 1.84
(m, 4H), 1.72 (t, 1H), 1.68-1.59 (m, 2H), 1.51 (m, 1H), 1.37 (m,
1H), 0.99 (t, 5H), 0.91 (t, 1H).
Method 3: Coupling with Alkyl Bromides
Example 3
Synthesis of
(S)--N-(1'-(3,3-dimethyl-2-oxobutyl)-3,4-dihydro-2H-spiro[naphthalene-1,4-
'-piperidine]-4-yl)acetamide (Compound No. 130)
##STR00317##
[0220] A suspension of the piperidine (B5) (24 mg, 0.09 mmol),
1-bromo-3,3-dimethylbutan-2-one (13.5 mg, 0.08 mmol) and sodium
carbonate (32 mg, 0.3 mmol) in DMF (1 ml) was stirred at 50.degree.
C. in a sealed vial for 16 hours. The mixture was cooled and
carefully neutralized with TFA and purified by reverse phase HPLC
to give the title compound no. 19 as a TFA salt. LC-MS: m/e=357.30
(M+H). R.sub.t=1.61 min. .sup.1H-NMR (500 MHz, DMSO-d.sub.6): 9.60
(br. s, 1H), 8.21 (d, 1H), 7.44 (d, 1H), 7.32 (t, 1H), 7.20 (t,
1H), 7.16 (d, 1H), 4.92 (q, 1H), 4.60 (d, 2H), 3.26 (m, 4H), 2.35
(m, 2H), 2.04 (dd, 1H), 1.87 (s, 3H), 1.80 (m, 3H), 1.71 (d, 1H),
1.63 (m, 1H), 1.16 (s, 9H).
[0221] A person skilled in the chemical arts can use the examples
and schemes along with known synthetic methodologies to synthesize
compounds of the present invention, including the compounds in
Table 2 below.
TABLE-US-00002 TABLE 2 Physical data for exemplary compounds.
Compound LC/MS LC/RT No. M + 1 min NMR 1 379.36 1.79 DMSO (d6):
9.17 (br.s, 1H), 7.47 (d, 1H), 7.45 (d, 1H), 7.34 (t, 1H), 7.32 (t,
1H), 4.45 (q, 1H), 3.45 (m, 2H), 3.15 (m, 4H), 3.05 (s, 3H), 2.17
(m, 2H), 2.09 (t, 1H), 1.96 (m, 1H), 1.89-1.74 (m, 3H), 1.71 (d,
1H), 1.59 (m, 2H), 0.93 (s, 9H). 2 441.4 1.21 3 369.3 2.1 4 315.2
1.38 DMSO (d6): 9.083 (m, 1H), 8.18 (d, 1H), 7.36 (d, 1H), 7.30 (t,
1H), 7.20 (t, 1H), 7.17 (d, 1H), 4.92 (m, 1H), 3.42 (m, 2H), 3.12
(m, 4H), 2.20 (m, 2H), 2.05 (m, 1H), 1.87 (s, 3H), 1.82 (m, 3H),
1.73 (d, 1H), 1.64 (m, 3H), 1.35 (m, 2H), 0.94 (t, 3H). 5 468.3 2.1
6 401.7 1.8 (300 MZ, CDCl3) 7.15 (dd, 1H), 6.94 (m, 2H), 5.93 (m,
1H), 3.64 (m, 2H), 2.80-3.05 (m, 6H), 2.80 (m, 1H), 2.60 (t, 2H),
2.30 (m, 1H), 1.64-1.92 (m, 12H), 0.95 (s, 9H) 7 453.3 2.6 8 414.3
1.7 9 427.7 1.8 10 440.6 1.9 11 375.4 1.01 12 373.6 2.88 13 468.3
1.9 14 414.3 2.75 15 468.3 1.9 16 359.3 1.3 DMSO (d6): 9.15 (m,
1H), 8.18 (d, 1H), 7.35 (d, 1H), 7.30 (t, 1H), 7.20 (t, 1H), 7.17
(d, 1H), 4.92 (ddd, 1H), 3.63 (s, 3H), 3.43 (m, 2H), 3.15 (m, 4H),
2.47 (m, 2H), 2.20 (m, 2H), 2.05 (dd, 1H), 1.95 (m, 2H), 1.87 (s,
3H), 1.82 (m, 3H), 1.73 (d, 1H), 1.62 (m, 1H). 17 443.4 1.09 18
399.3 1.9 19 458.3 2.17 20 432.4 0.86 21 401.6 1.7 22 458.4 1.01 23
482.4 2.2 24 469.8 2 25 426.3 1.8 26 472.6 1.1 27 417.6 1.13 28
443.4 1.14 29 458.4 0.94 30 469.3 2.2 31 399.3 2.1 32 379.6 2.1 33
418.6 0.92 34 442.7 1.7 35 371.2 1.79 36 516.3 2.1 37 286.6 2.01 1H
NMR (500 MHz, DMSO (d6)): 9.02 (d, 1H), 7.33 (d, 1H), 7.21 (t, 1H),
7.13 (t, 1H), 7.06 (d, 1H), 3.44 (d, 2H), 3.19-3.10 (m, 4H), 2.72
(t, 2H), 2.20 (td, 2H), 1.90-1.84 (m, 2H), 1.76-1.64 (m, 4H), 1.59
(dd, 2H), 0.94 (s, 9H). 38 454.3 2 39 427.2 2.4 40 441.4 1.16 41
454.7 1.8 42 429.7 1.9 43 395.3 2.1 44 439.8 1.9 45 385.49 2 DMSO
(d6): 9.43 (br. s), 8.18 (d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.19
(t, 1H), 7.16 (d, 1H), 4.92 (q, 1H), 3.5 (m, 2H), 3.14 (m, 4H),
2.25 (m, 2H), 2.05 (dd, 1H), 1.87 (s, 3H), 1.81 (m, 3H), 1.72 (d,
1H), 1.69-1.51 (m, 4H), 1.25 (dd, 1H), 1.09 (dd, 1H), 0.95 (d, 3H),
0.90 (s, 9H). 46 432.6 0.95 47 371.4 2.04 48 383.38 1.9 49 361.2
1.54 DMSO (d6): 9.28 (m, 1H), 8.18 (d, 1H), 7.35 (d, 1H), 7.30 (t,
1H), 7.20 (t, 1H), 7.17 (d, 1H), 4.92 (m, 1H), 3.44 (m, 2H), 3.21
(m, 4H), 2.80 (m, 1H), 2.20 (m, 2H), 2.06 (m, 1H), 2.05 (s, 3H),
1.91 (q, 2H), 1.87 (s, 3H), 1.83 (m, 3H), 1.74 (d, 1H), 1.63 (m,
1H), 1.27 (d, 3H). 50 415.7 1.78 51 386.3 2.02 (500 MHz, DMSO-d6):
9.07 (m, 1H), 7.36 (d, 1H), 7.29 (t, 1H), 7.21 (t, 1H), 7.13 (d,
1H), 4.94 (t, 1H), 3.44 (dd, 2H), 3.21-3.11 (m, 4H), 2.78 (s, 6H),
2.46 (s, 3H), 2.45 (m, 2H), 2.01 (d, 1H), 1.98 (q, 1H), 1.81 (m,
2H), 1.63-1.55 (m, 4H), 0.93 (s, 9H). 52 458.6 1.09 53 386.2 2.04
54 427.7 1.8 55 480.3 2 56 329.29 1.49 DMSO (d6): 8.90 (br. s),
8.18 (d, 1H), 7.45 (d, 1H), 7.31 (t, 1H), 7.20 (t, 1H), 7.16 (d,
1H), 4.92 (q, 1H), 3.5 (m, 2H), 3.21-3.06 (m, 3H), 2.95 (m, 1H),
2.35 (m, 2H), 2.06 (dd, 1H), 1.87 (s, 3H), 192-1.77 (m, 4H), 1.69
(d, 1H), 1.62 (m, 1H), 1.43 (m, 1H), 1.21 (m, 1H), 0.99 (d, 3H),
0.91 (t, 3H). 57 383.6 1.74 58 409.3 1.9 59 472.6 1.07 60 440.3 1.8
62 356.3 2.1 63 405.4 1.11 64 343.3 1.55 DMSO (d6): 9.23 (br. s,
1H), 8.18 (d, 1H), 7.35 (d, 1H), 7.30 (t, 1H), 7.20 (t, 1H), 7.16
(d, 1H), 4.92 (q, 1H), 3.45 (m, 2H), 3.21-3.11 (m, 4H), 2.24-2.14
(m, 2H), 2.06 (dd, 1H), 1.87 (s, 3H), 1.82 (m, 3H), 1.73 (d, 1H),
1.67-1.55 (m, 3H), 0.93 (s, 9H). 65 438.4 0.82 66 329.2 1.5 DMSO
(d6): 8.20 (m, 1H), 8.17 (d, 1H), 7.48 (d, 1H), 7.32 (t, 1H), 7.20
(t, 1H), 7.16 (d, 1H), 4.92 (m, 1H), 3.43 (br. t, 3H), 3.32 (m,
2H), 3.05 (d, 2H), 2.42 (ddd, 2H), 2.06 (dd, 1H), 1.87 (s, 3H),
1.83 (m, 2H), 1.75 (d, 1H), 1.65 (m, 1H), 1.09 (s, 9H). 67 416.4
0.95 68 397.3 2.11 DMSO (d6): 9.07 (m, 1H), 8.18 (d, 1H), 7.35 (d,
1H), 7.30 (t, 1H), 7.20 (t, 1H), 7.17 (d, 1H), 5.10 (t, 1H), 4.92
(ddd, 1H), 3.41 (m, 2H), 3.15 (m, 4H), 2.19 (m, 2H), 2.05 (dd, 1H),
1.98 (m, 2H), 1.87 (s, 3H), 1.83 (m, 3H), 1.73 (d, 1H), 1.67 (m,
2H), 1.66 (s, 3H), 1.59 (s, 3H), 1.50 (m, 2H), 1.32 (m, 1H), 1.19
(m, 1H), 0.91 (d, 3H). 69 423.3 1.9 70 387.3 2 71 454.3 1.9 72
472.4 1.09 73 343.3 1.59 DMSO (d6): 8.67 (br. s, 1H), 8.18 (d, 1H),
7.41 (d, 1H), 7.31 (t, 1H), 7.20 (t, 1H), 7.17 (d, 1H), 4.93 (q,
1H), 3.42 (m, 2H), 3.16 (t, 2H), 3.05 (t, 2H), 2.30 (qd, 2H), 2.07
(dd, 1H), 1.87 (s, 3H), 1.85-1.67 (m, 5H), 1.62 (m, 1H), 1.38 (m,
4H), 0.87 (t, 6H). 74 406.3 1.9 75 430.4 0.87 76 444.4 0.94 77
389.4 1.21 78 458.4 1.03 79 438.4 0.83 80 365.33 1.68 DMSO (d6):
9.19 (br.s, 1H), 7.47 (d, 1H), 7.45 (d, 1H), 7.35 (t, 1H), 7.23 (t,
1H), 4.45 (q, 1H), 3.43 (m, 2H), 3.14 (m, 4H), 3.05 (s, 3H), 2.18
(m, 2H), 2.08 (dd, 1H), 1.95 (m, 1H), 1.88-1.74 (m, 3H), 1.71 (d,
1H), 1.65-1.53 (m, 3H), 0.93 (d, 6H). 81 472.6 1.04 82 472.6 1.16
83 472.6 1.14 84 440.3 1.8 85 387.3 1.7 86 403.6 1.26 87 441.3 1.8
88 429.7 2.3 89 272.5 1.94 1H NMR (500 MHz, DMSO (d6)): 9.02 (s,
1H), 7.33 (d, 1H), 7.21 (t, 1H), 7.13 (t, 1H), 7.06 (d, 1H), 3.42
(d, 2H), 3.18-3.12 (m, 4H), 2.72 (t, 2H),
2.20 (td, 2H), 1.90-1.86 (m, 2H), 1.76-1.66 (m, 4H), 1.66-1.63 (m,
1H), 1.63-1.55 (m, 2H), 0.95 (d, 6H). 90 355.35 1.67 DMSO-d6: 9.44
(s, 1H), 7.43 (d, 1H), 7.31 (t, 1H), 7.20 (t, 1H), 6.93 (d, 1H),
5.14 (dd, 1H), 3.42 (dd, 2H), 3.24-3.09 (m, 5H), 2.87 (ddd, 1H),
2.41-2.29 (m, 4H), 2.07 (td, 1H), 1.92 (m, 3H), 1.87 (t, 1H), 1.74
(m, 1H), 1.66-1.56 (m, 5H), 0.93 (d, 6H). 91 387.6 1.8 92 417.6
1.05 93 445.4 1.04 94 453.3 1.9 95 301.2 1.27 DMSO (d6): 9.15 (m,
1H), 8.18 (d, 1H), 7.36 (d, 1H), 7.30 (t, 1H), 7.20 (t, 1H), 7.16
(d, 1H), 4.92 (m, 1H), 3.42 (m, 2H), 3.15 (m, 2H), 3.08 (m, 2H),
2.21 (ddd, 2H), 2.05 (dd, 1H), 1.87 (s, 3H), 1.81 (m, 3H),
1.76-1.58 (m, 4H), 0.94 (t, 3H). 96 432.6 0.93 97 311.1 1.83 DMSO
(d6): 9.17 (br. s, 1H), 7.43 (d, 1H), 7.40 (t, 1H), 7.36 (d, 1H),
7.28 (td, 1H), 4.35 (t, 1H), 3.45 (t, 2H), 3.21-3.12 (m, 4H), 2.24
(td, 1H), 2.16 (td, 1H), 2.10-1.96 (m, 4H), 1.77 (dd, 2H),
1.61-1.57 (m, 2H), 0.93 (s, 9H). 98 409.3 1.8 99 387.3 2.3 100
442.7 1.7 101 437.7 1.4 102 383.3 1.82 103 430.4 0.91 104 315.2
1.35 DMSO (d6): 8.78 (m, 1H), 8.18 (d, 1H), 7.41 (d, 1H), 7.31 (t,
1H), 7.20 (t, 1H), 7.16 (d, 1H), 4.92 (m, 1H), 3.41 (br. t, 2H),
3.15 (m, 2H), 3.00 (t, 2H), 2.30 (m, 2H), 2.12 (m 1H), 2.05 (dd,
1H), 1.87 (s, 3H), 1.80 (m, 3H), 1.70 (d, 1H), 1.63 (m, 1H), 0.99
(d, 6H). 105 -- -- 106 458.6 1.09 107 -- -- 108 406.3 2.1 109 440.3
1.7 110 453.6 2.1 111 434.7 1.7 112 515.4 2.3 113 454.4 1.9 114
414.3 2.4 115 423.3 2 116 415.7 1.8 117 336.6 2 1H NMR (300 MHz,
DMSO) 8.04 (dd, J = 1.4, 7.9 Hz, 1H), 7.93-7.87 (m, 1H), 7.65-7.55
(m, 2H), 3.6 (m, 2H), 3.32 (m, 2H), 3.22-3.15 (m, 2H), 3.09-2.98
(t, 2H), 2.50 (qn, J = 1.8 Hz, DMSO-d6), 2.38 (m, 2H), 1.98 (s,
1H), 1.93 (s, 1H), 1.61 (m, 2H), 0.96 (s, 9H) 118 409.3 2 119 387.2
1.14 120 338.5 1.7 121 454.7 1.8 122 383.7 1.82 123 357.2 1.72 (500
MHz, DMSO-d6): 9.14 (br.s, 1H), 7.40 and 7.38 (2d, 1H), 7.33 and
7.29 (2t, 1H), 7.24 and 7.20 (2t, 1H), 6.99 and 6.93 (2d, 1H), 5.67
(dd, 0.65 H), 5.03 (t, 0.33H), 3.43 (dd, 2H), 3.23-3.14 (m, 4H),
2.61 (s, 2H) and 2.43 (s, 1H, CH3), 2.45 (m, 2H), 2.17 (s, 1H) and
2.12 (s, 2H, CH3), 2.03-1.54 (m, 8H), 0.93 (s, 9H). 124 440.6 2 125
355.39 1.72 DMSO (d6): 9.11 (br.s, 1H), 8.40 (d, 1H), 7.36 (d, 1H),
7.31 (t, 1H), 7.21 (t, 1H), 7.16 (d, 1H), 4.95 (q, 1H), 3.43 (m,
2H), 3.16 (m, 4H), 2.20 (ddd, 2H), 2.08 (m, 1H), 1.83 (m, 3H), 1.73
(d, 1H), 1.68-1.54 (m, 5H), 0.93 (d, 6H), 0.78-0.63 (m, 4H). 126
468.4 1.7 127 442.3 1.8 128 437.7 1.4 129 409.2 1.9 131 384.6 2.34
300 MHz, DMSO- d6: 9.35 (m, 1H), 7.36-7.27 (m, 3H), 7.20 (td, 1H),
4.45 (m, 1H), 3.45 (m, 1H), 3.44 (d, 2H), 3.21-3.10 (m, 4H),
2.28-1.46 (m, 15H), 1.36-1.17 (m, 5H), 0.93 (s, 9H). 132 468.8 2.06
133 417.4 1.06 134 -- -- 135 427.3 1.9 136 448.2 1.6 137 440.3 1.9
138 458.6 1 139 -- -- 140 415.7 1.9 141 381.3 2.2 142 369.6 1.65
300 MHz, DMSO-d6: 9.03 (m, 1H), 7.37 (d, 1H), 7.27 (t, 1H), 7.12
(t, 1H), 6.94 (d, 1H), 5.19 (q, 1H), 3.44 (m, 2H), 3.22-3.10 (m,
4H), 2.69 (m, 4H), 2.29 (q, 1H), 2.25 (m, 2H), 2.08-1.92 (m, 2H),
1.65-1.55 (m, 6H), 0.94 (d, 6H). 143 454.3 1.8 144 426.3 1.7 145
445.6 1.1 146 440.4 1.9 147 387.3 1.9 148 358.3 1.87 DMSO (d6):
9.01 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.24 (d, 1H), 7.18 (t,
1H), 6.48 (d, 1H), 4.82 (q, 1H), 3.43 (d, 2H), 3.20-3.12 (m, 4H),
2.82 (s, 6H), 2.30 (td, 1H), 2.22 (dd, 1H), 2.06 (td, 1H), 1.93 (d,
1H), 1.83-1.77 (m, 1H), 1.73-1.55 (m, 6H), 0.93 (d, 6H). 149 472.4
1.11 150 327.1 1.71 DMSO (d6): 9.10 (s, 1H), 8.18 (d, 1H), 7.33 (t,
1H), 7.29 (d, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 5.29 (t, 1H), 4.92
(q, 1H), 3.76 (m, 2H), 3.34 (m, 2H), 3.16 (ddd, 2H), 2.16 (ddd,
2H), 2.07 (m, 1H), 1.87 (s, 3H), 1.81 (s, 3H), 1.75 (s, 3H),
1.86-1.79 (m, 4H), 1.66-1.59 (m, 1H). 151 423.3 2.1 152 427.3 2.1
153 519.7 2.34 300 MHz, DMSO- d6: 9.30 (m, 1H), 7.40-7.28 (m, 8H),
7.20 (td, 1H), 5.07 (s, 2H), 4.95 (t, 1H), 3.83-3.68 (m, 3H), 3.40
(m, 2H), 3.25-3.10 (m, 6H), 2.30-2.00 (m, 3H), 1.93-1.70 (m, 7H),
1.62-1.56 (m, 2H), 1.52-1.37 (m, 2H), 0.93 (s, 9H). 154 385.5 2.13
155 427.3 1.7 156 357.3 1.9 157 440.3 1.8 158 369.43 1.79 DMSO
(d6): 9.09 (br.s, 1H), 8.39 (d, 1H), 7.35 (d, 1H), 7.31 (t, 1H),
7.21 (t, 1H), 7.16 (d, 1H), 4.95 (q, 1H), 3.46 (m, 2H), 3.23-3.11
(m, 4H), 2.19 (ddd, 2H), 2.08 (m, 1H), 1.84 (m, 3H), 1.74 (d, 1H),
1.65 (ddd, 1H), 1.59 (m, 3H), 0.93 (s, 9H), 0.78-0.62 (m, 4H). 159
329.2 1.53 DMSO (d6): 9.23 (m, 1H), 8.18 (d, 1H), 7.36 (d, 1H),
7.30 (t, 1H), 7.20 (t, 1H), 7.17 (d, 1H), 4.92 (m, 1H), 3.43 (m,
2H), 3.14 (m, 4H), 2.20 (m, 2H), 2.04 (m, 1H), 1.87 (s, 3H), 1.81
(m, 3H), 1.72 (d, 1H), 1.59 (m, 4H), 0.92 (d, 6H). 160 440.3 1.8
161 393.7 2.17 162 414.3 2.76 163 432.4 0.89 164 371.8 2.17 165
427.4 0.92 166 498.3 2.1 167 468.3 1.7 168 387.6 1.8 7.14 (d, 1H),
6.94 (d, 2H), 5.35 (t, 1H), 3.68 (m, 2H), 2.90-3.30 (6H), 2.64 (mn,
2H), 2.45 (m1H), 2.30 (m, 1H), 1.80-2.05 (m, 4H), 1.63-1.75 (m,
6H), 0.94 (s, 9H). 169 454.3 1.9 170 441.3 2 171 428.7 1.6 172
327.2 1.49 DMSO (d6): 9.19 (m, 1H), 8.18 (d, 1H), 7.36 (d, 1H),
7.30 (t, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 5.84 (m, 1H), 5.11 (dq,
1H), 5.06 (dq, 1H), 4.92 (ddd, 1H), 3.43 (m, 2H), 3.14 (m, 4H),
2.20 (m, 2H), 2.11 (m, 2H), 2.03 (dd, 1H), 1.87 (s, 3H), 1.83 (m,
5H), 1.73 (d, 1H), 1.63 (m, 1H). 173 300.2 1.02 174 373.7 2.17 175
372.3 1.95 DMSO (d6): 9.01 (s,
1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.24 (d, 1H), 7.18 (t, 1H), 6.47
(d, 1H), 4.82 (m, 1H), 3.45 (d, 2H), 3.21-3.12 (m, 4H), 2.82 (s,
6H), 2.30 (td, 1H), 2.23 (dd, 1H), 2.05 (td, 1H), 1.93 (d, 1H),
1.83-1.77 (m, 1H), 1.74-1.65 (m, 3H), 1.58 (t, 2H), 0.94 (s, 9H).
176 383.8 2.43 177 361.4 0.91 178 411.8 2.34 179 382.39 1.6 DMSO
(d6): 9.43 (br. s), 8.18 (d, 1H), 7.39 (d, 1H), 7.30 (t, 1H), 7.20
(t, 1H), 7.16 (d, 1H), 4.92 (q, 1H), 3.5 (m, 2H), 3.15 (m, 4H),
2.25 (m, 2H), 2.05 (dd, 1H), 1.87 (s, 3H), 1.82 (m, 3H), 1.73 (m,
3H), 1.66-1.55 (m, 3H), 1.46 (m, 2H), 1.31 (s, 6H). .quadrature.
180 427.4 0.86 181 401.7 1.8 182 482.4 2.2 183 439.6 2.1 184 343.1
1.61 (500 MHz, DMSO-d6): 9.13 (br.s, 1H), 7.41 and 7.38 (2d, 1H),
7.33 and 7.29 (2t, 1H), 7.24 and 7.20 (2t, 1H), 6.99 and 6.93 (2d,
1H), 5.67 (dd, 0.65 H), 5.02 (t, 0.33H), 3.42 (dd, 2H), 3.23-3.10
(m, 4H), 2.61 (s, 2H) and 2.43 (s, 1H, CH3), 2.46 (m, 2H), 2.16 (s,
1H) and 2.11 (s, 2H, CH3), 2.03-1.54 (m, 9H), 0.93 and 0.89 (2d,
6H). 185 369.3 1.42 DMSO (d6): 9.41 (br. s, 1H), 8.18 (d, 1H), 7.36
(d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.16 (d, 1H), 4.92 (q, 1H),
3.45 (m, 2H), 3.20 (t, 4H), 2.46-2.35 (m, 2H), 2.27-2.18 (m, 2H),
2.06 (dd, 1H), 1.95 (m, 2H), 1.87 (s, 3H), 1.83 (m, 3H), 1.74 (d,
1H), 1.62 (m, 1H). 186 454.3 1.7 187 442.8 1.7 188 413.3 1.9 189
361.4 0.91 191 454.3 1.7 192 430.4 0.87 193 409.3 2 194 440.3 1.8
195 420.3 1.9 196 405.4 1.17 197 454.3 1.8 198 448.3 1.7 199 387.8
2.12 200 418.4 0.84 201 369.4 1.74 DMSO-d6: 9.87 (s, 1H), 7.45 (d,
1H), 7.30 (t, 1H), 7.20 (t, 1H), 6.93 (d, 1H), 5.14 (dd, 1H), 3.42
(t, 2H), 3.24-3.07 (m, 5H), 2.88 (m, 1H), 2.54 (td, 1H), 2.42-2.29
(m, 3H), 2.13 (td, 1H), 1.95-1.70 (m, 5H), 1.63 (m, 4H), 0.93 (s,
9H). 202 431.6 1.08 203 430.4 0.91 204 357.2 1.95 205 -- -- 206
372.3 1.94 (500 MHz, DMSO-d6): 9.00 (m, 1H), 7.37 (d, 1H), 7.29 (t,
1H), 7.21 (t, 1H), 7.13 (d, 1H), 4.94 (t, 1H), 3.44 (dd, 2H),
3.19-3.10 (m, 4H), 2.78 (s, 6H), 2.46 (s, 3H), 2.45 (m, 2H), 2.01
(d, 1H), 1.98 (q, 1H), 1.83 (m, 2H), 1.65-1.51 (m, 5H), 0.93 (d,
6H). 207 423.3 2.1 208 415.8 2.63 209 413.3 1.9 210 427.7 1.8 211
371.8 2.39 300 MHz, DMSO-d6 212 405.4 0.99 213 357.5 1.91 214 387.4
1.08 215 405.4 1.06 216 423.3 2 217 431.4 1.01 218 375.2 1.09 219
409.3 1.9 220 -- -- 221 415.7 1.8 222 401.6 1.8 223 448.8 1.4 224
397.6 1.91 300 MHz, DMSO-d6: 225 383.5 2.3 H NMR (500 MHz, DMSO)
9.02 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.34-7.27 (m, 2H),
7.19-7.16 (m, 2H), 5.36 (dd, J = 7.8, 15.8 Hz, 1H), 3.67-3.02 (m,
4H), 2.70-2.58 (m, 2H), 2.42-2.28 (m, 2H), 1.83-1.51 (m, 15H), 0.93
(s, 9H), 226 358.4 1.3 227 343.4 1.9 228 400.2 1.9 229 302.1 1.67
230 342.3 1.9 231 329.2 1.8 232 216.1 1.54 1H NMR (500 MHz, CDCl3):
7.41 (d, 1H), 7.10 (t, 1H), 7.00 (t, 1H), 6.95 (d, 1H), 2.70-2.66
(m, 4H), 2.28 (s, 3H), 2.20 (t, 2H), 2.11 (td, 2H), 1.76 (m, 2H),
1.71-1.64 (m, 2H), 1.53 (dd, 2H), 233 317.09 2.16 234 393.3 1.74
DMSO (d6): 9.32 (br.s, 1H), 8.19 (d, 1H), 7.43 (d, 2H), 7.34 (d,
1H), 7.28 (t, 1H), 7.18 (t, 1H), 7.15 (d, 1H), 7.02 (d, 2H), 4.92
(m, 1H), 4.30 (m, 2H), 4.06 (q, 2H), 3.23 (m, 4H), 2.17 (m, 2H),
2.05 (m, 1H), 1.86 (s, 3H), 1.82 (m, 3H), 1.73 (d, 1H), 1.62 (m,
1H), 1.33 (t, 3H). 235 358.3 1.5 236 329.3 1.5 237 345.4 1.5 238
313.4 1.7 239 362 3.02 CDCl3: 7.15 (s, 1H), 6.85 (s, 1H), 4.25
(brm, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 2.85 (brm, 2H), 2.59 (s,
2H), 1.89 (m, 2H), 1.50 (s, 9H), 1.47 (m, 2H) 241 330.2 1.2 242
313.4 1.6 243 315.4 1.6 244 329.4 1.8 245 358.4 1.3 246 302.2 1.59
247 341.2 1.9 248 383.5 2.3 249 330.2 1.2 250 316.2 1.73 251 384.5
2.1 252 316.2 3.47 (CDCl3, ppm) 7.52 (s, 1H), 7.44 (d, J = 8 Hz,
1H), 7.35 (d, J = 8 Hz), 1H), 4.18 (br s, 2H), 2.83 (t, J = 13 Hz,
2H), 2.60 (s, 2H), 2.39 (s, 3H), 1.94 (td, J = 4 Hz, 13 Hz, 2H),
1.48 (s, 9H), 1.44 (m, 2H). 253 343.2 1.92 254 317.09 2.16 255
407.3 3.5 256 303.06 1.63 257 373.5 1.6 258 383.3 1.4 259 302.2
1.56 260 359.3 2.94 DMS)(d6): 8.17 (d, 1H), 7.36 (d, 1H), 7.22
(ddd, 1H), 7.14 (m, 2H), 4.95 (m, 1H), 3.86 (m, 2H), 2.97 (m, 2H),
2.01 (m, 1H), 1.85 (s, 3H), 1.80 (m, 4H), 1.61 (m 2H), 1.48 (d,
1H), 1.42 (s, 9H). 261 359.4 3.09 CDCl3 (ppm): 7.06 (m, 3H), 5.58
(m, 1H), 5.46 (q, 1H, J = 8 Hz), 4.08 (br s, 2H), 3.72 (m, 1H),
2.85 (m, 2H), 2.74 (m, 1H), 2.33 (s, 3H), 2.03 (s, 3H), 1.98 (m,
1H), 1.82 (m, 1H), 1.60 (m, 2H), 1.48 (s. 9H). 262 340.2 1.3 263
341.4 1.8 264 357.5 2 H NMR (500 MHz, DMSO) 9.08 (s, 1H), 8.16 (d,
J = 8.2 Hz, 1H), 7.34-7.27 (m, 2H), 7.18 (dd, J = 7.3, 15.3 Hz,
2H), 5.37 (q, J = 7.9 Hz, 1H), 3.57-3.42 (m, 2H), 3.19-3.02 (m,
4H), 2.68 (dd, J = 7.9, 13.1 Hz, 1H), 2.36-2.07 (m, 4H), 1.90-1.54
(m, 8 H), 1.06-0.77 (m, 11H) 267 367.5 2 269 382.5 1.8 in DMSO-d6
271 iH NMR (CD3OD) 1.74-1.50 (m, 4H), 7.30-7.20 (m, 1H), 5.44 (t, J
= 7.9 Hz, 2H), 3.06-2.88 (m, 2H), 2.73 (dd, J = 7.8, 13.0 Hz, 1H),
2.32-2.21 (m, 2H), 2.08-2.00 (m, 1H), 1.74-1.50 (m, 4H), 1.48 (s,
9H), 1.18 (t, J = 7.6 Hz, 3H), 272 359.3 2.94 DMSO (d6): 8.17 (d,
1H), 7.36 (d, 1H), 7.22 (ddd, 1H), 7.14 (m, 2H), 4.95 (m, 1H), 3.86
(m, 2H), 2.97 (m, 2H), 2.01 (m, 1H), 1.85 (s, 3H), 1.80 (m, 4H),
1.61 (m 2H), 1.48 (d, 1H), 1.42 (s, 9H). 273 369.5 2.1 275 407.4
2.69 276 277 315.4 1.7 performed in DMSO-d6 279 371.3 3.2 280
359.19 3.02 DMSO (d6): 8.17 (d,
1H), 7.36 (d, 1H), 7.22 (ddd, 1H), 7.13 (m, 2H), 4.91 (td, 1H),
3.86 (m, 2H), 2.98 (m, 2H), 2.01 (dd, 1H), 1.86 (s, 3H), 1.61 (m,
4H), 1.80 (m, 2H), 1.48 (d, 1H), 1.42 (s, 9H). 282 383.5 2.3 287
386.3 2.2 performed 288 300.2 2.04 (DMSO-d6, ppm) 9.12 (br s, 1H),
7.59 (d, J = 8 Hz, 1H), 7.45 (m, 2H), 3.59 (d, J = 12 Hz, 2H), 3.14
(m, 2H), 3.07 (m, 2H), 2.73 (s, 2H), 2.39 (s, 3H), 2.15 (td, J = 3
Hz, 11 Hz, 2H), 1.75 (d, J = 14 Hz, 2H), 1.59 (m, 2H), 0.94 (s,
9H). 289 330.2 1.1 290 315.4 1.6 291 345.2 2 292 381.5 2.1 293
344.4 1.8 294 370.3 1.9 295 399.3 3.53 297 358.5 1.9 H NMR (500
MHz, DMSO) 9.08 (s, 1H), 7.33-7.14 (m, 4H), 6.55-6.48 (m, 1H),
5.32-5.24 (m, 2H), 3.54 (t, J = 13.3 Hz, 2H), 3.20-3.02 (m, 3H),
2.83 (s, 6H), 2.70 (dd, J = 7.8, 12.9 Hz, 1H), 2.36-2.28 (m, 1H),
1.83-1.52 (m, 6H), 0.98-0.90 (s, 9H), 298 374.3 3 299 369.5 2.2 300
355.3 2 H NMR (500 MHz, DMSO) 9.04 (s, 1H), 8.44 (d, J = 8.2 Hz,
1H), 7.35-7.17 (m, 4H), 5.36 (q, J = 7.9 Hz, 1H), 4.10-3.27 (m, 2H
partially obscured by solvent), 3.18-3.03 (m, 4H), 2.71-2.58 (m,
1H), 2.42-2.22 (m, 1H), 1.89-1.51 (m, 4H), 1.63-1.49 (m, 3H), 0.94
(s, 9H), 0.81-0.65 (m, 4H), 301 368.5 1.9 302 340.2 1.3 H NMR (500
MHz, DMSO) 9.02 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.34-7.27 (m,
2H), 7.19-7.16 (m, 2H), 5.36 (dd, J = 7.8, 15.8 Hz, 1H), 3.67-3.02
(m, 4H), 2.70-2.58 (m, 2H), 2.42-2.28 (m, 2H), 1.83-1.51 (m, 15H),
0.93 (s, 9H),
V. Assays for Detecting and Measuring Inhibition Properties of
Compounds
Functional Mobilization of Intracellular Calcium to Determine
Muscarinic Receptor Activity:
[0222] CHO cells expressing muscarinic receptors (M.sub.1 to
M.sub.5) are grown as monolayers in tissue culture flasks at
37.degree. C. in a humidified atmosphere containing 5% CO.sub.2 and
passaged every 3-5 days. The growth media is Dulbecco's modified
eagles medium (DMEM, Gibco Cat# 12430-054), containing 25 mM Hepes
and supplemented with Fetal Bovine Serum (Hyclone, cat#
SH30071.03), 0.1 mM of MEM non-essential amino acids (GIBCO, Cat#
11140-050), 1 mM MEM Sodium Pyruvate (GIBCO Cat# 11360-070) and 100
units/ml of Penicillin G and 100 .mu.g/ml of Streptomycin (GIBCO
Cat# 15140-122). The recombinant muscarinic receptor cell lines are
grown under antibiotic pressure with media containing 25 .mu.g/ml
zeocin and 500 m/ml G418 (M1-CHO), 4 .mu.g/ml puromycin, 50
.mu.g/ml zeocin and 2.5 .mu.g/ml blasticidin (M2 and M4-CHO) or 50
.mu.g/ml zeocin and 4 .mu.g/mlpuromycin (M3 and M5-CHO).
[0223] Cells are harvested at 80-90% confluence using Versene
(GIBCO Cat# 15040-066), collected by centrifugation and seeded
18-24 hrs prior to running the calcium assay at a density of
5,000-10,000 cells/well in back-walled, clear-bottomed 384-well
plates (BD Biocoat, poly-D-lysine, Cat#356663). The day of the
experiment, the cells are washed with a plate washer (Bioteck
Instruments, ELX 405) using bath1 buffer (140-mM NaCl, 4.5-mM KCl,
2-mM CaCl.sub.2, 1-mM MgCl.sub.2, 10-mM Hepes-Na, 10-mM Glucose, pH
7.4, with NaOH) containing 1 mM Probenecid. Next, the calcium dye
Fluo-3 (25 .mu.l/well of Fluo-3 AM at 4 .mu.M, Molecular Probes
F-1241, in Bath 1 buffer containing 1 mM Probenecid) is added to
the 25 .mu.l of Bath 1 remaining in each well after the plate wash
and the dye is loaded at 37.degree. C. in the tissue culture
incubator for 60-90 mM. The fluorescent dye is removed using the
plate washer with Bath 1 containing 1 mM Probenecid, leaving 25
.mu.l/well of this solution after the wash. Alternatively, cells
can be loaded with the calcium indicator from Molecular Devices
(Calcium 3 Assay Reagents, Cat # R7181) adding 5 .mu.l of a
5.times. solution dye in Bath 1 containing 1 mM Probenecid (10 ml
per dye flask cat# R7182 to generate a solution 20.times.) to 20
.mu.l of the same buffer. After loading for 60 min, the experiment
can be run without having to remove the dye.
[0224] Compounds are prepared at a 2.times. fold concentration in a
96-well plate (round bottom, Costar Corning cat# 3656), by
reconstituting the pre-spotted compounds in bath 1 containing 1 mM
probenecid. The final concentration DMSO is 0.5%, and the amount of
DMSO is normalized across the assay plate. To determine an agonist
action of the compounds on muscarinic receptors, the reconstituted
compounds are added (25 .mu.l compound/well) to the cell assay
plate (containing 25 .mu.l/well) using the multi-channel robotic
system of the FLIPR 3 Instrument (Molecular Devices, Sunnyvale,
Calif.). To determine a functional inhibitory action of the
compounds on muscarinic receptors, the reconstituted compounds are
added (25 .mu.l compound/well) to the assay plate and pre-incubated
for 15 min prior to adding 25 .mu.l of Carbachol at 3.times. the
EC80 for each muscarinic subtype. Alternatively, the compounds can
be co-applied simultaneously with the agonist. In both assay modes,
the fluorescence is recorded for 60 sec (excitation wavelength is
488 nM and emission wavelength 540 nm) using the FLIPR 3
instrument.
[0225] The potency, efficacy and selectivity of the muscarinic
compounds were evaluated by screening the compound activity across
the whole family (M.sub.1 to M.sub.5 cells). Compounds were also
screened for activity on other proteins such as other GPCRs and ion
channels to determine selectivity on M4 receptors.
[0226] The compounds of the present invention were found to
modulate the M.sub.1 and/or M.sub.4 muscarinic receptors
selectively over the other receptor types.
[0227] Examples of activities and efficacies of the muscarinic
compounds of formulae (I, Ia, Ib, Ic, Id, and Ie) on modulating
M.sub.1 and M.sub.4 receptors are shown below in Table 3. The
compound activity for the M.sub.1, M.sub.2, M.sub.3 and M.sub.4 is
illustrated with "+++" if activity was measured to be less than 2.0
.mu.M, "++" if activity was measured to be from 2.0 .mu.M to 5.0
.mu.M, "+" if activity was measured to be greater than 5.0 .mu.M,
and "-" if no data was available. The efficacy for M.sub.1 and
M.sub.4 modulation is illustrated with "+++" if efficacy was
calculated to be greater than 100%, "++" if efficacy was calculated
to be from 100% to 25%, "+" if efficacy was calculated to be less
than 25%, and "-" if no data was available. It should be noted that
100% efficacy is the maximum response obtained with the Carbachol
control.
TABLE-US-00003 TABLE 3 Compound activities and efficacies for
modulating M.sub.1 and M.sub.4 receptors. Compound M.sub.1 M.sub.1
M.sub.2 M.sub.2 M.sub.3 M.sub.3 M.sub.4 M.sub.4 No. Activity
Efficacy Activity Efficacy Activity Efficacy Activity Efficacy 1
+++ ++ ++ + + + +++ ++ 2 +++ ++ +++ ++ + + +++ ++ 3 + + + + + + +++
++ 4 ++ ++ + + + + ++ ++ 5 ++ + ++ + + + +++ ++ 6 + + + + + + +++
++ 7 ++ ++ + + + + +++ ++ 8 +++ ++ ++ + + + +++ ++ 9 + ++ + + + +
+++ ++ 10 + + + + + + +++ ++ 11 +++ ++ + + + + +++ ++ 12 +++ ++ +++
++ + + +++ ++ 13 + + + + + + +++ ++ 14 + ++ ++ + + + +++ ++ 15 +++
++ + + + + +++ ++ 16 ++ ++ + + + + + ++ 17 +++ ++ + + + + +++ ++ 18
+++ ++ +++ ++ + + +++ ++ 19 + + + + + + + + 20 +++ ++ +++ ++ + +
+++ ++ 21 +++ ++ +++ ++ + + +++ ++ 22 ++ ++ ++ + + + +++ ++ 23 ++ +
+ + + + +++ ++ 24 + + +++ ++ + + +++ ++ 25 + + + + + + +++ ++ 26
+++ ++ + + + + +++ ++ 27 +++ ++ +++ + + + +++ ++ 28 +++ ++ ++ + + +
+++ ++ 29 +++ ++ +++ ++ + + +++ ++ 30 + + + + + + ++ ++ 31 +++ ++
+++ + + + +++ ++ 32 +++ ++ +++ ++ + + +++ ++ 33 +++ ++ +++ ++ + +
+++ ++ 34 +++ ++ ++ + + + +++ ++ 35 + + + + + + +++ ++ 36 +++ ++ +
+ + + +++ ++ 37 ++ ++ ++ ++ + + +++ ++ 38 +++ ++ + + + + +++ ++ 39
+ ++ + + + + +++ ++ 40 +++ ++ +++ ++ + + +++ ++ 41 +++ ++ + + + +
+++ ++ 42 ++ ++ + + + + +++ ++ 43 +++ ++ +++ ++ + + +++ ++ 44 ++ ++
+ + + + +++ ++ 45 +++ ++ ++ + + ++ + + 46 +++ ++ +++ ++ + + +++ ++
47 ++ ++ + + + + ++ ++ 48 + + + + + + + + 49 ++ ++ + + + + +++ ++
50 + ++ + + + + +++ ++ 51 +++ ++ + + + + +++ ++ 52 +++ ++ +++ + + +
+++ ++ 53 + + + + + + +++ ++ 54 +++ ++ + + + + +++ ++ 55 ++ + +++ +
+ + +++ ++ 56 +++ ++ +++ ++ + + +++ ++ 57 ++ ++ + + + + +++ ++ 58
+++ ++ +++ ++ + + +++ ++ 59 +++ ++ ++ + + + +++ ++ 60 +++ ++ + + +
+ +++ ++ 61 + ++ + + + + + ++ 62 + + + + + + +++ ++ 63 +++ ++ +++ +
+ + +++ ++ 64 ++ + + + + + +++ ++ 65 +++ ++ ++ + + + +++ ++ 66 +++
++ + ++ + + +++ ++ 67 +++ ++ +++ ++ + + +++ ++ 68 +++ +++ +++ ++ +
+ +++ ++ 69 + + + + + + +++ ++ 70 +++ ++ +++ + + + +++ ++ 71 +++ ++
+++ ++ + + +++ ++ 72 ++ ++ ++ + + + +++ ++ 73 +++ ++ + + + + +++ ++
74 +++ ++ +++ ++ + + +++ ++ 75 ++ ++ ++ + + + +++ ++ 76 +++ ++ +++
++ + + +++ ++ 77 +++ ++ ++ + + + +++ ++ 78 +++ ++ +++ ++ + + +++ ++
79 +++ ++ +++ ++ + + +++ ++ 80 +++ ++ + + + + +++ ++ 81 ++ ++ + + +
+ +++ ++ 82 +++ ++ ++ + + + +++ ++ 83 +++ ++ + + + + +++ ++ 84 ++
++ +++ ++ + + +++ ++ 85 +++ ++ +++ ++ + + +++ ++ 86 +++ ++ + + + +
+++ ++ 87 + + + + + + +++ ++ 88 +++ ++ +++ ++ + + +++ ++ 89 + ++ +
+ + + +++ ++ 90 ++ ++ + + + + ++ ++ 91 +++ ++ +++ + + + +++ ++ 92
+++ ++ +++ ++ + + +++ ++ 93 ++ ++ + + + + +++ ++ 94 + ++ + + + +
+++ ++ 95 + ++ + + + + + ++ 96 +++ ++ +++ ++ + + +++ ++ 97 +++ ++
+++ ++ + + +++ ++ 98 +++ ++ + + + + +++ ++ 99 + + + + + + +++ ++
100 + + + + + + +++ ++ 101 +++ ++ + + + + ++ ++ 102 ++ ++ + + + +
+++ ++ 103 +++ ++ +++ + + + +++ ++ 104 ++ ++ + ++ + + ++ ++ 105 ++
+ + + + + +++ ++ 106 +++ ++ +++ ++ + + +++ ++ 107 ++ ++ ++ + + +
+++ ++ 108 +++ ++ +++ + + + +++ ++ 109 +++ ++ + + + + +++ ++ 110 +
++ + + + + +++ ++ 111 + + + + + + +++ ++ 112 ++ ++ + + + + +++ ++
113 + + + + + + +++ ++ 114 - - - - - - - - 115 +++ ++ +++ ++ + +
+++ ++ 116 + ++ + + + + +++ ++ 117 +++ ++ +++ ++ + + +++ ++ 118 ++
++ + + + + +++ ++ 119 +++ ++ +++ ++ + + +++ ++ 120 +++ ++ +++ ++ +
+ +++ ++ 121 +++ ++ + + + + +++ ++ 122 +++ ++ + + + + +++ ++ 123
+++ ++ + + + + +++ ++ 124 +++ ++ +++ ++ + + +++ ++ 125 +++ ++ ++ +
+ + +++ ++ 126 + + + + + + +++ ++ 127 +++ ++ ++ + + + +++ ++ 128 ++
++ + + + + +++ ++ 129 + + + + + + +++ ++ 130 ++ ++ + + + + +++ ++
131 - - - - - - - - 132 ++ ++ + + + + +++ ++ 133 +++ ++ +++ ++ + +
+++ ++ 134 + + + + + + +++ ++ 135 +++ ++ + + + + +++ ++ 136 ++ ++
++ + + + +++ ++ 137 +++ ++ + + + + +++ ++ 138 +++ ++ +++ ++ + + +++
++ 139 ++ + + + + + +++ ++ 140 ++ ++ + + + + +++ ++ 141 +++ ++ + +
+ + +++ ++ 142 ++ ++ + + + + + + 143 ++ ++ + + + + +++ ++ 144 +++
++ +++ ++ + + +++ ++ 145 +++ ++ +++ + + + +++ ++ 146 + ++ + + + +
+++ ++ 147 +++ ++ +++ ++ + + +++ ++ 148 + + + + + + ++ ++ 149 ++ ++
++ ++ + + +++ ++ 150 + ++ + + + + ++ ++ 151 +++ ++ + + + + +++ ++
152 + + + + + + +++ ++ 153 - - - - - - - - 154 +++ ++ + + + + +++
++ 155 +++ ++ ++ ++ + + +++ ++ 156 +++ ++ +++ ++ + + +++ ++ 157 ++
++ +++ + + + +++ ++ 158 +++ ++ +++ ++ + + +++ ++ 159 +++ ++ + + + +
+++ ++ 160 +++ ++ + + + + +++ ++ 161 +++ ++ + + + + +++ ++ 162 + ++
+ + + + +++ ++ 163 +++ ++ +++ ++ + + +++ ++ 164 +++ ++ + + + + +++
++ 165 +++ ++ +++ ++ + + +++ ++ 166 + ++ + + + + +++ ++ 167 +++ ++
+ + + + +++ ++ 168 ++ + + + + + +++ ++ 169 +++ ++ +++ + + + +++ ++
170 + + + + + + +++ ++ 171 +++ ++ +++ ++ + + +++ ++ 172 +++ ++ ++
++ + + +++ ++ 173 +++ ++ +++ ++ + + +++ ++ 174 ++ ++ + + + + +++ ++
175 + + + + + + +++ ++ 176 ++ + + + + + +++ ++ 177 +++ ++ +++ ++ +
+ +++ ++ 178 + + + + + + +++ ++ 179 +++ ++ + + + + + + 180 +++ ++
+++ ++ + + +++ ++ 181 ++ ++ + + + + +++ ++ 182 ++ ++ + + + + +++ ++
183 ++ ++ + + + + +++ ++ 184 +++ ++ + + + + +++ ++ 185 ++ ++ + + +
++ ++ ++ 186 ++ ++ + + + + +++ ++ 187 +++ ++ + + + + +++ ++ 188 + +
+ + + + +++ ++ 189 +++ ++ +++ + + + +++ ++ 190 +++ ++ +++ ++ + +
+++ ++ 191 +++ ++ + + + + +++ ++ 192 + + + + + + +++ ++ 193 +++ ++
+ + + + +++ ++ 194 +++ ++ + + + + +++ ++ 195 +++ ++ +++ ++ + + +++
++ 196 +++ ++ +++ ++ + + +++ ++ 197 +++ ++ +++ ++ + + +++ ++ 198
+++ ++ ++ + + + +++ ++ 199 ++ + + + + + +++ ++ 200 +++ ++ +++ ++ +
+ +++ ++ 201 +++ ++ + + + + +++ ++ 202 +++ ++ + + + + +++ ++ 203
+++ ++ +++ ++ + + +++ ++ 204 +++ ++ + + + + +++ ++ 205 +++ ++ + + +
+ +++ ++ 206 + + + + + + +++ ++ 207 ++ ++ + + + + +++ ++ 208 +++ ++
+++ + + + +++ ++ 209 +++ ++ + + + + +++ ++ 210 +++ + + + + + +++ ++
211 +++ ++ + + + + +++ ++ 212 +++ ++ + + + + +++ ++ 213 ++ ++ + + +
+ +++ ++ 214 +++ ++ +++ + + + +++ ++ 215 +++ ++ +++ ++ + + +++ ++
216 ++ ++ ++ ++ + + +++ ++ 217 ++ ++ + + + + +++ ++ 218 +++ ++ +++
+ + + +++ ++ 219 +++ ++ +++ ++ + + +++ ++ 220 + + + + + + +++ ++
221 ++ ++ + + + + +++ ++ 222 +++ ++ + + + + +++ ++ 223 + ++ + + + +
+++ ++ 224 +++ ++ + + + + +++ ++ 225 + + + + + + + + 226 + + + + +
+ + + 227 + + + + + + + + 228 - - - - - - - - 229 + + + + + + + +
230 +++ ++ + + + + +++ ++ 231 + + + + + + +++ + 232 + + + + + + + +
233 + ++ + + + + + + 234 ++ ++ + + + + ++ ++ 235 + + + + + + + +
236 + + + + + + + + 237 + ++ + + + + + ++ 238 + + + + + + + + 239 +
+ + + + + + + 241 + + + + + + + + 242 + ++ + + + + ++ ++ 243 + ++ +
++ + + +++ ++
244 +++ ++ + + + + +++ ++ 245 + + + + + + + + 246 + + + + + + + +
247 + ++ + + + + + + 248 ++ ++ + + + + + ++ 249 + + + + + + + + 250
+ ++ + + + + + ++ 251 + + + + + + + + 252 + + + + + + + + 253 + + +
+ + + + ++ 254 + ++ + + + + + + 255 + + + + + + + + 256 + + + + + +
+ + 257 +++ +++ +++ ++ + ++ +++ ++ 258 + + + + + + + + 259 + ++ + +
+ + + + 260 + + + + + + + + 261 + + + + + + + + 262 + + + + + + + +
263 + ++ + + + + ++ + 264 + + + + + + +++ ++ 267 + + + + + + + +
269 + ++ + + + + ++ ++ 271 + + + + + + + + 272 + + + + + + + + 273
+++ ++ + + + + +++ ++ 275 + + + + - - + + 276 + + + + + + + + 277
++ ++ + + + + +++ ++ 279 + + + + + + + + 280 + + + + + + + + 282
+++ ++ + + + + + + 287 - - - - - - - - 288 + ++ + + + + ++ ++ 289 +
+ + + + + + + 290 + ++ + + + + + ++ 291 - - - - - - - - 292 + + + +
+ + + + 293 + + + + + + + + 294 + + + + + + + + 295 + + + + + + + +
297 + + + + + + + + 298 + + + + + + + + 299 + + + + + + + + 300 +++
++ + + + + +++ + 301 + + + + + + + + 302 + + + + + + + +
VIII. Other Embodiments
[0228] It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims.
* * * * *