U.S. patent application number 14/919261 was filed with the patent office on 2016-02-11 for phosphatidylinositol 3-kinase inhibitors.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Jerry Evarts, Joshua Kaplan, Musong Kim, Leena Patel, Stephane Perreault, Gary Phillips, Jennifer A. Treiberg, Joshua Van Veldhuizen.
Application Number | 20160039793 14/919261 |
Document ID | / |
Family ID | 51177160 |
Filed Date | 2016-02-11 |
United States Patent
Application |
20160039793 |
Kind Code |
A1 |
Evarts; Jerry ; et
al. |
February 11, 2016 |
PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
Abstract
The present disclosure provides phosphatidylinositol 3-kinase
(PI3K) inhibitors of formula (I), ##STR00001## or pharmaceutically
acceptable salts or isomers thereof, in which n, m, R.sup.1,
R.sup.2, R.sup.4, and R.sup.3 are as defined herein. These
compounds are useful for treatment of conditions mediated by one or
more PI3K isoforms, such as PI3K.delta.. The present disclosure
further provides pharmaceutical compositions that include a
compound of formula (I), or pharmaceutically acceptable salts or
isomers thereof, and methods of using these compounds and
compositions to treat conditions mediated by one or more PI3K
isoforms, such as PI3K.delta..
Inventors: |
Evarts; Jerry; (Seattle,
WA) ; Kaplan; Joshua; (Foster City, CA) ; Kim;
Musong; (Bothell, WA) ; Patel; Leena; (Mercer
Island, WA) ; Perreault; Stephane; (Brier, WA)
; Phillips; Gary; (Issaquah, WA) ; Treiberg;
Jennifer A.; (Redmond, WA) ; Van Veldhuizen;
Joshua; (Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
51177160 |
Appl. No.: |
14/919261 |
Filed: |
October 21, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14304539 |
Jun 13, 2014 |
9221795 |
|
|
14919261 |
|
|
|
|
61835333 |
Jun 14, 2013 |
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Current U.S.
Class: |
514/266.21 ;
544/284 |
Current CPC
Class: |
A61P 37/02 20180101;
A61K 31/517 20130101; A61P 7/06 20180101; A61P 17/00 20180101; A61P
37/00 20180101; A61P 37/06 20180101; A61P 11/06 20180101; A61P
35/00 20180101; A61P 21/04 20180101; A61P 35/02 20180101; A61P
11/00 20180101; A61P 19/02 20180101; A61P 13/12 20180101; A61P
25/00 20180101; C07D 401/14 20130101; A61P 29/00 20180101 |
International
Class: |
C07D 401/14 20060101
C07D401/14 |
Claims
1. A compound having the structure of formula (I): ##STR00158## or
a pharmaceutically acceptable salt, isomer, or a mixture thereof,
wherein: n is 0, 1, 2, 3, or 4; each R.sup.1 is independently
selected from halo, cyano, alkyl, or alkylsulfonyl, wherein the
alkyl moiety may be optionally substituted with 1 to 3 halogen; m
is 0, 1, 2, or 3; each R.sup.2 is independently selected from halo,
--NH.sub.2, alkoxy, alkyl, or cycloalkyl, wherein the alkyl moiety
may be optionally substituted with 1 to 3 halogen; R.sup.3 is
hydrogen, alkyl, or cycloalkyl, wherein the alkyl moiety may be
optionally substituted with cycloalkyl; and R.sup.4 is cyano, halo,
or CONH.sub.2.
2. The compound of claim 1, wherein n is 1 or 2; each R.sup.1 is
independently selected from halo, cyano, alkyl, or alkylsulfonyl,
wherein the alkyl moiety may be optionally substituted with 1 to 3
halogen; m is 0, 1, or 2; each R.sup.2 is independently selected
from halo, alkoxy, alkyl, or cycloalkyl, wherein the alkyl moiety
may be optionally substituted with 1 to 3 halogen; R.sup.3 is
hydrogen, alkyl, or cycloalkyl, wherein the alkyl moiety may be
optionally substituted with cycloalkyl; and R.sup.4 is cyano.
3. The compound of claim 1, wherein each R.sup.1 is independently
selected from halo, cyano, C.sub.1-4alkyl, C.sub.1-4 haloalkyl, or
C.sub.1-4alkylsulfonyl.
4. The compound of claim 3, wherein each R.sup.1 is independently
selected from fluoro, chloro, iodo, bromo, cyano, methyl, ethyl,
propyl, butyl, fluoromethyl, fluoroethyl, difluoromethyl,
difluoroethyl, trifluoromethyl, trifluoroethyl, methylsulfonyl,
ethylsulfonyl, or propylsulfonyl.
5. The compound of claim 1, wherein each R.sup.2 is independently
selected from halo, --NH.sub.2, C.sub.1-4alkoxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, or C.sub.3-6cycloalkyl.
6. The compound of claim 5, wherein each R.sup.2 is independently
selected from --NH.sub.2, fluoro, chloro, iodo, bromo, methoxy,
ethoxy, propoxy, butoxy, pentoxy, hexoxy, methyl, ethyl, propyl,
butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl.
7. The compound of claim 1, wherein R.sup.3 is selected from
hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl.
8. The compound of claim 7, wherein R.sup.3 is selected from
hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, or
C.sub.3-6cycloalkylC.sub.1-4alkyl.
9. The compound of claim 8, wherein R.sup.3 is selected from
hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl,
cyclobutylmethyl, or cyclopropylbutyl.
10. The compound of claim 1, wherein R.sup.4 is selected from
cyano, fluoro, chloro, bromo, or CONH.sub.2.
11. The compound of claim 1, wherein n is 1.
12. The compound of claim 1, wherein n is 2.
13. The compound of claim 1, wherein m is 0.
14. The compound of claim 1, wherein m is 1.
15. The compound of claim 1, wherein m is 2.
16. The compound of claim 1, wherein the compound is a
(S)-enantiomer.
17. The compound of claim 1, wherein the compound is a
(R)-enantiomer.
18. The compound of claim 1, wherein the compound is an
atropisomer.
19. The compound of claim 1, wherein the compound is selected from
the group consisting of:
(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazol-
in-2-yl)propylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-
-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazol-
in-2-yl)-2-cyclopropylethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazol-
in-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazol-
in-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-(methylsulfonyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihyd-
roquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(4-oxo-3-(pyridin-3-yl)-5-(trifluoromethyl)-3,4-dihy-
droquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-(pyridi-
n-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2,4-diamino-6-(1-(3-(5-fluoropyridin-3-yl)-5-methyl-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-chloropyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-methoxypyridin-3-yl)-4-oxo-3,4-dihydr-
oquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-(difluoromethyl)pyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)pyridin-3-yl)--
3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-cyclopropylpyridin-3-yl)-4-oxo-3,4-di-
hydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(8-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazol-
in-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquin-
azolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydr-
oquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5,8-difluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquin-
azolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydr-
oquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroq-
uinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(cyclopropyl(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-di-
hydroquinazolin-2-yl)methylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydr-
oquinazolin-2-yl)-2-cyclopropylethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5,8-dichloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-3-(5-methylpyridin-3-yl)-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4--
dihydroquinazolin-2-yl)
(cyclopropyl)methylamino)pyrimidine-5-carbonitrile;
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-4-oxo--
3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-8-fluoro-4-oxo-
-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydr-
oquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroq-
uinazolin-2-yl) (cyclopropyl)methylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;
(R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihyd-
roquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihyd-
roquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(R)-2,4-Diamino-6-(((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydro-
quinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(R)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(R)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(methylsulfo-
nyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one;
(S)-2,4-Diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazo-
lin-2-yl)ethyl)amino)pyrimidine-5-carboxamide;
(S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(5--
fluoropyridin-3-yl)quinazolin-4(3h)-one;
(S)-2-(1-((2,6-Diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(py-
ridin-3-yl)quinazolin-4(3H)-one;
(S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(py-
ridin-3-yl)quinazolin-4(3H)-one;
(S)-2-(1-((2,6-Diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo--
3-(pyridin-3-yl)-3,4-dihydroquinazoline-8-carbonitrile;
(S)-2-(1-((2,6-Diamino-5-cyanopyrimidin-4-yl)amino)propyl)-6-fluoro-3-(5--
fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;
(S)-2-(Cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-flu-
oro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;
(S)-2,4-Diamino-6-((1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydr-
oquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-Diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazo-
lin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile;
(S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-flu-
oro-3-(pyridin-3-yl)quinazolin-4(3h)-one;
(S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydr-
oquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(5-f-
luoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-4-oxo-3-(pyrid-
in-3-yl)-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydr-
oquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-Diamino-6-(((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)--
4-oxo-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-Diamino-6-(((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)--
4-oxo-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-
-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-
-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl-
)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl-
)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-Diamino-6-((1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluoromethyl)-
-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-Diamino-6-((1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluoromethyl)-
-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-8-chloro-6-fluoro-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrim-
idin-4-yl)amino)ethyl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)ethyl)quinazolin-4(3H)-one;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)propyl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydro-
quinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)ethyl)-8-fluoroquinazolin-4(3H)-one;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloro-
pyrimidin-4-yl)amino)methyl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-(((3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroqu-
inazolin-2-yl) (cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,-
4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,-
4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-ox-
o-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-ox-
o-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo--
3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo--
3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4-oxo-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)butyl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydro-
quinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-
-4-yl)amino)butyl)-6-fluoroquinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4-oxo-3,-
4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloro-
pyrimidin-4-yl)amino)methyl)-8-fluoroquinazolin-4(3H)-one;
(S)-2,4-diamino-6-(((3-(6-aminopyridin-3-yl)-5-chloro-8-fluoro-4-oxo-3,4--
dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; and
(S)-4-amino-6-((1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquin-
azolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
20. The compound of claim 19, wherein the compound is an
atropisomer.
21. A pharmaceutical composition comprising: the compound, a
pharmaceutically acceptable salt, isomer, or a mixture thereof of
claim 1; and at least one pharmaceutically acceptable vehicle.
22. A method for treating a disease or condition in a human in need
thereof, comprising administering to the human a therapeutic
effective amount of the compound, a pharmaceutically acceptable
salt, isomer, or a mixture thereof of claim 1.
23. The method of claim 22, wherein the disease or condition is an
inflammatory disorder, an autoimmune disease, or a cancer.
24. The method of claim 22, wherein the disease or condition is
lymphoma, multiple myeloma, or leukemia.
25. The method of any of claims 22, wherein the disease or
condition is acute lymphocytic leukemia (ALL), acute myeloid
leukemia (AML), chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),
myeloproliferative disease (MPD), chronic myeloid leukemia (CML),
multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell
lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia
(WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell
lymphoma (DLBCL), pancreatic cancer, bladder cancer, colorectal
cancer, breast cancer, prostate cancer, renal cancer,
hepatocellular cancer, lung cancer, ovarian cancer, cervical
cancer, gastric cancer, esophageal cancer, head and neck cancer,
melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone
cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell
lung cancer, colon cancer, systemic lupus erythematosus (SLE),
myestenia gravis, rheumatoid arthritis (RA), acute disseminated
encephalomyelitis, idiopathic thrombocytopenic purpura, multiple
sclerosis (MS), Sjoegren's syndrome, autoimmune hemolytic anemia,
psoriasis, chronic obstructive pulmonary disease (COPD), or
asthma.
26. The method of claim 22, wherein the compound, a
pharmaceutically acceptable salt, isomer, or a mixture thereof, is
administered intravenously, intramuscularly, parenterally, nasally
or orally.
27. A kit comprises the compound, a pharmaceutically acceptable
salt, isomer, or a mixture thereof of claim 1, or a label and/or
instructions for use.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims the benefit of priority of
U.S. Application Ser. No. 61/835,333, filed Jun. 14, 2013. The
content of this provisional application is hereby incorporated
herein in its entirety.
FIELD
[0002] The present disclosure relates generally to inhibitors of
phosphatidylinositol 3-kinase (PI3K) activity and to novel
compounds that are selective inhibitors of PI3K delta activity.
BACKGROUND
[0003] Cell signaling via 3'-phosphorylated phosphoinositides has
been implicated in a variety of cellular processes, e.g., malignant
transformation, growth factor signaling, inflammation, and
immunity. See generally Rameh et al., J. Biol. Chem., 274:8347-8350
(1999). Phosphatidylinositol 3-kinase (PI 3-kinase; PI3K) is
responsible for generating these phosphorylated signaling products.
PI3K originally was identified as a protein associated with viral
oncoproteins and growth factor receptor tyrosine kinases that
phosphorylate phosphatidylinositol (PI) and its phosphorylated
derivatives at the 3'-hydroxyl of the inositol ring. See Panayotou
et al., Trends Cell Biol 2:358-60 (1992).
[0004] Three classes of the PI 3-kinase (PI3K) are proposed, based
on their substrate specificities. Class I PI3Ks phosphorylate
phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and
phosphatidylinositol-4,5-biphosphate (PIP.sub.2) to produce
phosphatidylinositol-3-phosphate (PIP),
phosphatidylinositol-3,4-biphosphate, and
phosphatidylinositol-3,4,5-triphosphate, respectively. Class II
PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, and
Class III PI3Ks phosphorylate PI.
[0005] The initial purification and molecular cloning of PI
3-kinase revealed that it was a heterodimer consisting of p85 and
p110 subunits. See Otsu et al., Cell, 65:91-104 (1991); Hiles et
al., Cell, 70:419-29 (1992). Since then, four distinct Class I
PI3Ks have been identified, designated as PI3K .alpha., .beta.,
.delta., and .gamma. isomers, each consisting of a distinct 110 kDa
catalytic subunit and a regulatory subunit. More specifically,
three of the catalytic subunits, i.e., p110.alpha., p110.beta., and
p110.delta., each interact with the same regulatory subunit, i.e.,
p85, whereas p110.gamma. interacts with a distinct p101 regulatory
subunit. As described below, the patterns of expression of each of
these PI3Ks in human cells and tissues also are distinct.
[0006] Identification of the p1106 isoform of PI 3-kinase is
described in Chantry et al., J. Biol. Chem., 272:19236-41 (1997).
It was observed that the human p1106 isoform is expressed in a
tissue-restricted fashion. It is expressed at high levels in
lymphocytes and lymphoid tissues, suggesting that the protein might
play a role in PI 3-kinase-mediated signaling in the immune system.
The p1106 isoform is described in U.S. Pat. Nos. 5,858,753;
5,882,910; and 5,985,589, each of which is incorporated herein by
reference. See also Vanhaesebroeck et al., Proc. Natl. Acad. Sci.
USA, 94:4330-5 (1997); and WO 97/46688.
[0007] Therefore, there is a need for therapeutic agents that
inhibit PI3K isomers to treat disorders or diseases that are
mediated by PI3K.
SUMMARY
[0008] The present application provides novel compounds that are
inhibitors of PI3K isoforms, such as PI3K.delta.. The application
also provides compositions, including pharmaceutical compositions,
kits that include the compounds, and methods of using and making
the compounds. The compounds provided herein are useful in treating
diseases, disorders, or conditions that are mediated by PI3K
isoforms, such as PI3K.delta.. The application also provides the
compounds for use in therapy. The application further provides
compounds for use in a method of treating a disease, disorder, or
condition that is mediated by PI3K isoforms. Moreover, the
application provides uses of the compounds in the manufacture of a
medicament for the treatment of a disease, disorder or condition
that is mediated by PI3K isoforms.
[0009] In one aspect, the PI3K inhibitor is a compound having the
structure of formula (I):
##STR00002##
[0010] or a pharmaceutically acceptable salt, tautomer, isomer, a
mixture of isomers, or prodrug thereof; wherein:
[0011] n is 0, 1, 2 or 3;
[0012] each R.sup.1 is independently halo, cyano, optionally
substituted alkylsulfonyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted heterocycloalkyl, or
optional substituted alkoxy;
[0013] m is 0, 1, 2, or 3;
[0014] each R.sup.2 is independently halo, optionally substituted
alkoxy, optionally substituted alkyl, optionally substituted
cycloalkyl, or optionally substituted heterocycloalkyl;
[0015] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkoxy,
or optionally substituted heterocycloalkyl; and
[0016] R.sup.4 is cyano.
[0017] In one aspect, the compounds having the structure of formula
(I) wherein:
[0018] n is 0, 1, 2 or 3;
[0019] each R.sup.1 is independently selected from halogen, cyano,
alkyl, or alkylsulfonyl, wherein the alkyl moiety may be optionally
substituted with 1 to 3 halogen;
[0020] m is 0, 1, 2 or 3;
[0021] each R.sup.2 is independently selected from halogen, alkoxy,
alkyl, or cycloalkyl, wherein the alkyl moiety may be optionally
substituted with 1 to 3 halogen;
[0022] R.sup.3 is hydrogen, alkyl, or cycloalkyl, wherein the alkyl
moiety may be optionally substituted with cycloalkyl; and
[0023] R.sup.4 is cyano.
[0024] In some embodiments, the compounds have the structure of
formula (I) wherein each R.sup.1 is independently selected from
halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.1-4
alkylsulfonyl. In certain embodiments, each R.sup.1 is
independently selected from fluoro, chloro, iodo, bromo, cyano,
methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl,
difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl,
methylsulfonyl, ethylsulfonyl, or propylsulfonyl.
[0025] In other embodiments, the compounds have the structure of
formula (I) wherein each R.sup.2 is independently selected from
halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or
C.sub.3-6 cycloalkyl. In yet other embodiments, each R.sup.2 is
independently selected from fluoro, chloro, iodo, bromo, methoxy,
ethoxy, propoxy, butoxy, pentoxy, hexoxy, methyl, ethyl, propyl,
butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl.
[0026] In certain embodiments, the compounds have the structure of
formula (I) wherein R.sup.3 is selected from hydrogen, alkyl,
cycloalkyl, or cycloalkylalkyl. In other embodiments, R.sup.3 is
selected from hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, or
C.sub.3-6 cycloalkylC.sub.1-4 alkyl. In yet other embodiments,
R.sup.3 is selected from hydrogen, methyl, ethyl, propyl, butyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl.
[0027] In additional embodiments, the compound having the structure
of formula (I) wherein
[0028] n is 0, 1, 2, 3, or 4;
[0029] each R.sup.1 is independently halo, cyano, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocycloalkyl, optional substituted alkoxy, or
SO.sub.2R.sup.1x wherein R.sup.1x is optionally substituted
alkyl;
[0030] m is 0, 1, 2, or 3;
[0031] each R.sup.2 is independently halo, --NH.sub.2, optionally
substituted alkoxyalkyl, optionally substituted alkyl, optionally
substituted cycloalkyl, or optionally substituted
heterocycloalkyl;
[0032] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted
alkoxyalkyl, or optionally substituted heterocycloalkyl; and
[0033] R.sup.4 is selected from halo, cyano, and --CONH.sub.2.
[0034] In one additional embodiment, the compound having the
structure of formula (I), wherein:
[0035] n is 0, 1, 2, 3, or 4;
[0036] each R.sup.1 is independently selected from halo, cyano,
alkyl, or alkylsulfonyl, wherein the alkyl moiety may be optionally
substituted with 1 to 3 halogen;
[0037] m is 0, 1, 2, or 3;
[0038] each R.sup.2 is independently selected from halo,
--NH.sub.2, alkoxy, alkyl, or cycloalkyl, wherein the alkyl moiety
may be optionally substituted with 1 to 3 halogen;
[0039] R.sup.3 is hydrogen, alkyl, or cycloalkyl, wherein the alkyl
moiety may be optionally substituted with cycloalkyl; and
[0040] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0041] In other additional embodiments, the compounds having the
structure of formula (I) wherein R.sup.4 is selected from the group
consisting of fluoro, chloro, bromo, iodo, cyano, and
--CONH.sub.2.
[0042] In some embodiment, the compounds have the structure of
formula (I) wherein n is 1 or 2. In another embodiment, n is 1. In
yet another embodiment, n is 2.
[0043] In other embodiments, the compounds have the structure of
formula (I) wherein m is 0, 1, or 2. In another embodiment, m is 0.
In other embodiment, m is 1. In yet another embodiment, m is 2.
[0044] In certain embodiments, the compounds have the structure of
formula (I), wherein: n is 1 or 2;
[0045] each R.sup.1 is independently selected from halogen, cyano,
alkylsulfonyl, or alkyl, wherein the alkyl moiety is optionally
substituted with halogen;
[0046] m is 0, 1, or 2;
[0047] each R.sup.2 is independently selected from halo, alkoxy,
alkyl, or cycloalkyl, wherein the alkoxy, alkyl or cycloalkyl
moieties are optionally substituted with halogen, alkyl, or
cycloalkyl;
[0048] R.sup.3 is hydrogen, alkyl, or cycloalkyl, wherein the alkyl
or cycloalkyl moieties are optionally substituted with halogen or
cycloalkyl; and
[0049] R.sup.4 is cyano.
[0050] In other embodiments, the compounds have the structure of
formula (I), wherein:
[0051] n is 1 or 2;
[0052] each R.sup.1 is independently selected from halogen, cyano,
C.sub.1-4alkyl, C.sub.1-4 haloalkyl, or C.sub.1-4alkylsulfonyl;
[0053] m is 0, 1, or 2;
[0054] each R.sup.2 is independently selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6
cycloalkyl.
[0055] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.3-6cycloalkylC.sub.1-4alkyl; and
[0056] R.sup.4 is cyano.
[0057] In another embodiment, the compounds have the structure of
formula (I), wherein:
[0058] n is 1 or 2;
[0059] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0060] m is 0, 1, or 2;
[0061] each R.sup.2 is independently selected from fluoro, chloro,
iodo, bromo, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy,
methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl,
difluoromethyl, difluoroethyl, trifluoromethyl, cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl;
[0062] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0063] R.sup.4 is cyano.
[0064] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0065] n is 2 and m is 2;
[0066] each R.sup.1 is independently selected from halogen, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0067] each R.sup.2 is independently selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or
C.sub.3-6 cycloalkyl;
[0068] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0069] R.sup.4 is cyano.
[0070] In other embodiments, the PI3K inhibitor is a compound
having the structure of formula (I) or a pharmaceutically
acceptable salt, tautomer, isomer, a mixture of isomers, prodrug,
or solvate thereof, wherein:
[0071] n is 1 and m is 2;
[0072] R.sup.1 is independently selected from halogen, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0073] each R.sup.2 is independently selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or
C.sub.3-6 cycloalkyl;
[0074] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0075] R.sup.4 is cyano.
[0076] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0077] n is 2 and m is 1;
[0078] each R.sup.1 is independently selected from halogen, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0079] R.sup.2 is selected from halogen, C.sub.1-4 alkoxy,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6 cycloalkyl;
[0080] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0081] R.sup.4 is cyano.
[0082] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0083] n is 1 and m is 1;
[0084] R.sup.1 is selected from halogen, cyano, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl;
[0085] R.sup.2 is selected from halogen, C.sub.1-4 alkoxy,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6 cycloalkyl;
[0086] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0087] R.sup.4 is cyano.
[0088] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0089] n is 1 and m is 0;
[0090] R.sup.1 is selected from halogen, cyano, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl;
[0091] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0092] R.sup.4 is cyano.
[0093] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0094] n is 2 and m is 0;
[0095] each R.sup.1 is independently selected from halogen, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0096] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0097] R.sup.4 is cyano.
[0098] In additional embodiments, the compounds have the structure
of formula (I), wherein:
[0099] n is 1 or 2;
[0100] each R.sup.1 is independently selected from halo, cyano,
alkylsulfonyl, or alkyl, wherein the alkyl moiety is optionally
substituted with halogen;
[0101] m is 0, 1, or 2;
[0102] each R.sup.2 is independently selected from halo,
--NH.sub.2, alkoxyalkyl, alkyl, or cycloalkyl, wherein the alkyl or
cycloalkyl moieties are optionally substituted with halogen, alkyl,
or cycloalkyl;
[0103] R.sup.3 is hydrogen, alkyl, or cycloalkyl, wherein the alkyl
or cycloalkyl moieties are optionally substituted with halogen or
cycloalkyl; and
[0104] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0105] In other embodiments, the compounds have the structure of
formula (I), wherein:
[0106] n is 1 or 2;
[0107] each R.sup.1 is independently selected from halo, cyano,
C.sub.1-4alkyl, C.sub.1-4 haloalkyl, or C.sub.1-4alkylsulfonyl;
[0108] m is 0, 1, or 2;
[0109] each R.sup.2 is independently selected from halo,
--NH.sub.2, C.sub.1-4alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6
cycloalkyl.
[0110] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.3-6cycloalkylC.sub.1-4alkyl; and
[0111] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0112] In another embodiment, the compounds have the structure of
formula (I), wherein:
[0113] n is 1 or 2;
[0114] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0115] m is 0, 1, or 2;
[0116] each R.sup.2 is independently selected from fluoro, chloro,
iodo, --NH.sub.2, bromo, methyl, ethyl, propyl, butyl,
fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl;
[0117] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0118] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0119] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0120] n is 2 and m is 2;
[0121] each R.sup.1 is independently selected from halo, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0122] each R.sup.2 is independently selected from halo,
--NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6
cycloalkyl;
[0123] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0124] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0125] In other embodiments, the PI3K inhibitor is a compound
having the structure of formula (I) or a pharmaceutically
acceptable salt, tautomer, isomer, a mixture of isomers, prodrug,
or solvate thereof, wherein:
[0126] n is 1 and m is 2;
[0127] R.sup.1 is independently selected from halo, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0128] each R.sup.2 is independently selected from halo,
--NH.sub.2, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
or C.sub.3-6 cycloalkyl;
[0129] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0130] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0131] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0132] n is 2 and m is 1;
[0133] each R.sup.1 is independently selected from halo, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0134] R.sup.2 is selected from halo, --NH.sub.2, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, or C.sub.3-6 cycloalkyl;
[0135] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0136] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0137] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0138] n is 1 and m is 1;
[0139] R.sup.1 is selected from halo, cyano, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl;
[0140] R.sup.2 is selected from halo, --NH.sub.2, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, or C.sub.3-6 cycloalkyl;
[0141] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0142] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0143] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0144] n is 1 and m is 0;
[0145] R.sup.1 is selected from halo, cyano, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl;
[0146] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0147] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0148] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0149] n is 2 and m is 0;
[0150] each R.sup.1 is independently selected from halo, cyano,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4
haloalkyl;
[0151] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0152] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0153] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0154] n is 1;
[0155] m is 1;
[0156] R.sup.1 is selected from halo, cyano, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl;
[0157] R.sup.2 is --NH.sub.2;
[0158] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.1-4 cycloalkylC.sub.1-4 alkyl;
and
[0159] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0160] In some embodiments, the PI3K inhibitor is a compound having
the structure of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, prodrug, or solvate
thereof, wherein:
[0161] n is 2;
[0162] m is 1;
[0163] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0164] each R.sup.2 is --NH.sub.2;
[0165] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0166] R.sup.4 is cyano, halo, or --CONH.sub.2.
[0167] In certain embodiments, the PI3K inhibitors are the
compounds selected from Table 1, or a pharmaceutically acceptable
salt, tautomer, isomer, a mixture of isomers, or prodrug thereof.
In some embodiments, the compounds are the atropisomers. In other
embodiments, the compounds are the (S)-enantiomer. In some other
embodiments, the compounds are the (R)-enantiomer. In other
additional embodiments, the compounds are atropisomers.
[0168] The application also provides a pharmaceutical composition
that includes a compound of formula (I) or a pharmaceutically
acceptable salt, tautomer, isomer, a mixture of isomers, or prodrug
thereof, together with at least one pharmaceutically acceptable
vehicle. Examples of pharmaceutically acceptable vehicle may be
selected from carriers, adjuvants, and excipients.
[0169] Also provided herein is a method of treating a disease or
condition in a human in need thereof by administering to the human
a therapeutically effective amount of a compound of formula (I) or
a pharmaceutically acceptable salt, tautomer, isomer, a mixture of
isomers, or prodrug thereof. Further provided is a compound of
formula (I) for use in a method of treating a disease, disorder or
condition that is mediated by PI3K isoforms. The application also
provides the use of a compounds of formula (I) in the manufacture
of a medicament for the treatment of a disease, disorder or
condition that is mediated by PI3K isoforms. In certain
embodiments, the disease or condition is associated or mediated by
PI3K. In some embodiments, the disease or condition is an
inflammatory disorder, an autoimmune disease, or a cancer. In
certain other embodiments, the disease or condition is an
inflammatory disorder. In other embodiments, the disease or
condition is an autoimmune disease. In additional embodiments, the
disease or condition is a cancer.
[0170] Also provided herein is a method of inhibiting kinase
activity of a phosphatidylinositol 3-kinase delta polypeptide by
contacting the polypeptide with a compound of formula (I) or a
pharmaceutically acceptable salt, tautomer, isomer, a mixture of
isomers, or prodrug thereof. Additionally provided herein is a
method of inhibiting kinase activity of a phosphatidylinositol
3-kinase beta polypeptide by contacting the polypeptide with a
compound of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, or prodrug thereof.
[0171] Further provided is a method of inhibiting excessive or
destructive immune reactions, comprising administering an effective
amount of a compound of formula (I) described herein or a
pharmaceutically acceptable salt, isomer, a mixture of isomers, or
prodrug thereof such as asthma, rheumatoid arthritis, multiple
sclerosis, and lupus. Moreover, provided is a method of inhibiting
excess or destructive immune reactions, comprising administering an
effective amount of a compound of formula (I) described herein or a
pharmaceutically acceptable salt, isomer, a mixture of isomers, or
prodrug thereof such as psoriasis, or chronic obstructive pulmonary
disease (COPD).
[0172] Also provided is a method of disrupting leukocyte function
comprising contacting the leukocytes with an effective amount of a
compound of formula (I) described herein or a pharmaceutically
acceptable salt, tautomer, isomer, a mixture of isomers, or prodrug
thereof.
[0173] Also provided is a method of inhibiting a growth or a
proliferation of cancer cells comprising contacting the cancer
cells with an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt, tautomer, isomer, a mixture of
isomers, or prodrug thereof.
[0174] In some embodiments, the cancer cells are of hematopoietic
origin. In certain embodiment, the cancer is lymphoma, leukemia, or
solid tumor.
[0175] Also provided is a kit that includes a compound of formula
(I) or a pharmaceutically acceptable salt, tautomer, isomer, a
mixture of isomers, or prodrug thereof. The kit may further
comprise a label and/or instructions for use of the compound in the
treatment of a disease or condition in a human in need thereof. In
some embodiments, the disease or condition may be associated or
mediated by PI3K.delta. activity. In some other embodiments, the
disease or condition may be associated or mediated by PI3K.delta.
and/or PI3K.beta. activity.
[0176] Also provided are articles of manufacture that include a
compound of formula (I) or a pharmaceutically acceptable salt,
tautomer, isomer, a mixture of isomers, or prodrug thereof, and a
container. In one embodiment, the container may be a vial, jar,
ampoule, preloaded syringe, or an intravenous bag.
DETAILED DESCRIPTION
[0177] The following description sets forth exemplary methods,
parameters and the like. It should be recognized, however, that
such description is not intended as a limitation on the scope of
the present disclosure but is instead provided as a description of
exemplary embodiments.
[0178] As used in the present specification, the following words,
phrases and symbols are generally intended to have the meanings as
set forth below, except to the extent that the context in which
they are used indicates otherwise.
[0179] A dash ("-") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --CONH.sub.2 is attached through the carbon atom.
[0180] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X". In some embodiments, the term "about"
includes the indicated amount.+-.10%. In other embodiments, the
term "about" includes the indicated amount.+-.5%.
[0181] "Alkyl" refers to a monoradical unbranched or branched
saturated hydrocarbon chain. As used herein, alkyl has 1 to 20
carbon atoms (i.e., C.sub.1-20 alkyl), 1 to 8 carbon atoms (i.e.,
C.sub.1-8 alkyl), 1 to 6 carbon atoms (i.e., C.sub.1-6 alkyl), or 1
to 4 carbon atoms (i.e., C.sub.1-4 alkyl). Examples of alkyl groups
include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,
hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue
having a specific number of carbons is named, all geometric isomers
having that number of carbons may be encompassed; thus, for
example, "butyl" can include n-butyl, sec-butyl, isobutyl and
t-butyl; "propyl" can include n-propyl and isopropyl.
[0182] "Cycloalkyl" refers to a cyclic alkyl group. As used herein,
cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C.sub.3-20
cycloalkyl), or 3 to 12 ring carbon atoms (i.e., C.sub.3-12
cycloalkyl), 3 to 8 ring carbon atoms (i.e., C.sub.3-8 cycloalkyl),
or 3 to 6 ring carbon atoms (i.e., C.sub.3-6 cycloalkyl). Examples
of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl.
[0183] "Heterocycloalkyl" refers to a cyclic alkyl group, with one
or more ring heteroatoms independently selected from nitrogen,
oxygen and sulfur. As used herein, heterocycloalkyl has 2 to 20
ring carbon atoms (i.e., C.sub.2-20 heterocycloalkyl), 2 to 12 ring
carbon atoms (i.e., C.sub.2-12 heterocycloalkyl), or 2 to 8 ring
carbon atoms (i.e., C.sub.2-8 heterocycloalkyl); and 1 to 5 ring
heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or
2 ring heteroatoms, or 1 ring heteroatom independently selected
from nitrogen, sulfur or oxygen. Examples of heterocycloalkyl
groups may include pyrrolidinyl, piperidinyl, piperazinyl,
oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
[0184] "Alkoxy" refers to the group "alkyl-O--". Examples of alkoxy
groups may include methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
1,2-dimethylbutoxy.
[0185] "Aryl" refers to an aromatic carbocyclic group having a
single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or
multiple fused rings (e.g., naphthyl, fluorenyl, and anthryl).
Examples of aryl groups may include 6 to 20 ring carbon atoms
(i.e., C.sub.6-20 aryl), or 6 to 12 carbon ring atoms (i.e.,
C.sub.6-12 aryl). Aryl, however, does not encompass or overlap in
any way with heteroaryl, separately defined below. If one or more
aryl groups are fused with a heteroaryl ring, the resulting ring
system is heteroaryl.
[0186] "Heteroaryl" refers to an aromatic group having a single
ring, multiple rings, or multiple fused rings, with one or more
ring heteroatoms independently selected from nitrogen, oxygen, and
sulfur. Heteroaryl may be an aromatic, monocyclic or bicyclic ring
containing one or more heteroatoms independently selected from
nitrogen, oxygen and sulfur with the remaining ring atoms being
carbon. As used herein, heteroaryl include 1 to 20 ring carbon
atoms (i.e., C.sub.1-20 heteroaryl), 1 to 12 ring carbon atoms
(i.e., C.sub.1-12 heteroaryl), or 1 to 8 carbon ring atoms (i.e.,
C.sub.1-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms,
1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring
heteroatom independently selected from nitrogen, oxygen, and
sulfur. Examples of heteroaryl groups include pyridyl, pyridazinyl,
pyrimidinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not
encompass or overlap with aryl as defined above.
[0187] As used herein, the term "substituted" means that any one or
more hydrogen atoms on the designated atom or group is replaced
with a moiety other than hydrogen, provided that the designated
atom's normal valence is not exceeded.
[0188] The terms "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances in which it does not. Also, the
term "optionally substituted" refers to any one or more hydrogen
atoms on the designated atom or group may or may not be replaced by
a moiety other than hydrogen.
[0189] "Substituted alkyl" refers to an alkyl group having one or
more substituents including, for example, hydroxyl, haloalkyl,
alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano,
halo, carboxyl, and NR.sub.2, where each R is independently
hydrogen, alkyl, haloalkyl, alkylC(O)--, alkylOC(O)--, or
H.sub.2NC(O)--. In some embodiments, a substituted alkyl may have 1
to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1
substituent. In other embodiment, a substituted alkyl may have 1 to
4 substituents. For example, a substituted alkyl is haloalkyl,
cycloalkylalkyl, or heterocycloalkylalkyl. In some embodiments, a
substituted alkyl is C.sub.1-6 haloalkyl, C.sub.1-6 cycloalkyl,
C.sub.1-6 heterocycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
cycloalkyl, or C.sub.1-4 heterocycloalkyl. In some other
embodiments, a substituted alkyl is C.sub.1-6 haloalkyl, C.sub.1-6
cycloalkylalkyl, C.sub.1-6 heterocycloalkylalkyl, C.sub.1-4
haloalkyl, C.sub.1-4 cycloalkylalkyl, or C.sub.1-4
heterocycloalkylalkyl. Examples of the substituted alkyl group may
include --CH.sub.2F, --CHF.sub.2, CF.sub.3, --CH.sub.2FCH.sub.3,
--CHF.sub.2CH.sub.3, --CH.sub.2CH.sub.2F, --CH.sub.2CF.sub.3,
cyciopropymethyl, cyclopropylethyl, cyclopropylpropyl,
cyclobutylmethyl, cyclobutylethyl, or cyclobutylpropyl.
[0190] "Substituted cycloalkyl" refers to a cycloalkyl group having
one or more substituents including, for example, alkyl, haloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkoxy, cyano, halo, carboxyl,
hydroxyl, and --NR.sub.2, where each R is independently hydrogen,
alkyl, haloalkyl, alkylC(O)--, alkylOC(O)--, or H.sub.2NC(O)--. In
some embodiments, a substituted cycloalkyl may have 1 to 5
substituents, 1 to 3 substituents, 1 to 2 substituents, or 1
substituent. In other embodiment, a substituted cycloalkyl may have
1 to 4 substituents. For example, a substituted alkyl is haloalkyl,
cycloalkylalkyl, or heterocycloalkylalkyl. In some embodiments, a
substituted alkyl is C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
C.sub.1-6 heterocycloalkyl, C.sub.1-4 haloalkyl, C.sub.3-4
cycloalkyl, or C.sub.1-4 heterocycloalkyl. In other example, a
substituted cycloalkyl is halocycloalkyl, or alkylcycloalkyl. In
some embodiments, a substituted cycloalkyl is C.sub.3-10
halocycloalkyl, C.sub.3-10cycloalkyl, C.sub.2-10 heterocycloalkyl
C.sub.3-6 halocycloalkyl, C.sub.3-6 cycloalkyl, or C.sub.2-5
heterocycloalkyl.
[0191] "Substituted heterocycloalkyl" refers to a heterocycloalkyl
group having one or more substituents including, for example,
alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cyano,
halo, carboxyl, hydroxyl, and --NR.sub.2, where each R is
independently hydrogen, alkyl, haloalkyl, alkylC(O)--,
alkylOC(O)--, or H.sub.2NC(O)--. In some embodiments, a substituted
heterocycloalkyl may have 1 to 5 substituents, 1 to 3 substituents,
1 to 2 substituents, or 1 substituent. In other embodiment, a
substituted heterocycloalkyl may have 1 to 4 substituents. In
certain embodiments, a substituted heterocycloalkyl may contain 1,
2 or 3 heteroatoms independently selected from nitrogen, oxygen,
and sulfur.
[0192] "Substituted aryl" refers to an aryl group having one or
more substituents including, for example, halo, --OR, --NR.sub.2,
--C(O)NR'.sub.2, --SO.sub.2NR'.sub.2, alkyl, haloalkyl,
heterocycloalkyl, heteroaryl, alkoxy, amino, cyano, and carboxyl,
where each R is independently hydrogen, alkyl, haloalkyl,
alkylC(O)--, alkylOC(O)--, or H.sub.2NC(O)-- and each R' is
independently hydrogen, alkyl, haloalkyl. In some embodiments, a
substituted aryl may have 1 to 5 substituents, 1 to 3 substituents,
1 to 2 substituents, or 1 substituent.
[0193] "Substituted heteroaryl" refers to a heteroaryl group having
one or more substituents including, for example, alkyl, haloalkyl,
halo, --NR.sub.2, --OR, --C(O)OR, heterocycloalkyl, aryl, and
cyano, where each R is independently hydrogen, alkyl, haloalkyl,
alkylC(O)--, alkylOC(O)--, or H.sub.2NC(O)--. In some embodiments,
a substituted heteroaryl may have 1 to 5 substituents, 1 to 3
substituents, 1 to 2 substituents, or 1 substituent. In other
embodiment, a substituted heteroaryl may have 1 to 4 substituents.
In certain embodiments, a substituted heteroaryl may contain 1, 2
or 3 heteroatoms independently selected from nitrogen, oxygen, and
sulfur.
[0194] "Substituted sulfonyl" refers to the group "SO.sub.2R" where
R refers to a substituent including, for example, alkyl, haloalkyl,
cycloalkyl, heterocycloalkyl, heteroaryl, and aryl and R is further
substituted with alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,
heteroaryl, or aryl. "Sulfonyl" refers to the group "--SO.sub.2R"
where R refers to a substituent including, for example, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl. In
some embodiments, the sulfonyl group is alkylsulfonyl, in which R
is alkyl. Examples of the sulfonyl groups may include
SO.sub.2CH.sub.3, SO.sub.2CH.sub.2CH.sub.3, or SO.sub.2Ph.
[0195] The term "halogen" or "halo" includes fluoro, chloro, bromo,
and iodo, and the term "halogen" includes fluorine, chlorine,
bromine, and iodine. "Haloalkyl" refers to an unbranched or
branched chain alkyl group as defined above, wherein one or more
hydrogen atoms are replaced by a halogen. For example, where a
residue is substituted with more than one halogen, it may be
referred to by using a prefix corresponding to the number of
halogen moieties attached. For example, dihaloaryl, dihaloalkyl,
and trihaloaryl refer to aryl and alkyl substituted with two ("di")
or three ("tri") halo groups, which may be, but are not
necessarily, the same halogen; thus, for example,
3,5-difluorophenyl, 3-chloro-5-fluorophenyl,
4-chloro-3-fluorophenyl, and 3,5-difluoro-4-chlorophenyl is within
the scope of dihaloaryl. Other examples of a haloalkyl group
include difluoromethyl (--CHF.sub.2) and trifluoromethyl
(--CF.sub.3).
[0196] Certain commonly used alternative chemical names may be
used. For example, a divalent group such as a divalent "alkyl"
group, a divalent "aryl" group, etc., may also be referred to as an
"alkylene" group or an "alkylenyl" group, an "arylene" group or an
"arylenyl" group, respectively. Also, unless defined otherwise,
where combinations of groups are referred to herein as one moiety,
e.g. arylalkyl, the last mentioned group contains the atom by which
the moiety is attached to the rest of the molecule.
PI3K Inhibitor Compounds
[0197] The present application provides the compounds that function
as inhibitors of PI3K isoforms, such as PI3K.delta.. In one aspect,
the PI3K inhibitors are the compound having formula (II):
##STR00003##
or a pharmaceutically acceptable salt, prodrug, or solvate thereof,
wherein:
[0198] A is N or CH;
[0199] n is 0, 1, 2, 3, or 4;
[0200] each R.sup.1 is independently selected from hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, optionally substituted heteroaryl,
halo, cyano, NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2,
OR.sup.1x, OCF.sub.3, N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x,
C(.dbd.O)R.sup.1x, C(.dbd.O)OR.sup.1x, aryl-OR.sup.1y, Het,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1x,
C(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x, alkylene-N(R.sup.1x).sub.2,
alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-OR.sup.1x, O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1x,
SO.sub.2N(R.sup.1x).sub.2, OSO.sub.2CF.sub.3, alkylene-aryl,
alkylene-Het, alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl, optionally
substituted cycloalkyl, optionally substituted heterocycloalkyl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het, or
NHC(.dbd.O)halo-alkyl,
[0201] wherein Het is a 5- or 6-membered heterocyclic ring
containing at least one heteroatom selected from the group
consisting of oxygen, nitrogen and sulfur, wherein the 5- or
6-membered heterocyclic ring is saturated, partially unsaturated or
fully unsaturated, and wherein Het is optionally substituted with
alkyl or C(.dbd.O)OR.sup.1x,
[0202] wherein R.sup.1x is independently hydrogen, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocycloalkyl, alkylene-N(R.sup.1x).sub.2,
optionally substituted aryl, arylalkyl, alkylenearyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl, or
alkyleneheteroaryl, or two R.sup.1x groups are taken together to
form a 5- or 6-membered ring, optionally containing at least one
heteroatom,
[0203] wherein R.sup.1y is hydrogen, optionally substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl,
arylalkyl, heteroarylalkyl, alkylenearyl, and
alkyleneheteroaryl;
[0204] m is 0, 1, 2, 3, or 4;
[0205] each R.sup.2 is independently selected from hydrogen, halo,
cyano, optionally substituted alkyl, optionally substituted
haloalkyl, optionally substituted alkoxy, optionally substituted
cycloalkyl, or NR.sup.2xR.sup.2y, wherein each R.sup.2x and
R.sup.2y is independently hydrogen, C(O)R.sup.2s or C(O)OR.sup.2s,
wherein R.sup.2s is optionally substituted alkyl;
[0206] R.sup.3 is hydrogen, optionally substituted cycloalkyl, or
optionally substituted alkyl; and
[0207] R.sup.4 is hydrogen, cyano, CON(R.sup.4a).sub.2,
SO.sub.2-alkyl, halo, or haloalkyl, where each R.sup.4a is
independently hydrogen or optionally substituted alkyl.
[0208] In one embodiment, the application provides the compounds
having the structure of formula (I) that function as inhibitors of
PI3K isoforms, such as PI3K.delta., The structure of formula (I) is
shown below:
##STR00004##
or a pharmaceutically acceptable salt, isomer, a mixture of
isomers, prodrug, or solvate thereof, wherein each of n, R.sup.1,
m, R.sup.2, R.sup.3 and R.sup.4 are as defined for formula
(II).
[0209] In other embodiments, the compound having the structure of
formula (I) wherein:
[0210] n is 0, 1, 2, 3, or 4;
[0211] each R.sup.1 is independently halo, cyano, optionally
substituted alkylsulfonyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted heterocycloalkyl, or
optionally substituted alkoxy;
[0212] m is 0, 1, 2, 3, or 4;
[0213] each R.sup.2 is independently halo, optionally substituted
alkoxy, optionally substituted alkyl, optionally substituted
cycloalkyl, or optionally substituted heterocycloalkyl;
[0214] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkoxy,
or optionally substituted heterocycloalkyl; and
[0215] R.sup.4 is cyano.
[0216] In other embodiments, the compounds having the structure of
formula (I), wherein:
[0217] n is 1, 2, or 3;
[0218] each R.sup.1 is independently halo, cyano, C.sub.1-6
alkylsulfonyl, or C.sub.1-6 alkyl, wherein the alkyl moiety is
optionally substituted with halogen or cycloalkyl;
[0219] m is 0, 1, 2, or 3;
[0220] each R.sup.2 is independently halo, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl, wherein the alkoxy,
alkyl, or cycloalkyl moieties are optionally substituted with
halogen, alkyl, or cycloalkyl;
[0221] R.sup.3 is hydrogen, C.sub.1-6 alkyl, or C.sub.3-6
cycloalkyl, wherein the alkyl or cycloalkyl moieties are optionally
substituted with halogen, alkyl, or cycloalkyl; and
[0222] R.sup.4 is cyano.
[0223] In yet other embodiments, the compounds having the structure
of formula (I), wherein:
[0224] n is 1 or 2;
[0225] each R.sup.1 is independently selected from halogen, cyano,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkylsulfonyl, or
C.sub.3-6 cycloalkylC.sub.1-4alkyl;
[0226] m is 0, 1, or 2;
[0227] each R.sup.2 is independently selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, or C.sub.3-6 cycloalkylC.sub.1-4alkyl;
[0228] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.3-6 cycloalkylC.sub.1-4alkyl;
and
[0229] R.sup.4 is cyano.
[0230] In another embodiment, the compounds having the structure of
formula (I), wherein:
[0231] n is 1 or 2;
[0232] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0233] m is 0, 1, or 2;
[0234] each R.sup.2 is independently selected from fluoro, chloro,
iodo, bromo, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy,
methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl,
difluoromethyl, difluoroethyl, trifluoromethyl, cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl;
[0235] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0236] R.sup.4 is cyano.
[0237] In other embodiments, the compound having the structure of
formula (I) wherein:
[0238] n is 0, 1, 2, 3, or 4;
[0239] each R.sup.1 is independently halo, cyano, optionally
substituted alkylsulfonyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted heterocycloalkyl, or
optionally substituted alkoxy;
[0240] m is 0, 1, 2, 3, or 4;
[0241] each R.sup.2 is independently halo, --NH.sub.2, optionally
substituted alkoxyalkyl, optionally substituted alkyl, optionally
substituted cycloalkyl, or optionally substituted
heterocycloalkyl;
[0242] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted
alkoxyalkyl, or optionally substituted heterocycloalkyl; and
[0243] R.sup.4 is cyano, halo or --CONH.sub.2.
[0244] In other embodiments, the compounds having the structure of
formula (I), wherein:
[0245] n is 1, 2, or 3;
[0246] each R.sup.1 is independently halo, cyano, C.sub.1-6
alkylsulfonyl, or C.sub.1-6 alkyl, wherein the alkyl moiety is
optionally substituted with halogen or cycloalkyl;
[0247] m is 0, 1, 2, or 3;
[0248] each R.sup.2 is independently halo, --NH.sub.2, C.sub.1-6
alkoxy, C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl, wherein the
alkoxy, alkyl, or cycloalkyl moieties are optionally substituted
with halogen, alkyl, or cycloalkyl;
[0249] R.sup.3 is hydrogen, C.sub.1-6 alkyl, or C.sub.3-6
cycloalkyl, wherein the alkyl or cycloalkyl moieties are optionally
substituted with halogen, alkyl, or cycloalkyl; and
[0250] R.sup.4 is cyano, halo or --CONH.sub.2.
[0251] In yet other embodiments, the compounds having the structure
of formula (I), wherein:
[0252] n is 1 or 2;
[0253] each R.sup.1 is independently selected from halo, cyano,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkylsulfonyl, or
C.sub.3-6 cycloalkylC.sub.1-4alkyl;
[0254] m is 0, 1, or 2;
[0255] each R.sup.2 is independently selected from halo,
--NH.sub.2, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.3-6 cycloalkyl, or C.sub.3-6 cycloalkylC.sub.1-4alkyl;
[0256] R.sup.3 is selected from hydrogen, C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, or C.sub.3-6 cycloalkylC.sub.1-4alkyl;
and
[0257] R.sup.4 is cyano, halo or --CONH.sub.2.
[0258] In another embodiment, the compounds having the structure of
formula (I), wherein:
[0259] n is 1 or 2;
[0260] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0261] m is 0, 1, or 2;
[0262] each R.sup.2 is independently selected from fluoro, chloro,
iodo, bromo, --NH.sub.2, methyl, ethyl, propyl, butyl,
fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl;
[0263] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0264] R.sup.4 is cyano, halo or --CONH.sub.2.
[0265] In another embodiment, the compounds having the structure of
formula (I), wherein:
[0266] n is 1 or 2;
[0267] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0268] m is 0, 1, or 2;
[0269] each R.sup.2 is independently selected from fluoro, chloro,
iodo, bromo, --NH.sub.2, methyl, ethyl, propyl, butyl,
fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl;
[0270] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0271] R.sup.4 is cyano.
[0272] In another embodiment, the compounds having the structure of
formula (I), wherein:
[0273] n is 1 or 2;
[0274] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0275] m is 0, 1, or 2;
[0276] each R.sup.2 is independently selected from fluoro, chloro,
iodo, bromo, --NH.sub.2, methyl, ethyl, propyl, butyl,
fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl;
[0277] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0278] R.sup.4 is fluoro, chloro, or bromo.
[0279] In another embodiment, the compounds having the structure of
formula (I), wherein:
[0280] n is 1 or 2;
[0281] each R.sup.1 is independently selected from fluoro, chloro,
iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl,
fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
trifluoroethyl, methylsulfonyl, ethylsulfonyl, or
propylsulfonyl;
[0282] m is 0, 1, or 2;
[0283] each R.sup.2 is independently selected from fluoro, chloro,
iodo, bromo, --NH.sub.2, methyl, ethyl, propyl, butyl,
fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl;
[0284] R.sup.3 is selected from hydrogen, methyl, ethyl, propyl,
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, or
cyclopropylbutyl; and
[0285] R.sup.4 is --CONH.sub.2.
[0286] In one embodiment of formula (I), n is 0. In some
embodiments, n is 1, 2, 3, or 4. In other embodiments, n is 1, 2 or
3. In certain embodiments, n is 1 or 2. In one embodiment, n is 1.
In the embodiment where n is 1, the R.sup.1 moiety may be located
on any position of the quinazolinone ring, as depicted below.
##STR00005##
[0287] In another embodiment, n is 2. In embodiments where n is 2,
both R.sup.1 may be the same or different. Two R.sup.1 moieties may
be located on any two positions of the quinazolinone ring as
depicted below. For example, two R.sup.1 moieties may be in para-,
meta- or ortho-positions to each other.
##STR00006##
[0288] In yet another embodiment, n is 3. In embodiments where n is
3, all R.sup.1 may be the same or different, or two R.sup.1 may be
the same and different from the third R.sup.1. Three R.sup.1
moieties may be located on any three positions of the quinazolinone
ring as depicted below. For example, the first R.sup.1 may be ortho
to the second R.sup.1, and the first R.sup.1 may be para to the
third R.sup.1.
##STR00007##
[0289] In yet another embodiment, n is 4. In embodiments where n is
4, all R.sup.1 may be the same or different, three R.sup.1 may be
the same and different from the fourth R.sup.1, two R.sup.1 may be
the same and different from the third and the fourth R.sup.1.
##STR00008##
[0290] In some embodiments of formula (I), each R.sup.1 is
independently halo, cyano, optionally substituted alkyl, optionally
substituted haloalkyl, optionally substituted alkoxy, optionally
substituted cycloalkyl, or optionally substituted alkylsulfonyl. In
certain embodiments, each R.sup.1 is independently halo, cyano,
optionally substituted alkyl, or optionally substituted
alkylsulfonyl.
[0291] In some other embodiments of formula (I), each R.sup.1 is
independently halo, cyano, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.1-4 haloalkyl, optionally substituted
C.sub.1-4 alkoxy, hydroxy, optionally substituted C.sub.3-6
cycloalkyl, or optionally substituted C.sub.1-6 alkylsulfonyl. In
certain embodiments, each R.sup.1 is independently halo, cyano,
optionally substituted C.sub.1-4 alkyl, optionally substituted
C.sub.3-6 alkoxy, optionally substituted C.sub.3-6 cycloalkyl, or
optionally substituted C.sub.1-4 alkylsulfonyl. In other
embodiments, each R.sup.1 is independently halo, cyano, C.sub.1-4
haloalkyl, C.sub.1-4 alkyl, or C.sub.1-4 alkylsulfonyl.
[0292] In certain embodiments of formula (I), each R.sup.1 is
independently selected from fluoro, chloro, iodo, bromo, cyano,
methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl,
difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl,
methylsulfonyl, ethylsulfonyl, or propylsulfonyl. In some
embodiments, each R.sup.1 is independently fluoro, chloro, iodo,
cyano, methyl, difluoromethyl (--CHF.sub.2), trifluoromethyl
(--CF.sub.3), ethyl, methoxy, methylsulfonyl (--SO.sub.2CH.sub.3),
cyclopropylmethyl, or cyclopropyl. In one embodiment, each R.sup.1
is independently fluoro, chloro, cyano, methylsulfonyl, methyl, or
trifluoromethyl.
[0293] In some embodiments of formula (I) where n is 1, R.sup.1 is
halo, cyano, optionally substituted alkyl, optionally substituted
haloalkyl, optionally substituted alkoxy, hydroxy, optionally
substituted alkylsulfonyl, or optionally substituted cycloalkyl. In
other embodiments of formula (I) wherein n is 1, R.sup.1 is
independently halo, cyano, C.sub.1-4 haloalkyl, C.sub.1-4 alkyl, or
C.sub.1-4 alkylsulfonyl. In certain embodiments where n is 1,
R.sup.1 is fluoro, chloro, iodo, bromo, cyano, methyl, ethyl,
propyl, butyl, --CHF.sub.2, --CF.sub.3, fluoroethyl, fluoropropyl,
methylsulfonyl, or ethylsulfonyl. In another embodiment where n is
1, R.sup.1 is fluoro, chloro, cyano, methyl, trifluoromethyl
(--CF.sub.3), or methylsulfonyl (--SO.sub.2CH.sub.3). In another
embodiment where n is 1, R.sup.1 is fluoro, chloro, bromo, cyano,
methyl, trifluoromethyl (--CF.sub.3), or methylsulfonyl
(--SO.sub.2CH.sub.3). The R.sup.1 moiety may be located on any
position of the quinazolinone ring.
[0294] In other embodiments of formula (I) where n is 2, both
R.sup.1 are independently halo, which may be the same (e.g., both
R.sup.1 are fluoro, chloro, or iodo) or different (e.g., one
R.sup.1 is fluoro and the other R.sup.1 is chloro). In other
embodiments where n is 2, one R.sup.1 is halo and the other R.sup.1
is optionally substituted alkyl. In other embodiments where n is 2,
one R.sup.1 is halo and the other R.sup.1 is optionally substituted
cycloalkyl. In other embodiments where n is 2, one R.sup.1 is halo
and the other R.sup.1 is cyano. In additional embodiments, each
R.sup.1 is independently selected from fluoro, chloro, bromo,
cyano, methyl, trifluoromethyl (--CF.sub.3), or methylsulfonyl
(--SO.sub.2CH.sub.3). In other embodiments of formula (I) where n
is 2, one R.sup.1 is bromo and the other R.sup.1 is fluoro.
[0295] In certain embodiments where n is 2, both R.sup.1 are
chloro, or both R.sup.1 are fluoro. In other embodiments where n is
2, one R.sup.1 is chloro and the other R.sup.1 is fluoro; one
R.sup.1 is chloro and the other R.sup.1 is methyl; one R.sup.1 is
fluoro and the other R.sup.1 is methyl; one R.sup.1 is fluoro and
the other R.sup.1 is cyano; one R.sup.1 is chloro and the other
R.sup.1 is cyano. In certain other embodiments where n is 2; one
R.sup.1 is bromo and the other R.sup.1 is fluoro. The two R.sup.1
moieties may be located at any two positions of the quinazolinone
ring as depicted below.
[0296] In some embodiments, the moiety
##STR00009##
of formula (I) is:
##STR00010##
[0297] In certain embodiments, the moiety
##STR00011##
of formula (I) is:
##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016##
In other embodiments, the moiety
##STR00017##
of formula (I) is
##STR00018##
[0298] Each and every variation of n and R.sup.1 may be combined
with each and every variation of m, R.sup.2 and R.sup.3 as
described for formula (I), as if each and every combination is
individually described.
[0299] In some embodiments of formula (I), m is 0. In certain
embodiments, m is 1, 2, 3, or 4. In other embodiments, m is 1, 2 or
3. In yet other embodiments, m is 1 or 2. In one embodiment, m is
1. The R.sup.2 moiety may be located on any position of the
pyridinyl ring, as depicted below.
##STR00019##
[0300] In another embodiment, m is 2. In embodiments where m is 2,
both R.sup.2 may be the same or different. The two R.sup.2 moieties
may be located on any two positions of the pyridinyl ring, as
depicted below.
##STR00020##
[0301] In yet another embodiment, m is 3. In embodiments where m is
3, all R.sup.2 may be the same or different, or two R.sup.2 may be
the same and different from the third R.sup.2. The three R.sup.2
moieties may be located on any three positions of the pyridinyl
ring, as depicted below.
##STR00021##
[0302] In certain embodiment, m is 4. In embodiments where m is 4,
all R.sup.2 may be the same or different, three R.sup.2 may be the
same and different from the fourth R.sup.2, or two R.sup.2 may be
the same and different from the third and the fourth R.sup.2.
##STR00022##
[0303] In some embodiments of formula (I), each R.sup.2 is
independently halo, cyano, optionally substituted alkyl, optionally
substituted heteroalkyl, optionally substituted haloalkyl,
optionally substituted alkoxy, optionally substituted
heterocycloalkyl, or optionally substituted cycloalkyl. In other
embodiments of formula (I), each R.sup.2 is independently halo,
cyano, optionally substituted alkyl, optionally substituted alkoxy,
optionally substituted haloalkyl, or optionally substituted
cycloalkyl. In certain embodiments of formula (I), each R.sup.2 is
independently halo, cyano, optionally substituted C.sub.1-6 alkyl,
optionally substituted C.sub.1-6 haloalkyl, optionally substituted
C.sub.1-6 alkoxy, or optionally substituted C.sub.3-8 cycloalkyl.
In some embodiments of formula (I), each R.sup.2 is independently
halo, --NH.sub.2, cyano, optionally substituted alkyl, optionally
substituted heteroalkyl, optionally substituted haloalkyl,
optionally substituted alkoxy, optionally substituted
heterocycloalkyl, or optionally substituted cycloalkyl. In certain
embodiments of formula (I), each R.sup.2 is independently halo,
--NH.sub.2, cyano, optionally substituted C.sub.1-6 alkyl,
optionally substituted C.sub.1-6 haloalkyl, optionally substituted
C.sub.1-6 alkoxy, or optionally substituted C.sub.3-8 cycloalkyl.
In certain embodiments of formula (I), each R.sup.2 is
independently halo, --NH.sub.2, cyano, optionally substituted
C.sub.1-4 alkyl, optionally substituted C.sub.1-4 haloalkyl,
optionally substituted C.sub.1-4 alkoxy, or optionally substituted
C.sub.3-6 cycloalkyl. In some embodiments, each R.sup.2 is
independently fluoro, chloro, iodo, bromo, --NH.sub.2, methoxy,
ethoxy, propoxy, butoxy, pentoxy, hexoxy, --CHF.sub.2, --CF.sub.3,
fluoroethyl, difluoroethyl, methyl, ethyl, propyl, butyl,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one
embodiment, each R.sup.2 is independently fluoro, chloro, methoxy,
methyl, --NH.sub.2, --CHF.sub.2, --CF.sub.3, or cyclopropyl.
[0304] In certain embodiments of formula (I), each R.sup.2 is
independently halo, cyano, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.1-4 haloalkyl, optionally substituted
C.sub.1-4 alkoxy, or optionally substituted C.sub.3-6 cycloalkyl.
In some embodiments, each R.sup.2 is independently fluoro, chloro,
iodo, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy,
--CHF.sub.2, --CF.sub.3, fluoroethyl, difluoroethyl, methyl, ethyl,
propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In one embodiment, each R.sup.2 is independently fluoro, chloro,
methoxy, methyl, --CHF.sub.2, --CF.sub.3, or cyclopropyl.
[0305] In some embodiments of formula (I) where m is 1, R.sup.2 is
halo, cyano, optionally substituted haloalkyl, optionally
substituted alkyl, optionally substituted cycloalkyl, or optionally
substituted alkoxy. In certain embodiments where m is 1, R.sup.2 is
fluoro, chloro, iodo, cyano, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, or C.sub.3-6 cycloalkyl. In other embodiments
where m is 1, R.sup.2 is fluoro, chloro, methoxy, methyl, ethoxy,
propoxy, butoxy, pentoxy, hexoxy, --CHF.sub.2, --CF.sub.3,
fluoroethyl, difluoroethyl, ethyl, propyl, cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl. In one embodiment where m is 1, R.sup.2
is fluoro, chloro, methoxy, methyl, difluoromethyl (--CHF.sub.2),
trifluoromethyl (--CF.sub.3), or cyclopropyl. The R.sup.2 moiety
may be located on any position of the pyridinyl ring. In certain
embodiments where m is 1, R.sup.2 is fluoro, chloro, iodo, bromo,
--NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, or C.sub.3-6 cycloalkyl. In other embodiments where m is 1,
R.sup.2 is fluoro, chloro, methoxy, methyl, ethoxy, propoxy,
butoxy, pentoxy, hexoxy, --NH.sub.2, --CHF.sub.2, --CF.sub.3,
fluoroethyl, difluoroethyl, ethyl, propyl, cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl. In one embodiment where m is 1, R.sup.2
is fluoro, chloro, --NH.sub.2, methoxy, methyl, difluoromethyl
(--CHF.sub.2), trifluoromethyl (--CF.sub.3), or cyclopropyl. The
R.sup.2 moiety may be located on any position of the pyridinyl
ring.
[0306] In some embodiments of formula (I) where m is 2, both
R.sup.2 are independently halo, which may be the same (e.g., both
R.sup.2 are fluoro or chloro) or different (e.g., one R.sup.2 is
fluoro and the other R.sup.2 is chloro). In other embodiments where
m is 2, both R.sup.2 are independently optionally substituted
alkyl, which may be the same (e.g., both R.sup.2 are methyl) or
which may be different (e.g., one R.sup.2 is methyl and the other
R.sup.2 is ethyl). In other embodiments where m is 2, both R.sup.2
are independently optionally substituted haloalkyl, which may the
same (e.g., both R.sup.2 are --CF.sub.3) or which may be different
(e.g., one R.sup.2 is --CF.sub.3 and the other R.sup.2 is
--CHF.sub.2). In yet other embodiments where m is 2, both R.sup.2
are independently optionally substituted alkoxy, which may be the
same (e.g., both R.sup.2 are methoxy) or which may be different
(e.g., one R.sup.2 is methoxy and the other R.sup.2 is ethoxy). In
some embodiments where m is 2, both R.sup.2 are independently
optionally substituted cycloalkyl, which may the same (e.g., both
R.sup.2 are cyclopropyl) or which may be different (e.g., one
R.sup.2 is methylcyclopropyl and the other R.sup.1 is cyclopropyl).
In other embodiments where m is 2, one R.sup.2 is halo and the
other R.sup.2 is cyano, one R.sup.2 is halo and the other R.sup.2
is optionally substituted haloalkyl, one R.sup.2 is halo and the
other R.sup.2 is optionally substituted alkyl, one R.sup.2 is halo
and the other R.sup.2 is optionally substituted alkoxy, one R.sup.2
is halo and the other R.sup.2 is optionally substituted cycloalkyl,
one R.sup.2 is optionally substituted alkyl and the other R.sup.2
is optionally substituted cycloalkyl, or one R.sup.2 is optionally
substituted alkyl and the other R.sup.2 is optionally substituted
alkoxy. In further embodiments, each R.sup.2 is independently
selected from fluoro, chloro, --NH.sub.2, methoxy, methyl,
difluoromethyl (--CHF.sub.2), trifluoromethyl (--CF.sub.3), or
cyclopropyl. In yet other embodiments where m is 2, one R.sup.2 is
--NH.sub.2 and the other R.sup.2 is optionally substituted
alkyl.
[0307] In certain embodiments of formula (I) where m is 2, both
R.sup.2 are fluoro, both R.sup.2 are chloro, both R.sup.2 are
methoxy, both R.sup.2 is methyl, or both R.sup.2 is cyclopropyl. In
yet other embodiments where m is 2, one R.sup.2 is fluoro and the
other R.sup.2 is chloro, one R.sup.2 is fluoro and the other
R.sup.2 is cyano, one R.sup.2 is chloro and the other R.sup.2 is
cyano, one R.sup.2 is fluoro and the other R.sup.2 is --CF.sub.3,
one R.sup.2 is fluoro and the other R.sup.2 is --CHF.sub.2, one
R.sup.2 is chloro and the other R.sup.2 is --CF.sub.3, one R.sup.2
is chloro and the other R.sup.2 is --CHF.sub.2, one R.sup.2 is
cyano and the other R.sup.2 is --CF.sub.3, one R.sup.2 is cyano and
the other R.sup.2 is --CHF.sub.2, one R.sup.2 is fluoro and the
other R.sup.2 is methyl, one R.sup.2 is chloro and the other
R.sup.2 is methyl, one R.sup.2 is fluoro and the other R.sup.2 is
cyclopropyl, or one R.sup.2 is chloro and the other R.sup.2 is
cyclopropyl. In additional embodiments, one R.sup.2 is --NH.sub.2
and the other R.sup.2 is methyl. The two R.sup.2 moieties may be
located on any two positions of the pyridinyl ring.
[0308] In yet other embodiments of formula (I) where m is 3, one or
two of R.sup.2 are independently halo, which may be the same (e.g.,
two R.sup.2 are fluoro) or which may be different (e.g., one
R.sup.2 is fluoro and another R.sup.2 is chloro), the third R.sup.2
is optionally substituted alkoxy (e.g., third R.sup.2 is methoxy).
In another embodiment where m is 3, one R.sup.2 is optionally
substituted alkyl, another R.sup.2 is optionally substituted
alkoxy, and the third R.sup.2 is halo. The three R.sup.2 moieties
may be located on any three positions of the pyridinyl ring.
[0309] In some embodiments, the moiety
##STR00023##
of formula (I) is:
##STR00024## ##STR00025##
In some other embodiments, the moiety
##STR00026##
of formula (I) is
##STR00027##
[0310] Each and every variation of m and R.sup.2 may be combined
with each and every variation of n, R.sup.1 and R.sup.3 as
described for formula (I), as if each and every combination is
individually described.
[0311] In some embodiments of formula (I), R.sup.3 is hydrogen,
optionally substituted alkyl, optionally substituted heteroalkyl,
optionally substituted heterocycloalkyl, or optionally substituted
cycloalkyl. In other embodiments of formula (I), R.sup.3 is
hydrogen, optionally substituted C.sub.1-6 alkyl, optionally
substituted C.sub.3-8 cycloalkylC.sub.1-6 alkyl or optionally
substituted C.sub.3-8 cycloalkyl. In one embodiment, R.sup.3 is
hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, or C.sub.3-6
cycloalkylC.sub.1-4 alkyl. In some embodiments, R.sup.3 is
hydrogen, methyl, ethyl, propyl, butyl, cyclopropylmethyl,
cyclopropylbutyl, cyclobutylmethyl, or cyclopropylethyl,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other
embodiments, R.sup.3 is methyl, ethyl, cyclopropylmethyl, or
cyclopropyl. In other embodiments, R.sup.3 is methyl, ethyl,
propyl, butyl, cyclopropylmethyl, or cyclopropyl.
[0312] Each and every variation of R.sup.3 may be combined with
each and every variation of n, R.sup.1, m and R.sup.2 as described
for formula (I), as if each and every combination is individually
described.
[0313] In additional embodiments, R.sup.4 is hydrogen, cyano,
--C(O)N(R.sup.4a).sub.2, or halo, wherein each R.sup.4a is
independently hydrogen or optionally substituted C.sub.1-6 alkyl.
In some additional embodiments, R.sup.4 is cyano, halo,
--C(O)N(R.sup.4a).sub.2 wherein each R.sup.4a is independently
hydrogen or C.sub.1-4 alkyl. In certain additional embodiments,
R.sup.4 is cyano, fluoro, bromo, chloro, or --C(O)NH.sub.2. In
certain embodiments, R.sup.4 is cyano, chloro, or --C(O)NH.sub.2.
It is understood by those skilled in the art that
"--C(.dbd.O)NH.sub.2", "--C(O)NH.sub.2", and "--CONH.sub.2" are
equivalent and used interchangeably. Each and every variation of
R.sup.4 may be combined with each and every variation of n,
R.sup.1, m, R.sup.2, and R.sup.3 as described herein, as if each
and every combination is individually described.
[0314] In some embodiments of formula (I),
[0315] n is 1 or 2;
[0316] each R.sup.1 is independently halo, cyano, C.sub.3-6
alkylsulfonyl, C.sub.1-4 haloalkyl, or C.sub.1-4 alkyl;
[0317] m is 0, 1 or 2;
[0318] each R.sup.2 is independently halo, C.sub.1-4 alkoxy,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6 cycloalkyl;
[0319] R.sup.3 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
or C.sub.3-6 cycloalkylC.sub.1-4 alkyl; and
[0320] R.sup.4 is cyano.
[0321] In one embodiment of formula (I),
[0322] n is 1 or 2;
[0323] each R.sup.1 is independently selected from fluoro, chloro,
methylsulfonyl, cyano, methyl, trifluoromethyl;
[0324] m is 0, 1 or 2;
[0325] each R.sup.2 is independently selected from fluoro, chloro,
methoxy, methyl, difluoromethyl, trifluoromethyl, or
cyclopropyl;
[0326] R.sup.3 is methyl, ethyl, cyclopropyl, or cyclopropylmethyl;
and
[0327] R.sup.4 is cyano.
[0328] In some other embodiments of formula (I),
[0329] n is 1 or 2;
[0330] each R.sup.1 is independently halo, cyano, C.sub.3-6
alkylsulfonyl, C.sub.1-4 haloalkyl, or C.sub.1-4 alkyl;
[0331] m is 0, 1 or 2;
[0332] each R.sup.2 is independently halo, --NH.sub.2, C.sub.1-4
alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6
cycloalkyl;
[0333] R.sup.3 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
or C.sub.3-6 cycloalkylC.sub.1-4 alkyl; and
[0334] R.sup.4 is cyano, halo or --CONH.sub.2
[0335] In one other embodiment of formula (I),
[0336] n is 1 or 2;
[0337] each R.sup.1 is independently selected from fluoro, chloro,
methylsulfonyl, cyano, methyl, trifluoromethyl;
[0338] m is 0, 1 or 2;
[0339] each R.sup.2 is independently selected from fluoro, chloro,
--NH.sub.2, methoxy, methyl, difluoromethyl, trifluoromethyl, or
cyclopropyl;
[0340] R.sup.3 is methyl, ethyl, cyclopropyl, or cyclopropylmethyl;
and
[0341] R.sup.4 is cyano, halo or --CONH.sub.2.
[0342] In some other embodiments of formula (I),
[0343] n is 1 or 2;
[0344] each R.sup.1 is independently halo, cyano, C.sub.3-6
alkylsulfonyl, C.sub.1-4 haloalkyl, or C.sub.1-4 alkyl;
[0345] m is 0, 1 or 2;
[0346] each R.sup.2 is independently halo, --NH.sub.2, C.sub.1-4
alkoxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6
cycloalkyl;
[0347] R.sup.3 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
or C.sub.3-6 cycloalkylC.sub.1-4 alkyl; and
[0348] R.sup.4 is halo or --CONH.sub.2.
[0349] In yet another embodiment of formula (I),
[0350] n is 1 or 2;
[0351] each R.sup.1 is independently selected from fluoro, chloro,
bromo, cyano, methyl, trifluoromethyl, and methylsulfonyl;
[0352] m is 0, 1, or 2;
[0353] each R.sup.2 is independently selected from fluoro, chloro,
bromo, methoxy, methyl, difluoromethyl, trifluoromethyl, and
cyclopropyl;
[0354] R.sup.3 is selected from methyl, ethyl, propyl, butyl,
cyclopropyl, and cyclopropylmethyl; and
[0355] R.sup.4 is chloro, fluoro, bromo, or --CONH.sub.2.
[0356] In some embodiments of formula (I) where n is 2, m is 2, and
R.sup.4 is cyano, the compounds have the structure of formula
(IA):
##STR00028##
or a pharmaceutically acceptable salt, isomer, a mixture of
isomers, prodrug, or solvate thereof, wherein:
[0357] each R.sup.1a and R.sup.1b can be independently selected
from the moieties defined for R.sup.1 of formula (I);
[0358] each R.sup.2a and R.sup.2b can be independently selected
from the moieties defined for R.sup.2 of formula (I); and
[0359] R.sup.3 is as defined for formula (I).
[0360] In other embodiments of formula (I) where n is 1, m is 2,
and R.sup.4 is cyano, the compounds have the structure of formula
(IB):
##STR00029##
or a pharmaceutically acceptable salt, isomer, a mixture of
isomers, prodrug, or solvate thereof, wherein:
[0361] R.sup.1 is as defined for formula (I);
[0362] each R.sup.2a and R.sup.2b can be independently selected
from the moieties defined for R.sup.2 of formula (I); and
[0363] R.sup.3 is as defined for formula (I).
[0364] In another embodiments where n is 2, m is 1, and R.sup.4 is
cyano, the compounds have the structure of formula (IC):
##STR00030##
or a pharmaceutically acceptable salt, tautomer, isomer, a mixture
of isomers, prodrug, or solvate thereof, wherein:
[0365] each R.sup.1a and R.sup.1b can be independently selected
from the moieties defined for R.sup.1 of formula (I);
[0366] R.sup.2 is as defined for formula (I); and
[0367] R.sup.3 is as defined for formula (I).
[0368] In another embodiments where n is 1, m is 1, and R.sup.4 is
cyano, the compounds have the structure of formula (ID):
##STR00031##
or a pharmaceutically acceptable salt, tautomer, isomer, a mixture
of isomers, or prodrug thereof, wherein:
[0369] R.sup.1 is as defined for formula (I);
[0370] R.sup.2 is as defined for formula (I); and
[0371] R.sup.3 is as defined for formula (I).
[0372] In another embodiments where n is 1, m is 0, and R.sup.4 is
cyano, the compounds have the structure of formula (IE):
##STR00032##
or a pharmaceutically acceptable salt, tautomer, isomer, a mixture
of isomers, or prodrug thereof, wherein:
[0373] R.sup.1 is as defined for formula (I); and
[0374] R.sup.3 is as defined for formula (I).
[0375] In another embodiments where n is 2, m is 0, and R.sup.4 is
cyano, the compounds have the structure of formula (IF):
##STR00033##
or a pharmaceutically acceptable salt, tautomer, isomer, a mixture
of isomers, or prodrug thereof, wherein:
[0376] each R.sup.1a and R.sup.1b can be selected from the moieties
defined for R.sup.1 of formula (I); and
[0377] R.sup.3 is as defined for formula (I).
[0378] It should be understood that the embodiments and structures
as described herein with respect to formula (I) are suitable for
compounds of any formulae detailed herein where applicable.
[0379] For compounds of the present application bearing one or more
chiral centers, each unique stereoisomer has an unique compound
number. As an example, the structure below bearing one chiral
center can be resolved into the (S) and (R) enantiomer.
##STR00034##
[0380] In any one of the foregoing embodiments, the compound
according to any of the formulae described herein or a
pharmaceutically acceptable salt thereof, is the
(S)-enantiomer.
[0381] In any one of the foregoing embodiments, the compound
according to any of the formulae described herein or a
pharmaceutically acceptable salt thereof, is the
(R)-enantiomer.
[0382] The application also provides a composition containing a
mixture of enantiomers of the compound according to any of the
formulae described herein or a pharmaceutically acceptable salt
thereof. In some embodiments, the composition contains the
(S)-enantiomer of the compound and is substantially free of its
corresponding (R)-enantiomer. In certain embodiments, a composition
substantially free of the (R)-enantiomer has less than or about
40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01% of the
(R)-enantiomer. In other embodiments, the composition containing
the (S)-enantiomer of a compound according to any of formulae
described herein or a pharmaceutically acceptable salt thereof,
predominates over its corresponding (R)-enantiomer by a molar ratio
of at least or about 9:1, at least or about 19:1, at least or about
40:1, at least or about 80:1, at least or about 160:1, or at least
or about 320:1.
[0383] The composition containing a compound according to any of
the formulae described herein or a pharmaceutically acceptable salt
thereof, may also contain the compound in enantiomeric excess
(e.e.). For instance, a compound with 95% (S)-isomer and 5%
(R)-isomer will have an e.e. of 90%. In some embodiments, the
compound has an e.e. of at least or about 60%, 75%, 80%, 85%, 90%,
95%, 98% or 99%. In some of the foregoing embodiments, the compound
is enantiomerically-enriched in the (S)-isomer of compound
according to any of the formula described herein.
[0384] Provided is also a composition comprising a mixture of the
(S)-enantiomer and the (R)-enantiomer of a compound according to
any of the formulae described herein or a pharmaceutically
acceptable salt thereof. In one embodiment, the mixture is a
racemic mixture. In other embodiments, the composition comprises
the (S)-enantiomer of a compound according to any of formulae
described herein or a pharmaceutically acceptable salt thereof,
wherein the (S)-enantiomer of the compound is present in excess of
over the corresponding the (R)-enantiomer of the compound, or a
pharmaceutically acceptable salt thereof.
[0385] In any one of the foregoing embodiments, the compound
according to any of the formulae described herein or a
pharmaceutically acceptable salt thereof, is an atropisomer. A
composition containing a mixture of atropisomers of the compound of
any of the formulae described herein or a pharmaceutically
acceptable salt thereof, is also provided herein. "Atropisomers"
refers to conformational stereoisomers which occur when rotation
about a single bond in the molecule is prevented, or greatly
hindered, as a result of steric interactions with other parts of
the molecule and the substituents at both ends of the single bond
are asymmetrical, i.e., they do not require a stereocenter. Where
the rotational barrier about the single bond is high enough, and
interconversion between conformations is slow enough, separation
and isolation of the isomeric species may be permitted.
Atropisomers are enantiomers without a single asymmetric atom. In
some embodiments, the compounds described herein may contain a
mixture of diastereomers.
[0386] In any one of the foregoing embodiments, the compound
according to any of the formulae described herein or a
pharmaceutically acceptable salt thereof, is the atropisomer. As an
example, atropisomers are exemplified by the below structures.
##STR00035##
[0387] Representative compounds of the present application are
listed in Table 1 below. The compounds in Table 1 are named using
ChemBioDraw Ultra 12.0 and it should be understood that other names
may be used to identify compounds of the same structure. Other
compounds or radicals may be named with common names, or systematic
or non-systematic names. The compounds may also be named using
other nomenclature systems and symbols that are commonly recognized
in the art of chemistry including, for example, Chemical Abstract
Service (CAS) and International Union of Pure and Applied Chemistry
(IUPAC), Table 1 shows the naming and numbering of the compounds
that represent the formulae described herein. The compounds
provided in Table 1 may be a single enantiomer (e.g.,
(S)-enantiomer, (R)-enantiomer), or the compounds may be present in
a composition having an enantiomeric mixture. Additional
representative compounds are listed in Table 1a below. As those in
Table 1, the compounds in Table 1a are named using ChemBioDraw
Ultra 12.0. The compounds provided in Table 1a may be a single
enantiomer (e.g., (S)-enantiomer, (R)-enantiomer), or the compounds
may be present in a composition having an enantiomeric mixture. In
some embodiments, the compounds provided in Tables 1 and 1a are
atropisomers.
TABLE-US-00001 TABLE 1 Representative Compounds No. STRUCTURE Name
1 ##STR00036## (S)-2,4- diamino- 6-(1-(5- chloro- 4-oxo-
3-(pyridin- 3-yl)-3,4- dihydro- quinazolin- 2-yl) ethylamino)
pyrimidine- 5-carbonitrile 2 ##STR00037## (S)-2,4- diamino-
6-(1-(5- chloro- 4-oxo- 3-(pyridin- 3-yl)-3,4- dihydro- quinazolin-
2-yl) propylamino) pyrimidine- 5-carbonitrile 3 ##STR00038##
(S)-2,4- diamino- 6-((5- chloro- 4-oxo- 3-(pyridin- 3-yl)-3,4-
dihydro- quinazolin- 2-yl) (cyclopropyl) methyl- amino) pyrimidine-
5- carbonitrile 4 ##STR00039## (S)-2,4- diamino- 6-(1-(5- chloro-
4-oxo- 3-(pyridin- 3-yl)-3,4- dihydro- quinazolin- 2-yl)-2-
cyclopropyl- ethylamino) pyrimidine-5- carbonitrile 5 ##STR00040##
(S)-2,4- diamino- 6-(1-(6- fluoro- 4-oxo- 3-(pyridin- 3-yl)-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile 7
##STR00041## (S)-2,4- diamino- 6-(1-(5- methyl- 4-oxo- 3-(pyridin-
3-yl)-3,4- dihydro- quinazolin- 2-yl) ethylamino) pyrimidine-
5-carbonitrile 8 ##STR00042## (S)-2,4- diamino- 6-(1-(5- (methyl-
sulfonyl)- 4-oxo- 3-(pyridin-3- yl)-3,4- dihydro- quinazolin- 2-yl)
ethylamino) pyrimidine- 5-carbonitrile 9 ##STR00043## (S)-2,4-
diamino- 6-(1-(4- oxo-3- (pyridin- 3-yl)-5- (trifluoro- methyl)-
3,4- dihydro- quinazolin- 2-yl) ethylamino) pyrimidine-
5-carbonitrile 10 ##STR00044## (S)-2-(1-(2,6- diamino-5- cyano-
pyrimidin-4- ylamino) ethyl)- 4-oxo-3- (pyridin- 3-yl)-3,4-
dihydro- quinazoline- 5- carbonitrile 11 ##STR00045## (S)-2,4-
diamino- 6-(1-(3- (5- fluoro- pyridin- 3-yl)-5- methyl-4- oxo-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile
12 ##STR00046## (S)-2,4- diamino- 6-(1-(5- chloro-3-(5-
fluoropyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl)
ethylamino) pyrimidine- 5-carbonitrile 13 ##STR00047## (S)-2,4-
diamino- 6-(1-(5- chloro-3-(5- chloropyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile
14 ##STR00048## (S)-2,4- diamino- 6-(1-(5- chloro-3-(5- methoxy-
pyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl) ethylamino)
pyrimidine- 5-carbonitrile 15 ##STR00049## (S)-2,4- diamino-
6-(1-(5- chloro-3-(5- (difluoro- methyl) pyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile
16 ##STR00050## (S)-2,4- diamino- 6-(1-(5- chloro-3-(5-
methylpyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl)
ethylamino) pyrimidine- 5-carbonitrile 17 ##STR00051## (S)-2,4-
diamino- 6-((5- chloro-3-(5- methylpyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin- 2-yl) (cyclopropyl) methyl- amino) pyrimidine-
5- carbonitrile 18 ##STR00052## (S)-2,4- diamino- 6-(1-(5-
chloro-4- oxo-3-(5- (trifluoro- methyl) pyridin- 3-yl)-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile
19 ##STR00053## (S)-2,4- diamino- 6-(1-(5- chloro-3-(5-
cyclopropyl- pyridin- 3-yl)- 4-oxo-3,4- dihydro- quinazolin- 2-yl)
ethylamino) pyrimidine- 5-carbonitrile 20 ##STR00054## (S)-2,4-
diamino- 6-(1-(5- chloro-3-(5- fluoropyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin- 2-yl) propylamino) pyrimidine- 5-carbonitrile
21 ##STR00055## (S)-2,4- diamino- 6-((5- chloro-3-(5-
fluoropyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl)
(cyclopropyl) methyl- amino) pyrimidine-5- carbonitrile 22
##STR00056## (S)-2,4- diamino- 6-(1-(8- chloro-4-oxo- 3-(pyridin-
3-yl)-3,4- dihydro- quinazolin- 2-yl) ethylamino) pyrimidine-
5-carbonitrile 23 ##STR00057## (S)-2,4- diamino- 6-(1-
(5,8-dichloro- 4-oxo-3- (pyridin-3- yl)-3,4- dihydro- quinazolin-
2-yl) ethylamino) pyrimidine- 5-carbonitrile 24 ##STR00058##
(S)-2,4- diamino- 6-(1-(5- chloro- 8-fluoro- 4-oxo-3- (pyridin-3-
yl)-3,4- dihydro- quinazolin- 2-yl) ethylamino) pyrimidine-
5-carbonitrile 25 ##STR00059## (S)-2,4- diamino- 6-(1-
(5,8-difluoro- 4-oxo-3- (pyridin-3- yl)-3,4- dihydro- quinazolin-
2-yl) ethylamino) pyrimidine- 5-carbonitrile 26 ##STR00060##
(S)-2,4- diamino- 6-(1-(5- chloro- 8-fluoro- 4-oxo-3- (pyridin-3-
yl)-3,4- dihydro- quinazolin- 2-yl) propylamino) pyrimidine-
5-carbonitrile 27 ##STR00061## (S)-2,4- diamino- 6-((5- chloro-
8-fluoro- 4-oxo-3- (pyridin-3- yl)-3,4- dihydro- quinazolin- 2-yl)
(cyclopropyl) methyl- amino) pyrimidine-5- carbonitrile 28
##STR00062## (S)-2,4- diamino-6- (cyclopropyl (5,8- dichloro-
4-oxo-3- (pyridin- 3-yl)-3,4- dihydro- quinazolin- 2-yl)
methylamino) pyrimidine-5- carbonitrile 29 ##STR00063## (S)-2,4-
diamino- 6-(1-(5- chloro- 8-fluoro- 4-oxo-3- (pyridin- 3-yl)-3,4-
dihydro- quinazolin- 2-yl)- 2- cyclopropyl- ethylamino)
pyrimidine-5- carbonitrile 30 ##STR00064## (S)-2,4- diamino- 6-(1-
(5,8-dichloro- 3-(5- fluoropyridin- 3-yl)-4- oxo-3,4- dihydro-
quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile 31
##STR00065## (S)-2,4- diamino- 6-(1-(5- chloro-8- fluoro-3-(5-
fluoropyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl)
ethylamino) pyrimidine- 5-carbonitrile 32 ##STR00066## (S)-2,4-
diamino- 6-(1-(5- chloro-8- fluoro-3-(5- methylpyridin- 3-yl)-4-
oxo-3,4- dihydro- quinazolin- 2-yl) ethylamino) pyrimidine-
5-carbonitrile 33 ##STR00067## (S)-2,4- diamino- 6-((5- chloro-8-
fluoro-3-(5- fluoropyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin-
2-yl) (cyclopropyl) methyl- amino) pyrimidine-5- carbonitrile 34
##STR00068## (S)-2-(1-(2,6- diamino-5- cyano- pyrimidin- 4-
ylamino) ethyl)- 8-fluoro- 4-oxo-3- (pyridin-3-yl)- 3,4- dihydro-
quinazoline- 5-carbonitrile 35 ##STR00069## (S)-2-(1-(2,6-
diamino-5- cyano- pyrimidin- 4- ylamino) propyl)-8- fluoro-4-oxo-
3-(pyridin- 3-yl)-3,4- dihydro- quinazoline- 5- carbonitrile 36
##STR00070## (S)-2,4- diamino- 6-(1-(5- chloro-6- fluoro- 4-oxo-3-
(pyridin- 3-yl)-3,4- dihydro- quinazolin- 2-yl) ethylamino)
pyrimidine- 5-carbonitrile 37 ##STR00071## (S)-2,4- diamino- 6-((5-
chloro- 6-fluoro- 4-oxo-3- (pyridin- 3-yl)-3,4- dihydro-
quinazolin-2- yl) (cyclopropyl) methyl- amino) pyrimidine-5-
carbonitrile 38 ##STR00072## (S)-2,4- diamino- 6-(1-(5-
chloro-3-(2- methylpyridin- 3-yl)-4- oxo-3,4- dihydro-
quinazolin-2- yl) ethylamino) pyrimidine- 5-carbonitrile 39
##STR00073## (S)-2,4- diamino- 6-(1-(5- chloro-3-(2- methylpyridin-
3-yl)-4- oxo-3,4- dihydro- quinazolin- 2- yl) ethylamino)
pyrimidine- 5-carbonitrile 40 ##STR00074## (S)-2,4- diamino-
6-(1-(5- chloro-3-(4- methylpyridin- 3-yl)-4- oxo-3,4- dihydro-
quinazolin- 2- yl) ethylamino) pyrimidine- 5-carbonitrile 41
##STR00075## (S)-2,4- diamino- 6-(1-(5- chloro-3-(4- methylpyridin-
3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl) ethylamino)
pyrimidine- 5-carbonitrile 42 ##STR00076## (S)-2,4- diamino-
6-(1-(5- chloro-6- fluoro-3-(4- methylpyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine- 5-carbonitrile
43 ##STR00077## (S)-2,4- diamino- 6-(1-(5- chloro-6- fluoro-3-(4-
methylpyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin-2- yl)
ethylamino) pyrimidine- 5-carbonitrile 44 ##STR00078## (S)-2,4-
diamino- 6-(1-(5- chloro-3- (5-fluoro-2- methylpyridin- 3-yl)-4-
oxo-3,4- dihydro- quinazolin- 2- yl)ethylamino) pyrimidine-
5-carbonitrile 45 ##STR00079## (S)-2,4- diamino- 6-(1-(5- chloro-3-
(5-fluoro-2- methylpyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin-
2-yl) ethylamino) pyrimidine- 5-carbonitrile 46 ##STR00080##
(S)-2,4- diamino- 6-(1-(5- chloro-3- (5-fluoro-4- methylpyridin-
3-yl)-4- oxo-3,4- dihydro- quinazolin- 2-yl) ethylamino)
pyrimidine- 5-carbonitrile 47 ##STR00081## (S)-2,4- diamino-
6-(1-(5- chloro-3- (5-fluoro-4- methylpyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin- 2-yl) ethylamino) pyrimidine-
5-carbonitrile
TABLE-US-00002 TABLE 1a Representative Compounds No. Structure Name
48 ##STR00082## (S)-2,4- Diamino-6- ((1-(5-chloro- 8-fluoro-
3-(5-fluoro- pyridin-3- yl)-4-oxo-3,4- dihydro- quinazolin-2-
yl)propyl) amino) pyrimidine-5- carbonitrile 49 ##STR00083##
(S)-2-(1-((2,6- diamino-5- chloro- pyrimidin-4- yl)amino) ethyl)-5-
(methyl- sulfonyl)- 3- (pyridin-3- yl)quinazolin- 4(3H)- one 50
##STR00084## (S)-2,4- Diamino-6- ((1-(5-chloro- 4-oxo-3- (pyridin-
3-yl)-3,4- dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5-
carboxamide 51 ##STR00085## (S)-5-Chloro- 2-(1- ((2,6- diamino-5-
chloro- pyrimidin-4- yl)amino) ethyl)-3-(5- fluoropyridin- 3-
yl)quinazolin- 4(3h)- one 52 ##STR00086## (S)-2-(1-((2,6-
Diamino-5- chloro- pyrimidin-4- yl)amino) ethyl)-5- fluoro-3-
(pyridin-3- yl)quinazolin- 4(3H)- one 53 ##STR00087## (S)-5-Chloro-
2-(1- ((2,6- diamino-5- chloro- pyrimidin-4- yl)amino) ethyl)-3-
(pyridin-3- yl)quinazolin- 4(3H)- one 54 ##STR00088##
(S)-2-(1-((2,6- Diamino-5- cyano- pyrimidin-4- yl)amino) ethyl)-6-
fluoro- 4-oxo-3- (pyridin- 3-yl)-3,4- dihydro- quinazoline-8-
carbonitrile 55 ##STR00089## (S)-2-(1-((2,6- Diamino-5- cyano-
pyrimidin- 4- yl)amino) propyl)-6- fluoro-3-(5- fluoropyridin-
3-yl)-4- oxo-3,4- dihydro- quinazoline-8- carbonitrile 56
##STR00090## (S)-2- (Cyclopropyl ((2,6- diamino-5- cyano-
pyrimidin- 4- yl)amino) methyl)-6- fluoro-3-(5- fluoropyridin-
3-yl)-4- oxo-3,4- dihydro- quinazoline-8- carbonitrile 57
##STR00091## (S)-2,4- Diamino-6- ((1-(5- chloro-3-(5-
fluoropyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin-2- yl)-3-
methylbutyl) amino) pyrimidine-5- carbonitrile 58 ##STR00092##
(S)-2,4- Diamino-6- ((1-(5-chloro- 4-oxo-3- (pyridin- 3-yl)-3,4-
dihydro- quinazolin-2- yl)-3- methylbutyl) amino) pyrimidine-5-
carbonitrile 59 ##STR00093## (S)-2- (cyclopropyl ((2,6- diamino-5-
chloro- pyrimidin- 4- yl)amino) methyl)-8- fluoro- 4-oxo-3-
(pyridin- 3-yl)-3,4- dihydro- quinazoline-5- carbonitrile 60
##STR00094## (S)-2,4- diamino- 6-((1- (5-bromo- 8-fluoro-3- (5-
fluoropyridin- 3-yl)- 4-oxo-3,4- dihydro- quinazolin-2- yl)ethyl)
amino) pyrimidine-5- carbonitrile 61 ##STR00095## (S)-2,4- diamino-
6-((1- (5-bromo-8- fluoro-4- oxo-3- (pyridin-3-yl)- 3,4-dihydro-
quinazolin- 2- yl)propyl) amino) pyrimidine-5- carbonitrile 62
##STR00096## (S)-2-(1-((2,6- diamino-5- cyano- pyrimidin- 4-
yl)amino) ethyl)-8- fluoro-3-(5- fluoropyridin- 3-yl)-4- oxo-3,4-
diliydro- quinazoline-5- carbonitrile 63 ##STR00097##
(S)-2-(1-((2,6- diamino-5- chloro- pyrimidin- 4- yl)amino)
ethyl)-4- oxo-3-(pyridin- 3-yl)-3,4- dihydro- quinazoline-5-
carbonitrile 64 ##STR00098## (S)-2,4- diamino- 6-((1- (5-bromo-
8-fluoro-4- oxo-3- (pyridin- 3-yl)- 3,4-dihydro- quinazolin- 2-
yl)ethyl) amino) pyrimidine-5- carbonitrile 65 ##STR00099##
(S)-2,4- Diamino-6- (((5-chloro- 8-fluoro-3- (5-fluoro-4-
methylpyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin-2- yl)
(cyclopropyl) methyl) amino) pyrimidine-5- carbonitrile 66
##STR00100## (S)-2,4- Diamino-6- (((5-chloro- 8-fluoro-3-
(5-fluoro-4- methylpyridin- 3-yl)-4- oxo-3,4- dihydro-
quinazolin-2- yl) (cyclopropyl) methyl) amino) pyrimidine-5-
carbonitrile 67 ##STR00101## (S)-2,4- diamino- 6-((1- (5-fluoro-
3-(5-fluoro- 4- methylpyridin- 3-yl)- 4-oxo-3,4- dihydro-
quinazolin-2- yl)ethyl)amino) pyrimidine-5- carbonitrile 68
##STR00102## (S)-2,4- diamino- 6-((1- (5-fluoro-3- (5-fluoro- 4-
methylpyridin- 3-yl)- 4-oxo-3,4- dihydro- quinazolin-2-
yl)ethyl)amino) pyrimidine-5- carbonitrile 69 ##STR00103## (S)-2,4-
diamino-6- (((5-chloro- 3-(5- fluoro-4- methylpyridin- 3-yl)-4-
oxo-3,4- dihydro- quinazolin-2- yl) (cyclopropyl) methyl) amino)
pyrimidine-5- carbonitrile 70 ##STR00104## (S)-2,4- diamino-6-
(((5-chloro- 3-(5- fluoro-4- methylpyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin-2- yl) (cyclopropyl) methyl) amino)
pyrimidine-5- carbonitrile 71 ##STR00105## (S)-2,4- diamino- 6-((1-
(5-chloro- 3-(5-fluoro- 4- methylpyridin- 3-yl)- 4-oxo-3,4-
dihydro- quinazolin-2- yl)propyl) amino) pyrimidine-5- carbonitrile
72 ##STR00106## (S)-2,4- diamino- 6-((1- (5-chloro- 3-(5-fluoro- 4-
methylpyridin- 3-yl)- 4-oxo-3,4- dihydro- quinazolin-2- yl)propyl)
amino) pyrimidine-5- carbonitrile 73 ##STR00107## (S)-2,4- diamino-
6-((1- (5-chloro- 8-fluoro-3- (5-fluoro-4- methylpyridin- 3-yl)-4-
oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5-
carbonitrile 74 ##STR00108## (S)-2,4- diamino- 6-((1- (5-chloro-
8-fluoro-3- (5-fluoro-4- methylpyridin- 3-yl)-4- oxo-3,4- dihydro-
quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile 75
##STR00109## (S)-2,4- diamino- 6-((1- (6-fluoro- 3-(5-fluoro- 4-
methylpyridin- 3-yl)- 4-oxo-3,4- dihydro- quinazolin-2- yl)ethyl)
amino) pyrimidine-5- carbonitrile 76 ##STR00110## (S)-2,4- diamino-
6-((1- (6-fluoro- 3-(5-fluoro- 4- methylpyridin- 3-yl)- 4-oxo-3,4-
dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile
77 ##STR00111## (S)-2,4- diamino- 6-((1- (5-chloro- 3-(4,5-
dimethyl- pyridin- 3-yl)- 4-oxo-3,4- dihydro- quinazolin-2-
yl)ethyl) amino) pyrimidine-5- carbonitrile 78 ##STR00112##
(S)-2,4- diamino- 6-((1- (5-chloro- 3-(4,5- dimethyl- pyridin-
3-yl)- 4-oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino)
pyrimidine-5- carbonitrile 79 ##STR00113## (S)-2,4- Diamino-6-
((1-(3-(4- methylpyridin- 3-yl)-4- oxo-5- (trifluoro- methyl)-3,4-
dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile
80 ##STR00114## (S)-2,4- Diamino-6- (1-(3-(4- methylpyridin-
3-yl)-4- oxo-5- (trifluoro- methyl)-3,4- dihydro- quinazolin-2-
yl)ethyl) amino) pyrimidine-5- carbonitrile 81 ##STR00115##
(S)-3-(6- aminopyridin- 3-yl)-8- chloro- 2-(1-((2,6- diamino-5-
chloro- pyrimidin-4- yl)amino) ethyl)-6- fluoro- quinazolin-
4(3H)-one 82 ##STR00116## (S)-2,4- diamino- 6-((1- (3-(6-amino-
pyridin-3- yl)-8-chloro- 6-fluoro-4- oxo-3,4- dihydro-
quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile 83
##STR00117## (S)-3-(6- aminopyridin- 3-yl)-5,8- dichloro-2-(1-
((2,6- diamino-5- chloro- pyrimidin- 4- yl)amino) ethyl)
quinazolin- 4(3H)-one 84 ##STR00118## (S)-2,4- diamino-6-((1-
(3-(6- aminopyridin- 3-yl)-5,8- dichloro- 4-oxo- 3,4-dihydro-
quinazolin- 2- yl)ethyl) amino) pyrimidine-5- carbonitrile 85
##STR00119## (S)-3-(6- aminopyridin- 3-yl)-5- chloro-2-(1- ((2,6-
diamino-5- chloro- pyrimidin- 4- yl)amino) ethyl) quinazolin-
4(3H)-one 86 ##STR00120## (S)-3-(6- aminopyridin- 3-yl)-5-
chloro-2-(1- ((2,6- diamino-5- chloro- pyrimidin-4- yl)amino)
propyl) quinazolin- 4(3H)-one 87 ##STR00121## (S)-2,4-
diamino-6-((1- (3-(6- aminopyridin- 3- yl)-5-chloro- 4-oxo-3,4-
dihydro- quinazolin-2- yl)propyl) amino) pyrimidine-5- carbonitrile
88 ##STR00122## (S)-3-(6- aminopyridin- 3-yl)-5- chloro-2-(1-
((2,6- diamino-5- chloro- pyrimidin-4- yl)amino) ethyl)-8- fluoro-
quinazolin- 4(3H)-one 89 ##STR00123## (S)-3-(6- aminopyridin-
3-yl)-5- chloro-2- (cyclopropyl ((2,6- diamino-5- chloro-
pyrimidin- 4- yl)amino) methyl) quinazolin- 4(3H)-one 90
##STR00124## (S)-2,4- diamino- 6-(((3- (6-amino- pyridin-3-yl)-
5-chloro- 4-oxo-3,4- dihydro- quinazolin-2- yl) (cyclopropyl)
methyl) amino) pyrimidine-5- carbonitrile 91 ##STR00125## (S)-2,4-
diamino- 6-((1- (3-(6- amino-4- methylpyridin- 3-yl)-5- chloro-4-
oxo-3,4- dihydro- quinazolin-2- yl)propyl) amino) pyrimidine-5-
carbonitrile 92 ##STR00126## (S)-2,4- diamino- 6-((1-
(3-(6-amino-4- methylpyridin- 3-yl)-5- chloro-4- oxo-3,4- dihydro-
quinazolin-2- yl)propyl) amino) pyrimidine-5- carbonitrile 93
##STR00127## (S)-2,4- diamino- 6-((1- (3-(6- amino-4-
methylpyridin- 3-yl)-5- chloro-4- oxo-3,4- dihydro- quinazolin-2-
yl)ethyl) amino) pyrimidine-5- carbonitrile 94 ##STR00128##
(S)-2,4- diamino- 6-((1- (3-(6- amino-4- methyl- pyridin- 3-yl)-5-
chloro-4- oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino)
pyrimidine-5- carbonitrile 95 ##STR00129## (S)-2,4- diamino- 6-((1-
(3-(6- amino-4- methylpyridin- 3-yl)- 5,8-dichloro- 4-oxo-3,4-
dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile
96 ##STR00130## (S)-2,4- diamino- 6-((1- (3-(6-amino-4-
methylpyridin- 3-yl)- 5,8-dichloro- 4-oxo-3,4- dihydro-
quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile 97
##STR00131## (S)-2,4- diamino-6-((1- (3-(6- aminopyridin- 3-
yl)-5-chloro- 4-oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino)
pyrimidine-5- carbonitrile 98 ##STR00132## (S)-2,4- diamino-
6-(((3- (6-amino-4- methylpyridin- 3-yl)- 5,8-dichloro- 4-oxo-3,4-
dihydro- quinazolin-2- yl) (cyclopropyl) methyl) amino)
pyrimidine-5- carbonitrile 99 ##STR00133## (S)-2,4- diamino-
6-(((3- (6-amino-4- methylpyridin- 3-yl)- 5,8-dichloro- 4-oxo-3,4-
dihydro- quinazolin-2- yl) (cyclopropyl) methyl) amino)
pyrimidine-5- carbonitrile 100 ##STR00134## (S)-3-(6- aminopyridin-
3-yl)-5- chloro-2-(1- ((2,6- diamino-5- chloro- pyrimidin- 4-
yl)amino) ethyl)-6- fluoro- quinazolin- 4(3H)-one 101 ##STR00135##
(S)-2,4- diamino-6-((1- (3-(6- aminopyridin- 3- yl)-5-chloro-
6-fluoro-4- oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino)
pyrimidine- 5-carbonitrile 102 ##STR00136## (S)-3-(6- aminopyridin-
3-yl)-5- chloro-2-(1- ((2,6- diamino-5- chloro- pyrimidin- 4-
yl)amino) butyl) quinazolin- 4(3H)-one 103 ##STR00137## (S)-2,4-
diamino- 6-((1- (3-(6- aminopyridin- 3- yl)-5-chloro- 4-oxo-3,4-
dihydro- quinazolin-2- yl)butyl) amino) pyrimidine-5- carbonitrile
104 ##STR00138## (S)-3-(6- aminopyridin- 3-yl)-5- chloro-2-(1-
((2,6- diamino-5- chloro- pyrimidin- 4- yl)amino) butyl)-6- fluoro-
quinazolin- 4(3H)-one 105 ##STR00139## (S)-2,4- diamino- 6-((1-
(3-(6- aminopyridin- 3- yl)-5-chloro- 6-fluoro-4- oxo-3,4- dihydro-
quinazolin-2- yl)butyl)amino) pyrimidine-5- carbonitrile 106
##STR00140## (S)-3-(6- aminopyridin- 3-yl)-5- chloro-2-
(cyclopropyl ((2,6- diamino-5- chloro- pyrimidin- 4- yl)amino)
methyl)-8- fluoro- quinazolin- 4(3H)-one 107 ##STR00141## (S)-2,4-
diamino- 6-(((3- (6- aminopyridin- 3-yl)- 5-chloro- 8-fluoro-4-
oxo-3,4- dihydro- quinazolin-2- yl) (cyclopropyl) methyl) amino)
pyrimidine-5- carbonitrile 108 ##STR00142## (S)-2,4- diamino-
6-((1- (3-(5- aminopyridin- 3- yl)-5-chloro- 4-oxo-3,4- dihydro-
quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile 109
##STR00143## (S)-4-amino- 6-((1-(3- (5- aminopyridin- 3-yl)-
5-chloro- 4-oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino)
pyrimidine-5- carbonitrile 110 ##STR00144## (R)-2,4- Diamino-
6-((1- (5-chloro- 8-fluoro-4- oxo-3- (pyridin-3-yl)- 3,4-dihydro-
quinazolin- 2- yl)ethyl) amino) pyrimidine-5- carbonitrile
111 ##STR00145## (R)-2,4- Diamino- 6-((1- (5-chloro- 8-fluoro-4-
oxo-3- (pyridin-3-yl)- 3,4-dihydro- quinazolin- 2- yl)propyl)
amino) pyrimidine-5- carbonitrile 112 ##STR00146## (R)-2,4-
Diamino-6- (((5-chloro- 8-fluoro-4- oxo-3- (pyndin-3-yl)-
3,4-dihydro- quinazolin- 2- yl) (cyclopropyl) methyl) amino)
pyrimidine-5- carbonitrile 113 ##STR00147## (R)-2,4- Diamino-
6-((1- (5-chloro- 8-fluoro-3-(5- fluoropyridin- 3-yl)-4- oxo-3,4-
dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5- carbonitrile
114 ##STR00148## (R)-2,4- diamino- 6-((1- (5-chloro- 3-(5-fluoro-4-
methylpyridin- 3-yl)-4- oxo-3,4- dihydro- quinazolin-2- yl)ethyl)
amino) pyrimidine-5- carbonitrile 115 ##STR00149## (R)-2,4-
diamino- 6-((1- (5-chloro- 3-(5-fluoro-4- methylpyridin- 3-yl)-4-
oxo-3,4- dihydro- quinazolin-2- yl)ethyl) amino) pyrimidine-5-
carbonitrile
[0388] In addition, the present application provides the compounds
according to any of the formulae described herein or
pharmaceutically acceptable salts, tautomers, isomers, prodrugs, or
solvates thereof, in which from 1 to n hydrogen atoms attached to a
carbon atom may be replaced by a deuterium atom or D, in which n is
the number of hydrogen atoms in the molecule. It is known that the
deuterium atom is a non-radioactive isotope of the hydrogen atom.
Such compounds may increase resistance to metabolism, and thus may
be useful for increasing the half-life of the compounds of any of
the formulae described herein or pharmaceutically acceptable salts,
isomers, prodrugs, or solvates thereof, when administered to a
mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of
Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984).
Such compounds are synthesized by means well known in the art, for
example by employing starting materials in which one or more
hydrogen atoms have been replaced by deuterium.
[0389] The present application also provides pharmaceutically
acceptable salts, hydrates, solvates, tautomeric forms, polymorphs,
and prodrugs of the compounds of any of the formulae described
herein.
[0390] "Pharmaceutically acceptable" or "physiologically
acceptable" refer to compounds, salts, compositions, dosage forms
and other materials which are useful in preparing a pharmaceutical
composition that is suitable for veterinary or human pharmaceutical
use. "Pharmaceutically acceptable salts" or "physiologically
acceptable salts" refer to salts of pharmaceutical compounds that
retain the biological effectiveness and properties of the
underlying compound, and which are not biologically or otherwise
undesirable. There are acid addition salts and base addition salts.
Pharmaceutically acceptable acid addition salts may be prepared
from inorganic and organic acids. Acids and bases useful for
reaction with an underlying compound to form pharmaceutically
acceptable salts (acid addition or base addition salts
respectively) are known to one of skill in the art. Similarly,
methods of preparing pharmaceutically acceptable salts from an
underlying compound (upon disclosure) are known to one of skill in
the art and are disclosed in for example, Berge, at al. Journal of
Pharmaceutical Science, January 1977 vol. 66, No. 1, and other
sources.
[0391] "Pharmaceutically acceptable salts" include, for example,
salts with inorganic acids and salts with an organic acid. In
addition, if the compounds described herein are obtained as an acid
addition salt, the free base can be obtained by basifying a
solution of the acid salt. Conversely, if the product is a free
base, an addition salt, particularly a pharmaceutically acceptable
addition salt, may be produced by dissolving the free base in a
suitable organic solvent and treating the solution with an acid, in
accordance with conventional procedures for preparing acid addition
salts from base compounds. Examples of pharmaceutically acceptable
salts include, but are not limited to salts with inorganic acids,
such as hydrochlorate, phosphate, diphosphate, hydrobromate,
sulfate, sulfinate, nitrate; as well as salts with an organic acid,
such as malate, maleate, fumarate, tartrate, succinate, citrate,
acetate, lactate, methanesulfonate, p-toluenesulfonate,
2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and
alkanoate such as acetate, HOOC--(CH.sub.2).sub.n--COOH where n is
0-4. Similarly, pharmaceutically acceptable cations include, but
are not limited to sodium, potassium, calcium, aluminum, lithium,
and ammonium. In addition, if the compounds described herein are
obtained as an acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Those skilled in the art
will recognize various synthetic methodologies that may be used to
prepare nontoxic pharmaceutically acceptable addition salts.
[0392] A "solvate" is formed by the interaction of a solvent and a
compound. Solvates of salts of the compounds of any of the formulae
described herein are also provided. Hydrates of the compounds of
any of the formulae are also provided.
[0393] A "prodrug" includes any compound that becomes a compound of
the formulae described herein when administered to a subject, e.g.,
upon metabolic processing of the prodrug.
[0394] In certain embodiments, provided are optical isomers,
racemates, or other mixtures thereof, of the compounds of any of
the formulae described herein or pharmaceutically acceptable salts,
prodrugs, or solvates thereof. In those situations, the single
enantiomer or diastereomer, i.e., optically active form, can be
obtained by asymmetric synthesis or by resolution of the racemate.
Resolution of racemates can be accomplished, for example, by
conventional methods such as crystallization in the presence of a
resolving agent, or chromatography, using, for example a chiral
high pressure liquid chromatography (HPLC) column. In addition,
provided are also Z- and E-forms (or cis- and trans-forms) of the
compounds of the formulae described herein or pharmaceutically
acceptable salts, prodrugs, or solvates thereof with carbon-carbon
double bonds. Provided are also all tautomeric forms of the
compounds of any of the formulae or pharmaceutically acceptable
salts, isomers, prodrugs, or solvates thereof.
[0395] In some embodiments, provided herein are the free base forms
of the compounds of the formulae described herein or
pharmaceutically acceptable salts, isomers, or mixture of isomers,
prodrugs or solvates thereof. In certain embodiments, provided
herein are the (S)-enantiomers of the compounds of the formulae
described herein or pharmaceutically acceptable salts, isomers, or
mixture of isomers, prodrugs or solvates thereof. In some other
embodiments, provided herein are the (R)-enantiomers of the
compounds of the formulae described herein or pharmaceutically
acceptable salts, isomers, or mixture of isomers, prodrugs or
solvates thereof.
[0396] In other embodiments, provided herein are the atropisomers
of the compounds of the formulae described herein or
pharmaceutically acceptable salts, isomers, or mixture of isomers,
prodrugs or solvates thereof.
[0397] Compositions provided herein that include a compound of the
formulae described herein or a pharmaceutically acceptable salt,
prodrug, or solvate thereof, may include racemic mixtures, or
mixtures containing an enantiomeric excess of one enantiomer or
single diastereomers or diastereomeric mixtures. All such isomeric
forms of these compounds are expressly included herein the same as
if each and every isomeric form were specifically and individually
listed.
[0398] In certain embodiments, provided herein are also crystalline
and amorphous forms of the compounds of the formulae described
herein or pharmaceutically acceptable salts, isomer, a mixture of
isomers, prodrugs, or solvates thereof.
[0399] In certain embodiments, provided are also chelates,
non-covalent complexes, and mixtures thereof, of the compounds of
the formula described herein or pharmaceutically acceptable salts,
prodrugs, or solvates thereof. A "chelate" is formed by the
coordination of a compound to a metal ion at two (or more) points.
A "non-covalent complex" is formed by the interaction of a compound
and another molecule wherein a covalent bond is not formed between
the compound and the molecule. For example, complexation can occur
through van der Waals interactions, hydrogen bonding, and
electrostatic interactions (also called ionic bonding).
Therapeutic Uses of the Compounds
[0400] The compounds of the formulae described herein or a
pharmaceutically acceptable salt, isomers, prodrug, or solvate
thereof may be used for the treatment of diseases and/or conditions
mediated by PI3K isomers, such as PI3K.delta.. Thus, provided
herein are methods for inhibiting one or more PI3K isomers, such as
PI3K .alpha., .beta., .delta., and .gamma.. In one embodiment,
provided are methods for inhibiting PI3K.delta. activity using a
compound of the formulae described herein or a pharmaceutically
acceptable salt, isomers, prodrug, or solvate thereof. The PI3K
isomers may be selectively or specifically inhibited. Additionally,
the compounds may be used to inhibit PI3K activity therapeutically
or prophylactically. Also, the compounds according to the present
application may be used in combination with other therapeutic
agents. The therapeutic agents may be in the forms of compounds,
antibodies, polypeptides, or polynucleotides. As used herein, the
terms "PI3K isomers" and "PI3K isoforms" are equivalent and used
interchangeably. In one embodiment, the application provides a
product comprising a compound described herein and an additional
therapeutic agent as a combined preparation for simultaneous,
separate or sequential use in therapy, e.g. a method of treating a
disease, disorder, or condition that is mediated by PI3K
isoforms.
[0401] Also, the therapeutic agents may be those that inhibit or
modulate the activities of Bruton's tyrosine kinase, spleen
tyrosine kinase, apoptosis signal-regulating kinase, Janus kinase,
lysyl oxidase, lysyl oxidase-like proteins, or matrix
metallopeptidase. In further embodiments, the therapeutic agents
may be those that inhibit or modulate the activities of
bromodomain-containing protein, adenosine A2B receptor, isocitrate
dehydrogenase, serine/threonine kinase TPL2, discoidin domain
receptor, serine/threonine-protein kinase, IKK, MEK, EGFR, histone
deacetylase, protein kinase C, or any combination thereof.
[0402] In some embodiments, the methods include administering a
compound of the formula described herein or a pharmaceutically
acceptable salt, isomers, prodrug, or solvate thereof, in a
therapeutically effective amount to a human in need thereof. The
method can be employed to treat a patient who has or is believed to
have a disease or condition whose symptoms or pathology is mediated
by PI3K.delta. expression or activity. Additionally, the method can
be employed to treat a patient who has or is believed to have a
disease or condition whose symptoms or pathology is mediated by
PI3K.beta. expression or activity. The patient may be a mammal or a
human.
[0403] In addition to the therapeutic uses, certain compounds of
any of the formulae described herein or a pharmaceutically
acceptable salt, isomers, prodrug, or solvate thereof, have one or
more properties selected from: (i) selectivity to any PI3K
isoforms, such as PI3K.delta.; (ii) hepatocyte stability; and (iii)
potency in a cellular assay. In one embodiment, certain compounds
of the formulae or a pharmaceutically acceptable salt, prodrug,
isomers, or solvate thereof, have selectivity to any PI3K isoforms,
such as PI3K.delta.. In other embodiments, certain compounds of the
formulae described herein or a pharmaceutically acceptable salt,
prodrug, or solvate thereof, have selectivity to at least
PI3K.delta.. In some other embodiments, certain compounds of the
formulae or a pharmaceutically acceptable salt, prodrug, isomers,
or solvate thereof, have selectivity to PI3K.delta. and/or
PI3K.beta.. In yet other embodiments, certain compounds of the
formulae or a pharmaceutically acceptable salt, prodrug, or solvate
thereof, have one of the properties selected from: (i) selectivity
to PI3K.delta.; (ii) hepatocyte stability; and (iii) potency in a
cellular assay. In yet other embodiments, certain compounds of the
formulas according to the present application or a pharmaceutically
acceptable salt, prodrug, or solvate thereof, have: selectivity to
PI3K.delta. and hepatocyte stability; or selectivity to PI3K.delta.
and potency in a cellular assay; or hepatocyte stability and
potency in a cellular assay. In some embodiments, certain compounds
of the formulae or a pharmaceutically acceptable salt, prodrug, or
solvate thereof, have selectivity to PI3K.delta., hepatocyte
stability, and potency in a cellular assay.
[0404] In another embodiment, certain compounds of the formulae
described herein or a pharmaceutically acceptable salt, isomers,
prodrug, or solvate thereof have hepatocyte stability. Hepatocyte
stability of a compound can be determined using any methods
currently known in the art, including the methods described in the
Examples below. For example, hepatocyte stability may be
characterized based on half-life. In some embodiments, the
half-life is greater than or about 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or
15 hours when incubated in human hepatocytes.
[0405] In yet another embodiment, certain compounds of the formulae
described herein or a pharmaceutically acceptable salt, prodrug, or
solvate thereof have potency in a cellular assay. Potency in a
cellular assay can be determined using any methods currently known
in the art, including the methods described in the Examples below.
In some embodiments, the activity in the cellular assay is less
than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM,
0.1 nM, or 0.01 nM.
[0406] For example, certain compounds inhibit at least one PI3K
isomer, including PI3K.delta.. For example, the compounds have an
EC.sub.50 in the described cellular assay less than 10 nM, and have
a half life in hepatocytes of greater than 3 hours.
[0407] "Treatment" or "treating" is an approach for obtaining
beneficial or desired results including clinical results.
Beneficial or desired clinical results may include one or more of
the following:
[0408] a) inhibiting the disease or condition (e.g., decreasing one
or more symptoms resulting from the disease or condition, and/or
diminishing the extent of the disease or condition);
[0409] b) slowing or arresting the development of one or more
clinical symptoms associated with the disease or condition (e.g.,
stabilizing the disease or condition, preventing or delaying the
worsening or progression of the disease or condition, and/or
preventing or delaying the spread (e.g., metastasis) of the disease
or condition); and/or
[0410] c) relieving the disease, that is, causing the regression of
clinical symptoms (e.g., ameliorating the disease state, providing
partial or total remission of the disease or condition, enhancing
effect of another medication, delaying the progression of the
disease, increasing the quality of life, and/or prolonging
survival.
[0411] "Prevention" or "preventing" means any treatment of a
disease or condition that causes the clinical symptoms of the
disease or condition not to develop. Compounds may, in some
embodiments, be administered to a subject (including a human) who
is at risk or has a family history of the disease or condition.
[0412] The terms "Subject" or "patient" refer to an animal, such as
a mammal (including a human), that has been or will be the object
of treatment, observation or experiment. The methods described
herein may be useful in human therapy and/or veterinary
applications. In some embodiments, the subject is a mammal. In one
embodiment, the subject is a human. "Human in need thereof" refers
to a human who may have or is suspect to have diseases or
conditions that would benefit from certain treatment; for example,
being treated with the PI3K inhibitor of the compounds according to
the present application.
[0413] The term "therapeutically effective amount" of a compound of
the present application or a pharmaceutically acceptable salt,
isomers, prodrug, or solvate thereof, means an amount sufficient to
effect treatment when administered to a subject, to provide a
therapeutic benefit such as amelioration of symptoms or slowing of
disease progression. For example, a therapeutically effective
amount may be an amount sufficient to decrease a symptom of a
disease or condition responsive to inhibition of PI3K.delta.
activity. The therapeutically effective amount may vary depending
on the subject, and disease or condition being treated, the weight
and age of the subject, the severity of the disease or condition,
and the manner of administering, which can readily be determined by
one or ordinary skill in the art.
[0414] The term "inhibition" indicates a decrease in the baseline
activity of a biological activity or process. The term "inhibition
of activity of PI3K isomers" or variants thereof refer to a
decrease in activity in any PI3K isomer (e.g., alpha, beta, gamma,
or delta) as a direct or indirect response to the presence of a
compound of any of the formula (I), (IA), (IB), (IC), (ID), (IE),
(IF), or (II) or a pharmaceutically acceptable salt, isomer, a
mixture of isomers, prodrug, or solvent thereof, relative to the
activity of PI3K isomer in the absence of such compound or a
pharmaceutically acceptable salt, isomer, a mixture of isomers,
prodrug, or solvent thereof. "Inhibition of PI3K.delta. activity"
or variants thereof refer to a decrease in PI3K.delta. activity as
a direct or indirect response to the presence of a compound of
formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (II) or a
pharmaceutically acceptable salt, isomer, a mixture of isomers,
prodrug, or solvate thereof, relative to the activity of
PI3K.delta. in the absence of such compound. In some embodiments,
the inhibition of PI3K.delta. activity may be compared in the same
subject prior to treatment, or other subjects not receiving the
treatment. In some other embodiments, the compounds inhibit
PI3K.delta. activity also inhibit PI3K (3 activity.
[0415] Without wishing to be bound to any theory, the decrease in
PI3K.delta. activity may be due to the direct interaction of the
compound with PI3K.delta., or due to the interaction of the
compounds described herein with one or more other factors that in
turn affect PI3K.delta. activity. For example, the presence of the
compounds of the formulae described herein or a pharmaceutically
acceptable salt, prodrug, or solvate thereof, may decrease
PI3K.delta. activity by directly binding to the PI3K.delta., by
causing (directly or indirectly) another factor to decrease
PI3K.delta. activity, or by (directly or indirectly) decreasing the
amount of PI3K.delta. present in the cell or organism.
[0416] The terms "a compound of the present application," "a
compound of any of the formulae described herein," or variant
thereof refers to a compound having the structure of any of the
formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (II). In some
embodiment, the PI3K inhibitors are the compounds having the
structure of the formula (I). In one embodiment, the PI3K
inhibitors are the compounds having the structure of the formula
(IA). In some embodiment, the PI3K inhibitors are the compounds
having the structure of the formula (IB). In certain embodiment,
the PI3K inhibitors are the compounds having the structure of the
formula (IC). In another embodiment, the PI3K inhibitors are the
compound having the structure of formula (ID). In yet another
embodiment, the PI3K inhibitors are the compounds having the
structure of formula (IE). In other embodiment, the PI3K inhibitors
are the compound having the structure of formula (IF).
[0417] The term "PI3K inhibitor" or variant thereof refers to a
compound that inhibits the activity of PI3K. The term "PI3K isoform
selective inhibitor" or variant thereof refers to a compound that
inhibits the activity of one or more PI3K isoforms more effectively
than the other remaining PI3K isoforms. By way of example, the term
"PI3K.delta. selective inhibitor" generally refers to a compound
that inhibits the activity of the PI3K.delta. isoform more
effectively than other isoforms of the PI3K family (e.g., PI3K
.alpha., .beta., or .gamma.). The term "PI3K.alpha. selective
inhibitor" generally refers to a compound that inhibits the
activity of the PI3K.alpha. isoform more effectively than other
isoforms of the PI3K family (e.g., PI3K .beta., .delta., or
.gamma.). The term "PI3K.beta. selective inhibitor" generally
refers to a compound that inhibits the activity of the PI3K.beta.
isoform more effectively than other isoforms of the PI3K family
(e.g., PI3K .alpha., .delta., or .gamma.). The term "dual
PI3K.alpha./.beta. selective inhibitor generally refers to a
compound that inhibits the activity of the PI3K.alpha. and
PI3K.beta. isoforms more effectively than other isoforms of the
PI3K family (e.g., PI3K .delta. or .gamma.).
[0418] The relative efficacies of compounds as inhibitors of an
enzyme activity (or other biological activity) can be established
by determining the concentrations at which each compound inhibits
the activity to a predefined extent and then comparing the results.
In one embodiment, the efficacy of a compound as an inhibitor of
one or more PI3K isoforms can be measured by the concentration that
inhibits 50% of the activity in a biochemical assay, i.e., the 50%
inhibitory concentration or "IC.sub.50". IC.sub.50 determinations
can be accomplished using conventional techniques known in the art,
including the techniques describes in the Examples below. In
general, an IC.sub.50 can be determined by measuring the activity
of a given enzyme in the presence of a range of concentrations of
the compound under study. The experimentally obtained values of
enzyme activity may then be plotted against the compound
concentrations used. The concentration of the inhibitor that shows
50% enzyme activity (as compared to the activity in the absence of
any inhibitor) is taken as the IC.sub.50 value. Analogously, other
inhibitory concentrations can be defined through appropriate
determinations of activity. For example, in some settings it may be
desirable to establish a 90% inhibitory concentration, i.e.,
IC.sub.90.
[0419] In one embodiment, a PI3K.delta. selective inhibitor is a
compound that exhibits a 50% inhibitory concentration (IC.sub.50)
with respect to PI3K.delta. that is at least 10-fold, in another
aspect at least 20-fold, and in another aspect at least 30-fold,
lower than the IC.sub.50 value with respect to any or all of the
other Class I PI3K family members. In another embodiment, a
PI3K.delta. selective inhibitor is a compound that exhibits an
IC.sub.50 with respect to PI3K.delta. that is at least 50-fold, in
another aspect at least 100-fold, in an additional aspect at least
200-fold, and in yet another aspect at least 500-fold, lower than
the IC.sub.50 with respect to any or all of the other PI3K Class I
family members. A PI3K.delta. selective inhibitor is typically
administered in an amount such that it selectively inhibits
PI3K.delta. activity, as described above.
[0420] In one embodiment, a PI3K.alpha. selective inhibitor is a
compound that exhibits a 50% inhibitory concentration (IC.sub.50)
with respect to PI3K that is at least 10-fold, in another aspect at
least 20-fold, and in another aspect at least 30-fold, lower than
the IC.sub.50 value with respect to any or all of the other Class I
PI3K family members. In another embodiment, a PI3K selective
inhibitor is a compound that exhibits an IC.sub.50 with respect to
PI3K that is at least 50-fold, in another aspect at least 100-fold,
in an additional aspect at least 200-fold, and in yet another
aspect at least 500-fold, lower than the IC.sub.50 with respect to
any or all of the other PI3K Class I family members. A PI3K.alpha.
selective inhibitor is typically administered in an amount such
that it selectively inhibits PI3K.alpha. activity, as described
above
[0421] In one embodiment, a PI3K selective inhibitor is a compound
that exhibits a 50% inhibitory concentration (IC.sub.50) with
respect to PI3K that is at least 10-fold, in another aspect at
least 20-fold, and in another aspect at least 30-fold, lower than
the IC.sub.50 value with respect to any or all of the other Class I
PI3K family members. In another embodiment, a PI3K selective
inhibitor is a compound that exhibits an IC.sub.50 with respect to
PI3K that is at least 50-fold, in another aspect at least 100-fold,
in an additional aspect at least 200-fold, and in yet another
aspect at least 500-fold, lower than the IC.sub.50 with respect to
any or all of the other PI3K Class I family members. A PI3K
selective inhibitor is typically administered in an amount such
that it selectively inhibits PI3K.beta. activity, as described
above.
[0422] In one embodiment, a dual PI3K.alpha./.beta. selective
inhibitor is a compound that exhibits a 50% inhibitory
concentration (IC.sub.50) with respect to PI3K.alpha. and
PI3K.beta. that is at least 10-fold, in another aspect at least
20-fold, and in another aspect at least 30-fold, lower than the
IC.sub.50 value with respect to any or all of the other Class I
PI3K family members. In another embodiment, a dual
PI3K.alpha./.beta. selective inhibitor is a compound that exhibits
an IC.sub.50 with respect to PI3K and PI3K that is at least
50-fold, in another aspect at least 100-fold, in an additional
aspect at least 200-fold, and in yet another aspect at least
500-fold, lower than the IC.sub.50 with respect to any or all of
the other PI3K Class I family members. In another embodiment, a
PI3K.beta./.delta. selective inhibitor is a compound that exhibits
an IC.sub.50 with respect to PI3K.beta. and PI3K.delta. that is at
least 10-fold, at least 20-fold, at least 50-fold, at least
100-fold, at least 200-fold, at least 300-fold, at least 400-fold,
and at least 500-fold, lower than the IC.sub.50 with respect to
either PI3K.alpha. or PI3K.gamma. or to both PI3K.alpha. and
PI3K.gamma.. A dual PI3K.alpha./.beta. selective inhibitor is
typically administered in an amount such that it selectively
inhibits PI3K.alpha. and PI3K.beta. activity, as described
above.
[0423] The methods described herein may be applied to cell
populations in vivo or ex vivo. "In vivo" means within a living
individual, as within an animal or human. In this context, the
methods described herein may be used therapeutically in an
individual. "Ex vivo" means outside of a living individual.
Examples of ex vivo cell populations include in vitro cell cultures
and biological samples including fluid or tissue samples obtained
from individuals. Such samples may be obtained by methods well
known in the art. Exemplary biological fluid samples include blood,
cerebrospinal fluid, urine, and saliva. Exemplary tissue samples
include tumors and biopsies thereof. In this context, the invention
may be used for a variety of purposes, including therapeutic and
experimental purposes. For example, the invention may be used ex
vivo to determine the optimal schedule and/or dosing of
administration of a PI3K.delta. selective inhibitor for a given
indication, cell type, individual, and other parameters.
Information gleaned from such use may be used for experimental
purposes or in the clinic to set protocols for in vivo treatment.
Other ex vivo uses for which the invention may be suited are
described below or will become apparent to those skilled in the
art. The selected compounds of the formula described herein or a
pharmaceutically acceptable salt, prodrug, or solvate thereof, may
be further characterized to examine the safety or tolerance dosage
in human or non-human subjects. Such properties may be examined
using commonly known methods to those skilled in the art.
[0424] Compared to other PI3K isoforms, PI3K.delta. is generally
expressed in hematopoietic cells. Consequently, the direct effects
of selective inhibitors of PI3K.delta. can be observed in
hematopoietic cells. Hematopoietic cells typically differentiate
into either lymphoid progenitor cells or myeloid progenitor cells,
both of which ultimately differentiate into various mature cell
types including leukocytes. Aberrant proliferation of hematopoietic
cells of one type often interferes with the production or survival
of other hematopoietic cell types, which can result in compromised
immunity, anemia, and/or thrombocytopenia. The methods described
herein may treat aberrant proliferation of hematopoietic cells by
inhibiting aberrant proliferation of hematopoietic cells. As a
result, these methods may also ameliorate the symptoms and
secondary conditions that result from a primary effect such as
excessive system or localized levels of leukocytes or
lymphocytes.
[0425] In some embodiments, the compounds described herein may be
used to treat subjects having various disease states, disorders,
and conditions (also collectively referred to as "indications")
involving aberrant proliferation of hematopoietic cells (including
excessive production of lymphoid progenitor cell-derived cells
and/or myeloid progenitor cell-derived cells). Such indications may
include, for example, leukemias, lymphomas, myeloproliferative
disorders, myelodysplastic syndromes, and plasma cell neoplasms. In
certain embodiments, the compounds described herein may be used to
treat hematologic malignancies, inflammation, autoimmune disorders,
allergic conditions, cardiovascular disease, and autoimmune
diseases. In certain embodiments, allergic conditions may include
all forms of hypersensitivity.
[0426] In other embodiments, the compounds described herein may be
used to treat cancers that are mediated by, dependent on or
associated with PI3K activity, such as PI3K.delta. activity. In
certain embodiments, the disease is a hematologic malignancy. In
particular embodiments, the hematologic malignancy is leukemia or
lymphoma. In specific embodiments, the disease is acute lymphocytic
leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic
leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic
syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid
leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin's
lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL),
mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's
macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and
diffuse large B-cell lymphoma (DLBCL). In one embodiment, the
disease is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell
acute lymphoblastic leukemia (B-ALL). The non-Hodgkin lymphoma
encompasses the indolent B-cell diseases that include, for example,
follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom
macroglobulinemia, and marginal zone lymphoma, as well as the
aggressive lymphomas that include, for example, Burkitt lymphoma,
diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma
(MCL).
[0427] In other embodiments, the disease is a solid tumor. In
particular embodiments, the solid tumor is from pancreatic cancer,
bladder cancer, colorectal cancer, breast cancer, prostate cancer,
renal cancer, hepatocellular cancer, lung cancer, ovarian cancer,
cervical cancer, gastric cancer, esophageal cancer, head and neck
cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors
(e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma
multiforme, and adult anaplastic astrocytoma), bone cancer, or soft
tissue sarcoma. In some embodiments, the solid tumor is from
non-small cell lung cancer, small-cell lung cancer, colon cancer,
CNS cancer, melanoma, ovarian cancer, renal cancer, prostate
cancer, or breast cancer.
[0428] In some embodiments, the disease is an autoimmune disease.
In particular embodiments, the autoimmune disease is systemic lupus
erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA),
acute disseminated encephalomyelitis, idiopathic thrombocytopenic
purpura, multiple sclerosis (MS), Sjoegren's syndrome, or
autoimmune hemolytic anemia. In other embodiments, the disease is
inflammation. In yet other embodiments, the disease is excessive or
destructive immune reactions, such as asthma, rheumatoid arthritis,
multiple sclerosis, and lupus. In yet other embodiments, the
disease is excessive or destructive immune reactions, such as
psoriasis or chronic obstructive pulmonary disease (COPD).
[0429] The present application also provides a method for treating
a subject, who has or is suspected of having a disease or condition
responsive or believed to be responsive to the inhibition of
PI3K.delta. activity by administering to the subject a compound of
the formulae described herein or a pharmaceutically acceptable
salt, prodrug, or solvate thereof.
[0430] Additionally, the application provides a method of
inhibiting kinase activity of a phosphatidylinositol 3-kinase delta
polypeptide by contacting the polypeptide with a compound of the
formulae described herein or a pharmaceutically acceptable salt,
prodrug, or solvate thereof.
[0431] Provided is also a method of disrupting leukocyte function
comprising contacting the leukocytes with an effective amount of a
compound of any of the formulae described herein or a
pharmaceutically acceptable salt, prodrug, or solvate thereof, in a
subject in need thereof (e.g., a human).
[0432] Provided is also a method of inhibiting a growth or a
proliferation of cancer cells of hematopoietic origin comprising
contacting the cancer cells with an effective amount of a compound
of the formulae described herein or a pharmaceutically acceptable
salt, prodrug, or solvate thereof.
Kits
[0433] Provided herein are also kits that include a compound of the
formulae of the present application or a pharmaceutically
acceptable salt, prodrug, or solvate thereof, and suitable
packaging. In one embodiment, a kit further includes instructions
for use. In one aspect, a kit includes a compound of the formulae
described herein or a pharmaceutically acceptable salt, prodrug, or
solvate thereof, and a label and/or instructions for use of the
compounds in the treatment of the indications, including the
diseases or conditions, described herein.
[0434] Provided herein are also articles of manufacture that
include a compound of any of the formulae described herein or a
pharmaceutically acceptable salt, prodrug, or solvate thereof, in a
suitable container. The container may be a vial, jar, ampoule,
preloaded syringe, and intravenous bag.
Pharmaceutical Compositions and Modes of Administration
[0435] Compounds provided herein are usually administered in the
form of pharmaceutical compositions. Thus, provides herein are also
pharmaceutical compositions that contain one or more of the
compounds of any of the formulae, including (I), (IA), (IB), (IC),
(ID), (IE), (IF), or (II), or a pharmaceutically acceptable salt,
isomers, prodrug, or solvate thereof, and one or more
pharmaceutically acceptable vehicles selected from carriers,
adjuvants and excipients. Suitable pharmaceutically acceptable
vehicles may include, for example, inert solid diluents and
fillers, diluents, including sterile aqueous solution and various
organic solvents, permeation enhancers, solubilizers and adjuvants.
Such compositions are prepared in a manner well known in the
pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences,
Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern
Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C.
T. Rhodes, Eds.).
[0436] The pharmaceutical compositions may be administered in
either single or multiple doses. The pharmaceutical composition may
be administered by various methods including, for example, rectal,
buccal, intranasal and transdermal routes. In certain embodiments,
the pharmaceutical composition may be administered by
intra-arterial injection, intravenously, intraperitoneally,
parenterally, intramuscularly, subcutaneously, orally, topically,
or as an inhalant.
[0437] One mode for administration is parenteral, for example, by
injection. The forms in which the pharmaceutical compositions
described herein may be incorporated for administration by
injection include, for example, aqueous or oil suspensions, or
emulsions, with sesame oil, corn oil, cottonseed oil, or peanut
oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous
solution, and similar pharmaceutical vehicles.
[0438] Oral administration may be another route for administration
of the compounds described herein. Administration may be via, for
example, capsule or enteric coated tablets. In making the
pharmaceutical compositions that include at least one compound of
any of the formulae described herein or a pharmaceutically
acceptable salt, prodrug, or solvate thereof, the active ingredient
is usually diluted by an excipient and/or enclosed within such a
carrier that can be in the form of a capsule, sachet, paper or
other container. When the excipient serves as a diluent, it can be
in the form of a solid, semi-solid, or liquid material, which acts
as a vehicle, carrier or medium for the active ingredient. Thus,
the compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosols (as a solid or in a liquid medium),
ointments containing, for example, up to 10% by weight of the
active compound, soft and hard gelatin capsules, sterile injectable
solutions, and sterile packaged powders.
[0439] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as methyl
and propylhydroxy-benzoates; sweetening agents; and flavoring
agents.
[0440] The compositions that include at least one compound of any
of the formulae described herein or a pharmaceutically acceptable
salt, prodrug, or solvate thereof, can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the subject by employing
procedures known in the art. Controlled release drug delivery
systems for oral administration include osmotic pump systems and
dissolutional systems containing polymer-coated reservoirs or
drug-polymer matrix formulations. Examples of controlled release
systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;
4,902,514; and 5,616,345. Another formulation for use in the
methods of the present invention employs transdermal delivery
devices ("patches"). Such transdermal patches may be used to
provide continuous or discontinuous infusion of the compounds
described herein in controlled amounts. The construction and use of
transdermal patches for the delivery of pharmaceutical agents is
well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252,
4,992,445 and 5,001,139. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0441] For preparing solid compositions such as tablets, the
principal active ingredient may be mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of any of the above formulae or a
pharmaceutically acceptable salt, prodrug, or solvate thereof. When
referring to these preformulation compositions as homogeneous, the
active ingredient may be dispersed evenly throughout the
composition so that the composition may be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules.
[0442] The tablets or pills of the compounds described herein may
be coated or otherwise compounded to provide a dosage form
affording the advantage of prolonged action, or to protect from the
acid conditions of the stomach. For example, the tablet or pill can
include an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer that serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0443] Compositions for inhalation or insufflation may include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. In other embodiments,
compositions in pharmaceutically acceptable solvents may be
nebulized by use of inert gases. Nebulized solutions may be inhaled
directly from the nebulizing device or the nebulizing device may be
attached to a facemask tent, or intermittent positive pressure
breathing machine. Solution, suspension, or powder compositions may
be administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner.
Dosing
[0444] The specific dose level of a compound of the formulae
described herein for any particular subject will depend upon a
variety of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion,
drug combination and the severity of the particular disease in the
subject undergoing therapy. For example, a dosage may be expressed
as a number of milligrams of a compound of the formula per kilogram
of the subject's body weight (mg/kg). Dosages of between about 0.01
and 150 mg/kg may be appropriate. Dosages of between about 0.001
and 10 mg/kg, between about 0.005 and 5 mg/kg, and between about
0.01 and 50 mg/kg may be appropriate. In some embodiments, about
0.01 and 100 mg/kg may be appropriate. In other embodiments a
dosage of between 0.05 and 60 mg/kg may be appropriate. Normalizing
according to the subject's body weight is particularly useful when
adjusting dosages between subjects of widely disparate size, such
as occurs when using the drug in both children and adult humans or
when converting an effective dosage in a non-human subject such as
dog to a dosage suitable for a human subject.
[0445] The daily dosage may also be described as a total amount of
a compound of the formulae administered per dose or per day. Daily
dosage of a compound may be between about 1 mg and 2,000 mg,
between about 1,000 to 2,000 mg/day, between about 1 to 1,000
mg/day, between about 1 to 500 mg/day, between about 5 to 400
mg/day, between about 10 to 300 mg/day, between about 25 to 250
mg/day, between about 50 to 225 mg/day, between about 75 to 200
mg/day, between about 100 to 150 mg/day, between about 1 to 100
mg/day between about between about 1 to 75 mg/day, between about 1
to 50 mg/day, between about 1 to 25 mg/day, between about 1 to 20
mg/day, between about 1 to 15 mg/day, between about 1 to 10 mg/day,
between about 1 to 5 mg/day, between about 5 to 100 mg/day, between
about between about 5 to 75 mg/day, between about 5 to 50 mg/day,
between about 5 to 25 mg/day, between about 5 to 15 mg/day, between
about 5 to 10 mg/day, between about 25 to 400 mg/day between about
between about 25 to 300 mg/day, between about 25 to 200 mg/day,
between about 25 to 150 mg/day, between about 25 to 125 mg/day,
between about 25 to 100 mg/day, between about 25 to 75 mg/day,
between about 25 to 50 mg/day, between about 25 to 40 mg/day,
between about 50 to 500 mg/day, between about 50 to 400 mg/day,
between about 50 to 300 mg/day, between about 50 to 250 mg/day,
between 50 to 225 mg/day, between about 50 to 200 mg/day, between
about 50 to 175 mg/day, between about 50 to 150 mg/day, between
about 50 to 125 mg/day, between about 50 to 100 mg/day, between
about 75 to 200 mg/day, between 75 to 150 mg/day, between 75 to 125
mg/day, between about 75 to 100 mg/day, between about 100 to 125
mg/day, between about 100 to 150 mg/day, between about 100 to 175
mg/day, between about 10 to 150 mg/day, between about 10 to 125
mg/day, between about 10 to 100 mg/day, or between about 10 to 50
mg/day. In other embodiments, daily dosage of a compound may be
between about 0.01 mg and 1,000 mg, between about 0.05 mg and 500
mg, between about 0.075 mg and 250 mg, between about 0.1 mg and 100
mg, between about 0.5 mg and 50 mg, between about 0.75 mg and 25
mg, between about 1 mg and 10 mg,
[0446] When administered orally, the total daily dosage for a human
subject may be between 1 mg and 1,000 mg, between about 1 to 100
mg/day, between about 1 to 50 mg/day, between about 5 to 50 mg/day,
between 5 to 25 mg/day, between about 5 to 75 mg/day, between about
10-500 mg/day, between about 10 to 150 mg/day, between about 10 to
200 mg/day, between about 50-300 mg/day, between about 75-200
mg/day, between about 75 to 150 mg/day, or between about 100-150
mg/day. In additional embodiments, daily dosage for a human may be
administered between about 0.01 mg and 1,000 mg, between about 0.05
mg and 500 mg, between about 0.075 mg and 250 mg, between about 0.1
mg and 100 mg, between about 0.5 mg and 50 mg, between about 0.75
mg and 25 mg, between about 1 mg and 10 mg,
[0447] The compounds of the present application or the compositions
thereof may be administered once, twice, three, or four times
daily, using any suitable mode described above. Also,
administration or treatment with the compounds according to any of
the formulae described herein may be continued for a number of
days; for example, commonly treatment would continue for at least 7
days, 14 days, or 28 days, for one cycle of treatment. In some
embodiments, the compounds or the composition thereof may be
administered continuously, i.e. every day. Treatment cycles are
well known in cancer chemotherapy, and are frequently alternated
with resting periods of about 1 to 28 days, commonly about 7 days
or about 14 days, between cycles. The treatment cycles, in other
embodiments, may also be continuous.
[0448] In a particular embodiment, the method comprises
administering to the subject an initial daily dose of about 1 to
500 mg of a compound of the above formula and increasing the dose
by increments until clinical efficacy is achieved. Increments of
about 5, 10, 25, 50, or 100 mg can be used to increase the dose. In
other embodiments, the methods comprising administering to the
subject an initial daily dose of about 0.01 to 100 mg of the
compound described herein and increasing the dose by increments of
about 0.01, 0.05, 0.1, 0.5, 1, 2, 2.5, 5, 10, 25, 50, or 100 mg.
The dosage can be increased daily, every other day, twice per week,
or once per week.
Synthesis of the Compounds of Formula (I)
[0449] The compounds of formula (I), (IA), (IB), (IC), (ID), (IE),
(IF), or (II) may be prepared using the methods disclosed herein
and routine modifications thereof, which will be apparent given the
disclosure herein and methods well known in the art. Conventional
and well-known synthetic methods may be used in addition to the
teachings herein. The synthesis of typical compounds described
herein may be accomplished as described in the following examples.
If available, reagents may be purchased commercially, e.g., from
Sigma Aldrich or other chemical suppliers.
General Synthesis
[0450] Typical embodiments of compounds described herein may be
synthesized using the general reaction schemes described below. It
will be apparent given the description herein that the general
schemes may be altered by substitution of the starting materials
with other materials having similar structures to result in
products that are correspondingly different. Descriptions of
syntheses follow to provide numerous examples of how the starting
materials may vary to provide corresponding products. Given a
desired product for which the substituent groups are defined, the
necessary starting materials generally may be determined by
inspection. Starting materials are typically obtained from
commercial sources or synthesized using published methods. For
synthesizing compounds which are embodiments described in the
present disclosure, inspection of the structure of the compound to
be synthesized will provide the identity of each substituent group.
The identity of the final product will generally render apparent
the identity of the necessary starting materials by a simple
process of inspection, given the examples herein. In general,
compounds described herein are typically stable and isolatable at
room temperature and pressure.
Synthetic Reaction Parameters
[0451] The terms "solvent", "inert organic solvent", or "inert
solvent" refer to a solvent inert under the conditions of the
reaction being described in conjunction therewith (including, for
example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, pyridine and the like).
Unless specified to the contrary, the solvents used in the
reactions of the present invention are inert organic solvents, and
the reactions are carried out under an inert gas, preferably
nitrogen.
[0452] The term "q.s." means adding a quantity sufficient to
achieve a stated function, e.g., to bring a solution to the desired
volume (i.e., 100%).
Compounds of Formula I
[0453] The compounds of formula (I) may be prepared using the
method shown in Reaction Scheme I.
##STR00150##
Step 1--Preparation of a Compound of Formula (1)
[0454] The compound of formula (1) can be made by combining
compounds (A), (B) and (C) in the presence of a dehydrating agent.
Compounds (A), (B) and (C) are commercially available or can be
made by the methods that are commonly known or used by one skilled
in the art. R.sup.1, R.sup.2, and R.sup.3 are defined as in the
formula (I). Compound (A) is mixed with Compound (B) in the
presence of a coupling agent such as diphenyl phosphite in a
solvent such as pyridine. After stirring at a temperature between
ambient and 100.degree. C. for 1 to 5 hours, compound (C) is added.
The mixture is further stirred at a temperature between ambient and
100.degree. C. for 5 to 24 hours and cooled to room temperature. To
extract the compound of formula (1), an organic solvent such as
ethyl acetate (EtOAc) is added. Then the reaction is washed with
mild acid, water, and brine. The organic phase is concentrated to
obtain the compound of formula (1). The compound of formula (1) is
purified by any suitable methods known in the art, such as
chromatography on silica gel. Alternatively, the compound of
formula (1) is used in the next step without purification. In some
instance, the compound of formula (1) is purified directly without
an aqueous work-up. In cases where an R.sup.1 is a cyano, the
corresponding bromide can be converted to a nitrile by methods
known in the art. For example, treatment of a bromide with zinc
cyanide in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium, at a temperature between
ambient and 100.degree. C. for 5 to 24 hours can give the compound
of formula (1).
Step 2--Preparation of a Compound of Formula (2)
[0455] The compound of formula (2) can be made by removing the
protecting group(s) from the compound of formula (1). The compound
of formula (1) is dissolved in a suitable solvent and treated with
a suitable acid. By way of example, suitable solvents include
dichloromethane or dioxane, and suitable acids include
trifluoroacetic acid, hydrochloric acid, or boron tribromide
(BBr.sub.3). The reaction is carried out at temperatures between
-78.degree. C. to ambient temperature. After the reaction is
complete, solvent is removed to obtain the compound of formula
(2).
Step 3--Preparation of a Compound of Formula (3)
[0456] The compound of formula (3) can be made by treating
5-substituted-2,4,6-trihalopyrimidine with ammonium hydroxide in a
suitable solvent such as dioxane, where the halo is either chloro
or fluoro. The reaction is carried out at an elevated temperature
between 30 and 80.degree. C. between 2 and 8 hours or when the
reaction was complete. Then, water is added to the cooled solution,
and the precipitate is collected by filtration. If necessary,
separation of regiosiomers is accomplished by standard methods,
such as chromatography. The nitrile can be converted to the
carboxamide under standard conditions.
Step 4--Preparation of a Compound of Formula (I)
[0457] The compound of formula (I) can generally be prepared by
coupling compound of formula (2) and compound of formula (3) in the
presence of a suitable base in a suitable solvent. An example of a
suitable base is diisopropylethylamine. An example of a suitable
solvent is N-methylpyrrolidone (NMP), DMF, DMSO, or isopropanol.
Also, an additive such as potassium fluoride may be used. The
reaction is typically performed at a temperature between 50.degree.
C. to 150.degree. C. for about 30 minutes to 24 hours.
Alternatively the reaction can be performed in a microwave at a
temperature between 100.degree. C. to 150.degree. C. for about 30
minutes to 24 hours. Water can be added to quench the reaction upon
completion, and the precipitate may be filtered then dissolved in
an organic solvent such as dichloromethane (DCM). The product can
be isolated by methods known in the art, for example by removal of
solvent under reduced pressure. The product can be purified using
any suitable methods known in the art, for example, chromatography
of the residue on a silica column. In certain instance, the product
can be purified using recrystallization or precipitation.
[0458] It should be understood that the compounds of formula (I)
can be prepared according to the methods provided in Reaction
Scheme 1, starting from materials known to one of skill in the
art.
Example 1
Preparation of a Compound of Formula (1)
A. Preparation of a Compound of Formula (1) Wherein n is 1, R.sup.1
is Chloro, m is 0, and R.sup.3 is Methyl
##STR00151##
[0460] Diphenyl phosphite (1.9 mL, 10 mmol) was added to a solution
of 2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and
(S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol)
in pyridine (3 mL). The reaction mixture was stirred at 40.degree.
C. for 2 hours. 3-Aminopyridine (274 mg, 3.48 mmol) was then added
to the reaction mixture, which was then stirred at 55.degree. C.
for 12 hours. The reaction mixture was cooled to room temperature
and loaded onto a hexane primed SiO.sub.2 column. The title
compound was then purified by eluting with EtOAc in hexanes (0-50%)
to afford (S)-tert-butyl
1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbam-
ate as a solid. ES/MS m/z=401.1 (M+H.sup.+).
B. Preparation of a Compound of Formula (1), Varying R.sup.1,
R.sup.2, and R.sup.3
[0461] Following the procedure described in Example 1A and Reaction
Scheme I with varying R.sup.1, R.sup.2 and R.sup.3 substituents,
other compounds of formula (1) were prepared including: [0462]
(S)-tert-butyl
1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)propylcarba-
mate, [0463] (S)-tert-butyl
(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methylcarbamate, [0464] (S)-tert-butyl
1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)-2-cyclopro-
pylethylcarbamate, [0465] (S)-tert-butyl
1-(6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbam-
ate, [0466] (S)-tert-butyl
1-(5-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbam-
ate, [0467] (S)-tert-butyl
1-(5-(methylsulfonyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)e-
thylcarbamate; [0468] (S)-tert-butyl
1-(4-oxo-3-(pyridin-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)-
ethylcarbamate; [0469] (S)-tert-butyl
1-(5-bromo-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbama-
te; [0470] (S)-tert-butyl
1-(3-(5-fluoropyridin-3-yl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0471] (S)-tert-butyl
1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0472] (S)-tert-butyl
1-(5-chloro-3-(5-chloropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0473] (S)-tert-butyl
1-(5-chloro-3-(5-methoxypyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)et-
hylcarbamate; [0474] (S)-tert-butyl
1-(5-chloro-3-(5-(difluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)ethylcarbamate; [0475] (S)-tert-butyl
1-(5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0476] (S)-tert-butyl
(5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methylcarbamate; [0477] (S)-tert-butyl
1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroquinazol-
in-2-yl)ethylcarbamate; [0478] (S)-tert-butyl
1-(5-chloro-3-(5-cyclopropylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-y-
l)ethylcarbamate; [0479] (S)-tert-butyl
1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)pro-
pylcarbamate; [0480] (S)-tert-butyl
(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methylcarbamate; [0481] (S)-tert-butyl
1-(8-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbam-
ate; [0482] (S)-tert-butyl
1-(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylca-
rbamate; [0483] (S)-tert-butyl
1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)et-
hylcarbamate; [0484] (S)-tert-butyl
1-(5,8-difluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylca-
rbamate; [0485] (S)-tert-butyl
1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)pr-
opylcarbamate; [0486] (S)-tert-butyl
(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)(cyc-
lopropyl)methylcarbamate; [0487] (S)-tert-butyl
cyclopropyl(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-y-
l)methylcarbamate; [0488] (S)-tert-butyl
1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)-2-
-cyclopropylethylcarbamate; [0489] (S)-tert-butyl
1-(5,8-dichloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)ethylcarbamate; [0490] (S)-tert-butyl
1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0491] (S)-tert-butyl
1-(5-chloro-8-fluoro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0492] (S)-tert-butyl
(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-
-yl) (cyclopropyl)methylcarbamate; [0493] (S)-tert-butyl
1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0494] (S)-tert-butyl
1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)pro-
pylcarbamate; [0495] (S)-tert-butyl
1-(5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)et-
hylcarbamate; [0496] (S)-tert-butyl
(5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methylcarbamate; [0497] (S)-tert-butyl
1-(5-chloro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0498] (S)-tert-butyl
1-(5-chloro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0499] (S)-tert-butyl
1-(5-chloro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0500] (S)-tert-butyl
1-(5-chloro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0501] (S)-tert-butyl
1-(5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0502] (S)-tert-butyl
1-(5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0503] (S)-tert-butyl
1-(5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0504] (S)-tert-butyl
1-(5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0505] (S)-tert-butyl
1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0506] (S)-tert-butyl
1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethylcarbamate; [0507] (S)-tert-butyl
(1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)propyl)carbamate; [0508] (S)-tert-butyl
(1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluoromethyl)-3,4-dihydroquinazo-
lin-2-yl)ethyl)carbamate; [0509] (S)-tert-butyl
(1-(8-cyano-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)et-
hyl)carbamate; [0510] (S)-tert-butyl
(1-(8-cyano-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)propyl)carbamate; [0511] (S)-tert-butyl
((8-cyano-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-
-yl) (cyclopropyl)methyl)carbamate; [0512] (S)-tert-butyl
(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-
-methylbutyl)carbamate; [0513] (R)-tert-butyl
(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)e-
thyl)carbamate; [0514] (S)-tert-butyl
(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)-3-methylb-
utyl)carbamate; [0515] (R)-tert-butyl
(1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)ethyl)carbamate; [0516] (R)-tert-butyl
(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)p-
ropyl)carbamate; [0517] (R)-tert-butyl
((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)(cy-
clopropyl)methyl)carbamate; [0518] (S)-tert-butyl
(1-(5-bromo-8-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate; [0519] (S)-tert-butyl
(1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)pr-
opyl)carbamate; [0520] (S)-tert-butyl
(1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)et-
hyl)carbamate; [0521] (S)-tert-butyl
((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl) (cyclopropyl)methyl)carbamate; [0522] (S)-tert-butyl
(1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)ethyl)carbamate; [0523] (S)-tert-butyl
((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin--
2-yl) (cyclopropyl)methyl)carbamate; [0524] (S)-tert-butyl
(1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)propyl)carbamate; [0525] (S)-tert-butyl
(1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydro-
quinazolin-2-yl)ethyl)carbamate; [0526] (S)-tert-butyl
(1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)ethyl)carbamate; [0527] (S)-tert-butyl
(1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-y-
l)ethyl)carbamate; [0528] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-8-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate; [0529] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl-
)ethyl)carbamate; [0530] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
yl)carbamate; [0531] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pro-
pyl)carbamate; [0532] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5-chloro-8-fluoro-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate; [0533] (S)-tert-butyl
((3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)(cycl-
opropyl)methyl)carbamate; [0534] (S)-tert-butyl
(1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-
-2-yl)propyl)carbamate; [0535] (S)-tert-butyl
(1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate; [0536] (S)-tert-butyl
(1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinaz-
olin-2-yl)propyl)carbamate; [0537] (S)-tert-butyl
((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazol-
in-2-yl) (cyclopropyl)methyl)carbamate; [0538] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate; [0539] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)but-
yl)carbamate; [0540] (S)-tert-butyl
(1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-
-2-yl)butyl)carbamate; [0541] (S)-tert-butyl
((3-(6-aminopyridin-3-yl)-5-chloro-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-
-yl)(cyclopropyl)methyl)carbamate; and [0542] (S)-tert-butyl
(1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)eth-
yl)carbamate.
C. Preparation of a Compound of Formula (1) Wherein n is 1, R.sup.1
is Cyano, m is 0, and R.sup.3 is Methyl
##STR00152##
[0544] To a solution of (S)-tert-butyl
1-(5-bromo-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbama-
te (255 mg, 0.58 mmol) in NMP (2 mL) was added zinc cyanide (74 mg,
0.63 mmol) and (PPh.sub.3).sub.4Pd (66 mg, 0.06 mmol). The
resulting suspension was degassed under Argon and heated to
80.degree. C. for 5 hours. The reaction was poured into EtOAc,
washed twice with aq. NaHCO.sub.3 and once with brine. Purification
by flash chromatography (0-75% EtOAc/hexanes) provided
(S)-tert-butyl
1-(5-cyano-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbama-
te 196 mg (87%). ES/MS 392.1 (M+H.sup.+).
D. Preparation of a Compound of Formula (1) where One R.sup.1=Cyano
and Varying Other R.sup.1, R.sup.2, and R.sup.3 [0545]
(S)-tert-butyl
1-(5-cyano-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)eth-
ylcarbamate; [0546] (S)-tert-butyl
1-(5-cyano-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)pro-
pylcarbamate;
Example 2
Preparation of a Compound of Formula (2)
A. Preparation of a Compound of Formula (2) Wherein n is 1, R.sup.1
is Chloro, m is 0, and R.sup.3 is Methyl
##STR00153##
[0548] Trifluoroacetic acid (3 mL) was added to a solution of
(S)-tert-butyl
1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate
(1 g, 2.5 mmol) in dichloromethane (3 mL). The mixture was stirred
at room temperature for 3 hours. The solvents was removed in vacuo
to obtain the title compound
(S)-2-(1-aminoethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one.
ES/MS m/z=301.7 (M+H.sup.+).
B. Preparation of a Compound of Formula (2), Varying R.sup.1,
R.sup.2, and R.sup.3
[0549] Following the procedure described in Example 2A and Reaction
Scheme I with varying R.sup.1, R.sup.2, and R.sup.3 substituents,
other compounds of formula (2) were prepared including: [0550]
(S)-2-(1-aminopropyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one;
[0551]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(pyridin-3-yl)quinazol-
in-4(3H)-one; [0552]
(S)-2-(1-amino-2-cyclopropylethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(-
3H)-one; [0553]
(S)-2-(1-aminoethyl)-6-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one;
[0554]
(S)-2-(1-aminoethyl)-5-methyl-3-(pyridin-3-yl)quinazolin-4(3H)-one-
; [0555]
(S)-2-(1-aminoethyl)-5-(methylsulfonyl)-3-(pyridin-3-yl)quinazoli-
n-4(3H)-one; [0556]
(S)-2-(1-aminoethyl)-3-(pyridin-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-
-one; [0557]
(S)-2-(1-aminoethyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carb-
onitrile; [0558]
(S)-2-(1-aminoethyl)-3-(5-fluoropyridin-3-yl)-5-methylquinazolin-4(3H)-on-
e; [0559]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoropyridin-3-yl)quinazolin-
-4(3H)-one; [0560]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-chloropyridin-3-yl)quinazolin-4(3H)-on-
e; [0561]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-methoxypyridin-3-yl)quinazoli-
n-4(3H)-one; [0562]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-(difluoromethyl)pyridin-3-yl)quinazoli-
n-4(3H)-one; [0563]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-methylpyridin-3-yl)quinazolin-4(3H)-on-
e; [0564]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(5-methylpyridin-3-y-
l)quinazolin-4(3H)-one; [0565]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-(trifluoromethyl)pyridin-3-yl)quinazol-
in-4(3H)-one; [0566]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-cyclopropylpyridin-3-yl)quinazolin-4(3-
H)-one; [0567]
(S)-2-(1-aminopropyl)-5-chloro-3-(5-fluoropyridin-3-yl)quinazolin-4(3H)-o-
ne; [0568]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(5-fluoropyridin-3--
yl)quinazolin-4(3H)-one; [0569]
(S)-2-(1-aminoethyl)-8-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one;
[0570]
(S)-2-(1-aminoethyl)-5,8-dichloro-3-(pyridin-3-yl)quinazolin-4(3H)-
-one; [0571]
(S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-o-
ne; [0572]
(S)-2-(1-aminoethyl)-5,8-difluoro-3-(pyridin-3-yl)quinazolin-4(-
3H)-one; [0573]
(S)-2-(1-aminopropyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)--
one; [0574]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quinaz-
olin-4(3H)-one; [0575]
(S)-2-(amino(cyclopropyl)methyl)-5,8-dichloro-3-(pyridin-3-yl)quinazolin--
4(3H)-one; [0576]
(S)-2-(1-amino-2-cyclopropylethyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quin-
azolin-4(3H)-one; [0577]
(S)-2-(1-aminoethyl)-5,8-dichloro-3-(5-fluoropyridin-3-yl)quinazolin-4(3H-
)-one; [0578]
(S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)quinazolin-
-4(3H)-one; [0579]
(S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(5-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0580]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-8-fluoro-3-(5-fluoropyridin-3-y-
l)quinazolin-4(3H)-one; [0581]
(S)-2-(1-aminoethyl)-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoli-
ne-5-carbonitrile; [0582]
(S)-2-(1-aminopropyl)-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazol-
ine-5-carbonitrile; [0583]
(S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-o-
ne; [0584]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-6-fluoro-3-(pyridin-3-
-yl)quinazolin-4(3H)-one; [0585]
(S)-2-(1-aminoethyl)-5-chloro-3-(2-methylpyridin-3-yl)quinazolin-4(3H)-on-
e; [0586]
(S)-2-(1-aminoethyl)-5-chloro-3-(2-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0587]
(S)-2-(1-aminoethyl)-5-chloro-3-(4-methylpyridin-3-yl)quinazolin-4(3H)-on-
e; [0588]
(S)-2-(1-aminoethyl)-5-chloro-3-(4-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0589]
(S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0590]
(S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0591]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0592]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0593]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0594]
(S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0595]
(S)-2-(1-aminopropyl)-5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)quinazoli-
n-4(3H)-one; [0596]
(S)-2-(1-aminoethyl)-3-(4-methylpyridin-3-yl)-5-(trifluoromethyl)quinazol-
in-4(3H)-one; [0597]
(S)-2-(1-aminoethyl)-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoli-
ne-8-carbonitrile; [0598]
(S)-2-(1-aminopropyl)-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydro-
quinazoline-8-carbonitrile; [0599]
(S)-2-(amino(cyclopropyl)methyl)-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo--
3,4-dihydroquinazoline-8-carbonitrile; [0600]
(S)-2-(1-amino-3-methylbutyl)-5-chloro-3-(5-fluoropyridin-3-yl)quinazolin-
-4(3H)-one; [0601]
(R)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-o-
ne; [0602]
(S)-2-(1-amino-3-methylbutyl)-5-chloro-3-(pyridin-3-yl)quinazol-
in-4(3H)-one; [0603]
(R)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)quinazolin-
-4(3H)-one; [0604]
(R)-2-(1-aminopropyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)--
one; [0605]
(R)-2-(amino(cyclopropyl)methyl)-5-chloro-8-fluoro-3-(pyridin-3-yl)quinaz-
olin-4(3H)-one; [0606]
(S)-2-(1-aminoethyl)-5-bromo-8-fluoro-3-(5-fluoropyridin-3-yl)quinazolin--
4(3H)-one; [0607]
(S)-2-(1-aminopropyl)-5-bromo-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-o-
ne; [0608]
(S)-2-(1-aminoethyl)-5-bromo-8-fluoro-3-(pyridin-3-yl)quinazoli-
n-4(3H)-one; [0609]
(S)-2-(1-aminoethyl)-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carb-
onitrile; [0610]
(S)-2-(1-aminoethyl)-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoli-
ne-5-carbonitrile; [0611]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-8-fluoro-3-(5-fluoro-4-methylpy-
ridin-3-yl)quinazolin-4(3H)-one; [0612]
(S)-2-(1-aminoethyl)-5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)quinazolin-
-4(3H)-one; [0613]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(5-fluoro-4-methylpyridin-3-y-
l)quinazolin-4(3H)-one; [0614]
(S)-2-(1-aminopropyl)-5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)quinazoli-
n-4(3H)-one; [0615]
(S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)q-
uinazolin-4(3H)-one; [0616]
(S)-2-(1-aminoethyl)-6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)quinazolin-
-4(3H) one; [0617]
(S)-2-(1-aminoethyl)-5-chloro-3-(4,5-dimethylpyridin-3-yl)quinazolin-4(3H-
)-one; [0618]
(S)-2-(1-aminoethyl)-3-(6-aminopyridin-3-yl)-8-chloro-6-fluoroquinazolin--
4(3H)-one; [0619]
(S)-2-(1-aminoethyl)-3-(6-aminopyridin-3-yl)-5,8-dichloroquinazolin-4(3H)-
-one; [0620]
(S)-2-(1-aminoethyl)-3-(6-aminopyridin-3-yl)-5-chloroquinazolin-4(3H)-one-
; [0621]
(S)-2-(1-aminopropyl)-3-(6-aminopyridin-3-yl)-5-chloroquinazolin--
4(3H)-one; [0622]
(S)-2-(1-aminoethyl)-3-(6-aminopyridin-3-yl)-5-chloro-8-fluoroquinazolin--
4(3H)-one; [0623]
(S)-2-(amino(cyclopropyl)methyl)-3-(6-aminopyridin-3-yl)-5-chloroquinazol-
in-4(3H)-one; [0624]
(S)-3-(6-amino-4-methylpyridin-3-yl)-2-(1-aminopropyl)-5-chloroquinazolin-
-4(3H)-one; [0625]
(S)-3-(6-amino-4-methylpyridin-3-yl)-2-(1-aminoethyl)-5-chloroquinazolin--
4(3H)-one; [0626]
(S)-3-(6-amino-4-methylpyridin-3-yl)-2-(1-aminopropyl)-5,8-dichloroquinaz-
olin-4(3H)-one; [0627]
(S)-2-(amino(cyclopropyl)methyl)-3-(6-amino-4-methylpyridin-3-yl)-5,8-dic-
hloroquinazolin-4(3H)-one; [0628]
(S)-2-(1-aminoethyl)-3-(6-aminopyridin-3-yl)-5-chloro-6-fluoroquinazolin--
4(3H)-one; [0629]
(S)-2-(1-aminobutyl)-3-(6-aminopyridin-3-yl)-5-chloroquinazolin-4(3H)-one-
; [0630]
(S)-2-(1-aminobutyl)-3-(6-aminopyridin-3-yl)-5-chloro-6-fluoroqui-
nazolin-4(3H)-one; [0631]
(S)-2-(amino(cyclopropyl)methyl)-3-(6-aminopyridin-3-yl)-5-chloro-8-fluor-
oquinazolin-4(3H)-one; and [0632]
(S)-2-(1-aminoethyl)-3-(5-aminopyridin-3-yl)-5-chloroquinazolin-4(3H)-one-
.
Example 3
Preparation of a Compound of Formula (3)
A. Preparation of a Compound of Formula (3) Wherein R.sup.4 is CN
and X is Cl (2,4-Diamino-6-Chloropyrimidine-5-Carbonitrile)
##STR00154##
[0634] Ammonium hydroxide (20 mL) was added to a solution of
2,4,6-trichloropyrimidine-5-carbonitrile (5.0 g, 24 mmol) in
dioxane (20 mL) at room temperature. The solution was warmed to
50.degree. C. and stirred for 3 hrs. The reaction mixture was
cooled to 10.degree. C. and water (50 mL) was added. The resulting
solid was filtered, washed with water, and dried under high vacuum
to obtain the title compound as a white solid (4.5 g).sup.13H NMR
(100 MHz, DMSO) 164.8, 162.6, 161.9, 115.8, 77.6. ES/MS m/z=169.9
(M+H).sup.+.
A. Preparation of a Compound of Formula (3), Varying R.sup.3
[0635] 2,4-diamino-6-chloropyrimidine-5-carboxamide; and [0636]
5-chloro-6-fluoropyrimidine-2,4-diamine;
Example 4
Preparation of a Compound of Formula (I)
A. Preparation of a Compound of Formula (I) Wherein n is 1, R.sup.1
is Chloro, m is 0, R.sup.3 is Methyl, and R.sup.4 is Cyano
(Compound 1)
##STR00155##
[0638] Potassium fluoride (138 mg, 2.38 mmol) was added to a
solution of
(S)-2-(1-aminoethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one
(400 mg, 1.33 mmol) and
2,4-diamino-6-chloropyrimidine-5-carbonitrile (237 mg, 1.4 mmol) in
diisopropylethylamine (1.0 mL, 6.0 mmol) and DMSO (3 mL). The
resultant mixture was heated to 90.degree. C. for 14 hours. Then it
was cooled to room temperature, filtered, and purified by HPLC
eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic
acid). The appropriate fractions were pooled and lyophilized to
obtain the title compound of
(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazo-
lin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile as a solid (479 mg).
1H NMR (400 MHz, DMSO) .delta. 8.74 (d, J=2.4 Hz, 0.5H), 8.58 (dd,
J=4.8, 1.5 Hz, 0.5H), 8.51 (dd, J=4.9, 1.7 Hz, 1.5H), 8.06 (dm,
J=8.5 Hz, 0.5H), 7.85 (dm, J=8.0 Hz, 0.5H), 7.8 (td, J=8.1, 1.4 Hz,
1H), 7.68 (ddd, J=8.2, 3.9, 1.2 Hz, 1H), 7.60 (dt, J=7.9, 1.3 Hz,
1H), 7.55 (ddd, J=8.1, 4.8, 0.7 Hz, 0.5H), 7.48 (ddt, J=8.1, 4.8,
0.7 Hz, 0.5H), 4.85 (m, 1H), 1.35 (d, J=6.8 Hz, 3H). ES/MS 434.1
(M+H.sup.+).
B. Preparation of a Compound of Formula (I), Varying R.sup.1,
R.sup.2 and R.sup.3
[0639] Other compounds of formula (I) were prepared including:
[0640]
(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroqu-
inazolin-2-yl)propylamino)pyrimidine-5-carbonitrile (Compound 2).
1H NMR (400 MHz, DMSO-d6) .delta. 8.83-8.35 (m, 2H), 8.00 (t, J=9.9
Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.70-7.38 (m, 3H), 6.75 (dd,
J=19.0, 7.5 Hz, 1H), 6.57 (s, 2H), 6.39-5.86 (m, 2H), 4.49 (td,
J=7.5, 3.9 Hz, 1H), 1.98-1.43 (m, 2H), 0.66 (q, J=6.9 Hz, 3H).
ES/MS 448.1 (M+H.sup.+);
[0641]
(S)-2,4-diamino-6-((5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquin-
azolin-2-yl)(cyclopropyl)methylamino)pyrimidine-5-carbonitrile
(Compound 3). 1H NMR (400 MHz, DMSO-d6) .delta. 8.65 (d, J=2.5 Hz,
1H), 8.58-8.42 (m, 1H), 7.95 (ddt, J=8.2, 2.7, 1.3 Hz, 1H),
7.87-7.72 (m, 1H), 7.66 (ddt, J=8.2, 4.2, 1.1 Hz, 1H), 7.63-7.44
(m, 1H), 7.38 (dd, J=8.1, 4.8 Hz, 1H), 6.72-6.43 (m, 3H), 6.18 (s,
2H), 5.72 (d, J=1.0 Hz, 1H), 4.53-4.27 (m, 1H), 1.46-0.95 (m, 2H),
0.07 (dd, J=5.7, 2.8 Hz, 2H). ES/MS 460.5 (M+H.sup.+);
[0642]
(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroqu-
inazolin-2-yl)-2-cyclopropylethylamino)pyrimidine-5-carbonitrile
(Compound 4). 1H NMR (400 MHz, DMSO-d6) .delta. 8.89-8.58 (m, 2H),
8.05 (dddd, J=50.5, 8.1, 2.5, 1.5 Hz, 1H), 7.82-7.64 (m, 1H),
7.68-7.45 (m, 3H), 6.84 (dd, J=7.5, 3.8 Hz, 1H), 6.70-6.37 (m, 2H),
6.39-6.02 (m, 2H), 4.70-4.42 (m, 1H), 1.91-1.76 (m, 1H), 1.48-1.22
(m, 1H), 0.60 (dtt, J=16.3, 7.9, 4.3 Hz, 1H), 0.26 (tt, J=8.5, 4.4
Hz, 1H), 0.20--0.17 (m, 2H), -0.48--0.92 (m, 1H). ES/MS 474.1
(M+H.sup.+);
[0643]
(S)-2,4-diamino-6-(1-(6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroqu-
inazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile (Compound 5). 1H
NMR (400 MHz, DMSO-d6) .delta. 8.80-8.46 (m, 2H), 7.97 (dddd,
J=25.8, 8.1, 2.5, 1.5 Hz, 1H), 7.82-7.68 (m, 3H), 7.50 (dddd,
J=27.4, 8.1, 4.9, 0.8 Hz, 1H), 6.88 (dd, J=15.9, 7.1 Hz, 1H), 6.50
(d, J=6.5 Hz, 2H), 6.22 (s, 2H), 4.73 (dt, J=9.6, 6.9 Hz, 1H), 1.30
(dd, J=6.7, 1.7 Hz, 3H). ES/MS 418.1 (M+H.sup.+);
[0644]
(S)-2,4-diamino-6-(1-(5-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroqu-
inazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile (Compound 7). 1H
NMR (400 MHz, DMSO-d6) .delta. 8.87-8.32 (m, 2H), 7.96 (dddt,
J=13.4, 8.1, 2.6, 1.4 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.51 (dtd,
J=11.7, 8.1, 4.9 Hz, 1H), 7.29 (dd, J=7.6, 1.5 Hz, 1H), 7.05-6.74
(m, 2H), 6.68-6.34 (m, 2H), 6.25 (s, 1H), 4.88-4.48 (m, 1H), 2.69
(s, 3H), 1.28 (d, J=6.7 Hz, 3H). ES/MS 414.5 (M+H.sup.+);
[0645]
(S)-2,4-diamino-6-(1-(5-(methylsulfonyl)-4-oxo-3-(pyridin-3-yl)-3,4-
-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 8). 1H NMR (400 MHz, DMSO-d6) .delta. 8.76 (dd, J=2.5,
0.7 Hz, 0.5H), 8.69 (dd, J=2.5, 0.7 Hz, 0.5H), 8.64 (dd, J=4.8, 1.5
Hz, 0.5H), 8.59 (dd, J=4.8, 1.5 Hz, 0.5H), 8.35-8.30 (m, 1H),
8.12-8.04 (m, 2H), 8.00 (dd, J=2.5, 1.6 Hz, 0.5H), 7.98 (dd, J=2.5,
1.5 Hz, 0.5H), 7.59 (ddd, J=8.1, 4.8, 0.8 Hz, 0.5H), 7.52 (ddd,
J=8.1, 4.8, 0.8 Hz, 0.5H), 6.97 (d, J=7.2 Hz, 0.5H), 6.94 (d, J=7.2
Hz, 0.5H), 6.55 (br s, 2H), 6.26 (br s, 2H), 4.80 (dt, J=8.5, 6.9
Hz, 1H), 3.49 (s, 3H), 1.36 (dd, J=6.6, 1.3 Hz, 3H). ES/MS 478.1
(M+H.sup.+);
[0646]
(S)-2,4-diamino-6-(1-(4-oxo-3-(pyridin-3-yl)-5-(trifluoromethyl)-3,-
4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 9). 1H NMR (400 MHz, DMSO-d6) .delta. 8.75 (d, J=2.5 Hz,
1H), 8.67-8.36 (m, 2H), 8.27-7.92 (m, 5H), 7.94-7.67 (m, 2H), 7.51
(dddd, J=31.6, 8.2, 4.8, 0.8 Hz, 2H), 4.89 (td, J=7.0, 4.3 Hz, 1H),
1.37 (d, J=6.6 Hz, 3H). ES/MS 468.1 (M+H.sup.+);
[0647]
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-(-
pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile (Compound 10).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (ddd, J=17.0, 2.5,
0.7 Hz, 1H), 8.59 (ddd, J=15.9, 4.8, 1.5 Hz, 1H), 8.11-8.03 (m,
1H), 8.03-7.91 (m, 3H), 7.63-7.40 (m, 1H), 6.88 (dd, J=13.2, 6.9
Hz, 1H), 6.52 (br. s, 2H), 6.24 (br. s, 2H), 4.70 (td, J=6.8, 4.6
Hz, 1H), 1.31 (d, J=6.7 Hz, 3H). ES/MS 425.1 (M+H.sup.+);
[0648]
(S)-2,4-diamino-6-(1-(3-(5-fluoropyridin-3-yl)-5-methyl-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 11). 1H NMR (400 MHz, DMSO-d6) .delta. 8.67-8.39 (m, 2H),
8.25-7.95 (m, 1H), 7.97-7.79 (m, 1H), 7.69 (td, J=7.8, 1.6 Hz, 1H),
7.58-7.38 (m, 1H), 7.40-7.18 (m, 1H), 6.91 (ddd, J=23.3, 7.2, 1.7
Hz, 1H), 6.53 (d, J=8.3 Hz, 2H), 6.21 (s, 2H), 4.96-4.37 (m, 1H),
2.70 (d, J=1.7 Hz, 3H), 1.32 (dt, J=6.6, 1.6 Hz, 3H). ES/MS 432.3
(M+H.sup.+);
[0649]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 12). 1H NMR (400 MHz, DMSO) .delta. 8.66 (m, 0.5H), 8.62
(d, J=2.8 Hz, 0.5H), 8.55 (d, J=2.6 Hz, 0.5H), 8.40 (m, 0.5H), 8.16
(dd, J=2.65, 2.0 Hz, 0.5H), 8.13 (dd, J=2.6, 2.0 Hz, 0.5H), 7.82
(ddd, J=8.0, 8.0, 2.2 Hz, 1H), 7.78 (m, 0.5H), 7.69 (ddd, 8.18,
3.7, 1.2 Hz, 1H), 7.61 (ddd, J=7.8, 2.15, 1.2 Hz, 1H), 4.86 (m,
1H), 1.37 (d, J=6.7 Hz, 1.5H), 1.36 (d, J=6.5 Hz, 1.5H). ES/MS
452.8 (M+H.sup.+);
[0650]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-chloropyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 13). 1H NMR (400 MHz, DMSO) .delta. 8.52 (d, J=5.6 Hz,
1H), 7.82 (t, J=8.0 Hz, 1H), 7.70 (dd, J=8.2, 1.0 Hz, 1H), 7.62
(dd, J=8.0, 1.1 Hz, 1H), 7.55 (dm, J=5.6 Hz, 1H), 5.03 (m, 1H),
1.38 (d, J=6.6 Hz, 3H). ES/MS 469.3 (M+H.sup.+);
[0651]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-methoxypyridin-3-yl)-4-oxo-3,4--
dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 14). 1H NMR (400 MHz, DMSO) .delta. 8.35 (d, J=1.9 Hz,
0.5H), 8.31 (d, J=2.8 Hz, 0.5H), 8.24 (d, J=2.7 Hz, 0.5H), 8.13 (d,
J=1.9 Hz, 0.5H), 7.84 (t, J=8.3 Hz, 1H), 7.78 (dd, J=2.7, 1.9 Hz,
0.5H), 7.72 (ddd, J=8.2, 1.8, 1.2 Hz, 1H), 7.64 (ddd, J=7.8, 1.3,
0.6 Hz, 1H), 7.41 (dd, J=2.8, 2.0 Hz, 1H), 4.98 (m, 1H), 3.85 (s,
1.5H), 3.79 (s, 1.5H), 1.40 (d, 3H). ES/MS 464.8 (M+H.sup.+);
[0652]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-(difluoromethyl)pyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 15). 1H NMR (400 MHz, DMSO) .delta. 8.9 (s, 0.5H), 8.75
(s, 0.5H), 8.69 (s, 0.5H), 8.67 (s, 0.5H), 8.33 (s, 0.5H), 7.96 (s,
0.5H), 7.81 (ddd, J=8.0, 8.0, 4.0 Hz, 0.5H), 7.70 (ddd, J=9.3, 8.2,
1.15 Hz, 0.5H), 7.61 (ddd, 7.8, 3.2, 1.2 Hz, 0.5H), 7.3 (m, 0.5H),
7.15 (m, 1H), 4.86 (m, 1H), 1.37 (d, J=6.7 Hz, 1.5H), 1.34 (d,
J=6.8 Hz, 1.5H). ES/MS 484.8 (M+H.sup.+);
[0653]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 16). 1H NMR (400 MHz, DMSO-d6) .delta. 8.55-8.23 (m, 2H),
7.91-7.70 (m, 1H), 7.73-7.44 (m, 3H), 6.92 (dd, J=22.9, 7.2 Hz,
1H), 6.51 (d, J=5.1 Hz, 2H), 6.20 (d, J=17.4 Hz, 2H), 4.78 (h,
J=6.6 Hz, 1H), 2.40-2.11 (m, 3H), 1.39-1.19 (m, 3H). ES/MS 448.1
(M+H.sup.+);
[0654]
(S)-2,4-diamino-6-((5-chloro-3-(5-methylpyridin-3-yl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)(cyclopropyl)methylamino)pyrimidine-5-carbonitrile
(Compound 17). 1H NMR (400 MHz, DMSO-d6) .delta. 8.54-8.17 (m, 2H),
7.88-7.47 (m, 3H), 6.71 (dd, J=57.5, 7.7 Hz, 1H), 6.51 (s, 2H),
6.10 (s, 2H), 4.48 (dt, J=26.1, 7.8 Hz, 1H), 2.42-2.02 (m, 3H),
1.61-1.28 (m, 1H), 0.64-0.30 (m, 3H), 0.25--0.11 (m, 1H). ES/MS
474.1 (M+H.sup.+);
[0655]
(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)pyridin--
3-yl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 18). 1H NMR (400 MHz, DMSO-d6) .delta. 9.24-8.72 (m, 2H),
8.58 (td, J=2.2, 0.7 Hz, 1H), 7.90-7.47 (m, 3H), 6.92 (dd, J=40.0,
7.3 Hz, 1H), 6.47 (d, J=21.5 Hz, 2H), 6.14 (s, 2H), 4.76 (dp,
J=26.9, 6.6 Hz, 1H), 1.32 (dd, J=12.3, 6.5 Hz, 3H). ES/MS 502.1
(M+H.sup.+);
[0656]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-cyclopropylpyridin-3-yl)-4-oxo--
3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 19). 1H NMR (400 MHz, DMSO-d6) .delta. 8.54-8.15 (m, 2H),
7.84-7.70 (m, 1H), 7.70-7.44 (m, 3H), 6.88 (dd, J=6.9, 4.8 Hz, 1H),
6.51 (s, 2H), 6.19 (s, 2H), 4.64 (dt, J=12.6, 6.7 Hz, 1H),
2.05-1.77 (m, 1H), 1.28 (dd, J=9.0, 6.7 Hz, 3H), 1.05-0.88 (m, 2H),
0.80-0.56 (m, 2H). ES/MS 474.1 (M+H.sup.+);
[0657]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile
(Compound 20). 1H NMR (400 MHz, DMSO-d6) .delta. 8.74-8.45 (m, 2H),
8.02 (ddt, J=103.9, 9.0, 2.1 Hz, 2H), 7.78 (td, J=8.0, 0.8 Hz, 1H),
7.61 (ddt, J=25.7, 8.0, 1.1 Hz, 1H), 6.77 (d, J=31.6 Hz, 1H), 6.55
(s, 2H), 6.19 (s, 2H), 4.77-4.39 (m, 1H), 2.05-1.57 (m, 2H),
0.82-0.44 (m, 3H). ES/MS 468.1 (M+H.sup.+);
[0658]
(S)-2,4-diamino-6-((5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)
(cyclopropyl)methylamino)pyrimidine-5-carbonitrile (Compound 21).
1H NMR (400 MHz, DMSO-d6) .delta. 8.65-8.17 (m, 2H), 8.19-7.25 (m,
4H), 6.85-6.24 (m, 3H), 6.13 (s, 2H), 4.45 (dt, J=20.2, 8.0 Hz,
1H), 1.42 (h, J=7.3 Hz, 1H), 0.58-0.25 (m, 3H), 0.08 (dq, J=10.0,
5.5, 5.1 Hz, 1H). ES/MS 478.1 (M+H.sup.+);
[0659]
(S)-2,4-diamino-6-(1-(8-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroqu-
inazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile (Compound 22).
1H NMR (400 MHz, DMSO-d6) .delta. 8.75 (d, J=2.5 Hz, 1H), 8.65-8.42
(m, 2H), 8.16-7.94 (m, 3H), 7.92-7.58 (m, 1H), 7.65-7.47 (m, 2H),
7.51-7.38 (m, 1H), 7.31 (s, 2H), 4.94 (h, J=6.7 Hz, 1H), 1.39 (dd,
J=6.6, 2.6 Hz, 3H). ES/MS 434.9 (M+H.sup.+);
[0660]
(S)-2,4-diamino-6-(1-(5,8-dichloro-4-oxo-3-(pyridin-3-yl)-3,4-dihyd-
roquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile (Compound
23). 1H NMR (400 MHz, DMSO-d6) .delta. 8.87-8.38 (m, 4H), 8.02
(tdd, J=7.4, 6.6, 5.6, 2.9 Hz, 2H), 7.89-7.65 (m, 2H), 7.65-7.32
(m, 3H), 5.03-4.68 (m, 1H), 1.57-1.15 (m, 3H). ES/MS 469.2
(M+H.sup.+);
[0661]
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4--
dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 24). 1H NMR (400 MHz, DMSO-d6) .delta. 8.80-8.42 (m, 2H),
8.12-7.81 (m, 1H), 7.80-7.68 (m, 1H), 7.62-7.51 (m, 1H), 7.46 (dt,
J=10.6, 5.3 Hz, 1H), 6.87 (dd, J=16.8, 7.0 Hz, 1H), 6.51 (d, J=5.7
Hz, 2H), 6.21 (d, J=21.8 Hz, 2H), 4.76-4.60 (m, 1H), 1.30 (dd,
J=6.6, 1.5 Hz, 3H). ES/MS 452.1 (M+H.sup.+);
[0662]
(S)-2,4-diamino-6-(1-(5,8-difluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihyd-
roquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile (Compound
25). 1H NMR (400 MHz, DMSO-d6) .delta. 8.73 (d, J=2.5 Hz, 1H),
8.65-8.36 (m, 1H), 8.02 (dt, J=8.2, 2.0 Hz, 1H), 8.02-7.70 (m, 6H),
7.55 (dd, J=8.1, 4.8 Hz, 1H), 7.47 (dd, J=8.1, 4.8 Hz, 1H),
7.47-7.25 (m, 1H), 4.83 (q, J=6.7 Hz, 1H), 1.48-1.26 (m, 3H). ES/MS
436.4 (M+H.sup.+);
[0663]
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4--
dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile
(Compound 26). 1H NMR (400 MHz, DMSO-d6) .delta. 8.81-8.46 (m, 2H),
8.10-7.80 (m, 1H), 7.71 (dd, J=9.7, 8.7 Hz, 1H), 7.64-7.38 (m, 2H),
6.76 (dd, J=20.9, 7.5 Hz, 1H), 6.58 (s, 2H), 6.19 (d, J=38.7 Hz,
2H), 4.54 (tt, J=7.8, 5.3 Hz, 1H), 1.91-1.59 (m, 2H), 0.69 (td,
J=7.2, 4.4 Hz, 3H). ES/MS 466.1 (M+H.sup.+);
[0664]
(S)-2,4-diamino-6-((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-di-
hydroquinazolin-2-yl)(cyclopropyl)methylamino)pyrimidine-5-carbonitrile
(Compound 27). 1H NMR (400 MHz, DMSO-d6) .delta. 8.76-8.39 (m, 2H),
8.00-7.64 (m, 2H), 7.68-7.22 (m, 2H), 6.74-6.41 (m, 3H), 6.15 (d,
J=24.2 Hz, 2H), 4.48 (td, J=7.8, 1.5 Hz, 1H), 1.54-1.24 (m, 1H),
0.53-0.21 (m, 3H), 0.07--0.13 (m, 1H). ES/MS 478.1 (M+H.sup.+);
[0665]
(S)-2,4-diamino-6-(cyclopropyl(5,8-dichloro-4-oxo-3-(pyridin-3-yl)--
3,4-dihydroquinazolin-2-yl)methylamino)pyrimidine-5-carbonitrile
(Compound 28). 1H NMR (400 MHz, DMSO-d6) .delta. 8.78-8.39 (m, 2H),
8.10-7.70 (m, 2H), 7.66-7.13 (m, 2H), 6.74-6.33 (m, 3H), 6.19 (s,
2H), 4.60 (t, J=7.6 Hz, 1H), 1.48-1.21 (m, 1H), 0.49-0.23 (m, 2H),
0.14--0.04 (m, 2H). ES/MS 494.1 (M+H.sup.+);
[0666]
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4--
dihydroquinazolin-2-yl)-2-cyclopropylethylamino)pyrimidine-5-carbonitrile
(Compound 29). 1H NMR (400 MHz, DMSO-d6) .delta. 9.00-8.41 (m, 2H),
8.25-7.82 (m, 1H), 7.80-7.38 (m, 3H), 6.86 (t, J=6.9 Hz, 1H), 6.58
(s, 2H), 6.25 (d, J=26.1 Hz, 2H), 4.59 (qd, J=7.7, 3.9 Hz, 1H),
2.02-1.68 (m, 1H), 1.38 (dddd, J=34.1, 13.0, 7.9, 4.1 Hz, 1H), 0.61
(h, J=6.3 Hz, 1H), 0.42--0.23 (m, 2H), -0.65 (ddq, J=72.7, 9.9, 4.8
Hz, 2H). ES/MS 492.1 (M+H.sup.+);
[0667]
(S)-2,4-diamino-6-(1-(5,8-dichloro-3-(5-fluoropyridin-3-yl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 30). 1H NMR (400 MHz, DMSO-d6) .delta. 8.78-8.30 (m, 2H),
8.25-7.64 (m, 2H), 7.59 (dt, J=8.5, 1.2 Hz, 1H), 6.87 (dd, J=24.3,
7.4 Hz, 1H), 6.51 (d, J=11.3 Hz, 2H), 6.23 (s, 2H), 4.87 (ddd,
J=13.5, 9.8, 6.7 Hz, 1H), 1.43-1.32 (m, 3H). ES/MS 486.0
(M+H.sup.+);
[0668]
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 31). 1H NMR (400 MHz, DMSO-d6) .delta. 8.83-8.25 (m, 2H),
8.23-7.66 (m, 2H), 7.59 (dd, J=8.8, 4.5 Hz, 1H), 6.90 (dd, J=23.2,
7.2 Hz, 1H), 6.52 (d, J=9.2 Hz, 2H), 6.24 (s, 2H), 4.97-4.46 (m,
1H), 1.33 (dd, J=6.6, 1.6 Hz, 3H). ES/MS 470.1 (M+H.sup.+);
[0669]
(S)-2,4-diamino-6-(1-(5-chloro-8-fluoro-3-(5-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 32). 1H NMR (400 MHz, DMSO-d6) .delta. 8.60-8.15 (m, 2H),
7.93-7.66 (m, 1H), 7.64-7.31 (m, 2H), 7.03-6.67 (m, 1H), 6.51 (d,
J=8.2 Hz, 2H), 6.18 (s, 2H), 4.81 (td, J=6.8, 4.8 Hz, 1H), 2.27
(ddd, J=63.2, 1.3, 0.7 Hz, 3H), 1.32 (dd, J=11.5, 6.6 Hz, 3H).
ES/MS 466.1 (M+H.sup.+);
[0670]
(S)-2,4-diamino-6-((5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-ox-
o-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methylamino)pyrimidine-5-carboni-
trile (Compound 33). 1H NMR (400 MHz, DMSO-d6) .delta. 8.67-8.25
(m, 2H), 8.07 (ddd, J=9.3, 2.7, 1.8 Hz, 1H), 7.93-7.47 (m, 2H),
6.83-6.41 (m, 3H), 6.14 (s, 2H), 4.48 (dt, J=20.2, 7.9 Hz, 1H),
1.67-1.32 (m, 1H), 0.65-0.29 (m, 3H), 0.27-0.01 (m, 1H). ES/MS
496.1 (M+H.sup.+);
[0671]
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro--
4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile
(Compound 34). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.74
(ddd, J=20.2, 2.4, 0.7 Hz, 1H), 8.64 (ddd, J=16.5, 4.8, 1.5 Hz,
1H), 8.14 (dd, J=8.4, 4.5 Hz, 1H), 8.09-7.91 (m, 2H), 7.65-7.49 (m,
1H), 6.93 (dd, J=15.4, 6.9 Hz, 1H), 6.57 (br. s, 2H), 6.37-6.14 (m,
2H), 4.82-4.69 (m, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS 443.1
(M+H.sup.+);
[0672]
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-8-fluoro-
-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile
(Compound 35). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.72
(ddd, J=7.6, 2.5, 0.7 Hz, 1H), 8.64 (ddd, J=10.1, 4.8, 1.5 Hz, 1H),
8.10 (dd, J=8.4, 4.5 Hz, 1H), 8.01 (dddd, J=11.2, 8.1, 2.5, 1.5 Hz,
1H), 7.92 (ddd, J=9.6, 8.5, 1.0 Hz, 1H), 7.64-7.50 (m, 1H),
6.85-6.71 (m, 1H), 6.55 (br. s, 2H), 6.23 (br. s, 2H), 4.63-4.46
(m, 1H), 1.92-1.61 (m, 2H), 0.68 (td, J=7.3, 5.4 Hz, 3H). ES/MS
457.1 (M+H.sup.+);
[0673]
(S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4--
dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 36). 1H NMR (400 MHz, DMSO-d6) .delta. 8.74-8.43 (m, 2H),
8.08-7.82 (m, 2H), 7.71 (ddd, J=9.1, 5.0, 3.2 Hz, 1H), 7.51 (dddd,
J=28.0, 8.1, 4.8, 0.8 Hz, 1H), 6.85 (dd, J=14.4, 7.0 Hz, 1H), 6.52
(s, 2H), 6.20 (d, J=25.5 Hz, 2H), 4.67 (h, J=6.7 Hz, 1H), 1.29 (d,
J=6.7 Hz, 3H). ES/MS 452.1 (M+H.sup.+);
[0674]
(S)-2,4-diamino-6-((5-chloro-6-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-di-
hydroquinazolin-2-yl)(cyclopropyl)methylamino)pyrimidine-5-carbonitrile
(Compound 37). 1H NMR (400 MHz, DMSO-d6) .delta. 8.74-8.32 (m, 2H),
8.04-7.86 (m, 1H), 7.82-7.58 (m, 1H), 7.44 (dddd, J=60.7, 8.1, 4.8,
0.8 Hz, 1H), 6.72-6.46 (m, 4H), 6.16 (s, 2H), 4.44 (td, J=7.9, 1.7
Hz, 1H), 1.52-1.19 (m, 1H), 0.39 (dddd, J=16.8, 9.7, 7.4, 4.2 Hz,
3H), 0.12--0.19 (m, 1H). ES/MS 478.1 (M+H.sup.+);
[0675]
(S)-2,4-diamino-6-(1-(5-chloro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 38). 1H NMR (400 MHz, DMSO) .delta. 8.31 (dd, J=5.2, 1.5
Hz, 1H), 7.94 (dd, J=7.8, 1.3 Hz, 1H), 7.82 (t, 8.11 Hz, 1H), 7.72
(dd, J=8.11, 1.16 Hz, 1H), 7.61 (dd, J=7.94, 1.04 Hz, 1H), 7.34
(dd, J=7.85, 4.85 Hz, 1H), 5.18 (m, 1H), 2.23 (s, 3H), 1.38 (d,
J=6.7 Hz, 3H). ES/MS 448.8 (M+H.sup.+);
[0676]
(S)-2,4-diamino-6-(1-(5-chloro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 39). 1H NMR (400 MHz, DMSO) .delta. 8.4 (dd, J=4.7, 1.6
Hz, 1H), 7.81 (dd, J=8.0, 1.6 Hz, 1H), 7.80 (t, 8.03 Hz, 1H), 7.66
(dd, J=8.21, 1.17 Hz, 1H), 7.59 (dd, J=7.8, 1.17 Hz, 1H), 7.27 (dd,
J=7.9, 4.8 Hz, 1H), 4.68 (m, 1H), 2.25 (s, 3H), 1.26 (d, J=6.67 Hz,
3H). ES/MS 448.8 (M+H.sup.+);
[0677]
(S)-2,4-diamino-6-(1-(5-chloro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 40). 1H NMR (400 MHz, DMSO) .delta. 8.68 (s, 1H), 8.37
(d, J=4.9 Hz, 1H), 8.31 (bs, 1H), 7.90 (bs, 1H), 7.83 (t, 8.09 Hz,
1H), 7.74 (dd, J=8.09, 1.22 Hz, 1H), 7.62 (dd, J=7.75, 1.22 Hz,
1H), 7.30 (d, J=5.25 Hz, 1H), 5.25 (m, 1H), 2.13 (s, 3H), 1.40 (d,
J=6.4 Hz, 3H). ES/MS 448.8 (M+H.sup.+);
[0678]
(S)-2,4-diamino-6-(1-(5-chloro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 41). 1H NMR (400 MHz, DMSO) .delta. 8.4 (s, 1H), 8.38 (d,
J=5.0 Hz, 1H), 8.11 (bs, 1H), 7.90 (bs, 1H), 7.83 (t, 7.86 Hz, 1H),
7.71 (dd, J=7.9, 1.25 Hz, 1H), 7.63 (dd, J=7.9, 1.25 Hz, 1H), 7.44
(d, J=5.0 Hz, 1H), 4.75 (m, 1H), 2.12 (s, 3H), 1.34 (d, J=6.6 Hz,
3H). ES/MS 448.8 (M+H.sup.+);
[0679]
(S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 42). 1H NMR (400 MHz, DMSO-d6) .delta. 8.54 (s, 1H),
8.41-8.26 (m, 1H), 7.93 (t, J=9.0 Hz, 1H), 7.84-7.66 (m, 1H), 7.19
(dt, J=5.0, 0.7 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.47 (s, 2H), 5.73
(s, 2H), 5.25-4.90 (m, 1H), 2.09 (s, 3H), 1.46-1.22 (m, 3H). ES/MS
466.1 (M+H.sup.+);
[0680]
(S)-2,4-diamino-6-(1-(5-chloro-6-fluoro-3-(4-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 43). 1H NMR (400 MHz, DMSO-d6) .delta. 8.58-8.30 (m, 2H),
7.93 (td, J=9.0, 1.3 Hz, 1H), 7.75 (ddd, J=9.0, 5.0, 1.4 Hz, 1H),
7.41 (d, J=5.0 Hz, 1H), 6.94 (d, J=7.4 Hz, 1H), 6.53 (s, 2H), 6.23
(s, 2H), 4.69 (qd, J=7.3, 5.8 Hz, 1H), 2.11 (d, J=1.5 Hz, 3H), 1.26
(dd, J=6.6, 1.5 Hz, 3H). ES/MS 466.1 (M+H.sup.+);
[0681]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 44). 1H NMR (400 MHz, DMSO) .delta. 8.3 (d, J=2.5 Hz,
2H), 8.16 (bs, 1H), 8.04 (dd, 8.8, 2.6 Hz, 1H), 7.83 (t, J=8.24 Hz,
1H), 7.74 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 5.25 (m, 1H),
2.20 (s, 3H), 1.40 (d, J=6.5 Hz, 3H). ES/MS 466.1 (M+H.sup.+);
[0682]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-2-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 45). 1H NMR (400 MHz, DMSO) .delta. 8.5 (d, J=2.8 Hz,
2H), 7.83 (t, J=8.15 Hz, 1H), 7.7 (dd, J=8.15, 1.3 Hz, 1H), 7.66
(dd, J=8.8, 2.7 Hz, 1H), 7.63 (dd, J=7.8, 1.4 Hz, 1H), 7.38 (m,
1H), 7.2 (ddt, J=8.1, 6.7, 1.13 Hz, 1H), 7.16 (ddd, J=6.4, 2.0, 1.2
Hz, 1H), 6.90 (bs, 1H), 4.77 (m, 1H), 2.25 (s, 3H), 1.36 (d, J=6.5
Hz, 3H). ES/MS 466.1 (M+H.sup.+);
[0683]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 46). 1H NMR (400 MHz, DMSO) .delta. 8.60 (s, 1H), 8.45
(s, 1H), 8.33 (bs, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.78 (dd, J=8.2,
1.2 Hz, 1H), 7.67 (dd, J=7.8, 1.2 Hz, 1H), 7.31 (bs, 1H), 5.30 (m,
1H), 2.08 (s, 3H), 1.44 (d, J=6.5 Hz, 3H). ES/MS 466.8
(M+H.sup.+);
[0684]
(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
(Compound 47). 1H NMR (400 MHz, DMSO) .delta. 8.49 (s, 1H), 8.32
(s, 1H), 7.87 (t, J=8.0 Hz, 2H), 7.76 (dd, J=8.2, 1.2 Hz, 1H), 7.67
(dd, J=7.9, 1.25 Hz, 1H), 4.86 (m, 1H), 2.14 (s, 3H), 1.39 (d,
J=6.67 Hz, 3H). ES/MS 466.8 (M+H.sup.+);
[0685]
(S)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 48). 1H NMR (400 MHz, DMSO-d6) .delta. 8.80-8.36 (m, 2H),
7.94-7.38 (m, 3H), 6.94-6.63 (m, 1H), 6.53 (d, J=8.1 Hz, 2H), 6.16
(s, 2H), 4.62 (t, J=7.8 Hz, 1H), 2.10-1.42 (m, 2H), 1.04-0.64 (m,
3H). ES/MS 484.1 (M+H.sup.+);
[0686]
(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(methy-
lsulfonyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 49): 1H
NMR (400 MHz, DMSO) .delta. 8.79-8.73 (m, 1H), 8.69-8.63 (m, 1H),
8.35-8.26 (m, 1H), 8.13-7.99 (m, 3H), 7.66-7.53 (m, 1H), 6.34-6.28
(m, 1H), 5.99 (br s, 2H), 5.54 (br s, 1H), 5.48 (br s, 1H),
4.71-4.60 (m, 1H), 3.48 (s, 3H), 1.36-1.32 (m, 3H). ES/MS 487.1
(M+H.sup.+);
[0687]
(S)-2,4-Diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (Compound 50).
1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (dd, J=27.8, 8.2 Hz,
1H), 8.20-7.86 (m, 1H), 7.76-7.42 (m, 2H), 7.02 (d, J=23.4 Hz, 1H),
6.27 (d, J=7.8 Hz, 1H), 5.96-5.52 (m, 1H), 4.57 (dd, J=7.5, 6.7 Hz,
1H), 4.08 (d, J=5.2 Hz, 1H), 3.13 (d, J=4.4 Hz, 2H), 1.34-1.03 (m,
3H). ES/MS 482.1 (M+H.sup.+);
[0688]
(S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-
-3-(5-fluoropyridin-3-yl)quinazolin-4(3h)-one (Compound 51).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.81-8.44 (m, 2H),
7.78-7.47 (m, 3H), 6.27 (dd, J=7.5, 5.0 Hz, 1H), 5.98-5.84 (m, 1H),
5.47 (s, 1H), 4.87-4.36 (m, 1H), 1.56-1.17 (m, 3H). ES/MS 462.2
(M+H.sup.+);
[0689]
(S)-2-(1-((2,6-Diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-
-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 52). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.90-8.34 (m, 2H), 8.10-7.62 (m,
2H), 7.66-7.42 (m, 1H), 7.29 (dd, J=11.0, 8.2 Hz, 1H), 6.18 (d,
J=110.3 Hz, 2H), 5.59 (s, 1H), 4.72-4.21 (m, 1H), 1.39-1.12 (m,
3H). ES/MS 426.9 (M+H.sup.+);
[0690]
(S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-
-3-(pyridin-3-yl)quinazolin-4(3H)-on (Compound 53). 1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.83-8.51 (m, 2H), 8.25-7.88 (m, 1H),
7.86-7.37 (m, 3H), 6.25 (t, J=8.2 Hz, 1H), 5.97 (s, 2H), 5.50 (d,
J=18.3 Hz, 2H), 4.65-4.45 (m, 1H), 1.27 (dd, J=6.7, 1.8 Hz, 3H).
ES/MS 444.1 (M+H.sup.+);
[0691]
(S)-2-(1-((2,6-Diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro--
4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-8-carbonitrile
(Compound 54): .sup.1H NMR (400 MHz, DMSO) .delta. 8.78 (d, J=2.4
Hz, 0.5H), 8.59 (m, 1H), 8.57 (t, J=2.8 Hz, 0.5H), 8.51 (dd, J=4.8,
1.6 Hz, 0.5H), 8.48 (d, J=2.4 Hz, 0.5H), 8.22 (m, 1H), 8.06 (m,
0.5H), 7.88 (bm, 4H), 7.79 (m, 0.5H), 7.58 (dd, J=8.0, 4.8 Hz,
0.5H), 7.47 (dd, J=8.0, 4.8 Hz, 0.5H), 5.02 (m, 1H), 1.46 (d, J=6.4
Hz, 3H). ES/MS 443.1 (M+H.sup.+);
[0692]
(S)-2-(1-((2,6-Diamino-5-cyanopyrimidin-4-yl)amino)propyl)-6-fluoro-
-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile
(Compound 55): .sup.1H NMR (400 MHz, DMSO) .delta. 8.71 (s, 1H),
8.64 (d, J=2.8 Hz, 1H), 8.58 (m, 3H), 8.34 (s, 1H), 8.23 (m, 2H),
8.18 (m, 1H), 7.84 (bs, 1H), 7.71 (m, 1H), 4.92 (m, 1H), 2.08 (m,
1H), 1.88 (m, 1H), 0.90 (m, 3H). ES/MS 475.1 (M+H.sup.+);
[0693]
(S)-2-(Cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-
-6-fluoro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonit-
rile (Compound 56): .sup.1H NMR (400 MHz, DMSO) .delta. 8.69 (s,
0.5H), 8.60 (m, 1.5H), 8.49 (d, J=2.4 Hz, 0.5H), 8.23 (m, 1.5H),
8.17 (m, 0.5H), 7.95 (bs, 1H), 7.78 (bs, 1H), 7.71 (bs, 1H), 7.59
(m, 0.5H), 4.60 (m, 1H), 1.64 (m, 1H), 0.60 (m, 1H), 0.50 (m, 2H),
0.29 (m, 1H). ES/MS 487.1 (M+H.sup.+);
[0694]
(S)-2,4-Diamino-6-((1-(5-chloro-3-(5-fluoropyridin-3-yl)-4-oxo-3,4--
dihydroquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile
(Compound 57). .sup.1H NMR (400 MHz, DMSO) .delta. 8.83-8.58 (m,
2H), 8.24 (dd, J=9.3, 2.2 Hz, 1H), 8.09 (m, 1H), 7.83-7.70 (m, 1H),
7.70-7.49 (m, 2H), 4.70 (m, 1H), 4.01-3.29 (br m, 5H) 1.81 (m, 1H),
1.50 (m, 2H), 0.78 (m, 3H), 0.48-0.33 (m, 3H). ES/MS 494.2
(M+H.sup.+);
[0695]
(R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-
-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 110). 1H NMR (400 MHz, DMSO) .delta. 8.75-8.51 (m, 2H),
8.05-7.89 (m, 1H), 7.84-7.75 (m, 1H), 7.67-7.45 (m, 2H), 4.83 (m,
1H) 4.42-3.27 (br m, 5H) 1.36 (d, J=6.6 Hz, 3H). ES/MS 452.1
(M+H.sup.+);
[0696]
(S)-2,4-Diamino-6-((1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroq-
uinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile
(Compound 58). 1H NMR (400 MHz, DMSO) .delta. 8.82-8.75 (m, 1H),
8.67 (ddd, J=13.2, 4.8, 1.5 Hz, 1H), 8.09 (ddd, J=8.3, 5.3, 3.3 Hz,
1H), 7.78 (td, J=8.1, 2.0 Hz, 1H), 7.69-7.55 (m, 3H), 7.51-6.88 (br
m, 5H) 4.70 (m, 1H), 1.83 (d, J=9.8 Hz, 1H), 1.50-1.37 (m, 2H),
0.76 (dd, J=9.3, 5.9 Hz, 3H), 0.37-0.25 (m, 3H). ES/MS 476.1
(M+H.sup.+);
[0697]
(R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoropyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 113). 1H NMR (400 MHz, DMSO) .delta. 8.68 (m, 1H),
8.58-8.42 (m, 1H), 8.15-7.81 (m, 2H), 7.66 (d, J=8.5 Hz, 1H),
7.56-7.37 (br m, 2H), 7.26-7.00 (br m, 2H), 6.83-6.67 (m, 1H) 4.92
(m, 1H), 1.39 (m, 3H). ES/MS 470.1 (M+H.sup.+);
[0698]
(S)-5-Chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-
-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3h)-one;
[0699]
(R)-2,4-Diamino-6-((1-(5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-
-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(compound 111). 1H NMR (400 MHz, DMSO) .delta. 8.82-8.50 (m, 2H),
8.15-7.93 (m, 1H), 7.91-7.74 (m, 2H), 7.71-7.48 (m, 3H), 7.41 (ddd,
J=8.6, 7.4, 1.4 Hz, 1H), 7.28-7.12 (m, 2H), 6.79-6.69 (m, 1H), 4.71
(m, 1H), 2.05-1.90 (m, 1H), 1.90-1.74 (m, 1H), 0.82-0.68 (m, 3H).
ES/MS 466.1 (M+H.sup.+);
[0700]
(R)-2,4-Diamino-6-(((5-chloro-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-d-
ihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile (Compound 112).
1H NMR (400 MHz, DMSO) .delta. 8.78-8.32 (m, 2H), 8.12-7.88 (m,
5H), 7.82 (m, 1H), 7.74-7.62 (m, 2H), 7.39 (m, 1H), 6.77-6.70 (m,
1H), 4.54-4.42 (m, 1H), 1.63-1.47 (m, 1H), 0.62-0.08 (m, 4H). ES/MS
478.1 (M+H.sup.+);
[0701]
(S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-3-(5-fluoropyridin-3-yl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 60). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.65-8.43 (m,
2H), 8.15-8.06 (m, 1H), 7.84-7.76 (m, 1H), 7.68 (t, J=9.2 Hz, 1H),
6.95-6.81 (m, 1H), 6.51 (d, J=10.8 Hz, 2H), 6.22 (s, 2H), 4.88-4.71
(m, 1H), 1.39-1.27 (m, 3H). ES/MS 514.0 (M+H.sup.+);
[0702]
(S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4--
dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 61). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.81-8.61 (m,
1H), 8.60-8.48 (m, 1H), 8.11-7.64 (m, 3H), 7.64-7.48 (m, 2H), 7.33
(br. s, 4H), 4.76-4.58 (m, 1H), 2.05-1.69 (m, 2H), 0.84-0.66 (m,
3H). ES/MS 510.1 (M+H.sup.+);
[0703]
(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro--
3-(5-fluoropyridin-3-yl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile
(Compound 62). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.73-8.45 (m, 2H), 8.24-7.83 (m, 3H), 7.83-7.01 (br. m, 5H),
5.03-4.87 (m, 1H), 1.42 (d, J=6.6 Hz, 3H). ES/MS 461.1
(M+H.sup.+);
[0704]
(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-4-oxo-3--
(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile (Compound 63).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.82-8.75 (m, 1H),
8.72-8.62 (m, 1H), 8.15-7.92 (m, 4H), 7.67-7.52 (m, 1H), 6.32-6.24
(m, 1H), 6.00 (s, 2H), 5.53 (d, J=17.8 Hz, 2H), 4.67-4.51 (m, 1H),
1.40-1.25 (m, 3H). ES/MS 434.1 (M+H.sup.+);
[0705]
(S)-2,4-diamino-6-((1-(5-bromo-8-fluoro-4-oxo-3-(pyridin-3-yl)-3,4--
dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 64). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.77-8.64 (m, 1H), 8.64-8.51 (m, 1H), 8.08-7.89 (m, 1H), 7.85-7.76
(m, 1H), 7.69 (t, J=9.2 Hz, 1H), 7.61-7.45 (m, 1H), 6.97-6.82 (m,
1H), 6.55 (d, J=5.4 Hz, 2H), 6.25 (br. d, J=16.7 Hz, 2H), 4.80-4.65
(m, 1H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 496.1 (M+H.sup.+);
[0706]
(S)-2,4-Diamino-6-(((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin--
3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)
(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile (Compound 65):
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.55 (m, 1H), 8.38 (m,
1H), 7.82 (dd, J=9.6, 8.8 Hz, 1H), 7.65 (dd, J=8.8, 4.5 Hz, 1H),
4.63 (t, J=8.7 Hz, 1H), 2.01 (s, 3H), 1.63 (m, 1H), 0.61 (m, 1H),
0.41 (m, 2H), 0.30 (m, 1H). ES/MS 510.1 (M+H.sup.+);
[0707]
(S)-2,4-Diamino-6-(((5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridin--
3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidin-
e-5-carbonitrile (Compound 66): 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.38 (s, 1H), 8.15 (s, 1H), 7.80 (dd, J=9.6, 8.8 Hz, 1H),
7.65 (dd, J=8.8, 4.5 Hz, 1H), 4.24 (t, J=8.34 Hz, 1H), 2.09 (s,
3H), 1.59 (m, 1H), 0.55 (m, 1H), 0.44 (m, 2H), 0.07 (m, 1H). ES/MS
510.1 (M+H.sup.+);
[0708]
(S)-2,4-diamino-6-((1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 67): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.55 (s, 1H),
8.39 (s, 1H), 7.90 (td, J=8.2, 8.2, 5.5 Hz, 1H), 7.62 (dd, J=8.3,
1.0 Hz, 1H) 7.37 (ddd, J=10.9, 8.2, 1.0 Hz, 1H), 5.28 (dd, J=8.6,
6.5 Hz, 1H), 2.05 (s, 3H), 1.40 (d, J=6.5 Hz, 3H). ES/MS 450.1
(M+H.sup.+);
[0709]
(S)-2,4-diamino-6-((1-(5-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 68): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.44 (s, 1H),
8.31 (s, 1H), 7.90 (td, J=8.2, 8.2, 5.5 Hz, 1H), 7.59 (dd, J=8.2,
1.0 Hz, 1H) 7.37 (ddd, J=11.0, 8.3, 1.1 Hz, 1H), 4.82 (p, J=6.8,
6.7 Hz, 1H), 2.08 (s, 3H), 1.36 (d, J=6.6 Hz, 3H). S/MS 450.1
(M+H.sup.+);
[0710]
(S)-2,4-diamino-6-(((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbo-
nitrile (Compound 69): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54
(s, 1H), 8.38 (s, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz,
1H), 7.64 (d, J=7.8 Hz, 1H), 4.60 (t, J=8.8 Hz, 1H), 2.00 (s, 3H),
1.62 (m, 1H), 0.61 (m, 1H), 0.41 (m, 2H), 0.30 (m, 1H). ES/MS 492.1
(M+H.sup.+);
[0711]
(S)-2,4-diamino-6-(((5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbo-
nitrile (Compound 70): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.39
(s, 1H), 8.16 (s, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.75 (dd, J=8.0, 1.2
Hz, 1H), 7.65 (dd, J=7.8, 1.2 Hz, 1H), 4.21 (t, J=8.4 Hz, 1H), 2.07
(s, 3H), 1.59 (m, 1H), 0.57 (m, 1H), 0.43 (m, 2H), 0.02 (m, 1H).
ES/MS 492.1 (M+H.sup.+);
[0712]
(S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 71): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H),
8.42 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.73 (dd, J=8.1, 1.3 Hz, 1H),
7.63 (dd, J=7.8, 1.3 Hz, 1H), 5.09 (q, J=7.8 Hz, 1H), 2.13 (dt,
J=13.9, 7.0 Hz, 1H), 2.00 (s, 3H), 1.79 (dt, J=14.5, 7.5 Hz, 1H),
0.82 (t, J=7.4 Hz, 1H). ES/MS 480.1 (M+H.sup.+);
[0713]
(S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 72): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.44 (s, 1H),
8.23 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.63
(d, J=8.0 Hz, 1H), 4.63 (q, J=7.1 Hz, 1H), 2.1 (s, 3H), 2.04 (dq,
J=13.9, 7.0 Hz, 1H), 1.67 (dp, J=14.3, 7.4, 7.2 Hz, 1H), 0.80 (t,
J=7.3 Hz, 1H). ES/MS 480.1 (M+H.sup.+);
[0714]
(S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridi-
n-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonit-
rile (Compound 73): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 68.57 (s,
1H), 8.42 (s, 1H), 7.82 (dd, J=9.6, 8.8 Hz, 1H), 7.65 (dd, J=8.8,
4.5 Hz, 1H), 5.28 (m, 1H), 2.05 (s, 3H), 1.42 (d, J=6.5 Hz, 3H).
ES/MS 484.1 (M+H.sup.+);
[0715]
(S)-2,4-diamino-6-((1-(5-chloro-8-fluoro-3-(5-fluoro-4-methylpyridi-
n-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonit-
rile (Compound 74): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.45 (s, 1H), 8.28 (s, 1H), 7.81 (dd, J=9.6, 8.8 Hz, 1H), 7.65 (dd,
J=8.8, 4.5 Hz, 1H), 4.83 (m, 1H), 2.12 (s, 3H), 1.36 (d, J=6.6 Hz,
3H). ES/MS 484.1 (M+H.sup.+);
[0716]
(S)-2,4-diamino-6-((1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 75): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.57 (s,
1H), 8.41 (s, 1H), 7.9-7.8 (m, 3H), 5.32 (m, 1H), 2.03 (s, 3H),
1.42 (d, J=6.5 Hz, 3H). ES/MS 450.1 (M+H.sup.+);
[0717]
(S)-2,4-diamino-6-((1-(6-fluoro-3-(5-fluoro-4-methylpyridin-3-yl)-4-
-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 76): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.45 (s,
1H), 8.29 (s, 1H), 7.9-7.8 (m, 3H), 4.86 (m, 1H), 2.08 (s, 3H),
1.37 (d, J=6.6 Hz, 3H). ES/MS 450.1 (M+H.sup.+);
[0718]
(S)-2,4-diamino-6-((1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 77): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.57 (s,
1H), 8.29 (s, 1H), 7.83 (t, J=8.2 Hz, 1H), 7.74 (dd, J=8.2, 1.3 Hz,
1H) 7.62 (dd, J=7.8, 1.3 Hz, 1H), 5.28 (m, 1H), 2.12 (s, 3H), 2.03
(s, 3H), 1.40 (d, J=6.5 Hz, 3H). ES/MS 462.1 (M+H.sup.+);
[0719]
(S)-2,4-diamino-6-((1-(5-chloro-3-(4,5-dimethylpyridin-3-yl)-4-oxo--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 78): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.24 (s, 1H),
8.21 (s, 1H), 7.82 (t, J=8.2 Hz, 1H), 7.71 (dd, J=8.2, 1.2 Hz, 1H)
7.62 (dd, J=7.8, 1.2 Hz, 1H), 4.83 (m, 1H), 2.30 (s, 3H), 2.05 (s,
3H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 462.1 (M+H.sup.+);
[0720]
(S)-2,4-Diamino-6-((1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluorom-
ethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 79). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.57 (d,
J=0.9 Hz, 1H), 8.33 (dd, J=4.9, 1.0 Hz, 1H), 8.17-7.90 (m, 3H),
7.36-7.07 (m, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.46 (s, 2H), 5.31-4.94
(m, 1H), 2.07 (s, 3H), 1.37 (d, J=6.4 Hz, 3H). ES/MS 482.2
(M+H.sup.+);
[0721]
(S)-2,4-Diamino-6-((1-(3-(4-methylpyridin-3-yl)-4-oxo-5-(trifluorom-
ethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 80). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.52 (s, 1H),
8.41 (d, J=5.0 Hz, 1H), 7.42 (dt, J=5.1, 0.7 Hz, 1H), 6.98 (d,
J=7.1 Hz, 1H), 6.52 (s, 2H), 4.74 (p, J=6.7 Hz, 1H), 2.08 (s, 3H),
1.27 (d, J=6.7 Hz, 3H). ES/MS 482.2 (M+H.sup.+);
[0722]
(S)-3-(6-aminopyridin-3-yl)-8-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one (Compound
81). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.11 (dt, J=9.6,
3.2 Hz, 1H), 8.06-7.96 (m, 1H), 7.80 (dd, J=8.0, 2.9 Hz, 1H), 7.53
(ddd, J=8.6, 5.3, 2.8 Hz, 1H), 6.59 (dd, J=8.7, 6.1 Hz, 1H), 6.39
(d, J=9.0 Hz, 2H), 6.03 (d, J=7.2 Hz, 2H), 5.62 (d, J=12.1 Hz, 2H),
4.79 (dt, J=30.2, 7.2 Hz, 1H), 1.36-1.21 (m, 3H). ES/MS 476.1
(M+H.sup.+);
[0723]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-8-chloro-6-fluoro-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 82). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.12
(dt, J=8.7, 2.3 Hz, 1H), 8.01 (dd, J=21.8, 2.6 Hz, 1H), 7.81 (dd,
J=8.3, 3.0 Hz, 1H), 7.51 (ddd, J=9.0, 6.3, 2.7 Hz, 1H), 6.89 (dd,
J=42.5, 6.9 Hz, 2H), 6.62-6.52 (m, 2H), 6.37 (d, J=6.6 Hz, 3H),
4.86 (dt, J=23.9, 6.6 Hz, 1H), 1.38-1.21 (m, 3H). ES/MS 467.1
(M+H.sup.+);
[0724]
(S)-3-(6-aminopyridin-3-yl)-5,8-dichloro-2-(1-((2,6-diamino-5-chlor-
opyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one (Compound 83).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.05-7.92 (m, 1H), 7.54
(ddt, J=11.5, 8.0, 3.4 Hz, 1H), 6.69-6.47 (m, 1H), 6.39 (dd, J=8.4,
4.1 Hz, 1H), 6.02 (d, J=6.5 Hz, 1H), 5.62 (d, J=10.2 Hz, 1H), 4.74
(dt, J=33.1, 7.0 Hz, 1H), 2.54 (s, 2H), 1.35-1.21 (m, 3H). ES/MS
492.1 (M+H.sup.+);
[0725]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5,8-dichloro-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 84). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.06-7.90 (m, 2H), 7.60-7.47 (m, 2H), 6.88 (dd, J=44.9, 6.9 Hz,
2H), 6.63-6.52 (m, 2H), 6.37 (d, J=8.0 Hz, 3H), 4.83 (dq, J=26.5,
6.7 Hz, 1H), 1.38-1.21 (m, 3H). ES/MS 483.1 (M+H.sup.+);
[0726]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)ethyl)quinazolin-4(3H)-one (Compound 85). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01 (dt, J=39.3, 2.5 Hz, 2H),
7.79-7.67 (m, 1H), 7.64-7.47 (m, 4H), 6.58 (ddd, J=11.5, 8.8, 2.0
Hz, 1H), 6.38-6.21 (m, 3H), 6.02 (d, J=8.8 Hz, 1H), 5.56 (d, J=13.9
Hz, 1H), 4.81-4.49 (m, 1H), 1.31 (ddd, J=12.4, 7.1, 2.2 Hz, 3H).
ES/MS 458.1 (M+H.sup.+);
[0727]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)propyl)quinazolin-4(3H)-one (Compound 86).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16-7.89 (m, 1H), 7.73
(td, J=8.0, 2.7 Hz, 1H), 7.62-7.47 (m, 4H), 6.61 (ddd, J=19.4, 8.8,
0.8 Hz, 1H), 6.35 (d, J=11.5 Hz, 1H), 6.18-6.01 (m, 3H), 5.56 (d,
J=15.9 Hz, 1H), 4.59 (dtd, J=35.7, 8.3, 3.6 Hz, 1H), 1.86-1.58 (m,
2H), 0.76-0.68 (m, 3H). ES/MS 472.1 (M+H.sup.+);
[0728]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-d-
ihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 87). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.19-7.89 (m, 1H), 7.76 (td, J=8.0, 2.4 Hz, 1H), 7.65-7.45 (m, 2H),
6.91-6.50 (m, 3H), 6.37 (s, 3H), 4.66 (dtd, J=30.1, 7.7, 3.9 Hz,
1H), 1.93-1.59 (m, 2H), 0.71 (td, J=7.3, 4.8 Hz, 3H). ES/MS 463.1
(M+H.sup.+);
[0729]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)ethyl)-8-fluoroquinazolin-4(3H)-one (Compound
88). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01 (d, J=37.3 Hz,
1H), 7.70 (t, J=9.3 Hz, 1H), 7.68-7.35 (m, 1H), 6.58 (t, J=8.4 Hz,
2H), 6.49-6.20 (m, 1H), 6.01 (s, 1H), 5.57 (d, J=12.7 Hz, 2H), 4.73
(s, 1H), 1.42-1.11 (m, 3H). ES/MS 476.1 (M+H.sup.+);
[0730]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(cyclopropyl((2,6-diamino-5--
chloropyrimidin-4-yl)amino)methyl)quinazolin-4(3H)-one (Compound
89). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.08-7.88 (m, 1H),
7.83-7.68 (m, 1H), 7.69-7.40 (m, 2H), 6.59 (dd, J=8.6, 3.1 Hz, 1H),
6.46-6.27 (m, 1H), 6.16-5.86 (m, 2H), 5.57 (d, J=6.6 Hz, 1H), 4.67
(q, J=8.1 Hz, 1H), 1.21 (d, J=22.0 Hz, 2H), 0.54-0.34 (m, 2H),
0.34-0.19 (m, 1H). ES/MS 484.1 (M+H.sup.+);
[0731]
(S)-2,4-diamino-6-(((3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dih-
ydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 90). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01-7.91 (m,
1H), 7.78 (td, J=8.0, 2.0 Hz, 1H), 7.66-7.54 (m, 2H), 7.48 (dd,
J=8.9, 3.0 Hz, 1H), 6.66 (d, J=9.5 Hz, 2H), 6.56 (dd, J=12.7, 8.7
Hz, 2H), 6.35 (s, 2H), 4.70 (dt, J=10.0, 7.3 Hz, 1H), 1.22 (d,
J=11.5 Hz, 1H), 0.45-0.37 (m, 2H), 0.18-0.02 (m, 2H). ES/MS 475.1
(M+H.sup.+);
[0732]
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4--
oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 91): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.87 (s,
1H), 7.80 (t, J=8.0 Hz, 1H), 7.61 (ddd, J=17.6, 7.9, 1.3 Hz, 1H),
6.67 (s, 1H), 6.49-6.41 (m, 2H), 6.21 (s, 1H), 4.82 (td, J=8.2, 4.2
Hz, 1H), 1.90 (s, 3H), 1.67 (dp, J=14.4, 7.2 Hz, 1H), 1.25 (dd,
J=11.4, 5.0 Hz, 1H), 0.74 (t, J=7.3 Hz, 3H). ES/MS 477.1
(M+H.sup.+);
[0733]
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4--
oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 92): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.94 (s,
1H), 7.80 (t, J=8.0 Hz, 1H), 7.61 (ddd, J=16.0, 8.0, 1.2 Hz, 2H),
6.86 (d, J=7.0 Hz, 1H), 6.63 (s, 2H), 6.45 (s, 1H), 6.35 (s, 2H),
6.27 (s, 2H), 4.78 (td, J=6.8, 4.8 Hz, 1H), 1.94 (s, 3H), 1.84-1.69
(m, 1H), 1.60 (dp, J=13.7, 7.0 Hz, 1H), 0.73 (t, J=7.3 Hz, 3H).
ES/MS 477.1 (M+H.sup.+);
[0734]
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 93): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.98 (s, 1H),
7.79 (t, J=8.0 Hz, 1H), 7.60 (ddd, J=13.9, 8.1, 1.2 Hz, 2H), 6.99
(d, J=6.6 Hz, 1H), 6.62 (s, 2H), 6.43 (s, 1H), 6.37 (s, 2H), 6.22
(s, 2H), 4.83 (p, J=6.6 Hz, 1H), 1.93 (s, 3H), 1.24 (d, J=6.7 Hz,
3H). ES/MS 463.1 (M+H.sup.+);
[0735]
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5-chloro-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 94): 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.98 (s, 1H),
7.80 (dd, J=7.8 Hz, 1H), 7.66-7.55 (m, 2H), 6.98 (d, J=6.6 Hz, 1H),
6.61 (s, 2H), 6.43 (t, J=0.8 Hz, 1H), 6.37 (s, 2H), 6.22 (s, 2H),
4.83 (p, J=6.6 Hz, 1H), 1.93 (d, J=0.7 Hz, 3H), 1.24 (d, J=6.7 Hz,
3H). ES/MS 463.1 (M+H.sup.+);
[0736]
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichlor-
o-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 95): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13 (s,
1H), 8.04 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.32 (s, 1H),
6.83 (s, 1H), 6.58 (s, 1H), 6.5 (s, 1H), 5.39 (q, J=7.1, 6.6 Hz,
1H), 2.05 (s, 3H), 1.45 (d, J=6.5 Hz, 3H). ES/MS 498.1
(M+H.sup.+);
[0737]
(S)-2,4-diamino-6-((1-(3-(6-amino-4-methylpyridin-3-yl)-5,8-dichlor-
o-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 96): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.05 (d,
J=8.5 Hz, 1H), 7.92 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 6.84 (s, 1H),
4.98 (p, J=6.7 Hz, 1H), 2.12 (s, 3H), 1.39 (d, J=6.6 Hz, 3H). ES/MS
498.1 (M+H.sup.+);
[0738]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 97): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.09-8.03 (m, 0.5H), 7.98-7.92 (m, 0.5H), 7.77 (td, J=8.0, 2.3 Hz,
1H), 7.58 (ddt, J=12.1, 7.9, 1.3 Hz, 1H), 6.89 (d, J=6.8 Hz, 0.5H),
6.81 (d, J=6.9 Hz, 0.5H), 6.64-6.52 (m, 2H), 6.33 (d, J=7.1 Hz,
2H), 4.73 (dp, J=30.3, 6.7 Hz, 1H), 1.32 (dd, J=14.1, 6.7 Hz, 3H).
ES/MS 449.1 (M+H.sup.+);
[0739]
(S)-2,4-diamino-6-(((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro--
4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-ca-
rbonitrile (Compound 98): .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.99 (d, J=8.5 Hz, 1H), 7.87 (s, 1H), 7.58 (d, J=8.5 Hz,
1H), 6.66 (s, 2H), 6.43 (ddd, J=8.4, 1.9, 1.2 Hz, 1H), 6.22 (s,
2H), 4.95 (dd, J=8.6, 6.2 Hz, 1H), 1.86 (d, J=0.8 Hz, 3H),
1.36-1.21 (m, 1H), 0.47-0.32 (m, 3H), 0.18-0.06 (m, 1H). ES/MS
524.1 (M+H.sup.+);
[0740]
(S)-2,4-diamino-6-(((3-(6-amino-4-methylpyridin-3-yl)-5,8-dichloro--
4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-ca-
rbonitrile (Compound 99): 1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.06 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.65 (d, J=8.5
Hz, 1H), 7.58 (s, 1H), 6.88 (s, 1H), 4.49 (t, J=8.1 Hz, 1H), 2.11
(s, 3H), 1.56 (tq, J=8.3, 5.2, 4.3 Hz, 1H), 0.63-0.40 (m, 3H),
0.14-0.03 (m, 1H). ES/MS 524.1 (M+H.sup.+);
[0741]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one (Compound
100). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01 (m, 1H),
7.93-7.82 (m, 1H), 7.72-7.46 (m, 2H), 6.58 (m, 1H), 6.35 (d, J=8.4
Hz, 2H), 6.25 (dd, J=21.7, 7.5 Hz, 2H), 6.02 (d, J=7.5 Hz, 2H),
5.56 (d, J=14.0 Hz, 2H), 4.81-4.55 (m, 1H), 1.30 (m, 3H). ES/MS
536.1 (M+H.sup.+);
[0742]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 101). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.42-7.84 (m, 3H), 7.84-7.46 (m, 3H), 7.75-7.50 (m, 4H), 7.01-6.63
(m, 1H), 5.00 (m, 1H), 1.38 (dd, J=19.7, 6.6 Hz, 3H). ES/MS 467.1
(M+H.sup.+);
[0743]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)butyl)quinazolin-4(3H)-one (Compound 102).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.02 (ddd, J=52.2, 2.7,
0.7 Hz, 1H), 7.87-7.41 (m, 3H), 6.61 (ddd, J=27.6, 8.7, 0.7 Hz,
1H), 6.49-5.85 (m, 4H), 5.53 (d, J=21.9 Hz, 1H), 4.69 (dtd, J=45.0,
8.8, 3.3 Hz, 1H), 2.01-1.55 (m, 2H), 1.35-0.77 (m, 2H), 0.61 (dt,
J=20.1, 7.4 Hz, 3H). ES/MS 486.1 (M+H.sup.+);
[0744]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-d-
ihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile
(Compound 103). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.21-7.87 (m, 1H), 7.82-7.19 (m, 3H), 6.95-6.46 (m, 3H), 6.32 (d,
J=6.8 Hz, 4H), 5.08-4.39 (m, 1H), 1.71 (dd, J=40.5, 13.9 Hz, 2H),
1.40-0.94 (m, 2H), 0.80-0.38 (m, 3H). ES/MS 477.1 (M+H.sup.+);
[0745]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyr-
imidin-4-yl)amino)butyl)-6-fluoroquinazolin-4(3H)-one (Compound
104). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.09 (dd, J=2.7, 0.7
Hz, 1H), 7.85 (td, J=9.0, 3.2 Hz, 1H), 7.72-7.37 (m, 3H), 6.62
(ddd, J=27.1, 8.7, 0.7 Hz, 1H), 6.34 (d, J=8.8 Hz, 2H), 6.16-5.84
(m, 4H), 5.53 (d, J=21.7 Hz, 2H), 4.69 (dtd, J=44.3, 9.0, 3.2 Hz,
1H), 1.68 (m, 2H), 1.43-0.87 (m, 2H), 0.61 (dt, J=20.1, 7.4 Hz,
3H). ES/MS 504.1 (M+H.sup.+);
[0746]
(S)-2,4-diamino-6-((1-(3-(6-aminopyridin-3-yl)-5-chloro-6-fluoro-4--
oxo-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile
(Compound 105). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.03 (dd,
J=57.4, 2.5 Hz, 1H), 7.93-7.34 (m, 3H), 6.88-6.42 (m, 3H), 6.33 (d,
J=23.6 Hz, 3H), 4.74 (m, 1H), 1.82-1.54 (m, 2H), 1.43-0.87 (m, 2H),
0.74-0.45 (m, 3H). ES/MS 495.1 (M+H.sup.+);
[0747]
(S)-3-(6-aminopyridin-3-yl)-5-chloro-2-(cyclopropyl((2,6-diamino-5--
chloropyrimidin-4-yl)amino)methyl)-8-fluoroquinazolin-4(3H)-one
(Compound 106). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.10 (s,
1H), 7.89-7.57 (m, 2H), 7.60-7.12 (m, 3H), 6.61 (s, 1H), 4.57 (s,
1H), 1.49 (d, J=22.8 Hz, 1H), 1.37-1.01 (m, 3H), 0.45 (s, 2H), 0.18
(d, J=21.1 Hz, 1H). ES/MS 502.1 (M+H.sup.+);
[0748]
(S)-2,4-diamino-6-(((3-(6-aminopyridin-3-yl)-5-chloro-8-fluoro-4-ox-
o-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbon-
itrile (Compound 107). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.96
(dd, J=20.6, 2.6 Hz, 1H), 7.80-7.64 (m, 1H), 7.67-7.36 (m, 2H),
6.65 (d, J=7.5 Hz, 2H), 6.62-6.24 (m, 6H), 4.72 (dt, J=10.3, 7.2
Hz, 1H), 1.24 (tt, J=12.5, 5.8 Hz, 1H), 0.50-0.25 (m, 3H),
0.15-0.03 (m, 1H). ES/MS 493.1 (M+H.sup.+);
[0749]
(S)-2,4-diamino-6-((1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 108). Exists as a .about.11 mixture of diastereomers. 1H
NMR (400 MHz, DMSO-d6) .delta. 7.97-7.90 (m, 1.5H), 7.85 (d, J=2.0
Hz, 0.5H), 7.78 (td, J=8.0, 2.4 Hz, 1H), 7.66-7.56 (m, 2H), 7.24
(s, 0.5H), 7.11 (s, 0.5H), 4.91 (p, J=7.3 Hz, 0.5H), 4.80 (p, J=6.8
Hz, 0.5H), 1.34 (dd, J=6.7, 1.4 Hz, 3H). ES/MS 449.1 (M+H.sup.+);
and
[0750]
(S)-4-amino-6-((1-(3-(5-aminopyridin-3-yl)-5-chloro-4-oxo-3,4-dihyd-
roquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
109). Exists as a .about.11 mixture of diastereomers. 1H NMR (400
MHz, DMSO-d6) .delta. 8.09 (s, 0.5H), 8.00 (d, J=2.5 Hz, 0.5H),
7.94 (s, 0.5H), 7.89 (d, J=2.4 Hz, 0.5H), 7.87 (s, 0.5H), 7.77 (td,
J=8.0, 2.5 Hz, 1H), 7.72 (d, J=6.9 Hz, 0.5H), 7.67-7.55 (m, 2.5H),
7.44 (s, 0.5H), 7.32 (d, J=14.0 Hz, 2.5H), 4.87 (p, J=7.1 Hz,
0.5H), 4.81 (p, J=6.7 Hz, 0.5H), 1.37 (dd, J=6.7, 3.1 Hz, 3H).
ES/MS 434.1 (M+H.sup.+).
C. Preparation of a Compound of Formula (I) Wherein n is 2, R.sup.1
is Cyano, R.sup.1 is Fluoro, m is 0, R.sup.3 is Cyclopropyl, and
R.sup.4 is Chloro
##STR00156##
[0752]
(S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-
-8-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one (141 mg, 0.3 mmol),
Zn(CN).sub.2 (40 mg, 0.35 mmol), and Pd(PPh3).sub.4 (34 mg, 0.03
mmol) were dissolved in NMP (3 mL). Argon was bubbled through (1
min.) and then heated to 120.degree. C. using microwave for 1 h.
The reaction mixture was purified by HPLC to give
(S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-fl-
uoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-5-carbonitrile
(Compound 59). 1H NMR (400 MHz, DMSO-d6) .delta. 8.80-8.54 (m, 1H),
8.51-8.31 (m, 1H), 8.19 (ddd, J=8.5, 4.5, 1.5 Hz, 1H), 8.09-7.89
(m, 2H), 7.83-7.50 (m, 5H), 7.46-7.26 (m, 2H), 4.48 (dt, J=14.0,
8.2 Hz, 1H), 1.66-1.48 (m, 1H), 0.63-0.38 (m, 3H), 0.16 (ddt,
J=15.4, 9.2, 4.4 Hz, 1H). ES/MS 478.1 (M+H.sup.+).
Example 5
Characterization of Compounds of Formula (I)
[0753] This Example characterizes the biological activity of the
compounds of formula (I) and further compares with Compounds X, Y
and Z having the following structures:
##STR00157##
[0754] Enzymatic activity of PI3K isoforms was measured to
determine the inhibitory activities to the PI3K isoforms
selectivity of the compounds tested, including the activities
against PI3K.delta.. A cellular assay measuring the inhibition of
basophil activation was used to assess the potency of the compounds
in a cellular assay. Stability in human hepatocytes was also
measured to assess the half-life of the tested compounds in human
subjects.
[0755] i. Enzymatic Activity of PI3K Isoforms
[0756] Enzymatic activity of the class I PI3K isoforms in the
presence of the compounds of Table 1 and Compounds X, Y and Z was
measured using a time-resolved fluorescence resonance energy
transfer (TR-FRET) assay. The TR-FRET assay was used to monitor
formation of the product 3,4,5-inositol triphosphate molecule
(PIP3) as it competed with fluorescently labeled PIP3 for binding
to the GRP-1 pleckstrin homology domain protein. An increase in
phosphatidylinositide 3-phosphate product results in a decrease in
TR-FRET signal as the labeled fluorophore is displaced from the
GRP-1 protein binding site.
[0757] Class I PI3K isoforms were expressed and purified as
heterodimeric recombinant proteins. All assay reagents and buffers
for the TR-FRET assay were purchased from Millipore. PI3K isoforms
were assayed under initial rate conditions in the presence of 25 mM
Hepes (pH 7.4), and 2.times.Km ATP (75-500 .mu.M), 2 .mu.M PIP2, 5%
glycerol, 5 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM
dithiothreitol, 1% (v/v) DMSO at the following concentrations for
each isoforms: PI3K.alpha., PI3K.beta. 3, and PI3K.delta. between
25 and 50 pM, and PI3K.gamma. at 2 nM. After an assay reaction time
of 30 minutes at 25.degree. C., reactions were terminated with a
final concentration of 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM
Europium labeled GRP-1 detector protein before reading TR-FRET on
an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 .mu.s
delay and 500 .mu.s read window).
[0758] Data were normalized based on positive (1 .mu.M wortmanin)
and negative (DMSO) controls. .alpha., .beta., .delta., and .gamma.
IC.sub.50 values were calculated from the fit of the dose-response
curves to a four-parameter equation. All IC.sub.50 values represent
geometric mean values if more than one value was obtained.
IC.sub.50 values were reported in units of nM.
[0759] Table 2 below summarizes the IC.sub.50 values (nM) that were
collected for PI3K.delta. for compounds in the Example. Table 2a
summarizes the IC.sub.50 (nM) values for PI3K.beta. and half life
(hours) values in cryopreserved human hepatocytes.
TABLE-US-00003 TABLE 2 The PI3K.delta. IC.sub.50 Values for
Representive Compounds Compound IC.sub.50 (nM) 1 0.6 2 2 3 0.6 4 5
5 14 7 0.4 8 9 9 2 10 9 11 0.8 12 2 13 8 14 4 15 4 16 1 17 4 18 18
19 5 20 3 21 2 22 6 23 0.7 24 0.4 25 8 26 1 27 1 28 0.6 29 8 30 1
31 1 32 2 33 2 34 21 35 35 36 4 37 5 38 13 39 1 40 9 41 0.4 42 27
43 4 44 34 45 6 46 38 47 0.5 48 4 49 67 50 2 51 7 52 63 53 4 54 10
55 60 56 30 57 14 58 14 59 380 60 1 61 1 62 42 63 95 64 0.6 65 42
66 3 67 120 68 7 69 60 70 3 71 49 72 1 73 59 74 1 75 510 76 14 77
75 78 0.8 79 2 80 27 81 84 82 5 83 12 84 0.5 85 3 86 9 87 0.6 88 6
89 9 90 0.6 91 4 92 0.8 93 2 94 0.5 95 4 96 1 97 0.8 98 21 99 640
100 48 101 8 102 15 103 1 104 94 105 9 106 31 107 1 108 0.6 109 2
110 61 111 9 112 7 113 620 114 220 115 4
TABLE-US-00004 TABLE 2a The PI3K.beta. IC.sub.50 and the Half- Life
Values for Representive Compounds Compound IC.sub.50 (nM) t.sub.1/2
(hours) 81 180 ND 82 5 >10 83 42 ND 84 1 10 85 9 >10 86 35 ND
87 0.8 >10 88 11 >10 89 27 ND 90 2 ND 91 99 ND 92 1 4 93 30
ND 94 1 10 95 28 ND 96 3 4 97 0.7 >10 98 160 ND 99 3600 ND 100
100 ND 101 11 ND 102 62 ND 103 3 ND 104 530 ND 105 41 ND 106 180 ND
107 3 ND 108 33 ND 109 460 ND ND: not determined.
[0760] ii. Activity on Basophils
[0761] Effect on basophil activation was measured in human whole
blood using the Flow2 CAST.RTM. kit (Buhlmann Laboratories AG,
Baselstrasse, Switzerland) following the protocol provided by the
manufacturer with minor modifications. Human whole blood was
collected into K.sub.2-EDTA venipuncture tubes. Whole blood samples
were treated with either DMSO (0.3% final) or a serial dilution of
compounds in DMSO for 60 minutes at 37.degree. C. Basophils were
then activated either with anti-Fc.epsilon.RI mAb or with fMLP. To
activate basophils using the anti-Fc.epsilon.RI mAb; 50 .mu.L of
whole blood was mixed with 110 .mu.L of stimulation buffer
(B-BAT-STB) and 20 .mu.l of anti-Fc.epsilon.RI (B-BAT-STCON). To
activate basophils with fMLP; 50 .mu.L of whole blood was mixed
with 80 .mu.L of stimulation buffer (B-BAT-STB) and 50 .mu.L of
fMLP (B--CCR-FMLP). Stimulation buffer was used as a negative
control. 20 .mu.L of the staining reagent (combination of
anti-human CD63-FITC and anti-human CCR3-PE mAbs) was then added to
each tube. The tubes were mixed gently and incubated for 25 minutes
at 37.degree. C. Subsequently, erythrocytes were lysed and fixed by
the addition of 2 mL of lysing solution (B-BAT-LYR) for 10 minutes
at room temperature. Cells were pelleted by centrifugation at 1200
rpm for 10 minutes at room temperature in a swing-out rotor.
Supernatant was aspirated and cell pellet resuspended in 400 .mu.L
of wash buffer. Flow cytometric analysis of the basophil activation
was performed on a FC500MPL flow cytometer (Beckman Coulter Inc.,
Fullerton, Calif.). CCR3-staining and side scatter were applied to
gate at least 200 basophils that expressed a high density of CCR3.
The percent CD63 positive cells within the gated basophil
population were determined in different treatment groups and
normalized to the vehicle control (0.3% DMSO) with
anti-Fc.epsilon.RI mAb of fMLP stimulus as 100%. Final compound
concentration was adjusted to correct for dilution effect of added
reagents. The EC.sub.50 values were calculated from the analysis of
the dose-response curves to a four-parameter equation. All
EC.sub.50 values represented geometric mean values and were
reported in units of nM. Table 3 below summarizes the EC.sub.50
data collected in the Example.
[0762] iii. Hepatocyte Stability
[0763] This assay was used to evaluate the metabolic stability of
test articles (TA) following incubation in cryopreserved
hepatocytes by monitoring parent drug disappearance via LC/MC. The
TA was incubated with 1 million hepatocytes/mL at 2 .mu.M substrate
in duplicate. The incubation was carried out at 37.degree. C. with
5% CO.sub.2 and saturating humidity. Samples were taken at 0, 1, 2,
and 4 hours to monitor the disappearance of TA and a half-life
(t.sub.1/2) was determined. Table 3 below summarizes the human
hepatocyte t.sub.1/2 values (hours) collected in the Example.
[0764] The symbols used in Table 3 below are as follows: [0765]
####=<1 nM *=<1 h [0766] ###=>1 nM AND <10 nM **>1
AND <3 h [0767] ##=>10 nM AND <50 nM ***=>3 AND <6 h
[0768] #=>50 nM ****=>6 AND <10 h [0769] *****=>10
h
TABLE-US-00005 [0769] TABLE 3 The EC.sub.50 and the Half-Life
Values for Representative Compounds Compound EC.sub.50 EC.sub.50
(nM) t.sub.1/2 t.sub.1/2 (hours) 1 #### 0.9 ***** >10 2 ### 2
***** >10 3 ### 2 ***** >10 4 ## 22 ND ND 5 ### 2 *****
>10 7 #### 0.3 ND ND 8 # 100 ND ND 9 ### 3 ***** >10 10 ## 17
ND ND 11 #### 0.5 *** 5 12 ### 1 ***** >10 13 ### 4 ND ND 14 ###
3 **** 8 15 ## 19 ***** >10 16 #### 0.7 ND ND 17 ### 5 ND ND 18
## 22 ND ND 19 ### 7 **** 7 20 ### 3 ***** >10 21 ### 4 *****
>10 22 ### 5 **** 9 23 #### 0.8 ***** >10 24 #### 0.3 *****
>10 25 ## 11 ND ND 26 #### 0.7 ***** >10 27 #### 0.7 *****
>10 28 ### 4 **** 9 29 ## 10 ***** >10 30 #### 0.7 **** 9 31
#### 0.5 ***** >10 32 #### 0.4 ***** >10 33 ### 5 *****
>10 34 ## 22 ND ND 35 # 62 ND ND 36 ### 2 ND ND 37 ## 16 ND ND
38 ### 9 ND ND 39 ### 2 *** 3 40 ### 7 ND ND 41 ### 4 ***** >10
42 ### 8 ND ND 43 ### 2 ND ND 44 ND ND ND ND 45 ### 7 *** 4 46 ND
ND **** 8 47 #### 0.4 ***** >10 ND: not determined.
[0770] The results from the above Example indicate that certain
compounds of formula (I) have greater stability in human
hepatocytes and longer half-life compared to compounds X, Y and Z.
By way of example, Table 4 below summarizes the t.sub.1/2 and
EC.sub.50 values of compounds 1, X, Y and Z.
TABLE-US-00006 TABLE 4 The Comparisons of the EC.sub.50 And the
Half-Life Values. Compound 1 Compound X Compound Y Compound Z
t.sub.1/2 >10 hours <2 hours <2 hours <5 hours
EC.sub.50 <1 nM >5 nM >10 nM <1 nM
* * * * *