U.S. patent application number 12/260051 was filed with the patent office on 2009-03-05 for pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith.
Invention is credited to Ashvinikumar V. Gavai, Harold Mastalerz, George L. Trainor, Dolatrai M. Vyas.
Application Number | 20090062288 12/260051 |
Document ID | / |
Family ID | 37441986 |
Filed Date | 2009-03-05 |
United States Patent
Application |
20090062288 |
Kind Code |
A1 |
Mastalerz; Harold ; et
al. |
March 5, 2009 |
PYRROLOTRIAZINE COMPOUNDS USEFUL AS KINASE INHIBITORS AND METHODS
OF TREATING KINASE-ASSOCIATED CONDITIONS THEREWITH
Abstract
The invention relates to at least one pyrrolotriazine
derivative, at least one pharmaceutical composition comprising at
least one pyrrolotriazine derivative, and at least one method of
using at least one pyrrolotriazine derivative to treat at least one
kinase associated condition.
Inventors: |
Mastalerz; Harold;
(Guilford, CT) ; Vyas; Dolatrai M.; (Madison,
CT) ; Trainor; George L.; (Wilmington, DE) ;
Gavai; Ashvinikumar V.; (Princeton Junction, NJ) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Family ID: |
37441986 |
Appl. No.: |
12/260051 |
Filed: |
October 28, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11426693 |
Jun 27, 2006 |
7442700 |
|
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12260051 |
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60696215 |
Jul 1, 2005 |
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Current U.S.
Class: |
514/243 ;
544/183 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 25/00 20180101; A61P 19/02 20180101; A61P 19/08 20180101; A61P
29/00 20180101; A61P 19/00 20180101; A61P 9/00 20180101; A61P 5/00
20180101; A61P 11/06 20180101; A61P 31/12 20180101; A61P 35/00
20180101; C07D 487/04 20130101; A61P 31/10 20180101; A61P 37/00
20180101; A61P 3/00 20180101; A61P 37/08 20180101 |
Class at
Publication: |
514/243 ;
544/183 |
International
Class: |
A61K 31/53 20060101
A61K031/53; C07D 253/10 20060101 C07D253/10; A61P 35/00 20060101
A61P035/00 |
Claims
1. A compound of Formula (I) ##STR00022## or pharmaceutically
acceptable salts thereof, wherein: Q.sup.1 is aryl, substituted
aryl, heteroaryl, or substituted heteroaryl; R.sup.1 is H,
--NR.sup.6C(.dbd.O)R.sup.7, --OR.sup.7, or
--C(.dbd.O)NR.sup.7R.sup.8; Q.sup.2 is aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; R.sup.2 is H, alkyl,
substituted alkyl, hydroxy (--OH), alkoxy, halogen, haloalkyl,
haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl,
substituted alkanoyl, alkanoyloxy, amino, aminoalkyl, substituted
aminoalkyl, alkylamino, substituted alkylamino, hydroxyalkyl,
disubstituted amino, amide, substituted amide, carbamate,
substituted carbamate, ureido, cyano, sulfonamide, substituted
sulfonamide, alkylsulfone, heterocycloalkyl, substituted
heterocycloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro,
thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, carbamoyl,
--NR.sup.6(C.dbd.O)R.sup.9, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heteroaryloxy, arylheteroaryl,
arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy,
aryloxyalkyl, aryloxyaryl, heterocycle, substituted heterocycle,
alkylcarbonyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl,
substituted heteroalkenyl, heteroalkynyl, substituted
heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino,
arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl,
arylalkylsulfonyl, alkylsulfonyl, arylcarbonylamino, or
alkylaminocarbonyl; R.sup.3, R.sup.4, and R.sup.5 are independently
selected from H, alkyl, substituted alkyl, hydroxy, alkoxy,
halogen, haloalkyl, haloalkoxy, alkanoyl, substituted alkanoyl,
amino, aminoalkyl, substituted aminoalkyl, alkylamino, substituted
alkylamino, amide, substituted amide, carbamate, ureido, cyano,
sulfonamide, substituted sulfonamide, alkylsulfone, cycloalkyl,
substituted cycloalkyl, nitro, thio, thioalkyl, alkylthio,
disubstituted amino, alkylsulfonyl, alkylsulfinyl, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, carbamoyl,
--NR.sup.6(C.dbd.O)R.sup.9, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and alkylcarbonyl. R.sup.6 is H, lower alkyl,
or substituted lower alkyl; R.sup.7 and R.sup.8 are independently
selected from H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocycloalkyl, substituted heterocycloalkyl,
heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted
heteroalkenyl, hetroalkynyl, or substituted heteroalkynyl; R.sup.9
is H, alkyl, substituted alkyl, alkoxy, aminoalkyl, substituted
aminoalkyl, alkylamino, substituted alkylamino, aryl, or
substituted aryl.
2. A compound according to claim 1, wherein Q.sup.2 is heteroaryl
or substituted heteroaryl.
3. A compound according to claim 1, wherein Q.sup.2 is pyrazole,
thiazole, or pyrimidine.
4. A compound according to claim 1, wherein R.sup.2 is H, alkyl,
substituted alkyl, cycloalkyl, or substituted cycloalkyl.
5. A compound according to claim 1, wherein Q.sup.1 is aryl or
substituted aryl.
6. A compound according to claim 1, wherein Q.sup.1 is phenyl or
substituted phenyl.
7. A compound according to claim 1, wherein R.sup.3, R.sup.4, and
R.sup.5 are independently selected from H, alkyl, substituted
alkyl, alkoxy, and halogen.
8. A compound according to claim 1, wherein R.sup.7 and R.sup.8 are
independently selected from H, alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, or substituted cycloalkyl.
9. A compound according to claim 1, wherein R.sup.1 is
--NR.sup.6C(.dbd.O)R.sup.7 and R.sup.2 is H, alkyl, substituted
alkyl, cycloalkyl, or substituted cycloalkyl.
10. A compound according to claim 1, having the formula
##STR00023## or a pharmaceutically acceptable salt thereof,
wherein: Q.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.7 are as defined hereinabove.
11. The compound according to claim 10, wherein Q.sup.1 is aryl or
substituted aryl.
12. A compound according to claim 10, having the formula
##STR00024## or a pharmaceutically acceptable salt thereof,
wherein: Q.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5
are as defined hereinabove.
13. A compound according to claim 12, wherein R.sup.1 is
--NR.sup.6C(.dbd.O)R.sup.7 and R.sup.2 is H, alkyl, substituted
alkyl, cycloalkyl, or substituted cycloalkyl.
14. A pharmaceutical composition comprising a) at least one
compound according to claim 1; b) optionally at least one
pharmaceutically-acceptable carrier and/or diluent; and c)
optionally at least one other anti-cancer agent
15. A method for treating at least one proliferative disease
comprising administering to a patient in need thereof a
therapeutically effective amount of at least one compound according
claim 1; optionally administering either simultaneously or
sequentially at least one other anti-cancer agent, and optionally
administering either simultaneously or sequentially at least one
other anti-cancer treatment.
16. The method according to claim 15, wherein the proliferative
disease is selected from cancer, bone disease, inflammatory
disease, autoimmune disease, metabolic disease, viral disease,
fungal disease, neurological and neurodegenerative disorders,
Alzheimer's disease, allergies and asthma, cardiovascular disease,
and hormone related disease.
17. The method according to claim 15, wherein the proliferative
disease is cancer.
18. The method according to claim 17, wherein the patient is a
human.
19. The method according to claim 15, wherein the patient is a
human.
20. A compound according to claim 1 selected from (i)
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2--
yl}sulfanyl)phenyl]cyclopropanecarboxamide;
N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrol-
o[2,1-f][1,2,4]triazin-4-amine;
N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triaz-
in-2-yl}sulfanyl)phenyl]acetamide;
3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin--
2-yl}sulfanyl)-N-methylbenzamide;
N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-][1,2,4]triazi-
n-4-amine; and
N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2--
yl)sulfanyl)phenyl)benzamide; and (ii) a pharmaceutically
acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
application Ser. No. 60/696,215, filed Jul. 1, 2005, the contents
of which are hereby incorporated herein by reference.
FIELD OF THE INVENTION
[0002] Disclosed herein is at least one pyrrolotriazine derivative,
at least one pharmaceutical composition comprising at least one
pyrrolotriazine derivative described herein, and at least one
method of using at least one pyrrolotriazine derivative disclosed
herein for treating at least one kinase associated condition.
BACKGROUND OF THE INVENTION
[0003] Hyperproliferative diseases, such as, for example, cancer
are generally characterized by uncontrolled cellular proliferation
and/or disruption in programmed cell death. The loss of a cell's
ability to control cellular proliferation is often caused by
genetic damage to the cellular pathways responsible for regulating
cellular functions, including but not limited to, for example,
metabolism, cell cycle progression, cell adhesion, vascular
function, apoptosis, and angiogenesis. As a result, one approach to
treating hyperproliferative diseases has involved targeting at
least one protein involved in regulating these cellular
functions.
[0004] The protein kinases are at least one class of proteins that
has been identified as playing an important role in regulating
cellular functions. Indeed, many diseases are associated with
abnormal cellular responses triggered by protein kinase-mediated
events. Such diseases include but are not limited to autoimmune
diseases, bone diseases, inflammatory diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease, and hormone
related diseases.
[0005] The protein kinases are a large and diverse group of enzymes
that are divided into groups based on the particular amino acids
(serine/threonine, tyrosine, lysine and histidine) that a
particular kinase targets. For example, receptor and non-receptor
tyrosine kinases target tyrosine kinase and cyclin dependent
kinases (CDKs) and mitogen activated protein kinases (MAPKs) target
both tyrosine and serine/threonine.
[0006] Exemplary protein kinases, include, but are not limited to,
for example, receptor tyrosine kinases (RTKs), such as, for
example, growth factors including, for example, type III receptor
tryrosine kinase (Flt3); non-receptor tyrosine kinases, such as,
for example, Src kinases including, for example, Src, Yes, Fyn,
Lyn, Lck, Blk, Hck, Fgr, and Yrk, Btk kinases, Csk kinases, ZAP70
kinases, and Kak kinases; serine/threonine kinases, such as, for
example, p90 ribosomal S6 kinases (RSK), including, for example,
RSK1/p90Rsk, RSK2, RSK3, and RSK4, checkpoint protein kinases,
including, for example, CHK1 and CHK2, AURORA kinases, including,
for example, aurora-A, aurora-B, and aurora-C, and Glycogen
synthase kinase 3 (GSK3); cyclin dependent kinases (CDKs)
including, for example, CDK1, CDK2, CDK4, CDK5, CDK6, CDK 7, and
cell division control 2 protein (CDC2); and mitogen-activated
protein kinases (MAPKs), such as, for example, mitogen-activated
protein kinase 1 (ERK), MAPK3, MAPK7, mitogen-activated protein
kinase 8 (JNK1), mitogen-activated protein kinase 14 (p38 alpha),
MAPK 10, JNK 3 alpha protein kinase, stress-activated protein
kinase JNK 2, and MAPK 14.
[0007] More recently, the Aurora kinases were discovered to be
involved in the growth of various types of cancer cells, and as a
result are being targeted to develop potential cancer treatments.
Accordingly, efforts have been undertaken to develop Aurora kinase
inhibitors that are therapeutically effective against cancer
cells.
SUMMARY OF THE INVENTION
[0008] Disclosed herein are compounds of Formula (I):
##STR00001## [0009] (I) or a pharmaceutically acceptable salt
thereof, wherein [0010] Q.sup.1 is aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; [0011] R.sup.1 is H,
--NR.sup.6C(.dbd.O)R.sup.7, --OR.sup.7, or
--C(.dbd.O)NR.sup.7R.sup.8; [0012] Q.sup.2 is aryl, substituted
aryl, heteroaryl, or substituted heteroaryl; [0013] R.sup.2 is H,
alkyl, substituted alkyl, hydroxy (--OH), alkoxy, halogen,
haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy,
alkanoyl, substituted alkanoyl, alkanoyloxy, amino, aminoalkyl,
substituted aminoalkyl, alkylamino, substituted alkylamino,
hydroxyalkyl, disubstituted amino, amide, substituted amide,
carbamate, substituted carbamate, ureido, cyano, sulfonamide,
substituted sulfonamide, alkylsulfone, heterocycloalkyl,
substituted heterocycloalkyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, cycloalkylalkyl,
cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl,
alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy,
carbamoyl, --NR.sup.6(C.dbd.O)R.sup.9, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heteroaryloxy, arylheteroaryl,
arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy,
aryloxyalkyl, aryloxyaryl, heterocycle, substituted heterocycle,
alkylcarbonyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl,
substituted heteroalkenyl, heteroalkynyl, substituted
heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino,
arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl,
arylalkylsulfonyl, alkylsulfonyl, arylcarbonylamino, or
alkylaminocarbonyl; [0014] R.sup.3, R.sup.4, and R.sup.5 are
independently selected from H, alkyl, substituted alkyl, hydroxy,
alkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, substituted
alkanoyl, amino, aminoalkyl, substituted aminoalkyl, alkylamino,
substituted alkylamino, amide, substituted amide, carbamate,
ureido, cyano, sulfonamide, substituted sulfonamide, alkylsulfone,
cycloalkyl, substituted cycloalkyl, nitro, thio, thioalkyl,
alkylthio, disubstituted amino, alkylsulfonyl, alkylsulfinyl,
carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl,
--NR.sup.6(C.dbd.O)R.sup.9, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and alkylcarbonyl. [0015] R.sup.6 is H, lower
alkyl, or substituted lower alkyl; [0016] R.sup.7 and R.sup.8 are
independently selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, heteroalkyl, substituted heteroalkyl,
heteroalkenyl, substituted heteroalkenyl, hetroalkynyl, or
substituted heteroalkynyl; and [0017] R.sup.9 is H, alkyl,
substituted alkyl, alkoxy, aminoalkyl, substituted aminoalkyl,
alkylamino, substituted alkylamino, aryl, or substituted aryl.
[0018] Further described herein is at least one pharmaceutical
composition comprising at least one compound in accordance with
Formula (I), optionally at least one pharmaceutically-acceptable
carrier and/or diluent, and optionally at least one other
anti-cancer agent.
[0019] Even further described herein is at least one method for
treating at least one proliferative disease comprising
administering to a patient in need thereof an effective amount of
at least one compound according to Formula (I), optionally
administering either simultaneously or sequentially at least one
other anti-cancer agent, and optionally administering either
simultaneously or sequentially at least one other anti-cancer
treatment.
[0020] Yet even further described herein is at least one Formula
(I) compound selected from: (i)
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f1
[1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide;
N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrol-
o[2,1-f][1,2,4]triazin-4-amine;
N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triaz-
in-2-yl}sulfanyl)phenyl]acetamide;
3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin--
2-yl}sulfanyl)-N-methylbenzamide;
N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triaz-
in-4-amine; and
N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2--
yl)sulfanyl)phenyl)benzamide; and (ii) pharmaceutically acceptable
salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The features and advantages of the invention may be more
readily understood by those of ordinary skill in the art upon
reading the following detailed description. It is to be appreciated
that certain features of the invention that are, for clarity
reasons, described above and below in the context of separate
embodiments, may also be combined to form a single embodiment.
Conversely, various features of the invention that are, for brevity
reasons, described in the context of a single embodiment, may also
be combined so as to form sub-combinations thereof.
[0022] Unless specifically stated otherwise herein, references made
in the singular may also include the plural. For example, "a" and
"an" may refer to either one, or one or more.
[0023] Embodiments identified herein as exemplary or preferred are
intended to be illustrative and not limiting.
[0024] Unless otherwise indicated, any heteroatom with unsatisfied
valences is assumed to have hydrogen atoms sufficient to satisfy
the valences.
[0025] The definitions set forth herein take precedence over
definitions set forth in any patent, patent application, and/or
patent application publication incorporated herein by
reference.
[0026] Definitions of terms used in describing the invention are
set forth hereinbelow. Unless otherwise indicated, the initial
definition provided for a group or term applies each time such
group or term is used individually or as part of another group.
[0027] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds.
[0028] The terms "alkyl" and "alk" refer to a straight chain or
branched chain saturated hydrocarbon radical containing from 1 to
12 carbon atoms and preferably from 1 to 6 carbon atoms. Exemplary
"alkyl" and/or "alk" groups include, but are not limited to, for
example, methyl, ethyl, propyl, isopropyl, 1-methylpropyl, n-butyl,
t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,
4,4-dimethylpentyl, diethylpentyl, octyl, 2,2,4-trimethylpentyl,
nonyl, decyl, undecyl, and dodecyl.
[0029] The term "substituted alkyl" refers to an alkyl group
substituted with at least one substituent at any available and
substitutable position. Exemplary substituents include, but are not
limited to, for example, hydrogen, alkyl, hydroxy (--OH), alkoxy,
halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl,
arylalkyloxy, alkanoyl, substituted alkanoyl, alkanoyloxy, amino,
aminoalkyl, substituted aminoalkyl, alkylamino, substituted
alkylamino, hydroxyalkyl, disubstituted amino, amide, substituted
amide, carbamate, substituted carbamate, ureido, cyano,
sulfonamide, substituted sulfonamide, alkylsulfone,
heterocycloalkyl, substituted heterocycloalkyl, cycloalkyl,
substituted cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro,
thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, carbamoyl,
--NR.sup.6(C.dbd.O)R.sup.9, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heteroaryloxy, arylheteroaryl,
arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy,
aryloxyalkyl, aryloxyaryl, heterocycle, substituted heterocycle,
alkylcarbonyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl,
substituted heteroalkenyl, heteroalkynyl, substituted
heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino,
arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl,
arylalkylsulfonyl, arylcarbonylamino, and alkylaminocarbonyl.
[0030] The term "lower alkyl" refers to an alkyl group containing
from 1 to 4 carbon atoms. It is of import to note that although the
term "lower alkyl" is encompassed within the definition of "alkyl",
the usage of the term "lower alkyl" is not intended to limit the
definition of the term "alkyl" either explicitly or implicitly to a
straight- or branched-chain saturated hydrocarbon radical
containing from 5 to 7 carbon atoms. Exemplary lower alkyl groups
include, but are not limited to, for example, methyl; ethyl;
propyl; isopropyl; n-butyl; t-butyl; isobutyl; pentyl; and
isopentyl
[0031] The term "substituted lower alkyl" refers to a lower alkyl
substituted at any available and substitutable position with at
least one alkyl, substituted alkyl, or substituent described above
in defining the term "substituted alkyl" as an exemplary alkyl
substituent.
[0032] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon rings having from 6 to 12 carbon atoms in the ring
portion. Exemplary aryl groups include but are not limited to, for
example, phenyl; naphthalenyl; biphenyl; and diphenyl groups. When
two aromatic rings are present, the aromatic rings of the aryl
group may either be joined at a single point (e.g., biphenyl), or
be fused (e.g., naphthalenyl). The term "aryl" also includes rings
having a second, third, fourth, or fifth ring fused thereto that is
a heterocyclo, substituted heterocyclo, heteroaryl, substituted
heteroaryl, aryl, substituted aryl, cycloalkyl, or substituted
cycloalkyl, provided in such cases the point of attachment is to
the aryl portion of the ring system. The term "aryl" further
includes rings having a second, third, fourth, or fifth ring
attached to the ring or ring system in a spiro fashion, wherein
such second, third, fourth, or fifth ring is a heterocyclo,
substituted heterocyclo, heteroaryl, substituted heteroaryl, aryl,
substituted aryl, cycloalkyl, or substituted cycloalkyl.
[0033] The term "substituted aryl" refers to an aryl substituted
with at least one substituent at any available and substitutable
ring position, or where valence allows on any rings fused or
attached thereto. Exemplary substituents include, but are not
limited to, for example, hydrogen; alkyl, substituted alkyl,
hydroxy (--OH), alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryl, aryloxy,
arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl,
alkanoylamino, amino, aminoalkyl, substituted aminoalkyl,
alkylamino, substituted alkylamino, disubstituted amino,
aminocarbonyl, arylamino, arylalkylamino, arylalkoxy, ureido,
cyano, sulfonamide, substituted sulfonamide, heterocycloalkyl,
substituted heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl,
substituted cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro,
thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy,
carboxyalkyl, carboxyalkoxy, alkoxycarbonyl, alkylcarbonyloxy,
carbamoyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylsulfonylamino, arylalkenyl, aryloxycarbonyl, arylthio,
arylthioalkyl, arylalkylthio, sulfonic acid, heteroaryl,
substituted heteroaryl, heteroarylthio, heteroaryloxy,
heteroarylalkenyl, heteroarylheteroaryl, heteroarylalkylthio,
heteroaryloxyalkyl, alkylcarbonyl, aminocarbonylaryl,
aminocarbonylalkyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl,
alkylaminocarbonyl, aminoalkylcarbonyl, arylaminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,
arylcarbonylamino, arylsulfonyl, heteroarylsulfonyl,
heterocycloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, and
arylsulfonylaminocarbonyl.
[0034] The term "substituted phenyl" refers to a phenyl substituted
with at least one substituent described above as a "substituted
aryl" substituent.
[0035] The terms "aryloxy", "arylamino", "arylalkylamino",
"arylthio", "arylalkanoylamino", "arylsulfonyl", "arylalkoxy",
"arylsulfinyl", "arylheteroaryl", "arylalkylthio", "arylcarbonyl",
"arylalkenyl", or "arylalkylsulfonyl" refer to an aryl or
substituted aryl bonded to an oxygen; an amino; an alkylamino; a
thio; an alkanoylamino; a sulfonyl; an alkoxy; a sulfinyl; a
heteroaryl or substituted heteroaryl; an alkylthio; a carbonyl; an
alkenyl; or an alkylsulfonyl, respectively
[0036] The term "arylsulfonylaminocarbonyl" refers to an
arylsulfonyl bonded to an aminocarbonyl.
[0037] The terms "aryloxyalkyl", "aryloxycarbonyl" or "aryloxyaryl"
refer to an aryloxy bonded to an alkyl or substituted alkyl; a
carbonyl; or an aryl or substituted aryl, respectively.
[0038] The term "arylalkyl" refers to an alkyl or substituted alkyl
in which at least one of the hydrogen atoms bonded to at least one
of the carbon atoms is replaced with an aryl or substituted aryl.
Typical arylalkyls include, but are not limited to, for example,
benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and
2-naphthophenylethan-1-yl.
[0039] The term "arylalkyloxy" refers to an arylalkyl bonded
through an oxygen linkage (--O-arylalkyl).
[0040] The terms "arylthioalkyl" or "arylsulfinylalkyl" refer to an
arylthio or an arylsulfinyl, respectively, bonded to an alkyl or
substituted alkyl.
[0041] The term "heteroaryl" refers to aromatic cyclic groups, such
as, for example, 5- to 6-membered monocyclic, 7- to 11-membered
bicyclic, or 10- to 16-membered tricyclic ring systems having at
least one heteroatom in at least one carbon atom-containing ring.
The carbon atom-containing ring may contain 1, 2, 3, or 4
heteroatom(s) selected from nitrogen, oxygen, and/or sulfur. The
heteroaryl group may be attached to another moiety at any available
point of attachment.
[0042] Exemplary monocyclic heteroaryl groups include, but are not
limited to, for example, pyrazolyl, imidazolyl, triazolyl,
oxazolyl, furyl, thiazolyl, isoxazolyl, thiazolyl, pyridyl
##STR00002##
pyridazinyl
##STR00003##
pyrimidinyl
##STR00004##
pyrazinyl
##STR00005##
and triazinyl. Unless reference is made to a specific point of
attachment, e.g., as in pyrid-2-yl, pyridazin-3-yl, it is intended
that such heteroaryl groups can be bonded to another moiety at any
available point of attachment.
[0043] Exemplary bicyclic heteroaryl groups include, but are not
limited to, for example, benzothiazolyl, benzoxazolyl,
benzoxadiazolyl, benzothienyl, quinolinyl, chromenyl, indolyl,
indazolyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzofuryl,
benzofurazanyl, benzopyranyl, cinnolinyl, quinoxalinyl,
pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,
furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), and
triazinylazepinyl.
[0044] The term "substituted heteroaryl" refers to a heteroaryl
substituted at any available and substitutable ring position, or
where valence allows on any rings fused or attached thereto, with
at least one aryl, substituted aryl, or substituent described above
in defining the term "substituted aryl" as an exemplary aryl
substituent.
[0045] The terms "heteroaryloxy", "heteroarylalkenyl",
"heteroarylheteroaryl", "heteroarylalkyl", "heteroarylalkoxy",
"heteroarylthio", "heteroarylsulfonyl", or "heteroarylalkylthio"
refer to a heteroaryl or substituted heteroaryl bonded to an
oxygen; an alkenyl or substituted alkenyl; a heteroaryl or
substituted heteroaryl; an alkyl or substituted alkyl; an alkoxy; a
thio; a sulfonyl; or an alkylthio, respectively.
[0046] The term "heteroaryloxyalkyl" refers to a heteroaryloxy
bonded to an alkyl or substituted alkyl.
[0047] The term "cycloalkyl" refers to a fully saturated or
partially unsaturated cyclic hydrocarbon group containing from 1 to
3 rings and 3 to 8 carbons per ring. Exemplary cycloalkyls include,
but are not limited to, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl,
and cyclohexenyl. A cycloalkyl ring may have a carbon ring atom
replaced with a carbonyl group (C.dbd.O). Cycloalkyls include such
rings having a second or third ring fused thereto that is a
heterocyclo, substituted heterocyclo, heteroaryl, substituted
heteroaryl, aryl or substituted aryl, provided that in such cases
the point of attachment is to the cycloalkyl portion of the ring
system. The term "cycloalkyl" also includes rings having a second
or third ring attached to the ring or ring system in a spiro
fashion.
[0048] The term "substituted cycloalkyl" refers to a cycloalkyl
substituted with at least one substitutent, preferably 1 to 4
substituents, more preferably 1 to 2 substituents, at any available
point of attachment on either the cycloalkyl ring, or where valence
allows on any rings fused or attached thereto. Exemplary
substituents include, but are not limited to, for example, alkyl,
substituted alkyl, and the substituents described in defining the
term "substituted alkyl" as exemplary alkyl substituents.
[0049] Exemplary cycloalkyls include but are not limited to, for
example,
##STR00006##
[0050] The term "heterocycloalkyl" refers to a saturated or
unsaturated cycloalkyl in which one or more carbons (and any
associated hydrogen atoms) are independently replaced with at least
one heteroatom selected from O and N.
[0051] The term "substituted heterocycloalkyl" refers to a
heterocycloalkyl substituted at any available and substitutable
ring position with at least one alkyl, substituted alkyl, or
substituent described above in defining the term "substituted
alkyl" as an exemplary alkyl substituent.
[0052] The terms "heterocycloalkylalkyl" or
"heterocycloalkylsulfonyl" refer to a heterocycloalkyl or
substituted heterocycloalkyl bonded to an alkyl or substituted
alkyl or a sulfonyl, respectively.
[0053] The terms "heterocycle", "heterocyclic", and "heterocyclo"
refer to fully saturated or partially or fully unsaturated,
aromatic or nonaromatic cyclic groups that are, for example, 4 to 7
membered monocyclic, 7 to 111 membered bicyclic, or 10 to 15
membered tricyclic ring systems that have at least one heteroatom
in at least one carbon atom containing ring. Each ring of the
heterocycle, heterocyclic, or heterocyclo containing a heteroatom
may have 1, 2 or 3 heteroatoms selected from N, O, and S, where the
N and/or S heteroatom(s) may optionally be oxidized and the N
heteroatom(s) may optionally be quaternized. The heterocycle,
heterocyclic, or heterocyclo may be attached to the remainder of
the molecule via any available heteroatom or carbon atom.
Heterocycle, heterocyclic, or heterocyclo include such rings having
a second or third ring fused thereto that is a heterocyclo,
substituted heterocyclo, heteroaryl, substituted heteroaryl, aryl,
substituted aryl, cycloalkyl, or substituted cycloalkyl, provided
in such cases the point of attachment is to the heterocycle,
heterocyclic, or heterocyclo portion of the ring system. The terms
"heterocycle", "heterocyclic", or "heterocyclol" also include rings
having a second or third ring attached to the ring or ring system
in a spiro fashion, wherein such second or third ring is a
heterocyclo, substituted heterocyclo, heteroaryl, substituted
heteroaryl, aryl, substituted aryl, cycloalkyl, or substituted
cycloalkyl.
[0054] Exemplary monocyclic heterocycles, heterocyclics, or
heterocyclos include, but are not limited to, for example,
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, homopiperazinyl, 2-oxohomopiperazinyl,
2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl,
N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl
sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,
thiiranyl, triazinyl, and triazolyl.
[0055] Exemplary bicyclic heterocycles, heterocyclics, or
heterocyclos include, but are not limited to, for example,
2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl,
benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,
tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,
cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl
(such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
indazolyl, isochromanyl, isoindolinyl, naphthyridinyl,
phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, and
thienothienyl.
[0056] The terms "substituted heterocycle", "substituted
heterocyclic", or "substituted heterocyclo" refer to a heterocycle,
heterocyclic, or heterocyclo, respectively, substituted at any
available point of attachment, or where valence allows on any rings
fused or attached thereto, with at least one alkyl, substituted
alkyl, or substituent described above in defining the term
"substituted alkyl" as an exemplary alkyl substituent.
[0057] The terms "heteroalkyl", "heteroalkenyl", or "heteroalkynyl"
refer to an alkyl, alkenyl, or alkynyl, respectively, in which one
or more of the carbon atoms (and any associated hydrogen atoms) are
each independently replaced with the same or different heteroatoms.
Typical heteroatoms include, but are not limited to, for example,
--O--, --S--, --O--O--, --S--S--, --O--S--, --NR.sup.a--,
.dbd.N--N.dbd., --N.dbd.N--, --N.dbd.N--NR', --PH--,
--P(O).sub.2--, --O--P(O).sub.2--, --S(O)--, --S(O).sub.2--, and
--SnH.sub.2--, wherein R.sup.a is hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted
aryl.
[0058] The terms "substituted heteroalkyl", "substituted
heteroalkenyl", or "substituted heteroalkynyl" refer to a
heteroalkyl, heteroalkenyl, or heteroalkynyl, respectively,
substituted with at least one alkyl, substituted alkyl, or
substituent described above in defining the term "substituted
alkyl" as an exemplary alkyl substituent.
[0059] The term "hydroxyalkyl" refers to an --R.sup.bOH, wherein
R.sup.b is an alkyl or substituted alkyl.
[0060] The term "amino" refers to --NH.sub.2.
[0061] The term "aminoalkyl" refers to an alkyl substituted with an
amino having having at least one hydrogen replaced with a group
chosen from alkyl, alkenyl, and cycloalkyl. Thus, aminoalkyl refers
to the group --R.sup.cNR.sup.dR.sup.e, wherein R.sup.c is an alkyl
and R.sup.d and R.sup.e are independently selected from hydrogen,
alkyl, alkenyl, and cycloalkyl, provided R.sup.d and R.sup.e are
not both hydrogen.
[0062] The term "substituted aminoalkyl" refers to an aminoalkyl
wherein at least one of the alkyl, alkenyl, or cycloalkyl moieties
is substituted with at least one, preferably 1 to 4, more
preferably 1 to 2 groups selected from those recited herein as
appropriate for the recited moiety. Thus, for example, a
substituted aminoalkyl refers to the group
--R.sup.cNR.sup.dR.sup.e, wherein R.sup.c is an alkyl or
substituted alkyl and R.sup.d and R.sup.e are independently
selected from H, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, cycloalkyl, and substituted cycloalkyl, provided R.sup.d
and R.sup.e are not both hydrogen as in that case the group would
be amino and not substituted aminoalkyl; and that at least one of
R.sup.c, R.sup.d, or R.sup.e is a substituted moiety.
[0063] The term "alkylamino" refers to an amino having at least one
hydrogen replaced with a group chosen from alkyl, alkenyl, and
cycloalkyl. Thus, alkylamino refers to the group --NR.sup.fR.sup.g,
wherein R.sup.f and R.sup.g are independently selected form H,
alkyl, alkenyl, and cycloalkyl, provided at least one of R.sup.f or
R.sup.g is an alkyl.
[0064] The term "substituted alkylamino" refers to an alkylamino
wherein at least one of the alkyl, alkenyl, or cycloalkyl moieties
is substituted with at least one, preferably 1 to 4, more
preferably 1 to 2 groups selected from those recited herein as
appropriate substituents for the recited moiety. Thus, for example,
a substituted alkylamino refers to the group --NR.sup.fR.sup.g,
wherein R.sup.f and R.sup.g are independently selected form H,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
and substituted cycloalkyl, provided at least one of R.sup.f or
R.sup.g is an alkyl and at least one of R.sup.f or R.sup.g is a
substituted moiety.
[0065] The term "disubstituted amino" refers to an amino having
both hydrogens replaced with a group chosen from alkyl, substituted
alkyl, alkenyl, substituted alkenyl, cycloalkyl, and substituted
cycloalkyl. Thus, for example, a disubstituted amino refers to the
group --NR.sup.hR.sup.i, wherein R.sup.h and R.sup.i are
independently selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, and substituted cycloalkyl.
[0066] The terms "halogen" and "halo" refer to chlorine, bromine,
fluorine, and iodine.
[0067] The terms "haloalkyl" or "haloalkoxy" refer to an alkyl or
substituted alkyl; or an alkoxy, respectively, bonded to a single
halogen or multiple halogens. Exemplary haloalkyls containing
multiple halogens include, but are not limited to, for example,
--CHCl.sub.2 and --CF.sub.3. Exemplary haloalkoxys containing
multiple halogens include, but are not limited to, for example,
trifluoromethoxy (--OCF.sub.3).
[0068] The term "alkoxy" refers to an alkyl, substituted alkyl,
alkanoyl, substituted alkanoyl, cycloalkyl or substituted
cycloalkyl bonded through an oxygen linkage (--O-alkyl,
--O-substituted alkyl, --O-alkanoyl, --O-substituted alkanoyl,
--O-cycloalkyl, or --O-substituted cycloalkyl). Exemplary alkoxy
groups include, but are not limited to, for example, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy,
pentoxy, isopentoxy, hexoxy, heptoxy, pentoxy, decanoxy,
undecanoxy, and dodecanoxy.
[0069] The terms "alkoxyalkyl" or "alkoxyarylthio" refer to an
alkyl or substituted alkyl; or an arylthio, respectively, bonded to
an alkoxy.
[0070] The term "alkenyl" refers to a straight or branched chain
hydrocarbon radical containing from 2 to 12 carbon atoms and at
least one carbon-carbon double bond. Exemplary alkenyls include,
but are not limited to, for example, ethenyl and allyl.
[0071] The term "substituted alkenyl" refers to an alkenyl
substituted with at least one substituent, preferably 1 to 4
substituents, more preferably 1 to 2 substituents, at any available
point of attachment. Exemplary substituents include, but are not
limited to, for example, alkyl, substituted alkyl, and the
substituents described above in defining the term "substituted
alkyl" as exemplary alkyl substituents.
[0072] The term "cycloalkenyl" refers to a cyclized alkenyl.
[0073] The term "substituted cycloalkenyl" refers to a cyclized
substituted alkenyl.
[0074] The term "alkanoyl" refers to an alkyl bonded through a
carbonyl (i.e.--C(.dbd.O)R.sup.j, wherein R.sup.j is an alkyl).
[0075] The term "substituted alkanoyl" refers to an alkanoyl
substituted with at least one substituent, preferably 1 to 4
substituents, more preferably 1 to 2 substituents, at any available
point of attachment. Exemplary substituents include, but are not
limited to, for example, alkyl, substituted alkyl, and the
substituents described above in defining the term "substituted
alkyl" as exemplary alkyl substituents.
[0076] The terms "alkanoylamino", "arylcarbonylamino",
"alkylcarbonylamino", or "arylsulfonylamino" refer to an alkanoyl
or substituted alkanoyl; an arylcarbonyl; an alkylcarbonyl; or an
arylsulfonyl, respectively, bonded to an amino.
[0077] The term "alkanoyloxy" refers to an alkanoyl or substituted
alkanoyl bonded to an oxygen.
[0078] The term "alkynyl" refers to a straight or branched chain
hydrocarbon radical containing from 2 to 12 carbon atoms and at
least one carbon-carbon triple bond. Exemplary alkynyls include,
but are not limited to, for example, ethynyl; propynyls, such as,
for example, prop-1-yn-1-yl and prop-2-yn-1-yl; and butynyls, such
as, for example, but-1-yn-1-yl, but-1-yn-3-yl, and
but-3-yn-1-yl.
[0079] The term "substituted alkynyl" refers to an alkynyl
substituted with at least one substituent, preferably 1 to 4
substituents, more preferably 1 to 2 substituents, at any available
point of attachment. Exemplary substituents include, but are not
limited to, for example, alkyl, substituted alkyl, and the
substituents described above in defining the term "substituted
alkyl" as exemplary alkyl substituents.
[0080] The term "alkylsulfone" refers to
--R.sup.kS(.dbd.O).sub.2R.sup.k, wherein R.sup.k is an alkyl or
substituted alkyl.
[0081] The term "oxo" refers to the divalent radical .dbd.O.
[0082] The term "carbamate" refers to the group
--OC(.dbd.O)NH.sub.2.
[0083] The term "amide" refers to the group
--C(.dbd.O)NH.sub.2.
[0084] The term "sulfonamide" refers to the group
--SO.sub.2NH.sub.2.
[0085] The terms "substituted amide", "substituted sulfonamide", or
"substituted carbamate" refer to an amide, sulfonamide, or
carbamate, respectively, having at least one hydrogen replaced with
a group chosen from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, cycloalkyl, and substituted cycloalkyl.
[0086] A substituted amide, for example, refers to the group
--C(.dbd.O)NR.sup.mR.sup.n wherein R.sup.m and R.sup.n are
independently selected from H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, and substituted cycloalkyl,
provided at least one of R.sup.m or R.sup.n is a substituted
moiety.
[0087] A substituted sulfonamide, for example, refers to the group
--SO.sub.2NR.sup.oR.sup.p wherein R.sup.o and R.sup.p are
independently selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, and substituted cycloalkyl,
provided at least one of R.sup.o or R.sup.p is a substituted
moiety.
[0088] A substituted carbamate, for example, refers to the group
--OC(.dbd.O)NR.sup.qR.sup.r wherein R.sup.q and R.sup.r are
independently selected from alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, and substituted cycloalkyl,
provided at least one of R.sup.q or R.sup.r is a substituted
moiety.
[0089] The term "ureido" refers to the group
--NHC(.dbd.O)NH.sub.2.
[0090] The term "cyano" refers to the group --CN.
[0091] The terms "cycloalkylalkyl" or "cycloalkylalkoxy" refer to a
cycloalkyl or substituted cycloalkyl bonded to an alkyl or
substituted alkyl; or an alkoxy, respectively.
[0092] The term "nitro" refers to the group --N(O).sub.2.
[0093] The term "thio" refers to the group --SH.
[0094] The term "alkylthio" refers to the group --SR.sup.s where
R.sup.s is an alkyl, substituted alkyl, cycloalkyl, or substituted
cycloalkyl.
[0095] The term "thioalkyl" refers to the group --R.sup.tS where
R.sup.t is an alkyl, substituted alkyl, cycloalkyl, or substituted
cycloalkyl.
[0096] The term "alkylsulfonyl" refers to the group
--S(.dbd.O).sub.2R.sup.u where R.sup.u is an alkyl, substituted
alkyl, cycloalkyl, or substituted cycloalkyl.
[0097] The term "alkylsulfinyl" refers to the group
--S(.dbd.O)R.sup.v where R.sup.v is an alkyl, substituted alkyl,
cycloalkyl, or substituted cycloalkyl.
[0098] The term "carboxy" refers to the group --C(.dbd.O)OH.
[0099] The terms "carboxyalkoxy" or "alkoxycarbonylalkoxy" refer to
a carboxy, or an alkoxycarbonyl, respectively, bonded to an
alkoxy.
[0100] The term "alkoxycarbonyl" refers to the group
--C(.dbd.O)OR.sup.w where R.sup.w is an alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl.
[0101] The term "arylalkoxycarbonyl" refers to an aryl or
substituted aryl bonded to an alkoxycarbonyl.
[0102] The terms "alkylcarbonyloxy" or "arylcarbonyloxy" refer to
the group --OC(.dbd.O)R.sup.x, where R.sup.x is an alkyl or
substituted alkyl, or an aryl or substituted aryl,
respectively.
[0103] The term "carbamoyl" refers to the groups
--OC(.dbd.O)NH.sub.2, --OC(.dbd.O)NHR.sup.x, and/or
--OC(.dbd.O)NR.sup.yR.sup.z, wherein R.sup.y and R.sup.z are
independently selected from alkyl and substituted alkyl.
[0104] The group --NR.sup.6(C.dbd.O)R.sup.9 refers to a group where
R.sup.6 is selected from hydrogen, lower alkyl and substituted
lower alkyl, and R.sup.9 is selected from hydrogen, alkyl,
substituted alkyl, alkoxy, aminoalkyl, substituted aminoalkyl,
alkylamino, substituted alkylamino, aryl and substituted aryl.
[0105] The term "carbonyl" refers to a C(.dbd.O).
[0106] The terms "alkylcarbonyl", "aminocarbonyl",
"alkylaminocarbonyl" "aminoalkylcarbonyl", or "arylaminocarbonyl"
refer to an alkyl or substituted alkyl; an amino; an alkylamino or
substituted alkylamino; an aminoalkyl or substituted aminoalkyl; or
an arylamino, respectively, bonded to a carbonyl.
[0107] The terms "aminocarbonylaryl" or "aminocarbonylalkyl" refer
to an aminocarbonyl bonded to an aryl or substituted aryl; or an
alkyl or substituted alkyl, respectively.
[0108] The term "sulfonyl" refers to the group S(.dbd.O).sub.2.
[0109] The term "sulfinyl" refers to an S(.dbd.O).
[0110] The term "carboxyalkyl" refers to an alkyl or substituted
alkyl bonded to a carboxy.
[0111] As used herein, the term "patient" encompasses all mammalian
species. A mammalian species includes, but is not limited to, for
example, humans and domestic animals, such as, for example, dogs,
cats, and horses.
[0112] The term "salt(s)", as employed herein, denotes acidic
and/or basic salts formed with inorganic and/or organic acids
and/or bases, and such term, as used herein, further includes
zwitterion(s) ("inner salts").
[0113] The terms "zwitterion(s)", as employed herein, denote
compound(s) containing both a basic moiety, including but not
limited to, for example, pyridine and imidazole; and an acidic
moiety including but not limited to, for example, a carboxylic
acid.
[0114] The term "pharmaceutically acceptable", as employed herein,
indicates the subject matter being identified as "pharmaceutically
acceptable" is suitable and physiologically acceptable for
administration to a patient. For example, the term
"pharmaceutically acceptable salt(s)" denotes suitable and
physiologically acceptable salt(s) for administration to a
patient.
[0115] The compounds of Formula (I) can also form salt(s). As a
result, when a compound of Formula (I) is referred to herein, such
reference includes, unless otherwise indicated, salts thereof. In
one embodiment, the compounds of Formula (I) form pharmaceutically
acceptable salts. In another embodiment, the compounds of Formula
(I) form salts that can, for example, be used to isolate and/or
purify the compounds of Formula (I). Salt(s) of the Formula (I)
compounds can be formed by, for example, reacting a Formula (I)
compound with, for example, an equivalent amount of acid or base in
a medium that allows the thusly formed salt to, for example, either
precipitate out, or be isolated via lyophilization.
[0116] Exemplary acidic salt(s) the compounds of Formula (I) can
form with inorganic and/or organic acids include, but are not
limited to, for example, acetates, such as are formed with acetic
or trihaloacetic acid; adipates; alginates; ascorbates; aspartates;
benzoates; benzenesulfonates; bisulfates; borates; butyrates;
citrates; camphorates; camphorsulfonates; cyclopentanepropionates;
digluconates; dodecylsulfates; ethanesulfonates; fumarates;
glucoheptanoates; glycerophosphates; hemisulfates; heptanoates;
hexanoates; hydrochlorides; hydrobromides; hydroiodides;
hydroxyethanesulfonates, such as, for example,
2-hydroxyethanesulfonates; lactates; maleates; methanesulfonates;
naphthalenesulfonates, such as, for example,
2-naphthalenesulfonates; nicotinates; nitrates; oxalates;
pectinates; persulfates; phenylpropionates, such as, for example,
3-phenylpropionates; phosphates; picrates; pivalates; propionates;
salicylates; succinates; sulfates, such as, for example, are formed
with sulfuric acid; sulfonates; tartrates; thiocyanates; and
toluenesulfonates, such as, for example, tosylates and
undecanoates. Such salts can be formed in accordance with methods
known to a person of ordinary skill in the art.
[0117] Exemplary basic salt(s) that the compounds of Formula (I)
can form with inorganic and/or organic bases include, but are not
limited to, for example, ammonium salts; alkali metal salts, such
as, for example, sodium, lithium and potassium salts: alkaline
earth metal salts, such as, for example, calcium and magnesium
salts; salts formed with organic bases, such as, for example,
benzathines, dicyclohexylamines, hydrabamines (such as, for
example, N,N-bis(dehydroabietyl)ethylenediamine),
N-methyl-D-glucamines, N-methyl-D-glycamides, and t-butyl amines;
salts formed with amino acids, such as, for example, arginine and
lysine; and salts formed by using agents, such as, for example,
lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl,
diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g.
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides), and aralkyl halides (e.g. benzyl and phenethyl bromides)
to quaternize basic nitrogen-containing groups. Such salts can be
formed in accordance with methods known to a person of ordinary
skill in the art.
[0118] All stereoisomer(s) and geometric isomer(s) of the compounds
of Formula (I), either in admixture or in pure or substantially
pure form are also contemplated herein. Specifically, all
enantiomers, tautomers, and diastereomers of the compounds of
Formula (I), as well as mixtures, compounds, racemic compounds,
racemic mixtures, and racemates produced therefrom are contemplated
herein. Even more particularly, all optically active isomers of the
compounds of Formula (I), including pure or substantially pure
optically active isomers, i.e., optically active isomers
substantially free of other isomers.
[0119] When a compound containing a single enantiomer of a compound
of Formula (I) is desired, such compound can be obtained by either
resolution of the final product or by stereospecific synthesis from
either isomerically pure starting material(s), or any convenient
intermediate(s). Resolution of the final product, an intermediate,
or a starting material can be effected by any suitable method known
in the art, including, for example, physical methods, such as, for
example, fractional crystallization, separation or crystallization
of diastereomeric derivatives, and separation by chiral column
chromatography. Individual optical isomers can be obtained from
racemates through, for example, conventional methods, such as, for
example, salt formation with an optically active acid followed by
crystallization. The chiral centers of the compounds in accordance
with Formula (I) can have the S or R configuration as defined by
the IUPAC 1974 Recommendations.
[0120] Prodrug(s) and/or solvate(s) of the compounds of Formula (I)
are further contemplated herein.
[0121] The term "prodrug(s)", as employed herein, denotes a
compound that, upon administration to a subject, undergoes chemical
conversion via metabolic and/or chemical processes in vivo to yield
a compound and/or derivative of Formula (I), or a salt and/or
solvate thereof. Various forms of prodrug(s) are well known in the
art. For examples of such prodrug derivatives, see: [0122] a)
Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et
al. (Academic Press, 1985); [0123] b) A Textbook of Drug Design and
Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter
5, "Design and Application of Prodrugs," by H. Bundgaard, p.
113-191 (1991); and [0124] c) H. Bundgaard, Advanced Drug Delivery
Reviews, 8, 1-38 (1992).
[0125] The term "solvate", as employed herein, denotes a compound
produced by the chemical interaction of at least one solvent with
at least one solute comprising at least one compound of Formula
(I). Exemplary solvates include, but are not limited to, for
example, hydrates.
[0126] All numbers expressing quantities of ingredients, properties
such as molecular weight, reaction conditions, and so forth that
are preceded by the word "about" are to be understood as only
approximations so that slight variations above and below the stated
number may be used to achieve substantially the same results as the
stated number. Accordingly, unless indicated to the contrary,
numerical parameters preceded by the word "about" are
approximations that may vary depending upon the desired properties
sought to be obtained by the invention. At the very least, and not
as an attempt to limit the application of the doctrine of
equivalents to the scope of the claims, each numerical parameter
should at least be construed in light of the number of reported
significant digits and by applying ordinary rounding
techniques.
[0127] It is to be understood that each of the variously stated
ranges is intended to be continuous so as to include each numerical
parameter between the stated minimum and maximum value of each
range. It is to be further understood that, while not intending to
limit the applicability of the doctrine of equivalents to the scope
of the claims, each numerical parameter should at least be
construed in a manner consistent with the reported number of
significant digits for each numerical parameter and by applying
ordinary rounding techniques. It is to be even further understood
that, while not intending to limit the applicability of the
doctrine of equivalents to the scope of the claims, even though a
number may be contained within a numerical range wherein at least
one of the minimum and maximum numbers of the range is or is not
preceded by the word "about", each numerical value contained within
the range may or may not be preceded by the word "about". For
Example, a range of about 1 to about 10 includes about 1, about 2,
2, about 3, 3, about 4, 4, about 5, 5, about 6, 6, about 7, 7,
about 8, 8, about 9, 9, and about 10; a range of about 1.1 to about
3.2 includes about 1.1, about 1.2, 1.2, about 1.3, 1.3, about 1.4,
1.4, about 1.5, 1.5, about 1.6, 1.6, about 1.7, 1.7, about 1.8,
1.8, about 1.9, 1.9, about 2.0, 2.0, about 2.1, 2.1, about 2.2,
2.2, about 2.3, 2.3, about 2.4, 2.4, about 2.5, 2.5, about 2.6,
2.6, about 2.7, 2.7, about 2.8, 2.8, about 2.9, 2.9, about 3.0,
3.0, about 3.1, 3.1, and about 3.2; and a range of about 1 to 4
includes about 1, 2, about 2, 3, about 3, and 4.
[0128] Further, when an amount, concentration, or other value or
parameter is given as a list of upper values and lower values, such
listings are intended to include all ranges formed by pairing any
upper value with any lower value, regardless of whether ranges are
separately disclosed.
[0129] Described herein are compounds of Formula (I):
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein Q.sup.1,
Q.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, and R.sup.9 are as defined hereinabove.
[0130] In one embodiment, Q.sup.2 is heteroaryl or substituted
heteroaryl.
[0131] In another embodiment, Q.sup.2 is pyrazole, thiazole, or
pyrimidine.
[0132] In yet another embodiment, R.sup.2 is hydrogen, alkyl,
substituted alkyl, cycloalkyl, or substituted cycloalkyl.
[0133] In a further embodiment, Q.sup.1 is aryl or substituted
aryl.
[0134] In an even further embodiment, Q.sup.1 is phenyl or
substituted phenyl.
[0135] In a still further embodiment, R.sup.3, R.sup.4, and R.sup.5
are independently selected from H, alkyl, substituted alkyl,
alkoxy, and halogen.
[0136] In yet still a further embodiment, R.sup.7 and R.sup.8 are
independently selected from hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl.
[0137] In still another embodiment, R.sup.1 is
NR.sup.6C(.dbd.O)R.sup.7.
[0138] In yet still a further embodiment, R.sup.1 is
--NR.sup.6C(.dbd.O)R.sup.7 and R.sup.2 is H, alkyl, substituted
alkyl, cycloalkyl, or substituted cycloalkyl.
[0139] In yet an even further embodiment, Q.sup.1 is phenyl or
substituted phenyl; Q.sup.2 is pyrazole, thiazole, or pyrimidine;
R.sup.1 is NR.sup.6C(.dbd.O)R.sup.7; R.sup.2 is hydrogen, alkyl,
substituted alkyl, cycloalkyl, or substituted cycloalkyl; R.sup.3,
R.sup.4, and R.sup.5 are independently selected from H, alkyl,
substituted alkyl, alkoxy, and halogen; and R.sup.7 is selected
from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, or substituted cycloalkyl.
[0140] Still further described herein is at least one
pharmaceutical composition comprising at least one compound in
accordance with Formula (I), optionally at least one
pharmaceutically-acceptable carrier and/or diluent, and optionally
at least one other anti-cancer agent.
[0141] Even further described herein is at least one method for
treating at least one proliferative disease comprising
administering to a patient in need thereof an effective amount of
at least one compound according to Formula (I), optionally
administering either simultaneously or sequentially at least one
other anti-cancer agent, and optionally administering either
simultaneously or sequentially at least one other anti-cancer
treatment.
[0142] The phrase "anti-cancer treatment" includes, but is not
limited to, for example, radiation therapy and surgery.
[0143] The phrase "other anti-cancer agent" includes any known
agent useful for treating cancer. Examples of other such
anti-cancer agent(s) include, but are not limited to, for example,
antiangiogenic agents, such as, for example, linomide, inhibitors
of integrin .alpha.v.beta.3 function, angiostatin, and razoxane;
antiestrogens, such as, for example, tamoxifen, toremifene,
raloxifene, droloxifene, and iodoxifene; progestogens, such as, for
example, megestrol acetate, hydroxyprogesterone, and
medroxyprogesterone; aromatase inhibitors, such as, for example,
anastrozole, testolactone, letrozole, borazole, and exemestane;
antihormones, such as, for example, aminoglutethimide; synthetic
estrogens, such as, for example, chlorotrianisene,
diethylstilbestrol and 17.alpha.-ethinylestradiol; synthetic
androgens, such as for example, dromostanolone propionate,
fluoxymesterone, and methyltestosterone; antiprogestogens;
antiandrogens, such as, for example, flutamide, nilutamide,
bicalutamide, and cyproterone acetate; androgens, such as, for
example, testosterone; synthetic glucocorticoids, such as, for
example, methylprednisolone, triamcinolone, prednisolone, and
prednisone; LHRH agonists and antagonists, such as, for example,
gosereline acetate and leuprolide; inhibitors of testosterone
5.alpha.-dihydroreductase, such as, for example, finasteride;
farnesyltransferase inhibitors; anti-invasion agents, such as, for
example, metalloproteinase inhibitors like marimastat and
inhibitors of urokinase plasminogen activator receptor function;
VEGF inhibitors, such as, for example, anti-VEGF antibodies
(Avastin) and small molecules, such as, for example, ZD6474,
SU6668, Vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055;
Her 1 and Her 2 inhibitors including, for example, anti-Her 2
antibodies (Herceptin); EGFR inhibitors, such as, for example,
gefitinib, erlotinib, ABX-EGF, EMD72000, 11F8, and cetuximab; Eg5
inhibitors, such as, for example, SB-715992, SB-743921, and
MKI-833; pan Her inhibitors, such as, for example, canertinib,
EKB-569, CI-1033, AEE-788, XL-647, mAb 2C4, and GW-572016; Src
inhibitors, such as, for example, Gleevac and Dasatinib; MEK-1
inhibitors; MAPK inhibitors; PI3 kinase inhibitors; Met inhibitors;
other Aurora kinase inhibitors; PDGF inhibitors, such as, for
example, imatinib; IGF1R inhibitors, such as, for example, those
disclosed in United States Patent Application No. 2004/0044203 A1;
other receptor and non-receptor tyrosine kinase inhibitors; other
serine/threonine kinase inhibitors; CDK inhibitors;
antimetabolites, such as, for example, methotrexate, idatrexate,
trimetrexate, 5-fluorouracil, tegafur, cytarabine, fludarabine,
6-thioguanine, DON (d-oxo-norleucine or AT-125) and
6-mercaptopurine; intercalating antitumor antibiotics, such as, for
example, doxorubicin, daunomycin, epirubicin, idarubicin,
mitomycin-C, dactinomycin, mitoxantrone, and mithramycin; platinum
derivatives, such as, for example, cisplatin, oxaliplatin, and
carboplatin; alkylating agents, such as, for example, nitrogen
mustard, melphalan, chlorambucil, busulphan, cyclophosphamide,
ifosfamide nitrosoureas, dacarbazine, hexamethyl melamine,
estramustine, and thiotepa; antimitotic agents, such as, for
example, vinblastine, vinflunine, Taxol.RTM.(paclitaxel),
Taxotere.RTM. (docetaxel), 7-O-methylthiomethylpaclitaxel,
4-desacetyl-4-methylcarbonatepaclitaxel,
3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debe-
nzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate
paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D,
epothilone analogs, i.e., ixabepilone, and derivatives thereof;
inhibitors of integrin signaling; topoisomerase inhibitors, such
as, for example, etoposide, teniposide, amsacrine, doxorubicin,
daunorubicin, irinotecan, and topotecan; cell cycle inhibitors,
such as, for example, flavopyridols; biological response modifiers,
such as, for example, interferon-alpha; monoclonal antibodies, such
as for example, rituximab, and gemtuzumab ozogamicin; proteasome
inhibitors, such as, for example, Velcade.RTM. (bortezomib); SN-8;
procarbazine; L-asparaginase; pyridobenzoindole derivatives;
ribonucleotide reductase inhibitors; mTOR inhibitors; leucovorin;
VM-26; interleukins; and hematopoietic growth factors.
[0144] The proliferative disease that can be treated in accordance
with the Formula (I) compounds of the invention include, but are
not limited to, for example, Aurora kinase associated diseases,
such as, for example, cancer, bone diseases, inflammatory diseases,
autoimmune diseases, metabolic diseases, viral diseases, fungal
diseases, neurological and neurodegenerative disorders, Alzheimer's
disease, allergies and asthma, cardiovascular diseases, and hormone
related diseases.
[0145] In one embodiment, at least one compound of Formula (I) is
used to treat cancer.
[0146] The cancers Formula (I) compound(s) can be used to treat
include, but are not limited to, for example, carcinoma, including,
for example, that of the bladder, breast, colon, kidney, liver,
lung (including small cell lung cancer), esophagus, gall bladder,
ovary, pancreas, stomach, cervix, thyroid, prostate, and skin
(including squamous cell carcinoma); hematopoietic tumors of
lymphoid lineage, such as, for example, leukemia, acute lymphocytic
leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell
lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell
lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid
lineage, such as, for example, acute and chronic myelogenous
leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
tumors of mesenchymal origin, including, for example, fibrosarcoma
and rhabdomyosarcoma; tumors of the central and peripheral nervous
system, including, for example, astrocytoma, neuroblastoma, glioma,
and schwannomas; and other tumors, such as, for example, melanoma,
seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,
keratoacanthoma, thyroid follicular cancer, and Kaposi's
sarcoma.
[0147] Yet even further described herein are compounds according to
Formula (I) including, but not limited to, for example,
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2--
yl}sulfanyl)phenyl]cyclopropanecarboxamide;
N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrol-
o[2,1-f][1,2,4]triazin-4-amine;
N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triaz-
in-2-yl}sulfanyl)phenyl]acetamide;
3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin--
2-yl}sulfanyl)-N-methylbenzamide;
N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triaz-
in-4-amine; and
N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2--
yl)sulfanyl)phenyl)benzamide; and pharmaceutically acceptable salts
thereof.
[0148] Due to the key role protein kinases play in regulating
cellular proliferation in general, inhibitors of such kinases may
act as reversible cytostatic agents, thereby making such inhibitors
useful to treat any disease process featuring abnormal cellular
proliferation, e.g., benign prostatic hyperplasia, familial
adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,
pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis,
restenosis following angioplasty or vascular surgery, hypertrophic
scar formation, inflammatory bowel disease, transplantation
rejection, endotoxic shock, and fungal infections.
[0149] Compounds of Formula (I) may modulate apoptosis, and
therefore may be useful in treating cancer, including but not
limited to, for example, the cancers already mentioned herein
above; treating viral infections, including but not limited to, for
example, herpes virus, pox virus, Epstein-Barr virus, Sindbis
virus, and adenovirus; preventing AIDS from developing in
HIV-infected individuals; treating autoimmune diseases, including
but not limited to, for example, systemic lupus, erythematosus,
autoimmune mediated glomerulonephritis, rheumatoid arthritis,
psoriasis, inflammatory bowel disease, and autoimmune diabetes
mellitus; treating neurodegenerative disorders, including but not
limited to, for example, Alzheimer's disease, AIDS-related
dementia, Parkinson's disease, amyotrophic lateral sclerosis,
retinitis pigmentosa, spinal muscular atrophy, and cerebellar
degeneration; treating myelodysplastic syndromes; treating aplastic
anemia; treating ischemic injury associated with myocardial
infarctions, strokes, and reperfusion injury; treating arrhythmias;
treating artherosclerosis; treating toxin-induced or alcohol
related liver diseases; treating hematological diseases, including
but not limited to, for example, chronic anemia and aplastic
anemia; treating degenerative diseases of the musculoskeletal
system, including but not limited to, for example, osteoporosis and
arthritis; treating aspirin-sensitive rhinosinusitis; treating
cystic fibrosis; treating multiple sclerosis; treating kidney
diseases; and treating cancer pain.
[0150] Compounds of Formula (I) may also modulate the level of
cellular RNA and DNA synthesis, and as a result could be useful in
treating viral infections, including but not limited to, for
example, HIV; human papilloma virus; herpes virus; pox virus;
Epstein-Barr virus; Sindbis virus; and adenovirus.
[0151] Compounds of Formula (I) may also be useful in the
chemoprevention of cancer. Chemoprevention is defined as inhibiting
the development of invasive cancer by blocking the initiating
mutagenic event, by blocking progression of pre-malignant cells
that have already suffered an insult, or by inhibiting tumor
relapse.
[0152] Compounds of Formula (I) may also be useful in inhibiting
tumor angiogenesis and metastasis.
[0153] The compounds of Formula (I) may further be employed
adjuvant to surgery. For example, at least one compound in
accordance with Formula (I) may be used in combination with
antibody therapy, or in concert with vaccine/immune modulating
agents used to treat cancer.
[0154] In one embodiment, the patient is an animal.
[0155] In another embodiment, the patient is a human.
[0156] The compounds of Formula (I) can be administered by any
means suitable for the condition to be treated, which can depend on
the need for site-specific treatment or quantity of drug to be
delivered.
[0157] A pharmaceutical composition comprising at least one
compound according to Formula (I) can, for example, be delivered
orally via any acceptable and suitable oral form, including but not
limited to, for example, tablets; troches; lozenges; aqueous or
oily suspensions; dispersible powders or granules; emulsions; hard
or soft capsules; syrups; and elixirs. Pharmaceutical compositions
intended for oral use can be prepared according to any method known
in the art for manufacturing pharmaceutical compositions. In order
to provide pharmaceutically elegant and palatable preparations, a
pharmaceutical composition in accordance with the invention can
contain at least one agent selected from sweetening agents,
flavoring agents, coloring agents, and preserving agents.
[0158] A tablet can be prepared by, for example, admixing at least
one compound according to Formula (I) with at least one non-toxic
pharmaceutically acceptable excipient suitable for the manufacture
of tablets, including but not limited to, for example, inert
diluents, such as, for example, calcium carbonate, sodium
carbonate, lactose, calcium phosphate, and sodium phosphate;
granulating and disintegrating agents, such as, for example,
microcrystalline cellulose, sodium crosscarmellose, corn starch,
and alginic acid; binding agents, such as, for example, starch,
gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents,
such as, for example, magnesium stearate, stearic acid, and talc.
Additionally, a tablet can either be uncoated, or coated by known
techniques to either mask the bad taste of an unpleasant tasting
drug, or delay disintegration and absorption of the active
ingredient in the gastrointestinal tract thereby sustaining the
effects of the active ingredient for a longer period. For example,
water soluble taste masking materials, including but not limited
to, for example, hydroxypropyl-methylcellulose and
hydroxypropyl-cellulose, or time delay materials, including but not
limited to, for example, ethyl cellulose and cellulose acetate
buryrate can be used.
[0159] Hard gelatin capsules can be prepared by, for example,
mixing at least one compound according to Formula (I) with at least
one inert solid diluent, including but not limited to, for example,
calcium carbonate; calcium phosphate; and kaolin. Soft gelatin
capsules can be prepared by mixing at least one compound according
to Formula (I) with at least one water soluble carrier, including
but not limited to, for example, polyethylene glycol; and oil
mediums, such as, for example, peanut oil, liquid paraffin, and
olive oil.
[0160] An aqueous suspension can be prepared by admixing at least
one compound according to formula (I) with at least one excipient
suitable for the manufacture of an aqueous suspension, including
but not limited to, for example, suspending agents, such as, for
example, sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing
or wetting agents, such as, for example, a naturally-occurring
phosphatide, such as, for example, lecithin; condensation products
of alkylene oxide with fatty acids, such as, for example,
polyoxyethylene stearate; condensation products of ethylene oxide
with long chain aliphatic alcohols, such as, for example
heptadecaethylene-oxycetanol; condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol,
such as, for example, polyoxyethylene sorbitol monooleate; and
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, such as, for example,
polyethylene sorbitan monooleate. An aqueous suspension can also
contain at least one preservative, such as, for example, ethyl and
n-propyl p-hydroxybenzoate; at least one coloring agent; at least
one flavoring agent; and/or at least one sweetening agent,
including but not limited to, for example, sucrose, saccharin, and
aspartame.
[0161] Oily suspensions can be prepared, for example, by suspending
at least one compound according to Formula (I) in either a
vegetable oil, such as, for example, arachis oil; olive oil; sesame
oil; and coconut oil, or in mineral oil, such as, for example,
liquid paraffin. An oily suspension can also contain a thickening
agent, such as, for example, beeswax; hard paraffin; and cetyl
alcohol. In order to provide a palatable oily suspension, at least
one of the sweetening agents already described hereinabove, and/or
at least one flavoring agent can be added to the oily suspension.
An oily suspension can further contain a preservative, including
but not limited to, for example, an anti-oxidant, such as, for
example, butylated hydroxyanisol, and alpha-tocopherol.
[0162] Dispersible powders and granules can be prepared by admixing
at least one compound according to Formula (I) with at least one
dispersing and/or wetting agent; at least one suspending agent;
and/or at least one preservative. Suitable dispersing agents,
wetting agents, and suspending agents are as already described
above. In addition, dispersible powders and granules can also
contain excipients, including but not limited to, for example,
sweetening agents; flavoring agents; and coloring agents, and/or
preservatives including but not limited to, for example,
anti-oxidants, such as, for example, ascorbic acid.
[0163] An emulsion of at least one compound according to Formula
(I) can be prepared as an oil-in-water emulsion. The oil phase can
be provided by but is not limited to, for example, a vegetable oil,
such as, for example, olive oil and arachis oil; a mineral oil,
such as, for example, liquid paraffin; and mixtures thereof.
Suitable emulsifying agents include but are not limited to, for
example, naturally-occurring phosphatides, such as, for example,
soy bean lecithin; esters or partial esters derived from fatty
acids and hexitol anhydrides, such as, for example, sorbitan
monooleate; and condensation products of partial esters with
ethylene oxide, such as, for example, polyoxyethylene sorbitan
monooleate. An emulsion can also contain a sweetening agent, a
flavoring agent, a preservative, and/or an antioxidant.
[0164] Syrups and elixirs can contain a sweetening agent, including
but not limited to, for example, glycerol; propylene glycol;
sorbitol; and sucrose. Syrups and elixirs can also contain a
demulcent, a preservative, a flavoring agent, a coloring agent,
and/or an antioxidant.
[0165] A pharmaceutical composition comprising at least one
compound according to Formula (I) can, for example, also be
delivered intravenously, subcutaneously, and/or intramuscularly via
any acceptable and suitable injectable form, including but not
limited to, for example, sterile aqueous solutions comprising
acceptable vehicles and solvents, such as, for example, water,
Ringer's solution, and isotonic sodium chloride solution; sterile
oil-in-water microemulsions; and aqueous or oleagenous
suspensions.
[0166] A sterile injectable oil-in-water microemulsion can be
prepared by 1) dissolving at least one compound according to
Formula (I) in an oily phase, such as, for example, a mixture of
soybean oil and lecithin; combining the compound containing oil
phase with a water and glycerol mixture; and 3) processing the
combination to form a microemulsion.
[0167] A compound according to Formula (I) can be introduced into a
patient's blood-stream by administering the Formula (I) compound
containing injectable solution and/or microemulsion as, for
example, a local bolus injection. If maintaining a constant
circulating concentration of the Formula (I) compound is desired, a
continuous intravenous delivery device, such as, for example, a
Deltec CADD-PLUS.TM. model 5400 intravenous pump, can be
utilized.
[0168] A sterile aqueous or oleaginous suspension can be prepared
in accordance with methods already known in the art. For example, a
sterile aqueous solution or suspension can be prepared with a
non-toxic parenterally-acceptable diluent or solvent, such as, for
example, 1,3-butane diol; and a sterile oleaginous suspension can
be prepared with a sterile non-toxic acceptable solvent or
suspending medium, such as, for example, sterile fixed oils
including but not limited to, for example, synthetic mono- or
diglycerides; and fatty acids including but not limited to, for
example, oleic acid.
[0169] A pharmaceutical composition comprising at least one
compound according to Formula (I) can, for example, further be
administered via any acceptable and suitable rectal form, including
but not limited to, for example, a suppository. A suppository can
be prepared by mixing at least one Formula (I) compound with a
suitable non-irritating excipient that is liquid at rectal
temperatures but solid at least one temperature below rectal
temperature. Exemplary non-irritating excipients include but are
not limited to, for example, cocoa butter; glycerinated gelatin;
hydrogenated vegetable oils; mixtures of polyethylene glycols of
various molecular weights; and fatty acid esters of polyethylene
glycol.
[0170] A compound in accordance with Formula (I) can further be
administered via any acceptable and suitable topical route
including but not limited to, for example, creams; ointments;
jellies; solutions; suspensions, transdermal patches; intranasal
inhalers, etc. For purposes of this application, topical
application shall include mouth washes and gargles.
[0171] Exemplary compositions for nasal aerosol or inhalation
administration include solutions that may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0172] An "effective amount" of a compound in accordance with the
Formula (I) can be determined by one of ordinary skill in the art,
and includes exemplary dosage amounts for a mammal of from about
0.05 to 100 mg/kg of body weight of active compound per day, which
may be administered in a single dose or in the form of individual
divided doses, such as from 1 to 4 times per day.
[0173] The specific dose level and frequency of dosage for any
particular subject, however, may be varied and generally depends on
a variety of factors, including, but not limited to, for example,
the bioavailability of the specific Formula (I) compound(s) in the
administered form; metabolic stability and length of action of the
specific Formula (I) compound(s); species, age, body weight,
general health, sex, and diet of the subject; mode and time of
administration; rate of excretion; drug combination; and severity
of the particular condition.
[0174] If formulated as a fixed dose, a combination product can,
for example, utilize a dosage of the compound of Formula (I) within
the dosage range described above and the dosage of another
anti-cancer agent/treatment within the approved dosage range for
such known anti-cancer agent/treatment. If a combination product is
inappropriate, the compound of Formula (I) and the other
anti-cancer agent/treatment can, for example, be administered
simultaneously or sequentially. If administered sequentially, the
invention is not limited to any particular sequence of
administration. For example, compounds of Formula (I) can be
administered either prior to, or after, administration of the known
anti-cancer agent or treatment.
[0175] The compounds of Formula (I) can also be formulated or
co-administered with other therapeutic agents that are selected for
their particular usefulness in administering therapies associated
with the aforementioned conditions. For example, the compounds of
the invention may be formulated with agents to prevent nausea,
hypersensitivity, and/or gastric irritation, such as, for example,
antiemetics and H.sub.1 and H.sub.2 antihistaminics.
[0176] The above other therapeutic agents, when employed in
combination with the compounds of Formula (I), can be used, for
example, in those amounts indicated in the Physicians' Desk
Reference (PDR) or as otherwise determined by one of ordinary skill
in the art.
[0177] In general, the compounds of Formula (I) can be prepared in
accordance with Scheme I and the general knowledge of one skilled
in the art. Tautomers and solvates (e.g., hydrates) of the
compounds of Formula (I) are also within the scope of the
invention. Methods of solvation are generally known in the art.
Accordingly, the compounds of the invention can be in the free or
hydrate form, and can be obtained by methods exemplified in Scheme
I. The abbreviations utilized in Steps 1-4 of Scheme I are as
defined in the Examples set forth hereinbelow.
##STR00008##
[0178] Step 1: Compound II can be prepared by heating a mixture of
the appropriately substituted 1-amino-1H-pyrrole-2-carboxamide with
a reagent, such as, for example, ethyl chloroformate and an
appropriate base, such as, for example, pyridine in a solvent, such
as, for example, dioxane. The resulting pyrrolotriazine-2,4-dione
II can then be heated with a chlorinating agent, such as, for
example, phosphorus oxychloride in the presence of a base, such as
for example, diisopropylethylamine to give compound III.
[0179] Step 2: Compound V is produced by coupling compound III with
an appropriately substituted aniline IV. The coupling can be
carried out in the presence of a base, such as, for example,
disopropylethylamine in a solvent, such as, for example, isopropyl
alcohol.
[0180] Step 3: A compound in accordance with Formula (I) is
obtained by treating compound V with an appropriately
functionalized arylthiol VI and a base, such as, for example,
potassium carbonate at elevated temperatures.
[0181] It is of import to note that other compounds of Formula (I)
can be readily prepared using methods generally known to a person
of ordinary skill in the art including but not limited to, for
example, the various methods of preparation utilized in the
Examples set forth hereinbelow.
Assays
[0182] At least one compound of Formula (I), including the
compounds described in the examples hereof, has been tested in at
least one assay described below and shown activity as an inhibitor
of at least one of Aurora kinase A, B, and/or C.
Cell-Based Assay for Histone H3 Phosphorylation
[0183] To determine the ability of compounds to inhibit the
function of the Aurora kinases in human cells, the phosphorylation
status of Histone H3 (HH3) on Serine 10 was analyzed. HH3 is a
chromatin protein phosphorylated on at least 2 serine residues
including Ser-10 and Ser-28. Ser-10 on centromeric HH3 is
phosphorylated in the G2 phase of the cell cycle and by mitosis.
Ser-10 is phosphorylated over the entire chromosome.
Phosphorylation at this site on HH3 regulates the initiation of
chromatin condensation and appears to require the Aurora
kinases.
[0184] Using this knowledge, an in-cell western assay was developed
to measure the extent of HH3 phosphorylation by Aurora kinases in
cells arrested in mitosis. Specifically, HCT-116 colorectal cancer
cells were plated in a 96 well plate and allowed to grow for 6
hours. After 6 hours, Nocodazole was added to the wells at a final
concentration of 15 ug/mL, and the cells were incubated for an
additional 16 hours. The Nocodazole treatment caused the cells to
arrest in mitosis with maximal HH3 phosphorylation. At the end of
the 16 hour Nocodazole treatment, the cells were treated with
various concentrations of compounds within the scope of Formula (I)
for about 2 hours to determine the ability of such Formula (I)
compounds to reverse Aurora Kinase dependent HH3 phosphorylation.
At the end of the experiment, Formula (I) compound and control
treated cells were fixed in 4% formaldehyde, and then stained with
a rabbit polyclonal antibody specific for the epitope containing
phosphorylated Ser-10 (Upstate #06-570). At the same time, cells
were also stained using a mouse monoclonal to a housekeeping
protein (anti-actin, Chemicon 1501R) to control for cell number in
each well. Primary antibodies were detected using Alexa dye labeled
secondary antibodies (anti-mouse-800 (Rockland #610-131-121), and
anti-rabbit-680 (Molecular Probes#A21076)). The assay plates were
subsequently analyzed for fluorescence in both channels (800 and
680) using a Licor Odyssey instrument. Fluorescence specific to
phospho-HH3 was normalized to fluorescence specific to actin.
Percent inhibition of HH3 phosphorylation relative to vehicle
treated cells was determined for each concentration of Formula (I)
compound tested. The concentration required to give 50% inhibition
of HH3 phosphorylation (P--HH3 IC50s) was also determined for each
Formula (I) compound tested.
Phenotypic Analysis of Cells Treated with Aurora Kinase
Inhibitors
[0185] The role of the Aurora kinases in regulating proper cell
division has been extensively studied. Genetic disruption of these
kinases in model organisms and mammalian cells has demonstrated
specific phenotypes associated with loss of Aurora kinase function.
Specifically, mitotic defects including the appearance of polyploid
cells resulting from failure at cytokinesis is a marked and
measurable phenotype in cells lacking Aurora kinase activity.
Furthermore, these polyploid cells undergo apoptosis upon
subsequent attempts at cell division. Based on these well
characterized phenotypes, a functional assay was developed to
simultaneously measure polyploidy and apoptosis in cells treated
with Aurora kinase inhibitors.
[0186] DNA content can be readily quantified by adding propidium
iodide (PI) to fixed cells. Propidium iodide binds cellular DNA and
fluoresces when illuminated. Fluorescence is directly proportional
to cellular DNA content. As a result, one can determine the
percentage of cells in a population at each phase of the cell cycle
and also the percentage of cells with greater than 4N DNA content
(polyploid cells) by using flow cytometry.
[0187] Numerous techniques are available to detect apoptosis in
mammalian cells. One event that occurs in most cell types once the
cell has committed to apoptotic cell death is the specific
proteolytic cleavage of the nuclear protein Poly-ADP Ribose
Polymerase (PARP). This cleavage is carried out by the apoptosis
effector caspases, CASP-3 and CASP-7. Commercial antibodies are
available that detect the 85 kDa fragment of cleaved PARP
(PARP-p85) present in apoptotic cells but not full length PARP
present in living cells. These antibodies are useful for
determining the fraction of apoptotic cells in a population at a
given time.
[0188] By combining PI staining for DNA content and staining for
PARP-p85, an assay was developed to track the induction of both
polyploidy and apoptosis in cells treated with various
concentrations of various Formula (I) compounds. The treated cells
were analyzed in accordance with such assay at a variety of times
following treatment. By using this assay, the Formula (I) compounds
that induced polyploidy after 24 hours of treatment and apoptosis
at 48 hours after treatment could be identified, and was consistent
with specific inhibition of the Aurora kinases.
Cell Cytotoxicity Assays
[0189] To determine the long term effects on cells treated with
compounds according to Formula (I), a cytotoxicity assay was used
to measure overall cellular viability following 72 hours of Formula
(I) compound exposure. The cytotoxicity assay uses soluble
tetrazolium salt, MTS, (Promega Corporation; Madison, Wis.) which
is metabolically converted to a colored product in living cells but
not dead cells.
[0190] Cells were seeded in 96 well culture plates. After 24 hours,
the Formula (I) compound was added and serial diluted. After 72
hours of exposure, the percent inhibition of MTS conversion
relative to vehicle treated cells was determined for each
concentration of Formula (I) compound tested. The concentration
required to give 50% inhibition of MTS conversion (MTS IC50s) was
also determined for each Formula (I) compound tested.
[0191] The cytotoxicity assay was performed on at least 12 human
cancer cell lines including breast (BT-549, DU4475, MDA-MB-468,
MDA-MB-231), prostate (PC-3, DU145, LNCaP), lung (NCI-H446,
SHP-77), ovary (A2780), colon (HCT116), and hematologic (CCRF-CEM).
This panel of cell lines enabled relative sensitivities of the
various lines to cell killing by each Formula (I) compound tested
to be determined.
IC.sub.50 Values
[0192] At least one compound of Formula (I) showed activity in at
least one of the above referenced assays via an IC.sub.50 value of
between about 0.01 to about 100 .mu.M. In one embodiment, at least
one compound of Formula (I) showed activity in at least one of the
above referenced assays via an IC.sub.50 value of less than about
1.0 .mu.M. In another embodiment, at least one compound of Formula
(I) showed activity in at least one of the above referenced assays
via an IC.sub.50 value of less than about 0.5 .mu.M.
EXAMPLES
[0193] The invention is further defined in the following Examples.
It should be understood that the Examples are given by way of
illustration only. From the above discussion and the Examples, one
skilled in the art can ascertain the essential characteristics of
the invention, and without departing from the spirit and scope
thereof, can make various changes and modifications to adapt the
invention to various uses and conditions. As a result, the
invention is not limited by the illustrative examples set forth
hereinbelow, but rather defined by the claims appended hereto.
[0194] All temperatures are in degrees Celsius (.degree. C.) unless
indicated otherwise herein.
[0195] All reactions were carried out with continuous magnetic
stirring under an atmosphere of dry nitrogen or argon. All
evaporations and concentrations were carried out on a rotary
evaporator under reduced pressure. Commercial reagents were used as
received without additional purification. Solvents were commercial
anhydrous grades and were used without further drying or
purification. Flash chromatography was performed using silica gel
(EMerck Kieselgel 60, 0.040-0.060 mm).
[0196] The following abbreviations are employed herein: n-BuOH:
n-butyl alcohol, CDCl.sub.3: chloroform-.sup.2H (1), D.sub.2O:
deuterium oxide, DCM: N-(3,4-dichlorophenyl)-2-methyl-acrylamide,
DMA: dimethylamine, DMF: dimethyl formamide, DMSO: dimethyl
sulfoxide, EDC: 1,2-dichloroethane, EtOH: ethanol, EtOAc: ethyl
acetate, HCl: hydrochloric acid, HOAc: acetic acid, IPA: isopropyl
alcohol, K.sub.2CO.sub.3: potassium carbonate, MeOH: methanol,
MgSO.sub.4: magnesium sulfate, NaHCO.sub.3: sodium bicarbonate,
Na.sub.2SO.sub.4: sodium sulfate, NH.sub.4Cl: ammonium chloride,
NH.sub.3: ammonia, N.sub.2: nitrogen, POCl.sub.3: phosphorous
oxychloride, THF: tetrahydrofuran, TFA: trifluoroacetic acid, Bn:
benzyl, Me: methyl, Et: ethyl, min.: minute(s), h or hr(s):
hour(s), L: liter, mL: milliliter, .mu.L: microliter, g: gram(s),
mg: milligram(s), mol.: moles, mmol: millimole(s), meq.:
milliequivalent, RT or rt: room temperature, ret. t.: HPLC
retention time (minutes), sat or sat'd: saturated, aq.: aqueous,
TLC: thin layer chromatography, HPLC: high performance liquid
chromatography, RP HPLC: reverse phase HPLC, Prep HPLC: preparative
reverse phase HPLC, LC/MS: high performance liquid
chromatography/mass spectrometry, MS: mass spectrometry, NMR:
nuclear magnetic resonance, and mp: melting point.
HPLC Conditions:
[0197] In Examples 1-4 the Analytical Reverse Phase HPLC ret. t.
was obtained with the column type and length, flow rate, and linear
gradient elution identified in each example. Unless indicated
otherwise herein, all gradients started with 100% solvent A
(MeOH:water:TFA=1:9:0.01) and 0% solvent B, and ended with 100%
solvent B (MeOH:water:TFA=1:9:0.01) and 0% solvent A. UV detection
was conducted at 220 nm.
[0198] Prep. HPLC was performed with a linear gradient elution
using H.sub.2O/MeOH mixtures buffered with 0.1% trifluoroacetic
acid and detection at 220 nm on one of the following columns:
Shimadzu S5 ODS-VP 20.times.100 mm (flow rate=9 mL/min), or YMC S10
ODS 50.times.500 mm (flow rate=50 mL/min), or YMC S10 ODS
30.times.500 mm (flow rate=20 mL/min).
[0199] All final products were characterized by .sup.1H NMR, RP
HPLC, electrospray ionization (ESI MS) or atmospheric pressure
ionization (API MS) mass spectrometry. .sup.1H NMR spectra were
obtained on either a 500 MHz JEOL or a 400 MHz Bruker instrument.
Field strengths are expressed in units of .quadrature. (parts per
million, ppm) relative to the solvent peaks, and peak
multiplicities are designated as follows: s, singlet; d, doublet;
dd, doublet of doublets; dm, doublet of multiplets; t, triplet; q,
quartet; br s, broad singlet; m, multiplet.
Example 1
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-y-
l}sulfanyl)phenyl]cyclopropanecarboxamide
##STR00009##
[0200] 1A. Pyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione
##STR00010##
[0202] Ethyl chloroformate (4.9 ml, 51 mmol) was added dropwise to
a stirred mixture of 1-amino-1H-pyrrole-2-carboxamide (5.85 gm,
46.7 mmol, Journal of Heterocyclic Chemistry, 1994, 31, 781) and
dry pyridine (4.2 mL, 51 mmol) in dry dioxane (48 mL) under N.sub.2
at RT. The mixture was heated at reflux for 1 hr and then the
solvent was removed. The residue was heated at 155.degree. C. for
17 hr and then allowed to cool to RT. The cooled residue was
triturated with MeOH. The solid precipitate was collected by
filtration and washed with cold MeOH to give 4.43 g 1A (63% yield).
.sup.1H NMR (DMSO-d.sub.6): 6.34 (br. s, 1H), 6.75 (br. s, 1H),
7.12 (br.s, 1H); MS: 152 (M+H).sup.+; and RP HPLC ret. t.: 0.36 min
(YMC Xterra S 7: 3.0.times.50 mm column, 2 min gradient, 5
mL/min.
[0203] 1B. 2,4-Dichloropyrrolo[1,2-f][1,2,4]triazine
##STR00011##
[0204] A mixture of 1A (4.7 gm, 31.1 mmol), POCl.sub.3 (8.81 mL, 3
equiv), and diisopropylethylamine (10.8 mL, 2 equiv) in toluene was
heated in a pressure vessel at 125.degree. C. for 24 hr. After
cooling to RT, the mixture was poured into an ice-cooled sat. aq.
solution of NaHCO.sub.3 with stirring. After 10 min, the aq. phase
was separated and washed with DCM (3.times.200 mL). The combined
organic phases were washed with brine, dried (Na.sub.2SO.sub.4),
and the solvent removed. Silica gel column chromatography (elution
with DCM) gave 4.25 g 1B (81% yield) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): 6.96 (m, 1H), 7.03 (m, 1H), 7.85 (m, 1H); MS: 187.9
(M+H).sup.+; and RP HPLC ret. t.: 1.63 min. (YMC Xterra S 5:
4.6.times.50 mm column, 2 min gradient, 5 mL/min).
1C.
2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[1,2-f][1,2,4]triazin-4-am-
ine
##STR00012##
[0206] A mixture of 1B (1.50 gm, 8 mmol),
5-methyl-1H-pyrazol-3-amine (801 mg, 1 equiv), and
diisopropylethylamine (2.37 mL, 1.7 equiv) in IPA (8 mL) was
stirred at RT overnight. MeOH (2 mL) was added and 1.7 g 1C (86%
yield) was collected by filtration. .sup.1H NMR (MeOH-d.sub.4):
2.35 (s, 3H), 6.58 (br. s, 1H), 6.71 (br.s, 1H), 7.02 (br. s, 1H),
7.59 (br.s, 1H); MS: 249 (M+H).sup.+; and RP HPLC ret. t.: 1.44 min
(Phenomenex-Luna S 10: 3.0.times.50 mm column, 2 min gradient, 4
mL/min).
[0207] 1D.
2-(4-Aminophenylthio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[1,2-f-
][1,2,4]triazin-4-amine
##STR00013##
[0208] A mixture of 1C (300 mg, 1.21 mmol), 4-aminobenzenethiol
(606 mg, 4 equiv) and K.sub.2CO.sub.3 (342 mg, 2 equiv) in dry DMF
under a N.sub.2 atmosphere was heated at 120.degree. C. After 1 hr,
the mixture was cooled to RT, diluted with 7 mL water, and left
stirring for 1 hr. The precipitate was collected by filtration,
washed with water and dried. Silica gel column chromatography (step
gradient elution with mixtures of DCM containing 0, 2.5, 5, 7.5,
10, 20% MeOH) gave 422 mg 1D as a white solid. .sup.1H NMR
(MeOH-d.sub.4): 2.25 (s, 3H), 5.87 (s, 1H), 6.62 (m, 1H), 6.77 (m,
2H), 6.93 (m, 1H), 7.36 (m, 2H), 7.47 (s, 1H); MS: 338 (M+H).sup.+;
and RP HPLC ret. t.: 2.04 min (Phenomenex-Luna S 10: 4.6.times.50
mm column, 3 min gradient, 4 mL/min).
1E.
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-
-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide
[0209] A solution of cyclopropanecarbonyl chloride (9.1 uL, 0.1
mmol) in dry DCM (0.8 mL) was added to a solution of 1D (33.7 mg,
0.1 mmol) in dry pyridine (0.8 mL) in a vial. The vial was sealed
and left stirring over the weekend. Prep. HPLC was used to isolate
13 mg 1E (27% yield) as the TFA salt. .sup.1H NMR (MeOH-d.sub.4):
0.84 (m, 2H), 0.91 (m, 2H), 1.72 (m, 1H), 2.12 (s, 3H), 5.80 (m,
1H), 6.63 (m, 1H), 7.02 (m, 1H), 7.56 (m, 1H), 7.58 (m, 4H); MS:
406 (M+H).sup.+; and RP HPLC ret. t.: 3.23 min (Phenomenex-Luna
S10: 4.6.times.50 mm column, 4 min gradient, 4 mL/min).
Example 2
N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo-
[2,1-f][1,2,4]triazin-4-amine
##STR00014##
[0211] 2A.
2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[1,2-f][1,2,4]-
triazin-4-amine
##STR00015##
[0212] A mixture of 1B (977 mg, 5.2 mmol),
5-cyclopropyl-1H-pyrazol-3-amine (640 mg, 1 equiv), and
diisopropylethylamine (1.54 mL, 1.7 equiv) in 5 mL IPA was stirred
at RT overnight. The precipitate was collected by filtration to
give 1.18 g 2A (83% yield). .sup.1H NMR (CDCl.sub.3): 0.67 (m, 2H),
0.86 (m, 2H), 1.77 (m, 1H), 6.6 (br. s, 1H), 6.54 (br.s, 1H), 6.79
(br. s, 1H), 7.42 (br.s, 1H); MS: 275 (M+H).sup.+; and RP HPLC ret.
t.: 1.56 min (Phenomenex-Luna S10: 3.0.times.50 mm column, 2 min
gradient, 4 mL/min).
[0213] 2B.
N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfa-
nyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine
[0214] A mixture of 2A (28 mg, 0.1 mmol), 3-methoxybenzenethiol (61
uL, 5 equiv) and K.sub.2CO.sub.3 (28 mg, 2 equiv) in dry DMF (0.1
mL) under an N.sub.2 atmosphere was heated at 120.degree. C. After
6 hr, the mixture was cooled to RT and applied to a Phenomenex
strata-X-C cationic cartridge. The cartridge was subsequently
washed with MeOH and a crude product was eluted with a 2 N solution
of NH.sub.3 in MeOH. The crude product was purified by prep. HPLC
to produce 17 mg 2B (44% yield). .sup.1H NMR (MeOH-d.sub.4): 0.61
(m, 2H), 0.92 (m, 2H), 1.80 (m, 1H), 3.81 (s, 3H), 5.8 (br.s, 1H),
6.63 (m, 1H), 6.94 (m, 1H), 7.01 (br.s, 1H), 7.21 (br.s, 1H), 7.37
(br.s, 1H), 7.49 (s, 1H), 7.75 (s, 1H); MS: 379 (M+H).sup.+; and RP
HPLC ret. t.: 1.88 min (Phenomenex-Luna S10: 4.6.times.50 mm
column, 3 min gradient, 4 mL/min).
Example 3
N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f]1,2,4]triazin-
-2-yl}sulfanyl)phenyl]acetamide
##STR00016##
[0216] A mixture of 2A (55 mg, 0.2 mmol),
N-(4-mercaptophenyl)acetamide (167 mg, 5 equiv) and K.sub.2CO.sub.3
(55 mg, 2 equiv) in dry DMF (0.1 mL) under an N.sub.2 atmosphere
was heated at 120.degree. C. After 3 hr, the mixture was cooled to
RT, diluted with MeOH, and filtered. Prep. HPLC was used to isolate
53 mg title product (66% yield). .sup.1H NMR (MeOH-d.sub.4): 0.60
(m, 2H), 0.92 (m, 2H), 1.79 (m, 1H), 2.16 (s, 3H), 5.8 (br.s, 1H),
6.61 (br., 1H), 6.93 (m, 1H), 7.47 (br.s, 1H), 7.57 (m, 2H), 7.71
(m, 2H); MS: 406 (M+H).sup.+; and RP HPLC ret. t.: 1.68 min
(Phenomenex-Luna S10: 4.6.times.50 mm column, 3 min gradient, 4
mL/min).
Example 4
3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-
-yl}sulfanyl)-N-methylbenzamide
##STR00017##
[0217] 4A.
3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]t-
riazin-2-ylthio)benzoic acid
##STR00018##
[0219] A mixture of 2A (99 mg, 0.36 mmol) and 3-mercaptobenzoic
acid (278 mg, 5 equiv) in 1.0 mL n-BuOH was heated in a Smith
Synthesizer microwave reactor (Personal Chemistry, Sweden) at
170.degree. C. for 15 hr. After cooling to RT, the mixture was
diluted with MeOH, and the precipitate was collected by filtration
to give 95 mg 4A (67% yield). .sup.1H NMR (DMSO-d.sub.6 with a drop
of D.sub.2O): 0.49 (m, 2H), 0.86 (m, 2H), 1.70 (m, 1H), 5.61 (s,
1H), 6.61 (m, 1H), 7.25 (m, 1H), 7.60 (m, 2H), 7.85 (m, 1H), 8.03
(m, 1H), 8.11 (s, 1H); MS: 393 (M+H).sup.+; and RP HPLC ret. t.:
1.76 min (Phenomenex-Luna S10: 4.6.times.50 mm column, 3 min
gradient, 4 mL/min).
4B.
3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triaz-
in-2-yl}sulfanyl)-N-methylbenzamide
[0220] Methylamine (0.28 mL, 1.4 equiv, 2.0 M solution in THF)
followed by EDC (58 mg, 1.5 equiv) were added to a suspension of 4A
(78 mg, 0.2 mmol) in dry DCM (0.5 mL) at RT under an N.sub.2
atmosphere. After stirring overnight, prep. HPLC was used to
isolate 34 mg 4B (43% yield). .sup.1H NMR (MeOH-d.sub.4): 0.57 (m,
2H), 0.92 (m, 2H), 1.77 (m, 1H), 2.92 (s, 3H), 5.74 (br.s, 1H),
6.62 (br., 1H), 6.94 (br.s, 1H), 7.48 (br.s, 1H), 7.56 (m, 1H),
7.79 (m, 1H), 7.95 (m, 1H), 8.12 (s, 1H); MS: 406 (M+H).sup.+; and
RP HPLC ret. t.: 1.63 min (Phenomenex-Luna S10: 4.6.times.50 mm
column, 3 min gradient, 4 mL/min).
Example 5
N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triazi-
n-4-amine
##STR00019##
[0222] Benzothiophenol (0.1 mL, 2 equiv) was added to suspension of
K.sub.2CO.sub.3 (151 mg, 2.3 eq.) in 1 mL DMF at rt. After 10 min,
1C (120 mg, 1 eq.) was added as a 3 mL DMF solution. The reaction
was stirred at 110.degree. C. overnight, resulting in product
formation as shown by LCMS. The reaction was then extracted using
ethyl acetate and the combined organic phases washed with water and
brine. The organic layer was dried with MgSO.sub.4 then
concentrated. The crude mixture was triturated with ethyl acetate
to obtain the final product. MS: 323 [M+H].sup.+; .sup.1H NMR
(DMSO-d.sub.6): 12.08 (s, 1H), 10.63 (s, 1H), 7.65 (m, 3H); 7.57
(d, 1H), 7.49 (d, 2H), 7.23 (s, 1H), 6.59 (t, 1H), 5.61 (s, 1H),
2.27 (s, 3H).
Example 6
N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-y-
l)sulfanyl)phenyl)benzamide
##STR00020##
[0223] 6A. N-(4-Mercapto-phenyl)-benzamide
##STR00021##
[0225] Benzoyl chloride (5.14 mL, 44.28 mL) was added dropwise to a
mixture of 4-aminophenol disulfide (5.0 g, 20.13 mmol) and TEA
(7.01 mL, 50.3 mmol) in 60 mL DCM at 0.degree. C. The reaction was
allowed to stir overnight. The resulting precipitate was collected
by filtration. The solid was washed with MeOH and water and then
dried. The solid was combined with 200 mL of concentrated HOAc, and
5.0 equiv of zinc powder was added. The reaction was monitored by
LCMS. When the reaction was complete, the acetic acid solution was
concentrated to approximately 20 mL in volume. The crude mixture
was then extracted with water and EtOAc. The organic layer was
dried with MgSO.sub.4 then concentrated. MS: 228 [M+H].sup.+;
.sup.1H NMR (DMSO-d.sub.6): 10.23 (s, 1H), 7.94 (d, 2H), 7.81 (d,
2H), 7.56 (m, 3H), 7.28 (d, 2H), 5.31 (s, 1H).
6B.
N-{4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-2-
-ylsulfanyl]-phenyl}-benzamide
[0226] 6A (184 mg, 2 equiv) was added to a suspension of
K.sub.2CO.sub.3 (255 mg, 2.3 equiv) in 5 mL DMF at rt. After 10
min., 1C (100 mg, 1 equiv) was added as a 1 mL DMF solution. The
reaction was stirred at 110.degree. C. overnight, resulting in
product formation as shown by LCMS. The reaction was then extracted
using EtOAc, and the combined organic phases were washed with water
and brine. The organic layer was dried with MgSO.sub.4 then
concentrated. The crude mixture was triturated with EtOAc to obtain
6B. MS: 442 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6): 12.05 (s, 1H),
10.85 (s, 1H), 10.64 (s, 1H), 8.00 (br. m, 5H), 7.45 (br. m, 6H),
7.23 (br. s, 1H), 6.59 (br. s, 1H), 5.8 (br. s, 1H) 2.2 (s,
1H).
* * * * *