U.S. patent application number 10/696178 was filed with the patent office on 2004-11-18 for methods of treating p38 kinase-associated conditions with pyrrolotriazine compounds.
Invention is credited to Barrish, Joel, Hynes, John, Leftheris, Katerina, Wrobleski, Stephen T..
Application Number | 20040229877 10/696178 |
Document ID | / |
Family ID | 27365008 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040229877 |
Kind Code |
A1 |
Leftheris, Katerina ; et
al. |
November 18, 2004 |
Methods of treating p38 kinase-associated conditions with
pyrrolotriazine compounds
Abstract
Methods of treating one or more conditions associated with p38
kinase activity are disclosed comprising administering to a patient
in need thereof at least one compound having the formula (I): 1 or
a pharmaceutically acceptable salt, prodrug, or solvate thereof,
wherein R.sub.3 is hydrogen, methyl, perfluoromethyl, methoxy,
halogen, cyano, or NH.sub.2, preferably methyl, and X, R.sub.1
through R.sub.6, and Z are as described in the specification.
Advantageously the groups -ZR.sub.4R.sub.5 taken together comprise
an --NH-substituted aryl.
Inventors: |
Leftheris, Katerina;
(Skillman, NJ) ; Hynes, John; (Washington
Crossing, PA) ; Wrobleski, Stephen T.; (Whitehouse
Station, NJ) ; Barrish, Joel; (Richboro, PA) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
27365008 |
Appl. No.: |
10/696178 |
Filed: |
October 29, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10696178 |
Oct 29, 2003 |
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10036293 |
Nov 7, 2001 |
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6670357 |
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60249877 |
Nov 17, 2000 |
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60310561 |
Aug 7, 2001 |
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Current U.S.
Class: |
514/243 ;
544/183 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 25/00 20180101; C07D 207/50 20130101; A61P 19/02 20180101;
A61P 19/10 20180101; C07D 487/04 20130101 |
Class at
Publication: |
514/243 ;
544/183 |
International
Class: |
A61K 031/53; C07D
487/04 |
Claims
We claim:
1. A method of treating one or more conditions associated with p38
kinase activity comprising administering to a patient in need
thereof at least one compound having the formula (I): 178or a
pharmaceutically acceptable salt, prodrug, or solvate thereof,
wherein: R.sub.3 is hydrogen, methyl, perfluoromethyl, methoxy,
halogen, cyano or NH.sub.2; X is selected from --O--,
--OC(.dbd.O)--, --S--, --S(.dbd.O)--, --SO.sub.2--, --C(.dbd.O)--,
--CO.sub.2--, --NR.sub.10--, --NR.sub.10C(.dbd.O)--,
--NR.sub.10C(.dbd.O)NR.sub.11--, --NR.sub.10CO.sub.2--,
--NR.sub.10SO.sub.2--, --NR.sub.10SO.sub.2NR.sub.11--,
--SO.sub.2NR.sub.10--, --C(.dbd.O)NR.sub.10--, halogen, nitro, and
cyano, or X is absent; Z is selected from O, S, N, and CR.sub.20,
wherein when Z is CR.sub.20, said carbon atom may form an
optionally-substituted bicyclic aryl or heteroaryl with R.sub.4 and
R.sub.5; R.sub.1 is hydrogen, --CH.sub.3, --OH, --OCH.sub.3, --SH,
--SCH.sub.3, --OC(.dbd.O)R.sub.21, --S(.dbd.O)R.sub.22,
--SO.sub.2R.sub.22, --SO.sub.2NR.sub.24R.sub.25,
--CO.sub.2R.sub.21, --C(.dbd.O)NR.sub.24R.su- b.25, --NH.sub.2,
--NR.sub.24R.sub.25, --NR.sub.21 SO.sub.2NR.sub.24R.sub.- 25,
--NR.sub.21SO.sub.2R.sub.22, --NR.sub.24C(.dbd.O)R.sub.25,
--NR.sub.24CO.sub.2R.sub.25, --NR.sub.21C(.dbd.O)NR.sub.24R.sub.25,
halogen, nitro, or cyano; R.sub.2 is selected from: a) hydrogen,
provided that R.sub.2 is not hydrogen when X is --S(.dbd.O)--,
--SO.sub.2--, --NR.sub.10CO.sub.2--, or --NR.sub.10SO.sub.2--; b)
alkyl, alkenyl, and alkynyl optionally substituted with up to four
R.sub.26 or pentafluoroalkyl; c) aryl and heteroaryl optionally
substituted with up to three R.sub.27; and d) heterocyclo and
cycloalkyl optionally substituted with keto (.dbd.O), up to three
R.sub.27, and/or having a carbon-carbon bridge of 3 to 4 carbon
atoms; or e) R.sub.2 is absent if X is halogen, nitro or cyano; (i)
R.sub.4 is substituted aryl, aryl substituted with NHSO.sub.2alkyl,
substituted heteroaryl, or an optionally-substituted bicyclic 7-11
membered saturated or unsaturated carbocyclic or heterocyclic ring,
and R.sub.5 is hydrogen, alkyl, or substituted alkyl, except when Z
is O or S, R.sub.5 is absent, or alternatively, (ii) R.sub.4 and
R.sub.5 taken together with Z form an optionally-substituted
bicyclic 7-11 membered aryl or heteroaryl; R.sub.6 is hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
substituted heterocyclo, --NR.sub.7R.sub.8, --OR.sub.7, or halogen;
R.sub.10 and R.sub.11 are independently selected from hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, heterocyclo, and substituted heterocyclo;
R.sub.7, R.sub.8, R.sub.21, R.sub.24, and R.sub.25 are
independently selected from hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, heterocylco, and substituted heterocyclo;
R.sub.20 is hydrogen, lower alkyl, or substituted alkyl, or
R.sub.20 may be absent if the carbon atom to which it is attached
together with R.sub.4 and R.sub.5 is part of an unsaturated
bicyclic aryl or heteroaryl; R.sub.22 is alkyl, substituted alkyl,
aryl, substituted aryl, heterocyclo, or substituted heterocyclo;
R.sub.26 is selected from halogen, trifluoromethyl, haloalkoxy,
keto (.dbd.O), nitro, cyano, --SR.sub.28, --OR.sub.28,
--NR.sub.28R.sub.29, --NR.sub.28SO.sub.2,
--NR.sub.28SO.sub.2R.sub.29, --SO.sub.2R.sub.28,
--SO.sub.2NR.sub.28R.sub.29, --CO.sub.2R.sub.28,
--C(.dbd.O)R.sub.28, --C(.dbd.O)NR.sub.28R.sub.29,
--OC(.dbd.O)R.sub.28, --OC(.dbd.O)NR.sub.28R.sub.29,
--NR.sub.28C(.dbd.O)R.sub.29, --NR.sub.28CO.sub.2R.sub.29,
.dbd.N--OH, .dbd.N--O-alkyl; aryl optionally substituted with one
to three R.sub.27; cycloalkyl optionally substituted with keto(=O),
one to three R.sub.27, or having a carbon-carbon bridge of 3 to 4
carbon atoms; and heterocyclo optionally substituted with keto
(.dbd.O), one to three R.sub.27, or having a carbon-carbon bridge
of 3 to 4 carbon atoms; wherein R.sub.28 and R.sub.29 are each
independently selected from hydrogen, alkyl, alkenyl, aryl,
aralkyl, C.sub.3-7cycloalkyl, and C.sub.3-7heterocycle, or may be
taken together to form a C.sub.3-7heterocycle; and wherein each
R.sub.28 and R.sub.29 in turn is optionally substituted with up to
two of alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, cyano,
nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl,
phenyloxy, and benzyloxy; and R.sub.27 is selected from alkyl,
R.sub.32, and C.sub.1-4alkyl substituted with one to three
R.sub.32, wherein each R.sub.32 group is independently selected
from halogen, haloalkyl, haloalkoxy, nitro, cyano, --SR.sub.30,
--OR.sub.30, --NR.sub.30R.sub.31, --NR.sub.30SO.sub.2,
--NR.sub.30SO.sub.2R.sub.31, --SO.sub.2R.sub.30,
--SO.sub.2NR.sub.30R.sub.31, --CO.sub.2R.sub.30,
--C(.dbd.O)R.sub.30, --C(.dbd.O)NR.sub.30R.sub.31,
--OC(.dbd.O)R.sub.30, --OC(.dbd.O)NR.sub.30R.sub.31,
--NR.sub.30C(.dbd.O)R.sub.31, --NR.sub.30CO.sub.2R.sub.31, and a 3
to 7 membered carbocyclic or heterocyclic ring optionally
substituted with alkyl, halogen, hydroxy, alkoxy, haloalkyl,
haloalkoxy, nitro, amino, or cyano, wherein R.sub.30 and R.sub.31
are each independently selected from hydrogen, alkyl, alkenyl,
aryl, aralkyl, C.sub.3-7cycloalkyl, and heterocycle, or may be
taken together to form a C.sub.3-7heterocycle.
2. The method of claim 1 comprising administering to the patient at
least one compound having the formula (I), or a pharmaceutically
acceptable salt, prodrug or solvate thereof, wherein: R.sub.3 is
methyl, --CF.sub.3, or --OCH.sub.3; X is selected from
--C(.dbd.O)--, --CO.sub.2--, --NR.sub.10--, --NR.sub.10C(.dbd.O)--,
--NR.sub.10CO.sub.2--, --NR.sub.10SO.sub.2--,
--SO.sub.2NR.sub.10--, and --C(.dbd.O)NR.sub.10--, or X is absent;
Z is N; R.sub.2 is hydrogen, C.sub.2-6alkyl, C.sub.1-4alkyl
substituted with up to four R.sub.26, pentafluoroalkyl, or aryl or
heteroaryl optionally substituted with up to two R.sub.27; R.sub.4
is phenyl substituted with one R.sub.12 and zero to three R.sub.13;
R.sub.5 and R.sub.10 independently are selected from hydrogen and
lower alkyl; R.sub.12 is carbamyl, sulfonamido, arylsulfonylamine,
or ureido, each of which is optionally substituted with up to two
of hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted
aryl, and aralkyl, or alkylsulfonylamine; R.sub.13 at each
occurrence is independently selected from alkyl, substituted alkyl,
halo, trifluoromethoxy, trifluoromethyl, --OR.sub.14,
--C(.dbd.O)alkyl, --OC(.dbd.O)alkyl, --NR.sub.15R.sub.16,
--SR.sub.15, --NO.sub.2, --CN, --CO.sub.2R.sub.15, --CONH.sub.2,
--SO.sub.3H, --S(.dbd.O)alkyl, --S(.dbd.O)aryl,
--NHSO.sub.2-aryl-R.sub.17, --NHSO.sub.2-alkyl,
--SO.sub.2NHR.sub.17, --CONHR.sub.17, and --NHC(.dbd.O)NHR.sub.17;
R.sub.14 is hydrogen, alkyl, or aryl; R.sub.15 is hydrogen or
alkyl; R.sub.16 is hydrogen, alkyl, aralkyl, or alkanoyl; and
R.sub.17 is hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy,
aryl, substituted aryl, or aralkyl.
3. A method of treating one or more conditions associated with p38
kinase activity comprising administering to a patient in need
thereof at least one compound having the formula (I): 179or a
pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein: R.sub.3 is hydrogen, methyl, perfluoromethyl, methoxy,
halogen, cyano or NH.sub.2; X is selected from --O--,
--OC(.dbd.O)--, --S--, --S(.dbd.O)--, --SO.sub.2--, --C(.dbd.O)--,
--CO.sub.2--, --NR.sub.10--, --NR.sub.10C(.dbd.O)--,
--NR.sub.10C(.dbd.O)NR.sub.11--, --NR.sub.10CO.sub.2--,
--NR.sub.10SO.sub.2--, --NR.sub.10SO.sub.2NR.sub.11--,
--SO.sub.2NR.sub.10--, --C(.dbd.O)NR.sub.10--, halogen, nitro, and
cyano, or X is absent; Z is O, S, N, or CR.sub.20; R.sub.1 is
hydrogen, --CH.sub.3, --OH, --OCH.sub.3, --SH, --SCH.sub.3,
--OC(.dbd.O)R.sub.21, --S(.dbd.O)R.sub.22, --SO.sub.2R.sub.22,
--SO.sub.2NR.sub.24R.sub.25, --CO.sub.2R.sub.21,
--C(.dbd.O)NR.sub.24R.sub.25, --NH.sub.2,
--NR.sub.21SO.sub.2NR.sub.24R.sub.25, --NR.sub.21SO.sub.2R.sub.22,
--NR.sub.24C(.dbd.O)R.sub.25, --NR.sub.24CO.sub.2R.sub.25,
--NR.sub.21C(.dbd.O)NR.sub.24R.sub.25, halogen, nitro, or cyano;
R.sub.2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl,
or heterocycloalkyl, or substituted heterocycloalkyl, or when X is
halo, nitro or cyano, R.sub.2 is absent, provided that R.sub.2 is
not hydrogen when X is --S(.dbd.O)--, --SO.sub.2--,
--NR.sub.10CO.sub.2--, or --NR.sub.10SO.sub.2--; R.sub.4 is
substituted aryl, aryl substituted with NHSO.sub.2alkyl,
substituted heteroaryl, or an optionally-substituted bicyclic 7-11
membered saturated or unsaturated carbocyclic or heterocyclic ring
system; R.sub.5 is hydrogen, alkyl, or substituted alkyl, except
that when Z is O or S, R.sub.5 is absent; R.sub.6 is hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
substituted heterocyclo, --NR.sub.7R.sub.8, --OR.sub.7, or halogen;
R.sub.7, R.sub.8, R.sub.10, R.sub.11, R.sub.21, R.sub.24, and
R.sub.25 are independently selected from hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, heterocyclo, and
substituted heterocyclo; R.sub.20 is hydrogen, lower alkyl, or
substituted alkyl; and R.sub.22 is alkyl, substituted alkyl, aryl,
substituted aryl, heterocyclo, or substituted heterocyclo.
4. The method of claim 3 comprising administering to the patient at
least one compound of formula (I), in which R.sub.4 and R.sub.5
taken together with Z form: 180or a pharmaceutically acceptable
salt, prodrug or solvate thereof, wherein: R.sub.12 is attached to
any available carbon atom of phenyl ring A and is selected from
carbamyl, sulfonamido, arylsulfonylamine, and ureido, each of which
is optionally substituted with up to one of hydroxy, alkyl,
substituted alkyl, alkoxy, aryl, substituted aryl, and aralkyl, or
C.sub.1-4alkylsulfonylamine; R.sub.13 is attached to any available
carbon atom of phenyl ring A and at each occurrence is
independently selected from alkyl, substituted alkyl, halo,
trifluoromethoxy, trifluoromethyl, --OR.sub.14, --C(.dbd.O)alkyl,
--OC(.dbd.O)alkyl, --NR.sub.15R.sub.16, --SR.sub.15, --NO.sub.2,
--CN, --CO.sub.2R.sub.15, --CONH.sub.2, --SO.sub.3H,
--S(.dbd.O)alkyl, --S(.dbd.O)aryl, --NHSO.sub.2-aryl-R.sub.17,
--NHSO.sub.2C.sub.1-4alkyl, --SO.sub.2NHR.sub.17, --CONHR.sub.17,
and --NHC(.dbd.O)NHR.sub.17; R.sub.14 is hydrogen, alkyl, or aryl;
R.sub.15 is hydrogen or alkyl; R.sub.16 is hydrogen, alkyl,
aralkyl, or alkanoyl; and R.sub.17 is hydrogen, hydroxy, alkyl,
substituted alkyl, alkoxy, aryl, substituted aryl, or aralkyl; and
n is 0, 1, 2 or 3.
5. The method of claim 3 comprising administering to the patient at
least one compound having the formula (II): 181or a
pharmaceutically acceptable salt, prodrug, or solvate thereof,
wherein: R.sub.3 is methyl or CF.sub.3; X is
--C(.dbd.O)NR.sub.10--, --NR.sub.10C(.dbd.O)--, --C(.dbd.O)--, or
--CO.sub.2--; R.sub.1 is hydrogen, --CH.sub.3, --OH, --OCH.sub.3,
halogen, nitro, or cyano; Y is --C(.dbd.O)NH--, --NHC(.dbd.O)NH--,
--NHSO.sub.2--, or --SO.sub.2NH--; R.sub.10 is hydrogen or lower
alkyl; R.sub.18 is selected from hydrogen, alkyl, alkoxy, aryl, and
aryl substituted with one to three R.sub.19, except that when Y is
--NHSO.sub.2--, R.sub.18 is C.sub.1-4alkyl, aryl or aryl
substituted with R.sub.19; R.sub.13 is attached to any available
carbon atom of phenyl ring A and at each occurrence is
independently selected from alkyl, substituted alkyl, halo,
trifluoromethoxy, trifluoromethyl, --OR.sub.14, --C(.dbd.O)alkyl,
--OC(.dbd.O)alkyl, --NR.sub.15R.sub.16, --SR.sub.15, --NO.sub.2,
--CN, --CO.sub.2R.sub.15, --CONH.sub.2, --SO.sub.3H,
--S(.dbd.O)alkyl, --S(.dbd.O)aryl, --NHSO.sub.2-aryl-R.sub.1- 7,
--NHSO.sub.2C.sub.1-4alkyl, --SO.sub.2NHR.sub.17, --CONHR.sub.17,
and --NHC(.dbd.O)NHR.sub.17; R.sub.14, R.sub.15, R.sub.16 and
R.sub.17 are hydrogen or alkyl; R.sub.19 at each occurrence is
selected from alkyl, halo, trifluoromethoxy, trifluoromethyl,
hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido,
nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl,
alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid,
alkysulfonyl, sulfonamido, and aryloxy, wherein each group R.sub.19
may be further substituted by hydroxy, alkyl, alkoxy, aryl, or
aralkyl; and n is 0, 1 or 2.
6. The method of claim 3, comprising administering to the patient
at least one compound having the formula (Ia), (Ib), or (Ic): 182or
a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein: R.sub.3 is methyl or CF.sub.3; R.sub.2a and R.sub.2c are
independently selected from hydrogen, C.sub.2-6alkyl, substituted
C.sub.1-4alkyl, aryl, substituted aryl, benzyl, and substituted
benzyl; R.sub.2b is heterocyclo or substituted heterocycle; and
R.sub.10 is hydrogen or lower alkyl.
7. The method according to claim 1 wherein the one or more
conditions associated with p38 kinase are selected from
inflammatory disorders.
8. The method of claim 7, in which the inflammatory disorder is
selected from asthma, adult respiratory distress syndrome, chronic
obstructive pulmonary disease, chronic pulmonary inflammatory
disease, diabetes, inflammatory bowel disease, osteoporosis,
psoriasis, graft vs. host rejection, atherosclerosis, and arthritis
including rhematoid arthritis, psoriatic arthritis, traumatic
arthritis, rubella arthritis, gouty arthritis and
osteoarthritis.
9. The method according to claim 1 wherein the one or more
conditions associated with p38 kinase are selected from autoimmune
diseases, destructive bone disorders, proliferative disorders,
angiogenic disorders, infectious diseases, neurodegenerative
diseases, and viral diseases.
10. The method according to claim 1 wherein the one or more
conditions associated with p38 kinase are selected from edema,
analgesia, fever, and pain.
11. The method according to claim 10 wherein the pain is selected
from neuromuscular pain, headache, pain caused by cancer, dental
pain, and arthritis pain.
Description
RELATED INVENTIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 10/036,293, filed Nov. 7, 2001, which claims
the benefit of U.S. Provisional Application No. 60/249,877, filed
Nov. 17, 2000, and U.S. Provisional Application No. 60/310,561,
filed Aug. 7, 2001, all of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] This invention relates to methods of treating conditions
associated with p38.alpha. and .beta. kinases and to
pyrrolotriazine compounds, more particularly, to pyrrolotriazine
carboxamide and benzamide compounds useful for treating p38
kinase-associated conditions.
BACKGROUND OF THE INVENTION
[0003] A large number of cytokines participate in the inflammatory
response, including IL-1, IL-6, IL-8 and TNF-.alpha..
Overproduction of cytokines such as IL-1 and TNF-.alpha. are
implicated in a wide variety of diseases, including inflammatory
bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis,
endotoxin shock, osteoporosis, Alzheimer's disease, and congestive
heart failure, among others [Henry et al., Drugs Fut., 24:1345-1354
(1999); Salituro et al., Curr. Med. Chem., 6:807-823 (1999)].
Evidence in human patients indicates that protein antagonists of
cytokines are effective in treating chronic inflammatory diseases,
such as, for example, monoclonal antibody to TNF-.alpha. (Enbrel)
[Rankin et al., Br. J. Rheumatol., 34:334-342 (1995)], and soluble
TNF-.alpha. receptor-Fc fusion protein (Etanercept) [Moreland et
al., Ann. Intern. Med., 130:478-486 (1999)].
[0004] The biosynthesis of TNF-.alpha. occurs in many cell types in
response to an external stimulus, such as, for example, a mitogen,
an infectious organism, or trauma. Important mediators of
TNF-.alpha. production are the mitogen-activated protein (MAP)
kinases, and in particular, p38 kinase. These kinases are activated
in response to various stress stimuli, including but not limited to
proinflammatory cytokines, endotoxin, ultraviolet light, and
osmotic shock. Activation of p38 requires dual phosphorylation by
upstream MAP kinase kinases (MKK3 and MKK6) on threonine and
tyrosine within a Thr-Gly-Tyr motif characteristic of p38
isozymes.
[0005] There are four known isoforms of p38, i.e., p38-.alpha.,
p38.beta., p38.gamma., and p38.delta.. The .alpha. and .beta.
isoforms are expressed in inflammatory cells and are key mediators
of TNF-.alpha. production. Inhibiting the p38.alpha. and .beta.
enzymes in cells results in reduced levels of TNF-.alpha.
expression. Also, administering p38.alpha. and .beta. inhibitors in
animal models of inflammatory disease has proven that such
inhibitors are effective in treating those diseases. Accordingly,
the p38 enzymes serve an important role in inflammatory processes
mediated by IL-1 and TNF-.alpha.. Compounds that reportedly inhibit
p38 kinase and cytokines such as IL-1 and TNF-.alpha. for use in
treating inflammatory diseases are disclosed in U.S. Pat. Nos.
6,277,989 and 6,130,235 to Scios, Inc; U.S. Pat. Nos. 6,147,080 and
5,945,418 to Vertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914,
5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat.
Nos. 5,932,576 and 6,087,496 to G. D. Searle & Co.; WO 00/56738
and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson &
Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase
inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for
the same purpose); WO 00/12497 (discusses the relationship between
p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine
compounds useful as p38 inhibitors).
[0006] The present invention provides methods of treating
conditions associated with p38 kinase activity comprising
administering to a patient in need thereof certain pyrrolotriazine
compounds. Pyrrolotriazine compounds useful as tyrosine kinase
inhibitors are disclosed in U.S. patent application Ser. No.
09/573,829 filed May 18, 2000, assigned to the present assignee.
Pyrrolotriazine compounds substituted with an acidic group
reportedly having sPLA.sub.2-inhibitory activity are disclosed in
WO 01/14378 A1 to Shionogi & Co., Ltd, published Mar. 1, 2001
in Japanese. Each of the patent applications, patents, and
publications referred to herein is incorporated herein by
reference.
SUMMARY OF THE INVENTION
[0007] The instant invention is directed to methods of treating one
or more conditions associated with p38 kinase activity comprising
administering to a patient in need thereof one or more
pharmaceutically-active compounds having the Formula (I): 2
[0008] or a pharmaceutically acceptable salt, prodrug, or solvate
thereof, wherein:
[0009] R.sub.3 is hydrogen, methyl, perfluoromethyl, methoxy,
halogen, cyano, or NH.sub.2;
[0010] X is selected from --O--, --OC(.dbd.O)--, --S--,
--S(.dbd.O)--, --SO.sub.2--, --C(.dbd.O)--, --CO.sub.2--,
--NR.sub.10--, --NR.sub.10C(.dbd.O)--,
--NR.sub.10C(.dbd.O)NR.sub.11--, --NR.sub.10CO.sub.2--,
--NR.sub.10SO.sub.2--, --NR.sub.10SO.sub.2NR.sub.1- 1--,
--SO.sub.2NR.sub.10--, --C(.dbd.O)NR.sub.10--, halogen, nitro, and
cyano, or X is absent;
[0011] Z is selected from O, S, N, and CR.sub.20, wherein when Z is
CR.sub.20, said carbon atom may form an optionally-substituted
bicyclic aryl or heteroaryl with R.sub.4 and R.sub.5;
[0012] R.sub.1 is hydrogen, --CH.sub.3, --OH, --OCH.sub.3, --SH,
--SCH.sub.3, --OC(.dbd.O)R.sub.21, --S(.dbd.O)R.sub.22,
--SO.sub.2R.sub.22, --SO.sub.2NR.sub.24R.sub.25,
--CO.sub.2R.sub.21, --C(.dbd.O)NR.sub.24R.sub.25, --NH.sub.2,
--NR.sub.24R.sub.25, --NR.sub.21SO.sub.2NR.sub.24R.sub.25,
--NR.sub.21SO.sub.2R.sub.22, --NR.sub.24C(.dbd.O)R.sub.25,
--NR.sub.24CO.sub.2R.sub.25, --NR.sub.21C(.dbd.O)NR.sub.24R.sub.25,
halogen, nitro, or cyano;
[0013] R.sub.2 is selected from:
[0014] a) hydrogen, provided that R.sub.2 is not hydrogen if X is
--S(.dbd.O)--, --SO.sub.2--, --NR.sub.10CO.sub.2--, or
--NR.sub.10SO.sub.2--;
[0015] b) alkyl, alkenyl, and alkynyl optionally substituted with
up to four R.sub.26;
[0016] c) aryl and heteroaryl optionally substituted with up to
three R.sub.27; and
[0017] d) heterocyclo and cycloalkyl optionally substituted with
keto (.dbd.O), up to three R.sub.27, and/or having a carbon-carbon
bridge of 3 to 4 carbon atoms; or
[0018] e) R.sub.2 is absent if X is halogen, nitro, or cyano;
[0019] (i) R.sub.4 is substituted aryl, aryl substituted with
NHSO.sub.2alkyl, substituted heteroaryl, or an
optionally-substituted bicyclic 7-11 membered saturated or
unsaturated carbocyclic or heterocyclic ring, and
[0020] R.sub.5 is hydrogen, alkyl, or substituted alkyl, except
when Z is O or S, R.sub.5 is absent, or alternatively,
[0021] (ii) R.sub.4 and R.sub.5 taken together with Z form an
optionally-substituted bicyclic 7-11 membered aryl or
heteroaryl;
[0022] R.sub.6 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, heterocyclo, substituted heterocyclo,
--NR.sub.7R.sub.8, --OR.sub.7, or halogen;
[0023] R.sub.10 and R.sub.11 are independently selected from
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heterocyclo, and substituted
heterocyclo;
[0024] R.sub.7, R.sub.8, R.sub.21, R.sub.24, and R.sub.25 are
independently selected from hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, heterocylco, and substituted
heterocyclo;
[0025] R.sub.20 is hydrogen, lower alkyl, or substituted alkyl, or
R.sub.20 may be absent if the carbon atom to which it is attached
together with R.sub.4 and R.sub.5 is part of an unsaturated
bicyclic aryl or heteroaryl;
[0026] R.sub.22 is alkyl, substituted alkyl, aryl, substituted
aryl, heterocyclo, or substituted heterocyclo;
[0027] R.sub.26 is selected from halogen, trifluoromethyl,
haloalkoxy, keto (.dbd.O), nitro, cyano, --SR.sub.28, --OR.sub.28,
--NR.sub.28R.sub.29, --NR.sub.28SO.sub.2,
--NR.sub.28SO.sub.2R.sub.29, --SO.sub.2R.sub.28,
--SO.sub.2NR.sub.28R.sub.29, --CO.sub.2R.sub.28,
--C(.dbd.O)R.sub.28, --C(.dbd.O)NR.sub.28R.sub.29,
--OC(.dbd.O)R.sub.28, --OC(.dbd.O)NR.sub.28R.sub.29,
--NR.sub.28C(.dbd.O)R.sub.29, --NR.sub.28CO.sub.2R.sub.29,
.dbd.N--OH, .dbd.N--O-alkyl; aryl optionally substituted with one
to three R.sub.27; cycloalkyl optionally substituted with
keto(.dbd.O), one to three R.sub.27, or having a carbon-carbon
bridge of 3 to 4 carbon atoms; and heterocyclo optionally
substituted with keto (.dbd.O), one to three R.sub.27, or having a
carbon-carbon bridge of 3 to 4 carbon atoms; wherein R.sub.28 and
R.sub.29 are each independently selected from hydrogen, alkyl,
alkenyl, aryl, aralkyl, C.sub.3-7cycloalkyl, and
C.sub.3-7heterocycle, or may be taken together to form a
C.sub.3-7heterocycle; and wherein each R.sub.28 and R.sub.29 in
turn is optionally substituted with up to two of alkyl, alkenyl,
halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, hydroxy,
alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy;
and
[0028] R.sub.27 is selected from alkyl, R.sub.32, and
C.sub.1-4alkyl substituted with one to three R.sub.32, wherein each
R.sub.32 group is independently selected from halogen, haloalkyl,
haloalkoxy, nitro, cyano, --SR.sub.30, --OR.sub.30,
--NR.sub.30R.sub.31, --NR.sub.30SO.sub.2,
--NR.sub.30SO.sub.2R.sub.31, --SO.sub.2R.sub.30,
--SO.sub.2NR.sub.30R.sub- .31, --CO.sub.2R.sub.30,
--C(.dbd.O)R.sub.30, --C(.dbd.O)NR.sub.30R.sub.31- ,
--OC(.dbd.O)R.sub.30, --OC(.dbd.O)NR.sub.30R.sub.31,
--NR.sub.30C(.dbd.O)R.sub.31, --NR.sub.30CO.sub.2R.sub.31, and a 3
to 7 membered carbocyclic or heterocyclic ring optionally
substituted with alkyl, halogen, hydroxy, alkoxy, haloalkyl,
haloalkoxy, nitro, amino, or cyano, wherein R.sub.30 and R.sub.31
are each independently selected from hydrogen, alkyl, alkenyl,
aryl, aralkyl, C.sub.3-7cycloalkyl, and heterocycle, or may be
taken together to form a C.sub.3-7heterocycle.
DESCRIPTION OF THE INVENTION
[0029] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification, unless otherwise
limited in specific instances, either individually or as part of a
larger group.
[0030] The term "alkyl" refers to straight or branched chain
unsubstituted hydrocarbon groups of 1 to 20 carbon atoms,
preferably 1 to 7 carbon atoms. The expression "lower alkyl" refers
to unsubstituted alkyl groups of 1 to 4 carbon atoms. When a
subscript is used with reference to an alkyl or other group, the
subscript refers to the number of carbon atoms that the group may
contain. The term "C.sub.0-4alkyl" includes a bond and alkyl groups
of 1 to 4 carbon atoms.
[0031] The term "substituted alkyl" refers to an alkyl group
substituted by one to four substituents selected from halo,
hydroxy, alkoxy, oxo (.dbd.O), alkanoyl, aryloxy, alkanoyloxy,
amino, alkylamino, arylamino, aralkylamino, disubstituted amines in
which the 2 amino substituents are selected from alkyl, aryl or
aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted
alkanoylamino, substituted arylamino, substituted aralkanoylamino,
thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono,
aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
sulfonamido, e.g. SO.sub.2NH.sub.2, substituted sulfonamido, nitro,
cyano, carboxy, carbamyl, e.g. CONH.sub.2, substituted carbamyl
e.g. CONHalkyl, CONHaryl, CONHaralkyl or cases where there are two
substituents on the nitrogen selected from alkyl, aryl or aralkyl;
alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted
or unsubstituted heterocyclos, such as indolyl, imidazolyl, furyl,
thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Where the substituent on the alkyl is further substituted, it will
be with alkyl, alkoxy, aryl, or aralkyl.
[0032] When the term alkyl is used in connection with another
group, as in heterocycloalkyl or cycloalkylalkyl, this means the
identified group is bonded directly through an alkyl group which
may be branched or straight chain. In the case of substituents, as
in "substituted cycloalkylalkyl," the alkyl portion of the group
may, besides being branched or straight chain, be substituted as
recited above for substituted alkyl groups and/or the connected
group may be substituted as recited herein for that group.
[0033] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0034] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6 to 12 carbon atoms in the ring portion,
such as phenyl, naphthyl, biphenyl and diphenyl groups. When the
aryl is substituted, each ring of the aryl may be substituted.
[0035] The term "substituted aryl" refers to an aryl group
substituted by one to four substituents selected from alkyl,
substituted alkyl, halo, trifluoromethoxy, trifluoromethyl,
hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino,
aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio,
ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl,
alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine,
sulfonic acid, alkysulfonyl, sulfonamido, and aryloxy. The
substituent may be further substituted by hydroxy, alkyl, alkoxy,
aryl, substituted aryl, substituted alkyl or aralkyl.
[0036] The term "aralkyl" refers to an aryl group bonded directly
through an alkyl group, such as benzyl, wherein the alkyl group may
be branched or straight chain. In the case of a "substituted
aralkyl," the alkyl portion of the group may, besides being
branched or straight chain, be substituted as recited above for
substituted alkyl groups and/or the aryl portion may be substituted
as recited for substituted aryl. Thus, the term "optionally
substituted benzyl" refers to the group 3
[0037] wherein each R group may be hydrogen or may also be selected
from alkyl, halogen, cyano, nitro, amino, hydroxy, alkoxy,
alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy, and other
groups recited above. At least two of these "R" groups should be
hydrogen and preferably at least five of the "R" groups is
hydrogen. A preferred benzyl group involves the alkyl-portion being
branched to define 4
[0038] The term "heteroaryl" refers to an aromatic group for
example, which is a 4 to 7 membered monocyclic, 7 to 11 membered
bicyclic, or 10 to 15 membered tricyclic ring system, which has at
least one heteroatom and at least one carbon atom-containing ring.
Each ring of the heteroaryl group containing a heteroatom can
contain one or two oxygen or sulfur atoms and/or from one to four
nitrogen atoms, provided that the total number of heteroatoms in
each ring is four or less and each ring has at least one carbon
atom. The fused rings completing the bicyclic and tricyclic groups
may contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen atoms may optionally be
quaternized. Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any
ring.
[0039] A "substituted heteroaryl" has one to four substituents on
any one or more of the rings comprising the heteraryl group. The
substituents may be selected from those recited below for
heterocycle groups.
[0040] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl
(i.e., 5
[0041] thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the
like.
[0042] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the
like.
[0043] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0044] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four double bonds.
[0045] The term "substituted alkenyl" refers to an alkenyl group
substituted by one to two substituents selected from halo, hydroxy,
alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,
alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl,
sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,
guanidino, and substituted and unsubstituted heterocycles,
including indolyl, imidazolyl, furyl, thienyl, thiazolyl,
pyrrolidyl, pyridyl, pyrimidyl and the like.
[0046] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four triple bonds.
[0047] The term "substituted alkynyl" refers to an alkynyl group
substituted by a substituent selected from halo, hydroxy, alkoxy,
alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,
alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl,
sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,
guanidino and substituted or unsubstituted heterocyclo, e.g.
imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,
pyrimidyl and the like.
[0048] The term "cycloalkyl" refers to a saturated or partially
unsaturated non-aromatic cyclic hydrocarbon ring system, preferably
containing 1 to 3 rings and 3 to 7 carbons per ring which may be
further fused with an unsaturated C.sub.3-C.sub.7 carbocylic ring.
Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and
adamantyl. A "substituted cycloalkyl" is substituted with one or
more alkyl or substituted alkyl groups as described above, or one
or more groups described above as alkyl substituents.
[0049] The terms "heterocycle", "heterocyclic" and "heterocyclo"
each refer to a fully saturated or unsaturated, aromatic or
nonaromatic cyclic group, for example, which is a 4 to 7 membered
monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered
tricyclic ring system, which has at least one heteroatom in at
least one carbon atom-containing ring. Thus, the term "heterocycle"
includes heteroaryl groups as described above. Each ring of the
heterocyclic group containing a heteroatom may have 1, 2 or 3
heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur
atoms, where the nitrogen and sulfur heteroatoms may also
optionally be oxidized and the nitrogen heteroatoms may also
optionally be quaternized. The heterocyclic group may be attached
at any heteroatom or carbon atom.
[0050] Exemplary monocyclic heterocyclic groups include
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, 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, and the like.
[0051] Exemplary bicyclic hetrocyclic groups include
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,
isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0052] Also included are smaller heterocyclos, such as epoxides and
aziridines.
[0053] A "substituted heterocycle" will be substituted with one or
more alkyl or aralkyl groups as described above, and/or one or more
groups described above as alkyl substituents.
[0054] Unless otherwise indicated, when reference is made to a
specifically-named heterocyclo or heteroaryl, the reference is
intended to include those systems having the maximum number of
non-cumulative double bonds or less than that maximum number of
double bonds. Thus, for example, the term "isoquinoline" refers to
isoquinoline and tetrahydroisoquinoline. The term "diazepine"
refers to a heterocyclo ring having at least one seven atom ring
with two nitrogen atoms in the seven membered ring, including a
fully saturated or unsaturated diazepine.
[0055] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0056] The term "haloalkyl" means an alkyl having one or more halo
substituents The term "perfluoromethyl" means a methyl group
substituted by one, two, or three fluoro atoms, i e., CH.sub.2F,
CHF.sub.2 and CF.sub.3. The term "perfluoroalkyl" means an alkyl
group having from one to five fluoro atoms, such as
pentafluoroethyl.
[0057] The term "haloalkoxy" means an alkoxy group having one or
more halo substituents. For example, "haloalkoxy" includes
--OCF.sub.3.
[0058] The term "carbocyclic" means a saturated or unsaturated
unsaturated monocyclic or bicyclic ring in which all atoms of all
rings are carbon. Thus, the term includes cycloalkyl and aryl
rings. The carbocyclic ring may be substituted in which case the
substituents are selected from those recited above for cycloalkyl
and aryl groups.
[0059] When the term "unsaturated" is used herein to refer to a
ring or group, the ring or group may be fully unsaturated or
partially unsaturated.
[0060] Definitions for the various other groups that are recited
above in connection with substituted alkyl, substituted alkenyl,
substituted alkynyl, substituted aryl, substituted heterocycle,
substituted cycloalkyl, and so forth, are as follows: alkoxy is
--OR.sup.a, alkanoyl is --C(.dbd.O)R.sup.a, aryloxy is --OAr,
alkanoyloxy is --OC(.dbd.O)R.sup.a, amino is --NH.sub.2, alkylamino
is --NHR.sup.a, arylamino is --NHAr, aralkylamino is
--NH--R.sup.b--Ar, disubstituted amine or dialkylamino is
--NR.sup.cR.sup.d, alkanoylamino is --NH--C(.dbd.O)R.sup.a,
aroylamino is --NH--C(.dbd.O)Ar, aralkanoylamino is
--NH--C(.dbd.O)R.sup.b--Ar, thiol is --SH, alkylthio is --SR.sup.a,
arylthio is --SAr, aralkylthio is --S--R.sup.b--Ar, alkylthiono is
--S(.dbd.O)R.sup.a, arylthiono is --S(.dbd.O)Ar, aralkylthiono is
--S(.dbd.O)R.sup.b--Ar, alkylsulfonyl is --SO.sub.(q)R.sup.a,
arylsulfonyl is --SO.sub.(q)Ar, arylsulfonylamine is
--NHSO.sub.(q)Ar, alkylsulfonylamine is --NHSO.sub.2R.sup.a,
aralkylsulfonyl is --SO.sub.(q)R.sup.bAr, sulfonamido is
--SO.sub.2NH.sub.2, nitro is --NO.sub.2, carboxy is --CO.sub.2H,
carbamyl is --CONH.sub.2, substituted carbamyl is
--C(.dbd.O)NHR.sup.c or --C(.dbd.O)NR.sup.cR.sup.d, alkoxycarbonyl
is --C(.dbd.O)OR.sup.a, carboxyalkyl is --R.sup.b--CO.sub.2H,
sulfonic acid is --SO.sub.3H, arylsulfonylamine is
--NHSO.sub.(q)Ar, guanidino is 6
[0061] and ureido is 7
[0062] wherein R.sup.a is alkyl as defined above, R.sup.b is
alkylene as defined above, R.sup.c and R.sup.d are selected from
alkyl, aryl, and aralkyl, Ar is an aryl as defined above, and q is
2 or 3.
[0063] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds.
[0064] The compounds of Formula (I) may form salts which are also
within the scope of this invention. Pharmaceutically acceptable
(i.e. non-toxic, physiologically acceptable) salts are preferred,
although other salts are also useful, e.g., in isolating or
purifying the compounds of this invention. All references to
compounds of Formula (I) herein are intended to include without
limitation compounds of Formulae (Ia) to (Ii) as well as compounds
of Formula (II) and (IIa)-(IIh). All references to compounds of
Formula (II) are intended to include compounds of Formulae (IIa) to
(IIh).
[0065] The compounds of Formula (I) may form salts with alkali
metals such as sodium, potassium and lithium, with alkaline earth
metals such as calcium and magnesium, with organic bases such as
dicyclohexylamine, tributylamine, pyridine and amino acids such as
arginine, lysine and the like. Such salts can be formed as known to
those skilled in the art.
[0066] The compounds for Formula (I) may form salts with a variety
of organic and inorganic acids. Such salts include those formed
with hydrogen chloride, hydrogen bromide, methanesulfonic acid,
sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid,
maleic acid, benzenesulfonic acid, toluenesulfonic acid and various
others (e.g., nitrates, phosphates, borates, tartrates, citrates,
succinates, benzoates, ascorbates, salicylates and the like). Such
salts can be formed as known to those skilled in the art.
[0067] Salt forms of the compounds may be advantageous for
improving the compound dissolution rate and oral bioavailability.
For select compounds of Formula (I), mesylate and/or bisulfate
salts were successfully obtained (see, e.g., Example 125 herein).
Both mesylate and bisulfate salts were found to be non-hygroscopic,
highly water soluble, and stable in solid state
[0068] In addition, zwitterions ("inner salts") may be formed.
[0069] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The definition of compounds according to the invention
embraces all the possible stereoisomers and their mixtures. It
embraces the racemic forms and the isolated optical isomers having
the specified activity. The racemic forms can be resolved by
physical methods, such as, for example, fractional crystallization,
separation or crystallization of diastereomeric derivatives or
separation by chiral column chromatography. The individual optical
isomers can be obtained from the racemates from the conventional
methods, such as, for example, salt formation with an optically
active acid followed by crystallization.
[0070] Compounds of the Formula (I) may also have prodrug forms.
Any compound that will be converted in vivo to provide the
bioactive agent (i.e., the compound for formula I) is a prodrug
within the scope and spirit of the invention.
[0071] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see:
[0072] 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. (Acamedic Press, 1985);
[0073] 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
[0074] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38
(1992), each of which is incorporated herein by reference.
[0075] It should further be understood that solvates (e.g.,
hydrates) of the compounds of Formula (I) are also with the scope
of the present invention. Methods of solvation are generally known
in the art.
Preferred Compounds
[0076] Preferred embodiments of the invention comprise methods of
treating conditions associated with p38 kinase activity comprising
administering preferred compounds of Formulae (I) and (II).
Preferred compounds are those having Formula (I), 8
[0077] and pharmaceutically acceptable salts, prodrugs, or solvates
thereof, wherein:
[0078] R.sub.3 is methyl, --CF.sub.3, or --OCF.sub.3,
[0079] X is selected from --C(.dbd.O)--, --CO.sub.2--,
--NR.sub.10C(.dbd.O)--, and --C(.dbd.O)NR.sub.10--, or X is
absent;
[0080] Z is N;
[0081] R.sub.1 is hydrogen, --CH.sub.3, --OH, --OCH.sub.3, --SH,
--SCH.sub.3, --OC(.dbd.O)R.sub.21, --S(.dbd.O)R.sub.22,
--SO.sub.2R.sub.22, --SO.sub.2NR.sub.24R.sub.25,
--CO.sub.2R.sub.21, --C(.dbd.O)NR.sub.24R.sub.25, --NH.sub.2,
--NR.sub.21SO.sub.2NR.sub.24R.s- ub.25,
--NR.sub.21SO.sub.2R.sub.22, --NR.sub.24C(.dbd.O)R.sub.25,
--NR.sub.24CO.sub.2R.sub.25, --NR.sub.21C(.dbd.O)NR.sub.24R.sub.25,
halogen, nitro, or cyano;
[0082] R.sub.2 is hydrogen, C.sub.2-6alkyl, substituted
C.sub.1-4alkyl, aryl, aralkyl, substituted aryl, substituted
aralkyl, cycloalkyl, substituted cycloalkyl, heterocycle, or
substituted heterocycle, or optionally-substituted cycloalkylalkyl
or heterocycloalkyl;
[0083] R.sub.4 is aryl or heteroaryl substituted with one R.sub.12
and zero to three R.sub.13;
[0084] R.sub.5 and R.sub.10 independently are selected from
hydrogen and lower alkyl;
[0085] R.sub.6 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, heterocyclo, substituted heterocyclo,
--NR.sub.7R.sub.8, --OR.sub.7, or halogen;
[0086] R.sub.12 is carbamyl, sulfonamido, arylsulfonylamine, or
ureido, each of which is optionally substituted with up to two of
hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl,
and aralkyl, or R.sub.12 is alkylsulfonylamine;
[0087] R.sub.13 at each occurrence is independently selected from
alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl,
--OR.sub.14, --C(.dbd.O)alkyl, --OC(.dbd.O)alkyl,
--NR.sub.15R.sub.16, --SR.sub.15, --NO.sub.2, --CN,
--CO.sub.2R.sub.15, --CONH.sub.2, --SO.sub.3H, --S(.dbd.O)alkyl,
--S(.dbd.O)aryl, --NHSO.sub.2-aryl-R.sub.17, --NHSO.sub.2-alkyl,
--SO.sub.2NHR.sub.17, --CONHR.sub.17, and
--NHC(.dbd.O)NHR.sub.17;
[0088] R.sub.14 is hydrogen, alkyl, or aryl;
[0089] R.sub.15 is hydrogen or alkyl;
[0090] R.sub.16 is hydrogen, alkyl, aralkyl, or alkanoyl;
[0091] R.sub.17 is hydrogen, hydroxy, alkyl, substituted alkyl,
alkoxy, aryl, substituted aryl, or aralkyl;
[0092] R.sub.7, R.sub.8, R.sub.10, R.sub.11, R.sub.21, R.sub.24,
and R.sub.25 are independently selected from hydrogen and
alkyl;
[0093] and R.sub.22 is alkyl or substituted alkyl.
[0094] In compounds of Formula (I), preferably the group R.sub.3 is
methyl, trifluoromethyl, or methoxy, most preferably methyl; X is
preferably --CO.sub.2--, --NR.sub.10C(.dbd.O)--, or
--C(.dbd.O)NR.sub.10--, more preferably --C(.dbd.O)NH--; Z is
preferably N; R.sub.4 is preferably substituted aryl or substituted
heteroaryl, more preferably phenyl substituted with at least one of
carbamyl, substituted carbamyl, arylsulfonylamido, substituted
arylsulfonylamido, ureido, or substituted ureido, and optionally
substituted with one or two C.sub.1-4alkyl or halogen. Most
preferably R.sub.4 is phenyl substituted with at least one of
--C(.dbd.O)NHO(C.sub.1-4alkyl) or --C(.dbd.O)NH(optionally
substituted phenyl), and also is optionally substituted with
C.sub.1-4alkyl. R.sub.5 is preferably hydrogen or lower alkyl, more
preferably hydrogen.
[0095] In preferred methods, R.sub.1 and R.sub.6 may be selected
from groups of substituents as defined herein; however,
advantageously they are selected from hydrogen, CH.sub.3, --OH,
--OCH.sub.3, halogen, nitro, and cyano, and most preferably R.sub.1
and R.sub.6 are hydrogen. R.sub.2 preferably is alkyl, aryl,
substituted aryl, aralkyl, substituted aralkyl, heteroaryl, or
substituted heteroaryl, more preferably straight or branched
C.sub.2-6alkyl or optionally-substituted benzyl. The mesylate salt
is the preferred form of salt.
[0096] Accordingly, preferred methods further comprise
administering compounds having the Formula (II), 9
[0097] and pharmaceutically acceptable salts, prodrugs, or solvates
thereof, wherein:
[0098] R.sub.3 is methyl, --CF.sub.3, or --OCH.sub.3;
[0099] X is --C(.dbd.O)NR.sub.10--, --NR.sub.10C(.dbd.O)--,
--C(.dbd.O)--, or --CO.sub.2--;
[0100] Y is --C(.dbd.O)NH--, --NHC(.dbd.O)NH--, or
--NHSO.sub.2--;
[0101] R.sub.10 is hydrogen or lower alkyl;
[0102] R.sub.18 is selected from hydrogen, alkyl, alkoxy, aryl, and
aryl substituted with one to three R.sub.19, except that when Y is
--NHSO.sub.2--, R.sub.18 is --C.sub.1-4alkyl, aryl or aryl
substituted with R.sub.19;
[0103] R.sub.13 is attached to any available carbon atom of phenyl
ring A and at each occurrence is independently selected from alkyl,
substituted alkyl, halo, trifluoromethoxy, trifluoromethyl,
--OR.sub.14, --C(.dbd.O)alkyl, --OC(.dbd.O)alkyl,
--NR.sub.15R.sub.16, --SR.sub.15, --NO.sub.2, --CN,
--CO.sub.2R.sub.15, --CONH.sub.2, --SO.sub.3H, --S(.dbd.O)alkyl,
--S(.dbd.O)aryl, --NHSO.sub.2-aryl-R.sub.17, --SO.sub.2NHR.sub.17,
--CONHR.sub.17, and --NHC(.dbd.O)NHR.sub.17;
[0104] R.sub.14, R.sub.15, R.sub.16 and R.sub.17 are hydrogen or
alkyl;
[0105] R.sub.19 at each occurrence is selected from alkyl, halo,
trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl,
alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy,
carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,
arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, and
aryloxy, wherein each group R.sub.19 may be further substituted by
hydroxy, alkyl, alkoxy, aryl, or aralkyl;
[0106] n is 0, 1 or 2, and
[0107] R.sub.1, R.sub.2 and R.sub.6 are as defined above for
compounds of Formula (I).
[0108] More preferred are methods of administering compounds having
the Formula (IIa) or (IIb): 10
[0109] and pharmaceutically acceptable salts, prodrugs, or solvates
thereof, wherein:
[0110] R.sub.3 is methyl;
[0111] R.sub.1 and R.sub.10 are hydrogen or --CH.sub.3;
[0112] R.sub.2 is selected from hydrogen; straight or branched
C.sub.2-6alkyl; cycloalkyl optionally substituted with keto and/or
up to two R.sub.27; phenyl optionally substituted with up to two
R.sub.27; heterocycle optionally substituted with keto and/or up to
two R.sub.27; and C.sub.1-4alkyl substituted with up to three of
halogen, trifluoromethyl, cyano, OR.sub.28, NR.sub.28R.sub.29,
CO.sub.2R.sub.28, aryl, heterocycle, and/or cycloalkyl, wherein the
aryl, heterocycle, and/or cycloalkyl in turn are optionally
substituted with up to two of halogen, hydroxy, alkoxy, haloalkyl,
haloalkoxy, nitro, cyano and alkyl;
[0113] R.sub.18 is hydroxy, C.sub.1-4alkoxy, phenyl, or phenyl
substituted with one or two R.sub.19;
[0114] R.sub.13 and R.sub.19 are selected from lower alkyl,
halogen, trifluoromethoxy, trifluoromethyl, hydroxy,
C.sub.1-4alkoxy, nitro, and cyano;
[0115] R.sub.27 at each occurrence is independently selected from
hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano,
nitro, amino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and
benzyloxy;
[0116] R.sub.28 and R.sub.29 at each occurrence are independently
selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; and
[0117] n is 0, 1 or2.
[0118] When R.sub.2 is a heterocyclo, advantageously it is selected
from diazepinyl, morpholinyl, piperidinyl, and pyrrolidinyl, said
heterocycle being optionally substituted with C.sub.1-4alkyl,
phenyl, and/or benzyl.
[0119] Most preferred are methods comprising administering
compounds having the formula, 11
[0120] in which R.sub.13a and R.sub.13b are hydrogen, CH.sub.3, OH,
OCH.sub.3, CF.sub.3, cyano, or halogen, R.sub.2 is C.sub.2-6alkyl
or optionally substituted benzyl, R.sub.33 is lower alkyl, and n is
0 or 1.
Utility
[0121] The compounds of the invention are selective inhibitors of
p38 kinase activity, and in particular, isoforms p38.alpha. and
p38.beta.. Accordingly, compounds of formula (I) have utility in
treating conditions associated with p38 kinase activity. Such
conditions include diseases in which cytokine levels are modulated
as a consequence of intracellular signaling via p38, and in
particular, diseases that are associated with an overproduction of
cytokines IL-1, IL-4, IL-8, and TNF-.alpha.. As used herein, the
terms "treating" or "treatment" encompass either or both responsive
and prophylaxis measures, e.g., designed to inhibit or delay the
onset of the disease or disorder, achieve a full or partial
reduction of the symptoms or disease state, and/or to alleviate,
ameliorate, lessen, or cure the disease or disorder and/or its
symptoms. When reference is made herein to inhibition of
"p-38.alpha./.beta. kinase," this means that either p38.alpha.
and/or p38.beta. kinase are inhibited. Thus, reference to an
IC.sub.50 value for inhibiting p-38.alpha./.beta. kinase means that
the compound has such effectiveness for inhibiting at least one of,
or both of, p38.alpha. and p38.beta. kinases.
[0122] In view of their activity as inhibitors of
p-38.alpha./.beta. kinase, compounds of Formula (I) are useful in
treating p-38 associated conditions including, but not limited to,
inflammatory diseases, autoimmune diseases, destructive bone
disorders, proliferative disorders, angiogenic disorders,
infectious diseases, neurodegenerative diseases, and viral
diseases.
[0123] More particularly, the specific conditions or diseases that
may be treated with the inventive compounds include, without
limitation, pancreatitis (acute or chronic), asthma, allergies,
adult respiratory distress syndrome, chronic obstructive pulmonary
disease, glomerulonephritis, rheumatoid arthritis, systemic lupus
erythematosis, scleroderma, chronic thyroiditis, Grave's disease,
autoimmune gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, atopic dermatitis,
chronic active hepatitis, myasthenia gravis, multiple sclerosis,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
psoriasis, graft vs. host disease, inflammatory reaction induced by
endotoxin, tuberculosis, atherosclerosis, muscle degeneration,
cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic
arthritis, rubella arthritis, acute synovitis, pancreatic
.beta.-cell disease; diseases characterized by massive neutrophil
infiltration; rheumatoid spondylitis, gouty arthritis and other
arthritic conditions, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoisosis, bone
resorption disease, allograft rejections, fever and myalgias due to
infection, cachexia secondary to infection, meloid formation, scar
tissue formation, ulcerative colitis, pyresis, influenza,
osteoporosis, osteoarthritis and multiple myeloma-related bone
disorder, acute myelogenous leukemia, chronic myelogenous leukemia,
metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis,
septic shock, and Shigellosis; Alzheimer's disease, Parkinson's
disease, cerebral ischemias or neurodegenerative disease caused by
traumatic injury; angiogenic disorders including solid tumors,
ocular neovasculization, and infantile haemangiomas; viral diseases
including acute hepatitis infection (including hepatitis A,
hepatitis B and hepatitis C), HIV infection and CMV retinitis,
AIDS<ARC or malignancy, and herpes; stroke, myocardial ischemia,
ischemia in stroke heart attacks, organ hyposia, vascular
hyperplasia, cardiac and renal reperfusion injury, thrombosis,
cardiac hypertrophy, thrombin-induced platelet aggregation,
endotoxemia and/or toxic shock syndrome, and conditions associated
with prostaglandin endoperoxidase syndase-2.
[0124] In addition, p38 inhibitors of this invention inhibit the
expression of inducible pro-inflammatory proteins such as
prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as
cyclooxygenase-2 (COX-2). Accordingly, additional p38-associated
conditions include edema, analgesia, fever and pain, such as
neuromuscular pain, headache, pain caused by cancer, dental pain
and arthritis pain. The inventive compounds also may be used to
treat veterinary viral infections, such as lentivirus infections,
including, but not limited to equine infectious anemia virus; or
retro virus infections, including feline immunodeficiency virus,
bovine immunodeficiency virus, and canine immunodeficiency
virus.
[0125] When the terms "p38 associated condition" or "p38 associated
disease or disorder" are used herein, each is intended to encompass
all of the conditions identified above as if repeated at length, as
well as any other condition that is affected by p38 kinase
activity.
[0126] The present invention thus provides methods for treating
such conditions, comprising administering to a subject in need
thereof an effective amount of at least one compound of Formula (I)
or a salt thereof. The methods of treating p38 kinase-associated
conditions may comprise administering compounds of Formula (I)
alone or in combination with each other and/or other suitable
therapeutic agents useful in treating such conditions. Exemplary of
such other therapeutic agents include corticosteroids, rolipram,
calphostin, CSAIDs, 4-substituted imidazo [1,2-A]quinoxalines as
disclosed in U.S. Pat. No. 4,200,750 and in S. Ceccarelli et al,
"Imidazo[1,2-a]quinoxalin-4-amines: A Novel Class of Nonxanthine
A.sub.1-Adenosine Receptor Antagonists," European Journal of
Medicinal Chemistry Vol.33, (1998), at pp. 943-955; Interleukin-10,
glucocorticoids, salicylates, nitric oxide, and other
immunosuppressants; nuclear translocation inhibitors, such as
deoxyspergualin (DSG); non-steroidal antiinflammatory drugs
(NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such
as prednisone or dexamethasone; antiviral agents such as abacavir;
antiproliferative agents such as methotrexate, leflunomide, FK506
(tacrolimus, Prograf); cytotoxic drugs such as azathiprine and
cyclophosphamide; TNF-.alpha. inhibitors such as tenidap, anti-TNF
antibodies or soluble TNF receptor, and rapamycin (sirolimus or
Rapamune) or derivatives thereof.
[0127] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may 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. In the methods of the present invention, such
other therapeutic agent(s) may be administered prior to,
simultaneously with, or following the administration of the
inventive compounds.
[0128] The present invention also provides pharmaceutical
compositions capable of treating p38-kinase associated conditions,
including TNF-.alpha., IL-1, and/or IL-8 mediated conditions, as
described above. The inventive compositions may contain other
therapeutic agents as described above and may be formulated, for
example, by employing conventional solid or liquid vehicles or
diluents, as well as pharmaceutical additives of a type appropriate
to the mode of desired administration (e.g., excipients, binders,
preservatives, stabilizers, flavors, etc.) according to techniques
such as those well known in the art of pharmaceutical
formulation.
[0129] The compounds of Formula (I) may be administered by any
means suitable for the condition to be treated, which may depend on
the need for site-specific treatment or quantity of drug to be
delivered. Topical administration is generally preferred for
skin-related diseases, and systematic treatment preferred for
cancerous or pre-cancerous conditions, although other modes of
delivery are contemplated. For example, the compounds may be
delivered orally, such as in the form of tablets, capsules,
granules, powders, or liquid formulations including syrups;
topically, such as in the form of solutions, suspensions, gels or
ointments; sublingually; bucally; parenterally, such as by
subcutaneous, intravenous, intramuscular or intrasternal injection
or infusion techniques (e.g., as sterile injectable aq. or non-aq.
solutions or suspensions); nasally such as by inhalation spray;
topically, such as in the form of a cream or ointment; rectally
such as in the form of suppositories; or liposomally. Dosage unit
formulations containing non-toxic, pharmaceutically acceptable
vehicles or diluents may be administered. The compounds may be
administered in a form suitable for immediate release or extended
release. Immediate release or extended release may be achieved with
suitable pharmaceutical compositions or, particularly in the case
of extended release, with devices such as subcutaneous implants or
osmotic pumps.
[0130] Exemplary compositions for topical administration include a
topical carrier such as PLASTIBASE.RTM. (mineral oil gelled with
polyethylene).
[0131] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may also be orally
delivered by sublingual and/or buccal administration, e.g., with
molded, compressed, or freeze-dried tablets. Exemplary compositions
may include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
GANTREZ.RTM.); and agents to control release such as polyacrylic
copolymer (e.g., CARBOPOL 934.RTM.). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0132] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which 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.
[0133] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0134] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0135] The effective amount of a compound of the present invention
may 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. It will be understood
that the specific dose level and frequency of dosage for any
particular subject may be varied and will depend upon a variety of
factors, including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
species, age, body weight, general health, sex and diet of the
subject, the mode and time of administration, rate of excretion,
drug combination, and severity of the particular condition.
Preferred subjects for treatment include animals, most preferably
mammalian species such as humans, and domestic animals such as
dogs, cats, horses, and the like. Thus, when the term "patient" is
used herein, this term is intended to include all subjects, most
preferably mammalian species, that are affected by mediation of p38
enzyme levels.
[0136] Compounds of formula (I), including the compounds described
in the examples hereof, have been tested in one or more of the
assays described below and have shown activity as inhibitors of
p38.alpha./.beta. enzymes and TNF-.alpha..
Biological Assays
[0137] Generation of p38 Kinases
[0138] cDNAs of human p38.alpha., .beta. and .gamma. isozymes were
cloned by PCR. These cDNAs were subcloned in the pGEX expression
vector (Pharmacia). GST-p38 fusion protein was expressed in E. Coli
and purified from bacterial pellets by affinity chromatography
using glutathione agarose. p38 fusion protein was activated by
incubating with constitutively active MKK6. Active p38 was
separated from MKK6 by affinity chromatography. Constitutively
active MKK6 was generated according to Raingeaud et al. [Mol. Cell.
Biol., 1247-1255 (1996)].
[0139] TNF-.alpha. Production by LPS-Stimulated PBMCs
[0140] Heparinized human whole blood was obtained from healthy
volunteers. Peripheral blood mononuclear cells (PBMCs) were
purified from human whole blood by Ficoll-Hypaque density gradient
centrifugation and resuspended at a concentration of
5.times.10.sup.6/ml in assay medium (RPMI medium containing 10%
fetal bovine serum). 50 ul of cell suspension was incubated with 50
ul of test compound (4.times. concentration in assay medium
containing 0.2% DMSO) in 96-well tissue culture plates for 5
minutes at RT. 100 ul of LPS (200 ng/ml stock) was then added to
the cell suspension and the plate was incubated for 6 hours at
37.degree. C. Following incubation, the culture medium was
collected and stored at -20.degree. C. TNF-.alpha. concentration in
the medium was quantified using a standard ELISA kit
(Pharmingen-San Diego, Calif.). Concentrations of TNF-.alpha. and
IC.sub.50 values for test compounds (concentration of compound that
inhibited LPS-stimulated TNF-.alpha. production by 50%) were
calculated by linear regression analysis.
[0141] p38 Assay
[0142] The assays were performed in V-bottomed 96-well plates. The
final assay volume was 60 .mu.l prepared from three 20 .mu.l
additions of enzyme, substrates (MBP and ATP) and test compounds in
assay buffer (50 mM Tris pH 7.5, 10 mM MgCl.sub.2, 50 mM NaCl and 1
mM DTT). Bacterially expressed, activated p38 was pre-incubated
with test compounds for 10 min. prior to initiation of reaction
with substrates. The reaction was incubated at 25.degree. C. for 45
min. and terminated by adding 5 .mu.l of 0.5 M EDTA to each sample.
The reaction mixture was aspirated onto a pre-wet filtermat using a
Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed with
PBS. The filtermat was then dried in a microwave oven for 1 min.,
treated with MeltilLex A scintillation wax (Wallac), and counted on
a Microbeta scintillation counter Model 1450 (Wallac). Inhibition
data were analyzed by nonlinear least-squares regression using
Prizm (GraphPadSoftware). The final concentration of reagents in
the assays are ATP, 1 .mu.M; [.gamma.-.sup.33P]ATP, 3 nM,; MBP
(Sigma, #M1891), 2.mu.g/well; p38, 10 nM; and DMSO, 0.3%.
[0143] TNF-.alpha. Production by LPS-Stimulated Mice
[0144] Mice (Balb/c female, 6-8 weeks of age, Harlan Labs;
n=8/treatment group) were injected intraperitoneally with 50 ug/kg
lipopolysaccharide (LPS; E coli strain 0111:B4, Sigma) suspended in
sterile saline. Ninety minutes later, mice were sedated by
CO.sub.2:O.sub.2 inhalation and a blood sample was obtained. Serum
was separated and analyzed for TNF-alpha concentrations by
commercial ELISA assay per the manufacturer's instructions (R&D
Systems, Minneapolis, Minn.).
[0145] Test compounds were administered orally at various times
before LPS injection. The compounds were dosed either as
suspensions or as solutions in various vehicles or solubilizing
agents.
Abbreviations
[0146] For ease of reference, the following abbreviations are
employed herein, including the methods of preparation and Examples
that follow:
[0147] Ph=phenyl
[0148] Bz=benzyl
[0149] t-Bu=tertiary butyl
[0150] Me=methyl
[0151] Et=ethyl
[0152] Pr=propyl
[0153] Iso-P=isopropyl
[0154] MeOH=methanol
[0155] EtOH=ethanol
[0156] EtOAc=ethyl acetate
[0157] Boc=tert-butyloxycarbonyl
[0158] CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
[0159] DCM=dichloromethane
[0160] DCE=1,2-dichloroethane
[0161] DMF=dimethyl formamide
[0162] DMSO=dimethyl sulfoxide
[0163] TFA=trifluoroacetic acid
[0164] THF=tetrahydrofuran
[0165] HATU=O-(7-Azabenzotriazol-1-yl-N,N,N',N'-tetramethyluronim
hexafluorophosphate
[0166] KOH=potassium hydroxide
[0167] K.sub.2CO.sub.3=potassium carbonate
[0168] POCl.sub.3=phosphorous oxychloride
[0169] KOtBu=potassium t-butoxide
[0170] EDC or EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
[0171] DIPEA=diisopropylethylamine
[0172] HOBt=1-hydroxybenzotriazole hydrate
[0173] m-CPBA=m-chloroperbenzoic acid
[0174] NaH=sodium hydride
[0175] NaOH=sodium hydroxide
[0176] Na.sub.2S.sub.2O.sub.3=sodium thiosulfate
[0177] Pd=palladium
[0178] Pd/C=palladium on carbon
[0179] min=minute(s)
[0180] L=liter
[0181] mL=milliliter
[0182] .mu.L=microliter
[0183] g=gram(s)
[0184] mg=milligram(s)
[0185] mol=moles
[0186] mmol=millimole(s)
[0187] meq=milliequivalent
[0188] RT or rt=room temperature
[0189] ret. t.=HPLC retention time (minutes)
[0190] sat or sat'd=saturated
[0191] aq.=aqueous
[0192] TLC=thin layer chromatography
[0193] HPLC=high performance liquid chromatography
[0194] RP HPLC=reverse phase HPLC
[0195] LC/MS=high performance liquid chromatography/mass
spectrometry
[0196] MS=mass spectrometry
[0197] NMR=nuclear magnetic resonance
[0198] mp=melting point
[0199] In the Examples, "HPLC Condition A" refers to YMC S5 ODS
4.6.times.50 mm Ballistic column, 4 mL/min flow rate, 4 min linear
gradient elution (Start solvent % B=0; Final solvent % B=100),
solvent A=10% MeOH/90% H.sub.2O/0.2% H.sub.3PO.sub.4.
Methods of Preparation
[0200] Compounds of formula I may generally be prepared according
to the following schemes and the knowledge of one skilled in the
art. In the schemes, the groups R.sub.1-R.sub.6, R.sub.10,
R.sub.13, R.sub.18, R.sub.23, X and Z are as described herein for
compounds of Formula (I). 12
[0201] An optionally substituted 2-formylpyrrole (1) is reacted
with an aminating reagent, such as hydroxylamine-O-sulfonic acid,
in an aq. solvent at rt, followed by treatment under cooling with a
base such as KOH, to form compound (2).
[0202] Compound (2) is reacted with an aq. base such as KOH at rt
to form compound (3). Compound (3) is reacted with an acylating
agent, such as formic acid, in an aq. solvent, to form compound
(4). Compound (4) is cyclized with a base such as sodium methoxide
in MeOH with heating to form compound (5). Compound (5) is
halogenated, e.g., with phosphorus oxybromide at elevated
temperature, to form compound (6). Compound (6) is reacted with an
amine such as an aniline in an organic solvent, such as
acetonitrile, to form product (7) of Scheme 1.
[0203] Compound (7) of Scheme 1 where R.sub.1=halogen can be
prepared from compound (7) of Scheme 1 where R.sub.1=hydrogen by
reaction with a halogenating agent such as bromine in a suitable
solvent such as acetic acid.
[0204] Compounds (1) may be obtained from substituted pyrroles by
formylation, e.g., by reaction with phosphorus oxychloride and DMF.
A methylpyrrole may be obtained by reduction of a formylpyrrole,
e.g., by reaction with lithium aluminum hydride. 13
[0205] Reacting an anion of tosylmethyl isocyanide (TosMIC) (1)
with a Michael acceptor such as ethyl crotonate provides
disubstituted pyrrole (2). Treatment of pyrrole (2) with an
acylating agent such as trichloroacetyl chloride in the presence of
a Lewis acid such as aluminum chloride at from rt to 50.degree. C.,
followed by treatment with sodium methoxide, affords trisubstituted
pyrrole (3). Compound (3) can be obtained by warming an aldehyde,
such as acetaldehyde, with 2 equivalents of ethyl isocyanoacetate
in the presence of a base, such as DBU, in an organic solvent, such
as THF. Alternatively, compound (3) can be obtained following the
procedure of M. Suzuki, M. Miyoshi, and K. Matsumoto J. Org. Chem.
1974, 39 (1980).
[0206] Pyrrole (3) can be aminated by an aminating reagent, such as
diphenyl phosphoryl hydroxylamine, in the presence of a base, such
as NaH, at rt in organic solvents, such as DMF, to form N-aminated
pyrrole (4). Compound (4) is cyclized by heating at from 120 to
195.degree. C. with formamide to afford 1,2,4-triazine (5).
Treatment of compound (5) with a halogenating agent, such as
phosphorous oxybromide, at from 60 to 115.degree. C., in the
presence or absence of a co-solvent such as DCE, affords compound
(6).
[0207] Compound (6) is reacted with an amine, such as an aniline in
an organic solvent, such as DMF, to obtain compound (7).
Alternatively, compound (7) can be obtained by treating (6) with an
anion of a heterocyclic compound, such as oxindole, in an organic
solvent such as THF.
[0208] An anion of TosMIC (1) can be made by treating a solution of
it in DMSO with a base such as NaH at rt or a solution of it in THF
with lithium hexamethyldisilazane at -78.degree. C. 14
[0209] A suitably N-protected ester of glycine, such as with benzyl
group, can be added to dialkyl methylene malonate at from rt to
80.degree. C. to obtain compound (1). Compound (1) is cyclized to
form pyrrole (2) upon treatment with a strong base, such as lithium
hexamethyldisilazane, at from -78.degree. C. to rt in an organic
solvent such as THF. Pyrrole (2) is alkylated by treatment with an
alkylating agent, such as iodomethane or dimethyl sulfate, in the
presence of a base, such as K.sub.2CO.sub.3, in an organic solvent,
such as acetone or DMF to yield compound (3).
[0210] Deprotection of compound (3) can be achieved, when
optionally protected by groups such as benzyl, by hydrogenation
over a catalyst, such as Pd, in the presence of ammonium formate.
Compound (4) is converted to compound (5) via cyclization as
described for compound (5) of Scheme 2.
[0211] Hydrolysis of the ester group in compound (5) can be
achieved by treatment with a base such as aq. KOH. The resulting
acid can be coupled with an amine in the presence of a coupling
agent, such as DCC or PyBrop. 15
[0212] Compound (5) from Scheme 3 can be converted to carboxylic
acid (1) (wherein R.sub.3 is methoxy or is as otherwise defined
herein) by treatment with a base such as aq. KOH. This acid
undergoes Curtis rearrangement by treatment with diphenyl
phosphoryl azide in the presence of an alcohol, such as benzyl
alcohol, in an organic solvent, such as 1,4-dioxane, to afford
compound (2).
[0213] The carbamate group of compound (2) can be deprotected, when
optionally protected by groups such as CBZ, by hydrogenation over a
catalyst, such as Pd, to obtain compound (3). The amino group of
compound (3) can be acylated to form compound (4), e.g., by
treatment with a carboxylic acid in the presence of a coupling
agent such as DCC, or sulfonylated, e.g., by treatment with a
sulfonyl chloride. Alternatively, the amino group of compound (3)
may be alkylated with alkyl halides or may undergo reductive
amination with aldehydes in the presence of a reducing agent, such
as sodium cyanoborohydride. 16
[0214] Suitably protected compound (1) (imino dicarboxylate) can be
cyclized by treatment with dialkyl oxalate in the presence of a
base, such as sodium methoxide, in an organic solvent, such as
MeOH. Compound (2) upon selective deprotection, such as with TFA
when optionally protected by tert-butyl ester, undergoes
decarboxylation to afford compound (3) where R.sup.1.dbd.H. This
step is omitted to form compound (3) where
R.sub.1.dbd.COOR.sup.21.
[0215] The hydroxy group of compound (3) can be etherified by
reaction with an alkylating agent, such as dimethyl sulfate.
Compound (4) can be deprotected by hydrogenation, when optionally
protected such as with a benzyl group, to obtain compound (5).
Compound (5) is then converted to compound (6) in an analogous
manner to that described for compound (4) of Scheme 3 and compounds
(4) through (7) of Scheme 2. 17
[0216] Compound (6) of Scheme 2 can be etherified at the
4-position, e.g., by treatment with phenoxide anion to form
compound (1). Reduction of compound (1) with a reducing agent, such
as DIBAL, in an organic solvent, such as toluene, affords alcohol
(2). Oxidation of the alcohol (2) can be achieved by treatment with
MnO.sub.2 at an elevated temperature in an organic solvent, such as
toluene, to form (3). Treatment of compound (3) with an oxidant,
such as m-CPBA in an organic solvent, such as DCM, followed by aq.
hydrolysis with a base, such as potassium bicarbonate, affords the
hydroxy compound (4).
[0217] Alkylation of the phenolic group of compound (4) with an
agent, such as iodomethane, in the presence of a base, such as NaH,
at from rt to 100.degree. C., affords compound (5). Hydrolysis of
compound (5) can be achieved by treatment with an acid, such as aq.
HCl, at an elevated temperature to afford (6). Compound (6) can be
converted to compound (7) with procedures analogous to those
described in Scheme 2. 18
[0218] Compound (3) from Scheme 6 can undergo a Wittig reaction,
e.g., with phosphonates such as methyl diethylphosphonoacetate, in
an organic solvent, such as DCE, in the presence of a base, such as
NaH, to afford compound (1). The double bond of compound (1) can be
hydrogenated by treatment with hydrogen in the presence of a
catalyst, such as Pd. Compound (2) can be converted to (3) by
procedures described in Scheme 2.
[0219] Hydrolysis of the ester, as described hereinbefore, followed
by coupling of the resulting acid with an amine in the presence of
a coupling agent, such as DCC, affords compound (4). 19
[0220] Commercially-available compound (1) can be reacted with
oxalyl chloride with heating and then concentrated in vacuo and
reacted with an amine R.sub.18NH.sub.2 in the presence of a base,
such as diisopropylamine, in an organic solvent, such as DCM to
yield compound (2). Compound (2) can be reacted with hydrogen in
the presence of a catalyst, such as Pd, in an alcoholic solvent,
such as EtOH, at rt to afford compound (3). Compound (3) can then
be used as in Scheme 9 to produce compounds (6) of Scheme 9. 20
[0221] 3-methyl-1-pyrrole-2,4-diethyl ester can be reacted with
chloramine in ether to produce compound (1). Reacting compound (1)
in formamide with acetic acid produces compound (2). Compound (2)
can be reacted with DIPEA and POCl.sub.3 in toluene to produce
compound (3). Compound (3) can be reacted with DIPEA and compound
(4) in DMF to produce compound (5). Compound (5) can be reacted in
THF with NaOH to produce an acid intermediate which upon treatment
with HOBt, EDCI and the appropriate amine (NR.sub.2R.sub.10) in DMF
produces compounds (6).
[0222] Compound (4) can be prepared by 1) reacting
commercially-available 4-amino-3-methylbenzoic acid and
N-(tert-butoxycarbonyl)anhydride in THF to produce a BOC-protected
aniline intermediate; 2) reacting the aniline intermediate with
-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt,
and DMF, followed by addition of methoxyamine hydrochloride and
DIPEA to produce a BOC-protected N-methoxyamide intermediate; and
3) reacting that methoxyamide intermediate in a solution of HCl in
dioxane to produce compound (4) as a hydrochloride salt.
Alternatively, compound (4) can be prepared as shown in Scheme 8.
21
[0223] A substituted hydroxamate (1) can be reacted with acid, such
as HCl, in anhydrous MeOH, to afford compound (2). Compound (2) can
be reacted with an aq. base such KOH with heating to form compound
(3). Compound (3) is reacted with an amine R.sub.18NH.sub.2 in the
presence of a coupling reagent, such as HATU, and a base such as
diisopropylamine, in an organic solvent, such as
N-methylpyrrolidinone to afford compounds (4). Alternatively,
compounds (4) may generally be prepared as outlined in Schemes 8
and 9. 22
[0224] Commercially-available compound (1a) can be reacted with a
sulfonyl chloride in the presence of a base, such as TEA, in an
organic solvent, such as DCM to yield compound (2). Reaction of
compound (2) with hydrogen in the presence of a catalyst, such as
Pd in a solvent, such as MeOH, yields compound (3). Reaction of
compound (3) with chloride (5) (compound 3 of scheme 9) in an
organic solvent, such as DMF, at rt affords compound (6).
[0225] Reaction of compound (6) with aq. KOH with heating affords
compound (7). Compound (7) can be reacted with an amine
R.sub.2NH.sub.2 in the presence of a coupling reagent, such as
EDCI, and a base such as diisopropylamine, in an organic solvent,
such as DMF to afford compound (8). 23
[0226] Chloropyrrolotriazine (1) (compound 3 of Scheme 9) can be
reacted with an aniline (1a) (e.g., compound 1 of Scheme 11) in
anhydrous DMF at rt to afford compound (2). Reaction of compound
(2) with an aq. base such as NaOH with heating affords compound
(3). Compound (3) can be reacted with an amine R.sub.2NH.sub.2 in
the presence of a coupling reagent, such as HOBt, with or without a
base such as diisopropylamine, in an organic solvent, such as DMF
to afford compound (4). Compound (4) can be reacted with hydrogen
in the presence of a catalyst, such as Pd/C, in an organic solvent,
such as MeOH to afford compound (5). Reaction of compound (5) with
an isocyanate in an organic solvent, such as DCE affords compound
(6). 24
[0227] Commercially-available compound (1a) (compound 1a of Schemes
11 and 12), can be reacted with carbonyl diimidazole and with an
amine R.sub.18NH.sub.2 in an organic solvent, such as DCE, to yield
compound (8). Reaction of compound (8) with hydrogen in the
presence of a catalyst, such as Pd, in an alcoholic solvent such as
EtOH affords compound (9). Reaction of (9) with chloride (1) in an
organic solvent, such as DMF, affords compound (10). Reaction of
(10) with aq. NaOH with heating affords product (11). Product (11)
can be reacted with an amine R.sub.2NH.sub.2 in the presence of a
coupling reagent, such as EDCI, and a base such as
diisopropylamine, in an organic solvent, such as DMF to afford
compound (7). 25
[0228] Glycine ethyl ester can be added to an alkyl alkoxy
methylene cyanoacetate at from rt to 80.degree. C. to obtain
compound (1). Compound (1) is cyclized to form pyrrole (2) upon
treatment with a strong base, such as lithium hexamethyldisilazane,
at from -78.degree. C. to rt in an organic solvent such as THF.
Pyrrole (2) is converted to a halide using sodium nitrite in an
organic solvent, such as DMF, and a halide source, such as CuBr to
yield compound (3). Compound (3) can be converted to compound (4)
using CuCN in an organic solvent such as NMP at elevated
temperatures. Alternatively, compound (2) can be directly converted
to compound (4) using sodium nitrite in an organic solvent, such as
DMF, and a cyanide source such as CuCN. Compounds (3) and (4) can
then be used as described in previous schemes (e.g., as compound 3
of Scheme 2), to form compounds of Formula (I) wherein R.sub.3 is
halogen or cyano.
[0229] In addition, other compounds of formula I may be prepared
using procedures generally known to those skilled in the art. In
particular, the following examples provide additional methods for
the preparation of the compounds of this invention.
[0230] The invention will now be further described by the following
working examples, which are preferred embodiments of the invention.
HPLC purifications were done on C18 reverse phase (RP) columns
using water MeOH mixtures and TFA as buffer solution. These
examples are illustrative rather than limiting. There may be other
embodiments that fall within the spirit and scope of the invention
as defined by the appended claims.
EXAMPLE 1
1-[2,3-Dihydro-6-(pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-1H-indol-1-yl]et-
hanone
[0231] 26
A. 4-Bromo-pyrrolo[2,1-f][1,2,4]triazine
[0232] A mixture of 50 mg (0.37 mmol) of
pyrrolo[2,1-f][1,2,4]triazin-4(3H- )-one [prepared as described in
S. A. Patil, B. A. Otter and R. S. Klein, J. Het. Chem., 31,
781-786 (1994)] and 0.5 g of phosphorus oxybromide was heated and
kept at 60.degree. C. for 20 min. under argon. A clear orange melt
was initially obtained which solidified to a yellow solid on
continued heating. Ice was added with vigorous stirring. The
mixture was extracted twice with EtOAc. The combined extracts were
washed with sat. NaHCO.sub.3 and brine, dried (MgSO.sub.4), and the
solvent removed to afford 63 mg of crude Compound A as an orange
oil which crystallized on standing. (M+H).sup.+=198.sup.+,
200.sup.+.
B. EXAMPLE 1
[0233] A solution of 60 mg (0.3 mmol) of Compound A and
1-acetyl-6-aminoindoline in 1.5 ml of acetonitrile was stirred
overnight at rt under argon. A white precipitate was obtained which
was removed by filtration. The filter cake was suspended in 10%
isopropanol/methylene chloride for extraction. Sat'd NaHCO.sub.3
was added and the mixture stirred until a solution was obtained.
The organic layer was separated and washed with brine, dried
(MgSO.sub.4), and the solvent removed. Purification by
chromatography on silica gel with EtOAc yielded 4% of Example 1 as
a white solid. (M+H).sup.+=294.
EXAMPLE 2
4-(2,3-Dihydro-1H-indol-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carb-
oxylic acid methyl ester
[0234] 27
A. Methylpyrrole-3-carboxylic acid methyl ester
[0235] To a 1.0 M solution of lithium hexamethyldisilazide in THF
(41 mL, 41 mmol) at -78.degree. C. was added dropwise over 45 min.
a solution of tosylmethyl isocyanide (8.1 g, 41 mmol) in THF. After
the reaction was stirred for an additional 45 min., a solution of
methyl crotonate in THF was added over 40 min. The reaction was
warmed to 25.degree. C. and stirred for 5 h. The reaction was
diluted with EtOAc and washed with sat. aq. NaHCO.sub.3. The
aqueous layer was extracted three times with EtOAc, dried
(Na.sub.2SO.sub.4), concentrated, and purified by chromatography on
silica gel eluting with a gradient of 20-30% EtOAc in hexanes to
provide Compound A.
B. 3-Methylpyrrole-2,4-dicarboxylic acid dimethyl ester
[0236] To a suspension of aluminum chloride (106.4 g, 798 mmol) in
DCE (700 mL) at -40.degree. C. under nitrogen was added dropwise
trichloroacetyl chloride (89 mL, 798 mmol). A solution of Compound
A (37 g, 266 mmol) in DCE (200 mL) was added. The reaction mixture
was gradually warmed to rt and stirred over the weekend (65 hr). A
cold and pre-prepared mixture of aluminum chloride (53.2 g) and
trichloroacetyl chloride (44.6 g) in DCE (450 mL) was added to the
reaction mixture. After an additional 24 hr, the mixture was
carefully poured into an ice-water bath (2 L) and the pH of the
solution adjusted to 2.0. The organic layer was separated and the
aqueous layer extracted with DCM. The combined organic extracts
were washed with 3 N HCl, brine, dried (Na.sub.2SO.sub.4), and
concentrated in vacuo to give a dark oil. This oil was dissolved in
MeOH (400 mL), and the resulting solution was cooled to 0.degree.
C. under nitrogen. To this solution was added sodium methoxide (25%
in MeOH) until the pH of the solution was 10. After 1 hr, the
mixture was concentrated and then diluted with ice water (1 L) and
the pH of the mixture was adjusted to 6. The mixture was extracted
with DCM (3.times.1 L). The combined extracts were washed with
NaHCO.sub.3, brine, dried (Na.sub.2SO.sub.4), and concentrated in
vacuo. The brown solid obtained was purified by chromatography on
silica gel eluting with EtOAc in hexanes to provide 44.3 g (84%) of
Compound B. MS: [M+H].sup.-=196.
C. 1-Amino-3-methylpyrrole-2,4-dicarboxylic acid dimethyl ester
[0237] To a suspension of NaH (60% in oil, 33 mg, 0.83 mmol) in DMF
(5 mL) at 0.degree. C. was added Compound B (46 g, 213 mmol) in DMF
(3 mL). After 10 min. at 0.degree. C., diphenyl phosphoryl
hydroxylamine (0.19 g, 0.83 mmol) was added neat followed by DMF (3
mL). The reaction mixture was stirred for 2 hrs at 25.degree. C.
and then quenched with pH 7 phosphate buffer (15 mL). The mixture
was extracted with EtOAc (4.times.20 mL). The combined extracts
were dried (Na.sub.2SO.sub.4) and after purification by
chromatography on silica gel eluting with 25-30% EtOAc in hexanes,
38 g (84%) of Compound C was obtained as white solid. ESI
[M+H].sup.-=213.1.
D. 5-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one-6-carboxylic acid
methyl ester
[0238] Compound C (38 g, 179 mmol) was combined with formamide (400
mL) and heated to 165.degree. C. for 6 hr. The reaction was diluted
with water (5 mL), extracted with EtOAc (3.times.10 mL), dried
(Na.sub.2SO.sub.4), and concentrated. The crude material was
purified by washing with ether/hexanes (7/3) to provide 33.4 g
(90%) of Compound D as a white solid. ESI MS: [M-H].sup.-=206.0
E.
4-Chloro-5-methyl-6-carbomethoxypyrrolo[2,1-f][1,2,4]triazine
[0239] 28
[0240] Phosphorous oxychloride (2.5 mL) was combined with Compound
D (100 mg, 0.483 mmol) and heated at 100.degree. C. overnight. The
melt was allowed to cool to rt and dissolved in EtOAc. The mixture
was neutralized with aq. NaHCO.sub.3 and extracted twice with
EtOAc. The combined organic washes were dried (Na.sub.2SO.sub.4),
and concentrated to provide 101 mg (93%) of Compound E. MS:
(M+H).sup.+=226.6.
F. EXAMPLE 2
[0241] A mixture of Compound E (20 mg, 0.09 mmol) and indoline (21
mg, 0.177 mmol) in CH.sub.3CN (1 mL) was shaken for 4 hrs. Then DMF
(0.2 mL) was added, and the crude mixture was purified by
preparative HPLC to provide 12.2 mg (45%) of Example 2 as a white
solid. [M+H].sup.+=309.2; .sup.1H NMR (CDCl.sub.3): .delta. 8.06
(s, 1H), 7.91 (s, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 6.93-6.91 (m,
2H), 4.15 (t, J=7.8 Hz, 2H), 3.81 (s, 3H), 3.09 (t, J=7.8 Hz, 2H),
2.35 (s, 3H).
EXAMPLES 3-6
[0242] 29
[0243] Compounds having the formula (Id), wherein the group R.sub.4
has the values listed in Table 1, were prepared following the
method of Example 2, using an appropriately-selected amine compound
in place of indoline in step F.
1TABLE 1 Ex. R.sub.4 Compound Name Data 3 30 4-[[3-
(Hydrazinocarbonyl)phenyl ]amino]-5-methylpyrrolo
[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester MS: [M +
H].sup.+ = 341.2; .sup.1H NMR(d-DMSO): .delta.7.79(s, 1H), 7.58(s,
1H), 7.11-7.05(m, 3H), 6.72(d, J=8.1Hz, 1H), 5.23(brs, 2H), 3.76(s,
3H), 2.67(s, 3H) 4 31 4-[3- (Acetylamino)phenyl]amin
o]-5-methylpyrrolo [2,1-f][1,2,4]triazine-6- carboxylic acid methyl
ester MS: [M + H].sup.+ = 340.2; .sup.1H NMR(CDCl.sub.3):
.delta.7.81(s, 1H), 7.75(s, 1H), 7.51(s, 1H), 7.20-7.07(m, 3H),
3.80(s, 3H), 2.84(s, 3H), 1.90 (s, 3H) 5 32
4-[(1-Acetyl-2,3-dihydro- 1H-indol-6-yl)amino]-5- methylpyrrolo
[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester MS: [M +
H].sup.+ = 366.2; .sup.1H NMR(CDCl.sub.3): .delta.8.14(d, J=8.6Hz,
1H), 7.95(s, 1H), 7.82(s, 1H), 7.51(s, 1H), 7.12 (d, J=8.6Hz, 1H),
4.03 (t, J=7.8Hz, 2H), 3.81 (s, 3H), 3.18(t, J=7.8 Hz, 2H), 2.67(s,
3H), 2.19(s, 3H) 6 33 5-Methyl-4-[[2-methyl-5-
[(methylsulfonyl)amino]phenyl]amin- o]pyrrolo
[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester MS: [M +
H].sup.+ = 390.2; .sup.1H NMR(CDCl.sub.3): .delta.8.04(brs, 1H),
7.95(s, 1H), 7.87(s, 1H), 7.09--6.99(m, 2H), 3.82(s, 3H), 3.00(s,
3H), 2.89 (s, 3H), 2.28(s, 3H)
EXAMPLE 7
4-(1H-Indazol-6-ylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxyli-
c acid methyl ester
[0244] 34
[0245] A mixture of Compound E from Example 2 (20 mg, 0.09 mmol)
and 6-aminoindazole (18 mg, 0.13 mmol) in CH.sub.3CN (1 mL) and
DMSO (0.5 mL) was shaken for 4 hrs. The mixture was filtered,
washed with CH.sub.3CN, and the crude material was purified by
preparative HPLC to provide Example 7 as a white solid (13 mg,
45%). [M+H].sup.+=323.1; .sup.1H NMR (CDCl.sub.3): .delta. 8.37 (s,
1H), 7.99 (s, 1H), 7.94 (d, J=7.4 Hz, 1H), 7.68 (d, J=4.2 Hz, 1H),
7.00 (dd, J=7.4, 4.2 Hz, 1H), 3.83 (s, 3H), 2.91 (s, 3H).
EXAMPLE 8
5-Methyl-4-[[3-[(methylsulfonyl)amino]phenyl]amino]pyrrolo[2,1-f][1,2,4]tr-
iazine-6-carboxylic acid methyl ester
[0246] 35
[0247] Compound E of Example 2 was dissolved in DMF (2 mL), and
then 3-(methylsulfonylamino)aniline(54 mg, 0.3 mmol) was added. The
reaction mixture was stirred for 4 hrs under argon at 25.degree. C.
The crude reaction mixture was purified by preparative HPLC. The
material obtained appeared to be a salt of the desired compound.
The material was dissolved in EtOAc and washed with sat'd
NaHCO.sub.3. Evaporating the solvent gave 24 mg (40%) of Example 8.
MS: [M+H].sup.+=376.2; .sup.1H NMR (d-DMSO): .delta. 8.89 (s, 1H),
8.14 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 7.34-7.32
(m, 2H), 7.01 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.02 (s, 3H), 2.82
(s, 3H).
EXAMPLE 9
4-[[3-(Aminosulfonyl)phenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-
-carboxylic acid methyl ester
[0248] 36
[0249] Compound E from Example 2 (20 mg, 0.09 mmol) was mixed with
3-aminobenzenesulfonamide (23 mg, 0.13 mmol) in DMF (1 mL) and
shaken for 4 hrs. Evaporating the extracting solvent and
purification by preparative HPLC gave 8.6 mg (58%) of Example 9 as
a solid. MS: [M+H].sup.+=362; .sup.1H NMR (d-DMSO): .delta. 9.08
(s, 1H), 8.18 (s, 2H), 7.98 (s, 1H), 7.91-7.89 (m, 1H), 7.62-7.58
(m, 2H), 7.42 (s, 2H), 3.81 (s, 3H), 2.84 (s, 3H)
EXAMPLES 10-14
[0250] 37
[0251] Compounds having the formula (Ie), wherein the groups Z,
R.sub.4, and R.sub.5 together have the values listed in Table 2,
were prepared following the method of Example 9, except instead of
3-aminobenzenesulfonamide, an appropriately-selected amino compound
was used.
2TABLE 2 Ex. -ZR.sub.4R.sub.5 Compound Name Data 10 38 4-[[3-
[(Butylamino)sulfonyl]phenyl]amino]-5- - methylpyrrolo
[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester MS: [M +
H].sup.+ = 418.2; .sup.1H NMR(CDCl.sub.3): .delta. 8.07(s, 1H),
7.97(s, 1H), 7.85(s, 1H), 7.84-7.82(m, 1H), 7.58(d, J=8.0Hz, 1H),
7.49-7.45(m, 2H), 3.82 (s, 3H), 2.93-2.89(m, # 2H), 2.81(s, 3H),
1.44-1.18(m, 4H), 0.84(t, J=7.4Hz, 3H) 11 39 4-[[3-(Aminosulfonyl)-
4-methylphenyl]amino]- 5-methylpyrrolo [2,1-f][1,2,4]triazine-6-
carboxylic acid methyl ester MS: [M + H].sup.+ = 376.2; .sup.1H
NMR(CDCl.sub.3): .delta. 8.05(s, 1H), 7.91(s, 1H), 6.97(d, J=7.8Hz,
1H), 6.31(s, 1H), 6.23(d, J= 7.8Hz, 1H), 4.22(t, J=7.7Hz, 2H),
3.84(s, 3H), 2.84(t, # J=7.7Hz, 2H), 2.55(s, 3H). 12 40
4-[[6-(Acetylamino)-3- pyridinyl]amino]-5- methylpyrrolo
[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester MS: [M +
H].sup.+ = 341.2; .sup.1H NMR (d-DMSO): .delta. 10.51 (s, 1H),
8.87(s, 1H), 8.53 (s, 1H), 8.14-8.01(m, 3H), 7.93(s, 1H), 3.80(s,
3H), 2.83(s, 3H), 2.32(s, 3H). 13 41 4-[(3,4-Dimethoxy-
phenyl)amino]-5- methylpyrrolo [2,1-f][1,2,4]triazine-6- carboxylic
acid methyl ester MS: [M + H].sup.+ = 343.2; .sup.1H NMR
(CDCl.sub.3): .delta. 7.91(s, 1H), 7.85(s, 1H), 7.21(s, 1H),
7.00(dd, J=8.6, 2.8 Hz, 1H), 6.82(d, J=8.6 Hz, 1H), 3.84-3.82(3s,
9H), 2.88(s, 3H) 14 42 4-(2,3-Dihydro-3-oxo- 1H-indazol-2-yl)-5-
methylpyrrolo[2,1- f][1,2,4]triazine-6- carboxylic acid methyl
ester MS: [M + H].sup.+ = 324.2; .sup.1H NMR (CDCl.sub.3): .delta.
9.65(s, 1H), 8.14(s, 1H), 7.85(s, 1H), 7.48(d, J=8.2Hz, 1H),
7.42-7.37(m, 2H), 7.14-7.12(m, 1H), 3.86 (s, 3H), 2.84(s, 3H) 15 43
4-[5-(Aminocarbonyl)- 2,3-dihydro-2-oxo-1H- indol-3-yl]-5-
methylpyrrolo[2,1- f][1,2,4]triazine-6- carboxylic acid methyl
ester MS: [M + H].sup.+ = 366.2; .sup.1H NMR
(CDC.sub.3/CD.sub.3OH): .delta.7.92(s, 1H), 7.76(s, 1H), 7.48(d,
J=8.0Hz, 1H), 7.25(s, 1H), 7.05(d, J=8.0Hz, 1H), 3.82(s, 3H),
2.25(s, 3H)
EXAMPLE 16
4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine--
6-carboxylic acid methyl ester
[0252] 44
[0253] A solution of oxindole (5.32 g, 40 mmol) in THF (150 ml) and
DMF (35 ml) was deoxygenated by purging with argon. This mixture
was placed in an ice bath, and NaH (60% in oil, 1.7 g, 42 mmol) was
added. After 30 min,
4-Chloro-5-methyl-6-carbomethoxypyrrolo[2,1-f][1,2,4]triazine
(Compound E of Example 2) (3.38 g, 15 mmol) was added. After 1 hr
at rt, the resulting mixture was neutralized with acetic acid. The
solvent was removed in vacuo. The residue was dissolved in DCM,
washed with brine, and dried (MgSO.sub.4). The solution was
concentrated to a solid residue which was triturated with DCM and
diethyl ether to afford the title compound as an orange solid (3.5
g, 72%). MS: [M+H].sup.+=323.1; .sup.1H NMR (CDCl.sub.3): .delta.
7.86 (s, 1H), 7.74 (s, 1H), 7.37 (s, 1H), 7.19 (d, J=7.6 Hz, 1H),
7.11 (t, J=7.6 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz,
1H), 3.84 (s, 3H), 2.34 (s, 3H).
EXAMPLE 17
4-(2,3-Dihydro-3-oxo-1H-indazol-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-
e-6-carboxylic acid methyl ester
[0254] 45
[0255] Example 17 above was prepared following the method of
Example 16, except 3-indazolinone was used in place of oxindole.
[M+H].sup.+=324; .sup.1H NMR (CDCl.sub.3): .delta. 8.16 (s, 1H),
8.02-7.99 (m, 2H), 7.83-7.81 (m, 1H), 7.58-7.54 (m, 1H), 7.46 (s,
1H), 3.87 (s, 3H), 2.66 (s, 3H).
EXAMPLE 18
4-(2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]-
triazine-6-carboxylic acid methyl ester
[0256] 46
[0257] To a 0.degree. C. mixture of NaH (60%, 5 mg, 0.106 mmol) in
DMF (0.5 mL) was added N-methyloxindole (22 mg, 0.15 mmol). The
reaction mixture was stirred for 10 min. at 0.degree. C. Compound E
of Example 2 (22 mg, 0.10 mmol) in DMF (1 mL) was added. The
reaction mixture was stirred for 45 min. at 25.degree. C. and then
quenched with pH 7 phosphate buffer. The mixture was extracted with
EtOAc. The combined extracts were dried (Na.sub.2SO.sub.4) and
purified by preparative HPLC to provide Example 18 as a yellow
solid. MS: [M+H].sup.+=337.2; .sup.1H NMR (CDCl.sub.3): .delta.
7.90 (s, 1H), 7.40 (s, 1H), 7.16 (m, 2H), 7.02 (t, J=7.6 Hz, 1H),
6.90 (d, J=7.6 Hz, 1H), 5.28 (s, 1H), 3.86 (s, 3H), 3.36 (s, 3H),
2.37 (s, 3H). 47
[0258] Compounds having the formula (1e), wherein the groups Z,
R.sub.4, and R.sub.5 together have the values listed in Table 3,
were prepared following the method of Example 18, except instead of
oxindole, an appropriately-substituted oxindole was used, and for
Examples 19 and 20, 2,3-dihydro-2-oxo-1H-benzimidazol (40.2 mg, 0.3
mmol) and (methylsulfonyl)amino]-2-oxo-1H-indole (90 mg, 0.4 mmol)
were used, respectively, in place of oxindole. After purification
by preparative HPLC, the desired material can be collected,
concentrated, and neutralized with aq. NaHCO.sub.3 or desilylated
with tetrabutylammonium fluoride.
3TABLE 3 Ex. -ZR.sub.4R.sub.5 Compound Name Data 19 48
4-(2,3-Dihydro-2-oxo- 1H-benzimidazol-1-yl)- 5-methylpyrrolo[2,1-
f][1,2,4]triazine-6- carboxylic acid methyl ester .sup.1H NMR
(CDCl.sub.3): .delta. 8.37 (s, 1H), 8.32(s, 1H), 7.95 (br, s, 1H),
7.21-7.10(m, 4H), 3.88(s, 3H), 2.51(s, 3H). 20 49 4-[2,3-Dihydro-5-
[(methylsulfonyl)amino]-2-oxo-1H-indol-3-yl]-5- methylpyrrolo[2,1-
f][1,2,4]triazine-6- carboxylic acid methyl ester .sup.1H NMR
(CD.sub.3OD): .delta.7.99(s, 1H), 7.69(s, 1H), 7.04-7.02(m, 2H),
6.92 (d, J=8.8Hz, 1H), 3.86 (s, 3H), 2.87(s, 3H), 2.39 (s, 3H). 21
50 4-[5-(Aminosulfonyl)- 2,3-dihydro-2-oxo-1H- indol-3-yl]-5-
methylpyrrolo[2,1- f][1,2,4]triazine-6- carboxylic acid methyl
ester MS: [M - H].sup.- = 400.1; .sup.1H NMR (CD.sub.3OD): .delta.
8.05 (s, 1H), 7.83(s, 1H), 7.65 (d, J=8.2Hz, 1H), 7.07 (d, J=8.3Hz,
2H), 3.84 (s, 3H), 2.28(s, 3H). 22 51 4-[2,3-Dihydro-5-[[(2-
hydroxyethyl)amino]sulf onyl]-2-oxo-1H-indol-3-
yl]-5-methylpyrrolo[2,1- f][1,2,4]triazine-6- carboxylic acid
methyl ester MS: [M + H].sup.+ = 446.2; .sup.1H NMR
(CDCl.sub.3/CD.sub.3OH): .delta.7.84(s, 1H), 7.55(s, 1H), 7.28(d,
J=8.6Hz, 1H), 7.20(s, 1H), 6.78(d, # J=8.6Hz, 1H), 3.78(s, 3H),
3.60(t, J=7.4Hz, 2H), 2.77(t, J=7.4Hz, 2H), 2.20(s, 3H). 234 52
4-[5- [(Dimethylamino)sulfon yl]-2,3-dihydro-2-oxo-
1H-indol-3-yl]-5- methylpyrrolo[2,1- f][1,2,4]triazine-6-
carboxylic acid methyl ester MS: [M + H].sup.+ = 430. .sup.1H NMR
(CDCl.sub.3): .delta. 9.56(s, 1H), 8.05(s, 1H), 7.65-7.54(m, 3H),
7.15(d, J=8.2Hz, 1H), 3.87(s, 3H), 2.73(s, 6H), 2.43 # (3H, s) 24
53 4-[2,3-Dihydro-5-
[(methylamino)sulfonyl]-2-oxo-1H-indol-3-yl]-5- methylpyrrolo[2,1-
f][1,2,4]triazine-6- carboxylic acid methyl ester MS: [M - H].sup.-
=414. .sup.1H NMR (CDCl.sub.3/CD.sub.3OH): .delta.7.98(s, 1H),
7.76(s, 1H), 7.54(s, 1H), 7.31(d, J=7.6Hz, 1H), 6.85(d, J=7.6Hz,
1H), 3.82(s, # 3H), 2.28(s, 3H), 2.21 (s, 3H).
EXAMPLE 25
5-Methyl-4-(1,2,3,4-tetrahydro-3-oxo-1-quinoxalinyl)pyrrolo[2,1-f][1,2,4]t-
riazine-6-carboxylic acid methyl ester
[0259] 54
[0260] Example 2, Compound E (23 mg, 0.1 mmol) was stirred with
1,2,3,4-tetrahydroquinoxalin-2-one (44.4 mg, 0.3 mmol) in DMF (0.5
mL) for 1 hr at 50.degree. C. Water was added, and the resulting
solid material was collected, washed with water, and dried. The
material was triturated with MeOH, filtered, and dried again to
provide 20 mg (59%) of Example 25 as a white solid. .sup.1H NMR
(d-DMSO): .delta. 8.30-8.25 (m, 2H), 7.12-7.03 (m, 2H), 6.83 (br s,
2H), 4.38 (s, 2H), 3.73 (s, 3H), 2.49 (s, 3H), 1.72 (s, 3H).
EXAMPLE 26
4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine--
6-carboxylic acid
[0261] 55
[0262] To a solution of Example 16 (3.3 g, 10.2 mmol) in MeOH (600
mL) was added KOH (1N aq. solution, 200 mL), and the mixture was
deoxygenated by purging with argon. The reaction mixture was heated
to 60.degree. C. for 20 hrs, then cooled and concentrated to about
50 mL. The residue was acidified with concentrated HCl to pH 4. The
yellow solid was collected, washed with water, and dried in vacuo
to afford the title compound (2.9 g, 92%). MS: [M+H].sup.+=307.1;
.sup.1H NMR (CD.sub.3OD): .delta. 7.94 (s, 1H), 7.71 (s, 1H),
7.18-7.10 (m, 2H), 6.94-6.86 (m, 2H), 2.45 (s, 3H).
EXAMPLE 27
4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methoxypyrrolo[2,1-f][1,2,4]triazine-
-6-carboxylic acid ethyl ester
[0263] 56
A.
[[(2-Ethoxy-2-oxoethyl)(phenylmethyl)amino]methylene]propanedioic
acid diethyl ester
[0264] N-benzylglycine ethyl ester (5.79 g, 30 mmol) was combined
with diethyl ethoxymethylene malonate (6.48 g, 30 mmol) and stirred
at 120.degree. C. for 1 hr. The crude material was used directly
for the next reaction.
B. 1-Phenylmethyl-3-hydroxypyrrole-2,4-dicarboxylic acid diethyl
ester
[0265] To a suspension of NaH (60% in oil, washed with hexanes, 500
mg, 12.5 mmol) in toluene (10 mL) was added Compound A (3.63 g, 10
mmol) in toluene (30 mL) dropwise at 50.degree. C. After 2 hr, the
mixture was poured into ice water and acidified with 1 N aq. HCl.
The mixture was extracted three times with EtOAc. The combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo.
The crude material was purified by chromatography on silica gel
eluting with 50% EtOAc in hexanes to provide 2.70 g (85%) of
Compound B as a pink oil.
C. 1-Phenylmethyl-3-methoxypyrrole-2,4-dicarboxylic acid diethyl
ester
[0266] Compound B (634 mg, 2 mmol) was stirred in acetone for 10
hrs at rt with methyl iodide (300 mg, 2.1 mmol) and K.sub.2CO.sub.3
(500 mg). The mixture was filtered, concentrated, and purified by
chromatography on silica gel eluting with 33% EtOAc in hexanes to
provide 470 mg (71%) of Compound C as a gel.
D. 3-methoxypyrrole-2,4-dicarboxylic acid diethyl
[0267] Compound C (27 g, 81.5 mmol) in EtOH (1 L) was mixed with
Pd/C (10%, 4 g) and ammonium formate (28 g) and hydrogenated at 40
psi at 90.degree. C. for 18 hrs. The reaction mixture was cooled to
rt, filtered, and concentrated. The crude material (brown oil) was
purified by chromatography on silica gel eluting with 25% EtOAc in
hexanes to provide 13 g (66%) of tan solid.
E. 1-Amino-3-methoxypyrrole-2,4-dicarboxylic acid diethyl ester
[0268] To a stirred suspension of NaH (60% in oil, 1.76 g, 70 mmol)
in DMF (350 mL) under nitrogen at 0.degree. C. was added dropwise a
solution of Compound D (13 g, 54 mmol) in DMF (200 mL). After 30
min, the mixture was diluted with DMF (750 mL), and then diphenyl
phosphoryl hydroxylamine (15.7 g, 67.4 mmol) was added and the
reaction mixture was allowed to warm to rt. After 6 hrs, the
mixture was concentrated and the residue diluted with water (1 L)
and extracted with EtOAc (3.times.1 L). The combined organic
extracts were dried (MgSO.sub.4), concentrated, and purified by
chromatography on silica gel eluting with 20% EtOAc in hexanes to
provide 13 g (93%) of solid.
F. 4-Hydroxy-5-methoxypyrrolo[2,1-f][1,2,4]triazine-6-carboxylic
acid ethyl ester
[0269] Compound E (100 mg, 0.39 mmol) was combined with formamide
(1 mL) and heated at 180.degree. C. for 6 hrs. The reaction mixture
was cooled to rt and diluted with water (5 mL). The solid which
formed was collected, washed with water, and dried to provide 70 mg
(76%) of Compound F.
G. 4-Chloro-5-methoxypyrrolo[2,1-f][1,2,4]triazine-6-carboxylic
acid ethyl ester
[0270] 57
[0271] Phosphorous oxychloride (1 mL) was combined with Compound F
(23.7 mg, 0.1 mmol) and heated at reflux for 2 hrs. The melt was
allowed to cool to rt and phosphorous oxychloride was removed on
rotary evaporator.
H. EXAMPLE 27
[0272] To a suspension of NaH (60%, 44 mg, 1.1 mmol) in THF (1 mL)
was added oxindole (133 mg, 1 mmol). The reaction mixture was
stirred for 20 min. at rt and Compound G (0.1 mmol) was added. The
reaction was stirred for 2 hrs at 25.degree. C. The crude material
was purified by preparative HPLC followed by chromatography on
silica gel eluting with EtOAc to provide 5.5 mg (16%) of Example 27
as a yellow solid. MS: [M+H].sup.+=353; .sup.1H NMR (CDCl.sub.3):
.delta. 8.42 (s, 0.4H), 8.10 (s, 0.6H), 7.79 (s, 1H), 7.75-6.88 (m,
4H), 4.33 (m, 2H), 3.57 (s, 3H), 1.37 (m, 3H).
EXAMPLE 28
5-Methyl-4-[[4-methyl-3-[(methylsulfonyl)amino]phenyl]amino]pyrrolo[2,1-f]-
[1,2,4]triazine-6-carboxylic acid methyl ester
[0273] 58
[0274] To a solution of Example 6 (16 mg, 51 .mu.mol) in pyridine
(1 mL) at 0.degree. C. was added
4-methyl-3-[(methylsulfonyl)aniline (4.4 .mu.L, 87 .mu.mol). The
reaction mixture was stirred for 1 hr at 0.degree. C. and then
warmed to 25.degree. C. and stirred for 4 hrs. Water (5 mL) was
added and the mixture was extracted with EtOAc (3.times.5 mL). The
combined organic extracts were washed with water (10 mL) and brine
(10 mL) and dried (Na.sub.2SO.sub.4). The crude material was
purified by chromatography on silica gel eluting with 2% MeOH in
chloroform to provide 6.9 mg (30%) of solid. MS: [M+H].sup.+=390.2;
.sup.1H NMR (CDCl.sub.3): .delta. 7.93 (s, 1H), 7.86 (s, 1H), 7.77
(s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=8.2 Hz,
1H), 6.25 (s, 1H), 3.82 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 2.24
(s, 3H)
EXAMPLE 29
[4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin--
6-yl]carbamic acid phenylmethyl ester
[0275] 59
[0276] To a solution of Example 26 (29 mg, 0.09 mmol) in
1,4-dioxane (0.6 mL) under Ar with powdered 4 .ANG. molecular
sieves was added TEA (10 .mu.L, 71 .mu.mol), diphenylphosphoryl
azide (15 .mu.L, 71 .mu.mol) and benzyl alcohol (12 .mu.L, 0.12
mmol). The reaction was warmed at 50.degree. C. for 15 hrs. The
mixture was concentrated in vacuo and chromatographed directly on
silica gel eluting with a gradient of 2-5% MeOH in chloroform to
provide 8 mg (50%) of an intermediate product as a white solid.
Phosphorous oxybromide (5 eq.) was combined with this intermediate
(16 mg, 0.054 mmol) and heated to 60.degree. C. for 20 min. The
melt was poured into ice water and extracted with EtOAc (4.times.5
mL). The extracts were washed with aq. NaHCO.sub.3, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in a mixture of CH.sub.3CN (0.5 mL) and DMF (0.1 mL), and
then 5-amino-o-cresol (10 mg, 0.081 mmol) was added. The reaction
mixture was stirred overnight under argon at 25.degree. C. Solvent
was removed in vacuo, and the crude material was purified by rotary
chromatography on a 1 mm silica gel plate eluting with 2% MeOH in
chloroform to afford the title compound as yellow oil (5 mg, 13%).
MS: [M+H].sup.+=414; .sup.1H NMR (CDCl.sub.3): .delta. 7.94 (s,
1H), 7.82 (s, 1H), 7.41-7.34 (m, 5H), 7.17-7.14 (m, 1H), 7.04-7.02
(m, 1H), 6.93-6.90 (m, 2H), 6.44 (s, 1H), 5.23 (s, 2H), 2.12 (s,
3H).
EXAMPLE 30
4-(2,3-Dihydro-6-methyl-2-oxo-1H-pyrazolo[2,3-d]pyrimidin-3-yl)-5--methylp-
yrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester
[0277] 60
A. 6-Methyl-5,7-diazaoxindole
[0278] To a solution of ethyl (4-amino-2-methylpyrimidin-5-yl)
acetate (WO 99/10349, 0.975 g, 5 mmol) in THF (30 ml), was slowly
added potassium t-butoxide (1 M in THF, 5 mL). After one hour, the
mixture was neutralized with acetic acid to pH 5. The volatiles
were removed in vacuo and the residue purified by flash column
chromatography (silica gel, 5-8% MeOH in DCM) to afford a yellow
solid (680 mg, 91%).
B. Methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl
ester
[0279] To a solution of 6-methyl-5,7-diazaoxindole (67 mg, 0.45
mmol) in DMF (2 ml) and THF (1 ml) was added NaH (60% in oil, 20
mg, 0.5 mmol). After stirring for 20 min, Compound E of Example 2
(34 mg, 0.15 mmol) was added. The mixture was stirred at rt
overnight and then neutralized with acetic acid. DCM (10 ml) was
added and the resulting precipitate was collected and washed with
small amounts of DCM and water and then dried in vacuo to give the
title compound as an orange solid (32 mg, 63%). MS: (M+H)=359
EXAMPLE 31
4-(2,3-Dihydro-2-oxo-1H-pyrazolo[2,3-b]pyridin-3-yl)-5-methylpyrrolo[2,1-f-
][1,2,4]triazine-6-carboxylic acid methyl ester
[0280] 61
[0281] To a solution of 7-azaoxindole (see Tetrahedron.Lett., Vol.
28 (1987), at p. 4027) (60 mg, 0.45 mmol) in DMF (2 mL) and THF (1
mL) was added NaH (60% in oil, 20 mg, 0.5 mmol). After stirring for
20 min, Compound E of Example 2 (34 mg, 0.15 mmol) was added, and
the mixture was stirred at rt overnight. The solution was
neutralized with acetic acid, and then DCM (10 ml) was added to the
mixture. The resulting solid was collected, washed with small
amounts of DCM and water and dried in vacuo to give a yellow solid
(35 mg, 72%). LC-MS: (M+H).sup.+=324.
EXAMPLE 32
4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxy-
lic acid methyl ester
[0282] 62
[0283] Example 2 was following using 2-methoxycarbonyl pyrrole as
the starting pyrrole to afford
4-chloro-6-carbomethoxypyrrolo[2,1-f][1,2,4]tr- iazine, which was
then converted to Example 32 using the same or similar procedure of
Example 31.
EXAMPLES 33-36
[0284] 63
[0285] Compounds having the formula (If), wherein R.sub.15 has the
values listed in Table 4, were prepared by following the procedure
of Example 32 using appropriate reagents known in the literature
(see, WO 97/42187).
4TABLE 4 Ex. R.sub.15 Compound name 33 F
4-[6-Fluoro-2-hydroxy-1H-indol-3-yl]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester
34 Br 4-[6-Bromo-2-hydroxy-1H-indol-3-yl]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester
35 CF.sub.3 4-[2,3-Dihydro-2-oxo-6-(trifluoromethyl)- 1H-indol-3-
yl]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxyl- ic acid
methyl ester 36 SO.sub.2Me 4-[2,3-Dihydro-6-(methy-
lsulfonyl)-2-oxo-1H-indol-3- yl]-5-methylpyrrolo[2,1-f][1,2,4]tri-
azine-6-carboxylic acid methyl ester
EXAMPLES 37-49
[0286] 64
[0287] To Example 26 (50 mg, 0.16 mmol) in DMF (1 mL) and DCM (0.5
mL) were added PyBrop (113 mg, 0.24 mmol) and DIPEA (0.08 mL, 0.5
mL). After 10 min, an appropriate amine was added. After 15 h, the
reaction mixture was purified by preparative RP HPLC to provide the
compounds of formula (Ig), above, wherein R.sub.2 and R.sub.10 have
the values listed in Table 5.
5TABLE 5 EX. R.sub.2 R.sub.10 Compound Name 37 65 CH.sub.3
4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-N,5-dimethyl-N-[2-(1-
pyrrolidinyl)ethyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide 38
66 H 4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[2-(1-
pyrrolidinyl)ethyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide 39
67 H 4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[3-(4-
morpholinyl)propyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide 40
68 H 4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[2-(4-
morpholinyl)ethyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide 41
69 H 4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[3-(4-methyl-
-1- piperazinyl)propyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide
42 70 H 4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[3-(1H-1-
,2,3-triazol- 1-yl)propyl]pyrrolol[2,1-
f][1,2,4]triazine-6-carboxamide 43 71 H
4-(2,3-Dihydro-2-oxo-1H-indol-3-
yl)-5-methyl-N-[3-(2H-1,2,3-triazol- 2-yl)propyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 44 72 H
4-(2,3-Dihydro-2-oxo-1H-indol-3-
yl)-5-methyl-N-[3-(1H-1,2,4-triazol- 1-yl)propyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 45 73 H
4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[3-(2-methyl-1H-
imidazol-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazine-6- carboxamide
46 74 H 4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methyl-N-[4-(4-
morpholinyl)butyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide 47
75 CH.sub.3 4-(2,3-Dihydro-2-oxo-1H-indol-3-
yl)-N,5-dimethyl-N-[3-(4- morpholinyl)propyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 48 H H
4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-5-methylpyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 49 H CH.sub.3
4-(2,3-Dihydro-2-oxo-1H-indol-3- yl)-N,5-dimethylpyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide
EXAMPLES 50-52
[0288] 76
[0289] Compounds having formula (Ih), wherein R.sub.15a and
R.sub.15b have the values listed in Table 6 below, were prepared by
the following process, using the appropriately substituted oxindole
in step C.
A. 5-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one-6-carboxylic
acid
[0290] To a solution of
5-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one-6-c- arboxylic acid
methyl ester (Compound D from Example 2, 1.035 g, 5.00 mmol) in a
mixture of THF/MeOH/water (50 mL, 3:1:1) was added lithium
hydroxide (2.062 g, 49.1 mmol). The reaction mixture was stirred at
55.degree. C. for 12 h, then cooled to 0.degree. C. and neutralized
by 3N HCl. The organic solvents were removed and the aqueous
solution brought to pH 4 with 1 N HCl. The resulting precipitate
was filtered, rinsed with cold water, and air dried to afford
Compound A as an off-white solid (0.965 g, 100%).
B.
4-Chloro-5-methyl-N-[3-(4-morpholinyl)propyl]pyrrolo[2,1-f][1,2,4]triaz-
ine-6-carboxamide
[0291] A suspension of Compound A (2.00 g, 10.4 mmol) in
phosphorous oxychloride (8 mL) was stirred at 100.degree. C. over 4
h. The solvent was removed in vacuo using toluene to assist in the
removal. The resulting green solid was suspended in acetonitrile
(20 mL) at 0.degree. C. and treated with sufficient TEA (5 mL) to
bring the solution to pH 10. 4-(3-aminopropyl)morpholine (1.5 mL,
10.3 mmol) was added, and the solution was allowed to stir at rt
over 1 h. The reaction mixture was poured into saturated sodium
bicarbonate solution and extracted with EtOAc. The organic layer
was dried (MgSO.sub.4) and the volatiles were removed in vacuo to
afford Compound B as a yellow solid (1.75 g, 50%).
C. EXAMPLES 50-52
[0292] To a solution of an appropriately substituted oxindole,
i.e., 5-fluoro oxindole for Example 50 (36 mg, 0.24 mmol) in DMF (1
mL) was added NaH (5.9 mg, 0.23 mmol). After 30 min at rt, a
solution of Compound B (24 mg, 0.072 mmol) in DMF (1 mL) was added
and the resulting mixture was stirred at rt over 1 h. The solvent
was removed in vacuo and the mixture purified by RP HPLC. MeOH in
the desired HPLC fractions was removed in vacuo and the resulting
aq. solution neutralized using sat'd sodium bicarbonate solution,
then extracted with EtOAc. The organic layer was dried (MgSO.sub.4)
and the volatiles were removed in vacuo. The solid obtained was
dissolved in acetonitrile/MeOH and treated with 1 N HCl in diethyl
ether. The mixture was stirred at rt over 1 h and the solvents
removed in vacuo. The HCl salt of the title compound was obtained
as an orange solid (18 mg, 51%).
6TABLE 6 Ex. R.sub.15a R.sub.15b Compound Name Data 50 F H
4-(5-Fluoro-2,3-dibydro-2-oxo- MS: 1H-indol-3-yl)-5-methyl-N-[ (M +
H).sup.+ = 3-(4-morpholinyl)propyl]pyrrolo 453.
[2,1-f][1,2,4]triazine-6- carboxamide 51 H F
4-(6-Fluoro-2,3-dihydro-2-oxo- -- 1H-indol-3-yl)-5-methyl-N-[
3-(4-morpholinyl)propyl]pyrro- lo [2,1-f][1,2,4]triazine-6-
carboxamide; 52 --SO.sub.2NH.sub.2 H 4-[5-(Aminosulfonyl)-2,3- --
dihydro-2-oxo-1H-indol-3-yl]-5- methyl-N-[3-(4-morpholinyl)
propyl]pyrrolo[2,1-f][1,2,4] triazine-6-carboxamide
EXAMPLE 53
4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine--
6-propanoic acid methyl ester
[0293] 77
A.
4-Phenoxy-5-methyl-6-carbomethoxypyrrolo[2,1-f][1,2,4]triazine
[0294] To a solution of phenol (705 mg, 7.5 mmol) in a mixture of
THF (10 mL) and DMF (10 mL) was added NaH (60% in oil, 300 mg, 7.5
mmol). After 30 min,
4-chloro-5-methyl-6-carbomethoxypyrrolo[2,1-f][1,2,4]triazine (675
mg, 3.0 mmol--Compound E from Example 2) was added. After 1 h, the
solvent was removed and the residue poured into 5% aq.
K.sub.2CO.sub.3 solution. The precipitate was collected, washed
with water, and dried in vacuo to afford Compound A as white solid
(800 mg, 94%). MS: (M+H).sup.+=284.
B.
4-Phenoxy-5-methyl-6-hydroxymethylpyrrolo[2,1-f][1,2,4]triazine
[0295] To a solution of Compound A (700 mg, 2.47 mmol) in toluene
(20 mL) at -60.degree. C., was added DIBAL (1.5 M in toluene, 6
mmol). After stirring at 0.degree. C. for 1 h, aq. 1N HCl (30 mL)
was added and the mixture stirred for 30 min. The mixture was then
diluted with DCM. The organic layer was separated, dried
(MgSO.sub.4), and concentrated. The residue was purified by flash
column chromatography (silica gel, 2% MeOH in DCM) to afford
Compound B as a solid (610 mg, 96%). MS: (M+H).sup.+=256.
C.
4-Phenoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxaldehyde
[0296] A mixture of Compound B (500 mg, 1.96 mmol) and MnO.sub.2
(3.0 g) in toluene (30 mL) was heated at 60.degree. C. for 1 h.
After cooling to rt, the mixture was filtered through a pad of
silica gel and washed with EtOAc. After concentration in vacuo,
Compound C was obtained as a white solid (420 mg, 85%). MS:
(M+H).sup.+=254
D. 4-Phenoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-propenoic acid
methyl ester.
[0297] DBU (1.42 mL, 9.49 mmol) was added to a solution of Compound
C (600 mg, 2.37 mmol) and methyl diethylphosphonoacetate (1.74 mL,
9.49 mmol) in DCE (20 mL). After stirring at rt overnight, the
reaction mixture was diluted with DCM and washed with aq. 2% citric
acid, brine, dried (MgSO.sub.4), and concentrated. The organic
extract was concentrated and the residue purified by chromatography
on silica gel and elution with 20% EtOAc/DCM to afford a white
solid (710 mg. 97%). MS: (M+H).sup.+=310.
E. 4-Hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-propanoic acid
methyl ester.
[0298] Pd/C (10%, 70 mg) was added to a solution of Compound D (710
mg, 2.30 mmol) in a solvent mixture EtOAc/MeOH/THF/AcOH (100 mL/100
mL/20 mL/2 mL). The suspension was stirred under hydrogen for 2 h.
The reaction mixture was passed through Celite, the Celite was
washed with MeOH, and the filtrate was concentrated in vacuo to
give crude product. Trituration with hexanes afforded Compound E as
a white solid (430 mg, 88%). MS:(M+H).sup.+=236.
F. 4-Chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-propanoic acid
methyl ester.
[0299] A mixture of DIPEA (0.24 mL, 1.4 mmol), Compound E (220 mg,
0.94 mmol) and POCl.sub.3 (3 mL) was heated in a sealed bottle at
80.degree. C. After 2 h, the mixture was cooled down to rt and
concentrated in vacuo to give a residue. The residue was
partitioned between DCM and aq. NaHCO.sub.3 solution. The DCM layer
was separated, dried (MgSO.sub.4), and concentrated in vacuo to
give a dark green solid. Purification by chromatography on silica
gel and elution with 20% EtOAc/DCM afforded Compound F as a yellow
solid (220 mg, 92%). MS: (M+H).sup.+=254.
G.
4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazi-
ne-6-propanoic acid methyl ester.
[0300] NaH (60% in oil, 28 mg, 0.71 mmol) was added to a solution
of oxindole (94 mg, 0.71 mmol) in DMF (2 mL) under argon. The
mixture was stirred for 10 min. and Compound F (60 mg, 0.24 mmol)
was added. After 1 h at RT, the reaction was quenched by the
addition of acetic acid and diluted with DCM. The organic solution
was washed with water, dried (MgSO.sub.4), and concentrated in
vacuo to give crude product. Purification by chromatography on
silica gel and elution with 20% EtOAc/DCM afforded the title
compound as a pure yellow solid (78 mg, 94%). MS:
(M+H).sup.+=351.
EXAMPLE 54
1,3-Dihydro-3-[5-methoxy-6-(phenylmethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-y-
l]-2H-indol-2-one
[0301] 78
A. 4-Hydroxy-5-methoxypyrrolo[2,1-f][1,2,4]triazine-6-methanol
[0302]
4-Hydroxy-5-methoxypyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid
ethyl ester (Compound F of Example 27 -3.56 g, 15 mmol) was
combined with lithium tri-tert-butoxyaluminohydride (1 M solution
in THF, 60 mL, 60 mmol) and heated at reflux overnight. The
reaction mixture was allowed to cool to rt and quenched with 1 N
aq. HCl. The mixture was concentrated to remove volatiles and the
remaining material was combined with 100 g of silica gel and
applied to a flash silica gel column which was eluted with EtOAc to
provide 2.65 g (90%) of Compound A. MS: [M+H].sup.+=196.
B. 2,2-Dimethylpropanoic acid
[6-(hydroxymethyl)-5-methoxy-4-oxopyrrolo[2,-
1-f][1,2,4]triazin-3(4H)-yl]methyl ester
[0303] Compound A (195 mg, 1 mmol) was dissolved in 1.5 mL of DMF.
NaH (60% in oil, 48 mg, 1.2 mmol) was added and the reaction
mixture was stirred at rt for 0.5 hr. Chloromethyl pivalate (181
mg, 1.2 mmol) was added and the mixture was stirred for 1 hr. Water
was added and the mixture was extracted with EtOAc (3.times.10 mL).
The combined extracts were dried (Na.sub.2SO.sub.4), concentrated
in vacuo and purified by flash column chromatography on silica gel
eluting with 33% EtOAc in hexanes to provide 260 mg (84%) of
Compound B as a solid. MS: [M+H].sup.+=310.
C. 2,2-Dimethylpropanoic acid
[6-formyl-5-methoxy-4-oxopyrrolo[2,1-f][1,2,-
4]triazin-3(4H)-yl]methyl ester
[0304] Compound B (740 mg, 2.39 mmol) was suspended in toluene (10
mL) with manganese dioxide (835 mg, 9.6 mmol) and heated at
100.degree. C. for 3 hr. The reaction mixture was cooled to rt,
filtered, and the precipitate was washed with EtOAc. The filtrate
was concentrated in vacuo to provide 660 mg (90%) of Compound C as
a solid. MS: [M+H].sup.+=308.
D. 2,2-Dimethylpropanoic acid
[6-formyloxy-5-methoxy-4-oxopyrrolo[2,1-f][1-
,2,4]triazin-3(4H)-yl]methyl ester
[0305] 79
[0306] Compound C (660 mg, 2.15 mmol) was dissolved in
CH.sub.2Cl.sub.2 (10 mL). M-chloroperoxybenzoic acid (57%, 745 mg,
2.46 mmol) was added with MgSO.sub.4 (2.0 g), and the reaction
mixture was stirred at rt for 5 hr. The mixture was filtered and
the filtrate washed with aq. NaHCO.sub.3 solution twice, dried
(MgSO.sub.4), and concentrated to provide 680 mg (98%) of Compound
D as a solid. MS: [M+H].sup.+=324.
E. 2,2-Dimethylpropanoic acid
[5-methoxy-4-oxo-6-(phenylmethoxy)pyrrolo[2,-
1-f][1,2,4]triazin-3(4H)-yl]methyl ester
[0307] Compound D (680 mg, 2.10 mmol, 1 eq) was dissolved in
acetone (10 mL) followed by the addition of benzyl bromide (430 mg,
2.5 mmol) and K.sub.2CO.sub.3 (1.0 g, 7.25 mmol). The reaction
mixture was stirred at 60.degree. C. for 10 hr, cooled to rt, and
filtered. The filtrate was concentrated and purified by flash
silica gel chromatography eluting with 25% EtOAc in hexanes to
provide 485 mg (60%) of Compound E as a gel. MS:
[M+H].sup.+=386;
F.
5-Methoxy-6-(phenylmethoxy)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one
[0308] Compound E (65 mg, 0.17 mmol) was stirred at rt in a mixture
of MeOH (1 mL) and ammonium hydroxide (0.2 mL) for 6 hrs. The
mixture was concentrated in vacuo, dissolved in CH.sub.2Cl.sub.2,
and purified by flash silica gel chromatography eluting with 33%
EtOAc in hexanes to provide 45 mg (97%) of compound F as a solid.
MS: [M+H].sup.+=272.
G.
4-Chloro-5-methoxy-6-(phenylmethoxy)pyrrolo[2,1-f][1,2,4]triazine
[0309] Compound F (44 mg, 0.16 mmol) was stirred with POCl.sub.3
(0.5 mL) at 60.degree. C. for 3 hr. The mixture was concentrated in
vacuo, dissolved in CH.sub.2Cl.sub.2 (2 mL), and stirred with solid
NaHCO.sub.3 for 10 min. The mixture was filtered and concentrated
to provide 46 mg (99%) of Compound G as a solid. MS:
[M+H].sup.+=286. (The Cl substituent may be replaced with OCH.sub.3
upon standing in MeOH); R.T.=3.265 min (YMC S5 ODS column
4.6.times.50 mm, 10-90% aq. MeOH over 4 minutes containing 0.2%
phosphoric acid, 4 mL/min, monitoring at 220 nm); .sup.1H NMR
(CDCl.sub.3): .delta. 8.01 (s, 1H), 7.45-7.30 (m, 6 H), 5.15 (s,
2H), 4.03 (s, 3H).
H.
1,3-Dihydro-3-[5-methoxy-6-(phenylmethoxy)pyrrolo[2,1-f][1,2,4]triazin--
4-yl]-2H-indol-2-one
[0310] To a suspension of NaH (60% in oil, 19.2 mg, 0.48 mmol) in
DMF (0.5 mL) was added oxindole (63.4 mg, 0.48 mmol). The reaction
mixture was stirred for 1 hr at RT. Compound G (38 mg, 0.16 mmol, 1
eq) was added, and the mixture was stirred for 1 hr. The mixture
was diluted with water and filtered. The resulting solid was
triturated with MeOH and dried to provide 38 mg (62%) of the titled
compound. MS: [M+H].sup.+=387; .sup.1H NMR (d-DMSO): .delta. 12.83
(br s, 1H), 10.64 (br s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.50-7.31
(m, 6H), 7.02-6.94 (m, 1H), 6.89-6.82 (m, 2H), 5.10 (s, 2H), 3.55
(s, 3H).
EXAMPLES 55-60
[0311] 80
[0312] Compounds having the formula (Ii), wherein R.sub.16a,
R.sub.16b, and R.sub.16c have the values listed in Table 7, below,
were prepared following the procedure described for Example 54,
except using a different phenylamine.
7TABLE 7 Ex R.sub.16a R.sub.16b R.sub.16c Compound Name Data 55 F H
CH.sub.3 4-[(5-Fluoro-2- [M + H].sup.+ = 315.2; .sup.1H
methylphenyl)amino]-5- NMR (CDCl.sub.3) .delta. methylpyrrolo
7.97(brs, 1H), 7.94 [2,1-f][1,2,4]triazine-6- (s, 1H), 7.88(s, 1H),
carboxylic acid methyl 7.13(t, J=8.2Hz, ester 1H), 6.77(dt, J=2.7,
8.3Hz, 1H), 3.87(s, 3H), 2.82(s, 3H), 2.27(s, 3H) 56 81 H CH.sub.3
4-[[5- [(Ethylamino)carbonyl]- 2-methylphenyllamino]-
5-methylpyrrolo [2,1-f][1,2,4]triazine-6- carboxylic acid methyl
ester [M + H].sup.+ = 368.23; .sup.1H NMR (CDCl.sub.3)
.delta.8.17(brs, 1H), 7.92 (s, 1H), 7.83(s, 1H), 7.46(d, J=7.8Hz,
1H), 7.23(d, J=7.7 Hz, 1H), 3.82(s, 3H), 3.40(M, 2H), 2.88(s, 3H),
2.30(s, 3H), 1.85(m, 3H). 57 H F CH.sub.3 4-[(4-Fluoro-2- [M +
H].sup.+ = 315.1; .sup.1H methylphenyl)amino]-5- NMR (CDCl.sub.3)
.delta. methylpyrrolo 7.99(s, 1H), 7.87(s,
[2,1-f][1,2,4]triazine-6- 1H), 7.68(brs, 1H), carboxylic acid
methyl 6.99(m, 2H), 3.88 ester (s, 3H), 2.85(s, 3H), 2.31(s, 3H).
58 H F H 4-[(4- [M + H].sup.+ = 301.1; .sup.1H
Fluorophenyl)amino]-5- NMR (CDCl.sub.3) .delta. methylpyrrolo
7.94(s, 1H), 7.85(s, [2,1-f][1,2,4]triazine-6- 1H), 7.54(m, 2H),
carboxylic acid methyl 7.05(t, J=8.8Hz, ester 2H), 3.82(s, 3H),
2.82(s, 3H). 59 82 H CH.sub.3 4-[[5-[[(3-
Methoxyphenyl)amino]carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo[2,1- f][1,2,4]triazine-6- carboxylic acid methyl
ester [M + H].sup.+ = 446.2. 60 83 H CH.sub.3
5-Methyl-4-[2-methyl-5- [(methylamino)
carbonyl]phenoxy]pyrrolo[2,1-f][1,- 2,4]triazine-6- carboxylic acid
methyl ester [M + H].sup.+ = 355.1.
EXAMPLE 61
N-Cyclobutyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-
pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide
[0313] 84
[0314] The compound of Example 61 was prepared as set forth below,
using the Scheme 9 described above, wherein Compounds (A)-(E) have
the structures indicated below.
[0315] A. 85
[0316] To a solution of the 3-methyl-1-pyrrole-2,4-diethyl ester
(100 mg) (J. Heterocyclic Chem Vol. 34 (1997), at pp. 177-193;
Heterocycles, Vol. 50 (1999), at pp. 853-866; Synthesis (1999), at
pp. 479-482) in DMF (0.44M) was added either NaH or KOtBu (1.2
equiv) at rt. This solution was stirred for 30-45 minutes.
Chloramine in ether (ca. 0.15M, 1 eq.) was added via syringe. The
solution was stirred for 1.5 h or until starting material was
converted to product as judged by HPLC analysis. The reaction was
then quenched with aq. Na.sub.2S.sub.2O.sub.3 and extracted with
EtOAc or Et.sub.2O. The organic extracts were washed with water and
brine and then dried over sodium sulfate. Compound A was obtained
in >90% yield. NH.sub.2Cl in ether was prepared according to the
procedure of Nunn, J. Chem. Soc. (C), (1971) at p. 823.
[0317] B. 86
[0318] To a solution of Compound A (2 g) in formamide (8 mL) was
added acetic acid (20% by weight), and the mixture was heated at
120.degree. C. for 24 h. The reaction mixture was cooled and water
added (32 mL) to precipitate the product. The solids were collected
by filtration and washed with EtOAc to furnish Compound B as a
yellow solid (90%).
[0319] C. 87
[0320] To a solution of Compound B (10 g, 45.2 mmol) in toluene
(150 mL) was added DIPEA (6.31 mL, 36.2 mmol, 0.8 equiv) and
POCl.sub.3 (5.05 mL, 54.2 mmol, 1.2 equiv) and the reaction mixture
heated at 120-125.degree. C. (oil bath temp) for 20 h. The reaction
mixture was cooled and poured into ice cold sat.
NaHCO.sub.3-water-toluene (450 mL-450 mL-150 mL) and stirred
rapidly to assure quenching of the excess POCl.sub.3. The layers
were separated (filtered through celite if a suspension forms) and
the organic layer was washed again with sat. NaHCO.sub.3. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to afford Compound C as a tan yellow solid
(9.9 g, 95%).
[0321] D. 88
[0322] A mixture of commercially-available 4-amino-3-methylbenzoic
acid (100 g, 0.66 mol) and N-(tert-butoxycarbonyl)anhydride (150 g,
0.68 mol) in THF (1000 mL) was slowly heated to 50.degree. C.
overnight. The resulting mixture was cooled to rt and the solvent
was removed on a rotary evaporator. The resulting solids were
triturated with hexanes and dried in vacuo to afford 151 g (91%) of
the crude BOC-protected aniline intermediate as a light pink
solid.
[0323] To the above, light-pink solid was added EDCI (127 g, 0.66
mol), HOBt (90 g, 0.66 mol), and DMF (1000 ml), and the resulting
mixture was stirred at rt for 30 minutes followed by addition of
methoxyamine hydrochloride (55 g, 0.66 mol) in one portion. After
stirring for 10 min, the mixture was cooled using an ice bath.
DIPEA (250 ml, 1.4 mol) was added at such a rate so as to maintain
the internal reaction temperature below 25.degree. C. After the
addition was complete, the ice bath was removed and the reaction
was stirred overnight at rt. The reaction mixture was partitioned
between 0.5 L of water and 1.5 L of EtOAc and the resulting layers
were separated. The aqueous portion was extracted with additional
EtOAc (400 mL.times.3), and the combined organic extracts were
washed with water (300 mL.times.3), cold 0.5 N aq. HCl (400
mL.times.2), and water (500 mL). The product was then extracted
with cold 0.5 N aq. NaOH (300 mL.times.3) and the combined basic
aqueous extracts were neutralized to pH=8 by a slow addition of
cold 0.5 N aq. HCl. The resulting solid which precipitated was
collected by filtration and washed with cold water. The wet solid
was decolorized in hot EtOH with active charcoal to give 106 g of
white solid as the BOC-protected N-methoxyamide intermediate.
[0324] To a slurry of the above solid (91 g, 0.32 mol) in
1,4-dioxane (400 mL) at rt was added a 4M solution of HCl in
dioxane (400 mL), and the resulting mixture was stirred at rt
overnight. Diethyl ether (1000 mL) was added and the precipitated
solid was collected by filtration and triturated with a hot
EtOH/H.sub.2O mixture (4:1 v/v). Drying the resulting solid in
vacuo afforded 53 g of the pure hydrochloride salt (Compound D) as
a white solid. .sub.1H NMR (d.sub.6-DMSO): .delta. 9.5-9.9 (br. s,
1H), 7.75 (s, 1H), 7.55 (d, 1H), 7.36 (d, 1H), 3.70 (s, 3H), 2.38
(s, 3H).
[0325] E. 89
[0326] To a solution of the Compound D (41.2 g, 190 mmol) in DMF
(230 mL) was added DIPEA (33.1 mL, 180.7 mmol, 0.95 equiv), and the
reaction vessel was heated to 55.degree. C. (oil bath temp). Solid
Compound C (45.6 g, 190 mmol) was added in several portions over 10
minutes and the flask was rinsed with DMF (150 mL) and added to the
reaction. The reaction was heated for 10 hours at 55.degree. C. and
cooled to rt. The mixture was then poured into 1.5 L water diluted
to 2.2 L with ice slowly over 10 minutes. The pH was adjusted to 6
and the solids were stirred for 1 h. The solids were filtered,
washed with water (2.times.200 mL) and dried on the filter to give
71.9 g crude ester. The solid was then suspended in acetonitrile
(450 mL) and heated with stirring at 50.degree. C. for 1 h. The
mixture was cooled and filtered to give 64.2 g product (>99%
purity). These solids were then dissolved in hot EtOH (2.8 L) and
decolorizing carbon (6.4 g) was added followed by heating at reflux
for 15 min. The mixture was then filtered through a pad of celite
and the reaction flask rinsed with hot EtOH (1 L). The hot filtrate
was then concentrated to .about.1 L of EtOH by distillation upon
which the product started to crystallize out of solution at a
volume of 2.5 L. The solution was cooled and placed in a cold room
with stirring for 40 h. The solids were filtered and rinsed with
1/1 EtOH/Et.sub.2O (500 mL) to give 58.5 g of Compound E as a white
solid (80%).
F. EXAMPLE 61
[0327] To a solution of ester Compound E (22.5 g, 58.7 mmol) in THF
(205 mL) was added 1 N NaOH (205 mL) and the reaction mixture
heated to 50.degree. C. for 16 h. The THF was removed in vacuo and
the mixture was acidified to pH 4-5 with 1N aq. HCl to precipitate
the product. The heterogeneous mixture was stirred for 1 h,
filtered and washed with water (150 mL) and ether (150 mL). The
collected solids were partially dried on the filter to give the
crude acid intermediate as a moist white solid which was used
without further purification.
[0328] To a solution of the moist acid in 300 mL of DMF was added
HOBt (11.9 g, 88.0 mmol), EDCI (16.9 g, 88.0 mmol) and 1.3
equivalents (117 mmol) of cyclopropyl-amine as the free base or as
the hydrochloride salt. The mixture was stirred for 30 min to
solubilize the solids, placed in a cold water bath, and DIPEA (20.4
mL, 117 mmol) was added slowly via syringe. The reaction mixture
was allowed to stir at rt for 1 h, then poured into rapidly stirred
ice water (1.2 L) to precipitate the product. After stirring for 3
h, the solids were collected by suction filtration, washed with
water (150 mL) and ether (2.times.100 mL), and allowed to air dry
by suction filtration to give Example 61 (92-98%) as a white
solid.
EXAMPLES 62-115
[0329] 90
[0330] Compounds having the formula (IIc), wherein R.sub.2 and
R.sub.10 have the values listed in Table 8 were prepared following
the same methods set forth above in Scheme 9 and Example 61, using
different amines (NR.sub.2R.sub.10) in the last step. Additionally,
each compound can be recrystallized using a 7 to 1 EtOH/water
mixture to afford analytically pure product as a white crystalline
solid.
8TABLE 8 Data Ex. R.sub.2 R.sub.10 Compound Name MS/HPLC 62
--CH.sub.2--C(CH.sub.3).sub.3 CH.sub.3
N-(2,2-Dimethylpropyl)-4-[[5- 439.3 [(methoxyamino)carbonyl]-2-
3.43 min methylphenyl]amino]-N,5- dimethylpyrrolo
[2,1-f][1,2,4]triazine-6-carboxamide 63 --CH--(CH.sub.3).sub.2 H
4-[[5-[(Methoxyamino)carbonyl]-2- 397.3
methylphenyl]amino]-5-methyl-N-(1- 2.79 min methylethyl)pyrrolo
[2,1-f][1,2,4]triazine-6-carboxamide 64 91 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2- methylpropyl)pyrrolo
[2,1-f][1,2,4]triazine-6-carboxamide 411.4 3.14 min 65
--CH.sub.2--C(CH.sub.3).sub.3 H N-(2,2-Dimethylpropyl)-4-[[5- 425.3
[(methoxyamino) 3.35 min Carbonyl]-2-methylphenyl]amino]-5-
methylpyrrolo[2,1-f] [1,2,4]triazine-6-carboxamide 66
--(CH.sub.2).sub.2CH.sub.3 H 4-[[5-[(Methoxyamino)carbonyl]-2-
397.2 methylphenyl]amino]-5-methyl-N- 2.88 min propylpyrrolo
[2,1-f][1,2,4]triazine-6- carboxamide 67 --C(CH.sub.3).sub.3 H
N-(1,1-Dimethylethyl)-4-[[5- 411.2 [(methoxyamino)carbonyl]-2- 3.11
min methylphenyl]amino]-5- methylpyrrolo[2,1 -f][1,2,4]triazine-6-
carboxamide 68 --(CH.sub.2).sub.2--OCH.sub.3 H
4-[[5-[(Methoxyamino)carbonyl]-2- 413.2 methylphenyl]amino]-N-(2-
1.99 min methoxyethyl)-5-methylpyrrolo[2,1-
f][1,2,4]triazine-6-carboxam- ide 69 92 H N-Cyclohexyl-4-[[5-
[(methoxyamino)carbonyl]-2- - methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 437.4 2.88 min
70 93 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[(1R)- 1-phenylethyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 459.3 2.85 min 71 94 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[(1S)- 1-phenylethyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 459.3 2.85 min 72 95 H
N-[(4-Fluorophenyl)methyl]-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazme-6-
carboxamide 463.4 2.83 min 73 96 H
4-[[5-[(Methoxyamino)carbonyl]-2- methylphenyl]amino]-N-[(2-
methoxyphenyl)methyl]-5- methylpyrrolo [2,1-f][1,2,4]triazine-6-
carboxamide 475.4 2.83 min 74 97 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(4- pyridinylmethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 446.2 1.45 min 75 98 H
4-[[5-[(Methoxyammo)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[2-(4- pyridinyl)ethyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 460.3 1.81 min 76 99 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[2-(1-
piperidinyl)ethyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide
466.4 1.56 min 77 100 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[2-(4- morpholinyl)ethyl]pyrrolo
[2,1- f][1,2,4]triazine-6-carboxamide 468.3 1.38 min 78 101 H
N-[(1R,2S)-2,3-Dihydro-1H-inden-1-yl]-
4-[[5-[(methoxyamino)carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 487.4 2.74 min
79 102 H N-[(1S,2R)-2,3-Dihydro-1H-inden-1- -yl]-
4-[[5-[(methoxyamino)carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo [2,1-f][1,2,4]triazine-6- carboxamide 487.2 2.74 min
80 103 H N-Cyclopropyl-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo [2,1-f][1,2,4]triazine-6-
carboxamide 395.3 2.64 min 81 104 H N-Cyclopentyl-4-[[5-
[(methoxyamino)carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 423.0 3.15 min
82 105 H N-[2-(4-Fluorophenyl)ethyl]-4-[[5-
[(methoxyamino)carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 477.3 3.53 min
83 106 H N-(Cyclohexylmethyl)-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 451.3 3.70 min 84 107 H
4-[[5-[(Methoxyamino)carbonyl]-2- methylphenyl]amino]-5-methyl-N-
[(tetrahydro-2- furanyl)methyl]pyrrolo [2,1-
f][1,2,4]triazine-6-carboxamide 439.3 2.76 min 85 108 H
N-(2-1H-Indol-3-ylethyl)-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 498.3 3.39 min 86 --(CH.sub.2).sub.3--CH.sub.3 H
N-Butyl-4-[[5- 411.2 [(methoxyamino)carbonyl]-2- 3.16 min
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-- 6-
carboxamide 87 109 H N-(Cyclopropyhnethyl)-4-- [[5-
[(methoxyamino)carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 409.1 2.90 min
88 110 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2-
methylbutyl)pyrrolo[2,1-f][1,2,4]triaz- ine- 6-carboxamide 425.3
3.43 min 89 111 H N-(2-Furanylmethyl)-4-[[5-
[(methoxyamino)carbonyl]-2- methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 435.1 2.95 min
90 112 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2- thienylmethyl)pyrrolo [2,1-
f][1,2,4]triazine-6-carboxamide 451.2 3.16 min 91 113 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2- phenoxyethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 475.3 3.43 min 92 114 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2- methylcyclohexyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 451.2 3.56 min 93
--CH.sub.2--CH.sub.3 CH.sub.3
N-Ethyl-4-[[5-[(methoxyamino)carbonyl]- 397.2
2-methylphenyl]amino]-N,5- 2.59 min
dimethylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 94
--CH.sub.2--CF.sub.3 H 4-[[5-[(Methoxyamino)carbonyl]-2- 437.1
methylphenyl]amino]-5-methyl-N-(2,2,2- 3.01 min
trifluoroethyl)pyrrolo [2,1- f[1,2,4]triazine-6-carboxamide 95
--CH.sub.2--CH.sub.2--F H N-(2-Fluoroethyl)-4-[[5- 401.2
[(methoxyamino)carbonyl]-2- 2.44 min methylphenyl]amino]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 96 115 H
N-(2,3-Dihydro-1H-inden-2-yl)-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 471.2 3.56 min 97 --CH.sub.2--CH.sub.3 H
N-Ethyl-4-[[5-[(methoxyamino)carbonyl]- 383.3
2-methylphenyl]amino]-5- 2.58 min
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 98 116 H
4-[[5-[(Methoxyamino)carbonyl]-2- methylphenyl]amino]-5-methy- l-N-
(2,2,3,3,3-pentafluoropropyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxa- mide 487.2 3.40 min 99
--(CH.sub.2).sub.2--N(CH.sub.3).sub- .2 H
4-[[5-[(Methoxyamino)carbonyl]-2- 426.5
methylphenyl]amino]-5,7-dimethyl-N-(1- 1.38 min
methylethyl)pyrrolo[2,1-f][1,2,4]triazine- 6-carboxamide 100 117 H
N-(4-Fluorophenyl)-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 449.2 2.92 min 101 118 H
4-[[5-[(Methoxyamino)carbonyl]-- 2- methylphenyl]amino]-N-(2-
methoxyphenyl)-5-methylpyrrolo[2,1- f][1,2,4]triazme-6-carboxamide
461.2 2.97 min 102 119 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-N-[(3- methoxyphenyl)methyl]-5-
methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 475.4 2.75 min
103 120 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[3-
(trifluoromethyl)phenyl]pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 499.1 3.39 min 104 121 H
N-[(2,6-Dichlorophenyl)methyl]-- 4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 513.1 3.10 min 105 122 H
N-[(1S)-1-Cyano-2-phenylethyl]-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 484.3 2.88 min 106 123 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2-
phenylethyl)pyrrolo[2,1-f][1,2,4]triaz- ine- 6-carboxamide 459.3
2.91 min 107 124 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(2- pyridinylmethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 446.2 1.51 min 108 125 H
4-[[5-[(Methoxyamino)carbonyl]-2- methylphenyl]amino]-5-methyl-N-
(phenylmethyl)pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide 445.2
2.69 min 109 126 H 4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-(4- methyl-2-thiazolyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 452.3 3.50 min 110 127 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[(1R)- 1-methylpropyl]pyrrolo [2,1-
f][1,2,4]triazine-6-carboxamide 411.2 3.20 min 111 128 H
4-[[5-[(Methoxyamino)carbonyl]-2-
methylphenyl]amino]-5-methyl-N-[(1S)- 1-methylpropyl]pyrrolo[2,1-
f][1,2,4]triazune-6-carboxamide 411.2 3.20 min 112 129 H
N-[(3-Fluorophenyl)methyl]-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazune-6-
carboxamide 463.2 2.84 min 113 130 H
N-[1-(4-Fluorophenyl)ethyl]-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 477.3 2.93 min 114 131 H
N-[(2,4-Difluorophenyl)methyl]-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 481.2 2.92 min 115 132 H
N-[(2,6-Difluorophenyl)methyl]-4-[[5- [(methoxyamino)carbonyl]-2-
methylphenyl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-
carboxamide 481.1 2.70 min
EXAMPLES 116-119
[0331] 133
[0332] Compounds having the formula (IId), wherein the R.sub.2
groups have the values listed in Table 9, were prepared following
the same methods set forth above in Scheme 9 and Examples
62-115.
9TABLE 9 Ex. R.sub.2 Compound Name Data 116 134
3-[[6-[(Hexahydro-4- methyl-1H-1,4-diazepin-1-
yl)carbonyl]-5-methyl pyrrolo[2,1-f][1,2,4]triazin-
4-yl]amino]-N-methoxy-4- methylbenzamide 452.1 1.63 min 117 135
N-Methoxy-4-methyl-3- [[5-methyl-6-(4- morpholinylcarbonyl)
pyrrolo[2,1-f][1,2,4]triazin- 4-yl]amino]benzamide 425.2 1.82 min
118 136 N-Methoxy-4-methyl-3- [[5-methyl-6-[[4- (phenylmethyl)-1-
piperidinyl]carbonyl]pyrrolo[2,1-f][1,2,4]triazin-
4-yl]amino]benzamide 513.4 3.45 min 119 137 N-Methoxy-4-methyl-3-
[[5-methyl-6-(1- pyrrolidinylcarbonyl)
pyrrolo[2,1-f][1,2,4]triazin- 4-yl]amino]benzamide 409.2 2.16
min
EXAMPLES 120-124
[0333] 138
[0334] Compounds having the formula (IIe), wherein X and R.sub.2
have the values listed in Table 10, were prepared following the
same or similar procedure as in Scheme 9 and Example 61, except in
the first step, commercially available
3-trifluoromethyl-1-pyrrole-2,4-diethyl ester was used instead of
3-methyl-1-pyrrole-2,4-diethyl ester.
10TABLE 10 Ex. Data No. X R.sub.2 Compound Name MS/HPLC 120 139
--CH.sub.2--CH.sub.3 4-[[5-[(Methoxyamino)carbonyl]-
2-methylphenyl]amino]-5- (trifluoromethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxylic acid ethyl ester 438.2 3.76 min 121
140 --CH.sub.2--CH.sub.3 N-Ethyl-4-[[5- [(methoxyamino)carbonyl]-
-2- methylphenyl]amino]-5- (trifluoromethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 437.2 2.99 min 122 141
--CH.sub.2--CH.sub.2--CH.sub.3 4-[[5-[(Methoxyamino)carbonyl]-
2-methylphenyl]amino]-N-propyl- 5-(trifluoromethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 451.3 3.21 min 123 142 143
4-[[5-[(Methoxyamino)carbonyl]- 2-methylphenyl]amino]-N-[(1S)-1-
methylpropyl]-5- (trifluoromethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carbox- amide 465.3 3.36 min 124 144 145
4-[[5-[(Methoxyamino)carb- onyl]- 2-methylphenyl]amino]-N-[(1S)-1-
phenylethyl]-5- (trifluorornethyl)pyrrolo[2,1-
f][1,2,4]triazine-6-carboxamide 513.2 1.72 min
EXAMPLE 125
N-Ethyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrro-
lo[2,1-f][1,2,4]triazine-6-carboxamide methane sulfonic acid
[0335] 146
[0336] Example 97 as a free base was charged with acetone (10 ml/g
Ex. 106), and the jacket was heated to 50-60.degree. C. Reflux was
started at 55-57.degree. C., and the mixture was stirred for 30
min. at 50-60.degree. C. Methanesulfonic acid (1.2 eq.) was added,
and a slight exotherm was observed. The slurry was stirred at
50-60.degree. C. until DSC showed in two consecutive samples the
complete conversion of the free base (mp 220-222.degree. C.) to the
mesylate salt (mp 259-261.degree. C.). The slurry was cooled to
20-25.degree. C. over about 30 min, and then stirred for at least
30 min. with the temp. kept at 20-25.degree. C. The slurry was then
filtered, washed with acetone, and dried in vacuo at 40-50.degree.
C. to an LOD<0.5% to provide Example 125 as a white crystalline
solid (yield 90-95%). [M+H].sup.+=478.4. The above procedure may be
used to prepare mesylate salts of other compounds of Formulae (I)
and (II) herein.
EXAMPLE 126
N-Ethyl-5-methyl-4-[[2-methyl-5-[[[3-(trifluoromethyl)phenyl]amino]carbony-
l]phenyl]amino]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide
[0337] 147
[0338] A. To a slurry of 2.0 g (4.2 mmol) of compound (1) from
Scheme 10, wherein R.sub.2 is ethyl, in 12 mL of anhydrous MeOH was
added 18 mL of a 4 N solution of anhydrous HCl in dioxane at rt.
The resulting clear solution was stirred at rt for 16 h and the
reaction mixture was concentrated in vacuo. The resulting oil was
dissolved in 16 mL of 1.5 N aq. KOH solution and heated to
50.degree. C. for 3 h. After cooling to rt, the mixture was diluted
with 50 mL of water and 10% aq. HCl was added until pH was
approximately 3 or 4. The resulting precipitated product was
collected by vacuum filtration and washed with 50 mL of water and
dried in vacuo to afford 1.47 g (99%) of compound (3) from Scheme
10. An analytical sample of this product was prepared by
recrystallization from 10% aq. acetonitrile. .sup.1H NMR
(CD.sub.3OD): .delta. 8.21 (br s, 1H), 8.11 (br s, 1H), 7.89-7.91
(m, 2H), 7.67 (br s, 1H), 7.44 (d, 1H), 3.40 (q, 2H), 2.86 (s, 3H),
2.36 (s, 3H), 1.25 (s, 3H). LCMS (M+H.sup.+)=354.2. HPLC (Condition
A): 2.24 min.
[0339] B. A mixture of Compound A (40 mg, 0.11 mmol), HATU (65 mg,
0.17 mmol), diisopropylamine (20 .mu.L, 0.11 mmol), and
3-trifluoromethylaniline (36 mg, 0.22 mmol) in 0.3 mL of
N-methylpyrrolidinone was heated at 80.degree. C. for 16 h, and the
reaction mixture was purified by RP preparative HPLC to afford 41
mg (74%) of Example 126 as a light tan solid. .sup.1H NMR
(CD.sub.3OD w/TFA): .delta. 8.28 (s, 1H), 8.19 (s, 1H), 8.16 (d,
1H), 8.11 (d, 1H), 7.84 (s, 1H), 7.71 (d, 1H), 7.58 (t, 2H), 7.47
(d, 1H), 3.44 (q, 2H), 2.94 (s, 3H), 2.47 (s, 3H), 1.26 (t, 3H).
LCMS (M+H.sup.+)=497.47. HPLC (Condition A): 3.30 min.
EXAMPLES 127-129
[0340] 148
[0341] Compounds of Formula (IIf) were prepared as described for
Example 126, except appropriate substrates and amines were selected
to afford compounds where R.sub.2 and R.sub.18 have the values
listed in Table 11.
11TABLE 11 Ex. R.sub.2 R.sub.18 Compound Name Data 127 Et 149
4-[[5-[[(4-Cyanophenyl) amino]carbonyl]-2- methylphenyl]amino]-N-
ethyl-5-methyl pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide .sup.1H
NMR (CD.sub.3OD): .delta.7.93(brs, 1H), 7.84-7.86(d, 3H), 7.74(d,
1H), 7.62(d, 2H), 7.58 (s, 1H), 7.40(d, 1H), 3.30(q, 2H), 3.21(s,
3H), 2.76(s, 3H), 1.14 # (t, 3H). LCMS (M + H.sup.+) =454.18. HPLC
(Condition A) 2.86 min. 128 150 151 5-Methyl-4-[[2-methyl-5-
[(phenylamino)carbonyl]phe- nyl]amino]-N-[(1S)-
1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxam- ide LCMS (M
+ H.sup.+) =505.27. HPLC (Condition A): 3.34 min. 129 152 153
4-[[5-[[(4-Cyano- phenyl)amino]carbonyl]- 2-methylphenyl]amino]-
5-methyl-N-[(1S)-1- phenylethyl]pyrrolo[2,1 - f][1,2,4]triazine-6-
carboxamide LCMS (M + H.sup.+) =530.23. HPLC (Condition A): 3.35
min.
EXAMPLE 130
N-Ethyl-4-[[5-[[(3-fluorophenyl)sulfonyl]amino]-2-methylphenyl]amino]-5-me-
thylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide
[0342] 154
[0343] To a solution of 4-methyl-3-nitroaniline [compound (11) from
Scheme 11)(3.72 g, 24.5 mmol)] in 150 ml of DCM at rt was added
3-fluorobenzenesulfonyl chloride (5.00 g, 25.7 mmol), followed by
TEA (7.0 ml, 50.2 mmol) via syringe. The resulting mixture was
stirred for 20 h and the solvent removed in vacuo. The residue was
dissolved in DCM (600 ml), washed with sat'd aq. NaHCO.sub.3, dried
over sodium sulfate, filtered, and concentrated in vacuo to give
8.00 g of dark solid which was triturated with DCM to afford 5.46 g
of yellow solid. A portion of this solid (1.63 g) was dissolved in
10 ml 1N aq. NaOH and 20 ml THF, and the solution was stirred at rt
for 20 h. The solvent was removed in vacuo and the residue
acidified with 3N HCl to a pH of 2. The resulting precipitated
solid was collected by filtration to afford 1.02 g (94%) of a light
yellow solid as the desired Compound A. HPLC (Condition A)=2.99
min. .sup.1HNMR(CDCl.sub.3) .delta. 7.67 (d, 1H), 7.59 (dd, 1H),
7.49 (m, 2H), 7.32 (m, 1H), 7.28 (m, 2H), 2.54 (s, 3H). 155
[0344] To 0.20 g (0.64 mmol) of Compound A in MeOH (10 ml) was
added 10% Pd/C (20 mg) and the mixture stirred under hydrogen
balloon for 6 h at rt. The solution was filtered through a pad of
celite and the solvent removed in vacuo to give 0.18 g (100%) of
Compound B as a colorless, glassy solid. HPLC (Conditions A): 1.77
min. LCMS M+H.sup.+ (m/z) 281. 156
[0345] Compound B (0.18 g, 0.64 mmol) and 0.15 g (0.64 mmol) of
4-chloro-5-methylpyrrolotriazine-6-ethylcarboxylate (compound 8 of
Scheme 11) in anhydrous DMF was stirred at rt for 20 h. The
reaction was quenched with addition of cold water and sat'd aq.
NaHCO.sub.3. The solid was collected, washed with water, and dried
in vacuo to give 0.27 g (91%) of Compound C as a light yellow
solid. HPLC (Condition A: 3.49 min. LCMS M+H.sup.+ (m/z) 484.
157
[0346] A solution of 0.27 g (56 mmol) of Compound C in 1 ml of 1N
aq. NaOH and 3 ml of MeOH was heated at 60.degree. C. for 12 hr.
The MeOH was removed in vacuo and the aqueous portion acidified
with IN aq. hydrogen chloride to pH .about.2. The resulting
precipitated solid was collected, washed with water, and dried in
vacuo to afford 0.25 g (98%) of Compound D as a pale yellow solid.
HPLC (Condition A): 2.93 min. LCMS M+H.sup.+ (m/z) 456.
[0347] E. Example 130
[0348] A mixture of 30 mg (66 .mu.mol) of Compound D, EDCI (19 mg,
98 .mu.mol), HOBt (13 mg, 98 .mu.mol) and Hunig's base (43 .mu.L,
0.25 mmol) was stirred at rt for 0.5 hr . Ethylamine hydrochloride
(10 mg, 0.13 mmol) was added and the mixture stirred for 16 hr. The
crude mixture was purified by RP preparative HPLC chromatography to
give Example 130. HPLC (Conditions A): 2.83 min. LCMS M+H.sup.+
(m/z) 483.
EXAMPLES 131-132
[0349] Examples 131 and 132 as shown in Table 12 were prepared from
Compound D of Example 130 and an appropriate amine as described in
Example 130, step E.
12TABLE 12 Ex Compound Compound Name Data 131 158 4-[[5-[[(3-
Fluorophenyl)sulfonyl]amin o]-2-methylphenyl]amino]-
N-[(1S)-2-methoxy-1- methylethyl]-5- methylpyrrolo[2,1-
f][1,2,4]triazine-6- carboxamide HPLC (Condition A): 2.89 min.
MH.sup.+(m/z) 527. 132 159 4-[[5-[[(3- Fluorophenyl)sulfonyl]amin
o]-2-methylphenyl]amino]- 5-methyl-N-[(1S)-1-
phenylethyl]pyrrolo[2,1- f][1,2,4]triazine-6- carboxamide HPLC
(Condition A): 3.23 min. MH.sup.+(m/z) 559.
EXAMPLES 133-141
[0350] 160
[0351] Compounds having the formula (IIg), wherein X and R.sub.2
have the values listed in Table 13 were prepared from
commercially-available
diethyl-2,4-dimethylpyrrole-3,5-dicarboxylate following the same or
similar procedure described above for the preparation of
5-desmethyl pyrrolotriazine.
13TABLE 13 Ex X R.sub.2 Compound Name Data 133 --CO.sub.2-- Et
4-[[5-[(Methoxy- 398.2, M + H amino)carbonyl]-2- 3.13 min, A
methylphenyl]amino]- 5,7-dimethylpyrrolo[2,1- f][1,2,4]triazine-6-
carboxylic acid ethyl ester 134 --C(.dbd.O)NH-- Et
N-Ethyl-4-[[5-[(methoxy 397.2, M + H amino)carbonyl]-2- 1.70 min, A
methylphenyl]amino]- 5,7-dimethylpyrrolo [2,1- f][1,2,4]triazine-6-
carboxamide 135 --C(.dbd.O)NH-- 161 4-[[5-[(Methoxy-
amino)carbonyl]-2- methylphenyl]amino]- 5,7-dimethyl-N-[(1S)-1-
phenylethyl]pyrrolo [2,1- f][1,2,4]triazine-6- carboxamide 473.3, M
+ H 2.51 min, A 136 --C(.dbd.O)NH-- --CH(CH.sub.3).sub.2
4-[[5-[(Methoxy- 411.2, M + H amino)carbonyl]-2- 1.81 min, A
methylphenyl]amino]- 5,7-dimethyl-N-(1- methylethyl)pyrrolo[2,1-
f][1,2,4]triazine-6- carboxamide 137 --C(.dbd.O)NH-- 162
4-[[5-[(Methoxy- amino)carbonyl]-2- methylphenyl]amino]-
5,7-dimethyl-N-(2- pyridinylmethyl)pyrrolo [2,1-f][1,2,4]triazine-
6-carboxamide 460.2, M + H 1.30 min, A 138 --CO.sub.2-- H
4-[[5-[(Methoxy 370.2, M + H amino)carbonyl]-2- 2.21 min, A
methylphenyl]amino]- 5,7-dimethylpyrrolo[2,1- f][1,2,4]triazine-6-
carboxylic acid 139 --C(.dbd.O)NH-- 163 4-[[5-[(Methoxy-
amino)carbonyl]-2- methylphenyl]amino]- 5,7-dimethyl-N-[2-(4-
morpholinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6- carboxamide
482.1, M + H 1.21 min, A 140 --C(.dbd.O)NH-- 164 4-[[5-[(Methoxy-
amino)carbonyl]-2- methylphenyl]amino]- 5,7-dimethyl-N-[2-(1-
piperidinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6- carboxamide
480.2, M + H 1.39 min, A 141 --C(.dbd.O)NH-- 165
N-[2-(Dimethylamino) ethyl]-4-[[5-[(methoxy amino)carbonyl]-2-
methylphenyl]amino]- 5,7-dimethylpyrrolo[2,1- f][1,2,4]triazine-6-
carboxamide 440.2, M + H 1.09 min, A
EXAMPLE 142
4-[[5-[[(Ethylamino)carbonyl]amino]-2-methylphenyl]amino]-5-methyl-N-propy-
l pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide
[0352] 166
A.
5-Methyl-4-[(2-methyl-5-nitrophenyl)amino]pyrrolo[2,1-f][1,2,4]triazine-
-6-carboxylic acid ethyl ester
[0353] 167
[0354] A suspension of chloropyrrolotriazine (compound 1 from
Scheme 12) (2.03 g, 8.47 mmol) and 3-nitro-5-methyl aniline (1.41
g, 9.3 mmol) in DMF (25 mL) was stirred at rt for 24 h. Water (125
mL) was added over 30 min and the solution stirred for 1 h upon
which the pH was adjusted to neutral with sat. aq. NaHCO.sub.3. The
solids were filtered, washed with water, and dried to give compound
A (2.589 g, 85% yield) as a pale tan solid.
B.
5-Methyl-4-1(2-methyl-5-nitrophenyl)amino]pyrrolo[2,1-f][1,2,4]triazine-
-6-carboxylic acid
[0355] 168
[0356] To a solution of Compound A (825 mg, 2.32 mmol) in THF (2
mL) and MeOH (1 mL) was added 1N NaOH (6 mL) and the reaction
heated at 60.degree. C. for 24 h. The reaction mixture was cooled,
concentrated to remove the organic solvents, and the pH was
adjusted to neutral with 1 N HCl. The solids were filtered, washed
with water, and dried to give compound B. LCMS (M+H.sup.+)=328.1.
HPLC (Condition A): 3.40 min.
C. 5-methyl-4-[(2-methyl-5-nitrophenyl)amino]-N-propylpyrrolo
[2,1-f][1,2,4]triazine-6-carboxamide
[0357] 169
[0358] A solution of compound B (2.32 mmol), EDCI (489 mg, 2.55
mmol), and HOBt (345 mg, 2.55 mmol) in DMF (6 mL) was stirred at rt
for 1 h, and then n-propyl amine (0.38 mL, 6.4 mmol) was added. The
reaction was stirred for 4 h and water was added to precipitate the
product. The solids were filtered and purified via column
chromatography on silica (33% ethyl acetatehexanes) to give
compound C (0.79 g, 93% yield) as a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 9.11 (s, 1H), 7.92 (m, 2H), 7.71 (s, 1H),
7.36 (d, J=8.4 Hz, 1H), 5.82 (br m, 1H), 3.34 (q, J=6.7 Hz, 2H),
2.86 (s, 3H), 2.41 (s, 3H), 1.58 (m, 2H), 1.16 (t, J=7.5 Hz, 3H).
LCMS (M+H.sup.+)=369.3. HPLC (Condition A): 3.42 min.
D. 4-[(5-Amino-2-methylphenyl)amino]-5-methyl-N-propylpyrrolo
[2,1-f][1,2,4]triazine-6-carboxamide
[0359] 170
[0360] A solution of compound C (794 mg, 2.16 mmol) and 10% Pd/C
(250 mg, wet) in MeOH (20 mL) was degassed and backfilled with
hydrogen three times and stirred for 2 h. The solution was filtered
and concentrated to give compound D (691 mg, 95% yield). .sup.1H
NMR (CDCl.sub.3): .delta. 7.94 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H),
7.23 (m, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.53 (dd, J=8.1, 2.2 Hz, 1H)
5.86 (br m, 1H), 3.43 (q, J=6.6 Hz, 2H), 2.91 (s, 3H), 2.27 (s,
3H), 1.68 (m, 2H), 1.02 (t, J=7.3 Hz, 3H). LCMS (M+H.sup.+)=339.2.
HPLC (Condition A): 2.39 min.
E. EXAMPLE 142
[0361] To a suspension of 25.6 g (0.076 mmol) of compound D in 0.3
mL of DCE was added 22 .mu.L of ethyl isocyanate at rt. The
reaction mixture was heated at 50.degree. C. for 12 h, then cooled,
and isopropanol was added (1 mL). The resulting precipitated
product was collected by vacuum filtration and washed with 1 mL of
isopropanol and dried in vacuo to afford 19.6 mg (63%) of the
titled compound as a pure product. .sup.1H NMR (CD.sub.3OD):
.delta. 7.94 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.23 (br s, 2H),
7.44 (d, 1H), 3.23 (q, 2H), 2.84 (s, 3H), 2.24 (s, 3H), 1.66 (m,
2H), 1.16 (t, 3H), 1.02 (t, 3H). LCMS (M+H.sup.+)=410.2. HPLC
(Condition A): 2.82 min.
EXAMPLES 143-148
[0362] 171
[0363] Compound having the formula (IIh), wherein R.sub.18 has the
values listed in Table 14 were prepared following the procedure
outlined for Example 142, using different isocyanates in the last
step.
14TABLE 14 Data Ex. R.sub.18 Compound Name MS/HPLC 143 172
5-Methyl-4-[[2-methyl-5-
[[(phenylamino)carbonyl]amino]phenyl]amino]-N-pr- opylpyrrolo
[2,1-f][1,2,4]triazine-6- carboxamide 458.2 3.40 min 144 173
5-Methyl-4-[[2-methyl-5- [[[(3-methylphenyl)amino]carbonyl-
]amino]phenyl]amino]- N-propylpyrrolo[2,1- f][1,2,4]triazine-6-
carboxamide 472.5 3.60 145 174 4-[[5-[[[(4-Cyanophenyl)am-
ino]carbonyl]amino]-2- methylphenyl]amino]-5-
methyl-N-propylpyrrolo[2,1- f][1,2,4]triazine-6- carboxamide 483.3
3.48 146 175 4-[[5-[[[(2,3-Dichlorophenyl) amino]carbonyl]amino]-2-
methylphenyl]amino]-5- methyl-N-propylpyrrolo[2,1-
f][1,2,4]triazine-6- carboxamide 526.2 3.98 147 176
4-[[5-[[[(4-Fluorophenyl) amino]carbonyl]amino]-
2-methylphenyl]amino]-5- methyl-N-propylpyrrolo[2,- 1-
f][1,2,4]triazine-6-carboxamide 476.2 3.48 148 177
5-Methyl-4-[[2-methyl-5-[[[[3-
(trifluoromethyl)phenyl]amino]carbonyl]ami- no]phenyl]amino]-N-
propylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide 526.1 3.87
min
EXAMPLES 149-152
[0364] The compounds named below were prepared using methods
analogous to the procedures described hereinbefore:
[0365] 149)
1,3-Dihydro-3-[5-methoxy-6-[[4-(4-methyl-1-piperazinyl)butyl]a-
mino]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2H-indol-2-one;
[0366] 150)
1,3-Dihydro-3-[5-methoxy-6-[[4-(4-morpholinyl)butyl]amino]pyrr-
olo[2,1-f][1,2,4]triazin-4-yl]-2H-indol-2-one;
[0367] 151)
1-[3-[4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1--
f][1,2,4]triazin-6-yl]-1-oxopropyl]-4-methylpiperazine; and
[0368] 152)
2-Methyl-5-[[5-methyl-6-[3-(2H-1,2,3-triazol-2-yl)propoxy]pyrr-
olo[2,1-f][1,2,4]triazin-4-yl]amino]phenol.
* * * * *