U.S. patent application number 14/560809 was filed with the patent office on 2015-11-12 for dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases.
The applicant listed for this patent is Deciphera Pharmaceuticals, LLC. Invention is credited to Daniel L. Flynn, Michael D. Kaufman, Peter A. Petillo.
Application Number | 20150320759 14/560809 |
Document ID | / |
Family ID | 48538348 |
Filed Date | 2015-11-12 |
United States Patent
Application |
20150320759 |
Kind Code |
A1 |
Flynn; Daniel L. ; et
al. |
November 12, 2015 |
DIHYDRONAPHTHYRIDINES AND RELATED COMPOUNDS USEFUL AS KINASE
INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
Abstract
The invention relates to dihydronaphthyridines and related
compounds; compositions comprising an effective amount of a
dihydronaphthyridine or a related compound; and methods for
treating or preventing proliferative diseases comprising the
administration of an effective amount of a dihydronaphthyridine or
a related compound.
Inventors: |
Flynn; Daniel L.; (Lawrence,
KS) ; Kaufman; Michael D.; (Lawrence, KS) ;
Petillo; Peter A.; (Lawrence, KS) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Deciphera Pharmaceuticals, LLC |
Lawrence |
KS |
US |
|
|
Family ID: |
48538348 |
Appl. No.: |
14/560809 |
Filed: |
December 4, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13801753 |
Mar 13, 2013 |
8940756 |
|
|
14560809 |
|
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|
Current U.S.
Class: |
514/210.18 ;
514/234.5; 514/253.04; 514/300 |
Current CPC
Class: |
C07D 471/04 20130101;
A01N 43/42 20130101; A61K 31/496 20130101; A61K 31/4375 20130101;
A61K 31/5377 20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/496 20060101 A61K031/496; A61K 31/4375
20060101 A61K031/4375 |
Claims
1. A method of treating a disease caused by the kinase activity of
c-KIT, oncogenic forms thereof, or polymorphs thereof, comprising
the administration of a compound of formula Ia ##STR00196## or a
pharmaceutically acceptable salt thereof, wherein: A is selected
from the group consisting of phenyl, naphthyl, and benzothienyl; G1
is a heteroaryl taken from the group consisting of pyrrolyl, furyl,
thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; G4
is a heterocyclyl taken from the group consisting of oxetanyl,
azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,
oxazolidinyl, imidazolonyl, pyranyl, tetrahydropyranyl, dioxalinyl,
piperidinyl, and morpholinyl; when A has one or more substitutable
sp2-hybridized carbon atom, each respective sp2 hybridized carbon
atom may be optionally substituted with a Z3 substituent; Z1 is
selected from the group consisting of --NH(R4), and --NHCOR8; in
the event that Z1 contains an alkyl or alkylene moiety, such
moieties may be further substituted with one or more C1-C6alkyls;
each Z2 is independently and individually selected from the group
consisting of hydrogen, C1-C6alkyl, C3-C8carbocyclyl, C1-C6 alkoxy,
hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3).sub.2N--, and
--(CH.sub.2).sub.nR5; in the event that Z2 contains an alkyl or
alkylene moiety, such moieties may be further substituted with one
or more C1-C6alkyls; each Z3 is independently and individually
selected from the group consisting of H, methyl, ethyl, isopropyl,
C3-C4 carbocyclyl, halogen, cyano, --(CH.sub.2).sub.k--N(R3).sub.2,
and --(CH.sub.2).sub.k--R5; R1 is selected from the group
consisting of C1-C4alkyl, branched C3-C5alkyl, and
C3-C5carbocyclyl; each R2 is independently and individually
selected from the group consisting of hydrogen, methyl, ethyl,
halogen, fluoroalkyl wherein the alkyl moiety can be partially or
fully fluorinated, cyano, and C2-C3alkynyl; each R3 is
independently and individually selected from the group consisting
of H, C1-C6alkyl, branched C3-C7alkyl, and C3-C8carbocyclyl; each
R4 is independently and individually selected from the group
consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,
C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched
hydroxyC2-C6alkyl, branched C1-C6alkoxyC2-C6alkyl,
--(CH.sub.2).sub.q--N(R7).sub.2, --(CH.sub.2).sub.q--R5,
--(CH.sub.2)C(O)R5, C3-C8carbocyclyl, hydroxyl substituted
C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, and
--(CH.sub.2).sub.n--R17; each R5 is independently and individually
selected from the group consisting of ##STR00197## and wherein the
symbol (##) is the point of attachment of the R5 moiety; each R5
may be optionally substituted with one or two R10 substituents;
each R7 is independently and individually selected from the group
consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,
C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6
alkyl, branched C1-C6alkoxyC2-C6alkyl, --(CH.sub.2).sub.q--R5,
--(CH.sub.2).sub.n--C(O)R5, --(CH.sub.2).sub.n--C(O)OR3,
C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy
substituted C3-C8carbocyclyl, and --(CH.sub.2).sub.n--R17; each R8
is independently and individually selected from the group
consisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl,
fluoroalkyl wherein the alkyl moiety is partially or fully
fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl,
Z3-substituted G1, Z3-substituted G1-C1-C6alkyl, Z2-substituted G4,
Z2-substituted G4-C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl,
cyanoC1-C6alkyl, --N(R4).sub.2, and R5; each R10 is independently
and individually selected from the group consisting of CO.sub.2H,
CO.sub.2C1-C6alkyl, CO--N(R4).sub.2, OH, C1-C6alkoxy, C1-C6alkyl,
and --N(R4).sub.2; each R17 is taken from the group comprising
phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl,
isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl,
azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl,
thiopyranyl, tetrahydropyranyl, dioxalinyl, pyrrolidinyl, and
piperidinyl; wherein R17 can be further substituted with one or
more Z2 or Z3 moieties; wherein two R3 or R4 moieties are
independently and individually taken from the group consisting of
C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl
and are attached to the same nitrogen atom, said moieties may
cyclize to form a C3-C7 heterocyclyl ring; and k is 1 or 2; n is
0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3.
2. The method of claim 1 wherein the compound of Formula Ia is a
compound of Formula Ib ##STR00198## or a pharmaceutically
acceptable salt thereof, wherein: A is phenyl, R1 is linear or
branched C1-C4alkyl, R2 is methyl or halogen, Z1 is --NH(R4) or
--NHCOR8.
3. The method of claim 1 wherein the kinase activity of c-KIT,
oncogenic forms thereof, or polymorphs thereof, wherein c-KIT
contains a missense mutatation, insertion mutation, or a deletion
mutation encoded by exons comprising Exon 9, Exon 11, Exon 13, Exon
14, Exon 17, or Exon 18, presenting either individually or in
combination, comprising the administration of a compound of formula
Ia or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 wherein the disease is selected from
gastrointestinal stromal tumors, ovarian cancer, melanoma, cervical
carcinomas, acute myeloid leukemia, germ cell tumors of the
seminoma or dysgerminoma, teratomas, mastocytosis, or mast cell
leukemia.
5. The method of claim 1 wherein the compound is selected from the
group consisting of
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea,
1-(4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridi-
n-3-yl)phenyl)-3-(3-cyanophenyl)urea,
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino-
)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-o-
xo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-phenylurea,
1-(3-chlorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-phenylurea
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea,
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(2-fluoro-phenyl)-urea,
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-thyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenyl urea,
1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea,
1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,-
2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea,
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea,
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2,4-difluorophenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea,
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H-pyran-4-ylamino)-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
(S)-1-(4-chloro-5-(1-ethyl-7-(1-methoxypropan-2-ylamino)-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1,6-naphthyrid-
in-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(4-bromo-5-(1-thyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphth-
yridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-brom-
o-2-fluorophenyl)-3-phenylurea,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chlo-
ro-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-2-dihydro-1,6-naphthyridin-3-
-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea,
1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)phenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2--
fluorophenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(3-fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-2-cyanoacetamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-cyanoacetamide,
1-(5-(7-acetamido-1-thyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-dif-
luorophenyl)-3-phenylurea,
N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea,
1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea methyl
(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-7-yl)carbamate,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-methoxyacetamide,
2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-di-
hydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea,
N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)acetamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-3-hydroxyazetidine-1-carboxamide,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
(R)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide,
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)pheny-
l)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-((4-methylpiperazin-1-yl)methy-
l)phenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)pheny-
l)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phe-
nyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea,
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)p-
henyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)form-
amide,
3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-
-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl)-1-ethy-
l-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)-
phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide,
3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea,
3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,-
6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)pheny-
l)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-iodophenyl)-3-phenylurea, and
1-(5-(1-ethyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6-n-
aphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea.
6. The method of claim 5 wherein the compound is selected from the
group consisting of
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-phenylurea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-phenylurea,
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea,
1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,-
2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2--
fluorophenyl)-3-phenylurea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)acetamide, and
3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-1,1-dimethylurea.
7. The method of claim 5 wherein the compound is
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea.
8. The method of claim 5 wherein the compound is
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea.
9. The method of claim 5 wherein the compound is
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea.
10. The method of claim 5 wherein the compound is
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-phenylurea.
11. The method of claim 5 wherein the compound is
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea.
12. The method of claim 5 wherein the compound is
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea.
13. The method of claim 5 wherein the compound is
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2--
fluorophenyl)-3-phenylurea.
14. The method of claim 5 wherein the compound is
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea.
15. The method of claim 5 wherein the compound is
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S. patent
application Ser. No. 13/491,394, filed on Jun. 7, 2012, entitled
"DIHYDRONAPHTHYRIDINES AND RELATED COMPOUNDS USEFUL AS KINASE
INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES," which is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] c-KIT (also known as KIT, CD117, and stem cell factor
receptor) is a 145 kDa transmembrane tyrosine kinase protein that
acts as a type-III receptor (Percira et al. J. Carcin. 2005, 4, pg.
19). The c-KIT proto-oncogene, located on chromosome 4q11-21,
encodes the c-KIT receptor, whose ligand is the stem cell factor
(SCF, steel factor, kit ligand, mast cell growth factor, Morstyn,
G. et al. Oncology 1994, 51(2), pg. 205; Yarden, Y. et al. Embo. J.
1987, 6(11), pg. 3341). The receptor has tyrosine-protein kinase
activity and binding of the ligand SCF leads to the
autophosphorylation of c-KIT and its association with substrates
such as phosphatidylinositol 3-kinase (PI3K). Tyrosine
phosphorylation by protein tyrosine kinases is of particular
importance in cellular signaling and can mediate signals for major
cellular processes, such as proliferation, survival,
differentiation, apoptosis, attachment, invasiveness and migration.
Defects in c-KIT are a cause of piebaldism, an autosomal dominant
genetic developmental abnormality of pigmentation characterized by
congenital patches of white skin and hair that lack melanocytes.
Gain-of-function mutations of the c-KIT gene and the expression of
constitutively phosphorylated c-KIT are found in most
gastrointestinal stromal tumors GIST) and mastocytosis. Further,
almost all gonadal seminomas/dysgerminomas exhibit c-KIT membranous
staining, and several reports have clarified that some (10-25%)
have a c-KIT gene mutation (Sakuma, Y. et al. Cancer Sci. 2004,
95(9), pg. 716). c-KIT defects have also been associated with
testicular tumors including germ cell tumors (GCT) and testicular
germ cell tumors (TGCT).
[0003] The role of c-KIT expression has been studied in hematologic
and solid tumors, such as acute leukemias (Cortes, J. et al. Cancer
2003, 97(11), pg. 2760) and GIST (Fletcher, J. et al. Hum. Pathol.
2002, 33(5), pg. 459). The clinical importance of c-KIT expression
in malignant tumors relies on studies with Gleevee.RTM. (imatinib
mesylate, STI571 (signal transduction inhibitor number 571),
Novartis Pharma AG Basel, Switzerland) that specifically inhibits
tyrosine kinase receptors (Lefevre, G. et al. J. Biol. Chem. 2004,
279(30), pg. 31769). Moreover, a clinically relevant breakthrough
has been the finding of anti-tumor effects of this compound in
GIST, a group of tumors regarded as being generally resistant to
conventional chemotherapy (de Silva, C. M.; Reid, R. Pathol. Oncol.
Res. 2003, 9(1), pp. 13-19). Most GISTs have primary activating
mutations in the genes encoding the closely related RTKs c-KIT
(75-80% of GIST) or PDGFR.alpha. (8% of the non-c-KIT mutated
GIST). c-KIT and PDGFR.alpha. mutations are mutually exclusive in
GIST (Rubin et al. Lancet 2007, 369, pg. 1731). The majority of
primary GIST-causing c-KIT mutations affect the juxtamembrane (JM)
region of the protein encoded by exon 11 (i.e. V560D) and consist
of in-frame deletions or insertions, or missense mutations. c-KIT
exon 11 mutations have been identified as primary mutations in
approximately 75% of GISTs. Such JM domain mutations disrupt the
autoinhibition mechanism of c-KIT kinase, leading to constitutive
kinase activity and cell-transforming events causative of GIST
(Chen, L. L. et al. Clin. Cancer Res. 2005, 11, pg. 3668-3677; Mol,
C. D., et al. J. Biol. Chem. 2004, 279. pg. 31655-31663).
[0004] GIST most often become Gleevec.RTM. resistant, and
molecularly targeted small molecule therapies that target c-KIT
secondary mutations remain elusive. GIST patients who relapse after
treatment with Gleevec.RTM. or Sutent.RTM. have disease still
driven by c-KIT mutations. These secondary mutations occur on the
same alleles as the primary JM-region mutation, and thus represent
even more aggressive activated forms of c-KIT than the original
primary mutation. These secondary mutants of c-KIT identified in
GIST lead to acquired drug resistance. Secondary mutations are
found in the extracellular domain of c-KIT (exon 9, i.e. AY501-502
duplication/insertion). ATP binding pocket (exon 13, i.e. K642E,
V654A; exon 14. i.e. T6701), and activation loop (exon 17. i.e.
N822K, D816H, D816V, D820A). These various secondary c-KIT
mutations have been reported: Heinrich, M. C. et al. J. Clin.
Oncol. 2006, 24, pg. 4764-4774; Debiec-Rychter, M., et al.
Gastroenterology 2005, 128, pg. 270-279; Wardelmann. E., et al.
Lancet Oncol. 2005, 6, pg. 249-251; Antonescu, C. R. et al. Clin.
Cancer. Res. 2005, 11, pg. 4182-4190. Sunitinib malate (Sutent.TM.,
Pfizer) is an inhibitor of multiple RTKs, notably in this context,
c-KIT and PDGFR.alpha., and has been shown to be effective against
certain imatinib-resistant c-KIT mutants, such as the ATP-binding
pocket mutants V654A and T670I. Certain Gleevec.RTM.-resistant
mutants are also resistant to sunitinib, such as D816H and D816V
which are located in the activation loop of the c-KIT catalytic
domain encoded by exon 17 (Corless et al. J. Clin. Oncol. 2004, 22,
pg. 3813; Heinrich et al. J. Clin. Oncol. 2008, 26. pg. 5352;
Gajiwala et al. Proc. Natl. Acad. Sci. USA 2009, 106:1542). Median
survival after progression due to Gleevec.RTM.-resistance remains
relatively short.
[0005] It has been demonstrated that complex, multiple secondary
c-KIT mutations can arise and vary within individual patients, such
variation in mutational status of c-KIT being demonstrated by
biopsy samples obtained from different progressing metastases
within each patient (Wardelmann, E., et al. Lancet Oncol. 2005, 6,
pg. 249-251; Fletcher, J. A. and Rubin, B. P., Curr. Opin in
Genetics & Develop., 2007, 17, pg. 3-7). This complex c-KIT
mutational heterogeneity within individual patients underscores an
unmet medical need to identify inhibitors of c-KIT kinase that are
effective across a broad spectrum of c-KIT primary and secondary
mutations. Such a broad spectrum c-KIT inhibitor would be of high
therapeutic value in the treatment of refractory GIST patients.
SUMMARY OF THE INVENTION
[0006] The present invention discloses the unexpected utility of
compounds that inhibit c-KIT kinase across a broad range of c-KIT
mutations, including complex occurrences of primary mutations (KIT
exon 9 or 11) and secondary KIT mutations (exons 13, 14, 17 and 18)
that may arise in individual, refractory GIST patients. Also
unexpected is the utility of compounds of the present invention to
inhibit the problematic exon 17 D816V c-KIT mutation, for which
there is currently no effective therapy. D816 mutations in c-KIT
have been demonstrated to cause mastocytosis, mast cell leukemia,
seminomas, dysgerminomas, lymphomas, and intracranial teratomas
(Ning, A. Q, Li, J., and Arceci, R. J. Leuk Lymphoma, 2001, 41, pg.
513-522; Beghini, A., et al. Blood, 2000, 95, pg. 726-727; Tian,
Q., et al. Am J. Pathol. 1999, 154, pg. 1643-1647; Nagata, H., et
al. Proc. Natl. Acad. Sci. USA, 1995, 92, 10560-10564; Longley, B.
J., et al. Nat. Genet., 1996, 12, pg. 312-314). The present
invention also discloses new compounds for the treatment of
diseases caused by c-KIT mutation, including new compounds for the
treatment of refractory GIST, mast cell leukemia, or
mastocytosis.
[0007] One aspect of the present invention provides a method of
treating a disease caused by the kinase activity of c-KIT,
oncogenic forms thereof, aberrant fusion proteins thereof or
polymorphs thereof, comprising the administration of a compound of
formula Ia
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein: A is
selected from the group consisting of phenyl, naphthyl, and
benzothienyl; G1 is a heteroaryl taken from the group consisting of
pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,
pyridinyl, and pyrimidinyl; G4 is a heterocyclyl taken from the
group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl,
pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl,
tetrahydropyranyl, dioxalinyl, piperidinyl, and morpholinyl; when A
has one or more substitutable sp2-hybridized carbon atom, each
respective sp2 hybridized carbon atom may be optionally substituted
with a Z3 substituent; Z1 is selected from the group consisting of
--NH(R4), and --NHCOR8; in the event that Z1 contains an alkyl or
alkylene moiety, such moieties may be further substituted with one
or more C1-C6alkyls; each Z2 is independently and individually
selected from the group consisting of hydrogen, C1-C6alkyl,
C3-C8carbocyclyl, C1-C6 alkoxy, hydroxyl, hydroxyC1-C6alkyl-,
cyano, (R3).sub.2N--, and --(CH.sub.2).sub.nR5: in the event that
Z2 contains an alkyl or alkylene moiety, such moieties may be
further substituted with one or more C1-C6alkyls: each Z3 is
independently and individually selected from the group consisting
of H, methyl, ethyl, isopropyl, C3-C4 carbocyclyl, halogen, cyano,
--(CH.sub.2).sub.k--N(R3).sub.2, and --(CH.sub.2).sub.k--R5; R1 is
selected from the group consisting of C1-C4alkyl, branched
C3-C5alkyl, and C3-C5carbocyclyl; each R2 is independently and
individually selected from the group consisting of hydrogen,
methyl, ethyl, halogen, fluoroalkyl wherein the alkyl moiety can be
partially or fully fluorinated, cyano, and C2-C3alkynyl: each R3 is
independently and individually selected from the group consisting
of H. C1-C6alkyl, branched C3-C7alkyl, and C3-C8carbocyclyl: each
R4 is independently and individually selected from the group
consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,
C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched
hydroxyC2-C6alkyl, branched C1-C6alkoxyC2-C6alkyl,
--(CH.sub.2).sub.q--N(R7).sub.2, --(CH.sub.2).sub.q--R5,
--(CH.sub.2).sub.nC(O)R5, C3-C8carbocyclyl, hydroxyl substituted
C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, and
--(CH.sub.2).sub.n--R17; each R5 is independently and individually
selected from the group consisting of
##STR00002##
and wherein the symbol (##) is the point of attachment of the R5
moiety: each R5 may be optionally substituted with one or two R10
substituents: each R7 is independently and individually selected
from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,
C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6
alkyl, branched C1-C6alkoxyC2-C6alkyl, --(CH.sub.2).sub.q--R5,
--(CH.sub.2).sub.n--C(O)R5, --(CH.sub.2).sub.n--C(O)OR3,
C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy
substituted C3-C8carbocyclyl, and --(CH.sub.2).sub.n--R17; each R8
is independently and individually selected from the group
consisting of hydrogen. C1-C6alkyl, branched C3-C7alkyl,
fluoroalkyl wherein the alkyl moiety is partially or fully
fluorinated, C3-C8carbocyclyl. Z3-substituted phenyl,
Z3-substituted G1. Z3-substituted G1-C1-C6alkyl, Z2-substituted G4,
Z2-substituted G4-C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl,
cyanoC1-C6alkyl, --N(R4).sub.2, and R5; each R10 is independently
and individually selected from the group consisting of CO.sub.2H,
CO.sub.2C1-C6alkyl, CO--N(R4).sub.2, OH, C1-C6alkoxy. C1-C6alkyl,
and --N(R4).sub.2; each R17 is taken from the group comprising
phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl,
isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl,
azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl,
thiopyranyl, tetrahydropyranyl, dioxalinyl, pyrrolidinyl, and
piperidinyl; wherein R17 can be further substituted with one or
more Z2 or Z3 moieties; wherein two R3 or R4 moieties are
independently and individually taken from the group consisting of
C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl
and are attached to the same nitrogen atom, said moieties may
cyclize to form a C3-C7 heterocyclyl ring; and k is 1 or 2; n is
0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3.
[0008] In one embodiment, the invention provides a method of
treating a disease caused by the kinase activity of c-KIT,
oncogenic forms thereof, aberrant fusion proteins thereof or
polymorphs thereof, wherein c-KIT contains a missense mutatation,
insertion mutation, or a deletion mutation encoded by exons
comprising Exon 9, Exon 11, Exon 13, Exon 14, Exon 17, or Exon 18,
presenting either individually or in combination, comprising the
administration of a compound of formula Ia or a pharmaceutically
acceptable salt thereof.
[0009] A second aspect of the present invention provides a method
of treating a disease selected from gastrointestinal stromal
tumors, ovarian cancer, pancreatic cancer, prostate cancer, lung
cancers, breast cancers, melanoma, renal cancers, hepatic cancers,
cervical carcinomas, metastasis of primary tumor sites, papillary
thyroid carcinoma, non-small cell lung cancer, mesothelioma,
hypereosinophilic syndrome, colonic cancers, acute myeloid
leukemia, germ cell tumors of the seminoma or dysgerminoma,
teratomas, mastocytosis, or mast cell leukemia, said method
comprising administering a therapeutically effective amount of a
compound of Formula Ia, or a pharmaceutically acceptable salt
thereof, to a patient.
[0010] A third aspect of the present invention provides a
pharmaceutical composition comprising a compound of Formula Ia, or
a pharmaceutically acceptable salt thereof, in association with a
pharmaceutically acceptable carrier, with the proviso that the
compound is not
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea, or
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea.
[0011] A fourth aspect of the present invention provides use of a
compound of Formula Ia or a pharmaceutically acceptable salt
thereof, for the manufacture of a medicament for the treatment of a
disease selected from gastrointestinal stromal tumors, ovarian
cancer, pancreatic cancer, prostate cancer, lung cancers, breast
cancers, melanoma, renal cancers, hepatic cancers, cervical
carcinomas, metastasis of primary tumor sites, papillary thyroid
carcinoma, non-small cell lung cancer, mesothelioma,
hypereosinophilic syndrome, colonic cancers, acute myeloid
leukemia, germ cell tumors of the seminoma or dysgerminoma,
teratomas, mastocytosis, or mast cell leukemia.
[0012] A fifth aspect of the present invention provides a compound
of formula Ia
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein: A is
selected from the group consisting of phenyl, naphthyl, and
benzothienyl; G1 is a heteroaryl taken from the group consisting of
pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,
pyridinyl, and pyrimidinyl; G4 is a heterocyclyl taken from the
group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl,
pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl,
tetrahydropyranyl, dioxalinyl, piperidinyl, and morpholinyl; when A
has one or more substitutable sp2-hybridized carbon atom, each
respective sp2 hybridized carbon atom may be optionally substituted
with a Z3 substituent; Z1 is selected from the group consisting of
--NH(R4), and --NHCOR8; in the event that Z1 contains an alkyl or
alkylene moiety, such moieties may be further substituted with one
or more C1-C6alkyls: each Z2 is independently and individually
selected from the group consisting of hydrogen. C1-C6alkyl,
C3-C8carbocyclyl, C1-C6 alkoxy, hydroxyl, hydroxyC1-C6alkyl-,
cyano, (R3).sub.2N--, and --(CH.sub.2)R5; in the event that Z2
contains an alkyl or alkylene moiety, such moieties may be further
substituted with one or more C1-C6alkyls; each Z3 is independently
and individually selected from the group consisting of H, methyl,
ethyl, isopropyl, C3-C4 carbocyclyl, halogen, cyano,
--(CH.sub.2).sub.k--N(R3).sub.2, and --(CH.sub.2).sub.k--R5; R1 is
selected from the group consisting of C1-C4alkyl, branched
C3-C5alkyl, and C3-C5carbocyclyl; each R2 is independently and
individually selected from the group consisting of hydrogen,
methyl, ethyl, halogen, fluoroalkyl wherein the alkyl moiety can be
partially or fully fluorinated, cyano, and C2-C3alkynyl; each R3 is
independently and individually selected from the group consisting
of H, C1-C6alkyl, branched C3-C7alkyl, and C3-C8carbocyclyl: each
R4 is independently and individually selected from the group
consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,
C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched
hydroxyC2-C6alkyl, branched C1-C6alkoxyC2-C6alkyl,
--(CH.sub.2).sub.q--N(R7).sub.2, --(CH.sub.2).sub.q--R5,
--(CH.sub.2).sub.nC(O)R5, C3-C8carbocyclyl, hydroxyl substituted
C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, and
--(CH.sub.2).sub.n--R17; each R5 is independently and individually
selected from the group consisting of
##STR00004##
and wherein the symbol (##) is the point of attachment of the R5
moiety; each R5 may be optionally substituted with one or two R10
substituents; each R7 is independently and individually selected
from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,
C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6
alkyl, branched C1-C6alkoxyC2-C6alkyl, --(CH.sub.2).sub.q--R5,
--(CH.sub.2).sub.n--C(O)R5, --(CH.sub.2).sub.n--C(O)OR3.
C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy
substituted C3-C8carbocyclyl, and --(CH.sub.2)--R17; each R8 is
independently and individually selected from the group consisting
of hydrogen, C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein
the alkyl moiety is partially or fully fluorinated,
C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted G1,
Z3-substituted G1-C1-C6alkyl, Z2-substituted G4, Z2-substituted
G4-C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, cyanoC1-C6alkyl.
--N(R4).sub.2, and R5; each R10 is independently and individually
selected from the group consisting of CO.sub.2H,
CO.sub.2C1-C6alkyl, CO--N(R4).sub.2, OH, C1-C6alkoxy, C1-C6alkyl,
and --N(R4).sub.2; each R17 is taken from the group comprising
phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl,
isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl,
azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl,
thiopyranyl, tetrahydropyranyl, dioxalinyl, pyrrolidinyl, and
piperidinyl; wherein R17 can be further substituted with one or
more Z2 or Z3 moieties; wherein two R3 or R4 moieties are
independently and individually taken from the group consisting of
C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl
and are attached to the same nitrogen atom, said moieties may
cyclize to form a C3-C7 heterocyclyl ring; and k is 1 or 2; n is
0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3; with the proviso
that the compound is not
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea, or
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea.
[0013] In any of the foregoing aspects:
[0014] In one embodiment, the compound of Formula Ia is a compound
wherein: A is phenyl; or a pharmaceutically acceptable salt
thereof.
[0015] In one embodiment, the compound of Formula Ia is a compound
wherein: A is naphthyl; or a pharmaceutically acceptable salt
thereof.
[0016] In one embodiment, the compound of Formula Ia is a compound
wherein: A is benzothienyl; or a pharmaceutically acceptable salt
thereof.
[0017] In one embodiment, the compound of Formula Ia is a compound
wherein: R1 is taken from the group consisting of C1-C4alkyl,
branched C3-C5alkyl, and C3-C5carbocyclyl; or a pharmaceutically
acceptable salt thereof.
[0018] In one embodiment, the compound of Formula Ia is a compound
wherein: R1 is C1-C4alkyl; or a pharmaceutically acceptable salt
thereof.
[0019] In one embodiment, the compound of Formula Ia is a compound
wherein: R1 is branched C3-C5alkyl; or a pharmaceutically
acceptable salt thereof.
[0020] In one embodiment, the compound of Formula Ia is a compound
wherein: R1 is C3-C5carbocyclyl; or a pharmaceutically acceptable
salt thereof.
[0021] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is selected from the group consisting of --NH(R4) and
--NHCOR8; or a pharmaceutically acceptable salt thereof.
[0022] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NH(R4); or a pharmaceutically acceptable salt
thereof.
[0023] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NH(R4) and R4 is H or C1-C6alkyl; or a
pharmaceutically acceptable salt thereof.
[0024] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NH(R4) and R4 is H; or a pharmaceutically
acceptable salt thereof.
[0025] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NH(R4) and R4 is C1-C6alkyl; or a pharmaceutically
acceptable salt thereof.
[0026] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically
acceptable salt thereof.
[0027] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NR4COR8; or a pharmaceutically acceptable salt
thereof.
[0028] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8; or a pharmaceutically acceptable salt
thereof.
[0029] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8 and R8 is hydrogen, C1-C6alkyl, branched
C3-C7alkyl, C3-C8carbocyclyl, --N(R4)2, or R5; or a
pharmaceutically acceptable salt thereof.
[0030] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8 and R8 is C1-C6alkyl; or a pharmaceutically
acceptable salt thereof.
[0031] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8 and R8 is branched C3-C7alkyl; or a
pharmaceutically acceptable salt thereof.
[0032] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8 and R8 is C3-C8carbocyclyl; or a
pharmaceutically acceptable salt thereof.
[0033] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8 and R8 is --N(R4)2; or a pharmaceutically
acceptable salt thereof.
[0034] In one embodiment, the compound of Formula Ia is a compound
wherein: Z1 is --NHCOR8 and R8 is R5; or a pharmaceutically
acceptable salt thereof.
[0035] In one embodiment, the compound of Formula Ia is a compound
wherein: each R2 is independently hydrogen, methyl, or halogen and
t is 2; or a pharmaceutically acceptable salt thereof.
[0036] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib
##STR00005##
wherein: R2 is hydrogen, methyl, or halogen; or a pharmaceutically
acceptable salt thereof.
[0037] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: R2 is hydrogen; or a pharmaceutically
acceptable salt thereof.
[0038] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: R2 is methyl; or a pharmaceutically
acceptable salt thereof.
[0039] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: R2 is halogen; or a pharmaceutically
acceptable salt thereof.
[0040] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is phenyl, R is C1-C4alkyl, branched
C3-C5alkyl, or C3-C5carbocyclyl, R2 is hydrogen, methyl, or
halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0041] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is phenyl. R1 is C1-C4alkyl. R2 is methyl
or halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0042] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is phenyl, R1 is ethyl, R2 is methyl or
halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0043] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is phenyl, R1 is ethyl, R2 is methyl or
halogen. Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically
acceptable salt thereof.
[0044] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is phenyl, R1 is ethyl, R2 is methyl, Z1
is --NH(R4) and R4 is methyl; or a pharmaceutically acceptable salt
thereof.
[0045] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is phenyl, R1 is ethyl, R2 is halogen, Z1
is --NH(R4) and R4 is methyl; or a pharmaceutically acceptable salt
thereof.
[0046] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is naphthyl, R1 is C1-C4alkyl, branched
C3-C5alkyl, or C3-C5carbocyclyl, R2 is hydrogen, methyl, or
halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0047] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is naphthyl, R1 is C1-C4alkyl, R2 is
methyl or halogen, and Z1 is --NH(R4) or --NHCOR8; or a
pharmaceutically acceptable salt thereof.
[0048] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is naphthyl, R1 is ethyl, R2 is methyl or
halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0049] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is naphthyl, R1 is ethyl. R2 is methyl or
halogen, Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically
acceptable salt thereof.
[0050] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is naphthyl. R1 is ethyl, R2 is methyl, Z1
is --NH(R4) and R4 is methyl; or a pharmaceutically acceptable salt
thereof.
[0051] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is naphthyl, R1 is ethyl, R2 is halogen,
Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically acceptable
salt thereof.
[0052] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is benzothienyl, R1 is C1-C4alkyl,
branched C3-C5alkyl, or C3-C5carbocyclyl, R2 is hydrogen, methyl,
or halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0053] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is benzothienyl, R1 is C1-C4alkyl, R2 is
methyl or halogen, and Z1 is --NH(R4) or --NHCOR8; or a
pharmaceutically acceptable salt thereof.
[0054] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is benzothienyl, R1 is ethyl, R2 is methyl
or halogen, and Z1 is --NH(R4) or --NHCOR8; or a pharmaceutically
acceptable salt thereof.
[0055] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is benzothienyl, R1 is ethyl, R2 is methyl
or halogen, Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically
acceptable salt thereof.
[0056] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is benzothienyl, R1 is ethyl, R2 is
methyl, Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically
acceptable salt thereof.
[0057] In one embodiment, the compound of Formula Ia is a compound
of Formula Ib wherein: A is benzothienyl, R1 is ethyl, R2 is
halogen. Z1 is --NH(R4) and R4 is methyl; or a pharmaceutically
acceptable salt thereof.
[0058] In some embodiments, the present invention provides a method
treating a disease caused by c-KIT kinase comprising
gastrointestinal stromal tumors, ovarian cancer, melanoma, cervical
carcinomas, acute myeloid leukemia, germ cell tumors of the
seminoma or dysgerminoma, teratomas, mastocytosis, or mast cell
leukemia, said method comprising administering to a patient a
therapeutically effective amount of a compound selected from
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, 1-(2-fluoro-5-(l
1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)pheny-
l)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(naphthalen-1-yl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea,
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6,-n-
aphthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea,
1-(4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridi-
n-3-yl)phenyl)-3-(3-cyanophenyl)urea,
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino-
)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-o-
xo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-phenylurea,
1-(3-chlorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2,4-di fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-phenylurea,
1-(5-(4-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-phenylurea,
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea,
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(2-fluoro-phenyl)-urea,
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
[0059]
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino-1-ethyl-2-oxo-1,2-dihydro-1-
,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea,
1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,-
2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea,
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea,
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2,4-difluorophenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea,
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H-pyran-4-ylamino)-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
(S)-1-(4-chloro-5-(1-ethyl-7-(1-methoxypropan-2-ylamino)-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea,
[0060]
1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-di-
hydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1,6-naphthyrid-
in-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-thyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-brom-
o-2-fluorophenyl)-3-phenylurea,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chlo-
ro-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea,
1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)phenyl)-3-phenylurea,
14-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-
-fluorophenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(3-fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylanilino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(3,5-difluoropbenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
abydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-2-cyanoacetamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-cyanoacetamide,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-di-
fluorophenyl)-3-phenylurea,
N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea,
1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea, methyl
(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-7-yl)carbamate,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-methoxyacetamide,
2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-di-
hydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea,
N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)acetamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-3-hydroxyazetidine-1-carboxamide,
l-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
(R)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide,
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-thyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl-
)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphth-
yridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl-
)phenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl-
)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3--
yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phen-
yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea,
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)p-
henyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)form-
amide,
3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-
-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-thyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl)-1-ethy-
l-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
[0061]
3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-
-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)-
phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide,
3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-
-oxo-2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea,
3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,-
6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)pheny-
l)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-iodophenyl)-3-phenylurea, and
1-(5-((1-ethyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6--
naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea; or a
pharmaceutically acceptable salt thereof.
[0062] In some embodiments, the present invention comprises a
compound selected from the group consisting of
1-(4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridi-
n-3-yl)phenyl)-3-(3-cyanophenyl)urea,
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino-
)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-o-
xo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-2-dihydro-1,6-naphthyridin-3-yl)-2,4--
difluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-phenylurea,
1-(3-chlorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-phenylurea,
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea,
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(2-fluoro-phenyl)-urea,
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea,
[0063]
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea,
1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,-
2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea,
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)phenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea,
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2,4-difluoropbenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea,
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H-pyran-4-ylamino)-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
(S)-1-(4-chloro-5-(1-ethyl-7-(1-methoxypropan-2-ylamino)-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea,
1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea,
[0064]
1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-di-
hydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1,6-naphthyrid-
in-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea,
1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-brom-
o-2-fluorophenyl)-3-phenylurea,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chlo-
ro-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea,
1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)phenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-1,-
2-fluorophenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(3-fluorophenyl)urea,
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea,
N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-2-cyanoacetamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-cyanoacetamide,
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-di-
fluorophenyl)-3-phenylurea,
N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea,
1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
1-(4-chloro-5-(1-thyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea, methyl
(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-7-yl carbamate,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-2-methoxyacetamide,
2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-di-
hydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-cyano-5-(1-thyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
-yl)-2-fluorophenyl)-3-phenylurea,
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea,
N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)acetamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-3-hydroxyazetidine-1-carboxamide,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
(R)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide,
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)acetamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)pheny-
l)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-((4-methylpiperazin-1-yl)methy-
l)phenyl)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)pheny-
l)urea,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-(4-methylpiperazin-1-yl)methyl)phen-
yl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea,
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea,
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide,
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea,
3-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide,
N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)p-
henyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)form-
amide,
3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-
-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide,
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl-1-ethyl-
-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
[0065]
3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-
-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)-
phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide,
3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea,
N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea,
3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,-
6-naphthyridin-7-yl)-1,1-dimethylurea,
3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)pheny-
l)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide,
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-iodophenyl)-3-phenylurea, and
1-(5-(1-ethyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6-n-
aphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea; or a
pharmaceutically acceptable salt thereof.
[0066] For convenience, certain terms employed in the
specification, examples and claims are collected here. Unless
defined otherwise, all technical and scientific terms used in this
disclosure have the same meanings as commonly understood by one of
ordinary skill in the art to which this disclosure belongs. The
initial definition provided for a group or term provided in this
disclosure applies to that group or term throughout the present
disclosure individually or as part of another group, unless
otherwise indicated.
[0067] The compounds of this disclosure include any and all
possible isomers, stereoisomers, enantiomers, diastereomers,
tautomers, pharmaceutically acceptable salts, and solvates thereof,
as well as crystalline polymorphic forms of the disclosed compounds
and any and all possible isomers, stereoisomers, enantiomers,
diastereomers, tautomers, pharmaceutically acceptable salts, and
solvates thereof. Thus, the terms "compound," "compounds," "test
compound," or "test compounds" as used in this disclosure refer to
the compounds of this disclosure and any and all possible isomers,
stereoisomers, enantiomers, diastereomers, tautomers,
pharmaceutically acceptable salts, solvates, and crystalline
polymorphs thereof.
DEFINITIONS
[0068] The term "alkyl" as used herein refers to straight chain
alkyl, wherein alkyl chain length is indicated by a range of
numbers, In exemplary embodiments, "alkyl" refers to an alkyl chain
as defined above containing 1, 2, 3, 4, 5, or 6 carbons (i.e.,
C1-C6 alkyl).
[0069] Examples of an alkyl include, but are not limited to,
methyl, ethyl, propyl, butyl, pentyl, and hexyl.
[0070] The term "branched alkyl" as used herein refers to an alkyl
chain wherein a branching point in the chain exists, and the total
number of carbons in the chain is indicated by a range of numbers.
In exemplary embodiments, "branched alkyl" refers to an alkyl chain
as defined above containing 3, 4, 5, 6, or 7 carbons (i.e., C3-C7
branched alkyl). Examples of branched alkyl include, but are not
limited to, iso-propyl, iso-butyl, secondary-butyl, tertiary-butyl,
2-pentyl, 3-pentyl, 2-hexyl, and 3-hexyl.
[0071] The term "alkoxy" as used herein refers to --O-(alkyl),
wherein "alkyl" is as defined above.
[0072] The term "branched alkoxy" as used herein refers to
--O-(branched alkyl), wherein "branched alkyl" is as defined
above.
[0073] The term "alkylene" as used herein refers to an alkyl moiety
interposed between two other atoms. In exemplary embodiments,
"alkylene" refers to an alkyl moiety as defined above containing 1,
2, or 3 carbons. Examples of an alkylene group include, but are not
limited to --CH.sub.2--, --CH.sub.2CH.sub.2--, and
--CH.sub.2CH.sub.2CH.sub.2--. In exemplary embodiments, alkylene
groups are branched.
[0074] The term "alkynyl" as used herein refers to a carbon chain
containing one carbon-carbon triple bond. In exemplary embodiments,
"alkynyl" refers to a carbon chain as described above containing 2
or 3 carbons (i.e., C2-C3 alkynyl). Examples of an alkynyl group
include, but are not limited to, ethyne and propyne.
[0075] The term "aryl" as used herein refers to a cyclic
hydrocarbon, where the ring is characterized by delocalized .pi.
electrons (aromaticity) shared among the ring members, and wherein
the number of ring atoms is indicated by a range of numbers. In
exemplary embodiments, "aryl" refers to a cyclic hydrocarbon as
described above containing 6, 7, 8, 9, or 10 ring atoms (i.e.,
C6-C10 aryl). Examples of an aryl group include, but are not
limited to, benzene, naphthalene, tetralin, indene, and indane.
[0076] The term "cycloalkyl" as used herein refers to a monocyclic
saturated carbon ring, wherein the number of ring atoms is
indicated by a range of numbers. In exemplary embodiments,
"cycloalkyl" refers to a carbon ring as defined above containing 3,
4, 5, 6, 7, or 8 ring atoms (i.e., C3-C8 cycloalkyl). Examples of a
cycloalkyl group include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl.
[0077] The term "halogen" or "halo" as used herein refers to
fluorine, chlorine, bromine, and iodine.
[0078] The term "heterocycle" or "heterocyclyl" as used herein
refers to a cyclic hydrocarbon, wherein at least one of the ring
atoms is an O, N, or S, wherein the number of ring atoms is
indicated by a range of numbers. Heterocyclyl moieties as defined
herein have C or N bonding hands. For example, in some embodiments,
a ring N atom from the heterocyclyl is the bonding atom of the
heterocylic moiety. In exemplary embodiments, "heterocyclyl" refers
to a cyclic hydrocarbon as described above containing 4, 5, or 6
ring atoms (i.e., C4-C6 heterocyclyl). Examples of a heterocycle
group include, but are not limited to, aziridine, oxirane,
thiirane, azetidine, oxetane, thietane, pyrrolidine,
tetrahydrofuran, pyran, thiopyran, thiomorpholine, thiomorpholine
S-oxide, thiomorpholine S-dioxide, oxazoline, tetrahydrothiophene,
piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine,
thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane,
and dioxane.
[0079] The term "heteroaryl" as used herein refers to a cyclic
hydrocarbon, where at least one of the ring atoms is an O, N, or S,
the ring is characterized by delocalized .pi. electrons
(aromaticity) shared among the ring members, and wherein the number
of ring atoms is indicated by a range of numbers. Heteroaryl
moieties as defined herein have C or N bonding hands. For example,
in some embodiments, a ring N atom from the heteroaryl is the
bonding atom of the heteroaryl moiety. In exemplary embodiments,
"heteroaryl" refers to a cyclic hydrocarbon as described above
containing 5 or 6 ring atoms (i.e., C5-C6 heteroaryl). Examples of
a heteroaryl group include, but are not limited to, pyrrole, furan,
thiene, oxazole, thiazole, isoxazole, isothiazole, imidazole,
pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine,
pyrimidine, pyrazine, pyridazine, and triazine.
[0080] The term "substituted" in connection with a moiety as used
herein refers to a further substituent which is attached to the
moiety at any acceptable location on the moiety. Unless otherwise
indicated, moieties can bond through a carbon, nitrogen, oxygen,
sulfur, or any other acceptable atom.
[0081] The term "salts" as used herein embraces pharmaceutically
acceptable salts commonly used to form alkali metal salts of free
acids and to form addition salts of free bases. The nature of the
salt is not critical, provided that it is pharmaceutically
acceptable. Suitable pharmaceutically acceptable acid addition
salts may be prepared from an inorganic acid or from an organic
acid. Exemplary pharmaceutical salts are disclosed in Stahl, P. H.,
Wermuth, C. G., Eds. Handbook of Pharmaceutical Salts: Properties,
Selection and Use; Verlag Helvetica Chimica Acta/Wiley-VCH: Zurich,
2002, the contents of which are hereby incorporated by reference in
their entirety. Specific non-limiting examples of inorganic acids
are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,
sulfuric and phosphoric acid. Appropriate organic acids include,
without limitation, aliphatic, cycloaliphatic, aromatic,
arylaliphatic, and heterocyclyl containing carboxylic acids and
sulfonic acids, for example formic, acetic, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,
glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,
phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
algenic, 3-hydroxybutyric, galactaric or galacturonic acid.
Suitable pharmaceutically acceptable salts of free acid-containing
compounds disclosed herein include, without limitation, metallic
salts and organic salts. Exemplary metallic salts include, but are
not limited to, appropriate alkali metal (group 1a) salts, alkaline
earth metal (group IIa) salts, and other physiological acceptable
metals. Such salts can be made from aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc. Exemplary organic salts can
be made from primary amines, secondary amines, tertiary amines and
quaternary ammonium salts, for example, tromethamine, diethylamine,
tetra-N-methylammonium, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine.
[0082] The terms "administer," "administering, or "administration"
as used herein refer to either directly administering a compound or
pharmaceutically acceptable salt of the compound or a composition
to a subject.
[0083] The term "carrier" as used herein encompasses carriers,
excipients, and diluents, meaning a material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material involved in carrying or
transporting a pharmaceutical agent from one organ, or portion of
the body, to another organ or portion of the body.
[0084] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0085] The terms "effective amount" and "therapeutically effective
amount" are used interchangeably in this disclosure and refer to an
amount of a compound that, when administered to a subject, is
capable of reducing a symptom of a disorder in a subject. The
actual amount which comprises the "effective amount" or
"therapeutically effective amount" will vary depending on a number
of conditions including, but not limited to, the particular
disorder being treated, the severity of the disorder, the size and
health of the patient, and the route of administration. A skilled
medical practitioner can readily determine the appropriate amount
using methods known in the medical arts.
[0086] The terms "isolated" and "purified" as used herein refer to
a component separated from other components of a reaction mixture
or a natural source. In certain embodiments, the isolate contains
at least about 50%, at least about 55%, at least about 60%, at
least about 65%, at least about 70%, at least about 75%, at least
about 80%, at least about 85%, at least about 90%, at least about
95%, or at least about 98% of the compound or pharmaceutically
acceptable salt of the compound by weight of the isolate.
[0087] The phrase "pharmaceutically acceptable" as used herein
refers to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0088] As used in this disclosure, the terms "patient" or "subject"
include, without limitation, a human or an animal. Exemplary
animals include, but are not limited to, mammals such as mouse,
rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee,
baboon, or rhesus monkey.
[0089] "Therapeutically effective amount" or "effective amount"
means the dosage of the compound, or pharmaceutically acceptable
salt thereof, or pharmaceutical composition containing an
exemplified compound of Formula I, or pharmaceutically acceptable
salt thereof, necessary to inhibit c-KIT signaling in a cancer
patient, and either destroy the target cancer cells or slow or
arrest the progression of the cancer in a patient. The exact dosage
required to treat a patient and the length of treatment time will
be determined by a physician in view of the stage and severity of
the disease as well as the specific needs and response of the
individual patient and the particular compound administered.
Although expressed as dosage on a per day basis, the dosing regimen
may be adjusted to provide a more optimal therapeutic benefit to a
patient. In addition to daily dosing, twice-a-day (BID) or
thrice-a-day (TID) dosing may be appropriate. BID dosing is
currently preferred.
[0090] The terms "treatment," "treat," and "treating," are meant to
include the full spectrum of intervention for the cancer from which
the patient is suffering, such as administration of the active
compound to alleviate, slow or reverse one or more of the symptoms
and to delay progression of the cancer even if the cancer is not
actually eliminated. Treating can be curing, improving, or at least
partially ameliorating the disorder. The patient to be treated is a
mammal, in particular a human being.
[0091] The term "hydrate" as used herein refers to a compound
disclosed herein which is associated with water in the molecular
form, i.e., in which the H--OH bond is not split, and may be
represented, for example, by the formula R.H.sub.2O, where R is a
compound disclosed herein. A given compound may form more than one
hydrate including, for example, monohydrates (R.H.sub.2O),
dihydrates (R.2H.sub.2O), trihydrates (R.3H.sub.2O), and the
like.
[0092] The term "solvate" as used herein refers to a compound
disclosed herein which is associated with solvent in the molecular
form, i.e., in which the solvent is coordinatively bound, and may
be represented, for example, by the formula R.(solvent), where R is
a compound disclosed herein. A given compound may form more than
one solvate including, for example, monosolvates (R.(solvent)) or
polysolvates (R.n(solvent)) wherein n is an integer greater than 1)
including, for example, disolvates (R.2(solvent)), trisolvates
(R.3(solvent)), and the like, or hemisolvates, such as, for
example, R.n/2(solvent), R.n/3(solvent), R.n/4(solvent) and the
like, wherein n is an integer. Solvents herein include mixed
solvents, for example, methanol/water, and as such, the solvates
may incorporate one or more solvents within the solvate.
[0093] The term "acid hydrate" as used herein refers to a complex
that may be formed through association of a compound having one or
more base moieties with at least one compound having one or more
acid moieties or through association of a compound having one or
more acid moieties with at least one compound having one or more
base moieties, said complex being further associated with water
molecules so as to form a hydrate, wherein said hydrate is as
previously defined and R represents the complex herein described
above.
[0094] Structural, chemical and stereochemical definitions are
broadly taken from IUPAC recommendations, and more specifically
from Glossary of Terms used in Physical Organic Chemistry (IUPAC
Recommendations 1994) as summarized by Miller, P. Pure Appl. Chem.
1994, 66, pp. 1077-1184 and Basic Terminology of Stereochemistry
(IUPAC Recommendations 1996) as summarized by Moss. G. P. Pure
Appl. Chem. 1996, 68, pp. 2193-2222.
[0095] Atropisomers are defined as a subclass of conformers which
can be isolated as separate chemical species and which arise from
restricted rotation about a single bond.
[0096] Regioisomers or structural isomers are defined as isomers
involving the same atoms in different arrangements.
[0097] Enantiomers are defined as one of a pair of molecular
entities which are mirror images of each other and
non-superimposable.
[0098] Diastereomers or diastereoisomers are defined as
stereoisomers other than enantiomers. Diastereomers or
diastereoisomers are stereoisomers not related as mirror images.
Diastereoisomers are characterized by differences in physical
properties, and by some differences in chemical behavior towards
achiral as well as chiral reagents.
[0099] The term "tautomer" as used herein refers to compounds
produced by the phenomenon wherein a proton of one atom of a
molecule shifts to another atom. See March, Advanced Organic
Chemistry: Reactions, Mechanisms and Structures, 4th Ed., John
Wiley & Sons, pp. 69-74 (1992). Tautomerism is defined as
isomerism of the general form
G-X-Y=Z.revreaction.X=Y-Z-G
where the isomers (called tautomers) are readily interconvertible;
the atoms connecting the groups X, Y and Z are typically any of C,
H, O, or S, and G is a group which becomes an electrofuge or
nucleofuge during isomerization. The most common case, when the
electrofuge is H.sup.+, is also known as "prototropy." Tautomers
are defined as isomers that arise from tautomerism, independent of
whether the isomers are isolable.
[0100] The exemplified compounds of the present invention are
preferably formulated as a pharmaceutical composition using a
pharmaceutically acceptable carrier and administered by a variety
of routes. Preferably, such compositions are for oral
administration. Such pharmaceutical compositions and processes for
preparing them are well known in the art. See. e.g., REMINGTON: THE
SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds.,
19.sup.th ed., Mack Publishing Co., 1995). In a particular
embodiment, the pharmaceutical composition comprises
1-(3,3-dimethylbutyl)-3-{2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyr-
ido[2,3-d]pyrimidin-6-yl]phenyl}urea, or a pharmaceutically
acceptable salt thereof, together with a pharmaceutically
acceptable carrier and optionally other therapeutic ingredients
particularly for treatment of cancer generally or a specific cancer
type.
[0101] The exemplified compounds of the present invention are
capable of reaction with a number of inorganic and organic acids to
form pharmaceutically acceptable acid addition salts. Such
pharmaceutically acceptable salts and common methodology for
preparing them are well known in the art. See, e.g., P. Stahl, et
al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND
USE, (VCHA/Wiley-VCH, 2002); S. M. Berge, et al., "Pharmaceutical
Salts, "Journal of Pharmaceutical Sciences, Vol. 66. No. 1, January
1977.
[0102] The compounds of Formula Ia, or a pharmaceutically
acceptable salt thereof, may be prepared by a variety of procedures
known in the art, as well as those described below. The specific
synthetic steps may be combined in different ways to prepare the
Formula Ia compounds, or a pharmaceutically acceptable salt
thereof.
[0103] The compounds employed as initial starting materials in the
synthesis of the compounds of Formula Ia are well known and, to the
extent not commercially available, are readily synthesized using
specific references provided, by standard procedures commonly
employed by those of ordinary skill in the art, or are found in
general reference texts.
[0104] Examples of known procedures and methods include those
described in general reference texts such as Comprehensive Organic
Transformations, VCH Publishers Inc, 1989; Compendium of Organic
Synthetic Methods, Volumes 1-10, 1974-2002. Wiley Interscience;
Advanced Organic Chemistry. Reactions Mechanisms, and Structure,
5.sup.th Edition, Michael B. Smith and Jerry March, Wiley
Interscience, 2001; Advanced Organic Chemistry, 4.sup.th Edition.
Part B, Reactions and Synthesis, Francis A. Carey and Richard J.
Sundberg, Kluwer Academic/Plenum Publishers, 2000, etc., and
references cited therein.
[0105] ChemDraw version 10 or 12 (CambridgeSoft Corporation,
Cambridge, Mass.) was used to name the structures of intermediates
and exemplified compounds.
[0106] The following abbreviations are used in this disclosure and
have the following definitions: "ADP" is adenosine diphosphate,
"AIBN" is azobisisobutyronitrile, "ATP" is adenosine triphosphate.
"BippyPhos" is
5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole,
"BrettPhos Palladacycle" is
chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-
-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), "conc." is
concentrated, "DBU" is 1,8-diazabicyclo[5.4.0]undec-7-ene, "DCM" is
dichloromethane, "DIEA" is N,N-diisopropylethylamine, "DMA" is
N,N-dimethylacetamide, "DMAP" is 4-(dimethylamino)pyridine, "DMF"
is N,N-dimethylformamide, "DMSO" is dimethylsulfoxide, "DPPA" is
diphenylphosphryl azide, "DTT" is dithiothreitol, "ESI" is
electrospray ionization, "Et.sub.2O" is diethylether, "EtOAc" is
ethyl acetate. "EtOH" is ethanol, "GST" is glutathione
S-transferase, "h" is hour or hours, "Hex" is hexane, "IC.sub.50"
is half maximal inhibitory concentration, "IPA" refers to isopropyl
alcohol, "KF/Al.sub.2O.sub.3" is potassium fluoride on alumina,
"mCPBA" is 3-chloroperbenzoic acid, "MeCN" is acetonitrile, "MeOH"
is methanol, "MHz" is megahertz, "min" is minute or minutes. "MS"
is mass spectrometry, "MTBE" is methyl tert-butyl ether, "NADH" is
nicotinamide adenine dinucleotide, "NBS" is N-bromosuccinimide,
"NMP" is 1-methyl-2-pyrrolidinone, "NMR" is nuclear magnetic
resonance, "PBS" is phosphate buffered saline. "Pd/C" is palladium
on carbon, "Pd(OAc).sub.2" is palladium(II) acetate,
"Pd.sub.2(dba).sub.3" is tris(dibenzylideneacetone)dipalladium(0),
"pet ether" is petroleum ether, "prep-HPLC" is preparative high
performance liquid chromatography, "prep-TLC" is preparative thin
layer chromatography. "RT" is room temperature which is also known
as "ambient temp," which will be understood to consist of a range
of normal laboratory temperatures ranging from 15-25.degree. C.,
"satd." is saturated. "t-butyl-X-Phos" is
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, "TEA" is
triethylamine, "TFA" is trifluoroacetic acid, "THF" is
tetrahydrofuran. "Tris" is tris(hydroxymethyl)aminomethane,
"Xantphos" is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and
"X-Phos" is
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
General Chemistry
[0107] The compounds of Formula Ia (1) are prepared by the general
synthetic methods illustrated in the schemes below and the
accompanying examples. Suitable reaction conditions for the steps
of these schemes are well known in the art and appropriate
substitutions of solvents and co-reagents are within the skill of
the art. Those skilled in the art will understand that synthetic
intermediates may be isolated and/or purified by well known
techniques as needed or desired, and that it will be possible to
use various intermediates directly in subsequent synthetic steps
with little or no purification. Furthermore, those skilled in the
art will appreciate that in some instances, the order in which
moieties are introduced is not critical. The particular order of
steps required to produce the compounds of Formula 1 is dependent
upon the particular compound being synthesized, the starting
compound, and the relative liability of the substituted moieties,
as is well appreciated by the ordinary skilled chemist. All
substituents, unless otherwise indicated, are as defined above.
[0108] The compounds of Formula Ia (1) frequently contain --NH
moieties in the Z1 position. It will be understood by those skilled
in the art that in some instances it may be advantageous to use an
amine protecting group during synthesis to temporarily mask one or
more --NH moieties. Said protecting group can be removed from any
subsequent intermediate leading to the synthesis of compound 1,
using standard conditions that effect removal of said protecting
group, said conditions of which will be familiar to those skilled
in the art. When not specified in a scheme, it will be understood
by those skilled in the art that the Z1 moiety represented in the
schemes below may optionally contain a standard NH-protecting group
that can be removed at any opportune time in the synthetic
sequence. For example, intermediates wherein Z1 is aminomethyl, may
be obtained directly by the introduction of methylamine into a
synthetic scheme, or alternately by introduction of a "protected"
form of methylamine, for example
1-(4-methoxyphenyl)-N-methylmethanamine to provide intermediates
wherein Z1 is 1-(4-methoxyphenyl)-N-methylmethanamino. Even if not
specifically drawn, the schemes below implicitly include
de-protection of any protected Z1 moiety immediately after
introduction, or optionally at any subsequent step of the
synthesis.
##STR00006##
[0109] Scheme 1 illustrates general preparations of compounds of
formula 1 from 7-chloro-naphthyridinone 2. Conversion of chloride 2
to Z1-substituted intermediate 3 can be accomplished by numerous
methods familiar to those skilled in art, the choice of which is
dictated by the specific nature of Z1. Further conversion of
intermediate 3 to ureas of formula 1 is accomplished by one of
three methods. In one embodiment, reaction of 3 with isocyanates of
formula 4 provides ureas of formula 1. Many isocyanates (4) are
commercially available and those that are not can be readily
prepared from the corresponding amines (9) by reaction of said
amines with phosgene or an equivalent such as triphosgene or
carbonyl diimidazole. Conditions to effect the transformation of 3
to 1 include treating 3 with 4 in an aprotic solvent such as DCM,
THF or EtOAc, optionally in the presence of a base, for example
pyridine, and optionally while heating said mixtures. In a second
embodiment, reaction of 3 with carbamates of formula 5 also affords
ureas of formula 1. Conditions to effect the transformation of 3 to
1 include treating 3 with 5 in an aprotic solvent such as
1,4-dioxane, THF or DMSO, in the presence of a base, for example
N-methylpyrrolidine, diisopropylethylamine, or triethylamine, and
heating the resulting mixture. Suitable carbamates (5) include
isopropenyl, 2,2,2,-trichloroethyl and phenyl (or substituted
phenyl) carbamates. These carbamates 5 can be readily prepared by
reaction with amines 9 with the appropriate chloroformate as
familiar to those skilled in the art. In a third embodiment,
carboxylic acids of formula 5 can be subjected to a Curtius
rearrangement in the presence of amine 3 to provide ureas of
formula 1. Conditions to effect said transformation include
combining amine 3, carboxylic acid 5 and diphenylphosphoryl azide
(DPPA), and a base, for example triethylamine, and heating said
mixture in an aprotic solvent, such as 1,4-dioxane, in a
temperature range of 50-120.degree. C. to effect the
rearrangement.
[0110] In addition to these methods, compound 3 can also be
converted to 1 via two-step process by first converting 3 to
carbamate 8, followed by reaction of carbamate 8 with amine 9. As
before, suitable carbamates (8) include isopropenyl,
2,2,2,-trichloroethyl and phenyl (or substituted phenyl)
carbamates. These carbamates 8 can be readily prepared by reaction
of amine 3 with the appropriate chloroformate 11 (for example,
R=2-propenyl, 2,2,2-trichloroethyl, or phenyl). In one embodiment,
reaction of amine 3 with isopropenyl chloroformate and sodium
bicarbonate in a mixed solvent of EtOAc and water provides
carbamate 8 (R=2-propenyl). Further treatment of carbamate 8 with
amine 2 in an aprotic solvent such as 1,4-dioxane, THF or DMSO, in
the presence of a base, for example N-methylpyrrolidine,
diisopropylethylamine, or triethylamine, and heating the resulting
mixture provides compounds of formula 1.
[0111] By analogy to the conversion of 3 to 1 or 3 to
8,7-chloro-naphthyridinone 2 can also be converted to urea 7 or
carbamate 10, respectively. Further conversion of urea 7 to urea 1
is then accomplished by reaction of 7 with a generic Z1 amine,
amide, urea or carbamic acid in the presence of a Palladium
catalyst (Buchwald-type coupling), as further illustrated
below.
##STR00007##
[0112] Scheme 2 illustrates the preparation of compounds of formula
15, compounds of formula 1 wherein Z1 is --NHR4. In one embodiment,
7-chloro-naphthyridinone 2 is reacted with amine 12a (P.dbd.H), or
12b (P is a standard amine protecting group such as 4-methoxybenzyl
or tert-butoxycarbonyl) to provide 13 or 14, respectively.
Conditions for the conversion of 2 to 13 or 14 include heating an
amine of formula 12a or 12b with chloride 2, optionally in the
presence of an additional base, for example DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene), and optionally in the
presence of microwave irradiation. When "P" represents a protecting
group, said group of 14 may be removed by suitable conditions
familiar to the skilled chemist, for example by treatment with TFA
when "P" is 4-methoxybenzyl, to provide 13. Using one of the three
methods described for scheme 1, compound 13 or 14 can be convened
to ureas 15 or 16, respectively. In the event that "P" represents a
protecting group, said group of 16 may be removed by suitable
conditions familiar to the skilled chemist to provide 15.
Alternately, as described in scheme 1, amines 13 or 14 can be
converted to carbamates 17 or 18. Further reaction of these
carbamates with amine 2 provides ureas 15 or 16. Finally, ureas 15
or 16 can also be prepared from chloride 7 (scheme 1) by reaction
with amine 12a or 12b in the presence of a suitable palladium
catalyst, for example the catalyst prepared from Pd(OAc).sub.2 or
Pd.sub.2(dba).sub.3 [tris(dibenzylideneacetone)dipalladium] and a
ligand such as Xantphos
[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] or BippyPhos
[5-(di-tert-butylphosphino)-1'3',5'-triphenyl-1'H-[1,4']bipyrazole]
in the presence of a base, for example K.sub.2CO.sub.3.
##STR00008##
[0113] Scheme 3 illustrates the preparation of 21, a compound of
formula 1 wherein Z1 is --N(R4)COR8. Using methods described in
scheme 2, treatment of chlorides 2 or 7 with generic carbonylamine
19 in the presence of a suitable palladium catalyst provides
amides, ureas, or carbamates (according to the R8 moiety) of
formula 20 or 21 respectively. Further conversion of 20 to 21 is
accomplished, as described above, by treatment of 20 with 4, 5, or
6. Alternately, 20 can first be converted to carbamate 22. As
described above, further treatment of 22 with amine 9 provides urea
21.
##STR00009##
[0114] Scheme 4 illustrates alternate preparations of 21, 27 and 28
starting from intermediate 15 (scheme 2). Treatment of 15 with a
carbonylation reagent 2 according to conditions familiar to the
skilled artisan affords urea 21. The X-moiety of 23 represents a
generalized leaving group. Examples of X--(CO)R8 23 include acid
chlorides (X.dbd.Cl, R8=alkyl) or anhydrides (X.dbd.O(CO)R8), and
chloroformates (X.dbd.Cl, R8=alkoxy). Those skilled in the art will
recognize that in the instance in which R8 is --NHR4, isocyanates
of formula R4-NCO can be substituted for 23. Additionally, when R8
is an amine, the resulting ureas 27 and 28 can be prepared by
reaction of a suitable carbamate 24 with amine 25 or heterocyclic
amine 26 respectively. Suitable carbamates include alkyl,
isopropenyl, 2,2,2,-trichloroethyl and phenyl (or substituted
phenyl) carbamates. These carbamates 24 can be readily prepared by
reaction of amine 15 with the appropriate chloroformate 11 (for
example, R=2-propenyl, 2,2,2-trichloroethyl, or phenyl).
##STR00010##
[0115] Scheme 5 illustrates the general preparation of
7-chloro-naphthyridinones 2. Treatment of ethyl
4,6-dichloronicotinate (29 see: Example C3) with R1-NH.sub.2 30
provides the 4-aminopyridine 31. Conditions for this transformation
include polar solvents such as DMF, THF, acetonitrile, dioxane,
water or mixtures thereof in the presence of optionally added bases
such as triethylamine at temperatures between 0.degree. C. and
100.degree. C. Reduction of 31 for example by treatment with
lithium aluminum hydride in THF at temperatures ranging from
0.degree. C. to room temp, provides alcohol 2. Oxidation of 32 with
manganese dioxide provides aldehyde 33. Condensation of 33 with
phenylacetate 34 provides general intermediate 2. Conditions for
this transformation include combining 33 and 34 in DMF or DMAc in
the presence of potassium carbonate or cesium carbonate with
optional heating (30-150.degree. C.) for a period of time ranging
from 1 h to 4 days. Alternate conditions include combining 33, 34
and alumina-supported potassium fluoride in DMAc with stirring
and/or optional sonication and/or optional heating (30-150.degree.
C.) for a period of 10 min to 48 h.
##STR00011##
[0116] Scheme 6 illustrates a general preparation of ester 34.
Nitration of R2-substituted phenylacetic acid 35, for example by
treatment with nitric acid and sulfuric acid provides 36. Acid 36
in turn is converted to ethyl ester 37, for example by heating in
EtOH in the presence of an acid, such as sulfuric acid. Finally,
reduction of the nitro group provides 34. Suitable conditions for
this transformation include both hydrogenation over a palladium or
nickel catalyst, or reduction with iron or zinc powder in the
presence of a proton source, for example ethanolic HCl, acetic
acid, or ammonium formate. Those skilled in the art will recognize
the existence of numerous alternative preparations of general ethyl
phenylacetate 34. One additional method is illustrated by the
conversion of benzyl alcohol 38 to mesylate 39, homologation of
mesylate 39 with cyanide to benzonitrile 40, and conversion of
nitrile 40 to ethyl ester 34 by treatment with EtOH and HCl.
Alcohol 38 can be obtained from the reduction of a suitably
substituted benzoic acid or aldehyde, a sample preparation of which
is disclosed below (Example A45).
EXAMPLES
[0117] The disclosure is further illustrated by the following
examples, which are not to be construed as limiting this disclosure
in scope or spirit to the specific procedures herein described. It
is to be understood that the examples are provided to illustrate
certain embodiments and that no limitation to the scope of the
disclosure is intended thereby. It is to be further understood that
resort may be had to various other embodiments, modifications, and
equivalents thereof which may suggest themselves to those skilled
in the art without departing from the spirit of the present
disclosure and/or scope of the appended claims.
[0118] General Method A:
[0119] To a stirring solution of carboxylic acid (0.50 mmol, 1.00
eq) and DPPA (0.75 mmol, 1.50 eq) in 1,4-dioxane (5.0 mL) at RT was
added TEA (1.5 mmol, 3.00 eq). After stirring for 30 min at RT, the
appropriate amine (0.76 mmol, 1.50 eq) was added and the mixture
was heated at 100.degree. C. After 2 h, the completed reaction was
cooled to RT, diluted with brine and extracted with EtOAc
(2.times.). The combined organics were washed with 3M HCl
(1.times.), satd. NaHCO.sub.3 (2.times.), and brine (1.times.),
dried (MgSO.sub.4), concentrated in vacuo to give the crude product
which was purified by flash column chromatography to afford the
target urea.
[0120] General Method B:
[0121] To a stirring suspension of isocyanate (0.51 mmol, 1.00 eq)
and pyridine (0.0418 mL, 0.51 mmol, 1.00 eq) in DCM (5 mL) at RT
was added the appropriate amine (0.51 mmol, 1.00 eq). A thick
suspension gradually formed. After 3.5 h, the solids were collected
by filtration, rinsed well with DCM and dried on the filter to
afford the desired urea.
##STR00012##
Example A1
[0122] Example A6 (1.61 g, 4.85 mmol),
4-methoxy-N-methylbenzylamine (1.10 g, 7.28 mmol) and DBU (1.09 mL,
7.28 mmol) were combined in NMP (20 mL) and heated at 180.degree.
C. under Ar overnight. The mixture was cooled to RT, poured into
H.sub.2O (200 mL) and the resulting solids were collected by
filtration and rinsed well with H.sub.2O. The solids were dried on
the filter to dampness, dissolved in EtOAc, dried (MgSO.sub.4), and
evaporated to afford
3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-((4-methoxybenzyl)(methyl)a-
mino)-1,6-naphthyridin-2(1H)-one (2.06 g) as a brittle brown foam
contaminated slightly with EtOAc and NMP. It was used as is in the
next reaction.
##STR00013##
Example A2
[0123] Using a procedure analogous to Example A8, Example A1 (2.06
g, 4.61 mmol) was converted to
3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(methylamino)-1,6-naphthyri-
din-2(1H)-one (1.16 g, 73% yield for 2 steps). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.58 (s, 1H), 6.94-6.92
(m, 1H), 6.83 (d, J=12.0 Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 4.87 (br
s, 2H), 4.12 (q, J=6.8 Hz, 2H), 2.84 (d, J=4.8 Hz, 3H), 1.94 (s,
3H), 1.19 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 327.2[M+H].sup.+.
##STR00014##
Example A3
[0124] A suspension mixture of Example B1 (3.5 g, 0.019 mol),
Example C2 (4.4 g, 0.019 mol) and KF/Al.sub.2O.sub.3 (10 g) in DMA
was stirred at RT for 10 min. poured into water, and extracted with
EtOAc (3.times.). The combined organic phases were washed with
brine, dried (Na.sub.2SO.sub.4), concentrated in vacuo and purified
by silica gel chromatography to give
3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1-
H)-one (4 g, 60% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.75 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.24 (d, J=10.8
Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 5.40 (s, 2H), 4.26-4.24 (m, 2H),
1.18 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 352.1 [M+H].sup.+.
##STR00015##
Example A4
[0125] A mixture of Example A3 (3 g, 8.5 mmol) and
1-(4-methoxyphenyl)-N-methylmethanamine (20 mL) was charged in a
sealed vessel, and then the mixture was heated at 200.degree. C.
overnight. Volatiles were removed and the residue was purified by
column chromatography to give
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1--
ethyl-1,6-naphthyridin-2(1H)-one (3 g, 73% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.47 (s, 1H), 7.70 (s, 1H), 7.18-7.17
(m, 3H), 6.86 (d, J=8.4 Hz, 2H), 6.73 (d, J=9.6 Hz, 1H), 6.30 (s,
1H), 5.31 (s, 2H), 4.84 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.70 (s,
3H), 3.12 (s, 3H), 1.11 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 467.2
[M+H].sup.+.
##STR00016##
Example A5
[0126] To a solution of Example A4 (3 g, 6.2 mmol) in DCM (100 mL)
was added TFA (20 mL) at RT, and the resulting mixture was stirred
at RT for 6 h. The mixture was extracted with water (2.times.) and
the combined aqueous layers were neutralized with NH.sub.3H.sub.2O.
The resulting precipitate was collected by filtration and dried to
give
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyri-
din-2(1H)-one (1 g, 44% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.46 (s, 1H), 7.75 (s, 1H), 7.1 (d, J=11.2
Hz, 1H), 7.0 (m, 1H), 6.73 (d, J=9.6 Hz, 1H), 6.43 (s, 1H), 4.95
(br s, 2H), 4.14 (m, 2H), 2.92 (s, 3H), 1.14 (t, J=6.8 Hz, 3H); MS
(ESI) m/z: 347.2 [M+H].sup.+.
##STR00017##
Example A6
[0127] Example C1 (1.32 g, 6.25 mmol, 1.00 eq), Example B1 (1.15 g,
6.25 mmol, 1.00 eq) and KF/Al.sub.2O.sub.3 (40.00 wt %, 9.08 g,
62.5 mmol, 10.00 eq) were combined in DMA (35 mL) and sonicated for
2 h. The solids were removed via filtration through diatomaceous
earth and washed with EtOAc. The combined filtrates were washed
with H.sub.2O (3.times.) and the combined aqueous layers were
back-extracted with EtOAc (1.times.). The combined organics were
washed with brine (2.times.), dried (MgSO.sub.4), evaporated and
purified by silica gel chromatography (EtOAc/Hex) to afford
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1-
H)-one (1.61 g, 78% yield) as a brittle foam. MS (ESI) m/z: 332.0
[M+H].sup.+.
##STR00018##
Example A7
[0128] A solution of Example A18 (22 g, 65.7 mmol),
(4-methoxy-benzyl)-methyl-amine (14.9 g, 98.5 mmol) and DBU (15 g,
98.5 mmol) in NMP (120 mL) was heated at 160.degree. C. for 5 h.
The mixture was poured into 200 mL of water while stirring and the
resulting solids were collected by filtration, washed with water,
dried and then washed with Et.sub.2O to give
3-(5-amino-2,4-difluoro-phenyl)-1-ethyl-7-[(4-methoxy-benzyl)-methyl-amin-
o]-1H-[1,6]naphthyridin-2-one (25 g. yield 85% yield). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 8.51 (s, 1H), 7.80 (s, 1H),
7.19-7.17 (d, J=8.7 Hz, 2H), 7.06 (t, J=10.2 Hz, 1H), 6.90-6.81 (m,
3H), 6.32 (s, 1H), 5.02 (s, 2H), 4.86 (s, 2H), 4.19 (q, J=6.9 Hz,
2H), 3.72 (s, 3H), 3.14 (s, 3H), 1.14 (t, J=6.9 Hz, 3H); MS (ESI):
m/z: 451.1 [M+H].sup.+.
##STR00019##
Example A8
[0129] TFA (3.64 g, 32.0 mmol) was added to Example A7 (0.48 g,
1.06 mmol) and the mixture was stirred for 90 min at RT. Water (50
mL) was added and the reaction mixture was carefully treated with
solid Na.sub.2CO.sub.3 until it was weakly basic. The product was
extracted with EtOAc (3.times.), the combined organics were washed
with water (1.times.), then brine and dried (Na.sub.2SO.sub.4) to
afford crude product which was stirred with DCM (2 mL) for 2 h. The
resultant suspension was filtered, washed with DCM and dried to
afford
3-(5-amino-2,4-difluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2-
(1H)-one as an off-white solid, (0.28 g, 60% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.39 (s, 1H), 7.73 (s, 1H),
7.06-7.01 (m, 2H), 6.79 (dd, J=10.0, 7.6 Hz, 1H), 6.21 (s, 1H),
4.99 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 2.84 (d, J=5.2 Hz, 3H), 1.19
(t, J=7.2 Hz, 3H); MS (ESI) m/z: 331.0 [M+H].sup.+.
##STR00020##
Example A9
[0130] A solution of Example A3 (1.90 g, 5.39 mmol),
4-methoxybenzylamine (1.110 g, 8.09 mmol) and DBU (1.232 g, 8.09
mmol) in NMP (15 mL) was heated at 150.degree. C. overnight. After
cooling to RT, the mixture was diluted with EtOAc (100 mL) and
water (100 mL). The organic phase was washed with water, then
brine, dried (Na.sub.2SO.sub.4), concentrated in vacuo and purified
by reverse phase chromatography (MeCN/H.sub.2O with 0.1% TFA) to
give the TFA salt of
7-(4-methoxybenzylamino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6--
naphthyridin-2(1H)-one. The salt was treated with satd. NaHCO.sub.3
(15 mL), allowed to stand and the resulting solid was collected by
filtration, washed with water and dried in vacuo to give
7-(4-methoxybenzylamino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6--
naphthyridin-2(1H)-one (901 mg, 36% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6). .delta. 1.10 (t, 3H), 3.69 (s, 3H), 4.05-4.00 (m,
2H), 4.50-4.45 (s, 2H), 5.30 (s, 2H), 6.28 (s, 1H), 6.71-6.69 (m,
1H), 6.87-6.85 (m, 2H), 7.18-7.15 (m, 1H), 7.28-7.26 (m, 2H), 7.52
(s, 1H), 7.64 (s, 1H), 8.36 (s, 1H); MS (ES-API) m/z: 453.2
[M+H].sup.+.
##STR00021##
Example A10
[0131] Example B2 (0.701 g, 3.53 mmol), Example C2 (0.817 g, 3.53
mmol), and 40% KF on alumina (3.59 g, 24.7 mmol) were combined in
DMA (5 mL) and the mixture was sonicated for 2 h. The mixture was
diluted with EtOAc (10 mL), the solids removed via filtration
through diatomaceous earth and washed with EtOAc. The filtrate was
washed with water (2.times.), and brine, dried (Na.sub.2SO.sub.4),
concentrated in vacuo and purified by silica gel chromatography
(EtOAc\Hex) to afford
3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-isopropyl-1,6-naphthyridin-
-2(1H)-one (0.99 g, 77% yield) as a white foam. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.87 (s, 1H), 8.10 (s, 1H), 7.96 (s,
1H), 7.38 (d, J=11.2 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 5.55 (s, 2H),
5.23 (br s, 1H), 1.65 (d, J=6.4 Hz, 6H); MS (ESI) m/z: 366.0
[M+H].sup.+.
##STR00022##
Example A11
[0132] (4-Methoxyphenyl)-N-methylmethanamine (0.56 g, 3.75 mmol)
and DBU (0.52 mL, 3.75 mmol) were added to a solution of Example
A10 (0.98 g, 2.68 mmol) in NMP (10 mL) and the mixture was heated
under Ar at 155.degree. C. for 24 h. The mixture was cooled to RT,
poured into water (50 mL) and extracted with EtOAc (2.times.). The
combined organics were washed with brine, dried (Na.sub.2SO.sub.4),
concentrated in vacuo and purified by chromatography (EtOAc\DCM) to
afford
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1--
isopropyl-1,6-naphthyridin-2(1H)-one (0.78 g, 60% yield) as a white
foam. MS (ESI) m/z: 481.0 (M+H.sup.+)
[0133] TFA (5.55 g, 48.7 mmol) was added to
7-((4-methoxybenzyl)methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-i-
sopropyl-1,6-naphthyridin-2(1H)-one (0.78 g, 1.62 mmol) and the
reaction was stirred for 90 min at RT. Water (50 mL) was added and
the reaction mixture was carefully treated with solid
Na.sub.2CO.sub.3 until it was faintly basic. The solution was
extracted with EtOAc (2.times.), and the combined organics were
washed with brine, dried (Na.sub.2SO.sub.4), concentrated in vacuo
and purified by silica gel chromatography (MeOH/DCM) to afford
3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-(methylamino)-1,6-napht-
hyridin-2(1H)-one (0.42 g, 72% yield) as a white amorphous solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.34 (s, 1H), 7.60 (s,
1H), 7.17 (d, J=11.2 Hz, 1H), 6.95 (q, J=4.8 Hz, 1H), 6.71 (d,
J=9.6 Hz, 1H), 6.41 (s, 1H), 5.30 (s, 2H), 5.08 (br s, 1H), 2.84
(d, J=4.8 Hz, 3H), 1.49 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 361.0
[M+H].sup.+.
##STR00023##
Example A12
[0134] A suspension of Example A3 (1.50 g, 4.26 mmol) in
2-methoxyethylamine (3 mL, 34.51 mm) was heated at 120.degree. C.
for 12 h. The reaction mixture was diluted with water and extracted
with EtOAc (3.times.). The combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated to provide
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-n-
aphthyridin-2(H)-one (1.56 g, 94% yield) as a white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.65 (s, 1H),
7.18 (d, J=11 Hz, 1H), 7.03 (m, 1H), 6.72 (d, J=9.5 Hz, 1H), 6.38
(s, 1H), 5.30 (s, 2H), 4.07 (m, 2H), 3.47 (m, 4H), 3.25 (s, 3H),
1.20 (s, 3H); MS(ESI) m/z: 391.1 [M+H].sup.+.
##STR00024##
Example A13
[0135] A mixture of Example C5 (2.191 g, 7.94 mmol). Example B1
(1.538 g, 8.33 mmol) and KF on alumina (40 wt %) (9.22 g, 63.5
mmol) in DMA (40 mL) was sonicated for 2 h. The mixture was
filtered through a shallow bed of silica gel and rinsed well with
EtOAc. The filtrate was washed with satd. NaHCO.sub.3 (1.times.),
5% LiCl (2.times.), then brine (1.times.), dried (MgSO.sub.4), and
concentrated to dryness to afford
3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H-
)-one (2.793 g, 89% yield) as a brown solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.77 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H),
7.37 (d, 1H), 6.77 (d, 1H), 5.45 (s, 2H), 4.27 (q, 2H), 1.20 (t,
3H); MS (ESI) m/z: 398.0 [M+H].sup.+.
##STR00025##
Example A14
[0136] A suspension of Example A13 (1.50 g, 3.78 mmol) in dioxane
(15 mL) was treated with methylamine (40% in water) (26.4 mL, 303
mmol) in a pressure tube and heated to 100.degree. C. overnight.
The mixture was cooled to RT, treated with a large amount of brine,
then diluted with EtOAc until all of the solids dissolved. The
layers were separated, the aqueous layer extracted with additional
EtOAc (1.times.) and the combined organics were washed with satd.
NaHCO.sub.3 (1.times.), dried (MgSO.sub.4) and concentrated to
dryness. The resulting solid was suspended in MeCN/H.sub.2O, frozen
and lyophilized to afford
3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyrid-
in-2(1H)-one (1.32 g, 89% yield) as a light brown solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 8.37 (s, 1H), 7.62 (s, 1H),
7.30 (d, 1H), 6.99 (q, 1H), 6.73 (d, 1H), 6.21 (s, 1H), 5.33 (s,
2H), 4.11 (q, 2H), 2.84 (d, 3H), 1.19 (t, 3H); MS (ESI) m/z: 393.0
[M+H].sup.+.
##STR00026##
Example A15
[0137] To a solution of Example A3 (1.00 g, 2.84 mmol) in DMF (10
mL) was added N,N-dimethylethanediamine (0.250 g, 2.84 mmol) and
the resulting reaction mixture was heated at 100.degree. C. for 36
h. The reaction mixture was diluted with water and extracted with
EtOAc (3.times.). The combined organic layers were washed with
brine, dried (MgSO.sub.4), and the solvent evaporated. The residue
was crystallized from IPA to provide
3-(5-amino-2-chloro-4-fluorophenyl)-7-(2-(dimethylamino)ethylamino)-1-eth-
yl-1,6-naphthyridin-2(1H)-one (0.98 g, 85% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.64 (s,
1H), 7.17 (d, J=11 Hz, 1H), 6.84 (m, 1H), 6.72 (d, J=9 Hz, 1H),
6.37 (s, 1H), 5.30 (s, 2H), 4.08 (m, 2H), 3.40 (m, 2H), 2.41 (t,
J=6 Hz, 2H), 2.20 (s, 6H), 1.18 (t, J=6 Hz, 3H); MS(ESI) m/z: 404.2
[M+H].sup.+.
##STR00027##
Example A16
[0138] To a solution of Example A3 (1.00 g, 2.84 mmol) in DMF (10
mL) was added N,N-dimethylpropaneamine (0.870 g, 8.52 mmol) and the
resulting reaction mixture was heated at 100.degree. C. for 36 h.
The mixture was diluted with water and extracted with EtOAc
(3.times.). The combined organic layers were washed with brine,
dried (MgSO.sub.4), and the solvent evaporated to provide
3-(5-amino-2-chloro-4-fluorophenyl)-7-(3-(dimethylamino)propylamino)-1-et-
hyl-1,6-naphthyridin-2(1H)-one (1.10 g, 93% yield) as an orange
foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.36 (s, 1H),
7.64 (s, 1H), 7.20 (d, J=11 Hz, 1H), 7.03 (m, 1H), 6.76 (d, J=9 Hz,
1H), 6.27 (s, 1H), 5.30 (s, 2H), 4.08 (m, 2H), 3.30 (m, 2H), 2.26
(t, J=6 Hz, 2H), 2.05 (m, 6H), 1.66 (m, 2H), 1.18 (t, J=6 Hz, 3H);
MS(ESI) m/z: 418.2.2 [M+H].sup.+.
##STR00028##
Example A17
[0139] A solution of Example A3 (0.25 g, 0.710 mmol) in THF (6 mL)
was treated with dimethylamine (2M in THF, 2.84 mL, 5.68 mmol) and
heated at 80.degree. C. overnight. Additional dimethylamine (2M in
THF, 5.68 mL, 11.36 mmol) was added over 3 days and the reaction
mixture was heated at 80.degree. C. The mixture was partitioned
between DCM and satd. NaHCO.sub.3 and extracted with DCM
(3.times.). The combined organic extracts were dried (MgSO.sub.4)
and evaporated. The crude product was purified by silica gel
chromatography (EtOAc/Hex) to give
3-(5-amino-2-chloro-4-fluorophenyl)-7-(dimethylamino)-1-ethyl-1,6-naphthy-
ridin-2(1H)-one (0.21 g, 82% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.45 (s, 1H), 7.69 (s, 1H), 7.18 (d, 1H),
6.73 (d, 1H), 6.29 (s, 1H), 5.31 (br s, 2H), 4.21 (q, 2H), 3.14 (s,
6H), 1.18 (t, 3H); MS (ESI) m/z: 361.1 [M+H].sup.+.
##STR00029##
Example A18
[0140] To a solution of Example B1 (19 g, 103.3 mmol) and Example
C4 (20.3 g, 103.3 mmol) in DMF (150 mL) was added K.sub.2CO.sub.3
(28.5 g, 206.6 mmol), and the reaction mixture was heated at
90.degree. C. overnight. The mixture was poured into water (300
mL), stirred at RT for 10 min and the resulting precipitate
collected by filtration, washed with water and dried to give
3-(5-amino-2,4-difluoro-phenyl)-7-chloro-1-ethyl-1H-[1,6]naphthyridin-2-o-
ne (22 g, 65% yield). .sup.1H NMR (400 MHz, DMSO-d): .delta. 8.76
(s, 1H), 8.07 (s, 1H), 7.71 (s, 1H), 7.11 (t, J=10.4 Hz, 1H), 8.84
(dd, J=10.0, 7.6 Hz, 1H), 5.09 (s, 2H), 4.25 (q, J=6.8 Hz, 2H),
1.19 (t, J=6.8 Hz, 3H).
##STR00030##
Example A19
[0141] To a suspension of Example A18 (0.180 g, 0.536 mmol) in
dioxane (5 mL) was added 2-methoxyethylamine (0.462 mL, 5.36 mmol)
and the mixture was heated at 100.degree. C. for 20 h. Solvent from
the reaction mixture was evaporated and the residue was stirred
with water (50 mL). The solids were filtered, washed and dried to
provide
3-(5-amino-2,4-difluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphth-
yridin-2(1H)-one (0.185 g, 92% yield) as a white solid. MS(ESI)
m/z: 375.1 [M+H].sup.+.
##STR00031##
Example A20
[0142] A mixture of Example B2 (5 g, 25 mmol), Example C1 (5.3 g,
25 mmol) and Cs.sub.2CO.sub.3 (21.4 g, 66 mmol) in DMF (50 mL) was
heated at 100.degree. C. overnight. The solid was removed by
filtration and the filter cake was washed with DMF. The organics
were concentrated and the residue was purified by silica gel
chromatography (EtOAc/pet ether) to give
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-isopropyl-1,6-naphthy-
ridin-2(1H)-one (1.7 g, 20% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.69 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H),
6.87-6.84 (d, J=12.4 Hz, 1H), 6.61-6.58 (d, J=9.6 Hz, 1H),
5.11-5.08 (br s, 1H), 4.93 (s, 2H), 1.93 (s, 3H), 1.50-1.48 (d,
J=6.8 Hz, 6H); MS (ESI) m/z: 346 [M+H]
##STR00032##
Example A21
[0143] A mixture of Example A20 and (4-methoxy-benzyl)-methyl-amine
(4.5 g, 30 mmol) was heated to 180.degree. C. under a N.sub.2
atmosphere for 8 h. The excess (4-methoxy-benzyl)-methyl-amine was
removed under reduced pressure to give the crude product, which was
suspended in 50% aqueous acetic acid and stirred for 30 min. The
mixture was extracted with EtOAc (3.times.) and the combined
organics were washed with brine, dried (MgSO.sub.4) and
concentrated to give
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1--
isopropyl-1,6-naphthyridin-2(1H)-one (1.0 g, 76.9% yield), which
was used in the next step without further purification.
[0144] To a solution of
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1--
isopropyl-1,6-naphthyridin-2(1H)-one (1.0 g, 2.2 mmol) in DCM (10
mL) was added TFA (3 mL) at RT. The resulting mixture was stirred
at RT for 6 h, then washed with H.sub.2O (6.times.). The combined
aqueous layers were neutralized with NH.sub.3.H.sub.2O, extracted
with DCM (3.times.) and the combined organic layers were washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated to
give
3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylamino)-1,6-napht-
hyridin-2(1H)-one (0.5 g, 66.8% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.41 (s, 1H), 7.60 (s, 1H), 6.95 (m, 1H),
6.90 (d, J=12.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.50 (s, 1H), 5.21
(br s, 1H), 4.95 (s, 2H), 2.92 (d, J=4.8 Hz, 3H), 2.02 (s, 3H),
1.58 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 341.2[M+H].sup.+.
##STR00033##
Example A22
[0145] Example A3 (0.50 g, 1.420 mmol), 4-aminotetrahydropyran
(0.431 g, 4.26 mmol) and TEA (0.394 mL, 2.84 mmol) were combined in
NMP (5 mL) and the mixture was heated at 180.degree. C. under
microwave irradiation for 6 h. Additional 4-aminotetrahydropyran
(0.2 mL) was added and the mixture was heated at 180.degree. C.
under microwave irradiation for 3 h more. The mixture was quenched
with water and extracted with EtOAc (3.times.). The organics were
washed with 5% LiCl, then brine, dried (Na.sub.2SO.sub.4),
concentrated to dryness and purified by silica gel column
chromatography (MeOH/DCM) to obtain
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydro-2H-pyran-4-ylam-
ino)-1,6-naphthyridin-2(1H)-one (0.31 g, 52% yield). MS (ESI) m/z:
417.1 [M+H].sup.+.
##STR00034##
Example A23
[0146] Example A3 (0.4 g, 1.14 mmol) and 3-methoxypropylamine (0.5
g, 5.69 mmol) were combined in NMP (5 mL) and heated at 120.degree.
C. for 24 h. The mixture was poured in water, extracted with EtOAc
(2.times.) and the combined organics were washed with brine, dried
(Na.sub.2SO.sub.4), concentrated to dryness and purified by silica
gel chromatography (MeOH/DCM) to afford
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(3-methoxypropylamino)-1,6--
naphthyridin-2(1H)-one (409 mg, 89% yield) as an orange solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.64 (s,
1H), 7.18 (d, J=11.2 Hz, 1H), 7.04 (t, J=5.6 Hz, 1H), 7.20 (d,
J=8.8 Hz, 1H), 6.27 (s, 1H), 5.30 (s, 2H), 4.09 (q, J=6.8 Hz, 2H),
3.41-3.30 (m, 4H), 3.23 (s, 3H), 1.80-1.73 (m, 2H), 1.18 (t, J=6.8
Hz, 3H); MS (ESI) m/z: 405.1 [M+H].sup.+.
##STR00035##
Example A24
[0147] A solution of Example C4 (5 g, 23.2 mmol), Example B2 (4.6
g, 23.2 mmol) and Cs.sub.2CO.sub.3 (15 g, 2eq) in DMF were heated
at 80.degree. C. overnight. The mixture was poured into water and
extracted with EtOAc. The combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4), concentrated to dryness and
purified by silica gel chromatography to give
3-(5-amino-2,4-difluorophenyl)-7-chloro-1-isopropyl-1,6-naphthyridin-2(1H-
)-one (4 g, 49% yield). MS (ESI) m/z: 350.2 [M+H].sup.+.
##STR00036##
Example A25
[0148] A mixture of Example A24 (4 g, 11.5 mmol) and methylamine
(30 mL) was heated to 100.degree. C. in a sealed vessel for 12 h,
then cooled to RT. The mixture was concentrated and residue was
washed with EtOAc to give
3-(5-amino-2,4-difluorophenyl)-1-isopropyl-7-(methylamino)-1,6-napht-
hyridin-2(1H)-one (3.5 g, 90% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6), .delta. 8.40 (s, 1H), 7.70 (s, 1H), 7.05 (t, J=10
Hz, 1H), 6.98 (m, 1H), 6.81 (t, J=7.6 Hz, 1H), 6.45 (s, 1H), 5.10
(br s, 1H), 5.06 (s, 2H), 2.87 (d, J=4.8 Hz, 3H), 1.53 (d, J=6.8
Hz, 6H); MS (ESI) m/z: 345.1 [M+H].sup.+.
##STR00037##
Example A26
[0149] Example A3 (0.150 g, 0.426 mmol) and
(S)-(+)-1-methoxy-2-propylamine (0.228 g, 2.56 mmol) were combined
in NMP (4 mL) and heated in the microwave at 180.degree. C. for 18
h. After cooling, the reaction was diluted with satd. LiCl and
extracted with EtOAc (2.times.). The combined organics were washed
successively with satd. LiCl (1.times.), H.sub.2O (1.times.), and
brine (1.times.), dried (MgSO.sub.4), filtered and evaporated. The
crude product was purified by silica gel chromatography (EtOAc/Hex)
to afford
(S)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methoxypropan-2-ylam-
ino)-1,6-naphthyridin-2(1H)-one (0.13 g, 75% yield). MS (ESI) m/z:
405.1 (M+H.sup.+), 407.1 (M+2+H.sup.+).
##STR00038##
Example A27
[0150] A solution of Example A6 (500 mg, 1.507 mmol) and
cyclopropylamine (860 mg, 15.07 mmol) in EtOH (15 mL) was heated at
100.degree. C. in a sealed vessel. After 20 h the reaction mixture
was treated with additional cyclopropylamine (860 mg, 15.07 mmol)
and catalytic DMAP (10 mg) and heated at 100.degree. C. for 23 h,
then 115.degree. C. for 10 days. The mixture was cooled to RT,
concentrated to dryness and the resulting residue dissolved in
EtOAc (30 mL) and washed successively with water (30 mL), satd.
NaHCO.sub.3 (30 mL) and brine (30 mL). The organic phase was dried
over Na.sub.2SO.sub.4, concentrated to dryness and purified by
reverse phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
aqueous solution was treated with satd. NaHCO.sub.3 (5 mL) and
allowed to stand. A solid formed which was collected by filtration
to yield
3-(5-amino-4-fluoro-2-methylphenyl)-7-(cyclopropylamino)-1-ethyl-1,-
6-naphthyridin-2(1H)-one (124 mg, 23% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H),
6.83 (d, 1H), 6.58 (d, 1H), 6.38 (s, 1H), 4.87 (s, 2H), 4.18-4.12
(m, 2H), 2.59 (m, 1H), 1.94 (s, 3H), 1.21 (t, 3H), 0.75 (m, 2H),
0.47 (m, 2H); MS (ES-API) m/z: 353.1 [M+H].sup.+.
##STR00039##
Example A28
[0151] To a suspension of Example A6 (0.500 g, 1.507 mmol) in
dioxane (10 mL) was added 2-methoxyethylamine (2 mL, 23.22 mmol)
and the mixture was heated at 100.degree. C. for 40 h. Solvent from
the reaction mixture was evaporated and the residue was diluted
with water (50 mL) and extracted with EtOAc (3.times.). The
combined organic layers were washed with brine, dried, and the
solvent evaporated to provide
3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-n-
aphthyridin-2(1H)-one (405 mg, 73% yield) as an orange-yellow
solid. MS(ESI) m/z: 371.2 [M+H].sup.+.
##STR00040##
Example A29
[0152] A solution of Example A13 (0.500 g, 1.261 mmol) and
2-methoxy ethylamine (0.947 g, 12.61 mmol) in NMP (5 mL) was heated
at 120.degree. C. After 4 h the reaction mixture was cooled and
partitioned between EtOAc and water. The organic layer was
separated and the aqueous layer was extracted with additional EtOAc
(1.times.). The combined organic layers were washed with brine,
dried and the solvent evaporated to provide
3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(2-methoxyethylamino-
)-1,6-naphthyridin-2(1H)-one (0.486 g, 89% yield) as brownish mass.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.37 (s, 1H), 7.62 (s,
1H), 7.30 (d, J=12 Hz, 1H), 7.04 (m, 1H), 6.72 (d, J=10 Hz, 1H)
6.39 (s, 1H), 5.33 (s, 2H), 4.08 (m, 2H), 3.50 (m, 4H), 3.27 (s,
3H), 1.18 (t, J=6 Hz, 3H); MS(ESI) m/z: 435.1/437.1
[M+H].sup.+.
##STR00041##
Example A30
[0153] To a solution of Example A3 (2.0 g, 5.7 mmol) in NMP (10 mL)
was added tetrahydro-furan-3-ylamine (1.5 g, 17.2 mmol) and DBU
(1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5
min and then it was heated in the microwave at 180.degree. C. for 1
h. The reaction mixture was cooled to RT, poured into water and
extracted with EtOAc (3.times.). The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4, concentrated under reduced
pressure and purified by silica gel chromatography to give
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-
-1,6-naphthyridin-2(1H)-one (0.57 g, 25% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.39 (s, 1H), 7.66 (s, 1H), 7.27 (d,
J=6.4 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H),
6.33 (s, 1H), 5.31 (s, 2H), 4.46-4.42 (m, 1H), 4.08 (q, J=6.8 Hz,
2H), 3.89-3.81 (m, 2H), 3.75-3.69 (m, 1H), 3.55-3.52 (m, 1H),
2.22-2.17 (m, 1H), 1.83-1.79 (m, 1H), 1.20 (t, J=6.8 Hz, 3H).
##STR00042##
Example A31
[0154] Example A13 (0.165 g, 0.416 mmol) and
2-(thiomethyl)ethylamine (0.38 g, 4.16 mmol) were combined in NMP
(2 mL) and the solution was heated in the microwave at 180.degree.
C. for 5 h. The mixture was poured into water (30 mL) and the
resultant suspension was filtered, washed with water and dried to
afford
3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)-1-
,6-naphthyridin-2(1H)-one (0.19 g, 100% yield) as an off-white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.37 (s, 1H),
7.62 (s, 1H), 7.30 (d, J=10.8 Hz, 1H), 7.15 (t, J=6.8 Hz, 1H), 7.32
(d, J=8.8 Hz, 1H), 6.33 (s, 1H), 5.33 (s, 2H), 4.09 (q, J=7.2 Hz,
2H), 3.53 (q, J=7.2 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.10 (s, 3H),
1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 451.1 [M+H].sup.+.
##STR00043##
Example A32
[0155] Example A13 (2.5 g, 6.35 mmol) and 4-methoxybenzylamine (50
mL) were combined and heated at 140.degree. C. overnight. The
reaction mixture was cooled to RT, then poured into water. The
resulting solid was collected via filtration, dried and purified by
silica gel chromatography (EtOAc/pet ether) to give
7-(4-methoxybenzylamino)-3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-1,6-n-
aphthyridin-2(1H)-one (2.5 g, 81% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.35 (s, 1H), 7.59 (s, 1H), 7.51-7.48 (t,
J=5.6 Hz, 1H), 7.29 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4
Hz, 2H), 6.70 (d, J=9.6 Hz, 1H), 6.27 (s, 1H), 5.31 (s, 2H), 4.45
(d, J=5.6 Hz, 2H), 4.06-4.01 (q, J=6.8 Hz, 2H), 3.53 (s, 3H),
1.10-1.07 (t, J=6.8 Hz, 3H).
##STR00044##
Example A33
[0156] Example A32 (2.5 g, 13.8 mmol) in TFA (30 mL) was stirred at
50-60.degree. C. for 2 days. The mixture was concentrated,
dissolved in EtOAc (100 mL) and washed with satd. NaHCO.sub.3
(3.times.), then brine (3.times.). The organic layer was dried with
Na.sub.2SO.sub.4, and concentrated to obtain crude product.
Hydrochloric acid (6 M, 100 mL) was added to the residue and the
solution was washed with EtOAc (3.times.). The aqueous layer was
neutralized with satd. NaHCO.sub.3 and then extracted with EtOAc
(3.times.). The organic layers were washed with brine (1.times.),
dried and concentrated to give
7-amino-3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(H)--
one (1 g, 53% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.56 (s, 1H), 7.79 (s, 1H), 7.73 (s, 2H), 7.37 (d, J=10.8 Hz, 1H),
6.77 (s, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.89-5.03 (br s, 2H),
4.14-4.08 (q, J=6.8 Hz, 2H), 1.25-1.21 (t, J=6.8 Hz, 3H).
##STR00045##
Example A34
[0157] A solution of Example A6 (2.5 g, 7.5 mmol) and
4-methoxybenzylamine (30 mL) was refluxed at 140.degree. C. for 2
h. After cooling to RT, the reaction mixture was poured into a 20%
aq. solution of acetic acid and stirred for 0.5 h. The mixture was
filtered to provide
7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6--
naphthyridin-2(1H)-one.
[0158] TFA (2 mL, 26.9 mmol) was added to a solution of
7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6--
naphthyridin-2(l 1H)-one in DCM (10 mL) and the reaction mixture
was refluxed at 50.degree. C. for 2 h. After cooling to RT, the
reaction mixture was washed with water and the combined aqueous
layers were neutralized with satd. NaHCO.sub.3. The aqueous layer
was extracted with EtOAc (3.times.) and the extracts were dried
(Na.sub.2SO.sub.4) and concentrated to give
7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(H)-
-one (0.9 g, 46% yield, over 2 steps). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 8.30 (s, 1H), 7.56 (s, 1H), 6.83 (d, J=12.3
Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.40 (s, 2H), 6.32 (s, 1H), 4.85
(s, 2H), 4.07 (q, J=6.9 Hz, 2H), 1.94 (s, 3H), 1.19 (t, J=6.9 Hz,
3H); MS (ESI) m/z: 313.3 [M+H].sup.+.
##STR00046##
Example A35
[0159] Example A9 (2 g, 4.4 mmol) in TFA (10 mL) was stirred at
60.degree. C. overnight, cooled to RT, added to water (10 mL) and
extracted with EtOAc (3.times.). The combined organics layers were
washed with brine, dried over Na.sub.2SO.sub.4, concentrated in
vacuo, and purified by silica gel chromatography to afford
7-amino-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H-
)-one (870 mg, 59% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.35 (s, 1H), 7.68 (s, 1H), 7.21 (d, J=10.8 Hz, 1H), 6.75
(d, J=9.6 Hz, 1H), 6.52 (s, 2H), 6.35 (s, 1H), 5.33 (s, 2H), 4.09
(q, J=6.8 Hz, 2H), 1.22 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 333.2
[M+H].sup.+.
##STR00047##
Example A36
[0160] A solution of Example A18 (1 g, 3 mmol) in
(4-methoxyphenyl)methanamine (10 mL) was heated at 130.degree. C.
overnight. The mixture was cooled to RT, poured into a mixture of
1:1 acetic acid and water (10 mL), stirred for 30 minutes, and
extracted with EtOAc (2.times.). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and the
filtrate concentrated to give a crude product which was purified by
silica gel chromatography to give
7-(4-methoxybenzylamino)-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6--
naphthyridin-2(1H)-one (1 g, 69% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.40 (s, 1H), 7.74 (s, 1H), 7.57-7.54 (m,
1H), 7.30 (d, J=8.4 Hz, 2H), 7.08-7.03 (m, 1H), 6.90 (d, J=4.4 Hz,
2H), 6.78-6.72 (m, 1H), 6.30 (s, 1H), 5.02 (s, 2H), 4.49 (d, J=6.0
Hz, 2H), 4.11-4.09 (q, J=7.2 Hz, 2H), 3.72 (s, 3H), 1.14-1.11 (t,
J=6.8 Hz, 3H).
##STR00048##
Example A37
[0161] To a solution of Example B3 (1 g, 5.5 mmol) and Example C5
(1.53 g, 5.5 mmol) in DMA (10 mL) was added KF/Al.sub.2O.sub.3 (3
g), and the mixture was stirred at RT for 10 min. The reaction
mixture was filtered, the filtrate concentrated and the residue
poured into water. The resulting solid was collected via
filtration, washed with water, dried under vacuum and washed with
MTBE to give
3-(5-amino-2-bromo-4-fluoro-phenyl)-7-chloro-1-methyl-1H-[1,6]naphthyridi-
n-2-one (1.5 g, 67% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.76 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.37 (d, J=11.2,
1 H), 6.75 (d, J=9.6 Hz, 1H), 5.44 (s, 2H), 3.62 (s, 3H).
##STR00049##
Example A38
[0162] A solution of Example B1 (6.0 g, 0.033 mol), ethyl
2-(3-amino-4-fluorophenyl)acetate (6.4 g, 0.033 mol) and
K.sub.2CO.sub.1 (9.17 g, 0.066 mol) in DMF (100 mL) was heated to
80.degree. C. overnight. The reaction mixture was poured into the
water and extracted with EtOAc (3.times.). The combined extracts
were washed with brine (3.times.), dried (MgSO.sub.4), concentrated
in vacuo and purified by chromatography to provide
3-(3-amino-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one
(7.0 g, 68% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.75 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.13 (dd, J=8.8, 2.0 Hz,
1H), 7.02 (dd, J=11.6, 8.4 Hz, 1H), 6.80 (m, 1H), 5.20 (s, 2H),
4.25 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 318.2
[M+H].sup.+.
##STR00050##
Example A39
[0163] Using the 2-step procedure of Example A4 and A5, Example A38
(0.85 g, 2.7 mmol) and 4-methoxybenzylmethylamine (10 mL) were
combined to provide
3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyrid-
in-2(1H)-one (0.45 g, 32% yield, 2 steps). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 8.40 (s, 1H), 7.77 (s, 1H), 7.11 (d, J=9.0
Hz, 1H), 6.95 (m, 2H), 6.76 (m, 1H), 6.19 (s, 1H), 5.09 (s, 2H),
4.14 (m, 2H), 2.85 (br s, 3H), 1.20 (t, J=6.0, 3 H); MS (ESI) m/z
(M+H.sup.+): 313.3.
##STR00051##
Example A40
[0164] KF/Al.sub.2O.sub.3 (40 wt %, 10 g, 69 mmol) was added to a
solution of Example B2 (6 g, 30 mmol) and ethyl
(3-amino-4-fluorophenyl)acetate (6 g, 30 mmol) in DMA (80 mL) and
stirred at RT for 1 h. The mixture was filtered and the filtrate
was concentrated under vacuum. The residue was poured into water,
and the precipitate was collected by filtration, washed with
Et.sub.2O, and dried in vacuo to give
3-(3-amino-4-fluorophenyl)-7-chloro-1-isopropyl-1,6-naphthyridin-2(1H)-on-
e (7 g, 70% yield). .sup.1H NMR (400 Hz, DMSO-d.sub.6): .delta.
8.71 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.11 (dd, J=9.2, 2.4 Hz,
1H), 7.05 (dd, J=11.6, 8.4 Hz, 1H), 6.76 (m, 1H), 5.18 (s, 2H),
5.15 (m, 1H), 1.52 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 332.0
[M+H].sup.+.
[0165] A mixture of
3-(3-amino-4-fluorophenyl)-7-chloro-1-isopropyl-1,6-naphthyridin-2(1H)-on-
e (4 g, 12.1 mmol) and (4-methoxybenzyl)methylamine (15 mL) was
degassed under reduced pressure, then heated to 180.degree. C.
under N.sub.2 for 4 h. After cooling, the reaction mixture was
diluted with Et.sub.2O. The precipitate was filtered, washed with
Et.sub.2O and dried in vacuo to give
3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-[(4-methoxybenzyl)-methyl--
amino]-1H-[1,6]naphthyridin-2-one (5.3 g) as a solid contaminated
with (4-methoxybenzyl)methylamine HCl salt.
[0166] The above prepared
3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-[(4-methoxy-benzyl)-methyl-amin-
o]-1H-[1,6]naphthyridin-2-one (5.3 g) was combined with TFA (50 mL)
in DCM (150 mL) and heated at reflux overnight. The volatiles were
removed under reduced pressure, the residue dissolved in 10% HCl
and washed with EtOAc (3.times.). The aqueous layer was made basic
(pH=11), extracted with EtOAc and the combined organics were dried
(Na.sub.2SO.sub.4) and concentrated to give
3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-methylamino-1H-[1,6]naphthyridi-
n-2-one (1.26 g, 32% yield over two steps). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.70 (s, 1H), 7.06 (dd, J=8.4,
2.0 Hz, 1H), 6.94 (dd, J=11.6, 8.4 Hz, 1H), 6.88 (m, 1H), 6.72 (m,
1H), 6.39 (s, 1H), 5.07 (m, 1H), 5.06 (s, 2H), 2.83 (d, J=4.8 Hz,
1H), 1.51 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 327.1 [M+H].sup.+.
##STR00052##
Example A41
[0167] Example C2 (3 g, 12.9 mmol), Example B3 (2.2 g, 12.9 mmol)
and KF/Al.sub.2O.sub.3 (40%, 6 g, 41 mmol) were combined in DMA (40
mL) and the resultant mixture was stirred at RT for 1 h. The
mixture was filtered and the filtrate was concentrated in vacuo.
The residue was washed with Et.sub.2O to give
3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(-
1H)-one (2.6 g, 60/% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.74 (s, 1H), 8.00 (s, 1H), 7.63 (s, 1H), 7.23 (d, J=11.2
Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 5.40 (s, 2H), 3.60 (s, 3H); MS
(ESI) m/z: 338.1 [M+H].sup.+.
[0168] A mixture of
3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(-
1H)-one (2.5 g, 7.4 mmol) and 4-methoxy-N-methylbenzylamine (4 mL)
was heated to 180.degree. C. under N.sub.2, for 3 h. After cooling,
the reaction mixture was diluted with Et.sub.2O. The precipitate
was filtered, washed with water, and dried to give
7-((4-methoxybenzyl)methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-m-
ethyl-1,6-naphthyridin-2(1H)-one (3 g, 89% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.47 (s, 1H), 7.77 (s, 1H) 7.22 (m,
2H), 7.17 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.86 (d, J=9.6
Hz, 1H), 6.30 (s, 1H), 5.32 (s, 2H) 4.87 (s, 1H), 3.72 (s, 3H),
3.52 (s, 3H), 3.09 (s, 3H); MS (ESI) m/z: 453.2[M+H].sup.+.
[0169] A solution of
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1--
methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.6 mmol) in DCM (50 mL)
was treated with TFA (20 mL) and the mixture was heated to reflux
overnight. The mixture was concentrated under reduced pressure, the
residue was dissolved in 10% HCl (50 mL), washed with EtOAc,
neutralized with satd. NaHCO.sub.3 and extracted with EtOAc
(3.times.). The combined organics were washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give
3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyr-
idin-2(1H)-one (1.6 g, 72% yield) .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.66 (s, 1H), 7.17 (d, J=10.8
Hz, 1H), 7.05 (m, 1H), 6.71 (d, J=9.6 Hz, 1), 6.15 (s, 1H), 5.30
(s, 2H), 3.47 (s, 3H), 3.42 (s, 1H), 2.84 (d, J=4.4 Hz, 3H); MS
(ESI) m/z: 333.1 [M+H].sup.+
##STR00053##
Example A42
[0170] Example B3 (3.2 g, 18.8 mmol). Example C6 (4.0 g, 18.8 mmol)
and Cs.sub.2CO.sub.3 (12.3 g, 37.6 mmol) were combined in DMF (80
mL) and heated to 80.degree. C. for 4 h. The reaction mixture was
poured into water (600 mL) and the precipitate was collected by
filtration and dried under reduced pressure to give
3-(5-amino-2-chlorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one
(5.0 g, 83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.74 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.09 (d, J=8.4 Hz, 1H),
6.57 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.52 (s, 1H), 5.31 (s, 2H), 3.60
(s, 3H).
[0171] A mixture of
3-(5-amino-2-chlorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one
(5 g, 15.67 mmol), 4-methoxybenzylmethylamine (3.6 g, 23.5 mmol)
and DBU (3.7 g, 23.5 mmol) in NMP (80 mL) was heated at 180.degree.
C. under N.sub.2 for 4 h. The reaction was cooled to RT and poured
into water (600 mL). The precipitate was collected by filtration
and dried in vacuo to give
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-meth-
yl-1,6-naphthyridin-2(1H)-one (6.5 g, 95% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.46 (s, 1H), 7.68 (s, 1H), 7.16 (d,
J=8.8 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H),
6.54-6.51 (m, 2H), 6.29 (s, 1H), 5.23 (s, 2H), 4.85 (s, 2H), 3.69
(s, 3H), 3.51 (s, 3H), 3.07 (s, 3H).
[0172] TFA (10 mL, 134 mmol) was added to a solution of
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,-
6-naphthyridin-2(1H)-one (4 g, 9.2 mmol) in DCM (50 mL) and heated
to reflux for 3 h. The reaction mixture was concentrated under
reduced pressure, dissolved in HCl, washed with EtOAc (3.times.),
neutralized with satd. Na.sub.2CO.sub.3 and extracted with EtOAc
(3.times.). The combined extracts were washed with brine, dried
over Na.sub.2SO.sub.4, concentrated under reduced pressure and
purified by chromatography to give
3-(5-amino-2-chlorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-
-2(1H)-one (1.7 g, 58% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.36 (s, 1H), 7.63 (s, 1H), 7.06-7.00 (m, 2H), 6.54-6.50
(m, 2H), 6.14 (s, 1H), 5.21 (s, 2H), 3.48 (s, 3H), 2.84 (d, J=4.8
Hz, 3H); MS (ESI) m/z: 314.9 [M+H].sup.+.
##STR00054##
Example A43
[0173] A solution of Example B3 (2 g, 11.8 mmol) in DMA (40 mL) was
treated with Example C1 (2.5 g, 11.8 mmol), followed by
KF/Al.sub.2O.sub.3 (40 wt %, 10 g, 68 mmol) and stirred at RT for 2
h. The mixture was filtered, the filtrate poured into water and the
precipitate was collected by filtration and dried to give
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(-
1H)-one (2.5 g, 69% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.72 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.88 (d, J=12.3
Hz, 1H), 6.60 (d, J=6 Hz, 1H), 4.95 (s, 2H), 3.60 (s, 3H), 1.95 (s,
3H); MS (ESI) m/z: 318.0 [M+H]+.
[0174]
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyri-
din-2(H)-one (1.36 g, 4.28 mmol, 1.00 eq),
4-methoxy-N-methylbenzylamine (0.971 g, 6.42 mmol, 1.50 eq) and DBU
(0.960 mL, 6.42 mmol, 1.50 eq) were combined in NMP (20 mL) and
heated at 180.degree. C. under Ar overnight. The mixture was cooled
to RT and poured onto H.sub.2O (200 mL). The resulting solids were
collected by filtration, rinsed very well with H.sub.2O, dried on
the filter to dampness and then dissolved in EtOAc. The solution
was dried (MgSO.sub.4), filtered and evaporated to afford
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1--
methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 100% yield) as a brittle
brown foam which was used as is in the next reaction. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.45 (s, 1H), 7.63 (s, 1H), 7.16
(d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.86-6.82 (m, 1H), 6.57
(d, J=9.6 Hz, 1H), 6.29 (s, 1H), 4.88 (br s, 2H), 4.85 (s, 2H),
3.69 (s, 3H), 3.52 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H); MS (ESI)
m/z: 433.3 [M+H].sup.+.
[0175]
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphen-
yl)-1-methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 4.3 mmol) and TFA
(9.5 mL, 121 mmol) were combined and stirred at RT overnight. The
mixture was treated slowly with 2M Na.sub.2CO.sub.3 until the
mixture was just faintly basic, then stirred at RT for 1 h. The
solids were collected by filtration, washed thoroughly with
H.sub.2O, dried partially in the air and then under high vacuum at
65.degree. C. The crude product was purified by flash column
chromatography (THF/EtOAc) to afford
3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylamino)-1,6-naphthyr-
idin-2(1H)-one (0.86 g, 64% yield) as an off-white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 8.35 (s, 1H), 7.58 (s, 1H),
6.99 (q, J=4.8 Hz, 1H), 6.56 (d, J=12.0 Hz, 1H), 6.56 (d, J=9.2 Hz,
1H), 6.15 (s, 1H), 4.87 (br s, 2H), 3.48 (s, 3H), 2.84 (d, J=5.2
Hz, 3H), 1.94 (s, 3H); MS (ESI) m/z: 313.2 [M+H].sup.+.
##STR00055##
Example A44
[0176] Example B3 (2 g, 9.3 mmol), Example C4 (1.6 g, 9.3 mmol) and
KF/Al.sub.2O.sub.3 (40%, 5 g, 34.4 mmol) were combined in DMA and
stirred for 10 min. The reaction mixture was poured into water and
extracted with EtOAc. The combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue was purified by chromatography to give
3-(5-amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-o-
ne (2 g, 68% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
8.41 (s, 1H), 7.73 (s, 1H), 7.06-7.03 (m, 1H), 6.81-6.75 (m, 1H),
6.15 (s, 1H), 4.98 (s, 2H), 3.48 (s, 3H); MS (ESI) m/z: 322.7
[M+H].sup.+.
[0177]
3-(5-Amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2-
(H)-one (2.4 g, 7.5 mmol) and 4-methoxy-N-methylbenzylamine (10 mL)
were combined in a sealed vessel and heated to 200.degree. C.
overnight. The volatiles were removed in vacuo and the residue was
purified by column chromatography to give
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methy-
l-1,6-naphthyridin-2(1H)-one (3 g, 91% yield), which was used in
the next step without further purification.
[0178] A solution of 7-((4-methoxybenzyl
Kmethyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2-
(1H)-one (3 g, 6.8 mmol) in DCM (100 mL) was treated with TFA (20
mL) and stirred at RT for 6 h. The mixture was extracted with water
and the combined aqueous layers were neutralized with
NH.sub.3.H.sub.2O. The precipitate was collected by filtration and
dried to give
3-(5-amino-2,4-difluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin--
2(1H)-one (661 mg, 30% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.39 (s, 1H), 7.78 (s, 1H), 7.08-6.93 (m, 2H), 6.80 (dd,
J=10.2, 8.1 Hz, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 3.50 (s, 3H), 2.84
(d, J=4.8 Hz, 3H); MS (ESI) m/z: 317.0 [M+H].sup.+.
##STR00056##
Example A45
[0179] A solution of 4-chloro-2-fluoroaniline (5.0 g, 34.3 mmol) in
acetic acid (3 mL) was treated with acetic anhydride (6.45 mL, 68.7
mmol) and stirred at RT for 2 h. The mixture was poured onto ice
water, stirred for 2 h and the resulting solid collected via
filtration and dried to afford N-(4-chloro-2-fluorophenyl)acetamide
(6.12 g, 95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.80 (s, 1H), 7.91 (t, J=8.7 Hz, 1H), 7.45 (dd, J=10.8, 2.4 Hz,
1H), 7.22 (d, J=8.9 Hz, 1H), 2.07 (s, 3H).
[0180] A -78.degree. C. solution of
N-(4-chloro-2-fluorophenyl)acetamide (2.00 g, 10.66 mmol) in THF
(40 mL), under Ar, was treated with butyl lithium (16.66 mL, 26.7
mmol), stirred at -78.degree. C. for 2.5 h, treated slowly with DMF
(1.651 mL, 21.32 mmol), stirred for 15 min at -78.degree. C. and
slowly warmed to RT. The mixture was stirred for 2 h, treated with
satd. NH.sub.4Cl, the layers separated and the aqueous layer
extracted with EtOAc (1.times.). The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4, concentrated to dryness
and purified via silica gel chromatography (EtOAc/Hex) to afford
N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 48% yield) as
an off-white solid. MS (ESI) m/z: 216.0 [M+H].sup.+.
[0181] A 0.degree. C. solution of
N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 5.10 mmol) in
MeOH (10 mL) was treated portion-wise with sodium borohydride
(0.193 g, 5.10 mmol), stirred at 0.degree. C. for 0.5 h, then
warmed to RT and concentrated to dryness. The residue was treated
with water, extracted with EtOAc (2.times.) and the combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford
N-(4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)acetamide (1.05 g, 95%
yield) as a white solid. MS (ESI) m/z: 218.0 [M+H].sup.+.
[0182] A 0.degree. C. of
N-(4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)acetamide (1.05 g,
4.82 mmol) and TEA (1.003 mL, 7.24 mmol) in DCM (30 mL) was treated
slowly with methanesulfonyl chloride (0.414 mL, 5.31 mmol), warmed
to RT and stirred for 2 h. The mixture was treated with satd.
NaHCO.sub.3, extracted with DCM (2.times.) and the combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford
3-acetamido-6-chloro-2-fluorobenzyl methanesulfonate (1.31 g, 74%
yield) as an off-white solid. MS (ESI) m/z: 296.0 [M+H].sup.+.
[0183] A solution of 3-acetamido-6-chloro-2-fluorobenzyl
methanesulfonate (1.31 g, 3.54 mmol) in DMSO (10 mL) was treated
with sodium cyanide (0.868 g, 17.72 mmol), stirred at RT overnight,
treated with water and extracted with EtOAc (2.times.). The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via silica
gel chromatography (EtOAc/Hex) to afford
N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (630 mg, 78%
yield) as a yellow solid. MS (ESI) m/z: 227.0 [M+H].sup.+.
[0184] HCl gas was bubbled into 0.degree. C. EtOH (30 mL), added to
N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (0.28 g, 1.235
mmol) and heated at 80.degree. C. for 7 h. The mixture was cooled
to RT, concentrated to dryness and the residue neutralized with
satd. NaHCO.sub.3. The mixture was extracted with EtOAc (2.times.)
and the combined organics were washed with brine, dried over
Na.sub.2SO.sub.4 and purified via silica gel chromatography
(EtOAc/Hex) to afford ethyl
2-(3-amino-6-chloro-2-fluorophenyl)acetate (250 mg, 87% yield) as
an off-white solid. MS (ESI) m/z: 232.1 [M+H].sup.+.
[0185] A solution of ethyl
2-(3-amino-6-chloro-2-fluorophenyl)acetate (0.252 g, 1.089 mmol) in
DMA (5 mL) was treated with Example B1 (0.201 g, 1.089 mmol) and KF
on alumina (40%, 1.107 g, 7.62 mmol) and sonicated for 1 h. The
mixture was diluted with EtOAc, filtered through diatomaceous earth
and rinsed well with EtOAc. The filtrate was washed with water,
then brine, dried over Na.sub.2SO.sub.4 and concentrated to dryness
to afford crude
3-(3-amino-6-chloro-2-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1-
H)-one (450 mg, 117% yield) as a white amorphous solid which was
used without further purification. MS (ESI) m/z: 352.0
[M+H].sup.+.
[0186] A solution of
3-(3-amino-6-chloro-2-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1-
H)-one (0.45 g, 1.150 mmol) in dioxane (5 mL) was treated with
methylamine (40% in water, 7.14 g, 92 mmol) and heated at
100.degree. C. overnight. The mixture was cooled to RT, treated
with brine and extracted with EtOAc (2.times.). The combined
organics were dried over Na.sub.2SO.sub.4, concentrated to dryness
and purified via silica gel chromatography (MeOH/DCM) to afford
3-(3-amino-6-chloro-2-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyri-
din-2(1H)-one (350 mg, 88% yield) as a white amorphous solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.41 (s, 1H), 7.74 (s,
1H), 7.07 (q, J=4.9 Hz, 1H), 7.03 (dd, J=8.7, 1.3 Hz, 1H), 6.77 (t,
J=9.0 Hz, 1H), 6.25 (s, 1H), 5.30 (s, 2H), 4.15-4.13 (q, J=7.0 Hz,
2H), 2.87 (d, J=4.9 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z:
347.1 [M+H].sup.+.
##STR00057##
Example A46
[0187] Using the three-step procedure of Example A42, Example B1
(3.5 g, 18.8 mmol), Example C6 (4.0 g, 18.8 mmol), Cs.sub.2CO.sub.3
(12.3 g, 37.6 mmol), 4-methoxybenzylmethylamine (3.6 g, 23.5 mmol)
and TFA (10 mL, 134 mmol) were combined to provide
3-(5-amino-2-chlorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-
-one (1.68 g, 27% yield over 3 steps). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.36 (s, 1H), 7.62 (s, 1H), 7.05 (dd, J=7.2,
2.0 Hz, 1H), 6.96 (q, J=4.8 Hz, 1H), 6.54-6.50 (m, 2H), 6.21 (s,
1H), 5.21 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 2.84 (d, J=4.8 Hz, 3H),
1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 329.2[M+H].sup.+.
##STR00058##
Example A47
[0188] A bi-phasic mixture of Example A4 (1.00 g, 2.142 mmol) in
EtOAc (25 mL) and satd. NaHCO.sub.3 (25 mL) was treated with
isopropenyl chloroformate (516 mg, 4.28 mmol) and stirred
vigorously at RT for 3 h. Hexane (10 mL) was added and the
resulting solid collected via filtration and dried. The layers of
the filtrate were separated, the organic layer washed with brine,
dried over Na.sub.2SO.sub.4, concentrated to dryness and combined
with the above-isolated solid to afford prop-1-en-2-yl
(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (1.168 g, 98%
yield). MS (ESI) m/z: 551.2 [M+H].sup.+.
##STR00059##
Example A48
[0189] A biphasic solution of Example A2 (300 mg, 0.919 mmol) in
EtOAc (10 mL) and satd. NaHCO.sub.3 (10 mL) was treated with
isopropenyl chloroformate (138 mg, 1.149 mmol) and stirred at RT
for 6 h. Additional isopropenyl chloroformate (50 .mu.L) was added
and the mixture stirred at RT overnight. The layers were separated,
the organic layer washed with brine, dried over Na.sub.2SO.sub.4
and concentrated to dryness to afford prop-1-en-2-yl
(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fl-
uoro-4-methylphenyl)carbamate (378 mg, 100% yield). MS (ESI) m/z:
411.2 [M+H].sup.+.
##STR00060##
Example A49
[0190] A 0.degree. C. solution of Example A14 (0.75 g, 1.917 mmol)
in a biphasic mixture of 1:1:1 EtOAc/THF/satd. NaHCO.sub.3 (90 mL)
was treated with isopropenyl chloroformate (0.220 mL, 2.013 mmol),
allowed to warm to RT and stirred overnight. Additional isopropenyl
chloroformate (0.220 mL, 2.013 mmol) was added, the mixture stirred
at RT for 3 h, then placed in the refrigerator overnight. The
mixture was extracted with EtOAc (2.times.) and the combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford prop-1-en-2-yl
(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3--
yl)-2-fluorophenyl)carbamate (960 mg, 105% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.81 (s, 1H), 8.39 (s, 1H), 7.72-7.61
(m, 3H), 7.04 (m, 1H), 6.23 (s, 1H), 4.72 (d, J=9.5 Hz, 2H), 4.13
(m, 2H), 2.85 (d, J=4.8 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.0 Hz,
3H); MS (ESI) m/z: 475.1 [M+H].sup.+.
##STR00061##
Example A50
[0191] A solution of Example 21 (0.1 g, 0.221 mmol) in pyridine (5
mL) was treated with isopropenyl chloroformate (0.027 mL, 0.243
mmol) and stirred at RT overnight. Water was added and the
resulting solid was collected via filtration and dried to afford
prop-1-en-2-yl
(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-7-yl)carbamate (105 mg, 89% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.82 (s, 1H), 9.10 (s, 1H), 8.72
(d, J=2.6 Hz, 1H), 8.70 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.99 (s,
1H), 7.91 (s, 1H), 7.57 (d, J=11.0 Hz, 1H), 7.41 (dd, J=8.2, 1.2
Hz, 2H), 7.26 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.80-4.79 (m, 2H),
4.21 (q, J=7.1 Hz, 2H), 1.96 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); MS
(ESI) m/z: 536.1 [M+H].sup.+.
##STR00062##
Example A51
[0192] A suspension of Example A5 (0.154 g, 0.444 mmol) in EtOAc
(2.5 mL) was treated with satd. NaHCO.sub.3 (2.5 mL) and
isopropenyl chloroformate (0.046 mL, 0.422 mmol) and the biphasic
mixture stirred vigorously at RT for 3.5 h. Additional isopropenyl
chloroformate (20 .mu.L) was added and the mixture was stirred at
RT overnight. The mixture was diluted with additional EtOAc and
satd. NaHCO.sub.3 and the layers separated. The organic layer was
washed with brine, dried over MgSO.sub.4 and concentrated to
dryness. The resulting residue was dissolved in pyridine (1.5 mL),
cooled to 0.degree. C., treated with isopropenyl chloroformate (15
.mu.L) and allowed to warm to RT. The mixture was re-cooled to
0.degree. C., treated with additional isopropenyl chloroformate (7
.mu.L) and allowed to warm to RT. The mixture was once again cooled
to 0.degree. C., treated with isopropenyl chloroformate (5 .mu.L),
allowed to warm to RT and stirred overnight. The mixture was
concentrated to dryness, treated with brine and extracted with
EtOAc (2.times.). The combined organics were dried over MgSO.sub.4,
concentrated to dryness and purified via silica gel chromatography
(EtOAc/Hex) to afford prop-1-en-2-yl
(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
-yl)-2-fluorophenyl)carbamate (141 mg, 74% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.80 (s, 1H), 8.40 (s, 1H), 7.75 (s,
1H), 7.64 (s, 1H), 7.55 (d, J=10.5 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H),
6.23 (s, 1H), 4.73 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9
Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), MS (ESI) m/z: 431.1
[M+H].sup.+.
##STR00063##
Example A52
[0193] A mixture of Example A10 (200 mg, 0.546 mmol) and pyridine
(173 mg, 2.184 mmol) in THF (5 mL) was treated with 3-fluorophenyl
isocyanate (90 mg, 0.655 mmol) and stirred at RT overnight. The
mixture was treated with water and EtOAc and most of the aqueous
layer was removed. DMF was added, the mixture concentrated to
dryness and purified via reverse-phase chromatography
(MeCN/H.sub.2O with 0.1% TFA). The organics were removed under
reduced pressure and the aqueous residue was treated with satd.
NaHCO.sub.3 and allowed to stand at RT. The resulting solid was
collected via filtration and dried to afford
1-(4-chloro-5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3--
yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea (153 mg, 56% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.31 (s, 1H), 8.80 (s,
1H), 8.76 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.84 (s,
1H), 7.59 (d, J=10.9 Hz, 1H), 7.46 (d, J=11.9 Hz, 1H), 7.29 (m,
1H), 7.07 (d, J=8.2 Hz, 1H), 6.79 (m, 1H), 5.12 (m, 1H), 1.52 (d,
J=6.6 Hz, 6H); MS (ESI) m/z: 503.1 [M+H].sup.+.
##STR00064##
Example A53
[0194] A suspension of Example A6 (0.161 g, 0.485 mmol) in EtOAc
(2.5 mL) was treated with satd. NaHCO.sub.3 (2.5 mL) followed by
isopropenyl chloroformate (0.080 mL, 0.728 mmol) and the bi-phasic
mixture stirred vigorously at RT for 2 h. The layers were
separated, the organic layer washed with brine dried over
MgSO.sub.4 and concentrated to dryness to afford prop-1-en-2-yl
(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4--
methylphenyl)carbamate (100% yield assumed). MS (ESI) m/z: 416.1
[M+H].sup.+.
##STR00065##
Example A54
[0195] A solution of Example A6 (0.200 g, 0.603 mmol) and TEA
(0.126 mL, 0.904 mmol) in THF (6 mL) was treated with phenyl
isocyanate (0.066 mL, 0.603 mmol and stirred at RT overnight. The
resulting solid was collected via filtration and dried to afford
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro--
4-methylphenyl)-3-phenylurea (211 mg, 78% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.01 (s, 1H), 8.77 (s, 1H), 8.51 (d,
J=2.3 Hz, 1H), 8.01-7.98 (m, 2H), 7.73 (s, 1H), 7.41 (dd, J=8.3,
1.2 Hz, 2H), 7.25 (dd, J=8.5, 7.3 Hz, 2H), 7.17 (d, J=12.2 Hz, 1H),
6.97-6.90 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 (t,
J=7.0 Hz, 3H); MS (ESI) m/z: 451.1 [M+H].sup.+.
##STR00066##
Example A55
[0196] A mixture of Example A10 (700 mg, 1.911 mmol) and pyridine
(605 mg, 7.65 mmol) in THF (15 mL) was treated with phenyl
isocyanate (250 mg, 2.103 mmol) and stirred at RT for 19 h. The
mixture was diluted with EtOAc, washed with satd. NaHCO.sub.3, then
brine, dried over Na.sub.2SO.sub.4, concentrated to dryness and
purified via reverse-phase chromatography (MeCN/H.sub.2O with 0.1%
TFA). The organics were removed under reduced pressure, the aqueous
residue treated with satd. NaHCO.sub.3 and allowed to stand at RT.
The resulting solid was collected via filtration and dried to
afford
1-(4-chloro-5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3--
yl)-2-fluorophenyl)-3-phenylurea (325 mg, 35% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.10 (s, 1H), 8.76 (s, 1H), 8.73
(m, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.58
(d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.27 (t, J=7.9 Hz, 2H),
6.97 (t, J=7.4 Hz, 1H), 5.11 (m, 1H), 1.52 (d, J=6.7 Hz, 6H); MS
(ESI) m/z: 485.1 [M+H].sup.+.
##STR00067##
Example A56
[0197] A solution of Example A6 (0.200 g, 0.603 mmol) and TEA
(0.126 mL, 0.904 mmol) in THF (6 mL) was treated with
3-fluorophenyl isocyanate (0.083 ml, 0.723 mmol) and stirred at RT
for 4 h. The mixture was concentrated to dryness and purified via
silica gel chromatography (EtOAc/Hex). The material was treated
with DCM and the solid collected via filtration. The filtrate was
concentrated to dryness, re-purified via silica gel chromatography
(MeOH/DCM) and combined with the isolated solid to afford
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-
-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (88 mg, 31%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.23 (s, 1H),
8.77 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 7.97 (d, J=8.4
Hz, 1H), 7.73 (s, 1H), 7.46 (dt, J=12.0, 2.3 Hz, 1H), 7.28 (m, 1H),
7.18 (d, J=12.2 Hz, 1H), 7.05 (ddd, J=8.2, 2.0, 0.9 Hz, 1H), 6.77
(td, J=8.3, 2.5 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21
(t, J=7.0 Hz, 3H); MS (ESI) m/z: 469.1 [M+H].sup.+.
##STR00068##
Example A57
[0198] A mixture of Example A34 (0.3 g, 0.960 mmol), phenyl
isocyanate (0.137 g, 1.153 mmol) and TEA (0.134 ml, 0.960 mmol) in
THF (5 mL) was stirred at RT for 4 h. The mixture was treated with
30% EtOAc/Hex, stirred for several minutes and the resulting solid
was collected via filtration and dried to afford
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-phenylurea (350 mg, 84% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.01 (s, 1H), 8.47 (s, 1H), 8.34 (s,
1H), 7.93 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz,
2H), 7.24-7.26 (m, 2H), 7.12 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz,
1H), 6.47 (s, 2H), 6.34 (s, 1H), 4.09 (q, J=7.3 Hz, 2H), 2.06 (s,
3H), 1.20 (t, J=7.0 Hz, 3H): MS (ESI) m/z: 432.1 [M+H].sup.+.
[0199] A solution of
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-phenylurea (0.35 g, 0.811 mmol) in pyridine (5 mL)
was treated with isopropenyl chloroformate (0.147 g, 1.217 mmol)
and stirred at RT for 1 h. Water was added, the mixture stirred for
10 minutes and the resulting solid was collected via filtration and
dried to afford prop-1-en-2-yl
(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-7-yl)carbamate (360 mg, 86% yield). MS (ESI) m/z:
516.2 [M+H].sup.+.
##STR00069##
Example B1
[0200] A 0.degree. C. solution of Example C3 (4.4 g, 20 mmol) in
MeCN (50 mL) was treated drop-wise with a solution of 65%
ethylamine in water (2.7 g, 39 mmol), warmed to RT and stirred. The
reaction was concentrated and the residue was washed with water to
give ethyl 6-chloro-4-(ethylamino)nicotinate (3.9 g, 91% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.51 (s, 1H), 8.08 (s,
1H), 6.53 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.78 (q, J=7.2 Hz, 2H),
1.28 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H); MS (ESI) m/z:
229.1[M+H].sup.+.
[0201] A -50.degree. C. solution of ethyl
6-chloro-4-(ethylamino)nicotinate (3.9 g, 17 mmol) in THF (50 mL)
was treated with LiAlH.sub.4 (3.6 g, 95 mmol), allowed to warm to
0.degree. C. and stirred for 1 h. The mixture was quenched with 10%
NaOH (3.6 mL), filtered and the filtrate treated with water and
extracted with EtOAc (3.times.). The combined organics were washed
with brine, dried (MgSO.sub.4) and concentrated in vacuo to provide
(6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 79% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.84 (s, 1H), 6.55 (s,
1H), 6.17 (m, 1H), 5.25 (t, J=5.2 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H),
3.23 (m, 2H), 1.23 (t, J=7.2 Hz, 3H).
[0202] To a solution of
(6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 13.4 mmol) in
DCM (30 mL) was added MnO.sub.2 (5.8 g, 67 mmol) and the reaction
mixture was stirred at RT overnight. The reaction mixture was
filtered and the filtrate was concentrated in vacuo to give
6-chloro-4-(ethylamino)nicotinaldehyde (2.2 g, 89% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 9.82 (s, 1H), 8.51 (br s, 1H),
8.27 (s, 1H), 6.56 (s, 1H), 3.28 (m, 2H), 1.31 (t, J=7.2 Hz, 3H);
MS (ESI) m/z: 185.0 [M+H].sup.+.
##STR00070##
Example B2
[0203] Using the three-step procedure of Example B1, Example C3 (20
g, 91 mmol) and isopropylamine (60% in water, 18 g, 182 mmol) were
converted to 6-chloro-4-(isopropylamino)nicotinaldehyde (16 g, 81%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.82 (s, 1H),
8.43-8.39 (m, 2H), 6.83 (s, 1H), 3.84 (m, 1H), 1.17 (d, J=6.4 Hz,
6H).
##STR00071##
Example B3
[0204] A 0.degree. C. solution of ethyl 4,6-dichloronicotinate (5
g, 22.8 mmol) in MeCN (30 mL) was treated drop-wise with aqueous
methylamine (65%, 5.2 g, 45.6 mmol), warmed to RT and stirred for 8
h. The mixture was concentrated to dryness, the residue suspended
in H.sub.2O and extracted with EtOAc (3.times.). The combined
extracts were washed with brine, dried (MgSO.sub.4) and
concentrated to give ethyl 6-chloro-4-(methylamino)nicotinate (4 g,
82% yield), which was used in the next step without further
purification. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.48 (s,
1H), 8.04 (d, J=4.5 Hz, 1H), 6.71 (s, 1H), 4.27 (q, J=6.9 Hz, 2H),
2.85 (d, J=5.1 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H).
[0205] A 0.degree. C. solution of ethyl
6-chloro-4-(methylamino)nicotinate (4 g, 18.7 mmol) in THF (40 mL),
under a N.sub.2 atmosphere, was treated portion-wise with
LiAlH.sub.4 (1.4 g, 37.4 mmol), stirred for 20 min, then carefully
treated with water followed by 2 N NaOH. The suspension was
filtered and the filtrate was concentrated to afford
(6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 91% yield),
which was used in next step without purification. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 7.96 (s, 1H), 6.63 (s, 1H), 6.46 (s,
1H), 5.04 (s, 1H), 4.39 (m, 2H), 2.81-2.68 (m, 3H).
[0206] A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol
(2.9 g, 16.7 mmol) and MnO.sub.2 (11.7 g, 133.6 mmol) in anhydrous
DCM (25 mL) was stirred at 30.degree. C. for 6 h. The reaction
mixture was cooled to RT and filtered. The filtrate was
concentrated in vacuo to give
6-chloro-4-(methylamino)nicotinaldehyde (2.5 g, 87% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.83 (s, 1H), 8.52 (br s, 1H),
8.40 (s, 1H), 6.75 (s, 1H), 2.87 (d, J=5.8 Hz, 3H); MS (ESI) m/z:
171.0 [M+H].sup.+.
##STR00072##
Example C1
[0207] To stirring fuming HNO.sub.3 (90 wt %, 30.0 mL, 643 mmol) at
-15.degree. C. was added 4-fluoro-2-methylphenylacetic acid (15 g,
89.2 mmol) in portions such that the internal temperature remained
below -10.degree. C. After completing the addition the reaction was
stirred with warming to 5.degree. C. over 15 min. The mixture was
poured onto ice (400 g), stirred vigorously until the ice had
completely melted and the resulting solid was collected by
filtration, rinsed well with H.sub.2O and dried on the filter to
afford 2-(4-fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 97%
yield) as a pale yellow solid. .sup.1H NMR (400 MHz,
acetone-d.sub.6): .delta. 8.06 (d, J=7.6 Hz, 1H), 7.36 (d, J=12.0
Hz, 1H), 3.84 (s, 2H), 2.44 (s, 3H).
[0208] 2-(4-Fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g,
86.5 mmol) and conc. H.sub.2SO.sub.4 (4.00 mL) were combined in
EtOH (300 mL) and heated at 85.degree. C. for 2.5 h. The mixture
was cooled to RT, concentrated, the residue dissolved in MTBE and
washed with H.sub.2O (2.times.), then brine (2.times.), dried
(MgSO.sub.4), and evaporated to afford ethyl
2-(4-fluoro-2-methyl-5-nitrophenyl)acetate (16.79 g, 81% yield) as
a dark orange oil which was used without further purification. MS
(ESI) m/z: 242.0 (M+H).sup.+.
[0209] A solution of ethyl
2-(4-fluoro-2-methyl-5-nitrophenyl)acetate (16.79 g, 69.6 mmol) in
EtOH (60 mL) was treated with 10% Pd/C (50% wet, 7.41 g, 3.48 mmol)
and hydrogenated (3.5 atm) for 2 h. The solids were removed via
filtration through diatomaceous earth, rinsed with EtOH and the
filtrate was concentrated to afford ethyl
2-(5-amino-4-fluoro-2-methylphenyl)acetate (13.18 g, 90% yield) as
a brown oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 6.80 (d,
J=12.4 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 4.86 (s, 2H), 4.05 (q,
J=7.2 Hz, 2H), 3.46 (s, 2H), 2.05 (s, 3H), 1.17 (t, J=7.2 Hz, 3H);
MS (ESI) m/z: 212.2 (M+H).sup.+.
##STR00073##
Example C2
[0210] HNO.sub.3 (10.35 g, 98.6 mmol) was added drop-wise to a
-10.degree. C. solution of 2-(2-chloro-4-fluorophenyl)acetic acid
(16.9 g, 89.6 mmol) in conc. H.sub.2SO.sub.4 (60 mL), stirred at
0.degree. C. for 10 min, then carefully poured into ice water. The
off-white solid was collected by filtration and dried to give
2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 98% yield).
.sup.1H NMR (400 Hz, DMSO-d.sub.6): .delta. 12.71 (br s, 1H), 8.33
(d, J=8.0 Hz, 1H), 7.92 (d, J=11.2 Hz, 1H), 3.85 (s, 2H).
[0211] A 0.degree. C. solution of
2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 88 mmol) in
EtOH (150 mL) was treated with sulfuryl dichloride (21 g, 0.17
mol), then heated to reflux for 1 h. The reaction mixture was
concentrated under reduced pressure and treated with satd.
Na.sub.2CO.sub.3 to pH 7-8. The resultant mixture was extracted
with EtOAc (3.times.) and the combined organic layers were washed
with brine, dried (MgSO.sub.4) and concentrated to give ethyl
2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 98% yield).
.sup.1H NMR (400 Hz, DMSO-d.sub.6): .delta. 8.32 (d, J=8.0 Hz, 1H),
7.91 (d, J=11.2 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.92 (s, 2H), 1.17
(t, J=7.2 Hz, 3H).
[0212] A solution of ethyl
2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 86.2 mmol) in
EtOH (200 mL) was stirred with Raney Ni (20% slurry in water, 5.0
g, 17 mmol) under a hydrogen atmosphere (30 psi) for 5 h. The
catalyst was removed by filtration and the filtrate was
concentrated to give ethyl
2-(5-amino-2-chloro-4-fluorophenyl)acetate (19 g, 95% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.10 (d, J=11.2 Hz,
1H), 6.71 (d, J=9.2 Hz, 1H), 5.27 (s, 2H), 4.05 (q, J=6.8 Hz, 2H),
3.57 (s, 2H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 232.0
[M+H].sup.+.
##STR00074##
Example C3
[0213] 3-Oxo-pentanedioic acid diethyl ester (101 g, 0.5 mmol),
triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102
g, 1 mol) were combined and heated to 120.degree. C. for 2 h. The
resulting mixture was cooled to RT and dissolved in DCM (1 L).
After further cooling to 0.degree. C., ammonia (30%, 80 mL) was
added and the reaction mixture was allowed to warm to RT overnight.
The product was extracted with water (2.times.) and the aqueous
layer was acidified to pH 5 with conc. HCl. The precipitate was
collected by filtration to afford ethyl 4,6-dihydroxynicotinate
(60.0 g, 60% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
7.99 (s, 1H), 5.58 (s, 1H), 4.23 (q, J=6.8, 14.0 Hz, 2H), 1.25 (t,
J=7.2 Hz, 3H); MS (ESI) m/z: 184.1 [M+H].sup.+.
[0214] Ethyl 4,6-dihydroxynicotinate (60 g, 0.328 mol) was added
slowly to POCl.sub.3 (500 mL), then heated to reflux for 2 h. The
resulting mixture was distilled under reduced pressure to remove
excess POCl.sub.3. The residue was poured into ice water and
stirred for 30 minutes before extracting with EtOAc (3.times.). The
combined extracts were washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo to give ethyl 4,6-dichloronicotinate (65 g,
90%, yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.80 (s,
1H), 7.95 (s, 1H), 4.34 (q, J=6.9 Hz, 2H), 1.31 (t, J=6.9 Hz, 3H);
MS (ESI) m/z: 220.1 [M+H].sup.+.
##STR00075##
Example C4
[0215] A 0.degree. C. solution of (2,4-difluoro-phenyl)acetic acid
(14.5 g, 0.084 mol) in H.sub.2SO.sub.4 (60 mL) was treated
drop-wise with 69% HNO.sub.3 (6 mL), stirred at 0.degree. C. for 35
min. then poured into ice water. The aqueous layer was extracted
with EtOAc, and the organic extracts were washed with brine, dried
(Na.sub.2SO.sub.4), concentrated in vacuo and purified by silica
gel chromatography to give (2,4-difluoro-5-nitro-phenyl)acetic acid
(16 g, 88% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.30 (t, J=8.0 Hz, 1H), 7.68 (m, 1H), 3.75 (s, 2H).
[0216] A solution of (2,4-difluoro-5-nitro-phenyl)acetic acid (16
g, 74 mmol) in EtOH (200 mL) and 98% H.sub.2SO.sub.4 (14 mL) was
refluxed at 80.degree. C. for 2.5 h under a N.sub.2 atmosphere. The
reaction mixture was poured into ice water, and the resultant
solution was extracted with Et.sub.2O. The combined organic
extracts were washed with brine, dried (Na.sub.2SO.sub.4),
concentrated in vacuo and purified by silica gel chromatography to
give ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16 g, 89% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.22 (t, J=8.1 Hz,
1H), 7.55 (t, J=11.1 Hz, 1H), 4.06 (m, 2H), 3.77 (s, 2H), 1.13 (t,
J=6.9 Hz, 3H).
[0217] A mixture of ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16
g, 130 mmol) and 10% Pd/C (1.6 g, 1.5 mmol) in EtOAc was
hydrogenated (30 psi) at RT for 12 h. The catalyst was filtered off
and the filtrate was evaporated. The residue was purified by column
chromatography to give ethyl 2-(5-amino-2,4-difluorophenyl)acetate
(14 g, 99% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
6.98 (t, J=9.9 Hz, 1H), 6.70 (t, J=7.8 Hz, 1H), 4.50 (s, 2H), 4.06
(m, 2H), 3.53 (s, 2H), 1.16 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 216.2
[M+H].sup.+.
##STR00076##
Example C5
[0218] Nitric acid (16.00 mL, 322 mmol) was cooled to -15.degree.
C. and treated portion-wise with 2-bromo-4-fluorophenylacetic acid
(10.00 g, 42.9 mmol) maintaining an internal temperature of
-10.degree. C. to -5.degree. C. Once the addition was complete the
mixture was warmed to 5.degree. C. over .about.15 minutes, poured
onto ice (200 mL), stirred vigorously until all of the ice melted,
and then filtered and rinsed with water. The resulting solid was
dissolved in EtOAc, washed with brine, dried (MgSO.sub.4) and
concentrated to dryness to afford
2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (10.93 g, 92% yield)
as a bright yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.29 (d, 1H), 8.04 (d, 1H), 3.85 (s, 2H).
[0219] A solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid
(5.00 g, 17.98 mmol) in EtOH (100 mL) was treated with concentrated
sulfuric acid (0.999 mL, 17.98 mmol) and heated at 85.degree. C.
overnight. The mixture was cooled to RT and the EtOH was removed
under reduced pressure. The resulting oil was dissolved in MTBE,
washed with water (2.times.) then brine (2.times.), dried
(MgSO.sub.4), and concentrated to dryness. The material was
purified by silica gel chromatography (EtOAc/Hex) to afford ethyl
2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (2.679 g, 49% yield) as a
yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.33 (d,
1H), 8.08 (d, 1H), 4.12 (q, 2H), 3.96 (s, 2H), 1.20 (t, 3H); MS
(ESI) m/z: 308.0 [M+H].sup.+.
[0220] A solution of ethyl
2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (2.127 g, 6.95 mmol) in
EtOH (70 mL) was treated with iron powder (3.88 g, 69.5 mmol) and
satd. ammonium chloride (14.48 mL, 69.5 mmol) and heated to
55.degree. C. for 1 h. The mixture was cooled to RT, filtered
through a pad of diatomaceous earth, rinsed well with EtOH and the
organics concentrated under reduced pressure. The resulting aqueous
residue was treated with satd. NaHCO.sub.3, extracted with EtOAc
(2.times.) and the combined organics were washed with water, dried
(MgSO.sub.4), and concentrated to afford ethyl
2-(5-amino-2-bromo-4-fluorophenyl)acetate (1.792 g, 93% yield) as
an amber oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.25 (d,
1H), 6.76 (d, 1H), 5.35 (s, 2H), 4.08 (q, 2H), 3.61 (s, 2H), 1.18
(t, 3H); MS (ESI) m/z: 278.0 [M+H].sup.+.
##STR00077##
Example C6
[0221] A mixture of (2-chlorophenyl)acetic acid (15 g, 88 mmol) in
conc. H.sub.2SO.sub.4 (100 mL) was cooled to -20.degree. C. and
treated drop-wise with conc. HNO.sub.3 (9.4 g, 97 mmol). The
resulting mixture was stirred at -20.degree. C. for 0.5 h, poured
into the ice-water, and extracted with EtOAc (3.times.). The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to give
(2-chloro-5-nitrophenyl)acetic acid (15 g, 79% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.58 (s, 1H), 8.35 (m, 1H), 7.96
(m, 1H), 4.12 (s, 2H).
[0222] Thionyl chloride (16.7 g, 0.14 mol) was added drop-wise to a
0.degree. C. solution of (2-chloro-5-nitro-phenyl)acetic acid (15
g, 0.07 mol) in EtOH (300 mL) and the resultant mixture was heated
at reflux overnight. The reaction mixture was concentrated under
reduced pressure, the residue poured into ice water, and extracted
with EtOAc (2.times.). The combined organics were washed with
brine, then satd. NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give ethyl
2-(2-chloro-5-nitrophenyl)acetate (17 g, 99% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.35 (d, J=2.8 Hz, 1H), 8.12 (dd,
J=8.4, 2.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H),
3.96 (s, 2H), 1.15 (t, J=7.2 Hz, 3H).
[0223] Iron powder (2.5 g, 44.7 mmol) was added portion-wise to a
solution of ethyl 2-(2-chloro-5-nitrophenyl)acetate (8 g, 4.68
mmol) and conc. HCl (12 M, 3.9 mL, 46.8 mmol) in EtOH (100 mL). The
resultant mixture was heated at 50.degree. C. for 2 h. The mixture
was filtered and the filtrate cake was washed with satd.
Na.sub.2CO.sub.3 until pH 8. The filter cake was further washed
with EtOAc and the combined filtrates were partitioned between
EtOAc and water. The organics were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to provide ethyl
2-(5-amino-2-chlorophenyl)acetate (5.6 g, 56% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 7.00 (d, J=8.4 Hz, 1H), 6.50 (s,
J=2.8 Hz, 1H), 6.44 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.20 (s, 2H), 4.05
(q, J=7.2 Hz, 2H), 3.56 (s, 2H), 1.15 (t, J=7.2 Hz, 3H).
##STR00078##
Example D1
[0224] A -20.degree. C. mixture of N-methylpiperazine (233 .mu.L,
2.097 mmol) and DIEA (452 mg, 3.49 mmol) in THF (12 mL) was treated
drop-wise with a solution of t-butyl (3-bromomethyl)phenylcarbamate
(500 mg, 1.747 mmol) in THF (3 mL) and stirred overnight as the
cooling bath expired. The mixture was diluted with EtOAc, washed
with satd. NaHCO.sub.3, then brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford tert-butyl
(3-((4-methylpiperazin-1-yl)methyl)phenyl)carbamate (544 mg, 102%
yield). MS (ESI) m/z: 306.2 [M+H].sup.+.
[0225] A solution of tert-butyl
(3-((4-methylpiperazin-1-yl)methyl)phenyl)carbamate (544 mg, 1.781
mmol) in dioxane (10 mL) was treated with HCl (g) for 10 min, then
stirred at RT for 3 h. The mixture was concentrated to dryness to
afford crude 3-((4-methylpiperazin-1-yl)methyl)aniline
trihydrochloride (505 mg, 90% yield) which was used without further
purification. MS (ESI) m/z: 306.2 [M+H].sup.+.
##STR00079##
Example D2
[0226] A mixture of 2-fluoro-5-nitrotoluene (0.750 g, 4.83 mmol).
NBS (1.549 g, 8.70 mmol) and AIBN (0.159 g, 0.967 mmol) in
trifluorotoluene (15 ml) was heated to reflux overnight. The
mixture was cooled RT, the solids removed via filtration and the
filtrate concentrated to dryness and purified via silica gel
chromatography (EtOAc/Hex) to afford .about.80% pure
2-(bromomethyl)-1-fluoro-4-nitrobenzene (956 mg, 63% yield).
[0227] A solution of .about.80% pure
2-(bromomethyl)-1-fluoro-4-nitrobenzene (0.956 g, 3.27 mmol) in THF
(10 mL) was added slowly drop-wise to a -20.degree. C. solution of
1-methylpiperazine (0.393 g, 3.92 mmol) and DIEA (1.142 mL, 6.54
mmol) in THF (20 mL), the mixture allowed to warm slowly to RT and
stirred overnight. The resulting solid was removed via filtration
and the filtrate was concentrated to dryness and purified via
silica gel chromatography (EtOAc, MeOH/DCM) to afford
1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (577 mg, 70% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.28 (dd, J=6.2, 3.0
Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.47 (t, J=9.1 Hz,
1H), 3.60 (s, 2H), 2.48-2.25 (br m, 8H), 2.14 (s, 3H); MS (ESI)
m/z: 254.1 [M+H].sup.+.
[0228] A solution of 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine
(0.577 g, 2.278 mmol) in EtOH (7 mL) was treated with satd.
NH.sub.4Cl (4.75 mL, 22.78 mmol) followed by iron (powder) (1.272
g, 22.78 mmol) and the mixture heated at 55.degree. C. overnight.
The mixture was cooled to RT and gravity-filtered through filter
paper, rinsing well with MeOH and DCM. The filtrate was
concentrated to dryness. The residue was treated with EtOAc and
water, then concentrated to dryness again. The resulting material
was treated with THF (20 mL), sonicated for several hours and the
solvent decanted from the solids. The solids were treated with
additional THF (20 mL), sonicated again and the solvent decanted.
The solids were treated with THF (20 mL) for a third time, stirred
vigorously overnight, then the liquid was decanted. The combined
decanted liquids were concentrated to dryness, treated with DCM,
filtered to remove solids and concentrated to dryness to afford
very hydroscopic 4-fluoro-3-((4-methylpiperazin-1-yl)methyl)aniline
(382 mg, 75% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
6.81 (m, 1H), 6.49 (m, 2H), 4.99 (s, 2H), 3.44 (s, 2H), 3.32 (s,
8H), 2.69 (s, 3H); MS (ESI) m/z: 224.2 [M+H].sup.+.
##STR00080##
Example D3
[0229] A mixture of 1-fluoro-2-methyl-4-nitrobenzene (2.5 g, 16.12
mmol) and NBS (3.16 g, 17.73 mmol) in trifluorotoluene (45 mL) was
treated with AIBN (66 mg, 0.403 mmol) and heated at 80.degree. C.
overnight. The mixture was cooled to RT, the solids removed via
filtration and the filtrate concentrated to dryness. The residue
was dissolved in EtOAc, washed with water, then brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via silica
gel chromatography (EtOAc/Hex) to afford
2-(bromomethyl)-1-fluoro-4-nitrobenzene (1.915 g, 50% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.53-8.52 (m, 1H),
8.28 (ddd, J=9.1, 4.4, 3.0 Hz, 1H), 7.55 (t, J=9.2 Hz, 1H), 4.80
(s, 2H).
[0230] A -20.degree. C. mixture of DIEA (552 mg, 4.27 mmol) and
morpholine (242 mg, 2.78 mmol) in THF (5 mL) was treated drop-wise
with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (500 mg,
2.137 mmol) in THF (5 mL) and stirred overnight as the cooling bath
expired. The mixture was treated with EtOAc, washed with water,
then brine, dried over Na.sub.2SO.sub.4 and concentrated to dryness
to afford 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg, 81% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.30 (dd, J=6.2, 3.0
Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.48 (t, J=9.1 Hz,
1H), 3.61 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.40 (t, J=4.4 Hz, 4H);
MS (ESI) m/z: 241.1 [M+H].sup.+.
[0231] A mixture of 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg,
1.723 mmol) in EtOAc (15 mL) was treated with 10% Pd/C (100 mg) and
hydrogenated (1 atm) for 3 h. The solids were removed via
filtration, rinsed with EtOAc and the filtrate concentrated to
dryness to afford 4-fluoro-3-(morpholinomethyl)aniline (200 mg, 55%
yield). MS (ESI) m/z: 211.1 [M+H].sup.+.
##STR00081##
Example 1
[0232] Using general method B, 1-isocyanatonaphthalene (0.051 g,
0.3 mmol) and Example A2 (0.1 g, 0.3 mmol) were combined to afford
1-(5-(l-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea as a white solid
(0.115 g, 77% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.16 (s, 1H), 9.05 (s, 1H), 8.45 (s, 1H), 8.19 (d, J=8.4 Hz, 1H),
8.08-8.04 (m, 2H), 7.96 (d, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.67-7.58
(m, 3H), 7.47 (t, J=8.0 Hz, 1H), 7.21 (d, J=12.4 Hz, 1H), 7.05-7.02
(m, 1H), 6.28 (s, 1H), 4.21-4.16 (m, 2H), 2.89 (d, J=4.8 Hz, 3H),
2.12 (s, 3H), 1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 496.3
[M+H].sup.+.
##STR00082##
Example 2
[0233] Using general method B, 1-isocyanatonaphthalene (0.045 g,
0.26 mmol) and Example A39 (0.1 g, 0.3 mmol) were combined to
afford
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)-3-(naphthalen-1-yl)urea as a white solid (0.062 g,
48% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.23 (s,
1H), 9.14 (s, 1H), 8.56-8.54 (m, 1H), 8.52 (s, 1H), 8.23 (d, J=8.4
Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.93 (s,
1H), 7.71-7.59 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 7.36-7.34 (m, 2H),
7.10-7.07 (m 1H), 6.29 (s, 1H), 4.23 (q, J=6.8 Hz, 2H), 2.92 (d,
J=4.8 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 482.0
[M+H].sup.+.
##STR00083##
Example 3
[0234] Using general method B, I-isocyanatobenzene (0.05 g, 0.420
mmol) and Example A5 (0.146 g, 0.420 mmol) were combined to provide
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea (0.180 g, 92% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. .delta. 9.16 (s, 1H), 8.75 (s,
1H), 8.45 (s, 1H), 8.22 (d, J=9 Hz, 1H), 7.78 (s, 1H), 7.58 (d,
J=10.5 Hz, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.30 (m, 2H), 7.08 (m,
1H), 7.00 (s, 1H), 6.27 (s, 1H), 4.18 (q, J=5 Hz, 2H), 2.89 (d, J=5
Hz, 3H), 1.24 (t, J=6 Hz, 3H); MS(ESI) m/z: 466.0 [M+H].sup.+.
##STR00084##
Example 4
[0235] Using general method A, 2,3-difluorobenzoic acid (0.100 g,
0.633 mmol) and Example A5 (0.219 g, 0.633 mmol) were combined to
provide
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea (0.172 g, 54%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.27 (s, 1H),
9.24 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=10 Hz, 1H), 7.96 (m, 1H),
7.77 (s, 1H), 7.58 (d, J=12 Hz, 1H), 7.18-7.00 (m, 3H), 6.27 (s,
1H), 4.17 (q, J=6 Hz, 2H), 2.90 (d, J=5.5 Hz, 3H), 1.24 (t, J=6 Hz,
3H); MS(ESI) m/z: 502.0 [M+H].sup.+.
##STR00085##
Example 5
[0236] Using general method B, phenyl isocyanate (0.036 g, 0.302
mmol) and Example A40 (0.1 g, 0.302 mmol) were combined to provide
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)phenyl)-3-phenylurea (0.94 g, 70% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.03 (s, 1H), 8.62 (s, 1H), 8.49
(s, 1H), 8.42 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.50 (s,
1H), 7.32 (m, 4H), 7.03 (m, 2H), 6.50 (br s, 1H), 3.40 (s, 1H),
2.91 (d, J=6 Hz, 3H), 1.60 (d, J=6 Hz, 6H); MS(ESI) m/z: 446.3
[M+H].sup.+.
##STR00086##
Example 6
[0237] Using general method B, 1-isocyanatonaphthalene (0.05 g,
0.29 mmol) and Example A5 (0.1 g, 0.29 mmol) were combined to
afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea as a white solid
(0.121 g, 79% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.26 (b rs, 2H), 8.48 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 8.21 (d,
J=8.8 Hz, 1H), 8.05 (dd, J=7.6 Hz, 0.8 Hz, 1H), 7.98 (d, J=8.4 Hz,
1H), 7.81 (s, 1H), 7.71-7.58 (m, 4H), 7.51 (t, J=8.0 Hz, 1H), 7.11
(q, J=4.8 Hz, 1H), 6.30 (s, 1H), 4.20 (q, J=6.8 Hz, 2H), 2.92 (d,
J=4.8 Hz, 3H), 1.27 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 516.0
[M+H].sup.+.
##STR00087##
Example 7
[0238] Using general method B, phenyl isocyanate (0.050 g, 0.420
mmol) was reacted with Example A41 (0.070 g, 0.210 mmol) in EtOAc
(2 mL) for 13 h to provide
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-phenylurea (0.080 g, 84% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.68 (br s, 1H),
8.40 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.74 (s, 1H), 7.53 (d, J=11.5
Hz, 1H), 7.41 (m, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.96 (m, 1H),
6.15 (s, 1H), 3.49 (s, 3H), 2.86 (d, J=5 Hz, 3H); MS(ESI) m/z:
452.0 [M+H].sup.+.
##STR00088##
Example 8
[0239] Using general method B, 1-isocyanatonaphthalene (0.050 g,
0.296 mmol) was reacted with Example A41 (0.070 g, 0.210 mmol) in
EtOAc (2 mL) at RT for 13 h to provide
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(naphthalen-1-yl)urea (0.07 g, 67%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.18 (s, 2H),
8.40 (s, 1H), 8.26 (d, J=9 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 7.98 (d,
J=7 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.60 (m, 3H), 7.43
(t, J=8 Hz, 1H), 7.11 (m, 1H), 7.26 (m, 1H), 6.16 (s, 1H), 3.49 (s,
3H), 2.86 (d, J=5 Hz, 3H); MS(ESI) m/z: 502.0 [M+H].sup.+.
##STR00089##
Example 9
[0240] Using general method B, 3-isocyanatobenzonitrile (0.050 g,
0.347 mmol) was reacted with Example A41 (0.070 g, 0.210 mmol) in
EtOAc (2 mL) for 13 h to provide
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea (0.090 g, 90% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.42 (s, 1H), 8.86 (br
s, 1H), 8.44 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.99 (m, 1H), 7.77 (s,
1H), 7.63 (m, 1H), 7.58 (d, J=11.5 Hz, 1H), 7.51 (t, J=7 Hz, 1H),
7.45 (m, 1H), 7.14 (m, 1H), 6.19 (s, 1H), 3.52 (s, 3H), 2.86 (d,
J=5 Hz, 3H); MS(ESI) m/z: 477.0 [M+H].sup.+.
##STR00090##
Example 10
[0241] Using general method A, 2,3-difluorobenzoic acid (0.071 g,
0.449 mmol). TEA (0.091 g, 0.898 mmol). DPPA (0.124 g, 0.449 mmol)
and Example A41 (0.100 g, 0.299 mmol) were combined to provide
1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea (0.070 g, 48%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.26 (br s,
1H), 9.22 (br s, 1H), 8.42 (s, 1H), 8.20 (d, J=10 Hz, 1H), 7.94 (m,
1H), 7.77 (s, 1H), 7.57 (d, J=12 Hz, 1H), 7.12 (m, 2H), 7.04 (m,
1H), 6.18 (s, 1H), 3.51 (s, 3H), 2.86 (d, J=5 Hz, 3H); MS(ESI) m/z:
488.0 [M+H].sup.+.
##STR00091##
Example 11
[0242] Using general method B, 3-isocyanatobenzonitrile (0.070 g,
0.486 mmol) was reacted with Example A42 (0.070 g, 0.222 mmol) in
EtOAc (2 mL) for 13 h to provide
1-(4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridi-
n-3-yl)phenyl)-3-(3-cyanophenyl)urea (55 mg, 54% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.13 (s, 1H), 9.07 (s, 1H),
8.45 (s, 1H), 8.00 (m, 1H), 7.79 (s, 1H), 7.69 (m, 1H), 7.59 (m,
1H), 7.52 (m, 1H), 7.47-7.44 (m, 3H), 7.17 (m, 1H), 6.22 (s, 1H),
3.55 (s, 3H), 290 (d, J=4.8 Hz, 3H); MS(ESI) m/z: 459.0
[M+H].sup.+.
##STR00092##
Example 12
[0243] Using general method B, 3-isocyanatobenzonitrile (0.032 g,
0.224 mmol) was reacted with Example A39 (0.070 g, 0.224 mmol) in
EtOAc (5 mL) for 20 h to provide
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)urea (17 mg, 17% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.39 (s, 1H), 8.71 (d, J=2.3 Hz,
1H), 8.46 (s, 1H), 8.36 (dd, J=8.0, 2.2 Hz, 1H), 8.00 (t, J=1.8 Hz,
1H), 7.87 (s, 1H), 7.63 (ddd, J=8.2, 2.2, 1.2 Hz, 1H), 7.49 (t,
J=7.9 Hz, 1H), 7.43 (dt, J=7.6, 1.4 Hz, 1H), 7.34-7.22 (m, 2H),
7.03 (m, 1H), 6.22 (s, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.85 (d, J=4.8
Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS(ESI) m/z: 457.2
[M+H].sup.+.
##STR00093##
Example 13
[0244] Using general method A, benzothiophene-3-carboxylic acid
(103 mg, 0.576 mmol), TEA (194 mg, 1.921 mmol), DPPA (165 mg, 0.600
mmol) and Example A43 (0.100 g, 0.299 mmol) were combined to
provide
1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino-
)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea (140 mg, 59%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.42 (s, 1H),
8.85 (s, 1H), 8.40 (s, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.0
Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.68 (d, J=6.5 Hz, 2H), 7.48 (m,
1H), 7.41 (m, 1H), 7.16 (d, J=12.3 Hz, 1H), 7.03 (m, 1H), 6.18 (s,
1H), 3.51 (s, 3H), 2.86 (d, J=4.4 Hz, 3H), 2.08 (s, 3H); MS(ESI)
m/z: 488.1 [M+H].sup.+.
##STR00094##
Example 14
[0245] Using general method A, benzo[b]thiophene-3-carboxylic acid
(0.101 g, 0.569 mmol), TEA (0.144 g, 1.423 mmol), DPPA (0.196 g,
0.711 mmol) and Example A44 (0.150 g, 0.474 mmol) were combined to
provide 1-(benzo[b]thiophen-3-yl)-3-(2,4-di
fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)phenyl)urea (177 mg, 76% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.39 (s, 1H), 8.85 (s, 1H), 8.43 (s, 1H),
8.26 (t, J=8.5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.0 Hz,
1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.44-7.36
(m, 2H), 7.12-7.10 (m, 1H), 6.17 (s, 1H), 3.51 (s, 3H), 2.86 (d,
J=4.8 Hz, 3H); MS(ESI) m/z: 492.0 [M+H].sup.+.
##STR00095##
Example 15
[0246] 3-Fluorophenyl isocyanate (81 mg, 0.444 mmol) was added to a
solution of Example A7 (200 mg, 0.444 mmol) in THF (5 mL) and the
mixture was stirred at RT overnight. The reaction was treated with
additional isocyanate (10 mg) and stirred at RT for a further 4 h.
The mixture was diluted with EtOAc, washed successively with water,
satd. NaHCO.sub.3, and brine, dried (Na.sub.2SO.sub.4),
concentrated in vacuo, purified by reverse phase chromatography
(MeCN/water with 0.1% TFA) and partially concentrated to give an
aqueous solution. The solution was diluted with satd. NaHCO.sub.3,
extracted with EtOAc (2.times.) and the combined organics were
washed with brine, dried (Na.sub.2SO.sub.4) and evaporated at
reduced pressure to give
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (207
mg, 79% yield, .about.75% pure) as a light yellow solid, which was
used without further purification. MS (ES-API) m/z: 588.2
[M+H].sup.+.
[0247] A solution of
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (267
mg, 0.421 mmol) in TFA (3 mL) was stirred at RT for 40 min. The
mixture was evaporated at reduced pressure, dissolved in EtOAc,
washed with satd. NaHCO.sub.3, then brine, dried
(Na.sub.2SO.sub.4), concentrated in vacuo, purified by reverse
phase chromatography (MeCN/water with 0.10% TFA) and partially
concentrated to give an aqueous solution. The aqueous solution was
diluted with satd. NaHCO.sub.3 and allowed to precipitate. The
white solid was collected by filtration, washed with water and
dried in vacuo to give
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (83 mg, 50%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.50 (br s,
1H), 8.80 (br s, 1H), 8.42 (s, 1H), 8.10-8.00 (m, 1H), 7.82 (s,
1H), 7.48 (d, 1H), 7.40-7.30 (m, 2H), 7.15-7.05 (m, 2H), 6.80-6.70
(m, 1H), 5.99 (s, 1H), 4.13 (m, 2H), 2.85 (s, 3H), 1.21 (m, 3H): MS
(ES-API) m/z: 468.1 [M+H].sup.+.
##STR00096##
Example 16
[0248] Phenyl isocyanate (58 mg, 0.488 mmol) was added to a
solution of Example A7 (200 mg, 0.444 mmol) and pyridine (140 mg,
1.776 mmol) in THF (5 mL) and the mixture was stirred at RT
overnight. The mixture was diluted with EtOAc, water and satd.
NaHCO.sub.3; the resulting precipitate was collected by filtration,
washed with EtOAc and dried in vacuo to give
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (219 mg, 87%
yield). MS (ES-API) m/z: 570.2 [M+H].sup.+.
[0249] A solution of
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (219 mg, 0.384
mmol) in TFA (2.0 mL) was stirred at RT for 1 h. The mixture was
concentrated in vacuo, dissolved in EtOAc, washed with satd.
NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4), warmed to reflux
in MeOH (5 mL) with the drying agent, filtered free of drying agent
(while hot), concentrated in vacuo and treated with 4M HCl/dioxane
(0.2 mL). The mixture was evaporated at reduced pressure and then
triturated with Et.sub.2O. The solid was collected by filtration,
purified by reverse phase chromatography (MeCN/water with 0.1% TFA)
and concentrated in vacuo to give an aqueous residue. The aqueous
solution was treated with satd. NaHCO.sub.3 and allowed to
precipitate. The solid was collected by filtration, washed with
water and dried in vacuo to give
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-phenylurea (87 mg, 50% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6), .delta. 9.01 (s, 1H), 8.52 (s, 1H), 8.42 (s,
1H), 8.12 (m, 1H), 7.81 (s, 1H), 7.42-7.24 (m, 5H), 7.05-6.94 (m,
2H), 6.23 (s, 1H), 4.13 (m, 2H), 2.85 (s, 3H), 1.20 (m, 3H); MS
(ES-API) m/z: 450.1 [M+H].sup.+.
##STR00097##
Example 17
[0250] Using a procedure analogous to Example 16, Example A7 (200
mg, 0.444 mmol) and 3-chlorophenyl isocyanate (58 mg, 0.488 mmol)
were combined to give
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-(3-chlorophenyl)urea (229
mg, 85% yield). MS (ES-API) m/z: 604.2 [M+H].sup.+.
[0251] Using a procedure analogous to Example 16,
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-(3-chlorophenyl)urea (219
mg, 0.384 mmol) was converted to
1-(3-chlorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)urea (98 mg, 53% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.20 (br s, 1H), 8.65
(br s, 1H), 8.42 (s, 1H), 8.08 (t, 1H), 7.82 (s, 1H), 7.70 (s, 1H),
7.38-7.19 (m, 3H), 7.05 (s, 1H), 7.01-6.99 (m, 1H), 6.21 (s, 1H),
4.14 (q, 2H), 2.85 (s, 3H), 1.19 (t, 3H); MS (ES-API) m/z: 488.1
[M+H].sup.+.
##STR00098##
Example 18
[0252] Using a procedure analogous to Example 16, Example A7 (200
mg, 0.444 mmol) and 3-cyanophenyl isocyanate (70 mg, 0.488 mmol)
were combined to give
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-(3-cyanophenyl)urea (240 mg,
91% yield). MS (ES-API) m/z: 595.2 [M+H].sup.+.
[0253] Using a procedure analogous to Example 16,
l-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2,4-difluorophenyl)-3-(3-cyanophenyl)urea (219 mg,
0.384 mmol) was converted to
1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2,4-difluorophenyl)urea (108 mg, 56% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.05 (br s, 2H), 8.42
(s, 1H), 8.06 (m, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.63-7.60 (m,
1H), 7.49-7.33 (m, 3H), 7.05 (br s, 1H), 6.23 (s, 1H), 4.14 (q,
2H), 2.85 (s, 3H), 1.20 (t, 3H); MS (ES-API) m/z: 475.2
[M+H].sup.+.
##STR00099##
Example 19
[0254] Using general method A, benzo[b]thiophene-3-carboxylic acid
(113 mg, 0.636 mmol), TEA (245 mg, 2.422 mmol), DPPA (200 mg, 0.727
mmol) and Example A8 (200 mg, 0.605 mmol) were combined and
purified via precipitation to provide
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (153 mg, 50%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.51 (s, 1H),
8.94 (s, 1H), 8.43 (s, 1H), 8.23 (t, 1H), 7.96-7.91 (m, 2H), 7.83
(s, 1H), 7.68 (s, 1H), 7.49-7.35 (m, 3H), 7.07-7.05 (m, 1H), 6.23
(s, 1H), 4.14 (q, 2H), 2.85 (s, 3H), 1.21 (t, 3H); MS (ES-API) m/z:
506.1 [M+H].sup.+.
##STR00100##
Example 20
[0255] DMF (0.2 mL) and 3-fluorophenyl isocyanate (67 mg, 0.486
mmol) were added to a slurry of Example A9 (200 mg, 0.442 mmol) and
pyridine (140 mg, 1.766 mmol) in THF (5 mL) and the mixture was
stirred at RT overnight. The mixture was diluted with EtOAc and
water, warmed, then cooled to RT and the resulting solid collected
via filtration. The solid was washed with EtOAc and dried in vacuo
to give
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (206 mg, 79%
yield). MS (ES-API) m/z: 590.2 [M+H].sup.+.
[0256] Using a procedure analogous to Example 15,
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (204 mg,
0.346 mmol) was converted to
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-(3-fluorophenyl)urea (66 mg, 40% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.29 (s, 1H), 8.74 (s, 1H),
8.35 (s, 1H), 8.13 (d, 1H), 7.77 (s, 1H), 7.53 (d, 1H), 7.47-7.43
(m, 1H), 7.32-7.26 (m, 1H), 7.07-7.04 (m, 1H), 6.81-6.76 (m, 1H),
6.54 (s, 2H), 6.33 (s, 1H), 4.08 (q, 2H), 1.20 (t, 3H); MS (ES-API)
m/z: 470.1 [M+H].sup.+.
##STR00101##
Example 21
[0257] DMF (0.2 mL) and phenyl isocyanate (58 mg, 0.486 mmol) were
added to a slurry of Example A9 (200 mg, 0.442 mmol) and pyridine
(140 mg, 1.766 mmol) in THF (5 mL) and the mixture stirred at RT
overnight. The mixture was diluted with EtOAc and water and warmed.
The organic phase was separated, washed with brine, dried
(Na.sub.2SO.sub.4), concentrated in vacuo, purified by reverse
phase chromatography (MeCN/water with 0.1% TFA) and concentrated to
give an aqueous residue. The aqueous residue was treated with satd.
NaHCO.sub.3 and allowed to precipitate. The solid was collected by
filtration, washed with water and dried in vacuo to provide
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (56 mg, 22% yield). MS
(ES-API) m/z: 572.2 [M+H].sup.+.
[0258] Using a procedure analogous to Example 15,
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (109 mg, 0.191 mmol)
was converted to
l-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea (45 mg, 53% yield). MS (ES-API) m/z:
452.1 [M+H].sup.+.
[0259] A 25 mg/mL solution of methanesulfonic acid in DCM (0.424
mL, 0.110 mmol) was added to a solution of
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea (45 mg, 0.100 mmol) in DCM (4 mL), the
mixture stirred for 15 min. and then evaporated at reduced pressure
to give a solid. The solid was dissolved in MeCN and water, frozen,
and lyophilized to give
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4--
chloro-2-fluorophenyl)-3-phenylurea methanesulfonate (1.4 equiv.)
(53 mg, 97% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.12 (s, 1H), 8.76 (s, 1H), 8.56 (s, 1H), 8.21 (d, 1H), 7.92 (s,
1H), 7.90 (br s, 2H), 7.60-7.56 (m, 1H), 7.42-7.40 (m, 2H),
7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 6.74 (s, 1H), 4.12 (q, 2H),
2.34 (s, .about.4H), 1.23 (t, 3H); MS (ES-API) m/z: 452.1
[M+H].sup.+.
##STR00102##
Example 22
[0260] Example A11 (0.12 g, 0.33 mmol), TEA (0.046 mL, 0.33 mmol)
and phenyl isocyanate (0.044 g, 0.36 mmol) were combined in THF (4
mL), stirred at RT for 20 h, concentrated in vacuo and purified by
silica gel chromatography (EtOAc/DCM) to afford
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-phenylurea (97 mg, 61% yield) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.07 (s,
1H), 8.67 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 8.16 (d, J=8.8 Hz, 1H),
7.67 (s, 1H), 7.51 (d, J=10.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H),
7.28-7.24 (m, 2H), 6.98-6.94 (m, 2H), 6.44 (s, 1H), 5.31-4.82 (br
s, 1H), 2.85 (d, J=4.8 Hz, 3H), 1.51 (d, J=7.2 Hz, 6H); MS (ESI)
m/z: 480.2 [M+H].sup.+.
##STR00103##
Example 23
[0261] A solution of pyridine (0.248 mL, 3.06 mmol) and phenyl
isocyanate (0.100 mL, 0.919 mmol) in DMF (0.4 mL) was added to a
solution of Example A2 (0.25 g, 0.766 mmol) in THF (5 mL) and the
mixture was stirred at RT. After 14 h, the solid was filtered,
washed with THF, and dried under vacuum to obtain
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-phenylurea (280 mg, 79% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.00 (s, 1H), 8.46 (d, J=2.0
Hz, 1H), 8.40 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.40
(m, 2H), 7.25 (m, 2H), 7.12 (d, J=12.4 Hz, 1H), 6.96 (m, 2H), 6.24
(s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 2.06 (s,
3H), 1.21 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 446.2 [M+H].sup.+.
##STR00104##
Example 24
[0262] A 0.degree. C. solution of Example A5 (200 mg 0.58 mmol) and
pyridine (68 mg, 0.87 mmol) in THF (20 mL) was treated with
1-fluoro-3-isocyanato-benzene (80 mg, 0.58 mmol), warmed to RT and
stirred for 3 h. The mixture was concentrated in vacuo and purified
by preparative HPLC to give
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1.6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea (193 mg, 69%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.34 (s, 1H),
8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.85 (s, 1H),
7.87-7.49 (br. s, 1H), 7.59 (d, J=10.8 Hz, 1H), 7.48 (d, J=11.6 Hz,
1H), 7.33 (m, 1H), 7.08 (m, 1H), 6.83 (m, 1H), 6.44 (s, 1H), 4.18
(m, 2H), 2.94 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1
[M+H].sup.+.
##STR00105##
Example 25
[0263] Using a procedure analogous to Example 24, Example A5 (400
mg 1.16 mmol) and 1-fluoro-2-isocyanato-benzene (158 mg, 1.16 mmol)
were converted to
1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1.6]naphthyridin--
3-yl)-2-fluoro-phenyl]-3-(2-fluoro-phenyl)-urea (144 mg, 26%
yield). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 9.22 (s, 1H),
9.10 (s, 1H), 8.52 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.12 (t, J=8
Hz, 1H), 7.87-7.57 (br. s, 1H), 7.86 (s, 1H), 7.59 (d, J=11.2 Hz,
1H), 7.26 (m, 1H), 7.13 (m, 1H), 7.04 (m, 1H), 6.47 (s, 1H), 4.18
(m, 2H), 2.95 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1
[M+H].sup.+.
##STR00106##
Example 26
[0264] A solution of Example A45 (0.09 g, 0.260 mmol) in THF (3 mL)
was treated with TEA (0.036 mL, 0.260 mmol) and phenyl isocyanate
(0.034 g, 0.285 mmol) and stirred at RT overnight. Additional
phenyl isocyanate (0.034 g, 0.285 mmol) was added and the mixture
heated at 60.degree. C. for 5 h. The mixture was concentrated to
dryness and purified via silica gel chromatography (MeOH/DCM) to
afford
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-phenylurea (101 mg, 84% yield) as a white
solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H),
8.65 (d, J=2.7 Hz, 1H), 8.44 (s, 1H), 8.20 (t, J=8.7 Hz, 1H), 7.86
(s, 1H), 7.46-7.45 (m, 2H), 7.35 (dd, J=9.0, 1.4 Hz, 1H), 7.30 (t,
J=7.8 Hz, 2H), 7.13 (q, J=4.9 Hz, 1H), 7.00 (t, J=7.4 Hz, 1H), 6.28
(s, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.88 (d, J=4.9 Hz, 3H), 1.23 (t,
J=7.0 Hz, 3H); MS (ESI): m/z 466.1 [M+H].sup.+.
##STR00107##
Example 27
[0265] A suspension of Example A12 (0.300 g, 0.768 mmol) in EtOAc
(6 mL) was treated with phenyl isocyanate (0.091 g, 0.768 mmol),
stirred at RT for 13 h and the resulting solid collected by suction
filtration. The white solids were stirred in boiling MeCN for 20
minutes followed by stirring at RT for 1 h. The solids were
collected by suction filtration, washed and dried to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.233 g, 60% yield) as
a white solid. MS(ESI) m/z: 510.2 [M+H].sup.+.
[0266] A suspension of
I-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-phenylurea, (0.233 g, 0.457 mmol)
in MeCN (10 mL) was treated with methanesulfonic acid (0.044 g,
0.457 mmol). The crystallized solids were filtered, washed and
dried to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-phenylurea methanesulfonate as a
white solid (0.210 g, 76% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.13 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H),
8.22 (d, J=9 Hz, 2H), 7.90 (s, 1H), 7.58 (d, J=12 Hz, 1H), 7.42 (d,
J=8 Hz, 2H), 7.26 (t, J=8 Hz, 2H) 6.97 (t, J=8.5 Hz, 1H), 6.74 (s,
1H), 4.16 (m, 2H), 3.57 (m, 4H), 3.29 (s, 3H), 2.34 (s, 3H), 1.20
(t, J=6 Hz, 3H); MS(ESI) m/z: 510.2.2 [M+H].sup.+.
##STR00108##
Example 28
[0267] To a suspension of Example A12 (0.300 g, 0.768 mmol) in
EtOAc (6 mL) was added 3-fluorophenyl isocyanate (0.105 g, 0.768
mmol). The mixture was stirred at RT for 13 h and solids from the
reaction mixture were collected by suction filtration. The white
solids were stirred in refluxing MeCN for 20 minutes, followed by
stirring at RT for 1 h. The solids were filtered, washed, and dried
to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea (0.300 g, 74%
yield) as white solid. MS(ESI) m/z: 528.2 [M+H].sup.+.
[0268] To a suspension of
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea, (0.300 g,
0.568 mmol) in MeCN (10 mL) was added methanesulfonic acid (0.055
g, 0.568 mmol). After stirring at RT for 1 h, the solvent was
completely evaporated and the residue was crystallized from EtOH to
provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea
methanesulfonate as a white solid (0.295 g, 83% i.degree. yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.37 (s, 1H), 8.84 (s,
1H), 8.55 (s, 1H), 8.30 (s, 1H), 8.18 (d, J=8 Hz, 1H), 7.91 (s,
1H), 7.59 (d, J=11 Hz, 1H), 7.47 (m, 1H), 7.29 (m, 1H), 7.07 (m,
1H), 6.77 (m, 2H), 4.15 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.37
(s, 3H), 1.20 (t, J=6 Hz, 3H): MS(ESI) m/z: 528.2 [M+H].sup.+.
##STR00109##
Example 29
[0269] To a suspension of Example A15 (0.300 g, 0.743 mmol) in
EtOAc (6 mL) was added phenyl isocyanate (0.088 g, 0.743 mmol) and
the mixture was stirred at RT for 13 h. The solids were filtered,
washed and dried to provide
1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (320
mg, 82% yield) as a white solid. MS(ESI) m/z: 524.2
[M+H].sup.+.
[0270] To a suspension of
1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.260 g, 0.497
mmol) in MeOH (1 mL) was added HCl (1.25 M in MeOH) (0.875 mL,
1.094 mmol) and the mixture was stirred at RT for 1 h. The reaction
mixture was diluted with EtOAc and the remaining solid was
filtered, washed and dried to provide
1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
dihydrochloride (267 mg, 90% yield) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.37 (s, 1H), 8.83 (s, 1H), 8.44
(s, 1H), 8.17 (d, J=9 Hz, 1H), 7.78 (m, 1H), 7.52 (d, J=11 Hz, 1H),
7.42 (m, 2H), 7.25 (m, 3H), 6.95 (t, J=8 Hz, 1H), 6.42 (s, 1H),
4.13 (m, 2H), 3.63 (m, 2H), 3.02 (s, 2H), 2.64 (s, 6), 1.20 (t, J=6
Hz, 3H); MS(ESI) m/z: 523.2 [M+H].sup.+.
##STR00110##
Example 30
[0271] To a suspension of Example A16 (0.320 g, 0.766 mmol) in
EtOAc (6 mL) was added phenyl isocyanate (0.091 g, 0.766 mmol) and
the mixture was stirred at RT for 13 h. The residue obtained after
evaporation of the solvent was purified by silica gel
chromatography (THF/EtOAc) to provide
1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (132 mg, 32%
yield) as a white solid. MS(ESI) m/z: 537.2 [M+H].sup.+.
[0272] To a suspension of
1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.130 g,
0.242 mmol) in MeOH (1 mL) was added HCl (1.25 M in MeOH, 0.426 mL,
0.533 mmol) and the mixture stirred at RT for 1 h. The reaction
mixture was diluted with EtOAc, filtered, washed and dried to
provide
1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
dihydrochloride (118 mg, 80% yield) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d): .delta. 9.44 (s, 1H), 8.86 (s, 1H), 8.43 (s,
1H), 8.17 (d, J=9 Hz, 1H), 7.76 (s, 1H), 7.52 (d, J=9 Hz, 1H), 7.42
(m, 2H), 7.25 (m, 3H), 6.96 (t, J=7 Hz, 1H), 6.34 (s, 1H), 4.12 (m,
2H), 3.42 (m, 2H), 3.10 (m, 2H), 2.75 (s, 6H), 1.93 (m, 2H), 1.18
(t, J=6 Hz, 3H); MS(ESI) m/z: 537.2. [M+H].sup.+.
##STR00111##
Example 31
[0273] A mixture of Example A14 (0.120 g, 0.307 mmol) and TEA
(0.043 mL, 0.307 mmol) in THF (3.0 mL) was treated with phenyl
isocyanate (0.040 g, 0.337 mmol) and stirred at RT for 4 h. Over
the course of the next 4 days the mixture was treated with
additional phenyl isocyanate (0.056 mL) and stirred at RT. The
resulting solid was filtered, rinsed with THF, then triturated with
MeOH to afford
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea (101 mg, 64.5% yield) as a
bright white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.09 (s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.17 (d, 1H), 7.70 (s,
1H), 7.65 (d, 1H), 7.41 (d, 2H), 7.27 (m, 2H), 7.03 (m, 1H), 6.96
(t, 1H), 6.23 (s, 1H), 4.13 (q, 2H), 2.86 (d, 3H), 1.20 (t, 3H); MS
(ESI) m/z: 510.1 [M+H].sup.+.
##STR00112##
Example 32
[0274] Example A5 (0.2 g, 0.577 mmol), benzothiophene-3-carboxylic
acid (0.134 g, 0.750 mmol) and TEA (0.322 mL, 2.307 mmol) were
suspended in dioxane (5 mL), treated with DPPA (0.186 mL, 0.865
mmol) and heated to 100.degree. C. for 3 h. The mixture was cooled
to RT and the precipitate was filtered off and dried to yield
1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,-
2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea (215
mg, 71% yield), which was suspended in refluxing MeCN (6 mL).
Methanesulfonic acid (0.027 mL, 0.412 mmol) was added, followed by
the addition of MeOH (1 mL). The mixture was cooled to RT, allowed
to stand for 2 h, treated with Et.sub.2O (3 mL) and sonicated for 5
min. The resulting solid was collected via filtration and dried to
yield
1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,-
2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea
meslyate (209 mg, 82% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.48 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.32 (d, 1H),
8.01 (br s, 1H), 7.96 (d, 1H), 7.91 (s, 1H), 7.86 (d, 1H), 7.68 (s,
1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.42 (t, 1H), 6.55 (s, 1H), 4.17
(q, 2H), 2.96 (s, 3H), 2.30 (s, 3H), 1.22 (t, 3H); MS (ESI) m/z:
522.1 [M+H].sup.+.
##STR00113##
Example 33
[0275] A solution of Example A46 (0.12 g, 0.365 mmol) in pyridine
(3 mL) was treated with phenyl isocyanate (0.044 mL, 0.401 mmol)
and stirred at RT overnight. The mixture was concentrated to
dryness, the residue treated with MeCN, sonicated and the resulting
solid collected via filtration and dried to afford
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)phenyl)-3-phenylurea (166 mg, 102% yield). MS (ESI) m/z:
448.1 [M+H].sup.+.
[0276] A suspension of
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)phenyl)-3-phenylurea (0.166 g, 0.371 mmol) in refluxing MeCN
(5 mL) was treated with methanesulfonic acid (0.026 mL, 0.408
mmol), cooled to RT, treated with water, frozen and lyophilized.
The resulting material was treated with EtOAc, sonicated and
collected via filtration to afford
1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)phenyl)-3-phenylurea methanesulfonate (172 mg, 85% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.96 (s, 1H), 8.81 (s,
1H), 8.54 (s, 1H), 8.08 (br s, 1H), 7.89 (s, 1H), 7.62 (t, J=1.4
Hz, 1H), 7.45-7.39 (m, 4H), 7.25 (t, J=7.8 Hz, 2H), 6.95 (t, J=7.3
Hz, 1H), 6.57 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 3H), 2.33
(s, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 448.1
[M+H].sup.+.
##STR00114##
Example 34
[0277] To a suspension of Example A12 (0.200 g, 0.512 mmol) in
EtOAc (5 mL) was added 1-fluoro-4-isocyanatobenzene (0.093 g, 0.681
mmol) and the mixture stirred at RT for 16 h. The solids were
filtered, washed and dried to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea (0.220 g, 81%
yield) as a white solid. MS(ESI) m/z: 528.2 [M+H].sup.+.
[0278] A suspension of
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea, (0.220 g,
0.417 mmol) in MeCN (10 mL) was treated with methanesulfonic acid
(0.044 g, 0.458 mmol) and stirred at RT for 20 h. The solids were
filtered, washed and dried to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea
methanesulfonate (212 mg, 74% yield) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.16 (s, 1H), 8.75 (s, 1H), 8.54
(s, 1H), 8.28 (b s, 1H), 8.19 (d, J=9 Hz, 1H), 7.89 (s, 1H), 7.58
(d, J=11 Hz, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.74 (s, 1H), 4.14
(m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.34 (s, 3H), 1.20 (t, J=6 Hz,
3H); MS(ESI) m/z: 528.2 [M+H].sup.+.
##STR00115##
Example 35
[0279] To a suspension of Example A12 (0.200 g, 0.512 mmol) in
EtOAc (5 mL) was added 1-fluoro-2-isocyanatobenzene (0.093 g, 0.681
mmol) and the mixture was stirred at RT for 16 h. The solids were
filtered, washed and dried to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea (0.220 g, 81%
yield) as a white solid. MS(ESI) m/z: 528.1 [M+H].sup.+.
[0280] A suspension of
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea (0.220 g,
0.417 mmol) in MeCN (10 mL) was treated with methanesulfonic acid
(0.040 g, 0.417 mmol) and stirred at RT for 20 h. The solids were
filtered, washed and dried to provide
1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea
methanesulfonate (205 mg, 79% yield) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.22 (s, 1H), 9.10 (s, 1H), 8.54
(s, 1H), 8.25 (d, J=9 Hz, 1H), 8.18 (br s, 1H), 8.10 (m, 1H), 7.89
(s, 1H), 7.60 (d, J=11 Hz, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 7.00
(m, 1H), 6.72 (s, 1H), 4.14 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H),
2.31 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS(ESI) m/z: 528.2
[M+H].sup.+.
##STR00116##
Example 36
[0281] To a suspension of Example A19 (0.200 g, 0.534 mmol) in
EtOAc (5 mL) was added phenyl isocyanate (0.085 g, 0.710 mmol) and
the mixture was stirred at RT for 16 h. The solids were filtered,
washed and dried to provide
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (201 mg, 76% yield)
as a white solid. MS(ESI) m/z: 494.2 [M+H].sup.+.
[0282] To a suspension of
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2,4-difluorophenyl)-3-phenylurea (0.200 g, 0.405 mmol) in
MeCN (10 mL) was added methanesulfonic acid (0.039 g, 0.405 mmol)
and the mixture stirred at RT for 1 h. The solvent was evaporated
and the residue crystallized from MeCN to provide
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2,4-difluorophenyl)-3-phenylurea methanesulfonate (190 mg,
80% yield) as a white solid .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.22 (s, 1H), 9.10 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H),
8.15 (t, J=8 Hz, 1H), 8.00 (s, 1H), 7.42 (m, 3H), 7.26 (m, 2H),
6.96 (t, J=7 Hz, 1H), 6.73 (s, 1H), 4.14 (m, 2H), 3.56 (m, 4H),
3.30 (s, 3H), 2.35 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS(ESI) m/z:
494.2 [M+H].sup.+.
##STR00117##
Example 37
[0283] To a suspension of Example A28 (0.400 g, 1.080 mmol) in
EtOAc (10 mL) was added phenyl isocyanate (0.171 g, 1.436 mmol) and
the mixture stirred at RT for 16 h. The solids were filtered,
washed, and dried to provide
1-(5-(l-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (500 mg, 95%
yield) as a white solid. MS(ESI) m/z: 490.2 [M+H].sup.+.
[0284] To a suspension of
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (0.500 g, 1.021 mmol)
in MeCN (10 mL) was added methanesulfonic acid (0.098 g, 1.021
mmol) and the mixture stirred at RT for 1 h. The solids were
filtered, washed, and dried to provide
1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea methanesulfonate as a
white solid (468 mg, 78% yield) .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.07 (s, 1H), 8.54 (m, 2H), 8.30 (br s, 1H),
7.98 (d, J=9 Hz, 1H), 7.83 (s, 1H), 7.42 (m, 2H), 7.25 (m, 2H),
7.16 (d, J=12 Hz, 1H), 6.94 (t, J=8 Hz, 1H), 6.77 (s, 1H), 4.18 (m,
2H), 3.60 (m, 4H), 3.30 (s, 3H), 2.31 (s, 3H), 2.07 (s, 3H), 1.20
(t, J=6 Hz, 3H); MS(ESI) m/z: 490.2 [M+H].sup.+.
##STR00118##
Example 38
[0285] To a suspension of Example A2 (0.09 g, 0.276 mmol) and TEA
(0.038 mL, 0.276 mmol) in THF (3 mL) was added 2-fluorophenyl
isocyanate (0.042 g, 0.303 mmol) and the mixture stirred at RT for
16 h. The solvent was removed and the resultant crude product was
purified by silica gel chromatography (MeOH/DCM) to afford
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea (61 mg, 48% yield) as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.97
(br s, 2H), 8.40 (s, 1H), 8.10 (t d, J=8.0 Hz, 1.6 Hz, 1H), 7.95
(d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.24-7.18 (m, 1H), 7.14-7.07 (m,
2H), 7.00-6.95 (m, 2H), 6.23 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.85
(d, J=6.4 Hz, 3H), 2.06 (s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI)
m/z: 464.2 [M+H].sup.+.
##STR00119##
Example 39
[0286] To a solution of Example A23 (0.105 g, 0.26 mmol) and TEA
(0.036 mL, 0.26 mmol) in THF (3 mL) was added phenyl isocyanate
(0.04 g, 0.337 mmol) and the suspension was stirred at RT for 2 h.
The suspension was filtered, washed with EtOAc and dried to afford
1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.12 g, 88% yield) as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08
(s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8 Hz,
1H), 7.72 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.42-7.40 (m, 2H),
7.28-7.24 (m, 2H), 7.08 (t, J=5.6 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H),
6.29 (s, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.41-3.31 (m, 4H), 3.23 (s,
3H), 1.81-1.75 (m, 2H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 524.2
[M+H].sup.+.
##STR00120##
Example 40
[0287] To a suspension of Example A25 (0.300 g, 0.871 mmol) in
EtOAc (5 mL) was added 3-fluorophenylisocyanate (0.119 g, 0.871
mmol) and the mixture stirred at RT for 2 h. The solids were
filtered, washed and dried to provide
1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naph-
thyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (0.364 g, 87% yield)
as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.24 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.07 (t, J=8 Hz, 1H),
7.76 (s, 1H), 7.46 (m, 1H), 7.31 (m, 2H), 7.07 (m, 1H), 7.00 (m,
1H), 6.77 (m, 1H), 6.43 (s, 1H), 5.19 (br s, 1H), 2.84 (br s, 3H),
1.50 (d, J=6 Hz, 6H); MS(ESI) m/z: 482.2 [M+H].sup.+.
##STR00121##
Example 41
[0288] Example A21 (0.20 g, 0.588 mmol) and 3-fluorophenyl
isocyanate (0.081 g, 0.588 mmol) were combined in THF (5 mL),
treated with TEA (0.163 mL, 1.175 mmol) and stirred at RT
overnight. The solvent was removed and the residue was purified by
reverse phase column chromatography (MeCN/H.sub.2O with 0.1% TFA).
Pure fractions were combined and co-concentrated with MeOH and the
remaining aqueous solution was treated with NaHCO.sub.3, and
extracted with EtOAc. The organics were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated, and dried under vacuum
to obtain
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea. The material was
suspended in MeCN (3 mL), treated with methanesulfonic acid (1 M in
DCM, 0.369 mL, 0.369 mmol), heated to reflux and allowed to cool to
RT. The solvent was then removed, Et.sub.2O added, and the solid
filtered and washed with Et.sub.2O to obtain
1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyr-
idin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea methanesulfonate
(190 mg, 57% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.26 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.11 (br s, 1H), 7.95 (d,
J=8.4 Hz, 1H), 7.77 (s, 1H), 7.47 (m, 1H), 7.28 (m, 1H), 7.17 (d,
J=12.4 Hz, 1H), 7.05 (m, 1H), 6.77 (m, 2H), 3.36 (m, 1H), 2.96 (s,
3H), 2.30 (s, 3H), 2.06 (s, 3H), 1.52 (d, J=6.8 Hz, 6H); MS (ESI)
m/z: 478.2 [M+H].sup.+.
##STR00122##
Example 42
[0289] Example A22 (0.15 g, 0.360 mmol) and phenyl isocyanate
(0.051 g, 0.432 mmol) were combined in THF (5 mL), treated with TEA
(0.100 mL, 0.720 mmol) and stirred at RT overnight. The solid was
filtered, washed with EtOAc, and dried under vacuum to obtain
1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H-pyran-4-ylamino)-1,2-dihydr-
o-1.6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.135 g, 70%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H),
8.68 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.72 (s, 1H),
7.52 (d, J=10.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (m, 3H), 7.07
(d, J=7.6 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.34 (s, 1H), 4.10 (q,
J=6.8 Hz, 2H), 3.86 (m, 2H), 3.42 (m, 2H), 1.88 (m, 2H), 1.44 (m,
2H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 536.2 [M+H].sup.+.
##STR00123##
Example 43
[0290] Example A26 (0.13 g, 0.321 mmol) was dissolved in EtOAc (10
mL), treated with phenyl isocyanate (0.037 mL, 0.337 mmol) and
stirred at RT overnight. Precipitated solids were collected by
filtration, rinsed with EtOAc, and dried on the filter to afford
(S)-1-(4-chloro-5-(1-ethyl-7-(1-methoxypropan-2-ylamino)-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.138 g, 82%
yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.03 (s, 1H), 8.68 (br s, 1H), 8.39 (s, 1H), 8.17 (d, 1H,
J=8.4 Hz), 7.72 (s, 1H), 7.52 (d, 1H, J=10.8 Hz), 7.42-7.40 (m,
2H), 7.28-7.24 (m, 2H), 6.98-6.92 (m, 2H), 6.39 (s, 1H), 4.26-4.20
(m, 1H), 4.09 (q, 2H, J=7.6 Hz), 3.40 (dd, 1H, J=4.0, 9.2 Hz), 3.34
(s, 3H), 3.34-3.28 (m, 1H), 1.19 (t, 3H, J=7.6 Hz), 1.15 (d, 3H,
J=6.4 Hz); MS (ESI) m/z: 524.2 [M+H].sup.+.
##STR00124##
Example 44
[0291] A solution of Example A2 (300 mg, 0.919 mmol) in pyridine (5
mL) was treated drop-wise with 3-fluorophenyl isocyanate (139 mg,
1.011 mmol) and stirred at RT. The mixture was diluted with EtOAc
and water and the remaining solid was collected via filtration,
washed with water and EtOAc and purified by reverse phase
chromatography (MeCN/water with 0.1% TFA). The organics were
removed under reduced pressure and the aqueous residue was treated
with satd. NaHCO.sub.3 (10 mL) and allowed to precipitate. The
solid was collected by filtration, washed with water and dried to
yield
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,66-naphthyridin-3-
-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (214 mg, 50%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.23 (s, 1H),
8.54 (s, 1H), 8.41 (s, 1H), 7.90 (d, 1H), 7.67 (s, 1H), 7.45 (d,
1H), 7.30-7.24 (m, 1H), 7.14-7.03 (m, 3H), 6.78-6.74 (m, 1H), 6.28
(s, 1H), 4.17-4.12 (m, 2H), 2.85 (s, 3H), 2.05 (s, 3H), 1.20 (t,
3H); MS (ES-API) m/z: 463.9 [M+H].sup.+.
##STR00125##
Example 45
[0292] A solution of Example A27 (124 mg, 0.352 mmol) in pyridine
(4 mL) was treated drop-wise with 3-fluorophenyl isocyanate (51 mg,
0.369 mmol) and stirred at RT. The mixture was diluted with EtOAc
and water, the remaining solid collected via filtration, washed
with Et.sub.2O, dried, and purified by reverse phase chromatography
(MeCN/water with 0.1% TFA). The organics were removed under reduced
pressure and the aqueous residue was treated with satd. NaHCO.sub.3
and extracted with hot EtOAc (2.times.). The combined organics were
dried hot over Na.sub.2SO.sub.4 and evaporated at reduced pressure
to give a white solid which was dried under reduced pressure to
yield
1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (75 mg, 43%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.22 (s, 1H),
8.53 (s, 1H), 8.40 (s, 1H), 7.91 (d, 1H), 7.68 (s, 1H), 7.47-7.44
(m, 1H), 7.34-7.26 (m, 2H), 7.15-7.11 (m, 1H), 7.06-7.03 (m, 1H),
6.80-6.72 (m, 1H), 6.41 (s, 1H), 4.21-4.15 (m, 2H), 2.20 (m, 1H),
2.06 (s, 3H), 1.23 (t, 3H), 0.79-0.74 (m, 2H), 0.50-0.47 (m, 2H);
MS (ES-API) m/z: 490.2 [M+H].sup.+.
##STR00126##
Example 46
[0293] To a solution of Example A3 (2.1 g, 5.96 mmol) in NMP (10
mL) was added 1-methyl-piperidin-4-ylamine (1.36 g, 11.9 mmol) and
DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture
for 5 min and then it was heated at 180.degree. C. for 12 h. The
reaction mixture was cooled to RT, poured into water and extracted
with EtOAc (3.times.). The combined organics were washed with
brine, dried over Na.sub.2SO.sub.4, concentrated under reduced
pressure, and the residue was purified by silica gel chromatography
to yield
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamin-
o)-1,6-naphthyridin-2(1H)-one (0.50 g, 19.5% yield) which was 70%
pure (30% de-methylated by-product) and used without further
purification.
[0294] A solution of
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamin-
o)-1,6-naphthyridin-2(1H)-one (200 mg, 0.465 mmol) and pyridine (70
mg, 0.95 mmol) in DCM (5 mL) was treated drop-wise with phenyl
isocyanate (112 mg, 0.93 mmol) and stirred at RT under nitrogen
overnight. The mixture was quenched with MeOH (5 mL), concentrated
under reduced pressure and purified by prep-TLC separation to give
1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 47%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.16 (s, 1H),
8.72 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.71 (s, 1H),
7.51 (d, J=10.8 Hz, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.26 (t, J=8.0
Hz, 2H), 7.02-6.94 (m, 2H), 6.33 (s, 1H), 4.11-4.05 (m, 2H),
3.81-3.78 (m, 1H), 2.78-2.75 (m, 2H), 2.20 (s, 3H), 2.12-2.05 (m,
2H), 1.90-1.88 (m, 2H), 1.52-1.47 (m, 2H), 1.21-1.18 (m, 3H); MS
(ESI) m/z: 549.3 [M+H].sup.+.
##STR00127##
Example 47
[0295] A solution of Example A30 (150 mg, 0.37 mmol) and pyridine
(59 mg, 0.74 mmol) in DCM (3 mL) was treated drop-wise with phenyl
isocyanate (53 mg, 0.44 mmol) and stirred at RT under nitrogen
overnight. The mixture was filtered and the filter cake was
purified by prep-HPLC separation to give
1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-phenylurea (49 mg, 25% yield).
.sup.1H NMR (400 MHz, CDCl3): .delta. 8.36 (s, 1H), 8.21 (s, 1H),
7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.40 (d, J=7.6
Hz, 2H), 7.22-7.18 (m, 2H), 6.97-6.91 (m, 2H), 6.14 (s, 1H), 5.08
(d, J=7.6 Hz, 1H), 4.46 (br s, 1H), 4.33 (q, J=6.4 Hz, 2H),
4.01-3.95 (m, 2H), 3.88-3.83 (m, 1H), 3.75 (dd, J=9.2 Hz, 2.8 Hz,
1H), 2.39-2.32 (m, 1H), 1.98-1.87 (m, 1H), 1.40 (t, J=6.4 Hz, 3H);
MS (ESI) m/z: 522.1 [M+H].sup.+.
##STR00128##
Example 48
[0296] 2-Methylsulfanyl-ethylamine (5 mL) and Example A3 (500 mg,
1.42 mmol) were added to a sealed tube and the mixture was heated
at 130.degree. C. overnight. The reaction mixture was concentrated
under vacuum, treated with water and extracted with EtOAc
(3.times.). The combined organics were washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated to give
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)--
1,6-naphthyridin-2(1H)-one (400 mg, 69% yield) which was used
directly without further purification.
[0297] To a solution of
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)--
1,6-naphthyridin-2(1H)-one (400 mg, 0.99 mmol) in DCM (20 mL) was
added phenyl isocyanate (200 mg, 1.68 mmol) and the mixture was
stirred overnight. The reaction mixture was quenched with MeOH and
concentrated under reduced pressure. The residue was washed with
Et.sub.2O to give
1-(4-chloro-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (200 mg, 39%
yield).
[0298] To a solution of
1-(4-chloro-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (200 mg, 0.38
mmol) in DCM (20 mL) was added 85% mCPBA (169 mg, 0.84 mmol) at RT.
The mixture was stirred for 2 h and then additional mCPBA (84 mg,
0.42 mmol) was added. The mixture was stirred for 1 h, washed
successively with satd. Na.sub.2SO.sub.3, satd. NaHCO.sub.3, and
brine, dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure. The residue was dissolved in MeOH and THF and NH.sub.4Cl
(222 mg, 4.2 mmol) was added, followed by Zn powder (273 mg, 4.2
mmol), and the mixture stirred for 30 minutes. The mixture was
filtered, the filtrate concentrated to dryness, treated with water,
extracted with 10% MeOH/DCM and the organic layer was concentrated
and purified by prep-HPLC to give
1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (96 mg, 45%
yield over two steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.75 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.15 (d, J=8.4 Hz, 1H),
7.77 (s, 1H), 7.49 (d, J=10.8 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.30
(m, 1H), 7.24 (m, 2H), 6.94 (m, 1H), 6.44 (s, 1H), 4.10 (q, J=7.2
Hz, 2H), 3.76 (m, 2H), 3.39 (t, J=6.4 Hz, 2H), 3.01 (s, 3H), 1.19
(t, J=6.8 Hz, 3H); MS (ESI): m/z 557.8 [M+H].sup.+.
##STR00129##
Example 49
[0299] A solution of Example A3 (500 mg, 1.42 mmol),
1-methyl-pyrrolidin-3-ylamine (170 mg, 1.7 mmol) and DBU (383 mg,
2.84 mmol) in NMP (5 mL) was heated with a microwave at 160.degree.
C. for 2 h. After cooling to RT, the mixture was purified by silica
gel chromatography to yield
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylami-
no)-1,6-naphthyridin-2(1H)-one (500 mg, 85% yield) as a yellow
oil.
[0300] To a solution of
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylami-
no)-1,6-naphthyridin-2(1H)-one (500 mg, 1.20 mmol) and pyridine
(140 mg, 1.8 mmol) in DCM (20 mL) was added phenyl isocyanate (215
mg, 1.8 mmol). The mixture was stirred at RT overnight,
concentrated, and purified by prep-HPLC separation to give
1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (53 mg, 8.4%
yield) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8
Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.41 (d, J=7.6 Hz,
2H), 7.28-7.23 (m, 3H), 6.98-6.95 (m, 1H), 6.35 (s, 1H), 4.39 (s,
1H), 4.11-4.09 (m, 2H), 2.77-2.71 (m, 1H), 2.65-2.61 (m, 1H),
2.44-2.36 (m, 2H), 2.26 (s, 3H), 2.23-2.20 (m, 1H), 1.68-1.62 (m,
1H), 1.64 (t, J=7.2 Hz, 3H).
##STR00130##
Example 50
[0301] A suspension of Example A14 (0.150 g, 0.383 mmol) and TEA
(0.053 mL, 0.383 mmol) in THF (2.5 mL) was treated with
3-fluorophenyl isocyanate (0.048 mL, 0.422 mmol) and stirred at RT,
under an Ar atmosphere, overnight. Additional 3-fluorophenyl
isocyanate (0.024 mL, 0.55 eq.) was added, the mixture stirred at
RT for 6 h, then treated again with 3-fluorophenyl isocyanate (1
drop) and the mixture stirred at RT overnight. The resulting solid
was filtered, rinsed with a small amount of THF and dried to afford
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea (166 mg, 82% yield) as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.30
(s, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.14 (d, 1H), 7.70 (s, 1H),
7.66 (d, 1H), 7.75 (m, 1H), 7.29 (q, 1H), 7.05 (m, 2H), 6.78 (m,
1H), 6.24 (s, 1H), 4.13 (q, 2H), 2.86 (d, 3H), 1.21 (t, 3H); MS
(ESI) m/z: 528.1 [M+H].sup.+.
##STR00131##
Example 51
[0302] To a solution of Example A29 (0.131 g, 1.103 mmol) in DCM (5
mL) was added phenyl isocyanate (0.480 g, 1.103 mmol) and the
reaction mixture was stirred at RT. After 2 h the solvent was
completely evaporated and the residue was crystallized from MeCN to
provide
1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.433 g, 70.8% yield)
as a white solid. MS(ESI) m/z: 554.1/556.1 [M+H].sup.+.
[0303] To a suspension of
1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.200 g, 0.361 mmol) in
MeCN (4 mL) was added methanesulfonic acid (0.035 g, 0.361 mmol)
and the mixture was stirred at RT for 30 minutes. The solvent was
completely evaporated and the residue was crystallized from MeCN to
provide
1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-phenylurea methanesulfonate (0.160
g, 67% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.23 (s, 1H), 9.04 (s, 1H), 8.53 (s, 1H),
8.22 (d, J=9 Hz, 2H), 7.87 (s, 1H), 7.70 (d, J=11 Hz, 1H), 7.41 (d,
J=9 Hz, 2H), 7.26 (t, J=7 Hz, 2H), 6.96 (t, J=7 Hz, 1H), 6.72 (s,
1H), 4.13 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.33 (s, 3H), 1.21
(d, J=6 Hz, 3H): MS(ESI) m/z: 554.1/556.1 [M+H].sup.+.
##STR00132##
Example 52
[0304] Phenyl isocyanate (0.067 g, 0.56 mmol) was added to a
solution of Example A31 (0.19 g, 0.43 mmol) and TEA (0.09 g, 0.87
mmol) in THF (3 mL) and stirred at RT for 1 h. The resultant
suspension was diluted with MTBE (3 mL), filtered, washed with MTBE
and dried to afford
1-(4-bromo-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6--
naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea as a white solid
(0.18 g, 74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.08 (s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.17 (d, J=8.4 Hz, 1H),
7.70 (s, 1H), 7.65 (d, J=10.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H),
7.28-7.17 (m, 3H), 6.96 (t, J=8.4 Hz, 1H), 6.35 (s, 1H), 4.11 (q,
J=6.4 Hz, 2H), 3.55 (q, J=6.0 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.10
(s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 570.1
[M+H].sup.+.
[0305] To a suspension of
I-(4-bromo-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6--
naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.18 g, 0.31 mmol)
in DCM (25 mL) was added 70-75% mCPBA (0.14 g, 0.63 mmol) and the
suspension was stirred at RT for 15 minutes. The mixture was
diluted with a 10% Na.sub.2SO.sub.3 solution (30 mL), the layers
were separated, and the organic layer was washed with satd.
NaHCO.sub.3 solution, then brine, dried (Na.sub.2SO.sub.4), and
concentrated. The crude product was purified by silica gel
chromatography (MeOH/DCM) to afford
1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro--
1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (115 mg, 61%
yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d): .delta.
9.08 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 8.18 (d, J=8.4 Hz, 1H),
7.74 (s, 1H), 7.66 (d, J=10.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H),
7.28-7.24 (m, 3H), 6.96 (t, J=7.6 Hz, 1H), 6.42 (s, 1H), 4.12 (q,
J=6.8 Hz, 2H), 3.77 (q, J=6.4 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.02
(s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 602.1
[M+H].sup.+.
##STR00133##
Example 53
[0306] A suspension of Example A32 (0.278 g, 0.559 mmol) in THF (6
mL) was treated with TEA (0.097 mL, 0.699 mmol) followed by phenyl
isocyanate (0.061 mL, 0.559 mmol) and stirred at RT overnight. The
resulting solids were collected by filtration, rinsed with THF and
dried under vacuum to afford
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (0.256 g, 74%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H),
8.68 (d, 1H, J=2.4 Hz), 8.4 (s, 1H), 8.16 (d, 1H, J=8.8 Hz), 7.69
(s, 1H), 7.65 (d, 1H, J=10.8 Hz), 7.56-7.53 (m, 1H), 7.42-7.39 (m,
2H), 7.30-7.24 (m, 4H), 6.96 (m, 1H), 6.89-6.86 (m, 2H), 6.31 (br
s, 1H), 4.49-4.47 (m, 2H), 4.07 (q, 2H, J=8.0 Hz), 3.70 (s, 3H),
1.12 (t, 3H, J=8.0 Hz); MS (ESI) m/z: 616.2 (M+H.sup.+), 618.2
(M+2+H.sup.+).
[0307]
1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphth-
yridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (0.256 g, 0.415
mmol) was dissolved in TFA (4 mL, 51.9 mmol) and stirred at RT.
After 4 h the reaction mixture was concentrated to dryness, the
residue was diluted with MeOH, and the precipitated solids were
removed by filtration. The filtrate was treated with satd.
NaHCO.sub.3 and the resulting solid collected by filtration, rinsed
with H.sub.2O, dried under vacuum, and purified by reverse phase
chromatography (MeCN/H2O with 0.1% TFA). The organics were removed
under reduced pressure, the aqueous residue treated with satd.
NaHCO.sub.3 and the resulting solids were collected by filtration,
washed with H.sub.2O and dried to afford
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2--
fluorophenyl)-3-phenylurea (90 mg, 44% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.68 (d, 1H, J=2.4 Hz),
8.36 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 7.70 (s, 1H), 7.65 (d, 1H,
J=10.8 Hz), 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m,
1H), 6.54 (br s, 2H), 6.34 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 1.20
(t, 3H, J=7.2 Hz); MS (ESI) m/z: 496.1 (M+H.sup.+), 498.1
(M+2+H.sup.+).
[0308]
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-br-
omo-2-fluorophenyl)-3-phenylurea (90 mg, 0.181 mmol) was suspended
in acetic anhydride (5 mL, 52.9 mmol) and heated at 110.degree. C.
for 4 h. The reaction was cooled to RT, poured onto ice (15 g), and
stirred overnight. The solids were collected, rinsed well with
H.sub.2O, air dried, then suspended in MeCN (2-3 mL) and heated at
80.degree. C. overnight. The solids were collected by filtration,
rinsed with MeCN and dried under vacuum to afford
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-brom-
o-2-fluorophenyl)-3-phenylurea (56 mg, 57% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 10.84 (s, 1H), 9.10 (s, 1H), 8.73 (d,
J=2.4 Hz, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.4 Hz, 1H),
7.95 (s, 1H), 7.7 (d, J=6.8 Hz, 1H), 7.42-7.40 (m, 2H), 7.28-7.24
(m, 2H), 6.98-6.95 (m, 1H), 4.19 (q, J=6.8 Hz, 2H), 2.15 (s, 3H),
1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 538.1 [M+H].sup.+.
##STR00134##
Example 54
[0309] Example A35 (0.200 g, 0.601 mmol) was dissolved in THF (6
mL) at RT and treated with TEA (0.109 mL, 0.781 mmol), followed by
phenyl isocyanate (0.066 mL, 0.601 mmol). After 2 h, the
precipitated solids were collected by filtration and rinsed with
THF to obtain
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-
-fluorophenyl)-3-phenylurea (200 mg, 74% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.12 (s, 1H), 8.7 (s, 1H), 8.35 (s,
1H), 8.16 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J=11.8 Hz, 1H),
7.43-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.96-6.94 (m, 1H), 6.54 (br
s, 2H), 6.34 (s, 1H), 4.08 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz,
3H); MS (ESI) m/z: 452.1 (M+H.sup.+), 454.1 (M+2+H.sup.+).
[0310]
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-ch-
loro-2-fluorophenyl)-3-phenylurea (0.100 g, 0.221 mmol) was
suspended in acetic anhydride (5 mL, 53.0 mmol) and stirred with
gradual heating to 110.degree. C. After 5 h, the mixture was cooled
to RT and diluted with MeCN (15 mL). The solids were collected by
filtration, rinsed with MeCN and dried to afford
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chlo-
ro-2-fluorophenyl)-3-phenylurea (107 mg, 98% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.84 (s, 1H), 9.13 (s, 1H), 8.74
(d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.8 Hz,
1H), 7.97 (s, 1H), 7.57 (d, J=4.0 Hz, 1H) 7.42-7.40 (m, 2H),
7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.14
(s, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 494.1
[M+H].sup.+.
##STR00135##
Example 55
[0311] A 0.degree. C. solution of Example A5 (200 mg, 0.58 mmol)
and pyridine (91 mg, 1.16 mmol) in DCM (4 mL) was treated drop-wise
with 1,3-difluoro-5-isocyanato-benzene (98 mg, 0.64 mmol) and
stirred at RT overnight as the cooling bath expired. The mixture
was concentrated to dryness and purified by prep-HPLC. The
resulting solution was treated with HCl (1 mL) and lyophilized to
give
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea hydrochloride (74
mg, 26% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.94
(s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.14 (b s, 1H), 8.13 (d, J=8.8
Hz, 1H), 7.88 (s, 1H), 7.57 (d, J=11.2 Hz, 1H), 7.16-7.12 (m, 2H),
6.78 (t, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.16-4.13 (m, 2H), 2.96 (s,
3H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 502.3 [M+H].sup.+.
##STR00136##
Example 56
[0312] A mixture of Example A37 (1.3 g, 3.4 mmol), methylamine
(25%, 30 mL) and EtOH (5 mL) were heated at 120.degree. C. in a
pressure vessel for 1 day. The mixture was cooled to RT, the solids
collected via filtration, washed with pet ether and dried to give
3-(5-amino-2-bromo-4-fluoro-phenyl)-1-methyl-7-methylamino-1H-[1,6]naphth-
yridin-2-one (1.06 g, 82.8% yield).
[0313] A solution of
3-(5-amino-2-bromo-4-fluoro-phenyl)-1-methyl-7-methylamino-1H-[1,6]naphth-
yridin-2-one (420 mg, 1.16 mmol) in DCM (25 mL) was treated with
phenyl isocyanate (0.19 g, 1.62 mmol) and TEA (0.326 g, 3.23 mmol)
and stirred at RT for 12 h. The mixture was concentrated under
reduced pressure and washed with MTBE (1.times.). The crude product
was purified by prep-HPLC separation (MeCN/H.sub.2O with 0.1% TFA)
to give
1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-nap-
hthyridin-3-yl)phenyl)-3-phenylurea (245 mg, 44% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.67 (s, 1H),
8.40 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=10.8
Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.28-7.24 (t, J=7.6 Hz, 2H),
7.04-7.03 (m, 1H), 6.98-6.94 (t, J=8 Hz, 1H), 6.17 (s, 1H), 3.50
(s, 3H), 2.85 (d, J=4.8 Hz, 3H).
##STR00137##
Example 57
[0314] To a solution of Example A33 (300 mg, 0.798 mmol) in DCM (20
mL) was added phenyl isocyanate (284 mg, 2.39 mmol) and TEA (241.7
mg, 2.39 mmol). The mixture was stirred at RT for 3 days and then
concentrated and purified by HPLC separation (MeCN/H.sub.2O with
0.1% TFA) to give
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2--
fluorophenyl)-3-phenylurea (20 mg, 5% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.17 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H),
8.15 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J=10.8 Hz, 1H), 7.41
(s, 1H), 7.39 (s, 1H), 7.26-7.22 (t, J=8.0 Hz, 2H), 6.96-6.93 (t,
J=7.2 Hz, 1H), 6.52 (s, 2H), 6.32 (s, 1H), 4.09-4.06 (q, J=5.2 Hz,
2H), 1.20-1.17 (t, J=5.2 Hz, 3H).
##STR00138##
Example 58
[0315] To a biphasic solution of 3-fluoroaniline (0.3 mL, 3.12
mmol) in 1:1 EtOAc/water (10 mL) was added isopropenyl
chloroformate (0.564 g, 4.68 mmol) and NaHCO.sub.3 (1.31 g, 15.6
mmol) and the mixture stirred at RT overnight. The layers were
separated and the aqueous layer was extracted with EtOAc. The
combined organic layers were concentrated to dryness and purified
by silica gel chromatography (EtOAc/Hex) to furnish prop-1-en-2-yl
3-fluorophenylcarbamate (125 mg, 21% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.14 (s, 1H), 7.35
(m, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 6.83 (m, 1H), 4.74 (m, 2H),
1.92 (s, 3H).
[0316] A solution of prop-1-en-2-yl 3-fluorophenylcarbamate (0.094
g, 0.480 mmol) and Example A34 (0.100 g, 0.320 mmol) in THF (3 mL)
was treated with a catalytic amount (1 drop) of 1-methylpyrrolidine
and the mixture heated at 60.degree. C. overnight. Additional
1-methylpyrrolidine (2 drops) was added and heating was continued
at 60.degree. C. for another 24 h. The mixture was cooled to RT,
the solid collected via filtration, rinsed with THF and dried to
afford
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(3-fluorophenyl)urea (123 mg, 85% yield) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.22 (s,
1H), 8.53 (s, 1H), 8.34 (s, 1H), 7.89 (d, 1H), 7.65 (s, 1H), 7.46
(m, 1H), 7.27 (q, 1H), 7.13 (d, 1H), 7.04 (d, 1H), 6.76 (m, 1H),
6.47 (s, 2H), 6.34 (s, 1H), 4.09 (q, 2H), 2.06 (s, 3H), 1.20 (t,
3H); MS (ESI) m/z: 450.2 [M+H].sup.+.
##STR00139##
Example 59
[0317] A mixture of I-benzothiophene carboxylic acid (0.131 g,
0.735 mmol)<autotext key="0C5A121E" name="[Reactants]" index="1"
field="Reactants" type="field" length="54"/> and TEA (0.188 mL,
1.348 mmol)<autotext key="0C3956B0" name="[Reactants]" index="3"
field="Reactants" type="field" length="26"/> in toluene (3.0
mL)<autotext key="0C3956B1" name="[Solvents]" index="1"
field="Solvents" type="field" length="17"/> was treated with
DPPA (0.198 mL, 0.919 mmol)<autotext key="0C3956B2"
name="[Reactants]" index="4" field="Reactants" type="field"
length="54"/> stirred at RT for 0.5 h, treated with Example A2
(0.200 g, 0.613 mmol)<autotext key="OCSA5BD9" name="[Reactants]"
index="2" field="Reactants" type="field" length="31"/> and
heated at 90.degree. C. for 3 days. The mixture was cooled to RT,
concentrated to dryness, treated with MeCN (5 mL) and heated at
70.degree. C. for 5 minutes. The solid was collected via
filtration, washed with MeCN, treated with MeOH, heated at
50.degree. C. and collected via filtration. The material was
purified via reverse-phase chromatography (MeCN/water with 0.1%
TFA). Water and NaHCO.sub.3 were added to the purified product and
the resultant precipitate was filtered and dried to afford
1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-
-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (69 mg, 21%
yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.39 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.06 (d, 1H),
7.96 (d, 1H), 7.87 (d, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.45 (m,
3H), 7.17 (d, 1H), 6.36 (s, 1H), 4.16 (m, 2H), 2.90 (d, 3H), 2.08
(s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 502.2 [M+H].sup.+.
##STR00140##
Example 60
[0318] A suspension of Example A2 (0.096 g, 0.29 mmol) in THF (3
mL) was treated with TEA (0.041 mL, 0.294 mmol) and
3,5-difluorophenyl isocyanate (0.114 g, 0.735 mmol) and stirred at
RT for 6 h. The mixture was treated with 60% EtOAc/Hex, stirred for
5 minutes and the resulting solid was collected via filtration and
dried to afford
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.11 g, 73%
yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.37 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=8.4
Hz, 1H), 7.66 (s, 1H), 7.13 (dd, J=10.0 Hz, 2.4 Hz, 3H), 6.98 (q,
J=4.8 Hz, 1H), 6.80-6.75 (m, 1H), 6.23 (s, 1H), 4.14 (q, J=6.8 Hz,
2H), 2.85 (d, J=4.8 Hz, 3H), 2.06 (s, 3H), 1.20 (t, J=6.8 Hz, 3H);
MS (ESI) m/z: 482.2 [M+H].sup.+.
##STR00141##
Example 61
[0319] A suspension of Example A2 (0.096 g, 0.29 mmol) in THF (3
mL) was treated with TEA (0.041 mL, 0.294 mmol) and 2,5-difluoro
phenyl isocyanate (0.055 g, 0.353 mmol) and stirred at RT for 2 h.
The mixture was treated with 60% EtOAc/Hex, stirred for 5 minutes
and the resulting solid was collected via filtration and dried to
afford
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.12 g, 85%
yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.18 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 8.02-7.97 (m,
1H), 7.94 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.30-7.24 (m, 1H), 7.14
(d, J=12.4 Hz, 1H), 6.98 (q, J=4.8 Hz, 1 H), 6.81-6.77 (m, 1H),
6.23 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 2.06
(s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 482.2
[M+H].sup.+.
##STR00142##
Example 62
[0320] A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5
mL) was treated with 2,5-difluorophenyl isocyanate (0.034 mL, 0.293
mmol) and stirred at RT overnight. The resulting solid was
collected via filtration and dried to yield
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahyd-
ro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea
(129 mg, 80% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.19 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.16 (t, 1H), 8.01-7.98
(m, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.31-7.27 (m, 1H), 7.18 (d,
2H), 6.87 (d, 2H), 6.82-6.80 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H),
4.19 (q, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, 3H); MS (ESI)
m/z: 606.3 [M+H].sup.+.
[0321] A solution of
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahyd-
ro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea
(0.129 g, 0.213 mmol) and anisole (0.233 mL, 2.130 mmol) in DCM (2
mL) was treated with TFA (2 mL, 26.0 mmol) and stirred at RT
overnight. The mixture was concentrated to dryness, treated with
EtOAc and satd. NaHCO.sub.3, stirred for 1 h and the resulting
solid collected via filtration and dried to afford
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (84 mg, 81%
yield). The material was suspended in MeCN (2 mL), treated with 0.5
N HCl (2.076 mL, 0.208 mmol), diluted with water (2 mL), frozen,
lyophilized, triturated with Et.sub.2O and the resulting solid was
collected via filtration and dried to yield
1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea hydrochloride
(85 mg, 94% yield). .sup.1H NMR (400 MHz, DMSO-d): .delta. 9.24 (s,
1H), 9.18 (s, 1H), 8.53 (s, 1H), 8.18 (t, 1H), 8.02-7.97 (m, 1H),
7.94 (s, 1H), 7.90 (br s, 1H), 7.42 (t, 1H), 7.32-7.26 (m, 1H),
6.84-6.80 (m, 1H), 6.48 (s, 1H), 4.19 (q, 2H), 2.94 (s, 3H), 1.21
(t, 3H); MS (ESI) m/z: 486.2 [M+H].sup.+.
##STR00143##
Example 63
[0322] A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5
mL) was treated with 3,5-difluorophenyl isocyanate (0.038 mL, 0.320
mmol) and stirred at RT overnight. Additional 3,5-difluorophenyl
isocyanate (0.038 mL, 0.320 mmol) was added and the mixture stirred
for 4 h. The resulting precipitate was collected via filtration and
dried to yield
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahyd-
ro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea
(112 mg, 69% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.38 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.05 (t, 1H), 7.86 (s,
1H), 7.38 (t, 1H), 7.19-7.14 (m, 4H), 6.86 (d, 2H), 6.80-6.77 (m,
1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.12
(s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H].sup.+.
[0323] A solution of
1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahyd-
ro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea
(0.112 g, 0.185 mmol) and anisole (0.202 mL, 1.849 mmol) in DCM (2
mL) was treated with TFA (2 mL, 26.0 mmol) and stirred at RT
overnight. The mixture was concentrated to dryness, treated with
EtOAc and satd. NaHCO.sub.3, stirred for 1 h and the resulting
solid collected via filtration and dried to afford
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (57 mg, 64%
yield). The material was dissolved in MeCN (2 mL), treated with
0.1N HCl (1.17 mL, 0.117 mmol), diluted with water (3 mL), frozen,
lyophilized, triturated with Et.sub.2O and the resulting solid was
collected via filtration and dried to yield
1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetr-
ahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea hydrochloride
(57 mg, 96% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.95 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.07 (t, 1H), 7.92 (s,
1H), 7.70 (br s, 1H), 7.40 (t, 1H), 7.15 (d, 2H), 6.82-6.77 (m,
1H), 6.43 (s, 1H), 4.15 (q, 2H), 2.91 (s, 3H), 1.21 (t, 3H); MS
(ESI) m/z: 486.2 [M+H].sup.+.
##STR00144##
Example 64
[0324] A suspension of Example 57 (135 mg, 0.272 mmol) in ethyl
cyanoacetate (2.307 g, 20.40 mmol) was heated at 105.degree. C. for
4.5 h, then at 125.degree. C. for 2 days. The mixture was treated
with NMP (0.3 mL), heated at 125.degree. C. for 5 h, then cooled to
RT and purified via silica gel chromatography (EtOAc/Hex). The
material was re-purified via silica gel chromatography (THF/Hex),
dissolved in 4:1 MeCN/H.sub.2O, frozen and lyophilized. The
material was treated with MTBE, the resulting solid collected via
filtration and dried to afford
N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-2-cyanoacetamide (13 mg, 8.5% yield) as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.17
(s, 1H), 9.10 (s, 1H), 8.74 (m, 2H), 8.23 (d, J=8.5 Hz, 1H), 8.17
(s, 1H), 7.98 (s, 1H), 7.70 (d, J=10.7 Hz, 1H), 7.41 (d, J=8.1 Hz,
2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.22 (q, J=7.2
Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 565.1
[M+H].sup.+.
##STR00145##
Example 65
[0325] A suspension of Example 21 (0.180 g, 0.398 mmol) in ethyl
cyanoacetate (3 ml, 28.1 mmol) was heated at 125.degree. C.
overnight. The mixture was treated with NMP (0.3 mL), heated at
125.degree. C. for 24 h, then cooled to RT and purified via silica
gel chromatography (EtOAc/Hex). The material was re-purified via
silica gel chromatography (THF/Hex), dissolved in 4:1
MeCN/H.sub.2O, frozen and lyophilized, treated with MTBE and the
resulting solid collected via filtration and dried to afford
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (22 mg, 11% yield) as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.17
(s, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.23 (d, J=8.6
Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.41
(d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.0 Hz, 1H),
4.22 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.0 Hz, 3H); MS
(ESI) m/z: 519.1 [M+H].sup.+.
##STR00146##
Example 66
[0326] A solution of Example A36 (1 g, 2.3 mmol) in TFA (10 mL) was
stirred at 60.degree. C. overnight. The solvent was removed and the
crude product was treated with satd. NaHCO.sub.3 and extracted with
EtOAc (2.times.). The combined organic extracts were washed with
brine, dried over Na.sub.2SO.sub.4, and evaporated to yield
7-amino-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
(600 mg, 83% yield), which was used in next step without
purification.
[0327] A solution of
7-amino-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one
(500 mg, 1.58 mmol) and TEA (638 mg, 6.32 mmol) in DCM (5 mL) was
treated drop-wise with phenyl isocyanate (503 mg, 4.8 mmol) and
stirred at RT overnight. The mixture was concentrated to dryness
and purified by silica gel chromatography (EtOAc/pet ether) to
afford
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluo-
rophenyl)-3-phenylurea (500 mg, 73% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.03 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H),
8.13 (m, 1H), 7.83 (s, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.39-7.34 (m,
1H), 7.29-7.25 (m, 2H), 6.99-6.95 (m, 1H), 6.58 (s, 2H), 6.34 (s,
1H), 4.13-4.08 (q, J=0.8 Hz, 2H), 1.22 (t, J=6.8 Hz, 3H).
[0328] A solution of
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluo-
rophenyl)-3-phenylurea (150 mg, 0.344 mmol) and TEA (174.2 mg, 1.72
mmol) in THF (3 mL) was treated drop-wise with acetyl chloride (81
mg, 1.03 mmol) at RT. The resulting mixture was stirred for 2 h and
the solvent was removed to give the crude product. It was diluted,
washed with brine, dried over Na.sub.2SO.sub.4, concentrated under
reduced pressure and purified by silica gel chromatography to give
N-acetyl-N-{3-[2,4-difluoro-5-(3-phenyl-ureido)-phenyl]-1-ethyl-2-oxo-1,2-
-dihydro-[1,6]naphthyridin-7-yl}-acetamide (150 mg, 84% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.86 (s, 1H), 9.41
(s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.27 (s, 1H), 8.20-8.16 (m,
1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.46-7.39 (m, 3H), 7.29-7.25 (m,
2H), 6.98-6.95 (m, 1H), 4.25-4.22 (t, J=7.2 Hz, 3H), 2.16 (s, 3H),
1.27 (s, 3H).
[0329] To a solution of
N-acetyl-N-{3-[2,4-difluoro-5-(3-phenyl-ureido)-phenyl]-1-ethyl-2-oxo-1,2-
-dihydro-[1.6]naphthyridin-7-yl}-acetamide (100 mg, 0.19 mmol) in
MeOH (2 mL) was added K.sub.2CO.sub.3 (79 mg, 0.57 mmol) and water
(1 mL), and the mixture was stirred overnight at RT. MeOH was
removed under reduced pressure and the residue was diluted with
water (8 mL). The mixture was extracted with EtOAc to give a crude
product which purified by prep-HPLC to give
1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl-
)-2,4-difluorophenyl)-3-phenylurea (32 mg, 23% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.85 (s, 1H), 9.08 (s, 1H), 8.74
(s, 1H), 8.61 (s, 1H), 8.27 (s, 1H), 8.21-8.16 (m, 1H), 8.07 (s,
1H), 7.45-7.40 (m, 3H), 7.30-7.26 (m, 2H), 7.00-6.96 (m, 1H),
4.24-4.18 (q, J=6.8 Hz, 2H), 2.16 (s, 3H), 1.28-1.25 (t, J=6.8 Hz,
3H); MS (ESI) m/z: 478.3 [M+H].sup.+.
##STR00147##
Example 67
[0330] A solution of Example A3 (0.20 g, 0.568 mmol) in THF (6 mL)
was treated with TEA (0.098 mL, 0.710 mmol) followed by
3,5-difluorophenyl isocyanate (0.092 g, 0.596 mmol) and stirred at
RT for 2 h. Additional 3,5-difluorophenyl isocyanate (0.14 g, 0.903
mmol) was added and the mixture stirred at RT overnight. More
3,5-difluorophenyl isocyanate (0.25 g, 1.61 mmol) was added and the
mixture stirred at RT for 24 h. The mixture was cooled to 0.degree.
C. and the solids collected via filtration and dried. The filtrate
was concentrated to dryness and purified via silica gel
chromatography (THF/Hex) and combined with the isolated solid to
afford
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-(3,5-difluorophenyl)urea (177 mg, 61% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.27 (br s, 2H), 8.79
(s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.57
(d, J=10.9 Hz, 1H), 7.16 (m, 2H), 6.77 (m, 1H), 4.27 (q, J=7.0 Hz,
2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 507.1 [M+H].sup.+.
[0331] A mixture of
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-(3,5-difluorophenyl)urea (178 mg, 0.351 mmol).
Xantphos (20.30 mg, 0.035 mmol), Cs.sub.2CO.sub.3 (229 mg, 0.702
mmol) and acetamide (104 mg, 1.754 mmol) in dioxane (3.5 mL) was
sparged with Ar for 10 min, treated with Pd.sub.2(dba).sub.3 (16.07
mg, 0.018 mmol) and heated at 100.degree. C. overnight. The mixture
was cooled to RT, treated with THF, the solids removed via
filtration through diatomaceous earth and rinsed well with THF. The
filtrate was washed with brine (3.times.), dried over MgSO.sub.4,
concentrated to dryness and purified via silica gel chromatography
(EtOAc/Hex). The material was suspended in 4:1 MeCN/H.sub.2O,
frozen and lyophilized; the resulting solid was triturated with
MTBE, collected via filtration and dried to afford
N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (9 mg, 4.8%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 10.86 (s, 1H),
9.48 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 8.17 (d,
J=8.5 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J=10.9 Hz, 1H), 7.17 (m, 2H),
6.84-6.83 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.27 (t,
J=7.1 Hz, 3H); MS (ESI) m/z: 530.1 [M+H].sup.+.
##STR00148##
Example 68
[0332] A solution of Example A4 (250 mg, 0.535 mmol) in pyridine (2
mL) was treated with 2,5-difluorophenyl isocyanate (91 mg, 0.589
mmol) and stirred at RT overnight. Additional 2,5-difluorophenyl
isocyanate (30 .mu.L, 0.256 mmol) was added and stirred at RT for 4
h. The mixture was concentrated to near-dryness, treated with EtOAc
and brine and the resulting solid was collected via filtration and
dried to afford
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea
(314 mg, 94% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.31 (s, 2H), 8.51 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.98 (m, 1H),
7.78 (s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.29 (m, 1H), 7.18 (d, J=8.4
Hz, 2H), 6.89-6.78 (m, 3H), 6.33 (s, 1H), 4.85 (s, 2H), 4.19 (q,
J=7.1 Hz, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, J=7.0 Hz, 3H);
MS (ESI) m/z: 622.2 [M+H].sup.+.
[0333] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea
(314 mg, 0.505 mmol) and anisole (273 mg, 2.52 mmol) was treated
with TFA (3.0 mL, 51.9 mmol) and stirred at RT for 2.5 h. The
mixture was concentrated to near-dryness, treated with EtOAc and
satd. NaHCO.sub.3 and the resulting solid collected via filtration
and dried to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (233 mg, 92%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.24 (m, 2H),
8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.97 (m, 1H), 7.73 (s, 1H),
7.54 (d, J=11.0 Hz, 1H), 7.27 (m, 1H), 7.02 (m, 1H), 6.80 (m, 1H),
6.23 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.19
(t, J=7.0 Hz, 3H); MS (ESI) m/z: 502.2 [M+H].sup.+.
##STR00149##
Example 69
[0334] A bi-phasic solution of Example A1 (0.15 g, 0.336 mmol) in
EtOAc (5 mL) and satd. NaHCO.sub.3 (4.2 mL) was treated with
isopropenyl chloroformate (0.061 g, 0.504 mmol) and stirred at RT
for 2 h. The layers were separated, the aqueous layer extracted
with EtOAc (1.times.) and the combined organics were washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated to dryness. The
solid was dissolved in THF (2 mL), treated with 1-methylpyrrolidine
(0.011 g, 0.134 mmol) and 3-chloro-5-fluoro aniline (0.098 g, 0.672
mmol) and heated at 55.degree. C. for 20 h. The mixture was cooled
to RT, concentrated to dryness and purified via silica gel
chromatography (EtOAc/Hex) to afford
1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-((4-methoxybenzyl)(methyl)ami-
no)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea
(105 mg, 51% yield). MS (ESI) m/z: 618.2 [M+H].sup.+.
[0335] A solution of
1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-((4-methoxybenzyl)(methyl)ami-
no)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea
(0.105 g, 0.170 mmol) in TFA (3 mL) was treated with anisole (0.093
ml, 0.849 mmol) and stirred at RT for 4 h. The mixture was
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The combined
fractions were neutralized with satd. NaHCO.sub.3, extracted with
EtOAc (2.times.) and the combined organics were washed with water,
then brine, dried over Na.sub.2SO.sub.4 and concentrated to dryness
to afford
1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (62 mg, 73%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.54 (s, 1H),
8.69 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.66 (s, 1H),
7.35 (s, 1H), 7.27 (dt, J=11.3, 2.1 Hz, 1H), 7.14 (d, J=12.1 Hz,
1H), 7.00-6.95 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.85
(d, J=4.9 Hz, 3H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI)
m/z: 498.2 [M+H].sup.+.
##STR00150##
Example 70
[0336] A solution of Example A50 (0.105 g, 0.196 mmol) in dioxane
(4 mL) was treated with dimethylamine (2M in THF, 4 mL, 8.0 mmol)
and stirred at RT overnight, 1-Methylpyrrolidine (0.1 ml) was added
and the mixture was stirred at RT for 24 h. Additional
1-methylpyrrolidine (0.1 ml) and dimethylamine (2M in THF, 2 mL,
4.0 mmol) were added and the mixture was stirred at RT for 3 days,
then heated at 40.degree. C. for 24 h. The mixture was cooled to
RT, the solid collected via filtration and dried to afford
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,-
2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (80 mg, 73%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.19 (s, 1H),
9.08 (s, 1H), 8.70 (m, 1H), 8.65 (s, 1H), 8.21 (d, J=8.6 Hz, 1H),
8.01 (s, 1H), 7.94 (s, 1H), 7.56 (d, J=11.0 Hz, 1H), 7.43-7.41 (m,
2H), 7.26 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H),
2.97 (s, 6H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 523.2
[M+H].sup.+.
##STR00151##
Example 71
[0337] A mixture of Example A47 (200 mg, 0.363 mmol), DIEA (188 mg,
1.452 mmol) and 3-chloro-5-fluoroaniline (211 mg, 1.452 mmol) in
dioxane (5 mL) was heated at 80.degree. C. overnight. The mixture
was cooled to RT, treated with EtOAc and satd. NaHCO.sub.3 and the
resulting solid collected via filtration and dried to afford crude
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea
(91 mg, 39% yield) which was carried on to the next step without
further purification. MS (ESI) m/z: 638.2 [M+H].sup.+.
[0338] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea
(91 mg, 0.143 mmol) and anisole (77 mg, 0.713 mmol) was stirred in
TFA (3 mL) at RT for 3 h. The mixture was concentrated to
near-dryness, dissolved in EtOAc and treated with satd.
NaHCO.sub.3. The layers were separated, the organic layer washed
with brine and dried over Na.sub.2SO.sub.4. Solids precipitated, so
THF, MeOH and DMF were added and the mixture was warmed to afford a
clear solution, then filtered to remove salts. The filtrate was
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The organics were
removed under reduced pressure, the aqueous residue neutralized
with satd. NaHCO.sub.3, extracted with warm EtOAc (2.times.) and
the combined organics were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (55 mg, 74%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.43 (s, 1H),
8.83 (s, 1H), 8.41 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.74 (s, 1H),
7.55 (d, J=10.9 Hz, 1H), 7.36 (s, 1H), 7.27 (dt, J=11.2, 2.1 Hz,
1H), 7.06-6.98 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86
(d, J=4.8 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 518.1
[M+H].sup.+.
##STR00152##
Example 72
[0339] A mixture of Example A47 (200 mg, 0.363 mmol), DIEA (188 mg,
1.452 mmol) and 3-chloro-5-methylaniline (182 mg, 1.452 mmol) in
dioxane (5 mL) was heated at 80.degree. C. overnight. The mixture
was cooled to RT, treated with EtOAc and satd. NaHCO.sub.3 and the
resulting solid collected via filtration and dried to afford crude
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea
(197 mg, 88% yield). MS (ESI) m/z: 618.2 [M+H].sup.+.
[0340] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea
(197 mg, 0.319 mmol) and anisole (172 mg, 1.594 mmol) was stirred
in TFA (4 mL) at RT for 3 h. The mixture was concentrated to
near-dryness, treated with EtOAc and satd. NaHCO.sub.3 and the
resulting solid collected via filtration and dried to afford
1-(4-chloro-5-(l-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (113 mg, 71%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.18 (br s,
1H), 8.80 (br s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.73
(s, 1H), 7.52 (d, J=10.8 Hz, 1H), 7.22 (d, J=11.5 Hz, 1H), 7.03 (br
s, 1H), 6.92 (s, 1H), 6.67-6.59 (m, 1H), 6.24 (s, 1H), 4.14 (q,
J=7.1 Hz, 2H), 2.86 (s, 3H), 2.25 (s, 3H), 1.21 (t, J=7.3 Hz, 3H);
MS (ESI) m/z: 498.1 [M+H].sup.+.
##STR00153##
Example 73
[0341] A mixture of Example 21 (100 mg, 0.221 mmol) in pyridine (3
mL) was treated drop-wise with methylchloroformate (23 mg, 0.243
mmol) and stirred at RT for 4 h. Additional methylchloroformate (50
L) was added and the mixture stirred overnight. The mixture was
treated with additional methylchloroformate (100 L) and stirred for
another 2 days. The mixture was concentrated to dryness, treated
with EtOAc and water and the resulting solid collected via
filtration. The material was purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA); the organics were
removed under reduced pressure and the aqueous mixture was
neutralized with satd. NaHCO.sub.3. The resulting solid was
collected via filtration, washed with water and dried to afford
methyl
(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-
-1,6-naphthyridin-7-yl)carbamate (101 mg, 87% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.56 (br s, 1H), 9.31-8.78 (m,
2H), 8.67 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.96 (s, 2H), 7.56 (d,
J=11.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H),
6.96 (t, J=7.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 1.25
(t, J=7.1 Hz, 3H); MS (ESI) m/z: 510.1 [M+H].sup.+.
##STR00154##
Example 74
[0342] A mixture of Example 21 (90 mg, 0.199 mmol) and pyridine (79
mg, 0.996 mmol) in THF (4 mL) was treated drop-wise with methoxy
acetyl chloride (27 mg, 0.249 mmol) and stirred at RT for 22 h.
Additional methoxy acetyl chloride (30 .mu.L, 0.328 mmol) was
added, the mixture heated at 40.degree. C. for 6 h, then cooled to
RT and stirred overnight. The mixture was treated with EtOAc and
water, stirred for 1 h, the resulting solid collected via
filtration and dried to afford
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-2-methoxyacetamide (76 mg, 72% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.39 (s, 1H), 9.09
(s, 1H), 8.73 (m, 2H), 8.27-8.20 (m, 2H), 8.00 (s, 1H), 7.58 (d,
J=10.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H),
6.97 (t, J=7.3 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.12 (s, 2H), 3.38
(s, 3H), 1.26 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 524.2
[M+H].sup.+.
##STR00155##
Example 75
[0343] A mixture of Example A18 (752 mg, 9.0 mmol),
Cs.sub.2CO.sub.3 (2.0 g, 6.0 mmol) and Xantphos (173 mg, 0.3 mmol)
in dioxane (10 mL) was sparged with N.sub.2, treated with
Pd.sub.2(dba).sub.3 (165 mg, 0.18 mmol), sparged again with N.sub.2
and heated at 100.degree. C. overnight. The mixture was cooled to
RT, poured into water and extracted with EtOAc (3.times.). The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via silica
gel chromatography to afford
N-(3-(5-amino-2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyri-
din-7-yl)-2-cyanoacetamide (500 mg, 44% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 11.15 (s, 1H), 8.71 (s, 1H), 8.14 (s,
1H), 7.98 (s, 1H), 7.06-7.11 (m, 1H), 6.80-6.85 (m, 1H), 5.06 (s,
2H) 4.22-4.18 (m, 2H), 4.08 (s, 2H), 1.25-1.22 (t, J=7.2 Hz,
3H).
[0344] A solution of
N-(3-(5-amino-2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyri-
din-7-yl)-2-cyanoacetamide (0.5 g, 1.3 mmol) and K?CO.sub.3 (448
mg, 3.25 mmol) in THF (4 mL) was treated drop-wise with phenyl
chloroformate (408 mg, 2.6 mmol) and heated at 60.degree. C.
overnight. The mixture was cooled to RT, concentrated to dryness,
treated with water and extracted with EtOAc (2.times.). The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, concentrated and purified via silica gel
chromatography to afford phenyl
(5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-
-2,4-difluorophenyl)carbamate (400 mg, 61% yield).
[0345] A solution of phenyl
(5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-
-2,4-difluorophenyl)carbamate (400 mg, 0.80 mmol) and aniline (158
mg, 1.6 mmol) in DMSO (3 mL) was heated at 60.degree. C. overnight
and purified via reverse-phase chromatography (MeCN/H.sub.2O with
0.1% TFA) to afford
2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-di-
hydro-1,6-naphthyridin-7-yl)acetamide (50 mg, 13% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 11.23 (s, 1H), 8.92 (s, 1H),
8.78 (s, 1H), 8.20-8.16 (m, 2H), 8.11 (s, 1H), 7.49-7.39 (m, 4H),
7.29-7.25 (m, 2H), 6.96 (t, J=7.2 Hz, 1H) 4.26-4.21 (q, J=6.8 Hz,
2H), 4.09 (s, 2H), 1.30-1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 503.2
[M+H].sup.+.
##STR00156##
Example 76
[0346] A solution of Example C5 (3 g, 10.9 mmol) in DMF (50 mL) was
treated with ZnCN.sub.2 (1.7 g, 16.4 mmol) and Pd(PPh.sub.3).sub.4
(1.26 g, 1.09 mmol), sparged with N.sub.2 and heated at 100.degree.
C. for 12 h. The mixture was cooled to RT, treated with water and
extracted with EtOAc (3.times.). The combined organics were washed
with brine (3.times.), dried over Na.sub.2SO.sub.4, concentrated to
dryness and purified via silica gel chromatography (EtOAc/pet
ether) to afford ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate
(600 mg, 25% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.19 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.13-4.11 (q, J=6.8
Hz, 2H), 3.66 (s, 2H), 1.23-1.19 (t, J=6.8 Hz, 3H).
[0347] A solution of ethyl
2-(5-amino-2-cyano-4-fluorophenyl)acetate (400 mg, 1.80 mmol) and
Example B1 (281 mg, 1.80 mmol) in DMF (20 mL) was treated with
Cs.sub.2CO.sub.3 (1.17 g, 3.60 mmol) and stirred at RT for 1 h. The
resulting solid was collected via filtration, washed with water and
dried to afford
4-amino-2-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fl-
uorobenzonitrile (420 mg, 68% yield). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 8.88 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.69
(d, J=11.6 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.43 (s, 2H), 4.38-4.33
(q, J=6.4 Hz, 2H), 1.30-1.26 (t, J=6.4 Hz, 3H).
[0348] A mixture of
4-amino-2-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fl-
uorobenzonitrile (420 mg, 1.23 mmol) and methylamine (25%, 50 mL)
was heated at 120.degree. C. in a pressure vessel for 1 day. The
mixture was cooled to RT, the solid collected via filtration and
purified via silica gel chromatography (EtOAc/pet ether) to afford
4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)-5-fluorobenzonitrile (250 mg, 610% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.42 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H),
7.53 (d, J=11.6 Hz, 1H), 7.09-7.08 (m, 1H), 6.81 (d, J=8.4 Hz, 1H),
6.23 (s, 2H), 4.16-4.11 (q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H),
1.22-1.18 (t, J=6.8 Hz, 3H).
[0349] A -70.degree. C. solution of
4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y-
l)-5-fluorobenzonitrile (100 mg, 0.296 mmol) in DCM was treated
drop-wise with n-BuLi (0.47 mL, 1.17 mmol), stirred at -60.degree.
C. for 40 min, treated with phenyl isocyanate (70.6 mg, 0.593
mmol), warmed to RT and stirred for 12 h. The mixture was
concentrated and purified by HPLC to afford
1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphth-
yridin-3-yl)-2-fluorophenyl)-3-phenylurea (22 mg, 16% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.28 (s, 1H), 9.08 (s,
1H), 8.46 (s, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.91 (s,
1H), 7.45-7.43 (m, 2H), 7.31-7.27 (m, 2H), 7.18-7.13 (q, J=4.8 Hz,
1H), 7.02-6.98 (m, 1H), 6.26 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 2.87
(d, J=4.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 457.3
[M+H].sup.+.
##STR00157##
Example 77
[0350] A mixture of Example A52 (153 mg, 0.304 mmol), t-butyl
X-phos (6.45 mg, 0.015 mmol), Cs.sub.2CO.sub.3 (198 mg, 0.608
mmol), Pd.sub.2(dba).sub.3 (28 mg, 0.030 mmol) and methylamine
(2.0N in THF, 2.0 mL, 4.0 mmol) in dioxane (3 mL) was sparged with
Ar and heated at 80.degree. C. for 4.5 h. The mixture was cooled to
RT, treated with EtOAc and DCM and the solids removed via
filtration through diatomaceous earth. The filtrate was
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The organics were
removed under reduced pressure and the aqueous layer was
neutralized with satd. NaHCO.sub.3. The mixture was extracted with
EtOAc (2.times.) and the combined organics were washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (22 mg, 14%
yield). MS (ESI) m/z: 498.1 [M+H].sup.+.
[0351] A mixture of
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (22 mg, 0.042
mmol) in MeCN (1.5 mL) was treated with 0.1N HCl (464 .mu.L, 0.046
mmol), frozen and lyophilized to afford
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea hydrochloride (19
mg, 84% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.58
(s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.83
(s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.50-7.38 (m, 2H), 7.32-7.25 (m,
1H), 7.07 (dd, J=8.2, 1.9 Hz, 1H), 6.82-6.73 (m, 2H), 5.12 (m, 1H),
2.96 (s, 3H), 1.52 (d, J=6.9 Hz, 6H); MS (ESI) m/z: 498.2
[M+H].sup.+.
##STR00158##
Example 78
[0352] A mixture of Example A56 (88 mg, 0.188 mmol),
Cs.sub.2CO.sub.3 (122 mg, 0.375 mmol) and acetamide (55.4 mg, 0.938
mmol) in dioxane (2 mL) was sparged with Ar for 15 minutes, treated
with Pd.sub.2(dba).sub.3 (8.59 mg, 9.38 .mu.mol) and Xantphos
(10.86 mg, 0.019 mmol), sparged again with Ar and heated to
100.degree. C. for 2.5 h. The mixture was cooled to RT, treated
with 10% MeOH/DCM and the solids removed via filtration through
diatomaceous earth. The filtrate was concentrated to dryness and
purified via silica gel chromatography (EtOAc/Hex). The material
was re-purified via reverse-phase chromatography (MeCN/H.sub.2O
with 0.1% TFA); the organics were removed under reduced pressure
and the aqueous residue was frozen and lyophilized. The resulting
material was treated with MTBE, the solid collected via filtration
and dried to afford
N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (12 mg, 13% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.80 (s, 1H), 9.23
(s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.95 (d, J=8.4
Hz, 1H), 7.89 (s, 1H), 7.46 (dt, J=12.0, 2.3 Hz, 1H), 7.28 (m, 1H),
7.17 (d, J=12.2 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.77 (td, J=8.5,
2.6 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H),
1.25 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 492.2 [M+H].sup.+.
##STR00159##
Example 79
[0353] A mixture of Example D1 (155 mg, 0.493 mmol), DIEA (146 mg,
1.126 mmol), 1-methylpyrrolidine (24 mg, 0.281 mmol) and Example
A47 (155 mg, 0.281 mmol) in dioxane (4 mL) was heated at 80.degree.
C. for 20 h. The mixture was cooled to RT, treated with EtOAc,
washed with satd. NaHCO.sub.3, then brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure and the aqueous
residue treated with satd. NaHCO.sub.3 and allowed to stand at RT.
The resulting solid was collected via filtration, washed with water
and dried to afford
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)me-
thyl)phenyl)urea (79 mg, 40% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.16 (s, 1H), 8.73 (s, 1H), 8.51 (s, 1H),
8.17 (d, J=8.6 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J=10.9 Hz, 1H), 7.39
(s, 1H), 7.27 (m, 1H), 7.20-7.15 (m, 3H), 6.91-6.84 (m, 3H), 6.32
(s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.70 (s, 3H), 3.37
(s, 2H), 3.13 (s, 3H), 2.40-2.19 (m, 8H), 2.11 (s, 3H), 1.13 (t,
J=6.9 Hz, 3H); MS (ESI) m/z: 698.3 [M+H].sup.+.
[0354] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)me-
thyl)phenyl)urea (78 mg, 0.112 mmol) and anisole (60 mg, 0.559
mmol) was stirred in TFA (2 mL) at RT for 2 h. The mixture was
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The organics were
removed under reduced pressure and the aqueous residue was treated
with satd. NaHCO.sub.3. The mixture was extracted with EtOAc
(2.times.) and the combined organics were washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-
urea (50 mg, 76% yield). MS (ESI) m/z: 578.2 [M+H].sup.+.
[0355] A mixture of
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
in MeCN (4 mL) was treated with 0.1N HCl (1.77 mL, 0.177 mmol),
frozen and lyophilized to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
dihydrochloride (53 mg, 91% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.46 (s, 1H), 8.89 (s, 1H), 8.42 (s, 1H),
8.14 (d, J=8.6 Hz, 1H), 7.75 (s, 1H), 7.50 (m, 2H), 7.35-7.19 (m,
3H), 6.96 (s, 1H), 6.33 (s, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.66-3.21
(m, 8H), 3.09-2.94 (br s, 2H), 2.86 (s, 3H), 2.68 (s, 3H), 1.16 (t,
J=7.0 Hz, 3H); MS (ESI) m/z: 578.3 [M+H].sup.+.
##STR00160##
Example 80
[0356] A mixture of Example A54 (0.211 g, 0.468 mmol). Bippyphos
(0.024 g, 0.047 mmol), acetamide (0.332 g, 5.62 mmol) and
K.sub.3PO.sub.4 (0.397 g, 1.872 mmol) in dioxane (5 mL) was sparged
with Ar for 15 min, treated with Pd.sub.2(dba).sub.3 (0.021 g,
0.023 mmol) and heated at 80.degree. C. overnight. The mixture was
cooled to RT, diluted with EtOAc and the solids were removed via
filtration. The filtrate was concentrated to dryness, dissolved in
EtOAc/THF, washed with brine (2.times.), dried over MgSO.sub.4 and
concentrated to dryness. The material was treated with acetone, the
solid collected via filtration and dried. The filtrate was
concentrated to dryness, purified via silica gel chromatography
(MeOH/DCM) and combined with the isolated solid. The material was
re-purified via reverse-phase chromatography (MeCN/H.sub.2O with
0.1% TFA); the combined fractions were partially concentrated, then
frozen and lyophilized to afford
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)acetamide (24 mg, 11% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.79 (s, 1H), 9.01 (s, 1H), 8.70
(s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.89
(s, 1H), 7.41 (d, J=7.8 Hz, 2H), 7.25 (t, J=7.5 Hz, 2H), 7.16 (dd,
J=12.3 Hz, 1H), 6.99-6.89 (m, 1H), 4.25-4.14 (m, 2H), 2.14 (s, 3H),
2.08 (s, 3H), 1.30-1.20 (m, 3H); MS (ESI) m/z: 474.2
[M+H].sup.+.
##STR00161##
Example 81
[0357] A suspension of Example A50 (0.202 g, 0.377 mmol) and
3-hydroxyazetidine hydrochloride (0.045 g, 0.415 mmol) in THF (4
mL) was treated with 1-methylpyrrolidine (0.050 ml, 0.471 mmol) and
heated at 55.degree. C. overnight. Additional 3-hydroxyazetidine
hydrochloride (0.150 g) and 1-methylpyrrolidine (0.30 mL) were
added and the mixture was heated at 55.degree. C. for another 24 h.
The mixture was cooled to RT, diluted with water and the remaining
solid collected via filtration, rinsed with THF and dried. The
solid was purified via reverse-phase chromatography (MeCN/H.sub.2O
with 0.1% TFA); the organics were removed under reduced pressure,
the aqueous residue neutralized with satd. NaHCO.sub.3, then
azeotroped with IPA to dryness. The residue was suspended in water,
the solid collected via filtration and dried to afford
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,-
2-dihydro-1,6-naphthyridin-7-yl)-3-hydroxyazetidine-1-carboxamide
(26 mg, 13%/yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.47 (s, 1H), 9.10 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.21 (d,
J=8.6 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.56 (d, J=11.0 Hz, 1H),
7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.97 (t, J=6.9 Hz,
1H), 5.64 (d, J=6.3 Hz, 1H), 4.47-4.37 (m, 1H), 4.26-4.09 (m, 4H),
3.81-3.72 (m, 2H), 1.25-1.23 (m, 3H); MS (ESI) m/z: 551.2
[M+H].sup.+.
##STR00162##
Example 82
[0358] A mixture of Example D1 (250 mg, 0.794 mmol), DIEA (252 mg,
1.949 mmol) and 1-methylpyrrolidine (41 mg, 0.487 mmol) in dioxane
(4 mL) was treated with Example A48: (200 mg, 0.487 mmol), heated
at 80.degree. C. for 4 h. then cooled to RT for 3 days. The mixture
was diluted with EtOAc, washed with 50% satd. NaHCO.sub.3, then
brine, dried over Na.sub.2SO.sub.4, concentrated to dryness and
purified via reverse-phase chromatography (MeCN/H.sub.2O with 0.1%
TFA). The organics were removed under reduced pressure and the
aqueous residue was treated with satd. NaHCO.sub.3, and allowed to
stand at RT. The resulting solid was collected via filtration,
washed with water and dried to afford
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
(62 mg, 22% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.03 (s, 1H), 8.45-8.41 (m, 2H), 7.93 (d, J=8.5 Hz, 1H), 7.66 (s,
1H), 7.41 (s, 1H), 7.28-7.16 (m, 2H), 7.12 (d, J=12.6 Hz, 1H), 6.97
(m, 1H), 6.87 (m, 1H), 6.24 (s, 1H), 4.14 (m, 2H), 3.39 (s, 2H),
2.86 (d, J=5.2 Hz, 3H), 2.43-2.26 (br m, 8H), 2. (s, 3H), 2.06 (s,
3H), 1.21 (t, J=7.9 Hz, 3H); MS (ESI) m/z: 558.3 [M+H].sup.+.
##STR00163##
Example 83
[0359] A mixture of Example D1 (250 mg, 0.794 mmol), DIEA (218 mg,
1.683 mmol) and 1-methylpyrrolidine (36 mg, 0.421 mmol) in dioxane
(4 mL) was treated with Example A49 (200 mg, 0.421 mmol), heated at
80.degree. C. for 4 h, then cooled to RT for 3 days. The mixture
was treated with EtOAc and DCM, washed with 50% satd. NaHCO.sub.3,
then brine, dried over Na.sub.2SO.sub.4, concentrated to dryness
and purified via reverse-phase chromatography (MeCN/H.sub.2O with
0.1% TFA). The organics were removed under reduced pressure, the
aqueous residue treated with satd. NaHCO.sub.3 and extracted with
EtOAc (2.times.). The combined organics were washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
(57 mg, 21% yield). MS (ESI) m/z: 622.2 [M+H].sup.+.
[0360] A suspension of
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
(55 mg, 0.088 mmol) in MeCN (4 mL) was treated with 0.1N HCl (1.81
mL, 0.181 mmol), frozen and lyophilized to afford
1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
dihydrochloride (60 mg, 93% yield). MS (ESI) m/z: 622.2
[M+H].sup.+.
##STR00164##
Example 84
[0361] A solution of Example A50 (0.098 g, 0.183 mmol) in THF (3
mL) was treated with (3R)-(+)-3-(dimethylamino)pyrrolidine (0.047
g, 0.549 mmol) and 1-methylpyrrolidine (2.088 mg, 0.018 mmol) and
heated at 55.degree. C. for 16 h. The mixture was concentrated to
dryness and purified via silica gel chromatography (MeOH/DCM) to
afford
(R)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide
(48 mg, 45% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.10 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.21 (d,
J=8.6 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.57 (d, J=11.0 Hz, 1H),
7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t,
J=7.4 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.68 (m, 2H), 3.39 (m, 1H),
3.20 (m, 1H), 2.19 (br s, 6H), 2.07 (m, 2H), 1.72 (m, 1H), 1.24 (t,
J=7.1 Hz, 3H); MS (ESI) m/z: 592.2 [M+H].sup.+.
##STR00165##
Example 85
[0362] A solution of Example A3 (500 mg, 1.420 mmol) and pyridine
(449 mg, 5.68 mmol) in THF (20 mL) was treated with phenyl
isocyanate (186 mg, 1.562 mmol) and stirred at RT for 20 h. The
mixture was accidentally treated with a few drops of SOCl.sub.2;
EtOAc, water and satd. NaHCO.sub.3 were added and the mixture
stirred at RT for 2 h. The resulting solid was collected via
filtration and dried. The layers of the filtrate were separated,
the organic layer washed with brine, dried over Na.sub.2SO.sub.4
and concentrated to dryness. The material was treated with EtOAc,
sonicated for 2 minutes, collected via filtration and combined with
the above-isolated solid to afford
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-phenylurea (366 mg, 54% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.10 (s, 1H), 8.79 (s, 1H), 8.74 (s,
1H), 8.24 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.60 (d,
J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H),
6.97 (t, J=7.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz,
3H).
[0363] A mixture of
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-phenylurea (185 mg, 0.393 mmol).
Pd.sub.2(dba).sub.3 (18 mg, 0.020 mmol), Bippyphos (20 mg, 0.039
mmol). K.sub.3PO.sub.4 (333 mg, 1.570 mmol) and
L-N-1-BOC-prolinamide (673 mg, 3.14 mmol) in dioxane (9 mL) was
sparged with Ar, heated at 90.degree. C. for 4 h, then cooled to RT
and stirred overnight. The mixture was cooled to RT, treated with
EtOAc, water and DMF, and the solids removed via filtration through
diatomaceous earth. The layers of the filtrate were separated, the
organic layer washed with brine, dried over Na.sub.2SO.sub.4,
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The organics were
removed under reduced pressure and the aqueous residue treated with
satd. NaHCO.sub.3 and extracted with EtOAc (2.times.). The combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford (S)-tert-butyl
2-((3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihy-
dro-1,6-naphthyridin-7-yl)carbamoyl)pyrrolidine-1-carboxylate (105
mg, 41% yield). MS (ESI) m/z: 648.9 [M+H].sup.+.
[0364] A mixture of (S)-tert-butyl
2-((3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihy-
dro-1,6-naphthyridin-7-yl)carbamoyl)pyrrolidine-1-carboxylate (115
mg, 0.177 mmol) in dioxane (3 mL) was treated with 1.25 N HCl in
MeOH (2.8 mL, 3.5 mmol) and heated at 50.degree. C. for 2 h. The
mixture was concentrated to dryness, treated with satd. NaHCO.sub.3
and extracted with EtOAc (2.times.). The combined organics were
washed with brine, dried over Na.sub.2SO.sub.4, concentrated to
dryness and purified via reverse-phase chromatography
(MeCN/H.sub.2O with 0.1% TFA). The organics were removed under
reduced pressure and the aqueous residue treated with satd.
NaHCO.sub.3 and extracted with EtOAc (2.times.). The combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide (27 mg, 30%
yield). MS (ESI) m/z: 549.2 [M+H].sup.+.
[0365] A mixture of
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide (43 mg,
0.078 mmol) in MeCN (3 mL) was treated with 0.1N HCl (aq.) (1.56
mL, 0.156 mmol), frozen and lyophilized. The material was treated
with MTBE, sonicated, the solid collected via filtration and dried
to afford
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide
dihydrochloride (31 mg, 63% yield). MS (ESI) m/z: 549.2
[M+H].sup.+.
##STR00166##
Example 86
[0366] A mixture of Example A55 (320 mg, 0.659 mmol).
Pd.sub.2(dba).sub.3 (30 mg, 0.033 mmol), Bippyphos (33 mg, 0.066
mmol). K.sub.3PO.sub.4 (560 mg, 2.64 mmol) and acetamide (389 mg,
6.59 mmol) in dioxane (8 mL) was sparged with Ar and heated to
90.degree. C. for 22 h. The mixture was cooled to RT, diluted with
DMF, stirred for 1 h and the solids were removed via filtration
through diatomaceous earth. The filtrate was concentrated to
dryness and purified via reverse-phase chromatography
(MeCN/H.sub.2O with 0.1% TFA). The organics were removed under
reduced pressure, the aqueous residue treated with satd.
NaHCO.sub.3 and extracted with EtOAc (2.times.). The combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated to dryness. The material was re-purified via silica
gel chromatography (EtOAc/Hex) to afford
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-ox-
o-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (33 mg, 9.8% yield).
MS (ESI) m/z: 508.2 [M+H].sup.+.
[0367] A mixture of
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)acetamide (33 mg, 0.065 mmol) in MeCN
(3 mL) was treated with 0.1N HCl (0.650 mL, 0.065 mmol), frozen and
lyophilized. The material was treated with Et.sub.2O, the solid
collected via filtration and dried to afford
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)acetamide hydrochloride (17 mg, 47%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.82 (s, 1H),
9.16 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.22 (d,
J=8.6 Hz, 1H), 7.93 (s, 1H), 7.56 (d, J=11.0 Hz, 1H), 7.42 (d,
J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 3.71
(m, 1H), 2.15 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 508.2
[M+H].sup.+.
##STR00167##
Example 87
[0368] A mixture of Example A51 (0.138 g, 0.320 mmol) and Example
D2 (0.100 g, 0.448 mmol) in dioxane (4 mL) was treated with
1-methylpyrrolidine (6.73 .mu.L, 0.064 mmol) and heated to
80.degree. C. overnight. The mixture was cooled to RT, treated with
a small amount of additional dioxane and the solids collected via
filtration and dried to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methy-
l)phenyl)urea (141 mg, 74% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.38 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.75 (s,
1H), 7.68 (dd, J=6.5, 2.8 Hz, 1H), 7.35 (d, J=10.8 Hz, 1H), 7.18
(m, 1H), 7.04 (t, J=9.2 Hz, 1H), 6.35 (s, 1H), 4.29 (q, J=7.2 Hz,
2H), 3.68 (s, 2H), 2.98 (s, 3H), 3.46-2.95 (br m, 8H), 2.83 (s,
3H), 1.34 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 596.2 [M+H].sup.+.
##STR00168##
Example 88
[0369] A solution of 3-fluoro-5-nitrotoluene (1.0 g, 6.45 mmol) in
trifluorotoluene (15 ml) was treated with NBS (1.721 g, 9.67 mmol)
and AIBN (0.212 g, 1.289 mmol) and heated at 105.degree. C.
overnight. The mixture was cooled to RT, the solids removed via
filtration and the filtrate concentrated to dryness to afford
1-(bromomethyl)-3-fluoro-5-nitrobenzene (95 mg, 63% yield).
[0370] A -20.degree. C. solution of
1-(bromomethyl)-3-fluoro-5-nitrobenzene (0.95 g, 4.06 mmol) and
DIEA (1.418 ml, 8.12 mmol) in THF (20 mL) was treated drop-wise
with a solution of 1-methylpiperazine (0.488 g, 4.87 mmol) in THF
(10 mL) and stirred at RT overnight as the cooling bath expired.
The solid was removed via filtration and the filtrate concentrated
to dryness and purified via silica gel chromatography (MeOH/DCM) to
afford 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (820 mg, 80%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.01 (s, 1H),
7.97 (dt, J=8.6, 2.3 Hz, 1H), 7.64 (dd, J=9.2, 2.2 Hz, 1H), 3.60
(s, 2H), 2.41 (s, 8H), 2.21 (s, 3H); MS (ESI) m/z: 254.1
[M+H].sup.+.
[0371] A solution of 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine
(0.15 g, 0.592 mmol) in MeOH (5 mL) was treated with 10% Pd--C(dry)
(0.063 g, 0.059 mmol) and hydrogenated (1 atm) for 3 h. The solids
were removed via filtration, rinsed with MeOH and the filtrate
concentrated to dryness to afford
3-fluoro-5-((4-methylpiperazin-1-yl)methyl)aniline (100% yield
assumed). MS (ESI) m/z: 224.1 [M+H].sup.+.
[0372] A mixture of
3-fluoro-5-((4-methylpiperazin-1-yl)methyl)aniline (0.13 g, 0.582
mmol). Example A51 (0.167 g, 0.388 mmol) and 1-methylpyrrolidine
(4.08 .mu.L, 0.039 mmol) in dioxane (5 mL) was heated at 60.degree.
C. for 2 days. The mixture was cooled to RT, concentrated to
dryness and the residue treated with Et.sub.2O. The solid was
collected via filtration, treated with EtOAc, stirred at RT for 2
h, then collected via filtration. The resulting solid was treated
with dioxane, stirred at RT overnight, collected via filtration and
dried to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)pheny-
l)urea (84 mg, 36% yield). .sup.1H NMR (400 MHz, pyridine): .delta.
10.20 (s, 1H), 9.16 (s, 1H), 8.85 (d, J=8.6 Hz, 1H), 8.61 (s, 1H),
7.91 (d, J=11.3 Hz, 1H), 7.71 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H),
7.36 (d, J=10.8 Hz, 1H), 6.87 (d, J=9.3 Hz, 1H), 6.26 (s, 1H), 4.21
(q, J=7.0 Hz, 2H), 3.36 (s, 2H), 3.08 (s, 3H), 2.70-2.50 (m, 8H),
2.35 (s, 3H), 1.19 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 596.3
[M+H].sup.+.
##STR00169##
Example 89
[0373] A mixture of Example D2 (0.060 g, 0.269 mmol) and Example
A48 (0.085 g, 0.207 mmol) in dioxane (2 mL) was treated with
1-methylpyrrolidine (2 drops) and heated to 80.degree. C.
overnight. The mixture was concentrated to dryness, treated with
EtOAc and the resulting solid collected via filtration and purified
via reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3, extracted with EtOAc (2.times.) and
the combined organics were washed with brine, dried over MgSO.sub.4
and concentrated to dryness to afford
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridi-
n-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)me-
thyl)phenyl)urea (39 mg, 33% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.84 (s, 1H), 8.87 (s, 1H), 8.73 (d, J=8.43
Hz, 1H), 8.62 (s, 1H), 7.96 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (ddd,
J=8.9, 4.5, 2.8 Hz, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.15 (t, J=9.2
Hz, 1H), 7.08 (d, J=12.0 Hz, 1H), 6.32 (s, 1H), 4.26 (q, J=7.1 Hz,
2H), 3.58 (s, 2H), 3.13 (d, J=4.8 Hz, 3H), 2.53 (br m, 4H), 2.31
(m, 7H), 2.13 (s, 3H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 576.2
[M+H].sup.+.
##STR00170##
Example 90
[0374] A suspension of Example A8 (0.078 g, 0.236 mmol) in EtOAc
(1.5 mL) was treated with satd. NaHCO.sub.3 (1.5 mL) followed by
isopropenyl chloroformate (0.036 mL, 0.331 mmol) and the bi-phasic
mixture stirred vigorously at RT overnight. The layers were
separated, the organic layer washed with brine, dried over
MgSO.sub.4 and concentrated to dryness to afford prop-1-en-2-yl
(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4--
difluorophenyl)carbamate (86 mg, 88% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.64 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H),
7.61 (s, 1H), 7.36 (t, J=10.2 Hz, 1H), 7.06 (m, 1H), 6.23 (s, 1H),
4.71 (d, J=7.9 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz,
3H), 1.91 (s, 3H), 1.20 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 415.1
[M+H].sup.+.
[0375] A mixture of Example D2 (0.060 g, 0.269 mmol) and
prop-1-en-2-yl
(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4--
difluorophenyl)carbamate (0.086 g, 0.208 mmol) in dioxane (2 mL)
was treated with 1-methylpyrrolidine (2 drops) and heated at
80.degree. C. overnight. The mixture was concentrated to dryness,
treated with EtOAc and the resulting solid collected via filtration
and purified via reverse-phase chromatography (MeCN/H.sub.2O with
0.1% TFA). The organics were removed under reduced pressure, the
aqueous residue treated with satd. NaHCO.sub.3, extracted with
EtOAc (2.times.) and the combined organics were washed with brine,
dried over MgSO.sub.4 and concentrated to dryness to afford
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,-
4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)ure-
a (37 mg, 31% yield). .sup.1H NMR (400 MHz, DMSO-d): .delta. 9.82
(s, 1H), 8.94 (s, 1H), 8.86 (t, J=8.5 Hz, 1H), 8.59 (s, 1H), 7.93
(dd, J=6.5, 2.8 Hz, 1H), 7.76 (m, 2H), 7.62 (s, 1H), 7.13 (t, J=9.5
Hz, 2H), 6.25 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 3.08
(d, J=4.9 Hz, 3H), 2.50 (br s, 4H), 2.30 (br s, 4H), 2.10 (s, 3H),
1.18 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 580.2 [M+H].sup.+.
##STR00171##
Example 91
[0376] A suspension of Example A3 (0.250 g, 0.710 mmol) in THF (10
mL) was treated with 3-cyanophenyl isocyanate (0.102 g, 0.710 mmol)
followed by pyridine (0.011 g, 0.142 mmol) and stirred at RT for 2
days. The mixture was concentrated to dryness and the residue
treated with MeCN. The solid was collected via filtration, treated
with MeOH and the resulting solid collected via filtration and
dried to afford
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-(3-cyanophenyl)urea (212 mg, 60% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.39 (s, 1H), 8.89 (s, 1H),
8.79 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.97 (t, J=1.8
Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=10.6 Hz, 2H), 7.44 (m, 2H), 4.27
(q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 496.1
[M+H].sup.+.
[0377] A mixture of
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-(3-cyanophenyl)urea (0.210 g, 0.423 mmol),
t-butyl X-Phos (0.020 g, 0.047 mmol), Pd.sub.2(dba).sub.3 (0.020 g,
0.022 mmol), Cs.sub.2CO.sub.3 (0.400 g, 1.228 mmol) and methylamine
(2.0M in THF, 4.0 mL, 8.0 mmol) in dioxane (5 mL) was heated at
90.degree. C. for 5 h, then cooled to RT stirred overnight. The
solids were removed via filtration, washed with DCM, then MeCN and
the filtrate concentrated to dryness and purified via silica gel
chromatography (EtOAc/DCM) to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (33 mg, 15% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.40 (s, 1H), 8.83 (s,
1H), 8.41 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.97 (t, J=1.8 Hz, 1H),
7.74 (s, 1H), 7.61-7.45 (m, 4H), 7.05 (d, J=5.1 Hz, 1H), 6.24 (s,
1H), 4.14 (d, J=7.4 Hz, 2H), 2.86 (d, J=4.9 Hz, 3H), 1.21 (t, J=7.0
Hz, 3H); MS (ESI) m/z: 491.1 [M+H].sup.+.
##STR00172##
Example 92
[0378] A suspension of Example A3 (0.200 g, 0.568 mmol) in
3-morpholinopropan-1-amine (1 mL) was subjected to microwave
irradiation at 160.degree. C. for 30 minutes. The mixture was
cooled to RT, treated with water and the aqueous liquid decanted.
The material was treated with MTBE and the resulting solid
collected via filtration to afford
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)amino)-
-1,6-naphthyridin-2(l H)-one (150 mg, 57% yield). MS (ESI) m/z:
460.1 [M+H].sup.+.
[0379] A solution of
3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)amino)-
-1,6-naphthyridin-2(1H)-one (0.140 g, 0.304 mmol) in pyridine (4
mL) was treated with phenyl isocyanate (0.040 g, 0.336 mmol) and
stirred at RT for 1 h. The mixture was concentrated to dryness,
treated with MeOH and the resulting solid was collected via
filtration to afford
1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,-
6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 61%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H),
8.68 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.72 (s, 1H),
7.52 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz,
2H), 7.10 (t, J=5.6 Hz, 1H), 6.97 (t, J=7.4 Hz, 1H), 6.28 (s, 1H),
4.06 (m, 2H), 3.56 (t, J=4.5 Hz, 4H), 3.34 (m, 2H), 2.34 (d, J=6.8
Hz, 6H), 1.70 (t, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI)
m/z: 579.2 [M+H].sup.+.
##STR00173##
Example 93
[0380] A solution of Example A34 (0.200 g, 0.640 mmol) in pyridine
(0.5 mL) was cooled to 0.degree. C. and treated slowly with
isopropenyl chloroformate (0.073 mL, 0.672 mmol). The mixture was
stirred at 0.degree. C. for 0.5 h, warmed to RT, concentrated to
dryness and purified via silica gel chromatography (EtOAc/Hex) to
afford prop-1-en-2-yl
(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-m-
ethylphenyl)carbamate (244 mg, 96% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.54 (s, 1H), 8.33 (s, 1H), 7.66 (s, 1H),
7.35 (m, 1H), 7.13 (d, J=11.7 Hz, 1H), 6.48 (s, 2H), 6.33 (s, 1H),
4.69 (d, J=8.4 Hz, 2H), 4.08 (q, J=7.3 Hz, 2H), 2.08 (s, 3H), 1.90
(s, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 397.1
[M+H].sup.+.
[0381] A mixture of Example D2 (0.100 g, 0.448 mmol) and
prop-1-en-2-yl
(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-m-
ethylphenyl)carbamate (0.142 g, 0.358 mmol) in dioxane (3 mL) was
treated with 1-methylpyrrolidine (3 drops) and heated at 80.degree.
C. overnight. The mixture was treated with DMSO (2 drops) and
heated at 80.degree. C. for an additional 24 h. The mixture was
cooled to RT, concentrated to dryness and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3, extracted with EtOAc (2.times.) and
the combined organics were washed with brine, dried over MgSO.sub.4
and concentrated to dryness to afford
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
(44 mg, 22% yield). .sup.1H NMR (400 MHz, pyridine-d.sub.5):
.delta. 9.87 (s, 1H), 8.89 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H),
7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (dt, J=8.7, 3.6 Hz, 1H), 7.64
(s, 1H), 7.26 (s, 2H), 7.15 (t, J=9.2 Hz, 1H), 7.07 (d, J=12.0 Hz,
1H), 6.56 (s, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 2.53 (s,
4H), 2.30 (m, 7H), 2.13 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI)
m/z: 562.2 [M+H].sup.+.
##STR00174##
Example 94
[0382] A mixture of 1-fluoro-2-methyl-4-nitrobenzene (2.5 g, 16.12
mmol) NBS (5.02 g, 28.2 mmol) and AIBN (265 mg, 1.612 mmol) in
trifluorotoluene (45 mL) was heated to reflux overnight. The
mixture was cooled to RT, filtered to remove solids and the
filtrate concentrated to dryness. The residue was dissolved in
Et.sub.2O, washed with water, then brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via silica
gel chromatography (EtOAc/Hex) to afford
2-(bromomethyl)-1-fluoro-4-nitrobenzene (698 mg, 18% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.53 (dd, J=6.4, 3.0
Hz, 1H), 8.28 (ddd, J=9.1, 4.4, 3.0 Hz, 1H), 7.55 (t, J=9.2 Hz,
1H), 4.80 (s, 2H).
[0383] A -20.degree. C. solution of DIEA (771 mg, 5.97 mmol) and
dimethylamine (2.0M in THF, 1.94 mL, 3.88 mmol) in THF (5 mL) was
treated drop-wise with a solution of
2-(bromomethyl)-1-fluoro-4-nitrobenzene (698 mg 2.98 mmol) in THF
(5 mL) and stirred at RT overnight as the cooling bath expired. The
mixture was treated with EtOAc, washed with water, then brine,
dried over Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine (494 mg, 84%
yield). MS (ESI) m/z: 199.1 [M+H].sup.+.
[0384] A mix of satd. NH.sub.4Cl (5.19 mL) in EtOH (8 mL) was
treated with 1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine
(494 mg, 2.49 mmol), followed by iron powder (1.39 g, 24.93 mmol)
and heated at 55.degree. C. overnight. The mixture was cooled to
RT, the solids removed via filtration through diatomaceous earth
and washed with 10% MeOH/DCM. The filtrate was concentrated to
dryness, the residue treated with DCM, sonicated and the resulting
solid collected via filtration, washed with THF and dried to afford
3-((dimethylamino)methyl)-4-fluoroaniline (305 mg, 72% yield). MS
(ESI) m/z: 169.1 [M+H].sup.+.
[0385] A mixture of Example A47 (200 mg, 0.363 mmol),
3-((dimethylamino)methyl)-4-fluoroaniline (300 mg, 1.815 mmol) and
1-methylpyrrolidine (31 mg, 0.363 mmol) in dioxane (4 mL) was
heated at 80.degree. C. overnight. The mixture was cooled to RT,
treated EtOAc and satd. NaHCO.sub.3, warmed to near reflux and the
resulting solid collected via filtration and dried to afford
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-f-
luorophenyl)urea (174 mg, 72% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.21 (br s, 1H), 8.80 (br s, 1H), 8.50 (s,
1H), 8.14 (d, J=9.1 Hz, 1H), 7.77 (s, 1H), 7.56-7.48 (m, 2H), 7.25
(m, 1H), 7.18 (d, J=8.3 Hz, 2H), 7.04 (m, 1H), 6.86 (d, J=8.4 Hz,
2H), 6.32 (s, 1H), 4.85 (s, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.70 (s,
3H), 3.36 (s, 2H), 3.13 (s, 3H), 2.13 (s, 6H), 1.13 (t, J=7.0 Hz,
3H); MS (ESI) m/z: 661.2 [M+H].sup.+.
[0386] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-f-
luorophenyl)urea (174 mg, 0.263 mmol) in TFA (2.0 mL) was stirred
at RT for 2.5 h. The mixture was concentrated to dryness, treated
with EtOAc and satd. NaHCO.sub.3, stirred for 0.5 h and the
resulting solid collected via filtration and dried to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea
(111 mg, 78% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.12 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.15 (d, J=8.7 Hz, 1H),
7.74 (s, 1H), 7.54-7.50 (m, 2H), 7.23 (m, 1H), 7.09-7.01 (m, 2H),
6.23 (s, 1H), 4.13 (q, J=6.8 Hz, 2H), 3.37 (s, 2H), 2.86 (d, J=4.4
Hz, 3H), 2.13 (s, 6H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 541.1
[M+H].sup.+
##STR00175##
Example 95
[0387] A mixture of Example A47 (200 mg, 0.363 mmol) and Example D3
(95 mg, 0.454 mmol) in dioxane (5 mL) was treated with
1-methylpyrrolidine (31 mg, 0.363 mmol) and heated at 70.degree. C.
overnight. The mixture was cooled to RT, treated with EtOAc and 50%
satd. NaHCO.sub.3 and stirred for 0.5 h. The resulting solid was
collected via filtration and dried to afford
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)-
phenyl)urea (152 mg, 60% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.12 (s, 1H), 8.62 (m, 1H), 8.50 (s, 1H),
8.16 (d, J=8.7 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 7.47
(m, 1H), 7.30 (m, 1H), 7.18 (m, 2H), 7.07 (t, J=9.2 Hz, 1H), 6.87
(m, 2H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.70
(s, 3H), 3.54-3.53 (m, 4H), 3.45 (s, 2H), 3.13 (s, 3H), 2.35 (m,
4H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 703.2 [M+H].sup.+.
[0388] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)-
phenyl)urea (152 mg, 0.216 mmol) in TFA (3 mL) was stirred under Ar
for 3 h. The mixture was concentrated to dryness, treated with
EtOAc and satd. NaHCO.sub.3 and stirred for 0.5 h. The resulting
solid was collected via filtration and dried to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea
(111 mg, 76% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.12 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J=8.7
Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 7.47 (dd, J=6.5,
2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.5, 2.8 Hz, 1H), 7.10-7.01 (m, 2H),
6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.53 (t, J=4.4 Hz, 4H), 3.44
(s, 2H), 2.86 (d, J=4.9 Hz, 3H), 2.35 (m, 4H), 1.20 (t, J=7.0 Hz,
3H); MS (ESI) m/z: 583.2 [M+H].sup.+.
##STR00176##
Example 96
[0389] A mixture of Example A50 (0.12 g, 0.224 mmol),
(3S)-(+)-3-(dimethylamino)pyrrolidine (0.077 g, 0.672 mmol) and
1-methylpyrrolidine (9.53 mg, 0.112 mmol) in THF (3 mL) was heated
at 60.degree. C. overnight. The mixture was cooled to RT,
concentrated to dryness and purified via silica gel chromatography
(MeOH/DCM) to afford
(S)--N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2--
dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide
(67 mg, 51% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.05
(s, 2H); 8.67 (s, 1H); 8.61 (s, 1H); 8.17 (d, J=8.6 Hz, 1H); 8.06
(s, 1H); 7.90 (s, 1H); 7.52 (d, J=11.0 Hz, 1H); 7.37 (d, J=8.1 Hz,
2H); 7.21 (t, J=7.8 Hz, 3H); 6.92 (m, 1H); 4.13 (q, J=6.9 Hz, 2H);
3.65 (m, 2H), 3.38 (m, 1H); 2.15 (m, 3H); 1.19 (t, J=6.9 Hz, 3H);
MS (ESI) m/z: 592.2 [M+H].sup.+.
##STR00177##
Example 97
[0390] A -20.degree. C. mixture of DIEA (552 mg, 4.27 mmol) and
pyrrolidine (152 mg, 2.137 mmol) in THF (5 mL) was treated
drop-wise with a solution of
2-(bromomethyl)-1-fluoro-4-nitrobenzene (500 mg, 2.137 mmol) in THF
(5 mL), allowed to warm to RT and stirred for 6 h. The mixture was
treated with EtOAc, washed with water, then brine, dried over
Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg, 94% yield). MS (ESI)
m/z: 225.1 [M+H].sup.+.
[0391] A mixture of 1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg,
2.007 mmol) in EtOAc (15 mL) was treated with 10% Pd/C (107 mg) and
hydrogenated (1 atm) for 3 h. Additional 10% Pd/C (100 mg) was
added and the mixture hydrogenated (1 atm) overnight. The solids
were removed via filtration through diatomaceous earth, washed with
EtOAc and the filtrate washed with water, then brine, dried over
Na.sub.2SO.sub.4 and concentrated to dryness to afford
4-fluoro-3-(pyrrolidin-1-ylmethyl)aniline (282 mg, 72% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6); .delta. 6.75 (dd, J=10.0, 8.7
Hz, 1H), 6.56 (dd, J=6.4, 2.9 Hz, 1H), 6.39 (ddd, J=8.7, 4.3, 2.9
Hz, 1H), 4.85 (s, 2H), 3.44 (d, J=1.5 Hz, 2H), 2.40 (m, 4H), 1.66
(m, 4H); MS (ESI) m/z: 195.1 [M+H].sup.+.
[0392] A mixture of Example A47 (200 mg, 0.363 mmol) and
4-fluoro-3-(pyrrolidin-1-ylmethyl)aniline (88 mg, 0.454 mmol) in
dioxane (5 mL) was treated with 1-methylpyrrolidine (31 mg, 0.363
mmol) and heated at 70.degree. C. overnight. The mixture was cooled
to RT, treated with EtOAc and 50% satd. NaHCO.sub.3 and stirred for
0.5 h. The resulting solid was collected via filtration and dried
to afford
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylme-
thyl)phenyl)urea (135 mg, 54% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.11 (s, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.50
(s, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.78 (s, 1H), 7.53 (d, J=11.0 Hz,
1H), 7.49 (dd, J=6.5, 2.8 Hz, 1H), 7.27 (m, 1H), 7.18 (d, J=8.5 Hz,
2H), 7.05 (t, J=9.3 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.32 (s, 1H),
4.85 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.55 (s, 2H),
3.13 (s, 3H), 2.43 (m, 4H), 1.66 (m, 4H), 1.13 (t, J=7.0 Hz, 3H);
MS (ESI) m/z: 687.2 [M+H].sup.+.
[0393] A mixture of
1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylme-
thyl)phenyl)urea (135 mg, 0.196 mmol) in TFA (3 mL) was stirred at
RT for 3 h. The mixture was concentrated to dryness, treated with
EtOAc and satd. NaHCO.sub.3 and stirred for 15 min. The resulting
solid was collected via filtration and dried to afford
1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-
-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea
(98 mg, 88% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.19 (br s, 1H), 8.71 (br s, 1H), 8.41 (s, 1H), 8.13 (m, 1H), 7.73
(s, 1H), 7.54-7.48 (m, 2H), 7.27 (m, 1H), 7.04 (m, 2H), 6.23 (s,
1H), 4.13 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 2.86 (s, 3H), 2.42 (m,
4H), 1.66 (m, 4H), 1.20 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 567.2
[M+H].sup.+.
##STR00178##
Example 98
[0394] A mixture of Example A52 (0.27 g, 0.536 mmol),
Cs.sub.2CO.sub.3 (0.524 g, 1.609 mmol), N,N-dimethylurea (0.236 g,
2.68 mmol) and Xantphos (0.093 g, 0.161 mmol) in dioxane (10 mL)
was sparged with Ar, treated with Pd.sub.2(dba).sub.3 (0.074 g,
0.080 mmol), sparged again with Ar and heated at 100.degree. C.
overnight. The mixture was cooled to RT, the solid removed via
filtration and washed with EtOAc. The filtrate was washed with
brine (2.times.), dried over Na.sub.2SO.sub.4, concentrated to
dryness and purified via silica gel chromatography (EtOAc/Hex). The
material was re-purified via reverse-phase chromatography
(MeCN/H.sub.2O with 0.1% TFA); the organics were removed under
reduced pressure and the aqueous residue was treated satd.
NaHCO.sub.3. The mixture was extracted with EtOAc (3.times.) and
the combined organics were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to dryness to afford
3-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (65 mg,
22% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.31 (s,
1H), 9.17 (s, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 8.17
(d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.58 (m, 1H), 7.48 (m, 1H), 7.30
(m, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.79 (m, 1H), 2.97 (s, 6H), 1.55
(d, J=7.0 Hz, 6H); MS (ESI) m/z: 555.1 [M+H].sup.+.
##STR00179##
Example 99
[0395] A solution of Example A10 (0.16 g, 0.437 mmol) in NMP (3 mL)
was treated with DBU (0.079 mL, 0.524 mmol) and
4-methoxybenzylamine (0.150 g, 1.092 mmol) and heated at
150.degree. C. overnight. Additional 4-methoxybenzylamine (0.05 mL)
was added and the mixture heated at 150.degree. C. for 24 h. The
mixture was cooled to RT, treated with brine and extracted with
EtOAc (3.times.). The combined organics were dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via silica
gel chromatography (EtOAc/Hex) to afford
3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-((4-methoxybenzyl)amino-
)-1,6-naphthyridin-2(1H)-one (110 mg, 54% yield). MS (ESI) m/z:
467.1 [M+H].sup.+.
[0396] A solution of
3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-((4-methoxybenzyl)amino-
)-1,6-naphthyridin-2(1H)-one (0.11 g, 0.236 mmol) in THF (5 mL) was
treated with TEA (0.1 mL) and 3-fluorophenyl isocyanate (0.032 mL,
0.259 mmol) and stirred at RT for 5 h. The mixture was concentrated
to dryness, treated with DCM and the solid collected via filtration
and dried to afford
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-o-
xo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea
(94 mg, 66% yield). MS (ESI) m/z: 604.1 [M+H].sup.+.
[0397] A mixture of
1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-oxo-1,2--
dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (0.094
g, 0.156 mmol) and anisole (0.085 mL, 0.778 mmol) was stirred in
TFA (1 mL) at RT for 3 h. The mixture was concentrated to dryness,
treated with EtOAc and satd. NaHCO.sub.3 and stirred for 1 h. The
resulting solid was collected via filtration and dried to afford
1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chlo-
ro-2-fluorophenyl)-3-(3-fluorophenyl)urea (70 mg, 93% yield). MS
(ESI) m/z: 484.1 [M+H].sup.+.
[0398] A solution of
1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chlo-
ro-2-fluorophenyl)-3-(3-fluorophenyl)urea (0.07 g, 0.145 mmol) in
pyridine (2 mL) was treated with acetyl chloride (0.011 mL, 0.159
mmol) and stirred at RT for 2 h. The mixture was concentrated to
dryness, treated with EtOAc, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to dryness. The material was
treated with Et.sub.2O and the solid collected via filtration to
afford
N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-
-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (65 mg, 84%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.81 (s, 1H),
9.31 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.18 (d,
J=8.6 Hz, 1H), 7.93 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.46 (dt,
J=11.9, 2.3 Hz, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.79 (td, J=8.5,
2.6 Hz, 1H), 5.36 (m, 1H), 2.14 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS
(ESI) m/z: 526.1 [M+H].sup.+.
##STR00180##
Example 100
[0399] A solution of Example D2 (0.117 g, 0.524 mmol) and Example
A53 (0.182 g, 0.437 mmol) in dioxane (4.5 mL) was treated with
catalytic 1-methylpyrrolidine (2 drops) and the mixture heated at
80.degree. C. overnight. The mixture was cooled to RT, concentrated
to dryness and purified via silica gel chromatography (MeOH/DCM) to
afford
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro--
4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
(123 mg, 49% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.06 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 8.00-7.95 (m, 2H), 7.73
(s, 1H), 7.45 (m, 1H), 7.31-7.26 (m, 1H), 7.17 (d, J=12.2 Hz, 1H),
7.05 (t, J=9.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.44 (s, 2H), 2.38
(br s, 8H), 2.17 (s, 3H), 2.07 (s, 3H), 1.20 (t, J=7.0 Hz, 3H); MS
(ESI) m/z: 581.2 [M+H].sup.+.
[0400] A mixture of
I-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro--
4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea
(0.120 g, 0.207 mmol), formamide (0.041 ml, 1.033 mmol) and
K.sub.2CO.sub.3 (0.057 g, 0.413 mmol) in dioxane (3 mL) was sparged
with Ar, treated with BrettPhos Palladacycle (8.05 mg, 10.33
.mu.mol), sparged again with Ar, and heated to 100.degree. C. for 1
h. The mixture was cooled to RT, treated with EtOAc and satd.
NaHCO.sub.3, filtered to remove insoluble material and the layers
separated. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated to dryness. The material was treated
with a small amount of DCM, allowed to stand at RT, and the
resulting solid collected via filtration and dried. The filtrate
was concentrated to dryness, layered with a small amount of DCM and
allowed to stand at RT overnight. The resulting solid was collected
via filtration and combined with the above-isolated solid to afford
N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)p-
henyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)form-
amide (53 mg, 44% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.38 (m, 1H), 9.05 (s, 1H), 8.69 (d, J=18.4 Hz, 1H), 8.44
(s, 1H), 8.21 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.43
(dd, J=6.5, 2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.4, 2.8 Hz, 1H), 7.16
(d, J=12.2 Hz, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.96 (s, 1H), 4.19 (m,
2H), 3.42 (s, 2H), 2.41-2.19 (m, 8H), 2.10 (s, 3H), 2.07 (s, 3H),
1.24 (m, 3H); MS (ESI) m/z: 590.2 [M+H].sup.+.
##STR00181##
Example 101
[0401] A mixture of Example A54 (308 mg, 0.665 mmol),
Cs.sub.2CO.sub.3 (650 mg, 1.996 mmol), N,N-dimethylurea (293 mg,
3.33 mmol) and Xantphos (115 mg, 0.20 mmol) in dioxane (10 mL) was
sparged with Ar, treated with Pd.sub.2(dba).sub.3 (91 mg, 0.100
mmol) and heated at 100.degree. C. overnight. The mixture was
cooled to RT, treated with EtOAc and DMF, the solids removed via
filtration through diatomaceous earth and washed with water and
EtOAc. The layers of the filtrate were separated, the organic layer
washed with satd. NaHCO3, then brine, dried over Na.sub.2SO.sub.4,
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The organics were
removed under reduced pressure and the aqueous residue treated with
satd. NaHCO.sub.3. The resulting solid was collected via filtration
and dried to afford
3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (35 mg, 10% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.18 (s, 1H), 9.01 (s,
1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.01 (s, 1H), 7.98 (d, J=8.4 Hz,
1H), 7.86 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.7 Hz, 2H),
7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.3 Hz, 1H), 4.18 (q, J=7.2 Hz,
2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI)
m/z: 503.2 [M+H].sup.+.
##STR00182##
Example 102
[0402] A suspension of N,N-dimethylazetidin-3-amine dihydrochloride
(0.071 g, 0.410 mmol) and N-methyl pyrrolidine (0.070 g, 0.821
mmol) in dioxane (4 mL) was heated at 55.degree. C. for 10 minutes,
treated with Example A50 (0.11 g, 0.205 mmol) and heated at
55.degree. C. for 16 h. The mixture was concentrated to dryness and
purified via silica gel chromatography (MeOH/DCM) to afford
N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide
(68 mg, 57% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.49 (s, 1H), 9.09 (s, 1H), 8.71 (d, J=2.6 Hz, 1H), 8.65 (s, 1H),
8.21 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.57 (d, J=11.0
Hz, 1H), 7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97
(t, J=7.3 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 4.06-4.01 (m, 2 H),
3.86-3.77 (m, 2H), 3.04 (m, 1H), 2.09 (s, 6H), 1.24 (t, J=7.0 Hz,
3H); MS (ESI) m/z: 578.2 [M+H].sup.+.
##STR00183##
Example 103
[0403] A mixture of Example A55 (0.2 g, 0.412 mmol),
Cs.sub.2CO.sub.3 (0.403 g, 1.236 mmol), N,N-dimethylurea (0.182 g,
2.060 mmol) and Xantphos (0.072 g, 0.124 mmol) in dioxane (10 mL)
was sparged with Ar, treated with Pd.sub.2(dba).sub.3 (0.057 g,
0.062 mmol), sparged again with Ar and heated at 100.degree. C.
overnight. The mixture was cooled to RT, the solids removed via
filtration and washed with water and EtOAc. The layers of the
filtrate were separated, the organic layer washed with brine, dried
over Na.sub.2SO.sub.4, concentrated to dryness and purified via
silica gel chromatography (EtOAc/Hex). The material was re-purified
via reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure and the aqueous
residue treated with satd. NaHCO.sub.3. The resulting solid was
collected via filtration and dried to afford
3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (25 mg, 6% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.16 (s, 1H), 9.11 (s,
1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 8.20 (d, J=8.6 Hz,
1H), 7.89 (s, 1H), 7.55 (d, J=11.0 Hz, 1H), 7.42 (m, 2H), 7.26 (t,
J=7.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 5.32 (m, 1H), 2.97 (s, 6H),
1.55 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 537.1 [M+H].sup.+.
##STR00184##
Example 104
[0404] A solution of benzo[b]thiophene-3-carboxylic acid (0.129 g,
0.723 mmol) in toluene (5 mL) was treated with TEA (0.167 mL, 1.206
mmol) and DPPA (0.195 ml, 0.904 mmol), stirred at RT for 5 min,
treated with Example A6 (0.20 g, 0.603 mmol) and heated at
100.degree. C. for 2 h. The mixture was cooled to RT and the
resulting solid collected via filtration to afford
1-(benzo[b]thiophen-3-yl)-3-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihy-
dro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (230 mg,
75% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.40 (s,
1H), 8.86 (s, 1H), 8.78 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.02 (s,
1H), 7.96 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.74 (s, 1H),
7.67 (s, 1H), 7.48 (m, 1 H), 7.41 (m, 1H), 7.20 (m, 1H), 4.28 (q,
J=7.1 Hz, 2H), 2.08 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z:
507.1 [M+H].sup.+.
[0405] A mixture of
1-(benzo[b]thiophen-3-yl)-3-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-na-
phthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.23 g, 0.454 mmol),
Cs.sub.2CO.sub.3 (0.443 g, 1.361 mmol), N,N-dimethylurea (0.200 g,
2.268 mmol) and Xantphos (0.079 g, 0.136 mmol) in dioxane (10 mL)
was sparged with Ar, treated with Pd.sub.2(dba).sub.3 (0.062 g,
0.068 mmol), sparged again with Ar and heated at 100.degree. C.
overnight. The mixture was cooled to RT, the solids removed via
filtration and rinsed with water and EtOAc. The layers of the
filtrate were separated, the organic layer washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated to dryness. The material was
treated with DCM, the solid removed via filtration and the filtrate
purified via silica gel chromatography (EtOAc/Hex) to afford
3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl)-1-ethy-
l-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (25 mg,
9% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.34 (s,
1H), 9.13 (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H), 8.03 (d, J=8.4 Hz,
1H), 7.97 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.83 (m, 2H), 7.62 (s,
1H), 7.45-7.40 (m, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.15 (d, J=12.3 Hz,
1H), 4.14 (d, J=8.0 Hz, 2H), 2.93 (s, 3H), 1.20 (m, 3H); MS (ESI)
m/z: 559.2 [M+H].sup.+.
##STR00185##
Example 105
[0406] A solution of Example A13 (0.300 g, 0.756 mmol) in pyridine
(8 mL) was cooled to 0.degree. C., treated slowly with phenyl
isocyanate (0.086 mL, 0.794 mmol), stirred at 0.degree. C. for 20
min then warmed to RT for 45 min. The solids were collected via
filtration, rinsed with a small amount of DCM and dried; the
filtrate was treated with satd. NaHCO.sub.3 and extracted with DCM.
The organic layer was washed with brine, dried over MgSO.sub.4,
concentrated to dryness, triturated with DCM, the solid collected
via filtration and combined with the above-isolated solid to afford
1-(4-bromo-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin--
3-yl)-2-fluorophenyl)-3-phenylurea (170 mg, 44% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.11 (s, 1H), 8.79 (s, 1H), 8.75
(d, J=2.5 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.75 (s,
1H), 7.71 (d, J=10.8 Hz, 1H), 7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.26
(t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H),
1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 515.0 [M+H].sup.+.
[0407] A suspension of
1-(4-bromo-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-
-fluorophenyl)-3-phenylurea (0.360 g, 0.698 mmol), N,N-dimethylurea
(0.307 g, 3.49 mmol) and Cs.sub.2CO.sub.3 (0.682 g, 2.094 mmol) in
dioxane (8 mL) was sparged with Ar, treated with XantPhos (0.121 g,
0.209 mmol) and Pd.sub.2(dba).sub.3 (0.096 g, 0.105 mmol), sparged
again with Ar and heated at 100.degree. C. overnight. The mixture
was cooled to RT, the solids removed via filtration and rinsed with
EtOAc. The filtrate was treated with brine, filtered again to
remove solids and the layers separated. The organic layer was
washed a second time with brine, dried over MgSO.sub.4,
concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The organics were
removed under reduced pressure, the aqueous residue treated with
satd. NaHCO.sub.3 and stirred for 1 h. The resulting solid was
collected via filtration and dried to afford
3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydr-
o-1,6-naphthyridin-7-yl)-1,1-dimethylurea (37 mg, 9% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.21 (s, 1H), 9.10 (s,
1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.01 (s,
1H), 7.91 (s, 1H), 7.69 (d, J=10.8 Hz, 1H), 7.42 (m, 2H), 7.26 (m,
2H), 6.97 (t, J=7.4 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 6H),
1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 567.1 [M+H].sup.+.
##STR00186##
Example 106
[0408] A mixture of Example A56 (320 mg, 0.682 mmol),
Cs.sub.2CO.sub.3 (667 mg, 2.047 mmol). N,N-dimethylurea (301 mg,
3.41 mmol) and Xantphos (118 mg, 0.205 mmol) in dioxane (5 mL) was
sparged with Ar, treated with Pd.sub.2(dba).sub.3 (94 mg, 0.102
mmol) and heated at 100.degree. C. overnight. The mixture was
cooled to RT, treated with EtOAc and DMF, the solids removed via
filtration through diatomaceous earth and washed with water and
EtOAc. The layers of the filtrate were separated, the organic layer
washed with satd. NaHCO.sub.3, then brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and stirred for 1 h. The resulting
solid was collected via filtration and dried to afford
3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-
-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (30 mg, 8%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.27 (s, 1H),
9.17 (s, 1H), 8.66-8.58 (m, 2H), 8.01 (s, 1H), 7.93 (m, 1H), 7.86
(s, 1H), 7.47 (m, 1H), 7.29 (m, 1 H), 7.17 (m, 1H), 7.06 (m, 1H),
6.76 (m, 1H), 4.18 (q, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t,
3H); MS (ESI) m/z: 521.2 [M+H].sup.+.
##STR00187##
Example 107
[0409] A bi-phasic mixture of Example A3 (250 mg, 0.710 mmol) in
EtOAc (10 mL) and satd. NaHCO.sub.3 (15 mL) was treated with
isopropenyl chloroformate 9120 mg, 0.984 mmol) and stirred at RT
for 2 h. The layers were separated, the organic layer washed with
water, then brine, dried over Na.sub.2SO.sub.4 and concentrated to
dryness to afford prop-1-en-2-yl
(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)carbamate (292 mg, 94% yield). MS (ESI) m/z: 436.0
[M+H].sup.+.
[0410] A mixture of prop-1-en-2-yl
(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluorophenyl)carbamate (182 mg, 0.416 mmol) and Example D3 (105 mg,
0.454 mmol) in dioxane (5 mL) was treated with 1-methylpyrrolidine
(35 mg, 0.416 mmol) and heated at 70.degree. C. overnight. The
mixture was cooled to RT, treated with EtOAc and 50% satd.
NaHCO.sub.3 and stirred for 0.5 h. The resulting solid was
collected via filtration and dried. The layers of the filtrate were
separated, the organics layer washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and stirred for 1 h. The resulting
solid was collected via filtration and combined with the
above-isolated solid to afford
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (155
mg, 63% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.14
(s, 1H), 8.79 (s, 1H), 8.68 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 8.09
(s, 1H), 7.75 (s, 1H), 7.59 (d, J=11.0 Hz, 1H), 7.48 (dd, J=6.5,
2.8 Hz, 1H), 7.30 (m, 1H), 7.07 (t, J=9.2 Hz, 1H), 4.27 (q, J=7.1
Hz, 2H), 3.56-3.51 (m, 4H), 3.44 (s, 2H), 2.35 (m, 4H), 1.20 (t,
J=7.0 Hz, 3H); MS (ESI) m/z: 588.1 [M+H].sup.+.
[0411] A mixture of
1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)--
2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (155
mg, 0.263 mmol). K.sub.2CO.sub.3 (73 mg, 0.570 mmol) and formamide
(59 mg, 1.317 mmol) in dioxane (3 mL) was sparged with Ar, treated
with BrettPhos Palladacycle (10 mg, 13 .mu.mol) and heated at
100.degree. C. for 2 h. The mixture was cooled to RT, treated with
EtOAc. DMF and 50% satd. NaHCO.sub.3 and the solid collected via
filtration. The layers of the filtrate were separated, the organics
layer washed with brine, dried over Na.sub.2SO.sub.4, concentrated
to dryness, combined with the isolated solid and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and stirred for 1 h. The resulting
solid was collected via filtration, dried and re-purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and extracted with EtOAc (3.times.).
The combined organics were dried over Na.sub.2SO.sub.4 and
concentrated to dryness to afford
N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)-
ureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide
(33 mg, 20% yield). MS (ESI) m/z: 597.2 [M+H].sup.+.
[0412] A suspension of
N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)-
phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide
(33 mg, 0.055 mmol) in MeCN (2 mL) was treated with 0.1N HCl (580
.mu.L, 0.058 mmol), frozen and lyophilized to afford
N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)-
phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide
hydrochloride (34 mg, 91% yield). MS (ESI) m/z: 597.2
[M+H].sup.+.
##STR00188##
Example 108
[0413] A mixture of Example A53 (400 mg, 0.962 mmol) and
3,5-difluoroaniline (186 mg, 1.443 mmol) in dioxane (5 mL) was
treated with 1-methylpyrrolidine (123 mg, 1.443 mmol) and heated at
70.degree. C. for 20 h. The mixture was cooled to RT, treated with
EtOAc and 50% satd. NaHCO.sub.3 and stirred for 1 h. The resulting
solid was collected via filtration and dried to afford
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro--
4-methylphenyl)-3-(3,5-difluorophenyl)urea (287 mg, 61% yield). MS
(ESI) m/z: 487.1 [M+H].sup.+.
[0414] A mixture of
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro--
4-methylphenyl)-3-(3,5-difluorophenyl)urea (287 mg, 0.589 mmol),
Cs.sub.2CO.sub.3 (576 mg, 1.768 mmol), N,N-dimethylurea (260 mg,
2.95 mmol) and Xantphos (102 mg, 0.177 mmol) in dioxane (5 mL) was
sparged with Ar, treated with Pd.sub.2(dba).sub.3 (81 mg, 0.088
mmol) and heated at 100.degree. C. overnight. The mixture was
cooled to RT, treated with water, EtOAc and DMF and the solids
removed via filtration through diatomaceous earth. The layers of
the filtrate were separated, the organic layer washed with brine,
dried over Na.sub.2SO.sub.4, concentrated to dryness and purified
via reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and stirred overnight. The resulting
solid was collected via filtration and dried to afford
3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1--
ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (18
mg, 5% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.41
(s, 1H), 9.17 (s, 1H), 8.65 (m, 2H), 8.01 (s, 1H), 7.90 (d, J=8.3
Hz, 1H), 7.86 (s, 1H), 7.20-7.11 (m, 3H), 6.78 (m, 1H), 4.18 (q,
J=7.1 Hz, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, J=7.1 Hz, 3H);
MS (ESI) m/z: 539.2 [M+H].sup.+.
##STR00189##
Example 109
[0415] A mixture of Example A20 (0.345 g, 0.998 mmol), phenyl
isocyanate (0.143 g, 1.197 mmol) and TEA (0.138 ml, 0.998 mmol) in
THF (5 mL) was stirred at RT for 3 h. The mixture was treated with
30% EtOAc/Hex, stirred for several minutes and the resulting solid
was collected via filtration and dried to afford
1-(5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-flu-
oro-4-methylphenyl)-3-phenylurea (350 mg, 75% yield). MS (ESI) m/z:
465.1 [M+H].sup.+.
[0416] A solution of
1-(5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-flu-
oro-4-methylphenyl)-3-phenylurea (0.35 g, 0.753 mmol) in dioxane (4
mL) and DMF (1 mL) was sparged with Ar, treated with
N-t-butylcarbamate (0.441 g, 3.76 mmol), Cs.sub.2CO.sub.3 (0.368 g,
1.129 mmol), X-Phos (0.036 g, 0.075 mmol) and Pd.sub.2(dba).sub.3
(0.034 g, 0.038 mmol) and the mixture heated at 80.degree. C. for
16 h. The mixture was cooled to RT, treated with THF and the solids
removed via filtration through diatomaceous earth. The filtrate was
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
dryness. The residue was suspended in 1:1 EtOAc/Hex, sonicated and
the solid collected via filtration to afford tert-butyl
(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dih-
ydro-1,6-naphthyridin-7-yl)carbamate (205 mg, 50% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 10.10 (s, 1H), 9.02 (s, 1H),
8.61 (s, 1H), 8.50 (s, 1H), 8.13 (s, 1H), 7.97 (d, J=8.4 Hz, 1H),
7.82 (s, 1H). 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.15
(d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5.28 (m, 1H), 2.07 (s,
3H), 1.57 (d, J=7.0 Hz, 6H), 1.49 (s, 9H); MS (ESI) m/z: 546.2
[M+H].sup.+.
[0417] A solution of tert-butyl
(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dih-
ydro-1,6-naphthyridin-7-yl)carbamate (0.2 g, 0.367 mmol) in MeOH (3
mL) was treated with HCl in dioxane (4 M, 0.916 mL, 3.67 mmol) and
stirred at RT for 16 h. The mixture was concentrated to dryness,
treated with pyridine (3 mL) and isopropenyl chloroformate (0.066
g, 0.550 mmol) and stirred at RT for 1 h. Water was added, the
mixture stirred for several minutes, extracted with 20% THF/EtOAc
(2.times.) and the combined organics were washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated to dryness. The residue was
treated with 30% EtOAc/Hex, sonicated and the resulting solid
collected via filtration to afford prop-1-en-2-yl
(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dih-
ydro-1,6-naphthyridin-7-yl)carbamate (175 mg, 90% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 1H), 9.02 (s, 1H),
8.66 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 7.98 (d, J=8.5 Hz, 1H),
7.85 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.15
(d, J=12.2 Hz, 1H), 6.95 (t, J=7.3 Hz, 1H), 5.33 (m, 1H), 4.81 (s,
1H), 4.77 (s, 1H), 2.07 (s, 3H), 1.96 (s, 3H), 1.56 (d, J=7.0 Hz,
6H); MS (ESI) m/z: 530.2 [M+H].sup.+.
[0418] A suspension of prop-1-en-2-yl
(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dih-
ydro-1,6-naphthyridin-7-yl)carbamate (0.1 g, 0.189 mmol) in dioxane
(3 mL) was treated with azetidine hydrochloride (0.071 g, 0.755
mmol) and 1-methylpyrrolidine (0.129 g, 1.511 mmol) and heated at
70.degree. C. for 16 h, then cooled to RT and stirred for 24 h. The
mixture was concentrated to dryness and purified via reverse-phase
chromatography (MeCN/H.sub.2O with 0.1% TFA). The fractions were
neutralized with satd. NaHCO.sub.3, extracted with EtOAc (2.times.)
and the combined organics were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to dryness to afford
N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-d-
ihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide (43 mg, 43%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.34 (s, 1H),
9.01 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 7.97 (d,
J=8.4 Hz, 1H), 7.80 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8
Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5.35 (m,
1H), 4.02 (t, J=7.5 Hz, 4H), 2.17 (t, J=7.7 Hz, 2H), 2.07 (s, 3H),
1.55 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 529.2 [M+H].sup.+.
##STR00190##
Example 110
[0419] A suspension of Example A57 (0.15 g, 0.291 mmol) in THF (4
mL) was treated with azetidine hydrochloride (0.109 g, 1.164 mmol)
and 1-methylpyrrolidine (0.248 g, 2.91 mmol) and heated at
60.degree. C. for 16 h. The mixture was concentrated to dryness and
purified via reverse-phase chromatography (MeCN/H.sub.2O with 0.1%
TFA). The fractions were neutralized with satd. NaHCO.sub.3,
extracted with EtOAc (2.times.) and the combined organics were
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
dryness to afford
N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihyd-
ro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide (53 mg, 35%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.37 (s, 1H),
9.05 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.97 (d,
J=8.4 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.25 (t, J=7.8
Hz, 2H), 7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 4.17 (q,
J=7.5 Hz, 2H), 4.02 (t, J=7.5 Hz, 4H), 2.17 (t, J=7.7 Hz, 2H), 2.07
(s, 3H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 515.2
[M+H].sup.+.
##STR00191##
Example 111
[0420] A mixture of Example A54 (222 mg, 0.492 mmol), Pd(OAc).sub.2
(6 mg, 0.026 mmol), Xantphos (31 mg, 0.053 mmol), K.sub.2CO.sub.3
(73 mg, 0.527 mmol) and 3-amino-6-methylpyridine (171 mg, 1.582
mmol) in dioxane (4 mL) was sparged with Ar and heated at
90.degree. C. for 4 h. The mixture was cooled to RT, treated with
EtOAc and 50% satd. NaHCO.sub.3 and the solids removed via
filtration through diatomaceous earth. The layers of the filtrate
were separated, the organics layer washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and stirred. The resulting solid was
collected via filtration and dried to afford
1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6-napht-
hyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (87 mg, 33%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.47 (s, 1H),
9.08 (s, 1H), 8.64 (d, J=2.7 Hz, 1H), 8.57 (s, 1H), 8.55 (s, 1H),
8.07 (dd, J=8.4, 2.7 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.79 (s, 1H),
7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.16 (t,
J=8.7 Hz, 2H), 6.94 (t, J=7.3 Hz, 1H), 6.73 (s, 1H), 4.16 (q, J=7.1
Hz, 2H), 2.40 (s, 3H), 2.08 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); MS
(ESI) m/z: 523.2 [M+H].sup.+.
##STR00192##
Example 112
[0421] A mixture of Example A18 (400 mg, 1.191 mmol) and pyridine
(471 mg, 5.96 mmol) in THF (10 mL) was treated drop-wise with
phenyl isocyanate (170 mg, 1.43 mmol) and stirred at RT overnight.
The mixture was treated with EtOAc and 50% satd. NaHCO.sub.3 and
stirred for 2 h. The resulting solid was collected via filtration
and dried to afford
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-diflu-
orophenyl)-3-phenylurea (211 mg, 38% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.07 (br s, 1H), 8.80 (s, 1H), 8.64 (br s,
1H), 8.22-8.15 (m, 2H), 7.74 (s, 1H), 7.46-7.39 (m, 3H), 7.26 (t,
J=7.8 Hz, 2H), 6.96 (t, J=7.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.20
(t, J=7.0 Hz, 3H); MS (ESI) m/z: 455.1 [M+H].sup.+.
[0422] A mixture of
1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-diflu-
orophenyl)-3-phenylurea (211 mg, 0.464 mmol), Cs.sub.2CO.sub.3 (453
mg, 1.392 mmol). N,N-dimethylurea (204 mg, 2.319 mmol) and Xantphos
(81 mg, 0.139 mmol) in dioxane (5 mL) was sparged with Ar, treated
with Pd.sub.2(dba).sub.3 (64 mg, 0.070 mmol) and heated at
100.degree. C. for 4 h. The mixture was cooled to RT, treated with
EtOAc, DMF and 50% satd. NaHCO.sub.3 and the solids removed via
filtration through diatomaceous earth. The layers of the filtrate
were separated, the organic layer washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to dryness and purified via
reverse-phase chromatography (MeCN/H.sub.2O with 0.1% TFA). The
organics were removed under reduced pressure, the aqueous residue
treated with satd. NaHCO.sub.3 and stirred. The resulting solid was
collected via filtration and dried to afford
3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,-
6-naphthyridin-7-yl)-1,1-dimethylurea (47 mg, 33% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.21 (s, 1H), 9.03 (s, 1H),
8.66 (s, 1H), 8.57 (s, 1H), 8.17 (dd, J=9.1, 7.8 Hz, 1H), 8.01 (d,
J=2.1 Hz, 2H), 7.45-7.38 (m, 3H), 7.26 (t, J=7.8 Hz, 2H), 6.96 (t,
J=7.4 Hz, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.97 (s, 6H), 1.24 (t, J=7.1
Hz, 3H); MS (ESI) m/z: 507.2 [M+H].sup.+.
##STR00193##
Example 113
[0423] A suspension of Example A57 (0.210 g, 0.407 mmol) in MeCN (8
mL) was treated with N,N-dimethylazetidin-3-amine dihydrochloride
(0.300 g, 1.733 mmol) followed by 1-methylpyrrolidine (0.150 g,
1.762 mmol) and heated at 70.degree. C. for 3 h. The mixture was
cooled to RT, concentrated to dryness and purified via silica gel
chromatography (MeOH/DCM) to afford
3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)pheny-
l)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide
(160 mg, 70% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.56 (s, 1H), 9.48 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.08 (s,
1H), 7.96 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.42 (dd, J=8.2, 1.2 Hz,
2H), 7.24 (t, J=7.8 Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.93 (t,
J=7.4 Hz, 1H), 4.21-3.91 (m, 6H), 3.32 (m, 1H), 2.73 (s, 6H), 2.07
(s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 558.3
[M+H].sup.+.
##STR00194##
Example 114
[0424] A solution of Example A39 (0.600 g, 1.921 mmol) in dioxane
(4 mL) and pyridine (4 mL) was treated with iodine (1.463 g, 5.76
mmol) and stirred at RT for 2 days. The mixture was treated with
satd. Na.sub.2S.sub.2O.sub.3, stirred for several minutes and
extracted with DCM (4.times.). The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated to
dryness. The residue was treated with MeOH and the resulting solid
was collected via filtration and dried to afford
3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-n-
aphthyridin-2(1H)-one (312 mg, 37% yield). MS (ESI) m/z: 439.0
[M+H].sup.+.
[0425] A suspension of
3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridi-
n-2(1H)-one (0.310 g, 0.707 mmol) in DCM (10 mL) was treated with
phenyl isocyanate (0.100 g, 0.839 mmol) followed by pyridine (0.060
g, 0.759 mmol) and stirred at RT for 3 h. The mixture was
concentrated to dryness and purified via silica gel chromatography
(EtOAc/Hex) to afford
1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2--
fluoro-4-iodophenyl)-3-phenylurea (120 mg, 29% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.66 (s, 1H), 8.41
(s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.64 (s,
1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 7.05 (m, 2H),
6.24 (s, 1H), 4.14 (d, J=8.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.22
(t, J=7.0 Hz, 3H); MS (ESI) m/z: 558.1 [M+H].sup.+.
##STR00195##
Example 115
[0426] A mixture of Example A54 (255 mg, 0.566 mmol), Pd(OAc).sub.2
(6.4 mg, 0.028 mmol), Xantphos (33 mg, 0.057 mmol), K.sub.2CO.sub.3
(117 mg, 0.848 mmol) and 4-amino-1-methylpyrazole (60 mg, 0.622
mmol) in dioxane (4 mL) was sparged with Ar and heated at
99.degree. C. overnight. The mixture was cooled to RT, treated with
EtOAc and DMF and the solids removed via filtration through
diatomaceous earth. The filtrate was concentrated to dryness and
purified via reverse-phase chromatography (MeCN/H.sub.2O with 0.1%
TFA). The organics were removed under reduced pressure, the aqueous
residue treated with satd. NaHCO.sub.3 and extracted with EtOAc
(2.times.). The combined organics were washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-(5-(1-ethyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6-n-
aphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (14 mg, 4%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.11 (s, 1H),
8.96 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 7.92-7.88 (m, 2H), 7.69
(s, 1H), 7.41 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.20 (t, J=7.8 Hz,
2H), 7.08 (d, J=12.3 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 6.46 (s, 1H),
4.07 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 2.02 (s, 3H), 1.17 (t, J=7.0
Hz, 3H); MS (ESI) m/z: 512.2 [M+H].sup.+.
[0427] The following assays demonstrate that certain compounds of
Formula Ia inhibit c-KIT kinase, and mutants thereof, in enzymatic
asssays and also inhibit cKIT kinase in GIST cell lines.
c-KIT kinase Assay
[0428] Activity of c-KIT kinase (Seq ID no. 1) was determined by
following the production of ADP from the kinase reaction through
coupling with the pyruvate kinase/lactate dehydrogenase system
(e.g., Schindler et al. Science (2000) 289: 1938-1942). In this
assay, the oxidation of NADH (measured by decrease in absorbance at
340 nm) was continuously monitored spectrophotometrically. The
reaction mixture (100 .mu.L) contained c-KIT (cKIT residues
T544-V976, 6 nM, polyE4Y (1 mg/mL), MgCl.sub.2 (10 mM), pyruvate
kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol
pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing
0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were
incubated with c-Kit (Seq ID no. 1) and other reaction reagents at
22.degree. C. for .about.30 min before ATP (200 .mu.M) was added to
start the reaction. The absorption at 340 nm was monitored
continuously for 2 hours at 30.degree. C. on Synergy 2 (BioTeK).
The reaction rate was calculated using the 0 to 1 h time frame.
Percent inhibition was obtained by comparison of reaction rate with
that of a control (i.e. with no test compound). IC.sub.50 values
were calculated from a series of percent inhibition values
determined at a range of inhibitor concentrations using software
routines as implemented in the GraphPad Prism software package.
c-KIT Protein Sequence (Seq ID No. 1)
[0429] The protein construct was prepared by deCODE Biostructures
using procedures known in the art. The construct contains residues
T544-V976 of cKit, an N-terminal tag, a GST-fusion sequence and a
TEV cleavage site.
TABLE-US-00001 MEHHHHHHHH EYMPMEMAPI LGYWKIKGLV QPTRLLLEYI
EEKYEEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVK LTQSMAIIRY IADKHNMLGG
CPKERAEISM LEGAVLDIRY GVSRIAYSKD FETLKVDFLS KLPEMLKMFE DRLCHKTYLN
GDHVTHPDFM LYDALDVVLY MDPMCLDAFP KLVCFKKRIE AIPQIDKYLK SSKYIAWPLQ
GWQATFGGGD HPPKSDLVPR HNQTSLYKKA GSAAAVLEEN LYFQGTYKYL QKPMYEVQWK
VVEEINGNNY VYIDPTQLPY DHKWEFPRNR LSFGKTLGAG AFGKVVEATA YGLIKSDAAM
TVAVKMLKPS AHLTEREALM SELKVLSYLG NHMNIVNLLG ACTIGGPTLV ITEYCCYGDL
LNFLRRKRDS FICSKQEDHA EAAIYKNLLH SKESSCSDST NEYMDMKPGV SYVVPTKADK
RRSVRIGSYI ERDVTPAIME DDELALDLED LLSFSYQVAK GMAFLASKNC IHRDLAARNI
LLTHGRITKI CDFGLARDIK NDSNYVVKGN ARLPVKWMAP ESIFNCVYTF ESDVWSYGIF
LWELFSLGSS PYPGMPVDSK FYKMIKEGFR MLSPEHAPAE MYDIMKTCWD ADPLKRPTFK
QIVQLTEKQI SESTNHIYSN LANCSPNRQK PVVDHSVRIN SVGSTASSSQ PLLVHDDV
c-KIT V654A Kinase Assay
[0430] Activity of c-KIT V654A kinase (Seq ID no. 2) was determined
by following the production of ADP from the kinase reaction through
coupling with the pyruvate kinase/lactate dehydrogenase system
(e.g., Schindler et al. Science (2000) 289: 1938-1942). In this
assay, the oxidation of NADH (measured by decrease in absorbance at
340 nm) was continuously monitored spectrophotometrically. The
reaction mixture (100 .mu.l) contained V654A c-Kit (residues
T544-V976 with N-terminal GST fusion, 47 nM), polyE4Y (1 mg/ml),
MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase
(0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and
ATP (200 .mu.M) in 90 mM Tris buffer containing 0.2%
octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was
started by mixing serial diluted test compound with the above
reaction mixture. The absorption at 340 nm was monitored
continuously for 6 hours at 30.degree. C. on Synergy 2 plate reader
(BioTech). Reaction rates around 3 to 5 h time frame were used to
calculate % inhibitions, from which IC.sub.50 values were generated
using GraphPad Prism.
c-KIT (V654A) Protein Sequence (Seq ID No. 2)
[0431] The protein construct was prepared by deCODE Biostructures
using procedures known in the art. The construct contains residues
T544-V976 of cKit, an N-terminal tag, a GST-fusion sequence and a
TEV cleavage site. This construct is identical to Seq ID no. 1
except for the V654A mutation.
TABLE-US-00002 MEHHHHHHHH EYMPMEMAPI LGYWKIKGLV QPTRLLLEYL
EEKYEEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVK LTQSMAIIRY IADKHNMIGG
CPKERAEISM LEGAVLDIRY GVSRIAYSKD FETLKVDFLS KLPEMLKMFE DRLCHKTYLN
GDHVTHPDFM LYDALDVVLY MDPMCLDAFP KLVCFKKRIE AIPQIDKYLK SSKYIAWPLQ
GWQATFGGGD HPPKSDLVPR HNQTSLYKKA GSAAAVLEEN LYFQGTYKYL QKPMYEVQWK
VVEEINGNNY VYIDPTQLPY DHKWEFPRNR LSFGKTLGAG AFGKVVEATA YGLIKSDAAM
TVAVKMLKPS AHLTEREALM SELKVLSYLG NHMNIANLLG ACTIGGPTLV ITEYCCYGDL
LNFLRRKRDS FICSKQEDHA EAALYKNLLH SKESSCSDST NEYMDMKPGV SYVVPTKADK
RRSVRIGSYI ERDVTPAIME DDELALDLED LLSFSYQVAK GMAFLASKNC IHRDLAARNI
LLTHGRITKI CDFGLARDIK NDSNYVVKGN ARLPVKWMAP ESIFNCVYTE ESDVWSYGIF
LWELESLGSS PYPGMPVDSK FYKMIKEGFR MLSPEHAPAE MYDIMKTCWD ADPLKRPTFK
QIVQLIEKQI SESTNHIYSN LANCSPNRQK PVVDHSVRIN SVGSTASSSQ PLLVHDDV
c-KIT D816H Kinase Assay
[0432] The kinase assay for c-KIT D816H kinase (Seq ID no. 3) was
performed using the conditions described above for c-KIT V654A
assay except that 10 nM of c-KIT D816H was used.
c-KIT (D816H) Protein Sequence (Seq ID No. 3)
[0433] The protein construct was prepared by deCODE Biostructures
using procedures known in the art. The construct contains residues
T544-V976 of cKit, an N-terminal tag, a GST-fusion sequence and a
TEV cleavage site. This construct is identical to Seq ID no. 1
except for the D816H mutation.
TABLE-US-00003 MEHHHHHHHH EYMPMEMAPI LGYWKIKGLV QPTRLLLFYL
EEKYFEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVK LTQSMAIIRY IADKHNMLGG
CPKERAEISM LEGAVLDIRY GVSRIAYSKD FETLKVDFLS KLPEMLKMFE DRLCHKTYLN
GDHVTHPDFM LYDALDVVLY MDPMCLDAFP KLVCFKKRIE AIPQIDKYLK SSKYIAWPLQ
GWQATEGGGD HPPKSDLVPR HNQTSLYKKA GSAAAVLEEN LYFQGTYKYL QKPMYEVQWK
VVEEINGNNY VYIDPTQLRY DHKWEFPRNR LSFGKTLGAG AFGKVVEATA YGLIKSDAAM
TVAVKMLKPS AHLTEREALM SELKVLSYLG NHMNIVNLLG ACTIGGPTLV ITEYCCYGDL
LNFLRRKRDS FICSKQEDHA EAALYKNLLH SKESSCSDST NEYMDMKPGV SYVVPTKADK
RRSVRIGSYI ERDVTPAIME DDELALDLED LLSFSYQVAK GMAFLASKNC IHRDLAARNI
LLTHGRITKI CDFGLARHIK NDSNYVVKGN ARLPVKWMAP ESIFNCVYTE ESDVWSYGIF
LWELFSLGSS PYPGMPVDSK FYKMIKEGFP MLSPEHAPAE MYDIMKTCWD ADPLKRPTEK
QIVQLIEKQI SESTNHIYSN LANCSPNRQK PVVDHSVRIN SVGSTASSSQ PLLVHDDV
c-KIT D816V kinase Assay
[0434] Activity of c-KIT D816V kinase (Seq ID no. 4) was determined
by following the production of ADP from the kinase reaction through
coupling with the pyruvate kinase/lactate dehydrogenase system
(e.g., Schindler et al. Science (2000) 289: 1938-1942). In this
assay, the oxidation of NADH (measured by decrease in absorbance at
340 nm) was continuously monitored spectrophotometrically. The
reaction mixture (100 .mu.L) contained D816V c-KIT (residues
T544-V976 with N-terminal GST fusion, 16 nM), polyE4Y (1 mg/mL).
ATP (200 uM), MgCl.sub.2 (10 mM), pyruvate kinase (4 units),
lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM),
NADH (0.28 mM) in 90 mM Tris buffer containing 0.001% Triton-X100
and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing
serial diluted test compound with the above reaction mixture. The
absorption at 340 nm was monitored continuously for 5 hours at
30.degree. C. on Synergy 2 plate reader (BioTech). Reaction rates
around 3 to 4 h time frame were used to calculate % inhibitions,
from which IC.sub.50 values are generated using GraphPad Prism.
c-KIT (D816V) Protein Sequence (Seq ID No. 4)
[0435] The protein construct was prepared by deCODE Biostructures
using procedures known in the art. The construct contains residues
T544-V976 of cKit, an N-terminal tag, a GST-fusion sequence and a
TEV cleavage site. This construct is identical to Seq ID no. 1
except for the DSI16V mutation.
TABLE-US-00004 MEHHHHHHHH EYMPMEMAPI LGYWKIKGLV QPTRLLLEYL
EEKYFEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVK LTQSMAIIRY IADKHNMLGG
CPKERAEISM LEGAVLDIRY GVSRIAYSKD FETLKVDFLS KLPEMLKMFE DRLCHKTYLN
GDHVTHPDFM LYDALDVVLY MDPMCLDAFP KLVCFKKRIE AIPQIDKYLK SSKYIAWPLQ
GWQATFGGGD HPPKSDLVPR HNQTSLYKKA GSAAAVLEEN LYFQGTYKYL QKPMYEVQWK
VVEEINGNNY VYIDPTQLPY DHKWEFPRNR LSFGKTLGAG AFGKVVEATA YGLIKSDAAM
TVAVKMLKPS AHLTEREALM SELKVLSYLG NHMNIVNLLG ACTIGGPTLV ITEYCCYGDL
LNFLRRKRDS FICSKQEDHA EAALYKNLLH SKESSCSDST NEYMDMKPGV SYVVPTKADK
RRSVRIGSYI ERDVTPAIME DDELALDLED LLSFSYQVAK GMAFLASKNC IHRDLAARNI
LLTHGRITKI CDFGLARVIK NDSNYVVKGN ARLPVKWMAP ESIFNCVYTE ESDVKSYGIF
LWELYSLGSS PYPGMPVDSK FYKMIKEGFR MLSPEHAPAE MYDIMKTCWD ADPLKRPTFK
QIVQLIEKQI SESTNHIYSN LANCSPNRQK PVVDHSVRIN SVGSTASSSQ PLLVHDDV
cKIT-VVDV Kinase Assay
[0436] c-KIT-VVDV is a mutant of c-KIT with V559 and V560 deleted
and D816V mutation. The kinase assay for c-KIT VVDV kinase (Seq ID
no. 5) was performed using the conditions described above for the
KIT-D816V assay except that 16 nM of c-KIT-VVDV was used.
c-KIT VVDV Protein Sequence (Seq ID No. 5)
[0437] The protein construct was prepared by deCODE Biostructures
using procedures known in the art. This construct contains residues
T544-V976 of cKit (except for the D816V mutation and the deletion
of residues V559 and V560), an N-terminal tag, a GST-fusion
sequence and a TEV cleavage site. This construct is identical to
Seq ID no. 1 except for the D816V mutation and the deletion of
residues V559 and V560.
TABLE-US-00005 MEHHEHHHHH EYMPMEMAPI LGYWKIKGLV QPTRLLLEYL
EEKYEEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVK LTQSMAIIRY IADKHNMLGG
CPKERAEISM LEGAVLDIRY GVSRIAYSKD FETLKVDFLS KLPEMLKMFE DRLCHKTYLN
GDHVTHPDFM LYDALDVVLY MDPMCLDAFP KLVCFKKRIE AIPQIDKYLK SSKYIAWPLQ
GWQATFGGGD HPPKSDLVPR HNQTSLYKKA GSAAAVLEEN LYFQGTYKYL QKPMYEVQWK
EEINGNNYVY IDPTQLPYDH KWEFPRNRLS FGKTLGAGAF GKVVEATAYG LIKSDAAMTV
AVKMLKPSAH LTEREALMSE LKVISYLGNH MNIVNLLGAC TIGGPTLVIT EYCCYGDLLN
FLRRKRDSFI CSKQEDHAEA ALYKNLLESK ESSCSDSTNE YMDMKPGVSY VVPTKADKRR
SVRIGSYTER DVTPAIMFDD ELALDLFDLL SFSYQVAKGM AFLASKNCIH RDLAARNILL
THGRITKICD FGLARVIKND SNYVVYGNAR LPVKWMAPES IFNCVYTFES DVWSYGIFLW
ELFSLGSSPY PGMPVDSKFY KMIKEGFRML SPEHAPAEMY DIMKTCWDAD PLKRPTFKQI
VQLIFKQTSE STNHIYSNLA NCSPNRQKPV VDHSVRINSV GSTASSSQPIL LVHDDV
c-KIT T670I Kinase Assay
[0438] The kinase assay for c-KIT T670I kinase (Seq ID no. 6) was
performed using the conditions described above for the KIT-D816V
assay except that 25 nM Kit T670I was used in the assay.
cKIT-T670I Protein Sequence (Seq ID No. 6)
[0439] The protein construct was prepared by deCODE Biostructures
using procedures known in the art. The construct contains residues
T544-V976 of cKit, an N-terminal tag, a GST-fusion sequence and a
TEV cleavage site. This construct is identical to Seq ID no. 1
except for the T670I mutation.
TABLE-US-00006 MEHHHHHHHH EYMPMEMAPI LGYWKIKGLV QPIRLLLEYL
EEKYEEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVK LTQSMAIIRY IADKHNMLGG
CPKERAEISM LEGAVLDIRY GVSRIAYSKD FETLKVDELS KLPEMLKMFE DRLCHKTYLN
GDHVTHPDFM LYDALDVVLY MDPMCLDAFP KLVCFKKRIE AIPQIDKYLK SSKYIAWPLQ
GWQATFGGGD HPPKSDLVPR HNQTSLYKKA GSAAAVLEEN LYFQGTYKYL QKPMYEVQWK
VVEEINGNNY VYIDPTQLPY DHKWEFPRNR LSFGKTLGAG AFGKVVEATA YGLIKSDAAM
TVAVKMLKPS AHLTEREALM SELKVLSYLG NHMNIVNLLG ACTIGGPTLV IIEYCCYGDL
LNFLRRKRDS FICSKQEDHA EAALYKNLLH SKESSCSDST NEYMDMKPGV SYVVPTKADK
RRSVRIGSYI ERDVTPAIME DDELALDLED LLSFSYQVAK GMAFLASKNC IHRDLAARNI
LLTHGRITKI CDFGLARDIK NDSNYVVKGN ARLPVKWMAP ESIPNCVYTE ESDVWSYGIF
LWELFSLGSS PYPGMPVDSK FYKMIKEGFR MLSPEHAPAE MYDIMKTCWD ADPLKRPTFK
QIVQLIEKQI SESTNHIYSN LANCSPNRQK PVVDHSVRIN SVGSTASSSQ PLLVHDDV
[0440] Using the enzymatic protocols described above, compounds of
Formula Ia are shown to be inhibitors in assays measuring the
kinase activity of KIT kinase, V654A KIT kinase, D816H KIT kinase,
D816V KIT kinase, a KIT kinase mutant containing V559+V560
deletions in addition to a D816V mutation (KIT-VVDV), and T670I KIT
kinase, as indicated below in Table 1.
TABLE-US-00007 TABLE 1 Activity of Compounds of Formula Ia in
Enyzmatic Assays of KIT kinase and mutant forms of KIT kinase. Ex
No KIT (wt) KIT-V654A KIT-D816H KIT-D816V KIT-VVDV KIT-T670I 1 ++++
NT +++ +++ +++ ++++ 2 NT NT NT ++ ++ ++++ 3 ++++ ++++ ++++ +++ ++++
+++ 4 ++++ ++++ ++++ +++ ++++ +++ 5 NT NT NT ++ ++ NT 6 ++++ +++
+++ +++ ++++ ++++ 7 NT NT NT +++ +++ +++ 8 NT NT NT +++ ++ +++ 9
++++ NT NT +++ +++ +++ 10 NT NT NT +++ +++ +++ 11 NT NT NT + NT NT
12 NT NT NT + ++ NT 13 NT NT NT +++ ++++ +++ 14 NT NT NT +++ +++
++++ 15 ++++ ++++ +++ +++ +++ +++ 16 ++++ ++++ +++ +++ +++ +++ 17
NT NT NT +++ ++ NT 18 ++++ NT NT ++ +++ +++ 19 ++++ NT NT ++++ +++
NT 20 ++++ +++ ++++ ++++ ++++ ++++ 21 ++++ ++++ ++++ +++ ++++ ++++
22 ++++ +++ +++ ++++ ++++ ++ 23 ++++ ++++ +++ +++ +++ +++ 24 ++++
++++ ++++ ++++ ++++ ++++ 25 ++++ ++++ +++ +++ ++++ ++++ 26 +++ NT
NT + + NT 27 ++++ +++ +++ +++ +++ +++ 28 +++ ++++ +++ +++ +++ +++
29 +++ NT NT ++ NT ++ 30 ++++ +++ ++ +++ +++ +++ 31 ++++ ++++ ++++
+++ ++++ +++ 32 ++++ +++ ++++ ++++ ++++ +++ 33 ++++ ++++ +++ +++ ++
++ 34 ++++ +++ +++ +++ NT +++ 35 ++++ +++ +++ +++ NT ++ 36 ++++ +++
+++ +++ +++ ++ 37 ++++ +++ +++ +++ NT ++ 38 ++++ NT +++ +++ NT ++
39 ++++ NT NT +++ NT +++ 40 ++++ +++ +++ +++ ++ ++ 41 ++++ +++ ++++
+++ NT + 42 +++ NT NT +++ NT ++ 43 +++ NT NT ++ NT ++ 44 ++++ +++
++++ +++ +++ +++ 45 ++++ +++ +++ +++ + +++ 46 +++ NT NT ++ NT + 47
++++ NT NT +++ NT + 48 +++ NT NT ++ NT + 49 +++ NT NT ++ NT ++ 50
++++ +++ +++ +++ ++ +++ 51 +++ +++ NT ++ ++ + 52 ++++ NT ++ NT NT
NT 53 ++++ +++ NT ++++ ++++ +++ 54 ++++ +++ ++++ ++++ ++++ +++ 55
+++ +++ ++++ +++ +++ +++ 56 ++++ NT NT +++ NT ++ 57 ++++ +++ +++ ++
NT ++++ 58 ++++ ++++ ++++ +++ NT +++ 59 +++ +++ +++ +++ +++ +++ 60
++++ +++ +++ +++ +++ ++ 61 ++++ +++ ++ +++ ++++ ++++ 62 ++++ NT NT
++ NT ++++ 63 ++++ ++++ NT +++ NT +++ 64 +++ NT NT ++ NT ++ 65 ++++
NT NT +++ NT +++ 66 ++++ NT NT +++ NT +++ 67 +++ +++ ++++ ++++ NT
++++ 68 ++++ +++ NT +++ NT +++ 69 +++ +++ NT ++ NT +++ 70 ++++ +++
+++ ++++ ++++ ++++ 71 +++ +++ NT ++ NT +++ 72 ++++ ++ NT +++ NT
++++ 73 +++ +++ +++ ++++ ++++ +++ 74 ++++ NT NT ++++ NT +++ 75 ++++
NT ++ ++ NT +++ 76 ++++ NT NT +++ NT ++ 77 ++++ +++ +++ ++++ NT ++
78 ++++ NT NT +++ NT +++ 79 ++++ ++ +++ ++ + +++ 80 ++++ NT ++++
+++ NT +++ 81 ++++ +++ ++++ +++ NT +++ 82 +++ NT NT ++ NT ++ 83
++++ NT NT ++ NT ++ 84 ++++ ++ +++ +++ NT +++ 85 +++ NT NT +++ NT
++ 86 ++++ +++ NT ++++ NT +++ 87 ++++ ++ +++ ++ NT +++ 88 ++++ +++
+++ ++ NT +++ 89 +++ ++ +++ ++ NT +++ 90 ++++ NT +++ + NT +++ 91
++++ +++ +++ +++ NT +++ 92 ++++ ++++ +++ +++ NT +++ 93 +++ ++ +++
++ NT +++ 94 ++++ NT NT + NT +++ 95 ++++ NT NT ++ NT +++ 96 ++++
+++ +++ +++ NT +++ 97 ++++ NT +++ + NT +++ 98 +++ +++ +++ ++++ NT
+++ 99 ++++ +++ +++ ++++ NT +++ 100 +++ ++ ++ ++ NT ++ 101 +++ +++
+++ +++ NT +++ 102 ++++ +++ +++ +++ NT +++ 103 +++ +++ +++ ++++ NT
+++ 104 +++ ++ +++ +++ NT +++ 105 +++ +++ +++ +++ NT +++ 106 +++
+++ ++++ +++ NT +++ 107 +++ NT NT + NT +++ 108 +++ ++ +++ +++ NT
+++ 109 +++ +++ +++ +++ NT +++ 110 +++ +++ +++ +++ NT +++ 111 +++
NT NT +++ NT ++ 112 ++++ NT ++++ +++ NT ++++ 113 +++ ++ ++++ +++ NT
+++ 114 +++ NT NT ++ NT + 115 ++++ +++ ++++ ++++ NT +++ NT: Not
Tested; +: IC.sub.50 > 1 uM; ++: 0.1 uM < IC.sub.50 .ltoreq.
1 uM; +++: 0.01 uM < IC.sub.50 .ltoreq. 0.1 uM; ++++: IC.sub.50
.ltoreq. 0.01 uM
GIST Cell Culture
[0441] GIST48, GIST430, and GIST882 cells were obtained from J.
Fletcher (Brigham and Women's Hospital, Boston, Mass.). GIST T1
cells were obtained from B. Rubin (Cleveland Clinic, Cleveland,
Ohio) and Professor Takahiro Taguchi (Kochi Medical School,
Nankoku, Kochi, Japan). Briefly, GIST48 and GIST 882 cells were
grown in RPMI 1640 medium supplemented with 15% characterized fetal
bovine serum (Invitrogen. Carlsbad, Calif.). 1 unitimL penicillin
G, 1 .mu.g/ml streptomycin, and 0.29 mg/mL L-glutamine at
37.degree. C., 5% CO.sub.2, and 95% humidity. GIST430 cells were
grown in Ham's F10 medium supplemented with 15% characterized fetal
bovine serum (Invitrogen, Carlsbad, Calif.), 30 mg/L bovine
pituitary extract (BD Biosciences. San Jose, Calif.), 0.5%
Mito+serum extender (BD Biosciences, San Jose, Calif.), 1 unit/mL
penicillin G, 1 .mu.g/ml streptomycin, and 0.29 mg/mL L-glutamine
at 37.degree. C., 5% CO.sub.2, 95% humidity. GIST T1 cells were
grown in DMEM medium supplemented with 10% characterized fetal
bovine serum (Invitrogen. Carlsbad, Calif.), 1 unit/mL penicillin
G, 1 .mu.g/ml streptomycin, and 0.29 mg/mL L-glutamine at
37.degree. C., 5% CO.sub.2, and 95% humidity. Cells were allowed to
expand until reaching 70-95% confluence at which point they were
subcultured or harvested for assay use.
GIST48 KIT Western Blot
[0442] Two hundred fifty thousand cells were added per well in a
24-well tissue-culture treated plate. Cells were then incubated
overnight at 37.degree. C., 5% CO.sub.2, 95% humidity. Medium was
aspirated, cells were washed with PBS, and serum-free RPMI1640
medium was added. A serial dilution of test compound was added to
plates containing cells and plates were incubated for 4 hours at
37.degree. C., 5% CO.sub.2. 95% humidity. Cells were washed with
PBS, then lysed. Cell lysates were separated by SDS-PAGE and
transferred to PVDF. Phospho-KIT (Tyr719) was detected using an
antibody from Cell Signaling Technology (Beverly, Mass.), ECL Plus
detection reagent (GE Healthcare, Piscataway, N.J.) and a Molecular
Devices Storm 840 phosphorimager in fluorescence mode. Blots were
stripped and probed for total KIT using an antibody from Santa Cruz
Biotech (Santa Cruz, Calif.). IC.sub.50 values were calculated
using Prism software (Graphpad, San Diego, Calif.).
GIST430 KIT Western Blot
[0443] One hundred fifty thousand cells were added per well in a
24-well tissue-culture treated plate. Cells were then incubated
overnight at 37.degree. C., 5% CO.sub.2, 95% humidity. Medium was
aspirated, cells were washed with PBS, and serum-free Ham's F10
medium was added. A serial dilution of test compound was added to
plates containing cells and plates were incubated for 4 hours at
37.degree. C., 5% CO.sub.2, 95% humidity. Cells were washed with
PBS, then lysed. Cell lysates were separated by SDS-PAGE and
transferred to PVDF. Phospho-KIT (Tyr719) was detected using an
antibody from Cell Signaling Technology (Beverly, Mass.), ECL Plus
detection reagent (GE Healthcare, Piscataway, N.J.) and a Molecular
Devices Storm 840 phosphorimager in fluorescence mode. Blots were
stripped and probed for total KIT using an antibody from Santa Cruz
Biotech (Santa Cruz, Calif.). IC.sub.50 values were calculated
using Prism software (Graphpad, San Diego, Calif.).
GIST 430 Cell Proliferation Assay
[0444] A serial dilution of test compound was dispensed into a
384-well black clear bottom plate (Corning, Corning, N.Y.). Two
thousand five-hundred cells were added per well in 50 .mu.L
complete growth medium. Plates were incubated for 115 hours at
37.degree. C., 5% CO.sub.2, 95% humidity. At the end of the
incubation period 10 .mu.L of a 440 .mu.M solution of resazurin
(Sigma, St. Louis, Mo.) in PBS was added to each well and incubated
for an additional 5 hours at 37.degree. C., 5% CO.sub.2, 95%
humidity. Plates were read on a Synergy2 reader (Biotek, Winooski,
Vt.) using an excitation of 540 nM and an emission of 600 nM. Data
was analyzed using Prism software (Graphpad, San Diego, Calif.) to
calculate IC.sub.50 values.
GIST882 KIT Western Blot
[0445] Two hundred fifty thousand cells were added per well in a
24-well tissue-culture treated plate. Cells were then incubated
overnight at 37.degree. C., 5% CO.sub.2, 95% humidity. Medium was
aspirated, cells were washed with PBS, and serum-free RPMI1640
medium was added. A serial dilution of test compound was added to
plates containing cells and plates were incubated for 4 hours at
37.degree. C., 5% CO.sub.2, 95% humidity. Cells were washed with
PBS, then lysed. Cell lysates were separated by SDS-PAGE and
transferred to PVDF. Phospho-KIT (Tyr719) was detected using an
antibody from Cell Signaling Technology (Beverly, Mass.), ECL Plus
detection reagent (GE Healthcare, Piscataway, N.J.) and a Molecular
Devices Storm 840 phosphorimager in fluorescence mode. Blots were
stripped and probed for total KIT using an antibody from Santa Cruz
Biotech (Santa Cruz, Calif.). IC.sub.50 values were calculated
using Prism software (Graphpad, San Diego, Calif.).
GIST T1 KIT Western Blot
[0446] One hundred twenty-five thousand cells were added per well
in a 24-well tissue-culture treated plate. Cells were then
incubated overnight at 37.degree. C., 5% CO.sub.2, 95% humidity.
Medium was aspirated, cells were washed with PBS, and serum-free
DMEM medium was added. A serial dilution of test compound was added
to plates containing cells and plates were incubated for 4 hours at
37.degree. C., 5% CO.sub.2, 95% humidity. Cells were washed with
PBS, then lysed. Cell lysates were separated by SDS-PAGE and
transferred to PVDF. Phospho-KIT (Tyr719) was detected using an
antibody from Cell Signaling Technology (Beverly, Mass.), ECL Plus
detection reagent (GE Healthcare, Piscataway, N.J.) and a Molecular
Devices Storm 840 phosphorimager in fluorescence mode. Blots were
stripped and probed for total KIT using an antibody from Santa Cruz
Biotech (Santa Cruz, Calif.). IC.sub.50 values were calculated
using Prism software (Graphpad, San Diego, Calif.).
GIST T1 Cell Proliferation Assay
[0447] A serial dilution of test compound was dispensed into a
384-well black clear bottom plate (Corning, Corning, N.Y.). One
thousand two-hundred fifty cells were added per well in 50 .mu.L
complete growth medium. Plates were incubated for 68 hours at
37.degree. C. 5% CO.sub.2, 95% humidity. At the end of the
incubation period 10 .mu.L of a 440 .mu.M solution of resazurin
(Sigma, St. Louis, Mo.) in PBS was added to each well and incubated
for an additional 4 hours at 37.degree. C., 5% CO.sub.2, 95%
humidity. Plates were read on a Synergy2 reader (Biotek, Winooski,
Vt.) using an excitation of 540 nM and an emission of 600 nM. Data
was analyzed using Prism software (Graphpad. San Diego, Calif.) to
calculate IC.sub.50 values.
[0448] In the cellular assays described above, the compounds of
formula Ia are demonstrated to suppress levels of phospho-KIT
(autophosphrorylation) in one or more GIST cell lines by western
blot analysis, as indicated in Table 2. Additionally or
alternately, compounds of formula Ia show antiproliferative effects
in GIST cell lines, as measured by reduction of cellular
proliferation in Table 2.
TABLE-US-00008 TABLE 2 Inhibitory effects of compounds of formula
Ia versus GIST cell lines Cell Proliferation Ex pKIT suppression by
western blot analysi GIST No GIST430 GIST48 GIST T1 GIST 882
GIST430 T1 1 ++++ +++ NT ++ NT NT 3 +++ ++ ++++ +++ +++ ++++ 4 +++
+++ NT ++++ NT ++++ 6 ++++ ++++ +++ +++ NT +++ 14 +++ ++++ NT ++++
NT NT 15 +++ +++ NT +++ NT NT 16 ++ ++ NT +++ NT NT 17 +++ +++ NT
NT NT NT 20 +++ ++ ++++ +++ NT NT 21 ++++ +++ ++++ +++ NT ++++ 22
+++ +++ ++++ +++ NT ++++ 23 +++ ++ ++++ +++ +++ ++++ 24 ++++ +++
++++ +++ NT ++++ 25 +++ +++ NT +++ NT ++++ 27 +++ +++ NT ++ ++ NT
28 +++ ++ ++++ +++ NT +++ 30 +++ ++ ++++ NT NT NT 31 ++++ +++ ++++
++ +++ ++++ 32 ++++ ++++ ++++ +++ +++ ++++ 33 +++ NT NT NT NT NT 36
++ ++ NT NT NT NT 38 +++ + NT NT +++ ++++ 39 NT NT NT NT +++ NT 40
NT NT NT NT ++ ++++ 41 +++ ++ NT NT NT NT 44 ++++ +++ ++++ +++ +++
++++ 50 ++++ ++ ++++ +++ NT +++ 51 +++ ++ NT +++ NT ++++ 53 ++++ ++
NT +++ NT ++++ 54 +++ +++ ++++ +++ NT ++++ 55 +++ + NT +++ NT ++++
57 +++ ++ ++++ ++ NT ++++ 58 +++ ++ NT ++ NT ++++ 59 +++ +++ ++++
+++ NT +++ 60 +++ + NT NT NT +++ 61 +++ + NT NT NT ++++ 63 +++ ++
NT NT NT ++++ 66 +++ ++ NT NT NT ++++ 67 ++++ ++++ NT +++ NT ++++
68 +++ ++ NT NT NT ++++ 70 ++++ +++ ++++ +++ NT ++++ 73 +++ +++ NT
+++ NT +++ 77 +++ +++ NT +++ NT ++++ 79 +++ +++ NT + NT ++++ 81 +++
+++ NT +++ NT ++++ 84 +++ +++ NT +++ NT NT 86 +++ ++++ NT ++++ NT
++++ 87 ++ +++ NT ++ NT +++ 88 +++ +++ ++++ ++ NT ++++ 97 NT NT NT
NT NT ++++ 93 NT NT NT NT NT +++ 95 NT NT NT NT NT ++++ 96 NT NT NT
NT NT ++++ 97 NT NT NT NT NT ++++ 98 NT NT NT NT NT ++++ 99 NT NT
NT NT NT ++++ 100 NT NT NT NT NT +++ 101 +++ + NT ++ NT ++++ 102
+++ +++ NT NT NT ++++ 103 NT NT NT NT NT +++ 104 NT NT NT NT NT +++
105 NT NT NT NT NT ++++ 106 NT NT NT NT NT ++++ 107 NT NT NT NT NT
+++ 108 +++ ++ NT NT NT NT 109 NT +++ NT NT NT NT 110 NT ++++ NT NT
NT NT NT: Not Tested, +: IC.sub.50 > 1 uM; ++: 0.1 uM <
IC.sub.50 .ltoreq. 1 uM; +++: 0.01 uM < IC.sub.50 .ltoreq. 0.1
uM; ++++: IC.sub.50 .ltoreq. 0.01 uM
CHO K1 Cell Culture
[0449] CHO K1 cells (catalog #CCL-61) were obtained from the
American Type Culture Collection, Manassas, Va. Briefly, cells were
grown in RPMI 1640 supplemented with 10% characterized fetal bovine
serum and 1% Penicillin-streptomycin-L-glutamine solution
(Invitrogen, Carlsbad. Calif.) at 37 degrees Celsius, 5% CO.sub.2,
95% RH. Cells were allowed to expand until reaching 70-95%
confluency at which point they were subcultured or harvested for
assay use.
CHO K1 Phospho-KIT ELISA
[0450] Forty thousand cells in RPMI 1640 supplemented with 10%
characterized fetal bovine serum and 1% MEM Non-essential amino
acids (Invitrogen, Carlsbad, Calif.) were added to each well of a
24-well tissue-culture treated plate (Nunc, Rochester, N.Y.). Cells
were then incubated overnight at 37.degree. C., 5% CO.sub.2, 95%
RH. Transfection-grade pcDNA3.2 V5 DEST expression vector
containing KIT variant, Lipofectamine LTX Reagent, and PLUS reagent
(Invitrogen, Carlsbad, Calif.) were diluted into Opti-MEM.RTM. I
medium (Invitrogen, Carlsbad, Calif.). The tube was incubated at
room temperature to allow formation of DNA-Lipofectamine LTX
complexes. The DNA-lipofectamine LTX complex mix was added directly
to each well and mixed gently. Eighteen hours post-transfection,
medium was replaced with serum-free RPMI medium. A serial dilution
of test compound was added, and plates were incubated for 4 hours
at 37.degree. C., 5% CO.sub.2, 95% RH. Cell lysates were prepared,
then phospho-c-KIT (Tyr719) was measured by using a Human
phospho-c-KIT ELISA kit (Cell Signaling, Beverly. Mass.). Data was
analyzed using Prism software (Graphpad, San Diego, Calif.) to
calculate IC.sub.50 values.
Plasmid DNA Constructs (pcDNA 3.2 V5 DEST Expression Vector) AY502
duplication/N882K KIT AY502 duplication/D820E KIT AY502
duplication/D816G KIT AY502 duplication/D820G KIT AY502
duplication/N822Y KIT AY502 duplication/N822H KIT WKV557-559
deletion/C557insertion/D820Y WKV557-559
deletion/C557insertion/D820A
V560D/N822K
V560D/Y823D
CHO K1 Phospho-KIT Western
[0451] One-hundred thousand cells in RPMI 1640 supplemented with
10% characterized fetal bovine serum and 1% MEM Non-essential amino
acids (Invitrogen, Carlsbad, Calif.) were added to each well of a
24-well tissue-culture treated plate (Nunc, Rochester, N.Y.). Cells
were then incubated overnight at 37.degree. C., 5% CO.sub.2, 95%
RH. Transfection-grade pcDNA3.2 V5 DEST expression vector
containing KIT variant and Lipofectamine LTX Reagent (Invitrogen,
Carlsbad, Calif.) were diluted into Opti-MEM.RTM. I medium
(Invitrogen, Carlsbad, Calif.). The tube was incubated at room
temperature to allow formation of DNA-Lipofectamine LTX complexes.
The DNA-lipofectamine LTX complex mix was added directly to each
well and mixed gently. Eighteen hours post-transfection, medium was
replaced with serum-free RPMI medium. A serial dilution of test
compound was added, and plates were incubated for 4 hours at
37.degree. C., 5% CO.sub.2, 95% RH. Cells were washed with PBS,
then lysed. Cell lysates were separated by SDS-PAGE and transferred
to PVDF. Phospho-KIT (Tyr719) was detected using an antibody from
Cell Signaling Technology (Beverly, Mass.), ECL Plus detection
reagent (GE Healthcare, Piscataway. N.J.) and a Molecular Devices
Storm 840 phosphorimager in fluorescence mode. Blots were stripped
and probed for total KIT using an antibody from Santa Cruz Biotech
(Santa Cruz, Calif.). IC.sub.50 values were calculated using Prism
software (Graphpad, San Diego, Calif.).
Plasmid DNA Constructs (pcDNA 3.2 V5 DEST Expression Vector)
D816V KIT
D820A KIT
[0452] VV559-560 deletion/D816V KIT
[0453] GIST most often become Gleevec.RTM. (imatinib) resistant,
and molecularly targeted small molecule therapies that target c-KIT
secondary mutations remain elusive. GIST patients who relapse after
treatment with Gleevec.RTM. (imatinib) or Sutent.RTM. (sunitinib)
have disease still driven by c-KIT mutations. These secondary
mutations occur on the same alleles as the primary JM-region
mutation, and thus represent even more aggressive activated forms
of c-KIT than the original primary mutation. The CHO K1 cellular
assays described above demonstrate that certain compounds of the
present invention inhibit many mutant forms of cKIT kinase that
have been detected in GIST patients that have acquired resistance
to imatinib or sunitinib treatment (Table 3).
TABLE-US-00009 TABLE 3 Activity of compounds against KIT Exon 17
primary or secondary mutations in transient transfected CHO K1
cells KIT kinase domain mutations Compound (primary/secondary)
Imatinib Sunitinib Ex 23 Ex 31 Ex 59 D816V + + + ++ ++++ D820A + +
+++ +++ +++ VV559-560 deletion/D816V + + ++ ++ +++ V560D/N822K + +
+++ +++ ++++ V560D/Y823D + ++ ++++ +++ ++++ AY502 duplication/D816G
+ NT +++ +++ NT AY502 duplication/D820E + NT NT +++ NT AY502
duplication/D820G + NT NT +++ NT AY502 duplication/N822H + NT NT
+++ NT AY502 duplication/N822K + NT NT +++ NT AY502
duplication/N822Y + NT NT +++ NT WKV557-559 deletion;
C557insertion/D820A + + +++ ++++ ++++ WKV557-559 deletion;
C557insertion/D820Y + NT NT ++++ NT NT: Not Tested +: IC.sub.50
> 1 uM; ++: 0.1 uM < IC.sub.50 .ltoreq. 1 uM; +++: 0.01 uM
< IC.sub.50 .ltoreq. 0.1 uM; ++++: IC.sub.50 .ltoreq. 0.01
uM
[0454] The compounds described in the present invention useful for
the treatment of c-KIT kinase-mediated diseases are structurally
related to compounds previously disclosed in WO2008/034008 as
inhibitors of the RAF-MEK-ERK pathway, more specifically as
inhibitors of RAF kinases. The use of the compounds of
WO2008/034008 as inhibitors of c-KIT kinase, however, was
unexpected, and hence not contemplated in WO2008/034008. Thus, the
unanticipated ability of the compounds to inhibit c-KIT, and more
importantly the oncogenic mutant forms of c-KIT kinase described
herein, constitutes a novel invention. Furthermore, it is not
obvious that inhibitors of RAF kinases should also potently inhibit
c-KIT kinase, as evidenced by the data below illustrating the
differential kinase inhibitory profile of marketed cKIT inhibitors
Imatinib.RTM. and Sunitinib.RTM. and marketed BRAF inhibitor
Vemurafenib.RTM..
TABLE-US-00010 BRAF(V600E) kinase c-KIT kinase IC.sub.50 (nM)
IC.sub.50 (nM) Imatinib .RTM. >50,000 14 Sunitinib .RTM. 5,000 6
Vemurafenib .RTM. 6 1,600
Sequence CWU 1
1
61676PRTArtificial SequenceSynthetic Polypeptide 1Leu Gly Tyr Trp
Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu 1 5 10 15 Leu Glu
Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp 20 25 30
Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe 35
40 45 Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln
Ser 50 55 60 Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met
Leu Gly Gly 65 70 75 80 Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu
Glu Gly Ala Val Asp 85 90 95 Ile Arg Tyr Gly Val Ser Arg Ile Ala
Tyr Ser Lys Asp Phe Glu Thr 100 105 110 Leu Lys Val Asp Phe Leu Ser
Lys Leu Pro Glu Met Leu Lys Met Phe 115 120 125 Glu Asp Arg Leu Cys
His Lys Thr Tyr Leu Asn Gly Asp His Val Thr 130 135 140 His Pro Asp
Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met 145 150 155 160
Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys 165
170 175 Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser
Lys 180 185 190 Tyr Ile Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly
Gly Gly Asp 195 200 205 His Pro Pro Lys Ser Asp Leu Val Pro Arg His
Asn Gln Thr Ser Leu 210 215 220 Tyr Lys Lys Ala Gly Ser Ala Ala Ala
Val Leu Glu Glu Asn Leu Tyr 225 230 235 240 Phe Gln Gly Thr Tyr Lys
Tyr Leu Gln Lys Pro Met Tyr Glu Val Gln 245 250 255 Trp Lys Val Val
Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp 260 265 270 Pro Thr
Gln Leu Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg 275 280 285
Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val 290
295 300 Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr
Val 305 310 315 320 Ala Val Lys Met Leu Lys Pro Ser Ala His Leu Thr
Glu Arg Glu Ala 325 330 335 Leu Met Ser Glu Leu Lys Val Leu Ser Tyr
Leu Gly Asn His Met Asn 340 345 350 Ile Val Asn Leu Leu Gly Ala Cys
Thr Ile Gly Gly Pro Thr Leu Val 355 360 365 Ile Thr Glu Tyr Cys Cys
Tyr Gly Asp Leu Leu Asn Phe Leu Arg Arg 370 375 380 Lys Arg Asp Ser
Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu Ala 385 390 395 400 Ala
Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser Asp 405 410
415 Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val
420 425 430 Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile Gly Ser
Tyr Ile 435 440 445 Glu Arg Asp Val Thr Pro Ala Ile Met Glu Asp Asp
Glu Leu Ala Leu 450 455 460 Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr
Gln Val Ala Lys Gly Met 465 470 475 480 Ala Phe Leu Ala Ser Lys Asn
Cys Ile His Arg Asp Leu Ala Ala Arg 485 490 495 Asn Ile Leu Leu Thr
His Gly Arg Ile Thr Lys Ile Cys Asp Phe Gly 500 505 510 Leu Ala Arg
Asp Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly Asn 515 520 525 Ala
Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Cys 530 535
540 Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu Trp
545 550 555 560 Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro Gly Met
Pro Val Asp 565 570 575 Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly Phe
Arg Met Leu Ser Pro 580 585 590 Glu His Ala Pro Ala Glu Met Tyr Asp
Ile Met Lys Thr Cys Trp Asp 595 600 605 Ala Asp Pro Leu Lys Arg Pro
Thr Phe Lys Gln Ile Val Gln Leu Ile 610 615 620 Glu Lys Gln Ile Ser
Glu Ser Thr Asn His Ile Tyr Ser Asn Leu Ala 625 630 635 640 Asn Cys
Ser Pro Asn Arg Gln Lys Pro Val Val Asp His Ser Val Arg 645 650 655
Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val 660
665 670 His Asp Asp Val 675 2469PRTArtificial SequenceSynthetic
Polypeptide 2Met Ser Tyr Tyr His His His His His His Asp Tyr Asp
Ile Pro Thr 1 5 10 15 Thr Glu Asn Leu Tyr Phe Gln Gly Ala Met Leu
Val Pro Arg Gly Ser 20 25 30 Pro Trp Gly Ser Thr Tyr Lys Tyr Leu
Gln Lys Pro Met Tyr Glu Val 35 40 45 Gln Trp Lys Val Val Glu Glu
Ile Asn Gly Asn Asn Tyr Val Tyr Ile 50 55 60 Asp Pro Thr Gln Leu
Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn 65 70 75 80 Arg Leu Ser
Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val 85 90 95 Val
Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr 100 105
110 Val Ala Val Lys Met Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu
115 120 125 Ala Leu Met Ser Glu Leu Lys Val Leu Ser Tyr Leu Gly Asn
His Met 130 135 140 Asn Ile Ala Asn Leu Leu Gly Ala Cys Thr Ile Gly
Gly Pro Thr Leu 145 150 155 160 Val Ile Thr Glu Tyr Cys Cys Tyr Gly
Asp Leu Leu Asn Phe Leu Arg 165 170 175 Arg Lys Arg Asp Ser Phe Ile
Cys Ser Lys Gln Glu Asp His Ala Glu 180 185 190 Ala Ala Leu Tyr Lys
Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser 195 200 205 Asp Ser Thr
Asn Glu Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val 210 215 220 Val
Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr 225 230
235 240 Ile Glu Arg Asp Val Thr Pro Ala Ile Met Glu Asp Asp Glu Leu
Ala 245 250 255 Leu Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr Gln Val
Ala Lys Gly 260 265 270 Met Ala Phe Leu Ala Ser Lys Asn Cys Ile His
Arg Asp Leu Ala Ala 275 280 285 Arg Asn Ile Leu Leu Thr His Gly Arg
Ile Thr Lys Ile Cys Asp Phe 290 295 300 Gly Leu Ala Arg Asp Ile Lys
Asn Asp Ser Asn Tyr Val Val Lys Gly 305 310 315 320 Asn Ala Arg Leu
Pro Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn 325 330 335 Cys Val
Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu 340 345 350
Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val 355
360 365 Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly Phe Arg Met Leu
Ser 370 375 380 Pro Glu His Ala Pro Ala Glu Met Tyr Asp Ile Met Lys
Thr Cys Trp 385 390 395 400 Asp Ala Asp Pro Leu Lys Arg Pro Thr Phe
Lys Gln Ile Val Gln Leu 405 410 415 Ile Glu Lys Gln Ile Ser Glu Ser
Thr Asn His Ile Tyr Ser Asn Leu 420 425 430 Ala Asn Cys Ser Pro Asn
Arg Gln Lys Pro Val Val Asp His Ser Val 435 440 445 Arg Ile Asn Ser
Val Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu 450 455 460 Val His
Asp Asp Val 465 3620PRTArtificial SequenceSynthetic Polypeptide
3Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1
5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His
Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys
Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile
Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg
Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys
Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp
Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe
Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met
Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135
140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe
Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro
Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp
Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His
Pro Pro Lys Ser Asp Leu Glu Val Leu 210 215 220 Phe Gln Gly Pro Glu
Phe Lys Gly Leu Arg Arg Gln Thr Tyr Lys Tyr 225 230 235 240 Leu Gln
Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val Glu Glu Ile 245 250 255
Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu Pro Tyr Asp 260
265 270 His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr
Leu 275 280 285 Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala
Tyr Gly Leu 290 295 300 Ile Lys Ser Asp Ala Ala Met Thr Val Ala Val
Lys Met Leu Lys Pro 305 310 315 320 Ser Ala His Leu Thr Glu Arg Glu
Ala Leu Met Ser Glu Leu Lys Val 325 330 335 Leu Ser Tyr Leu Gly Asn
His Met Asn Ile Val Asn Leu Leu Gly Ala 340 345 350 Cys Thr Ile Gly
Gly Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys Tyr 355 360 365 Gly Asp
Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser Phe Ile Cys 370 375 380
Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu 385
390 395 400 His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu Tyr
Met Asp 405 410 415 Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys
Ala Asp Lys Arg 420 425 430 Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu
Arg Asp Val Thr Pro Ala 435 440 445 Ile Met Glu Asp Asp Glu Leu Ala
Leu Asp Leu Glu Asp Leu Leu Ser 450 455 460 Phe Ser Tyr Gln Val Ala
Lys Gly Met Ala Phe Leu Ala Ser Lys Asn 465 470 475 480 Cys Ile His
Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Thr His Gly 485 490 495 Arg
Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg His Ile Lys Asn 500 505
510 Asp Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro Val Lys Trp
515 520 525 Met Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe Glu
Ser Asp 530 535 540 Val Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe
Ser Leu Gly Ser 545 550 555 560 Ser Pro Tyr Pro Gly Met Pro Val Asp
Ser Lys Phe Tyr Lys Met Ile 565 570 575 Lys Glu Gly Phe Arg Met Leu
Ser Pro Glu His Ala Pro Ala Glu Met 580 585 590 Tyr Asp Ile Met Lys
Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro 595 600 605 Thr Phe Lys
Gln Ile Val Gln Leu Ile Glu Lys Gln 610 615 620 4698PRTArtificial
SequenceSynthetic Polypeptide 4Met Glu His His His His His His His
His Glu Tyr Met Pro Met Glu 1 5 10 15 Met Ala Pro Ile Leu Gly Tyr
Trp Lys Ile Lys Gly Leu Val Gln Pro 20 25 30 Thr Arg Leu Leu Leu
Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 35 40 45 Tyr Glu Arg
Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 50 55 60 Gly
Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 65 70
75 80 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His
Asn 85 90 95 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser
Met Leu Glu 100 105 110 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser
Arg Ile Ala Tyr Ser 115 120 125 Lys Asp Phe Glu Thr Leu Lys Val Asp
Phe Leu Ser Lys Leu Pro Glu 130 135 140 Met Leu Lys Met Phe Glu Asp
Arg Leu Cys His Lys Thr Tyr Leu Asn 145 150 155 160 Gly Asp His Val
Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 165 170 175 Val Val
Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 180 185 190
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 195
200 205 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln
Ala 210 215 220 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu
Val Pro Arg 225 230 235 240 His Asn Gln Thr Ser Leu Tyr Lys Lys Ala
Gly Ser Ala Ala Ala Val 245 250 255 Leu Glu Glu Asn Leu Tyr Phe Gln
Gly Thr Tyr Lys Tyr Leu Gln Lys 260 265 270 Pro Met Tyr Glu Val Gln
Trp Lys Val Val Glu Glu Ile Asn Gly Asn 275 280 285 Asn Tyr Val Tyr
Ile Asp Pro Thr Gln Leu Pro Tyr Asp His Lys Trp 290 295 300 Glu Phe
Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly 305 310 315
320 Ala Phe Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser
325 330 335 Asp Ala Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser
Ala His 340 345 350 Leu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys
Val Leu Ser Tyr 355 360 365 Leu Gly Asn His Met Asn Ile Val Asn Leu
Leu Gly Ala Cys Thr Ile 370 375 380 Gly Gly Pro Thr Leu Val Ile Thr
Glu Tyr Cys Cys Tyr Gly Asp Leu 385 390 395 400 Leu Asn Phe Leu Arg
Arg Lys Arg Asp Ser Phe Ile Cys Ser Lys Gln 405 410 415 Glu Asp His
Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys 420 425 430 Glu
Ser Ser Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro 435 440
445 Gly Val Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val
450 455 460 Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala Ile
Met Glu 465 470 475 480 Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp Leu
Leu Ser Phe Ser Tyr 485 490 495 Gln Val Ala Lys Gly Met Ala Phe Leu
Ala Ser Lys Asn Cys Ile His 500 505 510 Arg Asp Leu Ala Ala Arg Asn
Ile Leu
Leu Thr His Gly Arg Ile Thr 515 520 525 Lys Ile Cys Asp Phe Gly Leu
Ala Arg Val Ile Lys Asn Asp Ser Asn 530 535 540 Tyr Val Val Lys Gly
Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro 545 550 555 560 Glu Ser
Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser 565 570 575
Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr 580
585 590 Pro Gly Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu
Gly 595 600 605 Phe Arg Met Leu Ser Pro Glu His Ala Pro Ala Glu Met
Tyr Asp Ile 610 615 620 Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys
Arg Pro Thr Phe Lys 625 630 635 640 Gln Ile Val Gln Leu Ile Glu Lys
Gln Ile Ser Glu Ser Thr Asn His 645 650 655 Ile Tyr Ser Asn Leu Ala
Asn Cys Ser Pro Asn Arg Gln Lys Pro Val 660 665 670 Val Asp His Ser
Val Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser 675 680 685 Ser Gln
Pro Leu Leu Val His Asp Asp Val 690 695 5696PRTArtificial
SequenceSynthetic Polypeptide 5Met Glu His His His His His His His
His Glu Tyr Met Pro Met Glu 1 5 10 15 Met Ala Pro Ile Leu Gly Tyr
Trp Lys Ile Lys Gly Leu Val Gln Pro 20 25 30 Thr Arg Leu Leu Leu
Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 35 40 45 Tyr Glu Arg
Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 50 55 60 Gly
Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 65 70
75 80 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His
Asn 85 90 95 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser
Met Leu Glu 100 105 110 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser
Arg Ile Ala Tyr Ser 115 120 125 Lys Asp Phe Glu Thr Leu Lys Val Asp
Phe Leu Ser Lys Leu Pro Glu 130 135 140 Met Leu Lys Met Phe Glu Asp
Arg Leu Cys His Lys Thr Tyr Leu Asn 145 150 155 160 Gly Asp His Val
Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 165 170 175 Val Val
Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 180 185 190
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 195
200 205 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln
Ala 210 215 220 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu
Val Pro Arg 225 230 235 240 His Asn Gln Thr Ser Leu Tyr Lys Lys Ala
Gly Ser Ala Ala Ala Val 245 250 255 Leu Glu Glu Asn Leu Tyr Phe Gln
Gly Thr Tyr Lys Tyr Leu Gln Lys 260 265 270 Pro Met Tyr Glu Val Gln
Trp Lys Glu Glu Ile Asn Gly Asn Asn Tyr 275 280 285 Val Tyr Ile Asp
Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe 290 295 300 Pro Arg
Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe 305 310 315
320 Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala
325 330 335 Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser Ala His
Leu Thr 340 345 350 Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val Leu
Ser Tyr Leu Gly 355 360 365 Asn His Met Asn Ile Val Asn Leu Leu Gly
Ala Cys Thr Ile Gly Gly 370 375 380 Pro Thr Leu Val Ile Thr Glu Tyr
Cys Cys Tyr Gly Asp Leu Leu Asn 385 390 395 400 Phe Leu Arg Arg Lys
Arg Asp Ser Phe Ile Cys Ser Lys Gln Glu Asp 405 410 415 His Ala Glu
Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser 420 425 430 Ser
Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val 435 440
445 Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile
450 455 460 Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala Ile Met Glu
Asp Asp 465 470 475 480 Glu Leu Ala Leu Asp Leu Glu Asp Leu Leu Ser
Phe Ser Tyr Gln Val 485 490 495 Ala Lys Gly Met Ala Phe Leu Ala Ser
Lys Asn Cys Ile His Arg Asp 500 505 510 Leu Ala Ala Arg Asn Ile Leu
Leu Thr His Gly Arg Ile Thr Lys Ile 515 520 525 Cys Asp Phe Gly Leu
Ala Arg Val Ile Lys Asn Asp Ser Asn Tyr Val 530 535 540 Val Lys Gly
Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser 545 550 555 560
Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly 565
570 575 Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro
Gly 580 585 590 Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu
Gly Phe Arg 595 600 605 Met Leu Ser Pro Glu His Ala Pro Ala Glu Met
Tyr Asp Ile Met Lys 610 615 620 Thr Cys Trp Asp Ala Asp Pro Leu Lys
Arg Pro Thr Phe Lys Gln Ile 625 630 635 640 Val Gln Leu Ile Glu Lys
Gln Ile Ser Glu Ser Thr Asn His Ile Tyr 645 650 655 Ser Asn Leu Ala
Asn Cys Ser Pro Asn Arg Gln Lys Pro Val Val Asp 660 665 670 His Ser
Val Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln 675 680 685
Pro Leu Leu Val His Asp Asp Val 690 695 6469PRTArtificial
SequenceSynthetic Polypeptide 6Met Ser Tyr Tyr His His His His His
His Asp Tyr Asp Ile Pro Thr 1 5 10 15 Thr Glu Asn Leu Tyr Phe Gln
Gly Ala Met Leu Val Pro Arg Gly Ser 20 25 30 Pro Trp Gly Ser Thr
Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val 35 40 45 Gln Trp Lys
Val Val Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile 50 55 60 Asp
Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn 65 70
75 80 Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys
Val 85 90 95 Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala
Ala Met Thr 100 105 110 Val Ala Val Lys Met Leu Lys Pro Ser Ala His
Leu Thr Glu Arg Glu 115 120 125 Ala Leu Met Ser Glu Leu Lys Val Leu
Ser Tyr Leu Gly Asn His Met 130 135 140 Asn Ile Val Asn Leu Leu Gly
Ala Cys Thr Ile Gly Gly Pro Thr Leu 145 150 155 160 Val Ile Ile Glu
Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg 165 170 175 Arg Lys
Arg Asp Ser Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu 180 185 190
Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser 195
200 205 Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val Ser Tyr
Val 210 215 220 Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile
Gly Ser Tyr 225 230 235 240 Ile Glu Arg Asp Val Thr Pro Ala Ile Met
Glu Asp Asp Glu Leu Ala 245 250 255 Leu Asp Leu Glu Asp Leu Leu Ser
Phe Ser Tyr Gln Val Ala Lys Gly 260 265 270 Met Ala Phe Leu Ala Ser
Lys Asn Cys Ile His Arg Asp Leu Ala Ala 275 280 285 Arg Asn Ile Leu
Leu Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe 290 295 300 Gly Leu
Ala Arg Asp Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly 305 310 315
320 Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn
325 330 335 Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly Ile
Phe Leu 340 345 350 Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro
Gly Met Pro Val 355 360 365 Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu
Gly Phe Arg Met Leu Ser 370 375 380 Pro Glu His Ala Pro Ala Glu Met
Tyr Asp Ile Met Lys Thr Cys Trp 385 390 395 400 Asp Ala Asp Pro Leu
Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu 405 410 415 Ile Glu Lys
Gln Ile Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu 420 425 430 Ala
Asn Cys Ser Pro Asn Arg Gln Lys Pro Val Val Asp His Ser Val 435 440
445 Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu
450 455 460 Val His Asp Asp Val 465
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