U.S. patent application number 13/437234 was filed with the patent office on 2012-10-04 for kinase inhibitors.
This patent application is currently assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED. Invention is credited to Jason W. Brown, Qing Dong, Bheema R. Paraselli, Nicholas Scorah, Jeffrey A. Stafford, Michael B. Wallace, Hasanthi Wijesekera.
Application Number | 20120252761 13/437234 |
Document ID | / |
Family ID | 41591726 |
Filed Date | 2012-10-04 |
United States Patent
Application |
20120252761 |
Kind Code |
A1 |
Brown; Jason W. ; et
al. |
October 4, 2012 |
KINASE INHIBITORS
Abstract
Compounds are provided for use with kinases that comprise a
compound selected from the group consisting of: ##STR00001##
wherein the variables are as defined herein. Also provided are
pharmaceutical compositions, kits and articles of manufacture
comprising such compounds; methods and intermediates useful for
making the compounds; and methods of using said compounds.
Inventors: |
Brown; Jason W.; (San Diego,
CA) ; Dong; Qing; (San Diego, CA) ; Paraselli;
Bheema R.; (San Diego, CA) ; Scorah; Nicholas;
(San Diego, CA) ; Stafford; Jeffrey A.; (San
Diego, CA) ; Wallace; Michael B.; (San Diego, CA)
; Wijesekera; Hasanthi; (Brookwater, AU) |
Assignee: |
TAKEDA PHARMACEUTICAL COMPANY
LIMITED
Osaka
JP
|
Family ID: |
41591726 |
Appl. No.: |
13/437234 |
Filed: |
April 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12103882 |
Apr 16, 2008 |
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13437234 |
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60912629 |
Apr 18, 2007 |
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Current U.S.
Class: |
514/81 ;
546/23 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 487/04 20130101; A61P 19/02 20180101; A61P 29/00 20180101;
C07D 401/12 20130101; A61P 25/28 20180101; C07D 241/18 20130101;
A61P 25/16 20180101; A61P 35/00 20180101; C07D 471/14 20130101;
C07D 471/04 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/81 ;
546/23 |
International
Class: |
A61K 31/675 20060101
A61K031/675; C07F 9/6561 20060101 C07F009/6561 |
Claims
1-92. (canceled)
93. The compound
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate or a
pharmaceutically acceptable salt thereof.
94. A pharmaceutical composition comprising the compound
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate or a
pharmaceutically acceptable salt thereof and a pharmaceutically
excipient.
Description
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/912,629 filed Apr. 18, 2007, which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds that may be used
to inhibit kinases as well as compositions of matter, kits and
articles of manufacture comprising these compounds. The present
invention also relates to methods for inhibiting kinases as well as
treatment methods using compounds according to the present
invention. In addition, the present invention relates to methods of
making the compounds of the present invention, as well as
intermediates useful in such methods. In particular, the present
invention relates to Aurora kinase inhibitors; compositions of
matter, kits and articles of manufacture comprising these
compounds; methods for inhibiting Aurora kinase; and methods of
making Aurora kinase inhibitors.
BACKGROUND OF THE INVENTION
[0003] The present invention relates to inhibitors of enzymes that
catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides,
compositions comprising the inhibitors, kits and articles of
manufacture comprising the inhibitors and compositions, methods of
making the inhibitors and compositions, and methods of using the
inhibitors and inhibitor compositions. The inhibitors and
compositions comprising them are useful for treating or modulating
disease in which phosphoryl transferases, including kinases, may be
involved, symptoms of such disease, or the effect of other
physiological events mediated by phosphoryl transferases, including
kinases. The invention also provides for methods of making the
inhibitor compounds and methods for treating diseases in which one
or more phosphoryl transferase, including kinase, activities is
involved.
[0004] Phosphoryl transferases are a large family of enzymes that
transfer phosphorous-containing groups from one substrate to
another. By the conventions set forth by the Nomenclature Committee
of the International Union of Biochemistry and Molecular Biology
(IUBMB) enzymes of this type have Enzyme Commission (EC) numbers
starting with 2.7.-.- (See, Bairoch A., The ENZYME database in
Nucleic Acids Res. 28:204-305 (2000)). Kinases are a class of
enzymes that function in the catalysis of phosphoryl transfer. The
protein kinases constitute the largest subfamily of structurally
related phosphoryl transferases and are responsible for the control
of a wide variety of signal transduction processes within the cell.
(See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts
Book, I and II, Academic Press, San Diego, Calif.). Protein kinases
are thought to have evolved from a common ancestral gene due to the
conservation of their structure and catalytic function. Almost all
kinases contain a similar 250-300 amino acid catalytic domain. The
protein kinases may be categorized into families by the substrates
they phosphorylate (e.g., protein-tyrosine,
protein-serine/threonine, histidine, etc.). Protein kinase sequence
motifs have been identified that generally correspond to each of
these kinase families (See, for example, Hanks, S. K.; Hunter, T.,
FASEB J. 9:576-596 (1995); Kinghton et al., Science, 253:407-414
(1991); Hiles et al., Cell 70:419-429 (1992); Kunz et al., Cell,
73:585-596 (1993); Garcia-Bustos et al., EMBO J., 13:2352-2361
(1994)). Lipid kinases (e.g. PI3K) constitute a separate group of
kinases with structural similarity to protein kinases.
[0005] Protein and lipid kinases regulate many different cell
processes including, but not limited to, proliferation, growth,
differentiation, metabolism, cell cycle events, apoptosis,
motility, transcription, translation and other signaling processes,
by adding phosphate groups to targets such as proteins or lipids.
Phosphorylation events catalyzed by kinases act as molecular on/off
switches that can modulate or regulate the biological function of
the target protein. Phosphorylation of target proteins occurs in
response to a variety of extracellular signals (hormones,
neurotransmitters, growth and differentiation factors, etc.), cell
cycle events, environmental or nutritional stresses, etc. Protein
and lipid kinases can function in signaling pathways to activate or
inactivate, or modulate the activity of (either directly or
indirectly) the targets. These targets may include, for example,
metabolic enzymes, regulatory proteins, receptors, cytoskeletal
proteins, ion channels or pumps, or transcription factors.
Uncontrolled signaling due to defective control of protein
phosphorylation has been implicated in a number of diseases and
disease conditions, including, for example, inflammation, cancer,
allergy/asthma, diseases and conditions of the immune system,
disease and conditions of the central nervous system (CNS),
cardiovascular disease, dermatology, and angiogenesis.
[0006] Initial interest in protein kinases as pharmacological
targets was stimulated by the findings that many viral oncogenes
encode structurally modified cellular protein kinases with
constitutive enzyme activity. These findings pointed to the
potential involvement of oncogene related protein kinases in human
proliferatives disorders. Subsequently, deregulated protein kinase
activity, resulting from a variety of more subtle mechanisms, has
been implicated in the pathophysiology of a number of important
human disorders including, for example, cancer, CNS conditions, and
immunologically related diseases. The development of selective
protein kinase inhibitors that can block the disease pathologies
and/or symptoms resulting from aberrant protein kinase activity has
therefore generated much interest.
[0007] Cancer results from the deregulation of the normal processes
that control cell division, differentiation and apoptotic cell
death. Protein kinases play a critical role in this regulatory
process. A partial non-limiting list of such kinases includes ab1,
Aurora-A, Aurora-B, Aurora-C, ATK, bcr-ab1, Blk, Brk, Btk, c-Kit,
c-Met, c-Src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR,
ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4,
FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak,
KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tie1, Tie2,
Trk, Yes and Zap70. In mammalian biology, such protein kinases
comprise mitogen activated protein kinase (MAPK) signaling
pathways. MAPK signaling pathways are inappropriately activated by
a variety of common disease-associated mechanisms such as mutation
of ras genes and deregulation of growth factor receptors (Magnuson
et al., Seminars in Cancer Biology 5:247-252 (1994)). Therefore the
inhibition of protein kinases is an object of the present
invention.
[0008] Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are
serine/threonine protein kinases that have been implicated in human
cancer, such as colon, breast and other solid tumors. Aurora-A
(also sometimes referred to as AIK) is believed to be involved in
protein phosphorylation events that regulate the cell cycle.
Specifically, Aurora-A may play a role in controlling the accurate
segregation of chromosomes during mitosis. Misregulation of the
cell cycle can lead to cellular proliferation and other
abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B and
Aurora-C have been found to be overexpressed (See, Bischoff et al.,
EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol.
143:1635-1646 (1998); Kimura et al., J. Biol. Chem.,
272:13766-13771 (1997)).
[0009] There is a continued need to find new therapeutic agents to
treat human diseases. The protein kinases, specifically but not
limited to Aurora-A, Aurora-B and Aurora-C are especially
attractive targets for the discovery of new therapeutics due to
their important role in cancer, diabetes, Alzheimer's disease and
other diseases.
SUMMARY OF THE INVENTION
[0010] The present invention relates to compounds that have
activity for inhibiting kinases. The present invention also
provides compositions, articles of manufacture and kits comprising
these compounds.
[0011] In one embodiment, a pharmaceutical composition is provided
that comprises a kinase inhibitor according to the present
invention as an active ingredient. Pharmaceutical compositions
according to the invention may optionally comprise 0.001%-100% of
one or more kinase inhibitors of this invention. These
pharmaceutical compositions may be administered or coadministered
by a wide variety of routes, including for example, orally,
parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery (for example by
catheter or stent), subcutaneously, intraadiposally,
intraarticularly, or intrathecally. The compositions may also be
administered or coadministered in slow release dosage forms.
[0012] The invention is also directed to kits and other articles of
manufacture for treating disease states associated with
kinases.
[0013] In one embodiment, a kit is provided that comprises a
composition comprising at least one kinase inhibitor of the present
invention in combination with instructions. The instructions may
indicate the disease state for which the composition is to be
administered, storage information, dosing information and/or
instructions regarding how to administer the composition. The kit
may also comprise packaging materials. The packaging material may
comprise a container for housing the composition. The kit may also
optionally comprise additional components, such as syringes for
administration of the composition. The kit may comprise the
composition in single or multiple dose forms.
[0014] In another embodiment, an article of manufacture is provided
that comprises a composition comprising at least one kinase
inhibitor of the present invention in combination with packaging
materials. The packaging material may comprise a container for
housing the composition. The container may optionally comprise a
label indicating the disease state for which the composition is to
be administered, storage information, dosing information and/or
instructions regarding how to administer the composition. The kit
may also optionally comprise additional components, such as
syringes for administration of the composition. The kit may
comprise the composition in single or multiple dose forms.
[0015] Also provided are methods for preparing compounds,
compositions and kits according to the present invention. For
example, several synthetic schemes are provided herein for
synthesizing compounds according to the present invention.
[0016] Also provided are methods for using compounds, compositions,
kits and articles of manufacture according to the present
invention.
[0017] In one embodiment, the compounds, compositions, kits and
articles of manufacture are used to inhibit kinases. In particular,
the compounds, compositions, kits and articles of manufacture are
used to inhibit an Aurora kinase.
[0018] In another embodiment, the compounds, compositions, kits and
articles of manufacture are used to treat a disease state for which
kinases possess activity that contributes to the pathology and/or
symptomology of the disease state.
[0019] In another embodiment, a compound is administered to a
subject wherein kinases activity within the subject is altered,
preferably reduced.
[0020] In another embodiment, a prodrug of a compound is
administered to a subject that is converted to the compound in vivo
where it inhibits kinases.
[0021] In another embodiment, a method of inhibiting kinases is
provided that comprises contacting kinases with a compound
according to the present invention.
[0022] In another embodiment, a method of inhibiting kinases is
provided that comprises causing a compound according to the present
invention to be present in a subject in order to inhibit kinases in
vivo.
[0023] In another embodiment, a method of inhibiting kinases is
provided that comprises administering a first compound to a subject
that is converted in vivo to a second compound wherein the second
compound inhibits kinases in vivo. It is noted that the compounds
of the present invention may be the first or second compounds.
[0024] In another embodiment, a therapeutic method is provided that
comprises administering a compound according to the present
invention.
[0025] In another embodiment, a method of inhibiting cell
proliferation is provided that comprises contacting a cell with an
effective amount of a compound according to the present
invention.
[0026] In another embodiment, a method of inhibiting cell
proliferation in a patient is provided that comprises administering
to the patient a therapeutically effective amount of a compound
according to the present invention.
[0027] In another embodiment, a method of treating a condition in a
patient which is known to be mediated by kinases, or which is known
to be treated by kinase inhibitors, comprising administering to the
patient a therapeutically effective amount of a compound according
to the present invention.
[0028] In another embodiment, a method is provided for using a
compound according to the present invention in order to manufacture
a medicament for use in the treatment of disease state which is
known to be mediated by kinases, or which is known to be treated by
kinase inhibitors.
[0029] In another embodiment, a method is provided for treating a
disease state for which kinases possess activity that contributes
to the pathology and/or symptomology of the disease state, the
method comprising: causing a compound according to the present
invention to be present in a subject in a therapeutically effective
amount for the disease state.
[0030] In another embodiment, a method is provided for treating a
disease state for which kinases possess activity that contributes
to the pathology and/or symptomology of the disease state, the
method comprising: administering a first compound to a subject that
is converted in vivo to a second compound such that the second
compound is present in the subject in a therapeutically effective
amount for the disease state. It is noted that the compounds of the
present invention may be the first or second compounds.
[0031] In another embodiment, a method is provided for treating a
disease state for which kinases possesses activity that contributes
to the pathology and/or symptomology of the disease state, the
method comprising: administering a compound according to the
present invention to a subject such that the compound is present in
the subject in a therapeutically effective amount for the disease
state.
[0032] It is noted in regard to all of the above embodiments that
the present invention is intended to encompass all pharmaceutically
acceptable ionized forms (e.g., salts) and solvates (e.g.,
hydrates) of the compounds, regardless of whether such ionized
forms and solvates are specified since it is well know in the art
to administer pharmaceutical agents in an ionized or solvated form.
It is also noted that unless a particular stereochemistry is
specified, recitation of a compound is intended to encompass all
possible stereoisomers (e.g., enantiomers or diastereomers
depending on the number of chiral centers), independent of whether
the compound is present as an individual isomer or a mixture of
isomers. Further, unless otherwise specified, recitation of a
compound is intended to encompass all possible resonance forms and
tautomers. With regard to the claims, the language "compound
comprising the formula" is intended to encompass the compound and
all pharmaceutically acceptable ionized forms and solvates, all
possible stereoisomers, and all possible resonance forms and
tautomers unless otherwise specifically specified in the particular
claim.
[0033] It is further noted that prodrugs may also be administered
which are altered in vivo and become a compound according to the
present invention. The various methods of using the compounds of
the present invention are intended, regardless of whether prodrug
delivery is specified, to encompass the administration of a prodrug
that is converted in vivo to a compound according to the present
invention. It is also noted that certain compounds of the present
invention may be altered in vivo prior to inhibiting kinases and
thus may themselves be prodrugs for another compound. Such prodrugs
of another compound may or may not themselves independently have
kinase inhibitory activity.
BRIEF DESCRIPTION OF THE FIGURES
[0034] FIG. 1 is a characteristic XRPD spectrum of an amorphous
form of Compound 88.
DEFINITIONS
[0035] Unless otherwise stated, the following terms used in the
specification and claims shall have the following meanings for the
purposes of this application.
[0036] "Alicyclic" means a moiety comprising a non-aromatic ring
structure. Alicyclic moieties may be saturated or partially
unsaturated with one, two or more double or triple bonds. Alicyclic
moieties may also optionally comprise heteroatoms such as nitrogen,
oxygen and sulfur. The nitrogen atoms can be optionally
quaternerized or oxidized and the sulfur atoms can be optionally
oxidized. Examples of alicyclic moieties include, but are not
limited to moieties with (C.sub.3-8) rings such as cyclopropyl,
cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,
cyclohexane, cyclohexene, cyclohexadiene, cycloheptane,
cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and
cyclooctadiene.
[0037] "Aliphatic" means a moiety characterized by a straight or
branched chain arrangement of constituent carbon atoms and may be
saturated or partially unsaturated with one, two or more double or
triple bonds.
[0038] "Alkenyl" means a straight or branched, carbon chain that
contains at least one carbon-carbon double bond (--CR.dbd.CR'-- or
--CR.dbd.CR'R'', wherein R, R' and R'' are each independently
hydrogen or further substituents). Examples of alkenyl include
vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl,
2-butenyl, 2-methyl-2-butenyl, and the like. In particular
embodiments, "alkenyl," either alone or represented along with
another radical, can be a (C.sub.2-20)alkenyl, a
(C.sub.2-15)alkenyl, a (C.sub.2-10)alkenyl, a (C.sub.2-5)alkenyl or
a (C.sub.2-3)alkenyl. Alternatively, "alkenyl," either alone or
represented along with another radical, can be a (C.sub.2)alkenyl,
a (C.sub.3)alkenyl or a (C.sub.4)alkenyl.
[0039] "Alkenylene" means a straight or branched, divalent carbon
chain having one or more carbon-carbon double bonds
(--CR.dbd.CR'--, wherein R and R' are each independently hydrogen
or further substituents). Examples of alkenylene include
ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the
like. In particular embodiments, "alkenylene," either alone or
represented along with another radical, can be a (C.sub.2-20)
alkenylene, a (C.sub.2-15) alkenylene, a (C.sub.2-10) alkenylene, a
(C.sub.2-5) alkenylene or a (C.sub.2-3) alkenylene. Alternatively,
"alkenylene," either alone or represented along with another
radical, can be a (C.sub.2) alkenylene, a (C.sub.3) alkenylene or a
(C.sub.4) alkenylene.
[0040] "Alkoxy" means an oxygen moiety having a further alkyl
substituent. The alkoxy groups of the present invention can be
optionally substituted.
[0041] "Alkyl" represented by itself means a straight or branched,
saturated or unsaturated, aliphatic radical having a chain of
carbon atoms, optionally with one or more of the carbon atoms being
replaced with an oxygen (See "oxaalkyl"), a carbonyl group (See
"oxoalkyl"), a sulfur (See "thioalkyl"), or a nitrogen (See
"azaalkyl"). (C.sub.X) alkyl and (C.sub.X-Y) alkyl are typically
used where X and Y indicate the number of carbon atoms in the
chain. For example, C.sub.1-6 alkyl includes alkyls that have a
chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl,
1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
Alkyl represented along with another radical (e.g., as in
arylalkyl, heteroarylalkyl and the like) means a straight or
branched, saturated or unsaturated aliphatic divalent radical
having the number of atoms indicated or when no atoms are indicated
means a bond (e.g., (C.sub.6-10)aryl(C.sub.1-3)alkyl includes,
benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,
2-pyridinylmethyl and the like). In particular embodiments,
"alkyl," either alone or represented along with another radical,
can be a (C.sub.1-20)alkyl, a (C.sub.1-15)alkyl, a
(C.sub.1-10)alkyl, a (C.sub.1-5)alkyl or a (C.sub.1-3)alkyl.
Alternatively, "alkyl," either alone or represented along with
another radical, can be a (C.sub.1)alkyl, a (C.sub.2)alkyl or a
(C.sub.3)alkyl.
[0042] "Alkynyl" means a straight or branched, carbon chain that
contains at least one carbon-carbon triple bond (--C.ident.C-- or
--C.ident.CR, wherein R is hydrogen or a further substituent).
Examples of alkynyl include ethynyl, propargyl,
3-methyl-1-pentynyl, 2-heptynyl and the like. In particular
embodiments, "alkynyl," either alone or represented along with
another radical, can be a (C.sub.2-20)alkynyl, a
(C.sub.2-15)alkynyl, a (C.sub.2-10)alkynyl, a (C.sub.2-5)alkynyl or
a (C.sub.2-3)alkynyl. Alternatively, "alkynyl," either alone or
represented along with another radical, can be a (C.sub.2)alkynyl,
a (C.sub.3)alkynyl or a (C.sub.4)alkynyl.
[0043] "Alkylene", unless indicated otherwise, means a straight or
branched, saturated or unsaturated, aliphatic, divalent radical.
(C.sub.X)alkylene and (C.sub.X-Y)alkylene are typically used where
X and Y indicate the number of carbon atoms in the chain. For
example, (C.sub.1-6) alkylene includes methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), trimethylene
(--CH.sub.2CH.sub.2CH.sub.2--), tetramethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 2-butenylene
(--CH.sub.2CH.dbd.CHCH.sub.2--), 2-methyltetramethylene
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--), pentamethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the like. In
particular embodiments, "alkylene," either alone or represented
along with another radical, can be a (C.sub.1-20)alkylene, a
(C.sub.1-15)alkylene, a (C.sub.1-10)alkylene, a (C.sub.1-5)alkylene
or a (C.sub.1-3)alkylene. Alternatively, "alkylene," either alone
or represented along with another radical, can be a
(C.sub.1)alkylene, a (C.sub.2)alkylene or a (C.sub.3)alkylene.
[0044] "Alkynylene" means a straight or branched, divalent carbon
chain having one or more carbon-carbon triple bonds
(--CR.ident.CR'--, wherein R and R' are each independently hydrogen
or further substituents). Examples of alkynylene include
ethyne-1,2-diyl, propyne-1,3-diyl, and the like. In particular
embodiments, "alkynylene," either alone or represented along with
another radical, can be a (C.sub.2-20) alkynylene, a (C.sub.2-15)
alkynylene, a (C.sub.2-10) alkynylene, a (C.sub.2-5) alkynylene or
a (C.sub.2-3) alkynylene. Alternatively, "alkenylene," either alone
or represented along with another radical, can be a (C.sub.2)
alkynylene, a (C.sub.3) alkynylene or a (C.sub.4) alkynylene.
[0045] "Alkylidene" means a straight or branched, saturated or
unsaturated, aliphatic radical connected to the parent molecule by
a double bond. (C.sub.X)alkylidene and (C.sub.X-Y)alkylidene are
typically used where X and Y indicate the number of carbon atoms in
the chain. For example, C.sub.1-6 alkylidene includes methylene
(.dbd.CH.sub.2), ethylidene (.dbd.CHCH.sub.3), isopropylidene
(.dbd.C(CH.sub.3).sub.2), propylidene (.dbd.CHCH.sub.2CH.sub.3),
allylidene (.dbd.CH--CH.dbd.CH.sub.2), and the like. In particular
embodiments, "alkylidene," either alone or represented along with
another radical, can be a (C.sub.1-20)alkylidene, a
(C.sub.1-15)alkylidene, a (C.sub.1-10)alkylidene, a
(C.sub.1-5)alkylidene or a (C.sub.1-3)alkylidene. Alternatively,
"alkylidene," either alone or represented along with another
radical, can be a (C.sub.1)alkylidene, a (C.sub.2)alkylidene or a
(C.sub.3)alkylidene.
[0046] "Amino" means a nitrogen moiety having two further
substituents where, for example, a hydrogen or carbon atom is
attached to the nitrogen. For example, representative amino groups
include --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH((C.sub.1-10)alkyl), --N((C.sub.1-10)alkyl).sub.2, --NH(aryl),
--NH(heteroaryl), --N(aryl).sub.2, --N(heteroaryl).sub.2, and the
like. Optionally, the two substituents together with the nitrogen
may also form a ring. Unless indicated otherwise, the compounds of
the invention containing amino moieties may include protected
derivatives thereof. Suitable protecting groups for amino moieties
include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the
like.
[0047] "Azaalkyl" means an alkyl, as defined above, except where
one or more of the carbon atoms forming the alkyl chain are
replaced with substituted or unsubstituted nitrogen atoms (--NR--
or --NRR', wherein R and R' are each independently hydrogen or
further substituents). For example, a (C.sub.1-10)azaalkyl refers
to a chain comprising between 1 and 10 carbons and one or more
nitrogen atoms.
[0048] "Animal" includes humans, non-human mammals (e.g., dogs,
cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the
like) and non-mammals (e.g., birds, and the like).
[0049] "Aromatic" means a moiety wherein the constituent atoms make
up an unsaturated ring system, all atoms in the ring system are
sp.sup.2 hybridized and the total number of pi electrons is equal
to 4n+2. An aromatic ring may be such that the ring atoms are only
carbon atoms or may include carbon and non-carbon atoms (see
"heteroaryl").
[0050] "Aryl" means a monocyclic or polycyclic ring assembly
wherein each ring is aromatic or when fused with one or more rings
forms an aromatic ring assembly. If one or more ring atoms is not
carbon (e.g., N, S), the aryl is a heteroaryl. (C.sub.X) aryl and
(C.sub.X-Y) aryl are typically used where X and Y indicate the
number of carbon atoms in the ring. In particular embodiments,
"aryl," either alone or represented along with another radical, can
be a (C.sub.3-14)aryl, a (C.sub.3-10)aryl, a (C.sub.3-7)aryl, a
(C.sub.8-10)aryl or a (C.sub.5-7)aryl. Alternatively, "aryl,"
either alone or represented along with another radical, can be a
(C.sub.5)aryl, a (C.sub.6)aryl, a (C.sub.7)aryl, a (C.sub.8)aryl, a
(C.sub.9)aryl or a (C.sub.10)aryl.
[0051] "Bicycloalkyl" means a saturated or partially unsaturated
fused, spiro or bridged bicyclic ring assembly. In particular
embodiments, "bicycloalkyl," either alone or represented along with
another radical, can be a (C.sub.4-15)bicycloalkyl, a
(C.sub.4-10)bicycloalkyl, a (C.sub.6-10)bicycloalkyl or a
(C.sub.8-10)bicycloalkyl. Alternatively, "bicycloalkyl," either
alone or represented along with another radical, can be a
(C.sub.8)bicycloalkyl, a (C.sub.9)bicycloalkyl or a
(C.sub.10)bicycloalkyl.
[0052] "Bicycloaryl" means a fused, spiro or bridged bicyclic ring
assembly wherein at least one of the rings comprising the assembly
is aromatic. (C.sub.X)bicycloaryl and (C.sub.X-Y)bicycloaryl are
typically used where X and Y indicate the number of carbon atoms in
the bicyclic ring assembly and directly attached to the ring. In
particular embodiments, "bicycloaryl," either alone or represented
along with another radical, can be a (a (C.sub.4-15)bicycloaryl, a
(C.sub.4-10)bicycloaryl, a (C.sub.6-10)bicycloaryl or a
(C.sub.8-10)bicycloaryl. Alternatively, "bicycloalkyl," either
alone or represented along with another radical, can be a
(C.sub.8)bicycloaryl, a (C.sub.9)bicycloaryl or a
(C.sub.10)bicycloaryl.
[0053] "Bridging ring" and "bridged ring" as used herein refer to a
ring that is bonded to another ring to form a compound having a
bicyclic or polycyclic structure where two ring atoms that are
common to both rings are not directly bound to each other.
Non-exclusive examples of common compounds having a bridging ring
include borneol, norbornane, 7-oxabicyclo[2.2.1]heptane, and the
like. One or both rings of the bicyclic system may also comprise
heteroatoms.
[0054] "Carbamoyl" means the radical --OC(O)NRR' where R and R' are
each independently hydrogen or further substituents.
[0055] "Carbocycle" means a ring consisting of carbon atoms.
[0056] "Carbocyclic ketone derivative" means a carbocyclic
derivative wherein the ring contains a --CO-- moiety.
[0057] "Carbonyl" means the radical --C(.dbd.O)-- and/or
--C(.dbd.O)R, wherein R is hydrogen or a further substituent. It is
noted that the carbonyl radical may be further substituted with a
variety of substituents to form different carbonyl groups including
acids, acid halides, aldehydes, amides, esters, and ketones.
[0058] "Carboxy" means the radical --C(.dbd.O)--O-- and/or
--C(.dbd.O)--OR, wherein R is hydrogen or a further substituent. It
is noted that compounds of the invention containing carboxy
moieties may include protected derivatives thereof, i.e., where the
oxygen is substituted with a protecting group. Suitable protecting
groups for carboxy moieties include benzyl, tert-butyl, and the
like.
[0059] "Cyano" means the radical --CN.
[0060] "Cycloalkyl" means a non-aromatic, saturated or partially
unsaturated, monocyclic, bicyclic or polycyclic ring assembly.
(C.sub.X) cycloalkyl and (C.sub.X-Y) cycloalkyl are typically used
where X and Y indicate the number of carbon atoms in the ring
assembly. For example, (C.sub.3-10) cycloalkyl includes
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,
decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thio cyclohexyl,
2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular
embodiments, "cycloalkyl," either alone or represented along with
another radical, can be a (C.sub.3-14)cycloalkyl, a
(C.sub.3-10)cycloalkyl, a (C.sub.3-7)cycloalkyl, a
(C.sub.8-10)cycloalkyl or a (C.sub.5-7)cycloalkyl. Alternatively,
"cycloalkyl," either alone or represented along with another
radical, can be a (C.sub.5)cycloalkyl, a (C.sub.6)cycloalkyl, a
(C.sub.7)cycloalkyl, a (C.sub.8)cycloalkyl, a (C.sub.9)cycloalkyl
or a (C.sub.10)cycloalkyl.
[0061] "Cycloalkylene" means a divalent saturated or partially
unsaturated, monocyclic, bicyclic or polycyclic ring assembly.
(C.sub.X) cycloalkylene and (C.sub.X-Y) cycloalkylene are typically
used where X and Y indicate the number of carbon atoms in the ring
assembly. In particular embodiments, "cycloalkylene," either alone
or represented along with another radical, can be a
(C.sub.3-14)cycloalkylene, a (C.sub.3-10)cycloalkylene, a
(C.sub.3-7)cycloalkylene, a (C.sub.8-10)cycloalkylene or a
(C.sub.5-7)cycloalkylene. Alternatively, "cycloalkylene," either
alone or represented along with another radical, can be a
(C.sub.5)cycloalkylene, a (C.sub.6)cycloalkylene, a
(C.sub.7)cycloalkylene, a (C.sub.8)cycloalkylene, a
(C.sub.9)cycloalkylene or a (C.sub.10)cycloalkylene.
[0062] "Disease" specifically includes any unhealthy condition of
an animal or part thereof and includes an unhealthy condition that
may be caused by, or incident to, medical or veterinary therapy
applied to that animal, i.e., the "side effects" of such
therapy.
[0063] "Fused ring" as used herein refers to a ring that is bonded
to another ring to form a compound having a bicyclic structure when
the ring atoms that are common to both rings are directly bound to
each other. Non-exclusive examples of common fused rings include
decalin, naphthalene, anthracene, phenanthrene, indole, furan,
benzofuran, quinoline, and the like. Compounds having fused ring
systems may be saturated, partially saturated, carbocyclics,
heterocyclics, aromatics, heteroaromatics, and the like.
[0064] "Halo" means fluoro, chloro, bromo or iodo.
[0065] "Halo-substituted alkyl", as an isolated group or part of a
larger group, means "alkyl" substituted by one or more "halo"
atoms, as such terms are defined in this application.
Halo-substituted alkyl includes haloalkyl, dihaloalkyl,
trihaloalkyl, perhaloalkyl and the like (e.g., halo-substituted
(C.sub.1-3)alkyl includes chloromethyl, dichloromethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the
like).
[0066] "Heteroatom" refers to an atom that is not a carbon atom.
Particular examples of heteroatoms include, but are not limited to,
nitrogen, oxygen, and sulfur.
[0067] "Heteroatom moiety" includes a moiety where the atom by
which the moiety is attached is not a carbon. Examples of
heteroatom moieties include --N.dbd., --NR--,
--N.sup.+(O.sup.-).dbd., --O--, --S-- or --S(O).sub.2--, wherein R
is hydrogen or a further substituent.
[0068] "Heteroalkyl" means alkyl, as defined in this application,
provided that one or more of the atoms within the alkyl chain is a
heteroatom. In particular embodiments, "heteroalkyl," either alone
or represented along with another radical, can be a
hetero(C.sub.1-20)alkyl, a hetero(C.sub.1-15)alkyl, a
hetero(C.sub.1-10)alkyl, a hetero(C.sub.1-5)alkyl, a
hetero(C.sub.1-3)alkyl or a hetero(C.sub.1-2)alkyl. Alternatively,
"heteroalkyl," either alone or represented along with another
radical, can be a hetero(C.sub.1)alkyl, a hetero(C.sub.2)alkyl or a
hetero(C.sub.3)alkyl.
[0069] "Heterobicycloalkyl" means bicycloalkyl, as defined in this
application, provided that one or more of the atoms within the ring
is a heteroatom. For example hetero(C.sub.9-12)bicycloalkyl as used
in this application includes, but is not limited to,
3-aza-bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl,
3-aza-bicyclo[3.1.0]hex-3-yl, and the like. In particular
embodiments, "heterobicycloalkyl," either alone or represented
along with another radical, can be a
hetero(C.sub.1-14)bicycloalkyl, a hetero(C.sub.4-14)bicycloalkyl, a
hetero(C.sub.4-9)bicycloalkyl or a hetero(C.sub.5-9)bicycloalkyl.
Alternatively, "heterobicycloalkyl," either alone or represented
along with another radical, can be a hetero(C.sub.5)bicycloalkyl,
hetero(C.sub.6)bicycloalkyl, hetero (C.sub.7)bicyclo alkyl,
hetero(C.sub.8)bicycloalkyl or a hetero(C.sub.9)bicycloalkyl.
[0070] "Heterocycloalkylene" means cycloalkylene, as defined in
this application, provided that one or more of the ring member
carbon atoms is replaced by a heteroatom. In particular
embodiments, "heterocycloalkylene," either alone or represented
along with another radical, can be a
hetero(C.sub.1-13)cycloalkylene, a hetero(C.sub.1-9)cycloalkylene,
a hetero(C.sub.1-6)cycloalkylene, a hetero(C.sub.5-9)cycloalkylene
or a hetero(C.sub.2-6)cycloalkylene. Alternatively,
"heterocycloalkylene," either alone or represented along with
another radical, can be a hetero(C.sub.2)cycloalkylene, a
hetero(C.sub.3)cycloalkylene, a hetero(C.sub.4)cycloalkylene, a
hetero(C.sub.5)cycloalkylene, a hetero(C.sub.6)cycloalkylene,
hetero(C.sub.7)cycloalkylene, hetero(C.sub.8)cycloalkylene or a
hetero(C.sub.9)cycloalkylene.
[0071] "Heteroaryl" means a monocyclic, bicyclic or polycyclic
aromatic group wherein at least one ring atom is a heteroatom and
the remaining ring atoms are carbon. Monocyclic heteroaryl groups
include, but are not limited to, cyclic aromatic groups having five
or six ring atoms, wherein at least one ring atom is a heteroatom
and the remaining ring atoms are carbon. The nitrogen atoms can be
optionally quaternerized and the sulfur atoms can be optionally
oxidized. Heteroaryl groups of this invention include, but are not
limited to, those derived from furan, imidazole, isothiazole,
isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine,
pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole,
1,3,4-thiadiazole, triazole and tetrazole. "Heteroaryl" also
includes, but is not limited to, bicyclic or tricyclic rings,
wherein the heteroaryl ring is fused to one or two rings
independently selected from the group consisting of an aryl ring, a
cycloalkyl ring, a cycloalkenyl ring, and another monocyclic
heteroaryl or heterocycloalkyl ring. These bicyclic or tricyclic
heteroaryls include, but are not limited to, those derived from
benzo[b]furan, benzo[b]thiophene, benzimidazole,
imidazo[4,5-c]pyridine, quinazo line, thieno[2,3-c]pyridine,
thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine,
imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,
quinoxaline, naphthyridine, quinolizine, indole, isoindole,
indazole, indoline, benzoxazole, benzopyrazole, benzothiazole,
imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,
imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,
imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,
pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,
pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine,
pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine,
pyrrolo[2,3-b]pyrazine, pyrazolo[1,5-a]pyridine,
pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine,
pyrrolo[1,2-a]pyrimidine, pyrrolo[1,2-a]pyrazine,
triazo[1,5-a]pyridine, pteridine, purine, carbazole, acridine,
phenazine, phenothiazene, phenoxazine,
1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole
and 2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings
can be attached to the parent molecule through either the
heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl group to which it is fused. The heteroaryl groups
of this invention can be substituted or unsubstituted. In
particular embodiments, "heteroaryl," either alone or represented
along with another radical, can be a hetero(C.sub.1-13)aryl, a
hetero(C.sub.2-13)aryl, a hetero(C.sub.2-6)aryl, a
hetero(C.sub.3-9)aryl or a hetero(C.sub.5-9)aryl. Alternatively,
"heteroaryl," either alone or represented along with another
radical, can be a hetero(C.sub.3)aryl, a hetero(C.sub.4)aryl, a
hetero(C.sub.5)aryl, a hetero(C.sub.6)aryl, a hetero(C.sub.7)aryl,
a hetero(C.sub.8)aryl or a hetero(C.sub.9)aryl.
[0072] "Heterobicycloaryl" means bicycloaryl, as defined in this
application, provided that one or more of the atoms within the ring
is a heteroatom. For example, hetero(C.sub.4-12)bicycloaryl as used
in this application includes, but is not limited to,
2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl,
and the like. In particular embodiments, "heterobicycloaryl,"
either alone or represented along with another radical, can be a
hetero(C.sub.1-14)bicycloaryl, a hetero(C.sub.4-14)bicycloaryl, a
hetero(C.sub.4-9)bicycloarylor a hetero(C.sub.5-9)bicycloaryl.
Alternatively, "heterobicycloaryl," either alone or represented
along with another radical, can be a hetero(C.sub.5)bicycloaryl,
hetero(C.sub.6)bicycloaryl, hetero(C.sub.7)bicycloaryl,
hetero(C.sub.8)bicycloaryl or a hetero(C.sub.9)bicycloaryl.
[0073] "Heterocycloalkyl" means cycloalkyl, as defined in this
application, provided that one or more of the atoms forming the
ring is a heteroatom selected, independently from N, O, or S,
Non-exclusive examples of heterocycloalkyl include piperidyl,
4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl,
1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl and
the like. In particular embodiments, "heterocycloalkyl," either
alone or represented along with another radical, can be a hetero
(C.sub.1-13)cyclo alkyl, a hetero (C.sub.1-9)cyclo alkyl, a hetero
(C.sub.1-6)cyclo alkyl, a hetero(C.sub.5-9)cycloalkyl or a
hetero(C.sub.2-6)cycloalkyl. Alternatively, "heterocycloalkyl,"
either alone or represented along with another radical, can be a
hetero(C.sub.2)cycloalkyl, a hetero(C.sub.3)cycloalkyl, a
hetero(C.sub.4)cycloalkyl, a hetero(C.sub.5)cycloalkyl, a
hetero(C.sub.6)cycloalkyl, hetero(C.sub.7)cycloalkyl,
hetero(C.sub.8)cycloalkyl or a hetero(C.sub.9)cycloalkyl.
[0074] "Hydroxy" means the radical --OH.
[0075] "IC.sub.50" means the molar concentration of an inhibitor
that produces 50% inhibition of the target enzyme.
[0076] "Imino" means the radical --CR(.dbd.NR') and/or
--C(.dbd.NR')--, wherein R and R' are each independently hydrogen
or a further substituent.
[0077] "Iminoketone derivative" means a derivative comprising the
moiety --C(NR)--, wherein R is a hydrogen or a further
substituent.
[0078] "Isomers" mean compounds having identical molecular formulae
but differing in the nature or sequence of bonding of their atoms
or in the arrangement of their atoms in space. Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers." Stereoisomers that are not mirror images of one
another are termed "diastereomers" and stereoisomers that are
nonsuperimposable mirror images are termed "enantiomers" or
sometimes "optical isomers." A carbon atom bonded to four
nonidentical substituents is termed a "chiral center." A compound
with one chiral center has two enantiomeric forms of opposite
chirality. A mixture of the two enantiomeric forms is termed a
"racemic mixture." A compound that has more than one chiral center
has 2.sup.n-1 enantiomeric pairs, where n is the number of chiral
centers. Compounds with more than one chiral center may exist as
ether an individual diastereomer or as a mixture of diastereomers,
termed a "diastereomeric mixture." When one chiral center is
present a stereoisomer may be characterized by the absolute
configuration of that chiral center. Absolute configuration refers
to the arrangement in space of the substituents attached to the
chiral center. Enantiomers are characterized by the absolute
configuration of their chiral centers and described by the R- and
S-sequencing rules of Cahn, Ingold and Prelog. Conventions for
stereochemical nomenclature, methods for the determination of
stereochemistry and the separation of stereoisomers are well known
in the art (e.g., see "Advanced Organic Chemistry", 4th edition,
March, Jerry, John Wiley & Sons, New York, 1992).
[0079] "Linker providing X atom separation" and "moiety providing X
atom separation" between two other moieties mean that the chain of
atoms directly linking the two other moieties is X atoms in length.
When X is given as a range (e.g., X.sub.1-X.sub.2), then the chain
of atoms is at least X.sub.1 and not more than X.sub.2 atoms in
length. It is understood that the chain of atoms can be formed from
a combination of atoms including, for example, carbon, nitrogen,
sulfur and oxygen atoms. Further, each atom can optionally be bound
to one or more substituents, as valencies allow. In addition, the
chain of atoms can form part of a ring. Accordingly, in one
embodiment, a moiety providing X atom separation between two other
moieties (R and R') can be represented by R-(L).sub.X-R' where each
L is independently selected from the group consisting of CR''R''',
NR'''', O, S, CO, CS, C.dbd.NR'''''', SO, SO.sub.2, and the like,
where any two or more of R'', R''', R'''' and R can be taken
together to form a substituted or unsubstituted ring.
[0080] "Nitro" means the radical --NO.sub.2.
[0081] "Oxaalkyl" means an alkyl, as defined above, except where
one or more of the carbon atoms forming the alkyl chain are
replaced with oxygen atoms (--O-- or --OR, wherein R is hydrogen or
a further substituent). For example, an oxa(C.sub.1-10) alkyl
refers to a chain comprising between 1 and 10 carbons and one or
more oxygen atoms.
[0082] "Oxoalkyl" means an alkyl, as defined above, except where
one or more of the carbon atoms forming the alkyl chain are
replaced with carbonyl groups (--C(.dbd.O)-- or --C(.dbd.O)--R,
wherein R is hydrogen or a further substituent. The carbonyl group
may be an aldehyde, ketone, ester, amide, acid or acid halide. For
example, an oxo(C.sub.1-10)alkyl refers to a chain comprising
between 1 and 10 carbon atoms and one or more carbonyl groups.
[0083] "Oxy" means the radical --O-- or --OR, wherein R is hydrogen
or a further substituent. Accordingly, it is noted that the oxy
radical may be further substituted with a variety of substituents
to form different oxy groups including hydroxy, alkoxy, aryloxy,
heteroaryloxy or carbonyloxy.
[0084] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary use as well as
human pharmaceutical use.
[0085] "Pharmaceutically acceptable salts" means salts of compounds
of the present invention which are pharmaceutically acceptable, as
defined above, and which possess the desired pharmacological
activity. Such salts include acid addition salts formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or with
organic acids such as acetic acid, propionic acid, hexanoic acid,
heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid
and the like.
[0086] Pharmaceutically acceptable salts also include base addition
salts which may be formed when acidic protons present are capable
of reacting with inorganic or organic bases. Acceptable inorganic
bases include sodium hydroxide, sodium carbonate, potassium
hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable
organic bases include ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine and the like.
[0087] "Polycyclic ring" includes bicyclic and multi-cyclic rings.
The individual rings comprising the polycyclic ring can be fused,
spiro or bridging rings.
[0088] "Prodrug" means a compound that is convertible in vivo
metabolically into an inhibitor according to the present invention.
The prodrug itself may or may not also have kinase inhibitory
activity. For example, an inhibitor comprising a hydroxy group may
be administered as an ester that is converted by hydrolysis in vivo
to the hydroxy compound. Suitable esters that may be converted in
vivo into hydroxy compounds include acetates, citrates, lactates,
tartrates, malonates, oxalates, salicylates, propionates,
succinates, fumarates, maleates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,
benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates,
quinates, esters of amino acids, and the like. Similarly, an
inhibitor comprising an amine group may be administered as an amide
that is converted by hydrolysis in vivo to the amine compound.
[0089] "Protected derivatives" means derivatives of inhibitors in
which a reactive site or sites are blocked with protecting groups.
Protected derivatives are useful in the preparation of inhibitors
or in themselves may be active as inhibitors. A comprehensive list
of suitable protecting groups can be found in T. W. Greene,
Protecting Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons, Inc. 1999.
[0090] "Ring" and "ring assembly" mean a carbocyclic or a
heterocyclic system and includes aromatic and non-aromatic systems.
The system can be monocyclic, bicyclic or polycyclic. In addition,
for bicyclic and polycyclic systems, the individual rings
comprising the polycyclic ring can be fused, spiro or bridging
rings.
[0091] "Subject" includes humans, non-human mammals (e.g., dogs,
cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the
like) and non-mammals (e.g., birds, and the like).
[0092] "Substituent convertible to hydrogen in vivo" means any
group that is convertible to a hydrogen atom by enzymological or
chemical means including, but not limited to, hydrolysis and
hydrogenolysis. Examples include hydrolyzable groups, such as acyl
groups, groups having an oxycarbonyl group, amino acid residues,
peptide residues, o-nitrophenylsulfenyl, trimethylsilyl,
tetrahydro-pyranyl, diphenylphosphinyl, and the like. Examples of
acyl groups include formyl, acetyl, trifluoroacetyl, and the like.
Examples of groups having an oxycarbonyl group include
ethoxycarbonyl, t-butoxycarbonyl[(CH.sub.3).sub.3C--OCO--],
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl,
.beta.-(p-toluenesulfonyl)ethoxycarbonyl, and the like. Examples of
suitable amino acid residues include amino acid residues per se and
amino acid residues that are protected with a protecting group.
Suitable amino acid residues include, but are not limited to,
residues of Gly (glycine), Ala (alanine; CH.sub.3CH(NH.sub.2)CO--),
Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys
(cysteine), Glu (glutamic acid), His (histidine), Ile (isoleucine),
Leu (leucine; (CH.sub.3).sub.2CHCH.sub.2CH(NH.sub.2)CO--), Lys
(lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser
(serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val
(valine), Nva (norvaline), Hse (homoserine), 4-Hyp
(4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine) and
13-Ala. Examples of suitable protecting groups include those
typically employed in peptide synthesis, including acyl groups
(such as formyl and acetyl), arylmethyloxycarbonyl groups (such as
benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t-butoxycarbonyl
groups [(CH.sub.3).sub.3C--OCO--], and the like. Suitable peptide
residues include peptide residues comprising two to five, and
optionally two to three, of the aforesaid amino acid residues.
Examples of such peptide residues include, but are not limited to,
residues of such peptides as Ala-Ala
[CH.sub.3CH(NH.sub.2)CO--NHCH(CH.sub.3)CO--], Gly-Phe, Nva-Nva,
Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and
Ala-Leu. The residues of these amino acids or peptides can be
present in stereochemical configurations of the D-form, the L-form
or mixtures thereof. In addition, the amino acid or peptide residue
may have an asymmetric carbon atom. Examples of suitable amino acid
residues having an asymmetric carbon atom include residues of Ala,
Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr. Peptide
residues having an asymmetric carbon atom include peptide residues
having one or more constituent amino acid residues having an
asymmetric carbon atom. Examples of suitable amino acid protecting
groups include those typically employed in peptide synthesis,
including acyl groups (such as formyl and acetyl),
arylmethyloxycarbonyl groups (such as benzyloxycarbonyl and
p-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups
[(CH.sub.3).sub.3C--OCO--], and the like. Other examples of
substituents "convertible to hydrogen in vivo" include reductively
eliminable hydrogenolyzable groups. Examples of suitable
reductively eliminable hydrogenolyzable groups include, but are not
limited to, arylsulfonyl groups (such as o-toluenesulfonyl); methyl
groups substituted with phenyl or benzyloxy (such as benzyl, trityl
and benzyloxymethyl); arylmethoxycarbonyl groups (such as
benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); and
halogenoethoxycarbonyl groups (such as
.beta.,.beta.,.beta.-trichloroethoxycarbonyl and
.beta.-iodoethoxycarbonyl).
[0093] "Substituted or unsubstituted" means that a given moiety may
consist of only hydrogen substituents through available valencies
(unsubstituted) or may further comprise one or more non-hydrogen
substituents through available valencies (substituted) that are not
otherwise specified by the name of the given moiety. For example,
isopropyl is an example of an ethylene moiety that is substituted
by --CH.sub.3. In general, a non-hydrogen substituent may be any
substituent that may be bound to an atom of the given moiety that
is specified to be substituted. Examples of substituents include,
but are not limited to, aldehyde, alicyclic, aliphatic,
(C.sub.1-10)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,
aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,
carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,
heterobicycloalkyl, heterocycloalkylene, heteroaryl,
heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone,
ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may
optionally also be substituted or unsubstituted. In one particular
embodiment, examples of substituents include, but are not limited
to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero (C.sub.3-12)cyclo alkyl,
(C.sub.9-12)bicyclo alkyl, hetero (C.sub.3-12)bicyclo alkyl,
(C.sub.4-12)aryl, hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl
and hetero(C.sub.4-12)bicycloaryl. In addition, the substituent is
itself optionally substituted by a further substituent. In one
particular embodiment, examples of the further substituent include,
but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-10)alkyl, carbonyl(C.sub.1-10)alkyl,
thiocarbonyl(C.sub.1-10)alkyl, sulfonyl(C.sub.1-10)alkyl,
sulfinyl(C.sub.1-10)alkyl, (C.sub.1-10)azaalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero (C.sub.3-12)cyclo alkyl,
(C.sub.9-12)bicyclo alkyl, hetero (C.sub.3-12)bicyclo alkyl,
(C.sub.4-12)aryl, hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl
and hetero(C.sub.4-12)bicycloaryl.
[0094] "Sulfinyl" means the radical --SO-- and/or --SO--R, wherein
R is hydrogen or a further substituent. It is noted that the
sulfinyl radical may be further substituted with a variety of
substituents to form different sulfinyl groups including sulfinic
acids, sulfinamides, sulfinyl esters, and sulfoxides.
[0095] "Sulfonyl" means the radical --SO.sub.2-- and/or
--SO.sub.2--R, wherein R is hydrogen or a further substituent. It
is noted that the sulfonyl radical may be further substituted with
a variety of substituents to form different sulfonyl groups
including sulfonic acids, sulfonamides, sulfonate esters, and
sulfones.
[0096] "Therapeutically effective amount" means that amount which,
when administered to an animal for treating a disease, is
sufficient to effect such treatment for the disease.
[0097] "Thio" denotes replacement of an oxygen by a sulfur and
includes, but is not limited to, --SR, --S-- and .dbd.S containing
groups.
[0098] "Thioalkyl" means an alkyl, as defined above, except where
one or more of the carbon atoms forming the alkyl chain are
replaced with sulfur atoms (--S-- or --S--R, wherein R is hydrogen
or a further substituent). For example, a thio(C.sub.1-10) alkyl
refers to a chain comprising between 1 and 10 carbons and one or
more sulfur atoms.
[0099] "Thiocarbonyl" means the radical --C(.dbd.S)-- and/or
--C(.dbd.S)--R, wherein R is hydrogen or a further substituent. It
is noted that the thiocarbonyl radical may be further substituted
with a variety of substituents to form different thiocarbonyl
groups including thioacids, thioamides, thioesters, and
thioketones.
[0100] "Treatment" or "treating" means any administration of a
compound of the present invention and includes:
[0101] (1) preventing the disease from occurring in an animal which
may be predisposed to the disease but does not yet experience or
display the pathology or symptomatology of the disease,
[0102] (2) inhibiting the disease in an animal that is experiencing
or displaying the pathology or symptomatology of the diseased
(i.e., arresting further development of the pathology and/or
symptomatology), or
[0103] (3) ameliorating the disease in an animal that is
experiencing or displaying the pathology or symptomatology of the
diseased (i.e., reversing the pathology and/or symptomatology).
[0104] It is noted in regard to all of the definitions provided
herein that the definitions should be interpreted as being open
ended in the sense that further substituents beyond those specified
may be included. Hence, a C.sub.1 alkyl indicates that there is one
carbon atom but does not indicate what are the substituents on the
carbon atom. Hence, a (C.sub.1) alkyl comprises methyl (i.e.,
--CH.sub.3) as well as --CRR''R where R, R', and R'' may each
independently be hydrogen or a further substituent where the atom
attached to the carbon is a heteroatom or cyano. Hence, CF.sub.3,
CH.sub.2OH and CH.sub.2CN, for example, are all (C.sub.1) alkyls.
Similarly, terms such as alkylamino and the like comprise
dialkylamino and the like.
[0105] "Crystalline", as the term is used herein, refers to a
material that contains a specific compound, which may be hydrated
and/or solvated, and has sufficient crystalline content to exhibit
a discernable diffraction pattern by XRPD or other diffraction
techniques. Often, a crystalline material that is obtained by
direct crystallization of a compound dissolved in a solution or
interconversion of crystals obtained under different
crystallization conditions, will have crystals that contain the
solvent used in the crystallization, termed a crystalline solvate.
Also, the specific solvent system and physical embodiment in which
the crystallization is performed, collectively termed
crystallization conditions, may result in the crystalline material
having physical and chemical properties that are unique to the
crystallization conditions, generally due to the orientation of the
chemical moieties of the compound with respect to each other within
the crystal and/or the predominance of a specific polymorphic form
of the compound in the crystalline material.
[0106] Depending upon the polymorphic form(s) of the compound that
are present in a composition, various amounts of the compound in an
amorphous solid state may also be present, either as a side product
of the initial crystallization, and/or a product of degradation of
the crystals comprising the crystalline material. Thus,
crystalline, as the term is used herein, contemplates that the
composition may include amorphous content; the presence of the
crystalline material among the amorphous material being detectably
among other methods by the composition having a discernable
diffraction pattern.
[0107] The amorphous content of a crystalline material may be
increased by grinding or pulverizing the material, which is
evidenced by broadening of diffraction and other spectral lines
relative to the crystalline material prior to grinding. Sufficient
grinding and/or pulverizing may broaden the lines relative to the
crystalline material prior to grinding to the extent that the XRPD
or other crystal specific spectrum may become undiscernable, making
the material substantially amorphous or quasi-amorphous.
[0108] Continued grinding would be expected to increase the
amorphous content and further broaden the XRPD pattern with the
limit of the XRPD pattern being so broadened that it can no longer
be discerned above noise. When the XRPD pattern is broadened to the
limit of being indiscernible, the material may be considered to no
longer be a crystalline material, and instead be wholly amorphous.
For material having increased amorphous content and wholly
amorphous material, no peaks should be observed that would indicate
grinding produces another form.
[0109] "Amorphous", as the term is used herein, refers to a
composition comprising a compound that contains too little
crystalline content of the compound to yield a discernable pattern
by XRPD or other diffraction techniques. Glassy materials are a
type of amorphous material. Amorphous materials do not have a true
crystal lattice, and are consequently glassy rather than true
solids, technically resembling very viscous non-crystalline
liquids. Rather than being true solids, glasses may better be
described as quasi-solid amorphous material. Thus, an amorphous
material refers to a quasi-solid, glassy material.
[0110] "Broad" or "broadened", as the term is used herein to
describe spectral lines, including XRPD, NMR and IR spectroscopy,
and Raman spectroscopy lines, is a relative term that relates to
the line width of a baseline spectrum. The baseline spectrum is
often that of an unmanipulated crystalline form of a specific
compound as obtained directly from a given set of physical and
chemical conditions, including solvent composition and properties
such as temperature and pressure. For example, broadened can be
used to describe the spectral lines of a XRPD spectrum of ground or
pulverized material comprising a crystalline compound relative to
the material prior to grinding. In materials where the constituent
molecules, ions or atoms, as solvated or hydrated, are not tumbling
rapidly, line broadening is indicative of increased randomness in
the orientation of the chemical moieties of the compound, thus
indicative of an increased amorphous content. When comparisons are
made between crystalline materials obtained via different
crystallization conditions, broader spectral lines indicate that
the material producing the relatively broader spectral lines has a
higher level of amorphous material.
[0111] "About" as the term is used herein, refers to an estimate
that the actual value falls within .+-.5% of the value cited.
Kinase Inhibitors
[0112] In one embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00002##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0113]
Z, Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are each
independently selected from the group consisting of C and N; [0114]
R.sub.1 is --Y.sub.1--R.sub.12, or R.sub.1 is absent when Z.sub.1
is N; [0115] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent
when Z.sub.2 is N, or R.sub.1 and R.sub.2 are taken together to
form a ring; [0116] Y.sub.1, Y.sub.2 and Y.sub.3 are each
independently absent or a linker providing 1 or 2 atom separation
between R.sub.12, R.sub.13 or R.sub.14 and the ring to which
Y.sub.1, Y.sub.2 or Y.sub.3 is attached, wherein the atoms of the
linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0117] R.sub.4
is selected from the group consisting of hydrogen, halo, nitro,
cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, carbonyl, amino,
(C.sub.1-5)alkylamino, (C.sub.1-5)alkyl, halo(C.sub.1-5)alkyl,
carbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl, amino
(C.sub.1-5)alkyl, aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0118] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicyoloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0119] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0120] R.sub.12 and R.sub.13 are each independently selected
from the group consisting of hydrogen, halo, nitro, cyano, thio,
oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a ring; and
[0121] R.sub.14 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicyoloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0122] In one variation of the above embodiment,
--Y.sub.3--R.sub.14 is not H when Z, Z.sub.1, Z.sub.2, Z.sub.3 and
Z.sub.5 are all C; R.sub.5 is a substituted amino group; and
R.sub.2 is methoxy or R.sub.7 is methyl or amino. In another
variation of the above embodiment and variation, R.sub.14 is not
3-chlorophenyl when R.sub.1, R.sub.5, R.sub.6 and R.sub.7 are each
H; Z and Z.sub.2 are each N; R.sub.2 and R.sub.4 are absent;
Z.sub.1, Z.sub.3, Z.sub.4 and Z.sub.5 are all C; and Y.sub.3 is
NH.
[0123] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00003##
[0124] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00004##
[0125] In yet another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00005##
[0126] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00006##
[0127] In still a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00007##
[0128] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00008##
[0129] In one variation of the above embodiment,
--Y.sub.1--R.sub.12 is absent when Z.sub.1 is N and
--Y.sub.2--R.sub.13 is absent when Z.sub.2 is N.
[0130] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00009##
[0131] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00010##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0132]
n is selected from the group consisting of 0, 1, 2, 3, 4 and 5; and
[0133] R.sub.15 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.15 are taken together to form a ring.
[0134] In one variation of the above embodiment, R.sub.15 is not
3-chloro when n is 1; R.sub.1, R.sub.5, R.sub.6 and R.sub.7 are
each H; Z and Z.sub.2 are each N; R.sub.2 and R.sub.4 are absent;
Z.sub.1, Z.sub.3, Z.sub.4 and Z.sub.5 are all C; and Y.sub.3 is
NH.
[0135] In yet another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00011##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0136]
n is selected from the group consisting of 0, 1, 2, 3, 4 and 5; and
[0137] R.sub.15 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.15 are taken together to form a ring.
[0138] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00012##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0139]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; and [0140]
R.sub.25 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring.
[0141] In one variation of the above embodiment, A.sub.1 is not CCl
when A, A.sub.2, A.sub.3 and A.sub.4 are each CH; R.sub.1, R.sub.5,
R.sub.6 and R.sub.7 are each H; Z and Z.sub.2 are each N; R.sub.2
and R.sub.4 are absent; Z.sub.1, Z.sub.3, Z.sub.4 and Z.sub.5 are
all C; and Y.sub.3 is NH.
[0142] In still a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00013##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0143]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; and [0144]
R.sub.25 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicyoloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring.
[0145] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00014##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0146]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; [0147]
R.sub.23 is selected from the group consisting of hydrogen,
carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a ring; and [0148] R.sub.25 is
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring.
[0149] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00015##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0150]
n is selected from the group consisting of 0, 1, 2, 3, 4 and 5; and
[0151] R.sub.15 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.15 are taken together to form a ring.
[0152] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00016##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0153]
n is selected from the group consisting of 0, 1, 2, 3, 4 and 5; and
[0154] R.sub.15 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.15 are taken together to form a ring.
[0155] In yet another embodiment, kinase inhibitors of the present
invention comprise
##STR00017##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0156]
n is selected from the group consisting of 0, 1, 2, 3, 4 and 5;
[0157] R.sub.15 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.15 are taken together to form a ring; and [0158]
R.sub.23 is selected from the group consisting of hydrogen,
carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a ring.
[0159] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00018##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0160]
R.sub.15 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0161] R.sub.23 is selected from the group consisting of
hydrogen, carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a ring.
[0162] In still a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00019##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0163]
n is selected from the group consisting of 0, 1, 2, 3, 4 and 5;
[0164] R.sub.15 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.15 are taken together to form a ring; and [0165]
R.sub.27 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C.sub.1-10)alkoxy,
(C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy, carbonyl,
oxycarbonyl, aminocarbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0166] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00020##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0167]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; and [0168]
R.sub.25 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring.
[0169] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00021##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0170]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; and [0171]
R.sub.25 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring.
[0172] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00022##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0173]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; [0174]
R.sub.23 is selected from the group consisting of hydrogen,
carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a ring; and [0175] R.sub.25 is
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring.
[0176] In yet another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00023##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0177]
A.sub.2 is selected from the group consisting of CR.sub.25 and N;
[0178] R.sub.25 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring; and [0179]
R.sub.27 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C.sub.1-10)alkoxy,
(C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy, carbonyl,
oxycarbonyl, aminocarbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0180] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00024##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0181]
A.sub.2 is selected from the group consisting of CR.sub.25 and N;
[0182] R.sub.25 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring; and [0183]
R.sub.27 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C.sub.1-10)alkoxy,
(C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy, carbonyl,
oxycarbonyl, aminocarbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0184] In still a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00025##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0185]
A.sub.2 is selected from the group consisting of CR.sub.25 and N;
[0186] R.sub.25 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring; and [0187]
R.sub.27 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C.sub.1-10)alkoxy,
(C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy, carbonyl,
oxycarbonyl, aminocarbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl, hetero
(C.sub.3-12)bicyclo alkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0188] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00026##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0189]
A.sub.2 is selected from the group consisting of CR.sub.25 and N;
[0190] R.sub.25 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a ring; and [0191]
R.sub.27 and R.sub.29 are each independently selected from the
group consisting of hydrogen, halo, nitro, cyano, thio, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-10)alkyl, carbonyl(C.sub.1-10)alkyl,
thiocarbonyl(C.sub.1-10)alkyl, sulfonyl(C.sub.1-10)alkyl,
sulfinyl(C.sub.1-10)alkyl, (C.sub.1-10)azaalkyl,
(C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.27 and R.sub.29 are taken together to form a substituted
or unsubstituted ring.
[0192] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00027##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0193]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted.
[0194] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00028##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0195]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted.
[0196] In yet another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00029##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0197]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted.
[0198] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00030##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0199]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted.
[0200] In still a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00031##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0201]
A is selected from the group consisting of CR.sub.25 and N; [0202]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted; [0203] R.sub.23 and
R.sub.24 are each independently selected from the group consisting
of hydrogen, carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero (C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.24 are taken together to form a ring; and [0204] R.sub.25 is
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0205] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00032##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0206]
A is selected from the group consisting of CR.sub.25 and N; [0207]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted; [0208] R.sub.25 is
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0209] R.sub.26 is selected from the group consisting of
hydrogen, carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1 )alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino (C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted.
[0210] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00033##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0211]
A is selected from the group consisting of CR.sub.25 and N; and
[0212] R.sub.25 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0213] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00034##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof.
[0214] In yet another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00035##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof.
[0215] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00036##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0216]
R.sub.22 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0217] R.sub.23 is selected from the group consisting of
hydrogen, carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.22 are taken together to form a ring.
[0218] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00037##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0219]
R.sub.2 is --Y.sub.2--R.sub.13; [0220] Y.sub.2 is absent or a
linker providing 1 or 2 atom separation between R.sub.13 and the
ring to which Y.sub.2 is attached, wherein the atoms of the linker
providing the separation are selected from the group consisting of
carbon, oxygen, nitrogen, and sulfur; [0221] R.sub.4 is selected
from the group consisting of hydrogen, halo, nitro, cyano, thio,
oxy, hydroxy, carbonyloxy, alkoxy, carbonyl, amino,
(C.sub.1-5)alkylamino, (C.sub.1-5)alkyl, halo(C.sub.1-5)alkyl,
carbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl, amino
(C.sub.1-5)alkyl, aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted; [0222] R.sub.5 and R.sub.6 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0223] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0224] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0225] R.sub.16 is selected from the group
consisting of amino, (C.sub.1-10)alkylamino, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-5)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted; and [0226] R.sub.23
is selected from the group consisting of hydrogen, carbonyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a substituted or unsubstituted
ring.
[0227] In still another embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00038##
[0228] or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof.
[0229] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00039##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein at
least a portion of the compound is present as Amorphous Form,
characterized by physical properties which comprise one or more of
the following: [0230] (a) may be formed by lyophilizing a solution
of Compound 88 in ACN and water; [0231] (b) has an XRPD spectrum
characterized by a diffuse halo with no discernable peaks; and/or
[0232] (c) shows 7.6 wt % Cl.sup.- present using ion
chromatography.
[0233] In yet another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00040##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0234]
Q is selected from the group consisting of CR.sub.1 and N; [0235]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; [0236]
R.sub.1 is --Y.sub.1--R.sub.12; [0237] R.sub.2 is
--Y.sub.2--R.sub.13; [0238] Y.sub.1 and Y.sub.2 are each
independently absent or a linker providing 1 or 2 atom separation
between R.sub.12 or R.sub.13 and the ring to which Y.sub.1 or
Y.sub.2 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0239] Y.sub.5 is absent or a linker
providing 1, 2, 3, 4, 5, 6, 7 or 8 atom separation between the O
and the N to which Y.sub.5 is attached, wherein the atoms of the
linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0240] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0241] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0242] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0243] R.sub.25 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a substituted or
unsubstituted ring; and [0244] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring.
[0245] In a further embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00041##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0246]
A, A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are each independently
selected from the group consisting of CR.sub.25 and N; [0247]
R.sub.1 is --Y.sub.1--R.sub.12; [0248] R.sub.2 is
--Y.sub.2--R.sub.13; [0249] Y.sub.1 and Y.sub.2 are each
independently absent or a linker providing 1 or 2 atom separation
between R.sub.12 or R.sub.13 and the ring to which Y.sub.1 or
Y.sub.2 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0250] Y.sub.5 is absent or a linker
providing 1, 2, 3, 4, 5, 6, 7 or 8 atom separation between the O
and the N to which Y.sub.5 is attached, wherein the atoms of the
linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0251] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0252] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0253] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0254] R.sub.25 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a substituted or
unsubstituted ring; and [0255] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring.
[0256] In still a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00042##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof.
[0257] In yet a further embodiment, kinase inhibitors of the
present invention comprise the formula:
##STR00043##
or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, wherein [0258]
R.sub.16 is selected from the group consisting of amino,
(C.sub.1-10)alkylamino, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted.
[0259] In another embodiment, kinase inhibitors of the present
invention comprise the formula:
##STR00044## ##STR00045##
[0260] or a polymorph, solvate, ester, tautomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof.
[0261] In another of its aspects, the present invention relates to
processes for preparing compounds of the present invention. In one
embodiment, the process comprises:
[0262] reacting a compound comprising the formula
##STR00046##
with a compound comprising the formula
##STR00047##
under conditions that form a first reaction product comprising the
formula
##STR00048##
[0263] treating the first reaction product under conditions that
form a second reaction product comprising the formula
##STR00049##
[0264] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00050##
[0265] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00051##
[0266] wherein [0267] Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and
Z.sub.5 are each independently selected from the group consisting
of C and N; [0268] R.sub.1 is --Y.sub.1--R.sub.12, or R.sub.1 is
absent when Z.sub.1 is N; [0269] R.sub.2 is --Y.sub.2--R.sub.13, or
R.sub.2 is absent when Z.sub.2 is N, or R.sub.1 and R.sub.2 are
taken together to form a ring; [0270] Y.sub.1 and Y.sub.2 are each
independently absent or a linker providing 1 or 2 atom separation
between R.sub.12 or R.sub.13 and the ring to which Y.sub.1 or
Y.sub.2 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0271] R.sub.4 is selected from the
group consisting of hydrogen, halo, nitro, cyano, thio, oxy,
hydroxy, carbonyloxy, alkoxy, carbonyl, amino,
(C.sub.1-5)alkylamino, (C.sub.1-5)alkyl, halo(C.sub.1-5)alkyl,
carbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl, amino
(C.sub.1-5)alkyl, aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0272] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0273] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0274] R.sub.12 and R.sub.13 are each independently selected
from the group consisting of hydrogen, halo, nitro, cyano, thio,
oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a ring; and
[0275] X.sub.1 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0276] In one variation of the above embodiment, the process
further comprises:
[0277] treating the fourth reaction product under conditions that
form a compound comprising the formula
##STR00052##
[0278] wherein [0279] Y.sub.3 is absent or a linker providing 1 or
2 atom separation between R.sub.14 and the ring to which Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; and [0280] R.sub.14 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0281] In another embodiment, the process comprises:
[0282] reacting a compound comprising the formula
##STR00053##
with a compound comprising the formula
##STR00054##
under conditions that form a first reaction product comprising the
formula
##STR00055##
[0283] reacting the first reaction product with
ethynyltrimethylsilane under conditions that form a second reaction
product comprising the formula
##STR00056##
[0284] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00057##
[0285] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00058##
[0286] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00059##
[0287] treating the fifth reaction product under conditions that
form a sixth reaction product comprising the formula
##STR00060##
[0288] treating the sixth reaction product under conditions that
form a seventh reaction product comprising the formula
##STR00061##
and
[0289] treating the seventh reaction product under conditions that
form a compound comprising the formula
##STR00062##
[0290] wherein [0291] Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0292] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0293] Y.sub.2 and Y.sub.3 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.13 or R.sub.14 and the ring to which Y.sub.2 or Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0294] R.sub.4 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
alkoxy, carbonyl, amino, (C.sub.1-5)alkylamino, (C.sub.1-5)alkyl,
halo(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, amino (C.sub.1-5)alkyl,
aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0295] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0296] R.sub.13 is selected
from the group consisting of hydrogen, halo, nitro, cyano, thio,
oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0297] R.sub.14 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0298] P is a protecting group; and [0299] X.sub.2 and X.sub.3 are
each independently selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0300] In still another embodiment, the process comprises:
[0301] reacting a compound comprising the formula
##STR00063##
with a compound comprising the formula
##STR00064##
under conditions that form a first reaction product comprising the
formula
##STR00065##
[0302] treating the first reaction product under conditions that
form a second reaction product comprising the formula
##STR00066##
[0303] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00067##
[0304] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00068##
[0305] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00069##
and
[0306] treating the fifth reaction product under conditions that
form a compound comprising the formula
##STR00070##
[0307] wherein [0308] Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0309] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0310] Y.sub.2 and Y.sub.3 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.13 or R.sub.14 and the ring to which Y.sub.2 or Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0311] R.sub.4 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
alkoxy, carbonyl, amino, (C.sub.1-5)alkylamino, (C.sub.1-5)alkyl,
halo(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, amino (C.sub.1-5)alkyl,
aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0312] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0313] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0314] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0315] R.sub.14 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0316] In yet another embodiment, the process comprises:
[0317] reacting a compound comprising the formula
##STR00071##
with a compound comprising the formula
##STR00072##
under conditions that form a first reaction product comprising the
formula
##STR00073##
[0318] treating the first reaction product under conditions that
form a second reaction product comprising the formula
##STR00074##
[0319] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00075##
[0320] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00076##
[0321] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00077##
and
[0322] reacting the fifth reaction product with a compound
comprising the formula HNR.sub.23R.sub.24 under conditions that
form a compound comprising the formula
##STR00078##
[0323] wherein [0324] Z, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0325] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0326] Y.sub.2 and Y.sub.3 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.13 or R.sub.14 and the ring to which Y.sub.2 or Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0327] R.sub.4 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
alkoxy, carbonyl, amino, (C.sub.1-5)alkylamino, (C.sub.1-5)alkyl,
halo(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, amino (C.sub.1-5)alkyl,
aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0328] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0329] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0330] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0331] R.sub.14 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0332] R.sub.23 and R.sub.24 are each independently selected
from the group consisting of hydrogen, carbonyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cyclo alkyl(C.sub.1-5)alkyl,
hetero (C.sub.3-12)cyclo alkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero (C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.24 are taken together to form a ring.
[0333] In another embodiment, the process comprises:
[0334] reacting a compound comprising the formula
##STR00079##
with a compound comprising the formula
##STR00080##
under conditions that form a first reaction product comprising the
formula
##STR00081##
[0335] treating the first reaction product under conditions that
form a second reaction product comprising the formula
##STR00082##
[0336] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00083##
[0337] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00084##
and
[0338] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00085##
[0339] wherein [0340] Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0341] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0342] Y.sub.2 and Y.sub.3 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.13 or R.sub.14 and the ring to which Y.sub.2 or Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0343] R.sub.5 and R.sub.6 are each independently
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0344] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0345] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0346] R.sub.27 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0347] In one variation of the above embodiment, the process
further comprises treating the fifth reaction product under
conditions that form a compound comprising the formula
##STR00086##
[0348] wherein [0349] R.sub.1 is --Y.sub.1--R.sub.12; [0350]
Y.sub.1 is absent or a linker providing 1 or 2 atom separation
between R.sub.12 and the ring to which Y.sub.1 is attached, wherein
the atoms of the linker providing the separation are selected from
the group consisting of carbon, oxygen, nitrogen, and sulfur; and
[0351] R.sub.12 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0352] In still another embodiment, the process comprises:
[0353] reacting a compound comprising the formula
##STR00087##
with a compound comprising the formula
##STR00088##
under conditions that form a first reaction product comprising the
formula
##STR00089##
[0354] reacting the first reaction product with a compound
comprising the formula
##STR00090##
under conditions that form a second reaction product comprising the
formula
##STR00091##
[0355] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00092##
[0356] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00093##
[0357] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00094##
and
[0358] reacting the fifth reaction product with a compound
comprising the formula
##STR00095##
under conditions that form a sixth reaction product comprising the
formula
##STR00096##
[0359] wherein
[0360] G.sub.1, G.sub.2, G.sub.3, G.sub.4 and G.sub.5 are each
independently a leaving group.
[0361] In yet another embodiment, the process comprises:
[0362] reacting a compound comprising the formula
##STR00097##
with a compound comprising the formula
##STR00098##
under conditions that form a first reaction product comprising the
formula
##STR00099##
[0363] reacting the first reaction product with a compound
comprising the formula
##STR00100##
under conditions that form a second reaction product comprising the
formula
##STR00101##
[0364] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00102##
[0365] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00103##
[0366] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00104##
and
[0367] reacting the fifth reaction product with a compound
comprising the formula
##STR00105##
under conditions that form a sixth reaction product comprising the
formula
##STR00106##
[0368] In a further embodiment, the process comprises:
[0369] reacting a compound comprising the formula
##STR00107##
with a compound comprising the formula
##STR00108##
under conditions that form a first reaction product comprising the
formula
##STR00109##
[0370] reacting the first reaction product with a compound
comprising the formula
##STR00110##
under conditions that form a second reaction product comprising the
formula
##STR00111##
[0371] treating the second reaction product under conditions that
form a third reaction product comprising the formula
##STR00112##
[0372] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00113##
[0373] reacting the fourth reaction product with a compound
comprising the formula
X.sub.4-G.sub.4
under conditions that form a fifth reaction product comprising the
formula
##STR00114##
[0374] reacting the fifth reaction product with a compound
comprising the formula
##STR00115##
under conditions that form a sixth reaction product comprising the
formula
##STR00116##
and
[0375] reacting the sixth reaction product with a compound
comprising the formula
##STR00117##
under conditions that form a seventh reaction product comprising
the formula
##STR00118##
[0376] wherein [0377] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0378] R.sub.1 is
--Y.sub.1--R.sub.12; [0379] R.sub.2 is --Y.sub.2--R.sub.13; [0380]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0381] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0382] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0383] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0384] R.sub.25 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or any two R.sub.25 are taken together to form a substituted or
unsubstituted ring; [0385] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring; and [0386] X.sub.4,
G.sub.1, G.sub.2, G.sub.3, G.sub.4, G.sub.5 and G.sub.6 are each
independently a leaving group.
[0387] In still a further embodiment, the process comprises:
[0388] reacting a compound comprising the formula
##STR00119##
with a compound comprising the formula
##STR00120##
under conditions that form a first reaction product comprising the
formula
##STR00121##
[0389] reacting the first reaction product with a compound
comprising the formula
X.sub.5-G.sub.8
under conditions that form a second reaction product comprising the
formula
##STR00122##
[0390] reacting the second reaction product with a compound
comprising the formula
##STR00123##
under conditions that form a third reaction product comprising the
formula
##STR00124##
[0391] treating the third reaction product under conditions that
form a fourth reaction product comprising the formula
##STR00125##
[0392] treating the fourth reaction product under conditions that
form a fifth reaction product comprising the formula
##STR00126##
[0393] reacting the fifth reaction product with a compound
comprising the formula
X.sub.6-G.sub.11
under conditions that form a sixth reaction product comprising the
formula
##STR00127##
and
[0394] reacting the sixth reaction product with a compound
comprising the formula
##STR00128##
under conditions that form a seventh reaction product comprising
the formula
##STR00129##
[0395] wherein [0396] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0397] R.sub.1 is
--Y.sub.1--R.sub.12; [0398] R.sub.2 is --Y.sub.2--R.sub.13; [0399]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0400] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0401] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0402] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0403] R.sub.25 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0404] R.sub.30 and R.sub.31 are each independently selected from
the group consisting of hydrogen, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido,
imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring; and [0405] X.sub.5,
X.sub.6, G.sub.7, G.sub.8, G.sub.9, G.sub.10, G.sub.11 and G.sub.12
are each independently a leaving group.
[0406] In still another of its aspects, the present invention
relates to compounds useful in preparing compounds of the present
invention. In one embodiment, such compounds comprise a formula
##STR00130##
[0407] wherein [0408] X.sub.1 is selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10alkyl, aryl(C.sub.1-10alkyl,
hetero(C.sub.1-10aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted.
[0409] Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are each
independently selected from the group consisting of C and N; [0410]
R.sub.1 is --Y.sub.1--R.sub.12, or R.sub.1 is absent when Z.sub.1
is N; [0411] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent
when Z.sub.2 is N, or R.sub.1 and R.sub.2 are taken together to
form a ring; [0412] Y.sub.1 and Y.sub.2 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.12 or R.sub.13 and the ring to which Y.sub.1 or Y.sub.2 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0413] R.sub.4 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
alkoxy, carbonyl, amino, (C.sub.1-5)alkylamino, (C.sub.1-5)alkyl,
halo(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, amino (C.sub.1-5)alkyl,
aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0414] R.sub.6 is
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that R.sub.6 is absent when the atom to which it
is bound is N; [0415] R.sub.7 is selected from the group consisting
of hydrogen, halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl,
each substituted or unsubstituted, with the proviso that R.sub.7 is
absent when the atom to which it is bound is N; and [0416] R.sub.12
and R.sub.13 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a ring.
[0417] In another embodiment, such compounds comprise a formula
##STR00131##
[0418] wherein [0419] Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0420] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0421] Y.sub.2 and Y.sub.3 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.13 or R.sub.14 and the ring to which Y.sub.2 or Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0422] R.sub.5 and R.sub.6 are each independently
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0423] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0424] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0425] R.sub.14 is selected from the group consisting of hydrogen,
halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0426] P is a protecting group.
[0427] In still another embodiment, such compounds comprise a
formula
##STR00132##
[0428] wherein [0429] Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0430] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0431] Y.sub.2 is absent or a linker providing 1 or 2
atom separation between R.sub.13 and the ring to which Y.sub.2 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0432] R.sub.4 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
alkoxy, carbonyl, amino, (C.sub.1-5)alkylamino, (C.sub.1-5)alkyl,
halo(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, amino (C.sub.1-5)alkyl,
aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0433] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0434] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; and [0435] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0436] In yet another embodiment, such compounds comprise a
formula
##STR00133##
[0437] wherein [0438] Z, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0439] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0440] Y.sub.2 and Y.sub.3 are each independently
absent or a linker providing 1 or 2 atom separation between
R.sub.13 or R.sub.14 and the ring to which Y.sub.2 or Y.sub.3 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0441] R.sub.4 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
alkoxy, carbonyl, amino, (C.sub.1-5)alkylamino, (C.sub.1-5)alkyl,
halo(C.sub.1-5)alkyl, carbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, amino (C.sub.1-5)alkyl,
aryl(C.sub.1-5)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-6)cycloalkyl and hetero(C.sub.3-6)cycloalkyl, each
substituted or unsubstituted, with the proviso that R.sub.4 is
absent when the atom to which it is bound is N; [0442] R.sub.5 and
R.sub.6 are each independently selected from the group consisting
of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0443] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0444] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0445] R.sub.14 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0446] In another embodiment, such compounds comprise a formula
##STR00134##
[0447] wherein [0448] Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each independently selected from the group consisting of C and N;
[0449] R.sub.2 is --Y.sub.2--R.sub.13, or R.sub.2 is absent when
Z.sub.2 is N; [0450] Y.sub.2 is absent or a linker providing 1 or 2
atom separation between R.sub.13 and the ring to which Y.sub.2 is
attached, wherein the atoms of the linker providing the separation
are selected from the group consisting of carbon, oxygen, nitrogen,
and sulfur; [0451] R.sub.5 and R.sub.6 are each independently
selected from the group consisting of hydrogen, halo, nitro, cyano,
thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
with the proviso that each of R.sub.5 and R.sub.6 is absent when
the atom to which it is bound is N; [0452] R.sub.7 is selected from
the group consisting of hydrogen, halo, hydroxy, alkoxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted, with the
proviso that R.sub.7 is absent when the atom to which it is bound
is N; [0453] R.sub.13 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and [0454] R.sub.27 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0455] In still another embodiment, such compounds comprise a
formula
##STR00135##
[0456] wherein
[0457] G.sub.2 is a leaving group.
[0458] In yet another embodiment, such compounds comprise a
formula
##STR00136##
[0459] wherein
[0460] G.sub.2 is a leaving group.
[0461] In a further embodiment, such compounds comprise a
formula
##STR00137##
[0462] In still a further embodiment, such compounds comprise a
formula
##STR00138##
[0463] In yet a further embodiment, such compounds comprise a
formula
##STR00139##
[0464] wherein [0465] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0466] R.sub.1 is
--Y.sub.1--R.sub.12; [0467] R.sub.2 is --Y.sub.2--R.sub.13; [0468]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0469] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0470] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0471] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; and [0472] G.sub.1 and G.sub.4 are each
independently a leaving group.
[0473] In another embodiment, such compounds comprise a formula
##STR00140##
[0474] wherein [0475] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0476] R.sub.1 is
--Y.sub.1--R.sub.12; [0477] R.sub.2 is --Y.sub.2--R.sub.13; [0478]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0479] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0480] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0481] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0482] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring; and [0483] G.sub.1 is
a leaving group.
[0484] In still another embodiment, such compounds comprise a
formula
##STR00141##
[0485] wherein [0486] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0487] R.sub.1 is
--Y.sub.1--R.sub.12; [0488] R.sub.2 is --Y.sub.2--R.sub.13; [0489]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0490] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0491] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0492] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0493] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring; and [0494] G.sub.10 is
a leaving group.
[0495] In yet another embodiment, such compounds comprise a
formula
##STR00142##
[0496] wherein [0497] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0498] R.sub.1 is
--Y.sub.1--R.sub.12; [0499] R.sub.2 is --Y.sub.2--R.sub.13; [0500]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0501] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0502] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0503] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0504] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring; and [0505] G.sub.10 is
a leaving group.
[0506] In a further embodiment, such compounds comprise a
formula
##STR00143##
[0507] wherein [0508] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0509] R.sub.1 is
--Y.sub.1--R.sub.12; [0510] R.sub.2 is --Y.sub.2--R.sub.13; [0511]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0512] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0513] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0514] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0515] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring.
[0516] In still a further embodiment, such compounds comprise a
formula
##STR00144##
[0517] wherein [0518] Y.sub.5 is absent or a linker providing 1, 2,
3, 4, 5, 6, 7 or 8 atom separation between the O and the N to which
Y.sub.5 is attached, wherein the atoms of the linker providing the
separation are selected from the group consisting of carbon,
oxygen, nitrogen, and sulfur; [0519] R.sub.1 is
--Y.sub.1--R.sub.12; [0520] R.sub.2 is --Y.sub.2--R.sub.13; [0521]
Y.sub.1 and Y.sub.2 are each independently absent or a linker
providing 1 or 2 atom separation between R.sub.12 or R.sub.13 and
the ring to which Y.sub.1 or Y.sub.2 is attached, wherein the atoms
of the linker providing the separation are selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur; [0522] R.sub.5
and R.sub.6 are each independently selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
[0523] R.sub.7 is selected from the group consisting of hydrogen,
halo, hydroxy, alkoxy, amino and (C.sub.1-5)alkyl, each substituted
or unsubstituted; [0524] R.sub.12 and R.sub.13 are each
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, oxy, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.12 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; [0525] R.sub.30 and R.sub.31 are each
independently selected from the group consisting of hydrogen, oxy,
hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
aza(C.sub.1-10)alkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.30 and R.sub.31 are taken together to form a substituted
or unsubstituted ring, or R.sub.30 and Y.sub.5 are taken together
to form a substituted or unsubstituted ring; and [0526] G.sub.11 is
a leaving group.
[0527] In one variation of the compounds and processes of each of
the above embodiments and variations, A is CR.sub.25. In another
variation of the compounds and processes of each of the above
embodiments and variations, A.sub.1 is CR.sub.25. In still another
variation of the compounds and processes of each of the above
embodiments and variations, A.sub.2 is CR.sub.25. In yet another
variation of the compounds and processes of each of the above
embodiments and variations, A.sub.3 is CR.sub.25. In a further
variation of the compounds and processes of each of the above
embodiments and variations, A.sub.4 is CR.sub.25.
[0528] In another variation of the compounds and processes of each
of the above embodiments and variations, Y.sub.1 is selected from
the group consisting of --CH.sub.2--, --NH--, --O-- and --S--.
[0529] In still another variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.1 is selected
from the group consisting of --O--, --(CR.sub.19R.sub.20).sub.m--,
--NR.sub.21--, --S-- and --S--CH.sub.2--; m is selected from the
group consisting of 0, 1, 2, 3, 4 and 5; R.sub.19 and R.sub.20 are
selected from the group consisting of hydrogen, halo, cyano, thio,
oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.19 and R.sub.12 are taken together to form a substituted
or unsubstituted ring; and R.sub.21 is selected from the group
consisting of hydrogen, carbonyloxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, oxycarbonyl, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.21 and R.sub.12 are taken together to form a substituted
or unsubstituted ring.
[0530] In yet another variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.1 is
--C(O)--NR.sub.23--; and R.sub.23 is selected from the group
consisting of hydrogen, carbonyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a substituted or unsubstituted
ring.
[0531] In a further variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.1 is
--C(O)--O--.
[0532] In still a further variation of the compounds and processes
of each of the above embodiments and variations, Y.sub.1 is
--NR.sub.23--C(O)--; and R.sub.23 is selected from the group
consisting of hydrogen, carbonyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.12 are taken together to form a ring.
[0533] In yet a further variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.2 is selected
from the group consisting of --CH.sub.2--, --NH--, --O-- and
--S--.
[0534] In another variation of the compounds and processes of each
of the above embodiments and variations, Y.sub.2 is selected from
the group consisting of --O--, --(CR.sub.19R.sub.20).sub.m--,
--NR.sub.21--, --S-- and --S--CH.sub.2--; m is selected from the
group consisting of 0, 1, 2, 3, 4 and 5; R.sub.19 and R.sub.20 are
selected from the group consisting of hydrogen, halo, cyano, thio,
oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.19 and R.sub.13 are taken together to form a substituted
or unsubstituted ring; and R.sub.21 is selected from the group
consisting of hydrogen, carbonyloxy, alkoxy, aryloxy,
heteroaryloxy, carbonyl, oxycarbonyl, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted,
or R.sub.21 and R.sub.13 are taken together to form a substituted
or unsubstituted ring.
[0535] In still another variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.3 is selected
from the group consisting of --CH.sub.2--, --NH--, --O-- and
--S--.
[0536] In yet another variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.3 is selected
from the group consisting of --O--, --(CR.sub.19R.sub.20).sub.m--,
--NR.sub.21--, --S-- and --S--CH.sub.2--; m is selected from the
group consisting of 0, 1, 2, 3, 4 and 5; R.sub.19 and R.sub.20 are
selected from the group consisting of hydrogen, halo, cyano, thio,
oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and R.sub.21 is selected from the group consisting of hydrogen,
carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0537] In a further variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.3 is
absent.
[0538] In still a further variation of the compounds and processes
of each of the above embodiments and variations,
--Y.sub.3--R.sub.14 is selected from the group consisting of aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0539] In yet a further variation of the compounds and processes of
each of the above embodiments and variations, Z is N. In another
variation of the compounds and processes of each of the above
embodiments and variations, Z.sub.1 is N. In still another
variation of the compounds and processes of each of the above
embodiments and variations, Z.sub.2 is N. In yet another variation
of the compounds and processes of each of the above embodiments and
variations, Z.sub.3 is N. In a further variation of the compounds
and processes of each of the above embodiments and variations,
Z.sub.4 is N. In still a further variation of the compounds and
processes of each of the above embodiments and variations, Z.sub.5
is N. In yet a further variation of the compounds and processes of
each of the above embodiments and variations, Z, Z.sub.2, Z.sub.3,
Z.sub.4 and Z.sub.5 are each C. In another variation of the
compounds and processes of each of the above embodiments and
variations, Z, Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 are
each C.
[0540] In still another variation of the compounds and processes of
each of the above embodiments and variations, R.sub.1 is selected
from the group consisting of hydrogen, halo, amino, alkoxy,
carbonyloxy, aminocarbonyl, sulfonyl, carbonylamino, sulfonylamino,
(C.sub.1-10)alkyl, hetero(C.sub.3-12)cycloalkyl and aryl, each
substituted or unsubstituted. In yet another variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.1 is a substituted or unsubstituted piperadinyl.
In a further variation of the compounds and processes of each of
the above embodiments and variations, R.sub.1 is a substituted or
unsubstituted 1-methyl(piperadin-4-yl).
[0541] In still a further variation of the compounds and processes
of each of the above embodiments and variations, R.sub.2 is
selected from the group consisting of hydrogen, halo, amino,
alkoxy, (C.sub.1-10)alkyl, hetero(C.sub.3-12)cycloalkyl and aryl,
each substituted or unsubstituted. In yet a further variation of
the compounds and processes of each of the above embodiments and
variations, R.sub.2 is hydrogen.
[0542] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.4 is selected from
the group consisting of hydrogen, halo and substituted or
unsubstituted (C.sub.1-5)alkyl. In still another variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.4 is methyl. In yet another variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.4 is trifluoromethyl. In a further variation of
the compounds and processes of each of the above embodiments and
variations, R.sub.4 is a substituted or unsubstituted oxaalkyl. In
still a further variation of the compounds and processes of each of
the above embodiments and variations, R.sub.4 is a substituted or
unsubstituted alkoxy. In yet a further variation of the compounds
and processes of each of the above embodiments and variations,
R.sub.4 is a substituted or unsubstituted aryloxy.
[0543] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.4 is
--Y.sub.4--R.sub.27; Y.sub.4 is absent or a linker providing 1 or 2
atom separation between R.sub.27 and the ring to which Y.sub.4 is
attached; and R.sub.27 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cyclo alkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted.
In one variation, Y.sub.4 is selected from the group consisting of
--CH.sub.2--, --NH--, --O-- and --S--. In another variation,
Y.sub.4 is absent.
[0544] In still another variation of the compounds and processes of
each of the above embodiments and variations, R.sub.4 is
--OR.sub.27 and R.sub.27 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0545] In yet another variation of the compounds and processes of
each of the above embodiments and variations, R.sub.4 is
--SR.sub.27 and R.sub.27 is selected from the group consisting of
hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,
(C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy, hetero(C.sub.1-10)aryloxy,
carbonyl, oxycarbonyl, aminocarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, (C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl,
imino(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or
unsubstituted.
[0546] In a further variation of the compounds and processes of
each of the above embodiments and variations, R.sub.4 is
--NR.sub.28--R.sub.27; R.sub.27 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,
carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,
amino, (C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl,
sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
hydroxy(C.sub.1-10)alkyl, carbonyl(C.sub.1-10)alkyl,
thiocarbonyl(C.sub.1-10)alkyl, sulfonyl(C.sub.1-10)alkyl,
sulfinyl(C.sub.1-10)alkyl, (C.sub.1-10)azaalkyl,
(C.sub.1-10)oxaalkyl, (C.sub.1-10)oxoalkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and R.sub.28 is selected from the group consisting of hydrogen,
oxy, hydroxy, carbonyloxy, (C.sub.1-10)alkoxy, (C.sub.4-12)aryloxy,
hetero(C.sub.1-10)aryloxy, carbonyl, oxycarbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, hydroxy(C.sub.1-10)alkyl,
carbonyl(C.sub.1-10)alkyl, thiocarbonyl(C.sub.1-10)alkyl,
sulfonyl(C.sub.1-10)alkyl, sulfinyl(C.sub.1-10)alkyl,
(C.sub.1-10)azaalkyl, imino(C.sub.1-10)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-10)alkyl,
aryl(C.sub.1-10)alkyl, hetero(C.sub.1-10)aryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, (C.sub.4-12)aryl,
hetero(C.sub.1-10)aryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted.
In one variation, R.sub.28 is selected from the group consisting of
hydrogen and a substituted or unsubstituted (C.sub.1-5)alkyl.
[0547] In still a further variation of the compounds and processes
of each of the above embodiments and variations, R.sub.5 is
selected from the group consisting of hydrogen, halo and
substituted or unsubstituted (C.sub.1-5)alkyl. In yet a further
variation of the compounds and processes of each of the above
embodiments and variations, R.sub.5 is hydrogen. In another
variation of the compounds and processes of each of the above
embodiments and variations, R.sub.5 is halo. In still another
variation of the compounds and processes of each of the above
embodiments and variations, R.sub.5 is a substituted or
unsubstituted (C.sub.1-5)alkyl.
[0548] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.6 is selected from
the group consisting of hydrogen, halo, amino, carbonyl, alkoxy and
(C.sub.1-5)alkyl, each substituted or unsubstituted. In a further
variation of the compounds and processes of each of the above
embodiments and variations, R.sub.6 is a substituted or
unsubstituted (C.sub.1-5)alkyl. In still another variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.6 is halo. In yet another variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.6 is selected from the group consisting of
methyl, ethyl, isopropyl and cyclopropyl, each substituted or
unsubstituted.
[0549] In a further variation of the compounds and processes of
each of the above embodiments and variations, R.sub.7 is selected
from the group consisting of hydrogen, hydroxy, amino and
(C.sub.1-5)alkyl, each substituted or unsubstituted. In still a
further variation of the compounds and processes of each of the
above embodiments and variations, R.sub.7 is hydrogen.
[0550] In yet a further variation of the compounds and processes of
each of the above embodiments and variations, R.sub.12 is selected
from the group consisting of hydrogen, halo, amino, alkoxy,
carbonyloxy, aminocarbonyl, sulfonyl, carbonylamino, sulfonylamino,
(C.sub.1-10)alkyl, hetero(C.sub.3-12)cycloalkyl and aryl, each
substituted or unsubstituted.
[0551] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.13 is selected from
the group consisting of hydrogen, halo, amino, alkoxy, carbonyloxy,
aminocarbonyl, sulfonyl, carbonylamino, sulfonylamino,
(C.sub.1-10)alkyl, hetero(C.sub.3-12)cycloalkyl and aryl, each
substituted or unsubstituted.
[0552] In still another variation of the compounds and processes of
each of the above embodiments and variations, R.sub.14 is selected
from the group consisting of halo, nitro, cyano, thio, hydroxy,
alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,
(C.sub.1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,
(C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted.
In yet another variation of the compounds and processes of each of
the above embodiments and variations, R.sub.14 is selected from the
group consisting of (C.sub.3-12)cycloalkyl,
hetero(C.sub.3-12)cycloalkyl, (C.sub.9-12)bicycloalkyl,
hetero(C.sub.3-12)bicycloalkyl, aryl, heteroaryl,
(C.sub.9-12)bicycloaryl and hetero(C.sub.4-12)bicycloaryl, each
substituted or unsubstituted. In a further variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.14 is selected from the group consisting of aryl
and heteroaryl, each substituted with a substituent selected from
the group consisting of halo, carbonyl, (C.sub.1-5)alkyl, alkoxy,
aminocarbonyl, amino and sulfonyl, each substituted or
unsubstituted.
[0553] In still a further variation of the compounds and processes
of each of the above embodiments and variations, R.sub.15 is
selected from the group consisting of (C.sub.1-10)alkyl,
--OR.sub.22, --C(O)--R.sub.22, --NR.sub.23--C(O)--R.sub.22,
--C(O)--NR.sub.23--R.sub.22, --SO.sub.2--R.sub.22,
--NR.sub.23--SO.sub.2--R.sub.22 and --SO.sub.2--NR.sub.23R.sub.24;
R.sub.22 is selected from the group consisting of hydrogen, halo,
nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carbonyl, amino, (C.sub.1-10)alkylamino, sulfonamido, imino,
sulfonyl, sulfinyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and R.sub.23 and R.sub.24 are each independently selected from the
group consisting of hydrogen, carbonyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.24 are taken together to form a ring.
[0554] In yet a further variation of the compounds and processes of
each of the above embodiments and variations, R.sub.16 is
--NR.sub.23--C(O)--R.sub.22; R.sub.22 is selected from the group
consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy,
aryloxy, heteroaryloxy, carbonyl, amino, (C.sub.1-10)alkylamino,
sulfonamido, imino, sulfonyl, sulfinyl, (C.sub.1-10)alkyl,
halo(C.sub.1-10)alkyl, carbonyl(C.sub.1-3)alkyl,
thiocarbonyl(C.sub.1-3)alkyl, sulfonyl(C.sub.1-3)alkyl,
sulfinyl(C.sub.1-3)alkyl, amino (C.sub.1-10)alkyl,
imino(C.sub.1-3)alkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.1-5)alkyl,
hetero(C.sub.8-12)bicycloaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl,
(C.sub.9-12)bicycloalkyl, hetero(C.sub.3-12)bicycloalkyl, aryl,
heteroaryl, (C.sub.9-12)bicycloaryl and
hetero(C.sub.4-12)bicycloaryl, each substituted or unsubstituted;
and R.sub.23 is selected from the group consisting of hydrogen,
carbonyl, (C.sub.1-10)alkyl, halo(C.sub.1-10)alkyl,
carbonyl(C.sub.1-3)alkyl, thiocarbonyl(C.sub.1-3)alkyl,
sulfonyl(C.sub.1-3)alkyl, sulfinyl(C.sub.1-3)alkyl, amino
(C.sub.1-10)alkyl, imino(C.sub.1-3)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl,
aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl,
(C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl and
heteroaryl, each substituted or unsubstituted, or R.sub.23 and
R.sub.24 are taken together to form a ring.
[0555] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.22 is a substituted
or unsubstituted (C.sub.3-6)cycloalkyl. In still another variation
of the compounds and processes of each of the above embodiments and
variations, R.sub.22 is a substituted or unsubstituted
cyclopropyl.
[0556] In yet another variation of the compounds and processes of
each of the above embodiments and variations, R.sub.23 and R.sub.24
are taken together to form a carbocyclic or heterocyclic
(C.sub.5-10) ring. In a further variation of the compounds and
processes of each of the above embodiments and variations, R.sub.23
and R.sub.24 are taken together to form a substituted or
unsubstituted piperazine.
[0557] In still a further variation of the compounds and processes
of each of the above embodiments and variations, R.sub.23 is
hydrogen.
[0558] In yet a further variation of the compounds and processes of
each of the above embodiments and variations, R.sub.25 is
hydrogen.
[0559] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.27 is a substituted
or unsubstituted heterocycloalkyl(C.sub.1-3)alkyl. In still another
variation of the compounds and processes of each of the above
embodiments and variations, R.sub.27 is a substituted or
unsubstituted piperadinyl(C.sub.1-3)alkyl. In yet another variation
of the compounds and processes of each of the above embodiments and
variations, R.sub.27 is a substituted or unsubstituted
1-methyl(piperadin-4-yl)(C.sub.1-3)alkyl. In a further variation of
the compounds and processes of each of the above embodiments and
variations, R.sub.27 is a substituted or unsubstituted
1-methyl(piperadin-4-yl)methyl. In still a further variation of the
compounds and processes of each of the above embodiments and
variations, R.sub.27 is a substituted or unsubstituted
amino(C.sub.1-5)alkyl. In yet a further variation of the compounds
and processes of each of the above embodiments and variations,
R.sub.27 is a substituted or unsubstituted dimethylaminopropyl.
[0560] In another variation of the compounds and processes of each
of the above embodiments and variations, R.sub.30 is a substituted
or unsubstituted (C.sub.1-5)alkyl. In still another variation of
the compounds and processes of each of the above embodiments and
variations, R.sub.30 is methyl.
[0561] In still another variation of the compounds and processes of
each of the above embodiments and variations, R.sub.31 is a
substituted or unsubstituted (C.sub.1-5)alkyl. In another variation
of the compounds and processes of each of the above embodiments and
variations, R.sub.31 is methyl.
[0562] In another variation of the compounds and processes of each
of the above embodiments and variations, P is selected from the
group consisting of benzyl and p-methoxybenzyl.
[0563] In still another variation of the compounds and processes of
each of the above embodiments and variations, G.sub.1 is halo. In
yet another variation of the compounds and processes of each of the
above embodiments and variations, G.sub.2 is halo. In still another
variation of the compounds and processes of each of the above
embodiments and variations, G.sub.3 is halo. In yet another
variation of the compounds and processes of each of the above
embodiments and variations, G.sub.4 is halo. In a further variation
of the compounds and processes of each of the above embodiments and
variations, G.sub.5 is --B(OH).sub.2.
[0564] In yet another variation of the compounds and processes of
each of the above embodiments and variations, Y.sub.5 is a
substituted or unsubstituted (C.sub.1-5)alkylene. In a further
variation of the compounds and processes of each of the above
embodiments and variations, Y.sub.5 is ethyl. In still a further
variation of the compounds and processes of each of the above
embodiments and variations, Y.sub.5 is propyl.
[0565] Particular examples of compounds according to the present
invention include, but are not limited to: [0566]
5-bromo-9H-pyrido[2,3-b]indole; [0567]
5-bromo-8-methyl-9H-pyrido[2,3-b]indole; [0568]
5-bromo-3,8-dimethyl-9H-pyrido[2,3-b]indole; [0569]
5-phenyl-9H-pyrido[2,3-b]indole; [0570]
5-(3-(methylsulfonyl)phenyl)-9H-pyrido[2,3-b]indole; [0571]
5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indole; [0572]
N-(3-(9H-pyrido[2,3-b]indol-5-yl)phenyl)ethanesulfonamide; [0573]
5-m-tolyl-9H-pyrido[2,3-b]indole; [0574]
N-cyclopropyl-3-(9H-pyrido[2,3-b]indol-5-yl)benzenesulfonamide;
[0575] 5-(3-methoxyphenyl)-9H-pyrido[2,3-b]indole; [0576]
5-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-2-methoxy-N-methylbenzenesulf-
onamide; [0577]
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N-methylbenzenesulfonamide;
[0578]
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N,N-dimethylbenzenesul-
fonamide; [0579]
5-(3-(ethylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3-b]indole; [0580]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole;
[0581]
N-(3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)propionamide;
[0582]
N-cyclopropyl-3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)benzamide;
[0583] N-(4-(9H-pyrido[2,3-b]indol-5-ylthio)phenyl)acetamide;
[0584] 5-(benzylthio)-9H-pyrido[2,3-b]indole; [0585]
5-(phenylthio)-9H-pyrido[2,3-b]indole; [0586]
5-(benzylthio)-8-methyl-9H-pyrido[2,3-b]indole; [0587]
5-(benzylthio)-3,8-dimethyl-9H-pyrido[2,3-b]indole; [0588]
7-Benzyl-5-(3-ethanesulfonyl-phenyl)-3-methyl-7,9-dihydro-dipyrido[2,3-b;
4',3'-d]pyrrol-8-one; [0589]
8-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0590]
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-ropane-1,3-diamine; [0591]
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-ethane-1,2-diamine; [0592]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(3-morpholin-4-yl-propyl)-amine; [0593]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(1-methyl-piperidin-4-yl)-amine; [0594]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-ylamino]-ethanol; [0595]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(1-methyl-piperidin-4-ylmethyl)-amine; [0596]
5-(3-Ethanesulfonyl-phenyl)-3,8-dimethyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0597]
5-(3-Ethanesulfonyl-phenyl)-8-ethyl-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0598]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole-8-carbonitrile; [0599]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole-8-carboxylic acid amide; [0600]
5-(3-Ethanesulfonyl-phenyl)-8-ethoxy-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0601]
{3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propyl}-dimethyl-amine; [0602]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-ethanol; [0603]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole; [0604]
3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-1-ol; [0605]
(R)-2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxymethyl]-propane-1,3-diol; [0606]
(S)-2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxymethyl]-propane-1,3-diol; [0607]
1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-2-methyl-propan-2-ol; [0608]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-phenoxy-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0609]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(thiazol-5-ylmethoxy)-9H-dipyrido[-
2,3-b; 4',3'-d]pyrrole; [0610]
5-(3-Ethanesulfonyl-phenyl)-8-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-9H-
-dipyrido[2,3-b; 4',3'-d]pyrrole; [0611]
(S)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [0612]
(R)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [0613]
L-Valine-2-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-ethyl ester; [0614]
L-Alanine-(R)-2-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-1-methyl-ethyl ester; [0615]
3-(3-Bromo-5-chloro-pyridin-2-ylamino)-5-chloro-1-(4-methoxy-benzyl)-1H-p-
yrazin-2-one; [0616]
3,8-Dichloro-5-(3-ethanesulfonyl-phenyl)-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0617]
3-Chloro-5-(3-ethanesulfonyl-phenyl)-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole; [0618]
(R)-1-[3-Chloro-5-(3-ethanesulfonyl-phenyl)-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [0619]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]methyl amine; [0620]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]methanethiol; [0621]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]ethanethiol; [0622]
8-Chloro-5-[3-(cyclopropylcarboxamide)phenyl]-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0623]
2-[5-(3-cyclopropylcarbonylamino-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]ethanethiol; [0624]
9-(3-Ethanesulfonyl-phenyl)-5H-pyrazino[2,3-b]indole; [0625]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-7-(trifluoromethyl)-9H-pyrido[2,-
3-b]indole acetate; [0626]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxy-
lic acid; [0627]
N-(2-(dimethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-py-
rido[2,3-b]indole-7-carboxamide; [0628]
N-(2-(methylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyri-
do[2,3-b]indole-7-carboxamide; [0629]
N-(2-(methoxy)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2-
,3-b]indole-7-carboxamide; [0630]
N-(2-(dimethylamino)ethyl)-N-methyl-5-(3-(ethylsulfonyl)phenyl)-3,8-dimet-
hyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0631]
N,N-dimethyl-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]ind-
ole-7-methylcarboxamide; [0632]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-yl)(4-m-
ethylpiperazin-1-yl)methanone; [0633]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-piperazin-1-yl)ethyl)-9H-py-
rido[2,3-b]indole-7-carboxamide; [0634]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-(4-methylpiperazin-1-yl)pro-
pyl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0635]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-yl)(mor-
pholino)methanone; [0636]
azetidin-1-yl(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]in-
dol-7-yl)methanone; [0637]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(tha-
iazolidin-3-yl)methanone; [0638]
(R)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0639]
(S)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0640]
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxyethyl)-3,8-dimethyl-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0641]
N-(2,3-dihydroxypropyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0642]
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxy-2-methylpropyl)-3,8-dimethyl-9H--
pyrido[2,3-b]indole-7-carboxamide; [0643]
5-(3-(ethylsulfonyl)phenyl)-N-(1-isopropylpiperidin-4-yl)-3,8-dimethyl-9H-
-pyrido[2,3-b]indole-7-carboxamide; [0644]
N-(1-ethylpiperidin-4-yl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide; [0645]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-thiazol-2-yl)-9H-pyrido[2,3-b]-
indole-7-carboxamide; [0646]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-(2,2,2-trifluoroethoxy)ethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide; [0647]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-3-yl)-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0648]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-4-yl)-9H-pyrid
o[2,3-b]indole-7-carboxamide; [0649]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-3-yl)-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0650]
5-(3-(ethylsulfonyl)phenyl)-N-(2-(2-hydroxyethoxy)ethyl-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide; [0651]
5-(3-(cyclopropanecarboxamido)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dime-
thyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0652]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide; [0653]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-((1-methylpiperidin-4-yl)methy-
l)-9H-pyrido[2,3-b]indole-7-carboxamide; [0654]
N-(3-(dimethylamino)propyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide; [0655]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-9H--
pyrido[2,3-b]indole-7-carboxamide; [0656]
(S)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide; [0657]
(R)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide; [0658]
5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-
-carboxamide; [0659]
5-(3-(cyclopropanecarboxamido)phenyl)-3,8-dimethyl-N-(1-methyl-piperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0660]
5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-
-carboxamide; [0661]
5-(3-(cyclopropylcarbamoyl)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dimethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide; [0662]
5-Amino-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitrile; [0663]
5-Iodo-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitrile; [0664]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitril-
e; [0665]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid amide; [0666]
5-Amino-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic acid methyl
ester; [0667] 5-Iodo-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid methyl ester; [0668]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid methyl ester; [0669]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl]-methano-
l; [0670]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl-
methyl]-dimethyl-amine; [0671]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-morpholin-4-ylmethyl-9H-pyrido[2,3-
-b]indole; [0672]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-(4-methyl-piperazin-1-ylmethyl)-9H-
-pyrido[2,3-b]indole; [0673]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-pyrrolidin-1-ylmethyl-9H-pyrido[2,-
3-b]indole; [0674]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-ylmethyl]-e-
thyl-amine; [0675]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid; [0676]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl]-(4-meth-
yl-piperazin-1-yl)-methanone; [0677]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (2-dimethylamino-ethyl)-amide; [0678]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (3-dimethylamino-propyl)-amide; [0679]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-(2H-tetrazol-5-yl)-9H-pyrido[2,3-b-
]indole; [0680]
(3-Dimethylamino-pyrrolidin-1-yl)-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9-
H-pyrido[2,3-b]indol-7-yl]-methanone; [0681]
N-ethyl-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxamide; [0682]
6-Bromo-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxylic acid methyl ester; [0683]
8-Bromo-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxylic acid methyl ester; [0684]
6-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester; [0685]
8-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester; [0686]
5-(benzylthio)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic acid;
[0687]
5-(benzylthio)-N-(2-(dimethylamino)ethyl)-3-methyl-9H-pyrido[2,3-b]indole-
-7-carboxamide; [0688]
5-(3-(N-ethylsulfamoyl)phenyl)-8-methoxy-3-methyl-N-(1-methylpiperidin-4--
yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0689]
5-(3-(cyclopropylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-
-9H-pyrido[2,3-b]indole-7-carboxamide; [0690]
5-choloro-8-methoxy-9H-pyrido[2,3-b]indole; [0691]
5-(3-(ethylsulfonyl)phenyl-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole;
[0692]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol;
[0693]
8-methoxy-3-methyl-5-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-9H-pyrido-
[2,3-b]indole; [0694]
(R)-8-methoxy-3-methyl-5-(3-(pyrrolidin-3-ylsulfonyl)phenyl)-9H-pyrido[2,-
3-b]indole; [0695]
N-cyclopropyl-4-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)picolinami-
de; [0696]
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)acet-
amide; [0697]
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)cyclopropaneca-
rboxamide; [0698]
N-cyclopropyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide;
[0699]
N,N-diethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benza-
mide; [0700]
5-(benzo[d][1,3]dioxol-5-yl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole;
[0701]
6-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-4H-chromen-4-one-
; [0702]
N-(2-hydroxyethyl)-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5--
yl)benzamide; [0703]
(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)(pyrrolidin-1-yl-
)methanone; [0704]
N-ethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzenesulfonami-
de; [0705]
8-ethoxy-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndole; [0706]
8-(difluoromethoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]-
indole; [0707]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(2,2,2-trifluoroethoxy)-9H-pyrido[-
2,3-b]indole; [0708]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [0709]
N-cyclopropyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2-
,3-b]indol-5-yl)benzamide; [0710]
5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole; [0711]
N-methyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]-
indole-5-yl)benzenesulfonamide; [0712]
N,N-dimethyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,-
3-b]indole-5-yl)benzenesulfonamide; [0713]
N-(3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol--
5-yl)phenyl)cyclopropanecarboxamide; [0714]
5-(3-(ethylthio)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-p-
yrido[2,3-b]indole; [0715]
5-(3-ethoxyphenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido-
[2,3-b]indole; [0716]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole;
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-3-yl)meth-
oxy)-9H-pyrido[2,3-b]indole; [0717]
(R)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-3-yl)meth-
oxy)-9H-pyrido[2,3-b]indole; [0718]
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-2-yl)meth-
oxy)-9H-pyrido[2,3-b]indole; [0719]
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(pyrrolidin-3-ylmethoxy)-9H-py-
rido[2,3-b]indole; [0720]
(R)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(pyrrolidin-3-ylmethoxy)-9H-py-
rido[2,3-b]indole;
[0721]
3-(5-chloro-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,N-dimethylpr-
opan-1-amine; [0722]
N-(3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)ph-
enyl)cyclopropanecarboxamide; [0723]
N-cyclopropyl-3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]in-
dol-5-yl)benzamide; [0724]
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-me-
thylbenzenesulfonamide; [0725]
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N--N-
-dimethylbenzenesulfonamide; [0726]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [0727]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole; [0728]
5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-3-(triflu-
oromethyl)-9H-pyrido[2,3-b]indole; [0729]
5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido-
[2,3-b]indole-3-carbonitrile; [0730]
2-(5-(3-(ethylsulfonyl)phenyl)-7-fluoro-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)-N,N-dimethylethanamine; [0731]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-7-fluoro-9H-pyrido[2,3-b]indol-8--
yloxy)-N,N-dimethylpropan-1-amine; [0732]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine; [0733]
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylethanamine; [0734]
5-(3-(ethylsulfonyl)phenyl)-8-(2-methoxyethoxy)-3-methyl-9H-pyrido[2,3-b]-
indole; [0735]
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)ace-
tonitrile; [0736]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
panenitrile; [0737]
(R)-8-(1-tert-butyldiphenylsilyloxy)propan-2-yloxy)-(5-(3-(ethylsulfonyl)-
phenyl)-3-methyl-9H-pyrido[2,3-b]indole; [0738]
(R)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-1-ol; [0739]
(S)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-1-ol; [0740]
1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-2-ol; [0741]
(S)-4-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)-2-methylpentan-2-ol; [0742]
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)eth-
anol; [0743]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol; [0744]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-9H-pyrido[2,3-b]indol-8-
-ol; [0745]
(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-ol;
[0746]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine; [0747]
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-diethylethanamine; [0748]
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylethanamine; [0749]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(2-(pyrrolidin-1-yl)ethoxy)-9H-pyr-
ido[2,3-b]indole; [0750]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-
-9H-pyrido[2,3-b]indole; [0751]
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)eth-
anol; [0752]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol; [0753]
(S)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)ethyl 2-aminopropanoate; [0754]
(S)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl 2-aminopropanoate; [0755]
(S)-3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl 2-aminopropanoate; [0756]
(R)-8-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy-5-(3-ethylsulfonyl)phenyl)-
-3-methyl-9H-pyrido[2,3-b]indole; [0757]
(S)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol; [0758]
(R)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol; [0759]
(R)-1-(dimethylamino)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2-
,3-b]indol-8-yloxy)propan-2-ol; [0760]
(R)-1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-2-ol; [0761]
(S)-1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-2-ol; [0762]
5-bromo-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-amine; [0763]
(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-a-
mine; [0764]
N-(3-(7-amino-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)-cyclo-
propanecarboxamide; [0765]
3-(dimethylamino)-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-py-
rido[2,3-b]indol-7-yl)propanamide; [0766]
N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-
-yl)-cyclopropanecarboxamide; [0767]
1-acetyl-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3--
b]indol-7-yl)piperidine-4-carboxamide; [0768]
3-(7-amino-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-cyclopropylbe-
nzamide; [0769]
3-(7-(cyclopropanecarboxamido)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-
-yl)-N-cyclopropylbenzamide; [0770]
7-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]i-
ndole; [0771]
7-chloro-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol;
[0772]
3-(7-chloro-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndol-8-yloxy)propan-1-ol; [0773]
N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-
-yl)-N-methylcyclopropanecarboxamide; [0774]
3-(dimethylamino)-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-py-
rido[2,3-b]indol-7-yl)-N-methylpropanamide; [0775]
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide; [0776]
4-(2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-
ethyl)morpholine; [0777]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)pro-
panenitrile; [0778]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(1-methylpiperidin-4-yloxy)-9H-pyr-
ido[2,3-b]indole; [0779]
3-(5-(3-(ethylsulfonyl)phenyl)-3-(trifluoromethyl)-9H-pyrido[2,3-b]indol--
8-yloxy)-N,N-dimethylpropan-1-amine; [0780]
(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)(morpholino)meth-
anone; [0781]
N-methoxy-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide;
[0782]
5-(3-Ethanesulfonyl-phenyl)-8-(cyclopropylmethoxy)-3-methyl-9H-dip-
yrido[2,3-b; 4',3'-d]pyrrole; [0783]
N-(2-(diethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide; and [0784]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-morpholinopropyl)-9H-pyrido-
[2,3-b]indole-7-carboxamide.
[0785] Particular examples of compounds according to the present
invention also include, but are not limited to: [0786]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide HCl salt; [0787]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole HCl salt; [0788]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole HCl salt; [0789]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine HCl salt; [0790]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine HCl salt; and [0791]
N-cyclopropyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2-
,3-b]indol-5-yl)benzamide HCl salt.
[0792] In addition, particular examples of compounds according to
the present invention include, but are not limited to: [0793]
N-(2-(methylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyri-
do[2,3-b]indole-7-carboxamide; [0794]
N-(2-(methoxy)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2-
,3-b]indole-7-carboxamide; [0795]
N-(2-(dimethylamino)ethyl)-N-methyl-5-(3-(ethylsulfonyl)phenyl)-3,8-dimet-
hyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0796]
N,N-dimethyl-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]ind-
ole-7-methylcarboxamide; [0797]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-yl)(4-m-
ethylpiperazin-1-yl)methanone; [0798]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-piperazin-1-yl)ethyl)-9H-py-
rido[2,3-b]indole-7-carboxamide; [0799]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-(4-methylpiperazin-1-yl)pro-
pyl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0800]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-yl)(mor-
pholino)methanone; [0801]
azetidin-1-yl(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]in-
dol-7-yl)methanone; [0802]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(tha-
iazolidin-3-yl)methanone; [0803]
(R)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0804]
(S)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0805]
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxyethyl)-3,8-dimethyl-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0806]
N-(2,3-dihydroxypropyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0807]
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxy-2-methylpropyl)-3,8-dimethyl-9H--
pyrido[2,3-b]indole-7-carboxamide; [0808]
5-(3-(ethylsulfonyl)phenyl)-N-(1-isopropylpiperidin-4-yl)-3,8-dimethyl-9H-
-pyrido[2,3-b]indole-7-carboxamide; [0809]
N-(1-ethylpiperidin-4-yl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide; [0810]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-thiazol-2-yl)-9H-pyrido[2,3-b]-
indole-7-carboxamide; [0811]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-(2,2,2-trifluoroethoxy)ethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide; [0812]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-3-yl)-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0813]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-4-yl)-9H-pyrid
o[2,3-b]indole-7-carboxamide; [0814]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-3-yl)-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0815]
5-(3-(ethylsulfonyl)phenyl)-N-(2-(2-hydroxyethoxy)ethyl-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide; [0816]
5-(3-(cyclopropanecarboxamido)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dime-
thyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0817]
N-(2-(dimethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-py-
rido[2,3-b]indole-7-carboxamide; [0818]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-((1-methylpiperidin-4-yl)methy-
l)-9H-pyrido[2,3-b]indole-7-carboxamide; [0819]
N-(3-(dimethylamino)propyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide; [0820]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-9H--
pyrido[2,3-b]indole-7-carboxamide; [0821]
(S)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide; [0822]
(R)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide; [0823]
5-(3-(cyclopropanecarboxamido)phenyl)-3,8-dimethyl-N-(1-methyl-piperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0824]
5-(3-(cyclopropylcarbamoyl)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dimethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide; [0825]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid amide; [0826]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl]-(4-meth-
yl-piperazin-1-yl)-methanone; [0827]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (2-dimethylamino-ethyl)-amide; [0828]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (3-dimethylamino-propyl)-amide; [0829]
(3-Dimethylamino-pyrrolidin-1-yl)-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9-
H-pyrido[2,3-b]indol-7-yl]-methanone; [0830]
N-ethyl-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxamide; [0831]
5-(benzylthio)-N-(2-(dimethylamino)ethyl)-3-methyl-9H-pyrido[2,3-b]indole-
-7-carboxamide; [0832]
5-(3-(N-ethylsulfamoyl)phenyl)-8-methoxy-3-methyl-N-(1-methylpiperidin-4--
yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0833]
5-(3-(cyclopropylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-
-9H-pyrido[2,3-b]indole-7-carboxamide; [0834]
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide; [0835]
N-(2-(diethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide; [0836]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-morpholinopropyl)-9H-pyrido-
[2,3-b]indole-7-carboxamide; [0837]
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide; [0838]
5-(3-(ethylsulfonyl)phenyl)-8-methyl-N-(1-methylpiperidin-4-yl)-9H-pyrido-
[2,3-b]indole-7-carboxamide; [0839]
5-(3-(cyclopropylsulfonyl)phenyl)-8-methyl-N-(1-methylpiperidin-4-yl)-9H--
pyrido[2,3-b]indole-7-carboxamide; [0840]
5-(3-(cyclopropylsulfonyl)phenyl)-3-fluoro-8-methyl-N-(1-methylpiperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0841]
3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-8-methyl-N-(1-methylpiperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0842]
5-(3-(ethylsulfonyl)phenyl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3,8-dime-
thyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0843]
2-(4-(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-c-
arboxamido)piperidin-1-yl)ethyl dihydrogen phosphate; [0844]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-
-8-methyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0845]
2-(4-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3-b]indol-
e-7-carboxamido)piperidin-1-yl)ethyl dihydrogen phosphate; [0846]
5-(3-(cyclopropylsulfonyl)phenyl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3,-
8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0847]
2-(4-(5-(3-(cyclopropylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indo-
le-7-carboxamido)piperidin-1-yl)ethyl dihydrogen phosphate; [0848]
3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-N-(1-(2-hydroxyethyl)piperidin-
-4-yl)-8-methyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0849]
2-(4-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3-b-
]indole-7-carboxamido)piperidin-1-yl)ethyl dihydrogen phosphate;
[0850]
5-(3-(ethylsulfonyl)phenyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-3,-
8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0851]
2-((2-(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7--
carboxamido)ethyl)(methyl)amino)ethyl dihydrogen phosphate; [0852]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-N-(2-((2-hydroxyethyl)(methyl)amino)-
ethyl)-8-methyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0853]
2-((2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3-b]indo-
le-7-carboxamido)ethyl)(methyl)amino)ethyl dihydrogen phosphate;
[0854]
5-(3-(cyclopropylsulfonyl)phenyl)-N-(2-((2-hydroxyethyl)(methyl)amino)eth-
yl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0855]
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]ind-
ole-7-carboxamido)ethyl)(methyl)amino)ethyl dihydrogen phosphate;
[0856]
3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-N-(2-((2-hydroxyethyl)(methyl)-
amino)ethyl)-8-methyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0857]
2-((2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3--
b]indole-7-carboxamido)ethyl)(methyl)amino)ethyl dihydrogen
phosphate; [0858]
N-(3-(ethyl(2-hydroxyethyl)amino)propyl)-5-(3-(ethylsulfonyl)pheny-
l)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0859]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indo-
le-7-carboxamido)propyl)amino)ethyl dihydrogen phosphate; [0860]
5-(3-(ethylsulfonyl)phenyl)-N-(3-((2-hydroxyethyl)(methyl)amino)propyl)-3-
,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0861]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7--
carboxamido)propyl)(methyl)amino)ethyl dihydrogen phosphate; [0862]
5-(3-(ethylsulfonyl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)-3,8-dimethyl--
9H-pyrido[2,3-b]indole-7-carboxamide; [0863]
5-(3-(ethylsulfonyl)phenyl)-N-((1s,4s)-4-hydroxycyclohexyl)-3,8-dimethyl--
9H-pyrido[2,3-b]indole-7-carboxamide; [0864]
5-(3-(ethylsulfonyl)phenyl)-N-(4-(hydroxymethyl)cyclohexyl)-3,8-dimethyl--
9H-pyrido[2,3-b]indole-7-carboxamide; [0865]
5-(3-(ethylsulfonyl)phenyl)-N-(4-(2-hydroxyethyl)cyclohexyl)-3,8-dimethyl-
-9H-pyrido[2,3-b]indole-7-carboxamide; [0866]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(4-(-
hydroxymethyl)piperidin-1-yl)methanone; [0867]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(4-(-
2-hydroxyethyl)piperidin-1-yl)methanone; [0868]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(4-h-
ydroxypiperidin-1-yl)methanone; [0869]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(2-(-
hydroxymethyl)pyrrolidin-1-yl)methanone; [0870]
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(2-(-
hydroxymethyl)morpholino)methanone; [0871]
5-(3-(ethylsulfonyl)phenyl)-N-(3-hydroxypropyl)-3,8-dimethyl-9H-pyrido[2,-
3-b]indole-7-carboxamide; [0872]
(R)-5-(3-(ethylsulfonyl)phenyl)-N-(3-hydroxybutyl)-3,8-dimethyl-9H-pyrido-
[2,3-b]indole-7-carboxamide; [0873]
(S)-5-(3-(ethylsulfonyl)phenyl)-N-(3-hydroxybutyl)-3,8-dimethyl-9H-pyrido-
[2,3-b]indole-7-carboxamide; [0874]
5-(3-(ethylsulfonyl)phenyl)-N-(3-hydroxy-3-methylbutyl)-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide; [0875]
(S)--N-(3-(dimethylamino)-2-hydroxypropyl)-5-(3-(ethylsulfonyl)phenyl)-3,-
8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0876]
(S)--N-(2-(dimethylamino)-3-hydroxypropyl)-5-(3-(ethylsulfonyl)phenyl)-3,-
8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0877]
N-(3-(ethyl(2-hydroxyethyl)amino)propyl)-5-(3-(ethylsulfonyl)phenyl)-3,8--
dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0878]
5-(3-(ethylsulfonyl)phenyl)-N-(3-((2-hydroxyethyl)(methyl)amino)propyl)-3-
,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0879]
N-(2-(ethyl(2-hydroxyethyl)amino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-d-
imethyl-9H-pyrido[2,3-b]indole-7-carboxamide; and [0880]
5-(3-(ethylsulfonyl)phenyl)-N-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-3,-
8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide.
[0881] In addition, particular examples of compounds according to
the present invention include, but are not limited to: [0882]
5-phenyl-9H-pyrido[2,3-b]indole; [0883]
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N-methylbenzenesulfonamide;
5 [0884]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole;
[0885]
8-chloro-5-[3-(ethylsulfonyl)phenyl]-3-methyl-9H-pyrido[4',':4,5]p-
yrrolo[2,3-b]pyridine; [0886]
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-propane-1,3-diamine; [0887]
5-(3-Ethanesulfonyl-phenyl)-8-ethoxy-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [0888]
3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-1-ol; [0889]
(S)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [0890]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid; [0891]
5-(3-(ethylsulfonyl)phenyl-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole;
[0892]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol;
[0893]
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)cyclopr-
opanecarboxamide; [0894]
N-ethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzenesulfonami-
de; [0895]
8-ethoxy-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndole; [0896]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(2,2,2-trifluoroethoxy)-9H-pyrido[-
2,3-b]indole; [0897]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol; and [0898]
(R)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol.
[0899] In addition, particular examples of compounds according to
the present invention include, but are not limited to: [0900]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide; [0901]
N-(2-(methoxy)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2-
,3-b]indole-7-carboxamide; [0902]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-(4-methylpiperazin-1-yl)pro-
pyl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0903]
(S)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide; [0904]
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxyethyl)-3,8-dimethyl-9H-pyrido[2,3-
-b]indole-7-carboxamide; [0905]
N-(1-ethylpiperidin-4-yl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide; [0906]
5-(3-(cyclopropanecarboxamido)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dime-
thyl-9H-pyrido[2,3-b]indole-7-carboxamide; [0907]
N-(2-(dimethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-py-
rido[2,3-b]indole-7-carboxamide; [0908]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-((1-methylpiperidin-4-yl)methy-
l)-9H-pyrido[2,3-b]indole-7-carboxamide; [0909]
(S)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide; [0910]
5-(3-(cyclopropanecarboxamido)phenyl)-3,8-dimethyl-N-(1-methyl-piperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [0911]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid amide; [0912]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (2-dimethylamino-ethyl)-amide; [0913]
5-(3-(N-ethylsulfamoyl)phenyl)-8-methoxy-3-methyl-N-(1-methylpiperidin-4--
yl)-9H-pyrido[2,3-b]indole-7-carboxamide; and [0914]
5-(3-(cyclopropylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-
-9H-pyrido[2,3-b]indole-7-carboxamide.
[0915] In addition, particular examples of compounds according to
the present invention include, but are not limited to: [0916]
{3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propyl}-dimethyl-amine; [0917]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole; [0918]
5-(3-Ethanesulfonyl-phenyl)-8-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-9H-
-dipyrido[2,3-b; 4',3'-d]pyrrole; [0919]
L-Valine-2-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-ethyl ester; [0920]
L-Alanine-(R)-2-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-1-methyl-ethyl ester; [0921]
3-Chloro-5-(3-ethanesulfonyl-phenyl)-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole; [0922]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [0923]
N-cyclopropyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2-
,3-b]indol-5-yl)benzamide; [0924]
5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole; [0925]
N-methyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]-
indole-5-yl)benzenesulfonamide; [0926]
N,N-dimethyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,-
3-b]indole-5-yl)benzenesulfonamide; [0927]
N-(3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol--
5-yl)phenyl)cyclopropanecarboxamide; [0928]
5-(3-(ethylthio)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-p-
yrido[2,3-b]indole; [0929]
5-(3-ethoxyphenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido-
[2,3-b]indole; [0930]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole; [0931]
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-3-yl)meth-
oxy)-9H-pyrido[2,3-b]indole; [0932]
(R)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-3-yl)meth-
oxy)-9H-pyrido[2,3-b]indole; [0933]
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-2-yl)meth-
oxy)-9H-pyrido[2,3-b]indole; [0934]
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(pyrrolidin-3-ylmethoxy)-9H-py-
rido[2,3-b]indole; [0935]
(R)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(pyrrolidin-3-ylmethoxy)-9H-py-
rido[2,3-b]indole; [0936]
3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ylo-
xy)-N,N-dimethylpropan-1-amine; [0937]
N-(3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)ph-
enyl)cyclopropanecarboxamide; [0938]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [0939]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole; [0940]
5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-3-(triflu-
oromethyl)-9H-pyrido[2,3-b]indole; [0941]
5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido-
[2,3-b]indole-3-carbonitrile; [0942]
2-(5-(3-(ethylsulfonyl)phenyl)-7-fluoro-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)-N,N-dimethylethanamine; [0943]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-7-fluoro-9H-pyrido[2,3-b]indol-8--
yloxy)-N,N-dimethylpropan-1-amine; [0944]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine; [0945]
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylethanamine; [0946]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine; [0947]
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-diethylethanamine; [0948]
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylethanamine; [0949]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(2-(pyrrolidin-1-yl)thoxy)-9H-pyri-
do[2,3-b]indole; [0950]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(2-(4-methylpiperazin-1-yl)thoxy)--
9H-pyrido[2,3-b]indole; [0951]
(S)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)ethyl 2-aminopropanoate; [0952]
(S)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl 2-aminopropanoate; [0953]
(R)-1-(dimethylamino)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2-
,3-b]indol-8-yloxy)propan-2-ol; [0954]
4-(2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-
ethyl)morpholine; [0955]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(1-methylpiperidin-4-yloxy)-9H-pyr-
ido[2,3-b]indole; [0956]
3-(5-(3-(ethylsulfonyl)phenyl)-3-(trifluoromethyl)-9H-pyrido[2,3-b]indol--
8-yloxy)-N,N-dimethylpropan-1-amine; [0957]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethanol; [0958]
di-tert-butyl-2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido-
[2,3-b]indol-8-yloxy)propyl)(ethyl)amino)ethyl phosphate; [0959]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; [0960]
N-cyclopropyl-3-(8-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-3-methyl-9H-py-
rido[2,3-b]indol-5-yl)benzamide; [0961]
di-tert-butyl-2-((3-(5-(3-(cyclopropylcarbamoyl)phenyl)-3-methyl-9H-pyrid-
o[2,3-b]indol-8-yloxy)propyl)(ethyl)amino)ethyl phosphate; [0962]
2-((3-(5-(3-(cyclopropylcarbamoyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol--
8-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; [0963]
2-((3-(4-chloro-6-methyl-9H-carbazol-1-yloxy)propyl)(ethyl)amino)-ethanol-
; [0964] di-tert-butyl
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propyl)amino)ethyl phosphate; [0965]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propyl)amino)ethyl dihydrogen phosphate; [0966]
3-(3-chloro-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol-5-y-
l)-N-cyclopropylbenzamide; [0967]
3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole; [0968]
5-(3-(ethylsulfonyl)phenyl)-3-fluoro-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [0969]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(ethyl)amino)ethanol; [0970]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(ethyl)amino)ethyl dihydrogen phosphate; [0971]
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-et-
hylbenzenesulfonamide; [0972]
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N,N--
dimethylbenzenesulfonamide; [0973]
(S)-3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl 2-aminopropanoate; [0974]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethanol; [0975]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; [0976]
1-(3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propyl)piperidin-4-ol; [0977]
8-(3-(1H-imidazol-1-yl)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-p-
yrido[2,3-b]indole; [0978]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethanol; [0979] di-tert-butyl
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl phosphate; [0980]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl dihydrogen phosphate, dihydrochloride;
[0981]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl dihydrogen phosphate; [0982]
(S)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-ol; [0983]
(S)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-yl dihydrogen phosphate; [0984]
(R)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-yl dihydrogen phosphate; [0985]
3-chloro-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-8-((1-methylpiperi-
din-4-yl)methoxy)-9H-pyrido[2,3-b]indol-5-amine; [0986]
5-(3-(cyclopropylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-9H--
pyrido[2,3-b]indole; [0987]
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(ethyl)amino)ethanol; [0988]
2-((2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(methyl)amino)ethanol; [0989]
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)et-
hyl)(methyl)amino)ethanol; [0990]
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(methyl)amino)ethanol; [0991]
1-(2-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)ethyl)piperidin-4-ol; [0992]
2-((2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(ethyl)amino)ethanol; [0993]
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)et-
hyl)(ethyl)amino)ethanol; [0994]
1-(2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8--
yloxy)ethyl)piperidin-4-ol; [0995]
1-(2-(5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)eth-
yl)piperidin-4-ol; [0996]
1-(2-(5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)ethyl)pip-
eridin-4-01; [0997]
1-(2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-
ethyl)piperidin-4-ol; [0998]
1-(2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-
ethyl)piperidin-4-ol; [0999]
N-cyclopropyl-3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]in-
dol-5-yl)benzamide; [1000]
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-me-
thylbenzenesulfonamide; [1001]
8-(2-(1H-imidazol-1-yl)ethoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-py-
rido[2,3-b]indole; [1002]
8-(2-(1H-imidazol-1-yl)ethoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-py-
rido[2,3-b]indole; [1003]
(1-(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)-1H-imidazol-4-yl)methanol; [1004]
(1-(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)-1H-imidazol-4-yl)methyl dihydrogen phosphate; [1005]
8-(3-(4H-1,2,4-triazol-4-yl)propoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-
-9H-pyrido[2,3-b]indole; [1006]
8-(3-(1H-1,2,3-triazol-1-yl)propoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-
-9H-pyrido[2,3-b]indole; [1007]
(1-(3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)-1H-imidazol-4-yl)methanol; [1008]
(1-(3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)-1H-imidazol-4-yl)methyl dihydrogen phosphate; [1009]
8-(3-(4H-1,2,4-triazol-4-yl)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-
-9H-pyrido[2,3-b]indole; [1010]
8-(3-(1H-1,2,3-triazol-1-yl)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-
-9H-pyrido[2,3-b]indole; [1011]
(1-(3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)-1H-imidazol-4-yl)methanol; [1012]
(1-(3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)-1H-imidazol-4-yl)methyl dihydrogen phosphate; [1013]
8-(3-(4H-1,2,4-triazol-4-yl)propoxy)-5-(3-(cyclopropylsulfonyl)phenyl)-3--
methyl-9H-pyrido[2,3-b]indole; [1014]
8-(3-(1H-1,2,3-triazol-1-yl)propoxy)-5-(3-(cyclopropylsulfonyl)phenyl)-3--
methyl-9H-pyrido[2,3-b]indole; [1015]
(1-(3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)-1H-imidazol-4-yl)methanol; [1016]
(1-(3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)-1H-imidazol-4-yl)methyl dihydrogen phosphate; [1017]
8-(3-(4H-1,2,4-triazol-4-yl)propoxy)-3-chloro-5-(3-(cyclopropylsulfonyl)p-
henyl)-9H-pyrido[2,3-b]indole; [1018]
8-(3-(1H-1,2,3-triazol-1-yl)propoxy)-3-chloro-5-(3-(cyclopropylsulfonyl)p-
henyl)-9H-pyrido[2,3-b]indole; [1019]
2-((2,2-difluoroethyl)(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[-
2,3-b]indol-8-yloxy)propyl)amino)ethanol; [1020]
2-((2,2-difluoroethyl)(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[-
2,3-b]indol-8-yloxy)propyl)amino)ethyl dihydrogen phosphate; [1021]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(2,2-difluoroethyl)amino)ethanol; [1022]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(2,2-difluoroethyl)amino)ethyl dihydrogen phosphate; [1023]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2-difluoroethyl)amino)ethanol; [1024]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2-difluoroethyl)amino)ethyl dihydrogen phosphate;
[1025]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2-difluoroethyl)amino)ethanol; [1026]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2-difluoroethyl)amino)ethyl dihydrogen phosphate;
[1027]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(2,2,2-trifluoroethyl)amino)ethanol; [1028]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(2,2,2-trifluoroethyl)amino)ethyl dihydrogen phosphate;
[1029]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(2,2,2-trifluoroethyl)amino)ethanol; [1030]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(2,2,2-trifluoroethyl)amino)ethyl dihydrogen phosphate;
[1031]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2,2-trifluoroethyl)amino)ethanol; [1032]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2,2-trifluoroethyl)amino)ethyl dihydrogen
phosphate; [1033]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]-
indol-8-yloxy)propyl)(2,2,2-trifluoroethyl)amino)ethanol; [1034]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(2,2,2-trifluoroethyl)amino)ethyl dihydrogen
phosphate; [1035]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndol-8-yloxy)propyl)amino)-2,2-difluoroethanol; [1036]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propyl)amino)-2,2-difluoroethyl dihydrogen phosphate; [1037]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(ethyl)amino)-2,2-difluoroethanol; [1038]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(ethyl)amino)-2,2-difluoroethyl dihydrogen phosphate;
[1039]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)-2,2-difluoroethanol; [1040]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)-2,2-difluoroethyl dihydrogen phosphate;
[1041]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)-2,2-difluoroethanol; [1042]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)-2,2-difluoroethyl dihydrogen phosphate;
[1043]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)-1,1-difluoropropyl)amino)ethanol;
[1044]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndol-8-yloxy)-1,1-difluoropropyl)amino)ethyl dihydrogen phosphate;
[1045]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)-1,1-difluoropropyl)(ethyl)amino)ethanol; [1046]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)-1,1-difluoropropyl)(ethyl)amino)ethyl dihydrogen phosphate;
[1047]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-1,1-difluoropropyl)(ethyl)amino)ethanol; [1048]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-1,1-difluoropropyl)(ethyl)amino)ethyl dihydrogen phosphate;
[1049]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)-1,1-difluoropropyl)(ethyl)amino)ethanol; [1050]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)-1,1-difluoropropyl)(ethyl)amino)ethyl dihydrogen phosphate;
[1051]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)-3,3-difluoropropyl)amino)ethanol; [1052]
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)-3,3-difluoropropyl)amino)ethyl dihydrogen phosphate; [1053]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)-3,3-difluoropropyl)(ethyl)amino)ethanol; [1054]
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)-3,3-difluoropropyl)(ethyl)amino)ethyl dihydrogen phosphate;
[1055]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3,3-difluoropropyl)(ethyl)amino)ethanol; [1056]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3,3-difluoropropyl)(ethyl)amino)ethyl dihydrogen phosphate;
[1057]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)-3,3-difluoropropyl)(ethyl)amino)ethanol; and [1058]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)-3,3-difluoropropyl)(ethyl)amino)ethyl dihydrogen
phosphate.
[1059] Particular examples of compounds according to the present
invention also include, but are not limited to: [1060]
{3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propyl}-dimethyl-amine; [1061]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole; [1062]
3-Chloro-5-(3-ethanesulfonyl-phenyl)-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole; [1063]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [1064]
N-cyclopropyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2-
,3-b]indol-5-yl)benzamide; [1065]
5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole; [1066]
N-(3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol--
5-yl)phenyl)cyclopropanecarboxamide; [1067]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole; [1068]
3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ylo-
xy)-N,N-dimethylpropan-1-amine; [1069]
N-(3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)ph-
enyl)cyclopropanecarboxamide; [1070]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole; [1071]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole; [1072]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine; [1073]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine; [1074]
(R)-1-(dimethylamino)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2-
,3-b]indol-8-yloxy)propan-2-ol; [1075]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethanol; [1076]
di-tert-butyl-2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido-
[2,3-b]indol-8-yloxy)propyl)(ethyl)amino)ethyl phosphate; [1077]
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; [1078]
3-(3-chloro-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol-5-y-
l)-N-cyclopropylbenzamide; [1079]
3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole; [1080]
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-et-
hylbenzenesulfonamide; [1081]
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; [1082]
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl dihydrogen phosphate; [1083]
(S)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-ol; [1084]
(S)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-yl dihydrogen phosphate; and
[1085]
(R)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-yl dihydrogen phosphate.
[1086] In addition, particular examples of compounds according to
the present invention include, but are not limited to: [1087]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-9H-pyrido[2,3-b]indole;
and [1088]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-ol.
[1089] Further particular examples of compounds according to the
present invention include, but are not limited to: [1090]
5-bromo-9H-pyrido[2,3-b]indole; [1091]
5-phenyl-9H-pyrido[2,3-b]indole; [1092]
5-bromo-8-methyl-9H-pyrido[2,3-b]indole; [1093]
5-bromo-3,8-dimethyl-9H-pyrido[2,3-b]indole; [1094]
5-(3-(methylsulfonyl)phenyl)-9H-pyrido[2,3-b]indole; [1095]
5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indole; [1096]
N-(3-(9H-pyrido[2,3-b]indol-5-yl)phenyl)ethanesulfonamide; [1097]
5-m-tolyl-9H-pyrido[2,3-b]indole; [1098]
N-cyclopropyl-3-(9H-pyrido[2,3-b]indol-5-yl)benzenesulfonamide;
[1099] 5-(3-methoxyphenyl)-9H-pyrido[2,3-b]indole; [1100]
5-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-2-methoxy-N-methylbenzenesulf-
onamide; [1101]
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N-methylbenzenesulfonamide;
[1102]
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N,N-dimethylbenzenesul-
fonamide; [1103]
5-(3-(ethylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3-b]indole; [1104]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole;
[1105]
N-(3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)propionamide;
[1106]
N-cyclopropyl-3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)benzamide;
[1107] N-(4-(9H-pyrido[2,3-b]indol-5-ylthio)phenyl)acetamide;
[1108] 5-(benzylthio)-9H-pyrido[2,3-b]indole; [1109]
5-(phenylthio)-9H-pyrido[2,3-b]indole; [1110]
5-(benzylthio)-8-methyl-9H-pyrido[2,3-b]indole; [1111]
5-(benzylthio)-3,8-dimethyl-9H-pyrido[2,3-b]indole; [1112]
8-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1113]
8-chloro-5-[3-(ethylsulfonyl)phenyl]-3-methyl-9H-pyrido[4',':4,5]pyrrolo[-
2,3-b]pyridine; [1114]
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-propane-1,3-diamine; [1115]
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-ethane-1,2-diamine; [1116]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(3-morpholin-4-yl-propyl)-amine; [1117]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(1-methyl-piperidin-4-yl)-amine; [1118]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-ylamino]-ethanol; [1119]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(1-methyl-piperidin-4-ylmethyl)-amine; [1120]
5-(3-Ethanesulfonyl-phenyl)-3,8-dimethyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1121]
5-(3-Ethanesulfonyl-phenyl)-8-ethyl-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1122]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole-8-carbonitrile; [1123]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole-8-carboxylic acid amide; [1124]
5-(3-Ethanesulfonyl-phenyl)-8-ethoxy-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1125]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-ethanol; [1126]
3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-1-ol; [1127]
(R)-2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxymethyl]-propane-1,3-diol; [1128]
(S)-2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxymethyl]-propane-1,3-diol; [1129]
1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-2-methyl-propan-2-ol; [1130]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-phenoxy-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1131]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(thiazol-5-ylmethoxy)-9H-dipyrido[-
2,3-b; 4',3'-d]pyrrole; [1132]
(5)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [1133]
(R)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [1134]
3-(3-Bromo-5-chloro-pyridin-2-ylamino)-5-chloro-1-(4-methoxy-benzyl)-1H-p-
yrazin-2-one; [1135]
5-Chloro-3-(5-chloro-3-trimethylsilanylethynyl-pyridin-2-ylamino)-1-(4-me-
thoxy-benzyl)-1H-pyrazin-2-one; [1136]
3,8-Dichloro-5-(3-ethanesulfonyl-phenyl)-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1137]
(R)-1-[3-Chloro-5-(3-ethanesulfonyl-phenyl)-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol; [1138]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]methyl amine; [1139]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]methanethiol.; [1140]
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]ethanethiol; [1141]
5-[3-(cyclopropylcarboxamide)phenyl]-7-(4-methoxybenzyl)-3-methyl-7,9-dih-
ydro-8H-pyrido[4',':4,5]pyrrolo[2,3-b]pyridin-8-one; [1142]
8-Chloro-5-[3-(cyclopropylcarboxamide)phenyl]-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole; [1143]
2-[5-(3-cyclopropylcarbonylamino-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]ethanethiol; [1144]
9-(3-Ethanesulfonyl-phenyl)-5H-pyrazino[2,3-b]indole; [1145]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-7-(trifluoromethyl)-9H-pyrido[2,-
3-b]indole acetate; [1146]
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxy-
lic acid; [1147]
5-(3-(cyclopropanecarboxamido)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dime-
thyl-9H-pyrido[2,3-b]indole-7-carboxamide; [1148]
5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-
-carboxamide; [1149]
5-(3-(cyclopropanecarboxamido)phenyl)-3,8-dimethyl-N-(1-methyl-piperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide; [1150]
5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-
-carboxamide; [1151]
5-(3-(cyclopropylcarbamoyl)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dimethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide; [1152]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitril-
e; [1153]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester; [1154]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl]-methano-
l; [1155]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl-
methyl]-dimethyl-amine; [1156]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-morpholin-4-ylmethyl-9H-pyrido[2,3-
-b]indole; [1157]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-(4-methyl-piperazin-1-ylmethyl)-9H-
-pyrido[2,3-b]indole; [1158]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-pyrrolidin-1-ylmethyl-9H-pyrido[2,-
3-b]indole; [1159]
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-ylmethyl]-e-
thyl-amine; [1160]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid; [1161]
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-(2H-tetrazol-5-yl)-9H-pyrido[2,3-b-
]indole; [1162]
6-Bromo-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxylic acid methyl ester; [1163]
8-Bromo-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxylic acid methyl ester; [1164]
6-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester; [1165]
8-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester; [1166]
5-(benzylthio)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic acid;
[1167]
5-(benzylthio)-N-(2-(dimethylamino)ethyl)-3-methyl-9H-pyrido[2,3-b]indole-
-7-carboxamide; [1168]
5-(3-(ethylsulfonyl)phenyl-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole;
[1169]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol;
[1170]
8-methoxy-3-methyl-5-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-9H-pyrido-
[2,3-b]indole; [1171]
(R)-8-methoxy-3-methyl-5-(3-(pyrrolidin-3-ylsulfonyl)phenyl)-9H-pyrido[2,-
3-b]indole; [1172]
N-cyclopropyl-4-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)picolinami-
de; [1173]
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)acet-
amide; [1174]
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)cyclopropaneca-
rboxamide; [1175]
N-cyclopropyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide;
[1176]
N,N-diethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benza-
mide; [1177]
5-(benzo[d][1,3]dioxol-5-yl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole;
[1178]
6-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-4H-chromen-4-one-
; [1179]
N-(2-hydroxyethyl)-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5--
yl)benzamide; [1180]
(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)(pyrrolidin-1-yl-
)methanone; [1181]
N-ethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzenesulfonami-
de; [1182]
8-ethoxy-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndole; [1183]
8-(difluoromethoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]-
indole; [1184]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(2,2,2-trifluoroethoxy)-9H-pyrido[-
2,3-b]indole; [1185]
5-(3-(ethylsulfonyl)phenyl)-8-(2-methoxyethoxy)-3-methyl-9H-pyrido[2,3-b]-
indole; [1186]
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)ace-
tonitrile; [1187]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
panenitrile; [1188]
(R)-8-(1-tert-butyldiphenylsilyloxy)propan-2-yloxy)-(5-(3-(ethylsulfonyl)-
phenyl)-3-methyl-9H-pyrido[2,3-b]indole; [1189]
(R)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-1-ol; [1190]
(S)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-1-ol; [1191]
1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-2-ol; [1192]
(S)-4-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)-2-methylpentan-2-ol; [1193]
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)eth-
anol; [1194]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol; [1195]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-9H-pyrido[2,3-b]indol-8-
-ol; [1196]
(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-ol;
[1197]
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)eth-
anol; [1198]
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide; [1199]
(R)-8-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy-5-(3-ethylsulfonyl)phenyl)-
-3-methyl-9H-pyrido[2,3-b]indole; [1200]
(S)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol; [1201]
(R)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol; [1202]
(R)-1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-2-ol; [1203]
(S)-1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-2-ol; [1204]
(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-a-
mine; [1205]
3-(dimethylamino)-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-py-
rido[2,3-b]indol-7-yl)propanamide; [1206]
N-(3-(7-amino-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)-cyclo-
propanecarboxamide; [1207]
N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-
-yl)-cyclopropanecarboxamide; [1208]
1-acetyl-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3--
b]indol-7-yl)piperidine-4-carboxamide; [1209]
3-(7-amino-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-cyclopropylbe-
nzamide; [1210]
3-(7-(cyclopropanecarboxamido)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-
-yl)-N-cyclopropylbenzamide; [1211]
7-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]i-
ndol; [1212]
7-chloro-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol;
[1213]
3-(7-chloro-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]i-
ndol-8-yloxy)propan-1-ol; [1214] tert-butyl
7-(tert-butoxycarbonyl(methyl)amino)-5-(3-(ethylsulfonyl)phenyl)-8-methox-
y-3-methyl-9H-pyrido[2,3-b]indole-9-carboxylate; [1215]
5-(3-(ethylsulfonyl)phenyl)-8-methoxy-N,3-dimethyl-9H-pyrido[2,3-b]indol--
7-amine; [1216]
N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-
-yl)-N-methylcyclopropanecarboxamide; [1217]
3-(dimethylamino)-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-py-
rido[2,3-b]indol-7-yl)-N-methylpropanamide; [1218]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)pro-
panenitrile; [1219]
(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)(morpholino)meth-
anone; [1220]
N-methoxy-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide;
[1221]
5-(3-Ethanesulfonyl-phenyl)-8-(cyclopropylmethoxy)-3-methyl-9H-dip-
yrido[2,3-b; 4',3'-d]pyrrole; [1222]
8-(3-(benzyloxy)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2-
,3-b]indole; [1223]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol; [1224]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(3-iodopropoxy)-9H-pyrido[2,3-b]in-
dole; [1225]
8-(3-(1H-imidazol-1-yl)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-p-
yrido[2,3-b]indole; and [1226]
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide.
[1227] It is noted that the compounds of the present invention may
be in the form of a pharmaceutically acceptable salt,
biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable
carbamate, solvate, hydrate or prodrug thereof. For example, the
compound optionally comprises a substituent that is convertible in
vivo to a different substituent such as a hydrogen.
[1228] In one particular variation, the compound is in the form of
a salt selected from the group consisting of a hydrochloric acid
salt, a trifluoroacetic acid salt, a toluenesulfonic acid salt, a
benzenesulfonic acid salt, a methanesulfonic acid salt, a succinic
acid salt, a tartaric acid salt, a citric acid salt, a fumaric acid
salt, a sulfuric acid salt, a phosphoric acid salt, a benzoic acid
salt, a bis-hydrogen chloride salt, a bis-trifluoroacetic acid
salt, a tosylate salt, a hemi-fumarate salt, a lactic acid salt, a
malic acid salt, a hippuric acid salt and a hydrobromic acid
salt.
[1229] In another particular variation, the compound is in the form
of a salt selected from the group consisting of a hydrochloric acid
salt, a toluenesulfonic acid salt, a hemi-fumarate salt, and a
hippuric acid salt. In still another particular variation, the
compound is in the form of a hydrochloric acid salt. In one
particular variation, the hydrochloric acid salt is formed in
acetonitrile. In yet another particular variation, the compound is
in the form of a hemi-fumarate salt. In one particular variation,
the hemi-fumarate salt is formed in methanol.
[1230] It is further noted that the compounds of the present
invention may optionally be solely or predominantly in the enol
tautomer in its active state. It is further noted that the compound
may be present in a mixture of stereoisomers, or the compound may
comprise a single stereoisomer.
[1231] The invention also provides pharmaceutical compositions
comprising, as an active ingredient, a compound according to any
one of the above embodiments and variations. In addition, the
composition may be a solid or liquid formulation adapted for oral
administration. In a further variation, the pharmaceutical
composition may be a tablet. In yet another variation, the
pharmaceutical composition may be a liquid formulation adapted for
parenteral administration.
[1232] In one embodiment, there is provided the pharmaceutical
composition comprising a compound according to any one of the above
embodiments and variations wherein the composition is adapted for
administration by a route selected from the group consisting of
orally, parenterally, intraperitoneally, intravenously,
intraarterially, transdermally, sublingually, intramuscularly,
rectally, transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery (for example by
catheter or stent), subcutaneously, intraadiposally,
intraarticularly, and intrathecally.
[1233] In another embodiment, there is provided the pharmaceutical
composition comprising:
[1234] a compound having the formula
##STR00145##
[1235] wherein at least a portion of the compound is present as
Amorphous Form, characterized by physical properties which comprise
one or more of the following: [1236] (a) may be formed by
lyophilizing a solution of Compound 88 in ACN and water; [1237] (b)
has an XRPD spectrum characterized by a diffuse halo with no
discernable peaks; and/or [1238] (c) shows 7.6 wt % Cl.sup.-
present using ion chromatography.
[1239] In still another embodiment, there is provided the
pharmaceutical composition comprising:
[1240] a compound having the formula
##STR00146## [1241] wherein at least a portion of the compound is
present as Amorphous Form characterized by physical properties
which comprise one or more of the following: [1242] (a) may be
formed by lyophilizing a solution of Compound 88 in ACN and water;
[1243] (b) has an XRPD spectrum characterized by a diffuse halo
with no discernable peaks; and/or [1244] (c) shows 7.6 wt %
Cl.sup.- present using ion chromatography; and
[1245] one or more pharmaceutical carriers.
[1246] In one variation of the above embodiments, between 0.1% and
100% of the compound (by weight) is present in the composition as
Amorphous Form. In a further variation of the above embodiments,
between 0.1% and 99% of the compound (by weight) is present in the
composition as Amorphous Form. In still another variation of the
above embodiments, greater than 0.1% of the compound (by weight) is
present in the composition as Amorphous Form. In yet another
variation of the above embodiments, greater than 1% of the compound
(by weight) is present in the composition as Amorphous Form. In
another variation of the above embodiments, greater than 5% of the
compound (by weight) is present in the composition as Amorphous
Form. In still another variation of the above embodiments, greater
than 10% of the compound (by weight) is present in the composition
as Amorphous Form. In yet another variation of the above
embodiments, greater than 50% of the compound (by weight) is
present in the composition as Amorphous Form. In a further
variation of the above embodiments, greater than 75% of the
compound (by weight) is present in the composition as Amorphous
Form. In still a further variation of the above embodiments,
greater than 90% of C the compound (by weight) is present in the
composition as Amorphous Form. In yet a further variation of the
above embodiments, greater than 99% of the compound (by weight) is
present in the composition as Amorphous Form. In another variation
of the above embodiments, greater than 99% of the compound (by
weight) is present in the composition as Amorphous Form.
[1247] In a further variation of the above embodiments and
variations, the composition is a pill or capsule adapted for oral
administration. In still a further variation of the above
embodiments and variations, the composition is in an oral dosage
form selected from the group consisting of pills, tablets,
capsules, emulsions, suspensions, microsuspensions, wafers,
sprinkles, chewing gum, powders, lyophilized powders, granules, and
troches. In yet a further variation of the above embodiments and
variations, the composition is in a parenteral dosage form selected
from the group consisting of suspensions, microsuspensions,
emulsions, solid forms suitable for suspension or emulsification
prior to injection, and implantable devices. In another variation
of the above embodiments and variations, the composition is adapted
for topical or transdermal administration. In still another
variation of the above embodiments and variations, the composition
is in a topical or transdermal dosage form selected from the group
consisting of suspensions, microsuspensions, emulsions, creams,
gels, ointments, lotions, tinctures, pastes, powders, foams,
aerosols, irrigations, sprays, suppositories, bandages, and dermal
patches. In still another variation of the above embodiments and
variations, the composition is in a pulmonary dosage form selected
from the group consisting of powders, aerosols, suspensions,
microsuspensions, and emulsions.
[1248] In yet another variation of the above embodiments and
variations, the polymorphic form of the compound is at least
partially preserved for a period of time following
administration.
[1249] The invention also provides a kit comprising a compound or
composition according to any one of the above embodiments and
variations, and instructions which comprise one or more forms of
information selected from the group consisting of indicating a
disease state for which the compound is to be administered, storage
information for the compound, dosing information and instructions
regarding how to administer the compound. In one variation, the kit
comprises the compound or composition in a multiple dose form.
[1250] In another embodiment, the present invention provides an
article of manufacture comprising a compound or composition
according to any one of the above embodiments and variations, and
packaging materials. In one variation, the packaging material
comprises a container for housing the compound or composition. The
container optionally comprises a label indicating a disease state
for which the compound or composition is to be administered,
storage information, dosing information and/or instructions
regarding how to administer the compound or composition. In regard
to the above embodiments and variations, the article of manufacture
optionally comprises the compound or composition in a multiple dose
form.
[1251] In another embodiment, the present invention provides a
therapeutic method comprising administering a compound or
composition according to any one of the above embodiments and
variations to a subject.
[1252] In yet another embodiment, the present invention provides a
method of inhibiting a kinase comprising contacting a kinase with a
compound or composition according to any one of the above
embodiments and variations.
[1253] In still another embodiment, there is provided a method of
inhibiting kinase comprising causing a compound or composition
according to any one of the above embodiments and variations to be
present in a subject in order to inhibit kinase in vivo.
[1254] In yet another of its aspects, there is provided a method of
treating a disease state for which a kinase possesses activity that
contributes to the pathology and/or symptomology of the disease
state, the method comprising administering a compound of any one of
the above embodiments and variations to a subject, wherein the
compound is present in the subject in a therapeutically effective
amount for the disease state.
[1255] The present invention also provides a method of inhibiting a
kinase comprising administering a first compound to a subject that
is converted in vivo to a second compound wherein the second
compound inhibits kinase in vivo, the second compound being a
compound according to any one of the above embodiments and
variations.
[1256] In yet another embodiment, there is provided a method of
preventing or treating a disease state for which a kinase possesses
activity that contributes to the pathology and/or symptomology of
the disease state comprising causing a compound or composition
according to any one of the above embodiments and variations to be
present in a subject in a therapeutically effective amount for the
disease state.
[1257] The present invention also provides a method of preventing
or treating a disease state for which a kinase possesses activity
that contributes to the pathology and/or symptomology of the
disease state comprising administering a first compound to a
subject that is converted in vivo to a second compound according to
any one of the above embodiments and variations wherein the second
compound is present in a subject in a therapeutically effective
amount for the disease state.
[1258] In addition, there is provided a method of preventing or
treating a disease state for which a kinase possesses activity that
contributes to the pathology and/or symptomology of the disease
state comprising administering a compound or composition according
to any one of the above embodiments and variations, wherein the
compound or composition is present in the subject in a
therapeutically effective amount for the disease state.
[1259] In each of the above embodiments and variations, the kinase
is optionally an Aurora kinase. In particular variations of each of
the above embodiments and variations, the kinase is an Aurora-B
kinase.
[1260] In another embodiment, there is provided a method for
treating cancer comprising administering a therapeutically
effective amount of a compound or composition of the present
invention to a mammalian species in need thereof. In one
embodiment, the cancer is selected from the group consisting of
squamous cell carcinoma, astrocytoma, Kaposi's sarcoma,
glioblastoma, non small-cell lung cancer, bladder cancer, head and
neck cancer, melanoma, ovarian cancer, prostate cancer, breast
cancer, small-cell lung cancer, glioma, colorectal cancer,
genitourinary cancer, gastrointestinal cancer, thyroid cancer, skin
cancer, kidney cancer, rectal cancer, colonic cancer, cervical
cancer, mesothelioma, pancreatic cancer, liver cancer, uterus
cancer, cerebral tumor cancer, urinary bladder cancer and blood
cancers including multiple myeloma. In particular embodiments, the
compound or method is useful for inhibiting growth of cancer, for
suppressing metastasis of cancer, for suppressing apoptosis and the
like.
[1261] In another embodiment, there is provided a method for
treating inflammation, inflammatory bowel disease, psoriasis, or
transplant rejection, comprising administration to a mammalian
species in need thereof of a therapeutically effective amount of a
compound or composition according to the present invention.
[1262] In another embodiment, there is provided a method for
preventing or treating amyotrophic lateral sclerosis, corticobasal
degeneration, Down syndrome, Huntington's Disease, Parkinson's
Disease, postencephelatic parkinsonism, progressive supranuclear
palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma
and other chronic neurodegenerative diseases, Bipolar Disease,
affective disorders, depression, schizophrenia, cognitive
disorders, hair loss and contraceptive medication, comprising
administration to a mammalian species in need thereof of a
therapeutically effective amount of a compound or composition
according to any one of the above embodiments.
[1263] In yet another embodiment, there is provided a method for
preventing or treating mild Cognitive Impairment, Age-Associated
Memory Impairment, Age-Related Cognitive Decline, Cognitive
Impairment No Dementia, mild cognitive decline, mild neurocognitive
decline, Late-Life Forgetfulness, memory impairment and cognitive
impairment and androgenetic alopecia, comprising administering to a
mammal, including man in need of such prevention and/or treatment,
a therapeutically effective amount of a compound or composition
according to any one of the above embodiments.
[1264] In a further embodiment, there is provided a method for
preventing or treating dementia related diseases, Alzheimer's
Disease and conditions associated with kinases, comprising
administration to a mammalian species in need thereof of a
therapeutically effective amount of a compound or composition
according to any one of the above embodiments. In one particular
variation, the dementia related diseases are selected from the
group consisting of Frontotemporal dementia Parkinson's Type,
Parkinson dementia complex of Guam, HIV dementia, diseases with
associated neurofibrillar tangle pathologies, predemented states,
vascular dementia, dementia with Lewy bodies, Frontotemporal
dementia and dementia pugilistica.
[1265] In another embodiment, there is provided a method for
treating arthritis comprising administration to a mammalian species
in need thereof of a therapeutically effective amount of a compound
or composition according to any one of the above embodiment.
[1266] In still another embodiment, there is provided a compound
according to any one of the above embodiments and variations for
use as a medicament.
[1267] In yet another embodiment, there is provided a compound
according to any one of the above embodiments and variations for
use in the manufacture of a medicament for inhibiting a kinase.
[1268] In a further embodiment, there is provided a compound
according to any one of the above embodiments and variations for
use in the manufacture of a medicament for treating a disease state
for which a kinase possesses activity that contributes to the
pathology and/or symptomology of the disease state.
[1269] In still a further embodiment, there is provided a compound
according to any one of the above embodiments and variations for
use in the manufacture of a medicament for treating cancer,
inflammation, inflammatory bowel disease, psoriasis, transplant
rejection, amyotrophic lateral sclerosis, corticobasal
degeneration, Down syndrome, Huntington's Disease, Parkinson's
Disease, postencephelatic parkinsonism, progressive supranuclear
palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma
and other chronic neurodegenerative diseases, Bipolar Disease,
affective disorders, depression, schizophrenia, cognitive
disorders, hair loss, contraception, mild Cognitive Impairment,
Age-Associated Memory Impairment, Age-Related Cognitive Decline,
Cognitive Impairment No Dementia, mild cognitive decline, mild
neurocognitive decline, Late-Life Forgetfulness, memory impairment,
cognitive impairment, androgenetic alopecia, dementia related
diseases, and Alzheimer's Disease.
Salts, Hydrates, and Prodrugs of Kinase Inhibitors
[1270] It should be recognized that the compounds of the present
invention may be present and optionally administered in the form of
salts, hydrates and prodrugs that are converted in vivo into the
compounds of the present invention. For example, it is within the
scope of the present invention to convert the compounds of the
present invention into and use them in the form of their
pharmaceutically acceptable salts derived from various organic and
inorganic acids and bases in accordance with procedures well known
in the art.
[1271] When the compounds of the present invention possess a free
base form, the compounds can be prepared as a pharmaceutically
acceptable acid addition salt by reacting the free base form of the
compound with a pharmaceutically acceptable inorganic or organic
acid, e.g., hydrohalides such as hydrochloride, hydrobromide,
hydroiodide; other mineral acids and their corresponding salts such
as sulfate, nitrate, phosphate, etc.; and alkyl and
monoarylsulfonates such as ethanesulfonate, toluenesulfonate and
benzenesulfonate; and other organic acids and their corresponding
salts such as acetate, tartrate, maleate, succinate, citrate,
benzoate, salicylate and ascorbate. Further acid addition salts of
the present invention include, but are not limited to: adipate,
alginate, arginate, aspartate, bisulfate, bisulfite, bromide,
butyrate, camphorate, camphorsulfonate, caprylate, chloride,
chlorobenzoate, cyclopentanepropionate, digluconate,
dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,
galacterate (from mucic acid), galacturonate, glucoheptaoate,
gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,
iso-butyrate, lactate, lactobionate, malate, malonate, mandelate,
metaphosphate, methanesulfonate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate,
3-phenylpropionate, phosphate, phosphonate and phthalate. It should
be recognized that the free base forms will typically differ from
their respective salt forms somewhat in physical properties such as
solubility in polar solvents, but otherwise the salts are
equivalent to their respective free base forms for the purposes of
the present invention.
[1272] When the compounds of the present invention possess a free
acid form, a pharmaceutically acceptable base addition salt can be
prepared by reacting the free acid form of the compound with a
pharmaceutically acceptable inorganic or organic base. Examples of
such bases are alkali metal hydroxides including potassium, sodium
and lithium hydroxides; alkaline earth metal hydroxides such as
barium and calcium hydroxides; alkali metal alkoxides, e.g.
potassium ethanolate and sodium propanolate; and various organic
bases such as ammonium hydroxide, piperidine, diethanolamine and
N-methylglutamine. Also included are the aluminum salts of the
compounds of the present invention. Further base salts of the
present invention include, but are not limited to: copper, ferric,
ferrous, lithium, magnesium, manganic, manganous, potassium, sodium
and zinc salts. Organic base salts include, but are not limited to,
salts of primary, secondary and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines and
basic ion exchange resins, e.g., arginine, betaine, caffeine,
chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine),
dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, iso-propylamine, lidocaine, lysine,
meglumine, N-methyl-D-glucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethanolamine, triethylamine, trimethylamine, tripropylamine and
tris-(hydroxymethyl)-methylamine (tromethamine). It should be
recognized that the free acid forms will typically differ from
their respective salt forms somewhat in physical properties such as
solubility in polar solvents, but otherwise the salts are
equivalent to their respective free acid forms for the purposes of
the present invention.
[1273] Compounds of the present invention that comprise basic
nitrogen-containing groups may be quaternized with such agents as
(C.sub.1-4) alkyl halides, e.g., methyl, ethyl, iso-propyl and
tert-butyl chlorides, bromides and iodides; di (C.sub.1-4) alkyl
sulfates, e.g., dimethyl, diethyl and diamyl sulfates;
(C.sub.10-18) alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl
and stearyl chlorides, bromides and iodides; and aryl (C.sub.1-4)
alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such
salts permit the preparation of both water-soluble and oil-soluble
compounds of the present invention.
[1274] N-oxides of compounds according to the present invention can
be prepared by methods known to those of ordinary skill in the art.
For example, N-oxides can be prepared by treating an unoxidized
form of the compound with an oxidizing agent (e.g.,
trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic
acid, meta-chloroperoxybenzoic acid, or the like) in a suitable
inert organic solvent (e.g., a halogenated hydrocarbon such as
dichloromethane) at approximately 0.degree. C. Alternatively, the
N-oxides of the compounds can be prepared from the N-oxide of an
appropriate starting material.
[1275] Prodrug derivatives of compounds according to the present
invention can be prepared by modifying substituents of compounds of
the present invention that are then converted in vivo to a
different substituent. It is noted that in many instances, the
prodrugs themselves also fall within the scope of the range of
compounds according to the present invention. For example, prodrugs
can be prepared by reacting a compound with a carbamylating agent
(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl
carbonate, or the like) or an acylating agent. Further examples of
methods of making prodrugs are described in Saulnier et al. (1994),
Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
[1276] Protected derivatives of compounds of the present invention
can also be made. Examples of techniques applicable to the creation
of protecting groups and their removal can be found in T. W.
Greene, Protecting Groups in Organic Synthesis, 3.sup.rd edition,
John Wiley & Sons, Inc. 1999.
[1277] Compounds of the present invention may also be conveniently
prepared, or formed during the process of the invention, as
solvates (e.g. hydrates). Hydrates of compounds of the present
invention may be conveniently prepared by recrystallization from an
aqueous/organic solvent mixture, using organic solvents such as
dioxin, tetrahydrofuran or methanol.
[1278] A "pharmaceutically acceptable salt", as used herein, is
intended to encompass any compound according to the present
invention that is utilized in the form of a salt thereof,
especially where the salt confers on the compound improved
pharmacokinetic properties as compared to the free form of compound
or a different salt form of the compound. The pharmaceutically
acceptable salt form may also initially confer desirable
pharmacokinetic properties on the compound that it did not
previously possess, and may even positively affect the
pharmacodynamics of the compound with respect to its therapeutic
activity in the body. An example of a pharmacokinetic property that
may be favorably affected is the manner in which the compound is
transported across cell membranes, which in turn may directly and
positively affect the absorption, distribution, biotransformation
and excretion of the compound. While the route of administration of
the pharmaceutical composition is important, and various
anatomical, physiological and pathological factors can critically
affect bioavailability, the solubility of the compound is usually
dependent upon the character of the particular salt form thereof,
which it utilized. One of skill in the art will appreciate that an
aqueous solution of the compound will provide the most rapid
absorption of the compound into the body of a subject being
treated, while lipid solutions and suspensions, as well as solid
dosage forms, will result in less rapid absorption of the
compound.
Preparation of Kinase Inhibitors
[1279] Various methods may be developed for synthesizing compounds
according to the present invention. Representative methods for
synthesizing these compounds are provided in the Examples. It is
noted, however, that the compounds of the present invention may
also be synthesized by other synthetic routes that others may
devise.
[1280] It will be readily recognized that certain compounds
according to the present invention have atoms with linkages to
other atoms that confer a particular stereochemistry to the
compound (e.g., chiral centers). It is recognized that synthesis of
compounds according to the present invention may result in the
creation of mixtures of different stereoisomers (enantiomers,
diastereomers). Unless a particular stereochemistry is specified,
recitation of a compound is intended to encompass all of the
different possible stereoisomers.
[1281] Various methods for separating mixtures of different
stereoisomers are known in the art. For example, a racemic mixture
of a compound may be reacted with an optically active resolving
agent to form a pair of diastereoisomeric compounds. The
diastereomers may then be separated in order to recover the
optically pure enantiomers. Dissociable complexes may also be used
to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
Diastereomers typically have sufficiently distinct physical
properties (e.g., melting points, boiling points, solubilities,
reactivity, etc.) that they can be readily separated by taking
advantage of these dissimilarities. For example, diastereomers can
typically be separated by chromatography or by
separation/resolution techniques based upon differences in
solubility. A more detailed description of techniques that can be
used to resolve stereoisomers of compounds from their racemic
mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,
Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc.
(1981).
Composition Comprising Kinase Inhibitors
[1282] A wide variety of compositions and administration methods
may be used in conjunction with the kinase inhibitors of the
present invention. Such compositions may include, in addition to
the kinase inhibitors of the present invention, conventional
pharmaceutical excipients, and other conventional, pharmaceutically
inactive agents. Additionally, the compositions may include active
agents in addition to the kinase inhibitors of the present
invention. These additional active agents may include additional
compounds according to the invention, and/or one or more other
pharmaceutically active agents.
[1283] The compositions may be in gaseous, liquid, semi-liquid or
solid form, formulated in a manner suitable for the route of
administration to be used. For oral administration, capsules and
tablets are typically used. For parenteral administration,
reconstitution of a lyophilized powder, prepared as described
herein, is typically used.
[1284] Compositions comprising kinase inhibitors of the present
invention may be administered or coadministered orally,
parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation,
vaginally, intraoccularly, via local delivery (for example by
catheter or stent), subcutaneously, intraadiposally,
intraarticularly, or intrathecally. The compounds and/or
compositions according to the invention may also be administered or
coadministered in slow release dosage forms.
[1285] The kinase inhibitors and compositions comprising them may
be administered or coadministered in any conventional dosage form.
Co-administration in the context of this invention is intended to
mean the administration of more than one therapeutic agent, one of
which includes a kinase inhibitor, in the course of a coordinated
treatment to achieve an improved clinical outcome. Such
co-administration may also be coextensive, that is, occurring
during overlapping periods of time.
[1286] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application may optionally include one or
more of the following components: a sterile diluent, such as water
for injection, saline solution, fixed oil, polyethylene glycol,
glycerine, propylene glycol or other synthetic solvent;
antimicrobial agents, such as benzyl alcohol and methyl parabens;
antioxidants, such as ascorbic acid and sodium bisulfite; chelating
agents, such as ethylenediaminetetraacetic acid (EDTA); buffers,
such as acetates, citrates and phosphates; agents for the
adjustment of tonicity such as sodium chloride or dextrose, and
agents for adjusting the acidity or alkalinity of the composition,
such as alkaline or acidifying agents or buffers like carbonates,
bicarbonates, phosphates, hydrochloric acid, and organic acids like
acetic and citric acid. Parenteral preparations may optionally be
enclosed in ampules, disposable syringes or single or multiple dose
vials made of glass, plastic or other suitable material.
[1287] When kinase inhibitors according to the present invention
exhibit insufficient solubility, methods for solubilizing the
compounds may be used. Such methods are known to those of skill in
this art, and include, but are not limited to, using cosolvents,
such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN,
or dissolution in aqueous sodium bicarbonate. Derivatives of the
compounds, such as prodrugs of the compounds may also be used in
formulating effective pharmaceutical compositions.
[1288] Upon mixing or adding kinase inhibitors according to the
present invention to a composition, a solution, suspension,
emulsion or the like may be formed. The form of the resulting
composition will depend upon a number of factors, including the
intended mode of administration, and the solubility of the compound
in the selected carrier or vehicle. The effective concentration
needed to ameliorate the disease being treated may be empirically
determined.
[1289] Compositions according to the present invention are
optionally provided for administration to humans and animals in
unit dosage forms, such as tablets, capsules, pills, powders, dry
powders for inhalers, granules, sterile parenteral solutions or
suspensions, and oral solutions or suspensions, and oil-water
emulsions containing suitable quantities of the compounds,
particularly the pharmaceutically acceptable salts, preferably the
sodium salts, thereof. The pharmaceutically therapeutically active
compounds and derivatives thereof are typically formulated and
administered in unit-dosage forms or multiple-dosage forms.
Unit-dose forms, as used herein, refers to physically discrete
units suitable for human and animal subjects and packaged
individually as is known in the art. Each unit-dose contains a
predetermined quantity of the therapeutically active compound
sufficient to produce the desired therapeutic effect, in
association with the required pharmaceutical carrier, vehicle or
diluent. Examples of unit-dose forms include ampoules and syringes
individually packaged tablet or capsule. Unit-dose forms may be
administered in fractions or multiples thereof. A multiple-dose
form is a plurality of identical unit-dosage forms packaged in a
single container to be administered in segregated unit-dose form.
Examples of multiple-dose forms include vials, bottles of tablets
or capsules or bottles of pint or gallons. Hence, multiple dose
form is a multiple of unit-doses that are not segregated in
packaging.
[1290] In addition to one or more kinase inhibitors according to
the present invention, the composition may comprise: a diluent such
as lactose, sucrose, dicalcium phosphate, or
carboxymethylcellulose; a lubricant, such as magnesium stearate,
calcium stearate and talc; and a binder such as starch, natural
gums, such as gum acaciagelatin, glucose, molasses,
polyvinylpyrrolidine, celluloses and derivatives thereof, povidone,
crospovidones and other such binders known to those of skill in the
art. Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, or otherwise mixing
an active compound as defined above and optional pharmaceutical
adjuvants in a carrier, such as, for example, water, saline,
aqueous dextrose, glycerol, glycols, ethanol, and the like, to form
a solution or suspension. If desired, the pharmaceutical
composition to be administered may also contain minor amounts of
auxiliary substances such as wetting agents, emulsifying agents, or
solubilizing agents, pH buffering agents and the like, for example,
acetate, sodium citrate, cyclodextrine derivatives, sorbitan
monolaurate, triethanolamine sodium acetate, triethanolamine
oleate, and other such agents. Actual methods of preparing such
dosage forms are known in the art, or will be apparent, to those
skilled in this art; for example, see Remington's Pharmaceutical
Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975.
The composition or formulation to be administered will, in any
event, contain a sufficient quantity of a kinase inhibitor of the
present invention to reduce kinases activity in vivo, thereby
treating the disease state of the subject.
[1291] Dosage forms or compositions may optionally comprise one or
more kinase inhibitors according to the present invention in the
range of 0.005% to 100% (weight/weight) with the balance comprising
additional substances such as those described herein. For oral
administration, a pharmaceutically acceptable composition may
optionally comprise any one or more commonly employed excipients,
such as, for example pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, talcum, cellulose derivatives, sodium
crosscarmellose, glucose, sucrose, magnesium carbonate, sodium
saccharin, talcum. Such compositions include solutions,
suspensions, tablets, capsules, powders, dry powders for inhalers
and sustained release formulations, such as, but not limited to,
implants and microencapsulated delivery systems, and biodegradable,
biocompatible polymers, such as collagen, ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid
and others. Methods for preparing these formulations are known to
those skilled in the art. The compositions may optionally contain
0.01%-100% (weight/weight) of one or more kinase inhibitors,
optionally 0.1-95%, and optionally 1-95%.
[1292] In one variation, the composition comprises at least 0.1%,
0.25%, 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 80%, 85%, 90%, 95%, 97%,
or 99% (by weight) of one or more kinase inhibitors according to
the present invention. In particular variations, greater than 0.1%,
1%, 5%, 10%, 25%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or 99% (by
weight) of one or more kinase inhibitors according to the present
invention is present in the composition as a single crystalline or
amorphous form. The composition may optionally be a pharmaceutical
composition. The pharmaceutical composition may optionally further
include one or more pharmaceutical carriers.
[1293] Salts, preferably sodium salts, of the kinase inhibitors may
be prepared with carriers that protect the compound against rapid
elimination from the body, such as time release formulations or
coatings. The formulations may further include other active
compounds to obtain desired combinations of properties.
Formulations for Oral Administration
[1294] Oral pharmaceutical dosage forms may be as a solid, gel or
liquid. Examples of solid dosage forms include, but are not limited
to tablets, capsules, granules, and bulk powders. More specific
examples of oral tablets include compressed, chewable lozenges and
tablets that may be enteric-coated, sugar-coated or film-coated.
Examples of capsules include hard or soft gelatin capsules.
Granules and powders may be provided in non-effervescent or
effervescent forms. Each may be combined with other ingredients
known to those skilled in the art.
[1295] In certain embodiments, kinase inhibitors according to the
present invention are provided as solid dosage forms, preferably
capsules or tablets. The tablets, pills, capsules, troches and the
like may optionally contain one or more of the following
ingredients, or compounds of a similar nature: a binder; a diluent;
a disintegrating agent; a lubricant; a glidant; a sweetening agent;
and a flavoring agent.
[1296] Examples of binders that may be used include, but are not
limited to, microcrystalline cellulose, gum tragacanth, glucose
solution, acacia mucilage, gelatin solution, sucrose and starch
paste.
[1297] Examples of lubricants that may be used include, but are not
limited to, talc, starch, magnesium or calcium stearate, lycopodium
and stearic acid.
[1298] Examples of diluents that may be used include, but are not
limited to, lactose, sucrose, starch, kaolin, salt, mannitol and
dicalcium phosphate.
[1299] Examples of glidants that may be used include, but are not
limited to, colloidal silicon dioxide.
[1300] Examples of disintegrating agents that may be used include,
but are not limited to, crosscarmellose sodium, sodium starch
glycolate, alginic acid, corn starch, potato starch, bentonite,
methylcellulose, agar and carboxymethylcellulose.
[1301] Examples of coloring agents that may be used include, but
are not limited to, any of the approved certified water soluble FD
and C dyes, mixtures thereof; and water insoluble FD and C dyes
suspended on alumina hydrate.
[1302] Examples of sweetening agents that may be used include, but
are not limited to, sucrose, lactose, mannitol and artificial
sweetening agents such as sodium cyclamate and saccharin, and any
number of spray-dried flavors.
[1303] Examples of flavoring agents that may be used include, but
are not limited to, natural flavors extracted from plants such as
fruits and synthetic blends of compounds that produce a pleasant
sensation, such as, but not limited to peppermint and methyl
salicylate.
[1304] Examples of wetting agents that may be used include, but are
not limited to, propylene glycol monostearate, sorbitan monooleate,
diethylene glycol monolaurate and polyoxyethylene lauryl ether.
[1305] Examples of anti-emetic coatings that may be used include,
but are not limited to, fatty acids, fats, waxes, shellac,
ammoniated shellac and cellulose acetate phthalates.
[1306] Examples of film coatings that may be used include, but are
not limited to, hydroxyethylcellulose, sodium
carboxymethylcellulose, polyethylene glycol 4000 and cellulose
acetate phthalate.
[1307] If oral administration is desired, the salt of the compound
may optionally be provided in a composition that protects it from
the acidic environment of the stomach. For example, the composition
can be formulated in an enteric coating that maintains its
integrity in the stomach and releases the active compound in the
intestine. The composition may also be formulated in combination
with an antacid or other such ingredient.
[1308] When the dosage unit form is a capsule, it may optionally
additionally comprise a liquid carrier such as a fatty oil. In
addition, dosage unit forms may optionally additionally comprise
various other materials that modify the physical form of the dosage
unit, for example, coatings of sugar and other enteric agents.
[1309] Compounds according to the present invention may also be
administered as a component of an elixir, suspension, syrup, wafer,
sprinkle, chewing gum or the like. A syrup may optionally comprise,
in addition to the active compounds, sucrose as a sweetening agent
and certain preservatives, dyes and colorings and flavors.
[1310] The kinase inhibitors of the present invention may also be
mixed with other active materials that do not impair the desired
action, or with materials that supplement the desired action, such
as antacids, H2 blockers, and diuretics. For example, if a compound
is used for treating asthma or hypertension, it may be used with
other bronchodilators and antihypertensive agents,
respectively.
[1311] Examples of pharmaceutically acceptable carriers that may be
included in tablets comprising kinase inhibitors of the present
invention include, but are not limited to binders, lubricants,
diluents, disintegrating agents, coloring agents, flavoring agents,
and wetting agents. Enteric-coated tablets, because of the
enteric-coating, resist the action of stomach acid and dissolve or
disintegrate in the neutral or alkaline intestines. Sugar-coated
tablets may be compressed tablets to which different layers of
pharmaceutically acceptable substances are applied. Film-coated
tablets may be compressed tablets that have been coated with
polymers or other suitable coating. Multiple compressed tablets may
be compressed tablets made by more than one compression cycle
utilizing the pharmaceutically acceptable substances previously
mentioned. Coloring agents may also be used in tablets. Flavoring
and sweetening agents may be used in tablets, and are especially
useful in the formation of chewable tablets and lozenges.
[1312] Examples of liquid oral dosage forms that may be used
include, but are not limited to, aqueous solutions, emulsions,
suspensions, solutions and/or suspensions reconstituted from
non-effervescent granules and effervescent preparations
reconstituted from effervescent granules.
[1313] Examples of aqueous solutions that may be used include, but
are not limited to, elixirs and syrups. As used herein, elixirs
refer to clear, sweetened, hydroalcoholic preparations. Examples of
pharmaceutically acceptable carriers that may be used in elixirs
include, but are not limited to solvents. Particular examples of
solvents that may be used include glycerin, sorbitol, ethyl alcohol
and syrup. As used herein, syrups refer to concentrated aqueous
solutions of a sugar, for example, sucrose. Syrups may optionally
further comprise a preservative.
[1314] Emulsions refer to two-phase systems in which one liquid is
dispersed in the form of small globules throughout another liquid.
Emulsions may optionally be oil-in-water or water-in-oil emulsions.
Examples of pharmaceutically acceptable carriers that may be used
in emulsions include, but are not limited to non-aqueous liquids,
emulsifying agents and preservatives.
[1315] Examples of pharmaceutically acceptable substances that may
be used in non-effervescent granules, to be reconstituted into a
liquid oral dosage form, include diluents, sweeteners and wetting
agents.
[1316] Examples of pharmaceutically acceptable substances that may
be used in effervescent granules, to be reconstituted into a liquid
oral dosage form, include organic acids and a source of carbon
dioxide.
[1317] Coloring and flavoring agents may optionally be used in all
of the above dosage forms.
[1318] Particular examples of preservatives that may be used
include glycerin, methyl and propylparaben, benzoic add, sodium
benzoate and alcohol.
[1319] Particular examples of non-aqueous liquids that may be used
in emulsions include mineral oil and cottonseed oil.
[1320] Particular examples of emulsifying agents that may be used
include gelatin, acacia, tragacanth, bentonite, and surfactants
such as polyoxyethylene sorbitan monooleate.
[1321] Particular examples of suspending agents that may be used
include sodium carboxymethylcellulose, pectin, tragacanth, Veegum
and acacia. Diluents include lactose and sucrose. Sweetening agents
include sucrose, syrups, glycerin and artificial sweetening agents
such as sodium cyclamate and saccharin.
[1322] Particular examples of wetting agents that may be used
include propylene glycol monostearate, sorbitan monooleate,
diethylene glycol monolaurate and polyoxyethylene lauryl ether.
[1323] Particular examples of organic acids that may be used
include citric and tartaric acid.
[1324] Sources of carbon dioxide that may be used in effervescent
compositions include sodium bicarbonate and sodium carbonate.
Coloring agents include any of the approved certified water soluble
FD and C dyes, and mixtures thereof.
[1325] Particular examples of flavoring agents that may be used
include natural flavors extracted from plants such fruits, and
synthetic blends of compounds that produce a pleasant taste
sensation.
[1326] For a solid dosage form, the solution or suspension, in for
example propylene carbonate, vegetable oils or triglycerides, is
preferably encapsulated in a gelatin capsule. Such solutions, and
the preparation and encapsulation thereof, are disclosed in U.S.
Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage
form, the solution, e.g., for example, in a polyethylene glycol,
may be diluted with a sufficient quantity of a pharmaceutically
acceptable liquid carrier, e.g. water, to be easily measured for
administration.
[1327] Alternatively, liquid or semi-solid oral formulations may be
prepared by dissolving or dispersing the active compound or salt in
vegetable oils, glycols, triglycerides, propylene glycol esters
(e.g. propylene carbonate) and other such carriers, and
encapsulating these solutions or suspensions in hard or soft
gelatin capsule shells. Other useful formulations include those set
forth in U.S. Pat. Nos. Re 28,819 and 4,358,603.
[1328] Injectables, Solutions, and Emulsions
[1329] The present invention is also directed to compositions
designed to administer the kinase inhibitors of the present
invention by parenteral administration, generally characterized by
injection, either subcutaneously, intramuscularly or intravenously.
Injectables may be prepared in any conventional form, for example
as liquid solutions or suspensions, solid forms suitable for
solution or suspension in liquid prior to injection, or as
emulsions.
[1330] Examples of excipients that may be used in conjunction with
injectables according to the present invention include, but are not
limited to water, saline, dextrose, glycerol or ethanol. The
injectable compositions may also optionally comprise minor amounts
of non-toxic auxiliary substances such as wetting or emulsifying
agents, pH buffering agents, stabilizers, solubility enhancers, and
other such agents, such as for example, sodium acetate, sorbitan
monolaurate, triethanolamine oleate and cyclodextrins. Implantation
of a slow-release or sustained-release system, such that a constant
level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795)
is also contemplated herein. The percentage of active compound
contained in such parenteral compositions is highly dependent on
the specific nature thereof, as well as the activity of the
compound and the needs of the subject.
[1331] Parenteral administration of the formulations includes
intravenous, subcutaneous and intramuscular administrations.
Preparations for parenteral administration include sterile
solutions ready for injection, sterile dry soluble products, such
as the lyophilized powders described herein, ready to be combined
with a solvent just prior to use, including hypodermic tablets,
sterile suspensions ready for injection, sterile dry insoluble
products ready to be combined with a vehicle just prior to use and
sterile emulsions. The solutions may be either aqueous or
nonaqueous.
[1332] When administered intravenously, examples of suitable
carriers include, but are not limited to physiological saline or
phosphate buffered saline (PBS), and solutions containing
thickening and solubilizing agents, such as glucose, polyethylene
glycol, and polypropylene glycol and mixtures thereof.
[1333] Examples of pharmaceutically acceptable carriers that may
optionally be used in parenteral preparations include, but are not
limited to aqueous vehicles, nonaqueous vehicles, antimicrobial
agents, isotonic agents, buffers, antioxidants, local anesthetics,
suspending and dispersing agents, emulsifying agents, sequestering
or chelating agents and other pharmaceutically acceptable
substances.
[1334] Examples of aqueous vehicles that may optionally be used
include Sodium Chloride Injection, Ringers Injection, Isotonic
Dextrose Injection, Sterile Water Injection, Dextrose and Lactated
Ringers Injection.
[1335] Examples of nonaqueous parenteral vehicles that may
optionally be used include fixed oils of vegetable origin,
cottonseed oil, corn oil, sesame oil and peanut oil.
[1336] Antimicrobial agents in bacteriostatic or fungistatic
concentrations may be added to parenteral preparations,
particularly when the preparations are packaged in multiple-dose
containers and thus designed to be stored and multiple aliquots to
be removed. Examples of antimicrobial agents that may be used
include phenols or cresols, mercurials, benzyl alcohol,
chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,
thimerosal, benzalkonium chloride and benzethonium chloride.
[1337] Examples of isotonic agents that may be used include sodium
chloride and dextrose. Examples of buffers that may be used include
phosphate and citrate. Examples of antioxidants that may be used
include sodium bisulfate. Examples of local anesthetics that may be
used include procaine hydrochloride. Examples of suspending and
dispersing agents that may be used include sodium
carboxymethylcellulose, hydroxypropyl methylcellulose and
polyvinylpyrrolidone. Examples of emulsifying agents that may be
used include Polysorbate 80 (TWEEN 80). A sequestering or chelating
agent of metal ions include EDTA.
[1338] Pharmaceutical carriers may also optionally include ethyl
alcohol, polyethylene glycol and propylene glycol for water
miscible vehicles and sodium hydroxide, hydrochloric acid, citric
acid or lactic acid for pH adjustment.
[1339] The concentration of a kinase inhibitor in the parenteral
formulation may be adjusted so that an injection administers a
pharmaceutically effective amount sufficient to produce the desired
pharmacological effect. The exact concentration of a kinase
inhibitor and/or dosage to be used will ultimately depend on the
age, weight and condition of the patient or animal as is known in
the art.
[1340] Unit-dose parenteral preparations may be packaged in an
ampoule, a vial or a syringe with a needle. All preparations for
parenteral administration should be sterile, as is know and
practiced in the art.
[1341] Injectables may be designed for local and systemic
administration. Typically a therapeutically effective dosage is
formulated to contain a concentration of at least about 0.1% w/w up
to about 90% w/w or more, preferably more than 1% w/w of the kinase
inhibitor to the treated tissue(s). The kinase inhibitor may be
administered at once, or may be divided into a number of smaller
doses to be administered at intervals of time. It is understood
that the precise dosage and duration of treatment will be a
function of the location of where the composition is parenterally
administered, the carrier and other variables that may be
determined empirically using known testing protocols or by
extrapolation from in vivo or in vitro test data. It is to be noted
that concentrations and dosage values may also vary with the age of
the individual treated. It is to be further understood that for any
particular subject, specific dosage regimens may need to be
adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the formulations. Hence, the concentration
ranges set forth herein are intended to be exemplary and are not
intended to limit the scope or practice of the claimed
formulations.
[1342] The kinase inhibitor may optionally be suspended in
micronized or other suitable form or may be derivatized to produce
a more soluble active product or to produce a prodrug. The form of
the resulting mixture depends upon a number of factors, including
the intended mode of administration and the solubility of the
compound in the selected carrier or vehicle. The effective
concentration is sufficient for ameliorating the symptoms of the
disease state and may be empirically determined.
[1343] Lyophilized Powders
[1344] The kinase inhibitors of the present invention may also be
prepared as lyophilized powders, which can be reconstituted for
administration as solutions, emulsions and other mixtures. The
lyophilized powders may also be formulated as solids or gels.
[1345] Sterile, lyophilized powder may be prepared by dissolving
the compound in a sodium phosphate buffer solution containing
dextrose or other suitable excipient. Subsequent sterile filtration
of the solution followed by lyophilization under standard
conditions known to those of skill in the art provides the desired
formulation. Briefly, the lyophilized powder may optionally be
prepared by dissolving dextrose, sorbitol, fructose, corn syrup,
xylitol, glycerin, glucose, sucrose or other suitable agent, about
1-20%, preferably about 5 to 15%, in a suitable buffer, such as
citrate, sodium or potassium phosphate or other such buffer known
to those of skill in the art at, typically, about neutral pH. Then,
a kinase inhibitor is added to the resulting mixture, preferably
above room temperature, more preferably at about 30-35.degree. C.,
and stirred until it dissolves. The resulting mixture is diluted by
adding more buffer to a desired concentration. The resulting
mixture is sterile filtered or treated to remove particulates and
to insure sterility, and apportioned into vials for lyophilization.
Each vial may contain a single dosage or multiple dosages of the
kinase inhibitor.
Topical Administration
[1346] The kinase inhibitors of the present invention may also be
administered as topical mixtures. Topical mixtures may be used for
local and systemic administration. The resulting mixture may be a
solution, suspension, emulsions or the like and are formulated as
creams, gels, ointments, emulsions, solutions, elixirs, lotions,
suspensions, tinctures, pastes, foams, aerosols, irrigations,
sprays, suppositories, bandages, dermal patches or any other
formulations suitable for topical administration.
[1347] The kinase inhibitors may be formulated as aerosols for
topical application, such as by inhalation (see, U.S. Pat. Nos.
4,044,126, 4,414,209, and 4,364,923, which describe aerosols for
delivery of a steroid useful for treatment inflammatory diseases,
particularly asthma). These formulations for administration to the
respiratory tract can be in the form of an aerosol or solution for
a nebulizer, or as a microfine powder for insufflation, alone or in
combination with an inert carrier such as lactose. In such a case,
the particles of the formulation will typically have diameters of
less than 50 microns, preferably less than 10 microns.
[1348] The kinase inhibitors may also be formulated for local or
topical application, such as for topical application to the skin
and mucous membranes, such as in the eye, in the form of gels,
creams, and lotions and for application to the eye or for
intracisternal or intraspinal application. Topical administration
is contemplated for transdermal delivery and also for
administration to the eyes or mucosa, or for inhalation therapies.
Nasal solutions of the kinase inhibitor alone or in combination
with other pharmaceutically acceptable excipients can also be
administered.
Formulations for Other Routes of Administrations
[1349] Depending upon the disease state being treated, other routes
of administration, such as topical application, transdermal
patches, and rectal administration, may also be used. For example,
pharmaceutical dosage forms for rectal administration are rectal
suppositories, capsules and tablets for systemic effect. Rectal
suppositories are used herein mean solid bodies for insertion into
the rectum that melt or soften at body temperature releasing one or
more pharmacologically or therapeutically active ingredients.
Pharmaceutically acceptable substances utilized in rectal
suppositories are bases or vehicles and agents to raise the melting
point. Examples of bases include cocoa butter (theobroma oil),
glycerin-gelatin, carbowax, (polyoxyethylene glycol) and
appropriate mixtures of mono-, di- and triglycerides of fatty
acids. Combinations of the various bases may be used. Agents to
raise the melting point of suppositories include spermaceti and
wax. Rectal suppositories may be prepared either by the compressed
method or by molding. The typical weight of a rectal suppository is
about 2 to 3 gm. Tablets and capsules for rectal administration may
be manufactured using the same pharmaceutically acceptable
substance and by the same methods as for formulations for oral
administration.
Examples of Formulations
[1350] The following are particular examples of oral, intravenous
and tablet formulations that may optionally be used with compounds
of the present invention. It is noted that these formulations may
be varied depending on the particular compound being used and the
indication for which the formulation is going to be used.
Oral Formulation
TABLE-US-00001 [1351] Compound of the Present Invention 10-100 mg
Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring
Water q.s. to 100 mL
Intravenous Formulation
TABLE-US-00002 [1352] Compound of the Present Invention 0.1-10 mg
Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate
1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0
mL
Tablet Formulation
TABLE-US-00003 [1353] Compound of the Present Invention 1%
Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica
.sup. 1%.
Kits Comprising Kinase Inhibitors
[1354] The invention is also directed to kits and other articles of
manufacture for treating diseases associated with kinases. It is
noted that diseases are intended to cover all conditions for which
the kinases possesses activity that contributes to the pathology
and/or symptomology of the condition.
[1355] In one embodiment, a kit is provided that comprises a
composition comprising at least one kinase inhibitor of the present
invention in combination with instructions. The instructions may
indicate the disease state for which the composition is to be
administered, storage information, dosing information and/or
instructions regarding how to administer the composition. The kit
may also comprise packaging materials. The packaging material may
comprise a container for housing the composition. The kit may also
optionally comprise additional components, such as syringes for
administration of the composition. The kit may comprise the
composition in single or multiple dose forms.
[1356] The invention also provided are kits and other articles of
manufacture comprising a composition that comprises one or more
compounds of the present invention, wherein the one or more
compounds of the present invention are present as a single
crystalline or amorphous form. In one variation, the composition
comprises at least 0.1%, 0.25%, 0.5%, 1%, 5%, 10%, 25%, 50%, 75%,
80%, 85%, 90%, 95%, 97%, or 99% of the one or more compounds of the
present invention where greater than 0.1%, 1%, 5%, 10%, 25%, 50%,
75%, 80%, 85%, 90%, 95%, 97% or 99% of the one or more compounds of
the present invention (by weight) is present in the composition as
a single crystalline or amorphous form. The composition in the kits
and articles of manufacture may optionally be a pharmaceutical
composition. The pharmaceutical composition may optionally further
include one or more pharmaceutical carriers. In regard to each of
the above embodiments including a pharmaceutical composition, the
pharmaceutical composition may optionally be formulated such that a
portion of the one or more compounds of the present invention is
present as a single crystalline or amorphous form for a period of
time subsequent to administration of the pharmaceutical formulation
to a human.
[1357] In another embodiment, an article of manufacture is provided
that comprises a composition comprising at least one kinase
inhibitor of the present invention in combination with packaging
materials. The packaging material may comprise a container for
housing the composition. The container may optionally comprise a
label indicating the disease state for which the composition is to
be administered, storage information, dosing information and/or
instructions regarding how to administer the composition. The kit
may also optionally comprise additional components, such as
syringes for administration of the composition. The kit may
comprise the composition in single or multiple dose forms.
[1358] It is noted that the packaging material used in kits and
articles of manufacture according to the present invention may form
a plurality of divided containers such as a divided bottle or a
divided foil packet. The container can be in any conventional shape
or form as known in the art which is made of a pharmaceutically
acceptable material, for example a paper or cardboard box, a glass
or plastic bottle or jar, a re-sealable bag (for example, to hold a
"refill" of tablets for placement into a different container), or a
blister pack with individual doses for pressing out of the pack
according to a therapeutic schedule. The container that is employed
will depend on the exact dosage form involved, for example a
conventional cardboard box would not generally be used to hold a
liquid suspension. It is feasible that more than one container can
be used together in a single package to market a single dosage
form. For example, tablets may be contained in a bottle that is in
turn contained within a box. Typically the kit includes directions
for the administration of the separate components. The kit form is
particularly advantageous when the separate components are
preferably administered in different dosage forms (e.g., oral,
topical, transdermal and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing physician.
[1359] One particular example of a kit according to the present
invention is a so-called blister pack. Blister packs are well known
in the packaging industry and are being widely used for the
packaging of pharmaceutical unit dosage forms (tablets, capsules,
and the like). Blister packs generally consist of a sheet of
relatively stiff material covered with a foil of a preferably
transparent plastic material. During the packaging process recesses
are formed in the plastic foil. The recesses have the size and
shape of individual tablets or capsules to be packed or may have
the size and shape to accommodate multiple tablets and/or capsules
to be packed. Next, the tablets or capsules are placed in the
recesses accordingly and the sheet of relatively stiff material is
sealed against the plastic foil at the face of the foil which is
opposite from the direction in which the recesses were formed. As a
result, the tablets or capsules are individually sealed or
collectively sealed, as desired, in the recesses between the
plastic foil and the sheet. Preferably the strength of the sheet is
such that the tablets or capsules can be removed from the blister
pack by manually applying pressure on the recesses whereby an
opening is formed in the sheet at the place of the recess. The
tablet or capsule can then be removed via said opening.
[1360] Another specific embodiment of a kit is a dispenser designed
to dispense the daily doses one at a time in the order of their
intended use. Preferably, the dispenser is equipped with a
memory-aid, so as to further facilitate compliance with the
regimen. An example of such a memory-aid is a mechanical counter
that indicates the number of daily doses that has been dispensed.
Another example of such a memory-aid is a battery-powered
micro-chip memory coupled with a liquid crystal readout, or audible
reminder signal which, for example, reads out the date that the
last daily dose has been taken and/or reminds one when the next
dose is to be taken.
Dosage, Host and Safety
[1361] The compounds of the present invention are stable and can be
used safely. In particular, the compounds of the present invention
are useful as kinase inhibitors for a variety of subjects (e.g.,
humans, non-human mammals and non-mammals). The optimal dose may
vary depending upon such conditions as, for example, the type of
subject, the body weight of the subject, the route of
administration, and specific properties of the particular compound
being used. In general, the daily dose for oral administration to
an adult (body weight of about 60 kg) is about 1 to 1000 mg, about
3 to 300 mg, about 10 to 200 mg, about 100 to 500 mg, about 150 to
450 mg, about 200 to 400 mg, or about 200 to 300 mg. It will be
appreciated that the daily dose can be given in a single
administration or in multiple (e.g., 2 or 3) portions a day.
Combination Therapies
[1362] A wide variety therapeutic agents may have a therapeutic
additive or synergistic effect with kinase inhibitors according to
the present invention. Combination therapies that comprise one or
more compounds of the present invention with one or more other
therapeutic agents can be used, for example, to: 1) enhance the
therapeutic effect(s) of the one or more compounds of the present
invention and/or the one or more other therapeutic agents; 2)
reduce the side effects exhibited by the one or more compounds of
the present invention and/or the one or more other therapeutic
agents; and/or 3) reduce the effective dose of the one or more
compounds of the present invention and/or the one or more other
therapeutic agents. For example, such therapeutic agents may
additively or synergistically combine with the kinase inhibitors to
inhibit undesirable cell growth, such as inappropriate cell growth
resulting in undesirable benign conditions or tumor growth.
[1363] In one embodiment, a method is provided for treating a cell
proliferative disease state comprising treating cells with a
compound according to the present invention in combination with an
anti-proliferative agent, wherein the cells are treated with the
compound according to the present invention before, at the same
time, and/or after the cells are treated with the
anti-proliferative agent, referred to herein as combination
therapy. It is noted that treatment of one agent before another is
referred to herein as sequential therapy, even if the agents are
also administered together. It is noted that combination therapy is
intended to cover when agents are administered before or after each
other (sequential therapy) as well as when the agents are
administered at the same time.
[1364] Examples of therapeutic agents that may be used in
combination with kinase inhibitors include, but are not limited to,
anticancer agents, alkylating agents, antibiotic agents,
antimetabolic agents, hormonal agents, plant-derived agents, and
biologic agents.
[1365] Alkylating agents are polyfunctional compounds that have the
ability to substitute alkyl groups for hydrogen ions. Examples of
alkylating agents include, but are not limited to,
bischloroethylamines (nitrogen mustards, e.g. chlorambucil,
cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil
mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g.
busulfan), nitrosoureas (e.g. carmustine, lomustine, streptozocin),
nonclassic alkylating agents (altretamine, dacarbazine, and
procarbazine), platinum compounds (carboplastin and cisplatin).
These compounds react with phosphate, amino, hydroxyl, sulfihydryl,
carboxyl, and imidazole groups. Under physiological conditions,
these drugs ionize and produce positively charged ion that attach
to susceptible nucleic acids and proteins, leading to cell cycle
arrest and/or cell death. Combination therapy including a kinase
inhibitor and an alkylating agent may have therapeutic synergistic
effects on cancer and reduce sides affects associated with these
chemotherapeutic agents.
[1366] Antibiotic agents are a group of drugs that produced in a
manner similar to antibiotics as a modification of natural
products. Examples of antibiotic agents include, but are not
limited to, anthracyclines (e.g. doxorubicin, daunorubicin,
epirubicin, idarubicin and anthracenedione), mitomycin C,
bleomycin, dactinomycin, plicatomycin. These antibiotic agents
interfere with cell growth by targeting different cellular
components. For example, anthracyclines are generally believed to
interfere with the action of DNA topoisomerase II in the regions of
transcriptionally active DNA, which leads to DNA strand scissions.
Bleomycin is generally believed to chelate iron and forms an
activated complex, which then binds to bases of DNA, causing strand
scissions and cell death. Combination therapy including a kinase
inhibitor and an antibiotic agent may have therapeutic synergistic
effects on cancer and reduce sides affects associated with these
chemotherapeutic agents.
[1367] Antimetabolic agents are a group of drugs that interfere
with metabolic processes vital to the physiology and proliferation
of cancer cells. Actively proliferating cancer cells require
continuous synthesis of large quantities of nucleic acids,
proteins, lipids, and other vital cellular constituents. Many of
the antimetabolites inhibit the synthesis of purine or pyrimidine
nucleosides or inhibit the enzymes of DNA replication. Some
antimetabolites also interfere with the synthesis of
ribonucleosides and RNA and/or amino acid metabolism and protein
synthesis as well. By interfering with the synthesis of vital
cellular constituents, antimetabolites can delay or arrest the
growth of cancer cells. Examples of antimetabolic agents include,
but are not limited to, fluorouracil (5-FU), floxuridine (5-FUdR),
methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),
mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine
phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
Combination therapy including a kinase inhibitor and a
antimetabolic agent may have therapeutic synergistic effects on
cancer and reduce sides affects associated with these
chemotherapeutic agents.
[1368] Hormonal agents are a group of drug that regulate the growth
and development of their target organs. Most of the hormonal agents
are sex steroids and their derivatives and analogs thereof, such as
estrogens, androgens, and progestins. These hormonal agents may
serve as antagonists of receptors for the sex steroids to down
regulate receptor expression and transcription of vital genes.
Examples of such hormonal agents are synthetic estrogens (e.g.
diethylstibestrol), antiestrogens (e.g. tamoxifen, toremifene,
fluoxymesterol and raloxifene), antiandrogens (bicalutamide,
nilutamide, flutamide), aromatase inhibitors (e.g.,
aminoglutethimide, anastrozole and tetrazole), ketoconazole,
goserelin acetate, leuprolide, megestrol acetate and mifepristone.
Combination therapy including a kinase inhibitor and a hormonal
agent may have therapeutic synergistic effects on cancer and reduce
sides affects associated with these chemotherapeutic agents.
[1369] Plant-derived agents are a group of drugs that are derived
from plants or modified based on the molecular structure of the
agents. Examples of plant-derived agents include, but are not
limited to, vinca alkaloids (e.g., vincristine, vinblastine,
vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g.,
etoposide (VP-16) and teniposide (VM-26)), taxanes (e.g.,
paclitaxel and docetaxel). These plant-derived agents generally act
as antimitotic agents that bind to tubulin and inhibit mitosis.
Podophyllotoxins such as etoposide are believed to interfere with
DNA synthesis by interacting with topoisomerase II, leading to DNA
strand scission. Combination therapy including a kinase inhibitor
and a plant-derived agent may have therapeutic synergistic effects
on cancer and reduce sides affects associated with these
chemotherapeutic agents.
[1370] Biologic agents are a group of biomolecules that elicit
cancer/tumor regression when used alone or in combination with
chemotherapy and/or radiotherapy. Examples of biologic agents
include, but are not limited to, immuno-modulating proteins such as
cytokines, monoclonal antibodies against tumor antigens, tumor
suppressor genes, and cancer vaccines. Combination therapy
including a kinase inhibitor and a biologic agent may have
therapeutic synergistic effects on cancer, enhance the patient's
immune responses to tumorigenic signals, and reduce potential sides
affects associated with this chemotherapeutic agent.
[1371] Cytokines possess profound immunomodulatory activity. Some
cytokines such as interleukin-2 (IL-2, aldesleukin) and interferon
have demonstrated antitumor activity and have been approved for the
treatment of patients with metastatic renal cell carcinoma and
metastatic malignant melanoma. IL-2 is a T-cell growth factor that
is central to T-cell-mediated immune responses. The selective
antitumor effects of IL-2 on some patients are believed to be the
result of a cell-mediated immune response that discriminate between
self and nonself. Examples of interleukins that may be used in
conjunction with kinase inhibitor include, but are not limited to,
interleukin 2 (IL-2), and interleukin 4 (IL-4), interleukin 12
(IL-12).
[1372] Interferon include more than 23 related subtypes with
overlapping activities, all of the IFN subtypes within the scope of
the present invention. IFN has demonstrated activity against many
solid and hematologic malignancies, the later appearing to be
particularly sensitive.
[1373] Other cytokines that may be used in conjunction with a
kinase inhibitor include those cytokines that exert profound
effects on hematopoiesis and immune functions. Examples of such
cytokines include, but are not limited to erythropoietin,
granulocyte-CSF (filgrastin), and granulocyte, macrophage-CSF
(sargramostim). These cytokines may be used in conjunction with a
kinase inhibitor to reduce chemotherapy-induced myelopoietic
toxicity.
[1374] Other immuno-modulating agents other than cytokines may also
be used in conjunction with a kinase inhibitor to inhibit abnormal
cell growth. Examples of such immuno-modulating agents include, but
are not limited to bacillus Calmette-Guerin, levamisole, and
octreotide, a long-acting octapeptide that mimics the effects of
the naturally occurring hormone somatostatin.
[1375] Monoclonal antibodies against tumor antigens are antibodies
elicited against antigens expressed by tumors, preferably
tumor-specific antigens. For example, monoclonal antibody
HERCEPTIN.RTM. (Trastruzumab) is raised against human epidermal
growth factor receptor2 (HER2) that is overexpressed in some breast
tumors including metastatic breast cancer. Overexpression of HER2
protein is associated with more aggressive disease and poorer
prognosis in the clinic. HERCEPTIN.RTM. is used as a single agent
for the treatment of patients with metastatic breast cancer whose
tumors over express the HER2 protein. Combination therapy including
kinase inhibitor and HERCEPTIN.RTM. may have therapeutic
synergistic effects on tumors, especially on metastatic
cancers.
[1376] Another example of monoclonal antibodies against tumor
antigens is RITUXAN.RTM. (Rituximab) that is raised against CD20 on
lymphoma cells and selectively deplete normal and malignant
CD20.sup.+ pre-B and mature B cells. RITUXAN.RTM. is used as single
agent for the treatment of patients with relapsed or refractory
low-grade or follicular, CD20+, B cell non-Hodgkin's lymphoma.
Combination therapy including kinase inhibitor and RITUXAN.RTM. may
have therapeutic synergistic effects not only on lymphoma, but also
on other forms or types of malignant tumors.
[1377] Tumor suppressor genes are genes that function to inhibit
the cell growth and division cycles, thus preventing the
development of neoplasia. Mutations in tumor suppressor genes cause
the cell to ignore one or more of the components of the network of
inhibitory signals, overcoming the cell cycle check points and
resulting in a higher rate of controlled cell growth--cancer.
Examples of the tumor suppressor genes include, but are not limited
to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1 and BRCA2.
[1378] DPC-4 is involved in pancreatic cancer and participates in a
cytoplasmic pathway that inhibits cell division. NF-1 codes for a
protein that inhibits Ras, a cytoplasmic inhibitory protein. NF-1
is involved in neurofibroma and pheochromocytomas of the nervous
system and myeloid leukemia. NF-2 encodes a nuclear protein that is
involved in meningioma, schwanoma, and ependymoma of the nervous
system. RB codes for the pRB protein, a nuclear protein that is a
major inhibitor of cell cycle. RB is involved in retinoblastoma as
well as bone, bladder, small cell lung and breast cancer. P53 codes
for p53 protein that regulates cell division and can induce
apoptosis. Mutation and/or inaction of p53 is found in a wide
ranges of cancers. WT1 is involved in Wilms tumor of the kidneys.
BRCA1 is involved in breast and ovarian cancer, and BRCA2 is
involved in breast cancer. The tumor suppressor gene can be
transferred into the tumor cells where it exerts its tumor
suppressing functions. Combination therapy including a kinase
inhibitor and a tumor suppressor may have therapeutic synergistic
effects on patients suffering from various forms of cancers.
[1379] Cancer vaccines are a group of agents that induce the body's
specific immune response to tumors. Most of cancer vaccines under
research and development and clinical trials are tumor-associated
antigens (TAAs). TAA are structures (i.e. proteins, enzymes or
carbohydrates) which are present on tumor cells and relatively
absent or diminished on normal cells. By virtue of being fairly
unique to the tumor cell, TAAs provide targets for the immune
system to recognize and cause their destruction. Example of TAAs
include, but are not limited to gangliosides (GM2), prostate
specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic
antigen (CEA) (produced by colon cancers and other adenocarcinomas,
e.g. breast, lung, gastric, and pancreas cancers), melanoma
associated antigens (MART-1, gp100, MAGE 1,3 tyrosinase),
papillomavirus E6 and E7 fragments, whole cells or portions/lysates
of antologous tumor cells and allogeneic tumor cells.
[1380] An adjuvant may be used to augment the immune response to
TAAs. Examples of adjuvants include, but are not limited to,
bacillus Calmette-Guerin (BCG), endotoxin lipopolysaccharides,
keyhole limpet hemocyanin (GKLH), interleukin-2 (IL-2),
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
cytoxan, a chemotherapeutic agent which is believe to reduce
tumor-induced suppression when given in low doses.
EXAMPLES
1. Preparation of Kinase Inhibitors
[1381] Various methods may be developed for synthesizing compounds
according to the present invention. Representative methods for
synthesizing these compounds are provided in the Examples. It is
noted, however, that the compounds of the present invention may
also be synthesized by other synthetic routes that others may
devise.
[1382] It will be readily recognized that certain compounds
according to the present invention have atoms with linkages to
other atoms that confer a particular stereochemistry to the
compound (e.g., chiral centers). It is recognized that synthesis of
compounds according to the present invention may result in the
creation of mixtures of different stereoisomers (enantiomers,
diastereomers). Unless a particular stereochemistry is specified,
recitation of a compound is intended to encompass all of the
different possible stereoisomers.
[1383] Various methods for separating mixtures of different
stereoisomers are known in the art. For example, a racemic mixture
of a compound may be reacted with an optically active resolving
agent to form a pair of diastereoisomeric compounds. The
diastereomers may then be separated in order to recover the
optically pure enantiomers. Dissociable complexes may also be used
to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
Diastereomers typically have sufficiently distinct physical
properties (e.g., melting points, boiling points, solubilities,
reactivity, etc.) that they can be readily separated by taking
advantage of these dissimilarities. For example, diastereomers can
typically be separated by chromatography or by
separation/resolution techniques based upon differences in
solubility. A more detailed description of techniques that can be
used to resolve stereoisomers of compounds from their racemic
mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,
Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc.
(1981).
[1384] Compounds according to the present invention can also be
prepared as a pharmaceutically acceptable acid addition salt by
reacting the free base form of the compound with a pharmaceutically
acceptable inorganic or organic acid. Alternatively, a
pharmaceutically acceptable base addition salt of a compound can be
prepared by reacting the free acid form of the compound with a
pharmaceutically acceptable inorganic or organic base. Inorganic
and organic acids and bases suitable for the preparation of the
pharmaceutically acceptable salts of compounds are set forth in the
definitions section of this application. Alternatively, the salt
forms of the compounds can be prepared using salts of the starting
materials or intermediates.
[1385] The free acid or free base forms of the compounds can be
prepared from the corresponding base addition salt or acid addition
salt form. For example, a compound in an acid addition salt form
can be converted to the corresponding free base by treating with a
suitable base (e.g., ammonium hydroxide solution, sodium hydroxide,
and the like). A compound in a base addition salt form can be
converted to the corresponding free acid by treating with a
suitable acid (e.g., hydrochloric acid, etc).
[1386] The N-oxides of compounds according to the present invention
can be prepared by methods known to those of ordinary skill in the
art. For example, N-oxides can be prepared by treating an
unoxidized form of the compound with an oxidizing agent (e.g.,
trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic
acid, meta-chloroperoxybenzoic acid, or the like) in a suitable
inert organic solvent (e.g., a halogenated hydrocarbon such as
dichloromethane) at approximately 0.degree. C. Alternatively, the
N-oxides of the compounds can be prepared from the N-oxide of an
appropriate starting material.
[1387] Compounds in an unoxidized form can be prepared from
N-oxides of compounds by treating with a reducing agent (e.g.,
sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,
sodium borohydride, phosphorus trichloride, tribromide, or the
like) in an suitable inert organic solvent (e.g., acetonitrile,
ethanol, aqueous dioxane, or the like) at 0 to 80.degree. C.
[1388] Prodrug derivatives of the compounds can be prepared by
methods known to those of ordinary skill in the art (e.g., for
further details see Saulnier et al. (1994), Bioorganic and
Medicinal Chemistry Letters, Vol. 4, p. 1985). For example,
appropriate prodrugs can be prepared by reacting a non-derivatized
compound with a suitable carbamylating agent (e.g.,
1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or
the like).
[1389] Protected derivatives of the compounds can be made by
methods known to those of ordinary skill in the art. A detailed
description of the techniques applicable to the creation of
protecting groups and their removal can be found in T. W. Greene,
Protecting Groups in Organic Synthesis, 3.sup.rd edition, John
Wiley & Sons, Inc. 1999.
[1390] Compounds according to the present invention may be
conveniently prepared, or formed during the process of the
invention, as solvates (e.g. hydrates). Hydrates of compounds of
the present invention may be conveniently prepared by
recrystallization from an aqueous/organic solvent mixture, using
organic solvents such as dioxin, tetrahydrofuran or methanol.
[1391] Compounds according to the present invention can also be
prepared as their individual stereoisomers by reacting a racemic
mixture of the compound with an optically active resolving agent to
form a pair of diastereoisomeric compounds, separating the
diastereomers and recovering the optically pure enantiomer. While
resolution of enantiomers can be carried out using covalent
diastereomeric derivatives of compounds, dissociable complexes are
preferred (e.g., crystalline diastereoisomeric salts).
Diastereomers have distinct physical properties (e.g., melting
points, boiling points, solubilities, reactivity, etc.) and can be
readily separated by taking advantage of these dissimilarities. The
diastereomers can be separated by chromatography or, preferably, by
separation/resolution techniques based upon differences in
solubility. The optically pure enantiomer is then recovered, along
with the resolving agent, by any practical means that would not
result in racemization. A more detailed description of the
techniques applicable to the resolution of stereoisomers of
compounds from their racemic mixture can be found in Jean Jacques
Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and
Resolutions, John Wiley & Sons, Inc. (1981).
[1392] As used herein the symbols and conventions used in these
processes, schemes and examples are consistent with those used in
the contemporary scientific literature, for example, the Journal of
the American Chemical Society or the Journal of Biological
Chemistry. Standard single-letter or three-letter abbreviations are
generally used to designate amino acid residues, which are assumed
to be in the L-configuration unless otherwise noted. Unless
otherwise noted, all starting materials were obtained from
commercial suppliers and used without further purification.
Specifically, the following abbreviations may be used in the
examples and throughout the specification:
TABLE-US-00004 g (grams); mg (milligrams); L (liters); mL
(milliliters); .mu.L (microliters); psi (pounds per square inch); M
(molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz
(megahertz); mol (moles); mmol (millimoles); RT (ambient
temperature); min (minutes); h (hours); mp (melting point); TLC
(thin layer chromatography); Tr (retention time); RP (reverse
phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine);
TFA (trifluoroacetic acid); TFAA (trifluoroacetic THF
(tetrahydrofuran); anhydride); DMSO (dimethylsulfoxide); EtOAc
(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane);
DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N'- CDI
(1,1-carbonyldiimidazole); dimethylpropyleneurea); IBCF (isobutyl
chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide);
HOBT (1-hydroxybenzotriazole); Et.sub.2O (diethyl ether); EDCI
(ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl);
FMOC (9-fluorenylmethoxy- carbonyl); DCC
(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl);
atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS
(trimethylsilyl); TIPS (triisopropylsilyl); TBS
(t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me
(methyl); OMe (methoxy); Et (ethyl); Et (ethyl); tBu (tert-butyl);
HPLC (high pressure liquid chromatography); BOP
(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF
(tetra-n-butylammonium fluoride); mCPBA (meta-chloroperbenzoic
acid.
[1393] All references to ether or Et.sub.2O are to diethyl ether;
brine refers to a saturated aqueous solution of NaCl. Unless
otherwise indicated, all temperatures are expressed in .degree. C.
(degrees Centigrade). All reactions conducted under an inert
atmosphere at RT unless otherwise noted.
[1394] .sup.1H NMR spectra were recorded on a Bruker Avance 400.
Chemical shifts are expressed in parts per million (ppm). Coupling
constants are in units of Hertz (Hz). Splitting patterns describe
apparent multiplicities and are designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), br (broad).
[1395] Low-resolution mass spectra (MS) and compound purity data
were acquired on a Waters ZQ LC/MS single quadrupole system
equipped with electrospray ionization (ESI) source, UV detector
(220 and 254 nm), and evaporative light scattering detector (ELSD).
Thin-layer chromatography was performed on 0.25 mm E. Merck silica
gel plates (60E-254), visualized with UV light, 5% ethanolic
phosphomolybdic acid, Ninhydrin or p-anisaldehyde solution. Flash
column chromatography was performed on silica gel (230-400 mesh,
Merck).
[1396] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance,
Calif.), Sigma (St. Louis, Mo.), or may be prepared by methods well
known to a person of ordinary skill in the art, following
procedures described in such standard references as Fieser and
Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and
Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds,
vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic
Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991;
March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons,
New York, N.Y.; and Larock: Comprehensive Organic Transformations,
VCH Publishers, New York, 1989.
[1397] The entire disclosure of all documents cited throughout this
application are incorporated herein by reference.
2. Synthetic Schemes for Kinase Inhibitors of the Present
Invention
[1398] Kinase inhibitors according to the present invention may be
synthesized according to the reaction scheme shown below. Other
reaction schemes could be readily devised by those skilled in the
art. It should also be appreciated that a variety of different
solvents, temperatures and other reaction conditions can be varied
to optimize the yields of the reactions.
[1399] In the reactions described hereinafter it may be necessary
to protect reactive functional groups, for example hydroxy, amino,
imino, thio or carboxy groups, where these are desired in the final
product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with
standard practice, for examples see T. W. Greene and P. G. M. Wuts
in "Protective Groups in Organic Chemistry" John Wiley and Sons,
1991.
Experimental Methods
[1400] General synthetic routes for producing compounds of the
present invention are shown in Schemes 1-8.
##STR00147##
[1401] Referring to Scheme 1, Compound A and Compound B are mixed
and treated under a variety of conditions to form Compound C. For
example, the mixture of Compound A and Compound B can be subjected
to microwave irradiation, either neat or in an appropriate solvent,
at temperatures ranging from 80.degree. C. to 200.degree. C. The
nitro group in Compound C is reduced by, for example, catalytic
hydrogenation or metal reductions (e.g., with SnCl.sub.2) to form
Compound D. Compound D is converted to Compound E using NaNO.sub.2
under suitable conditions (e.g., in AcOH). Compound E is treated
with an acid (e.g., o-phosphoric acid) or under flash vacuum at
150.degree. C. to 350.degree. C. to obtain Compound F. If X.sub.1
in Compound F is halo, Compound F can be further converted to
Compound G either by treating with alcohol, amine, thiol or by
Suzuki type coupling.
##STR00148## ##STR00149##
[1402] Referring to Scheme 2, Compound H is reacted with Compound I
using Sonogashira type coupling to give Compound J. Compound J is
reacted with ethynyltrimethylsilane under suitable conditions
(e.g., Pd mediated in the presence or absence of a base) to provide
Compound K. Compound K is transformed to Compound L under
Diels-Alder reaction conditions (e.g., heating to a temperature
between 100.degree. C. and 200.degree. C.). The TMS group in
Compound L is converted to a halo group to yield Compound M.
Compound M is further converted to Compound N either by treating
with alcohol, amine or thiol, or by Suzuki type coupling.
Deprotection of Compound N provides Compound O. Compound O is
treated with PDX.sub.3 to obtain Compound P. Compound P is further
converted to Compound Q either by treating with alcohol, amine or
thiol, or by Suzuki type coupling.
##STR00150## ##STR00151##
[1403] Referring to Scheme 3, Ullmann coupling of Compound R with
Compound S provides Compound T. The nitro group in Compound T is
reduced (e.g., by catalytic hydrogenation or metal reductions such
as with Fe) to form Compound U. Compound U is cyclized to form
Compound V. Compound V subjected to Sandmeyer reaction conditions
to provide Compound W. Compound W is further converted to Compound
X either by treating with alcohol, amine or thiol, or by Suzuki
type coupling. The cyano group of Compound X is hydrolyzed by
treating Compound X with a base (e.g., KOH) to obtain Compound
Y.
##STR00152## ##STR00153##
[1404] Referring to Scheme 4, Ullmann coupling of Compound R with
Compound Z provides Compound AA. Compound AA is further converted
to Compound AB either by treating with alcohol, amine or thiol, or
by Suzuki type coupling. The nitro group in Compound AB is reduced
(e.g., by catalytic hydrogenation or metal reductions such as with
Fe) to form Compound AC. Compound AC is cyclized to form Compound
AD. Compound AD is treated with acid to provide Compound AE.
Peptide coupling of Compound AE with a suitable amine provides
Compound AF.
##STR00154##
[1405] Referring to Scheme 5, Suzuki type coupling of Compound R
with a boronic acid (Compound AG) under Pd mediated conditions
(e.g., Pd(PPh.sub.3).sub.4 in presence of base such as
Na.sub.2CO.sub.3 in a suitable solvent at temperatures ranging from
50.degree. C. to 200.degree. C.) provides Compound AH. Compound AH
is subjected to nitration conditions (e.g.,
HNO.sub.3/H.sub.2SO.sub.4) to obtain Compound AI. The nitro groups
in Compound AI are reduced (e.g., by catalytic hydrogenation or
metal reductions such as with Fe) to form Compound AJ. Compound AJ
is cyclized to form Compound AK. Compound AK is further converted
to Compound AL either by treating with alcohol, amine or thiol, or
by Suzuki type coupling. Compound AI can be converted to the
corresponding halo derivative (Compound AM with R.sub.1=halo) by
Sandmeyers reaction or to the corresponding amides (Compound AM
with R.sub.1=NHCOR.sub.28) by peptide coupling with suitable
acids.
##STR00155## ##STR00156##
[1406] Referring to Scheme 6, Ullmann coupling of Compound AN with
Compound AO provides Compound AP. Compound AP is further converted
to Compound AR by Suzuki type coupling. The nitro group in Compound
AR is reduced (e.g., by catalytic hydrogenation or metal reductions
such as with Fe) to form Compound AS. Compound AS is cyclized to
form Compound AT. Compound AT is hydrolyzed with acid to provide
Compound AU. Peptide coupling of Compound AU with suitable amines
like AV provides Compound AW.
##STR00157## ##STR00158##
[1407] Referring to Scheme 7, Compound AX is alkylated either by
Mitsunobu reaction or base mediated nucleophilic substitution
reaction with different alkyl halides to provide Compound AZ.
Buchwald reaction of aromatic amine BA with Compound AZ forms
Compound BB. Intramolecular Heck reaction is carried out on
Compound BB to provide Compound BC. By functional group
manipulation on Compound BC the protected hydroxyl group is
converted to a suitable leaving group in Compound BF via Compound
BD. Direct displacement of the leaving group in Compound BF by a
suitable amine BG provides Compound BH. Suzuki type coupling
reaction between Compound BH and Compound BI can be performed to
form Compound BJ.
##STR00159## ##STR00160##
[1408] Referring to Scheme 8, an aromatic nucleophilic substitution
on Compound BK with BL provides Compound BM. Via aromatic
electrophilic substitution reaction the aromatic ring can be
properly halogenated to get Compound BO. Buchwald reaction on
Compound BO with Compound BP provides Compound BO. The nitro groups
in Compound BQ is reduced (e.g., by catalytic hydrogenation or
metal reductions such as with Fe) to form Compound BR. Compound BR
is cyclized to form Compound BS. Compound BS can be converted to
the corresponding halo derivative (Compound BU with G.sub.11=halo)
by Sandmeyers reaction. Compound BU is further converted to
Compound BW either by treating with alcohol, amine or thiol, or by
Suzuki type coupling with Compound BV.
[1409] In each of the above reaction procedures or schemes, the
various substituents may be selected from among the various
substituents otherwise taught herein.
[1410] Descriptions of the syntheses of particular compounds
according to the present invention based on the above reaction
scheme are set forth herein.
3. Examples of Kinase Inhibitors
[1411] The present invention is further exemplified, but not
limited by, the following examples that describe the synthesis of
particular compounds according to the invention.
Compound 1: N-(3-bromophenyl)-3-nitropyridin-2-amine
##STR00161##
[1413] 2-Chloro-3-nitropyridine (2.0 g, 12.6 mmol, 1 eq) was
reacted with 5-bromoaniline (4.12 ml, 37.8 mmol, 3 eq) for 20
minutes at 180.degree. C. in a microwave reactor. The product was
isolated by column chromatography to provide the title compound as
a red solid (4.9 g). [M+H] calc'd for
C.sub.11H.sub.8BrN.sub.3O.sub.2, 293. found 293.
Compound 2: N2-(3-bromophenyl)pyridine-2,3-diamine
##STR00162##
[1415] Compound 1 (4.9 g, 16.6 mmol) was dissolved in ethanol (20
ml). Tin (II) Chloride dihydrate (7.5 g, 33.3 mmol) was added and
the solution stirred at 70.degree. C. for 4 hours to provide the
title compound. The product was confirmed by LC-MS. Addition of
excess triethylamine caused a solid to form. The solid was filtered
and the solution evaporated to leave an off white solid. The solid
as recrystallized from ethanol to provide the title compound (3.8
g, 86%). [M+H] calc'd for C.sub.11H.sub.10BrN.sub.3, 265. found
265.
Compound 3: 3-(3-bromophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine
##STR00163##
[1417] Compound 2 (3.8 g, 14.4 mmol) was dissolved in a mixture of
acetic acid (4 mL), water (4 mL) and methylene chloride (4 mL). The
mixture was cooled to 0.degree. C., then sodium nitrate (1.29 g,
18.7 mmol) was slowly added. Upon completion of the addition of
sodium nitrate, the mixture was brought to room temperature and
stirred for 20 minutes. The intended product was confirmed by
LC-MS. The reaction mixture was diluted with methylene chloride (30
mL) and washed with water (3.times.30 mL). The organic layer was
dried over magnesium sulfate and then evaporated to provide the
title compound (2.9 g, 73%). [M+H] calc'd for
C.sub.11H.sub.7BrN.sub.4, 274. found, 274.
Compound 4: 5-bromo-9H-pyrido[2,3-b]indole
##STR00164##
[1419] Compound 3 (2.8 g, 10.2 mmol) was dissolved in
ortho-phosphoric acid (40 mL). The mixture was heated to
150.degree. C. for 18 hours, and the intended product confirmed by
LC-MS. The mixture was cooled to 0.degree. C. and neutralized with
aqueous NaOH. The crude product was extracted with methylene
chloride and purified by Preparative HPLC to provide Compound 4
(180 mg, 9%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.16 (d,
J=7.8 Hz 1H) 8.48 (s, 1H) 7.62 (d, J=7.8 Hz 1H) 7.52 (d, J=6.8 Hz
1H) 7.44 (m, 2H). [M+H] calc'd for C.sub.17H.sub.12N.sub.2, 245.
found 245.
Compound 5: 5-phenyl-9H-pyrido[2,3-b]indole
##STR00165##
[1421] Compound 4 (20 mg, 0.081 mmol) was mixed with phenylboronic
acid (20 mg, 0.16 mmol) and Pd(PPh.sub.3).sub.4 (19 mg, 0.016 mmol)
in a solution comprising dioxane (3 mL) and a saturated
K.sub.2CO.sub.3 solution (1 mL). The mixture was heated in a
microwave reactor at 150.degree. C. for 20 minutes. Purification by
HPLC afforded the title compound as a tan solid (4 mg, 22%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.39 (s, 1H) 8.10 (d,
J=7.84 Hz, 1H) 7.67 (m, 2H) 7.60 (m, 5H) 7.27 (m, 2H). [M+H] calc'd
for C.sub.17H.sub.12N.sub.2, 245. found 245.
Compound 6: 5-bromo-8-methyl-9H-pyrido[2,3-b]indole
##STR00166##
[1423] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 4 except
that 5-bromo-2-methylaniline was used as the starting material.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.16 (d, J=7.8 Hz 1H)
8.48 (s, 1H) 7.62 (d, J=7.8 Hz 1H) 7.52 (d, J=6.8 Hz 1H) 7.44 (m,
2H) 2.27 (s, 3H). [M+H] calc'd for C.sub.17H.sub.12N.sub.2, 257.
found 257.
Compound 7: 5-bromo-3,8-dimethyl-9H-pyrido[2,3-b]indole
##STR00167##
[1425] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 4.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.48 (s, 3H) 2.52
(s, 3H) 7.18 (d, J=7.83 Hz, 1H) 7.31 (d, J=7.83 Hz, 1H) 8.37 (d,
J=2.02 Hz, 1H) 8.65 (d, J=1.77 Hz, 1H) 12.01 (s, 1H). [M+H] calc'd
for C.sub.13H.sub.11BrN.sub.2 275, 277. found, 275.2, 277.2.
Compound 8: 5-(3-(methylsulfonyl)phenyl)-9H-pyrido[2,3-b]indole
##STR00168##
[1427] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5 using
3-methylsulfonylphenylboronic acid. Yield=27%. .sup.1H NMR (400
MHz, DMSO) .delta. 8.40 (d, J=0.076 Hz, 1H) 8.15 (s, 1H) 8.08 (d,
J=8.56 Hz, 1H) 8.02 (d, J=7.6 Hz, 1H) 7.87 (t, 1H) 7.68 (d, J=6.04,
1H) 7.59 (m, 2 H) 7.19 (d, J=8.6 Hz, 1H) 7.03 (m, 1H) 3.32 (s, 3H).
[M+H] calc'd for C.sub.18H.sub.14N.sub.2O.sub.2S, 323. found,
323.
Compound 9: 5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indole
##STR00169##
[1429] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5 using
3-ethylsulfonylphenylboronic acid. Yield=48%. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.46 (s, 1H) 8.15 (s, 1H) 8.09 (t, 2H) 8.02 (d,
J=7.84 Hz, 1H) 7.88 (t, 1H) 7.74 (m, 2H) 7.35 (m, 2H) 3.30 (s, 2H)
1.28 (m, 3H). [M+H] calc'd for C.sub.19H.sub.16N.sub.2O.sub.2S,
337. found 337.
Compound 10:
N-(3-(9H-pyrido[2,3-b]indol-5-yl)phenyl)ethanesulfonamide
##STR00170##
[1431] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5 using
3-(methanesulfonylamino) phenylboronic acid. Yield=63%. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.42 (s, 1H) 8.28 (d, J=7.6 Hz 1H)
7.70 (d, J=4.04 Hz 2H) 7.57 (t, 1H) 7.52 (s, 1H) 7.41 (m, 1H) 7.32
(d, J=7.32 Hz 1H) 7.24 (d, J=8.6 Hz, 1H) 7.31 (t, 1H) 2.93 (s, 3H).
[M+H] calc'd for C.sub.18H.sub.15N.sub.3O.sub.2S, 338. found
338.
Compound 11: 5-m-tolyl-9H-pyrido[2,3-b]indole
##STR00171##
[1433] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5 using
m-tolylboronic acid. Yield=18%. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.35 (s, 1H) 8.01 (d, J=7.84 Hz 1H) 7.62 (d, J=4.8 Hz 2H)
7.45 (t, 1H) 7.39 (m, 3H) 7.21 (t, 1H) 7.16 (m, 1H) 3.30 (m, 3H).
[M+H] calc'd for C.sub.18H.sub.14N.sub.2 259. found 259.
Compound 12:
N-cyclopropyl-3-(9H-pyrido[2,3-b]indol-5-yl)benzenesulfonamide
##STR00172##
[1435] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5 using
3-(N-cyclopropylsulfamoyl)phenylboronic acid. Yield=19%. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.38 (s, 1H) 8.12 (s, 1H) 8.06
(d, J=7.84 Hz 1H) 7.97 (d, J=8.6 Hz 1H) 7.90 (m, 1H) 7.81 (t, 1H)
7.68 (m, 2H) 7.28 (d, J=6.32 Hz 1H) 7.18 (t, 1H) 2.26 (m, 1H) 1.28
(s, 2 H) 0.53 (m, 2H). [M+H] calc'd for
C.sub.20H.sub.17N.sub.3O.sub.2S 364. found 364.
Compound 13: 5-(3-methoxyphenyl)-9H-pyrido[2,3-b]indole
##STR00173##
[1437] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5 using
3-methoxyphenylboronic acid. Yield=42%. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.02 (d, J=7.08 1H) 7.60 (m, 2H) 7.48 (t, 1H)
7.22 (m, 1H) 7.17 (d, J=8.08 Hz 2H) 7.12 (m, 1H) 7.10 (d, J=9.08 Hz
1H) 3.85 (s, 3 H). [M+H] calc'd for C.sub.18H.sub.14N.sub.2O 275.
found, 275.
Compound 14:
5-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-2-methoxy-N-methylbenzenesulf-
onamide
##STR00174##
[1439] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.27 (s, 3H) 2.53
(d, J=5.05 Hz, 3H) 2.59 (s, 3H) 4.01 (s, 3H) 7.00 (d, J=7.33 Hz,
1H) 7.18 (q, J=5.05 Hz, 1H) 7.32 (d, J=7.58 Hz, 1H) 7.43 (d, J=8.59
Hz, 1H) 7.58 (d, J=1.52 Hz, 1H) 7.82 (dd, J=8.34, 2.27 Hz, 1H) 7.92
(d, J=2.27 Hz, 1H) 8.27 (d, J=2.02 Hz, 1H) 11.91 (s, 1H). [M+H]
calc'd for C.sub.21H.sub.21N.sub.3O.sub.3S 396. found, 396.3.
Compound 15:
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N-methylbenzenesulfonamide
##STR00175##
[1441] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.26 (s, 3H) 2.48
(s, 3H) 2.61 (s, 3H) 7.06 (d, J=7.33 Hz, 1H) 7.36 (d, J=6.82 Hz,
1H) 7.51 (d, J=2.02 Hz, 1H) 7.60 (q, J=5.05 Hz, 1H) 7.82 (d, J=7.58
Hz, 1H) 7.86-7.93 (m, 2H) 8.00 (t, J=1.52 Hz, 1H) 8.27 (d, J=2.02
Hz, 1H) 11.96 (s, 1H). [M+H] calc'd for
C.sub.20H.sub.19N.sub.3O.sub.2S 366. found, 366.3.
Compound 16:
3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)-N,N-dimethylbenzenesulfonamid-
e
##STR00176##
[1443] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.27 (s, 3H) 2.62
(s, 3H) 2.70 (s, 6H) 7.08 (d, J=7.58 Hz, 1H) 7.38 (d, J=7.33 Hz,
1H) 7.51 (s, 1H) 7.86-7.96 (m, 4H) 8.31 (br. s., 1H) 12.11 (s, 1H).
[M+H] calc'd for C.sub.21H.sub.21N.sub.3O.sub.2S 380. found,
380.3.
Compound 17:
5-(3-(ethylsulfonyl)phenyl)-8-methyl-9H-pyrido[2,3-b]indole
##STR00177##
[1445] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
Yield=51%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.41 (s, 1H)
8.13 (s, 1H) 8.08 (d, J=8.08 Hz 1H) 7.99 (t, 2H) 7.86 (t, 1H) 7.52
(d, J=8.08 Hz 1H) 7.23 (m, 2H) 2.70 (s, 3H) 1.28 (m, 3H). [M+H]
calc'd for C.sub.20H.sub.18N.sub.2O.sub.2S 351. found, 351.
Compound 18:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole
##STR00178##
[1447] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.27 (s, 1H) 8.17 (t,
J=3.83 Hz, 1H) 8.07 (d, J=7.83 Hz 1H) 7.98 (d, J=8.08 Hz, 1H) 7.92
(s, 1H) 7.86 (t, J=7.71 Hz, 1H) 7.51 (d, J=8.59 Hz, 1H) 7.23 (d,
J=7.58 Hz, 1H) 2.68 (s, 3H) 2.38 (s, 3H) 1.28 (t, J=7.33 Hz, 3H).
[M+H] calc'd for C.sub.21H.sub.20N.sub.2O.sub.2S. found, 364.
Compound 19:
N-(3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)propionamide
##STR00179##
[1449] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.20 (t, J=7.58 Hz,
3H) 1.93 (s, 2H) 2.41 (s, 3H) 2.68 (s, 3H) 7.21 (d, J=7.58 Hz, 1H)
7.31 (dt, J=7.07, 1.64 Hz, 1H) 7.50 (d, J=8.84 Hz, 1H) 7.47 (s, 1H)
7.54 (dd, J=3.41, 1.64 Hz, 2 H) 7.97 (t, J=1.64 Hz, 1H) 8.29 (br.
s., 1H) [M+H] calc'd for C.sub.22H.sub.21N.sub.3O, 344. found,
344.
Compound 20:
N-cyclopropyl-3-(3,8-dimethyl-9H-pyrido[2,3-b]indol-5-yl)benzamide
##STR00180##
[1451] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 5.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.65 (dd, J=3.79,
2.02 Hz, 2H) 0.82 (dd, J=7.20, 2.15 Hz, 2H) 1.93 (s, 1H) 2.37 (s,
3H) 2.68 (s, 3H) 2.88 (td, J=7.20, 4.04 Hz, 1H) 7.22 (d, J=7.58 Hz,
1H) 7.50 (dd, J=7.58, 0.76 Hz, 1H) 7.53-7.59 (m, 1H) 7.66 (t,
J=7.71 Hz, 1H) 7.77 (dt, J=7.64, 1.48 Hz, 1H) 7.91 (d, J=0.76 Hz,
1H) 7.95 (dt, J=7.64, 0.98 Hz, 1H) 8.05 (t, J=1.77 Hz, 1H) 8.24
(br. s., 1 H) [M+H] calc'd for C.sub.23H.sub.21N.sub.3O, 355.
found, 355.
Compound 21:
N-(4-(9H-pyrido[2,3-b]indol-5-ylthio)phenyl)acetamide
##STR00181##
[1453] The title compound was synthesized by mixing Compound 4 (25
mg, 0.10 mmol, 4-mercapto-N-methylbenzamide (21 .mu.l, 0.20 mmol),
CS.sub.2CO.sub.3 (33 mg, 0.10 mmol) and
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (7 mg,
0.01 mmol) in DMF and heating at 170.degree. C. for 20 minutes in a
microwave reactor. The product was purified by HPLC (Yield=42%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.97 (d, J=7.84 1H) 8.41
(d, J=5.56 Hz 1H) 7.55 (m, 3H) 7.50 (t, 1H) 7.40 (q, 1H) 7.36 (d,
J=8.84 Hz 2H) 7.12 (d, J=7.36 Hz 1H) 2.11 (s, 3H). [M+H] calc'd for
C.sub.19H.sub.15N.sub.3OS 334. found, 334.
Compound 22: 5-(benzylthio)-9H-pyrido[2,3-b]indole
##STR00182##
[1455] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound
21.Yield=39%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.40 (s,
1H) 8.15 (s, 1H) 8.10 (d, J=7.84 Hz 1H) 8.01 (d, J=8.56 Hz 2H) 7.87
(t, 1H) 7.71 (t, 2H) 7.32 (d, J=8.36 Hz 1H) 7.24 (q, 1H) 1.28 (t,
2H). [M+H] calc'd for C.sub.18H.sub.14N.sub.2S 291. found, 291.
Compound 23: 5-(phenylthio)-9H-pyrido[2,3-b]indole
##STR00183##
[1457] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 21.
Yield=18%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.66 (d,
J=7.84 Hz 1H) 8.33 (s, 1H) 7.56 (d, J=8.32 Hz 1H) 7.45 (t, 1H) 7.25
(m, 3 H) 7.21 (d, J=7.93 Hz 2H) 7.14 (q, 1H) 1.30 (t, 2H). [M+H]
calc'd for C.sub.17H.sub.12N.sub.2S 277. found, 277.
Compound 24: 5-(benzylthio)-8-methyl-9H-pyrido[2,3-b]indole
##STR00184##
[1459] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 21.
Yield=14%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.88 (d,
J=7.84 Hz 1H) 8.34 (s, 1H) 7.74 (s, 1H) 7.19 (m, 6H) 7.11 (d,
J=7.56 Hz 1H) 6.89 (s, 1H) 2.28 (s, 3H). [M+H] calc'd for
C.sub.19H.sub.16N.sub.2S 305. found, 305.
Compound 25: 5-(benzylthio)-3,8-dimethyl-9H-pyrido[2,3-b]indole
##STR00185##
[1461] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 21.
.sup.1H NMR (400 MHz, MeOD) .delta. ppm 2.54 (s, 4H) 2.59 (s, 3H)
4.27 (s, 2H) 7.18 (dd, J=7.45, 1.39 Hz, 1H) 7.16-7.19 (m, 1H) 7.21
(dd, J=6.19, 1.39 Hz, 2H) 7.25 (d, J=9.09 Hz, 1H) 7.24 (s, 1H) 7.87
(s, 1H) 8.22 (br. s., 1H) 8.91 (d, J=1.52 Hz, 1H). [M+H] calc'd for
C.sub.20H.sub.18N.sub.2S, 319. found, 319.
Compound 26:
1-Benzyl-3-(3-bromo-5-methyl-pyridin-2-ylamino)-5-chloro-1H-pyrazin-2-one
##STR00186## ##STR00187##
[1463] 2-Amino-3-bromo-5-methyl-pyridine (1.0 g, 5.35 mmol) was
added to a solution of sodium hydride (60%, 321 mg, 8.0 mmol) in
dry THF (20 mL) at r.t. under nitrogen. After 30 minutes,
1-benzyl-3,5-dichloro-2(1H)-pyrazinone (see Vekemans, et. al., J.
Heterocyclic Chem., 20, (1983), 919-923) (1.36 g, 5.35 mmol) was
added, and the reaction stirred at 72.degree. C. for 4 h. The
solution was concentrated in vacuo and the residue was dissolved in
CH.sub.2Cl.sub.2. Organics were washed with H.sub.2O and brine,
dried (MgSO.sub.4), and concentrated. Purification by silica gel
chromatography (2:1:1 hexanes/EtOAc/CH.sub.2Cl.sub.2) provided the
title compound as a pale yellow solid (860 mg, 40%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.51 (s, 1H), 8.27 (s, 1H), 8.00
(s, 1H), 7.43 (s, 1H), 7.29-7.39 (m, 5H), 5.07 (s, 2H), 2.29 (s,
3H). MS (ES) [m+H] calc'd for C.sub.17H.sub.14BrClN.sub.4O, 405,
407. found 405, 407.
Compound 27:
1-Benzyl-5-chloro-3-(5-methyl-3-trimethylsilanylethynyl-pyridin-2-ylamino-
)-1H-pyrazin-2-one
##STR00188##
[1465] Compound 26 (2.0 g, 4.9 mmol), triphenylphosphine (52 mg,
0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (173 mg,
0.25 mmol), triethylamine (1.03 mL, 7.4 mmol), and TMS-acetylene
(1.05 mL, 7.4 mmol) were combined in THF (20 mL) at r.t. under
nitrogen. After stirring 10 min, copper iodide (40 mg) was added,
and the reaction stirred for 8 h. The reaction was diluted with
EtOAc, washed with brine, dried (MgSO.sub.4), and concentrated in
vacuo. Purification by silica gel chromatography (2:1:2
hexanes/EtOAc/CH.sub.2Cl.sub.2) provided the title compound as a
pale yellow solid (2.0 g, 96%). MS (ES) [m+H] calc'd for
C.sub.21H.sub.23ClN.sub.4OSi, 423, 425. found 423, 425.
Compound 28:
7-Benzyl-3-methyl-5-trimethylsilanyl-7,9-dihydro-dipyrido[2,3-b;
4',3'-d]pyrrol-8-one
##STR00189##
[1467] Compound 27 (3.5 g, 8.29 mmol) was dissolved in bromobenzene
(150 mL). The solution was heated at 140.degree. C. under N.sub.2
for 7 hours. The solution was evaporated and the residue was
purified by flash chromatography (3% MeOH/CH.sub.2Cl.sub.2) to
provide the title compound as a tan solid (2.5 g, 83%). .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.22 (s, 1H), 7.27-7.39 (m, 6H),
5.40 (s, 2H), 2.57 (s, 3H). MS (ES) [m+H] calc'd for
C.sub.21H.sub.23N.sub.3OSi, 362. found 362.
Compound 29: 7-Benzyl-5-iodo-3-methyl-7,9-dihydro-dipyrido[2,3-b;
4',3'-d]pyrrol-8-one
##STR00190##
[1469] Compound 28 (2.5 g, 6.93 mmol) dissolved in dry ethanol (200
mL) and stirred under nitrogen at 0.degree. C. Silver
tetrafluoroborate (1.45 g, 7.45 mmol) was added, and the solution
stirred for 10 minutes. Iodine (1.85 g, 7.3 mmol) was added, and
the reaction stirred 1 h as a precipitate began to form. After
evaporation of the solvent, the solid was taken up in
CH.sub.2Cl.sub.2 and washed with water, which caused an insoluble
precipitate to form. The solid was collected by filtration and
washed with ethyl acetate to provide the title compound (2.5 g,
87%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.74 (s, 1H),
8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.25-7.36 (m, 5H), 5.26
(s, 2H), 2.46 (s, 3H). MS (ES) [m+H] calc'd for
C.sub.18H.sub.14IN.sub.3O, 416. found 416.
Compound 30:
7-Benzyl-5-(3-ethanesulfonyl-phenyl)-3-methyl-7,9-dihydro-dipyrido[2,3-b;
4',3'-d]pyrrol-8-one
##STR00191##
[1471] Compound 29 (2.82 g, 6.79 mmol), 3-ethansulfonylboronic acid
(1.59 g, 7.46 mmol), and saturated potassium carbonate solution (2
mL) were combined in dioxane (8 mL) in a flask purged with
nitrogen. Tetrakis(triphenylphosphine)palladium(0) (1.57 g, 1.36
mmol) was added, and the reaction stirred at 150.degree. C. in the
microwave for 20 min. The solution was filtered, and the solid was
washed with water and then DCM to provide the title compound as an
off-white solid (1.7 g, 55%). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 12.73 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.92-7.99 (m,
2H), 7.83 (t, 1H, J=7.6 Hz), 7.68 (s, 1H), 7.54 (s, 1H), 7.23-7.40
(m, 5H), 5.34 (s, 2H), 3.39 (q, 2H, J=7.2 Hz), 2.27 (s, 3H), 1.15
(t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.23N.sub.3O.sub.3S, 458. found 458.
Compound 31:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7,9-dihydro-dipyrido[2,3-b;
4',3'-d]pyrrol-8-one
##STR00192##
[1473] Compound 30 (24 mg, 0.053 mmol) was stirred in acetic
anhydride (2 mL) under reflux overnight. Solvent was removed in
vacuo, and the residue was subjected to hydrogenation with 20%
palladium hydroxide on carbon (25 mg) in acetic acid (5 mL) under
an atmosphere of hydrogen at 36.degree. C. for 4 h. The reaction
was filtered through Celite and concentrated in vacuo. Purification
by prep HPLC provided the title compound as a white solid (4.6 mg,
24%). .sup.1H NMR (400 MHz, MeOD-d.sub.4/CDCl.sub.3): .delta. 8.41
(br s, 1H), 8.12 (s, 1H), 8.02 (d, 1H, J=8.0 Hz), 7.92 (d, 1H,
J=8.0 Hz), 7.80 (t, 1H, J=8.0 Hz), 7.67 (s, 1H), 7.30 (br s, 1H),
7.14 (s, 1H), 3.25 (q, 2H, J=7.2 Hz), 2.35 (s, 3H), 1.31 (t, 3H,
J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.19H.sub.17N.sub.3O.sub.3S, 368. found 368.
Compound 32:
8-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole
##STR00193##
[1475] Compound 31 (50 mg, 0.136 mmol) was stirred in POCl.sub.3 (2
mL) with dimethylaniline (0.1 mL) at 108.degree. C. under nitrogen
for 16 h. The solution was concentrated and the residue dissolved
in CH.sub.2Cl.sub.2. Ice and saturated NaHCO.sub.3 solution were
added, and organics were extracted twice with CH.sub.2Cl.sub.2,
dried (MgSO.sub.4), and concentrated in vacuo. Purification by
silica gel chromatography (3% MeOH/CH.sub.2Cl.sub.2) provided the
title compound as a pale yellow solid (36 mg, 69%). .sup.1H NMR
(400 MHz, MeOD-d.sub.4/CDCl.sub.3): .delta. 8.46 (s, 1H), 8.22 (s,
1H), 8.14 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 8.01 (d, 1H, J=8.0 Hz),
7.89 (t, 1H, J=8.0 Hz), 7.84 (s, 1H), 7.76 (s, 1H), 3.28 (q, 2H,
J=7.2 Hz), 2.38 (s, 3H), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H]
calc'd for C.sub.19H.sub.16ClN.sub.3O.sub.2S, 386, 388. found 386,
388.
[1476] Alternatively, Compound 32 was synthesized from Compound 33
as follows.
Compound 33: 2-(4-methoxybenzylamino)acetonitrile-HCl
##STR00194## ##STR00195##
[1478] In an appropriate round bottom flask, 4-methoxyybenzylamine
(50.57 g, 368.66 mmol) was first suspended in anhydrous THF (800
mL), treated with triethylamine (39.05 g, 385.89 mmol) and cooled
in an ice/water bath. Bromoacetonitrile (41.33 g, 344.54 mmol) was
added last and the reaction mixture was slowly warmed to ambient
temperature, under N.sub.2. After 3 h, the reaction was
concentrated in vacuo, diluted with ethyl acetate (500 mL) and
transferred to a 1 L separatory funnel containing 400 mL of water.
After separating the two layers, the aqueous layer was washed with
additional ethyl acetate (2.times.100 mL). The combined organic
layers were washed with brine (2.times.300 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo to afford a cloudy white solid.
Chromatography on silica gel with ethyl acetate/hexanes (2/3)
afforded clear oil (46.4 g, 76%) which was confirmed by .sup.1H-NMR
and analytical LCMS. After suspending the clear oil in diethyl
ether, 1.4 eqv of 4N HCl/dioxane (92.1 mL, 368.63 mmol) was added
and the mixture was concentrated in vacuo affording a white solid
that was carried on as is without further purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 2.94 (t, J=6.06 Hz, 1H) 3.54
(d, J=7.07 Hz, 2H) 3.67 (d, J=5.56 Hz, 2H) 3.73 (s, 3H) 6.88 (d,
J=8.59 Hz, 2 H) 7.23 (d, J=8.59 Hz, 2H). ESI-MS: m/z 177.3
(M+H).sup.+.
Compound 34: 3,5-dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one
##STR00196##
[1480] To the 1 L round bottom flask containing
2-(4-methoxybenzylamino) acetonitrile-HCl (55.6 g, 261.43 mmol),
under N.sub.2, was added chlorobenzene (414 mL) followed by oxalyl
chloride (99.54 g, 784.27 mmol). After stirring at ambient
temperature for 30 minutes, triethylamine-HCl (179.9 g, 1307.13
mmol) was added and mixture was allowed to stir overnight at
ambient temperature. The reaction mixture was concentrated in
vacuo, and the crude was taken up with DCM (700 mL) and transferred
to a 2 L reparatory funnel. The organic layer was then washed with
water (2.times.600 mL) and brine (2.times.500 mL). After drying
(MgSO.sub.4), the organic layer was filtered and concentrated to a
clear, brown oil. Chromatography on silica gel with ethyl
acetate/DCM (3/97) afforded a light yellow crystalline solid (63.1
g, 84.6%). The desired product was verified by .sup.1H-NMR and
analytical LCMS. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
3.73 (s, 3H) 5.02 (s, 2H) 6.92 (d, J=8.59 Hz, 2H) 7.36 (d, J=8.59
Hz, 2H) 8.24 (s, 1H). ESI-MS: m/z 307.2 (M+Na).sup.+.
Compound 35:
3-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-
-2(1H)-one
##STR00197##
[1482] An oven dried, 2 L, three necked round bottom flask was
charged with NaH (60% dispersion in oil, 11.9 g, 298.11 mmol),
suspended in anhydrous tetrahydrofuran (500 mL) and cooled in an
ice bath. To the cooled mixture, was added the solution of
2-amino-3-bromo-5-methylpyridine (39.4 g, 210.433 mmol, 150 mL of
anhydrous THF). The ice bath was removed and the reaction was
allowed to warm to room temperature over a 1 h period. Via addition
funnel, the solution of
3,5-dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (50.0 g, 175.36
mmol, 150 mL anhydrous tetrahydrofuran) was added in a rapid,
drop-wise fashion, attached a reflux condenser and stirred in an
oil bath heated at 72.degree. C. (exothermic reaction occurred upon
heating). After 3 h, the flask was removed from the oil bath,
cooled to room temperature, quenched with isopropanol (15 mL) and
BHT (0.075 g), and concentrated in vacuo to a dark crude.
Chromatography on silica gel plug with ethyl acetate/DCM (3/97)
afforded the desired product as a light tan solid. The mix
fractions were combined, concentrated and the desired product was
purified by recrystallization in ethyl acetate/diethyl ether and
isolated by vacuum filtration. The two solid pools were combined
(43 g, 56% yield) and verified by .sup.1H-NMR and analytical LCMS.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.30 (s, 3H) 3.74
(s, 3H) 5.00 (s, 2H) 6.93 (d, J=8.84 Hz, 2H) 7.39 (s, 2H) 7.42 (s,
1H) 8.01 (s, 1H) 8.28 (s, 1H) 9.50 (s, 1H). ESI-MS: m/z 437.2
(M+H).sup.+.
Compound 36:
5-chloro-1-(4-methoxybenzyl)-3-(5-methyl-3-((trimethylsilyl)ethynyl)pyrid-
in-2-ylamino)pyrazin-2(1H)-one
##STR00198##
[1484] In a 1 L round bottom combined
3-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-
-2(1H)-one (51.90 g, 119.12 mmol), triphenylphosphine (1.56 g, 5.96
mmol), (Ph.sub.3P)PdCl.sub.2 (4.18 g, 5.96 mmol) and suspended in
anhydrous THF (450 mL). Triethylamine (18.08 g, 178.68 mmol) and
trimethylsilyl acetylene (35.10 g, 357.36 mmol) were added next and
mixture was stirred at ambient temperature, under N.sub.2 for 10
minutes. Copper iodide (catalytic) was added last and reaction was
stirred at ambient temperature. Reaction was monitored by
analytical LCMS at one hour intervals and CuI was added until
reaction is complete. The completed reaction was concentrated in
vacuo, taken up with ethyl acetate (700 mL) and brine (300 mL) and
filtered off undissolved solids before taking on to extraction. The
organic layer was washed with additional brine (4.times.300 mL),
dried with MgSO.sub.4, filtered and concentrated in vacuo.
Chromatography on silica gel plug with ethyl acetate/hexanes (1/9),
two attempts, afforded the desired product (43.36 g. 81% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.11 (s, 9H) 2.26
(s, 3H) 3.73 (s, 3H) 5.00 (s, 2H) 6.91 (d, J=8.59 Hz, 2H) 7.38 (d,
J=8.59 Hz, 2H) 7.45 (s, 1H) 7.74 (d, J=2.27 Hz, 1H) 8.25 (d, J=2.27
Hz, 1H) 9.51 (s, 1H). ESI-MS: m/z 453.3 (M+H).sup.+.
Compound 37:
7-(4-methoxybenzyl)-3-methyl-5-trimethylsilyl-7,9-dihydro-8H-pyrido[4',':-
4,5]pyrrolo[2,3-b]pyridin-8-one
##STR00199##
[1486] In a 2 L round bottom flask,
5-chloro-1-(4-methoxybenzyl)-3-(5-methyl-3-((trimethylsilyl)ethynyl)pyrid-
in-2-ylamino)pyrazin-2(1H)-one (35.2 g, 77.85 mmol) was taken up
with anhydrous toluene (880 mL), attached a reflux condenser and
transferred to an oil bath that was heated to 130.degree. C. The
reaction was stirred in the oil bath for 94 h and concentrated in
vacuo to afford a brown solid. The crude was suspended in ethyl
acetate (200 mL) and heated to a mild boil. The solids were
collected by filtration, washed with additional ethyl acetate,
diethyl ether and dried in vacuo to provide the title compound as a
pale yellow powder (27.4 g, 89%). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.43 (s, 9H) 2.56 (s, 3H) 3.80 (s, 3H)
5.30 (s, 2H) 6.89 (d, J=8.59 Hz, 2H) 7.11 (s, 1H) 7.35 (d, J=8.84
Hz, 2H) 8.22 (s, 1H) 8.52 (d, J=1.52 Hz, 1H). ESI-MS: m/z 392.4
(M+H).sup.+.
Compound 38:
5-iodo-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-pyrido[4',':4,5]pyrrol-
o[2,3-b]pyridin-8-one
##STR00200##
[1488] In a 2 L round bottom flask,
7-(4-methoxybenzyl)-3-methyl-5-trimethylsilyl-7,9-dihydro-8H-pyrido[4',':-
4,5]pyrrolo[2,3-b]pyridin-8-one (18.6 g, 47.505 mmol) was suspended
in ethanol (1 L) and DCM (150 mL), then cooled in an ice bath. To
the cooled mixture was added silver tetrafluoroborate (AgBF.sub.4,
10.17 g, 52.3 mmol) and after 15 minutes of stirring, iodine (18.08
g, 71.3 mmol) was added. The reaction was stirred at 0.degree. C.
for one hour followed by five hours at ambient temperature. The
crude yellow solid was collected by filtration, suspended in 10% wt
Na.sub.2S.sub.2O.sub.3 (700 mL) and stirred for 1 h. The solid was
collected by filtration and again washed with 10% wt
Na.sub.2S.sub.2O.sub.3. The product (light yellow solid) was
collected by filtration, washed with water and diethyl ether and
dried under high vacuum. The material was taken forward without
further purification. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 2.59 (s, 3H) 3.81 (s, 3H) 5.26 (s, 2H) 6.90 (d, J=8.84 Hz, 2H)
7.34 (d, J=8.59 Hz, 2H) 7.44 (s, 1H) 8.51 (s, 1H) 8.92 (s, 1H).
ESI-MS: m/z 446.2 (M+H).sup.+.
Compound 39:
5-[3-(ethylsulfonyl)phenyl]-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-p-
yrido[4',':4,5]pyrrolo[2,3-b]pyridin-8-one.
##STR00201##
[1490] In an appropriate microwave reaction vessel was placed,
5-iodo-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-pyrido[4',':4,5]pyrrol-
o[2,3-b]pyridin-8-one (8.0 g, 17.967 mmol), 3-(ethylsulfonyl)phenyl
boronic acid (4.62 g, 21.6 mmol), and
Tetrakis(triphenylphosphine)Pd(0) (6.23 g, 5.4 mmol). The solids
were then suspended in a dioxane/saturated K.sub.2CO.sub.3 solution
(40.0 mL, 4/1) and the mixture was heated in a large scale CEM
microwave for 20 minutes at 150.degree. C. The reaction mixture was
diluted with DCM (400 mL), then filtered off undissolved solids.
The organic layer was washed with brine (300 mL), dried with
MgSO.sub.4, filtered and concentrated in vacuo affording an orange
solid. The crude solid was washed with a hot ethyl acetate/hexanes
solution (400 mL, 1/1) followed by a hot ethanol/DCM solution (400
mL, 4/1). The product was isolated by filtration, washed with ether
and dried under vacuum affording an off-white solid. (6.83 g, 78%)
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.36 (t, J=7.45 Hz,
3H) 2.44 (s, 3H) 3.20 (q, J=7.33 Hz, 2H) 3.80 (s, 3H) 5.37 (s, 2H)
6.90 (d, J=8.59 Hz, 2H) 7.16 (s, 1H) 7.37 (d, J=8.59 Hz, 3H) 7.75
(t, J=7.71 Hz, 1H) 7.78-7.87 (m, 2H) 8.03 (d, J=7.58 Hz, 1H) 8.12
(s, 1H) 8.43 (s, 1H). ESI-MS: m/z 488.3 (M+H).sup.+.
Compound 40:
8-chloro-5-[3-(ethylsulfonyl)phenyl]-3-methyl-9H-pyrido[4',':4,5]pyrrolo[-
2,3-b]pyridine
##STR00202##
[1492] A 500 mL round bottom flask equipped with an N.sub.2 inlet
and reflux condenser was charged with
5-[3-(ethylsulfonyl)phenyl]-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-p-
yrido[4',':4,5]pyrrolo[2,3-b]pyridin-8-one (19.3 g, 39.6 mmol),
tetramethylammonium chloride (4.77 g, 43.542 mmol), and POCl.sub.3
(249.5 g, 1626.9 mmol) at room temperature, transferred to an oil
bath and heated at 100.degree. C. The reaction was monitored by
HPLC, and determined to be complete after 2 h. The mixture was
allowed to cool to ambient temperature. A separate 3 neck, 3 L
flask was fitted with a cold thermometer, and two addition funnels.
To this flask was added a solution of 33% by weight aqueous
K.sub.3PO.sub.4 (1500 mL), cooled in a dry ice/acetone bath,
followed by the drop-wise addition of the aryl chloride suspension.
The internal temperature was kept between 5 to 20.degree. C. and
the pH was carefully monitored and maintained at 11.5 during the
quench using a slow addition of 10M KOH when necessary. The
suspension was allowed to stir for 10 min at 5.degree. C. after the
addition was complete, and at ambient temperature for 2 h. The
crude product was extracted from the aqueous layer with DCM
(5.times.500 mL), dried with MgSO.sub.4, filtered and concentrated
in vacuo to a total volume of about 500 mL. The solution was
allowed to sit at ambient temperature overnight. The precipitate
was collected by filtration, washed with additional DCM and dried,
affording a light grey solid (9.79 g) which was confirmed by
analytical LCMS and .sup.1H-NMR as the free base. The DCM mother
liquor was concentrated and taken up with a methanol/DCM mixture
(300 mL, 15/85). To the light green solution was slowly added 30 mL
4N HCl in dioxane and the mixture were stirred for one hour at
ambient temperature. 1200 mL of MTBE was slowly added and the
resultant suspension was filtered. Chromatography on silica gel
plug with methanol/DCM (3/97) afforded a yellow solid. The solid
was washed with warm methanol (30 mL) and the resulting product was
collected by filtration and washed with diethyl ether, affording an
additional 1.7 g of the product as a free base. (9.79+1.7=11.49 g,
75% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18
(t, J=7.33 Hz, 3H) 2.32 (s, 3H) 3.44 (q, J=7.33 Hz, 2H) 7.70 (d,
J=1.26 Hz, 1H) 7.93 (t, J=7.71 Hz, 1H) 8.04-8.15 (m, 2H) 8.21 (d,
J=10.61 Hz, 2H) 8.53 (d, J=1.52 Hz, 1H) 12.78 (br. s., 1H). ESI-MS:
m/z 386.3 (M+H).sup.+.
Compound 41:
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-propane-1,3-diamine
##STR00203##
[1494] Compound 40 (16 mg, 0.041 mmol) was heated with
3-dimethylamino-1-propylamine (1 mL) at 206.degree. C. in the
microwave for 30 min. Purification by prep-HPLC provided the title
compound as a pale yellow solid (10.2 mg, 55%). .sup.1H NMR (400
MHz, MeOD-d.sub.4): .delta. 8.65 (br s, 1H), 8.17 (s, 1H), 8.12 (d,
1H, J=7.6 Hz), 7.98 (d, 1H, J=7.6 Hz), 7.91 (t, 1H, J=7.6 Hz), 7.67
(s, 1H), 7.66 (s, 1H), 3.80 (t, 2H, J=6.8 Hz), 3.28-3.43 (m, 4H),
2.96 (s, 6H), 2.29-2.38 (m, 5H), 1.28 (t, 3H, J=7.2 Hz). MS (ES)
[m+H] calc'd for C.sub.24H.sub.29N.sub.5O.sub.2S, 452. found
452.
Compound 42:
N-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-N,N-dimethyl-ethane-1,2-diamine
##STR00204##
[1496] The title compound was prepared in 77% yield using
N,N-dimethylethylenediamine in the procedure outlined for the
preparation of Compound 41. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.53 (br s, 1H), 8.15 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 7.97
(d, 1H, J=7.6 Hz), 7.88 (t, 1H, J=7.6 Hz), 7.73 (s, 1H), 7.72 (s,
1H), 4.11 (t, 2H, J=5.6 Hz), 3.66 (t, 2H, J=5.6 Hz), 3.32 (q, 2H,
J=7.2 Hz), 3.06 (s, 6H), 2.37 (s, 3H), 1.29 (t, 3H, J=7.6 Hz). MS
(ES) [m+H] calc'd for C.sub.23H.sub.27N.sub.5O.sub.2S, 438. found
438.
Compound 43:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(3-morpholin-4-yl-propyl)-amine
##STR00205##
[1498] The title compound was prepared in 81% yield using
1-(3-aminopropyl)-morpholine in the procedure outlined for the
preparation of Compound 41. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.52 (s, 1H), 8.18 (s, 1H), 8.14 (d, 1H, J=7.6 Hz), 7.99
(d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.66 (s, 1H), 7.65 (s,
1H), 3.82-4.03 (m, 4H), 3.81 (t, 2H, J=6.4 Hz), 3.20-3.55 (m, 8H),
2.32-2.40 (m, 5H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.31N.sub.5O.sub.3S, 494. found 494.
Compound 44:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(1-methyl-piperidin-4-yl)-amine
##STR00206##
[1500] The title compound was prepared in 31% yield using
4-amino-1-methyl-piperidine in the procedure outlined for the
preparation of Compound 41. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.53 (br s, 1H), 8.19 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.01
(d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.72 (s, 1H), 7.67 (s,
1H), 4.23-4.31 (m, 1H), 3.69-3.77 (m, 2H), 3.20-3.38 (m, 4H), 2.97
(s, 3H), 2.46-2.54 (m, 2H), 2.36 (s, 3H), 2.01-2.15 (m, 2H), 1.29
(t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.25H.sub.29N.sub.5O.sub.2S, 464. found 464.
Compound 45:
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-ylamino]-ethanol
##STR00207##
[1502] The title compound was prepared in 88% yield using
ethanolamine in the procedure outlined for the preparation of
Compound 41. .sup.1H NMR (400 MHz, MeOD-d.sub.4): .delta. 8.51 (s,
1H), 8.20 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.00 (d, 1H, J=7.6 Hz),
7.90 (t, 1H, J=7.6 Hz), 7.64 (s, 1H), 7.63 (s, 1H), 3.99 (t, 2H,
J=4.8 Hz), 3.82 (t, 2H, J=4.8 Hz), 3.33 (q, 2H, J=7.2 Hz), 2.35 (s,
3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.21H.sub.22N.sub.4O.sub.3S, 411. found 411.
Compound 46:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]-(1-methyl-piperidin-4-ylmethyl)-amine
##STR00208##
[1504] The title compound was prepared in 55% yield using
4-aminomethyl-1-methyl-piperidine in the procedure outlined for the
preparation of Compound 41. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.55 (s, 1H), 8.22 (s, 1H), 8.16 (d, 1H, J=7.6 Hz), 8.03
(d, 1H, J=7.6 Hz), 7.94 (t, 1H, J=7.6 Hz), 7.69 (s, 1H), 7.68 (s,
1H), 3.60-3.70 (m, 4H), 3.33 (q, 2H, J=7.2 Hz), 3.03-3.12 (m, 2H),
2.92 (s, 3H), 2.39 (s, 3H), 2.21-2.30 (m, 3H), 1.69-1.79 (m, 2H),
1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.31N.sub.5O.sub.2S, 478. found 478.
Compound 47:
5-(3-Ethanesulfonyl-phenyl)-3,8-dimethyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole
##STR00209##
[1506] Trimethylaluminum (2.0 M, 70 .mu.L 0.14 mmol) was added to a
solution of Compound 40 (9.0 mg, 0.023 mmol) and
tetrakis(triphenylphosphine)palladium (0) (13.3 mg, 0.012 mmol) in
dioxane (1 mL) under nitrogen in sealed tube. The reaction was
heated at 120.degree. C. in the microwave for 20 min and then
concentrated in vacuo. Purification by prep-HPLC provided the title
compound as a pale yellow solid (8.2 mg, 96%). .sup.1H NMR (400
MHz, MeOD-d.sub.4): .delta. 8.68 (s, 1H), 8.43 (s, 1H), 8.32 (s,
1H), 8.21 (d, 1H, J=7.6 Hz), 8.11 (d, 1H, J=7.6 Hz), 7.97 (t, 1H,
J=7.6 Hz), 7.81 (s, 1H), 3.34 (q, 2H, J=7.2 Hz), 3.14 (s, 3H), 2.39
(s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.20H.sub.19N.sub.3O.sub.2S, 366. found 366.
Compound 48:
5-(3-Ethanesulfonyl-phenyl)-8-ethyl-3-methyl-9H-dipyrido[2,3-b;
4',3'd]pyrrole
##STR00210##
[1508] The title compound was prepared in 68% yield using
triethylaluminum in the procedure outlined for the preparation of
Compound 47. .sup.1H NMR (400 MHz, MeOD-d.sub.4): .delta. 8.69 (s,
1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.21 (d, 1H, J=7.6 Hz), 8.12 (d,
1H, J=7.6 Hz), 7.98 (t, 1H, J=7.6 Hz), 7.80 (s, 1H), 3.51 (q, 2H,
J=7.6 Hz), 3.33 (q, 2H, J=7.2 Hz), 2.39 (s, 3H), 1.57 (t, 3H, J=7.6
Hz), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.21H.sub.21N.sub.3O.sub.2S, 380. found 380.
Compound 49:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole-8-carbonitrile
##STR00211##
[1510] Zinc cyanide (5.0 mg, 0.037 mmol) was added to a solution of
Compound 40 (12.0 mg, 0.031 mmol) and
tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.009 mmol) in DMF
(1 mL) under nitrogen in sealed tube. The reaction was heated at
160.degree. C. in the microwave for 30 min and then concentrated in
vacuo. Purification by prep-HPLC provided the title compound as a
pale yellow solid (10 mg, 86%). .sup.1H NMR (400 MHz,
MeOD-d.sub.4): .delta. 8.76 (br s, 1H), 8.48 (s, 1H), 8.26 (s, 1H),
8.16 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.91 (t, 1H, J=7.6
Hz), 7.81 (s, 1H), 3.29 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 1.35 (t,
3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.20H.sub.16N.sub.4O.sub.2S, 377. found 377.
Compound 50:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole-8-carboxylic acid amide
##STR00212##
[1512] To a stirred solution of Compound 49 (10 mg, 0.027 mmol) in
THF (1 mL) was added a solution of KOH (25 mg, 0.44 mmol) and 30%
H.sub.2O.sub.2 (0.5 mL). The reaction was stirred for 3 h at r.t.
Purification by prep-HPLC provided the title compound as an
off-white solid (8.2 mg, 77%). .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.49 (br s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.15 (d, 1H,
J=7.6 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.92 (t, 1H, J=7.6 Hz), 7.85 (s,
1H), 3.32 (q, 2H, J=7.2 Hz), 2.39 (s, 3H), 1.31 (t, 3H, J=7.6 Hz).
MS (ES) [m+H] calc'd for C.sub.20H.sub.18N.sub.4O.sub.3S, 395.
found 395.
Compound 51:
5-(3-Ethanesulfonyl-phenyl)-8-ethoxy-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole
##STR00213##
[1514] Compound 40 (4 mg, 0.01 mmol) was heated in a solution of
sodium ethoxide in ethanol (21 wt. %, 0.5 mL) at 200.degree. C. in
the microwave for 30 min. Purification by prep-HPLC provided the
title compound as a pale yellow solid (3.2 mg, 78%). .sup.1H NMR
(400 MHz, MeOD-d.sub.4): .delta. 8.47 (br s, 1H), 8.18 (s, 1H),
8.03 (d, 1H, J=7.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.81-7.89 (m, 3H),
4.63 (q, 2H, J=7.2 Hz), 3.26 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.56
(t, 3H, J=7.6 Hz), 1.32 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for
C.sub.21H.sub.21N.sub.3O.sub.3S, 396. found 396.
Compound 52:
{3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propyl}-dimethyl-amine
##STR00214##
[1516] 3-Dimethylamino-1-propanol (100 mL, 0.84 mmol) was added to
a solution of sodium hydride (60%, 34 mg, 0.84 mmol) in dry dioxane
(1 mL) under nitrogen. After stirring for 20 min, Compound 40 (30
mg, 0.11 mmol) was added, and the reaction stirred at 180.degree.
C. in the microwave for 1 h. The solution was concentrated and
purified by prep-HPLC to provide the title compound as a pale
yellow solid (30 mg, 69%). .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.42 (br s, 1H), 8.24 (s, 1H), 8.10 (d, 1H, J=7.6 Hz), 8.03
(d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.89 (s, 1H), 7.82 (s,
1H), 4.75 (t, 2H, J=5.6 Hz), 3.46-3.54 (m, 2H), 3.34 (q, 2H, J=7.2
Hz), 3.01 (s, 6H), 2.38-2.46 (m, 2H), 2.38 (s, 3H), 1.32 (t, 3H,
J=7.6 Hz). MS (ES) [m+H] calc'd for
C.sub.24H.sub.28N.sub.4O.sub.3S, 453. found 453.
Compound 53:
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-ethanol
##STR00215##
[1518] The title compound was prepared in 18% yield using ethylene
glycol in the procedure outlined for the preparation of Compound
52. .sup.1H NMR (400 MHz, MeOD-d.sub.4): .delta. 8.47 (br s, 1H),
8.19 (s, 1H), 8.02-8.09 (m, 2H), 7.97 (d, 1H, J=7.6 Hz), 7.94 (s,
1H), 7.88 (t, 1H, J=7.6 Hz), 4.68 (t, 2H, J=4.8 Hz), 4.05 (t, 2H,
J=4.8 Hz), 3.31 (q, 2H, J=7.2 Hz), 2.41 (s, 3H), 1.29 (t, 3H, J=7.6
Hz). MS (ES) [m+H] calc'd for C.sub.21H.sub.21N.sub.3O.sub.4S, 412.
found 412.
Compound 54:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole
##STR00216##
[1520] The title compound was prepared in 78% yield using
1-methyl-piperidine-3-methanol in the procedure outlined for the
preparation of Compound 52. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.42 (br s, 1H), 8.20 (s, 1H), 8.06 (d, 1H, J=7.6 Hz), 7.99
(d, 1H, J=7.6 Hz), 7.81-7.89 (m, 3H), 4.51 (d, 2H, J=6.4 Hz),
3.57-3.63 (m, 2H), 3.32 (q, 2H, J=7.2 Hz), 3.02-3.13 (m, 2H), 2.90
(s, 3H), 2.36 (s, 3H), 2.24-2.32 (m, 3H), 1.61-1.73 (m, 2H), 1.29
(t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.30N.sub.4O.sub.3S, 479. found 479.
Compound 55:
3-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-1-ol
##STR00217##
[1522] The title compound was prepared in 30% yield using
1,3-propanediol in the procedure outlined for the preparation of
Compound 52. .sup.1H NMR (400 MHz, MeOD-d.sub.4): .delta. 8.52 (br
s, 1H), 8.23 (s, 1H), 8.09 (d, 1H, J=7.6 Hz), 7.96-8.03 (m, 2H),
7.93 (s, 1H), 7.89 (t, 1H, J=7.6 Hz), 4.75 (t, 2H, J=6.4 Hz), 3.88
(t, 2H, J=6.4 Hz), 3.34 (q, 2H, J=7.2 Hz), 2.41 (s, 3H), 2.16-2.22
(m, 2H), 1.32 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.23N.sub.3O.sub.4S, 426. found 426.
Compound 56:
(R)-2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxymethyl]-propane-1,3-diol
##STR00218##
[1524] The title compound was prepared in 68% yield using
(S)-2,2-dimethyl-1,3-dioxolane-4-methanol in the procedure outlined
for the preparation of Compound 52, followed by deprotection in
TFA/H.sub.2O/THF (1:1:5) for 3 h. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.37 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H),
7.96-8.04 (m, 2H), 7.80-7.88 (m, 2H), 7.69 (s, 1H), 4.40-4.90 (m,
4H), 3.91-3.99 (m, 1H), 3.52-3.60 (m, 2H), 3.55 (q, 2H, J=7.2 Hz),
2.29 (s, 3H), 1.18 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.23N.sub.3O.sub.5S, 442. found 442.
Compound 57:
(S)-2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxymethyl]-propane-1,3-diol
##STR00219##
[1526] The title compound was prepared in 65% yield using
(R)-2,2-dimethyl-1,3-dioxolane-4-methanol in the procedure outlined
for the preparation of Compound 52, followed by deprotection in
TFA/H.sub.2O/THF (1:1:5) for 3 h. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.37 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H),
7.96-8.04 (m, 2H), 7.80-7.88 (m, 2H), 7.69 (s, 1H), 4.40-4.90 (m,
4H), 3.91-3.99 (m, 1H), 3.52-3.60 (m, 2H), 3.55 (q, 2H, J=7.2 Hz),
2.29 (s, 3H), 1.18 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.23N.sub.3O.sub.5S, 442. found 442.
Compound 58:
1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-2-methyl-propan-2-ol
##STR00220##
[1528] The title compound was prepared in 16% yield using
2-benzyloxy-2-methyl-1-propanol (see Fleming, et. al., Can. J.
Chem., 52, (1974), 888-892) in the procedure outlined for the
preparation of compound 52, followed by benzyl deprotection by
hydrogenation at 1 atm with 10% Pd/C in MeOH for 1 h. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 12.40 (s, 1H), 8.45 (s, 1H), 8.15
(s, 1H), 7.98-8.05 (m, 2H), 7.82-7.89 (m, 2H), 7.71 (s, 1H), 4.27
(s, 2H), 3.40 (q, 2H, J=7.2 Hz), 2.31 (s, 3H), 1.30 (s, 6H), 1.17
(t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.23H.sub.25N.sub.3O.sub.4S, 440. found 440.
Compound 59:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-phenoxy-9H-dipyrido[2,3-b;
4',3'-d]pyrrole
##STR00221##
[1530] The title compound was prepared in 30% yield using phenol in
the procedure outlined for the preparation of Compound 52. .sup.1H
NMR (400 MHz, MeOD-d.sub.4): .delta. 8.40 (br s, 1H), 8.18 (s, 1H),
8.03 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=7.6 Hz), 7.77-7.85 (m, 3H),
7.40-7.48 (m, 2H), 7.21-7.29 (m, 3H), 3.21 (q, 2H, J=7.2 Hz), 2.38
(s, 3H), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.25H.sub.21N.sub.3O.sub.3S, 444. found 444.
Compound 60:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-8-(thiazol-5-ylmethoxy)-9H-dipyrido[-
2,3-b; 4',3'-d]pyrrole
##STR00222##
[1532] The title compound was prepared in 20% yield using
thiazole-5-methanol in the procedure outlined for the preparation
of Compound 52. .sup.1H NMR (400 MHz, MeOD-d.sub.4): .delta. 8.98
(br s, 1H), 8.34 (br s, 1H), 8.19 (s, 1H), 7.96-8.07 (m, 3H), 7.90
(s, 1H), 7.80-7.87 (m, 2H), 5.91 (s, 2H), 3.26 (q, 2H, J=7.2 Hz),
2.35 (s, 3H), 1.32 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.23H.sub.20N.sub.4O.sub.3S.sub.2, 465. found 465.
Compound 61:
5-(3-Ethanesulfonyl-phenyl)-8-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-9H-
-dipyrido[2,3-b; 4',3'-d]pyrrole
##STR00223##
[1534] The title compound was prepared in 24% yield using
1-ethyl-piperidine-3-methanol in the procedure outlined for the
preparation of Compound 52. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.49 (br s, 1H), 8.20 (s, 1H), 8.03-8.10 (m, 2H), 7.99 (d,
1H, J=7.6 Hz), 7.95 (s, 1H), 7.89 (t, 1H, J=7.6 Hz), 4.56 (d, 2H,
J=6.4 Hz), 3.65-3.73 (m, 2H), 3.21-3.36 (m, 4H), 3.02-3.12 (m, 2H),
2.43 (s, 3H), 2.24-2.40 (m, 3H), 1.80-1.90 (m, 2H), 1.43 (t, 3H,
J=7.2 Hz), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.27H.sub.32N.sub.4O.sub.3S, 493. found 493.
Compound 62:
(S)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol
##STR00224##
[1536] The title compound was prepared in 13% yield using
(S)-2-benzyloxy-1-propanol (see Mislow, et. al., J. Am. Chem. Soc.,
82, (1960), 5512-5513) in the procedure outlined for the
preparation of Compound 52, followed by benzyl deprotection by
hydrogenation at 1 atm with 10% Pd/C in MeOH for 1 h. .sup.1H NMR
(400 MHz, MeOD-d.sub.4): .delta. 8.43 (br s, 1H), 8.21 (s, 1H),
8.09 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.82-7.90 (m, 3H),
4.29-4.59 (m, 3H), 3.36 (q, 2H, J=7.6 Hz), 2.39 (s, 3H), 1.38 (d,
3H, J=6.4 Hz), 1.30 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.23N.sub.3O.sub.4S, 426. found 426.
Compound 63:
(R)-1-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol
##STR00225##
[1538] The title compound was prepared in 56% yield using
(S)-2-benzyloxy-1-propanol (see Mulzer, et. al., Tetrahedron Lett.,
24, (1983), 2843-2846) in the procedure outlined for the
preparation of Compound 52, followed by benzyl deprotection by
hydrogenation at 1 atm with 10% Pd/C in MeOH for 1 h. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 12.40 (s, 1H), 8.44 (s, 1H), 8.16
(s, 1H), 8.00-8.07 (m, 2H), 7.85-7.92 (m, 2H), 7.71 (s, 1H),
4.30-4.40 (m, 2H), 4.08-4.15 (m, 1H), 3.43 (q, 2H, J=7.2 Hz), 2.31
(s, 3H), 1.26 (d, 3H, J=6.4 Hz), 1.18 (t, 3H, J=7.2 Hz). MS (ES)
[m+H] calc'd for C.sub.22H.sub.23N.sub.3O.sub.4S, 426. found
426.
Compound 64:
L-Valine-2-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-ethyl ester
##STR00226##
[1540] BOC-L-valine (51 mg, 0.23 mmol) and compound 53 (80 mg, 0.19
mmol) were stirred in CH.sub.2Cl.sub.2 (6 mL) at r.t. DIEA (51
.mu.L, 0.29 mmol) and HATU (110 mg, 0.29 mmol) were added, and the
reaction stirred for 6 h. Organics were washed with 0.1 N HCl and
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue was stirred in 33% TFA/CH.sub.2Cl.sub.2 (3 mL) for 1 h,
concentrated, and purified by prep-HPLC to provide the title
compound as a pale yellow powder (68 mg, 68%). .sup.1H NMR (400
MHz, MeOD-d.sub.4): .delta. 8.40 (br s, 1H), 8.19 (s, 1H), 8.06 (d,
1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.81-7.88 (m, 3H), 4.69-4.96
(m, 4H), 3.97 (d, 1H, J=4.8 Hz), 3.33 (q, 2H, J=7.2 Hz), 2.35 (s,
3H), 2.20-2.30 (m, 1H), 1.29 (t, 3H, J=7.2 Hz), 0.93-1.02 (m, 6H).
MS (ES) [m+H] calc'd for C.sub.26H.sub.30N.sub.4O.sub.5S, 511.
found 511.
Compound 65:
L-Alanine-(R)-2-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-1-methyl-ethyl ester
##STR00227##
[1542] The title compound was prepared in 79% yield using
BOC-L-alanine and Compound 63 in the procedure outlined for the
preparation of compound 64. .sup.1H NMR (400 MHz, MeOD-d.sub.4):
.delta. 8.46 (br s, 1H), 8.19 (s, 1H), 8.05 (d, 1H, J=7.6 Hz), 7.98
(d, 1H, J=7.6 Hz), 7.79-7.88 (m, 3H), 5.51-5.59 (m, 1H), 4.60-4.85
(m, 2H), 4.12 (q, 1H, J=7.2 Hz), 3.33 (q, 2H, J=7.2 Hz), 2.34 (s,
3H), 1.55 (d, 3H, J=7.2 Hz), 1.51 (d, 3H, J=6.4 Hz), 1.29 (t, 3H,
J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.25H.sub.28N.sub.4O.sub.5S, 497. found 497.
Compound 66:
3-(3-Bromo-5-chloro-pyridin-2-ylamino)-5-chloro-1-(4-methoxy-benzyl)-1H-p-
yrazin-2-one
##STR00228##
[1544] The title compound was prepared in 58% yield from
2-amino-3-bromo-5-chloropyridine and
3,5-dichloro-1-(4-methoxy-benzyl)-1H-pyrazin-2-one in a manner
analogous to that for the preparation of Compound 26. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.58 (s, 1H), 8.51 (d, 1H, J=2.4
Hz), 8.40 (d, 1H, J=2.4 Hz), 7.51 (s, 1H), 7.36 (d, 2H, J=8.8 Hz),
6.92 (d, 2H, J=8.8 Hz), 5.00 (s, 2H), 3.73 (s, 3H). MS (ES) [m+H]
calc'd for C.sub.17H.sub.13BrCl.sub.2N.sub.4O.sub.2, 455, 457, 459.
found 455, 457, 459.
Compound 67:
5-Chloro-3-(5-chloro-3-trimethylsilanylethynyl-pyridin-2-ylamino)-1-(4-me-
thoxy-benzyl)-1H-pyrazin-2-one
##STR00229##
[1546] The title compound was prepared in 89% yield from compound
66 according to the procedure outline for the preparation of
Compound 27. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.68 (s,
1H), 8.46 (d, 1H, J=2.8 Hz), 8.07 (d, 1H, J=2.8 Hz), 7.54 (s, 1H),
7.37 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.8 Hz), 5.00 (s, 2H), 3.72
(s, 3H), 0.16 (s, 9H). MS (ES) [m+H] calc'd for
C.sub.22H.sub.22Cl.sub.2N.sub.4O.sub.2Si, 473, 475. found 473,
475.
Compound 68:
3-Chloro-7-(4-methoxy-benzyl)-5-trimethylsilanyl-7,9-dihydro-dipyrido[2,3-
-b; 4',3'-d]pyrrol-8-one
##STR00230##
[1548] Compound 67 (5.8 g, 12.3 mmol) and DIEA (3.2 mL, 18.4 mmol)
were dissolved in toluene (600 mL), and the solution was heated at
reflux under N.sub.2 for four days. The solution was concentrated
and purified by flash chromatography (30% EtOAc/CH.sub.2Cl.sub.2)
to provide the title compound as a tan solid (4.4 g, 87%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 12.98 (s, 1H), 8.54 (d, 1H,
J=2.4 Hz), 8.20 (d, 1H, J=2.4 Hz), 7.37 (s, 1H), 7.32 (d, 2H, J=8.8
Hz), 6.90 (d, 2H, J=8.8 Hz), 5.25 (s, 2H), 3.71 (s, 3H), 0.39 (s,
9H). MS (ES) [m+H] calc'd for C.sub.21H.sub.22ClN.sub.3O.sub.2Si,
412, 414. found 412, 414.
Compound 69:
3-Chloro-5-iodo-7-(4-methoxy-benzyl)-7,9-dihydro-dipyrido[2,3-b;
4',3'-d]pyrrol-8-one
##STR00231##
[1550] The title compound was prepared in quantitative yield from
compound 68 according to the procedure outline for the preparation
of Compound 29. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.12
(s, 1H), 8.84 (d, 1H, J=2.4 Hz), 8.59 (d, 1H, J=2.4 Hz), 7.94 (s,
1H), 7.34 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.8 Hz), 5.19 (s, 2H),
3.71 (s, 3H). MS (ES) [m+H] calc'd for
C.sub.18H.sub.13Cl.sub.1N.sub.3O.sub.2, 466, 468. found 466,
468.
Compound 70:
3-Chloro-5-(3-ethanesulfonyl-phenyl)-7-(4-methoxy-benzyl)-7,9-dihydro-dip-
yrido[2,3-b; 4',3'-d]pyrrol-8-one
##STR00232##
[1552] The title compound was prepared in 48% yield from compound
69 according to the procedure outline for the preparation of
Compound 30. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.12 (s,
1H), 8.52 (d, 1H, J=2.4 Hz), 8.06 (d, 1H, J=2.4 Hz), 7.80-7.99 (m,
3H), 7.73 (s, 1H), 7.65 (s, 1H), 7.39 (d, 2H, J=8.8 Hz), 6.89 (d,
2H, J=8.8 Hz), 5.27 (s, 2H), 3.70 (s, 3H), 3.39 (q, 2H, J=7.2 Hz),
1.15 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.22ClN.sub.3O.sub.4S, 508, 510. found 508, 510.
Compound 71:
3,8-Dichloro-5-(3-ethanesulfonyl-phenyl)-9H-dipyrido[2,3-b;
4',3'-d]pyrrole
##STR00233##
[1554] Phosphorous oxychloride (8 mL) was added to a mixture of
compound 70 (1.05 g, 2.07 mmol) and ammonium chloride (380 mg, 2.28
mmol), and the reaction was heated at 108.degree. C. for 4 h. The
reaction was concentrated in vacuo and quenched with ice. The
precipitated was collected by filtration and washed with H.sub.2O
and cold MeOH to provide the title compound as a pale yellow solid
(660 mg, 79%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.12
(s, 1H), 8.69 (d, 1H, J=2.4 Hz), 8.25 (s, 1H), 8.20 (d, 1H, J=2.4
Hz), 8.04-8.10 (m, 2H), 7.93 (t, 1H, J=7.6 Hz), 7.80 (s, 1H), 3.42
(q, 2H, J=7.2 Hz), 1.17 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.18H.sub.13Cl.sub.2N.sub.3O.sub.2S, 406, 408. found 406,
408.
Compound 72:
3-Chloro-5-(3-ethanesulfonyl-phenyl)-8-(1-methyl-piperidin-4-ylmethoxy)-9-
H-dipyrido[2,3-b; 4',3'-d]pyrrole
##STR00234##
[1556] The title compound was prepared in 14% yield using compound
71 and 1-methyl-piperidine-3-methanol in the procedure outlined for
the preparation of Compound 52. .sup.1H NMR (400 MHz,
MeOD-d.sub.4): .delta. 8.49 (s, 1H), 8.17 (d, 1H, J=1.6 Hz), 8.08
(d, 1H, J=7.6 Hz), 7.99 (d, 1H, J=7.6 Hz), 7.82-7.90 (m, 2H), 7.80
(s, 1H), 4.52 (d, 2H, J=6.0 Hz), 3.56-3.62 (m, 2H), 3.33 (q, 2H,
J=7.2 Hz), 3.02-3.11 (m, 2H), 2.90 (s, 3H), 2.25-2.33 (m, 3H),
1.60-1.72 (m, 2H), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.25H.sub.27ClN.sub.4O.sub.3S, 499, 501. found 499, 501.
Compound 73:
(R)-1-[3-Chloro-5-(3-ethanesulfonyl-phenyl)-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yloxy]-propan-2-ol
##STR00235##
[1558] The title compound was prepared in 15% yield using
(S)-2-benzyloxy-1-propanol (see Mulzer, et. al., Tetrahedron Lett.,
24, (1983), 2843-2846) and Compound 71 in the procedure outlined
for the preparation of compound 52, followed by benzyl deprotection
by hydrogenation at 1 atm with 10% Pd/C in MeOH for 1 h. .sup.1H
NMR (400 MHz, MeOD-d.sub.4): .delta. 8.49 (s, 1H), 8.17 (s, 1H),
8.06 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.80-7.89 (m, 3H),
4.30-4.59 (m, 3H), 3.32 (q, 2H, J=7.2 Hz), 1.32-1.40 (m, 6H). MS
(ES) [m+H] calc'd for C.sub.21H.sub.20ClN.sub.3O.sub.4S, 446, 448.
found 446, 448.
Compound 74:
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]methyl amine
##STR00236##
[1560] The title compound was prepared using methyl amine in the
procedure outlined for the preparation of Compound 41. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. ppm 1.30 (s, 3H) 2.37 (s, 3H) 7.64
(s, 1H) 7.66 (dd, J=2.02, 0.76 Hz, 1H) 7.91 (t, J=7.71 Hz, 1H)
8.01-8.04 (m, J=7.71, 1.14, 0.88, 0.88 Hz, 1H) 8.15 (ddd, J=7.89,
1.83, 1.14 Hz, 1H) 8.22 (t, J=1.64 Hz, 1H) 8.53 (s, 1H) [M+H]
calc'd for C.sub.20H.sub.20N.sub.4O.sub.2S, 381. found, 381.
Compound 75:
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]methanethiol
##STR00237##
[1562] The title compound was prepared using methanethiol in the
procedure outlined for the preparation of Compound 41. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. ppm 1.28-1.31 (m, 3H) 2.38 (s, 3H)
2.85 (s, 3H) 7.82 (s, 1H) 7.92 (t, J=7.45 Hz, 1H) 8.05-8.08 (m,
J=7.71, 1.14, 0.88, 0.88 Hz, 1H) 8.14 (ddd, J=7.64, 1.20, 1.01 Hz,
1H) 8.27 (dd, J=3.66, 0.63 Hz, 1H) 8.30 (s, 1H) 8.49 (s, 1H) [M+H]
calc'd for C.sub.20H.sub.19N.sub.3O.sub.2S.sub.2, 398. found,
398.
Compound 76:
2-[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]ethanethiol
##STR00238##
[1564] The title compound was prepared using ethanethiol in the
procedure outlined for the preparation of Compound 41. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. ppm 1.30 (t, J=7.33 Hz, 3H) 1.45 (t,
J=7.33 Hz, 3H) 1.93 (s, 3H) 2.37 (s, 2H) 3.44 (d, J=7.33 Hz, 2H)
7.82 (s, 1 H) 7.92 (t, J=7.71 Hz, 1H) 8.07 (dt, J=7.77, 1.42 Hz,
1H) 8.13 (dt, J=7.83, 1.52 Hz, 1H) 8.27 (t, J=1.77 Hz, 1H) 8.31 (s,
1H) 8.50 (br. s., 1H) [M+H] calc'd for
C.sub.21H.sub.21N.sub.3O.sub.2S.sub.2, 412. found, 412.
Compound 77:
5-[3-(cyclopropylcarboxamide)phenyl]-7-(4-methoxybenzyl)-3-methyl-7,9-dih-
ydro-8H-pyrido[4',':4,5]pyrrolo[2,3-b]pyridin-8-one
##STR00239##
[1566] The title compound was prepared using the similar procedure
outlined for the preparation of Compound 39. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.63 (ddd, J=3.79, 1.77, 1.52 Hz, 2H)
0.81 (dd, J=7.33, 2.02 Hz, 2H) 2.31 (s, 2H) 2.66 (s, 3H) 3.76 (s,
3H) 5.34 (s, 2H) 6.89 (d, J=8.84 Hz, 2H) 7.35 (d, J=8.84 Hz, 2H)
7.40 (s, 1H) 7.64 (d, J=7.83 Hz, 1H) 7.60 (t, J=2.02 Hz, 1H) 7.75
(d, J=2.78 Hz, 1H) 7.92 (dd, J=7.96, 1.14 Hz, 1H) 8.00 (t, J=1.64
Hz, 1H) 8.34 (d, J=2.02 Hz, 1H) [M+H] calc'd for
C.sub.29H.sub.26N.sub.4O.sub.3, 479. found, 479.
Compound 78:
8-Chloro-5-[3-(cyclopropylcarboxamide)phenyl]-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrole
##STR00240##
[1568] The title compound was prepared from Compound 77 using the
similar procedure outlined for the preparation of compound 40.
[M+H] calc'd for C.sub.21H.sub.17ClN.sub.4O, 377.1. found,
377.2.
Compound 79:
2-[5-(3-cyclopropylcarbonylamino-phenyl)-3-methyl-9H-dipyrido[2,3-b;
4',3'-d]pyrrol-8-yl]ethanethiol
##STR00241##
[1570] The title compound was prepared using ethanethiol in the
procedure outlined for the preparation of Compound 41. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. ppm 0.88 (d, J=7.83 Hz, 2H) 0.97 (t,
J=2.40 Hz, 2H) 1.44 (t, J=7.33 Hz, 3H) 2.38 (s, 3H) 3.41 (d, J=7.33
Hz, 2H) 7.39 (d, J=7.83 Hz, 1H) 7.56 (t, J=7.83 Hz, 1H) 7.66 (d,
J=8.84 Hz, 1H) 7.85 (s, 1H) 8.26 (s, 1H) 8.48 (br. s., 1H) 10.26
(s, 1H) [M+H] calc'd for C.sub.23H.sub.22N.sub.4OS, 403. found,
403.
Compound 80:1-Acetyl-4-bromo-1,2-dihydro-indol-3-one
##STR00242##
[1572] 4-Bromo-1H-indole-3-carbaldehyde (4.0 g, 17.8 mmol) was
stirred in acetic anhydride (20 mL) at reflux for 4 h. The reaction
was cooled and concentrated in vacuo. Cold MeOH was added to
precipitate a white solid, which was collected by filtration to
provide the title compound (3.5 g, 74%). MS (ES) [m+H] calc'd for
C.sub.11H.sub.8BrNO.sub.2, 266, 268. found 266, 268.
[1573] 1-Acetyl-4-bromo-1H-indole-3-carbaldehyde (3.5 g, 13.2 mmol)
was dissolved in CH.sub.2Cl.sub.2 (50 mL). 3-Chloroperbenzoic acid
(3.9 g, 15.8 mmol) was added, and the reaction stirred 16 h at r.t.
The solution was washed with sat. NaHCO.sub.3 and brine, dried
(MgSO.sub.4), and concentrated. The residue was stirred with
K.sub.2CO.sub.3 (100 mg) in MeOH (50 mL) for 2 min. The solution
was concentrated and purified by silica gel chromatography (100%
CH.sub.2Cl.sub.2) to provide the title compound as a faintly blue
solid (880 mg, 26%). MS (ES) [m+H] calc'd for
C.sub.10H.sub.8BrNO.sub.2, 254, 256. found 254, 256.
Compound 81: 9-Bromo-5H-pyrazino[2,3-b]indole
##STR00243##
[1575] 1-Acetyl-4-bromo-1,2-dihydro-indol-3-one (460 mg, 1.81 mmol)
was dissolved in CH.sub.2Cl.sub.2 (8 mL). Bromine (111 .mu.L, 2.2
mmol) was added slowly, and the reaction stirred for 20 min and
then was concentrated in vacuo. The residue was dissolved in THF (8
mL). Ethylenediamine (244 .mu.L, 3.6 mmol) was added, and the
reaction stirred for 16 h at r.t. Triethylamine (2 mL) and MeOH (4
mL) were added, and the reaction stirred while left open to air for
24 h. The solution was concentrated in vacuo and purified by silica
gel chromatography (8% MeOH/CH.sub.2Cl.sub.2) to provide the title
compound as a red solid (248 mg, 55%). MS (ES) [m+H] calc'd for
C.sub.10H.sub.6BrN.sub.3, 248, 250. found 248, 250.
Compound 82:
9-(3-Ethanesulfonyl-phenyl)-5H-pyrazino[2,3-b]indole
##STR00244##
[1577] Compound 81 (50 mg, 0.2 mmol),
3-ethanesulfonyl-phenylboronic acid (65 mg, 0.3 mmol),
tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol), and
potassium carbonate (83 mg, 0.6 mmol), were combined in dioxane (2
mL) and H.sub.2O (0.2 mL) in a sealed tube under nitrogen. The
reaction was heated at 150.degree. C. in the microwave for 20 min
and then concentrated in vacuo. Purification by silica gel
chromatography (5% MeOH/CH.sub.2Cl.sub.2) provided the title
compound as a light orange solid (46 mg, 68%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.42 (t, 1H, J=2.8 Hz), 8.31 (d, 1H, J=2.8
Hz), 8.24 (d, 1H, J=2.8 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.96 (d, 1H,
J=7.6 Hz), 7.60-7.75 (m, 3H), 7.31 (dd, 1H, J=7.2, 1.2 Hz), 3.33
(q, 2H, J=7.2 Hz), 1.37 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.18H.sub.15N.sub.3O.sub.2S, 338. found 338.
Compound 83:
3-(6-chloro-3-methyl-2-nitro-4-(trifluoromethyl)phenyl)-2-fluoro-5-methyl-
pyridine
##STR00245## ##STR00246##
[1579] 2-Fluoro-3-iodo-5-picoline (15.0 g, 63 mmol) was added drop
wise during 2 h as a solution in NMP (20 mL) to a stirred
suspension of 3,4-dichlororo-2-nitro-6-(trifluoromethyl)-toluene
(52.1 g, 190 mmol) and copper (12.1 g, 190 mmol) in NMP (115 mL) at
190.degree. C. After completion of the reaction (2.5 h), the
mixture was cooled to room temperature, filtered, rinsed with NMP
(3.times.5 mL) followed by EtOAc (1.times.100 mL). The filtrate was
diluted with EtOAc (400 mL) affording a turbid solution. The
organic layer was partitioned with sat. NaHCO.sub.3 (150 mL)
affording a suspension/emulsion. H.sub.2O (50 mL) and MeOH (50 mL)
were added to aid solubility. The aqueous layer was washed with
EtOAc (5.times.150 mL). The organic layers were combined, dried
(MgSO.sub.4), and concentrated in vacuo. The crude product was
purified by silica gel chromatography (98:2 Toluene:EtOAc) to
provide the title compound as a tan solid (11.4 g, 52%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 8.34 (s, 1H), 8.26 (s, 1H),
7.86-7.89 (m, 1H), 2.4 (s, 3H), 2.34 (s, 3H). MS (ES) [m+H] calc'd
for C.sub.14H.sub.9ClF.sub.4N.sub.2O.sub.2, 349. found 349.2.
Compound 84:
3-(3'-(ethylsulfonyl)-4-methyl-3-nitro-5-(trifluoromethyl)biphenyl-2-yl)--
2-fluoro-5-methylpyridine
##STR00247##
[1581] A mixture of Compound 83 (6.0 g, 17.2 mmol),
3-ethylsulfonylphenylboronic acid (4.79 g, 22.4 mmol),
bis(dibenzylideneacetone)Pd(0) (1.48 g, 2.6 mmol),
tricyclohexylphosphine (1.45 g, 5.2 mmol), Cs.sub.2CO.sub.3 (14.0
g, 43 mmol), and dioxane (60 mL) was heated at reflux for 4.5 hr.
After completion the reaction was cooled to room temperature,
filtered, rinsed with dioxane, and concentrated in vacuo. The
resulting oil was reconstituted in EtOAc (75 mL) washed with
H.sub.2O (1.times.30 mL) and brine (1.times.30 mL), dried
(MgSO.sub.4), and concentrated in vacuo. The crude product was
purified by silica gel chromatography (4:1 hexanes/EtOAc) to
provide the title compound as a tan solid (6.5 g, 78%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.15 (s, 1H), 8.04 (s, 1H),
7.90-7.93 (m, 1H), 7.80-7.82 (m, 1H), 7.60-7.70 (m, 3H), 3.1-3.2
(m, 2H), 2.49 (s, 3H), 2.25 (s, 3H), 0.85 (t, 3H). MS (ES) [m+H]
calc'd for C.sub.22H.sub.18F.sub.4N.sub.2O.sub.4S, 483. found
483.3.
Compound 85:
3'-(ethylsulfonyl)-2-(2-fluoro-5-methylpyridin-3-yl)-4-methyl-5-(trifluor-
omethyl)biphenyl-3-amine
##STR00248##
[1583] A mixture of Compound 84 (6.4 g, 13.3 mmol), iron (3.7 g,
66.3 mmol), HOAc, (32 mL), and H.sub.2O (11 mL) was heated at
80.degree. C. for 2 h. After completion the reaction was
concentrated in vacuo. The residue was reconstituted in
dichloromethane (100 mL), filtered, and rinsed with dichloromethane
(3.times.30 mL). The organic phase was washed with sat. NaHCO.sub.3
(1.times.100 mL) and brine (1.times.50 mL), dried (MgSO.sub.4),
filtered, and concentrated in vacuo. The crude product was purified
by silica gel chromatography (1:1 hexanes/EtOAc) to provide the
title compound as a tan solid (5.0 g, 83%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.93 (s, 1H), 7.67-7.7.71 (m, 2H), 7.53 (t,
1H), 7.46-7.48 (m, 1H), 7.42 (s, 1H), 6.93 (s, 1H), 5.09 (s, 2H),
3.11 (q, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 0.85 (t, 3H). MS (ES)
[m+H] calc'd for C.sub.22H.sub.20F.sub.4N.sub.2O.sub.2S, 453. found
453.3.
Compound 86:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-7-(trifluoromethyl)-9H-pyrido[2,-
3-b]indole acetate
##STR00249##
[1585] Compound 85 (4.9 g, 10.8 mmol) was dissolved in HOAc (35 mL)
and heated at reflux for 3 h. The reaction mixture was cooled to
room temperature affording a crystalline product. The resulting
suspension was filtered, rinsed with HOAc (3.times.5 mL) followed
by H.sub.2O (3.times.10 mL) and the solids dried in vacuo to
provide the title compound as a white solid (3.73 g, 70%). NMR
analysis confirmed that the product was isolated as the
mono-acetate salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
12.35 (s, 1H), 12.0 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 8.04-8.09
(m, 2H), 7.90 (t, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 3.43 (q, 2H),
2.76 (s, 3H), 2.28 (s, 3H), 1.91 (s, 3H), 1.18 (t, 3H). MS (ES)
[m+H] calc'd for C.sub.22H.sub.19F.sub.3N.sub.2O.sub.2S, 433. found
433.3.
Compound 87:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxy-
lic acid
##STR00250##
[1587] Compound 86 (3.6 g, 7.3 mmol) was dissolved in concentrated
H.sub.2SO.sub.4 (30 mL) and heated at 120.degree. C. for 30 min.
The reaction was cooled to room temperature and poured over ice
affording a white precipitate. The resulting suspension was
filtered, rinsed with H.sub.2O (3.times.30 mL) followed by IPA
(3.times.10 mL) and dried in vacuo to provide the title compound as
a white solid (3.2 g, quant.). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 12.20 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 8.02-8.07 (m,
2H), 7.89 (t, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 3.43 (q, 2H), 2.85
(s, 3H), 2.28 (s, 3H), 1.18 (t, 3H). MS (ES) [m+H] calc'd for
C.sub.22H.sub.20N.sub.2O.sub.4S, 409. found 409.3.
Compound 88:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide
##STR00251##
[1589] A mixture of Compound 87 (11.3 g, 27.6 mmol),
1-methylpiperidin-4-amine (9.47 g, 82.9 mmol), HATU (13.66 g, 35.9
mmol), DIEA (17.88 g, 138 mmol), DMF (250 mL), and DCM (250 mL) was
stirred at room temperature for 30 minutes. The resulting
suspension was filtered, rinsed with DMF (10 mL.times.4) and
concentrated in vacuo. The residue was dissolved in DMSO (77 mL),
filtered, and the filtrate was purified by preparative HPLC
(ACN/H.sub.2O with TFA). Following HPLC purification, the pure
fractions were combined, basified with sodium bicarbonate and
concentrated in vacuo to half volume. The resulting suspension was
filtered, rinsed with H.sub.2O (200 mL.times.5) and dried in vacuo
to provide Compound 88 as a white solid (11.41 g, 81.8%).
[1590] The hydrochloride salt of Compound 88 was prepared as
follows. To a stirred suspension of Compound 88 (8.7 g) in ACN (175
mL) and H.sub.2O (175 mL) was added 1N HCl (18.1 mL, 1.05 eq)
affording a yellow solution. After 15 minutes, the solution was
frozen on dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide hydrochloride as a yellow solid
(9.02 g, 96.7%). The above process provided
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide hydrochloride as an amorphous
material ("Amorphous Form"), which may be characterized as having
one or more of the following physical characteristics (it being
noted that a composition need not necessarily exhibit all of these
characteristics in order to indicate the presence of Amorphous
Form): [1591] (a) may be formed by lyophilizing a solution of
Compound 88 in ACN, water, and HCl; [1592] (b) has an XRPD spectrum
characterized by a diffuse halo with no discernable peaks; and/or
[1593] (c) shows 7.6 wt % Cl.sup.- present using ion
chromatography.
[1594] The crystalline hydrochloride salt of Compound 88 was
prepared as follows. To a stirred suspension of Compound 88 (0.55
g) in IPA (2.5 mL) and H.sub.2O (2.5 mL) was added 12.1N HCl
(1.05-1.10 eq) affording a yellow solution. After stirring for 45
minutes, crystallization occurred and additional IPA (15 mL) was
added at room temperature. The resulting suspension was allowed to
stir overnight. The solids were isolated by filtration and dried in
vacuo at 60.degree. C. to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide hydrochloride as a tan to gold
colored solid (0.51 g, 87%).
[1595] The dihydrochloride salt of Compound 88 was prepared as
follows. To a stirred suspension of Compound 88 (101 mg) in ACN
(2.5 mL) and H.sub.2O (2.5 mL) was added 12.1N HCl (0.42 mL, 2.1
eq) affording a yellow solution. After 5 minutes, the solution was
frozen on dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide dihydrochloride as a yellow solid
(0.108 g).
[1596] The benzenesulfate salt of Compound 88 was prepared as
follows. To a stirred suspension of Compound 88 (98 mg) in ACN (2.5
mL) and H.sub.2O (2.5 mL) was added benzenesulfonic acid (32 mg,
1.05 eq) to give a slightly cloudy solution that was warmed to
assist solubility. After 5 minutes, the solution was frozen on dry
ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-y-
l)-9H-pyrido[2,3-b]indole-7-carboxamide benzenesulfonate (118
mg).
[1597] The methanesulfonate salt of Compound 88 was prepared as
follows. To a stirred suspension of Compound 88 (101 mg) in ACN
(2.5 mL) and H.sub.2O (2.5 mL) was added methanesulfonic acid
(0.014 mL, 1.05 eq) affording a clear solution. After 5 minutes,
the solution was frozen on dry ice/acetone and lyophilized to
provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide methane sulfonate (116 mg).
[1598] The succinate salt of Compound 88 was prepared as follows.
To a stirred suspension of Compound 88 (100 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added succinic acid (25 mg, 1.05 eq) to give
a clear solution. After 5 minutes, the solution was frozen on dry
ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide succinate (119 mg).
[1599] The tartrate salt of Compound 88 was prepared as follows. To
a stirred suspension of Compound 88 (108 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added L-tartaric acid (34 mg, 1.05 eq)
affording a clear solution. After 5 minutes, the solution was
frozen on dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide tartrate (137 mg).
[1600] The citrate salt of Compound 88 was as follows. To a stirred
suspension of Compound 88 (104 mg) in ACN (2.5 mL) and H.sub.2O
(2.5 mL) was added citric acid (42 mg, 1.05 eq) affording a clear
solution. After 5 minutes, the solution was frozen on dry
ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-y-
l)-9H-pyrido[2,3-b]indole-7-carboxamide citrate (142 mg).
[1601] The fumarate salt of Compound 88 was prepared as follows. To
a stirred suspension of Compound 88 (104 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added fumaric acid (25 mg, 1.05 eq) affording
a very slightly cloudy solution. After 5 minutes, the solution was
frozen on dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide fumarate (123 mg).
[1602] The sulfate salt of Compound 88 was prepared as follows. To
a stirred suspension of Compound 88 (107 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added sulfuric acid (0.012 mL, 1.05 eq)
affording a yellow solution. After 5 minutes, the solution was
frozen on dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide sulfate (125 mg).
[1603] The phosphate salt of Compound 88 was prepared as follows.
To a stirred suspension of Compound 88 (104 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added phosphoric acid (0.015 mL, 1.05 eq)
affording a slightly cloudy solution that was warmed to assist
solubility. After 5 minutes, the solution was frozen on dry
ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-y-
l)-9H-pyrido[2,3-b]indole-7-carboxamide phosphate (122 mg).
[1604] The benzoate salt of Compound 88 was prepared as follows. To
a stirred suspension of Compound 88 (100 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added benzoic acid (25 mg, 1.05 eq) affording
a clear solution containing a very small amount of suspended
benzoic acid crystals. After 5 minutes, the solution was frozen on
dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide benzoate (118 mg).
[1605] The bis-trifluoroacetic acid salt of Compound 88 was
prepared as follows. Following HPLC purification (ACN/H.sub.2O with
TFA) of crude Compound 88, the pure fractions were combined and
lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide bis(2,2,2-trifluoroacetate) as a
yellow solid.
[1606] The tosylate salt of Compound 88 was prepared as follows. To
a stirred suspension of Compound 88 (103 mg) in ACN (2.5 mL) and
H.sub.2O (2.5 mL) was added p-toluenesulfonic acid (39 mg, 1.05 eq)
affording a clear solution. After 5 minutes, the solution was
frozen on dry ice/acetone and lyophilized to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide tosylate (130 mg).
[1607] The hemi-fumarate salt of Compound 88 was prepared as
follows. To a stirred solution of Compound 88 (360 mg) in MeOH at
58.degree. C. was added 0.5M fumaric acid (0.53 eq) in MeOH. After
15 minutes crystallization occurred and the resulting suspension
was cooled to room temperature and allowed to stir for an
additional 2 hours. The solids were isolated by filtration and
dried in vacuo to provide
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide hemifumarate as a white crystalline
powder (219.24 mg, 50%).
Compound 89:
N-(2-(methylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyri-
do[2,3-b]indole-7-carboxamide
##STR00252##
[1609] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.63 (t, J=5.31 Hz, 3H) 2.67 (s, 3H) 3.12 (ddd,
J=11.87, 6.32, 6.06 Hz, 2H) 3.42 (q, J=7.41 Hz, 2H) 3.56 (q, J=6.15
Hz, 2H) 7.28 (s, 1 H) 7.51 (s, 1H) 7.91 (t, J=7.83 Hz, 1H) 8.04
(ddd, J=16.36, 7.77, 1.14 Hz, 2H) 8.12 (s, 1 H) 8.33 (s, 1H) 8.43
(br. s., 1H) 8.57 (t, J=5.68 Hz, 1H) 12.09 (s, 1H) ESI-MS: m/z 465
(m+H).sup.+
Compound 90:
N-(2-(methoxy)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2-
,3-b]indole-7-carboxamide
##STR00253##
[1611] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.63 (s, 3H) 3.29 (s, 3H) 3.37-3.51 (m, 6H) 7.12
(s, 1H) 7.53 (d, J=1.26 Hz, 1H) 7.89 (t, J=7.71 Hz, 1H) 7.99-8.06
(m, 2H) 8.12 (s, 1 H) 8.31 (s, 1H) 8.43 (t, J=5.31 Hz, 1H) 12.05
(s, 1H) ESI-MS: m/z 466 (m+H).sup.+
Compound 91:
N-(2-(dimethylamino)ethyl)-N-methyl-5-(3-(ethylsulfonyl)phenyl)-3,8-dimet-
hyl-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00254##
[1613] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.20 Hz,
3H) 2.26 (s, 3H) 2.64 (br. s., 3H) 2.86 (s, 3H) 2.91 (s, 3H)
3.35-3.45 (m, 6H) 7.06 (s, 1H) 7.47 (s, 1H) 7.89 (t, J=7.71 Hz, 1H)
8.00-8.09 (m, 3H) 8.31 (s, 1H) 9.49 (br. s., 1H) 12.11 (s, 1H).
ESI-MS: m/z 493 (m+H).sup.+
Compound 92:
N,N-dimethyl-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]ind-
ole-7-methylcarboxamide
##STR00255##
[1615] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.46 (br. s., 3H) 2.84 (s, 3H) 3.05 (br. s., 3H)
3.33-3.50 (m, 2H) 6.97 (s, 1H) 7.52 (d, J=1.52 Hz, 1H) 7.87 (t,
J=7.71 Hz, 1H) 8.02 (t, J=7.33 Hz, 2H) 8.10 (s, 1H) 8.30 (d, J=1.52
Hz, 1H) 12.08 (s, 1H). ESI-MS: m/z 436 (m+H).sup.+
Compound 93:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-yl)(4-m-
ethylpiperazin-1-yl)methanone
##STR00256##
[1617] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.57 (br. s., 3H) 2.82-2.85 (br, 3H) 3.10-3.68 (m,
9H) 4.77 (m, 1H) 7.10 (br. d., 1H) 7.51 (br. d, J=7.83 Hz, 1H) 7.90
(t, J=7.33 Hz, 1H) 7.99-8.13 (m, 3H) 8.32 (s, 1H) 9.96 (br. s., 1H)
12.15 (s, 1H). ESI-MS: m/z 491 (m+H).sup.+
Compound 94:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-piperazin-1-yl)ethyl)-9H-py-
rido[2,3-b]indole-7-carboxamide
##STR00257##
[1619] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.66 (s, 3H) 3.17-3.45 (m, 12H) 3.59 (q, J=5.64
Hz, 2H) 7.20 (s, 1H) 7.52 (s, 1H) 7.90 (t, J=7.71 Hz, 1H) 8.04 (m,
2H) 8.12 (s, 1H) 8.33 (d, J=2.02 Hz, 1H) 8.56 (t, J=5.68 Hz, 1H)
8.99 (br. s., 1H) 12.10 (s, 1H). ESI-MS: m/z 520 (m+H).sup.+
Compound 95:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-(4-methylpiperazin-1-yl)pro-
pyl)-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00258##
[1621] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.83 Hz,
3H) 1.87 (br. s., 2H) 2.27 (s, 3H) 2.64 (s, 3H) 2.82 (br. s., 3H)
3.03 (br. s., 4H) 3.31-3.49 (m, 8H) 7.15 (s, 1H) 7.52 (s, 1H) 7.90
(t, J=7.71 Hz, 1H) 8.00-8.07 (m, 2H) 8.11 (s, 1H) 8.32 (d, J=2.02
Hz, 1H) 8.49-8.53 (m, 1H) 12.08 (s, 1H) ESI-MS: m/z 548
(m+H).sup.+
Compound 96:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-yl)(mor-
pholino)methanone
##STR00259##
[1623] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.38 (t, J=7.33 Hz,
3H) 2.37 (s, 3H) 2.71 (s, 3H) 3.23 (q, J=7.33 Hz, 2H) 3.39 (m, 2H)
3.64 (d, J=13.14 Hz, 1H) 3.64 (d, J=5.05 Hz, 1H) 3.80-4.01 (m, 4H)
7.04 (s, 1H) 7.62 (s, 1H) 7.78 (t, J=7.71 Hz, 1H) 7.93 (dt, J=7.77,
1.42 Hz, 1H) 8.07 (ddd, J=7.71, 1.64, 1.52 Hz, 1H) 8.24 (t, J=1.64
Hz, 1H) 8.34 (d, J=1.77 Hz, 1H) 10.97 (br. s., 1H) ESI-MS: m/z 478
(m+H).sup.+
Compound 97:
azetidin-1-yl(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]in-
dol-7-yl)methanone
##STR00260##
[1625] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.37 (t, J=7.45 Hz,
3H) 2.28-2.41 (m, 5H) 2.75 (s, 3H) 3.23 (q, J=7.58 Hz, 2H) 4.03 (t,
J=7.58 Hz, 2H) 4.30 (t, J=7.96 Hz, 2H) 7.12 (s, 1H) 7.61 (s, 1H)
7.77 (t, J=7.96 Hz, 1H) 7.94 (ddd, J=7.89, 1.45, 1.26 Hz, 1H) 8.06
(dd, J=8.21, 1.39 Hz, 1H) 8.22 (t, J=1.52 Hz, 1H) 8.33 (d, J=1.26
Hz, 1H) 10.25 (br. s., 1H). ESI-MS: m/z 448 (m+H).sup.+
Compound 98:
(5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indol-7-yl)(tha-
iazolidin-3-yl)methanone
##STR00261##
[1627] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.56 (s, 3H) 2.99 (m, 1H) 3.12 (m, 1H) 3.43-3.51
m, 3H) 3.89 (m, 1H) 4.32 (s, 1H) 4.71 (s, 1H) 7.06 (d, J=3.03 Hz,
1H) 7.52 (br. s., 1H) 7.88 (t, J=7.83 Hz, 1H) 7.98-8.07 (m, 2H)
8.12 (d, J=1.52 Hz, 1H) 8.32 (d, J=1.77 Hz, 1H) 12.11 (br. s., 1H).
ESI-MS: m/z 480 (m+H).sup.+
Compound 99:
(R)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide
##STR00262##
[1629] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.82 Hz,
3H) 1.17 (t, J=7.33 Hz, 3H) 2.26 (s, 3H) 2.62 (s, 3H) 3.30-3.45 (m,
2H) 3.41 (q, J=7.33 Hz, 2H) 4.00-4.06 (m, 1H) 7.12 (s, 1H) 7.51 (d,
J=1.26 Hz, 1H) 7.89 (t, J=7.71 Hz, 1H) 7.99-8.05 (m, 2H) 8.11 (m,
2H) 8.30 (s, 1H) 12.04 (s, 1H) ESI-MS: m/z 466 (m+H).sup.+
Compound 100:
(S)-5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxypropyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide
##STR00263##
[1631] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.10 (d, J=6.32 Hz,
3H) 1.17 (t, J=7.33 Hz, 3H) 2.27 (s, 3H) 2.64 (s, 3H) 3.22 (t,
J=6.06 Hz, 2H) 3.42 (q, J=7.33 Hz, 2H) 3.72-3.88 (m, 1H) 7.17 (s,
1H) 7.55 (d, J=1.52 Hz, 1H) 7.89 (t, J=7.71 Hz, 1H) 8.03 (m, 2H)
8.13 (t, J=1.64 Hz, 1H) 8.31 (d, J=1.52 Hz, 1H) 8.34 (t, J=5.94 Hz,
1H) 12.09 (s, 1H). ESI-MS: m/z 466 (m+H).sup.+
Compound 101:
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxyethyl)-3,8-dimethyl-9H-pyrido[2,3-
-b]indole-7-carboxamide
##STR00264##
[1633] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.63 (s, 3H) 3.34 (q, J=6.23 Hz, 2H) 3.42 (q,
J=7.33 Hz, 2H) 3.53 (t, J=6.19 Hz, 2H) 7.17 (s, 1H) 7.53 (d, J=1.77
Hz, 1H) 7.89 (t, J=7.71 Hz, 1H) 8.03 (m, 2H) 8.13 (t, J=1.64 Hz,
1H) 8.34 (t, J=5.68 Hz, 1H) 8.31 (d, J=1.52 Hz, 1H) 12.05 (s, 1H).
ESI-MS: m/z 452 (m+H).sup.+
Compound 102:
N-(2,3-dihydroxypropyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrid-
o[2,3-b]indole-7-carboxamide
##STR00265##
[1635] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.64 (s, 3H) 3.22 (ddd, J=13.14, 6.44, 6.19 Hz,
1H) 3.35-3.45 (m, 5H) 3.66 (qd, J=5.60, 5.43 Hz, 1H) 7.18 (s, 1H)
7.54 (s, 1H) 7.89 (t, J=7.83 Hz, 1H) 8.03 (m, 2H) 8.13 (s, 1H)
8.29-8.35 (m, 2H) 12.09 (s, 1H). ESI-MS: m/z 482 (m+H).sup.+
Compound 103:
5-(3-(ethylsulfonyl)phenyl)-N-(2-hydroxy-2-methylpropyl)-3,8-dimethyl-9H--
pyrido[2,3-b]indole-7-carboxamide
##STR00266##
[1637] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17-1.14 (m, 9H)
2.27 (s, 3H) 2.64 (s, 3H) 3.26 (d, J=6.32 Hz, 2H) 3.41 (q, J=7.33
Hz, 2H) 7.16 (s, 1H) 7.54 (s, 1H) 7.89 (t, J=7.71 Hz, 1H) 8.04 (d,
J=7.58 Hz, 2H) 8.13 (t, J=1.64 Hz, 1H) 8.25 (t, J=5.94 Hz, 1H) 8.31
(d, J=1.26 Hz, 1H) 12.07 (s, 1H). ESI-MS: m/z 480 (m+H).sup.+
Compound 104:
5-(3-(ethylsulfonyl)phenyl)-N-(1-isopropylpiperidin-4-yl)-3,8-dimethyl-9H-
-pyrido[2,3-b]indole-7-carboxamide
##STR00267##
[1639] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13-1.27 (m, 9H)
1.72-1.84 (m, 2H) 2.05-2.17 (m, 2H) 2.27 (s, 3H) 2.63 (s, 3H) 3.13
(m, 3H) 3.42 (m, 4H) 4.08 (m, 1H) 7.12 (s, 1H) 7.53 (d, J=1.77 Hz,
1H) 7.89 (t, J=7.71 Hz, 1H) 8.04 (m, 2H) 8.09-8.14 (s, 1H) 8.32 (d,
J=1.52 Hz, 1H) 8.55 (d, J=7.58 Hz, 1H) 9.11 (br. s., 1H) 12.11 (s,
1H). ESI-MS: m/z 533 (m+H).sup.+
Compound 105:
N-(1-ethylpiperidin-4-yl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide
##STR00268##
[1641] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.14-1.25 (m, 6H)
1.73 (m, 2H) 2.00-2.12 (m, 2H) 2.27 (s, 3H) 2.63 (s, 3H) 3.00-3.17
(m, 4H) 3.42 (q, J=7.33 Hz, 2H) 3.53 (m, 2H) 7.12 (s, 1H) 7.52 (d,
J=1.26 Hz, 1H) 7.89 (t, J=7.71 Hz, 1H) 7.99-8.07 (m, 2H) 8.11 (s,
1H) 8.31 (s, 1H) 8.53 (d, J=7.58 Hz, 1H) 9.17 (br. s., 1H) 12.08
(s, 1H). ESI-MS: m/z 519 (m+H).sup.+
Compound 106:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-thiazol-2-yl)-9H-pyrido[2,3-b]-
indole-7-carboxamide
##STR00269##
[1643] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 2.30 (s, 3H) 2.72 (s, 3H) 3.42 (q, J=7.41 Hz, 2H) 7.30 (d,
J=3.54 Hz, 1H) 7.41 (s, 1H) 7.56 (d, J=3.79 Hz, 1H) 7.63 (s, 1H)
7.90 (t, J=7.83 Hz, 1H) 8.04 (d, J=7.59 Hz, 1H) 8.12 (d, J=7.58 Hz,
1H) 8.21 (s, 1H) 8.36 (s, 1H) 12.25 (s, 1 H) 12.66 (br. s., 1H).
ESI-MS: m/z 491 (m+H).sup.+
Compound 107:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-(2,2,2-trifluoroethoxy)ethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00270##
[1645] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 2.27 (s, 3H) 2.63 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.47 (q,
J=5.56 Hz, 2H) 3.75 (t, J=5.68 Hz, 2H) 4.11 (q, J=9.52 Hz, 2H) 7.14
(s, 1H) 7.56 (s, 1 H) 7.91 (t, J=7.83 Hz, 1H) 7.99-8.06 (m, 2H)
8.12 (s, 1H) 8.32 (s, 1H) 8.49 (t, J=5.68 Hz, 1H) 12.10 (s, 1H).
ESI-MS: m/z 534 (m+H).sup.+
Compound 108:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-3-yl)-9H-pyrido[2,3-
-b]indole-7-carboxamide
##STR00271##
[1647] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 1.56-1.69 (m, 2H) 1.96-1.88 (m, 2H) 2.27 (s, 3H) 2.63 (s, 3 H)
2.82 (m, 2H) 3.22 (m, 1H) 3.42 (m, 3H) 4.16 (m, 1H) 7.16 (s, 1H)
7.51 (s, 1H) 7.90 (t, J=7.71 Hz, 1H) 7.99-8.08 (m, 2H) 8.11 (t,
J=1.64 Hz, 1H) 8.32 (d, J=2.02 Hz, 1H) 8.51 (d, J=7.58 Hz, 1H)
8.58-8.74 (m, 2H) 12.09 (s, 1H). ESI-MS: m/z 491 (m+H).sup.+
Compound 109:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-4-yl)-9H-pyrid
o[2,3-b]indole-7-carboxamide
##STR00272##
[1649] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 1.60-1.77 (m, 2H) 2.05-2.03 (m, 2H) 2.27 (s, 3H) 2.62 (s, 3 H)
3.04 (q, J=9.85 Hz, 2H) 3.33-3.29 (m, 2H) 3.42 (q, J=7.49 Hz, 2H)
4.10 (m, 1H) 7.12 (s, 1H) 7.51 (d, J=1.52 Hz, 1H) 7.89 (t, J=7.71
Hz, 1H) 7.99-8.08 (m, 2H) 8.11 (s, 1H) 8.32 (d, J=1.52 Hz, 1H)
8.34-8.42 (m, 1H) 8.51 (d, J=7.58 Hz, 1H) 8.60-8.66 (m, 1H) 12.08
(s, 1H). ESI-MS: m/z 491 (m+H).sup.+
Compound 110:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(piperidin-3-yl)-9H-pyrido[2,3-
-b]indole-7-carboxamide
##STR00273##
[1651] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.45 Hz,
3H) 1.57-1.69 (m, 2H) 1.83-2.01 (m, 2H) 2.27 (s, 3H) 2.63 (s, 3H)
2.74-2.90 (m, 2H) 3.21 (m, 1H) 3.42 ((m, 3H)) 4.17 (m, 1H) 7.16 (s,
1H) 7.51 (s, 1H) 7.90 (t, J=7.58 Hz, 1H) 8.03 (m, 2H) 8.11 (s, 1H)
8.32 (s, 1H) 8.50 (d, J=7.58 Hz, 1H) 8.58-8.71 (m, 2H) 12.09 (s,
1H). ESI-MS: m/z 491 (m+H).sup.+
Compound 111:
5-(3-(ethylsulfonyl)phenyl)-N-(2-(2-hydroxyethoxy)ethyl-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide
##STR00274##
[1653] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.20 Hz,
3H) 2.27 (s, 3H) 2.63 (s, 3H) 3.37-3.58 (m, 11H) 7.14 (s, 1H) 7.55
(s, 1H) 7.88 (t, J=7.83 Hz, 1H) 8.04-8.03 (m, 2H) 8.12 (s, 1H) 8.31
(s, 1H) 8.41 (t, J=5.68 Hz, 1H) 12.08 (s, 1H). ESI-MS: m/z 496
(m+H).sup.+
Compound 112:
5-(3-(cyclopropanecarboxamido)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dime-
thyl-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00275##
[1655] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.75-0.84 (m, 4H)
1.80 (t, J=4.93 Hz, 1H) 2.27 (s, 3H) 2.64 (s, 3H) 2.87 (d, J=4.55
Hz, 6H) 3.29 (q, J=5.56 Hz, 2H) 3.61 (q, J=5.64 Hz, 2H) 7.16 (s,
1H) 7.27 (d, J=7.33 Hz, 1H) 7.50 (t, J=7.71 Hz, 1H) 7.63 (d, J=8.34
Hz, 1H) 7.68 (s, 1H) 7.99 (s, 1H) 8.29 (s, 1 H) 8.58 (t, J=5.43 Hz,
1H) 9.39 (br. s., 1H) 10.38 (s, 1H) 11.99 (s, 1H); ESI-MS: m/z
calc'd for C.sub.28H.sub.31N.sub.5O.sub.2 469.25. found 470.4
(M+H).sup.+
Compound 113:
N-(2-(dimethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-py-
rido[2,3-b]indole-7-carboxamide
##STR00276##
[1657] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.04 (s, 1H),
8.28-8.31 (m, 2H), 8.12 (s, 1H), 8.01-8.05 (m, 2H), 7.89 (t, 1H),
7.52 (s, 1H), 7.12 (s, 1H), 3.43 (q, 2H), 2.63 (s, 3H), 2.27 (s,
3H), 2.20 (s, 6H), 1.17 (t, 3H). MS (ES) [m+H] calc'd for
C.sub.26H.sub.30N.sub.4O.sub.3S, 479. found 479.4.
Compound 114:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-((1-methylpiperidin-4-yl)methy-
l)-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00277##
[1659] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 1.38 (d, J=10.86 Hz, 2H) 1.78 (br. s., 1H) 1.91 (d, J=13.39 Hz,
2 H) 2.27 (s, 3H) 2.63 (s, 3H) 2.75 (d, J=4.80 Hz, 3H) 2.86-2.97
(m, 2H) 3.20 (t, J=6.19 Hz, 2H) 3.42 (q, J=7.33 Hz, 4H) 7.14 (s,
1H) 7.51 (d, J=1.26 Hz, 1H) 7.89 (t, J=7.71 Hz, 1H) 8.03 (dd,
J=10.61, 8.59 Hz, 2H) 8.12 (s, 1H) 8.32 (d, J=1.52 Hz, 1H) 8.50 (q,
J=6.06 Hz, 1H) 9.18 (br. s., 1H) 12.08 (s, 1H); ESI-MS: m/z calc'd
for C.sub.29H.sub.34N.sub.4O.sub.3S 518.24. found 519.4
(M+H).sup.+
Compound 115:
N-(3-(dimethylamino)propyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-p-
yrido[2,3-b]indole-7-carboxamide
##STR00278##
[1661] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 1.85-1.95 (m, 1H) 1.91 (d, J=7.83 Hz, 1H) 2.27 (s, 3H) 2.65 (s,
3H) 2.80 (d, J=4.80 Hz, 6H) 3.13 (dt, J=10.36, 5.18 Hz, 2H) 3.34
(q, J=6.32 Hz, 2H) 3.42 (q, J=7.41 Hz, 2H) 7.17 (s, 1H) 7.52 (s,
1H) 7.90 (t, J=7.71 Hz, 1H) 8.04 (t, J=9.09 Hz, 2H) 8.12 (s, 1H)
8.32 (d, J=1.52 Hz, 1H) 8.53 (t, J=5.81 Hz, 1H) 9.35 (br. s., 1H)
12.08 (s, 1H); ESI-MS: m/z calc'd for
C.sub.27H.sub.32N.sub.4O.sub.3S 492.22. found 493.4 (M+H).sup.+
Compound 116:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-9H--
pyrido[2,3-b]indole-7-carboxamide
##STR00279##
[1663] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
3H) 1.87 (dd, J=7.20, 4.93 Hz, 2H) 2.03 (t, J=6.82 Hz, 2H) 2.27 (s,
3 H) 3.08 (dd, J=10.48, 7.45 Hz, 2H) 3.36 (q, J=5.89 Hz, 2H) 3.42
(q, J=7.33 Hz, 2H) 3.63 (td, J=12.88, 5.56 Hz, 4H) 7.24 (s, 1H)
7.52 (s, 1H) 7.90 (t, J=7.71 Hz, 1H) 8.04 (dd, J=14.27, 7.71 Hz,
2H) 8.12 (s, 1H) 8.33 (d, J=1.52 Hz, 1H) 8.62 (t, J=5.68 Hz, 1H)
9.53 (br. s., 1H) 12.10 (s, 1H); ESI-MS: m/z calc'd for
C.sub.28H.sub.32N.sub.4O.sub.3S 504.22. found 505.4 (M+H).sup.+
Compound 117:
(S)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide
##STR00280##
[1665] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.45 Hz,
3H) 1.20-2.0 (m, 6H) 2.27 (s, 3H) 2.62 (s, 3H) 2.70-4.4 (m, 8H)
7.12 (s, 1H) 7.52 (s, 1H) 7.91 (d, J=7.58 Hz, 1H) 8.01 (d, J=8.84
Hz, 1H) 8.06 (d, J=8.84 Hz, 1H) 8.11 (d, J=1.52 Hz, 1H) 8.33 (s,
1H) 8.62 (d, J=7.83 Hz, 1H). [M+H] calc'd for
C.sub.28H.sub.32N.sub.2O.sub.2S 505. found, 505.4.
Compound 118:
(R)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-3-yl)-9-
H-pyrido[2,3-b]indole-7-carboxamide
##STR00281##
[1667] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 88.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.45 Hz,
3H) 1.20-2.0 (m, 6H) 2.27 (s, 3H) 2.62 (s, 3H) 2.70-4.40 (m, 8H)
7.13 (s, 1H) 7.53 (d, J=1.01 Hz, 1H) 7.90 (t, J=7.83 Hz, 1H) 8.04
(dd, J=17.43, 8.34 Hz, 2H) 8.11 (d, J=1.52 Hz, 1H) 8.33 (s, 1H)
8.62 (d, J=7.83 Hz, 1H) 12.11 (s, 1H). [M+H] calc'd for
C.sub.28H.sub.32N.sub.2O.sub.2S 505. found, 505.4.
Compound 119:
5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-
-carboxamide
##STR00282##
[1669] The title compound was synthesized from
5-chloro-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxalic acid and
1-methylpiperidin-4-amine using an analogous procedure to that
described in the preparation of Compound 88. .sup.1H NMR (400 MHz,
DMSO-d.sub.6 with TFD) .delta. ppm 1.70-2.2 (m, 4H) 2.53 (br. s.,
3H) 2.58 (s, 3H) 2.74-2.82 (m, 3H) 2.80-4.10 (m, 5H) 7.29 (s, 1H)
8.47 (s, 1H) 8.70 (s, 1H). [M+H] calc'd for
C.sub.20H.sub.18N.sub.2O.sub.2S 371. found, 371.4.
Compound 120:
5-(3-(cyclopropanecarboxamido)phenyl)-3,8-dimethyl-N-(1-methyl-piperidin--
4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00283##
[1671] The title compound was synthesized from Compound 119 and
3-(cyclopropanecarboxamido) phenyl boronic acid using an analogous
procedure to that described in the preparation of Compound 84.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.77-0.82 (m, 4H)
1.53 (qd, J=11.66, 3.41 Hz, 2H) 1.79-1.82 (m, 3H) 1.95 (t, J=10.86
Hz, 2H) 2.15 (s, 3H) 2.27 (s, 3H) 2.59 (s, 3H) 2.74 (d, J=11.12 Hz,
2H) 3.75 (m, 1H) 6.98 (s, 1H) 7.27 (d, J=7.58 Hz, 1H) 7.49 (t,
J=7.96 Hz, 1H) 7.69 (d, J=2.02 Hz, 2H) 7.91 (s, 1H) 8.25-8.30 (m,
2H) 10.37 (s, 1H) 11.92 (br. s., 1H); [M+H] calc'd for
C.sub.30H.sub.34N.sub.5O.sub.2, 496.3. found, 496.4.
Compound 121:
5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-
-carboxamide
##STR00284##
[1673] The title compound was synthesized from
5-chloro-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxalic acid and
N,N-dimethylethane-1,2-diamine using an analogous procedure to that
described in the preparation of Compound 88. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 2.20 (s, 6H) 2.42 (t, J=6.69 Hz, 2H) 2.49
(br. s., 3H) 2.55 (s, 3 H) 3.35 (d, J=6.57 Hz, 2H) 7.18 (s, 1H)
8.31 (t, J=5.56 Hz, 1H) 8.40 (d, J=2.02 Hz, 1H) 8.53 (s, 1H) 12.14
(s, 1H). [M+H] calc'd for C.sub.18H.sub.21ClN.sub.4O 345. found,
345.4.
Compound 122:
5-(3-(cyclopropylcarbamoyl)phenyl)-N-(2-(dimethylamino)ethyl)-3,8-dimethy-
l-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00285##
[1675] The title compound was synthesized from
5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-
-carboxamide and 3-(cyclopropylcarbamoyl)phenyl boronic acid using
an analogous procedure to that described in the preparation of
Compound 84. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.57
(dd, J=3.92, 2.40 Hz, 2H) 0.71 (dd, J=6.95, 2.40 Hz, 2H) 1.23 (s,
1H) 2.26 (s, 3H) 2.65 (s, 3H) 2.87 (d, J=5.05 Hz, 6H) 3.29 (q,
J=5.98 Hz, 2H) 3.61 (q, J=6.15 Hz, 2H) 7.20 (s, 1H) 7.50 (s, 1H)
7.66 (t, J=7.83 Hz, 1H) 7.77 (d, J=7.83 Hz, 1H) 7.98 (d, J=7.83 Hz,
1H) 8.08 (s, 1H) 8.31 (d, J=1.77 Hz, 1H) 8.57-8.61 (m, 1H) 8.59 (d,
J=4.55 Hz, 1H) 12.05 (s, 1H). [M+H] calc'd for
C.sub.28H.sub.31N.sub.5O.sub.2 470. found, 470.4.
Compound 123:
4-(2-Fluoro-5-methyl-pyridin-3-yl)-3,5-dinitro-benzonitrile
##STR00286##
[1677] 4-Chloro-3,5-dinitro-benzonitrile (200 mg, 0.88 mmol),
2-fluoro-3-iodo-5-picolione (208 mg, 0.88 mmol), and copper (45
.mu.m powder, 168 mg, 2.6 mmol) were combined in DMF (2 mL) in a
sealed tube purged with nitrogen. The reaction was heated at
150.degree. C. for 30 min in the microwave. The reaction was
diluted with acetone and the solids were removed by filtration. The
solution was concentrated in vacuo. The crude product was purified
by silica gel chromatography (80% CH.sub.2Cl.sub.2/hexanes) to
provide the title compound as a faintly yellow solid (119 mg, 45%),
which was slow to crystallize. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.50 (s, 2H), 8.16 (d, 1H, J=1.2 Hz), 7.42 (dd, 1H, J=8.8,
2.0 Hz), 2.38 (s, 3H). MS (ES) [m+H] calc'd for
C.sub.13H.sub.7FN.sub.4O.sub.4, 303. found 303.
Compound 124:
3,5-Diamino-4-(2-fluoro-5-methyl-pyridin-3-yl)-benzonitrile
##STR00287##
[1679] Compound 123 (119 mg, 0.39 mmol) was stirred in HOAc (3 mL)
with H.sub.2O (0.5 mL) and stirred at 76.degree. C. Iron powder
(.about.325 mesh, 88 mg, 1.56 mmol) was added, and the reaction
stirred for 4 h. The solution was concentrated in vacuo, diluted
with EtOAc (30 mL), and made basic with sat. NaHCO.sub.3. The
material was then filtered through Celite, and the organics were
separated, dried (MgSO.sub.4), and concentrated in vacuo to provide
the title compound as a brown oil (148 mg, 66%). MS (ES) [m+H]
calc'd for C.sub.13H.sub.11FN.sub.4, 243. found 243.
Compound 125:
5-Amino-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitrile
##STR00288##
[1681] Compound 124 (148 mg, 0.61 mmol) was dissolved in dioxane (2
mL) and pyridinium chloride (80 mg), and the solution was heated at
180.degree. C. in the microwave for 15 minutes. The solution was
concentrated in vacuo. Purification by flash chromatography (20%
acetone/CH.sub.2Cl.sub.2) to provide the title compound as an
off-white solid (118 mg, 87%). MS (ES) [m+H] calc'd for
C.sub.13H.sub.10N.sub.4, 223. found 223.
Compound 126:
5-Iodo-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitrile
##STR00289##
[1683] Compound 125 (118 mg, 0.53 mmol) was dissolved in HOAc (2
mL) and H.sub.2O (1 mL), and the solution stirred at 0.degree. C.
Concentrated HCl (120 mL) in H.sub.2O (120 mL) was added, and the
reaction stirred for 5 min. Sodium nitrite (54 mg, 0.78 mmol) in
H.sub.2O (120 mL) was added dropwise, and the red solution stirred
for 10 min. A solution of iodine (10 mg) and potassium iodide (129
mg, 0.78 mmol) in H.sub.2O (300 .mu.L) was added dropwise, and the
brown frothy solution stirred for 30 min at 0.degree. C. and then
30 min while warming to r.t. The reaction was diluted with H.sub.2O
(5 mL) and extracted with CHCl.sub.3. Organics were dried
(MgSO.sub.4) and concentrated in vacuo. Purification by silica gel
chromatography provided the title compound as a faintly yellow
solid (108 mg, 61%). MS (ES) [m+H] calc'd for
C.sub.13H.sub.81N.sub.3, 334. found 334.
Compound 127:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carbonitril-
e
##STR00290##
[1685] The title compound was prepared in 43% yield from Compound
126 according to the procedure outlined in the preparation of
Compound 84. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.34 (s,
1H), 8.21 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.00 (t, 1H, J=7.6 Hz),
7.89-7.98 (m, 2H), 7.59 (s, 1H), 7.49 (s, 1H), 3.35 (q, 2H, J=7.2
Hz), 2.33 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.21H.sub.17N.sub.3O.sub.2S, 376. found 376.
Compound 128:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid amide
##STR00291##
[1687] Compound 127 (30 mg, 0.08 mmol) was dissolved in dioxane (2
mL) and stirred at r.t. A solution of potassium hydroxide (25 mg,
0.44 mmol) in 30% H.sub.2O.sub.2 solution (1 mL) was added, and the
reaction stirred for 18 h. The solution was neutralized with 1N HCl
and concentrated in vacuo. Purification by silica gel
chromatography (5 to 8% MeOH/CH.sub.2Cl.sub.2 g provided the title
compound as a white solid (14.8 mg, 47%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.28 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 8.10
(d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.88 (t, 1H, J=7.6 Hz),
7.68 (s, 1H), 7.62 (s, 1H), 3.34 (q, 2H, J=7.2 Hz), 2.31 (s, 3H),
1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.21H.sub.19N.sub.3O.sub.3S, 394. found 394.
Compound 129:
4-(2-Fluoro-5-methyl-pyridin-3-yl)-3,5-dinitro-benzoic acid methyl
ester
##STR00292##
[1689] The title compound was prepared from
4-chloro-3,5-dinitro-benzoic acid methyl ester in 94% yield
according to the procedure outline for the preparation of Compound
123. MS (ES) [m+H] calc'd for C.sub.14H.sub.10FN.sub.3O.sub.6, 336.
found 336.
Compound 130:
3,5-Diamino-4-(2-fluoro-5-methyl-pyridin-3-yl)-benzoic acid methyl
ester
##STR00293##
[1691] Compound 129 (2.02, 6.03 mmol) was stirred in MeOH (150 mL)
with 10% Pd/C (200 mg) under a hydrogen atmosphere for 1.5 h. The
reaction was filtered through Celite and concentrated to provide
the title compound as a brown solid (1.64 g, 99%). MS (ES) [m+H]
calc'd for C.sub.14H.sub.14FN.sub.3O.sub.2, 276. found 276.
Compound 131: 5-Amino-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid methyl ester
##STR00294##
[1693] The title compound was prepared in 88% yield from example
Compound 130 according to the procedure outlined for the
preparation of Compound 125. MS (ES) [m+H] calc'd for
C.sub.14H.sub.13N.sub.3O.sub.2, 256. found 256.
Compound 132: 5-Iodo-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid methyl ester
##STR00295##
[1695] The title compound was prepared in 69% yield from Compound
131 according to the procedure outlined for the preparation of
Compound 126. MS (ES) [m+H] calc'd for
C.sub.14H.sub.11IN.sub.2O.sub.2, 367. found 367.
Compound 133:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid methyl ester
##STR00296##
[1697] The title compound was prepared in 65% yield from Compound
132 according to the procedure outlined in the preparation of
Compound 84. MS (ES) [m+H] calc'd for
C.sub.22H.sub.20N.sub.2O.sub.4S, 409. found 409.
Compound 134:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl]-methano-
l
##STR00297##
[1699] LAH reduction of Compound 133 provided the title compound.
.sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.29 (t, J=7.45 Hz, 5H)
2.40 (s, 4H) 7.34 (s, 1H) 7.74 (d, J=0.51 Hz, 1H) 7.90 (t, J=7.83
Hz, 2H) 7.99 (s, 1H) 8.03 (ddd, J=7.71, 1.39, 1.26 Hz, 2H) 8.11 (d,
J=7.07 Hz, 1H) 8.22 (t, J=1.52 Hz, 1H) 8.27 (br. s., 1H) [M+H]
calc'd for C.sub.21H.sub.20N.sub.2O.sub.3S, 381. found, 381.
Compound 135:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-ylmethyl]-d-
imethyl-amine
##STR00298##
[1701] Methanesulfonyl chloride (18 .mu.L, 0.24 mmol) was added to
a solution of Compound 134 (46 mg, 0.12 mmol) and
diisopropylethylamine (43 .mu.L, 0.25 mmol) in THF (1 mL) at
0.degree. C. After stirring for 3 h, dimethylamine (2M, 1 mL, 2
mmol) was added, and the reaction stirred for 16 h. The solution
was concentrated in vacuo and purified by prep-HPLC to provide the
title compound as a pale yellow oil (32 mg, 65%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.36 (br s, 1H), 8.22 (s, 1H), 8.13 (d,
1H, J=7.6 Hz), 8.05 (d, 1H, J=7.6 Hz), 7.88-7.94 (m, 2H), 7.85 (s,
1H), 7.44 (s, 1H), 4.57 (s, 2H), 3.33 (q, 2H, J=7.2 Hz), 2.94 (s,
6H), 2.39 (s, 3H), 1.30 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.23H.sub.25N.sub.3O.sub.2S, 408. found 408.
Compound 136:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-morpholin-4-ylmethyl-9H-pyrido[2,3-
-b]indole
##STR00299##
[1703] The title compound was prepared from Compound 134 and
morpholine according to the procedure outline for the preparation
of Compound 135. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.42 (br
s, 1H), 8.24 (s, 1H), 8.14 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6
Hz), 7.97 (s, 1H), 7.90 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.48 (s,
1H), 4.62 (s, 2H), 4.00-4.09 (m, 2H), 3.71-3.80 (m, 2H), 3.41-3.50
(m, 2H), 3.27-3.32 (m, 4H), 2.39 (s, 3H), 1.29 (t, 3H, J=7.2 Hz).
MS (ES) [m+H] calc'd for C.sub.25H.sub.27N.sub.3O.sub.3S, 450.
found 450.
Compound 137:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-(4-methyl-piperazin-1-ylmethyl)-9H-
-pyrido[2,3-b]indole
##STR00300##
[1705] The title compound was prepared from Compound 134 and
1-methylpiperazine according to the procedure outline for the
preparation of Compound 135. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.39 (br s, 1H), 8.23 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.05
(s, 1H), 8.03 (d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.83 (s,
1H), 7.49 (s, 1H), 4.38 (s, 2H), 3.48-3.56 (m, 2H), 3.26-3.40 (m,
6H), 2.95 (s, 3H), 2.41 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES)
[m+H] calc'd for C.sub.26H.sub.30N.sub.4O.sub.2S, 463. found
463.
Compound 138:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-pyrrolidin-1-ylmethyl-9H-pyrido[2,-
3-b]indole
##STR00301##
[1707] The title compound was prepared from Compound 134 and
pyrrolidine according to the procedure outline for the preparation
of Compound 135. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.36 (br
s, 1H), 8.23 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=7.6
Hz), 7.96 (s, 1H), 7.91 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.47 (s,
1H), 4.62 (s, 2H), 3.51-3.60 (m, 2H), 3.20-3.36 (m, 4H), 2.39 (s,
3H), 2.15-2.23 (m, 2H), 1.99-2.07 (m, 2H), 1.29 (t, 3H, J=7.2 Hz).
MS (ES) [m+H] calc'd for C.sub.25H.sub.27N.sub.3O.sub.2S, 434.
found 434.
Compound 139:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-ylmethyl]-e-
thyl-amine
##STR00302##
[1709] The title compound was prepared from Compound 134 and
ethylamine according to the procedure outline for the preparation
of Compound 135. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.19 (s,
1H), 8.13 (s, 1H), 8.04 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz),
7.84 (t, 1H, J=7.6 Hz), 7.64 (s, 1H), 7.54 (s, 1H), 7.22 (s, 1H),
4.25 (s, 2H), 3.34 (q, 2H, J=7.2 Hz), 2.99-3.07 (m, 2H), 2.25 (s,
3H), 1.20-1.29 (m, 6H). MS (ES) [m+H] calc'd for
C.sub.23H.sub.25N.sub.3O.sub.2S, 408. found 408.
Compound 140:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid
##STR00303##
[1711] Compound 133 (260 mg, 0.64 mmol) was dissolved 1N NaOH (1
mL) and MeOH (2 mL) at 60.degree. C. for 2 h. The reaction was
allowed to cool, and was acidified with 1 N HCl and extracted with
CHCl.sub.3. Organics were dried (MgSO.sub.4) and concentrated to
provide the title compound as a white solid (228 mg, 90%). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.34 (br s, 1H), 8.29 (s, 1H),
8.21 (s, 1H), 8.11 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.90
(t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.79 (s, 1H), 3.31 (q, 2H, J=7.2
Hz), 2.35 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.21H.sub.18N.sub.2O.sub.4S, 395. found 395.
Compound 141:
[5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indol-7-yl]-(4-meth-
yl-piperazin-1-yl)-methanone
##STR00304##
[1713] Compound 140 (40 mg, 0.1 mmol) and HOBT (17 mg, 0.11 mmol)
were dissolved in CH.sub.2Cl.sub.2 (2 mL) at r.t. EDC (29 mg, 0.15
mmol) and 1-methylpiperazine (45 mL, 0.4 mmol) were added, and the
reaction stirred for 3 h. Organics were washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. Purification by
prep-HPLC provided the title compound as a pale yellow solid (32
mg, 67%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.36 (s, 1H),
8.22 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz),
7.87-7.95 (m, 2H), 7.80 (s, 1H), 7.40 (s, 1H), 3.39-3.62 (m, 4H),
3.31 (q, 2H, J=7.2 Hz), 3.16-3.30 (m, 4H), 2.95 (s, 3H), 2.38 (s,
3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.28N.sub.4O.sub.3S, 477. found 477.
Compound 142:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (2-dimethylamino-ethyl)-amide
##STR00305##
[1715] The title compound was prepared in 65% yield according to
the procedure outlined for the preparation of Compound 141. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.38 (br s, 1H), 8.23 (s, 1H),
8.20 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=7.6 Hz), 7.91
(t, 1H, J=7.6 Hz), 7.84 (s, 1H), 7.75 (s, 1H), 3.80-3.86 (m, 2H),
3.42 (t, 2H, J=5.6 Hz), 3.34 (q, 2H, J=7.2 Hz), 3.01 (s, 6H), 2.38
(s, 3H), 1.30 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.25H.sub.28N.sub.4O.sub.3S, 465. found 465.
Compound 143:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid (3-dimethylamino-propyl)-amide
##STR00306##
[1717] The title compound was prepared in 63% yield according to
the procedure outlined for the preparation of Compound 141. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.39 (br s, 1H), 8.24 (s, 1H),
8.19 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=7.6 Hz),
7.88-7.96 (m, 2H), 7.78 (s, 1H), 3.56 (t, 2H, J=6.4 Hz), 3.20-3.35
(m, 4H), 2.93 (s, 6H), 2.39 (s, 3H), 2.02-2.11 (m, 2H), 1.30 (t,
3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.26H.sub.30N.sub.4O.sub.3S, 478. found 478.
Compound 144:
5-(3-Ethanesulfonyl-phenyl)-3-methyl-7-(2H-tetrazol-5-yl)-9H-pyrido[2,3-b-
]indole
##STR00307##
[1719] Compound 127 (14 mg, 0.037 mmol), sodium azide (9.7 mg, 0.15
mmol), and ammonium chloride (8.0 mg, 0.15 mmol) were dissolved in
DMF (1 mL) and heated at 158.degree. C. in the microwave for 1 h.
Purification by prep-HPLC provided the title compound as a white
solid (12 mg, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.35 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.02-8.11
(m, 2H), 7.94 (t, 1H, J=5.6 Hz), 7.83 (s, 1H), 7.54 (s, 1H), 3.44
(q, 2H, J=7.2 Hz), 2.27 (s, 3H), 1.17 (t, 3H, J=7.2 Hz). MS (ES)
[m+H] calc'd for C.sub.21H.sub.18N.sub.6O.sub.2S, 419. found
419.
Compound 145:
(3-Dimethylamino-pyrrolidin-1-yl)-[5-(3-ethanesulfonyl-phenyl)-3-methyl-9-
H-pyrido[2,3-b]indol-7-yl]-methanone
##STR00308##
[1721] The title compound was prepared in 71% yield according to
the procedure outlined for the preparation of Compound 141. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.33 (br s, 1H), 8.21 (s, 1H),
8.11 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz), 7.90 (t, 1H, J=7.6
Hz), 7.81 (s, 1H), 7.76 (s, 1H), 7.40 (s, 1H), 3.71-4.16 (m, 5H),
3.32 (q, 2H, J=7.2 Hz), 2.85-3.05 (m, 6H), 2.45-2.55 (m, 1H), 2.35
(s, 3H), 2.16-2.24 (m, 1H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H]
calc'd for C.sub.27H.sub.30N.sub.4O.sub.3S, 491. found 491.
Compound 146:
N-ethyl-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxamide
##STR00309##
[1723] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 141.
.sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.28 (dt, J=10.29, 7.23 Hz,
7H) 2.37 (s, 3H) 3.32-3.36 (m, 2H) 3.48 (q, J=7.33 Hz, 2H) 7.71 (d,
J=1.52 Hz, 1H) 7.85 (s, 1H) 7.91 (t, J=7.83 Hz, 1H) 8.06 (ddd,
J=7.70, 1.39, 1.26 Hz, 1H) 8.11-8.14 (m, 1H) 8.12 (d, J=1.52 Hz,
1H) 8.24 (t, J=1.77 Hz, 1H) 8.33 (s, 1H) [M+H] calc'd for
C.sub.23H.sub.23N.sub.3O.sub.3S, 422. found, 422.
Compound 147:
6-Bromo-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxylic acid methyl ester
##STR00310##
[1725] N-Bromosuccinimide (59 mg, 0.33 mmol) was added to a
solution of Compound 133 (128 mg, 0.31 mmol) in CH.sub.2Cl.sub.2 (3
mL) at r.t. The reaction was stirred for 18 h at 30.degree. C. and
was then concentrated in vacuo. Purification by prep-HPLC provided
the title compound as a white solid (36 mg, 24%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 12.28 (br s, 1H), 8.23 (s, 1H), 8.15-8.19
(m, 2H), 7.98 (s, 1H), 7.87 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=7.6
Hz), 7.08 (s, 1H), 4.03 (s, 3H), 3.22 (q, 2H, J=7.2 Hz), 2.34 (s,
3H), 1.33 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.19BrN.sub.2O.sub.4S, 487, 489. found 487, 489.
Compound 148:
8-Bromo-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-car-
boxylic acid methyl ester
##STR00311##
[1727] The title compound was isolated in 8% yield during for the
preparation of Compound 147. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 13.32 (br s, 1H), 8.23 (s, 1H), 8.10-8.20 (m, 3H), 7.94 (d,
1H, J=7.6 Hz), 7.79-7.88 (m, 2H), 4.02 (s, 3H), 3.22 (q, 2H, J=7.2
Hz), 2.49 (s, 3H), 1.35 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.19BrN.sub.2O.sub.4S, 487, 489. found 487, 489.
Compound 149:
6-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester
##STR00312##
[1729] N-Chlorosuccinimide (79 mg, 0.59 mmol) was added to a
solution of Compound 133 (220 mg, 0.54 mmol) in CH.sub.2Cl.sub.2 (3
mL) and HOAc (1 mL) at r.t. The reaction was stirred for 18 h at
32.degree. C. and was then concentrated in vacuo. Purification by
prep-HPLC provided the title compound as a white solid (88 mg,
37%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 14.20 (br s, 1H),
8.23 (s, 1H), 8.11-8.19 (m, 2H), 8.00 (s, 1H), 7.87 (t, 1H, J=7.6
Hz), 7.74 (d, 1H, J=7.6 Hz), 7.28 (s, 1H), 4.01 (s, 3H), 3.23 (q,
2H, J=7.2 Hz), 2.37 (s, 3H), 1.34 (t, 3H, J=7.2 Hz). MS (ES) [m+H]
calc'd for C.sub.22H.sub.19ClN.sub.2O.sub.4S, 443, 445. found 443,
445.
Compound 150:
8-Chloro-5-(3-ethanesulfonyl-phenyl)-3-methyl-9H-pyrido[2,3-b]indole-7-ca-
rboxylic acid methyl ester
##STR00313##
[1731] The title compound was isolated in 5% yield during for the
preparation of Compound 149. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 13.70 (br s, 1H), 8.30 (s, 1H), 8.11-8.26 (m, 3H), 7.94 (d,
1H, J=7.6 Hz), 7.80-7.88 (m, 2H), 4.03 (s, 3H), 3.23 (q, 2H, J=7.2
Hz), 2.50 (s, 3H), 1.36 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for
C.sub.22H.sub.19ClN.sub.2O.sub.4S, 443, 445. found 443, 445.
Compound 151:
5-(benzylthio)-3-methyl-9H-pyrido[2,3-b]indole-7-carboxylic
acid
##STR00314##
[1733] The title compound was synthesized using an analogous
procedure to that described in the preparation of Compound 21.
.sup.1H NMR (400 MHz, MeOD 6 ppm 2.52 (s, 3H) 4.39 (s, 2H)
7.15-7.29 (m, 3H) 7.34 (d, J=7.83 Hz, 2H) 7.87 (s, 2H) 7.92 (s, 1H)
8.07 (s, 1H) 8.30 (s, 1H) 8.75 (br. s., 1H) [M+H] calc'd for
C.sub.20H.sub.16N.sub.2O.sub.2S, 349. found, 349.
Compound 152:
5-(benzylthio)-N-(2-(dimethylamino)ethyl)-3-methyl-9H-pyrido[2,3-b]indole-
-7-carboxamide
##STR00315##
[1735] The title compound was synthesized from Compound 151 using
an analogous procedure to that described in the preparation of
Compound 141. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 2.53 (s, 3H)
3.02 (s, 6H) 3.43 (t, J=5.81 Hz, 2H) 3.82 (t, J=5.81 Hz, 2H) 4.42
(s, 2H) 7.16-7.26 (m, 3H) 7.31 (d, J=7.83 Hz, 2H) 7.82 (d, J=1.26
Hz, 1H) 7.96 (s, 1H) 8.30 (s, 1H) 8.80 (s, 1H) [M+H] calc'd for
C.sub.24H.sub.26N.sub.4OS, 419. found, 419.
Compound 153:
5-(3-(N-ethylsulfamoyl)phenyl)-8-methoxy-3-methyl-N-(1-methylpiperidin-4--
yl)-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00316##
[1737] The title compound was synthesized from compound 119 and
3-(N-ethylsulfamoyl)phenylboronic acid using an analogous procedure
to that described in the preparation of Compound 84. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.28 (s, 1H) 8.13 (s, 1 H) 8.04
(m, 1H) 7.88 (m, 1H) 7.75 (m, 1H) 7.81 (t, J=7.84 Hz, 1H) 7.24 (s,
1H) 4.22 (m, 1H) 3.62 (m, br, 2H) 3.22 (m, 2H) 3.01 (q, J=7.32 Hz,
2H) 2.92 (s, 3H) 2.72 (s, 3 H) 2.36 (m, 5H) 1.93 (m, 2H) 1.11 (t,
J=7.32 Hz, 3H). [M+H] calc'd for C.sub.28H.sub.34N.sub.5O.sub.3S,
520. found, 520.
Compound 154:
5-(3-(cyclopropylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-
-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00317##
[1739] The title compound was synthesized from compound 119 and
3-(cyclopropylsulfonyl)phenylboronic acid using an analogous
procedure to that described in the preparation of Compound 84.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.32 (s, 1H) 8.19
(s, 1H) 8.11 (m, 1H) 7.99 (m, 1H) 7.89 (m, 2H) 7.3 (s, 1H) 4.22 (m,
1H) 3.74 (m, 1H) 3.65 (m, 2H) 3.22 (m, 2H) 2.93 (s, 3H) 2.72 (s,
3H) 2.36 (m, 5H) 1.93 (m, 2H) 1.28 (m, 2H) 1.14 (m, 2H). [M+H]
calc'd for C.sub.29H.sub.33N.sub.4O.sub.3S, 517. found, 517.
Compound 155:
3-bromo-N-(5-chloro-2-methoxyphenyl)-5-methylpyridin-amine
##STR00318##
[1741] In a oven dried 50 mL round bottom flask were sequentially
added 4-chloro-2-iodo-1-methoxybenzene (1.13 g, 4.2 mmol),
3-bromo-5-methylpyridin-2-amine (945 mg, 5.05 mmol),
Pd.sub.2(dba).sub.3 (192 mg, 0.21 mmol), xantphos (146 mg, 0.25
mmol) and Na.sup.tBuO (605 mg, 6.3 mmol) at room temperature. The
solid materials were kept under vacuum for 5 min. and then refilled
with nitrogen. This process was repeated thrice before adding dry,
degassed dioxane (10 mL). The heterogeneous mixture was stirred at
room temperature for 15 min. and then at 100.degree. C. for 1 h.
Finally upon completion of the reaction, it was diluted with ether
and filtered through a small pad of silica gel with several
washings. All the washings and filtrate concentrated in vacuum and
the crude residue was further purified by flash chromatography to
provide title compound (1.16 g, 84%). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 2.26 (s, 3H) 3.94 (s, 3H) 6.81 (d, J=8.59
Hz, 1H) 6.93 (dd, J=8.72, 2.65 Hz, 1H) 7.65 (d, J=2.02 Hz, 1H) 7.77
(br. s, 1H) 8.07 (d, J=1.26 Hz, 1H) 8.58 (d, J=2.27 Hz, 1H). [M+H]
calc'd for C.sub.13H.sub.13ClN.sub.2O, 326.98. found 327.2.
Compound 156: 5-choloro-8-methoxy-9H-pyrido[2,3-b]indole
##STR00319##
[1743] To a stirred solution of Compound 155 (1.0 g, 3.05 mmol) in
anhydrous and degassed DMF (10 mL), were added Pd(OAc).sub.2 (69
mg, 0.31 mmol) and DBU (1.37 mL, 9.15 mmol), under nitrogen. After
being stirred for 6 h. at 155.degree. C. the reaction was quenched
by addition of water (20 mL). The solid precipitates out was
filtered and washed thoroughly with water. The residue was dried
under vacuum and purified by flash chromatography to furnish the
title compound (488 mg, 65%).
Compound 157:
5-(3-(ethylsulfonyl)phenyl-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole
##STR00320##
[1745] To a stirred solution of Compound 156 (400 mg, 1.62 mmol)
and 3-(ethylsulfonyl)phenylboronic acid (694 mg, 3.24 mmol) in
anhydrous and degassed dioxane (8 mL), were added Pd(dba).sub.2
(140 mg, 0.24 mmol), PCy.sub.3 (0.68 mL, 20% wt solution in
toluene, 0.49 mmol) and Cs.sub.2CO.sub.3 (1.32 g, 4.05 mmol), under
nitrogen. After being stirred for 6 h. under reflux (oil bath
temperature 125.degree. C.) the reaction was diluted with EtOAc and
filtered through a small pad of celite. The residue was washed
thoroughly with EtOAc and 10% MeOH in CH.sub.2Cl.sub.2. All the
washings and filtrate were concentrated in vacuum and the crude
residue was triturated with ether and then with MeOH. The crude
mass was dried under vacuum to give title compound (493 mg, 80%)
which was used directly for next step without further purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz,
2H) 2.26 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 4.02 (s, 3H) 7.06-7.18 (m,
2H) 7.53 (br. s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.98 (t, J=6.95 Hz,
1H) 8.05-8.10 (m, 1 H) 8.26 (d, J=2.02 Hz, 1H) 12.03 (s, 1H). [M+H]
calc'd for C.sub.21H.sub.21N.sub.2O.sub.3S, 381.12. found
381.3.
Compound 158:
5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol
##STR00321##
[1747] Compound 157 (450 mg, 1.18 mmol) and pyridine hydrochloride
(2.73 g, 23.6 mmol) were taken in a sealed tube and heated at
215.degree. C. for 12 h. The black mass was dissolved in water and
extracted twice with 5% EtOH in CH.sub.2Cl.sub.2. The combined
organic extracts were concentrated and the residual mass was
purified by flash chromatography to provide the title compound (259
mg, 60%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t,
J=7.33 Hz, 3H) 2.25 (s, 3H) 3.40 (q, J=7.49 Hz, 2H) 6.97 (s, 2H)
7.54 (d, J=1.77 Hz, 1H) 7.83 (t, J=7.71 Hz, 1H) 7.94-7.98 (m, 2H)
8.06 (t, J=1.64 Hz, 1H) 8.24 (d, J=1.77 Hz, 1H) 10.08 (s, 1H) 11.73
(s, 1H). [M+H] calc'd for C.sub.20H.sub.18N.sub.2O.sub.3S 367.
found, 367.1.
Compound 159:
8-methoxy-3-methyl-5-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-9H-pyrido[2,3-b]-
indole
##STR00322##
[1749] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.72-1.68 (m, 4H) 2.25 (s, 3H) 3.23-3.19 (m, 4H) 4.02 (s, 3H) 7.07
(d, J=8.4 Hz, 1H) 7.15 (d, J=8.0 Hz, 1H) 7.47 (d, J=1.26 Hz, 1H)
7.83 (d, J=7.58 Hz, 1H) 7.90-7.94 (m, 3H) 8.26 (d, J=1.77 Hz, 1H)
12.03 (s, 1H); [M+H] calc'd for C.sub.23H.sub.24N.sub.3O.sub.3S,
422.2. found, 422.3.
Compound 160:
(R)-8-methoxy-3-methyl-5-(3-(pyrrolidin-3-ylsulfonyl)phenyl)-9H-pyrido[2,-
3-b]indole
##STR00323##
[1751] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.92-2.02 (m, 2H) 2.26 (s, 3H) 2.74-2.87 (m, 2H) 3.03 (dd, J=8.0,
8.1, Hz, 1H) 3.11 (dd, J=5.31, 8.0 Hz, 1H) 3.17 (d, J=5.31 Hz, 1H)
4.02 (s, 3H) 7.09 (d, J=8.1 Hz, 1H) 7.15 (d, J=8.0 Hz, 1H) 7.51 (d,
J=1.26 Hz, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.97 (d, J=7.96 Hz, 1H) 8.01
(d, J=8.0 Hz, 1H) 8.07 (d, J=1.52 Hz, 1H) 8.26 (d, J=1.52 Hz, 1H)
12.04 (s, 1H); [M+H] calc'd for C.sub.23H.sub.23N.sub.3O.sub.3S,
422.2. found, 422.3.
Compound 161:
N-cyclopropyl-4-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)picolinami-
de
##STR00324##
[1753] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 0.74 (br. s.,
2H) 0.88 (d, J=9.35 Hz, 2H) 2.37 (s, 3H) 4.11 (s, 3H) 7.22 (s, 2H)
7.82 (br. s., 1H) 7.94 (s, 1H) 8.26 (br. s., 1H) 8.36 (br. s., 1H)
8.76 (br. s., 1H) [M+H] calc'd for C.sub.22H.sub.20N.sub.4O.sub.2,
373. found, 373.
Compound 162:
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)acetamide
##STR00325##
[1755] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.24
(s, 1H) 8.18 (s, 1H) 7.93 (s, 1H) 7.56 (m, 1H) 7.52 (t, J=7.56 Hz,
1H) 7.34 (m, 1H) 7.22 (d, J=8.08 Hz, 1H) 7.18 (d, J=8.08 Hz, 1H)
4.11 (s, 3H) 2.40 (s, 3H) 2.17 (s, 3H). [M+H] calc'd for
C.sub.21H.sub.20N.sub.3O.sub.2, 346. found, 346.
Compound 163:
N-(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)cyclopropaneca-
rboxamide
##STR00326##
[1757] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.44
(s, 1H) 8.25 (s, 1H) 8.00 (s, 1H) 7.52 (m, 2H) 7.27 (m, 3H) 4.11
(s, 3H) 2.43 (s, 3H) 1.80 (m, 1H) 0.95 (m, 2H) 0.88 (m, 2H). [M+H]
calc'd for C.sub.23H.sub.22N.sub.3O.sub.2, 372. found, 372.
Compound 164:
N-cyclopropyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide
##STR00327##
[1759] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.26
(s, 1H) 8.07 (s, 1H) 7.91 (m, 2H) 7.77 (m, 1H) 7.66 (t, J=7.56 Hz,
1H) 7.24 (m, 2H) 4.12 (s, 3H) 2.80 (m, 1H) 2.38 (s, 3H) 0.82 (m,
2H) 0.66 (m, 2H). [M+H] calc'd for C.sub.23H.sub.22N.sub.3O.sub.2,
372. found, 372.
Compound 165:
N,N-diethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide
##STR00328##
[1761] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.26
(s, 1H) 8.07 (s, 1H) 7.91 (m, 2H) 7.77 (m, 1H) 7.66 (t, J=7.56 Hz,
1H) 7.24 (m, 2H) 4.12 (s, 3H) 3.99 (q, J=7.52 Hz, 4H) 2.38 (s, 3H)
1.35 (t, J=7.52 Hz, 6H). [M+H] calc'd for
C.sub.24H.sub.25N.sub.3O.sub.2, 387. found, 387.2
Compound 166:
5-(benzo[d][1,3]dioxol-5-yl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indole
##STR00329##
[1763] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.14
(s, 1H) 7.20 (d, J=8.36 Hz, 1H) 7.18 (d, J=8.36 Hz, 1H) 7.04 (m,
4H) 6.10 (s, 2H) 4.11 (s, 3H) 2.42 (s, 3H). [M+H] calc'd for
C.sub.20H.sub.17N.sub.2O.sub.3, 333; found, 333.
Compound 167:
6-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-4H-chromen-4-one
##STR00330##
[1765] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.37
(s, 1H) 8.29 (m, 2H) 8.07 (m, 2H) 7.84 (d, J=8.84 Hz, 1H) 7.31 (m,
2H) 6.48 (d, J=5.8 Hz, 1H) 4.15 (s, 3H) 2.40 (s, 3H). [M+H] calc'd
for C.sub.22H.sub.rN.sub.2O.sub.3, 357. found, 357.
Compound 168:
N-(2-hydroxyethyl)-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benza-
mide
##STR00331##
[1767] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.30
(s, 1H) 8.12 (m, 2H) 8.00 (m, 1H) 7.72 (m, 1H) 7.70 (t, J=7.84 Hz,
1H) 7.34 (m, 2H) 4.14 (s, 3H) 3.75 (t, J=5.8 Hz, 2H) 3.56 (t, J=5.8
Hz, 2H) 2.43 (s, 3 H). [M+H] calc'd for
C.sub.22H.sub.22N.sub.3O.sub.3, 376. found, 376.
Compound 169:
(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)(pyrrolidin-1-yl-
)methanone
##STR00332##
[1769] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.27
(s, 1H) 8.03 (s, 1H) 7.70 (m, 4H) 7.26 (d, J=8.32 Hz, 1H) 7.21 (d,
J=8.32 Hz, 1H) 4.12 (s, 3H) 3.64 (t, J=6.84 Hz, 2H) 3.58 (t, J=6.84
Hz, 2H) 2.41 (s, 3H) 1.95 (m, 4H). [M+H] calc'd for
C.sub.22H.sub.22N.sub.3O.sub.3, 376. found, 376.
Compound 170:
N-ethyl-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzenesulfonami-
de
##STR00333##
[1771] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.00
(t, J=7.20 Hz, 3H) 2.26 (s, 3H) 2.86 (dd, J=7.33, 5.81 Hz, 2H) 4.02
(s, 3H) 7.07 (d, J=8.08 Hz, 1H) 7.12-7.18 (m, 1H) 7.52 (s, 1H) 7.69
(t, J=5.81 Hz, 1H) 7.79 (d, J=7.58 Hz, 1H) 7.84 (d, J=1.52 Hz, 1H)
7.89 (d, J=7.58 Hz, 1H) 8.00 (d, J=1.77 Hz, 1H) 8.26 (d, J=1.77 Hz,
1H) 12.06 (s, 1H); ESI-MS: m/z calc'd for
C.sub.21H.sub.21N.sub.3O.sub.3S 395.13. found 396.3 (M+H).sup.+
Compound 171:
8-ethoxy-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indole
##STR00334##
[1773] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
157. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t,
J=7.33 Hz, 3H) 1.48 (t, J=6.95 Hz, 3H) 2.26 (s, 3H) 3.41 (q, J=7.49
Hz, 2 H) 4.31 (q, J=7.24 Hz, 2H) 7.07-7.11 (m, 1H) 7.09 (d, J=6.32
Hz, 1H) 7.12-7.17 (m, 1 H) 7.56 (s, 1H) 7.85 (t, J=7.71 Hz, 1H)
8.00 (d, J=1.26 Hz, 1H) 7.97 (dd, J=3.41, 1.64 Hz, 1H) 8.08 (s, 1H)
8.28 (br. s., 1H) 12.03 (br. s., 1H); ESI-MS: m/z calc'd for
C.sub.22H.sub.22N.sub.2O.sub.3S 394.14. found 395.3 (M+H).sup.+
Compound 172:
8-(difluoromethoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]-
indole
##STR00335##
[1775] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
157. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t,
J=7.33 Hz, 3H) 2.27 (s, 3H) 3.42 (q, J=7.33 Hz, 2H) 7.17 (d, J=8.08
Hz, 1H) 7.40 (t, J=7.36 Hz, 1H) 7.42 (s, 1H) 7.50 (s, 1H) 7.89 (t,
J=7.71 Hz, 1H) 8.0-8.1 (m, 2H) 8.11 (t, J=1.77 Hz, 1H) 8.33 (br.
s., 1H) 12.36 (s, 1H). [M+H] calc'd for
C.sub.21H.sub.18F.sub.2N.sub.2O.sub.3S 417. found, 417.3.
Compound 173:
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(2,2,2-trifluoroethoxy)-9H-pyrido[-
2,3-b]indole
##STR00336##
[1777] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
157. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t,
J=7.45 Hz, 3H) 2.27 (s, 3H) 3.42 (q, J=7.33 Hz, 2H) 5.03 (q, J=9.01
Hz, 2 H) 7.13 (d, J=8.34 Hz, 1H) 7.32 (d, J=8.34 Hz, 1H) 7.54 (d,
J=1.26 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 8.00 (td, J=8.72, 1.26 Hz,
2H) 8.09 (t, J=1.64 Hz, 1H) 8.31 (d, J=1.77 Hz, 1H) 12.23 (s, 1H).
[M+H] calc'd for C.sub.22H.sub.19F.sub.3N.sub.2O.sub.3S 449. found,
449.3.
Compound 174:
4-((4-chloro-2-iodophenoxy)methyl)-1-methylpiperidine
##STR00337##
[1779] To a stirred solution of 4-chloro-2-iodophenol (1.72 g, 6.75
mmol) in anhydrous THF (10.0 mL) were sequentially added
(1-methylpiperidin-4-yl)methanol (1.31 g, 10.14 mmol) and triphenyl
phosphine (2.66 g, 10.14 mmol). The reaction mixture was cooled to
0.degree. C., and to it diisopropyl-azodicarboxylate (1.96 mL,
10.14 mmol) was added in drop wise manner. After the addition was
over, stirring continued for another 0.5 h at 0.degree. C. and then
for 12 h at room temperature. Solvents were removed in vacuum and
the residue was purified by silica gel column chromatography,
providing Compound 172 (1.85 g, 75%). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.60-1.63 (m, 2H) 1.63 (br. s., 1H)
1.93-2.00 (m, 3H) 2.19 (t, J=11.24 Hz, 2H) 2.42 (s, 3H) 3.07 (br.
d, J=11.62 Hz, 2H) 3.84 (d, J=6.32 Hz, 2H) 6.69 (d, J=8.59 Hz, 1H)
7.25 (dd, J=8.0, 3.6 Hz, 1H) 7.73 (d, J=2.53 Hz, 1H). [M+H] calc'd
for C.sub.13H.sub.18ClINO, 366.0. found 366.2.
Compound 175:
3-bromo-N-(5-chloro-2-((1-methylpiperidin-4-yl)methoxy)phenyl)-5-methylpy-
ridin-2-amine
##STR00338##
[1781] In a oven dried 50 mL round bottom flask were sequentially
added Compound 174 (620 mg, 1.69 mmol),
3-bromo-5-methylpyridin-2-amine (381 mg, 2.03 mmol),
Pd.sub.2(dba).sub.3 (77 mg, 0.08 mmol), xantphos (59 mg, 0.10 mmol)
and Na.sup.tBuO (244 mg, 2.53 mmol) at room temperature. The solid
materials were kept under vacuum for 5 min. and then refilled with
nitrogen. This process was repeated thrice before adding dry,
degassed dioxane (8 mL). The heterogeneous mixture was stirred at
room temperature for 15 min. and then at 100.degree. C. for 2 h.
Finally upon completion of the reaction, it was diluted with EtOAc
and filtered through a small pad of silica gel with several
washings. All the washings and filtrate concentrated in vacuum and
the crude residue was further purified by flash chromatography to
provide pure Compound 175 (574 mg, 80%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.53 (br. m, 2H) 2.06 (br. m, 3H) 2.23
(s, 3H) 2.77 (s, 3H) 3.00 (br. m, 2H) 3.48 (br. d, J=12.8 Hz, 2H)
4.03 (br. s., 2H) 6.94-7.01 (m, 1H) 7.08 (d, J=8.84 Hz, 1H) 7.86
(s, 1H) 7.93 (d, J=1.52 Hz, 1H) 8.14 (s, 1H) 8.61 (d, J=2.53 Hz,
1H) 9.07 (br. s., 1H). [M+H] calc'd for
C.sub.19H.sub.24BrClN.sub.3O, 424.07. found 424.2.
Compound 176:
5-chloro-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]ind-
ole
##STR00339##
[1783] To a stirred solution of Compound 175 (450 mg, 1.06 mmol) in
anhydrous and degassed DMF (3 mL), were added Pd(OAc).sub.2 (59 mg,
0.26 mmol) and DBU (0.48 mL, 3.18 mmol), under nitrogen. After
being stirred for 6 h. at 155.degree. C. the reaction was quenched
by addition of water (5 mL). The solid precipitates out was
filtered and washed thoroughly with water. The residue was dried
under vacuum and purified by flash chromatography to furnish
Compound 176 (237 mg, 65%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.44 (br. m., 2H) 1.85-1.98 (m, 5H) 2.33 (br. d, J=2.02
Hz, 2H) 2.43 (s, 3H) 2.97 (s, 3H) 4.02 (d, J=6.57 Hz, 2H) 7.02 (d,
J=8.59 Hz, 1H) 7.14 (d, J=8.34 Hz, 1H) 8.36 (s, 1H), 8.49 (s, 1H).
[M+H] calc'd for C.sub.19H.sub.23ClN.sub.3O, 344.15. found
344.2.
Compound 177:
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole
##STR00340##
[1785] To a stirred solution of Compound 176 (170 mg, 0.49 mmol)
and 3-(ethylsulfonyl)phenylboronic acid (265 mg, 1.24 mmol) in
anhydrous and degassed dioxane (5 mL), were added Pd(dba).sub.2 (70
mg, 0.12 mmol), PCy.sub.3 (0.34 mL, 20% wt solution in toluene,
0.24 mmol) and Cs.sub.2CO.sub.3 (479 mg, 1.47 mmol), under
nitrogen. After being stirred for 6 h. under reflux (oil bath
temperature 125.degree. C.) the reaction was diluted with EtOAc and
filtered through a small pad of celite. The residue was washed
thoroughly with EtOAc and 10% MeOH in CH.sub.2Cl.sub.2. All the
washings and filtrate were concentrated in vacuum and the crude
residue was triturated with ether and then with MeOH and then
purified through preparative HPLC to give Compound 177 as a yellow
solid (176 mg, 75%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.20 (t, J=7.34 Hz, 3H) 1.50-1.61 (m, 2 H) 2.13-2.20 (m, 1H)
2.23-2.31 (m, 5H) 2.82 (s, 3H) 2.98-3.09 (m, 2H) 3.39 (q, J=7.34
Hz, 2H) 3.54 (d, J=10.60 Hz, 2H) 4.12 (d, J=6.52 Hz, 2H) 7.06-7.17
(m, 2H) 7.53 (s, 1H) 7.85 (t, J=7.74 Hz, 1H) 7.96 (d, J=7.66 Hz,
1H) 8.00 (d, J=7.66 Hz, 1H) 8.06 (s, 1H) 8.28 (d, J=1.47 Hz, 1H)
11.83 (br. s., 1H), [M+H] calc'd for
C.sub.27H.sub.32N.sub.3O.sub.3S, 478.2. found, 478.4; [M+H+TFA]
calc'd for C.sub.29H.sub.33N.sub.3O.sub.5F.sub.3S, 592.2. found,
592.4.
[1786] The hydrogen chloride salt of compound 177 was prepared by
using an analogous procedure outlined in the preparation of the HCl
salt of compound 88.
[1787] The bis-trifluoroacetic acid salt of compound 177 was
prepared by using an analogous procedure outlined in the
preparation of the TFA salt of compound 88.
Compound 178:
N-cyclopropyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2-
,3-b]indol-5-yl)benzamide
##STR00341##
[1789] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.28 (s, 1H) 8.07
(s, 1H) 7.92 (m, 3H) 7.79 (m, 1H) 7.67 (t, J=7.56 Hz, 1H) 7.25 (d,
J=8.36 Hz, 1H) 7.21 (d, J=8.36 Hz, 1H) 4.24 (d, J=6.08 Hz, 2H) 3.65
(br, m, 2H) 3.14 (m, 2H) 2.94 (m, 4H) 2.38 (m, 6H) 1.75 (m, 2H)
0.83 (m, 2H) 0.66 (m, 2H). [M+H] calc'd for
C.sub.29H.sub.33N.sub.4O.sub.2, 469. found, 469.
Compound 179:
5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole
##STR00342##
[1791] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.28 (s, 1H) 8.18
(s, 1H) 8.05 (m, 2H) 7.93 (m, 1H) 7.85 (t, J=7.56 Hz, 1H) 7.27 (m,
2H) 4.21 (d, J=5.8 Hz, 2H) 3.65 (br, m, 2H) 3.14 (m, 2H) 2.94 (s,
3H) 2.85 (m, 1H) 2.40 (m, 6H) 1.75 (m, 2H) 1.29 (m, 2H) 1.14 (m,
2H). [M+H] calc'd for C.sub.28H.sub.32N.sub.3O.sub.3S, 490. found,
490.
Compound 180:
N-methyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]-
indole-5-yl)benzenesulfonamide
##STR00343##
[1793] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.28 (s, 1H) 8.18
(s, 1H) 8.05 (m, 2H) 7.93 (m, 1H) 7.85 (t, J=7.56 Hz, 1H) 7.27 (m,
2H) 4.21 (d, J=5.8 Hz, 2H) 3.65 (br, m, 2H) 3.14 (m, 2H) 2.94 (s,
3H) 2.85 (m, 1H) 2.47 (d, J=6.2 Hz, 3H) 1.75 (m, 2H) 1.29 (m, 2H)
1.14 (m, 2H). [M+H] calc'd for C.sub.26H.sub.30N.sub.4O.sub.3S,
479. found, 479.2
Compound 181:
N,N-dimethyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,-
3-b]indole-5-yl)benzenesulfonamide
##STR00344##
[1795] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.28 (s, 1H) 8.18
(s, 1H) 8.05 (m, 2H) 7.93 (m, 1H) 7.85 (t, J=7.56 Hz, 1H) 7.27 (m,
2H) 4.21 (d, J=5.8 Hz, 2H) 3.65 (br m, 2H) 3.14 (m, 2H) 2.94 (s,
3H) 2.85 (m, 1H) 2.66 (s, 3H) 1.75 (m, 2H) 1.29 (m, 2H) 1.14 (m,
2H). [M+H] calc'd for C.sub.27H.sub.32N.sub.4O.sub.3S, 493. found,
493.2
Compound 182:
N-(3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol--
5-yl)phenyl)cyclopropanecarboxamide
##STR00345##
[1797] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.78-0.80 (m, 4H)
1.45-1.55 (m, 2H) 1.75-1.84 (m, 1H) 2.09-2.18 (m, 1H) 2.27 (s, 3H)
2.54 (s, 3H) 2.80 (d, J=4.80 Hz, 2H) 2.96-3.08 (m, 2H) 3.53 (d,
J=11.37 Hz, 2H) 4.08 (d, J=6.82 Hz, 2H) 6.98 (d, J=8.08 Hz, 1H)
7.09 (d, J=8.34 Hz, 1H) 7.22 (d, J=7.83 Hz, 1H) 7.46 (t, J=7.83 Hz,
1H) 7.61 (d, J=8.08 Hz, 1H) 7.72 (d, J=1.26 Hz, 1H) 7.91 (s, 1H)
8.25 (d, J=1.77 Hz, 1H) 9.23 (br. s., 1H) 10.33 (s, 1H) 11.89 (s,
1H); [M+H] calc'd for C.sub.29H.sub.33N.sub.4O.sub.2, 469.3. found,
469.5; [M+H+TFA] calc'd for C.sub.31H.sub.34N.sub.4O.sub.4F.sub.3,
583.3. found, 583.5.
Compound 183:
5-(3-(ethylthio)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-p-
yrido[2,3-b]indole
##STR00346##
[1799] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28 (t, J=7.20 Hz,
3H) 1.48-1.56 (m, 2H) 2.09-2.20 (m, 1H) 2.25 (br. s., 2H) 2.27 (s,
3H) 2.80 (d, J=4.55 Hz, 3H) 3.03 (q, J=7.16 Hz, 4H) 3.53 (d,
J=11.37 Hz, 2H) 4.08 (d, J=6.82 Hz, 2H) 7.00 (d, J=8.08 Hz, 1H)
7.10 (d, J=8.34 Hz, 1H) 7.36-7.52 (m, 4H) 7.59 (s, 1H) 8.27 (s, 1H)
9.41 (br. s., 1H) 11.95 (s, 1H); [M+H] calc'd for
C.sub.27H.sub.32N.sub.3OS, 446.2. found, 446.4; [M+H+TFA] calc'd
for C.sub.29H.sub.33N.sub.3O.sub.3F.sub.3S, 560.2. found,
560.4.
Compound 184:
5-(3-ethoxyphenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido-
[2,3-b]indole
##STR00347##
[1801] The title compound was synthesized using an analogous
procedure to that outlined in the preparation of Compound 177.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.35 (t, J=6.95 Hz,
3H) 1.44-1.56 (m, 2H) 2.10-2.18 (m, 1H) 2.25 (br. s., 5H) 2.80 (d,
J=4.80 Hz, 3H) 2.97-3.07 (m, 2H) 3.52 (d, J=11.62 Hz, 2H) 4.06-4.09
(m, 4H) 6.98-7.14 (m, 5H) 7.44 (t, J=7.71 Hz, 1H) 7.64 (s, 1H) 8.25
(s, 1H) 9.28 (br. s., 1H) 11.87 (s, 1H); [M+H] calc'd for
C.sub.27H.sub.32N.sub.3O.sub.2, 430.2. found, 430.5; [M+H+TFA]
calc'd for C.sub.29H.sub.33N.sub.3O.sub.4F.sub.3, 544.2. found,
544.4.
Compound 185:
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole
##STR00348##
[1803] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
177. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.29 (t, J=7.33 Hz,
3H) 1.71 (d, J=11.37 Hz, 2H) 2.27-2.40 (m, 6H) 3.11 (t, J=12.25 Hz,
2H) 3.51 (d, J=12.88 Hz, 2H) 4.20 (br. s., 2H) 7.28 (br. s., 2H)
7.86 (t, J=7.70 Hz, 1H) 7.92-8.00 (m, 1H) 8.00-8.08 (m, 2H) 8.18
(br. s., 1H) 8.29 (br. s., 1H) [M+H] calc'd for
C.sub.26H.sub.29N.sub.3O.sub.3S, 464. found, 464.
Compound 186:
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-3-yl)meth-
oxy)-9H-pyrido[2,3-b]indole
##STR00349##
[1805] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
177. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.31 (s, br,
1H) 8.19 (s, 1H) 8.06 (m, 1H) 8.00 (m, 1H) 7.89 (m, 2H) 7.27 (m,
2H) 4.38 (m, 2H) 3.91 (m, 2H) 3.50 (m, 1H) 3.35 (t, J=7.32 Hz, 2H)
3.19 (m, 1H) 3.07 (s, 3H) 2.6-2.25 (m, 6H) 1.31 (t, J=7.32 Hz, 3H).
[M+H] calc'd for C.sub.26H.sub.30N.sub.3O.sub.3S, 464. found,
464.
Compound 187:
(R)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-3-yl)meth-
oxy)-9H-pyrido[2,3-b]indole
##STR00350##
[1807] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
177. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.31 (s, br,
1H) 8.19 (s, 1H) 8.06 (m, 1H) 8.00 (m, 1H) 7.89 (m, 2H) 7.27 (m,
2H) 4.38 (m, 2H) 3.91 (m, 2H) 3.50 (m, 1H) 3.35 (t, J=7.32 Hz, 2H)
3.19 (m, 1H) 3.07 (s, 3H) 2.6-2.25 (m, 6H) 1.31 (t, J=7.32 Hz, 3H).
[M+H] calc'd for C.sub.26H.sub.30N.sub.3O.sub.3S, 464. found,
464.
Compound 188:
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpyrrolidin-2-yl)meth-
oxy)-9H-pyrido[2,3-b]indole
##STR00351##
[1809] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t,
J=7.33 Hz, 3H) 1.71-1.77 (m, 4H) 2.12 (m, 1H) 2.26 (s, 3H) 2.45 (s,
3H) 2.78 (br. s., 1H) 3.03 (m, 1H) 3.41 (q, J=7.33 Hz, 2H) 4.07
(dd, J=9.60, 6.32 Hz, 1H) 4.28 (dd, J=9.85, 5.05 Hz, 1H) 7.06 (d,
J=8.01 Hz, 1H) 7.16 (d, J=8.08 Hz, 1H) 7.54 (s, 1H) 7.84 (t, J=7.71
Hz, 1H) 7.98 (t, J=7.58 Hz, 2H) 8.08 (s, 1H) 8.28 (s, 1H) 12.06 (s,
1H); [M+H] calc'd for C.sub.26H.sub.30N.sub.3O.sub.3S, 464.2.
found, 464.4.
Compound 189:
(S)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(pyrrolidin-3-ylmethoxy)-9H-py-
rido[2,3-b]indole
##STR00352##
[1811] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
177. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.29-8.21 (m,
2H) 8.07 (m, 1H) 8.00-7.92 (m, 2H) 7.86 (m, 1H) 7.27 (m, 2H)
4.50-4.12 (m, 4H) 3.70-3.48 (m, 1H) 3.35 (t, J=7.32 Hz, 2H) 3.19
(m, 1H) 2.58 (m, 3H) 2.37 (s, 3H) 1.31 (t, J=7.32 Hz, 3H). [M+H]
calc'd for C.sub.25H.sub.28N.sub.3O.sub.3S, 450. found, 450.
Compound 190:
(R)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-(pyrrolidin-3-ylmethoxy)-9H-py-
rido[2,3-b]indole
##STR00353##
[1813] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
177. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.29-8.21 (m,
2H) 8.07 (m, 1H) 8.00-7.92 (m, 2H) 7.86 (m, 1H) 7.27 (m, 2H)
4.50-4.12 (m, 4H) 3.70-3.48 (m, 1H) 3.35 (t, J=7.32 Hz, 2H) 3.19
(m, 1H) 2.58 (m, 3H) 2.37 (s, 3H) 1.31 (t, J=7.32 Hz, 3H). [M+H]
calc'd for C.sub.25H.sub.28N.sub.3O.sub.3S, 450. found, 450.
Compound 191:
3-(4-chloro-2-iodophenoxy)-N,N-dimethylpropan-1-amine
##STR00354##
[1815] The title compound was synthesized using
4-chloro-2-iodophenol and 3-(dimethylamino)propan-1-ol, in an
analogous procedure to that outlined in the preparation of Compound
174. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.99-2.15 (m,
2H) 2.38 (s, 6H) 2.67 (t, J=7.33 Hz, 2H) 4.07 (t, J=6.06 Hz, 2H)
6.73 (d, J=8.84 Hz, 1H) 7.25 (d, J=2.53 Hz, 1H) 7.74 (d, J=2.53 Hz,
1H). [M+H] calc'd for C.sub.11H.sub.16ClINO, 339.99. found,
340.2.
Compound 192:
3-bromo-N-(5-chloro-2-(3-(dimethylamino)propoxy)phenyl)-5-methylpyridin-2-
-amine
##STR00355##
[1817] The title compound was synthesized by using an analogous
synthetic method as outlined in the preparation of Compound 175.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.18 (m, 2H) 2.23
(s, 3H) 2.80 (s, 6H) 3.19-3.28 (m, 2H) 4.18 (t, J=5.81 Hz, 2H)
6.96-7.02 (m, 1H) 7.04-7.09 (m, 1H) 7.82 (s, 1H) 7.93 (d, J=1.26
Hz, 1H) 8.13 (s, 1H) 8.56 (d, J=2.78 Hz, 1H). [M+H] calc'd for
C.sub.17H.sub.22BrClN.sub.3O, 398.06. found, 398.2.
Compound 193:
3-(5-chloro-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,N-dimethylpropan-1--
amine
##STR00356##
[1819] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
176. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.91-1.99 (m,
2H), 2.21 (s, 6H), 2.47 (S, 3H), 2.52-2.56 (m, 2H), 4.19 (t, J=3.6
Hz, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.14 (d, J=7.84 Hz, 1H), 8.36 (s,
1H), 8.49 (d, J=1.8 Hz, 1H), 12.25 (s, 1H); [M+H] calc'd for
C.sub.17H.sub.21ClN.sub.3O, 318.13. found, 318.2
Compound 194:
3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ylo-
xy)-N,N-dimethylpropan-1-amine
##STR00357##
[1821] The title compound was synthesized from Compound 191 using
an analogous procedure to that outlined in the preparation of
Compound 177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28
(m, 4H) 2.21-2.24 (m, 2H) 2.26 (m, 5H) 2.47 (s, 3H) 3.32 (q, J=7.2
Hz, 2H) 3.47-3.52 (m, 2H) 4.29 (t, J=5.43 Hz, 2H) 7.05 (d, J=8.08
Hz, 1H) 7.13 (d, J=8.08 Hz, 1H) 7.54 (s, 1H) 7.62 (t, J=7.71 Hz,
1H) 7.72 (d, J=7.58 Hz, 1H) 7.93 (d, J=7.83 Hz, 1H) 8.03 (s, 1H)
8.28 (s, 1H) 8.55 (d, J=4.04 Hz, 1H) 9.60 (br. s., 1H) 11.93 (s,
1H); [M+H] calc'd for C.sub.26H.sub.29N.sub.3O.sub.3S, 464.6.
found, 464.6.
Compound 195:
N-(3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)ph-
enyl)cyclopropanecarboxamide
##STR00358##
[1823] The title compound was synthesized from Compound 193 using
an analogous procedure to that outlined in the preparation of
Compound 177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.75-0.81 (m, 4H) 1.80 (m, 1H) 2.22 (dd, J=9.98, 5.43 Hz, 2H) 2.27
(s, 3H) 2.88 (s, 3H) 2.89 (s, 3H) 3.46-3.51 (m, 2H) 4.28 (t, J=5.56
Hz, 2H) 6.99 (d, J=8.08 Hz, 1H) 7.10 (d, J=8.08 Hz, 1H) 7.23 (d,
J=7.83 Hz, 1H) 7.46 (t, J=7.83 Hz, 1H) 7.61 (d, J=9.09 Hz, 1H) 7.74
(d, J=1.26 Hz, 1H) 7.92 (s, 1H) 8.27 (d, J=1.52 Hz, 1H) 9.63 (br.
s., 1H) 10.34 (s, 1H) 11.90 (s, 1H); [M+H] calc'd for
C.sub.27H.sub.31N.sub.4O.sub.2, 443.2. found, 443.3.
Compound 196: 3'-(ethylsulfonyl)biphenyl-4-ol
##STR00359## ##STR00360##
[1825] 4-Bromophenol (10.0 g, 57.8 mmol),
3-(ethylsulfonyl)phenylboronic acid (13.6 g, 63.6 mmol) and
Pd(PPh.sub.3).sub.4 (3.3 g, 0.05 mmol) were taken in a mixture of
dioxane and saturated aqueous potassium carbonate solution (3:1,
280 mL) and heated at 100.degree. C. for 5 h. After disappearance
of starting material (as monitored by TLC), dioxane was removed in
vacuum and the organic matter was extracted with EtOAc. Organic
extract was washed with brine and dried over Na.sub.2SO.sub.4,
concentrated and purified by flash chromatography to yield compound
196 (12.8 g, 85%).
Compound 197: 3'-(ethylsulfonyl)-3-iodobiphenyl-4-ol
##STR00361##
[1827] Compound 196 (11.1 g, 42.3 mmol) was dissolve in MeOH (150
mL) and to it were sequentially added NO (6.98 g, 46.5 mmol) and
NaOH (1.95 g, 48.6 mmol). The mixture was cooled to 0.degree. C.
and aqueous NaOCl (23.2 mL, 13% solution in water; 23.2 mL was
diluted to 100 mL before addition) was added dropwise over a period
of 2.5 h. at 0.degree. C. to 5.degree. C. The resulting slurry was
further stirred for 1 h. and finally quenched with 10% aqueous
Na.sub.2SO.sub.3 solution. With 5% aqueous HCl the pH of the
solution was adjusted to 7. MeOH was partially removed in vacuum,
and the remaining aqueous layer was extracted with EtOAc. Organic
layer was washed with brine, dried (Na.sub.2SO.sub.4), concentrated
and the solid was triturated with ether. The white residue was
dried to provide compound 197 (11.4 g, 70%). 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.12 (t, J=7.45 Hz, 3H) 6.99 (d, J=8.34
Hz, 1H) 7.62 (dd, J=8.59, 2.27 Hz, 1H) 7.69 (t, J=7.83 Hz, 1H) 7.80
(br. d, J=8.08 Hz, 1H) 7.97 (d, J=7.83 Hz, 1H) 8.01-8.03 (m, 1H)
8.07 (d, J=2.27 Hz, 1H) 10.65 (s, 1H). [M+H] calc'd for
C.sub.14H.sub.15IO.sub.3S, 388.96. found, 389.0.
Compound 198:
4-((3'-(ethylsulfonyl)-3-iodobiphenyl-4-yloxy)methyl)-1-methylpiperidine
##STR00362##
[1829] To a stirred solution of compound 197 (1.06 g, 2.73 mmol) in
anhydrous benzene (8.0 mL) were sequentially added
(1-methylpiperidin-4-yl)methanol (529 mg, 4.09 mmol) and triphenyl
phosphine (1.07 g, 4.09 mmol.). The reaction mixture was cooled to
0.degree. C., and to it diisopropyl-azodicarboxylate (0.79 mL, 4.09
mmol) was added in drop wise manner. After the addition was over,
stirring continued for another 0.5 h at 0.degree. C. and then for
12 h at room temperature. Solvents were removed in vacuum and the
residue was purified by silica gel column chromatography, providing
compound 198 (982 mg, 72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (t, J=7.33 Hz, 3H) 1.42 (qd, J=11.87, 3.54 Hz, 1H)
1.77-1.90 (m, 4H) 2.17 (s, 2H) 2.81 (d, J=11.12 Hz, 2H) 3.40 (q,
J=7.33 Hz, 2H) 3.96 (d, J=5.81 Hz, 2H) 7.10 (d, J=8.0 Hz, 1H) 7.71
(t, J=7.71 Hz, 1H) 7.75 (dd, J=8.59, 2.27 Hz, 1H) 7.82 (d, J=7.83
Hz, 1H) 8.01 (d, J=7.58 Hz, 1H) 8.05 (br. m, 1 H) 8.16 (d, J=3.9
Hz, 1H). [M+H] calc'd for C.sub.21H.sub.27INO.sub.3S, 500.07.
found, 500.2.
Compound 199:
3-bromo-5-chloro-N-(3'-(ethylsulfonyl)-4-((1-methylpiperidin-4-yl)methoxy-
)biphenyl-3-yl)pyridin-2-amine
##STR00363##
[1831] In a oven dried 50 mL round bottom flask were sequentially
added compound 198 (1.18 g, 2.36 mmol), compound
3-bromo-5-chloropyridin-2-amine (589 mg, 2.83 mmol),
Pd.sub.2(dba).sub.3 (108 mg, 0.12 mmol), xantphos (208 mg, 0.36
mmol) and Na.sup.tBuO (340 mg, 3.51 mmol) at room temperature. The
solid materials were kept under vacuum for 5 min. and then refilled
with nitrogen. This process was repeated thrice before adding dry,
degassed dioxane (10 mL). The heterogeneous mixture was stirred at
room temperature for 15 min. and then at 100.degree. C. for 2 h.
Finally upon completion of the reaction, it was diluted with EtOAc
and filtered through a small pad of silica gel with several
washings. All the washings and filtrate concentrated in vacuum and
the crude residue was further purified by flash chromatography to
provide pure compound 199 (956 mg, 70%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.14 (t, J=7.33 Hz, 3H) 1.42-1.57 (m, 2H)
1.92 (d, J=13.89 Hz, 2H) 1.98 (br. m, 3H) 2.60 (s., 3H) 2.67 (br.
m, 2H) 3.38 (q, J=7.58 Hz, 2H) 4.06 (d, J=6.06 Hz, 2H) 7.22 (d,
J=8.59 Hz, 1H) 7.43 (dd, J=8.59, 2.27 Hz, 1H) 7.74 (t, J=7.71 Hz,
1H) 7.84 (d, J=7.83 Hz, 1H) 7.99 (d, J=7.58 Hz, 1H) 8.04 (t, J=1.64
Hz, 1H) 8.05 (s, 1H) 8.25 (s, 1H) 8.63 (d, J=2.53 Hz, 1H). [M+H]
calc'd for C.sub.26H.sub.30BrClN.sub.3O.sub.3S, 578.08. found,
578.2.
Compound 200:
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole
##STR00364##
[1833] To a stirred solution of compound 199 (1.13 g, 1.95 mmol) in
anhydrous and degassed DMF (8 mL), were added Pd(OAc).sub.2 (44 mg,
0.19 mmol) and DBU (0.88 mL, 5.86 mmol), under nitrogen. After
being stirred for 6 h. at 155.degree. C. the reaction was quenched
by addition of water (10 mL). The solid precipitates out was
filtered and washed thoroughly with water. The residue was dried
under vacuum and purified by preparative HPLC to furnish compound
200 (388 mg, 40%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.17 (t, J=7.33 Hz, 3H) 1.41 (qd, J=11.62, 3.03 Hz, 2H) 1.86-1.96
(m, 5H) 2.19 (s, 3 H) 2.84 (br. d, J=10.86 Hz, 2H) 3.41 (q, J=7.49
Hz, 2H) 4.09 (d, J=6.32 Hz, 2H) 7.11-7.21 (m, 2H) 7.62 (d, J=2.53
Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 8.00 (t, J=7.83 Hz, 2H) 8.05 (s,
1H) 8.45 (d, J=2.53 Hz, 1H) 12.45 (s, 1H); [M+H] calc'd for
C.sub.26H.sub.29ClN.sub.3O.sub.3S, 498.2. found, 498.2; [M+H+TFA]
calc'd for C.sub.28H.sub.30ClN.sub.3O.sub.5F.sub.3S, 612.2. found,
612.1.
[1834] The hydrogen chloride salt of compound 200 was prepared by
using an analogous procedure outlined in the preparation of the HCl
salt of compound 88.
[1835] The bis-trifluoroacetic acid salt of compound 200 was
prepared by using an analogous procedure outlined in the
preparation of the TFA salt of compound 88.
Compound 201:
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(piperidin-4-ylmethoxy)-9H-pyrido[-
2,3-b]indole
##STR00365##
[1837] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.32 (t, J=7.33 Hz,
3H) 1.60-1.72 (m, 5H) 2.31 (d, J=13.89 Hz, 2H) 3.11 (td, J=12.82,
2.40 Hz, 2H) 3.51 (d, J=12.63 Hz, 2H) 4.19 (d, J=6.57 Hz, 2H)
7.11-7.15 (m, 1H) 7.16-7.20 (m, 1H) 7.64 (d, J=2.27 Hz, 1H) 7.85
(t, J=7.71 Hz, 1H) 7.95 (ddd, J=7.71, 1.39, 1.26 Hz, 1H) 8.05 (ddd,
J=8.08, 1.52, 1.26 Hz, 1H) 8.13 (t, J=1.52 Hz, 1H) 8.31 (s, 1H)
Compound 202:
5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-3-(triflu-
oromethyl)-9H-pyrido[2,3-b]indole
##STR00366##
[1839] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.72 (s, 1H)
8.15 (s, 1H) 8.10 (m, 1H) 7.99 (m, 1H) 7.93 (s, 1H) 7.88 (t, J=7.6
Hz, 1H) 7.28 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 4.24 (d,
J=6.32 Hz, 2H) 3.65 (br, m, 2H) 3.43 (q, J=7.32 Hz, 2H) 3.14 (br,
m, 2H) 2.95 (s, 3H) 2.38 (br, m, 3H) 1.68 (m, br, 2H) 1.31 (t,
J=7.32 Hz, 3H). [M+H] calc'd for
C.sub.27H.sub.29F.sub.3N.sub.3O.sub.3S, 532. found, 532.
Compound 203:
5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido-
[2,3-b]indole-3-carbonitrile
##STR00367##
[1841] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.63 (s, 1H)
8.22 (s, 1H) 8.09 (m, 1H) 7.98 (m, 1H) 7.94 (m, 2H) 7.89 (t, J=7.84
Hz, 1H) 7.26 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 4.24 (d,
J=6.28 Hz, 2H) 3.65 (m, br, 2H) 3.38 (q, J=7.32 Hz, 2H) 3.15 (br,
m, 2H) 2.95 (s, 3H) 2.42 (br, m, 3H) 1.72 (br, m, 2H) 1.31 (t,
J=7.32 Hz, 3H). [M+H] calc'd for C.sub.27H.sub.29N.sub.4O.sub.3S,
489. found, 489.
Compound 204:
2-(5-(3-(ethylsulfonyl)phenyl)-7-fluoro-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)-N,N-dimethylethanamine
##STR00368##
[1843] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.29 (t, J=7.45 Hz,
3H) 2.32 (s, 3H) 3.13 (s, 6H) 3.74 (t, J=4.8 Hz, 2H) 4.64 (t,
J=4.80 Hz, 2H) 7.11 (d, J=12.63 Hz, 1H) 7.59 (s, 1H) 7.88 (t,
J=7.71 Hz, 1H) 7.98 (dd, J=6.82, 2.02 Hz, 1H) 8.10 (dd, J=7.45,
1.64 Hz, 1H) 8.16 (t, J=1.64 Hz, 1H) 8.26 (s, 1H) [M+H] calc'd for
C.sub.24H.sub.26FN.sub.3O.sub.3S, 456. found, 456.
Compound 205:
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-7-fluoro-9H-pyrido[2,3-b]indol-8--
yloxy)-N,N-dimethylpropan-1-amine
##STR00369##
[1845] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.31 (t, J=7.45 Hz,
3H) 2.34 (br. s., 2H) 3.00 (s, 6H) 3.54 (d, J=8.08 Hz, 2H) 4.46 (t,
J=6.19 Hz, 2H) 7.09 (d, J=12.63 Hz, 1H) 7.57 (d, J=2.27 Hz, 1H)
7.89 (d, J=7.07 Hz, 1H) 7.97 (d, J=9.35 Hz, 1H) 8.09-8.14 (m, 2H)
8.35 (s, 1H) [M+H] calc'd for C.sub.24H.sub.25ClFN.sub.3O.sub.3S,
490. found, 490.
Compound 206:
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine
##STR00370##
[1847] A 5 mL microwave vial was charged with Compound 158 (290 mg,
0.79 mmol), 3-(dimethylamino)propyl-4-methylbenzenesulfonate (224
mg, 0.87 mmol), potassium carbonate (218 mg, 1.58 mmol) and 2 mL of
anhydrous DMF, under nitrogen atmosphere. The reaction mixture was
heated at 200.degree. C. for 30 min. in microwave with high
absorption. The reaction was quenched with addition of water, and
the solid precipitate out was collected by filtration and purified
through preparative HPLC to provide title compound as a light
yellow solid (143 mg, 40%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.17 (t, J=7.33 Hz, 3H) 1.99 (qd, J=6.61, 6.44 Hz, 2H)
2.20 (s, 6H) 2.26 (s, 3H) 2.53-2.56 (m, 2H) 3.41 (q, J=7.33 Hz, 2H)
4.25 (t, J=6.19 Hz, 2H) 7.05-7.09 (m, 1H) 7.11-7.14 (m, 1H) 7.54
(d, J=1.52 Hz, 1H) 7.85 (t, J=7.83 Hz, 1H) 7.98 (t, J=6.95 Hz, 2H)
8.06-8.08 (m, 1H) 8.27 (d, J=1.77 Hz, 1H) 12.13 (s, 1H); [M+H]
calc'd for C.sub.25H.sub.30N.sub.3O.sub.3S, 452.2. found,
452.4.
[1848] The hydrogen chloride salt of compound 206 was prepared by
using an analogous procedure outlined in the preparation of the HCl
salt of compound 88.
[1849] The bis-trifluoroacetic acid salt of compound 206 was
prepared by using an analogous procedure outlined in the
preparation of the TFA salt of compound 88.
Compound 207:
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylethanamine
##STR00371##
[1851] The title compound was synthesized from Compound 158 using
an analogous procedure to that outlined in the preparation of
Compound 206 using 2-bromo-N,N-dimethylethanamine. .sup.1H NMR (400
MHz, MeOD) .delta. ppm 1.29 (t, J=7.33 Hz, 3H) 2.32 (s, 3H) 2.91
(t, J=5.31 Hz, 2H) 4.34 (t, J=5.43 Hz, 2H) 7.07-7.14 (m, 2H) 7.65
(d, J=2.02 Hz, 1H) 7.82 (t, J=7.83 Hz, 1H) 7.94-7.98 (m, 1H) 8.02
(dd, J=7.33, 1.52 Hz, 1H) 8.15 (t, J=1.64 Hz, 1H) 8.20 (d, J=2.02
Hz, 1H) [M+H] calc'd for C.sub.24H.sub.27N.sub.3O.sub.3S, 438.
found, 438.
Compound 208:
5-(3-(ethylsulfonyl)phenyl)-8-(2-methoxyethoxy)-3-methyl-9H-pyrido[2,3-b]-
indole
##STR00372##
[1853] The title compound was synthesized from Compound 158 using
an analogous procedure to that outlined in the preparation of
Compound 206 using 2-bromoethylmethylether. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.22 (s, 1H) 8.19 (s, 1H) 8.14 (m, 1H) 8.06 (m,
1H) 7.91 (m, 1H) 7.81 (m, 1H) 7.28 (d, J=8.32 Hz, 1H) 7.22 (d,
J=8.32 Hz, 1H) 4.44 (m, 2H) 3.95 (m, 2H) 3.58 (s, 3H) 3.23 (q,
J=7.32 Hz, 2H) 2.49 (s, 3H) 1.37 (t, J=7.32 Hz, 3H). [M+H] calc'd
for C.sub.23H.sub.25N.sub.2O.sub.4S, 425. found, 425.
Compound 209:
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)ace-
tonitrile
##STR00373##
[1855] The title compound was synthesized from Compound 158 and
2-bromoacetonitrile using an analogous procedure to that outlined
in the preparation of Compound 206. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.36 (t, J=7.33 Hz, 3H) 2.32 (s, 3H) 3.22
(q, J=7.33 Hz, 2H) 5.14 (s, 2H) 7.31-7.37 (m, 2H) 7.82 (t, J=7.71
Hz, 1H) 7.91 (d, J=7.83 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H) 8.11-8.15
(m, 2H) 8.22 (s, 1H) 14.04 (br. s., 1H) [M+H] calc'd for
C.sub.22H.sub.19N.sub.3O.sub.3S, 406. found, 406.
Compound 210:
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
panenitrile
##STR00374##
[1857] The title compound was synthesized from Compound 158 and
3-bromopropionitrile using an analogous procedure to that outlined
in the preparation of Compound 206. .sup.1H NMR (400 MHz, MeOD)
.delta. ppm 1.28 (t, J=7.33 Hz, 3H) 2.30 (s, 3H) 3.10 (t, J=6.69
Hz, 2H) 5.12 (t, J=6.82 Hz, 2H) 7.00-7.05 (m, 2H) 7.53 (dd, J=2.02,
0.76 Hz, 1H) 7.81 (t, J=7.45 Hz, 1H) 7.92 (ddd, J=7.89, 1.45, 1.26
Hz, 1H) 8.02 (dt, J=7.83, 1.52 Hz, 1H) 8.10 (t, J=1.89 Hz, 1H) 8.26
(d, J=2.02 Hz, 1H) [M+H] calc'd for
C.sub.23H.sub.21N.sub.3O.sub.3S, 421. found, 421.
Compound 211:
(R)-8-(1-tert-butyldiphenylsilyloxy)propan-2-yloxy)-(5-(3-(ethylsulfonyl)-
phenyl)-3-methyl-9H-pyrido[2,3-b]indole
##STR00375##
[1859] To a stirred solution of Compound 158 (75 mg, 0.204 mmol) in
anhydrous THF (3.0 mL) were sequentially added
(R)-(tert-butyldiphenylsilyloxy)propan-2-ol (77 mg, 0.245 mmol) and
triphenyl phosphine (81 mg, 0.31 mmol). The reaction mixture was
cooled to 0.degree. C., and to it diisopropyl-azodicarboxylate (60
.mu.L, 0.31 mmol) was added in drop wise manner. After the addition
was over, stirring continued for another 0.5 h at 0.degree. C. and
then for 12 h at room temperature. Solvents were removed in vacuum
and the residue was purified by silica gel column chromatography,
provided the title compound (108 mg, 80%).
Compound 212:
(R)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-1-ol
##STR00376##
[1861] Compound 211 (100 mg, 0.15 mmol) was taken in a THF (3 mL)
and stirred for 12 h at room temperature with TBAF (0.19 mL, 0.19
mmol, 1 M solution in THF). The reaction mixture was diluted with
EtOAc and washed with aqueous NH.sub.4Cl and brine. The organic
extract was dried over Na.sub.2SO.sub.4, concentrated and purified
by preparative HPLC to provide the title compound (50 mg, 73%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.45 Hz,
3H) 1.36 (d, J=6.06 Hz, 3H) 2.26 (s, 3H) 3.40 (q, J=7.41 Hz, 2H)
3.63-3.72 (m, 2H) 4.63 (m, 1H) 4.90 (t, J=6.19 Hz, 1H) 7.07 (d,
J=8.08 Hz, 1H) 7.15-7.19 (m, 1H) 7.56 (s, 1H) 7.85 (t, J=7.71 Hz,
1H) 7.97-7.99 (m, 2H) 8.07-8.10 (m, 1H) 8.27 (d, J=2.02 Hz, 1H)
11.82 (s, 1H); [M+H] calc'd for C.sub.23H.sub.25N.sub.2O.sub.4S,
425.2. found, 425.3.
Compound 213:
(S)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-1-ol
##STR00377##
[1863] The title compound was synthesized from Compound 158 using
an analogous procedure to that outlined in the preparation of
Compound 212. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17
(t, J=7.45 Hz, 3H) 1.36 (d, J=6.06 Hz, 3H) 2.26 (s, 3H) 3.40 (q,
J=7.41 Hz, 2H) 3.63-3.72 (m, 2H) 4.63 (m, 1H) 4.90 (t, J=6.19 Hz,
1H) 7.07 (d, J=8.08 Hz, 1H) 7.15-7.19 (m, 1H) 7.56 (s, 1H) 7.85 (t,
J=7.71 Hz, 1H) 7.97-7.99 (m, 2H) 8.07-8.10 (m, 1H) 8.27 (d, J=2.02
Hz, 1H) 11.82 (s, 1H); [M+H] calc'd for
C.sub.23H.sub.25N.sub.2O.sub.4S, 425.2. found, 425.3.
Compound 214:
1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-2-ol
##STR00378##
[1865] The title compound was synthesized from Compound 158 using
an analogous procedure to that outlined in the preparation of
Compound 212. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.28
(s, 1H) 8.19 (m, 1H) 8.06 (m, 1H) 8.00 (m, 1H) 7.92 (s, 1H) 7.87
(t, J=8.0 Hz, 1H) 7.26 (m, 2H) 4.31 (m, 2H) 4.10 (m, 1H) 3.30 (q,
J=7.5 Hz, 2H) 2.40 (s, 3H) 1.40 (d, J=8 Hz, 3H) 1.31 (t, J=7.5 Hz,
3H). [M+H] calc'd for C.sub.23H.sub.25N.sub.2O.sub.4S, 425. found,
425.
Compound 215:
(S)-4-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)-2-methylpentan-2-ol
##STR00379##
[1867] The title compound was synthesized from Compound 158 using
an analogous procedure to that outlined in the preparation of
Compound 212. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.16
(t, J=7.33 Hz, 3H) 1.17 (d, J=6.2 Hz, 3H) 1.43 (s, 3H) 1.46 (s, 3H)
1.93 (d, J=5.81 Hz, 2H) 2.26 (s, 3H) 3.41 (q, J=6.33 Hz, 2H) 4.05
(m, 1H) 7.07 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 7.53 (s,
1H) 7.86 (t, J=7.58 Hz, 1H) 8.00 (dd, J=7.71, 1.64 Hz, 2H)
8.09-8.11 (m, 1H) 8.28 (s, 1H) 11.95 (s, 1H); [M+H] calc'd for
C.sub.26H.sub.31N.sub.2O.sub.4S, 467.2. found, 467.3.
Compound 216:
2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)eth-
anol
##STR00380##
[1869] The title compound was synthesized from Compound 158 and
2-bromoethanol using an analogous procedure to that outlined in the
preparation of Compound 206. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.30 (s, 1H) 8.19 (m, 1H) 8.06 (m, 1H)
8.00 (m, 2H) 7.87 (t, J=8.0 Hz, 1H) 7.26 (m, 2H) 4.38 (t, J=4 Hz,
2H) 4.08 (t, J=4 Hz, 2H) 3.30 (q, J=7.5 Hz, 2H) 2.41 (s, 3H) 1.31
(t, J=7.5 Hz, 3H). [M+H] calc'd for
C.sub.22H.sub.23N.sub.2O.sub.4S, 411. found, 411.
Compound 217:
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol
##STR00381##
[1871] The title compound was synthesized from Compound 158 and
3-bromopropanol using an analogous procedure to that outlined in
the preparation of Compound 206. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz, 3H) 2.01 (t, J=6.19
Hz, 2H) 2.27 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.72 (q, J=5.98 Hz,
2H) 4.30 (t, J=6.19 Hz, 2H) 4.57 (t, J=5.18 Hz, 1H) 7.06-7.17 (m,
2H) 7.55 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 8.00 (br. s., 1H) 7.98 (d,
J=5.05 Hz, 2H) 8.08 (s, 1H) 8.28 (s, 1H) 11.99 (s, 1H); [M+H]
calc'd for C.sub.23H.sub.25N.sub.2O.sub.4S 425.15. found 425.3
Compound 218:
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-9H-pyrido[2,3-b]indol-8-
-ol
##STR00382##
[1873] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t,
J=7.45 Hz, 3H) 3.42 (q, J=7.33 Hz, 2H) 4.05 (s, 3H) 7.15-7.19 (m,
1H) 7.21-7.25 (m, 1H) 7.62 (d, J=2.27 Hz, 1H) 7.88 (t, J=7.71 Hz,
1H) 7.98-8.03 (m, 2H) 8.06 (t, J=1.64 Hz, 1H) 8.44 (d, J=2.53 Hz,
1H) 12.47 (s, 1H). [M+H] calc'd for
C.sub.20H.sub.18ClN.sub.2O.sub.3S 401. found, 401.2.
Compound 219:
(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-ol
##STR00383##
[1875] The title compound was prepared from Compound 218 by using
an analogous procedure to that outlined in the preparation of
Compound 158. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.35
(s, 1H) 8.15 (m, 1H) 8.07 (m, 1H) 7.97 (m, 1H) 7.88 (t, J=8.0 Hz,
1H) 7.66 (s, 1H) 7.23 (d, J=8.36 Hz, 1H) 7.16 (d, J=8.36 Hz, 1H)
4.44 (t, J=5.8 Hz, 2 H) 3.72 (t, J=8.0 Hz, 2H) 3.43 (q, J=7.32 Hz,
2H) 3.03 (s, 6H) 2.41 (m, 2H) 1.34 (t, J=7.32 Hz, 3H). [M+H] calc'd
for C.sub.24H.sub.27ClN.sub.3O.sub.3S, 472. found, 472.
Compound 220:
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine
##STR00384##
[1877] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. Compound 220 was isolated as yellow solid. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.35 (s, 1H) 8.15 (m, 1H)
8.07 (m, 1H) 7.97 (m, 1H) 7.88 (t, J=8.0 Hz, 1H) 7.66 (s, 1H) 7.23
(d, J=8.36 Hz, 1H) 7.16 (d, J=8.36 Hz, 1H) 4.44 (t, J=5.8 Hz, 2H)
3.72 (t, J=8.0 Hz, 2H) 3.43 (q, J=7.32 Hz, 2H) 3.03 (s, 6H) 2.41
(m, 2H) 1.34 (t, J=7.32 Hz, 3H). [M+H] calc'd for
C.sub.24H.sub.27ClN.sub.3O.sub.3S, 472. found, 472.
[1878] The trifluoroacetic acid salt of compound 220 was prepared
by using an analogous procedure outlined in the preparation of the
TFA salt of compound 88.
Compound 221:
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-diethylethanamine
##STR00385##
[1880] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.37
(s, 1H) 8.15 (m, 1H) 8.07 (m, 1H) 7.97 (m, 1H) 7.88 (t, J=8.0 Hz,
1H) 7.67 (s, 1H) 7.30 (d, J=8.08 Hz, 1H) 7.20 (d, J=8.08 Hz, 1H)
4.67 (t, J=4.0 Hz, 2 H) 3.80 (t, J=4.0 Hz, 2H) 3.51 (m, 4H) 3.41
(q, J=8.0 Hz, 2H) 1.45 (t, J=7.36 Hz, 6H) 1.33 (t, J=8.0 Hz, 3H).
[M+H] calc'd for C.sub.25H.sub.29ClN.sub.3O.sub.3S, 486. found,
486.
Compound 222:
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylethanamine
##STR00386##
[1882] The title compound was prepared from Compound 219 and
2-bromo-N,N'-dimethylethanamine using an analogous procedure to
that outlined in the preparation of Compound 206. Compound 222 was
isolated as light yellow solid. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.40 (s, 1H) 8.14 (m, 1H) 8.10 (m, 1H)
8.00 (m, 1H) 7.89 (t, J=8.0 Hz, 1H) 7.69 (s, 1H) 7.28 (d, J=8.08
Hz, 1H) 7.20 (d, J=8.08 Hz, 1H) 4.68 (t, J=5.0 Hz, 2H) 3.80 (t,
J=5.0 Hz, 2H) 3.43 (q, J=7.32 Hz, 2H) 3.13 (s, 6H) 1.33 (t, J=7.32
Hz, 3H). [M+H] calc'd for C.sub.23H.sub.25ClN.sub.3O.sub.3S, 458.
found, 458.
[1883] The trifluoroacetic acid salt of compound 222 was prepared
by using an analogous procedure outlined in the preparation of the
TFA salt of compound 88.
Compound 223:
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(2-(pyrrolidin-1-yl)ethoxy)-9H-pyr-
ido[2,3-b]indole
##STR00387##
[1885] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.40
(s, 1H) 8.13 (m, 1H) 8.10 (m, 1H) 7.98 (m, 1H) 7.90 (t, J=8.0 Hz,
1H) 7.89 (s, 1H) 7.28 (d, J=8.32 Hz, 1H) 7.20 (d, J=8.32 Hz, 1H)
4.65 (t, J=5.0 Hz, 2H) 3.87 (t, J=5.0 Hz, 2H) 3.40 (q, J=7.32 Hz,
2H) 3.25 (br, 4H) 2.25 (br, 4H) 1.33 (t, J=7.32 Hz, 3H). [M+H]
calc'd for C.sub.25H.sub.27ClN.sub.3O.sub.3S, 484. found, 484.
Compound 224:
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-
-9H-pyrido[2,3-b]indole
##STR00388##
[1887] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.47 (s,
1H) 7.90 (m, 3H) 7.88 (t, J=8.0 Hz, 1H) 7.64 (s, 1H) 7.28 (d,
J=8.08 Hz, 1H) 7.20 (d, J=8.08 Hz, 1H) 4.46 (t, J=5.0 Hz, 2H)
3.75-3.0 (m, br, 10H) 2.80 (s, 3H) 1.18 (t, J=7.6 Hz, 3H). [M+H]
calc'd for C.sub.26H.sub.30ClN.sub.4O.sub.3S, 513. found, 513.
Compound 225:
2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)eth-
anol
##STR00389##
[1889] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 216. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.39
(s, 1H) 8.14 (m, 1H) 8.06 (m, 1H) 8.00 (m, 1H) 7.87 (t, J=8.0 Hz,
1H) 7.71 (d, J=4.0 Hz, 1H) 7.21 (d, J=8.0 Hz, 1H) 7.16 (d, J=8.0
Hz, 1H) 4.36 (t, J=4 Hz, 2H) 4.07 (t, J=4 Hz, 2H) 3.30 (q, J=7.5
Hz, 2H) 1.31 (t, J=7.5 Hz, 3H). [M+H] calc'd for
C.sub.21H.sub.20ClN.sub.2O.sub.4S, 431. found, 431.
Compound 226:
(S)-2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)ethyl 2-aminopropanoate
##STR00390##
[1891] The title compound was prepared from Compound 216 by using
an analogous procedure to that outlined in the preparation of
Compound 65. .sup.1H NMR (400 MHz, DMSO) .delta. ppm 1.18 (t,
J=7.33 Hz, 3H) 1.40 (d, J=7.33 Hz, 3H) 2.27 (s, 3H) 3.42 (q, J=7.33
Hz, 2H) 4.20 (d, J=5.05 Hz, 1H) 4.53 (t, J=4.42 Hz, 2H) 4.58-4.69
(m, 2H) 7.12 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 7.55 (s,
1H) 7.87 (t, J=7.83 Hz, 1H) 8.00 (dd, J=12.63, 7.58 Hz, 2H) 8.08
(s, 1H) 8.29 (s, 1H) 8.33 (br. s., 2H) 11.95 (s, 1H) [M+H] calc'd
for C.sub.25H.sub.27N.sub.3O.sub.5S, 482. found, 482.
Compound 227:
(S)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl 2-aminopropanoate
##STR00391##
[1893] The title compound was prepared from Compound 217 by using
an analogous procedure to that outlined in the preparation of
Compound 65. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17
(t, J=7.33 Hz, 3H) 1.39 (d, J=7.07 Hz, 3H) 2.20-2.24 (m, 2H) 2.26
(s, 3H) 4.14 (m, 1H) 4.32 (t, J=5.68 Hz, 2H) 4.54-4.58 (m., 2H)
7.08-7.11 (m, 1 H) 7.12-7.16 (m, 1H) 7.55 (s, 1H) 7.85 (t, J=7.83
Hz, 1H) 7.98 (dd, J=10.23, 8.46 Hz, 2H) 8.06 (s, 1H) 8.28 (br. s.,
3H) 12.07 (s, 1H); [M+H] calc'd for
C.sub.26H.sub.30N.sub.3O.sub.5S, 496.2. found, 496.4.
Compound 228:
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00392##
[1895] The title compound was synthesized from
5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-
-carboxamide and 3-(cyclopropylcarbamoyl)phenylboronic acid using
an analogous procedure to that described in the preparation of
compound 88. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.77-0.82 (m, 4H) 1.53 (qd, J=11.66, 3.41 Hz, 2H) 1.79-1.82 (m, 3H)
1.95 (t, J=10.86 Hz, 2H) 2.15 (s, 3H) 2.27 (s, 3H) 2.59 (s, 3H)
2.74 (d, J=11.12 Hz, 2H) 3.75 (m, 1H) 6.98 (s, 1 H) 7.27 (d, J=7.58
Hz, 1H) 7.49 (t, J=7.96 Hz, 1H) 7.69 (d, J=2.02 Hz, 2H) 7.91 (s,
1H) 8.25-8.30 (m, 2H) 10.37 (s, 1H) 11.92 (br. s., 1H); [M+H]
calc'd for C.sub.30H.sub.33N.sub.5O.sub.2, 496.3. found, 496.4.
Compound 229:
(R)-8-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy-5-(3-ethylsulfonyl)phenyl)-
-3-methyl-9H-pyrido[2,3-b]indole
##STR00393##
[1897] To a stirred solution of Compound 158 (160 mg, 0.44 mmol) in
anhydrous THF (2.5 mL) were sequentially added
(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (82 .mu.L, 0.66 mmol)
and triphenyl phosphine (173 mg, 0.66 mmol.). The reaction mixture
was cooled to 0.degree. C., and to it diisopropyl-azodicarboxylate
(128 .mu.L, 0.66 mmol) was added in drop wise manner. After the
addition was over, stirring continued for another 0.5 h at
0.degree. C. and then for 12 h at room temperature. Solvents were
removed in vacuum and the residue was purified by silica gel column
chromatography, providing the title compound (148 mg, 70%). [M+H]
calc'd for C.sub.26H.sub.28N.sub.2O.sub.5S, 481.1. found,
481.3.
Compound 230:
(S)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol
##STR00394##
[1899] Compound 229 (120 mg, 0.25 mmol) was taken in a mixture of
THF-TFA-H.sub.2O (3:1:1, 5 mL) and stirred for 6 h at room
temperature. The reaction mixture was diluted with methylene
chloride and washed with aqueous NaHCO.sub.3 and brine. The organic
extract was dried over Na.sub.2SO.sub.4, concentrated and purified
to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.17 (t, J=7.33 Hz, 3H) 2.27 (s, 3H) 3.41 (q, J=7.41
Hz, 2 H) 3.60 (t, J=5.81 Hz, 2H) 3.96 (m, 1H) 4.11 (dd, J=9.60,
6.06 Hz, 1H) 4.27 (dd, J=9.60, 4.29 Hz, 1H) 4.73 (t, J=5.68 Hz, 1H)
4.99 (d, J=5.31 Hz, 1H) 7.07-7.15 (m, 2 H) 7.57 (d, J=1.77 Hz, 1H)
7.85 (t, J=7.71 Hz, 1H) 7.97 (t, J=1.64 Hz, 1H) 7.99 (m, 1 H) 8.09
(t, J=1.64 Hz, 1H) 8.28 (d, J=2.02 Hz, 1H) 11.93 (s, 1H); [M+H]
calc'd for C.sub.23H.sub.25N.sub.2O.sub.5S, 441.1. found,
441.3.
Compound 231:
(R)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propane-1,2-diol
##STR00395##
[1901] The title compound was prepared from Compound 158 using an
analogous procedure to the procedure described for the preparation
of Compound 230. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.17 (t, J=7.33 Hz, 3H) 2.27 (s, 3H) 3.41 (q, J=7.41 Hz, 2H) 3.60
(t, J=5.81 Hz, 2H) 3.96 (m, 1H) 4.11 (dd, J=9.60, 6.06 Hz, 1H) 4.27
(dd, J=9.60, 4.29 Hz, 1H) 4.73 (t, J=5.68 Hz, 1H) 4.99 (d, J=5.31
Hz, 1H) 7.07-7.15 (m, 2H) 7.57 (d, J=1.77 Hz, 1H) 7.85 (t, J=7.71
Hz, 1H) 7.97 (t, J=1.64 Hz, 1H) 7.99 (m, 1H) 8.09 (t, J=1.64 Hz,
1H) 8.28 (d, J=2.02 Hz, 1H) 11.93 (s, 1H); [M+H] calc'd for
C.sub.23H.sub.25N.sub.2O--.sub.5S, 441.1. found, 441.4.
Compound 232:
(R)-1-(dimethylamino)-3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2-
,3-b]indol-8-yloxy)propan-2-ol
##STR00396##
[1903] To a solution of Compound 231 (75 mg, 0.17 mmol) in a
mixture of DMF and CH.sub.2Cl.sub.2 (5 mL, 2:3) were sequentially
added triethyl amine (5 .mu.L, 0.34 mmol) and p-toluenesulfonyl
chloride (50 mg, 0.26 mmol) at 0.degree. C. Slowly the reaction
temperature was raised to room temperature and stirred for 12 h.
The reaction was diluted with CH.sub.2Cl.sub.2 and the organic
layer was successively washed with NH.sub.4Cl and brine solution.
Solvents were dried over Na.sub.2SO.sub.4 and removed under vacuum.
The residual mass was directly used for next step.
[1904] The crude mass was taken in 1 mL of MeOH and treated with
0.5 mL of dimethyl amine in a sealed tube, at 80.degree. C. for 6
h. Solvents were removed and directly subjected to preparative HPLC
purification to give the title compound (22 mg, 27% for two steps).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.45 Hz,
3H) 2.26 (s, 3H) 2.32 (s, 6H) 2.66-2.73 (m, 2H) 4.05-4.16 (m, 2H)
4.25 (dd, J=9.09, 3.28 Hz, 1H) 7.07-7.16 (m, 2H) 7.57 (s, 1H) 7.85
(t, J=7.71 Hz, 1H) 7.98 (dt, J=7.7 7, 1.80 Hz, 2H) 8.09 (s, 1H)
8.29 (d, J=1.77 Hz, 1H) 12.02 (s, 1H); [M+H] calc'd for
C.sub.25H.sub.30N.sub.3O.sub.4S, 468.2. found, 468.3.
Compound 233:
(R)-1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-2-ol
##STR00397##
[1906] A 5 mL microwave vial was charged with Compound 158 (200 mg,
0.545 mmol), (R)-2-methyloxirane (191 .mu.L, 2.72 mmol), triethyl
amine (8 .mu.L, 0.054 mmol) and 2 mL of EtOH. The reaction mixture
was heated at 140.degree. C. for 40 min. in microwave. Solvents
were removed in vacuum and the residue was purified by preparative
HPLC to yield the title compound (46 mg, 20%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz, 3H) 1.25 (d,
J=6.06 Hz, 3H) 2.27 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.94 (m, 1 H)
4.09-4.16 (m, 2H) 4.97 (d, J=4.04 Hz, 1H) 7.07-7.14 (m, 2H) 7.57
(s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.96-8.00 (m, 2H) 8.09 (s, 1H) 8.28
(d, J=1.52 Hz, 1H) 11.94 (s, 1H); [M+H] calc'd for
C.sub.23H.sub.25N.sub.2O.sub.4S, 425.2. found, 425.3.
Compound 234:
(S)-1-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propan-2-ol
##STR00398##
[1908] The title compound was prepared from Compound 158 using an
analogous procedure as described for the preparation of Compound
233. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t,
J=7.33 Hz, 3H) 1.25 (d, J=6.06 Hz, 3H) 2.27 (s, 3H) 3.41 (q, J=7.33
Hz, 2H) 3.94 (m, 1H) 4.09-4.16 (m, 2H) 4.97 (d, J=4.04 Hz, 1H)
7.07-7.14 (m, 2H) 7.57 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.96-8.00
(m, 2H) 8.09 (s, 1H) 8.28 (d, J=1.52 Hz, 1H) 11.94 (s, 1H); [M+H]
calc'd for C.sub.23H.sub.25N.sub.2O.sub.4S, 425.2. found,
425.3.
Compound 235:
3-2(-bromo-5-methoxyphenyl)-2-fluoro-5-methyl-pyridine
##STR00399## ##STR00400##
[1910] To a mixture of 2-fluoro-3-iodo-5-methylpyridine (4.65 g,
19.6 mmol) and Pd(PPh.sub.3).sub.4 (2.26 g, 1.96 mmol) in DME (200
mL) were added a solution of 2-bromo-5-methoxyphenylboronic acid
(4.99 g, 21.6 mmol) in EtOH (15 mL). To the above mixture was added
an aqueous solution of Na.sub.2CO.sub.3 (3 M, 39.2 mL) and the
mixture was heated under reflux for 16 h. The solution was filtered
through a celite bed, concentrated and the remaining aqueous layer
was extracted with ether, washed successively with water, 5%
aqueous NaOH, 10% aqueous HCl, saturated aqueous NaHCO.sub.3 and
brine. Organic layer was dried (Na.sub.2SO.sub.4) and concentrated
and purified by flash chromatography to yield the title compound
(5.3 g, 91%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.34
(s, 3H) 3.78 (s, 3H) 6.99 (dd, J=8.72, 3.16 Hz, 1H) 7.02-7.04 (m,
1H) 7.64 (d, J=8.84 Hz, 1H) 7.76 (dd, J=9.47, 1.89 Hz, 1H) 8.11 (s,
1H). [M+H] calc'd for C.sub.13H.sub.12BrFNO, 296.0. found
296.2.
Compound 236:
346-bromo-3-methoxy-2,4-dinitrophenyl)-2-fluoro-5-methylpyridine
##STR00401##
[1912] Compound 235 (2.0 g, 6.75 mmol) was added to a mixture of
conc. HNO.sub.3 (90%) and conc. H.sub.2SO.sub.4 (95-98%) (20 mL,
2:3) at -20.degree. C. Slowly the reaction was warmed to -5.degree.
C. and stirred for another 1.5 h. The crude mixture was poured into
ice-water, solid precipitates out and collected by filtration,
washed thoroughly with water and dried under vacuum to provide the
title compound (2.08 g, 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 2.34 (s, 3H) 3.97 (s, 3H) 7.87 (dd, J=9.22, 2.15 Hz,
1H) 8.27 (s, 1H) 8.78 (s, 1H). [M+H] calc'd for
C.sub.13H.sub.10BrFN.sub.3O.sub.5, 385.97. found 386.2.
Compound 237:
5-4-(2-fluoro-5-methylpyridine-3-yl)-methoxybenzene-1,3-diamine
##STR00402##
[1914] To Compound 236 (1.02 g, 2.65 mmol) in AcOH--H.sub.2O (8 mL,
3:1) at 80.degree. C. was added iron powder (1.48 g, 26.5 mmol) and
stirred for 2.0 h. Solvents were removed under vacuum and the
residue was dissolved in CH.sub.2Cl.sub.2, and washed with aqueous
NaHCO.sub.3 and brine. The organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated and purified by flash
chromatography to yield the title compound (830 mg, 96%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.30 (s, 2H) 3.59 (s, 2H)
4.46 (s, 2H) 5.09 (s, 2H) 6.34 (s, 1H) 7.56 (dd, J=4.0, 12.0 Hz,
1H), 8.02 (s, 1H). [M+H] calc'd for C.sub.13H.sub.14BrFN.sub.3O,
326.02. found 326.2.
Compound 238:
5-bromo-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-amine
##STR00403##
[1916] Compound 237 (5.0 g, 15.32 mmol) was taken into a mixture of
dioxane-H.sub.2O (100 mL, 1:4) and to it was added aqueous HCl (9.6
mL, 1.6 N in water). The reaction mixture was heated reflux for 6
h. Reaction was diluted with EtOAc and washed with aqueous
NaHCO.sub.3 and brine. The organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated and purified by flash
chromatography to yield the title compound (4.2 g, 89%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.41 (s, 3H) 3.77 (s, 3H)
5.36 (s, 2H) 6.81 (s, 1H) 8.12 (d, J=2.27 Hz, 1H) 8.33 (d, J=2.02
Hz, 1H) 11.65 (s, 1H); [M+H] calc'd for C.sub.13H.sub.13BrN.sub.3O,
306.02. found, 306.2.
Compound 239:
(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-a-
mine
##STR00404##
[1918] A 15 mL microwave vial was charged with Compound 238 (500
mg, 1.63 mmol), 3-(ethylsulfonyl)phenylboronic acid (419 mg, 1.96
mmol) and Pd(PPh.sub.3).sub.4 (188 mg, 0.16 mmol). To the mixture
was added dioxane (5 mL) and a saturated aqueous solution of
K.sub.2CO.sub.3 (2.5 mL). The reaction mixture was heated at
140.degree. C. for 20 min. in microwave. The reaction was diluted
with EtOAc and washed with water and brine. The organic extracts
were dried (Na.sub.2SO.sub.4) and concentrated and purified by
flash chromatography to yield the title compound (528 mg, 82%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.16 (t, J=7.33 Hz,
3H) 2.20 (s, 3H) 3.83 (s, 3H) 5.29 (s, 2H) 6.57 (s, 1H) 7.27 (d,
J=2.24 Hz, 1H) 7.83 (t, J=7.58 Hz, 1H) 7.94 (d, J=3.28 Hz, 1H) 7.98
(d, J=7.33 Hz, 1H) 8.02-8.05 (m, 2H) 11.59 (s., 1H); [M+H] calc'd
for C.sub.21H.sub.21N.sub.3O.sub.4S, 396.2. found, 396.3.
Compound 240:
3-(dimethylamino)-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-py-
rido[2,3-b]indol-7-yl)propanamide
##STR00405##
[1920] To a suspension of Compound 239 (150 mg, 0.38 mmol) in
pyridine (2.0 mL) was added 3-(dimethylamino)propanoyl chloride (71
mg, 0.38 mmol) and the reaction mixture was heated at 105.degree.
C. for 5 h. and quenched with aqueous NH.sub.4Cl solution. Organic
matter was extracted with CH.sub.2Cl.sub.2 (with 10% EtOH) and
washed with brine. The organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated and purified by preparative
HPLC to yield the title compound (103 mg, 55%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.16 (t, J=7.33 Hz, 3H) 2.24 (s, 3H)
2.33 (s, 6H) 2.56 (t, J=5.81 Hz, 2H) 2.62 (t, J=5.31 Hz, 2H) 3.41
(q, J=7.33 Hz, 2H) 3.93 (s, 3H) 7.41 (d, J=1.26 Hz, 1H) 7.87 (t,
J=7.71 Hz, 1H) 7.93-7.97 (m, 1H) 8.03 (d, J=8.84 Hz, 1H) 8.06 (s,
2H) 8.22 (d, J=2.02 Hz, 1H) 10.99 (br. s., 1H) 12.07 (s, 1H); [M+H]
calc'd for C.sub.26H.sub.31N.sub.4O.sub.4S, 495.2. found,
495.4.
Compound 241:
N-(3-(7-amino-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)-cyclo-
propanecarboxamide
##STR00406##
[1922] The title compound was prepared from Compound 238 by using
an analogous procedure to that outlined in the preparation of
Compound 239. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.77-0.81 (m, 4H) 1.79 (p, J=6.06 Hz, 1H) 2.20 (s, 3H) 3.82 (s, 3H)
5.21 (s, 2H) 6.48 (s, 1H) 7.18 (d, J=7.58 Hz, 1H) 7.45-7.41 (m, 2H)
7.63 (d, J=8.34 Hz, 1H) 7.83 (s, 1H) 8.00 (s, 1H) 10.31 (s, 1H)
11.47 (s, 1H); [M+H] calc'd for C.sub.23H.sub.22N.sub.4O.sub.2,
387.17. found, 387.13.
Compound 242:
N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-
-yl)-cyclopropanecarboxamide
##STR00407##
[1924] The title compound was prepared from Compound 239 by using
an analogous procedure to that outlined in the preparation of
Compound 240. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.82
(br. s., 4H) 1.16 (t, J=7.33 Hz, 3H) 2.17 (m., 1H) 2.25 (s, 3H)
3.95 (s, 3H) 7.44 (br. s., 1H) 7.78 (br. s., 1H) 7.87 (d, J=7.58
Hz, 1H) 7.96 (d, J=3.28 Hz, 1H) 8.01 (d, J=7.33 Hz, 1H) 8.07 (br.
s., 1H) 8.23 (br. s., 1H) 9.88 (br. s., 1H) 12.07 (br. s., 1H);
[M+H] calc'd for C.sub.25H.sub.26N.sub.3O.sub.4S, 464.2. found,
464.3.
Compound 243:
1-acetyl-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3--
b]indol-7-yl)piperidine-4-carboxamide
##STR00408##
[1926] The title compound was prepared from Compound 239 by using
an analogous procedure to that outlined in the preparation of
Compound 240. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.16
(t, J=7.33 Hz, 3H) 1.45 (qd, J=12.25, 3.92 Hz, 1H) 1.60 (qd,
J=12.08, 3.92 Hz, 1H) 1.86 (t, J=12.13 Hz, 1H) 1.85 (d, J=1.77 Hz,
1H) 2.01 (s, 3H) 2.25 (s, 3H) 2.57-2.65 (m, 1H) 2.87 (m, 1H) 3.08
(t, J=13.89 Hz, 1H) 3.41 (q, J=7.33 Hz, 2H) 3.88 (d, J=13.89 Hz,
1H) 3.93 (s, 3H) 4.42 (d, J=13.39 Hz, 1H) 7.44 (d, J=1.26 Hz, 1H)
7.70 (s, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.96 (d, J=7.83 Hz, 1H) 8.02
(d, J=7.83 Hz, 1H) 8.06 (d, J=1.52 Hz, 1H) 8.24 (d, J=1.77 Hz, 1H)
9.62 (s, 1H) 12.09 (s, 1H); [M+H] calc'd for
C.sub.29H.sub.33N.sub.4O.sub.5S, 549.2. found, 549.4.3.
Compound 244:
3-(7-amino-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-cyclopropylbe-
nzamide
##STR00409##
[1928] The title compound was prepared from Compound 238 by using
an analogous procedure to that outlined in the preparation of
Compound 239. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.77-0.80 (m, 4H) 1.79 (m, 1H) 2.20 (s, 3H) 3.82 (s, 3H) 5.21 (s,
2H) 6.48 (s, 1H) 7.18 (d, J=7.8 Hz, 1H), 7.41-7.45 (m, 2H) 7.62 (d,
J=8.0 Hz, 1H) 7.83 (br. s, 1H) 8.00 (br. s, 1H) 10.31 (s, 1H) 11.47
(s, 1H); [M+H] calc'd for C.sub.23H.sub.22N.sub.4O.sub.2, 387.2.
found, 387.4.
Compound 245:
3-(7-(cyclopropanecarboxamido)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-
-yl)-N-cyclopropylbenzamide
##STR00410##
[1930] The title compound was prepared from Compound 244 by using
an analogous procedure to that outlined in the preparation of
Compound 240. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.53-0.57 (m, 2H) 0.68-0.71 (m, 2H) 0.81 (br. m, 4H) 2.17 (m, 1H)
2.23 (s, 3H) 2.87 (m, 1H) 3.94 (s, 3H) 7.40 (s, 1H) 7.63 (t, J=7.71
Hz, 1H) 7.72-7.71 (m, 2H) 7.94 (d, J=7.58 Hz, 1H) 8.01 (s, 1H) 8.21
(d, J=1.77 Hz, 1H) 8.54 (d, J=4.04 Hz, 1H) 9.84 (s, 1H) 12.00 (s,
1H); [M+H] calc'd for C.sub.27H.sub.27N.sub.4O.sub.3, 455.2. found,
455.4.
Compound 246:
7-chloro-5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]i-
ndole
##STR00411##
[1932] To a suspension of compound 239 (19.0 mg, 0.05 mmol) in
CH.sub.3CN (1 mL) was taken CuCl.sub.2 (9.7 mg, 0.072 mmol) and
.sup.t-BuONO (12.6 mL, 0.096 mmol). The reaction mixture was heated
at 65.degree. C. for 30 min. and quenched with aqueous NH.sub.4Cl
solution. Organic matter was extracted with EtOAc and washed with
brine. The organic extracts were dried (Na.sub.2SO.sub.4) and
concentrated and purified by preparative HPLC to yield the title
compound (4.2 mg, 21%). .sup.1H NMR (400 MHz, Acetone) .delta. ppm
1.16 (t, J=7.33 Hz, 3H) 2.26 (s, 3H) 4.00 (s, 3H) 7.24 (s, 1H) 7.45
(s, 1H) 7.88 (t, J=7.71 Hz, 1H) 8.01 (dt, J=1.26, 8.02 Hz, 2H) 8.11
(s, 1H) 8.31 (s, 1H) 12.38 (s, 1H); [M+H] calc'd for
C.sub.21H.sub.20ClN.sub.2O.sub.3, 415.1. found, 415.3.
Compound 247:
7-chloro-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-ol
##STR00412##
[1934] The title compound was prepared from Compound 246 by using
an analogous procedure to that outlined in the preparation of
Compound 158. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.16
(t, J=7.33 Hz, 3H) 2.25 (s, 3H) 3.41 (q, J=7.58 Hz, 2H) 7.23 (s, 1
H) 7.46 (s, 1H) 7.87 (t, J=7.71 Hz, 1H) 8.03 (t, J=7.20 Hz, 2H)
8.11 (s, 1H) 8.31 (s, 1 H) 12.27 (br. s., 1H); [M+H] calc'd for
C.sub.20H.sub.17ClN.sub.2O.sub.3S, 401.1. found, 401.3.
Compound 248:
3-(7-chloro-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propan-1-ol
##STR00413##
[1936] The title compound was synthesized from Compound 247 and
3-bromopropan-1-ol using an analogous procedure to that outlined in
the preparation of Compound 206. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.16 (t, J=7.33 Hz, 3H) 1.99-2.06 (m, 2H)
2.25 (s, 3H) 3.41 (q, J=7.58 Hz, 2H) 3.71 (br. s., 2H) 4.26 (t,
J=6.44 Hz, 2H) 4.81 (br. s., 1 H) 7.23 (s, 1H) 7.46 (s, 1H) 7.87
(t, J=7.71 Hz, 1H) 8.03 (t, J=7.20 Hz, 2H) 8.11 (s, 1 H) 8.31 (s,
1H) 12.27 (br. s., 1H); [M+H] calc'd for
C.sub.23H.sub.24ClN.sub.2O.sub.4S, 459.1. found, 459.3.
Compound 249: tert-butyl
5-bromo-7-(tert-butoxycarbonylamino)-8-methoxy-3-methyl-9H-pyrido[2,3-b]i-
ndole-9-carboxylate
##STR00414## ##STR00415##
[1938] To a solution of Compound 238 (660 mg, 2.15 mmol) in a
mixture of CH.sub.2Cl.sub.2-THF (4 mL, 1:1) was added (Boc).sub.2O
(1.24 mL, 5.38 mmol) and the mixture was heated in a sealed tube
for 24 h at a temperature of 50.degree. C. Solvents were removed
under vacuum and the crude residue was purified by flash
chromatography to provide Compound 249 (762 mg, 70%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.49 (s, 9H) 1.62 (s, 9H) 2.48
(s, 3H) 3.74 (s, 3H) 7.91 (s, 1H) 3.74 (s, 3H) 8.38 ((dd, J=1.5,
4.0 Hz, 1H), 8.62 ((dd, J=1.5, 4.0 Hz, 1H), 8.99 (s, 1H). [M+H]
calc'd for C.sub.23H.sub.29BrN.sub.3O.sub.5, 506.12. found
506.3.
Compound 250: tert-butyl
5-bromo-7-(tert-butoxycarbonyl(methyl)amino)-8-methoxy-3-methyl-9H-pyrido-
[2,3-b]indole-9-carboxylate
##STR00416##
[1940] To a solution of Compound 249 (610 mg, 1.2 mmol) in dry DMF
(3 mL) was added NaH (60 mg, 1.51 mmol) at 0.degree. C. and the
mixture was stirred for 20 min. To this ice cold reaction mixture
was added MeI (0.72 mL, 1.44 mmol, 2 M solution) and stirred for
another 30 min. at 0.degree. C. Slowly the temperature was raised
to room temperature and stirred for an additional hour. Reaction
was quenched with water and extracted with ether, washed with
brine, dried over Na.sub.2SO.sub.4 and finally purified flash
chromatography to furnish Compound 250 (468 mg, 75%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.35 (s, 9H) 1.63 (s, 9H) 3.20
(s, 3H) 3.77 (s, 3H) 7.52 (s, 1H) 8.44 (s, 1H) 8.68 (s, 1H). [M+H]
calc'd for C.sub.24H.sub.31BrN.sub.3O.sub.5, 520.14. found
520.3.
Compound 251: tert-butyl
7-(tert-butoxycarbonyl(methyl)amino)-5-(3-(ethylsulfonyl)phenyl)-8-methox-
y-3-methyl-9H-pyrido[2,3-b]indole-9-carboxylate
##STR00417##
[1942] A 5 mL microwave vial was charged with Compound 250 (520 mg,
1.0 mmol), 3-(ethylsulfonyl)phenylboronic acid (321 mg, 1.5 mmol)
and Pd(PPh.sub.3).sub.4 (116 mg, 0.10 mmol). To the mixture was
added dioxane (2 mL) and a saturated aqueous solution of
K.sub.2CO.sub.3 (1 mL). The reaction mixture was heated at
140.degree. C. for 20 min. in microwave. The reaction was diluted
with EtOAc and washed with water and brine. The organic extracts
were dried (Na.sub.2SO.sub.4) and concentrated and the crude
Compound 251 was taken forward for Boc deprotection.
Compound 252:
5-(3-(ethylsulfonyl)phenyl)-8-methoxy-N,3-dimethyl-9H-pyrido[2,3-b]indol--
7-amine
##STR00418##
[1944] The crude residue from previous step (Compound 251) was
dissolved in 3 mL CH.sub.2Cl.sub.2 and to it were sequentially
added 0.2 mL of anisole and 1 mL of TFA. The mixture was stirred at
room temperature for 2 h. Solvent was removed in vacuum and the
residue was basified with saturated aqueous NaHCO.sub.3 and
extracted with EtOAc. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4 and finally purified flash
chromatography to furnish Compound 252 (287 mg, 70%, for 2
steps).
Compound 253:
N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-7-
-yl)-N-methylcyclopropanecarboxamide
##STR00419##
[1946] To a solution of Compound 252 (150 mg, 0.37 mmol) in dry THF
(3 mL) was added cyclopropylcarbonyl chloride (34 .mu.L, 0.37 mmol)
at 0.degree. C. Slowly the temperature was raised to room
temperature and stirred for an additional hour. Reaction was
quenched with aqueous NaHCO.sub.3 solution and extracted with
EtOAc, washed with brine, dried over Na.sub.2SO.sub.4 and finally
purified preparative HPLC to provide Compound 253 (132 mg, 75%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.63 (br. d, J=8.1
Hz, 2H) 0.80 (br. s., 2H) 1.18 (t, J=7.45 Hz, 3H) 1.48 (td, J=8.02,
3.92 Hz, 1H) 2.27 (s, 3H) 3.26 (s, 3H) 3.41 (q, J=7.45 Hz, 2H) 3.98
(s, 3H) 7.17 (s, 1H) 7.54 (s, 1H) 7.88 (t, J=7.71 Hz, 1H) 8.04 (d,
J=8.08 Hz, 2H) 8.14 (s, 1H) 8.31 (d, J=1.26 Hz, 1H) 12.31 (s, 1H);
[M+H] calc'd for C.sub.26H.sub.28N.sub.3O.sub.4S, 478.2. found,
478.3.
Compound 254:
3-(dimethylamino)-N-(5-(3-(ethylsulfonyl)phenyl)-8-methoxy-3-methyl-9H-py-
rido[2,3-b]indol-7-yl)-N-methylpropanamide
##STR00420##
[1948] The title compound was prepared from Compound 252 by using
an analogous procedure to that outlined in the preparation of
Compound 240. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17
(t, J=7.33 Hz, 3H) 2.02 (br. s., 6H) 2.19-2.33 (m, 7H) 3.26 (s, 3
H) 3.96 (s, 3H) 7.14 (s, 1H) 7.53 (s, 1H) 7.88 (t, J=7.71 Hz, 1H)
8.03 (d, J=8.08 Hz, 2 H) 8.12 (s, 1H) 8.32 (d, J=1.26 Hz, 1H) 12.31
(s, 1H); [M+H] calc'd for C.sub.27H.sub.33N.sub.4O.sub.4S, 509.2.
found, 509.3.
Compound 255:
4-(2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-
ethyl)morpholine
##STR00421##
[1950] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.12
(s, 1H) 8.00 (m, 1H) 7.92 (m, 1H) 7.74 (t, J=7.84 Hz, 1H) 7.64 (s,
1H) 7.09 (m, 1H) 7.02 (m, 1H) 6.84 (s, 1H) 4.40 (t, J=5.0 Hz, 2H)
4.11 (br. m, 4H) 3.80 (br. m, 4H) 3.55 (t, J=5.0 Hz, 2H) 3.30 (q,
J=7.32 Hz, 2H) 1.27 (t, J=7.32 Hz, 3 H). [M+H] calc'd for
C.sub.25H.sub.27ClN.sub.3O.sub.4S, 500. found, 500.
Compound 256:
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)pro-
panenitrile
##STR00422##
[1952] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.39
(d, J=2.24 Hz, 1H) 8.08 (m, 1H) 8.06 (m, 1H) 7.92 (m, 1H) 7.84 (t,
J=7.56 Hz, 1H) 7.54 (d, J=2.24 Hz, 1H) 7.08 (d, J=8.08 Hz, 1H) 7.06
(d, J=8.08 Hz, 1H) 5.13 (t, J=6.84 Hz, 2H) 3.30 (q, J=7.32 Hz, 2H)
3.13 (t, J=6.84 Hz, 2H) 1.27 (t, J=7.32 Hz, 3H). [M+H] calc'd for
C.sub.22H.sub.19ClN.sub.3O.sub.3S, 440. found, 440.
Compound 257:
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(1-methylpiperidin-4-yloxy)-9H-pyr-
ido[2,3-b]indole
##STR00423##
[1954] The title compound was prepared from Compound 219 by using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.44
(br, 2H) 8.15 (s, 1H) 8.05 (m, 2H) 7.90 (t, J=7.84 Hz, 1H) 7.70 (s,
1H) 7.30 (s, 1H) 4.76 (br, 1H) 3.56 (m, br, 2H) 3.33 (m, 4H) 3.12
(s, 3H) 2.80 (m, 2H) 1.30 (m, 5H). [M+H] calc'd for
C.sub.25H.sub.27ClN.sub.3O.sub.3S, 484. found, 484.
Compound 258:
3-(5-(3-(ethylsulfonyl)phenyl)-3-(trifluoromethyl)-9H-pyrido[2,3-b]indol--
8-yloxy)-N,N-dimethylpropan-1-amine
##STR00424##
[1956] The title compound was synthesized by using an analogous
synthetic sequence to that outlined in the preparation of Compound
200. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.72 (s, 1H)
8.15 (s, 1H) 8.10 (m, 1H) 7.99 (m, 1H) 7.93 (s, 1H) 7.88 (t, J=7.6
Hz, 1H) 7.28 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 4.44 (t,
J=5.8 Hz, 2H) 3.72 (t, J=8.0 Hz, 2H) 3.43 (q, J=7.32 Hz, 2H) 3.03
(s, 6H) 2.41 (m, 2H) 1.34 (t, J=7.32 Hz, 3 H). [M+H] calc'd for
C.sub.25H.sub.27F.sub.3N.sub.3O.sub.3S, 506. found, 506.
Compound 259:
(3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)phenyl)(morpholino)meth-
anone
##STR00425##
[1958] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.30
(s, 1H) 8.15 (s, 1H) 7.73 (m, 2H) 7.69 (m, 2H) 7.34 (d, J=8.32 Hz,
1H) 7.29 (d, J=8.32 Hz, 1H) 4.14 (s, 3H) 3.63-3.85 (m, 8H) 2.44 (s,
3H). [M+H] calc'd for C.sub.24H.sub.24N.sub.3O.sub.3, 402. found,
402.
Compound 260:
N-methoxy-3-(8-methoxy-3-methyl-9H-pyrido[2,3-b]indol-5-yl)benzamide
##STR00426##
[1960] The title compound was synthesized from Compound 156 using
an analogous procedure to that outlined in the preparation of
Compound 157. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.24
(s, 1H) 8.08 (m, 1H) 8.03 (m, 1H) 7.90 (m, 1H) 7.84 (m, 1H) 7.68
(t, J=8.08 Hz, 1H) 7.21 (d, J=8.08 Hz, 1H) 7.18 (d, J=8.08 Hz, 1H)
4.11 (s, 3H) 3.85 (s, 3H) 2.35 (s, 3H). [M+H] calc'd for
C.sub.21H.sub.20N.sub.3O.sub.3, 362. found, 362.
Compound 261:
5-(3-Ethanesulfonyl-phenyl)-8-(cyclopropylmethoxy)-3-methyl-9H-dipyrido[2-
,3-b; 4',3'-d]pyrrole
##STR00427##
[1962] The title compound was prepared using cyclopropanamine in
the procedure outlined for the preparation of compound 52. .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.35 (s, 1H) 8.20 (s, 1H)
8.02 (m, 2H) 7.83 (m, 3H) 3.43 (q, J=7.32 Hz, 2H) 3.0 (m, 1H) 2.37
(s, 3H) 1.31 (t, J=7.32 Hz, 3H) 0.93 (m, 2H) 0.67 (m, 2H). [M+H]
calc'd for C.sub.22H.sub.23N.sub.4O.sub.2S, 407. found, 407.
Compound 262:
N-(2-(diethylamino)ethyl)-5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyr-
ido[2,3-b]indole-7-carboxamide
##STR00428##
[1964] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 88.
ESI-MS: m/z calc'd for C.sub.28H.sub.34N.sub.4O.sub.3S 506.2. found
507.4 [M+H].sup.+
Compound 263:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(3-morpholinopropyl)-9H-pyrido-
[2,3-b]indole-7-carboxamide
##STR00429##
[1966] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 88.
ESI-MS: m/z calc'd for C.sub.29H.sub.34N.sub.4O.sub.4S 534.6. found
535.7 [M+H].sup.+
Compound 264: 1-(3-(benzyloxy)propoxy)-4-chloro-2-iodobenzene
##STR00430## ##STR00431##
[1968] To a stirred solution of 4-chloro-2-iodophenol (20.0 g, 78.6
mmol) in anhydrous THF (300.0 mL) were sequentially added
3-(benzyloxy)propan-1-ol (18.75 mL, 117.9 mmol) and triphenyl
phosphine (30.92 g, 117.9 mmol.). The reaction mixture was cooled
to 0.degree. C., and to it diisopropylazodicarboxylate (22.8 mL,
117.9 mmol) was added in drop wise manner. After the addition was
over, stirring continued for another 0.5 h at 0.degree. C. and then
for 12 h at room temperature. Solvents were removed in vacuum and
the residue was purified by silica gel column chromatography,
providing the title compound 264 (28.5 g, 90%). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 2.08 (p, J=5.2 Hz, 2H) 3.69 (t,
J=5.68 Hz, 2H) 4.06 (t, J=6.06 Hz, 2H) 4.49 (s, 2H) 6.68 (d, J=8.84
Hz, 1H) 7.19-7.30 (m, 6H) 7.69 (d, J=2.53 Hz, 1H).
Compound 265:
N-(2-(3-(benzyloxy)propoxy)-5-chlorophenyl)-3-bromo-5-methylpyridin-2-ami-
ne
##STR00432##
[1970] In a oven dried 1.0 L round bottom flask were sequentially
added compound 264 (31.0 g, 76.9 mmol),
3-bromo-5-methylpyridin-2-amine (15.84 g, 84.69 mmol),
Pd.sub.2(dba).sub.3 (3.52 g, 3.84 mmol), xantphos (6.67 g, 11.53
mmol) and Na.sup.tBuO (11.09 g, 115.3 mmol) at room temperature.
The solid materials were kept under vacuum for 5 min. and then
refilled with nitrogen. This process was repeated thrice before
adding dry, degassed dioxane (300 mL). The heterogeneous mixture
was stirred at room temperature for 15 min. and then at 90.degree.
C. for 2 h. Finally upon completion of the reaction, it was diluted
with ether and filtered through a small plug of silica gel with
several washings. All the washings and filtrate were combined and
concentrated in vacuum and the crude residue was further purified
by flash chromatography to provide the title compound 265 (26.6,
75%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.07 (p,
J=6.13 Hz, 2H) 2.22 (s, 3H) 3.66 (t, J=6.32 Hz, 2 H) 4.18 (t,
J=6.06 Hz, 2H) 4.48 (s, 2H) 6.95 (dd, J=2.4, 8.59, Hz, 1H) 7.06 (d,
J=8.59 Hz, 1H) 7.18-7.29 (m, 5H) 7.82 (s, 1H) 7.89 (d, J=2.02 Hz,
1H) 8.12 (s, 1H) 8.60 (d, J=2.53 Hz, 1H); [M+H] calc'd for
C.sub.22H.sub.23BrClN.sub.2O.sub.2, 461.1. found, 461.2.
Compound 266:
8-(3-(benzyloxy)propoxy)-5-chloro-3-methyl-9H-pyrido[2,3-b]indole
##STR00433##
[1972] To a stirred solution of compound 265 (25.7 g, 55.65 mmol)
in anhydrous and degassed DMF (200 mL), were added Pd(OAc).sub.2
(1.25 g, 5.56 mmol) and DBU (24.9 mL, 166.9 mmol), under nitrogen.
After being stirred for 6 h. at 155.degree. C. the reaction was
cooled to ambient temperature and quenched by addition of water
(250 mL). The solid precipitates out, filtered and washed
thoroughly with water. The residue was triturated with ether and
filtered, dried under vacuum to get the title compound 266 (12.72
g, 60%) and used directly for the next step. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 2.06 (p, J=6.25 Hz, 2H) 2.47 (s, 3H) 3.75
(t, J=6.32 Hz, 2H) 4.25 (t, J=6.19 Hz, 2H) 4.50 (s, 2H) 7.03 (d,
J=8.34 Hz, 1H) 7.14 (d, J=8.34 Hz, 1H) 7.21-7.33 (m, 5H) 8.36 (d,
J=2.02 Hz, 1H) 8.50 (d, J=1.26 Hz, 1H) 12.09 (s, 1H); [M+H] calc'd
for C.sub.22H.sub.22ClN.sub.2O.sub.2, 381.1. found, 381.3.
Compound 267:
3-(5-chloro-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)propan-1-ol
##STR00434##
[1974] Compound 266 (6.5 g, 17.06 mmol) was taken in a solution of
25% formic acid in MeOH (400 mL) and treated with 10% Pd--C (1.5 g)
under N.sub.2-atmosphere. After being stirred for 24 h, the
reaction mixture was filtered through a small plug of celite. The
filter cake was washed several times with THF. The combined
filtrate and washings were concentrated and dissolved in minimum
volume of hot DMF and the solution was basified with 30% aqueous
NH.sub.3. Solid precipitated out and collected by filtration. The
solid residue washed thoroughly with water, dried under vacuum to
furnish the title compound 267 (3.47 g, 70%) which was used for
next step without further purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.96 (p, J=6.13 Hz, 2H) 2.47 (s, 3H) 3.69
(q, J=5.81 Hz, 2 H) 4.23 (t, J=6.19 Hz, 2H) 4.55 (t, J=5.18 Hz, 1H)
7.03 (d, J=8.34 Hz, 1H) 7.14 (d, J=8.59 Hz, 1H) 8.35 (s, 1H) 8.49
(s, 1H) 12.09 (s, 1H); [M+H] calc'd for
C.sub.15H.sub.16ClN.sub.2O.sub.2, 290.1. found, 291.3.
Compound 268:
5-chloro-8-(3-iodopropoxy)-3-methyl-9H-pyrido[2,3-b]indole
##STR00435##
[1976] To a suspension of compound 267 (4.7 g, 16.16 mmol) in
CH.sub.2Cl.sub.2 (150 mL) were sequentially added triphenyl
phosphine (6.36 g, 24.2 mmol), imidazole (1.54 g, 22.62 mmol) and
iodine (4.93 g, 19.39 mmol) at room temperature under N.sub.2
atmosphere. After being stirred for 16 h, the reaction mixture was
directly filtered and the solid obtained was washed twice with
ether to provide the title compound 268 as yellow solid, which was
directly used for next step without further purification.
Compound 269:
2-((3-(5-chloro-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)propyl)-(ethyl)ami-
no)ethanol
##STR00436##
[1978] The crude product 268 (5.4 g, 16.72 mmol) obtained in
previous step was taken in anhydrous DMF (50 mL) and treated with
2-(ethylamino)ethanol (4.89 mL, 50.16 mmol) under N.sub.2
atmosphere. The reaction mixture was heated at 50.degree. C. for 4
h., cooled to room temperature and water (100 mL) was added to it.
Solid precipitate out, filtered and washed with water (3.times.50
mL). Residue was dried under vacuum and then subjected to silica
gel column purification to provide the title compound 269 (2.81 g,
48% after 2 steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.94 (t, J=7.07 Hz, 3H) 1.90 (p, J=6.51 Hz, 2H) 2.47 (s, 3H)
2.48-2.53 (m, 4H) 2.68 (t, J=6.82 Hz, 2H) 3.44 (t, J=6.44 Hz, 2H)
4.19 (t, J=6.19 Hz, 2H) 4.32 (br. s., 1H) 7.01 (d, J=8.34 Hz, 1H)
7.11 (d, J=8.34 Hz, 1H) 8.35 (d, J=2.02 Hz, 1H) 8.49 (d, J=1.52 Hz,
1H) 12.14 (br. s., 1H); [M+H] calc'd for
C.sub.19H.sub.25ClN.sub.3O.sub.2, 362.2. found, 362.2.
Compound 270:
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethanol
##STR00437##
[1980] To a stirred solution of compound 269 (1.2 g, 3.32 mmol) and
2-(3-(cyclopropylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(2.55 g, 8.29 mmol) in anhydrous and degassed dioxane (50 mL), were
added Pd(dba).sub.2 (286 mg, 0.5 mmol), PCy.sub.3 (1.4 mL, 20% wt
solution in toluene, 0.99 mmol) and Cs.sub.2CO.sub.3 (3.24 g, 9.96
mmol), under nitrogen. After being stirred for 6 h. under reflux
(oil bath temperature 120.degree. C.) the reaction was diluted with
EtOAc and filtered through a small pad of celite. The residue was
washed thoroughly with EtOAc and 10% MeOH in CH.sub.2Cl.sub.2. All
the washings and filtrate were concentrated in vacuum and the crude
residue was purified through preparative HPLC to furnish the title
compound 270 (1.31 g, 78%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.09 (td, J=6.69, 3.28 Hz, 2H) 1.15 (dd, J=4.80, 2.02
Hz, 2H) 1.29 (t, J=7.20 Hz, 3H) 2.24-2.28 (m, 2H) 2.28 (s, 3H)
2.98-3.05 (m, 1H) 3.23-3.32 (m, 4 H) 3.54-3.51 ((br. m, 2H) 3.80
(t, J=5.18 Hz, 2H) 4.33 (t, J=5.56 Hz, 2H) 7.10 (d, J=8.1 Hz, 1H)
7.16 (d, J=8.1 Hz, 1H) 7.58 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.96
(d, J=7.83 Hz, 1H) 8.01 (d, J=7.83 Hz, 1H) 8.09 (m, 1H) 8.30 (s,
1H) 9.28 (br. s., 1H) 12.03 (s, 1H); [M+H] calc'd for
C.sub.28H.sub.34N.sub.3O.sub.4S, 508.2. found, 508.2.
Compound 271:
di-tert-butyl-2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido-
[2,3-b]indol-8-yloxy)propyl)(ethyl)amino)ethyl phosphate
##STR00438##
[1982] To a solution of compound 270 (1.53 g, 3.02 mmol) in dry DMF
(15 mL) were sequentially added tetrazole (26.8 mL, 12.08 mmol, 0.4
M solution in CH.sub.3CN) and di-tert-butyl-diethylphosphoramidite
(1.81 mL, 6.05 mmol) at room temperature and stirred for 3 h. under
N.sub.2 atmosphere. The reaction mixture was then cooled to
-60.degree. C. and a solution of monoperoxyphthalic acid magnesium
salt (896 mg, 1.81 mmol) in DMF (10 mL) was slowly added to it. The
resultant mixture was stirred for 1.5 h at -60.degree. C., after
which a solution of sodium metabisulfite (5.74 g, 30.2 mmol) in
water (20 mL) was added into it. The mixture was then slowly
allowed to warm to ambient temperature. Solvents were removed under
vacuum and the residue was purified by silicagel chromatography
followed by preparative HPLC to provide the title compound 271 (1.1
g, 52%).
Compound 272:
2-((3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
##STR00439##
[1984] Compound 271 (462 mg, 0.66 mmol) was taken in 4N HCl in
dioxane (10 mL) and stirred for 16 h. at room temperature. Solvents
were removed in vacuum, and the title compound 272 was obtained as
yellow dihydrochloride salt (427 mg, 98%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.06-1.11 (m, 2H) 1.13-1.16 (m, 2H) 1.32
(t, J=7.20 Hz, 3H) 2.29 (s, 3H) 2.34-2.31 (m, 2H), 2.98-3.05 (m,
1H) 3.29 (q, J=7.07 Hz, 2H) 3.47 (t, J=4.67 Hz, 2H) 3.54 (br. t,
J=7.2 Hz, 2H) 4.28-4.35 (m, 4H) 7.11-7.14 (m, 1H) 7.16-7.20 (m, 1H)
7.65 (d, J=1.26 Hz, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.96 (dt, J=7.7 7,
1.29 Hz, 1H) 8.01 (dt, J=7.83, 1.39 Hz, 1H) 8.09 (t, J=1.77 Hz, 1H)
8.31 (d, J=1.77 Hz, 1H) 12.35 (br. s., 1H); [M+H] calc'd for
C.sub.28H.sub.35N.sub.3O.sub.7PS, 588.2. found, 588.1.
[1985] The free base of Compound 272 was prepared as follows. To a
solution of Compound 272 (730 mg, 1.105 mmol) in MeOH (15 mL) was
added cyclohexeneoxide (2.23 mL, 22.1 mmol, 20 eq) and stirred for
48 h. White solid separated out. The reaction mixture was diluted
with diethylether and filtered. The residue was washed thoroughly
with diethylether and dried in high vacuum for 24 h to provide the
free base (630 mg, 97%) as white solid.
[1986] The disodium salt of Compound 272 was prepared as follows.
To a stirred suspension of the free base form of Compound 272 (116
mg, 0.197 mmol) in MeOH (4 mL) was added a solution of NaOMe (0.87
mL, 0.434 mmol, 0.5 M solution in MeOH) at 0.degree. C. The
resulting mixture was stirred for 1 h 0.degree. C. and 1 h at room
temperature, by which time reaction mixture turned homogenous and
light yellow in color. Solvents were removed and the residue were
dried in high vacuum for 24 h to provide the bis sodium salt of 272
(122 mg, 98%) as light yellow solid.
Compound 273:
N-cyclopropyl-3-(8-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-3-methyl-9H-py-
rido[2,3-b]indol-5-yl)benzamide
##STR00440##
[1988] The title compound 273 (188 mg, 72%) was synthesized from
compound 269 (195 mg, 0.54 mmol) and
3-(cyclopropylcarbamoyl)phenylboronic acid using an analogous
procedure as outlined in the preparation of compound 270. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.53-0.59 (m, 2H) 0.68-0.71
(m, 2H) 1.29 (td, J=7.14, 2.91 Hz, 3H) 2.22-2.26 (m, 2H) 2.25 (s,
3H) 2.87 (dd, J=7.45, 3.66 Hz, 1H) 3.27 (br. d, J=2.78 Hz, 4 H)
3.48-3.67 (br. m, 4H) 4.31 (br. s., 2H) 7.05 (dd, J=7.96, 3.41 Hz,
1H) 7.12 (dd, J=3.28, 8.4 Hz, 1H) 7.53 (br. s., 1H) 7.62 (td,
J=7.71, 3.28 Hz, 1H) 7.71 (m, 1H) 7.92 (br. d, J=8.34 Hz, 1H) 8.03
(br. s., 1H) 8.27 (br. s., 1H) 8.55 (br. s., 1H) 9.21 (br. s., 1H)
11.96 (br. s., 1H); [M+H] calc'd for
C.sub.29H.sub.35N.sub.4O.sub.3, 487.3. found, 487.2.
Compound 274:
di-tert-butyl-2-((3-(5-(3-(cyclopropylcarbamoyl)phenyl)-3-methyl-9H-pyrid-
o[2,3-b]indol-8-yloxy)propyl)(ethyl)amino)ethyl phosphate
##STR00441##
[1990] The title compound was prepared from compound 273 using an
analogous procedure to that described in the preparation of
compound 271.
Compound 275:
2-((3-(5-(3-(cyclopropylcarbamoyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol--
8-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
##STR00442##
[1992] The title compound was prepared from compound 274 using an
analogous procedure to that described in the preparation of
compound 272. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.54-0.59 (m, 2H) 0.67-0.72 (m, 2H) 1.32 (t, J=7.20 Hz, 3H) 2.26
(s, 3H) 2.34 2.29 (m, 2H) 2.87 (td, J=7.33, 4.04 Hz, 1H) 3.29 (q,
J=7.07 Hz, 2H) 3.48 (t, J=4.67 Hz, 2H) 3.57 (br. t., J=7.62 Hz, 2H)
4.25-4.34 (m, 4H) 7.07 (d, J=8.08 Hz, 1H) 7.15 (d, J=8.08 Hz, 1H)
7.58 (d, J=1.26 Hz, 1H) 7.62 (t, J=7.71 Hz, 1H) 7.73 (d, J=7.83 Hz,
1H) 7.93 (dd, J=7.58, 1.26 Hz, 1H) 8.04 (t, J=1.52 Hz, 1H) 8.28 (d,
J=1.77 Hz, 1H) 8.56 (d, J=4.29 Hz, 1H) 12.22 (br. s., 1H); [M+H]
calc'd for C.sub.29H.sub.36N.sub.4O.sub.6P, 567.2. found,
567.1.
Compound 276:
2-((3-(4-chloro-6-methyl-9H-carbazol-1-yloxy)propyl)(ethyl)amino)-ethanol
##STR00443##
[1994] The title compound (1.15 g, 55%) was synthesized from
compound 269 (1.53 g, 4.24 mmol) and 3-(ethylsulfonyl)phenylboronic
acid using an analogous procedure as outlined in the preparation of
compound 270. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17
(t, J=7.33 Hz, 3H) 1.29 (t, J=7.20 Hz, 3H) 2.2-2.27 (m, 2H) 2.27
(s, 3H) 3.24-3.32 (m, 4H) 3.41 (q, J=7.33 Hz, 2H) 3.48-3.55 (m, 2H)
3.80 (t, J=5.05 Hz, 2H) 4.32 (t, J=5.68 Hz, 2H) 7.10 (d, J=8.4, Hz,
1H) 7.15 (d, J=8.4, Hz, 1H) 7.56 (d, J=1.52 Hz, 1H) 7.86 (t, J=7.71
Hz, 1H) 7.96-8.02 (m, 2H) 8.07 (t, J=1.64 Hz, 1H) 8.30 (d, J=1.77
Hz, 1H) 9.25 (br. s., 1H) 12.03 (s, 1H); [M+H] calc'd for
C.sub.27H.sub.33N.sub.3O.sub.4S, 496.2. found, 496.4.
Compound 277: di-tert-butyl
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propyl)amino)ethyl phosphate
##STR00444##
[1996] The title compound 277 was synthesized from compound 276
(124 mg, 0.25 mmol) using an analogous procedure as outlined for
the preparation of compound 272. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.98 (t, J=7.07 Hz, 3H) 1.17 (t, J=7.33
Hz, 3H) 1.36 (s, 18H) 1.95 (m, 2H) 2.26 (s, 3H) 2.57 (q, J=7.33 Hz,
2H) 2.70 (t, J=6.44 Hz, 2H) 2.76 (t, J=6.82 Hz, 2H) 3.40 (q, J=7.33
Hz, 2H) 3.89 (q, J=7.33 Hz, 2H) 4.26 (t, J=6.06 Hz, 2H) 7.05 (d,
J=8.4 Hz, 1H) 7.12 (d, J=8.4 Hz, 1H) 7.54 (s, 1H) 7.85 (t, J=7.71
Hz, 1H) 7.98 (dt, J=1.2, 7.6 Hz, 2H) 8.07 (t, J=1.64 Hz, 1H) 8.27
(d, J=2.02 Hz, 1H) 12.02 (s, 1 H); [M+H] calc'd for
C.sub.35H.sub.51N.sub.3O.sub.7PS, 688.3. found, 688.6.
Compound 278:
2-(ethyl(3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)propyl)amino)ethyl dihydrogen phosphate
##STR00445##
[1998] The dihydrochloride salt of the title compound 278 was
synthesized from compound 277 using an analogous procedure as
outlined for the preparation of compound 272. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz, 3H) 1.33 (t, J=7.20
Hz, 3 H) 2.29 (s, 3H) 2.28-2.36 (m, 2H) 3.29 (q, J=6.99 Hz, 2H)
3.41 (q, J=7.33 Hz, 2H) 3.48 (br. m, 2H) 3.57 (br. T, J=7.6 Hz, 2H)
4.29-4.36 (m, 4H) 7.14-7.23 (m, 2H) 7.70 (s, 1H) 7.86 (t, J=7.71
Hz, 1H) 7.99 (t, J=8.34 Hz, 2H) 8.09 (s, 1H) 8.33 (s, 1H) 10.86
(br. s., 1H) 12.59 (br. s., 1H); [M+H] calc'd for
C.sub.27H.sub.35N.sub.3O.sub.7PS, 576.2. found, 576.1.
Compound 279: 1-methyl-4-((4-nitrophenoxy)methyl)piperidine
##STR00446## ##STR00447##
[2000] To a mixture of p-chloro nitrobenzene (6.0 g, 38 mmol) and
1-methyl-4-piperidinemethanol (4.91 g, 38 mmol) in anhydrous DMSO
(60 mL) was added NaH (1.82 g, 45.6 mmol) in small portions at room
temperature under N.sub.2-atmosphere. After the addition was
complete the reaction mixture was warmed at 40.degree. C. and
stirred for another [2001] 2 h. The reaction was quenched with
water, and the product was extracted with EtOAc. The organic layer
was washed with brine and dried over Na.sub.2SO.sub.4. The crude
product was recrystallized from ether to yield 6.6 g (69%) of the
title compound as an orange solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.59-1.72 (m, 2H) 1.92 (d, J=11.37 Hz, 3
H) 2.19 (t, J=11.49 Hz, 2H) 2.44 (s, 3H) 3.09 (d, J=11.12 Hz, 2H)
3.93 (d, J=5.31 Hz, 2 H) 6.93 (d, J=9.2 Hz, 2H) 8.20 (d, J=9.6 Hz,
2H); [M+H] calc'd for C.sub.13H.sub.19N.sub.2O.sub.3, 251.2. found,
251.4.
Compound 280:
4-((2-iodo-4-nitrophenoxy)methyl)-1-methylpiperidine
##STR00448##
[2003] An oven-dried 200 mL round bottomed flask was charged with
compound 279 (6.0 g, 23.9 mmol) and solid iodine (3.03 g, 11.9
mmol). To it was slowly added conc. H.sub.2SO.sub.4 (40 mL)
followed by portion wise addition of NaIO.sub.3 (2.36 g, 11.9
mmol), maintaining the reaction temperature below 30.degree. C.
After 4 h the reaction mixture was poured into cold water (160 mL).
10% aqueous Na.sub.2SO.sub.3 (160 mL) was added and the mixture
stirred for 1 h. Solid separated out and was collected by
filtration. The filtrate was basified using 50% aqueous NaOH
solution, and extracted with ether. The ether layer was washed with
brine, dried over Na.sub.2SO.sub.4. Solvent was removed under
reduced pressure to get the second crop of iodinated product. The
combined solid was purified by silica gel column chromatography to
obtain 5.0 g (56%) of the title compound. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 2.24 (br. m., 5H) 2.78-2.88 (m, 2H) 2.89
(d, J=4.80 Hz, 3H) 3.70 (d, J=11.87 Hz, 2H) 4.07 (d, J=3.54 Hz, 2H)
6.84 (d, J=9.09 Hz, 1H) 8.26 (dd, J=2.8, 8.8 Hz, 1H) 8.68 (d,
J=2.78 Hz, 1H); [M+H] calc'd for C.sub.13H.sub.18IN.sub.2O.sub.3,
377.0. found, 377.2.
Compound 281:
3-bromo-5-chloro-N-(2-((1-methylpiperidin-4-yl)methoxy)-5-nitrophenyl)pyr-
idin-2-amine
##STR00449##
[2005] In an oven-dried 200 mL round bottom flask were sequentially
added compound 280 (5.0 g, 13.3 mmol),
3-bromo-5-chloropyridin-2-amine (2.76 g, 13.3 mmol),
Pd.sub.2(dba).sub.3 (610 mg, 0.66 mmol), xantphos (1.15 g, 1.99
mmol) and Na.sup.tBuO (1.92 g, 19.93 mmol) at room temperature. The
solid materials were kept under vacuum for 5 min. and then refilled
with nitrogen. This process was repeated thrice before adding dry,
degassed dioxane (60 mL). The heterogeneous mixture was stirred at
room temperature for 15 min. and then at 100.degree. C. for 1 h.
After completion, the mixture was diluted with CH.sub.2Cl.sub.2 and
filtered through a small plug of silica gel. The filtrate was
concentrated in vacuo and the crude residue was purified by flash
chromatography to provide 3.76 g (62%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.39 (dq, J=3.6,
12.0 Hz, 2H) 1.71-1.78 (m, 3H) 1.92 (t, J=11.37 Hz, 2H) 2.18 (s,
3H) 2.81 (br. d, J=10.86 Hz, 2H) 4.11 (d, J=6.06 Hz, 2H) 7.27 (d,
J=9.09 Hz, 1H) 7.96 (dd, J=8.97, 2.91 Hz, 1H) 8.29 (d, J=2.0 Hz,
1H) 8.37 (d, J=2.0 Hz, 1H) 9.23 (d, J=3.03 Hz, 1H); [M+H] calc'd
for C.sub.18H.sub.21BrClN.sub.4O.sub.3, 455.0. found, 455.2.
Compound 282:
N1-(3-bromo-5-chloropyridin-2-yl)-6-((1-methylpiperidin-4-yl)methoxy)benz-
ene-1,3-diamine
##STR00450##
[2007] A mixture of compound 281, ammonium metavanadate (0.053 g,
0.45 mmol), phosphorous acid, triphenyl ester (0.1 mL, 0.4 mmol),
and 5% Pt/C (0.35 g) was stirred overnight under hydrogen. After
completion the reaction was filtered through celite and
concentrated in vacuo. The residue was reconstituted in
dichloromethane (5 mL), passed through a small plug of silica gel
and the appropriate fractions dried in vacuo. The crude product was
recrystallized from acetonitrile to yield 1.75 g (52.0%) of the
title compound as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.25-1.44 (m, 2H) 1.66-1.83 (m, 3H) 1.93-2.12 (m, 2H)
2.24 (s, 3H) 2.87 (d, J=11.12 Hz, 2H) 3.80 (d, J=5.81 Hz, 2H) 4.70
(br. s., 2H) 6.20 (dd, J=8.59, 2.78 Hz, 1H) 6.75 (d, J=8.84 Hz, 1H)
7.66 (d, J=2.78 Hz, 1H) 7.91 (s, 1H) 8.18-8.20 (m, 1H) 8.20-8.21
(m, 1H). [M+H] calc'd for C.sub.18H.sub.22BrClN.sub.4O, 427. found
427.2.
Compound 283:
3-chloro-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol-5-amin-
e
##STR00451##
[2009] A mixture of Pd(OAc).sub.2 (6.3 mg, 5 mol %),
2-(Dicyclohexylphosphino)biphenyl (9.9 mg, 5 mol %), DBU (0.17 ml,
1.12 mmol), and degassed DMAc (1 ml) was stirred for 30 minutes at
80.degree. C. Next, compound 282 (0.24 g, 0.56 mmol) was added and
the mixture was stirred overnight at 130.degree. C. After
completion H.sub.2O was added to the mixture affording a
suspension. The resulting solids were filtered, rinsed with
H.sub.2O, and dried in vacuo to yield 0.17 g (87.2%) of the title
compound as a dark brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.18-1.39 (m, 2H) 1.67-1.90 (m, 5H) 2.16 (s, 3H) 2.80
(d, J=10.36 Hz, 2H) 3.87 (d, J=6.32 Hz, 2H) 5.35 (s, 2H) 6.37 (d,
J=8.34 Hz, 1H) 6.85 (d, J=8.59 Hz, 1H) 8.31 (d, J=2.53 Hz, 1H) 8.65
(d, J=2.27 Hz, 1H) 11.84 (br. s., 1H). [M+H] calc'd for
C.sub.18H.sub.21ClN.sub.4O, 345. found 345.3.
Compound 284:
3-chloro-5-iodo-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol-
e
##STR00452##
[2011] To a mixture of compound 283 (0.16 g, 0.47 mmol) and 6N HCl
(3.3 ml) at 0.degree. C. was added sodium nitrite (0.035 g, 0.5
mmol) as a solution in H.sub.2O (3 ml) during 5 minutes. The
mixture was allowed to warm to room temperature during 1 hour.
Next, potassium iodide (0.24 g, 1.44 mmol) was added as a solution
in H.sub.2O during 5 minutes. After completion the reaction was
diluted with methanol (1.0 ml) and 10% sodium sulfite (6.6 ml)
followed by 5N NaOH (3.3 ml) affording a suspension. The resulting
solids were filtered, rinsed with H.sub.2O, and dried in vacuo to
yield 0.17 g (78.7%) of the title compound as a dark brown solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.29-1.44 (m, 2H)
1.60-2.20 (m, 5H) 2.29 (br. s., 3H) 2.94 (m, 2H) 4.02 (d, J=6.57
Hz, 2H) 6.94 (d, J=8.84 Hz, 1H) 7.59 (d, J=8.34 Hz, 1H) 8.56 (br.
s., 1H) 9.00 (br. s., 1H) 12.49 (br. s., 1H). [M+H] calc'd for
C.sub.18H.sub.19Cl.sub.1N.sub.3O, 456. found 456.2.
Compound 285:
3-(3-chloro-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol-5-y-
l)-N-cyclopropylbenzamide
##STR00453##
[2013] A mixture of compound 284 (0.17 g, 0.37 mmol),
3-(cyclopropylcarbamoyl)phenylboronic acid (152 mg, 0.74 mmol),
Pd(PPh.sub.3).sub.4 (21.5 mg, 5 mol %), potassium carbonate (0.1 g,
0.74 mmol), degassed DMAc (4 ml) and H.sub.2O (1.5 ml) was stirred
for 30 minutes at room temperature. Next, the mixture was heated at
90.degree. C. for 1 hour. After completion, the reaction was
filtered, rinsed with methanol, and concentrated in vacuo. The
crude product was purified by Preparative HPLC to yield 0.048 g
(26.5%) of the title compound as an off-white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.57 (dd, J=3.79, 2.27 Hz, 2H)
0.69 (dd, J=6.95, 2.40 Hz, 2H) 1.34-1.48 (m, 2H) 1.82-1.97 (m, 5H)
2.19 (s, 3H) 2.85 (m, 3H) 4.08 (d, J=6.57 Hz, 2H) 7.08 (d, J=8.08
Hz, 1H) 7.17 (d, J=8.34 Hz, 1H) 7.59 (d, J=2.53 Hz, 1H) 7.64 (t,
J=7.71 Hz, 1H) 7.74 (ddd, J=7.71, 1.39, 1.26 Hz, 1H) 7.94 (dt,
J=7.83, 1.39 Hz, 1H) 8.03 (t, J=1.52 Hz, 1H) 8.43 (d, J=2.27 Hz,
1H) 8.54 (d, J=4.04 Hz, 1H) 12.38 (s, 1H). [M+H] calc'd for
C.sub.28H.sub.29Cl.sub.1N.sub.4O.sub.2 489. found, 489.4.
Compound 286:
3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)met-
hoxy)-9H-pyrido[2,3-b]indole
##STR00454##
[2015] The title compound was prepared using an analogous procedure
to that described in the preparation of compound 285. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.08-1.21 (m, 4H) 1.45-1.58 (m,
2H) 1.90-2.35 (m, 4H) 2.81 (d, J=4.80 Hz, 3H) 2.97-3.10 (m, 3H)
3.55 (m, 1H) 4.12 (d, J=7.07 Hz, 2H) 7.13-7.17 (m, 1H) 7.21-7.25
(m, 1H) 7.65 (d, J=2.27 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.97 (ddd,
J=7.71, 1.39, 1.26 Hz, 1H) 8.02-8.07 (m, 2H) 8.47 (d, J=2.53 Hz,
1H) 12.43 (s, 1H). [M+H] calc'd for
C.sub.27H.sub.28ClN.sub.3O.sub.3S 510. found, 510.2.
Compound 287:
5-(3-(ethylsulfonyl)phenyl)-3-fluoro-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole
##STR00455##
[2017] The title compound was prepared using an analogous procedure
to that described in the preparation of compound 285. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.16 (t, J=7.33 Hz, 3H)
1.42-1.61 (m, 2H) 1.80-2.35 (m, 5H) 2.81 (d, J=4.55 Hz, 3H)
2.94-3.10 (m, 2H) 3.42 (q, J=7.33 Hz, 2H) 3.54 (d, J=11.62 Hz, 2H)
4.12 (d, J=7.07 Hz, 2H) 7.10-7.16 (m, 1H) 7.19-7.24 (m, 1H) 7.43
(dd, J=9.60, 2.78 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.95-8.06 (m, 4H)
8.47 (dd, J=2.78, 1.52 Hz, 1H) 12.30 (s, 1H). [M+H] calc'd for
C.sub.26H.sub.28FN.sub.3O.sub.3S 482. found, 482.4.
Compound 288:
4-(3-(benzyloxy)propoxy)-3'-(ethylsulfonyl)-3-iodobiphenyl
##STR00456##
[2019] To a stirred solution of compound 197 (9.79 g, 25.2 mmol),
3-benzyloxy-1-propanol (5.03 g, 30.3 mmol) and triphenylphosphine
(8.6 g, 33 mmol) in benzene (100 mL) was added DIAD (6.35 mL, 33
mmol) at 0.degree. C. during 15 minutes. The reaction mixture was
warmed to room temperature over a period of 1 h and further stirred
for another 12 h. After completion, the mixture was concentrated in
vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 (10 mL) and
purified on silica gel to yield 6.1 g (45.1%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t,
J=7.33 Hz, 3H) 2.01-2.09 (m, 2H) 3.39 (q, J=7.16 Hz, 2H) 3.69 (t,
J=6.32 Hz, 2H) 4.19 (t, J=6.06 Hz, 2H) 4.51 (s, 2H) 7.17 (d, J=7.83
Hz, 1H) 7.13 (d, J=8.84 Hz, 1H) 7.23-7.33 (m, 5H) 7.69-7.85 (m, 2H)
8.07 (t, J=1.77 Hz, 1H) 8.01 (dt, J=7.83, 1.39 Hz, 1H). [M+Na]
calc'd for C.sub.24H.sub.25IO.sub.4SNa, 559. found 559.2.
Compound 289:
N-(4-(3-(benzyloxy)propoxy)-3'-(ethylsulfonyl)biphenyl-3-yl)-3-bromo-5-ch-
loropyridin-2-amine
##STR00457##
[2021] A mixture of Pd(OAc).sub.2 (0.124 g, 5 mol %), xantphos
(0.318 g, 5 mol %), and degassed toluene (30 mL) was stirred at
80.degree. C. for 30 minutes. This mixture was added to a reaction
flask charged with 3-bromo-5-chloropyridin-2-amine (2.51 g, 12.1
mmol), compound 288 (5.90 g, 11 mmol), Cs.sub.2CO.sub.3 (7.17 g, 22
mmol), and degassed toluene (30 mL). The mixture was heated at
reflux for 5 hours. After completion, the mixture was diluted with
EtOAc, washed with H.sub.2O (100 mL.times.1) and brine (100
mL.times.1). The organic layer was dried (MgSO.sub.4), and
concentrated in vacuo to yield 5.0 g (73.8%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.15 (t, J=7.33 Hz,
3H) 2.01-2.10 (m, 2H) 3.38 (q, J=7.41 Hz, 2H) 3.62 (t, J=6.32 Hz,
2H) 4.24 (t, J=6.06 Hz, 2H) 4.47 (s, 2H) 7.20-7.33 (m, 5H) 7.42
(dd, J=8.59, 2.27 Hz, 1H) 7.75 (t, J=7.83 Hz, 1H) 7.85 (t, J=1.26
Hz, 1H) 7.83 (d, J=1.26 Hz, 1H) 7.97-8.02 (m, 2H) 8.05 (t, J=1.77
Hz, 1H) 8.22 (d, J=0.51 Hz, 1H) 8.23-8.25 (m, 1H) 8.62 (d, J=2.27
Hz, 1H). [M+H] calc'd for C.sub.29H.sub.28BrClN.sub.2O.sub.4S, 617.
found 617.0.
Compound 290:
8-(3-(benzyloxy)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2-
,3-b]indole
##STR00458##
[2023] A mixture of compound 289 (4.99 g, 8.1 mmol), Pd(OAc).sub.2
(0.182 g, 10 mol %), DBU (3.63 mL, 24.3 mmol) and DMF (40 mL) was
stirred overnight at 155.degree. C. After completion the mixture
was filtered through celite and diluted with CH.sub.2Cl.sub.2. The
organic layer was washed with H.sub.2O and brine. The organic layer
was dried (MgSO.sub.4) and concentrated in vacuo. The residue was
dissolved in CH.sub.2Cl.sub.2 (7 mL) and purified on silica gel to
yield 2.1 g (48.1%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz, 3H) 2.11-2.19 (m, 2H)
3.42 (q, J=7.41 Hz, 2H) 3.78 (t, J=6.32 Hz, 2H) 4.34 (t, J=6.06 Hz,
2H) 4.53 (s, 2H) 7.12-7.17 (m, 1H) 7.20-7.35 (m, 6H) 7.63 (d,
J=2.27 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.97-8.04 (m, 2H) 8.07 (t,
J=1.64 Hz, 1H) 8.45 (d, J=2.27 Hz, 1H) 12.42 (s, 1H). [M+H] calc'd
for C.sub.29H.sub.27ClN.sub.2O.sub.4S, 535. found 535.4.
Compound 291:
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)pro-
pan-1-ol
##STR00459##
[2025] To a mixture of compound 290 (1.862 g, 3.48 mmol) and
CH.sub.2Cl.sub.2 (35 mL) was added BBr.sub.3 as a 1M solution in
CH.sub.2Cl.sub.2 (3.48 mL, 3.48 mmol) at 0.degree. C. After
completion, the mixture was quenched with saturated NaHCO.sub.3
(125 mL) and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(25 mL.times.3). The organic extracts were combined, washed with
brine, dried (MgSO.sub.4), and concentrated in vacuo. The residue
was dissolved in CH.sub.2Cl.sub.2 and purified on silica gel to
yield 0.925 g (60%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz, 3H) 1.98-2.05 (m, 2H)
3.42 (q, J=7.33 Hz, 2H) 3.72 (q, J=6.06 Hz, 2H) 4.32 (t, J=6.32 Hz,
2H) 4.58 (t, J=5.05 Hz, 1H) 7.13-7.17 (m, 1H) 7.20-7.24 (m, 1H)
7.63 (d, J=2.27 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 8.00 (m, 2 H)
7.97-8.04 (m, 1H) 8.06 (t, J=1.64 Hz, 1H) 8.45 (d, J=2.27 Hz, 1H)
12.42 (s, 1H). [M+H] calc'd for C.sub.22H.sub.21ClN.sub.2O.sub.4S,
445. found 445.3.
[2026] In addition, the title compound was prepared from Compound
219 by using an analogous procedure to that outlined in the
preparation of Compound 216. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.45 (s, 1H) 8.06 (m, 1H) 8.01 (m, 2H)
7.87 (t, J=8.0 Hz, 1H) 7.63 (s, 1H) 7.23 (d, J=8.32 Hz, 1H) 7.16
(d, J=8.32 Hz, 1H) 4.34 (t, J=6.32 Hz, 2H) 3.72 (t, J=6.32 Hz, 2H)
3.43 (q, J=7.32 Hz, 2H) 2.02 (m, 2H) 1.18 (t, J=7.32 Hz, 3H). [M+H]
calc'd for C.sub.22H.sub.22ClN.sub.2O.sub.4S, 445. found, 445.
Compound 292:
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-(3-iodopropoxy)-9H-pyrido[2,3-b]in-
dole
##STR00460##
[2028] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 268.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 2.29-2.37 (m, 2H) 3.42 (q, J=7.33 Hz, 2H) 3.70 (t, J=6.95 Hz,
2H) 4.27 (t, J=5.68 Hz, 2H) 7.15 (d, J=8.08 Hz, 1H) 7.21-7.25 (m,
1H) 7.64 (d, J=2.53 Hz, 1H) 7.88 (t, J=7.71 Hz, 1H) 7.98-8.03 (m,
2H) 8.07 (t, J=1.52 Hz, 1H) 8.46 (d, J=2.27 Hz, 1H) 12.47 (s, 1H).
[M+H] calc'd for C.sub.22H.sub.20ClIN.sub.2O.sub.3S, 555.0. found
555.3.
Compound 293:
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(ethyl)amino)ethanol
##STR00461##
[2030] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 269.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94-1.08 (m, 2H)
1.18 (t, J=7.33 Hz, 3H) 1.95-2.05 (m, 2H) 2.55-2.68 (m, 3H)
2.70-2.88 (m, 2H) 3.42 (q, J=7.33 Hz, 3H) 3.50 (m, 2H) 4.29 (t,
J=6.06 Hz, 2H) 7.13-7.17 (m, 1H) 7.19-7.24 (m, 1H) 7.63 (d, J=2.53
Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.98-8.03 (m, 2H) 8.06 (t, J=1.64
Hz, 1H) 8.45 (d, J=2.27 Hz, 1H) 12.43 (br. s., 1H). [M+H] calc'd
for C.sub.26H.sub.30ClN.sub.3O.sub.4S, 516.0. found 516.3.
Compound 294:
2-((3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(ethyl)amino)ethyl dihydrogen phosphate
##STR00462##
[2032] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 272.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t, J=7.33 Hz,
3H) 1.32 (t, J=7.20 Hz, 3H) 2.25-2.34 (m, 2H) 3.30 (q, J=7.33 Hz, 2
H) 3.42 (q, J=7.33 Hz, 2H) 3.46-3.50 (m, 2H) 3.50-3.57 (m, 2H)
4.25-4.30 (m, 2H) 4.35 (t, J=5.43 Hz, 2H) 7.15-7.19 (m, 1H)
7.21-7.25 (m, 1H) 7.64 (d, J=2.53 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H)
7.98-8.04 (m, 2H) 8.06 (t, J=1.64 Hz, 1H) 8.47 (s, 1H) 12.50 (s,
1H). [M+H] calc'd for C.sub.26H.sub.31ClN.sub.3O.sub.7PS 596. found
596.3.
Compound 295:
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-et-
hylbenzenesulfonamide
##STR00463##
[2034] The title compound was synthesized from Compound 191 using
an analogous procedure to that outlined in the preparation of
Compound 177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.02
(t J=7.2 Hz, 3H) 2.21-2.24 (m, 2H) 2.26 (m, 5H) 2.47 (s, 3H) 3.32
(q, J=7.2 Hz, 2H) 3.47-3.52 (m, 2H) 4.29 (t, J=5.43 Hz, 2H) 7.05
(d, J=8.08 Hz, 1H) 7.13 (d, J=8.08 Hz, 1H) 7.54 (s, 1H) 7.62 (t,
J=7.71 Hz, 1H) 7.72 (d, J=7.58 Hz, 1H) 7.93 (d, J=7.83 Hz, 1H) 8.03
(s, 1H) 8.28 (s, 1H) 8.55 (d, J=4.04 Hz, 1H) 9.60 (br. s., 1H)
11.93 (s, 1H); [M+H] calc'd for C.sub.25H.sub.30N.sub.4O.sub.3S,
467.2. found, 467.2.
Compound 296:
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N,N--
dimethylbenzenesulfonamide
##STR00464##
[2036] The title compound was synthesized from Compound 191 using
an analogous procedure to that outlined in the preparation of
Compound 177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
2.21-2.24 (m, 2H) 2.26 (s, 3H) 2.66 (s, 6H) 2.88 (s, 3H) 2.89 (s, 3
H) 3.47-3.52 (m, 2H) 4.29 (t, J=5.43 Hz, 2H) 7.05 (d, J=8.08 Hz,
1H) 7.13 (d, J=8.08 Hz, 1H) 7.54 (s, 1H) 7.62 (t, J=7.71 Hz, 1H)
7.72 (d, J=7.58 Hz, 1H) 7.93 (d, J=7.83 Hz, 1H) 8.03 (s, 1H) 8.28
(s, 1H) 8.55 (d, J=4.04 Hz, 1H) 9.60 (br. s., 1H) 11.93 (s, 1 H);
[M+H] calc'd for C.sub.25H.sub.30N.sub.4O.sub.3S, 467.2. found,
467.2.
Compound 297:
(S)-3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl 2-aminopropanoate
##STR00465##
[2038] The title compound was prepared from Compound 291 by using
an analogous procedure to that outlined in the preparation of
Compound 65. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.36
(s, 1H) 8.12 (s, 1H) 8.08 (m, 1H) 7.97 (m, 1H) 7.88 (t, J=7.84 Hz,
1H) 7.69 (s, 1H) 7.21 (d, J=8.32 Hz, 1H) 7.16 (d, J=8.32 Hz, 1H)
4.65 (m, 2H) 4.42 (t, J=6.08 Hz, 2H) 4.14 (q, J=7.32 Hz, 1H) 3.36
(q, J=7.6 Hz, 2H) 2.39 (m, 2H) 1.55 (d, J=7.32 Hz, 3H) 1.33 (t,
J=7.6 Hz, 3H). [M+H] calc'd for C.sub.25H.sub.27ClN.sub.3O.sub.5S,
516. found, 516.
Compound 298:
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethanol
##STR00466##
[2040] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 269.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.85 (br. s., 2H)
0.97-1.20 (m, 8H) 1.23 (s, 1H) 1.86-2.09 (m, 2H) 2.94-3.08 (m, 1 H)
3.47 (br. s., 2H) 4.30 (br. s., 2H) 7.10-7.18 (m, 1H) 7.18-7.26 (m,
1H) 7.64 (d, J=2.27 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.93-8.00 (m,
1H) 8.06 (s, 1H) 8.03 (d, J=7.83 Hz, 1H) 8.46 (d, J=2.02 Hz, 1H).
ESI-MS: m/z 528.3 (M+H).sup.+.
Compound 299:
2-((3-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
##STR00467##
[2042] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 272.
[M+H] calc'd for C.sub.27H.sub.31ClN.sub.3O.sub.7PS 608.5. found
608.3.
Compound
300:1-(3-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,-
3-b]indol-8-yloxy)propyl)piperidin-4-ol
##STR00468##
[2044] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 270. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.85 (br. s., 2 H) 0.97-1.20
(m, 8H) 1.23 (s, 1H) 1.86-2.09 (m, 2H) 2.94-3.08 (m, 1H) 3.47 (br.
s., 2H) 4.30 (br. s., 2H) 7.10-7.18 (m, 1H) 7.18-7.26 (m, 1H) 7.64
(d, J=2.27 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.93-8.00 (m, 1H) 8.06
(s, 1H) 8.03 (d, J=7.83 Hz, 1H) 8.46 (d, J=2.02 Hz, 1H). ESI-MS:
m/z 520.1 (M+H).sup.+.
Compound 301:
8-(3-(1H-imidazol-1-yl)propoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-p-
yrido[2,3-b]indole
##STR00469##
[2046] The title compound was isolated as a byproduct in the
preparation of compound 293. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.18 (t, J=7.45 Hz, 3H) 2.28-2.37 (m, 2H) 3.40 (q,
J=7.58 Hz, 2H) 4.16 (t, J=5.68 Hz, 2H) 4.46 (t, J=6.95 Hz, 2H)
7.06-7.22 (m, 3H) 7.40 (br. s., 1H) 7.65 (d, J=2.27 Hz, 1H) 7.88
(t, J=7.71 Hz, 1H) 7.98-8.09 (m, 4 H) 8.48 (d, J=2.27 Hz, 1H) 12.50
(s, 1H). [M+H] calc'd for C.sub.25H.sub.23ClN.sub.4O.sub.3S, 495.0.
found 495.3.
Compound 302:
3'-(ethylsulfonyl)-3-iodo-4-(3-iodopropoxy)biphenyl
##STR00470## ##STR00471##
[2048] The title compound 302 was synthesized via Mitsunobu
reaction using 1-iodopropanol and 197, following the method as
described earlier for compound 198. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.32 (t, J=7.33 Hz, 3H) 2.35 (p, J=6.06
Hz, 2H) 3.17 (q, J=7.49 Hz, 2H) 3.51 (t, J=6.57 Hz, 2H) 4.16 (t,
J=5.68 Hz, 2H) 6.92 (d, J=8.4 Hz, 1H) 7.56 (dd, J=2.4, 8.8 Hz, 1H)
7.63 (t, J=8.0 Hz, 1H) 7.80 (br. d, J=8.1 Hz, 1H) 7.86 (br. d,
J=8.1 Hz, 1H) 8.03-8.05 (m, 2H).
Compound 303:
2-((3-(3'-(ethylsulfonyl)-3-iodobiphenyl-4-yloxy)propyl)(methyl)amino)-et-
hanol
##STR00472##
[2050] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 269. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 1.32 (t, J=7.45 Hz, 3H) 2.06
(t, J=6.82 Hz, 2H) 2.33 (s, 3H) 2.60 (t, J=5.2 Hz, 2H) 2.73 (t,
J=7.07 Hz, 2H) 3.17 (q, J=7.58 Hz, 2H) 3.62 (t, J=5.56 Hz, 2H) 4.14
(t, J=6.06 Hz, 2H) 6.89 (d, J=8.34 Hz, 1H) 7.55 (dd, J=8.59, 2.27
Hz, 1H) 7.63 (t, J=7.83 Hz, 1H) 7.81 (ddd, J=7.83, 1.89, 1.14 Hz,
1H) 7.85 (ddd, J=7.83, 1.77, 1.01 Hz, 1H) 8.04 (d, J=2.27 Hz, 1H)
8.05 (t, J=1.64 Hz, 1H). [M+H] calc'd for
C.sub.20H.sub.271NO.sub.4S, 504.06. found 504.1.
Compound 304:
2-((3-(3-(3-bromo-5-methylpyridin-2-ylamino)-3'-(ethylsulfonyl)biphenyl-4-
-yloxy)propyl)(methyl)amino)ethanol
##STR00473##
[2052] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 265. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.15 (td, J=7.33, 1.52 Hz, 3H)
1.95 (t, J=6.57 Hz, 2H) 2.21 (s, 3H) 2.22 (s, 3H) 2.42 (t, J=6.19
Hz, 2H) 2.57 (t, J=6.95 Hz, 2H) 3.38 (dd, J=7.45, 1.39 Hz, 2H) 3.46
(q, J=6.6 Hz, 1H) 4.20 (t, J=5.68 Hz, 2H) 4.36 (br. s., 1H) 7.18
(d, J=8.59 Hz, 1H) 7.34 (d, J=8.59 Hz, 1H) 7.75 (t, J=7.07 Hz, 1H)
7.84 (dd, J=7.6, 1.01 Hz, 1H) 7.89 (d, J=11.37 Hz, 2H) 7.98 (dd,
J=7.71, 1.14 Hz, 1H) 8.08 (s, 1H) 8.04 (d, J=1.26 Hz, 1H) 8.86 (d,
J=1.77 Hz, 1H). [M+H] calc'd for C.sub.26H.sub.33BrN.sub.3O.sub.4S,
562.13. found 562.2.
Compound 305:
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethanol
##STR00474##
[2054] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 266. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz, 3H) 2.27
(m, 5H) 2.89 (d, J=5.05 Hz, 3H) 3.15-3.20 (m, 2H) 3.41 (q, J=7.33
Hz, 2 H) 3.44-3.57 (m, 2H) 3.80 (t, J=5.31 Hz, 2H) 4.31 (t, J=6.1
Hz, 2H) 7.09-7.12 (m, 1 H) 7.14-7.17 (m, 1H) 7.56 (d, J=1.52 Hz,
1H) 7.86 (t, J=7.71 Hz, 1H) 7.99 (dd, J=12.38, 7.83 Hz, 1H) 7.99
(dd, J=9.47, 7.71 Hz, 1H) 8.07 (t, J=1.77 Hz, 1H) 8.30 (d, J=2.02
Hz, 1H) 9.35 (br. s., 1H) 11.99 (s, 1H). [M+H] calc'd for
C.sub.26H.sub.32N.sub.3O.sub.4S, 482.2. found 482.2.
Compound 306: di-tert-butyl
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl phosphate
##STR00475##
[2056] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 271.
Compound 307:
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl dihydrogen phosphate,
dihydrochloride
##STR00476##
[2058] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 272. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz, 3H) 2.28
(m, 5H) 2.91 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.48 (br. m., 2H) 3.56
(br. m., 2H) 4.27 (ddd, J=7.20, 5.18, 5.05 Hz, 2H) 4.32 (t, J=5.43
Hz, 2H) 7.10-7.13 (m, 1 H) 7.15-7.19 (m, 1H) 7.59 (d, J=1.77 Hz,
1H) 7.86 (t, J=7.83 Hz, 1H) 8.01 (t, J=1.52 Hz, 1H) 8.08 (t, J=1.77
Hz, 1H) 8.30 (d, J=1.77 Hz, 1H) 12.18 (br. s., 1H). [M+H] calc'd
for C.sub.26H.sub.33N.sub.3O.sub.7PS, 562.2. found 562.2.
Compound 308:
2-((3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy-
)propyl)(methyl)amino)ethyl dihydrogen phosphate
##STR00477##
[2060] Compound 307 (181 mg, 0.285 mmol) was dissolved in MeOH (3.5
mL) and treated with cyclohexeneoxide (0.57 mL, 5.7 mmol) at room
temperature. The solution was stirred at ambient temperature for 48
h. during which time a white solid precipitated. The reaction
mixture was diluted with ether (5 mL) and the solid was recovered
by filtration, washed with ether and dried in vacuo to give the
title compound as white solid (150 mg, 94%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz, 3H) 2.20-2.29 (m, 2H)
2.26 (s, 3H) 2.78 (s, 3H) 3.25 (br. m., 2H) 3.34-3.44 (m, 4H) 4.03
(dd, J=13.26, 6.95 Hz, 2H) 4.31 (t, J=5.68 Hz, 2H) 7.07-7.16 (m,
2H) 7.55 (d, J=1.26 Hz, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.98 (ddd,
J=7.14, 5.62, 1.64 Hz, 2H) 8.06-8.11 (m, 1H) 8.28 (d, J=2.02 Hz,
1H) 12.35 (br. s., 1H). [M+H] calc'd for
C.sub.26H.sub.33N.sub.3O.sub.7PS, 562.2. found 562.2.
Compound 309: (S)-2-((4-chloro-2-iodophenoxy)methyl)oxirane
##STR00478## ##STR00479##
[2062] The title compound 309 was synthesized via Mitsunobu
reaction using (R)-(+)-glycidol and 4-chloro-2-iodophenol,
following the method as described earlier for compound 198. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.88 (dd, J=2.8, 5.2 Hz,
1H) 2.91 (dd, J=4.8, 5.2 Hz, 1H) 3.38-3.41 (m, 1H) 4.02 (dd,
J=11.24, 5.18 Hz, 1H) 4.30 (dd, J=11.12, 2.78 Hz, 1H) 6.77 (d,
J=8.84 Hz, 1H) 7.27 (dd, J=8.59, 2.53 Hz, 1H) 7.76 (d, J=2.53 Hz,
1H). [M+H] calc'd for C.sub.9H.sub.9ClIO.sub.2, 310.9. found
310.9.
Compound 310:
(S)-3-bromo-N-(5-chloro-2-(oxiran-2-ylmethoxy)phenyl)-5-methylpyridin-2-a-
mine
##STR00480##
[2064] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 265. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 2.26 (s, 3H) 2.85 (dd, J=4.93,
2.65 Hz, 1H) 2.95 (t, J=4.55 Hz, 1H) 3.43 (ddd, J=3.85, 3.03, 2.72
Hz, 1H) 4.06 (dd, J=10.86, 5.56 Hz, 1H) 4.35 (dd, J=10.99, 2.91 Hz,
1H) 6.79-6.83 (m, 1H) 6.87 (d, J=2.53 Hz, 1H) 7.63 (d, J=2.02 Hz,
1H) 7.83 (s, 1H) 8.07 (d, J=1.77 Hz, 1H) 8.73 (d, J=2.53 Hz, 1H).
[M+H] calc'd for C.sub.15H.sub.15BrClN.sub.2O.sub.2, 368.99. found
369.2.
Compound 311:
(S)-1-(2-(3-bromo-5-methylpyridin-2-ylamino)-4-chlorophenoxy)-3-(dimethyl-
amino)propan-2-ol
##STR00481##
[2066] To a suspension of compound 310 (708 mg, 1.92 mmol) in EtOH
(8 mL) was added dimethyl amine (2.87 mL, 5.75 mmol, 2 M solution
in THF) and the resulting mixture was heated in a sealed tube at
60.degree. C. for 4 h. After completion of the reaction the
solvents were removed in vacuo and the crude mass was purified by
flash chromatography to provide compound 311 (583 mg, 91%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.18 (s, 6H) 2.22 (s, 3H)
2.38 (dd, J=12.1, 6.57 Hz, 1H) 2.47 (d, J=5.81 Hz, 1H) 3.94-4.03
(m, 2H) 4.08 (dd, J=3.54, 9.6 Hz, 1H) 4.94 (d, J=4.29 Hz, 1H) 6.95
(dd, J=8.34, 2.27 Hz, 1H) 7.05 (d, J=8.59 Hz, 1H) 7.91 (d, J=2.02
Hz, 1H) 7.94 (s, 1H) 8.13 (d, J=2.02 Hz, 1H) 8.57 (d, J=2.78 Hz,
1H). [M+H] calc'd for C.sub.17H.sub.22BrClN.sub.3O.sub.2, 414.1.
found 414.2.
Compound 312:
(S)-1-(5-chloro-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-3-(dimethylamino)-
propan-2-ol
##STR00482##
[2068] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 266. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 2.22 (s, 6H) 2.39 (dd, J=12.25,
5.94 Hz, 1H) 2.48 (s, 3H) 2.55 (dd, J=12.4, 6.4 Hz, 1H) 3.96-4.08
(m, 2H) 4.15-4.22 (m, 1H) 4.88 (br. s., 1H) 7.03 (d, J=8.34 Hz, 1H)
7.14 (d, J=8.34 Hz, 1H) 8.36 (d, J=1.77 Hz, 1H) 8.50 (s, 1H) 12.12
(s, 1H). [M+H] calc'd for C.sub.17H.sub.21ClN.sub.3O.sub.2, 334.1.
found 334.4.
Compound 313:
(S)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-ol
##STR00483##
[2070] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 270. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.06-1.1 (m, 2H) 1.13-1.18 (m,
2H) 2.24 (s, 6H) 2.28 (s, 3H) 2.45 (m, 1H) 2.56 (m, 1H) 3.02 (dd,
J=12.88, 3.03 Hz, 1H) 4.02-4.12 (m, 2H) 4.25 (br. d, J=6.06 Hz, 1H)
4.93 (d, J=4.55 Hz, 1H) 7.06-7.10 (m, 1H) 7.11-7.16 (m, 1H) 7.59
(s, 1H) 7.84 (t, J=7.83 Hz, 1H) 7.94-8.01 (m, 2H) 8.09 (t, J=1.64
Hz, 1H) 8.29 (d, J=2.02 Hz, 1H) 12.02 (s, 1H). [M+H] calc'd for
C.sub.26H.sub.30N.sub.3O.sub.4S, 480.2. found 480.1.
Compound 314:
(S)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-yl dihydrogen phosphate
##STR00484##
[2072] The title compound was obtained as a dihydrochloride salt
following the same procedure as depicted in the synthesis of
compound 272. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 6 ppm
1.06-1.19 (m, 4H) 2.28 (s, 3H) 2.97 (s, 6H) 3.00 (dd, J=8.84, 3.79
Hz, 1H) 3.63 (d, J=13.64 Hz, 2H) 3.97 (dd, J=13.64, 9.60 Hz, 1H)
4.39 (dd, J=10.4, 3.2 Hz, 1H) 4.53 (dd, J=10.4, 4.8 Hz, 1H) 4.96
(br. m, 1H) 7.09-7.19 (m, 2H) 7.58 (s, 1H) 7.85 (t, J=7.83 Hz, 1H)
7.96 (d, J=7.58 Hz, 1H) 8.02 (d, J=7.83 Hz, 1H) 8.08 (s, 1H) 8.31
(d, J=1.52 Hz, 1H) 12.01 (s, 1H). [M+H] calc'd for
C.sub.26H.sub.31N.sub.3O.sub.7PS, 560.2. found 560.2.
Compound 315:
(R)-1-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)-3-(dimethylamino)propan-2-yl dihydrogen phosphate
##STR00485##
[2074] The title compound was obtained as a dihydrochloride salt
following the same procedure as depicted in the synthesis of
compound 272. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.06-1.19 (m, 4H) 2.28 (s, 3H) 2.97 (s, 6H) 3.00 (dd, J=8.84, 3.79
Hz, 1H) 3.63 (d, J=13.64 Hz, 2H) 3.97 (dd, J=13.64, 9.60 Hz, 1H)
4.39 (dd, J=10.4, 3.2 Hz, 1H) 4.53 (dd, J=10.4, 4.8 Hz, 1H) 4.96
(br. m, 1H) 7.09-7.19 (m, 2H) 7.58 (s, 1H) 7.85 (t, J=7.83 Hz, 1H)
7.96 (d, J=7.58 Hz, 1H) 8.02 (d, J=7.83 Hz, 1H) 8.08 (s, 1H) 8.31
(d, J=1.52 Hz, 1H) 12.01 (s, 1H). [M+H] calc'd for
C.sub.26H.sub.31N.sub.3O.sub.7PS, 560.2. found 560.2.
Compound 316:
3-chloro-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-8-((1-methylpiperi-
din-4-yl)methoxy)-9H-pyrido[2,3-b]indol-5-amine
##STR00486##
[2076] To a 15 mL screw cap vial was added
3-chloro-5-iodo-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2,3-b]indol-
e (77 mg, 0.168 mmol), 33-methyl-4-(4-methylpiperazin-1-yl)aniline
(42 mg, 0.203 mmol), PALLADIUM(II) ACETATE (2.0 mg, 0.008 mmol),
XANTPHOS (5.0 mg, 0.008 mmol) and CESIUM CARBONATE (110 mg, 0.338
mmol) in toluene (2 mL). The reaction was stirred at 115.degree. C.
for 3 h. The reaction was cooled to room temperature, filtered and
purified by prep HPLC-MS to give the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.00 (d, J=6.32 Hz, 1H), 1.19
(d, J=6.06 Hz, 1H), 1.50 (br. s., 2H), 2.17 (s, 3H), 2.23 (d,
J=1.77 Hz, 1H), 2.72-2.92 (m, 6H), 2.92-3.03 (m, 2H), 3.03-3.12 (m,
2H), 3.12-3.28 (m, 3H), 3.41-3.60 (m, 4H), 4.02 (d, 2H), 6.60-6.75
(m, 1H), 6.75-6.84 (m, 1H), 6.91 (s, 1H), 7.01-7.09 (m, 1H), 7.88
(br. s., 1H), 8.04 (d, J=2.02 Hz, 1H), 8.38 (d, J=2.27 Hz, 1H),
12.11 (s, 1H). ESI-MS: m/z 533.4 (M+H).sup.+.
Compound 317:
5-(3-(cyclopropylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)-9H--
pyrido[2,3-b]indole
##STR00487##
[2078] The title compound was isolated as a byproduct in the
preparation of compound 286. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.03-1.19 (m, 4H), 1.40 (dd, J=11.87, 3.03 Hz, 2H),
1.86-1.99 (m, 4H), 2.18 (s, 3H), 2.83 (d, J=11.87 Hz, 2H), 3.01
(dd, J=12.63, 2.78 Hz, 1H), 4.08 (d, J=6.57 Hz, 2H), 7.04 (dd,
J=7.83, 4.80 Hz, 1H), 7.06-7.11 (m, 1 H), 7.12-7.17 (m, 1H), 7.71
(dd, J=7.96, 1.39 Hz, 1H), 7.84 (t, J=7.71 Hz, 1H), 7.98 (dd,
J=13.26, 7.71 Hz, 2H), 8.02-8.07 (m, 1H), 8.42 (dd, J=4.67, 1.39
Hz, 1H), 12.20 (s, 1H). ESI-MS: m/z 510.3 (M+H).sup.+.
Compound 318:
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(ethyl)amino)ethanol
##STR00488##
[2080] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 270. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.98-1.20 (m, 4H), 1.29 (t,
J=7.20 Hz, 3H), 2.49 (s, 3H), 3.31-3.50 (m, 4H), 3.62-3.76 (m, 2H),
3.80 (t, J=5.05 Hz, 2H), 4.54 (d, J=4.04 Hz, 2H), 7.08-7.17 (m,
1H), 7.22 (t, J=4.04 Hz, 1H), 7.61 (d, J=7.58 Hz, 1H), 7.82-8.05
(m, 2H), 8.10 (d, J=8.84 Hz, 1H), 8.31 (d, J=2.02 Hz, 1H), 8.39 (d,
J=2.27 Hz, 1H), 8.53 (d, J=1.52 Hz, 1H), 9.15 (br. s., 1H), 12.09
(s, 1H). ESI-MS: m/z 494.4 (M+H).sup.+.
Compound 319:
2-((2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(methyl)amino)ethanol
##STR00489##
[2082] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 293.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
[2083] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.11 (m,
2H), 1.17 (d, J=2.59 Hz, 2H), 2.89-2.95 (m, 1H), 2.99-3.05 (m, 4H),
3.04 (s, 3H), 3.74-3.80 (m, 2H), 3.80-3.86 (m, 2 H), 7.17-7.25 (m,
1H), 7.28 (s, 1H), 7.69 (d, J=0.19 Hz, 1H), 7.82-7.92 (m, 1H),
7.96-8.01 (m, 1H), 8.04 (d, J=1.45 Hz, 1H), 8.07 (dt, J=1.23, 0.58
Hz, 1H), 8.50 (dd, J=2.40, 0.13 Hz, 1H), 12.35 (s, 1H). ESI-MS: m/z
500.2 (M+H).sup.+.
Compound 320:
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)et-
hyl)(methyl)amino)ethanol
##STR00490##
[2085] The title compound was isolated as a byproduct in the
preparation of compound 319. ESI-MS: m/z 466.3 (M+H).sup.+.
Compound 321:
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(methyl)amino)ethanol
##STR00491##
[2087] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 270. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.02-1.12 (m, 1H), 1.12-1.19
(m, 1H), 1.44-1.58 (m, 2H), 2.28 (s, 3H), 3.03 (s, 3H), 3.22-3.28
(m, 2H), 3.29-3.37 (m, 2H), 3.75-3.81 (m, 2H), 3.80-3.86 (m, 2H),
4.53-4.67 (m, 1H), 7.14 (d, J=8.08 Hz, 1H), 7.22 (d, J=8.34 Hz,
1H), 7.61 (s, 1H), 7.76 (d, J=8.59 Hz, 1H), 7.86 (t, J=7.71 Hz,
1H), 8.00-8.07 (m, 1H), 8.08 (t, J=1.77 Hz, 1H), 8.31 (d, J=1.52
Hz, 1H), 11.98 (s, 1H). ESI-MS: m/z 480.3 (M+H).sup.+.
Compound 322:
1-(2-(5-(3-(cyclopropylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8--
yloxy)ethyl)piperidin-4-ol
##STR00492##
[2089] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 270. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.09 (dd, J=7.83, 2.27 Hz, 2H),
1.15 (ddd, J=4.99, 2.78, 2.59 Hz, 2H), 1.57-1.72 (m, 1H), 1.78-1.87
(m, 1H), 1.99-2.09 (m, 1H), 2.28 (s, 3H), 3.02 (dd, J=12.63, 3.03
Hz, 1H), 3.12-3.25 (m, 1H), 3.38 (d, J=12.88 Hz, 1H), 3.48-3.56 (m,
1H), 3.69 (dd, J=14.65, 4.29 Hz, 3H), 4.58 (d, J=4.80 Hz, 2H),
7.11-7.17 (m, 1H), 7.20-7.25 (m, 1H), 7.61 (s, 1H), 7.86 (t, J=7.71
Hz, 1H), 7.96 (d, J=1.26 Hz, 1H), 8.02 (d, J=7.83 Hz, 1H), 8.08 (s,
1H), 8.30-8.35 (m, 1H), 11.99 (d, J=9.09 Hz, 1H). ESI-MS: m/z 506.4
(M+H).sup.+.
Compound 323:
2-((2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-
-yloxy)ethyl)(ethyl)amino)ethanol
##STR00493##
[2091] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 293.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.09 (ddd, J=15.92,
7.96, 2.15 Hz, 2H), 1.17 (d, J=5.05 Hz, 2H), 1.31 (t, J=7.20 Hz, 3
H), 3.00 (ddd, J=12.69, 9.66, 4.93 Hz, 1H), 3.31 (br. s., 1H),
3.40-3.50 (m, 1H), 3.61-3.79 (m, 2H), 3.82 (t, J=5.05 Hz, 2H), 4.46
(t, J=4.80 Hz, 2H), 4.62 (d, J=4.29 Hz, 2H), 6.99 (d, J=8.84 Hz,
1H), 7.17-7.26 (m, 1H), 7.30 (d, J=8.08 Hz, 1H), 7.65-7.78 (m, 2
H), 7.68-7.70 (m, 1H), 7.98 (d, J=7.58 Hz, 1H), 8.05 (d, J=9.09 Hz,
1H), 8.45 (d, J=2.53 Hz, 1H), 8.50 (d, J=2.27 Hz, 1H), 12.38 (s,
1H). ESI-MS: m/z 506.5 (M+H).sup.+.
Compound 324:
2-((2-(5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)et-
hyl)(ethyl)amino)ethanol
##STR00494##
[2093] The title compound was isolated as a byproduct in the
preparation of compound 323. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.03-1.13 (m, 1H), 1.13-1.20 (m, 2H), 1.33 (t, 3H),
1.46-1.58 (m, 1H), 1.59-1.71 (m, 1H), 2.90-2.96 (m, 1H), 2.96-3.06
(m, 1H), 3.16-3.29 (m, 1H), 3.31-3.41 (m, 1H), 3.42-3.59 (m, 1H),
3.70-3.79 (m, 1 H), 3.83 (s, 2H), 4.46-4.52 (m, 1H), 4.56-4.67 (m,
2H), 7.07-7.12 (m, 1H), 7.18 (d, J=0.13 Hz, 1H), 7.24 (d, 1H), 7.74
(s, 1H), 7.87 (d, J=0.44 Hz, 1H), 7.97 (br. s., 1H), 8.05 (dd,
J=2.49, 0.35 Hz, 2H), 8.43-8.49 (m, 1H), 12.17 (s, 1H). ESI-MS: m/z
480.4 (M+H).sup.+.
Compound 325:
1-(2-(3-chloro-5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8--
yloxy)ethyl)piperidin-4-ol
##STR00495##
[2095] The title compound was synthesized using an analogous
procedure to that described in the preparation of compound 293.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.01-1.22 (m, 4H),
1.84 (m, 4H), 2.93-3.09 (m, 1H), 3.11-3.32 (m, 1H), 3.32-3.44 (m,
1H), 3.44-3.58 (m, 1H), 3.58-3.76 (m, 2H), 4.60 (d, J=4.55 Hz, 2H),
7.20 (d, J=8.08 Hz, 1H), 7.26-7.31 (m, 1H), 7.63-7.76 (m, 2H), 7.88
(t, J=7.96 Hz, 2H), 7.97 (d, J=7.83 Hz, 2H), 8.05 (d, J=1.26 Hz,
1H), 8.49 (t, J=2.15 Hz, 1H), 12.36 (d, J=10.86 Hz, 1H). ESI-MS:
m/z 526.4 (M+H).sup.+.
Compound 326:
1-(2-(5-(3-(cyclopropylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)eth-
yl)piperidin-4-ol
##STR00496##
[2097] The title compound was isolated as a byproduct in the
preparation of compound 325. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.06-1.20 (m, 4H), 1.57-1.74 (m, 2H), 1.79-2.01 (m,
2H), 2.96-3.05 (m, 1H), 3.25 (t, J=6.95 Hz, 1H), 3.33 (t, J=6.69
Hz, 1H), 3.55 (d, J=9.35 Hz, 1H), 3.47 (t, J=5.68 Hz, 1H), 3.72
(br. s., 2H), 4.60 (d, J=3.79 Hz, 2H), 7.03-7.19 (m, 2H), 7.20-7.33
(m, 1H), 7.75 (d, J=7.07 Hz, 1H), 7.86 (t, J=7.71 Hz, 1H), 7.97 (d,
J=7.58 Hz, 1H), 8.00-8.08 (m, 2H), 8.46 (d, J=4.80 Hz, 1H), 12.13
(d, J=9.35 Hz, 1H). ESI-MS: m/z 494.4 (M+H).sup.+.
Compound 327:
1-(2-(5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)ethyl)pip-
eridin-4-ol
##STR00497##
[2099] The title compound was isolated as a byproduct in the
preparation of compound 329. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.18 (t, J=7.33 Hz, 3H), 1.58-1.73 (m, 1H), 1.80-1.90
(m, 1H), 1.90-1.99 (m, 1H), 1.99-2.10 (m, 1H), 2.28 (s, 3H),
3.08-3.29 (m, 1H), 3.41 (q, J=7.16 Hz, 2H), 3.35-3.46 (m, 1H),
3.46-3.61 (m, 1H), 3.61-3.76 (m, 3H), 4.59 (d, J=4.55 Hz, 2H),
7.09-7.17 (m, 1H), 7.18-7.25 (m, 1H), 7.57 (s, 1 H), 7.88 (d,
J=7.58 Hz, 1H), 7.99 (dd, J=15.16, 7.83 Hz, 2H), 8.08 (s, 1H), 8.31
(s, 1H), 11.96 (d, J=8.34 Hz, 1H). ESI-MS: m/z 494.4
(M+H).sup.+.
Compound 328:
1-(2-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8
##STR00498##
[2101] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 270. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.17 (t, J=7.33 Hz, 3H), 1.65 (t, J=9.73
Hz, 1H), 1.79-1.90 (m, 1H), 1.90-2.02 (m, 2H), 3.04-3.32 (m, 1H),
3.33-3.40 (m, 2H), 3.40 (q, J=7.83 Hz, 2 H), 3.46-3.56 (m, 1H),
3.61-3.76 (m, 2H), 4.37-4.45 (m, 1H), 4.60 (d, J=4.80 Hz, 2 H),
7.02-7.20 (m, 2H), 7.66-7.79 (m, 2H), 7.86 (t, J=7.83 Hz, 1H),
7.92-8.11 (m, 3 H), 8.45 (d, J=4.55 Hz, 1H), 12.10 (d, J=9.09 Hz,
1H). ESI-MS: m/z 480.4 (M+H).sup.+.
Compound 329:
1-(2-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-
ethyl)piperidin-4-ol
##STR00499##
[2103] The title compound was synthesized following the same
procedure as depicted in the synthesis of compound 293. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.19 (t, J=7.45 Hz, 3H),
1.52-1.73 (m, 1H), 1.88-2.01 (m, 1H), 3.13-3.29 (m, 1H), 3.31-3.45
(m, 3H), 3.51-3.57 (m, 3H), 3.60-3.78 (m, 2H), 4.42-4.49 (m, 1H),
4.61 (d, J=4.80 Hz, 2 H), 7.12-7.34 (m, 2H), 7.58-7.80 (m, 2H),
7.80-7.93 (m, 2H), 7.93-8.11 (m, 2H), 8.48 (t, J=1.77 Hz, 1H),
12.33 (d, J=10.61 Hz, 1H). ESI-MS: m/z 514.3 (M+H).sup.+.
Compound 330:
N-cyclopropyl-3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]in-
dol-5-yl)benzamide
##STR00500##
[2105] The title compound was synthesized from Compound 191 using
an analogous procedure to that outlined in the preparation of
Compound 177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.54-0.58 (m, 2H) 0.66-0.73 (m, 2H) 2.21-2.24 (m, 2H) 2.26 (s, 3 H)
2.85 (m, 1H) 2.88 (s, 3H) 2.89 (s, 3H) 3.47-3.52 (m, 2H) 4.29 (t,
J=5.43 Hz, 2H) 7.05 (d, J=8.08 Hz, 1H) 7.13 (d, J=8.08 Hz, 1H) 7.54
(s, 1H) 7.62 (t, J=7.71 Hz, 1H) 7.72 (d, J=7.58 Hz, 1H) 7.93 (d,
J=7.83 Hz, 1H) 8.03 (s, 1H) 8.28 (s, 1H) 8.55 (d, J=4.04 Hz, 1H)
9.60 (br. s., 1H) 11.93 (s, 1H); [M+H] calc'd for
C.sub.27H.sub.31N.sub.4O.sub.2, 443.2. found, 443.3.
Compound 331:
3-(8-(3-(dimethylamino)propoxy)-3-methyl-9H-pyrido[2,3-b]indol-5-yl)-N-me-
thylbenzenesulfonamide
##STR00501##
[2107] The title compound was synthesized from Compound 191 using
an analogous procedure to that outlined in the preparation of
Compound 177. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
2.21-2.24 (m, 2H) 2.26 (s, 3H) 2.47 (s, 3H) 2.88 (s, 3H) 2.89 (s, 3
H) 3.47-3.52 (m, 2H) 4.29 (t, J=5.43 Hz, 2H) 7.05 (d, J=8.08 Hz,
1H) 7.13 (d, J=8.08 Hz, 1H) 7.54 (s, 1H) 7.62 (t, J=7.71 Hz, 1H)
7.72 (d, J=7.58 Hz, 1H) 7.93 (d, J=7.83 Hz, 1H) 8.03 (s, 1H) 8.28
(s, 1H) 8.55 (d, J=4.04 Hz, 1H) 9.60 (br. s., 1H) 11.93 (s, 1 H);
[M+H] calc'd for C.sub.24H.sub.28N.sub.4O.sub.3S, 453.2. found,
453.4.
Compound 332:
5-(3-(cyclopropylcarbamoyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl-
)-9H-pyrido[2,3-b]indole-7-carboxamide
##STR00502##
[2109] The title compound was synthesized from
5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-
-carboxamide and 3-(cyclopropylcarbamoyl)phenylboronic acid using
an analogous procedure to that described in the preparation of
compound 88. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80
(d, J=5.81 Hz, 4H) 1.53 (qd, J=11.62, 3.03 Hz, 2H) 1.82 (br. s.,
1H) 1.79 (d, J=5.56 Hz, 2 H) 1.95 (t, J=10.86 Hz, 2H) 2.15 (s, 3H)
2.27 (s, 3H) 2.59 (s, 3H) 2.74 (br. d, J=10.86 Hz, 2H) 3.75 (dt,
J=7.33, 3.66 Hz, 1H) 6.98 (s, 1H) 7.27 (d, J=7.58 Hz, 1H) 7.49 (t,
J=7.83 Hz, 1H) 7.69 (br. s., 2H) 7.91 (s, 1H) 8.24-8.31 (m, 2H)
10.37 (s, 1H) 11.92 (br. s., 1H) [M+H] calc'd for
C.sub.30H.sub.34N.sub.5O.sub.2, 496.3. found, 496.4.
Compound 333:
8-(2-(1H-imidazol-1-yl)ethoxy)-5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-py-
rido[2,3-b]indole
##STR00503##
[2111] The title compound was synthesized from Compound 158 using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.15
(t, J=7.33 Hz, 3H), 2.27 (s, 3H), 3.40 (q, J=7.24 Hz, 2H),
4.53-4.63 (m, 2H), 4.68-4.79 (m, 2H), 7.06-7.16 (m, 1H), 7.25 (d,
J=8.59 Hz, 1H), 7.69-7.75 (m, 1H), 7.75-7.82 (m, 2H), 7.82-7.91 (m,
1H), 7.92-8.08 (m, 1H), 8.17 (dd, J=13.39, 2.02 Hz, 2H), 8.50 (s,
1H), 9.16 (s, 1H), 12.03 (s, 1H). ESI-MS: m/z 461.2
(M+H).sup.+.
Compound 334:
8-(2-(1H-imidazol-1-yl)ethoxy)-3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-py-
rido[2,3-b]indole
##STR00504##
[2113] The title compound was synthesized from Compound 219 using
an analogous procedure to that outlined in the preparation of
Compound 206. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.14
(d, J=7.49 Hz, 3H), 3.37 (q, J=7.49 Hz, 2H), 4.49 (t, J=4.93 Hz, 2
H), 4.67 (t, J=4.80 Hz, 2H), 7.00 (d, J=8.84 Hz, 1H), 7.16 (d,
J=8.59 Hz, 1H), 7.38 (dd, J=10.48, 1.89 Hz, 1H), 7.59-7.72 (m, 1H),
7.66 (dd, J=8.97, 2.65 Hz, 1H), 7.74 (quin, J=3.92 Hz, 1H),
7.80-7.90 (m, 1H), 8.02 (t, J=1.77 Hz, 1H), 8.12 (d, J=2.53 Hz,
1H), 8.30 (s, 1H), 8.41 (d, J=2.27 Hz, 1H), 9.15 (s, 1H). ESI-MS:
m/z 481.2 (M+H).sup.+.
Compounds 335-353
##STR00505##
TABLE-US-00005 [2114] Compound Name Structure 335
5-(3-(ethylsulfonyl)phenyl)- N-((1r,4r)-4- hydroxycyclohexyl)-
3,8-dimethyl-9H-pyrido [2,3-b]indole-7-carboxamide ##STR00506## 336
5-(3-(ethylsulfonyl)phenyl)- N-((1s,4s)-4- hydroxycyclohexyl)-
3,8-dimethyl-9H-pyrido [2,3-b]indole-7-carboxamide ##STR00507## 337
5-(3-(ethylsulfonyl)phenyl)- N-(4-(hydroxymethyl)
cyclohexyl)-3,8-dimethyl- 9H-pyrido[2,3-b]indole-7- carboxamide
##STR00508## 338 5-(3-(ethylsulfonyl)phenyl)- N-(4-(2-hydroxyethyl)
cyclohexyl)-3,8-dimethyl- 9H-pyrido[2,3-b]indole-7- carboxamide
##STR00509## 339 (5-(3-(ethylsulfonyl)phenyl)- 3,8-dimethyl-9H-
pyrido[2,3-b]indol-7-yl) (4-(hydroxymethyl)piperidin-
1-yl)methanone ##STR00510## 340 (5-(3-(ethylsulfonyl)phenyl)-
3,8-dimethyl-9H-pyrido [2,3-b]indol-7-yl)(4-(2-
hydroxyethyl)piperidin- 1-yl)methanone ##STR00511## 341
(5-(3-(ethylsulfonyl)phenyl)- 3,8-dimethyl-9H-
pyrido[2,3-b]indol-7- yl)(4-hydroxypiperidin- 1-yl)methanone
##STR00512## 342 (5-(3-(ethylsulfonyl)phenyl)- 3,8-dimethyl-9H-
pyrido[2,3-b]indol-7- yl)(2-(hydroxymethyl)
pyrrolidin-1-yl)methanone ##STR00513## 343
(5-(3-(ethylsulfonyl)phenyl)- 3,8-dimethyl-9H-
pyrido[2,3-b]indol-7-yl)(2- (hydroxymethyl)morpholino) methanone
##STR00514## 344 (5-(3-(ethylsulfonyl)phenyl)- N-(3-hydroxypropyl)-
3,8-dimethyl-9H- pyrido[2,3-b]indole-7- carboxamide ##STR00515##
345 (R)-5-(3-(ethylsulfonyl)phenyl)- N-(3-hydroxybutyl)-3,8-
dimethyl-9H-pyrido[2,3-b] indole-7-carboxamide ##STR00516## 346
(S)-5-(3-(ethylsulfonyl)phenyl)- N-(3-hydroxybutyl)-3,8-
dimethyl-9H-pyrido[2,3-b] indole-7-carboxamide ##STR00517## 347
5-(3-(ethylsulfonyl)phenyl)- N-(3-hydroxy-3-
methylbutyl)-3,8-dimethyl- 9H-pyrido[2,3-b]indole- 7-carboxamide
##STR00518## 348 (S)-N-(3-(dimethylamino)-2- hydroxypropyl)-5-(3-
(ethylsulfonyl)phenyl)- 3,8-dimethyl-9H-pyrido[2,3-b]
indole-7-carboxamide ##STR00519## 349 (S)-N-(2-(dimethylamino)-3-
hydroxypropyl)-5-(3- (ethylsulfonyl)phenyl)-
3,8-dimethyl-9H-pyrido[2,3-b] indole-7-carboxamide ##STR00520## 350
N-(3-(ethyl(2-hydroxyethyl) amino)propyl)-5-(3-
(ethylsulfonyl)phenyl)- 3,8-dimethyl-9H-pyrido
[2,3-b]indole-7-carboxamide ##STR00521## 351
5-(3-(ethylsulfonyl)phenyl)- N-(3-((2-hydroxyethyl)
(methyl)amino)propyl)- 3,8-dimethyl-9H-pyrido
[2,3-b]indole-7-carboxamide ##STR00522## 352 N-(2-(ethyl(2-
hydroxyethyl)amino) ethyl)-5-(3-(ethylsulfonyl)
phenyl)-3,8-dimethyl- 9H-pyrido[2,3-b]indole- 7-carboxamide
##STR00523## 353 5-(3-(ethylsulfonyl)phenyl)-
N-(2-((2-hydroxyethyl) (methyl)amino)ethyl)- 3,8-dimethyl-9H-pyrido
[2,3-b]indole-7-carboxamide ##STR00524##
[2115] Compounds 335-353 can be prepared as follows. Crude
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxy-
lic acid (Compound 87; e.g., 124.3 g, 0.244 mol) is heated with NMP
to give a thin slurry (e.g., 1.0 L of NMP heated to 70.degree. C.
for 39 min). The heat is removed and the mixture cooled (e.g., to
16.degree. C. with the aid of a cold water bath). Appropriate amine
(2.0 equiv) is added, followed by HBTU (92.6 g, 1.0 equiv) in
portions over about 26 min. Over the next 2.5 h, additional HBTU
(e.g., 4.7 and 4.65 g) can be added and the mixture stirred (e.g.,
overnight) until the reaction proceeds to completion (e.g., >99%
conversion as indicated by HPLC analysis). The mixture is then be
filtered (e.g., through a Celite impregnated pad, which is rinsed
twice with NMP (27 and 39 g)). To the filtrate is added a solution
of KOH (27.7 g, 1.7 equiv at 85% based on theoretical
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxy-
lic acid) in water (250 mL) to give a solution with pH 11.7. After
solids begin to form (e.g., about 15 min), water (500 mL) is added
(e.g., over 30 min at 28-29.degree. C.). After about 3 h at room
temperature, the solids are removed by filtration, and the wet cake
is rinsed with water (e.g., 1150 mL in several portions), and dried
in a vacuum oven (45-55.degree. C.) to give the desired product.
HPLC analysis can be used to indicate purity (AUC at 215 nm).
[2116] Compounds according to the present invention can also be
prepared as pharmaceutically acceptable salts. In addition, to the
salts described above, salts of compounds of the present inventions
can be formed using, for example, the following acids: benzoic
acid, fumaric acid, HBr, HCl, hippuric acid, lactic acid, maleic
acid, malic acid, MSA, phosphoric acid, p-TSA, succinic acid,
sulfuric acid, tartaric acid, and the like. The salts of the above
acids can be prepared by adding 0.5 to 2.0 equivalents of the
appropriate acid in any of a variety of solvents (such as MeCN,
EtOH, MeOH, DMA, THF, AcOH, and the like, or mixtures thereof) at a
temperature of between about 10.degree. C. and 75.degree. C.
[2117] For example, the mono HCl salt of
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide (Compound 113) was prepared as
follows. To a solution of
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-py-
rido[2,3-b]indole-7-carboxamide (2.105 g) in MeOH (20 mL) was added
4.38 mL of 1N aqueous HCl. The mixture was stirred for 15-30 min at
25.degree. C. The solvent was removed to near dryness, and the
resultant white solid filtered and dried to provide 2.23 g of the
title compound. Mono HCl salts of the following compounds were also
prepared using an analogous procedure: [2118]
5-(3-(ethylsulfonyl)phenyl)-3-methyl-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole (Compound 177 and 183); [2119]
3-chloro-5-(3-(ethylsulfonyl)phenyl)-8-((1-methylpiperidin-4-yl)methoxy)--
9H-pyrido[2,3-b]indole (Compound 200); [2120]
3-(5-(3-(ethylsulfonyl)phenyl)-3-methyl-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine (Compound 206); [2121]
3-(3-chloro-5-(3-(ethylsulfonyl)phenyl)-9H-pyrido[2,3-b]indol-8-yloxy)-N,-
N-dimethylpropan-1-amine (Compound 220); and [2122]
N-cyclopropyl-3-(3-methyl-8-((1-methylpiperidin-4-yl)methoxy)-9H-pyrido[2-
,3-b]indol-5-yl)benzamide (Compound 178).
[2123] In addition to the foregoing, the above reaction schemes and
variations thereof can be used to prepare the following:
##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529##
##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534##
##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539##
##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544##
##STR00545##
Characterization of the Amorphous Form of Compound 88
[2124] The Amorphous Form of Compound 88 was characterized by XRPD
and Ion Chromatograpgy.
[2125] 1. X-Ray Powder Diffraction (XRPD)
[2126] X-ray powder diffraction (XRPD) analyses were performed
using a Shimadzu XRD-6000 diffractometer. Real time data were
collected using Cu--K.alpha. radiation starting at approximately
3.degree. 2.theta. at a scan rate of 2.degree./min with a step size
of 0.04.degree.. The tube voltage and amperage were set to 40 kV
and 40 mA, respectively. The pattern is displayed from 2.5 to
45.degree. 2.theta.. Samples were prepared for analysis by placing
them on Si zero-return ultra-micro sample holders.
[2127] The resulting XRPD spectrum of the amorphous form of
Compound 88 shows a diffuse halo with no discernable peaks, which
confirms that the material is amorphous.
[2128] 2. Ion Chromatography (IC)
[2129] Ion Chromatography (IC) was performed using a Dionex DX600
Ion Chromatograph using a Dionex IonPac AS17, 250.times.4 mm column
and a Dionex IonPac AS17, 50.times.4 mm guard column. The column
temperature was 35.+-.2.degree. C. The detector was operated in a
suppressed conductivity mode with a Dionex ASRS Ultra 4 mm
suppressor and a suppressor current of 220 mA. Mobile phase A was
purified water and mobile phase B was potassium hydroxide (KOH),
which was delivered using an eluent generator. A flow rate of 1.5
mL/min and an injection volume of 10 .mu.L were used. The following
gradient conditions were used:
TABLE-US-00006 Time Mobile Concentration (min) Phase A of KOH (mM)
0.0 100% 5 3.0 100% 5 10.0 100% 15 20.0 100% 60 20.1 100% 5 30.0
100% 5
[2130] IC analysis of the amorphous form of Compound 88 showed 7.6
wt % Cl.sup.- present, which is 1.0 wt % higher than expected for a
mono-HCl salt.
Biological Testing
[2131] The activity of compounds as protein kinase inhibitors may
be assayed in vitro, in vivo or in a cell line. In vitro assays
include assays that determine inhibition of either the
phosphorylation activity or ATPase activity of the activated
protein kinase. Alternate in vitro assays quantitate the ability of
the inhibitor to bind to the protein kinase Inhibitor binding may
be measured by radiolabelling the inhibitor prior to binding,
isolating the inhibitor/protein kinase complex and determining the
amount of radiolabel bound. Alternatively, inhibitor binding may be
determined by running a competition experiment where new inhibitors
are incubated with the protein kinase bound to known
radioligands.
[2132] A. Determination of Inhibition of AIK
[2133] The inhibitory properties of compounds relative to Aurora
B/INCENP may be determined by the Direct Fluorescence Polarization
detection method (FP) using a Greiner small volume black
384-well-plate format under the following reaction conditions: 50
mM Hepes pH 7.3, 10 mM MgCl.sub.2, 10 mM NaCl, 1 mM DTT, 0.01%
Brij35, 5FAM-GRTGRRNSI-NH.sub.2 (Provided by Anaspec), 5% DMSO, 10
uM ATP and 0.8 nM Aurora B/INCENP. Detection of the reaction
product is performed by addition of Progressive IMAP binding
reagent (Molecular Devices). Reaction product may be determined
quantitatively by FP using an Analyst HT plate reader (Molecular
Devices) with an excitation wavelength at 485 nm and emission at
530 nm and using a Fluorescein 505 dichroic mirror.
[2134] The assay reaction may be initiated as follows: 2 ul of
(3.times.) 300 nM Fl-Peptide/30 uM ATP was added to each well of
the plate, followed by the addition of 2 ul of (3.times.) inhibitor
(2 fold serial dilutions for 11 data points for each inhibitor)
containing 15% DMSO. Two microliters of (3.times.) 2.4 nM
AuroraB/INCENP solution may be added to initiate the reaction
(final enzyme concentration was 0.8 nM for Aurora B/INCENP). The
reaction mixture may then be incubated at room temperature for 45
min, and quenched and developed by addition of 20 ul of 1 to 400
diluted Progressive IMAP binding reagent in 1.times. proprietary
Progressive IMAP binding buffer A. Fluorescence polarization
readings of the resulting reaction mixtures may be measured after a
60-minute incubation at room temperature.
[2135] IC.sub.50 values may be calculated by non-linear curve
fitting of the compound concentrations and fluorescent polarization
values to the standard IC.sub.50 equation. As a reference point for
this assay, Staurosporine showed an IC.sub.50 of <10 nM.
IC.sub.50 values for select compounds of the invention against AIK
B are given in Table 1.
TABLE-US-00007 TABLE 1 IC.sub.50 of Exemplified Compounds Against
AIK B COMPOUND IC.sub.50 (nM) 5 .gtoreq.11 15 .ltoreq.5 18 6-10 40
.ltoreq.5 41 6-10 51 6-10 52 6-10 54 6-10 55 .ltoreq.5 62 .ltoreq.5
72 .ltoreq.5 88 6-10 90 6-10 95 .gtoreq.11 100 .ltoreq.5 101
.ltoreq.5 105 .gtoreq.11 112 .gtoreq.11 113 6-10 114 .gtoreq.11 117
.gtoreq.11 120 6-10 128 .ltoreq.5 140 .ltoreq.5 142 6-10 153
.gtoreq.11 154 6-10 157 .ltoreq.5 158 .ltoreq.5 163 .gtoreq.11 170
.ltoreq.5 171 6-10 173 .gtoreq.11 177 6-10 178 .gtoreq.11 179 6-10
182 6-10 185 .ltoreq.5 194 .ltoreq.5 195 .gtoreq.11 200 .ltoreq.5
201 .ltoreq.5 206 .ltoreq.5 217 .ltoreq.5 220 .ltoreq.5 231
.ltoreq.5 232 6-10 270 .ltoreq.5 271 .ltoreq.5 272 6-10 285 6-10
286 6-10 295 6-10 299 .ltoreq.5 308 .ltoreq.5 313 .ltoreq.5 314
.ltoreq.5 315 .ltoreq.5
[2136] B. Determination of Inhibition of c-KIT
[2137] The inhibitory properties of compounds relative to c-Kit may
be determined by the Time-Resolved Fluorescence Resonance Energy
Transfer (TR-FRET) method using a small volume black 384-well-plate
(Greiner) format under the following reaction conditions: 50 mM
Hepes pH 7.3, 10 mM MgCl.sub.2, 10 mM NaCl, 1 mM DTT, 0.01% Brij35,
250 nM Biotin-EGPWLEEEEEAYGWMDF peptide (provided by SYNPEP), 5%
DMSO, 100 uM ATP. Detection of the reaction product may be
performed by addition of Streptavidin-APC (Prozyme) and
Eu-Anti-phosphotyrosine antibody (Perkin Elmer). Reaction product
may be determined quantitatively by TR-FRET reading using an
Analyst HT plate reader (Molecular Devices) with an excitation
wavelength at 330 nm and emission at 615 nm (Europium) compared to
330 nm excitation (Europium) and emission 665 nm (APC) and using an
Europium 400 dichroic mirror.
[2138] The assay reaction may be initiated as follows: 4 ul of
(2.5.times.) 625 nM Biotin-Peptide/250 uM ATP was added to each
well of the plate, followed by the addition of 2 ul of (5.times.)
inhibitor (2.5 fold serial dilutions for 11 data points for each
inhibitor) containing 25% DMSO. 4 ul of (2.5.times.) c-Kit solution
may be added to initiate the reaction (final enzyme concentration
was 0.13 nM for c-Kit). The reaction mixture may then be incubated
at room temperature for 30 min, and quenched and developed by
addition of 10 ul of (2.times.) 3.2 nM Eu-Antibody and 25 nM
Streptavidin-APC in 50 mM Hepes pH 7.3, mM EDTA, 0.1% Triton X-100
buffer. TR-FRET readings of the resulting reaction mixtures may be
measured after a 60-minute incubation at room temperature on the
Analyst HT.
[2139] IC.sub.50 values may be calculated by non-linear curve
fitting of the compound concentrations and ratio metric Eu:APC
values to the standard IC.sub.50 equation. As a reference point for
this assay, Staurosporine showed an IC.sub.50 of <5 nM.
[2140] The following abbreviations have been used: [2141] ATP
Adenosine Triphophatase [2142] BSA Bovine Serum Albumin [2143] EDTA
Ethylenediaminetetraacetic acid [2144] GSK3 Glycogen synthase
kinase 3 [2145] MOPS Morpholinepropanesulfonic acid [2146] SPA
Scintillation Proximity Assay
[2147] It will be apparent to those skilled in the art that various
modifications and variations can be made in the compounds,
compositions, kits, and methods of the present invention without
departing from the spirit or scope of the invention. Thus, it is
intended that the present invention cover the modifications and
variations of this invention provided they come within the scope of
the appended claims and their equivalents.
* * * * *