U.S. patent application number 14/976476 was filed with the patent office on 2016-04-21 for imidazotriazinecarbonitriles useful as kinase inhibitors.
The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Bin Chen, Libing Chen, Brian E. Fink, Ashvinikumar V. Gavai, Amy C. Hart, Liqi He, Tram N. Huynh, Walter Lewis Johnson, Jennifer lnghrim, Harold Mastalerz, Ashok Vinayak Purandare, Xiaopeng Sang, Christine M. Tarby, John S. Tokarski, Wayne Vaccaro, Honghe Wan, Guifen Zhang, Yong Zhang, Yufen Zhao, Kurt Zimmermann.
Application Number | 20160108050 14/976476 |
Document ID | / |
Family ID | 48833089 |
Filed Date | 2016-04-21 |
United States Patent
Application |
20160108050 |
Kind Code |
A1 |
Purandare; Ashok Vinayak ;
et al. |
April 21, 2016 |
IMIDAZOTRIAZINECARBONITRILES USEFUL AS KINASE INHIBITORS
Abstract
The invention provides compounds of Formula (I) ##STR00001## and
pharmaceutically acceptable salts thereof. The Formula (I)
imidazotriazines inhibit protein kinase activity thereby making
them useful as anticancer agents.
Inventors: |
Purandare; Ashok Vinayak;
(Pennington, NJ) ; Fink; Brian E.; (Yardley,
PA) ; Johnson; Walter Lewis; (Waterbury, CT) ;
Hart; Amy C.; (Ewing, NJ) ; He; Liqi;
(Furlong, PA) ; Huynh; Tram N.; (Pennington,
NJ) ; lnghrim; Jennifer; (Plainsboro, NJ) ;
Mastalerz; Harold; (Guilford, CT) ; Sang;
Xiaopeng; (Glastonbury, CT) ; Tarby; Christine
M.; (Lawrenceville, NJ) ; Wan; Honghe;
(Pennington, NJ) ; Vaccaro; Wayne; (Yardley,
PA) ; Zhang; Guifen; (Wallingford, CT) ; Zhao;
Yufen; (Pennington, NJ) ; Zimmermann; Kurt;
(Durham, CT) ; Zhang; Yong; (Princeton Junction,
NJ) ; Chen; Libing; (Newtown, PA) ; Chen;
Bin; (Pennington, NJ) ; Tokarski; John S.;
(Princeton, NJ) ; Gavai; Ashvinikumar V.;
(Princeton Junction, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Family ID: |
48833089 |
Appl. No.: |
14/976476 |
Filed: |
December 21, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14414152 |
Jan 12, 2015 |
9273057 |
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PCT/US2013/050247 |
Jul 12, 2013 |
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14976476 |
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61671179 |
Jul 13, 2012 |
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61790511 |
Mar 15, 2013 |
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Current U.S.
Class: |
514/63 ;
514/210.18; 514/210.21; 514/243; 514/80; 540/575; 544/184 |
Current CPC
Class: |
C07D 471/10 20130101;
C07F 9/65616 20130101; C07D 487/22 20130101; A61K 31/675 20130101;
A61K 31/541 20130101; A61P 35/02 20180101; A61K 31/5377 20130101;
C07F 9/6561 20130101; A61K 31/5383 20130101; A61K 31/55 20130101;
A61K 31/551 20130101; A61P 19/02 20180101; C07D 519/00 20130101;
A61P 43/00 20180101; A61K 31/53 20130101; A61P 17/08 20180101; A61P
29/00 20180101; C07F 9/6521 20130101; C07F 7/1804 20130101; C07D
487/08 20130101; C07D 487/10 20130101; C07D 487/04 20130101; A61P
35/00 20180101; A61K 45/06 20130101; C07D 498/04 20130101; A61P
17/06 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07F 9/6561 20060101 C07F009/6561; C07F 7/18 20060101
C07F007/18; C07D 519/00 20060101 C07D519/00 |
Claims
1. A compound according to Formula (I): ##STR00902## or a
pharmaceutically acceptable salt thereof, wherein R.sub.1 is
selected from the group consisting of H, F, Cl, Br, CN, and
C.sub.1-6alkyl; R.sub.2 is selected from the group consisting of
aryl substituted with 1-5 R.sub.6 and heteroaryl substituted with
1-5 R.sub.6; R.sub.3 is selected from the group consisting of
hydrogen and C.sub.1-6alkyl substituted with 1-5 R.sub.e;
optionally R.sub.2 and R.sub.3 together with the nitrogen atom to
which they are attached form a heterocyclic ring substituted with
1-5 R.sub.6; R.sub.4 is selected from the group consisting of H,
C.sub.1-6alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
--(CH.sub.2).sub.r--C.sub.3-10 carbocyclyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.5 is selected from the group consisting of H and
C.sub.1-6alkyl substituted with 1-5 R.sub.e; R.sub.6, at each
occurrence, is independently selected from the group consisting of
H, F, Cl, Br, CN, --(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7,
NO.sub.2, --OR.sub.b, --C(.dbd.O)NR.sub.7R.sub.7,
--C(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--NR.sub.aC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e,
--(CR.sub.gR.sub.g).sub.rC.sub.3-6carbocyclyl substituted with 1-5
R.sub.8, and --(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with
1-5 R.sub.8; or two adjacent R.sub.6 groups are taken together with
the ring atoms to which they are attached to form a fused
heterocyclyl or carbocyclyl, each substituted with 1-5 R.sub.8;
R.sub.7, at each occurrence, is independently selected from the
group consisting of H, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom
to which they are both attached form a heterocyclic ring
substituted with 1-5 R.sub.8; R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with
1-5 R.sub.e, .dbd.O, --(CR.sub.gR.sub.g).sub.rOR.sub.b,
--(CR.sub.gR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)(CR.sub.gR.sub.g).sub.rR.sub.d,
--(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CR.sub.gR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CR.sub.gR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rR.sub.d,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.-
d,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.s-
ub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aC(.dbd.-
O) R.sub.b,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a-
,
--(CR.sub.gR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.sub.-
aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)(CR.sub.gR.sub.g).sub.rOC(.dbd.O)R.sub.-
b --(CR.sub.gR.sub.g).sub.rS(O).sub.pNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--OPO.sub.3H.sub.2,
--(CR.sub.gR.sub.g).sub.rNR.sub.aC(.dbd.O)O(CR.sub.gR.sub.g).sub.rO(CR.su-
b.gR.sub.g).sub.rO(CR.sub.gR.sub.g).sub.rO(CR.sub.gR.sub.g).sub.rO(CR.sub.-
gR.sub.g).sub.rO(CR.sub.gR.sub.g).sub.rOC.sub.1-4alkyl,
--(CR.sub.gR.sub.g).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.e and --(CR.sub.gR.sub.g).sub.r-heterocyclyl substituted
with 1-5 R.sub.e; R.sub.a, at each occurrence, is independently
selected from the group consisting of H, CN, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted with
1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted with
1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.e, at each occurrence, is independently selected
from the group consisting of H, N.sub.3, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, --OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; R.sub.f, at each occurrence,
is independently selected from the group consisting of H,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
C.sub.1-5alkyl (optionally substituted with F, Cl, OH, NH.sub.2),
C.sub.3-6 cycloalkyl optionally substituted with NH.sub.2,
--(CH.sub.2).sub.rS(O).sub.pC.sub.1-4alkyl,
--NHC(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)OC.sub.1-4alkyl, --C(.dbd.O)C.sub.1-4alkyl,
--(CH.sub.2).sub.rphenyl, --(CH.sub.2).sub.rheterocyclyl optionally
substituted with alkyl and CN, or R.sub.f and R.sub.f together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
R.sub.g, at each occurrence, is independently selected from the
group consisting of H, F, OH, and C.sub.1-5alkyl; p, at each
occurrence, is independently selected from the group consisting of
zero, 1, and 2; and r, at each occurrence, is independently
selected from the group consisting of zero, 1, 2, 3, 4, and 5.
2. The compound according to claim 1 of Formula (II): ##STR00903##
or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is
selected from the group consisting of aryl substituted with 1-4
R.sub.6 and heteroaryl substituted with 1-4 R.sub.6, wherein said
heteroaryl comprises carbon atoms and 1-4 heteroatoms selected from
the group consisting of N, NR.sub.6a, O, and S(O).sub.p; R.sub.4 is
selected from the group consisting of H, C.sub.1-4alkyl substituted
with 1-4 R.sub.e, C.sub.3-6cyclcoalkyl substituted with 1-4
R.sub.e, aryl substituted with 1-4 R.sub.e, and heterocyclyl
substituted with 1-4 R.sub.e; R.sub.6, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
CN, --OR.sub.b, --(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7,
--C(.dbd.O)NR.sub.7R.sub.7, --NR.sub.aC(.dbd.O)OR.sub.b,
--NR.sub.aC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
--C(.dbd.O)R.sub.b, C.sub.1-4alkyl substituted with 1-3 R.sub.e,
--(CR.sub.gR.sub.g).sub.rC.sub.3-6carbocyclyl substituted with 1-3
R.sub.8, and --(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with
1-3 R.sub.8; R.sub.6a is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-3 R.sub.e, and
--(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with 1-5 R.sub.8;
R.sub.7, at each occurrence, is independently selected from the
group consisting of H, C.sub.1-5 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-4 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-4 R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom
to which they are both attached form a heterocyclic ring comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.8a, O, and S(O).sub.p and substituted with 1-5
R.sub.8; R.sub.8, at each occurrence, is independently selected
from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)O(CHR.sub.g).sub.rO(CHR.sub.g).sub.rO-
(CHR.sub.g).sub.rO(CHR.sub.g).sub.rO(CHR.sub.g).sub.rO(CHR.sub.g).sub.rOC.-
sub.1-4alkyl, --(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4
R.sub.e and --(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4
R.sub.e; and R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CR.sub.gR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e.
3. The compound according to claim 2 or a pharmaceutically
acceptable salt thereof, wherein R.sub.2 is selected from the group
consisting of 4- to 7-membered monocyclic or 8- to 12-membered
bicyclic aryl substituted with 1-4 R.sub.6 and 4- to 7-membered
monocyclic or 7- to 12-membered bicyclic heteroaryl comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.6a, and substituted with 1-4 R.sub.6; R.sub.4 is
selected from the group consisting of C.sub.1-4alkyl substituted
with 1-3 R.sub.e, C.sub.3-6cycloalkyl, phenyl substituted with 1-3
R.sub.e, and 5- to 6-membered heteroaryl comprising carbon atoms
and 1-4 heteroatoms selected from the group consisting of N, NH,
NC.sub.1-4alkyl, O, and S(O).sub.p and substituted with 1-3
R.sub.e; R.sub.6, at each occurrence, is independently selected
from the group consisting of H, F, Cl, Br, CN, --OR.sub.b,
--(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7,
--C(.dbd.O)NR.sub.7R.sub.7, --NHC(.dbd.O)OR.sub.b, C.sub.1-4alkyl
substituted with 1-3 R.sub.e, C.sub.3-6 cycloalkyl substituted with
1-3 R.sub.8, and --(CR.sub.gR.sub.g).sub.r-5- to 6-membered
heterocyclyl substituted with 1-3 R.sub.8; R.sub.7, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.8a, O, and S(O).sub.p and substituted with 1-4
R.sub.8; and R.sub.8, at each occurrence, is independently selected
from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e; and
R.sub.8a is selected from the group consisting of H, C.sub.1-4alkyl
substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl substituted with
1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e.
4. The compound according to claim 3 or a pharmaceutically
acceptable salt thereof, wherein R.sub.2 is selected from the group
consisting of ##STR00904## R.sub.6a is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-3 R.sub.e, and
heterocyclyl substituted with 1-4 R.sub.e; R.sub.6, at each
occurrence, is independently selected from the group consisting of
H, F, Cl, Br, CN, NR.sub.7R.sub.7, --C(.dbd.O)NR.sub.7R.sub.7,
--NHC(.dbd.O)OR.sub.b, C.sub.1-4alkyl substituted with 1-3 R.sub.e,
C.sub.3-6 cycloalkyl substituted with 1-3 R.sub.8, and 5- to
6-membered heterocyclyl substituted with 1-3 R.sub.8; and R.sub.e,
at each occurrence, is independently selected from the group
consisting of H, N.sub.3, C.sub.1-6alkyl substituted with 1-5
R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, CO.sub.2H, --OPO.sub.3H.sub.2,
--OSi(C.sub.1-4alkyl).sub.3, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f.
5. The compound according to claim 4 of Formula (IIIa) or (IV):
##STR00905## or a pharmaceutically acceptable salt thereof, wherein
Q is selected from the group consisting of CR.sub.6 and N; R.sub.4
is selected from the group consisting of C.sub.1-4alkyl substituted
with 1-3 R.sub.e, C.sub.3-6cycloalkyl substituted with 1-3 R.sub.e,
and 5- to 6-membered heteroaryl comprising carbon atoms and 1-4
heteroatoms selected from the group consisting of N, NH,
NC.sub.1-4alkyl, O, and S(O).sub.p and substituted with 1-3
R.sub.e; R.sub.6a is selected from the group consisting of H and
C.sub.1-4alkyl optionally substituted with OH, and 5- to 6-membered
heterocyclyl substituted with 1-3 R.sub.8; R.sub.6 is selected from
the group consisting of H, F, Cl, Br, CN, and C.sub.1-4alkyl
substituted with 1-2 R.sub.e; and R.sub.8 is selected from the
group consisting of H, C.sub.1-4alkyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d, and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e.
6. The compound according to claim 2 of Formula (Vb): ##STR00906##
or a pharmaceutically acceptable salt thereof, wherein R.sub.4 is
selected from the group consisting of C.sub.1-4alkyl substituted
with 1-3 R.sub.e, C.sub.3-6cycloalkyl substituted with 1-3 R.sub.e,
aryl substituted with 1-3 R.sub.e, and heterocyclyl substituted
with 1-3 R.sub.e; R.sub.6b, at each occurrence, is selected from
the group consisting of H, F, C.sub.1-4alkyl substituted with 1-2
R.sub.e, --OR.sub.b, --(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7,
--C(O)NR.sub.7R.sub.7, --C(.dbd.O)R.sub.b
--NR.sub.aC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC.sub.3-6cycloalkyl, and
--(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with 1-3 R.sub.8;
R.sub.6c is selected from the group consisting of H, F, Cl, Br, and
--OR.sub.b; R.sub.6d is selected from the group consisting of CN,
--NHC(.dbd.O)O(C.sub.1-4alkyl), OCHF.sub.2, and CHF.sub.2; R.sub.7,
at each occurrence, is independently selected from the group
consisting of H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.8a, O, and S(O).sub.p and substituted with 1-4
R.sub.8; R.sub.8, at each occurrence, is independently selected
from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.8a is selected from the group consisting of H, C.sub.1-4alkyl
substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl substituted with
1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.a, at each occurrence, is independently selected from the
group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6 alkenyl substituted with 1-5 R.sub.e, C.sub.2-6
alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted with
1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.e, at each occurrence, is independently selected
from the group consisting of H, N.sub.3, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, --OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; R.sub.f, at each occurrence,
is independently selected from the group consisting of H,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
C.sub.1-5alkyl (optionally substituted with F, Cl, OH, NH.sub.2),
C.sub.3-6 cycloalkyl optionally substituted with NH.sub.2,
--(CH.sub.2).sub.rS(O).sub.pC.sub.1-4alkyl,
--NHC(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)OC.sub.1-4alkyl, --C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.rphenyl, --(CH.sub.2).sub.rheterocyclyl optionally
substituted with alkyl and CN, or R.sub.f and R.sub.f together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
R.sub.g, at each occurrence, is independently selected from the
group consisting of H, F, OH, and C.sub.1-5alkyl; p, at each
occurrence, is independently selected from the group consisting of
zero, 1, and 2; and r, at each occurrence, is independently
selected from the group consisting of zero, 1, 2, 3, 4, and 5.
7. The compound according to claim 6 or a pharmaceutically
acceptable salt thereof, wherein R.sub.6b is selected from H,
##STR00907## wherein - - - is an optional bond; R.sub.8a is
selected from the group consisting of H, C.sub.1-4alkyl substituted
with 1-5 R.sub.e, C.sub.2-4 alkenyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rOR.sub.b, --(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.e, at each occurrence, is independently selected from the
group consisting of H, C.sub.1-6alkyl substituted with 1-5 R.sub.f,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br,
--(CH.sub.2).sub.rCN, NO.sub.2, .dbd.O, CO.sub.2H,
--OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl, --(CH.sub.2).sub.rOH,
--(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2-phenyl,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; R.sub.f, at each occurrence,
is independently selected from the group consisting of H,
C.sub.1-5alkyl, OH, OC.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and
phenyl, heterocyclyl substituted with alkyl and CN, or R.sub.f and
R.sub.f together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; and R.sub.g, at each occurrence, is independently
selected from the group consisting of H and C.sub.1-5alkyl.
8. The compound according to claim 6 of Formula (VIa): ##STR00908##
or a pharmaceutically acceptable salt thereof, wherein R.sub.4 is
selected from the group consisting of C.sub.1-4alkyl substituted
with 1-3 R.sub.e, C.sub.3-6cycloalkyl and heterocyclyl substituted
with 1-3 R.sub.e; R.sub.7 and R.sub.7 together with the nitrogen
atom to which they are both attached form a 4- to 7-membered
monocyclic or 7- to 12-membered bicyclic heterocycle containing
carbon atoms and additional 1-3 heteroatoms selected from the group
consisting of NR.sub.8a, O, and S(O).sub.2 and substituted with 1-4
R.sub.8; R.sub.8, at each occurrence, is independently selected
from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.8a is selected from the group consisting of H, C.sub.1-4alkyl
substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl substituted with
1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.a, at each occurrence, is independently selected from the
group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6 alkenyl substituted with 1-5 R.sub.e, C.sub.2-6
alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted with
1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; R.sub.e, at each occurrence, is independently selected
from the group consisting of H, N.sub.3, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, --OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; R.sub.f, at each occurrence,
is independently selected from the group consisting of H,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
C.sub.1-5alkyl (optionally substituted with F, Cl, OH, NH.sub.2),
C.sub.3-6 cycloalkyl optionally substituted with NH.sub.2,
--(CH.sub.2).sub.rS(O).sub.pC.sub.1-4alkyl,
--NHC(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)OC.sub.1-4alkyl, --C(.dbd.O)C.sub.1-4alkyl,
--(CH.sub.2).sub.rphenyl, --(CH.sub.2).sub.rheterocyclyl optionally
substituted with alkyl and CN, or R.sub.f and R.sub.f together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
R.sub.g, at each occurrence, is independently selected from the
group consisting of H, F, OH, and C.sub.1-5alkyl; p, at each
occurrence, is independently selected from the group consisting of
zero, 1, and 2; and r, at each occurrence, is independently
selected from the group consisting of zero, 1, 2, 3, 4, and 5.
9. The compound according to claim 8 or a pharmaceutically
acceptable salt thereof, wherein NR.sub.7R.sub.7 is selected from
the group consisting of ##STR00909## ##STR00910## R.sub.8, at each
occurrence, is independently selected from the group consisting of
H, F, Cl, Br, C.sub.1-4alkyl substituted with 1-4 R.sub.e, .dbd.O,
C.sub.2-4 alkenyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rOR.sub.b, --(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.8a is selected from the group consisting of H, C.sub.1-4alkyl
substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl substituted with
1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
R.sub.a, at each occurrence, is independently selected from the
group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring selected from
the group consisting of ##STR00911## R.sub.b, at each occurrence,
is independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
R.sub.e, at each occurrence, is independently selected from the
group consisting of C.sub.1-6 alkyl substituted with 1-5 R.sub.f,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5alkyl, --(CH.sub.2).sub.rOH,
SH, NH, NH(C.sub.1-5alkyl), N(C.sub.1-5alkyl).sub.2, and
--NHC(.dbd.O)OC.sub.1-5alkyl; m, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, and
3; and r, at each occurrence, is independently selected from the
group consisting of zero, 1, 2, 3, 4, and 5.
10. The compound according to claim 9 or a pharmaceutically
acceptable salt thereof, wherein R.sub.4 is selected from the group
consisting of C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and
heterocyclyl, each substituted with 1-3 R.sub.e; R.sub.6c is
selected from the group consisting of F and Cl; and R.sub.6d is
selected from the group consisting of CN,
--NHC(.dbd.O)O(C.sub.1-4alkyl), --OCHF.sub.2 and CHF.sub.2;
NR.sub.7R.sub.7 is selected from the group consisting of
##STR00912## R.sub.8 is selected from the group consisting of F,
C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2,
--NHC(.dbd.O)NR.sub.aR.sub.a, and --NHS(O).sub.2(C.sub.1-4alkyl);
and R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl, S(O).sub.2C.sub.1-4alkyl, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e.
11. The compound according to claim 10 or a pharmaceutically
acceptable salt thereof, wherein R.sub.4 is selected from the group
consisting of methyl, ethyl, propyl, and cyclopropyl; R.sub.6c is
Cl; R.sub.6d is selected from the group consisting of CN,
OCHF.sub.2, and CHF.sub.2; NR.sub.7R.sub.7 is selected from the
group consisting of ##STR00913## R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NHC(.dbd.O)C.sub.1-4alkyl,
--NHC(.dbd.O)OC.sub.1-4alkyl, and --NHS(O).sub.2(C.sub.1-4alkyl);
and m, at each occurrence, is independently selected from the group
consisting of zero, 1, and 2.
12. The compound according to claim 2 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is H; R.sub.2 is selected
from the group consisting of ##STR00914## R.sub.4 is selected from
the group consisting of CH.sub.2CH.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, ##STR00915## R.sub.6a is
selected from the group consisting of H and CH.sub.3,
CH.sub.2CH.sub.3, and CH.sub.2CHOHCH.sub.3; R.sub.6b is selected
from the group consisting of --NR.sub.7R.sub.7 and ##STR00916## - -
- is an optional bond; R.sub.6d is selected from the group
consisting of CN, --NHC(.dbd.O)OCH.sub.3, and CHF.sub.2; R.sub.7
and R.sub.7 together with the nitrogen atom to which they are both
attached form a heterocyclic ring selected from the group
consisting of ##STR00917## R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2,
--NHC(.dbd.O)NR.sub.aR.sub.a, and --NHS(O).sub.2(C.sub.1-4alkyl);
R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl, S(O).sub.2C.sub.1-4alkyl, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e; R.sub.a, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e; or
R.sub.a and R.sub.a together with the nitrogen atom to which they
are both attached form a heterocyclic ring selected from the group
consisting of ##STR00918## R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
R.sub.e, at each occurrence, is independently selected from the
group consisting of F, Cl, Br, CN, NO.sub.2,
--(CH.sub.2).sub.rOC.sub.1-5alkyl, --(CH.sub.2).sub.rOH, NH.sub.2,
NH(C.sub.1-5alkyl), N(C.sub.1-5alkyl).sub.2,
--NHC(.dbd.O)OC.sub.1-5alkyl, --(CH.sub.2).sub.r-heterocyclyl, and
C.sub.1-6 alkyl optionally substituted OH; and r, at each
occurrence, is independently selected from the group consisting of
zero, 1, and 2.
13. A compound according to claim 1 or a pharmaceutically
acceptable salt thereof selected from the exemplified examples.
14. A pharmaceutical composition comprising one or more compounds
according to claim 1 and a pharmaceutically acceptable carrier.
15. A method for treating cancer, psoriasis and rheumatoid
arthritis, comprising administering to a mammalian species in need
thereof, a therapeutically effective amount of one or more
compounds according to claim 1.
16. The method according to claim 15 wherein the cancer is
carcinoma of the prostate, pancreatic ductal adenocarcinoma,
breast, colon, lung, ovary, pancreas and thyroid, neuroblastoma,
glioblastoma, medulloblastoma, melanoma, multiple myeloma, and/or
acute myelogenous leukemia (AML).
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. Ser. No.
14/414,152 filed on Jan. 12, 2015, now allowed, which is a 371
International Application of PCT/US2013/050247, filed Jul. 12, 2013
which in turn claims the priority benefit of U.S. Provisional
Application U.S. Ser. No. 61/671,179 filed Jul. 13, 2012 and U.S.
Ser. No. 61/790,511 filed Mar. 15, 2013, hereby incorporated by
reference in their entireties.
FIELD OF THE INVENTION
[0002] The invention relates to novel substituted imidazotriazine
compounds useful as protein kinase inhibitors. The invention also
relates to methods of using the compounds in the treatment of
proliferative and other types of diseases and to pharmaceutical
compositions containing the compounds.
BACKGROUND OF THE INVENTION
[0003] The invention relates to fused heterocyclic compounds which
inhibit protein kinase enzymes, compositions which contain protein
kinase inhibiting compounds and methods of using inhibitors of
protein kinase enzymes to treat diseases which are characterized by
an overexpression or upregulation of protein kinases. Protein
kinases mediate intracellular signal transduction. They do this by
affecting a phosphoryl transfer from a nucleoside triphosphate to a
protein acceptor that is involved in a signaling pathway. There are
a number of kinases and pathways through which extracellular and
other stimuli cause a variety of cellular responses to occur inside
the cell. An extracellular stimulus may affect one or more cellular
responses related to cell growth, migration, differentiation,
secretion of hormones, activation of transcription factors, muscle
contraction, glucose metabolism, and control of protein synthesis
and regulation of cell cycle.
[0004] Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events. These
diseases include autoimmune diseases, inflammatory diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease or
hormone-related diseases. Accordingly, there has been a substantial
effort in medicinal chemistry to find protein kinase inhibitors
that are effective as therapeutic agents.
[0005] Serine/threonine kinases are a class of protein kinases that
are among the most promising drug targets for future small molecule
inhibitors. Inhibition of serine/threonine kinases is likely to
have relevance to the treatment of cancer, diabetes and a variety
of inflammatory disorders. The successful development of
GLEEVEC.RTM. as a Bcr/Abl protein kinase inhibitor has provided
further evidence that protein kinases including protein kinase CK2
are valid drug targets for potential cancer therapies.
[0006] Protein kinase CK2 (formerly known as casein kinase II) is a
highly conserved serine/threonine kinase. Protein kinase CK2 is
ubiquitously distributed and constitutively active in eukaryotes.
In mammals, the enzyme exists in two isozymic forms due to
variations in the catalytic subunits of the enzyme. The CK2
holoenzyme is a heterotetrameric complex composed of two catalytic
.alpha. (CK2A1) subunits or .alpha.' (CK2A2) subunits and two
regulatory .beta.-subunits. The formation of CK2 complexes
containing the catalytic subunits requires dimerization of the
regulatory .beta.-subunits. CK2 interacts with a variety of
cellular proteins and has been implicated in cell replication such
as cell proliferation and differentiation, cellular survival, and
tumorigenesis. With respect to tumorigenesis, protein kinase CK2
has been implicated in kidney tumors (Stalter et al., "Asymmetric
expression of protein kinase CK2 subunits in human kidney tumors",
Biochem. Biophys. Res. Commun., 202:141-147 (1994)), mammary gland
tumors (Landesman-Bollag et al., "Protein kinase CK2 in mammary
gland tumorigenesis", Oncology, 20:3247-3257 (2001)), lung
carcinoma (Daya-Makin et al., "Activation of a tumor-associated
protein kinase (p40TAK) and casein kinase II in human squamous cell
carcinomas and adenocarcinomas of the lung", Cancer Res.,
54:2262-2268 (1994)), head and neck carcinoma (Faust et al.,
"Antisense oligonucleotides against protein kinase CK2-.alpha.
inhibit growth of squamous cell carcinoma of the head and neck in
vitro", Head Neck, 22:341-346 (2000)), and prostate cancer (Wang et
al., "Role of protein kinase CK2 in the regulation of tumor
necrosis factor-related apoptosis inducing ligand-induced apoptosis
in prostate cancer cells", Cancer Res., 66:2242-2249 (2006)).
[0007] Inhibitors of protein kinases are widely sought and small
molecule compounds capable of modulating protein kinases have been
reported. For example, pyrazolotriazines as CK2 kinase inhibitors
were reported by Nie et al. (Bioorganic & Medicinal Chemistry
Letters, 17:4191-4195 (2007); 18:619-623 (2008)). In addition,
certain imidazotriazine compounds were disclosed in WO 2007/038314,
published Apr. 5, 2007, US 2008/0045536, published Feb. 21, 2008,
WO 2008/116064, published Sep. 25, 2008, all assigned to the
present assignee. The present invention relates to a new class of
imidazotriazine-carbonitriles found to be effective inhibitors of
protein kinases, particularly the CK2 kinase. These novel compounds
are provided to be useful as pharmaceuticals with desirable
stability, bioavailability, therapeutic index and toxicity values
that are important to their drugability.
SUMMARY OF THE INVENTION
[0008] The invention is directed to fused heterocyclic compounds of
Formulae (I)-(VIII) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates or prodrugs thereof, which inhibit
protein kinase enzymes, especially protein kinase CK2 for the
treatment of cancer such as non-small cell lung cancer.
[0009] The present invention also provides processes and
intermediates for making the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0010] The present invention also provides pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and
at least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0011] The present invention also provides methods for inhibiting
the activity of protein kinase CK2 comprising administering to a
host in need of such treatment a therapeutically effective amount
of at least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0012] The present invention also provides methods for inhibiting
angiogenesis or treating cancers comprising administering to a host
in need of such treatment a therapeutically effective amount of at
least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0013] The present invention also provides the compounds of the
present invention or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, for use in
therapy.
[0014] The present invention also provides the use of the compounds
of the present invention or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
in preparing a medicament for the treatment of cancer in a human
patient, particularly a cancer such as non-small cell lung cancer
receptive to treatment via inhibition of the CK2 enzyme.
[0015] These and other features of the invention will be set forth
in the expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The invention provides for novel imidazotriazine compounds
useful as therapeutic agents, pharmaceutical compositions employing
such novel compounds and for methods of using such compounds.
[0017] In accordance with the invention, there are disclosed
compounds of Formula (I) including enantiomers, diastereomers,
tautomers, pharmaceutically-acceptable salts, prodrugs, hydrates,
or solvates thereof,
##STR00002##
wherein [0018] R.sub.1 is selected from the group consisting of H,
F, Cl, Br, CN, and C.sub.1-6alkyl; R.sub.2 is selected from the
group consisting of aryl substituted with 1-5 R.sub.6 and
heteroaryl substituted with 1-5 R.sub.6; [0019] R.sub.3 is selected
from the group consisting of hydrogen and C.sub.1-6alkyl
substituted with 1-5 R.sub.e; [0020] optionally R.sub.2 and R.sub.3
together with the nitrogen atom to which they are attached form a
heterocyclic ring substituted with 1-5 R.sub.6; [0021] R.sub.4 is
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.e, --(CH.sub.2).sub.rOR.sub.b,
--(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
--(CH.sub.2).sub.r--C.sub.3-10 carbocyclyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0022] R.sub.5 is selected from the group consisting of H
and C.sub.1-6alkyl substituted with 1-5 R.sub.e; [0023] R.sub.6, at
each occurrence, is independently selected from the group
consisting of H, F, Cl, Br, CN,
--(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7, NO.sub.2, --OR.sub.b,
--C(.dbd.O)NR.sub.7R.sub.7, --C(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b,
--NR.sub.aC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e,
--(CR.sub.gR.sub.g).sub.rC.sub.3-6carbocyclyl substituted with 1-5
R.sub.8, and --(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with
1-5 R.sub.8; or two adjacent R.sub.6 groups are taken together with
the ring atoms to which they are attached to form a fused
heterocyclyl or carbocyclyl, each substituted with 1-5 R.sub.8;
[0024] R.sub.7, at each occurrence, is independently selected from
the group consisting of H, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom
to which they are both attached form a heterocyclic ring
substituted with 1-5 R.sub.8; [0025] R.sub.8, at each occurrence,
is independently selected from the group consisting of H, F, Cl,
Br, C.sub.1-6 alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with
1-5 R.sub.e, .dbd.O, --(CR.sub.gR.sub.g).sub.rOR.sub.b,
--(CR.sub.gR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)(CR.sub.gR.sub.g).sub.rR.sub.d,
--(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CR.sub.gR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CR.sub.gR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rR.sub.d,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rC(.dbd.O)OR.sub-
.d,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.-
sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aC(.dbd.-
O)R.sub.b,
--(CR.sub.gR.sub.g).sub.rOC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.su-
b.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)NR.sub.a-
R.sub.a,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CR.sub.gR.sub.g).sub.rC(.dbd.O)(CR.sub.gR.sub.g).sub.rOC(.dbd.O)R.sub.-
b --(CR.sub.gR.sub.g).sub.rS(O).sub.pNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--OPO.sub.3H.sub.2,
--(CR.sub.gR.sub.g).sub.rNR.sub.aC(.dbd.O)O(CR.sub.gR.sub.g).sub.rO(CR.su-
b.gR.sub.g).sub.rO(CR.sub.gR.sub.g).sub.rO(CR.sub.gR.sub.g).sub.rO(CR.sub.-
gR.sub.g).sub.rO(CR.sub.gR.sub.g).sub.rOC.sub.1-4alkyl,
--(CR.sub.gR.sub.g).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.e and --(CR.sub.gR.sub.g).sub.r-heterocyclyl substituted
with 1-5 R.sub.e; [0026] R.sub.a, at each occurrence, is
independently selected from the group consisting of H, CN,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl
substituted with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with
1-5 R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted
with 1-5 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted
with 1-5 R.sub.e; or R.sub.a and R.sub.a together with the nitrogen
atom to which they are both attached form a heterocyclic ring
substituted with 1-5 R.sub.e; [0027] R.sub.b, at each occurrence,
is independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted
with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0028] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; [0029] R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0030] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, N.sub.3, C.sub.1-6alkyl
substituted with 1-5 R.sub.f, C.sub.2-6alkenyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, --OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0031] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, --(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
C.sub.1-5alkyl (optionally substituted with F, Cl, OH, NH.sub.2),
C.sub.3-6 cycloalkyl optionally substituted with NH.sub.2,
--(CH.sub.2).sub.rS(O).sub.pC.sub.1-4alkyl,
--NHC(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)OC.sub.1-4alkyl, --C(.dbd.O)C.sub.1-4alkyl,
--(CH.sub.2).sub.rphenyl, --(CH.sub.2).sub.rheterocyclyl optionally
substituted with alkyl and CN, or R.sub.f and R.sub.f together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0032] R.sub.g, at each occurrence, is independently selected from
the group consisting of H, F, OH, and C.sub.1-5alkyl; [0033] p, at
each occurrence, is independently selected from the group
consisting of zero, 1, and 2; and [0034] r, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, 3,
4, and 5.
[0035] In another aspect, there are disclosed compounds of Formula
(II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein
##STR00003##
wherein [0036] R.sub.2 is selected from the group consisting of
aryl substituted with 1-4 R.sub.6 and heteroaryl substituted with
1-4 R.sub.6, wherein said heteroaryl comprises carbon atoms and 1-4
heteroatoms selected from the group consisting of N, NR.sub.6a, O,
and S(O).sub.p; [0037] R.sub.4 is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-4 R.sub.e,
C.sub.3-6cyclcoalkyl substituted with 1-4 R.sub.e, aryl substituted
with 1-4 R.sub.e, and heterocyclyl substituted with 1-4 R.sub.e;
[0038] R.sub.6, at each occurrence, is independently selected from
the group consisting of H, F, Cl, Br, CN, --OR.sub.b,
--(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7,
--C(.dbd.O)NR.sub.7R.sub.7, --NR.sub.aC(.dbd.O)OR.sub.b,
--C(.dbd.O)R.sub.b, C.sub.1-4alkyl substituted with 1-3 R.sub.e,
--(CR.sub.gR.sub.g).sub.rC.sub.3-6carbocyclyl substituted with 1-3
R.sub.8, and --(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with
1-3 R.sub.8; [0039] R.sub.6a is selected from the group consisting
of H, C.sub.1-4alkyl substituted with 1-3 R.sub.e, and
--(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with 1-5 R.sub.8;
[0040] R.sub.7, at each occurrence, is independently selected from
the group consisting of H, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom
to which they are both attached form a heterocyclic ring comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.8a, O, and S(O).sub.p and substituted with 1-5
R.sub.8; [0041] R.sub.8, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)O(CHR.sub.g).sub.rO(CHR.sub.g).sub.rO-
(CHR.sub.g).sub.rO(CHR.sub.g).sub.rO(CHR.sub.g).sub.rO(CHR.sub.g).sub.r
OC.sub.1-4alkyl, --(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl
substituted with 1-5 R.sub.e, --(CHR.sub.g).sub.r-aryl substituted
with 1-4 R.sub.e and --(CHR.sub.g).sub.r-heterocyclyl substituted
with 1-4 R.sub.e; and [0042] R.sub.8a is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-5 R.sub.e,
C.sub.2-4 alkenyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rOR.sub.b, --(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CR.sub.gR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
other variables are as defined in Formula (I) above.
[0043] In another aspect, there are disclosed compounds of Formula
(II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0044] R.sub.2 is selected from the group
consisting of 4- to 7-membered monocyclic or 8- to 12-membered
bicyclic aryl substituted with 1-4 R.sub.6 and 4- to 7-membered
monocyclic or 7- to 12-membered bicyclic heteroaryl comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.6a, and substituted with 1-4 R.sub.6; [0045] R.sub.4
is selected from the group consisting of C.sub.1-4alkyl substituted
with 1-3 R.sub.e, C.sub.3-6cycloalkyl, phenyl substituted with 1-3
R.sub.e, and 5- to 6-membered heteroaryl comprising carbon atoms
and 1-4 heteroatoms selected from the group consisting of N, NH,
NC.sub.1-4alkyl, O, and S(O).sub.p and substituted with 1-3
R.sub.e; [0046] R.sub.6, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, CN, --OR.sub.b,
--(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7,
--C(.dbd.O)NR.sub.7R.sub.7, --NHC(.dbd.O)OR.sub.b, C.sub.1-4alkyl
substituted with 1-3 R.sub.e, C.sub.3-6 cycloalkyl substituted with
1-3 R.sub.8, and --(CR.sub.gR.sub.g).sub.r-5- to 6-membered
heterocyclyl substituted with 1-3 R.sub.8; [0047] R.sub.7, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.8a, O, and S(O).sub.p and substituted with 1-4
R.sub.8; and [0048] R.sub.8, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e; and
[0049] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
other variables are as defined in Formula (I) above.
[0050] In another aspect, there are disclosed compounds of Formula
(II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0051] R.sub.2 is selected from the group
consisting of
[0051] ##STR00004## [0052] R.sub.6a is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-3 R.sub.e, and
heterocycly substituted with 1-4 R.sub.e; [0053] R.sub.6, at each
occurrence, is independently selected from the group consisting of
H, F, Cl, Br, CN, NR.sub.7R.sub.7, --C(.dbd.O)NR.sub.7R.sub.7,
--NHC(.dbd.O)OR.sub.b, C.sub.1-4alkyl substituted with 1-3 R.sub.e,
C.sub.3-6 cycloalkyl substituted with 1-3 R.sub.8, and 5- to
6-membered heterocyclyl substituted with 1-3 R.sub.8; and [0054]
R.sub.e, at each occurrence, is independently selected from the
group consisting of H, N.sub.3, C.sub.1-6alkyl substituted with 1-5
R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, CO.sub.2H, --OPO.sub.3H.sub.2,
--OSi(C.sub.1-4alkyl).sub.3, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5 alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5 alkyl,
--S(O).sub.2NH.sub.2, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; other variables are as defined
in Formula (I) above.
[0055] In another aspect, there are disclosed compounds of Formula
(IIIa) or (IV) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein
##STR00005##
wherein [0056] Q is selected from the group consisting of CR.sub.6
and N; [0057] R.sub.4 is selected from the group consisting of
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6cycloalkyl
substituted with 1-3 R.sub.e, and 5- to 6-membered heteroaryl
comprising carbon atoms and 1-4 heteroatoms selected from the group
consisting of N, NH, NC.sub.1-4alkyl, O, and S(O).sub.p and
substituted with 1-3 R.sub.e; [0058] R.sub.6a is selected from the
group consisting of H and C.sub.1-4alkyl optionally substituted
with OH, and 5- to 6-membered heterocyclyl substituted with 1-3
R.sub.8; [0059] R.sub.6 is selected from the group consisting of H,
F, Cl, Br, CN, and C.sub.1-4alkyl substituted with 1-2 R.sub.e; and
[0060] R.sub.8 is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d, and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
other variables are as defined in Formula (I) above.
[0061] In another aspect, there are disclosed compounds of Formula
(Vb) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein
##STR00006##
wherein [0062] R.sub.4 is selected from the group consisting of
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6cycloalkyl
substituted with 1-3 R.sub.e, aryl substituted with 1-3 R.sub.e,
and heterocyclyl substituted with 1-3 R.sub.e; [0063] R.sub.6b, at
each occurrence, is selected from the group consisting of H, F,
C.sub.1-4alkyl substituted with 1-2 R.sub.e, --OR.sub.b,
--(CR.sub.gR.sub.g).sub.rNR.sub.7R.sub.7, --C(O)NR.sub.7R.sub.7,
--C(.dbd.O)R.sub.b
--NR.sub.aC(.dbd.O)(CR.sub.gR.sub.g).sub.rNR.sub.aR.sub.a,
--(CR.sub.gR.sub.g).sub.rC.sub.3-6cycloalkyl, and
--(CR.sub.gR.sub.g).sub.rheterocyclyl substituted with 1-3 R.sub.8;
[0064] R.sub.6c is selected from the group consisting of H, F, Cl,
Br, and --OR.sub.b; [0065] R.sub.6d is selected from the group
consisting of CN, --NHC(.dbd.O)O(C.sub.1-4alkyl), OCHF.sub.2, and
CHF.sub.2; [0066] R.sub.7, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.8; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.8a, O, and S(O).sub.p and substituted with 1-4
R.sub.8; [0067] R.sub.8, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, C.sub.1-4alkyl
substituted with 1-4 R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted
with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0068] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0069] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6 alkenyl substituted with 1-5 R.sub.e, C.sub.2-6
alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; [0070] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted
with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0071] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; [0072] R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0073] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, N.sub.3, C.sub.1-6alkyl
substituted with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, --OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0074] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, --(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
C.sub.1-5alkyl (optionally substituted with F, Cl, OH, NH.sub.2),
C.sub.3-6 cycloalkyl optionally substituted with NH.sub.2,
--(CH.sub.2).sub.rS(O).sub.pC.sub.1-4alkyl,
--NHC(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)OC.sub.1-4alkyl, --C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.rphenyl, --(CH.sub.2).sub.rheterocyclyl optionally
substituted with alkyl and CN, or R.sub.f and R.sub.f together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0075] R.sub.g, at each occurrence, is independently selected from
the group consisting of H, F, OH, and C.sub.1-5alkyl; [0076] p, at
each occurrence, is independently selected from the group
consisting of zero, 1, and 2; and [0077] r, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, 3,
4, and 5.
[0078] In another aspect, there are disclosed compounds of Formula
(Vb) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein
R.sub.6b is selected from H,
##STR00007##
wherein [0079] - - - is an optional bond; [0080] R.sub.8a is
selected from the group consisting of H, C.sub.1-4alkyl substituted
with 1-5 R.sub.e, C.sub.2-4 alkenyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rOR.sub.b, --(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0081] R.sub.e, at each occurrence, is independently selected from
the group consisting of H, C.sub.1-6alkyl substituted with 1-5
R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, CO.sub.2H, --OPO.sub.3H.sub.2,
--OSi(C.sub.1-4alkyl).sub.3, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2-phenyl,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0082] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-5alkyl, OH, OC.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and
phenyl, heterocyclyl substituted with alkyl and CN, or R.sub.f and
R.sub.f together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; and [0083] R.sub.g, at each occurrence, is
independently selected from the group consisting of H and
C.sub.1-5alkyl; other variables are as defined in Formula (Vb)
above.
[0084] In another aspect, there are disclosed compounds of Formula
(VIa) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein
##STR00008##
wherein [0085] R.sub.4 is selected from the group consisting of
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6cycloalkyl
and heterocyclyl substituted with 1-3 R.sub.e; [0086] R.sub.7 and
R.sub.7 together with the nitrogen atom to which they are both
attached form a 4- to 7-membered monocyclic or 7- to 12-membered
bicyclic heterocycle containing carbon atoms and additional 1-3
heteroatoms selected from the group consisting of NR.sub.8a, O, and
S(O).sub.2 and substituted with 1-4 R.sub.8; [0087] R.sub.8, at
each occurrence, is independently selected from the group
consisting of H, F, Cl, Br, C.sub.1-4alkyl substituted with 1-4
R.sub.e, .dbd.O, C.sub.2-4 alkenyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rOR.sub.b, --(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0088] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0089] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6 alkenyl substituted with 1-5 R.sub.e, C.sub.2-6
alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; [0090] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted
with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0091] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; [0092] R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0093] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, N.sub.3, C.sub.1-6alkyl
substituted with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, --OPO.sub.3H.sub.2, --OSi(C.sub.1-4alkyl).sub.3,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rO(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2R.sub.f,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.NH)NR.sub.fR.sub.f,
--(CH.sub.2).sub.rC(.dbd.O)(CH.sub.2).sub.rR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0094] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, --(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
C.sub.1-5alkyl (optionally substituted with F, Cl, OH, NH.sub.2),
C.sub.3-6 cycloalkyl optionally substituted with NH.sub.2,
--(CH.sub.2).sub.rS(O).sub.pC.sub.1-4alkyl,
--NHC(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)OC.sub.1-4alkyl, --C(.dbd.O)C.sub.1-4alkyl,
--(CH.sub.2).sub.rphenyl, --(CH.sub.2).sub.rheterocyclyl optionally
substituted with alkyl and CN, or R.sub.f and R.sub.f together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0095] R.sub.g, at each occurrence, is independently selected from
the group consisting of H, F, OH, and C.sub.1-6alkyl; [0096] p, at
each occurrence, is independently selected from the group
consisting of zero, 1, and 2; and [0097] r, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, 3,
4, and 5; other variables are as defined in Formula (Vb) above.
[0098] In another aspect, there are disclosed compounds of Formula
(VIa) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0099] NR.sub.7R.sub.7 is selected from the group
consisting of
[0099] ##STR00009## ##STR00010## [0100] R.sub.8, at each
occurrence, is independently selected from the group consisting of
H, F, Cl, Br, C.sub.1-4alkyl substituted with 1-4 R.sub.e, .dbd.O,
C.sub.2-4 alkenyl substituted with 1-5 R.sub.e,
--(CHR.sub.g).sub.rOR.sub.b, --(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)(CH.sub.2).sub.rOR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c, --OPO.sub.3H.sub.2,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0101] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl substituted with 1-5 R.sub.e, C.sub.2-4 alkenyl
substituted with 1-5 R.sub.e, --(CHR.sub.g).sub.rOR.sub.b,
--(CHR.sub.g).sub.rS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.rNR.sub.a(CR.sub.gR.sub.g).sub.rC(.dbd.O)R.sub.d,
--(CHR.sub.g).sub.rNHC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)OR.sub.d,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aC(.dbd.O)
R.sub.b,
--(CHR.sub.g).sub.rOC(.dbd.O)(CHR.sub.g).sub.rNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.a(CHR.sub.g).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rC(.dbd.O)OR.sub.b,
--(CHR.sub.g).sub.rC(.dbd.O)(CHR.sub.g).sub.rOC(.dbd.O)R.sub.b,
--(CHR.sub.g).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pNR.sub.aR.sub.a,
--(CHR.sub.g).sub.rNR.sub.aS(O).sub.pR.sub.c,
--(CHR.sub.g).sub.r--C.sub.3-6 cycloalkyl substituted with 1-5
R.sub.e, --(CHR.sub.g).sub.r-aryl substituted with 1-4 R.sub.e and
--(CHR.sub.g).sub.r-heterocyclyl substituted with 1-4 R.sub.e;
[0102] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring selected from
the group consisting of
[0102] ##STR00011## [0103] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0104] R.sub.e, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl substituted with 1-5
R.sub.f, --(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2,
.dbd.O, CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
--(CH.sub.2).sub.rOH, SH, NH, NH(C.sub.1-5alkyl),
N(C.sub.1-5alkyl).sub.2, and --NHC(.dbd.O)OC.sub.1-5alkyl; [0105]
m, at each occurrence, is independently selected from the group
consisting of zero, 1, 2, and 3; [0106] r, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, 3,
4, and 5; other variables are as defined in Formula (VIa)
above.
[0107] In another aspect, there are disclosed compounds of Formula
(VIa) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0108] R.sub.4 is selected from the group
consisting of C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and
heterocyclyl, each substituted with 1-3 R.sub.e; [0109] R.sub.6c is
selected from the group consisting of F and Cl; and [0110] R.sub.6d
is selected from the group consisting of CN,
--NHC(.dbd.O)O(C.sub.1-4alkyl), and CHF.sub.2; [0111]
NR.sub.7R.sub.7 is selected from the group consisting of
[0111] ##STR00012## [0112] R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2,
--NHC(.dbd.O)NR.sub.aR.sub.a, and --NHS(O).sub.2(C.sub.1-4alkyl);
and [0113] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl, S(O).sub.2C.sub.1-4alkyl, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e; other variables are as
defined in Formula (VIa) above.
[0114] In another aspect, there are disclosed compounds of Formula
(VIa) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0115] R.sub.4 is selected from the group
consisting of methyl, ethyl, propyl, and cyclopropyl; [0116]
R.sub.6c is Cl; [0117] R.sub.6d is selected from the group
consisting of CN, OCHF.sub.2, and CHF.sub.2; [0118] NR.sub.7R.sub.7
is selected from the group consisting of
[0118] ##STR00013## [0119] R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NHC(.dbd.O)C.sub.1-4alkyl,
--NHC(.dbd.O)OC.sub.1-4alkyl, and --NHS(O).sub.2(C.sub.1-4alkyl);
and [0120] m, at each occurrence, is independently selected from
the group consisting of zero, 1, and 2.
[0121] In another aspect, there are disclosed compounds of Formula
(Vb) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0122] R.sub.1 is H; [0123] R.sub.2 is selected
from the group consisting of
[0123] ##STR00014## [0124] R.sub.4 is selected from the group
consisting of CH.sub.2CH.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
[0124] ##STR00015## [0125] R.sub.6a is selected from the group
consisting of H and CH.sub.3, CH.sub.2CH.sub.3, and
CH.sub.2CHOHCH.sub.3; [0126] R.sub.6b is selected from the group
consisting of --NR.sub.7R.sub.7 and
[0126] ##STR00016## [0127] - - - is an optional bond; [0128]
R.sub.6d is selected from the group consisting of CN,
--NHC(.dbd.O)OCH.sub.3, and CHF.sub.2; [0129] R.sub.7 and R.sub.7
together with the nitrogen atom to which they are both attached
form a heterocyclic ring selected from the group consisting of
[0129] ##STR00017## [0130] R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2,
--NHC(.dbd.O)NR.sub.aR.sub.a, and --NHS(O).sub.2(C.sub.1-4alkyl);
[0131] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl, S(O).sub.2C.sub.1-4alkyl, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e; [0132] R.sub.a, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e; or
R.sub.a and R.sub.a together with the nitrogen atom to which they
are both attached form a heterocyclic ring selected from the group
consisting of
[0132] ##STR00018## [0133] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0134] R.sub.e, at each occurrence, is independently selected from
the group consisting of F, Cl, Br, CN, NO.sub.2,
--(CH.sub.2).sub.rOC.sub.1-5alkyl, --(CH.sub.2).sub.rOH, NH.sub.2,
NH(C.sub.1-5alkyl), N(C.sub.1-5alkyl).sub.2,
--NHC(.dbd.O)OC.sub.1-5alkyl, --(CH.sub.2).sub.r-heterocyclyl, and
C.sub.1-6 alkyl optionally substituted OH; and [0135] r, at each
occurrence, is independently selected from the group consisting of
zero, 1, and 2.
[0136] In another aspect, there are disclosed compounds of Formula
(I) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00019##
wherein [0137] R.sub.1 is selected from the group consisting of H,
F, Cl, Br, CN, and C.sub.1-6alkyl; [0138] R.sub.2 is selected from
the group consisting of aryl substituted with 1-5 R.sub.6 and
heteroaryl substituted with 1-5 R.sub.6; [0139] R.sub.3 is selected
from the group consisting of hydrogen and C.sub.1-6alkyl
substituted with 1-5 R.sub.e; [0140] R.sub.4 is selected from the
group consisting of H, C.sub.1-6alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0141] R.sub.5 is selected from the group consisting of H
and C.sub.1-6alkyl substituted with 1-5 R.sub.e; [0142] R.sub.6, at
each occurrence, is independently selected from the group
consisting of H, F, Cl, Br, CN, --NR.sub.7R.sub.7 NO.sub.2,
--OR.sub.b, --C(.dbd.O)NR.sub.7R.sub.7,
--NR.sub.aC(.dbd.O)OR.sub.b, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.3-6carbocyclyl substituted with 1-5 R.sub.8, and
heterocyclyl substituted with 1-5 R.sub.8; [0143] R.sub.7, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.8; [0144] R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, .dbd.O,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rOC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0145] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, C.sub.2-6 alkenyl substituted with 1-5 R.sub.e, C.sub.2-6
alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; [0146] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, C.sub.2-6 alkenyl substituted
with 1-5 R.sub.e, C.sub.2-6 alkynyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0147] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, C.sub.2-6alkenyl substituted with 1-5 R.sub.e,
C.sub.2-6alkynyl substituted with 1-5 R.sub.e,
C.sub.3-6carbocyclyl, and heterocyclyl; [0148] R.sub.d, at each
occurrence, is independently selected from the group consisting of
H, OH, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
C.sub.2-6alkenyl substituted with 1-5 R.sub.e, C.sub.2-6alkynyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0149] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0150] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-5alkyl, OH, OC.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and
phenyl, or R.sub.f and R.sub.f together with the nitrogen atom to
which they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; [0151] p, at each occurrence, is
independently selected from the group consisting of zero, 1, and 2;
and [0152] r, at each occurrence, is independently selected from
the group consisting of zero, 1, 2, 3, and 4.
[0153] In another embodiment, R.sub.4 is selected from the group
consisting of --(CH.sub.2)OR.sub.b, --(CH.sub.2CH.sub.2)OR.sub.b,
--(CH(CH.sub.3)CH.sub.2)OR.sub.b,
--(C(CH.sub.3).sub.2CH.sub.2)OR.sub.b,
--(CH.sub.2CH(CH.sub.3))OR.sub.b,
--(CH.sub.2C(CH.sub.3).sub.2)OR.sub.b, --(CH.sub.2)NR.sub.aR.sub.a,
--(CH.sub.2CH.sub.2) NR.sub.aR.sub.a,
--(CH(CH.sub.3)CH.sub.2)NR.sub.aR.sub.a,
--(C(CH.sub.3).sub.2CH.sub.2)NR.sub.aR.sub.a,
--(CH.sub.2CH(CH.sub.3))NR.sub.aR.sub.a, and
--(CH.sub.2C(CH.sub.3).sub.2)NR.sub.aR.sub.a, wherein R.sub.a, at
each occurrence, is independently selected from the group
consisting of H and C.sub.1-6 alkyl substituted with 1-3 R.sub.e;
or R.sub.a and R.sub.a together with the nitrogen atom to which
they are attached form a heterocyclic ring selected from the group
consisting of oxetanyl, imidazolidinyl, imidazolinyl, imidazolyl,
indazolyl, indolinyl, indolizinyl, indolyl, isoquinolinyl,
isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, pyrimidinyl,
piperazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,
quinolinyl, tetrazolyl, thiazolyl, triazinyl, and triazolyl.
[0154] In another embodiment, R.sub.4 is substituted with 1-3
R.sub.e and is selected from the group consisting of phenyl,
naphthyl, biphenyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl.
[0155] In another embodiment, R.sub.4 is
--(CH.sub.2).sub.0-2-heterocyclyl substituted with 1-3 R.sub.e,
wherein said heterocyclyl is selected from the group consisting of
azetidinyl, oxetanyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl,
tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl,
isoindolyl, indolinyl, isoindolinyl, benzimidazolyl,
benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
[0156] In another aspect, there are disclosed compounds of Formula
(II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00020##
wherein [0157] R.sub.2 is selected from the group consisting of
aryl substituted with 1-4 R.sub.6 and heteroaryl substituted with
1-4 R.sub.6, wherein said heteroaryl comprises carbon atoms and 1-4
heteroatoms selected from the group consisting of N, NR.sub.6a, O,
and S(O).sub.p; [0158] R.sub.4 is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-5 R.sub.e,
--(CR.sub.4aR.sub.4b).sub.rOR.sub.b,
--(CR.sub.4aR.sub.4b).sub.rS(O).sub.pR.sub.c,
--(CR.sub.4aR.sub.4b).sub.rC(.dbd.O)R.sub.d,
--(CR.sub.4aR.sub.4b).sub.rNR.sub.aR.sub.a,
--(CR.sub.4aR.sub.4b).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.4aR.sub.4b).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CR.sub.4aR.sub.4b).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CR.sub.4aR.sub.4b).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.4aR.sub.4b).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.4aR.sub.4b).sub.rC(.dbd.O)OR.sub.b,
--(CR.sub.4aR.sub.4b).sub.rNR.sub.aS(O).sub.2R.sub.c,
--(CR.sub.4aR.sub.4b).sub.r--C.sub.3-6carbocyclyl substituted with
1-4 R.sub.e, --(CR.sub.4aR.sub.4b).sub.r-heterocyclyl substituted
with 1-4 R.sub.e; [0159] R.sub.4a, at each occurrence, is
independently selected from the group consisting of H and
C.sub.1-4alkyl; [0160] R.sub.4b, at each occurrence, is
independently selected from the group consisting of H and
C.sub.1-4alkyl; [0161] R.sub.6, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
.dbd.O, CN, --OR.sub.b, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d,
--NR.sub.7R.sub.7,
--(CR.sub.2aR.sub.2b).sub.rC(.dbd.O)NR.sub.7R.sub.7,
--NR.sub.aC(.dbd.O)R.sub.d, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.7R.sub.7, --NR.sub.aC(.dbd.O)NR.sub.7R.sub.7,
--(CR.sub.2aR.sub.2b).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.7R.sub.7, --NR.sub.aS(O).sub.2NR.sub.7R.sub.7,
--NR.sub.2S(O).sub.2R.sub.c, C.sub.1-4 alkyl substituted with 1-3
R.sub.e, --(CR.sub.2aR.sub.2b).sub.r--C.sub.3-6carbocyclyl
substituted with 1-3 R.sub.e, and
--(CR.sub.2aR.sub.2b).sub.r-heterocyclyl substituted with 1-3
R.sub.e; [0162] R.sub.2a, at each occurrence, is independently
selected from the group consisting of H and C.sub.1-4alkyl; [0163]
R.sub.2b, at each occurrence, is independently selected from the
group consisting of H and C.sub.1-4alkyl; and [0164] R.sub.7, at
each occurrence, is independently selected from the group
consisting of H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.8; [0165] R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, .dbd.O,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rOC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e; and
[0166] r, at each occurrence, is independently selected from the
group consisting of zero, 1, 2, and 3.
[0167] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0168] R.sub.2 is selected from the group
consisting of aryl substituted with 1-4 R.sub.6 and heteroaryl
substituted with 1-4 R.sub.6, wherein said heteroaryl comprises
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.6a, O, and S(O).sub.p; [0169] R.sub.4 is selected from
the group consisting of H, C.sub.1-4alkyl substituted with 1-4
R.sub.e, C.sub.3-6cyclcoalkyl substituted with 1-4 R.sub.e, aryl
substituted with 1-4 R.sub.e, and heterocyclyl substituted with 1-4
R.sub.e; [0170] R.sub.6, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, CN,
--NR.sub.7R.sub.7, --C(.dbd.O)NR.sub.7R.sub.7,
--NR.sub.aC(.dbd.O)R.sub.d, --NR.sub.aC(.dbd.O)OR.sub.b,
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6carbocyclyl
substituted with 1-3 R.sub.8, and heterocyclyl substituted with 1-3
R.sub.8; [0171] R.sub.6a is selected from the group consisting of H
and C.sub.1-4alkyl substituted with 1-3 R.sub.e; [0172] R.sub.7 and
R.sub.7 together with the nitrogen atom to which they are both
attached form a heterocyclic ring comprising carbon atoms and 1-4
heteroatoms selected from the group consisting of N, NR.sub.8a, O,
and S(O).sub.p and substituted with 1-5 R.sub.8; [0173] R.sub.8, at
each occurrence, is independently selected from the group
consisting of H, F, Cl, Br, C.sub.1-4alkyl substituted with 1-4
R.sub.e, .dbd.O, --OR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.d, --NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.d, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)R.sub.d, --OC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
NR.sub.aC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b,
S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, and heterocyclyl substituted with 1-4
R.sub.e; [0174] R.sub.8a is selected from the group consisting of
H, C.sub.1-4alkyl, S(O).sub.pR.sub.c, and heterocyclyl substituted
with 1-4 R.sub.e; [0175] p, at each occurrence, is independently
selected from the group consisting of zero, 1, and 2.
[0176] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0177] R.sub.4 is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.r--C.sub.3-6cycloalkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 1-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.e; other
variables are as defined in Formula (II) above.
[0178] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0179] R.sub.2 is selected from the group
consisting of phenyl substituted with 1-3 R.sub.6 and heteroaryl
substituted with 1-3 R.sub.6; [0180] R.sub.4 is selected from the
group consisting of H, C.sub.1-6alkyl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --C.sub.3-6cycloalkyl substituted with
1-3 R.sub.e, aryl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.r-4- to 6-membered saturated monocyclic
heterocyclyl substituted with 1-3 R.sub.e, and
--(CH.sub.2).sub.r-5- to 6-membered heteroaryl substituted with 1-3
R.sub.e; [0181] R.sub.6, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, .dbd.O, CN,
--OR.sub.b, --S(O).sub.2R.sub.c, --C(.dbd.O)R.sub.d,
--NR.sub.7R.sub.7, --(CH.sub.2).sub.rC(.dbd.O)NR.sub.7R.sub.7,
--NHC(.dbd.O)R.sub.d, --NHC(.dbd.O)OR.sub.b,
--NHC(.dbd.O)NR.sub.7R.sub.7, --(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.7R.sub.7, --NHS(O).sub.2NR.sub.7R.sub.7,
--NHS(O).sub.2R.sub.c, C.sub.1-4alkyl substituted with 1-3 R.sub.e,
non-aromatic heterocyclyl substituted with 1-3 R.sub.e, and
heteroaryl substituted with 1-3 R.sub.e; [0182] R.sub.7, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.8; [0183] R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, .dbd.O,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rOC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0184] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-4 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with 1-3
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring, having 1 to
3 heteroatoms selected from the group consisting of N, O, S, and
substituted with 1-3 R.sub.e; [0185] R.sub.b, at each occurrence,
is independently selected from the group consisting of H, C.sub.1-4
alkyl substituted with 1-3 R.sub.e, and heterocyclyl; [0186]
R.sub.c, at each occurrence, is independently C.sub.1-4 alkyl
substituted with 1-3 R.sub.e; [0187] R.sub.d, at each occurrence,
is independently selected from the group consisting of H and
C.sub.1-4 alkyl substituted with 1-3 R.sub.e; [0188] R.sub.e, at
each occurrence, is independently selected from the group
consisting of H, C.sub.1-4 alkyl substituted with 1-4 R.sub.f, F,
Cl, Br, .dbd.O, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, and --(CH.sub.2).sub.rNR.sub.fR.sub.f; and
[0189] R.sub.f, at each occurrence, is independently selected from
the group consisting of H and C.sub.1-3alkyl or R.sub.f and R.sub.f
together with the nitrogen atom to which they are both attached
form a heterocyclic ring; [0190] r, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, and
3; and [0191] m, at each occurrence, is independently selected from
the group consisting of zero, 1, 2, and 3.
[0192] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0193] R.sub.2 is selected from the group
consisting of 4- to 7-membered monocyclic or 8- to 12-membered
bicyclic aryl substituted with 1-4 R.sub.6 and 4- to 7-membered
monocyclic or 7- to 12-membered bicyclic heteroaryl substituted
with 1-4 R.sub.6; [0194] R.sub.4 is selected from the group
consisting of H, C.sub.1-4alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2c).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
--(CH.sub.2).sub.r--C.sub.3-6cycloalkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.e;
[0195] R.sub.6, at each occurrence, is independently selected from
the group consisting of H, F, Cl, Br, .dbd.O, CN, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d, --NR.sub.7R.sub.7,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.7R.sub.7, --NHC(.dbd.O)R.sub.d,
--NHC(.dbd.O)OR.sub.b, --OC(.dbd.O)NR.sub.7R.sub.7,
--NHC(.dbd.O)NR.sub.7R.sub.7, --(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.7R.sub.7, --NHS(O).sub.2NR.sub.7R.sub.7,
--NHS(O).sub.2R.sub.c, or C.sub.1-6 alkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-6 carbocyclyl substituted with
1-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-3 R.sub.e; [0196] R.sub.7, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.8; and [0197] R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, .dbd.O,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rOC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e; other
variables are as defined in Formula (II) above.
[0198] In another embodiment, there are disclosed compounds of
formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0199] R.sub.2 is selected from the group
consisting of 4- to 7-membered monocyclic or 8- to 12-membered
bicyclic aryl substituted with 1-4 R.sub.6 and 4- to 7-membered
monocyclic or 7- to 12-membered bicyclic heteroaryl comprising
carbon atoms and 1-4 heteroatoms selected from the group consisting
of N, NR.sub.6a, and substituted with 1-4 R.sub.6; [0200] R.sub.4
is selected from the group consisting of C.sub.1-4alkyl substituted
with 1-3 R.sub.e, C.sub.3-6cycloalkyl, phenyl substituted with 1-3
R.sub.e, and 4- to 6-membered heterocyclyl comprising carbon atoms
and 1-4 heteroatoms selected from the group consisting of N, NH,
NC.sub.1-4alkyl, O, and S(O).sub.p and substituted with 1-3
R.sub.e; [0201] R.sub.6, at each occurrence, is independently
selected from the group consisting of H, F, Cl, Br, CN,
--NR.sub.7R.sub.7, --C(.dbd.O)NR.sub.7R.sub.7,
--NHC(.dbd.O)OR.sub.b, C.sub.1-4alkyl substituted with 1-3 R.sub.e
and 5- to 6-membered heterocyclyl substituted with 1-3 R.sub.8;
[0202] R.sub.7 and R.sub.7 together with the nitrogen atom to which
they are both attached form a heterocyclic ring comprising carbon
atoms and 1-4 heteroatoms selected from the group consisting of N,
NR.sub.8a, O, and S(O).sub.p and substituted with 1-4 R.sub.8; and
[0203] R.sub.8a is selected from the group consisting of H and
C.sub.1-4alkyl, S(O).sub.pR.sub.c, and heterocyclyl substituted
with 1-4 R.sub.e; other variables are as defined in Formula (II)
above.
[0204] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0205] R.sub.2 is selected from the group
consisting of
[0205] ##STR00021## [0206] - - - represents an optional bond;
[0207] R.sub.6a, at each occurrence, is independently selected from
the group consisting of H, C.sub.1-4 alkyl substituted with 1-3
R.sub.e, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d,
C(.dbd.O)OR.sub.b; and [0208] m, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, 3,
and 4; other variables are as defined in Formula (II) above.
[0209] In another embodiment, there are disclosed compounds of
formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0210] R.sub.2 is selected from the group
consisting of
[0210] ##STR00022## [0211] R.sub.6a is selected from the group
consisting of H and C.sub.1-4alkyl substituted with 1-2 R.sub.e;
[0212] R.sub.6, at each occurrence, is independently selected from
the group consisting of H, F, Cl, Br, CN, --NR.sub.7R.sub.7,
--C(.dbd.O)NR.sub.7R.sub.7, --NR.sub.aC(.dbd.O)R.sub.d,
--NR.sub.aC(.dbd.O)OR.sub.b, C.sub.1-4alkyl substituted with 1-3
R.sub.e, and heterocyclyl substituted with 1-3 R.sub.8; [0213]
R.sub.7 and R.sub.7 together with the nitrogen atom to which they
are both attached form a heterocyclic ring comprising carbon atoms
and 1-4 heteroatoms selected from the group consisting of N,
NR.sub.8a, O, and S(O).sub.p and substituted with 1-4 R.sub.8;
[0214] R.sub.e, at each occurrence, is independently selected from
the group consisting of C.sub.1-6alkyl and OH; and [0215] m, at
each occurrence, is independently selected from the group
consisting of zero, 1, 2, 3, and 4; other variables are as defined
in Formula (II) above.
[0216] In another embodiment of the compounds of Formulae (I) and
(II), R.sub.2 is heteroaryl selected from the group consisting of
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl,
quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl,
thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl,
benzofuryl, benzothienyl, benzthiazolyl, benzoxazinyl, isoxazolyl,
pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,
isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,
benzodioxolanyl, and benzodioxane, each of which is substituted
with 1-4 R.sub.6.
[0217] In another embodiment, there are disclosed compounds of
formula (III) or (IV) including enantiomers, diastereomers,
tautomers, pharmaceutically-acceptable salts, prodrugs, hydrates,
or solvates thereof,
##STR00023##
wherein [0218] R.sub.4 is selected from the group consisting of
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6cycloalkyl
substituted with 1-3 R.sub.e, and 4- to 6-membered heterocyclyl
comprising carbon atoms and 1-4 heteroatoms selected from the group
consisting of N, NH, NC.sub.1-4alkyl, O, and S(O).sub.p and
substituted with 1-3 R.sub.e; [0219] R.sub.6a is selected from the
group consisting of H and C.sub.1-4alkyl optionally substituted
with OH; and [0220] R.sub.6 is selected from the group consisting
of H, F, Cl, Br, CN, and C.sub.1-4alkyl substituted with 1-2
R.sub.e.
[0221] In another embodiment, there are disclosed compounds of
formula (Va) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00024##
wherein [0222] R.sub.4 is selected from the group consisting of H,
C.sub.1-6alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.r--C.sub.3-6cycloalkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 1-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.e;
[0223] R.sub.6, at each occurrence, is independently selected from
the group consisting of H, F, Cl, Br, .dbd.O, CN, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d, --NR.sub.7R.sub.7,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.7R.sub.7, --NHC(.dbd.O)R.sub.d,
--NHC(.dbd.O)OR.sub.b, --OC(.dbd.O)NR.sub.7R.sub.7,
--NHC(.dbd.O)NR.sub.7R.sub.7, --(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.7R.sub.7, --NHS(O).sub.2NR.sub.7R.sub.7,
--NHS(O).sub.2R.sub.c, or C.sub.1-4 alkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-6 carbocyclyl substituted with
1-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-3 R.sub.e; [0224] R.sub.7, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.8; [0225] R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, .dbd.O,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rOC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0226] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom
to which they are both attached form a heterocyclic ring
substituted with 1-5 R.sub.e; [0227] R.sub.b, at each occurrence,
is independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0228] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; [0229]
R.sub.d, at each occurrence, is independently selected from the
group consisting of H, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.e; [0230] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0231] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-5 alkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring; and [0232] m, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, 3,
and 4.
[0233] In another embodiment, there are disclosed compounds of
Formula (Va) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0234] R.sub.4 is selected from the group
consisting of H, C.sub.1-6alkyl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rNR.sub.aR.sub.a,
--C.sub.3-6cycloalkyl substituted with 1-3 R.sub.e, aryl
substituted with 1-3 R.sub.e, 4-, 5-, or 6-membered non-aromatic
monocyclic heterocyclyl substituted with 1-3 R.sub.e, and 5- or
6-membered heteroaryl substituted with 1-3 R.sub.e; [0235] R.sub.7
and R.sub.7 together with the nitrogen atom to which they are both
attached form a heterocyclic ring substituted with 1-5 R.sub.8;
[0236] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-4 alkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with 1-3
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a monocyclic heterocyclic ring
substituted with 1-3 R.sub.e; [0237] R.sub.b, at each occurrence,
is independently selected from the group consisting of H and
C.sub.1-4 alkyl substituted with 1-3 R.sub.e, and heterocyclyl;
[0238] R.sub.c, at each occurrence, is independently selected from
the group consisting of C.sub.1-4 alkyl substituted with 1-3
R.sub.e and heterocyclyl; [0239] R.sub.d, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-4
alkyl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-3
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-3
R.sub.e; [0240] R.sub.e, at each occurrence, is independently
selected from the group consisting of C.sub.1-4 alkyl substituted
with 1-4 R.sub.f, F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H,
--(CH.sub.2).sub.rOC.sub.1-5 alkyl, --(CH.sub.2).sub.rOH, SH, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0241] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H and C.sub.1-4alkyl or R.sub.f and R.sub.f together with the
nitrogen atom to which they are both attached form a heterocyclic
ring; other variables are as defined in Formula (Va) above.
[0242] In another embodiment, there are disclosed compounds of
Formula (Va) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0243] R.sub.6, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
CN, .dbd.O, O--C.sub.1-4alkyl substituted with 1-3 R.sub.e,
--O(CH.sub.2).sub.rNR.sub.aC.sub.1-4alkyl-O--(CH.sub.2).sub.rOC.sub.1-4al-
kyl, --O(CH.sub.2).sub.r-heterocyclyl, --S(O).sub.2C.sub.1-4alkyl,
--C(.dbd.O)C.sub.1-4alkyl, --NH.sub.2, --N(C.sub.1-4alkyl).sub.2,
--NHCN, --NR.sub.a(CH.sub.2).sub.rNR.sub.aC.sub.1-4alkyl,
--NR.sub.a(CH.sub.2).sub.rOC.sub.1-4alkyl,
--NH(CH.sub.2).sub.r-heterocyclyl,
--(CH.sub.2).sub.rC(.dbd.O)NH.sub.2, --C(.dbd.O)NH-heterocyclyl,
--C(.dbd.O)NH(CH.sub.2).sub.rN(C.sub.1-4alkyl).sub.2,
--C(.dbd.O)-heterocyclyl, --NHC(.dbd.O)C.sub.1-4alkyl,
--NHC(.dbd.O)OC.sub.1-4alkyl, --NHC(.dbd.O)NHC.sub.1-4alkyl,
C(.dbd.O)OC.sub.1-4alkyl, --(CH.sub.2).sub.rC(.dbd.O)OH,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH-heterocyclyl,
--S(O).sub.2NHC.sub.1-4alkyl, --S(O).sub.2-heterocyclyl substituted
with 1-3 R.sub.e, --NH.sub.2S(O).sub.2NH.sub.2,
--NHS(O).sub.2C.sub.1-4alkyl, C.sub.1-4alkyl, CF.sub.3,
--(CH.sub.2).sub.rOH, C.sub.3-6carbocyclyl substituted with 1-3
R.sub.e, non-aromatic heterocyclyl substituted with 1-3 R.sub.e,
and 5- or 6-membered heteroaryl substituted with 1-3 R.sub.e.
[0244] In another embodiment, there are disclosed compounds of
formula (V) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00025##
wherein [0245] R.sub.4 is selected from the group consisting of
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6cycloalkyl
substituted with 1-3 R.sub.e, aryl substituted with 1-3 R.sub.e,
and heterocyclyl substituted with 1-3 R.sub.e; [0246] R.sub.6b is
selected from the group consisting of --NR.sub.7R.sub.7 and
heterocyclyl substituted with 1-3 R.sub.8 [0247] R.sub.6c is
selected from the group consisting of F, Cl, and Br; [0248]
R.sub.6d is selected from the group consisting of CN,
--NHC(.dbd.O)O(C.sub.1-4alkyl), and CHF.sub.2; [0249] R.sub.7 and
R.sub.7 together with the nitrogen atom to which they are both
attached form a heterocyclic ring comprising carbon atoms and 1-4
heteroatoms selected from the group consisting of N, NR.sub.8a, O,
and S(O).sub.p and substituted with 1-4 R.sub.8; [0250] R.sub.8 is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-4alkyl substituted with 1-4 R.sub.e, .dbd.O, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d, --NR.sub.aR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.d,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)R.sub.d,
--OC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
NR.sub.aC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b,
S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, and heterocyclyl substituted with 1-4
R.sub.e; [0251] R.sub.8a is selected from the group consisting of
H, C.sub.1-4alkyl, S(O).sub.2R.sub.c, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e; [0252] R.sub.a, at each
occurrence, is independently selected from the group consisting of
H, CN, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; [0253] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0254] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; [0255]
R.sub.d, at each occurrence, is independently selected from the
group consisting of H, OH, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.e; [0256] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f, and
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f; [0257] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-5 alkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring.
[0258] In another embodiment, there are disclosed compounds of
formula (V) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0259] R.sub.6b is
##STR00026##
[0259] wherein [0260] - - - is an optional bond; [0261] R.sub.8 is
independently selected from the group consisting of H, F, Cl,
C.sub.1-4alkyl substituted with 1-4 R.sub.e, .dbd.O, --OH,
--C(.dbd.O)R.sub.d, --NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.d, --NHC(.dbd.O)OR.sub.b, --OC(.dbd.O)R.sub.d,
NHC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b, and heterocyclyl
substituted with 1-4 R.sub.e; [0262] R.sub.8b is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e, --C(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)(CR.sub.gR.sub.g).sub.rOR.sub.b,
--C(.dbd.O)(CR.sub.gR.sub.g).sub.rOC(.dbd.O)R.sub.b--(CR.sub.gR.sub.g).su-
b.r--C.sub.3-10carbocyclyl substituted with 1-5 R.sub.e and
--(CR.sub.gR.sub.g).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0263] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, --(CH.sub.2).sub.rCN,
NO.sub.2, .dbd.O, CO.sub.2H, --OPO.sub.3H.sub.2,
--OSi(C.sub.1-4alkyl).sub.3, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, --(CH.sub.2).sub.rS(O).sub.2C.sub.1-5alkyl,
--(CH.sub.2).sub.rS(O).sub.2-phenyl,
--(CH.sub.2).sub.rNHS(O).sub.2C.sub.1-5alkyl, --S(O).sub.2NH.sub.2,
SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0264] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-5alkyl, OH, OC.sub.1-5alkyl, C.sub.3-6 cycloalkyl, and
phenyl, heterocyclyl substituted with alkyl and CN, or R.sub.f and
R.sub.f together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; other variables are as defined in Formula (I)
above.
[0265] In another embodiment, there are disclosed compounds of
formula (V) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0266] R.sub.6b is
##STR00027##
[0266] wherein [0267] R.sub.8 is independently selected from the
group consisting of H, F, Cl, .dbd.O, --OH, --C(.dbd.O)R.sub.d,
--NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.d, --NHC(.dbd.O)OR.sub.b, --OC(.dbd.O)R.sub.d,
NHC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b; other variables
are as defined in Formula (V) above.
[0268] In another embodiment, there are disclosed compounds of
formula (VI) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00028##
wherein [0269] R.sub.4 is selected from the group consisting of
C.sub.1-4alkyl substituted with 1-3 R.sub.e, C.sub.3-6cycloalkyl
and heterocyclyl substituted with 1-3 R.sub.e; [0270] R.sub.6c is
selected from the group consisting of F, Cl, and Br; [0271]
R.sub.6d is selected from the group consisting of CN,
--NHC(.dbd.O)O(C.sub.1-4alkyl), and CHF.sub.2; [0272] R.sub.7 and
R.sub.7 together with the nitrogen atom to which they are both
attached form a 4- to 7-membered monocyclic or 7- to 12-membered
bicyclic heterocycle containing carbon atoms and additional 1-3
heteroatoms selected from the group consisting of NR.sub.8a, O, and
S(O).sub.2 and substituted with 1-4 R.sub.8; [0273] R.sub.8 is
independently selected from the group consisting of F, Cl,
C.sub.1-4alkyl substituted with 1-4 R.sub.e, .dbd.O, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d, --NR.sub.aR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.d,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)R.sub.d,
--OC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
NR.sub.aC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b,
S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, and heterocyclyl substituted with 1-4
R.sub.e; [0274] R.sub.8a is selected from the group consisting of
H, C.sub.1-4alkyl, S(O).sub.2R.sub.c, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e; [0275] R.sub.a, at each
occurrence, is independently selected from the group consisting of
H, CN, C.sub.1-6 alkyl substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.e; [0276] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, --(CH.sub.2).sub.r-aryl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6cycloalkyl substituted with 1-5
R.sub.e and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; [0277] R.sub.c, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl substituted
with 1-5 R.sub.e, aryl, C.sub.3-6cycloalkyl, and heterocyclyl;
[0278] R.sub.d, at each occurrence, is independently selected from
the group consisting of H, OH, C.sub.1-6 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-5 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-5 R.sub.e; [0279] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f, and
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f; and [0280] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-5 alkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring.
[0281] In another embodiment, there are disclosed compounds of
formula (VI) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0282] NR.sub.7R.sub.7 is selected from the group
consisting of
[0282] ##STR00029## [0283] R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e,
.dbd.O, --OH, --O(C.sub.1-4alkyl), --NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.C)OR.sub.b,
--OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2, --NHC(.dbd.O)NR.sub.aR.sub.a,
--NHS(O).sub.2(C.sub.1-4alkyl); [0284] R.sub.8a is selected from
the group consisting of H, C.sub.1-4alkyl,
S(O).sub.2C.sub.1-4alkyl, and 5- to 6-membered heterocyclyl
substituted with 1-4 R.sub.e; [0285] R.sub.a, at each occurrence,
is independently selected from the group consisting of H, CN,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e; or
R.sub.a and R.sub.a together with the nitrogen atom to which they
are both attached form a heterocyclic ring selected from the group
consisting of
[0285] ##STR00030## [0286] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0287] R.sub.e, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl substituted with 1-5
R.sub.f, --(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2,
.dbd.O, CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5alkyl,
--(CH.sub.2).sub.rOH, SH, NH, NH(C.sub.1-5alkyl),
N(C.sub.1-5alkyl).sub.2, and --NHC(.dbd.O)OC.sub.1-5alkyl; [0288]
m, at each occurrence, is independently selected from the group
consisting of zero, 1, and 2; and [0289] r, at each occurrence, is
independently selected from the group consisting of zero, 1, and
2.
[0290] In another embodiment, there are disclosed compounds of
formula (VI) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0291] R.sub.4 is selected from the group
consisting of C.sub.1-4alkyl, C.sub.3-6cycloalkyl, and
heterocyclyl, each substituted with 1-3 R.sub.e; [0292] R.sub.6c is
selected from the group consisting of F and Cl; and [0293] R.sub.6d
is selected from the group consisting of CN,
--NHC(.dbd.O)O(C.sub.1-4alkyl), and CHF.sub.2; [0294]
NR.sub.7R.sub.7 is selected from the group consisting of
[0294] ##STR00031## [0295] R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e,
.dbd.O, --OH, --O(C.sub.1-4alkyl), --NHC(.dbd.O)(C.sub.1-4alkyl),
--NR.sub.aC(.dbd.O)O(C.sub.1-4alkyl),
--OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2, and
--NHS(O).sub.2(C.sub.1-4alkyl); [0296] m, at each occurrence, is
independently selected from the group consisting of zero, 1, 2, and
3.
[0297] In another embodiment, there are disclosed compounds of
formula (VI) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, [0298] R.sub.4 is selected from the group consisting of
methyl, ethyl substituted with F and Cl, propyl, cyclopropyl,
and
[0298] ##STR00032## [0299] R.sub.6c is Cl; [0300] R.sub.6d is
selected from the group consisting of CN and CHF.sub.2.
[0301] In another embodiment, there are disclosed compounds of
formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein [0302] R.sub.1 is H; [0303] R.sub.2 is selected
from the group consisting of
[0303] ##STR00033## [0304] R.sub.4 is selected from the group
consisting of CH.sub.2CH.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
[0304] ##STR00034## [0305] R.sub.6a is selected from the group
consisting of H and CH.sub.3, CH.sub.2CH.sub.3, and
CH.sub.2CHOHCH.sub.3; [0306] R.sub.6b is selected from the group
consisting of --NR.sub.7R.sub.7 and
[0306] ##STR00035## [0307] - - - is an optional bond; [0308]
R.sub.6d is selected from the group consisting of CN,
--NHC(.dbd.O)OCH.sub.3, and CHF.sub.2; [0309] R.sub.7 and R.sub.7
together with the nitrogen atom to which they are both attached
form a heterocyclic ring selected from the group consisting of
[0309] ##STR00036## [0310] R.sub.8 is selected from the group
consisting of F, C.sub.1-4alkyl substituted with 1-4 R.sub.e, --OH,
--O(C.sub.1-4alkyl), --NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --OC(.dbd.O)(CH.sub.2).sub.rNH.sub.2,
--NHC(.dbd.O)NR.sub.aR.sub.a, and --NHS(O).sub.2(C.sub.1-4alkyl);
[0311] R.sub.8a is selected from the group consisting of H,
C.sub.1-4alkyl, S(O).sub.2C.sub.1-4alkyl, and 5- to 6-membered
heterocyclyl substituted with 1-4 R.sub.e; [0312] R.sub.a, at each
occurrence, is independently selected from the group consisting of
H, C.sub.1-6 alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e; or
R.sub.a and R.sub.a together with the nitrogen atom to which they
are both attached form a heterocyclic ring selected from the group
consisting of
[0312] ##STR00037## [0313] R.sub.b, at each occurrence, is
independently selected from the group consisting of H, C.sub.1-6
alkyl substituted with 1-5 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0314] R.sub.e, at each occurrence, is independently selected from
the group consisting of F, Cl, Br, CN, NO.sub.2,
--(CH.sub.2).sub.rOC.sub.1-5alkyl, --(CH.sub.2).sub.rOH, NH.sub.2,
NH(C.sub.1-5alkyl), N(C.sub.1-5alkyl).sub.2,
--NHC(.dbd.O)OC.sub.1-5alkyl, --(CH.sub.2).sub.r-heterocyclyl, and
C.sub.1-6 alkyl optionally substituted OH; and [0315] r, at each
occurrence, is independently selected from the group consisting of
zero, 1, and 2.
[0316] Further embodiments of the invention relate to compounds of
Formulae (VII)-(VIII) below, wherein the variables, where they
appear, can be selected from the group consisting of any of the
embodiments as set forth above for compounds of Formula (I), (II),
(III), (IIIa), (IV), (V), (Va), (Vb), (VI) and/or (VIa) (including
as recited in any of the further embodiments).
##STR00038##
[0317] In another embodiment of the compounds of Formula (I),
[0318] R.sub.6, at each occurrence, is independently selected from
the group consisting of H, F, Cl, Br, .dbd.O, CN, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.d, --NR.sub.7R.sub.7,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.7R.sub.7,
--NR.sub.aC(.dbd.O)R.sub.d, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.7R.sub.7, --NR.sub.aC(.dbd.O)NR.sub.7R.sub.7,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.7R.sub.7,
--NR.sub.aS(O).sub.2NR.sub.7R.sub.7, --NR.sub.aS(O).sub.2R.sub.c,
or C.sub.1-6 alkyl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6 carbocyclyl substituted with 1-3
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-3
R.sub.e; [0319] R.sub.a, at each occurrence, is independently
selected from the group consisting of H, CN, C.sub.1-4 alkyl
substituted with 1-3 R.sub.e, --(CH.sub.2).sub.r-heterocyclyl
substituted with 1-3 R.sub.e; or R.sub.a and R.sub.a together with
the nitrogen atom to which they are both attached form a monocyclic
heterocyclic ring substituted with 1-3 R.sub.e; [0320] R.sub.b, at
each occurrence, is independently selected from the group
consisting of H and C.sub.1-4 alkyl substituted with 1-3 R.sub.e,
and heterocyclyl; [0321] R.sub.c, at each occurrence, is
independently selected from the group consisting of C.sub.1-4 alkyl
substituted with 1-3 R.sub.e, C.sub.2-4 alkenyl substituted with
1-3 R.sub.e, and C.sub.2-4 alkynyl substituted with 1-3 R.sub.e;
[0322] R.sub.d, at each occurrence, is independently selected from
the group consisting of H, C.sub.1-4 alkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with
1-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with
1-3 R.sub.e; [0323] R.sub.e, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6alkyl substituted
with 1-5 R.sub.f, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; [0324] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H and C.sub.1-4alkyl or R.sub.f and R.sub.f together with the
nitrogen atom to which they are both attached form a heterocyclic
ring; [0325] n, at each occurrence, is independently selected from
the group consisting of zero, 1, 2, 3, and 4; and [0326] r, at each
occurrence is independently selected from the group consisting of
zero, 1, 2, and 3.
[0327] In another embodiment of the compounds of Formula (I),
R.sub.6, at each occurrence, is independently selected from the
group consisting of H, F, Cl, Br, CN, O--C.sub.1-4alkyl substituted
with 1-3 R.sub.e,
--O(CH.sub.2).sub.rNR.sub.aC.sub.1-4alkyl-O--(CH.sub.2).sub.rOC.sub.1-4al-
kyl, --O(CH.sub.2).sub.r-heterocyclyl, --S(O).sub.2C.sub.1-4alkyl,
--C(.dbd.O)C.sub.1-4alkyl, --NH.sub.2, --N(C.sub.1-4alkyl).sub.2,
--NHCN, --NR.sub.a(CH.sub.2).sub.rNR.sub.aC.sub.1-4alkyl,
--NR.sub.a(CH.sub.2).sub.rOC.sub.1-4alkyl,
--NH(CH.sub.2).sub.r-heterocyclyl,
--(CH.sub.2).sub.rC(.dbd.O)NH.sub.2, --C(.dbd.O)NH-heterocyclyl,
--C(.dbd.O)NH(CH.sub.2).sub.rN(C.sub.1-4alkyl).sub.2,
--C(.dbd.O)-heterocyclyl, --NHC(.dbd.O)C.sub.1-4alkyl,
--NHC(.dbd.O)OC.sub.1-4alkyl, --NHC(.dbd.O)NHC.sub.1-4alkyl,
C(.dbd.O)OC.sub.1-4alkyl, --(CH.sub.2).sub.rC(.dbd.O)OH,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH-heterocyclyl,
--S(O).sub.2NHC.sub.1-4alkyl, --S(O).sub.2-heterocyclyl substituted
with 1-3 R.sub.e, --NH.sub.2S(O).sub.2NH.sub.2,
--NHS(O).sub.2C.sub.1-4alkyl, C.sub.1-4alkyl, CF.sub.3,
--(CH.sub.2).sub.rOH, C.sub.3-6carbocyclyl substituted with 1-3
R.sub.e, non-aromatic heterocyclyl substituted with 1-3 R.sub.e,
and 5- or 6-membered heteroaryl substituted with 1-3 R.sub.e.
[0328] In another embodiment of the compounds of Formula (I),
[0329] R.sub.2 is selected from the group consisting of phenyl
substituted with 1-3 R.sub.6 and
[0329] ##STR00039## [0330] - - - represents an optional bond;
[0331] R.sub.6, at each occurrence, is independently selected from
the group consisting of H, F, Cl, Br, .dbd.O, CN, --OR.sub.b,
--S(O).sub.2R.sub.c, --C(.dbd.O)R.sub.d, --NR.sub.7R.sub.7,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.7R.sub.7, --NHC(.dbd.O)R.sub.d,
--NHC(.dbd.O)OR.sub.b, --NHC(.dbd.O)NR.sub.7R.sub.7,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.7R.sub.7,
--NHS(O).sub.2NR.sub.7R.sub.7, --NHS(O).sub.2R.sub.c,
C.sub.1-4alkyl substituted with 1-3 R.sub.e, non-aromatic
heterocyclyl substituted with 1-3 R.sub.e, and heteroaryl
substituted with 1-3 R.sub.e; [0332] R.sub.6a, at each occurrence,
is independently selected from the group consisting of H, C.sub.1-4
alkyl substituted with 1-3 R.sub.e, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.d, C(.dbd.O)OR.sub.b; [0333] R.sub.4 is selected
from the group consisting of H, C.sub.1-6alkyl substituted with 1-3
R.sub.e, --(CH.sub.2).sub.rOR.sub.b, --C.sub.3-6cycloalkyl
substituted with 1-3 R.sub.e, aryl substituted with 1-3 R.sub.e,
--(CH.sub.2).sub.r-4- to 6-membered saturated monocyclic
heterocyclyl substituted with 1-3 R.sub.e, and
--(CH.sub.2).sub.r-5- to 6-membered heteroaryl substituted with 1-3
R.sub.e; [0334] R.sub.7, at each occurrence, is independently
selected from the group consisting of H, C.sub.1-6 alkyl
substituted with 1-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 1-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 1-5
R.sub.e; or R.sub.7 and R.sub.7 together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 1-5 R.sub.8; [0335] R.sub.8, at each occurrence, is
independently selected from the group consisting of H, F, Cl, Br,
C.sub.1-6 alkyl substituted with 1-5 R.sub.e, .dbd.O,
--(CH.sub.2).sub.rOR.sub.b, --(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)R.sub.d,
--(CH.sub.2).sub.rOC(.dbd.O)(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-5 R.sub.e;
[0336] R.sub.a, at each occurrence, is independently selected from
the group consisting of H, CN, C.sub.1-4 alkyl substituted with 1-5
R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with 1-3
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring, having 1 to
3 heteroatoms selected from the group consisting of N, O, S, and
substituted with 1-3 R.sub.e; [0337] R.sub.b, at each occurrence,
is independently selected from the group consisting of H, C.sub.1-4
alkyl substituted with 1-3 R.sub.e, and heterocyclyl; [0338]
R.sub.c, at each occurrence, is independently C.sub.1-4 alkyl
substituted with 1-3 R.sub.e; [0339] R.sub.d, at each occurrence,
is independently selected from the group consisting of H and
C.sub.1-4 alkyl substituted with 1-3 R.sub.e; [0340] R.sub.e, at
each occurrence, is independently selected from the group
consisting of H, C.sub.1-6alkyl substituted with 1-5 R.sub.f,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.r-heterocyclyl, F, Cl, Br, CN,
NO.sub.2, .dbd.O, CO.sub.2H, --(CH.sub.2).sub.rOC.sub.1-5 alkyl,
--(CH.sub.2).sub.rOH, SH, --(CH.sub.2).sub.rNR.sub.fR.sub.f,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.f, and
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.f; and [0341] R.sub.f, at each
occurrence, is independently selected from the group consisting of
H and C.sub.1-3alkyl or R.sub.f and R.sub.f together with the
nitrogen atom to which they are both attached form a heterocyclic
ring; [0342] r, at each occurrence, is independently selected from
the group consisting of zero, 1, 2, and 3; and [0343] m, at each
occurrence, is independently selected from the group consisting of
zero, 1, 2, and 3.
[0344] In still another embodiment, R.sub.2 is substituted with 1-5
R.sub.6 and is selected from the group consisting of phenyl and
naphthyl.
[0345] In another embodiment, R.sub.2 is substituted with 1-5
R.sub.6 and is heteroaryl selected from the group consisting of
thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,
thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl,
quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and
tetrahydroisoquinolinyl.
[0346] In another embodiment, R.sub.2 is selected from the group
consisting of
##STR00040##
[0347] In another embodiment, R.sub.6, at each occurrence, is
independently selected from the group consisting of F, Cl, Br,
--OCF.sub.3, --OCHF.sub.2, --CF.sub.3, CN, NO.sub.2, CH.sub.3,
--OH, --OCH.sub.3, NH.sub.2, --N(CH.sub.2CH.sub.3).sub.2,
--NHC(.dbd.O)CH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHC(.dbd.O)OCH.sub.3, --NHC(.dbd.O)CH(CH.sub.3).sub.2,
--NHC(.dbd.O)CH.sub.2CH.sub.3, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3, --S(O).sub.2CH.sub.3,
--S(O).sub.2NHCH.sub.3, --N(CH.sub.3)C(.dbd.O)CH.sub.3,
--NHS(O).sub.2NH.sub.2, --C(.dbd.O)-heterocyclyl substituted with
1-5 R.sub.e, --(CH.sub.2).sub.r-5- to 6-membered heterocyclyl
comprising carbon atoms and 1-4 heteroatoms selected from the group
consisting of N, O, and S(O).sub.p, wherein said heterocyclyl is
substituted with 1-5 R.sub.e. Non-limiting examples of the
heterocyclyl include pyrrolidine, imidazole, pyrazole, oxazole,
oxadiazole, thiazole, triazole, tetrazole, piperazine, piperidine,
and morpholine.
[0348] In another embodiment, R.sub.6 is substituted with 1-2
R.sub.e and is selected from the group consisting of:
##STR00041##
[0349] In another aspect, the present invention provides a compound
selected from the exemplified examples or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate
thereof
[0350] In another aspect, the present invention provides a compound
selected from any subset list of compounds within the scope of the
exemplified examples or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof
[0351] All aspects of the compounds, including individual variable
definitions, may be combined with other aspects to form additional
compounds. For example, in one embodiment of Formula (I), R.sub.1
is hydrogen and R.sub.2 is aryl. In another embodiment, R.sub.1 can
be hydrogen and R.sub.2 can be heteroaryl.
[0352] The compounds of Formulae (I)-(VIII) may form salts with
alkali metals such as sodium, potassium and lithium, with alkaline
earth metals such as calcium and magnesium, with organic bases such
as dicyclohexylamine, tributylamine, pyridine and amino acids such
as arginine, lysine and the like. Such salts can be formed as known
to those skilled in the art.
[0353] The compounds for Formulae (I)-(VIII) may form salts with a
variety of organic and inorganic acids. Such salts include those
formed with hydrogen chloride, hydrogen bromide, methanesulfonic
acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic
acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and
various others (e.g., nitrates, phosphates, borates, tartrates,
citrates, succinates, benzoates, ascorbates, salicylates and the
like). Such salts can be formed as known to those skilled in the
art.
[0354] In addition, zwitterions ("inner salts") may be formed.
[0355] The present invention is also intended to include all
isotopes of atoms occurring in the present compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. By way of general example and without limitation,
isotopes of hydrogen include deuterium and tritium. Isotopes of
carbon include .sup.13C and .sup.14C. Isotopically-labeled
compounds of the invention can generally be prepared by
conventional techniques known to those skilled in the art or by
processes analogous to those described herein, using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
otherwise employed.
[0356] Compounds of the Formulae (I)-(VIII) may also have prodrug
forms. Since prodrugs are known to enhance numerous desirable
qualities of pharmaceuticals (e.g., solubility, bioavailability,
manufacturing, etc.) the compounds of the present invention may be
delivered in prodrug form. Thus, the present invention is intended
to cover prodrugs of the presently claimed compounds, methods of
delivering the same and compositions containing the same.
"Prodrugs" are intended to include any covalently bonded carriers
that release an active parent drug of the present invention in vivo
when such prodrug is administered to a mammalian subject. Prodrugs
of the present invention are prepared by modifying functional
groups present in the compound in such a way that the modifications
are cleaved, either in routine manipulation or in vivo, to the
parent compound. Prodrugs include compounds of the present
invention wherein a hydroxy, amino, or sulfhydryl group is bonded
to any group that, when the prodrug of the present invention is
administered to a mammalian subject, it cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate, and benzoate derivatives of alcohol and amine functional
groups in the compounds of the present invention.
[0357] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see: [0358] a) Design of
Prodrugs, H. Bundgaard, ed., Elsevier (1985), and Methods in
Enzymology, 112:309-396, K. Widder et al., eds., Academic Press
(1985); [0359] b) Bundgaard, H., Chapter 5, "Design and Application
of Prodrugs," A Textbook of Drug Design and Development, pp.
113-191, P. Krosgaard-Larsen et al., eds., Harwood Academic
Publishers (1991); and [0360] c) Bundgaard, H., Adv. Drug Deliv.
Rev., 8:1-38 (1992).
[0361] It should further be understood that solvates (e.g.,
hydrates) of the compounds of Formulae (I)-(VIII) are also within
the scope of the invention. Methods of solvation are generally
known in the art. The inventive compounds may either be in the free
or hydrate form.
[0362] Compounds of this invention may have one or more asymmetric
centers. Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms of compounds of the present
invention are included in the present invention. Many geometric
isomers of olefins, C.dbd.N double bonds, and the like can also be
present in the compounds, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms. The present compounds can be isolated in optically active or
racemic forms. It is well known in the art how to prepare optically
active forms, such as by resolution of racemic forms or by
synthesis from optically active starting materials. All chiral,
(enantiomeric and diastereomeric) and racemic forms and all
geometric isomeric forms of a structure are intended, unless the
specific stereochemistry or isomer form is specifically indicated.
When no specific mention is made of the configuration (cis, trans
or R or S) of a compound (or of an asymmetric carbon), then any one
of the isomers or a mixture of more than one isomer is intended.
The processes for preparation can use racemates, enantiomers, or
diastereomers as starting materials. All processes used to prepare
compounds of the present invention and intermediates made therein
are considered to be part of the present invention. When
enantiomeric or diastereomeric products are prepared, they can be
separated by conventional methods, for example, by chromatography
or fractional crystallization. Compounds of the present invention,
and salts thereof, may exist in multiple tautomeric forms, in which
hydrogen atoms are transposed to other parts of the molecules and
the chemical bonds between the atoms of the molecules are
consequently rearranged. It should be understood that all
tautomeric forms, insofar as they may exist, are included within
the invention.
DEFINITIONS
[0363] The following are definitions of terms used in this
specification and appended claims. The initial definition provided
for a group or term herein applies to that group or term throughout
the specification and claims, individually or as part of another
group, unless otherwise indicated.
[0364] In accordance with a convention used in the art,
##STR00042##
is used in structural formulas herein to depict the bond that is
the point of attachment of the moiety or substituent to the core or
backbone structure.
[0365] 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.
[0366] As used herein, the term "alkyl" or "alkylene" is intended
to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, "C.sub.1-10 alkyl" (or alkylene), is intended to include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10 alkyl groups. Additionally, for
example, "C.sub.1-C.sub.6 alkyl" denotes alkyl having 1 to 6 carbon
atoms. Alkyl groups can be unsubstituted or substituted so that one
or more of its hydrogens are replaced by another chemical group.
Example alkyl groups include, but are not limited to, methyl (Me),
ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g.,
n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl,
neopentyl), and the like.
[0367] "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogen. Examples of haloalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl,
pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,
heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include "fluoroalkyl" which is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more fluorine atoms.
[0368] The term "halogen" or "halo" refers to fluorine (F),
chlorine (Cl), bromine (Br) and iodine (I).
[0369] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group
as defined above with the indicated number of carbon atoms attached
through an oxygen bridge. For example, "C.sub.1-6 haloalkoxy", is
intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6 haloalkoxy groups. Examples of haloalkoxy include, but
are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy,
pentafluorothoxy, and the like. Similarly, "haloalkylthio" or
"thiohaloalkoxy" represents a haloalkyl group as defined above with
the indicated number of carbon atoms attached through a sulphur
bridge; for example trifluoromethyl-S--, pentafluoroethyl-S--, and
the like.
[0370] As used herein, "carbocycle," "carbocyclic residue," or
"carbocyclyl" is intended to mean any stable 3-, 4-, 5-, 6-, or
7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or
13-membered bicyclic or tricyclic hydrocarbon ring, any of which
may be saturated, partially unsaturated, unsaturated or aromatic.
Examples of such carbocycles include, but are not limited to,
cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,
cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,
fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and
tetrahydronaphthyl (tetralin). As shown above, bridged rings are
also included in the definition of carbocycle (e.g.,
[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise
specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, and indanyl. When the term "carbocycle," "carbocyclic
residue," or "carbocyclyl" is used, it is intended to include
"aryl". A bridged ring occurs when one or more carbon atoms link
two non-adjacent carbon atoms. Preferred bridges are one or two
carbon atoms. It is noted that a bridge always converts a
monocyclic ring into a tricyclic ring. When a ring is bridged, the
substituents recited for the ring may also be present on the
bridge.
[0371] The term "aryl" refers to monocyclic, bicyclic, tricyclic
aromatic hydrocarbon groups having 6 to 15 carbon atoms in the ring
portion, such as phenyl, naphthyl, biphenyl and diphenyl groups,
each of which may be substituted. Aryl groups which are bicyclic or
tricyclic must include at least one fully aromatic ring but the
other fused ring or rings may be aromatic or non-aromatic. When an
aryl is substituted with a further heterocyclic ring, said ring may
be attached to the aryl through a carbon atom or a heteroatom and
said ring in turn is optionally substituted with one to two
substituents as valence allows.
[0372] The terms "aryloxy", "arylamino", "arylalkylamino",
"arylthio", "arylalkanoylamino", "arylsulfonyl", "arylalkoxy",
"arylsulfinyl", "arylheteroaryl", "arylalkylthio", "arylcarbonyl",
"arylalkenyl", or "arylalkylsulfonyl" refer to an aryl or
substituted aryl bonded to an oxygen; an amino; an alkylamino; a
thio; an alkanoylamino; a sulfonyl; an alkoxy; a sulfinyl; a
heteroaryl or substituted heteroaryl; an alkylthio; a carbonyl; an
alkenyl; or an alkylsulfonyl, respectively.
[0373] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four double bonds.
[0374] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four triple bonds.
[0375] An "alkylidene" group refers to an alkylene group consisting
of at least two carbon atoms and at least one carbon--carbon double
bond. Substituents on this group include those in the definition of
"substituted alkyl".
[0376] The term "cycloalkyl" refers to an optionally substituted,
saturated cyclic hydrocarbon ring systems, preferably containing 1
to 3 rings and 3 to 7 carbons per ring. Exemplary groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary
substituents include one or more alkyl groups as described above,
or one or more groups described above as alkyl substituents.
[0377] As used herein, the term "heterocycle," "heterocyclyl,"
"heterocyclic ring" or "heterocyclic group" is intended to mean a
stable 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-,
9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic heterocyclic ring
which is saturated, partially unsaturated or fully unsaturated or
aromatic, and which consists of carbon atoms and 1, 2, 3 or 4
heteroatoms independently selected from the group consisting of N,
O and S; and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring. The
nitrogen and sulfur heteroatoms may optionally be oxidized (i.e.,
N.fwdarw.O and S(O).sub.p). The nitrogen atom may be substituted or
unsubstituted (i.e., N or NR wherein R is H or another substituent,
if defined). The heterocyclic ring may be attached to its pendant
group at any heteroatom or carbon atom that results in a stable
structure. The heterocyclic rings described herein may be
substituted on carbon or on a nitrogen atom if the resulting
compound is stable. A nitrogen in the heterocycle may optionally be
quaternized. It is preferred that when the total number of S and O
atoms in the heterocycle exceeds 1, then these heteroatoms are not
adjacent to one another. It is preferred that the total number of S
and O atoms in the heterocycle is not more than 1. When the term
"heterocycle," "heterocyclyl," "heterocyclic ring" or "heterocyclic
group" is used, it is intended to include heteroaryl.
[0378] Examples of heterocycles include, but are not limited to,
acridinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl,
quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
1,3,4-triazolyl, and xanthenyl. Also included are fused ring and
spiro compounds containing, for example, the above
heterocycles.
[0379] Preferred 5- to 10-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,
1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,
isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,
imidazolopyridinyl, and pyrazolopyridinyl.
[0380] Preferred 5- to 6-membered heterocycles include, but are not
limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[0381] Bridged rings are also included in the definition of
heterocycle. A bridged ring occurs when one or more atoms (i.e., C,
O, N, or S) link two non-adjacent carbon or nitrogen atoms.
Preferred bridges include, but are not limited to, one carbon atom,
two carbon atoms, one nitrogen atom, two nitrogen atoms, and a
carbon-nitrogen group. It is noted that a bridge always converts a
monocyclic ring into a tricyclic ring. When a ring is bridged, the
substituents recited for the ring may also be present on the
bridge.
[0382] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or
10-membered bicyclic groups, and 11- to 14-membered tricyclic
groups which have at least one heteroatom (O, S or N) in at least
one of the rings, said heteroatom-containing ring preferably having
1, 2, or 3 heteroatoms selected from the group consisting of O, S,
and N. Each ring of the heteroaryl group containing a heteroatom
can contain one or two oxygen or sulfur atoms and/or from one to
four nitrogen atoms provided that the total number of heteroatoms
in each ring is four or less and each ring has at least one carbon
atom. Heteroaryl groups can be substituted or unsubstituted. The
nitrogen atom may be substituted or unsubstituted (i.e., N or NR
wherein R is H or another substituent, if defined). The nitrogen
and sulfur heteroatoms may optionally be oxidized (i.e., N.fwdarw.O
and S(O).sub.p) and the nitrogen atoms may optionally be
quaternized.
[0383] Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any ring.
The heteroaryl ring system may contain zero, one, two or three
substituents.
[0384] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl and the like.
[0385] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazinyl,
indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,
cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,
dihydroisoindolyl, and the like.
[0386] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0387] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0388] As referred to herein, the term "substituted" means that one
or more hydrogen atoms is replaced with a non-hydrogen group,
provided that normal valencies are maintained and that the
substitution results in a stable compound. When a substituent is
keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced.
Keto substituents are not present on aromatic moieties. When a ring
system (e.g., carbocyclic or heterocyclic) is said to be
substituted with a carbonyl group or a double bond, it is intended
that the carbonyl group or double bond be part (i.e., within) of
the ring. Ring double bonds, as used herein, are double bonds that
are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N,
or N.dbd.N).
[0389] In cases wherein there are nitrogen atoms (e.g., amines) on
compounds of the present invention, these may be converted to
N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or
hydrogen peroxides) to afford other compounds of this invention.
Thus, shown and claimed nitrogen atoms are considered to cover both
the shown nitrogen and its N-oxide (N.fwdarw.O) derivative.
[0390] When any variable occurs more than one time in any
constituent or formula for a compound, its definition at each
occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 1-3 R.sub.e, then said group may optionally be
substituted with up to three R.sub.e groups and R.sub.e at each
occurrence is selected independently from the definition of
R.sub.e. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
[0391] When a dotted ring is used within a ring structure, this
indicates that the ring structure may be saturated, partially
saturated or unsaturated.
Utility
[0392] The compounds of the invention may be used to modulate
kinase activities.
[0393] Applicants have discovered that compounds of Formulae
(I)-(VIII) have particular utility in treating proliferative
conditions associated with the modulation of kinase activity, and
particularly the inhibition of serine/threonine kinase activities.
The compounds of the present invention can be used to treat
proliferative disorders associated with abnormal kinase activity.
As used herein, the terms "treating" and "treatment" encompass
either or both responsive and prophylaxis measures, e.g., measures
designed to inhibit or delay the onset of the disease or disorder,
achieve a full or partial reduction of the symptoms or disease
state, and/or to alleviate, ameliorate, lessen, or cure the disease
or disorder and/or its symptoms.
[0394] Accordingly, one aspect of the invention is the use of a
compound of the Formulae (I)-(VIII), or a pharmaceutically
acceptable salt thereof in the manufacture of a medicament for use
in the production of an antiproliferative effect in a warm-blooded
animal such as a human being.
[0395] According to a further feature of the invention there is
provided a method for producing an antiproliferative effect in a
warm-blooded animal, such as a human being, in need of such
treatment which comprises administering to said animal an effective
amount of a compound of Formulae (I)-(VIII) or a pharmaceutically
acceptable salt thereof as defined herein before.
[0396] The anti-proliferative treatment defined herein before may
be applied as a sole therapy or may involve, in addition to a
compound of the invention, one or more other substances and/or
treatments. Such treatment may be achieved by way of the
simultaneous, sequential or separate administration of the
individual components of the treatment. The compounds of this
invention may also be useful in combination with known anti-cancer
and cytotoxic agents and treatments, including radiation. Compounds
of Formulae (I)-(VIII) may be used sequentially with known
anticancer or cytotoxic agents and treatment, including radiation
when a combination formulation is inappropriate.
[0397] The term "anti-cancer" agent includes any known agent that
is useful for the treatment of cancer including the following:
17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,
prednisone, fluoxymesterone, dromostanolone propionate,
testolactone, megestrolacetate, methylprednisolone,
methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene,
hydroxyprogesterone, aminoglutethimide, estramustine,
medroxyprogesteroneacetate, leuprolide, flutamide, toremifene,
ZOLADEX.RTM.; matrix metalloproteinase inhibitors; VEGF inhibitors,
such as anti-VEGF antibodies (AVASTIN.RTM.) and small molecules
such as ZD6474 and SU6668; Vatalanib, BAY-43-9006, SU11248,
CP-547632, and CEP-7055; HER 1 and HER 2 inhibitors including
anti-HER2 antibodies (HERCEPTIN.RTM.); EGFR inhibitors including
gefitinib, erlotinib, ABX-EGF, EMD72000, 11F8, and cetuximab; Eg5
inhibitors, such as SB-715992, SB-743921, and MKI-833; pan Her
inhibitors, such as canertinib, EKB-569, CI-1033, AEE-788, XL-647,
mAb 2C4, and GW-572016; Src inhibitors, e.g., GLEEVEC.RTM. and
dasatinib; CASODEX.RTM. (bicalutamide, Astra Zeneca), Tamoxifen;
MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 kinase
inhibitors; PDGF inhibitors, such as imatinib; anti-angiogenic and
antivascular agents which, by interrupting blood flow to solid
tumors, render cancer cells quiescent by depriving them of
nutrition; castration, which renders androgen dependent carcinomas
non-proliferative; inhibitors of non-receptor and receptor tyrosine
kinases; inhibitors of integrin signaling; tubulin acting agents
such as vinblastine, vincristine, vinorelbine, vinflunine,
paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel,
4-desacetyl-4-methylcarbonatepaclitaxel,
3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debe-
nzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate
paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D,
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pen-
tamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17
oxabicyclo[14.1.0]heptadecane-5,9-dione (ixabepilone),
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazol-
yl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabic-
yclo[14.1.0]-heptadecane-5,9-dione, and derivatives thereof; other
CDK inhibitors, antiproliferative cell cycle inhibitors,
epidophyllotoxin, etoposide, VM-26; antineoplastic enzymes, e.g.,
topoisomerase I inhibitors, camptothecin, topotecan, SN-38;
procarbazine; mitoxantrone; platinum coordination complexes such as
cisplatin, carboplatin and oxaliplatin; biological response
modifiers; growth inhibitors; antihormonal therapeutic agents;
leucovorin; tegafur; antimetabolites such as purine antagonists
(e.g., 6-thioguanine and 6-mercaptopurine; glutamine antagonists,
e.g., DON (AT-125; d-oxo-norleucine); ribonucleotide reductase
inhibitors; mTOR inhibitors; and haematopoietic growth factors.
[0398] Additional cytotoxic agents include cyclophosphamide,
doxorubicin, daunorubicin, mitoxanthrone, melphalan, hexamethyl
melamine, thiotepa, cytarabin, idatrexate, trimetrexate,
dacarbazine, L-asparaginase, bicalutamide, leuprolide,
pyridobenzoindole derivatives, interferons, and interleukins.
[0399] In the field of medical oncology it is normal practice to
use a combination of different forms of treatment to treat each
patient with cancer. In medical oncology the other component(s) of
such treatment in addition to the antiproliferative treatment
defined herein may be surgery, radiotherapy or chemotherapy. Such
chemotherapy may cover three main categories of therapeutic
agent:
[0400] (i) antiangiogenic agents that work by different mechanisms
from those defined herein before (for example, linomide, inhibitors
of integrin .alpha.v.beta.3 function, angiostatin, razoxane);
[0401] (ii) cytostatic agents such as antiestrogens (for example,
tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene),
progestogens (for example, megestrol acetate), aromatase inhibitors
(for example, anastrozole, letrozole, borazole, exemestane),
antihormones, antiprogestogens, antiandrogens (for example,
flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH
agonists and antagonists (for example, gosereline acetate,
leuprolide), inhibitors of testosterone 5.alpha.-dihydroreductase
(for example, finasteride), farnesyltransferase inhibitors,
anti-invasion agents (for example, metalloproteinase inhibitors
such as marimastat and inhibitors of urokinase plasminogen
activator receptor function) and inhibitors of growth factor
function, (such growth factors include for example, EGF, FGF,
platelet derived growth factor and hepatocyte growth factor, such
inhibitors include growth factor antibodies, growth factor receptor
antibodies such as AVASTIN.RTM. (bevacizumab) and ERBITUX.RTM.
(cetuximab); tyrosine kinase inhibitors and serine/threonine kinase
inhibitors); and
[0402] (iii) antiproliferative/antineoplastic drugs and
combinations thereof, as used in medical oncology, such as
antimetabolites (for example, antifolates such as methotrexate,
fluoropyrimidines such as 5-fluorouracil, purine and adenosine
analogues, cytosine arabinoside); intercalating antitumour
antibiotics (for example, anthracyclines such as doxorubicin,
daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin,
mithramycin); platinum derivatives (for example, cisplatin,
carboplatin); alkylating agents (for example, nitrogen mustard,
melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide,
nitrosoureas, thiotepa; antimitotic agents (for example, vinca
alkaloids like vincristine, vinorelbine, vinblastine and
vinflunine) and taxoids such as TAXOL.RTM. (paclitaxel), Taxotere
(docetaxel) and newer microbtubule agents such as epothilone
analogs (ixabepilone), discodermolide analogs, and eleutherobin
analogs; topoisomerase inhibitors (for example, epipodophyllotoxins
such as etoposide and teniposide, amsacrine, topotecan,
irinotecan); cell cycle inhibitors (for example, flavopyridols);
biological response modifiers and proteasome inhibitors such as
VELCADE.RTM. (bortezomib).
[0403] As stated above, the Formulae (I)-(VIII) compounds of the
invention are of interest for their antiproliferative effects. Such
compounds of the invention are expected to be useful in a wide
range of disease states including cancer, psoriasis, and rheumatoid
arthritis.
[0404] More specifically, the compounds of Formulae (I)-(VIII) are
useful in the treatment of a variety of cancers, including (but not
limited to) the following: [0405] carcinoma, including that of the
prostate, pancreatic ductal adenocarcinoma, breast, colon, lung,
ovary, pancreas, and thyroid; [0406] tumors of the central and
peripheral nervous system, including neuroblastoma, glioblastoma,
and medulloblastoma; and [0407] other tumors, including melanoma
and multiple myeloma.
[0408] Due to the key role of kinases in the regulation of cellular
proliferation in general, inhibitors could act as reversible
cytostatic agents which may be useful in the treatment of any
disease process which features abnormal cellular proliferation,
e.g., benign prostate hyperplasia, familial adenomatosis polyposis,
neurofibromatosis, pulmonary fibrosis, arthritis, psoriasis,
glomerulonephritis, restenosis following angioplasty or vascular
surgery, hypertrophic scar formation and inflammatory bowel
disease.
[0409] The compounds of Formula (I)-(VIII) are especially useful in
treatment of tumors having a high incidence of serine/threonine
kinase activity, such as prostate, colon, brain, thyroid and
pancreatic tumors. Additionally, the compounds of the invention may
be useful in treatment of sarcomas and pediatric sarcomas. By the
administration of a composition (or a combination) of the compounds
of this invention, development of tumors in a mammalian host is
reduced.
[0410] Compounds of Formula (I)-(VIII) may also be useful in the
treatment of other cancerous diseases (such as acute myelogenous
leukemia) that may be associated with signal transduction pathways
operating through kinases such as DYRK1a, CDK, and GSK3.beta.. The
inventive compositions may contain other therapeutic agents as
described above and may be formulated, for example, by employing
conventional solid or liquid vehicles or diluents, as well as
pharmaceutical additives of a type appropriate to the mode of
desired administration (e.g., excipients, binders, preservatives,
stabilizers, flavors, etc.) according to techniques such as those
well known in the art of pharmaceutical formulation.
[0411] Accordingly, the present invention further includes
compositions comprising one or more compounds of Formula (I)-(VIII)
and a pharmaceutically acceptable carrier.
[0412] A "pharmaceutically acceptable carrier" refers to media
generally accepted in the art for the delivery of biologically
active agents to animals, in particular, mammals. Pharmaceutically
acceptable carriers are formulated according to a number of factors
well within the purview of those of ordinary skill in the art.
These include, without limitation: the type and nature of the
active agent being formulated; the subject to which the
agent-containing composition is to be administered; the intended
route of administration of the composition; and, the therapeutic
indication being targeted. Pharmaceutically acceptable carriers
include both aqueous and non-aqueous liquid media, as well as a
variety of solid and semi-solid dosage forms. Such carriers can
include a number of different ingredients and additives in addition
to the active agent, such additional ingredients being included in
the formulation for a variety of reasons, e.g., stabilization of
the active agent, binders, etc., well known to those of ordinary
skill in the art. Descriptions of suitable pharmaceutically
acceptable carriers, and factors involved in their selection, are
found in a variety of readily available sources such as, for
example, Remington's Pharmaceutical Sciences, 17th ed. (1985),
which is incorporated herein by reference in its entirety.
[0413] The pharmaceutical compositions of the invention containing
the active ingredient may be in a form suitable for oral use, for
example, as Tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, or syrups or elixirs. Compositions intended for oral
use may be prepared according to any method known to the art for
the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents
and preserving agents in order to provide pharmaceutically elegant
and palatable preparations.
[0414] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0415] The pharmaceutical compositions may be in the form of
sterile injectable aqueous solutions. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. The sterile injectable
preparation may also be a sterile injectable oil-in-water
microemulsion where the active ingredient is dissolved in the oily
phase. For example, the active ingredient may be first dissolved in
a mixture of soybean oil and lecithin. The oil solution then
introduced into a water and glycerol mixture and processed to form
a microemulation.
[0416] The injectable solutions or microemulsions may be introduced
into a patient's blood-stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.RTM. Model 5400 intravenous pump.
[0417] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension for
intramuscular and subcutaneous administration. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above.
[0418] The compounds of Formulae (I)-(VIII) may be administered by
any means suitable for the condition to be treated, which may
depend on the need for site-specific treatment or quantity of drug
to be delivered. Topical administration is generally preferred for
skin-related diseases, and systematic treatment preferred for
cancerous or pre-cancerous conditions, although other modes of
delivery are contemplated. For example, the compounds may be
delivered orally, such as in the form of Tablets, capsules,
granules, powders, or liquid formulations including syrups;
topically, such as in the form of solutions, suspensions, gels or
ointments; sublingually; bucally; parenterally, such as by
subcutaneous, intravenous, intramuscular or intrasternal injection
or infusion techniques (e.g., as sterile injectable aq. or non-aq.
solutions or suspensions); nasally such as by inhalation spray;
topically, such as in the form of a cream or ointment; rectally
such as in the form of suppositories; or liposomally. Dosage unit
formulations containing non-toxic, pharmaceutically acceptable
vehicles or diluents may be administered. The compounds may be
administered in a form suitable for immediate release or extended
release. Immediate release or extended release may be achieved with
suitable pharmaceutical compositions or, particularly in the case
of extended release, with devices such as subcutaneous implants or
osmotic pumps.
[0419] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0420] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release Tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may also be orally
delivered by sublingual and/or buccal administration, e.g., with
molded, compressed, or freeze-dried Tablets. Exemplary compositions
may include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
Gantrez); and agents to control release such as polyacrylic
copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0421] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0422] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0423] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0424] When a compound according to this invention is administered
into a human subject, the daily dosage will normally be determined
by the prescribing physician with the dosage generally varying
according to the age, weight, sex and response of the individual
patient, as well as the severity of the patient's symptoms.
Exemplary dosage amounts for a mammal may include from about 0.05
to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000
mg/kg of body weight of active compound per day, which may be
administered in a single dose or in the form of individual divided
doses, such as from 1 to 4 times per day. It will be understood
that the specific dose level and frequency of dosage for any
particular subject may be varied and will depend upon a variety of
factors, including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
species, age, body weight, general health, sex and diet of the
subject, the mode and time of administration, rate of excretion,
drug combination, and severity of the particular condition.
Preferred subjects for treatment include animals, most preferably
mammalian species such as humans, and domestic animals such as
dogs, cats, horses, and the like. Thus, when the term "patient" is
used herein, this term is intended to include all subjects, most
preferably mammalian species, which are affected by mediation of
protein kinase enzyme levels.
[0425] If formulated as a fixed dose, a combination product can,
for example, utilize a dosage of the compound of Formulae (I)-(III)
within the dosage range described above and the dosage of another
anti-cancer agent/treatment within the approved dosage range for
such known anti-cancer agent/treatment. If a combination product is
inappropriate, the compounds of Formulae (I)-(III) and the other
anti-cancer agent/treatment can, for example, are administered
simultaneously or sequentially. If administered sequentially, the
present invention is not limited to any particular sequence of
administration. For example, compounds of Formulas (I)-(III) can be
administered either prior to, or after, administration of the known
anti-cancer agent or treatment.
Biological Assays
A. CK2 Kinase Assay
[0426] The effectiveness of compounds of the present invention as
inhibitors of protein kinases can be readily tested by assays known
to those skilled in the art. For example, in vitro protein kinase
assays may be conducted with a relevant purified protein kinase and
an appropriate synthetic substrate to determine the inhibitory
activity of the compounds. Assays for inhibition of CK2 by the
instant compounds were performed in 384-well plates with reaction
mixtures containing 10 .mu.M of peptide substrate
(RRRADDSDDDDD-NH.sub.2), [.gamma.-.sup.33P]ATP (10 .mu.Ci) at 25
.mu.M (CK2A1) or 5 .mu.M (CK2A2), 20 mM Hepes (pH 7.4), 100 mM
NaCl, 10 mM MgCl.sub.2, 0.25 mM dithiothreitol, Brij-35 at 0.015%,
and recombinant CK2A1 (10 nM, Invitrogen) or CK2A2 (5 nM, Upstate
Biotechnology). Reaction mixtures were incubated at 30.degree. C.
for 1 hour, and reaction products were captured by binding to
phosphocellulose (P81) filter plates. Incorporation of radioactive
phosphate into the peptide substrate was determined by liquid
scintillation counting. The potency of compounds in inhibiting CK2
is expressed as IC.sub.50, defined as the concentrations of
compounds required to inhibit the enzymatic activity by 50%.
[0427] The inhibitory activity of the instant compounds may also be
measured by recombinant CK2 holoenzyme kinase assays. The assays
were performed in U-bottom 384-well plates. The final assay volume
was 30 .mu.l prepared from 15 .mu.l additions of enzyme and
substrates (fluoresceinated peptide FL-RRRADDSDDDDD-NH2 and ATP)
and test compounds in assay buffer (20 mM HEPES pH 7.4, 10 mM
MgCl.sub.2, 100 mM NaCl, 0.015% Brij35 and 0.25 mM DTT). The
reaction was initiated by the combination of bacterially expressed,
CK2 .alpha./.beta. or CK2 .alpha.'/.beta. holoenzyme with
substrates and test compounds. The reaction was incubated at room
temperature for 60 minutes and terminated by adding 30 .mu.l of 35
mM EDTA to each sample. The reaction mixture was analyzed on the
Caliper LABCHIP.RTM. 3000 (Caliper, Hopkinton, Mass.) by
electrophoretic separation of the fluorescent substrate and
phosphorylated product. Inhibition data were calculated by
comparison to no enzyme control reactions for 100% inhibition and
vehicle-only reactions for 0% inhibition. The final concentration
of reagents in the CK2 .alpha./.beta. assay was 25 .mu.M ATP, 1.5
.mu.M FL-RRRADDSDDDDD-NH2, 50 pM CK2 .alpha./.beta. holoenzyme, and
1.6% DMSO. The final concentration of reagents in the CK2
.alpha.'/.beta. assay was 10 .mu.M ATP, 1.5 .mu.M
FL-RRRADDSDDDDD-NH2, 100 pM CK2 .alpha.'/.beta. holoenzyme, and
1.6% DMSO. Dose response curves were generated to determine the
concentration required inhibiting 50% of kinase activity
(IC.sub.50). Compounds were dissolved at 10 mM in dimethylsulfoxide
(DMSO) and evaluated at eleven concentrations. IC.sub.50 values
were derived by non-linear regression analysis.
B. Cell Proliferation Inhibition Assay
[0428] Compounds were evaluated for their ability to inhibit cell
proliferation, using an assay that measures mitochondrial metabolic
activity that is directly correlated with cell numbers. Cells were
plated at 2000 cells/well in 96-well plates and were cultured for
24 h in RPMI-1640 supplemented with 2% fetal bovine serum, before
test compounds were added. Compounds were diluted in culture medium
such that the final concentration of dimethyl sulfoxide never
exceeded 1%. Following the addition of compounds, the cells were
cultured for an additional 72 h before cell viability was
determined by measuring the conversion of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
dye using the CellTiter96 kit (Promega) or by measuring the
conversion of
[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-
)-2H-tetrazolium (MTS) dye using the CELLTITER 96.RTM. AQueous
(Promega).
[0429] The following compounds were found to have the IC.sub.50
described in Table A when measured in the CK2 kinase assays
described above.
TABLE-US-00001 TABLE A CK2A1 (CK2.alpha./.beta.) Example No.
(IC.sub.50, nM) 1 0.90 2 0.54 3 0.42 4 0.64 5 0.44 6 0.15 7 0.17 8
0.53 9 0.66 10 0.51 11 0.68 12 1.15 13 1.70 14 0.70 15 1.98 16 1.00
17 0.59 18 0.55 19 1.27 20 4.90 21 1.16 22 0.68 23 1.40 24 1.00 25
0.49 26 1.03 27 0.87 28 0.57 29 0.31 30 0.92 31 0.61 32 0.80 33
0.54 34 0.92 35 0.38 36 0.32 37 0.35 38 1.20 39 0.46 40 2.49 41
0.94 42 2.58 43 1.82 44 0.33 45 0.96 46 1.31 47 1.73 48 0.71 49
0.23 50 0.63 51 2.47 52 0.66 53 2.69 54 1.61 55 0.29 56 1.14 57
0.30 58 0.68 59 0.59 60 1.35 61 0.96 62 3.02 63 0.70 64 0.71 65
1.44 66 0.58 67 0.48 68 0.67 69 0.47 70 0.54 71 0.76 72 0.79 73
0.74 74 0.55 75 0.41 76 0.75 77 0.69 78 0.41 79 0.53 80 0.47 81
1.80 82 0.79 83 0.63 84 0.50 85 0.57 86 0.72 87 0.76 88 0.60 89
2.90 90 0.53 91 0.49 92 1.12 93 0.46 94 0.96 95 0.92 96 0.63 97
0.53 98 0.36 99 0.32 100 0.55 101 1.27 102 1.10 103 0.83 104 0.70
105 0.42 106 1.23 107 0.59 108 1.37 109 4.09 110 0.58 111 0.68 112
2.56 113 1.01 114 1.57 115 31.02 116 0.68 117 0.22 118 0.84 119
1.56 120 0.69 121 1.05 122 0.80 123 0.55 124 1.01 125 0.75 126
29.89 127 0.62 128 4.77 129 5.13 130 178.40 131 91.56 132 20.88 133
0.30 134 0.45 135 0.68 136 22.00 137 3.06 138 0.64 139 0.45 140
2.68 141 0.67 142 0.67 143 0.78 144 1.11 145 5.48 146 1.19 147 1.17
148 1.03 149 0.91 150 1.31 151 0.59 152 0.53 153 0.65 154 0.40 155
0.42 156 0.36 157 0.80 158 0.65 159 0.48 160 0.24 161 0.21 162 0.69
163 0.27 164 0.57 165 0.54 166 0.44 167 0.30 168 0.68 169 2.59 170
0.93 171 0.85 172 0.51 173 0.41 174 0.72 175 1.06 176 1.53 177 0.94
178 0.77 179 1.36 180 0.51 181 0.88 182 0.66 183 0.64 184 1.37 185
1.09 186 1.06 187 0.94 188 200.00 189 220.10 190 0.48 191 0.66 192
2.12 193 6.00 194 1.25 195 0.50 196 0.80 197 5.00 198 0.65 199 0.45
200 2.51 201 2.95 202 0.83 203 1.79 204 0.87 205 1.95 206 1.29 207
0.31 208 0.57 209 0.56 210 0.71 211 0.90 212 0.78 213 4.00 214 4.55
215 0.62 216 1.02 217 0.60 218 8.54 219 0.59 220 0.70 221 1.34 222
1.17 223 0.95 224 5.87 225 2.00 226 0.48 227 0.59 228 0.51 229 0.21
230 1.04 231 0.45 232 0.62 233 0.58 234 1.60 235 3.86 236 0.78 237
0.41 238 1.35 239 0.49 240 0.47 241 0.59 242 1.30 243 2.08 244
0.97
245 0.51 246 0.96 247 1.74 248 3.27 249 2.22 250 0.73 251 1.48 252
3.83 253 1.50 254 0.68 255 0.53 256 0.75 257 0.97 258 1.93 259 1.29
260 2.12 261 2.44 262 5.00 263 9.61 264 2.97 265 3.49 266 2.97 267
6.16 268 15.25 269 13.86 270 0.82 271 1.22 272 0.58 273 2.11 274
1.42 275 3.36 276 6.04 277 2.56 278 0.86 279 0.76 280 2.09 281 0.27
282 10.00 283 0.79 284 1.10 285 0.14 286 4.40 287 1.17 288 0.91 289
0.59 290 0.47 291 0.59 292 2.00 293 1.89 294 1.17 295 1.21 296 0.94
297 3.05 298 0.49 299 1.00 300 1.62 301 0.72 302 1.70 303 0.69 304
0.80 305 0.65 306 1.29 307 0.88 308 1.67 309 1.31 310 2.87 311 0.96
312 0.37 313 0.29 314 1.40 315 0.37 316 1.87 317 0.99 318 0.78 319
0.28 320 0.35 321 0.66 322 1.78 323 0.59 324 0.78 325 0.57 326 0.86
327 4.71 328 0.53 329 0.34 330 0.55 331 2.32 332 0.41 333 0.46 334
1.10 335 3.97 336 0.74 337 16.00 338 0.82 339 0.47 340 6.00 341
1.00 342 0.37 343 3.00 344 3.00 345 0.80 346 2.03 347 173.50 348
1.42 349 2.75 350 1.74 351 0.88 352 2.73 353 0.87 354 0.52 355 5.23
356 0.72 357 1.68 358 0.87 359 1.58 360 0.73 361 0.85 362 0.84 363
0.78 364 1.33 365 3.28 366 0.78 367 1.17 368 3.62 369 1.58 370 0.35
371 3.61 372 0.94 373 0.99 374 1.37 375 0.43 376 0.83 377 0.61 378
0.81 379 2.61 380 0.65 381 0.53 382 0.39 383 0.77 384 0.43 385 2.22
386 5.79 387 5.75 388 5.13 389 3.39 390 8.00 391 0.13 392 7.54 393
0.43 394 0.27 395 0.22 396 1.44 397 1.80 398 3.30 399 0.23 400 0.49
401 0.38 402 0.16 403 0.69 404 0.54 405 0.48 406 2.12 407 1.76 408
1.39 409 1.32 410 0.68 411 0.76 412 0.43 413 0.39 414 0.99 415
25.51 416 0.68 417 0.31 418 13.06 419 8.62 420 60.08 421 0.61 422
2.73 423 9.80 424 5.12 425 0.73 426 0.38 427 0.78 428 1.39 429 1.28
430 0.97 431 2.25 432 2.90 433 23.09 434 0.61 435 1.13 436 2.51 437
0.83 438 0.73 439 0.75 440 0.88 441 1.17 442 0.77 443 2.93 444 0.76
445 2.90 446 3.48 447 0.89 448 0.88 449 0.91 450 1.50 451 5.52 452
0.82 453 1.04 454 1.25 455 0.49 456 2.90 457 4.90 458 16.44 459
1.27 460 1.62 461 2.46 462 3.00 463 1.00 464 0.57 465 1.66 466 1.31
467 0.45 468 0.30 469 1.48 470 1.50 471 0.87 472 1.70 473 0.56 474
1.55 475 1.78 476 2.98 477 2.43 478 1.31 479 1.07 480 0.86 481 0.93
482 1.52 483 0.87 484 0.81 485 0.77 486 1.61 487 0.73 488 0.60 489
1.40 490 0.94 491 1.33 492 0.64 493 2.03 494 1.99 495 4.89
496 1.82 497 0.82 498 5.48 499 3.93 500 3.92 501 2.64 502 3.27 503
3.67 504 4.07 505 5.42 506 4.33 507 16.85 508 4.73 509 5.11 510
4.24 511 4.62 512 5.80 513 3.08 514 3.90 515 4.84 516 4.09 517 3.66
518 10.35 519 3.20 520 4.96 521 3.35 522 3.69 523 4.77 524 7.45 525
3.20 526 0.42 527 1.91 528 0.40 529 1.33 530 6.24 531 0.44 532 0.85
533 0.43 534 0.51 535 0.91 536 1.55 537 1.04 538 2.10 539 0.93 540
6.02 541 0.57 542 1.35 543 1.10 544 28.20 545 1.55 546 2.70 547
2.30 548 0.80 549 1.25 550 0.83 551 1.23 552 6.31 553 5.55 554 5.03
555 1.23 556 3.68 557 2.05 558 5.37 559 2.37 560 1.15 561 2.08 562
3.33 563 0.79 564 4.86 565 180.00 566 0.10 567 4.06 568 1.97 569
0.70 570 1.91 571 3.95 572 0.66 573 1.30 574 0.44 575 0.98 576 1.59
577 0.72 578 0.99 579 4.10 580 3.20 581 3.59 582 5.90 583 2.90 584
1.54 585 3.28 586 1.58 587 8.02 588 3.08 589 7.56 590 1.83 591 3.82
592 0.44 593 1.35 594 1.14 595 1.44 596 0.60 597 0.62 598 0.51 599
0.40 600 0.53 601 1.41 602 4.34 603 2.85 604 0.99 605 0.91 606 0.72
607 0.56 608 1.48 609 1.39 610 1.08 611 0.65 612 0.43 613 1.62 614
2.50 615 0.18 616 0.86 617 0.34 618 2.07 619 1.66 620 1.77 621 1.62
622 1.09 623 3.05 624 2.94 625 5.80 626 0.74 627 0.83 628 9.85 629
6.00 630 0.68 631 1.10 632 1.45 633 1.20 634 3.00 635 1.83 636 1.00
637 4.79 638 0.80 639 1.28 640 2.22 641 4.01 642 0.76 643 2.12 644
0.85 645 1.75 646 1.48 647 1.94 648 0.85 649 1.01 650 1.09 651 1.51
652 0.83 653 1.84 654 2.68 655 2.82 656 6.73 657 4.20 658 2.27 659
0.40 660 0.35 661 1.56 662 0.48 663 0.77 664 0.98 665 0.67 666 0.30
667 0.65 668 0.76 669 0.52 670 0.76 671 1.71 672 0.62 673 0.49 674
1.74 675 0.24 676 0.41 677 0.47 678 1.87 679 1.22 680 3.73 681 0.64
682 0.32 683 0.14 684 1.34 685 0.95 686 1.30 687 0.99 688 2.40 689
1.00 690 3.40 691 1.81 692 1.81 693 1.10 694 1.48 695 3.70 696 1.48
697 0.20 698 1.36 699 0.97 700 0.57 701 2.68 702 2.48 703 1.82 704
1.40 705 0.89 706 1.76 707 1.35 708 0.52 709 2.94 710 0.75 711 2.64
712 1.18 713 5.48 714 44.65 715 10.78 716 32.62 717 1.38 718 0.68
719 7.41 720 2.48 721 1.35 722 0.16 723 1.92 724 1.51 725 1.39 726
2.34 727 1.23 728 1.38 729 1.68 730 1.22 731 1.46 732 25.38 733
2.24 734 6.07 735 4.37 736 4.86 737 0.38 738 0.27 739 0.45 740 1.74
741 0.89 742 0.57 743 0.44 744 1.12 745 1.24 746 1.36
747 1.62 748 1.40 749 0.70 750 0.90 751 1.30 752 4.93 753 2.46 754
2.93 755 2.70 756 4.43 757 13.64 758 1.40 759 1.60 760 1.20 761
10.04 762 2.1 763 1.35 764 2.00 765 23.22 766 6.00 767 18.07 768
4.00 769 3.00 770 9.00 771 7.00 772 14.09 773 0.64 774 4.05 775
2.35 776 1.20 777 0.64 778 1.09 779 0.63 780 0.67 781 0.71 782 0.58
783 3.76 784 1.88 785 6.67 786 1.41 787 1.66 788 0.62 789 0.61 790
1.52 791 1.52 792 1.03 793 0.81 794 1.41 795 1.12 796 1.69 797 6.61
798 1.80 799 2.46 800 2.14 801 2.16 802 6.90 803 2.80 804 1.70 805
5.35 806 0.84 807 0.73 808 0.44 809 1.00 810 3.82 811 1.88 812 4.61
813 4.48 814 24.95 815 18.74 816 5.20 817 5.05 818 2.49 819 5.81
820 5.96 821 2.72 822 1.74 823 2.00 824 0.80 825 0.30 826 0.32 827
0.75 828 0.36 829 0.72 830 0.35 831 0.71 832 0.54 833 1.81 834 0.60
835 0.98 836 1.44 837 2.42 838 0.54 839 1.19 840 1.74 841 2.31 842
2.05 843 2.16 844 1.83 845 0.92 846 17.28
[0430] Compounds of the present invention exhibit enhanced CK2
inhibitory activity over the compounds disclosed in WO 2007/038314
and US 2008/0045536. Comparing the data in Table A and Table B,
compounds of the invention herein, e.g., compounds of Formula (I)
(including Formulae (II), (III), (Ma), (IV), (V), (Va), (Vb), (VI),
(VIa), (VII), (VIII)), are surprisingly advantageous for their CK2
enzyme inhibition activity and/or other drugability properties.
TABLE-US-00002 TABLE B CK2A1 CK2A2 Example No. Structure IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) XIII (WO 2007/038314, pages 80-81)
XIII(1) (US 2008/0045536 Page 54) ##STR00043## 1.8 0.331
Methods of Preparation
[0431] The compounds of the present invention may be prepared by
methods such as those illustrated in the following schemes.
Solvents, temperatures, pressures, and other reaction conditions
may readily be selected by one of ordinary skill in the art.
Starting materials are commercially available or readily prepared
by one of ordinary skill in the art. These schemes are illustrative
and are not meant to limit the possible techniques one skilled in
the art may use to manufacture compounds disclosed herein.
Different methods may be evident to those skilled in the art.
Additionally, the various steps in the synthesis may be performed
in an alternate sequence or order to give the desired compound(s).
All documents cited herein are incorporated herein by reference in
their entirety.
[0432] In general, the time taken to complete a reaction procedure
will be judged by the person performing the procedure, preferably
with the aid of information obtained by monitoring the reaction by
methods such as HPLC or TLC. A reaction does not have to go to
completion to be useful to this invention. The methods for the
preparation of various heterocycles used to this invention can be
found in standard organic reference books, for example, Katritzky,
A. R. et al., eds., Comprehensive Heterocyclic Chemistry, The
Structure, Reactions, Synthesis and Uses, of Heterocyclic
Compounds, First Edition, Pergamon Press, New York (1984), and
Katritzky, A. R. et al., eds., Comprehensive Heterocyclic Chemistry
II, A Review of the Literature 1982-1995: The Structure, Reactions,
Synthesis and Uses, of Heterocyclic Compounds, Pergamon Press, New
York (1996).
[0433] Unless otherwise specified, the various substituents of the
compounds are defined in the same manner as the Formula (I)
compound of the invention.
[0434] Compounds of general formula (I) may be prepared by as
described in Scheme A
##STR00044##
[0435] Halogenation of imidazotriazine 1 with electrophilic reagent
such as N-bromosuccinamide in suitable solvent provides
haloimidazotriazine 2. Treatment of 2 with nucleophilic metal
cynide reagent (such as zinc or copper cyanide) with or without
transition metal catalyst would give cyanoimidazotriazine 3.
Nucleophiles (such as amines) add under neat or in appropriate
solvent to provide imidazotriazine 4. See e.g. Journal of The
Chemical Society, Perkins Transactions I, Vol. 20 (1999) at pp.
2929. Treatment of imidazotriazine 4 with a suitable oxidizing
agent (such as MCPBA) in a suitable solvent (such as DMF) provides
imidazotriazine 5. Treatment of imidazotriazine 5 with a
nucleophile (such as an amine) under neat conditions provides
imidazotriazine (I).
[0436] Similarly, compounds of general formula (II) could be
prepared in analogous manner using readily cleavable R.sub.5 (such
as 4-methoxybenzyl or t-butyloxycaronyl) and unmasking it at the
end using suitable conditions.
[0437] Alternatively the compounds of general formula (I) could
also be prepared according to Scheme B. Ester of
imidazole-2-carboxylic acid 1 could be electrophilically aminated,
condensed with ethyl chloroformate and cyclized with ammonia to
afford imidazotriazine diaone 4. Halogenation followed by treatment
with POCl.sub.3 would afford dichloro compound 6. Displacement of
4-Cl with suitable amine followed by cyanation and then subsequent
displacement of Cl atom would yield desired imidazotriazine I.
##STR00045## ##STR00046##
EXAMPLES
[0438] The following Examples illustrate embodiments of the
inventive compounds and starting materials, and are not intended to
limit the scope of the claims. For ease of reference, the following
abbreviations are used herein: [0439] Aq=aqueous [0440]
BOC=tert-butoxycarbonyl [0441] bp=boiling point [0442] Bu=butyl
[0443] DMAP=4-dimethylaminopyridine [0444] DIPEA or
DIEA=N,N-diisopropylethylamine [0445] DME=1,2-dimethoxyethane
[0446] DMF=dimethyl formamide [0447]
EDCI=1-3-dimethylaminopropyl)-3-ethylcarbodiimide [0448] Et=ethyl
[0449] Et.sub.2O=diethyl ether [0450] HOBT=1-hydroxybenzotriazole
[0451] EtOAc=ethyl acetate [0452] EtOH=ethanol [0453] g=gram(s)
[0454] H=hydrogen [0455] l=liter [0456] mCPBA--meta chloro
perbenzoic acid [0457] Me=methyl [0458] MeCN=acetonitrile [0459]
MeOH=methanol [0460] NMP=1-methyl-2-pyrrolidinone [0461] Ph=phenyl
[0462] Pr=propyl [0463] PS=polystyrene [0464] TEA=triethylamine
[0465] TFA=trifluoroacetic acid [0466] mg=milligram(s) [0467] ml or
mL=milliliter [0468] .mu.l=microliter [0469] mmol=millimole [0470]
.mu.mol=micromole [0471] mol=mole [0472] mp=melting point [0473]
room temperature=room temperature [0474] HPLC=high pressure liquid
chromatography [0475] LC/MS=liquid chromatography/mass
spectrometry
Preparation of Intermediates
Intermediate 1
##STR00047##
[0476] tert-butyl 3-bromo-2-chloro-5-cyanophenylcarbamate
[0477] (I1A): To a solution of 4-hydroxybenzonitrile (1 g, 8.39
mmol) in acetic acid (20 mL) was added bromine (1.038 mL, 20.15
mmol) dropwise at room temperature. The mixture was stirred for 30
minutes. The mixture was poured onto ice; the solid was collected
by filtration, rinsed with water and dried to give 2.25 g of
3,5-dibromo-4-hydroxybenzonitrile as white solid product.
[0478] MS (ESI) m/z 277.
[0479] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.77 (2H, s),
6.37 (1H, br. s.)
[0480] (I1B): To a suspension of 3,5-dibromo-4-hydroxybenzonitrile
(2.11 g, 7.62 mmol) in acetic acid (70 mL) was added sodium nitrite
(2.63 g, 38.1 mmol) in small portion, evolving bubbles and bromine
were observed. After addition, the mixture was stirred at
50.degree. C. overnight. Reaction was cooled to room temperature;
water (250 ml) was added and extracted with EtOAc for two times.
The combined extracts were washed with water and brine, dried over
MgSO4 filtered and the filtrate was concentrated to give yellow
orange solid. The solid was treated with small amount of MeOH,
collected by filtration, rinsed with MeOH, dried to afford 1.56 g
of 3-bromo-4-hydroxy-5-nitrobenzonitrile as yellow solid.
[0481] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.26 (2H, s),
8.11 (1H, d, J=1.72 Hz), 8.44 (1H, d, J=1.94 Hz)
[0482] (I1C): DMF (2 mL) was cooled to -20.degree. C. and treated
gradually in dropwise manner with oxalyl chloride (0.216 mL, 2.469
mmol). After 10 min, a solution of
3-bromo-4-hydroxy-5-nitrobenzonitrile (200 mg, 0.823 mmol) in DMF
(2 mL) was added slowly via syringe while maintaining internal
temperature below -10.degree. C. After addition, the mixture was
allowed to warm to room temperature and then heated at 100.degree.
C. for 1.5 h. The reaction mixture was cooled and poured into
ice-water; the solid was collected by filtration, rinsed with water
and dried to give 172 mg of 3-bromo-4-chloro-5-nitrobenzonitrile as
tan solid. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.13 (1H, d,
J=1.76 Hz), 8.02 (1H, d, J=1.98 Hz)
[0483] (I1D): A mixture of 3-bromo-4-chloro-5-nitrobenzonitrile
(0.99 g, 3.79 mmol), iron (1.057 g, 18.93 mmol) and ammonium
chloride (2.025 g, 37.9 mmol) in THF, MeOH and water (60 ml, 1:1:1)
was heated to reflux for 1 h. More iron (0.5 g) and NH.sub.4Cl (2
g) added, heated for another 2 h and then cooled to room
temperature. Filtered off solid, the filtrate was concentrated to
remove the organic solvent. The residue was diluted with water,
extracted with EtOAc twice, dried and concentrated to dryness. The
resulting solid was trituard with EtOAc, solid was filtered off
through celite pad and the filtrate was concentrated to give 0.88 g
of 3-amino-5-bromo-4-chlorobenzonitrile as yellow solid which was
used as such in the next reaction. Intermediate 1: To a solution of
3-amino-5-bromo-4-chlorobenzonitrile (0.88 g, 3.80 mmol) in DCM (25
mL) was added TEA (1.590 mL, 11.41 mmol), BOC.sub.2O (1.059 mL,
4.56 mmol) and DMAP (0.464 g, 3.80 mmol). The mixture was stirred
at room temperature for 16 h. The reaction mixture was
concentrated, the crude product was purified using ISCO silica gel
column (24 g, EtOAc/hexane=0-30%) to give 0.667 g of tert-butyl
3-bromo-2-chloro-5-cyanophenylcarbamate as white solid
[0484] MS (ESI) m/z 331.
[0485] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.62 (1H, d,
J=1.76 Hz), 7.59 (1H, d, J=1.98 Hz), 7.21 (1H, br. s.), 1.57 (9H,
s)
Intermediate 2
##STR00048##
[0486]
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile
[0487] (I2A): A mixture of
7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (6 g,
20.61 mmol), zinc cyanide (1.694 g, 14.42 mmol) and zinc powder
(0.270 g, 4.12 mmol) in DMA (150 mL) in a 350 mL round bottom
pressure flask was degassed by evacuating with vacuum and back
filling with nitrogen three times.
bis(tri-t-butylphosphine)palladium (0) (1.053 g, 2.061 mmol) was
added and the above process was repeated three times. The reaction
mixture was heated at 100.degree. C. for 4 hours. LCMS showed
completion of reaction with small amount of de-bromination
byproduct and mostly product. The reaction mixture was filtered
through a plug of Celite and the filtrate was concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel using an automated ISCO system (330 g column, eluting
with 0-10% ethyl acetate/dichloromethane).
2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(3.35 g) was obtained as a light yellow solid.
[0488] MS (ESI) m/z 238.0.
[0489] 1H NMR (500 MHz, CDCl3) .delta.: 8.05 (s, 1H), 2.73 (s, 3H),
2.66 (s, 3H).
[0490] (I2B): Cyclopropanamine (2.69 mL, 42.4 mmol) was added to a
suspension of
2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(3.35 g, 14.12 mmol) in THF (30 mL) and the resulting mixture was
heated at 50.degree. C. overnight. Solvent was evaporated and the
crude product was purified by flash chromatography on silica gel
using an automated ISCO system (120 g column, eluting with 5-30%
ethyl acetate/hexanes).
4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (3.39 g) was obtained as light yellow solid.
[0491] MS (ESI) m/z 247.1.
[0492] (I2C): Sodium hydride (60% in mineral oil, 0.890 g, 22.02
mmol) was added to a solution of
4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (3.39 g, 13.76 mmol) in DMF (110 mL) at room temperature and
the resulting mixture was stirred for 30 min.
1-(chloromethyl)-4-methoxybenzene (3.05 mL, 22.02 mmol) was added
and the reaction mixture was heated at 80.degree. C. for 2 h. The
reaction solution was quenched with ethyl acetate/sodium
bicarbonate saturated solution. The organic phase was separated,
washed with 10% lithium chloride solution, dried and concentrated.
The crude product was purified by flash chromatography on silica
gel using an automated ISCO system (220 g column, eluting with
5-20% ethyl acetate/hexanes).
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile (4.59 g) was obtained as an off-white
solid.
[0493] MS (ESI) m/z 367.1.
[0494] .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.94 (s, 1H),
7.21 (d, J=5.1 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 3.81 (s, 3H), 2.59
(s, 3H), 1.05 (d, J=5.5 Hz, 2H), 0.86 (br. s., 2H).
[0495] Intermediate 2: mCPBA (7.02 g, 31.3 mmol) was added to a
solution of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2-
,4]triazine-7-carbonitrile (4.59 g, 12.53 mmol) in dichloromethane
(120 mL) at room temperature and the reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was diluted with
dichloromethane and washed with 20% sodium thiosulfate and
saturated sodium bicarbonate. The organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo, the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (220 g column, eluting with 0-10% ethyl
acetate/dichloromethane).
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (4.74 g) was obtained as a white
foaming solid.
[0496] MS (ESI) m/z 399.1.
[0497] 1H NMR shows a mixture of two rotomers in the ration of 1.2
to 1 (500 MHz, chloroform-d) .delta. 8.14 (s, 1H), 7.36 (d, J=8.3
Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.91-6.83 (m, 2H), 5.72 (s, 1H),
5.09 (s, 1H), 3.80 (s, 3H), 3.61-3.53 (m, 0.55H), 3.42 (s, 1.36H),
3.35 (s, 1.64H), 3.07-2.99 (m, 0.45H), 1.24-1.17 (m, 1.1H),
1.16-1.11 (m, 0.9H), 1.03-0.96 (m, 1.1H), 0.96-0.90 (m, 0.9H).
Intermediate 3
##STR00049##
[0498]
4-((4-methoxybenzyl)(2,2,2-trifluoroethyl)amino)-2-(methylsulfonyl)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0499] (I3A): 2,2,2-trifluoroethanamine (1252 mg, 12.64 mmol) was
added to a solution of
2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(I2A), 300 mg, 1.264 mmol) in NMP (3 mL) and the resulting mixture
was heated at 120.degree. C. for 5 h. The reaction mixture was
diluted with ethyl acetate and washed with saturated sodium
bicarbonate. The organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (40 g column, eluting with 0-40% ethyl
acetate/dichloromethane).
2-(methylthio)-4-((2,2,2-trifluoroethyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (363 mg) was obtained as a white solid.
[0500] MS (ESI) m/z 289.0
[0501] (I3B): The compound was prepared from
2-(methylthio)-4-((2,2,2-trifluoroethyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile using a method analogous to that used to prepare
intermediate I2C.
4-((4-methoxybenzyl)(2,2,2-trifluoroethyl)amino)-2-(methylthio)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (405 mg) was obtained as a white
solid.
[0502] MS (ESI) m/z 409.1
[0503] Intermediate 3: The compound was prepared from
4-((4-methoxybenzyl)(2,2,2-trifluoroethyl)amino)-2-(methylthio)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (405 mg, 0.992 mmol) using a
method analogous to that used to prepare intermediate 2.
4-((4-methoxybenzyl)(2,2,2-trifluoroethyl)amino)-2-(methylsulfonyl)imidaz-
o[2,1-f][1,2,4]triazine-7-carbonitrile (395 mg) was obtained as a
white solid.
[0504] MS (ESI) m/z 441.1
Intermediate 4
##STR00050##
[0505] methyl
3-bromo-5-(tert-butoxycarbonylamino)-4-chlorobenzoate
[0506] (I4A): Methyl 4-hydroxy-3-nitrobenzoate (15 g, 76 mmol) was
suspended in acetic acid (152 ml) and then treated with NBS (20.31
g, 114 mmol). The mixture became a homogeneous yellow solution
which was stirred for 2 h. The mixture was quenched with water and
the suspension was filtered. Methyl
3-bromo-4-hydroxy-5-nitrobenzoate (20 g) was obtained as a yellow
solid.
[0507] MS (ESI) m/z 276, 278. (M, M+2)
[0508] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 11.48 (1H, s),
8.80 (1H, d, J=1.98 Hz), 8.53 (1H, d, J=1.98 Hz), 3.95-3.99 (3H,
m).
[0509] (I4B): Anhydrous DMF (242 ml) was cooled to -20.degree. C.
in a dry ice/acetone bath and the internal temperature was
monitored carefully and maintained at or below this temperature.
Neat oxalyl chloride (9.51 ml, 109 mmol) was then slowly added
dropwise via addition funnel and the vessel was properly vented to
allow the escape of gases generated. Following the addition, the
cloudy-white suspension was stirred at -20.degree. C. for 30 min. A
solution containing methyl 3-bromo-4-hydroxy-5-nitrobenzoate (10 g,
36.2 mmol) in DMF (121 ml) was then added slowly, not allowing the
internal temp to exceed -10.degree. C. Following the addition, the
suspension was warmed to room temperature and then heated to
100.degree. C. for 2 h. The reaction was cooled to room temperature
and stirred over weekend. The dark brown solution was poured into
ice water and diluted with EtOAc. The aqueous phase was extracted
twice with EtOAc. The combined organics were washed with water and
brine, and then dried over anhydrous sodium sulfate. Filtration and
concentration afforded methyl 3-bromo-4-chloro-5-nitrobenzoate (10
g) as a yellow solid that was dried in vacuo overnight.
[0510] MS (ESI) m/z 294. (M+H)
[0511] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.50 (1H, d,
J=1.98 Hz), 8.35 (1H, d, J=1.98 Hz), 3.95-4.00 (3H, s)
[0512] (I4C): Fe powder (2.84 g, 50.9 mmol) was added to a solution
of methyl 3-bromo-4-chloro-5-nitrobenzoate (5 g, 16.98 mmol) in
AcOH (29.3 ml). The suspension was heated to 60.degree. C. 1 h. The
vessel was cooled to room temperature and then AcOH was removed via
rotovap. The residue was placed in a 1 L beaker and was carefully
neutralized with saturated sodium bicarbonate. The precipitate was
removed via filtration through Celite and the filtrate was
extracted with EtOAc. The organics were combined, washed with water
and brine, and then dried over sodium sulfate. Filtration and
concentration afforded methyl 3-amino-5-bromo-4-chlorobenzoate
(4.19 g)) as a yellow solid.
[0513] MS (ESI), m/z 264
[0514] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.67 (1H, d,
J=1.76 Hz), 7.38 (1H, d, J=1.76 Hz), 4.33 (2H, br. s.), 3.90 (3H,
s)
[0515] (I4D): Methyl 3-amino-5-bromo-4-chlorobenzoate (2.16 g, 8.17
mmol), BOC2O (3.79 ml, 16.33 mmol) and DMAP (0.100 g, 0.817 mmol)
were dissolved in THF (40.8 ml) at room temperature. TEA (2.85 ml,
20.42 mmol) was added and the reaction was stirred at room
temperature for 5 h. After 5 h, still about 30% starting material
in the reaction. Added another 1.8 g of BOC.sub.2O (3.79 ml, 16.33
mmol) to the reaction mixture and let stir overnight. The reaction
mixture was concentrated and the residue was partitioned between
EtOAc and H2O. The organic layer was washed twice with water and
once with brine, then concentrated and purified by flash column
chromatography, eluting with 0-50% EtOAc/Hex. Methyl
3-(bis(tert-butoxycarbonyl)amino)-5-bromo-4-chlorobenzoate (3.06
g).
[0516] MS (ESI), m/z 350 (M-C6H12O2), loss of Boc and ester
hydrolysis.
[0517] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 8.25 (1H, d, J=1.98
Hz), 7.99 (1H, d, J=1.98 Hz), 3.90 (3H, s), 1.39 (18H, s)
[0518] Intermediate 4: Methyl
3-(bis(tert-butoxycarbonyl)amino)-5-bromo-4-chlorobenzoate (3.06 g,
6.58 mmol) was dissolved in a solution of TFA (1.015 ml, 13.17
mmol) in CH.sub.2Cl.sub.2 (32.9 ml). The reaction was stirred at rt
for 45 min, and then sat. NaHCO.sub.3 solution was added. The
reaction mixture was diluted with a little more CH.sub.2Cl.sub.2
and washed 2.times. with sat. NaHCO3 to remove any residual TFA.
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to provide methyl
3-bromo-5-(tert-butoxycarbonylamino)-4-chlorobenzoate (2.33 g) as a
cream solid.
[0519] MS (ESI), m/z 350 (M-CH3, ester hydrolysis product).
[0520] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.83 (1H, d,
J=1.98 Hz), 8.02 (1H, d, J=1.76 Hz), 7.15 (1H, s), 3.96 (3H, s),
1.58 (9H, s).
Intermediate 5
##STR00051##
[0521] tert-butyl methyl
(5-bromo-4-chloro-1,3-phenylene)bis(4-methoxybenzylcarbamate)
[0522] (I5A): A stirred solution of methyl
3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (1 g, 2.74
mmol, Intermediate 4) in THF (15 mL), MeOH (3.75 mL) and water
(3.75 mL) was treated with LiOH (0.263 g, 10.97 mmol). The reaction
was stirred at rt for 2 h. The reaction mixture was concentrated
and the white residue was suspended in water, then neutralized with
AcOH to pH .about.6-7. The suspension was stirred for 30 min, then
the white solid was collected by filtration and dried in air to
yield 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoic acid
(0.95 g).
[0523] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 8.85 (s., 1H), 8.04
(d, J=1.54 Hz, 1H), 7.91 (d, J=1.76, 1H), 5.74 (s, 1H), 1.46 (s,
9H)
[0524] (I5B): A stirred mixture of
3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoic acid (6 g,
17.11 mmol) in dioxane (342 mL) was treated with TEA (7.16 mL, 51.3
mmol), followed by DPPA (9.18 mL, 42.8 mmol). The reaction was
heated at 70.degree. C. under N2 for 1.5 h, then methanol (15 mL,
17.11 mmol) was added, and the reaction heated at 70.degree. C.
overnight. The reaction was quenched with water, then extracted
(3.times.) with EtOAc. The combined organic extracts were dried
over Mg.sub.2SO.sub.4, filtered and concentrated. The crude
material was purified by flash column chromatography, eluting with
0-17% EtOAc/Hex, to yield tert-butyl methyl
(5-bromo-4-chloro-1,3-phenylene)dicarbamate (2.2 g)
[0525] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.06 (d, J=2.4
Hz, 1H), 7.75 (br. s, 1H), 7.11 (br. s, 1H), 6.63 (br. s., 1H),
3.78 (s, 3H), 1.54 (s, 9H
[0526] Intermediate 5: A stirred solution of tert-butyl methyl
(5-bromo-4-chloro-1,3-phenylene)dicarbamate (710 mg, 1.870 mmol) in
DMF (10 mL) was treated with NaHMDS (3.93 mL, 3.93 mmol) at
0.degree. C. dropwise. The reaction mixture was stirred for 15 min,
and 1-(chloromethyl)-4-methoxybenzene (0.533 mL, 3.93 mmol) was
added. The reaction was stirred for 45 min, then heated at
75.degree. C. for 1.5 h. The reaction was quenched with half
saturated NH.sub.4Cl solution and extracted with EtOAc 3.times..
The organic layers were combined, dried over Mg.sub.2SO.sub.4,
filtered and concentrated. The crude material was purified by flash
column chromatography, eluting with 0%-40% EtOAc/Hex. The desired
fractions were concentrated to yield tert-butyl methyl
(5-bromo-4-chloro-1,3-phenylene)bis(4-methoxybenzylcarbamate)
(953.4 mg).
[0527] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.30 (br. s, 1H),
7.07 (d, J=8.36 Hz, 2H), 7.00 (d, J=8.58 Hz, 2H), 6.84-6.75 (m,
4H), 3.79 (s, 3H), 3.78 (s, 2H), 3.66 (s, 3H), 1.59-1.52 (m, 3H),
1.34 (br. s, 6H)
Intermediate 6
##STR00052##
[0528] Tert-butyl
(7-cyano-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl-
)carbamate
[0529] (I6A):
4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (200 mg, 0.812 mmol, Intermediate 2) and Boc.sub.2O (0.283
mL, 1.218 mmol) were taken up in THF (4 mL) and cooled to 0.degree.
C. LiHMDS (1.218 mL, 1.218 mmol) was added dropwise, and the
reaction was brought to rt. The reaction mixture was stirred for 6
h. An additional 0.5 eq each of Boc.sub.2O and LiHMDS was added and
the reaction was stirred at rt for 1 h. The reaction was quenched
with water and extracted with EtOAc. The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography, eluting with 0-50%
EtOAc/Hex. The fractions were combined to give tert-butyl
(7-cyano-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)car-
bamate (180 mg) as a colorless foam.
[0530] MS (ESI) m/z 369 (M+Na)
[0531] 1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.08 (s, 1H),
3.24-3.12 (m, 1H), 2.66 (s, 3H), 1.47 (s, 9H), 1.08-0.97 (m, 2H),
0.81-0.68 (m, 2H)
[0532] (I6B): Tert-butyl
(7-cyano-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)car-
bamate (180 mg, 0.520 mmol) was taken up in DCM (5 mL) and mCPBA
(291 mg, 1.299 mmol) was added. The reaction was stirred at rt for
2 h. The reaction mixture was diluted with DCM and washed with 20%
Na.sub.2S2O.sub.3 and saturated sodium bicarbonate. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The remaining white solid was purified by flash column
chromatography, eluting with 0-50% EtOAc/Hex. Tert-butyl
(7-cyano-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl-
)carbamate (163 mg) was obtained as a white solid.
[0533] MS (ESI) m/z 401 (M+Na)
[0534] 1H NMR (400 MHz, DMSO-d6) .delta. 8.77 (s, 1H), 3.46 (s,
3H), 3.26-3.19 (m, 1H), 1.45 (s, 9H), 1.06-0.94 (m, 2H), 0.88-0.73
(m, 2H)
[0535] (I6C):
4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (200 mg, 0.812 mmol) and Boc.sub.2O (0.283 mL, 1.218 mmol)
were taken up in THF (4 mL) and cooled to 0.degree. C. LiHMDS
(1.218 mL, 1.218 mmol) was added dropwise, and the reaction was
brought to rt. The reaction mixture was stirred for 6 h. An
additional 0.5 eq each of Boc2O and LiHMDS was added and the
reaction was stirred at rt for 1 h. The reaction was quenched with
water and extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography, eluting with 0-50%
EtOAc/Hex. The fractions were combined to give tert-butyl
(7-cyano-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)car-
bamate (180 mg) as a colorless foam.
[0536] MS (ESI) m/z 369 (M+Na)
[0537] 1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.08 (s, 1H),
3.24-3.12 (m, 1H), 2.66 (s, 3H), 1.47 (s, 9H), 1.08-0.97 (m, 2H),
0.81-0.68 (m, 2H)
[0538] Intermediate 6:
Tert-butyl(7-cyano-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclo-
propyl)carbamate (180 mg, 0.520 mmol) was taken up in DCM (5 mL)
and mCPBA (291 mg, 1.299 mmol) was added. The reaction was stirred
at rt for 2 h. The reaction mixture was diluted with DCM and washed
with 20% Na.sub.2S2O.sub.3 and saturated sodium bicarbonate. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The remaining white solid was purified by flash
column chromatography, eluting with 0-50% EtOAc/Hex. Tert-butyl
(7-cyano-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl-
)carbamate (163 mg) was obtained as a white solid.
[0539] MS (ESI) m/z 401 (M+Na)
[0540] 1H NMR (400 MHz, DMSO-d6) .delta. 8.77 (s, 1H), 3.46 (s,
3H), 3.26-3.19 (m, 1H), 1.45 (s, 9H), 1.06-0.94 (m, 2H), 0.88-0.73
(m, 2H)
Intermediate 7
##STR00053##
[0541]
4-(ethyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[1,2-f][1,-
2,4]triazine-7-carbonitrile
[0542] (I7A): A mixture of
2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (70
mg, 0.295 mmol) and N-(4-methoxybenzyl)ethanamine (180 mg, 1.089
mmol) in dry THF (2 mL) (Aldrich, Sure seal) was treated with DIEA
(0.35 mL, 2.004 mmol). The mixture was heated in microwave at
115.degree. C. for 8 hrs. The reaction mixture was concentrated.
The residue was triturated with cold MeOH. The solid was collected
by filtration, washed with cold MeOH and water (4.times.10 mL),
dried under vacuum to give 98 mg of desired product, which was used
as such in the next step.
[0543] (I7B): mCPBA (343 mg, 1.531 mmol) was added to a solution of
4-(ethyl(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (217 mg, 0.612 mmol) in DCM (5 mL) at room
temperature and the reaction mixture was stirred at rt for 2 h.
LCMS showed completion of reaction. The reaction mixture was
diluted with DCM and washed with 20% Na.sub.2S2O.sub.3 and
saturated sodium bicarbonate. The organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel using an
automated biotage system (40 g column, eluting with 0-10% ethyl
acetate in dichloromethane) to give 235 mg of desired product.
[0544] MS (ESI) m/z 387.3 (M+1).
[0545] 1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.11 (d, J=0.8 Hz,
1H), 7.40 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.97-6.79 (m,
2H), 5.72 (s, 1H), 5.06 (s, 1H), 4.44 (q, J=7.0 Hz, 1H), 4.00-3.83
(m, 1H), 3.82 (d, J=3.5 Hz, 3H), 3.39 (d, J=15.1 Hz, 3H), 1.42-1.23
(m, 3H)
Intermediate 8
##STR00054##
[0546] tert-butyl
(3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate
[0547] (I8A): Methyl
3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (5 g, 13.71
mmol, Intermediate 4) was dissolved in THF (91 mL) at 0.degree. C.
under N.sub.2. Lithium aluminum hydride solution (10 ml, 10.00
mmol, 1 M in THF) was added dropwise. The reaction mixture was
stirred for 2 hours at which point reaction appeared complete by
LC/MS. Water (1.4 mL) was added slowly and resulted in a vigorous
quench. 1 M aq. NaOH soln (1.4 mL) was added dropwise, followed by
a final addition of H2O (4.2 mL). The mixture was stirred
vigorously for 15 minutes and then several scoops of MgSO.sub.4
were added. The reaction was diluted with Et2O, stirred for 1 hour
and then filtered through celite. Concentrated afforded tert-butyl
(3-bromo-2-chloro-5-(hydroxymethyl)phenyl)carbamate (4.08 g).
[0548] 1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.19 (d, J=2.0 Hz,
1H), 7.39 (d, J=2.0 Hz, 1H), 7.14 (br. s., 1H), 4.69 (s, 2H), 1.57
(s, 9H).
[0549] (I8B): tert-Butyl
(3-bromo-2-chloro-5-(hydroxymethyl)phenyl)carbamate (4.08 g, 12.12
mmol) was dissolved in CH.sub.2Cl.sub.2 (60.6 mL) at room
temperature. Dess-Martin Periodinane (5.14 g, 12.12 mmol) was added
and the reaction was stirred at room temperature overnight. The
reaction was complete by TLC, and was diluted with water and
filtered through celite. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.) and the combined organics were dried
over Na.sub.2SO.sub.4 and concentrated. Column chromatography (220
g SiO2, 0 to 10% EtOAc-hexane, gradient elution) afforded the
expected product tert-butyl
(3-bromo-2-chloro-5-formylphenyl)carbamate (2.45 g).
[0550] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.00 (s, 1H),
8.75 (dd, J=1.3, 0.4 Hz, 1H), 7.76-7.44 (m, 2H), 7.13 (br. s., 1H),
1.58 (s, 9H).
[0551] (I8C): tert-Butyl (3-bromo-2-chloro-5-formylphenyl)carbamate
(2.45 g, 7.32 mmol) was dissolved in CH.sub.2Cl.sub.2 (36.6 ml) at
room temperature. DAST (1.451 ml, 10.98 mmol) was added and the
reaction was stirred at room temperature overnight. The reaction
was not complete by TLC and an additional 700 .mu.L of DAST was
added. After 5 hours, a trace of starting material still remained.
Another 350 .mu.L of DAST was added and the reaction stirred
overnight. Sat. aq. NaHCO.sub.3 solution was added and the reaction
was stirred vigorously for 30 minutes. The reaction was filtered
through celite and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organics were dried over
Na.sub.2SO.sub.4 and concentrated. Column chromatography (220 g
SiO.sub.2, 0 to 10% EtOAc-hexane, gradient elution) afforded the
expected product tert-butyl
(3-bromo-2-chloro-5-(difluoromethyl)phenyl)carbamate (1.82 g).
[0552] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.47-8.34 (m,
1H), 7.55-7.42 (m, 1H), 7.20 (br. s., 1H), 6.78-6.41 (m, 1H), 1.57
(s, 9H).
[0553] Intermediate 8: tert-Butyl
(3-bromo-2-chloro-5-(difluoromethyl)phenyl)carbamate (1.82 g, 5.10
mmol) was dissolved in DMF (11.1. mL) at room temperature. NaHMDS
(6.12 mL, 6.12 mmol) was added dropwise and the reaction was
stirred for 30 minutes before the addition of 4-methoxybenzyl
chloride (0.904 mL, 6.64 mmol) and stirring overnight. The reaction
mixture was diluted with EtOAc causing a ppt to form. 10% aq. LiCl
solution was added and the two layers became clear with stirring.
The mixture was poured into a separatory funnel and the organic
layer was washed with an extra equivalent of 10% aq. LiCl solution.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Column chromatography (220 g SiO.sub.2, 0 to 8% EtOAc-hexane,
gradient elution) afforded the expected product tert-butyl
(3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate
(2.29 g).
Intermediate 9
##STR00055##
[0554]
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-f][1,2,4]-
triazine-7-carbonitrile
[0555] (I9A): Ammonium chloride (121 g, 2355 mmol) and MTBE (4.5
lit) were charged into 20 lit. RBF at room temperature, IT was
cooled to -20.degree. C. and then ammonium hydroxide saturated
solution 2 lit. was added at -20.degree. C. and Sodium hypochlorite
was added at -20.degree. C. for 1 hr. After addition it was stirred
for 30 min at -20.degree. C. MTBE layer was separated and washed
with 200 ml of brine, separated MTBE layer dried with sodium
sulphate. 15.degree. C. and used as such in next reaction
[0556] (I9B): NaH (34.2 g, 856 mmol) charged into 20 lit. round
bottom flask at room temperature under N2 atmosphere. It was cooled
to 0.degree. C. and DMF added slowly for 15 min at 0.degree. C.
under N2 atmosphere. After addition the suspension was stirred for
5 min and then ethyl 1H-imidazole-2-carboxylate (100 g, 714 mmol)
dissolved in 1 lit. of DMF was added slowly for 30 min at 0.degree.
C. After addition the reaction mixture was stirred for 2 hrs at
room temperature. Chloramine solution in MTBE (I9A) layer charged
at -20.degree. C. After addition it was bring to 15.degree. C. the
mixture was stirred for 2 hrs at 15.degree. C. under/N2 atmosphere.
The reaction mixture was cooled 0.degree. C. and quenched with 1.5
Lit of 10% Na.sub.2S.sub.2O.sub.3, separated the organic layer and
Then aqueous layer was back extracted with ethyl acetate (3
lit.times.4). Combined organic layer was washed with 2.times.300 ml
of brine, separated the organic layer and dried with anhydrous
sodium sulfate, it was concentrated to remove the MTBE and ethyl
acetate, Crude was taken as such along with DMF for next step.
[0557] MS(ESI) m/z: 146
[0558] (I9C): In 10 lit. round bottom flask charged ethyl
1-amino-1H-imidazole-2-carboxylate (70 g, 451 mmol) along with DMF
and DCM (1200 ml) was added and cooled to 10-15.degree. C. Then
pyridine was added (35 ml) at single lot. Followed by slow addition
of ethyl chloroformate (30 ml) and stirred at same temperature for
1.5 hrs. After 1.5 hrs additional pyridine (25 ml) and ethyl
chloroformate (20 ml) was added. The reaction mixture was stirred
for additional 30 minutes. The reaction mixture was concentrated
under high vacuum and the crude residue was diluted with ethyl
acetate and given saturated aqueous citric acid (250 ml) washing.
The organic layer was separated. The citric acid layer was
extracted with EtOAc (3.times.500 ml). All organic layers combined
and washed with brine (2.times.150 ml), dried with sodium sulphate
and concentrated to get the syrupy gel. The syrupy gel was
triturated with ether-hexane mixture to give 65 g of ethyl
1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate as pale yellow
solid.
[0559] MS(ESI) m/z: 228
[0560] (I9D): ethyl
1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate (120 g, 528
mmol) was dissolved in 800 ml of 2-propanol purged the ammonia gas
for 1 hr. to increase the volume up to three times approximately at
-50.degree. C. Then reaction mixture was charged into an autoclave
with 2 kg of ice. It was heated at 120.degree. C. for 20 hrs while
maintaining 8-10 kg pressure. The reaction mixture was cooled and
concentrated under high vacuum to remove the water and 2-propanol
The crude solid was suspended in minimum amount of methanol and
stirred for 5 min and filtered to give 59 g of imidazo[2,1
f][1,2,4]triazine-2,4(1H,3H)-dione as off-white solid.
[0561] (I9E): In a 3 liter 4-necked round bottom flask was taken
imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (30 g, 197 mmol) and
water (50 mL). The mixture was cooled to 10 to 15.degree. C.
N-bromosuccinimide (24.57 g, 138 mmol) was added portion wise while
maintaining the temperature. After completion of addition, mixture
was stirred at room temperature for 1 hr. Solid was filtered and
washed with water (100 ml). The filtrate was extracted with
dichloromethane (2.times.150 ml). The aqueous layer was
concentrated to dryness. Compound was taken in 800 ml Solid was
taken in 800 ml of methanol and filtered. 35 g of the solid was
taken in 700 ml of water and heated to 80.degree. C. for 1 hour and
filtered in hot condition using sintered funnel. Allowed to bring
to room temperature slowly. Precipated solid was filtered to afford
f][1,2,4]triazine-2,4(1H,3H)-dione.
[0562] MS(ESI) m/z: 231
[0563] (I9F): Phosphoryl trichloride (200 mL, 2178 mmol) was added
to a mixture of
7-bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (20 g, 87
mmol) and triethylamine hydrochloride (24 g, 174 mmol) in 500 ml
pressure tube. The reaction was heated to 110.degree. C. for 24
hrs. The reaction mixture was cooled to room temperature and
concentrated using high vacuum pump. The residue was suspended in
toluene and azotroped with toluene (3.times.250 ml). The residue
was taken in a cooled mixture of 1000 ml of ethyl acetate and 500
ml of saturated sodium bicarbonate solution. The organic layer was
separated. Aqueous layer was extracted with ethyl acetate
(3.times.300 ml). Combined organic layer was washed with aqueous
sodium bicarbonate solution (2.times.150 ml) and 100 ml of brine
solution. The organic layer was dried over sodium sulphate and
concentrated to give 51 g of
7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine.
[0564] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.99 (s, 1H)
[0565] Intermediate 9: The title intermediate was prepared in
similar manner as Intermediate 10 from I9F.
Intermediate 10
##STR00056##
[0566]
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile
[0567] (I10A): A solution of
7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (Intermediate
I9F)(10 g, 37.3 mmol) in anhydrous THF (300 ml) was treated with
N-(4-methoxybenzyl)ethanamine (8.01 ml, 46.7 mmol), resulting in
the immediate precipitation of a solid. The reaction was stirred
for 1 hour; the mixture was concentrated in vacuo. To the residue
was added EtOAc (100 ml) and the mixture stirred 10 min. The salts
were filtered off and the filtrate was washed with 0.5M citric
acid, sat. NaHCO.sub.3, water and brine. The solution was dried
over Na.sub.2SO.sub.4 and solvents removed to afford
7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin--
4-amine (15.8 g).
[0568] MS (ESI): m/z 398
[0569] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.80 (d, J=17.5
Hz, 1H), 7.37-7.31 (m, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.90 (dd,
J=12.3, 8.8 Hz, 2H), 5.67 (s, 1H), 4.93 (s, 1H), 4.39-4.22 (m, 1H),
3.74 (d, J=4.3 Hz, 3H), 3.67-3.54 (m, 1H), 1.27-1.09 (m, 3H)
[0570] Intermediate 10: To an oven dried 500 ml round bottom flask
was added
7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]tr-
iazin-4-amine (12.5 g, 31.5 mmol) and copper(I) cyanide (9.0 g, 100
mmol). The flask was caped under nitrogen and NMP (250 mL) was
added. The mixture stirred 5 min at 25.degree. C. and the flask was
evacuated and back-filled with nitrogen 3.times.. The reaction
stirred at 135.degree. C. (oil bath) 21 hr. The reaction cooled to
25.degree. C., diluted with ethyl acetate (500 ml) and filter
through celite bed. The bed was washed with EtOAc 3.times.100 ml
and the filtrate washed with water 1.times.300 ml and brine
3.times.150 ml. The organics dried with sodium sulphate and remove
solvent. The material was crystallized from IPA and filtered to
afford
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (11 g).
[0571] MS (ESI): m/z 343
[0572] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.41 (d, J=16.2
Hz, 1H), 7.42-7.27 (m, 2H), 6.97-6.85 (m, 2H), 5.66 (s, 1H), 4.95
(s, 1H), 4.33-4.23 (m, 1H), 3.74 (d, J=3.5 Hz, 3H), 3.62 (d, J=7.0
Hz, 1H), 1.30-1.10 (m, 3H)
Intermediate 11
##STR00057##
[0573]
2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl-
(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0574] (I11A): Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate
(Intermediate 1)(4.5 g, 13.57 mmol), Pd.sub.2dba.sub.3 (0.746 g,
0.814 mmol), BINAP (0.676 g, 1.086 mmol) and Cs.sub.2CO.sub.3 (8.84
g, 27.1 mmol) were suspended in toluene (12.0 mL) at room
temperature. Tert-butyl piperazine-1-carboxylate (3.29 g, 17.64
mmol) was added and the reaction was degassed and purged with
Argon, degassed for 6 times. The reaction mixture was heated at
105.degree. C. for overnight. On completion of the reaction, the
reaction mixture was cooled to room temperature, diluted with ethyl
acetate, filtered through celite and concentrated. The Crude
material was purified by column chromatography (ISCO), using 0-10%
ethyl acetate-hexane as eluent. Pure fractions were concentrated to
obtain tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperazine-1-car-
boxylate (3.0 g) as an off-white solid.
[0575] MS (ESI) m/z 437.2
[0576] (I11B): To the stirred solution of tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperazine-1-car-
boxylate (2.0 g, 4.58 mmol) in dichloromethane (40 mL) was added
trifluoroacetic acid (8.89 mL, 115 mmol) slowly drop wise at room
temperature, stirred it for 3 hours at room temperature. On
completion of the reaction, the reaction mixture was diluted with
methylene chloride (300 mL), cooled it to 0.degree. C., basified
with ammonia solution and extracted twice, the organic layer was
washed with brine, dried over anhydrous sodium sulfate and
concentrated. The crude material was washed with diethyl ether
several times and dried under vacuum to get
3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g) as a brown
color solid.
[0577] MS (ESI) m/z 237.5
[0578] (I11C): To the stirred solution of
3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g, 4.22 mmol)
in dichloromethane (10 mL) was added Boc.sub.2O (0.981 mL, 4.22
mmol) at 0.degree. C., drop wise over a period of 10 minutes
followed by triethylamine (0.883 mL, 6.34 mmol). The reaction
mixture was allowed to warm to room temperature, stirred it for 1
hour. The reaction mixture was diluted with methylene chloride (100
mL), washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and
concentrated at 45.degree. C. to get tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g)
as a brown solid. The crude material was washed with diethyl ether
four times and dried under vacuum to get tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g)
as an off-white solid.
[0579] MS (ESI) m/z 335.1
[0580] (I11D): To the stirred solution of tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.0 g,
2.97 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (Intermediate 9)(1.16 g, 3.27 mmol), in
dry Dioxane (35 mL), added Cs.sub.2CO.sub.3 (1.64 g, 5.03 mmol) and
degassed for 10 minutes. added 1,1'-Bis(diphenylphosphino)ferrocene
(115 mg, 0.205 mmol), and
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (172 mg, 0.297
mmol) followed by addition of Pd(OAc).sub.2 (220 mg, 0.980 mmol),
reaction mixture degassed and purged with argon for 10 minutes,
reaction placed on pre-heated oil bath at 100.degree. C. for 4
hour. On completion of the reaction, the reaction mixture was
cooled to room temperature, filtered through celite washed with
ethyl acetate (20 mL), organic layer concentrated to get dark brown
semi solid. The solid was purified by Combiflash using 12 g Redisep
column, using 0-10% methanol-chloroform as eluent. Pure fractions
were concentrated to get off-white solid (1.3 g). This solid was
dissolved in tetrahydrofuran (25 mL) added methanol for
crystallization to get off-white solid, filtered the solid and
dried under vacuum to get tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazine-1-carboxylate
(900 mg) as an off-white solid.
[0581] MS (ESI) m/z 655.2
[0582] Intermediate 11: To the stirred solution of tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazine-1-carboxylate
(3.5 g, 5.34 mmol) in dry dichloromethane (60 mL) was added
2,6-lutidine (1.867 mL, 16.03 mmol), followed by addition of
trimethylsilyl triflate (2.90 mL, 16.03 mmol) at room temperature.
The reaction mixture stirred at room temperature for 1 hour. On
completion of the reaction, the reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
organic layer was separated and aqueous layer was extracted with
dichloromethane twice, dried over sodium sulfate, concentrated
under reduced pressure to get (4.5 g) off-white solid. This solid
was washed with n-Hexane and diethyl ether twice (50 mL) to remove
2,6-lutidine to get
2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (2.9
g) as off-white solid.
[0583] MS (ESI) m/z 555.2
Intermediate 12
##STR00058##
[0584]
2-((3-(4-Aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cycl-
opropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0585] (I12A): A round bottom flask was charged with tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (5.79 g, 17.48 mmol),
tert-butyl piperidin-4-ylcarbamate (3.5 g, 17.48 mmol), cesium
carbonate (11.4 g, 35 mmol), Pd.sub.2(dba).sub.3 (1.600 g, 1.748
mmol) and BINAP (1.088 g, 1.748 mmol) in toluene (58.3 ml). The
flask was evacuated and purged with nitrogen (4.times.) and heated
at 100.degree. C. overnight. The reaction mixture was cooled to
room temperature, diluted with methanol and vacuum filtered through
a pad of Celite. The filtrate was concentrated in vacuo. The crude
residue was purified by column chromatography on the ISCO system
(120 g, 0-100% EtOAc/CH.sub.2Cl.sub.2) to provide I12A (4.316 g) as
a yellow solid.
[0586] MS (ESI) m/z 451.1
[0587] (I12B): To a round bottom flask charged with I12A (4.36 g,
9.67 mmol) in dichloromethane (51.6 ml) was added TFA (12.89 ml).
The reaction mixture was stirred at room temperature 4 h. The
reaction mixture was concentrated in vacuo. Toluene was added to
the crude material and it was concentrated in vacuo (3.times.). The
product was left on the vacuum overnight and used as is in the next
reaction. To a round bottom flask charged with
3-amino-5-(4-aminopiperidin-1-yl)-4-chlorobenzonitrile (2.425 g,
9.67 mmol) in dichloromethane (97 ml) was added triethylamine (6.74
ml, 48.4 mmol) and Boc.sub.2O (3.37 ml, 14.51 mmol). The reaction
mixture was stirred at room temperature for 2 h. The reaction
mixture was diluted with dichloromethane and poured into a
separatory funnel containing saturated aqueous sodium bicarbonate.
The aqueous layer was extracted with dichloromethane. The combined
organics were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. Material was taken up
in a minimal amount of dichloromethane and ether. After sitting for
1 h, the solid was isolated by filtration. The filtrate contained
additional product and was purified by column chromatography on the
ISCO system (80 g, 0-20% EtOAc/CH.sub.2Cl.sub.2). tert-Butyl
(1-(3-amino-2-chloro-5-cyanophenyl)piperidin-4-yl)carbamate (2.82
g).
[0588] MS (ESI) m/z 351.1
[0589] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.74 (d, J=1.8
Hz, 1H), 6.69 (d, J=1.8 Hz, 1H), 4.29 (s, 2H), 3.64 (br. s., 1H),
3.29 (d, J=12.3 Hz, 2H), 2.75 (t, J=10.8 Hz, 2H), 2.14-2.02 (m,
2H), 1.69-1.57 (m, 2H), 1.47 (s, 9H)
[0590] (I12C):
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9, 0.912 g, 2.57 mmol), tert-butyl
(1-(3-amino-2-chloro-5-cyanophenyl)piperidin-4-yl)carbamate (0.902
g, 2.57 mmol), Pd(OAc).sub.2 (0.173 g, 0.771 mmol), DPPF (0.143 g,
0.257 mmol), Xantphos (0.149 g, 0.257 mmol), and cesium carbonate
(1.675 g, 5.14 mmol) were combined in a round bottom flask and
dioxane (17.14 ml) was added. The flask was evacuated and
backfilled with nitrogen (3.times.), then heated at 100.degree. C.
for 1 h. The reaction mixture was filtered through Celite, rinsing
with EtOAc. The organic layer was concentrated and the material was
purified by column chromatography on the ISCO Companion (80 g,
0-100% EtOAc/Hex). tert-Butyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate
(1.14 g) was obtained as a yellow foam.
[0591] MS (ESI) m/z 669.1 (M+H)
[0592] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.94 (s, 1H),
7.19 (d, J=8.6 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.85 (d, J=8.6 Hz,
2H), 4.51 (br. s., 1H), 3.79 (s, 3H), 3.71 (s, 2H), 3.66 (br. s.,
1H), 3.29 (d, J=11.4 Hz, 2H), 2.80 (t, J=10.7 Hz, 2H), 2.10 (d,
J=11.0 Hz, 2H), 1.71-1.59 (m, 3H), 1.48 (s, 9H), 1.14 (br. s., 2H),
0.95-0.86 (m, 2H)
[0593] Intermediate 12: To a round bottom flask charged with
tert-butyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate
(I12C) (0.517 g, 0.773 mmol) in dichloromethane (5.15 ml) was added
anisole (1.688 ml, 15.45 mmol), followed by the slow addition of
trifluoroacetic acid (2.381 ml, 30.9 mmol). The reaction mixture
was stirred at room temperature 2 d. The reaction mixture was
warmed to 45.degree. C. for 1 h. The reaction mixture was cooled to
room temperature and concentrated in vacuo. After cooling to room
temperature, 25 mL 2 N ammonia/methanol was added and a white solid
crashed out of solution. The slurry was stirred for 30 min and the
solid was isolated by vacuum filtration washing with cold methanol.
2-((3-(4-Aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.1563 g) was
isolated as a white solid. Material used as is in subsequent
transformations.
[0594] MS (ESI) m/z 449.1
Intermediate 13
##STR00059##
[0595]
2-((2-Chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclop-
ropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0596] (I13A): A round bottom flask was charged with tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1)(5.39 g,
16.25 mmol), 4-((tert-butyldimethylsilyl)oxy)piperdine (3.5 g,
16.25 mmol), cesium carbonate (10.5 g, 32.5 mmol),
Pd.sub.2(dba).sub.3 (1.488 g, 1.625 mmol) and BINAP (1.012 g, 1.625
mmol) in toluene (54.2 ml). The flask was evacuated and purged with
nitrogen (4.times.) and heated at 100.degree. C. 2 d. After cooling
to room temperature, the reaction mixture was diluted with ethyl
acetate and vacuum filtered through a pad of Celite. The filtrate
was concentrated in vacuo. The crude residue was purified by column
chromatography on the ISCO system (330 g, 60-95%
CH.sub.2Cl.sub.2/Hex) to provide tert-butyl
(3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanopheny-
l)carbamate (3.27 g) as a yellow solid.
[0597] MS (ESI) m/z 466.1
[0598] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.27 (d, J=1.5
Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 3.92 (dt, J=7.0, 3.7 Hz, 1H),
3.24-3.14 (m, 2H), 2.83 (ddd, J=11.3, 7.9, 3.1 Hz, 2H), 1.98-1.88
(m, 2H), 1.80-1.68 (m, 2H), 1.55 (s, 9H), 0.93 (s, 9H), 0.09 (s,
6H)
[0599] (I13B): To a round bottom flask charged with tert-butyl
(3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanopheny-
l)carbamate (I13A) (3.27 g, 7.02 mmol) in dichloromethane (35.1 ml)
and cooled to 0.degree. C. was added 2,6-lutidine (2.451 ml, 21.05
mmol). Trimethylsilyl trifluoromethanesulfonate (3.80 ml, 21.05
mmol) was added drop wise over 5 min. After 1 h, the reaction
mixture was quenched by the addition of saturated aqueous sodium
bicarbonate and dichloromethane. The mixture was transferred to a
separatory funnel and the aqueous layer was extracted with
dichloromethane (3.times.). The combined organics were washed with
brine, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The crude residue was purified by column
chromatography on the ISCO system (120 g, 0-50%
EtOAc/CH.sub.2Cl.sub.2).
3-amino-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzon-
itrile (1.892 g) was isolated as a sticky yellow oil.
[0600] MS (ESI) m/z 366.1
[0601] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.72 (s, 2H),
4.28 (s, 2H), 3.95-3.85 (m, 1H), 3.20 (ddd, J=11.2, 7.5, 3.3 Hz,
2H), 2.83 (ddd, J=11.3, 7.9, 3.2 Hz, 2H), 1.98-1.86 (m, 2H),
1.80-1.68 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H)
[0602] (I13C):
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 1) (0.646 g, 1.820 mmol),
3-amino-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzon-
itrile (I13B) (0.666 g, 1.820 mmol), Pd(OAc).sub.2 (0.123 g, 0.546
mmol), DPPF (0.101 g, 0.182 mmol), Xantphos (0.105 g, 0.182 mmol),
and cesium carbonate (1.186 g, 3.64 mmol) were combined in a round
bottom flask and dioxane (12.13 ml) was added. The flask was
evacuated and backfilled with nitrogen (3.times.), then heated at
100.degree. C. 10 h. The reaction mixture was diluted with ethyl
acetate and vacuum filtered through a pad of Celite. The filtrate
was concentrated in vacuo and the crude material purified by column
chromatography on the ISCO system (40 g, 0-100% EtOAc/Hex).
2-((3-(4-((tert-Butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanoph-
enyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tria-
zine-7-carbonitrile (0.9309 g) was isolated as a dark yellow
solid.
[0603] MS (ESI) m/z 684.1
[0604] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.93 (s, 1H),
7.19 (d, J=8.1 Hz, 2H), 6.99 (d, J=2.0 Hz, 1H), 6.85 (d, J=8.6 Hz,
2H), 3.93 (br. s., 1H), 3.79 (s, 3H), 3.71 (s, 2H), 3.21 (d, J=7.5
Hz, 2H), 2.88 (d, J=8.1 Hz, 2H), 2.00-1.89 (m, 2H), 1.77 (br. s.,
2H), 1.14 (br. s., 2H), 0.98-0.86 (m, 11H), 0.10 (s, 6H)
[0605] (I13D): To a round bottom flask charged with
2-((3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanoph-
enyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tria-
zine-7-carbonitrile (I13C) (1.446 g, 2.113 mmol) in tetrahydrofuran
(21.13 ml) and cooled to 0.degree. C. was added TBAF (4.23 ml, 4.23
mmol). The reaction mixture was stirred at room temperature 2 d.
The reaction mixture was poured into a separatory funnel containing
saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous
layer was extracted with ethyl acetate (3.times.). The combined
organics were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The crude residue was
taken up in dichloromethane. A white precipitate was isolated by
filtration. The filtrate was purified by column chromatography on
the ISCO system (40 g, 0-50% EtOAc/CH2Cl2). The precipitate was
combined with the column isolate to provide
2-((2-chloro-5-cyano-3-(4-hydroxypiperidin-1-yl)phenyl)amino)-4-(cyclopro-
pyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(0.816 g) as a white solid.
[0606] MS (ESI) m/z 570.0
[0607] Intermediate 13: To a round bottom flask charged with
2-((2-chloro-5-cyano-3-(4-hydroxypiperidin-1-yl)phenyl)amino)-4-(cyclopro-
pyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(0.27 g, 0.474 mmol) in wet dichloromethane (3.16 ml) was added
Dess-Martin periodinate (0.402 g, 0.947 mmol). The reaction mixture
was stirred at room temperature 2.5 h. The reaction mixture was
diluted with dichloromethane and quenched by the addition of sodium
thiosulfate doped saturated aqueous sodium bicarbonate (25 g/100
mL). The mixture was stirred until 2 clear layers were visible. The
mixture was transferred to a separatory funnel and the aqueous
layer was extracted with dichloromethane (3.times.). The combined
organics were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo.
2-((2-Chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(0.2465 g) was isolated as a yellow solid.
[0608] MS (ESI) m/z 568.1
Intermediate 14
##STR00060##
[0609] tert-butyl (3-bromo-5-cyano-2-fluorophenyl)carbamate
[0610] (I14A): 4-fluorobenzonitrile (4.35 g, 35.9 mmol) was
dissolved in sulfuric acid (40 ml, 750 mmol). The solution was
cooled to 0.degree. C. NBS (13.56 g, 75 mmol) was added. The
reaction mixture was allowed to slowly warm to room temperature,
then stirred for 3 days at room temperature. The reaction mixture
was poured onto ice. The slurry was diluted with ice cold water to
a total volume of .about.500 ml. The colorless precipitate was
collected by filtration. Solids were washed with water, then aq.
NaHCO3 solution until the run-off was pH neutral, then washed with
water again, and then dried in an air stream over the weekend (2.5
days). 3,5-dibromo-4-fluorobenzamide (9.85 g) was obtained.
Estimated purity .about.60%. The crude product contains some
tri-bromo-byproduct and a regioisomeric dibromo-compound and was
used in the next reaction without further purification.
[0611] MS(ESI) m/z 294/296/298 (with 2 Br isotope pattern),
[0612] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.21 (d,
J.sub.HF=6 Hz, 2H), 8.18 (bs, 1H), 7.70 (bs, 1H).
[0613] .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -97.6 (t,
J.sub.HF.about.6 Hz).
[0614] (I14B): Phosphoryl trichloride (8.0 ml, 86 mmol) was added
to a suspension of 3,5-dibromo-4-fluorobenzamide (11.27 g, crude,
.about.22.7 mmol) in acetonitrile (400 ml) at room temperature. The
reaction mixture was heated to reflux for 30 minutes. Additional
phosphoryl trichloride (8.0 ml, 86 mmol) was added and the mixture
heated to reflux for an additional hour, then stirred at room
temperature overnight. A precipitate had formed and was removed by
filtration. (The product is well soluble in acetonitrile) The
reaction mixture was evaporated to dryness, and then partitioned
between EtOAc and aq. NaHCO3 solution. The organic layer was washed
one more time with aq. NaHCO3 solution, once with brine, then dried
over MgSO4, filtered and evaporated to dryness. Purification by
column chromatography on silica (gradient 100% hexanes to 25% DCM
in hexanes). 3,5-dibromo-4-fluorobenzonitrile (7.5 g) was obtained.
The material is (by 1H NMR and 19F NMR) a 76:17:7 mixture of
3,5-dibromo-4-fluorobenzonitrile (desired product),
2,3,5-tribromo-4-fluorobenzonitrile (over-bromination) and
2,5-dibromo-4-fluorobenzonitrile (wrong regio-isomer). The material
was used without further purification in the next reaction.
[0615] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.41 (d,
J.sub.HF=6 Hz, 2H).
[0616] .sup.19F NMR (400 MHz, DMSO-d.sub.6) .delta. -91.7 (t,
J.sub.HF.about.6 Hz).
[0617] Intermediate 14: A 500 ml round bottom flask vial was loaded
with 3,5-dibromo-4-fluorobenzonitrile (5.7 g, 15.53 mmol) (76%
pure, rest di-bromo-regioisomer and tribromo-analog), tert-butyl
carbamate (2.63 g, 22.45 mmol) palladium(ii) acetate (177 mg, 0.788
mmol), XANTPHOS (1.14 g, 1.970 mmol) and cesium carbonate (19.3 g,
59.2 mmol). The flask was evacuated and back-filled with nitrogen 2
times. 1,4-Dioxane (200 ml) was added and the flask evacuated and
back-filled with nitrogen 2 times. The reaction mixture was heated
(with vigorous stirring) to 90.degree. C. for 15 hours in an oil
bath. The reaction mixture was cooled to room temperature, filtered
through a layer of Celite, evaporated and purified by column
chromatography on silica. (750 g cartridge, gradient from 100%
hexanes to 20% EtOAc in hexanes, product elutes at .about.17 to 21
column volumes). tert-butyl
(3-bromo-5-cyano-2-fluorophenyl)carbamate (2.93 g) was
isolated.
[0618] MS(ESI) m/Z 315/317
[0619] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.65 (bs, 1H),
8.16 (dd, J=6.6, 1.6 Hz, 1H), 8.03 (dd, J=6.0, 2.0 Hz, 1H), 1.49
(s, 9H).
Example 1
##STR00061##
[0620]
2-((2-chloro-5-cyano-3-(4-methyl-1-piperazinyl)phenyl)amino)-4-(cyc-
lopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0621] (1A): A mixture of tert-butyl
3-bromo-2-chloro-5-cyanophenylcarbamate (Intermediate 1) (300 mg,
0.905 mmol), 1-methylpiperazine (0.110 mL, 0.995 mmol),
Pd(OAc).sub.2 (20.31 mg, 0.090 mmol), racemic BINAP (56.3 mg, 0.090
mmol) and Cs.sub.2CO.sub.3 (590 mg, 1.809 mmol) in Toluene (5 mL)
was purged with bubbling N.sub.2 for 2 min. The mixture was then
heated at 110.degree. C. for overnight. Reaction mixture was cooled
to room temperature, diluted with EtOAc, washed with water and
brine, dried over MgSO4 and concentrated. The crude was purified by
ISCO (24 g, MeOH/DCM=0-4.5%) to give 136 mg of
-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenylcarbamate as yellow
oil.
[0622] MS (ESI) m/z 351.
[0623] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.32 (1H, d,
J=1.76 Hz), 7.20 (1H, s), 6.98-7.08 (1H, m), 3.07 (4H, t, J=4.40
Hz), 2.63 (4H, br. s.), 2.39 (3H, s), 1.57 (9H, s)
[0624] (1B): To a solution of tert-butyl
2-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenylcarbamate (135 mg,
0.385 mmol) in DCM (1.4 mL) was added TFA (0.6 mL, 3.89 mmol). The
mixture was stirred at reaction mixture. The solvent was evaporated
under vacuum, the residue was dissolved in EtOAc, washed with small
amount of sat NaHCO.sub.3, and brine, dried over MgSO.sub.4,
filtered, concentrated, and the residue was purified by ISCO (12 g,
EtOAc/DCM=0-60%) to give 82 mg of
3-amino-4-chloro-5-(4-methylpiperazin-1-yl)benzonitrile
[0625] MS (ESI) m/z 251.
[0626] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 6.85 (1H, d, J=1.98
Hz), 6.70 (1H, d, J=1.98 Hz), 5.80 (2H, s), 3.31 (3H, s), 2.90-2.99
(4H, m), 2.23-2.30 (4H, m)
[0627] (1C): A mixture of
2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (5.27 g, 24.82
mmol) and 1-bromopyrrolidine-2,5-dione (6.19 g, 34.8 mmol) in DMF
(15 mL) was stirred at room temperature for 2 hours. The reaction
was diluted with water, and the product extracted with
dichloromethane (3.times.50 mL). The organic layer was washed with
brine, dried and concentrated. The crude product mixture was
purified via ISCO (0-50% of ethyl acetate/dichloromethane in 10
minutes, 80 g silica column) to give the pure product
7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (4.61
g).
[0628] MS (ESI) m/z 290.
[0629] 1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.60 (s, 1H), 2.69
(s, 3H), 2.64 (s, 3H).
[0630] (1D): To a 25 mL flask was added a mixture of
7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (2.0 g,
6.87 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.34 g, 7.56 mmol)
in anhydrous THF (20 mL). The reaction solution was cooled to
-78.degree. C. and treated drop wise with 1.0 M lithium
bis(trimethylsilyl)amide in THF solution (20.61 mL, 20.61 mmol, 3
eq, 1M solution in THF). The reaction was stirred at -78.degree. C.
for 1 hour, then allowed to come to room temperature and stirred
for 3 hours. The reaction was quenched with saturated ammonium
chloride. The product was extracted with ethyl acetate; the organic
layer was dried with sodium sulfate and concentrated in vacuo. The
crude product mixture was purified via ISCO (0-100% of ethyl
acetate/heptane in 10 minutes, 24 g silica column) to give the pure
product
7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2-
,1-f][1,2,4]triazin-4-amine (2.1 g)
[0631] MS (ESI) m/z 420
[0632] (1E): A solution of
7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2,1-f][1,-
2,4]triazin-4-amine (2.3 g, 5.47 mmol) in dichloromethane (10 mL)
was treated with m-CPBA (3.07 g, 13.68 mmol) at room temperature.
The reaction mixture was stirred for 2 hours. The reaction solution
was washed with 5% Na2S.sub.2O.sub.3 (2.times.10 mL), 1 N
Na.sub.2CO.sub.3 (2.times.10 mL) and brine. The organic layer was
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness to
afford the crude product mixture. The crude product mixture was
purified via ISCO (0-50% of ethyl acetate/dichloromethane in 10
minutes, 80 g silica column) to give the pure product
7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2,1-f][1,-
2,4]triazin-4-amine (2.1 g).
[0633] MS (ESI) m/z 451.84
[0634] (1F): In a round-bottom flask, a mixture of
7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylsulfonyl)imidazo[2,1-f-
][1,2,4]triazin-4-amine (0.115 g, 0.254 mmol), zinc cyanide (0.021
g, 0.178 mmol), and zinc powder (4.99 mg, 0.076 mmol) in DMA (30
mL) was degassed by evacuating with vacuum and back filling with
nitrogen. The mixture was treated with
bis(tri-t-butylphosphine)palladium (0) (0.026 g, 0.051 mmol),
degassed again as described above, and the reaction was heated at
100.degree. C. for 4 hours. The reaction mixture was filtered and
the filtrate diluted with ethyl acetate, washed with water, brine,
dried with sodium sulfate and concentrated in vacuo. The crude
product mixture was purified via ISCO (0-15% of
methanol/dichloromethane in 20 minutes, 40 g silica column) to give
the pure product
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (75 mg).
[0635] MS (ESI) m/z 398.97
[0636] (1G): To a vial was charged
3-amino-4-chloro-5-(4-methylpiperazin-1-yl)benzonitrile (56.6 mg,
0.226 mmol) and tetrahydrofuran (3 mL). To the reaction solution
was added sodium hydride (9.03 mg, 0.226 mmol). The solution was
stirred at room temperature for 1 hour, then a solution of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[1,2-f][1,-
2,4]triazine-7-carbonitrile (60 mg, 0.151 mmol) in tetrahydrofuran
(Volume: 3 mL) was added. The solution was then stirred at room
temperature for 3 hours and then heated to 80.degree. C. for 3
hours. The reaction solution was diluted with ethyl acetate, and
the organic layer washed with NaHCO.sub.3 solution and brine, dried
with sodium sulfate and concentrated in vacuo to give the crude
product mixture. The crude product mixture was purified via ISCO
(0-15% of methanol/dichloromethane in 15 minutes, 24 g silica
column) to give
2-((2-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenyl)amino)-4-(cycloprop-
yl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
MS (ESI) m/z 568.96
[0637] Example 1: In a vial was added
2-((2-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenyl)amino)-4-(cycloprop-
yl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
dichloromethane (2 mL), anisole (0.1 mL) and TFA (0.2 mL). The
reaction solution was stirred at 80.degree. C. for 1 hour. The
solution was concentrated and purified by PREP HPLC to give
2-(2-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenylamino)-4-(cyclopropyl-
amino)imidazo[1,2-f][1,2,4]triazine-7-carbonitrile, 2 TFA (11.1
mg)
[0638] MS (ESI) m/z 448.96
[0639] 1H NMR (400 MHz, METHANOL-d4) .delta. 8.70 (d, J=1.8 Hz,
1H), 8.00 (s, 1H), 7.28 (d, J=1.5 Hz, 1H), 3.80-3.53 (m, 4H), 3.41
(br. s., 2H), 3.19 (br. s., 2H), 3.10-2.93 (m, 4H), 1.06-0.91 (m,
2H), 0.82 (dd, J=3.6, 2.1 Hz, 2H).
[0640] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 1
TABLE-US-00003 TABLE 1 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 2 ##STR00062##
2-((2-chloro-5-cyano-3-(4-methyl-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
484.94 1.57 3 ##STR00063## 4-(cyclopropylamino)-2-((1-methyl-
1H-benzimidazol- 5-yl)amino)imidazo[2,1- f][1,2,4]triazine-7-
carbonitrile 345.37 1.78 4 ##STR00064## 2-((2-chloro-5-cyano-3-
(4-(methylsulfonyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
512.98 1.80 5 ##STR00065## 2-((2-chloro-5-cyano-3-
((1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]hept-2-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 460.93 1.7 6 ##STR00066##
2-43-cyanoano-1-methyl- 1H-indazol-5-yl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
370.38 1.72 7 ##STR00067## (+/-) 2-((2-chloro-5-cyano-3-
(3-hydroxy-1- pyrrolidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
436.88 1.79 8 ##STR00068## 2-((2-chloro-5-cyano-3-(1,4-
diazabicyclo[3.2.1]oct-4- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
461.93 1.63 9 ##STR00069## (+/-) methyl ((3R,4R)-1-(2-
chloro-5-cyano-3-((7- cyano-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)- 4-hydroxy-3-
pyrrolidinyl)carbamate 509.93 1.81 10 ##STR00070## (+/-)
N-((3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-4-hydroxy-3- pyrrolidinyl)acetamide 493.93 1.83 11
##STR00071## (+/-) methyl ((3S,4S)-1-(2- chloro-5-cyano-3-((7-
cyano-4- (cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methyl-3- pyrrolidinyl)carbamate 506.96 2.93 12
##STR00072## 2-((2-chloro-5-cyano-3-(4- (4-methyl-1-piperazinyl)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 533.05 2.83 13 ##STR00073## (+/-)
methyl ((3aR,5r,6aS)- 2-(2-chloro-5-cyano-3-((7- cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)octahydro- cyclopenta[c]pyrrol-5- yl)carbamate
532.99 2.69 14 ##STR00074## methyl ((3S,4R)-1-(2-chloro-
5-cyano-3-((7-cyano-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2- yl)amino)phenyl)-4-methoxy-3-
pyrrolidinyl)carbamate 522.96 2.7 15 ##STR00075##
2-((2-chloro-5-cyano-3-(4- (1-methyl-4-piperidinyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 532.05 2.86 16 ##STR00076##
2-((2-chloro-5-cyano-3-(4-(1- hydroxy-1-methylethyl)-
1-piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 491.98 2.76 17 ##STR00077## (+/-)
methyl ((3S,5S)-1-(2- chloro-5-cyano-3-((7- cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-yl)amino)phenyl)-
5-hydroxy-3- piperidinyl)carbamate) 522.96 2.76 18 ##STR00078##
2-((3-(4-amino-4-methyl-1- piperidinyl)-2-chloro-5-
cyanophenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 462.95 2.97 19 ##STR00079## (+/-)
2-((2-chloro-5-cyano-3- ((3R,4R)-3-hydroxy-4- methyl-1-
pyrrolidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 449.90 2.93 20 ##STR00080## (+/-)
2-((2-chloro-5-cyano-3- ((3S,4R)-3-hydroxy-4- methyl-1-
pyrrolidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 449.90 2.86 21 ##STR00081## (+/-)
methyl ((3S,4R)-1-(2- chloro-5-cyano-3-((7- cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methyl-3- pyrrolidinyl)carbamate 506.96 2.5 22
##STR00082## 2-((2-chloro-5-cyano-3-(7-methyl-2,7-
diazaspiro[3.5]non-2- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
488.99 3.62 23 ##STR00083## 2-((2-chloro-5-cyano-3- (6-methyl-2,6-
diazaspiro[3.3]hept-2- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
460.93 3.85 24 ##STR00084## (+/-) 2-((2-chloro-5-cyano-3-
((3R,5S)-3,4,5-trimethyl- 1-piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
476.97 3.31 25 ##STR00085## (+/-) 2-((2-chloro-5-cyano-
3-(1-methyl-1,7- diazaspiro[4.4]non-7- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
488.99 3.11 26 ##STR00086## (+/-) 2-((2-chloro-5-cyano-
3-(8-methyl-2,8- diazaspiro[4.5]dec-2- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
503.01 3.18 27 ##STR00087## (+/-) 2-((2-chloro-5-cyano-
3-(2-methyl-2,8- diazaspiro[4.5]dec-8-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
503.01 4.18 28 ##STR00088## (+/-) 2-((2-chloro-5-cyano-3-
(3-(methylamino)-1- pyrrolidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
448.92 3.81 29 ##STR00089## 2-((2-chloro-5-cyano-3-(3-
(4-methyl-1,4-diazepan-1- yl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
518.03 4.41 30 ##STR00090## 2-((3-((3S,4R)-3-amino-4-
methoxy-1-pyrrolidinyl)-2- chloro-5-cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
464.92 3.71 31 ##STR00091## (+/-)2-((2-chloro-5-cyano-3-
(1,7-diazaspiro[4.4]non- 7-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
474.96 3.99 32 ##STR00092## (+/-) 1-((3S,4R)-1-(2-chloro-5-
cyano-3-((7-cyano-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2- yl)amino)phenyl)-4-methoxy- 3-pyrrolidinyl)-3-
ethylurea 536.00 3.34 33 ##STR00093## (+/-) 2-((2-chloro-5-cyano-
3-(2-(1-hydroxy-1- methylethyl)-4- morpholinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
493.96 3.28 34 ##STR00094## (+/-) 2-((2-chloro-5-cyano-3-
(3-(1-hydroxy-1- methylethyl)-4-methyl-1-
piperazinyl)phenyl)amino)- 4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 507.00 3.97 35 ##STR00095##
2-((2-chloro-5-cyano-3-(3,4- dimethyl-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 462.95 2.98 36 ##STR00096##
2-((3-((3S,4S)-4-amino-3- hydroxy-4-methyl-1-
piperidinyl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
478.95 3.91 37 ##STR00097## 2-((2-chloro-5-cyano-3-((2S)-
2-(1-hydroxy-1- methylethyl)-4- morpholinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
493.96 2.43 38 ##STR00098## 2-((2-chloro-5-cyano-3-
((2R)-2-(1-hydroxy-1- methylethyl)-4- morpholinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
493.96 2.67 39 ##STR00099## 2-((2-chloro-5-cyano-3-(4-hydroxy-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 449.90 3.26 40 ##STR00100##
(R)-2-(3-(3-aminopiperidin-1- yl)-2-chloro-5- cyanophenylamino)-4-
(cyclopropylamino)imidazo[1,2- f][1,2,4]triazine-7- carbonitrile
448.92 1.69 41 ##STR00101## methyl ((3R)-1-(2-chloro-5-
cyano-3-((7-cyano-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2- yl)amino)phenyl)-3- piperidinyl)carbamate
506.96 2.67 42 ##STR00102## 2-((2-chloro-5-cyano-3-((3R)-
3-(3-oxetanylamino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
504.98 3.96 43 ##STR00103## 2-((2-chloro-5-cyano-3-((3R)-
3-((2-hydroxy-2- methylpropyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 521.03 3.59 44 ##STR00104##
2-((2-chloro-5-cyano-3-((3R)- 3-(3-oxetanylamino)-1-
pyrrolidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 490.96 2.82 45 ##STR00105##
2-((2-chloro-5-cyano-3-((3R)-3- (3-hydroxy-3-methyl-
1-azetidinyl)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
519.01 3.48 46 ##STR00106## (R)-2-(3-(3-aminopyrrolidin-
1-yl)-2-chloro-5- cyanophenylamino)-4-
(cyclopropylamino)imidazo[1,2- f][1,2,4]triazine-7- carbonitrile
434.89 3.13 47 ##STR00107## (R)-2-(2-chloro-5-cyano-3-
(3-(3-hydroxy-3- methylazetidin-1-yl)pyrrolidin-
1-yl)phenylamino)-4- (cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7- carbonitrile 504.98 3.78 48 ##STR00108##
2-((2-chloro-5-cyano-3-(2-oxa- 7-azaspiro[3.5]non-7-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 475.94 3.93 49 ##STR00109##
2-((2-chloro-5-cyano-3-(4- morpholinylamino)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile
450.89 3.76 50 ##STR00110## 2-((3-((2-aminoethyl)(methyl)amino)-
2-chloro-5- cyophenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 422.88 3.86 51 ##STR00111##
2-((2-chloro-5-cyano-3- (methyl(2-(3- oxetanylamino)ethyl)-
amino)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 478.95 3.769 .sup.a * = HPLC
conditions YMC S5 ODS 4.6 .times. 50 mm, 10-90% aqueous methanol
containing 0.2% H.sub.3PO.sub.4, 5 min. gradient, monitored at 220
nm
Example 52
##STR00112##
[0641]
2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)-1-piperazinyl)phenyl)-
amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0642] (52A): To the stirred solution of
2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Intermediate 11) (0.100 g, 0.180 mmol) in DMF (2.0 mL) and
N,N-diisopropylethylamine, (63 .mu.L, 0.361 mmol) was added
2,2-difluoroethyl trifluoromethanesulfonate (0.046 g, 0.216 mmol)
at room temperature. The reaction mixture was stirred at room
temperature for overnight. On completion of the reaction, the
reaction mixture was diluted with ethyl acetate and washed with
water. The organic layer was separated and aqueous layer was
extracted with ethyl acetate twice. The combined organic layers
were dried over sodium sulfate, filtered and concentrated in vacuum
to give off-white solid, which was purified by flash chromatography
on silica gel using an automated ISCO system (12 g Redisep column,
eluting with 0-5% methanol/chloroform) to get
2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile (100 mg) as an off-white solid.
[0643] MS (ESI) m/z 617.2
[0644] (52B): To the stirred solution of
2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)-piperazin-1-yl)phenyl)amino-
)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile (120 mg, 0.194 mmol) in dry dichloromethane (2.0 mL) was
added anisole (0.1 mL, 0.915 mmol) and trifluoroacetic acid (0.3
mL, 3.87 mmol) at room temperature. The reaction mixture stirred at
room temperature for overnight. On completion of the reaction, the
reaction mixture was diluted with dichloromethane and washed with
saturated sodium bicarbonate. The organic layer was separated and
aqueous layer was extracted with dichloromethane twice. The
combined organic layers were dried over sodium sulfate, filtered
and concentrated in vacuo to give off-white solid. This was
purified by preparative HPLC to afford
2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(50 mg, 0.098 mmol, 50.5% yield) as an off-white solid
[0645] MS (ESI) m/z 499.2
[0646] Example 52: To the stirred solution of
((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-4-
-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(0.045 g, 0.090 mmol) in dry acetonitrile (2.0 mL), water (4.0 mL)
was added 1N HCl (90 .mu.L, 0.090 mmol) at room temperature. The
reaction mixture stirred at room temperature for 10 minutes. The
reaction mixture converted in to clear solution. This mixture was
freeze dried and lyophilized to afford
2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
hydrochloride (48.0 mg) as an off-white solid.
[0647] MS (ESI) m/z 499.2
[0648] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.9.35-9.34 (d,
J=4.4 Hz, 1H), 8.91 (s, 1H), 8.21 (s, 1H), 8.15 (d, J=1.5 Hz, 1H),
7.41 (s, 1H), 6.50 (m, 1H), 3.32-3.15 (m, 8H), 3.04-2.92 (m, 2H),
0.79-0.78 (m, 4H).
[0649] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 52
TABLE-US-00004 TABLE 2 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 53 ##STR00113## methyl
3-(4-(2-chloro-5-cyano-3- ((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperazinyl)- 1-azetidinecarboxylate 548.01 3.57
54 ##STR00114## (+/-) 2-((2-chloro-5-cyano-3-(4-(2-
hydroxy-1-methylethyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
492.97 3.78 55 ##STR00115## (+/-) 2-((2-chloro-5-cyano-3-(4-
(tetrahydro-3-furanyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
504.98 3.80 56 ##STR00116## 2-((2-chloro-5-cyano-3-(4-(2-
methoxyethyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
492.97 3.72 57 ##STR00117## 2-((2-chloro-5-cyano-3-(4-((2R)-
2-hydroxypropyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
492.97 3.72 58 ##STR00118## 2-((2-chloro-5-cyano-3-(4-((2S)-2-
hydroxypropyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
492.97 3.79 59 ##STR00119## (+/-) 2-((2-chloro-5-cyano-3-(4-
((3R,4S)-4-hydroxytetrahydro-3- furanyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 520.98 3.63 60 ##STR00120## methyl
4-(4-(2-chloro-5-cyano-3- ((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperazinyl)- 1-piperidinecarboxylate 576.06
3.81 61 ##STR00121## 2-((2-chloro-5-cyano-3-(4-(1-(2-
methoxyethyl)-3-azetidinyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
548.05 3.83 62 ##STR00122## 2-((2-chloro-5-cyano-3-(4-(2-
oxocyclobutyl)piperazin-1- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
502.97 3.93 63 ##STR00123## 2-((2-chloro-5-cyano-3-(4-(1-(2-
methoxyethyl)-4-piperidinyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
576.11 2.83 64 ##STR00124## (+/-) 2-((2-chloro-5-cyano-3-(4-(2-
methoxy-1-methylethyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
507.00 3.69 65 ##STR00125## 2-((2-chloro-5-cyano-3-(4-(2-
(methylsulfonyl)ethyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
541.04 2.7 66 ##STR00126## (+/-) 2-((2-chloro-5-cyano-3-(4-(3-
fluoro-2-hydroxypropyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
510.96 3.86 67 ##STR00127## methyl 4-(2-chloro-5-cyano-3-((7-
cyano-4- (cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1- piperazinecarboxylate 492.93 3.76 68
##STR00128## 2-methoxyethyl 4-(2-chloro-5- cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1- piperazinecarboxylate 536.98 3.76 69
##STR00129## N-((1S)-2-(4-(2-chloro-5-cyano-3- ((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperazinyl)- 1- methylethyl)methanesulfonamide
570.08 3.97 70 ##STR00130## 2-((2-chloro-5-cyano-3-(4-(1-(2-
(methylsulfonyl)ethyl)-3- azetidinyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 596.12 2.93 71 ##STR00131##
2-(methylamino)ethyl 4-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1- piperazinecarboxylate 536.00 2.86 72
##STR00132## 2-((2-chloro-5-cyano-3-(4-(1- methyl-3-azetidinyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 504.00 2.52 73 ##STR00133##
2-((2-chloro-5-cyano-3-(4-(1- (methylsulfonyl)-3-azetidinyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 568.06 3.62 74 ##STR00134##
2-((2-chloro-5-cyano-3-(4- (cyclopropylcarbonyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 502.97 3.85 75 ##STR00135##
2-(2-chloro-5-cyano-3-(4-(2,2- difluoroacetyl)piperazin-1-
yl)phenylamino)-4- (cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 512.91 3.61 76 ##STR00136##
N-(2-(4-(2-chloro-5-cyano-3-((7- cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperazinyl)- 2-oxoethyl)acetamide 533.98 3.76
77 ##STR00137## 2-((2-chloro-5-cyano-3-(4- (methoxyacetyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 506.96 3.83.sup.a 78 ##STR00138##
2-(2-chloro-5-cyano-3-(4-(2- hydroxyacetyl)piperazin-1-
yl)phenylamino)-4- (cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 492.93 4.185 79 ##STR00139##
2-((2-chloro-5-cyano-3-(4-(2- hydroxy-2-methylpropanoyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 520.98 3.81 80 ##STR00140## (+/-)
2-((2-chloro-5-cyano-3-(4- lactoyl-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
506.96 4.41 81 ##STR00141## (+/-) 2-((2-chloro-5-cyano-3-(4-
((2-oxo-4- imidazolidinyl)carbonyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
546.98 3.71 82 ##STR00142## 2-((2-chloro-5-cyano-3-(4-(3-(1-
piperidinyl)propanoyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
574.09 3.99 83 ##STR00143## 2-((3-(4-(1-acetyl-L-prolyl)-1-
piperazinyl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
574.05 3.34 84 ##STR00144## (+/-) 2-((2-chloro-5-cyano-3-(4-
(tetrahydro-2-furanylcarbonyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
532.99 3.28 85 ##STR00145## 2-((3-(4-acetyl-1-piperazinyl)-2-
chloro-5-cyanophenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 476.93 3.97 86 ##STR00146##
2-((2-chloro-5-cyano-3-(4- (cyclopropylacetyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 517.00 2.98 87 ##STR00147##
2-((2-chloro-5-cyano-3-(4-(3- methoxypropanoyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 520.98 3.91 88 ##STR00148##
2-((2-chloro-5-cyano-3-(4-((2- methoxyethoxy)acetyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 551.01 4.43 89 ##STR00149##
2-((2-chloro-5-cyano-3-(4- ((methylsulfonyl)acetyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 555.02 4.67 90 ##STR00150##
2-(2-chloro-5-cyano-3-(4-(3- hydroxypropanoyl)piperazin-1-
yl)phenylamino)-4- (cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 506.96 3.26 91 ##STR00151##
2-((2-chloro-5-cyano-3-(4-(3- hydroxy-3-methylbutanoyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 535.01 3.69 92 ##STR00152## (+/-)
2-((2-chloro-5-cyano-3-(4- ((1-methyl-3- piperidinyl)carbonyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 560.06 2.67 93 ##STR00153##
4-(4-(2-chloro-5-cyano-3-((7- cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperazinyl)- 4-oxo-1-butanesulfonamide 584.06
3.96 94 ##STR00154## (+/-) 2-(2-chloro-5-cyano-3-(4-
(morpholine-2-carbonyl)piperazin- 1-yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2- f][1,2,4]triazine-7-carbonitrile
548.01 3.59 95 ##STR00155## 2-((2-chloro-5-cyano-3-(4-
(tetrahydro-2H-pyran-4-ylacetyl)- 1-piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
561.05 2.82 96 ##STR00156## 2-((2-chloro-5-cyano-3-(4-(4-(1H-
imidazol-1-yl)butanoyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
571.05 3.48 97 ##STR00157## 2-((2-chloro-5-cyano-3-(4-(1H-
imidazol-1-ylacetyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
542.99 3.13 98 ##STR00158## 557.02 3.78 99 ##STR00159##
2-((2-chloro-5-cyano-3-(4-(1H- tetrazol-5-ylacetyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 544.97 3.93 100 ##STR00160##
2-((2-chloro-5-cyano-3-(4-(4- morpholinylacetyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 562.04 3.76 101 ##STR00161##
methyl 3-(4-(2-chloro-5-cyano-3- ((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperazinyl)- 1-azetidinecarboxylate 536.00 3.86
102 ##STR00162## (+/-) 2-((2-chloro-5-cyano-3-(4-
(trans-3-hydroxycyclobutyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
504.98 3.76 103 ##STR00163## (+/-) 2-((2-chloro-5-cyano-3-(4-
(tetrahydro-3-furanyl)-1- piperazinyl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile 492.97
3.82 104 ##STR00164## 2-((2-chloro-5-cyano-3-(4-(3-
cyano-3-oxetanyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
515.97 3.91 105 ##STR00165## 2-(2-chloro-5-cyano-3-(4-(oxetan-
3-yl)piperazin-1-yl)phenylamino)- 4-(cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 490.96 3.88 106 ##STR00166## (+/-)
2-((2-chloro-5-cyano-3-(4- (cis-3-cyanocyclobutyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 514.00 3.96 107 ##STR00167##
2-((2-chloro-5-cyano-3-(4-(trans- 3-cyanocyclobutyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 514.00 3.98 * = HPLC
conditions
YMC S5 ODS 4.6 .times. 50 mm, 10-90% aqueous methanol containing
0.2% H.sub.3PO.sub.4, 5 min. gradient, monitored at 220 nm
##STR00168##
Example 108
##STR00169##
[0650]
2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin--
1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile
[0651] (108A): To a vial charged with
2-((2-chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Intermediate 13) (30 mg, 0.053 mmol) and
3,3-difluorocyclobutanamine (6.79 mg, 0.063 mmol) in methanol (132
.mu.l) and tetrahydrofuran (132 .mu.l) was added trimethyl
orthoformate (58.4 .mu.l, 0.528 mmol). The reaction mixture was
stirred at room temperature. Sodium cyanoborohydride (6.64 mg,
0.106 mmol) was added and the reaction mixture was stirred at room
temperature 6 h. The reaction mixture was diluted with water and
methanol and filtered. The solid was taken up in DMF and
partitioned between water and ethyl acetate. The aqueous layer was
washed with ethyl acetate (3.times.). The combined organics were
washed with 10% lithium chloride solution, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The crude
material was taken forward as is.
[0652] MS (ESI) m/z 659.5
[0653] Example 108: To a round bottom flask charged with
2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin-1-yl)p-
henyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tri-
azine-7-carbonitrile (34.9 mg, 0.053 mmol) in dichloromethane (530
.mu.l) was added anisole (116 .mu.l, 1.060 mmol), followed by the
slow addition of trifluoroacetic acid (408 .mu.l, 5.30 mmol). The
reaction mixture was stirred at room temperature 2 d. Excess TFA
was removed in vacuo. The crude residue was taken up in MeOH and
free based using a Phenomenex Strata 1 g SCX column. The crude
solid was purified via preparative LC/MS and provided
2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin-1-yl)p-
henyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitr-
ile (3.4 mg).
[0654] MS (ESI) m/z 539.1
[0655] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=4.0
Hz, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.28
(d, J=1.3 Hz, 1H), 3.26 (d, J=11.8 Hz, 1H), 3.03-2.92 (m, 1H),
2.84-2.66 (m, 4H), 2.59 (br. s., 1H), 2.35 (d, J=11.4 Hz, 2H), 1.87
(d, J=11.1 Hz, 2H), 1.51-1.36 (m, 2H), 0.78 (d, J=5.4 Hz, 4H)
[0656] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 108
TABLE-US-00005 TABLE 3 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 109 ##STR00170## (+/-)
2-((2-chloro-5-cyano-3-(4- (2,6-dimethyl-4-morpholinyl)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 547.06 3.57 110 ##STR00171##
2-((2-chloro-5-cyano-3-(4-(3- oxetanylamino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 504.98 3.78 111 ##STR00172##
2-(2-chloro-5-cyano-3-(4-(3- hydroxy-3-methylazetidin-1-
yl)piperidin-1-yl)phenylamino)- 4- (cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 519.01 3.88 112 ##STR00173## (+/-)
2-((2-chloro-5-cyano-3-(4- (tetrahydro-3-furanylamino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 519.01 1.7 113 ##STR00174## (+/-)
2-((2-chloro-5-cyano-3-(4- ((3-((phenylsulfonyl)methyl)-3-
oxetanyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
659.17 4.72 114 ##STR00175## (+/-) 2-((2-chloro-5-cyano-3-(4-
((3-(cyanomethyl)-3- oxetanyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 544.02 3.79 115 ##STR00176##
2-((2-chloro-5-cyano-3-(4- (isopropylamino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 491.00 3.93 116 ##STR00177## (+/-)
2-((2-chloro-5-cyano-3-(4- ((1-methyl-5-oxo-3-
pyrrolidinyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
546.04 3.81 117 ##STR00178## (+/-) 2-((2-chloro-5-cyano-3-(4-
((1,1-dioxidotetrahydro-3- thiophenyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 567.08 3.83 118 ##STR00179## ethyl
4-((1-(2-chloro-5-cyano- 3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-4- piperidinyl)amino)-1- piperidinecarboxylate
604.12 4.13 119 ##STR00180## (+/-) 2-((2-chloro-5-cyano-3-(4-
((3-cyanocyclobutyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
528.02 3.83 120 ##STR00181## (+/-) 2-((2-chloro-5-cyano-3-
(4-(((1S,3S)-3- hydroxycyclopentyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 533.04 3.69 121 ##STR00182## (+/-)
2-((2-chloro-5-cyano-3- (4-(((1R,3S)-3-
hydroxycyclopentyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
533.04 3.71 122 ##STR00183## (+/-) 2-((2-chloro-5-cyano-3-(4-
(((2R,3S)-2-methyltetrahydro-3- furanyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 533.04 3.86 123 ##STR00184## (+/-)
2-((2-chloro-5-cyano-3-(4- (((2S,3S)-2-methyltetrahydro-3-
furanyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
533.04 3.88 124 ##STR00185## 2-((2-chloro-5-cyano-3-(4-
((1,2,2,6,6-pentamethyl-4- piperidinyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 602.19 3.76 125 ##STR00186##
2-((2-chloro-5-cyano-3-(4- (tetrahydro-2H-pyran-4- ylamino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 533.04 3.97 126 ##STR00187##
2-((2-chloro-5-cyano-3-(4- ((2,2,2-trifluoroethyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 530.94 3.93 127 ##STR00188## (+/-)
2-(2-chloro-5-cyano-3-(4- ((1R,2R)-2-
fluorocyclohexylamino)piperidin- 1-yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2- f][1,2,4]triazine-7-carbonitrile
549.06 3.86 128 ##STR00189## (+/-)2-(2-chloro-5-cyano-3-(4-
((1R,2S)-2- fluorocyclohexylamino)piperidin- 1-yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2- f][1,2,4]triazine-7-carbonitrile
549.06 3.75 129 ##STR00190## 2-((2-chloro-5-cyano-3-(4-((1,1-
dioxido-3-thietanyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
553.05 3.62 130 ##STR00191## 2-((2-chloro-5-cyano-3-(4-((2,2-
difluoroethyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
512.95 3.85 131 ##STR00192## 2-((3-(4-
(bis(cyclopropylmethyl)amino)- 1-piperidinyl)-2-chloro-5-
cyanophenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 557.10 3.31 132 ##STR00193##
2-((2-chloro-5-cyano-3-(4-((2- methoxyethyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 507.00 3.11 133 ##STR00194## (+/-)
2-((2-chloro-5-cyano-3- (4-((cis-3- hydroxycyclobutyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 519.01 3.18 134 ##STR00195## (+/-)
2-((2-chloro-5-cyano-3- (4-((trans-3- hydroxycyclobutyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 519.01 4.18 135 ##STR00196## (+/-)
2-((2-chloro-5-cyano-3-(4- (((3S,4R)-4-hydroxytetrahydro-3-
furanyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
535.01 3.81 136 ##STR00197## 2-((2-chloro-5-cyano-3-(4-
((cyclopropylmethyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
503.01 4.41 137 ##STR00198## 2-((2-chloro-5-cyano-3-(4-(((2R)-
2-fluoro-3-hydroxy-3- methylbutyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 553.04 3.71 138 ##STR00199##
(+/-).2-(2-chloro-5-cyano-3- (4-(2- hydroxypropylamino)piperidin-1-
yl)phenylamino)-4- (cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 507.00 3.99 139 ##STR00200## (+/-)
2-((2-chloro-5-cyano-3- (4-((3,3,3-trifluoro-2-
hydroxypropyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
560.97 3.34 140 ##STR00201## 2-(2-chloro-5-cyano-3-(4-((3-
methylisoxazol-5- yl)methylamino)piperidin-1- yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2- f][1,2,4]triazine-7-carbonitrile
544.02 3.97 141 ##STR00202## 2-((2-chloro-5-cyano-3-(4-
((cyanomethyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
487.96 2.98 142 ##STR00203## (+/-) 2-((2-chloro-5-cyano-3-
(4-((1-cyclopropyl-2- methoxyethyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 547.06 3.91 143 ##STR00204##
2-((2-chloro-5-cyano-3-(4-((2- hydroxy-2-methylpropyl)amino)-
1-piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 521.03 3.28 144 ##STR00205## (+/-)
2-((2-chloro-5-cyano-3- (4-((3-fluoro-2- hydroxypropyl)amino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 524.99 3.43 145 ##STR00206##
2-((2-chloro-5-cyano-3-(4-(((2R)- 2-hydroxy-3-
methoxypropyl)amino)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
537.03 2.67 146 ##STR00207## methyl (1-(2-chloro-5-cyano-3-
((7-cyano-4- (cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-4- piperidinyl)carbamate 506.96 3.26 147
##STR00208## 2-((2-chloro-5-cyano-3-(4-(3,3-
difluoro-1-azetidinyl)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
524.97 3.69 148 ##STR00209## (+/-) 2-((2-chloro-5-cyano-3-(4-
(2-(1-hydroxy-1-methylethyl)-4- morpholinyl)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 577.09 3.67 149 ##STR00210## (+/-)
methyl ((3S,4S)-1-(1-(2- chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazin-2-
yl)amino)phenyl)-4-piperidinyl)- 4-methyl-3- pyrrolidinyl)carbamate
590.09 3.96 150 ##STR00211## methyl ((3S,4R)-1-(1-(2-chloro-
5-cyano-3-((7-cyano-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2- yl)amino)phenyl)-4-piperidinyl)- 4-methoxy-3-
pyrrolidinyl)carbamate 606.09 3.59 *= HPLC conditions YMC S5 ODS
4.6 .times. 50 mm, 10-90% aqueous methanol containing 0.2%
H.sub.3PO.sub.4, 5 min. gradient.
Example 151
##STR00212##
[0657]
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[0658] (151A): A mixture of benzyl 3-oxoazetidine-1-carboxylate
(1.026 g, 5 mmol), 1-methylpiperazine (0.833 mL, 7.50 mmol) and
acetic acid (0.429 mL, 7.50 mmol) in 1,2-dichloroethane (5 mL) was
stirred at room temperature for 3 h. Sodium triacetoxyborohydride
(2.119 g, 10.00 mmol) was added and the reaction mixture was
stirred at room temperature overnight. A small amount of water was
added to the reaction mixture and the reaction mixture was directly
loaded onto a 120 g ISCO column and eluted with 1-12% 2N ammonia in
methanol/dichloromethane). benzyl
3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (1.45 g) was
obtained as brown oil.
[0659] MS (ESI) m/z 290.2
[0660] .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.39-7.28 (m,
5H), 5.09 (s, 2H), 4.05-3.97 (m, 2H), 3.89 (dd, J=9.0, 5.3 Hz, 2H),
3.20-3.10 (m, 1H), 2.66-2.35 (m, 13H), 2.32 (s, 3H), 2.01 (s,
1H).
[0661] (151B): A mixture of benzyl
3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (1.45 g, 5.01
mmol) and Pd/C (0.320 g, 0.150 mmol) in methanol (30 mL) was
hydrogenated at 30 psi over the weekend. The reaction mixture was
filtered through celite and the filtrate was concentrated. The
crude product 1-(azetidin-3-yl)-4-methylpiperazine (0.78 g, 5.02
mmol, 100% yield) was obtained as colorless oil and used without
purification.
[0662] MS (ESI) m/z 156.1
[0663] (151C): The title compound
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile
was prepared starting from 1-(azetidin-3-yl)-4-methylpiperazine
using a method analogous to that used to prepare Example 1A-B.
[0664] MS (ESI) m/z 306.2
[0665] Example 151: The title compound was prepared from
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile
using a method analogous to that used to prepare Example 1.
[0666] MS (ESI) m/z 504.4
[0667] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.50 (d, J=1.7
Hz, 1H), 7.87 (s, 1H), 7.51 (s, 1H), 6.72 (d, J=1.7 Hz, 1H), 6.48
(d, J=1.7 Hz, 1H), 4.28 (t, J=7.4 Hz, 2H), 3.94 (dd, J=7.6, 6.0 Hz,
2H), 3.30 (quin, J=6.3 Hz, 1H), 3.06 (tq, J=7.1, 3.5 Hz, 1H), 2.51
(br. s., 8H), 2.34 (s, 3H), 1.69 (s, 2H), 1.15-1.08 (m, 2H),
0.85-0.79 (m, 2H).
[0668] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 151
TABLE-US-00006 TABLE 4 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 152 ##STR00213##
2-((2-chloro-5-cyano-3-(3-(4-morpholinyl)-1-
azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
490.96 3.67 153 ##STR00214## methyl
4-(1-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-3-azetidinyl)-1- piperazinecarboxylate 548.01 3.82
154 ##STR00215## (+/-) methyl
((3S,4S)-1-(1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl)amino)phenyl)-3-azetidinyl)-3-
hydroxy-4-piperidinyl)carbamate 578.03 4.31 155 ##STR00216##
2-((2-chloro-5-cyano-3-(3-(1-piperazinyl)-1-
azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
489.97 3.12 156 ##STR00217##
2-((2-chloro-5-cyano-3-(3-(4-methyl-3-oxo-1-
piperazinyl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
517.98 3.72 157 ##STR00218##
2-((2-chloro-5-cyano-3-(3-(4-hydroxy-4-methyl-1-
piperidinyl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
519.01 4.19 158 ##STR00219##
2-(2-chloro-5-cyano-3-(3-(4-(2-hydroxypropan-2-
yl)piperidin-1-yl)azetidin-1-yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2-f][1,2,4]triazine-7- carbonitrile
547.06 3.63 159 ##STR00220## (+/-)
2-((2-chloro-5-cyano-3-(3-(3-hydroxy-1-
pyrrolidinyl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
490.96 3.81 160 ##STR00221## (+/-)
2-((2-chloro-5-cyano-3-(3-(3-(methylsulfonyl)-
1-pyrrolidinyl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
553.05 4.13 161 ##STR00222## (+/-)
2-((2-chloro-5-cyano-3-(3-(3-methoxy-1-
pyrrolidinyl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
504.98 3.93 162 ##STR00223## (+/-) methyl
((3S,4R)-1-(1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-3-azetidinyl)-4-
methyl-3-pyrrolidinyl)carbamate 562.04 3.83 .sup.c 163 ##STR00224##
(+/-) methyl ((3S,4S)-1-(1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-3-azetidinyl)-4-
methyl-3-pyrrolidinyl)carbamate 562.04 3.69 164 ##STR00225##
2-((2-chloro-5-cyano-3-(3-(4-methoxy-1-piperidinyl)-
1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
519.01 4.27 165 ##STR00226##
(+/-)2-(2-chloro-5-cyano-3-(3-(2-(2-hydroxypropan-
2-yl)morpholino)azetidin-1-yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2-f][1,2,4]triazine-7- carbonitrile
549.04 3.86 166 ##STR00227## 4-chloro-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)-5-(3-(3-oxetanylamino)-1- azetidinyl)benzamide 494.95
3.76 167 ##STR00228##
2-((2-chloro-5-cyano-3-(3-hydroxy-1,3'-biazetidin-1'-
yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 476.93 4.26 168 ##STR00229##
2-((2-chloro-5-cyano-3-(3-hydroxy-3-methyl-1,3'-
biazetidin-1'-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
490.96 3.97 169 ##STR00230##
2-((2-chloro-5-cyano-3-(3-(4-methyl-4-oxido-1-
piperazinyl)-1-azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
520.00 3.93 170 ##STR00231## 4-(1-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-3-azetidinyl)-1,1- dimethylpiperazin-1-ium 519.03
3.76 * = HPLC conditions YMC S5 ODS 4.6 .times. 50 mm, 10-90%
aqueous methanol containing 0.2% H.sub.3PO.sub.4, 5 min. gradient,
monitored at 220 nm
Example 171
##STR00232##
[0669] (+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0670] (171A): tert-butyldimethylchlorosilane (6.51 g, 43.2 mmol)
was added to a solution of (+/-)(3R,4R)-benzyl
4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate
(prepared according to a published literature procedure: Fink,
Brian, et al., WO 2005/066176, 10.1 g, 28.8 mmol) and imidazole
(3.92 g, 57.6 mmol) in DMF (60 mL). The mixture was stirred at room
temperature overnight. Ice water was added and the reaction mixture
was extracted with ether twice, the combined extracts were washed
with brine, dried over magnesium sulfate, filtered and concentrated
in vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (330 g column, eluting
with 5-20% ethyl acetate/dichloromethane) to give
(+/-)-(3R,4R)-benzyl
4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-
-1-carboxylate (13.3 g,) as a white solid.
[0671] MS (ESI) m/z 465.4
[0672] 1H NMR (500 MHz, DMSO-d6) .delta. 7.42-7.29 (m, 5H), 6.69
(d, J=7.2 Hz, 1H), 5.17-4.95 (m, 2H), 3.99-3.67 (m, 2H), 3.43-3.35
(m, 2H), 3.05-2.68 (m, 2H), 1.69 (d, J=11.1 Hz, 1H), 1.38 (s, 10H),
0.83 (br. s., 9H), 0.03 (br. s., 6H).
[0673] (171B): A mixture of (+/-)-(3R,4R)-benzyl
4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-
-1-carboxylate (13 g, 28.0 mmol) and Pd/C (5% on carbon, 1.786 g,
0.839 mmol) in methanol (250 mL) was hydrogenated at 30 psi
overnight. The mixture was filtered through Celite and the filtrate
was concentrated in vacuo and further dried under high vacuum at
40.degree. C. overnight. The crude product was used without
purification. (+/-)-tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate
(8.8 g) was obtained as a white solid.
[0674] MS (ESI) m/z 331.2
[0675] (171C): The compound was prepared starting from tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate
(4.5 g, 13.61 mmol) using procedure for Example 1A. After flash
chromatography on silica gel using an automated ISCO system (330 g
column, eluting with 0-10% ethyl acetate/dichloromethane), 3.8 g of
(+/-)-3-N-Boc-amino-5-((3R,4R)-4-N-Boc-amino-3-((tert-butyldimethylsilyl)-
oxy)piperidin-1-yl)-4-chlorobenzonitrile was obtained as an
off-white solid.
[0676] MS (ESI) m/z 581.3
[0677] 1H NMR (400 MHz, chloroform-d) .delta. 8.32 (d, J=1.8 Hz,
1H), 7.19 (s, 1H), 6.99 (d, J=1.8 Hz, 1H), 4.42 (br. s., 1H), 3.67
(td, J=9.4, 4.6 Hz, 1H), 3.49 (d, J=7.9 Hz, 1H), 3.38 (ddd, J=11.4,
4.6, 2.3 Hz, 1H), 3.24-3.15 (m, 1H), 2.80 (td, J=11.7, 2.3 Hz, 1H),
2.57 (dd, J=11.4, 9.5 Hz, 1H), 2.21-2.13 (m, 1H), 1.76-1.63 (m,
1H), 1.56 (s, 9H), 1.48 (s, 9H), 0.91 (s, 9H), 0.14 (s, 3H), 0.11
(s, 3H).
[0678] (171D):
(+/-)-3-N-Boc-amino-5-((3R,4R)-4-N-Boc-amino-3-((tert-butyldimethylsilyl)-
oxy)piperidin-1-yl)-4-chlorobenzonitrile (118 mg, 0.203 mmol) was
treated with TFA (25% in 1,2-dichloroethane, 2 mL) at room
temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate/1N
aqueous sodium hydroxide (pH 10). The layers were separated and
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo to give
(+/-)-3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidi-
n-1-yl)-4-chlorobenzonitrile (77 mg) as a brown oil. The crude
product was used without purification.
[0679] MS (ESI) m/z 381.2 (M+H).
[0680] (171E):
(+/-)3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-
-1-yl)-4-chlorobenzonitrile (77 mg, 0.203 mmol) was dissolved in
dichloromethane (5 mL), triethylamine (0.057 mL, 0.406 mmol) and
dimethyldicarbonate (40.8 mg, 0.305 mmol) were added at 0 C. The
reaction mixture was stirred at room temperature for 1 h. Solvent
was evaporated and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (24 g
column, eluting with 0-25% ethyl acetate/dichloromethane) to afford
(+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (76 mg) as a light yellow oil.
[0681] MS (ESI) m/z 439.2 (M+H)
[0682] 1H NMR (500 MHz, chloroform-d) .delta. 6.77 (d, J=1.9 Hz,
1H), 6.69 (d, J=1.7 Hz, 1H), 4.61 (br. s., 1H), 4.37 (s, 2H), 3.70
(s, 4H), 3.58-3.49 (m, 1H), 3.42 (ddd, J=11.4, 4.6, 2.5 Hz, 1H),
3.26-3.19 (m, 1H), 2.77 (td, J=11.8, 2.5 Hz, 1H), 2.56 (dd, J=11.4,
9.7 Hz, 1H), 2.14 (d, J=11.9 Hz, 1H), 0.89 (s, 10H), 0.10 (d, J=5.3
Hz, 6H).
[0683] (171F): The compound was prepared starting from (+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (76 mg, 0.173 mmol) and intermediate 6
according to procedure for Example 1G. (+/-)-methyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate (78 mg) was obtained as a white
solid.
[0684] MS (ESI) m/z 757.5 (M+H).
[0685] (171G): The compound was prepared starting from (+/-)-methyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate (78 mg, 0.103 mmol) according
to general procedure for tert-butyldimethylsilyl/triisopropylsilyl
deprotection. 63 mg of (+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4--
yl)carbamate was obtained as a white solid.
[0686] MS (ESI) m/z 643.2 (M+H).
[0687] Example 171: The compound was prepared starting from
(+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4--
yl)carbamate (63 mg) according to procedure reported for Example 1.
(+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(25 mg,) was obtained as a white solid.
[0688] MS (ESI) m/z 523.1
[0689] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.81 (s, 1H),
7.87 (s, 1H), 7.58 (s, 1H), 7.05-6.98 (m, 1H), 6.77 (br. s., 1H),
4.82 (br. s., 1H), 3.73-3.82 (m, 4H), 3.66-3.39 (m, 2H), 3.30 (d,
J=10.5 Hz, 1H), 3.06 (dd, J=6.8, 3.5 Hz, 1H), 2.89-2.79 (m, 1H),
2.68 (t, J=10.3 Hz, 1H), 2.14 (d, J=10.5 Hz, 1H), 1.83-1.72 (m,
1H), 1.11 (q, J=6.7 Hz, 2H), 0.97-0.88 (m, 2H), 0.85-0.78 (m,
2H).
Example 172
##STR00233##
[0690]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)-
acetamide
[0691] (172A): Acetic anhydride (0.011 mL, 0.119 mmol) was added to
a solution of
(+/-)-3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidi-
n-1-yl)-4-chlorobenzonitrile (Example 171D), (41 mg, 0.108 mmol) in
dichloromethane (5 mL) at 0.degree. C. The reaction mixture was
stirred at room temperature for 1 h. Solvent was evaporated and the
crude product was purified by flash chromatography on silica gel
using an automated ISCO system (24 g column, eluting with 0.5-5%
methanol/dichloromethane).
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethy-
lsilyl)oxy)piperidin-4-yl)acetamide (44 mg) was obtained as a
colorless oil which solidified upon standing.
[0692] MS (ESI) m/z 423.2 (M+H).
[0693] Example 172: The title compound was prepared starting from
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 1) and
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethy-
lsilyl)oxy)piperidin-4-yl)acetamide using a method analogous to
that used to prepare Example 171.
[0694] MS (ESI) m/z 507.4
[0695] 1H NMR (500 MHz, DMSO-d6) .delta. 9.33 (d, J=4.2 Hz, 1H),
8.83 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=1.7 Hz, 1H), 7.82 (d, J=7.5
Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 4.99 (d, J=4.7 Hz, 1H), 3.61-3.50
(m, 2H), 3.61-3.50 (m, 2H), 3.41 (d, J=11.7 Hz, 1H), 3.19 (t,
J=16.5 Hz, 2H), 3.24-3.14 (m, 2H), 3.03-2.94 (m, 1H), 2.82-2.73 (m,
1H), 1.90 (d, J=10.0 Hz, 1H), 1.94-1.87 (m, 1H), 1.85 (s, 3H),
1.64-1.45 (m, 2H), 1.37-1.22 (m, 2H), 0.79 (d, J=5.3 Hz, 4H).
Example 173
##STR00234##
[0696] Methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0697] (173A): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1, 600 mg,
1.809 mmol),
(3R,4R)-4-((E)-(4-methoxybenzylidene)amino)piperidin-3-ol (424 mg,
1.809 mmol) ((prepared according to a published literature
procedure: Fink, Brian, et al., WO 2005/066176),
Pd.sub.2(dba).sub.3 (49.7 mg, 0.054 mmol),
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (101 mg, 0.163 mmol),
and cesium carbonate (1474 mg, 4.52 mmol) in dioxane (20 mL) was
evacuated and filled with nitrogen three times and heated at
110.degree. C. overnight. The reaction mixture was diluted with
dichloromethane and filtered through Celite. The filtrate was
concentrated and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (40 g
column, eluting with 0-10% 2N ammonia in methanol/dichloromethane)
to give tert-butyl
(3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carba-
mate (568 mg,) as a brown solid.
[0698] MS (ESI) m/z 367.2
[0699] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.30 (d, J=1.4
Hz, 1H), 7.19 (s, 1H), 7.00 (d, J=1.9 Hz, 1H), 3.54 (td, J=9.2, 4.4
Hz, 1H), 3.50-3.44 (m, 1H), 3.29-3.20 (m, 1H), 2.75 (td, J=11.6,
2.4 Hz, 1H), 2.65 (ddd, J=10.8, 8.7, 4.6 Hz, 1H), 2.59 (dd, J=10.8,
9.7 Hz, 1H), 2.23 (br. s., 3H), 2.03-1.95 (m, 1H), 1.72-1.61 (m,
1H).
[0700] (173B): Dimethyl dicarbonate (164 mg, 1.227 mmol) was added
to a solution of
tert-butyl(3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanoph-
enyl)carbamate (300 mg, 0.818 mmol) and triethylamine (0.228 mL,
1.636 mmol) in dichloromethane (2 mL) at 0.degree. C. and the
resulting solution was stirred at room temperature for 1.5 h.
Solvent was evaporated and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (40 g
gold column, eluting with 0-30% ethyl acetate/dichloromethane).
Methyl
((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-hydroxypiperidin-4--
yl)carbamate (150 mg) was obtained as a white solid.
[0701] MS (ESI) m/z 425.4
[0702] .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.34 (d, J=1.8
Hz, 1H), 7.19 (s, 1H), 7.01 (d, J=2.0 Hz, 1H), 4.81 (br. s., 1H),
3.81-3.69 (m, 4H), 3.65-3.42 (m, 3H), 3.30-3.21 (m, 1H), 2.82 (td,
J=11.6, 2.5 Hz, 1H), 2.71-2.60 (m, 1H), 2.13 (d, J=8.8 Hz, 1H),
1.82-1.69 (m, 1H), 1.57 (s, 9H).
[0703] (173C): Triisopropylsilyl trifluoromethanesulfonate (0.288
mL, 1.060 mmol) was added to a solution of
((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-hydroxypiperidin-4--
yl)carbamate (150 mg, 0.353 mmol) and triethylamine (0.196 mL,
1.412 mmol) in dichloromethane (5 mL) and the resulting mixture was
stirred at room temperature overnight. The reaction mixture was
partitioned between saturated sodium bicarbonate and
dichloromethane. The layers were separated and aqueous layer was
extracted with dichloromethane two more times. The combined organic
layer was dried over magnesium sulfate, filtered and concentrated
in vacuo. The crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 0-10% ethyl acetate/dichloromethane). Methyl
((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-((triisopropylsilyl-
)oxy)piperidin-4-yl)carbamate (242 mg) was obtained as a brown
oil.
[0704] MS (ESI) m/z 581.3
[0705] (173D): Methyl
((3R,4R)-1-(2-chloro-5-cyano-3-(N-Boc-amino)phenyl)-3-((triisopropylsilyl-
)oxy)piperidin-4-yl)carbamate (242 mg, 0.354 mmol) was treated with
TFA (25% in 1,2-dichloroethane, 4 mL, 12.98 mmol) at room
temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with cold saturated sodium
bicarbonate/1N aqueous sodium hydroxide (pH 10), the organic layer
was dried over magnesium sulfate, filtered and concentrated in
vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 0-20% ethyl acetate/dichloromethane). Methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)pip-
eridin-4-yl)carbamate (135 mg) was obtained as a white solid.
[0706] MS (ESI) m/z 481.3
[0707] Example 173: The title compound was prepared starting from
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 2) and
N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-4-((tert-butyldimethylsilyl-
)oxy)pyrrolidin-3-yl)acetamide using a method analogous to that
used to prepare Example 7.
[0708] MS (ESI) m/z 523.1 (M+H);
[0709] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.89-8.78 (m,
1H), 7.89 (s, 1H), 7.59 (s, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.76 (br.
s., 1H), 4.83 (br. s., 1H), 3.83-3.69 (m, 4H), 3.67-3.53 (m, 2H),
3.40-3.26 (m, 1H), 3.08 (dd, J=6.9, 3.3 Hz, 1H), 2.89-2.81 (m, 1H),
2.70 (t, J=10.4 Hz, 1H), 2.34-2.11 (m, 1H), 1.95-1.73 (m, 1H),
1.16-1.09 (m, 2H), 0.87-0.80 (m, 2H).
Example 174
##STR00235##
[0710] methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0711] (174A): (+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyl
dimethylsilyl)oxy)piperidin-4-yl)carbamate (Example 171E, 927 mg,
2.112 mmol) was separated by chiral SFC (Berger SFC MGIII, Column:
Lux Cel-4 25.times.3 cm ID, 5 .mu.m; Flow rate: 85.0 mL/min; Mobile
Phase: 85/15 CO.sub.2/methanol; Detector Wavelength: 220 nm).
Methyl
((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (406 mg) was obtained as a white
foaming solid. The enantiomeric purity of each fraction was
estimated to be greater than 99.5%.
[0712] (174B): methyl
((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate was prepared starting from
methyl
((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (127 mg, 0.289 mmol) according to
general procedure for the coupling of aniline to
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile, method described for Example 7. Methyl
((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate (180 mg) was obtained as a
white solid.
[0713] MS (ESI) m/z 757.5 (M+H)
[0714] .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.94 (s, 1H),
7.21 (d, J=8.6 Hz, 2H), 6.98 (d, J=1.7 Hz, 1H), 6.87 (d, J=8.6 Hz,
2H), 4.55 (d, J=7.2 Hz, 1H), 3.81 (s, 3H), 3.77-3.73 (m, 1H), 3.72
(s, 3H), 3.60-3.51 (m, 1H), 3.44 (ddd, J=11.4, 4.5, 2.1 Hz, 1H),
3.25 (d, J=11.7 Hz, 1H), 2.86 (td, J=11.7, 2.2 Hz, 1H), 2.65 (dd,
J=11.4, 9.4 Hz, 1H), 2.22 (dd, J=13.2, 4.3 Hz, 1H), 1.48 (s, 6H),
1.16 (q, J=6.5 Hz, 2H), 0.93 (s, 12H), 0.15 (s, 3H), 0.13 (s,
3H).
[0715] Example 174: Methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
was prepared starting from methyl
((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate using a method analogous to
that used to prepare Example 171.
[0716] MS (ESI) m/z 523.3
[0717] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.80 (d, J=1.7
Hz, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.02 (d, J=1.7 Hz, 1H), 6.76
(br. s., 1H), 4.81 (br. s., 1H), 3.80-3.72 (m, 4H), 3.64-3.42 (m,
3H), 3.30 (d, J=10.0 Hz, 1H), 3.06 (td, J=7.0, 3.5 Hz, 1H),
2.87-2.79 (m, 1H), 2.68 (t, J=10.4 Hz, 1H), 2.14 (d, J=9.4 Hz, 1H),
1.82-1.71 (m, 1H), 1.14-1.08 (m, 2H), 0.85-0.79 (m, 2H).
Example 175
##STR00236##
[0718]
N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)methan-
esulfonamide
[0719] (175A): tert-butyl
(3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyano
phenyl)carbamate (Example 173A, 326 mg, 0.889 mmol) was treated
with TFA (25% in 1,2-dichloroethane, 3 mL) at room temperature for
1 h. Solvent was evaporated and to the residue was added
dichloromethane and concentrated again. The crude was dried in
vacuo overnight and then dissolved in methanol, 2N ammonia in
methanol was added to neutralize TFA and then solvent was
evaporated. The crude intermediate
3-amino-5-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-4-chlorobenzonitrile
was dissolved in THF/Water (10:1) and triethylamine (0.186 mL,
1.333 mmol) and di-tert-butyl dicarbonate (255 mg, 1.17 mmol) was
added at 0.degree. C. and the reaction solution was stirred at room
temperature overnight. Solvent was evaporated and the crude product
was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 0-40% ethyl
acetate/dichloromethane). tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (230 mg) was obtained as a light yellow solid.
[0720] MS (ESI) m/z 367.3
[0721] (175B): Chlorotriisopropylsilane (0.547 mL, 2.194 mmol) was
added to a solution of tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (230 mg, 0.627 mmol) and imidazole (213 mg, 3.13 mmol) in DMF
(5 mL) and the resulting solution was stirred at room temperature
overnight. LCMS showed half conversion. More imidazole (2 eq, 85
mg) and Chlorotriisopropylsilane (0.2 mL) were added and stirring
continued for 3 h. There was still 30% SM left. More imidazole (100
mg) and Chlorotriisopropylsilane (0.2 mL) were added and the
reaction was stirred overnight. The reaction mixture was
partitioned between ethyl acetate and water, the layers were
separated and the organic layer was washed with water two more
times, dried over magnesium sulfate, filtered and concentrated in
vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 10-30% ethyl acetate/hexanes). tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)pip-
eridin-4-yl)carbamate (300 mg) was obtained as a white solid.
[0722] MS (ESI) m/z 523.5
[0723] (175C): tert-butyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl-
)oxy)piperidin-4-yl)carbamate was prepared starting from
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 2) and tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)pip-
eridin-4-yl)carbamate using a method analogous to that used to
prepare Example 171.
[0724] (175D): TFA (1 mL, 3.24 mmol) was added to a solution of
tert-butyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl-
)oxy)piperidin-4-yl)carbamate (184 mg, 0.219 mmol) and anisole (20
.mu.l, 0.183 mmol) in dichloromethane (1 mL) and the reaction
solution was stirred at 30.degree. C. overnight. The reaction
mixture was diluted with dichloromethane and washed with cold
saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10),
the organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo, the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (24 g
column, eluting with 1-4% methanol/dichloromethane).
2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-
-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (126 mg) was obtained as a white solid.
[0725] MS (ESI) m/z 621.4
[0726] (175E): Methanesulfonyl chloride (7.5 .mu.l, 0.10 mmol) was
added to a solution of
2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-
-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (25 mg, 0.040 mmol) and triethylamine (17 .mu.l, 0.120
mmol) in dichloromethane (1 mL) and the reaction solution was
stirred at room temperature overnight. The crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (12 g column, eluting with 0-40% ethyl
acetate/dichloromethane).
N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin--
4-yl)methanesulfonamide (28 mg) was obtained as a white solid.
[0727] MS (ESI) m/z 699.3
[0728] Example 175: TBAF (1M in THF, 0.048 mL, 0.048 mmol) was
added to a solution of
N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin--
4-yl)methanesulfonamide (28 mg, 0.040 mmol) in THF (2 mL) and the
reaction mixture was stirred at room temperature overnight. Solvent
was evaporated and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (12 g
column, eluting with 0-6% methanol/dichloromethane).
N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)methanesulfo-
namide (21 mg) was obtained as a white solid.
[0729] MS (ESI) m/z 543.2
[0730] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (br. s.,
1H), 8.84 (br. s., 1H), 8.20 (s, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.31
(d, J=1.7 Hz, 1H), 7.17 (d, J=6.9 Hz, 1H), 5.20 (d, J=5.5 Hz, 1H),
3.51 (tt, J=9.7, 5.0 Hz, 1H), 3.45-3.38 (m, 1H), 3.25-3.17 (m, 2H),
3.06 (br. s., 1H), 3.01-2.95 (m, 4H), 2.83-2.72 (m, 1H), 2.01-1.92
(m, 1H), 1.66 (qd, J=12.2, 4.2 Hz, 1H), 0.79 (d, J=5.3 Hz, 4H).
Example 176
##STR00237##
[0731] 2-methoxyethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0732] (176A): 2-methoxyethyl carbonochloridate (5.08 mg, 0.037
mmol) was added to a solution of
2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-
-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (Example 174D, 19 mg, 0.031 mmol) and triethylamine
(8.53 .mu.l, 0.061 mmol) in dichloromethane (1 mL) and the reaction
solution was stirred at room temperature overnight. More
2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added
and stirring continued over the weekend, still about 30% SM left.
More triethylamine (100 .mu.L) and 2-methoxyethyl carbonochloridate
(20 .mu.L) was added and stirred for another day. The reaction
mixture was diluted with dichloromethane and washed with cold
saturated sodium bicarbonate. The organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo, and the
crude product was purified by flash chromatography on silica gel
using an automated ISCO system (24 g column, eluting with 0-40%
ethyl acetate/dichloromethane) to give 2-methoxyethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4--
yl)carbamate (12 mg).
[0733] MS (ESI) m/z 723.4
[0734] (176B): The title compound was prepared starting from
2-methoxyethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4--
yl)carbamate using a method analogous to that used to prepare
Example 175.
[0735] MS (ESI) m/z 567.2
[0736] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.35 (br. s.,
1H), 8.87 (br. s., 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.32 (d, J=2.0
Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 5.02 (d, J=5.0 Hz, 1H), 4.10-4.04
(m, 2H), 3.54-3.49 (m, 3H), 3.20-3.14 (m, 4H), 2.98 (quin, J=5.6
Hz, 1H), 2.81-2.71 (m, 1H), 1.88 (d, J=10.9 Hz, 1H), 1.60-1.54 (m,
4H), 0.78 (d, J=5.0 Hz, 4H).
Example 177
##STR00238##
[0737] (+/-)-2-(dimethylamino)ethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0738] (177A): di-tert-butyl dicarbonate (0.206 g, 0.945 mmol) was
added to a solution of
(+/-)-3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidi-
n-1-yl)-4-chlorobenzonitrile (Example 171D, 0.3 g, 0.787 mmol) and
triethylamine (0.220 mL, 1.575 mmol) in dichloromethane (5 mL) at
0.degree. C. and the reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel using an automated ISCO system (80 g
column, eluting with 5-30% ethyl acetate/dichloromethane).
(+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (342 mg) was obtained as a colorless
oil which was used as such in the next reaction.
[0739] (177B): A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 2, 185 mg, 0.464 mmol),
(+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethyl
silyl)oxy)piperidin-4-yl)carbamate (223 mg, 0.464 mmol) and cesium
carbonate (302 mg, 0.927 mmol) in DMF (5 mL) was heated at
50.degree. C. for 4 h. LCMS showed completion of reaction. The
reaction mixture was diluted with ethyl acetate and the solid was
filtered off. The filtrate was concentrated in vacuo and the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 10-35% ethyl
acetate/hexanes). (+/-)-tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate (270 mg) was obtained as a
white solid.
[0740] MS (ESI) m/z 799.4
[0741] (177C): TFA (25% in 1,2-dichloroethane, 4 mL, 12.98 mmol)
was added to a solution of (+/-)-tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate (270 mg, 0.338 mmol) and
anisole (0.148 mL, 1.351 mmol) in 1,2-dichloroethane (2 mL) and the
resulting solution was heated at 30.degree. C. overnight The
reaction mixture was diluted with dichloromethane and washed with
cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH
10), the layers were separated and aqueous layer was extracted with
dichloromethane/methanol (4/1) two more times. The combined organic
layers were dried over magnesium sulfate, filtered and concentrated
in vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 1-7% methanol/dichloromethane to afford
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piper-
idin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f-
][1,2,4]triazine-7-carbonitrile (119 mg,) and then 6-16% 2 N
ammonia in methanol/dichloromethane to give
(+/-)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e (8 mg,).
[0742] MS (ESI) m/z 579.4
[0743] (177D): A solution of
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (32 mg, 0.055 mmol) in THF (1 mL) was
added to CDI (35.8 mg, 0.221 mmol) in THF (1 mL) at 0.degree. C.
and the reaction mixture was stirred at room temperature overnight.
In a 1-dram vial charged with 2-(dimethylamino)ethanol (44.6 mg,
0.500 mmol) in THF (1 mL) was added lithium
bis(trimethylsilyl)amide (1M in THF, 0.884 mL, 0.884 mmol) at
0.degree. C. and the resulting reaction solution was stirred at
room temperature for 10 min before added to the above intermediate.
The reaction mixture was stirred at room temperature for 1 h
Solvent was evaporated and the residue was partitioned between
dichloromethane and saturated sodium bicarbonate. The layers were
separated and the organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (24 g column, eluting with 1-8% methanol/dichloromethane).
(+/-)-2-(dimethylamino)ethyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperi-
din-4-yl)carbamate (34 mg) was obtained as a white solid.
[0744] MS (ESI) m/z 694.4
[0745] Example 177: TBAF (1M in THF, 0.059 mL, 0.059 mmol) was
added to a solution of (+/-)-2-(dimethylamino)ethyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperi-
din-4-yl)carbamate (34 mg, 0.049 mmol) in THF (1 mL) and the
resulting solution was stirred at room temperature overnight.
Solvent was evaporated and the residue was partitioned between
dichloromethane and saturated sodium bicarbonate. The layers were
separated and aqueous layer was extracted with
dichloromethane/methanol (4/1) two more times. The combined organic
layers were dried over magnesium sulfate, filtered and concentrated
in vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (24 g gold column,
eluting with 2-12% 2 N ammonia in methanol/dichloromethane).
(+/-)-2-(dimethylamino)ethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(22 mg) was obtained as a white solid.
[0746] MS (ESI) m/z 580.2
[0747] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.79 (d, J=1.7
Hz, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.02
(d, J=1.9 Hz, 1H), 5.20 (br. s., 1H), 4.33-4.12 (m, 2H), 3.76 (br.
s., 1H), 3.65-3.51 (m, 2H), 3.35-3.27 (m, 1H), 3.07 (tq, J=7.1, 3.5
Hz, 1H), 2.82 (td, J=11.6, 2.1 Hz, 1H), 2.68 (t, J=9.8 Hz, 1H),
2.60 (t, J=5.4 Hz, 2H), 2.32 (s, 6H), 2.17-2.10 (m, 1H), 1.83-1.69
(m, 1H), 1.16-1.07 (m, 2H), 0.86-0.80 (m, 2H).
Example 178
##STR00239##
[0748] 2-morpholinoethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0749] The title compound was prepared from
2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-
-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (Example 175D) and 2-morpholinoethanol using a method
analogous to that used to prepare Example 177.
[0750] MS (ESI) m/z 622.4
[0751] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.81 (d, J=1.7
Hz, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.98
(br. s., 1H), 5.02 (br. s., 1H), 4.27 (br. s., 2H), 3.81-3.71 (m,
6H), 3.63-3.53 (m, 2H), 3.36-3.28 (m, 1H), 3.11-3.04 (m, 1H), 2.84
(td, J=11.7, 2.2 Hz, 1H), 2.67 (t, J=5.5 Hz, 3H), 2.54 (br. s.,
4H), 2.19-2.11 (m, 1H), 1.77 (qd, J=11.8, 3.9 Hz, 1H), 1.15-1.09
(m, 2H), 0.86-0.80 (m, 2H).
Example 179
##STR00240##
[0752] (+/-)-oxetan-3-yl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0753] The title compound was prepared from
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (Example 177C) and oxetan-3-ol using a
method analogous to that used to prepare Example 177.
[0754] MS (ESI) m/z 565.2
[0755] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.82 (d, J=1.7
Hz, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 7.03 (d, J=1.9 Hz, 1H), 6.95
(d, J=2.2 Hz, 1H), 5.53-5.45 (m, 1H), 5.05 (d, J=6.7 Hz, 1H), 4.92
(t, J=6.9 Hz, 2H), 4.74-4.65 (m, 2H), 3.80 (tt, J=9.2, 4.6 Hz, 1H),
3.66-3.51 (m, 2H), 3.37-3.22 (m, 2H), 3.07 (tq, J=7.1, 3.5 Hz, 1H),
2.85 (t, J=10.8 Hz, 1H), 2.70 (t, J=10.1 Hz, 1H), 2.25-2.13 (m,
1H), 1.86-1.75 (m, 1H), 1.15-1.09 (m, 2H), 0.87-0.80 (m, 2H).
Example 180
##STR00241##
[0756] (+/-)-1-(oxetan-3-yl)azetidin-3-yl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[0757] (180A): A mixture of oxetan-3-one (0.5 g, 6.94 mmol),
azetidin-3-ol hydrochloride (1.140 g, 10.41 mmol) and 4 A molecular
sieves (1.5 g) in dichloromethane (10 mL) was stirred at room
temperature for 4 h. Sodium triacetoxyborohydride (2.94 g, 13.88
mmol) was added and the reaction mixture was stirred at room
temperature overnight. The precipitate was filtered through a pad
of celite and the filtrate was diluted with ethyl acetate (more
precipitate appeared) and filtered again. The filtrate was
concentrated in vacuo and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (80 g
column, eluting with 3-10% 2N ammonia in methanol/dichloromethane).
1-(oxetan-3-yl)azetidin-3-ol was obtained as colorless oil.
[0758] MS (ESI) m/z 130.0
[0759] .sup.1H NMR (400 MHz, chloroform-d) .delta. 4.71 (t, J=6.7
Hz, 2H), 4.56-4.48 (m, 3H), 3.78 (tt, J=6.6, 5.3 Hz, 1H), 3.69-3.63
(m, 2H), 3.10-3.04 (m, 2H).
[0760] Example 180: The title compound was prepared from
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (Example 177C) and
1-(oxetan-3-yl)azetidin-3-ol using a method analogous to that used
to prepare Example 177.
[0761] MS (ESI) m/z 620.1
[0762] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.81 (d, J=1.7
Hz, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.89
(d, J=2.5 Hz, 1H), 5.19-5.12 (m, 1H), 5.03 (d, J=7.2 Hz, 1H), 4.73
(t, J=6.8 Hz, 2H), 4.55 (ddd, J=6.9, 5.2, 2.1 Hz, 2H), 3.88-3.82
(m, 1H), 3.81-3.75 (m, 1H), 3.72 (t, J=7.4 Hz, 2H), 3.64-3.52 (m,
2H), 3.35-3.25 (m, 3H), 3.07 (tq, J=7.1, 3.5 Hz, 1H), 2.89-2.80 (m,
1H), 2.70 (t, J=10.3 Hz, 1H), 2.18 (d, J=10.5 Hz, 1H), 1.83-1.76
(m, 2H), 1.15-1.09 (m, 2H), 0.86-0.81 (m, 2H).
Example 181
##STR00242##
[0763]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)-
morpholine-4-carboxamide
[0764] (181A): TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 mmol) was
added to a solution of (+/-)-tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)am-
ino)phenyl)piperidin-4-yl)carbamate (Example 20B, 180 mg, 0.225
mmol) and anisole (0.098 mL, 0.901 mmol) in dichloromethane (1 mL)
and the resulting reaction mixture was stirred at room temperature
for 1 h. LCMS showed consumption of starting material and formation
of two products (desired product and loss of Boc and PMB
by-product). The reaction mixture was diluted with dichloromethane,
washed cold saturated sodium bicarbonate/1N aqueous sodium
hydroxide (pH 10). The layers were separated and aqueous layer was
extracted with dichloromethane two more times. The combined organic
layer was dried over magnesium sulfate, filtered and concentrated
in vacuo. The crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 1-3% methanol/dichloromethane) to give
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazine-7-carbonitrile (114 mg) and
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (30 mg).
[0765] MS (ESI) m/z 699.3 (M+H).
[0766] (181B): A solution of
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg, 0.057 mmol) in
THF (1 mL) was added to CDI (37.1 mg, 0.229 mmol) in THF (1 mL) at
0.degree. C. and the reaction mixture was stirred at room
temperature overnight. Morpholine (39.9 mg, 0.458 mmol) was added
and the reaction mixture was stirred at room temperature for 1 h.
LCMS showed completion of reaction. Solvent was evaporated and the
residue was partitioned between dichloromethane and saturated
sodium bicarbonate. The layers were separated and the organic layer
was dried over magnesium sulfate, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel using an automated ISCO system (24 g column, eluting
with 2-6% 2 N ammonia in methanol/dichloromethane).
(+/-)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-(-
(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
-2-yl)amino)phenyl)piperidin-4-yl)morpholine-4-carboxamide (34 mg)
was obtained as a white solid.
[0767] MS (ESI) m/z 812.5 (M+H).
[0768] Example 181:
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)morpho-
line-4-carboxamide was prepared from
(+/-)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-(-
(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
-2-yl)amino)phenyl)piperidin-4-yl)morpholine-4-carboxamide using a
method analogous to that used to prepare Example 171.
[0769] MS (ESI) m/z 578.2
[0770] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.32 (d, J=4.2
Hz, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=1.9 Hz, 1H), 7.32
(d, J=1.9 Hz, 1H), 6.36 (d, J=7.5 Hz, 1H), 3.67-3.60 (m, 1H),
3.59-3.55 (m, 2H), 3.38-3.20 (m, 11H), 3.01-2.95 (m, 1H), 2.81-2.74
(m, 1H), 1.98-1.82 (m, 1H), 1.61 (qd, J=12.2, 4.3 Hz, 1H),
0.81-0.77 (m, 4H).
Example 182
##STR00243##
[0771]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)-
-4-methylpiperazine-1-carboxamide
[0772] The title compound was prepared from
(+/-)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e (byproduct from Example 177), using a method analogous to that
used to prepare Example 181.
[0773] MS (ESI) m/z 591.2
[0774] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.80 (d, J=1.7
Hz, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.85
(d, J=2.2 Hz, 1H), 4.55 (d, J=5.3 Hz, 1H), 3.77-3.68 (m, 2H),
3.63-3.56 (m, 1H), 3.47 (q, J=4.5 Hz, 4H), 3.40-3.33 (m, 1H), 3.07
(tq, J=7.0, 3.6 Hz, 1H), 2.83 (td, J=11.8, 2.2 Hz, 1H), 2.65 (dd,
J=11.5, 9.3 Hz, 1H), 2.46 (t, J=5.0 Hz, 4H), 2.35 (s, 3H),
2.10-2.04 (m, 1H), 1.86-1.76 (m, 2H), 1.15-1.09 (m, 2H), 0.86-0.81
(m, 2H).
Example 183
##STR00244##
[0775]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)-
-2-morpholinoacetamide
[0776] (183A): A mixture of
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171E, 40 mg,
0.057 mmol), 2-morpholinoacetic acid (9.96 mg, 0.069 mmol) and HATU
(26.1 mg, 0.069 mmol) in DMF (1 mL) was stirred at room temperature
for 6 h. The reaction mixture was diluted with dichloromethane and
was filtered. The filtrate was concentrated in vacuo and the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (24 g column, eluting with 5-50% ethyl
acetate/hexanes).
(+/-)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-(-
(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
-2-yl)amino)phenyl)piperidin-4-yl)-2-morpholinoacetamide (46 mg)
was obtained as a white solid.
[0777] MS (ESI) m/z 826.6
[0778] Example 183: The title compound was prepared from
(+/-)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-(-
(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
-2-yl)amino)phenyl)piperidin-4-yl)-2-morpholinoacetamide using a
method analogous to that used to prepare Example 171.
[0779] MS (ESI) m/z 592.3
[0780] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=4.2
Hz, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.64
(d, J=6.9 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H), 5.00 (d, J=5.5 Hz, 1H),
3.70-3.56 (m, 6H), 3.46-3.38 (m, 1H), 3.23 (d, J=11.1 Hz, 1H),
3.03-2.88 (m, 3H), 2.84-2.74 (m, 1H), 2.59-2.53 (m, 1H), 2.46 (br.
s., 3H), 1.95-1.85 (m, 1H), 1.63 (qd, J=12.1, 4.0 Hz, 1H), 0.79 (d,
J=5.3 Hz, 4H).
Example 184
##STR00245##
[0781]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)-
-2-(4-methylpiperazin-1-yl)acetamide
[0782] Prepared analogous manner as example 183
[0783] MS (ESI) m/z 605.3
[0784] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=4.4
Hz, 1H), 8.84 (s, 1H), 8.21 (s, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.63
(br. s., 1H), 7.33 (d, J=1.7 Hz, 1H), 7.15-7.05 (m, 2H), 6.90-6.77
(m, 2H), 5.01 (d, J=5.3 Hz, 1H), 3.83-3.77 (m, 1H), 3.74-3.69 (m,
3H), 3.67-3.55 (m, 2H), 3.42 (d, J=9.7 Hz, 1H), 3.23 (d, J=11.7 Hz,
1H), 3.06-2.94 (m, 3H), 2.84-2.76 (m, 2H), 2.44 (br. s., 2H), 1.91
(d, J=8.9 Hz, 1H), 1.68-1.55 (m, 1H), 0.79 (d, J=5.3 Hz, 4H).
Example 185
##STR00246##
[0785]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)-
-2-(4-methylpiperazin-1-yl)acetamide
[0786] Prepared analogous manner as example 180
[0787] MS (ESI) m/z 581.1
Example 186
##STR00247##
[0788]
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(methylamino)pipe-
ridin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-
-7-carbonitrile
[0789] (186A): A mixture of benzyl
7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (0.7 g, 3.00 mmol)
and methanamine (3.75 mL, 30.0 mmol) in ethanol (5 mL) was heated
in a sealed reaction pressure vessel at 70.degree. C. overnight.
The reaction mixture was cooled to room temperature and
concentrated to dryness. The residue was dissolved in
dichloromethane (5.00 mL), triethylamine (0.502 mL, 3.60 mmol) and
di-tert-butyl dicarbonate (0.766 mL, 3.30 mmol) were added and the
reaction mixture was stirred at room temperature for 4 h. The
reaction mixture was washed with water and brine, dried over
magnesium sulfate and concentrated to give colorless oil.
[0790] The above oil was dissolved in DMF (5.00 mL), imidazole
(0.409 g, 6.00 mmol) and tert-butyldimethylchlorosilane (0.678 g,
4.50 mmol) was added. The mixture was stirred at room temperature
overnight. Water was added and the reaction mixture was extracted
with ethyl acetate (3.times.), the organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo, the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (80 g gold column, eluting with 5-30% ethyl
acetate/hexanes) to give (+/-)-(3R,4R)-benzyl
3-((tert-butoxycarbonyl)(methyl)amino)-4-((tert-butyldimethylsilyl)oxy)pi-
peridine-1-carboxylate (Isomer A, 0.697 g) and (+/-)-(3R,4R)-benzyl
4-((tert-butoxycarbonyl)(methyl)amino)-3-((tert-butyldimethylsilyl)oxy)pi-
peridine-1-carboxylate (Isomer B, 0.556 g). The structures were
confirmed by NMR studies (.sup.1H-1D, .sup.13C-1D, COSY, NOESY,
dept-.sup.1H-.sup.13C-HSQC, .sup.1H-.sup.13C-HMBC).
[0791] Isomer A (+/-)-(3R,4R)-benzyl
3-((tert-butoxycarbonyl)(methyl)amino)-4-((tert-butyldimethylsilyl)oxy)pi-
peridine-1-carboxylate:
[0792] MS (ESI) m/z 479.5
[0793] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.39-7.27
(m, 5H), 5.12 (br. s., 2H), 4.82 (s, 2H), 4.09 (dt, J=13.7, 2.0 Hz,
1H), 4.00 (d, J=10.3 Hz, 2H), 3.61 (br. s., 1H), 3.06 (br. s., 1H),
2.82 (br. s., 4H), 2.05-1.92 (m, 1H), 1.51-1.37 (m, 11H), 0.89-0.85
(m, 9H), 0.11-0.06 (m, 6H).
[0794] Isomer B (+/-)-(3R,4R)-benzyl
4-((tert-butoxycarbonyl)(methyl)amino)-3-((tert-butyldimethylsilyl)oxy)pi-
peridine-1-carboxylate:
[0795] MS (ESI) m/z 501.5
[0796] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.39 (d,
J=4.7 Hz, 5H), 5.29-4.96 (m, 2H), 4.84 (s, 2H), 4.27 (br. s., 1H),
4.20-4.11 (m, 1H), 3.94-3.56 (m, 2H), 2.79 (br. s., 4H), 2.72-2.53
(m, 1H), 1.84 (br. s., 1H), 1.65 (br. s., 1H), 1.47 (s, 9H), 0.89
(d, J=2.8 Hz, 9H), 0.26-0.11 (m, 6H).
[0797] (186B): (+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)(methyl)carbamate was prepared starting from
(+/-)-(3R,4R)-benzyl
4-((tert-butoxycarbonyl)(methyl)amino)-3-((tert-butyldimethylsilyl)oxy)pi-
peridine-1-carboxylate using a method analogous to that used to
prepare Example 171C-D.
[0798] MS (ESI) m/z 495.3
[0799] Example 186: The title compound was prepared from
(+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)(methyl)carbamate using a method analogous to
that used to prepare Example 174.
[0800] MS (ESI) m/z 479.3
[0801] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.69 (d,
J=1.9 Hz, 1H), 7.87 (s, 1H), 7.01 (d, J=1.9 Hz, 1H), 3.62 (td,
J=9.6, 4.7 Hz, 1H), 3.43 (ddd, J=10.8, 4.7, 2.2 Hz, 1H), 3.02 (tt,
J=7.2, 3.7 Hz, 1H), 2.71 (td, J=11.9, 2.2 Hz, 1H), 2.57 (t, J=10.4
Hz, 1H), 2.43 (s, 3H), 2.36 (ddd, J=11.3, 9.2, 4.4 Hz, 1H),
2.11-2.05 (m, 1H), 1.54 (qd, J=12.2, 4.2 Hz, 1H), 1.02-0.98 (m,
2H), 0.80-0.74 (m, 2H).
Example 187
##STR00248##
[0802] (+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)(methyl)carbam-
ate
[0803] (187A): (+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)(methyl)carbamate (Example 186B, 78 mg, 0.158
mmol) was treated with TFA (25% in 1,2-dichloroethane, 0.012 mL,
0.158 mmol) at room temperature for 1 h. The reaction mixture was
diluted with dichloromethane and washed with cold saturated sodium
bicarbonate/1N aqueous sodium hydroxide (pH 10). The organic layer
was dried over magnesium sulfate, filtered and concentrated in
vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (12 g column, eluting
with 1-10% 2 N ammonia in methanol/dichloromethane) to give
(+/-)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(methylamino)-
piperidin-1-yl)-4-chlorobenzonitrile (54 mg) was obtained as a
colorless oil.
[0804] MS (ESI) m/z 495.3.
[0805] To a solution of
(+/-)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(methylamino)-
piperidin-1-yl)-4-chlorobenzonitrile (54 mg, 0.137 mmol) and
triethylamine (0.022 mL, 0.158 mmol) in dichloromethane (3 mL) at
0.degree. C. was added dimethyl dicarbonate (21.12 mg, 0.158 mmol)
in dichloromethane (1 mL) and the reaction solution was stirred at
room temperature for 2 h. Solvent was evaporated and the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (24 g column, eluting with 0-25% ethyl
acetate/dichloromethane). (+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)(methyl)carbamate (59 mg) was obtained as a light
yellow solid.
[0806] MS (ESI) m/z 453.2 (M+H).
[0807] Example 187: The title compound was prepared from
(+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)(methyl)carbamate using a method analogous to
that used to prepare Example 171.
[0808] MS (ESI) m/z 537.1
[0809] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.89-8.80 (m,
1H), 7.92-7.86 (m, 1H), 7.61 (s, 1H), 7.04 (dd, J=4.2, 1.7 Hz, 1H),
6.76 (br. s., 1H), 3.76 (br. s., 2H), 3.72-3.62 (m, 1H), 3.47-3.35
(m, 1H), 3.08 (td, J=6.9, 3.3 Hz, 1H), 3.01-2.80 (m, 5H), 2.26-2.01
(m, 1H), 2.01-1.83 (m, 1H), 1.19-1.08 (m, 2H), 0.87-0.80 (m,
2H).
Example 188
##STR00249##
[0810]
(+/-)-2-((3-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)-2-chloro-5-cy-
anophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile
[0811] (188A): TBAF, 1 M in THF (0.774 mL, 0.774 mmol) was added to
a solution of
(+/-)-3-N-Boc-amino-5-((3R,4R)-4-N-Boc-amino-3-((tert-butyldimethylsilyl)-
oxy)piperidin-1-yl)-4-chlorobenzonitrile (Example 171C, 300 mg,
0.516 mmol) in THF (2 mL) and the reaction mixture was stirred at
room temperature overnight. Solvent was evaporated and the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 5-60% ethyl
acetate/dichloromethane) to give (+/-)-tert-butyl
((3R,4R)-1-(3-N-Boc-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl-
)carbamate (254 mg) was obtained as a colorless oil.
[0812] MS (ESI) m/z 467.2
[0813] (188B): Sodium hydride (60% in mineral oil, 15.83 mg, 0.396
mmol) was added to a solution of (+/-)-tert-butyl
((3R,4R)-1-(3-N-Boc-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl-
)carbamate (154 mg, 0.330 mmol) and iodomethane (61.9 .mu.l, 0.989
mmol) in THF at room temperature and the reaction mixture was
stirred for 6 h. The reaction was quenched with addition of water
and extracted with ethyl acetate (three times). The combined
organic layers were dried over magnesium sulfate, filtered and
concentrated in vacuo, the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (40 g
column, eluting with 0-30% ethyl acetate/dichloromethane).
(+/-)-tert-butyl
((3R,4R)-1-(3-N-Boc-amino-2-chloro-5-cyanophenyl)-3-methoxypiperidin-4-yl-
)carbamate (95 mg) was obtained as a colorless oil.
[0814] MS (ESI) m/z 481.2
[0815] (188C): (+/-)-tert-butyl
((3R,4R)-1-(3-N-Boc-amino-2-chloro-5-cyanophenyl)-3-methoxypiperidin-4-yl-
)carbamate (95 mg, 0.198 mmol) was treated with TFA (25% in
1,2-dichloroethane, 2 mL, 6.49 mmol) at room temperature for 1 h.
Solvent was evaporated and the crude was redissolved in
dichloromethane and concentrated again. The crude product was dried
under vacuum overnight and neutralized with triethylamine and
concentrated. The crude product was used without purification.
[0816] MS (ESI) m/z 281.2 (M+H).
[0817] (188D): di-tert-butyl dicarbonate (0.028 mL, 0.119 mmol) in
dichloromethane (1 mL) was added to a solution of
(+/-)-3-amino-5-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)-4-chlorobenzoni-
trile (0.028 g, 0.099 mmol) and triethylamine (0.028 mL, 0.198
mmol) in dichloromethane (1 mL) at 0.degree. C. and the resulting
reaction solution was stirred at room temperature for 2 h Solvent
was evaporated and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (24 g
column, eluting with 0-30% ethyl acetate/dichloromethane).
(+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-methoxypiperidin-4-yl)carba-
mate (26 mg) was obtained as a colorless oil.
[0818] MS (ESI) m/z 381.1
[0819] Example 188: The title compound was prepared from
(+/-)-tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-methoxypiperidin-4-yl)carba-
mate using a method analogous to that used to prepare Example
171.
[0820] MS (ESI) m/z 479.1
[0821] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.94 (s,
1H), 6.71 (d, J=1.7 Hz, 1H), 6.61 (d, J=1.7 Hz, 1H), 5.00 (td,
J=9.6, 4.4 Hz, 1H), 4.00 (ddd, J=11.0, 4.6, 1.9 Hz, 1H), 3.32-3.27
(m, 1H), 3.10-3.03 (m, 2H), 2.95-2.90 (m, 1H), 2.88 (s, 3H), 2.58
(t, J=10.4 Hz, 1H), 2.14-2.08 (m, 1H), 1.80 (qd, J=12.3, 4.3 Hz,
1H), 0.98-0.89 (m, 2H), 0.79-0.71 (m, 2H).
Example 189
##STR00250##
[0822] (+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-methoxypiperidin-4-yl)carbamate
[0823] (189A): Dimethyl dicarbonate (15.93 mg, 0.119 mmol) in
dichloromethane (1 mL) was added to a solution of
(+/-)-3-amino-5-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)-4-chlorobenzoni-
trile (Example 41C, 27.8 mg, 0.099 mmol) and triethylamine (0.028
mL, 0.198 mmol) in dichloromethane (1 mL) at 0.degree. C. and the
resulting reaction solution was stirred at room temperature for 2
h. Solvent was evaporated and the crude product was purified by
flash chromatography on silica gel using an automated ISCO system
(24 g column, eluting with 0-50% ethyl acetate/dichloromethane).
(+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-methoxypiperidin-4-yl)carba-
mate (15 mg) was obtained as a colorless oil.
[0824] MS (ESI) m/z 339.0
[0825] Example 189: The title compound was prepared (+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-methoxypiperidin-4-yl)carba-
mate using a method analogous to that used to prepare Example
171.
[0826] MS (ESI) m/z 537.1
[0827] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.94 (s,
1H), 6.72 (d, J=1.7 Hz, 1H), 6.62 (d, J=1.7 Hz, 1H), 5.23 (td,
J=9.6, 4.7 Hz, 1H), 3.88 (ddd, J=16.6, 11.5, 4.9 Hz, 2H), 3.64 (br.
s., 3H), 3.4-4.269 (m, 1H), 3.07 (tt, J=7.3, 3.7 Hz, 1H), 2.92 (t,
J=11.7 Hz, 1H), 2.88 (s, 3H), 2.75 (t, J=10.4 Hz, 1H), 2.26 (d,
J=8.3 Hz, 1H), 1.93-1.83 (m, 1H), 0.96-0.91 (m, 2H), 0.77-0.71 (m,
2H).
Example 190
##STR00251##
[0828]
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-hydroxypiperidin-3-yl)-
acetamide
[0829] (190A):
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-4-((tert-butyldimethy-
l silyl)oxy)piperidin-3-yl)acetamide was prepared starting from
(+/-)-tert-butyl ((3R,4R)-4-hydroxypiperidin-3-yl)carbamate
(prepared according to a published literature procedure: Fink,
Brian, et al., WO 2005/066176) using a method analogous to that
used to prepare Example 171.
[0830] MS (ESI) m/z 423.2
[0831] (190B):
(+/-)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-hydroxypiperidin-3-yl)acetam-
ide was prepared starting from
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 2) and
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-4-((tert-butyldimethy-
lsilyl)oxy)piperidin-3-yl)acetamide using a method analogous to
that used to prepare Example 171.
[0832] MS (ESI) m/z 507.1
[0833] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.31 (br. s.,
1H), 8.83 (br. s., 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.77 (d, J=7.5
Hz, 1H), 7.31 (s, 1H), 4.86 (d, J=5.3 Hz, 1H), 3.73 (d, J=4.7 Hz,
1H), 2.97 (d, J=4.7 Hz, 1H), 2.76 (t, J=10.5 Hz, 1H), 2.00 (d,
J=9.7 Hz, 1H), 1.85 (s, 3H), 1.63 (d, J=10.0 Hz, 1H), 0.78 (d,
J=5.3 Hz, 4H).
Example 191
##STR00252##
[0834] (+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-4-hydroxypiperidin-3-yl)carbamate
[0835] The title compound was prepared starting from
(+/-)-tert-butyl ((3R,4R)-4-hydroxypiperidin-3-yl)carbamate
(prepared according to a published literature procedure: Fink,
Brian, et al., WO 2005/066176) using a method analogous to that
used to prepare Example 171.
[0836] MS (ESI) m/z 523.2
[0837] .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.80 (d, J=1.5
Hz, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.94
(d, J=2.2 Hz, 1H), 5.37 (br. s, 1H), 3.83 (br. s., 2H), 3.72 (s,
3H), 3.51 (d, J=10.3 Hz, 1H), 3.29-3.19 (m, 1H), 3.06 (tq, J=7.0,
3.6 Hz, 1H), 2.95-2.86 (m, 1H), 2.85-2.74 (m, 1H), 2.56 (br. s.,
1H), 2.24-2.13 (m, 1H), 1.92-1.81 (m, 1H), 1.14-1.06 (m, 2H),
0.85-0.78 (m, 2H).
Example 192
##STR00253##
[0838]
(+/-)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylami-
no)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)ami-
no)piperidin-3-yl 2-amino-3-methylbutanoate
[0839] (192A): A mixture of
(S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (30.4 mg,
0.140 mmol), Tetramethylfluoroformamidinium hexafluorophosphate
(37.0 mg, 0.140 mmol) and triethyl amine (0.039 mL, 0.280 mmol) in
dichloromethane (1 mL) was stirred at room temperature for 1 h.
(+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4--
yl)carbamate (Example 171, 18 mg, 0.028 mmol) and DMAP (0.342 mg,
2.80 .mu.mol) were added and the reaction solution was stirred at
room temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo, the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (12 g
column, eluting with 5-30% ethyl acetate/dichloromethane).
(+/-)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methox-
ybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxyc-
arbonyl)amino)piperidin-3-yl
2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (23 mg) was
obtained as a colorless oil.
[0840] MS (ESI) m/z 842.5 (M+H)
[0841] Example 192: TFA (25% in DCE, 2 ml) was added to a solution
of
(+/-)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methox-
ybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxyc-
arbonyl)amino)piperidin-3-yl
2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (23 mg, 0.027
mmol) and anisole (0.012 ml, 0.109 mmol) in DCE (1 mL) and the
resulting solution was stirred at 35.degree. C. overnight. The
reaction mixture was concentrated and purified by prep-HPLC to give
the title compound (13 mg) as a white solid.
[0842] MS (ESI) m/z 622.2 (M+H)
[0843] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.82 (s, 1H),
7.88 (s, 1H), 7.59 (s, 1H), 7.00 (d, J=1.9 Hz, 1H), 6.86 (d, J=2.2
Hz, 1H), 5.03 (td, J=9.5, 4.3 Hz, 1H), 4.96-4.86 (m, 1H), 3.86 (br.
s., 1H), 3.70 (d, J=6.7 Hz, 3H), 3.61-3.51 (m, 1H), 3.40-3.31 (m,
1H), 3.11-3.03 (m, 1H), 2.92-2.76 (m, 2H), 2.33-2.21 (m, 1H),
2.17-2.02 (m, 1H), 1.87-1.77 (m, 1H), 1.15-1.08 (m, 2H), 1.01 (t,
J=6.7 Hz, 3H), 0.91 (dd, J=10.0, 6.7 Hz, 3H), 0.86-0.80 (m, 2H)
[0844] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 192
TABLE-US-00007 TABLE 4 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 193 ##STR00254##
(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-
4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4-
((methoxycarbonyl)amino)-3-piperidinyl glycinate 580.01 2.57 194
##STR00255## (3R,4R)-1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4-
((methoxycarbonyl)amino)-3-piperidinyl
1-aminocyclopropanecarboxylate 606.04 2.78 195 ##STR00256##
(3R,4R)-1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4-
((methoxycarbonyl)amino)-3-piperidinyl L-alaninate 594.03 2.80 196
##STR00257## (3R,4R)-1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4-
((methoxycarbonyl)amino)-3-piperidinyl 4-morpholinylacetate 650.10
2.73 197 ##STR00258## (3R,4R)-1-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4-
((methoxycarbonyl)amino)-3-piperidinyl 2-(phosphonooxy)propanoate
675.00 2.72 198 ##STR00259##
(2E)-4-(((3S,4S)-1-(2-chloro-5-cyano-3- ((7-cyano-4-
(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4- ((methoxycarbonyl)amino)-3-
piperidinyl)oxy)-4-oxo-2-butenoic acid 621.01 3.79 199 ##STR00260##
(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-
4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazin-2-yl)amino)phenyl)-4-
((methoxycarbonyl)amino)-3-piperidinyl
(4-(phosphonooxy)phenyl)acetate 737.07 3.63 *= HPLC conditions YMC
S5 ODS 4.6 .times. 50 mm, 10-90% aqueous methanol containing 0.2%
H.sub.3PO.sub.4, 5 min. gradient, monitored at 220 nm
Example 200
##STR00261##
[0845] methyl
(4-chloro-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2--
yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)carbamate
[0846] (200A): Methyl
3-((tert-butoxycarbonyl)amino)-4-chloro-5-(4-methylpiperazin-1-yl)benzoat-
e was prepared starting from methyl
3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate
(Intermediate 3) and 1-methylpiperazine according to procedure for
example 1A
[0847] MS (ESI) m/z 384.3
[0848] .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.56 (d, J=1.8
Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.15 (s, 1H), 3.93 (s, 3H), 3.10
(t, J=4.2 Hz, 4H), 2.64 (br. s., 4H), 2.39 (s, 3H), 1.57 (s,
9H).
[0849] (200B): Lithium hydroxide (2.61 mL, 5.21 mmol) was added to
a solution of methyl
3-((tert-butoxycarbonyl)amino)-4-chloro-5-(4-methylpiperazin-1-yl)benzoat-
e (1.0 g, 2.61 mmol) in THF (10 mL) and methanol (2.5 mL). The
resulting mixture was stirred at room temperature overnight. The
reaction mixture was concentrated and azeotroped with acetonitrile
to afford 1.30 g of crude product which was used as is without
further purification.
[0850] MS (ESI) m/z 370.1
[0851] (200C): To a solution of crude
3-((tert-butoxycarbonyl)amino)-4-chloro-5-(4-methylpiperazin-1-yl)benzoic
acid (2.61 mmol) in dioxane (34 mL) were added diphenylphosphoryl
azide (2.220 mL, 10.30 mmol) and triethylamine (1.914 mL, 13.74
mmol). The reaction mixture was heated at 80.degree. C. for 3
hours. Methanol (5 mL) was added and the reaction was heated for
another two hours. The reaction was cooled to room temperature.
Solvent was evaporated and the residue was partitioned between
dichloromethane and saturated sodium bicarbonate. The layers were
separated and aqueous layer was extracted with dichloromethane two
more times. The combined organic layers were dried over magnesium
sulfate, filtered and concentrated in vacuo, the crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (80 g column, eluting with 50-100% ethyl
acetate/hexanes with 2% triethyl amine) to give tert-butyl methyl
(4-chloro-5-(4-methylpiperazin-1-yl)-1,3-phenylene)dicarbamate (630
mg).
[0852] MS (ESI) m/z 399.2
[0853] .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.79 (d, J=2.4
Hz, 1H), 7.25 (br. s., 1H), 7.16 (s, 1H), 6.66 (s, 1H), 3.79 (s,
3H), 3.09 (br. s., 4H), 2.63 (br. s., 4H), 2.39 (s, 3H), 1.56 (s,
9H).
[0854] (200D): methyl
(3-amino-4-chloro-5-(4-methylpiperazin-1-yl)phenyl)carbamate was
prepared starting from tert-butyl methyl
(4-chloro-5-(4-methylpiperazin-1-yl)-1,3-phenylene)dicarbamate
using a method analogous to that used to prepare Example 171D.
[0855] MS (ESI) m/z 299.1 (M+H).
[0856] Example 200: The title compound was prepared from
3-amino-4-chloro-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzonitrile
using a method analogous to that used to prepare Example 171.
[0857] MS (ESI) m/z 532.3
[0858] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.32 (d, J=4.2
Hz, 1H), 8.79 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=1.7 Hz, 1H), 7.29
(d, J=1.9 Hz, 1H), 3.39-3.25 (m, 9H, overlapping with water),
3.03-2.95 (m, 1H), 2.70 (t, J=11.1 Hz, 2H), 2.34 (br. s., 4H), 2.16
(s, 3H), 1.87 (d, J=11.4 Hz, 2H), 1.65-1.53 (m, 2H), 0.80 (d, J=5.5
Hz, 4H).
[0859] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 200
TABLE-US-00008 TABLE 5 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 201 ##STR00262## methyl
(4-chloro-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)-5-(3-(4-morpholinyl)-1- azetidinyl)phenyl)carbamate
539.00 3.57 202 ##STR00263## (+/-) methyl (4-chloro-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)-5-((3S,4R)-3-fluoro-4- ((methoxycarbonyl)amino)-1-
piperidinyl)phenyl)carbamate 572.99 4.23 203 ##STR00264## methyl
(4-chloro-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)-5-(3-(4-methyl-1-piperazinyl)-1-
azetidinyl)phenyl)carbamate 552.04 3.80 204 ##STR00265## methyl
(4-chloro-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)-5-(3-(4-methoxy-1-piperidinyl)-1-
azetidinyl)phenyl)carbamate 567.05 4.2 205 ##STR00266## methyl
(4-chloro-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)-5-(4-(4-morpholinyl)-1- piperidinyl)phenyl)carbamate
567.05 4.42 206 ##STR00267## methyl
3-(7-cyano-4-(cyclopropylamino)imidazo[1,2-
f][1,2,4]triazin-2-ylamino)-4-fluoro-5-(4-(oxetan-3-
yl)piperazin-1-yl)phenylcarbamate 522.54 3.79 .sup.c *= HPLC
conditions CHROMOLITH .RTM. column 4.6 .times. 50 mm eluting with
10-90% aqueous methanol over 5 min. containing 0.1% TFA, 4 mL/min,
monitoring at 220 nm.
Example 207
##STR00268##
[0860]
2-(2-chloro-5-cyano-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phen-
ylamino)-4-(cyclopropylamino)imidazo[1,2-f][1,2,4]triazine-7-carbonitrile
[0861] (207A): A mixture of
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahyd-
ropyridine (300 mg, 1.345 mmol), tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1)(372 mg,
1.120 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II)
dichloride (92 mg, 0.112 mmol), and Cs.sub.2CO.sub.3 (1095 mg, 3.36
mmol) in DMF (8 ml) in a microwave vial was flushed with N2 and
heated at 80.degree. C. for 6 h. This was diluted with EtOAc (200
ml), washed with water (40 ml.times.4), brine, and dried over
Na.sub.2SO.sub.4. Removal of the solvent followed by silica gel
chromatography eluting with DCM containing 0 to 3% MeOH gave
tert-butyl
(2-chloro-5-cyano-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)carba-
mate (321 mg) as a solid.
[0862] MS (ESI) m/z 348.22
[0863] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.48 (d, J=1.7 Hz,
1H), 7.20 (s, 1H), 7.14 (d, J=2.0 Hz, 1H), 5.69 (dt, J=3.2, 1.7 Hz,
1H), 3.12 (q, J=2.7 Hz, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.53-2.30 (m,
5H), 1.57-1.51 (m, 9H).
[0864] (207B): A solution of tert-butyl
(2-chloro-5-cyano-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)carba-
mate (90 mg, 0.207 mmol) in DCM (2 ml) and TFA (1 mL) was stirred
at room temperature for 2 h. Removal of the solvents was followed
by preparative HPLC (100.times.30 mm Luna C18 column, Solvent A=10%
Methanol, 90% H.sub.2O, 0.1% TFA; solvent B=90% Methanol, 10%
H.sub.2O, 0.1% TFA, Flow rate 42 ml per min, 0-60% B, over 20 min).
The HPLC fractions containing the product were applied onto a
cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer.
This was washed with methanol and product was eluted with 2 N
solution of ammonia in methanol. Removal of the solvents left
3-amino-4-chloro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzonit-
rile (43 mg) as a solid.
[0865] MS (ESI) m/z 248.10 (M+1)
[0866] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 7.02 (d,
J=2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 5.69 (tt, J=3.3, 1.6 Hz,
1H), 3.14 (q, J=2.7 Hz, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.53-2.46 (m,
2H), 2.42 (s, 3H).
[0867] Example 207: A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 4, 52.4 mg, 0.131 mmol),
3-amino-4-chloro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile
(31 mg, 0.125 mmol) and Cs2CO3 (82 mg, 0.250 mmol) in DMF (1 mL)
was heated at 70.degree. C. for 2 h. The reaction mixture was
diluted with ethyl acetate and washed with water. Removal of the
solvent was followed by preparative HPLC (100.times.30 mm Luna C18
column, Solvent A=10% Methanol, 90% H.sub.2O, 0.1% TFA; solvent
B=90% Methanol, 10% H.sub.2O, 0.1% TFA, Flow rate 42 ml per min,
20-100% B, over 20 min). The HPLC fractions containing the PMB
protected product was applied onto a cartridge of Phenomenex
Strata-X-C 33 um cation mixed-mode polymer. This was washed with
methanol and product was eluted with 2 N solution of ammonia in
methanol. Removal of the solvents left 47 mg of material which was
dissolved in DCM (2 ml) and treated with anisole (0.027 mL, 0.250
mmol) and TFA (1 mL). After 2 hr, additional TFA (1 mL) was added
and the reaction was left stirring at room temperature
overnight.
[0868] Removal of the solvents was followed by preparative HPLC
(100.times.30 mm Luna C18 column, Solvent A=10% Methanol, 90%
H.sub.2O, 0.1% TFA; solvent B=90% Methanol, 10% H.sub.2O, 0.1% TFA,
Flow rate 42 ml per min, 15-100% B, over 20 min). The fractions
containing the product were applied onto a cartridge of Phenomenex
Strata-X-C 33 um cation mixed-mode polymer. This was washed with
methanol and the product was eluted with 2 N solution of ammonia in
methanol. Removal of the solvents left
2-((2-chloro-5-cyano-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(20.2 mg) as a white solid.
[0869] MS (ESI) m/z 446.17
[0870] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.99 (d, J=1.8 Hz,
1H), 7.88 (s, 1H), 7.61 (s, 1H), 7.19 (s, 1H), 6.89 (br. s., 1H),
5.75 (dt, J=3.2, 1.6 Hz, 1H), 3.24 (m., 2H), 3.07 (td, J=7.1, 3.3
Hz, 1H), 2.80 (m, 2H), 2.56 (br. s., 2H), 2.52 (s, 3H), 1.18-1.07
(m, 2H), 0.92-0.75 (m, 2H).
Example 208
##STR00269##
[0871]
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0872] (208A): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (1.0 g, 3.02 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.206
g, 0.302 mmol), and copper(I) iodide (0.115 g, 0.603 mmol) in a dry
microwave vial was flushed with nitrogen. N,N-dimethylacetamide (3
mL) was added followed by
(1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (9.52 mL,
9.05 mmol, approximately 1 M solution in N,N-dimethylacetamide
prepared as described in the Journal of Organic Chemistry, 2004,
69, 5120). The vial was sealed and heated at 80.degree. C.
overnight. After cooling to room temperature, the reaction was
partitioned between EtOAc and sat. aq. NH.sub.4Cl solution. This
was left stirring for 30 min. The aqueous phase was washed with
EtOAc and the combined organic phases were washed with brine and
dried with sodium sulfate. Removal of the solvents followed by
radial silica gel chromatography eluting with hexane containing 5
to 30% EtOAc afforded tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperidine-1-car-
boxylate (0.376 g) as a white solid.
[0873] MS (ESI) m/z 458.21 (M+23)
[0874] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.48 (d, J=1.7
Hz, 1H), 7.23-7.16 (m, 2H), 4.30 (br. s., 2H), 3.21-3.12 (m, 1H),
2.94-2.76 (m, 2H), 1.90-1.78 (m, 2H), 1.58-1.54 (m, 11H), 1.51 (s,
9H)
[0875] (208B): To a solution of tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperidine-1-car-
boxylate (370 mg, 0.849 mmol) in DCM (24 mL) was added TFA (12 mL).
After 2 h, the solvents were removed. The residue was taken in MeOH
and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation
mixed-mode polymer. This was washed with methanol and product was
eluted with 2 N solution of ammonia in methanol. Removal of the
solvents left 3-amino-4-chloro-5-(piperidin-4-yl)benzonitrile (196
mg) which was used as such in the next reaction.
[0876] MS (ESI) m/z 236.01)
[0877] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 6.98 (d, J=2.0 Hz,
1H), 6.87 (d, J=2.0 Hz, 1H), 5.84 (s, 2H), 3.08-2.91 (m, 3H),
2.65-2.54 (m, 2H), 1.63 (d, J=12.8 Hz, 2H), 1.47 (qd, J=12.3, 3.8
Hz, 2H).
[0878] (208C): To a suspension of
3-amino-4-chloro-5-(piperidin-4-yl)benzonitrile (168 mg, 0.713
mmol) in DCM (2 ml) was added Et3N (0.099 mL, 0.713 mmol), followed
by di-tert-butyl dicarbonate (163 mg, 0.748 mmol). After stirring
at room temperature overnight, the solvents were removed to leave
tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (257 mg)
as a white solid which was used as such.
[0879] MS (ESI) m/z 358.12
[0880] (208D): A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (142 mg, 0.357 mmol), tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (100 mg,
0.298 mmol) and Cs.sub.2CO.sub.3 (194 mg, 0.596 mmol) in DMF (3 mL)
was heated at 70.degree. C. for 2 h. This was diluted with EtOAc,
washed with water and brine and dried over Na.sub.2SO.sub.4. The
crude mixture containing
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was
carried forward to next step.
[0881] Example 208: The crude intermediate was dissolved in DCE (1
mL) and anisole (20.70 .mu.L), and TFA (0.5 mL) were added. The
resulting mixture was heated at 50.degree. C. for 3 h. Removal of
the solvents was followed by preparative HPLC (Waters XBridge C18,
19.times.200 mm, 5-.mu.m particles; Guard Column: Waters XBridge
C18, 19.times.10 mm, 5-.mu.m particles; Mobile Phase A: water with
20-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with
20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a
5-minute hold at 100%. B; Flow: 20 mL/min.). Fractions containing
the desired product were combined and dried via centrifugal
evaporation to afford
2-((2-chloro-5-cyano-3-(4-piperidinyl)phenyl)amino)-4-(cyclopropylamino)i-
midazo[2,1-f][1,2,4]triazine-7-carbonitrile (164 mg) as a
solid.
[0882] MS (ESI) m/z 433.91
Example 209
##STR00270##
[0883]
2-(2-chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenylamino)-4-(cyclo-
propylamino)imidazo[1,2,f][1,2,4]triazine-7-carbonitrile
[0884] (209A): A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (142 mg, 0.357 mmol), tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (100 mg,
0.298 mmol) and Cs.sub.2CO.sub.3 (194 mg, 0.596 mmol) in DMF (3 mL)
was heated at 70.degree. C. for 2 h. This was diluted with EtOAc,
washed with water and brine and dried over Na.sub.2SO.sub.4. After
the solvent was removed, the crude Boc protected intermediate was
dissolved in DCE (1 mL). TFA (0.5 mL) was added and the reaction
was stirred at room temperature for 1 h. The solvents were removed
and the residue was taken up in MeOH and applied onto a cartridge
of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was
washed with methanol and product was eluted with 2 N solution of
ammonia in methanol. Removal of the solvents left
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (164
mg) as a solid which was used as such in the next reaction.
[0885] MS (ESI) m/z 554.29 (M+1)
[0886] Example 209: Sodium triacetoxyborohydride (24.10 mg, 0.114
mmol) was added to a stirred suspension of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30.0
mg, 0.038 mmol), formaldehyde 37% in water (8.47 .mu.L, 0.114 mmol)
and HOAc (16.27 .mu.L, 0.190 mmol) in DCE (379 .mu.L) at room
temperature for 30 min. Sat. aq. NaHCO.sub.3 solution was slowly
added (gas evolution) and the reaction was left stirring for 10
min. It was extracted with DCM. The organic phase was dried with
sodium sulfate and the solvents were removed. The crude
intermediate was dissolved in DCE (1 mL) and anisole (20.70 .mu.L,
0.190 mmol), and TFA (0.5 mL) were added. The resulting mixture was
heated at 50.degree. C. for 3 h. Removal of the solvents was
followed by preparative HPLC (Waters XBridge C18, 19.times.200 mm,
5-.mu.m particles; Guard Column: Waters XBridge C18, 19.times.10
mm, 5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 methanol: water with 20-mM ammonium
acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold
at 100%. B; Flow: 20 mL/min.). Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford 14.9 mg of
2-((2-chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cycloprop-
ylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
[0887] MS (ESI) m/z 448.20
[0888] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.36 (br. s.,
1H), 8.90 (br. s., 1H), 8.36-8.29 (m, 1H), 8.22 (s, 1H), 7.58 (d,
J=1.8 Hz, 1H), 3.01-2.87 (m, 4H), 2.22 (s, 3H), 2.00 (td, J=10.8,
4.1 Hz, 2H), 1.81-1.67 (m, 4H), 0.80 (s, 4H).
[0889] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 209
TABLE-US-00009 TABLE 6 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 210 ##STR00271##
2-((2-chloro-5-cyano-3-(1-(3-oxetanyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
489.97 4.37 211 ##STR00272##
2-(2-chloro-5-cyano-3-(1-(2-methoxyethyl)piperidin-4-
yl)phenylamino)-4-(cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 491.98 3.28 212 ##STR00273##
2-(2-chloro-5-cyano-3-(1-(2,2-difluoroethyl)piperidin-
4-yl)phenylamino)-4-(cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 497.94 3.80 213 ##STR00274##
2-(2-chloro-5-cyano-3-(1'-cyclopropyl-1,4'-bipiperidin-
4-yl)phenylamino)-4-(cyclopropylamino)imidazo[1,2-
f][1,2,4]triazine-7-carbonitrile 557.10 4.37 214 ##STR00275##
2-((2-chloro-5-cyano-3-(1-((2S)-2-hydroxypropyl)-4-
piperidinyl)phenyl)amino)-4-(ethylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 479.97 3.72 215 ##STR00276##
2-((2-chloro-5-cyano-3-(1-(cyclopropylmethyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
488.00 3.89 216 ##STR00277## (S)-2-(2-chloro-5-cyano-3-(1-(2-
hydroxypropyl)piperidin-4-yl)phenylamino)-4-
(cyclopropylamino)imidazo[1,2-f][1,2,4]triazine-7- carbonitrile
491.98 3.53 217 ##STR00278##
2-((3-(1-((3R,4R)-4-amino-3-hydroxycyclohexyl)-4-
piperidinyl)-2-chloro-5-cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
547.06 3.91 218 ##STR00279## 2-(3-(1-((3R,4R)-4-amino-3-(tert-
butyldimethylsilyloxy)cyclohexyl)piperidin-4-yl)-2-
chloro-5-cyanophenylamino)-4-
(cyclopropylamino)imidazo[1,2-f][1,2,4]triazine-7- carbonitrile
661.33 4.68 219 ##STR00280##
2-((2-chloro-5-cyano-3-(1-(2-hydroxy-2-methylpropyl)-
4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
506.01 4.14 220 ##STR00281## 2-[4-(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)piperidin-1-yl]acetamide 491.1 3.89 221
##STR00282## 2-((3-(1-(3,3-bis(hydroxymethyl)cyclobutyl)-4-
piperidinyl)-2-chloro-5-cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
548.05 3.22 222 ##STR00283##
2-((2-chloro-5-cyano-3-(1-(2-oxaspiro[3.3]hept-6-yl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
530.03 3.63 223 ##STR00284##
2-((2-chloro-5-cyano-3-(1-(3-~2~H)-3-oxetanyl-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
490.98 4.34 224 ##STR00285##
2-((2-chloro-5-cyano-3-(1-(3,3,3-trifluoropropyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
529.96 4.12 225 ##STR00286##
2-((2-chloro-5-cyano-3-(1-((3-methyl-3-
oxetanyl)methyl)-4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
518.02 *= HPLC conditions YMC S5 ODS 4.6 .times. 50 mm, 10-90%
aqueous methanol containing 0.2% H.sub.3PO.sub.4, 5 min. gradient,
monitored at 220 nm
Example 226
##STR00287##
[0890] methyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)piperidine-1-carboxylate
[0891] To a solution of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Intermediate 208A) (30 mg, 0.054 mmol) in CH.sub.2Cl.sub.2 (2 mL)
at 0.degree. C. was added triethylamine (0.015 mL, 0.108 mmol)
followed by methyl chloroformate (diluted with CH.sub.2CL.sub.2,
10V %) (0.046 mL, 0.060 mmol) drop wise. The reaction completed
within 1 h at 0.degree. C. To the reaction mixture was added
anisole (0.023 mL, 0.271 mmol), followed by TFA (0.6 ml), and then
heated at 50.degree. C. for 3 h.
[0892] The solvent was evaporated. To the residue was added 2N
NH.sub.3 in MeOH (8 ml) and stirred for 10 min, The resulting solid
was collected by filtration, rinsed with 2N NH.sub.3 in MeOH (1
ml.times.2), air dried to give methyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)piperidine-1-carboxylate (14.5 mg).
[0893] MS (ESI) m/z 492.28
[0894] 1H NMR (500 MHz, CHLOROFORM-d) d 8.96 (d, J=1.8 Hz, 1H),
7.88 (s, 1H), 7.61 (s, 1H), 7.20 (d, J=1.8 Hz, 1H), 6.86 (br. s.,
1H), 4.36 (m., 2H), 3.76 (s, 3H), 3.27 (tt, J=12.1, 3.1 Hz, 1H),
3.07 (td, J=7.0, 3.4 Hz, 1H), 2.96-3.06 (m, 1H), 1.91 (d, J=13.1
Hz, 2H), 1.72-1.54 (m, 3H), 1.16-1.06 (m, 2H), 0.87-0.77 (m,
2H).
[0895] The compounds listed below were prepared by the similar
synthetic procedure used for Example 226
TABLE-US-00010 TABLE 7 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 227 ##STR00288##
2-((2-chloro-5-cyano-3-(1-(methoxyacetyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
505.97 4.57 .sup.c 228 ##STR00289##
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperidinyl)-1,1-dimethyl-2- oxoethyl acetate
562.03 4.78 229 ##STR00290##
2-((3-(1-acetyl-4-piperidinyl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
475.94 4.80 230 ##STR00291##
2-((2-chloro-5-cyano-3-(1-(cyanoacetyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
500.95 4.71 .sup.c 231 ##STR00292##
2-((2-chloro-5-cyano-3-(1-(2-hydroxy-2-
methylpropanoyl)-4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
519.99 4.72 232 ##STR00293## 2-((2-chloro-5-cyano-3-(1-((1-
hydroxycyclopropyl)carbonyl)-4- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
517.98 4.79 .sup.c 233 ##STR00294##
2-((2-chloro-5-cyano-3-(1-((3-methyl-3-
oxetanyl)carbonyl)-4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
532.01 4.43 234 ##STR00295##
2-((2-chloro-5-cyano-3-(1-(2,2-dimethylpropanoyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
518.02 4.78 235 ##STR00296##
2-((2-chloro-5-cyano-3-(1-(3,3-dimethylbutanoyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
532.05 4.54 236 ##STR00297##
2-((2-chloro-5-cyano-3-(1-(cyclopropylcarbonyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
501.98 4.82 237 ##STR00298##
2-((2-chloro-5-cyano-3-(1-(3,3,3-trifluoropropanoyl)-
4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
543.94 4.63 238 ##STR00299## 3-oxetanyl
4-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-1-piperidinecarboxylate 533.98 4.67 239
##STR00300## 2-((2-chloro-5-cyano-3-(1-(2-methylalanyl)-4-
piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
519.01 4.18 240 ##STR00301##
2-((3-(1-L-alanyl-4-piperidinyl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
504.98 4.10 241 ##STR00302##
2-((3-(1-D-alanyl-4-piperidinyl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
504.98 4.13 * = HPLC conditions CHROMOLITH .RTM. column 4.6 .times.
50 mm eluting with 10-90% aqueous methanol over 4 min. containing
0.1% TFA, 4 mL/min, monitoring at 220 nm.
Example 242
##STR00303##
[0896]
2-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)ph-
enyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitri-
le
[0897] (242A): Cesium carbonate (672 mg, 2.063 mmol), BINAP (64.2
mg, 0.103 mmol), 1-(oxetan-3-yl)piperazine (176 mg, 1.238 mmol) and
Pd.sub.2(dba).sub.3 (94 mg, 0.103 mmol) were weighed into a 25 mL
round bottom flask at room temperature. A solution of tert-butyl
(3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate
in toluene (4294 .mu.l, 1.031 mmol) was added and the reaction was
degassed 3 times by evacuating the flask under vacuum and then
purging with N.sub.2. The reaction mixture was heated to
106.degree. C. for 16 h and then cooled to room temperature. The
reaction mixture was diluted with EtOAc, sonicated, filtered
through celite and concentrated. The product was purified by column
chromatography (40 g SiO2, 30 to 100% EtOAc-hexane gradient
elution) to afford 312 mg of tert-butyl
(2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-m-
ethoxybenzyl)carbamate.
[0898] MS (ESI) m/z 538.4
[0899] (242B): Anisole (633 .mu.l, 5.80 mmol) was added to a
solution of tert-butyl
(2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-m-
ethoxybenzyl)carbamate (312 mg, 0.58 mmol) in DCE (3 mL), followed
by the addition 2.8 mL of TFA. The reaction was stirred at
60.degree. C. for 3 h. The residue was partitioned between
CH.sub.2Cl.sub.2 and sat. NaHCO.sub.3, and extracted into
CH.sub.2Cl.sub.2 (3.times.). The solution was dried over
Na.sub.2SO.sub.4 and concentrated. The residue was dissolved in
MeOH and loaded onto a 5 g Strata SCX ion exchange cartridge,
washing with MeOH. The desired product was eluted with 7 N
NH.sub.3--CH.sub.3OH. After concentration, 163.4 mg of
2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline
was obtained.
[0900] MS (ESI) m/z 318.1 (M.sup.++H).
[0901] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 6.70-6.66 (m,
1H), 6.64-6.60 (m, 1H), 6.61-6.38 (m, 1H), 4.72 (quin, J=6.3 Hz,
4H), 4.26 (s, 2H), 3.64 (quin, J=6.4 Hz, 1H), 3.21-3.07 (m, 4H),
2.69-2.47 (m, 4H).
[0902] (242C): A mixture of
2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline
(50 mg, 0.157 mmol),
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (94 mg, 0.236 mmol) and cesium
carbonate (103 mg, 0.315 mmol) in DMF (1574 .mu.l) was stirred at
40.degree. C. for 72 h. The reaction mixture was cooled to room
temperature, diluted with H.sub.2O and extracted with EtOAc
(3.times.). The combined organics were washed with 10% LiCl
solution and concentrated. Column chromatography (12 g SiO.sub.2, 0
to 100% EtOAc-hexane gradient elution) afforded
2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)a-
mino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-
-carbonitrile (76.7 mg).
[0903] MS (ESI) m/z 636.4 (M.sup.++H).
[0904] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.05 (s, 1H),
7.95 (s, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.00-6.78 (m, 3H), 4.73
(quin, J=6.3 Hz, 4H), 3.82 (s, 3H), 3.65 (quin, J=6.5 Hz, 1H), 3.16
(t, J=4.7 Hz, 4H), 2.99 (s, 1H), 2.92 (s, 1H), 2.59 (d, J=5.3 Hz,
4H), 1.13-1.04 (m, 2H), 0.89 (d, J=4.8 Hz, 2H)
[0905] Example 242:
2-((2-Chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)a-
mino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-
-carbonitrile (69 mg, 0.108 mmol) was dissolved in DCE (1 mL) at
room temperature. Anisole (59.2 .mu.l, 0.542 mmol) followed by 200
.mu.L of TFA were added and the reaction was stirred at 40.degree.
C. overnight and concentrated. The residue was dissolved in MeOH
and loaded onto a 1 g/6 mL Strata SCX ion exchange column, washing
with CH.sub.3OH. The desired product was eluted with 7 N
NH.sub.3--CH.sub.3OH, concentrated under a stream of N2. Column
chromatography (12 g SiO2, 0 to 20% CH.sub.3OH--CH.sub.2Cl.sub.2
gradient elution) followed by trituration with ACN afforded
2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)a-
mino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(14.6 mg).
[0906] MS (ESI) m/z 516.3
[0907] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.27 (d, J=4.8
Hz, 1H), 8.67 (s, 1H), 8.20 (s, 1H), 7.99-7.85 (m, 1H), 7.13-7.07
(m, 1H), 7.21-6.84 (m, 1H), 4.63-4.55 (m, 2H), 4.50 (t, J=6.2 Hz,
2H), 3.53 (quin, J=6.4 Hz, 1H), 3.13-2.98 (m, 5H), 2.48 (d, J=1.3
Hz, 4H), 0.84-0.69 (m, 4H).
[0908] The compounds listed below were prepared by the similar
synthetic procedure used for Example 242
TABLE-US-00011 TABLE 8 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 243 ##STR00304## methyl
(3R,4R)-1-(2-chloro-3- (7-cyano-4- (cyclopropylamino)imidazo
[1,2-f][1,2,4]triazin-2- ylamino)-5- (difluoromethyl)phenyl)-3-
hydroxypiperidin-4- ylcarbamate 547.95 3.67 244 ##STR00305##
2-((2-chloro-5- (difluoromethyl)-3-(4-methyl- 4-(4-morpholinyl)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 558.03 3.78 245 ##STR00306##
2-((3-(4-amino-4-methyl-1- piperidinyl)-2-chloro-5-
(difluoromethyl)phenyl)amino)- 4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 487.94 2.80 246 ##STR00307##
2-((2-chloro-5- (difluoromethyl)-3-(1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
459.89 3.75 247 ##STR00308## 2-((2-chloro-5- (difluoromethyl)-3-(4-
(tetrahydro-2H-pyran-4-yl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
544.01 4.72 .sup.c 248 ##STR00309## 2-((2-chloro-3-(4-(2,2-
difluoroethyl)-1-piperazinyl)-5- (difluoromethyl)phenyl)amino)-
4-(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
523.92 3.96 .sup.c 249 ##STR00310## (+/-) 2-((2-chloro-5-
(difluoromethyl)-3-(4-(2- hydroxypropyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 517.97 3.78 250 ##STR00311##
(+/-) 2-((2-chloro-5- (difluoromethyl)-3-(4-(2-
hydroxy-3-methoxypropyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
548.00 4.21 251 ##STR00312## methyl ((3S,4S)-1-(2-chloro-3-
((7-cyano-4- (cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)-5- (difluoromethyl)phenyl)-4- methoxy-3-
pyrrolidinyl)carbamate 547.95 4.67 252 ##STR00313## methyl
((3S,4R)-1-(2-chloro-3- ((7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)-5- (difluoromethyl)phenyl)-4-
methoxy-3- pyrrolidinyl)carbamate 547.95 4.81 253 ##STR00314##
2-((2-chloro-5- (difluoromethyl)-3-(4-(1- methyl-3-azetidinyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 529.00 4.01 254 ##STR00315##
2-((2-chloro-5- (difluoromethyl)-3-((2,3-
dihydroxypropyl)amino)phenyl) amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 464.86 3.32 255 ##STR00316##
2-((2-chloro-5- (difluoromethyl)-3-(4-hydroxy-
1-piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 474.90 4.32 256 ##STR00317##
2-((2-chloro-5- (difluoromethyl)-3-(4-(3- oxetanylamino)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 529.98 4.42 257 ##STR00318##
2-((2-chloro-5- (difluoromethyl)-3-(4-(3- hydroxy-3-methyl-1-
azetidinyl)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
544.01 4.35 258 ##STR00319## 2-((2-chloro-5-
(difluoromethyl)-3-(4-(3- fluoro-1-azetidinyl)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 531.97 4.65 259 ##STR00320##
2-((2-chloro-5- (difluoromethyl)-3-(3-(4-(1-
hydroxy-1-methylethyl)-1- piperidinyl)-1-
azetidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 572.06 4.83 260 ##STR00321##
2-((2-chloro-5- (difluoromethyl)-3-(3-(4- methoxy-1-piperidinyl)-1-
azetidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 544.01 4.69 261 ##STR00322##
(+/-) 2-((2-chloro-5- (difluoromethyl)-3-(3-((2,3-
dihydroxypropyl)amino)-1- azetidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
519.94 3.24 362 ##STR00323## (+/-) 2-((2-chloro-5-
(difluoromethyl)-3-(3-((3- hydroxy-2- methoxypropyl)amino)-1-
azetidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 533.97 4.44 263 ##STR00324##
2-((2-chloro-5- (difluoromethyl)-3-(3-methoxy- 1,3'-biazetidin-1'-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 515.95 4.19 264 ##STR00325##
2-((2-chloro-5- (difluoromethyl)-3-(4-((3-
methyl-3-oxetanyl)methyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
544.01 4.16 265 ##STR00326## (+/-) 2-(2-chloro-5-
(difluoromethyl)-3-(4- (tetrahydrofuran-3- yl)piperazin-1-
yl)phenylamino)-4- (cyclopropylamino)imidazo
[1,2-f][1,2,4]triazine-7- carbonitrile 529.98 3.98 266 ##STR00327##
2-((3-(4-(1-acetyl-3- azetidinyl)-1-piperazinyl)-2- chloro-5-
(difluoromethyl)phenyl)amino)- 4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 557.01 4.01 267 ##STR00328##
2-((2-chloro-5- (difluoromethyl)-3-(4-((1-
methyl-3-azetidinyl)methyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
543.02 3.43 268 ##STR00329## 2-((2-chloro-3-(4-(3-cyano-3-
oxetanyl)-1-piperazinyl)-5- (difluoromethyl)phenyl)amino)-
4-(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
540.96 4.65 269 ##STR00330## 2-(2-chloro-5-(difluoromethyl)-
3-(4-(3- (phenylsulfonylmethyl)oxetan- 3-yl)piperazin-1-
yl)phenylamino)-4- (cyclopropylamino)imidazo
[1,2-f][1,2,4]triazine-7- carbonitrile 670.14 4.82 270 ##STR00331##
2-((2-chloro-5- (difluoromethyl)-3-(4-(3-(2-
hydroxyethyl)-3-oxetanyl)-1- piperazinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
560.01 4.02 271 ##STR00332## 2-((2-chloro-5-
(difluoromethyl)-3-(4-(3-(1- hydroxyethyl)-3-oxetanyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 560.01 4.11 272 ##STR00333##
2-((2-chloro-5- (difluoromethyl)-3-(4-(1,1-
dioxidothietan-3-yl)piperazin- 1-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
564.02 3.88 273 ##STR00334## 2-((2-chloro-5-
(difluoromethyl)-3-(4-((3- methyl-3-oxetanyl)carbonyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 557.99 4.54 274 ##STR00335##
2-((2-chloro-5- (difluoromethyl)-3-(4-(3- methyl-3-oxetanyl)-1-
piperazinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 529.98 4.21 275 ##STR00336##
2-((2-chloro-5- (difluoromethyl)-3-(4- morpholinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
460.87 4.72 276 ##STR00337## 2-((2-chloro-5-
(difluoromethyl)-3-(4-(3- oxetanyl)-1- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
514.97 4.60 277 ##STR00338## 2-((2-chloro-5-
(difluoromethyl)-3-(4-(2- hydroxy-1- (hydroxymethyl)ethyl)-1-
piperidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 532.98 3.87 278 ##STR00339##
2-((2-chloro-5- (difluoromethyl)-3-(3-(4- methyl-1-piperazinyl)-1-
azetidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 529.00 3.72 279 ##STR00340##
2-((2-chloro-5- (difluoromethyl)-3-(3-(4- morpholinyl)-1-
azetidinyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 515.95 4.21 280 ##STR00341##
(+/-) 2-((2-chloro-5- (difluoromethyl)-3-(2-(1-
hydroxy-1-methylethyl)-4- morpholinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
518.95 4.73 YMC S5 ODS 4.6 .times. 50 mm, 10-90% aqueous methanol
containing 0.2% H.sub.3PO.sub.4, 5 min. gradient, monitored at 220
nm
Example 281
##STR00342##
[0909] methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4-yl)carbama-
te
[0910] (281A): To a solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4
methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hyd-
roxypiperidin-4-yl)carbamate (Example 173D) (0.010 g, 0.016 mmol)
in DCM (1 mL) was added pyridine (0.0063 mL, 0.078 mmol) and cooled
to -20.degree. C. POCl.sub.3 (0.003 mL, 0.031 mmol) was added to
the above reaction and stirred for 20 min. and warmed to room
temperature in 30 min. then added water (0.5 mL) and stirred for
additional 10 min. After completion of starting material (by LCMS),
reaction mixture was concentrated at 30.degree. C. and residue was
purified by reverse phase preparative HPLC and fractions were
lyophilized to give
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1
f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4-yl)carbam-
ate (0.007 g) as a white solid.
[0911] MS (ESI) m/z 723.6
[0912] Example 281: To a solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)a-
mino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piper-
idin-4 yl)carbamate (0.007 g, 0.009 mmol) in DCE (1 mL) was added
anisole (0.006 mL, 0.055 mmol) followed by TFA (25% in DCE) (1.1
mL, 3.57 mmol) and at 35.degree. C. for overnight. After completion
of starting material (by LCMS), reaction mixture was concentrated
and residue was taken in DCM (5 mL) concentrated under vacuum, the
same thing was repeated one more time with 5 mL DCM. The resultant
mixture was purified by reverse phase preparative HPLC and
collected fractions were lyophilized to give methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phos-
phonooxy)piperidin-4 yl)carbamate (0.003 g) as white solid.
[0913] MS (ESI) m/z 723.6
[0914] Preparative HPLC: Column: Xteera C18
(250.times.19.times.10.mu.); Solvent A=10 mM Ammonium acetate
pH-4.6; Solvent B=Acetonitrile; Time (min)/% B: 0/20, 7/50, 17/50,
18/100; Flow Rate=16 mL/min; Wavelength=220 & 254 nm; Product
Retention time=16.10 min.
[0915] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm 8.64 (s,
1H), 8.00 (s, 1H), 7.22 (s, 1H), 4.58 (br. s, 1H), 4.29-4.19 (m,
1H), 3.86 (dd, J=11.67, 2.64 Hz, 1H), 3.66 (s, 3H), 3.56-3.49 (m,
2H), 3.09-3.05 (m, 1H), 2.86-2.75 (m, 3H), 2.68 (s, 1H), 2.29 (br.
s, 1H), 1.74-1.67 (m, 1H), 1.03-0.97 (m, 2H), 0.84-0.79 (m, 2H)
Example 282
##STR00343##
[0916] methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4-yl)carbama-
te
[0917] Example 282 was prepared in analogous manner as example
281
[0918] Preparative HPLC: Column: Xteera C18
(250.times.19.times.10.mu.); Solvent A=10 mM Ammonium acetate
pH-4.6 adjusted with AcOH; Solvent B=Acetonitrile; Time (min)/% B:
0/10, 10/70, 15/70, 16/100; Flow Rate=16 mL/min; Wavelength=220
& 254 nm; Product Retention time=10.70 min.
[0919] MS (ESI) m/z 601 (M-1)
[0920] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.87 (br. s,
1H), 8.20 (s, 1H), 8.14 (d, J=2.01 Hz, 1H), 7.82 (d, J=8.28 Hz,
1H), 7.60 (d, J=8.28 Hz, 1H), 7.32 (d, J=1.51 Hz, 1H), 4.03-3.96
(m, 1H), 3.51 (s, 3H), 3.24-3.09 (m, 4H), 3.01-2.94 (m, 1H),
2.76-2.62 (m, 3H), 2.34-2.30 (s, 1H), 1.40-1.31 (m, 1H), 0.80-0.7
(m, 4H)
Example 283
##STR00344##
[0921]
2-((3-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-2-chloro-5-cyanophen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile-
, HCl
[0922] (283A): (3R,4S)-tert-butyl
4-amino-3-fluoropiperidine-1-carboxylate (300 mg, 1.374 mmol) was
taken up in DCM (8 mL) and a solution of sodium bicarbonate (346
mg, 4.12 mmol) in water (1 mL) was added. The reaction mixture was
cooled to 0.degree. C. and benzyl chloroformate (0.235 mL, 1.649
mmol) was added dropwise. The reaction was stirred at 0.degree. C.
for 30 min, then brought to room temperature and stirred overnight.
The reaction mixture was diluted with DCM and water, and the
organic layer was collected. The aqueous layer was re-extracted
with DCM and the organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography, eluting with 0-30%
EtOAc/Hex. The fractions were combined and concentrated to give
(3R,4S)-tert-butyl
4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylate
(450 mg) as a colorless glass.
[0923] MS (ESI) m/z 375 (M+Na)
[0924] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.39-7.28 (m,
5H), 5.30 (d, J=9.0 Hz, 1H), 5.08 (s, 2H), 4.80-4.47 (m, 1H),
4.51-3.99 (m, 2H), 3.88-3.63 (m, 1H), 3.13-2.58 (m, 2H), 1.70
(dddd, J=9.8, 6.3, 4.0, 3.2 Hz, 2H), 1.44 (s, 9H)
[0925] (283B): Benzyl ((3R,4S)-3-fluoropiperidin-4-yl)carbamate,
HCl was prepared from (3R,4S)-tert-butyl
4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylate
using standard Boc deprotection procedure with TFA.
[0926] MS (ESI) m/z 253
[0927] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.71 (d, J=7.7
Hz, 1H), 7.42-7.28 (m, 5H), 5.06 (s, 2H), 5.01-4.84 (m, 1H),
3.98-3.73 (m, 1H), 3.56-3.43 (m, 1H), 3.36 (dd, J=13.4, 0.7 Hz,
1H), 3.24 (dd, J=19.1, 13.6 Hz, 2H), 3.04 (td, J=9.6, 6.3 Hz, 1H),
1.98-1.70 (m, 2H)
[0928] (283C): Tert-butyl
(3-((3R,4S)-4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidin-1-yl)-2-chlo-
ro-5-cyanophenyl)carbamate was prepared from benzyl
((3R,4S)-3-fluoropiperidin-4-yl)carbamate using standard Cbz
protection method.
[0929] MS (ESI) m/z 503
[0930] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.33 (d, J=1.8
Hz, 1H), 7.44-7.30 (m, 5H), 7.19 (s, 1H), 6.99 (d, J=2.0 Hz, 1H),
5.22-5.08 (m, 3H), 4.94-4.70 (m, 1H), 4.01-3.77 (m, 1H), 3.74-3.57
(m, 1H), 3.43-3.32 (m, 1H), 3.08-2.90 (m, 1H), 2.89-2.78 (m, 1H),
2.13-1.99 (m, 1H), 1.99-1.90 (m, 1H), 1.55 (s, 9H)
[0931] (283D): Benzyl
((3R,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-fluoropiperidin-4-yl)carbam-
ate was prepared from tert-butyl
(3-((3R,4S)-4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidin-1-yl)-2-chlo-
ro-5-cyanophenyl)carbamate using the methods described in Example
1D.
[0932] MS (ESI) m/z 403
[0933] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.55 (d, J=7.5
Hz, 1H), 7.41-7.29 (m, 5H), 6.84 (d, J=2.0 Hz, 1H), 6.70 (d, J=2.0
Hz, 1H), 5.81 (s, 2H), 5.06 (s, 2H), 4.90-4.67 (m, 1H), 3.83-3.60
(m, 1H), 3.54-3.39 (m, J=11.2 Hz, 1H), 3.13-2.90 (m, 1H), 2.75 (t,
J=10.7 Hz, 1H), 2.58-2.53 (m, 1H), 1.98-1.88 (m, 1H), 1.68 (d,
J=12.8 Hz, 1H)
[0934] Example 283: Benzyl
((3R,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-fluoropiperidin-4-yl)carbam-
ate (75 mg, 0.186 mmol),
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (96 mg, 0.242 mmol, Intermediate 2),
and Cs.sub.2CO.sub.3 (182 mg, 0.559 mmol) in DMF were heated at
70.degree. C. for 3 h. The reaction mixture was diluted with water
and a white solid crashed out. The solid was collected by vacuum
filtration, rinsing with water, and dried under vacuum overnight.
The material was taken up in DCE (2 mL) and anisole (0.041 mL,
0.372 mmol) was added, followed by TFA (0.574 mL, 7.45 mmol). The
reaction was stirred at room temperature overnight. The reaction
was heated at 50.degree. C. for 1 h to deprotect the remaining
starting material; a mixture of the Cbz-protected and deprotected
product was detected. The solvent was removed in vacuo and the
material was dissolved in MeOH. The solution was loaded onto an SCX
column (5 g, benzenesulfonic acid sorbent) and rinsed with MeOH,
then 7N NH.sub.3/MeOH to release the product. The material was
purified by flash column chromatography, eluting with 0-70%
EtOAc/Hex, then switching to 20% (2N NH.sub.3/MeOH)/DCM to recover
the Cbz-deprotected product. The SCX column and silica-gel column
were flushed with 1:1 DMF/MeOH to obtain additional material, which
was purified by preparative HPLC. The fractions were concentrated
and azeotroped 3.times. with toluene. The material from the flash
column and preparative HPLC purifications were combined and
triturated with MeOH to provide 13 mg of product. The material was
dissolved in 1 ml of 1:1 CH.sub.3CN/H.sub.2O and 1M HCl in water
(26 .mu.L, 26 .mu.mol) was added. The material was frozen in a dry
ice bath and lyophilized overnight.
2-((3-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-2-chloro-5-cyanophenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
HCl (11.6 mg) was isolated.
[0935] MS (ESI) m/z 467
[0936] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.34 (d, J=5.5
Hz, 1H), 8.88 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.90
(br. s, 2H), 7.34 (d, J=2.0 Hz, 1H), 5.09-4.82 (m, 1H), 3.65 (t,
J=14.1 Hz, 1H), 3.57-3.41 (m, J=7.7 Hz, 1H), 3.24-3.07 (m, 2H),
2.97 (tt, J=7.5, 4.8 Hz, 1H), 2.86 (t, J=11.6 Hz, 1H), 2.15-1.77
(m, 2H), 0.85-0.74 (m, 4H)
Example 284
##STR00345##
[0937] methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-fluoropiperidin-4-yl)carbamate,
HCl
[0938] (284A): (3R,4S)-tert-butyl
4-amino-3-fluoropiperidine-1-carboxylate (100 mg, 0.458 mmol) was
dissolved in DCM (5 mL) and Et.sub.3N (0.128 mL, 0.916 mmol) was
added, followed by dropwise addition of dimethyldicarbonate (92 mg,
0.687 mmol). The reaction was stirred at room temperature for 1 h.
The solvent was removed in vacuo and the material purified by flash
column chromatography, eluting with 0-4% MeOH/DCM.
(3R,4S)-tert-butyl
3-fluoro-4-((methoxycarbonyl)amino)piperidine-1-carboxylate (135
mg) was obtained as a colorless gum.
[0939] MS (ESI) m/z 299 (M+Na).
[0940] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 4.96 (br.
s., 1H), 4.82-4.57 (m, 1H), 4.55-4.06 (m, 2H), 3.90-3.72 (m, 1H),
3.70 (s, 3H), 3.11-2.62 (m, 2H), 1.86-1.69 (m, 2H), 1.47 (s,
9H)
[0941] (284B): (3R,4S)-tert-butyl
3-fluoro-4-((methoxycarbonyl)amino)piperidine-1-carboxylate (127
mg, 0.460 mmol) was taken up in DCM (5 mL) and TFA (0.708 mL, 9.19
mmol) was added. The reaction was stirred at room temperature for 1
h. The solvent was removed in vacuo and the material was dissolved
in MeOH. The solution was loaded onto an SCX column (5 g,
benzenesulfonic acid sorbent) and the column was rinsed with MeOH,
followed by 7N NH.sub.3/MeOH to obtain the product. The solvent was
removed in vacuo to obtain methyl
((3R,4S)-3-fluoropiperidin-4-yl)carbamate (113.5 mg) as a colorless
gum. The crude material was taken onto the next step without
further purification.
[0942] MS (ESI) m/z 177 (M+H).
[0943] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 5.10 (d,
J=8.4 Hz, 1H), 4.94-4.71 (m, 1H), 4.00-3.80 (m, 1H), 3.71 (s, 3H),
3.59 (t, J=12.4 Hz, 1H), 3.40 (d, J=12.8 Hz, 1H), 3.17-2.98 (m,
1H), 2.91 (ddd, J=12.9, 8.0, 7.0 Hz, 1H), 2.02-1.87 (m, 2H)
[0944] (284C): Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate
(90 mg, 0.271 mmol, Intermediate 1), methyl
((3R,4S)-3-fluoropiperidin-4-yl)carbamate (62.2 mg, 0.353 mmol),
Pd.sub.2(dba).sub.3 (24.85 mg, 0.027 mmol), BINAP (16.90 mg, 0.027
mmol), Cs.sub.2CO.sub.3 (265 mg, 0.814 mmol), and toluene (1 mL)
were combined in a 2 dram vial. The vial was evacuated and
backfilled with argon, and the reaction was heated at 110.degree.
C. overnight. The reaction was cooled to room temperature and
diluted with EtOAc. The solution was filtered through celite,
rinsing with EtOAc, and the filtrate was concentrated in vacuo. The
material was purified by flash column chromatography 0-30%
EtOAc/Hex to obtain 58 mg of the intermediate. The material was
taken up in 1 ml DCM and TFA (0.418 mL, 5.43 mmol) was added. The
reaction was stirred at room temperature for 1 h. The solvent was
removed in vacuo and the material was taken up in MeOH. The
solution was loaded onto an SCX column (2 g, benzenesulfonic acid
sorbent) and rinsed with MeOH, then 7N NH.sub.3/MeOH solution to
obtain the product. Methyl
((3R,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-fluoropiperidin-4-yl-
)carbamate (methyl
((3R,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-fluoropiperidin-4-yl)carbam-
ate (29 mg) was obtained as an orange solid.
[0945] MS (ESI) m/z 327 (M+H).
[0946] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 6.76 (d,
J=1.8 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 5.08 (d, J=7.9 Hz, 1H),
4.90-4.67 (m, 1H), 4.35 (br. s., 2H), 4.00-3.78 (m, 1H), 3.77-3.60
(m, 4H), 3.45-3.34 (m, 1H), 3.07-2.88 (m, 1H), 2.87-2.72 (m, 1H),
2.16-1.99 (m, 1H), 1.96-1.84 (m, 1H)
[0947] Example 284:
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (30 mg, 0.075 mmol, Intermediate 2),
methyl
((3R,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-fluoropiperidin-4-yl)carbam-
ate (29.0 mg, 0.089 mmol), and Cs.sub.2CO.sub.3 (73.6 mg, 0.226
mmol) in DMF (1 mL) were heated at 80.degree. C. for 4 h. The
reaction was diluted with EtOAc and washed 2.times. with water and
once with brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude material was
purified by flash column chromatography, eluting with 0-50%
EtOAc/Hex. 43 mg of the intermediate was obtained. The material was
taken up in DCE (2 mL) and anisole (0.016 mL, 0.151 mmol) was
added, followed by the addition of TFA (0.116 mL, 1.506 mmol). The
reaction was stirred at room temperature overnight. The solvent was
removed in vacuo and the material was taken up in MeOH. The
solution was loaded onto an SCX column (5 g, benzenesulfonic acid
sorbent) and rinsed with MeOH, then 7N NH.sub.3/MeOH solution to
recover the product. The product was purified by flash column
chromatography, eluting with 0-2.5% MeOH/DCM. The material was
repurified by preparative HPLC. The fractions were combined and
concentrated, then the material was taken up in EtOAc, and washed
with sat'd NaHCO.sub.3. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give 6.4 mg of
product. The material was converted to the HCl salt by suspending
it in 1 ml 1:1 ACN/H.sub.2O and adding aq. 1N HCl (12.2 .mu.L, 12.2
.mu.mol). The solution was frozen in a dry ice bath and lyophilized
overnight. Methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-fluoropiperidin-4-yl)carbamate,
HCl (6.0 mg) was obtained as an off-white solid.
[0948] MS (ESI) m/z 525
[0949] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.32 (br. s.,
1H), 8.84 (br. s., 1H), 8.19 (br. s., 1H), 8.10 (br. s., 1H), 7.43
(br. s., 1H), 7.32 (br. s., 1H), 4.99-4.63 (m, 1H), 3.83-3.65 (m,
1H), 3.64-3.37 (m, 5H), 3.15-3.03 (m, 1H), 3.01-2.78 (m, 2H),
2.15-1.85 (m, 1H), 1.70 (br. s., 1H), 0.78 (br. s., 4H)
[0950] The compounds listed below were prepared by the similar
synthetic procedure used for Example 284
TABLE-US-00012 TABLE 9 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 285 ##STR00346## methyl
((3S,4R)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-3-fluoro-4- piperidinyl)carbamate 524.95 3.57 286
##STR00347## methyl (1-(2-chloro-5-cyano- 3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-3,3- dimethyl-4- piperidinyl)carbamate 535.01 3.78
287 ##STR00348## methyl ((3R,4R)-1-(2-chloro-
5-cyano-3-((7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)phenyl)-4- (fluoromethyl)-3-
pyrrolidinyl)carbamate 524.95 4.80 288 ##STR00349## methyl
((3S,4S)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methoxy- 3-pyrrolidinyl)carbamate 522.96 4.73
289 ##STR00350## N-((3S,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methoxy- 3-pyrrolidinyl) methanesulfonamide
543.01 4.82 290 ##STR00351## 1-((3S,4R)-1-(2-chloro-5-
cyano-3-((7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)phenyl)-4-methoxy-
3-pyrrolidinyl)-3-(3- oxetanyl)urea 564.01 4.79 291 ##STR00352##
3-oxetanyl ((3S,4R)-1-(2- chloro-5-cyano-3-((7-cyano-
4-(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methoxy- 3-pyrrolidinyl)carbamate 564.99 4.51
292 ##STR00353## (+/-) methyl ((3S,4S)-1-(2-
chloro-5-cyano-3-((7-cyano- 4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)phenyl)-4-ethyl-3-
pyrrolidinyl)carbamate 520.98 4.69 293 ##STR00354## methyl
((3S,4S)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methyl-3- pyrrolidinyl)carbamate 520.2 4.79 294
##STR00355## methyl ((3R,4R)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methyl-3- pyrrolidinyl)carbamate 506.96 4.82 295
##STR00356## methyl ((3S,5R)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-5-hydroxy- 3-piperidinyl)carbamate 522.96 4.89 296
##STR00357## (+/-) methyl ((3S,4R)-1-(2-
chloro-5-cyano-3-((7-cyano- 4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)phenyl)-3-ethyl-4-
piperidinyl)carbamate 535.01 4.32 297 ##STR00358## (+/-) methyl
((3S,4S)-1-(1-(2- chloro-5-cyano-3-((7-cyano-
4-(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-3- azetidinyl)-4-methoxy-3- pyrrolidinyl)carbamate
578.03 4.83 298 ##STR00359## methyl ((3S,4R)-1-(1-(2-
chloro-5-cyano-3-((7-cyano- 4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)phenyl)-3-
azetidinyl)-4-methoxy-3- pyrrolidinyl)carbamate 578.03 4.45 299
##STR00360## methyl ((3S,4R)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-3-fluoro-4- piperidinyl)carbamate 524.95 4.76 *=
HPLC conditions YMC S5 ODS 4.6 .times. 50 mm, 10-90% aqueous
methanol containing 0.2% H.sub.3PO.sub.4, 5 min. gradient,
monitored at 220 nm
Example 300
##STR00361##
[0951] (+/-)
2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[0952] (300A): To a round bottom flask charged with
(+/-)-4-benzylmorpholine-2-carboxylic acid, HCl (0.5 g, 1.940 mmol)
in dichloromethane (9.70 ml) was added Hunig's base (1.017 ml, 5.82
mmol), morpholine (0.203 ml, 2.328 mmol) and EDC (0.446 g, 2.328
mmol). The reaction mixture was stirred at room temperature ON.
DMAP (tip), additional morpholine (1.164 ml, 2.328 mmol) and
Hunig's base (1.017 ml, 5.82 mmol) were added and stirring
continued for 16 h. The reaction mixture was poured into a
separatory funnel containing 1:1 saturated aqueous sodium
bicarbonate and dichloromethane. The aqueous layer was extracted
with dichloromethane (2.times.). The combined organics were washed
with brine, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The crude material was purified by column
chromatography on the ISCO system (24 g, 0-20% (20%
MeOH/CH.sub.2Cl.sub.2)/CH.sub.2Cl.sub.2.
(4-Benzylmorpholin-2-yl)(morpholino)methanone (0.17 g) was isolated
as oil.
[0953] MS (ESI) m/z 292.2
[0954] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.35-7.22 (m,
5H), 4.22 (dd, J=10.1, 2.6 Hz, 1H), 3.96-3.89 (m, 1H), 3.75-3.43
(m, 11H), 2.91 (dt, J=12.0, 2.1 Hz, 1H), 2.72-2.66 (m, 1H), 2.41
(dd, J=11.9, 10.1 Hz, 1H), 2.26 (td, J=11.5, 3.4 Hz, 1H)
[0955] (300B) To a round bottom flask charged with
(4-benzylmorpholin-2-yl)(morpholino)methanone (0.17 g, 0.585 mmol)
in DCE (1.952 ml) and cooled to 0.degree. C. was added
1-chloroethyl chloroformate (0.082 ml, 0.761 mmol) dropwise. The
reaction mixture was stirred at 0.degree. C. 3 h and room
temperature for 16 h. The reaction mixture was concentrated in
vacuo. Methanol (1.952 ml) was added and the reaction mixture was
heated at 60.degree. C. 2 h. The reaction mixture was cooled to
room temperature and concentrated in vacuo. The crude residue was
triturated with ether leaving a white solid.
Morpholin-2-yl(morpholino)methanone, HCl (118 mg) was isolated as a
white solid.
[0956] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 4.72 (dd,
J=7.0, 3.7 Hz, 1H), 4.02-3.95 (m, 2H), 3.78-3.57 (m, 6H), 3.56-3.45
(m, 2H), 3.39-3.33 (m, 2H), 3.25 (dt, J=13.0, 3.9 Hz, 1H),
3.19-3.08 (m, 1H)
[0957] (300C): The compound was prepared starting from
morpholin-2-yl(morpholino)methanone, HCl (0.118 g, 0.499 mmol),
using procedure for Example 1A. After flash chromatography on
silica gel using an automated ISCO system (24 g column, eluting
with 0-100% ethyl acetate/dichloromethane), tert-butyl
(2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)carbamate
(90.9 mg) was isolated as a yellow glass.
[0958] MS (ESI) m/z 451.3 (M+H)
[0959] (300D): To a round bottom flask charged with tert-butyl
(2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)carbamate
(91 mg, 0.202 mmol) was added dichloromethane (1076 .mu.l) and TFA
(269 .mu.l). The reaction mixture was stirred at room temperature 3
h. Excess TFA was removed by concentration in vacuo. The crude
residue was free based using a Phenomenex Strata 1 g SCX column.
The column was flushed with 3 column volumes methanol and 3 column
volumes 3.5 N ammonia/methanol. The ammonia layers were
concentrated in vacuo to provide
3-amino-4-chloro-5-(2-(morpholine-4-carbonyl)morpholino)benzonitr-
ile (68 mg, 0.194 mmol, 96%)
[0960] MS (ESI) m/z 351.1 (M+H)
[0961] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.79 (d, J=1.8
Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 4.44-4.32 (m, 3H), 4.09-4.02 (m,
1H), 3.86 (td, J=11.2, 2.4 Hz, 1H), 3.78-3.65 (m, 6H), 3.59-3.50
(m, 2H), 3.40 (dt, J=12.2, 2.3 Hz, 1H), 3.16 (dd, J=11.7, 1.5 Hz,
1H), 3.03 (dd, J=12.2, 10.0 Hz, 1H), 2.92 (td, J=11.6, 3.1 Hz,
1H)
[0962] (300E): A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (38.6 mg, 0.097 mmol),
3-amino-4-chloro-5-(2-(morpholine-4-carbonyl)morpholino)benzonitrile
(34 mg, 0.097 mmol) and Cs.sub.2CO.sub.3 (63.2 mg, 0.194 mmol) in
DMF (692 .mu.l) was heated at 50.degree. C. for 4 h. After cooling
to room temperature ON, the reaction mixture was transferred to a
separatory funnel containing ethyl acetate and saturated aqueous
sodium bicarbonate. The aqueous layer was extracted with ethyl
acetate (3.times.). The combined organics were washed with 10%
lithium chloride solution, dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. Material carried forward as
is.
[0963] MS (ESI) m/z 669.5 (M+H)
[0964] Example 300: To a round bottom flask charged with
2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile (64.9 mg, 0.097 mmol) in dichloromethane (485 .mu.l) was
added anisole (21.19 .mu.l, 0.194 mmol), followed by TFA (224
.mu.l, 2.91 mmol). The reaction mixture was stirred at room
temperature for 16 h. Additional TFA (224 .mu.l, 2.91 mmol) was
added. Stir at room temperature ON. Additional TFA (224 .mu.l, 2.91
mmol) was added and the reaction mixture was stirred at room
temperature ON. Excess TFA was removed by concentration in vacuo.
The crude residue was taken up in methanol and free based using a
Phenomenex Strata 1 g SCX column. The column was flushed with 3
column volumes methanol and 3 column volumes 3.5 N
ammonia/methanol. The ammonia layers were concentrated in vacuo.
The crude material was purified by neutral phase preparatory LC/MS
chromatography to provide (+/-)
2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(13 mg).
[0965] MS (ESI) m/z 549.2 (M+H)
[0966] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.35 (d, J=4.5
Hz, 1H), 8.93 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=1.5 Hz, 1H), 7.38
(d, J=2.0 Hz, 1H), 4.46 (dd, J=9.9, 2.5 Hz, 1H), 4.05 (s, 2H), 3.97
(d, J=10.4 Hz, 1H), 3.84-3.76 (m, 1H), 3.66-3.50 (m, 6H), 3.16 (d,
J=11.4 Hz, 1H), 3.00-2.90 (m, 3H), 0.82-0.73 (m, 4H)
Example 301
##STR00362##
[0967] (+/-)
2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(oxetan-3-ylamino)piperidin-1-
-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile, HCl
[0968] (301A): (+/-)
2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2--
chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (Example 171C)(60 mg, 0.104 mmol) was taken up
in MeOH (1 mL) and THF (1 mL) and trimethyl orthoformate (0.859 mL,
7.77 mmol), AcOH (0.024 mL, 0.414 mmol), and oxetan-3-one (0.066
mL, 1.036 mmol) were added. The reaction was stirred at room
temperature for 2 h, then NaCNBH.sub.3 (65.1 mg, 1.036 mmol) was
added and the reaction was stirred at room temperature overnight.
The reaction mixture was diluted with EtOAc and washed with sat'd
NaHCO.sub.3, then brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography, eluting with 0-3%
MeOH/DCM.
(+/-)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino-
)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was obtained as a
white foam.
[0969] MS (ESI) m/z 635
[0970] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.77 (d, J=2.0
Hz, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 6.98 (d, J=2.0 Hz, 1H),
6.90-6.84 (m, 1H), 4.87 (dt, J=12.9, 6.5 Hz, 2H), 4.51-4.39 (m,
2H), 4.21-4.05 (m, 2H), 3.76-3.69 (m, 1H), 3.45-3.36 (m, 1H),
3.30-3.18 (m, 1H), 3.09-3.01 (m, 1H), 2.81-2.69 (m, 1H), 2.59-2.39
(m, 2H), 1.98-1.87 (m, 1H), 1.64-1.53 (m, 1H), 1.15-1.05 (m, 2H),
0.94 (s, 9H), 0.86-0.74 (m, 2H), 0.19 (s, 3H), 0.14 (s, 3H).
[0971] Example 301:
(+/-)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino-
)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg, 0.047 mmol) was taken
up in THF (1 mL) and TBAF (0.057 mL, 0.057 mmol) was added. The
reaction was stirred at room temperature for 5 h. The solvent was
removed in vacuo and the material was purified by flash column
chromatography, eluting with 0-10% MeOH/DCM. The fractions were
concentrated and the material was repurified by preparative HPLC to
provide 13.4 mg of product. The material was taken up in 1 ml of
1:1 ACN/H.sub.2O and 1N HCl (0.026 mL, 0.026 mmol) was added. The
solution was frozen in a dry ice bath and lyophilized overnight.
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(oxetan-3-ylamino)piper-
idin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine--
7-carbonitrile, HCl (13.6 mg) was obtained as a white solid.
[0972] MS (ESI) m/z 521
[0973] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=4.4
Hz, 1H), 8.87 (s, 1H), 8.20 (s, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.33
(d, J=1.9 Hz, 1H), 5.85 (br. s., 1H), 4.76-4.68 (m, 3H), 4.68-4.62
(m, 1H), 4.56 (br. s., 1H), 3.75 (br. s., 1H), 3.50-3.38 (m, 2H),
2.97 (dddd, J=11.6, 7.2, 4.4, 3.4 Hz, 2H), 2.75 (t, J=12.6 Hz, 1H),
2.56 (dd, J=11.4, 10.0 Hz, 1H), 1.97 (d, J=15.5 Hz, 1H), 1.67 (br.
s., 1H), 0.81-0.76 (m, 4H).
Example 302
##STR00363##
[0974]
2-((2-chloro-5-cyano-3-((3R,4S)-3-methoxy-4-(oxetan-3-ylamino)pyrro-
lidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-
-7-carbonitrile, HCl
[0975] Prepared in similar manner as Example 301
[0976] MS (ESI) m/z 521
[0977] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.27 (d, J=1.7
Hz, 1H), 8.73 (br. s., 1H), 8.18 (s, 1H), 7.77 (d, J=1.9 Hz, 1H),
7.00 (d, J=1.9 Hz, 1H), 4.72-4.58 (m, 2H), 4.35 (q, J=6.2 Hz, 2H),
4.03-3.91 (m, 1H), 3.75-3.70 (m, 1H), 3.70-3.59 (m, 1H), 3.38 (dd,
J=11.1, 1.9 Hz, 1H), 3.35-3.31 (m, 2H), 3.30 (s, 4H), 3.04-2.96 (m,
1H), 2.45 (br. s., 1H), 0.78 (d, J=5.3 Hz, 4H).
Example 303
##STR00364##
[0978]
(S)-2-((2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,-
4]oxazin-8(1H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]t-
riazine-7-carbonitrile, HCl
[0979] (303A): To a round bottom flask charged with (S)-tert-butyl
3-(hydroxymethyl)piperazine-1-carboxylate (0.5 g, 2.312 mmol) in
DMF (2.167 ml) was added sodium bicarbonate (0.388 g, 4.62 mmol).
The reaction mixture was heated at 70.degree. C., at which point a
solution of 3-bromo-2-methylpropene (0.350 ml, 3.47 mmol) in DMF
(0.722 ml) was added dropwise over 30 min with an addition funnel.
After stirring at room temperature for 16 h, the reaction mixture
was transferred to a separatory funnel containing water and ether.
The aqueous layer was extracted with ether (2.times.). The combined
organics were washed with 10% lithium chloride solution, dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo.
Material used crude in subsequent chemistry.
[0980] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.91 (d, J=12.8
Hz, 1H), 3.78 (dd, J=11.3, 5.4 Hz, 1H), 3.69-3.55 (m, 2H), 3.51
(dd, J=11.4, 3.3 Hz, 1H), 3.37 (d, J=13.4 Hz, 2H), 3.23-3.11 (m,
1H), 2.81 (d, J=13.2 Hz, 2H), 2.48 (br. s., 2H), 2.21 (ddd, J=12.2,
8.6, 3.4 Hz, 1H), 1.75 (s, 3H), 1.47 (s, 9H)
[0981] (303B): To a round bottom flask charged with (S)-tert-butyl
3-(hydroxymethyl)-4-(2-methylallyl)piperazine-1-carboxylate (0.1 g,
0.370 mmol) in acetonitrile (3.70 ml) was added N-iodosuccinimide
(0.125 g, 0.555 mmol) and potassium carbonate (0.077 g, 0.555
mmol). The reaction mixture was stirred at room temperature for 16
h. The reaction mixture was quenched with 20% sodium thiosulfate
solution and stirred 30 min. The mixture was transferred to a
separatory funnel and extracted with ethyl acetate (3.times.). The
combined organics were washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo.
(9aS)-tert-butyl
3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxy-
late (0.156 g) was isolated as a yellow oil. Material used crude in
subsequent chemistry.
[0982] (303C): (9aS)-tert-butyl
3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxy-
late (108 mg, 0.273 mmol) was taken up in DCM (3 mL) and TFA (0.42
mL, 5.45 mmol) was added. The reaction was stirred at room
temperature for 1 h. The solvent was removed in vacuo and the
material was taken up in MeOH. The solution was loaded onto an SCX
column (5 g, benzenesulfonic acid sorbent) and rinsed with MeOH,
then 7N NH.sub.3/MeOH solution to release the product. The solvent
was removed in vacuo give
(9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine
(79 mg) as an orange oil.
[0983] MS (ESI) m/z 297
[0984] .sup.1H NMR (400 MHz, MeOD) .delta. 4.01 (d, J=10.8 Hz, 1H),
3.56-3.51 (m, 1H), 3.50-3.44 (m, 1H), 3.38-3.32 (m, 1H), 2.99-2.83
(m, 3H), 2.83-2.61 (m, 2H), 2.45-2.37 (m, 1H), 2.30 (d, J=11.9 Hz,
1H), 2.20 (tdd, J=8.5, 5.6, 3.7 Hz, 1H), 2.14-2.04 (m, 1H), 1.23
(s, 3H)
[0985] (303D):
(9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine
(53 mg, 0.179 mmol) was dissolved in MeOH (5 ml) and Et.sub.3N
(0.037 mL, 0.268 mmol) was added. The flask was purged with Ar, and
Pd/C (19.05 mg, 0.018 mmol) was added. A balloon with H.sub.2 was
attached and the flask was evacuated and filled with H.sub.2
3.times.. The reaction was stirred over the weekend. The reaction
mixture was filtered through celite, rinsing with MeOH. The solvent
was removed in vacuo to give
(S)-3,3-dimethyloctahydropyrazino[2,1-c][1,4]oxazine (20 mg) as a
yellow solid. The crude material was taken onto the next step.
[0986] MS (ESI) m/z 171
[0987] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 5.10-4.90 (m,
1H), 3.58-3.41 (m, 2H), 3.31-3.15 (m, 1H), 3.14-2.94 (m, 2H),
2.77-2.69 (m, 1H), 2.55 (dd, J=12.1, 10.8 Hz, 1H), 2.49-2.29 (m,
3H), 2.14 (d, J=11.4 Hz, 1H), 1.34 (s, 3H), 1.17 (s, 3H)
[0988] (303E): (S)-tert-butyl
(2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H-
)-yl)phenyl)carbamate was prepared from
(S)-3,3-dimethyloctahydropyrazino[2,1-c][1,4]oxazine using the
method described in Example 1G.
[0989] MS (ESI) m/z 421
[0990] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.33-8.24 (m,
1H), 7.18 (s, 1H), 6.96 (d, J=1.8 Hz, 1H), 3.91 (br. s, 1H),
3.60-3.46 (m, 2H), 3.29-3.17 (m, 1H), 3.11-3.01 (m, 1H), 2.99-2.85
(m, 1H), 2.80-2.71 (m, 1H), 2.59-2.44 (m, 2H), 2.44-2.30 (m, 1H),
2.15 (d, J=11.2 Hz, 1H), 1.58-1.49 (m, 9H), 1.37 (s, 3H), 1.19 (s,
3H)
[0991] (303F): (S)-tert-butyl
(2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H-
)-yl)phenyl)carbamate (87 mg, 0.207 mmol) was taken up in DCM (2
mL) and cooled to 0.degree. C. 2,6-Lutidine (0.072 mL, 0.620 mmol)
was added, followed by dropwise addition of trimethylsilyl
trifluoromethanesulfonate (0.112 mL, 0.620 mmol). The reaction was
stirred at 0.degree. C. for 30 min, then warmed to room temperature
and stirred for 30 min. The solvent was removed in vacuo and the
material was purified by flash column chromatography, eluting with
0-2% (2N NH.sub.3/MeOH)/DCM.
(S)-3-amino-4-chloro-5-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8-
(1H)-yl)benzonitrile (22 mg) was obtained as a yellow glass.
[0992] MS (ESI) m/z 321 (M+H)
[0993] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.74 (d, J=2.0
Hz, 1H), 6.66 (d, J=1.8 Hz, 1H), 4.34 (s, 2H), 3.60-3.44 (m, 2H),
3.30-3.21 (m, 1H), 3.13-3.06 (m, 1H), 2.94-2.85 (m, 1H), 2.80-2.68
(m, 1H), 2.57-2.34 (m, 4H), 2.15 (d, J=11.2 Hz, 1H), 1.37 (s, 3H),
1.19 (s, 3H)
[0994] (303G):
(S)-2-((2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxaz-
in-8(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile was prepared from
(S)-3-amino-4-chloro-5-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8-
(1H)-yl)benzonitrile using the method described in Example 1.
[0995] MS (ESI) m/z 639
[0996] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.78 (br. s.,
1H), 7.93 (s, 1H), 7.58-7.47 (m, 1H), 7.19 (d, J=8.6 Hz, 2H), 6.96
(d, J=1.8 Hz, 1H), 6.88-6.81 (m, 2H), 5.70 (s, 2H), 3.78 (s, 3H),
3.64-3.44 (m, 2H), 3.32-3.20 (m, 1H), 3.14-3.03 (m, 1H), 3.03-2.86
(m, 2H), 2.85-2.72 (m, 1H), 2.59-2.47 (m, 3H), 2.47-2.34 (m, 1H),
2.18 (d, J=11.2 Hz, 1H), 1.39 (s, 3H), 1.21 (s, 3H), 1.18-1.09 (m,
2H), 0.98-0.85 (m, 2H)
[0997] Example 303:
(S)-2-((2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxaz-
in-8(1H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile, HCl was prepared from
(S)-2-((2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxaz-
in-8(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile using the method described in
Example 1
[0998] MS (ESI) m/z 519
[0999] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.41-9.19 (m,
1H), 8.84 (br. s, 1H), 8.19 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.32
(d, J=2.0 Hz, 1H), 3.53-3.36 (m, 2H), 3.27 (d, J=1.8 Hz, 1H), 3.10
(d, J=10.8 Hz, 1H), 3.03-2.93 (m, 1H), 2.93-2.82 (m, 1H), 2.75 (dd,
J=8.8, 2.4 Hz, 1H), 2.64-2.53 (m, 2H), 2.37-2.25 (m, 1H), 2.26-2.12
(m, 1H), 1.99 (d, J=11.0 Hz, 1H), 1.29 (s, 3H), 1.10 (s, 3H), 0.78
(d, J=5.7 Hz, 4H)
Example 304
##STR00365##
[1000]
2-((2-chloro-5-cyano-3-(4-methyl-4-morpholinopiperidin-1-yl)phenyl)-
amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
HCl
[1001] Prepared using similar procedure as example 303
[1002] MS (ESI) m/z 533
[1003] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.83-9.65 (m,
1H), 9.41-9.28 (m, 1H), 8.88 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=1.8
Hz, 1H), 7.38 (d, J=0.9 Hz, 1H), 4.01 (d, J=11.9 Hz, 2H), 3.80 (t,
J=12.0 Hz, 2H), 3.44 (d, J=11.4 Hz, 4H), 3.21-3.06 (m, J=11.9 Hz,
2H), 3.03-2.82 (m, J=16.1, 16.1 Hz, 3H), 2.15-1.86 (m, 4H), 1.41
(s, 3H), 0.78 (d, J=6.2 Hz, 4H)
Example 305
##STR00366##
[1004]
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-methoxypyrrolidin-
-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile, HCl
[1005] Prepared in similar manner as Example 171 from
(+/-)-(3R,4R)-tert-butyl
3-hydroxy-4-methoxypyrrolidine-1-carboxylate.
[1006] MS (ESI) m/z 466
[1007] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.28 (d, J=4.0
Hz, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.06
(d, J=2.0 Hz, 1H), 5.26 (d, J=3.7 Hz, 1H), 4.18 (t, J=4.0 Hz, 1H),
3.82-3.65 (m, 3H), 3.30 (s, 3H), 3.28-3.22 (m, J=9.2 Hz, 1H), 3.13
(dd, J=10.6, 2.2 Hz, 1H), 2.99 (quin, J=5.6 Hz, 1H), 0.78 (d, J=5.3
Hz, 4H)
Example 306
##STR00367##
[1008]
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-morpholinopiperid-
in-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile
[1009] (306A): A mixture of benzyl
7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (prepared according
to a published literature procedure: Fink, Brian, et al., WO
2005/066176, 700 mg, 3.00 mmol), morpholine (0.581 mL, 6.00 mmol),
and lithium perchlorate (639 mg, 6.00 mmol) in acetonitrile (10 mL)
was heated at 80.degree. C. for 4 h. Solvent was evaporated and the
crude intermediate was dissolved in dichloromethane (10 mL),
imidazole (654 mg, 9.60 mmol) and tert-butyldimethylchlorosilane
(1357 mg, 9.00 mmol) were added. The reaction mixture was stirred
at room temperature overnight. The reaction was diluted with
dichloromethane and washed with water and brine, dried over sodium
sulfate, filtered, and concentrated. The crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (220 g gold column, eluting with 5-30% ethyl
acetate/hexanes) to give (+/-)-(3R,4R)-benzyl
4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylate
(Isomer A, 0.39 g,) as a colorless oil and (+/-)-(3R,4R)-benzyl
3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate
(Isomer B, 0.43 g) as a colorless oil. The structures were
confirmed by NMR studies .sup.13C-1D, COSY, NOESY,
dept-.sup.1H-.sup.13C-HSQC, .sup.1H-.sup.13C-HMBC).
[1010] Isomer A (+/-)-(3R,4R)-benzyl
4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylate:
[1011] MS (ESI) m/z 435.5
[1012] .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.42-7.30 (m,
5H), 5.25-5.03 (m, 2H), 3.99 (td, J=5.5, 3.1 Hz, 1H), 3.77-3.44 (m,
8H), 2.77-2.44 (m, 4H), 2.22-2.06 (m, 1H), 2.06-1.96 (m, 1H), 1.44
(br. s., 1H), 0.92 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
[1013] Isomer B (+/-)-(3R,4R)-benzyl
3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate:
[1014] MS (ESI) m/z 435.5
[1015] .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.41-7.31 (m,
5H), 5.23-5.06 (m, 2H), 4.20-3.86 (m, 2H), 3.77-3.57 (m, 5H), 2.98
(br. s., 2H), 2.68-2.54 (m, 4H), 2.34 (ddd, J=10.3, 7.9, 3.9 Hz,
1H), 1.85 (br. s., 1H), 1.56-1.43 (m, 1H), 0.91 (s, 9H), 0.12 (br.
s., 6H).
[1016] (306B): A mixture of (+/-)-(3R,4R)-benzyl
3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate
(Isomer A, 0.43 g, 0.989 mmol) and Pd/C (0.063 g, 0.030 mmol) in
methanol (20 mL) was hydrogenated at 30 psi overnight. The reaction
mixture was filtered through a pad of Celite and the filtrate was
concentrated in vacuo.
(+/-)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)mo-
rpholine (278 mg) was obtained as a colorless oil. The crude was
used without purification.
[1017] MS (ESI) m/z 301.3
[1018] (306C): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (116 mg, 0.349 mmol),
(+/-)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholin-
e (100 mg, 0.333 mmol), Pd.sub.2dba.sub.3 (9.14 mg, 9.98 .mu.mol),
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (18.65 mg, 0.030 mmol),
and cesium carbonate (217 mg, 0.666 mmol) in Dioxane (2 mL) was
evacuated and filled with nitrogen three times and heated at
110.degree. C. overnight. The reaction mixture was diluted with
dichloromethane and filtered through Celite, the filtrate was
concentrated and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (24 g
column, eluting with 5-25% ethyl acetate/hexanes). (+/-)-tert-butyl
(3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)--
2-chloro-5-cyanophenyl)carbamate (138 mg) was obtained as a white
solid.
[1019] MS (ESI) m/z 551.3
[1020] (306D):
(+/-)-tert-butyl-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopi-
peridin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg, 0.250 mmol)
was treated with TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 mmol)
at room temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with cold saturated sodium
bicarbonate/1N aqueous sodium hydroxide (pH 10). The layers were
separated and aqueous layer was extracted with dichloromethane two
more times. The combined organic layers were dried over magnesium
sulfate, filtered and concentrated in vacuo, the crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (24 g column, eluting with 5-40% ethyl
acetate/hexanes).
(+/-)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopip-
eridin-1-yl)-4-chlorobenzonitrile (106 mg) was obtained as a
yellow/brown solid.
[1021] MS (ESI) m/z 451.3
[1022] Example 306: The title compound was prepared from
(+/-)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopip-
eridin-1-yl)-4-chlorobenzonitrile using a method analogous to that
used to prepare Example 171.
[1023] MS (ESI) m/z 535.3
[1024] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=4.4
Hz, 1H), 8.81 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.30
(d, J=1.7 Hz, 1H), 4.57 (d, J=3.9 Hz, 1H), 3.72 (tt, J=9.3, 4.6 Hz,
1H), 3.60 (t, J=4.4 Hz, 4H), 3.47-3.38 (m, 1H), 3.03-2.95 (m, 1H),
2.75-2.57 (m, 5H), 2.40-2.28 (m, 1H), 1.80 (dd, J=12.8, 3.3 Hz,
1H), 1.62 (qd, J=12.3, 4.0 Hz, 1H), 0.79 (d, J=5.3 Hz, 4H).
Example 307
##STR00368##
[1025]
2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(4-morpholinyl)-1-pyrro-
lidinyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile
[1026] Prepared in similar manner as example 306.
[1027] MS (ESI) m/z 521.2 (M+H); 1H NMR (500 MHz, DMSO-d6) .delta.
9.30 (d, J=4.2 Hz, 1H), 8.77 (br. s., 1H), 8.20 (s, 1H), 7.90 (br.
s., 1H), 7.16 (br. s., 1H), 5.21 (br. s., 1H), 4.24 (br. s., 1H),
3.61 (br. s., 4H), 3.54-3.45 (m, 2H), 3.42 (br. s., 1H), 3.04-2.96
(m, 1H), 2.77 (br. s., 1H), 2.65 (br. s., 2H), 1.25 (s, 1H), 0.79
(d, J=5.5 Hz, 4H).
Example 308
##STR00369##
[1028]
(R)-2-((2-chloro-5-cyano-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1-
H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile
[1029] (308A):
(R)-3-amino-4-chloro-5-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)benz-
onitrile was prepared starting from
(R)-octahydropyrazino[2,1-c][1,4]oxazine using a method analogous
to that used to prepare Example 171C and 171D.
[1030] MS (ESI) m/z 293.0 (M+H).
[1031] Example 308: The title compound was prepared from
(R)-3-amino-4-chloro-5-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)benz-
onitrile using a method analogous to that used to prepare Example
171
[1032] MS (ESI) m/z 491.2
[1033] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.80 (d, J=1.9
Hz, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 7.01 (d, J=1.7 Hz, 1H), 6.85
(d, J=1.7 Hz, 1H), 3.92 (dd, J=11.2, 2.9 Hz, 1H), 3.80-3.72 (m,
2H), 3.38-3.28 (m, 2H), 3.14-3.09 (m, 1H), 3.07 (td, J=7.1, 3.3 Hz,
1H), 3.01 (td, J=11.4, 2.6 Hz, 1H), 2.90 (dt, J=11.1, 2.4 Hz, 1H),
2.75 (d, J=11.4 Hz, 1H), 2.67-2.56 (m, 2H), 2.56-2.49 (m, 2H),
1.15-1.09 (m, 2H), 0.85-0.81 (m, 2H).
Example 309
##STR00370##
[1034]
(S)-2-((2-chloro-5-cyano-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1-
H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile
[1035] The title compound was prepared from
(S)-octahydropyrazino[2,1-c][1,4]oxazine using a method analogous
to that used to prepare Example 308.
[1036] MS (ESI) m/z 491.2
[1037] .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.79 (d, J=1.8
Hz, 1H), 7.90-7.83 (m, 1H), 7.59 (s, 1H), 6.99 (d, J=1.8 Hz, 1H),
6.86 (br. s., 1H), 3.90 (dd, J=11.3, 2.8 Hz, 1H), 3.79-3.69 (m,
2H), 3.38-3.26 (m, 2H), 3.13-3.04 (m, 2H), 2.99 (td, J=11.3, 2.4
Hz, 1H), 2.92-2.84 (m, 1H), 2.73 (d, J=11.7 Hz, 1H), 2.66-2.46 (m,
3H), 1.14-1.06 (m, 2H), 0.85-0.78 (m, 2H).
Example 310
##STR00371##
[1038]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,-
4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile, 2HCl
[1039] (310A): 2-chloroacetyl chloride (7.56 mg, 0.067 mmol) in
dichloromethane (0.5 mL) was added to a mixture of
(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1--
yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171D), (39 mg,
0.056 mmol) and triethylamine (0.016 mL, 0.112 mmol) in
dichloromethane (1 mL) at 0.degree. C. and the reaction mixture was
stirred at for 1 h. The reaction mixture was diluted with
dichloromethane and washed with water. The organic layer was dried
over magnesium sulfate, filtered and concentrated in vacuo, The
crude product was purified by flash chromatography on silica gel
using an automated ISCO system (12 g column, eluting with 5-40%
ethyl acetate/dichloromethane to afford
(+/-)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-(-
(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
-2-yl)amino)phenyl)piperidin-4-yl)-2-chloroacetamide (43 mg) as a
white solid.
[1040] MS (ESI) m/z 775.2 (M+H).
[1041] (310B): To
(+/-)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-(-
(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
-2-yl)amino)phenyl)piperidin-4-yl)-2-chloroacetamide (43 mg, 0.055
mmol) in THF (1 mL) was added TBAF (1M in THF, 0.112 mL, 0.112
mmol) and the reaction solution was stirred at room temperature
overnight. Solvent was evaporated and the crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (24 g column, eluting with 0.5-4%
methanol/dichloromethane) to give
(+/-)-2-chloro-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hy-
droxypiperidin-4-yl)acetamide (22 mg) as a white solid.
[1042] MS (ESI) m/z 661.1 (M+H).
[1043] (310C): Sodium hydride (60% in mineral oil, 8.0 mg, 0.200
mmol) was added to a solution of
(+/-)-2-2-chloro-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3--
hydroxypiperidin-4-yl)acetamide (22 mg, 0.033 mmol) in THF (2 mL)
and the reaction mixture was stirred at room temperature for 2 h.
Reaction was quenched with water and extracted with dichloromethane
(three times). The organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (12 g column, eluting with 20-100% ethyl acetate/hexanes).
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1-
,4]oxazin-6(7H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazine-7-carbonitrile (15 mg) was obtained as a
white solid.
[1044] Example 310: TFA (25% in 1,2-dichloroethane, 2 mL, 6.49
mmol) was added to
(+/-)-2-((2-chloro-5-cyano-34(4aR,8aR)-2-oxohexahydro-1H-pyrido[-
3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)am-
ino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (15 mg, 0.024
mmol) and anisole (10.48 .mu.l, 0.096 mmol) in 1,2-dichloroethane
(1 mL) and the reaction mixture was stirred at 40.degree. C. for 5
h. Solvent was evaporated and the residue was redissolved in
dichloromethane and concentrated again. After drying under vacuum
overnight, the crude product was washed with hexanes (3.times.1 mL)
and dichloromethane/hexanes (1/2 mixture, 3.times.1 mL). The
resulting TFA salt was converted to HCl salt.
[1045] MS (ESI) m/z 505.1 (M+H);
[1046] .sup.1H NMR (500 MHz, mixture of
methanol-d.sub.4/chloroform-d) .delta. 8.76 (d, J=1.7 Hz, 1H), 7.90
(s, 1H), 7.07 (d, J=1.7 Hz, 1H), 4.34-4.24 (m, 2H), 3.65 (td,
J=9.4, 4.2 Hz, 1H), 3.55 (ddd, J=10.9, 4.2, 1.8 Hz, 1H), 3.42-3.35
(m, 2H), 3.05 (tt, J=7.3, 3.8 Hz, 1H), 2.84 (td, J=12.0, 2.1 Hz,
1H), 2.76 (t, J=10.4 Hz, 1H), 2.09-2.01 (m, 1H), 1.82 (qd, J=12.2,
4.2 Hz, 1H), 1.07-1.00 (m, 2H), 0.83-0.76 (m, 2H).
Example 311
##STR00372##
[1047]
2-((2-chloro-5-cyano-3-(4-(3-methyl-3-oxetanyl)-1-piperazinyl)pheny-
l)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1048] (311A): A clear solution of
3-((phenylsulfonyl)methylene)oxetane (450 mg, 1.284 mmol) in
methanol (10 mL) was treated with 1-benzhydrylpiperazine (389 mg,
1.541 mmol) and stirred at 50.degree. C. overnight, more
3-((phenylsulfonyl)methylene)oxetane (100 mg) was added, stirred at
50.degree. C. overnight and, concentrated. The crude was purified
by ISCO (40 g), eluted with ethyl acetate: hexane=0-50%, the
desired fractions were concentrated to yield
1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine
(670 mg) as a white solid.
[1049] MS (ESI) m/z 463.5
[1050] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.99-7.94
(m, 2H), 7.72-7.60 (m, 1H), 7.59-7.52 (m, 2H), 7.39 (d, J=7.3 Hz,
4H), 7.33-7.26 (m, 4H), 7.22 (d, J=7.3 Hz, 2H), 4.77 (d, J=6.8 Hz,
2H), 4.65 (d, J=7.0 Hz, 2H), 4.22 (s, 1H), 3.67 (s, 2H), 2.58 (t,
J=4.6 Hz, 4H), 2.29 (br. s., 4H).
[1051] (311B): To a suspension of
1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine
(2.49 g, 5.38 mmol) in MeOH (50 mL), THF (10 mL) was added
MAGNESIUM (0.654 g, 26.9 mmol) which was pretreated with 1.0 N HCl
and rinsed with MeOH, stirred at rt overnight. The Et.sub.2O was
added and followed by Na.sub.2SO.sub.4.10H.sub.2O, stirred at room
temperature for 1 hr, filtered. and filtrate was concentrated. The
crude was purified by 40 g ISCO silica column, eluted with EA:
HX=0-100%, the desired fractions were concentrated to yield
1-benzhydryl-4-(3-methyloxetan-3-yl)piperazine (1.08 g) as a white
solid.
[1052] MS (ESI) m/z 323.3
[1053] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.46-7.38
(m, 4H), 7.31-7.24 (m, 4H), 7.22-7.15 (m, 2H), 4.57 (d, J=5.5 Hz,
2H), 4.26 (s, 1H), 4.21 (d, J=5.7 Hz, 2H), 2.57-2.28 (m, 8H), 1.40
(s, 3H)
[1054] (311C): A Parr shaker bottle charged with
1-benzhydryl-4-(3-methyloxetan-3-yl)piperazine (0.24 g, 0.744 mmol)
and MeOH (10 mL) was added Pd(OH).sub.2 (0.045 g, 0.320 mmol),
purged with N.sub.2, and shaked under H.sub.2 (50 psi) overnight.
The catalyst was removed by filter through a celite pad; the
filtrate was concentrated to yield 153 mg of mixture of
1-(3-methyloxetan-3-yl)piperazine and diphenylmethane ratio (1:1),
which was directly carried over to next step.
[1055] MS (ESI) m/z 211.1
[1056] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.35-7.26
(m, 4H), 7.23-7.15 (m, 6H), 4.59 (d, J=5.3 Hz, 2H), 4.22 (d, J=5.7
Hz, 2H), 4.00 (s, 2H), 3.00-2.86 (m, 4H), 2.43-2.27 (m, 4H),
1.45-1.34 (m, 3H)
[1057] Example 311: The title compound was prepared using a method
analogous to that used to prepare Example 1 from example 311C.
[1058] MS (ESI) m/z 505.7
Example 312
##STR00373##
[1059] (+/-)
2-((2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)ph-
enyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitri-
le
[1060] (312A): (+/-) Tert-butyl
3-(hydroxymethyl)piperazine-1-carboxylate (3.07 g, 14.19 mmol),
oxetan-3-one (1.820 mL, 28.4 mmol), AcOH (1.625 mL, 28.4 mmol), and
4 .ANG. molecular sieves were taken up in DCM (16 mL) and MeOH
(16.00 mL), and the reaction was stirred at room temperature
overnight. Sodium cyanoborohydride (4.46 g, 71.0 mmol) was added
and the reaction was stirred at room temperature for 2 h. The
reaction mixture was filtered through celite, rinsing with MeOH.
The solvent was removed in vacuo and the material was quenched with
2M K.sub.3PO.sub.4 solution, and then extracted 2.times. with
EtOAc. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography (0-8% MeOH/DCM). (+/-)
Tert-butyl
3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (2.40 g)
was obtained as a colorless oil.
[1061] MS (ESI) m/z 273 (M+H)
[1062] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.71-4.62 (m,
4H), 4.03 (quin, J=6.8 Hz, 1H), 3.57-3.31 (m, 6H), 2.73 (td,
J=10.2, 3.6 Hz, 1H), 2.53 (br. s, 1H), 2.37-2.26 (m, 1H), 1.65 (d,
J=0.4 Hz, 1H), 1.47 (s, 9H)
[1063] (312B): (+/-) Tert-butyl
3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (1 g,
3.67 mmol) was taken up in DMF (2 mL) and imidazole (0.500 g, 7.34
mmol) and TBS-Cl (0.609 g, 4.04 mmol) were added. The reaction was
stirred at room temperature over the weekend. An additional 0.2 eq.
of TBS-Cl and 0.5 eq. of imidazole were added, and the reaction
mixture was heated at 40.degree. C. overnight, then at 45.degree.
C. for 24 h. The reaction mixture was diluted with EtOAc and washed
with water 4.times.. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography (0-60% EtOAc/Hex). (+/-)
Tert-butyl
3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carb-
oxylate (665 mg) was obtained as a colorless oil.
[1064] MS (ESI) m/z 387 (M+H)
[1065] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.85-4.51 (m,
4H), 3.95 (quin, J=6.8 Hz, 1H), 3.65-3.37 (m, 5H), 3.31 (dd,
J=13.1, 6.5 Hz, 1H), 2.75-2.53 (m, 1H), 2.52-2.36 (m, 1H),
2.34-2.17 (m, 1H), 1.46 (s, 9H), 0.96-0.85 (m, 9H), 0.05 (s,
6H)
[1066] (312C): Tert-butyl
3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carb-
oxylate (714 mg, 1.847 mmol) was taken up in DCM (8 mL) and TFA
(2.85 mL, 36.9 mmol) was added. The reaction was stirred at room
temperature for 30 min. The solvent was removed in vacuo and the
material was dissolved in MeOH. The solution was loaded onto an SCX
column (3.times.5 g, benzenesulfonic acid sorbent) and the columns
were flushed with MeOH, then 7N NH.sub.3/MeOH to release the
product. (+/-)
2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(oxetan-3-yl)piperazine
(517 mg) was obtained as a yellow oil.
[1067] MS (ESI) m/z 287 (M+H)
[1068] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 4.68-4.20 (m,
4H), 3.80 (quin, J=6.9 Hz, 1H), 3.57-3.38 (m, 2H), 3.29 (br. s,
2H), 2.81 (dd, J=11.9, 3.3 Hz, 1H), 2.77-2.65 (m, 2H), 2.58 (dd,
J=12.1, 6.6 Hz, 1H), 2.28 (dtd, J=6.4, 5.9, 3.2 Hz, 1H), 2.15-2.03
(m, 1H), 0.90-0.82 (m, 9H), 0.03 (s, 6H)
[1069] (312D): (+/-) Tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (545 mg, 1.644 mmol),
2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(oxetan-3-yl)piperazine
(518 mg, 1.808 mmol), Pd2(dba)3 (151 mg, 0.164 mmol), BINAP (102
mg, 0.164 mmol), Cs.sub.2CO.sub.3 (1071 mg, 3.29 mmol), and Toluene
(16 mL) were combined in a 2 dram vial. The vial was evacuated and
backfilled with Ar 3.times., and the reaction was heated at
105.degree. C. for 18 h. The reaction was cooled to room
temperature and diluted with MeOH. The solution was filtered
through celite and the filtrate concentrated in vacuo. The crude
material was purified by flash column chromatography (0-50%
EtOAc/Hex). (+/-) tert-butyl
(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazin-1-y-
l)-2-chloro-5-cyanophenyl)carbamate (551 mg) was obtained as an
orange glass.
[1070] MS (ESI) m/z 537 (M)
[1071] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.32 (d, J=2.0
Hz, 1H), 7.18 (s, 1H), 6.98 (d, J=1.8 Hz, 1H), 4.80-4.55 (m, 4H),
4.05 (quin, J=6.9 Hz, 1H), 3.79-3.56 (m, 2H), 3.21-3.14 (m, 1H),
3.13-2.97 (m, 2H), 2.97-2.83 (m, 2H), 2.73 (qd, J=6.0, 3.1 Hz, 1H),
2.65-2.47 (m, 1H), 1.55 (s, 9H), 0.88 (s, 9H), 0.03 (d, J=6.8 Hz,
6H)
[1072] (312E): (+/-) Tert-butyl
(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazin-1-y-
l)-2-chloro-5-cyanophenyl)carbamate (551 mg, 1.026 mmol) was taken
up in THF (5 mL) and TBAF (1.539 mL, 1.539 mmol) was added
dropwise. The reaction was stirred at room temperature for 1 h. The
reaction mixture was diluted with EtOAc and washed with water, then
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The material was purified by flash column
chromatography (0-100% 20% (2N NH.sub.3/MeOH)/DCM). (+/-)
Tert-butyl
(2-chloro-5-cyano-3-(3-(hydroxymethyl)-4-(oxetan-3-yl)piperazin-1-yl)phen-
yl)carbamate (416 mg) was obtained as an orange glass.
[1073] MS (ESI) m/z 423 (M+H)
[1074] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.35 (d, J=2.0
Hz, 1H), 7.17 (s, 1H), 7.01 (d, J=1.8 Hz, 1H), 4.83-4.59 (m, 4H),
4.15 (quin, J=6.9 Hz, 1H), 3.88-3.75 (m, 1H), 3.69 (dt, J=11.2, 5.5
Hz, 1H), 3.31-2.89 (m, 5H), 2.78-2.66 (m, 1H), 2.66-2.52 (m, 1H),
2.32 (t, J=5.1 Hz, 1H), 1.55 (s, 9H)
[1075] (312F): (+/-) Tert-butyl
(2-chloro-5-cyano-3-(3-(hydroxymethyl)-4-(oxetan-3-yl)piperazin-1-yl)phen-
yl)carbamate (660 mg, 1.561 mmol) was taken up in DCM (10 mL) and
cooled to -40.degree. C. Deoxofluor (0.432 mL, 2.341 mmol) was
added dropwise, and the reaction was stirred at -40.degree. C. for
30 min, then warmed to rt over 30 min. The reaction continued to
stir at room temperature for 1 h. The reaction mixture was diluted
with DCM and washed with 2M K.sub.3PO.sub.4 solution, then brine.
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The mixture was purified by flash column
chromatography (0-20% EtOAc/DCM) to give two peaks.
[1076] Peak 1--Identified as, (+/-) tert-butyl
(2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl)ca-
rbamate (107 mg, 0.252 mmol, 16.14% yield) as a yellow gum.
[1077] MS (ESI) m/z 425 (M+H)
[1078] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.31 (d, J=2.0
Hz, 1H), 7.16 (s, 1H), 7.09 (d, J=1.8 Hz, 1H), 5.06-4.82 (m, 1H),
4.77-4.67 (m, 2H), 4.58 (t, J=6.1 Hz, 2H), 3.86 (quin, J=6.4 Hz,
1H), 3.51 (d, J=6.4 Hz, 1H), 3.43-3.38 (m, 1H), 3.32-3.14 (m, 2H),
3.06-2.91 (m, 2H), 2.74 (ddd, J=11.7, 6.4, 3.6 Hz, 1H), 2.60 (ddd,
J=12.4, 8.3, 3.5 Hz, 1H), 1.55 (s, 9H)
[1079] Peak 2 Identified as (+/-) tert-butyl
(2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)pheny-
l)carbamate (315 mg, 0.741 mmol, 47.5% yield) as a white foam.
[1080] MS (ESI) m/z 425 (M+H)
[1081] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.35 (d, J=1.9
Hz, 1H), 7.17 (s, 1H), 6.99 (d, J=1.7 Hz, 1H), 4.83-4.65 (m, 4H),
4.64-4.39 (m, 1H), 4.13-4.02 (m, 1H), 3.53-3.38 (m, 1H), 3.15-2.99
(m, 5H), 2.96 (ddt, J=11.4, 5.5, 2.8 Hz, 1H), 2.68 (ddt, J=8.7,
5.6, 3.0 Hz, 1H), 1.55 (s, 9H)
[1082] (312G): (+/-) Tert-butyl
(2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)pheny-
l)carbamate (Peak 2)(315 mg, 0.741 mmol) was taken up in DCM (4 mL)
and TFA (1.142 mL, 14.83 mmol) was added. The reaction was stirred
at room temperature for 1 h. The solvent was removed in vacuo and
the material was taken up in MeOH and loaded onto an SCX column (5
g, benzenesulfonic acid sorbent). The column was rinsed with MeOH,
then 7N NH.sub.3/MeOH to release the product. The solvent was
removed in vacuo to give (+/-)
3-amino-4-chloro-5-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)benzon-
itrile (234 mg) as a yellow foam.
[1083] MS (ESI) m/z 325 (M+H)
[1084] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.78 (d, J=2.0
Hz, 1H), 6.70 (d, J=2.0 Hz, 1H), 4.90-4.65 (m, 4H), 4.63-4.44 (m,
1H), 4.32 (br. s., 2H), 4.16-4.05 (m, 1H), 3.76-3.23 (m, 1H),
3.16-3.00 (m, 5H), 2.99-2.89 (m, 1H), 2.72-2.60 (m, 1H)
[1085] (312H): (+/-)
2-((2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)ph-
enyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tria-
zine-7-carbonitrile was prepared according to the method described
in Example 1G.
[1086] MS (ESI) m/z 643 (M)
[1087] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.82 (br. s.,
1H), 7.94 (s, 1H), 7.52 (br. s, 1H), 7.19 (d, J=8.8 Hz, 2H), 6.98
(d, J=1.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 5.70 (br. s., 2H),
4.88-4.64 (m, J=0.4 Hz, 4H), 4.63-4.39 (m, J=9.5, 5.1 Hz, 1H),
4.18-4.05 (m, 1H), 3.79 (s, 3H), 3.22-2.83 (m, 8H), 2.69 (s, 1H),
1.14 (s, 2H), 1.00-0.84 (m, 2H)
[1088] Example 312: (+/-)
2-((2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)ph-
enyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tria-
zine-7-carbonitrile (131 mg, 0.204 mmol) was taken up in DCE (2 mL)
and anisole (0.067 mL, 0.611 mmol) was added, followed by TFA
(0.314 mL, 4.07 mmol). The reaction was stirred at room temperature
overnight. An additional 40 eq. of TFA was added and the reaction
was stirred for 2 h, then an additional 60 eq. of TFA and was
added, followed by stirring for 1 h. The solvent was removed in
vacuo and the material was dissolved in MeOH. The material was
loaded onto an SCX column (5 g, benzenesulfonic acid) and the
column was flushed with MeOH, then 1:1 DCM/7N NH.sub.3 in MeOH to
obtain the product. The solvent was removed in vacuo and the
material was dissolved in DMF. A solid precipitated out, which was
collected by vacuum filtration and rinsed with MeOH. The solid was
suspended in 1 ml of 1:1 CH.sub.3CN/H.sub.2O and lyophilized
overnight. (+/-)
2-((2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-
-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile was obtained as a beige solid.
[1089] MS (ESI) m/z 523 (M+H)
[1090] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.32 (br. s.,
1H), 8.84 (br. s., 1H), 8.19 (s, 1H), 8.13 (d, J=0.8 Hz, 1H),
7.39-7.31 (m, 1H), 4.80-4.37 (m, 5H), 4.05-3.91 (m, 1H), 3.13-3.01
(m, 4H), 3.01-2.78 (m, 4H), 2.55 (s, 1H), 0.78 (d, J=5.5 Hz,
4H)
Example 313
##STR00374##
[1091] (+/-)
2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1092] (313A): (+/-) Tert-butyl
(2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl)ca-
rbamate (107 mg, 0.252 mmol, Example 312F, Peak 1) was taken up in
DCM (1.5 mL) and TFA (0.388 mL, 5.04 mmol) was added. The reaction
was stirred at room temperature for 30 min. The solvent was removed
in vacuo and the material taken up in MeOH. The solution was loaded
onto an SCX column (5 g, benzenesulfonic acid sorbent) and flushed
with MeOH, then 7N NH.sub.3/MeOH to obtain the product. The
material was purified by flash column chromatography (0-25%
EtOAc/DCM).
3-amino-4-chloro-5-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)benzonitri-
le (67 mg) was obtained as a yellow glass.
[1093] MS (ESI) m/z 325 (M+H)
[1094] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.77 (d, J=2.0
Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 5.09-4.81 (m, 1H), 4.74-4.66 (m,
2H), 4.57 (t, J=6.1 Hz, 2H), 4.37 (br. s., 2H), 3.84 (quin, J=6.3
Hz, 1H), 3.64-3.52 (m, 1H), 3.46-3.34 (m, 1H), 3.31-3.15 (m, 2H),
3.03-2.91 (m, 2H), 2.78-2.68 (m, 1H), 2.58 (ddd, J=12.4, 8.3, 3.7
Hz, 1H)
[1095] (313B): (+/-)
2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl-
)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-
-7-carbonitrile was prepared using the method described in Example
312H.
[1096] MS (ESI) m/z 643 (M)
[1097] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.77 (br. s.,
1H), 7.93 (s, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.18 (d, J=8.6 Hz, 2H),
7.06 (d, J=1.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 2H), 5.69 (br. s., 2H),
5.09-4.83 (m, 1H), 4.79-4.64 (m, 2H), 4.58 (t, J=6.1 Hz, 2H), 3.86
(dt, J=12.5, 6.3 Hz, 1H), 3.78 (s, 3H), 3.67-3.38 (m, 3H),
3.35-3.16 (m, 2H), 3.06-2.91 (m, 2H), 2.80-2.70 (m, 1H), 2.61 (ddd,
J=12.2, 8.0, 3.5 Hz, 1H), 1.23-1.05 (m, 2H), 0.95-0.84 (m, 2H)
[1098] Example 313: (+/-)
2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl-
)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-
-7-carbonitrile (89 mg, 0.138 mmol) was taken up in DCE (1 mL) and
anisole (0.076 mL, 0.692 mmol) was added, followed by TFA (0.640
mL, 8.30 mmol). The reaction was stirred at room temperature
overnight. An additional 1 ml of TFA was added, and the reaction
was stirred at room temperature for 4 h. The solvent was removed in
vacuo and the material dissolved in MeOH. The material was loaded
onto an SCX column (5 g, benzenesulfonic acid sorbent) and the
column was flushed with MeOH, then 1:1 DCM/7N NH.sub.3/MeOH to
obtain the product. The solvent was removed in vacuo and the crude
material was purified by preparative HPLC.
2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(12 mg) was obtained as a yellow solid.
[1099] MS (ESI) m/z 523 (M+H)
[1100] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H),
8.12-8.06 (m, 1H), 7.53-7.42 (m, 1H), 5.10-4.85 (m, 1H), 4.58 (t,
J=6.6 Hz, 2H), 4.42-4.30 (m, 2H), 3.76 (quin, J=6.1 Hz, 1H),
3.66-3.52 (m, 1H), 3.48-3.35 (m, 1H), 3.31-3.10 (m, 2H), 3.01-2.77
(m, 3H), 2.71-2.63 (m, 1H), 2.57-2.51 (m, 1H), 0.85-0.70 (m,
4H)
Example 314
##STR00375##
[1101] (+/-)
2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazi-
n-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile
[1102] (314A): (+/-) 1-benzyl 3-methyl piperazine-1,3-dicarboxylate
(5 g, 17.97 mmol, contained <20% of 1-benzyl 3-methyl
4-methylpiperazine-1,3-dicarboxylate), oxetan-3-one (2.304 mL, 35.9
mmol), AcOH (2.057 mL, 35.9 mmol), and 4 .ANG. MS were taken up in
DCM (10 mL) and MeOH (10.00 mL), and the reaction was stirred at rt
overnight. An additional 1 eq. of oxetanone was added and the
reaction was heated at 45.degree. C. for 4 h. The reaction was
cooled to room temperature, then to 0.degree. C. Sodium
cyanoborohydride (1.694 g, 26.9 mmol) was added, and the reaction
was warmed to room temperature and stirred overnight. The reaction
mixture was diluted with MeOH and filtered through celite. The
solvent was removed in vacuo and the material dissolved in EtOAc.
The organic layer was washed with 2M K.sub.3PO.sub.4 solution, then
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated to give 5.9 g of yellow oil. The material was
purified by flash column chromatography, eluting with 0-3%
MeOH/DCM. 400 mg of pure (+/-) 1-benzyl 3-methyl
4-(oxetan-3-yl)piperazine-1,3-dicarboxylate was obtained as well as
3 g of a 3:1 mixture of 1-benzyl 3-methyl
4-(oxetan-3-yl)piperazine-1,3-dicarboxylate and 1-benzyl 3-methyl
4-methylpiperazine-1,3-dicarboxylate (ratio determined by .sup.1H
NMR).
[1103] MS (ESI) m/z 335 (M+H)
[1104] .sup.1H NMR (400 MHz, MeOD) .delta. 7.46-7.23 (m, 5H),
5.28-4.96 (m, 2H), 4.72 (t, J=6.5 Hz, 1H), 4.67-4.51 (m, 3H),
4.43-4.24 (m, 1H), 4.10 (quin, J=7.0 Hz, 1H), 4.00 (dd, J=12.5, 0.4
Hz, 1H), 3.70-3.43 (m, 4H), 3.30-3.18 (m, 1H), 3.17-2.89 (m, 2H),
2.78-2.52 (m, 1H)
[1105] (314B): A 3:1 mixture of (+/-) 1-benzyl 3-methyl
4-(oxetan-3-yl)piperazine-1,3-dicarboxylate (1.57 g, 4.70 mmol) and
1-benzyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate (458 mg,
1.565 mmol) were taken up in MeOH (20 ml) and the solution was
purged with N.sub.2. 5% Pd/C (0.999 g, 0.470 mmol) was added, and
the solution was again sparged with N.sub.2. A balloon with H.sub.2
was added, and the flask was evacuated and backfilled with hydrogen
3.times.. The reaction was hydrogenated at atmospheric pressure
overnight. The reaction mixture was filtered through celite,
rinsing with MeOH. The solvent was removed in vacuo to give 869 mg
of material. A 3:1 mixture of (+/-) methyl
1-(oxetan-3-yl)piperazine-2-carboxylate (688 mg, 3.44 mmol, 73%
yield) and (+/-) methyl 1-methylpiperazine-2-carboxylate was
obtained (181 mg).
[1106] MS (ESI) m/z 201 (M+H)
[1107] .sup.1H NMR (400 MHz, MeOD) .delta. 4.74 (t, J=6.6 Hz, 1H),
4.69-4.53 (m, 3H), 4.04 (quin, J=7.0 Hz, 1H), 3.69 (s, 3H),
3.34-3.32 (m, 1H), 3.22-3.14 (m, 1H), 2.95 (dd, J=12.9, 3.9 Hz,
1H), 2.92-2.74 (m, 4H), 2.61-2.54 (m, 1H)
[1108] (314C): (+/-) Tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (1.52 g, 4.58 mmol), a
3:1 mixture of methyl 1-(oxetan-3-yl)piperazine-2-carboxylate
(0.688 g, 3.44 mmol) and methyl 1-methylpiperazine-2-carboxylate
(0.181 g, 1.144 mmol), Pd.sub.2(dba).sub.3 (0.420 g, 0.458 mmol),
BINAP (0.285 g, 0.458 mmol), Cs.sub.2CO.sub.3 (2.240 g, 6.88 mmol),
and Toluene (40 mL) were combined in a round bottom flask. The
flask was evacuated and backfilled with N.sub.2 3.times., and the
reaction was heated at 105.degree. C. for 18 h. The reaction was
cooled to room temperature and an additional 0.05 eq. each of
catalyst and ligand were added. The reaction vial was resealed,
evacuated and backfilled with N.sub.2 3.times., then heated at
105.degree. C. for 2 h. The reaction was cooled to room temperature
and diluted with EtOAc. The solution was filtered through celite
and the filtrate concentrated in vacuo. The crude material was
purified by flash column chromatography 0-5% MeOH/DCM, and then
repurified with 0-20% Acetone/DCM. 292 mg of pure methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)-
piperazine-2-carboxylate was obtained, along with 592 mg of a 3:1.7
mixture of methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)-
piperazine-2-carboxylate and methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methyl
piperazine-2-carboxylate. Estimated yields based on .sup.1H NMR:
methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)-
piperazine-2-carboxylate (683 mg) and methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methylpiperaz-
ine-2-carboxylate (201 mg).
[1109] MS (ESI) m/z 451 (M+H)
[1110] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.34 (d, J=1.8
Hz, 1H), 7.16 (s, 1H), 6.99 (d, J=2.0 Hz, 1H), 4.88 (t, J=6.6 Hz,
1H), 4.76-4.59 (m, 3H), 4.23 (quin, J=7.0 Hz, 1H), 3.70 (s, 3H),
3.60-3.51 (m, 2H), 3.43-3.35 (m, 1H), 3.27-3.14 (m, 1H), 3.09 (dd,
J=11.1, 3.4 Hz, 1H), 2.98-2.89 (m, 1H), 2.85 (dt, J=11.1, 3.4 Hz,
1H), 1.55 (s, 9H)
[1111] Analytical data for methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methyl
piperazine-2-carboxylate
[1112] MS (ESI) m/z 409 (M+H)
[1113] (314D): Methyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)-
piperazine-2-carboxylate (292 mg, 0.648 mmol) was taken up in THF
(3 mL) and water (0.3 ml) and lithium hydroxide monohydrate (38.1
mg, 0.907 mmol) was added. The reaction was heated at 40.degree. C.
for 2 h, then cooled to room temperature and stirred overnight.
Some starting material was still detected by LCMS, so the reaction
was warmed to 40.degree. C. and heated for 2 h. The reaction was
cooled to room temperature and the solvent removed in vacuo. The
material was azeotroped 3.times. with toluene to give
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)-
piperazine-2-carboxylate, lithium salt (292 mg) as a yellow
solid.
[1114] MS (ESI) m/z 437 (M+2H)
[1115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.81 (br. s.,
1H), 7.76 (d, J=1.3 Hz, 1H), 7.05 (br. s, 1H), 4.67 (t, J=6.6 Hz,
1H), 4.52 (t, J=6.6 Hz, 1H), 4.40 (q, J=5.9 Hz, 2H), 4.06-3.92 (m,
1H), 3.13-2.86 (m, 3H), 2.76-2.60 (m, 1H), 2.37-2.25 (m, 1H), 1.44
(s, 9H)
[1116] (314E):
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)-
piperazine-2-carboxylate, lithium salt (200 mg, 0.452 mmol) was
azeotroped 3.times. with toluene and 4 .ANG. molecular sieves were
added. THF (3 mL) was added, followed by DIPEA (0.118 mL, 0.677
mmol), morpholine (0.117 mL, 1.355 mmol), and T3P (0.538 mL, 0.903
mmol). The reaction was stirred at room temperature for 1 h. The
reaction mixture was filtered through a small pad of celite,
rinsing with EtOAc. The solvent was removed in vacuo and the
material was purified by flash column chromatography (0-4%
MeOH/DCM). Tert-butyl
(2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-
-yl)phenyl)carbamate (112 mg) was obtained as an off-white
solid.
[1117] MS (ESI) m/z 506 (M+H)
[1118] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.35 (d, J=2.0
Hz, 1H), 7.15 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.89-4.69 (m, 2H),
4.62-4.52 (m, 2H), 4.05 (quin, J=6.9 Hz, 1H), 3.73-3.59 (m, 9H),
3.32 (d, J=9.7 Hz, 1H), 3.23-3.13 (m, J=7.3 Hz, 3H), 3.07 (q, J=9.2
Hz, 1H), 2.70 (t, J=10.1 Hz, 1H), 1.57-1.55 (m, 9H)
[1119] (314F): (+/-) Tert-butyl
(2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-
-yl)phenyl)carbamate (112 mg, 0.221 mmol) was taken up in DCM (3
mL) and TFA (0.341 mL, 4.43 mmol) was added. The reaction was
stirred at room temperature for 1 h. The solvent was removed in
vacuo and the material was azeotroped 2.times. with DCM and
2.times. with MeOH, and then dried under vacuum. The solid was
dissolved in EtOAc, and then washed with 2M K.sub.3PO4 solution.
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The material was purified by flash column
chromatography (0-5% MeOH/DCM). (+/-)
3-amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1--
yl)benzonitrile (36 mg) was obtained as a colorless foam.
[1120] MS (ESI) m/z 406 (M+H)
[1121] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.78 (d, J=1.8
Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 4.87-4.71 (m, 2H), 4.55 (t, J=6.8
Hz, 2H), 4.38 (s, 2H), 4.02 (quin, J=7.2 Hz, 1H), 3.73-3.53 (m,
9H), 3.31-2.94 (m, 5H), 2.76-2.59 (m, 1H)
[1122] (314G): (+/-) Tert-butyl
(2-chloro-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate
(Intermediate 1)(30 mg, 0.090 mmol),
3-amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1--
yl)benzonitrile (36.4 mg, 0.090 mmol), palladium (II) acetate (6.04
mg, 0.027 mmol), dppf (4.97 mg, 8.96 .mu.mol), Xantphos (5.19 mg,
8.96 .mu.mol), and cesium carbonate (52.6 mg, 0.161 mmol) were
combined in a 10 ml flask and Dioxane (1 mL) was added. The flask
was evacuated and backfilled with N.sub.2 3.times., then heated at
100.degree. C. for 1 h. The reaction was cooled to room temperature
and filtered through celite, rinsing with EtOAc. The solvent was
removed in vacuo and the crude material was purified by flash
column (0-5% MeOH/DCM). (+/-) Tert-butyl
(2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperaz-
in-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropy-
l)carbamate (45 mg) was obtained as a yellow glass.
[1123] MS (ESI) m/z 704 (M)
[1124] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.62 (d, J=1.8
Hz, 1H), 8.06 (s, 1H), 7.70 (s, 1H), 7.07 (d, J=1.8 Hz, 1H), 4.79
(dt, J=13.5, 6.9 Hz, 2H), 4.58 (t, J=6.9 Hz, 2H), 4.06 (quin, J=7.2
Hz, 1H), 3.78-3.56 (m, 9H), 3.33 (d, J=11.9 Hz, 1H), 3.27-3.15 (m,
4H), 3.14-3.04 (m, 1H), 2.79-2.67 (m, 1H), 1.51 (s, 9H), 1.14-1.02
(m, 2H), 0.87-0.74 (m, 2H)
[1125] Example 314: (+/-) Tert-butyl
(2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperaz-
in-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropy-
l)carbamate (40 mg, 0.057 mmol) was taken up in DCE (275 .mu.L) and
anisole (31.0 .mu.L, 0.284 mmol) was added. The reaction was cooled
to 0.degree. C., and TFA (92 .mu.L, 1.193 mmol) was added. The
reaction was stirred at 0.degree. C. for 30 min, then warmed to
room temperature and stirred for 1.5 h. The solvent was removed in
vacuo and the material was azeotroped 2.times. with toluene to
remove the excess TFA. The crude material was purified by
preparative HPLC to provide (+/-)
2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazi-
n-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (3.9 mg).
[1126] MS (ESI) m/z 604 (M)
[1127] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (br. s.,
1H), 8.90 (br. s., 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.34 (s, 1H),
4.66-4.52 (m, J=2.4 Hz, 2H), 4.42 (q, J=6.9 Hz, 2H), 4.17-4.06 (m,
1H), 3.99 (quin, J=7.2 Hz, 1H), 3.73 (s, 1H), 3.55 (br. s, 7H),
3.15-3.09 (m, 1H), 3.08-3.01 (m, 4H), 2.96 (quin, J=5.3 Hz, 1H),
2.59 (s, 1H), 0.77 (d, J=5.5 Hz, 4H)
[1128] The compounds listed below were prepared by the similar
synthetic procedure used for Example 314
TABLE-US-00013 TABLE 10 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 315 ##STR00376## (+/-)
4-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-1-(3-fluoro-2-hydroxypropyl)-N,N-
dimethyl-2-piperazinecarboxamide 582.04 4.23 316 ##STR00377## (+/-)
4-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-1-(3-fluoro-2-hydroxypropyl)-N,N-
dimethyl-2-piperazinecarboxamide 4.30 1.78 .sup.c 317 ##STR00378##
4-(2-chloro-5-cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-1-(2-hydroxy-2-methylpropyl)-N,N-
dimethylpiperazine-2-carboxamide 578.08 4.67 .sup.a YMC S5 ODS 4.6
.times. 50 mm, 10-90% aqueous methanol containing 0.2%
H.sub.3PO.sub.4, 5 min. gradient, monitored at 220 nm
Example 318
##STR00379##
[1129]
2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1130] To a suspension of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 208)(60 mg,
0.138 mmol) in a mixture solvent of methanol (0.7
ml)/CH.sub.2CL.sub.2 (0.7 ml) was added trimethyl orthoformate (0.7
mL, 6.33 mmol), (The suspension converted to a clear solution
within 1 min.), tert-butyl 3-oxoazetidine-1-carboxylate (237 mg,
1.383 mmol), and acetic acid (0.032 mL, 0.553 mmol). The mixture
was stirred at Rt for 40 min and then sodium cyanoborohydride (87
mg, 1.383 mmol) was added and stirred at room temperature for
overnight. The reaction mixture was partitioned between EtOAc and
diluted aq. NaHCO.sub.3, The aqueous layer was extracted with
EtOAc; the combined organic layer was washed with brine and
concentrated. The crude intermediate was purified by prep HPLC
(100.times.30 mm Luna C18 column, Solvent A=10% Methanol, 90%
H.sub.2O, 0.1% TFA; solvent B=90% Methanol, 10% H.sub.2O, 0.1% TFA,
Flow rate 42 ml per min, 20-100% B, over 20 min). The HPLC
fractions containing the intermediate were applied onto a
cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode
polymer. This was washed with methanol and product was eluted with
2 N solution of ammonia in methanol/DCM (1:1). Removal of the
solvents left 46 mg intermediate as a white solid which was
dissolved in DCM (2 ml) and TFA (1 ml) was added. The resulting
mixture was stirred at room temperature for 0.5 hour. Removal of
the solvent and the residue was taken in MeOH/DCM and applied onto
a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode
polymer. This was washed with methanol and product was eluted with
2 N solution of ammonia in methanol/DCM (1:1). Removal of the
solvents left the product (39 mg) as a white solid
[1131] MS (ESI) m/z 489.28 (M+1)
[1132] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.87 (d,
J=1.8 Hz, 1H), 7.89 (s, 1H), 7.27 (d, J=2.0 Hz, 1H), 3.72-3.64 (m,
2H), 3.62-3.56 (m, 2H), 3.35-3.26 (m, 1H), 3.11 (tt, J=12.1, 3.5
Hz, 1H), 3.03 (tt, J=7.3, 3.7 Hz, 1H), 2.94 (d, J=11.6 Hz, 2H),
2.09-1.99 (m, 2H), 1.96-1.87 (m, 2H), 1.72 (qd, J=12.5, 3.4 Hz,
2H), 1.06-0.98 (m, 2H), 0.84-0.75 (m, 2H)
Example 319
##STR00380##
[1133]
2-((3-(1-(1-acetylazetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[1134] To a suspension of
2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 318) (25 mg, 0.051 mmol) and triethylamine (0.014 mL,
0.102 mmol) in CH.sub.2Cl.sub.2 (1.5 mL) was added dropwise acetyl
chloride (4.41 mg, 0.056 mmol, diluted with DCM, 10V % in DCM, 44
uL) at 0.degree. C. The suspension converted to a clear solution in
a few min, and continued stirring at 0.degree. C. for 1 h. Removal
of the solvent, and the crude material was purified via preparative
LC/MS with the following conditions: Column: Waters XBridge C18,
19.times.200 mm, 5-.mu.m particles; Mobile Phase A: water with
20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 20-mM ammonium acetate; Gradient: 20-60% B over 20 minutes,
then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions
containing the desired product were combined and dried via
centrifugal evaporation left the titled product (15.6 mg)
[1135] MS (ESI) m/z 531.15 (M+1)
[1136] 1H NMR (500 MHz, DMSO-d6) .delta. 9.35 (br. s., 1H), 8.91
(br. s., 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.55 (br. s., 1H), 4.21
(m, 2H), 3.93 (m, 2H), 3.56-3.27 (m, 3H), 3.17 (m, 2H), 2.95 (d,
J=4.9 Hz, 1H), 2.90 (s, 1H), 2.74 (s, 1H), 2.00-1.66 (m, 6H), 0.78
(d, J=5.2 Hz, 4H).
Example 320
##STR00381##
[1137] methyl
3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)azetidine-1-carboxy
[1138] The title compound was prepared from
2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 318) and methyl chloroformate using a method analogous to
that used to prepare Example 319.
[1139] HPLC Rt 3.088 min
[1140] MS (ESI) m/z 547.17 (M+1)
Example 321
##STR00382##
[1141]
2-((2-chloro-5-cyano-3-(1-(1-(methylsulfonyl)azetidin-3-yl)piperidi-
n-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile
[1142] The title compound was prepared from
2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 318) and methanesulfonyl chloride using a method analogous
to that used to prepare Example 319 HPLC Rt 3.020 min
[1143] MS ESI) m/z 567.27 (M+1)
[1144] The compounds listed below were prepared by the similar
synthetic procedure used for Example 209
TABLE-US-00014 TABLE 11 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 322 ##STR00383##
2-((2-chloro-5-cyano-3-(1-(1-((2S)-2-hydroxypropyl)-
3-azetidinyl)-4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
547.06 3.67 323 ##STR00384##
2-((2-chloro-5-cyano-3-(1-(1-(cyclopropylmethyl)-3-
azetidinyl)-4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
543.08 3.78 324 ##STR00385##
2-((2-chloro-5-cyano-3-(1-(1-(2-hydroxy-2-
melhylpropyl)-3-azetidinyl)-4- piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
561.09 3.80 325 ##STR00386##
2-((2-chloro-5-cyano-3-(1-(1-(2-methoxyethyl)-3-
azetidinyl)-4-piperidinyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
547.06 3.92 CHROMOLITH .RTM. column 4.6 .times. 50 mm eluting with
10-90% aqueous methanol over 5 min. containing 0.1% TFA, 4 mL/min,
monitoring at 220 nm.
Example 326
##STR00387##
[1145] (+/-) methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1146] Prepared in analogous manner as Example 171 from
Intermediate 2 and example 171E
[1147] MS (ESI) m/z 511.6 (M+1).
[1148] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.19 (br. s., 1H),
8.87 (s, 1H), 8.20 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.33 (d, J=1.7
Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.00 (d, J=5.4 Hz, 1H), 3.55 (s,
4H), 3.50-3.36 (m, 3H), 3.31-3.16 (m, 2H), 2.77 (t, J=11.1 Hz, 1H),
2.55 (br. s., 1H), 1.93-1.82 (m, 1H), 1.57 (qd, J=12.2, 4.1 Hz,
1H), 1.19 (t, J=7.2 Hz, 3H)
Example 327
##STR00388##
[1149] methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1150] Prepared in similar way as Example 174 from intermediate 2
in place intermediate 6
[1151] MS (ESI): m/z 511.6 (M+1).
[1152] 1H NMR (500 MHz, DMSO-d6) .delta. 9.26-9.10 (m, 1H), 8.86
(br. s., 1H), 8.20 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.33 (d, J=1.7
Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 4.99 (d, J=5.2 Hz, 1H), 3.55 (s,
4H), 3.50-3.36 (m, 3H), 3.31-3.17 (m, 2H), 2.77 (t, J=11.3 Hz, 1H),
2.55 (br. s., 1H), 1.92-1.81 (m, 1H), 1.62-1.49 (m, 1H), 1.19 (t,
J=7.2 Hz, 3H)
Example 328
##STR00389##
[1153] methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1154] (328A):
4-(ethyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]tr-
iazine-7-carbonitrile (Intermediate 7, 70 mg, 0.181 mmol), methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (Example 173D, 80 mg, 0.181 mmol) and
Cs.sub.2CO.sub.3 (177 mg, 0.543 mmol) were mixed with DMF (2 mL) in
an sealed microwave vial. The mixture was heated in oil bath at
60.degree. C. for 2 hrs. The mixture was diluted with 50 ml EtOAc,
and then filtered. The filtrate was washed with water (3.times.50
ml), then brine; dried over MgSO.sub.4, filtered and concentrated
to dryness to give 140 mg of product, which will be used as it
is.
[1155] (328B): methyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)ph-
enyl)piperidin-4-yl)carbamate (140 mg, 0.188 mmol) was dissolved
into tetrahydrofuran (2 mL). TBAF 1M in THF (0.244 mL, 0.244 mmol)
was added. The mixture was stirred at room temperature overnight.
The mixture was concentrated to dryness, then diluted with EtOAc
(50 ml) and washed with sat. NaHCO.sub.3. The water layer was
extracted with 20 ml EtOAc. The combined organic layer was washed
with brine, dried over MgSO.sub.4, filtered and concentrated to
dryness to give 128 mg of product, which was used further without
purification.
[1156] Example 328: methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (128 mg, 0.183 mmol) was mixed with anisole (0.5 mL, 4.58
mmol) and DCE (2 mL). TFA (0.75 mL, 9.73 mmol) was added. The
mixture was stirred at room temperature for 2 hrs. LC/MS showed
that there was still large amount of starting material was left.
The mixture was heated at 40.degree. C. for 1 hr. The mixture was
concentrated to dryness in high-vac. 10 ml 2N NH.sub.3/MeOH was
added and stirred for 30 mins. The white precipitate was collected
by filtration and washed with water and 2 ml cold MeOH and dried
under air-suction to give 40 mg desired product methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-
-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate.
[1157] MS (ESI) m/z 511.6
[1158] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.26-9.10 (m, 1H),
8.86 (br. s., 1H), 8.20 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.33 (d,
J=1.7 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 4.99 (d, J=5.2 Hz, 1H), 3.55
(s, 3H), 3.60-3.36 (m, 4H), 3.31-3.17 (m, 2H), 2.77 (t, J=11.3 Hz,
1H), 2.55 (br. s., 1H), 1.92-1.81 (m, 1H), 1.62-1.49 (m, 1H), 1.19
(t, J=7.2 Hz, 3H)
Alternative Synthesis of Example 328
[1159] (328A1): A 3-liter 3-neck flask was loaded with
4-chlorobenzonitrile (65 g, 472 mmol), equipped with a mechanical
stirrer and internal thermometer. The flask was immersed into a
(-5.degree. C.) bath and sulfuric acid (700 ml) was added (forms a
homogeneous solution). The solution was cooled to an internal
temperature of 0.degree. C. NBS (170 g, 945 mmol) was added to this
solution. The reaction mixture is slurry with solid NBS. The
reaction mixture was stirred while the ice bath slowly melted.
Stirring was continued for 16 hours while the reaction mixture
warmed to room temperature. NMR analysis of an aliquot shows mostly
mono-bromination. The reaction mixture was heated to 30.degree. C.
for 16 hours. The reaction mixture was poured onto 3.5 kg ice in a
6 liter 3-neck flask (that was immersed into an ice-water-bath)
with mechanical stirrer and the resulting slurry stirred for 1
hour, then filtered. Solids were washed on the filter funnel with
10% NH.sub.4OH 2.times. (2 L), water 3.times. (2 L), and dried in a
nitrogen stream. 148 g (crude quantitative)
3,5-dibromo-4-chlorobenzamide were obtained and used without
further purification.
[1160] MS (ESI) m/z 310/312/314/316
[1161] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.24 (s, 2H),
8.22 (bs, 1H), 7.72 (bs, 1H).
[1162] (328B1): Phosphoryl trichloride (90 ml, 966 mmol) was added
to a suspension of 3,5-dibromo-4-chlorobenzamide (148 g, crude,
.about.380 mmol) in acetonitrile (1500 ml) at reflux. The reaction
mixture was heated to reflux for additional 90 minutes. The
reaction mixture was evaporated to dryness, and then partitioned
between EtOAc and aq. NaHCO.sub.3 solution. The organic layer was
washed one more time with aq. NaHCO.sub.3 solution, once with
brine, then dried over MgSO4, filtered and evaporated to dryness to
give 3,5-dibromo-4-chlorobenzonitrile (110 g). The material was
used without further purification in the next reaction.
[1163] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.89 (s, 2H).
[1164] (328C1): A 5-liter 3-neck flask was loaded with
3,5-dibromo-4-chlorobenzonitrile (79 g, 188 mmol),
(3R,4R)-4-((E)-(4-methoxybenzylidene)amino)piperidin-3-ol (47 g,
171 mmol), Pd.sub.2(dba).sub.3 (5.15 g, 5.63 mmol), BINAP (10.62 g,
17.05 mmol), and Cs.sub.2CO.sub.3 (222 g, 682 mmol) and flushed
with nitrogen. Dioxane (2000 ml) was added. The reaction mixture
was heated to 95.degree. C. for 18 hours. LCMS shows significant
amount of remaining starting material. Additional
Pd.sub.2(dba).sub.3 (1.57 g, 1.715 mmol) and BINAP (2.13 g, 3.42
mmol) were added and the temperature increased to 100.degree. C.
for 6 hours. The flask was opened under a nitrogen blanket.
Pd.sub.2(dba).sub.3 (5.15 g, 5.63 mmol), XANTPHOS (9.87 g, 17.05
mmol) and O-t-butyl carbamate (49.9 g, 426 mmol) were added and the
flask flushed with nitrogen again. The reaction mixture was heated
to 100.degree. C. for 24 hours. Celite was added to the reaction
mixture, which was then stirred briefly and filtered through a
layer of Celite. Solids were washed with DCM. The filtrate was
concentrated to give a brown foam (115 g) that was purified by
chromatography on silica (3000 g cartridge). (Loaded as a solution
in DCM, eluted with a gradient from 100% DCM to 10% MeOH in DCM (to
solvolyze the imine), then a gradient from 10% to 20% of (2M
NH.sub.3 in MeOH) in DCM.). tert-butyl
(3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carba-
mate (27.3 g) was obtained.
[1165] MS (ESI) m/z 367/369
[1166] (328D1): A solution of tert-butyl
(3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carba-
mate (27.3 g, 55.8 mmol, .about.75% pure) and DIPEA (48.7 mL, 279
mmol) in MeOH (500 mL) at 0.degree. C. (acetone/ice bath, bath temp
.about.-10.degree. C.) was treated with Methyl Chlorocarbonate
(12.94 ml, 167 mmol) (slow addition, keeping internal
temperature<+3.degree. C.). The reaction was stirred for 1 hour
at 0.degree. C., and then concentrated in vacuo. The residue was
partitioned between EtOAc and 0.5 M citric acid. The organic layer
was washed with sat. NaHCO3 solution and brine, then dried over
MgSO4, filtered and evaporated to dryness. The crude was purified
by chromatography on silica (750 g), using gradient elution from
100% hexanes to 50% EtOAc+50% DCM. Product containing fractions
were combined and evaporated to a sticky oil to give methyl
((3R,4R)-1-((3-N-Boc-amino)-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4--
yl)carbamate (19.7 g).
[1167] MS (ESI) m/z 423/425,
[1168] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.90 (s, 1H),
7.71 (d, J=1.7 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.08 (d, J=7 Hz,
1H), 4.98 (d, J=5.3 Hz, 1H), 3.56 (s, 3H), 3.57-3.49 (m, 2H),
3.45-.3.13 (m, 3H), 2.77 (dt, J=1.5, 12.0 Hz, 1H), 1.92-1.84 (m,
1H), 1.62-1.48 (m, 1H), 1.49 (s, 9H).
[1169] (328E1): methyl
((3R,4R)-1-(3-N-BOC-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl-
)carbamate (19.7 g, 34.8 mmol) was dissolved in DCE (100 ml). TFA
(25 ml, 324 mmol) was added and the mixture stirred at room
temperature for 21 hours under a gentle nitrogen stream. The
reaction mixture was evaporated to dryness and dissolved in ammonia
(2 molar in MeOH) (200 ml, 400 mmol) and stirred at room
temperature for 2 hours. The reaction mixture was evaporated to
dryness, then partitioned between aqueous NaHCO3 solution and
EtOAc. The organic layer was washed brine, dried over MgSO4,
filtered and evaporated to dryness (18.3 g pale brown foam). The
crude was purified by column chromatography on silica (1500 g
silica, gradient from 100% hexanes to (70% acetone+30% hexanes)
over 60 column volumes). Product containing fractions were combined
and evaporated to dryness to give a pale brown solidified foam
methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (10.9 g)
[1170] MS (ESI) m/z 323/325
[1171] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.06 (b, 1H),
6.85 (d, J=2.0 Hz, 1H), 6.70 (d, J=1.8 Hz, 1H), 5.82 (b, 2H), 4.93
(d, J=5.0 Hz, 1H), 3.55 (s, 3H), 3.55-3.45 (m, 1H), 3.35-3.30 (m,
1H), 3.28-3.21 (m, 1H), 3.17-3.11 (m, 1H), 2.67 (dt, J=2, 10 Hz,
1H), 2.43 (t, J=10.6 Hz, 1H), 1.89-1.82 (m, 1H), 1.56 (dq, J=4.0,
12.3 Hz, 1H).
[1172] (328F1): A 1 liter round bottom flask was loaded with
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (12.05 g, 35.2 mmol, Intermediate 10), methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (10.9 g, 28.5 mmol), Pd(OAc)2 (377 mg, 1.679 mmol), XANTPHOS
(990 mg, 1.711 mmol) and Potassium phosphate (17.1 g, 81 mmol). The
vial was evacuated and back-filled with nitrogen 4 times. Toluene
(320 mL) was added and the flask was again evacuated and
back-filled with nitrogen 4 times, and then heated with stirring to
90.degree. C. for 16 hours. LCMS shows product and both starting
materials as separate peaks. (.about.5:1:1 ratio by UV). The flask
was opened under nitrogen, additional palladium(II) acetate (190
mg, 0.846 mmol), XANTPHOS (500 mg, 0.864 mmol) and potassium
phosphate tribasic (7.5 g, 35.3 mmol) were added and the flask
re-sealed, flushed with nitrogen again and heating continued for
additional 6 hours. Celite was added to the reaction mixture. The
suspension was stirred briefly, and then filtered through a layer
of Celite. Solids were washed with DCM. The filtrate was
concentrated to brown foam. (23.9 g). Purification by column
chromatography on silica (1500 g) using a gradient from 100%
CH.sub.2Cl.sub.2 to (50% EtOAc+50% CH2Cl2) gave methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (11.2 g).
[1173] MS (ESI) m/z 629/631
[1174] Example 328A: Prepared in identical way as Example 328
Example 329
##STR00390##
[1175]
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1176] Prepared in similar manner as intermediate 12
[1177] MS (ESI) m/z (M+1). 436.91
[1178] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.19 (t, J=5.8 Hz,
1H), 8.86 (s, 1H), 8.20 (s, 1H), 7.95 (d, J=1.7 Hz, 1H), 7.33 (d,
J=1.7 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 3.55 (s, 3H), 3.51-3.42 (m,
3H), 3.28 (d, J=12.0 Hz, 2H), 2.78 (t, J=11.2 Hz, 2H), 1.87 (d,
J=10.4 Hz, 2H), 1.65-1.54 (m, 2H), 1.19 (t, J=7.2 Hz, 3H)
Example 330
##STR00391##
[1179] methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)piperidin-4-yl)carbamate
[1180]
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 329)
(40 mg, 0.092 mmol) was mixed with N,N-diisopropylethylamine (0.2
ml, 1.145 mmol) in MeOH (1 ml) and THF (1 ml). methyl
carbonochloridate (0.05 ml, 0.646 mmol) was added. The mixture was
stirred at room temperature for 1 hr. LC/MS showed product
formation. The white precipitate was formed and collected by
filtration, washed with cold MeOH (15 ml), then water (5 ml) and
dried with air-suction to give 31.7 mg of desired product.
[1181] MS (ESI): m/z 495.3
[1182] 1H NMR (500 MHz, DMSO-d6) .delta. 9.19 (t, J=5.8 Hz, 1H),
8.86 (s, 1H), 8.20 (s, 1H), 7.95 (d, J=1.7 Hz, 1H), 7.33 (d, J=1.7
Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 3.55 (s, 3H), 3.51-3.42 (m, 3H),
3.28 (d, J=12.0 Hz, 2H), 2.78 (t, J=11.2 Hz, 2H), 1.87 (d, J=10.4
Hz, 2H), 1.65-1.54 (m, 2H), 1.19 (t, J=7.2 Hz, 3H)
Example 331
##STR00392##
[1183] methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-fluoro-4-piperidinyl)carbamate
[1184] The title compound was prepared using procedure similar to
Example 284
[1185] MS (ESI): m/z 512.94 (M+H)
Example 332
##STR00393##
[1186] ethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1187] (332A): A solution of tert-butyl
(3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)carba-
mate (Example 173A) (300 mg, 0.818 mmol) and DIPEA (0.428 mL, 2.453
mmol) in MeOH (15 mL) at 0.degree. C. (ice bath) was treated with
ethyl chloroformate (0.078 mL, 0.818 mmol). The reaction was
stirred for 1 hour, and then the mixture was concentrated in vacuo.
To the residue was added EtOAc (50 ml) and the mixture washed with
0.5M citric acid, sat. NaHCO.sub.3, water and brine. The solution
was dried over Na.sub.2SO.sub.4 and solvents removed. To the crude
material was added. DCE (5 mL) and TFA (2 mL, 26.0 mmol); the
reaction stirred 2 h at 25.degree. C. and solvents removed. The
material was diluted with DCM and washed with sat. NaHCO.sub.3 and
water. The organics dried over Na.sub.2SO.sub.4 and removed
solvent. The material was purified on silica gel 25% EtOAc-DCM to
afford ethyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (110 mg).
[1188] MS (ESI): m/z 325
[1189] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 6.99-7.13
(1H, m), 6.83 (1H, d, J=1.83 Hz), 6.62-6.74 (1H, m), 5.78-5.85 (2H,
m), 4.82-5.02 (1H, m), 3.54 (3H, s), 3.45-3.52 (1H, m), 3.27 (1H,
br. s.), 3.08-3.16 (1H, m), 2.61-2.72 (1H, m), 2.41 (1H, s),
1.69-1.97 (1H, m), 1.34-1.67 (1H, m)
[1190] (332B):
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (42 mg, 0.123 mmol), ethyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (40 mg, 0.118 mmol), DPPF (4.58 mg, 8.26 umol),
Cs.sub.2CO.sub.3 (65.4 mg, 0.201 mmol), Xantphos (6.83 mg, 0.012
mmol), Palladium(II)Acetate (7.95 mg, 0.035 mmol) and 1,4-dioxane
(2 ml) were combined in a microwave vial. The vial was evacuated
and backfilled with Nitrogen 3.times.. The reaction stirred at
100.degree. C. for 3 hr. The reaction mixture cooled to 25.degree.
C., diluted with EtOAc and washed with brine and dried
(Na.sub.2SO.sub.4). The solvents were removed and the material
purified on silica gel 25% EtOAc in DCM to afford ethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (50 mg).
[1191] MS (ESI): m/z 646
[1192] Example 332: To
ethyl((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)am-
ino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-y-
l)carbamate (50 mg, 0.068 mmol), in DCE (0.8 mL) was added anisole
(0.1 mL, 0.915 mmol) and TFA (0.5 mL, 6.49 mmol); the mixture
stirred 2 h at 25.degree. C. and solvent was removed. 2N
NH.sub.3/MeOH (5 ml) was added and the mixture stirred for 30 min
at 25.degree. C. The solution was stored at -20.degree. C. and a
white precipitate formed. The material was collected by filtration,
washed with 20 ml cold MeOH, 5 ml ether and dried under air-suction
for 0.5 h to afford ethyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (10
mg).
[1193] MS (ESI): m/z 525
[1194] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.30-9.10 (m,
1H), 8.96-8.75 (m, 1H), 8.20 (s, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.32
(d, J=1.8 Hz, 1H), 7.11-6.91 (m, 1H), 4.97 (d, J=5.5 Hz, 1H), 4.00
(d, J=7.0 Hz, 2H), 3.60-3.49 (m, 1H), 3.49-3.42 (m, 2H), 3.42-3.34
(m, 1H), 3.28 (d, J=8.1 Hz, 1H), 3.24-3.16 (m, 1H), 2.82-2.71 (m,
1H), 2.47 (br. s., 1H), 1.88 (d, J=8.7 Hz, 1H), 1.65-1.48 (m, 1H),
1.18 (td, J=7.1, 4.5 Hz, 6H)
[1195] The compounds listed below were prepared by the similar
synthetic procedure used for Example 284
TABLE-US-00015 TABLE 12 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 333 ##STR00394## methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methoxy-3-pyrrolidinyl) carbamate 510.94 3.96
334 ##STR00395## methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methoxy-3-pyrrolidinyl) carbamate 510.94 3.98
.sup.c 335 ##STR00396## methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methyl-3-pyrrolidinyl) carbamate 494.95 4.32 336
##STR00397## methyl ((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)-4-methyl-3-pyrrolidinyl) carbamate 494.95 4.28
.sup.a YMC S5 ODS 4.6 .times. 50 mm, 10-90% aqueous methanol
containing 0.2% H.sub.3PO.sub.4, 5 min. gradient, monitored at 220
nm
Example 337
##STR00398##
[1196] methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4-yl)carbamate
[1197] To a suspension of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(Example 328) (25 mg, 0.049 mmol) in DCM (2 mL) at 0.degree. C.,
was added pyridine (0.012 mL, 0.147 mmol) followed by POCl.sub.3
(0.014 mL, 0.147 mmol), DMAP (0.598 mg, 0.0048 mmol). After
stirring for 15 min. reaction was warmed to 35.degree. C. and
stirring continued for overnight. After confirming the product
formation by LC-MS, reaction mixture was hydrolyzed with water (2
mL) and stirred for 10 minutes at room temperature. The reaction
was concentrated under vacuum and purified by preparative HPLC and
collected fractions lyophilized to yield methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4-yl)carbamate
(22 mg) as an off white solid.
[1198] Preparative HPLC: Column: Inertsil ODS (19.times.250)
mm.times.5 u; Solvent A=10 mM Ammonium acetate pH-4.5 with Acetic
acid; Solvent B=MeOH; Time (min)/% B: 0/20, 10/70, 15/100; Flow
Rate=16 mL/min; Wavelength=220 & 254 nm; Product Retention
time=9.37 min.
[1199] MS (ESI): m/z 589.0
[1200] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.73 (br.
S., 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.32 (s, 1H), 4.03-3.97 (m,
1H), 3.57-3.44 (m, 6H), 3.24-3.21 (m, 2H), 2.78-2.63 (m, 2H),
2.36-2.31 (m, 1H), 1.41-1.32 (m 1H), 1.22 (t, J=6.8 Hz, 3H)
Example 338
##STR00399##
[1201] methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)-4-piperidinyl)carbamate
[1202] Prepared in similar manner as Example 338 from Example
327.
[1203] MS (ESI): m/z 589.0
[1204] 1H NMR (500 MHz, DMSO-d6) .delta. 9.19 (t, J=5.7 Hz, 1H),
8.85 (s, 1H), 8.20 (s, 1H), 8.02 (d, J=1.7 Hz, 1H), 7.35 (d, J=1.7
Hz, 1H), 7.13 (d, 7.9 Hz, 1H), 4.18 (m, 1H), 3.67 (m, 1H), 3.65 (s,
3H), 3.53-3.43 (m, 3H), 3.24 (m, 1H), 2.81 (m, 2H), 1.96 (m, 1H),
1.68 (dq, J=3.2, 12 Hz, 1H), 1.19 (t, J=7.2 Hz, 3H).
Example 339
##STR00400##
[1205]
(+/-)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo-
[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperid-
in-3-yl 2-(phosphonooxy)propanoate
[1206] (339A): To a solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxy
piperidin-4-yl)carbamate (0.040 g, 0.063 mmol),
2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.067 g, 0.19
mmol) in DCM (2 mL) was added DCC (0.039 g, 0.190 mmol) followed
DMAP (0.77 mg, 0.006 mmol) and stirred at room temperature for 30
min. After completion of starting material (by LC-MS), reaction
mixture was diluted with DCM (50 mL), filtered through celite and
filtrate was washed with water and brine solution (5 mL). Combined
organic extracts were dried over anhydrous Na.sub.2SO.sub.4,
concentrated and purified by flash chromatography on silica gel
using an ISCO system (eluted with 1:1 Hexanes and EtOAc) to give
diastereomeric mixture of (3R,4R)
1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin--
3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g,) as
gummy liquid.
[1207] MS (ESI) m/z 962.1 (M-1)
[1208] Example 339: To a solution of
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)im-
idazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)pi-
peridin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g,
0.062 mmol) in DCE (3 mL) was added anisole (0.028 mL, 0.258 mmol)
followed by TFA (25% in DCE) (4.98 mL, 16.15 mmol) and stirred at
35.degree. C. for overnight. After completion of the starting
material (by LC-MS), solvent was removed under vacuum at 30.degree.
C. (LC-MS showed PMB cleavage along with anticipated
de-benzylation). The crude mixture was purified by reverse phase
preparative HPLC to give diastereomeric mixture of
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,-
4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl-2-(p-
hosphonooxy)propanoate (0.014 g) as an off-white solid.
[1209] Preparative HPLC: Column: Sunfire C18 (19.times.150)
mm.times.5 u; Solvent A=10 mM Ammonium acetate pH-4.6 adjusted with
AcOH; Solvent B=Acetonitrile; Time (min)/% B: 0/20, 8/70, 12/70;
Flow Rate=16 mL/min; Wavelength=220 & 254 nm;
[1210] Product Retention time=7.066 min.
[1211] MS (ESI) m/z 663.0
[1212] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.98-9.36
(br. m, 1H), 8.25 (s, 1H), 8.03-7.96 (m, 1H), 7.49-7.24 (br. m,
3H), 4.85-4.72 (m, 1H), 4.52-4.42 (m, 1H), 3.68-3.52 (m, 9H),
2.89-2.71 (m, 3H), 2.00-1.93 (m, 1H), 1.82-1.66 (m, 1H) 1.29-1.14
(m, 6H)
Example 340
##STR00401##
[1213]
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-
-3-yl 2-(phosphonooxy)propanoate
[1214] (340A): To a solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (0.090 g, 0.143 mmol) in DCM (3 mL) was added
(S)-2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.150 g, 0.428
mmol) followed by DCC (0.088 g, 0.428 mmol), DMAP (1.74 mg, 0.014
mmol) and stirred at room temperature for overnight. After
completion of starting material (by LC-MS), reaction mixture was
diluted with DCM (50 mL), filtered through celite and filtrate was
washed with water and brine solution (5 mL). Combined organic
extracts were dried over anhydrous Na.sub.2SO.sub.4, concentrated
to give
(S)-((3R,4R)-1-(2-chloro-5-cyano-3-(7-cyano-4-(ethyl(4-methoxybenzyl)amin-
o)imidazo[1,2-f][1,2,4]triazin-2-ylamino)phenyl)-4-(methoxycarbonylamino)p-
iperidin-3-yl)-2-(bis(benzyloxy)phosphoryloxy)propanoate (0.1 g) as
gummy liquid. This was taken for next step without any
purification.
[1215] MS m/z 963.2
[1216] Example 340: Prepared using the similar procedure as used
for Example 339.
[1217] MS (ESI) m/z 663.0
[1218] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.17 (br. s,
1H), 8.86 (br. s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.39-7.29 (m,
2H), 7.13 (br. s, 1H), 6.57 (br. s, 1H), 4.83-4.78 (m, 1H),
4.57-4.46 (m, 1H), 3.71-3.47 (m, 8H), 2.88-2.72 (m, 2H), 1.95-1.91
(m, 1H), 1.78-1.67 (m, 1H), 1.29 (d, J=6.78 Hz, 3H) 1.22-1.13 (m,
3H)
Example 341
##STR00402##
[1219]
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-
-3-yl 2-hydroxypropanoate
[1220] (341A): A mixture of (S)-methyl 2-hydroxypropanoate (1.5 g,
14.41 mmol), 1-(chloromethyl)-4-methoxybenzene (3.38 g, 21.61
mmol), DIPEA (4.03 ml, 23.05 mmol) and sodium iodide (0.150 g,
1.001 mmol) was heated to 150.degree. C. for 2 h. Reaction mixture
then was cooled to room temperature diluted with EtOAc (100 mL) and
washed with saturated NaHCO3 solution (2.times.50 mL) and brine.
Combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The crude mixture was purified
by flash chromatography on silica gel using an ISCO system (eluted
with 9:1 Hexanes and EtOAc) to give (S)-methyl
2-((4-methoxybenzyl)oxy)propanoate (2 g) as a gummy liquid.
[1221] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.25 (d,
J=6.9 Hz, 2H), 6.91 (d, J=6.9 Hz, 2H), 4.48 (d, J=10.5 Hz, 1H),
4.34 (d, J=10.5 Hz, 1H), 4.11-4.04 (m, 1H), 3.74 (s, 3H), 3.67 (s,
3H), 1.29 (d, J=6.6 Hz, 3H)
[1222] (341B): To a solution of (S)-methyl
2-((4-methoxybenzyl)oxy)propanoate (1 g, 4.46 mmol) in THF (20 mL)
and MeOH (6 mL) at 0.degree. C. was added lithium hydroxide (0.225
g, 9.38 mmol) and stirred for 3 h. Then warmed to room temperature
in 30 min. After completion of starting material (by TLC), reaction
mixture was concentrated and the resultant residue was taken EtOAc
(100 ml), acidified by 1.5N HCl (up to pH 1) and extracted into
EtOAc (2.times.100 ml). Combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, concentrated to give
(S)-2-((4-methoxybenzyl)oxy)propanoic acid (0.6 g) was obtained as
a gummy liquid.
[1223] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.41 (br.
s, 1H), 7.27 (d, J=4.8 Hz, 2H), 6.91 (d, J=4.8 Hz, 2H), 4.51 (d,
J=11.4 Hz, 1H), 4.32 (d, J=11.4 Hz, 1H), 3.99-3.92 (m, 1H), 3.74
(s, 3H), 1.29 (d, J=4.8 HZ, 3H)
[1224] (341C): To a solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (0.050 g, 0.079 mmol) in DCM (2 mL) was added
(S)-2-((4-methoxybenzyl)oxy)propanoic acid (0.050 g, 0.238 mmol)
followed by DCC (0.049 g, 0.238 mmol), DMAP (0.968 mg, 0.008 mmol)
and stirred at room temperature for 1 h. After completion of
starting material (by TLC), reaction mixture was diluted with DCM
(15 mL), filtered through celite and filtrate was washed with water
(10 mL) and brine. Combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, concentrated and purified by flash
chromatography on silica gel using an ISCO system (eluted with 4:6
Hexanes and EtOAc) to give
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amin-
o)piperidin-3-yl-2-((4-methoxybenzyl)oxy)propanoate (0.050 g) as a
gummy solid. The purity of the compound was 57% with major DCU
impurity. Product was taken for next step without further
purification.
[1225] MS (ESI) m/z 823.2
[1226] Example 341: To a solution of
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amin-
o)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amin-
o)piperidin-3-yl 2-((4-methoxybenzyl)oxy)propanoate (0.050 g, 0.061
mmol) in DCE (3 mL) was added anisole (0.027 ml, 0.243 mmol)
followed by TFA (25% in DCE) (4.68 mL, 15.18 mmol) and stirred at
35.degree. C. for overnight. The reaction mixture was concentrated
at 30.degree. C. and resultant residue was washed with diethyl
ether to give solid and this was purified by reverse phase
preparative HPLC and collected fractions were lyophilized to give
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
2-hydroxypropanoate (0.005 g) as a white solid.
[1227] Preparative HPLC: Column: SUNFIRE C-18 (19.times.150)
mm.times.5 u; Solvent A=10 mM Ammonium acetate pH-4.5 with AcOH;
Solvent B=Acetonitrile; Time (min)/% B: 0/30, 12/70, 15/100; Flow
Rate=16 mL/min; Wavelength=220 & 254 nm; Product Retention
time=8.30 min.
[1228] MS (ESI) (ESI) m/z 583.2
[1229] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.18 (t,
J=5.65 Hz, 1H), 8.90 (s, 1H), 8.19 (s, 1H), 7.95 (d, J=1.76 Hz,
1H), 7.38 (d, J=1.76 Hz, 1H), 7.28-7.25 (m, 1H), 5.37 (d, J=5.77
Hz, 1H), 4.83-4.76 (m, 1H), 4.14-4.05 (m, 1H), 3.70-3.59 (m, 1H),
3.53 (s, 3H), 3.49-3.27 (m, 4H), 2.91-2.71 (m, 2H), 1.94 (d, J=9.03
Hz, 1H), 1.80-1.67 (m, 1H), 1.24 (d, J=7.03 Hz, 3H), 1.18 (t,
J=7.15 Hz, 3H)
Example 342
##STR00403##
[1230]
(R)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-
-3-yl 2-(phosphonooxy)propanoate
[1231] Prepared using method similar to Example 340 and purified
using preparative HPLC as below.
[1232] Preparative HPLC: Column: Sunfire C-18 (250.times.19)
mm.times.5 u; Solvent A=10 mm ammonium acetate ph 4.6 adjusted by
AcOH; Solvent B=Acetonitrile; Time (min)/% B: 0/10, 10/50, 15/100;
Flow Rate=16 mL/min; Wavelength=220 & 254 nm; Product Retention
time=11.04 min.
[1233] MS (ESI) m/z 663.0 (M+1)
[1234] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.16 (br. s,
1H), 8.21-8.16 (m, 1H), 8.02-7.96 (m, 1H), 7.37-7.32 (m, 3H),
4.80-4.74 (m, 1H), 4.48-4.44 (m, 1H), 3.63-3.34 (m, 8H), 2.88-2.70
(m, 3H), 1.92-1.89 (m, 1H), 1.79-1.74 (m, 1H), 1.24-1.16 (m,
6H)
Example 343
##STR00404##
[1235]
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f-
][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-y-
l 4-(phosphonooxy)butanoate
[1236] (343A): To a suspension of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (100 mg, 0.158 mmol) and
4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (141 mg, 0.475 mmol)
in DCM (5 mL) at 0.degree. C., was added DCC (98 mg, 0.475 mmol)
followed by DMAP (1.936 mg, 0.016 mmol) and stirred at room
temperature for overnight. After completion of the starting
material (by LC-MS), reaction mixture was diluted with DCM (2 mL)
and filtered through celite and filtrate was washed with water and
brine. Combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4, concentrated. The resultant residue was purified
by flash chromatography on silica gel using an ISCO system (eluted
with 7:3 Hexanes and EtOAc) to afford
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4
(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phen-
yl)-4-((methoxycarbonyl)amino)piperidin-3-yl
4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg) as pale yellow
solid.
[1237] MS (ESI) m/z 910.2
[1238] Example 343: To a solution of
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)im-
idazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)pi-
peridin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg,
0.079 mmol) in DCE (2 mL) at 0.degree. C. was added TFA (25% in
DCE) (6.10 mL, 19.79 mmol) followed by anisole (0.035 mL, 0.317
mmol) and stirred at 35.degree. c. for overnight. After completion
of the starting material (by LC-MS), reaction was concentrated and
purified by reverse phase preparative HPLC and collected fractions
were lyophilized to give
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,-
4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
4-(phosphonooxy)butanoate (4 mg) as an off white solid.
[1239] Preparative HPLC: Column: Symmetry C-18(250.times.19) mm, 7
u; Solvent A=10 mM Ammonium acetate; Solvent B=Acetonitrile; Time
(min)/% B: 0/10, 10/50; Flow Rate=16 mL/min; Wavelength=220 &
254 nm; Product Retention time=11.75 min.
[1240] MS (ESI) m/z 677.0
[1241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.18-8.14
(m, 1H), 8.95-8.89 (m, 2H), 7.63-7.59 (m, 1H), 7.39-7.22 (m, 4H),
4.79-4.71 (m, 1H), 3.65-3.42 (m, 10H), 3.28-3.22 (m 1H), 2.85-2.80
(m 1H), 2.64-2.55 (m, 1H), 2.23-2.20 (m, 2H), 1.92-1.89 (m, 1H),
1.71-1.65 (m, 2H), 1.18-1.11 (m, 3H)
Example 344
##STR00405##
[1242]
(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f-
][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-y-
l 2-(4-(phosphonooxy)phenyl)acetate
[1243] Prepared using methodology similar to the one used for
Example 343
[1244] MS (ESI) m/z 725
[1245] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.19 (s,
1H), 7.90 (d, J=1.51 Hz, 1H), 7.36 (d, J=1.51 Hz, 1H), 7.31-7.27
(m, 1H), 7.04 (br. s, 4H), 6.80-6.65 (br., 1H), 4.81-4.76 (m, 1H),
3.65-3.42 (m, 10H), 3.33-3.20 (m, 2H) 2.87 (t, J=10.04 Hz, 1H),
2.73 (t, J=10.67 Hz, 1H), 1.94 (br. m, 1H), 1.78-1.70 (m, 1H), 1.13
(t, J=7.15 Hz, 3H)
Example 345
##STR00406##
[1246] sodium
(((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,-
2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl)ox-
y)methyl phosphate
[1247] (345A): To a stirred solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(Example 328) (25 mg, 0.049 mmol) in acetic anhydride (0.046 ml,
0.489 mmol) at 0.degree. C. was added DMSO (0.052 ml, 0.734 mmol)
followed by acetic acid (0.084 ml, 1.468 mmol) and stirring
continued for 4 day at room temperature. LCMS showed approx 45%
desired compound, with no starting material remaining. Reaction
mixture was diluted with ethyl acetate and washed with 10%
Na.sub.2CO.sub.3 (3 ml) and brine. Combined organic extracts were
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. Resulted 30
mg crude residue was purified by reverse phase preparative HPLC and
collected fractions were lyophilized to give methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-((methylthio)methoxy)piperidin-4-yl)carbam-
ate (18 mg) as an off white solid Preparative HPLC: Column:
Inertsil ODS (250.times.19) mm, 5 u; Solvent A=10 mM Ammonium
acetate pH-4.5 with AcOH; Solvent B=Acetonitrile; Time (min)/% B:
0/30, 10/70, 15/100; Flow Rate=16 mL/min; Wavelength=220 & 254
nm; Product Retention time=18.84 min.
[1248] LC-MS (ESI) m/z 571.2
[1249] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.21-9.15
(m, 1H), 9.87 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.37 (s, 1H),
7.20-7.15 (m, 1H), 4.73 (s, 2H), 4.04 (s, 3H), 3.71-3.39 (m, 8H),
3.28-3.19 (m, 1H), 2.80-2.73 (m, 1H), 2.62-2.58 (m, 1H), 1.86-1.82
(m, 1H), 1.72-1.63 (m, 1H), 1.19 (t, J=5.2 Hz, 3H)
[1250] Example 345: To a stirred solution of methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-((methylthio)methoxy)piperidin-4-yl)carbam-
ate (18 mg, 0.032 mmol) in THF (2 mL) at 0.degree. C. was added NIS
(14.18 mg, 0.063 mmol) followed by crystalline phosphoric acid
(15.44 mg, 0.158 mmol) and allowed to warm to room temperature in 1
h. After TLC showed completion of starting material, reaction
mixture was diluted with methanol (2 ml) and treated with 1M
Na.sub.2S.sub.2O.sub.3 until it becomes colorless, then pH adjusted
to 10 (approx) by addition of solid Na.sub.2CO.sub.3. Resultant
precipitate was removed by filtration and submitted for LC-MS,
which showed major product. The filtrate was concentrated and
lyophilized to give crude off white solid. This was purified by
reverse phase preparative HPLC to give pure sodium
(((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,-
2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl)ox-
y)methyl phosphate (9 mg) as an off white solid.
[1251] Preparative HPLC: Column: Sunfire C-18 (250.times.19) mm, 5
u; Solvent A=water; Solvent B=Acetonitrile; Time (min)/% B: 0/10,
10/50, 15/100; Flow Rate=16 mL/min; Wavelength=220 & 254 nm;
Product Retention time=5.74 min.
[1252] LC-MS (ESI) m/z 619.0 (M-1) (of corresponding acid)
[1253] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.10 (s,
1H), 8.07 (br. s, 1H), 7.24 (br. s, 1H), 4.87-4.78 (m, 2H),
3.96-3.88 (m, 1H), 3.56-3.47 (m, 8H), 3.28-3.15 (m, 2H), 2.69-2.50
(m, 2H), 2.05 (br. d, J=8.4 Hz, 1H), 1.53-1.48 (m, 1H), 1.20-1.11
(m, 3H)
Example 346
##STR00407##
[1254]
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-
-3-yl 2-amino-3-methylbutanoate
[1255] Prepared using methodology similar to the one used for
Example 194
[1256] MS (ESI) m/z 610.2
[1257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.20 (s,
1H), 7.98 (d, J=1.76 Hz, 1H), 7.37 (d, J=1.76 Hz, 1H), 7.27 (d,
J=8.53 Hz, 1H), 6.52 (br. s, 1H), 6.29 (br. s, 1H), 4.83-4.79 (m,
1H), 3.74-3.61 (m, 1H), 3.53 (s, 3H), 3.46 (q, J=7.28 Hz, 4H), 3.09
(d, J=5.52 Hz, 1H), 2.94-2.83 (m, 1H) 2.76 (t, J=10.54 Hz, 1H),
1.98-1.69 (m, 4H), 1.26-1.12 (m, 4H), 0.87 (d, J=6.78 Hz, 3H), 0.81
(d, J=6.78 Hz, 3H)
Example 347
##STR00408##
[1258]
2-((6-cyanopyridin-2-yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1-
,2,4]triazine-7-carbonitrile
[1259] (347A): To a round bottom flask charged with methyl
6-((tert-butoxycarbonyl)amino)picolinate (1 g, 3.96 mmol) was added
ammonia in MeOH (10 ml, 70.0 mmol). The reaction mixture was
stirred at room temperature 3 h. The reaction mixture was
concentrated in vacuo, providing a white fluffy solid. Material
carried forward as is.
[1260] MS (ES-) m/z 236.4 (M-H)
[1261] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.12 (dd, J=7.9,
1.3 Hz, 1H), 7.90-7.80 (m, 2H), 7.54 (d, J=11.0 Hz, 1H), 7.17 (br.
s., 1H), 5.51 (br. s., 1H), 1.55 (s, 9H)
[1262] (347B): To a round bottom flask charged with tert-butyl
(6-carbamoylpyridin-2-yl)carbamate (0.940 g, 3.96 mmol) in
dichloromethane (7.92 ml) was added triethylamine (1.380 ml, 9.90
mmol). The reaction mixture was cooled to 0.degree. C. and
trifluoroacetic anhydride (0.671 ml, 4.75 mmol) was added dropwise.
The reaction mixture was stirred at 0.degree. C. 90 min. The
reaction mixture was quenched with saturated aqueous sodium
bicarbonate and transferred to a separatory funnel. The aqueous
layer was extracted with dichloromethane (2.times.). The combined
organics were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The crude residue was
purified by column chromatography on the ISCO system (40 g, 0-15%
EtOAc/Hex) to provide tert-butyl (6-cyanopyridin-2-yl)carbamate
(0.538 g).
[1263] MS (ES-) m/z 218.3 (M-H)
[1264] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.22 (dd, J=8.7,
0.8 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.36 (dd, J=7.5, 0.9 Hz, 1H),
7.31 (br. s., 1H), 1.54 (s, 9H)
[1265] (347C): To a round bottom flask charged with tert-butyl
(6-cyanopyridin-2-yl)carbamate (0.5383 g, 2.455 mmol) in
dichloromethane (9.82 ml) was added TFA (2.455 ml). The reaction
mixture was stirred at room temperature 4 h. Excess TFA was removed
in vacuo. The crude residue was taken up in methanol and free based
using 2 parallel Phenomenex 5 g SCX columns. The columns were
flushed with three column volumes methanol and three column volumes
3.5 N ammonia/methanol. The ammonia layers were concentrated in
vacuo to provide 6-aminopicolinonitrile (0.312 g).
[1266] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.56-7.47 (m,
1H), 7.06 (dd, J=7.3, 0.7 Hz, 1H), 6.68 (dd, J=8.6, 0.7 Hz, 1H),
4.70 (br. s., 2H)
[1267] (347D): The compound was prepared starting from
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (50 mg, 0.125 mmol) and
6-aminopicolinonitrile (17.94 mg, 0.151 mmol) using the procedure
for Example 1E. Material was carried forward into the next step as
is.
[1268] MS (ESI) m/z 438.4 (M+H)
[1269] Example 347: To a round bottom flask charged with
2-((6-cyanopyridin-2-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imida-
zo[2,1-f][1,2,4]triazine-7-carbonitrile (54.7 mg, 0.125 mmol) in
dichloromethane (625 .mu.l) was added anisole (27.3 .mu.l, 0.250
mmol) and TFA (385 .mu.l, 5.00 mmol). The reaction mixture was
stirred at room temperature ON. Additional TFA (1 mL) was added.
The reaction mixture was warmed to 50.degree. C. ON. Excess TFA was
removed by concentration in vacuo. The crude residue was purified
by neutral phase preparatory LC/MS chromatography to provide
2-((6-cyanopyridin-2-yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]t-
riazine-7-carbonitrile (0.7)
[1270] MS (ESI) m/z 318.2 (M+H)
[1271] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.34 (s, 1H),
9.45 (d, J=4.5 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.26 (s, 1H),
8.05-7.97 (m, 1H), 7.60 (d, J=7.4 Hz, 1H), 3.16-3.08 (m, 1H),
0.90-0.75 (m, 4H)
Example 348
##STR00409##
[1272]
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(ethylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1273] The title compound was prepared in analogous manner as
Example 208
[1274] MS (ESI) m/z 422.18 (M+1)
[1275] 1H NMR (500 MHz, DMSO-d6) d 9.19 (br. s., 1H), 8.85 (br. s.,
1H), 8.20 (s, 1H), 8.17 (br. s., 1H), 7.55 (br. s., 1H), 4.09 (d,
J=4.7 Hz, 2H), 3.45 (d, J=7.0 Hz, 2H), 3.05 (d, J=11.7 Hz, 2H),
2.61 (t, J=12.0 Hz, 2H), 1.69 (d, J=12.4 Hz, 2H), 1.56 (d, J=10.1
Hz, 2H), 1.18 (t, J=7.2 Hz, 3H)
Example 349
##STR00410##
[1276]
2-((2-chloro-5-cyano-3-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-
-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1277] The title compound was prepared similar manner as Example
210.
[1278] MS (ESI) m/z 478.26 (M+1)
[1279] Following additional examples were prepared in similar was
as Example 349
TABLE-US-00016 TABLE 13 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 350 ##STR00411##
2-((2-chloro-5-cyano-3-(1-(3-~2~H)-3-oxetanyl-4-
piperidinyl)phenyl)amino)-4-(ethylamino)imidazo
[2,1-f][1,2,4]triazine-7-carbonitrile 478.96 2.88 351 ##STR00412##
2-((2-chloro-5-cyano-3-(1-methyl-4-
piperidinyl)phenyl)amino)-4-(ethylamino)imidazo
[2,1-f][1,2,4]triazine-7-carbonitrile 435.92 2.67 352 ##STR00413##
2-((2-chloro-5-cyano-3-(1-(2-methoxyethyl)-4-
piperidinyl)phenyl)amino)-4-(ethylamino)imidazo
[2,1-f][1,2,4]triazine-7-carbonitrile 479.97 2.70 353 ##STR00414##
2-((2-chloro-5-cyano-3-(1-(2-hydroxy-2-
methylpropyl)-4-piperidinyl)phenyl)amino)-4-
(ethylamino)imidazol[2,1-f][1,2,4]triazine-7- carbonitrile 494.00
2.79 354 ##STR00415## 2-((3-(1-acetyl-4-piperidinyl)-2-chloro-5-
cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 463.93 3.81 355 ##STR00416##
2-((2-chloro-5-cyano-3-(1-(1-(methylsulfonyl)-3-
azetidinyl)-4-piperidinyl)phenyl)amino)-4-
(ethylamino)imidazol[2,1-f][1,2,4]triazine-7- carbonitrile 555.06
2.98 356 ##STR00417##
2-((3-(1-(1-acetyl-3-azetidinyl)-4-piperidinyl)-2-
chloro-5-cyanophenyl)amino)-4-
(ethylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile 519.01
2.95 CHROMOLITH .RTM. column 4.6 .times. 50 mm eluting with 10-90%
aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min,
monitoring at 220 nm.
Example 357
##STR00418##
[1280]
2-((2-chloro-5-cyano-3-(1-(1-methylpiperidin-4-yl)azetidin-3-yl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[1281] (357A): A solution of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) (3.48 g,
9.45 mmol) in DMF (35 ml) was cooled in an ice bath and NaHMDS
(14.17 ml, 14.17 mmol) was added. After 20 min, removal of the
cooling bath, stirring at 0.degree. C. to room temperature for 10
min, then cooled in the ice bath again, and 4-methoxybenzyl
chloride (1.929 ml, 14.17 mmol) was added and the reaction was
removed from the cooling bath and left stirring at room temperature
for overnight. The reaction was partitioned between EtOAc and sat.
aq. NH.sub.4Cl. The aqueous phase was extracted with EtOAc and the
combined organic phases were washed with brine. After drying with
sodium sulfate, the solvents were removed and the residue was
purified by flush silica gel column chromatography (160 g column),
eluting with hexane containing 2 to 10% EtOAc to give tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (4.05 g)
as a white solid
[1282] MS (ESI) m/z 475.13
[1283] 1H NMR (500 MHz, CHLOROFORM-d) d 7.78 (d, J=1.1 Hz, 1H),
7.10 (d, J=8.7 Hz, 3H), 6.81 (d, J=7.2 Hz, 2H), 5.09 (d, J=14.3 Hz,
1H), 4.23 (d, J=15.0 Hz, 1H), 3.78 (s, 3H), 1.68-1.29 (m, 9H)
[1284] (357B): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (1 g,
1.882 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.129
g, 0.188 mmol), and copper(I) iodide (0.072 g, 0.376 mmol) in
N,N-Dimethylacetamide (0.6 mL) in a dry microwave vial was
evacuated and backfilled with N.sub.2 for 3 times.
(1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (5.94 mL,
5.64 mmol, approximately 0.95 M solution in N,N-dimethylacetamide
prepared as described in the Journal of Organic Chemistry, 2004,
69, 5120) was then added. The mixture was evacuated and backfilled
with N.sub.2 one more time and then heated at 80.degree. C. for
overnight. After cooling to room temperature, the reaction was
partitioned between EtOAc and sat. aq. NH.sub.4Cl solution. This
was left stirring for 30 min. The aqueous phase was extracted with
EtOAc and the combined organic phases were washed with brine and
dried with sodium sulfate. Removal of the solvents followed by
silica gel chromatography eluting with hexane containing 5 to 15%
EtOAc to afford tert-butyl 3-(3-((tert-butoxy
carbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)azetidine-1-carbo-
xylate (0.98 g).
[1285] (357C): To a solution of tert-butyl
3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl-
)azetidine-1-carboxylate (0.98 g, 1.856 mmol) in DCM (20 ml) was
added anisole (5.70 mL, 5.64 mmol), followed by TFA (10 ml), After
1.5 h, the solvent was removed. The residue was taken in MeOH and
applied onto a cartridge of Phenomenex Strata-X-C 33 um cation
mixed-mode polymer. This was washed with methanol and product was
eluted with 2 N solution of ammonia in methanol. Removal of the
solvents left 3-amino-5-(azetidin-3-yl)-4-chlorobenzonitrile (441
mg) which was used as such in the next reaction.
[1286] MS (ESI) m/z 208.03 [M+1]
[1287] (357D): To a suspension of
3-amino-5-(azetidin-3-yl)-4-chlorobenzonitrile (507 mg, 2.100 mmol)
in DCM (50 mL) was added Et.sub.3N (0.293 mL, 2.100 mmol), followed
by di-tert-butyl dicarbonate (481 mg, 2.205 mmol). After stirring
at room temperature overnight, the solvent was removed to leave
tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate (786 mg)
which was used as such in the next step.
[1288] MS (ESI) m/z 330.15 [M+23
[1289] 1H NMR (500 MHz, DMSO-d6) d 7.10 (d, J=1.4 Hz, 1H), 7.05 (d,
J=1.8 Hz, 1H), 5.92 (s, 2H), 4.20 (d, J=17.9 Hz, 2H), 4.05-3.97 (m,
1H), 3.96-3.88 (m, 2H), 1.39 (s, 9H)]
[1290] (357E): A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (155 mg, 0.390 mmol), tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate
(Intermediate 9) (100 mg, 0.325 mmol) and Cs.sub.2CO.sub.3 (212 mg,
0.650 mmol) in DMF (3.5 ml) was heated at 70.degree. C. for 2 h.
This was diluted with EtOAc, washed with water and brine, and dried
over Na.sub.2SO.sub.4, removal of the solvent and purified by
radial silica gel chromatography, eluting with DCM containing 0 to
2% MeOH to give the Boc protected intermediate. This was dissolved
in DCE (1 ml), TFA (0.5 ml) was added and the mixture was stirred
at room temperature for 1 h. LCMS indicated that Boc-removed, and
along with about 14% of both Boc and PMB removed product. Removal
of the solvent and the residue was taken in MeOH and applied onto a
cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer.
This was washed with methanol and product was eluted with a mixture
of (1:1) DCM: 2 N solution of ammonia in methanol. Removal of the
solvents left 107 mg product as a solid which was used in next
reaction as such.
[1291] MS (ESI) m/z 526.31 [M+1]
[1292] Example 357: To a solution of
2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-meth-
oxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (53
mg, 0.084 mmol) in methanol (1.2 ml) was added trimethyl
orthoformate (0.6 mL, 5.43 mmol), 1-methylpiperidin-4-one (0.1 ml,
0.866 mmol) and acetic acid (10 .mu.L, 0.175 mmol). The mixture was
stirred at room temperature for 40 min and then sodium
cyanoborohydride (42.0 mg, 0.669 mmol) was added. After 4 h, the
reaction mixture was partitioned between EtOAc and dilutes aq.
NaHCO.sub.3 solution. The organic layer was washed with brine, and
dried over Na.sub.2SO.sub.4. Removal of the solvent left the crude
intermediate. To this was added DCE (1 ml), anisole (0.046 ml,
0.418 mmol), and TFA (0.5 ml). The resulting mixture was heated at
50.degree. C. for 3 h. the solvents were removed and the crude
material was purified by prep-HPLC (100.times.30 mm Luna C18
column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90%
Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml/min, 20-100% B, over
20 min). The HPLC fractions containing the product were applied
onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode
polymer. This was washed with methanol and product was eluted with
a mixture of 2 N solution of ammonia in methanol and
dichloromethane (1:1). Removal of the solvents afforded
2-((2-chloro-5-cyano-3-(1-(1-methylpiperidin-4-yl)azetidin-3-yl)phenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(35.2 mg) as a white solid.
[1293] MS (ESI) m/z 503.30 [M+1]
[1294] 1H NMR (500 MHz, CHLOROFORM-d) d 8.95 (d, J=1.7 Hz, 1H),
7.88 (s, 1H), 7.56 (s, 1H), 7.31-7.28 (m, 1H), 6.93 (br. s., 1H),
4.08-3.97 (m, 1H), 3.92-3.83 (m, 2H), 3.15-3.00 (m, H), 2.82 (d,
J=11.6 Hz, 2H), 2.29 (s, 3H), 2.02 (t, J=9.3 Hz, 3H), 1.75 (dd,
J=13.0, 2.9 Hz, 2H), 1.49-1.34 (m, 2H), 1.17-1.06 (m, 2H),
0.87-0.77 (m, 2H)
Example 358
##STR00419##
[1295]
2-((2-chloro-5-cyano-3-(1-(oxetan-3-yl)azetidin-3-yl)phenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1296] The title compound, was prepared from
2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-meth-
oxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 357E) and oxetan-3-one using a method analogous to that
used to prepare Example 301.
[1297] HPLC Rt 2.746 min
[1298] MS: (ESI) m/z 466.22 [M+1]
Example 359
##STR00420##
[1299]
2-((2-chloro-5-cyano-3-(1-(oxetan-3-yl)azetidin-3-yl)phenyl)amino)--
4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1300] The title compound, was prepared in analogous manner as
Example 358
[1301] HPLC Rt 2.873 min
[1302] MS (ESI) m/z 450.22
Example 360
##STR00421##
[1303]
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phe-
nyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1304] (360A):
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile
(Example 151C) (40 mg, 0.131 mmol),
4-(ethyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]tr-
iazine-7-carbonitrile (Intermediate 7) (50.5 mg, 0.131 mmol), and
Cs2CO3 (128 mg, 0.392 mmol) in DMF were heated at 45.degree. C. for
14 h. LC/MS showed product formation. The mixture was filtered and
rinsed with CH.sub.2Cl.sub.2, then concentrated and the crude was
taken forward to the next reaction.
[1305] Example 360:
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)am-
ino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (Example 107A) (80 mg, 0.131 mmol) was treated with TFA (0.5
mL, 6.49 mmol) and anisole (0.072 mL, 0.655 mmol) in DCE (1.5 mL).
The mixture was stirred at room temperature for 24 hr. The mixture
was concentrated to dryness, and then purified by prep-HPLC to give
17.6 mg desired product.
[1306] MS(ESI): m/z 492.4 (M+1).
[1307] 1H NMR (400 MHz, DMSO-d6) d 9.16 (t, J=5.6 Hz, 1H), 8.68 (s,
1H), 8.20 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H),
4.19 (t, J=7.5 Hz, 2H), 3.84 (dd, J=8.0, 5.5 Hz, 2H), 3.55-3.42 (m,
2H), 3.4-3.3 (m, 2H), 3.29-3.12 (m, 1H), 2.35 (d, J=1.8 Hz, 6H),
2.18 (s, 3H), 1.21 (t, J=7.2 Hz, 3H)
[1308] Following additional examples were prepared in similar was
as Example 360
TABLE-US-00017 TABLE 14 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 361 ##STR00422## (+/-)
2-((2-chloro-5-cyano-3-(2-(1-hydroxy-1-
methylethyl)-4-morpholinyl)phenyl)amino)-4-
(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile 481.95
2.88 362 ##STR00423## (+/-)
2-((2-chloro-5-cyano-3-(3-(methylamino)-1-
pyrrolidinyl)phenyl)amino)-4-(ethylamino)imidazo
[2,1-f][1,2,4]triazine-7-carbonitrile 436.91 2.67 .sup.c CHROMOLITH
.RTM. column 4.6 .times. 50 mm eluting with 10-90% aqueous methanol
over 4 min. containing 0.1% TFA, 4 mL/min, monitoring at 220
nm.
Example 363
##STR00424##
[1309]
2-((2-chloro-5-cyano-3-(4-(oxetan-3-ylamino)piperidin-1-yl)phenyl)a-
mino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1310]
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 329)
(48 mg, 0.110 mmol) was taken up in THF (2 mL) and Methanol (2 mL)
and trimethyl orthoformate (0.5 mL, 4.52 mmol), AcOH (0.05 mL,
0.873 mmol) in a round bottom flask. Oxetan-3-one (0.1 mL, 1.560
mmol) was added. The reaction mixture was stirred at room
temperature for 15 mins. Sodium cyanoborohydride (50 mg, 0.796
mmol) was added and the reaction was stirred at room temperature
for 2 hrs. LC/MS showed about 40% conversion to the desired
product. Another batch of oxetan-3-one (0.1 mL, 1.560 mmol),
trimethyl orthoformate (0.5 mL, 4.52 mmol), AcOH (0.05 mL, 0.873
mmol) and sodium cyanoborohydride (50 mg, 0.796 mmol) were added to
the reaction mixture and let stirred for another 30 mins. LC/MS
showed completed conversion to the product. The mixture was
concentrated to almost dryness, diluted with EtOAc and washed with
NaHCO3, then brine, dried over MgSO4 and concentrated. The crude
was then purified by PREP-HPLC to give 21.3 mg of desired
product
[1311] MS(ESI): m/z 493.6 (M+1).
[1312] 1H NMR (400 MHz, DMSO-d6) d 9.18 (br. s., 1H), 8.80 (br. s.,
1H), 8.20 (br. s., 1H), 7.96 (br. s., 1H), 7.31 (br. s., 1H), 4.66
(br. s., 2H), 4.35 (br.s., 2H), 4.00 (br. s., 1H), 3.48 (br. s.,
4H), 2.72 (br. s., 3H), 1.99-1.70 (m, 3H), 1.44 (d, J=8.3 Hz, 2H),
1.21 (br. s., 3H)
Example 364
##STR00425##
[1313]
(R)-2-((2-chloro-5-cyano-3-(4-((2-hydroxypropyl)amino)piperidin-1-y-
l)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1314]
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 329)
(30 mg, 0.069 mmol), was dissolved in MeOH (0.5 mL)/DCM (0.5 mL) in
an one dram vial. To this was added triethylamine (0.019 mL, 0.137
mmol), followed by (R)-2-methyloxirane (39.9 mg, 0.687 mmol). The
reaction mixture was stirred at 25.degree. C. 16 hr. The crude
material was purified via preparative LC/MS with the following
conditions:
[1315] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles;
[1316] Guard Column: Waters XBridge C18, 19.times.10 mm, 5 .mu.m
particles; Mobile Phase A: water;
[1317] Mobile Phase B: methanol; Buffer: 20-mM ammonium acetate;
Gradient: 30-95% B over 19.5 minutes, then a 14.0 minute hold at
95% B; Flow: 20 mL/min. Fractions containing the desired product
were combined and dried via centrifugal evaporation to afford
(R)-2-((2-chloro-5-cyano-3-(4-((2-hydroxypropyl)amino)piperidin-1-yl)phen-
yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(2 mg).
[1318] MS(ESI): m/z 495
[1319] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.25-9.09 (m,
1H), 8.87 (br. s., 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.34 (s, 1H),
5.46-5.21 (m, 1H), 4.07-3.92 (m, 2H), 3.39-3.31 (m, 2H), 3.26-3.12
(m, 2H), 3.08-2.96 (m, 1H), 2.87-2.68 (m, 3H), 2.24-2.06 (m, 2H),
1.87-1.65 (m, 2H), 1.31-1.07 (m, 7H)
Example 365
##STR00426##
[1320]
2-((2-chloro-5-cyano-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)-
phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1321]
2-((2-chloro-5-cyano-3-(4-(oxetan-3-ylamino)piperidin-1-yl)phenyl)a-
mino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 363) (20 mg, 0.041 mmol) was dissolved in MeOH (0.5
mL)/THF (0.5 mL) in an one dram vial. Trimethyl orthoformate (0.336
ml, 3.04 mmol), acetic acid (9.29 .mu.l, 0.162 mmol), and
formaldehyde (3.73 .mu.l, 0.041 mmol) were added. The reaction
mixture stirred at 25.degree. C. 5 min and 1M sodium
cyanoborohydride in THF (0.406 ml, 0.406 mmol) was added; the
reaction stirred at 25.degree. C. 10 min. The crude material was
purified via preparative LC/MS with the following conditions:
[1322] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 20-100% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min.
[1323] Fractions containing the desired product were combined and
dried via centrifugal evaporation to afford
2-((2-chloro-5-cyano-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)phenyl-
)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(10 mg).
[1324] MS(ESI): m/z 507
[1325] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.17 (br. s.,
1H), 8.82 (br. s., 1H), 8.19 (s, 1H), 7.95 (br. s., 1H), 7.29 (br.
s., 1H), 4.52 (br. s., 4H), 4.11-3.85 (m, 1H), 3.34 (d, J=10.7 Hz,
4H), 2.79-2.60 (m, 2H), 2.19 (br. s., 3H), 1.68 (br. s., 4H), 1.19
(t, J=6.9 Hz, 4H)
Example 366
##STR00427##
[1326] methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)piperidin-4-yl)(oxetan-3-yl)carbamate
[1327]
2-((2-chloro-5-cyano-3-(4-(oxetan-3-ylamino)piperidin-1-yl)phenyl)a-
mino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 363) (20 mg, 0.041 mmol) in MeOH (6 mL)/THF (3 mL) at
0.degree. C. (ice bath) was added DIPEA (21.26 .mu.l, 0.122 mmol)
and methyl carbonochloride [(60 .mu.l, 0.775 mmol) total 3.times.
(20 .mu.l, 0.258 mmol) portions]. The reaction stirred at
25.degree. C. for 30 min and the mixture was diluted with EtOAc,
washed with sat'd NaHCO.sub.3 and brine. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The crude material
was purified via preparative LC/MS with the following conditions:
Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m) particles;
Guard Column: Waters XBridge C18, 19.times.10 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)piperidin-4-yl)(oxetan-3-yl)carbamate (5.8
mg).
[1328] MS(ESI): m/z 551
[1329] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.17 (br. s.,
1H), 8.82 (s, 1H), 8.18 (s, 1H), 7.96 (br. s., 1H), 7.31 (br. s.,
1H), 4.92-4.70 (m, 3H), 4.62 (br. s., 2H), 3.65 (s, 5H), 3.37-3.27
(m, 2H), 2.85-2.65 (m, 3H), 2.20-1.99 (m, 2H), 1.74-1.57 (m, 2H),
1.27-1.09 (m, 3H)
Example 367
##STR00428##
[1330]
2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)i-
midazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1331] A mixture of tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate (Example
357D) (154 mg, 0.500 mmol),
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (Intermediate 10) (172 mg, 0.500 mmol),
Cs.sub.2CO.sub.s (326 mg, 1.00 mmol), DPPF (27.7 mg, 0.050 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (29 mg, 0.050 mmol),
and Pd(OAc).sub.2 (34 mg, 0.150 mmol) in a microwave vial was
flushed with nitrogen. Dioxane (5 mL) was added and vial was sealed
and heated at 100.degree. C. for 3 hr. After cooling to room
temperature, the reaction was partitioned between EtOAc and water
and then filtered through celite. The solvent was removed and
radial silica gel chromatography eluting with hexane containing 5
to 40% EtOAc afforded tert-butyl
3-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)-imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)azetidine-1-carboxylate (207
mg, 67% yield) as a foam. It was dissolved in DCM (0.6 mL) and
anisole (30 uL, 0.272 mmol) and TFA (0.4 mL) were added. After 2
hr, the solvent was removed and the residue was applied onto an SCX
cartridge using a 1:1 mixture of DCM and MeOH. This was washed with
MeOH and eluted with a 1:1 mixture of 1N NH.sub.3 in MeOH and DCM
to give crude
2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (70 mg). A sample was
purified by preparative HPLC (Column: Waters XBridge C18,
19.times.200 mm, 5-.mu.m particles; Mobile Phase A: water with
20-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with
20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min) to give the title
compound. This was converted to the mono HCl salt.
[1332] MS (ESI) m/z 394.2
[1333] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.18 (br. s., 1H),
8.20 (s, 2H), 7.67 (s, 1H), 4.11 (quin, J=7.8 Hz, 1H), 3.79 (t,
J=8.0 Hz, 2H), 3.66 (t, J=7.6 Hz, 2H), 3.45 (q, J=7.1 Hz, 2H), 1.19
(t, J=7.2 Hz, 3H).
Example 368
##STR00429##
[1334]
(S)-2-((2-chloro-5-cyano-3-(1-(2-hydroxypropyl)azetidin-3-yl)phenyl-
)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1335] A suspension of
2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (Example 367) (16 mg, 0.041
mmol) and (S)-(-)-propylene oxide (0.085 mL, 1.22 mmol) in a
mixture of NMP (0.8 mL) and MeOH (0.2 mL) was stirred at 50.degree.
C. for 4.5 hr. The solvent was removed and the product was purified
by preparative HPLC (Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min) to give the title compound (6.1 mg).
This was converted to the mono HCl salt.
[1336] MS (ESI) m/z 452.4 (M+1).
[1337] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.21 (br. s., 1H),
9.00 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.74 (br. s., 1H), 5.30
(br. s., 1H), 4.51-4.18 (m, 5H), 3.90 (br. s., 1H), 3.20 (br. s.,
1H), 3.05 (d, J=10.1 Hz, 1H), 2.90 (d, J=7.3 Hz, 1H), 1.25-1.17 (m,
3H), 1.10 (d, J=6.1 Hz, 3H).
Example 369
##STR00430##
[1338]
2-((2-chloro-5-cyano-3-(1-(2-cyanoacetyl)azetidin-3-yl)phenyl)amino-
)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1339] A mixture of
2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (15 mg, 0.038 mmol),
2-cyanoacetic acid (4.9 mg, 0.057 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.4
mg, 0.065 mmol), and HOBT monohydrate (9.9 mg, 0.065 mmol) in NMP
(1 mL) was stirred at room temperature for 4 hr. Preparative HPLC
(Waters XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile
Phase A: water; Mobile Phase B: methanol; Buffer: 20-mM ammonium
acetate; Gradient: 30-95% B over 19.5 minutes, then a 14.0 minute
hold at 95% B; Flow: 20 mL/min) afforded the title compound (3.6
mg). This was converted to the mono HCl salt.
[1340] MS (ESI) m/z 641.3 (M+1).
[1341] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.20 (br. s., 1H),
8.94 (br. s., 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H),
4.62-4.52 (m, 1H), 4.38-4.26 (m, 2H), 4.22 (d, J=7.6 Hz, 1H),
4.11-4.03 (m, 1H), 3.83-3.70 (m, 2H), 1.19 (t, J=6.9 Hz, 3H).
Example 370
##STR00431##
[1342]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,-
4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile
[1343] (370A):
(+/-)-3-amino-5-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-4-chlorobenzoni-
trile (prepared from Example 171D) (1.0 g, 3.75 mmol) and potassium
acetate (0.736 g, 7.50 mmol) were dissolved in acetone (20
ml)+water (6 mL). The solution was cooled to 0.degree. C. under
nitrogen. Chloroacetic chloride (0.373 ml, 4.69 mmol) was added
dropwise and the mixture stirred at 0.degree. C. for 10 minutes,
then at room temperature for 60 minutes. The reaction mixture was
partitioned between EtOAc and aq. NaHCO.sub.3 solutions. The
organic layer was washed with brine and dried over MgSO.sub.4.
MgSO.sub.4 was removed by filtration and volatiles evaporated in
vacuum to afford
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4--
yl)-2-chloroacetamide (0.61 g); The material was used without
further purification.
[1344] MS (ESI) m/z 343
[1345] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.78 (d, J=1.8
Hz, 1H), 6.71 (d, J=1.8 Hz, 1H), 6.69 (d, J=6.3 Hz, 1H), 4.38-4.30
(m, 2H), 4.18-4.13 (m, 2H), 4.06 (s, 2H), 3.92-3.75 (m, 2H),
3.60-3.51 (m, 1H), 3.40-3.35 (m, 1H), 3.36-3.27 (m, 1H), 2.87-2.74
(m, 1H), 2.71-2.59 (m, 1H), 2.21-2.09 (m, 1H), 2.06 (s, 1H),
1.92-1.75 (m, 1H), 1.27 (t, J=7.2 Hz, 1H)
[1346] (370B):
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4--
yl)-2-chloroacetamide (549 mg, 1.600 mmol) was dissolved in
anhydrous THF. The solution was cooled to 0.degree. C. sodium
hydride (96 mg, 2.399 mmol) and tetrabutylammonium bromide (77 mg,
0.240 mmol) were added (briefly opening the reaction flask to air).
The reaction mixture was stirred at 0.degree. C. for 5 minutes,
then the ice bath was removed and the mixture stirred at room
temperature for 1.5 hours. The reaction was quenched with aq. NH4Cl
solution. The reaction mixture was partitioned between water and
EtOAc. The organic layer was washed with brine (+small amount of
NaHCO3 solution), then dried over MgSO4. The organic layer was
filtered and evaporated to dryness to give 0.85 g crude colorless
solid, which was purified via silica gel chromatography: gradient
from 100% DCM to 100% EtOAc, then isocratic at 100% EtOAc to afford
(+/-)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]o-
xazin-6(7H)-yl)benzonitrile (197 mg).
[1347] MS (ESI) m/z 307
[1348] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 6.80 (d, J=1.7
Hz, 1H), 6.73 (d, J=1.9 Hz, 1H), 6.08-5.97 (m, 1H), 4.36 (d, J=17.0
Hz, 3H), 3.73-3.62 (m, 1H), 3.62-3.54 (m, 1H), 3.52 (d, J=5.5 Hz,
1H), 3.44-3.32 (m, 2H), 2.82-2.67 (m, 2H), 2.02-1.94 (m, 1H),
1.92-1.81 (m, 1H)
[1349] (370C):
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (33.5 mg, 0.098 mmol), (Intermediate 10),
(+/-)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]o-
xazin-6(7H)-yl)benzonitrile (30 mg, 0.098 mmol), DPPF (3.8 mg, 6.85
.mu.mol), Cs.sub.2CO.sub.3 (65.4 mg, 0.201 mmol), Xantphos (5.66
mg, 9.78 .mu.mol), palladium(II)Acetate (6.83 mg, 0.029 mmol) and
1,4-dioxane (2 ml) were combined in a microwave vial. The vial was
evacuated and backfilled with Nitrogen 3.times.. The reaction
stirred at 100.degree. C. for 3 hr. The reaction mixture cooled to
25.degree. C., diluted with EtOAc and washed with brine and dried
(Na.sub.2SO.sub.4). The solvents were removed and the material
purified on silica gel 5% MeOH in DCM to afford
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3-
,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl(4
methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
[1350] MS (ESI) m/z 613
[1351] Example 370:
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1-
,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile was taken up in DCE (0.8 mL),
anisole (0.043 mL, 0.391 mmol) and TFA (0.5 mL, 6.49 mmol). The
mixture stirred 2 h at 25.degree. C. and solvent was removed. The
crude material was purified via preparative LC/MS with the
following conditions: Column: Waters XBridge C18, 19.times.200 mm,
5-.mu.m particles; Guard Column: Waters XBridge C18, 19.times.10
mm, 5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 25-65% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
(+/-)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiper-
idin-4-yl)-2-chloroacetamide (2.2 mg).
[1352] MS (ESI) m/z 493
[1353] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.27-9.09 (m,
1H), 8.95-8.75 (m, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.98 (s, 1H),
7.39 (s, 1H), 4.14 (s, 2H), 3.33-3.18 (m, 3H), 2.95-2.87 (m, 1H),
2.87-2.79 (m, 1H), 2.79-2.68 (m, 2H), 2.04-1.89 (m, 1H), 1.72-1.60
(m, 1H), 1.60-1.42 (m, 1H), 1.19 (s, 3H)
Example 371
##STR00432##
[1354]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][-
1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile
[1355] (371A):
(+/-)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]o-
xazin-6(7H)-yl)benzonitrile (Example 370B) (144 mg, 0.469 mmol) was
dissolved in Tetrahydrofuran (10 ml) in a 20 ml scintillation vial.
Borane-methyl sulfide complex (2 M in THF) (0.493 ml, 0.986 mmol)
was added, the vial was capped and the reaction mixture heated to
90.degree. C. for 3 hours. The reaction mixture was partitioned
between EtOAc and aq. NH4Cl solution. The organic layer was washed
with brine, then dried over MgSO4, filtered and evaporated to
dryness to give
(+/-)-3-amino-4-chloro-5-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-
-6(7H)-yl)benzonitrile (129.5 mg)
[1356] MS (ESI) m/z 293
[1357] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 6.84 (d,
J=2.0 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 3.93-3.83 (m, 1H), 3.77-3.64
(m, 1H), 3.47-3.38 (m, 1H), 3.38-3.34 (m, 1H), 3.29-3.25 (m, 1H),
3.09-2.96 (m, 1H), 2.94-2.86 (m, 1H), 2.83-2.74 (m, 1H), 2.62-2.47
(m, 2H), 1.88-1.78 (m, 1H), 1.76-1.62 (m, 2H)
[1358] (371B): To a suspension of
(+/-)-3-amino-4-chloro-5-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-
-6(7H)-yl)benzonitrile (130 mg, 0.444 mmol) in DCM (5 ml) was added
TEA (0.062 mL, 0.444 mmol), and di-tert-butyl dicarbonate (105 mg,
0.481 mmol). The reaction mixture stirred at 25.degree. C. 2 hr.
The mixture was diluted with DCM and washed with sat. NaHCO.sub.3,
brine, and dried over Na.sub.2SO.sub.4. The material was purified
on silica gel 0-50% EtOAc in DCM to afford
(+/-)-(4aR,8aR)-tert-butyl
6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine--
1-carboxylate (100 mg).
[1359] MS (ESI) m/z 393
[1360] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 6.89-6.82
(m, 1H), 6.75-6.64 (m, 1H), 3.99-3.87 (m, 2H), 3.83-3.75 (m, 1H),
3.74-3.66 (m, 1H), 3.47-3.41 (m, 1H), 3.39-3.35 (m, 1H), 3.31-3.27
(m, 1H), 3.25-3.17 (m, 1H), 2.77-2.69 (m, 1H), 2.66-2.53 (m, 2H),
2.12-2.04 (m, 1H), 1.50 (s, 9H)
[1361] (371C):
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (Intermediate 10) (85.0 mg, 0.248 mmol),
(+/-)-(4aR,8aR)-tert-butyl
6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine--
1-carboxylate (97.0 mg, 0.248 mmol), DPPF (9.62 mg, 0.017 mmol),
Cs.sub.2CO.sub.3 (137 mg, 0.422 mmol), Xantphos (14.35 mg, 0.025
mmol), Palladium(II)Acetate (16.7 mg, 0.074 mmol) and 1,4-dioxane
(2 ml) were combined in a microwave vial. The vial was evacuated
and backfilled with Nitrogen (3.times.). The reaction stirred at
100.degree. C. for 3 hr. The reaction mixture cooled to 25.degree.
C., diluted with EtOAc, washed with brine and dried
(Na.sub.2SO.sub.4). The solvents were removed and the material
purified on silica gel 25% EtOAc in DCM to afford
(+/-)-(4aR,8aR)-tert-butyl
6-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazin-
e-1-carboxylate (75 mg).
[1362] MS (ESI) m/z 702
[1363] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.48-8.23
(m, 1H), 8.10-7.98 (m, 1H), 7.32-7.23 (m, 2H), 7.21-7.14 (m, 1H),
6.94-6.85 (m, 2H), 5.71 (s, 1H), 5.51 (s, 3H), 5.00-4.94 (m, 1H),
4.44-4.31 (m, 1H), 3.98-3.88 (m, 2H), 3.79 (s, 2H), 3.76-3.67 (m,
2H), 3.54-3.43 (m, 1H), 3.42-3.34 (m, 2H), 3.29-3.19 (m, 1H),
2.89-2.73 (m, 1H), 2.72-2.58 (m, 2H), 2.03 (s, 1H), 1.50 (s, 9H),
1.26 (t, J=7.2 Hz, 3H)
[1364] Example 371: (+/-)-(4aR,8aR)-tert-butyl
6-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazin-
e-1-carboxylate (75 mg, 0.104 mmol) was taken up in DCE (2 mL),
anisole (0.05 mL, 0.458 mmol) and TFA (0.5 mL, 6.49 mmol). The
mixture stirred 2 h at 25.degree. C. and solvents removed. 50 ml 2N
NH3/MeOH was added and stirred for 30 min. The white precipitate
was collected by filtration and washed with 20 ml cold MeOH, then
ether and dried under air-suction for 2 hrs to give
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]ox-
azin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (38 mg).
[1365] MS (ESI) m/z 479
[1366] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.28-9.10 (m,
1H), 8.91-8.81 (m, 1H), 8.20 (s, 1H), 8.00-7.92 (m, 1H), 7.35 (s,
1H), 3.79-3.71 (m, 1H), 3.55-3.42 (m, 3H), 3.28-3.20 (m, 3H), 3.17
(d, J=5.2 Hz, 1H), 2.88-2.72 (m, 3H), 2.66-2.57 (m, 1H), 2.40-2.34
(m, 1H), 1.80-1.68 (m, 1H), 1.59-1.44 (m, 1H), 1.19 (t, J=7.2 Hz,
3H)
Example 372
##STR00433##
[1367] (+/-)-(4aR,8aR)-methyl
6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazi-
n-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate
[1368]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][-
1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (Example 371) (10 mg, 0.021 mmol, was taken up
in MeOH (1 mL) and DIPEA 20 .mu.L was added. The reaction was
stirred at 5.degree. C. (ice bath) and methyl carbonochloridate
(1.617 .mu.l, 0.021 mmol) was added; the reaction stirred at
25.degree. C. 1 hr. The solvents removed and the crude material was
purified via preparative LC/MS with the following conditions:
Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m particles;
Guard Column: Waters XBridge C18, 19.times.10 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 40-100% B over 15 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford (+/-)-(4aR,8aR)-methyl
6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazi-
n-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate
(7.8 mg).
[1369] MS (ESI) m/z 537
[1370] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.25-9.09 (m,
1H), 8.89-8.75 (m, 1H), 8.28-8.14 (m, 1H), 8.03-7.90 (m, 1H),
7.43-7.27 (m, 1H), 3.94-3.80 (m, 2H), 3.71-3.64 (m, 1H), 3.64-3.55
(m, 4H), 3.23-3.12 (m, 2H), 2.89 (s, 2H), 2.83-2.75 (m, 1H), 2.73
(s, 2H), 2.70-2.56 (m, 2H), 2.09-1.77 (m, 1H), 1.36-1.01 (m,
3H)
Example 373
##STR00434##
[1371]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-methylhexahydro-1H-pyrido-
[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazine-7-carbonitrile
[1372]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][-
1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (Example 371) (13 mg, 0.027 mmol) was taken up
in MeOH (0.5 mL) and THF (0.5 mL) and trimethyl orthoformate (0.225
mL, 2.036 mmol), AcOH (6.22 .mu.l, 0.109 mmol), and formaldehyde
(2.492 .mu.l, 0.027 mmol) were added. The reaction was stirred at
25.degree. C. for 5 min, then NaCNBH4 (0.271 mL, 0.271 mmol) was
added and the reaction stirred at 25.degree. C. 1 hr. The reaction
mixture was diluted with EtOAc and washed with sat'd NaHCO3, then
brine. The organic layer was dried over Na2SO4, and concentrated.
The crude material was purified via preparative LC/MS with the
following conditions: Column: Waters XBridge C18, 19.times.200 mm,
5-.mu.m particles; Guard Column: Waters XBridge C18, 19.times.10
mm, 5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 50-100% B over 15 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-methylhexahydro-1H-pyrido[3,4-b-
][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]tri-
azine-7-carbonitrile (12.2 mg).
[1373] MS (ESI) m/z 493
[1374] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.26-9.09 (m,
1H), 8.98-8.70 (m, 1H), 8.31-8.13 (m, 1H), 8.04-7.88 (m, 1H),
7.40-7.19 (m, 1H), 3.83-3.73 (m, 1H), 3.70-3.58 (m, 1H), 3.50-3.47
(m, 2H), 3.29-3.23 (m, 3H), 2.86-2.73 (m, 1H), 2.73-2.57 (m, 2H),
2.18 (br. s., 4H), 2.11-2.00 (m, 1H), 1.79-1.66 (m, 1H), 1.47-1.33
(m, 1H), 1.28-1.09 (m, 3H)
Example 374
##STR00435##
[1375]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-(oxetan-3-yl)hexahydro-1H-
-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile
[1376]
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][-
1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (Example 371) (10 mg, 0.021 mmol) was taken up
in MeOH (0.5 mL) and THF (0.5 mL) and trimethyl orthoformate (0.173
mL, 1.566 mmol), AcOH (4.78 .mu.l, 0.084 mmol), and oxetan-3-one
(0.013 mL, 0.209 mmol) were added. The reaction was stirred at
25.degree. C. for 2 hr, then NaCNBH.sub.4 (0.209 mL, 0.209 mmol)
was added and the reaction stirred at 25.degree. C. overnight. The
reaction mixture was diluted with EtOAc and washed with sat'd
NaHCO3, then brine. The organic layer was dried over Na2SO4,
filtered, and concentrated. The crude material was purified via
preparative LC/MS with the following conditions: Column: Waters
XBridge C18, 19.times.200 mm, 5-.mu.m particles; Guard Column:
Waters) (Bridge C18, 19.times.10 mm, 5-.mu.m particles; Mobile
Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5
acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B
over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
The material was further purified via preparative LC/MS with the
following conditions: Column: Waters XBridge C18, 19.times.200 mm,
5-.mu.m particles; Guard Column: Waters XBridge C18, 19.times.10
mm, 5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM
ammonium acetate; Gradient: 40-80% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-(oxetan-3-yl)hexahydro-1H-pyrid-
o[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (2.4 mg).
[1377] MS (ESI) m/z 535
[1378] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.30-9.07 (m,
1H), 8.95-8.69 (m, 1H), 8.32-8.11 (m, 1H), 8.06-7.85 (m, 1H),
7.44-7.16 (m, 1H), 4.72-4.34 (m, 4H), 3.88-3.75 (m, 2H), 3.74-3.59
(m, 5H), 2.79-2.67 (m, 1H), 2.66-2.55 (m, 2H), 2.16-1.99 (m, 1H),
1.97-1.82 (m, 1H), 1.75-1.63 (m, 1H), 1.57-1.37 (m, 2H), 1.18 (br.
s., 3H)
Example 375
##STR00436##
[1379]
2-((2-chloro-5-cyano-3-((3aR,7aR)-2-oxohexahydrooxazolo[5,4-c]pyrid-
in-5(2H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile
[1380] (375A):
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (Intermediate 10) (350.0 mg, 1.021 mmol), tert-butyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (412.0 mg, 1.123 mmol), DPPF (39.6 mg, 0.071 mmol),
Cs.sub.2CO.sub.3 (566 mg, 1.736 mmol), Xantphos (59.1 mg, 0.102
mmol), Palladium(II)Acetate (68.8 mg, 0.306 mmol) and 1,4-dioxane
(11 ml) were combined in a microwave vial. The vial was evacuated
and backfilled with Nitrogen 3.times.. The reaction stirred at
100.degree. C. for 3 hr. The reaction mixture cooled to 25.degree.
C., diluted with EtOAc, washed with brine and dried
(Na.sub.2SO.sub.4). The solvents were removed and the material
purified on silica gel 25% EtOAc in DCM to afford tert-butyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(335 mg).
[1381] MS (ESI) m/z 673
[1382] (375B): tert-butyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)car-
bamate (335 mg, 0.373 mmol) was mixed with anisole (0.2 mL, 1.831
mmol), DCE (3 mL) and TFA (1 mL, 12.98 mmol). The mixture was
stirred at 25.degree. C. for 12 hr. The mixture was concentrated to
dryness under high-vac and 50 ml 2N NH3/MeOH was added and the
mixture stirred for 30 min. A white precipitate formed and was
collected by filtration, washed with 20 ml cold MeOH, 10 ml ether,
and dried under air-suction to give
2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(200 mg).
[1383] MS (ESI) m/z 453
[1384] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39-9.03 (br.
s, 1H), 9.02-8.77 (br.s, 1H), 8.20 (s, 1H), 8.16-8.08 (m, 1H), 7.95
(d, J=1.8 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 5.01 (d, J=4.3 Hz, 1H),
4.18-4.02 (m, 1H), 3.73 (d, J=18.8 Hz, 1H), 3.46 (q, J=7.2 Hz, 1H),
3.30-3.10 (m, 3H), 2.73 (s, 1H), 2.48-2.37 (m, 2H), 1.88-1.73 (m,
1H), 1.50-1.35 (m, 1H), 1.29-1.07 (m, 3H)
[1385] Example 375: A solution of
2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30
mg, 0.066 mmol) and DIPEA (0.035 mL, 0.199 mmol) in ethane-1,2-diol
1 mL at 0.degree. C. (ice bath) was treated with 4-nitrophenyl
carbonochloridate (18 mg, 0.089 mmol). The reaction was stirred for
0.5 hour and the reaction is complete. The reaction mixture was
diluted with THF 1 ml/EtOAc 30 ml, washed 2.times. brine (5 ml) and
dried over Na.sub.2SO.sub.4. The solvents removed and the crude
material was purified via preparative LC/MS with the following
conditions: Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 35-80% B over 25 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
2-((2-chloro-5-cyano-3-((3aR,7aR)-2-oxohexahydrooxazolo[5,4-c]pyri-
din-5(2H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (6.0 mg).
[1386] MS (ESI) m/z 479
[1387] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.09-8.27 (m,
1H), 8.20 (s, 1H), 7.99 (br. s., 1H), 7.83 (br. s., 1H), 7.46 (br.
s., 1H), 4.09-3.95 (m, 1H), 3.68-3.58 (m, 1H), 3.46 (br. s., 3H),
3.41-3.38 (m, 1H), 3.39-3.37 (m, 1H), 3.24-3.13 (m, 1H), 3.01-2.84
(m, 1H), 2.08-1.94 (m, 1H), 1.87-1.66 (m, 1H), 1.19 (br. s.,
3H)
Example 376
##STR00437##
[1388] 2,5,8,11,14,17-hexaoxanonadecan-19-yl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1389] A solution of
2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 375B) (30 mg, 0.066 mmol) and DIPEA (0.035 mL, 0.199 mmol)
in MeOH (1.5 mL) was added to 2,5,8,11,14,17-hexaoxanonadecan-19-yl
carbonochloridate (121 mg, 0.337 mmol). The reaction was stirred
for 0.5 hour and the reaction was complete. The solvents removed
and the crude material was purified via preparative LC/MS with the
following conditions: Column: Waters XBridge C18, 19.times.200 mm,
5-.mu.m particles; Guard Column: Waters XBridge C18, 19.times.10
mm, 5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 50-90% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. The material was further
purified via preparative LC/MS with the following conditions:
Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m particles;
Guard Column: Waters XBridge C18, 19.times.10 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 35-75% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford 2,5,8,11,14,17-hexaoxanonadecan-19-yl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(14.8 mg).
[1390] MS (ESI) m/z 775
[1391] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.13-8.42 (m,
1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.32 (br. s., 1H), 7.20 (br. s.,
1H), 5.12-4.85 (m, 1H), 4.06 (br. s., 2H), 3.66-3.39 (m, 28H), 3.24
(s, 5H), 2.84-2.69 (m, 1H), 2.02-1.80 (m, 1H), 1.66-1.44 (m, 1H),
1.19 (t, J=7.2 Hz, 3H)
Example 377
##STR00438##
[1392]
2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(((S)-2-hydroxypropyl)a-
mino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile
[1393] To a solution of
2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 375B) (50 mg, 0.110 mmol) and DIPEA (0.031 mL, 0.221 mmol)
in MeOH (0.5 mL)/DCM (0.5 ml) was added (S)-2-methyloxirane (64.1
mg, 1.104 mmol). The reaction was stirred for 16 hours. The
solvents were removed and the crude material was purified via
preparative LC/MS with the following conditions: Column: Waters
XBridge C18, 19.times.200 mm, 5-.mu.m particles; Guard Column:
Waters XBridge C18, 19.times.10 mm, 5-.mu.m particles; Mobile Phase
A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5
acetonitrile: water with 20-mM ammonium acetate; Gradient: 10-55% B
over 25 minutes, then a 8-minute hold at 100% B; Flow: 20 mL/min.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to afford
2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(((S)-2-hydroxypropyl)amino)p-
iperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (14.5 mg).
[1394] MS (ESI) m/z 511
[1395] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.24-9.15 (m,
1H), 8.86 (s, 1H), 8.20 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.97-7.93
(m, 1H), 7.35 (d, J=1.8 Hz, 1H), 5.84-5.68 (m, 1H), 5.38-5.12 (m,
1H), 3.91 (s, 1H), 3.86-3.71 (m, 1H), 3.46 (d, J=6.1 Hz, 3H),
3.08-2.92 (m, 2H), 2.74 (s, 3H), 2.62-2.54 (m, 1H), 2.23-2.10 (m,
1H), 1.80-1.65 (m, 1H), 1.23-1.16 (m, 3H), 1.14 (d, J=6.4 Hz,
3H)
Example 378
##STR00439##
[1396]
2-((2-chloro-5-cyano-3-(1-(3-(cyanomethyl)oxetan-3-yl)piperidin-4-y-
l)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile
[1397] To a solution of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 208D) (30 mg, 0.054 mmol) in a mixture solvent
{CH.sub.2Cl.sub.2 (1 ml)/MeOH (0.5 ml)} was added Et.sub.3N (0.011
ml, 0.081 mmol) followed by 2-(oxetan-3-ylidene)acetonitrile (36.0
mg, 0.379 mmol). The reaction mixture was heated at 50.degree. C.
for 2 days. The reaction mixture was partitioned between EtOAc and
water. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, removal of the solvent and the crude
PMB-protected product was purified by silica gel chromatography,
eluting with DCM containing 0 to 2% MeOH.
[1398] The PMB-protected product was dissolved in DCE (2 ml), and
added anisole (0.059 ml, 0.541 mmol), followed by TFA (0.5 ml). The
resulting mixture was stirred at room temperature overnight.
Removal of the solvent, and the crude material was purified by
prep. HPLC (100.times.30 mm Luna C18 column, Solvent A=10%
Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1%
TFA, Flow rate 42 ml/min, 20-100% B, over 20 min). The HPLC
fractions containing the product were applied onto a cartridges of
Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was
washed with methanol and product was eluted with large amount of 2
N solution of ammonia in methanol/DCM (1:1). Removal of the
solvents left
2-((2-chloro-5-cyano-3-(1-(3-(cyanomethyl)oxetan-3-yl)piperidin-4-yl)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(10.6 mg) as a solid.
[1399] MS (ESI) m/z 529.27 (M+1).
[1400] 1H NMR (500 MHz, CDCl3/METHANOL-d4) d 8.88 (d, J=2.0 Hz,
1H), 7.86 (s, 1H), 7.25 (d, J=1.8 Hz, 1H), 4.67 (d, J=6.4 Hz, 2H),
4.46 (d, J=6.7 Hz, 2H), 3.16-3.06 (m, 1H), 3.02 (dt, J=7.4, 3.5 Hz,
1H), 2.90 (s, 2H), 2.78 (d, J=11.3 Hz, 2H), 2.50-2.35 (m, 2H), 1.92
(d, J=11.0 Hz, 2H), 1.80-1.67 (m, 2H), 1.07-0.98 (m, 2H), 0.81-0.72
(m, 2H)
Example 379
##STR00440##
[1401]
2-((2-chloro-5-cyano-3-(1-(3-vinyloxetan-3-yl)piperidin-4-yl)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1402] (379A): To a solution of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(375D) (50 mg, 0.090 mmol) in dry THF (0.3 mL) was added
1,8-Diazabicyclo[5.4.0]undec-7-ene (diluted with THF, 10V %) (0.013
mL, 9.02 .mu.mol) at room temperature. The mixture was cooled in an
ice/NaCl bath (-15.degree. C.). To this was added
2-(oxetan-3-ylidene)acetaldehyde (36 mg, 0.367 mmol), and left
stirring at -15.degree. C. to 0.degree. C. for 2.5 h, then the
mixture was put in the freezer for 7 days. To the reaction mixture
was added MeOH (1 mL), then sodium borohydride (10.30 mg, 0.271
mmol) at room temperature and stirred for 2 hrs. Diluted with
EtOAc, washed with NaHCO3, water, brine, and dried over
Na.sub.2SO.sub.4. Solvent was removed. The crude material was
purified by radial chromatography, eluting with DCM containing 0 to
1% MeOH to give
2-((2-chloro-5-cyano-3-(1-(3-(2-hydroxyethyl)oxetan-3-yl)piperidin-4-yl)p-
henyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tri-
azine-7-carbonitrile (29 mg).
[1403] Example 379:
2-((2-chloro-5-cyano-3-(1-(3-(2-hydroxyethyl)oxetan-3-yl)piperidin-4-yl)p-
henyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tri-
azine-7-carbonitrile was dissolved in CH.sub.2Cl.sub.2 (1.5 mL),
flushed with N.sub.2, and cooled to -78.degree. C., then added DAST
(14.29 mg, 0.089 mmol). The reaction mixture was allowed to warm
slowly to room temperature and stirred for overnight. To the
reaction mixture was added anisole (23.97 mg, 0.222 mmol) followed
by TFA (0.5 ml), left stirring at room temperature over weekend.
Solvent was removed. The crude material was purified via
preparative LC/MS with the following conditions: Column: Waters
XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A:
water with 20-mM ammonium acetate; Mobile Phase B: 95:5
acetonitrile: water with 20-mM ammonium acetate; Gradient: 10-50% B
over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
Fractions containing the desired product were combined and dried
via centrifugal evaporation left the title compound (2.9 mg).
[1404] MS: (ESI) m/z 516.15 (M+1).
[1405] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (d, J=7.3
Hz, 1H), 8.92 (br. s., 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.58 (br.
s., 1H), 5.26 (m 1H), 4.63 (m, 2H), 4.27-4.24 (t, J=8.7 Hz, 2H),
3.83-3.63 (m, 2H), 3.04-2.94 (m, 2H), 2.91 (m, 1H), 2.79-2.71 (m,
3H), 2.11-1.92 (m, 4H), 0.80-0.78 (m, 4H)
Example 380
##STR00441##
[1406]
(+/-)-2-((2-chloro-5-cyano-3-(1-(3-fluoro-2-hydroxypropyl)-4-piperi-
dinyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile
[1407] Prepared in similar manner as Example 57
[1408] MS: (ESI) m/z 510.15
Example 381
##STR00442##
[1409] methyl
((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazi-
n-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate
[1410] (381A): methyl
((3R,4R)-1-(3-amino-5-cyano-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carba-
mate was prepared in similar manner as Example 328E1 from
intermediate 17.
[1411] (381B):
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (Intermediate 7) (50 mg, 0.146 mmol), methyl
((3R,4R)-1-(3-amino-5-cyano-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carba-
mate (46 mg, 0.149 mmol), DPPF (5.66 mg, 10.21 mot),
Cs.sub.2CO.sub.3 (81 mg, 0.248 mmol), Xantphos (8.44 mg, 0.015
mmol), Palladium(II)Acetate (9.82 mg, 0.044 mmol) and 1,4-dioxane
(2 ml) were combined in a microwave vial. The vial was evacuated
and backfilled with Nitrogen 3.times.. The reaction stirred at
100.degree. C. for 3 hr. The reaction mixture cooled to 25.degree.
C., diluted with EtOAc and washed with brine and dried
(Na.sub.2SO.sub.4). The solvents were removed and the material
purified on silica gel 25% EtOAc in DCM to afford methyl
((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)car-
bamate (60 mg)
[1412] MS: (ESI) m/z 615
[1413] Example 381: To methyl
((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)car-
bamate (60 mg, 0.098 mmol), in DCE (1.5 mL) was added ANISOLE (0.1
mL, 0.915 mmol) and TFA (1.0 mL, 12.98 mmol); the mixture stirred 2
h at 25.degree. C. and solvent was removed. The crude material was
purified via preparative LC/MS with the following conditions:
Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m particles;
Guard Column: Waters XBridge C18, 19.times.10 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford methyl
((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazi-
n-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate
(3.8 mg).
[1414] MS: (ESI) m/z 495
[1415] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.30-9.01 (m,
2H), 8.30-8.06 (m, 1H), 7.93-7.68 (m, 1H), 7.26-7.14 (m, 1H),
7.12-6.97 (m, 1H), 5.18-4.84 (m, 1H), 3.34-3.17 (m, 9H), 2.88-2.70
(m, 1H), 2.63-2.53 (m, 1H), 1.96-1.71 (m, 1H), 1.62-1.41 (m, 1H),
1.19 (br. s., 3H)
Example 382
##STR00443##
[1416]
2-((5-cyano-2-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[1417] (382A):
3-amino-4-fluoro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile
was prepared in analogous manner as Example 151C using intermediate
17
[1418] Example 382:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (60 mg, 0.169 mmol),
3-amino-4-fluoro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile
(48 mg, 0.166 mmol), DPPF (6.44 mg, 0.012 mmol), Cs.sub.2CO.sub.3
(92 mg, 0.282 mmol), Xantphos (9.60 mg, 0.017 mmol),
Palladium(II)Acetate (11.17 mg, 0.050 mmol) and 1,4-dioxane (2 ml)
were combined in a microwave vial. The vial was evacuated and
backfilled with Nitrogen 3.times.. The reaction stirred at
100.degree. C. for 3 hr. The reaction mixture was cooled to
25.degree. C., diluted with EtOAc, washed with brine and dried
(Na.sub.2SO.sub.4). The solvents were removed and DCE (1 mL)/TFA
(0.5 mL) was added. The reaction stirred 3 h and solvents were
removed. The crude material was purified via preparative LC/MS with
the following conditions: Column: Waters XBridge C18, 19.times.200
mm, 5-.mu.m particles; Guard Column: Waters) (Bridge C18,
19.times.10 mm, 5-.mu.m particles; Mobile Phase A: water with 20-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
20-mM ammonium acetate; Gradient: 50-100% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
2-((5-cyano-2-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(16.9 mg).
[1419] MS: (ESI) m/z 488
[1420] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.54-9.23 (m,
1H), 9.23-9.07 (m, 1H), 8.25-8.07 (m, 1H), 7.82-7.66 (m, 1H),
6.86-6.48 (m, 1H), 4.07 (br. s., 2H), 3.87-3.67 (m, 3H), 3.25-3.15
(m, 3H), 3.10-2.76 (m, 5H), 2.69-2.53 (m, 4H), 0.79 (br. s.,
4H)
Example 383
##STR00444##
[1421]
2-((5-cyano-2-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phe-
nyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1422] Prepared in identical manner as Example 382 from
Intermediate 10
[1423] MS: (ESI) m/z 476
[1424] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.19-9.14 (m,
1H), 9.14-9.09 (m, 1H), 8.22-8.15 (m, 1H), 8.01-7.90 (m, 1H),
7.66-7.53 (m, 1H), 6.79-6.66 (m, 1H), 4.20-4.02 (m, 2H), 3.88-3.74
(m, 2H), 3.55-3.45 (m, 4H), 2.98-2.83 (m, 4H), 2.73 (s, 5H),
1.28-1.11 (m, 3H)
Example 384
##STR00445##
[1425]
2-((5-cyano-2-fluoro-3-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1426] The title compound was prepared using a method analogous to
that used to prepare Example 210.
[1427] MS (ESI) m/z 474.25 (M+1)
Example 385
##STR00446##
[1428] methyl
(3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-
-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)carbamate
[1429] (385A): 1-fluoro-4-nitrobenzene (5.0 g, 35.4 mmol) was
dissolved in sulfuric acid (50 ml, 938 mmol). The solution was
warmed to 60.degree. C. with stirring. NBS (14.02 g, 78 mmol) was
added in portions during .about.30 minutes. The reaction mixture
was stirred at 60.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and extracted with toluene (no water
added). The organic layer was washed with water, and then
NaHCO.sub.3 solution, then brine, dried over MgSO.sub.4, filtered
and evaporated to dryness to give 10.4 g crude
1,3-dibromo-2-fluoro-5-nitrobenzene (10.4 g), which solidified
after a few hours. The crude product was used "as is" in the next
step.
[1430] 1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 8.48 (d, J=5.5 Hz,
2H)
[1431] (385B): A 250 ml round bottom flask was charged with iron
powder (325 mesh) (2.6 g, 46.6 mmol),
1,3-dibromo-2-fluoro-5-nitrobenzene (2.0 g, 4.01 mmol) and acetic
acid (50 ml). The flask was evacuated and back-filled with nitrogen
twice, and then stirred at room temperature for 1 hour. The
reaction mixture turned into very thick slurry. Acetic acid (50 ml)
was added and the mixture stirred for an additional hour. The
reaction mixture was poured into EtOAc. The EtOAc solution was
washed with water (2.times.), NaHCO.sub.3+Na.sub.2CO.sub.3 solution
until CO.sub.2 evolution stopped, then once with brine, then dried
over MgSO4, filtered and evaporated to dryness to give 1.6 g crude
3,5-dibromo-4-fluoroaniline (1.6 g). The product was used without
further purification in the next experiment.
[1432] MS (ESI) m/z 309
[1433] 1H NMR (400 MHz, dmso-d6) .delta. ppm 6.83 (d, J=5.3 Hz,
2H), 5.46 (br, 2H)
[1434] (385C): 3,5-dibromo-4-fluoroaniline (1.6 g, 4.16 mmol) was
dissolved in DCM (41.6 ml). Pyridine (0.90 ml, 11.13 mmol) was
added and the reaction mixture cooled to 0-5.degree. C. Methyl
chloroformate (0.66 ml, 8.52 mmol) was added drop wise via syringe.
The reaction mixture was stirred at 0-5.degree. C. for 1 hour. The
reaction mixture was diluted with additional 50 ml dichloromethane
and washed with 0.5 M citric acid twice, NaHCO3 solution once and
brine once, then dried over MgSO4, filtered and evaporated to
dryness. Chromatography on silica (gradient from 100% hexanes to
100% DCM) gave methyl (3,5-dibromo-4-fluorophenyl)carbamate (1.22
g) as a colorless fluffy solid.
[1435] MS (ESI) m/z 324
[1436] 1H NMR (400 MHz, dmso-d6) .delta. ppm 9.98 (s, 1H), 7.78 (d,
J=5.5 Hz, 2H), 3.71 (s, 3H)
[1437] (385D): A stirred solution of methyl
(3,5-dibromo-4-fluorophenyl)carbamate (0.82 g, 2.508 mmol) in DMF
(20 mL) was treated with sodium bis(trimethylsilyl)amide (3.01 mL,
3.01 mmol), stirred at room temperature for 30 minutes, then
1-(chloromethyl)-4-methoxybenzene (0.410 mL, 3.01 mmol) was added,
stirred at 70.degree. C. for two hours. The reaction mixture was
partitioned between NH4Cl solution and EtOAc. The organic layer was
washed with NaHCO3 solution (2.times.), then brine, then dried over
MgSO4, filtered and evaporated to dryness to give 1.40 g colorless
film, which was purified by column chromatography on silica (120 g
silica, gradient from 100% hexanes to 20% EtOAc in hexanes) to give
methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (1.01
g)
[1438] MS (ESI) m/z 446
[1439] 1H NMR (400 MHz, dmso-d6) .delta. ppm 7.63 (d, J=5.8 Hz,
2H), 7.15 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.82 (s, 2H),
3.73 (s, 3H).
[1440] (385E): A round bottom flask was loaded with methyl
(3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (350 mg,
0.744 mmol), (S)-BINAP (69.5 mg, 0.112 mmol), Cesium carbonate (969
mg, 2.97 mmol) and Pd.sub.2dba.sub.3 (34.1 mg, 0.037 mmol). The
flask was evacuated and filled with nitrogen 3 times. Dioxane (10
mL) and 1-methylpiperazine (0.091 mL, 0.818 mmol) were added and
the vial evacuated and filled with nitrogen 3 times. The reaction
mixture was heated to 90.degree. C. for 20 hours. Benzophenone
imine (0.187 mL, 1.116 mmol) was added, the temperature increased
to 110.degree. C. and stirring under nitrogen continued for 24
hours. The reaction mixture was cooled to room temperature
(immersed into a room temperature water bath). Dioxane (10 ml) and
aq. HCl (1.0 molar, 10 ml, 10 mmol) were added and the reaction
mixture stirred at room temperature for 2 hours. The reaction
mixture was partitioned between EtOAc and aq. NaHCO3 solution. The
organic layer was washed with NaHCO3 solution and brine, then dried
over MgSO4, filtered and concentrated in vacuum. The crude was
purified by column chromatography on silica (80 g cartridge,
gradient from 100% EtOAc to 20% MeOH in EtOAc) gave methyl
(3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carba-
mate (207 mg)
[1441] MS (ESI) m/z 403
[1442] 1H NMR (400 MHz, dmso-d6) .delta. ppm 7.12 (d, J=8.8 Hz,
2H), 6.87 (d, J=8.8 Hz, 2H), 6.15 (dd, J=7.3, 2.3 Hz, 1H), 5.91
(dd, J=7.0, 2.3 Hz, 1H), 4.99 (s, 2H), 4.65 (s, 2H), 3.74 (s, 3H),
3.61 (s, 3H), 2.91-2.85 (m, 4H), 2.45-2.40 (m, 4H), 2.21 (s, 3H).
(385F): methyl
(3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carba-
mate (50 mg, 0.093 mmol),
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (44.6 mg, 0.112 mmol) and
Cs.sub.2CO.sub.3 (91 mg, 0.280 mmol) in DMF (1 ml) were heated at
45.degree. C. for 14 hours. LCMS showed product formation
(m/e+=721, [M+H]+). The mixture was poured onto a Phenomenex Strata
XC cation exchange resin (2 g adsorbent). The cartridge was washed
with MeOH and CH.sub.3CN. The product was eluted with a 1:1 mixture
of CH.sub.3CN and a 2 molar solution of NH.sub.3 in MeOH.
Evaporation to dryness gave crude methyl
(3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tr-
iazin-2-yl)amino)-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenz-
yl)carbamate (69.5 mg). The material was used in the following PMB
deprotection reaction without further purification.
[1443] MS (ESI) m/z 721
[1444] Example 385: methyl
(3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tr-
iazin-2-yl)amino)-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenz-
yl)carbamate (59.6 mg, 0.062 mmol) [crude product from above] was
dissolved in ClCH.sub.2CH.sub.2Cl (10 ml). anisole (1 ml, 9.15
mmol) and TFA (2 ml, 26.0 mmol) were added and the mixture stirred
at room temperature for 1 hour, then heated for 3 hours at
48.degree. C. The reaction mixture was evaporated to a volume of
.about.2 ml. The residue was diluted with MeOH and filtered through
a Waters MCX cation exchange cartridge (1 g adsorbent). The
cartridge was washed with MeOH+CH.sub.3CN. The product was eluted
with a 1:1 mixture of CH.sub.3CN and a 2 molar solution of NH.sub.3
in MeOH. Evaporation to dryness gave a yellow film. The crude
material was purified via preparative LC/MS with the following
conditions:
[1445] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 10-100% B over 20 minutes, then a
4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal
evaporation.
[1446] 11.6 mg methyl
(3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-
-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)carbamate was
obtained.
[1447] MS (ESI) m/z 481
[1448] 1H NMR (500 MHz, dmso-d6) .delta. ppm 9.53 (br. s, 1H), 9.11
(br. s, 1H), 8.92 (s, 1H), 8.15 (s, 1H), 7.35 (dd, J=5.6, 2.0 Hz,
1H), 6.94 (br. s., 1H), 3.65 (s, 3H), 3.15-3.09 (m, 1H), 2.99 (br.
s., 4H), 2.47 (br. s., 4H), 2.23 (s, 3H), 0.81-0.70 (m, 4H).
Example 386
##STR00447##
[1449] methyl
(3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-flu-
oro-5-(4-methylpiperazin-1-yl)phenyl)carbamate
[1450] Prepared in analogous manner as Example 385
[1451] MS (ESI) m/z 469
[1452] 1H NMR (500 MHz, dmso-d6) .delta. ppm) 9.54 (br. s., 1H),
9.00 (t, J=5.8 Hz, 1H), 8.89 (s, 1H), 8.16 (s, 1H), 7.28 (dd,
J=5.6, 2.0 Hz, 1H), 6.95 (d, J=4.9 Hz, 1H), 3.66 (s, 3H), 3.49
(quin, J=6.8 Hz, 2H), 3.00 (br. s., 4H), 2.47 (br. s., 4H), 2.23
(s, 3H), 1.17 (t, J=7.2 Hz, 3H)
Example 387
##STR00448##
[1453] methyl
(3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-
-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate
[1454] (387A): A round bottom flask was loaded with methyl
(3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (Example
385D) (0.42 g, 0.892 mmol), (S)-BINAP (0.083 g, 0.134 mmol), cesium
carbonate (1.163 g, 3.57 mmol), tert-butyl piperazine-1-carboxylate
(0.188 g, 0.982 mmol) and Pd.sub.2dba.sub.3 (0.041 g, 0.045 mmol).
The flask was evacuated and filled with nitrogen 3 times. Dioxane
(10 mL) was added and the vial evacuated and filled with nitrogen 3
times. The reaction flask was immersed into a 90.degree. C. oil
bath and stirred at 90.degree. C. for 19 hours. Benzophenone imine
(0.225 mL, 1.339 mmol) was added, the temperature increased to
110.degree. C. and stirring under nitrogen continued for 24 hours.
Dioxane (10 ml) and aq. HCl (1.0 molar, 10 ml, 10 mmol) were added
and the reaction mixture stirred at room temperature for 2 hours.
The reaction mixture was partitioned between EtOAc and aq.
NaHCO.sub.3 solution. The organic layer was washed with NaHCO.sub.3
solution and brine, then dried over MgSO.sub.4, filtered and
concentrated in vacuum to give 0.94 g brown oil, which was purified
by column chromatography on silica (120 g cartridge, gradient from
100% hexanes to 100% EtOAc) to give tert-butyl
4-(3-amino-2-fluoro-5-((4-methoxybenzyl)(methoxycarbonyl)amino)phenyl)pip-
erazine-1-carboxylate (317 mg).
[1455] MS (ESI) m/z 489
[1456] 1H NMR (400 MHz, dmso-d6) .delta. ppm 7.12 (d, J=8.8 Hz,
2H), 6.87 (d, J=8.8 Hz, 2H), 6.18 (dd, J=7.0, 2.3 Hz, 1H), 5.94
(dd, J=6.8, 2.3 Hz, 1H), 5.04 (s, 2H), 4.66 (s, 2H), 3.73 (s, 3H),
3.61 (s, 3H), 3.49-3.39 (m, 4H), 2.89-2.77 (m, 4H), 1.44 (s,
9H).
[1457] (387B): tert-butyl
4-(3-amino-2-fluoro-5-((4-methoxybenzyl)(methoxycarbonyl)amino)phenyl)pip-
erazine-1-carboxylate (317 mg, 0.474 mmol) was dissolved in
ClCH.sub.2CH.sub.2Cl (4 ml). Trifluoroacetic acid (1 ml, 12.98
mmol) was added and the reaction mixture was stirred at room
temperature for 2 hours, and then evaporated to dryness. 470.1 mg
crude methyl
(3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate,
TFA (470.1 mg) were isolated. The material was used for a next
step
[1458] MS (ESI) m/z 389
[1459] (387C): methyl
(3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate
(470 mg, 0.605 mmol) (crude product from above, contains DCE and
TFA) was dissolved in methanol (5 ml)+Tetrahydrofuran (5 ml).
oxetan-3-one (0.15 ml, 2.56 mmol), Trimethyl orthoformate (1 ml,
9.05 mmol) and potassium acetate (119 mg, 1.210 mmol) were added
and the mixture stirred at room temperature for 15 minutes. pH was
checked to be .about.4.5. Sodium cyanoborohydride (160 mg, 2.55
mmol) was added and stirring at room temperature continued for 20
hours. The reaction mixture was partitioned between EtOAc and
dilutes aq. NaHCO.sub.3 solution. The organic layer was washed with
brine, then dried over MgSO4 and evaporated to dryness to give
crude methyl
(3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzy-
l)carbamate (248.4 mg) which was used without further
purification.
[1460] MS (ESI) m/z 445
[1461] (387D):
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 3) (58.4 mg, 0.146 mmol),
methyl
(3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzy-
l)carbamate (62 mg, 0.098 mmol) and Cs.sub.2CO.sub.3 (95 mg, 0.293
mmol) in DMF (1 ml) were heated at 70.degree. C. for 80 minutes.
Additional
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (58.4 mg, 0.146 mmol) and
Cs.sub.2CO.sub.3 (95 mg, 0.293 mmol) were added and the mixture
stirred at 45.degree. C. for 16 hours. The mixture was partitioned
between EtOAc and dilutes aq. NH.sub.4Cl solution. The organic
layer was washed twice with dilute NaHCO.sub.3 solution, once with
brine, then dried over MgSO.sub.4, filtered and evaporated to
dryness to give methyl
(3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tr-
iazin-2-yl)amino)-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4
methoxybenzyl)carbamate (134.4 mg). The material was used in the
following reaction without further purification.
[1462] MS (ESI) m/z 763 consistent with [M+H]+.
[1463] Example 387: methyl
(3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tr-
iazin-2-yl)amino)-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-meth-
oxybenzyl)carbamate (74.8 mg, 0.098 mmol) was dissolved in
ClCH.sub.2CH.sub.2Cl (5 ml). Anisole (1 ml, 9.15 mmol) and TFA (2
ml, 26.0 mmol) were added and the mixture stirred at 55.degree. C.
for 3 hours. The reaction mixture was concentrated in vacuum and
purified via preparative LC/MS with the following conditions:
[1464] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 30-70% B over 12 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min.
[1465] Fractions containing the desired product were combined and
dried via centrifugal evaporation to give methyl
(3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-
-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (8.8
mg) were obtained.
[1466] MS (ESI) m/z 523
[1467] 1H NMR (500 MHz, dmso-d6) .delta. ppm 9.53 (br. s., 1H),
9.09 (br. s., 1H), 8.89 (s, 1H), 8.13 (s, 1H), 7.38-7.35 (m, 1H),
6.94-6.90 (m, 1H), 4.56 (t, J=6.0 Hz, 2H), 4.47 (t, J=6.0 Hz, 2H),
3.64 (s, 3H), 3.56-3.53 (m, 1H), 3.09 (br. s., 1H), 3.02 (br. s.,
4H), 2.42 (br. s., 4H), 0.78-0.70 (m, 4H).
Example 388
##STR00449##
[1468] methyl
((3S,4S)-1-(5-carbamoyl-2-chloro-3-((7-cyano-4-(cyclopropylamino)imidazo[-
2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1469] (388A): methyl
((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate (Example 174A) (91 mg, 0.207 mmol) was
dissolved in tetrahydrofuran (10 ml). DMAP (13.3 mg, 0.109 mmol)
was added, followed by BO.sub.C2O (0.8 ml, 3.45 mmol) and DIPEA
(0.30 ml, 1.72 mmol). The reaction mixture was stirred at room
temperature for 2 days. The reaction mixture was partitioned
between 0.5 M aq. citric acid and EtOAc. The organic layer was
washed with NaHC.sub.O3 solution, then brine, dried over
MgS.sub.O4, filtered and evaporated to give 483.5 mg crude
di-tert-butyl
(3-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((methoxycarbonyl)amino)pi-
peridin-1-yl)-2-chloro-5-cyanophenyl)iminodicarbonate (483.5 mg).
The crude was used "as is" in the next reaction.
[1470] MS (ESI) m/z 639
[1471] (388B): di-tert-butyl
(3-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((methoxycarbonyl)amino)pi-
peridin-1-yl)-2-chloro-5-cyanophenyl)iminodicarbonate (128 mg, 0.20
mmol) was dissolved in DMSO (10 mL). K.sub.2CO.sub.3 (400 mg, 2.89
mmol) was added, followed by H.sub.2O.sub.2 (0.6 ml, 5.87 mmol).
The reaction mixture was stirred at room temperature. Dioxane (10
mL) and Methanol (10 mL) were added and the reaction mixture was
refluxed for 15 minutes (reference Boger, Dale L et al. Journal of
the American Chemical Society (2007), 129(49), 15391-15397). The
reaction mixture was partitioned between EtOAc and aq.
Na.sub.2S.sub.2O.sub.3 solution (+NH.sub.4Cl solution). The organic
layer was washed with NaHCO.sub.3 solution (+small amount of
Na.sub.2S.sub.2O.sub.3) twice, then with brine once, then dried
over MgSO.sub.4. 125 mg (colorless solid) crude product methyl
((3S,4S)-1-(3-(N-BOC-amino)-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldim-
ethylsilyl)oxy)piperidin-4-yl)carbamate were obtained.
[1472] MS (ESI) m/z 557
[1473] (388C): methyl
((3S,4S)-1-(3-(N-BOC-amino)-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldim-
ethylsilyl)oxy)piperidin-4-yl)carbamate (125 mg, 0.168 mmol) was
dissolved in ClCH.sub.2CH.sub.2Cl (10 ml). Trifluoroacetic acid (3
ml, 38.9 mmol) was added and the reaction mixture was stirred at
room temperature for 2 hours, and then evaporated to dryness. The
crude was purified by column chromatography on silica (40 g
cartridge, gradient from 100% DCM to 100% EtOAc, then hold at 100%
EtOAc) to give methyl
((3S,4S)-1-(3-amino-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldimethylsil-
yl)oxy)piperidin-4-yl)carbamate (67 mg).
[1474] MS (ESI) m/z 457/
[1475] 1H NMR (400 MHz, dmso-d6) .delta. ppm 7.82 (br. s., 1H),
7.20 (br. s., 1H), 7.06-6.98 (m, 2H), 6.82 (d, J=1.8 Hz, 1H), 5.43
(br. s., 2H), 3.73-3.62 (m, 1H), 3.53 (s, 3H), 3.12 (d, J=12.5 Hz,
1H), 2.75 (t, J=11.0 Hz, 1H), 2.40 (t, J=10.7 Hz, 1H), 1.85-1.62
(m, 2H), 0.87-0.82 (m, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
[1476] Example 388: methyl
((3S,4S)-1-(3-amino-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldimethylsil-
yl)oxy)piperidin-4-yl)carbamate (65 mg, 0.114 mmol),
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 3) (47.6 mg, 0.119 mmol),
and Cs.sub.2CO.sub.3 (320 mg, 0.982 mmol) in DMF (1 ml) were heated
at 80.degree. C. for 4 hours. The reaction mixture was partitioned
between EtOAc and aq. NH.sub.4Cl solution. The organic layer was
washed with dilute NaHCO.sub.3 solution, then brine, then dried
over MgSO.sub.4, filtered and evaporated to dryness. 89.1 mg crude
The crude was dissolved in ClCH.sub.2CH.sub.2Cl (5 ml). Anisole (1
ml, 9.15 mmol) and trifluoroacetic acid (2 ml, 26.0 mmol) were
added and the mixture stirred for 2 hours at 70.degree. C. The
reaction mixture was evaporated to dryness, dissolved in
Acetonitrile (10 ml)+Water (1 ml) and trifluoroacetic acid (1 ml,
13.0 mmol) and stirred overnight at room temperature. The reaction
mixture was evaporated to dryness, dissolved in DMSO and purified
via preparative LC/MS with the following conditions:
[1477] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 methanol: water with 20-mM ammonium
acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min.
[1478] Fractions containing the desired product were combined and
dried via centrifugal evaporation.
[1479] methyl
((3S,4S)-1-(5-carbamoyl-2-chloro-3-((7-cyano-4-(cyclopropylamino)imidazo[-
2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(7.7 mg) was obtained.
[1480] MS (ESI) m/z 541
[1481] 1H NMR (500 MHz, dmso-d6) .delta. ppm 9.20 (br. s., 1H),
8.77 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.98 (br. s.,
1H), 7.42-7.37 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 4.99 (br. s., 1H),
3.55 (s, 3H), 3.58-3.51 (m, 2H), 3.43-3.37 (m, 1H), 3.24 (d, J=10.4
Hz, 1H), 3.04-2.98 (m, 1H), 2.73-2.66 (m, 1H), 2.57-2.53 (m, 1H),
1.92-1.85 (m, 1H), 1.59 (qd, J=12.2, 4.2 Hz, 1H), 0.76-0.71 (m,
4H).
Example 389
##STR00450##
[1482] (+/-)-methyl
((3R,4R)-1-(5-carbamoyl-2-chloro-3-((7-cyano-4-(ethylamino)imidazo[2,1-f]-
[1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[1483] Prepared in analogous manner as Example 388.
[1484] MS (ESI) m/z 529
[1485] 1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.05 (t, J=5.6 Hz,
1H), 8.77 (s, 1H), 8.16 (s, 1H), 8.00 (br. s., 1H), 7.93 (d, J=1.5
Hz, 1H), 7.40 (m, 2H), 7.09 (d, J=8.2 Hz, 1H), 5.00 (d, J=4.3 Hz,
1H), 3.54 (s, 3H), 3.57-3.47 (m, 2H), 3.34-3.19 (m, 2H), 2.76-2.64
(m, 1H), 1.93-1.83 (m, 1H), 1.64-1.52 (m, 1H), 1.15 (t, J=7.2 Hz,
3H) The two missing proton signals are most likely hidden under the
very large water and DMSO signals.
Example 390
##STR00451##
[1486]
2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)ph-
enyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1487] Prepared in analogous manner as Example 247
[1488] MS (ESI) m/z 504.4
[1489] 1H NMR (500 MHz, DMSO-d6) d 9.14 (br. s., 1H), 8.69 (s, 1H),
8.19 (s, 1H), 7.81 (s, 1H), 7.15-6.87 (m, 2H), 4.57 (t, J=6.5 Hz,
2H), 4.49 (t, J=6.1 Hz, 2H), 3.56-3.41 (m, 3H), 3.06 (br. s., 4H),
2.47 (br. s., 3H), 1.18 (t, J=7.2 Hz, 3H)
Example 391
##STR00452##
[1490]
2-((3-cyano-1-methyl-1H-indazol-5-yl)amino)-4-((1,5-dimethyl-1H-1,2-
,4-triazol-3-yl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
HCl
[1491] (391A): 1,5-dimethyl-1H-1,2,4-triazol-3-amine (170 mg, 1.517
mmol) was taken up in 6 ml of anhydrous THF and cooled to 0.degree.
C. Sodium tert-butoxide (243 mg, 2.53 mmol) was added and the
reaction was stirred at 0.degree. C. for 5 min. Next, a solution of
2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Intermediate (300 mg, 1.264 mmol) in 8 ml of THF was added, and
the reaction was brought to rt. The reaction was stirred at room
temperature for 1 h. The solvent was removed in vacuo and the
material was dissolved in EtOAc. The organic layer was washed once
with water, and the aqueous layer was re-extracted with EtOAc. The
organic layers were combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imida-
zo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg) as a yellow solid.
The crude material was taken onto the next step without further
purification.
[1492] MS (ESI) m/z 302
[1493] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.48 (br. s,
1H), 8.00 (s, 1H), 3.85 (s, 3H), 2.63 (s, 3H), 2.48 (s, 3H)
[1494] (391B):
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f-
][1,2,4]triazine-7-carbonitrile (157 mg, 0.521 mmol) was taken up
in DMF (6 mL) under argon and NaH (22.92 mg, 0.573 mmol) was added.
The reaction mixture was stirred at room temperature for 30 min,
and then alpha-chloro-4-methoxytoluene (0.074 mL, 0.547 mmol) was
added. The reaction mixture was heated at 80.degree. C. for 3 h.
The reaction was quenched with saturated NaHCO3 solution and
extracted 3.times. with EtOAc. The organic layers were combined,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to give
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methylt-
hio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (185 mg) as a red
solid.
[1495] MS (ESI) m/z 422
[1496] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.73 (s,
1H), 7.39 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.28 (s, 2H),
3.81 (s, 3H), 3.78 (s, 3H), 2.56 (s, 3H), 2.48 (s, 3H)
[1497] (391C):
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methylt-
hio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (185 mg, 0.439
mmol) was taken up in DCM (5 mL) and mCPBA (246 mg, 1.097 mmol) was
added. The reaction was stirred at room temperature for 2 h. The
reaction mixture was diluted with DCM and quenched with saturated
NaHCO.sub.3. The organic layer was collected, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography eluting with 0-3% MeOH/DCM.
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methyls-
ulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (132 mg) was
obtained as a yellow solid.
[1498] MS (ESI) m/z 454
[1499] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.92 (s,
1H), 7.46 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.35 (br. s.,
2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.34 (s, 3H), 2.52 (s, 3H)
[1500] (391D): 5-nitro-1H-indazole (2 g, 12.26 mmol) was taken up
in DMF (40 mL) and NIS (5.52 g, 24.52 mmol) was added. The reaction
was stirred at room temperature for 72 h. The reaction mixture was
diluted with EtOAc and washed with saturated sodium bisulfite
solution, water, and then 2.times. with brine. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated to give
3-iodo-5-nitro-1H-indazole (3.4 g) as a yellow solid.
[1501] MS (ESI) m/z 290 (M+H).
[1502] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 14.11 (br.
s., 1H), 8.37-8.31 (m, 1H), 8.25 (dd, J=9.2, 2.2 Hz, 1H), 7.76 (d,
J=9.2 Hz, 1H)
[1503] (391E): 3-iodo-5-nitro-1H-indazole (6.9 g, 23.87 mmol) was
taken up in NMP (90 mL) and copper (I) cyanide (4.28 g, 47.7 mmol)
was added. The reaction was heated at 160.degree. C. for 1 h, and
then cooled to room temperature. The reaction mixture was diluted
with EtOAc and filtered through celite, rinsing with EtOAc. The
filtrate was washed 2.times. with water and 2.times. with brine.
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude material was purified by flash column
chromatography eluting with 0%-50% EtOAc/Hex. 0.91 g of
5-nitro-1H-indazole-3-carbonitrile was obtained.
[1504] .sup.1H NMR (400 MHz, MeOD) .delta. ppm 8.91-8.78 (m, 1H),
8.43 (dd, J=9.2, 2.2 Hz, 1H), 7.91 (dd, J=9.2, 0.7 Hz, 1H)
[1505] (391F): 5-nitro-1H-indazole-3-carbonitrile (150 mg, 0.797
mmol) was taken up in DMA (4 mL) and K.sub.2CO.sub.3 (331 mg, 2.392
mmol) was added, followed by drop wise addition of Met (0.060 mL,
0.957 mmol). The reaction was stirred at room temperature
overnight. The reaction mixture was quenched with a saturated
solution of NaHCO.sub.3 and Na.sub.2S.sub.2O.sub.3, and then
diluted with EtOAc. The organic layer was washed with saturated
NaHCO.sub.3, then brine, and dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The material was purified by flash column
chromatography eluting with 0%-50% EtOAc/Hex.
1-methyl-5-nitro-1H-indazole-3-carbonitrile (134 mg) was obtained
as a yellow solid.
[1506] MS (ESI) m/z 203 (M+H).
[1507] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.85 (dd,
J=2.0, 0.7 Hz, 1H), 8.39 (dd, J=9.4, 2.1 Hz, 1H), 8.14 (dd, J=9.2,
0.7 Hz, 1H), 4.28 (s, 3H)
[1508] (391G): 1-methyl-5-nitro-1H-indazole-3-carbonitrile (134 mg,
0.663 mmol) was taken up in EtOH (6 mL) and Water (6 mL). Iron
powder (259 mg, 4.64 mmol) and ammonium chloride (319 mg, 5.97
mmol) were added, and the reaction mixture was brought to reflux
and heated for 15 min. The reaction was cooled to room temperature
and filtered through celite, washing with EtOH, then EtOAc. The
solvent was removed in vacuo, and the reaction mixture taken up in
EtOAc. The organic layer was washed with saturated NaHCO.sub.3
solution, then brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The material was purified by flash column
chromatography eluting with 0%-80% EtOAc/Hex.
1-methyl-5-nitro-1H-indazole-3-carbonitrile (48.5 mg) was obtained
as a yellow solid.
[1509] MS (ESI) m/z 173 (M+H).
[1510] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.56 (d,
J=9.0 Hz, 1H), 6.96 (dd, J=9.0, 2.0 Hz, 1H), 6.71 (dd, J=2.0, 0.7
Hz, 1H), 5.36 (s, 2H), 4.06 (s, 3H)
[1511] Example 391: 5-amino-1-methyl-1H-indazole-3-carbonitrile
(24.68 mg, 0.143 mmol) was taken up in 1 ml DMF (2 mL) and NaH
(11.47 mg, 0.287 mmol) was added portion wise under argon. The
reaction was stirred at room temperature for 10 min. Next, a
solution of
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methyls-
ulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (65 mg, 0.143
mmol) in 1 ml DMF was added. The reaction was stirred at room
temperature for 2.5 h. The reaction mixture was diluted with EtOAc
and washed with water 2.times., then brine 2.times.. The material
was dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
aqueous layer was filtered to collect additional material. This was
combined with the compound obtained from the organic layer. The
intermediate was taken up in DCM (2 mL) and anisole (0.031 mL,
0.287 mmol) and TFA (0.110 mL, 1.433 mmol) were added. The reaction
stirred at room temperature overnight, and then heated at
35.degree. C. for 2 h to obtain complete conversion to the product.
The solvent was removed in vacuo and the material taken up in MeOH,
then filtered through an SCX column (5 g, benzenesulfonic acid
sorbent). The column was rinsed with 7N NH.sub.3/MeOH solution to
recover the product. The product was purified by flash column
chromatography (0-6% MeOH/DCM; 12 g ISCO gold column). The material
was taken up in a small amount of DCM/MeOH and hexane was added to
precipitate the compound. The product was collected by filtration
to yield 5 mg of product. The material was taken up in 1 ml of 1:1
ACN/H.sub.2O and 1N aq. HCl (0.143 mL, 0.143 mmol) was added drop
wise. The solution was lyophilized overnight to yield
2-((3-cyano-1-methyl-1H-indazol-5-yl)amino)-4-((1,5-dimethyl-1H-1,2,4-tri-
azol-3-yl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, HCl
(4.7 mg) as a brown solid.
[1512] MS (ESI) m/z 426
[1513] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 10.08 (br.
s., 1H), 8.31 (s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.84-7.74 (m, 1H),
4.16 (s, 3H), 3.82 (s, 3H), 2.53 (d, J=2.8 Hz, 3H)
Example 392
##STR00453##
[1514]
(R)-2-((3-cyano-1-(2-hydroxypropyl)-1H-indazol-5-yl)amino)-4-((1,5--
dimethyl-1H-1,2,4-triazol-3-yl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile, HCl
[1515] (392A): 5-nitro-1H-indazole-3-carbonitrile (600 mg, 3.19
mmol, Example 391E) was taken up in DMF (3 ml), and K.sub.2CO.sub.3
(580 mg, 4.20 mmol) and (R)-2-methyloxirane (1.85 ml, 26.4 mmol)
were added. The reaction mixture was heated at 85.degree. C. for 1
h. The reaction mixture was partitioned between half-saturated aq.
NH.sub.4Cl solution and EtOAc. The organic layer was washed with
half-saturated aq. NaHCO.sub.3 solution, then brine, dried over
MgSO.sub.4, filtered and evaporated to dryness. The crude material
was purified by flash column chromatography eluting with 0-50%
EtOAc/DCM.
(R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (760 mg)
was obtained as a colorless film.
[1516] MS (ESI) m/z 247
[1517] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.84 (d,
J=2.0 Hz, 1H), 8.37 (dd, J=9.4, 2.1 Hz, 1H), 8.15 (d, J=9.5 Hz,
1H), 5.00 (d, J=5.3 Hz, 1H), 4.55 (dtd, J=14.1, 12.7, 5.8 Hz, 2H),
4.16-4.06 (m, 1H), 1.16 (d, J=6.5 Hz, 3H)
[1518] (392B): A solution of
(R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (0.76 g,
2.93 mmol) in EtOH (10 ml) was added to a suspension of iron
(powder) (1.310 g, 23.46 mmol) and ammonium chloride (1.569 g, 29.3
mmol) in water (10 ml). The reaction mixture was heated in a
microwave reactor at 80.degree. C. for 15 min. The reaction vial
was cooled to room temperature and the reaction mixture was
filtered through celite, rinsing with EtOH, water, EtOH again, and
then EtOAc. The filtrates were combined and diluted with EtOAc. The
organic layer was washed with saturated aq. NaHCO.sub.3 solution,
water, then brine, then dried over MgSO.sub.4, filtered, and
evaporated to dryness.
(R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (470 mg)
was obtained as a pale yellow solid.
[1519] MS (ESI) m/z 217 (M+H).
[1520] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.58 (d,
J=9.0 Hz, 1H), 6.92 (dd, J=9.0, 2.0 Hz, 1H), 6.70 (d, J=2.0 Hz,
1H), 5.35 (s, 2H), 4.94 (d, J=5.0 Hz, 1H), 4.30 (dd, J=5.9, 2.9 Hz,
2H), 4.15-3.97 (m, 1H), 1.08 (d, J=6.3 Hz, 3H)
[1521] (392C):
(R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (180 mg,
0.832 mmol) was taken up in DCM (6 mL) and imidazole (227 mg, 3.33
mmol) and DMAP (10.17 mg, 0.083 mmol) were added, followed by
TBS-Cl (439 mg, 2.91 mmol). The reaction was stirred at room
temperature overnight. The reaction mixture was quenched with
saturated NH.sub.4Cl solution and diluted with DCM. The organic
layer was collected and washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude material
was purified by flash column chromatography eluting with 0-40%
EtOAc/Hex.
(R)-5-amino-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole-3-carb-
onitrile (230.5 mg) was obtained as an orange solid.
[1522] MS (ESI) m/z 331 (M+H).
[1523] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.57 (d,
J=9.0 Hz, 1H), 6.93 (dd, J=9.0, 2.0 Hz, 1H), 6.70 (d, J=1.5 Hz,
1H), 4.53-4.29 (m, 2H), 4.29-4.19 (m, 1H), 1.20 (d, J=5.9 Hz, 3H),
0.72-0.52 (m, 9H), -0.19 (s, 3H), -0.56 (s, 3H)
[1524] Example 392:
(R)-5-amino-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole-3-carb-
onitrile (38.0 mg, 0.115 mmol),
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methyls-
ulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (43.5 mg,
0.096 mmol, Example 55C), Cs.sub.2CO.sub.3 (94 mg, 0.288 mmol), and
DMSO (1 mL) were heated in a sealed vial at 80.degree. C. under an
argon atmosphere for 8 h. The reaction mixture was diluted with
EtOAc and washed once with water and 2.times. with brine. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude material was purified by flash column
chromatography eluting with 0-2% MeOH/DCM. 11 mg of the
intermediate was obtained. The compound was dissolved in DCE (1 ml)
and anisole (0.021 mL, 0.192 mmol) and TFA (0.148 mL, 1.919 mmol)
were added. The reaction was heated at 40.degree. C. for 3 h, then
an additional 0.5 ml of TFA was added and the reaction was stirred
at room temperature for 72 h. The solvent was removed in vacuo and
the material dissolved in MeOH. The solution was loaded onto an SCX
column (5 g, benzenesulfonic acid sorbent), which was rinsed with
MeOH, then a 7N solution of ammonia in methanol to recover the
product. The solvent was removed in vacuo and the product purified
by flash column chromatography eluting with 0-5% MeOH/DCM. The
product was repurified by preparative HPLC and the product
converted to the free base by dissolving in EtOAc and extraction
with saturated aq. NaHCO.sub.3 solution to provide 2.2 mg of the
final product. The material was taken up in 1 ml of 1:1
ACN/H.sub.2O and 1N HCl in water (4.7 .mu.L, 4.7 .mu.mol) was
added. The solution was frozen in a dry ice bath and lyopholized
overnight to give
(R)-2-((3-cyano-1-(2-hydroxypropyl)-1H-indazol-5-yl)amino)-4-((1,5-dimeth-
yl-1H-1,2,4-triazol-3-yl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e, HCl (1.0 mg) as an off-white solid.
[1525] MS (ESI) m/z 470
[1526] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.75 (s,
1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.83 (q, J=9.2 Hz, 2H), 7.02 (br.
s., 1H), 4.42 (t, J=5.3 Hz, 2H), 4.11 (dt, J=11.9, 5.8 Hz, 1H),
3.80 (s, 3H), 2.44 (s, 3H), 1.15-1.07 (m, 3H)
Example 393
##STR00454##
[1527]
(R)-2-((3-cyano-1-(2-hydroxypropyl)-1H-indazol-5-yl)amino)-4-(cyclo-
propylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, HCl
[1528]
(R)-5-amino-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole--
3-carbonitrile (49.8 mg, 0.151 mmol, Example 392C),
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 2) (50 mg, 0.125 mmol),
Cs.sub.2CO.sub.3 (123 mg, 0.376 mmol), and DMSO (2 mL) were heated
in a sealed vial at 80.degree. C. for 8 h. The reaction mixture was
diluted with EtOAc and washed once with water and 2.times. with
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The intermediate was taken up in DCE (2 mL) and
anisole (0.027 mL, 0.251 mmol) and TFA (0.483 mL, 6.27 mmol) were
added. The reaction was stirred at room temperature overnight. The
solvent was removed in vacuo and the material taken was up in MeOH.
The solution was loaded onto an SCX column (5 g, benzenesulfonic
acid sorbent) and rinsed with MeOH, then 7N NH.sub.3/MeOH to obtain
the product. The product was purified by flash column
chromatography, eluting with 0-30% EtOAc/DCM. The material was then
triturated with MeOH to give 9.5 mg of an off-white solid. The
compound was suspended in 1 ml of a 1:1 mixture of
CH.sub.3CN/H.sub.2O and aq. 1N HCl (23 .mu.L, 23 .mu.mol) was
added. The solution was frozen in a dry ice bath and lyophilized
overnight.
(R)-2-((3-cyano-1-(2-hydroxypropyl)-1H-indazol-5-yl)amino)-4-(cyclopropyl-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, HCl (9.5 mg)
was obtained as an off-white solid.
[1529] MS (ESI) m/z 415
[1530] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.76 (br.
s., 1H), 9.32 (br. s., 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.85 (d,
J=9.2 Hz, 1H), 7.77-7.69 (m, 1H), 4.98 (br. s., 1H), 4.43 (t, J=5.5
Hz, 1H), 4.19-3.99 (m, J=11.8, 11.8 Hz, 1H), 3.21-3.09 (m, 1H),
1.14 (d, J=6.2 Hz, 3H), 0.98-0.73 (m, J=4.8 Hz, 4H)
Example 394
##STR00455##
[1531]
(S)-2-((3-cyano-1-(1-(2-hydroxypropyl)piperidin-4-yl)-1H-indol-5-yl-
)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1532] (394A): To a solution of 5-nitro-1H-indole-3-carbonitrile
(2.0 g, 10.69 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate
(4.30 g, 21.37 mmol) and triphenylphosphine (5.61 g, 21.37 mmol) in
90 ml THF was slowly added DEAD (3.38 mL, 21.37 mmol) in 50 ml of
THF over 3 hrs. The mixture was stirred 32 hrs at 25.degree. C. The
mixture was concentrated and purified on silica: 100% DCM 500 ml,
then (5-60% EtOAc in Hexanes) to give tert-butyl
4-(3-cyano-5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (1.3
g).
[1533] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.80 (s, 1H),
8.59-8.43 (m, 1H), 8.31-8.18 (m, 1H), 8.13-8.04 (m, 1H), 4.93-4.80
(m, 1H), 4.23-4.03 (m, 2H), 3.06-2.85 (m, 2H), 2.09-1.96 (m, 2H),
1.94-1.80 (m, 2H), 1.45-1.36 (m, 9H)
[1534] tert-butyl
4-(3-cyano-5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (1.02 g,
2.75 mmol), Iron (0.923 g, 16.52 mmol), and ammonium chloride
(1.031 g, 19.28 mmol) were suspended in a mixture of Ethanol (10
mL)/Water (10 mL). The reaction mixture was heated in oil bath at
85.degree. C. for 20 min. The reaction mixture was filtered through
Celite, and then washed with water, MeOH and EtOAc. The combined
filtrates were concentrated to almost dryness, and then mixed with
aq. NaHCO.sub.3 and EtOAc. The organic layer was washed with brine,
dried over MgSO.sub.4, filtered and evaporated to dryness to give
tert-butyl
4-(5-amino-3-cyano-1H-indol-1-yl)piperidine-1-carboxylate (200
mg).
[1535] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.16 (s, 1H),
7.44 (d, J=8.8 Hz, 1H), 6.73 (d, J=1.4 Hz, 1H), 6.69 (s, 1H), 4.97
(br. s., 2H), 4.61-4.45 (m, 1H), 4.24-3.94 (m, 2H), 3.07-2.82 (m,
2H), 2.04-1.89 (m, 2H), 1.88-1.71 (m, 2H), 1.44 (s, 9H)
[1536] (394B): A mixture of
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (Intermediate 10) (200 mg, 0.583 mmol), tert-butyl
4-(5-amino-3-cyano-1H-indol-1-yl)piperidine-1-carboxylate (199 mg,
0.583 mmol), Pd(OAc).sub.2 (13.10 mg, 0.058 mmol), Brettphos (62.6
mg, 0.117 mmol) and K.sub.2CO.sub.3 (242 mg, 1.750 mmol) was
suspended in Dioxane (4 mL) in a 5 ml microwave vial. The vial was
sealed, flushed with nitrogen 4 times, and then heated in microwave
at 115.degree. C. for 2 hr. The mixture was diluted with CH.sub.3CN
and CH.sub.2Cl.sub.2, filtered through celite and concentrated. The
crude was carried forward in the next reaction.
[1537] MS (ESI) m/z 647
[1538] tert-butyl
4-(3-cyano-5-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,-
4]triazin-2-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (500
mg, 0.503 mmol) was mixed with anisole (0.5 mL, 4.58 mmol) and DCE
(5 mL). TFA (1 mL, 12.98 mmol) was added. The mixture was stirred
at 25.degree. C. for 24 hrs. LC/MS showed product formation. The
mixture was concentrated to dryness, diluted with MeOH and applied
onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode
polymer. This was washed with methanol and product was eluted with
2 N solution of ammonia in methanol. Removal of the solvents left
2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as solid.
[1539] MS (ESI) m/z 427
[1540] Example 394:
2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)imidazo-
[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.044 mmol) was
dissolved in MeOH (0.5 mL)/DCM (0.5 mL) in an one dram vial. To
this was added TEA (0.012 mL, 0.088 mmol) and (S)-2-methyloxirane
(25.5 mg, 0.440 mmol). The reaction mixture was stirred at
25.degree. C. 16 hr. The solvents were removed and the crude
material was purified via preparative LC/MS with the following
conditions:
[1541] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 20-60% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min.
[1542] Fractions containing the desired product were combined and
dried via centrifugal evaporation to afford
(S)-2-((3-cyano-1-(1-(2-hydroxypropyl)piperidin-4-yl)-1H-indol-5-yl)amino-
)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.9
mg).
[1543] MS (ESI) m/z 485
[1544] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.17-9.96 (m,
1H), 9.55-9.37 (m, 1H), 9.19-8.97 (m, 1H), 8.18 (s, 1H), 7.86-7.78
(m, 1H), 7.69-7.60 (m, 1H), 5.59-5.34 (m, 1H), 4.88-4.67 (m, 1H),
4.30-4.16 (m, 1H), 3.81-3.68 (m, 1H), 3.67-3.54 (m, 2H), 3.31-3.11
(m, 3H), 3.08-2.97 (m, 1H), 2.90 (s, 2H), 2.74 (s, 2H), 2.30-2.16
(m, 2H), 1.28 (t, J=7.2 Hz, 3H), 1.21-1.09 (m, 3H)
Example 395
##STR00456##
[1545]
(R)-2-((3-cyano-1-(1-(2-hydroxypropyl)piperidin-4-yl)-1H-indol-5-yl-
)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1546] Prepared in analogous manner as Example 394
[1547] MS (ESI) m/z 485
[1548] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.16-9.95 (m,
1H), 9.48 (s, 1H), 9.16-9.00 (m, 1H), 8.28-8.13 (m, 2H), 7.99-7.93
(m, 1H), 7.87-7.75 (m, 1H), 7.69-7.56 (m, 1H), 5.60-5.42 (m, 1H),
4.85-4.72 (m, 1H), 4.28-4.10 (m, 1H), 3.84-3.68 (m, 1H), 3.65-3.55
(m, 2H), 3.28-3.11 (m, 2H), 3.08-2.97 (m, 1H), 2.90 (s, 2H), 2.74
(s, 2H), 2.30-2.14 (m, 2H), 1.28 (s, 3H), 1.21-1.09 (m, 3H)
Example 396
##STR00457##
[1549]
2-((3-cyano-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-5-yl)amino)--
4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1550]
2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)i-
midazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.059 mmol) in
Methanol (2 ml)/Tetrahydrofuran (2 ml) was added oxetan-3-one
(0.052 ml, 0.879 mmol), acetic acid (6.71 .mu.l, 0.117 mmol) and
trimethyl orthoformate (0.350 ml, 3.17 mmol). The mixture was
stirred at 25.degree. C. for 15 min. Sodium cyanoborohydride (29
mg, 0.461 mmol) was added and the reaction stirred at room
temperature 12 hr. The solvents were removed and the crude material
was purified via preparative LC/MS with the following
conditions:
[1551] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Guard Column: Waters XBridge C18, 19.times.10 mm,
5-.mu.m particles; Mobile Phase A: water with 20-mM ammonium
acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM
ammonium acetate; Gradient: 30-80% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min.
[1552] Fractions containing the desired product were combined and
dried via centrifugal evaporation to afford
2-((3-cyano-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-5-yl)amino)-4-(eth-
ylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13.6 mg).
[1553] MS (ESI) m/z 483
[1554] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.16-11.86 (m,
1H), 9.49 (s, 1H), 9.21-8.96 (m, 1H), 8.33-8.21 (m, 2H), 8.18 (s,
1H), 7.99-7.91 (m, 1H), 7.88-7.75 (m, 1H), 7.66-7.52 (m, 1H),
5.01-4.63 (m, 5H), 4.54-4.37 (m, 1H), 3.68-3.48 (m, 3H), 3.20-2.99
(m, 2H), 2.90 (s, 3H), 2.74 (s, 3H), 2.37-2.17 (m, 2H), 1.28 (s,
3H)
Example 397
##STR00458##
[1555]
Methyl-4-chloro-3-(7-cyano-4-(cyclopropylamino)imidazo[1,2-f][1,2,4-
]triazin-2-ylamino)-5-(1-methylpiperidin-4-yl)phenylcarbamate
[1556] (397A): A mixture of methyl
(3-bromo-4-chloro-5-nitrophenyl)carbamate (229 mg, 0.740 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahyd-
ropyridine (150 mg, 0.672 mmol),
tetrakis(triphenylphosphine)palladium (0) (78 mg, 0.067 mmol) and
K.sub.3PO.sub.4 (527 mg, 2.487 mmol) in a microwave vial was
flushed with nitrogen. A nitrogen sparged mixture of dioxane (5602
.mu.L) and water (1120 .mu.L) was added and the vial was sealed and
heated at 80.degree. C. overnight. The reaction was partitioned
between EtOAc and water. The aqueous phase was extracted with EtOAc
and the combined organic phases were washed with brine and dried
with sodium sulfate. After removal of the solvents, the crude
material was applied onto a cartridge of Phenomenex Strata-X-C 33
um cation mixed-mode polymer. This was washed with methanol and the
product was eluted with 2 N solution of ammonia in methanol.
Removal of the solvent left methyl
(4-chloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitrophenyl)carba-
mate (213 mg) as a solid which was used as such.
[1557] MS (ESI) m/z 326.07
[1558] 1H NMR (500 MHz, CHLOROFORM-d) d 8.43 (s, 1H), 7.94 (br. s.,
1H), 5.68 (dt, J=3.1, 1.6 Hz, 1H), 3.76 (s, 3H), 3.11 (q, J=2.7 Hz,
2H), 3.04 (br. s., 1H), 2.69 (t, J=5.6 Hz, 2H), 2.51-2.4 (m, 2H),
2.40 (s, 3H)
[1559] (397B): A mixture of methyl
(4-chloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitrophenyl)carba-
mate (213 mg, 0.654 mmol) and platinum (IV) oxide (240 mg, 0.654
mmol) in a mixture of MeOH (50 mL) and ethyl acetate (3 mL) was
hydrogenated (balloon of H.sub.2). The reaction completed within 1
h. The catalyst was removed by filtration through a celite pad and
the pad was rinsed with MeOH. The solvent was removed and radial
silica gel chromatography, eluting with DCM containing 0 to 3% MeOH
gave methyl
(3-amino-4-chloro-5-(1-methylpiperidin-4-yl)phenyl)carbamate (131
mg) as a white solid.
[1560] MS (ESI) m/z 298.10 (M+1)
[1561] 1H NMR (400 MHz, METHANOL-d4) .delta. 7.04 (d, J=1.8 Hz,
1H), 6.64 (d, J=2.5 Hz, 1H), 3.73 (s, 3H), 3.09-2.91 (m, 3H), 2.35
(s, 3H), 2.26-2.13 (m, 2H), 1.91-1.80 (m, 2H), 1.72 (dd, J=12.8,
3.3 Hz, 2H)
[1562] (397C): A mixture of
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (Intermediate 2) (77 mg, 0.193 mmol),
methyl (3-amino-4-chloro-5-(1-methylpiperidin-4-yl)phenyl)carbamate
(48 mg, 0.161 mmol) and Cs.sub.2CO.sub.3 (158 mg, 0.484 mmol) in
DMF (1.2 mL) was heated at 70.degree. C. for 3 h. It was diluted
with EtOAc and washed with water. Removal of the solvent was
followed by preparative HPLC (100.times.30 mm Luna C18 column,
Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol,
10% H2O, 0.1% TFA, Flow rate 42 ml/min, 20-100% B, over 20 min).
The solvent was removed from the fractions containing the
intermediate on a speed vac. The intermediate was dissolved in DCE
(3 mL) and anisole (0.088 mL, 0.806 mmol) and TFA (1.5 mL) were
added. This was heated at 50.degree. C. for 3 h. Removal of the
solvents was followed by preparative HPLC (100.times.30 mm Luna C18
column, Solvent A=10% Methanol, 90% H.sub.2O, 0.1% TFA; solvent
B=90% Methanol, 10% H.sub.2O, 0.1% TFA, Flow rate 42 ml/min,
20-100% B, over 20 min). The HPLC fractions containing the product
were applied onto a cartridge of Phenomenex Strata-X-C 33 um cation
mixed-mode polymer. This was washed with methanol and product was
eluted with 2 N solution of ammonia in methanol. Removal of the
solvents left methyl
(4-chloro-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2--
yl)amino)-5-(1-methylpiperidin-4-yl)phenyl)carbamate (7 mg) as a
solid.
[1563] MS (ESI) m/z 496.20
[1564] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.52 (s, 1H),
7.84 (s, 1H), 7.52 (s, 1H), 7.21 (br. s., 1H), 6.79 (s, 1H), 6.63
(br. s., 1H), 3.79 (s, 3H), 3.51 (s, 3H), 3.25-3.03 (m, 3H), 2.32
(d, J=8.2 Hz, 2H), 2.03-1.86 (m, 5H), 1.06-0.95 (m, 2H), 0.82-0.71
(m, 2H).
Example 398
##STR00459##
[1565] methyl
(4-chloro-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)ami-
no)-5-(1-methylpiperidin-4-yl)phenyl)carbamate
[1566] Prepared in analogous manner as Example 397
[1567] MS (ESI) m/z 484.3
[1568] 1H NMR (500 MHz, DMSO-d6) d 9.73 (s, 1H), 9.04 (t, J=5.6 Hz,
1H), 8.66 (s, 1H), 8.17 (s, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.28 (d,
J=1.8 Hz, 1H), 3.67 (s, 3H), 3.48-3.43 (m, 2H), 2.96-2.81 (m, 3H),
2.21 (s, 3H), 2.05-1.94 (m, 2H), 1.75 (d, J=12.5 Hz, 2H), 1.59 (qd,
J=12.3, 3.8 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H)
Example 399
##STR00460##
[1569]
2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imida-
zo[2,1-f][1,2,4]triazine-7-carbonitrile
[1570] (399A): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) (200 mg,
0.603 mmol), potassium vinyltrifluoroborate (121 mg, 0.905 mmol),
and [1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (44
mg, 0.060 mmol) in a microwave vial was flushed with nitrogen. EtOH
(3 mL) and TEA (126 .mu.L, 0.905 mmol) were added and the mixture
was degassed and flushed with nitrogen. This was sealed and heated
at 80.degree. C. for 18 hr. It was diluted with water and extracted
with a mixture of EtOAc:hexane=3:1. The organic phase was washed
with brine and dried with sodium sulfate. Removal of the solvents
followed by silica gel radial chromatography eluting with hexane
containing 0 to 20% EtOAc afforded tert-butyl
(2-chloro-5-cyano-3-vinylphenyl)carbamate (122 mg) as a white
solid.
[1571] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.51 (d, J=1.5
Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.20 (br. s., 1H), 7.04 (dd,
J=17.4, 11.0 Hz, 1H), 5.81 (d, J=17.4 Hz, 1H), 5.54 (d, J=11.3 Hz,
1H), 1.58-1.54 (m, 9H).
[1572] (399B): A solution of tert-butyl
(2-chloro-5-cyano-3-vinylphenyl)carbamate (122 mg, 0.438 mmol) in a
mixture of TFA (1.9 mL) and DCM (1.9 mL) was stirred at room
temperature for 1 hr. The solvents were removed and the residue was
dissolved in DCM. This was washed with saturated aq. NaHCO.sub.3
solution. The organic phase was separated and dried with sodium
sulfate. Removal of the solvent left
3-amino-4-chloro-5-vinylbenzonitrile (76 mg) as a white solid.
[1573] MS (ESI) m/z 179.0 (M+1)
[1574] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.23 (d, J=1.8
Hz, 1H), 7.04 (dd, J=17.4, 11.0 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H),
5.78 (dd, J=17.5, 0.7 Hz, 1H), 5.50 (dd, J=11.0, 0.6 Hz, 1H), 4.35
(br. s., 2H).
[1575] (399C): A mixture of 3-amino-4-chloro-5-vinylbenzonitrile
(75 mg, 0.42 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (149 mg, 0.420 mmol),
Cs.sub.2CO.sub.3 (274 mg, 0.840 mmol), DPPF (23 mg, 0.042 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (24 mg, 0.042 mmol),
and Pd(OAc).sub.2 (28 mg, 0.13 mmol) in a microwave vial was
flushed with nitrogen. Dioxane (3.5 mL) was added and the vial was
sealed and heated at 100.degree. C. for 4 hr. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed from the filtrate and radial silica gel chromatography
eluting with hexane containing 5 to 40% EtOAc afforded
2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (106 mg, 51%
yield) as an oil. This was dissolved in DCM (3 mL) and anisole
(0.582 mL, 5.33 mmol) and TFA (3 mL) were added. After stirring at
room temperature overnight, the solvent was removed and the yellow
solid was dissolved in DCM. This was washed with a saturated aq.
NaHCO.sub.3 solution and the organic phase was separated. The
aqueous phase contained some suspended yellow solid and was exacted
2.times. with DCM. The combined organic phases were dried with
sodium sulfate and the solvent was removed. The residue was
suspended in a mixture of EtOAc:hexane=1:1 and filtration gave the
title compound (59 mg) as a light yellow solid.
[1576] MS (ESI) m/z 377.2
[1577] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.36 (d, J=4.1 Hz,
1H), 8.93 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.23-8.18 (m, 1H), 7.94
(d, J=2.0 Hz, 1H), 7.06 (dd, J=17.4, 11.1 Hz, 1H), 6.08 (d, J=17.5
Hz, 1H), 5.60 (d, J=11.6 Hz, 1H), 2.99-2.90 (m, 1H), 0.84-0.72 (m,
4H) 9.36 (d, J=4.1 Hz, 1H), 8.93 (s, 1H), 8.37 (d, J=2.0 Hz, 1H),
8.23-8.18 (m, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.06 (dd, J=17.4, 11.1
Hz, 1H), 6.08 (d, J=17.5 Hz, 1H), 5.60 (d, J=11.6 Hz, 1H),
2.99-2.90 (m, 1H), 0.84-0.72 (m, 4H).
Example 400
##STR00461##
[1578]
2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imid-
azo[2,1-f][1,2,4]triazine-7-carbonitrile
[1579] (400): A suspension of
2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile (Example 399) (210 mg, 0.557
mmol) in acetone (50 mL) was heated to give a cloudy solution.
After cooling to room temperature; water (5 mL), osmium tertroxide
(0.350 mL, 2.5 wt % in t-BuOH, 0.028 mmol) and sodium periodate
(262 mg, 1.23 mmol) were added. After overnight stirring,
additional water (20 mL) was added and the reaction was left
stirring for 1 day. Most of the acetone was removed and the
suspended solid was collected by filtration, washed with water, and
air dried to leave
2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (188 mg) as a light yellow
solid.
[1580] MS (ESI) m/z 379.0 (M+1)
[1581] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 10.34 (s, 1H), 9.41
(d, J=3.5 Hz, 1H), 9.27 (s, 1H), 8.71 (d, J=1.5 Hz, 1H), 8.23 (s,
1H), 7.96 (d, J=1.5 Hz, 1H), 2.92 (d, J=4.1 Hz, 1H), 0.82-0.75 (m,
4H).
Example 401
##STR00462##
[1582]
2-((2-chloro-5-cyano-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)ph-
enyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitri-
le
[1583] A solution of
2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (Example 400) (18 mg, 0.048
mmol), 1-(methylsulfonyl)piperazine (9.5 mg, 0.058 mmol),
trimethylorthoformate (0.027 mL, 0.242 mmol), and acetic acid (3
.mu.L, 0.05 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL)
was stirred at room temperature for 15 min. A solution of sodium
cyanoborohydride (0.097 mL, 1M in THF mL, 0.097 mmol) was added and
the reaction was left stirring at room temperature overnight.
Additional sodium cyanoborohydride (0.097 mL, 1M in THF mL, 0.097
mmol) was added and the reaction was left stirring for 1 day. A
saturated aq. solution of NaHCO.sub.3 solution was added and, after
15 min, this was extracted with a mixture of 5% MeOH in DCM
(5.times.). The combined organic extracts were dried with sodium
sulfate and the solvent was removed. Silica gel radial
chromatography of the residue eluting with DCM containing 0 to 2%
MeOH afforded the title compound (7.9 mg) as foam.
[1584] MS (ESI) m/z 527.2 (M+1)
[1585] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.00 (d, J=1.8
Hz, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 6.79
(br. s., 1H), 3.72 (s, 2H), 3.34-3.28 (m, 4H), 3.07 (tq, J=7.1, 3.5
Hz, 1H), 2.83 (s, 3H), 2.73-2.64 (m, 4H), 1.16-1.07 (m, 2H),
0.87-0.78 (m, 2H).
Example 402
##STR00463##
[1586] 2
2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1587] The title compound (7.3 mg, 38% yield) was obtained as a
side product in Example 401.
[1588] MS (ESI) m/z 381.2 (M+1).
[1589] .sup.1H NMR (400 MHz, METHANOL-d4/CHLOROFORM-d) .delta. 8.90
(d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.57-7.51 (m, 1H), 4.73 (s, 2H),
3.01 (dt, J=7.2, 3.5 Hz, 1H), 1.06-0.98 (m, 2H), 0.81-0.73 (m,
2H).
Example 403
##STR00464##
[1590]
2-((2-chloro-5-cyano-3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)pheny-
l)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
HCl salt
[1591] (403A): A nitrogen sparged mixture of THF (2.2 mL) and water
(0.22 mL) was added to a nitrogen flushed mixture of potassium
(4-Boc-piperazin-1-yl)methyl trifluoroborate (200 mg, 0.653 mmol),
tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate
1) (197 mg, 0.594 mmol),
2-dicyclohexylphosphino-2'-4'-6'-trisisopropylbiphenyl (34.0 mg,
0.071 mmol), Pd(OAc).sub.2 (8.0 mg, 0.036 mmol), and
Cs.sub.2CO.sub.3 (580 mg, 1.78 mmol) in a microwave vial. This was
sealed and heated at 80.degree. C. for 17 hr. The reaction was
extracted 3.times. with EtOAc and the combined organic extracts
were washed with brine and dried with sodium sulfate. Removal of
the solvent followed by silica gel radial chromatography eluting
with hexane containing 10 to 50% EtOAc afforded tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzyl)piperazine-1-car-
boxylate (59 mg) as a film.
[1592] MS (ESI) m/z 451.1
[1593] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.50 (d, J=1.5
Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.18 (s, 1H), 3.61 (s, 2H),
3.50-3.43 (m, 4H), 2.46 (br. s., 4H), 1.58-1.54 (m, 9H), 1.48 (s,
9H).
[1594] (403B): TFA (1.0 mL) was added to a solution of tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzyl)piperazine-1-car-
boxylate (59 mg, 0.13 mmol) in DCM (1.0 mL) at room temperature.
After 1 hr, the solvent was removed and the residue was dissolved
in MeOH and applied onto an SCX column. This was washed with MeOH
and the product was eluted with 2N NH.sub.3 in MeOH to give
3-amino-4-chloro-5-(piperazin-1-ylmethyl)benzonitrile (22 mg) as
oil.
[1595] MS (ESI) m/z 251.0
[1596] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.26-7.21 (m,
1H), 6.94-6.89 (m, 1H), 4.33 (br. s., 2H), 3.56 (s, 2H), 2.95-2.90
(m, 4H), 2.50 (br. s., 4H).
[1597] (403C): A solution of
3-amino-4-chloro-5-(piperazin-1-ylmethyl)benzonitrile (22 mg, 0.088
mmol), Boc.sub.2O (24 mg, 0.097 mmol), and TEA (0.013 mL, 0.097
mmol) in DCM (0.5 mL) was stirred at room temperature overnight.
The solvents were removed and radial silica gel chromatography
eluting with hexane containing 0 to 30% EtOAc afforded tert-butyl
4-(3-amino-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate (28 mg)
as film.
[1598] MS (ESI) m/z 351.1
[1599] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.20 (d, J=1.8
Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 4.35 (s, 2H), 3.59 (s, 2H),
3.49-3.44 (m, 4H), 2.46 (br. s., 4H), 1.48 (s, 9H).
[1600] (403D): A mixture of tert-butyl
4-(3-amino-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate (28 mg,
0.079 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (Intermediate 9) (28 mg, 0.079 mmol),
Cs.sub.2CO.sub.3 (51.4 mg, 0.158 mmol), DPPF (4.4 mg, 7.9 .mu.mol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (4.6 mg, 7.9
.mu.mol), and in a microwave vial was flushed with nitrogen.
Dioxane (0.7 mL) was added and the vial was sealed and heated at
100.degree. C. for 3 hr. The reaction was diluted with EtOAc and
filtered through celite. The solvent was removed and radial silica
gel chromatography with hexane containing 5 to 40% EtOAc afforded
tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl)piperazine-1-carboxylate
(22 mg) as an oil.
[1601] MS (ESI) m/z 669.3 (M+1).
[1602] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.10-8.58 (m,
1H), 7.95 (s, 1H), 7.48 (d, J=1.8 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H),
6.85 (d, J=8.8 Hz, 2H), 5.78-5.58 (m, 1H), 3.82-3.77 (m, 3H), 3.71
(s, 2H), 3.65 (s, 2H), 3.52-3.44 (m, 4H), 3.04-2.83 (m, 1H), 2.48
(t, J=4.4 Hz, 4H), 1.50-1.46 (m, 9H), 1.20-1.07 (m, 2H), 0.92 (dd,
J=4.1, 1.1 Hz, 2H).
[1603] Example 403: A solution of tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl)piperazine-1-carboxylate
(22 mg, 0.033 mmol) and anisole (0.090 mL, 0.822 mmol) in DCM (0.5
mL) and TFA (0.5 mL) was left stirring at room temperature
overnight. The solvent was removed and the residue was dissolved in
MeOH and applied onto a SCX column. The column was washed with MeOH
and then eluted with 2 N NH.sub.3 in MeOH with DCM to give crude
2-((2-chloro-5-cyano-3-(piperazin-1-ylmethyl)phenyl)amino)-4-(cyclopropyl-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (15 mg). The
crude was dissolved in a mixture of DCM (0.25 mL) and MeOH (0.25
mL) and oxetan-3-one (48 mg, 0.67 mmol), trimethylorthoformate
(0.19 mL, 1.7 mmol), and acetic acid (0.019 mL, 0.33 mmol) were
added. After stirring for 15 min, sodium cyanoborohydride (1M in
THF, 0.33 mL, 0.33 mmol) was added and the reaction was left
stirring for 3 hrs. The reaction was partitioned between EtOAc and
sat. aq. NaHCO.sub.3 solution. After stirring for 15 min, the
aqueous phase was separated and washed with EtOAc. The combined
organic phases were washed with brine, dried with sodium sulfate,
and the solvent removed. Preparative HPLC (Column: Waters XBridge
C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A: water with
20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 20-mM ammonium acetate; Gradient: 20-100% B over 16 minutes,
then a 5-minute hold at 100% B; Flow: 20 mL/min) afforded the title
compound (5.9 mg, 39%). It was converted to the mono HCl salt.
[1604] MS (ESI) m/z 505.4
[1605] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 8.92 (br. s., 1H),
8.38 (s, 1H), 8.22 (s, 1H), 7.69-7.56 (m, 1H), 4.56 (br. s., 4H),
3.66 (br. s., 2H), 3.58-3.39 (m, 2H), 3.32-3.25 (m, 1H), 2.99-2.93
(m, 1H), 2.66-2.54 (m, 2H), 2.50-2.10 (m, 4H), 0.79 (d, J=5.5 Hz,
4H).
Example 404
##STR00465##
[1606]
2-((2-chloro-5-cyano-3-(morpholinomethyl)phenyl)amino)-4-(cycloprop-
ylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1607] (404A): A nitrogen sparged mixture of THF (1.6 mL) and water
(0.16 mL) was added to a nitrogen flushed mixture of
4-((difluoroboryl)methyl)morpholin-4-ium fluoride (0.112 g, 0.663
mmol), tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate
(Intermediate 1) (0.20 g, 0.603 mmol),
2-dicyclohexylphosphino-2'-4'-6'-trisisopropylbiphenyl (0.069 g,
0.15 mmol), Pd(OAc).sub.2 (0.016 g, 0.072 mmol), and
Cs.sub.2CO.sub.3 (0.590 g, 1.809 mmol) in a microwave vial. This
was sealed and heated at 80.degree. C. for 22 hr. The reaction was
extracted 3.times. with EtOAc and the combined organic extracts
were washed with brine and dried with sodium sulfate. Removal of
the solvent followed by silica gel radial chromatography eluting
with hexane containing to 30% EtOAc afforded tert-butyl
(2-chloro-5-cyano-3-(morpholinomethyl)phenyl)carbamate (46 mg) as a
film.
[1608] MS (ESI) m/z 352.2
[1609] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.50 (d, J=1.8
Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.18 (s, 1H), 3.77-3.71 (m, 4H),
3.60 (s, 2H), 2.55-2.49 (m, 4H), 1.56-1.54 (m, 9H).
[1610] (404B): A solution of tert-butyl
(2-chloro-5-cyano-3-(morpholinomethyl)phenyl)carbamate (45 mg,
0.128 mmol) in a mixture of DCM (2 mL) and TFA (2 mL) was left
stirring at room temperature for 1 hr. The solvent was removed and
the residue was dissolved in MeOH and applied onto an SCX column.
This was washed with MeOH and the product was eluted with 2N
NH.sub.3 in MeOH. The solvent was removed to leave
3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg).
[1611] MS (ESI) m/z 252.0
[1612] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.21 (d, J=2.0
Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 4.34 (br. s., 2H), 3.77-3.72 (m,
4H), 3.57 (s, 2H), 2.55-2.49 (m, 4H).
[1613] Example 404: A mixture of
3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg, 0.13
mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (47 mg, 0.13 mmol),
Cs.sub.2CO.sub.3 (85 mg, 0.262 mmol), DPPF (7.3 mg, 0.013 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (7.6 mg, 0.013 mmol)
in a microwave vial was flushed with nitrogen. Dioxane (1 mL) was
added and the vial was sealed and heated at 100.degree. C. for 4
hr. The reaction was diluted with EtOAc and filtered through
celite. The solvent was removed and radial silica gel
chromatography eluting with hexane containing 5 to 40% EtOAc
afforded
2-((2-chloro-5-cyano-3-(morpholinomethyl)phenyl)amino)-4-(cyclopropyl(4-m-
ethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (33
mg, 44% yield) as an oil. This was dissolved in DCM (1.5 mL) and
anisole (0.158 mL, 1.447 mmol) and TFA (0.9 mL) were added. After
stirring at room temperature overnight, the solvent was removed and
the residue was dissolved in MeOH and applied onto a SCX column.
This was washed with MeOH and then eluted with 2 N NH.sub.3 in MeOH
with DCM. Silica gel radial chromatography eluting with DCM
containing 1% MeOH gave the title compound (19 mg) as a white
solid.
[1614] MS (ESI) m/z 450.2
[1615] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.98 (d, J=2.0
Hz, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 6.87
(br. s., 1H), 3.80-3.73 (m, 4H), 3.66 (s, 2H), 3.06 (td, J=7.0, 3.5
Hz, 1H), 2.60-2.52 (m, 4H), 1.16-1.07 (m, 2H), 0.87-0.77 (m,
2H).
Example 405
##STR00466##
[1616]
2-((2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azeti-
din-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-
-carbonitrile
[1617] (405A): 1,3-Dibromo-2-chloro-5-(difluoromethoxy)benzene
(4.38 g, 13.02 mmol), tert-butyl carbamate (1.220 g, 10.42 mmol),
palladium(ii) acetate (0.146 g, 0.651 mmol), XANTPHOS (0.942 g,
1.628 mmol) and cesium carbonate (16.97 g, 52.1 mmol) were
suspended in dioxane (87 ml) at room temperature. The reaction
mixture was degassed through evacuating under vacuum and
backfilling with N.sub.2 (Repeated 3.times.) and heated to
105.degree. C. for 2 h. After cooling to room temperature, the
reaction mixture was diluted with EtOAc, filtered through celite
and concentrated. Column chromatography (120 g SiO.sub.2, 0 to 20%
EtOAc-hexane gradient elution) afforded tert-butyl
(3-bromo-2-chloro-5-(difluoromethoxy)phenyl)carbamate (2.79 g).
[1618] MS (ESI) m/z 372.1
[1619] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.13 (d, J=2.6
Hz, 1H), 7.18 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.9 Hz, 1H), 6.78-6.28
(m, 1H), 1.57 (s, 9H)
[1620] (405B): tert-Butyl
(3-bromo-2-chloro-5-(difluoromethoxy)phenyl)carbamate (2.78 g, 7.46
mmol) was dissolved in DMF (37.3 ml) at room temperature. NaHMDS
(8.95 ml, 8.95 mmol) was added drop wise and the reaction mixture
was stirred for 30 min before the addition of 4-methoxybenzyl
chloride (1.321 ml, 9.70 mmol). The reaction was allowed to stir
overnight. EtOAc (250 mL) was added and the organic layer was
washed with 10% LiCl solution (2.times., dried over
Na.sub.2SO.sub.4 and concentrated. Column chromatography (120 g
SiO2, 0 to 10% EtOAc-hexane gradient elution) afforded tert-butyl
(3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate
as a clear oil (2.68 g)
[1621] MS (ESI) m/z 435.9
[1622] (405C): 1-(Azetidin-3-yl)-4-methylpiperazine (95 mg, 0.609
mmol), tert-butyl
(3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate
(300 mg, 0.609 mmol), cesium carbonate (397 mg, 1.218 mmol),
Pd2(dba)3 (27.9 mg, 0.030 mmol) and BINAP (56.9 mg, 0.091 mmol)
were suspended in toluene (6088 .mu.l) at room temperature. The
reaction was degassed under vacuum and backfilled with N.sub.2 (4
times), and then heated to 105.degree. C. for 4 h. After cooling to
room temperature, the reaction mixture was diluted with EtOAc,
filtered through celite and concentrated. Column chromatography (24
g SiO2, 0 to 10% CH3OH--CH2Cl2 gradient elution) afforded
tert-butyl
(2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)-
phenyl)(4-methoxybenzyl)carbamate (213.1 mg).
[1623] MS (ESI) m/z 567.5
[1624] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.22-7.07 (m,
2H), 6.82 (d, J=8.6 Hz, 2H), 6.38-5.93 (m, 3H), 5.10 (d, J=15.0 Hz,
1H), 4.40-4.09 (m, 3H), 3.97-3.70 (m, 5H), 3.26 (t, J=6.5 Hz, 1H),
2.69-2.42 (m, 8H), 2.34 (s, 3H), 1.59-1.27 (m, 9H)
[1625] (405D): tert-butyl
(2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)-
phenyl)(4-methoxybenzyl)carbamate (210 mg, 0.370 mmol) was
dissolved in CH.sub.2Cl.sub.2 (3000 .mu.l). Anisole (405 .mu.l,
3.70 mmol) was added, followed by TFA (1000 .mu.L) and the reaction
mixture was stirred at room temperature overnight. After
concentrated, the residue was dissolved in MeOH and loaded on top
of a 5 g Phenomenex Cation exchange cartridge, washing with MeOH.
The desired product was eluted from the column using 7 N
NH.sub.3--CH.sub.3OH. Concentrated and drying afforded
2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)a-
niline (129 mg), palladium(ii) acetate as a light amber oil (129.2
mg).
[1626] MS (ESI) m/z 347.2
[1627] (405E):
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (120 mg, 0.338 mmol),
2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)a-
niline (129 mg, 0.372 mmol), palladium(ii) acetate (22.78 mg, 0.101
mmol), XANTPHOS (19.57 mg, 0.034 mmol), DPPF (18.75 mg, 0.034 mmol)
and CESIUM CARBONATE (220 mg, 0.676 mmol) were suspended in Dioxane
(3382 .mu.l) at rt. The reaction vessel was evacuated and purged
with N.sub.2 (4 times) and then heated to 105.degree. C. for 4 h.
After cooling to room temperature, the reaction mixture was diluted
with EtOAc, filtered through celite and concentrated. Column
chromatography (40 g SiO2, 0 to 10% CH.sub.3OH--CH.sub.2Cl.sub.2
gradient elution) gave
2-((2-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1--
yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (139.8 mg).
[1628] MS (ESI) m/z 665.5
[1629] Example 405:
2-((2-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1--
yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (140 mg, 0.210 mmol) was dissolved in DCE
(2105 .mu.l) at rt. Anisole (115 .mu.L) was added, followed by TFA
(400 .mu.L) and the reaction was heated to 50.degree. C. for 2 h.
After concentration, the crude compound was treated with 7 N
NH.sub.3--CH.sub.3OH and sonicated. The tan precipitate was
collected by filtration and further triturated with ACN to afford
the expected product as a cream solid (32.3 mg).
[1630] MS (ESI) m/z 545.4 (M+1).
[1631] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.27 (br. s.,
1H), 8.40-8.28 (m, 1H), 8.20 (d, J=0.9 Hz, 1H), 7.54-7.40 (m, 1H),
7.39-6.97 (m, 1H), 6.17 (d, J=2.6 Hz, 1H), 4.16 (t, J=7.5 Hz, 2H),
3.86-3.75 (m, 2H), 3.24-3.15 (m, 1H), 3.15-3.03 (m, 1H), 2.46-2.28
(m, 8H), 2.20 (d, J=1.3 Hz, 3H), 0.79 (d, J=5.7 Hz, 4H).
Example 406
##STR00467##
[1632]
2-(2-chloro-5-(difluoromethoxy)-3-morpholinophenylamino)-4-(cyclopr-
opylamino)imidazo[1,2-f][1,2,4]triazine-7-carbonitrile
[1633] Prepared in analogous manner as Example 405
[1634] MS (ESI) m/z 477.87
Example 407
##STR00468##
[1635]
2-((2-chloro-5-(difluoromethyl)-3-(1-(3-oxetanyl)-4-piperidinyl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[1636] Prepared in analogous manner as Example 242.
[1637] MS (ESI) m/z 514.97
Example 408
##STR00469##
[1638]
2-((2-chloro-5-cyano-3-(4-(3-oxetanyl)-1-piperazinyl)phenyl)amino)--
4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1639] Prepared using the procedure similar to Example 242.
[1640] MS (ESI) m/z 478.95
Example 409
##STR00470##
[1641]
2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)amino)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.H-
Cl
[1642] (409A): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (Example
357A) (300 mg, 0.624 mmol), tert-butyl
4-aminopiperidine-1-carboxylate (162 mg, 0.811 mmol),
Pd.sub.2(dba).sub.3 (28.6 mg, 0.031 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (36.1 mg, 0.062
mmol), and Cs.sub.2CO.sub.3 (610 mg, 1.872 mmol) in a dried
microwave vial was flushed with nitrogen. Dioxane (6 mL) was added
and the vial was sealed and heated at 95.degree. C. overnight. The
reaction was diluted with EtOAc and filtered through celite.
Removed solvent from the filtrate followed by radial silica gel
chromatography eluting with hexane containing 0 to 40% EtOAc to
give tert-butyl
4-((3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanopheny-
l)amino)piperidine-1-carboxylate (211 mg, 56% yield) as a foam.
This was dissolved in DCM (3 mL) and anisole (0.202 ml, 1.847 mmol)
and TFA (2 ml) were added. After 4 hr, the solvents were removed
and the residue was taken up in MeOH and applied onto an SCX
column. This was washed with MeOH, and then eluted with 2N NH.sub.3
in MeOH. Removal of the solvents followed by silica gel radial
chromatography with DCM containing 0 to 12% 2 N NH.sub.3 in MeOH
gave 3-amino-4-chloro-5-(piperidin-4-ylamino)benzonitrile (84
mg).
[1643] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 6.40 (d, J=1.8
Hz, 1H), 6.33 (d, J=1.7 Hz, 1H), 4.36 (d, J=7.8 Hz, 1H), 4.20 (br.
s., 2H), 3.43-3.33 (m, 1H), 3.15 (dt, J=12.9, 3.5 Hz, 2H),
2.80-2.71 (m, 2H), 2.10-2.02 (m, 2H), 1.47-1.37 (m, 2H).
[1644] (409B): A solution of
3-amino-4-chloro-5-(piperidin-4-ylamino)benzonitrile (54.8 mg,
0.219 mmol), Boc.sub.2O (53 mg, 0.240 mmol), and TEA (33.5 .mu.L,
0.240 mmol) in DCM (0.5 mL) was stirred at room temperature for 1
hr. The solvent was removed and radial silica gel chromatography
eluting with hexane containing 0 to 30% EtOAc afforded tert-butyl
4-((3-amino-2-chloro-5-cyanophenyl)amino)piperidine-1-carboxylate
(57.6 mg).
[1645] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.43 (d, J=1.8
Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 4.34 (d, J=7.8 Hz, 1H), 4.21 (s,
2H), 4.12-4.01 (m, 2H), 3.52-3.37 (m, 1H), 3.06-2.90 (m, 2H),
2.06-1.98 (m, 2H), 1.49 (s, 9H), 1.47-1.37 (m, 2H).
[1646] (409C): A mixture of tert-butyl
4-((3-amino-2-chloro-5-cyanophenyl)amino)piperidine-1-carboxylate
(57 mg, 0.16 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (58 mg, 0.16 mmol),
Cs.sub.2CO.sub.3 (106 mg, 0.325 mmol), DPPF (9 mg, 0.016 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (9 mg, 0.016 mmol),
and Pd(OAc).sub.2 (11 mg, 0.049 mmol) in a microwave vial was
flushed with nitrogen. Dioxane (3 mL) was added and the vial was
sealed and heated at 100.degree. C. for 3 hr. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed from the filtrate and radial silica gel chromatography with
DCM containing to 10% EtOAc afforded tert-butyl
4-((2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)piperidine-1-carboxylate
(74 mg, 68% yield) as a white solid. This was dissolved in DCM (1
mL) and anisole (0.238 mL, 2.18 mmol) and TFA (1 mL) were added.
After stirring at room temperature overnight, the solvent were
removed and the residue was applied onto a SCX column. This was
washed with MeOH and the crude product was eluted with 2 N NH.sub.3
in MeOH. Removal solvents followed by silica gel radial
chromatography eluting with DCM containing 0 to 5% 2N NH.sub.3 in
MeOH) afforded
2-((2-chloro-5-cyano-3-(piperidin-4-ylamino)phenyl)amino)-4-(-(cyclopropy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg, 0.085
mmol, 78% yield) as a white solid. This was suspended in a mixture
of MeOH (0.5 mL) and DCM (0.5 mL). Oxetan-3-one (117 mg, 1.62
mmol), triethylorthoformate (0.448 mL, 4.05 mmol), and acetic acid
(0.046 mL, 0.811 mmol) were added with stirring. After 15 min.
sodium cyanoborohydride (1 M in THF, 0.811 mL, 0.811 mmol) was
added and the reaction was left stirring for 4 hrs. It was
partitioned between EtOAc and sat. aq. NaHCO.sub.3 solution. After
stirring for 15 min, the aqueous phase was separated and washed
with EtOAc. The combined organic phases were washed with brine and
dried with sodium sulfate. Preparative HPLC (Column: Waters XBridge
C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A: water with
20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 20-mM ammonium acetate; Gradient: 20-100% B over 25 minutes,
then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title
compound (7.3 mg). This was converted to the mono HCl salt.
[1647] MS (ESI) m/z 505.2
[1648] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.32 (br. s., 1H),
8.65 (br. s., 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.73 (br. s., 1H),
7.03 (br. s., 1H), 5.78 (br. s., 1H), 4.89 (br. s., 2H), 4.68 (br.
s., 2H), 4.37 (br. s., 1H), 3.70 (br. s., 1H), 2.98 (br. s., 2H),
2.08 (br. s., 2H), 1.91 (br. s., 3H), 0.78 (br. s., 4H).
Example 410
##STR00471##
[1649]
2-((2-chloro-5-cyano-4-(piperidin-4-ylamino)phenyl)amino)-4-(cyclop-
ropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1650] (410A): Sodium bis(trimethylsilyl)amide (1M in THF, 37.0 mL,
37.0 mmol) was added to a solution of
5-amino-2-bromo-4-chlorobenzonitrile (3.43 g, 14.8 mmol) in dry THF
(75 ml) at 0.degree. C. After stirring for 15 min at 0.degree. C.,
a solution of di-tert-butyl dicarbonate (3.56 g, 16.3 mmol) in THF
(10 ml) was added. The reaction was allowed to warm to room
temperature overnight. Aqueous 0.1 N HCl was slowly added to bring
the pH to 10. The reaction was extracted twice with EtOAc and the
combined organic phases were washed with brine, dried over
Na.sub.2SO.sub.4. The solvent was removed and column chromatography
with hexane/EtOAc as eluent afforded tert-butyl
(4-bromo-2-chloro-5-cyanophenyl)carbamate (2.76 gm) as a white
solid.
[1651] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.65 (s, 1H),
7.69 (s, 1H), 7.06 (br. s., 1H), 1.57 (s, 9H).
[1652] (410B): A mixture of tert-butyl
(4-bromo-2-chloro-5-cyanophenyl)carbamate (150 mg, 0.452 mmol),
tert-butyl 4-aminopiperidine-1-carboxylate (118 mg, 0.588 mmol),
Pd.sub.2(dba).sub.3 (20.7 mg, 0.023 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (26 mg, 0.045 mmol),
and Cs.sub.2CO.sub.3 (442 mg, 1.36 mmol) in a dried microwave vial
was flushed with nitrogen. Dioxane (4 mL) was added and the vial
was sealed and heated at 95.degree. C. overnight. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed from the filtrate and radial silica gel chromatography of
eluting with hexane/EtOAc afforded tert-butyl
4-((4-((tert-butoxycarbonyl)amino)-5-chloro-2-cyanophenyl)amino)piperidin-
e-1-carboxylate (168 mg). This was dissolved in DCM (4 mL) and TFA
(4 mL) was added. After 1 hr, the solvent was removed and the
residue was dissolve in MeOH and applied onto an SCX column. After
washing with MeOH, the product was eluted with 2 N NH.sub.3 in
MeOH. Removal of the solvents left tert-butyl
4-((4-((tert-butoxycarbonyl)amino)-5-chloro-2-cyanophenyl)amino)piperidin-
e-1-carboxylate (89 mg) as an oil. A portion of this (49.6 mg,
0.198 mmol) was dissolved in DCM (1 mL) and Boc.sub.2O (0.051 ml,
0.218 mmol) and TEA (0.030 ml, 0.218 mmol) were added. After
stirred at room temperature for 1 hr, the solvent was removed and
radial silica gel chromatography with hexane containing 0 to 30%
EtOAc afforded tert-butyl
4-((4-amino-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate
(67 mg) as a yellow oil that solidified.
[1653] .sup.1H NMR (500 MHz, CHLOROFORM-d) d 6.85 (s, 1H), 6.67 (s,
1H), 4.09-3.98 (m, 2H), 3.38 (s, 1H), 2.93 (br. s., 2H), 2.03-1.96
(m, 2H), 1.47 (s, 9H), 1.43-1.34 (m, 2H).
[1654] Example 410: A mixture of
cyanophenyl)amino)piperidine-1-carboxylate (67 mg, 0.191 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (57 mg, 0.161 mmol),
Cs.sub.2CO.sub.3 (124 mg, 0.382 mmol), DPPF (10.6 mg, 0.019 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (11.1 mg, 0.019
mmol), and Pd(OAc).sub.2 (12.9 mg, 0.057 mmol) in a microwave vial
was flushed with nitrogen. Dioxane (4 mL) was added and the vial
was sealed and heated at 100.degree. C. for 3 hr. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed and radial silica gel chromatography with DCM containing 0
to 10% EtOAc afforded tert-butyl
4-((5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)piperidine-1-carboxylate
(94 mg, 74% yield) as a film. This was dissolved in DCM (1.5 mL)
and anisole (0.152 mL, 1.39 mmol) and TFA (1 mL) were added and
left stirring at room temperature overnight. The solvents were
removed and the residue was applied onto a SCX column. This was
washed with MeOH and the crude product was eluted with 2 N NH3 in
MeOH mixed with DCM. Removal of the solvent left 62 mg of impure
2-((2-chloro-5-cyano-4-(piperidin-4-ylamino)phenyl)amino)-4-(cyclopropyla-
mino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile. A sample was
purified by preparative HPLC
[1655] (Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min) to give the pure title compound.
[1656] MS (ESI) m/z 449.3
[1657] .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.18 (d, J=4.5 Hz,
1H), 8.70 (s, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.35 (s, 1H), 7.22
(s, 1H), 7.10 (s, 1H), 6.24 (d, J=8.0 Hz, 1H), 3.74 (d, J=7.5 Hz,
1H), 3.33 (d, J=11.8 Hz, 3H), 3.10-2.92 (m, 3H), 2.03 (d, J=12.5
Hz, 2H), 1.83-1.68 (m, 2H), 0.78-0.74 (m, 4H).
Example 411
##STR00472##
[1658]
2-((2-chloro-5-cyano-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1659] A suspension of
2-((2-chloro-5-cyano-4-(piperidin-4-ylamino)phenyl)amino)-4-(cyclopropyla-
mino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 410) (36
mg, 0.080 mmol), oxetan-3-one (116 mg, 1.604 mmol),
trimethylorthoformate (0.443 mL, 4.01 mmol), and acetic acid (0.046
mL, 0.802 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL) was
stirred at room temperature for 15 min. Sodium cyanoborohydride (1M
in THF, 0.802 mL, 0.802 mmol) was added and the reaction was left
stirring for 9 hrs. It was partitioned between EtOAc and sat. aq.
NaHCO.sub.3 solution. After stirring for 15 min, the aqueous phase
was separated and washed with EtOAc (3.times.) and then a mixture
of 10% MeOH in DCM (4.times.). The combined organic phases were
dried with sodium sulfate and the solvent removed. Preparative
HPLC
[1660] (Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: water with 20-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium
acetate; Gradient: 10-100% B over 30 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min) afforded the title compound (13
mg).
[1661] MS (ESI) m/z 505.3
[1662] .sup.1H NMR (500 MHz, DMSO-d6) d 9.15 (d, J=4.0 Hz, 1H),
8.66 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.80 (br. s., 1H), 7.06
(br. s., 1H), 4.86 (br. s., 2H), 4.67 (br. s., 2H), 4.36 (br. s.,
1H), 3.70 (br. s., 1H), 3.31-3.25 (m, 1H), 3.30-3.17 (m, 2H), 2.94
(d, J=4.3 Hz, 3H), 2.15-1.79 (m, 5H), 0.75 (br. s., 4H).
Example 412
##STR00473##
[1663]
2-((4-((2-aminoethyl)(methyl)amino)-2-chloro-5-cyanophenyl)amino)-4-
-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1664] (412A): A solution of tert-butyl
(4-bromo-2-chloro-5-cyanophenyl)carbamate (1.0 g, 3.02 mmol) in DMF
(10 mL) was cooled in an ice bath and NaHMDS (1 M solution in THF,
4.52 ml, 4.52 mmol) was added. After 20 min, 4-methoxybenzyl
chloride (0.616 ml, 4.52 mmol) was added and the reaction was
removed from the bath and left stirring at room temperature
overnight. The reaction was partitioned between EtOAc and sat. aq.
NH.sub.4Cl solution. The aqueous phase was extracted with EtOAc and
the combined organic extracts were washed with brine. After drying
with sodium sulfate, the solvents were removed and silica gel
chromatography with hexane containing 0 to 30% EtOAc afforded
tert-butyl
(4-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (1.04 g)
as a white solid.
[1665] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.75 (br. s.,
1H), 7.11 (d, J=8.5 Hz, 3H), 6.84 (d, J=7.9 Hz, 2H), 5.04 (d,
J=14.6 Hz, 1H), 4.29 (d, J=14.6 Hz, 1H), 3.82 (s, 3H), 1.56-1.31
(m, 9H).
[1666] (412B): A mixture of tert-butyl
(4-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (363 mg,
0.803 mmol), tert-butyl (2-(methylamino)ethyl)carbamate (182 mg,
1.05 mmol), Pd.sub.2(dba).sub.3 (51.5 mg, 0.056 mmol), BINAP (105
mg, 0.169 mmol), and Cs.sub.2CO.sub.3 (524 mg, 1.61 mmol) in a dry
microwave vial was flushed with nitrogen. Toluene (5 mL) was added
and the vial was sealed and heated at 100.degree. C. overnight. The
reaction was diluted with EtOAc and filtered through celite. The
solvent was removed from the filtrate and silica gel radial
chromatography eluting with hexane containing 5 to 30% EtOAc
afforded tert-butyl
(4-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)-2-chloro-5-cyanop-
henyl)(4-methoxybenzyl)carbamate (397 mg) as an oil.
[1667] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.17-6.89 (m,
4H), 6.82 (d, J=7.6 Hz, 2H), 5.04 (d, J=14.5 Hz, 1H), 4.85 (br. s.,
1H), 4.17 (d, J=14.6 Hz, 1H), 3.81 (s, 3H), 3.58-3.33 (m, 4H), 3.02
(br. s., 3H), 1.61-1.32 (m, 18H).
[1668] (412C): TFA (4 mL) was added to a solution of tert-butyl
(4-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)-2-chloro-5-cyanop-
henyl)(4-methoxybenzyl)carbamate (397 mg, 0.728 mmol) and anisole
(1.59 ml, 14.8 mmol) in DCM (5 ml) at room temperature for 3 hr.
The solvents were removed and the residue was taken up in MeOH,
applied onto an SCX column. This was washed with MeOH and then
eluted with 2N NH.sub.3 in MeOH. Removal of the solvents left
5-amino-2-((2-aminoethyl)(methyl)amino)-4-chlorobenzonitrile as an
oil.
[1669] MS (ESI) m/z 225.1
[1670] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.04 (s, 1H),
6.95 (s, 1H), 4.05 (br. s., 2H), 3.11 (t, J=6.3 Hz, 2H), 2.89 (t,
J=6.3 Hz, 2H), 2.80 (s, 3H), 1.52 (br. s., 2H).
[1671] (412D): A solution of
5-amino-2-((2-aminoethyl)(methyl)amino)-4-chlorobenzonitrile (153
mg, 0.681 mmol), Boc.sub.2O (163 mg, 0.749 mmol), and TEA (104
.mu.L, 0.749 mmol) in DCM (1 mL) was stirred at room temperature
for 2 hr. The solvent was removed and radial silica gel
chromatography with hexane containing 0 to 30% EtOAc afforded
tert-butyl
(2-((4-amino-5-chloro-2-cyanophenyl)(methyl)amino)ethyl)carbamate
(207 mg) as an oil.
[1672] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.03 (s, 1H),
6.96 (s, 1H), 4.96 (br. s., 1H), 4.04 (s, 2H), 3.35 (q, J=6.0 Hz,
2H), 3.22-3.16 (m, 2H), 2.82 (s, 3H), 1.44 (s, 9H).
[1673] (412E): A mixture of tert-butyl
(2-((4-amino-5-chloro-2-cyanophenyl)(methyl)amino)ethyl)carbamate
(207 mg, 0.637 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (226 mg, 0.637 mmol),
Cs.sub.2CO.sub.3 (415 mg, 1.28 mmol), DPPF (35.3 mg, 0.064 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (36.9 mg, 0.064
mmol), and Pd(OAc).sub.2 (42.9 mg, 0.191 mmol) in a microwave vial
was flushed with nitrogen. Dioxane (9 mL) was added and the vial
was sealed and heated at 100.degree. C. for 4 hr. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed and radial silica gel chromatography with hexane containing
5 to 40% EtOAc afforded tert-butyl
(2-((5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)im-
idazo[2,1-f][1,2,4]triazin-2
yl)amino)phenyl)(methyl)amino)ethyl)carbamate (283 mg) as an
oil.
[1674] MS (ESI) m/z 643.3
[1675] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.79 (br. s.,
1H), 7.95-7.88 (m, 1H), 7.19 (d, J=8.5 Hz, 2H), 7.16-6.98 (m, 2H),
6.85 (d, J=8.7 Hz, 2H), 5.85-5.53 (m, 1H), 4.88 (br. s., 1H), 3.79
(s, 3H), 3.41 (d, J=2.9 Hz, 4H), 2.97 (s, 3H), 2.94-2.81 (m, 1H),
1.52-1.38 (m, 9H), 1.13 (d, J=4.0 Hz, 2H), 0.93-0.82 (m, 2H).
[1676] Example 412: A solution of tert-butyl
(2-((5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)im-
idazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)(methyl)amino)ethyl)carbamate
(283 mg, 0.440 mmol) and anisole (0.481 mL, 4.40 mmol) in DCM (3
mL) and TFA (3 mL) was left stirring at room temperature overnight.
The solvents were removed and the residue was dissolved in MeOH and
applied onto a SCX column. This was washed with MeOH and then
eluted with 2 N NH.sub.3 in MeOH mixed with DCM. Removal of the
solvents followed by silica gel radial chromatography eluting with
DCM containing 0 to 5% 2N NH.sub.3 in MeOH afforded the title
compound (146 mg) as oil that solidified.
[1677] MS (ESI) 423.1
[1678] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.79 (s, 1H),
7.84 (s, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 6.95 (br. s., 1H), 3.37
(t, J=6.5 Hz, 2H), 3.08-3.00 (m, 3H), 2.98 (s, 3H), 1.60-1.30 (m,
2H), 1.12-1.07 (m, 2H), 0.83-0.77 (m, 2H).
Example 413
##STR00474##
[1679]
2-((2-chloro-5-cyano-4-(methyl(2-(oxetan-3-ylamino)ethyl)amino)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1680] A solution of
2-((4-((2-aminoethyl)(methyl)amino)-2-chloro-5-cyanophenyl)amino)-4-(cycl-
opropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example
412) (63 mg, 0.149 mmol), oxetan-3-one (215 mg, 2.98 mmol),
trimethylorthoformate (0.823 mL, 7.45 mmol), and acetic acid (0.085
mL, 1.490 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL) was
stirred at room temperature for 15 min. Added sodium
cyanoborohydride (1M in THF, 1.49 mL, 1.49 mmol) and left the
reaction stirring for 3 hrs. The reaction was partitioned between
EtOAc and sat. aq. NaHCO.sub.3 solution. After stirring for 15 min,
the aqueous phase was separated and washed with EtOAc. The combined
organic phases were washed with brine, dried with sodium sulfate,
and the solvent removed. Preparative HPLC (Column: Waters XBridge
C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A: water with
20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 20-mM ammonium acetate; Gradient: 20-60% B over 20 minutes,
then a 5-minute hold at 100% B; Flow: 20 mL/min) afforded the title
compound (10 mg).
[1681] MS (ESI) m/z 379.2
[1682] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.22 (br. s., 1H),
8.75 (br. s., 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.19 (s, 1H), 4.61
(t, J=6.6 Hz, 2H), 4.29 (t, J=6.3 Hz, 2H), 3.88 (quin, J=6.4 Hz,
1H), 3.41-3.37 (m, 2H), 3.00-2.93 (m, 4H), 2.72 (t, J=7.0 Hz, 2H),
0.78 (d, J=5.5 Hz, 4H).
Example 414
##STR00475##
[1683]
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2-
,1-f][1,2,4]triazine-7-carbonitrile
[1684] (414A): A suspension of 2,4-difluoro-5-nitrobenzonitrile
(1.0 g, 5.43 mmol) and Pd/C 10% (0.1 g, 0.94 mmol) in MeOH (20 mL)
was hydrogenated (balloon) for 5 hr. This was filtered and the
solvent was removed. Flash chromatography on silica gel eluting
with hexane containing 20% EtOAc gave
5-amino-2,4-difluorobenzonitrile (0.59 g) as a light yellow
solid.
[1685] MS (ESI) 155.0
[1686] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 6.98 (dd, J=9.1,
6.0 Hz, 1H), 6.93 (dd, J=10.5, 8.5 Hz, 1H), 3.84 (br. s., 2H).
[1687] (414B): A mixture of 5-amino-2,4-difluorobenzonitrile (300
mg, 1.947 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (691 mg, 1.947 mmol),
Cs.sub.2CO.sub.3 (1268 mg, 3.89 mmol), DPPF (108 mg, 0.195 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (113 mg, 0.195
mmol), and Pd(OAc).sub.2 (131 mg, 0.584 mmol) in a microwave vial
was flushed with nitrogen. Dioxane (16 mL) was added and the vial
was sealed and heated at 100.degree. C. for 4 hr. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed and radial silica gel chromatography eluting with hexane
containing 5 to 40% EtOAc afforded
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amin-
o)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (799 mg) as a
foam.
[1688] Example 414: A portion of
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amin-
o)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (61 mg, 0.129 mmol)
was dissolved in DCM (1.5 mL) and anisole (0.141 mL, 1.291 mmol)
and TFA (1 mL) was added. After stirring at room temperature
overnight, the solvents were removed. Preparative HPLC (Column:
Waters XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile
Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5
acetonitrile: water with 20-mM ammonium acetate; Gradient: 30-100%
B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min)
afforded the title compound (36 mg).
[1689] MS (ESI) m/z 353.1
[1690] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.36 (br. s., 2H),
8.47 (t, J=7.6 Hz, 1H), 8.20 (s, 1H), 7.74 (t, J=10.1 Hz, 1H), 2.96
(d, J=4.6 Hz, 1H), 0.88-0.49 (m, 4H).
Example 415
##STR00476##
[1691]
2-((5-cyano-2-fluoro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)oxy)ph-
enyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitri-
le
[1692] (415A): DMAP (10.3 mg, 0.085 mmol) was added to a solution
of
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amin-
o)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 414B) (200
mg, 0.423 mmol), TEA (0.089 mL, 0.635 mmol) and Boc.sub.2O (148 mg,
0.677 mmol) in THF (1 mL) at room temperature. After 15 min, the
reaction was diluted with EtOAc, washed with water followed by
brine. After drying with sodium sulfate, the solvent was removed
and silica gel radial chromatography eluting with hexane containing
10 to 30% EtOAc afforded tert-butyl
(5-cyano-2,4-difluorophenyl)(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino-
)imidazo[2,1-f][1,2,4]triazin-2-yl)carbamate (203 mg) as a
foam.
[1693] MS (ESI) m/z 573.2
[1694] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.09-7.94 (m,
1H), 7.74-7.41 (m, 1H), 7.23-6.62 (m, 4H), 5.71-5.49 (m, 1H), 4.72
(br. s., 1H), 3.81 (d, J=11.3 Hz, 2H), 3.90-3.72 (m, 3H), 3.68-2.43
(m, 1H), 1.57-1.53 (m, 9H), 0.88 (br. s., 4H).
Example 415
[1695] NaH (60% in mineral oil, 13.4 mg, 0.335 mmol) was added to a
solution of 1,2,2,6,6-pentamethylpiperidin-4-ol (53.8 mg, 0.314
mmol) in dry DMF (1 mL) at room temperature. After stirring for 30
min, added solid tert-butyl
(5-cyano-2,4-difluorophenyl)(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino-
)imidazo[2,1-f][1,2,4]triazin-2-yl)carbamate (60 mg, 0.11 mmol).
After 0.5 hr. Saturated. aq. NH.sub.4Cl solution was added and the
reaction was extracted with DCM. The organic phase was washed with
water and dried with sodium sulfate. After removal of the solvent,
the crude tert-butyl
(5-cyano-2-fluoro-4-((1,2,2,6,6-pentamethylpiperidin-4-yl)oxy)phenyl)(7-c-
yano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-y-
l)carbamate (76 mg) was dissolved in DCM (1.5 mL) and anisole
(0.287 mL, 2.62 mmol) and TFA (1.5 mL) were added. After stirring
at room temperature overnight, the solvent was removed and the
residue was dissolved in MeOH and applied onto a SCX column. The
column was washed with MeOH and the crude product was eluted with 2
N NH.sub.3 in MeOH mixed with DCM. Removal of the solvents followed
by silica gel radial chromatography eluting with DCM containing 0
to 6% MeOH afforded the title compound (16.8 mg) as a film.
[1696] MS (ESI) m/z 504.2
[1697] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.77 (d, J=9.0
Hz, 1H), 7.85 (s, 1H), 6.94 (d, J=2.6 Hz, 1H), 6.80 (d, J=12.5 Hz,
2H), 4.55 (tt, J=11.0, 4.0 Hz, 1H), 3.02 (dd, J=7.0, 3.7 Hz, 1H),
2.31 (s, 3H), 2.02 (d, J=3.8 Hz, 2H), 1.74 (t, J=11.6 Hz, 2H), 1.24
(s, 5H), 1.27-1.22 (m, 6H), 1.15 (s, 6H), 1.12-1.08 (m, 2H),
0.83-0.78 (m, 2H).
Example 416
##STR00477##
[1698]
2-((5-cyano-2-fluoro-4-(2-morpholinoethoxy)phenyl)amino)-4-(cyclopr-
opylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1699] The title compound was obtained as the major product from
the reaction between tert-butyl
(5-cyano-2,4-difluorophenyl)(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino-
)-imidazo[2,1-f][1,2,4]triazin-2-yl)carbamate (Example 414B) and
2-morpholinoethanol according to the procedure described in Example
415.
[1700] MS (ESI) m/z 464.2
[1701] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.32-9.26 (m, 1H),
9.22-9.14 (m, 1H), 8.29-8.22 (m, 1H), 8.21-8.16 (m, 1H), 7.48-7.39
(m, 1H), 4.60 (br. s., 2H), 3.99 (br. s., 2H), 3.80 (br. s., 2H),
3.69-3.49 (m, 4H), 3.31-3.22 (m, 2H), 2.96 (d, J=4.3 Hz, 1H),
0.82-0.76 (m, 4H).
Example 417
##STR00478##
[1702]
(S)-2-((5-cyano-2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1703] The title compound was similarly obtained as the major
product from the reaction between tert-butyl
(5-cyano-2,4-difluorophenyl)(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino-
)-imidazo[2,1-f][1,2,4]triazin-2-yl)carbamate (Example 414B) and
(R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate according
to the procedure described in Example 416 followed by removal of
the Boc protecting group with TFA.
[1704] MS (ESI) m/z 450.4 (M+1).
[1705] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.31-9.27 (m, 1H),
9.20-9.17 (m, 1H), 8.28-8.23 (m, 1H), 8.21-8.17 (m, 1H), 7.51-7.44
(m, 1H), 4.41 (d, J=5.2 Hz, 2H), 4.09 (d, J=11.3 Hz, 1H), 3.94 (d,
J=12.5 Hz, 1H), 3.75-3.66 (m, 2H), 3.29 (br. s., 2H), 3.22-3.12 (m,
1H), 2.96 (d, J=4.6 Hz, 1H), 0.79 (br. s., 4H).
Example 418
##STR00479##
[1706]
2-((5-cyano-2-fluoro-4-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1707] The title compound was similarly obtained as the major
product from the reaction between tert-butyl
(5-cyano-2,4-difluorophenyl)(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino-
)-imidazo[2,1-f][1,2,4]triazin-2-yl)carbamate (Example 414B) and
2,2,6,6-tetramethylpiperidin-4-ol according to the procedure
described in Example 416.
[1708] MS (ESI) m/z 464.2
[1709] .sup.1H NMR (500 MHz, DMSO-d6) d 9.31-9.28 (m, 1H),
9.20-9.16 (m, 1H), 8.28-8.23 (m, 1H), 8.20-8.17 (m, 1H), 7.56-7.49
(m, 1H), 5.19-5.09 (m, 1H), 2.97 (d, J=5.2 Hz, 1H), 2.20 (d, J=10.4
Hz, 2H), 1.79-1.70 (m, 2H), 1.51 (s, 6H), 1.49 (s, 6H), 0.79 (d,
J=5.5 Hz, 4H).
Example 419
##STR00480##
[1710]
2-((5-cyano-4-fluoro-2-((1,2,2,6,6-pentamethylpiperidin-4-yl)oxy)ph-
enyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitri-
le
[1711] NaH (60% in mineral oil, 18 mg, 0.45 mmol) added to a
solution of 1,2,2,6,6-pentamethylpiperidin-4-ol (73 mg, 0.43 mmol)
in dry DMF (1 mL) at room temperature. This was left stirring for
30 min and then solid
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile (Example 414) (50 mg, 0.14 mmol) was
added. The reaction was left stirring at room temperature for 3/4
hr and then heated at 55.degree. C. for 7 hr. It was quenched with
sat. aq. NH.sub.4Cl solution (0.5 mL) and diluted with DCM. After
washing with water (3.times.), the organic phase was dried with
sodium sulfate. The solvent was removed and radial silica gel
chromatography with DCM containing 0 to 3% MeOH and then 1 to 4% 2N
NH.sub.3 in MeOH afforded the title compound (37 mg) as a
glass.
[1712] MS (ESI) m/z 504.2
[1713] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.91 (d, J=7.0
Hz, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 6.80-6.70 (m, 2H), 4.73-4.64
(m, 1H), 3.07 (tq, J=7.0, 3.6 Hz, 1H), 2.32 (s, 3H), 2.09 (dd,
J=12.4, 4.0 Hz, 2H), 1.81-1.75 (m, 2H), 1.27 (s, 6H), 1.18 (s, 6H),
1.14-1.09 (m, 2H), 0.85-0.78 (m, 2H).
Example 420
##STR00481##
[1714]
2-((5-cyano-2,4-bis((1,2,2,6,6-pentamethylpiperidin-4-yl)oxy)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1715] The title compound was obtained as minor product (10 mg)
during the preparation of Example 419.
[1716] MS (ESI) m/z 555.5
[1717] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.24 (br. s., 1H),
8.29 (br. s., 1H), 8.17 (br. s., 2H), 7.00 (br. s., 1H), 5.10 (br.
s., 2H), 3.02 (br. s., 1H), 2.73 (br. s., 4H), 2.45-1.75 (m, 10H),
1.34 (br. s., 24H), 0.80 (d, J=12.5 Hz, 4H).
Example 421
##STR00482##
[1718]
2-((5-cyano-4-fluoro-2-(2-morpholinoethoxy)phenyl)amino)-4-(cyclopr-
opylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1719] The title compound was obtained as the major product (34)
from the reaction between
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile (Example 414) and 2-morpholinoethanol
according to the procedure described in Example 419.
[1720] MS (ESI) m/z 464.4
[1721] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.36 (d, J=3.4 Hz,
1H), 8.68 (br. s., 1H), 8.51 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 7.41
(d, J=11.0 Hz, 1H), 4.59 (br. s., 2H), 4.02-3.77 (m, 4H), 3.71-3.46
(m, 4H), 3.19 (br. s., 2H), 3.02 (d, J=3.1 Hz, 1H), 0.86-0.76 (m,
4H).
Example 422
##STR00483##
[1722]
2-((5-cyano-2,4-bis(2-morpholinoethoxy)phenyl)amino)-4-(cyclopropyl-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1723] The title compound was obtained as the minor product (33)
from the reaction between
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile (Example 414) and 2-morpholinoethanol
according to the procedure described in Example 419.
[1724] MS (ESI) m/z 575.5.2
[1725] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.26 (br. s., 1H),
8.36 (br. s., 1H), 8.27 (br. s., 1H), 8.18 (s, 1H), 4.45 (br. s.,
4H), 3.92-3.54 (m, 9H), 3.93-3.52 (m, 10H), 3.28-2.53 (m, 11H),
0.78 (br. s., 4H).)
Example 423
##STR00484##
[1726]
2-((5-cyano-4-fluoro-2-(piperidin-4-yloxy)phenyl)amino)-4-(cyclopro-
pylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1727] The title compound was obtained as the major product from
the reaction between
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile (Example 414) and tert-butyl
4-hydroxypiperidine-1-carboxylate according to the procedure
described in Example 419 and the subsequent removal of the Boc
protecting group with TFA.
[1728] MS (ESI) m/z 434.1 (M+1).
[1729] .sup.1H NMR (500 MHz, METHANOL-d4) .delta. 8.81 (d, J=7.2
Hz, 1H), 7.96 (s, 1H), 7.12 (d, J=10.8 Hz, 1H), 4.76-4.68 (m, 1H),
3.19-3.10 (m, 2H), 3.05 (dt, J=7.3, 3.5 Hz, 1H), 2.80 (ddd, J=13.0,
9.8, 3.0 Hz, 2H), 2.19-2.07 (m, 2H), 1.87-1.75 (m, 2H), 1.04-0.94
(m, 2H), 0.85-0.75 (m, 2H).
Example 424
##STR00485##
[1730]
(S)-2-((5-cyano-4-fluoro-2-(morpholin-3-ylmethoxy)phenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1731] The title compound was obtained as the major product from
the reaction between
2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile (Example 414) and (R)-tert-butyl
3-(hydroxymethyl)morpholine-4-carboxylate according to the
procedure described in Example 423.
[1732] MS (ESI) m/z 450.3
Example 425
##STR00486##
[1733]
2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)a-
mino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1734] (425A): Sodium triacetoxyborohydride (3.18 g, 15.00 mmol)
and acetic acid (0.859 mL, 15.00 mmol) were added to a solution of
piperidin-4-ol (1.011 g, 10 mmol) and oxetan-3-one (0.721 g, 10.00
mmol) in DCE (35 mL) and the reaction mixture was stirred at room
temperature overnight. Celite was added to the sticky reaction
mixture and the reaction mixture was filtered, the filtrate was
concentrated in vacuo to give brown oil. The solid was purified by
flash chromatography on silica gel using an automated ISCO system
(120 g column, eluting with 0-8% 2 N ammonia in
methanol/dichloromethane). 1-(oxetan-3-yl)piperidin-4-ol (0.80 g)
was obtained as a white solid.
[1735] (425B): A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (5 g,
27.3 mmol), hydroxylamine hydrochloride (2.467 g, 35.5 mmol),
p-toluenemethanesulfonic acid (0.779 g, 4.10 mmol) and magnesium
sulfate (26.3 g, 218 mmol) in toluene (25 ml) was heated at reflux
for 6 hours. The reaction mixture was cooled to room temperature;
the reaction mixture was partitioned between ethyl acetate and
water. The layers were separated and aqueous layer was extracted
with ethyl acetate two more times. The combined organic layers were
washed with water and brine, dried over magnesium sulfate, filtered
and concentrated in vacuo to a small volume and a brown precipitate
formed. The precipitate was collected by filtration and after
drying under vacuum to give 4.1 g of
4-chloro-3-hydroxy-5-nitrobenzonitrile.
[1736] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.19 (s, 1H),
10.45 (br. s., 2H), 8.07 (s, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.39 (d,
J=1.9 Hz, 1H)
[1737] (425C): DIAD (0.368 mL, 1.781 mmol) was added to a solution
of 4-chloro-3-hydroxy-5-nitrobenzonitrile (265 mg, 1.336 mmol),
1-(oxetan-3-yl)piperidin-4-ol (200 mg, 1.272 mmol) and
triphenylphosphine resin (3 mmol/g loading, 890 mg, 2.672 mmol) in
THF (5 mL) and the reaction mixture was stirred at room temperature
overnight. The reaction mixture was filtered and the filtrate was
concentrated. The crude containing
4-chloro-3-nitro-5-(1-(oxetan-3-yl)piperidin-4-yloxy)benzonitrile
was carried forward without purification.
[1738] (425D): A mixture of
4-chloro-3-nitro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile
(430 mg, 1.272 mmol) and Pd/C (271 mg, 0.127 mmol) in methanol (20
mL) was hydrogenated at 20 PSI for 1.5 h. The reaction mixture was
filtered through a pad of celite and the filtrate was concentrated
in vacuo. The crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g gold column,
eluting with 1-5% 2 N ammonia in methanol/dichloromethane).
3-amino-4-chloro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile
(50 mg) was obtained as a foaming solid.
[1739] MS (ESI) m/z 308.3
[1740] (425E): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (57.6 mg, 0.162 mmol),
3-amino-4-chloro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile
(50 mg, 0.162 mmol), palladium(II) acetate (9.67 mg, 0.043 mmol),
xantphos (9.40 mg, 0.016 mmol), DPPF (9.01 mg, 0.016 mmol) and
cesium carbonate (138 mg, 0.422 mmol) in dioxane (1 ml) was
evacuated and back filled with nitrogen three time and was heated
at 60.degree. C. for 2 h. The reaction mixture was filtered through
a pad of celite, the filtrate was concentrated and the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (24 g gold column, eluting with 0-6% 2 N
ammonia in methanol/dichloromethane). Compound from ISCO was
suspended in methanol (1 ml) and the white precipitate was
collected by filtration.
2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)--
4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile (50 mg) was obtained as a white solid.
[1741] MS (ESI) m/z 626.4 (M+H)
[1742] .sup.1H NMR (500 MHz, mixture of methanol-d4/chloroform-d)
.delta. 7.99 (s, 1H), 7.57 (s, 1H), 7.20 (d, J=8.3 Hz, 2H), 6.97
(d, J=1.7 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 4.76-4.70 (m, 2H), 4.64
(t, J=6.2 Hz, 2H), 3.77 (s, 3H), 3.57 (quin, J=6.5 Hz, 1H), 2.57
(t, J=8.5 Hz, 2H), 2.36 (br. s., 2H), 2.09-2.00 (m, 2H), 1.99-1.91
(m, 2H), 1.10 (d, J=6.4 Hz, 2H), 0.94-0.89 (m, 2H)
[1743] Example 425: TFA (25% in DCE, 2 ml, 6.49 mmol) was added to
a solution of
2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)--
4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile (50 mg, 0.080 mmol) and anisole (0.035 ml, 0.319 mmol) in
DCE (1 mL) and the reaction mixture was heated at 45.degree. C. for
3 hours. Solvent was evaporated in vacuo and the residue was dried
under vacuum overnight. The residue was washed with hexane
(2.times.2 ml), dissolved in acetonitrile (2 ml) and 2N ammonia in
methanol was added to give a suspension. Solvent was evaporated
until a very small amount and the precipitate was collected by
filtration.
2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(27 mg) was obtained as a white solid.
[1744] MS (ESI) m/z 506.4
[1745] .sup.1H NMR (500 MHz, mixture of methanol-d4/chloroform-d)
.delta. 8.67 (d, J=1.4 Hz, 1H), 7.92 (s, 1H), 6.99 (d, J=1.7 Hz,
1H), 4.76-4.69 (m, 2H), 4.65 (t, J=6.2 Hz, 2H), 3.58 (quin, J=6.5
Hz, 1H), 3.05 (tt, J=7.2, 3.7 Hz, 1H), 2.58 (t, J=8.3 Hz, 2H), 2.37
(d, J=4.4 Hz, 2H), 2.11-2.01 (m, 2H), 2.01-1.92 (m, 2H), 1.06-0.98
(m, 2H), 0.84-0.77 (m, 2H)
Example 426
##STR00487##
[1746]
(+/-)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)p-
henyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitr-
ile
[1747] (426A): DIAD (0.309 mL, 1.495 mmol) was added to a solution
of 4-chloro-3-hydroxy-5-nitrobenzonitrile (Example 425B) (223 mg,
1.122 mmol), (+/-)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate
(200 mg, 1.068 mmol) and triphenylphosphine resin (3 mmol/g
loading, 560 mg, 2.136 mmol) in THF (5 mL) and the reaction mixture
was stirred at room temperature overnight. The reaction mixture was
filtered and the filtrate was concentrated, the crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (40 g column, eluting with 0-20% ethyl
acetate/dichloromethane). (+/-)-tert-butyl
3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (272
mg) was obtained as a yellow solid.
[1748] MS (ESI) m/z 389.9
[1749] (426B): A mixture of (+/-)-tert-butyl
3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (278
mg, 0.756 mmol) and Pd/C (80 mg, 0.038 mmol) in Methanol (20 mL)
was hydrogenated at 20 psi for 2 h. The reaction mixture was
filtered through a pad of celite and the filtrate was concentrated.
The crude product was purified by flash chromatography on silica
gel using an automated ISCO system (40 g column, eluting with 5-60%
ethyl acetate/hexanes) to give (+/-)-tert-butyl
3-(3-amino-2-chloro-5-cyanophenoxy)pyrrolidine-1-carboxylate (48
mg).
[1750] MS (ESI) m/z 360.0
[1751] .sup.1H NMR (500 MHz, chloroform-d) .delta. 6.72 (br. s.,
1H), 6.52 (d, J=1.1 Hz, 1H), 4.91 (br. s., 1H), 4.44 (br. s., 2H),
3.68-3.50 (m, 4H), 2.21 (br. s., 2H), 1.49 (s, 9H)
[1752] (426C): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (50 mg, 0.141 mmol),
(+/-)-tert-butyl
3-(3-amino-2-chloro-5-cyanophenoxy)pyrrolidine-1-carboxylate (47.6
mg, 0.141 mmol), palladium(II) acetate (8.38 mg, 0.037 mmol),
Xantphos (8.15 mg, 0.014 mmol), DPPF (7.81 mg, 0.014 mmol) and
cesium carbonate (119 mg, 0.366 mmol) in dioxane (1 ml) was
evacuated and back filled with nitrogen three time and was heated
at 70.degree. C. for 3 h. The reaction mixture was filtered through
a pad of celite, the filtrate was concentrated, the crude product
was purified by flash chromatography on silica gel using an
automated ISCO system (40 g gold column, eluting with 0-40% ethyl
acetate/dichloromethane). (+/-)-tert-butyl
3-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenoxy)pyrrolidine-1-carboxylate
(60 mg) was obtained as a colorless oil which was carried as such
to the next reaction.
[1753] MS (ESI) m/z 656.0
[1754] (426D): (+/-)-tert-butyl
3-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenoxy)pyrrolidine-1-carboxylate
(60 mg, 0.091 mmol) was treated with TFA (25% in DCE, 2 ml, 6.49
mmol) at room temperature for 1 h. The reaction mixture was diluted
with dichloromethane and washed with saturated sodium
bicarbonate/1N sodium hydroxide (pH 10). The aqueous layer was
extracted with dichloromethane/methanol (4/1) two more times. The
combined organic layers were dried over magnesium sulfate, filtered
and concentrated in vacuo; the crude product (36 mg) was used in
next reaction without purification.
[1755] MS (ESI) m/z 556.1
[1756] (426E): A mixture of
(+/-)-2-((2-chloro-5-cyano-3-(pyrrolidin-3-yloxy)phenyl)amino)-4-(cyclopr-
opyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(36 mg, 0.065 mmol), oxetan-3-one (8.30 .mu.l, 0.129 mmol), acetic
acid (7.41 .mu.l, 0.129 mmol) and molecular sieves (30 mg) in
dichloromethane (1 mL)/Methanol (1 mL) was stirred at room
temperature overnight. Sodium cyanoborohydride (12.21 mg, 0.194
mmol) was added and the reaction mixture was stirred for 1 h. The
reaction mixture was filtered through a plug of celite and the
filtrate was concentrated. The crude product (38 mg) was used
without purification.
[1757] MS (ESI) m/z 612.0
[1758] Example 426: TFA (25% in DCE, 2 ml, 26.0 mmol) was added to
a solution of
(+/-)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)phenyl)-
amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine--
7-carbonitrile (38 mg, 0.062 mmol) and anisole (0.027 ml, 0.248
mmol) in DCE (1 mL) and the reaction mixture was heated at
60.degree. C. for 2 hours. Solvent was evaporated in vacuo and the
residue was dried under vacuum overnight. The crude was trituated
with hexane 3.times.1 ml, dissolved in acetonitrile and neutralized
with 2N ammonia in methanol. Solvent was evaporated to give a solid
which was purified by flash chromatography on silica gel using an
automated ISCO system (24 g gold column, eluting with 1-4% 2 N
ammonia in methanol/dichloromethane).
(+/-)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)phenyl)-
amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(22 mg) was obtained as a white solid.
[1759] MS (ESI) m/z 492.0 (M+H)
[1760] .sup.1H NMR (500 MHz, mixture of methanol-d4/chloroform-d)
.delta. 8.69 (d, J=1.7 Hz, 1H), 7.92 (s, 1H), 6.89 (d, J=1.7 Hz,
1H), 5.05-4.96 (m, 1H), 4.77 (td, J=6.7, 1.7 Hz, 2H), 4.67 (dt,
J=12.6, 6.2 Hz, 2H), 3.88-3.80 (m, 1H), 3.11 (dd, J=11.1, 6.1 Hz,
1H), 3.05 (tt, J=7.2, 3.7 Hz, 1H), 2.88-2.80 (m, 2H), 2.70 (ddd,
J=9.2, 7.5, 5.3 Hz, 1H), 2.39 (dq, J=14.1, 7.2 Hz, 1H), 2.16-2.07
(m, 1H), 1.06-1.00 (m, 2H), 0.83-0.78 (m, 2H)
Example 427
##STR00488##
[1761]
2-((2-chloro-5-cyano-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-
phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile
[1762] (427A): A solution of piperidin-4-ol (100 mg, 0.989 mmol)
and 3-((phenylsulfonyl)methylene)oxetane (prepared according to a
published literature procedure: Wuitschik et al. J. Med. Chem.
53(8) 3227-3246, 2010, 416 mg, 1.977 mmol) in methanol (5 mL) was
heated at 50.degree. C. for 20 h. Solvent was evaporated in vacuo
and the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 0-8% 2 N ammonia in methanol/dichloromethane).
1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-ol (300 mg)
was obtained as a colorless oil.
[1763] MS (ESI) m/z 312.0
[1764] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.95 (dd, J=8.5,
1.2 Hz, 2H), 7.69-7.63 (m, 1H), 7.60-7.55 (m, 2H), 4.67 (s, 4H),
3.72-3.62 (m, 1H), 3.57 (s, 2H), 2.71-2.61 (m, 2H), 2.39-2.30 (m,
2H), 1.95 (s, 1H), 1.84-1.73 (m, 2H), 1.49-1.38 (m, 2H)
[1765] (427B):
1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-ol (300 mg,
0.963 mmol, 97) was dissolved in methanol (5 mL) and magnesium
(pre-treated with 1N HCl and rinsed with methanol, 120 mg, 4.94
mmol) was added. The reaction mixture was sonicated for 1 min and
stirred overnight. The reaction mixture was diluted with ethyl
acetate and celite was added. The mixture was filtered and the
filtrate was concentrated and purified by flash chromatography on
silica gel using an automated ISCO system (24 g column, eluting
with 2-12% 2 N ammonia in methanol/dichloromethane).
1-(3-methyloxetan-3-yl)piperidin-4-ol (78 mg) as a white solid.
[1766] MS (ESI) m/z 172.1
[1767] .sup.1H NMR (500 MHz, chloroform-d) .delta. 4.55 (d, J=5.3
Hz, 2H), 4.20 (d, J=5.8 Hz, 2H), 3.66 (br. s., 1H), 2.56-2.44 (m,
3H), 2.33 (br. s., 1H), 2.17-2.09 (m, 2H), 1.94-1.84 (m, 2H), 1.58
(dtd, J=12.8, 9.2, 3.6 Hz, 2H), 1.34 (s, 3H)
[1768] (427C): DIAD (0.132 mL, 0.638 mmol) was added to a solution
of 4-chloro-3-hydroxy-5-nitrobenzonitrile (95 mg, 0.478 mmol),
1-(3-methyloxetan-3-yl)piperidin-4-ol (78 mg, 0.456 mmol) and
triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in
THF (2 mL) and the reaction mixture was stirred at room temperature
overnight. The reaction mixture was filtered and the filtrate was
concentrated, the crude product was purified by flash
chromatography on silica gel using an automated ISCO system (24 g
column, eluting with 1-6% 2 N ammonia in methanol/dichloromethane).
4-chloro-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-5-nitrobenzonitri-
le (106 mg) was obtained as a yellow solid.
[1769] MS (ESI) m/z 352.0
[1770] (427D): Ammonium chloride (584 mg, 10.92 mmol) and zinc (356
mg, 5.46 mmol) were added to a solution of
4-chloro-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-5-nitrobenzonitri-
le (96 mg, 0.273 mmol) in methanol (10 mL) and the reaction mixture
was stirred at room temperature for 2 hours. The reaction mixture
was filtered through celite and the filtrate was concentrated, the
crude was purified by flash chromatography on silica gel using an
automated ISCO system (loaded onto a 24 g dry column, 24 g column,
eluting with 0-6% 2 N ammonia in methanol/dichloromethane).
3-amino-4-chloro-5-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)benzonitri-
le (87 mg) was obtained as a foaming solid.
[1771] MS (ESI) m/z 322.0
[1772] (427E): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (Intermediate 9) (47.4 mg, 0.134 mmol),
3-amino-4-chloro-5-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)benzonitri-
le (43 mg, 0.134 mmol), palladium(II) acetate (7.95 mg, 0.035
mmol), xantphos (7.73 mg, 0.013 mmol), DPPF (7.41 mg, 0.013 mmol)
and cesium carbonate (113 mg, 0.347 mmol) in dioxane (2 ml) was
evacuated and back filled with nitrogen three time and was heated
at 80.degree. C. for 6 h. The reaction mixture was filtered through
a pad of celite, the filtrate was concentrated and the crude was
purified by prep-HPLC.
2-((2-chloro-5-cyano-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)phenyl-
)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-
-7-carbonitrile (35 mg) was obtained.
[1773] MS (ESI) m/z 640.1
[1774] .sup.1H NMR (500 MHz, Methanol-d4) .delta. 7.98 (s, 1H),
7.20 (d, J=8.3 Hz, 2H), 7.10 (d, J=1.7 Hz, 1H), 6.84 (d, J=8.6 Hz,
2H), 5.04 (d, J=7.5 Hz, 2H), 4.43 (d, J=7.5 Hz, 2H), 3.77 (s, 3H),
3.24-3.12 (m, 2H), 2.45-2.33 (m, 2H), 2.27 (d, J=13.6 Hz, 2H), 1.80
(s, 3H), 1.09 (d, J=6.4 Hz, 2H), 0.96-0.88 (m, 2H)
[1775] Example 427: TFA (25% in DCE, 2 ml, 6.49 mmol) was added to
a solution of
2-((2-chloro-5-cyano-3-methyloxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-
-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile (35 mg, 0.055 mmol) and anisole (0.024 ml, 0.219 mmol) and
the reaction mixture was heated at 35.degree. C. overnight. Solvent
was evaporated and the residue was dried under vacuum. The crude
was washed with hexane (3.times.1 ml), dissolved in acetonitrile
and neutralized with 2N ammonia in methanol, after concentration,
the crude product was purified by flash chromatography on silica
gel using an automated ISCO system (24 g gold column, eluting with
0-4% 2 N ammonia in methanol/dichloromethane).
2-((2-chloro-5-cyano-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
HCl (21 mg) was obtained as a white solid.
[1776] MS (ESI) m/z 520.1
[1777] .sup.1H NMR (500 MHz, mixture of methanol-d4/chloroform-d)
.delta. 8.67 (d, J=1.7 Hz, 1H), 7.93 (s, 1H), 6.99 (d, J=1.7 Hz,
1H), 4.63 (d, J=5.8 Hz, 2H), 4.28 (d, J=5.8 Hz, 2H), 3.05 (tt,
J=7.3, 3.8 Hz, 1H), 2.70-2.60 (m, 2H), 2.34 (ddd, J=11.0, 6.7, 3.7
Hz, 2H), 2.10-2.01 (m, 2H), 1.96 (td, J=6.5, 3.1 Hz, 2H), 1.44 (s,
3H), 1.07-0.99 (m, 2H), 0.83-0.77 (m, 2H)
Example 428
##STR00489##
[1778]
2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)-1-piperazinyl)phenyl)-
amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1779] Prepared in analogous manner as Example 52
[1780] MS (ESI) m/z 486.92
[1781] 1H NMR (400 MHz, DMSO-d6) .delta. 9.42-9.26 (m, 1H), 8.90
(s, 1H), 8.32-8.02 (m, 2H), 7.49 (d, J=1.5 Hz, 1H), 3.62-3.19 (m,
8H), 3.09-2.86 (m, 1H), 0.78 (d, J=5.7 Hz, 4H).
Example 429
##STR00490##
[1782]
2-((2-chloro-5-cyano-3-(4-((2R)-2-hydroxypropyl)-1-piperazinyl)phen-
yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1783] Prepared in analogous manner as Example 57
[1784] MS (ESI) m/z 480.96
[1785] 1H NMR (400 MHz, DMSO-d6) .delta. 9.42-9.26 (m, 1H), 8.90
(s, 1H), 8.32-8.02 (m, 2H), 7.49 (d, J=1.5 Hz, 1H), 3.62-3.19 (m,
8H), 3.09-2.86 (m, 1H), 0.78 (d, J=5.7 Hz, 4H).
Example 430
##STR00491##
[1786]
(+/-)-2-((2-chloro-5-cyano-3-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2-
-f]heptan-2-yl)phenyl)amino)-4-((2,2,2-trifluoroethyl)amino)imidazo[2,1-f]-
[1,2,4]triazine-7-carbonitrile
[1787] (430A):
(+/-)-3-amino-4-chloro-5-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan--
2-yl)benzonitrile was prepared starting from tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) and
(+/-)-(1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane
dihydrobromide using a method analogous to that used to prepare
Example 1.
[1788] MS (ESI) m/z 263.2
[1789] 1H NMR (400 MHz, DMSO-d6) .delta. 6.67 (d, J=1.8 Hz, 1H),
6.59 (d, J=1.5 Hz, 1H), 4.39 (br. s., 1H), 4.09 (br. s., 1H),
3.84-3.71 (m, 1H), 3.42 (d, J=10.8 Hz, 2H), 3.10 (d, J=10.3 Hz,
1H), 2.73 (br. s., 3H), 2.16 (br. s., 1H), 2.00 (d, J=11.0 Hz,
1H).
[1790] Example 430: The compound was prepared from
4-((4-methoxybenzyl)(2,2,2-trifluoroethyl)amino)-2-(methylsulfonyl)imidaz-
o[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2) and
(+/-)-3-amino-4-chloro-5-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan--
2-yl)benzonitrile using a method analogous to that used to prepare
Example 1.
[1791] MS (ESI) m/z 503.1
[1792] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.67 (br. s.,
1H), 9.00 (s, 1H), 8.26 (s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.10 (d,
J=1.7 Hz, 1H), 4.33-4.21 (m, 3H), 3.67 (dd, 2.5 Hz, 1H), 3.40 (s,
1H), 2.84 (dd, J=9.8, 2.1 Hz, 1H), 2.71 (d, J=9.7 Hz, 1H), 2.28 (s,
3H), 1.86 (d, J=9.2 Hz, 1H), 1.73 (d, J=9.4 Hz, 1H).
Example 431
##STR00492##
[1793] (+/-)-methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)(methyl)carbam-
ate
[1794] (431A): A steel autoclave charged with tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1, 500 mg,
1.508 mmol), palladium(II) acetate (1.693 mg, 7.54 .mu.mol), DPPF
(62.7 mg, 0.113 mmol), triethylamine (0.631 mL, 4.52 mmol) and
ethanol (40 mL) was evacuated and filled with nitrogen three times
to remove the air from the reaction vessel and then filled with
carbon monoxide to 80 psi and heated at 100.degree. C. for 5 h. The
reaction mixture was cooled to room temperature and concentrated in
vacuo; the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (80 g column, eluting
with 5-20% ethyl acetate/hexanes). ethyl
3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzoate (222 mg)
was obtained as a colorless oil.
[1795] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.72 (d, J=1.7
Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.35 (s, 1H), 4.42 (q, J=7.1 Hz,
2H), 1.55 (s, 9H), 1.41 (t, J=7.1 Hz, 3H).
[1796] (431B): 1N NaOH (1.367 mL, 1.367 mmol) was added to a
solution of ethyl
3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzoate (222 mg,
0.684 mmol) in methanol (1 mL) and the reaction mixture was stirred
at room temperature for 2 h. 1N HCl was added to neutralize the
reaction mixture to pH 5 and the reaction mixture was then
concentrated in vacuo and lyophilized to give a crude white solid
(309 mg, 65% pure). The crude was used in next step without
purification.
[1797] MS (ESI) m/z 319.2
[1798] (431C): HATU (150 mg, 0.394 mmol) was added to a solution of
crude 3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzoic acid
(Example 431B) (150 mg, 0.329 mmol),
(+/-)-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol, 3 HCl (97 mg,
0.329 mmol) and diisopropyl ethylamine (0.230 mL, 1.314 mmol) in
DMF (1 mL) and the resulting reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate and washed with saturated sodium bicarbonate. The organic
layer was dried over magnesium sulfate, filtered and concentrated
in vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (24 g column, eluting
with 2-12% 2N ammonia in methanol/dichloromethane) to give
(+/-)-tert-butyl
(2-chloro-5-cyano-3-(3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidine-1-ca-
rbonyl)phenyl)carbamate (119 mg).
[1799] MS (ESI) m/z 464.4.
[1800] (431D): tert-Butyldimethylsilyl trifluoromethanesulfonate
(0.240 mL, 1.026 mmol) was added to a solution of (+/-)-tert-butyl
(2-chloro-5-cyano-3-(3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidine-1-ca-
rbonyl)phenyl)carbamate (119 mg, 0.256 mmol) and imidazole (69.8
mg, 1.026 mmol) in DMF (3 mL) and the reaction solution was stirred
at room temperature over the weekend. The reaction mixture was
diluted with ethyl acetate and washed with saturated sodium
bicarbonate. The organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (40 g column, eluting with 1-6% methanol/dichloromethane).
(+/-)-tert-butyl
(3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidin-
e-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg) was
obtained as a colorless oil.
[1801] MS (ESI) m/z 578.4
[1802] (431E): (+/-)-tert-butyl
(3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidin-
e-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg, 0.208 mmol)
was treated with TFA (25% in 1,2-dichloroethane, 2 mL, 6.49 mmol)
at room temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with cold saturated sodium
bicarbonate/1N aqueous sodium hydroxide (pH 10). The organic layer
was dried over magnesium sulfate, filtered and concentrated in
vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (40 g column, eluting
with 1-7.5% methanol/dichloromethane).
(+/-)-3-amino-5-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1--
yl)pyrrolidine-1-carbonyl)-4-chlorobenzonitrile (86 mg) was
obtained as a brown oil.
[1803] MS (ESI) m/z 478.4
[1804] Example 431: The title compound was prepared
(+/-)-3-amino-5-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1--
yl)pyrrolidine-1-carbonyl)-4-chlorobenzonitrile using a method
analogous to that used to prepare Example 1.
[1805] MS (ESI) m/z 562.3.1
[1806] .sup.1H NMR (400 MHz, chloroform-d) .delta. 9.10 (d, J=1.5
Hz, 0.5H), 8.99 (d, J=1.5 Hz, 0.5H), 7.87 (d, J=4.0 Hz, 1H), 7.58
(d, J=6.2 Hz, 1H), 7.25 (dd, J=8.58, 1.54 Hz, 1H), 7.02 (br. s.,
1H), 4.50 (q, J=5.7 Hz, 0.5H), 4.40 (q, J=5.9 Hz, 0.5H), 4.05 (dd,
J=13.0, 6.6 Hz, 0.5H), 3.98 (dd, J=12.8, 7.5 Hz, 0.5H), 3.73-3.45
(m, 2H), 3.28-3.12 (m, 1H), 2.98 (q, J=6.6 Hz, 1H), 2.85-2.58 (m,
4H), 2.57-2.37 (m, 5H), 2.31 (s, 1.5H), 2.27 (s, 1.5H), 1.14-1.06
(m, 2H), 0.85-0.79 (m, 2H).
Example 432
##STR00493##
[1807]
2-((2-chloro-5-cyano-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-(cyc-
lopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1808] Prepared in similar manner as Example 410.
[1809] MS (ESI) m/z 448.92
Example 433
##STR00494##
[1810]
2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropylamino)imida-
zo[2,1-f][1,2,4]triazine-7-carbonitrile
[1811] (433A):
2-Bromo-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (Intermediate 9) (168 mg, 0.421 mmol),
4-amino-5-chloropyrimidine-2-carbonitrile (65 mg, 0.421 mmol)
Pd.sub.2(DBA).sub.3 (77 mg, 0.084 mmol), xantphos (48.7 mg, 0.084
mmol) and cesium carbonate (274 mg, 0.841 mmol) were suspended in
dioxane (4206 .mu.l) at rt. The reaction was degassed using the
vacuum/purge method (4 times) to put the reaction under N.sub.2.
The reaction was heated to 70.degree. C. for 4 h before cooling to
room temperature, diluting with EtOAc, filtered through celite and
concentrated. The crude product was purified by column
chromatography (40 g SiO2, 0 to 100% EtOAc-hexane gradient elution)
to afford 30 mg of
2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1812] MS (ESI) m/z 473.2 (M+1).
[1813] Example 433:
2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was dissolved in
DCE. Anisole (50 .mu.L) was added followed by TFA (200 .mu.L) and
the reaction was stirred at 50.degree. C. overnight. The reaction
was concentrated and dried under vacuum. The crude product was
purified by preparative LC/MS with the following conditions:
[1814] Column: Waters XBridge C18, 19.times.250 mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
10-mM ammonium acetate; Gradient: 0-100% B over 15 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min.
[1815] Fractions concentrated and dried via centrifugal evaporation
to afford 3.6 mg of
2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile.
[1816] MS (ESI) m/z 353.1 (M+1).
[1817] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.77 (s, 1H).
9.59 (br. s., 1H), 8.83 (br. s., 1H), 8.36 (s, 1H), 3.08-2.98 (m,
1H), 0.84-0.70 (m, 4H).
Example 434
##STR00495##
[1818]
(+/-)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,-
2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,-
4]triazine-7-carbonitrile
[1819] (434A): A solution of LiAlH.sub.4 in THF (2M in THF, 20 ml,
40 mmol) was added slowly to a solution of
(+/-)-(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione
(prepared according to a published literature procedure:
Pharmaceutical Chemistry Journal, Vol 46, No. 2, 96 (2012), 2 g,
11.75 mmol) in THF (60 mL) and the resulting mixture was heated at
reflux for 5 h. The reaction was quenched with careful addition of
0.6 ml of water, 0.6 ml of 15% NaOH and 1.2 ml water. Celite and
anhydrous magnesium sulfate were then added and the mixture stirred
for 1 h. The mixture was filtered and the filtrate was concentrated
to give (+/-)-(7R)-octahydropyrrolo[1,2-a]pyrazin-7-ol (0.925 g)
which was used without further purification.
[1820] (434B): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (413 mg, 1.245 mmol),
(+/-)-(7R)-octahydropyrrolo[1,2-a]pyrazin-7-ol (177 mg, 1.245
mmol), Pd2dba3 (114 mg, 0.124 mmol), BINAP (233 mg, 0.373 mmol),
and cesium carbonate (1217 mg, 3.73 mmol) in dioxane (25 ml) was
evacuated and back filled with nitrogen 3 times and heated at
105.degree. C. overnight. The reaction mixture was filtered through
a plug of celite and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (80 g column, eluting with 1-6% 2 N ammonia
in methanol/dichloromethane) to give two regioisomers.
[1821] Isomer A (cis): (+/-)-tert-butyl
(2-chloro-5-cyano-3-((7R,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1-
H)-yl)phenyl)carbamate (113 mg).
[1822] MS (ESI) m/z 393.0 (M+H)
[1823] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.29 (d, J=1.4
Hz, 1H), 7.19 (s, 1H), 7.01 (d, J=1.9 Hz, 1H), 4.43-4.32 (m, 1H),
3.35 (dt, J=10.6, 2.2 Hz, 1H), 3.27 (dd, J=11.1, 1.9 Hz, 1H),
3.12-3.08 (m, 1H), 3.06 (d, J=10.0 Hz, 1H), 2.97 (td, J=11.3, 2.9
Hz, 1H), 2.69 (t, J=10.3 Hz, 1H), 2.61 (br. s., 1H), 2.48-2.35 (m,
3H), 2.28 (tdd, J=9.8, 7.0, 2.5 Hz, 1H), 1.55 (s, 9H), 1.46-1.39
(m, 1H)
[1824] Isomer B (trans): (+/-)-tert-butyl
(2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1-
H)-yl)phenyl)carbamate (304 mg).
[1825] MS (ESI) m/z 393.0 (M+H)
[1826] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.26 (d, J=1.4
Hz, 1H), 7.19 (s, 1H), 6.97 (d, J=1.9 Hz, 1H), 4.54-4.45 (m, 1H),
3.52 (dd, J=9.7, 6.7 Hz, 1H), 3.33 (dt, J=10.8, 2.0 Hz, 1H), 3.23
(dd, J=11.0, 1.8 Hz, 1H), 3.02 (dt, J=10.8, 2.3 Hz, 1H), 2.85 (td,
J=11.2, 2.8 Hz, 1H), 2.73-2.64 (m, 2H), 2.58 (td, J=11.0, 2.9 Hz,
1H), 2.51 (t, J=10.3 Hz, 1H), 2.24 (dd, J=9.6, 5.1 Hz, 1H),
1.84-1.72 (m, 2H), 1.52 (s, 9H) (434C): (+/-)-tert-butyl
(2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1-
H)-yl)phenyl)carbamate (Isomer B, 304 mg, 0.774 mmol) was treated
with 25% TFA in dichloroethane (6 ml, 19.47 mmol) at room
temperature for 1 h. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate/1N
sodium hydroxide (pH 10). The aqueous layer was extracted with
dichloromethane two more times. The combined organic layers were
dried over magnesium sulfate, filtered and concentrated in vacuo.
The crude product was purified by flash chromatography on silica
gel using an automated ISCO system (24 g gold column, eluting with
2-5% 2 N ammonia in methanol/dichloromethane).
(+/-)-3-amino-4-chloro-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazi-
n-2(1H)-yl)benzonitrile (181 mg) was obtained as a white solid.
[1827] MS (ESI) m/z 293.0 (M+H)
[1828] (434D): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (60.6 mg, 0.171 mmol),
(+/-)-3-amino-4-chloro-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazi-
n-2(1H)-yl)benzonitrile (50 mg, 0.171 mmol), palladium(II) acetate
(10.16 mg, 0.045 mmol), Xantphos (9.88 mg, 0.017 mmol), DPPF (9.47
mg, 0.017 mmol) and cesium carbonate (145 mg, 0.444 mmol) in
dioxane (3 ml) was evacuated and back filled with nitrogen three
time and was heated at 80.degree. C. for 5 h. The reaction mixture
was filtered through a celite pad, the filtrate was concentrated.
And the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (24 g gold column,
eluting with 0.5-5% 2 N ammonia in methanol/dichloromethane). It
was further purified by prep-HPLC (Pursuit XRs 10 u C18 column,
30.times.250 mm, room temperature 13.171 min, 30-100% gradient
aqueous methanol over 12 minutes containing 0.1% TFA, 40 ml/min at
254 nm).
(+/-)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[-
2,1-f][1,2,4]triazine-7-carbonitrile (57 mg) was obtained as a
brown solid.
[1829] MS (ESI) m/z 611.1 (M+H)
[1830] Example 434: 25% TFA in dichloroethane (2 ml, 6.49 mmol) was
added to a solution of
(+/-)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[-
2,1-f][1,2,4]triazine-7-carbonitrile (57 mg, 0.093 mmol) and
anisole (0.041 ml, 0.373 mmol) in dichloroethane (1 mL) and the
reaction mixture was heated at 60.degree. C. for 2 hours. LCMS
showed completion of reaction and formation of product and TFA
ester of product. Solvent was evaporated and the crude was dried
under vacuum overnight. The crude was washed with hexane (3.times.1
ml), dissolved in acetonitrile and neutralized with 2N ammonia in
methanol, after concentration, the crude product was suspended in
methanol (1 ml). The precipitate was collected by filtration,
washed with methanol (0.5 ml), dried under vacuum.
(+/-)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]tria-
zine-7-carbonitrile (31 mg)
[1831] MS (ESI) m/z 491.0 (M+H), room temperature=0.69 min, Waters
Acquity BEH C18 1.7 .mu.m column, 2.1.times.50 mm, 2-98% aqueous
acetonitrile containing 0.05% TFA, gradient time 1 minute, flow
rate 0.8 mL/min, monitored at 254 nm.
[1832] .sup.1H NMR (500 MHz, mixture of
methanol-d.sub.4/chloroform-d) .delta. 8.71 (d, J=1.8 Hz, 1H), 7.91
(s, 1H), 7.07 (d, J=1.8 Hz, 1H), 4.50-4.41 (m, 1H), 3.49 (dd,
J=9.9, 6.8 Hz, 1H), 3.42 (d, J=11.0 Hz, 1H), 3.10-3.00 (m, 2H),
2.95-2.85 (m, 1H), 2.74 (d, J=9.5 Hz, 1H), 2.66-2.55 (m, 2H), 2.25
(dd, 5.5 Hz, 1H), 1.85-1.73 (m, 2H), 1.06-0.97 (m, 2H), 0.83-0.75
(m, 2H)
[1833] The compounds listed below were prepared by similar
synthetic procedures described in Example 434
TABLE-US-00018 TABLE 15 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 435 ##STR00496##
(+/-)-2-((2-chloro-5-cyano- 3-((7R,8aR)-7- hydroxyhexahydropyrrolo
[1,2-a]pyrazin-2(1H)- yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 491.0 0.69 436 ##STR00497##
(+/-)-2-((2-chloro-5-cyano- 3-((7R,8aS)-7- hydroxyhexahydropyrrolo
[1,2-a]pyrazin-2(1H)- yl)phenyl)amino)-4- (ethylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 479.0 0.69 437 ##STR00498##
(+/-)-2-((2-chloro-5-cyano- 3-((7R,8aR)-7- fluorohexahydropyrrolo
[1,2-a]pyrazin-2(1H)- yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 493.0 0.72 *= HPLC
conditions: Waters Acquity BEH C18 1.7 .mu.m column, 2.1 .times. 50
mm, 2-98% aqueous acetonitrile containing 0.05% TFA, gradient time
1 minute, flow rate 0.8 mL/min, monitored at 254 nm.
Example 438
##STR00499##
[1834]
(+/-)-2-((2-chloro-5-cyano-3-((8R,8aS)-8-hydroxyhexahydropyrrolo[1,-
2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,-
4]triazine-7-carbonitrile
[1835] (438A): To a stirred 0.degree. C. suspension of
(2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (5.44 g, 41.5 mmol)
in anhydrous methanol (50 mL) was added drop wise thionyl chloride
(4.24 mL, 58.1 mmol), after 1 h dissolution of starting material
was complete. The reaction mixture was stirred at room temperature
24 h then evaporated under reduced pressure to a very small amount
and white precipitate formed. To the suspension was added ethyl
ether (20 ml) and the precipitate was collected by filtration,
washed with ether and dried in vacuo to furnish (2S,3S)-methyl
3-hydroxypyrrolidine-2-carboxylate, HCl (7.06 g) as a white
solid.
[1836] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 4.69 (td,
J=3.3, 1.9 Hz, 1H), 4.31 (d, J=1.9 Hz, 1H), 3.89 (s, 3H), 3.59-3.52
(m, 2H), 2.12-2.06 (m, 2H)
[1837] (438B):
(8S)-8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione was
prepared starting from (2S,3S)-methyl
3-hydroxypyrrolidine-2-carboxylate, HCl following a published
literature procedure: Pharmaceutical Chemistry Journal, Vol 46, No.
2, 96 (2012),
[1838] Example 438: The title compounds was prepared from
(8S)-8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione by similar
synthetic procedures described in Example 434.
[1839] MS (ESI) m/z 491.0 (M+H), room temperature=0.69 min, Waters
Acquity BEH C18 1.7 .mu.m column, 2.1.times.50 mm, 2-98% aqueous
acetonitrile containing 0.05% TFA, gradient time 1 minute, flow
rate 0.8 mL/min, monitored at 254 nm.
[1840] .sup.1H NMR (500 MHz, mixture of
methanol-d.sub.4/chloroform-d) .delta. 8.72 (d, J=1.7 Hz, 1H), 7.93
(s, 1H), 7.12 (d, J=1.7 Hz, 1H), 4.06-3.96 (m, 1H), 3.59 (d, J=10.5
Hz, 1H), 3.37-3.34 (m, 1H), 3.11-3.01 (m, 3H), 2.88 (td, J=11.4,
2.8 Hz, 1H), 2.69 (t, J=10.4 Hz, 1H), 2.61-2.50 (m, 2H), 2.38-2.26
(m, 2H), 1.73-1.62 (m, 1H), 1.08-0.98 (m, 2H), 0.84-0.76 (m,
2H)
Example 439
##STR00500##
[1841]
(S)-2-((2-chloro-5-cyano-3-(morpholin-3-ylmethoxy)phenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1842] (439A): 4M HCl in dioxane (2.428 mL, 9.71 mmol) was added to
a solution of (R)-tert-butyl
3-(hydroxymethyl)morpholine-4-carboxylate (211 mg, 0.971 mmol) in
methanol (2 mL) and the reaction mixture was stirred at room
temperature for 3 hours. Solvent was evaporated in vacuo to give a
white solid and the crude was dried under vacuum overnight. The
crude (R)-morpholin-3-ylmethanol HCl salt was used without
purification.
[1843] (439B): A mixture of (R)-morpholin-3-ylmethanol, HCl salt
(149 mg, 0.971 mmol), 2,4-dimethoxybenzaldehyde (161 mg, 0.971
mmol), sodium acetate (80 mg, 0.971 mmol), acetic acid (0.056 ml,
0.971 mmol) and sodium triacetoxyborohydride (288 mg, 1.359 mmol)
in dichloroethane (20 mL) was stirred at room temperature
overnight. The reaction mixture was partitioned between
dichloromethane and saturated sodium bicarbonate. The layers were
separated and aqueous layer was extracted with dichloromethane two
more times. The combined organic layers were dried over magnesium
sulfate, filtered and concentrated in vacuo, the crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (40 g column, eluting with 10-100% acetone/hexanes,
monitor at 232 nm).
(R)-(4-(2,4-dimethoxybenzyl)morpholin-3-yl)methanol (104 mg) was
obtained as a colorless oil.
[1844] MS (ESI) m/z 268.0 (M+H)
[1845] (439C):
(S)-4-chloro-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)-5-nitrobe-
nzonitrile, and DIAD (0.119 mL, 0.584 mmol) was added to a
suspension of 4-chloro-3-hydroxy-5-nitrobenzonitrile (85 mg, 0.428
mmol), (R)-(4-(2,4-dimethoxybenzyl)morpholin-3-yl)methanol (104 mg,
0.389 mmol) and polymer bound triphenylphosphine (3 mmol/g loading,
0.542 g, 1.627 mmol) in THF (3 mL) and the reaction mixture was
stirred at room temperature overnight. The reaction mixture was
filtered and the filtrate was concentrated in vacuo, the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g gold column, eluting with 10-35% ethyl
acetate/hexanes). Two isomers were isolated and their structures
were determined by NMR studies.
[1846] Isomer A:
(+/-)-4-chloro-3-((4-(2,4-dimethoxybenzyl)-1,4-oxazepan-6-yl)oxy)-5-nitro-
benzonitrile (30 mg).
[1847] MS (ESI) m/z 448.2 (M+H)
[1848] .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.58 (d, J=1.7
Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.42 (dd,
J=8.2, 2.4 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 4.63-4.57 (m, 1H), 4.18
(dd, J=13.0, 5.8 Hz, 1H), 4.03 (dd, J=13.0, 4.7 Hz, 1H), 3.97-3.91
(m, 1H), 3.85-3.82 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.62 (d,
J=3.6 Hz, 2H), 3.06-2.79 (m, 4H)
[1849] Isomer B:
(S)-4-chloro-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)-5-nitrobe-
nzonitrile (73 mg).
[1850] MS (ESI) m/z 448.2
[1851] .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.66 (d, J=1.9
Hz, 1H), 7.29 (d, J=1.7 Hz, 2H), 6.48-6.43 (m, 2H), 4.43 (dd,
J=9.2, 4.2 Hz, 1H), 4.23 (dd, J=9.2, 6.9 Hz, 1H), 3.95 (dd, J=11.1,
3.1 Hz, 1H), 3.87 (d, J=14.1 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H),
3.77-3.69 (m, 3H), 3.62 (d, J=14.1 Hz, 1H), 3.10-3.02 (m, 1H), 2.84
(ddd, J=12.2, 6.1, 3.1 Hz, 1H), 2.53 (ddd, J=12.0, 6.7, 3.2 Hz,
1H)
[1852] (439D): Zinc (107 mg, 1.630 mmol) was added to a mixture of
(S)-4-chloro-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)-5-nitrobe-
nzonitrile (isomer B, 73 mg, 0.163 mmol) and ammonium chloride (174
mg, 3.26 mmol) in methanol (5 mL) and the reaction mixture was
stirred at room temperature for 2 hours. More zinc (107 mg, 1.630
mmol) was added and stirring continued until reactions complete.
The reaction mixture was diluted with dichloromethane and ammonium
chloride precipitated. Solids were filtered and the filtrate was
concentrated. The residue was partitioned between dichloromethane
and saturated sodium bicarbonate. The layers were separated and
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (12 g column, eluting with 5-35% ethyl acetate/hexanes) to
give
(S)-3-amino-4-chloro-5-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)be-
nzonitrile (53 mg) as a oil.
[1853] MS (ESI) m/z 418.1 (M+H)
[1854] .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.28 (d, J=8.0
Hz, 1H), 6.68 (d, J=1.7 Hz, 1H), 6.55 (d, J=1.7 Hz, 1H), 6.50-6.45
(m, 2H), 4.40-4.33 (m, 3H), 4.07 (dd, J=9.2, 7.2 Hz, 1H), 3.98 (dd,
J=11.4, 3.1 Hz, 1H), 3.90 (d, J=13.9 Hz, 1H), 3.82 (s, 3H), 3.79
(s, 3H), 3.76 (ddd, J=8.5, 5.7, 2.8 Hz, 1H), 3.73-3.66 (m, 2H),
3.58 (d, J=13.9 Hz, 1H), 3.01 (tt, J=6.9, 3.6 Hz, 1H), 2.81 (ddd,
J=12.0, 5.5, 2.8 Hz, 1H), 2.51-2.42 (m, 1H)
[1855] (439E): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (47.2 mg, 0.133 mmol),
(S)-3-amino-4-chloro-5-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)be-
nzonitrile (53 mg, 0.127 mmol), palladium(ii) acetate (7.55 mg,
0.034 mmol), Xantphos (7.34 mg, 0.013 mmol), DPPF (7.03 mg, 0.013
mmol) and cesium carbonate (107 mg, 0.330 mmol) in dioxane (1 ml)
was evacuated and back filled with nitrogen three time and was
heated at 80.degree. C. for 10 h. The reaction mixture was filtered
through a celite pad and the filtrate was concentrated. the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (80 g column, eluting with 5-40% ethyl
acetate/hexanes) to give
(S)-2-((2-chloro-5-cyano-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methox-
y)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile (80 mg) as a light yellow solid.
[1856] MS (ESI) m/z 736.2 (M+H)
[1857] Example 439: 50% TFA in dichloroethane (1 ml) was added to a
solution of
(S)-2-((2-chloro-5-cyano-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methox-
y)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile (80 mg, 0.109 mmol) and anisole (0.095 ml,
0.869 mmol) in a 1-dram vial and the reaction mixture was heated at
60.degree. C. for 4 hours. The reaction mixture was concentrated
and residue was dried under vacuum overnight. The crude was
dissolved in acetonitrile (2 ml) and neutralized with 2N ammonia in
methanol (2 ml); white precipitate formed and was collected by
filtration. This material was further purified by flash
chromatography on silica gel using an automated ISCO system (24 g
gold column, eluting with 1-6% 2 N ammonia in
methanol/dichloromethane).
(S)-24(2-chloro-5-cyano-3-(morpholin-3-ylmethoxy)phenyl)amino)-4-(cyclopr-
opylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35 mg) was
obtained as a white solid.
[1858] MS (ESI) m/z 466.1 (M+H)
[1859] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 8.70 (br. s., 1H), 7.92 (s, 1H), 6.97 (br. s., 1H),
4.10-3.95 (m, 3H), 3.85 (dt, J=11.6, 2.7 Hz, 1H), 3.60 (ddd,
J=11.7, 7.9, 5.1 Hz, 1H), 3.50 (dd, J=11.1, 9.4 Hz, 1H), 3.33 (dt,
J=3.1, 1.6 Hz, 3H), 3.05 (tt, J=7.1, 3.7 Hz, 1H), 3.02-2.97 (m,
2H), 1.06-0.99 (m, 2H), 0.84-0.78 (m, 2H)
Example 440
##STR00501##
[1860]
(+/-)-2-((3-((1,4-oxazepan-6-yl)oxy)-2-chloro-5-cyanophenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1861] The title compounds was prepared from
4-chloro-3-((4-(2,4-dimethoxybenzyl)-1,4-oxazepan-6-yl)oxy)-5-nitrobenzon-
itrile (Example 439C, isomer A) by similar synthetic procedures
described in Example 439.
[1862] MS (ESI) m/z 466.3 (M+H)
[1863] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (br. s.,
1H), 8.75 (br. s., 1H), 8.21 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 7.40
(s, 1H), 4.82 (t, J=4.9 Hz, 1H), 4.02-3.96 (m, 1H), 3.93-3.87 (m,
1H), 3.78 (dt, J=12.1, 4.0 Hz, 1H), 3.56 (ddd, J=11.9, 7.6, 3.7 Hz,
1H), 3.29 (dd, J=14.0, 5.5 Hz, 1H), 3.02-2.95 (m, 1H), 2.94-2.89
(m, 2H), 2.88-2.83 (m, 2H), 0.82-0.77 (m, 4H)
Example 441
##STR00502##
[1864]
2-((2-chloro-5-cyano-3-(morpholin-2-ylmethoxy)phenyl)amino)-4-(cycl-
opropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1865] The title compounds were prepared from (+/-)-tert-butyl
2-((2-chloro-5-cyano-3-nitrophenoxy)methyl)morpholine-4-carboxylate
by similar synthetic procedures described in Example 439.
[1866] MS (ESI) m/z 466.3 (M+H)
[1867] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 8.70 (d, J=1.7 Hz, 1H), 7.92 (s, 1H), 6.98 (d, J=1.7 Hz,
1H), 4.16-4.11 (m, 1H), 4.09-4.04 (m, 1H), 3.97-3.89 (m, 2H), 3.69
(td, J=11.3, 2.9 Hz, 1H), 3.10-3.02 (m, 2H), 2.94-2.79 (m, 3H),
1.06-1.00 (m, 2H), 0.83-0.78 (m, 2H)
Example 442
##STR00503##
[1868]
(+/-)-2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(-
6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile
[1869] (442A): BOC anhydride (5.40 mL, 23.28 mmol) in
dichloromethane (5 ml) was added to a solution of 5-azaindole (2.5
g, 21.16 mmol) and triethylamine (4.42 mL, 31.7 mmol) in
dichloromethane (30 mL) over 5 min and gas evolved quickly. The
reaction mixture was stirred at room temperature for 0.5 hour. The
reaction mixture was diluted with dichloromethane and washed with
water and brine. The organic layer was dried over magnesium
sulfate, filtered and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel using an automated
ISCO system (80 g column, eluting with 5-30% ethyl
acetate/hexanes). tert-butyl
1H-pyrrolo[3,2-c]pyridine-1-carboxylate (4.455 g) was obtained as a
yellow oil.
[1870] MS (ESI) m/z 219.0 (M+H)
[1871] .sup.1H NMR (500 MHz, chloroform-d) .delta. 8.91 (d, J=0.8
Hz, 1H), 8.49 (d, J=5.8 Hz, 1H), 8.00 (d, J=5.3 Hz, 1H), 7.63 (d,
J=3.6 Hz, 1H), 6.67 (dd, J=3.7, 0.7 Hz, 1H), 1.71 (s, 9H)
[1872] (442B): A mixture of tert-butyl
1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.45 g, 11.23 mmol) and
palladium hydroxide on carbon (20%, 1 g, 1.424 mmol) in ethanol (8
ml)/acetic acid (16 mL) was hydrogenated at 50 psi and 60.degree.
C. overnight. The reaction mixture was filtered through celite.
Solvent was evaporated in vacuo and the residue was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo, The crude was be used without
purification. tert-butyl
octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.896 g) was
obtained as a colorless oil.
[1873] (442C): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (440 mg, 1.326 mmol),
tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (300
mg, 1.326 mmol), Pd2dba3 (121 mg, 0.133 mmol), BINAP (248 mg, 0.398
mmol), and cesium carbonate (1296 mg, 3.98 mmol) in Dioxane (12 mL)
was evacuated and back filled with nitrogen 3.times. and heated at
105.degree. C. overnight. The reaction mixture was filtered through
a plug of celite and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (80 g column, eluting with 5-35% ethyl
acetate/hexanes). tert-butyl
5-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)octahydro-1H-pyr-
rolo[3,2-c]pyridine-1-carboxylate (358 mg) was obtained as a
foaming solid.
[1874] MS (ESI) m/z 477.1 (M+H)
[1875] (442D): tert-butyl
5-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)octahydro-1H-pyr-
rolo[3,2-c]pyridine-1-carboxylate (358 mg, 0.751 mmol) was treated
with 25% TFA in dichloroethane (2 ml, 6.49 mmol) at room
temperature for 1 h. Solvent was evaporated in vacuo and the
residue was diluted with dichloromethane and washed with water and
brine. The organic layer was dried over magnesium sulfate, filtered
and concentrated in vacuo, the crude intermediate was dissolved in
dichloromethane (10 mL). Triethylamine (0.209 ml, 1.501 mmol) and
BOC anhydride (0.261 ml, 1.126 mmol) were added subsequently. The
reaction mixture was stirred at room temperature for 1 h and the
reaction was complete. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (40 g column, eluting with 10-30% ethyl acetate/hexanes) to
give tert-butyl
5-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-c-
arboxylate (266 mg) as a colorless oil.
[1876] MS (ESI) m/z 377.1 (M+H)
[1877] (442E): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (263 mg, 0.741 mmol), tert-butyl
5-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-c-
arboxylate (266 mg, 0.706 mmol), palladium(ii) acetate (42.0 mg,
0.187 mmol), xantphos (40.8 mg, 0.071 mmol), DPPF (39.1 mg, 0.071
mmol) and cesium carbonate (598 mg, 1.835 mmol) in dioxane (10 ml)
was evacuated and back filled with nitrogen three time and was
heated at 80.degree. C. for 10 h. The reaction mixture was filtered
through a celite pad and the filtrate was concentrated. the crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (80 g column, eluting with 5-40% ethyl
acetate/hexanes) to give tert-butyl
5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyri-
dine-1-carboxylate (360 mg) as a foaming solid.
[1878] MS (ESI) m/z 695.2 (M+H)
[1879] (442F): TMS-OTf (0.281 ml, 1.553 mmol) was added to a
solution of tert-butyl
5-(2-chloro-5-cyano-34(7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imida-
zo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyrid-
ine-1-carboxylate (360 mg, 0.518 mmol) and 2,6-lutidine (0.181 ml,
1.553 mmol) in dichloromethane (3 ml) and the reaction mixture was
stirred at room temperature for 2 hours. The reaction mixture was
diluted with dichloromethane and washed with saturated sodium
bicarbonate. The aqueous layer was extracted with dichloromethane
two more times. The combined organic layers were dried over
magnesium sulfate, filtered and concentrated in vacuo, The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 5-40% ethyl
acetate/hexanes).
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (288 mg) was obtained as an off-white solid.
[1880] MS (ESI) m/z 595.2 (M+H)
[1881] Example 442: A solution of
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (58 mg, 0.097 mmol), anisole (0.043 ml, 0.390
mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) was heated at
35.degree. C. overnight. Solvent was evaporated in vacuo and the
crude was dissolved in acetonitrile (1 ml) and neutralized with 2N
ammonia in methanol (1 ml). The crude product was purified by flash
chromatography on silica gel using an automated ISCO system (24 g
gold column, eluting with 1-12% 2 N ammonia in
methanol/dichloromethane).
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(41 mg) was obtained as a white solid.
[1882] MS (ESI) m/z 475.3 (M+H)
[1883] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 7.92 (s, 1H), 7.58 (s, 1H), 7.07 (d, J=1.9 Hz, 1H), 3.25
(q, J=5.8 Hz, 1H), 3.17 (ddd, J=11.2, 9.2, 5.7 Hz, 1H), 3.11-2.98
(m, 4H), 2.98-2.90 (m, 2H), 2.46-2.37 (m, 1H), 2.07-1.86 (m, 4H),
1.06-0.99 (m, 2H), 0.83-0.78 (m, 2H)
Example 443
##STR00504##
[1884]
2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin--
5(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-
-carbonitrile
[1885] (443A): Sodium triacetoxyborohydride (20.66 mg, 0.097 mmol)
was added to a solution of
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (Example 442F, 29 mg, 0.049 mmol),
paraformaldehyde (14.63 mg, 0.487 mmol) and acetic acid (5.58
.mu.l, 0.097 mmol) in dichloromethane (2 mL) and the reaction
mixture was stirred at room temperature for 5 hours. More
paraformaldehyde (14.63 mg, 0.487 mmol) and sodium
triacetoxyborohydride (20.66 mg, 0.097 mmol) were added and
stirring continued overnight. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (80 g column, eluting with 5-30% ethyl acetate/hexanes).
2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)--
yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (27 mg) was obtained as a white solid.
[1886] MS (ESI) m/z 595.2 (M+H)
[1887] Example 443: A solution of
2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)--
yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4-
]triazine-7-carbonitrile (27 mg, 0.044 mmol), anisole (0.024 ml,
0.222 mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) was
stirred at 35.degree. C. overnight. Solvent was evaporated and the
residue was washed with hexane (2.times.1 ml) and dissolved in 0.5
ml of acetonitrile, neutralized with 1 ml 2N ammonia in methanol.
Solvent was again evaporated. The crude material was purified via
preparative LC/MS with the following conditions:
[1888] Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
10-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a
0-minute hold at 100% B; Flow: 20 mL/min.
[1889]
2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin--
5(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-
-carbonitrile (19.7 mg) was obtained as a white solid.
[1890] MS (ESI) m/z 595.2 (M+H)
[1891] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br. s.,
1H), 8.83 (s, 1H), 8.20 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.26 (d,
J=1.2 Hz, 1H), 3.10-3.02 (m, 2H), 2.99 (br. s., 2H), 2.89-2.82 (m,
1H), 2.66 (t, J=11.0 Hz, 1H), 2.38 (br. s., 1H), 2.29 (br. s., 1H),
2.22 (s, 3H), 2.21-2.13 (m, 1H), 1.90-1.80 (m, 3H), 1.37-1.28 (m,
1H), 0.79 (d, J=5.5 Hz, 4H)
Example 444
##STR00505##
[1892]
2-((2-chloro-5-cyano-3-(1-(oxetan-3-yl)hexahydro-1H-pyrrolo[3,2-c]p-
yridin-5(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]tri-
azine-7-carbonitrile
[1893] The title compound was prepared from
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (Example 443F) using the methods described in
Example 210.
[1894] MS (ESI) m/z 531.3 (M+H)
[1895] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 8.69 (d, J=1.7 Hz, 1H), 7.89 (s, 1H), 7.04 (d, J=1.9 Hz,
1H), 4.79-4.74 (m, 2H), 4.73-4.68 (m, 2H), 3.94 (quin, J=6.7 Hz,
1H), 3.14-2.97 (m, 5H), 2.92-2.85 (m, 1H), 2.75 (q, J=5.4 Hz, 1H),
2.62 (td, J=9.6, 6.7 Hz, 1H), 2.54-2.42 (m, 1H), 2.02-1.92 (m, 1H),
1.89-1.76 (m, 2H), 1.73-1.65 (m, 1H), 1.06-0.99 (m, 2H), 0.82-0.77
(m, 2H)
Example 445
##STR00506##
[1896] methyl
5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylat-
e
[1897] Methyl chloroformate (5.66 .mu.l, 0.073 mmol) was added to a
solution of
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (Example 443F, 29 mg, 0.049 mmol) and
triethylamine (0.020 ml, 0.146 mmol) in dichloromethane (2 mL) and
the reaction mixture was stirred at room temperature overnight.
Solvent was evaporated in vacuo and the crude intermediate was
purified by flash chromatography on silica gel using an automated
ISCO system (24 g column, eluting with 1-4% 2 N ammonia in
methanol/dichloromethane) to give 28 mg of methyl
5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyri-
dine-1-carboxylate.
[1898] Anisole (0.027 ml, 0.244 mmol) and 25% TFA in dichloroethane
(2 ml, 6.49 mmol) were added to methyl
5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyri-
dine-1-carboxylate (28 mg, 0.0429 mmol) and the resulting solution
was stirred at room temperature over the weekend. Solvent was
evaporated in vacuo and the residue was dissolved in acetonitrile
and neutralized with 2N ammonia in methanol. Desired product
precipitated and was collected by filtration. methyl
5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylat-
e (17.2 mg) was obtained as a white solid.
[1899] MS (ESI) m/z 533.4 (M+H)
[1900] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 8.71 (d, J=1.9 Hz, 1H), 7.92 (s, 1H), 7.06 (d, J=1.7 Hz,
1H), 3.94 (br. s., 1H), 3.71 (br. s., 3H), 3.63-3.55 (m, 1H),
3.51-3.42 (m, 1H), 3.21 (br. s., 1H), 3.13-3.01 (m, 2H), 2.84-2.69
(m, 1H), 2.57-2.39 (m, 2H), 2.28-2.10 (m, 1H), 2.01-1.78 (m, 2H),
1.06-0.99 (m, 2H), 0.83-0.77 (m, 2H).
Example 446
##STR00507##
[1901]
2-((3-(1-acetylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)-2-chlor-
o-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-
-carbonitrile
[1902] The title compound was prepared from
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (Example HW-443F) using the methods described in
Example 445.
[1903] MS (ESI) m/z 517.4 (M+H)
[1904] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 8.71 (d, J=1.7 Hz, 1H), 7.92 (s, 1H), 7.07 (d, J=1.9 Hz,
1H), 4.18 (dt, J=10.5, 6.7 Hz, 1H), 4.01-3.92 (m, 1H), 3.76-3.68
(m, 1H), 3.61-3.48 (m, 1H), 3.47-3.36 (m, 1H), 3.27-3.20 (m, 1H),
3.13-3.01 (m, 2H), 2.81-2.57 (m, 2H), 2.43 (d, J=6.4 Hz, 1H),
2.16-1.87 (m, 5H), 1.07-0.97 (m, 2H), 0.84-0.76 (m, 2H)
Example 447
##STR00508##
[1905]
(+/-)-2-((2-chloro-5-cyano-3-(1-(2-hydroxypropyl)hexahydro-1H-pyrro-
lo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f]-
[1,2,4]triazine-7-carbonitrile
[1906] A mixture of
2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)pheny-
l)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (Example 443F, 29 mg, 0.049 mmol) and
2-(=/-)-methyloxirane (14.15 mg, 0.244 mmol) in ethanol (0.8
mL)/THF (0.2 mL) in a sealed 1-dram vial was heated at 80.degree.
C. overnight. A clear solution was observed and LCMS showed
completion of reaction. Solvent was evaporated and to the crude
intermediate were added anisole (0.027 ml, 0.244 mmol) and 25% TFA
in dichloroethane (2 ml, 6.49 mmol) and the resulting solution was
stirred at 35.degree. C. overnight. Solvent was evaporated and the
crude was purified by prep-HPLC to give the title compound (9.8 mg)
as a white solid.
[1907] MS (ESI) m/z 532.2 (M+H)
[1908] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br. s.,
1H), 8.83 (br. s., 1H), 8.20 (s, 1H), 8.05 (d, J=1.2 Hz, 1H), 7.29
(d, J=1.2 Hz, 1H), 3.70 (br. s., 1H), 3.22-3.15 (m, 2H), 3.05-2.94
(m, 3H), 2.93 (br. s., 1H), 2.81 (t, J=10.7 Hz, 1H), 2.62-2.56 (m,
2H), 2.39-2.27 (m, 2H), 2.10 (dd, J=12.5, 3.4 Hz, 1H), 1.88-1.79
(m, 3H), 1.42 (br. s., 1H), 1.06 (d, J=6.1 Hz, 3H), 0.79 (d, J=5.5
Hz, 4H).
[1909] The compounds listed below were prepared by similar
synthetic procedures described in Example 447
TABLE-US-00019 TABLE 16 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 448 ##STR00509##
2-((2-chloro-5-cyano-3-(1-((R)-3-fluoro-2-
hydroxypropyl)hexahydro-1H-pyrrolo[3,2-c]pyridin-
5(6H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
551.3 1.57 449 ##STR00510##
2-((2-chloro-5-cyano-3-(1-((S)-3-fluoro-2-
hydroxypropyl)hexahydro-1H-pyrrolo[3,2-c]pyridin-
5(6H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
551.2 1.69 450 ##STR00511## 2-((2-chloro-5-cyano-3-(1-(2-hydroxy-2-
methylpropyl)hexahydro-1H-pyrrolo[3,2-c]pyridin-
5(6H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
547.4 1.65 451 ##STR00512##
(+/-)-2-((2-chloro-5-cyano-3-(1-((3S,4R)-4-
hydroxytetrahydrofuran-3-yl)hexahydro-1H-
pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
561.2 1.54 452 ##STR00513##
2-((2-chloro-5-cyano-3-(1-((3R,4R)-4-hydroxy-1,1-
dioxidotetrahydrothiophen-3-yl)hexahydro-1H-
pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
609.5 0.73** 453 ##STR00514##
2-((2-chloro-5-cyano-3-(1-((3S,4S)-4-hydroxy-1,1-
dioxidotetrahydrothiophen-3-yl)hexahydro-1H-
pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
609.4 0.75** * = HPLC conditions Waters Acquity UPLC BEH C18 1.7
.mu.m column, 2.1 x 50 mm, 5-95% aqueous acetonitrile containing
0.1% trifluoroacetic acid, 3 min. gradient, flow rate 1.11 ml/min,
monitored at 220 nm. ** = LCMS conditions: Waters Acquity BEH C18
1.7 .mu.m column, 2.1 x 50 mm, 2-98% aqueous acetonitrile
containing 0.05% TFA, gradient time 1 minute, flow rate 0.8 mL/min,
monitored at 254 nm.
Example 454
##STR00515##
[1910]
(+/-)-2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[2,3-c]pyridin-6(-
2H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile
[1911] The title compound was prepared from 6-azaindole using the
methods described in Example 443
[1912] MS (ESI) m/z 475.2 (M+H)
[1913] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 8.78 (d, J=1.7 Hz, 1H), 7.94 (s, 1H), 7.14 (d, J=1.7 Hz,
1H), 3.79-3.73 (m, 1H), 3.64-3.56 (m, 2H), 3.44 (ddd, J=12.1, 10.5,
4.3 Hz, 1H), 3.29 (d, J=11.9 Hz, 1H), 3.18 (dd, J=13.3, 2.8 Hz,
1H), 3.04 (tt, J=7.2, 3.7 Hz, 1H), 2.93 (td, J=11.3, 2.6 Hz, 1H),
2.53 (d, J=4.2 Hz, 1H), 2.33-2.21 (m, 1H), 2.06-1.92 (m, 2H), 1.77
(dtd, J=14.3, 10.7, 4.0 Hz, 1H), 1.06-0.98 (m, 2H), 0.84-0.77 (m,
2H)
Example 455
##STR00516##
[1914]
2-((2-chloro-5-cyano-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1915] The title compound was prepared from tert-butyl
hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate using the methods
described in Example 443
[1916] MS (ESI) m/z 461.0 (M+H)
[1917] .sup.1H NMR (500 MHz, mixture of methanol-d/chloroform-d)
.delta. 7.93 (s, 1H), 7.58 (s, 1H), 7.07 (s, 1H), 3.71-3.60 (m,
2H), 3.49 (d, J=9.7 Hz, 2H), 3.22-3.14 (m, 4H), 3.12-3.00 (m, 3H),
1.06-0.99 (m, 2H), 0.84-0.77 (m, 2H)
[1918] The compounds listed below were prepared by similar
synthetic procedures described in Examples 443, 445 and 446
TABLE-US-00020 TABLE 17 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 456 ##STR00517##
(+/-)-2-((2-chloro-5-cyano-3- (1-methylhexahydro-1H-
pyrrolo[2,3-c]pyridin-6(2H)- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
489.3 0.74 457 ##STR00518## (+/-)-2-((2-chloro-5-cyano-3-
(1-(oxetan-3-yl)hexahydro- 1H-pyrrolo[2,3-c]pyridin-
6(2H)-yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 531.4 0.74 458 ##STR00519##
(+/-)-methyl 6-(2-chloro-5- cyano-3-((7-cyano-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)octahydro- 1H-pyrrolo[2,3-c]pyridine-1- carboxylate
533.4 1.02 459 ##STR00520## (+/-)-2-((2-chloro-5-cyano-3-
(1-(3-fluoro-2- hydroxypropyl)hexahydro- 1H-pyrrolo[2,3-c]pyridin-
6(2H)-yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 551.1 0.84 460 ##STR00521##
(+/-)-2-((2-chloro-5-cyano-3- (1-(2- hydroxypropyl)hexahydro-
1H-pyrrolo[2,3-c]pyridin- 6(2H)-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
533.1 0.75 461 ##STR00522## 2-((2-chloro-5-cyano-3-(5-
methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
475.3 0.73 462 ##STR00523## methyl 5-(2-chloro-5-cyano-
3-((7-cyano-4- (cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)hexahydro- pyrrolo[3,4-c]pyrrole-2(1H)- carboxylate
519.3 0.96 * = HPLC conditions Waters Acquity BEH C18 1.7 .mu.m
column, 2.1 x 50 mm, 2-98% acqueous acetonitrile containing 0.05%
TFA, gradient time 1 minute, flow rate 0.8 mL/min, monitored at 254
nm.
Example 463
##STR00524##
[1919]
2-((3-(2-oxa-6-azaspiro[3.5]nonan-6-ylmethyl)-2-chloro-5-cyanopheny-
l)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1920] A suspension of
2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (Example 400) (20 mg, 0.053
mmol), acetic acid (9.07 .mu.l, 0.158 mmol) and
2-oxa-6-azaspiro[3.5]nonane (16.79 mg, 0.132 mmol) in THF (0.5 ml)
was stirred at room temperature to for 5 min. to achieve solution.
DCE (0.5 mL) was added and after 25 min, sodium
triacetoxyborohydride (33.6 mg, 0.158 mmol) was added. LCMS
analysis found the desired mass of the product. The mixture was
stirred overnight. The reaction mixture was then quenched with
saturated aqueous NaHCO3 and stirred for 10 minutes. It was dried
with a stream of nitrogen and then dissolved in DMF (1.5 mL) and
purified by reverse-phase preparative LCMS.
[1921] MS (ESI) m/z 490.3 (M+H), room temperature=4.34 min
[1922] The compounds listed below were prepared by similar
synthetic procedures described in Examples 463
TABLE-US-00021 TABLE 18 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 464 ##STR00525##
2-[(2-chloro-5-cyano-3-{[(2-cyanoethyl)
(methyl)amino]methyl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
447.2 2.77 465 ##STR00526## 2-[(2-chloro-5-cyano-3-{[4-(2-
hydroxyethyl)piperazin-1- yl]methyl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
493.2 2.13 466 ##STR00527## 2-{[2-chloro-5-cyano-3-({[2-(morpholin-
4-yl)ethyl]amino}methyl)phenyl]amino}-
4-(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
493.2 2.24 467 ##STR00528## 2-[(2-chloro-5-cyano-3-{[(pyridin-2-
ylmethyl)amino]methyl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
471.1 1.66 468 ##STR00529##
2-({3-[(tert-butylamino)methyl]-2-chloro- 5-cyanophenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
436.3 3.82 469 ##STR00530## 2-[(2-chloro-5-cyano-3-{[(2,2-
dimethylpropyl)amino]methyl}phenyl)
amino]-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7-carbonitrile 450.2 3.29 470 ##STR00531##
2-[(2-chloro-5-cyano-3- {[(cyclopropylmethyl)amino]methyl}
phenyl)amino]-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 434.2 3.96 471 ##STR00532##
1-[(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazin-2-
yl]amino}phenyl)methyl]piperidine-4- carboxamide 491.2 2.29 472
##STR00533## 2-({3-[(4-tert-butylpiperazin-1-
yl)methyl]-2-chloro-5- cyanophenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
505.3 2.27 473 ##STR00534## N-[(3S)-1-[(2-chloro-5-cyano-3-{[7-
cyano-4-(cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)methyl]pyrrolidin-3- yl]acetamide 491.2 2.38 474
##STR00535## 2-[(2-chloro-5-cyano-3-{[(2- cyanoethyl)(oxolan-2-
ylmethyl)amino]methyl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
517.2 3.00 475 ##STR00536## 2-[(2-chloro-5-cyano-3-{[(2-
methoxyethyl)(methyl)amino]methyl} phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
452.3 4.16 476 ##STR00537## 2-[(2-chloro-5-cyano-3-{[4-(2-
methoxyethyl)piperazin-1- yl]methyl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
507.3 3.96 477 ##STR00538## 2-({2-chloro-5-cyano-3-[(4,4-
difluoropiperidin-1- yl)methyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
484.3 4.38 478 ##STR00539## methyl
4-[(2-chloro-5-cyano-3-{[7-cyano-
4-(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazin-2-
yl]amino}phenyl)methyl]piperazine-1- carboxylate 507.2 2.91 479
##STR00540## 2-[(2-chloro-5-cyano-3-{[(oxetan-3-
yl)amino]methyl}phenyl)amino]-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 436.1 3.62
Example 480
##STR00541##
[1923]
2-({3-[4-(1-acetylazetidin-3-yl)piperazin-1-yl]-2-chloro-5-cyanophe-
nyl}amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[1924] (480A): To a solution of
2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (500
mg, 0.901 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was added
tert-butyl 3-oxoazetidine-1-carboxylate (185 mg, 1.081 mmol),
acetic acid (0.052 mL, 0.901 mmol). The reaction mixture was
stirred at room temperature for overnight. The reaction mixture was
cooled to 0.degree. C., added sodium cyanoborohydride (113 mg,
1.802 mmol) and the reaction mixture was allowed to come to room
temperature and stirred for 5 h at the same temperature. The
solvent was removed completely under vacuum, the resultant residue
was dissolved in ethyl acetate (100 ml), washed it with 10% NaHCO3
solution, brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The crude material was purified via ISCO (12 gm
silica Redisep, 0 to 10% CH3OH--CHCl3 gradient elution). The
fractions were concentrated to get the tert-butyl
3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)azetidine-1-c-
arboxylate (500 mg) as a off white solid.
[1925] MS (ESI+) m/z 711.8 (M+H).
[1926] (481B): To a solution of tert-butyl
3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)azetidine-1-c-
arboxylate (400 mg, 0.563 mmol) in dichloromethane (4.0 mL) at
0.degree. C., was added 2,6-lutidine (0.197 mL, 1.690 mmol). After
that TMS-OTf (0.305 mL, 1.690 mmol) was added drop wise. The
reaction mixture was allowed to warm to room temperature and
stirred for 5 h. The reaction mixture was diluted with
dichloromethane (50 mL) and poured into a separating funnel
containing liquor ammonia (5 mL). The aqueous layer was extracted
with dichloromethane (2.times.50 mL). The combined organic layer
were washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The crude material was washed
with pentane (3.times.10 ml) and diethyl ether (3.times.5 mL).
After the washing the resultant solid was dried under vacuum to get
2-((3-(4-(azetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(-
cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (250 mg) as a off white solid.
[1927] MS (ESI+) m/z 610.2 (M+H)+.
[1928] (481C): To a solution of
2-((3-(4-(azetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(-
cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (100 mg, 0.164 mmol) in DCM (1.0 mL) was added TEA (0.069 mL,
0.492 mmol) followed by acetyl chloride (0.014 mL, 0.197 mmol) in a
drop wise manner. The reaction mixture was allowed to warm to room
temperature and stirred for overnight. The reaction mixture was
diluted with dichloromethane (50 mL) and poured into a separating
funnel containing saturated aqueous sodium bicarbonate (10 mL). The
aqueous layer was extracted with dichloromethane (2.times.50 mL).
The combined organics were washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated under vacuum. The crude
material was precipitated from DCM/Hexane (Dissolved in minimum
amount of DCM, precipitated by adding Hexane), filtered and dried
to get the
2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (110 mg) as a off white solid.
[1929] MS (ESI+) m/z 651.8 (M+H)+.
[1930] Example 481: To a solution of
2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (110 mg, 0.169 mmol) in DCE (1.1 mL) and anisole
(0.108 mL, 0.985 mmol) was added TFA (0.296 mL, 3.84 mmol) slowly
drop wise at room temperature and the reaction mixture was heated
at 50.degree. C. for overnight. The reaction mixture was
concentrated to remove solvent completely; the resultant residue
was washed with hexane to remove anisole. The residue was diluted
with Ethyl acetate, washed with aq. ammonia solution, brine, dried
over Na2SO4 and concentrated. The crude material was purified by
reverse phase HPLC, the fractions were concentrated and the
resultant solid was dissolved in HPLC grade Chloroform (20 ml),
washed with 10% NaHCO3 solution, brine, dried over Na2SO4 and
concentrated. The solid was dissolved in Acetonitrile/water (1:3).
Froze the mixture using a dry-ice acetone bath and then dried under
lyophilization for 2 days. Lyophlization afforded
2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(50 mg) as a off white solid.
[1931] To a suspension of
2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(48 mg, 0.090 mmol) in acetonitrile (1.0 mL) and water (1.0 mL) was
added HCl (0.090 mL, 0.090 mmol) at room temperature slowly over a
period of 10 sec. After addition of HCl, suspension became clear
solution. Froze the mixture using a dry-ice acetone bath and then
dried under lyophilization for overnight. Lyophlization afforded
2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
HCl (48 mg) as a off white solid.
[1932] MS (ESI+) m/z 533.0 (M+H)+.
[1933] 1H NMR (400 MHz, DMSO-d6): .delta. ppm 11.34 (bs, 1H), 9.35
(d, J=4.00 Hz, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 8.17 (d, J=1.20 Hz,
1H), 7.44 (s, 1H), 4.036-4.422 (m, 5H), 3.493-3.615 (m, 4H),
3.169-3.346 (m, 4H), 2.935-3.001 (m, 1H), 1.802 (s, 3H),
0.779-0.794 (m, 4H).
[1934] The compounds listed below were prepared by similar
synthetic procedures described in Examples 480
TABLE-US-00022 TABLE 19 HPLC Reten- Exam- tion ple Time No.
Structure Name (min.)* [M + H].sup.+ 481 ##STR00542##
2-[(2-chloro-5-cyano-3-{4-[1- (1- hydroxycyclopropanecarbonyl)
azetidin-3-yl]piperazin-1- yl1phenyl)amino]-4-
(cycloproplamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.19 574.2 482 ##STR00543## 2-[(2-chloro-5-cyano-3-{4-[1-
(3-methoxypropanoyl)azetidin- 3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.61 576.2 483 ##STR00544## 2-{[2-chloro-5-cyano-3-(4-{1-
[2-(oxan-4-yl)acetyl]azetidin- 3-yl}piperazin-1-
yl)phenyl]amino}-4- (cyclopropylamino)imidaxo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.24 616.2 484 ##STR00545##
2-[(2-chloro-5-cyano-3-{4-[1- (2-hydroxy-2-
methylpropanoyl)azetidin-3- yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.56 576.3 485 ##STR00546## 2-({2-chloro-5-cyano-3-[4-(1-
cyclopropanecarbonylazetidin- 3-yl)piperazin-1- yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.24 558.2 486 ##STR00547## 2-[(2-chloro-5-cyano-3-{4-[1-
(2-methanesulfonylacetyl) azetidin-3-yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.19 610.1 487 ##STR00548##
2-[(2-chloro-5-cyano-3-{4-[1- (2-hydroxypropanoyl)azetidin-
3-yl]piperazin-1- yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.50 562.2 488 ##STR00549##
2-[(2-chloro-5-cyano-3-{4-[1- (2-hydroxyacetyl)azetidin-3-
yl]piperazin-1- yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.12 548.1 489 ##STR00550##
2-[(2-chloro-5-cyano-3-{4-[1- (morpholine-2- carbonyl)azetidin-3-
yl]piperazin-1- yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.40 603.2 490 ##STR00551##
2-[(2-chloro-5-cyano-3-{4-[1- (3-hydroxy-3-
methylbutanoyl)azetidin-3- yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.14 590.3 491 ##STR00552## 2-[(2-chloro-5-cyano-3-{4-[1-
(2,2-difluoroacetyl)azetidin-3- yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.28 568.1 492 ##STR00553## N-(2-{3-[4-(2-chloro-5-cyano-
3-{[7-cyano-4- (cyclopropylamino)imidazo [2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)piperazin-1- yl]azetidin-1-yl}-2-
oxoethyl)acetamide 1.12 589.2 493 ##STR00554##
2-{[2-chloro-5-cyano-3-(4-{1- [2-(morpholin-4-
yl)acetyl]azetidin-3- yl}piperazin-1- yl)phenyl]amino}-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.10 617.2 494 ##STR00555## 2-[(2-chloro-5-cyano-3-{4-[1-
(3-hydroxy-2,2- dimethylpropanoyl)azetidin-3- yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.64 590.2 495 ##STR00556##
2-[(2-chloro-5-cyano-3-{4-[1- (3-hydroxypropanoyl)azetidin-
3-yl]piperazin-1- yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.14 562.2 496 ##STR00557##
2-{[2-chloro-5-cyano-3-(4-{1- [3-(1H-imidazol-1-
yl)propanoyl]azetidin-3- yl}piperazin-1- yl)phenyl]amino}-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
2.29 612.4 497 ##STR00558## 2-[(2-chloro-5-cyano-3-{4-[1-
(2-methoxyacetyl)azetidin-3- yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.14 562.2 498 ##STR00559## 2-{[2-chloro-5-cyano-3-(4-{1-
[(2S,4R)-4- hydroxypyrrolidine-2- carbonyl]azetidin-3-
yl}piperazin-1- yl)(phenyl]amino}-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.25 603.4 499 ##STR00560##
2-[(2-chloro-5-cyano-3-{4-[1- (2-fluoro-2-
methylpropanoyl)azetidin-3- yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.30 578.4 500 ##STR00561## 2-[(3-{4-[1-(1-
aminocyclopropanecarbonyl) azetidin-3-yl]piperazin-1-yl}-
2-chloro-5- cyanophenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.45 573.4 501 ##STR00562##
2-[(3-{4-[1-(3-amino-3- methylbutanoyl)azetidin-3-
yl]piperazin-1-yl}-2-chloro-5- cyanophenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.32 589.4 502 ##STR00563## 2-{[3-(4-[1-[(2R)-2-amino-3,3
dimethylbutanol]azetidin-3- yl}piperazin-1-yl)-2-chloro-5-
cyanophenyl]amino}-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.59 603.5 503 ##STR00564##
2-{[2-chloro-5-cyano-3-(4-{1- [(2S,4S)-4-fluoropyrrolidine-
2-carbonyl]azetidin-3- yl}piperazin-1- yl)phenyl]amino}-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.50 605.4 504 ##STR00565## 2-[(2-chloro-5-cyano-3-{4-[1-
(cyclopropanesulfonyl) azetidin-3-yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.30 594.4 505 ##STR00566##
2-{[3-(4-{1-[(2S)-2-amino-3,3- dimethylbutanoyl]azetidin-3-
yl}piperazin-1-yl)-2-chloro-5- cyanophenyl]amino}-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.59 603.4 506 ##STR00567## 2-[(2-chloro-5-cyano-3-{4-[1-
(5-oxopyrrolidine-2- carbonyl)azetidin-3- yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.39 601.4 507 ##STR00568##
2-[(2-chloro-5-cyano-3-{4-[1- (2,2,2-trifluoroethanesulfonyl)
azetidin-3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.43 636.4 508 ##STR00569## 2-[(2-chloro-5-cyano-3-{4-[1-
(3-hydroxy-3- methylpentanoyl)azetidin-3- yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.69 604.4 509 ##STR00570##
2-[(2-chloro-5-cyano-3-{4-[1- (4- hydroxycyclohexanecarbonyl)
azetidin-3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.62 616.4 510 ##STR00571## 2-{[2-chloro-5-cyano-3-(4-{1-
[(2S)-3,3,3-trifluoro-2- hydroxypropanoyl]azetidin-3-
yl}piperazin-1- yl)phenyl]amino}-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.70 616.4 511 ##STR00572##
2-[(2-chloro-5-cyano-3-{4-[1- (3-ethoxypropanoyl)azetidin-
3-yl]piperazin-1- yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.65 590.4 512 ##STR00573##
2-[(2-chloro-5-cyano-3-{4-[1- (4- hydroxycyclohexanecarbonyl)
azetidin-3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.19 616.4 513 ##STR00574## 2-{[2-chloro-5-cyano-3-(4-{1-
[(2R)-2-methoxypropanoyl] azetidin-3-yl}piperazin-1-
yl)phenyl]amino}-4- (cycloproplamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.60 576.4 514 ##STR00575##
2-{[2-chloro-5-cyano-3-(4-{1- [(3S)-3-hydroxybutanoyl]
azetidin-3-yl}piperazin-1- yl)phenyl]amino}-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.12 576.4 515 ##STR00576## 2-[(2-chloro-5-cyano-3-{4-[1-
(3-methyloxetane-3- carbonyl)azetidin-3- yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.18 588.4 516 ##STR00577##
2-[(2-chloro-5-cyano-3-{4-[1- (2,2-difluoropropanoyl)
azetidin-3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.31 582.4 517 ##STR00578## 2-[(2-chloro-5-cyano-3-{4-[1-
(oxolane-2-carbonyl)azetidin- 3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.55 588.4 518 ##STR00579## propan-2-yl 3-[4-(2-chloro-5-
cyano-3-{[7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl]amino}phenyl)piperazin-1-
yl]azetidine-1-carboxylate 2.00 576.4 519 ##STR00580##
3-{3-[4-(2-chloro-5-cyano-3- {[7-cyano-4- (cyclopropylamino)
imidazo[2,1-f][1,2,4]triazin-2- yl]amino}phenyl)piperazin-1-
yl]azetidin-1-yl}-3- oxopropanamide 1.38 575.3 520 ##STR00581##
2-[(2-chloro-5-cyano-3-{4-[1- (2- ethoxycyclopropanecarbonyl)
azetidin-3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.74 602.5 521 ##STR00582## 2-{[2-chloro-5-cyano-3-(4-{1-
[(2S)-2-methoxypropanoyl] azetidin-3-yl}piperazin-1-
yl)phenyl]amino}-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 1.23 576.3 522 ##STR00583##
2-[(2-chloro-5-cyano-3-{4-[1- (3-methyloxetane-3-
carbonyl)azetidin-3- yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
1.59 588.3 523 ##STR00584## 2-[(2-chloro-5-cyano-3-{4-[1-
(oxolane-3-carbonyl)azetidin- 3-yl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1.2.4]triazine-7- carbonitrile
1.55 588.4 524 ##STR00585## 2-{[3-(4-{[2,2-
bis(hydroxymethyl)butanoyl] azetidin-3-yl}piperazin-1-yl)-
2-chloro-5- cyanophenyl]amino}-4- (cyclopropylamino)
imidazol[2,1-f][1,2,4] triazine-7-carbonitrile 1.53 620.4
The compounds listed below were prepared by the similar synthetic
procedure used for Table 2
TABLE-US-00023 TABLE 20 HPLC Retention Example Time # Structure
Name [M + H].sup.+ (min.) 525 ##STR00586##
2-((2-chloro-5-cyano-3-(4-(oxetan-3-
yl)piperidin-1-yl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 490.4 1.00 526 ##STR00587##
2-((2-chloro-5-cyano-3-(4-(1,3- dihydroxypropan-2-yl)piperidin-1-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 508.4 0.83 527 ##STR00588##
2-((2-chloro-5-cyano-3-(4-((4,4- dimethyloxetan-2-
yl)methyl)piperazin-1- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
533.4 0.74 528 ##STR00589## 2-((2-chloro-5-cyano-3-(4-(((4R)-4-
methyloxetan-2-yl)methyl)piperazin- 1-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
519.0 0.75 529 ##STR00590## 2-((2-chloro-5-cyano-3-(4-(((4S)-4-
methyloxetan-2-yl)methyl)piperazin- 1-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
519.0 0.75 530 ##STR00591## (E)-2-((2-chloro-5-cyano-3-(4-(4-
methylpenta-2,4-dien-1-yl)piperazin- 1-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
515.4 0.79 531 ##STR00592## 2-((2-chloro-5-cyano-3-(4-
((tetrahydrofuran-2- yl)methyl)piperazin-1- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
519.3 0.72 532 ##STR00593## 2-((3-(4-((1,4-dioxan-2-
yl)methyl)piperazin-1-yl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
535.3 0.71 533 ##STR00594## (3-(hydroxymethyl)oxetan-3- yl)methyl
4-(2-chloro-5-cyano-3-((7- cyano-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazin-2-
yl)amino)phenyl)piperazine-1- carboxylate 579.4 0.83 534
##STR00595## (tetrahydrofuran-2-yl)methyl 4-(2-
chloro-5-cyano-3-((7-cyano-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazin-2- yl)amino)phenyl)piperazine-1- carboxylate 563.3
0.96 535 ##STR00596## rac-2-((2-chloro-5-cyano-3-(4-
((3R,4R)-4-hydroxy-1,1- dioxidotetrahydrothiophen-3-
yl)piperazin-1-yl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 569.3 0.71 536 ##STR00597##
2-((2-chloro-5-cyano-3-(4-(3-(2- hydroxy-2-methylpropyl)oxetan-3-
yl)piperazin-1-yl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 563.4 0.76 537 ##STR00598##
2-((2-chloro-5-cyano-3-(4-(3-(2-
hydroxyethyl)oxetan-3-yl)piperazin-1- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
535.3 0.71 538 ##STR00599## 2-((2-chloro-5-cyano-3-(4-(3-
(hydroxymethyl)oxetan-3- yl)piperazin-1-yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
521.3 0.67 539 ##STR00600## 2-((2-chloro-5-cyano-3-(4-(1,3-
dihydroxypropan-2-yl)piperazin-1- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
509.3 0.71 540 ##STR00601## N-((3-(4-(2-chloro-5-cyano-3-((7-
cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-2-
yl)amino)phenyl)piperazin-1- yl)oxetan-3-yl)methyl)acetamide 562.4
0.69 541 ##STR00602## 2-((3-(3-(4-acetylpiperazin-1-
yl)azetidin-1-yl)-2-chloro-5- cyanophenyl)amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
532.4 0.71 542 ##STR00603## 2-((2-chloro-5-cyano-3-(4-(3-
methyloxetan-3-yl)piperazin-1- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile 593.3
0.68
[1935] The compounds listed below were prepared by the similar
synthetic procedure used for Table 8
TABLE-US-00024 TABLE 21 HPLC Retention Example Time # Structure
Name [M + H].sup.+ (min.)* 544 ##STR00604## ethyl
1-(2-chloro-3-((7- cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)-5- (difluoromethyl)phenyl)
piperidine-4-carboxylate 531.3 1.09 545 ##STR00605##
1-(2-chloro-3-((7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)-5- (difluoromethyl)phenyl)
piperidine-4-carboxylic acid 503.0 0.92 546 ##STR00606##
2-((2-chloro-5- (difluoromethyl)-3-(4-(4- methylpiperazine-1-
carbonyl)piperidin-1- yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 585.4 0.74 547 ##STR00607##
1-(2-chloro-3-((7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)-5- (difluoromethyl)phenyl)-N-
(oxetan-3-yl)piperidine-4- carboxamide 558.3 0.85
The compounds listed below were prepared by the similar synthetic
procedure used for Compound 383
TABLE-US-00025 TABLE 22 HPLC Retention Example Time # Structure
Name [M + H].sup.+ (min.) 548 ##STR00608##
2-((5-cyano-2-fluoro-3-(4- (oxetan-3-yl)piperazin-1-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 474.2 1.10 549 ##STR00609##
2-((5-cyano-2-fluoro-3-(4-(3- fluoro-2- hydroxypropyl)piperazin-1-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 494.2 1.16 550 ##STR00610##
2-((3-(4-(azetidin-3- yl)piperazin-1-yl)-5-cyano-2-
fluorophenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 473.2 1.06 551 ##STR00611##
2-((3-(4-(1-acetylazetidin-3- yl)piperazin-1-yl)-5-cyano-2-
fluorophenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 515.2 1.10 552 ##STR00612##
rac-2-((5-cyano-2-fluoro-3- (4-((3R,4S)-4-
hydroxytetrahydrofuran-3- yl)piperazin-1- yl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
504.2 1.12 553 ##STR00613## rac-2-((5-cyano-2-fluoro-3-
(4-((3R,4R)-4-hydroxy-1,1- dioxidotetrahydrothiophen-3-
yl)piperazin-1- yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 552.2 1.11 554 ##STR00614##
2-((5-cyano-2-fluoro-3-(4- (tetrahydrofuran-3- yl)piperazin-1-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 488.2 1.12 555 ##STR00615##
2-((5-cyano-3-(4-(3- cyanooxetan-3-yl)piperazin-
1-yl)-2-fluorophenyl)amino)- 4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 500.4 0.90 556 ##STR00616##
2-((5-cyano-2-fluoro-3-(4- (oxetan-3-yl)piperazin-1-
yl)phenyl)amino)-4- (ethylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 462.2 1.11
Following compounds are prepared similar to compound 405
TABLE-US-00026 TABLE 23 HPLC Retention Example Time # Structure
Name [M + H].sup.+ (min.) 557 ##STR00617## 2-((2-chloro-5-
(difluoromethoxy)-3-(4- (oxetan-3-yl)piperazin-1-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 532.0 0.73 558 ##STR00618##
2-((2-chloro-5- (difluoromethoxy)-3- (piperazin-1-
yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 467.0 0.76 559 ##STR00619##
2-((3-(4-(1-acetylazetidin- 3-yl)piperazin-1-yl)-2- chloro-5-
(difluoromethoxy)phenyl) amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 573.3 0.70 560 ##STR00620##
2-((3-(4-(azetidin-3- yl)piperazin-1-yl)-2- chloro-5-
(difluoromethoxy)phenyl) amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 531.4 0.68 561 ##STR00621##
2-((2-chloro-5- (difluoromethoxy)-3-(4-(3- methyloxetan-3-
yl)piperazin-1- yl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 546.0 0.74 562 ##STR00622##
methyl 3-(4-(2-chloro-3- ((7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl)amino)-5- (difluoromethoxy)phenyl)
piperazin-1-yl)azetidine-1- carboxylate 589.3 0.74
Example 563
##STR00623##
[1936]
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide
[1937] (563A): Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate
(834 mg, 2.52 mmol), tert-butyl
2-(dimethylcarbamoyl)piperazine-1-carboxylate (647 mg, 2.52 mmol),
Pd.sub.2(dba).sub.3 (230 mg, 0.252 mmol), BINAP (157 mg, 0.252
mmol), Cs.sub.2CO.sub.3 (1229 mg, 3.77 mmol), and toluene (20 mL)
were combined in a 250 ml flask. The flask was evacuated and
backfilled with N.sub.2 3.times., and the reaction was heated at
105.degree. C. for 12 h. LCMS indicated SM was still present, so an
additional 0.1 eq. each of catalyst and ligand were added, and the
reaction was again purged with N.sub.2 and heated at 105.degree. C.
for 13 h. An additional 0.1 eq. each of catalyst and ligand were
added, and the reaction was again purged with N.sub.2 and heated at
105.degree. C. for 2 h. The reaction was cooled to room temperature
and diluted with EtOAc. The solution was filtered through celite
and the filtrate concentrated in vacuo. The crude material was
purified by flash column chromatography (0-50% EtOAc/Hex; 120 g
column). Tert-butyl
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-(dimethylcarb-
amoyl)piperazine-1-carboxylate (450 mg) was obtained as an orange
glass.
[1938] MS (ESI+) m/z 508 (M)
[1939] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.34 (d, J=1.5
Hz, 1H), 7.16 (s, 1H), 6.97 (d, J=1.8 Hz, 1H), 5.01 (br. s., 1H),
4.12-3.99 (m, J=10.1 Hz, 1H), 3.98-3.89 (m, 1H), 3.60-3.52 (m, 1H),
3.19 (s, 1H), 3.11-2.96 (m, 6H), 2.95-2.84 (m, 2H), 1.55 (s, 9H),
1.49 (s, 9H)
[1940] (563B):
Tert-butyl-4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-di-
methylcarbamoyl)piperazine-1-carboxylate (450 mg, 0.886 mmol) was
taken up in DCM (4 mL) and TFA (1.365 mL, 17.72 mmol) was added.
The reaction was stirred at room temperature for 1 h. The solvent
was removed in vacuo and the material azeotroped 3.times. with
toluene. The crude material was dried under vacuum. The
intermediate was taken up in DCM (4 mL) and Et.sub.3N (0.370 mL,
2.66 mmol) and BOC.sub.2O (0.267 mL, 1.152 mmol) were added. The
reaction was stirred at room temperature for 1 h. The reaction
mixture was diluted with DCM and washed with water, then brine. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The material was purified by flash column
chromatography (0-100% EtOAc/DCM; 40 g column). Tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)-2-(dimethylcarbamoyl)piperazine-1-carb-
oxylate (227 mg) was obtained as a yellow solid.
[1941] MS (ESI+) m/z 408 (M=+1)
[1942] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 6.89 (d, J=1.9
Hz, 1H), 6.68 (d, J=1.9 Hz, 1H), 5.58-5.51 (m, 2H), 4.86 (dd,
J=5.0, 2.2 Hz, 1H), 3.86-3.68 (m, 2H), 3.56-3.47 (m, 1H), 3.23-3.11
(m, 1H), 2.93 (quin, J=4.4 Hz, 7H), 2.82 (td, J=11.1, 5.0 Hz, 1H),
1.41 (s, 9H)
[1943] (563C):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (197 mg, 0.555 mmol), tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)-2-(dimethylcarbamoyl)piperazine-1-carb-
oxylate (227 mg, 0.557 mmol), palladium (II) acetate (37.4 mg,
0.167 mmol), DPPF (30.8 mg, 0.056 mmol), Xantphos (32.1 mg, 0.056
mmol), and cesium carbonate (271 mg, 0.833 mmol) were combined in a
100 ml round bottom flask and dioxane (5 mL) was added. The flask
was evacuated and backfilled with N.sub.2 3.times., then heated at
100.degree. C. for 1 h. Some SM remaining by LCMS. The reaction was
cooled to room temperature and an additional 0.15 eq. catalyst and
0.05 eq of each ligand was added. The flask was purged with N.sub.2
and heated for an additional 30 min. The reaction was cooled to
room temperature and filtered through celite, rinsing with EtOAc.
The solvent was removed in vacuo to leave a brown solid. The crude
material was purified by flash column chromatography (0-40%
EtOAc/DCM; 40 g column). Tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazin-
e-1-carboxylate (321 mg) was obtained as a yellow solid.
[1944] MS (ESI+) m/z 726 (M)
[1945] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.82 (br. s.,
1H), 7.94 (s, 1H), 7.51 (br. s., 1H), 7.25-7.13 (m, 2H), 6.95 (d,
J=1.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 5.70 (br. s., 2H), 5.03 (br.
s., 1H), 4.06 (br. s., 1H), 4.01-3.89 (m, 1H), 3.79 (s, 3H),
3.66-3.53 (m, 1H), 3.29-2.97 (m, 8H), 2.93 (dd, J=11.8, 5.0 Hz,
2H), 1.49 (s, 9H), 1.15 (br. s, 2H), 0.97-0.86 (m, 2H)
[1946] (563D):
Tert-butyl-4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl-
)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoy-
l)piperazine-1-carboxylate (200 mg, 0.275 mmol) was taken up in DCM
(2 mL) and cooled to 0.degree. C. 2,6-Lutidine (0.096 mL, 0.826
mmol) was added, followed by drop wise addition of TMS-OTf (0.149
mL, 0.826 mmol). The reaction was stirred at 0.degree. C. for 10
min, then brought to room temperature and stirred for 20 min. The
reaction was quenched with 2M K.sub.3PO.sub.4 solution and
extracted 2.times. with DCM. The organic layers were combined,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 188
mg of a yellow solid. The material was purified by flash column
chromatography (0-70% 10% MeOH/DCM; 24 g column).
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carbo-
xamide (133 mg) was obtained as a yellow solid.
[1947] MS (ESI+) m/z 626 (M).
[1948] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.43 (br. s.,
1H), 8.17 (s, 1H), 8.10-7.98 (m, 1H), 7.23 (d, J=2.2 Hz, 1H),
7.21-7.15 (m, 2H), 6.86 (d, J=8.9 Hz, 2H), 5.46-5.21 (m, 2H), 3.87
(dd, J=10.3, 3.1 Hz, 1H), 3.74 (s, 3H), 3.34-3.21 (m, 1H),
3.16-3.05 (m, 3H), 3.01-2.86 (m, 8H), 2.72 (td, J=11.2, 3.1 Hz,
1H), 2.64 (dd, J=11.8, 9.8 Hz, 1H), 0.97-0.83 (m, 4H)
[1949] Example 563:
Tert-butyl-4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl-
)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-dimethylcarbamoyl-
)piperazine-1-carboxylate (120 mg, 0.165 mmol) was taken up in DCE
(1 mL) and anisole (0.090 mL, 0.826 mmol) was added, followed by
TFA (0.255 mL, 3.30 mmol). The reaction was stirred at room
temperature overnight. An additional 40 eq. of TFA was added, and
the reaction was heated at 40.degree. C. for 5 h. The solvent was
removed in vacuo and the material azeotroped with toluene 3.times.
to remove the excess TFA. 10 ml of 2N NH.sub.3 in MeOH was added,
and the solution was stirred for 20 min. The solvent was removed in
vacuo and the material was triturated with MeOH/Et20 (1:20 ratio).
The solid was collected by vacuum filtration to give
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1-
,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide
(57 mg) as a yellow solid. 20 mg was further purified by
preparative HPLC to provide
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f-
][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide
(2.8 mg).
[1950] MS (ESI+) m/z 506 (M+1)
[1951] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.43-9.25 (m,
1H), 8.96 (d, J=0.9 Hz, 1H), 8.20 (s, 1H), 8.12 (d, J=1.8 Hz, 1H),
7.42 (d, J=2.0 Hz, 1H), 4.51 (d, J=11.4 Hz, 1H), 3.59 (d, J=12.8
Hz, 1H), 3.36 (d, J=8.4 Hz, 2H), 3.17 (br. s., 1H), 3.13-3.03 (m,
4H), 3.04-2.94 (m, 2H), 2.94-2.83 (m, 3H), 2.81 (dd, J=12.4, 10.9
Hz, 1H), 0.84-0.69 (m, 4H)
Example 564
##STR00624##
[1952]
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2--
carboxamide
[1953]
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide
(37 mg, 0.073 mmol, Example 563) was taken up in MeOH (0.2 mL) and
THF (0.2 mL) and oxetan-3-one (9.38 .mu.l, 0.146 mmol) and
trimethyl orthoformate (0.081 mL, 0.731 mmol) were added. The
reaction was stirred at room temperature for 3 h. Next, sodium
cyanoborohydride (9.19 mg, 0.146 mmol) and one drop of AcOH were
added and the reaction was stirred at room temperature overnight.
Only a trace of product detected by LCMS, so an additional 2 eq.
each of oxetanone and NaCNBH.sub.3 were added, and the reaction was
heated at 50.degree. C. for 8 h. The reaction was cooled to room
temperature and an additional 2 eq. each of oxetanone and reducing
agent were added. The reaction was stirred at room temperature over
the weekend. An additional 2 eq. each of oxetanone and NaCNBH.sub.3
were added, along with 1 drop of AcOH, and the reaction was heated
at 50.degree. C. for 6 h. The reaction was cooled to room
temperature and water was added; a yellow solid crashed out. The
solid was collected by filtration and purified by preparative HPLC
to provide
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carbox-
amide (1.9 mg).
[1954] MS (ESI+) m/z 562 (M)
[1955] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.36-9.28 (m,
1H), 8.86 (s, 1H), 8.19 (s, 1H), 8.12-8.08 (m, 1H), 7.34-7.29 (m,
1H), 4.60-4.51 (m, 2H), 4.41 (t, J=6.7 Hz, 1H), 4.35 (t, J=6.7 Hz,
1H), 4.02-3.91 (m, 1H), 3.19-3.09 (m, 2H), 3.09-3.00 (m, 4H), 2.96
(tt, J=8.0, 5.0 Hz, 2H), 2.83 (s, 1H), 2.77 (s, 3H), 2.58-2.52 (m,
2H), 0.87-0.68 (m, 4H)
Example 565
##STR00625##
[1956]
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperaz-
ine-2-carboxamide
[1957] (565A):
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carbo-
xamide (38 mg, 0.061 mmol, Example 563D) was taken up in DMF (0.5
mL) and Cs.sub.2CO.sub.3 (39.5 mg, 0.121 mmol) and
2-bromo-1,1-difluoroethane (5.79 .mu.l, 0.073 mmol) were added. The
reaction was heated at 80.degree. C. for 2 h. The reaction mixture
was cooled to room temperature and diluted with EtOAc. The organic
layer was extracted 2.times. with water and once with brine, then
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dime-
thyl piperazine-2-carboxamide (37 mg) was obtained as an orange
glass. The crude material was taken onto the next step.
[1958] MS (ESI+) m/z 690 (M)
[1959] Example 565:
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dime-
thylpiperazine-2-carboxamide (37 mg, 0.054 mmol) was taken up in
DCE (0.5 mL) and anisole (0.029 mL, 0.268 mmol) was added, followed
by TFA (0.124 mL, 1.608 mmol). The reaction was stirred at room
temperature overnight. LCMS indicates mostly SM is present. An
additional 30 eq. of TFA was added and the reaction was heated at
50.degree. C. After 4 h, an additional 30 eq. of TFA was added, and
the reaction heated for 1.5 h. The solvent was removed in vacuo and
the material azeotroped 2.times. with toluene, then triturated with
Et2O to remove anisole. The material was purified by preparative
HPLC to provide
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2--
carboxamide (20.1 mg,) as a yellow solid.
[1960] MS (ESI+) m/z 570 (M+1)
[1961] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.13 (br. s.,
1H), 8.13 (s, 1H), 7.68 (d, J=1.9 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H),
6.57-6.16 (m, 1H), 4.29 (br. s., 2H), 3.89 (dt, J=7.0, 3.0 Hz, 1H),
3.45-3.31 (m, J=11.5, 2.4 Hz, 1H), 3.16 (d, J=11.1 Hz, 1H),
3.08-3.02 (m, 2H), 2.95-2.87 (m, 2H), 2.85 (br. s., 3H), 2.75 (s,
3H), 2.60 (br. s., 1H), 0.73-0.54 (m, 4H)
Example 566
##STR00626##
[1962]
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1963] (566A): 5-amino-2-bromo-4-chlorobenzonitrile (1 g, 4.32
mmol), prop-2-en-1-ol (0.382 mL, 5.62 mmol), Pd.sub.2(dba).sub.3
(0.079 g, 0.086 mmol),
di-tert-butyl(2'-methyl-[1,1'-biphenyl]-2-yl)phosphine (0.081 g,
0.259 mmol), and N-cyclohexyl-N-methylcyclohexanamine (1.388 mL,
6.48 mmol) were combined in a 20 dram vial and CH.sub.3CN (8 mL)
was added. The vial was evacuated and backfilled with Ar 4.times.,
and the reaction was heated at 90.degree. C. for 45 min. The
reaction was cooled to room temperature and diluted with water,
extracting 3.times. with EtOAc. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give 1.3 g of a
yellow glass. The material was purified by flash column
chromatography (0-70% EtOAc/Hex; 80 g column).
5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (262 mg) was obtained
as yellow foam.
[1964] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.83-9.80 (m,
1H), 7.25 (s, 1H), 6.98 (s, 1H), 3.10-3.00 (m, 2H), 2.87-2.79 (m,
2H)
[1965] (566B): 5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (200
mg, 0.959 mmol) was taken up in MeOH (2 mL) and THF (2 mL) and
cooled to 0.degree. C. NaBH.sub.4 (54.4 mg, 1.438 mmol) was added,
and the reaction was stirred at 0.degree. C. for 6 h (reaction
followed by TLC). The reaction was quenched with water and
extracted 2.times. with DCM. The organic layers were combined,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
material was purified by flash column chromatography (0-50%
EtOAc/DCM; 40 g column).
5-amino-4-chloro-2-(3-hydroxypropyl)benzonitrile (125 mg) was
obtained as a yellow glass.
[1966] .sup.1H NMR (400 MHz, MeOD) .delta. 7.26 (s, 1H), 7.05 (s,
1H), 3.57 (t, J=6.4 Hz, 2H), 2.77-2.68 (m, 2H), 1.88-1.70 (m,
2H)
[1967] (566C):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (211 mg, 0.595 mmol),
5-amino-4-chloro-2-(3-hydroxypropyl)benzonitrile (125 mg, 0.595
mmol), palladium (II) acetate (40.1 mg, 0.178 mmol), DPPF (33.0 mg,
0.059 mmol), Xantphos (34.4 mg, 0.059 mmol), and cesium carbonate
(388 mg, 1.189 mmol) were combined in a 20 dram vial and dioxane (6
mL) was added. The vial was evacuated and backfilled with N.sub.2
3.times., then heated at 100.degree. C. for 30 min. The reaction
was cooled to room temperature and the reaction mixture was
filtered through celite, rinsing with EtOAc. The solvent was
removed in vacuo and the material was purified by ISCO Companion
(0-3% MeOH/DCM; 12 g column).
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (253
mg) was obtained as a yellow glass.
[1968] MS (ESI+) m/z 529 (M+1)
[1969] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.98 (d, J=4.4
Hz, 1H), 7.93 (s, 1H), 7.39 (s, 1H), 7.33 (br. s, 1H), 7.19 (d,
J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.70 (br. s, 2H), 3.79 (s,
3H), 3.74-3.68 (m, 2H), 2.99-2.85 (m, 3H), 1.98-1.89 (m, 2H), 1.49
(t, J=5.3 Hz, 1H), 1.20-1.08 (m, 2H), 0.95-0.86 (m, 2H)
[1970] Example 566:
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30
mg, 0.057 mmol) was taken up in DCE (0.6 mL) and anisole (0.031 mL,
0.284 mmol) was added, followed by TFA (0.175 mL, 2.268 mmol). The
reaction was stirred at room temperature overnight. LCMS indicates
formation of the TFA ester. The solvent was removed in vacuo and
the material dissolved in 2N NH.sub.3 in MeOH. The solution was
stirred at room temperature for 30 min. The solvent was removed in
vacuo and the material was triturated with Et2O to remove the
anisole. The material was purified by preparative HPLC to provide
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropylamino-
)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.2 mg).
[1971] MS (ESI+) m/z 409 (M+1)
[1972] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.38-9.30 (m, 1H),
8.88 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.63 (s, 1H), 4.60 (t,
J=5.0 Hz, 2H), 3.00-2.90 (m, 1H), 2.79 (dt, J=7.8, 4.0 Hz, 2H),
1.83-1.71 (m, 2H), 0.82-0.72 (m, 4H)
Example 567
##STR00627##
[1973]
2-((2-chloro-5-cyano-4-(3-morpholinopropyl)phenyl)amino)-4-(cyclopr-
opylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1974] (567A): To a solution of
5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (50 mg, 0.240 mmol,
Example 566A) in THF (0.5 mL) at room temperature was added
morpholine (37.6 mg, 0.431 mmol), sodium cyanoborohydride (30.1 mg,
0.479 mmol), and a drop of acetic acid. The reaction was stirred at
room temperature for 1 h at which point LCMS indicated full
conversion. The reaction was quenched with aq. Na.sub.2CO.sub.3 and
extracted with DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude material
was purified by flash column chromatography (0-10% MeOH/DCM) to
give 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile (54 mg) as
yellow oil.
[1975] MS (ESI+) m/z 280 (M+1)
[1976] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.21 (s, 1H),
6.97 (s, 1H), 4.19 (br. s., 2H), 3.74-3.67 (m, 4H), 2.78-2.68 (m,
2H), 2.47-2.38 (m, 4H), 2.36 (t, J=7.2 Hz, 2H), 1.80 (quin, J=7.4
Hz, 2H)
[1977] Example 567: To
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (53.2 mg, 0.15 mmol), cesium carbonate (98 mg,
0.300 mmol), palladium(II) acetate (10.10 mg, 0.045 mmol), DPPF
(8.32 mg, 0.015 mmol) and Xantphos (8.68 mg, 0.015 mmol) was added
a solution of 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile
(46.2 mg, 0.165 mmol) in dioxane (1 mL). The reaction was heated to
100.degree. C. for 1.5 h at which point LCMS showed full
conversion. The reaction mixture was cooled to room temperature and
diluted with EtOAc, filtered through a pad of celite, concentrated
and purified by flash column chromatography. The intermediate was
then treated with TFA/DCM/anisole (0.25 mL, 0.25 mL, 0.25 mL) and
stirred overnight at room temperature. The reaction mixture was
concentrated in vacuo and then diluted with MeOH (3 ml), loaded
onto an SCX column, washed with MeOH (3.times.4 mL), and then 7N
NH.sub.3/MeOH (4 mL). The ammonia filtrate was collected,
concentrated in vacuo, and purified by preparative HPLC to give
2-((2-chloro-5-cyano-4-(3-morpholinopropyl)phenyl)amino)-4-(cyclopropylam-
ino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (4.8 mg) as an
off-white solid.
[1978] MS (ESI+) m/z 478 (M+1)
[1979] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.30 (br. s.,
1H), 8.83 (br. s., 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.66 (s, 1H),
3.55 (t, J=4.4 Hz, 4H), 2.95 (dt, J=11.1, 5.5 Hz, 1H), 2.84-2.75
(m, 2H), 2.37-2.24 (m, 6H), 1.81-1.72 (m, 2H), 0.78 (d, J=5.5 Hz,
4H)
Example 568
##STR00628##
[1980]
2-((2-chloro-5-cyano-4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)p-
ropyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile
[1981] (568A):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (170 mg, 0.479 mmol),
5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (100 mg, 0.479 mmol,
Example 566A), palladium(II) acetate (32.3 mg, 0.144 mmol), DPPF
(26.6 mg, 0.048 mmol), Xantphos (27.7 mg, 0.048 mmol), and cesium
carbonate (312 mg, 0.958 mmol) were combined in a 50 ml round
bottom flask and dioxane (4 mL) was added. The flask was evacuated
and backfilled with N.sub.2 3.times., then heated at 100.degree. C.
for 2 h. The reaction was cooled to room temperature and filtered
through celite, rinsing with EtOAc. The solvent was removed in
vacuo and the material was purified by flash column chromatography
(0-80% EtOAc/Hex; 40 g column).
2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methox-
ybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (49 mg)
was obtained.
[1982] MS (ESI+) m/z 527 (M+1)
[1983] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.83 (s, 1H),
9.01 (br. s., 1H), 7.94 (s, 1H), 7.41 (s, 1H), 7.19 (d, J=8.6 Hz,
2H), 6.85 (d, J=8.8 Hz, 2H), 5.70 (br. s., 2H), 3.79 (s, 3H),
3.19-3.06 (m, 2H), 2.92-2.86 (m, 2H), 2.86-2.79 (m, J=4.5, 2.8 Hz,
1H), 1.23-1.06 (m, 2H), 0.97-0.85 (m, 2H)
[1984] (568B):
2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methox-
ybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (49 mg,
0.093 mmol) was taken up in THF (1 mL) and
2-(piperidin-4-yl)propan-2-ol (26.6 mg, 0.186 mmol), AcOH (5.32
.mu.l, 0.093 mmol), and sodium cyanoborohydride (11.69 mg, 0.186
mmol) were added. The reaction was stirred at room temperature
overnight. The reaction mixture was quenched with 2M
K.sub.3PO.sub.4 solution and extracted with EtOAc. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The material was purified by flash column chromatography (0-100%
EtOAc/DCM then flushed with 10% MeOH/DCM; 24 g column).
2-((2-chloro-5-cyano-4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)propyl)-
phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tr-
iazine-7-carbonitrile (43 mg) was obtained as a yellow glass.
[1985] MS (ESI+) m/z 654 (M)
[1986] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.96 (br. s.,
1H), 7.93 (s, 1H), 7.38 (s, 1H), 7.32 (br. s., 1H), 7.19 (d, J=8.8
Hz, 2H), 6.89-6.80 (m, 2H), 5.69 (br. s., 2H), 3.78 (s, 3H),
3.15-3.00 (m, 2H), 2.92 (s, 1H), 2.81 (t, J=7.7 Hz, 2H), 2.43 (t,
J=7.5 Hz, 2H), 2.05-1.83 (m, 4H), 1.81-1.68 (m, 2H), 1.55-1.39 (m,
2H), 1.35-1.23 (m, 1H), 1.24-1.09 (m, 9H), 0.97-0.85 (m, 2H)
[1987] Example 568:
2-((2-chloro-5-cyano-4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)propyl)-
phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]tr-
iazine-7-carbonitrile (43 mg, 0.066 mmol) was taken up in DCE (1
mL) and anisole (0.036 mL, 0.329 mmol) was added, followed by TFA
(0.203 mL, 2.63 mmol). The reaction was stirred at room temperature
overnight. LCMS indicated some SM still remaining. An additional 40
eq. of TFA was added and the reaction was heated at 50.degree. C.
for 1 h. The reaction was cooled to room temperature, the solvent
was removed in vacuo and the material dissolved in MeOH. The
material was loaded onto an SCX column (1 g, benzenesulfonic acid)
and the column was flushed with MeOH, then 2N NH.sub.3/MeOH to
obtain the product. The solvent was removed in vacuo and the
purified by preparative HPLC.
2-((2-chloro-5-cyano-4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)propyl)-
phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (21.8 mg) was obtained.
[1988] MS (ESI+) m/z 534 (M)
[1989] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39-9.28 (m,
1H), 8.85 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.65 (s, 1H),
2.98-2.84 (m, 3H), 2.81-2.74 (m, 2H), 2.25 (t, J=7.0 Hz, 2H),
1.84-1.67 (m, 4H), 1.65-1.56 (m, 2H), 1.29-1.05 (m, 3H), 1.00 (s,
6H), 0.77 (d, J=5.5 Hz, 4H)
Example 569
##STR00629##
[1990]
2-((2-chloro-5-cyano-4-(3-(3-hydroxyazetidin-1-yl)propyl)phenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[1991] (569A):
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (95
mg, 0.180 mmol, Example 566C) was taken up in DCM (1.5 mL) and
cooled to 0.degree. C. Et.sub.3N (0.038 mL, 0.269 mmol) was added,
followed by MsCl (0.017 mL, 0.216 mmol). The reaction was stirred
at 0.degree. C. for 30 min. The reaction was diluted with DCM and
washed with saturated NH4Cl solution. The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated.
1-(3-(5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)propyl)azetidin-3-yl
methanesulfonate (101 mg) was obtained. The crude material was
taken onto the next step.
[1992] MS (ESI+) m/z 607 (M)
[1993] (569B):
3-(5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)propyl methanesulfonate
(45 mg, 0.074 mmol) was taken up in acetonitrile (1 mL) and
Et.sub.3N (0.015 mL, 0.111 mmol) and azetidin-3-ol (6.50 mg, 0.089
mmol) were added. The reaction was heated at 60.degree. C.
overnight. A mixture of product and SM detected by LCMS. An
additional 1.2 eq of amine in 0.2 ml of DMF was added, and the
reaction was heated at 60.degree. C. overnight. The reaction
mixture was cooled to room temperature and diluted with EtOAc. The
organic layer was washed 2.times. with water and once with brine,
then dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
material was purified by flash column chromatography (0-10%
MeOH/DCM; 24 g column).
2-((2-chloro-5-cyano-4-(3-(3-hydroxyazetidin-1-yl)propyl)phenyl)amino)-4--
(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (13 mg) was obtained as a purple glass.
[1994] MS (ESI+) m/z 584 (M)
[1995] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.97 (d, J=2.0
Hz, 1H), 7.93 (s, 1H), 7.36 (s, 2H), 7.19 (d, J=8.6 Hz, 2H),
6.90-6.80 (m, 2H), 5.91-5.57 (m, 2H), 4.47 (dt, J=11.6, 5.7 Hz,
1H), 3.79 (s, 3H), 3.77-3.67 (m, 2H), 3.13-2.97 (m, 2H), 2.92 (dt,
J=15.6, 7.6 Hz, 1H), 2.81 (dd, J=8.5, 6.9 Hz, 2H), 2.58 (t, J=7.3
Hz, 2H), 1.81-1.66 (m, 2H), 1.22-1.05 (m, 2H), 0.96-0.87 (m,
2H)
[1996] Example 569:
2-((2-chloro-5-cyano-4-(3-(3-hydroxyazetidin-1-yl)propyl)phenyl)amino)-4--
(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (13 mg, 0.022 mmol) was taken up in DCE (0.5 mL) and anisole
(0.012 mL, 0.111 mmol) was added, followed by TFA (0.069 mL, 0.890
mmol). The reaction was stirred at room temperature overnight. The
solvent was removed in vacuo and the material dissolved in MeOH.
The material was loaded onto an SCX column (1 g, benzenesulfonic
acid) and the column was flushed with MeOH, then 2N NH.sub.3/MeOH
to obtain the product. The solvent was removed in vacuo and the
material was purified by preparative HPLC.
2-((2-chloro-5-cyano-4-(3-(3-hydroxyazetidin-1-yl)propyl)phenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(3.6 mg) was obtained.
[1997] MS (ESI+) m/z 464 (M+1)
[1998] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.87 (s, 1H),
8.34 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 4.23-4.10
(m, J=5.4 Hz, 1H), 3.90 (s, 2H), 2.93 (br. s., 1H), 2.79-2.73 (m,
2H), 2.42 (br. s., 2H), 1.90 (s, 2H), 1.67-1.55 (m, J=6.7 Hz, 2H),
0.77 (d, J=5.0 Hz, 4H)
Example 570
##STR00630##
[1999]
2-((2-chloro-5-cyano-4-(3-(3-methoxyazetidin-1-yl)propyl)phenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2000] (570A):
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (82
mg, 0.155 mmol, Example 566C) was taken up in DCM (1 mL) and cooled
to 0.degree. C. Dess-Martin periodinane (85 mg, 0.202 mmol) was
added, and the reaction was stirred at room temperature for 1.5 h.
An additional 0.2 eq. of Dess-Martin (13 mg) was added and the
reaction stirred for 1 h. The reaction mixture was quenched with 2M
K.sub.3PO.sub.4 solution and extracted 2.times. with DCM. The
organic layers were combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The material was purified by flash
column chromatography (0-60% EtOAc/Hex; 40 g column).
2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methox-
ybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg)
was obtained as a yellow glass.
[2001] MS (ESI+) m/z 527 (M+1)
[2002] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.82 (s, 1H),
9.00 (d, J=0.9 Hz, 1H), 7.93 (s, 1H), 7.40 (s, 2H), 7.19 (d, J=8.6
Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.70 (br. s., 2H), 3.78 (s, 3H),
3.19-3.06 (m, 2H), 2.98-2.79 (m, 3H), 1.21-1.03 (m, 2H), 0.96-0.87
(m, 2H)
[2003] (570B):
2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methox-
ybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg,
0.076 mmol) was taken up in THF (0.5 mL) and a solution of
3-methoxyazetidine (9.92 mg, 0.114 mmol) in MeOH (0.2 mL) was
added, followed by a drop of AcOH and sodium cyanoborohydride (9.54
mg, 0.152 mmol). The reaction was stirred at room temperature for 1
h. The reaction was diluted with EtOAc and washed with water, then
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The material was purified by flash column
chromatography (0-10% MeOH/DCM; 24 g column).
2-((2-chloro-5-cyano-4-(3-(3-methoxyazetidin-1-yl)propyl)phenyl)amino)-4--
(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (30 mg) was obtained as a colorless glass.
[2004] MS (ESI+) m/z 598 (M)
[2005] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.98 (br. s,
1H), 7.92 (s, 1H), 7.44-7.29 (m, 2H), 7.19 (d, J=8.6 Hz, 2H),
6.95-6.79 (m, 2H), 5.69 (br. s., 2H), 4.26-4.13 (m, 1H), 4.10-3.98
(m, 2H), 3.78 (s, 3H), 3.34-3.20 (m, 5H), 3.04-2.73 (m, 5H),
1.92-1.73 (m, 2H), 1.24-1.06 (m, 2H), 0.98-0.86 (m, 2H)
[2006] Example 570:
2-((2-chloro-5-cyano-4-(3-(3-methoxyazetidin-1-yl)propyl)phenyl)amino)-4--
(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (36 mg, 0.060 mmol) was taken up in DCE (1 mL) and anisole
(0.033 mL, 0.301 mmol) was added, followed by TFA (0.185 mL, 2.408
mmol). The reaction was stirred at room temperature over the
weekend. The solvent was removed in vacuo and the material
dissolved in MeOH. The material was loaded onto an SCX column (1 g,
benzenesulfonic acid) and the column was flushed with MeOH, then 2N
NH.sub.3/MeOH to obtain the product. The solvent was removed in
vacuo and purified by preparative HPLC.
2-((2-chloro-5-cyano-4-(3-(3-methoxyazetidin-1-yl)propyl)phenyl)amino)-4--
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(15.8 mg) was obtained.
[2007] MS (ESI+) m/z 478 (M+1)
[2008] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (d, J=3.4
Hz, 1H), 8.88 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.63 (s, 1H),
3.95 (d, J=6.1 Hz, 1H), 3.55 (s, 2H), 3.14 (s, 3H), 2.98-2.91 (m,
2H), 2.85-2.73 (m, 3H), 2.45 (br. s., 2H), 1.62 (dt, J=8.7, 4.2 Hz,
2H), 0.77 (d, J=5.7 Hz, 4H)
Example 571
##STR00631##
[2009]
2-((2-chloro-5-cyano-4-(4-(3-methoxyazetidin-1-yl)butyl)phenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2010] (571A): 5-amino-2-bromo-4-chlorobenzonitrile (4 g, 17.28
mmol) and N-cyclohexyl-N-methylcyclohexanamine (5.55 mL, 25.9 mmol)
were combined in a 250 ml flask and 2 ml of DMF was added. The
flask was evacuated and backfilled with Ar 4.times.. A suspension
of Pd.sub.2 (dba) 3 (0.316 g, 0.346 mmol) and
di-tert-butyl(2'-methyl-[1,1'-biphenyl]-2-yl)phosphine (0.324 g,
1.037 mmol) in CH.sub.3CN (32 mL) was heated at 60.degree. C. for 1
min until the solids dissolved and then cooled to room temperature.
The solution was added to the flask by syringe, and then
but-3-en-1-ol (1.933 mL, 22.46 mmol) was added. The reaction was
heated at 90.degree. C. for 45 min. The reaction was cooled to room
temperature and diluted with H.sub.2O, extracting 3.times. with
EtOAc. The organic layers were dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The material was purified by flash
column chromatography (0-70% EtOAc/Hex; 330 g column).
5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (0.9 g) was obtained as
yellow foam.
[2011] MS (ESI+) m/z 222 (M)
[2012] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.80 (s, 1H),
7.22 (s, 1H), 6.98 (s, 1H), 4.20-4.16 (m, 2H), 2.80-2.70 (m, 2H),
2.61-2.46 (m, 2H), 1.97 (quin, J=7.5 Hz, 2H)
[2013] (571B): 5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (544 mg,
2.443 mmol) was taken up in MeOH (6 mL) and THF (2.000 mL) and
cooled to 0.degree. C. NaBH.sub.4 (277 mg, 7.33 mmol) was added,
and the reaction was stirred at 0.degree. C. for 2 h (reaction
followed by TLC until no SM detected). The reaction was quenched
with water and extracted 2.times. with DCM. The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The material was purified by flash column chromatography (0-50%
EtOAc/DCM; 40 g column).
5-amino-4-chloro-2-(4-hydroxybutyl)benzonitrile (260 mg) was
obtained as a yellow glass.
[2014] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.20 (s, 1H),
6.97 (s, 1H), 4.17 (br. s., 2H), 3.68 (q, J=6.1 Hz, 2H), 2.73 (t,
J=7.5 Hz, 2H), 1.77-1.57 (m, 4H), 1.51 (q, J=5.3 Hz, 1H)
[2015] (571C):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (269 mg, 0.758 mmol),
5-amino-4-chloro-2-(4-hydroxybutyl)benzonitrile (170 mg, 0.758
mmol), palladium(II) acetate (51.1 mg, 0.227 mmol), DPPF (42.0 mg,
0.076 mmol), Xantphos (43.9 mg, 0.076 mmol), and cesium carbonate
(494 mg, 1.516 mmol) were combined in a 20 dram vial and dioxane (8
mL) was added. The vial was evacuated and backfilled with N.sub.2
3.times., then heated at 100.degree. C. for 30 min. The reaction
mixture was cooled to room temperature and filtered through celite,
rinsing with EtOAc. The solvent was removed in vacuo and the
material was purified by flash column chromatography (0-40%
EtOAc/DCM; 80 g column).
2-((2-chloro-5-cyano-4-(4-hydroxybutyl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186
mg) was obtained as a yellow foam.
[2016] MS (ESI+) m/z 543 (M)
[2017] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.10-8.88 (m,
1H), 7.94 (s, 1H), 7.36 (s, 2H), 7.19 (d, J=8.6 Hz, 2H), 6.85 (d,
J=8.6 Hz, 2H), 5.71 (br. s., 2H), 3.79 (s, 3H), 3.76-3.65 (m, 2H),
2.91 (br. s., 1H), 2.82 (t, J=7.6 Hz, 2H), 1.82-1.60 (m, 4H),
1.38-1.30 (m, 1H), 1.18-1.08 (m, 2H), 0.96-0.84 (m, 2H)
[2018] (571D):
2-((2-chloro-5-cyano-4-(4-hydroxybutyl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186
mg, 0.343 mmol) was taken up in DCM (3 mL) and cooled to 0.degree.
C. Dess-Martin periodinane (189 mg, 0.445 mmol) was added, and the
reaction was stirred at room temperature for 1.5 h. The reaction
mixture was quenched with 2M K.sub.3PO.sub.4 solution and extracted
2.times. with DCM. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography (0-60% EtOAc/Hex; 40 g
column).
2-((2-chloro-5-cyano-4-(4-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxy-
benzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (135 mg)
was obtained as a yellow glass.
[2019] MS (ESI+) m/z 541 (M)
[2020] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.84-9.78 (m,
1H), 8.98 (br. s, 1H), 7.92 (s, 1H), 7.35 (s, 2H), 7.22-7.15 (m,
2H), 6.86-6.78 (m, 2H), 5.69 (d, J=1.3 Hz, 2H), 3.77 (s, 3H),
2.99-2.86 (m, 1H), 2.84-2.77 (m, 2H), 2.61-2.51 (m, 2H), 2.03-1.94
(m, 2H), 1.19-1.06 (m, 2H), 1.00-0.85 (m, 2H)
[2021] (571E):
2-((2-chloro-5-cyano-4-(4-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxy-
benzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (22 mg,
0.041 mmol) was taken up in THF (0.3 mL) and a solution of
3-methoxyazetidine (5.31 mg, 0.061 mmol) in MeOH (0.1 mL) was
added, followed by a drop of AcOH and sodium cyanoborohydride (5.11
mg, 0.081 mmol). The reaction was stirred at room temperature for 1
h. The reaction was diluted with EtOAc and washed with water, then
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The material was purified by flash column
chromatography (0-7% MeOH/DCM; 24 g column).
2-((2-chloro-5-cyano-4-(4-(3-methoxyazetidin-1-yl)butyl)phenyl)amino)-4-(-
cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (12 mg) was obtained as a yellow glass.
[2022] MS (ESI+) m/z 612 (M)
[2023] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.08-8.85 (m,
1H), 7.93 (s, 1H), 7.36 (s, 2H), 7.24-7.14 (m, 2H), 6.85 (d, J=8.6
Hz, 2H), 5.69 (br. s., 2H), 4.27-4.18 (m, 1H), 4.18-4.05 (m, 2H),
3.79 (s, 3H), 3.40-3.28 (m, 5H), 3.00-2.84 (m, 3H), 2.82-2.72 (m,
2H), 1.75-1.65 (m, 2H), 1.65-1.55 (m, 2H), 1.14 (s, 2H), 0.97-0.86
(m, 2H)
[2024] Example 571:
2-((2-chloro-5-cyano-4-(4-(3-methoxyazetidin-1-yl)butyl)phenyl)amino)-4-(-
cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (12 mg, 0.020 mmol) was taken up in DCE (1 mL) and anisole
(10.71 .mu.l, 0.098 mmol) was added, followed by TFA (0.060 mL,
0.784 mmol). The reaction was stirred at room temperature
overnight. Some SM still remaining by LCMS, so an additional 60
.mu.L of TFA was added and the reaction was heated at 50.degree. C.
for 1 h. The solvent was removed in vacuo and the material
dissolved in MeOH. The material was loaded onto an SCX column (1 g,
benzenesulfonic acid) and the column was flushed with MeOH, then 2N
NH.sub.3/MeOH to obtain the product. The solvent was removed in
vacuo and purified by preparative HPLC to provide
2-((2-chloro-5-cyano-4-(4-(3-methoxyazetidin-1-yl)butyl)phenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10
mg).
[2025] MS (ESI+) m/z 492 (M+1)
[2026] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.00 (s, 1H),
7.87 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.73-6.67 (m, 1H), 3.63
(br. s., 2H), 3.36 (s, 3H), 3.06 (ddt, J=10.6, 7.0, 3.6 Hz, 2H),
3.02-2.86 (m, J=5.3 Hz, 4H), 2.83 (t, J=7.4 Hz, 2H), 1.82-1.71 (m,
2H), 1.37-1.23 (m, 2H), 1.11 (ddt, J=7.1, 5.7, 3.6 Hz, 2H),
0.85-0.78 (m, 2H)
Example 572
##STR00632##
[2027]
2-((2-chloro-5-cyano-4-(4-morpholinobutyl)phenyl)amino)-4-(cyclopro-
pylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2028] (572A): To a solution of
5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (35 mg, 0.157 mmol) in
THF (0.5 mL) at room temperature was added morpholine (24.65 mg,
0.283 mmol), sodium cyanoborohydride (19.76 mg, 0.314 mmol), and a
drop of acetic acid. The reaction was stirred at room temperature
for 1 h at which point LCMS indicated full conversion. The reaction
was quenched with aq. Na.sub.2CO.sub.3, extracted w/DCM,
concentrated and purified by flash column chromatography (0-10%
MeOH/DCM) to give
5-amino-4-chloro-2-(4-morpholinobutyl)benzonitrile (29 mg) as a
yellow oil.
[2029] MS (ESI+) m/z 294 (M+1)
[2030] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.20 (s, 1H),
6.97 (s, 1H), 4.13 (br. s., 2H), 3.78-3.67 (m, 4H), 2.73 (t, J=7.6
Hz, 2H), 2.48-2.40 (m, 4H), 2.40-2.32 (m, 2H), 1.72-1.46 (m,
4H)
[2031] Example 572: To
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (53.2 mg, 0.15 mmol), cesium carbonate (98 mg,
0.300 mmol), palladium(II) acetate (10.10 mg, 0.045 mmol), DPPF
(8.32 mg, 0.015 mmol) and Xantphos (8.68 mg, 0.015 mmol) was added
a solution of 5-amino-4-chloro-2-(4-morpholinobutyl)benzonitrile
(48.5 mg, 0.165 mmol) in dioxane (1 mL). The reaction was heated at
100.degree. C. for 1.5 h at which point LCMS showed full
conversation. The reaction was cooled to room temperature and
diluted with EtOAc, filtered through a pad of celite, concentrated
and purified by flash column chromatography. The intermediate was
then treated with TFA/DCM/anisole (0.25 mL, 0.25 mL, 0.25 mL) and
stirred overnight at room temperature. The reaction mixture was
concentrated in vacuo and then diluted with MeOH (3 ml), loaded
onto an SCX column, washed with MeOH (3.times.4 mL), and then 7N
NH.sub.3/MeOH (4 mL). The ammonia filtrate was collected,
concentrated in vacuo, and purified by preparative HPLC to give
2-((2-chloro-5-cyano-4-(4-morpholinobutyl)phenyl)amino)-4-(cyclopropylami-
no)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.5 mg) as an
off-white solid.
[2032] LCMS room temperature=0.73 min
[2033] MS (ESI+) m/z 492 (M+1)
Example 573
##STR00633##
[2034]
2-((2-chloro-5-cyano-3-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)pheny-
l)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2035] (573A): Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate
(6.2 g, 18.70 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.22
g, 20.57 mmol)), PdCl.sub.2(DPPF)-CH.sub.2Cl.sub.2 adduct (0.458 g,
0.561 mmol), and potassium acetate (5.51 g, 56.1 mmol)) were
charged to a 250 mL round bottom flask, which was evacuated and
refilled w/ Ar. Dioxane (80 mL) was added, and the reaction was
heated to 90.degree. C. overnight. The reaction mixture was cooled
to room temperature, diluted w/EtOAc, washed with brine, and
concentrated in vacuo. The material was purified by flash column
chromatography (0-100% Hexanes/EtOAc; 330 g column). Tert-butyl
(2-chloro-5-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)c-
arbamate (6 g) was obtained as a white solid.
[2036] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.64 (d, J=1.8
Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.22 (s, 1H), 1.55 (s, 9H), 1.38
(s, 12H)
[2037] (573B): Tert-butyl
(2-chloro-5-cyano-3-(3-hydroxyprop-1-en-2-yl)phenyl)carbamate (161
mg, 0.521 mmol) was taken up in EtOH (3 mL) and the solution was
purged with N.sub.2. Next, Pd/C (55.5 mg, 0.052 mmol) was added and
the solution was again evacuated and purged with N.sub.2 3.times..
Next, a balloon with H.sub.2 was added, and the reaction was
stirred for 1 h. The reaction mixture was filtered through celite,
rinsing with MeOH. The solvent was removed in vacuo and the
material was purified by flash column chromatography (0-50%
EtOAc/Hex; 40 g column). Tert-butyl
(2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)carbamate (36 mg)
was obtained as a colorless glass.
[2038] MS (ESI+) m/z 311 (M+1)
[2039] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.45 (dd, J=1.5,
0.4 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.20 (br. s., 1H), 3.83-3.69
(m, 2H), 3.54 (sxt, J=6.7 Hz, 1H), 1.54 (s, 9H), 1.29 (d, J=7.0 Hz,
3H)
[2040] (573C): Tert-butyl
(2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)carbamate (50 mg,
0.161 mmol) was taken up in CH.sub.2Cl.sub.2 (1 mL) and TFA (0.248
mL, 3.22 mmol) was added. The reaction was stirred at room
temperature for 1.5 h. Two peaks detected by LCMS--the desired
product and TFA ester. The solvent was removed in vacuo and the
material dried under vacuum overnight to provide 41 mg of material.
The material was converted to the free base by dissolving the
material in MeOH and passing through an SCX column (1 g,
benzenesulfonic acid sorbent), rinsing first with MeOH, then 2N
NH.sub.3 in MeOH to release the product. The solvent was removed in
vacuo to give 3-amino-4-chloro-5-(1-hydroxypropan-2-yl)benzonitrile
(25 mg) as a yellow glass.
[2041] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.96 (d, J=2.0
Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 4.35 (br. s., 2H), 3.83-3.68 (m,
2H), 3.53 (sxt, J=6.7 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H)
[2042] (573D):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (42 mg, 0.118 mmol),
3-amino-4-chloro-5-(1-hydroxypropan-2-yl)benzonitrile (24.94 mg,
0.118 mmol), palladium(II) acetate (7.97 mg, 0.036 mmol), DPPF
(6.56 mg, 0.012 mmol), Xantphos (6.85 mg, 0.012 mmol), and cesium
carbonate (77 mg, 0.237 mmol) were combined in a 2 dram vial and
dioxane (1.2 mL) was added. The vial was evacuated and backfilled
with N.sub.2 3.times., then heated at 100.degree. C. for 1.5 h. The
reaction was cooled to room temperature and filtered through
celite, rinsing with EtOAc. The solvent was removed in vacuo and
the material was purified by flash column chromatography (0-3%
MeOH/DCM; 40 g column).
2-((2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)amino)-4-(cyclopropyl-
(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(37 mg) was obtained as a yellow glass.
[2043] MS (ESI+) m/z 529 (M+1)
[2044] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.93 (br. s.,
1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.19 (d,
J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.70 (br. s, 2H), 3.86-3.76
(m, 5H), 3.59 (dq, J=13.1, 6.8 Hz, 1H), 2.91 (s, 1H), 1.32 (d,
J=7.0 Hz, 3H), 1.17-1.10 (m, 2H), 0.95-0.87 (m, 2H)
[2045] (573E):
2-((2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)amino)-4-(cyclopropyl-
(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(37 mg, 0.070 mmol) was taken up in DCM (1 mL) and the solution was
cooled to 0.degree. C. Dess-Martin periodinane (35.6 mg, 0.084
mmol) was added, and the reaction was stirred at 0.degree. C. for
1.5 h. Some SM still remaining, so an additional 0.4 eq. (12 mg) of
Dess-Martin was added, and the reaction was stirred for 30 min. The
reaction was quenched with 2M K.sub.3PO.sub.4 and extracted with
DCM. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The material was purified by flash column
chromatography (0%-60% EtOAc/Hex; 12 g column).
2-((2-chloro-5-cyano-3-(1-oxopropan-2-yl)phenyl)amino)-4-(cyclopropyl(4-m-
ethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25
mg) was obtained as a glassy liquid.
[2046] MS (ESI+) m/z 526 (M)
[2047] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.74 (s, 1H),
9.06 (br. s, 1H), 7.95 (s, 1H), 7.53 (br. s., 1H), 7.19 (d, J=8.8
Hz, 2H), 7.10 (d, J=2.0 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 5.71 (br.
s, 2H), 4.19 (q, J=7.4 Hz, 1H), 3.79 (s, 3H), 2.93 (br. s, 1H),
1.52 (d, J=7.0 Hz, 3H), 1.15 (s, 2H), 0.96-0.88 (m, 2H)
[2048] (573F):
2-((2-chloro-5-cyano-3-(1-oxopropan-2-yl)phenyl)amino)-4-(cyclopropyl(4-m-
ethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25
mg, 0.047 mmol) was taken up in THF (0.5 mL) and a solution of
azetidin-3-ol (6.94 mg, 0.095 mmol) in MeOH (0.333 mL) was added. A
drop of AcOH was added and the solution was stirred for 10 min.
Next, sodium cyanoborohydride (5.96 mg, 0.095 mmol) was added and
the reaction was stirred for 1 h. The reaction was diluted with
EtOAc and washed with 2M K.sub.3PO.sub.4 solution. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The material was purified by flash column chromatography (0-10%
MeOH/DCM; 12 g column).
2-((2-chloro-5-cyano-3-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)phenyl)amin-
o)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile (17.5 mg) was obtained as a yellow glass.
[2049] MS (ESI+) m/z 584 (M)
[2050] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.92 (br. s,
1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.24-7.11 (m, 3H), 6.85 (d, J=8.8
Hz, 2H), 5.70 (br. s., 2H), 4.41 (quin, J=5.8 Hz, 1H), 3.79 (s,
3H), 3.69-3.61 (m, 2H), 3.47-3.37 (m, 1H), 3.06-2.97 (m, 2H), 2.91
(br. s., 1H), 2.79-2.60 (m, 2H), 1.27 (d, J=6.8 Hz, 3H), 1.20-1.07
(m, 2H), 0.98-0.87 (m, 2H)
[2051] Example 573:
2-((2-chloro-5-cyano-3-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)phenyl)amin-
o)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile (17.5 mg, 0.030 mmol) was taken up in DCE (1 mL) and
anisole (0.016 mL, 0.150 mmol) was added, followed by TFA (0.092
mL, 1.198 mmol). The reaction was stirred at room temperature
overnight. Some starting material was still remaining, so an
additional 20 eq. (46 .mu.L) of TFA was added and the reaction was
heated at 50.degree. C. for 2 h. The solvent was removed in vacuo
and the material dissolved in MeOH. The material was loaded onto an
SCX column (1 g, benzenesulfonic acid) and the column was flushed
with MeOH, then 2N NH.sub.3/MeOH to obtain the product. The solvent
was removed in vacuo and the material purified by preparative HPLC.
2-((2-chloro-5-cyano-3-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)phenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(6.6 mg,) was obtained.
[2052] MS (ESI+) m/z 464 (M+1)
[2053] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.35 (d, J=3.0
Hz, 1H), 8.89 (br. s., 1H), 8.28 (br. s., 1H), 8.20 (s, 1H), 7.61
(d, J=0.7 Hz, 1H), 4.33-4.02 (m, 1H), 3.48-3.26 (m, 3H), 3.01-2.92
(m, 2H), 2.88-2.82 (m, 1H), 2.46 (br. s., 2H), 1.18 (d, J=6.4 Hz,
3H), 0.78 (d, J=5.4 Hz, 4H)
Example 574
##STR00634##
[2054]
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclop-
ropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2055] (574A): Tert-butyl
(2-chloro-5-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)c-
arbamate (864 mg, 2.282 mmol),
(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoe-
thyl)phenyl]palladium(II) chloride (84 mg, 0.114 mmol), and
potassium phosphate, dibasic (1192 mg, 6.85 mmol) were added to a
100 ml flask, and the flask was purged with N.sub.2.
3-bromobut-3-en-1-ol (0.226 mL, 2.282 mmol) and THF (12 mL) were
added, followed by water (2.182 mL). The reaction was heated at
60.degree. C. for 1 h. The reaction was cooled to room temperature
and diluted with EtOAc. The organic layer was washed with water,
then brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The material was purified by flash column
chromatography (0-50% EtOAc/Hex; 120 g column). Tert-butyl
(2-chloro-5-cyano-3-(4-hydroxybut-1-en-2-yl)phenyl)carbamate (317
mg) was obtained as a colorless glass.
[2056] MS (ESI+) m/z 323 (M+1)
[2057] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.52 (d, J=1.5
Hz, 1H), 7.19 (br. s., 1H), 7.16 (d, J=1.8 Hz, 1H), 5.43 (s, 1H),
5.14 (s, 1H), 3.67 (q, J=5.9 Hz, 2H), 2.68 (t, J=6.3 Hz, 2H), 1.55
(s, 9H)
[2058] (574B): Tert-butyl
(2-chloro-5-cyano-3-(4-hydroxybut-1-en-2-yl)phenyl)carbamate (272
mg, 0.843 mmol) was taken up in EtOH (8 mL) and the flask was
evacuated and filled with N.sub.2 3.times.. Next, platinum (IV)
oxide (19.14 mg, 0.084 mmol) was added, and the flask was purged
again. The reaction was stirred under 1 atm hydrogen at room
temperature for 3 h. The reaction was monitored by TLC. The
reaction mixture was filtered through celite, rinsing with MeOH.
The solvent was removed in vacuo and the material was purified by
flash column chromatography (0-40% EtOAc/Hex; 40 g column).
Tert-butyl
(2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)carbamate (161 mg)
was obtained as a colorless glassy liquid.
[2059] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.45 (d, J=1.3
Hz, 1H), 7.22 (s, 1H), 7.20 (br. s., 1H), 3.73-3.56 (m, 2H),
3.56-3.46 (m, 1H), 1.95-1.79 (m, 2H), 1.55 (s, 9H), 1.28 (d, J=6.8
Hz, 3H)
[2060] (574C): Tert-butyl
(2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)carbamate (184 mg,
0.566 mmol) was taken up in DCM (6 mL) and TFA (1.746 mL, 22.66
mmol) was added. The reaction was stirred at room temperature for 1
h. LCMS indicates a mixture of the alcohol and the TFA ester. The
solvent was removed in vacuo and the material dissolved in 2N
NH.sub.3 in MeOH. The solution was stirred at room temperature for
10 min and the solvent removed in vacuo.
3-amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile (162 mg) was
obtained. The crude material was taken forward without
purification.
[2061] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.92 (d, J=1.3
Hz, 1H), 6.87 (d, J=1.3 Hz, 1H), 4.35 (br. s., 2H), 3.70-3.55 (m,
2H), 3.48 (dq, J=14.1, 7.0 Hz, 1H), 1.94-1.77 (m, 2H), 1.25 (d,
J=6.8 Hz, 3H)
[2062] (574D):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (218 mg, 0.614 mmol),
3-amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile (138 mg, 0.614
mmol), palladium(II) acetate (41.4 mg, 0.184 mmol), DPPF (34.1 mg,
0.061 mmol), Xantphos (35.6 mg, 0.061 mmol), and cesium carbonate
(400 mg, 1.229 mmol) were combined in a 50 ml flask and dioxane (6
mL) was added. The flask was evacuated and backfilled with N.sub.2
3.times., then heated at 100.degree. C. for 1 h. The reaction was
cooled to room temperature and filtered through celite, rinsing
with EtOAc. The solvent was removed in vacuo. The material was
purified by flash column chromatography (0%-50% EtOAc/DCM; 80 g
column).
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(179 mg) was obtained as an orange glass.
[2063] MS (ESI+) m/z 543 (M)
[2064] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.89 (br. s.,
1H), 7.92 (s, 1H), 7.55 (br. s, 1H), 7.23-7.13 (m, 3H), 6.84 (d,
J=8.6 Hz, 2H), 5.69 (br. s, 2H), 3.77 (s, 3H), 3.67-3.49 (m, 3H),
3.00-2.85 (m, 1H), 1.97-1.77 (m, 2H), 1.36-1.27 (m, 3H), 1.20-1.06
(m, 2H), 0.94-0.86 (m, 2H)
[2065] Example 574:
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(25 mg, 0.046 mmol) was taken up in DCE (0.5 mL) and anisole (10.06
.mu.l, 0.092 mmol) was added, followed by TFA (0.142 mL, 1.842
mmol). The reaction was heated at 50.degree. C. for 2 h. The
solvent was removed in vacuo and the material dissolved in 2N
NH.sub.3 in MeOH. The solution was stirred for 10 min to cleave the
ester, and the solvent was removed in vacuo. The material purified
by preparative HPLC.
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyla-
mino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.7 mg) was
obtained.
[2066] MS (ESI+) m/z 423 (M+1)
[2067] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.35 (d, J=3.7
Hz, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.59 (s, 1H),
4.48 (t, J=4.9 Hz, 1H), 3.48-3.40 (m, 2H), 2.96 (dq, 5.2 Hz, 1H),
1.83 (dq, J=13.4, 6.5 Hz, 1H), 1.72 (dt, J=13.4, 6.7 Hz, 1H), 1.20
(d, J=7.3 Hz, 3H), 0.77 (d, J=4.9 Hz, 4H)
Example 575
##STR00635##
[2068]
2-((2-chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2069] (575A):
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(179 mg, 0.330 mmol, Example 574D) was taken up in DCM (3 mL) and
the solution was cooled to 0.degree. C. Dess-Martin periodinane
(168 mg, 0.396 mmol) was added, and the reaction was stirred at
0.degree. C. for 1 h. Some SM still remaining, so an additional 0.4
eq. (56 mg) of Dess-Martin was added, and the reaction was stirred
for 30 min. The reaction was quenched with 2M K.sub.3PO.sub.4 and
extracted with DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
purified by flash column chromatography (0%-60% EtOAc/Hex; 40 g
column).
2-((2-chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (131
mg) was obtained as a yellow glass.
[2070] MS (ESI+) m/z 541 (M)
[2071] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.77 (s, 1H),
9.06-8.83 (m, J=0.2 Hz, 1H), 7.94 (s, 1H), 7.54 (br. s., 1H),
7.23-7.14 (m, 3H), 6.85 (d, J=8.6 Hz, 2H), 5.70 (br. s., 2H),
4.00-3.87 (m, 1H), 3.82-3.72 (m, 3H), 3.01-2.88 (m, 1H), 2.87-2.67
(m, 2H), 1.34 (d, J=6.8 Hz, 3H), 1.17-1.09 (m, 2H), 0.94-0.87 (m,
2H)
[2072] (575B):
2-((2-chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (23
mg, 0.043 mmol) was taken up in THF (0.3 mL) and a solution of
azetidin-3-ol (6.21 mg, 0.085 mmol) in MeOH (0.200 mL) was added. A
drop of AcOH was added and the solution was stirred for 10 min.
Next, sodium cyanoborohydride (5.34 mg, 0.085 mmol) was added and
the reaction was stirred for 1 h. The reaction was diluted with
EtOAc and washed with 2M K.sub.3PO.sub.4 solution. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The material was purified by flash column chromatography (0-10%
MeOH/DCM; 12 g column).
2-((2-chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino-
)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile (13 mg) was obtained as a yellow glass.
[2073] MS (ESI+) m/z 598 (M)
[2074] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.88 (br. s.,
1H), 7.91 (s, 1H), 7.51 (br. s, 1H), 7.24 (d, J=0.4 Hz, 1H), 7.19
(d, J=8.8 Hz, 2H), 6.88-6.78 (m, 2H), 5.66 (br. s., 2H), 4.70 (s,
1H), 4.27-4.11 (m, 2H), 3.77 (s, 3H), 3.74-3.65 (m, 2H), 3.47-3.33
(m, 1H), 3.09-2.98 (m, 1H), 2.98-2.85 (m, 2H), 2.01-1.78 (m, 2H),
1.31 (d, J=7.0 Hz, 3H), 1.11 (s, 2H), 0.90 (s, 2H)
[2075] Example 575:
2-((2-chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino-
)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile (13 mg, 0.022 mmol) was taken up in DCE (1 mL) and
anisole (0.012 mL, 0.109 mmol) was added, followed by TFA (0.067
mL, 0.869 mmol). The reaction was stirred at room temperature
overnight. Some SM still remaining, so an additional 40 eq. (67
.mu.L) of TFA was added and the reaction was heated at 50.degree.
C. for 1 h. The solvent was removed in vacuo and the material
dissolved in MeOH. The material was loaded onto an SCX column (1 g,
benzenesulfonic acid) and the column was flushed with MeOH, then 2N
NH.sub.3/MeOH to obtain the product. The solvent was removed in
vacuo and the material purified by preparative HPLC.
2-((2-chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino-
)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(8.6 mg) was obtained.
[2076] MS (ESI+) m/z 478 (M+1)
[2077] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br. s.,
1H), 8.86 (br. s., 1H), 8.27 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.59
(d, J=1.2 Hz, 1H), 4.12 (quin, J=6.1 Hz, 1H), 3.48 (dd, J=12.8, 6.1
Hz, 2H), 3.36-3.28 (m, 1H), 2.95 (dt, J=11.1, 5.7 Hz, 1H),
2.69-2.56 (m, 2H), 2.39-2.19 (m, 2H), 1.69-1.48 (m, 2H), 1.19 (d,
J=6.7 Hz, 3H), 0.77 (d, J=5.5 Hz, 4H)
Example 576
##STR00636##
[2078]
2-((2-chloro-5-cyano-3-(4-((3,3,3-trifluoropropyl)amino)butan-2-yl)-
phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile
[2079]
2-((2-chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(22 mg, 0.041 mmol, Example 575A) was taken up in THF (1 mL) and
3,3,3-trifluoropropan-1-amine, HCl (12.16 mg, 0.081 mmol) and
Et.sub.3N (0.011 mL, 0.081 mmol) were added. The reaction was
stirred at room temperature for 10 min, then AcOH (4.66 .mu.l,
0.081 mmol) and sodium triacetoxyborohydride (25.9 mg, 0.122 mmol)
were added and the reaction was stirred at room temperature for 1
h. The reaction mixture was diluted with EtOAc and extracted with
2M K.sub.3PO.sub.4 solution. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude
intermediate was taken up in DCE (1 mL) and anisole (0.022 mL,
0.203 mmol) and TFA (0.125 mL, 1.627 mmol) were added. The reaction
was stirred at room temperature overnight. LCMS indicates some SM
still remaining, so the reaction was heated at 50.degree. C. for 3
h. The solvent was removed in vacuo and the material dissolved in
MeOH. The material was loaded onto an SCX column (1 g,
benzenesulfonic acid) and the column was flushed with MeOH, then
2.sub.N NH3/MeOH to obtain the product. The solvent was removed in
vacuo and purified by preparative HPLC.
2-((2-chloro-5-cyano-3-(4-((3,3,3-trifluoropropyl)amino)butan-2-yl)-
phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (10.5 mg) was obtained.
[2080] MS (ESI) m/z 518 (M+1)
[2081] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br. s.,
1H), 8.85 (br. s., 1H), 8.29 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.61
(d, J=1.8 Hz, 1H), 2.96 (quin, J=5.5 Hz, 1H), 2.77-2.65 (m, 2H),
2.55-2.43 (m, 2H), 2.43-2.27 (m, 2H), 1.87-1.61 (m, 2H), 1.21 (d,
J=7.3 Hz, 3H), 0.77 (d, J=5.5 Hz, 4H)
Example 577
##STR00637##
[2082]
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2083] (577A): Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate
(500 mg, 1.508 mmol), 2-(di-t-butylphosphino)-2'-methylbiphenyl
(14.13 mg, 0.045 mmol), and Pd.sub.2(dba).sub.3 (13.81 mg, 0.015
mmol) were combined in a 40 dram vial which was evacuated and
backfilled 3.times. with N.sub.2. To this was added acetonitrile (3
mL), N,N-dicyclohexylmethylamine (0.388 mL, 1.809 mmol), and
prop-2-en-1-ol (0.154 mL, 2.262 mmol). The vial was again evacuated
and backfilled with N.sub.2 3.times., and heated at 90.degree. C.
for 3 h. The reaction mixture was cooled to room temperature and
the solvent removed in vacuo. The material was purified by flash
column chromatography (0%-50% EtOAc/Hex; 80 g column). Tert-butyl
(2-chloro-5-cyano-3-(3-oxopropyl)phenyl)carbamate (184 mg) was
obtained as a yellow glass.
[2084] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.83 (s, 1H),
8.46 (d, J=1.8 Hz, 1H), 7.21 (d, J=1.8 Hz, 1H), 7.16 (s, 1H),
3.15-3.01 (m, 2H), 2.87-2.77 (m, 2H), 1.54 (s, 9H) (577B):
Tert-butyl (2-chloro-5-cyano-3-(3-oxopropyl)phenyl)carbamate (113
mg, 0.366 mmol) was taken up in THF (2 mL) and 1-methylpiperazine
(0.081 mL, 0.732 mmol) and acetic acid (0.042 mL, 0.732 mmol) were
added. The reaction was stirred for 10 min, and then sodium
triacetoxyborohydride (233 mg, 1.098 mmol) was added. The reaction
was stirred at room temperature for 1 h. The reaction mixture was
quenched with saturated NaHCO.sub.3 and extracted with EtOAc. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The material was purified by flash column
chromatography (0-10% MeOH/DCM; 24 g column). Tert-butyl
(2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)carbamate
(120 mg) was obtained as a colorless oil.
[2085] MS (ESI+) m/z 393 (M+1)
[2086] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.44 (d, J=1.7
Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.17 (s, 1H), 2.83-2.75 (m, 2H),
2.47 (br. s., 8H), 2.41-2.33 (m, 2H), 2.30 (s, 3H), 1.80 (dt,
J=14.9, 7.5 Hz, 2H), 1.55 (s, 9H)
[2087] (577C): Tert-butyl
(2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)carbamate
(49 mg, 0.125 mmol) was taken up in DCM (0.8 mL) and TFA (0.192 mL,
2.494 mmol) was added. The reaction was stirred at room temperature
for 1 h. The solvent was removed in vacuo and the material
azeotroped 2.times. with toluene. The material was dried under
vacuum overnight.
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile,
TFA (88 mg,) was obtained as an off-white solid.
[2088] MS (ESI+) m/z 293 (M+1)
[2089] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.01 (d, J=2.0
Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 3.64-3.37 (m, 2H), 2.98 (br. s.,
8H), 2.82 (s, 3H), 2.69 (t, J=7.8 Hz, 2H), 1.87 (dt, J=14.4, 7.3
Hz, 2H)
[2090] (577D):
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile,
TFA (104 mg) was converted to the free base by dissolving in MeOH
and passing through an SCX column, first rinsing with MeOH, then 2N
NH.sub.3 in MeOH to release the material. To this aniline (38.8 mg,
0.132 mmol) in a 2 dram vial was added
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (47 mg, 0.132 mmol), palladium(II) acetate (8.92
mg, 0.040 mmol), DPPF (7.34 mg, 0.013 mmol), Xantphos (7.67 mg,
0.013 mmol), cesium carbonate (86 mg, 0.265 mmol) and dioxane (1
ml). The vial was evacuated and backfilled with N.sub.2 3.times.,
then heated at 100.degree. C. for 1 h. The reaction was cooled to
room temperature and filtered through celite, rinsing with EtOAc.
The solvent was removed in vacuo and the material purified by flash
column chromatography (0-10% MeOH/DCM; 24 g column).
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4--
(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (48 mg) was obtained as a yellow glass.
[2091] MS (ESI+) m/z (M+1)
[2092] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.90 (br. s.,
1H), 7.93 (s, 1H), 7.52 (br. s., 1H), 7.23-7.14 (m, 3H), 6.84 (d,
J=8.4 Hz, 2H), 5.69 (br. s., 2H), 3.78 (s, 3H), 2.95-2.86 (m, J=6.4
Hz, 1H), 2.82 (t, J=7.6 Hz, 2H), 2.47 (br. s., 8H), 2.42-2.36 (m,
2H), 2.29 (s, 3H), 1.82 (quin, J=7.5 Hz, 2H), 1.19-1.08 (m, 2H),
0.94-0.87 (m, 2H) Example 577:
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4--
(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (48 mg, 0.079 mmol) was taken up in DCE (0.8 mL) and anisole
(0.043 mL, 0.393 mmol) was added, followed by TFA (0.242 mL, 3.14
mmol). The reaction was heated at 50.degree. C. for 5 h. The
solvent was removed in vacuo and the material dissolved in MeOH.
The material was loaded onto an SCX column (1 g, benzenesulfonic
acid) and the column was flushed with MeOH, then 2N NH.sub.3/MeOH
to obtain the product. The solvent was removed in vacuo and the
material was purified by preparative HPLC.
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4--
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(20.8 mg) was obtained.
[2093] MS (ESI+) m/z 491 (M+1)
[2094] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br. s.,
1H), 8.85 (s, 1H), 8.28 (d, J=1.8 Hz, 1H), 8.19 (s, 1H), 7.56 (d,
J=1.2 Hz, 1H), 3.00-2.91 (m, J=3.7 Hz, 1H), 2.77 (t, J=7.6 Hz, 2H),
2.30 (t, J=6.7 Hz, 10H), 2.14 (s, 3H), 1.73 (quin, J=7.2 Hz, 2H),
0.77 (d, J=5.5 Hz, 4H)
Example 578
##STR00638##
[2095]
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)ami-
no)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2096] (578A):
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4--
(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
was prepared from
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile and
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile
using the procedure described in Example 577D.
[2097] MS (ESI+) m/z 599 (M)
[2098] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.78-8.57 (m,
1H), 7.91 (d, J=10.3 Hz, 1H), 7.45-7.33 (m, 1H), 7.25-7.15 (m, 2H),
6.88 (t, J=7.9 Hz, 2H), 5.68 (s, 1H), 4.98 (s, 1H), 4.37 (q, J=6.9
Hz, 1H), 3.80 (s, 3H), 3.75 (q, J=7.2 Hz, 1H), 2.83 (q, J=7.5 Hz,
2H), 2.63-2.35 (m, 10H), 2.31 (s, 3H), 1.83 (dq, J=14.4, 7.2 Hz,
2H), 1.41-1.20 (m, 3H)
[2099] Example 578:
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4--
(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was
prepared from
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4--
(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
using the procedure found in Example 577.
[2100] MS (ESI+) m/z 479 (M+1)
[2101] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.18 (t, J=5.8
Hz, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 8.15 (d, J=1.8 Hz, 1H), 7.58
(d, J=1.8 Hz, 1H), 3.40-3.31 (m, 2H), 2.77 (t, J=7.6 Hz, 2H),
2.45-2.23 (m, J=7.0, 7.0 Hz, 10H), 2.16 (s, 3H), 1.82-1.65 (m, 2H),
1.17 (t, J=7.3 Hz, 3H)
[2102] The compounds listed below were prepared by the similar
synthetic procedure used for Examples 52
TABLE-US-00027 TABLE 24 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 579 ##STR00639## 2-methoxyethyl 3-[4-(2-
chloro-5-cyano-3-{[7-cyano- 4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazin- 2-yl]amino}phenyl)piperazin-
1-yl]pyrrolidine-1- carboxylate 606.2 6.734 580 ##STR00640##
2-[(2-chloro-5-cyano-3-{4- [(3-hydroxyoxetan-3-
yl)methyl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
521.2 6.48 581 ##STR00641## 2-({2-chloro-5-cyano-3-[4-(2-
oxopyrrolidin-3-yl)piperazin- 1-yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
518.2 6.346 582 ##STR00642## 2-({2-chloro-5-cyano-3-[4-
(1,1-dioxo-1.lamda..sup.6-thiolan-3- yl)piperazin-1-yl]phenyl}
amino)-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazine-
7-carbonitrile 553.2 6.674 583 ##STR00643##
2-({2-chloro-5-cyano-3-[4-(1- methylazetidin-3-
yl)piperazin-1-yl]phenyl} amino)-4-(ethylamino)
imidazo[2,1-f][1,2,4]triazine- 7-carbonitrile 493.2 6.206 584
##STR00644## 2-[(3-{4-[2-(azetidin-1- yl)acetyl]piperazin-1-yl}-2-
chloro-5-cyanophenyl) amino]-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazine- 7-carbonitrile 533.2 7.013 585
##STR00645## 2-[(2-chloro-5-cyano-3-{4-[2- (3-methoxyazetidin-1-
yl)acetyl]piperazin-1- yl}phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
563.2 7.151 586 ##STR00646## 2-[(2-chloro-5-cyano-3-{4-[1-
(3-fluoro-2-hydroxypropyl) azetidin-3-yl]piperazin-1-
yl}phenyl)amino]-4- (ethylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 555.2 7.084 587 ##STR00647##
2-({2-chloro-5-cyano-3-[4-(2- fluorocyclopentyl)piperazin-
1-yl]phenyl}amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 521.8 9.765 588 ##STR00648##
2-{[2-chloro-5-cyano-3-(4- {1-[(2R)-2-hydroxypropyl]
azetidin-3-yl}piperazin-1- yl)phenyl]amino}-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
549 6.184 589 ##STR00649## 2-[(2-chloro-5-cyano-3-{4- [(1S,2S)-2-
hydroxycyclopentyl] piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
519.8 9.301 590 ##STR00650## 2-({2-chloro-5-cyano-3-[4-(2-
hydroxyethyl)piperazin-1- yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
478.8 6.236 591 ##STR00651## methyl 3-[4-(2-chloro-5-
cyano-3-{[7-cyano-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2- yl]amino}phenyl)piperazin-1-
yl]pyrrolidine-1-carboxylate 561.8 6.676 592 ##STR00652##
1-methylazetidin-3-yl 4-(2- chloro-5-cyano-3-{[7-cyano-
4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-
2-yl]amino}phenyl) piperazine-1-carboxylate 548.2 7.24 593
##STR00653## 2-{[2-chloro-5-cyano-3-(4- cyclopropylpiperazin-1-
yl)phenyl]amino}-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 475 6.688 594 ##STR00654##
2-[(2-chloro-5-cyano-3-{4- [(3R,4R)-4-fluorooxolan-3-
yl]piperazin-1-yl}phenyl) amino]-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazine- 7-carbonitrile 523 7.166 595
##STR00655## 2-({2-chloro-5-cyano-3-[4- (3,3-
difluoropropyl)piperazin-1- yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
514 6.954 596 ##STR00656## 2-({2-chloro-5-cyano-3-[4-(2-
methoxpropyl)piperazin-1- yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
507.2 6.812 597 ##STR00657## 2-({2-chloro-5-cyano-3-[4-
(morpholin-2- ylmethyl)piperazin-1- yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
534.2 5.298 598 ##STR00658## 2-({2-chloro-5-cyano-3-[4-
(morpholin-3- ylmethyl)piperazin-1- yl]phenyl}amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
535 5.65 599 ##STR00659## 2-[4-(2-chloro-5-cyano-3-{[7-
cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-
2-yl]amino}phenyl)piperazin- 1-yl]-N- (cyclopropanesulfonyl)
acetamide 596.4 6.938 600 ##STR00660##
2-[4-(2-chloro-5-cyano-3-{[7- cyano-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazin- 2-yl]amino}phenyl)piperazin-
1-yl]acetamide 493.8 9.168 601 ##STR00661##
2-[(2-chloro-5-cyano-3-{4- [(1r,3r)-3-fluorocyclobutyl]
piperazin-1-yl}phenyl) amino]-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazine- 7-carbonitrile 505 (M - H) 7.16 602
##STR00662## 2-[(2-chloro-5-cyano-3-{4- [(2S)-2-hydroxy-3-
methoxypropyl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
524.2 6.582 603 ##STR00663## 2-[(2-chloro-5-cyano-3-{4-
[(3-methyloxetan-3- yl)methyl]piperazin-1- yl}phenyl)amino]-4-
(ethylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile 505 (M -
H) 6.619 604 ##STR00664## 2-[(2-chloro-5-cyano-3-{4-[3-
hydroxy-2-(hydroxymethyl)- 2-methylpropyl]piperazin-1-
yl}phenyl)amino]-4- (ethylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 525.2 6.588 605 ##STR00665##
2-({3-[4-(1-acetylazetidin-3- yl)piperazin-1-yl]-2-chloro-5-
cyanophenyl}amino)-4- (ethylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 521.8 6.36 606 ##STR00666##
2-[(2-chloro-5-cyano-3-{4- [(2R)-2-hydroxy-3-
methoxypropyl]piperazin-1- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
524 6.469 607 ##STR00667## 2-[4-(2-chloro-5-cyano-3-{[7-
cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-
2-yl]amino}phenyl)piperazin- 1-yl]-N- methanesulfonylacetamide
570.8 6.845 608 ##STR00668## 2-[(2-chloro-5-cyano-3-{4-[1-
(1-hydroxypropan-2- yl)azetidin-3-yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 548 6.246 609 ##STR00669##
2-({2-chloro-5-cyano-3-[4- (oxan-2-ylmethyl)piperazin-
1-yl]phenyl}amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 534 7.362 610 ##STR00670##
2-[(2-chloro-5-cyano-3-{4- [(1s,3s)-3- hydroxycyclobutyl]piperazin-
1-yl}phenyl)amino]-4- (ethylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 493 6.257 611 ##STR00671##
2-[4-(2-chloro-5-cyano-3-{[7- cyano-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazin- 2-yl]amino}phenyl)piperazin-
1-yl]-N-methylacetamide 507 6.329 612 ##STR00672##
2-({3-[4-(azetidin-3- yl)piperazin-1-yl]-2-chloro-5-
cyanophenyl}amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 491 NA 613 ##STR00673##
2-[(2-chloro-5-cyano-3-{4- [(1r,3r)-3-hydroxycyclobutyl]
piperazin-1-yl}phenyl) amino]-4-(ethylamino)
imidazo[2,1-f][1,2,4]triazine- 7-carbonitrile 493 9.467 614
##STR00674## 2-[(2-chloro-5-cyano-3-{4-[1-
(3-fluoro-2-hydroxypropyl) azetidin-3-yl]piperazin-1-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 566.8 6.447 ##STR00675##
Example 615
##STR00676##
[2103]
2-((2-chloro-5-cyano-3-((2-hydroxyethyl)amino)phenyl)amino)-4-(cycl-
opropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2104] (615A): A 3-neck round bottom flask was equipped with a
condenser. The flask was loaded with
4-chloro-3,5-dinitrobenzonitrile (4.5 g, 19.18 mmol) and acetic
acid (60 mL). The solution was heated to 110.degree. C. Iron
(powder) (2.5 g, 44.8 mmol) was added slowly (in three portions),
saw bubbling and also color changed to dark red. The mixture was
stirred vigorously for 2 h at 110.degree. C. LC-MS indicated
desired monoamine and diamine. Then it was cooled to room
temperature and diluted with DCM and saturated aqueous sodium
bicarbonate solution was slowly added to neutralize. After
separating the layers, the aqueous layer was further extracted with
DCM. The combined organic extracts were washed with water, brine,
dried over MgSO.sub.4, filtered and concentrated. Purification via
flash chromatography (0-20% EtOAc in DCM, 120 g) gave
3-amino-4-chloro-5-nitrobenzonitrile (1.8 g,) and
3,5-diamino-4-chlorobenzonitrile (1 g) as bright yellow solid and
brown solid respectively.
[2105] MS (ESI+) m/z 167.9 (diamine), 198.0 (monoamine)
[2106] Monoamine: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.44
(d, J=2.0 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 4.72 (br. s., 2H)
[2107] Diamine: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.44
(s, 2H), 4.20 (br. s., 4H) (615B): To a solution of
3,5-diamino-4-chlorobenzonitrile (200 mg, 1.193 mmol) in DMF (2 mL)
was added Hunig's base (2.501 mL, 14.32 mmol) followed by
2-bromoethanol (0.506 mL, 7.16 mmol). The resulting solution was
heated at 100.degree. C. for 10 h. LC-MS indicated ca. 30%
conversion. It was passed through a pad of celite, rinsed with
EtOAc. After concentration, purification via silica gel
chromatography (0-70% EtOAc in Hexanes, 24 g) gave
3-amino-4-chloro-5-((2-hydroxyethyl)amino)benzonitrile (75 mg) as
an orange oil.
[2108] MS (ESI+) m/z 212.05
[2109] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.44 (d, J=2.0
Hz, 1H), 6.33 (d, J=1.8 Hz, 1H), 3.89 (t, J=5.3 Hz, 2H), 3.33 (q,
J=5.3 Hz, 2H)
[2110] (615C): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (126 mg, 0.354 mmol),
3-amino-4-chloro-5-((2-hydroxyethyl)amino)benzonitrile (75 mg,
0.354 mmol), palladium(II) acetate (21.08 mg, 0.094 mmol), XANTPHOS
(20.50 mg, 0.035 mmol), DPPF (19.65 mg, 0.035 mmol) and cesium
carbonate (300 mg, 0.921 mmol) in Dioxane (3 mL) was evacuated and
back filled with nitrogen three time and was heated at 60.degree.
C. for 1 h. The reaction mixture was filtered through a pad of
Celite, rinsed with EtOAc and the filtrate was concentrated.
Purification via flash chromatography (0-70% EtOAc in Hexane, 24 g)
gave
2-((2-chloro-5-cyano-3-((2-hydroxyethyl)amino)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(65 mg) as a light yellow foam.
[2111] MS (ESI+) m/z 530.06.
[2112] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.92 (s, 2H),
7.19 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.58 (d, J=1.8 Hz,
1H), 4.88 (t, J=5.3 Hz, 2H), 3.92 (q, J=5.0 Hz, 2H), 3.78 (s, 3H),
3.36 (q, J=5.5 Hz, 2H), 1.98 (t, J=5.1 Hz, 1H), 1.13 (d, J=4.4 Hz,
2H), 0.96-0.84 (m, 2H)
[2113] Example 615: TFA (1 ml) was added to a solution of
2-((2-chloro-5-cyano-3-((2-hydroxyethyl)amino)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(60 mg, 0.113 mmol) and anisole (0.049 ml, 0.453 mmol) in
dichloroethane (1 mL) and the reaction mixture was heated at
60.degree. C. for 2 h. LC-MS showed formation of product and TFA
ester of product. Solvent was evaporated and the crude was dried
under vacuum for 10 min. The crude was washed with hexane
(3.times.1 mL), dissolved in methanol and neutralized with 7N
ammonia in methanol, saw grey precipitate. After concentration,
triturated with MeOH and about 40 mg of the crude product was
obtained after filtering. Further purification by preparative HPLC
gave the title compound (4.4 mg) as a white solid.
[2114] MS (ESI+) m/z 409.99
[2115] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.29 (br. s.,
1H), 8.62 (s, 1H), 8.18 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 6.88 (d,
J=1.2 Hz, 1H), 5.72 (t, J=5.8 Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 3.58
(q, J=5.5 Hz, 2H), 3.26 (q, J=5.5 Hz, 2H), 2.97 (br. s., 1H),
0.84-0.70 (m, 4H)
Example 616
##STR00677##
[2116]
2-((2-chloro-5-cyano-3-((2-(2-methoxyethoxy)ethyl)amino)phenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2117] (616A): To a solution of 3,5-diamino-4-chlorobenzonitrile
(220 mg, 1.313 mmol) in DMF (3 mL) was added Hunig's Base (2.75 mL,
15.75 mmol) followed by 1-bromo-2-(2-methoxyethoxy)ethane (1442 mg,
7.88 mmol). The resulting solution was heated at 100.degree. C. for
16 h. LC-MS indicated ca. 30% conversion. It was diluted with EtOAc
and water. After separating the layers, the aqueous layer was
further extracted with EtOAc. The combined organic extracts were
washed with water, brine, dried over MgSO.sub.4, filtered and
concentrated. Purification via silica gel chromatography (0-70%
EtOAc in Hexanes, 24 g) gave
3-amino-4-chloro-5-((2-(2-methoxyethoxy)ethyl)amino)benzonitrile
(100 mg) as an orange oil.
[2118] MS (ESI+) m/z 270.0
[2119] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.28 (d, J=1.8
Hz, 1H), 6.11 (d, J=1.8 Hz, 1H), 4.16-4.11 (m, 1H), 3.57-3.50 (m,
2H), 3.49-3.43 (m, 2H), 3.41-3.34 (m, 2H), 3.21 (s, 3H), 3.15 (t,
J=5.3 Hz, 2H)
[2120] Example 616: The title compound was prepared from
3-amino-4-chloro-5-((2-(2-methoxyethoxy)ethyl)amino)benzonitrile
using a method analogous to that used to prepare Example 615.
[2121] MS (ESI+) m/z 468.05
[2122] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.31 (br. s.,
1H), 8.64 (s, 1H), 8.19 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 6.93 (d,
J=1.2 Hz, 1H), 5.75 (t, J=5.8 Hz, 1H), 3.60 (t, J=5.8 Hz, 2H), 3.55
(dd, J=5.5, 3.7 Hz, 2H), 3.48-3.42 (m, 2H), 3.24 (s, 3H), 3.01-2.91
(m, 1H), 0.82-0.73 (m, 4H) (one CH.sub.2 is buried under water
peak)
Example 617
##STR00678##
[2123]
2-((2-chloro-5-cyano-3-((3-hydroxypropyl)amino)phenyl)amino)-4-(cyc-
lopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2124] The title compound was prepared from
3-amino-4-chloro-5-((3-hydroxypropyl)amino)benzonitrile using a
method analogous to that used to prepare Example 615.
[2125] MS (ESI+) m/z 424.3
[2126] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.29 (d, J=3.7
Hz, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.67 (s, 1H), 6.82 (s, 1H),
5.98 (t, J=5.5 Hz, 1H), 4.69 (t, J=4.3 Hz, 1H), 3.51 (q, J=5.5 Hz,
2H), 3.25 (q, J=6.1 Hz, 2H), 2.96 (d, J=4.3 Hz, 1H), 1.79-1.61 (m,
2H), 0.86-0.66 (m, 4H)
Example 618
##STR00679##
[2127]
2-((2-chloro-5-cyano-3-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2128] (618A): To the solution of
3-amino-4-chloro-5-nitrobenzonitrile (300 mg, 1.518 mmol) in DCM
(10 mL) at 0.degree. C. was added TEA (0.317 mL, 2.278 mmol) and
then 2-bromoacetyl bromide (0.145 mL, 1.670 mmol) was added drop
wise. The reaction mixture was stirred at 0.degree. C. for 3 h.
LC-MS indicated a new peak. Then it was diluted with DCM and
saturated aqueous sodium bicarbonate solution was added. After
separating the layers, the aqueous layer was further extracted with
DCM. The combined organic extracts were washed with water, brine,
dried over MgSO.sub.4, filtered and concentrated. The crude was
used in the next step without purification. To a solution of above
obtained crude 2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide
(500 mg, 1.570 mmol) in DCM (4 mL) was added TEA (0.438 mL, 3.14
mmol) then a solution of 2-(methylamino)ethanol (118 mg, 1.570
mmol) in THF (4 mL) was added slowly. After stirring at room
temperature for 1 h, LC-MS indicated completion. After
concentration purification via flash chromatography (0-5% MeOH in
DCM, 12 g) gave
N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(methyl)amino)aceta-
mide (170 mg) as a yellow oil,
[2129] MS (ESI+) m/z 313.0
[2130] (618B): To a solution of triphenylphosphine (252 mg, 0.959
mmol) in THF (2 mL) was added DIAD (0.187 mL, 0.959 mmol). The
reaction mixture was stirred for 10 min. Then a solution of
N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(methyl)amino)aceta-
mide (120 mg, 0.384 mmol) in THF (2 mL) was added drop wise. The
reaction mixture was then stirred at room temperature for 2 h.
LC-MS indicated the desired peak, but the reaction was about
.about.80% complete. It was diluted with EtOAc and water. The
aqueous layer was extracted with EtOAc and the combined organic
layer was washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. Purification via silica gel
chromatography (0-100% EtOAc in Hexanes, 12 g) gave
4-chloro-3-(4-methyl-2-oxopiperazin-1-yl)-5-nitrobenzonitrile (40
mg) as a off-white solid.
[2131] MS (ESI+) m/z 295.0
[2132] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.12 (d, J=2.0
Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 3.65 (br. s., 2H), 3.45-3.21 (m,
2H), 3.01-2.75 (m, 2H), 2.45 (s, 3H)
[2133] (618C): To a solution of
4-chloro-3-(4-methyl-2-oxopiperazin-1-yl)-5-nitrobenzonitrile (40
mg, 0.136 mmol) in MeOH (4 mL) was added ammonium chloride (218 mg,
4.07 mmol) and zinc (133 mg, 2.036 mmol) (in two portions, after
the first portion, reaction was not complete). After stirring at
room temperature for 12 h. LC-MS indicated completion. Then 5 mL of
saturated aqueous sodium bicarbonate solution was added followed by
10 mL of EtOAc. The mixture was filtered through a pad of Celite
and the filter cake was washed EtOAc. The solvent from the filtrate
was evaporated. Purification via flash chromatography (0-10% MeOH
in DCM, 24 g) gave
3-amino-4-chloro-5-(4-methyl-2-oxopiperazin-1-yl)benzonitrile (28
mg) as an off-white solid.
[2134] MS (ESI+) m/z 264.6
[2135] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.00-6.83 (m,
1H), 6.80-6.64 (m, 1H), 3.54-3.34 (m, 2H), 3.29-2.98 (m, 2H),
2.85-2.53 (m, 2H), 2.25 (s, 3H) (618D): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (40 mg, 0.113 mmol),
3-amino-4-chloro-5-(4-methyl-2-oxopiperazin-1-yl)benzonitrile (28
mg, 0.106 mmol), palladium(ii) acetate (12 mg, 0.053 mmol),
XANTPHOS (12 mg, 0.021 mmol), DPPF (12 mg, 0.022 mmol) and cesium
carbonate (90 mg, 0.275 mmol) in Dioxane (1.5 mL) was evacuated and
back filled with nitrogen three time and was heated at 80.degree.
C. for 3 h. LC-MS showed reaction was complete. The reaction
mixture was filtered through a pad of Celite, rinsed with EtOAc and
the filtrate was concentrated and purification via flash
chromatography (0-70% EtOAc in Hexane, 24 g) gave
2-((2-chloro-5-cyano-3-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyc-
lopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e (60 mg) as a light oil.
[2136] MS (ESI+) m/z 583.2
[2137] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.94 (s, 1H),
7.24-7.11 (m, 4H), 6.84 (d, J=8.6 Hz, 2H), 5.30 (s, 2H), 3.78 (s,
3H), 3.62 (t, J=5.4 Hz, 2H), 3.38-3.21 (m, 2H), 3.00-2.77 (m, 3H),
2.44 (s, 3H), 1.14 (br. s., 2H), 0.97-0.85 (m, 2H)
[2138] Example 618: TFA (1 mL) was added to a solution of
2-((2-chloro-5-cyano-3-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyc-
lopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e (60 mg, 0.103 mmol) and ANISOLE (0.045 mL, 0.412 mmol) (one drop)
in DCE (1 mL). The reaction mixture was heated at 60.degree. C. for
2 h. LC-MS showed completion of reaction. Solvent was evaporated
and the crude was dried under vacuum for 10 min. The crude was
dissolved in methanol and neutralized with 7N ammonia in methanol.
After stirring for 10 min it was concentrated, purification via
flash chromatography (0-10% MeOH in DCM, 24 g) gave 35 mg impure
product. Further purification via preparative HPLC gave the title
compound (9.6 mg) as a light yellow solid.
[2139] MS (ESI+) m/z 463.1
[2140] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39 (d, J=3.7
Hz, 1H), 9.12 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H),
3.62 (d, J=6.7 Hz, 1H), 3.52-3.42 (m, 1H), 3.20-3.09 (m, 2H), 2.97
(d, J=4.9 Hz, 1H), 2.79 (br. s., 1H), 2.74 (d, J=7.9 Hz, 1H), 2.31
(s, 3H), 0.78 (d, J=5.5 Hz, 4H)
Example 619
##STR00680##
[2141]
N-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-2-((2-hydroxyethyl)(methyl)amino)acetamid-
e
[2142] The title compound was prepared using a method analogous to
that used to prepare Example 618
[2143] MS (ESI+) m/z 481.1
[2144] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.20 (br. s.,
1H), 9.38 (d, J=3.7 Hz, 1H), 9.09 (s, 1H), 8.26 (s, 1H), 8.23-8.17
(m, 1H), 4.63 (br. s., 1H), 3.63-3.50 (m, 2H), 3.29 (br. s., 2H),
2.98-2.91 (m, 1H), 2.62 (br. s., 2H), 2.40 (br. s., 3H), 0.86-0.71
(m, 4H)
Example 620
##STR00681##
[2145]
N-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylamino)acetamide
[2146] The title compound was prepared using a method analogous to
that used to prepare Example 618.
[2147] MS (ESI+) m/z 451.0
[2148] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.01 (br. s.,
1H), 9.37 (br. s., 1H), 9.10 (s, 1H), 8.30-8.15 (m, 2H), 3.18 (br.
s., 2H), 2.93 (d, J=4.9 Hz, 1H), 2.36 (s, 6H), 0.77 (d, J=5.5 Hz,
4H)
Example 621
##STR00682##
[2149]
N-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-2-morpholinoacetamide
[2150] The title compound was prepared using a method analogous to
that used to prepare Example 618.
[2151] MS (ESI+) m/z 493.1
[2152] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.32 (s, 1H),
8.20 (d, J=10.4 Hz, 2H), 6.60 (br. s., 1H), 3.67 (br. s., 4H), 3.23
(s, 2H), 2.92 (br. s., 1H), 2.59 (br. s., 4H), 0.77 (br. s.,
4H)
Example 622
##STR00683##
[2153]
(+/-)-2-((2-chloro-5-cyano-3-(4-(3-fluoro-2-hydroxypropyl)-2-oxopip-
erazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile
[2154] (622A): To the solution of
3-amino-4-chloro-5-nitrobenzonitrile (300 mg, 1.518 mmol) in DCM
(12 mL) at 0.degree. C. was added TEA (0.635 mL, 4.56 mmol) and
then 2-bromoacetyl bromide (0.291 mL, 3.34 mmol) was added drop
wise. The reaction mixture was stirred at 0.degree. C. for 1 h.
LC-MS indicated a new peak. Then it was diluted with DCM and
saturated aqueous sodium bicarbonate solution was added. After
separating the layers, the aqueous layer was further extracted with
DCM. The combined organic extracts were washed with water, brine,
dried over MgSO.sub.4, filtered and concentrated. Purification via
flash chromatography (0-70% EtOAc in DCM, 40 g) gave
2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (400 mg) as a
light yellow solid.
[2155] To a solution of above obtained
2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (400 mg, 1.256
mmol) in DCM (6 mL) was added TEA (0.350 mL, 2.51 mmol) then a
solution of 2-((2,4,6-trimethoxybenzyl)amino)ethanol (364 mg, 1.507
mmol) in THF (2 mL) was added slowly. After stirring at room
temperature for 1 h, LC-MS indicated completion. After
concentration purification via flash chromatography (0-70% EtOAc in
Hexane, 24 g) gave
N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(2,4,6-trimethoxybe-
nzyl)amino)acetamide (400 mg) as a yellow oil.
[2156] MS (ESI+) m/z 479.3
[2157] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.89 (d, J=1.8
Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 6.03 (s, 2H), 3.84 (d, J=3.5 Hz,
2H), 3.79 (s, 6H), 3.74 (s, 5H), 3.40 (s, 2H), 2.83 (t, J=5.4 Hz,
2H)
[2158] (622B): To a solution of triphenylphosphine (263 mg, 1.002
mmol) in THF (2 mL) was added DIAD (0.195 mL, 1.002 mmol). The
reaction mixture was stirred for 10 min. Then a solution of
N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(2,4,6-trimethoxybe-
nzyl)amino)acetamide (160 mg, 0.334 mmol) in THF (1.000 mL) was
added drop wise. The reaction mixture was then stirred at room
temperature for 3 h. LC-MS indicated the desired peak. It was
diluted with EtOAc and water. The aqueous layer was extracted with
EtOAc and the combined organic layer was washed with water, brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification via silica gel chromatography (0-100% EtOAc in
Hexanes, 12 g) gave
4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzon-
itrile (30 mg) as a yellow solid. TFA (1 mL) was added to the above
obtained solution of
4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzon-
itrile (30 mg, 0.065 mmol) and ANISOLE (0.028 mL, 0.260 mmol) in
DCM (1 mL) and the reaction mixture was stirred at room temperature
for 2 h. LC-MS showed completion. Solvent was evaporated and
purification via flash chromatography (0-10% MeOH in DCM, 24 g)
gave 4-chloro-3-nitro-5-(2-oxopiperazin-1-yl)benzonitrile (20 mg)
as a yellow oil.
[2159] To the above obtained solution of
4-chloro-3-nitro-5-(2-oxopiperazin-1-yl)benzonitrile (20 mg, 0.071
mmol) in MeOH (4 mL) was added ammonium chloride (114 mg, 2.138
mmol), and zinc (69.9 mg, 1.069 mmol). After stirring at room
temperature for 1 h. LC-MS indicated completion. Then 5 mL of
saturated aqueous sodium bicarbonate was added followed by 10 mL of
EtOAc. The mixture was filtered through a pad of Celite and the
filter cake was washed with EtOAc. The solvent from the filtrate
was combined and evaporated. Purification via flash chromatography
(0-10% MeOH in DCM, 12 g) gave about 15 mg diamine.
[2160] This amine was dissolved in THF (2.000 mL) and DCM (2.000
mL), then TEA (0.030 mL, 0.214 mmol) was added followed by
BOC.sub.2O (0.033 mL, 0.143 mmol). After stirring at room
temperature for 2 h, LC-MS indicated completion, it was
concentrated and purification via flash chromatography (0-10% MeOH
in DCM, 12 g) gave tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)-3-oxopiperazine-1-carboxylate
(20 mg) as an off-white solid.
[2161] MS (ESI+) m/z 295.1 (mass of carbamic acid)
[2162] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.82 (d, J=1.8
Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 4.05-3.87 (m, 2H), 3.69-3.57 (m,
1H), 3.55-3.43 (m, 1H), 3.41-3.29 (m, 2H), 1.23 (s, 9H)
[2163] (622C): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (72.8 mg, 0.205 mmol), tert-butyl
4-(3-amino-2-chloro-5-cyanophenyl)-3-oxopiperazine-1-carboxylate
(60 mg, 0.171 mmol), palladium(II) acetate (12 mg, 0.053 mmol),
XANTPHOS (12 mg, 0.021 mmol), DPPF (12 mg, 0.022 mmol) and cesium
carbonate (145 mg, 0.445 mmol) in Dioxane (2 mL) was evacuated and
back filled with nitrogen three time and was heated at 80.degree.
C. for 3 h. LC-MS showed reaction was complete. The reaction
mixture was filtered through a pad of Celite, rinsed with EtOAc,
DCM and the filtrate was concentrated and purification via flash
chromatography (0-10% MeOH in DCM, 12 g) gave tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate
(85 mg) as a yellow oil.
[2164] MS (ESI+) m/z 669.6
[2165] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.95 (s, 1H),
7.22 (d, J=2.0 Hz, 1H), 7.19 (d, J=8.6 Hz, 3H), 6.85 (d, J=8.6 Hz,
2H), 4.40-4.21 (m, 2H), 4.01-3.86 (m, 1H), 3.84-3.74 (m, 4H), 3.64
(t, J=5.2 Hz, 2H), 2.05 (s, 2H), 1.63 (br. s., 1H), 1.52 (s, 9H),
1.22-1.09 (m, 2H), 0.96-0.88 (m, 2H)
[2166] (622D): TFA (2 mL) was added to a solution of tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate
(85 mg, 0.127 mmol) in DCM (4 mL) and the reaction mixture was
stirred at room temperature for 1 h. Solvent was evaporated and the
crude was dried under vacuum for 10 min. The crude was dissolved in
MeOH and neutralized with 7N ammonia in methanol. After stirring
for 10 min it was concentrated and purification via flash
chromatography (0-10% MeOH in DCM, 12 g) gave
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(50 mg) as a light yellow oil.
[2167] MS (ESI+) m/z 569.4
[2168] Example 622: A suspension of
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(18 mg, 0.032 mmol) and 2-(fluoromethyl)oxirane (24.06 mg, 0.316
mmol) in Ethanol (0.8 mL)/THF (0.2 mL) in a sealed 1-dram vial was
heated at 90.degree. C. for 5 h. LC-MS indicated completion. After
cooling to room temperature, it was concentrated. Then it was
dissolved in dichloroethane (1 mL), then 1 drop of anisole was
added followed by 1 mL of TFA. The reaction mixture was stirred at
60.degree. C. for 1 h. LC-MS indicated completion, then it was
cooled and concentrated. The crude was dissolved in methanol and
neutralized with 7N ammonia in methanol. After stirring for 10 min
it was concentrated, purification via preparative HPLC gave the
title compound (6.1 mg) as a yellow solid.
[2169] MS (ESI+) m/z 525.3
[2170] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39 (d, J=3.7
Hz, 1H), 9.12 (s, 1H), 8.46 (s, 1H), 8.21 (s, 1H), 7.73 (s, 1H),
5.14 (d, J=4.9 Hz, 1H), 4.51-4.24 (m, 2H), 3.94 (br. s., 1H), 3.61
(d, J=5.5 Hz, 1H), 3.47 (d, J=4.9 Hz, 1H), 3.33-3.23 (m, 2H),
3.03-2.80 (m, 3H), 2.61-2.52 (m, 1H), 0.78 (br. s., 4H)
Example 623
##STR00684##
[2171]
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazin-1-yl)acetamide
[2172] To solution of
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 628) (10 mg, 0.018 mmol) in DMF (0.5 mL) was added
2-bromoacetamide (4.85 mg, 0.035 mmol) followed by K.sub.2CO.sub.3
(29.1 mg, 0.211 mmol) and it was stirred at room temperature for 1
h, LC-MS indicated completion. Purification via flash
chromatography (0-10% MeOH in DCM, 12 g) gave 9 mg of the PMB
protected product. This was dissolved in 1 mL of dichloroethane and
then 1 drop of anisole was added followed by 0.5 mL of TFA. The
solution was heated at 60.degree. C. for 1 h. LC-MS indicated
completion, and then it was cooled and concentrated. The crude was
dissolved in methanol and neutralized with 7N ammonia in methanol.
After stirring for 10 min it was concentrated, purification via
preparative HPLC gave the title compound as a yellow solid (4.7
mg).
[2173] MS (ESI+) m/z 506.3
[2174] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.37 (br. s.,
1H), 9.10 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.70 (d,
J=1.8 Hz, 1H), 7.40 (br. s., 1H), 7.19 (br. s., 1H), 3.72-3.56 (m,
2H), 3.39-3.25 (m, 2H), 3.16-3.04 (m, 2H), 2.96 (d, J=4.9 Hz, 2H),
2.88 (s, 1H), 0.86-0.67 (m, 4H)
Example 624
##STR00685##
[2175]
(+/-)-2-((2-chloro-5-cyano-3-(4-(2-hydroxypropyl)-2-oxopiperazin-1--
yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile
[2176] A suspension of
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(16 mg, 0.028 mmol) and 2-methyloxirane (8.17 mg, 0.141 mmol) in
Ethanol (0.8 mL) and THF (0.2 mL) in a sealed 1-dram vial was
heated at 80.degree. C. for 6 h. LC-MS indicated completion. After
concentration, purification via flash chromatography (0-10% MeOH in
DCM, 12 g) gave 20 mg of the PMB protected product. This was
dissolved in 1 mL of dichloroethane and then 1 drop of anisole was
added followed by 0.5 mL of TFA. The solution was heated at
60.degree. C. for 1 h. LC-MS indicated completion, and then it was
cooled and concentrated. The crude was dissolved in methanol and
neutralized with 7N ammonia in methanol. After stirring for 10 min
it was concentrated, purification via preparative HPLC gave the
title compound as a yellow solid (4.1 mg).
[2177] MS (ESI+) m/z 507.5
[2178] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.46 (d, J=1.8
Hz, 1H), 8.18 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 4.61 (d, J=3.7 Hz,
1H), 4.23 (br. s., 1H), 3.83 (br. s., 1H), 3.34-3.19 (m, 2H),
3.02-2.90 (m, 2H), 2.86-2.76 (m, 1H), 2.45-2.29 (m, 2H), 1.07 (d,
J=6.1 Hz, 3H), 0.83-0.71 (m, 4H)
Example 625
##STR00686##
[2179]
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazin-1-yl)-N-methylacetamide
[2180] To solution of
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyla-
mino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 628) (20
mg, 0.045 mmol) in DMF (0.5 mL) was added 2-bromo-N-methylacetamide
(13.54 mg, 0.089 mmol) followed by K.sub.2CO.sub.3 (73.9 mg, 0.535
mmol) at room temperature and stirred at room temperature for 1 h,
LC-MS indicated completion. Purification via preparative HPLC gave
the title compound as a yellow solid (5.9 mg).
[2181] MS (ESI+) m/z 520.3
[2182] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39 (d, J=3.7
Hz, 1H), 9.12 (s, 1H), 8.47 (d, J=1.2 Hz, 1H), 8.21 (s, 1H), 7.87
(br. s., 1H), 7.69 (d, J=1.8 Hz, 1H), 3.66 (br. s., 1H), 3.49 (d,
J=11.6 Hz, 1H), 3.34-3.26 (m, 2H), 3.21-3.08 (m, 2H), 2.97 (d,
J=4.3 Hz, 2H), 2.89 (br. s., 1H), 2.64 (d, J=4.9 Hz, 3H), 0.78 (br.
s., 4H)
Example 626
##STR00687##
[2183]
(+/-)-2-((2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1-
,2-a]pyrazin-2(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2-
,4]triazine-7-carbonitrile
[2184] (626A): To a solution (+/-)-1-benzyl
3-methylpiperazine-1,3-dicarboxylate (500 mg, 1.797 mmol) in
1,2-Dichloroethane (16 mL) were added
tert-butyl(2-oxoethyl)carbamate (343 mg, 2.156 mmol), Acetic acid
(0.514 mL, 8.98 mmol). After stirring for 20 min, sodium
triacetoxyborohydride (571 mg, 2.69 mmol) was added. The reaction
mixture was stirred under N.sub.2 for 12 h. LC-MS indicated desired
product. The solvent was removed in vacuo and purification via
flash chromatography (0-10% MeOH in DCM, 24 g) gave 100 mg the
intermediate. This was then dissolved in 2 mL of DCM then 1 mL of
TFA was added. After stirring at room temperature for 1 h, saw the
desired deprotected product by LC-MS. DCM and TFA were removed
under vacuum and then it was dissolved in 2 mL of MeCN, to this
stirred solution was added 2 mL of 2 M ammonia in MeOH. After
stirring for 1 h, saw the cyclized product by LC-MS. The solvent
was removed in vacuo and purification via flash chromatography
(0-10% MeOH in DCM, 24 g) gave (+/-)-benzyl
9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (80 mg)
as a light yellow oil.
[2185] MS (ESI+) m/z 290.1
[2186] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.44-7.29 (m,
5H), 6.14 (br. s., 1H), 5.24-5.07 (m, 2H), 4.63 (d, J=11.2 Hz, 1H),
4.13 (d, J=7.3 Hz, 1H), 3.57 (td, J=11.6, 4.7 Hz, 1H), 3.23 (dt,
J=11.3, 3.5 Hz, 1H), 3.12-2.94 (m, 1H), 2.93-2.78 (m, 3H), 2.70
(dd, J=10.6, 2.9 Hz, 1H), 2.56 (td, J=11.9, 4.2 Hz, 1H), 2.28 (td,
J=11.6, 3.3 Hz, 1H)
[2187] (626B): To a solution of (+/-)-benzyl
9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (160
mg, 0.553 mmol) in THF (5 mL) at 0.degree. C. was added sodium
hydride (24.33 mg, 0.608 mmol). The ice bath was removed and
stirred for 10 min; saw bubbling but some NaH solid still remained.
Then iodomethane (0.038 mL, 0.608 mmol) was added and after
stirring for 10 min at room temperature, most NaH solid was
dissolved. After another 30 min, LC-MS indicated completion. It was
quenched with water and diluted with EtOAc. After separating the
layers, the aqueous layer was further extracted with EtOAc. The
combined organic extracts were washed with water, brine, dried over
MgSO.sub.4, filtered and concentrated. Purification via flash
chromatography (0-5% MeOH in DCM, 12 g) gave (+/-)-benzyl
8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate
(120 mg) as a light yellow oil.
[2188] MS (ESI+) m/z 304.13
[2189] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.42-7.28 (m,
5H), 5.21-5.07 (m, 2H), 4.68 (d, J=9.9 Hz, 1H), 4.20-4.01 (m, 1H),
3.56 (td, J=11.8, 5.0 Hz, 1H), 3.12 (dd, J=11.6, 3.9 Hz, 1H),
3.03-2.87 (m, 5H), 2.86-2.74 (m, 2H), 2.69-2.51 (m, 2H), 2.23 (td,
J=11.6, 3.3 Hz, 1H)
[2190] (626C): To a solution of (+/-)-benzyl
8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate
(120 mg, 0.396 mmol) in Methanol (2 mL) under nitrogen was added
10% Pd/C (126 mg, 0.119 mmol). Purged 3 times with vacuum and
nitrogen then purge three times with vacuum and hydrogen (balloon).
Stir under hydrogen balloon for 2 h. LC-MS indicated completion.
Filtered through a pad of celite and concentrated. The crude (100
mg) was used as is in subsequent step as yellow oil.
[2191] MS (ESI+) m/z 170.14
[2192] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 3.80 (dd,
J=12.5, 2.0 Hz, 1H), 3.51 (td, J=11.8, 5.1 Hz, 1H), 3.33 (d, J=12.5
Hz, 1H), 3.17-3.07 (m, 2H), 2.99 (td, J=12.3, 3.4 Hz, 1H),
2.93-2.84 (m, 5H), 2.79 (dd, J=12.4, 11.3 Hz, 1H), 2.72-2.59 (m,
2
[2193] (626D): A mixture of crude (+/-)-tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (78 mg, 0.236 mmol),
2-methyloctahydro-1H-pyrazino[1,2-a]pyrazin-1-one (40 mg, 0.236
mmol), Pd.sub.2dba.sub.3 (21.65 mg, 0.024 mmol), BINAP (44.2 mg,
0.071 mmol) and Cs.sub.2CO.sub.3 (231 mg, 0.709 mmol) in Dioxane
(2.5 mL) was evacuated and filled with nitrogen 3 times and heated
at 105.degree. C. for 8 h. LC-MS showed completion of reaction. The
reaction mixture was filtered through a plug of Celite and the
filtrate was concentrated. Purification via flash chromatography
(0-5% MeOH in DCM, 12 g) gave (+/-)-tert-butyl
(2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(-
6H)-yl)phenyl)carbamate (60 mg) as a yellow oil.
[2194] MS (ESI+) m/z 420.05
[2195] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.30 (d, J=1.8
Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=1.8 Hz, 1H), 3.86 (dt, J=11.5,
2.6 Hz, 1H), 3.59 (td, J=11.8, 5.2 Hz, 1H), 3.28-3.10 (m, 2H),
3.03-2.90 (m, 6H), 2.89-2.82 (m, 1H), 2.73-2.61 (m, 2H), 2.56 (td,
J=10.8, 3.0 Hz, 1H), 1.53 (s, 9H)
[2196] Example 626: To a solution of racemic tert-butyl
(2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(-
6H)-yl)phenyl)carbamate (60 mg, 0.143 mmol) in DCM (1.5 mL) was
added 1 mL of TFA. After stirring for 1 h, LC-MS indicated
completion. It was concentrated and purification via flash
chromatography (0-5% MeOH in DCM, 12 g) gave racemic
3-amino-4-chloro-5-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6-
H)-yl)benzonitrile (35 mg, 0.109 mmol, 77% yield) as a yellow
solid.
[2197] A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (38.8 mg, 0.109 mmol), above obtained
3-amino-4-chloro-5-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6-
H)-yl)benzonitrile (35 mg, 0.109 mmol), palladium(II) acetate (6.51
mg, 0.029 mmol), XANTPHOS (6.33 mg, 10.94 .mu.mol), DPPF (6.07 mg,
10.94 .mu.mol) and cesium carbonate (93 mg, 0.285 mmol) in Dioxane
(1.5 mL) was evacuated and back filled with nitrogen three time and
was heated at 60.degree. C. for 2 h. LC-MS showed reaction was only
.about.50% complete. The reaction mixture was filtered through a
pad of celite, rinsed with EtOAc and the filtrate was concentrated
and purification via flash chromatography (0-70% EtOAc in Hexane,
24 g) gave 40 mg with ca. 80% purity. This was used without further
purification in subsequent step. TFA (1 mL) was added to a solution
of above obtained
2-((2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-
-2(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f-
][1,2,4]triazine-7-carbonitrile (40 mg, 0.063 mmol) and anisole
(0.027 mL, 0.251 mmol) in dichloroethane (1 mL) and the reaction
mixture was heated at 60.degree. C. for 1 h. LC-MS showed
completion of reaction. Solvent was evaporated and the crude was
dried under vacuum for 10 min. The crude was dissolved in
acetonitrile and neutralized with 7N ammonia in methanol. After
stirring for 10 min it was concentrated, purification via
preparative HPLC gave the title compound (14.3 mg) as a white
solid.
[2198] MS (ESI+) m/z 518.6
[2199] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br. s.,
1H), 8.90 (br. s., 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.35 (s, 1H),
3.73 (d, J=11.0 Hz, 1H), 3.51-3.42 (m, 2H), 3.25-3.13 (m, 2H),
3.04-2.87 (m, 4H), 2.82 (s, 3H), 2.62-2.53 (m, 2H), 2.40 (t, J=10.4
Hz, 1H), 0.84-0.70 (m, 4H)
Example 627
##STR00688##
[2200]
2-((2-chloro-5-cyano-3-(2-oxo-1,3-oxazinan-3-yl)phenyl)amino)-4-(cy-
clopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2201] To a solution of
2-((2-chloro-5-cyano-3-((3-hydroxypropyl)amino)phenyl)amino)-4-(cycloprop-
yl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(15 mg, 0.028 mmol) in dichloroethane (1 mL) was added Hunig's Base
(0.048 mL, 0.276 mmol) followed by triphosgene (40.9 mg, 0.138
mmol). After stirring at room temperature for 1 h, LC-MS indicated
the desired peak. After concentration, purification via flash
chromatography (0-10% MeOH in DCM, 12 g) gave 15 mg of the PMB
protected product. This was dissolved in 1 mL of dichloroethane and
then 1 drop of anisole was added followed by 0.5 mL of TFA. The
solution was heated at 60.degree. C. for 1 h. LC-MS indicated
completion, and then it was cooled and concentrated. The crude was
dissolved in methanol and neutralized with 7N ammonia in
methanol.
[2202] After stirring for 10 min it was concentrated, purification
via preparative HPLC gave the title compound as a yellow solid (4.2
mg).
[2203] MS (ESI+) m/z 450.2
[2204] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (br. s.,
1H), 9.13 (br. s., 1H), 8.44 (br. s., 1H), 7.81 (br. s., 1H), 4.39
(br. s., 2H), 2.97 (br. s., 1H), 2.14 (br. s., 2H), 0.78 (br. s.,
6H)
Example 628
##STR00689##
[2205]
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclop-
ropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2206] TFA (1 mL) was added to a solution of tert-butyl
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate
(10 mg, 0.015 mmol) and anisole (6.53 .mu.l, 0.060 mmol) in DCE (1
mL) and the reaction mixture was heated at 60.degree. C. for 30
min. LC-MS indicated completion, then it was cooled and
concentrated. The crude was dissolved in methanol and neutralized
with 7N ammonia in methanol. After stirring for 10 min it was
concentrated, purification via preparative HPLC gave the title
compound as a yellow solid (3.8 mg).
[2207] MS (ESI+) m/z 449.3
[2208] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (d, J=4.3
Hz, 1H), 9.10 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.67
(d, J=1.8 Hz, 1H), 3.58 (d, J=6.1 Hz, 2H), 3.19-3.03 (m, 2H), 2.97
(d, J=4.3 Hz, 1H), 0.83-0.72 (m, 4H) (2 protons buried under the
water peak)
Example 629
##STR00690##
[2209]
2-((3-cyano-5-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclop-
ropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2210] The title compound was obtained as a side product during
preparation of Example 618.
[2211] MS (ESI+) m/z 429.3
[2212] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.96 (s, 1H),
9.38 (d, J=4.0 Hz, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.44 (s, 1H),
3.69 (t, J=5.2 Hz, 2H), 3.48-3.41 (m, 1H), 3.07 (br. s., 1H),
2.77-2.67 (m, 3H), 2.28 (s, 3H), 0.90-0.74 (m, 4H)
Example 630
##STR00691##
[2213]
2-((2-chloro-5-cyano-3-((2-hydroxyethyl)amino)phenyl)amino)-4-(ethy-
lamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2214] The title compound was prepared using a method analogous to
that used to prepare Example 615.
[2215] MS (ESI+) m/z 398.2
[2216] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.15 (t, J=5.5
Hz, 1H), 8.61 (s, 1H), 8.18 (s, 1H), 7.55 (d, J=1.2 Hz, 1H), 6.90
(d, J=1.2 Hz, 1H), 5.72 (t, J=5.5 Hz, 1H), 4.89 (t, J=5.5 Hz, 1H),
3.58 (q, J=5.5 Hz, 2H), 3.50-3.45 (m, 2H), 3.26 (q, J=5.7 Hz, 2H),
1.18 (t, J=7.3 Hz, 3H)
Example 631
##STR00692##
[2217]
2-((2-chloro-5-cyano-3-(4-(4-methoxybenzyl)-2-oxopiperazin-1-yl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[2218] The title compound was prepared using a method analogous to
that used to prepare Example 618.
[2219] MS (ESI+) m/z 569.3
[2220] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (d, J=3.7
Hz, 1H), 9.13 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.74 (s, 1H),
7.28 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 3.75 (s, 3H), 3.59
(br. s., 3H), 3.44 (br. s., 1H), 3.17 (d, J=6.1 Hz, 2H), 3.02-2.91
(m, 1H), 2.84 (br. s., 1H), 2.73 (s, 1H), 0.78 (d, J=5.5 Hz,
4H)
Example 632
##STR00693##
[2221]
11-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)-
amino)-6-oxo-1,2,3,5,6,7-hexahydrobenzo[e][1,4,7]oxadiazonine-9-carbonitri-
le
[2222] (632A): To a solution of
2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (30 mg, 0.094
mmol) in DCM (2 mL) was added a solution of 2-aminoethanol (5.75
mg, 0.094 mmol) in THF (2 mL) then CESIUM CARBONATE (30.7 mg, 0.094
mmol) was added. After stirring at room temperature for 1.5 h,
LC-MS indicated completion. After concentration purification via
flash chromatography (0-100% EtOAc in Hexane, 12 g) gave
N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)amino)acetamide
as a yellow solid (15 mg).
[2223] MS (ESI+) m/z 263.0
[2224] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.76 (d, J=1.8
Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 4.05 (s, 2H), 3.72 (t, J=5.1 Hz,
2H), 3.24 (t, J=5.1 Hz, 2H)
[2225] Example 632: The title compound was prepared from
N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)amino)acetamide
using a method analogous to that used to prepare Example 618.
[2226] MS (ESI+) m/z 431.2
[2227] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.70 (s, 1H),
9.32 (d, J=3.7 Hz, 1H), 9.16 (s, 1H), 8.46 (s, 1H), 8.21 (s, 1H),
6.88 (d, J=1.2 Hz, 1H), 3.68 (s, 2H), 3.57 (d, J=4.9 Hz, 2H), 3.12
(d, J=3.7 Hz, 1H), 2.95 (t, J=4.3 Hz, 2H), 0.89-0.70 (m, 4H)
Example 633
##STR00694##
[2228]
2-((3-(4-(1-acetylazetidin-3-yl)-2-oxopiperazin-1-yl)-2-chloro-5-cy-
anophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile
[2229] The title compound was prepared using a method analogous to
that used to prepare Example 622.
[2230] MS (ESI+) m/z 546.1
[2231] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39 (br. s.,
1H), 9.12 (br. s., 1H), 8.46 (d, J=1.8 Hz, 1H), 8.21 (s, 1H), 7.73
(s, 1H), 4.15 (q, J=7.5 Hz, 1H), 4.04 (d, J=4.3 Hz, 1H), 3.93-3.84
(m, 1H), 3.73 (dd, J=10.1, 4.6 Hz, 1H), 3.68-3.58 (m, 1H), 3.50
(dd, J=11.3, 5.2 Hz, 1H), 3.36-3.29 (m, 2H), 3.21 (s, 1H), 3.16 (d,
J=4.3 Hz, 1H), 3.02-2.93 (m, 1H), 2.86-2.76 (m, 1H), 1.77 (s, 3H),
0.88-0.72 (m, 4H)
Example 634
##STR00695##
[2232]
2-((2-chloro-5-cyano-3-(4-(2-hydroxyethyl)-2-oxopiperazin-1-yl)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2233] To a solution of
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(10 mg, 0.018 mmol) in DMF (0.5 mL) was added cesium carbonate (25
mg, 0.077 mmol) followed by
(2-bromoethoxy)(tert-butyl)dimethylsilane (8 mg, 0.033 mmol). The
reaction mixture was stirred at room temperature overnight. LC-MS
indicated desired product. It was then filtered through a pad of
Celite, rinsed with EtOAc. The crude was dissolved in DCE (1 mL),
anisole (7.68 .mu.l, 0.070 mmol) (one drop) was added followed by
TFA (0.5 mL, 6.49 mmol). The resulting reaction mixture was heated
at 60.degree. C. for 1 h. LC-MS indicated completion, and then it
was cooled and concentrated. The crude was dissolved in methanol
and neutralized with 7N ammonia in methanol. After stirring for 10
min it was concentrated, purification via preparative HPLC gave the
title compound as a yellow solid (3.4 mg).
[2234] HPLC Rt=0.61 min
[2235] MS (ESI+) m/z 493.4
Example 635
##STR00696##
[2236]
2-((2-chloro-5-cyano-3-(4-methyl-2-oxo-1,4-diazepan-1-yl)phenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2237] The title compound was prepared using a method analogous to
that used to prepare Example 618.
[2238] MS (ESI+) m/z 477.3
[2239] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.37 (br. s.,
1H), 9.06 (br. s., 1H), 8.40 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.61
(d, J=1.8 Hz, 1H), 3.74 (br. s., 1H), 3.67-3.53 (m, 2H), 3.16 (d,
J=5.5 Hz, 1H), 2.97 (br. s., 1H), 2.89 (d, J=7.9 Hz, 2H), 2.42 (s,
3H), 1.97 (br. s., 1H), 1.84 (br. s., 1H), 0.86-0.69 (m, 4H) MS
(ESI+) m/z
Example 636
##STR00697##
[2240]
2-((2-chloro-5-cyano-3-(4-ethyl-2-oxopiperazin-1-yl)phenyl)amino)-4-
-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2241] To a solution of
2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(17 mg, 0.030 mmol) in DCM (2 mL) was added acetaldehyde (13.16 mg,
0.299 mmol) and acetic acid (3.42 .mu.l, 0.060 mmol). After
stirring for 15 min, sodium triacetoxyborohydride (12.66 mg, 0.060
mmol) was added. After stirring at room temperature for 2 h, LC-MS
indicated completion. After concentration, purification via flash
chromatography (0-10% MeOH in DCM, 12 g) gave 20 mg of the PMB
protected product. This was dissolved in 1 mL of DCE and then 1
drop of anisole was added followed by 0.5 mL of TFA. The solution
was heated at 60.degree. C. for 2.5 h. LC-MS indicated completion,
and then it was cooled and concentrated. The crude was dissolved in
methanol and neutralized with 7N ammonia in methanol. After
stirring for 10 min it was concentrated, purification via
preparative HPLC gave the title compound as a yellow solid (10
mg).
[2242] HPLC Rt=0.66 min
[2243] MS (ESI+) m/z 477.4
Example 637
##STR00698##
[2244]
2-((3-(1-(1-acetylazetidin-3-yl)piperidin-4-yl)-2-fluoro-5-cyanophe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[2245] (637A)--The title compound was prepared by the similar
synthetic procedure used for Example 318
[2246] HPLC Rt, 2.860 min
[2247] MS (ESI) m/z 473.30 (M+1)
[2248] Example 637. The title compound was prepared by the similar
synthetic procedure used for Example 319 from Example 318
[2249] HPLC Rt, 2.971 min
[2250] MS (ESI) m/z 515.33 (M+1)
Example 638
##STR00699##
[2251]
2-((2-chloro-5-cyano-3-(1-(1-(2,2,2-trifluoroacetyl)azetidin-3-yl)p-
iperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile
[2252] The title compound was prepared by the similar synthetic
procedure used Example 319 from Example 318
[2253] HPLC Rt, 3.236 min
[2254] MS (ESI) m/z 585.31 (M+1)
Example 639
##STR00700##
[2255]
(+/-)-2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidaz-
o[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-yl)propanamide
[2256] A mixture of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208), (20
mg, 0.046 mmol), 2-bromopropionamide (8.41 mg, 0.055 mmol), sodium
iodide (8.29 mg, 0.055 mmol) and Et.sub.3N (0.025 mL, 0.138 mmol)
in DMF (1.2 mL) was stirred at room temperature for 2 days. The
crude material was purified via preparative LC/MS with the
following conditions: Column: XBridge C18, 19.times.mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
(+/-)-2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imida-
zo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-yl)propanamide
(4.8 mg).
[2257] HPLC Rt, 3.138 min
[2258] MS (ESI) m/z 505.28 (M+1)
Example 640
##STR00701##
[2259]
(+/-)-2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)propanamide
[2260] The title compound was prepared by the similar synthetic
procedure used for Example 639,
[2261] HPLC Rt, 3.20 min
[2262] MS (ESI) m/z 493.40 (M+1)
Example 641
##STR00702##
[2263]
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-2-methylpropanamide
[2264] A mixture of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
(Example 208D) (25 mg, 0.045 mmol), 2-bromo-2-methylpropanamide
(37.5 mg, 0.226 mmol), sodium iodide (33.8 mg, 0.226 mmol) and
Cs.sub.2CO.sub.3 (58.8 mg, 0.180 mmol) in CH.sub.3CN (1.2 mL) was
heated at 120.degree. C. for 2 h using microwave irradiation. The
reaction mixture was diluted with DCM, filtered to remove insoluble
material. The filtrate was concentrated. The residue was dissolved
in DCE (1 mL). To this was added TFA (0.5 ml), anisole (0.1 ml,
0.918 mmol), and then heated at 50.degree. C. for 3 h. Solvent was
removed. The residue was applied onto a cartridge of Phenomenex
Strata-X-C 33 um cation mixed-mode polymer. This was washed with
methanol and product was eluted with large amount (3 CV) of mixture
of 2 N solution of ammonia in methanol/DCM (1:1). Removal of the
solvents left 23 mg material which was further purified via
preparative LC/MS with the following conditions: Column: XBridge
C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A: 5:95
methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5
methanol: water with 10-mM ammonium acetate; Gradient: 50-100% B
over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to afford
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-2-methylpropanamide
(3.6 mg).
[2265] HPLC Rt, 3.185 min
[2266] MS (ESI) m/z 519.16 (M+1)
Example 642
##STR00703##
[2267]
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-N-methylacetamide
[2268] A mixture of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
Example 208D (in 12163-US-psp), (25 mg, 0.045 mmol),
2-chloro-n-methylacetamide (97 mg, 0.090 mmol), sodium iodide
(13.53 mg, 0.090 mmol) and Et.sub.3N (0.024 mL, 0.135 mmol) in DMF
(1.2 mL) in a microwave vial was heated at 100.degree. C. in a
microwave reactor for 2 h. The reaction mixture was diluted with
EtOAc, washed with water, brine, and dried over Na.sub.2SO.sub.4.
Removal of the solvent followed by silica gel chromatography
eluting with DCM containing 0 to 2% MeOH to afford the
PMB-protected product which was dissolved in DCM (0.7 ml), and TFA
(0.7 ml) and anisole (0.025 mL, 0.226 mmol) were added. The
resulting mixture was heated at 50.degree. C. for 3 h. After
removal of solvent the residue was taken in MeOH/DCM and applied
onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode
polymer. This was washed with methanol and product was eluted with
large amount (5 CV) of mixture of 2 N solution of ammonia in
methanol and DCM (1:1). Removal of the solvents to afford
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-N-methylacetamide
(15.6 mg).
[2269] PLC room temperature T, 3.086 min
[2270] MS (ESI) m/z 505.30 (M+1)
Example 643
##STR00704##
[2271]
2-((2-chloro-5-cyano-3-(1-(1-hydroxy-2-methylpropan-2-yl)piperidin--
4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile
[2272] (643A): methyl
2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)i-
midazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-2-methylprop-
anoate was prepared by the similar synthetic procedure used for
Example 640
[2273] HPLC Rt, 3.800 min
[2274] MS (ESI) m/z 654.92 (M+1)
[2275] Example 643: To a solution of 7(A) (26 mg, 0.040 mmol) in
THF (1 ml) under nitrogen was added drop wise lithium borohydride
2M in THF (160 .mu.L, 0.318 mmol). After stirring at room
temperature for 0.5 h, the mixture was heated at 60.degree. C. for
2 h. The reaction mixture was cooled to room temperature and
partitioned between EtOAc and sat. aq. NH.sub.4Cl solution. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4.
Removal of the solvent and the crude PMB-protected product was
dissolved in DCM (1 mL), and anisole (87 .mu.L, 0.795 mmol) and TFA
(0.5 mL) were added. The resulting mixture was stirred at room
temperature overnight. Solvent was removed. The crude material was
purified via preparative LC/MS with the following conditions:
Column: XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile
Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile
Phase B: 95:5 methanol: water with 10-mM ammonium acetate;
Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B;
Flow: 20 mL/min. Fractions containing the desired product were
combined and dried via centrifugal evaporation to afford
2-((2-chloro-5-cyano-3-(1-(1-hydroxy-2-methylpropan-2-yl)piperidin-4-yl)p-
henyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitr-
ile (2.4 mg).
[2276] HPLC Rt, 3.176 min
[2277] MS (ESI) m/z 506.67 (M+1)
Example 644
##STR00705##
[2278]
2-((2-chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2279] To the stirred suspension of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208) (20 mg,
0.046 mmol) in THF (1 ml) was added drop wise a solution of
1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (12.75 mg, 0.055 mmol)
in MeOH (0.4 ml) at 0.degree. C. under nitrogen. The reaction
mixture was allowed to warm to room temperature and stirred for 5
days (converted to clear solution). Solvent was removed. The crude
material was purified via preparative LC/MS with the following
conditions: Column: XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
10-mM ammonium acetate; Gradient: 30-70% B over 18 minutes, then a
7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford
2-((2-chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)a-
mino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(6.6 mg).
[2280] HPLC Rt, 3.230 min
[2281] MS (ESI) m/z 502.66 (M+1)
Example 645 & 646
##STR00706##
[2282] Cis and trans
2-((2-chloro-5-cyano-3-(1-(2-hydroxycyclobutyl)piperidin-4-yl)phenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2283] To the stirred solution of
1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (16.64 mg, 0.072 mmol)
in MeOH (0.5 ml) was added drop wise a solution of
2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
(208D), (20 mg, 0.036 mmol) in THF (0.6 ml) at 0.degree. C. under
nitrogen. The reaction mixture was stirred at 0.degree. C. to room
temperature overnight.
[2284] The reaction mixture was cooled to 0.degree. C., and sodium
borohydride (4.10 mg, 0.108 mmol) was added. After stirring at
0.degree. C. for 30 min, removal of the cooling bath, and stirred
at room temperature for 0.5 h.
[2285] The reaction mixture was cooled to 0.degree. C. again, to
this was added sat. aq. sodium bicarbonate solution (1 ml), and
stirred for 2 minutes. Then the reaction mixture was partitioned
between EtOAc and water. The organic layer was washed with brine,
and dried over Na.sub.2SO.sub.4. After removal of solvent, the
crude PMB-protected product was dissolved in DCM (1 ml), and
anisole (0.1 ml, 0.918 mmol), and TFA (0.5 ml) were added. The
resulting mixture was stirred at room temperature overnight.
Removal of the solvents followed by preparative LC/MS purification
with the following conditions: Column: XBridge C18, 19.times.200
mm, 5-.mu.m particles; Mobile Phase A: 5:95 methanol: water with
10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with
10-mM ammonium acetate; Gradient: 40-100% B over 20 minutes, then a
10-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired products were combined and dried via centrifugal
evaporation to give two isomers, 2.2 mg of isomer 1, and 3.9 mg of
the isomer 2, (Examples 645 and 646). The relative
stereochemistries of the isomers were not defined.
Example 645
[2286] HPLC Rt, 2.20 min
[2287] MS (ESI) m/z 504.71 (M+1)
Example 646
[2288] HPLC Rt, 2.15 min
[2289] MS (ESI) m/z 504.71 (M+1)
Example 647
##STR00707##
[2290]
2-((2-chloro-5-cyano-3-(3-hydroxy-1-(1-methylpiperidin-4-yl)azetidi-
n-3-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile
[2291] (647A): To a solution of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (100 mg,
0.221 mmol) in THF (0.5 ml) at 0.degree. C. under nitrogen was
added drop wise isopropylmagnesium lithium chloride (1.3 M in THF)
(0.187 mL, 0.244 mmol). After stirring at 0.degree. C. for 30 min,
removal of the cooling bath and stirred at room temperature for 30
min. LCMS showed that Br/Mg exchange completed (M+23=395 found).
The reaction mixture was cooled to -14.degree. C. (NaCl-ice bath),
to this was added drop wise a solution of tert-butyl
3-oxoazetidine-1-carboxylate (41.7 mg, 0.244 mmol) in THF (0.5 mL),
and left stirring in the cooling bath for 1 h, during this time the
temperature rose to -4.degree. C. The reaction was quenched with
saturated. aqueous NH4Cl solution (1 ml). Diluted with EtOAc,
washed with water, brine, and dried over sodium sulfate. Solvent
was removed. The crude Boc and PMB protected product was dissolved
in CH.sub.2Cl.sub.2 (0.8 mL), and anisole (0.025 mL) and TFA (0.4
ml) were added. The resulting mixture was stirred at room
temperature for 2 h. Solvent was removed. The residue was taken in
MeOH and applied onto a cartridge of Phenomenex Strata-X-C 33 um
cation mixed-mode polymer. This was washed with methanol and
product was eluted with 2 N solution of ammonia in methanol.
Removal of the solvents left
3-amino-4-chloro-5-(3-hydroxyazetidin-3-yl)benzonitrile (38.6 mg)
as a light yellow solid which was used on next step as such.
[2292] HPLC Rt, 0.388 min
[2293] MS (ESI) m/z 224.07 (M+1)
[2294] 1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 7.04 (d, J=1.8
Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 4.19 (d, J=10.2 Hz, 2H), 3.84 (d,
J=10.7 Hz, 2H).
[2295] (647B): To a suspension of
3-amino-4-chloro-5-(3-hydroxyazetidin-3-yl)benzonitrile (38.6 mg,
0.116 mmol) in DCM (2.5 mL) was added Et.sub.3N (0.023 mL, 0.165
mmol), followed by di-tert-butyl dicarbonate (37.9 mg, 0.173 mmol).
The reaction mixture was stirred at room temperature overnight.
Removal of the solvent gave crude product which was used on next
step as it was.
[2296] HPLC Rt, 3.288 min
[2297] MS (ESI) m/z 346.43 (M+23 found, not ionized)
[2298] (647C): A mixture of tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate
(Example 647B) (37.4 mg, 0.116 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (49.2 mg, 0.139 mmol), DPPF (6.40 mg, 0.012
mmol), Cs.sub.2CO.sub.3 (75 mg, 0.231 mmol), XANTPHOS (6.68 mg,
0.012 mmol), and palladium(II) acetate (7.78 mg, 0.035 mmol) in a
microwave vial in dioxane (1 mL) was evacuated and backfilled with
nitrogen for 3 times, then the mixture was heated in an oil bath at
100.degree. C. for 3 hours. The reaction mixture was diluted with
EtOAc, washed with water, brine, and dried over Na.sub.2SO.sub.4.
Removal of the solvent and the crude material was purified by
radial silica gel chromatography eluting with hexane containing 10
to 40% EtOAc to afford 40.5 mg of tert-butyl
3-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxy
azetidine-1-carboxylate
[2299] HPLC Rt, 4.545 min
[2300] MS (ESI) m/z 642.93 (M+1).
[2301] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.03 (br. s., 1H),
7.92 (s, 1H), 7.54 (d, J=9.9 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J=8.1
Hz, 2H), 6.85 (d, J=8.2 Hz, 2H), 5.71 (br. s., 1H), 5.02 (br. s.,
1H), 4.48 (d, J=9.8 Hz, 2H), 4.25 (d, J=9.8 Hz, 2H), 3.78 (s, 3H),
2.99-2.85 (m, 1H), 1.46 (s, 9H), 1.14 (m, 2H), 0.96-0.91 (m, 2H
[2302] (647D): The above material, (Example 647C) was dissolved in
DCM (5 mL), and TFA (2.5 ml) was added. The resulting mixture was
stirred at room temperature for 30 min. Removal of the solvent. The
residue was taken in DCM/MeOH and applied onto a cartridge of
Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was
washed with methanol, and product was eluted with large amount of
mixture of 2 N solution of ammonia in methanol and DCM (1:1).
Removal of the solvents left
2-((2-chloro-5-cyano-3-(3-hydroxyazetidin-3-yl)phenyl)amino)-4-(cycloprop-
yl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(14.4 mg) as a solid.
[2303] HPLC Rt, 3.513 min
[2304] MS (ESI) m/z 542.72 (M+1).
[2305] Example 647: To a suspension of
2-((2-chloro-5-cyano-3-(3-hydroxyazetidin-3-yl)phenyl)amino)-4-(cycloprop-
yl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile,
(Example 647D), (14.4 mg, 0.027 mmol) in methanol (0.5 ml) was
added trimethyl orthoformate (0.2 ml, 1.809 mmol),
1-methylpiperidin-4-one (30.1 mg, 0.266 mmol) and acetic acid (6.08
.mu.l, 0.106 mmol). The mixture was stirred at room temperature for
40 min. Then sodium cyanoborohydride 1 M in THF (0.22 mL, 0.213
mmol) was added and the reaction mixture was left stirring at room
temperature overnight. The reaction mixture was diluted with EtOAc,
washed with water, brine, and dried over Na.sub.2SO.sub.4. Removal
of the solvents followed by radial silica gel chromatography
eluting with DCM containing 0 to 2% MeOH afforded the PMB-protected
product which was dissolved in DCM (3 ml), and anisole (0.015 mL,
0.133 mmol) and TFA (1.5 ml) were added. The mixture was left
stirring at room temperature overnight.
[2306] Solvent was removed. The crude material was purified via
preparative LC/MS with the following conditions: Column: XBridge
C18, 19.times.mm, 5-.mu.m particles; Mobile Phase A: 5:95 methanol:
water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:
water with 10-mM ammonium acetate; Gradient: 20-100% B over 15
minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions
containing the desired product were combined and dried via
centrifugal evaporation to afford
2-((2-chloro-5-cyano-3-(3-hydroxy-1-(1-methylpiperidin-4-yl)azetidin-3-yl-
)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (5.8 mg) as a solid.
[2307] MS (ESI) m/z 519.72 (M+1).
[2308] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (br. s.,
1H), 9.01 (br. s., 1H), 8.41 (br. s., 1H), 8.22 (s, 1H), 7.62 (br.
s., 1H), 3.72-3.70 (m, 2H), 3.35-3.33 (m, 2H), 3.09-3.07 (m, 1H),
2.97-2.95 (m, 2H), 2.90 (s, 1H), 2.74-2.67 (m, 5H), 1.92-1.89 (m.,
3H), 1.66-1.63 (m., 2H), 0.80-0.77 (m, 4H)
Example 648
##STR00708##
[2309]
2-((2-chloro-5-cyano-3-(4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[2310] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2311] HPLC Rt, 2.905 min
[2312] MS (ESI) m/z 506.69 (M+1).
Example 649
##STR00709##
[2313]
2-((2-chloro-5-cyano-3-(4-hydroxy-1-methylpiperidin-4-yl)phenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2314] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2315] HPLC Rt, 3.000 min
[2316] MS (ESI) m/z 464.57 (M+1).
Example 650
##STR00710##
[2317]
2-((3-(1-(1-acetylazetidin-3-yl)-4-hydroxypiperidin-4-yl)-2-chloro--
5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile
[2318] The title compound was prepared by the similar synthetic
procedure used for Example 647
[2319] HPLC Rt, 2.901 min
[2320] MS (ESI) m/z 547.77 (M+1).
Example 651
##STR00711##
[2321]
2-((2-chloro-5-cyano-3-(3-hydroxypyrrolidin-3-yl)phenyl)amino)-4-(c-
yclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2322] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2323] HPLC Rt, 2.931 min
[2324] MS (ESI) m/z 436.30 (M+1).
Example 652
##STR00712##
[2325]
2-((2-chloro-5-cyano-3-(3-hydroxy-1-(oxetan-3-yl)pyrrolidin-3-yl)ph-
enyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitri-
le
[2326] The title compound was prepared by the similar synthetic
procedure used for Example 647
[2327] HPLC Rt, 2. 815 min
[2328] MS (ESI) m/z 492.22 (M+1).
Example 653
##STR00713##
[2329]
2-((2-chloro-5-cyano-3-(3-hydroxyoxetan-3-yl)phenyl)amino)-4-(cyclo-
propylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2330] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2331] HPLC Rt, 3.678 min
[2332] MS (ESI) m/z 423.48 (M+1).
Example 654
##STR00714##
[2333]
2-((2-chloro-5-cyano-3-(hydroxy(piperidin-4-yl)methyl)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2334] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2335] HPLC Rt, 2. 908 min
[2336] MS (ESI) m/z 464.65 (M+1).
Example 655
##STR00715##
[2337]
2-((2-chloro-5-cyano-3-(hydroxy(1-(oxetan-3-yl)piperidin-4-yl)methy-
l)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile
[2338] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2339] HPLC Rt, 2. 871 min
[2340] MS (ESI) m/z 520.72 (M+1).
Example 656
##STR00716##
[2341]
2-((2-chloro-5-cyano-3-(hydroxy(1-(oxetan-3-yl)azetidin-3-yl)methyl-
)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile
[2342] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2343] HPLC Rt, 2. 995 min
[2344] MS (ESI) m/z 492.67 (M+1).
Example 657
##STR00717##
[2345]
2-((2-chloro-5-cyano-3-(hydroxy(3-methyloxetan-3-yl)methyl)phenyl)a-
mino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2346] The title compound was prepared by the similar synthetic
procedure used for Example 647.
[2347] HPLC Rt, 3.680 min
[2348] MS (ESI) m/z 451.52 (M+1).
Example 658
##STR00718##
[2349]
2-((2-chloro-5-cyano-3-(3-fluoro-1-(1-methylpiperidin-4-yl)azetidin-
-3-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile
[2350] (658A): To a solution of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate
(Intermediate (500 mg, 1.107 mmol) in THF (2.5 ml) at 0.degree. C.
was added drop wise isopropylmagnesium lithium chloride (1.3 M in
THF) (0.937 mL, 1.218 mmol) under nitrogen. After stirring at
0.degree. C. for 30 min, removal of the cooling bath and stirred at
room temperature for 30 min. The reaction mixture was cooled to
-14.degree. C. (NaCl-ice bath), to this was added drop wise a
solution of tert-butyl 3-oxoazetidine-1-carboxylate (208 mg, 1.218
mmol) in THF (2 mL), and left stirring in the cooling bath for 2 h,
during this time the temperature rose to -4.degree. C. The reaction
was quenched with sat. aqueous NH4Cl solution (5 ml), and diluted
with EtOAc, washed with water, brine, and dried over
Na.sub.2SO.sub.4. Solvent was removed. The crude residue was
purified by ISCO (12 g) column chromatography, eluting with hexane
containing 0 to 40% EtOAc to afford tert-butyl
3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl-
)-3-hydroxy azetidine-1-carboxylate (408 mg).
[2351] HPLC Rt, 4.321 min
[2352] MS: (ESI) m/z 566.71 (M+23)
[2353] (658B): To a solution of tert-butyl
3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl-
)-3-hydroxy azetidine-1-carboxylate (408 mg, 0.75 mmol) in dry
CH.sub.2Cl.sub.2 (12 mL) at -78.degree. C. under nitrogen was added
diethylaminosulfur trifluoride (153 .mu.L, 0.90 mmol). The mixture
was allowed to warm to 0.degree. C. over 4 h and quenched by adding
1M aqueous NaOH at -5.degree. C. The reaction mixture was diluted
with EtOAc, washed with water, brine, and dried over sodium
sulfate. Solvent was removed. The residue was purified by ISCO
column (12 g) chromatography, eluting with hexane containing 0 to
40% EtOAc to afford tert-butyl
3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl-
)-3-fluoroazetidine-1-carboxylate (321 mg).
[2354] HPLC Rt, 4.670 min
[2355] MS: (ESI) m/z 568.77 (M+23, not ionized)
[2356] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.60 (br. s., 1H),
7.18 (br. s., 1H), 7.10 (d, J=8.2 Hz, 2H), 6.83 (d, J=7.6 Hz, 2H),
5.10 (d, J=14.5 Hz, 1H), 4.64-4.36 (m, 4H), 4.25 (d, J=14.5 Hz,
1H), 3.81 (s, 3H), 1.61-1.31 (m, 18H).
[2357] 19F NMR (500 MHz, CHLOROFORM-d) .delta. 139.28
[2358] (658C):
3-amino-4-chloro-5-(3-fluoroazetidin-3-yl)benzonitrile
[2359] To a solution of tert-butyl
3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl-
)-3-fluoroazetidine-1-carboxylate, (Example 658B) (321 mg) in DCM
(15 ml) was added anisole (0.5 mL, 4.52 mmol), followed by TFA (7
ml). The resulting mixture was stirred at room temperature
overnight. Solvent was removed. The residue was taken in MeOH and
applied onto a cartridge of Phenomenex Strata-X-C 33 um cation
mixed-mode polymer. This was washed with methanol and the product
was eluted with 2 N solution of ammonia in methanol. Removal of the
solvents left
3-amino-4-chloro-5-(3-fluoroazetidin-3-yl)benzonitrile (127 mg) as
a solid.
[2360] HPLC Rt, 1.573 min
[2361] MS: (ESI) m/z 226.20 (M+1).
[2362] 1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 7.13 (t, J=1.8
Hz, 1H), 6.99-6.91 (m, 1H), 4.34-4.20 (m, 2H), 4.15-4.02 (m,
2H)
[2363] 19F NMR (500 MHz, METHANOL-d.sub.4) .delta. 142.132
[2364] (658D) tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate
To a suspension of
3-amino-4-chloro-5-(3-fluoroazetidin-3-yl)benzonitrile (127 mg,
0.563 mmol) in DCM (10 mL)) was added Et.sub.3N (0.118 mL, 0.844
mmol), followed by di-tert-butyl dicarbonate (135 mg, 0.619 mmol).
The reaction mixture was stirred at room temperature overnight.
Removal of the solvent and the residue was purified by ISCO column
(4 g) chromatography, eluting with hexane containing 0 to 40% EtOAc
to afford tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate
(163 mg, 0.500 mmol, 89% yield) as a white solid.
[2365] HPLC Rt, 3.968 min
[2366] MS: (ESI) m/z 348.37 (M+23 found).
[2367] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.10 (t, J=1.5 Hz,
1H), 7.01 (t, J=1.8 Hz, 1H), 4.59-4.49 (m, 2H), 4.46-4.35 (m, 2H),
1.46 (s, 9H)
[2368] 19F NMR (500 MHz, CHLOROFORM-d) .delta. 138.73
[2369] (658E)
2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
A mixture of tert-butyl
3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate
(21-D), (163 mg, 0.500 mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol),
Cs.sub.2CO.sub.3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050
mmol), and palladium(II) acetate (33.7 mg, 0.150 mmol) in a
microwave vial in dioxane (4.5 mL) was evacuated and backfilled
with nitrogen for three times, and then was heated in an oil bath
at 100.degree. C. for 5 h The reaction mixture was cooled to room
temperature, diluted with EtOAc, filtered through celite to remove
insoluble material. The filtrate was washed with water, and brine.
After drying with sodium sulfate, the solvents were removed and the
product was purified by ISCO column (4 g) chromatography, eluting
with hexane containing 0 to 35% EtOAc to afford 167 mg of the
Boc-PMB-protected product which was dissolved in DCM (6 ml), added
TFA (3 ml), and left stirring at room temperature for 30 min.
Removal of the solvent. The crude was applied onto a cartridge of
Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was
washed with methanol and product was eluted with a mixture of 2 N
solution of ammonia in methanol and DCM (1:1). Removal of the
solvents left
2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(143 mg) as a solid which was used on next step as such.
[2370] HPLC Rt, 3.880 min
[2371] MS (ESI) m/z 544.78 (M+1).
[2372] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.14 (br. s., 1H),
8.02-7.89 (m, 1H), 7.33 (t J=1.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H),
6.86 (d, J=8.4 Hz, 2H), 5.71 (br. s., 1H), 5.01 (br. s., 1H),
4.43-4.08 (m, 4H), 3.79 (s, 3H), 3.01-2.76 (m, 1H), 1.23-1.03 (m,
2H), 0.98-0.80 (m, 2H)
[2373] 19F NMR (500 MHz, CHLOROFORM-d) .delta. 135.83
[2374] Example 658: To a solution of
2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 658E), (25 mg, 0.046 mmol) in methanol (0.5 ml) was added
trimethyl orthoformate (0.2 ml, 1.809 mmol),
1-methylpiperidin-4-one (52.0 mg, 0.460 mmol) and acetic acid
(10.52 .mu.l, 0.184 mmol). The mixture was stirred at room
temperature for 40 min. Then sodium cyanoborohydride 1 M in THF
(0.22 mL, 0.368 mmol) was added and left stirring at room
temperature overnight. The reaction mixture was diluted with EtOAc,
washed with water, brine and dried over Na.sub.2SO.sub.4. Removal
of the solvents and the residue was purified by ISCO column
chromatography, eluting with DCM containing 0 to 2% MeOH to afford
the Boc and PMB-protected product which was dissolved in DCM (3
ml), and anisole (0.025 mL, 0.230 mmol) and TFA (1.5 ml) were
added. The mixture was stirred at room temperature overnight.
Removal of the solvents followed by preparative LC/MS with the
following conditions: Column: XBridge C18, 19.times.200 mm, 5-.mu.m
particles. Mobile Phase A: 5:95 methanol: water with 10-mM ammonium
acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium
acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to
afford
2-((2-chloro-5-cyano-3-(3-fluoro-1-(1-methylpiperidin-4-yl)azetidin-3-yl)-
phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (14.6 mg).
[2375] HPLC Rt, 2.970 min
[2376] MS (ESI) m/z 521.77 (M+1).
[2377] 1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.38 (br. s., 1H),
9.14 (br. s., 1H), 8.49 (s, 1H), 8.22 (s, 1H), 7.84 (s, 1H),
3.95-3.73 (m, 4H), 3.21-3.18 (m, 2H), 3.01-2.85 (m, 3H), 2.67 (s,
3H), 1.86-1.92 (m, 2H), 1.56-1.53 (m, 2H), 0.79-0.76 (m, 4H).
Example 659
##STR00719##
[2378]
2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cycl-
opropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2379] The title compound was prepared by treatment of (Example
658E) with TFA and anisole in DCM overnight, followed by prep HPLC
purification
[2380] HPLC Rt, 3.303 min
[2381] MS (ESI) m/z 424.51 (M+1).
Example 660
##STR00720##
[2382]
2-((2-chloro-5-cyano-3-(3-fluorooxetan-3-yl)phenyl)amino)-4-(cyclop-
ropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2383] The title compound was prepared by the similar synthetic
procedure used for Example 658.
[2384] HPLC Rt, 4.010 min
[2385] MS (ESI) m/z 424.49 (M+1).
Example 661
##STR00721##
[2386]
2-((2-chloro-5-cyano-3-(4-fluoro-1-methylpiperidin-4-yl)phenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2387] The title compound was prepared by the similar synthetic
procedure used for Example 658.
[2388] HPLC Rt, 3.243 min
[2389] MS (ESI) m/z 466.64 (M+1).
Example 662
##STR00722##
[2390]
2-((2-chloro-5-cyano-3-(fluoro(piperidin-4-yl)methyl)phenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2391] The title compound was prepared by the similar synthetic
procedure used for Example 658.
[2392] HPLC Rt, 3.453 min
[2393] MS (ESI) m/z 466.59 (M+1).
Example 663
##STR00723##
[2394]
2-((3-((1-acetylpiperidin-4-yl)fluoromethyl)-2-chloro-5-cyanophenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2395] The title compound was prepared by the similar synthetic
procedure used for Example 658.
[2396] HPLC Rt, 4.145 min
[2397] MS (ESI) m/z 508.4 (M+1).
[2398] Examples 637 to 663 used following HPLC condition for
analysis:
Start % B=0
Final % B=100
Gradient Time=4 min
[2399] Flow Rate=0.8 ml/min
Wavelength=220 nm
Solvent Pair=Methanol:Water:0.1% TFA
Solvent A=5% Water:95% Methanol:0.1% TFA
Solvent B=95% Water:5% Methanol:0.1% TFA
Column=PHENOMENEX-LUNA 2.0.times.50 mm 3 um
Oven Temp.=40
[2400] The compounds in the following Table were similarly prepared
as Example 463. In cases were the starting amine was an HCl salt,
an equivalent amount of TEA was added. In the cases of diamines
where one of the amino groups was protected as a Boc derivative,
the Boc group of the crude product was removed by treatment with
TFA in DCM.
TABLE-US-00028 TABLE 25 HPLC Exam- Retention ple Time No. Structure
Name [M + H].sup.+ (min.) 664 ##STR00724## 2-((2-chloro-5-cyano-3-
(((tetrahydro-2H-pyran-4- yl)amino)methyl)phenyl)amino)-
4-(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
464.16 3.70 665 ##STR00725## 2-((3-(2-oxa-7-
azaspiro[3.5]nonan-7-ylmethyl)- 2-chloro-5-cyanophenyl)amino)-
4-(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
490.18 4.09 666 ##STR00726## 2-((2-chloro-5-cyano-3-((3-
oxopiperazin-1- yl)methyl)phenyl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
463.14 3.55 667 ##STR00727## 2-((2-chloro-5-cyano-3-
((dimethylamino)methyl)phen- yl)amino)-4-
(cyclopropylamino)imidazo[2,1- f][1,2,4]triazine-7-carbonitrile
408.14 3.98 668 ##STR00728## 2-((2-chloro-5-cyano-3- (piperazin-1-
ylmethyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 449.16 3.48 669 ##STR00729##
2-((2-chloro-5-cyano-3-((6- hydroxy-1,4-diazepan-1-
yl)methyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 479.17 3.40 670 ##STR00730##
2-((2-chloro-5-cyano-3-((4- methylpiperazin-1-
yl)methyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 463.18 3.86 671 ##STR00731##
2-((2-chloro-5-cyano-3-((1,1- dioxidothiomorpholino)methyl)
phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 498.11 3.62 672 ##STR00732##
2-((2-chloro-5-cyano-3-((4- hydroxypiperidin-1-
yl)methyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 464.16 3.77 673 ##STR00733##
2-((2-chloro-5-cyano-3-((3- hvdroxyazetidin-1-
yl)methyl)phenyl)amino)-4- (cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 436.10 3.58 674 ##STR00734##
2-((2-chloro-5-cyano-3-(((1- hydroxy-2-methylpropan-2-
yl)amino)methyl)phenyl)amino)- 4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 452.16 3.61
Example 675
##STR00735##
[2401]
2-((3-acetyl-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imid-
azo[2,1-f][1,2,4]triazine-7-carbonitrile
[2402] (675A): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) (750 mg,
2.262 mmol), potassium isopropenyltrifluoroborate (502 mg, 3.39
mmol), and
[1,1'-bis(diphenylphospino)-ferrocene]dichloropalladium(II) (83 mg,
0.11 mmol) in a microwave vial was flushed with nitrogen. EtOH (11
mL) and TEA (0.473 mL, 3.39 mmol) were added and the mixture was
degassed and flushed with nitrogen 3 times. This was sealed and
heated at 80.degree. C. overnight. It was diluted with water and
extracted with a mixture of EtOAc:hexane=3:1. The organic phase was
washed with brine and dried with sodium sulfate. Removal of the
solvents followed by silica gel chromatography eluting with hexane
containing 0 to 20% EtOAc afforded tert-butyl
(2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)carbamate (583 mg) as a
white solid.
[2403] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.51 (d, J=1.8 Hz,
1H), 7.22 (br. s., 1H), 7.17 (d, J=2.0 Hz, 1H), 5.33-5.29 (m, 1H),
5.00 (d, J=0.8 Hz, 1H), 2.08 (t, J=1.1 Hz, 3H), 1.56 (s, 9H)
[2404] (675B): A solution of tert-butyl
(2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)carbamate (583 mg, 2.00
mmol) in a mixture of TFA (7.68 mL, 100 mmol) and DCM (8 mL) was
stirred at room temperature for 1 hr. The solvents were removed and
the residue was suspended in DCM. This was washed with saturated
aq. sodium bicarbonate solution and then dried with sodium sulfate.
Removal of the solvent left
3-amino-4-chloro-5-(prop-1-en-2-yl)benzonitrile (367 mg) as oil
which was used as such.
[2405] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 6.94 (d, J=1.8 Hz,
1H), 6.90-6.87 (m, 1H), 5.29-5.26 (m, 1H), 4.99 (dd, J=1.5, 0.9 Hz,
1H), 4.19 (br. s., 2H), 2.08 (t, J=1.2 Hz, 3H)
[2406] (675C): A mixture of
3-amino-4-chloro-5-(prop-1-en-2-yl)benzonitrile (367 mg, 1.91
mmol),
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (676 mg, 1.91 mmol), Cs.sub.2CO.sub.3 (1.24 gm,
3.81 mmol), DPPF (106 mg, 0.191 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (110 mg, 0.191 mmol)
and Pd(OAc)2 (128 mg, 0.572 mmol) in a microwave vial that was
flushed with nitrogen. Dioxane (16 mL) was added and the vial was
sealed and heated at 100.degree. C. for 4 hr. The reaction was
diluted with EtOAc and filtered through celite. The solvent was
removed from the filtrate and radial silica gel chromatography
eluting with hexane containing 5 to 40% EtOAc afforded
2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopro-
pyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(748 mg) as a solid.
[2407] MS (ESI) m/z 511.30 (M+1)
[2408] (675D): A solution of
2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropyl(4-met-
hoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (748
mg, 1.46 mmol) and anisole (4.00 mL, 36.6 mmol) in DCM (23 mL) and
TFA (23 mL, 290 mmol) was left stirring at room temperature
overnight. The solvents were removed and the yellow solid was
suspended in DCM. This was washed with saturated aq. NaHCO.sub.3
solution and dried with sodium sulfate. The solvent was removed and
the residue was suspended in a mixture of EtOAc:hexane=1:1. This
was filtered to give
2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (365 mg) as a light
yellow solid.
[2409] MS (ESI) m/z 391.17 (M+1)
[2410] 1H NMR (500 MHz, DMSO-d6) .delta. 9.36 (d, J=4.1 Hz, 1H),
8.95 (s, 1H), 8.37-8.32 (m, 1H), 8.21 (s, 1H), 7.48 (d, J=2.0 Hz,
1H), 5.35 (t, J=1.5 Hz, 1H), 5.03 (s, 1H), 3.04-2.86 (m, 1H), 2.08
(s, 3H), 0.82-0.74 (m, 4H).
[2411] Example 675:
2-((2-Chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (300 mg, 0.768 mmol)
was dissolved in a mixture of acetone (70 mL) and water (7 mL).
0504 (2.5 wt % in t-BuOH, 0.482 mL, 0.038 mmol) and NaIO.sub.4 (361
mg, 1.69 mmol) were added. After stirring at room temperature for 3
hr, water (25 mL) was added and the reaction was left stirring for
6 days. During this time, 3 additions of 0504 solution (0.5 mL) and
one addition of NaIO.sub.4 (150 mg) were made. The acetone was
removed and the suspended solid was collected by filtration, washed
with water, and air-dried to leave the title compound (282 mg) as a
tan solid.
[2412] MS (ESI) m/z 393.13 (M+1)
[2413] 1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.39 (1H, d, J=4.12
Hz), 9.15 (1H, s), 8.53 (1H, d, J=1.98 Hz), 8.22 (1H, s), 7.88 (1H,
d, J=1.98 Hz), 2.94 (1H, d, J=4.27 Hz), 2.61 (3H, s), 0.78-0.80
(4H, m)
Example 676
##STR00736##
[2414]
2-((2-chloro-5-cyano-3-(2-hydroxypropan-2-yl)phenyl)amino)-4-(cyclo-
propylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2415] A solution of
2-((3-acetyl-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (Example 675) (60 mg, 0.15 mmol)
in THF (8 mL) was cooled in an ice bath and MeMgBr (3 M in THF,
0.26 mL, 0.76 mmol) was added and the reaction was allowed to warm
to room temperature. It was quenched with sat. aq. NH.sub.4Cl
solution and extracted twice with EtOAc. The organic extracts were
washed with brine, dried with sodium sulfate, and the solvent
removed. HPLC purification afforded 7.7 mg of the title
compound,
[2416] MS (ESI) m/z 409.18 (M+1)
[2417] 1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.94 (1H, d,
J=1.98 Hz), 7.90 (1H, s), 7.83 (1H, d, J=1.98 Hz), 7.76 (1H, br.
s.), 7.70 (1H, s), 3.11 (1H, tq, J=7.18, 3.66 Hz), 1.81 (6H, s),
1.10-1.13 (2H, m), 0.85-0.88 (2H, m).
Example 677
##STR00737##
[2418]
(+/-)-2-((2-chloro-5-cyano-3-(1-hydroxyethyl)phenyl)amino)-4-(cyclo-
propylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2419] Solid NaBH.sub.4 (58 mg, 1.53 mmol) was added to an
ice-cooled solution of
2-((3-acetyl-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,-
1-f][1,2,4]triazine-7-carbonitrile (Example 675) (120 mg, 0.305
mmol) in THF (8 mL). This was allowed to warm to room temperature
over 1 hr. It was quenched with 2 mL of 1 N NaOH and extracted with
EtOAc. The organic phase was washed with brine and dried with
sodium sulfate. The solvent was removed and radial silica gel
chromatography eluting with DCM containing 0 to 3% MeOH afforded
2-((2-chloro-5-cyano-3-(1-hydroxyethyl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (62 mg) as a white
solid.
[2420] MS (ESI) m/z 395.15 (M+1)
[2421] 1H NMR (500 MHz, METHANOL-d4) .delta. 8.87-8.82 (m, 1H),
7.80 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 5.19 (q, J=6.4 Hz, 1H), 2.99
(tt, J=7.2, 3.8 Hz, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.05-0.96 (m, 2H),
0.79-0.72 (m, 2H).
Example 678
##STR00738##
[2422]
(+/-)-2-((2-chloro-5-cyano-3-(1-(4-(methylsulfonyl)piperazin-1-yl)e-
thyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile
[2423] (678A): A solution of
2-((2-chloro-5-cyano-3-(1-hydroxyethyl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 677) (56 mg,
0.14 mmol) in THF (4 mL) was cooled in an ice bath and
methanesulfonyl chloride (28 .mu.L, 0.36 mmol) was added. The bath
was removed and quenched after 5 min with a little water. This was
extracted with EtOAc and the organic extracts were washed with
brine and dried with sodium sulfate. The solvent was removed to
leave
1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)ethyl methanesulfonate (67 mg) as a white
solid that was used as such.
[2424] MS (ESI) m/z 473.20 (M+1)
[2425] 1H NMR (500 MHz, METHANOL-d4) .delta. 8.99 (d, J=1.8 Hz,
1H), 7.88-7.82 (m, 1H), 7.49 (d, J=2.0 Hz, 1H), 6.13 (d, J=6.6 Hz,
1H), 3.05-2.97 (m, 4H), 1.69 (d, J=6.6 Hz, 3H), 1.03 (dd, J=7.1,
1.3 Hz, 2H), 0.78 (td, J=2.6, 1.3 Hz, 2H)
[2426] Example 678: A mixture of
1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)ethyl methanesulfonate (36 mg, 0.076
mmol), 1-(methylsulfonyl)piperazine (37 mg, 0.23 mmol) and
potassium carbonate (31 mg, 0.23 mmol) in dry acetonitrile (1 mL)
in a sealed vial was heated at 80.degree. C. for 5 hr. Water was
added and the reaction was extracted twice with EtOAc. The organic
extracts were washed with brine and dried with sodium sulfate.
Removal of the solvent followed by radial silica gel chromatography
eluting with DCM containing 0 to 1% MeOH afforded the title
compound (6 mg) as a film.
[2427] MS (ESI) m/z 541.30 (M+1)
[2428] 1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.96 (1H, d,
J=1.98 Hz), 7.89 (1H, s), 7.61 (1H, s), 7.59 (1H, d, J=1.98 Hz),
6.82 (1H, d, J=1.98 Hz), 4.00 (1H, q, J=6.66 Hz), 3.21-3.34 (4H,
m), 3.07 (1H, tq, J=7.10, 3.56 Hz), 2.83 (3H, s), 2.68-2.77 (2H,
m), 2.50-2.58 (2H, m), 1.35 (3H, d, J=6.71 Hz), 1.09-1.15 (2H, m),
0.81-0.86 (2H, m)
Example 679
##STR00739##
[2429]
(+/-)-2-((2-chloro-5-cyano-3-(1-(3-oxopiperazin-1-yl)ethyl)phenyl)a-
mino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2430] This was similarly prepared as Example 678 from
1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]-
triazin-2-yl)amino)phenyl)ethyl methanesulfonate and
piperazin-2-one (22.74 mg).
[2431] HPLC Rt, 3.64 min
[2432] MS (ESI) m/z 477.16 (M+1)
Example 680
##STR00740##
[2433]
(+/-)-2-((2-chloro-5-cyano-3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl-
)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2434] TBAF (1 M in THF, 0.026 mL, 0.026 mmol) was added to a
suspension of (trifluoromethyl)trimethylsilane (2 M solution in
THF, 0.079 mL, 0.16 mmol) and
2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (20 mg, 0.053 mmol) in
dry THF (1 mL) under nitrogen in an ice bath. The bath was removed
and the reaction was left stirring at room temperature overnight.
Aqueous 1 N HCl was added and the reaction was left stirring for 20
min. This was neutralized with 1.3 N potassium phosphate buffer and
extracted three times with EtOAc. The organic extracts were washed
with brine and dried with sodium sulfate. Radial silica gel
chromatography eluting with DCM containing 0 to 15% EtOAc afforded
the title compound (4.1 mg) as oil.
[2435] HPLC Rt, 4.11 min
[2436] MS (ESI) m/z 449.15 (M+1)
[2437] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.14 (d, J=1.8 Hz,
1H), 7.89 (s, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.59 (s, 1H), 6.88 (br.
s., 1H), 5.72 (d, J=5.8 Hz, 1H), 3.39 (br. s., 1H), 3.07 (td,
J=7.0, 3.4 Hz, 1H), 1.17-1.09 (m, 2H), 0.87-0.80 (m, 2H)
Example 681
##STR00741##
[2438]
(+/-)-2-((2-chloro-5-cyano-3-(1,2-dihydroxyethyl)phenyl)amino)-4-(c-
yclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2439] (35): An aliquot of the reaction mixture in Example 400 was
removed when diol formation was complete as judged by LCMS. It was
quenched with 5% aq. sodium thiosulfate solution and extracted with
EtOAc. The organic extract was washed with brine and dried with
sodium sulfate. HPLC purification afforded the title compound as
oil.
[2440] MS (ESI) m/z 411.10 (M+1)
[2441] 1H NMR (500 MHz, DMSO-d6) .delta. ppm 8.84-8.98 (1H, m),
8.31-8.38 (1H, m), 8.21 (1H, s), 7.91-7.96 (1H, m), 7.59-7.65 (1H,
m), 5.74 (1H, d, J=4.58 Hz), 4.86-5.03 (2H, m), 3.54-3.62 (1H, m),
3.40-3.45 (1H, m), 2.92-2.99 (1H, m), 0.78 (4H, d, J=5.49 Hz)
Example 682
##STR00742##
[2442]
(+/-)-2-((2-chloro-5-cyano-3-(1,2-dihydroxypropan-2-yl)phenyl)amino-
)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2443] Osmium tetroxide (2.5 wt % in t-BuOH, 0.032 mL, 2.6 .mu.mol)
followed by NaIO.sub.4 (11 mg, 0.051 mmol) were added to a solution
of
2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 675A) (20 mg,
0.051 mmol) in a mixture of acetone (2 mL) and water (0.2 mL). This
was stirred at room temperature for 3 days during which time three
more additions of osmium tetroxide (2.5 wt % in t-BuOH, 0.032 mL,
2.6 .mu.mol) were made. The solvent was removed and the residue was
partitioned between DCM and water. The organic phase was separated
and dried with sodium sulfate. The solvent was removed and HPLC of
the residue afforded the title compound (6.8 mg) which was
converted to the mono HCl salt by adding 2N HCl in ether to a
solution of the title compound in a mixture of DCE:MeOH=1:1 and
then removing the solvent.
[2444] MS (ESI) m/z 425.12 (M+1)
[2445] 1H NMR (500 MHz, DMSO-d6) .delta. 9.43-9.23 (m, 1H), 8.87
(br. s., 1H), 8.31 (s, 1H), 8.23-8.15 (m, 1H), 7.89 (s, 1H), 5.45
(s, 1H), 4.81 (t, J=5.5 Hz, 1H), 3.92 (dd, J=10.8, 6.0 Hz, 1H),
3.70 (dd, J=10.8, 5.3 Hz, 1H), 2.96 (br. s., 1H), 1.56 (s, 3H),
0.78 (br. s., 4H).
Example 683
##STR00743##
[2446]
2-((3-(azidomethyl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylami-
no)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2447] A mixture of
2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropylamino)i-
midazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 402) (120 mg,
0.315 mmol), diphenylphosphoryl azide (0.102 mL, 0.473 mmol) and
DBU (0.071 mL, 0.473 mmol) in dry dioxane (3 mL) was heated at
70.degree. C. for 20 hr. It was diluted with EtOAc and washed with
water. The aqueous phase was washed with EtOAc and the combined
organic phases were washed with brine and dried with sodium
sulfate. Removal of the solvents followed by radial silica gel
chromatography eluting with DCM containing 0 to 3% MeOH afforded
2-((3-(azidomethyl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl-
amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as a
white solid.
[2448] MS (ESI) m/z 406.10 (M+1)
[2449] 1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.30-9.42 (1H, m),
9.00-9.11 (1H, m), 8.44-8.52 (1H, m), 8.18-8.25 (1H, m), 7.70-7.76
(1H, m), 4.68 (2H, s), 2.92-2.98 (1H, m), 0.78 (4H, d, J=5.19
Hz)
Example 684
##STR00744##
[2450]
2-((2-chloro-5-cyano-3-(1-hydroxy-2-morpholinoethyl)phenyl)amino)-4-
-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2451] (684A): Added MCPBA (70% wet, 3330 mg, 13.5 mmol) in
portions to an ice-cooled suspension of
2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile (Example 399) (339 mg, 0.900
mmol) in CHCl.sub.3 (90 mL). The bath was removed and the reaction
was left stirring at room temperature for 2 days. This was diluted
with CHCl.sub.3 and washed with 5% aq. NaHSO.sub.3 solution and
then 3 times 1 N Na.sub.2CO.sub.3 solution. After drying with
sodium sulfate, the solvent was removed and radial silica gel
chromatography eluting with DCM containing 0 to 10% EtOAc afforded
2-((2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)amino)-4-(cyclopropylamino)imi-
dazo[2,1-f][1,2,4]triazine-7-carbonitrile (293 mg) as a white
solid.
[2452] 1H NMR (500 MHz, mixture of CHLOROFORM-d and METHANOL-d4)
.delta. 8.96-8.91 (m, 1H), 7.85-7.81 (m, 1H), 7.18 (d, J=1.8 Hz,
1H), 4.20-4.15 (m, 1H), 3.26-3.17 (m, 1H), 3.05-2.97 (m, 1H),
2.69-2.64 (m, 1H), 1.05-0.99 (m, 2H), 0.79-0.74 (m, 2H)
[2453] (684B): Added morpholine (0.040 mL, 0.46 mmol) to a solution
of
2-((2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)amino)-4-(cyclopropylamino)imi-
dazo[2,1-f][1,2,4]triazine-7-carbonitrile (9.1 mg, 0.023 mmol) in a
mixture of DCE (1.0 mL) and MeOH (0.5 mL) in a vial. This was
sealed and heated at 70.degree. C. overnight. The reaction was
diluted with DCM and washed with water. The organic phase was dried
with sodium sulfate and the solvent was removed. Radial silica gel
chromatography eluting with DCM containing 0 to 3% MeOH afforded
the title compound (5 mg) as a film.
[2454] MS (ESI) m/z 480.1 (M+1)
[2455] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.00 (d, J=1.8 Hz,
1H), 7.89 (s, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.54 (s, 1H), 6.82 (br.
s., 1H), 5.21 (dd, J=10.2, 2.9 Hz, 1H), 4.12 (br. s., 1H),
3.89-3.71 (m, 4H), 3.07 (tq, J=7.1, 3.6 Hz, 1H), 2.82 (dd, J=12.5,
3.1 Hz, 3H), 2.59-2.48 (m, 2H), 2.33 (dd, J=12.5, 10.4 Hz, 1H),
1.15-1.10 (m, 2H), 0.86-0.80 (m, 2H).
[2456] The compounds in the following Table were similarly
prepared. In the case of amines that were available as HCl salts,
an equivalent amount of TEA was added.
TABLE-US-00029 TABLE 26 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 685 ##STR00745##
2-((2-chloro-5-cyano-3-(1- hydroxy-2-((2- methoxyethyl)amino)ethyl)
phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 468.16 3.34 686 ##STR00746##
2-((2-chloro-5-cyano-3-(1- hydroxy-2-(4- methylpiperazin-1-
yl)ethyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 493.19 3.32 687 ##STR00747##
2-((2-chloro-5-cyano-3-(1- hydroxy-2-(4- (methylsulfonyl)piperazin-
1-yl)ethyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 557.15 3.50 688 ##STR00748##
2-((2-chloro-5-cyano-3-(1- hydroxy-2-(4- hydroxypiperidin-1-
yl)ethyl)phenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 494.3 3.55 689 ##STR00749##
2-((3-(2-(4-acetylpiperazin- 1-yl)-1-hydroxyethyl)-2- chloro-5-
cyanophenyl)amino)-4- (cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 521.19 3.58 690 ##STR00750##
2-((2-chloro-5-cyano-3-(1- hydroxy-2-(4-hydroxy-4-
methylpiperidin-1- yl)ethyl)phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
508.2 3.58 691 ##STR00751## 2-((2-chloro-5-cyano-3-(1-
hydroxy-2-((2-hydroxy-2- methylpropyl)amino)ethyl) phenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
482.17 3.36 692 ##STR00752## 2-((3(2-(tert-butylamino)-
1-hydroxyethyl)-2-chloro- 5-cyanophenyl)amino)-4-
(cyclopropylamino)imidazo [2,1-f][1,2,4]triazine-7- carbonitrile
466.18 3.57 693 ##STR00753## 2-((2-chloro-5-cyano-3-(1-
hydroxy-2-((1-hydroxy-2- methylpropan-2-
yl)amino)ethyl)phenyl)amino)- 4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazine-7- carbonitrile 482.17 3.46
[2457] Following HPLC condition for analysis:
Start % B=0
Final % B=100
Gradient Time=4 min
[2458] Flow Rate=0.8 ml/min
Wavelength=220 nm
Solvent Pair=Methanol:Water:0.1% TFA
Solvent A=5% Water:95% Methanol:0.1% TFA
Solvent B=95% Water:5% Methanol:0.1% TFA
Column=PHENOMENEX-LUNA 2.0.times.50 mm 3 um
Oven Temp.=40
Example 694
##STR00754##
[2459]
(+/-)-2-((2-chloro-5-cyano-3-(4-methylmorpholin-2-yl)phenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2460] (694A): Added m-CPBA 50% (1.92 gm, 5.56 mmol) in portions to
an ice-cooled solution of tert-butyl
(2-chloro-5-cyano-3-vinylphenyl)carbamate (Example 399A) (517 mg,
1.86 mmol) in DCM (30 mL). The bath was removed and the reaction
was left stirring at room temperature overnight. Added additional
50% MCPBA (0.6 gm) and left stirring overnight. Added 20 mL of 0.5
M NaHCO.sub.3 solution and left stirring for 4 hr. The aqueous
phase was separated and washed with DCM. The combined organic
phases were washed three times with 1 N Na.sub.2CO.sub.3 solution.
After drying with sodium sulfate, the solvents were removed to
leave crude tert-butyl
(2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)carbamate (516 mg, 94%
yield). This was dissolved in a mixture of DCE (12 mL) and MeOH (6
mL) in a microwave vial. Ethanolamine (2.12 mL, 35.0 mmol) was
added and the vial was sealed and heated at 60.degree. C.
overnight. The solvent was removed and the residue was taken up in
DCM and washed with water (2.times.) and brine. After drying with
sodium sulfate, the solvent was removed and radial silica gel
chromatography eluting with DCM containing 0 to 14% MeOH and then
10% 2N NH.sub.3 in MeOH afforded tert-butyl
(2-chloro-5-cyano-3-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)phenyl)carb-
amate (337 mg).
[2461] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.50 (d, J=1.4 Hz,
1H), 7.63 (d, J=1.8 Hz, 1H), 7.15 (s, 1H), 5.16-5.06 (m, 1H),
3.80-3.65 (m, 2H), 3.04 (dd, J=12.5, 2.6 Hz, 1H), 2.86 (tdd,
J=17.6, 12.6, 4.5 Hz, 2H), 2.78-2.33 (m, 4H), 1.56 (s, 9H). (694B):
Added Boc.sub.2O (264 .mu.l, 1.14 mmol) to a solution of tert-butyl
(2-chloro-5-cyano-3-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)phenyl)carb-
amate (337 mg, 0.947 mmol) in THF (10 mL). After stirring at room
temperature for 2 hr, the reaction was diluted with EtOAc and
washed with brine. The organic phase was dried with sodium sulfate
and the solvent was removed. Radial silica gel chromatography
eluting with DCM containing 0 to 10% MeOH afforded tert-butyl
(2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxyethyl-
)(2-hydroxyethyl)carbamate (389 mg) as a foam.
[2462] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.50 (d, J=1.4 Hz,
1H), 7.63 (d, J=1.8 Hz, 1H), 7.15 (s, 1H), 5.16-5.06 (m, 1H),
3.80-3.65 (m, 2H), 3.04 (dd, J=12.5, 2.6 Hz, 1H), 2.86 (tdd,
J=17.6, 12.6, 4.5 Hz, 2H), 2.78-2.33 (m, 4H), 1.56 (s, 9H).
[2463] (694C): Diethyl azodicarboxylate (203 .mu.L, 1.28 mmol) was
added to a solution of tert-butyl
(2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxyethyl-
)(2-hydroxyethyl)carbamate (389 mg, 0.853 mmol) and
triphenylphosphine (336 mg, 1.28 mmol) in dry toluene (9.0 mL) at
room temperature. This was left stirring overnight. Water was added
and the reaction was extracted with EtOAc. The organic phase was
dried with sodium sulfate and the solvent was removed. Radial
silica gel chromatography eluting with hexane containing 0 to 20%
EtOAc afforded tert-butyl
2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)morpholine-4-car-
boxylate (252 mg) as a colorless foam.
[2464] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.55 (d, J=1.7 Hz,
1H), 7.58 (d, J=1.8 Hz, 1H), 7.17 (s, 1H), 4.78-4.68 (m, 1H),
4.44-3.68 (m, 4H), 3.05 (br. s., 1H), 2.59 (br. s., 1H), 1.56 (s,
9H), 1.50 (s, 9H).
[2465] (694D): TFA (4.5 mL) was added to a solution of tert-butyl
2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)morpholine-4-car-
boxylate (252 mg, 0.575 mmol) in DCM (4.5 mL) at room temperature.
After 0.5 hr, the solvent was removed. The residue in was dissolved
in MeOH and this was applied onto an SCX column. After washing with
MeOH, the product was eluted with 2N NH.sub.3 in MeOH to give
3-amino-4-chloro-5-(morpholin-2-yl)benzonitrile (132 mg) as an oil.
This was dissolved in DCM (7 mL) and TEA (0.096 mL, 0.69 mmol) and
BOC.sub.2O (0.16 mL, 0.69 mmol) were added. After stirring
overnight, the solvent was removed and radial silica gel
chromatography eluting with hexane containing 0 to 30% EtOAc
afforded tert-butyl
2-(3-amino-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (203
mg).
[2466] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.27 (d, J=1.5 Hz,
1H), 6.98 (d, J=2.0 Hz, 1H), 4.72 (d, J=9.3 Hz, 1H), 4.45-4.20 (m,
3H), 4.12-3.84 (m, 2H), 3.78-3.67 (m, 1H), 3.11-2.93 (m, 1H),
2.71-2.48 (m, 1H), 1.50 (s, 9H).
[2467] (694E): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (213 mg, 0.601 mmol), Cs.sub.2CO.sub.3 (392 mg,
1.20 mmol), DPPF (33 mg, 0.060 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (35 mg, 0.060 mmol),
tert-butyl
2-(3-amino-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (203 mg,
0.601 mmol) and Pd(OAc).sub.2 (41 mg, 0.18 mmol) in a microwave
vial were flushed with nitrogen. Dioxane (5 mL) was added and the
vial was sealed and heated at 100.degree. C. for 4 hr. The reaction
was diluted with EtOAc and filtered through celite. The solvent was
removed and radial silica gel chromatography eluting with hexane
containing 5 to 40% EtOAc afforded tert-butyl
2-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholine-4-carboxylate
as a foam. It was dissolved in DCM (9 mL) and anisole (1.64 mL, 15
mmol) followed by TFA (9 mL) were added. After stirring overnight,
the solvents were removed and the residue was dissolved in MeOH.
and applied onto an SCX column. It was washed with MeOH, and the
crude product was eluted with 2N NH.sub.3 in MeOH. Radial silica
gel chromatography eluting with DCM containing 0 to 10% MeOH afford
2-((2-chloro-5-cyano-3-(morpholin-2-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (96 mg) as a foam.
[2468] MS (ESI) m/z 436.51 (M+1)
[2469] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 8.98 (d, J=1.8 Hz,
1H), 7.88 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 6.96 (br.
s., 1H), 4.88 (dd, J=9.9, 2.1 Hz, 1H), 4.11 (dd, J=11.4, 2.6 Hz,
1H), 3.84 (td, J=11.5, 2.7 Hz, 1H), 3.28 (d, J=12.2 Hz, 1H),
3.11-2.91 (m, 3H), 2.59 (dd, J=12.2, 10.2 Hz, 1H), 1.15-1.08 (m,
2H), 0.86-0.79 (m, 2H).
[2470] Example 694: A suspension of
2-((2-chloro-5-cyano-3-(morpholin-2-yl)phenyl)amino)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (21 mg, 0.048 mmol),
formaldehyde (37% solution in water, 5 .mu.L, 0.072 mmol) and HOAc
(4 .mu.L, 0.072 mmol) in DCE (0.4 mL) was stirred at room
temperature for 5 min. Sodium triacetoxyborohydride (1 M in THF, 96
uL, 0.096 mmol) was added and after 0.5 hr the reaction was
quenched with sat. aq. NaHCO.sub.3 solution and extracted with DCM.
The organic extracts were dried with sodium sulfate and the solvent
was removed. Radial silica gel chromatography eluting with DCM
containing 0 to 5% MeOH afforded the title compound (3.8 mg, 15%
yield) as a film.
[2471] MS (ESI) m/z 450.55 (M+1)
[2472] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.00 (d, J=1.8 Hz,
1H), 7.88 (s, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.57 (s, 1H), 6.89 (br.
s., 1H), 4.98 (dd, J=9.9, 2.1 Hz, 1H), 4.11 (dd, J=11.4, 2.3 Hz,
1H), 3.91 (td, J=11.6, 2.4 Hz, 1H), 3.10-3.04 (m, 2H), 2.80 (d,
J=11.6 Hz, 1H), 2.29 (td, J=11.6, 3.4 Hz, 1H), 1.87 (dd, J=11.4,
10.1 Hz, 1H), 1.15-1.09 (m, 2H), 0.86-0.80 (m, 2H).
Example 695
##STR00755##
[2473]
(+/-)-2-((3-(4-acetylmorpholin-2-yl)-2-chloro-5-cyanophenyl)amino)--
4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2474] Acetyl chloride (1 M in DCM, 0.072 mL, 0.072 mmol) was added
to an ice-cooled solution of
(+/-)-2-(2-chloro-5-cyano-3-(morpholin-2-yl)phenoxy)-4-(cyclopropylamino)-
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (21 mg, 0.048 mmol)
and TEA (0.013 mL, 0.096 mmol) in dry DCM (2 mL). The bath was
removed and the reaction was diluted with DCM and washed with water
after 1 hr. It was dried with sodium sulfate and the solvent was
removed. Radial silica gel chromatography with DCM containing 0 to
5% MeOH afforded the title compound (15.6 mg) as a film.
[2475] MS (ESI) m/z 478.61 (M+1)
[2476] 1H NMR (500 MHz, CHLOROFORM-d) .delta. 9.05 (dd, J=6.5, 1.8
Hz, 1H), 7.89 (d, J=5.0 Hz, 1H), 7.66-7.49 (m, 2H), 6.85 (d, J=18.2
Hz, 1H), 4.97-4.56 (m, 2H), 4.21-3.71 (m, 3H), 3.50-2.43 (m, 3H),
2.19 (d, J=1.7 Hz, 3H), 1.18-1.06 (m, 2H), 0.87-0.78 (m, 2H).
Example 696
##STR00756##
[2477]
(+/-)-2-((2-chloro-5-cyano-3-((3-(trifluoromethyl)piperazin-1-yl)me-
thyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile
[2478] (696A): Added methanesulfonyl chloride (0.153 ml, 1.97 mmol)
to an ice-cooled solution of
2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropylamino)i-
midazo[2,1-f][1,2,4]triazine-7-carbonitrile (300 mg, 0.788 mmol) in
THF (20 ml). The bath was removed and after 15 min, water was added
and the reaction was extracted with EtOAc. The organic extracts
were washed with brine and dried with sodium sulfate. The solvent
was removed to leave crude
2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)benzyl methanesulfonate (323 mg) as a tan
solid
[2479] 1H NMR (400 MHz, DMSO-d6 and D2O) .delta. 8.54 (d, J=2.0 Hz,
1H), 8.20 (s, 1H), 7.79 (d, J=1.8 Hz, 1H), 5.39 (s, 2H), 3.33 (s,
3H), 2.98-2.91 (m, 1H), 0.80-0.78 (m, 4H).
[2480] Example 696: A mixture of
2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]tri-
azin-2-yl)amino)benzyl methanesulfonate (25 mg, 0.054 mmol),
2-(trifluoromethyl)piperazine (25.2 mg, 0.163 mmol) and
K.sub.2CO.sub.3 (23 mg, 0.16 mmol) in dry acetonitrile (1 mL) in a
sealed vial was heated at 80.degree. C. for 2 hr. Water was added
and the reaction was extracted twice with EtOAc. The organic
extracts were washed with brine and dried with sodium sulfate.
Preparative HPLC afforded the title compound (17 mg, 57% yield)
which was converted to the mono HCl salt by adding 2N HCl in ether
to a solution of the title compound in a mixture of DCE:MeOH=1:1
and then removing the solvent.
[2481] MS (ESI) m/z 517.15 (M+1)
[2482] 1H NMR (500 MHz, DMSO-d6) .delta. 9.37 (d, J=3.7 Hz, 1H),
8.93 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.68 (br. s., 1H),
7.37-7.08 (m, 2H), 3.71 (br. s., 3H), 3.04-2.91 (m, 3H), 2.84 (br.
s., 1H), 2.74 (br. s., 1H), 2.31 (br. s., 2H), 0.79 (br. s.,
4H).
Example 697
##STR00757##
[2483]
(+/-)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)am-
ino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2484] (697A): To a round bottom flask charged with
(+/-)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (2 g,
9.21 mmol) in DMF (2 mL) was added imidazole and TBS-Cl (1.387 g,
9.21 mmol). The reaction mixture was stirred at room temperature 2
d. The reaction mixture was poured into a separatory funnel
containing half-saturated aqueous ammonium chloride and ether. The
aqueous layer was extracted with ether (2.times.). The combined
organics were washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo. (+/-)-tert-Butyl
2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine-4-carboxylate
(3.039 g,) was isolated as a white pasty solid.
[2485] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.03 (d, J=13.0
Hz, 1H), 3.87 (dd, J=11.2, 2.6 Hz, 2H), 3.71 (dd, J=10.6, 4.8 Hz,
1H), 3.60-3.41 (m, 3H), 2.99-2.86 (m, 1H), 2.73-2.61 (m, 1H), 1.47
(s, 9H), 0.90 (s, 9H), 0.07 (s, 6H)
[2486] (697B): To a round bottom flask charged with
(+/-)-tert-butyl
2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine-4-carboxylate
(3.04 g, 9.17 mmol) in dichloromethane (45.8 ml) and cooled to
0.degree. C. was added 2,6-lutidine (2.136 ml, 18.34 mmol).
Trimethylsilyl trifluoromethanesulfonate (3.31 ml, 18.34 mmol) was
added drop wise over 5 min. The reaction was slowly warmed to room
temperature over 4 h. The reaction mixture was quenched by the
addition of saturated aqueous sodium bicarbonate and
dichloromethane. The mixture was transferred to a separatory funnel
and the aqueous layer was extracted with dichloromethane
(3.times.). The combined organics were washed with brine, dried
over anhydrous sodium sulfate, filtered and concentrated in vacuo.
The crude residue was purified by column chromatography on the ISCO
system (0-10% MeOH/CH.sub.2Cl.sub.2).
(+/-)-2-(((tert-Butyldimethylsilyl)oxy)methyl)morpholine (1.692 g)
was isolated as a clear oil.
[2487] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 3.90 (dt,
J=11.6, 2.4 Hz, 1H), 3.73-3.64 (m, 2H), 3.63-3.51 (m, 2H), 3.09
(dd, J=12.2, 2.1 Hz, 1H), 2.97 (br. s., 1H), 2.93-2.87 (m, 2H),
2.67 (dd, J=12.3, 9.9 Hz, 1H), 0.89 (s, 9H), 0.06 (s, 6H)
[2488] (697C): A round bottom flask was charged with tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (2.020 g, 6.09 mmol),
(+/-)-2-(((tert-butyl dimethylsilyl)oxy)methyl)morpholine (1.692 g,
7.31 mmol), Pd.sub.2(dba).sub.3 (0.558 g, 0.609 mmol) and BINAP
(0.379 g, 0.609 mmol) in toluene (20.31 ml). The flask was
evacuated and purged with nitrogen (4.times.) and heated at
100.degree. C. 8 h and cooled to room temperature ON. The reaction
mixture was diluted with ethyl acetate and vacuum filtered through
a pad of Celite. The filtrate was concentrated in vacuo. The crude
residue was purified by column chromatography on the ISCO system
(80 g, 0-100% EtOAc/CH.sub.2Cl.sub.2) to provide (+/-)-tert-butyl
(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanop-
henyl)carbamate (1.2321 g) as a yellow solid.
[2489] MS (ESI) m/z 482.4 (M+1)
[2490] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.33 (d, J=1.5
Hz, 1H), 7.19 (s, 1H), 6.98 (d, J=1.8 Hz, 1H), 4.03-3.96 (m, 1H),
3.86 (td, J=11.1, 2.4 Hz, 1H), 3.81-3.73 (m, 2H), 3.65-3.56 (m,
1H), 3.36 (d, J=11.2 Hz, 1H), 3.11 (dd, J=11.6, 1.9 Hz, 1H), 2.88
(td, J=11.2, 3.1 Hz, 1H), 2.58 (dd, J=11.2, 9.9 Hz, 1H), 1.55 (s,
9H), 0.91 (s, 9H), 0.08 (d, J=1.5 Hz, 6H)
[2491] (697D): To a round bottom flask charged with
(+/-)-tert-butyl
(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanop-
henyl)carbamate (1.2321 g, 2.56 mmol) in Dichloromethane (12.78 ml)
and cooled to 0.degree. C. was added 2,6-lutidine (0.595 ml, 5.11
mmol). Trimethyl trifluoromethanesulfonate (0.924 ml, 5.11 mmol)
was added drop wise over several minutes. The reaction mixture was
stirred at 0.degree. C. 2 h and warmed to room temperature ON. The
reaction mixture was poured into a separatory funnel containing 1:1
dichloromethane: saturated aqueous sodium bicarbonate. The aqueous
layer was extracted with dichloromethane (2.times.). The combined
organics were dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The crude residue was purified by column
chromatography on the ISCO system (40 g, 0-50%
EtOAc/CH.sub.2Cl.sub.2).
(+/-)-3-Amino-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-4-ch-
lorobenzonitrile (0.860 g) was isolated as a yellow sticky
solid.
[2492] MS (ESI) m/z 382.1 (M+1)
[2493] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.77 (d, J=1.8
Hz, 1H), 6.69 (d, J=1.8 Hz, 1H), 4.32 (br. s., 2H), 4.02-3.95 (m,
1H), 3.86 (td, J=11.1, 2.4 Hz, 1H), 3.82-3.71 (m, 2H), 3.64-3.55
(m, 1H), 3.42-3.35 (m, 1H), 3.15 (dd, J=11.6, 2.1 Hz, 1H), 2.84
(td, J=11.2, 3.1 Hz, 1H), 2.61-2.52 (m, 1H), 0.91 (s, 9H), 0.08 (d,
J=1.3 Hz, 6H)
[2494] (697E):
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (0.799 g, 2.251 mmol),
(+/-)-3-amino-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-4-ch-
lorobenzonitrile (0.860 g, 2.251 mmol), palladium acetate (0.152 g,
0.675 mmol), DPPF (0.125 g, 0.225 mmol), Xantphos (0.130 g, 0.225
mmol), and cesium carbonate (1.467 g, 4.50 mmol) were combined in a
round bottom flask and dioxane (15.01 ml) was added. The flask was
evacuated and backfilled with nitrogen (3.times.), then heated at
100.degree. C. 1 h. The reaction mixture was diluted with ethyl
acetate and vacuum filtered through a pad of Celite. The filtrate
was concentrated in vacuo and the crude material purified by column
chromatography on the ISCO system (40 g, 0-5%
MeOH/CH.sub.2Cl.sub.2). LCMS indicated the final product was
contaminated with some of the aniline sm. Material carried forward
as is.
[2495] MS (ESI) m/z 700.5 (M+1)
[2496] (697F): To around bottom flask charged with
(+/-)-2-((3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-
-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][-
1,2,4]triazine-7-carbonitrile (1.576 g, 2.251 mmol) in THF (11.26
ml) was added TBAF (3.38 ml, 3.38 mmol). The reaction mixture was
stirred at room temperature 2.5 h. The reaction mixture was poured
into a separatory funnel containing 1:1 saturated aqueous ammonium
chloride and ethyl acetate. The aqueous layer was extracted with
ethyl acetate (2.times.). The combined organics were dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
crude solid was taken up in minimal dichloromethane and purified by
column chromatography on the ISCO system (80 g, 0-50%
EtOAc/CH.sub.2Cl.sub.2).
(+/-)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-
-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (0.926 g) was isolated as a yellow solid.
[2497] MS (ESI) m/z 586.3 (M+1)
[2498] Example 697: To a round bottom flask charged with
(+/-)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-
-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (35.2 mg, 0.06 mmol) in dichloromethane (200 .mu.l) was
added anisole (32.8 .mu.l, 0.300 mmol), followed by trifluoroacetic
acid (185 .mu.l, 2.400 mmol). The reaction mixture was stirred at
room temperature ON. LCMS indicated primarily the trifluoroacetate
product was present. Excess TFA was removed in vacuo. The residue
was treated with toluene and concentrated in vacuo (2.times.). The
crude solid was treated with 2 N NH.sub.3/MeOH (.about.1.5 mL)--a
solid immediately precipitated out. After 20 min, the solid was
isolated by vacuum filtration. LCMS indicated the solid was the
desired alcohol product. The crude material was purified via
preparative LC/MS with the following conditions: Column: Waters
XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A:
5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase
B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:
15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20
mL/min. Fractions containing the desired product were combined and
dried via centrifugal evaporation.
(+/-)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-
-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(3.5 mg) was isolated.
[2499] MS (ESI) m/z 466.2 (M+1).
[2500] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (d, J=4.3
Hz, 1H), 8.88 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.32
(d, J=1.2 Hz, 1H), 4.77 (t, J=5.8 Hz, 1H), 3.92 (d, J=11.0 Hz, 1H),
3.73-3.65 (m, 1H), 3.62 (d, J=7.9 Hz, 1H), 3.49 (dt, J=11.0, 5.5
Hz, 1H), 3.43-3.36 (m, 1H), 3.29 (d, J=11.6 Hz, 1H), 3.16 (d,
J=11.0 Hz, 1H), 3.01-2.92 (m, 1H), 2.87-2.79 (m, 1H), 2.58 (t,
J=11.0 Hz, 1H), 0.78 (d, J=5.5 Hz, 4H)
Example 698
##STR00758##
[2501]
(+/-)-2-({2-chloro-5-cyano-3-[3-(hydroxymethyl)-4-methylpiperazin-1-
-yl]phenyl}amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile
[2502] Prepared in analogous manner as Example 697.
[2503] HPLC Rt, 1.12 min
[2504] LC/MS: m/z 466.2 (M+1).
Example 699
##STR00759##
[2505]
(+/-)-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[-
2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl
ethylcarbamate
[2506] (699A): To a vial was charged with
2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cycl-
opropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(Example 1) (30 mg, 0.051 mmol) in tetrahydrofuran (256 .mu.l) was
added ethyl isocyanate (4.86 .mu.l, 0.061 mmol). The vial was
capped and heated at 50.degree. C. over the weekend. Reaction
temperature was raised to 70.degree. C. for 6 h to get full
conversion. Solvent was removed in vacuo and the crude residue was
taken forward as is.
[2507] MS (ESI) m/z 657.0 (M+1)
[2508] Example 699: To a vial charged with
(+/-)-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)ami-
no)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl
ethylcarbamate (33.5 mg, 0.051 mmol) in dichloromethane (204 .mu.l)
was added anisole (27.9 .mu.l, 0.255 mmol), followed by
trifluoroacetic acid (157 .mu.l, 2.040 mmol). The reaction mixture
was stirred at room temperature ON. Excess TFA was removed by
concentration in vacuo. The crude residue was taken up in methanol
and free based using a 1 g Phenomenex Strata SCX column. The column
was flushed with 3 column volumes MeOH and 1 column volume 7 N
NH.sub.3/MeOH. The ammonia containing fraction was concentrated in
vacuo. The crude material was purified via preparative LC/MS with
the following conditions: Column: Waters XBridge C18, 19.times.250
mm, 5-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water
with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:
water with 10-mM ammonium acetate; Gradient: 15-100% B over 15
minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions
containing the desired product were combined and dried via
centrifugal evaporation.
(+/-)-(4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f]-
[1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl
ethylcarbamate (5.9 mg) was isolated.
[2509] MS (ESI) m/z 537.2 (M+1)
[2510] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (d, J=3.7
Hz, 1H), 8.89 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.34 (s, 1H),
7.25-7.18 (m, 1H), 4.07-3.91 (m, 3H), 3.81 (br. s., 1H), 3.68 (t,
J=10.7 Hz, 1H), 3.27-3.12 (m, 2H), 3.04-2.93 (m, 3H), 2.88-2.80 (m,
1H), 2.67 (t, J=11.0 Hz, 1H), 1.00 (t, J=7.0 Hz, 3H), 0.77 (d,
J=5.5 Hz, 4H)
Example 700
##STR00760##
[2511]
(+/-)-N-((4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imida-
zo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl)methanesul-
fonamide
[2512] (700A): To a round bottom flask charged with
(+/-)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-
-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile (0.05 g, 0.085 mmol) in THF (0.427 ml) was added
triethylamine (0.036 ml, 0.256 mmol) and methanesulfonyl chloride
(9.97 .mu.l, 0.128 mmol). The reaction mixture was stirred at room
temperature 2 h. The reaction mixture was poured into a separatory
funnel containing 1:1 saturated aqueous sodium bicarbonate: ethyl
acetate. The aqueous layer was extracted with ethyl acetate
(3.times.). The combined organics were dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo.
(4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imi-
dazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl
methanesulfonate was isolated as a pale yellow solid and used as is
for further chemistry.
[2513] MS (ESI) m/z 663.9 (M+1)
[2514] (700B): A vial was charged with
(+/-)-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)ami-
no)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl
methanesulfonate (56.5 mg, 0.085 mmol) and 4-methoxybenzylamine
(33.3 .mu.l, 0.255 mmol) in acetonitrile (904 .mu.l). Potassium
carbonate (58.7 mg, 0.425 mmol) was added and the vial was capped
and heated at 80.degree. C. ON. After cooling to room temperature,
the reaction mixture was diluted with water and ethyl acetate. The
aqueous layer was extracted with ethyl acetate (3.times.). The
combined organics were dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo.
(+/-)-2-((2-Chloro-5-cyano-3-(2-(((4-methoxybenzyl)amino)methyl)morpholin-
o)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile (38.9 mg) was isolated as a white solid and
used as is in subsequent chemistry.
[2515] MS (ESI) m/z 705.5 (M+1)
[2516] (700C): To a round bottom flask charged with
(+/-)-2-((2-chloro-5-cyano-3-(2-(((4-methoxybenzyl)amino)methyl)morpholin-
o)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile (38.9 mg, 0.055 mmol) in tetrahydrofuran
(276 .mu.l) was added triethylamine (13.84 .mu.l, 0.099 mmol) and
methanesulfonyl chloride (5.59 .mu.l, 0.072 mmol). The reaction
mixture was stirred at room temperature ON. The reaction mixture
was diluted with ethyl acetate and transferred to a separatory
funnel containing saturated aqueous sodium bicarbonate. The aqueous
layer was extracted with ethyl acetate (3.times.). The combined
organics were dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The crude material was taken forward into
the deprotection.
[2517] MS (ESI) m/z 783.0 (M+1)
[2518] Example 700: To a round bottom flask charged with
(+/-)-N-((4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)-
amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl-
)-N-(4-methoxybenzyl)methanesulfonamide (43.1 mg, 0.055 mmol) in
dichloromethane (220 .mu.l) was added anisole (30.0 .mu.l, 0.275
mmol), followed by trifluoroacetic acid (169 .mu.l, 2.200 mmol).
The reaction mixture was stirred at room temperature ON. Excess TFA
was removed by concentration in vacuo. The crude residue was taken
up in methanol and free based on a 1 g Phenomenex Strata SCX
column. The column was flushed with 3 column volumes MeOH and 1
column volume 7 N NH.sub.3/MeOH. The ammonia containing fraction
was concentrated in vacuo. The crude material was purified via
preparative LC/MS with the following conditions: Column: Waters
XBridge C18, 19.times.250 mm, 5-.mu.m particles; Mobile Phase A:
5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase
B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:
10-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20
mL/min. Fractions containing the desired product were combined and
dried via centrifugal evaporation.
(+/-)-N-((4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl)methanesulfonami-
de (3.9 mg) was isolated.
[2519] MS (ESI) m/z 543.1 (M+1)
[2520] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=4.3
Hz, 1H), 8.86 (s, 1H), 8.17 (d, J=14.0 Hz, 2H), 7.31 (s, 1H), 7.16
(t, J=6.1 Hz, 1H), 3.94 (d, J=11.0 Hz, 1H), 3.69 (t, J=10.1 Hz,
2H), 3.27 (d, J=11.6 Hz, 1H), 3.20-3.01 (m, 3H), 3.00-2.79 (m, 5H),
2.60 (t, J=10.7 Hz, 1H), 0.84-0.69 (m, 4H)
[2521] The compounds in the following Table were similarly prepared
as Example 700.
TABLE-US-00030 TABLE 27 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 701 ##STR00761##
2-{[2-chloro-5-cyano-3-(2-{[(2-hydroxy-2-
methylpropyl)(methyl)amino}methyl}morpholin-4-yl)
phenyl]amino}-4-(cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbontrile 551.1 1.80 702 ##STR00762##
2-{[2-chloro-5-cyano-3-(2-{[(2-methoxyethyl)
(methyl)amino]methyl}morpholin-4-yl)phenyl]
amino}-4-(cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbontrile 537.2 1.56 703 ##STR00763##
[4-(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)-1-methylpiperazin-2-yl]methyl N- ethylcarbamate
550.2 1.66 704 ##STR00764##
2-({2-chloro-5-cyano-3-[(2S)-2-({[(1R)-1-
cyclopropy1-2-methoxyethyl]amino}methyl)
morpholin-4-yl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
563.3 1.62 705 ##STR00765##
2-[(2-chloro-5-cyano-3-{2-[(3-fluoroazetidin-1-
yl)methyl]morpholin-4-yl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
523.2 1.71 706 ##STR00766##
2-({2-chloro-5-cyano-3-[(3S)-3-({[(1R)-1-
cyclopropyl-2-methoxyethyl]amino}methyl)-4-
methylpiperazin-1-yl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
576.3 1.73 707 ##STR00767## 2-{[2-chloro-5-cyano-3-(3-{[(2-
methoxyethyl)(methyl)amino]methyl}-4-
methylpiperazin-1-yl)phenyl]amino}-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
550.3 1.57 708 ##STR00768##
2-[(2-chloro-5-cyano-3-{3-[(3-fluoroazetidin-1-
yl)methyl]-4-methylpiperazin-1-yl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
536.2 1.64 709 ##STR00769##
2-{[2-chloro-5-cyano-3-(2-{[(2-hydroxy-2-
methylpropyl)amino]methyl}morpholin-4-yl)phenyl]
amino}-4-(cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbontrile 537.2 1.41 710 ##STR00770## methyl
N-{[4-(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)morpholin-2-yl]methyl}carbamate 523.1 1.72 711
##STR00771## 1-{[4-(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)morpholin-2-yl]methyl}-3-ethylurea 536.2 1.58 712
##STR00772## N-{[4-(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)morpholin-2-yl]methyl}acetamide 507.1 1.54 713
##STR00773## methyl N-{[4-(2-chloro-5-cyano-3-{[7-cyano-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-
yl]aminolphenyl)-1-methylpiperazin-2- yl]methyl}carbamate 536.2
1.63 * = HPLC conditions Waters Acquity BEH C18 1.7 .mu.m column,
2.1 .times. 50 mm, 2-98% aqueous acetonitrile containing 0.05% TFA,
gradient time 2 minute, flow rate 0.8 mL/min, monitored at 254
nm.
Example 714
##STR00774##
[2522]
2-((2-chloro-5-cyano-3-(4-(methyl(1-methyl-5-oxopyrrolidin-3-yl)ami-
no)piperidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]t-
riazine-7-carbonitrile
[2523] (714A): A vial was charged with
2-((2-chloro-5-cyano-3-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)piperidin-
-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile (35 mg, 0.053 mmol) and iodomethane
(3.94 .mu.l, 0.063 mmol) in tetrahydrofuran (263 .mu.l). Cesium
carbonate (34.2 mg, 0.105 mmol) was added and the reaction mixture
was stirred at room temperature 5 h. The reaction mixture was
quenched with water and ethyl acetate. The aqueous layer was
extracted with ethyl acetate (2.times.). The combined organics were
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The crude material was used as is in the final
deprotection.
[2524] MS (ESI) m/z 680.1 (M+1)
[2525] Example 714: To a round bottom flask charged with
2-((2-chloro-5-cyano-3-(4-(methyl(1-methyl-5-oxopyrrolidin-3-yl)amino)pip-
eridin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile (36.1 mg, 0.053 mmol) in
dichloromethane (265 .mu.l) was added anisole (28.9 .mu.l, 0.265
mmol) and trifluoroacetic acid (204 .mu.l, 2.65 mmol). The reaction
mixture was stirred at room temperature ON. Excess TFA was removed
by concentration in vacuo. The crude material was purified via
preparative LC/MS with the following conditions: Column: Waters
XBridge C18, 19.times.200 mm, 5-.mu.m particles; Mobile Phase A:
5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase
B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:
15-100% B over 20 minutes, then a 0-minute hold at 100% B; Flow: 20
mL/min. Fractions containing the desired product were combined and
dried via centrifugal evaporation.
2-((2-Chloro-5-cyano-3-(4-(methyl(1-methyl-5-oxopyrrolidin-3-yl)amino)pip-
eridin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (4.5 mg) was isolated.
[2526] MS (ESI) m/z 560.2 (M+1)
[2527] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.14 (br. s.,
1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.51 (s, 1H), 3.59-3.48 (m, 2H),
3.36 (br. s., 3H), 3.29 (d, J=11.6 Hz, 3H), 3.06 (d, J=4.9 Hz, 1H),
2.77-2.66 (m, 5H), 2.62 (br. s., 1H), 2.45 (dd, J=16.5, 7.3 Hz,
1H), 2.04 (dd, J=16.8, 4.6 Hz, 1H), 1.90 (s, 2H), 1.40 (d, J=11.0
Hz, 2H), 0.68-0.39 (m, 4H)
[2528] The compounds in the following Table were similarly prepared
as Example 714
TABLE-US-00031 TABLE 28 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 715 ##STR00775##
2-[(2-chloro-5-cyano-3-{4-[ethyl(1-methyl-5-
oxopyrrolidin-3-yl)amino]piperidin-1-yl}phenyl)
amino]-4-(cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 574.3 1.64 716 ##STR00776##
2-[(2-chloro-5-cyano-3-{4-[(1-methyl-5-
oxopyrrolidin-3-yl)(propan-2-yl)amino]piperidin-1-
yl}phenyl)amino]-4-(cyclopropylamino)imidazo[2,1-
f][1,2,4]triazine-7-carbonitrile 588.3 1.79 * = HPLC conditions
Waters Acquity BEH C18 1.7 .mu.m column, 2.1 .times. 50 mm, 2-98%
aqueous acetonitrile containing 0.05 TFA, gradient time 2 minute,
flow rate 0.8 mL/min, monitored at 254 nm.
Example 717
##STR00777##
[2529]
2-((2-chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amin-
o)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2530] (717A): A vial was charged with
1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo-
le (0.117 g, 0.498 mmol), tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (0.15 g, 0.452 mmol),
PdCl.sub.2(DPPF) (0.033 g, 0.045 mmol) and dioxane (3.62 ml). The
slurry was evacuated and backfilled with nitrogen (4.times.).
Phosphoric acid, potassium salt (0.588 ml, 1.176 mmol) was added
and the vial was capped and warmed to 85.degree. C. 2 h. The
reaction mixture was diluted with ethyl acetate and vacuum filtered
through a pad of Celite. The filtrate was concentrated and the
crude residue purified by column chromatography on the ISCO system
(12 g, 0-70% EtOAc/Hex) to provide tert-butyl
(2-chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)carbamate
(82.7 mg) as a yellow oil.
[2531] MS (ESI) m/z 361.1 (M+1)
[2532] (717B): To a round bottom flask charged with tert-butyl
(2-chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)carbamate
(87.2 mg, 0.242 mmol) in dichloromethane (1812 .mu.l) was added TFA
(604 .mu.l). The reaction mixture was stirred at room temperature 2
h. Excess TFA was removed in vacuo. This material was used as is in
subsequent chemistry.
[2533] MS (ESI) m/z 261.0 (M+1)
[2534] (717C):
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (42.6 mg, 0.120 mmol),
3-amino-4-chloro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzonitrile,
TFA (45 mg, 0.120 mmol), palladium acetate (8.09 mg, 0.036 mmol),
DPPF (6.66 mg, 0.012 mmol), Xantphos (6.95 mg, 0.012 mmol), and
cesium carbonate (117 mg, 0.360 mmol) were combined in a vial and
dioxane (801 .mu.l) was added. The vial was evacuated and
backfilled with nitrogen (3.times.), then heated at 100.degree. C.
4 h. The reaction mixture was diluted with ethyl acetate and vacuum
filtered through a pad of Celite. The filtrate was concentrated in
vacuo and the crude material purified by column chromatography on
the ISCO system (12 g, 0-5% MeOH/CH.sub.2Cl.sub.2).
2-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(-
cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (30 mg) was isolated as a pale yellow solid.
[2535] MS (ESI) m/z 579.1 (M+1)
[2536] Example 717: To a round bottom flask charged with
2-((2-chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(-
cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile (30 mg, 0.052 mmol) in dichloromethane (345 .mu.l) was added
anisole (22.64 .mu.l, 0.207 mmol), followed by trifluoroacetic acid
(200 .mu.l, 2.59 mmol). The reaction mixture was stirred at room
temperature 2 d. Excess TFA was removed by concentration in vacuo.
The crude residue was taken up in methanol and free based using a
Phenomenex Strata SCX 1 g column. The column was flushed with 3
column volumes MeOH and 1 column volume 7 N NH.sub.3/MeOH. The
ammonia containing fraction was concentrated in vacuo. The crude
material was purified via preparative LC/MS with the following
conditions: Column: Waters XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
10-mM ammonium acetate; Gradient: 20-100% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal
evaporation.
2-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(-
cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (8
mg) was isolated.
[2537] MS (ESI) m/z 459.1 (M+1)
[2538] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.35 (br. s.,
1H), 8.93 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.50 (d,
J=1.8 Hz, 1H), 3.71 (s, 3H), 3.01 (br. s., 1H), 2.08 (s, 3H), 1.99
(s, 3H), 0.84-0.75 (m, 4H)
[2539] The compounds in the following Table were similarly prepared
as Example 717.
TABLE-US-00032 TABLE 29 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 718 ##STR00778##
2-[(2-chloro-5-cyano-3-{1-[2-(morpholin-4-yl)ethyl]-
1H-pyrazol-4-yl}phenyl)amino]-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile 530.2 1.68 719
##STR00779## 2-[(2-chloro-5-cyano-3-{1-[2-(dimethylamino)ethyl]-
3,5-dimethyl-1H-pyrazol-4-yl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
516.2 1.54 * = HPLC conditions Waters Acquity BEH C18 1.7 .mu.m
column, 2.1 .times. 50 mm, 2-98% aqueous acetonitrile containing
0.05% TFA, gradient time 2 minute, flow rate 0.8 mL/min, monitored
at 254 nm.
Example 720
##STR00780##
[2540]
2-((2-chloro-5-cyano-4-(3-morpholinobutyl)phenyl)amino)-4-(cyclopro-
pylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2541] (720A): 5-amino-2-bromo-4-chlorobenzonitrile (1.1 g, 4.75
mmol), but-3-en-2-ol (0.445 g, 6.18 mmol), Pd.sub.2(dba).sub.3
(0.044 g, 0.048 mmol),
di-tert-butyl(2'-methyl-[1,1'-biphenyl]-2-yl)phosphine (0.045 g,
0.143 mmol), and N-cyclohexyl-N-methylcyclohexanamine (1.392 g,
7.13 mmol) were combined in a 20 dram vial and CH.sub.3CN (8 mL)
was added. The vial was evacuated and backfilled with Ar 4.times.,
and the reaction was heated at 90.degree. C. for 45 min. The
reaction was cooled to room temperature and diluted with water,
extracting 3.times. with EtOAc. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The material
was then purified by flash column chromatography (0-70% EtOAc/Hex;
80 g column). 5-amino-4-chloro-2-(3-oxobutyl)benzonitrile (635 mg)
was obtained as yellow foam.
[2542] MS (ESI) m/z 223.0 (M+1)
[2543] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.27 (s, 1H),
6.99 (s, 1H), 4.18 (br. s., 2H), 2.99 (t, J=7.5 Hz, 2H), 2.80 (t,
J=7.5 Hz, 2H), 2.18 (s, 3H)
[2544] (720B):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (150 mg, 0.423 mmol),
5-amino-4-chloro-2-(3-oxobutyl)benzonitrile (104 mg, 0.465 mmol),
palladium (II) acetate (28.5 mg, 0.127 mmol), DPPF (23.4 mg, 0.042
mmol), Xantphos (24.5 mg, 0.042 mmol), and cesium carbonate (207
mg, 0.643 mmol) were combined in a 20 dram vial and dioxane (2 mL)
was added. The vial was evacuated and backfilled with N.sub.2
3.times., then heated at 90.degree. C. for 1.5 h. The reaction was
cooled to room temperature and the reaction mixture was filtered
through celite, rinsing with EtOAc. The solvent was removed in
vacuo and the material was purified by ISCO Companion (0-100%
EtOAc/Hexane).
2-((2-chloro-5-cyano-4-(3-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxy-
benzyl) amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (172 mg)
was obtained as a yellow foam.
[2545] MS (ESI) m/z 541.0 (M+1)
[2546] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.96 (s, 1H),
7.44 (s, 1H), 7.21 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 3.82
(s, 3H), 3.07 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.20 (s,
3H), 1.31 (m, 1H), 1.17 (m., 2H), 0.93 (m, 2H)
[2547] Example 720:
2-((2-chloro-5-cyano-4-(3-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxy-
benzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg,
0.070 mmol) and morpholine (9.2 mg, 0.10 mmol) was taken up in THF
(0.2 mL) and MeOH (0.2 mL). Trimethyl orthoformate (0.078 mL, 0.070
mmol) and sodium cyanoborohydride (8.8 mg, 0.14 mmol) was then
added. The reaction was stirred at room temperature overnight. The
reaction was diluted with EtOAc and washed with aq. NaHCO.sub.3,
then brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The material was taken up in DCM (0.25
mL) and anisole (0.025 mL) was added, followed by TFA (0.25 mL).
The reaction was stirred at room temperature overnight. The
reaction was then concentrated in vacuo and purified by preparative
HPLC to provide
2-((2-chloro-5-cyano-4-(3-morpholinobutyl)phenyl)amino)-4-(cyclopropylami-
no)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (15.3 mg, 0.030
mmol, 42.5% yield).
[2548] MS (ESI) m/z 492.1 (M+1)
[2549] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.33 (d, J=3.7
Hz, 1H), 8.86 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.67 (s, 1H),
3.55 (d, J=5.4 Hz, 3H), 3.17 (d, J=5.4 Hz, 1H), 2.95 (d, J=4.4 Hz,
1H), 2.88-2.75 (m, 2H), 2.49-2.45 (m, 2H), 2.31 (br. s., 2H), 1.79
(d, J=8.4 Hz, 1H), 1.60 (d, J=6.4 Hz, 1H), 0.94 (d, J=6.4 Hz, 3H),
0.85-0.72 (m, 4H)
[2550] The compounds in the following Table were similarly prepared
as Example 720
TABLE-US-00033 TABLE 30 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 721 ##STR00781##
2-({2-chloro-5-cyano-4-[2- (morpholin-4-ylmethyl)propyl]
phenyl}amino)-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 492.3 0.64.sup.A 722 ##STR00782##
2-{[2-chloro-5-cyano-4-(3- hydroxybutyl)phenyl]amino}-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
423.1 1.64 723 ##STR00783## 2-({2-chloro-5-cyano-3-[4-
hydroxy-3-(4-methylpiperazin-1- yl)butyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
521.2 1.35 724 ##STR00784## 2-({2-chloro-5-cyano-4-[3-(3-
hydroxyazetidin-1- yl)butyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
478.1 1.34 Analysis condition: Condition A: Column-Sunfire C18 35
um, 3.0 .times. 150 mm, Flow = 0.5 mL/min Solvent-Mobile Phase A:
0.05% TFA in H2O:MeCN (95:5); mobile Phase B: 0.05% TFA in H2O:MeCN
(5:95) Gradient: 10-100% B over 12 min, then a 3 min hold at 100%
B; Detection: UV at 220 Condition B: Column: Waters Acquity UPLC
BEH C18, 2.1 .times. 50 mm, 1.7-.mu.m particles; Mobile Phase A:
5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase
B: 95:5 acetonitrile: water with 10 mM ammonium acetate;
Temperature: 50.degree. C.; Gradient: 0-100% B over 3 minutes, then
a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at
220 nm.
Example 725
##STR00785##
[2551] (=/-) cis and
trans-2-((2-chloro-5-cyano-3-(3-morpholinocyclohexyl)phenyl)amino)-4-(cyc-
lopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2552] (725A): To a 20 gram dram vial was charged with tert-butyl
(2-chloro-5-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)c-
arbamate (Example 573A) (379 mg, 1 mmol) and
chloro(1,5-cyclooctadiene)rhodium(I) dimer (9.86 mg, 0.020 mmol).
Dioxane (10 mL) was then added, followed by aq. KOH (2 M, 1 mL).
The resulting solution was then evacuated and refilled with N.sub.2
before cyclohex-2-enone (144 mg, 1.500 mmol) was added via a
syringe. The resulting reaction was heated at 80.degree. C. for 1 h
before it was cooled to room temperature. The reaction was diluted
with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude material was
purified by flash column chromatography (0-60% EtOAc/Hexane) to
give tert-butyl
(2-chloro-5-cyano-3-(3-oxocyclohexyl)phenyl)carbamate (145 mg) as
white foam.
[2553] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.64-8.39 (m,
1H), 7.27 (d, J=1.8 Hz, 1H), 7.24-7.18 (m, 1H), 3.63-3.26 (m, 1H),
2.70-2.36 (m, 5H), 2.29-2.18 (m, 1H), 2.14-2.07 (m, 1H), 1.90-1.81
(m, 2H), 1.56 (s, 9H)
[2554] (725B): To tert-butyl
(2-chloro-5-cyano-3-(3-oxocyclohexyl)phenyl)carbamate (145 mg,
0.416 mmol) was added 30% TFA in DCM (2 mL). The resulting solution
was stirred at room temperature for 2 h before it was concentrated
in vacuo to give 3-amino-4-chloro-5-(3-oxocyclohexyl)benzonitrile,
TFA salt as a yellow solid (150 mg).
[2555] MS (ESI) m/z 270.9 (M+Na)
[2556] (725C):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (140 mg, 0.395 mmol),
3-amino-4-chloro-5-(3-oxocyclohexyl)benzonitrile, TFA salt (143 mg,
0.395 mmol), palladium (II) acetate (26.6 mg, 0.118 mmol), DPPF
(21.9 mg, 0.039 mmol), Xantphos (22.8 mg, 0.039 mmol), and cesium
carbonate (257 mg, 0.789 mmol) were combined in a 10 dram vial and
dioxane (2 ml) was added. The vial was evacuated and backfilled
with N.sub.2 3.times., then heated at 90.degree. C. for 1.5 h. The
reaction was cooled to room temperature and the reaction mixture
was filtered through celite, rinsing with EtOAc. The solvent was
removed in vacuo and the material was purified by ISCO Companion
(0-100% EtOAc/Hexane).
(+/-)-2-((2-chloro-5-cyano-3-(3-oxocyclohexyl)phenyl)amino)-4-(cyclopropy-
l(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(127 mg) was obtained as a yellow foam.
[2557] MS (ESI) m/z 567.0 (M+1)
[2558] Example 725: To a vial was charged with
2-((2-chloro-5-cyano-3-(3-oxocyclohexyl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (31
mg, 0.055 mmol)) and morpholine (7.14 mg, 0.082 mmol). Methanol
(176 .mu.l) and tetrahydrofuran (176 .mu.l) was then added,
followed by trimethyl orthoformate (78 .mu.l, 0.704 mmol) and
sodium cyanoborohydride (6.87 mg, 0.109 mmol). A drop of AcOH was
added and the reaction mixture was stirred at room temperature
overnight. The reaction was diluted with EtOAc and washed with aq.
NaHCO.sub.3, then brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
taken up in DCM (0.25 mL) and anisole (0.025 mL) was added,
followed by TFA (0.25 mL). The reaction was stirred at room
temperature overnight. The reaction was then concentrated in vacuo
and the two Diastereomers were separated by preparative HPLC.
[2559] Diastereomer 1: (5.7 mg, 0.011 mmol, 19.5% yield).
[2560] LCMS room temperature=1.34 min
[2561] MS (ESI) m/z 518.2 (M+1)
[2562] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.40-9.28 (m,
1H), 8.87 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 3.64
(br. s., 2H), 2.94 (d, J=4.7 Hz, 1H), 2.41 (br. s., 2H), 2.31 (br.
s., 1H), 2.01 (br. s., 2H), 1.86-1.35 (m, 6H), 0.85-0.66 (m,
4H)
[2563] Diastereomer 2: (4.5 mg, 0.008 mmol, 15% yield).
[2564] LCMS room temperature=1.88 min
[2565] MS (ESI) m/z 518.2 (M+1)
[2566] The compounds in the following Table were similarly prepared
as Example 725.
TABLE-US-00034 TABLE 31 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 726 ##STR00786##
2-({2-chloro-5-cyano-3-[(1S,3R)-3-(3-fluoroazetidin-
1-yl)cyclohexyl]phenyl}amino)-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Isomer 1) 506.1 2.27
727 ##STR00787## 2-({2-chloro-5-cyano-3-[(1S,3R)-3-
(methylamino)cyclohexyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
462.1 1.35 728 ##STR00788##
2-({2-chloro-5-cyano-3-[(1S,3S)-3-{[(2R)-oxolan-2-
ylmethyl]amino}cyclohexyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
532.2 1.68 729 ##STR00789##
2-({2-chloro-5-cyano-3-[(1S,3R)-3-(3-fluoroazetidin-
1-yl)cyclohexyl]phenyl}amino)-4-(cyclopropylamino)
imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Isomer 2) 506.1 2.27
730 ##STR00790## 2-({2-chloro-5-cyano-3-[(1S,3R)-3-(3-
hydroxyazetidin-1-yl)cyclohexyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
(Isomer 1) 504.1 1.42 731 ##STR00791##
2-({2-chloro-5-cyano-3-[(1S,3R)-3-(3-
hydroxyazetidin-1-yl)cyclohexyl]phenyl}amino)-4-
(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7- carbonitrile
(Isomer 2) 504.3 1.38 Analysis condition: Column: Waters Acquity
UPLC BEH C18, 2.1 .times. 50 mm, 1.7-.mu.m particles; Mobile Phase
A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile
Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate;
Temperature: 50.degree. C.; Gradient: 0-100% B over 3 minutes, then
a 0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at
220 nm.
Example 732
##STR00792##
[2567]
2-((2-chloro-5-cyano-4-(4-((2,2,2-trifluoroethyl)amino)pentan-2-yl)-
phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonit-
rile
[2568] (732A): 5-amino-2-bromo-4-chlorobenzonitrile (0.5 g, 2.16
mmol), (E)-pent-3-en-2-one (0.273 g, 3.24 mmol),
Pd.sub.2(dba).sub.3 (0.020 g, 0.022 mmol),
di-tert-butyl(2'-methyl-[1,1'-biphenyl]-2-yl)phosphine (0.020 g,
0.065 mmol), and N-cyclohexyl-N-methylcyclohexanamine (0.633 g,
3.24 mmol) were combined in a 20 dram vial and CH.sub.3CN (4 mL)
was added. The vial was evacuated and backfilled with N2, and the
reaction was heated at 90.degree. C. for 3 h. The reaction was
cooled to room temperature and diluted with water, extracting
3.times. with EtOAc. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The material
was purified by flash column chromatography (0-100% EtOAc/Hex).
(E)-5-amino-4-chloro-2-(4-oxopent-2-en-2-yl)benzonitrile (120 mg)
was obtained as a yellow solid.
[2569] MS (ESI) m/z 256.9 (M+Na)
[2570] (732B):
(E)-5-amino-4-chloro-2-(4-oxopent-2-en-2-yl)benzonitrile (120 mg,
0.51 mmol) and Pd(OH).sub.2 on carbon (10% w/w, 10 mg) was
suspended in MeOH (3 mL). Acetic acid (0.06 mL) was then added and
the reaction was stirred at room temperature under a balloon of
H.sub.2 for 48 h. The reaction was then filtered through a pad of
Celite, washing with EtOAc. The eluent was then concentrated in
vacuo and the material was purified on ISCO (0-80% EtOAc/Hexane) to
give 5-amino-4-chloro-2-(4-oxopentan-2-yl)benzonitrile (73 mg) as a
white solid.
[2571] MS (ESI) m/z 237.0 (M+1)
[2572] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.24-7.20 (m,
1H), 7.02-6.97 (m, 1H), 4.20 (br. s., 2H), 3.61 (sxt, J=7.0 Hz,
1H), 2.83 (dd, J=16.5, 7.3 Hz, 1H), 2.73 (dd, J=16.9, 7.5 Hz, 1H),
2.18-2.13 (m, 3H), 1.31 (d, J=6.8 Hz, 4H)
[2573] (732C):
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (100 mg, 0.282 mmol),
5-amino-4-chloro-2-(4-oxopentan-2-yl)benzonitrile (67 mg, 0.282
mmol), palladium (II) acetate (18.9 mg, 0.085 mmol), DPPF (15.6 mg,
0.028 mmol), Xantphos (16.3 mg, 0.028 mmol), and cesium carbonate
(184 mg, 0.564 mmol) were combined in a 10 dram vial and dioxane (2
mL) was added. The vial was evacuated and backfilled with N.sub.2
3.times., then heated at 90.degree. C. for 1 h. The reaction was
cooled to room temperature and the reaction mixture was filtered
through celite, rinsing with EtOAc. The solvent was removed in
vacuo and the material was purified by ISCO Companion (0-100%
EtOAc/Hexane).
2-((2-chloro-5-cyano-4-(4-oxopentan-2yl)phenyl)amino)-4-(cyclopropyl(4-me-
thoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (97
mg) was obtained as a yellow foam.
[2574] MS (ESI) m/z 555.1 (M+1)
[2575] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (br. s.,
1H), 8.61 (d, J=3.7 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.96 (s, 1H),
7.51-7.28 (m, 1H), 3.07-2.75 (m, 1H), 2.26 (br. s., 1H), 2.20 (br.
s., 1H), 1.69-1.20 (m, 2H), 0.99 (t, J=7.2 Hz, 3H), 0.75 (dd,
J=11.9, 6.2 Hz, 3H), 0.53 (d, J=5.0 Hz, 4H)
[2576] Example 732: To a vial was charged with
2-((2-chloro-5-cyano-4-(4-oxopentan-2-yl)phenyl)amino)-4-(cyclopropyl(4-m-
ethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (20
mg, 0.036 mmol)) and 2,2,2-trifluorethanamine, HCl (9.8 mg, 0.072
mmol) in THF (1 mL), triethylamine (10.04 .mu.l, 0.072 mmol) was
added and the reaction mixture was stirred at room temperature for
10 min. Acetic acid (4.13 .mu.l, 0.072 mmol) and sodium
triacetoxyborohydride (22.91 mg, 0.108 mmol) was then added. The
reaction was then stirred at room temperature for 7 days. The
reaction was diluted with EtOAc and washed with aq. NaHCO.sub.3,
then brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The material was taken up in DCM (0.25
mL) and anisole (0.025 mL) was added, followed by TFA (0.25 mL).
The reaction was stirred at room temperature overnight. The
reaction was then concentrated in vacuo and then purified by
preparative HPLC to give
2-((2-chloro-5-cyano-4-(4-((2,2,2-trifluoroethyl)amino)pentan-2-yl)p-
henyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitr-
ile (9.6 mg, 49%).
[2577] MS (ESI) m/z 518.2 (M+1)
[2578] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.11 (br. s.,
1H), 8.61 (d, J=3.7 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.96 (s, 1H),
7.51-7.28 (m, 1H), 3.07-2.75 (m, 1H), 2.26 (br. s., 1H), 2.20 (br.
s., 1H), 1.69-1.20 (m, 2H), 0.99 (t, J=7.2 Hz, 3H), 0.75 (dd,
J=11.9, 6.2 Hz, 3H), 0.53 (d, J=5.0 Hz, 4H)
[2579] The compounds in the following Table were similarly prepared
as Example 732
TABLE-US-00035 TABLE 32 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 733 ##STR00793##
2-({2-chloro-5-cyano-4-[4- (methylamino)pentan-2-yl]phenyl}
amino)-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazine-7-
carbonitrile 450.2 1.40 734 ##STR00794##
2-[(2-chloro-5-cyano-4-{4-[(3,3,3- trifluoropropyl)amino]pentan-2-
yl}phenyl)amino]-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile (Isomer 1) 532.2 2.04 735
##STR00795## 2-[(2-chloro-5-cyano-4-{4-[(3,3,3-
trifluoropropyl)amino]pentan-2- yl}phenyl)amino]-4-
(cyclopropylamino)imidazo[2,1-f] [1,2,4]triazine-7-carbonitrile
(Isomer 2) 532.1 2.11 736 ##STR00796##
2-({2-chloro-5-cyano-4-[4-(3- hydroxy-3-methylazetidin-1-
yl)pentan-2-yl]phenyl}amino)-4- (cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazine-7-carbonitrile 506.2 1.46 Analysis condition:
Column: Waters Acquity UPLC BEH C18, 2.1 .times. 50 mm, 1.7-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10
mM ammonium acetate; Temperature: 50.degree. C.; Gradient: 0-100% B
over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11
mL/min; Detection: UV at 220 nm.
Example 737
##STR00797##
[2580]
2-((2-chloro-5-cyano-3-(1,1-difluoro-2-hydroxyethyl)phenyl)amino)-4-
-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2581] (737A): To a vial was charged with tert-butyl
(2-chloro-5-cyano-3-(3-hydroxyprop-1-en-2-yl)phenyl)carbamate (350
mg, 1.134 mmol) and DCM (5 mL). The resulting solution was then
cooled to 0.degree. C., and triethylamine (0.316 mL, 2.267 mmol)
was added, followed by acetyl chloride (0.121 mL, 1.700 mmol). The
reaction was then stirred for 1 h before it was taken up with DCM,
washed with brine, dried over sodium sulfate, and concentrated in
vacuo.
[2582] The crude material was then dissolved in DCM (5 mL), and
4-methylmorpholine 4-oxide (159 mg, 1.360 mmol) was added, followed
by osmium tetroxide (0.712 mL, 0.057 mmol) (2.5% in isopropanol).
The reaction was then stirred at room temperature until LCMS
indicated reaction completion. The reaction was then quenched with
sat. NaHSO3 solution and extracted with DCM. The organic layer was
washed with brine, dried over sodium sulfate, and concentrated in
vacuo to give the crude diol.
[2583] The crude diol was dissolved in acetone (8 mL), and water (2
mL) was added, followed by sodium periodate (485 mg, 2.267 mmol).
The reaction was then stirred at room temperature overnight before
it was filtered through a pad of celite, rinsing with acetone. The
solvent was then concentrated in vacuo and then taken up with DCM.
The solution was then washed with brine, dried over sodium sulfate,
concentrate in vacuo, and purified on ISCO (0-100% EtOAc/hexane) to
give
2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-oxoethyl
acetate (298 mg) as a white solid.
[2584] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.76 (d, J=1.8
Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.26 (s, 1H), 5.08 (s, 2H), 2.18
(s, 3H), 1.57 (s, 9H)
[2585] (737B): To a vial was charged with
2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-oxoethyl
acetate (195 mg, 0.553 mmol) and DCM (0.5 mL). DAST (0.584 mL, 4.42
mmol) was added drop wise via a syringe. The reaction was then
stirred at room temperature overnight. The reaction was then taken
up with DCM and poured into aq. NaHCO.sub.3. After gas evolution
has ceased, the DCM layer was separated and concentrated in vacuo.
The crude material was then purified on ISCO (0-30% EtOAC/hexane)
to give
2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2,2-difluoroeth-
yl acetate (63 mg) as a colorless oil.
[2586] MS (ESI) m/z 397.0 (M+Na)
[2587] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.79 (d, J=1.5
Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.31 (s, 1H), 4.73 (t, J=12.9 Hz,
2H), 2.07 (s, 3H), 1.58 (s, 9H)
[2588] (737C): To a vial was charged with
2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2,2-difluoroeth-
yl acetate (63 mg, 0.168 mmol) and MeOH (1 mL). NaOH (30 mg) was
then added, and the reaction was stirred at room temperature for 30
min at which point LCMS showed full deprotection of the acetate.
The reaction was then taken up with EtOAc and washed with brine,
dried over sodium sulfate, and concentrated in vacuo. The resulting
material was then treated with TFA/DCM (30%, 1 mL) at room
temperature for 2 h and then concentrated in vacuo.
[2589] To the crude material was added
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (30 mg, 0.085 mmol), palladium (II) acetate (5.7
mg, 0.025 mmol), DPPF (4.7 mg, 0.008 mmol), Xantphos (4.9 mg, 0.08
mmol), and cesium carbonate (55 mg, 0.17 mmol). Dioxane (2 mL) was
then added, and the reaction was evacuated and backfilled with N2,
then heated at 90.degree. C. for 1.5 h. The reaction was cooled to
room temperature and the reaction mixture was filtered through
celite, rinsing with EtOAc. The solvent was removed in vacuo and
the material was purified by ISCO Companion (0-100% EtOAc/Hexane).
2-((2-chloro-5-cyano-3-(1,1-difluoro-2-hydroxyethyl)
phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]t-
riazine-7-carbonitrile (40 mg) was obtained as a yellow foam.
[2590] MS (ESI) m/z 551.0 (M+1)
[2591] Example 737:
2-((2-chloro-5-cyano-3-(1,1-difluoro-2-hydroxyethyl)phenyl)amino)-4-(cycl-
opropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(40 mg, 0.036 mmol) was taken up in DCM (0.7 mL) and anisole (0.7
mL) was added, followed by TFA (0.7 mL). The reaction was stirred
at room temperature overnight. The solvent was removed in vacuo and
the material dissolved in MeOH. The material was loaded onto an SCX
column (1 g, benzenesulfonic acid) and the column was flushed with
MeOH, then 2N NH.sub.3/MeOH to obtain the product. The solvent was
removed in vacuo and the material was purified by preparative HPLC.
2-((2-chloro-5-cyano-3-(1,1-difluoro-2-hydroxyethyl)phenyl)amino)-4-(cycl-
opropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.6 mg)
was obtained.
[2592] MS (ESI) m/z 431.0 (M+1)
[2593] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.40 (br. s.,
1H), 9.18 (s, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 7.74 (s, 2H), 5.83
(s, 1H), 4.06 (d, J=6.1 Hz, 3H), 2.97-2.91 (m, 1H), 0.78 (d, J=5.4
Hz, 6H)
Example 738
##STR00798##
[2594]
2-((2-chloro-5-cyano-3-(1,1-difluoro-3-(4-methylpiperazin-1-yl)prop-
yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile
[2595] (738A):
2-((2-chloro-5-cyano-3-(1,1-difluoro-3-hydroxypropyl)phenyl)amino)-4-(cyc-
lopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e (25 mg, 0.044 mmol, prepared following a procedure analogous to
that for the synthesis of Example 737C (Example 737)) was dissolved
in DCM (1 mL). Triethylamine (0.1 mL) and TsCl (12 mg) was then
added, followed by DMAP (2 mg). The reaction was then stirred at
room temperature for 1 h and additional TsCl (6 mg) was added. The
reaction was then stirred at room temperature for 2.5 h and then
diluted with DCM (10 mL), washed with aq, NaHCO.sub.3, dried over
sodium sulfate, and concentrated in vacuo. The resulting tosylate
was then dissolved in ACN (0.5 mL), and 1-methylpiperazine (0.15
mL) was added. The reaction was then heated at 90.degree. C. for 3
h before it was cooled to room temperature, diluted with EtOAc,
washed sequentially with aq. NaHCO3 and brine, dried over sodium
sulfate, and concentrated in vacuo to give
2-((2-chloro-5-cyano-3-(1,1-difluoro-3-(4-methylpiperazin-1-yl)propyl)phe-
nyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (29 mg) as a yellow foam.
[2596] MS (ESI) m/z 647.4 (M+1)
[2597] Example 738:
2-((2-chloro-5-cyano-3-(1,1-difluoro-3-(4-methylpiperazin-1-yl)propyl)phe-
nyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (29 mg, 0.039 mmol) was taken up in DCM (0.3 mL)
and anisole (0.3 mL) was added, followed by TFA (0.3 mL). The
reaction was stirred at 40.degree. C. for 4 h. The solvent was
removed in vacuo and the material dissolved in MeOH. The material
was loaded onto an SCX column (1 g, benzenesulfonic acid) and the
column was flushed with MeOH, then 2N NH.sub.3/MeOH to obtain the
product. The solvent was removed in vacuo and purified by
preparative HPLC.
2-((2-chloro-5-cyano-3-(1,1-difluoro-3-(4-methylpiperazin-1-yl)propyl)phe-
nyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e (13.5 mg) was obtained.
[2598] MS (ESI) m/z 527.3 (M+1)
[2599] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H),
8.21 (s, 1H), 7.76 (s, 1H), 2.94 (br. s., 1H), 2.67-2.54 (m, 2H),
2.38 (t, J=6.6 Hz, 3H), 2.23 (br. s., 2H), 0.78 (d, J=5.4 Hz,
5H)
Example 739
##STR00799##
[2600]
(+/-)-2-((2-chloro-5-cyano-3-(2-(morpholin-2-yl)ethyl)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2601] (739A): tert-butyl(3-bromo-4-chloro-5-cyanophenyl)carbamate
(Intermediate 1) (0.97 g, 2.93 mmol) and
N-cyclohexyl-N-methylcyclohexanamine (1.013 g, 5.18 mmol),
Pd.sub.2(dba).sub.3 (0.040 g, 0.043 mmol),
di-tert-butyl(2'-methyl-[1,1'-biphenyl]-2-yl)phosphine (0.040 g,
0.130 mmol), and but-3-ene-1,2-diol (0.571 g, 6.48 mmol) were
combined in a 20 dram vial and CH.sub.3CN (6 mL) was added. The
vial was evacuated and backfilled with N.sub.2 4.times., and the
reaction was heated at 90.degree. C. for 3 h. The reaction was
cooled to room temperature and diluted with water, extracting
3.times. with EtOAc. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The material
was purified by flash column chromatography (0-50% EtOAc/Hex).
Tert-butyl(2-chloro-5-cyano-3oxobutyl_phenyl)carbamate (675 mg) was
obtained as a yellow solid.
[2602] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.47 (d, J=1.8
Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.16 (s, 1H), 4.25 (d, J=4.4 Hz,
2H), 3.12 (t, J=7.6 Hz, 2H), 3.02 (t, J=4.7 Hz, 1H), 2.76 (t, J=7.5
Hz, 2H), 1.54 (s, 9H)
[2603] (739B): To a round bottom flask was added tert-butyl
(2-chloro-5-cyano-3-(4-hydroxy-3-oxobutyl)phenyl)carbamate (500 mg,
1.476 mmol) and MeOH (1 mL). The solution was then cooled to
0.degree. C. before NaBH.sub.4 (100 mg) was added. The reaction was
then stirred at 0.degree. C. for 30 min and then slowly warmed to
room temperature, and stirred for additional 1 h. The reaction was
then quenched with aq. NaHCO3, extracted with EtOAc, washed with
brine, dried over sodium sulfate, and concentrated in vacuo.
[2604] The residue was then dissolved in DCM (10 mL). Pyridine (1
mL) was added. After the reaction was cooled to 0.degree. C. Ts-Cl
(310 mg, 1.623 mmol) was added, and the reaction was then allowed
to warm to room temperature and stirred for 5 h. The reaction was
then taken up with DCM, washed with brine, and concentrated in
vacuo to give
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxy
butyl 4-methylbenzenesulfonate (810 mg) as a yellow solid.
[2605] MS (ESI) m/z 495.2 (M+H)
[2606] (739C): To a vial was charged with
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxybutyl
4-methylbenzenesulfonate (100 mg, 0.202 mmol), triethylamine (0.084
mL, 0.606 mmol), 2-aminoethanol (24.68 mg, 0.404 mmol) and
acetonitrile (1 mL). The reaction was then heated at 60.degree. C.
for 5 h before it was cooled to room temperature, and then quenched
with aq. NaHCO3. The crude reaction was then extracted with EtOAc,
dried over sodium sulfate, and concentrated in vacuo.
[2607] The resulting compound was then dissolved in DCM (2 mL),
BOC.sub.2O (0.154 mL, 0.664 mmol) was added, followed by
triethylamine (0.1 mL). The resulting solution was stirred at room
temperature for 2 h before it was washed with brine, and
concentrated in vacuo to give tert-butyl
(4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxybutyl-
)(2-hydroxyethyl)carbamate (77 mg) as a yellow oil.
[2608] MS (ESI) m/z 484 (M+H)
[2609] (739D): To a vial was charged with tert-butyl
(4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxybutyl-
)(2-hydroxyethyl)carbamate (77 mg, 0.16 mmol), and
triphenylphosphine (116 mg, 0.443 mmol) and THF (1 mL). The
resulting solution was cooled to 0.degree. C. before DEAD (0.175
mL, 0.443 mmol) was added drop wise. The resulting solution was
stirred for 15 min at 0.degree. C. before it was allowed to slowly
warm to room temperature and stirred overnight. The reaction was
then concentrated in vacuo and purified on ISCO. The resulting
compound was then treated with TFA/DCM (30%, 2 mL) at room
temperature for 3 h and then concentrated in vacuo to give
3-amino-4-chloro-5-(2-(morpholin-2-yl)ethyl)benzonitrile, TFA salt
as a yellow oil (16 mg).
[2610] MS (ESI) m/z 266.1 (M+H)
[2611] Example 739: To a vial was added
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (21 mg, 0.06 mmol), cesium carbonate (31 mg,
0.095 mmol), palladium(II) acetate (2.7 mg, 0.012 mmol), DPPF (2.2
mg, 0.004 mmol) and Xantphos (2.29 mg, 0.004 mmol),
3-amino-4-chloro-5-(2-(morpholin-2-yl)ethyl)benzonitrile, TFA salt
as a yellow oil (15 mg, 0.039 mmol), and dioxane (1 mL). The
resulting mixture was evacuated and refilled with N.sub.2 and then
heated at 90.degree. C. for 1.5 h. The reaction was cooled to room
temperature and diluted with EtOAc, filtered through a pad of
celite, concentrated in vacuo, and purified by flash column
chromatography. The intermediate was then treated with
TFA/DCM/anisole (0.25 mL, 0.25 mL, 0.25 mL) and stirred overnight
at room temperature. The reaction mixture was concentrated in vacuo
and then diluted with MeOH (3 ml), loaded onto an SCX column,
washed with MeOH (3.times.4 mL), and then 7N NH.sub.3/MeOH (4 mL).
The ammonia filtrate was collected, concentrated in vacuo, and
purified by preparative HPLC to give
(+/-)-2-((2-chloro-5-cyano-3-(2-(morpholin-2-yl)ethyl)phenyl)amino)-4-(cy-
clopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.3
mg).
[2612] MS (ESI) m/z 464.2 (M+H)
[2613] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.32 (s, 1H),
8.19 (s, 1H), 7.53 (s, 1H), 3.77 (d, J=10.8 Hz, 1H), 3.34 (br. s.,
1H), 2.95 (br. s., 1H), 2.86 (br. s., 1H), 2.86-2.75 (m, 2H),
2.72-2.62 (m, 2H), 2.40 (t, J=11.1 Hz, 1H), 1.90 (s, 2H), 1.65 (d,
J=7.1 Hz, 2H), 0.77 (br. s., 5H)
Example 740
##STR00800##
[2614]
(R)-methyl(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,-
1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate
[2615] A 4 ml vial was loaded with methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(Example 328) (31 mg, 0.061 mmol) and Dess-Martin Periodinane (52
mg, 0.123 mmol). DMSO (1 ml) was added (complete dissolution of
starting material). The reaction mixture was stirred at room
temperature for 1.5 hours. The reaction was quenched by addition of
2-Propanol (0.10 ml, 1.298 mmol). The reaction mixture was poured
into a dilute solution of NaHCO3 and NH4Cl in water. The product
precipitated as an off-white solid, which was collected by
filtration, washed with water and dried in an air-stream. An
analytically pure sample was obtained via purification by prep HPLC
with the following conditions: Column: XBridge C18, 19.times.mm,
5-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10-mM ammonium acetate; Gradient: 20-80% B over 20 minutes,
then a 0-minute hold at 100% B; Flow: 20 mL/min. Fractions
containing the desired product were combined and dried via
centrifugal evaporation. The material was further purified via
preparative LC/MS with the following conditions: Column: XBridge
C18, 19.times.mm, 5-.mu.m particles; Mobile Phase A: 5:95
acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:
25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20
mL/min. Fractions containing the desired product were combined and
dried via centrifugal evaporation to give (R)-methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (4.2 mg). The
product exists as a mixture of ketone and hydrate (and if analyzed
in MeOH solution also mono- and dimethyl-acetal)
[2616] MS (ESI) m/z 509/511 ([M+H]+, 1 Cl isotope pattern).
Example 741
##STR00801##
[2617] methyl
((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[2618] A 20 ml vial was loaded with methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(131 mg, 0.255 mmol) and Dess-Martin Periodinane (405 mg, 0.955
mmol). DMSO (4 ml) was added (complete dissolution of starting
material). The reaction mixture was stirred at room temperature for
1.5 hours. Excess Dess-Martin reagent was quenched by addition of
2-PROPANOL (1.0 ml, 13 mmol). After 5 minutes (to allow for
consumption of excess Dess-Martin reagent) NaBH4 (73 mg, 1.930
mmol) was added (exotherm, foaming) and the mixture stirred at room
temperature for 1 hour. The reaction mixture was diluted with 100
ml water (+small amount of NH4Cl and NaHCO3 to buffer pH). A
colorless precipitate forms and was collected by filtration. Solids
were washed with water and dried in a nitrogen stream overnight to
give 99 mg off-white solid, which is a mixture of
diastereoisomeres. The desired product was isolated after prep
HPLC. Column: XBridge C18, 19.times.mm, 5-.mu.m particles; Mobile
Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium
acetate; Gradient: 30-80% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation. The
yield of the product methyl
((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate was
3.9 mg, and its estimated purity by LCMS analysis was 94%. Two
analytical LC/MS injections were used to determine the final
purity. Injection 1 conditions: Column: Waters BEH C18,
2.0.times.50 mm, 1.7-.mu.m particles; Mobile Phase A: 5:95
acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature:
40.degree. C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4
minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min;
Detection: UV at 220 nm. Injection 2 conditions: Column: Waters BEH
C18, 2.0.times.50 mm, 1.7-.mu.m particles; Mobile Phase A: 5:95
methanol: water with 10 mM ammonium acetate; Mobile Phase B: 95:5
methanol: water with 10 mM ammonium acetate; Temperature:
40.degree. C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4
minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min;
Detection: UV at 220 nm.
[2619] LC/MS: m/z+=511/513 ([M+H]+, 1 Cl isotope pattern).
[2620] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 50.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 3 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
[2621] 1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.18 (br, 1H), 8.82
(br, 1H), 8.20 (s, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.32 (d, J=1.6 Hz,
1H), 6.85 (d, J=7.1 Hz, 1H), 4.77 (br, 1H), 3.83 (m, 1H), 3.66 (m,
1H), 3.56 (s, 3H), 3.46 (q, J=7 Hz, 2H), 3.28-3.18 (m, 2H), 3.03
(d, J=10.4 Hz, 1H), 2.82 (br. t., J=8.8 Hz, 1H), 1.98-1.89 (m, 1H),
1.67-1.60 (m, 1H), 1.18 (t, J=7 Hz, 3H).
Example 742
##STR00802##
[2622] methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[2623] Target compound: was prepared from methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(Example 327) following the procedure described for example
741.
[2624] MS (ESI) m/z 511/513 ([M+H]+, 1 Cl isotope pattern).
[2625] 1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.18 (br, 1H), 8.82
(br, 1H), 8.20 (s, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.32 (d, J=1.6 Hz,
1H), 6.85 (d, J=7.1 Hz, 1H), 4.77 (br, 1H), 3.83 (m, 1H), 3.66 (m,
1H), 3.56 (s, 3H), 3.46 (q, J=7 Hz, 2H), 3.28-3.18 (m, 2H), 3.03
(d, J=10.4 Hz, 1H), 2.82 (br. t., J=8.8 Hz, 1H), 1.98-1.89 (m, 1H),
1.67-1.60 (m, 1H), 1.18 (t, J=7 Hz, 3H).
Example 743
##STR00803##
[2626] methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
[2627] Example 743: was prepared from methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
(example 174) following the procedure described for example
741.
[2628] MS (ESI) m/z 523/525 (1 Cl isotope pattern)
[2629] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.34 (br, 1H), 8.82
(br, 1H), 8.21 (s, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.32 (d, J=1.6 Hz,
1H), 6.83 (d, J=7.3 Hz, 1H), 4.76 (d, J=4.7 Hz, 1H), 3.84 (m, 1H),
3.67 (m, 1H), 3.57 (s, 3H), 3.28-3.18 (m, 2H), 3.03-2.96 (m, 1H),
2.83 (br. t., J=8.8 Hz, 1H), 2.59-2.50 (m, 1H), 1.98-1.89 (m, 1H),
1.70-1.60 (m, 1H), 0.80 (d, J=7.5 Hz, 4H).
Example 744 and 745
##STR00804##
[2630] methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-(oxetan-3-ylamino)piperidin-4-yl)car-
bamate and methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-(oxetan-3-ylamino)piperidin-4-yl)car-
bamate
[2631] (744A): (S)-methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate was
obtained from methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate
following the procedure described for example 741.
[2632] LC/MS: m/z+=521/523 ([M+H]+, 1 Cl isotope pattern).
[2633] Examples 744 and 745: (S)-methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (21 mg,
0.040 mmol) was dissolved in DMF (2.5 ml)+Methanol (1 ml).
Oxetan-3-amine (15 mg, 0.205 mmol) and trimethyl orthoformate (0.5
ml, 4.52 mmol) were added. Acetic acid (0.05 ml, 0.873 mmol) was
added drop wise until pH .about.5. The reaction mixture was stirred
at room temperature for 10 minutes. sodium cyanoborohydride (21 mg,
0.334 mmol) was added and stirring at rt. continued for 1 hour. The
reaction mixture was concentrated under a nitrogen stream
overnight. The crude was dissolved in DMSO, filtered and purified
by reversed phase HPLC with the following conditions: Column:
XBridge C18, 19.times.mm, 5-.mu.m particles; Mobile Phase A: 5:95
acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:
30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20
mL/min. Fractions containing the desired product were combined and
dried via centrifugal evaporation. Two diastereomeric products were
separated.
[2634] Methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-(oxetan-3-ylamino)piperidin-4-yl)car-
bamate (Example 744) (first eluting isomer on XBridge C18 column,
acetonitrile-water gradient with 10-mM ammonium acetate, 5.5 mg)
and methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imida-
zo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(oxetan-3-ylamino)piperidin-4-
-yl)carbamate (Example 745) (second eluting isomer on XBridge C18
column, acetonitrile-water gradient with 10-mM ammonium acetate,
6.1 mg, 10.45 umol, 26% yield)
[2635] HPLC Rt, 2.49 min. (example 744) and 2.61 min (example
745)
[2636] MS (ESI) m/z 578.3 (consistent with [M+H]+) for examples 744
and 745.
[2637] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 40.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
[2638] 1H NMR (500 MHz, dmso-d6, example 744) .delta. ppm 9.34 (br,
1H), 8.85 (br, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.30 (s, 1H), 7.16
(d, J=8.3 Hz, 1H), 4.62-4.58 (m, 2H), 4.33-4.22 (m, 2H), 4.00 (m,
1H), 3.57 (s, 3H), 3.35-3.18 (m, 4H), 3.01-2.95 (m, 1H), 2.76 (br.
t., J=12.5 Hz, 1H), 2.62 (br, 1H), 2.41 (t, J=10.2 Hz, 1H), 1.90
(br. d., J=10.4 Hz, 1H), 1.63-1.53 (m, 1H), 0.79 (d, J=5.5 Hz,
4H).
[2639] 1H NMR (500 MHz, dmso-d6, example 745) .delta. ppm 9.34 (br,
1H), 8.86 (br, 1H), 8.21 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.31 (d,
J=1.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 4.59 (t, J=6.4 Hz, 2H), 4.27
(t, J=6.3 Hz, 1H), 4.23 (t, J=, 6.3 Hz, 1H), 3.98 (quint, J=6.0 Hz,
1H), 3.66 (br, 1H), 3.58 (s, 3H), 3.13-3.06 (m, 1H), 3.01-2.93 (m,
3H), 2.87-2.80 (m, 2H), 1.87-1.79 (m, 1H), 1.74-1.66 (m, 1H), 0.79
(d, J=5.5 Hz, 4H) One proton signal missing, is very likely hidden
under DMSO signal.
Examples 746 and 747
##STR00805##
[2640] methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(oxetan-3-ylamino)piperidin-4-yl)carbamate
and methyl
((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(oxetan-3-ylamino)piperidin-4-yl)carbamate
[2641] Examples 746 and 747: were prepared from (R)-methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate and
oxetane-3-amine following the procedure described for examples 744
and 745
[2642] HPLC Rt, 1.64 min. (example 746) and 1.72 min (example
747)
[2643] MS (ESI) m/z 566.3 (consistent with [M+H]+) for examples 746
and 747.
[2644] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 50.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 3 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
Example 748 and 749
##STR00806##
[2645] methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-((2,2-difluoroethyl)amino)piperidin--
4-yl)carbamate and methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-((2,2-difluoroethyl)amino)piperidin--
4-yl)carbamate
[2646] Examples 748 and 749: were prepared from (S)-methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate and
2,2-difluoroethylamine following the procedure described for
examples 744 and 745.
[2647] Analytical data for methyl
((3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-((2,2-difluoroethyl)amino)piperidin--
4-yl)carbamate (example 748)
[2648] HPLC Rt, 1.92 min.
[2649] MS (ESI) m/z 586.3 (consistent with [M+H]+)
[2650] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 50.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 3 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
[2651] Analytical data for methyl
((3R,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-3-((2,2-difluoroethyl)amino)piperidin--
4-yl)carbamate (example 749)
[2652] HPLC Rt, 3.12 min.
[2653] MS (ESI) m/z 586.3 (consistent with [M+H]+)
[2654] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 40.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm, retention
time in minutes. MS signals are reported for positive ions
(m/e+)
Example 750 and 751
##STR00807##
[2655] methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)c-
arbamate and methyl
((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)c-
arbamate
[2656] Examples 751 and 752: (R)-methyl
(1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (44 mg, 0.039
mmol) was dissolved in DMF (2.5 ml) and methanol (1 ml).
oxetan-3-amine (20 .mu.l, 0.039 mmol) and trimethyl orthoformate
(0.25 ml, 2.262 mmol) were added. Acetic acid (0.05 ml, 0.873 mmol)
was added drop wise until pH .about.5. The reaction mixture was
stirred at room temperature for 10 minutes. sodium cyanoborohydride
(21 mg, 0.334 mmol) was added and stirring at room temperature
continued for 1 hour. Formaldehyde (50 .mu.l, 0.672 mmol) and
additional sodium cyanoborohydride (21 mg, 0.334 mmol) and acetic
acid (0.05 ml, 0.873 mmol) were added and the mixture stirred at
room temperature for 3 hours, then evaporated in a nitrogen stream
overnight. The crude mixture of the 2 diastereomeric products was
dissolved in DMSO, filtered and purified by prep HPLC with the
following conditions: Column: XBridge C18, 19.times.mm, 5-.mu.m
particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium
acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium
acetate; Gradient: 50-90% B over 30 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation to give
methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)c-
arbamate (1.7 mg) (Example 750) and methyl
((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)c-
arbamate (1.9 mg) (Example 751)
[2657] Analytical data for methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)c-
arbamate (example 750)
[2658] HPLC Rt, 2.85 min.
[2659] MS (ESI) m/z 580.3 (consistent with [M+H]+)
[2660] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 40.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
[2661] 1H NMR (500 MHz, dmso-d6) .delta. ppm 9.19 (br, 1H), 8.87
(br, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.35 (s, 1H), 7.00 (d, J=8.8
Hz, 1H), 4.54 (t, J=6.2 Hz, 1H), 4.49 (t, J=6.8 Hz, 1H), 4.44 (q,
J=6.5 Hz, 2H), 4.08 (quint, J=6.8 Hz, 1H), 3.64-3.53 (m, 1H), 3.55
(s, 3H), 3.46 (q, J=7.0 Hz, 2H), 3.26-3.17 (m, 2H), 2.74 (t, J=11.3
Hz, 1H), 2.66-2.59 (m, 2H), 2.24 (s, 3H), 1.93-1.88 (m, 1H),
1.63-1.55 (m, 1H), 1.20 (t, J=7.1 Hz, 3H)
[2662] Analytical data for methyl
((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)c-
arbamate (example 751)
[2663] HPLC Rt, 2.83 min.
[2664] MS (ESI) m/z 580.3 (consistent with [M+H]+)
[2665] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 40.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
[2666] 1H NMR (500 MHz, dmso-d6) .delta. ppm 9.19 (br, 1H), 8.85
(br, 1H), 8.20 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.33 (d, J=1.5 Hz,
1H), 7.18 (d, J=7.9 Hz, 1H), 4.51-4.41 (m, 4H), 4.08-4.01 (br, 1H),
3.99 (quint, J=6.8 Hz, 1H), 3.59 (s, 3H), 3.50.3.45 (m, 1H), 3.48
(q, J=7.0 Hz, 2H), 3.15-3.08 (t, J=10.8 Hz, 1H), 3.01-2.93 (m, 2H),
2.70-2.64 (m, 1H), 2.25 (s, 3H), 1.83-1.76 (m, 1H), 1.75-1.68 (m,
1H), 1.20 (t, J=7.1 Hz, 3H).
[2667] The compounds in the following Table were similarly prepared
as Examples 744-751
TABLE-US-00036 TABLE 33 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.) 752 ##STR00808## methyl
N-[(3R,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(propan-2-yl)amino]piperidin-4- yl]carbamate 564.5 1.57 753
##STR00809## methyl N-[(4S)-3-{[(1S)-1-
carbamoylethyl]amino}-1-(2-chloro-5-cyano-
3-{[7-cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)piperidin-4-yl]carbamate 593.5 1.56 754
##STR00810## methyl N-[(3R,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(3-methyloxetan-3-yl)amino]piperidin-4- yl]carbamate 592.5 1.77
755 ##STR00811## methyl N-[(3S,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3- [(2-hydroxy-2-
methylpropyl)amino]piperidin-4- yl]carbamate 594.6 1.78 756
##STR00812## methyl N-[(3R,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(propan-2-yl)amino]piperidin-4- yl]carbamate 564.5 1.78 757
##STR00813## methyl N-[(3S,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-[(3,3,3-
trifluoro-2-hydroxypropyl)amino]piperidin-4- yl]carbamate 622.3
2.10 758 ##STR00814## methyl N-[(3R,4R)-3-{[(1S)-1-
carbamoylethyl]amino}-1-(2-chloro-5-cyano-
3-{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)piperidin-4- yl]carbamate 581.2
2.30 759 ##STR00815## methyl N-[(3S,4R)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-[(2-
hydroxy-2-methylpropyl)amino]piperidin-4- yl]carbamate 582.3 1.65
760 ##STR00816## methyl N-[(3S,4R)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-[(2-
hydroxy-2-methylpropyl)amino]piperidin-4- yl]carbamate 582.4 1.78
761 ##STR00817## methyl N-[(3S,4R)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-[(3,3,3-
trifluoro-2-hydroxypropyl)amino]piperidin-4- yl]carbamate 622.3
2.13 762 ##STR00818## methyl N-[(3R,4S)-3-[(1-
carbamoylethyl)amino]-1-(2-chloro-5-cyano-
3-{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)piperidin-4- yl]carbamate 581.3
1.57 763 ##STR00819## methyl N-[(4S)-1-(2-chloro-5-cyano-3-{[7-
cyano-4-(cyclopropylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-
[methyl(oxetan-3-yl)amino]piperidin-4- yl]carbamate 592.4 1.76 764
##STR00820## methyl N-[(3S,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(cyanomethyl)(methyl)amino]piperidin-4- yl]carbamate 575.3 1.82
765 ##STR00821## methyl N-[(3S,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(2-hydroxy-2-methylpropyl)(methyl) amino]piperidin-4-yl]carbamate
608.5 1.84 766 ##STR00822## methyl
N-[(3R,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(cyanomethyl)(methyl)amino]piperidin-4- yl]carbamate 575.3 1.84
767 ##STR00823## methyl N-[(3R,4S)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(cyclopropylamino)imidazo
[2,1-f][1,2,4]triazin-2-yl]amino}phenyl)-3-
[(2-hydroxy-2-methylpropyl)(methyl) amino]piperidin-4-yl]carbamate
608.5 1.86 768 ##STR00824## methyl N-[(3R,4R)-3-{[(1S)-1-
carbamoylethyl](methyl)amino}-1-(2-chloro-
5-cyano-3-{[7-cyano-4-(ethylamino) imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)piperidin-4-yl]carbamate 595.4 1.63 769
##STR00825## methyl N-[(3S,4R)-3-{[(1S)-1-
carbamoylethyl](methyl)amino}-1-(2-chloro-
5-cyano-3-{[7-cyano-4-(ethylamino) imidazo[2,1-f][1,2,4]triazin-2-
yl]amino}phenyl)piperidin-4-yl]carbamate 595.4 1.67 770
##STR00826## methyl N-[(3R,4R)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-[(2-
hydroxy-2-methylpropyl)(methyl) amino]piperidin-4-yl]carbamate
596.4 1.87 771 ##STR00827## methyl
N-[(3S,4R)-1-(2-chloro-5-cyano-3-
{[7-cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-[(2-
hydroxy-2-methylpropyl)(methyl) amino]piperidin-4-yl]carbamate
596.4 1.88 772 ##STR00828## methyl
N-[(4R)-1-(2-chloro-5-cyano-3-{[7-
cyano-4-(ethylamino)imidazo[2,1-f]
[1,2,4]triazin-2-yl]amino}phenyl)-3-{[(2S)-
2,3-dihydroxypropyl](methyl)amino} piperidin-4-yl]carbamate 598.4
1.52 Analysis condition: Column: Waters Acquity UPLC BEH C18, 2.1
.times. 50 mm, 1.7-.mu.m particles; Mobile Phase A: 5:95
acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature:
50.degree. C.; Gradient: 0-100% B over 3 minutes, then a
0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220
nm.
Example 773
##STR00829##
[2668]
2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hep-
tan-2-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile
[2669] (773A): A 5 ml microwave vial was loaded with
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (71.8 mg, 0.209 mmol),
3-amino-4-chloro-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)b-
enzonitrile (50 mg, 0.190 mmol), Pd(OAc)2 (6.41 mg, 0.029 mmol),
XANTPHOS (17.62 mg, 0.030 mmol) and Potassium phosphate (145 mg,
0.685 mmol). The vial was evacuated and back-filled with nitrogen 4
times. Toluene (2 ml) was added and the flask was again evacuated
and back-filled with nitrogen 4 times, and then heated with
stirring to 80.degree. C. for 5 hours. The reaction mixture was
cooled to room temperature, filtered through Celite and solids
washed with dichloromethane. Evaporation to dryness gave 163 mg
crude product
2-((2-chloro-5-cyano-34(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-y-
l)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile, which was used "as is" in the following
deprotection reaction.
[2670] MS (ESI) m/z 569 ([M+H]+)
[2671] Example 773:
2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2--
yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile (163 mg, 0.186 mmol) (crude, <=0.190 mmol)
was dissolved in ClCH.sub.2CH.sub.2Cl (10 mL). Anisole (1 ml, 9.15
mmol) and TFA (2 ml, 26.0 mmol) were added and the mixture stirred
at room temperature for 3 hours. The reaction mixture was
evaporated to a sticky oil, dissolved in DMSO and purified by prep
HPLC to give 48.5 mg of
2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2--
yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
Preparative HPLC Conditions
[2672] Column: XBridge C18, 19.times.mm, 5-.mu.m particles; Mobile
Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium
acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold
at 100% B; Flow: 20 mL/min. Fractions containing the desired
product were combined and dried via centrifugal evaporation. The
product was converted to the mono-HCl salt by addition of 1
equivalent aqueous 1.00 N HCl to a MeOH/DMF solution of the free
base and re-evaporation.
[2673] MS (ESI) m/z 449.3
[2674] 1H NMR (500 MHz, dmso-d6) .delta. ppm 10.39 (br, 1H), 9.20
(t, J=5.6 Hz, 1H), 8.83 (br, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 7.29
(br, 1H), 4.55 (br, 1H), 4.33 (br, 1H), 3.90 (d, J=11.9 Hz, 1H),
3.90-3.81 (m, 1H), 3.64 (d, J=10.9 Hz, 1H), 3.51-3.45 (m, 2H),
3.14-3.07 (m, 1H), 2.85 (br.s., 3H), 2.42-2.36 (m, 1H), 2.17-2.09
(m, 1H), 1.21 (t, J=7.1 Hz, 3H).
Examples 774 and 775
##STR00830##
[2675]
2-(6-cyano-3-((1S,2S)-2-((dimethylamino)methyl)cyclopropyl)-1H-indo-
l-1-yl)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
and
2-(6-cyano-3-((1R,2R)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-yl-
)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2676] (774A): A 5 ml microwave vial was loaded with
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (Intermediate 10) (110 mg, 0.321 mmol),
rac-3-((1r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indole-6-carbonit-
rile (50 mg, 0.209 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Brettphos
(CAS 1070663-78-3) (35 mg, 0.065 mmol) and Cs2CO3 (powder, 80 mesh,
210 mg, 0.645 mmol). The vial was sealed, evacuated and flushed
with nitrogen 4.times.. Dioxane (3 ml) was added and the vial
evacuated and backfilled with nitrogen 4 times. The reaction was
heated to 110.degree. C. for 12 hours. LCMS shows m/e+=546,
consistent with [M+H]+ of product. Only trace of indole starting
material remaining. The reaction mixture was allowed to cool to
room temperature, diluted with acetonitrile and filtered through
Celite. The Celite was washed with acetonitrile. The combined
solutions were evaporated to dryness. The crude was purified by
column chromatography on silica. (40 g cartridge, load sample as
solution in dichloromethane, elute with gradient from 100% DCM to
100% EtOAc (product doesn't elute), then a gradient from 100%
dichloromethane to 80% DCM+20% (MeOH+1% aq. conc. NH4OH). Product
containing fractions were combined and evaporated to dryness to
give 92.8 mg pale yellow film
(+/-)-2-(6-cyano-3-((1r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indo-
l-1-yl)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile (92.8 mg, 0.163 mmol)
[2677] MS (ESI) m/z 546.7
[2678] Examples 774 and 775: The PMB group of
(+/-)-2-(6-cyano-3-41r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-
-1-yl)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile was cleaved using the method described in the previous
example 773.
[2679] The purified racemic product was separated into the
enantiomers by chromatography on a Chiralpak AS 21.times.250 mm 10
um column, isocratic at 10% Ethanol and 90% (Heptane+0.1%
diethylamine) over 50 minutes. Products were collected by UV at 254
nm.
[2680] Example 774 is first eluting enantiomer and was arbitrarily
assigned as
2-(6-cyano-3-((1S,2S)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-yl-
)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13.8
mg).
[2681] Example 775 is second eluting enantiomer and was arbitrarily
assigned as
2-(6-cyano-3-41R,2R)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-yl)-
-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13.1
mg).
[2682] Analytical data for
2-(6-cyano-3-((1S,2S)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-yl-
)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(example 774) and
2-(6-cyano-3-(1R,2R)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-
-yl)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
(Example 775) HPLC Rt, 2.17 min.
[2683] LC/MS: m/z-=424.3 (consistent with [M-H]-),
[2684] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 40.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
[2685] 1H NMR (500 MHz, dmso-d6) .delta. ppm 9.65 (br, 1H), 8.80
(s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.54
(d, J=7.9 Hz, 1H), 3.66 (q, J=7 Hz, 2H), 2.35 (dq, J.sub.d=15 Hz,
J.sub.q=7 Hz, 2H), 2.23 (s, 6H), 1.84-1.78 (m, 1H), 1.31 (t, J=7
Hz, 3H), 1.22-1.17 (m, 1H), 1.06-1.02 (m, 1H), 0.87-0.81 (m,
1H).
Example 776
##STR00831##
[2686]
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidi-
n-1-yl)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]tri-
azine-7-carbonitrile
[2687] (776A):
(+/-)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (29 mg, 0.046 mmol) was dissolved in DMF (1 ml) in a 4
ml vial. DIPEA (0.25 ml, 1.431 mmol) was added and the mixture
warmed to 70.degree. C. A solution of 2-(chloromethyl)oxirane (100
.mu.l, 1.279 mmol) in DMF (1 ml) was added slowly. The reaction
mixture was kept at 70.degree. C. for 30 minutes. The crude
reaction mixture was filtered through a MCX cartridge (Waters, 5 g
adsorbent). The cartridge was washed with MeOH and the product
eluted with a 1:1 mixture of (CH.sub.3CN+2 molar solution of
NH.sub.3 in MeOH). Evaporation to dryness gave 30 mg of
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidin-1-yl-
)piperidin-1-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f-
][1,2,4]triazine-7-carbonitrile. The crude was used "as is" in the
following deprotection
[2688] MS (ESI) m/z 629/631 reaction.
[2689] Examples 776: The PMB group of
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidin-1-yl-
)piperidin-1-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f-
][1,2,4]triazine-7-carbonitrile was cleaved using the method
described in the previous examples 773 HPLC Rt, 2.50 min.
[2690] MS (ESI) m/z 509/511 (1 Cl isotope, consistent with [M+H]+)
and m/e-=507/509 (1 Cl isotope, consistent with [M-H]-.
[2691] HPLC conditions: Column: Waters BEH C18, 2.0.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile: water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water
with 10 mM ammonium acetate; Temperature: 40.degree. C.; Gradient:
0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute
hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
Example 777
##STR00832##
[2692]
(+/-)-2-((2-chloro-5-cyano-3-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]-
pyridin-6(2H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]tr-
iazine-7-carbonitrile
[2693] (777A): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) (1314
mg, 3.96 mmol), (+/-)-(4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine
(500 mg, 3.96 mmol), Pd2dba3 (363 mg, 0.396 mmol), BINAP (740 mg,
1.189 mmol), and Cs2CO3 (3873 mg, 11.89 mmol) in Dioxane (25 mL)
was evacuated and filled with nitrogen 3 times and heated at
105.degree. C. overnight. The reaction mixture was filtered through
a plug of celite and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (80 g column, eluting with 0%-10%
Methanol/DCM). Correct fractions were collected and concentrated to
gave tert-butyl
(2-chloro-5-cyano-3-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-y-
l)phenyl)carbamate (813 mg)
[2694] MS (ESI) m/z 377 (M+1)
[2695] (777B): (+/-)-tert-butyl
(2-chloro-5-cyano-3-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-y-
l)phenyl)carbamate (800 mg, 2.123 mmol) in DCM (10 mL) was treated
with TFA (3.11 mL, 40.3 mmol) at room temperature for 1 h. Solvent
was evaporated and the residue was redissolved in DCM and
concentrated again. Remained TFA was neutralized with TEA and
excess TEA was evaporated in vacuo.
[2696] BOC.sub.2O (0.591 mL, 2.55 mmol) was added to a solution of
the above crude intermediate in DCM (15 mL) and the reaction
mixture was stirred at room temperature overnight. Solvent was
evaporated in vacuo and the crude product was purified by flash
chromatography on silica gel using an automated ISCO system 80
column, eluting with 0-70% ethyl acetate/hexanes).
(+/-)-(4aS,7aS)-tert-butyl
6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-c-
arboxylate (501 mg, 1) was obtained as a white solid.
[2697] MS (ESI) m/z 377 (M+1)
[2698] (777C): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (395 mg, 1.114 mmol), (4aS,7aS)-tert-butyl
6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-c-
arboxylate (420 mg, 1.114 mmol), palladium(II) acetate (66.3 mg,
0.295 mmol), XANTPHOS (64.5 mg, 0.111 mmol), DPPF (61.8 mg, 0.111
mmol) and cesium carbonate (944 mg, 2.90 mmol) in Dioxane (7 ml)
was evacuated and back filled with nitrogen three time and was
heated at 80.degree. C. for 5 h. The reaction mixture was filtered
through a celite pad and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system 40 g column, eluting with 0-5% MeOH in DCM
(+/-)-(4aS,7aS)-tert-butyl6-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(-
4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octah-
ydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (379 mg) was obtained
as a brown solid.
[2699] MS (ESI) m/z 695 (M+1)
[2700] Example 777D: TFA (0.382 mL, 4.96 mmol) was added to a
solution of (4aS,7aS)-tert-butyl
6-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imid-
azo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,4-b]pyri-
dine-1-carboxylate (50 mg, 0.072 mmol) and anisole (0.031 mL, 0.288
mmol) in DCE (1 mL) and the reaction mixture was heated at
60.degree. C. for 1 hour. The solvent was removed in vacuo and the
material azeotroped with toluene 3.times. to remove the excess TFA.
10 ml of 2N NH.sub.3 in MeOH was added, and the solution was
stirred for 20 min. The solvent was removed in vacuo and the
material was triturated with MeOH/Et2O (1:20 ratio). The solid was
collected by vacuum filtration to give a yellow solid which was
purified by prep-HPLC to give
2-((2-chloro-5-cyano-3-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H-
)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-car-
bonitrile (23.9 mg) HPLC Rt, 0.74 min.
[2701] LC/MS: m/z 475 (M+1).
[2702] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H),
7.76 (s, 1H), 7.02 (s, 2H), 3.87-3.62 (m, 3H), 3.17 (t, J=8.1 Hz,
1H), 3.10 (d, J=10.1 Hz, 1H), 3.00 (br. s., 1H), 2.93-2.81 (m, 2H),
2.23 (br. s., 2H), 1.76-1.55 (m, 6H), 1.38 (d, J=15.5 Hz, 2H)
Example 778
##STR00833##
[2703]
2-((2-chloro-5-cyano-3-((4aS,7aS)-1-(oxetan-3-yl)hexahydro-1H-pyrro-
lo[3,4-b]pyridin-6(2H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f]-
[1,2,4]triazine-7-carbonitrile
[2704] The title compound was prepared using a method used to
prepare Example 387C
[2705] MS (ESI) m/z 531 (M+1).
Example 779
##STR00834##
[2706]
(+/-)-2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]dec-
an-8-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile
[2707] (779A): To a solution of tert-butyl
1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (330 mg, 1.298 mmol)
and iodomethane (0.085 mL, 1.362 mmol) in THF (10 mL) was cooled in
an ice bath. Sodium hydride (78 mg, 1.946 mmol) was added and the
ice bath was removed. The reaction was stirred at room temperature
for 4 hrs. The reaction mixture was diluted with EtOAc and washed
with sat NaHCO3; the aqueous layer was extracted with EtOAc. Then
the combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude product was purified by chromatography (silica gel,
Hexanes/EtOAc gradient 0 to 100% EtOAc) to give tert-butyl
2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (315
mg).
[2708] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.03-3.88 (m,
1H), 3.56-3.44 (m, 1H), 3.35-3.23 (m, 2H), 3.19-3.12 (m, 1H),
3.03-2.91 (m, 1H), 2.83 (d, J=1.8 Hz, 3H), 2.27 (s, 1H), 1.99-1.76
(m, 2H), 1.56 (t, J=5.7 Hz, 3H), 1.44 (s, 9H)
[2709] (779B): To a solution of tert-butyl
2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (315 mg,
1.174 mmol) in DCM (5 mL) was added TFA (1.718 mL, 22.30 mmol) and
the mixture was stirred at room temperature for 2 h. The reaction
was concentrated under reduced pressure to obtain crude and
purified by SCX cartridge, loading with MeOH, washed with
additional MeOH. Product was recovered eluting with 2M NH.sub.3 in
MeOH. Solvent evaporation gave
2-methyl-2,8-diazaspiro[4.5]decan-1-one (177 mg).
[2710] MS (ESI) m/z 169 (M+1).
[2711] (779C): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (349 mg, 1.052 mmol),
2-methyl-2,8-diazaspiro[4.5]decan-1-one (177 mg, 1.052 mmol),
Pd2dba3 (96 mg, 0.105 mmol), BINAP (197 mg, 0.316 mmol), and
Cs.sub.2CO.sub.3 (1028 mg, 3.16 mmol) in Dioxane (15 mL) was
evacuated and filled with nitrogen 3.times. and heated at
105.degree. C. overnight. The reaction mixture was filtered through
a plug of celite and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 10% to 100% EtOAc
in Hexane) to give tert-butyl
(2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)-
carbamate (197 mg)
[2712] MS (ESI) m/z 419 (M+1).
[2713] (779D):
tert-butyl-(2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-
-yl)phenyl)carbamate (336 mg, 0.802 mmol) in DCM (3 mL) was treated
with TFA (1.174 mL, 15.24 mmol) at room temperature for 2 h.
Solvent was evaporated and the residue was redissolved in DCM and
concentrated again. The reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (40 g column, eluting with 0-10% methanol/dichloromethane).
3-amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonit-
rile (179 mg) was obtained as alight yellow oil.
[2714] MS (ESI) m/z 319 (M+1).
[2715] (779F): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (167 mg, 0.471 mmol),
3-amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonit-
rile (150 mg, 0.471 mmol), palladium(II) acetate (28.0 mg, 0.125
mmol), XANTPHOS (27.2 mg, 0.047 mmol), DPPF (26.1 mg, 0.047 mmol)
and cesium carbonate (399 mg, 1.223 mmol) in dioxane (5 ml) was
evacuated and back filled with nitrogen three time and was heated
at 80.degree. C. for 3 h. The reaction mixture was filtered through
a celite pad and the filtrate was concentrated. The crude product
was purified by flash chromatography on silica gel using an
automated ISCO system (24 g column, eluting with 10% to 100% EtOAc
in Hexane) to give
(+/-)-2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-y-
l)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]-
triazine-7-carbonitrile (137 mg) as a light yellow solid.
[2716] MS (ESI) m/z 637 (M+1).
[2717] Example 779: TFA (0.417 mL, 5.41 mmol) was added to a
solution of
2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phen-
yl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (50 mg, 0.078 mmol) and anisole (0.034 mL, 0.314
mmol) in DCE (1 mL) and the reaction mixture was heated at
60.degree. C. for 1 hours. The solvent was removed in vacuo and the
material azeotroped with toluene 3.times. to remove the excess TFA.
10 ml of 2N NH.sub.3 in MeOH was added, and the solution was
stirred for 20 min. The solvent was removed in vacuo and the
material was purified by prep-HPLC to give
2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(17.4 mg).
[2718] MS (ESI) m/z 517 (M+1).
[2719] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.35 (d, J=4.0
Hz, 1H), 8.85 (s, 1H), 7.33 (s, 1H), 3.39-3.30 (m, 1H), 3.24 (s,
1H), 3.08-2.91 (m, 4H), 2.74 (s, 3H), 2.51 (br. s., 1H), 2.23 (s,
2H), 1.72 (br. s., 4H), 0.79 (d, J=5.7 Hz, 4H)
Example 780
##STR00835##
[2720]
2-((2-chloro-5-cyano-3-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-
an-8-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile
[2721] The title compound was prepared from tert-butyl
2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate using a method
analogous to that used to prepare Example 779.
[2722] MS (ESI) m/z 519 (M+1).
[2723] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.44-9.25 (m,
1H), 8.97-8.82 (m, 1H), 7.41-7.32 (m, 1H), 3.40 (s, 2H), 3.15-2.94
(m, 5H), 2.90 (s, 3H), 1.95 (br. s., 4H), 0.79 (d, J=5.5 Hz,
4H)
Example 781
##STR00836##
[2724]
(+/-)-2-((2-chloro-5-cyano-3-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4-
.5]decan-8-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile
[2725] The title compound was prepared from tert-butyl
2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate and
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile using a method analogous to that used to prepare
Example 779.
[2726] MS (ESI) m/z 507 (M+1).
[2727] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.20 (br. s.,
1H), 8.88 (s, 1H), 8.20 (s, 1H), 8.03-7.90 (m, 1H), 7.46-7.32 (m,
1H), 3.53-3.43 (m, 1H), 3.39-3.30 (m, 3H), 3.09 (d, J=10.8 Hz, 3H),
2.78 (s, 3H), 1.95 (br. s., 4H), 1.29-1.10 (m, 4H)
Example 782
##STR00837##
[2728]
(+/-)-2-((2-chloro-5-cyano-3-(2-methyl-3-oxo-2,8-diazaspiro[4.5]dec-
an-8-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile
[2729] The title compound was prepared from tert-butyl
3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate using a method
analogous to that used to prepare Example 781
[2730] MS (ESI) m/z 517 (M+1).
[2731] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39-9.29 (m,
1H), 8.89-8.78 (m, 1H), 8.24-8.17 (m, 1H), 8.14-8.07 (m, 1H),
7.36-7.26 (m, 1H), 3.38 (s, 1H), 3.23 (s, 2H), 3.12-2.91 (m, 4H),
2.74 (s, 3H), 2.23 (s, 2H), 1.82-1.59 (m, 4H), 0.79 (d, J=6.1 Hz,
4H)
Example 783
##STR00838##
[2732]
(+/-)-2-((2-chloro-5-cyano-3-(2-methyl-3-oxo-2,8-diazaspiro[4.5]dec-
an-8-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile
[2733] The title compound was prepared from
3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate and
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile using a method analogous to that used to prepare
Example 779
[2734] MS (ESI) m/z 505 (M+1).
[2735] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.32-9.08 (m,
1H), 8.91-8.76 (m, 1H), 8.27-8.12 (m, 1H), 8.03-7.90 (m, 1H),
7.43-7.23 (m, 1H), 3.55-3.44 (m, 2H), 3.28-3.18 (m, 2H), 3.12-2.92
(m, 4H), 2.74 (s, 3H), 2.31-2.12 (m, 2H), 1.87-1.56 (m, 4H),
1.27-1.10 (m, 3H)
Example 784
##STR00839##
[2736]
(+/-)-2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]dec-
an-8-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbon-
itrile
[2737] The title compound was prepared from
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile using a method analogous to that used to prepare
Example 779
[2738] MS (ESI) m/z 505 (M+1).
[2739] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.28-9.13 (m,
1H), 8.93-8.77 (m, 1H), 8.25-8.16 (m, 1H), 8.01-7.87 (m, 1H),
7.42-7.24 (m, 1H), 3.29-3.19 (m, 4H), 2.88-2.79 (m, 2H), 2.78-2.71
(m, 4H), 2.03-1.95 (m, 2H), 1.93-1.80 (m, 2H), 1.51-1.43 (m, 2H),
1.23-1.13 (m, 4H)
Example 785
##STR00840##
[2740]
(+/-)-2-((2-chloro-5-cyano-3-(1-methyl-2-oxo-1,4,8-triazaspiro[4.5]-
decan-8-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-
-7-carbonitrile
[2741] The title compound was prepared from tert-butyl
2-oxo-1,4,8-triazaspiro[4.5]decane-8-carboxylate using a method
analogous to that used to prepare Example 779
[2742] MS (ESI) m/z 518 (M+1).
[2743] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.40-9.29 (m,
1H), 8.91-8.79 (m, 1H), 8.25-8.17 (m, 1H), 8.15-8.07 (m, 1H),
7.40-7.26 (m, 1H), 3.26 (br. s., 4H), 3.09-2.94 (m, 3H), 2.71 (s,
4H), 2.16-1.99 (m, 2H), 1.62-1.49 (m, 2H), 0.79 (br. s., 4H)
Example 786
##STR00841##
[2744]
2-((3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2745] (786A): A stirred solution of tert-butyl
2,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (400 mg,
1.445 mmol) in DCM (5 mL) was treated with TEA (0.604 mL, 4.34
mmol), followed by Ac.sub.2O (0.164 mL, 1.734 mmol), stirred at
room temperature for 2 h. To this reaction mixture was added TFA
(2.115 mL, 27.5 mmol) and stirred at room temperature for 1 h.
Concentrated under reduced pressure to obtain crude material which
purified by SCX cartridge, loading with MeOH, washed with
additional MeOH. Product was recovered eluting with 2M NH.sub.3 in
MeOH. Solvent evaporation gave
1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone (165 mg)
[2746] MS (ESI) m/z 183 (M+1).
[2747] (786B): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (291 mg, 0.878 mmol),
1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone (160 mg, 0.878 mmol),
Pd.sub.2dba.sub.3 (80 mg, 0.088 mmol), BINAP (164 mg, 0.263 mmol),
and Cs.sub.2CO.sub.3 (858 mg, 2.63 mmol) in Dioxane (15 mL) was
evacuated and filled with nitrogen 3.times. and heated at
105.degree. C. overnight. The reaction mixture was filtered through
a plug of celite and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 10% to 100% EtOAc
in Hexane) gave tert-butyl
(3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)carbam-
ate (192 mg)
[2748] MS (ESI) m/z 433 (M+1).
[2749] (786C):
tert-butyl(3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophe-
nyl)carbamate (100 mg, 0.231 mmol) in DCM (2 mL) was treated with
TFA (0.338 mL, 4.39 mmol) at room temperature for 2 h. Solvent was
evaporated and the residue was diluted with dichloromethane and
washed with saturated sodium bicarbonate. The aqueous layer was
extracted with dichloromethane two more times. The combined organic
layers were dried over magnesium sulfate, filtered and concentrated
in vacuo, the crude product was purified by flash chromatography on
silica gel using an automated ISCO system (24 g gold column,
eluting with 0-5% methanol/dichloromethane).
3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-5-amino-4-chlorobenzonitrile
(70 mg) was obtained as a light yellow oil.
[2750] MS (ESI) m/z 333 (M+1).
[2751] (786D): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (37.3 mg, 0.105 mmol),
3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-5-amino-4-chlorobenzonitrile
(35 mg, 0.105 mmol), palladium(II) acetate (6.26 mg, 0.028 mmol),
XANTPHOS (6.08 mg, 10.52 .mu.mol), DPPF (5.83 mg, 10.52 .mu.mol)
and cesium carbonate (89 mg, 0.273 mmol) in dioxane (2 ml) was
evacuated and back filled with nitrogen three time and was heated
at 80.degree. C. for 3 h. The reaction mixture was filtered through
a celite pad and the filtrate was concentrated. The crude product
was purified by flash chromatography on silica gel using an
automated ISCO system (24 g column, eluting with 0-10%
Methanol/DCM).
2-((3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)ami-
no)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (37 mg) was obtained as a light yellow solid.
[2752] MS (ESI) m/z 651 (M+1).
[2753] Example 786: TFA (0.302 mL, 3.92 mmol) was added to a
solution of
2-((3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)ami-
no)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile (37 mg, 0.057 mmol) and anisole (0.025 mL, 0.227 mmol)
in DCE (1.0 mL) and the reaction mixture was heated at 60.degree.
C. for 1 hours. The solvent was removed in vacuo and the material
azeotroped with toluene 3.times. to remove the excess TFA. 10 ml of
2N NH.sub.3 in MeOH was added, and the solution was stirred for 20
min. The solvent was removed in vacuo and the material was purified
by prep-HPLC.
2-((3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)ami-
no)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(16 mg).
[2754] MS (ESI) m/z 531 (M+1).
[2755] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.43-9.27 (m,
1H), 8.88-8.77 (m, 1H), 8.22-8.17 (m, 1H), 8.13-8.08 (m, 1H),
7.39-7.32 (m, 1H), 3.56-3.43 (m, 3H), 3.27-3.20 (m, 1H), 3.10-2.87
(m, 5H), 1.95 (d, J=8.5 Hz, 3H), 1.89-1.81 (m, 1H), 1.80-1.73 (m,
1H), 1.71-1.61 (m, 4H), 0.79 (d, J=5.5 Hz, 4H)
Example 787
##STR00842##
[2756]
2-((3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophen-
yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2757] The title compound was prepared from
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-c-
arbonitrile using a method analogous to that used to prepare
Example 786.
[2758] MS (ESI) m/z 519 (M+1).
[2759] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.27-9.11 (m,
1H), 8.90-8.74 (m, 1H), 8.19 (s, 1H), 8.02-7.92 (m, 1H), 7.46-7.28
(m, 1H), 3.57-3.43 (m, 4H), 3.23 (s, 1H), 3.10-2.89 (m, 5H), 1.95
(d, J=8.5 Hz, 3H), 1.89-1.82 (m, 1H), 1.80-1.73 (m, 1H), 1.66 (br.
s., 4H), 1.19 (t, J=7.0 Hz, 3H)
Example 788
##STR00843##
[2760]
(+/-)-2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[-
2,3-a]pyrazin-5(3H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,-
2,4]triazine-7-carbonitrile
[2761] (788A): To a solution of tert-butyl
3-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 6.94 mmol) in DCM
(15 mL), under nitrogen at 0.degree. C., TEA (3.38 mL, 24.27 mmol)
were added, followed by the slow addition of methanesulfonyl
chloride (2.383 g, 20.81 mmol). After 12 h of vigorous stirring at
room temperature, reaction mixture was taken up with DCM/Water,
phase separated and the aqueous one back extracted with DCM.
Collected organic were dried over Na.sub.2SO.sub.4 and concentrated
under vacuum to give crude material that was purified by
chromatography on silica eluting with 0% to 20% MeOH in DCM to give
tert-butyl
4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylat-
e (1.13 g) as colorless form.
[2762] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.50-3.97 (m,
5H), 3.78-3.65 (m, 1H), 3.13-3.20 (s, 2H), 3.09 (s, 3H), 3.00 (s,
3H), 1.53-1.44 (m, 9H)
[2763] (788B): To a solution of tert-butyl
4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methylpiperazine-1-carboxylate
(1.85 g, 4.97 mmol) in dry THF (20 mL), under nitrogen at
-78.degree. C., sec-butyllithium (3.90 mL, 5.46 mmol) in Hexane
were added drop wise. After 30 min the mixture was allowed to
slowly reach room temperature. After 2.5 h the reaction was
quenched with 10 ml of water, taken up with 30 ml EtOAc and the
phases separated. The aqueous was back extracted with EtOAc
(2.times.30 ml). Collected organics were dried over
Na.sub.2SO.sub.4 and concentrated under vacuum to give crude
material that was purified by chromatography on silica eluting with
0% to 70% EtOAc in Hexane to get tert-butyl
tetrahydro-2H-isothiazolo[2,3-a]pyrazine-5(3H)-carboxylate
1,1-dioxide (296 mg) as white solid.
[2764] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 4.45-4.09 (m,
2H), 3.49-3.37 (m, 1H), 3.34-3.07 (m, 3H), 2.87-2.77 (m, 1H),
2.74-2.59 (m, 2H), 2.49-2.36 (m, 1H), 2.07-1.92 (m, 1H), 1.50 (s,
9H)
[2765] (788C): tert-butyl
tetrahydro-2H-isothiazolo[2,3-a]pyrazine-5 (3H)-carboxylate
1,1-dioxide (200 mg, 0.724 mmol) in DCM (3 mL) was treated with TFA
(1.059 mL, 13.75 mmol) at room temperature for 1 h. Solvent was
evaporated and the residue was redissolved in DCM and concentrated
again. The crude was purified by SCX cartridge, loading with MeOH,
washed with additional MeOH. Product was recovered eluting with 2M
NH.sub.3 in MeOH. Solvent evaporation give
hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (107 mg)
[2766] MS (ESI) m/z 177 (M+1).
[2767] (788D): A mixture of tert-butyl
(3-bromo-2-chloro-5-cyanophenyl)carbamate (160 mg, 0.482 mmol),
hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (85 mg, 0.482
mmol), Pd2dba3 (44.2 mg, 0.048 mmol), BINAP (90 mg, 0.145 mmol),
and Cs.sub.2CO.sub.3 (471 mg, 1.447 mmol) in Dioxane (5 mL) was
evacuated and filled with nitrogen 3.times. and heated at
105.degree. C. overnight. The reaction mixture was filtered through
a plug of celite and the filtrate was concentrated. The crude
product was purified by flash chromatography on silica gel using an
automated ISCO system (40 g column, eluting with 1-10% Methanol in
DCM) to give tert-butyl
(2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5-
(3H)-yl)phenyl)carbamate (77 mg)
[2768] MS (ESI) m/z 427 (M+1)
[2769] (788E):
tert-butyl-(2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3--
a]pyrazin-5(3H)-yl)phenyl)carbamate (70 mg, 0.164 mmol) in DCM (1
mL) was treated with TFA (0.240 mL, 3.12 mmol) at room temperature
for 2 h. Solvent was evaporated and the residue was diluted with
dichloromethane and washed with saturated sodium bicarbonate. The
aqueous layer was extracted with dichloromethane two more times.
The combined organic layers were dried over magnesium sulfate,
filtered and concentrated in vacuo, the crude product was purified
by flash chromatography on silica gel using an automated ISCO
system (24 g column, eluting with 0-5% methanol/dichloromethane).
3-amino-4-chloro-5-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(-
3H)-yl)benzonitrile (37 mg) was obtained as a yellow solid.
[2770] MS (ESI) m/z 327 (M+1)
[2771] (788F): A mixture of
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile (40.2 mg, 0.113 mmol),
3-amino-4-chloro-5-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(-
3H)-yl)benzonitrile (37 mg, 0.113 mmol), palladium(II) acetate
(6.74 mg, 0.030 mmol), XANTPHOS (6.55 mg, 0.011 mmol), DPPF (6.28
mg, 0.011 mmol) and cesium carbonate (96 mg, 0.294 mmol) in Dioxane
(2 ml) was evacuated and back filled with nitrogen three time and
was heated at 80.degree. C. for 3 h. The reaction mixture was
filtered through a celite pad and the filtrate was concentrated.
The crude product was purified by flash chromatography on silica
gel using an automated ISCO system (24 g column, eluting with 0-5%
Methanol/DCM).
2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazi-
n-5(3H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1--
f][1,2,4]triazine-7-carbonitrile (21 mg) was obtained as a light
brown solid
[2772] MS (ESI) m/z 645 (M+1)
[2773] Example 788: TFA (0.107 mL, 1.390 mmol) was added to a
solution of
2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazi-
n-5(3H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1--
f][1,2,4]triazine-7-carbonitrile (13 mg, 0.020 mmol) and anisole
(8.80 .mu.l, 0.081 mmol) in DCE (0.3 mL) and the reaction mixture
was heated at 60.degree. C. for 1 hours. The solvent was removed in
vacuo and the material azeotroped with toluene 3.times. to remove
the excess TFA. 2 ml of 2N NH.sub.3 in MeOH was added, and the
solution was stirred for 20 min. The solvent was removed in vacuo
and the material was purified by prep-HPLC to give
2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazi-
n-5
(3H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-
e-7-carbonitrile (5.1 mg)
[2774] MS (ESI) m/z 525 (M+1)
[2775] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.43-9.26 (m,
1H), 8.92 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.40 (s, 1H),
3.53-3.43 (m, 2H), 3.32-3.22 (m, 2H), 3.05-2.94 (m, 1H), 2.87 (br.
s., 2H), 2.74 (s, 3H), 2.46-2.33 (m, 1H), 2.08-1.89 (m, 1H), 0.79
(d, J=5.5 Hz, 4H)
Example 789
##STR00844##
[2776]
N-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)acetamide
[2777] The title compound was prepared from tert-butyl
piperazin-1-ylcarbamate Using a method to prepare Intermediate 11
and method analogous to that used to prepare Example 1
[2778] HPLC Rt, 0.88 min.
[2779] MS (ESI) m/z 491 (M+1)
Example 790
##STR00845##
[2780] methyl
(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4-
]triazin-2-yl)amino)phenyl)piperazin-1-yl)carbamate
[2781] The title compound was prepared using a method analogous to
that used to prepare Example 1
[2782] HPLC Rt, 0.95 min.
[2783] MS (ESI) m/z 507 (M+1).
Example 791
##STR00846##
[2784]
2-((4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)amino)acetamide
[2785] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2786] HPLC Rt, 0.69 min.
[2787] MS (ESI) m/z 507 (M+1).
Example 792
##STR00847##
[2788]
2-((2-chloro-5-cyano-3-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-
-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2789] The title compound was prepared from tert-butyl
2,7-diazaspiro[3.5]nonane-2-carboxylate using a method to prepare
Intermediate 11 and method analogous to that used to prepare
Example 1.
[2790] HPLC Rt, 0.8 min.
[2791] MS (ESI) m/z 475 (M+1)
Example 793
##STR00848##
[2792]
2-((3-(2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)-2-chloro-5-cyanophen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2793] The title compound was prepared using a method analogous to
that used to prepare Example 480 from example 792
[2794] HPLC Rt, 0.96 min.
[2795] MS (ESI) m/z 517 (M+1)
Example 794
##STR00849##
[2796]
(R)-2-((2-chloro-5-cyano-3-(2-(2-hydroxypropanoyl)-2,7-diazaspiro[3-
.5]nonan-7-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile
[2797] The title compound was prepared using a method analogous to
that used to prepare Example 793
[2798] HPLC Rt, 0.96 min.
[2799] MS (ESI) m/z 547 (M+1)
Example 795
##STR00850##
[2800]
(S)-2-((2-chloro-5-cyano-3-(2-(2-hydroxypropanoyl)-2,7-diazaspiro[3-
.5]nonan-7-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triaz-
ine-7-carbonitrile
[2801] The title compound was prepared using a method analogous to
that used to prepare Example 794
[2802] HPLC Rt, 0.94 min.
[2803] MS (ESI) m/z 547 (M+1)
Example 796
##STR00851##
[2804]
(+/-)-2-((2-chloro-5-cyano-3-(2-(3-fluoro-2-hydroxypropyl)-2,7-diaz-
aspiro[3.5]nonan-7-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2-
,4]triazine-7-carbonitrile
[2805] The title compound was prepared using a method analogous to
that used to prepare Example 52 from example 792
[2806] HPLC Rt, 0.85 min.
[2807] MS (ESI) m/z 551 (M+1)
Example 797
##STR00852##
[2808]
(+/-)-2-((2-chloro-5-cyano-3-(2-(2-hydroxypropyl)-2,7-diazaspiro[3.-
5]nonan-7-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazi-
ne-7-carbonitrile
[2809] The title compound was prepared using a method analogous to
that used to prepare example 52
[2810] HPLC Rt, 0.76 min.
[2811] LC/MS: m/z 533 (M+1)
Example 798
##STR00853##
[2812]
2-((2-chloro-5-cyano-3-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2813] The title compound was prepared using a method analogous to
that used to prepare Example 1
[2814] HPLC Rt, 0.75 min.
[2815] MS (ESI) m/z 489 (M+1)
Example 799
##STR00854##
[2816]
2-(7-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-N-methy-
lacetamide
[2817] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2818] HPLC Rt, 0.74 min.
[2819] MS (ESI) m/z 546 (M+1)
Example 800
##STR00855##
[2820]
2-(7-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)acetamid-
e
[2821] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2822] HPLC Rt, 0.72 min.
[2823] MS (ESI) m/z 532 (M+1)
Example 801
##STR00856##
[2824]
2-((2-chloro-5-cyano-3-(2-ethyl-2,7-diazaspiro[3.5]nonan-7-yl)pheny-
l)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2825] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2826] HPLC Rt, 0.76 min.
[2827] MS (ESI) m/z 503 (M+1)
Example 802
##STR00857##
[2828]
(+/-)-2-(7-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidaz-
o[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)pr-
opanamide
[2829] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2830] HPLC Rt, 0.73 min.
[2831] MS (ESI) m/z 546 (M+1)
Example 803
##STR00858##
[2832]
2-(7-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1--
f][1,2,4]triazin-2-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methy-
lpropanamide
[2833] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2834] HPLC Rt, 0.74 min.
[2835] LC/MS: m/z 560 (M+1)
Example 804
##STR00859##
[2836]
2-((2-chloro-5-cyano-3-(2-(2-oxo-2-(piperazin-1-yl)ethyl)-2,7-diaza-
spiro[3.5]nonan-7-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,-
4]triazine-7-carbonitrile
[2837] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2838] HPLC Rt, 0.69 min.
[2839] LC/MS: m/z 601 (M+1)
Example 805
##STR00860##
[2840]
2-((2-chloro-5-cyano-3-(2-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-
,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-
-f][1,2,4]triazine-7-carbonitrile
[2841] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2842] HPLC Rt, 0.74 min.
[2843] MS (ESI) m/z 582 (M+1)
Example 806
##STR00861##
[2844]
2-((3-(7-acetyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-chloro-5-cyanophen-
yl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2845] The title compound was prepared from tert-butyl
2,7-diazaspiro[3.5]nonane-7-carboxylate using a method to prepare
Intermediate 11 and method analogous to that used to prepare
Example 52.
[2846] HPLC Rt, 0.91 min.
[2847] MS (ESI) m/z 517 (M+1)
Example 807
##STR00862##
[2848]
(+/-)-2-((2-chloro-5-cyano-3-(7-(3-fluoro-2-hydroxypropyl)-2,7-diaz-
aspiro[3.5]nonan-2-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2-
,4]triazine-7-carbonitrile
[2849] The title compound was prepared using a method analogous to
that used to prepare Example 52
[2850] HPLC Rt, 0.75 min.
[2851] MS (ESI) m/z 551 (M+1)
Example 808
##STR00863##
[2852]
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-
-3-yl 2-amino-5-guanidinopentanoate trihydrochloride
[2853] (808A): To a solution of (Example 328) methyl
((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2-
,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (50
mg, 0.098 mmol), BOC-ARG(BOC)2-OH (96 mg, 0.202 mmol), DMAP (2.391
mg, 0.020 mmol) and DCC (60.6 mg, 0.294 mmol) were dissolved in DCM
(5 mL) under nitrogen. The reaction mixture was stirred at room
temperature 12 hr; the LCMS showed complete conversion. The solvent
was removed and the material was diluted with acetone and filtered
(removes 1,3-dicyclohexylurea).
[2854] The solvent was removed and the material was diluted with
DCM and applied on a silica gel column eluting with 10-80%
Acetone-Hexane to afford
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[-
2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidi-
n-3-yl
5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-2-((tert-butoxycarbon-
yl)amino)pentanoate (94 mg).
[2855] MS (ESI): m/z 967 (M+1)
[2856] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.23-9.17 (m,
1H), 9.13-8.98 (m, 2H), 8.90-8.83 (m, 1H), 8.25-8.16 (m, 1H),
8.03-7.97 (m, 1H), 7.33-7.28 (m, 1H), 7.28-7.16 (m, 2H), 4.88-4.76
(m, 1H), 3.99-3.91 (m, 1H), 3.82-3.73 (m, 2H), 3.59-3.51 (m, 3H),
3.49-3.42 (m, 2H), 3.42-3.36 (m, 1H), 3.29-3.22 (m, 1H), 2.93-2.83
(m, 1H), 2.78-2.68 (m, 1H), 1.98-1.90 (m, 1H), 1.78-1.68 (m, 2H),
1.66-1.52 (m, 4H), 1.46 (s, 9H), 1.39 (s, 18H), 1.21-1.15 (m,
3H)
[2857] Example 808:
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-2-((tert-butoxycarbonyl)ami-
no)pentanoate (93 mg, 0.096 mmol) in a 20 mL microwave flask was
added Acetonitrile (3 mL) and 14 eq HCl (40 .mu.l, 1.316 mmol). The
flask was caped and the reaction stirred at 70.degree. C. 2 hr
(amino acids other then Arginine were run at room temperature). The
reaction was complete by LCMS and the mixture stirred at room
temperature overnight to precipitate
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
2-amino-5-guanidinopentanoate, 3 HCl (31 mg) as a white solid.
[2858] MS (ESI): m/z 667 (M+1)
[2859] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.28-9.18 (m,
1H), 8.94-8.82 (m, 1H), 8.57-8.40 (m, 3H), 8.22 (s, 1H), 8.07-7.97
(m, 1H), 7.74-7.62 (m, 1H), 7.40-7.29 (m, 2H), 5.00-4.84 (m, 1H),
4.09-3.98 (m, 1H), 3.75-3.65 (m, 1H), 3.62-3.54 (m, 3H), 3.53-3.43
(m, 3H), 3.19-3.06 (m, 2H), 2.96-2.78 (m, 2H), 2.07-1.96 (m, 1H),
1.88-1.71 (m, 3H), 1.70-1.58 (m, 1H), 1.57-1.45 (m, 1H), 1.26-1.12
(m, 3H)
[2860] The compounds listed below were prepared by the similar
synthetic procedure used for Example 808
TABLE-US-00037 TABLE 34 Ex- HPLC am- Retention ple Time No.
Structure Name [M + H].sup.+ (min.)* 809 ##STR00864##
(S)-(3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2-amino-3-(1H-
imidazol-5-yl)propanoate dihydrochloride 648.00 3.12 810
##STR00865## (2S,3R)-(3R,4R)-1-(2-chloro- 5-cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2-amino-3- hydroxybutanoate
hydrochloride 612.32 3.38 811 ##STR00866##
(S)-(3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2,5- diaminopentanoate
dihydrochloride 625.36 3.12 812 ##STR00867##
(S)-(3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2,4- diaminobutanoate
dihydrochloride 611.34 3.12 813 ##STR00868##
(S)-(3R,4R)-1-(2-chloro-5- yano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl pyrrolidine-2- carboxylate
hydrochloride 608.35 3.38 814 ##STR00869##
(S)-5-((3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl) 1-methyl 2-
aminopentanedioate hydrochloride 654.38 3.42 815 ##STR00870##
(S)-1-tert-butyl 4-((3R,4R)-1- (2-chloro-5-cyano-3-((7-cyano-
4-(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl) 2-aminosuccinate
hydrochloride 682.44 3.58 816 ##STR00871##
(3R,4R)-1-(2-chloro-5-cyano- 3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 5-aminopentanoate
hydrochloride 610.37 3.40 817 ##STR00872##
(3R,4R)-1-(2-chloro-5-cyano- 3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 4-aminobutanoate
hydrochloride 596.34 3.41 818 ##STR00873##
(R)-(3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2,4-diamino-4- oxobutanoate
hydrochloride 625.5 2.29.sup.b 819 ##STR00874##
(S)-(3R,4R)-1-(2-chloro-5- cyano-3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 3-amino-5- methylhexanoate
hydrochloride 638.6 2.63.sup.b 820 ##STR00875##
(3R,4R)-1-(2-chloro-5-cyano- 3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2-((1r,4R)-4-
aminocyclohexyl)acetate hydrochloride 650.6 2.54.sup.b 821
##STR00876## (3R,4R)-1-(2-chloro-5-cyano- 3-((7-cyano-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazin-2- yl)amino)phenyl)-4-
((methoxycarbonyl)amino) piperidin-3-yl 2-((S)-2-
aminopropanamido)acetate hydrochloride 639.5 2.36.sup.b HPLC
conditions; .sup.b = HPLC conditions *PHENOMENEX-LUNA 2.0 .times.
50 mm 3 um, 0-100% aqueous methanol containing 0.1% TFA min.
gradient, Gradient Time = 4 min, Flow Rate = .8 ml/min, monitored
at 254 nm .sup.bPHENOMENEX-LUNA 2.0 .times. 50 mm 3 um, 0-100%
aqueous acetonitrile containing 0.1% TFA min. gradient, Gradient
Time = 4 min, Flow Rate = .8 ml/min, monitored at 220 nm
Example 822
##STR00877##
[2861]
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-
-3-yl 2-((S)-2,6-diaminohexanamido)-3-methylbutanoatete
dihydrochloride
[2862] (822A):
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
2-amino-3-methylbutanoate dihydrochloride was prepared by the
synthetic procedure used for Example 821A
[2863] MS (ESI): m/z 610 (M+1)
[2864] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.27-9.15 (m,
1H), 8.89 (s, 1H), 8.50-8.35 (m, 3H), 8.21 (s, 1H), 8.06-7.95 (m,
1H), 7.42-7.28 (m, 2H), 5.06-4.88 (m, 1H), 3.93-3.84 (m, 2H), 3.56
(s, 4H), 3.50-3.41 (m, 2H), 3.30-3.19 (m, 1H), 2.99-2.90 (m, 1H),
2.89-2.79 (m, 1H), 2.23-2.12 (m, 1H), 2.04-1.94 (m, 1H), 1.83-1.69
(m, 1H), 1.25-1.13 (m, 3H), 1.03-0.86 (m, 6H)
[2865] Example 822: To an ice cooled solution of
(S)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid (30 mg, 0.087
mmol) in dry DCM (1 mL) was added TBTU (27.5 mg, 0.086 mmol) and
TEA (0.030 mL, 0.214 mmol) under N.sub.2 atmosphere. The reaction
mixture was stirred 0.5 h at the same temperature and
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
2-amino-3-methylbutanoate dihydrochloride (36.5 mg, 0.053 mmol) was
added. The reaction stirred 1 h at room temperature; the LCMS
showed complete conversion. The reaction mixture was diluted with
DCM, washed with water, and dried over Na.sub.2SO.sub.4. The
solvent was removed and the reaction mixture was taken-up in DCM
and purified on a silica gel column: eluting with 10-80%
acetone-hexane to afford
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
2-((S)-2,6-bis((tert-butoxycarbonyl)amino)hexanamido)-3-methylbutanoate.
[2866] To this intermediate was added acetonitrile (2 mL) and HCl
(0.013 mL, 0.428 mmol) (8 eq); the reaction stirred at room
temperature overnight (Arginine stirred at 70.degree. C. 2 h) to
precipitate
(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][-
1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl
2-((S)-2,6-diaminohexanamido)-3-methylbutanoate, 2 HCl (15 mg) as a
white solid.
[2867] MS (ESI): m/z 738 (M+1)
[2868] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. 8.48 (d,
J=1.7 Hz, 1H), 8.02 (s, 1H), 7.29-7.15 (m, 1H), 5.03-4.94 (m, 1H),
4.46-4.32 (m, 1H), 4.06-3.97 (m, 1H), 3.84-3.75 (m, 1H), 3.68 (d,
J=7.1 Hz, 5H), 3.64-3.55 (m, 1H), 3.10-3.01 (m, 2H), 2.99-2.90 (m,
1H), 2.81-2.70 (m, 1H), 2.32-2.21 (m, 1H), 2.16-2.10 (m, 1H),
2.04-1.85 (m, 3H), 1.85-1.75 (m, 2H), 1.68-1.55 (m, 2H), 1.36 (s,
3H), 1.32 (s, 4H), 1.03 (s, 6H)
[2869] The compound listed below was prepared by the similar
synthetic procedure used for Example 822
TABLE-US-00038 TABLE 35 HPLC Ex- Reten- am- tion ple [M + Time No.
Structure Name H].sup.+ (min.)* 823 ##STR00878## (S)-(3R,4R)-1-(2-
chloro-5-cyano-3-((7- cyano-4-(ethylamino) imidazo[2,1-f]
[1,2,4]triazin-2- yl)amino)phenyl)-4- ((methoxycarbonyl)
amino)piperidin- 3-yl 2-((S)-2- amino-5- guanidinopentan- amido)-3-
methylbutanoate trihydrochloride 766.53 3.32* * = HPLC conditions
*PHENOMENEX-LUNA 2.0 .times.50 mm 3 um, 0-100% aqueous methanol
containing 0.1% TFA min. gradient, Gradient Time = 4 min, Flow Rate
= .8 ml/min, monitored at 254 nm
[2870] The compounds listed below were prepared by the similar
synthetic procedure used for Example 394
TABLE-US-00039 TABLE 36 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 824 ##STR00879##
(+/-)-2-((3-cyano-1-(1-(3- fluoro-2- hydroxypropyl)piperidin-
4-yl)-1H-indol-5- yl)amino)-4- (ethylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 503.4 2.37 825 ##STR00880##
(+/-)-2-((3-cyano-1-(1-(4- hydroxytetrahydrofuran-
3-yl)piperidin-4-yl)-1H- indol-5-yl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 513.4
2.14 826 ##STR00881## 2-((3-cyano-1-(1- ((3S,4R)-4-
hydroxytetrahydrofuran- 3-yl)piperidin-4-yl)-1H-
indol-5-yl)amino)-4- (ethylamino)imidazo[2,1- f][1,2,4]triazine-7-
carbonitrile 513.4 2.11 827 ##STR00882## 2-((3-cyano-1-(1-
((3S,4R)-4- hydroxytetrahydrofuran- 3-yl)piperidin-4-yl)-1H-
indol-5-yl)amino)-4- (ethylamino)imidazo[2,1- f][1,2,4]triazine-7-
carbonitrile 513.4 2.10 828 ##STR00883## 2-((3-cyano-1-(1-
((3R,4R)-4-hydroxy-1,1- dioxidotetrahydrothiophen-
3-yl)piperidin-4-yl)- 1H-indol-5-yl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 561.5
2.22 829 ##STR00884## 2-((3-cyano-1-(1- ((3R,45)-4-hydroxy-1,1-
dioxidotetrahydrothiophen- 3-yl)piperidin-4-yl)-
1H-indol-5-yl)amino)-4- (ethylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 561.3 2.42 830 ##STR00885##
(R)-2-((3-cyano-1-(1-(2- hydroxy-3- morpholinopropyl)piperidin-
4-yl)-1H-indol-5- yl)amino)-4- (ethylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 570.6 2.13 * = HPLC conditions
*Waters BEH C18, 2.0 .times. 50 mm, 1.7-.mu.m particles; Mobile
Phase A: 5:95 Acetonitrile: water with 10 mM ammonium acetate;
Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium
acetate; Temperature: 40.degree. C.; Gradient: 0.5 min hold at 0%
B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow:
1 mL/min; Detection: UV at 220 nm.
Example 831
##STR00886##
[2871] tert-butyl
3-(4-(3-cyano-5-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl-
)amino)-1H-indol-1-yl)piperidin-1-yl)azetidine-1-carboxylate
[2872] This compound was prepared by the synthetic procedure used
for Example 396
[2873] MS (ESI): m/z 582 (M+1)
[2874] .sup.1H NMR (500 MHz, Acetone) .delta. 8.31-8.25 (m, 1H),
8.15-8.08 (m, 1H), 8.02 (s, 1H), 7.84-7.79 (m, 1H), 7.74-7.68 (m,
1H), 7.66-7.60 (m, 1H), 7.36-7.27 (m, 1H), 4.61-4.48 (m, 1H),
4.11-3.99 (m, 2H), 3.91-3.82 (m, 2H), 3.82-3.74 (m, 2H), 3.32-3.22
(m, 1H), 3.15-3.07 (m, 2H), 2.23 (s, 4H), 2.13-2.11 (m, 1H), 1.56
(s, 10H), 1.46 (s, 3H)
Example 832
##STR00887##
[2875]
2-((1-(1-(azetidin-3-yl)piperidin-4-yl)-3-cyano-1H-indol-5-yl)amino-
)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2876] This compound was prepared by the deprotection procedure
used for Example 394
[2877] MS (ESI): m/z 482 (M+1)
[2878] The compounds listed below were prepared by the similar
synthetic procedure used for Example 394
TABLE-US-00040 TABLE 37 HPLC Retention Example Time No. Structure
Name [M + H].sup.+ (min.)* 833 ##STR00888##
(R)-2-((3-cyano-1-(1-(1-(2- hydroxypropyl)azetidin-
3-yl)piperidin-4-yl)-1H- indol-5-yl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 540.5
2.39 834 ##STR00889## (S)-2-((3-cyano-1-(1-(1-(2-
hydroxypropyl)azetidin- 3-yl)piperidin-4-yl)-1H-
indol-5-yl)amino)-4- (ethylamino)imidazo[2,1- f][1,2,4]triazine-7-
carbonitrile 540.4 2.23 * = HPLC conditions Waters BEH C18, 2.0
.times. 50 mm, 1.7-.mu.m particles; Mobile Phase A: 5:95
Acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature:
40.degree. C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4
minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min;
Detection: UV at 220 nm.
Example 835
##STR00890##
[2879]
2-((3-cyano-1-(1-(1-(oxetan-3-yl)azetidin-3-yl)piperidin-4-yl)-1H-i-
ndol-5-yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitril-
e
[2880] This compound was prepared by the deprotection procedure
used for Example 374
[2881] MS (ESI): m/z 538 (M+1)
Example 836
##STR00891##
[2882] methyl
3-(4-(3-cyano-5-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl-
)amino)-1H-indol-1-yl)piperidin-1-yl)azetidine-1-carboxylate
[2883] This compound was prepared by the deprotection procedure
used for Example 372
[2884] MS (ESI): m/z 540 (M+1)
Example 837
##STR00892##
[2885]
2-((1-(1-(1-acetylazetidin-3-yl)piperidin-4-yl)-3-cyano-1H-indol-5--
yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2886] This compound was prepared by the deprotection procedure
used for Example 319
[2887] MS (ESI): m/z 524 (M+1)
Example 838
##STR00893##
[2888] (+/-)-2-((2-chloro-5-cyano-3-((3
aR,7aR)-1-(oxetan-3-yl)-2-oxohexahydrooxazolo[5,4-c]pyridin-5(2H)-yl)phen-
yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
[2889] (838A): (+/-)-tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)ph-
enyl)piperidin-4-yl)carbamate was prepared starting from
(+/-)-methyl
((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)o-
xy)piperidin-4-yl)carbamate and intermediate 10 according to
procedure for Example 1G.
[2890] (838B): To (+/-)-tert-butyl
((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-
-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)ph-
enyl)piperidin-4-yl)carbamate (600 mg, 0.762 mmol) in acetonitrile
(19 mL) at 5.degree. C. was added HF (1 mL); the reaction wormed to
25.degree. C. stirring 4 hr. The LCMS confirms the formation of the
desired material and solvents were removed. The crude material was
diluted with EtOAc and washed 4.times. with sat. NaHCO.sub.3,
water, and brine. The solvent dried over Na.sub.2SO.sub.4 and
solvent removed to afford
(+/-)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (470 mg).
[2891] MS (ESI): m/z 573 (M+1)
[2892] (838C):
(+/-)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7--
carbonitrile (390 mg, 0.681 mmol) was mixed with anisole (0.372 mL,
3.40 mmol) and DCE (3 mL). TFA (1.049 mL, 13.61 mmol) was added and
the mixture was stirred at 25.degree. C. for 1 hr. The mixture was
concentrated to dryness under high-vac. 30 ml 2N NH.sub.3/MeOH was
added and stirred for 30 min. The white precipitate was collected
by filtration and washed with 20 ml cold MeOH, ether, and dried
under air-suction for 2 hrs to give
rac-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanopheny-
l)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(193 mg).
[2893] MS (ESI): m/z 453 (M+1)
[2894] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.98-8.64 (m,
1H), 8.20 (s, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.31 (d, J=1.9 Hz, 1H),
5.16-4.88 (m, 1H), 3.57-3.40 (m, 2H), 3.29-3.14 (m, 3H), 2.83-2.68
(m, 1H), 2.48-2.39 (m, 2H), 2.15-2.01 (m, 1H), 1.87-1.76 (m, 1H),
1.50-1.38 (m, 1H), 1.20 (s, 3H)
[2895] (838D):
(+/-)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophe-
nyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
(80 mg, 0.177 mmol) was taken up in MeOH (1.0 mL) and DMF (1.0 mL)
and trimethyl orthoformate (1.464 mL, 13.25 mmol), AcOH (0.040 mL,
0.707 mmol), and oxetan-3-one (0.113 mL, 1.766 mmol) were added.
The reaction was stirred at room temperature for 2 h, then
NaCNBH.sub.3 (111 mg, 1.766 mmol) was added and the reaction
stirred at 25.degree. C. overnight.
[2896] The reaction mixture was diluted with EtOAc; washed with
saturated NaHCO3, and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated. The material was purified on
silica gel 5% MeOH-DCM to afford 838D,
rac-2-((2-chloro-5-cyano-3-43R,4R)-3-hydroxy-4-(oxetan-3-ylamino)piperidi-
n-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carboni-
trile (90 mg) as a white solid.
[2897] MS (ESI): m/z 509 (M+1)
[2898] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.29-9.11 (m,
1H), 8.94-8.72 (m, 1H), 8.20 (s, 1H), 8.05-7.87 (m, 1H), 7.39-7.22
(m, 1H), 5.08-4.91 (m, 1H), 4.73-4.54 (m, 2H), 4.42-4.24 (m, 2H),
4.14-3.95 (m, 1H), 3.52-3.42 (m, 2H), 3.42-3.35 (m, 2H), 3.26-3.14
(m, 1H), 2.78-2.62 (m, 1H), 2.49-2.43 (m, 1H), 2.35-2.22 (m, 1H),
1.88-1.76 (m, 1H), 1.47-1.30 (m, 1H), 1.19 (s, 3H)
[2899] Example 838: To
(+/-)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(oxetan-3-ylamino)piper-
idin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carb-
onitrile (90 mg, 0.177 mmol) in DMF (5 mL) was added
1,1'-carbonyldiimidazole (200 mg, 1.233 mmol) and the reaction
stirred at 25.degree. C. 16 hr. The crude material was purified via
preparative LC/MS with the following conditions: Column: XBridge
C18, 19.times.mm, 5-.mu.m particles; Mobile Phase A: 5:95
acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B:
95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient:
30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20
mL/min. Fractions containing the desired product were combined and
dried via centrifugal evaporation to afford
rac-2-((2-chloro-5-cyano-3-((3aR,7aR)-1-(oxetan-3-yl)-2-oxohexahydrooxazo-
lo[5,4-c]pyridin-5
(2H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbo-
nitrile (48.8 mg).
[2900] MS (ESI): m/z 535 (M+1)
[2901] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39-9.11 (m,
1H), 9.03-8.81 (m, 1H), 8.20 (s, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.49
(d, J=1.7 Hz, 1H), 4.82 (s, 3H), 4.76-4.66 (m, 2H), 4.19-4.06 (m,
1H), 3.74-3.60 (m, 2H), 3.47 (s, 3H), 3.20-3.16 (m, 1H), 3.01-2.91
(m, 1H), 2.35-2.25 (m, 1H), 2.07-1.93 (m, 1H), 1.20 (t, J=7.2 Hz,
3H)
[2902] The compounds listed below were prepared by the similar
synthetic procedure used for Example 838.
TABLE-US-00041 TABLE 38 Chiral HPLC SFC Retention Retention Example
Time Time No. Structure Name [M + H].sup.+ (min.).sup.a
(min.).sup.b,c 839 ##STR00894## 2-((2-chloro-5-cyano-3-
((3aR,7aR)-1-(oxetan-3-yl)- 2-oxohexahydrooxazolo
[5,4-c]pyridin-5(2H)- yl)phenyl)amino)-4- (ethylamino)imidazo[2,1-
f][1,2,4]triazine-7- carbonitrile 535.2 3.87 41.69 840 ##STR00895##
2-((2-chloro-5-cyano-3- ((3aS,7aS)-1-(oxetan-3-yl)-
2-oxohexahydrooxazolo [5,4-c]pyridin-5(2H)- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 535.2
3.88 39.69 841 ##STR00896## 2-((2-chloro-5-cyano-3-
((3aR,7aR)-2-oxo-1-((S)- tetrahydrofuran-3-
yl)hexahydrooxazolo[5,4- c]pyridin-5(2H)- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 549.3
3.80 33.11 842 ##STR00897## 2-((2-chloro-5-cyano-3-
((3aR,7aR)-2-oxo-1-((S)- tetrahydrofuran-3-
yl)hexahydrooxazolo[5,4- c]pyridin-5(2H)- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 549.3
4.16 35.25 843 ##STR00898## 2-((2-chloro-5-cyano-3-
((3aR,7aR)-2-oxo-1-((S)- tetrahydrofuran-3-
yl)hexahydrooxazolo[5,4- c]pyridin-5(2H)- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 549.3
4.16 36.77 844 ##STR00899## 2-((2-chloro-5-cyano-3-
((3aR,7aR)-2-oxo-1-((S)- tetrahydrofuran-3-
yl)hexahydrooxazolo[5,4- c]pyridin-5(2H)- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 549.3
4.16 37.84 845 ##STR00900## 2-((2-chloro-5-cyano-3-
((3aR,7aR)-2-oxo-1- (tetrahydro-2H-pyran-4-
yl)hexahydrooxazolo[5,4- c]pyridin-5(2H)- yl)phenyl)amino)-4-
(ethylamino)imidazo[2,1- f][1,2,4]triazine-7- carbonitrile 563.3
3.96 39.4 .sup.(1)The compound was prepared by the similar
synthetic procedure used for Example 838 using chiral intermediate
(375B)HPLC conditions; .sup.b,c = Chiral SFC .sup.aWaters BEH C18,
2.0 .times. 50 mm, 1.7-.mu.m particles; Mobile Phase A: 5:95
methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5
methanol:water with 10 mM ammonium acetate; Temperature: 40.degree.
C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a
0.5-minute hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220
nm. Chiralpak IB preparative column, 30 .times. 250 mm, 5 .mu.m;
Mobile Phase: 90% MeOH (0.1% DEA) in CO2, 100 bar; Temp: 35.degree.
C.; Flow rate: 40.0 mL/min. for 22 min. UV monitored @ 254 nm
Injection: 0.75 ml of ~5mg/mL solution in 1:1:1 DMSO:MeOH:CHCl3
(~44 mg purified by stacked injection) .sup.cChiralpak IB
preparative column, 30 .times. 250 mm, 5 .mu.m; Mobile Phase: 90%
EtOH (0.1% DEA) in CO2, 100 bar; Temp: 35.degree. C.; Flow rate:
40.0 mL/min. for 22 min. UV monitored @ 254 nm Injection: 0.45 ml
of ~5 mg/mL solution in 1:1 MeOH: DMSO (~29 mg purified by stacked
injection)
Example 846
##STR00901##
[2903] (3R,4R)-methyl
4-((2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate
[2904] (846A): A solution of
(3R,4R)-4-((E)-(4-methoxybenzylidene)amino)piperidin-3-ol (400 mg,
1.707 mmol) and DIPEA (0.447 mL, 2.56 mmol) in MeOH (50 mL) at
0.degree. C. (ice bath) was treated with Methyl Chlorocarbonate (1
mL, 12.94 mmol). The reaction was stirred for 12 hour, and then the
mixture was concentrated. The crude material was diluted with MeOH
and applied on a SCX column (Phenomenex, Strata XC). The column was
eluted with 2N ammonia in methanol and solvent removed to afford
(3R,4R)-methyl
3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate
(499 mg).
[2905] 1H NMR (500 MHz, MeOH-d4) .delta. ppm 8.33 (s, 1H), 7.74 (d,
J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.26 (br, 1H), 4.13 (br. d.,
J=13 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.63-3.57 (m, 1H), 3.18
(q, J=8 Hz, 1H), 2.93 (br, 1H), 2.77 (br, 1H), 1.83-1.77 (m, 1H),
1.37-1.32 (m, 1H).
[2906] (846B): To a solution of (3R,4R)-methyl
3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate
(499 mg, 1.707 mmol) in MeOH (17 ml) was added water (1 ml, 55.5
mmol) and TFA (2 ml, 26.0 mmol). The reaction was stirred at
50.degree. C. overnight. The reaction mixture was applied on a SCX
column (Phenomenex, Strata XC) and eluted with 2N ammonia in
methanol. The solvents removed to afford (3R,4R)-methyl
4-amino-3-hydroxypiperidine-1-carboxylate (290 mg).
[2907] 1H NMR (500 MHz, MeOH-d4) .delta. ppm 4.21 (br, 1H), 4.11
(br. d., J=12.5 Hz, 1H), 3.71 (s, 3H), 3.30-3.24 (m, 1H), 2.87 (br,
1H), 2.81-2.75 (m, 1H), 2.64 (br, 1H), 1.97-1.90 (m, 1H), 1.46-1.36
(m, 1H).
[2908] (846C): A mixture of 3,5-dibromo-4-chlorobenzonitrile (160
mg, 0.542 mmol), (3R,4R)-methyl
4-amino-3-hydroxypiperidine-1-carboxylate (88 mg, 0.505 mmol),
Pd.sub.2(dba).sub.3 (69.4 mg, 0.076 mmol), BINAP (47.2 mg, 0.076
mmol), and Cs.sub.2CO.sub.3 (494 mg, 1.516 mmol) in a dry microwave
vial was flushed with nitrogen. Toluene (3.7 mL) was added and the
vial was sealed and heated at 105.degree. C. for 4 hours. The
reaction was partitioned between EtOAc and water. The organic phase
was washed with brine and dried with sodium sulfate. Removal of the
solvent followed by silica gel chromatography eluting with hexane
containing 20% to 50% EtOAc afforded (3R,4R)-methyl
4-((3-bromo-2-chloro-5-cyanophenyl)amino)-3-hydroxypiperidine-1-carboxyla-
te (20 mg).
[2909] MS (ESI): m/z 386/388/390 ([M-H
[2910] 1H NMR (500 MHz, MeOH-d4) .delta. ppm 7.28 (d, J=1.5 Hz,
1H), 7.25 (d, J=1.5 Hz, 1H), 4.22 (br, 1H), 4.08 (br. d., J=11.5
Hz, 1H), 3.71 (s, 3H), 3.59-3.53 (m, 1H), 3.52-3.46 (m, 1H), 3.03
(br, 1H), 2.84 (br, 1H), 2.08-2.02 (m, 1H), 1.56-1.47 (m, 1H).
[2911] Example 846: A oven-dried 10 ml microwave flask was loaded
with
2-amino-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-ca-
rbonitrile (16 mg, 0.049 mmol), (3R,4R)-methyl
4-((3-bromo-2-chloro-5-cyanophenyl)amino)-3-hydroxypiperidine-1-carboxyla-
te (19 mg, 0.049 mmol), Pd(OAc)2 (3 mg, 0.013 mmol), XANTPHOS (8
mg, 0.014 mmol) and Cs2CO3 (50 mg, 0.153 mmol). The flask was
evacuated and back-filled with nitrogen 4 times. 1,4-Dioxane (0.5
mL) was added and the flask was again evacuated and back-filled
with nitrogen 4 times, then heated with stirring to 70.degree. C.
for 2 hours. The reaction is complete by LCMS analysis. The
reaction mixture was diluted with EtOAc, washed with water, brine
and dried over Na.sub.2SO.sub.4. The solvent removed to afford
(3R,4R)-methyl
4-((2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxy-
late (30.9 mg). The material was used as is.
[2912] MS (ESI): m/z 631.25 (M+1)
[2913] To (3R,4R)-methyl
4-((2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2-
,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxy-
late (30.9 mg, 0.049 mmol) was added DCE (3 mL), anisole (5.35
.mu.l, 0.049 mmol) and TFA (0.5 mL, 6.49 mmol); the reaction
stirred 2 hr at 40.degree. C. and solvents removed. The crude
material was purified via preparative LC/MS with the following
conditions: Column: XBridge C18, 19.times.200 mm, 5-.mu.m
particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with
10-mM ammonium acetate; Gradient: 10-60% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to afford (3R,4R)-methyl
4-((2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triaz-
in-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate (5.1
mg).
[2914] MS (ESI): m/z 511.2 (M+1)
[2915] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.24-9.03 (m,
1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.06 (s, 1H),
5.53-5.39 (m, 1H), 5.32-5.18 (m, 1H), 4.11-3.95 (m, 1H), 3.95-3.78
(m, 1H), 3.60 (s, 5H), 3.07-2.85 (m, 1H), 2.83-2.60 (m, 1H),
1.98-1.83 (m, 1H), 1.51-1.34 (m, 1H), 1.19 (t, J=7.2 Hz, 3H)
* * * * *