U.S. patent application number 13/890949 was filed with the patent office on 2013-10-03 for methods of use of diazacarbazoles for treating cancer.
This patent application is currently assigned to Genentech, Inc.. The applicant listed for this patent is Genentech, Inc.. Invention is credited to Huifen Chen, Hazel Joan Dyke, Charles Ellwood, Emanuela Gancia, Lewis J. Gazzard, Simon Goodacre, Samuel Kintz, Joseph Lyssikatos, Calum MacLeod, Karen Williams.
Application Number | 20130261104 13/890949 |
Document ID | / |
Family ID | 41066724 |
Filed Date | 2013-10-03 |
United States Patent
Application |
20130261104 |
Kind Code |
A1 |
Chen; Huifen ; et
al. |
October 3, 2013 |
METHODS OF USE OF DIAZACARBAZOLES FOR TREATING CANCER
Abstract
Methods of use of compounds of formula (I) for treating cancer:
##STR00001## wherein X, Y, X, R.sup.3, R.sup.5 and R.sup.6 are as
defined herein.
Inventors: |
Chen; Huifen; (Burlingame,
CA) ; Dyke; Hazel Joan; (Harlow, UK) ;
Ellwood; Charles; (Harlow, UK) ; Gancia;
Emanuela; (Harlow, UK) ; Gazzard; Lewis J.;
(Belmont, CA) ; Goodacre; Simon; (Harlow, UK)
; Kintz; Samuel; (Redwood City, CA) ; Lyssikatos;
Joseph; (Piedmont, CA) ; MacLeod; Calum;
(Harlow, UK) ; Williams; Karen; (Harlow,
UK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
41066724 |
Appl. No.: |
13/890949 |
Filed: |
May 9, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12997066 |
Jan 31, 2011 |
8501765 |
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PCT/US09/03492 |
Jun 10, 2009 |
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13890949 |
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61148001 |
Jan 28, 2009 |
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61060746 |
Jun 11, 2008 |
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Current U.S.
Class: |
514/210.21 ;
514/211.15; 514/217.07; 514/228.5; 514/232.8; 514/252.04;
514/253.03; 514/255.05; 514/265.1; 514/275; 514/278; 514/293 |
Current CPC
Class: |
C07D 491/107 20130101;
A61P 43/00 20180101; C07D 495/04 20130101; A61K 31/5377 20130101;
C07D 471/14 20130101; A61K 31/496 20130101; A61K 31/497 20130101;
A61K 31/506 20130101; C07D 519/00 20130101; A61K 31/501 20130101;
A61K 31/519 20130101; A61K 31/553 20130101; A61K 31/4375 20130101;
A61K 31/55 20130101; A61P 35/00 20180101; C07D 513/04 20130101;
A61K 31/541 20130101; A61K 45/06 20130101; A61P 35/02 20180101 |
Class at
Publication: |
514/210.21 ;
514/293; 514/253.03; 514/232.8; 514/211.15; 514/217.07; 514/278;
514/228.5; 514/252.04; 514/275; 514/255.05; 514/265.1 |
International
Class: |
C07D 471/14 20060101
C07D471/14; A61K 31/496 20060101 A61K031/496; A61K 31/5377 20060101
A61K031/5377; C07D 513/04 20060101 C07D513/04; C07D 495/04 20060101
C07D495/04; A61K 45/06 20060101 A61K045/06; A61K 31/541 20060101
A61K031/541; A61K 31/501 20060101 A61K031/501; A61K 31/506 20060101
A61K031/506; A61K 31/497 20060101 A61K031/497; A61K 31/519 20060101
A61K031/519; A61K 31/4375 20060101 A61K031/4375; C07D 491/107
20060101 C07D491/107 |
Claims
1. A method of inhibiting abnormal cell growth or treating a
hyperproliferative disorder in a mammal comprising administering to
said mammal a therapeutically effective amount of a compound of
formula (I), or a salt thereof: ##STR00756## X is CR.sup.2 or N; Y
is CR.sup.4 or N; Z is CR.sup.8 or N; provided that no more than
one of X, Y and Z is N at the same time; R.sup.2 is H, halo, CN,
CF.sub.3, --OCF.sub.3, OH, --NO.sub.2, C.sub.1-C.sub.5 alkyl,
--O(C.sub.1-C.sub.5 alkyl), --S(C.sub.1-C.sub.5 alkyl), or
N(R.sup.22).sub.2; R.sup.3 is H, halo, CN, --O--R.sup.9,
--N(R.sup.22)--R.sup.9, --S(O).sub.p--R.sup.9, or R.sup.9; p is 0,
1 or 2; R.sup.4 is H, halo, CN, CF.sub.3, --OCF.sub.3, OH,
--NO.sub.2, --(CR.sup.14R.sup.15).sub.nC(.dbd.Y)OR.sup.11,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nS(O).sub.pR.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y)R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')OR.sup.11,
--(CR.sup.14R.sup.15)--NR.sup.12C(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15)--NR.sup.12SO.sub.2R.sup.11,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15)--S(O).sub.2NR.sup.11R.sup.12, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one to four R.sup.13
groups; each n is independently 0-5; R.sup.5 is H, halo, CN,
CF.sub.3, --OCF.sub.3, OH, --NO.sub.2,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')OR.sup.11,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nS(O).sub.pR.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')OR.sup.11,
(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12SO.sub.2R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')NR.sup.11R.sup.12;
--(CR.sup.14R.sup.15)--S(O).sub.2NR.sup.11R.sup.12, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl wherein the
said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one to four R.sup.13
groups; R.sup.6 is CN, --CF.sub.3, --OCF.sub.3, halo,
--C(.dbd.Y')NR.sup.11R.sup.12; --OR.sup.11,
--OC(.dbd.Y').sub.R.sup.11, --NR.sup.11R.sup.12;
NR.sup.12C(.dbd.Y')R.sup.11,
--NR.sup.12C(.dbd.Y')NR.sup.11R.sup.12;
NR.sup.12S(O).sub.qR.sup.11; --SR.sup.11, --S(O)R.sup.11,
--S(O).sub.2R.sup.11, --OC(.dbd.Y')NR.sup.11R.sup.12,
S(O).sub.2NR.sup.11R.sup.12, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are
optionally substituted by one to four R.sup.13 groups; R.sup.8 is
H, halo, CN, NO.sub.2, N(R.sup.22).sub.2, OH, O(C.sub.1-C.sub.3
alkyl), or C.sub.1-C.sub.3 alkyl, wherein each said alkyl is
optionally substituted with one to three fluoro groups; each
R.sup.9 is independently alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, wherein each member of R.sup.9 is
independently substituted with one to three R.sup.10 groups; each
R.sup.10 is independently H, CN, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, halo, R.sup.11, --OR.sup.11,
--NR.sup.12C(.dbd.Y.dbd.)R.sup.11,
--NR.sup.12C(.dbd.NR.sup.12)R.sup.11,
--NR.sup.12S(O).sub.qR.sup.11, --SR.sup.11, --NR.sup.11R.sup.12,
oxo, --C(.dbd.Y')OR.sup.11, --C(.dbd.Y')NR.sup.11R.sup.12,
--S(O).sub.qR.sup.11, NR.sup.12C(Y')OR.sup.11,
--NR.sup.12C(.dbd.Y')NR.sup.11R.sup.12; --OC(.dbd.Y')R.sup.11,
--OC(.dbd.Y')NR.sup.11R.sup.12, or --S(O).sub.2NR.sup.11R.sup.12;
each q independently is 1 or 2; R.sup.11 and R.sup.12 are
independently H, alkyl, cycloalkyl, heterocyclyl, aryl or
heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one to four R.sup.13
groups, wherein two geminal R.sup.13 groups are optionally taken
together with the atom to which they are attached to form a 3-6
membered ring having additional 0-2 heteroatoms selected from O, S,
and N, said ring being optionally substituted with one to four
R.sup.18 groups; R.sup.11 and R.sup.12 are optionally taken
together with the attached N atom to form a 4-7 membered ring
having additional 0-2 heteroatoms selected from O, S, and N, said
ring being optionally substituted with one to four R.sup.13 groups;
each R.sup.13 is independently halo, CN, CF.sub.3, --OCF.sub.3,
--NO.sub.2, oxo, --(CR.sup.14R.sup.15).sub.nC(.dbd.Y')R.sup.16,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nSR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(.dbd.Y)R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(.dbd.Y')OR.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.17C(.dbd.Y')NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.17SO.sub.2R.sup.16,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')R.sup.16,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O)R.sup.16,
--(CR.sup.14R.sup.15)--S(O).sub.2R.sup.16,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16; R.sup.14 and R.sup.15 are independently selected from H,
alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said
alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally
substituted with one to four R.sup.18 groups; R.sup.16 and R.sup.17
are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or
heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one to four R.sup.18
groups; R.sup.16 and R.sup.17 are optionally taken together with
the attached N atom to form a 5-6 membered ring having additional
0-2 heteroatoms selected from O, S, and N, said ring being
optionally substituted with one to four R.sup.18 groups; each
R.sup.18 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl, halo, CN, CF.sub.3, --OCF.sub.3, --NO.sub.2, oxo,
--(CR.sup.19R.sup.20).sub.nC(.dbd.Y')R.sup.23,
--(CR.sup.19R.sup.20).sub.n C(.dbd.Y')OR.sup.23,
--(CR.sup.19R.sup.20).sub.n C(.dbd.Y')NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nNR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nOR.sup.23,
--(CR.sup.19R.sup.20).sub.n--SR.sup.23,
--(CR.sup.19R.sup.20).sub.nNR.sup.24C(.dbd.Y `)R.sup.23,
--(CR.sup.19R.sup.20).sub.nNR.sup.24C(.dbd.Y`)OR.sup.23,
--(CR.sup.19R.sup.20).sub.nNR.sup.22C(.dbd.Y')NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nNR.sup.24SO.sub.2R.sup.23,
--(CR.sup.19R.sup.20).sub.nOC(.dbd.Y')R.sup.23,
--(CR.sup.19R.sup.20).sub.n OC(.dbd.Y')NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nS(O)R.sup.23,
--(CR.sup.19R.sup.20).sub.nS(O).sub.2R.sup.23, or
--(CR.sup.19R.sup.20).sub.nS(O).sub.2NR.sup.23R.sup.24, wherein
said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are
optionally substituted with one to four R.sup.21 groups; R.sup.19
and R.sup.20 are independently H, alkyl, cycloalkyl, heterocyclyl,
aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one to four
R.sup.25 groups; R.sup.23 and R.sup.24 are independently H, alkyl,
cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl,
cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally
substituted with one to four R.sup.21 groups; R.sup.23 and R.sup.24
are optionally taken together with the attached N atom to form a
5-6 membered ring having additional 0-2 heteroatoms selected from
O, S, and N, said ring being optionally substituted with one to
four R.sup.21 groups; each R.sup.21 is independently H, alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF.sub.3,
--OCF.sub.3, --NO.sub.2, oxo, --C(.dbd.Y)R.sup.25,
--C(.dbd.Y')OR.sup.25, --C(.dbd.Y')NR.sup.25R.sup.26,
--NR.sup.25R.sup.26, --OR.sup.25, --SR.sup.25,
--NR.sup.26C(.dbd.Y')R.sup.25, --NR.sup.26C(.dbd.Y')OR.sup.25,
--NR.sup.22C(.dbd.Y')NR.sup.25R.sup.26, NR.sup.26SO.sub.2R.sup.25,
--OC(.dbd.Y')R.sup.25, --OC(.dbd.Y')NR.sup.25R.sup.26,
--S(O)R.sup.25, --S(O).sub.2R.sup.25, or
--S(O).sub.2NR.sup.25R.sup.26, wherein said alkyl, cycloalkyl,
heterocyclyl, aryl, and heteroaryl are optionally substituted with
one to four R.sup.25 groups; each R.sup.25 and R.sup.26 is
independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one to four groups
selected from halo, --CN, --OCF.sub.3, --CF.sub.3, --NO.sub.2,
--C.sub.1-C.sub.6 alkyl, --OH, oxo, --SH, --O(C.sub.1-C.sub.6
alkyl), --S(C.sub.1-C.sub.6 alkyl), --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.6 alkyl), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)(C.sub.1-C.sub.6
alkyl), --NHC(O)(C.sub.1-C.sub.6 alkyl),
--NHSO.sub.2(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)SO.sub.2(C.sub.1-C.sub.6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHC(O)NH(C.sub.1-C.sub.6
alkyl), --NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)O(C.sub.1-C.sub.6 alkyl), and
--N(C.sub.1-C.sub.6 alkyl)C(O)O(C.sub.1-C.sub.6 alkyl); R.sup.25
and R.sup.26 are optionally taken together with the attached N atom
to form a 5-6 membered ring having additional 0-2 heteroatoms
selected from O, S, and N, said ring being optionally substituted
with one to four groups selected from halo, --CN, --OCF.sub.3,
CF.sub.3, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --OH, oxo, --SH,
--O(C.sub.1-C.sub.6 alkyl), --S(C.sub.1-C.sub.6 alkyl), --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.6 alkyl), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)(C.sub.1-C.sub.6
alkyl), --NHC(O)(C.sub.1-C.sub.6 alkyl),
--NHSO.sub.2(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)SO.sub.2(C.sub.1-C.sub.6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHC(O)NH(C.sub.1-C.sub.6
alkyl), --NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)O(C.sub.1-C.sub.6 alkyl), and
--N(C.sub.1-C.sub.6 alkyl)C(O)O(C.sub.1-C.sub.6 alkyl); Y' is
independently O, NR.sup.22, or S; and each R.sup.22 is
independently H or C.sub.1-C.sub.5 alkyl.
2. The method of claim 1, wherein the compounds of formula (I) are
those wherein X is CR.sup.2.
3. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.2 is H.
4. The method of claim 1, wherein the compounds of formula (I) are
those wherein Y is CR.sup.4.
5. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.4 is H.
6. The method of claim 1, wherein the compounds of formula (I) are
those wherein Z is CR.sup.8.
7. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.8 is H.
8. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.3 is Br.
9. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.3 is H.
10. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.3 is R.sup.9.
11. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3
alkynyl, C.sub.6 aryl, or 5-6 membered monocyclic or 8-10-membered
bicyclic heteroaryl having 1 to 2 ring atoms selected from N, O and
S; and wherein each member of R.sup.9 is independently substituted
with one to two R.sup.10 groups.
12. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.9 is isopropyl, propynyl, phenyl, pyrazolyl,
furanyl, thienyl, pyridyl, imidazolyl, pyrimidinyl, benzothienyl,
thiazolyl, tetrahydrothienopyridinyl, tetrahydrothiazolopyridinyl,
isothiazolyl, tetrahydropyridinyl, tetrahydroisoquinolinyl,
triazolyl, dihydrobenzodioxinyl, dihydroindolyl, oxazolyl, or
tetrahydrobenzothienyl, wherein each member of R.sup.9 is
independently substituted with one to two R.sup.10 groups.
13. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.10 is halo, R.sup.11, --OR.sup.11, CN,
--CF.sub.3, --OCF.sub.3, NR.sup.12C(.dbd.O)R.sup.11,
--NR.sup.12S(O).sub.qR.sup.11, --SR.sup.11, --NR.sup.11R.sup.12,
--C(.dbd.O)NR.sup.11R.sup.12, oxo, --S(O).sub.qR.sup.11,
--S(O).sub.2NR.sup.11R.sup.12, or --C(.dbd.O)OR.sup.11, wherein
R.sup.11 and R.sup.12 are optionally taken together with the
attached N atom to form a 4-7 membered ring having additional 0-2
heteroatoms selected from O, S, and N, said ring being optionally
substituted with one to four R.sup.13 groups.
14. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.10 is R.sup.11.
15. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.11 is C.sub.1-C.sub.6 alkyl, or 4-6 membered
monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2
heteroatoms selected from N and O, wherein said alkyl and
heterocyclyl are optionally substituted with one to four R.sup.13
groups, wherein two geminal R.sup.13 groups are optionally taken
together with the atom to which they are attached to form a
six-membered ring having 0-2 heteroatom selected from O, S, and N,
said ring being optionally substituted with one to four R.sup.18
groups.
16. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.11 is C.sub.1-C.sub.6 alkyl, wherein alkyl is
optionally substituted with one to two R.sup.13 groups and wherein
each R.sup.13 is independently halo, CN, CF.sub.3, --OCF.sub.3,
oxo, --(CR.sup.14R.sup.15).sub.nC(O)OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16.
17. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.11 is 4-6 membered monocyclic or 8-10 membered
bicyclic heterocyclyl having 1 to 2 heteroatoms selected from N and
O, wherein said alkyl and heterocyclyl are optionally substituted
with one to two R.sup.13 groups and wherein each R.sup.13 is
independently halo, CN, CF.sub.3, --OCF.sub.3, oxo,
(CR.sup.14R.sup.15).sub.nC(O)OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16.
18. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.10 is --OR.sup.11.
19. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.11 is H, C.sub.1-C.sub.4 alkyl, or 4-6 membered
monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2
nitrogen atoms, wherein said alkyl or heterocyclyl is optionally
substituted with one to two R.sup.13 groups, wherein each R.sup.13
is independently halo, CN, CF.sub.3, --OCF.sub.3, oxo,
--(CR.sup.14R.sup.15)--C(O)OR.sup.16,
(CR.sup.14R.sup.15).sub.nC(O)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17or
R.sup.16.
20. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.5 is H.
21. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.5 is
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.11R.sup.12,
(CR.sup.14R.sup.15).sub.nNR.sup.12C(O)R.sup.11,
--(CR14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11, C.sub.1-C.sub.6 alkyl, or 4-6
membered monocyclic or 7-10 membered bicyclic heterocyclyl having 1
to 2 nitrogen atoms, wherein said alkyl or heterocyclyl is
optionally substituted with one to two R.sup.13 groups; wherein
R.sup.14 and R.sup.15 are H; n is 0-2; each R.sup.11 is
independently H, C.sub.1-C.sub.4 alkyl, or 5-6 membered monocyclic
heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or
heterocyclyl is optionally substituted with one to two R.sup.13
groups; and R.sup.13 is OH, O(C.sub.1-C.sub.3 alkyl), or
C.sub.1-C.sub.3 alkyl.
22. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.6 is CN, halo, --C(O)NR.sup.11R.sup.12,
--OR.sup.11, --NR.sup.11R.sup.12, --NR.sup.12C(O)R.sup.11,
C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 cycloalkyl, 5-6 membered
heterocyclyl having 1 to 2 heteroatoms, C.sub.6 aryl, or 5-6
membered heteroaryl having 1 to 2 heteroatoms; wherein said alkyl
is substituted with one to two R.sup.13 groups except H; and said
cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally
substituted by one to two R.sup.13 groups; wherein heteroatoms are
selected from N, O and S; wherein each R.sup.12 is H or
C.sub.1-C.sub.3 alkyl and each R.sup.11 is independently H or
C.sub.1-C.sub.3 alkyl optionally substituted by one to two R.sup.13
groups.
23. The method of claim 1, wherein the compounds of formula (I) are
those wherein R.sup.6 is CN.
24. (canceled)
25. The method of claim 1, wherein the compounds of formula (I) are
selected from the group consisting of: ##STR00757## ##STR00758##
##STR00759## ##STR00760## ##STR00761## ##STR00762## ##STR00763##
##STR00764## ##STR00765## ##STR00766## ##STR00767## ##STR00768##
##STR00769## ##STR00770## ##STR00771## ##STR00772## ##STR00773##
##STR00774## ##STR00775## ##STR00776## ##STR00777## ##STR00778##
##STR00779## ##STR00780## ##STR00781## ##STR00782## ##STR00783##
##STR00784## ##STR00785## ##STR00786## ##STR00787## ##STR00788##
##STR00789## ##STR00790## ##STR00791## ##STR00792## ##STR00793##
##STR00794## ##STR00795## ##STR00796## ##STR00797## ##STR00798##
##STR00799## ##STR00800## ##STR00801## ##STR00802## ##STR00803##
##STR00804## ##STR00805## ##STR00806## ##STR00807## ##STR00808##
##STR00809## ##STR00810## ##STR00811## ##STR00812## ##STR00813##
##STR00814## ##STR00815## ##STR00816## ##STR00817## ##STR00818##
##STR00819##
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. The method of any one of claims 1 to 25 and 33 to 44 wherein
the hyperproliferative disorder is cancer in a mammal.
31. The method of claim 30, wherein cancer is selected from breast
cancer, prostate cancer, pancreatic cancer, colorectal cancer,
ovarian cancer, non-small cell lung cancer, malignant brain tumors,
sarcomas, melanoma, lymphoma, myelomas leukemia and acute
myelogenous leukemia (AML).
32. (canceled)
33. The method of claim 1, wherein the compound of formula (I) is:
##STR00820## or a pharmaceutically acceptable salt thereof.
34. The method of claim 1, wherein the compound of formula (I) is:
##STR00821## or a pharmaceutically acceptable salt thereof.
35. The method of claim 1, wherein the compound of formula (I) is:
##STR00822## or a pharmaceutically acceptable salt thereof.
36. The method of claim 1, wherein the compound of formula (I) is:
##STR00823## or a pharmaceutically acceptable salt thereof.
37. The method of claim 1, wherein the compound of formula (I) is:
##STR00824## or a pharmaceutically acceptable salt thereof.
38. The method of claim 1, wherein the compound of formula (I) is:
##STR00825## or a pharmaceutically acceptable salt thereof.
39. The method of claim 1, wherein the compound of formula (I) is:
##STR00826## or a pharmaceutically acceptable salt thereof.
40. The method of claim 1, wherein the compound of formula (I) is:
##STR00827## or a pharmaceutically acceptable salt thereof.
41. The method of claim 1, wherein the compound of formula (I) is:
##STR00828## or a pharmaceutically acceptable salt thereof.
42. The method of claim 1, wherein the compound of formula (I) is:
##STR00829## or a pharmaceutically acceptable salt thereof.
43. The method of claim 1, wherein the compound of formula (I) is:
##STR00830## or a pharmaceutically acceptable salt thereof.
44. The method of claim 1, wherein the compound of formula (I) is:
##STR00831## or a pharmaceutically acceptable salt thereof.
45. The method of claim 1, comprising administering a second
therapeutic agent selected from the group consisting of: Erlotinib
(TARCEVA.RTM., Genentech/OSI Pharm.), Bortezomib (VELCADE.RTM.,
Millennium Pharm.), Fulvestrant (FASLODEX.RTM., AstraZeneca),
Sutent (SU11248, Pfizer), Letrozole (FEMARA.RTM., Novartis),
Imatinib mesylate (GLEEVEC.RTM., Novartis), PTK787/ZK 222584
(Novartis), Oxaliplatin (Eloxatin.RTM., Sanofi), Leucovorin,
Rapamycin (Sirolimus, RAPAMUNE.RTM., Wyeth), Lapatinib
(TYKERB.RTM., GSK572016, Glaxo Smith Kline), Lonafarnib (SCH
66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib
(IRESSA.RTM., AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkyl
sulfonates comprising busulfan, improsulfan and piposulfan;
aziridines comprising benzodopa, carboquone, meturedopa, and
uredopa; ethylenimines and methylamelamines comprising altretamine,
triethylenemelamine, triethylenephosphoramide,
triethylenethiophosphoramide and trimethylomelamine; acetogenins
comprising bullatacin and bullatacinone; bryostatin; callystatin;
CC-1065 comprising its adozelesin, carzelesin and bizelesin
synthetic analogs; cryptophycins comprising cryptophycin 1 and
cryptophycin 8; dolastatin; duocarmycin comprising the synthetic
analogs, KW-2189 and CB1-TM1; eleutherobin; pancratistatin; a
sarcodictyin; spongistatin; folic acid analogs comprising
denopterin, methotrexate, pteropterin, and trimetrexate; purine
analogs comprising fludarabine, 6-mercaptopurine, thiamiprine, and
thioguanine; pyrimidine analogs comprising ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, and floxuridine; androgens comprising calusterone,
dromostanolone propionate, epitiostanol, mepitiostane, and
testolactone; anti-adrenals comprising aminoglutethimide, mitotane,
and trilostane; folic acid replenisher comprising frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine; diaziquone; elfornithine; elliptinium acetate; an
epothilone; etoglucid; gallium nitrate; lentinan; lonidainine;
maytansinoids comprising maytansine and ansamitocins; mitoguazone;
mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet;
pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSK.RTM. polysaccharide complex (JHS Natural
Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran;
spirogermanium; tenuazonic acid; triaziquone;
2,2',2''-trichlorotriethylamine; trichothecenes comprising T-2
toxin, verracurin A, roridin A and anguidine); urethan;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); chloranmbucil; 6-thioguanine;
mercaptopurine; ifosfamide; mitoxantrone; novantrone; edatrexate;
daunomycin; aminopterin; capecitabine (XELODA.RTM.); ibandronate;
CPT-11; difluoromethylornithine (DMFO); anti-hormonal agents that
act to regulate or inhibit hormone action on tumors comprising
anti-estrogens and selective estrogen receptor modulators (SERMs),
comprising tamoxifen comprising NOLVADEX.RTM.; tamoxifen citrate,
raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene,
LY117018, onapristone, and FARESTON.RTM. (toremifine citrate);
aromatase inhibitors that inhibit the enzyme aromatase, which
regulates estrogen production in the adrenal glands, comprising
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca);
anti-androgens comprising flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; troxacitabine comprising 1,3-dioxolane
nucleoside cytosine analogs; protein kinase inhibitors; lipid
kinase inhibitors; antisense oligonucleotides, comprising those
which inhibit expression of genes in signaling pathways implicated
in aberrant cell proliferation, comprising PKC-alpha, Ralf and
H-Ras; ribozymes comprising VEGF expression inhibitors comprising
ANGIOZYME.RTM. and HER2 expression inhibitors; vaccines comprising
gene therapy vaccines, comprising ALLOVECTIN.RTM., LEUVECTIN.RTM.,
and VAXID.RTM.; PROLEUKIN.RTM. rIL-2; a topoisomerase 1 inhibitor
comprising LURTOTECAN.RTM.; ABARELIX.RTM. rmRH; anti-angiogenic
agents comprising bevacizumab (AVASTIN.RTM., Genentech); inhibitors
of MEK, comprising MAP kinase kinase, comprising XL518 (Exelixis,
Inc.) and AZD6244 (Astrazeneca); inhibitors of Raf, comprising
XL281 (Exelixis, Inc.), PLX4032 (Plexxikon), and ISIS5132 (Isis
Pharmaceuticals); inhibitors of mTor comprising rapamycin, AP23573
(Ariad Pharmaceuticals), temsirolimus (Wyeth Pharmaceuticals) and
RAD001 (Novartis); inhibitors of PI3K (phosphoinositide-3 kinase),
comprising SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals),
BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor,
Exelixis, Inc.), and GDC-0941 (Genentech); inhibitors of cMet,
comprising PHA665752 (Pfizer), XL-880 (Exelixis, Inc.), ARQ-197
(ArQule), and CE-355621; DNA damaging agent comprising thiotepa and
CYTOXAN.RTM. cyclosphosphamide; alkylating agents comprising
cis-platin; carboplatin; cyclophosphamide; nitrogen mustards
comprising chlorambucil, chlornaphazine, chlorophosphamide,
estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide
hydrochloride, melphalan, novembichin, phenesterine, prednimustine,
trofosfamide, uracil mustard; busulphan; nitrosoureas comprising
carmustine, chlorozotocin, fotemustine, lomustine, nimustine,
ranimnustine and temozolomide; antimetabolites comprising
antifolates comprising fluoropyrimidines like 5-fluorouracil (5-FU)
and tegafur, raltitrexed, methotrexate, cytosine arabinoside,
hydroxyurea and GEMZAR.RTM. (gemcitabine); antitumour antibiotics
comprising enediyne antibiotics comprising calicheamicin comprising
calicheamicin gamma1I and calicheamicin omegaI1; anthracyclines
comprising adriamycin; dynemicin, comprising dynemicin A;
bisphosphonates, comprising clodronate; an esperamicin;
neocarzinostatin chromophore and related chromoprotein enediyne
antibiotic chromophores, aclacinomysins, actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, carabicin, caminomycin,
carzinophilin, chromomycinis, dactinomycin, daunorubicin,
detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN.RTM.
(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins comprising
mitomycin C, mycophenolic acid, nogalamycin, olivomycins,
peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin,
streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and
zorubicin; antimitotic agents comprising vinca alkaloids like
vincristine, vinblastine, vindesine and NAVELBINE.RTM.
(vinorelbine) and taxoids like taxoids, e.g., TAXOL.RTM.
(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.),
ABRAXANE.TM. (Cremophor-free), albumin-engineered nanoparticle
formulations of paclitaxel, and TAXOTERE.RTM. (doxetaxel;
Rhone-Poulenc Rorer, Antony, France); topoisomerase inhibitors
comprising RFS 2000, epipodophyllotoxins like etoposide and
teniposide, amsacrine, a camptothecin comprising the synthetic
analog topotecan, and irinotecan and SN-38 and cytodifferentiating
agents comprising retinoids comprising all-trans retinoic acid,
13-cis retinoic acid and fenretinide; an agent that modulates the
apoptotic response comprising inhibitors of IAP (inhibitor of
apoptosis proteins) comprising AEG40826 (Aegera Therapeutics); and
inhibitors of bcl-2 comprising GX15-070 (Gemin X Biotechnologies),
CND0103 (Apogossypol; Coronado Biosciences), HA14-1 (ethyl
2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate-
), AT101 (Ascenta Therapeutics), ABT-737 and ABT-263 (Abbott); and
pharmaceutically acceptable salts thereof.
46. The method of claim 45, wherein the second therapeutic agent is
selected from the group consisting of Gemcitabine, Irinotecan,
SN-38, arabinoside ("Ara-C") and a topoisomerase inhibitor 1 or
2.
47. A method of treating cancer selected from the group consisting
of breast cancer, colorectal cancer, prostate cancer, pancreatic
cancer, ovarian cancer, non-small cell lung cancer, malignant brain
tumors, sarcomas, melanoma, lymphoma, myelomas, leukemia and acute
myelogenous leukemia (AML) in a mammal comprising administering to
said mammal a therapeutically effective amount of a compound
selected from the group consisting of: ##STR00832## ##STR00833## or
a pharmaceutically acceptable salt thereof and a second
chemotherapeutic agent selected from the group consisting of
Gemcitabine, Irinotecan, SN-38, arabinoside ("Ara-C") and a
topoisomerase inhibitor 1 or 2.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/060,746, filed Jun. 11, 2008 and U.S.
Provisional Application No. 61/148,001, filed Jan. 28, 2009, the
disclosure of both are incorporated herein by reference in their
entirety.
[0002] The invention relates to 1,7-diazacarbazole compounds which
are useful as kinase inhibitors, more specifically useful as
checkpoint kinase 1 (chk1) inhibitors, thus useful as cancer
therapeutics. The invention also relates to compositions, more
specifically pharmaceutical compositions comprising these compounds
and methods of using the same to treat various forms of cancer and
hyperproliferative disorders, as well as methods of using the
compounds for in vitro, in situ, and in vivo diagnosis or treatment
of mammalian cells, or associated pathological conditions.
[0003] Individual cells replicate by making an exact copy of their
chromosomes, and then segregating these into separate cells. This
cycle of DNA replication, chromosome separation and division is
regulated by mechanisms within the cell that maintain the order of
the steps and ensure that each step is precisely carried out.
Involved in these processes are the cell cycle checkpoints
(Hartwell et al., Science, Nov. 3, 1989, 246(4930):629-34) where
cells may arrest to ensure DNA repair mechanisms have time to
operate prior to continuing through the cycle into mitosis. There
are two such checkpoints in the cell cycle--the G1/S checkpoint
that is regulated by p53 and the G2/M checkpoint that is monitored
by the serine/threonine kinase checkpoint kinase 1 (chk1).
[0004] Chk1 and chk2 are structurally unrelated yet functionally
overlapping serine/threonine kinases activated in response to
genotoxic stimuli (reviewed in Bartek et al., Nat. Rev. Mol. Cell.
Biol. 2001, vol. 2, pp. 877-886). Chk1 and chk2 relay the
checkpoint signals from the ATM and ATR, which phosphorylate and
activate them. Chk2 is a stable protein expressed throughout the
cell cycle, activated mainly by ATM in response to double-strand
DNA breaks (DSBs). In contrast, Chk1 protein expression is largely
restricted to S and G2 phases. In response to DNA damage, ChK1 is
phosphorylated and activated by ATM/ATR, resulting in cell cycle
arrest in the S and G2/M phases to allow for repair of DNA damage
(reviewed in Cancer Cell, Bartek and Lukas, Volume 3, Issue 5, May
2003, Pages 421-429. Inhibition of Chk1 has been shown to abrogate
cell cycle arrest leading to enhanced tumor cell death following
DNA damage by a range of chemotherapeutics. Cells lacking intact G1
checkpoints are particularly dependent on S and G2/M checkpoints
and are therefore expected to be more sensitive to chemotherapeutic
treatment in the presence of a chk1 inhibitor, whereas normal cells
with functional G1 checkpoints would be predicted to undergo less
cell death.
[0005] The invention relates to 1,7-diazacarbazoles of Formula (I),
(I-a), and/or (I-b) (and/or solvates, hydrates and/or salts
thereof) with kinase inhibitory activity, more specifically with
chk1 inhibitory activity. The compounds of the present invention
are also useful as inhibitors of Glycogen Synthase Kinase-3
(GSK-3), KDR kinase, and FMS-like tyrosine kinase 3 (FLT3).
Accordingly, the compounds of the invention and compositions
thereof are useful in the treatment of hyperproliferative disorders
such as cancer.
##STR00002## [0006] X is CR.sup.2 or N; [0007] Y is CR.sup.4 or N;
[0008] Z is CR.sup.8 or N; provided that no more than one of X, Y
and Z is N at the same time; [0009] R.sup.2 is H, halo, CN,
CF.sub.3, --OCF.sub.3, OH, --NO.sub.2, C.sub.1-C.sub.5 alkyl,
--O(C.sub.1-C.sub.5 alkyl), --S(C.sub.1-C.sub.5 alkyl), or
N(R.sup.22).sub.2; [0010] R.sup.3 is H, halo, CN, --O--R.sup.9,
--N(R.sup.22)--R.sup.9, --S(O).sub.p--R.sup.9, or R.sup.9; [0011] p
is 0, 1 or 2; [0012] R.sup.4 is H, halo, CN, CF.sub.3, --OCF.sub.3,
OH, --NO.sub.2, --(CR.sup.14R.sup.15).sub.nC(.dbd.Y')OR.sup.11,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nS(O).sub.pR.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')OR.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y'')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12SO.sub.2R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.11R.sup.12, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one to four
R.sup.13 groups; [0013] each n is independently 0-5; [0014] R.sup.5
is H, halo, CN, CF.sub.3, --OCF.sub.3, OH, --NO.sub.2,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')OR.sup.11,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nS(O).sub.pR.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')OR.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12SO.sub.2R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')R.sup.11,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.11R.sup.12, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl
wherein the said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one to four
R.sup.13 groups; [0015] R.sup.6 is H, CN, --CF.sub.3, --OCF.sub.3,
halo, --C(.dbd.Y')OR.sup.11, --C(.dbd.Y')NR.sup.11R.sup.12,
--OR.sup.11, --OC(.dbd.Y')R.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(.dbd.Y')R.sup.11,
--NR.sup.12C(.dbd.Y')NR.sup.11R.sup.12,
--NR.sup.12S(O).sub.qR.sup.11, --SR.sup.11, --S(O)R.sup.11,
--S(O).sub.2R.sup.11, --OC(.dbd.Y')NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are
optionally substituted by one to four R.sup.13 groups; [0016]
R.sup.7 is H, OH, CN, O(C.sub.1-C.sub.3 alkyl), or C.sub.1-C.sub.4
alkyl, wherein each said alkyl is optionally substituted with one
to three groups independently selected from halo, N(R.sup.22).sub.2
or OR.sup.22; [0017] R.sup.8 is H, halo, CN, NO.sub.2,
N(R.sup.22).sub.2, OH, O(C.sub.1-C.sub.3 alkyl), or C.sub.1-C.sub.3
alkyl, wherein each said alkyl is optionally substituted with one
to three fluoro groups; [0018] each R.sup.9 is independently alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
wherein each member of R.sup.9 is independently substituted with
one to three R.sup.10 groups; [0019] each R.sup.10 is independently
H, CN, --CF.sub.3, --OCF.sub.3, --NO.sub.2, halo, R.sup.11,
--OR.sup.11, --NR.sup.12C(.dbd.Y')R.sup.11,
--NR.sup.12C(.dbd.NR.sup.12)R.sup.11,
--NR.sup.12S(O).sub.qR.sup.11, --SR.sup.11, --NR.sup.11R.sup.12,
oxo, --C(.dbd.Y')OR.sup.11, --C(.dbd.Y')NR.sup.11R.sup.12,
--S(O).sub.qR.sup.11, --NR.sup.12C(.dbd.Y')OR.sup.11,
--NR.sup.12C(.dbd.Y')NR.sup.11R.sup.12, --(.dbd.Y')R.sup.11,
--OC(.dbd.Y')NR.sup.11R.sup.12, or --S(O).sub.2NR.sup.11R.sup.12;
[0020] each q independently is 1 or 2; [0021] R.sup.11 and R.sup.12
are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or
heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one to four R.sup.13
groups, wherein two geminal R.sup.13 groups are optionally taken
together with the atom to which they are attached to form a 3-6
membered ring having additional 0-2 heteroatoms selected from O, S,
and N, said ring being optionally substituted with one to four
R.sup.18 groups; [0022] R.sup.11 and R.sup.12 are optionally taken
together with the attached N atom to form a 4-7 membered ring
having additional 0-2 heteroatoms selected from O, S, and N, said
ring being optionally substituted with one to four R.sup.13 groups;
[0023] each R.sup.13 is independently halo, CN, CF.sub.3,
--OCF.sub.3, --NO.sub.2, oxo,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')R.sup.16,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(.dbd.Y')NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nSR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(.dbd.Y')R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(.dbd.Y')OR.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.17C(.dbd.Y')NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.17SO.sub.2R.sup.16,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')R.sup.16,
--(CR.sup.14R.sup.15).sub.nOC(.dbd.Y')NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O)R.sup.16,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2R(CR.sup.14R.sup.15).sub.nS(O).sub.2-
NR.sup.16R.sup.17, or R.sup.16; [0024] R.sup.14 and R.sup.15 are
independently selected from H, alkyl, cycloalkyl, heterocyclyl,
aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one to four
R.sup.18 groups; [0025] R.sup.16 and R.sup.17 are independently H,
alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said
alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally
substituted with one to four R.sup.18 groups; [0026] R.sup.16 and
R.sup.17 are optionally taken together with the attached N atom to
form a 5-6 membered ring having additional 0-2 heteroatoms selected
from O, S, and N, said ring being optionally substituted with one
to four R.sup.18 groups; [0027] each R.sup.18 is independently H,
alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN,
CF.sub.3, --OCF.sub.3, --NO.sub.2, oxo,
--(CR.sup.19R.sup.20).sub.nC('Y')R.sup.23,
--(CR.sup.19R.sup.20).sub.nC(.dbd.Y')OR.sup.23,
--(CR.sup.19R.sup.20).sub.nC(.dbd.Y')NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.n NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nOR.sup.23,
--(CR.sup.19R.sup.20).sub.n--SR.sup.23,
--(CR.sup.19R.sup.20).sub.nNR.sup.24C(.dbd.Y')R.sup.23,
--(CR.sup.19R.sup.20).sub.nNR.sup.24C(.dbd.Y')OR.sup.23,
--(CR.sup.19R.sup.20).sub.nNR.sup.22C(.dbd.Y')NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nNR.sup.24SO.sub.2R.sup.23,
--(CR.sup.19R.sup.20).sub.nOC(.dbd.Y')R.sup.23,
--(CR.sup.19R.sup.20).sub.nOC(.dbd.Y')NR.sup.23R.sup.24,
--(CR.sup.19R.sup.20).sub.nS(O)R.sup.23,
--(CR.sup.19R.sup.20).sub.nS(O).sub.2R.sup.23, or
--(CR.sup.19R.sup.20).sub.nS(O).sub.2NR.sup.23R.sup.24, wherein
said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are
optionally substituted with one to four R.sup.21 groups; [0028]
R.sup.19 and R.sup.20 are independently H, alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one to four R.sup.25 groups; [0029] R.sup.23 and R.sup.24 are
independently H, alkyl, cycloalkyl, heterocyclyl, aryl or
heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one to four R.sup.21
groups; [0030] R.sup.23 and R.sup.24 are optionally taken together
with the attached N atom to form a 5-6 membered ring having
additional 0-2 heteroatoms selected from O, S, and N, said ring
being optionally substituted with one to four R.sup.21 groups;
[0031] each R.sup.21 is independently H, alkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, halo, CN, CF.sub.3, --OCF.sub.3,
--NO.sub.2, oxo, --C(.dbd.Y')R.sup.25, --C(.dbd.Y')OR.sup.25,
--C(.dbd.Y')NR.sup.25R.sup.26, --NR.sup.25R.sup.26, --OR.sup.25,
--SR.sup.25, NR.sup.26C(.dbd.Y')NR.sup.25,
--NR.sup.26C(.dbd.Y')OR.sup.25,
NR.sup.22C(.dbd.Y')NR.sup.25R.sup.26, --NR.sup.26SO.sub.2R.sup.25,
--OC(.dbd.Y')R.sup.25, --OC(.dbd.Y')NR.sup.25R.sup.26,
--S(O)R.sup.25, --S(O).sub.2R.sup.25, or
--S(O).sub.2NR.sup.25R.sup.26, wherein said alkyl, cycloalkyl,
heterocyclyl, aryl, and heteroaryl are optionally substituted with
one to four R.sup.25 groups; [0032] each R.sup.25 and R.sup.26 is
independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one to four groups
selected from halo, --CN, --OCF.sub.3, --CF.sub.3, --NO.sub.2,
--C.sub.1-C.sub.6 alkyl, --OH, oxo, --SH, --O(C.sub.1-C.sub.6
alkyl), --S(C.sub.1-C.sub.6 alkyl), --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.6 alkyl), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)(C.sub.1-C.sub.6
alkyl), --NHC(O)(C.sub.1-C.sub.6 alkyl),
--NHSO.sub.2(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)SO.sub.2(C.sub.1-C.sub.6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHC(O)NH(C.sub.1-C.sub.6
alkyl), --NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)O(C.sub.1-C.sub.6 alkyl), and
--N(C.sub.1-C.sub.6 alkyl)C(O)O(C.sub.1-C.sub.6 alkyl); [0033]
R.sup.25 and R.sup.26 are optionally taken together with the
attached N atom to form a 5-6 membered ring having additional 0-2
heteroatoms selected from O, S, and N, said ring being optionally
substituted with one to four groups selected from halo, --CN,
--OCF.sub.3, CF.sub.3, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --OH,
oxo, --SH, --O(C.sub.1-C.sub.6 alkyl), --S(C.sub.1-C.sub.6 alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --SO.sub.2(C.sub.1-C.sub.6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.6 alkyl), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)(C.sub.1-C.sub.6
alkyl), --NHC(O)(C.sub.1-C.sub.6 alkyl),
--NHSO.sub.2(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)SO.sub.2(C.sub.1-C.sub.6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-C.sub.6 alkyl), --SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHC(O)NH(C.sub.1-C.sub.6
alkyl), --NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)O(C.sub.1-C.sub.6 alkyl), and
--N(C.sub.1-C.sub.6 alkyl)C(O)O(C.sub.1-C.sub.6 alkyl); [0034] Y'
is independently O, NR.sup.22, or S; and [0035] each R.sup.22 is
independently H or C.sub.1-C.sub.5 alkyl.
[0036] The present invention includes a composition (e.g., a
pharmaceutical composition) comprising a compound of Formula (I),
(I-a), and/or (I-b) (and/or solvates, hydrates and/or salts
thereof) and a carrier (a pharmaceutically acceptable carrier). The
present invention also includes a composition (e.g., a
pharmaceutical composition) comprising a compound of Formula (I),
(I-a), and/or (I-b) (and/or solvates, hydrates and/or salts
thereof) and a carrier (a pharmaceutically acceptable carrier),
further comprising a second chemotherapeutic agent. The present
compositions are therefore useful for inhibiting abnormal cell
growth or treating a hyperproliferative disorder in a mammal (e.g.,
human), such as cancer.
[0037] The present invention includes a method of inhibiting
abnormal cell growth or treating a hyperproliferative disorder in a
mammal (e.g., human) such as cancer comprising administering to
said mammal a therapeutically effective amount of a compound of
Formula (I), (I-a), and/or (I-b) (and/or solvates, hydrates and/or
salts thereof) or a composition thereof, alone or in combination
with a second chemotherapeutic agent.
[0038] The present invention includes a method of using the present
compounds for in vitro, in situ, and in vivo diagnosis or treatment
of mammalian cells, organisms, or associated pathological
conditions. Also included are methods for making the present
compounds.
[0039] Reference will now be made in detail to certain embodiments
of the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated embodiments, it will
be understood that they are not intended to limit the invention to
those embodiments. On the contrary, the invention is intended to
cover all alternatives, modifications, and equivalents which may be
included within the scope of the present invention as defined by
the claims. One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described. In the event that one or more of the incorporated
literature, patents, and similar materials differs from or
contradicts this application, including but not limited to defined
terms, term usage, described techniques, or the like, this
application controls.
[0040] The term "alkyl" as used herein refers to a saturated linear
or branched-chain monovalent hydrocarbon radical of one to twelve
carbon atoms. Examples of alkyl groups include, but are not limited
to, methyl (Me, --CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3),
1-propyl (n-Pr, n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl
(i-Pr, i-propyl, --CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2 CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, 1-heptyl,
1-octyl, and the like.
[0041] The term "alkenyl" refers to linear or branched-chain
monovalent hydrocarbon radical of two to twelve carbon atoms with
at least one site of unsaturation, i.e., a carbon-carbon, sp.sup.2
double bond, wherein the alkenyl radical includes radicals having
"cis" and "trans" orientations, or alternatively, "E" and "Z"
orientations. Examples include, but are not limited to, ethylenyl
or vinyl (--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
and the like.
[0042] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical of two to twelve carbon atoms with at least one
site of unsaturation, i.e., a carbon-carbon, sp triple bond.
Examples include, but are not limited to, ethynyl (--C.ident.CH),
propynyl (propargyl, --CH.sub.2C.ident.CH), and the like.
[0043] The term "cycloalkyl" refers to a monovalent non-aromatic,
saturated or partially unsaturated ring having 3 to 12 carbon atoms
as a monocyclic ring or 6 to 12 carbon atoms as a bicyclic ring.
Bicyclic carbocycles having 6 to 12 atoms can be arranged, for
example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and
bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a
bicyclo [5,6] or [6,6] system, or as bridged systems such as
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and
bicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,
cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,
1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl,
cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the
like.
[0044] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-14 carbon atoms derived by the removal of one hydrogen atom from
a single carbon atom of a parent aromatic ring system. Some aryl
groups are represented in the exemplary structures as "Ar". Aryl
includes bicyclic radicals comprising an aromatic ring fused to a
saturated, partially unsaturated ring, or aromatic carbocyclic or
heterocyclic ring. Typical aryl groups include, but are not limited
to, radicals derived from benzene (phenyl), substituted benzenes,
naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronapthalene,
1,2,3,4-tetrahydronapthyl, and the like.
[0045] The terms "heterocycle," "heterocyclyl" and "heterocyclic
ring" are used interchangeably herein and refer to a saturated or a
partially unsaturated (i.e., having one or more double bonds within
the ring) carbocyclic radical of 3 to 14 ring atoms in which at
least one ring atom is a heteroatom selected from nitrogen, oxygen
and sulfur, the remaining ring atoms being C, where one or more
ring atoms is optionally substituted independently with one or more
substituents described below. A heterocycle may be a monocycle
having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4
heteroatoms selected from N, O, and S) or a bicycle having 6 to 10
ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected
from N, O, and S), for example: a bicyclo [4,5], [5,5], [5,6], or
[6,6] system or a bridged [2.1.1], [2.2.1], [2.2.2] or [3.2.2]
system. Heterocycles are described in Paquette, Leo A.; "Principles
of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968),
particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of
Heterocyclic Compounds, A series of Monographs" (John Wiley &
Sons, New York, 1950 to present), in particular Volumes 13, 14, 16,
19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclyl"
also includes radicals where heterocycle radicals are fused with a
saturated, partially unsaturated ring, or aromatic carbocyclic or
heterocyclic ring. Examples of heterocyclic rings include, but are
not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,
tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,
thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,
thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,
diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
pyrazolidinylimidazolinyl, imidazolidinyl,
3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and
azabicyclo[2.2.2]hexanyl. Spiro moieties are also included within
the scope of this definition. Examples of a heterocyclic group
wherein ring atoms are substituted with oxo (.dbd.O) moieties are
pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.
[0046] The term "heteroaryl" refers to a monovalent aromatic
radical of 5- or 6-membered rings, and includes fused ring systems
(at least one of which is aromatic) of 5-16 atoms, containing one
or more heteroatoms independently selected from nitrogen, oxygen,
and sulfur. Examples of heteroaryl groups are pyridinyl (including,
for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl,
pyrimidinyl (including, for example, 4-hydroxypyrimidinyl),
pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl,
isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,
triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, and furopyridinyl.
[0047] The heterocycle or heteroaryl groups may be carbon
(carbon-linked) or nitrogen (nitrogen-linked) attached where such
is possible. By way of example and not limitation, carbon bonded
heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6
of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2,
4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine,
position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene,
tetrahydrothiophene, pyrrole or pyrrolidine, position 2, 4, or 5 of
an oxazole, imidazole or thiazole, position 3, 4, or 5 of an
isoxazole, pyrazole, or isothiazole, position 2 or 3 of an
aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4,
5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of
an isoquinoline.
[0048] By way of example and not limitation, nitrogen bonded
heterocycles or heteroaryls are bonded at position 1 of an
aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline,
3-pyrroline, imidazole, imidazolidine, 2-imidazoline,
3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,
piperidine, piperazine, indole, indoline, 1H-indazole,
2-oxo-1,2-dihydropyridine, or 4-oxo-1,4-dihydropyridine; position 2
of a isoindole, or isoindoline; position 4 of a morpholine; and
position 9 of a carbazole, or .beta.-carboline.
[0049] The term "halo" refers to F, Cl, Br or I. The heteroatoms
present in heteroaryl or heterocyclyl include the oxidized forms
such as N.sup.+.fwdarw.O.sup.-, S(O) and S(O).sub.2.
[0050] The terms "treat" and "treatment" refer to both therapeutic
treatment and prophylactic or preventative measures, wherein the
object is to prevent or slow down (lessen) an undesired
physiological change or disorder, such as the development or spread
of cancer. For purposes of this invention, beneficial or desired
clinical results include, but are not limited to, alleviation of
symptoms, diminishment of extent of disease, stabilized (i.e., not
worsening) state of disease, delay or slowing of disease
progression, amelioration or palliation of the disease state, and
remission (whether partial or total), whether detectable or
undetectable. "Treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment. Those in
need of treatment include those already with the condition or
disorder as well as those prone to have the condition or disorder
or those in which the condition or disorder is to be prevented.
[0051] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent
growth and/or kill existing cancer cells, it may be cytostatic
and/or cytotoxic. For cancer therapy, efficacy can be measured, for
example, by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
[0052] The terms "abnormal cell growth" and "hyperproliferative
disorder" are used interchangeably in this application. "Abnormal
cell growth", as used herein, unless otherwise indicated, refers to
cell growth that is independent of normal regulatory mechanisms.
This includes, for example, the abnormal growth of: (1) tumor cells
(tumors) that proliferate by expressing a mutated tyrosine kinase
or overexpression of a receptor tyrosine kinase; (2) benign and
malignant cells of other proliferative diseases in which aberrant
tyrosine kinase activation occurs; (3) any tumors that proliferate
by receptor tyrosine kinases; (4) any tumors that proliferate by
aberrant serine/threonine kinase activation; and (5) benign and
malignant cells of other proliferative diseases in which aberrant
serine/threonine kinase activation occurs.
[0053] The terms "cancer" and "cancerous" refer to or describe the
physiological condition in mammals that is typically characterized
by unregulated cell growth. A "tumor" comprises one or more
cancerous cells. Tumors include solid and liquid tumors. Examples
of cancer include, but are not limited to, carcinoma, lymphoma,
blastoma, sarcoma, myeloma, and leukemia or lymphoid malignancies.
More particular examples of such cancers include squamous cell
cancer (e.g., epithelial squamous cell cancer), lung cancer
including small-cell lung cancer, non-small cell lung cancer
("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the
lung, cancer of the peritoneum, hepatocellular cancer, gastric or
stomach cancer including gastrointestinal cancer, pancreatic
cancer, glioblastoma, cervical cancer, ovarian cancer, liver
cancer, bladder cancer, hepatoma, breast cancer, colon cancer,
rectal cancer, colorectal cancer, malignant brain tumors, melanoma,
endometrial or uterine carcinoma, salivary gland carcinoma, kidney
or renal cancer, prostate cancer, vulval cancer, thyroid cancer,
hepatic carcinoma, anal carcinoma, penile carcinoma, head and neck
cancer, as well as acute myelogenous leukemia (AML).
[0054] A "chemotherapeutic agent" is a chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include Erlotinib (TARCEVA.RTM., Genentech/OSI Pharm.), Bortezomib
(VELCADE.RTM., Millennium Pharm.), Fulvestrant (FASLODEX.RTM.,
AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA.RTM.,
Novartis), Imatinib mesylate (GLEEVEC.RTM., Novartis), PTK787/ZK
222584 (Novartis), Oxaliplatin (Eloxatin.RTM., Sanofi), Leucovorin,
Rapamycin (Sirolimus, RAPAMUNE.RTM., Wyeth), Lapatinib
(TYKERB.RTM., GSK572016, Glaxo Smith Kline), Lonafarnib (SCH
66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib
(IRESSA.RTM., AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkyl
sulfonates such as busulfan, improsulfan and piposulfan; aziridines
such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and methylamelamines including altretamine,
triethylenemelamine, triethylenephosphoramide,
triethylenethiophosphoramide and trimethylomelamine; acetogenins
(especially bullatacin and bullatacinone); bryostatin; callystatin;
CC-1065 (including its adozelesin, carzelesin and bizelesin
synthetic analogs); cryptophycins (particularly cryptophycin 1 and
cryptophycin 8); dolastatin; duocarmycin (including the synthetic
analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a
sarcodictyin; spongistatin; folic acid analogs such as denopterin,
methotrexate, pteropterin, trimetrexate; purine analogs such as
fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine
analogs such as ancitabine, azacitidine, 6-azauridine, carmofur,
cytarabine, dideoxyuridine, doxifluridine, enocitabine,
floxuridine; androgens such as calusterone, dromostanolone
propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals
such as aminoglutethimide, mitotane, trilostane; folic acid
replenisher such as frolinic acid; aceglatone; aldophosphamide
glycoside; aminolevulinic acid; eniluracil; bestrabucil;
bisantrene; edatraxate; defofamine; demecolcine; diaziquone;
elformithine; elliptinium acetate; an epothilone; etoglucid;
gallium nitrate; lentinan; lonidainine; maytansinoids such as
maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;
nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;
podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.
polysaccharide complex (JHS Natural Products, Eugene, Oreg.);
razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid;
triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine);
urethan; dacarbazine; mannomustine; mitobronitol; mitolactol;
pipobroman; gacytosine; arabinoside ("Ara-C"); chloranmbucil;
6-thioguanine; mercaptopurine; ifosfamide; mitoxantrone;
novantrone; edatrexate; daunomycin; aminopterin; capecitabine
(XELODA.RTM.); ibandronate; CPT-11; difluoromethylomithine (DMFO);
and pharmaceutically acceptable salts, acids and derivatives of any
of the above.
[0055] Also included in the definition of "chemotherapeutic agent"
are: (i) anti-hormonal agents that act to regulate or inhibit
hormone action on tumors such as anti-estrogens and selective
estrogen receptor modulators (SERMs), including, for example,
tamoxifen (including NOLVADEX.RTM.; tamoxifen citrate), raloxifene,
droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and FARESTON.RTM. (toremifine citrate); (ii) aromatase
inhibitors that inhibit the enzyme aromatase, which regulates
estrogen production in the adrenal glands, such as, for example,
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca); (iii)
anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; as well as troxacitabine (a
1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase
inhibitors; (v) lipid kinase inhibitors; (vi) antisense
oligonucleotides, particularly those which inhibit expression of
genes in signaling pathways implicated in aberrant cell
proliferation, such as, for example, PKC-alpha, Ralf and H-Ras;
(vii) ribozymes such as VEGF expression inhibitors (e.g.,
ANGIOZYME.RTM.) and HER2 expression inhibitors; (viii) vaccines
such as gene therapy vaccines, for example, ALLOVECTIN.RTM.,
LEUVECTIN.RTM., and VAXID.RTM.; PROLEUKIN.RTM. rIL-2; a
topoisomerase 1 inhibitor such as LURTOTECAN.RTM.; ABARELIX.RTM.
rmRH; (ix) anti-angiogenic agents such as bevacizumab
(AVASTIN.RTM., Genentech); and (x) pharmaceutically acceptable
salts, acids and derivatives of any of the above.
[0056] Other examples of "chemotherapeutic agents" that can be used
in combination with the present compounds include inhibitors of MEK
(MAP kinase kinase), such as XL518 (Exelixis, Inc.) and AZD6244
(Astrazeneca); inhibitors of Rat such as XL281 (Exelixis, Inc.),
PLX4032 (Plexxikon), and ISIS5132 (Isis Pharmaceuticals);
inhibitors of mTor (mammalian target of rapamycin), such as
rapamycin, AP23573 (Ariad Pharmaceuticals), temsirolimus (Wyeth
Pharmaceuticals) and RAD001 (Novartis); inhibitors of PI3K
(phosphoinositide-3 kinase), such as SF-1126 (PI3K inhibitor,
Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis),
XL-147 (PI3K inhibitor, Exelixis, Inc.), and GDC-0941 (Genentech);
inhibitors of cMet, such as PHA665752 (Pfizer), XL-880 (Exelixis,
Inc.), ARQ-197 (ArQule), and CE-355621; and pharmaceutically
acceptable salts, acids and derivatives of any of the above.
[0057] Examples of a "chemotherapeutic agent" also include a DNA
damaging agent such as thiotepa and CYTOXAN.RTM. cyclosphosphamide;
alkylating agents (for example cis-platin; carboplatin;
cyclophosphamide; nitrogen mustards such as chlorambucil,
chlornaphazine, chlorophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; busulphan; nitrosoureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, and ranimnustine; and
temozolomide); antimetabolites (for example antifolates such as
fluoropyrimidines like 5-fluorouracil (5-FU) and tegafur,
raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and
GEMZAR.RTM. (gemcitabine); antitumour antibiotics such as the
enediyne antibiotics (e.g., calicheamicin, especially calicheamicin
gammall and calicheamicin omegaIl (Angew Chem. Intl. Ed. Engl.
(1994) 33:183-186); anthracyclines like adriamycin; dynemicin,
including dynemicin A; bisphosphonates, such as clodronate; an
esperamicin; as well as neocarzinostatin chromophore and related
chromoprotein enediyne antibiotic chromophores), aclacinomysins,
actinomycin, authramycin, azaserine, bleomycins, cactinomycin,
carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,
ADRIAMYCIN.RTM. (doxorubicin), morpholino-doxorubicin,
cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and
deoxydoxorubicin, epirubicin, esorubicin, idarubicin,
marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,
ubenimex, zinostatin, and zorubicin; antimitotic agents (for
example vinca alkaloids like vincristine, vinblastine, vindesine
and NAVELBINE.RTM. (vinorelbine) and taxoids like taxoids, e.g.,
TAXOL.RTM. (paclitaxel; Bristol-Myers Squibb Oncology, Princeton,
N.J.), ABRAXANE.TM. (Cremophor-free), albumin-engineered
nanoparticle formulations of paclitaxel (American Pharmaceutical
Partners, Schaumberg, Ill.), and TAXOTERE.RTM. (doxetaxel;
Rhone-Poulenc Rorer, Antony, France); topoisomerase inhibitors (for
example RFS 2000, epipodophyllotoxins like etoposide and
teniposide, amsacrine, a camptothecin (including the synthetic
analog topotecan), and irinotecan and SN-38) and
cytodifferentiating agents (for example retinoids such as all-trans
retinoic acid, 13-cis retinoic acid and fenretinide); and
pharmaceutically acceptable salts, acids and derivatives of any of
the above.
[0058] A "chemotherapeutic agent" also includes an agent that
modulates the apoptotic response including inhibitors of IAP
(inhibitor of apoptosis proteins) such as AEG40826 (Aegera
Therapeutics); and inhibitors of bcl-2 such as GX15-070 (Gemin X
Biotechnologies), CNDO103 (Apogossypol; Coronado Biosciences),
HA14-1 (ethyl
2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate-
), AT101 (Ascenta Therapeutics), ABT-737 and ABT-263 (Abbott); and
pharmaceutically acceptable salts, acids and derivatives of any of
the above.
[0059] The term "prodrug" as used in this application refers to a
precursor or derivative form of a compound of the invention that is
capable of being enzymatically or hydrolytically activated or
converted into the more active parent form. See, e.g., Wilman,
"Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions,
14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al.,
"Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed
Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press
(1985). The prodrugs of this invention include, but are not limited
to, ester-containing prodrugs, phosphate-containing prodrugs,
thiophosphate-containing prodrugs, sulfate-containing prodrugs,
peptide-containing prodrugs, D-amino acid-modified prodrugs,
glycosylated prodrugs, .beta.-lactam-containing prodrugs,
optionally substituted phenoxyacetamide-containing prodrugs,
optionally substituted phenylacetamide-containing prodrugs,
5-fluorocytosine and other 5-fluorouridine prodrugs which can be
converted into the more active cytotoxic free drug. Examples of
cytotoxic drugs that can be derivatized into a prodrug form for use
in this invention include, but are not limited to, compounds of the
invention and chemotherapeutic agents such as described above.
[0060] A "metabolite" is a product produced through metabolism in
the body of a specified compound or salt thereof. Metabolites of a
compound may be identified using routine techniques known in the
art and their activities determined using tests such as those
described herein. Such products may result for example from the
oxidation, hydroxylation, reduction, hydrolysis, amidation,
deamidation, esterification, deesterification, enzymatic cleavage,
and the like, of the administered compound. Accordingly, the
invention includes metabolites of compounds of the invention,
including compounds produced by a process comprising contacting a
compound of this invention with a mammal for a period of time
sufficient to yield a metabolic product thereof.
[0061] A "liposome" is a small vesicle composed of various types of
lipids, phospholipids and/or surfactant which is useful for
delivery of a drug (such as chk inhibitors disclosed herein and,
optionally, a chemotherapeutic agent) to a mammal. The components
of the liposome are commonly arranged in a bilayer formation,
similar to the lipid arrangement of biological membranes.
[0062] The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic
products, that contain information about the indications, usage,
dosage, administration, contraindications and/or warnings
concerning the use of such therapeutic products.
[0063] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0064] The term "stereoisomer" refers to compounds which have
identical chemical constitution and connectivity, but different
orientations of their atoms in space that cannot be interconverted
by rotation about single bonds.
[0065] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as crystallization,
electrophoresis and chromatography.
[0066] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0067] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. The compounds of the
invention may contain asymmetric or chiral centers, and therefore
exist in different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L, or R and S, are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and l or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or l
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer may also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate, which may occur where there has
been no stereoselection or stereospecificity in a chemical reaction
or process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0068] The term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons. For example, any reference to a
structure of 2-hydroxypyridine include its tautomer
2-oxo-1,2-dihydropyridine, also known as 2-pyridone, and vice
versa. Similarly, compounds of Formula (I-a) include the tautomeric
form, i.e., Formula (I-c) and compounds of Formula (I-b) include
the tautomeric form, i.e., Formula (I-d).
##STR00003##
[0069] The phrase "pharmaceutically acceptable salt" as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound of the invention. Exemplary salts include, but
are not limited, to sulfate, citrate, acetate, oxalate, chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal
(e.g., sodium and potassium) salts, alkaline earth metal (e.g.,
magnesium) salts, and ammonium salts. A pharmaceutically acceptable
salt may involve the inclusion of another molecule such as an
acetate ion, a succinate ion or other counter ion. The counter ion
may be any organic or inorganic moiety that stabilizes the charge
on the parent compound. Furthermore, a pharmaceutically acceptable
salt may have more than one charged atom in its structure.
Instances where multiple charged atoms are part of the
pharmaceutically acceptable salt can have multiple counter ions.
Hence, a pharmaceutically acceptable salt can have one or more
charged atoms and/or one or more counter ion.
[0070] If the compound of the invention is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, or
with an organic acid, such as acetic acid, methanesulfonic acid,
maleic acid, succinic acid, mandelic acid, fumaric acid, malonic
acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a
pyranosidyl acid, such as glucuronic acid or galacturonic acid, an
alpha hydroxy acid, such as citric acid or tartaric acid, an amino
acid, such as aspartic acid or glutamic acid, an aromatic acid,
such as benzoic acid or cinnamic acid, a sulfonic acid, such as
p-toluenesulfonic acid or ethanesulfonic acid, or the like.
[0071] If the compound of the invention is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include, but are not
limited to, organic salts derived from amino acids, such as glycine
and arginine, ammonia, primary, secondary, and tertiary amines, and
cyclic amines, such as piperidine, morpholine and piperazine, and
inorganic salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum and lithium.
[0072] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0073] A "solvate" refers to an association or complex of one or
more solvent molecules and a compound of the invention. Examples of
solvents that form solvates include, but are not limited to, water,
isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,
and ethanolamine. The term "hydrate" refers to the complex where
the solvent molecule is water.
[0074] The term "protecting group" refers to a substituent that is
commonly employed to block or protect a particular functionality
while reacting other functional groups on the compound. For
example, an "amino-protecting group" is a substituent attached to
an amino group that blocks or protects the amino functionality in
the compound. Suitable amino-protecting groups include acetyl,
trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ),
2-(trimethylsilyl)ethoxymethyl (SEM) and
9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a
"hydroxy-protecting group" refers to a substituent of a hydroxy
group that blocks or protects the hydroxy functionality. Suitable
protecting groups include acetyl and t-butyldimethylsilyl. A
"carboxy-protecting group" refers to a substituent of the carboxy
group that blocks or protects the carboxy functionality. Common
carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general
description of protecting groups and their use, see T. W. Greene,
Protective Groups in Organic Synthesis, John Wiley & Sons, New
York, 1991.
[0075] The terms "compound of this invention," and "compounds of
the present invention", "compounds of Formula (I), (I-a), or (I-b)"
and "compounds of Formula (I), (I-a), and/or (I-b)", unless
otherwise indicated, include compounds of Formula (I), (I-a), or
(I-b) and stereoisomers, geometric isomers, tautomers, solvates,
metabolites, salts (e.g., pharmaceutically acceptable salts) and
prodrugs thereof. Unless otherwise stated, structures depicted
herein are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds of Formula (I), (I-a), or (I-b), wherein one or more
hydrogen atoms are replaced deuterium or tritium, or one or more
carbon atoms are replaced by a .sup.13C- or .sup.14C-enriched
carbon are within the scope of this invention.
[0076] The present invention provides 1,7-diazacarbazoles of
Formula (I), (I-a), and/or (I-b) (and/or solvates, hydrates and/or
salts thereof) as described above with kinase inhibitory activity,
such as chkl, GSK-3, KDR and/or FLT3 inhibitory activities. The
present compounds are particularly useful as chk1 kinase
inhibitors.
[0077] In certain embodiments of the present invention, X is
CR.sup.2, and all other variables are as defined in Formula (I),
(I-a), or (I-b). In certain embodiments of the present invention,
R.sup.2 is H, CF.sub.3, C.sub.1-C.sub.5 alkyl, or O(C.sub.1-C.sub.5
alkyl), and all other variables are as defined in Formula (I),
(I-a), or (I-b). In certain embodiments of the present invention,
R.sup.2 is H, CF.sub.3, C.sub.1-C.sub.3 alkyl, or O(C.sub.1-C.sub.3
alkyl), and all other variables are as defined in Formula (I),
(I-a), or (I-b). In certain embodiments of the present invention,
R.sup.2 is H, and all other variables are as defined in Formula
(I), (I-a), or (I-b).
[0078] In certain embodiments of the present invention, X is N, and
all other variables are as defined in Formula (I), (I-a), or
(I-b).
[0079] In certain embodiments of the present invention, Y is
CR.sup.4, and all other variables are as defined in Formula (I),
(I-a), or (I-b), or as defined in any one of the embodiments
herein. In certain embodiments of the present invention, R.sup.4 is
H, and all other variables are as defined in Formula (I), (I-a), or
(I-b), or as defined in any one of the embodiments herein.
[0080] In certain embodiments of the present invention, Y is N, and
all other variables are as defined in Formula (I), (I-a), or (I-b),
or as defined in any one of the embodiments herein.
[0081] In certain embodiments of the present invention, Z is
CR.sup.8, and all other variables are as defined in Formula (I),
(I-a), or (I-b), or as defined in any one of the embodiments
herein. In certain embodiments of the present invention, R.sup.8 is
H, and all other variables are as defined in Formula (I), (I-a), or
(I-b), or as defined in any one of the embodiments herein.
[0082] In certain embodiments of the present invention, Z is N, and
all other variables are as defined in Formula (I), (I-a), or (I-b),
or as defined in any one of the embodiments herein.
[0083] In certain embodiments of the present invention, R.sup.3 is
H; and all other variables are as defined in Formula (I), (I-a), or
(I-b), or as defined in any one of the embodiments herein.
[0084] In certain embodiments of the present invention, R.sup.3 is
halo, --O--R.sup.9, --N(R.sup.22)--R.sup.9, --S(O).sub.p--R.sup.9,
or R.sup.9; and all other variables are as defined in Formula (I),
(I-a), or (I-b), or as defined in any one of the embodiments
herein.
[0085] In certain embodiments of the present invention, R.sup.3 is
halo, and all other variables are as defined in Formula (I), (I-a),
or (I-b), or as defined in any one of the embodiments herein.
[0086] In certain embodiments of the present invention, R.sup.3 is
Br, and all other variables are as defined in Formula (I), (I-a),
or (I-b), or as defined in any one of the embodiments herein. In In
certain embodiments of the present invention, R.sup.3 is F or Cl,
and all other variables are as defined in Formula (I), (I-a), or
(I-b), or as defined in any one of the embodiments herein.
[0087] In certain embodiments of the present invention, R.sup.3 is
CN, and all other variables are as defined in Formula (I), (I-a),
or (I-b), or as defined in any one of the embodiments herein.
[0088] In certain embodiments of the present invention, R.sup.9 is
alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl and
wherein each member of R.sup.9 is independently substituted with
one to three R.sup.10 groups; and all other variables are as
defined in Formula (I), (I-a), or (I-b), or as defined in any one
of the embodiments herein.
[0089] In certain embodiments of the present invention, R.sup.9 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3 alkynyl, C.sub.6 cycloalkyl,
5-6-membered heterocyclyl having 1 to 2 nitrogen ring atoms,
C.sub.6 aryl, or 5-6 membered monocyclic or 8-10-membered bicyclic
heteroaryl and wherein each member of R.sup.9 is independently
substituted with one to two R.sup.10 groups; and all other
variables are as defined in Formula (I), (I-a) or (I-b), or as
defined in any one of the embodiments herein.
[0090] In certain embodiments of the present invention, R.sup.9 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3 alkynyl, C.sub.6 aryl, or
5-6 membered monocyclic or 8-10-membered bicyclic heteroaryl having
1 to 2 ring atoms selected from N, O and S; and wherein each member
of R.sup.9 is independently substituted with one to two R.sup.10
groups; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0091] In certain embodiments of the present invention, R.sup.9 is
isopropyl, propynyl, phenyl, pyrazolyl, furanyl, thienyl, pyridyl,
imidazolyl, pyrimidinyl, benzothienyl, thiazolyl,
tetrahydrothienopyridinyl, tetrahydrothiazolopyridinyl,
isothiazolyl, tetrahydropyridinyl, tetrahydroisoquinolinyl,
triazolyl, dihydrobenzodioxinyl, dihydroindolyl, or oxazolyl,
wherein each member of R.sup.9 is independently substituted with
one to two R.sup.10 groups; and all other variables are as defined
in Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0092] In certain embodiments of the present invention, R.sup.9 is
cyclohexyl or piperidinyl, and wherein each member of R.sup.9 is
independently substituted with one to two R.sup.10 groups; and all
other variables are as defined in Formula (I), (I-a) or (I-b), or
as defined in any one of the embodiments herein.
[0093] In certain embodiments of the present invention, R.sup.3 is
R.sup.9 and R.sup.9 is as defined in any one of the embodiments
herein, and all other variables are as defined in Formula (I),
(I-a) or (1-b), or as defined in any one of the embodiments
herein.
[0094] In certain embodiments of the present invention, R.sup.3 is
OR.sup.9, and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0095] In certain embodiments of the present invention, R.sup.3 is
OR.sup.9 and R.sup.9 is as defined in any one of the embodiments
herein, and all other variables are as defined in Formula (I),
(I-a) or (1-b), or as defined in any one of the embodiments
herein.
[0096] In certain embodiments of the present invention, R.sup.3 is
OR.sup.9 and R.sup.9 is phenyl optionally substituted with one to
three R.sup.10 groups; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0097] In certain embodiments of the present invention, R.sup.3 is
OR.sup.9, and R.sup.9 is alkyl or heterocyclyl wherein said alkyl
or heterocyclyl is optionally substituted with one to three
R.sup.10 groups; and all other variables are as defined in Formula
(I), (I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0098] In certain embodiments of the present invention, R.sup.3 is
OR.sup.9, and R.sup.9 is C.sub.1-C.sub.2 alkyl optionally
substituted with one to two R.sup.10 groups selected from
N(Me).sub.2, NHEt, N-methylpiperidinyl and OCH.sub.3; and all other
variables are as defined in Formula (I), (I-a) or (I-b), or as
defined in any one of the embodiments herein.
[0099] In certain embodiments of the present invention, R.sup.3 is
OR.sup.9, and R.sup.9 is piperidinyl or pyrrolidinyl wherein
piperidinyl or pyrrolidinyl is optionally substituted with one to
three R.sup.10 groups; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0100] In certain embodiments of the present invention, R.sup.3 is
--N(R.sup.22)--R.sup.9, and R.sup.9 is defined in any one of the
embodiments herein; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0101] In certain embodiments of the present invention, R.sup.3 is
--N(R.sup.22)--R.sup.9, and R.sup.9 is alkyl optionally substituted
with one to three R.sup.10 groups; and all other variables are as
defined in Formula (I), (I-a) or (I-b), or as defined in any one of
the embodiments herein.
[0102] In certain embodiments of the present invention, R.sup.3 is
--N(R.sup.22)--R.sup.9, and R.sup.9 is C.sub.1-C.sub.2 alkyl
optionally substituted with one to two R.sup.10 groups selected
from oxo, NR.sup.11R.sup.12; and all other variables are as defined
in Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein. In certain embodiments of the present
invention, R.sup.3 is NH-ethyl or NHC(O)(N-pyrrolidinyl); and all
other variables are as defined in Formula (I), (I-a) or (I-b), or
as defined in any one of the embodiments herein.
[0103] In certain embodiments of the present invention, R.sup.3 is
hydrogen, fluoro, chloro, bromo, cyano, trifluoromethyl, methyl,
(2-propyl), (2-hydroxy-2-propyl), (2-fluoro-2-propyl), cyclopropyl,
methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,
(2-hydroxyethyl)oxy, (2,2,2-trifluoroethyl)oxy, methylsulfonyl, or
aminosulfonyl; all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0104] In certain embodiments of the present invention, R.sup.3 is
R.sup.9 wherein R.sup.9 is alkyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl and wherein each member of
R.sup.9 is independently substituted with one to three R.sup.10
groups; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0105] In certain embodiments of the present invention, R.sup.3 is
R.sup.9 wherein R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3
alkynyl, C.sub.4-C.sub.6 cycloalkyl, C.sub.6 aryl, 4-6 membered
heterocyclyl or 5-6 membered monocyclic or 8-10-membered bicyclic
heteroaryl having 1 to 2 ring atoms selected from N, O and S; and
wherein each member of R.sup.9 is independently substituted with
one to two R.sup.10 groups; and all other variables are as defined
in Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0106] In certain embodiments of the present invention, R.sup.3 is
R.sup.9 wherein R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3
alkynyl, C.sub.6 aryl, or 5-6 membered monocyclic or 8-10-membered
bicyclic heteroaryl having 1 to 2 ring atoms selected from N, O and
S; and wherein each member of R.sup.9 is independently substituted
with one to two R.sup.10 groups; and all other variables are as
defined in Formula (I), (I-a) or (I-b), or as defined in any one of
the embodiments herein.
[0107] In certain embodiments of the present invention, R.sup.3 is
R.sup.9 wherein R.sup.9 is isopropyl, propynyl, phenyl, pyrazolyl,
furanyl, thienyl, pyridyl, imidazolyl, pyrimidinyl, benzothienyl,
thiazolyl, tetrahydrothienopyridinyl, tetrahydrothiazolopyridinyl,
isothiazolyl, tetrahydropyridinyl, tetrahydroisoquinolinyl,
triazolyl, dihydrobenzodioxinyl, dihydroindolyl, oxazolyl, or
tetrahydrobenzothienyl, wherein each member of R.sup.9 is
independently substituted with one to two R.sup.10 groups; and all
other variables are as defined in Formula (I), (I-a) or (I-b), or
as defined in any one of the embodiments herein.
[0108] In certain embodiments of the present invention, R.sup.3 is
R.sup.9 wherein R.sup.9 is cyclohexyl or piperidinyl, wherein each
member of R.sup.9 is independently substituted with one to two
R.sup.10 groups; and all other variables are as defined in Formula
(I), (I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0109] In certain embodiments of the present invention, R.sup.10 is
H, halo, R.sup.11, --OR.sup.11, CN, --CF.sub.3, --OCF.sub.3,
--NR.sup.12C(.dbd.O)R.sup.11, --NR.sup.12S(O).sub.qR.sup.11,
--SR.sup.11, --NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
oxo, --S(O).sub.qR.sup.11, --S(O).sub.2NR.sup.11R.sup.12, or
--C(.dbd.O)OR.sup.11, wherein R.sup.11 and R.sup.12 are optionally
taken together with the attached N atom to form a 4-7 membered ring
having additional 0-2 heteroatoms selected from O, S, and N, said
ring being optionally substituted with one to four R.sup.13 groups;
and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0110] In certain embodiments of the present invention, R.sup.10 is
halo, R.sup.11, --OR.sup.11, CN, --CF.sub.3, --OCF.sub.3,
--NR.sup.12C(.dbd.O)R.sup.11, --NR.sup.12S(O).sub.qR.sup.11,
--SR.sup.11, --NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
oxo, --S(O).sub.qR.sup.11, --S(O).sub.2NR.sup.11R.sup.12, (or
--C(.dbd.O)OR.sup.11, wherein R.sup.11 and R.sup.12 are optionally
taken together with the attached N atom to form a 4-7 membered ring
having additional 0-2 heteroatoms selected from O, S, and N, said
ring being optionally substituted with one to four R.sup.13 groups;
and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0111] In certain embodiments of the present invention, R.sup.10 is
halo; CN; --CF.sub.3; --OCF.sub.3; --NR.sup.12C(O)R.sup.11 wherein
R.sup.12 is H and R.sup.11 is C.sub.1-C.sub.4 alkyl;
--NR.sup.12S(O).sub.2R.sup.11 wherein R.sup.12 is H and R.sup.11 is
C.sub.1-C.sub.4 alkyl; --SR.sup.11 wherein is H or C.sub.1-C.sub.4
alkyl; --NR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are
independently H or C.sub.1-C.sub.4 alkyl and R.sup.11 and R.sup.12
are optionally taken together with the attached N atom to form a
6-membered ring having additional 0-2 heteroatoms selected from O,
S, and N, said ring being optionally substituted with one R.sup.22
group; --C(.dbd.Y')NR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12
are independently H or C.sub.1-C.sub.4 alkyl; oxo;
--S(O).sub.2R.sup.11 wherein R.sup.11 is C.sub.1-C.sub.4 alkyl,
C.sub.5-C.sub.6 cycloalkyl or a 5-6 membered heterocyclyl having 1
to 2 heteroatoms selected from N and O; or
--S(O).sub.2NR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are
independently H or C.sub.1-C.sub.4 alkyl; and all other variables
are as defined in Formula (I), (I-a), or (I-b), or as defined in
any one of the embodiments herein.
[0112] In certain embodiments of the present invention, R.sup.10 is
F, Cl, CN, --CF.sub.3, --OCF.sub.3, --OH, --NHC(O)CH.sub.3,
--NHS(O).sub.2CH.sub.3, --SCH.sub.3, --NH.sub.2, --N(Et).sub.2,
--C(O)NH.sub.2, --C(O)NH(p-methoxybenzyl), --C(O)N(Et).sub.2, oxo,
--S(O).sub.2CH.sub.3, --S(O).sub.2N(CH.sub.3).sub.2, N-morpholinyl,
N-piperidinyl, N-piperazinyl, or CO.sub.2H, and all other variables
are as defined in Formula (I), (I-a) or (I-b), or as defined in any
one of the embodiments herein.
[0113] In certain embodiments of the present invention, R.sup.10 is
R.sup.11, and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0114] In certain embodiments of the present invention, R.sup.10 is
R.sup.11 wherein R.sup.11 is alkyl or heterocyclyl, wherein said
alkyl and heterocyclyl are optionally substituted with one to four
R.sup.13 groups, wherein two geminal R.sup.13 groups are optionally
taken together with the atom to which they are attached to form a
3-6 membered ring having additional 0-2 heteroatom selected from O,
S, and N, said ring being optionally substituted with one to four
R.sup.18 groups; and all other variables are as defined in Formula
(I), (I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0115] In certain embodiments of the present invention, R.sup.10 is
R.sup.11 wherein R.sup.11 is C.sub.1-C.sub.6 alkyl, or 4-6 membered
(e.g., 5-6 membered) monocyclic or 8-10-membered bicyclic
heterocyclyl having 1 to 2 heteroatoms selected from N and O,
wherein said alkyl and heterocyclyl are optionally substituted with
one to four R.sup.13 groups, wherein two geminal R.sup.13 groups
are optionally taken together with the atom to which they are
attached to form a six-membered ring having 0-2 heteroatom selected
from O, S, and N, said ring being optionally substituted with one
to four R.sup.18 groups; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0116] In certain embodiments of the present invention, R.sup.10 is
R.sup.11 wherein R.sup.11 is C.sub.1-C.sub.6 alkyl, or 4-6 membered
(e.g., 5-6 membered) monocyclic or 8-10-membered bicyclic
heterocyclyl having 1 to 2 heteroatoms selected from N and O,
wherein said alkyl and heterocyclyl are optionally substituted with
one to two R.sup.13 groups and wherein each R.sup.13 is
independently halo, CN, CF.sub.3, --OCF.sub.3, oxo,
--(CR.sup.14R.sup.15).sub.nC(O)OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0117] In certain embodiments of the present invention, R.sup.10 is
R.sup.11 wherein R.sup.11 is C.sub.1-C.sub.6 alkyl, wherein alkyl
is optionally substituted with one to two R.sup.13 groups and
wherein each R.sup.13 is independently halo, CN, CF.sub.3,
--OCF.sub.3, oxo, --(CR.sup.14R.sup.15).sub.nC(O)OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0118] In certain embodiments of the present invention, R.sup.10 is
R.sup.11 wherein R.sup.11 is methyl, ethyl, i-butyl, t-butyl,
CH.sub.2R.sup.27 wherein R.sup.27 is N(methyl).sub.2, OH,
OCH.sub.3, CH.sub.2OH, piperazinyl, piperidinyl, morpholinyl,
pyrrolyl, azetidinyl, C(CH.sub.3).sub.2-piperidinyl, wherein
piperazinyl or piperidinyl is optionally substituted with one to
two groups selected from methyl, ethyl, hydroxy or
(CH.sub.2).sub.2OH; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0119] In certain embodiments of the present invention, R.sup.10 is
R.sup.11 wherein R.sup.11 is 5-6 membered monocyclic or
8-10-membered bicyclic heterocyclyl having 1 to 2 heteroatoms
selected from N and O, wherein said alkyl and heterocyclyl are
optionally substituted with one to two R.sup.13 groups and wherein
each R.sup.13 is independently halo, CN, CF.sub.3, --OCF.sub.3,
oxo, --(CR.sup.14R.sup.15).sub.nC(O)OR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0120] In certain embodiments of the present invention, R.sup.10 is
--OR.sup.11; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0121] In certain embodiments of the present invention, R.sup.10 is
--OR.sup.11 wherein R.sup.11 is H, alkyl or heterocyclyl, wherein
said alkyl or heterocyclyl is optionally substituted with one to
four R.sup.13 groups and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0122] In certain embodiments of the present invention, R.sup.10 is
--OR.sup.11 wherein R.sup.11 is H, C.sub.1-C.sub.4 alkyl, or 4-6
membered (e.g., 5-6 membered) monocyclic or 8-10-membered bicyclic
heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or
heterocyclyl is optionally substituted with one to four R.sup.13
groups; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0123] In certain embodiments of the present invention, R.sup.10 is
--OR.sup.11 wherein R.sup.11 is H, C.sub.1-C.sub.4 alkyl, or 4-6
membered (e.g., 5-6 membered) monocyclic or 8-membered bicyclic
heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or
heterocyclyl is optionally substituted with one to two R.sup.13
groups, wherein each R.sup.13 is independently halo, CN, CF.sub.3,
--OCF.sub.3, oxo, --(CR.sup.14R.sup.15).sub.nC(O)OR.sup.16,
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nNR.sup.16R.sup.17,
--(CR.sup.14R.sup.15).sub.nOR.sup.16,
--(CR.sup.14R.sup.15).sub.nNR.sup.16C(O)R.sup.17,
--(CR.sup.14R.sup.15).sub.nS(O).sub.2NR.sup.16R.sup.17, or
R.sup.16; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments herein.
In certain embodiments, R.sup.10 is OH or OCH.sub.3; and all other
variables are as defined in Formula (I), (I-a) or (I-b), or as
defined in any one of the embodiments herein.
[0124] In certain embodiments of the present invention, R.sup.3 is
selected from:
##STR00004## ##STR00005##
H, F, Cl, Br, iPr or CO.sub.2CH.sub.3; and all other variables are
as defined in Formula (I), (I-a) or (I-b), or as defined in any one
of the embodiments herein.
[0125] In certain embodiments of the present invention, R.sup.4 is
H; and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0126] In certain embodiments of the present invention, R.sup.5 is
H, halo, --(CR.sup.14R.sup.15).sub.nC(O)NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(O)R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nSR.sup.11, alkyl, heterocyclyl or
heteroaryl, wherein the said alkyl, heterocyclyl or heteroaryl is
optionally substituted with one to four R.sup.13 groups; and all
other variables are as defined in Formula (I), (I-a) or (I-b), or
as defined in any one of the embodiments herein.
[0127] In certain embodiments of the present invention, R.sup.5 is
H, halo, --(CR.sup.14R.sup.15).sub.nC(O)NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(O)R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.n--OR.sup.11,
--(CR.sup.14R.sup.15).sub.nSR.sup.11, alkyl, or heterocyclyl,
wherein the said alkyl or heterocyclyl is optionally substituted
with one to four R.sup.13 groups; and all other variables are as
defined in Formula (I), (I-a) or (I-b), or as defined in any one of
the embodiments herein.
[0128] In certain embodiments of the present invention, R.sup.5 is
halo or C.sub.2-C.sub.6 alkenyl; and all other variables are as
defined in Formula (I), (I-a) or (I-b), or as defined in any one of
the embodiments herein.
[0129] In certain embodiments of the present invention, R.sup.5 is
H; and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0130] In certain embodiments of the present invention, R.sup.5 is
Cl, Br or F; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0131] In certain embodiments of the present invention, R.sup.5 is
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(O)R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nSR.sup.11, C.sub.1-C.sub.6 alkyl, or 4-6
membered (e.g., 5-6 membered) monocyclic or 7-10 membered bicyclic
heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or
heterocyclyl is optionally substituted with one to two R.sup.13
groups; wherein R.sup.14 and R.sup.15 are H; n is 0-2; each
R.sup.11 is independently H, C.sub.1-C.sub.4 alkyl or 5-6 membered
monocyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said
alkyl or heterocyclyl is optionally substituted with one to two
R.sup.13 groups; and all other variables are as defined in Formula
(I), (I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0132] In certain embodiments of the present invention, R.sup.5 is
--(CR.sup.14R.sup.15).sub.nC(O)NR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nNR.sup.12C(O)R.sup.11,
--(CR.sup.14R.sup.15).sub.nNR.sup.11R.sup.12,
--(CR.sup.14R.sup.15).sub.nOR.sup.11,
--(CR.sup.14R.sup.15).sub.nSR.sup.11, C.sub.1-C.sub.6 alkyl, or 4-6
membered (e.g., 5-6 membered) monocyclic or 7-10 membered bicyclic
heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or
heterocyclyl is optionally substituted with one to two R.sup.13
groups; wherein R.sup.14 and R.sup.15 are H; n is 0-2; each
R.sup.11 is independently H, C.sub.1-C.sub.4 alkyl, or 5-6 membered
monocyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said
alkyl or heterocyclyl is optionally substituted with one to two
R.sup.13 groups; R.sup.13 is OH, O(C.sub.1-C.sub.3 alkyl), or
C.sub.1-C.sub.3 alkyl; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0133] In certain embodiments of the present invention, R.sup.5 is
--(CR.sup.14R.sup.15).sub.nOR.sup.11, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or halo; and all other variables are as
defined in Formula (I), (I-a) or (I-b), or as defined in any one of
the embodiments herein.
[0134] In certain embodiments of the present invention, R.sup.5 is
--OR.sup.11; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0135] In certain embodiments of the present invention, R.sup.5 is
--NR.sup.11; and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0136] In certain embodiments of the present invention, R.sup.5 is
C.sub.1-C.sub.6 alkyl, or 4-6 membered (e.g., 5-6 membered)
monocyclic or 7-10 membered bicyclic heterocyclyl having 1 to 2
nitrogen atoms wherein the point of attachment is via a carbon atom
on said heterocyclyl, wherein said alkyl or heterocyclyl is
optionally substituted with one to two R.sup.13 groups; and all
other variables are as defined in Formula (I), (I-a) or (I-b), or
as defined in any one of the embodiments herein.
[0137] In certain embodiments of the present invention, R.sup.5 is
5-6 membered heteroaryl; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein. In certain embodiments, R.sup.5 is imidazolyl;
and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0138] In certain embodiments of the present invention, R.sup.5 is
F, ethyl, OH, OEt, O(CH.sub.2).sub.2OH, O(pyrrolidinyl), Br,
--CH.dbd.CH.sub.2, or O(CH.sub.2).sub.2OCH.sub.3, and all other
variables are as defined in Formula (I), (I-a) or (I-b), or as
defined in any one of the embodiments herein.
[0139] In certain embodiments of the present invention, R.sup.5 is
tropinyl, quinuclideinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or azetidine wherein said tropinyl, quinuclideinyl,
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azetidine
is optionally substituted with one or more F; and all other
variables are as defined in Formula (I), (I-a) or (I-b), or as
defined in any one of the embodiments herein.
[0140] In certain embodiments of the present invention, R.sup.5 is
selected from the following; and all other variables are as defined
in Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein: ethyl, OH, ethoxy,
O(CH.sub.2CH.sub.2)OCH.sub.3,
##STR00006## ##STR00007## ##STR00008## ##STR00009##
[0141] In certain embodiments of the present invention, R.sup.6 is
H; and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0142] In certain embodiments of the present invention, R.sup.6 is
CN, --CF.sub.3, --OCF.sub.3, halo, --C(.dbd.Y')OR.sup.11,
--C(.dbd.Y')NR.sup.11R.sup.12, --OR.sup.11, --OC(.dbd.Y')R.sup.11,
--NR.sup.11R.sup.12, --NR.sup.12C(.dbd.Y')R.sup.11,
--NR.sup.12C(.dbd.Y')NR.sup.11R.sup.12,
--NR.sup.12S(O).sub.qR.sup.11, --SR.sup.11, --S(O)R.sup.11,
--S(O).sub.2R.sup.11, --OC(.dbd.Y')NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are
optionally substituted by one to four R.sup.13 groups; and all
other variables are as defined in Formula (I), (I-a) or (I-b), or
as defined in any one of the embodiments herein.
[0143] In certain embodiments of the present invention, R.sup.6 is
CN, CF.sub.3, --OCF.sub.3, halo, --C(O)OR.sup.11,
--C(O)NR.sup.11R.sup.12, --OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)R.sup.11, --NR.sup.12C(.dbd.NR.sup.12)R.sup.11,
--NR.sup.12S(O).sub.2R.sup.11, --SR.sup.11, --S(O).sub.2R.sup.11,
alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said
alkyl is substituted with one to four R.sup.13 groups except H and
said heterocyclyl or heteroaryl is optionally substituted by one to
four R.sup.13 groups; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0144] In certain embodiments of the present invention, R.sup.6 is
CN, halo, --C(O)NR.sup.11R.sup.12, --OR.sup.11,
--NR.sup.11R.sup.12, --NR.sup.12C(O)R.sup.11, alkyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein said alkyl is
substituted with one to two R.sup.13 groups except H, and said
heteroaryl is optionally substituted by one to two R.sup.13 groups;
and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0145] In certain embodiments of the present invention, R.sup.6 is
CN, halo, --C(O)NR.sup.11R.sup.12, --OR.sup.11,
--NR.sup.11R.sup.12, --NR.sup.12C(O)R.sup.11, C.sub.1-C.sub.3
alkyl, C.sub.3-C.sub.6 cycloalkyl, 5-6 heterocyclyl having 1 to 2
heteroatoms, C.sub.6 aryl, or 5-6 or 9-membered heteroaryl having 1
to 4 heteroatoms; wherein said alkyl is substituted with one to two
R.sup.13 groups except H; and said cycloalkyl, aryl, heterocyclyl
or heteroaryl is optionally substituted by one to two R.sup.13
groups; wherein heteroatoms are selected from N, O and S; wherein
each R.sup.12 is H or C.sub.1-C.sub.3 alkyl and each R.sup.11 is
independently H or C.sub.1-C.sub.3 alkyl optionally substituted by
one to two R.sup.13 groups; and all other variables are as defined
in Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0146] In certain embodiments of the present invention, R.sup.6 is
CN, halo, --C(O)NR.sup.11R.sup.12, --OR.sup.11,
--NR.sup.11R.sup.12, --NR.sup.12C(O)R.sup.11, C.sub.1-C.sub.3
alkyl, or 5-6 or 9-membered heteroaryl having 1 to 4 heteroatoms
selected from N, O and S, wherein said alkyl is substituted with
one to two R.sup.13 groups (wherein R.sup.13 is OR.sup.16 where
R.sup.16 is H or alkyl), and said heteroaryl is optionally
substituted by one to two R.sup.13 groups (wherein R.sup.13 is
OR.sup.16, NR.sup.16R.sup.17, or C.sub.1-C.sub.2 alkyl optionally
substituted with R.sup.18 where each of R.sup.16 and R.sup.17 is
independently H or alkyl); wherein each R.sup.12 is H or
C.sub.1-C.sub.3 alkyl and each R.sup.11 is independently H or
C.sub.1-C.sub.3 alkyl optionally substituted by one to two R.sup.13
groups (wherein R.sup.13 is OR.sup.16 where R.sup.16 is H or
alkyl); and all other variables are as defined in Formula (I),
(I-a) or (I-b), or as defined in any one of the embodiments
herein.
[0147] In certain embodiments of the present invention, R.sup.6 is
CN, F, Cl, Br, --C(O)OH, --C(O)NH.sub.2,
--C(O)NHCH.sub.2CH.sub.2OH, --C(O)N(CH.sub.3).sub.2, --OCH.sub.3,
--CH.sub.2OH, --C(CH.sub.3).sub.2OH, pyridyl, pyrazolyl,
pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,
pyrazinyl, imidazopyrimidinyl, pyridazinyl, triazolyl, tetrazolyl,
thiadiazolyl, oxadiazolyl, --C(O)--N-pyrrolidinyl, --C(O)NHEt, or
--C(O)NH(CH.sub.2).sub.2NH.sub.2, wherein said pyridyl, pyrazolyl,
pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,
pyrazinyl, imidazopyrimidinyl, pyridazinyl, triazolyl, tetrazolyl,
thiadiazolyl, and oxadiazolyl are optionally substituted with 1-2
groups selected from methyl, methoxy, NH.sub.2, and benzyl; and all
other variables are as defined in Formula (I), (I-a) or (1-b), or
as defined in any one of the embodiments herein.
[0148] In certain embodiments of the present invention, R.sup.6 is
CN; and all other variables are as defined in Formula (I), (I-a) or
(I-b), or as defined in any one of the embodiments herein.
[0149] In certain embodiments of the present invention, R.sup.6 is
pyridyl, or pyrazolyl optionally substituted with methyl; and all
other variables are as defined in Formula (I), (I-a) or (1-b), or
as defined in any one of the embodiments herein.
[0150] In certain embodiments of the present invention, R.sup.7 is
H, or C.sub.1-C.sub.4 alkyl optionally substituted with one to
three halo groups or OH; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0151] In certain embodiments of the present invention, R.sup.7 is
H, methyl or ethyl; and all other variables are as defined in
Formula (I), (I-a) or (I-b), or as defined in any one of the
embodiments herein.
[0152] In certain embodiments, R.sup.10 is methyl, ethyl or
R.sup.30 as defined in Formula (II) below.
[0153] In certain embodiments, compounds are of Formula (H):
##STR00010##
wherein R.sup.6 is CN,
##STR00011##
and R.sup.30 is
##STR00012## ##STR00013## ##STR00014##
[0155] In certain embodiments, compounds are of Formula (H),
wherein R.sup.6 is
##STR00015##
wherein R.sup.13 is OCH.sub.3, O-piperidinyl,
O-(1-ethyl)piperidinyl or O(CH.sub.2).sub.2N(CH3).sub.2.
[0156] In certain embodiments, compounds are of Formula (II),
wherein R.sup.30 is
##STR00016##
wherein
##STR00017##
is
##STR00018##
[0157] In certain embodiments, compounds are of Formula (III):
##STR00019##
wherein R.sup.40 is
##STR00020##
[0158] Another embodiment of the present invention includes title
compounds described herein Examples 1-403 and compounds below.
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026##
wherein each R.sup.3 is independently H, hydrogen, fluoro, chloro,
bromo, cyano, trifluoromethyl, methyl, (2-propyl),
(2-hydroxy-2-propyl), (2-fluoro-2-propyl), cyclopropyl, methoxy,
ethoxy, difluoromethoxy, trifluoromethoxy, (2-hydroxyethyl)oxy,
(2,2,2-trifluoroethyl)oxy, methylsulfonyl, or aminosulfonyl.
[0159] The present compounds are prepared according to the
procedures described below in the schemes and examples, or by
methods known in the art. The starting materials and various
intermediates may be obtained from commercial sources, prepared
from commercially available compounds, or prepared using well known
synthetic methods. Accordingly, methods for making the present
compounds of Formula (I), (I-a) or (I-b) according to Scheme 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11a, 11b, 11c, 11d, 11c, 11d, 11e, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and/or 27
(27-1, 27-2, and 27-3) are within the scope of the present
invention.
[0160] For example, 9H-dipyrido[2,3-b;4',3'-d]pyrrole (also
referred to as diazacarbazole herein) compounds of formula (1-4)
may be prepared using the synthetic route outlined in Scheme 1.
##STR00027##
[0161] Compounds of formula (1-1) may be prepared using published
methods described in the literature. Intermediates of formula (1-1)
may then be brominated in the presence of a suitable brominating
agent, such as bromine, in a suitable solvent such as acetic acid,
at a temperature between 20.degree. C. and 120.degree. C., to
obtain compounds of formula (1-2).
[0162] Compounds of formula (1-3) can be obtained by reaction of
intermediate (1-2) with an appropriate source of ammonia, such as
ammonia gas, in a suitable solvent such as methanol, at a
temperature between 20.degree. C. and 65.degree. C.
[0163] Intermediates of formula (1-3) may then be dehydrated in the
presence of a suitable dehydrating agent, such as trifluoroacetic
anhydride, in a suitable solvent such as THF, at a temperature from
20.degree. C. to the boiling point of the solvent, to obtain
compounds of formula (1-4).
##STR00028##
[0164] Compounds of formula (2-4) may also be prepared according to
the procedure shown in Scheme 2 (wherein R.sup.3' is R.sup.3 or
intermediate moieties that may be manipulated to give R.sup.3, and
R.sup.6' is R.sup.6 or intermediate moieties that may be
manipulated to give R.sup.6). The boronic acid of formula (2-2,
where R.dbd.H) may be prepared from compounds of formula (2-1) by
treatment with a base such as butyllithium in the presence of an
alkyl borate such as trimethyl borate in a suitable solvent such as
THF at a temperature between -78.degree. C. and ambient
temperature.
[0165] Alternatively, the boronate ester of formula (2-2, where
R=alkyl) may be prepared from compounds of formula (2-1) with the
appropriate alkylatodiboron in the presence of a catalyst such as
bis(diphenylphosphino)ferrocene palladium(II) dichloride, using a
suitable base such as potassium acetate in a solvent such as
dioxane at a temperature from room temperature to the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C.
[0166] Compounds of formula (2-4) may be prepared according to the
procedure shown in Scheme 2 by reaction of compounds of formula
(2-2) with appropriate halide of formula (2-3) (incorporating
appropriate substituents R.sup.3'), in the presence of a catalyst
such as bis(triphenylphosphine) palladium(II)dichloride, with a
base such as aqueous sodium carbonate in a suitable co-solvent such
as acetonitrile at a temperature from room temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0167] The protecting group (P.sub.1) of compounds of formula
(2-1), (2-2) and (2-4) may be manipulated at any stage of the
synthesis. A protecting group such as SEM (trimethylsilyl
ethoxymethyl), can be installed using an alkylating agent such as
SEM-chloride, in a solvent such as DMF in the presence of a
suitable base such as sodium hydride. Compounds of general formula
(2-4) where P.sub.1 is a protecting group such as SEM may be
de-protected using a reagent such as tetrabutylammonium fluoride in
a solvent such as THF at a temperature between -20.degree. C. and
50.degree. C. to provide compounds where P.sub.1 is H.
##STR00029##
[0168] Compounds of general formula (3-4) may also be prepared
according to the procedure shown in Scheme 3 (wherein R.sup.3' is
R.sup.3 or intermediate moieties that may be manipulated to give
R.sup.3, and R.sup.6' is R.sup.6 or intermediate moieties that may
be manipulated to give R.sup.6). Stannanes of general formula (3-2)
may be prepared from compounds of formula (3-1) with a base and the
appropriate tin halide in a suitable solvent such as THF.
[0169] Alternatively, stannanes of general formula (3-2) may be
prepared from compounds of formula (3-1) with the appropriate
alkylditin (containing suitable R groups) in the presence of a
catalyst such as tetrakis(triphenylphosphine) palladium(0) in a
suitable solvent such as toluene at a temperature from room
temperature to the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150.degree. C.
[0170] Compounds of general formula (3-4) may be prepared from
compounds of general formula (3-2) with the appropriate halide or
triflate of formula (3-3), in the presence of a catalyst such as
tetrakis(triphenylphosphine) palladium(0) in a suitable solvent
such as dioxane at a temperature from room temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
##STR00030##
[0171] Compounds of general formula (4-6) may be obtained from
commercial sources or prepared using published methods described in
the literature. Compounds of general formula (4-6) may also be
prepared according to the procedure shown in Scheme 4.
[0172] Compounds of general formula (4-3) may be obtained from
compounds of formula (4-1) by reaction with a halogenated pyridine
or triflate of formula (4-2) in the presence of a transition metal
catalyst such as bis(triphenylphosphine) palladium(II) dichloride,
a base such as aqueous sodium carbonate in a suitable solvent such
as acetonitrile at a temperature from room temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0173] The 2-cyanopyridines of formula (4-4) may be prepared from
2-halopyridines of formula (4-3) by reaction with an inorganic
cyanide such as zinc cyanide, in the presence of a transition metal
catalyst such as tetrakis(triphenylphosphine) palladium(0), in a
solvent such as DMF, at a temperature from 50.degree. C. to reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 200.degree. C. The
aminopyridine (4-4) may then be halogenated with a halogenating
agent such as N-bromosuccinimide in a solvent such as DMF at a
temperature between room temperature and 50.degree. C. to give
intermediates of formula (4-5).
[0174] Cyclisation of compounds with general formula (4-5) with a
suitable base such as sodium hexamethyldisilazide in a suitable
solvent such as THF at a temperature between 0.degree. C. and
50.degree. C. may give compounds of general formula (4-6).
##STR00031##
[0175] Compounds of general formulae (5-2), (5-3) and (5-4) may be
prepared using published methods described in the literature.
Compounds of formulae (5-2), (5-3) and (5-4) may also be prepared
using the synthetic routes outlined in Scheme 5 (wherein R.sup.3'
is R.sup.3 or intermediate moieties that may be manipulated to give
R.sup.3).
[0176] Compounds of general formula (5-2) may be obtained from
compounds of formula (5-1) by reaction with a reagent such as
n-butyllithium in a polar aprotic solvent such as THF or
diethylether at temperatures between -100.degree. C. and 0.degree.
C. and quenched with a boronic ester such as trimethyl borate or
triisopropyl borate.
[0177] Compounds of general formula (5-3) may be obtained from
compounds of formula (5-1) by reaction with a reagent such as
bis(pinacolato)diborane in the presence of a catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the
presence of a base such as potassium acetate in a suitable solvent
such as dioxane, or a mixture of two or more appropriate solvents,
at a temperature between room temperature to the reflux temperature
of the solvent or solvents, or under microwave irradiation at a
temperature between 70.degree. C. and 160.degree. C.
[0178] Compounds of general formula (5-4) may be obtained from
compounds of formula (5-1) by reaction with a reagent such as
hexamethylditin or triethyltin chloride in the presence of a
catalyst such as tetrakis(triphenylphosphine)palladium (0), in the
presence of a base such as potassium carbonate in a suitable
solvent such as DMF, or a mixture of two or more appropriate
solvents, at a temperature between room temperature to the reflux
temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0179] Alternatively, these compounds of general formula (5-4) may
be obtained from compounds of formula (5-1) by reaction with a
reagent such as n-butyllithium in a suitable aprotic solvent such
as THF at temperatures between -100.degree. C. and 25.degree. C.
and then reacted with a reagent such as hexamethylditin or
triethyltin chloride in a suitable aprotic solvent such as THF at
temperatures between -100.degree. C. and 50.degree. C.
##STR00032##
[0180] Compounds of general formula (6-3) may be prepared using
published methods described in the literature. Compounds of formula
(6-3) may also be prepared using the synthetic routes outlined in
Scheme 6 (wherein R.sup.3' is R.sup.3 or intermediate moieties that
may be manipulated to give R.sup.3, and R.sup.6' is R.sup.6 or
intermediate moieties that may be manipulated to give R.sup.6).
Compounds of general formula (6-3) may be obtained from compounds
of formula (6-1) by reaction with a boronic acid or boronate ester
of formula (6-2) (incorporating appropriate substituents R.sup.3'),
or by reaction with an aryl or alkyl tin compound of formula (6-4)
(incorporating appropriate substituents R.sup.3'), in the presence
of a catalyst such as
bis(triphenylphosphine)palladium(II)dichloride,
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II), an
aqueous base such as sodium carbonate, in a suitable solvent such
as acetonitrile or combination of solvents, at a temperature
between room temperature to the reflux temperature of the solvent,
or under microwave irradiation at a temperature between 70.degree.
C. and 150.degree. C.
##STR00033##
[0181] Compounds of general formula (7-8) may be prepared using
published methods described in the literature. Compounds of formula
(7-8) may also be prepared using the synthetic routes outlined in
Scheme 7 (wherein R.sup.6' is R.sup.6 or intermediate moieties that
may be manipulated to give R.sup.6). Compounds of general formula
(7-3) may be obtained from compounds of general formula (7-1) and a
suitable alkyne (7-2) (incorporating a group R.sup.10 that could be
either maintained without modification after coupling, or that
could later be modified to give other groups)R.sup.10 by reaction
in the presence of a catalyst system such as
tetrakis(triphenylphosphine) palladium(0) and copper (I) iodide in
the presence of a base such as triethylamine and a suitable solvent
such as N,N-dimethylformamide at a temperature between room
temperature and the boiling point of the solvent. Such a coupling
reaction could also be carried out in the presence of palladium on
carbon, triphenylphosphine, copper (I) iodide and triethylamine in
the presence of a suitable solvent such as acetonitrile at a
temperature between room temperature and the reflux temperature of
the solvent or solvents, or under microwave irradiation at a
temperature between 70.degree. C. and 160.degree. C.
[0182] Compounds of general formula (7-6) may be obtained from
compounds of general formula (7-3) and hydrogen in the presence of
a suitable catalyst such as Lindlar catalyst or palladium on barium
sulfate in the presence of quinoline and a suitable solvent such as
methanol or ethanol. Compounds of general formula (7-6) may also be
obtained by reaction of a compound of general formula (7-1) with a
suitable alkene (7-4) (incorporating a group R.sup.10 that could be
either maintained without modification after coupling or that could
later be modified to give other groups R.sup.10) in the presence of
a base such as triethylamine or potassium carbonate, a phosphine
such as triphenyl phosphine, a metal species such as palladium
acetate and a solvent such as acetonitrile at a temperature between
room temperature and the boiling point of the solvent. Compounds of
general formula (7-6) may also be obtained by the reaction of a
compound of general formula (7-1) by reaction with a vinyl stannane
(7-5) (incorporating a group R.sup.10 that could be either
maintained without modification after coupling or that could later
be modified to give other groups)R.sup.10 in the presence of a
metal species such as tetrakis(triphenylphosphine)palladium (0) in
a suitable solvent such as toluene.
[0183] Compounds of general formula (7-8) may be obtained from
compounds of general formula (7-3) or (7-6) by reaction with
hydrogen in the presence of a catalyst such as palladium on carbon
or platinum oxide monohydrate in a suitable solvent such as
methanol or ethanol.
[0184] Compounds of general formula (7-8) may also be obtained by
reaction of compounds of general formula (7-1) by reaction with a
suitable alkyl zinc reagent (7-7) in the presence of a catalyst
such as allyl palladium (II) chloride dimer or
bis(tri-tert-butylphosphine)palladium (0) and a suitable solvent
such as 1,4-dioxane at a temperature between room temperature and
the boiling point of the solvent.
##STR00034##
[0185] Compounds of general formula (8-3) may be prepared from
compounds of general formula (8-1) by reaction with a suitable
1,3-dipole such as trimethylsilylazide in a suitable solvent such
as toluene at a temperature between room temperature and the
boiling point of the solvent.
[0186] Compounds of general formula (8-2) may be obtained from
compounds of general formula (8-1) and hydrogen in the presence of
a suitable catalyst such as Lindlar catalyst or palladium on barium
sulfate in the presence of quinoline and a suitable solvent such as
methanol or ethanol.
[0187] Compounds of general formula (8-3) may be obtained by
reaction of compounds of general formula (8-2) with a suitable
1,3-dipole (or its precursors, incorporating a group R.sup.10 that
could be either maintained without modification after coupling or
that could later be modified to give other R.sup.10 groups) such as
N-methoxymethyl-N-(trimethylsilylmethyl) benzylamine and lithium
fluoride in a solvent such as acetonitrile with ultrasonic
treatment, or nitroethane and phenyl isocyanate in a suitable
solvent such as toluene in the presence of a base such as
triethylamine at a temperature between 0.degree. C. and the boiling
point of the solvent.
##STR00035##
[0188] Compounds of general formula (9-2) may be prepared using
published methods described in the literature. Compounds of formula
(9-2) may be prepared using the synthetic routes outlined in Scheme
9 (wherein R.sup.9' is R.sup.9 or intermediate moieties that may be
manipulated to give R.sup.9, and R.sup.6' is R.sup.6 or
intermediate moieties that may be manipulated to give R.sup.6).
[0189] Compounds of general formula (9-2) may be obtained from
compounds of formula (9-1) by reaction with compounds of general
formula (HY'--R.sup.9') in the presence of reagents such as
copper(II) iodide or copper powder in the presence of a base such
as cesium carbonate in a suitable solvent such as DMF at a
temperature between room temperature and the reflux temperature of
the solvent, or under microwave irradiation at a temperature
between 70.degree. C. and 240.degree. C., which may be similar to
conditions described in the literature by Ullmann.
[0190] Compounds of general formula (9-2) may be obtained from
compounds of formula (9-1) by reaction with compounds of general
formula (HY'-R.sup.9') in the presence of a catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the
presence of a base such as potassium tert-butoxide in a suitable
solvent such as DME, or a mixture of two or more appropriate
solvents, at a temperature between room temperature and the reflux
temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C., which may be similar to conditions described in the literature
by Buchwald and Hartwig.
##STR00036##
[0191] Compounds of general formula (10-7), (10-8) and (10-9) may
be prepared using published methods described in the literature
(WO2006001754). Compounds of formula (10-7), (10-8) and (10-9) may
be prepared using the synthetic routes outlined in Scheme 10
(wherein R.sup.3' is R.sup.3 or intermediate moieties that may be
manipulated to give R.sup.3, and R.sup.5' is R.sup.5 or
intermediate moieties that may be manipulated to give R.sup.5).
Compounds with a general formula (10-2) may be prepared from
compounds of formula (10-1) by deprotonation using a suitable base
such as lithium diisopropylamide in a suitable solvent such as THF
at a temperature between -78.degree. C. and room temperature
followed by addition of a suitable methylating agent such as methyl
iodide. The intermediate (10-2) may then be brominated with a
brominating agent such as N-bromosuccinimide in a solvent such as
carbon tetrachloride at a temperature between room temperature and
the reflux temperature of the solvent to give compounds of formula
(10-3).
[0192] Compounds of formula (10-3) may be converted to compounds of
formula (10-4) by displacement with tosylaminoacetonitrile using a
suitable base such as sodium hydride in a solvent such as DMF at a
temperature between -20.degree. C. and 50.degree. C. Intermediates
(10-4) may then be cyclised with a suitable base such as lithium
hexamethylsilylamide in a solvent such as THF at a temperature
between -20.degree. C. and 50.degree. C. to provide compounds of
general formula (10-5). The phenol (10-5) may then be reacted with
an appropriate alcohol (R.sup.11'OH) using a phosphine and a
coupling reagent such as diisopropylazodicarboxylate in an
appropriate solvent such as THF to provide ethers of general
formula (10-7).
[0193] Alternatively, the phenol intermediate (10-5) may be
converted to the triflate using a reagent such as triflic anhydride
in the presence of a base such as triethylamine in a suitable
solvent such as dichloromethane at a temperature between
-50.degree. C. and 20.degree. C. The triflate (10-6) may then be
converted to compounds of general formula (10-9) by reaction with a
boronic acid or boronate ester of formula (10-10) in the presence
of a transition metal catalyst such as bis(triphenylphosphine)
palladium(II)dichloride, a base such as aqueous sodium carbonate in
a suitable solvent such as acetonitrile at a temperature from room
temperature to the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150.degree. C. Alternatively, the triflate may be converted to
compounds of general formula (10-8) by displacement with a suitable
amine either (HNR.sup.11'R.sup.12') as solvent or in a solvent such
as 2-propanol at a temperature between ambient temperature and the
reflux point of the solvent.
[0194] Compounds of general formula (10-8) may be obtained from
compounds of formula (10-6) by reaction with compounds of general
formula (HNR.sup.11'R.sup.12') in the presence of a catalyst such
as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in
the presence of a base such as potassium tert-butoxide in a
suitable solvent such as DME, or a mixture of two or more
appropriate solvents, at a temperature from room temperature to the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C., which may be similar to conditions described in the literature
by Buchwald and Hartwig.
##STR00037##
[0195] Compounds of general formula (11-6) may be prepared using
published methods described in the literature. Compounds of formula
(11-6) may be prepared using the synthetic routes outlined in
Scheme 11a (wherein R.sup.3' is R.sup.3 or intermediate moieties
that may be manipulated to give R.sup.3, and wherein R.sup.6' is
R.sup.6 or intermediate moieties that may be manipulated to give
R.sup.6). Compounds of the formula (11-1) may be converted via acyl
hydrazide formation, diazotization and Curtius rearrangement to
give compounds of the formula (11-4), which maybe further converted
by Sandmeyer reaction to compounds of the formula (11-5).
Similarly, compounds of formula (11-4) may undergo Sandmeyer
reaction to provide other 6-substituted derivatives such as
6-fluoro (11-7), 6-chloro (11-8), 6-iodo (11-9), 6-alkylthio
(11-10), 6-hydroxy (11-11) and 6-cyano (11-12) as outlined in
Scheme 11b.
##STR00038##
[0196] Compounds of the formula (11-5) are useful for the
introduction of group R.sup.6 (or group R.sup.6' which may be
converted into group R.sup.6) in various ways, to generate
compounds of the formula (11-6), for example, by coupling with
organic boronic acid derivatives in the presence of a palladium
catalyst. Similarly, organic stannanes (eg. R.sup.6'SnR.sub.3),
organozinc (R.sup.6'ZnCl) and other reagents can be used in the
place of organic boronic acids. In particular compounds of the
formula (11-6) where R.sup.6' represents such groups as alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl may
be prepared in this manner. Compounds of the formula (11-5) may
also be converted into organic boronic acid derivatives of the type
(11-13), which may give compounds of the formula (11-6) by coupling
with organic halide or triflate derivatives in the presence of a
palladium catalyst, as outlined in Scheme 11c. Similarly (11-5) may
be converted to an organic stannane, organozinc and other
derivatives to be used in the place of organic boronic acids in
palladium catalyst-mediated couplings to give compounds of the
formula (11-6).
##STR00039##
[0197] Compounds of general formula (11-5) are useful in the
preparation of derivatives through nucleophilic aromatic
displacement reactions utilizing nucleophilic reagents R-NuH, which
may be facilitated in the presence of base, as outlined in Scheme
11d. Examples of such reagents and reactions are alcohols yielding
compounds of the formula (11-14), thiols yielding compounds of the
formula (11-15), primary and secondary amines yielding compounds of
the formula (11-16), and heterocycles such as imidazole which
yields compounds of the formula (11-17). Such displacement
reactions may also be facilitated by the presence of a palladium,
copper or other catalyst yielding compounds of the general formula
(11-18), as outlined in Scheme 11d.
##STR00040##
[0198] Compounds of general formula (11-5) are useful in the
preparation of derivatives through nucleophilic aromatic
displacement reactions utilizing nucleophilic reagents R-NuH, which
may be facilitated in the presence of base, as outlined in. Scheme
11d. Examples of such reagents and reactions are alcohols yielding
compounds of the formula (11-14), thiols yielding compounds of the
formula (11-15), primary and secondary amines yielding compounds of
the formula (11-16), and heterocycles such as imidazole which
yields compounds of the formula (11-17). Such displacement
reactions may also be facilitated by the presence of a palladium,
copper or other catalyst yielding compounds of the general formula
(11-18), for example reactions of alcohols and alkyl amines, as
outlined in Scheme 11d.
##STR00041##
[0199] Compounds of the formula (11-1) are also of use as
intermediates for the preparation of benzylic alcohols through
nucleophilic addition of organometallic or hydride transfer
reagents to the ester function, for example methylmagnesium
bromide, to provide tertiary alcohols of the formula (11-19), as
outlined in Scheme 11e. Compounds of the formula (11-1) may also be
subject to partial reduction of the ester function to yield
aldehydes of the formula (11-20), for example using hydride
transfer reagents such as diisobutylaluminium hydride. Such
intermediates as (11-20) may be transformed through nucleophilic
addition of organometallic reagents to the aldehyde function, for
example ethylmagnesium bromide, to provide secondary alcohols of
the formula (11-21). Such benzylic alcohols may further be
transformed by O-alkylation, for example utilizing alkyl halide and
base, such as transformation of compounds of the formula (11-21) to
ether products of the formula (11-22). Aldheydes of the formula
(11-20) may also be subject to reductive amination utilizing amines
and hydride transfer reagents, for example sodium cyanoborohydride,
yielding benzylic amines of the general formula (11-22), as
outlined in Scheme 11e.
[0200] Reagents and conditions given in Schemes 11a, 11b, 11c, 11d
and 11e are examples of those that may be used, and comparable
methods utilizing alternative reagents can be found in the
literature.
##STR00042##
[0201] Compounds of general formula (12-1) may be prepared using
methods described herein, and compounds of formula (12-6) may be
prepared using the synthetic routes outlined in Scheme 12 (wherein
R.sup.3' is R.sup.3 or intermediate moieties that may be
manipulated to give R.sup.3, and wherein E is a generalized
functional group derived from reaction with an electrophilic
reagent following suitable work-up procedure, and P is a suitable
protecting group). Carboxylic ester compounds of the formula (12-1)
may be saponified to generate compounds of the formula (12-2), for
example using aqueous lithium hydroxide. Alternatively, compounds
of the formula (12-1) may be transformed into carboxamide compounds
of the formula (12-4), by treatment for example with neat
tert-butylamine. Compounds such as (12-2) may be treated two or
more equivalents of with strong base, for example lithium
tetramethylpiperidide, and quenched with a variety of electrophilic
reagents, to generate derivatives of the general formula (12-3), in
which the 5-position has become substituted with a functionality E
derived form the electrophilic reagent. Such a transformation is
exemplified by in the literature (WO 2003022849). For example,
suitable electophilic reagents yielding derivatives with functional
groups E include, respectively: ethyl iodide yielding 5-ethyl;
formaldehyde yielding 5-hydroymethyl; dimethylformamide yielding
5-formyl; trimethylborate yielding 5-boronic acid ester, which may
be further transformed to 5-hydroxy through oxidation using basic
hydrogen peroxide. Similarly, carboxamide compounds of the formula
(12-4) yield products of the formula (12-5) upon similar treatment,
and these products may be further converted to the 6-cyano
derivatives of formula (12-6) by treatment with acidic dehydrating
agents, for example phosphorous oxychloride.
[0202] Reagents and conditions given in Scheme 12 are examples of
those that may be used, and comparable methods utilizing
alternative reagents can be found in the literature.
##STR00043##
[0203] In a similar manner to that outlined in Scheme 14, compounds
of the general formula (13-4) may be prepared using the synthetic
routes outlined in Scheme 13 (wherein R.sup.3' is R.sup.3 or
intermediate moieties that may be manipulated to give R.sup.3,
R.sup.5' is R.sup.5 or intermediate moieties that may be
manipulated to give R.sup.5, R.sup.6' is R.sup.6 or intermediate
moieties that may be manipulated to give R.sup.6, and R.sup.8' is
R.sup.8 or intermediate moieties that may be manipulated to give
R.sup.8). For example, iodo-amino-heterocycle compounds of the
formula (13-4) may be coupled with heterocycle-boronic acids of the
formula (13-2) utilizing a suitable palladium catalyst and base,
for example dichlorobis(triphenylphosphine)palladium(0) and
potassium acetate in a suitable solvent, to yield biaryl compounds
of the formula (13-3). Such compounds may be further transformed
through treatment with base, for example sodium
hexamethyldisilazide in a suitable solvent, to yield tricyclic
compounds of the general formula (13-4). Thus further substitution
of the tricycle, for example at the 3-, 5-, 6-, and 8-positions,
may be achieved through utilizing compounds of the formula (13-1)
and (13-2) in which one or more functionality R.sup.3', R.sup.5',
R.sup.6' or R.sup.8' is already in place.
[0204] Compounds of formula (14-7) and (14-9) may be prepared using
the synthetic routes outlined in Scheme 14.
##STR00044##
[0205] Compounds of general formula (14-3) may be obtained from
compounds of formula (14-1) by reaction with a boronic acid or
boronate ester of formula (14-2), in the presence of a catalyst
such as bis(triphenylphosphine)palladium(II) dichloride, a base
such as aqueous sodium carbonate in a suitable solvent such as
acetonitrile at a temperature between room temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C. Compounds
of general formula (14-3) may be cyclised to obtain compounds of
formula (14-4) with a suitable base such as sodium
hexamethyldisilazane in a suitable solvent such as THF at a
temperature between 0.degree. C. and 50.degree. C.
[0206] Compounds of general formula (14-4) may then be converted to
compounds of general formula (14-6) by reaction with a boronic acid
or boronate ester (incorporating appropriate substituents
R.sup.6'), in the presence of a catalyst such as
bis(triphenylphosphine) palladium(II) dichloride, a base such as
aqueous sodium carbonate in a suitable solvent such as acetonitrile
at a temperature between room temperature and the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C. Alternatively,
Compounds of formula (14-4) may be coupled with an aryl or alkyl
tin compound (incorporating appropriate substituents R.sup.6'), in
the presence of a catalyst such as bis(triphenylphosphine)
palladium(II) dichloride or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), with
or without an aqueous base such as sodium carbonate, in a suitable
solvent such as acetonitrile at a temperature between room
temperature and the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150.degree. C.
[0207] Compounds of general formula (14-6) may be obtained from
compounds of formula (14-4) by reaction with compounds of general
formula (HX--R.sub.6') in the presence of a catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II), in
the presence of a base such as potassium tert-butoxide in a
suitable solvent such as DME, or a mixture of two or more
appropriate solvents, at a temperature between room temperature and
the reflux temperature of the solvent or solvents, or under
microwave irradiation at a temperature between 70.degree. C. to
160.degree. C., as which may be similar to conditions described in
the literature by Buchwald and Hartwig.
[0208] Intermediates of formula (14-6) may then be halogenated in
the presence of a suitable halogenating agent, such as bromine, in
a solvent such as acetic acid, at a temperature between 20.degree.
C. and 120.degree. C., to obtain compounds of formula (14-7).
Compounds of formula (14-7) may then be converted to compounds of
formula (14-9) using methods described in Scheme 9.
[0209] Alternatively, compounds of formula (14-4) may be
halogenated to give compounds of formula (14-5), then converted to
compounds of formula (14-8) by reaction with a boronic acid,
boronate ester or stannane then converted to compounds of formula
(14-9) using similar conditions to those described for the
introduction of R.sup.3'.
##STR00045##
[0210] Compounds (15-1) may be prepared using the methods described
herein. Subjecting compounds of the general formula (15-1) to
reaction with methanesulfonyl chloride, in the presence of a base
such as triethylamine, in a suitable solvent such as
dichloromethane at a temperature between 0.degree. C. and the
reflux temperature of the solvent, yields compounds of formula
(15-2).
[0211] Compounds of the general formula (15-3) may be obtained from
compounds (15-2) by reaction with an amine, in the presence of a
base such as triethylamine, in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent.
[0212] Compounds of general formula (16-3) may be prepared
according to the procedure shown in Scheme 16.
##STR00046##
[0213] Compounds (16-1) may be prepared using the methods described
in Scheme 2. Subjecting compounds of the general formula (16-1) to
reaction with an oxidant such as N-methylmorpholine-N-oxide, in a
suitable solvent such as tetrahydrofuran, at a temperature between
ambient temperature and the reflux temperature of the solvent,
yields compound of formula (16-2).
[0214] Compounds of the general formula (16-3) may be obtained from
compounds (16-2) by reaction with an alkyl halide, in the presence
of a catalyst such as copper (I) iodide, a ligand such as
N,N-dimethylglycine, a base such as cesium carbonate in a suitable
solvent such as dioxane, at a temperature between ambient
temperature and reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. to
150.degree. C.
[0215] Compounds of general formula (17-13) may be prepared
according to the procedure shown in Scheme 17.
##STR00047##
[0216] Compounds (17-1) and (17-4) may be obtained from commercial
sources or prepared using published methods described in the
literature. Compounds of general formula (17-2) may be obtained
from compounds of formula (17-1) by reaction with an organometallic
reagent such as a boronic acid or ester, in the presence of a
transition metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous potassium fluoride in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0217] Compounds of the general formula (17-3) may be obtained from
compounds of formula (17-2) by reaction with a base such as lithium
diisopropylamide and a boronate source such as triisopropylborate,
in a suitable solvent such as THF, at a temperature between
-78.degree. C. and ambient temperature.
[0218] 5-Bromo-6-chloro-4-iodo-nicotinic acid (17-5) may be
obtained from 5-bromo-6-chloro-nicotinic acid (17-4) by reaction
with a base, such as n-butyl lithium, an amine such as
2,2,6,6-tetramethylpiperidine and an iodine source, such as solid
iodine, in a suitable solvent, such as THF at a temperature between
-78.degree. C. and ambient temperature.
5-Bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester (17-6) may be obtained from 5-bromo-6-chloro-4-iodo-nicotinic
acid (17-5) by reaction with diphenylphosphoryl azide in the
presense of a base such as triethylamine and tert-butanol, in a
suitable solvent such as toluene at a temperature between ambient
temperature to reflux temperature of the solvent.
5-Bromo-6-chloro-4-iodo-pyridin-3-ylamine (17-7) may be obtained
from 5-bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester (17-6) by reaction with trifluoroacetic acid in a suitable
solvent such as DCM at a temperature between -10.degree. C. and the
reflux temperature of the solvent.
[0219] Compounds of general formula (17-8) may be obtained from
compounds of formula (17-3) by reaction with
5-bromo-6-chloro-4-iodo-pyridin-3-ylamine (xiii) in the presence of
a transition metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous potassium fluoride in a suitable solvent such as
acetonitrile at a temperature from ambient temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0220] Cyclisation of compounds with general formula (17-8) with a
suitable base such as sodium hexamethylsilazide in a suitable
solvent such as THF at a temperature between 0.degree. C. and
50.degree. C. yields compounds of general formula (17-9).
[0221] Compounds of the general formula (17-10) may be obtained
from compounds (17-8) by reaction with an organometallic reagent
such as a boronic acid or ester, in the presence of a transition
metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous potassium fluoride in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0222] Cyclisation of compounds with general formula (17-10) with a
suitable base such as sodium hexamethylsilazide in a suitable
solvent such as THF at a temperature between 0.degree. C. and
50.degree. C. yields compounds of general formula (17-12).
[0223] Compounds of the general formula (17-13) may be obtained
from compounds (17-12) by reaction with an organometallic reagent
such as a boronic acid or ester, in the presence of a transition
metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous potassium fluoride in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0224] Compounds of the general formula (17-11) may be obtained
from compound (17-10) by reaction with an organometallic reagent
such as a boronic acid or ester, in the presence of a transition
metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous potassium fluoride in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0225] Cyclisation of compounds with general formula (17-11) with a
suitable base such as sodium hexamethylsilazide in a suitable
solvent such as THF at a temperature between 0.degree. C. and
50.degree. C. may give compounds of general formula (17-13).
[0226] Compounds of formula (18-8) may be prepared using the
synthetic routes outlined in Scheme 18.
##STR00048##
[0227] Compounds (18-1) and (18-2) may be obtained from commercial
sources, prepared using published methods described in the
literature, or from methods described in Scheme 3.
5-Bromo-6'-chloro-2-fluoro-[3,4']bipyridinyl-3'-ylamine (18-3) may
be obtained from 5-bromo-2-fluoropyridine-3-boronic acid (18-2) by
reaction with 6-chloro-4-iodo-pyridin-3-ylamine (18-1) in the
presence of a transition metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II), a
base such as aqueous sodium carbonate in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. to 150.degree. C.
[0228] 3-Bromo-6-chloro-1,7-diazacarbazole (18-4) may be obtained
from 5-bromo-6'-chloro-2-fluoro-[3,4']bipyridinyl-3'-ylamine (18-3)
by cyclisation with a suitable base such as sodium
hexamethylsilazide in a suitable solvent such as THF at a
temperature between 0.degree. C. and 50.degree. C.
[0229] Compounds of the general formula (18-5) may be obtained from
compound (18-4) by reaction with an organometallic reagent such as
a boronic acid or ester, in the presence of a transition metal
catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous sodium carbonate in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0230] Compounds of the general formula (18-8) may be obtained from
compound (18-5) by reaction with an organometallic reagent such as
a boronic acid or ester, in the presence of a transition metal
catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous sodium carbonate in a suitable solvent such as
acetonitrile at a temperature from ambient temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. to 150.degree. C.
[0231] Compounds of the general formula (18-6) may be obtained from
compound (18-3) by reaction with an organometallic reagent such as
a boronic acid or ester, in the presence of a transition metal
catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base
such as aqueous sodium carbonate in a suitable solvent such as
acetonitrile at a temperature between ambient temperature and the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 15.0.degree. C.
[0232] Compounds of the general formula (18-7) may be obtained from
compound (18-6) by reaction with an organometallic reagent such as
a boronic acid or ester, in the presence of a transition metal
catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II), a base such as aqueous sodium carbonate in a
suitable solvent such as acetonitrile at a temperature between
ambient temperature and the reflux temperature of the solvent, or
under microwave irradiation at a temperature between 70.degree. C.
and 150.degree. C.
[0233] Cyclisation of compounds with general formula (18-7) with a
suitable base such as sodium hexamethylsilazide in a suitable
solvent such as THF at a temperature between 0.degree. C. and
50.degree. C. may give compounds of general formula (18-8).
##STR00049##
[0234] Compounds of formula (19-1) and (19-2) may be synthesized
following procedures described in the literature or following the
route outlined in scheme 17. Compounds of formula (19-3) may be
obtained from compounds of formula (19-1) by reaction with a
boronic acid or boronate ester of formula (19-2), in the presence
of a catalyst such as bis(triphenylphosphine)palladium(II)
dichloride, a base such as aqueous sodium carbonate in a suitable
solvent such as acetonitrile at a temperature between room
temperature and the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150.degree. C. Compounds of general formula (19-3) may be cyclised
to obtain compounds of formula (19-4) with a base such as sodium
hexamethyldisilazane in a suitable solvent such as TI-IF at a
temperature between 0.degree. C. and 50.degree. C. Intermediates of
formula (19-4) may then be halogenated in the presence of a
suitable halogenating agent, such as iodine monochloride, in a
solvent such as acetic acid, at a temperature between 20.degree. C.
and the reflux point of the solvent, to obtain compounds of formula
(19-5).
[0235] Compounds of formula (19-5) may then be converted to
compounds of fomula (19-6) by reaction with a boronic acid or
boronate ester (incorporating appropriate substituents R.sup.3'),
in the presence of a catalyst such as bis(triphenylphosphine)
palladium(II) dichloride, a base such as aqueous sodium carbonate
in a suitable solvent such as acetonitrile at a temperature between
room temperature and the reflux temperature of the solvent, or
under microwave irradiation at a temperature between 70.degree. C.
and 150.degree. C. Alternatively, compounds of formula (19-5) may
be coupled with an aryl or alkyl tin compound (incorporating
appropriate substituents R.sup.3'), in the presence of a catalyst
such as bis(triphenylphosphine) palladium(II) dichloride or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), with
or without an aqueous base such as sodium carbonate, in a suitable
solvent such as acetonitrile at a temperature between room
temperature and the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150'.degree. C.
[0236] Compounds of formula (19-6) may be converted to compounds of
formula (19-8) by reaction with an iodine source such as sodium
iodide using a copper catalyst such as a combination of copper (I)
iodide and N,N'-dimethylethylenediamine in a solvent such as
1,4-dioxane at a temperature between room temperature and the
reflux point of the solvent.
[0237] Compounds of formula (19-7) may be obtained from compounds
of formula (19-6) and (19-8) by reaction with compounds of general
formula (R.sup.6'-M) by reaction with a boronic acid, boronate
ester or stannane using similar conditions to those described
previously for the introduction of R.sup.3'.
##STR00050##
[0238] Compounds of formula (20-1) may be synthesized following
procedures described in the literature or following routes outlined
in schemes 1, 4, 10, 13, 14, 17 and 18. Compounds of formula (20-1)
may be converted to compounds of formula (20-2) by reaction with an
iodine source such as sodium iodide using a copper catalyst such as
a combination of copper (I) iodide and N,N'-dimethylethylenediamine
in a solvent such as 1,4-dioxane at a temperature between room
temperature and the reflux point of the solvent.
[0239] Compounds of formula (20-1) may also be converted to
compounds of general formula (20-3) using a catalyst such as
palladium in a solvent such as ethanol under an atmosphere of
hydrogen at a temperature from room temperature to 50.degree.
C.
##STR00051##
[0240] Compounds of formula (21-1) may be synthesized following
procedures described in the literature or following routes outlined
in schemes 1, 4, 10, 13, 14, 17 and 18. Compounds of formula (21-1)
(where X is a leaving group such as Br or I) may be converted to
compounds of formula (21-2) using a source of carbon monoxide, such
as molybdenum hexacarbonyl in the presence of a catalyst such as
Herman's catalyst, containing the appropriate amine (21-12)
(HNR.sup.11'R.sup.12'), a base such as
1,8-diazabicyclo[5,4,0]undec-7-ene in a solvent such as 1,4-dioxane
at a temperature between room temperature and the reflux point of
the solvent. Compounds of formula (21-1) may also be converted to
compounds of formula (21-3) using a source of carbon monoxide, such
as molybdenum hexacarbonyl in the presence of a catalyst such as
Herman's catalyst, containing the appropriate alcohol (21-13)
(HOR.sup.11'), a base such as 1,8-diazabicyclo[5,4,0]undec-7-ene in
a solvent such as 1,4-dioxane at a temperature between room
temperature and the reflux point of the solvent. Compounds of
formula (21-1) may be converted to compounds of formula (21-4)
using a reagent (21-14) such as zinc (II) cyanide in the presence
of a catalyst such as tetrakis(triphenylphosphine)palladium (0) in
a solvent such as DMF at a temperature between room temperature and
the reflux point of the solvent, or under microwave irradiation at
a temperature between 70.degree. C. and 150.degree. C.
[0241] Compounds of formula (21-1) may be converted to compounds of
formula (21-5) using a reagent such as sodium trifluoroacetate in
the presence of a catalyst such as copper (I) iodide in a solvent
such as DMF at a temperature between room temperature and the
reflux point of the solvent.
[0242] Compounds of formula (21-6) may be prepared from compounds
of formula (21-1) with a base such as n-butyllithium in a solvent
such as THF with the appropriate tin halide (21-15) (where X' is a
leaving group such as Cl or Br). Alternatively, compounds of
formula (21-6) may be prepared from compounds of formula (21-1)
with the appropriate alkylditin (21-16) (containing suitable R
groups) in the presence of a catalyst such as
tetrakis(triphenylphosphine) palladium(0) in a suitable solvent
such as toluene at a temperature from room temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0243] Compounds of formula (21-7) may be prepared from compounds
of formula (21-1) by treatment with a base such as n-butyllithium
in the presence of an alkyl borate (21-17) such as trimethyl borate
in a suitable solvent such as THF at a temperature between
-78.degree. C. and ambient temperature. Alternatively, compounds of
formula (21-7) may be prepared from compounds of formula (21-1)
with the appropriate alkylatodiboron (21-18) in the presence of a
catalyst such as bis(diphenylphosphino)ferrocene palladium(II)
dichloride, using a suitable base such as potassium acetate in a
solvent such as dioxane at a temperature from room temperature to
the reflux temperature of the solvent, or under microwave
irradiation at a temperature between 70.degree. C. and 150.degree.
C.
[0244] Compounds of formula (21-8) may be obtained from compounds
of formula (21-1) by reaction with compounds of formula (21-19)
(HSR.sup.9') in the presence of a catalyst such as palladium (II)
acetate/JOSIPHOS using a base such as potassium tert-butoxide in a
suitable solvent such as DME at a temperature from room temperature
to the reflux temperature of the solvent or solvents, or under
microwave irradiation at a temperature between 70.degree. C. and
160.degree. C.
[0245] Compounds of formula (21-9) may be obtained from compounds
of formula (21-1) with a suitable alkyne (21-20) (incorporating a
R.sup.10' group that could be either maintained without
modification after coupling, or that could later be modified to
give other groups)R.sup.10) by reaction in the presence of a
catalyst system such as tetrakis(triphenylphosphine)palladium (0)
and copper (I) iodide in the presence of a base such as
triethylamine and a suitable solvent such as N,N-dimethylformamide
at a temperature between room temperature and the boiling point of
the solvent. Such a coupling reaction could also be carried out in
the presence of palladium on carbon, triphenylphosphine, copper (I)
iodide and triethylamine in the presence of a suitable solvent such
as acetonitrile at a temperature between room temperature and the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0246] Compounds of formula (21-1) may be converted to compounds of
formula (21-10) by reaction with a boronic acid or boronate ester
(21-21) (incorporating appropriate substituents R.sup.3'), in the
presence of a catalyst such as bis(triphenylphosphine)palladium(II)
dichloride, a base such as aqueous sodium carbonate in a suitable
solvent such as acetonitrile at a temperature between room
temperature and the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150.degree. C. Alternatively, compounds of formula (21-1) may be
coupled with an aryl or alkyl tin compound (21-21) (incorporating
appropriate substituents R.sup.3'), in the presence of a catalyst
such as bis(triphenylphosphine)palladium(II) dichloride or
[1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (II), with
or without an aqueous base such as sodium carbonate, in a suitable
solvent such as acetonitrile at a temperature between room
temperature and the reflux temperature of the solvent, or under
microwave irradiation at a temperature between 70.degree. C. and
150.degree. C.
[0247] Compounds of formula (21-11) may be prepared from compounds
of formula (21-6) with the appropriate halide or triflate of
formula (21-22) (R.sup.3'--X''), in the presence of a catalyst such
as tetrakis(triphenylphosphine)palladium(0) in a suitable solvent
such as 1,4-dioxane at a temperature from room temperature to the
reflux temperature of the solvent, or under microwave irradiation
at a temperature between 70.degree. C. and 150.degree. C.
[0248] Compounds of formula (21-11) may also be prepared by
reaction of compounds of formula (21-7) with appropriate halide of
formula (21-22) (R.sup.3'--X''), (incorporating appropriate
substituents R.sup.3'), in the presence of a catalyst such as
bis(triphenylphosphine)palladium(II)dichloride, with a base such as
aqueous sodium carbonate in a suitable co-solvent such as
acetonitrile at a temperature from room temperature to the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C.
##STR00052##
[0249] Compounds of formula (22-1) may be synthesized following
procedures described in the literature or following routes outlined
in scheme 9. Compounds of formula (22-1) may be converted to
compounds of formula (22-2) by treatment with a suitable alkylating
agent (22-11) R.sup.9'--X or R.sup.22'--X (where X is a suitable
leaving group such as Cl, Br, I, OMs or OTf) using a suitable base
such as cesium carbonate in a solvent such acetonitrile at a
temperature between room temperature and the reflux point of the
solvent. Alternatively, compounds of formula (22-1) may be
converted to compounds of formula (22-3) by reaction with a
suitable aldehyde (22-12) R.sup.9'CHO or R.sup.22'CHO and a
suitable hydride source such as sodium triacetoxyborohydride in a
solvent such as 1,2-dichloroethane at a temperature between
0.degree. C. and 50.degree. C.
[0250] Compounds of formula (22-1) may also be converted to
compounds of formula (22-4) using a reagent such as sodium nitrite
in an acidic solution such as aqueous hydrochloric acid, aqueous
hydrobromic acid or aqueous sulfuric acid. Compounds of formula
(22-4) may then be converted to the fluoro compounds of formula
(22-10) with a reagent such as sodium tetrafluoroborate; to the
chloro derivatives of formula (22-9) with a reagent such as copper
(I) chloride; to the iodo compounds of formula (22-8) with a
reagent such as potassium iodide; the alkylthio compounds of
formula (22-7) with a reagent such as NaSR.sup.9' and the cyano
derivatives (22-5) with reagents such as copper (I) cyanide and
potassium cyanide all carried out at a temperature between
0.degree. C. and the reflux point of the solvent.
##STR00053##
[0251] Compounds of formula (23-1) may be synthesized following
procedures described in the literature or following the route
outlined in scheme 10. Compounds of formula (23-3), (23-4) and (-5)
may be prepared using the synthetic route outlined in Scheme 23.
Compounds of formula (23-1) may be converted to the compounds of
formula (23-4) by reaction with a suitable chloride source such as
phosphorus pentachloride in a suitable solvent such as
chlorobenzene at a temperature from room temperature to the reflux
point of the solvent.
[0252] Compounds of formula (23-1) may also be converted to
compounds of formula (23-2) using a reagent such as
nonafluorobutanesulfonic anhydride in the presence of a base such
as pyridine in a suitable solvent such as dichloromethane at a
temperature between -50.degree. C. and 20.degree. C. Compounds of
formula (23-2) may be converted to compounds of formula (23-3) by
reaction with a suitable bromide source such as
tetra-n-butylammonium bromide in a solvent such as 1,4-dioxane at a
temperature from room temperature to the reflux temperature of the
solvent, or under microwave irradiation at a temperature between
70.degree. C. and 150.degree. C.
[0253] Compounds of formula (23-2) may be converted to the
compounds of formula (23-5) by reaction with a suitable iodide
source such as tetra-n-butylammonium iodide in a solvent such as
1,4-dioxane at a temperature from room temperature to the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C.
##STR00054##
[0254] Compounds of formula (24-1) may be synthesized following
procedures described in the literature or following the route
outlined in scheme 10. Compounds of formula (24-2) may be obtained
through alkylation of compounds of formula (24-1) with a suitable
alkylating agent (24-3) R.sup.11'--X (where X is a suitable leaving
group such as Cl, Br, I, OMs or OTf) using a suitable base such as
cesium carbonate in a solvent such as acetonitrile at a temperature
between room temperature and the reflux point of the solvent.
##STR00055##
[0255] Compounds of formula (25-1) may be synthesized following
procedures described in the literature or following the route
outlined in scheme 23. Compounds of formula (25-1) (where X is a
leaving group such as Br or I) may be converted to compounds of
formula (25-2) by reaction with a suitable alkenyl tin reagent of
formula (25-10) such as vinyltributyl tin in the presence of a
transition metal catalyst such as
tetrakis(triphenylphosphine)palladium(0) in a suitable solvent such
as 1,4-dioxane at a temperature between room temperature and the
reflux point of the solvent. Compounds of formula (25-2) may be
converted to compounds of formula (25-3) by treatment with a
reagent such as ozone in a suitable solvent such as methanol at a
temperature between -78.degree. C. and room temperature followed by
decomposition of the ozonide with a reagent such as dimethylsufide.
Compounds of formula (25-3) may be converted to compounds of
formula (25-4) by reaction with a suitable amine of formula (25-11)
(HNR.sup.16'R.sup.17') and a suitable hydride source such as sodium
triacetoxyborohydride in a solvent such as 1,2-dichloroethane at a
temperature between 0.degree. C. and 50.degree. C.
[0256] Compounds of formula (25-1) (where X is a leaving group such
as Br or I) may be converted to compounds of formula (25-5) by
reaction with a potassium alkyl trifluoroborate or alkyl borate of
formula (25-12) in the presence of a transition metal catalyst such
as [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride,
a base such as aqueous potassium carbonate in a suitable solvent
such as DMF at a temperature from room temperature to the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C. Compounds of
formula (25-5) may also be obtained from compounds of formula
(25-1) by reaction with an aryl or alkyl tin compound of formula
(25-12) (incorporating appropriate substituents R.sup.5') in the
presence of a catalyst such as bis(triphenyl phosphine)palladium
(II) dichloride or [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium (II), an aqueous base such as sodium carbonate,
in a suitable solvent such as acetonitrile or combination of
solvents, at a temperature between room temperature to the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C.
[0257] Alternatively, compounds of formula (25-7) may be obtained
from compounds of formula (25-1) (where X is a leaving group such
as Br or I) and a suitable alkyne (25-13) (incorporating a
R.sup.10' group that could be either maintained without
modification after coupling, or that could later be modified to
give other groups R.sup.10) by reaction in the presence of a
catalyst system such as tetrakis(triphenyl phosphine)palladium(0)
and copper (I) iodide in the presence of a base such as
triethylamine and a suitable solvent such as N,N-dimethylformamide
at a temperature between room temperature and the boiling point of
the solvent. Such a coupling reaction could also be carried out in
the presence of palladium on carbon, triphenylphosphine, copper (I)
iodide and triethylamine in the presence of a suitable solvent such
as acetonitrile at a temperature between room temperature and the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0258] Compounds of formula (25-1) (where X is a leaving group such
as F, Cl, Br or I) may be converted to compounds of formula (25-6)
by displacement with a suitable amine of formula (25-11)
(HNR.sup.11'R.sup.12') either as solvent or in a solvent such as
NMP at a temperature between ambient temperature and the reflux
point of the solvent. Compounds of formula (25-3) may also be
obtained from compounds of formula (25-1) (where X is a leaving
group such as Br or I) by reaction with compounds of formula
(25-11) (HNR.sup.11'R.sup.12') in the presence of a catalyst such
as [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II), in
the presence of a base such as potassium tert-butoxide in a
suitable solvent such as DME, or a mixture of two or more
appropriate solvents, at a temperature from room temperature to the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0259] Compounds of formula (25-8) may be obtained from compounds
of formula (25-1) (where X is a leaving group such as Br or I) by
reaction with compounds of general formula (25-14) (HSR.sup.11') in
the presence of a catalyst such as palladium(II) acetate/JOSIPHOS
in the presence of a base such as potassium tert-butoxide in a
suitable solvent such as DME, or a mixture of two or more
appropriate solvents, at a temperature from room temperature to the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0260] The sulfide intermediates of formula (25-8) may be converted
to sulfoxides and sulfones of formula (25-9) by oxidation with a
suitable oxidizing agent such as oxone in a solvent such as acetone
at a temperature between 0.degree. C. and 50.degree. C.
##STR00056##
[0261] Compounds of formula (26-1) may be synthesized following
procedures described in the literature or following the route
outlined in scheme 10. Compounds of formula (26-1) may be converted
to compounds of formula (26-2) by treatment with an acid such as
hydrochloric acid in a solvent such as water at a temperature
between room temperature and the reflux point of the solvent, or in
a sealed vessel at a temperature between 70.degree. C. and
140.degree. C.
[0262] Compounds of formula (26-2) may then be reacted with an
appropriate alcohol (26-10) (R.sup.11'OH) using a phosphine and a
coupling reagent such as diisopropylazodicarboxylate in an
appropriate solvent such as THF to provide ethers of general
formula (26-3). Alternatively, compounds of formula (26-3) may be
obtained through alkylation of compounds of general formula (26-2)
with a suitable alkylating agent (26-11) R.sup.11'--X (where X is a
suitable leaving group such as Cl, Br, I, OMs or OTO using a
suitable base such as cesium carbonate in a solvent such as
acetonitrile at a temperature between room temperature and the
reflux point of the solvent.
[0263] Compounds of formula (26-2) may also be converted to the
nonaflates (26-5) using a reagent such as nonafluorobutanesulfonic
anhydride in the presence of a base such as pyridine in a suitable
solvent such as dichloromethane at a temperature between
-50.degree. C. and 20.degree. C.
[0264] Compounds of formula (26-5) may be converted to compounds of
formula (26-4) by displacement with a suitable amine of general
formula (26-12) (HNR.sup.11'R.sup.12') either as solvent or in a
solvent such as NMP at a temperature between ambient temperature
and the reflux point of the solvent. Compounds of formula (26-4)
may also be obtained from compounds of formula (26-5) by reaction
with compounds of general formula (26-12) (HNR.sup.11'R.sup.12') in
the presence of a catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the
presence of a base such as potassium tert-butoxide in a suitable
solvent such as DME, or a mixture of two or more appropriate
solvents, at a temperature from room temperature to the reflux
temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0265] Alternatively, compounds of formula (26-7) may be obtained
from compounds of formula (26-5) with a suitable alkyne (26-14)
(incorporating a R.sup.10' group that could be either maintained
without modification after coupling, or that could later be
modified to give other groups R.sup.10) by reaction in the presence
of a catalyst system such as tetrakis(triphenylphosphine)palladium
(0) and copper (I) iodide in the presence of a base such as
triethylamine and a suitable solvent such as N,N-dimethylformamide
at a temperature between room temperature and the boiling point of
the solvent. Such a coupling reaction could also be carried out in
the presence of palladium on carbon, triphenylphosphine, copper (I)
iodide and triethylamine in the presence of a suitable solvent such
as acetonitrile at a temperature between room temperature and the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0266] The nonaflate intermediates (26-5) may be converted to
compounds of formula (26-8) by reaction with a potassium alkyl
trifluoroborate or alkyl borate of formula (26-15) in the presence
of a transition metal catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride, a
base such as aqueous potassium carbonate in a suitable solvent such
as DMF at a temperature from room temperature to the reflux
temperature of the solvent, or under microwave irradiation at a
temperature between 70.degree. C. and 150.degree. C. Compounds of
general formula (26-8) may also be obtained from compounds of
formula (26-5) by reaction with an aryl or alkyl tin compound
(incorporating appropriate substituents R.sup.5'), in the presence
of a catalyst such as bis(triphenylphosphine)palladium (II)
dichloride or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), an
aqueous base such as sodium carbonate, in a suitable solvent such
as acetonitrile or combination of solvents, at a temperature
between room temperature to the reflux temperature of the solvent,
or under microwave irradiation at a temperature between 70.degree.
C. and 150.degree. C.
[0267] Compounds of formula. (26-6) may be obtained from compounds
of formula (26-5) (where X is a leaving group such as Br or I) by
reaction with compounds of formula (26-13) (HSR.sup.11') in the
presence of a catalyst such as palladium (II) acetate/JOSIPHOS in
the presence of a base such as potassium tert-butoxide in a
suitable solvent such as DME, or a mixture of two or more
appropriate solvents, at a temperature from room temperature to the
reflux temperature of the solvent or solvents, or under microwave
irradiation at a temperature between 70.degree. C. and 160.degree.
C.
[0268] The sulfide intermediates of formula (26-6) may be converted
to sulfoxides and sulfones of formula (26-9) by oxidation with a
suitable oxidizing agent such as oxone in a solvent such as acetone
at a temperature between 0.degree. C. and 50.degree. C.
Scheme 27
##STR00057##
##STR00058## ##STR00059##
##STR00060##
[0270] Compounds of formula (27-4) may be synthesized following
procedures described in the literature or by the method outlined in
Scheme 27-1. Compound (27-1) may be converted to compound (27-2) by
treatment with ammonia in a suitable solvent such as methanol by
heating in a sealed vessel at a temperature up to 150Error! Not a
valid link.C. Compound (27-2) may be converted to compound (27-3)
by treatment with a dehydrating agent in a suitable solvent at an
appropriate temperature, such as trifluoroacetic acid anhydride in
the presence of triethylamine at between 0Error! Not a valid link.0
and ambient temperature. Compound (27-3) may be converted to
protected compounds of formula (27-4) by literature methods wherein
P' represents a suitable protecting group, such as the
2-trimethylsilanylethoxy methyl derivative by treatment with
2-trimethylsilanylethoxymethyl chloride and sodium hydride in
tetrahydrofuran.
[0271] Compounds of formula (27-4) may also be synthesized from
compounds of formula (27-5) as outlined in Scheme 27-2, by a
literature or other reduction method, such as by hydrogenation in
the presence of a carbon-supported palladium catalyst in a suitable
solvent such as tetrahydrofuran, or by treatment with zinc powder
and ammonium formate in tetrahydrofuran.
[0272] Compounds of formula (27-10) may be synthesized from
compounds of formula (27-4) as outlined in Scheme 27-2. Compounds
of the formula (27-4) may be converted to compounds of formula
(27-6) by treatment with an oxidant in a suitable solvent, such as
urea-hydrogen peroxide adduct and Error! Not a valid link.in
chloroform at ambient temperature. Compounds (27-6) may be
converted to compounds (27-7) by treatment with an electrophilic
agent and chloride source, such as methanesulfonyl chloride in
N,N-dimethylformamide at ambient temperature. Compounds (27-7) may
be deoxygenated to compounds (27-8) by treatment with a suitable
reducing agent, such as triethylamine in the presence of
[1,1'-bis(diphenyl phosphino)ferrocene]dichloropalladium(II) in
acetonitrile under microwave irradiation.
[0273] Compounds of formula (27-8) may also be synthesized by the
method outlined in scheme 27-3. Compounds (27-4) may also be
converted to compounds of formula (27-11) by treatment with an
oxidant in a suitable solvent, such as urea-hydrogen peroxide
adduct and Error! Not a valid link.in chloroform. Compounds (27-11)
may be converted to compounds (27-8) by treatment with a suitable
agent such as methanesulfonyl chloride in N,N-dimethylformamide at
ambient temperature.
[0274] Compounds of formula (27-8) may be converted to compounds of
formula (27-9) by treatment with an alcohol, represented by
R.sup.9OH, in the presence of a suitable base such as sodium
hydride, in a suitable solvent such as tetrahydrofuran, at a
temperature between ambient temperature and the boiling point of
the solvent, or at a temperature in excess of the boiling point of
the solvent in a sealed vessel. Compounds of formula (27-9) may be
converted to compounds (27-10) by removal of the protecting group
represented by P.sup.1, such as the 2-trimethylsilanylethoxymethyl
protecting group, for example by treatment with tetrabutylammonium
fluoride in tetrahydrofuran, or as a further example by treatment
with aqueous hydrobromic acid in dioxane followed by treatment with
aqueous sodium hydroxide.
[0275] It will be appreciated that where appropriate functional
groups exist, compounds described in the formulae of Schemes 1-27
or any intermediates used in their preparation may be further
derivatised by one or more standard synthetic methods employing
substitution, oxidation, reduction, or cleavage reactions.
Particular substitution approaches include conventional alkylation,
arylation, heteroarylation, acylation, sulfonylation, halogenation,
nitration, formylation and coupling procedures.
[0276] In a further example primary amine (--NH.sub.2) groups may
be alkylated using a reductive alkylation process employing an
aldehyde or a ketone and a borohydride, for example sodium
triacetoxyborohydride or sodium cyanoborohydride, in a solvent such
as a halogenated hydrocarbon, for example 1,2-dichloroethane, or an
alcohol such as ethanol, where necessary in the presence of an acid
such as acetic acid at around ambient temperature. Secondary amine
(--NH--) groups may be similarly alkylated employing an
aldehyde.
[0277] In a further example, primary amine or secondary amine
groups may be converted into amide groups (--NHCOR' or --NRCOR') by
acylation. Acylation may be achieved by reaction with an
appropriate acid chloride in the presence of a base, such as
triethylamine, in a suitable solvent, such as dichloromethane, or
by reaction with an appropriate carboxylic acid in the presence of
a suitable coupling agent such HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) in a suitable solvent such as dichloromethane.
Similarly, amine groups may be converted into sulphonamide groups
(--NHSO.sub.2R' or --NR''SO.sub.2R') groups by reaction with an
appropriate sulphonyl chloride in the presence of a suitable base,
such as triethylamine, in a suitable solvent such as
dichloromethane. Primary or secondary amine groups can be converted
into urea groups (--NHCONR'R.sup.11 or --NRCONR'R'') by reaction
with an appropriate isocyanate in the presence of a suitable base
such as triethylamine, in a suitable solvent, such as
dichloromethane.
[0278] An amine (--NH.sub.2) may be obtained by reduction of a
nitro (--NO.sub.2) group, for example by catalytic hydrogenation,
using for example hydrogen in the presence of a metal catalyst, for
example palladium on a support such as carbon in a solvent such as
ethyl acetate or an alcohol e.g. methanol. Alternatively, the
transformation may be carried out by chemical reduction using for
example a metal, e.g. tin or iron, in the presence of an acid such
as hydrochloric acid.
[0279] In a further example, amine (--CH.sub.2NH.sub.2) groups may
be obtained by reduction of nitriles (--CN), for example by
catalytic hydrogenation using for example hydrogen in the presence
of a metal catalyst, for example palladium on a support such as
carbon, or Raney nickel, in a solvent such as an ether e.g. a
cyclic ether such as tetrahydrofuran, at a temperature from
-78.degree. C. to the reflux temperature of the solvent.
[0280] In a further example, amine (--NH.sub.2) groups may be
obtained from carboxylic acid groups (--CO.sub.2H) by conversion to
the corresponding acyl azide (--CON.sub.3), Curtius rearrangement
and hydrolysis of the resultant isocyanate (--N.dbd.C.dbd.O).
[0281] Aldehyde groups (--CHO) may be converted to amine groups
(--CH.sub.2NR'R'')) by reductive amination employing an amine and a
borohydride, for example sodium triacetoxyborohydride or sodium
cyanoborohydride, in a solvent such as a halogenated hydrocarbon,
for example dichloromethane, or an alcohol such as ethanol, where
necessary in the presence of an acid such as acetic acid at around
ambient temperature.
[0282] In a further example, aldehyde groups may be converted into
alkenyl groups (--CH.dbd.CHR') by the use of a Wittig or
Wadsworth-Emmons reaction using an appropriate phosphorane or
phosphonate under standard conditions known to those skilled in the
art.
[0283] Aldehyde groups may be obtained by reduction of ester groups
(such as --CO.sub.2Et) or nitriles (--CN) using diisobutylaluminium
hydride in a suitable solvent such as toluene. Alternatively,
aldehyde groups may be obtained by the oxidation of alcohol groups
using any suitable oxidising agent known to those skilled in the
art.
[0284] Ester groups (--CO.sub.2R') may be converted into the
corresponding acid group (--CO.sub.2H) by acid- or base-catalused
hydrolysis, depending on the nature of R. If R is t-butyl,
acid-catalysed hydrolysis can be achieved for example by treatment
with an organic acid such as trifluoroacetic acid in an aqueous
solvent, or by treatment with an inorganic acid such as
hydrochloric acid in an aqueous solvent.
[0285] Carboxylic acid groups (--CO.sub.2H) may be converted into
amides (CONHR' or --CONR'R'') by reaction with an appropriate amine
in the presence of a suitable coupling agent, such as HATU, in a
suitable solvent such as dichloromethane.
[0286] In a further example, carboxylic acids may be homologated by
one carbon (i.e --CO.sub.2H to --CH.sub.2CO.sub.2H) by conversion
to the corresponding acid chloride (--COCl) followed by
Arndt-Eistert synthesis.
[0287] In a further example, --OH groups may be generated from the
corresponding ester (e.g. --CO.sub.2R'), or aldehyde (--CHO) by
reduction, using for example a complex metal hydride such as
lithium aluminium hydride in diethyl ether or tetrahydrofuran, or
sodium borohydride in a solvent such as methanol. Alternatively, an
alcohol may be prepared by reduction of the corresponding acid
(--CO.sub.2H), using for example lithium aluminium hydride in a
solvent such as tetrahydrofuran, or by using borane in a solvent
such as tetrahydrofuran.
[0288] Alcohol groups may be converted into leaving groups, such as
halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy,
e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g.
p-toluenesulfonyloxy group using conditions known to those skilled
in the art. For example, an alcohol may be reacted with thioyl
chloride in a halogenated hydrocarbon (e.g. dichloromethane) to
yield the corresponding chloride. A base (e.g. triethylamine) may
also be used in the reaction.
[0289] In another example, alcohol, phenol or amide groups may be
alkylated by coupling a phenol or amide with an alcohol in a
solvent such as tetrahydrofuran in the presence of a phosphine,
e.g. triphenylphosphine and an activator such as diethyl-,
diisopropyl, or dimethylazodicarboxylate. Alternatively alkylation
may be achieved by deprotonation using a suitable base e.g. sodium
hydride followed by subsequent addition of an alkylating agent,
such as an alkyl halide.
[0290] Aromatic halogen substituents in the compounds may be
subjected to halogen-metal exchange by treatment with a base, for
example a lithium base such as n-butyl or t-butyl lithium,
optionally at a low temperature, e.g. around -78.degree. C., in a
solvent such as tetrahydrofuran, and then quenched with an
electrophile to introduce a desired substituent. Thus, for example,
a formyl group may be introduced by using N,N-dimethylformamide as
the electrophile. Aromatic halogen substituents may alternatively
be subjected to metal (e.g. palladium or copper) catalysed
reactions, to introduce, for example, acid, ester, cyano, amide,
aryl, heteraryl, alkenyl, alkynyl, thio- or amino substituents.
Suitable procedures which may be employed include those described
by Heck, Suzuki, Stille, Buchwald or Hartwig.
[0291] Aromatic halogen substituents may also undergo nucleophilic
displacement following reaction with an appropriate nucleophile
such as an amine or an alcohol. Advantageously, such a reaction may
be carried out at elevated temperature in the presence of microwave
irradiation.
[0292] The compounds of the present invention are tested for their
capacity to inhibit chk1 activity and activation (primary assays)
and for their biological effects on growing cells (secondary
assays) as described below. The compounds having IC.sub.50 of less
than 10 .mu.M (more preferably less than 5 .mu.M, even more
preferably less than 1 .mu.M, most preferably less than 0.5 .mu.M)
in the chk1 activity and activation assay of Example i, and
EC.sub.50 of less than 10 .mu.M (more preferably less than 5 .mu.M,
most preferably less than 1 .mu.M) in the cellular assay of Example
ii, are useful as chk1 inhibitors.
[0293] The present invention includes a composition (e.g., a
pharmaceutical composition) comprising a compound of Formula (I),
(I-a) and/or (I-b), (and/or solvates, hydrates and/or salts
thereof) and a carrier (a pharmaceutically acceptable carrier). The
present invention also includes a composition (e.g., a
pharmaceutical composition) comprising a compound of Formula (I),
(I-a) and/or (I-b) (and/or solvates, hydrates and/or salts thereof)
and a carrier (a pharmaceutically acceptable carrier), further
comprising a second chemotherapeutic agent such as those described
herein. The present invention also includes a composition (e.g., a
pharmaceutical composition) comprising a compound of Formula (I),
(I-a) and/or (I-b) (and/or solvates, hydrates and/or salts thereof)
and a carrier (a pharmaceutically acceptable carrier), further
comprising a second chemotherapeutic agent such as a DNA damaging
agent including those described herein. The present compositions
are useful for inhibiting abnormal cell growth or treating a
hyperproliferative disorder such as cancer in a mammal (e.g.,
human). For example, the present compounds and compositions are
useful for treating breast cancer, colorectal cancer, ovarian
cancer, non-small cell lung cancer, malignant brain tumors,
sarcomas, melanoma, lymphoma, myelomas and/or leukemia in a mammal
(e.g., human).
[0294] The present invention includes a method of inhibiting
abnormal cell growth or treating a hyperproliferative disorder such
as cancer in a mammal (e.g., human) comprising administering to
said mammal a therapeutically effective amount of a compound of
Formula (I), (I-a) and/or (I-b) (and/or solvates, hydrates and/or
salts thereof) or a composition thereof. For example, the present
invention includes a method of treating breast cancer, colorectal
cancer, ovarian cancer, non-small cell lung cancer, malignant brain
tumors, sarcomas, melanoma, lymphoma, myelomas and/or leukemia in a
mammal (e.g., human), comprising administering to said mammal a
therapeutically effective amount of a compound of Formula (I),
(I-a) and/or (I-b) (and/or solvates, hydrates and/or salts thereof)
or a composition thereof.
[0295] The present invention includes a method of inhibiting
abnormal cell growth or treating a hyperproliferative disorder such
as cancer in a mammal (e.g., human) comprising administering to
said mammal a therapeutically effective amount of a compound of
Formula (I), (I-a) and/or (I-b) (and/or solvates, hydrates and/or
salts thereof) or a composition thereof, in combination with a
second chemotherapeutic agent such as those described herein. The
present invention also includes a method of inhibiting abnormal
cell growth or treating a hyperproliferative disorder such as
cancer in a mammal (e.g., human) comprising administering to said
mammal a therapeutically effective amount of a compound of Formula
(I), (I-a) and/or (I-b) (and/or solvates, hydrates and/or salts
thereof) or a composition thereof, in combination with a second
chemotherapeutic agent such as a DNA damaging agent including those
described herein. For example, the present invention includes a
method of treating breast cancer, colorectal cancer, ovarian
cancer, non-small cell lung cancer, malignant brain tumors,
sarcomas, melanoma, lymphoma, myelomas and/or leukemia in a mammal
(e.g., human), comprising administering to said mammal a
therapeutically effective amount of a compound of Formula (I),
(I-a) and/or (I-b) (and/or solvates, hydrates and/or salts thereof)
or a composition thereof, in combination with a second
chemotherapeutic agent such as those described herein. The present
invention also includes a method of treating breast cancer,
colorectal cancer, ovarian cancer, non-small cell lung cancer,
malignant brain tumors, sarcomas, melanoma, lymphoma, myelomas
and/or leukemia in a mammal (e.g., human), comprising administering
to said mammal a therapeutically effective amount of a compound of
Formula (I), (I-a) and/or (I-b) (and/or solvates, hydrates and/or
salts thereof) or a composition thereof, in combination with a
second chemotherapeutic agent such as such as a DNA damaging agent
including those described herein.
[0296] The present invention includes a method of using the present
compounds for in vitro, in situ, and in vivo diagnosis or treatment
of mammalian cells, organisms, or associated pathological
conditions.
[0297] Administration of the compounds of the present invention
(hereinafter the "active compound(s)") can be effected by any
method that enables delivery of the compounds to the site of
action. These methods include oral routes, intraduodenal routes,
parenteral injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion), topical, inhalation and
rectal administration.
[0298] The amount of the active compound administered will be
dependent on the subject being treated, the severity of the
disorder or condition, the rate of administration, the disposition
of the compound and the discretion of the prescribing physician.
However, an effective dosage is in the range of about 0.001 to
about 100 mg per kg body weight per day, preferably about 1 to
about 35 mg/kg/day, in single or divided doses. For a 70 kg human,
this would amount to about 0.05 to 7 g/day, preferably about 0.05
to about 2.5 g/day. In some instances, dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, provided that such larger doses are first
divided into several small doses for administration throughout the
day.
[0299] The active compound may be applied as a sole therapy or in
combination with one or more chemotherapeutic agents, for example
those described herein. Such conjoint treatment may be achieved by
way of the simultaneous, sequential or separate dosing of the
individual components of treatment.
[0300] The pharmaceutical composition may, for example, be in a
form suitable for oral administration as a tablet, capsule, pill,
powder, sustained release formulations, solution, suspension, for
parenteral injection as a sterile solution, suspension or emulsion,
for topical administration as an ointment or cream or for rectal
administration as a suppository. The pharmaceutical composition may
be in unit dosage forms suitable for single administration of
precise dosages. The pharmaceutical composition will include a
conventional pharmaceutical carrier or excipient and a compound
according to the invention as an active ingredient. In addition, it
may include other medicinal or pharmaceutical agents, carriers,
adjuvants, etc.
[0301] Exemplary parenteral administration forms include solutions
or suspensions of active compounds in sterile aqueous solutions,
for example, aqueous propylene glycol or dextrose solutions. Such
dosage forms can be suitably buffered, if desired.
[0302] Suitable pharmaceutical carriers include inert diluents or
fillers, water and various organic solvents. The pharmaceutical
compositions may, if desired, contain additional ingredients such
as flavorings, binders, excipients and the like. Thus for oral
administration, tablets containing various excipients, such as
citric acid may be employed together with various disintegrants
such as starch, alginic.acid and certain complex silicates and with
binding agents such as sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tableting purposes. Solid
compositions of a similar type may also be employed in soft and
hard filled gelatin capsules. Preferred materials, therefore,
include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration the active compound therein may be
combined with various sweetening or flavoring agents, coloring
matters or dyes and, if desired, emulsifying agents or suspending
agents, together with diluents such as water, ethanol, propylene
glycol, glycerin, or combinations thereof.
[0303] Methods of preparing various pharmaceutical compositions
with a specific amount of active compound are known, or will be
apparent, to those skilled in this art. For examples, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Ester, Pa., 15.sup.th Edition (1975).
EXAMPLES
Abbreviations
[0304] ACN Acetonitrile [0305] AIBN
2,2'-Azobis(2-methylproprionitrile) [0306] ATP
Adenosine-5'-triphosphate [0307] Biotage Pre-packed silica
Biotage.RTM. SNAP Cartridge for flash chromatography [0308] t-BME
t-Butyl methyl ether [0309] CDCl.sub.3 Deuterated chloroform [0310]
DCM Dichloromethane [0311] DIPEA Diisopropylethylamine [0312] DMAP
4-Dimethylaminopyridine [0313] DME 1,2-Dimethoxyethane [0314] DMF
Dimethylformamide [0315] DMSO Dimethylsulfoxide [0316] DMSO-d.sub.6
Deuterated dimethylsulfoxide [0317] EtOAc Ethyl acetate [0318] EtOH
Ethanol [0319] h Hour [0320] HCl Hydrochloric acid [0321] HM-N
Isolute.RTM. HM-N is a modified form of diatomaceous earth that can
efficiently absorb aqueous samples [0322] HOBt
1-Hydroxybenzotriazole [0323] IMS Industrial methylated spirits
[0324] LDA Lithium diisopropylamide [0325] HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl
uroniumhexafluorophosphate [0326] LCMS Liquid Chromatography Mass
Spectroscopy [0327] LDA Lithium diisopropylamide [0328] MeOH
Methanol [0329] mmol Millimoles [0330] mol Moles [0331] N Normal
(concentration) [0332] NaHCO.sub.3 Sodium bicarbonate [0333] NaOH
Sodium hydroxide [0334] NBS N-Bromosuccinimide [0335] NMR Nuclear
magnetic resonance [0336] PyBOP
(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
[0337] SCX-2 Strong cationic exchange resin [0338] Si-SPE
Pre-packed Isolute.RTM. silica flash chromatography cartridge
[0339] Si-ISCO Pre-packed ISCO.RTM. silica flash chromatography
cartridge [0340] THF Tetrahydrofuran [0341] TFA Trifluoroacetic
acid [0342] TLC Thin layer chromatography [0343] TMS
Trimethylsilyl
[0344] General Experimental Conditions
[0345] .sup.1H NMR spectra were recorded at ambient temperature
using a Varian Unity Inova (400 MHz):spectrometer with a triple
resonance 5 mm probe. Chemical shifts are expressed in ppm relative
to tetramethylsilane. The following abbreviations have been used:
br=broad signal, s=singlet, d=doublet, dd=double doublet,
t=triplet, q=quartet, m=multiplet.
[0346] High Pressure Liquid Chromatography--Mass Spectrometry
(LCMS) experiments to determine retention times (R.sub.T) and
associated mass ions were performed using one of the following
Methods.
[0347] Method A: Experiments performed on a Waters Micromass ZQ
quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC
system with diode array detector. This system uses a Higgins
Clipeus 5 micron C18 100.times.3.0 mm column and a 1 ml/minute flow
rate. The initial solvent system was 95% water containing 0.1%
formic acid (solvent A) and 5% acetonitrile containing 0.1% formic
acid (solvent B) for the first minute followed by a gradient up to
5% solvent A and 95% solvent B over the next 14 minutes. The final
solvent system was held constant for a further 5 minutes.
[0348] Method B: Experiments performed on a Waters Platform LC
quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC
system with diode array detector and 100 position autosampler using
a Phenomenex Luna C18(2) 30.times.4.6 mm column and a 2 ml/minute
flow rate. The solvent system was 95% water containing 0.1% formic
acid (solvent A) and 5% acetonitrile containing 0.1% formic acid
(solvent B) for the first 0.50 minutes followed by a gradient up to
5% solvent A and 95% solvent B over the next 4 minutes. The final
solvent system was held constant for a further 0.50 minutes.
[0349] Method C: Experiments performed on a Shimadzu LCMS-2010EV
liquid chromatography mass spectrometer linked to a Shimadzu
LC-20AB LC system with diode array detector. Uses a Shim-pack
XR-ODS 2.2 micron 30.times.3.0 mm column and a 1.2 ml/minute flow
rate. The initial solvent system was 10% water containing 0.038%
trifluoroacetic acid (solvent A) and 90% acetonitrile containing
0.019% trifluoroacetic acid (solvent B), followed by a gradient up
to 80% solvent A and 90% solvent B over 2 minutes.
[0350] Method D: Experiments performed on an Agilent 1100 HPLC with
Agilent MSD mass spectrometer using ESI as ionization source using
an Agilent ZORBAX SB-C 18 100.times.3.0 mm column and a 0.7
ml/minute flow rate. The solvent system was a gradient starting
with 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with
0.05% TFA (solvent B), ramping up to 5% solvent A and 95% solvent B
over 25 minutes. The final solvent system was held constant for a
further 5 minutes.
[0351] Method E: Experiments performed on an Agilent 1100 HPLC with
Agilent MSD mass spectrometer using ESI as ionization source using
an Agilent ZORBAX SB-C 18 30.times.2.1 mm column and a 0.6
ml/minute flow rate. The solvent system was a gradient starting
with 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with
0.05% TFA (solvent B), ramping up to 5% solvent A and 95% solvent B
over 9 minutes. The final solvent system was held constant for a
further 1 minute.
[0352] Method F: Experiments performed on a Waters Micromass ZQ2000
quadrupole mass spectrometer using ESI as ionization source using a
Higgins Clipeus 5 micron C18 100.times.3.0 mm column and a 1
ml/minute flow rate. The solvent system was a gradient starting
with 85% water with 0.1% formic acid (solvent A) and 15% methanol
with 0.1% formic acid (solvent B), ramping up to 5% solvent A and
95% solvent B over 12 minutes. The final solvent system was held
constant for a further 1 minute.
[0353] Method G: Experiments performed on a Waters Platform LC
quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC
system with diode array detector and 100 position autosampler using
a Phenomenex Luna C18(2) 30.times.4.6 mm column and a 2 ml/minute
flow rate. The solvent system was 95% water containing 0.1% formic
acid (solvent A) and 5% methanol containing 0.1% formic acid
(solvent B) for the first 0.50 minutes followed by a gradient up to
5% solvent A and 95% solvent B over the next 4 minutes. The final
solvent system was held constant for a further 0.50 minutes.
[0354] Method H: Experiments performed on a Waters Quattro Micro
triple quadrupole mass spectrometer using ESI as ionization source
using a Higgins Clipeus 5 micron C18 100.times.3.0 mm column and a
1 ml/minute flow rate. The solvent system was a gradient starting
with 85% water with 0.1% formic acid (solvent A) and 15% methanol
with 0.1% formic acid (solvent B), ramping up to 5% solvent A and
95% solvent B over 12 minutes. The final solvent system was held
constant for a further 1 minute.
[0355] Microwave experiments were carried out using a Biotage
Initiator 60.TM. which uses a single-mode resonator and dynamic
field tuning. Temperature from 40-250.degree. C. can be achieved,
and pressures of up to 30 bar can be reached. Alternatively, a CEM
Discover microwave was also used for some of the experiments.
[0356] Unless specified, typically preparative HPLC purification
refers to the use of an Xbridge.TM. Prep C18 10 .mu.m OBD.TM.
19.times.100 mm column or a similar C18 column unless stated
otherwise. Methods are generally run on a gradient of 5-85%
acetonitrile/water modified with either 0.1% formic acid or 0.1%
ammonium hydroxide over 20 minutes at a flow rate of 35 mL/min.
General Methods
[0357] Boronic acids and boronate esters were prepared from the
appropriate aryl halide intermediate by using the general coupling
methods described below. All aryl halide intermediates were either
commercially available, prepared using literature methods or could
be readily prepared by those skilled in the art. In some cases the
intermediate was not isolated, and the coupling reaction performed
on the crude boronic acid/boronate ester. Suzuki reactions were
performed using either commercially available boronic
acids/boronate esters or from compounds prepared using the
procedures detailed below. If necessary, any protecting groups were
then removed using one of the deprotection conditions described
below. Stille reactions were performed using either commercially
available stannanes or from compounds prepared using the procedures
detailed below. If necessary, any protecting groups were then
removed using one of the deprotection conditions described
below.
General Methylation of Piperidine Derivative Method
[0358] The appropriate BOC-protected/HCl salt/free amine piperidine
derivative (1-2 eq.) was dissolved in a solution of aqueous
formaldehyde in formic acid, and the mixture was heated with
microwave irradiation (100-160.degree. C.) for between 5 and 15
minutes. The resultant residue was loaded onto an Isolute.RTM.
SCX-2 cartridge. The cartridge was then washed with acetonitrile
before the desired product was eluted using 2M ammonia in MeOH.
General Mesylate Displacement Methods
[0359] Method A: A mixture of
6-cyano-3-(4-methanesulfonyloxymethyl-phenyl)-dipyrido[2,3-b;4',3'-d]pyrr-
ole-9-carboxylic acid tert-butyl ester (1 eq.), amine (1.1-1.5 eq.)
and triethylamine (1.1-1.5 eq.) in acetonitrile was stirred between
ambient temperature and 50.degree. C. until analysis (TLC/LCMS)
showed complete consumption of starting material. The reaction
mixture was allowed to cool to ambient temperature and was then
partitioned between ethyl acetate and water. The organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The resultant residue was subjected to
purification by one of the general methods described below.
[0360] Method B: A mixture of methanesulfonic acid
4-[6-cyano-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]-
pyrrol-3-yl]-benzyl ester (1 eq.), amine (1.1-1.5 eq.) and
triethylamine (1.1-1.5 eq.) in acetonitrile was stirred between
ambient temperature and 50.degree. C. until analysis (TLC/LCMS)
showed complete consumption of starting material. The reaction
mixture was allowed to cool to ambient temperature and was then
partitioned between ethyl acetate and water. The organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The resultant residue was subjected first to
deprotection, and then purification, by the general methods
described below.
[0361] Method C: A mixture of methanesulfonic acid
4-[6-cyano-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]-
pyrrol-3-yl]-benzyl ester (1 eq.), amine (1.1-1.5 eq.) and
triethylamine (1.1-1.5 eq.) in acetonitrile was heated with
microwave irradiation (100-150-.degree. C.) for between 1 and 30
minutes until analysis (TLC/LCMS) showed complete consumption of
starting material. The reaction mixture was allowed to cool to
ambient temperature and was then partitioned between ethyl acetate
and water. The organic layer was separated, dried over anhydrous
sodium sulfate, filtered and evaporated in vacuo. The resultant
residue was subjected first to deprotection, and then purification,
by the general methods described below.
[0362] Method D:
9-Benzenesulfonyl-5-(3-chloropropyl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipy-
rido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1 eq.) was treated with
a large excess of the amine (50-300 eq.) and the mixture was heated
with microwave irradiation (between 90.degree. C. and 140.degree.
C.) for between 1 and 30 minutes until analysis (TLC/LCMS) showed
complete consumption of starting material. The reaction mixture was
allowed to cool to ambient temperature and was then subjected to
purification by the general methods described below.
[0363] Method E: Methanesulfonic acid
3-[9-benzenesulfonyl-6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-
-b;4',3'-d]pyrrol-5-yl]-propyl ester (1 eq.) was treated with a
large excess of the amine (50-300 eq.) and the mixture was heated
with microwave irradiation (between 90.degree. C. and 140.degree.
C.) for between 1 and 30 minutes until reaction was deemed
complete. The reaction mixture was allowed to cool to ambient
temperature and was then subjected to purification by the general
methods described below.
[0364] Method F: A mixture of
9-benzenesulfonyl-3-(1-methyl-1H-pyrazol-4-yl)-5-piperidin-4-ylmethyl-9H--
dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1 eq.), alkyl halide
(1.1-1.5 eq.) and triethylamine (1.1-1.5 eq.) in acetonitrile was
heated at reflux for between 5 and 60 minutes until the reaction
was deemed complete. The reaction mixture was allowed to cool to
ambient temperature and was then subjected to purification by the
general methods described below.
General Boronic Acid/Boronate Ester Preparation Method
[0365] Method A: The appropriate aryl halide (1-3 eq.) was
suspended in a mixture of THF under an inert atmosphere then
n-butyl lithium (1-3 eq.) was added at -78.degree. C. After between
5 and 30 minutes at this temperature, trialkylborate (1-3 eq.) was
added then the reaction mixture was warmed to ambient temperature
and quenched by the addition of ammonium chloride. The resultant
residue was purified by one of the general purification methods
described below or used crude in the next step.
[0366] Method B: The appropriate aryl halide (1-3 eq.) was
suspended in a mixture of dioxane and DMSO before
bis(pinacolato)diboron (1-2 eq.), potassium acetate and
1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was then heated with
microwave irradiation (100-160.degree. C.) for between 1 and 20
minutes. The resultant residue was purified by one of the general
purification methods described below or used crude in the next
step.
[0367] Method C: The appropriate (bromomethyl)phenyl boronic acid
(1 eq.) was stirred with sodium iodide (0.05 eq.) and potassium
carbonate (3.0 eq.) in acetonitrile and the appropriate amine (1.2
eq.) added. The mixture was heated to 50.degree. C. for 2 h and
then cooled to ambient temperature or stirred at room temperature
until reaction complete, then the volatile components were removed
in vacuo and the residue re-suspended in MeOH. The remaining solid
was removed by filtration then the methanolic solution was
collected and concentrated to dryness under reduced pressure. The
resulting boronic acid was used with no further purification.
[0368] Method D: The appropriate electrophile (1-2 eq.) and
potassium carbonate (3-5 eq.) were added to
4,4,5,5-tetramethyl-2(1H-pyrazol-4-yl)-1,3,2-dioxaborolane in
acetonitrile and the mixture was stirred under reflux for between 1
and 7 days. The residue was purified by one of the general
purification methods described below.
General Suzuki Coupling Method
[0369] Method A: The appropriate boronic acid/boronate
ester/triflate (1-3 eq.) was suspended in acetonitrile before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1 eq.), aqueous sodium carbonate solution and
bis(triphenylphosphine)palladium(II) dichloride (5-10 mol %) were
added and the reaction mixture was then heated with microwave
irradiation (100-160.degree. C.) for between 1 and 30 minutes. The
resultant residue was purified by one of the general purification
methods described below.
[0370] Method B: The appropriate boronic acid/boronate ester (1-3
eq.) was suspended in a mixture of dioxane and DMSO before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1 eq.), aqueous potassium acetate solution and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was then heated with
microwave irradiation (100-160.degree. C.) for between 1 and 20
minutes. The resultant residue was purified by one of the general
purification methods described below.
[0371] Method C: The appropriate boronic acid/boronate ester (1-3
eq.) was suspended in DME before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1 eq.), aqueous cesium carbonate solution and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was then heated with
microwave irradiation (100-160.degree. C.) for between 1 and 20
minutes. The resultant residue was purified by one of the general
purification methods described below.
[0372] Method D: The appropriate boronic acid/boronate ester (1-3
eq.) was suspended in acetonitrile before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile (1 eq.), aqueous sodium carbonate solution or
potassium fluoride solution, and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was then heated with
microwave irradiation (100-160.degree. C.) for between 1 and 30
minutes. The resultant residue was purified by one of the general
purification methods described below.
[0373] Method E: The appropriate boronic acid/boronate ester (1-3
eq.) was suspended in DME/IMS before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile (1 eq.), aqueous cesium carbonate solution and
tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) were added,
and the reaction mixture was heated with microwave irradiation
(100-160.degree. C.) for between 1 and 30 minutes. The resultant
mixture was purified by one of the general purification methods
described below.
[0374] Method F:
3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyl
ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile was
suspended in acetonitrile before the appropriate aryl/heteroharyl
bromide (1-3 eq.), aqueous sodium carbonate or potassium fluoride
solution solution and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was then heated with
microwave irradiation (100-160.degree. C.) for between 1 and 60
minutes. The resultant mixture was purified by one of the general
purification methods described below.
[0375] Method G: The appropriate aryl halide (1-3 eq.) was
suspended in DME/IMS before
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyleth-
oxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1
eq.), aqueous cesium carbonate solution and
tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) were added
and the reaction mixture was then heated with microwave irradiation
(100-160.degree. C.) for between 1 and 30 minutes. The resultant
mixture was purified by one of the general purification methods
described below.
[0376] Method H: The appropriate aryl halide (1-3 eq.) was
suspended in acetonitrile before
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyleth-
oxy methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1
eq.), aqueous sodium carbonate solution and
bis(triphenylphosphine)palladium(II) dichloride (5-10 mol %) were
added and the reaction mixture was then heated with microwave
irradiation (100-160.degree. C.) for between 1 and 30 minutes. The
resultant mixture was purified by one of the general purification
methods described below.
[0377] Method I: The appropriate boronic acid/boronate ester (1.5
eq.) was suspended in DMF before
6-chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole (1.5 eq.), aqueous sodium carbonate solution and
tetrakis(triphenylphosphine)palladium(0) (5 mol %) were added and
the reaction mixture was then heated with microwave irradiation
(140.degree. C.) for 60-90 minutes. The resultant mixture was
purified by one of the general purification methods described
below.
[0378] Method J: The appropriate boronic acid/boronate ester (1.5
eq.) was suspended in acetonitrile before
6-chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole (1.5 eq.), aqueous potassium carbonate solution and
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mol
%) were added and the reaction mixture was then heated with
microwave irradiation (140.degree. C.) for 60 minutes. The
resultant mixture was purified by one of the general purification
methods described below.
[0379] Method K: The appropriate aryl triflate (1-3 eq.) was
suspended in DME/IMS before
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyleth-
oxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1
eq.), aqueous cesium carbonate solution and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was then heated with
microwave irradiation (100-160.degree. C.) for between 1 and 30
minutes.
[0380] Method L:
9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile (1 eq.) was suspended in
tetrahydrofuran before the appropriate potassium alkylhalide
trifluoroborate (2 eq.), aqueous sodium carbonate or potassium
fluoride solution solution and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) were added and the reaction mixture was refluxed for 16
hours. The reaction mixture was allowed to cool to ambient
temperature and was then partitioned between THF and brine. The
organic layer was separated, dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo. The resultant residue was
subjected to purification, by the general methods described
below.
[0381] Method M: A mixture of 4-methylenepiperidine-1-carboxylic
acid tert-butyl ester (1 eq.) and 9-borabicyclo[3.3.1]nonane (1
eq.) was heated to reflux for 1 hour before it was added to a
degassed suspension of
9-benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-
-b;4',3'-d]pyrrole-6-carbonitrile (1-3 eq.), aqueous sodium
carbonate or potassium fluoride solution solution and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10
mol %) in DMF. The reaction mixture was then heated (60.degree. C.)
for between 5 and 75 minutes. The reaction mixture was allowed to
cool to ambient temperature and was then partitioned between ethyl
acetate and brine. The organic layer was separated, dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo. The
resultant residue was subjected to purification, by the general
methods described below.
[0382] Method N: The appropriate boronic acid/boronate ester (1-3
eq.) was suspended in anhydrous acetonitrile before the appropriate
5-substituted
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (1 eq.), aqueous sodium carbonate solution or potassium
fluoride solution, and 1,1'-[bis(diphenyl
phosphino)ferrocene]dichloro palladium(II) (5-10 mol %) were added
and the reaction mixture was then heated with microwave irradiation
(100-160.degree. C.) for between 1 and 30 minutes. The resultant
residue was purified by one of the general purification methods
described below. (Deviation: .sup.2 Dioxane was used as a solvent
instead of acetonitrile).
General Stille Coupling Methods
[0383] Method A: The appropriate stannane (1-3 eq.) was suspended
in anhydrous dioxane before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1 eq.) and
tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) were added
and the reaction mixture was then irradiated in the microwave
(100-160.degree. C.) for between 15 and 75 minutes. The resultant
mixture was purified by one of the general purification methods
described below.
[0384] Method B: The appropriate stannane (1-3 eq.) was suspended
in anhydrous dioxane before
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile or
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1 eq.) and
tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) and lithium
chloride (1-3 eq.) were added and the reaction mixture was then
irradiated in the microwave (100-160.degree. C.) for between 15 and
30 minutes. The resultant mixture was purified by one of the
general purification methods described below.
[0385] Method C: The appropriate stannane (1-3 eq.) was suspended
in anhydrous dioxane before the appropriate 5-substituted
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (1 eq.), tetrakis(triphenylphosphine)palladium(0) (5-10
mol %) and copper thiophene carboxylate (5-30 mol %) were added and
the reaction mixture was then heated with microwave irradiation
(100-160.degree. C.) for between 1 and 30 minutes. The resultant
residue was purified by one of the general purification methods
described below.
General Sonagashira Coupling Methods
[0386] Method A: The appropriate acetylene (1.0 eq.) was added to a
solution of
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1.0 eq.),
tetrakis(triphenylphosphine)palladium(0) (10 mol %), and copper (I)
iodide (25 mol %) in anhydrous DMF, under nitrogen. The reaction
mixture was irradiated in the microwave (100.degree. C.) for 10
minutes. The resulatant mixture was concentrated in vacuo and the
resultant residue was purified by one of the general purification
methods described below.
General Ullmann Coupling Methods
[0387] Method A: The appropriate phenol (1.5 eq.) was added to a
suspension of
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1 eq.), N,N-dimethylglycine (50 mol %), copper
(I) iodide (12.5 mol %), and cesium carbonate (2.0 eq.) in
anhydrous dioxane, under argon. The reaction mixture was then
heated (100-120.degree. C.) in a sealed tube for between 1 and 3
days. The mixture was concentrated in vacuo and the resultant
residue was purified by one of the general purification methods
described below.
[0388] Method B: The appropriate aryl bromide (1-2 eq.) was added
to a suspension of
3-hydroxy-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]p-
yrrole-6-carbonitrile (1 eq.), N,N-dimethylglycine (50 mol %),
copper (I) iodide (15 mol %), and cesium carbonate (2.0 eq.) in
anhydrous dioxane, under argon. The reaction mixture was then
heated under microwave irradiation (150.degree. C.) for between 1
and 2 hours. The mixture was concentrated in vacuo and the
resultant residue was purified by one of the general purification
methods described below.
General Buchwald Coupling Method
[0389] Method A: The appropriate amine (1-2 eq.) was added to a
suspension of
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyl-
-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1
eq.) and copper (II) acetate (5 mol %) in methanol, under argon.
The reaction mixture was then heated under microwave irradiation
(85-130.degree. C.) for 1-30 minutes. The mixture was concentrated
in vacuo and the resultant residue was purified by one of the
general purification methods described below.
General Mitsunobu Method
[0390] Method A: A solution of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (1 eq.), the appropriate hydroxypiperidine carboxylic
acid tert-butyl ester (5 eq.) and triphenylphosphine (5 eq.) in
anhydrous DMF or anhydrous THF was treated dropwise with diethyl
azodicarboxylate (5 eq.) and the mixture stirred at a temperature
between ambient and 50.degree. C. for between 2 and 65 hours. The
resultant reaction mixture was diluted with ethyl acetate and
washed with brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The resultant residue was subjected to
purification, by the general methods described below.
[0391] Method B:
3-Hydroxy-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrro-
le-6-carbonitrile (1 eq.), the appropriate hydroxyamine (2-4 eq.)
and triphenylphosphine (2-4 eq.) in THF was treated dropwise with
diethyl azodicarboxylate (2-4 eq.) and the mixture stirred at a
temperature between ambient and 50.degree. C. for between 2 and 65
hours. The resultant reaction mixture was diluted with DCM and
washed with brine, dried over anhydrous sodium sulfate and
concentrated in vacuo. The resultant residue was subjected to
purification, by the general methods described below.
General Bromide Displacement Methods
[0392] Method A:
9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile (1 eq.) was heated in the
appropriate amine (5 eq.) at 160.degree. C. until the reaction
deemed complete. The reaction mixture was cooled then diluted with
water and extracted with an appropriate solvent. The resultant
residue was purified by one of the general purification methods
described below.
[0393] Method B:
9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile (1 eq.) was heated with the
appropriate amine (2-3 eq.) and triethylamine (10-12 eq.) in
1-methyl-2-pyrrolidinone (3 mL) under microwave irradiation or
thermally in a sealed tube at 160-180.degree. C. until the reaction
was deemed complete. The reaction mixture was allowed to cool then
evaporated. The resultant residue was purified by one of the
general purification methods described below.
[0394] Method C:
9-Benzenesulfonyl-3,5-dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboni-
trile (1 eq.) or
3,5-dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1
eq.) was heated in the appropriate amine (5 eq.) at 160.degree. C.
until the reaction deemed complete. The reaction mixture was cooled
then diluted with water and extracted with an appropriate solvent.
The resultant residue was purified by one of the general
purification methods described below.
[0395] Method D:
9-Benzenesulfonyl-3,5-dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboni-
trile (1 eq.) or
3,5-dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1
eq.) was heated with the appropriate amine (2-3 eq.) and
triethylamine (10-12 eq.) in 1-methyl-2-pyrrolidinone (3 mL) under
microwave irradiation or thermally in a sealed tube at
160-180.degree. C. until the reaction was deemed complete. The
reaction mixture was allowed to cool then evaporated. The resultant
residue was purified by one of the general purification methods
described below.
[0396] Method E:
9-Benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile (1 eq.) was treated with the
appropriate amine (10-50 eq.) in tetrahydrofuran (3 mL) and then
the reaction mixture was stirred at ambient temperature until the
reaction was deemed complete. The reaction mixture was allowed to
cool then evaporated. The resultant residue was purified by one of
the general purification methods described below.
General Reduction Methods
[0397] Method A: A solution of the appropriately 5-substituted
9-benzenesulfonyl-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitril-
e or 5-substituted
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1.eq) in
a mixture of DMF and ethyl acetate (1:1 v/v) was treated with Pd/C
(10% w/w) and triethylamine (1-5 eq.) then placed under an
atmosphere of hydrogen and the reaction mixture was stirred at
ambient temperature until the reaction was deemed complete. The
reaction mixture was purged with argon then the Pd/C was removed by
filtration then the filtrate evaporated. The resultant residue was
purified by one of the general purification methods described
below:
[0398] Method B: A solution of the appropriately 5-substituted
9-benzenesulfonyl-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitril-
e or 5-substituted
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1.eq) in
a mixture of ethanol and tetrahydrofuran (1:1 v/v) was treated with
Pd/C (10% w/w) then placed under an atmosphere of hydrogen and the
reaction mixutre was stirred at ambient temperature until the
reaction was deemed complete. The reaction mixture was purged with
argon then the Pd/C was removed by filtration then the filtrate
evaporated. The resultant residue was purified by one of the
general purification methods described below.
General Alkylation Methods
[0399] Method A: A solution of the
9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile (1 eq), cesium carbonate (1-5
eq.), sodium iodide (0.5-2 eq.) and 1,3-dibromopropane in DMF was
heated under microwave irradiation (85-150.degree. C.) for between
1 and 30 minutes until the reaction was deemed complete. The
reaction mixture was then concentrated in vacuo and subjected to
purification by one of the general methods described below.
[0400] Method B: A solution of the
9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile (1 eq), cesium carbonate (1-5
eq.), sodium iodide (0.5-2 eq.) and 1,2-dibromoethane in DMF was
heated under microwave irradiation (85-150.degree. C.) for between
1 and 30 minutes until the reaction was deemed complete. The
reaction mixture was then concentrated in vacuo and subjected to
purification by one of the general methods described below.
[0401] Method C: To a solution of the appropriate amine (2 eq.) in
tetrahydrofuran was added sodium hydride (60% dispersion in mineral
oil, 2-4 eq.). The reaction mixture was stirred at ambient
temperature for 5 minutes, then a mixture of
4-chloro-9-(2-trimethylsilanyl
ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile with
4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]py-
rrole-6-carbonitrile (1 eq.) was added in one portion and the
reaction mixture was stirred at this temperature for 10 minutes
before being warmed to 40.degree. C. for 5 h. The mixture was
diluted with water and ethyl acetate then the organic layer was
separated, dried over anhydrous sodium sulfate, filtered,
concentrated in vacuo, and purified using one of the general
methods described below.
General Deprotection Methods
[0402] Method A: 6N HCl (aqueous solution or in dioxane) was added
to a mixture of the protected substrate in an appropriate solvent
and the reaction mixture was stirred between ambient temperature
and 75.degree. C., until the reaction was deemed complete. The
reaction mixture was concentrated in vacuo and subjected to
purification by one of the general methods described below.
[0403] Method B: TFA was added to a mixture of the protected
substrate in an appropriate solvent at ambient temperature. The
mixture was stirred until the reaction was deemed complete. The
reaction mixture was concentrated in vacuo and subjected to
purification by one of the general methods described below.
[0404] Method C: The tertiary amine was dissolved or suspended in
DCM and treated with an excess (at least 2 equivalents) of
1-chloroethyl chloroformate. DIPEA (at least 1 equivalent) was
added and the resultant mixture was heated under reflux. When
analysis by LCMS showed that starting material (or any
1-chloroethyl carbamate of starting material) had been consumed the
solution was cooled and concentrated in vacuo. The residue was
taken up in methanol and heated at reflux until analysis by LCMS
showed complete consumption of the intermediates. The reaction
mixture was then cooled and concentrated in vacuo. The residue was
subjected to purification by one of the general methods described
below.
[0405] Method D: IN TBAF in THF was added to a mixture of the
protected substrate in an appropriate solvent. The reaction mixture
was stirred between ambient temperature and 55.degree. C. until the
reaction was deemed complete. The resultant solution was
concentrated in vacuo before subjecting the crude material to
purification by one of the general methods described below.
Alternatively, the crude material was partitioned between water and
ethyl acetate and the organic layer was dried, concentrated in
vacuo, before subjecting the crude material to one of the general
purification methods described below.
[0406] Method E: 2N ammonia in methanol was added to a mixture of
the protected substrate. The reaction mixture was stirred at
ambient temperature until the reaction was deemed complete. The
resultant solution was concentrated in vacuo before subjecting the
crude material to purification by one of the general methods
described below. Alternatively, the crude material was partitioned
between water and ethyl acetate and the organic layer was dried,
concentrated in vacuo, before subjecting the crude material to one
of the general purification methods described below.
[0407] Method F: 48% aqueous hydrobromic acid was added to a
mixture of the protected substrate. The reaction mixture was
stirred at 75.degree. C. until the reaction was deemed complete.
The cooled reaction mixture was basified to pH 12 with 6N sodium
hydroxide solution and then adjusted to pH 7-9 with dropwise
addition of 1N aqueous hydrochloric acid then the resultant solid
was collected by filtration and purified using one of the general
methods described below.
General Purification Methods
[0408] Method A: Si-SPE or Si-ISCO, ethyl acetate/DCM gradient.
[0409] Method B: Si-SPE or Si-ISCO or manual silica column,
methanol/DCM gradient.
[0410] Method C: A solution of the substrate in methanol was loaded
onto an Isolute.RTM.SCX-2 cartridge. The cartridge was then washed
with methanol before the desired product was eluted using 2N
ammonia in MeOH.
[0411] Method D: Reverse phase HPLC Phenomenex Gemini C18, 20 mM
triethylamine in water/acetonitrile gradient.
[0412] Method E: Si-SPE or Si-ISCO, 2N ammonia in methanol/DCM
gradient.
[0413] Method F: Ethyl acetate/methanol recrystallisation.
[0414] Method G: Solid filtered from reaction mixture and resultant
solid washed thoroughly with water.
[0415] Method H: Reaction mixture was diluted with water, filtered
and the resulting solid washed with THF.
[0416] Method I: Reverse phase HPLC Phenomenex Gemini C 18, 0.1%
formic acid in water/0.1% formic acid in acetonitrile gradient.
[0417] Method J: Si-SPE or Si-ISCO, isopropanol/DCM gradient.
[0418] Method K: Solid isolated from reaction mixture and washed
with ethanol.
[0419] Method L: Si-SPE or Si-ISCO, cyclohexane/ethyl acetate
gradient.
[0420] Method M: C18-ISCO, 10-100% methanol/water gradient
[0421] Method N: Redisep Basic Alumina-ISCO, ethyl
acetate/cyclohexane gradient
[0422] Method 0: Redisep, Basic Alumina-ISCO, methanol/DCM
gradient
[0423] Method P: Biotage, Snap KP-NH, Amino Silica-ISCO, ethyl
acetate/cyclohexane gradient
[0424] Method Q: Biotage, Snap KP-NH, Amino Silica-ISCO,
methanol/DCM gradient
[0425] Method R: Si-SPE or Si-ISCO or Biotage Snap-Si, THF/pentane
gradient Method S: Reverse phase HPLC Phenomenex Gemini C 18,
water/methanol gradient
[0426] Method R: Solid isolated from reaction mixture and
triturated with an appropriate solvent.
[0427] Method S: Solid isolated from reaction mixture and washed
with methanol and diethyl ether.
[0428] Method T: Reverse phase HPLC Phenomenex Gemini C18, 0.1%
ammonium hydroxide in water/methanol gradient.
Deviations from Purification General Methods:
[0429] .sup.1 Triturated in hot methanol; .sup.2 triturated in
ethyl acetate; .sup.3 triturated in acetonitrile; .sup.4
recrystallised from DMSO-water; .sup.5 triturated in diethyl ether;
.sup.6 triturated in DCM; .sup.7 recrystallised from acetonitrile;
.sup.8 recrystallised from ethyl acetate; .sup.9 recrystallised
from methanol.
SYNTHESIS OF INTERMEDIATES
Preparation of
3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00061##
[0430] Step 1:
3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid methyl
ester
##STR00062##
[0432] Bromine (6.76 ml, 132.0 mmol) was added to a mixture of
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid methyl ester
(10.0 g, 44.0 mmol) and sodium acetate (11.2 g, 136.4 mmol) in
acetic acid (360 mL) and then the reaction mixture was heated at
100.degree. C. for 90 minutes. The reaction mixture was then cooled
to ambient temperature and the solvent removed under reduced
pressure then the residue was treated with saturated sodium
thiosulfate solution (40 mL) followed by water (100 mL) and then
the pH of the aqueous solution was adjusted to 7 by the addition of
saturated sodium hydrogen carbonate solution. The resultant
precipitate was collected by filtration and the solid was washed
with water (20 mL) then dried at 60.degree. C. until constant
weight was achieved, to afford the desired material as an off-white
solid (14.0 g, quantitative yield). .sup.1H NMR (DMSO-D.sub.6, 300
MHz): 9.13 (d, J=2.3 Hz, 1H), 9.00 (d, J=2.0 Hz, 2H), 8.70 (d,
J=2.3 Hz, 1H), 3.92 (s, 3H). LCMS (Method B): R.sub.T=2.92 min,
M+H.sup.+=306/308.
Step 2: 3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
amide
##STR00063##
[0434] In a steel bomb, a saturated solution of ammonia in methanol
was prepared by passing gaseous ammonia through methanol (250 mL)
then 3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
methyl ester (14.0 g, 38.3 mol) was added. The vessel was sealed,
then the reaction mixture was heated at 140.degree. C. (15 bar) for
18 h. After this time, the reaction vessel was allowed to cool to
ambient temperature then the reaction mixture was transferred to a
round-bottomed flask and the solvent was removed in vacuo to afford
a solid residue. The resultant solid residue was collected by
filtration, washed with methanol (50 mL) and then dried to yield
the desired product as a grey solid (9.47 g, 85%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 11.53 (s, 1H), 9.14 (d, J=2.3 Hz, 1H),
8.96 (d, J=1.1 Hz, 1H), 8.91 (d, J=1.1 Hz, 1H), 8.71 (d, J=2.3 Hz,
1H), 8.07 (s, 1H), 7.52 (s, 1H). LCMS (Method B): R.sub.T=2.49 min,
M+H.sup.+=291/293.
Step 3:
3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00064##
[0436] To a cooled solution (0.degree. C.) of a mixture of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid amide
(5.0 g, 17.2 mmol) and triethylamine (24.0 mL, 172 mmol) in THF
(200 mL) was slowly added trifluoroacetic anhydride (12.0 mL, 86
mmol). Upon complete addition, the reaction mixture was allowed to
warm to ambient temperature and the stirring was continued for an
additional 4 h. After this time, the solvent was removed in vacuo
and the resultant residue was loaded onto H-MN. The residue was
then purified by flash chromatography (silica, 330 g column, ISCO,
0-100% ethyl acetate in hexane) to afford the title compound as a
pale brown solid (2.30 g, 49%). .sup.1H NMR (DMSO-D.sub.6, 300
MHz): 13.05 (s, 1H), 9.08-9.04 (m, 2H), 8.91 (d, J=1.1 Hz, 1H),
8.79 (d, J=2.3 Hz, 1H). LCMS (Method B): R.sub.T=2.98 min,
M+H+=271, 273.
Preparation of
3-Bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b:4',3'-d]pyrr-
ole-6-carbonitrile
##STR00065##
[0438] To a suspension of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (300 mg,
1.1 mmol) in DMF (2.5 mL), under an inert atmosphere, was added
sodium hydride (65 mg, 1.3 mmol) and the reaction mixture was
allowed to stir at ambient temperature for 30 minutes. The reaction
mixture was cooled to 0.degree. C. and
2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.3 mmol) was
added dropwise and then the resultant suspension was allowed to
warm to room temperature. Water (0.5 mL) was added to the resultant
suspension to quench the reaction, the solvent was removed in vacuo
and the resultant residue was purified by flash chromatography
(silica, 12 g column, ISCO, 0-15% ethyl acetate in cyclohexane) to
afford the title compound as an off-white crystalline solid (266
mg, 62%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.18 (d, J=1.2 Hz,
1H), 8.74 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.34 (d, J=1.2
Hz, 1H), 5.98 (s, 1H), 3.56-3.60 (m, 2H), 0.94-0.98 (m, 2H), 0.08
(s, 9H). LCMS (Method B): R.sub.T=4.55 min, M+H.sup.+=(403,
405).
Preparation of
3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyleth-
oxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00066##
[0440] A mixture of
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (1.41 g, 3.5 mmol), bis(pinacolato)diboron (980
mg, 3.85 mmol), potassium acetate (1.0 g, 10.5 mmol) and
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg,
0.175 mmol) in dioxane (18 mL) and DMSO (2 mL) was heated at
120.degree. C., in a sealed vial and under argon, for 18 h. The
reaction mixture was allowed to cool to ambient temperature then
quenched by the addition of saturated aqueous sodium bicarbonate
solution (200 mL) and extracted into ethyl acetate (200 mL). The
organic layer was dried over sodium sulfate, filtered and
evaporated in vacuo and the resultant residue was purified by flash
chromatography (silica, 80 g column, ISCO, 0-50% ethyl acetate in
cyclohexane) to afford the title compound as a white crystalline
solid (1.32 g, 84%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 9.16 (d,
J=1.0 Hz, 1H), 9.05 (d, J=1.6 Hz, 1H), 8.86 (d, J=1.6 Hz, 1H), 8.37
(d, J=1.0 Hz, 1H), 6.03 (s, 2H), 3.61-3.54 (m, 2H), 1.41 (s, 12H),
0.94-0.87 (m, 2H), -0.10 (s, 9H). LCMS (Method B): R.sub.T=5.0 min,
M+H.sup.+=451.
Preparation of
6-Cyano-3-(4-methanesulfonyloxymethylphenyl)-dipyrido[2,3-b;4',3'-d]pyrro-
le-9-carboxylic acid tert-butylester
##STR00067##
[0441] Step 1:
6-Cyano-3-(4-hydroxymethylphenyl)-dipyrido[2,3-b;4',3'-d]pyrrole-9-carbox-
ylic acid ten-butyl ester
##STR00068##
[0443] A mixture of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (1.00 g,
3.70 mmol), 4-bromomethylbenzeneboronic acid (1.18 g, 5.50 mmol)
and 1,1'-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II)
(152 mg, 0.19 mmol) in acetonitrile (40 mL) and 2N aqueous
potassium fluoride solution (20 mL) was devided equally across four
25 mL microwave vials. Each vial was degassed with nitrogen for 10
minutes before the reaction mixtures were heated under microwave
irradiation at 175.degree. C. for 90 minutes. The reaction mixtures
were then allowed to cool to ambient temperature, combined, diluted
with water (100 mL), the resultant solid collected by filtration,
washed with water (50 mL) and diethyl ether (40 mL) and left to air
dry. The resultant grey solid was suspended in acetonitrile (250
mL), di-tert-butyldicarbonate (2.00 g, 9.17 mmol) was added and the
resulting reaction mixture stirred at 50.degree. C. for 1.5 h. The
mixture was allowed to cool to ambient temperature, filtered to
remove the solid and the filtrate was evaporated in vacuo. The
resultant residue was purified by flash column chromatography
(silica, 80 g column, ISCO, 0-70% ethyl acetate in DCM) to afford
the title compound as a white solid (385 mg, 26%). .sup.1H NMR
(CDCl.sub.3, 400 MHz): 9.67 (d, J=1.0 Hz, 1H), 9.08 (d, J=2.3 Hz,
1H), 8.56 (d, J=2.3 Hz, 1H), 8.38 (d, J=1.0 Hz, 1H), 7.68 (d, J=8.0
Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 4.81 (d, J=5.9 Hz, 2H), 1.82 (s,
9H), 1.75 (t, J=5.9 Hz, 1H). LCMS (Method B): R.sub.T=2.70 min,
M(--C.sub.5H.sub.9O.sub.2)+H.sup.+=301.
Step 2:
6-Cyano-3-(4-methanesulfonyloxymethyl-phenyl)-dipyrido[2,3-b:4',3'-
-d]pyrrole-9-carboxylic acid tert-butylester
##STR00069##
[0445] Methanesulfonyl chloride (60 .mu.L, 0.70 mmol) was added to
a solution of
6-cyano-3-(4-hydroxymethyl-phenyl)-dipyrido[2,3-b;4',3'-d]pyrrole-9-carbo-
xylic acid tert-butyl ester (224 mg, 0.60 mmol) and triethylamine
(110 .mu.L, 0.80 mmol) in DCM (20 mL). The mixture was allowed to
warm to ambient temperature and stirred for 2 h. The mixture was
diluted with DCM (200 mL) and washed with water (100 mL). The
organic phase was separated, dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo to afford the title compound as
yellow oil (374 mg, 99%).
Preparation of Methanesulfonic acid 4-[6-cyano-9-(2-trimethyl
silanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-3-yl]-benzyl
ester
##STR00070##
[0446] Step 1:
(4-Hydroxymethyl-phenyl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[-
2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00071##
[0448] A mixture of
3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile (700 mg, 0.87 mmol),
4-hydroxymethylbenzeneboronic acid (400 mg, 1.32 mmol) and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.5
mg, 0.064 mmol) in acetonitrile (21 mL) and 2N aqueous potassium
fluoride solution (21 mL) was devided equally across two 25 mL
microwave vials. Each vial was degassed with nitrogen for 10
minutes before the mixtures were heated under microwave irradiation
at 140.degree. C. for 30 minutes. The reaction mixtures were
allowed to cool to ambient temperature, combined and diluted with
water (50 mL). The precipitate was collected by filtration, washed
with water (50 mL) and left to air dry. The resultant grey solid
was purified by flash column chromatography (silica, 40 g column,
ISCO, 0-100% ethyl acetate in cyclohexane). The isolated solid was
then triturated with hot t-BME to afford the title compound as a
light grey solid (646 mg, 26%). LCMS (Method B): R.sub.T=4.11 min,
M+H.sup.+=431.
Step 2: Methanesulfonic acid
4-[6-cyano-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]-
pyrrol-3-yl]-benzyl ester
##STR00072##
[0450] Methane sulfonyl chloride (366 mg, 0.25 ml, 3.20 mmol) was
added to a suspension of
(4-hydroxymethyl-phenyl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[-
2,3-b;4',3'-d]pyrrole-6-carbonitrile (646 mg, 1.56 mmol) and
Silicycles' polymer supported diethylamine (2.5 g, 3.30 mmol) in
acetonitrile (25 mL). The mixture was stirred at ambient
temperature for 1 h. The resin was removed by filtration, washed
with acetonitrile (50 mL) and the filtrate evaporated in vacuo to
afford a pale yellow solid (737 mg, 96%). .sup.1H NMR
(CH.sub.3CN-D.sub.3, 400 MHz): 9.30 (d, J=1.1 Hz, 1H), 9.12 (d,
J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 8.75 (d, J=1.1 Hz, 1H),
7.89-7.85 (m, 2H), 7.65-7.63 (m, 2H), 6.14 (s, 2H), 4.79 (s, 2H),
3.92 (s, 3H), 3.75 (t, J=8.1 Hz, 2H), 1.01 (t, J=8.1 Hz, 2H), 0.00
(s, 9H).
Step 3:
3-Hydroxy-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4'-
,3'-d]pyrrole-6-carbonitrile
##STR00073##
[0452] To a solution of
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyleth-
oxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (245
mg, 0.54 mmol) in THF (2.0 mL), under an inert atmosphere, was
added N-methylmorpholine-N-oxide (191 mg, 1.63 mmol) and the
reaction mixture was heated under reflux for 90 minutes. The
reaction mixture was allowed to cool to ambient temperature and the
solvent removed in vacuo. The residue was purified by flash
chromatography (silica, 12 g column, ISCO 0-50% ethyl acetate in
cyclohexane) to afford the title compound as a white solid (180 mg,
97%). .sup.1H NMR (CD.sub.3OD, 300 MHz): 9.10 (d, J=1.0 Hz, 1H),
8.64 (d, J=1.3 Hz, 1H), 8.35 (d, J=2.7 Hz, 1H), 8.04 (d, J=2.7 Hz,
1H), 5.99 (s, 2H), 3.59 (t, J=8.0 Hz, 2H), 0.86 (t, J=8.0 Hz, 2H),
-0.14 (s, 9H). LCMS (Method B): R.sub.T=3.75 min,
M+H.sup.+=341.
Preparation of
3-tert-Butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,-
3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00074##
[0454] A mixture of
3-bromo-9-(2-trimethylsilanylethoxymethyl)dipyrido[2,3-b;4',3'-d]pyrrole--
6-carbonitrile (1.53 g, 3.79 mmol), tert-butyl carbamate (888 mg,
7.58 mmol), and cesium carbonate (2.47 g, 7.58 mmol) were suspended
in 1,4-dioxane (30 mL) degassed and purged with nitrogen three
times. 4,5-bis(Diphenylphosphino)-9,9-dimethylxanthene (219 mg,
0.379 mmol) and tris(dibenzylideneacetone)dipalladium(0) (173 mg,
0.189 mmol) were added and the reaction mixture heated at
90.degree. C. for 25 h. The cooled reaction mixture was
pre-absorbed onto silica gel and purified by flash chromatography
on silica (silica, 120 g column, Biotage, 10-60% EtOAc in heptane)
to afford the title compound as a white-yellow solid (1.3 g, 80%).
.sup.1H NMR (400 MHz, DMSO-D.sub.6): 9.74 (s, 1H), 9.26 (s, 1H),
9.02 (s, 1H), 8.95 (s, 1H), 8.67 (d, J=2.4, 1H), 5.98 (s, 2H), 3.55
(t, J=7.9, 2H), 1.52 (s, 9H), 0.81 (t, J=7.9, 2H), -0.12--0.23 (m,
9H).
Preparation of
3-Amino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrrole-
-6-carbonitrile
##STR00075##
[0456]
3-tert-Butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)dipyri-
do[2,3-b;4',3'-d]pyrrole-6-carbonitrile (505 mg, 1.15 mmol) in DCM
(30 mL) was treated with TFA (0.78 mL) and allowed to stir for 2.5
days at ambient temperature. The reaction mixture was treated with
saturated sodium bicarbonate and diluted with DCM and water. The
layers were separated, the aqueous phase was extracted further with
DCM, and the combined organic phase was dried over sodium sulfate,
filtered and concentrated in vacuo. The resultant residue was
dissolved in ethyl acetate and pre-absorbed onto silica gel and
purified by flash chromatography (silica, 24 g column, Biotage,
1-100% EtOAc in heptane) to afford the title compound as a yellow
solid (152 mg, 39%). LCMS (Method D): R.sub.T=2.40 min,
M+H.sup.+=340.
Preparation of
3-Chloro-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrrol-
e-6-carbonitrile
##STR00076##
[0458] A solution of
3-amino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrrole-
-6-carbonitrile (45.4 mg, 0.134 mmol) in 2M aqueous sulfuric acid
(2.0 mL) and AcOH (1.0 mL) was cooled to 0.degree. C. and treated
with a solution of sodium nitrite (10.2 mg, 0.147 mmol) in water
(0.30 mL). After 20 min, the solution of the diazonium salt was
added slowly to a cooled (0.degree. C.) solution of copper (I)
chloride (29.1 mg, 0.294 mmol) in 1M hydrochloric acid (0.60 mL).
The reaction mixture was allowed to warm to ambient temperature
then diluted with DCM and water. The layers were separated, the
aqueous phase extracted further with DCM, and the combined organic
phases were dried over sodium sulfate and concentrated in vacuo.
The resultant residue was dissolved in ethyl acetate and
pre-absorbed onto silica gel and purified by flash chromatography
(silica, 4 g column, Biotage, 1-50% EtOAc in heptane) to afford the
title compound as a yellow-orange solid (20 mg, 43%). LCMS (Method
D): R.sub.T=3.61 min, M+H.sup.+=359/361.
Preparation of
4-Chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile
##STR00077##
[0459] Step 1:
9-(2-Trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-6-ca-
rbonitrile
##STR00078##
[0461] A mixture of
3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile (5.6 g, 14 mmol), ammonium formate (8.8 g, 139
mmol), and zinc (9.1 g, 139 mmol) in tetrahydrofuran (85 mL) was
heated at 75.degree. C. for 10 h. The reaction was allowed to cool,
filtered over a pad of celite, and washed with DCM (200 mL). The
filtrate was concentrated in vacuo and then purified by flash
chromatography (silica, 120 g, ISCO, 5-45% ethyl acetate in
heptane) to afford the title compound as a white solid (3.6 g,
80%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.17 (s, 1H), 8.73 (dd,
J=4.8 Hz, 1.5 Hz, 1H), 8.46 (dd, J=7.8 Hz, 1.5 Hz, 1H), 8.39 (s,
1H), 7.39 (dd, J=7.8 Hz, 4.8 Hz, 1H), 6.01 (s, 2H), 3.60 (t, J=8.0
Hz, 2H), 0.93 (t, J=8.0 Hz, 2H), -0.09 (s, 9H).
Step 2:
9-(2-Trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le-6-carbonitrile-1,7-dioxide
##STR00079##
[0463] To a suspension of hydrogen peroxide-urea adduct (5.9 g,
62.2 mmol) in chloroform (40 mL) was added trifluoroacetic
anhydride (8.7 mL, 61.6 mmol) dropwise over 10 minutes. The
reaction mixture was stirred at room temperature for 5 minutes and
then to this was added
9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-ca-
rbonitrile (2.0 g, 6.0 mmol) as a solution in chloroform (30 mL).
Note: an exotherm is observed upon addition of the substrate. The
reaction mixture was stirred at room temperature for 10 minutes and
then at 50.degree. C. for 30 minutes. The reaction mixture was
cooled to room temperature, treated with saturated sodium
thiosulfate solution (20 mL), and diluted with water (50 mL) and
methanol (10 mL). The layers were separated and the organic layer
was washed with 0.5N hydrochloric acid (50 mL), dried over sodium
sulfate, filtered, concentrated in vacuo, and purified by flash
chromatography (silica, 80 g, ISCO, 0-10% methanol in
dichloromethane) to afford the title compound as a pale yellow
solid (930 mg, 40%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.86 (s,
1H), 8.39 (d, J=6.4 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J=8.1 Hz, 1H),
7.32 (dd, J=7.9 Hz, 6.5 Hz, 1H), 6.55 (s, 2H), 3.73 (t, J=8.0, 2H),
0.93 (t, J=8.0, 2H), -0.04 (s, 9H).
Step 3:
4-Chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrid[2,3-b;4',3'-
-d]pyrrole-6-carbonitrile-7-oxide
##STR00080##
[0465] A mixture of
9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-ca-
rbonitrile-1,7-dioxide (2.1 g, 5.9 mmol) in N,N-dimethylformamide
(50 mL) was treated with methanesulfonyl chloride (0.78 mL, 10.0
mmol), and the reaction mixture was stirred at room temperature for
7 h. The reaction mixture was then diluted with ethyl acetate (150
mL) and water (200 mL). The layers were separated and the organic
layer was dried over sodium sulfate, filtered, concentrated in
vacuo, and purified by flash chromatography (silica, 40 g, ISCO,
5-85% ethyl acetate in heptane) to afford the title compound as a
6.5:1 mixture with
2-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile-7-oxide respectively as an off-white solid (1.7
g, 77%). The mixture was used in the next step without any further
purification. .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.86 (s, 1H), 8.39
(d, J=6.4 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.32 (dd,
J=7.9 Hz, 6.5 Hz, 1H), 6.55 (s, 2H), 3.73 (t, J=8.0 Hz, 2H), 0.93
(t, J=8.0 Hz, 2H), -0.04 (s, 9H).
Step 4:
4-Chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole-6-carbonitrile
##STR00081##
[0467] A solution of
4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile-7-oxide with
2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]py-
rrole-6-carbonitrile-7-oxide (6.5:1, 220 mg, 0.59 mmol),
1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (17
mg, 0.02 mmol), and triethylamine (0.24 mL, 1.8 mmol) in
acetonitrile (3.1 mL) was heated under microwave irradiation at
130.degree. C. for 20 minutes. The cooled reaction mixture was
concentrated in vacuo and purified by flash chromatography (silica,
40 g, ISCO, 5-85% ethyl acetate in heptane) to afford the title
compound as a 6.5:1 mixture of the title compound with
2-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile as an off-white solid (180 mg, 80%). The
mixture was used in subsequent steps without any further
purification. .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.20 (d, J=0.9 Hz,
1H), 8.74 (d, J=0.9 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.39 (d, J=5.3
Hz, 1H), 6.02 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.94 (t, J=8.0 Hz,
2H), -0.08 (s, 9H).
[0468]
2-Chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole-6-carbonitrile
##STR00082##
[0469] The title compound was prepared following the procedure from
the previous step. .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.17 (s, 1H),
8.38 (d, J=8.2 Hz, 1H), 8.35 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 5.97
(s, 2H), 3.61 (t, J=8.0 Hz, 2H), 0.95 (t, J=8.0 Hz, 2H), -0.07 (s,
9H).
Preparation of
9-Benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitr-
ile
##STR00083##
[0470] Step 1:
1-Benzenesulfonyl-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid methyl ester
##STR00084##
[0472] To
1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxyli- c
acid methyl ester (0.27 g, 0.88 mmol) in 1,2-dichloroethane (5.0
mL) was added NBS (0.178 g, 1.00 mmol) and AIBN (0.032 g, 0.20 mmol
and the reaction mixture was heated under reflux for 1 h. After
cooling to ambient temperature the solvent was removed by
evaporation and the resultant residue was purified by flash
chromatography (silica, 5 g column, ISCO, 0-65% DCM in pentane) to
afford the title compound as a white solid (0.26 g, 72%). LCMS
(Method B): R.sub.T=3.95 min, M+H.sup.+=409/411.
Step 2:
1-Benzenesulfonyl-2-{[cyanomethyl-(toluene-4-sulfonyl)amino]-methy-
l}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester
##STR00085##
[0474] To a cooled (0.degree. C.) mixture of
1-benzenesulfonyl-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid methyl ester (1.64 g, 4.00 mmol) and
N-cyanomethyl-4-methyl-benzenesulfonamide (0.93 g, 4.40 mmol) in
dry THF (10 mL) was added sodium hydride (0.176 g, 60% dispersion
in mineral oil, 4.40 mmol) in two equal portions. The reaction
mixture was stirred at 0.degree. C. for 15 minutes then allowed to
warm to room temperature. After 66 h the reaction mixture was
diluted with DCM (60 mL) and saturated aqueous sodium carbonate
solution (25 mL). The layers were separated and the aqueous phase
was extracted with DCM (2.times.25 mL). The combined organic phase
was dried over anhydrous magnesium sulfate and concentrated in
vacuo. The residue was triturated with THF (5 mL) and the resultant
solid dried in vacuo to afford the title compound as a beige solid
(1.72 g, 80%). LCMS (Method B): R.sub.T=3.91 min,
M+H.sup.+=539.
Step 3:
9-Benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-ca-
rbonitrile
##STR00086##
[0476] Lithium bis(trimethylsilyl)amide (9.6 mL, 1N solution in
THF, 9.60 mmol) was added dropwise to a cooled (-78.degree. C.)
suspension of
1-benzenesulfonyl-2-{[cyanomethyl(toluene-4-sulfonyl)amino]methyl}-1H-pyr-
rolo[2,3-b]pyridine-3-carboxylic acid methyl ester (1.72 g, 3.19
mmol) in dry THF (50 mL). The reaction mixture was allowed to warm
to -30.degree. C., stirred at -30.degree. C. for 2 h, before
warming to ambient temperature. The reaction mixture was quenched
with saturated aqueous ammonium chloride solution (30 mL) and water
(50 mL). The aqueous phase was extracted with DCM (2.times.20 mL)
and the combined organic phase was washed with brine and
concentrated in vacuo. The resultant solid was triturated with THF
(2.times.4 mL) to afford the title compound. The filtrate was
purified by flash chromatography (silica, 5 g column, Si-SPE, ethyl
acetate then 10-20% MeOH in DCM) to afford the remaining title
compound. The two batches of material were combined to afford a
yellow solid (1.03 g, 90%). LCMS (Method B): R.sub.T=3.26 min,
M+H.sup.+=351.
Preparation of
9-Benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile
##STR00087##
[0477] Step 1:
1-Benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid methyl ester
##STR00088##
[0479] A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid methyl ester (15.0 mmol), benzenesulfonyl chloride (11.9 g,
8.61 mL, 67.5 mmol) and triethylamine (9.61 g, 13.2 mmol) in dry
THF (100 mL) was heated under reflux for 19 h. The resultant
suspension was allowed to cool to ambient temperature and diluted
with saturated aqueous sodium carbonate solution (50 mL) and
extracted with DCM (2.times.50 mL) and THF (1.times.50 mL). The
combined organic phase was dried over anhydrous magnesium sulfate
and concentrated in vacuo. The resultant residue was purified by
flash chromatography (silica, 50 g cartridge, Si-SPE, 0-100% DCM in
pentane). The relevant fractions were concentrated in vacuo and the
residue was triturated with pentane (10 mL) to afford the title
compound as a white solid (5.25 g, 88%). LCMS (Method B):
R.sub.T=4.11 min, M+H.sup.+=395/397.
Step 2:
1-Benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-car-
boxylic acid methyl ester
##STR00089##
[0481] A solution of
1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid methyl ester (1.58 g, 4.0 mmol) in dry THF (14.0 mL) was added
dropwise to a cold (-78.degree. C.) solution of LDA [freshly
prepared from diisopropylamine (0.67 mL, 4.8 mmol) and 2.5N
n-butyllithium (1.92 mL, 4.8 mmol in hexanes) in THF (14 mL)]. The
reaction mixture was stirred at -78.degree. C. for 45 minutes
before the addition of iodomethane (0.30 mL, 4.72 mmol), then the
reaction mixture was warmed to 10.degree. C. over 3.5 h. A solution
of sodium dihydrogen phosphate (25 mL) was then added and the
resultant mixture was allowed to warm to ambient temperature and
the phases were separated. The aqueous phase was extracted with DCM
(2.times.15 mL) and the combined organic phase was washed with
brine, dried over anhydrous magnesium sulfate and concentrated in
vacuo. The resultant residue was purified by chromatography
(silica, 10 g cartridge, Si-SPE, DCM then ethyl acetate) and
trituration with pentane to afford the title compound (0.42 g,
25%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.43 (d, J=2.3 Hz, 1H),
8.40 (d, J=2.3 Hz, 1H), 8.20-8.16 (m, 2H), 7.65-7.59 (m, 1H),
7.54-7.49 (m, 2H), 3.94 (s, 3H), 3.16 (s, 3H).
Step 3:
1-Benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine--
3-carboxylic acid methyl ester
##STR00090##
[0483] To a solution of
1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid methyl ester (0.42 g, 1.0 mmol) in 1,2-dichloroethane (9 mL)
were added NBS (0.20 g, 1.1 mmol) and AIBN (30 mg, 0.2 mmol) and
the reaction mixture was heated under reflux for 45 minutes. The
reaction mixture was allowed to cool to ambient temperature and was
diluted with pentane (4.0 mL), the solid was removed by filtration
and the liquors were then concentrated in vacuo. The resultant
residue was purified by chromatography (silica, 5 g cartridge,
Si-SPE, 30-100% DCM in pentane) to afford the title compound as a
white solid (0.46 g, 90%). LCMS (Method B): R.sub.T=4.55 min,
M+H.sup.+=489.
Step 4:
1-Benzenesulfonyl-5-bromo-2-{[cyanomethyl-(toluene-4-sulfonyl)amin-
o]-methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl
ester
##STR00091##
[0485] Sodium hydride (48 mg, 60% dispersion in mineral oil, 12.0
mmol) was added to a cooled (0.degree. C.) mixture of
1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbo-
xylic acid methyl ester (0.56 g, 1.16 mmol) and
N-cyanomethyl-4-methyl-benzenesulfonamide (0.25 g, 1.20 mmol) in
dry THF (3.5 mL). The reaction mixture was stirred at 0.degree. C.
for 15 minutes, then allowed to warm to ambient temperature and
stirred for 18 h. The reaction mixture was then diluted with DCM
(40 mL), saturated aqueous sodium carbonate solution (20 mL) and
water (20 mL). The organic phase was separated, washed with brine,
dried over anhydrous magnesium sulfate and concentrated in vacuo.
The resultant residue was purified by flash column chromatography
(silica, 5 g cartridge, Si-SPE, DCM) to afford the title compound
as a beige solid (0.59 g, 80%). LCMS (Method B): R.sub.T=4.28 min,
M+H.sup.+=617/619.
Step 5:
9-Benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile
##STR00092##
[0487] Lithium bis(trimethylsilyl)amide (2.34 mL of a 1N solution
in THF, 2.34 mmol) was added dropwise to a cooled (-78.degree. C.)
suspension of
1-benzenesulfonyl-5-bromo-2-{[cyanomethyl-(toluene-4-sulfonypamino]methyl-
}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.48 g,
0.78 mmol) in dry THF (12 mL). The reaction mixture was allowed to
slowly warm to -10.degree. C. and then quenched with saturated
aqueous ammonium chloride solution (8 mL). The reaction mixture was
diluted with water and washed with DCM (2.times.10 mL). The
combined organic phase was dried over anhydrous magnesium sulfate
and concentrated in vacuo. The resultant residue was purified by
flash chromatography (silica, 5 g cartridge, Si-SPE, 10-100% THF in
DCM) to afford the title compound as a brown solid (0.20 g, 60%).
LCMS (Method B): R.sub.T=3.83 min, M+H.sup.+=429/431.
Preparation of 1,1,2,2,3,3,4,4,4-Nonafluoro-butane-1-sulfonic acid
9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yl
ester
##STR00093##
[0489] Pyridine (23.5 mL, 290 mmol) was added to a suspension of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (5.01 g, 11.7 mmol) in DCM (400 mL) at room
temperature. The resultant solution was cooled to 0.degree. C. then
nonafluorobutanesulfonic anhydride (7.16 mL, 23.4 mmol) was added
portionwise over 15 minutes maintaining the internal temperature
below 5.degree. C. The reaction mixture was stirred for 15 minutes
at 0.degree. C. then at room temperature for 3 h. The solution was
cooled to 0.degree. C. and 1M hydrochloric acid (290 mL) was added
then the mixture was extracted with DCM (.times.3) and the combined
organic phase was dried over sodium sulfate, filtered and
evaporated. The residue was triturated with DCM and the resultant
solid collected by filtration. The filtrate was purified by
chromatography (silica, 50 g column, DCM) and the appropriate
fractions were combined with the solid collected previously and
dried to afford the title compound (6.63 g, 80%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 9.93 (s, 1H); 8.86 (d, J=2.2 Hz, 1H); 8.75
(d, J=2.2 Hz, 1H); 8.30-8.24 (m, 2H); 7.73-7.65 (m, 1H); 7.61-7.52
(m, 2H).
Preparation of
9-Benzenesulfonyl-3,5-dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboni-
trile
##STR00094##
[0491] A mixture of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic
acid
9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yl
ester (6.63 g, 9.3 mmol) and tetra n-butylammonium bromide (11.3 g,
35 mmol) in 1,4-dioxane (400 mL) was heated under reflux for 2 h.
The reaction mixture was evaporated to about a third of the
original volume then left to stand overnight. The residue was taken
up in DCM and purified twice by flash chromatography (silica, 70 g
column, DCM) to afford the title compound (1.79 g, 39%). .sup.1H
NMR (DMSO-D.sub.6, 300 MHz): 9.73 (d, J=0.6 Hz, 1H); 9.10 (d, J=2.3
Hz, 1H); 8.99 (d, J=2.3 Hz, 1H); 8.28-8.21 (m, 2H); 7.82-7.74 (m,
1H); 7.68-7.57 (m, 2H).
Preparation of
9-Benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile
##STR00095##
[0493] A mixture of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (500 mg, 1.16 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(500 mg, 2.40 mmol) and [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) (200 mg, 0.25 mmol) in 2N aqueous
potassium acetate (3.6 mL) and acetonitrile (7.2 mL) was heated
under microwave irradiation at 140.degree. C., for 30 minutes. The
reaction mixture was allowed to cool to ambient temperature, 1M
hydrochloric acid (7.5 mL) was added and the mixture was stirred at
room temperature for 1 h. The resulting precipitate was collected
by filtration, washed with acetonitrile (5 mL) and left to air dry
to afford the title compound as a crude brown solid (500 mg, 99%).
LCMS (Method G): R.sub.T=3.84 min, M+H=431.
Preparation of 1,1,2,2,3,3,4,4,4-Nonafluoro-butane-1-sulfonic acid
9-benzenesulfonyl-6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrol-5-yl ester
##STR00096##
[0495] 1,1,2,2,3,3,4,4,4-Nonafluorobutanesulfonic anhydride (0.75
g, 0.40 mL, 1.3 mmol) was added dropwise to a suspension of
9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile (106 mg, 0.25 mmol) in pyridine
(0.7 mL, 8.0 mmol) and dry DCM (7 mL) at 0.degree. C. The reaction
mixture was then allowed to warm to ambient temperature and stirred
for 4 h. The reaction mixture was treated with 1N hydrochloric acid
(6 mL) and the phases were separated. The aqueous phase was
extracted with DCM (2.times.10 mL), the combined organic phase was
dried over anhydrous magnesium sulfate and concentrated in vacuo.
The resultant residue was purified by chromatography (silica, 2 g
column, Si-SPE, gradient of DCM/EtOAc) and further trituration with
pentane (2 mL) to afford the title compound as a white solid (150
mg, 84%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.95 (s, 1H), 8.99 (d,
J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.35-8.32 (m, 2H), 7.86 (d,
J=0.8 Hz, 1H), 7.74-7.68 (m, 2H), 7.61-7.56 (m, 2H), 4.04 (s, 3H).
LCMS (Method G): R.sub.T=4.80 min, M+H.sup.+=713.
Preparation of
9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile
##STR00097##
[0497] A mixture of 1,1,2,2,3,3,4,4-octafluoropentane-1-sulfonic
acid
9-benzenesulfonyl-6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrol-5-yl ester (150 mg, 0.2 mmol) and tetrabutylammonium
bromide (240 mg, 0.75 mmol) in dry dioxane (10 mL) was heated at
reflux for 1 h. The reaction mixture was allowed to cool to ambient
temperature and was then concentrated in vacuo. The resultant
residue was purified by chromatography (silica, 2 g column, Si-SPE,
gradient of DCM/EtOAc) and further trituration with acetonitrile (2
mL) to afford the title compound as a white solid (60 mg, 60%).
.sup.1H NMR (CDCl.sub.3, 400 MHz): 9.84 (s, 1H), 8.95-8.92 (m, 2H),
8.27-8.24 (m, 2H), 7.84 (d, J=0.9 Hz, 1H), 7.74 (s, 1H), 7.65-7.60
(m, 1H), 7.55-7.49 (m, 2H), 4.01 (s, 3H). LCMS (Method G):
R.sub.T=4.56 min, M+H.sup.+=493.
Preparation of
9-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b-
;4',3'-d]pyrrole-6-carbonitrile
##STR00098##
[0499] A solution of
9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4',3'-d-
]pyrrole-6-carbonitrile (102 mg, 0.2 mmol) in acetonitrile (10 mL)
was treated with ethyl iodide (34 mg, 17.4 .mu.L, 0.2 mmol). The
reaction mixture was heated for 24 h at 50.degree. C., until
analysis (TLC/LCMS) showed complete consumption of starting
material. The reaction mixture was allowed to cool to ambient
temperature and was then concentrated in vacuo. The resultant
residue was partitioned between ethyl acetate (10 mL) and 1M sodium
carbonate solution (5 mL). The organic layer was separated, dried
over anhydrous sodium sulfate, filtered and evaporated in vacuo.
The resultant residue was purified by chromatography (silica,
Si-SPE, EtOAc) to afford the title compound as a white solid (72
mg, 60%). .sup.1H NMR (CDCl.sub.3, 400 MHz,): 9.56 (s, 1H), 8.76
(d, J=2.3 Hz, 1H), 8.65 (s, 1H), 8.25-8.22 (m, 2H), 7.67-7.62 (m,
1H), 7.54-7.49 (m, 2H), 5.15 (s, 1H), 2.96 (s, 2H), 2.48 (s, 2H),
2.23 (s, 4H), 2.02 (d, J=16.9 Hz, 2H), 1.18-1.04 (m, 3H). LCMS
(Method G): R.sub.T=3.5 min, M+H.sup.+=541.
Preparation of 6-Bromo-3-iodo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00099##
[0500] Step 1: 6-Bromo-4-iodo-nicotinic acid
##STR00100##
[0502] n-Butyllithium (2.5M in hexanes, 297 mL, 0.743 mol) was
added over 1 h to a cooled (-25.degree. C.) solution of
2,2,6,6,-tetramethylpiperidine (131 mL, 0.77 mol) in
tetrahydrofuran (1 L). The mixture was left to stir for 16 h at
-25.degree. C. then cooled to -55.degree. C. before addition of
solid 6-bromonicotinic acid (50.0 g, 0.25 mmol). The mixture was
allowed to warm to -20.degree. C. and stirred for 2 h. The reaction
mixture was cooled to -70.degree. C. then poured onto a pre-cooled
(-70.degree. C.) solution of iodine (188.5 g, 0.74 mol) in
tetrahydrofuran (500 mL). The mixture was then poured into the
original reaction vessel and the contents allowed to warm to
ambient temperature and stirred for 1 h. The solvent was evaporated
and the resultant residue dissolved in water (500 mL) and washed
with dichloromethane (3.times.300 mL). The aqueous phase was
separated and the pH adjusted to 2 by the addition of concentrated
hydrochloric acid. Aqueous sodium metabisulfite solution (20% w/w,
30 mL) was added and the solid which deposited was collected by
filtration. The resultant solid was washed with water (75 mL) and
pentane (75 mL) and dried at 75.degree. C. under vacuum to furnish
the title compound as a tan solid (53.1 g, 65%). .sup.1H NMR
(DMSO-D.sub.6, 300 MHz): 8.62 (s, 1H), 8.35 (s, 1H). LCMS (Method
B): R.sub.T=2.16 min, M+H.sup.+=328/330.
Step 2: (6-Bromo-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester
##STR00101##
[0504] A mixture of 6-bromo-4-iodo-nicotinic acid (18.3 g, 55.7
mmol), diphenylphosphorylazide (18 mL, 83.6 mmol) and triethylamine
(23.5 mL, 167.2 mmol) in tert-butanol (110 mL) and toluene (120 mL)
was heated at 110.degree. C. for 3 h. The mixture was allowed to
cool to ambient temperature then evaporated under reduced pressure.
The resultant oil was treated with water (150 mL) and extracted
with ethyl acetate (2.times.300 mL). The combined organic layer was
dried over anhydrous sodium sulfate, filtered and evaporated to
give a black solid. The resultant black solid was triturated with
methanol (75 mL), collected by filtration, then washed with diethyl
ether (30 mL) and left to air dry to afford the title compound as a
brown solid (7.5 g, 34%). The remaining filtrate was evaporated and
purified by flash chromatography on a pad of silica. The pad was
washed with 20% ethyl acetate in cyclohexane. Collecting all
fractions containing product followed by evaporation in vacuo and
trituation with cyclohexane afforded further title compound (8.9 g,
40%) as a white solid (combined yield--16.4 g, 74%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 8.95 (s, 1H), 7.87 (s, 1H), 6.64 (s, 1H),
1.54 (s, 9H). LCMS (Method B): R.sub.T=3.83 min,
M+H.sup.+=399/401.
Step 3: 6-Bromo-4-iodo-pyridin-3-ylamine
##STR00102##
[0506] (6-Bromo-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester
(13.6 g, 34.1 mmol) was dissolved in dichloromethane (150 mL) and
trifluoroacetic acid (50 mL) was then added. The resultant solution
was stirred at ambient temperature for 2 h then evaporated under
reduced pressure. The resultant residue was treated with a
saturated solution of sodium hydrogen carbonate and the resultant
solid was treated with water (50 mL) then extracted with ethyl
acetate (2.times.200 mL). The combined organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure to afford the title compound as an off-white solid (10.0
g, 98%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.81 (s, 1H), 7.73 (s,
1H), 4.14 (s, 2H). LCMS (Method B): R.sub.T=3.03 min,
M+H.sup.+=299/301.
Step 4: 6'-Bromo-2-fluoro-[3,4']bipyridinyl-3'-ylamine
##STR00103##
[0508] A mixture of 6-bromo-4-iodo-pyridin-3-ylamine (10.0 g, 33.4
mmol), 2-fluoropyridine-3-boronic acid (5.2 g, 36.8 mmol) and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (2.73 g, 3.34 mmol) in acetonitrile (150
mL) and 1N aqueous potassium fluoride solution (150 mL) was
degassed with nitrogen for 20 minutes. The reaction mixture was
heated at 70.degree. C. for 2.5 h, allowed to cool to ambient
temperature and then partitioned between ethyl acetate (400 mL) and
water (150 mL). The organic layer was separated, dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo. The
resultant solid residue was triturated with dichloromethane:
methanol (1:1, 100 mL), collected by filtration and washed with
diethyl ether (50 mL) to furnish the title compound as a brown
solid (3.5 g, 39%). The filtrate was evaporated and purified by
passing the resultant residue through a pad of silica eluting with
ethyl acetate:cyclohexane (1:1). Collection of the appropriate
fractions and evaporation to dryness afforded a solid that was then
triturated with diethyl ether to afford the title compound as a
brown solid (3.7 g, 42%) (combined yield--7.22 g, 81%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 8.34 (ddd, J=4.9, 2.0, 1.2 Hz, 1H), 7.99 (s,
1H), 7.85 (ddd, J=9.4, 7.4, 2.0 Hz, 1H), 7.37 (ddd, J=7.4, 4.9, 2.0
Hz, 1H), 7.22 (s, 1H), 3.75 (s, 2H). LCMS (Method B): R.sub.T=2.78
min, M+H.sup.+=268/270.
Step 5: 6-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00104##
[0510] A solution of 6'-bromo-2-fluoro-[3,4']bipyridinyl-3'-ylamine
(7.22 g, 26.9 mmol) in THF (75 mL) was added dropwise over 10
minutes to sodium bis-(trimethylsilyl)amide (1N solution in THF, 54
mL, 53.9 mmol). The reaction mixture was left to stir for 2.5 h
then 1N aqueous potassium fluoride solution (7 mL) was added and
the solvent evaporated in vacuo. The residue was diluted with water
(100 mL) and the resultant solid was collected by filtration,
washed with water (20 mL) and diethyl ether:pentane (1:1, 20 mL)
and left to air dry. The resultant solid was triturated with
methanol (50 mL), collected by filtration, washed with methanol (10
mL) and diethyl ether (20 mL) and pentane (20 mL) and left to air
dry to afford the title compound as a brown solid (5.0 g, 75%).
.sup.1H NMR (DMSO-D.sub.6, 300 MHz): 8.73-8.69 (m, 2H), 8.63 (dd,
J=4.8, 1.7 Hz, 1H), 8.48 (dd, J=1.0 Hz, 1H), 7.33 (dd, J=7.8, 4.8
Hz, 1H). LCMS (Method B): R.sub.T=2.43 min, M+H.sup.+=248/250.
Step 6: 6-Bromo-3-iodo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00105##
[0512] A solution of iodine monochloride (32.5 g, 200 mmol) in
acetic acid (120 mL) was added portionwise over 2 h to a mixture of
6-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (5.0 g, 20 mmol) and
sodium acetate (18.2 g, 221 mmol) in acetic acid (120 mL) at
100.degree. C. The reaction mixture was cooled to ambient
temperature and poured into saturated sodium metabisulfite solution
(20% w/w, 400 mL). The resultant precipitate was collected by
filtration and the solid was washed with water (50 mL) and diethyl
ether (2.times.50 mL) then dried at 45.degree. C. until constant
weight was achieved, to afford the title compound as a grey solid
(6.3 g, 83%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 12.49 (s, 1H),
9.14 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.71 (s, 1H), 8.49
(s, 1H). LCMS (Method B): R.sub.T=3.40 min, M+H.sup.+=374/376.
Preparation of
3-Bromo-6-chloro-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00106##
[0513] Step 1: 6-Chloro-4-iodo-pyridin-3-ylamine
##STR00107##
[0515] (6-Chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester (3.67 g, 10.3 mmol) was dissolved in DCM (32 mL) and TFA (8
mL) was added. The reaction mixture was stirred at ambient
temperature for 2 h and then evaporated in vacuo. The resultant
residue was treated with 5N aqueous sodium hydroxide solution (25
mL), diluted with water (100 mL) and extracted into ethyl acetate
(2.times.100 mL). The combined organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford the title compound as yellow solid (2.37 g, 90%). .sup.1H
NMR (CD.sub.3OD, 300 MHz): 7.80 (s, 1H), 7.60 (s, 1H), 4.14 (s,
2H). LCMS (Method B): R.sub.T=3.00 min, M+H.sup.+=255.
Step 2: 5-Bromo-6'-chloro-2-fluoro-[3,4']bipyridinyl-3'-ylamine
##STR00108##
[0517] A mixture of 6-chloro-4-iodo-pyridin-3-ylamine (2.37 g, 9.31
mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.64 g, 12.0 mmol)
and 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(0.76 g, 0.93 mmol) in acetonitrile (35 mL) and 1N aqueous
potassium fluoride solution (35 mL) was degassed with nitrogen for
20 minutes. The reaction mixture was heated at 80.degree. C. for 3
h, allowed to cool to ambient temperature then partitioned between
ethyl acetate (100 mL) and water (75 mL). The organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The resultant solid residue was triturated
using 1:1 DCM/methanol, collected by filtration, washed with
diethyl ether and ethyl acetate to afford the title compound as a
tan solid (1.37 g, 49%). The filtrate was concentrated under
reduced pressure and the resiude was purified by flash
chromatography (silica, 80 g column, ISCO, 0-40% ethyl acetate in
pentane) to afford further title compound as a brown solid (0.73 g,
26%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 8.46 (dd, J=2.5, 1.3 Hz,
1H), 8.24 (dd, J=8.3, 2.5 Hz, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 5.57
(s, 2H). LCMS (Method B): R.sub.T=3.21 min, M+H.sup.+=304.
Step 3: 3-Bromo-6-chloro-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00109##
[0519] A solution of
5-bromo-6'-chloro-2-fluoro-[3,4']ipyridinyl-3'-ylamine (2.21 g,
7.32 mmol) in THF (124 mL) was added dropwise over 10 minutes to
sodium his-(trimethylsilyl)amide ON solution in THF, 14.6 mL, 14.6
mmol). The reaction mixture was stirred for 1 h at ambient
temperature and then quenched by the addition of water (2 mL). The
resultant brown solution was partitioned between ethyl acetate (75
mL) and brine (50 mL). An off-white solid precipitated and was
collected by filtration to afford the title compound as a grey
solid (1.01 g, 49%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 9.01 (d,
J=2.3 Hz, 1H), 8.73 (s, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.35 (s, 1H).
LCMS (Method B): R.sub.T=3.33 min, M+H.sup.+=284.
Preparation of 4-(4-Bromobenzyl)-1-methylpiperidine
##STR00110##
[0521] A mixture of 4-(4-bromobenzyl)-piperidine (290 mg, 1.14
mmol), formic acid (12 mL) and 37% aqueous formaldehyde (0.30 mL,
3.75 mmol) was divided into three portions. Each portion was heated
at 150.degree. C. for 5 minutes in a microwave reactor. The
combined cold mixture was loaded onto a 5 g SCX-2 cartridge which
was then washed with methanol (30 mL) then 2 N ammonia in methanol
(50 mL). Concentration of the combined basic fractions in vacuo
gave the title compound (300 mg, 98%) as a colourless oil. LCMS
(Method B): R.sub.T=2.18 min, M+H.sup.+=268, 270.
Preparation of 4-(3-Bromo-5-methoxyphenoxy)-1-methylpiperidine
##STR00111##
[0523] To a suspension of sodium hydride (60% in mineral oil, 600
mg, 15.0 mmol) in DMF (20 mL) at 65.degree. C. was slowly added a
solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF
(7.0 mL). After stirring for 30 minutes, a solution of
3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added
and the reaction mixture was stirred at 65.degree. C. for 24 h. The
reaction mixture was allowed to cool to ambient temperature then
was poured into water (200 mL) and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were loaded onto a
SCX-2 cartridge, which was then washed with acetonitrile then
eluted with 2N ammonia in methanol. Concentration of the basic
methanolic fractions in vacuo gave the title compound (1.5 g, 50%).
.sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H),
6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H),
4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m,
5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B):
R.sub.T=2.1 min, M+H.sup.+=300.
Preparation of 4-(3,5-Dibromophenoxy)-1-methylpiperidine
##STR00112##
[0525] To a suspension of sodium hydride (60% in mineral oil, 600
mg, 15.0 mmol) in DMF (20 mL), at 65.degree. C., was slowly added a
solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF
(7.0 mL). After stirring for 1 h, a solution of
1,3-dibromo-5-fluorobenzene (1.26 mL, 10.0 mmol) in DMF (7.0 mL)
was added and the reaction mixture was stirred at 65.degree. C. for
3 days. The mixture was allowed to cool to ambient temperature then
poured into water (100 mL) and extracted with ethyl acetate (150
mL). The organic layer was washed with water (100 mL) and loaded
onto an SCX-2 cartridge, which was then washed with acetonitrile
and eluted with 2N ammonia in methanol. Concentration of the basic
methanolic fraction in vacuo gave the title compound (1.88 g, 54%).
.sup.1H NMR (CDCl.sub.3, 400 MHz): 7.22 (t, J=1.6 Hz, 1H), 6.98 (d,
J=1.7 Hz, 2H), 4.31-4.23 (m, 1H), 2.69-2.59 (m, 2H), 2.37-2.18 (m,
5H), 2.01-1.92 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B):
R.sub.T=2.3 min, M+H.sup.+=350.
Preparation of 1-(4-Bromo-2,6-difluorobenzyl)-piperidine
##STR00113##
[0527] Methane sulfonyl chloride (0.38 mL, 4.93 mmol) was added
dropwise to a cooled (0.degree. C.) solution of
(4-bromo-2,6-difluorophenyl)-methanol (1.00 g, 4.48 mmol) and
triethylamine (0.75 mL, 5.38 mmol) in DCM (50 mL). The reaction
mixture was allowed to warm to ambient temperature and stirred for
2 h. The mixture was diluted with DCM (30 mL) and washed with water
(20 mL). The organic phase was separated, dried over anhydrous
sodium sulfate, filtered and evaporated in vacuo to afford a
colourless oil. The oil was dissolved in acetonitrile (30 mL),
piperidine (0.53 mL, 5.38 mmol) and potassium carbonate (0.93 g,
6.72 mmol) were added and the reaction mixture was heated at
50.degree. C. for 90 minutes. The reaction mixture was allowed to
cool to ambient temperature and the solid removed by filtration.
The filtrate was evaporated in vacuo and the resultant residue
purified by flash column chromatography (silica, 12 g column, ISCO,
0-40% ethyl acetate in cyclohexane) to afford the title compound as
a colourless oil (1.23 g, 99%). .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.07 (d, J=6.6 Hz, 2H), 3.62 (t, J=1.7 Hz, 2H), 2.41 (t, J=5.1 Hz,
4H), 1.59-1.50 (m, 4H), 1.42-1.33 (m, 2H). LCMS (Method B):
R.sub.T=1.67 min, M+H.sup.+=290/292.
Preparation of 1-[1-(4-Bromophenyl)-1-methyl-ethyl]-piperidine
##STR00114##
[0529] In a three necked round bottom flask fitted with a condenser
and nitrogen stream, was placed a small quantity of ground glass
and magnesium turnings (190 mg, 7.40 mmol). The mixture was stirred
for 30 minutes under vacuum then placed under nitrogen and iodine
added (one small crystal), followed by the rapid addition of
1,4-dibromobenzene (2.43 g, 10.3 mmol) in 15 ml of anhydrous
diethyl ether. The reaction mixture was then heated under reflux
for 5 minutes. After this time, a solution of
1-(1-cyano-1-methylethyl)-piperidine (1.0 g, 6.60 mmol) in
anhydrous THF was added dropwise resulting in the formation of a
white precipitate. The reaction mixture was heated under reflux for
1.5 h, before cooling to ambient temperature. The resultant mixture
was treated with saturated aqueous potassium carbonate solution and
extracted with DCM. The organic extract was dried over magnesium
sulfate and concentrated in vacuo. The crude residue was purified
by column chromatography (silica, 12 g column, ISCO, 0-40% ethyl
acetate in cyclohexane) to afford the title compound (200 mg, 95%)
as a colourless oil. LCMS (Method B): R.sub.T=1.99 min,
M+H.sup.+=282, 284.
Preparation of 1-(4-Bromobenzyl)-azetidine
##STR00115##
[0531] A solution of 4-bromobenzyl bromide (1.00 g, 4.0 mmol) and
triethylamine (0.84 ml, 6.0 mmol) in THF (20 mL) was stirred at
ambient temperature for 10 minutes. Azetidine (0.54 ml, 8.0 mmol)
was then added and a white precipitate resulted. The slurry was
stirred at ambient temperature for 18 h then evaporated in vacuo.
The resultant residue was partitioned between DCM and saturated
aqueous sodium hydrogen carbonate, the organic phase was separated,
dried over magnesium sulfate and concentrated in vacuo to afford
the title compound (0.76 g, 3.40 mmol) as a colourless oil. .sup.1H
NMR (CDCl.sub.3, 400 MHz): 7.42 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.2
Hz, 2H), 3.50 (s, 2H), 3.19 (t, J=7.0 Hz, 4H), 2.08 (p, J=7.0 Hz,
2H).
Preparation of 1-(4-Bromobenzyl)-cis-2,6-dimethylpiperidine
##STR00116##
[0533] A mixture of 1-bromo-4-bromomethylbenzene (500 mg, 2.0
mmol), cis-2,6-dimethylpiperidine (0.30 mL, 2.2 mmol) and potassium
carbonate (332 mg, 2.4 mmol) in acetonitrile (20 mL) was heated
under reflux for 2 h. The reaction mixture was allowed to cool to
ambient temperature, the solid removed by filtration and the
filtrate evaporated in vacuo. The resultant residue was partitioned
between ethyl acetate (100 mL) and water (25 mL). The organic phase
was dried over anhydrous sodium sulfate, filtered and evaporated in
vacuo to give the title compound as a pale brown oil (464 mg, 82%).
.sup.1H NMR (CDCl.sub.3, 300 MHz): 7.40 (d, J=8.3 Hz, 2H), 7.27 (d,
J=7.0 Hz, 2H), 3.71 (s, 2H), 2.56-2.36 (m, 2H), 1.68-1.61 (m, 1H),
1.61-1.47 (m, 2H), 1.33-1.24 (m, 3H), 1.01 (d, J=6.2 Hz, 6H). LCMS
(Method B): R.sub.T=0.8 min, M+H.sup.+=282/284.
Preparation of 4-(4-Bromophenyl)-4-hydroxypiperidine-1-carboxylic
acid tert-butyl ester
##STR00117##
[0535] Triethylamine (3.69 mL, 26.3 mmol) was added to a solution
of 4-(4-bromo-phenyl)-piperidin-4-ol (5.18 g, 20.2 mmol) and
di-tert-butyl dicarbonate (5.30 g, 20.2 mmol) in DCM (60 mL). The
resultant reaction mixture was stirred at ambient temperature for
18 h, then diluted with water (100 mL) and extracted into DCM
(3.times.50 mL). The combined organic phase was concentrated in
vacuo and the residue purified by flash chromatography (silica, 40
g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the
title compound as a white solid (7.03 g, 98%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.49 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz,
2H), 4.04 (d, J=13.0 Hz, 2H), 3.29-3.15 (m, 2H), 1.96 (td, J=13.0,
5.0 Hz, 2H), 1.69 (dd, J=14.0, 2.5 Hz, 2H), 1.48 (s, 9H). LCMS
(Method B): R.sub.T=3.88 min.
Preparation of 4-(4-Bromophenyl)-4-methoxypiperidine-1-carboxylic
acid tert-butyl ester
##STR00118##
[0537] Sodium hydride (76 mg, 1.90 mmol) was added portionwise to a
solution of 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid
tert-butyl ester (519 mg, 1.46 mmol) in anhydrous THF (10 mL) at
0.degree. C. After 1 h, methyl iodide (136 .mu.L, 2.19 mmol) was
added and the reaction mixture was allowed to warm to ambient
temperature and stirred for 18 h. The reaction was quenched by the
addition of water (10 mL), the organic layer was separated and the
aqueous layer back-extracted with DCM (3.times.10 mL). The combined
organic phase was concentrated in vacuo to afford the title
compound (607 mg, quantitative). .sup.1H NMR (CDCl.sub.3, 400 MHz):
7.49 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 3.97 (d, J=13.0 Hz,
2H), 3.15 (t, J=13.0 Hz, 2H), 2.97 (s, 3H), 1.97 (d, J=13.5 Hz,
2H), 1.83-1.74 (m, 2H), 1.47 (s, 9H). LCMS (Method B): R.sub.T=4.61
min.
Preparation of 4-(4-Bromophenyl)-4-fluoropiperidine-1-carboxylic
acid tert-butyl ester
##STR00119##
[0539] [Bis(2-Methoxyethyl)amino]sulfur trifluoride (2.1 mL, 11.4
mmol) was added to a stirred solution of
4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl
ester (810 mg, 2.28 mmol) in anhydrous DCM (25 mL), at -78.degree.
C. The reaction mixture was allowed to warm to ambient temperature
and stirred for 72 h. The reaction mixture was quenched by the
addition of saturated aqueous potassium carbonate (10 mL) and
extracted into DCM (3.times.10 mL). The combined organic phase was
concentrated in vacuo and the residue purified by flash
chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in
cyclohexane) to afford the title compound as a colourless oil (738
mg, 91%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.50 (d, J=8.5 Hz,
2H), 7.24 (d, J=8.5 Hz, 2H), 4.19-4.05 (m, 2H), 3.29-3.05 (m, 2H),
2.04-1.84 (m, 4H), 1.49 (s, 9H). LCMS (Method B): R.sub.T=4.55
min.
Preparation of 1-(5-Bromothiophen-3-ylmethyl)-piperidine
##STR00120##
[0540] Step 1: 5-Bromothiophene-3-carboxylic acid
##STR00121##
[0542] To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0
mmol) in acetic acid (140 mL), was added dropwise, a solution of
bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction
mixture was stirred for 30 minutes and then poured into water. The
resultant solid was collected by filtration to afford the title
compound as a grey solid (2.07 g, 26%). LCMS (Method B):
R.sub.T=2.9 min, M+H.sup.+=208.
Step 2: (5-Bromothiophen-3-yl)-piperidin-1-yl-methanone
##STR00122##
[0544] To a solution of 5-bromothiophene-3-carboxylic acid (1.03 g,
5.00 mmol) in acetonitrile (10 mL), were added HATU (2.09 g, 5.50
mmol), DIPEA (2.6 mL, 15.0 mmol) and piperidine (1.0 mL, 10.0 mmol)
and the reaction mixture was stirred at room temperature for 24 h.
The reaction mixture was diluted with ethyl acetate (75 mL) and was
washed with saturated aqueous citric acid (2.times.50 mL). The
orgainic layer was concentrated in vacuo and the resultant residue
was loaded onto an SCX-2 cartridge. Eluting with acetonitrile and
evaporation of the organic fraction in vacuo afforded the title
compound as an off-white solid (1.00 g, 73%). LCMS (Method B):
R.sub.T=3.3 min, M+H.sup.+=274.
Step 3: 1-(5-Bromothiophen-3-ylmethyl)-piperidine
##STR00123##
[0546] To a solution of
(5-bromothiophen-3-yl)-piperidin-1-yl-methanone (907 mg, 3.30 mmol)
in DCM (33 mL) was added tetrabutylammonium borohydride (2.54 g,
9.90 mmol) portionwise over 10 minutes. The reaction mixture was
heated under reflux for 19 h then further tetrabutylammonium
borohydride (2.54 mg, 9.90 mmol) was added to the reaction mixture,
in four portions over 6 h. and then the reaction mixture was heated
under reflux for 18 h. After this time the reaction mixture was
partitioned between DCM (100 mL) and saturated aqueous sodium
bicarbonate solution (100 mL). The organic layer was dried over
sodium sulfate, the solvent was removed in vacuo and the residue
was purified by flash chromatography (silica, 40 g column, ISCO,
0-50% ethyl acetate in cyclohexane) to afford an oil which
solidified on standing to afford the title compound as a white
solid (301 mg, 35%). .sup.1H NMR (CDCl.sub.3, 300 MHz):7.23 (d,
J=1.7 Hz, 1H), 7.15 (d, J=1.7 Hz, 1H), 3.91 (s, 2H), 2.97-2.87 (m,
2H), 2.72-2.62 (m, 2H), 2.15-2.06 (m, 2H), 1.70-1.52 (m, 2H),
1.41-1.25 (m, 2H); LCMS (Method B): R.sub.T=4.0 min,
M+H.sup.+=260.
Preparation of 1-(2-Bromothiazol-4-ylmethyl)-piperidine
##STR00124##
[0548] The title compound was prepared from
(2-bromothiazol-4-yl)-methanol, following the procedure outlined
above for 1-(4-bromo-2,6-difluoro-benzyl)-piperidine, to afford the
title compound as a yellow oil. .sup.1H NMR (CDCl.sub.3, 300
MHz):7.09 (s, 1H), 3.61 (d, J=0.9 Hz, 2H), 3.19 (t, J=5.4 Hz, 1H),
2.45 (t, J=5.1 Hz, 4H), 1.69-1.62 (m, 4H), 1.48-1.41 (m, 2H). LCMS
(Method B): R.sub.T=0.8 min, M+H.sup.+=261/263.
Preparation of Trifluoromethanesulfonic acid
3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl ester
##STR00125##
[0549] Step 1: 3,5-Dimethoxy-4-piperidin-1-ylmethyl-phenol
##STR00126##
[0551] A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (0.30 g,
1.65 mmol), piperidine (0.20 mL, 1.98 mmol) and acetic acid (0.47
mL, 8.25 mmol) in methanol (20 mL) was stirred for 20 minutes
before addition of sodium cyanoborohydride (0.27 g, 4.30 mmol). The
reaction mixture was allowed to stir at ambient temperature for 4 h
then loaded onto a 10 g SCX-2 cartridge which was then washed with
methanol (30 mL) and then eluted with 2N ammonia in methanol (50
mL). Concentration of the combined basic fractions in vacuo
afforded the title compound (220 mg, 53%) as a white solid. .sup.1H
NMR (DMSO-D.sub.6, 300 MHz): 9.39 (s, 1H), 6.03 (s, 2H), 3.66 (s,
6H), 3.30 (s, 2H), 2.32-2.24 (m, 4H), 1.42-1.35 (m, 4H), 1.34-1.26
(m, 2H). LCMS (Method B): R.sub.T=1.90 min, M+H.sup.+=252.
Step 2: Trifluoromethanesulfonic acid
3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl ester
##STR00127##
[0553] To a cooled solution (-20.degree. C.) of
3,5-dimethoxy-4-piperidin-1-ylmethyl-phenol (0.22 g, 0.88 mmol) and
pyridine (1.0 mL) in DCM (5 mL) was added trifluoromethanesulfonic
anhydride (0.18 mL, 1.05 mmol) over 5 minutes. After complete
addition, the reaction mixture was allowed to warm to ambient
temperature and stirring was continued for 2 h. The resultant
mixture was diluted with DCM (50 mL) and washed with water (20 mL).
The organic phase was separated, dried over anhydrous sodium
sulfate, filtered and evaporated in vacuo. The resultant residue
was purified by flash column chromatography (silica, 5 g, SPE
column, 0-50% ethyl acetate in cyclohexane) to afford an orange oil
which crystallized on standing to yield the title compound (93 mg,
28%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 6.44 (s, 2H), 3.81 (s,
6H), 3.60 (s, 2H), 2.46 (t, J=5.0 Hz, 4H), 1.56 (p, J=5.8 Hz, 4H),
1.43-1.36 (m, 2H). LCMS (Method B): R.sub.T=2.77 min,
M+H.sup.+=384.
Preparation of 1-(4-Bromo-2-methoxybenzyl)-piperidine
##STR00128##
[0555] To a stirred solution of
4-bromo-1-chloromethyl-2-methoxybenzene (1.50 g, 6.36 mmol) in
acetonitrile (64 mL) was added potassium carbonate (1.05 g, 6.36
mmol) and piperidine (0.63 mL, 6.36 mmol) then the reaction mixture
was heated under reflux for 15 h. The reaction mixture was cooled
to ambient temperature and then filtered, the filtrate was then
concentrated under reduced pressure to afford a residue that was
then loaded onto an SCX-2 cartridge (10 g) and eluted with 2N
ammonia in methanol to afford the title compound (1.73 g, 96%).
.sup.1H NMR (CDCl.sub.3, 300 MHz): 7.23 (d, J=8.1 Hz, 1H), 7.05
(dd, J=8.1, 1.9 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 3.80 (s, 3H), 3.45
(s, 2H), 2.39 (t, J=5.0 Hz, 4H), 1.62-1.51 (m, 4H), 1.47-1.39 (m,
2H).
Preparation of
1-[2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-pip-
eridine
##STR00129##
[0557] A degassed mixture of 1-(4-bromo-2-methoxybenzyl)-piperidine
(1.73 g, 6.1 mmol), bis(pinacolato)diborane (1.86 g, 7.3 mmol),
1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (249
mg, 0.31 mmol) and potassium acetate (1.79 mg, 18.3 mmol) in
dioxane (31 mL) and DMSO (5 mL) was heated under microwave
irradiation at 150.degree. C. for 30 minutes. The cooled reaction
mixture was diluted with ethyl acetate (100 mL) then filtered and
the filtrate was washed with water (100 mL). The organic phase was
dried over anhydrous sodium sulfate, filtered and evaporated in
vacuo to afford the title compound as a beige solid (2.2 g,
quantitative yield) that was used in the next step without further
purification. NMR (CDCl.sub.3, 300 MHz): 7.42 (d, J=0.7 Hz, 2H),
7.29 (s, 1H), 3.87 (s, 3H), 3.85 (s, 2H), 2.72-2.64 (m, 4H),
1.74-1.65 (m, 4H), 1.50-1.39 (m, 2H), 1.35 (s, 12H).
Preparation of
2-Bromo-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
##STR00130##
[0559] To a suspension of
2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.86 g, 8.50 mmol)
in THF (30.6 mL) was added acetic acid (17 mL) then the reaction
temperature was reduced to 0.degree. C. and sodium borohydride
(2.55 g, 42.5 mmol) was added in portions. After the addition was
complete, the reaction mixture was heated at 60.degree. C. for 1 h
then the reaction mixture was cooled to ambient temperature and
quenched by the addition of water. The resultant solution was
partitioned between ethyl acetate (75 mL) and 1N sodium hydroxide
solution (50 mL) and the layers separated. The organic phase was
collected then dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo to give the title compound (1.87 g, 89%).
.sup.1H NMR (MeOD, 300 MHz): 6.78 (s, 1H), 3.50 (s, 2H), 2.81 (s,
4H), 2.62 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).
Preparation of
4,4-Dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzyl]-p-
iperidine
##STR00131##
[0560] Step 1: 1-(4-Bromobenzyl)-4,4-dimethylpiperidine
##STR00132##
[0562] A mixture of 4-bromobenzyl bromide (500 mg, 2.0 mmol) and
4,4-dimethylpiperidine (249 mg, 2.2 mmol) and potassium carbonate
(331 mg, 2.4 mmol) in acetonitrile (20 mL) was heated under reflux
for 2 h. The reaction mixture was then cooled to ambient
temperature and the reaction mixture concentrated under reduced
pressure. The resultant oil was loaded onto an SCX-2 cartridge (10
g) and eluted with 2N ammonia in methanol to afford the title
compound (323 mg, 57%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.42 (d,
J=8.31 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 3.44 (s, 2H), 2.35 (t,
J=5.44 Hz, 4H), 1.37 (t, J=5.60 Hz, 4H), 0.90 (s, 6H).
Step 2:
4,4-Dimethyl-1-1.sup..about.4-(4,4,5,5-tetramethyl-[1,3,2]dioxabor-
olan-2-yl)-benzyl]-piperidine
##STR00133##
[0564] A degassed mixture of
1-(4-bromobenzyl)-4,4-dimethylpiperidine (320 mg, 1.1 mmol),
bis(pinacolato)diborane (346 mg, 1.4 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.4
mg, 0.06 mmol) and potassium acetate (334 mg, 3.4 mmol) in dioxane
(5.8 mL) and DMSO (0.6 mL) was heated under microwave irradiation
at 150.degree. C. for 30 minutes. The cooled reaction mixture was
diluted with ethyl acetate (50 mL) then filtered and the filtrate
was washed with water (75 mL). The organic phase was dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford the title compound as a brown oil (264 mg, 71%) that was
used in the next step without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.77 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.7 Hz,
2H), 3.63 (s, 2H), 2.47 (t, J=5.3 Hz, 4H), 1.43 (t, J=5.6 Hz, 4H),
1.38-1.31 (m, 12H), 0.91 (s, 6H).
Preparation of
(2S,6R)-2,6-Dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-b-
enzyl]-piperidine
##STR00134##
[0566] A degassed mixture of
(2S,6R)-1-(4-bromobenzyl)-2,6-dimethylpiperidine (1.70 g, 6.0
mmol), bis(pinacolato)diborane (1.83 g, 7.2 mmol),
1,1'-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (245
mg, 0.3 mmol) and potassium acetate (1.76 mg, 18.0 mmol) in dioxane
(31 mL) and DMSO (4 mL) was heated under microwave irradiation at
150.degree. C. for 30 minutes. The cooled reaction mixture was
diluted with ethyl acetate (100 mL) then filtered and the filtrate
was washed with water (100 mL). The organic phase was dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford the title compound as a beige solid (1.54 g, 78%) that was
used in the next step without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.75 (d, J=7.7 Hz, 2H), 7.39 (d, J=7.6 Hz,
2H), 3.88 (s, 2H), 2.58-2.25 (m, 2H), 1.51-1.70 (m, 4H), 1.43-1.21
(m, 14H), 1.10 (d, J=6.2 Hz, 6H).
Preparation of Trifluoromethanesulfonic acid
3-methoxy-4-piperidin-1-ylmethyl-phenylester
##STR00135##
[0567] Step 1: 3-Methoxy-4-piperidin-1-ylmethylphenol
##STR00136##
[0569] To a pre-stirred solution of 4-hydroxy-2-methoxybenzaldehyde
(1.02 g, 6.7 mmol), titanium isopropoxide (2.14 mL, 7.0 mmol) and
piperidine (0.70 mL, 7.0 mmol) in DCM (20 mL) was added sodium
triacetoxyborohydride (2.84 g, 13.4 mmol) in portions. After 3 h
the reaction mixture was quenched by the addition of methanol (1.0
mL) and then the solvents were removed under reduced pressure to
afford a residue. The resultant residue was then loaded onto an
SCX-2 cartridge (10 g) and eluted with 2N ammonia in methanol to
afford the title compound (456 mg, 30%). .sup.1H NMR (CD.sub.3OD,
300 MHz): 7.17 (d, J=8.3 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 6.43 (dd,
J=8.2, 2.2 Hz, 1H), 4.07 (s, 2H), 3.84 (s, 3H), 3.16-2.99 (m, 4H),
1.84-1.73 (m, 4H), 1.67-1.56 (m, 2H).
Step 2: Trifluoromethanesulfonic acid
3-methoxy-4-piperidin-1-ylmethyl-phenylester
##STR00137##
[0571] To a stirred solution of
3-methoxy-4-piperidin-1-ylmethylphenol (456 mg, 2.06 mmol) and
diisopropylamine (0.77 mL, 4.54 mmol) in DCM (10 mL) at 0.degree.
C. was added N-phenyltriflamide (958 mg, 2.68 mmol). After the
addition was complete the reaction mixture was allowed to warm to
ambient temperature and then stirred overnight. The reaction
mixture was concentrated under reduced pressure and then purified
by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol
in DCM) to afford the title compound as a colourless oil (408 mg,
56%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.60 (d, J=8.4 Hz, 1H),
6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 3.93 (s, 2H),
3.89 (s, 3H), 2.87-2.74 (m, 4H), 1.82-1.75 (m, 4H), 1.57-1.50 (m,
2H).
Preparation of 1-(4-Bromo-2,6-diethylbenzyl)-piperidine
##STR00138##
[0572] Step 1: 4-Bromo-2,6-diethylbenzonitrile
##STR00139##
[0574] 4-Bromo-2,6-diethylaniline (4.80 g, 21.0 mmol) was suspended
in a mixture of water (25 mL) and concentrated hydrochloric acid
(8.0 mL) then sonicated for 10 minutes. The resultant suspension
was cooled to 0.degree. C. and a solution of sodium nitrite (1.60
g, 23.1 mmol) in water (5 mL) was slowly added, maintaining the
reaction temperature below 5.degree. C. After 30 minutes, the
reaction mixture was neutralised by the careful addition of sodium
bicarbonate, then the resultant suspension was added in aliquots to
a solution of copper (I) cyanide (2.26 g, 25.2 mmol) and potassium
cyanide (3.43 g, 52.6 mmol) in water (25 mL) at 70.degree. C. After
complete addition, heating at 70.degree. C. was continued for 1 h
then the reaction mixture was cooled to ambient temperature. Water
and DCM were added then the organic phase was collected, dried over
anhydrous sodium sulfate and concentrated in vacuo to afford a
brown residue that was purified by flash chromatography (silica, 80
g column, ISCO, 0-10% ethyl acetate in cyclohexane) to afford the
title compound as an off-white solid (4.43 g, 88%). NMR
(DMSO-D.sub.6, 300 MHz): 7.58 (s, 2H), 2.78 (q, J=7.6 Hz, 4H), 1.21
(t, J=7.6 Hz, 6H).
Step 2: 4-Bromo-2,6-diethylbenzylamine
##STR00140##
[0576] Under an inert atmosphere, lithium aluminuium hydride (359
mg, 9.4 mmol) was suspended in anhydrous THF (9 mL) was cooled to
0.degree. C. and then a solution of 4-bromo-2,6-diethylbenzonitrile
(1.73 g, 7.36 mmol) in anhydrous THF (3 mL) was added dropwise. The
reaction mixture was then allowed to warm to ambient temperature
and stirring was continued for 20 h. Sodium sulfate decahydrate (6
g) was then added to quench the reaction and the resultant reaction
mixture was filtered then the filtrate was then evaporated under
reduced pressure. The resultant oil was purified by flash
chromatography (silica, 50 g column, ISCO, 0-10% methanol in DCM)
to afford the title compound as an orange oil (96 mg, 5%). .sup.1H
NMR (DMSO-D.sub.6, 400 MHz): 7.18 (s, 2H), 3.68 (s, 2H), 2.73-2.64
(m, 4H), 2.52-2.48 (m, 2H), 1.19-1.11 (m, 6H).
Step 3: 1-(4-Bromo-2,6-diethylbenzyl)-piperidine
##STR00141##
[0578] 4-Bromo-2,6-diethylbenzylamine (90 mg, 0.37 mmol),
1,5-dibromopentane (56 .mu.L, 0.41 mmol) and potassium carbonate
(206 mg, 1.5 mmol) were suspended in dioxane (5 mL) and heated at
100.degree. C. overnight. The reaction mixture was then cooled to
ambient temperature, the solid removed by filtration and the
filtrate concentrated in vacuo to afford an orange oil. The
resultant oil was purified by flash chromatography (silica, 12 g
column, ISCO, 0-10% methanol in DCM) to afford the title compound
as yellow oil (66 mg, 58%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.16
(s, 2H), 3.38 (s, 2H), 2.80-2.62 (m, 4H), 2.35 (s, 4H), 1.54-1.34
(m, 6H), 1.27-1.13 (m, 6H).
Preparation of Trifluoromethanesulfonic acid
3,5-dichloro-4-piperidin-1-yl methylphenyl ester
##STR00142##
[0579] Step 1: 3,5-Dichloro-4-piperidin-1-ylmethylphenol
##STR00143##
[0581] To a pre-stirred solution of
2,6-dichloro-4-hydroxybenzaldehyde (1.88, 9.8 mmol) and piperidine
(1.07 mL, 10.8 mmol) in DCM (40 mL) was added sodium
triacetoxyborohydride (3.13 g, 14.8 mmol) in portions. After 14 h
the reaction mixture was quenched by the addition of water (50 mL),
the pH of the solution adjusted to 2 by the addition of
hydrochloric acid and the solution washed with DCM (50 mL). The pH
of the aqueous phase was then adjusted to 9 by the addition of
saturated aqueous sodium carbonate and then the organic component
was extracted with DCM (50 mL), dried over anhydrous sodium sulfate
and evaporated under reduced pressure to afford the title compound
as a beige solid (2.03 g, 80%) that was used without further
purification. .sup.1H NMR (CD.sub.3OD, 300 MHz): 6.81-6.77 (m, 2H),
3.72 (s, 2H), 2.67-2.57 (m, 4H), 1.64-1.54 (m, 4H), 1.51-1.44 (m,
2H).
Step 2: Trifluoromethanesulfonic acid
3,5-dichloro-4-piperidin-1-ylmethylphenyl ester
##STR00144##
[0583] To a stirred solution of
3,5-dichloro-4-piperidin-1-ylmethylphenol (290 mg, 1.1 mmol) and
pyridine (0.36 mL, 4.5 mmol) in DCM (10 mL) at -20.degree. C. was
added trifluoromethanesulfonyl chloride (0.38 mL, 2.2 mmol). After
the addition was complete the reaction was allowed to warm to
ambient temperature and stirred for 10 minutes. The mixture was
diluted with DCM (20 mL), washed with water (10 mL). The organic
phase was separated, dried over anhydrous sodium sulfate, filtered
and evaporated in vacuo to afford a residue that was purified by
flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl
acetate in cyclohexane) to afford the title compound as a
colourless oil (334 mg, 76%). .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.26 (s, 2H), 3.66 (s, 2H), 2.53-2.44 (m, 4H), 1.58-1.48 (m, 4H),
1.50-1.34 (m, 2H).
Preparation of Trifluoromethanesulfonic acid
3-chloro-5-methoxy-4-piperidin-1-ylmethyl-phenyl ester
##STR00145##
[0584] Step 1: 1-(2-Chloro-4,6-dimethoxybenzyl)-piperidine
##STR00146##
[0586] To a pre-stirred solution of
2-chloro-4,6-dimethoxybenzaldehyde (2.7 g, 13.5 mmol) and
piperidine (1.46 mL, 14.9 mmol) in DCM (50 mL) at 0.degree. C. was
added sodium triacetoxyborohydride (4.29 g, 20.0 mmol) in portions.
The reaction mixture was then allowed to warm to ambient and
stirred for an additional 3 h before the addition of water (50 mL).
The pH of the aqueous phase was adjusted to 2 by the addition of
hydrochloric acid and then washed with DCM (50 mL). The pH of the
aquous phase was then adjusted to 9 by the addition of saturated
aqueous sodium carbonate and then the organic component was
extracted into DCM (50 mL), dried over sodium sulfate and
evaporated under reduced pressure to afford the title compound as a
beige solid (3.3 g, 91%) that was used without further
purification. NMR (CDCl.sub.3, 300 MHz): 6.60 (d, J=2.4 Hz, 1H),
6.43 (d, J=2.4 Hz, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H),
3.6-2.57 (v br m, 4H), 2.29-1.88 (br m, 4H), 1.71-1.40 (br m,
2H).
Step 2: 3-Chloro-5-methoxy-4-piperidin-1-ylmethylphenol
##STR00147##
[0588] Hydroiodic acid (57% solution, 5 mL) was added to
1-(2-chloro-4,6-dimethoxybenzyl)-piperidine (360 mg, 1.3 mol) and
the mixture heated at 60.degree. C. for 2 h. The reaction mixture
was cooled to ambient temperature, diluted with saturated aqueous
sodium carbonate solution (20 mL) and extracted with DCM
(3.times.30 mL). The combined organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford an beige solid that was then purified by flash
chromatography (silica, 12 g column, ISCO, 0-15% (2N ammonia in
methanol) in DCM) to afford the title compound as a white solid
(277 mg, 88%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.08 (d, J=2.2
Hz, 1H), 5.96 (d, J=2.2 Hz, 1H), 3.61 (s, 3H), 3.59 (s, 2H), 3.31
(br s, 1H), 2.74-2.64 (m, 4H), 1.70-1.62 (m, 4H), 1.60-1.43 (m,
2H).
Step 3: Trifluoromethanesulfonic acid
3-chloro-5-methoxy-4-piperidin-1-ylmethylphenyl ester
##STR00148##
[0590] To a stirred solution of
3-chloro-5-methoxy-4-piperidin-1-ylmethylphenol (223 mg, 0.87 mmol)
and pyridine (0.28 mL, 3.5 mmol) in DCM (10 mL) at -20.degree. C.
was added trifluoromethanesulfonyl chloride (0.29 mL, 1.7 mmol).
After the addition was complete the reaction mixture was allowed to
warm to ambient temperature then diluted with DCM (20 mL) then
washed with water (10 mL). The organic phase was separated, dried
over anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford an oil that was purified by flash chromatography (silica, 12
g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the
title compound as a red oil (341 mg, 73%). .sup.1H NMR (CDCl.sub.3,
300 MHz): 7.06 (d, J=2.3 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 4.40 (s,
2H), 4.05 (s, 3H), 3.72-3.42 (m, 1H), 3.06-2.72 (m, 1H), 2.23-1.75
(m, 4H), 1.73-1.36 (m, 4H).
Preparation of Trifluoromethanesulfonic acid
3-methoxy-5-methyl-4-piperidin-1-ylmethylphenyl ester
##STR00149##
[0591] Step 1:
1-[2-Methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzyl]-piperidine
##STR00150##
[0593] To a pre-stirred solution of
2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzaldehyde (2.14
g, 8.6 mmol) and piperidine (0.93 mL, 9.4 mmol) in DCM (35 mL) at
0.degree. C. was added sodium triacetoxyborohydride (2.72 g, 12.8
mmol) in portions. The reaction mixture was allowed to warm to
ambient temperature and then partitioned between water (30 mL) and
ethyl acetate (75 mL). The organic phase was dried over anhydrous
sodium sulfate, filtered and evaporated in vacuo to afford the
title compound as a colourless oil (2.78 g, quantitiative yield)
that was used in the next step without further purification.
.sup.1H NMR (CDCl.sub.3, 400 MHz): 6.51 (d, J=2.4 Hz, 1H), 6.45 (d,
J=2.4 Hz, 1H), 5.40 (t, J=3.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.76 (s,
3H), 3.64-3.55 (m, 1H), 3.39 (s, 2H), 2.42-2.27 (m, 7H), 2.07-1.93
(m, 1H), 1.90-1.77 (m, 2H), 1.75-1.52 (m, 3H), 1.54-1.44 (m, 4H),
1.43-1.34 (m, 2H).
Step 2: 3-Methoxy-5-methyl-4-piperidin-1-ylmethylphenol
##STR00151##
[0595] 1N Hydrochloric acid (10 mL) was added to
1-[2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzyl]-piperidine
(2.33 g, 7.3 mmol) in methanol (30 mL) and the reaction mixture was
stirred at ambient temperature for 2 h. The pH of the solution was
adjusted to 9 by the addition of saturated aqueous sodium carbonate
solution (20 mL) and the aqueous phase was extracted with DCM
(3.times.30 mL). The combined organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford a colourless oil. The resultant oil was purified by flash
chromatography (silica, 12 g column, ISCO, 0-15% (2N ammonia in
MeOH) in DCM) to afford the title compound as a white solid (570
mg, 33%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.14 (d, J=2.4 Hz,
1H), 5.99 (s, 1H), 3.68 (s, 3H), 3.49 (s, 2H), 2.56-2.46 (m, 4H),
2.25 (s, 3H), 1.65-1.51 (m, 4H), 1.48-1.36 (s, 2H).
Step 3: Trifluoromethanesulfonic acid
3-methoxy-5-methyl-4-piperidin-1-ylmethylphenyl ester
##STR00152##
[0597] To a stirred solution
3-methoxy-5-methyl-4-piperidin-1-ylmethylphenol (563 mg, 2.4 mmol)
and pyridine (0.77 mL, 10.0 mmol) in DCM (20 mL) at 0.degree. C.
was added trifluoromethanesulfonyl chloride (0.81 mL, 4.8 mmol).
After the addition was complete the reaction was allowed to warm to
ambient temperature. The mixture was diluted with DCM (20 mL) and
washed with water (10 mL). The organic phase was separated, dried
over anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford an oil that was purified by flash chromatography (silica, 40
g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the
title compound as a red oil (698 mg, 58%). NMR (CDCl.sub.3, 300
MHz): 6.82 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.28 (s, 2H),
3.96 (s, 3H), 3.67-3.35 (m, 1H), 2.99-2.66 (m, 1H), 2.47 (s, 3H),
2.21-1.75 (m, 4H), 1.73-1.35 (m, 4H).
Preparation of 1-(4-Bromo-2-fluorobenzyl)-piperidine
##STR00153##
[0599] To a pre-stirred solution of 4-bromo-2-fluorobenzaldehyde
(1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40
mL) at 0.degree. C. was added sodium triacetoxyborohydride (2.85 g,
13.4 mmol) in portions. The reaction mixture was allowed to warm to
ambient temperature and stirred for an additional 14 h. The
reaction was quenched by the addition of water (30 mL) and
extracted with ethyl acetate (75 mL). The organic phase was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo to afford the title compound as a colourless
oil (2.6 g, 84%) that was used in the next step without further
purification. NMR (CDCl.sub.3, 400 MHz): 7.33-7.17 (m, 3H), 3.49
(d, J=1.6 Hz, 2H), 2.43-2.33 (m, 4H), 1.61-1.53 (m, 4H), 1.46-1.38
(m, 2H).
Preparation of 1-(4-Bromo-2-ethoxybenzyl)-piperidine
##STR00154##
[0601] Sodium hydride (306 mg, 60%, 7.6 mmol) was added in portions
to a solution of 1-(4-bromo-2-fluorobenzyl)-piperidine (520 mg, 1.9
mmol) and ethyl urethane (0.91 mL, 7.6 mmol) in dioxane (10 mL)
under an atmosphere of nitrogen. The reaction mixture was then
sonicated for 30 minutes until gas evolution ceased then heated at
140.degree. C. overnight in a sealed tube. The reaction mixture was
diluted with water and extracted with DCM (3.times.30 mL). The
combined organic layer was dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo to afford a colourless oil that
was then purified by flash chromatography (silica, 12 g column,
ISCO, 0-10% methanol in DCM) to afford the title compound as a
white solid (416 mg, 74%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.23
(d, J=8.1 Hz, 1H), 7.03 (dd, J=8.1, 1.9 Hz, 1H), 6.95 (d, J=1.9 Hz,
1H), 3.99 (q, J=7.0 Hz, 2H), 3.47 (s, 2H), 2.46-2.35 (m, 4H),
1.61-1.53 (m, 4H), 1.45-1.36 (m, 5H).
Preparation of 1-(4-Bromo-2-trifluoromethoxybenzyl)-piperidine
##STR00155##
[0603] To a pre-stirred solution of
4-bromo-2-trifluoromethoxybenzaldehyde (1.82 g, 9.0 mmol) and
piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0.degree. C. was
added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions.
The reaction mixture was then allowed to warm to ambient
temperature and stirred for an additional 14 h. The reaction was
quenched by the addition of water (30 mL) and extracted into ethyl
acetate (75 mL). The organic phase was sparated, dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford the title compound as a colourless oil (2.6 g, 84%) that was
used in the next step without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.47 (d, J=8.2 Hz, 1H), 7.41 (d, J=1.9 Hz,
1H), 7.39-7.35 (m, 1H), 3.46 (s, 2H), 2.42-2.32 (m, 4H), 1.64-1.51
(m, 4H), 1.48-1.37 (m, 2H).
Preparation of 1-(3-Bromo-5-methoxybenzyl)-piperidine
##STR00156##
[0605] To a pre-stirred solution of 3-bromo-5-methoxybenzaldehyde
(0.56 g, 2.61 mmol) and piperidine (0.29 mL, 3.93 mmol) in DCM (10
mL) at 0.degree. C. was added sodium borohydride (197 mg, 5.22
mmol) in portions. The reaction mixture was allowed to warm to
ambient temperature and stirred for an additional 2 h. The reaction
was quenched by the addition of water (30 mL) and extracted into
ethyl acetate (75 mL) then washed with water (50 mL) then the
organic phase was dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo to afford the title compound as a colourless
oil (510 mg, 69%) that was used in the next step without further
purification. .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.08-7.06 (m, 1H),
6.94-6.91 (m, 1H), 6.83-6.80 (s, 1H), 3.79 (s, 3H), 3.39 (s, 2H),
2.40-2.30 (s, 4H), 1.61-1.51 (m, 4H), 1.47-1.38 (m, 2H).
Preparation of 4-[1-(4-Bromobenzyl)-piperidin-4-yl]-morpholine
##STR00157##
[0607] 4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with
4-piperidin-4-yl-morpholine (0.67 g, 4.0 mmol) and triethylamine
(0.42 mL, 3.0 mmol) in THF (20 mL) at ambient temperature for 28 h
then a further 1.5 eq of triethylamine was added and stirring
continued for 16 h. The mixture was diluted with water (50 mL) and
extracted with ethyl acetate (50 mL). The organic phase was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The resultant residue was purified by flash
chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in
cyclohexane then 0-10% (2N ammonia in methanol) in DCM) to afford
the title compound as an off-white solid (0.62 g, 92%). .sup.1H NMR
(CDCl.sub.3, 400 MHz): 7.44-7.40 (m, 2H), 7.21-7.15 (m, 2H),
3.74-3.69 (m, 4H), 3.42 (s, 2H), 2.93-2.85 (m, 2H), 2.56-2.50 (m,
4H), 2.22-2.13 (m, 1H), 2.00-1.91 (m, 2H), 1.82-1.74 (m, 2H),
1.59-1.47 (m, 2H).
Preparation of [1-(4-Bromobenzyl)-piperidin-4-yl]-dimethylamine
##STR00158##
[0609] 4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with
4-dimethylaminopiperidine (0.51 g, 4.0 mmol) and triethylamine
(0.42 mL, 3.0 mmol) in THF (20 mL) at ambient temperature for 96 h.
The mixture was diluted with water (50 mL) and extracted with ethyl
acetate (50 mL). The organic phase was separated, dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford the title compound (0.51 g, 86%). .sup.1H NMR (CDCl.sub.3,
400 MHz): 7.44-7.40 (m, 2H), 7.21-7.16 (m, 2H), 3.43 (s, 2H),
2.91-2.85 (m, 2H), 2.27 (s, 6H), 2.17-2.07 (m, 1H), 2.00-1.91 (m,
2H), 1.80-1.72 (m, 2H), 1.58-1.45 (m, 2H).
Preparation of 4-(4-Bromobenzyl)-2,2-dimethylmorpholine
##STR00159##
[0611] A mixture of 4-bromobenzyl bromide (1.5 g, 6.0 mmol),
2,2-dimethylmorpholine (0.69 g, 6.0 mmol) and potassium carbonate
(0.99 g, 7.2 mmol) in acetonitrile (60 mL) was heated at 85.degree.
C. for 20 h. The mixture was allowed to cool to ambient temperature
and the solid was removed by filtration and the filtrate
evaporated. The resultant residue was dissolved in DCM/methanol and
loaded onto a 20 g SCX-2 cartridge which was washed with methanol
then 2N ammonia in methanol. Concentration of the combined basic
fractions afforded the title compound (1.65 g, 97%) as an orange
oil. .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.44 (d, J=8.0 Hz, 2H),
7.22 (d, J=8.0 Hz, 2H), 3.75 (t, J=4.8 Hz, 2H), 3.39 (s, 2H), 2.37
(t, J=4.6 Hz, 2H), 2.16 (s, 2H), 1.23 (s, 6H).
Preparation of
cis-4-(4-Bromo-2-ethoxybenzyl)-2,6-dimethylmorpholine
##STR00160##
[0612] Step 1:
cis-4-(4-Bromo-2-fluorobenzyl)-2,6-dimethylmorpholine
##STR00161##
[0614] To a suspension of 4-bromo-2-fluorobenzyl bromide (1.0 g,
3.7 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in THF (37 mL)
was added cis-2,6-dimethylmorpholine (0.43 g, 3.7 mmol). The
reaction mixture was heated under reflux for 6 h and then cooled,
the solid removed by filtration and the filtrate was evaporated.
The resultant residue was loaded onto a 10 g SCX-2 cartridge which
was washed with methanol then 2N ammonia in methanol. Concentration
of the combined basic fractions in vacuo afforded the title
compound (76 mg, 7%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.28-7.19
(m, 3H), 3.73-3.59 (m, 2H), 3.49 (d, J=1.5 Hz, 2H), 2.71-2.64 (m,
2H), 1.86-1.73 (m, 2H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G):
R.sub.T=2.84 min, M+H.sup.+=302.
Step 2: cis-4-(4-Bromo-2-ethoxybenzyl)-2,6-dimethylmorpholine
##STR00162##
[0616] To a solution of cis
4-(4-bromo-2-fluorobenzyl)-2,6-dimethylmorpholine (0.76 g, 2.5
mmol) in 1,4-dioxane (7.5 mL) under nitrogen was added ethyl
urethane (1.2 mL, 10.0 mmol) followed by portionwise addition of
sodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol).
The reaction mixture was heated at 100.degree. C. for 24 h then
partitioned between DCM and water and the phases were separated.
The aqueous phase was further extracted with DCM and the combined
organic layers were dried over sodium sulfate, filtered and
evaporated. The residue was purified by flash chromatography
(silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane) to
afford the title compound (0.114 g, 14%). .sup.1H NMR (CD.sub.3OD
and CDCl.sub.3, 300 MHz): 7.22 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1,
1.9 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H),
3.75-3.62 (m, 2H), 3.47 (s, 2H), 2.75-2.66 (m, 2H), 1.86-1.76 (m,
2H), 1.41 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method
G): R.sub.T=3.24 min, M+H.sup.+=328.
Preparation of 2-Bromo-4,5,6,7-tetrahydrobenzo[b]thiophene
##STR00163##
[0617] Step 1: 4,5,6,7-Tetrahydrobenzo[b]thiophene
##STR00164##
[0619] Aluminium trichloride (0.61 g, 4.60 mmol) in anhydrous
diethyl ether (5 mL) was placed under an atmosphere of argon and
lithium aluminium hydride (1M in diethyl ether, 4.6 mL, 4.60 mmol)
was added dropwise. The resultant solution was stirred for 2
minutes and then a solution of 6,7-dihydro-4-benzo[b]thiophen-4-one
(0.59 g, 3.83 mmol) in diethyl ether (10 mL) was added dropwise.
The reaction mixture was stirred at ambient temperature for 4.5 h
then was quenched with water (5 mL) followed by 6M sulfuric acid
(10 mL) before being extracted into diethyl ether (4.times.15 mL).
The combined organic phase was washed with water (20 mL) and brine,
dried over sodium sulfate, filtered and evaporated to afford the
title compound (0.49 g, 91%). .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.04 (d, J=5.2 Hz, 1H), 6.75 (d, J=5.1 Hz, 1H), 2.83-2.72 (m, 2H),
2.67-2.59 (m, 2H), 1.89-1.74 (m, 4H).
Step 2: 2-Bromo-4,5,6,7-tetrahydrobenzo[b]thiophene
##STR00165##
[0621] 4,5,6,7-Tetrahydrobenzo[b]thiophene (0.252 g, 1.79 mmol) was
dissolved in chloroform (10 mL), cooled to 0.degree. C. and
N-bromosuccinimide (0.334 g, 1.88 mmol) was added. The reaction
mixture was stirred at 0.degree. C. for 1 h then at ambient
temperature for 1.75 h and then heated at 40.degree. C. for a
further 4 h. The reaction mixture was cooled to room temperature,
concentrated in vacuo and the residue diluted with water and
extracted with diethyl ether (4.times.10 mL). The combined organic
phase was washed with water and brine, dried over sodium sulfate,
filtered and evaporated to afford the title compound (0.35 g, 88%)
as a brown oil. .sup.1H NMR (CDCl.sub.3, 300 MHz): 6.69 (s, 1H),
2.73-2.59 (m, 2H), 2.58-2.49 (m, 2H), 1.88-1.70 (m, 4H).
Preparation of 6-(4-Bromobenzyl)-2-oxa-6-aza-spiro[3.3]heptane
##STR00166##
[0623] A mixture of 2-oxa-6-aza-spiro[3.3]heptane (-3.72 mmol),
4-bromobenzyl bromide (0.39 g, 1.54 mmol), potassium carbonate
(0.64, 4.63 mmol) and sodium iodide (11 mg, 0.08 mmol) in THF (10
mL) was stirred at ambient temperature for 16 h. The solid was
removed by filtration, washed with THF and the combined filtrate
was evaporated. The resultant residue was purified by flash
chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in
pentane then 10% methanol in DCM) to afford the title compound
(0.28 g, 68%) as a viscous oil which crystallised on standing to a
pale yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.46-7.40 (m,
2H), 7.15-7.09 (m, 2H), 4.73 (s, 4H), 3.48 (s, 2H), 3.35 (s,
4H).
Preparation of 1-[2-(4-Bromophenyl)-ethyl]-piperidine
##STR00167##
[0625] Methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added to a
solution of 2-(4-bromophenyl)-ethanol (1.0 g, 4.97 mmol) and
triethylamine (0.84 mL, 5.96 mmol) in DCM (20 mL) at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 15 minutes
then at ambient temperature for 2 h. The reaction mixture was
partitioned between water and DCM and the organic phase was dried
over sodium sulfate, filtered and evaporated to give a colourless
oil. The resultant residue was dissolved in acetonitrile (10 mL),
piperidine (0.491 mL, 4.97 mmol) and potassium carbonate (0.823 g,
5.96 mmol) were added and the reaction mixture was heated at
70.degree. C. for 2.5 h. The reaction mixture was allowed to cool
to ambient temperature then partitioned between ethyl acetate and
water. The organic phase was dried over sodium sulfate, filtered
and evaporated and the resultant residue dissolved in methanol and
loaded onto a 10 g SCX-2 cartridge. The column was washed with
methanol then eluted with 2N ammonia in methanol and the basic
fractions were evaporated to afford the title compound (1.27 g,
95%) as a colourless oil. .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.41-7.36 (m, 2H), 7.10-7.04 (m, 2H), 2.79-2.71 (m, 2H), 2.54-2.40
(m, 6H), 1.66-1.56 (m, 4H), 1.50-1.40 (m, 2H).
Preparation of 1-(4-Bromobenzyl)-3-methyl-piperidin-3-ol
##STR00168##
[0627] A mixture of 4-bromobenzyl bromide (0.50 g, 2.0 mmol),
triethylamine (0.42 mL, 3.0 mmol) and 3-methyl-piperidin-3-ol (0.46
g, 4.0 mmol) in THF (20 mL) was stirred at ambient temperature for
16 h. The reaction mixture was evaporated and the resultant residue
diluted with saturated aqueous sodium bicarbonate solution and
extracted with ethyl acetate (2.times.50 mL). The combined organic
layer was dried over sodium sulfate, filtered and evaporated to
afford the title compound (0.50 g, 88%). .sup.1H NMR (CDCl.sub.3,
300 MHz): 7.49-7.43 (m, 2H), 7.23-7.15 (m, 2H), 3.78 (s, 2H),
3.69-3.59 (m, 2H), 2.63-2.51 (m, 2H), 2.14 (br s, 1H), 1.77-1.49
(m, 4H), 1.15 (s, 3H).
Preparation of 1-(4-Bromobenzyl)-4-methoxy-4-methylpiperidine
##STR00169##
[0628] Step 1: 4-Hydroxy-4-methylpiperidine-1-carboxylic acid
tert-butyl ester
##STR00170##
[0630] To a solution of 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at
-25 to -30.degree. C. was added methyl magnesium bromide (3M in
diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The
reaction mixture was allowed to warm to room temperature and
stirred for 2 h. Water (20 mL) was then added dropwise, followed by
saturated ammonium chloride (20 mL) and the ether layer was
separated. The aqueous phase was further extracted with ether (50
mL) and the combined organic layer was dried over sodium sulfate,
filtered and evaporated to afford the title compound (2.09 g, 97%).
.sup.1H NMR (CDCl.sub.3, 300 MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m,
2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s,
3H).
Step 2: 4-Methoxy-4-methylpiperidine
##STR00171##
[0632] A suspension of sodium hydride (60% dispersion in mineral
oil, 0.44 g, 11.66 mmol) in DMF (20 mL) was cooled to 0.degree. C.
then 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl
ester (2.09 g, 9.72 mmol) in DMF (5 mL) was added. The reaction
mixture was stirred at room temperature for 1 h then sodium iodide
(3.03 mL, 48.6 mmol) was added and stirring continued at room
temperature for 16 h then heated at 70.degree. C. for 16 h. The
reaction mixture was allowed to cool to room temperature and
ice-cold brine was added before the mixture was extracted with
ethyl acetate (2.times.100 mL). The combined organic phase was
dried over sodium sulfate, filtered and evaporated and the
resultant residue was purified by flash chromatography (silica,
Biotage 50 g column, 0-20% ethyl acetate in cyclohexane) to afford
a colourless oil (0.94 g). The resultant oil was dissolved in DCM
(5 mL) and TFA (5 mL) and stirred at ambient temperature for 2 h.
The reaction mixture was loaded onto an SCX-2 cartridge which was
washed with acetonitrile and methanol then eluted with 2N ammonia
in methanol. The basic methanol fractions were evaporated to afford
the title compound (0.50 g, 40%) .sup.1H NMR (CDCl.sub.3, 300 MHz):
3.19 (s, 3H), 2.96-2.85 (m, 2H), 2.81-2.70 (m, 2H), 1.79-1.66 (m,
2H), 1.51-1.38 (m, 2H), 1.15 (s, 3H) plus 1 exchangeable not
observed.
Step 3: 1-(4-Bromobenzyl)-4-methoxy-4-methylpiperidine
##STR00172##
[0634] A mixture of 4-bromobenzyl bromide (0.44 g, 1.74 mmol),
triethylamine (0.37 mL, 2.61 mmol) and 4-methoxy-4-methylpiperidine
(0.45 g, 3.49 mmol) in THF (10 mL) was stirred at ambient
temperature for 16 h. The solvent was evaporated and the resultant
residue was diluted with saturated aqueous sodium bicarbonate
solution and extracted with ethyl acetate (2.times.50 mL). The
combined organic layer was dried over sodium sulfate, filtered and
evaporated to afford the title compound as a yellow oil (0.50 g,
96%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.45-7.39 (m, 2H),
7.22-7.17 (m, 2H), 3.44 (s, 2H), 3.17 (s, 3H), 2.52-2.42 (m, 2H),
2.36-2.25 (m, 2H), 1.79-1.70 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (s,
3H).
Preparation of 4-(4-Bromobenzyl)-thiomorpholine
##STR00173##
[0636] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.82 mL, 8.0
mmol) in THF (10 mL) was stirred at ambient temperature for 16 h.
The solvent was evaporated and the resultant residue diluted with
saturated aqueous sodium bicarbonate solution and extracted with
ethyl acetate (2.times.50 mL). The combined organic layer was dried
over sodium sulfate, filtered and evaporated to afford the title
compound as an off-white solid (1.13 g, quantitative yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.16 (m,
2H), 3.45 (s, 2H), 3.15-3.09 (m, 1H), 2.76-2.60 (m, 6H), 2.62-2.57
(m, 1H).
Preparation of 4-(4-Bromobenzyl)-thiomorpholine 1,1-dioxide
##STR00174##
[0638] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine 1,1-dioxide
(1.09 g, 8.0 mmol) in THF (10 mL) was stirred at ambient
temperature for 16 h. The solvent was evaporated and the resultant
residue diluted with saturated aqueous sodium bicarbonate solution
and extracted with ethyl acetate (2.times.50 mL). The combined
organic layer was dried over sodium sulfate, filtered and
evaporated to afford the title compound (0.90 g, 74%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.50-7.44 (m, 2H), 7.22-7.16 (m, 2H), 3.60
(s, 2H), 3.09-3.02 (m, 4H), 3.00-2.94 (m, 4H).
Preparation of 4-(4-Bromobenzyl)-thiomorpholine 1-oxide
##STR00175##
[0640] A mixture of 4-(4-bromobenzyl)-thiomorpholine (0.20 g, 0.735
mmol) was dissolved in DCM (10 mL) under a nitrogen atmosphere and
m-chloroperbenzoic acid (0.13 g, 0.74 mmol) was added portionwise.
The reaction mixture was stirred at room temperature for 1 h then
purified by flash chromatography (silica, Biotage 50 g column,
0-75% (10% methanol in DCM)) to afford the title compound (0.125 g,
59%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 7.55-7.49 (m, 2H),
7.31-7.25 (m, 2H), 3.53 (s, 2H), 2.92-2.80 (m, 4H), 2.78-2.65 (m,
2H), 2.64-2.54 (m, 2H). LCMS (Method G): R.sub.T=2.66 min,
M+H.sup.+=289.
Preparation of 4-(4-Bromobenzyl)-piperazin-2-one
##STR00176##
[0642] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and piperazin-2-one (0.81 g, 8.0
mmol) in THF (20 mL) was stirred at ambient temperature for 16 h.
The solvent was evaporated and the resultant residue diluted with
saturated aqueous sodium bicarbonate solution and extracted with
ethyl acetate (2.times.50 mL). The combined organic layer was dried
over sodium sulfate, filtered and evaporated to afford the title
compound (1.0 g, 93%). .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
7.49-7.43 (m, 2H); 7.24-7.16 (m, 2H); 6.20 (s, 1H); 3.53 (s, 2H);
3.38-3.32 (m, 2H); 3.15 (s, 2H); 2.66-2.59 (m, 2H).). LCMS (Method
G): R.sub.T=2.54 min, M-H.sup.+=268.
Preparation of (4-Bromobenzyl)-diethylamine
##STR00177##
[0644] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and diethylamine (0.84 mL, 8.0
mmol) in THF (20 mL) was stirred at ambient temperature for 16 h.
The solvent was evaporated and the resultant residue diluted with
saturated aqueous sodium bicarbonate solution and extracted with
ethyl acetate (2.times.50 mL). The combined organic layer was dried
over sodium sulfate, filtered and evaporated to afford the title
compound (0.85 g, 88%). .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.45-7.38 (m, 2H), 7.27-7.18 (m, 2H), 3.50 (s, 2H), 2.50 (q, J=7.1
Hz, 4H), 1.03 (t, J=7.1 Hz, 6H). LCMS (Method G): R.sub.T=1.98 min,
M-H.sup.+=242.
Preparation of (S)-1-(4-Bromobenzyl)-piperidin-3-ol
##STR00178##
[0646] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and (S)-3-methyl-piperidin-3-ol
(1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient
temperature for 16 h. The solvent was evaporated and the resultant
residue diluted with saturated aqueous sodium bicarbonate solution
and extracted with ethyl acetate (2.times.50 mL). The combined
organic layer was dried over sodium sulfate, filtered and
evaporated. The resultant residue was purified by flash
chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate
in cyclohexane) to afford the title compound (0.8 g, 74%). .sup.1H
NMR (CDCl.sub.3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2H),
3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H),
1.86-1.70 (m, 1H), 1.67-1.45 (m, 3H) plus 1 exchangeable not
observed. LCMS (Method G): R.sub.T=1.42 min, M+H.sup.+=270.
Preparation of (R)-1-(4-Bromobenzyl)-piperidin-3-ol
##STR00179##
[0648] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and (R)-3-methyl-piperidin-3-ol
(1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient
temperature for 16 h. The solvent was evaporated and the resultant
residue diluted with saturated aqueous sodium bicarbonate solution
and extracted with ethyl acetate (2.times.50 mL). The combined
organic layer was dried over sodium sulfate, filtered and
evaporated. The material was purified by flash chromatography
(silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane)
to afford the title compound (0.75 g, 69%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2H),
3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H),
1.86-1.70 (m, 1H) 1.67-1.45 (m, 3H) plus 1 exchangeable not
observed. LCMS (Method G): R.sub.T=2.00 min, M+H.sup.+=270.
Preparation of 4-(3-Bromophenyl)-1-methyl-piperidine
##STR00180##
[0650] A mixture of 4-(3-bromophenyl)-1-N-Boc piperidine (430 mg,
1.26 mmol), formic acid (5 mL) and formaldehyde (0.5 mL) was heated
under microwave irradiation at 150.degree. C. for 10 minutes. The
cooled reaction mixture was loaded onto a 70 g SCX-2 cartridge
which was washed with methanol (200 mL) and then eluted with 2N
ammonia in methanol (200 mL). Concentration of the combined basic
fractions in vacuo afforded the title compound (318 mg, 99%) as a
brown oil. .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.38-7.36 (m, 1H);
7.35-7.29 (m, 1H); 7.17-7.14 (m, 2H); 3.03-2.92 (m, 2H); 2.52-2.37
(m, 1H); 2.32 (s, 3H); 2.10-1.99 (m, 2H); 1.87-1.69 (m, 4H).
Preparation of 3-(4-Bromophenyl)-3-hydroxypiperidine-1-carboxylic
acid tert-butyl ester
##STR00181##
[0652] n-Butyllithium (2.5 M in hexanes, 8.2 mL, 20.5 mmol) was
added over 10 min to a solution of 1-bromo-4-iodobenzene (5.79 g,
20.5 mmol) in THF (100 mL) at -78.degree. C. After 15 min, a
solution of 1-boc-3-piperidone (3.71 g, 18.6 mmol) in THF (10 mL)
was added and the resultant reaction mixture was left to stir at
-78.degree. C. for 1 h, then warmed to 0.degree. C. and quenched by
the addition of saturated aqueous ammonium chloride (50 mL). The
mixture was allowed to warm to ambient temperature and partitioned
between ethyl acetate (400 mL) and water (150 mL). The organic
layer was separated, dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The resultant residue was
purified by flash chromatography (silica, 80 g column, ISCO, 0-100%
ethyl acetate in cyclohexane) to afford the title compound as a
colourless gum (3.69 g, 56%). .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.52-7.46 (m, 2H); 7.42-7.36 (m, 2H); 4.16-3.87 (m, 2H); 3.13 (d,
J=13.7 Hz, 1H); 2.92-2.77 (m, 1H); 2.03-1.53 (m, 4H); 1.47 (s,
9H).
Preparation of 3-(4-Bromo-phenyl)-1-methyl-piperidin-3-ol
##STR00182##
[0654] A mixture of
3-(4-bromo-phenyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl
ester (1.39 g, 3.9 mmol), formic acid (18.4 mL) and formaldehyde
(1.6 mL) was heated under microwave irradiation at 150.degree. C.
for 5 minutes. The cooled reaction mixture was loaded onto a 70 g
SCX-2 cartridge which was washed with methanol (200 mL) and then
eluted with 2N ammonia in methanol (200 mL). Concentration of the
combined basic fractions in vacuo afforded the title compound (978
mg, 93%) as a brown oil. LCMS (Method B): R.sub.T=1.84 min,
M+H.sup.+=270.
Preparation of 3-(3-Bromophenyl)-3-hydroxypiperidine-1-carboxylic
acid tert-butyl ester
##STR00183##
[0656] n-Butyllithium (2.5 M in hexanes, 7.6 mL, 19.0 mmol) was
added over 10 min to a solution of 1-bromo-3-iodobenzene (5.37 g,
19.0 mmol) in THF (100 mL) at -78.degree. C. After 15 min, a
solution of 1-boc-3-piperidone (3.44 g, 17.3 mmol) in THF (10 mL)
was added and the resultant reaction mixture was left to stir at
-78.degree. C. for 1 h, then warmed to 0.degree. C. and quenched by
the addition of saturated aqueous ammonium chloride (50 mL). The
mixture was allowed to warm to ambient temperature and partitioned
between ethyl acetate (400 mL) and water (150 mL). The organic
layer was separated, dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The resultant residue was
purified by flash chromatography (silica, 80 g column, ISCO, 0-100%
ethyl acetate in cyclohexane) to afford the title compound as a
colourless gum (1.99 g, 33%). NMR (CDCl.sub.3, 300 MHz): 7.70-7.67
(m, 1H); 7.46-7.40 (m, 2H); 7.24-7.20 (m, 1H); 4.15-3.88 (m, 2H);
3.21-3.08 (m, 1H); 2.93-2.79 (m, 1H); 2.03-1.82 (m, 2H); 1.75-1.51
(m, 2H); 1.48 (s, 9H). LCMS (Method B): R.sub.T=3.88 min,
M-[Boc-18].sup.+238.
Preparation of 4-[(3,3-Dimethylpyrrolidine)-methyl]phenyl boronic
acid
##STR00184##
[0658] A mixture of 4-(bromomethyl)benzene boronic acid (565 mg,
2.63 mmol), 3,3-dimethylpyrrolidine (390 mg, 3.94 mmol), potassium
carbonate (1.09 g, 7.88 mmol) and sodium iodide (20 mg, 0.13 mmol)
in acetonitrile (30 mL) were stirred at ambient temperature for 18
h. The resultant reaction mixture was evaporated in vacuo to afford
the crude title compound as a yellow solid (quantitative yield),
which was used without further purification. LCMS (Method B):
R.sub.T=1.69 min, M+H.sup.+=234
Preparation of 4-[(3,3-Difluoropyrrolidine)-methyl]phenyl boronic
acid
##STR00185##
[0660] A mixture of 4-(bromomethyl)benzene boronic acid (517 mg,
2.40 mmol), 3,3-difluoropyrrolidine hydrochloride (415 mg, 2.89
mmol), potassium carbonate (1.33 g, 9.62 mmol) and sodium iodide
(18 mg, 0.12 mmol) in acetonitrile (30 mL) were stirred at ambient
temperature for 18 h. The resultant reaction mixture was evaporated
in vacuo to afford the crude title compound as a white solid
(quantitative yield), which was used without further purification.
.sup.1H NMR (MeOD, 300 MHz): 7.48 (d, J=7.7 Hz, 2H); 7.11 (d, J=7.7
Hz, 2H); 3.58 (s, 2H); 2.89-2.70 (m, 4H); 2.32-2.14 (m, 2H). LCMS
(Method B): R.sub.T=1.46 min, M+H.sup.+=242.
Preparation of 4-[(3-Trifluoromethylpiperidine)-methyl]phenyl
boronic acid
##STR00186##
[0662] A mixture of 4-(bromomethyl)benzene boronic acid (473 mg,
2.20 mmol), 3-trifluoromethylpiperidine (403 mg, 2.63 mmol) and
potassium carbonate (910 mg, 6.60 mmol) in acetonitrile (30 mL)
were stirred at ambient temperature for 18 h. The reaction mixture
was evaporated in vacuo and the resultant residue suspended in MeOH
and the solid removed by filtration. The filtrate was evaporated to
afford the title compound as a yellow solid (quantitative yield),
which was used without further purification. .sup.1H NMR (MeOD, 300
MHz): 7.49 (d, J=7.6 Hz, 2H); 7.11 (d, J=7.7 Hz, 2H); 3.56-3.43 (m,
2H); 3.10-3.01 (m, 1H); 2.98-2.88 (m, 1H); 2.46-2.24 (m, 1H);
2.00-1.85 (m, 3H); 1.81-1.70 (m, 1H); 1.67-1.43 (m, 1H); 1.34-1.14
(m, 1H). LCMS (Method G): R.sub.T=1.85 min, M+H.sup.+=288.
Preparation of 4-[(3-Fluoropiperidine)-methyl]phenyl boronic
acid
##STR00187##
[0664] A mixture of 4-(bromomethyl)benzene boronic acid (419 mg,
1.95 mmol), 3-fluoropiperidine (326 mg, 2.34 mmol) and potassium
carbonate (1.08 g, 7.71 mmol) in acetonitrile (30 mL) were stirred
at ambient temperature for 18 h. The reaction mixture was
evaporated in vacuo and the resultant residue suspended in MeOH and
the solid removed by filtration. The filtrate was evaporated to
afford the title compound as a yellow solid (quantitative yield),
which was used without further purification. .sup.1H NMR (MeOD, 300
MHz): 7.48 (d, J=7.6 Hz, 2H); 7.11 (d, J=7.7 Hz, 2H); 4.72-4.44 (m,
1H); 3.50 (s, 2H); 2.77-2.60 (m, 1H); 2.54-2.27 (m, 3H); 1.90-1.73
(m, 2H); 1.67-1.44 (m, 2H). LCMS (Method G): R.sub.T=1.35 min,
M+H.sup.+=238.
Preparation of 1-(4-Bromobenzyl)-piperidine-4-carbonitrile
##STR00188##
[0666] A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol),
triethylamine (0.84 mL, 6.0 mmol) and piperidine-4-carbonitrile
(880 mg, 8.0 mmol) in THF (20 mL) was stirred at ambient
temperature for 18 h. The reaction mixture was evaporated in vacuo
and the residue partitioned between saturated sodium bicarbonate
solution (100 mL) and dichloromethane (100 mL). The organic phase
was separated, dried over sodium sulfate, filtered and evaporated
in vacuo. The resultant residue was purified by flash
chromatography (silica, Biotage 50 g column, 0-100% ethyl acetate
in cyclohexane) to afford the title compound (1.10 g, 99%). .sup.1H
NMR (CDCl.sub.3, 300 MHz): 7.46-7.41 (m, 2H); 7.21-7.15 (m, 2H);
3.44 (s, 2H); 2.70-2.57 (m, 3H); 2.38-2.22 (m, 2H); 1.99-1.74 (m,
4H). LCMS (Method B): R.sub.T=1.82 min, M+H.sup.+=280.
Preparation of
(4-Bromo-2-methoxy-benzyloxy)-tert-butyldimethylsilane
##STR00189##
[0668] tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was
added to a mixture of (4-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6
mol) and imidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the
resultant mixture was stirred at ambient temperature for 66 h. The
mixture was concentrated to about a third of the original volume
then diluted with water and extracted with diethyl ether
(.times.3). The combined organic layer was dried over magnesium
sulfate, filtered and evaporated. The resultant residue was
purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl
ether in pentane) to afford the title compound as a colourless oil
(1.51 g, 98%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.34 (dt, J=8.1,
1.05 Hz, 1H); 7.11 (dd, J=8.1, 1.8 Hz, 1H); 6.95 (d, J=1.8 Hz, 1H);
4.69 (d, J=1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08
(m, 6H).
Preparation of cis-1-(4-Bromobenzyl)-3,5-dimethylpiperidine and
trans-1-(4-Bromobenzyl)-3,5-dimethylpiperidine
##STR00190##
[0670] A suspension of 4-bromobenzyl bromide (4.0 g, 16.0 mmol),
cis, trans-(3,5-dimethylpiperidine) (1.81 g, 16.0 mmol) and
potassium carbonate (2.65 g, 19.2 mmol) in THF (160 mL) was heated
under reflux for 24 h. The reaction mixture was allowed to cool to
ambient temperature, the solid removed by filtration and the
filtrate evaporated in vacuo. The resultant residue was loaded onto
a 50 g SCX-2 cartridge which was washed with methanol then eluted
with 2N ammonia in methanol. Concentration of the combined basic
fractions in vacuo followed by flash chromatography of the
resultant residue (silica, 330 g column, ISCO, 0-25% ethyl acetate
in pentane) afforded cis-1-(4-bromobenzyl)-3,5-dimethylpiperidine
(1.60 g, 35%) as a colourless oil. .sup.1H NMR (CDCl.sub.3, 300
MHz): 7.47-7.39 (m, 2H); 7.20 (d, J=8.0 Hz, 2H); 3.42 (s, 2H);
2.82-2.71 (m, 2H); 1.76-1.61 (m, 4H); 1.51-1.37 (m, 2H); 0.82 (d,
J=6.4 Hz, 6H).
[0671] Further elution furnished
trans-1-(4-bromobenzyl)-3,5-dimethylpiperidine (956 mg, 21%) as a
colourless oil. .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.42 (d, J=8.2
Hz, 2H); 7.21 (d, J=8.1 Hz, 2H); 3.46-3.26 (m, 2H); 2.40-2.28 (m,
2H); 2.08-1.96 (m, 2H); 1.95-1.80 (m, 2H); 1.32-1.23 (m, 2H); 0.94
(d, J=6.7 Hz, 6H).
Preparation of 1-(4-Bromo-2-chloro-benzyl)-piperidine
##STR00191##
[0673] To a pre-stirred solution of 4-bromo-2-chlorobenzaldehyde
(1.01 g, 4.6 mmol) and piperidine (500 .mu.L, 5.0 mmol) in DCM (20
mL) at 0.degree. C. was added sodium triacetoxyborohydride (1.46 g,
6.9 mmol) in portions. The reaction mixture was allowed to warm to
ambient temperature and then partitioned between water (50 mL) and
dichloromethane (50 mL). The organic phase was separated, washed
with saturated aqueous sodium carbonate (50 mL), dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo. The
resultant residue was loaded onto a 20 g SCX-2 cartridge which was
washed with methanol then 2N ammonia in methanol. Concentration of
the combined basic fractions in vacuo afforded the title compound
as a colourless oil (1.15 g, 87%). .sup.1H NMR (CDCl.sub.3, 400
MHz): 7.50-7.48 (m, 1H); 7.40-7.33 (m, 2H); 3.50 (s, 2H); 2.46-2.38
(m, 4H); 1.62-1.53 (m, 4H); 1.49-1.40 (m, 2H). LCMS (Method B):
R.sub.T=2.03 min, M+H.sup.+=288.
Preparation of (4-Bromobenzyloxy)-tert-butyldimethylsilane
##STR00192##
[0675] tert-Butyldimethylsilyl chloride (2.42 g, 16 mmol) was added
to a mixture of (4-bromophenyl)methanol (2.0 g, 107 mmol) and
imidazole (1.09 g, 16 mmol) in DMF (30 mL) and the resultant
mixture was stirred at ambient temperature for 72 h. The mixture
was concentrated to one third of the original volume then diluted
with water (50 mL) and extracted with diethyl ether (3.times.50
mL). The combined organic layer was dried over anhydrous sodium
sulfate, filtered and evaporated in vacuo. The resultant residue
was purified by chromatography (silica, 50 g column, Si-SPE, 0-5%
diethyl ether in pentane) to afford the title compound as a
colourless oil (3.21 g, 100%). .sup.1H NMR (CDCl.sub.3, 400 MHz):
7.45-7.42 (m, 2H); 7.21-7.17 (m, 2H); 4.68 (s, 2H); 0.93 (s, 9H);
0.09 (s, 6H).
Preparation of
[1-(4-Bromophenyl)-1-methylethoxy]-tert-butyldimethylsilane
##STR00193##
[0677] tert-Butyldimethylsilyl chloride (2.10 g, 14 mmol) was added
to a mixture of 2-(4-bromophenyl)-propan-2-ol (2.0 g, 9.3 mmol) and
imidazole (0.95 g 14 mmol) in DMF (30 mL) and the resultant mixture
was stirred at 80.degree. C. for 24 h. The mixture was concentrated
to one third of the original volume then diluted with water (50 mL)
and extracted with diethyl ether (3.times.50 mL). The combined
organic layer was dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The resultant residue was purified by
chromatography (silica, 50 g column, Si-SPE, 0-5% diethyl ether in
pentane) to afford the title compound as a colourless oil (1.39 g,
46%). .sup.1H NMR (MeOD, 400 MHz): 7.46-7.37 (m, 4H); 1.56 (s, 6H);
0.95-0.91 (m, 9H); 0.06 (s, 6H).
Preparation of
1-(5-Tributylstannanylisothiazol-3-ylmethyl)-piperidine
##STR00194##
[0678] Step 1: 1-(5-Bromoisothiazol-3-ylmethyl)-piperidine
##STR00195##
[0680] 5-Bromo-3-bromomethylisothiazole (1.92 g, 7.5 mmol),
triethylamine (1.57 mL, 11.2 mmol) and piperidine (1.5 mL, 15.0
mmol) in DCM (10 mL) were stirred for 16 h at ambient temperature.
The reaction mixture was partitioned between water (50 mL) and
ethyl acetate (75 mL). The organic phase was separated, dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford the title compound as a colourless oil (1.49 g, 97%) that
was used in the next step without further purification. .sup.1H NMR
(CDCl.sub.3, 400 MHz): 7.25 (s, 1H), 3.59 (s, 2H), 2.46-2.33 (m,
4H), 1.62-1.53 (m, 4H), 1.48-1.38 (m, 2H).
Step 2: 1-(5-Tributylstannanylisothiazol-3-ylmethyl)-piperidine
##STR00196##
[0682] To a cold (-78.degree. C.) solution of nBuLi (2.5M in
hexanes, 0.88 mL, 0.35 mmol) in anhydrous THF (20 mL) was added
diisopropylamine (0.32 mL, 2.2 mmol). The solution was allowed to
warm to -20.degree. C. for 30 minutes then cooled to -78.degree. C.
before addition of a solution of
(1-(5-bromoisothiazol-3-ylmethyl)-piperidine (600 mg, 1.2 mmol) in
anhydrous THF (5 mL). After 30 minutes, the reaction mixture was
allowed to warm to ambient tempertaure and saturated aqueous sodium
hydrogen carbonate was added. The aqueous phase was extracted with
DCM (3.times.50 mL), the combined organic phase was dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo to
afford a colourless oil that was purified by flash chromatography
(silica, 12 g column, ISCO, 0-40% acetone in DCM) to afford the
title compound as a colourless oil (110 mg, 73%). .sup.1H NMR
(CDCl.sub.3, 400 MHz): 7.23 (s, 1H), 3.74 (s, 2H), 2.49-2.36 (m,
4H), 1.69-1.50 (m, 10H), 1.48-1.40 (m, 2H), 1.39-1.19 (m, 6H),
1.18-1.12 (m, 6H), 0.95-0.86 (m, 9H).
Preparation of
1-(5-Tributylstannanylthiazol-2-ylmethyl)-piperidine
##STR00197##
[0684] To a cold (-78.degree. C.) solution of
1-thiazol-2-ylmethylpiperidine (2.73 g, 15.0 mmol) anhydrous THF
(100 mL) was added n-butyllithium (8.95 mL, 16.5 mmol). After 30
minutes, a solution of tributyltin chloride (4.93 mL, 18.2 mmol) in
anhydrous THF (40 mL) was to the reaction mixture. After 10
minutes, the solution was allowed to warm to ambient tempertaure
and saturated aqueous sodium hydrogen carbonate was added. The
aqueous phase was extracted with tert-butylmethyl ether (3.times.50
mL). The combined organic phase was dried over anhydrous sodium
sulfate, filtered and evaporated in vacuo to afford a colourless
oil that was then purified by flash chromatography (silica, 12 g
column, ISCO, 0-40% ethyl acetate in cyclohexane) to afford the
title compound as a colourless oil (5.1 g, 72%). .sup.1H NMR
(CDCl.sub.3, 400 MHz): 7.62 (t, J=6.4 Hz, 1H), 3.88 (s, 2H),
2.54-2.47 (m, 4H), 1.69-1.49 (m, 10H), 1.50-1.40 (m, 2H), 1.40-1.26
(m, 6H), 1.15-1.08 (m, 6H), 0.95-0.85 (m, 9H).
Preparation of
5-Ethyl-2-tributylstannanyl-4,5,6,7-tetrahydro-thiazolo[4,5c]pyridine
##STR00198##
[0686] To a cold (-78.degree. C.) solution of
5-ethyl-4,5,6,7-tetrahydrothiazolo-[4,5-c]pyridine (262 g, 1.56
mmol) anhydrous THF (10 mL) was added n-butyllithium (2.5M in
hexanes, 0.68 mL, 1.72 mmol). After 30 minutes, a solution of
tributyltin chloride (0.51 mL, 1.87 mmol) in anhydrous THF (5 mL)
was to the reaction mixture. After 10 minutes, the solution was
allowed to warm to ambient temperature and saturated aqueous sodium
hydrogen carbonate was added. The aqueous phase was extracted with
ethyl acetate (50 mL), dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo to afford a colourless oil (450
mg, quantitative yield) that was used in the next step without
purification. .sup.1H NMR (CDCl.sub.3, 300 MHz): 3.78 (m, 1H),
2.96-2.88 (m, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.64 (q, J=7.2 Hz, 2H),
1.62-1.49 (m, 6H), 1.36-1.12 (m, 12H), 0.94-0.82 (m, 12H).
Preparation of 1-Methyl-5-(trimethylstannyl)-1H-1,2,3-triazole
##STR00199##
[0688] To a stirred solution of 1-methyl-1H-1,2,3-triazole (0.5 g,
6.0 mmol) in anhydrous tetrahydrofuran (50 mL) at -78.degree. C.
under an atmosphere of nitrogen was added n-butyllithium (2.5M
solution in hexanes, 2.6 mL, 6.6 mmol) dropwise over ten minutes.
On complete addition the reaction was allowed to warm to
-30.degree. C. and stirred for 2 h. A solution of
chlorotrimethylstannane (1.3 g, 6.6 mmol) in tetrahydrofuran (2 mL)
was added dropwise over 10 minutes then the reaction mixture was
allowed to warm to room temperature over 2 h. The reaction was
quenched by the addition of saturated ammonium chloride solution (5
mL) then diluted with water (20 mL). The solvent was evaporated in
vacuo and the aqueous phase extracted with ethyl acetate
(2.times.30 mL). The combined organic layer was dried over sodium
sulfate, filtered and concentrated to afford a pale yellow oil (1.4
g, 90%). .sup.1H NMR (DMSO-D.sub.6,400 MHz): 7.61 (s, 1H), 4.04 (s,
3H), 0.40 (s, 9H).
Preparation of
1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)-1H-1-
,2,3-triazole
##STR00200##
[0689] Step 1:
1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-iodo-1H-1,2,3-triazole
##STR00201##
[0691] A mixture of tert-butyldimethyl(prop-2-ynyloxy)silane (1.2
mL, 5.9 mmol), (azidomethyl)benzene (0.81 mL, 6.5 mmol),
N-bromosuccinimide (1.25 g, 7.0 mmol), copper (I) iodide (1.23 g,
6.5 mmol) and N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) in
tetrahydrofuran (48 mL) was stirred at room temperature for 3 h.
The mixture was concentrated in vacuo and the resultant residue was
dissolved in ethyl acetate (75 mL) and washed with water (50 mL).
The layers were separated, the organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated to afford a
residue that was purified by flash chromotagraphy (silica, 40 g
column, ISCO, 0-25% ethyl acetate in heptane) to afford the title
compound as a white solid (970 mg, 40%). .sup.1H NMR (DMSO-D.sub.6,
400 MHz,) .delta. 7.34 (m, 3H), 7.18 (m, 2H), 5.63 (s, 2H), 4.65
(s, 2H), 0.85 (s, 9H), 0.07 (s, 6H).
Step 2:
1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstanny-
l)-1H-1,2,3-triazole
##STR00202##
[0693] A degassed mixture of
1-benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-iodo-1H-1,2,3-triazole
(450 mg, 1.0 mmol), bis(triphenylphosphine) palladium(II)
dichloride (37 mg, 0.05 mmol), hexamethylditin (0.65 mL, 3.1 mmol)
and N,N-diisopropylethylamine (0.36 mL, 2.1 mmol) in 1,4-dioxane (8
mL) was heated at 105.degree. C. for 2 h. The reaction mixture was
quenched with water (1 mL) and concentrated to afford a residue
that was purified by flash chromotagraphy (silica, 40 g column,
ISCO, 0-25% ethyl acetate in heptane) to afford the title compound
as a yellow oil (270 mg, 55%). .sup.1H NMR (DMSO-D.sub.6, 400
MHz,): 7.31 (m, 3H), 6.94 (m, 2H), 5.62 (s, 2H), 4.72 (s, 2H), 0.83
(s, 9H), 0.20 (s, 9H), 0.03 (s, 6H).
Preparation of 1-Isopropyl-4-tributylstannanyl-1H-pyrazole
##STR00203##
[0695] n-Butyllithium (2.5M in hexanes, 1.38 mL, 3.45 mmol) was
added over 15 min to a solution of 4-bromo-1-isopropyl-1H-pyrazole
(500 mg, 2.65 mmol) in diethyl ether (10 mL) at -78.degree. C.
After 30 min, a solution of tri-n-butylstannane chloride (920
.mu.L, 3.45 mmol) in diethyl ether (1 mL) was added and the
resultant reaction mixture was left to stir at -78.degree. C. for 1
h, then allowed to warm to ambient temperature. The reaction
mixture was diluted with diethyl ether (40 mL) and washed with
water (20 mL), then brine (20 mL). The organic layer was separated,
dried over sodium sulfate, filtered and evaporated in vacuo to
afford the title product as a colourless oil (98 mg, 94%) which was
used without further purification. .sup.1H NMR (CDCl.sub.3, 400
MHz): 7.46-7.42 (m, 1H); 7.28 (t, J=4.2 Hz, 1H); 4.59-4.43 (m, 1H);
1.58-1.42 (m, 12H); 1.39-1.24 (m, 6H); 1.02-0.77 (m, 15H).
Preparation of 7-(4-Bromobenzyl)-2-oxa-7-aza-spiro[3.5]nonane
##STR00204##
[0697] A mixture of 4-bromobenzyl bromide (0.26 g, 1.04 mmol),
triethylamine (0.21 mL, 2.07 mmol) and 2-oxa-7-azaspiro[3.5]nonane
(0.50 g, 2.07 mmol) in THF (20 mL) was heated under reflux for 5 h.
The reaction mixture was cooled to ambient temperature, the solid
removed by filtration and the filtrate was concentrated under
reduced pressure. The resultant residue was loaded onto an SCX-2
cartridge (10 g) and eluted with 2N ammonia in MeOH to afford the
title compound (0.30 g, 97%). .sup.1H NMR (CDCl.sub.3, 300 MHz):
7.47-7.41 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 4.40 (s, 4H), 3.45-3.40
(m, 2H), 2.38-2.28 (s, 2H), 1.92-1.86 (s, 4H). LCMS (Method B):
R.sub.T=1.89 min, M+H.sup.+=296/298.
Preparation of 2-(4-Bromobenzyl)-2-aza-bicyclo[2.2.1]heptane
##STR00205##
[0699] A stirred solution of 4-bromobenzyl bromide (66 mg, 0.26
mmol), triethylamine (0.22 mL, 1.56 mmol) and
2-azabicyclo[2.2.1]heptane (71 mg, 0.52 mmol) in THF (10 mL) was
heated under reflux for 5 h. The reaction mixture was cooled to
ambient temperature, the solid removed by filtration and the
filtrate concentrated under reduced pressure to afford the title
compound (70 mg, quantitiative yield) that was used in the next
step without further purification. LCMS (Method B): R.sub.T=2.04
min, M+H.sup.+=266/268.
Preparation of
2-Bromo-6-ethyl-4,5,6,7-tetrahydrothieno[2,3c]pyridine
##STR00206##
[0700] Step 1: 2-Bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
hydrobromide
##STR00207##
[0702] A solution of bromine (139 mg, 0.87 mmol) in acetic acid
(0.5 mL) was added to a solution of
4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride (150 mg, 0.85
mmol) in acetic acid (3 mL) and the mixture left to stir at ambient
temperature for 1.5 h. The resultant precipitate was collected by
filtration, washed with diethyl ether and left to air dry to afford
the title compound as an off-white solid (230 mg, 90%). .sup.1H NMR
(DMSO-D.sub.6, 300 MHz): 9.19 (s, 2H), 7.09 (s, 1H), 4.29-4.26 (m,
2H), 2.86-2.78 (m, 2H), 2.52-2.48 (m, 2H). LCMS (Method B):
R.sub.T=1.65 min, M+H.sup.+=218/220.
Step 2: 2-Bromo-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
##STR00208##
[0704] Sodium borohydride (146 mg, 3.85 mmol) was added to cooled
(0.degree. C.) a suspension of
2-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrobromide (230
mg, 0.77 mmol) in acetic acid (1.5 mL) and tetrahydrofuran (2.8
mL). On complete addition the mixture was heated to 60.degree. C.
for 3 h. The mixture was allowed to cool to ambient temperature
then partitioned between ethyl acetate and water. The pH of the
aqueous phase was adjusted to 10 by the addition of 3N sodium
hydroxide solution and the layers separated. The organic layer was
washed with brine, dried over anhydrous sodium sulfate and
evaporated to give the title compound as a yellow oil (181 mg,
96%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 6.93 (s, 1H), 3.50-3.47
(m, 2H), 3.66-2.46 (m, 6H), 1.05 (t, J=7.2 Hz, 3H). LCMS (Method
B): R.sub.T=1.79 min, M+H.sup.+=246/248.
Preparation of Trifluoromethanesulfonic acid
2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl ester
##STR00209##
[0705] Step 1: 2-Ethyl-6,8-dimethoxy-3,4-dihydroisoquinolinium
iodide
##STR00210##
[0707] Ethyl iodide (0.6 mL, 7.32 mmol) was added to a solution of
6,8-dimethoxy-3,4-dihydroisoquinoline (700 mg, 3.66 mmol) in
acetonitrile (15 mL) and the mixture was left to stir in the dark
for 20 h. The resultant precipitate was collected by filtration,
washed with acetonitrile and left to air dry to afford the title
compound as a yellow solid (750 mg, 95%). .sup.1H NMR (CD.sub.3OD,
300 MHz): 8.96 (s, 1H), 6.63 (d, J=2.2 Hz, 1H), 6.61 (d, J=2.2 Hz,
1H), 4.02-3.88 (m, 7H), 3.18 (t, J=7.9 Hz, 2H), 2.03 (s, 5H), 1.47
(t, J=7.3 Hz, 3H).
Step 2: 2-Ethyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline
##STR00211##
[0709] Sodium borohydride (260 mg, 6.86 mmol) was added to a cooled
(0.degree. C.) solution of
2-ethyl-6,8-dimethoxy-3,4-dihydroisoquinolinium iodide (1.19 g,
3.43 mmol) in methanol (15 mL). On complete addition the mixture
was allowed to warm to ambient temperature and stirred for 1.5 h.
The mixture was evaporated in vacuo and the resultant residue was
partitioned between diethyl ether and water. The organic phase was
dried over sodium sulfate, filtered and evaporated to afford the
title compound as a yellow oil (741 mg, 98%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 6.27 (d, J=2.3 Hz, 1H), 6.24 (d, J=2.3 Hz,
1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.51-3.47 (m, 2H), 2.89-2.83 (m,
2H), 2.71-2.64 (m, 2H), 2.60 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz,
3H). LCMS (Method B): R.sub.T=1.62 min, M+H.sup.+=222.
Step 3: 2-Ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol
##STR00212##
[0711] A mixture of
2-ethyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (280 mg, 1.27
mmol) in 48% aqueous hydrobromic acid (3 mL) was heated at
65.degree. C. for 24 h. The mixture was added to saturated sodium
hydrogen carbonate solution and extracted with ethyl acetate
(3.times.50 mL). The combined organic phase was washed with water,
dried over anhydrous sodium sulfate, filtered and evaporated in
vacuo. The resultant solid was purified by flash chromatography
(silica, 12 g column, ISCO, 0-20% (2N ammonia in MeOH) in DCM) to
afford the title compound as an off white solid (153 mg, 58%).
.sup.1H NMR (CDCl.sub.3, 300 MHz): 6.11 (d, J=2.2 Hz, 1H), 5.93 (d,
J=2.2 Hz, 1H), 3.67 (s, 3H), 3.55-3.49 (m, 2H), 2.72-2.58 (m, 6H),
1.21 (t, J=7.2 Hz, 3H). LCMS (Method B): R.sub.T=1.58 min,
M+H.sup.+=208.
Step 4: Trifluoromethanesulfonic acid
2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl ester
##STR00213##
[0713] Triflic anhydride (0.54 mL, 3.2 mmol) was added dropwise
over 15 minutes to a suspension of
2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol (328 mg, 1.6
mmol) in pyridine (0.52 mL, 6.4 mmol) and DCM (15 mL). The reaction
mixture was allowed to warm to ambient temperature and stirred for
2 h. The mixture was diluted with DCM (60 mL), washed with water
(100 mL), dried over sodium sulfate, filtered and evaporated in
vacuo. The resultant solid was purified by flash chromatography
(silica, 12 g column, ISCO, 0-100% ethyl acetate in pentane) to
afford the title compound as a yellow solid (341 mg, 63%). .sup.1H
NMR (CDCl.sub.3, 300 MHz): 6.76 (d, J=2.3 Hz, 1H), 6.68 (d, J=2.3
Hz, 1H), 4.30-4.10 (m, 2H), 3.87 (s, 3H), 3.50-3.37 (m, 2H),
3.36-3.10 (s, 4H), 1.51 (t, J=7.2 Hz, 3H). LCMS (Method B):
R.sub.T=2.39 min, M+H.sup.+=340.
Preparation of
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
##STR00214##
[0715] A mixture of 5-bromothiazole (0.54 mL, 6.1 mmol),
bis(pinacolato)diboron (1.56 g, 6.1 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250
mg, 0.3 mmol), and potassium acetate (1.8 g, 18.3 mmol) in
1,4-dioxane (20 mL) was heated at 100.degree. C. for 12 h. The
cooled reaction mixture was diluted with DCM (50 mL) and washed
with water (15 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo. The resultant
residue was purified by flash chromatography through a thin pad of
silica eluting with DCM to afford the title compound as a brown
solid which was used without further purification.
Preparation of 2-Methyl-5-(trimethylstannyl)thiazole
##STR00215##
[0717] To a cooled (-78.degree. C.) solution of 2-methylthiazole
(1.0 g, 10 mmol) in anhydrous diethyl ether (20 mL) under an
atmosphere of nitrogen was added n-butyllithium (2.5M solution in
hexanes, 5.2 mL, 13 mmol) dropwise over 10 minutes. The reaction
mixture was stirred for 1 h and then allowed to warm to 0.degree.
C. and stirred for 1 h. The reaction mixture was then cooled to
-78.degree. C. and a solution of chlorotrimethylstannane (1.8 g,
9.0 mmol) in anhydrous diethyl ether (10 mL) was added dropwise
over 10 minutes. The reaction mixture was stirred for 30 minutes
and then allowed to warm to room temperature and stirred for 16 h.
The reaction was quenched with water (20 mL) and extracted with
ethyl acetate (2.times.50 mL). The combined organic layer was dried
over sodium sulfate, filtered, and evaporated in vacuo to afford
the title compound as a yellow oil which was used without any
further purification.
Preparation of 1,2-Dimethyl-5-(tributylstannyl)-1H-imidazole
##STR00216##
[0719] The title compound was prepared following a similar
procedure to previous example using
5-bromo-1,2-dimethyl-1H-imidazole and tributylchlorostannane.
Preparation of 3-(Trimethylstannyl)imidazo[1,2-a]pyrimidine
##STR00217##
[0721] To a cooled (-78.degree. C.) solution of
3-bromoimidazo[1,2-a]pyrimidine (1.0 g, 5.1 mmol) in anhydrous
tetrahydrofuran (40 mL) under an atmosphere of nitrogen was added
isopropylmagnesium chloride (2.0M solution in tetrahydrofuran, 2.8
mL, 5.6 mmol) dropwise over 10 minutes. The reaction was stirred
for 2 h then a solution of chlorotrimethylstannane (1.1 g, 5.6
mmol) in tetrahydrofuran (10 mL) was added dropwise over 10
minutes. The reaction mixture was stirred for 30 minutes then
allowed to warm to room temperature. The reaction was quenched with
water (20 mL) and extracted with DCM (2.times.50 mL). The combined
organic layer was dried over sodium sulfate, filtered, and
evaporated in vacuo to afford the title compound as an orange oil
which was used without any further purification.
[0722] Compounds of the Examples in Table 1 were made via
procedures described above using appropriate starting materials,
reagents and general Suzuki conditions.
TABLE-US-00001 TABLE 1 Boronic acid/ LCMS ester Final R.sub.T,
prepa- Cou- puri- M + Ex- ration pling fication H.sup.+, am-
general Meth- Meth- Meth- ple Structure/Name Method od od(s) od
.sup.1H NMR (ppm) 1 ##STR00218## 3-[4-(1-Methyl-piperidin-4-yl)-
phenyl]-9H-dipyrido[2,3-b;4',3'- d]pyrrole-6-carbonitrile B A
E.sup.2 5.8, 368, A (DMSO-D.sub.6, 300 MHz): 12.87 (br s, 1H),
9.05-9.02 (m, 2H), 8.99 (d, J = 2.3 Hz, 1H), 8.93 (d, J = 1.0 Hz,
1H), 7.73 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 2.94-2.84
(m, 2H), 2.54-2.47 (m, 1H), 2.21 (s, 3H), 2.04-1.94 (m, 2H),
1.82-1.66 (m, 4H). 2 ##STR00219## 4-[3-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-phenyl]- piperazine-1-carboxylic acid
tert-butyl ester A A G 11.6, 455, A (DMSO-D.sub.6, 300 MHz):
9.02-8.95 (m, 3H), 8.85 (s, 1H), 7.41-7.32 (m, 2H), 7.24 (d, J =
7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 3.51 (m, 4H), 3.24 (m, 4H),
1.44 (s, 9H). 3 ##STR00220## 3-(4-Pyrrolidin-1-yl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile A A none 11.7, 340,
A (DMSO-D.sub.6, 400 MHz): 12.78 (br. s, 1H), 9.01 (d, J = 1.0 Hz,
1H), 8.95-8.91 (m, 3H), 7.63 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.5
Hz, 2H), 3.33-3.25 (m, 4H), 2.01-1.95 (m, 4H). 4 ##STR00221##
N-{2-[4-(6-Cyano-9H-dipyrido [2,3-b;4',3'-d]pyrrol-3-yl)-
phenoxy]-ethyl}- methanesulfonamide A A B 8.4, 408, A
(DMSO-D.sub.6, 400 MHz): 12.85 (s, 1H), 9.05-9.00 (m, 2H), 8.98 (d,
J = 2.3 Hz, 1H), 8.94-8.91 (m, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.31
(t, J = 5.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 2H), 4.12 (t, J = 5.6 Hz,
2H), 3.41- 3.35 (m, 2H), 2.98 (s, 3H). 5 ##STR00222##
3-[4-(1-Methyl-piperidin-4- ylmethyl)-phenyl]-9H-
dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile A A E.sup.3 6.24,
382, A (DMSO-D.sub.6, 300 MHz): 9.06 (d, J = 2.3 Hz, 1H), 9.04 (d,
J = 1.0 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.0 Hz,
1H), 7.72 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 2.73 (d, J
= 10.7 Hz, 2H), 2.57 (d, J = 6.6 Hz, 2H), 2.12 (s, 3H), 1.80 (t, J
= 5.8 Hz, 2H), 1.60-1.40 (m, 3H), 1.30-1.10 (m, 2H). 6 ##STR00223##
3-(4-Piperidin-1-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile C A B 5.83, 368,
A (DMSO-D.sub.6, 300 MHz): 9.09-9.01 (m, 3H), 8.95 (d, J = 1.0 Hz,
1H), 7.76 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 3.50 (s,
2H), 2.37 (m, 4H), 1.55-1.48 (m, 4H), 1.41 (m, 2H). 7 ##STR00224##
3-(4-Morpholin-4-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile C A H.sup.1 5.43,
370, A (DMSO-D.sub.6, 300 MHz): 9.09-9.01 (m, 3H), 8.94 (d, J = 1.1
Hz, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 3.60
(m, 4H), 3.54 (s, 2H), 2.40 (m, 4H). 8 ##STR00225##
3-[4-(4-Benzyl-morpholin-2-yl)- phenyl]-9H-dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile A A A.sup.3 6.77, 446, A (DMSO-D.sub.6, 400
MHz): 12.90 (br. s, 1H), 9.10 (d, J = 2.3 Hz, 1H), 9.07 (d, J = 1.1
Hz, 1H), 9.00 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.77
(d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.35-7.30 (m, 4H),
7.29-7.24 (m, 1H), 4.59 (dd, J = 10.1, 2.3 Hz, 1H), 3.98-3.93 (m,
1H), 3.72 (td, J = 11.4, 2.4 Hz, 1H), 3.56 (d, J = 13.0 Hz, 1H),
3.53 (d, J = 13.0 Hz, 1H), 2.91 (d, J = 11.5 Hz, 1H), 2.72 (d, J =
11.5 Hz, 1H), 2.20 (td, J = 11.5, 3.3 Hz, 1H), 2.08-2.01 (m, 1H). 9
##STR00226## 3-(3-Piperidin-1-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile C A B.sup.1 5.94,
368, A (CDCl.sub.3, 300 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.91 (d, J
= 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 1.0 Hz, 1H)
7.66 (s, 1 H), 7.57 (d, J = 7.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H),
7.39 (d, J = 7.1 Hz, 1H), 3.60 (s, 2H), 2.47 (m, 4H), 1.63 (m, 4H),
1.48 (m, 2H). 10 ##STR00227## 3-(3-Morpholin-4-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile C A B.sup.1 5.59,
370, A (CDCl.sub.3, 300 MHz): 9.03 (s, 1H), 8.90 (s, 1H), 8.69 (s,
1H), 8.48 (s, 1H), 7.66 (s, 1H), 7.58 (m, 1H), 7.52 (br. t, J = 7.8
Hz, 1H), 7.43 (m, 1H), 3.76 (m, 4H), 3.63 (s, 2H), 2.54 (m, 4H). 11
##STR00228## 4-[4-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-benzyl)- piperazine-1- carboxylic acid
tert-butyl ester A A B.sup.1 6.75, 469, A (CDCl.sub.3, 300 MHz):
9.02 (d, J = 1.1 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H); 8.68 (d, J =
2.2 Hz, 1H); 8.48 (d, J = 1.1 Hz, 1H); 7.65 (br d, J = 7.9 Hz, 2H);
7.50 (br d, J = 7.9 Hz, 2H); 3.62 (s, 2H); 3.55-3.44 (m, 4H); 2.47
(m, 4H); 1.46 (s, 9H) 12 ##STR00229##
3-[4-(4-Ethyl-piperazin-1-yl)-phenyl]-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile A A B.sup.1 5.83,
383, A (DMSO-D.sub.6, 400 MHz): 12.76 (s, 1H); 9.00-8.86 (m, 4H);
7.62 (d, J = 8.4 Hz, 2H); 7.05 (d, J = 8.4 Hz, 2H); 3.18 (m, 4H);
2.48 (m, 4H); 2.34 (q, J = 7.2 Hz, 2H); 1.00 (t, J = 7.2 Hz, 3H).
13 ##STR00230## 3-[4-((2S,6R)-2,6-Dimethyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile B A B 6.26, 396, A (DMSO-D.sub.6,
300 MHz): 9.05 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.00
(d, J = 2.3 Hz, 1H), 8.93 (d, J = 1.1 Hz, 1H), 7.72 (d, J = 8.1 Hz,
2H), 7.54 (d, J = 8.0 Hz, 2H), 3.78 (s, 2H), 2.55-2.42 (m, 2H),
1.66-1.52 (m, 3H), 1.37-1.20 (m, 3H), 1.00 (d, J = 6.2 Hz, 6H).
[0723] Compounds of the Examples in Table 2 were prepared via
procedures described above using appropriate starting materials,
reagents and general Suzuki conditions.
TABLE-US-00002 TABLE 2 LCMS Boronic Final R.sub.T, acid/ Cou- puri-
M + Ex- ester pling Depro- fication H.sup.+, am- general Meth-
tection Meth- Meth- ple Structure/Name Method od Method od(s) od
.sup.1H NMR (ppm) 14 ##STR00231## 3-(3-Piperazin-1-yl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile From Example 1 N/A A
G.sup.1 5.81, 355, A (DMSO-D.sub.6, 300 MHz): 12.99 (s, 1H), 9.30
(s, 2H), 9.11 (d, J = 2.2 Hz, 1H), 9.06-9.01 (m, 2H), 8.95 (s, 1H),
7.47-7.39 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.09-7.03 (m, 1H),
3.53 (m, 4H), 3.26 (s, 4H). 15 ##STR00232##
3-(4-Morpholin-4-yl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile NA D A G.sup.1 9.1, 356, A (DMSO-D.sub.6, 400 MHz):
12.88 (s, 1H), 9.04-9.02 (m, 2H), 8.98 (d, J = 2.3 Hz, 1H), 8.94
(d, J = 1.0 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.4 Hz,
2H), 3.81 (t, J = 4.6 Hz, 4H), 3.24 (t, J = 4.6 Hz, 4H). 16
##STR00233## 3-[3-(1-Methyl-piperidin-4-yl)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile B D A F
6.1, 368, A (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 10.35 (s, 1H),
9.09 (d, J = 2.2 Hz, 1H), 9.06 (d, J = 1.0 Hz, 1H), 9.02 (d, J =
2.2 Hz, 1H), 8.95 (s, 1H), 7.72- 7.65 (m, 2H), 7.53 (t, J = 7.6 Hz,
1H), 7.32 (d, J = 7.6 Hz, 1H), 3.53 (d, J = 12.0 Hz, 2H), 3.16-3.06
(m, 2H), 2.95-2.90 (m, 1H), 2.80 (d, J = 4.6 Hz, 3H), 2.13-2.04 (m,
4H). 17 ##STR00234## 3-[4-((S)-Pyrrolidin-3-yloxy)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile A D B C,
E 5.64, 356, A (DMSO-D.sub.6, 400 MHz): 8.99-8.93 (m, 2H), 8.92 (d,
J = 2.3 Hz, 1H), 8.87 (d, J = 1.1 Hz, 1H), 7.67 (d, J = 8.3 Hz,
2H), 7.03 (d, J = 8.3 Hz, 2H), 4.92- 4.85 (m, 1H), 3.14-2.99 (m,
1H), 2.94-2.71 (m, 3H), 2.06-1.95 (m, 1H), 1.80-1.72 (m, 1H). 18
##STR00235## 3-[4-((R)-Pyrrolidin-3-yloxy)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile A D B C,
E 5.64, 356, A (DMSO-D.sub.6, 300 MHz): 9.03 (d, J = 1.0 Hz, 1H),
9.01 (d, J = 2.3 Hz, 1H), 8.97 (d, J = 2.3 Hz, 1H), 8.92 (d, J =
1.1 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H),
4.98-4.90 (m, 1H), 3.15- 3.08 (m, 1H), 2.97-2.81 (m, 3H), 2.08-2.02
(m, 1H), 1.85-1.75 (m, 1H). 19 ##STR00236##
3-[4-(Piperidin-3-yloxy)-phenyl]-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile A D B C, E 5.85,
370, A (DMSO-D.sub.6, 300 MHz): 9.02 (d, J = 1.1 Hz, 1H), 9.00 (d,
J = 2.3 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.92 (d, J = 1.1 Hz,
1H), 7.71 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.37-4.29
(m, 1H), 3.19- 3.09 (m, 1H), 2.84-2.73 (m, 1H), 2.59-2.44 (m, 2H),
2.12-2.02 (m, 1H), 1.75-1.63 (m, 1H), 1.57- 1.43 (m, 2H). 20
##STR00237## 3-[4-(4-Hydroxy-1-methyl-piperidin-
4-yl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile B D
A A 5.3, 384, A (DMSO-D.sub.6, 300 MHz): 12.80 (br. s, 1H), 9.08
(d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz, 1H),9.03 (d, J = 2.3 Hz,
1H),8.95 (d, J = 1.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.65 (d, J
= 8.3 Hz, 2H), 4.99 (s, 1H), 2.71 (d, J = 10.4 Hz, 2H), 2.57-2.46
(m, 2H), 2.32 (s, 3H), 2.13-2.01 (m, 2H), 1.67 (d, J = 13.0 Hz,
2H). 21 ##STR00238## 3-(4-(2-Dimethylamino-ethoxy)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile NA D A A
5.6, 358, A (DMSO-D.sub.6, 300 MHz): 12.75 (br. s, 1H), 9.05- 9.02
(m, 2H), 8.99 (d, J = 2.3 Hz, 1H), 8.95 (d, J = 1.1 Hz, 1H), 7.75
(d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 4.14 (t, J = 5.8 Hz,
2H), 2.68 (t, J = 5.8 Hz, 2H), 2.26 (s, 6H). 22 ##STR00239##
3-[3-(4-Methyl-piperazin-1-yl)-phenyl]-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile A A A B 5.86,
368, A (DMSO-D.sub.6, 300 MHz): 9.09-8.98 (m, 3H), 8.95 (s, 1H),
7.42-7.30 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz,
1H), 3.33 (s, 4H), 2.50 (s, 4H), 2.25 (s, 3H). 23 ##STR00240##
3-(4-Morpholin-2-yl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile From Example 8 NA C C.sup.2 5.57, 356, A
(DMSO-D.sub.6, 300 MHz): 9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1
Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.95 (d, J = 1.1 Hz, 1H), 7.78
(d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 4.47 (dd, J = 10.2,
2.4 Hz, 1H), 3.92 (dt, J = 10.9, 2.2 Hz, 1H), 3.58- 3.69 (m, 1H),
2.99 (dd, J = 12.3, 2.5 Hz, 1H), 2.80-2.74 (m, 2H), 2.59- 2.54 (m,
1H). 24 ##STR00241## 3-[3-(1-Methyl-piperidin-4-yloxy)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile B D A G,
E 6.15, 384, A (DMSO-D.sub.6, 300 MHz): 12.90 (s, 1H), 9.09 (d, J =
2.3 Hz, 1H), 9.04 (s, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.95 (s, 1H),
7.44 (t, J = 8.0 Hz, 1H), 7.40- 7.32 (m, 2H), 7.02 (d, J = 8.1 Hz,
1H), 4.63-4.43 (m, 1H), 2.69-2.59 (m, 2H), 2.30-2.13 (m, 5H),
2.05-1.93 (m, 2H), 1.75- 1.64 (m, 2H). 25 ##STR00242##
3-[1-(2-Pyrrolidin-1-yl-ethyl)-1H-
pyrazol-4-yl]-9H-dipyrido[2,3-b;4',3'- d]pyrrole-6-carbonitrile D D
A E, K 5.07, 358, A (DMSO-D.sub.6, 400 MHz): 12.88 (s, 1H), 10.93
(s, 1H), 9.02 (d, J = 1.0 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.97
(d, J = 2.2 Hz, 1H), 8.85 (d, J = 1.0 Hz, 1H), 8.42 (s, 1H), 8.12
(s, 1H), 4.65 (t, J = 6.3 Hz, 2H), 3.70 (q, J = 6.0 Hz, 2H),
3.57-3.46 (m, 2H), 3.02-2.94 (m, 2H), 2.04-1.93 (m, 2H), 1.91-1.82
(m, 2H). 26 ##STR00243## 3-[4-(1-Methyl-piperidin-4-yloxy)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile B D A G,
E 6.05, 384, A (DMSO-D.sub.6, 400 MHz): 12.82 (s, 1H), 9.03 (d, J =
1.1 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.97 (d, J = 2.3 Hz, 1H),
8.94 (d, J = 1.1 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.12 (d, J =
8.5 Hz, 2H), 4.49-4.42 (m, 1H), 2.68-2.60 (m, 2H), 2.27-2.15 (m,
5H), 2.02-1.93 (m, 2H), 1.73- 1.63 (m, 2H). 27 ##STR00244##
3-(4-Piperazin-1-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile C A B B.sup.1,
F.sup.1,2,5 4.92, 369, A (DMSO-D.sub.6, 400 MHz): 12.54 (br. s,
1H), 9.03 (m, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.97 (d, J = 2.2 Hz,
1H), 8.83 (m, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz,
2H), 3.68 (s, 2H), 3.14 (t, J = 5.1 Hz, 4H), 2.69 (t, J = 5.1 Hz,
4H). 28 ##STR00245## 3-(3,5-Dimethoxy-4-piperidin-1-
ylmethyl-phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
NA A A E 6.42, 428, A (DMSO-D.sub.5, 300 MHz): 9.13 (d, J = 2.3 Hz,
1H), 9.11 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.0 Hz, 1H), 8.94 (d, J
= 1.0 Hz, 1H), 7.05 (s, 2H), 3.90 (s, 6H), 3.50 (s, 2H), 2.41- 2.36
(m, 4H), 1.49-1.40 (m, 4H), 1.29-1.38 (m, 2H). 29 ##STR00246##
3-[4-(4-Methoxy-piperidin-4-yl)- phenyl]-9H-dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile B D B D 5.99, 384, A (DMSO-D.sub.6, 400
MHz): 9.12 (d, J = 2.0 Hz, 1H), 9.07-9.05 (m, 2H), 8.95 (d, J = 1.0
Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 3.30-
3.23 (m, 2H), 3.20-3.07 (m, 2H), 2.97 (s, 3H), 2.30-2.20 (m, 2H),
2.15- 2.05 (m, 2H). 30 ##STR00247##
3-[4-(3-Hydroxy-piperidin-3-yl)- phenyl]-9H-dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile B D B D 5.51, 370, A (DMSO-D.sub.6, 400
MHz): 9.06 (d, J = 2.5 Hz, 1H), 9.04 (d, J = 1.0 Hz, 1H), 9.01 (d,
J = 2.5 Hz, 1H), 8.93 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 8.0 Hz,
2H), 7.67 (d, J = 8.0 Hz, 2H), 2.98-2.88 (m, 1H), 2.88- 2.81 (m,
1H), 2.70-2.64 (m, 1H), 2.61-2.52 (m, 1H), 2.02-1.95 (m, 1H),
1.86-1.80 (m, 1H), 1.78- 1.70 (m, 1H), 1.49-1.41 (m, 1H). 31
##STR00248## 3-[3-(3-Hydroxy-piperidin-3-yl)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile B D B D
5.77, 370, A (DMSO-D.sub.6, 400 MHz): 9.09 (d, J = 2.0 Hz, 1H),
9.05 (d, J = 1.0 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.99 (d, J =
1.0 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58 (d, J =
8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 2.98-2.91 (m, 2H), 2.76-2.68
(m, 1H), 2.67-2.53 (m, 1H), 2.07 (td, J = 8.5, 4.0 Hz, 1H),
1.90-1.85 (m, 1H), 1.81-1.73 (m, 1H), 1.51- 1.44 (m, 1H). 32
##STR00249## 3-[4-(3-Hydroxy-1-methyl-piperidin-
3-yl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile B D
B B 5.58, 384, A (DMSO-D.sub.6, 400 MHz): 9.11 (d, J = 2.0 Hz, 1H),
9.06 (d, J = 1.0 Hz, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.95 (d, J =
1.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H),
3.27-3.22 (m, 2H), 3.17- 3.16 (m, 1H), 3.09-2.97 (m, 1H), 2.75 (s,
3H), 2.20-1.99 (m, 2H), 1.88- 1.81 (m, 2H). 33 ##STR00250##
3-[4-(4-Fluoro-piperidin-4-yl)- phenyl]-9H-dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile B D B B 6.15, 372, A (DMSO-D.sub.6, 400
MHz): 9.11 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 1.0 Hz, 1H), 9.04 (d,
J = 2.0 Hz, 1H), 8.95 (d, J = 1.0 Hz, 1H), 7.87 (d, J = 8.0 Hz,
2H), 7.58 (d, J = 8.0 Hz, 2H), 3.14-2.95 (m, 2H), 3.03- 2.95 (m,
2H), 2.26-2.13 (m, 2H), 2.10-1.95 (m, 2H). 34 ##STR00251##
3-[4-(3,3-Dimethyl-pyrrolidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C A -- B 6.32, 382, A
(DMSO-D.sub.6, 400 MHz): 12.89 (br s, 1H), 9.08 (d, J = 2.3 Hz,
1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.94 (d, J
= 1.1 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H),
3.63 (s, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.29 (s, 2H), 1.55 (t, J =
7.0 Hz, 2H), 1.07 (s, 6H). 35 ##STR00252##
3-[4-(3,3-Difluoro-pyrrolidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C D -- B, S 6.44, 390, A
(DMSO-D.sub.6, 300 MHz): 12.89 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H),
9.05 (d, J = 1.0 Hz, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.95 (d, J =
1.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.99 Hz, 2H),
3.70 (s, 2H), 2.91 (t, J = 13.3 Hz, 2H), 2.77-2.70 (m, 2H),
2.34-2.21 (m, 2H). 36 ##STR00253##
3-[4-(3-Trifluoromethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C* D -- B.sup.8 6.67, 436, A
(DMSO-D.sub.6, 400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H),
9.04 (d, J = 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J =
1.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H),
3.61 (s, 2H), 3.03-2.95 (m, 1H), 2.87-2.79 (m, 1H), 2.03- 1.93 (m,
2H), 1.92-1.83 (m, 1H), 1.76-1.67 (m, 1H), 1.60-1.47 (m, 1H),
1.32-1.18 (m, 1H). 37 ##STR00254##
3-[4-(3-Fluoro-piperidin-1-ylmethyl)-
phenyl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile C* D -- B
5.76, 386, A (DMSO-D.sub.6, 400 MHz): 12.91 (s, 1H), 9.09 (d, J =
2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H),
8.94 (d, J = 1.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J =
8.0 Hz, 2H), 4.74-4.57 (m, 1H), 3.59 (s, 2H), 2.78-2.64 (m, 1H),
2.49- 2.36 (m, 2H), 2.35-2.24 (m, 1H), 1.91-1.65 (m, 2H), 1.62-1.41
(m, 2H). 38 ##STR00255## 3-(3-Piperidin-1-ylmethyl-isothiazol-
5-yl)-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile monoformate
Stille B -- D 5.70, 375, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz):
9.03 (d, J = 1.0 Hz, 1H), 8.97 (d, J = 2.2 Hz, 1H), 8.92 (d, J =
2.2 Hz, 1H), 8.68 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 4.12 (s, 2H),
2.99-2.86 (m, 4H), 1.85-1.74 (m, 4H), 1.66-1.55 (m, 2H). 39
##STR00256## 3-(2-Piperidin-1-ylmethyl-
thiazol-5-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
Stille B -- .sup.5 5.55, 375, A (DMSO-D.sub.6, 400 MHz): 9.06-9.02
(m, 3H), 8.94 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 3.81 (s, 2H),
2.56-2.49 (m, 4H), 1.62- 1.52 (m, 4H), 1.49-1.38 (m, 2H). 40
##STR00257## 3-(5-Ethyl-4,5,6,7-tetrahydro-thiazolo
[4,5-c]pyridin-2-yl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile Stille B -- B.sup.4 5.62,
360, A (DMSO-D.sub.6, 400 MHz): 12.90 (s, 1H), 9.02 (d, J = 1.1 Hz,
1H), 8.96 (d, J = 2.3 Hz, 1H), 8.95 (d, J = 1.1 Hz, 1H), 8.93 (d, J
= 2.3 Hz, 1H), 7.32 (s, 1H), 3.63 (s, 2H), 2.77- 2.65 (m, 4H), 2.57
(q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). *no sodium iodide
used in this reaction
[0724] The compounds of the Examples in Table 3 were prepared via
general Suzuki procedures described above, employing commercially
available boronic acids.
TABLE-US-00003 TABLE 3 LCMS Ex- Cou- Depro- R.sub.T, M + am- pling
tection Purification H.sup.+, ple Structure/Name Method Method
Method(s) Method .sup.1H NMR (ppm) 41 ##STR00258##
3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile E A E, H 4.38,
276, A (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.35 (s, 2H), 9.04
(d, J = 1.0 Hz, 1H), 8.93 (d, J = 1.0 Hz, 1H), 8.91 (d, J = 2.3 Hz,
1H), 8.88 (d, J = 2.3 Hz, 1H), 6.36 (s, 1H), 3.82 (s, 2H),
3.42-3.35 (s, 2H), 2.89-2.81 (s, 2H). 42 ##STR00259##
3-(3,5-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile D A G.sup.2, J 10.0, 331, A (DMSO-D.sub.6, 400 MHz):
12.91 (s, 1H), 9.11 (d, J = 2.3 Hz, 1H), 9.05- 9.03 (m, 2H), 8.93
(d, J = 1.0 Hz, 1H), 6.96 (d, J = 2.2 Hz, 2H), 6.57 (t, J = 2.2 Hz,
1H), 3.85 (s, 6H). 43 ##STR00260##
3-[4-Pyrrolidin-1-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile B NA B 5.69, 354,
A (CD.sub.3OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.95 (d, J = 2.2
Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 1.1 Hz, 1H), 7.82
(d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 4.16 (s, 2H),
3.12-3.05 (m, 4H), 2.06-2.01 (m, 4H). 44 ##STR00261##
3-[4-(1-Piperidin-1-yl-ethyl)-phenyl]-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile B NA B 2.28, 382,
A (CDCl.sub.3, 400 MHz): 9.02 (t, J = 1.0 Hz, 1H), 8.91 (dd, J =
2.1, 0.9 Hz, 1H), 8.73 (dd, J = 2.3, 1.3 Hz, 1H), 8.53 (t, J = 1.1
Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 3.67
(q, J = 6.7 Hz, 1H), 2.68-2.50 (m, 4H), 1.73-1.63 (m, 4H), 1.56 (d,
J = 6.8 Hz, 3H), 1.50-1.44 (m, 2H).
[0725] Compounds of the Examples in Table 4 were made via
procedures described above using appropriate starting materials,
reagents and general Suzuki Methods.
TABLE-US-00004 TABLE 4 De- LCMS pro- Puri- R.sub.T, Cou- tec- fica-
M + Ex- pling tion tion H.sup.+, am- Meth- Meth- Meth- Meth- ple
Structure/Name od od od(s) od .sup.1H NMR (ppm) 45 ##STR00262##
3-[3-Methoxy-5-(1-methyl-piperidin- 4-
yloxy)-phenyl]-9H-dipyrido[2,3-b; 4',3'-d]pyrrole-6-carbonitrile F
A E.sup.5 6.4, 414, A (DMSO-D.sub.6, 400 MHz): 12.85 (s, 1H), 9.10
(d, J = 2.3 Hz, 1H), 9.04- 9.02 (m, 2H), 8.94 (d, J = 1.1 Hz, 1H),
6.95 (dt, J = 9.8, 1.8 Hz, 2H), 6.57 (t, J = 2.2 Hz, 1H), 4.56-4.49
(m, 1H), 3.85 (s, 3H), 2.68-2.60 (m, 2H), 2.29-2.16 (m, 5H),
2.03-1.92 (m, 2H), 1.74-1.63 (m, 2H). 46 ##STR00263##
3-(3,5-Difluoro-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile F D B 5.87, 404, A (DMSO-D.sub.6,
300 MHz): 9.19 (d, J = 2.3 Hz, 1H), 9.10 (d, J = 2.3 Hz, 1H), 9.05
(d, J = 1.1 Hz, 1H), 8.87 (d, J = 1.1 Hz, 1H), 7.61 (d, J = 8.6 Hz,
2H), 3.58 (s, 2H), 2.43-2.37 (m, 4H), 1.51-1.44 (m, 4H), 1.39-1.32
(m, 2H). 47 ##STR00264## 3-[3-Bromo-5-(1-methyl-pipendin-4-
yloxy-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile F A
G.sup.3, E 7.1, 462, A (DMSO-D.sub.6, 400 MHz): 12.85 (s, 1H), 9.14
(d, J = 2.3 Hz, 1H), 9.06- 9.04 (m, 2H), 8.93 (d, J = 1.1 Hz, 1H),
7.58 (dd, J = 1.6, 1.5 Hz, 1H), 7.40 (dd, J = 2.1, 1.7 Hz, 1H),
7.23 (dd, J = 2.2, 1.7 Hz, 1H), 4.63-4.56 (m, 1H), 2.67-2.59 (m,
2H), 2.28- 2.15 (m, 5H), 2.02-1.91 (m, 2H), 1.74-1.64 (m, 2H). 48
##STR00265## 3-(4,5,6,7-Tetrahydro-thieno[3,2-c]
pyridin-2-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile G A
H, B 5.33, 332, A (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.44 (br.
s, 1H), 9.00 (d, J = 1.1 Hz, 1H), 8.94-8.93 (m, 2H), 8.94 (d, J =
1.0 Hz, 1H), 7.39 (s, 1H), 4.20 (s, 2H), 3.41 (m, 2H), 3.08 (t, J =
6.0 Hz, 2H). 49 ##STR00266## 3-(5-Ethyl-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridin-2-yl)-9H- dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile G A H, B 2.17, 360, A (DMSO-D.sub.6, 400
MHz): 13.02 (s, 1H), 10.68 (s, 1H), 9.05 (d, J = 1.0 Hz, 1H), 9.00
(s, 2H), 8.99 (s, 1H), 7.42 (s, 1H), 4.51 (d, J = 15.0 Hz, 1H),
4.27-4.16 (m, 1H), 3.85-3.73 (m, 1H), 3.40-3.14 (m, 5H), 1.36 (t, J
= 7.2 Hz, 3H). 50 ##STR00267## 3-(4-Piperidin-1-ylmethyl-thiophen-
2-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile F D
J.sup.3,5 5.8, 374, A (DMSO-D.sub.6, 400 MHz): 12.90 (br. s, 1H),
9.05 (d, J = 2.3 Hz, 1H), 9.02 (d, J = 1.1 Hz, 1H), 9.00 (d, J =
2.3 Hz, 1H), 8.96 (d, J = 1.1 Hz, 1H), 7.53 (d, J = 1.4 Hz, 1H),
7.34 (d, J = 1.3 Hz, 1H), 3.45 (s, 2H), 2.40-2.33 (m, 4H),
1.56-1.48 (m, 4H), 1.42- 1.37 (m, 2H). 51 ##STR00268##
3-(4-Piperidin-1-ylmethyl-thiazol- 2-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile F D E 5.45, 375, A (CDCl.sub.3,
300 MHz): 9.21 (d, J = 2.1 Hz, 1H), 9.05 (d, J = 2.1 Hz, 1H), 9.02
(d, J = 1.1 Hz, 1H), 8.50 (d, J = 1.1 Hz, 1H), 3.79 (s, 2H),
2.63-2.55 (m, 4H), 1.71-1.62 (m, 4H), 1.54- 1.46 (m, 2H). 52
##STR00269## 3-(4,5,6,7-Tetrahydro-thiazolo[5,4-
c]pyridin-2-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile F
D E 4.66, 333, A (DMSO-D.sub.6, 300 MHz): 9.29 (s, 1H), 9.19 (s,
1H), 9.07 (s, 1H), 9.05 (s, 1H), 4.05 (s, 2H), 3.14-3.07 (m, 2H),
2.85-2.79 (m, 2H). 53 ##STR00270##
3-(4-Azetidin-1-ylmethyl-phenyl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile G D B 5.48, 340,
A (DMSO-D.sub.6, 400 MHz): 9.07 (d, J = 2.3 Hz, 1H), 9.04 (d, J =
1.1 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H),
7.75 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.62 (s, 2H),
3.19 (t, J = 6.9 Hz, 4H), 2.02 (p, J = 7.0 Hz, 2H). 54 ##STR00271##
3-[4-(1-Methyl-1-piperidin-1-yl- ethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B 6.24, 396, A (DMSO-D.sub.6,
400 MHz): 9.07 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.01
(d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 8.1 Hz,
2H), 7.44 (d, J = 8.0 Hz, 2H), 3.62 (s, 2H), 3.19 (t, J = 6.9 Hz,
4H), 2.02 (p, J = 7.0 Hz, 2H). 55 ##STR00272##
3-(3-Methoxy-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile K D B, G.sup.4 6.29, 398, A
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 9.02 (s, 1H), 8.90 (d, J =
2.2 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.51 (s, 1H), 7.47 (d, J =
7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.14 (s, 1H), 3.95 (s, 3H),
3.64 (s, 2H), 2.58-2.45 (s, 4H), 1.65-1.56 (m, 4H), 1.52-1.39 (m,
2H) 56 ##STR00273## 3-(3,5-Diethyl-4-piperidin-1-
ylmethyl-phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B.sup.4 2.53, 424, B (CDCl.sub.3, 300 MHz): 9.02 (s, 1H), 8.90
(d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 1.0 Hz,
1H), 7.33 (s, 2H), 3.54 (s, 2H), 2.89 (q, J = 7.5 Hz, 4H),
2.51-2.38 (m, 4H), 1.60-1.39 (m, 6H), 1.36-1.22 (m, 6H). 57
##STR00274## 3-(3,5-Dichloro-4-piperidin-1-
ylmethyl-phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
K D B.sup.4 6.55, 436, A (CDCl.sub.3 plus CD.sub.3OD, 300 MHz):
9.03 (s, 1H), 8.85 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.48 (d, J =
0.9 Hz, 1H), 7.62 (s, 2H), 3.79 (s, 2H), 2.64- 2.52 (s, 4H),
1.64-1.53 (m, 4H), 1.51-1.38 (m, 2H). 58 ##STR00275##
3-(3-Chloro-5-methoxy-4-piperidin-
1-ylmethyl-phenyl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile K D B.sup.4 6.80, 432, A
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.97 (s, 1H), 8.83 (d, J =
2.2 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 1.0 Hz, 1H),
7.26 (d, J = 1.7 Hz, 1H), 6.98 (d, J = 1.7 Hz, 1H), 3.90 (s, 3H),
3.77 (s, 2H), 2.70-2.55 (m, 4H), 1.68-1.55 (m, 4H), 1.51-1.37 (m,
2H). 59 ##STR00276## 3-(3-Methoxy-5-methyl-4-piperidin-
1-ylmethyl-phenyl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile K D B.sup.4 6.68, 412, A
(CDCl.sub.3, 300 MHz): 8.93 (s, 1H), 8.82-8.80 (m, 1H), 8.59 (d, J
= 2.1 Hz, 1H), 8.42 (s, 1H), 7.02 (s, 1H), 6.91 (s, 1H), 3.84 (s,
3H), 3.50 (s, 2H), 2.48-2.34 (m, 7H), 1.55- 1.43 (m, 4H), 1.43-1.31
(m, 2H). 60 ##STR00277## 3-(3-Ethoxy-4-piperidin-1-ylmethyl-
phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile G D
B.sup.4 6.78, 412, A (DMSO-D.sub.6, 400 MHz): 12.94 (s, 1H), 9.12
(s, 1H), 9.07 (s, 1H), 9.05 (d, J = 1.1 Hz, 1H), 8.94 (d, J = 1.0
Hz, 1H), 7.52 (s, 1H), 7.41 (m, 2H), 4.23 (d, J = 7.8 Hz, 2H),
1.72- 1.50 (m, 4H), 1.49-1.33 (m, 5H). 61 ##STR00278##
3-(3-Fluoro-4-piperidin-1-ylmethyl- phenyl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B.sup.4 6.13, 386, A
(DMSO-D.sub.6 plus TFA-D, 400 MHz): 9.22 (d, J = 2.3 Hz, 1H), 9.14
(d, J = 2.3 Hz, 1H), 9.09 (d, J = 1.0 Hz, 1H), 8.92 (d, J = 1.0 Hz,
1H), 7.82-7.91 (m, 2H), 7.78 (t, J = 7.8 Hz, 1H), 4.44 (s, 2H),
3.40-3.52 (m, 2H), 2.96-3.09 (m, 2H), 1.81-1.94 (m, 2H), 1.62-1.78
(m, 2H), 1.36-1.50 (m, 1H), 1.20-1.34 (m, 1H). 62 ##STR00279##
3-(4-Piperidin-1-ylmethyl-3- trifluoromethoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile G D B.sup.4 6.91,
452, A (DMSO-D.sub.6, 400 MHz): 12.96 (br s, 1H), 9.14 (d, J = 2.3
Hz, 1H), 9.06- 9.04 (m, 2H), 8.95 (d, J = 1.1 Hz, 1H), 7.86 (dd, J
= 8.0, 1.8 Hz, 1H), 7.76-7.74 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H),
3.55 (s, 2H), 2.43-2.35 (m, 4H), 1.57-1.48 (m, 4H), 1.46- 1.36 (m,
2H). 63 ##STR00280## 3-(3-Methoxy-5-piperidin-1-
ylmethyl-phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B.sup.4 6.37, 398, A (CDCl.sub.3 plus DMSO-D.sub.6, 400 MHz):
9.02 (s, 1H), 8.91-8.87 (m, 1H), 8.70-8.66 (m, 1H), 8.48 (s, 1H),
7.24 (s, 1H), 7.09 (s, 1H), 6.99 (s, 1H), 3.92 (s, 3H), 3.57 (s,
2H), 2.53-2.39 (s, 4H), 1.69-1.58 (m, 4H), 1.54- 1.42 (m, 2H). 64
##STR00281## 3-[4-(3-Hydroxy-piperidin-1-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B.sup.4 5.39, 384, A (DMSO-D.sub.6, 400 MHz): 12.91 (s, 1H),
9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J =
2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H),
7.46 (d, J = 8.0 Hz, 2H), 4.58 (d, J = 4.8 Hz, 1H), 3.58 (d, J =
13.3 Hz, 1H), 3.53-3.43 (m, 2H), 2.83 (dd, J = 10.4, 3.9 Hz, 1H),
2.72-2.65 (m, 1H), 1.94-1.86 (m, 1H), 1.85-1.78 (m, 1H), 1.77- 1.70
(m, 1H), 1.67-1.59 (m, 1H), 1.51-1.38 (m, 1H), 1.13-1.02 (m, 1H).
65 ##STR00282## 3-[4-(4-Fluoro-piperidin-1-ylmethyl)-
phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile G D
B.sup.4 5.95, 386, A (DMSO-D.sub.6, 400 MHz): 12.91 (s, 1H), 9.08
(d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 2.3 Hz,
1H), 8.94 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.47 (d, J
= 7.8 Hz, 2H), 4.81-4.60 (m, 1H), 3.55 (s, 2H), 2.62-2.49 (m, 2H),
2.39- 2.28 (m, 2H), 1.96-1.80 (m, 2H), 1.80-1.67 (s, 2H). 66
##STR00283## 3-(2-Ethyl-1,2,3,4-tetrahydro-
isoquinolin-7-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B.sup.4 5.53, 354, A (DMSO-D.sub.6, 400 MHz): 12.86 (s, 1H),
9.05 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 1.1 Hz, 1H), 8.98 (d, J =
2.3 Hz, 1H), 8.93 (d, J = 1.1 Hz, 1H), 7.56 (dd, J = 7.9, 1.9 Hz,
1H), 7.51 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 3.65 (s,
2H), 2.90-2.83 (m, 2H), 2.73-2.66 (m, 2H), 2.57- 2.51 (m, 2H), 1.13
(t, J = 7.2 Hz, 3H). 67 ##STR00284## 3-(2-Ethyl-1,2,3,4-tetrahydro-
isoquinolin-6-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B 5.68, 354, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.01 (d,
J = 1.0 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz,
1H), 8.48 (d, J = 1.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.22 (d, J = 7.8
Hz, 1H), 3.78 (s, 2H), 3.13-3.02 (m, 2H), 2.94-2.83 (m, 2H),
2.76-2.65 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H) 68 ##STR00285##
3-[4-(4-Trifluoromethyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B 6.58, 436, A (CDCl.sub.3
plus CD.sub.3OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.89 (d, J =
2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 1.0 Hz, 1H),
7.64 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 3.61 (s, 2H),
3.08-3.01 (m, 2H), 2.11-1.99 (m, 3H), 1.91-1.83 (m, 2H), 1.75-1.61
(m, 2H). 69 ##STR00286## 3-(4-[1,4]Oxazepan-4-ylmethyl-
phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile G D B
5.68, 384, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.02 (s, 1 H),
8.90 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H),
7.65 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.7 Hz, 2H), 3.87 (t, J =
6.1 Hz, 2H), 3.81-3.74 (m, 4H), 2.84- 2.69 (m, 4H), 2.02-1.90 (s,
2H). 70 ##STR00287## 3-[4-(2-Aza-bicyclo[2.2.1]hept-2-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B 6.11, 380, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.03-9.00
(m, 1H), 8.91-8.88 (m, 1H), 8.70-8.67 (m, 1H), 8.50-8.48 (m, 1H),
7.64 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 3.80-3.68 (m,
2H), 3.18 (s, 1H), 2.86-2.80 (m, 1H), 2.41 (s, 1H), 2.34 (d, J =
9.3 Hz, 1H), 1.93-1.83 (m, 1H), 1.79-1.72 (m, 1H), 1.68-1.56 (m,
1H), 1.53- 1.43 (m, 1H), 1.42-1.39 (m, 2H). 71 ##STR00288##
3-(4-Azepan-1-ylmethyl-phenyl)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile G D B 6.36, 382, A (CDCl.sub.3 plus
CD.sub.3OD, 400 MHz): 9.02-9.00 (m, 1H), 8.91-8.89 (m, 1H),
8.71-8.68 m, 1H), 8.50-8.48 (m, 1H), 7.66-7.62 (m, 2H), 7.53- 7.49
(m, 2H), 3.74 (s, 2H), 3.42-3.35 (m, 4H), 2.74-2.67 (m, 5H), 1.74-
1.62 (m, 3H). 72 ##STR00289## 3-[4-(8-Aza-bicyclo[3.2.1]oct-8-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B 6.31, 394, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.02 (d,
J = 1.0 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz,
1H), 8.49 (d, J = 1.0 Hz, 1H), 7.66-7.62 (m, 2H), 7.58-7.53 (m,
2H), 3.64- 3.59 (m, 2H), 3.26-3.21 (m, 2H), 2.14-1.99 (m, 2H),
1.86-1.75 (m, 2H), 1.71-1.64 (m, 2H), 1.63-1.46 (m, 2H), 1.44-1.36
(m, 2H). 73 ##STR00290## 3-[4-(4-Methoxy-piperidin-1-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B 5.89, 398, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.02 (d,
J = 1.0 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz,
1H), 8.50 (d, J = 1.0 Hz, 1H), 7.67-7.60 (m, 2H), 7.49 (d, J = 8.0
Hz, 2H), 3.60 (s, 2H), 3.36 (s, 3H), 3.33-3.24 (m, 2H), 2.30-2.21
(m, 2H), 1.99- 1.89 (m, 2H), 1.71-1.60 (m, 2H). 74 ##STR00291##
3-[4-(4-Hydroxy-4-methyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B 5.69, 398, A (CDCl.sub.3
plus CD.sub.3OD, 400 MHz): 9.02-9.01 (m, 1H), 8.90 (d, J = 2.2 Hz,
1H), 8.69 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H), 7.66-7.62
(m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 3.16 (s, 1H),
2.64-2.56 (m, 2H), 2.55-2.46 (m, 2H), 1.75- 1.60 (m, 4H), 1.26 (s,
3H). 75 ##STR00292## 1-[4-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-benzyl]- piperidine-4-carboxylic acid amide
G D B 5.58, 411, A (DMSO-D.sub.6, 400 MHz): 12.89 (s, 1H), 9.08 (d,
J = 2.2 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 2.3 Hz,
1H), 8.94 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.46 (d, J
= 7.9 Hz, 2H), 7.20 (s, 1H), 6.70 (s, 1H), 3.52 (s, 2H), 2.89-2.82
(m, 2H), 2.11-2.01 (m, 1H), 2.00-1.89 (m, 2H), 1.72-1.64 (m, 2H),
1.63-1.50 (m, 2H). 76 ##STR00293##
3-[4-(2-Oxa-7-aza-spiro[3.5]non-7- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile G D B 5.77, 410, A
(CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H),
8.90 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.49 (d, J =
1.0 Hz, 1H), 7.67-7.62 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.45 (s,
4H), 3.56 (s, 2H), 2.48-2.31 (m, 4H), 1.97-1.87 (m, 4H). 77
##STR00294## 3-[4-(4-Cyano-piperidin-1-ylmethyl)-
phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile G D B
5.86,
393, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.02 (d, J = 1.1 Hz,
1H), 8.89 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (d, J
= 1.1 Hz, 1H), 7.67-7.61 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.61
(s, 2H), 2.77-2.66 (m, 3H), 2.49-2.36 (s, 2H), 2.03-1.86 (m, 4H).
78 ##STR00295## 3-(3-Methyl-3H-imidazol-4-yl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile F D L, G 4.33, 275,
A (DMSO-D.sub.6, 300 MHz): 12.98 (br s, 1H), 9.06 (s, 1H), 8.96 (s,
1H), 8.92 (s, 1H), 8.83 (s, 1H), 7.81 (s, 1H), 7.20 (s, 1H), 3.76
(s, 3H). 79 ##STR00296## 3-Imidazol-1-yl-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile Buchwald A D L.sup.4 4.16, 261, A
(DMSO-D.sub.6, 300 MHz): 13.35 (s, 1H), 9.70 (s, 1H), 9.21 (d, J =
2.6 Hz, 1H), 9.15 (s, 1H), 9.12 (d, J = 2.6 Hz, 1H), 8.92 (s, 1H),
8.32 (s, 1H), 7.99 (s, 1H). 80 ##STR00297##
3-(1-Methyl-1H-pyrazol-3-yl)-9H- dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile F D L.sup.4 7.44, 275, A (DMSO-D.sub.6,
300 MHz): 12.88 (br s, 1H), 9.14 (s, 2H), 9.02 (s, 1H), 8.98 (s,
1H), 7.82 (s, 1H), 6.84 (s, 1H), 3.94 (s, 3H). 81 ##STR00298##
3-(2-Methyl-2H-[1,2,4]triazol-3-yl)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile F D L.sup.4 6.05, 276, A (DMSO-D.sub.6,
300 MHz): 13.16 (br s, 1H), 9.24-9.19 (m, 1H), 9.13-9.06 (m, 2H),
9.03 (s, 1H), 8.10 (s, 1H), 4.09 (s, 3H). 82 ##STR00299##
3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)- 9H-dip
do[2,3-b;4',3'-d]pyrrole-6- carbonitrile F D A.sup.4 9.72, 329, A
(DMSO-D.sub.6, 300 MHz): 12.86 (br s, 1H), 8.87-9.07 (m, 4H), 7.28
(d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.4, 2.3 Hz, 1H), 7.02 (d, J =
8.3 Hz, 1H), 4.27 (s, 4H). 83 ##STR00300##
3-(1H-Imidazol-2-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile A D L, B 4.32, 261, A
(DMSO-D.sub.6, 400 MHz): 12.93 (s, 1H), 12.74 (s, 1H), 9.26 (m,
2H), 9.05 (d, J = 1.1 Hz, 1H), 8.96 (d, J = 1.1 Hz, 1H), 7.34 (s,
1H), 7.12 (s, 1H). 84 ##STR00301## 3-(2-Ethyl-8-methoxy-1,2,3,4-
tetrahydro-isoquinolin-6-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile A D L, B 6.04, 384, A (CDCl.sub.3 plus CD.sub.3OD,
400 MHz): 9.01 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.65
(d, J = 2.2 Hz, 1H), 8.50 (d, J = 1.0 Hz, 1H), 7.03 (d, J = 1.3 Hz,
1H), 6.92 (d, J = 1.6 Hz, 1H), 3.94 (s, 3H), 3.67 (s, 2H), 3.03 (t,
J = 5.9 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 2.70 (q, J = 7.2 Hz,
2H), 1.26 (t, J = 7.2 Hz, 3H). 85 ##STR00302##
3-[4-((3S,5R)-3,5-Dimethyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile A D L, B 6.68, 396, A
(DMSO-D.sub.6 plus TFA-D, 400 MHz): 13.00 (s, 1H), 9.15 (d, J = 2.3
Hz, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.07 (d, J = 1.1 Hz, 1H), 8.94
(d, J = 1.1 Hz, 1H), 7.94 (d, J = 7. 9 Hz, 2H), 7.75 (d, J = 8.0
Hz, 2H), 4.39-4.32 (m, 2H), 3.34-3.26 (m, 2H), 2.05- 1.91 (m, 2H),
1.80-1.72 (m, 1H), 0.90 (s, 3H), 0.89 (s, 3H). 86 ##STR00303##
3-[4-(4-Morpholin-4-yl-piperidin-1-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
F D E.sup.5 4.7, 453, A (CDCl.sub.3, 400 MHz): 10.17 (s, 1H), 9.09
(s, 1H), 8.97-8.96 (m, 1H), 8.65 (dd, J = 2.2, 0.9 Hz, 1H), 8.45
(s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2 H), 3.73
(t, J = 4.4 Hz, 4H), 3.59 (s, 2H), 3.04-2.97 (m, 2H), 2.57 (t, J =
4.4 Hz, 4H), 2.28-2.18 (m, 1H), 2.09-1.99 (m, 2H), 1.88-1.80 (m,
2H), 1.67-1.53 (m, 2H). 87 ##STR00304##
3-[4-(4-Dimethylamino-piperidin-1-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
F D E.sup.3 4.6, 411, A (DMSO-D.sub.6, 400 MHz): 12.84 (br s, 1H),
9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J =
2.3 Hz, 1H), 8.95 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H),
7.46 (d, J = 8.0 Hz, 2H), 3.51 (s, 2H), 2.90-2.83 (m, 2H), 2.17 (s,
6H), 2.10-2.01 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.67 (m, 2H),
1.45-1.31 (m, 2H). 88 ##STR00305## 3-[4-(2,2-Dimethyl-morpholin-4-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G.sup.a D R, B.sup.3 5.95, 398, A (CDCl.sub.3 plus CD.sub.3OD, 300
MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.83 (d,
J = 2.2 Hz, 1H), 8.64 (d, J = 1.1 Hz, 1H), 7.69 (d, J = 8.0 Hz,
2H), 7.52 (d, J = 8.0 Hz, 2H), 3.83-3.78 (m, 2H), 3.57 (s, 2H),
2.53-2.45 (m, 2H), 2.28 (s, 2H), 1.29 (s, 6H). 89 ##STR00306##
3-[4-((2R,6S)-2,6-Dimethyl-morpholin-
4-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G.sup.a D B.sup.3 5.98, 398, A
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 9.02 (d, J = 1.0 Hz, 1H),
8.93 (d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.61 (d, J =
1.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H),
3.83-3.69 (m, 2H), 3.61 (s, 2H), 2.85-2.76 (m, 2H), 1.92-1.80 (m,
2H), 1.18 (d, J = 6.3 Hz, 6H). 90 ##STR00307##
3-(4-((2R,6S)-2,6-Dimethyl-morpholin-
4-ylmethyl)-3-ethoxy-phenyl]-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile G.sup.a D R, B 7.51, 442, F (CDCl.sub.3 plus
CD.sub.3OD, 300 MHz): 9.02 (d, J = 1. Hz, 1H), 8.92 (d, J = 2.2 Hz,
1H), 8.81 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 1.1 Hz, 1H), 7.47 (d, J
= 7.8 Hz, 1H), 7.28 (dd, J = 7.7, 1.7 Hz, 1H), 7.21 (d, J = 1.7 Hz,
1H), 4.22 (q, J = 7.0 Hz, 2H), 3.82-3.69 (m, 2H), 3.68 (s, 2H),
2.89-2.80 (m, 2H), 1.99-1.88 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H),
1.18 (d, J = 6.3 Hz, 6H). 91 ##STR00308##
3-(4,5,6,7-Tetrahydrobenzo[b] thiophen-2-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile F D A, H.sup.7 12.5, 331, A;
(DMSO-D.sub.6, 300 MHz): 12.90 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H),
8.95 (d, J = 2.3 Hz, 2H), 8.93 (d, 2.3 Hz, 1H), 7.29 (s, 1H),
2.81-2.74 (m, 2H), 2.66-2.60 (m, 2H), 1.88-1.73 (m, 4H). 92
##STR00309## 4-(6-Cyano-9H-dipyrido[2,3-b;4',3'-
d]pyrrol-3-yl)-benzoic acid F.sup.b D B.sup.9, H.sup.9 7.93, 315, A
(DMSO-D.sub.6, 300 MHz): 13.00 (s, 1H), 9.20 (d, J = 2.2 Hz, 1H),
9.10 (d, J = 2.2 Hz, 1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.11 (d, J =
8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H). 93 ##STR00310##
3-[4-(2-Oxa-6-aza-spiro[3.3]hept-6-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
F.sup.c D H.sup.3 5.57, 382, A (DMSO-D.sub.6, 400 MHz): 12.90 (s,
1H), 9.07 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.01 (d, J
= 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H),
7.41 (d, J = 8.0 Hz, 2H), 4.63 (s, 4H), 3.56 (s, 2H). 94
##STR00311## 3-[4-(2-Piperidin-1-yl-ethyl)-phenyl]-
9H-dipyrido[2,3-b;4',3'- d]pyrrole-6-carbonitrile G D B,.sup.3
6.23, 382, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.01 (d, J =
1.0 Hz, 1 H), 8.88 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1 H),
8.49 (d, J = 1.0 Hz, 1H), 7.62-7.57 (m, 2H), 7.41-7.36 (m, 2H),
2.95- 2.87 (m, 2H), 2.68-2.61 (m, 2H), 2.54 (s, 4H), 1.71-1.62 (m,
4H), 1.56-1.46 (m, 2H). 95 ##STR00312##
(Z)-3-{5-[4-(3-Hydroxy-3-methyl- piperidin-1-ylmethyl)-phenyl]-2-
methyl-1H-pyrrolo[2,3-b]pyridin-
3-yl}-2-methyleneamino-acrylonitrile G D E 5.48, 416 (M + 18), A
(DMSO-D.sub.6, 400 MHz): 9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1
Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1 H), 7.76
(d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.36 (s, 1H), 3.81
(s, 2H), 3.40-3.34 (m, 2H), 2.42 (s, 2H), 1.46-1.38 (m, 4H), 1.08
(s, 3H). 96 ##STR00313## 3-[4-(4-Methoxy-4-methyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B 6.27, 412 (M + 18), A
(CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.01 (d, J = 1.0 Hz, 1H),
8.89 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (d, J =
1.1 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.48 (m, 2H), 3.60 (s, 2H),
3.20 (s, 3H), 2.63-2.55 (m, 2H), 2.46-2.36 (m, 2H), 1.85-1.76 (m,
2H), 1.65-1.55 (m, 2H), 1.18 (s, 3H). 97 ##STR00314##
3-(4-Thiomorpholin-4-ylmethyl- phenyl-9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile G D B 5.98, 386, A (CDCl.sub.3 plus
CD.sub.3OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.89 (d, J = 2.2
Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 1.1 Hz, 1H),
7.66-7.61 (m, 2H), 7.51-7.46 (m, 2 H), 3.62 (s, 2H), 2.81-2.76 (m,
4H), 2.75-2.69 (m, 4H). 98 ##STR00315## 3-[4-(1,1-Dioxo-1lambda*6*-
thiomorpholin-4-ylmethyl)- phenyl]-9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile G D L, B.sup.3,1 7.43, 418, A
(DMSO-D.sub.6, 400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H),
9.05 (d, J = 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J =
1.1 Hz, 1H), 7.82-7.77 (m, 2H), 7.54-7.49 (m, 2H), 3.76 (s, 2H),
3.18-3.10 (m, 4H), 2.97-2.89 (m, 4H). 99 ##STR00316##
3-[4-(1-Oxo-thiomorpholin-4- ylmethyl)-phenyl]-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile G D B 5.34, 402, A
(DMSO-D.sub.6, 400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H),
9.05 (d, J = 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J =
1.1 Hz, 1H), 7.81-7.76 (m, 2H), 7.53-7.48 (m, 2H), 3.66 (s, 2H),
2.97-2.84 (m, 4H), 2.82-2.62 (m, 4H). 100 ##STR00317##
3-[4-(3-Oxo-piperazin-1-ylmethyl)- phenyl)-9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile G D B 5.50, 383, A (CDCl.sub.3 plus
CD.sub.3OD, 400 MHz): 9.02 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.72
(d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.51
(d, J = 7.9 Hz, 2H), 3.70 (s, 2H), 3.42-3.36 (m, 2H), 3.20 (s, 2H),
2.76-2.71 (m, 2H). 101 ##STR00318##
3-(4-Diethylaminomethyl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile G D B, B.sup.3 5.90,
356, A (CDCl.sub.3, 400 MHz): 10.27 (s, 1H), 9.09 (s, 1H), 8.98 (d,
J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.45 (s, 1H), 7.63 (d, J
= 7.9 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 3.68 (s, 2H), 2.66-2.54
(m, 4H), 1.11 (t, J = 7.1 Hz, 6H). 102 ##STR00319##
3-[4-((S)-3-Hydroxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B, B.sup.3 5.45, 384, A
(CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 9.02-9.00 (m, 1H), 8.90 (d,
J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 1.0 Hz,
1H), 7.64 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 3.85-3.73
(m, 1H), 3.62 (s, 2H), 2.84-2.72 (m, 1H), 2.64-2.52 (m, 1H),
2.37-2.18 (m, 2H), 1.89-1.74 (m, 2H), 1.67-1.52 (m, 1H), 1.48- 1.34
(m, 1H). 103 ##STR00320## 3-[4-((R)-3-Hydroxy-piperidin-1-
ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
G D B, B.sup.3 5.54, 384, A (CDCl.sub.3 plus CD.sub.3OD, 400 MHz):
9.02-9.00 (m, 1H), 8.90-8.87 (m, 1H), 8.70-8.66 (m, 1H), 8.50-8.48
(m, 1H), 7.66-7.61 (m, 2H), 7.50- 7.45 (m, 2H), 3.84-3.75 (m, 1H),
3.61 (s, 2H), 2.79-2.70 (m, 1H), 2.59-2.50 (m, 1H), 2.37-2.22 (s,
2H), 1.85-1.75 (m, 2H), 1.64-1.52 (m, 1H), 1.48-1.37 (m, 1H). 104
##STR00321## 3-[4-((3S,5S)-3,5-Dimethyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile G D B 7.17, 396, F (DMSO-D.sub.6,
400 MHz): 12.89 (s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1
Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.93 (d, J = 1.1 Hz, 1H), 7.77
(d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 3.54-3.40 (m, 2H),
2.44- 2.35 (m, 2H), 2.12-1.98 (m, 2H), 1.94-1.82 (m, 2H), 1.31-1.24
(m, 2H), 0.94 (d, J = 6.8 Hz, 6H). 105 ##STR00322##
3-(6-Piperidin-1-ylmethyl-pyridin-3- yl)-9H-dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile F B R.sup.3 5.51, 369, A (DMSO-D.sub.6, 400
MHz): 12.99 (s, 1H), 9.16 (dd, J = 5.4, 2.3 Hz, 1H), 9.09-9.07 (m,
2H), 8.95-8.93 (m, 2H), 8.21 (dd, J = 8.1, 2.5 Hz, 1H), 7.61 (d, J
= 8.1 Hz, 1H), 3.64 (s, 2H), 2.44 (s, 4H), 1.56 (p, J = 5.5 Hz,
4H), 1.47-1.41 (m, 2H). 106 ##STR00323##
3-(5-Piperidin-1-ylmethyl-pyridin-2-yl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile F B R.sup.6 5.46,
369, A (DMSO-D.sub.6, 400 MHz): 12.99 (s, 1H), 9.48 (d, J = 2.2 Hz,
1H), 9.43 (d, J = 2.2 Hz, 1H), 9.07 (d, J = 1.1 Hz, 1H), 9.04 (s,
1H), 8.65 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.89 (dd,
J = 8.2, 2.2 Hz, 1H), 3.55 (s, 2H), 2.36 (s, 4H), 1.58-1.50 (m,
4H), 1.43 (d, J = 7.0 Hz, 2H). 107 ##STR00324##
3-(3-Chloro-4-piperidin-1-ylmethyl-
phenyl)-9H-dipyrido[2,3-b;4',3'- d]pyrrole-6-carbonitrile G D
R.sup.3/7 6.38, 402, A (CD.sub.3OD, 400 MHz): 8.83 (d, J = 2.1 Hz,
1H), 8.70 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.92 (s,
1H), 4.71 (t, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.89 (t, J = 7.8 Hz,
2H), 2.66 (s, 4H), 2.33-2.23 (m, 2H), 1.88-1.83 (m, 4H). 108
##STR00325## 3-(6-Ethyl-4,5,6,7-tetrahydro-thieno
[2,3-c]pyridin-2-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile H D B 5.62, 360, A (DMSO-D.sub.6,
400 MHz): 12.90 (br s, 1H); 9.02 (d, J = 1.1 Hz, 1H); 8.96 (d, J =
2.3 Hz, 1H); 8.95 (d, J = 1.1 Hz, 1H); 8.93 (d, J = 2.3 Hz, 1H);
7.33 (s, 1H); 3.64 (s, 2H); 2.76-2.66 (m, 4H); 2.57 (q, J = 7.2 Hz,
2H); 1.11 (t, J = 7.15 Hz, 3H).
.sup.a1-1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
used as catalyst .sup.bAryl iodide used in coupling .sup.cTHF used
as solvent indicates data missing or illegible when filed
[0726] The compounds of the Examples in Table 5 were prepared from
commercially available amines using the general Mesylate
Displacement Methods described above.
TABLE-US-00005 TABLE 5 LCMS Depro- Puri- R.sub.T, Mesylate tec-
fica- M + Ex- displace- tion tion H.sup.+, am- ment Meth- Meth-
Meth- ple Structure/Name Method od od(s) od .sup.1H NMR (ppm) 109
##STR00326## 3-[4-((3S,5R)-3,5-Dimethyl-piperidin-
1-ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A NA B 6.10, 396, A
(CDCl.sub.3, 400 MHz): 9.00 (dd, J = 1.1, 0.5 Hz, 1H), 8.91 (d, J =
2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.51 (dd, J = 1.1, 0.5 Hz,
1H), 7.65 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 3.60 (s,
2H), 2.91-2.88 (m, 1H), 2.90-2.84 (m, 1H), 1.79-1.68 (m, 4H), 1.55
(t, J = 11 Hz, 2H), 0.86 (d, J = 6.4 Hz, 6H). 110 ##STR00327##
3-[4-(4,4-Dimethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A NA B 6.60, 396, A
(CDCl.sub.3, 400 MHz): 9.01 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.72
(d, J = 2.2 Hz, 1H), 8.52 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.51
(d, J = 8.0 Hz, 2H), 3.65 (s, 2H), 2.56-2.48 (m, 4H), 1.47 (t, J =
5.6 Hz, 4H), 0.96 (s, 6H). 111 ##STR00328##
3-[4-(3,3-Dimethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A NA L 6.34, 396, A
(CDCl.sub.3, 300 MHz): 10.69 (s, 1H), 9.12 (d, J = 1.1 Hz, 1H),
9.00 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.46 (d, J =
1.0 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H),
3.53 (s, 2H), 2.43-2.35 (m, 2H), 2.09-2.05 (m, 2H), 1.68-1.57 (m,
2H), 1.26 (t, J = 6.8 Hz, 2H), 0.97 (s, 6H). 112 ##STR00329##
3-[4-(2,2-Dimethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile B D B 2.31, 396, A
(CDCl.sub.3, 400 MHz): 10.07 (br. s, 1H), 9.09 (d, J = 1.0 Hz, 1H),
8.96 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.45 (d, J =
1.0 Hz, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H),
3.59 (s, 2H), 2.44-2.39 (m, 2H), 1.52 (m, 2H), 1.38-1.30 (m, 2H),
1.16 (s, 6H), 0.94 (t, J = 7.3 Hz, 2H). 113 ##STR00330##
3-[4-(4-Hydroxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A NA B 5.41, 384, A
(CDCl.sub.3, 400 MHz): 9.02 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.71
(d, J = 2.2 Hz, 1H), 8.52 (m, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.50
(d, J = 7.9 Hz, 2H), 3.72-3.63 (m, 1H), 3.63 (s, 2H), 2.90-2.83 (m,
2H), 2.30- 2.20 (m, 2H), 1.95-1.86 (m, 2H), 1.68-1.57 (m, 2H). 114
##STR00331## 3-[4-(3-Hydroxy-pyrrolidin-1-
ylmethyl)-phenyl]-9H-dipyrido [2,3-b;4',3'-d]pyrrole-6-carbonitrile
A NA B 5.41, 370, A (CDCl.sub.3, 400 MHz): 9.02 (s, 1H), 8.90 (d, J
= 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.52 (s, 1H), 7.67 (d, J =
8.0 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H), 4.44-4.38 (m, 1H), 3.81 (s,
2H), 3.74-3.54 (br. m, 1H), 2.94 (q, J = 8.0 Hz, 1H), 2.89- 2.81
(m, 1H), 2.77-2.69 (m, 1H), 2.66-2.55 (m, 1H), 2.25 (dt, J = 14.1,
7.0 Hz, 1H), 1.85-1.76 (m, 1H). 115 ##STR00332##
3-{4-[4-(2-Hydroxy-ethyl)-piperidin-
1-ylmethyl]-phenyl)-9H-dipyrido[2,
3-b;4',3'-d]pyrrole-6-carbonitrile A NA B.sup.6 5.62, 412, A
(CD.sub.3OD, 400 MHz): 9.01 (d, J = 1.0 Hz, 1H), 8.97 (d, J = 2.2
Hz, 1H), 8.95 (d, J = 2.2 Hz, 1H), 8.75 (d, J = 1.0 Hz, 1H), 7.82
(d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 4.53 (s, 1H), 3.99
(s, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.28-3.19 (m, 2H), 2.72 (s, 1H),
2.68-2.49 (m, 2H), 1.94-1.82 (m, 2H), 1.70-1.60 (m, 2H), 1.52 (q, J
= 6.5 Hz, 2H), 1.47-1.34 (m, 2H). 116 ##STR00333##
3-[4-(4,4-Difluoro-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile C D L 5.93, 404, A (DMSO-D.sub.6,
400 MHz): 12.91 (s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1
Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.78
(d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 2.58-
2.51 (m, 4H), 2.05-1.92 (m, 4H).
[0727] The compounds of the Examples in Table 6 were prepared from
alkynes using the general Sonagashira Method described above.
TABLE-US-00006 TABLE 6 Depro- Puri- LCMS Ex- Sonagashira tec- fica-
R.sub.T, am- coupling tion tion M + H.sup.+, ple Structure/Name
Method Method Method(s) Method .sup.1H NMR (ppm) 117 ##STR00334##
3-(3-Dimethylamino-prop-1-ynyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile A NA M 4.60, 276, A
(CDCl.sub.3, 400 MHz): 9.18 (d, J = 1.2 Hz, 1H), 8.74 (d, J = 2.3
Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 1 Hz, 1H), 5.98 (s,
1H), 3.56-3.60 (m, 2H), 0.94- 0.98 (m, 2H), 0.08 (s, 9H). 118
##STR00335## 3-Piperidin-4-ylethynyl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A A I 5.22, 302, A
(DMSO-D.sub.6, 400 MHz): 9.02 (d, J = 1.1 Hz, 1H), 8.87 (d, J = 1.0
Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H),
3.00-2.93 (m, 2H), 2.83-2.74 (m, 1H), 2.65-2.57 (m, 2H), 1.88- 1.82
(m, 2H), 1.61-1.50 (m, 2H). 119 ##STR00336##
3-Piperidin-3-ylethynyl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A A I 5.25, 302, A
(DMSO-D.sub.6, 400 MHz): 9.02 (d, J = 1.1 Hz, 1H), 8.88 (d, J = 1.1
Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 3.10
(d, J = 10.6 Hz, 1H), 2.84- 2.77 (m, 1H), 2.71-2.52 (m, 3H),
2.09-1.99 (m, 1H), 1.69-1.55 (m, 2H), 1.46-1.36 (m, 1H).
[0728] The compounds of the Examples in Table 7 were prepared from
commercially available phenols or aryl bromides using the general
Ullmann Methods described above.
TABLE-US-00007 TABLE 7 Puri- LCMS fica- R.sub.T, Ex- Ullmann Depro-
tion M + am- Coupling tection Meth- H.sup.+, ple Structure/Name
Method Method od(s) Method .sup.1H NMR (ppm) 120 ##STR00337##
3-(3,5-Dimethoxy-phenoxy)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile A D I 10.1, 347, A (DMSO-D.sub.6, 400 MHz): 13.09 (s,
1H), 9.03 (d, J = 1.1 Hz, 1H), 8.91 (d, J = 1.1 Hz, 1H), 8.58 (d, J
= 2.7 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 6.31 (t, J = 2.2 Hz, 1H),
6.20 (d, J = 2.2 Hz, 2H), 3.71 (s, 6H). 121 ##STR00338##
3-(3-Piperazin-1-yl-phenoxy)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile A A B 6.1, 371, A (DMSO-D.sub.6, 400 MHz): 8.98 (d, J
= 1.1 Hz, 1H), 8.88 (s, 1H), 8.84 (d, J = 1.1 Hz, 1H), 8.52 (d, J =
2.7 Hz, 1H), 8.46 (d, J = 2.7 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H),
6.73 (dd, J = 8.3, 2.3 Hz, 1H), 6.69 (t, J = 2.3 Hz, 1H), 6.43 (dd,
J = 8.1, 2.2 Hz, 1H), 3.33-3.28 (m, 4H), 3.18-3.12 (m, 4H). 122
##STR00339## 3-(4-Morpholin-4-ylmethyl-phenoxy)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile B A B 5.7, 386, A
(DMSO-D.sub.6, 300 MHz): 9.03 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 1.0
Hz, 1H), 8.59 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 2.7 Hz, 1H), 7.33
(d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 3.57 (t, J = 4.5 Hz,
4H), 3.44 (s, 2H), 2.35 (t, J = 4.2 Hz, 4H). 123 ##STR00340##
3-(4-Piperidin-1-ylmethyl-phenoxy)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile B D B 6.0, 384, A
(DMSO-D.sub.6, 300 MHz): 9.03 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 1.0
Hz, 1H), 8.59 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 2.7 Hz, 1H), 7.30
(d, J = 8.4 Hz, 2H), 7.02 (t, J = 8.4 Hz, 2H), 3.40 (s, 2H),
2.35-2.27 (m, 4H), 1.54-1.43 (m, 4H), 1.43-1.33 (d, J = 7.2 Hz,
2H).
[0729] The compounds of the Examples in Table 8 were prepared from
commercially available boronic acids.
TABLE-US-00008 TABLE 8 LCMS Ex- R.sub.T/ am- Coupling Purification
M + H.sup.+/ ple Structure/Name Method Method(s) Method .sup.1H NMR
(ppm) 124 ##STR00341## 3-(4-Fluoro-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A B, H 9.94, 289, A
(DMSO-D.sub.6, 300 MHz): 12.96 (s, 1H), 9.09-9.00 (m, 3H),
8.95-8.90 (m, 1H), 7.86 (dd, J = 8.7, 5.5 Hz, 2H), 7.46-7.33 (m,
2H). 125 ##STR00342## 3-[4-(4-Methyl-piperazin-1-yl)-
phenyl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile A B 5.66,
369, A (DMSO-D.sub.6, 300 MHz): 12.84 (s, 1H), 9.03-8.93 (m, 4H),
7.67 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 3.22 (m, 4H),
2.54- 2.46 (m, 4H), 2.24 (s, 3H). 126 ##STR00343##
3-(1-Methyl-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile A G.sup.4 6.90, 275, A (DMSO-D.sub.6, 300 MHz):
12.79 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.96 (d, J = 2.2 Hz, 1H),
8.92 (d, J = 2.2 Hz, 1H), 8.84 (d, J = 1.1 Hz, 1H), 8.24 (s, 1H),
7.97 (s, 1H), 3.92 (s, 3H). 127 ##STR00344##
3-[1-(2-Morpholin-4-yl-ethyl)-1H- pyrazo-4-yl]-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile D D 5.0, 374, A (DMSO-D.sub.6, 400
MHz): 12.98 (s, 1H), 9.04-9.02 (m, 1H), 8.98 (d, J = 2.2 Hz, 1H),
8.96-8.94 (m, 1H), 8.87 (d, J = 1.1 Hz, 1H), 8.32 (d, J = 0.8 Hz,
1H), 8.01 (d, J = 0.8 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.59 (t, J
= 4.5 Hz, 4H), 2.79 (t, J = 6.6 Hz, 2H), 2.46 (m, 4H). 128
##STR00345## 3-(1-Methyl-1H-imidazol-2-yl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile Stille A D 4.1, 275,
A (DMSO-D.sub.6, 400 MHz): 12.52 (br s, 1H), 9.04 (d, J = 1.1 Hz,
1H), 8.94 (d, J = 1.1 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.81 (d, J
= 2.2 Hz, 1H), 7.79-7.76 (m, 1H), 7.18 (d, J = 1.1 Hz, 1H), 3.75
(s, 3H). 129 ##STR00346## 3-(2-Methoxy-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.17, 301,
C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.01 (s, 1H), 8.92 (s,
1H), 8.82 (s, 1H), 8.74 (s, 1H), 7.41-7.37 (m, 2H), 7.16-7.14 (m,
1H), 7.09-7.07 (m, 1H), 3.77 (s, 3H) 130 ##STR00347##
3-Phenyl-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile C
Preparative HPLC 1.18, 271, C (DMSO-D.sub.6, 400 MHz): 12.89 (s,
1H), 9.06-9.01 (m, 3H), 8.99-8.91 (m, 1H), 7.79-7.77 (m, 2H),
7.54-7.50 (m, 2H), 7.38-7.42 (m, 1H) 131 ##STR00348##
3-(4-Methoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile C Preparative HPLC 1.42, 301, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.15-8.89 (m, 4H), 7.70
(br, 2H), 7.12 (br, 2H), 3.75 (s, 3H) 132 ##STR00349##
4-(6-Cyano-9H-dipyrido[2,3- b;4',3'-d]pyrrol-3-yl)-N,N-
diethyl-benzamide C Preparative HPLC 1.20, 370, C (DMSO-D.sub.6,
400 MHz): 12.96 (s, 1H), 9.11 (s, 1H), 9.10 (s, 2H), 8.91 (s, 1H),
7.85-7.83 (d, J = 8.0 Hz, 2H), 7.49-7.47 (d, J = 8.4 Hz, 2H),
3.30-3.10 (m, 4H), 1.20-1.08 (m, 6H) 133 ##STR00350##
3-m-Tolyl-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile C
Preparative HPLC 1.25, 285, C (DMSO-D.sub.6, 400 MHz): 12.90 (s,
1H), 9.04-8.97 (m, 3H), 8.92 (s, 1H), 7.06-7.56 (m, 2H), 7.42-7.38
(m, 1H), 7.23- 7.21 (m, 1H), 2.40 (s, 3H) 134 ##STR00351##
3-(4-tert-Butyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.40, 327, C (DMSO-D.sub.6, 400
MHz): 12.89 (s, 1H), 9.03-9.02 (m, 2H), 8.98 (s, 1H), 8.93 (s, 1H),
7.73-7.71 (d, J = 8.4 Hz, 2H), 7.55-7.53 (d, J = 8.4 Hz, 2H), 1.32
(s, 9H) 135 ##STR00352## 3-(4-Isopropoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C Preparative HPLC
1.28, 329, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.01-8.91 (m,
4H), 7.70-7.68 (d, J = 8.4 Hz, 2H), 7.07-7.05 (d, J = 8.8 Hz, 2H),
4.71- 4.65 (m, 1H), 1.29-1.28 (d, J = 6.0 Hz, 6H) 136 ##STR00353##
3-(3-Hydroxymethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.26, 301, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.28 (m, 4H), 7.75 (s, 1H), 7.68-7.66 (m, 1H),
7.51- 7.48 (m, 1H), 7.38-7.36 (m, 1H), 5.50 (br, 1H), 4.61 (s, 2H)
137 ##STR00354## 3-p-Tolyl-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.24, 285, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.04-8.93 (m, 4H),
7.70-7.68 (d, J = 8.0 Hz, 2H), 7.35-7.33 (d, J = 8.0 Hz, 2H), 2.36
(s, 3H) 138 ##STR00355## N-[3-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-phenyl]- acetamide C Preparative HPLC 1.27,
328, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 10.11 (s, 1H),
9.04-8.98 (m, 3H), 8.92 (s, 1H), 8.02 (s, 1H), 7.59-7.56 (m, 1H),
7.48- 7.43 (m, 2H), 2.07 (s, 3H) 139 ##STR00356##
3-(4-Methanesulfonyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.26, 349, C (DMSO-D.sub.6, 400
MHz): 13.01 (s, 1H), 9.21 (s, 1H), 9.11 (s, 1H), 9.06 (s, 1H), 8.95
(s, 1H), 8.12-8.04 (m, 4H), 3.28 (s, 3H) 140 ##STR00357##
3-(2-Hydroxy-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.05, 287,
C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.85 (s, 1H), 9.09 (s,
1H), 9.02 (s, 1H), 8.96 (s, 1H), 8.91 (s, 1H), 7.47-7.45 (m, 1H),
7.33-7.28 (m, 1H), 7.09-7.00 (m, 2H) 141 ##STR00358##
3-(2-Hydroxymethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.02, 301, C (DMSO-D.sub.6, 400
MHz): 13.02 (s, 1H), 9.13 (s, 1H), 9.00 (s, 1H), 8.87 (s, 1H), 8.79
(s, 1H), 7.66 (m, 1H), 7.69-7.44 (m, 3H), 5.32-5.29 (m, 1H), 4.53-
4.52 (d, J = 5.2 Hz, 2H) 142 ##STR00359##
3-(2-Trifluoromethoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.25, 355, C (DMSO-D.sub.6, 400
MHz): 13.05 (s, 1H), 9.05 (s, 1H), 8.94 (s, 1H), 8.91 (s, 1H), 8.78
(s, 1H), 7.70-7.67 (m, 1H), 7.63-7.53 (m, 3H) 143 ##STR00360##
3-(3-Methylsulfanyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.24, 317, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.11 (s, 1H), 9.03 (s, 2H), 8.94 (s, 1H), 7.65
(s, 1H), 7.58-7.56 (m, 1H), 7.45-7.49 (m, 1H), 7.32-7.30 (m, 1H),
2.57 (s, 3H) 144 ##STR00361## 3-Furan-2-yl-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.10, 261, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.06 (s, 1H), 9.00-8.99 (m,
2H), 8.92 (s, 1H), 7.83 (s, 1H), 7.06-7.05 (d, J = 3.2 Hz, 1H),
6.65-6.55 (m, 1H) 144 ##STR00362## 3-(4-Chloro-2-ethoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C Preparative HPLC
1.30, 349, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.04 (s, 1H),
8.93-8.90 (m, 2H), 8.83 (s, 1H), 7.50 (s, 1H), 7.42-7.39 (m, 1H),
7.18- 7.16 (d, J = 8.8 Hz, 1H), 4.10- 4.05 (m, 2H), 1.28-1.24 (m,
3H) 145 ##STR00363## 3-(4-Ethyl-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.56, 299,
C (DMSO-D.sub.6, 400 MHz): 12.89 (s, 1H), 9.04-9.02 (m, 2H), 8.98
(s, 1H), 8.92 (s, 1H), 7.72-7.70 (d, J = 8.0 Hz, 2H), 7.38-7.36 (d,
J = 8.4 Hz, 2H), 2.69-2.64 (m, 2H), 1.20-1.24 (m, 3H) 146
##STR00364## 3-(3,4-Difluoro-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.48, 307,
C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.11 (s, 1H), 9.04-9.03
(m, 2H), 8.89 (s, 1H), 7.97-7.91 (m, 1H), 7.70-7.58 (m, 2H) 147
##STR00365## 3-(2-Ethyl-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.27, 299,
C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.04 (s, 1H), 8.93 (s,
1H), 8.74 (s, 1H), 8.83 (s, 1H), 7.40-7.36 (m, 2H), 7.33-7.27 (m,
2H), 2.61-2.55 (m, 2H), 1.04-1.01 (m, 3H) 148 ##STR00366##
3-(2-Fluoro-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.29, 289,
C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.02 (s, 1H), 8.96-8.94
(m, 2H), 8.84 (s, 1H), 7.71-7.69 (m, 1H), 7.40-7.36 (m, 1H),
7.37-7.35 (m, 2H) 149 ##STR00367## 3-o-Tolyl-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.22, 285, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H),
8.78 (s, 1H), 8.67 (s, 1H), 7.37-7.33 (m, 4H), 2.29 (s, 3H) 150
##STR00368## 3-(4-Trifluoromethoxy-phenyl)-
9H-dipyrido[2,3-b;4',3'- d]pyrrole-6-carbonitrile C Preparative
HPLC 1.56, 355, C (DMSO-D.sub.6, 400 MHz): 13.01 (s, 1H), 9.11 (s,
1H), 9.05-9.02 (m, 2H), 8.92 (s, 1H), 7.94-7.92 (d, J = 8.4 Hz,
2H), 7.55-7.53 (d, J = 8.4 Hz, 2H) 151 ##STR00369##
3-(4-Trifluoromethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.54, 339, C (DMSO-D.sub.6, 400
MHz): 9.25 (s, 1H), 9.16-9.12 (m, 2H), 9.00 (s, 1H), 8.13-8.11 (d,
J = 8.4 Hz, 1H), 7.98-7.96 (d, J = 8.4 Hz, 1H) 152 ##STR00370##
3-(4-Ethoxy-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.23, 315,
C (DMSO-D.sub.6, 400 MHz): 12.89 (s, 1H), 9.02-9.00 (m, 2H), 8.96
(s, 1H), 8.92 (s, 1H), 7.73-7.71 (d, J = 8.8 Hz, 2H), 7.08-7.07 (d,
J = 8.8 Hz, 2H), 4.11-4.06 (m, 2H), 1.37-1.34 (m, 3H) 153
##STR00371## 3-(4-Methylsulfanyl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C Washing with THF
and methanol 1.24, 317, C (DMSO-D.sub.6, 400 MHz): 12.89 (s, 1H),
9.07 (s, 1H), 9.03 (s, 1H), 9.00 (s, 1H), 8.94 (s, 1H), 7.77-7.75
(d, J = 8.4 Hz, 2H), 7.43-7.41 (d, J = 8.4 Hz, 2H), 2.53 (s, 3H)
154 ##STR00372## 3-(3-Chloro-4-ethoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C Preparative HPLC
1.27, 323, C (DMSO-D.sub.6, 400 MHz): 12.73 (s, 1H), 8.89-8.82 (m,
3H), 8.72 (s, 1H), 7.71 (s, 1H), 7.58-7.55 (d, J = 8.4 Hz, 1H),
7.13-7.11 (d, J = 8.4 Hz, 1H), 4.04-3.99 (m, 2H), 1.25-1.14 (m, 3H)
155 ##STR00373## 3-(4-Fluoro-2-methoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C Preparative HPLC
1.48, 319, C (DMSO-D.sub.6, 400 MHz): 12.89 (s, 1H), 9.03 (s, 1H),
8.94 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 7.48-7.44 (m, 1H),
7.12-7.09 (m, 1H), 6.94-6.93 (m, 1H), 3.82 (s, 3H) 156 ##STR00374##
3-(3-Methoxy-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Preparative HPLC 1.44, 301,
C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.04 (s, 1H), 8.99-8.96
(m, 2H), 8.88 (s, 1H), 7.42-7.39 (m, 1H), 7.32-7.28 (m, 2H),
6.98-6.89 (m, 1H), 3.81 (s, 3H) 157 ##STR00375##
3-(4-Hydroxymethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.24, 301, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.15 (s, 1H), 9.11-9.08 (m, 2H), 9.02 (s, 1H),
7.86-7.84 (d, J = 8.4 Hz, 2H), 7.57-7.55 (d, J = 8.4 Hz, 2H),
5.35-5.20 (s, 1H), 4.65 (s, 2H) 158 ##STR00376##
3-(3-Chloro-4-fluoro-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.24, 317, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.11 (s, 1H), 9.03-9.02 (m, 2H), 8.88 (s, 1H),
8.06-8.03 (m, 1H), 7.84-7.81 (m, 1H), 7.61-7.56 (m, 1H) 159
##STR00377## N-[2-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-phenyl]- acetamide C Preparative HPLC 1.22,
328, C (DMSO-D.sub.6, 400 MHz): 13.01 (s, 1H), 9.46 (s, 1H), 9.12
(s, 1H), 9.05 (s, 1H), 8.85 (s, 1H), 8.71 (s, 1H), 7.70-7.65 (m,
1H), 7.53-7.45 (m, 2H), 7.42-7.39 (m, 1H), 1.93 (s, 3H) 160
##STR00378## 3-Thiophen-2-yl-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile C Washing with THF and methanol
1.46, 277, C (DMSO-D.sub.6, 400 MHz): 13.13 (s, 1H), 9.23-9.21 (m,
3H), 9.19-9.15 (m, 1H), 7.81-7.80 (m, 2H), 7.39-7.37 (m, 1H) 161
##STR00379## 3-(2-Chloro-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C Washing with THF
and methanol 1.33, 305, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H),
9.03 (s, 1H), 8.92 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 7.63-7.16
(m, 1H), 7.54-7.61 (m, 1H), 7.48-7.45 (m, 2H) 162 ##STR00380##
3-(3-Chloro-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Washing with THF and
methanol 1.28, 305, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.12
(s, 1H), 9.02-9.01 (m, 2H), 8.88 (s, 1H), 7.87 (s, 1H), 7.78-7.76
(m 1H), 7.56- 7.52 (m, 1H), 7.47-7.45 (m, 1H) 163 ##STR00381##
3-(3-Fluoro-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Washing with methanol 1.31,
289, C (DMSO-D.sub.6, 400 MHz): 13.09 (s, 1H), 9.02 (s, 1H),
8.95-8.94 (m, 2H), 8.84 (s, 1H), 7.82-7.81 (m, 2H), 7.69-7.60 (m,
1H), 7.42-7.39 (m, 1H) 164 ##STR00382##
3-(3-Trifluoromethoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C Preparative HPLC 1.57, 355, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.14 (s, 1H), 9.04-9.02 (m, 2H), 8.90 (s, 1H),
7.79 (s, 1H), 7.68-7.67 (m, 1H), 7.65- 7.63 (m, 1H), 7.73-7.41 (m,
1H) 165 ##STR00383## 3-(4-Chloro-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Washing with THF and
methanol
1.57, 305, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.07 (s, 1H),
9.01-8.99 (m, 2H), 8.90 (s, 1H), 7.82-7.80 (d, J = 8.4 Hz, 2H),
7.59-7.57 (d, J = 8.4 Hz, 2H) 166 ##STR00384##
3-(3-Aminophenyl)-9H-dipyrido [2,3-b;4',3'-d]pyrrole-6-carbonitrile
C Washing with methanol 0.83, 286, C (DMSO-D.sub.6, 400 MHz): 13.01
(s, 1H), 9.07-9.03 (m, 2H), 8.95-8.94 (m, 2H), 7.82-7.80 (m, 1H),
7.75 (s, 1H), 7.66-7.62 (s, 1H), 7.40-7.44 (m, 1H) 167 ##STR00385##
3-(4-Cyano-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Washing with methanol and
DMF 1.12, 296, C (DMSO-D.sub.6, 400 MHz): 13.18 (s, 1H), 9.34 (s,
1H), 9.24 (s, 1H), 9.19 (s, 1H), 9.06 (s, 1H), 8.20-8.15 (m, 4H)
168 ##STR00386## 3-(4-Hydroxy-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Washing with methanol 1.13,
287, C (DMSO-D.sub.6, 400 MHz): 12.80 (s, 1H), 8.99 (s, 1H), 8.94
(s, 1H), 8.89 (s, 2H), 7.60-7.57 (d, J = 8.4 Hz, 2H), 6.90-6.88 (d,
J = 8.8 Hz, 2H) 169 ##STR00387## 3-(3-Cyano-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile C Washing with methanol and
DMF none (DMSO-D.sub.6, 400 MHz): 13.10 (s, 1H), 9.32 (s, 1H),
9.26-9.22 (m, 2H), 9.03 (s, 1H), 8.47 (s, 1H), 8.33-8.31 (m, 1H),
8.06- 8.03 (m, 1H), 7.98-7.88 (m, 1H) 170 ##STR00388##
3-(3-Trifluoromethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile C Precipitate from DMF 1.39, 339, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.21 (s, 1H), 9.10 (s, 1H), 9.04 (s, 1H), 8.94
(s, 1H), 8.15 (s, 2H), 7.79 (s, 2H) 171 ##STR00389##
3-(2-Fluoro-5-hydroxymethyl- phenyl)-9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile C Preparative HPLC 1.30, 319, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.02 (s, 1H), 8.96 (s, 2H),
8.83 (s, 1H), 7.61-7.51 (m, 1H), 7.40-7.32 (m, 2H), 5.31- 5.28 (m,
1H), 4.55-4.54 (d, J = 5.6 Hz, 2H) 172 ##STR00390##
3-(2-Methylsulfanyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.34, 317, C (DMSO-D.sub.6,
400 MHz): 12.96 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 8.91 (s, 1H),
8.78 (s, 1H), 8.64 (s, 1H), 7.49-7.38 (m, 2H), 7.35-7.25 (m, 2H),
2.38 (s, 3H) 173 ##STR00391## 3-(3-Fluoro-4-methoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile D Washing with
methanol and DMF 1.50, 319, C (DMSO-D.sub.6, 400 MHz): 12.89 (s,
1H), 9.05 (s, 1H), 9.02-8.99 (m, 2H), 8.89 (s, 1H), 7.73-7.69 (m,
1H), 7.61-7.59 (d, J = 8.4 Hz, 1H), 7.35-7.30 (m, 1H), 3.90 (s, 3H)
174 ##STR00392## 3-(2,4-Difluoro-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile D Washing with
methanol then further purified by preparative HPLC 1.32, 307, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.02 (s, 1H), 8.93 (s, 2H),
8.81 (s, 1H), 7.74-7.68 (m, 1H), 7.47-7.41 (m, 1H), 7.28- 7.24 (m,
1H) 175 ##STR00393## 3-(4-Chloro-3-fluoro-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile D Washing with
methanol and DMF 1.41, 323/ 325, C (DMSO-D.sub.6, 400 MHz): 12.96
(s, 1H), 9.13 (s, 1H), 9.04-9.01 (m, 2H), 8.87 (s, 1H), 7.91-7.81
(m, 1H), 7.73-7.68 (m, 2H) 176 ##STR00394##
3-(3,4-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol and DMF 1.11. 331, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.02-8.97 (m, 3H), 8.88 (s,
1H), 7.36-7.32 (m, 1H), 7.30-7.27 (m, 1H), 7.08-7.06 (d, J = 8.4
Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H) 177 ##STR00395##
3-(3,5-Difluoro-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.35, 307, C (DMSO-D.sub.6,
400 MHz): 13.16 (s, 1H), 9.34 (s, 1H), 9.25 (s, 1H), 9.21 (s, 1H),
9.03 (s, 1H), 7.78-7.76 (d, J = 6.8 Hz, 2H), 7.47-7.42 (m, 1H) 178
##STR00396## 3-(2,5-Difluoro-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile D Washing with
methanol 1.20, 307, C (DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.03
(s, 1H), 9.03 (s, 1H), 8.99 (s, 1H), 8.86 (s, 1H), 7.60-7.56 (m,
1H), 7.47-7.41 (m, 1H), 7.33-7.31 (m, 1H) 179 ##STR00397##
3-(2,5-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.29, 331, C (DMSO-D.sub.6,
400 MHz): 12.87 (s, 1H), 9.02 (s, 1H), 8.93 (s, 1H), 8.86 (s, 1H),
8.79 (s, 1H), 7.11-7.09 (d, J = 9.2 Hz, 1H), 7.02-7.01 (m, 1H),
6.98-6.96 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H) 181 ##STR00398##
3-(2,3-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.28, 331, C (DMSO-D.sub.6,
400 MHz): 12.89 (s, 1H), 9.01 (s, 1H), 8.94 (s, 1H), 8.93 (s, 1H),
8.82 (s, 1H), 8.75 (s, 1H), 7.18-7.16 (m, 1H), 7.13-7.12 (m, 1H),
7.04-7.01 (m, 1H), 3.84 (s, 3H), 3.54 (s, 3H) 182 ##STR00399##
3-(2,3-Difluoro-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.32, 307, C (DMSO-D.sub.6,
400 MHz): 13.23 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 9.12 (s, 1H),
9.05 (s, 1H), 7.69-7.67 (m, 2H), 7.55-7.54 (m, 1H) 183 ##STR00400##
3-(2-Chloro-5-methoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol and DMF 1.24, 335, C
(DMSO-D.sub.6, 400 MHz): 13.19 (s, 1H), 9.20 (s, 1H), 9.10 (s, 1H),
9.03 (s, 1H), 8.90 (s, 1H), 7.70-7.68 (d, J = 8.8 Hz, 1H), 7.29 (s,
1H), 7.22-7.19 (m, 1H), 3.97 (s, 3H) 184 ##STR00401##
3-(3-Fluoro-5-methyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol and DMF 1.27, 303, C
(DMSO-D.sub.6, 400 MHz): 12.96 (s, 1H), 9.13 (s, 1H), 9.05 (s, 2H),
8.92 (s, 1H), 7.52 (s, 1H), 7.50-7.47 (d, J = 10.4 Hz, 1H),
7.11-7.09 (d, J = 9.6 Hz, 1H), 2.44 (s, 3H) 185 ##STR00402##
3-(3-Chloro-5-methoxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol and DMF 1.40, 335, C
(DMSO-D.sub.6, 400 MHz): 13.11 (s, 1H), 9.32 (s, 1H), 9.22-9.19 (m,
2H), 9.02 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.24 (s, 1H), 4.04
(s, 3H) 186 ##STR00403## N-[4-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-phenyl]- acetamide D Preparative HPLC 0.98,
328, C (DMSO-D.sub.6, 400 MHz): 12.92 (s, 1H), 10.10 (s, 1H), 9.02
(s, 2H), 8.98 (s, 1H), 8.92 (s, 1H), 7.74 (s, 4H), 2.07 (s, 3H) 187
##STR00404## N-[4-(6-Cyano-9H-dipyrido[2,3-
b;4',3'-d]pyrrol-3-yl)-phenyl]- methanesulfonamide D Washing with
THF and water then MeCN 1.15, 364, C (DMSO-D.sub.6, 400 MHz): 12.89
(s, 1H), 9.88 (s, 1H), 9.01-9.00 (m, 2H), 8.96 (s, 1H), 8.90 (s,
1H), 7.77-7.75 (d, J = 8.8 Hz, 2H), 7.36-7.33 (d, J = 8.4, 2H),
3.02 (s, 3H) 188 ##STR00405## 3-(3-Methanesulfonyl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile C Washing with
methanol 1.15, 349, C (DMSO-D.sub.6, 400 MHz): 13.01 (s, 1H), 9.23
(s, 1H), 9.13 (s, 1H), 9.06 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H),
8.20-8.19 (d, J = 7.6 Hz, 1H), 7.98-7.96 (d, J = 8.0 Hz, 1H),
7.85-7.81 (m, 1H), 3.33 (s, 3H) 189 ##STR00406##
4-(6-Cyano-9H-dipyrido[2,3-b;4',3'-
d]pyrrol-3-yl)-N,N-dimethyl-benzene sulfonamide C Preparative HPLC
1.11, 378, C (DMSO-D.sub.6, 400 MHz): 13.01 (s, 1H), 9.20 (s, 1H),
9.11 (s, 1H), 9.05 (s, 1H), 8.94 (s, 1H), 8.10-8.08 (d, J = 8.4 Hz,
2H), 7.91-7.89 (d, J = 8.4 Hz, 2H), 2.66 (s, 6H) 190 ##STR00407##
3-(6-Cyano-9H-dipyrido[2,3-b;4',3'-
d]pyrrol-3-yl)-N,N-dimethyl-benzene sulfonamide C Preparative HPLC
1.22, 378, C (DMSO-D.sub.6, 400 MHz): 13.01 (s, 1H), 9.19 (s, 1H),
9.09 (s, 1H), 9.04 (s, 1H), 8.99 (s, 1H), 8.19-8.17 (m, 1H), 8.09
(s, 1H), 7.80-7.84 (m, 2H), 2.68 (s, 6H) 191 ##STR00408##
3-(3-Fluoro-5-hydroxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.21, 305, C (DMSO-D.sub.6,
400 MHz): 12.92 (s, 1H), 9.04-9.00 (m, 1H), 9.12 (s, 1H), 8.94 (s,
1H), 8.90 (s, 1H), 7.06-7.00 (m, 2H), 6.62- 6.59 (m, 1H) 192
##STR00409## 3-(5-Fluoro-2-hydroxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile D Washing with
methanol 1.21, 305, C (DMSO-D.sub.6, 400 MHz): 12.86 (s, 1H), 9.74
(s, 1H), 9.00 (s, 1H), 8.94-8.92 (m, 2H), 8.85 (s, 1H), 7.27-7.23
(m, 1H), 7.07- 6.95 (m, 2H) 193 ##STR00410##
3-(3-Fluoro-pyridin-4-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Washing with methanol 1.06, 290, C (DMSO-D.sub.6,
400 MHz): 13.15 (s, 1H), 9.14 (s, 1H), 9.07 (s, 1H), 9.00-8.99 (m,
2H), 8.78 (s, 1H), 8.60 (s, 1H), 7.86-7.83 (m, 1H) 194 ##STR00411##
3-(4-Hydroxy-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile C Preparative HPLC 0.85, 305, C (DMSO-D.sub.6, 400
MHz): 13.15 (s, 1H), 9.61 (s, 1H), 9.05 (s, 1H), 8.97 (s, 1H),
8.87-8.86 (m, 2H), 8.09 (s, 1H), 7.65-7.63 (d, J = 8.8 Hz, 2H),
7.52 (s, 1H), 6.91-6.89 (d, J = 8.8 Hz, 2H) 195 ##STR00412##
3-(3-Isopropyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile D Preparative HPLC 0.98, 313, C (DMSO-D.sub.6, 400
MHz): 12.96 (s, 1H), 9.07 (s, 1H), 9.02-8.99 (m, 2H), 8.94 (s, 1H),
7.65 (s, 1H), 7.60-7.58 (d, J = 6.8 Hz, 1H), 7.46-7.42 (m, 1H),
7.30- 7.28 (d, J = 7.2 Hz, 1H), 3.00- 2.97 (m, 1H), 1.28-1.27 (d, J
= 6.8 Hz, 6H)
[0730] Preparative HPLC condition used in Table 8:
[0731] Autopurification system equipped with a YMC s-5.mu. RP
column (12 .mu.m, 250.times.20 mm; flowrate, 15 mL/min; solvent
A:0.1% TFA/water; solvent B: 0.1% TFA/CH.sub.3CN; gradient:30-60% B
over 13 min; UV detector fraction collection.
TABLE-US-00009 Time(min) Flowrate(mL/min) solvent A % solvent B % 0
15 30 70 12 15 60 40 12.2 18 100 0 15.2 18 100 0 17 15 30 70
[0732] The compounds of the Examples in Table 9 were prepared via
the general Mitsunobu methods followed by the general deprotection
methods described above.
TABLE-US-00010 TABLE 9 LCMS Ex- Depro- Final R.sub.T, am- Mitunobu
tection purification M + H.sup.+, ple Structure/Name Method Method
Method(s) Method .sup.1H NMR (ppm) 196 ##STR00413##
3-[2-(dimethylamino) ethoxy]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6
carbonitrile B F I 2.70, 282, E (400 MHz, DMSO-D.sub.6): 12.66 (s,
1H), 8.98 (s, 1H), 8.85 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.44 (d,
J = 2.8 Hz, 1H), 4.22 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 5.8 Hz,
2H), 2.26 (s, 6H). 197 ##STR00414## 3-[3-(dimethylamino)
propoxy]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6- carbonitrile B F I
2.79, 296, E (400 MHz, DMSO-D.sub.6): 12.65 (s, 1H), 8.98 (s, 1H),
8.87 (s, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H),
4.16 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.0 Hz, 2H), 2.17 (s, 6H),
1.94 (p, J = 6.8 Hz, 2H). 198 ##STR00415##
3-(piperidin-4-yloxy)-9H- dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 6.46, 294, D 400 MHz, DMSO-D.sub.6):
8.93 (d, J = 0.9 Hz, 1H), 8.77 (s, 1H), 8.43-8.35 (m, 2H),
4.47-4.35 (m, 1H), 4.03 (m, 1H), 2.99 (dt, J = 12.9, 4.1 Hz, 2H),
2.62-2.53 (m, 1H), 1.99 (m, 2H), 1.59-1.42 (m, 2H), 1.18 (m, 1H).
199 ##STR00416## 3-(2-(ethylamino)ethoxy)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 6.04, 282, D (400 MHz,
DMSO-D.sub.6): 8.99 (s, 1H), 8.87 (s, 1H), 8.48 (d, J = 2.8 Hz,
1H), 8.45-8.41 (m, 1H), 4.18 (t, J = 5.6 Hz, 2H), 2.97 (t, J = 5.6
Hz, 2H), 2.64 (q, J = 7.1 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H) 200
##STR00417## 3-(pyrrolidin-2-ylmethoxy)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 2.77, 294, E (500 MHz,
DMSO-D.sub.6): 8.99 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 0.9 Hz, 1H),
8.48 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.30 (s, 1H),
4.12-4.01 (m, 2H), 3.64-3.56 (m, 2H), 3.00-2.89 (m, 2H), 2.01-1.93
(m, 1H), 1.77 (m, 2H), 1.58 (m, 1H). 201 ##STR00418##
3-((S)-Pyrrolidin-3-yloxy)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 2.65, 280, E (400 MHz,
DMSO-D.sub.6): 8.99 (s, 1H), 8.90 (s, 1H), 8.43 (d, J = 2.8 Hz,
1H), 8.41 (d, J = 2.8 Hz, 1H), 5.00 (t, J = 5.6 Hz, 1H), 3.19 (dd,
J = 12.4, 5.2 Hz, 2H), 3.05-2.95 (m, 2H), 2.94-2.85 (m, 1H), 2.13
(m, 1H), 1.96-1.85 (m, 1H). 202 ##STR00419##
3-((1-methylpiperidin-4- yl)methoxy)-9H- dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 7.06, 322, D (400 MHz,
DMSO-D.sub.6): 12.65 (s, 1H), 8.98 (d, J = 0.9 Hz, 1H), 8.86 (d, J
= 0.9 Hz, 1H), 8.46 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 2.9 Hz, 1H),
4.10-3.93 (m, 2H), 2.84 (d, J = 10.1 Hz, 1H), 2.71-2.56 (m, 1H),
2.15 (s, 3H), 2.13-2.01 (m, 1H), 1.91 (m, 1H), 1.81-1.71 (m, 1H),
1.66 (m, 1H), 1.60-1.43 (m, 1H), 1.24 (s, 1H), 1.21- 1.06 (m, 1H).
203 ##STR00420## 3-(piperidin-3-yloxy)-9H- dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 6.48, 294, D (400 MHz,
DMSO-D.sub.6): 8.96 (d, J = 0.8 Hz, 1H), 8.83 (s, 1H), 8.43 (m,
2H), 4.29 (m, 1H), 3.16 (m, 1H), 2.84-2.75 (m, 1H), 2.64-2.51 (m,
2H), 2.11 (s, 1H), 1.76-1.67 (m, 1H), 1.51 (m, 2H). 204
##STR00421## 3-(2-methoxyethoxy)-9H- dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile B F I 9.04, 269, D (400 MHz,
DMSO-D.sub.6): 12.66 (s, 1H), 8.98 (d, J = 0.9 Hz, 1H), 8.84 (d, J
= 0.9 Hz, 1H), 8.48 (d, J = 2.9 Hz, 1H), 8.42 (d, J = 2.9 Hz, 1H),
4.29-4.23 (m, 2H), 3.75 (m, 2H), 3.35 (s, 3H). 205 ##STR00422##
3-ethoxy-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6- carbonitrile B F I
10.53, 239, D (400 MHz, DMSO-D.sub.6): 8.96 (d, J = 0.9 Hz, 1H),
8.82 (d, J = 0.9 Hz, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.37 (d, J =
2.9 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz,
3H).
Example 206
3-(2,3-Dihydroindol-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00423##
[0733] Step 1:
3-(2,3-Dihydro-indol-1-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrid-
o[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00424##
[0735] Indoline (67 mg, 0.56 mmol) was added to a solution of
3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile (210 mg, 0.52 mmol), tribasic potassium
phosphate (164 mg, 0.77 mmol) and
dicyclohexyl-(2',6'-diisopropoxy-biphenyl-2-yl)-phosphane (88 mg,
0.19 mmol) in anhydrous toluene (5.0 mL). The reaction mixture was
degassed with nitrogen for 10 minutes, heated at 110.degree. C. for
18 h and then allowed to cool to ambient temperature. The resultant
mixture was poured into water (40 mL) and extracted with DCM
(2.times.40 mL). The combined organic phase was separated, dried
over anhydrous sodium sulfate, filtered and evaporated in vacuo.
The resultant residue was purified by flash chromatography (silica,
12 g column, ISCO, 0-40% ethyl acetate in cyclohexane) and the
isolated solid triturated with diethylether/pentane and air dried
to afford the title compound as a yellow powder (124 mg, 54%). LCMS
(Method B): R.sub.T=4.83 min, M+H.sup.+=442.
Step 2:
3-(2,3-Dihydroindol-1-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
onitrile
##STR00425##
[0737]
3-(2,3-Dihydroindol-1-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-di-
pyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (124 mg) was subjected
to general deprotection Method A. The resultant residue was
purified by flash chromatography (silica, 40 g column, ISCO, 0-20%
MeOH in DCM), then HPLC (20-90% MeCN over 30 min, 15 mL/min) to
afford the title compound as an orange solid (10.5 mg). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.70 (s, 1H), 9.00 (d, J=1.1 Hz, 1H),
8.96 (d, J=1.1 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.70 (d, J=2.7 Hz,
1H), 7.22 (d, J=7.3 Hz, 1H), 7.11-7.01 (m, 2H), 6.76 (td, J=7.1,
1.4 Hz, 1H), 4.05 (t, J=8.4 Hz, 2H), 3.17 (t, J=8.4 Hz, 2H). LCMS
(Method A): R.sub.T=10.52 min, M+H.sup.+=311.
Example 207
3-[4-(8-Aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4',3'--
d]pyrrole-6-carbonitrile
##STR00426##
[0738] Step 1:
8-(4-Bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-one
##STR00427##
[0740] A stirred solution of 1-bromo-4-bromomethylbenzene (0.39 g,
1.56 mmol), triethylamine (0.45 mL, 3.20 mmol) and
8-azabicyclo[3.2.1]octan-3-one (0.33 mL, 2.32 mmol) in THF (10 mL)
was heated under reflux for 5 h. The reaction mixture was allowed
to cool to ambient temperature and the solid removed by filtration.
The filtrate was concentrated under reduced pressure to afford a
residue that was purified by flash chromatography (silica, 50 g
column, Biotage, 0-100% DCM in ethyl acetate) to afford the title
compound as an off-white solid (400 mg, 90%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.48-7.43 (m, 2H), 7.32-7.28 (m, 2H), 3.69
(s, 2H), 3.49-3.43 (m, 2H), 2.66 (dd, J=16.0, 4.3 Hz, 2H),
2.26-2.17 (m, 2H), 2.14-2.06 (m, 2H), 1.66-1.56 (s, 2H). LCMS
(Method B): R.sub.T=1.86 min, M+H.sup.+=294/296.
Step 2: 8-(4-Bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-ol
##STR00428##
[0742] Sodium borohydride (95 mg, 1.50 mmol) was added to a
solution of 8-(4-bromobenzyl)-8-azabicyclo-[3.2.1]octan-3-one (0.22
g, 0.75 mmol) in methanol (10 mL) and the reaction mixture was
stirred for 30 minutes. The reaction was diluted with water (10 mL)
and extracted into DCM (3.times.20 mL). The combined organic layer
was washed with saturated aqueous sodium bicarbonate solution (10
mL), dried over anhydrous sodium sulfate, filtered and evaporated
in vacuo to afford the title compound as an off-white solid (200
mg, 90%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.43 (dd, J=8.3, 2.0
Hz, 3H), 7.29-7.23 (m, 2H), 3.60-3.45 (m, 2H), 3.23-3.10 (m, 2H),
2.16-1.40 (m, 8H). LCMS (Method B): R.sub.T=1.90 min,
M+H.sup.+=296/298.
Step 3:
3-[4-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-t-
rimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonit-
rile
##STR00429##
[0744] A degassed mixture of
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyleth-
oxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (217
mg, 0.48 mmol), 8-(4-bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-ol
(157 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (33
mg, 5 mol %) and cesium carbonate (157 mg, 0.48 mmol) in a mixture
of DME (5 mL), IMS (2 mL) and water (1.3 mL) was heated under
microwave irradiation at 100.degree. C. for 30 minutes. The cooled
reaction mixture was purified by flash chromatography (silica, 50 g
column, Biotage, 0-5% (2N ammonia in MeOH) in DCM) to afford the
title compound as an off-white solid (155 mg, 60%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 9.21-9.17 (m, 1H), 8.95 (d, J=2.1 Hz, 1H),
8.61 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 7.67-7.53 (m, 4H), 6.04 (s,
2H), 3.70-3.58 (m, 4H), 3.35-3.15 (m, 2H), 2.20-1.60 (m, 10H), 0.95
(t, J=8.2 Hz, 2H), 0.00 (s, 9H). LCMS (Method B): R.sub.T=2.92 min,
M+H.sup.+=540.
Step 4: Imidazole-1-carbothioic acid
O-(8-{4-[6-cyano-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',-
3'-d]pyrrol-3-yl]-benzyl}-8-aza-bicyclo[3.2.1]oct-3-yl) ester
##STR00430##
[0746] A solution of
3-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethy-
lsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
(155 mg, 0.29 mmol), DMAP (5 mg, catalytic) and
N,N'-thiocarbonyldiimidazole (455 mg, 8.76 mmol) in DCM (10 mL) was
heated under reflux for 12 h. The cooled reaction mixture was
purified by flash chromatography (silica, 50 g column, Biotage,
0-5% MeOH in DCM) to afford the title compound as a white solid
(182 mg, 97%). NMR (CDCl.sub.3, 300 MHz): 9.28-9.25 (m, 1H), 9.04
(dd, J=7.0, 2.2 Hz, 1H), 8.69-8.66 (m, 1H), 8.51 (d, J=1.0 Hz, 1H),
8.47-8.39 (m, 1H), 7.81-7.61 (m, 5H), 7.15-7.10 (m, 1H), 6.12 (s,
2H), 4.35 (s, 2H), 3.76-3.61 (m, 4H), 2.32-2.17 (m, 4H), 2.13-1.93
(m, 5H), 1.08-0.96 (m, 2H), 0.00 (s, LCMS (Method B): R.sub.T=3.13
min, M+H.sup.+=650.
Step 5:
3-[[4-(8-Aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethyls-
ilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00431##
[0748] To a solution of imidazole-1-carbothioic acid
O-(8-{4-[6-cyano-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',-
3'-d]pyrrol-3-yl]-benzyl}-8-aza-bicyclo[3.2.1]oct-3-yl) ester (182
mg, 0.28 mmol) and AIBN (60 mg, 0.36 mmol) in toluene (10 mL) under
an argon atmosphere was added tributyltin hydride (0.58 mL, 1.85
mmol). On complete addition, the reaction was heated at 110.degree.
C. for 15 minutes then allowed to cool to ambient temperature. The
mixture was concentrated in vacuo and the resultant residue was
purified by flash chromatography (silica, 50 g column, Biotage,
0-5% MeOH in DCM) to afford the title compound as a white solid
(123 mg, 84%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 9.26 (d, J=1.0
Hz, 1H), 9.03 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.51 (d,
J=1.0 Hz, 1H), 7.72-7.60 (m, 4H), 6.12 (s, 2H), 3.74-3.65 (m, 4H),
3.37-3.22 (m, 2H), 2.16-1.40 (m, 10H), 1.06-0.97 (m, 2H), 0.00 (s,
9H). LCMS (Method B): R.sub.T=2.96 min, M+H.sup.+=524.
Step 6:
3-[4-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9H-dip-
yrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00432##
[0750] A solution of
3-[4-(8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanyl-e-
thoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (120
mg, 0.23 mmol) in TBAF (1N in THF, 3 mL) and the reaction mixture
was heated at 55.degree. C. for 16 h. The mixture was then
concentrated in vacuo and the resultant residue purified by flash
column chromatography (silica, 50 g column, Biotage, 0-20% MeOH in
DCM) to afford the title compound as an off-white solid (85 mg,
94%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 9.01 (d, J=1.0 Hz, 1H),
8.90 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.49 (d, J=1.0 Hz,
1H), 7.64 (d, J=8.0 Hz, 2H), 7.58-7.51 (m, 2H), 3.64-3.57 (m, 2H),
3.39-3.37 (m, 2H), 2.11-2.04 (m, 2H), 1.90-1.72 (m, 2H), 1.68-1.33
(m, 6H). LCMS (Method A): R.sub.T=6.31 min, M+H.sup.+=394.
Example 208
6-Cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e-N-oxide
##STR00433##
[0752] A mixture of
6-cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (110 mg, 0.30 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine
(102 mg, 0.39 mmol) in DCM (5.8 mL) was stirred at room temperature
for 2 h. The solid was collected by filtration and washed with DCM
(3.times.20 mL) to afford a bright yellow solid (100 mg, 90%).
.sup.1H NMR (400 MHz, DMSO-D.sub.6): 8.98 (s, 1H), 8.91 (s, 1H),
8.90 (s, 1H), 8.83 (s, 1H), 7.66 (m, 4H), 4.43 (s, 2H), 3.13 (m,
2H), 2.14 (m, 2H), 1.59 (m, 4H), 1.34 (m, 2H). LCMS (method D):
R.sub.T=8.82 min, M+H.sup.+=384.
Example 209
3-[4-(1-Ethyl-piperidin-2-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6--
carbonitrile
##STR00434##
[0753] Step 1: 2-(4-Bromophenyl)pyridine
##STR00435##
[0755] 1,4-Dibromobenzene (5.90 g, 25.0 mmol) was dissolved in
anhydrous diethyl ether (40 mL) and flushed with argon before the
solution was cooled to -78.degree. C. and n-butyl lithium (2.5M in
hexanes, 10.2 mL, 25.6 mmol) was added dropwise at a rate that
maintained the temperature below -70.degree. C. The reaction
mixture was stirred at this temperature for 30 minutes then
2-fluoropyridine (1.72 mL, 20.0 mmol) was added dropwise and
stirring continued at -78.degree. C. for 1 h then the reaction
mixture was allowed to warm to room temperature and stirred for 1
h. The reaction mixture was poured onto water (50 mL) and extracted
with diethyl ether (3.times.50 mL). The combined organic layers
were washed with 5% HCl (3.times.200 mL) then the pH of the aqueous
phase was adjusted to 10 by the addition of potassium hydroxide and
the aqueous phase was extracted with diethyl ether (3.times.200
mL). The combined organic phase was dried over sodium sulfate,
filtered and evaporated to afford the title compound (2.7 g, 58%).
NMR (CDCl.sub.3, 300 MHz): 8.71-8.66 (m, 1H), 7.91-7.85 (m, 2H),
7.79-7.67 (m, 2H), 7.64-7.57 (m, 2H), 7.28-7.22 (m, 1H).
Step 2: 2-(4-Bromophenyl)-1-ethyl-1,2,3,6-tetrahydropyridine
##STR00436##
[0757] To a solution of 2-(4-bromophenyl)pyridine (2.7 g, 11.5
mmol) in DMF (50 mL) was added ethyl iodide (1.9 mL, 23.1 mmol) and
the reaction mixture was heated to 80.degree. C. for 16 h. The
mixture was cooled then evaporated and the resultant residue
dissolved in methanol (100 mL) before addition of sodium
borohydride (1.5 g, 39.2 mmol) portionwise. The reaction mixture
was stirred at ambient temperature for 1 h then evaporated and
saturated aqueous sodium carbonate solution was added. The mixture
was extracted with ethyl acetate (2.times.100 mL). The combined
organic layer was dried over sodium sulfate, filtered and
evaporated then the residue was purified by flash chromatography
(silica, Biotage 100 g column, 50% ethyl acetate in cyclohexane) to
afford the title compound (0.9 g, 29%), which was used without
further purification. .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.47-7.42
(m, 2H), 7.24-7.19 (m, 2H), 5.86-5.74 (m, 2H), 3.47-3.35 (m, 2H),
2.98-2.87 (m, 1H), 2.64-2.46 (m, 1H), 2.33-2.26 (m, 2H), 2.13-2.00
(m, 1H), 0.99 (t, J=7.2 Hz, 3H).
Step 3:
3-[4-(1-Ethylpiperidin-2-yl)-phenyl]-9-(2-trimethylsilanylethoxyme-
thyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00437##
[0759] A degassed mixture of
2-(4-bromophenyl)-1-ethyl-1,2,3,6-tetrahydropyridine (0.13 g, 0.49
mmol),
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethyl
silanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
(0.20 g, 0.44 mmol), cesium carbonate (0.15 g) and
tetrakis(triphenylphosphine)palladium(0) (30 mg) in DME (5 mL), IMS
(2 mL) and water (1.3 mL) was heated under microwave irradiation at
140.degree. C. for 30 minutes. The reaction mixture was allowed to
cool to ambient temperature then purified by flash chromatography
(silica, Biotage 50 g column, 0-100% (5% methanol in DCM)) to
afford a colurless residue (95 mg). The resultant residue was
dissolved in IMS (10 mL) and the flask degassed with nitrogen.
Palladium on carbon (10% by wt., 11 mg) was added and the reaction
mixture placed under an atmosphere of hydrogen and stirred for 16
h. The solid was removed by filtration and the filtrate evaporated
to afford the title compound (85 mg) which was used without further
purification. .sup.1H NMR (CHCl.sub.3, 400 MHz,): 9.18 (d, J=1.0
Hz, 1H), 8.95 (d, J=2.2 Hz, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.42 (d,
J=1.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.53 (m, 2H), 6.04 (s, 2H),
3.67-3.59 (m, 2H), 3.40-3.20 (m, 2H), 2.79-2.67 (m, 1H), 2.37-2.16
(m, 2H), 1.93-1.73 (m, 4H), 1.46-1.35 (m, 2H), 1.34-1.20 (m, 2H),
1.05-0.78 (m, 3H), -0.07 (s, 9H).
Step 4:
3-[4-(1-Ethylpiperidin-2-yl)-phenyl]-9H-dipyrido[2,3-b:4',3'-d]pyr-
role-6-carbonitrile
##STR00438##
[0761] A solution of
3-[4-(1-ethyl-piperidin-2-yl)-phenyl]-9-(2-trimethylsilanylethoxy
methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (75 mg,
0.147 mmol) in TBAF (1M in THF, 1.5 mL, 1.47 mmol) was heated at
55.degree. C. for 16 h. The reaction mixture was concentrated in
vacuo and the resultant residue was partitioned between water and
ethyl acetate. The organic layer was separated, dried over sodium
sulfate, filtered and evaporated to give a yellow solid. The
resultanat solid was purified by flash chromatography (silica,
Biotage 50 g column, 0-100% (10% methanol in DCM)) to afford the
title compound (11 mg, 20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
12.89 (s, 1H), 9.08 (d, J=2.3 Hz, 1H), 9.04 (d, J=1.1 Hz, 1H), 9.02
(d, J=2.3 Hz, 1H), 8.93 (d, J=1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H),
7.49 (d, J=8.0 Hz, 2H), 3.16-3.07 (m, 2H), 2.54-2.42 (m, 1H),
2.11-1.93 (m, 2H), 1.79-1.64 (m, 3H), 1.63-1.20 (m, 3H), 0.89 (t,
J=7.1 Hz, 3H). LCMS (Method A): R.sub.T=6.23 min; M+H.sup.+=382
Example 210
3-(Oxazol-2-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00439##
[0763] A solution of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (101 mg,
0.369 mmol) and lithium chloride (46.9 mg, 1.11 mmol) in DMF (0.63
mL) was treated with DIPEA (161 .mu.L, 0.922 mmol) and
2-(tri-n-butylstannyl)oxazole (232 .mu.L, 1.11 mmol), and then
degassed by the bubbling of nitrogen for 5 minutes.
Tetrakis(triphenylphosphine)palladium(0) (21.3 mg, 18.4 .mu.mol,
5.0 mol %) was added and the mixture heated at 165.degree. C. for
15 hours. The mixture was allowed to cool and treated with
saturated aqueous potassium fluoride solution at ambient
temperature. The resulting solids were removed by filtration and
washed with 20% methanol in DCM and water. The filtrate was
filtered through a pad of celite, washing with 20% methanol in DCM.
The layers were separated, the aqueous phase extracted into 20%
methanol in DCM, and the combined organic phases concentrated in
vacuo. The residue was dissolved in AcOH with sonication and
heating, filtered hot, and allowed to cool. The resulting
suspension was treated with water and then filtered to collect the
tan-gray solid, which was redissolved in DMF and purified by
preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium
hydroxide] to afford a tan solid (43.5 mg, 45%). .sup.1H NMR (400
MHz, DMSO-D.sub.6): 9.29 (d, J=2.2 Hz, 1H), 9.26 (d, J=2.2 Hz, 1H),
9.03 (m, 1H), 8.97 (m, 1H), 8.28 (m, 1H), 7.43 (m, 1H). LCMS
(Method D): R.sub.T=8.29 min, M+H.sup.+=262.
Example 211
3-(Thiazol-2-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00440##
[0765] A solution of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (100 mg,
0.366 mmol) and lithium chloride (46.6 mg, 1.10 mmol) in DMF (0.63
mL) was treated with DIPEA (159 uL, 0.915 mmol) and
2-(tri-n-butylstannyl)thiazole (345 uL, 1.10 mmol), and then
degassed by the bubbling of nitrogen for 5 minutes.
Tetrakis(triphenylphosphine)palladium(0) (21.2 mg, 18.3 umol, 5.0
mol %) was added and the mixture heated at 165.degree. C. for 15
hours. The mixture was allowed to cool and treated with saturated
aqueous potassium fluoride solution at ambient temperature. The
resulting solids were removed by filtration and washed with 20%
methanol in DCM and water. The filtrate was filtered through a pad
of celite, washing with 20% methanol in DCM. The layers were
separated, the aqueous phase extracted into 20% methanol in DCM,
and the combined organic phases concentrated in vacuo. The residue
was dissolved in AcOH with sonication and heating, filtered hot and
allowed to cool. The resulting suspension was treated with water
and then filtered to collect the off-white solid. This solid was
purified by preparative HPLC [0-30% MeCN/water modified with 0.1%
formic acid] to afford an off-white solid powder (5.0 mg, 18%).
.sup.1H NMR (400 MHz, DMSO-D.sub.6): 9.26 (s, 1H), 9.24 (s, 1H),
9.01 (s, 1H), 8.94 (s, 1H), 7.96 (d, J=3.2 Hz, 1H), 7.80 (d, J=3.2
Hz, 1H). LCMS (Method D): R.sub.T=9.31 min, M+H.sup.+=278.
Example 212
3-Ethylamino-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00441##
[0766] Step 1:
3-(tert-Butylcarbonyl)ethylamino-9-(2-trimethylsilanylethoxymethyl)-dipyr-
ido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00442##
[0768] To a solution of
3-tert-butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,-
3-b;4',3'-d]pyrrole-6-carbonitrile (108 mg, 0.25 mmol) in THF (2.0
mL) was added sodium hydride (14.2 mg, 0.59 mmol). After the
bubbling had ceased, iodoethane (47.3 .mu.L, 0.592 mmol) was added
and the reaction mixture heated at 55.degree. C. overnight. The
cooled reaction mixture was diluted with water and EtOAc, the
layers separated, and the aqueous phase extracted into EtOAc. The
combined organic phase was dried over sodium sulfate, filtered, and
concentrated in vacuo. The resultant residue was dissolved in EtOAc
and absorbed onto silica gel for purification by flash
chromatography (silica, 12 g column, Biotage, 1-50% EtOAc in
heptane) to afford the title compound as a viscous yellow oil (96
mg, 83%).
Step 2:
3-ethylamino-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00443##
[0770] A solution of
3-(tert-butylcarbonyl)ethylamino-9-(2-trimethylsilanyl-ethoxymethyl)-dipy-
rido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (161 mg, 0.345 mmol) in
1,4-dioxane (500 .mu.L) was treated with 48% aqueous hydrobromic
acid (500 .mu.L) and heated at 75.degree. C. for 10 min. The cooled
reaction mixture was basified to pH 12 with 6N aqueous sodium
hydroxide solution and then adjusted to pH 7-9 with dropwise
addition of 1N hydrochloric acid. The solid was collected via
centrifugation, the aqueous supernate discarded, and the solid
dissolved in 1-2 mL of DMSO and purified by preparative HPLC (5-85%
MeCN in water (0.1% NH.sub.4OH) over 30 min, 35 mL/min) to afford
the title compound as a yellow solid (22 mg, 26%). .sup.1H NMR
(DMSO-D.sub.6, 500 MHz): 8.89 (d, J=1.0 Hz, 1H), 8.78 (d, J=0.9 Hz,
1H), 8.22 (d, J=2.7 Hz, 1H), 7.78 (d, J=2.7 Hz, 1H), 5.76 (t, J=5.5
Hz, 1H), 3.20-3.07 (m, 2H), 1.25 (t, J=7.1 Hz, 3H). LCMS (Method
E): R.sub.T=2.69 min, M+H.sup.+=238.1.
Example 213
3(1-Pyrrolidinylcarbonylamino)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboni-
trile
##STR00444##
[0771] Step 1:
3-Amino-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00445##
[0773] A solution of
3-tert-butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,-
3-b;4',3'-d]pyrrole-6-carbonitrile (101 mg, 0.229 mmol) in
1,4-dioxane (1.0 mL) was treated with a solution of 4M HCl in
1,4-dioxane (6 mL). After 1 h, an additional portion of 4.0M HCl in
1,4-dioxane (1.5 mL) was added to the reaction mixture. After 4.5 h
at ambient temperature, the solvent was evaporated to afford an
orange solid (70 mg, quantitative yield). The solid was used
without purification.
Step 2:
3-(1-Pyrrolidinylcarbonylamino)-9H-dipyrido[2,3-b;4',3'-d]pyrrole--
6-carbonitrile
##STR00446##
[0775] A solution of
3-amino-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (47.9 mg,
0.229 mmol) in pyridine (6.1 mL) was treated with
pyrrolidine-1-carbonyl chloride (83.4 .mu.L, 0.755 mmol) and heated
at 60.degree. C. for 4 h. The cooled reaction mixture was treated
with saturated aqueous sodium bicarbonate solution then diluted
with 20% MeOH in DCM and water. The layers were separated, the
aqueous phase extracted with 20% MeOH in DCM, and the combined
organic phase was dried over sodium sulfate and concentrated in
vacuo. The resultant residue was dissolved in DCM/methanol,
absorbed onto silica gel, and purified by flash chromatography
(silica, 4 g column, Biotage, 1-20% methanol in DCM containing 0.1%
7N ammonia in MeOH). Collecting appropriate fractions afforded a
yellow solid which was further purified by preparative HPLC (5-85%
MeCN in water (0.1% NH.sub.4OH) over 30 min, 35 mL/min) to afford
the title compound as an off-white solid (8.0 mg, 11%). .sup.1H NMR
(400 MHz, DMSO-D.sub.6): 12.92 (s, 1H), 8.78 (s, 1H), 8.70 (dd,
J=4.7, 1.4 Hz, 1H), 8.60 (dd, J=7.9, 1.4 Hz, 1H), 7.47 (dd, J=7.9,
4.8 Hz, 1H), 4.71 (dd, J=8.7, 4.6 Hz, 1H), 2.85 (m, 2H), 2.07 (m,
4H), 1.92 (m, 2H). LCMS (Method E): R.sub.T=3.36 min,
M+H.sup.+=307.
Example 214
3-Chloro-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00447##
[0777] A solution of
3-chloro-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrrol-
e-6-carbonitrile (24.2 mg, 67.4 .mu.mol) in THF (1.3 mL) was
treated with TBAF (398 .mu.L, 1.35 mmol) and heated to 60.degree.
C. for 2 h. The reaction mixture was cooled to ambient temperature
and the solvent removed in vacuo. The resultant residue was
dissolved in DCM/EtOAc, absorbed onto silica gel, and purified by
flash chromatography (silica, 4 g column, Biotage, 1-20% methanol
in DCM containing 0 1% 7N ammonia in MeOH). Collecting appropriate
fractions afforded a solid which was further purified by
preparative HPLC (5-85% MeCN in water (0.1% NH.sub.4OH) over 30
min, 35 mL/min) to afford the title compound as an off-white solid
(10 mg, 66%). NMR (400 MHz, DMSO-D.sub.6): 13.07 (s, 1H), 9.05 (d,
J=0.9 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.92 (d, J=0.9 Hz, 1H), 8.73
(d, J=2.4 Hz, 1H). LCMS (Method E): R.sub.T=3.98 min,
M+H.sup.+=229.
Example 215
3-(3-Hydroxy-3-methylbut-1-ynyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbo-
nitrile
##STR00448##
[0778] Step 1:
3-(3-Hydroxy-3-methylbut-1-ynyl)-9-(2-trimethylsilanylethoxymethyl)-dipyr-
ido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00449##
[0780] In a flame dried flask, a mixture of
3-bromo-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrrole-
-6-carbonitrile (203 mg, 0.503 mmol) and copper (I) iodide (9.58
mg, 50.3 .mu.mol) in 1,4-dioxane (5.3 mL) was degassed and flushed
with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (58.1 mg,
50.3 .mu.mol) and 2-methyl-3-butyn-2-ol (244 .mu.L, 2.52 mmol) were
added and the reaction mixture was degassed, purged with nitrogen,
and heated at 105.degree. C. for 70 min. The cooled reaction
mixture was diluted with DCM and water, the layers separated, and
the aqueous phase extracted into DCM. The combined organic phase
was dried over sodium sulfate and concentrated in vacuo. The
resultant residue was dissolved in EtOAc and absorbed onto silica
gel for purification by flash chromatography (silica, 25 g column,
Biotage, 1-100% EtOAc in heptane) to afford further title compound
as a white-yellow solid (254 mg, 124%). The solid was used without
further purification. .sup.1H NMR (DMSO-D.sub.6, 400 MHz,): 9.33
(s, 1H), 8.98 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.76 (d, J=1.9 Hz,
1H), 6.03 (s, 2H), 5.55 (s, 1H), 3.57 (t, J=7.9 Hz, 2H), 1.51 (s,
6H), 0.82 (t, J=8.0 Hz, 2H), -0.16 (s, 9H).
Step 2:
3-(3-Hydroxy-3-methylbut-1-ynyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-
-6-carbonitrile
##STR00450##
[0782] A solution of
3-(3-hydroxy-3-methylbut-1-ynyl)-9-(2-trimethylsilanyl-ethoxymethyl)dipyr-
ido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (254 mg, 0.624 mmol) in
THF (12 mL) was treated with TBAF (3.7 mL, 12.5 mmol) and heated to
60.degree. C. for 24 h. The reaction mixture was allowed to cool to
ambient temperature and the solvent removed in vacuo. The resultant
residue was dissolved in DCM, absorbed onto silica gel, and
purified by flash chromatography (Biotage, 25 g, 1-100% EtOAc in
hepatne). The light orange solid was further purified by
preparative HPLC (5-85% MeCN in water (0.1% NH.sub.4OH) over 30
min, 35 mL/min) to afford the title compound as an off-white solid
(21 mg, 12%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz,): 12.99 (s, 1H),
9.04 (s, 1H), 8.93 (s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0
Hz, 1H), 5.53 (s, 1H), 1.55 (s, 6H). LCMS (Method D): R.sub.T=9.66
min, M+H.sup.+=277.
Example 216
3-Hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00451##
[0784] A solution of
3-hydroxy-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',31-d]pyrro-
le-6-carbonitrile (90.9 mg, 0.267 mmol) in 1,4-dioxane (500 .mu.L)
was treated with 48% aqueous hydrobromic acid (500 .mu.L) and
heated at 75.degree. C. for 10 min. The cooled reaction mixture was
basified to pH 12 with 6N aqueous sodium hydroxide solution and
then adjusted to pH 7-9 with dropwise addition of 1N hydrochloric
acid. The solid was collected via centrifugation, the aqueous
supernate discarded, and the solid dissolved in 1-2 mL of DMSO and
purified by preparative HPLC (0-30% MeCN in water (0.1% formic
acid) over 30 min, 35 mL/min) to afford the title compound as an
off-white solid (19 mg, 33%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz,):
12.51 (s, 1H), 9.94 (s, 1H), 8.94 (s, 1H), 8.87 (s, 1H), 8.32 (d,
J=2.7 Hz, 1H), 8.08 (d, J=2.7 Hz, 1H). LCMS (Method E):
R.sub.T=2.90 min, M+H.sup.+=211.
Example 217
3-(Pyridin-2-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00452##
[0786] A solution of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (150 mg,
0.549 mmol) and lithium chloride (69.9 mg, 1.65 mmol) in DMF (0.94
mL) was treated with DIPEA (239 .mu.L, 1.37 mmol) and
2-(tributylstannyl)pyridine (607 .mu.L, 1.65 mmol), and then
degassed by the bubbling of nitrogen for 5 minutes.
Tetrakis(triphenylphosphine)palladium(0) (31.7 mg, 27.5 .mu.mol,
5.0 mol %) was added and the mixture heated at 165.degree. C. for
15 h. The mixture was allowed to cool and treated with saturated
aqueous potassium fluoride at ambient temperature. The resulting
solids were removed by filtration and washed with 20% methanol in
DCM and water. The filtrate was filtered through a pad of celite,
washing with 20% methanol in DCM. The layers were separated, the
aqueous phase extracted into 20% methanol in DCM, and the combined
organic phases concentrated in vacuo to afford a solid residue.
This solid was purified by preparative HPLC (0-30% MeCN/water
modified with 0.1% formic acid) to afford an off-white solid powder
(8.9 mg, 6.0%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz,): 13.01 (s,
1H), 9.49 (d, J=2.2 Hz, 1H), 9.43 (d, J=2.2 Hz, 1H), 9.04 (dd,
J=11.6, 0.8 Hz, 2H), 8.75 (d, J=4.0 Hz, 1H), 8.15 (d, J=8.0 Hz,
1H), 7.98 (td, J=7.8, 1.8 Hz, 1H), 7.43 (dd, J=6.7, 4.9 Hz, 1H).
LCMS (Method D): R.sub.T=7.26 min, M+H.sup.+=272.
[0787] Compounds of the Examples in Table 10 were made via
procedures described above using appropriate starting materials,
reagents and following the procedures outlined in the general
methods.
TABLE-US-00011 TABLE 10 Ex- General General Final LCMS R.sub.T, am-
Akylation Deprotection purification M + H.sup.+, ple Structure/Name
Method Method Method(s) Method .sup.1H NMR (ppm) 218 ##STR00453##
4-(Piperidin-4-yloxy)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C F T 5.67, 294, D (DMSO-D.sub.6, 400 MHz): 8.97 (s,
1H), 8.52 (d, J = 5.8 Hz, 1H), 8.47 (s, 1H), 7.10 (d, J = 5.9 Hz,
1H), 4.95 (m, 1H), 3.11-3.03 (m, 2H), 2.76 (m, 2H), 2.08 (m, 2H),
1.88- 1.67 (m, 2H). 219 ##STR00454## 4-[2-(diethylamino)ethoxy]-
9H-dipyrido[2,3-b;4',3'- d]pyrrole-6-carbonitrile C F T 6.00, 310,
D (DMSO-D.sub.6, 400 MHz): 12.76 (s, 1H), 8.97 (s, 1H), 8.55 (d, J
= 5.7 Hz, 1H), 8.50 (s, 1H), 7.06 (d, J = 5.8 Hz, 1H), 4.41 (t, J =
5.5 Hz, 2H), 3.02 (s, 2H), 2.65 (d, J = 6.8 Hz, 4H), 1.04 (t, J =
7.1 Hz, 6H). 220 ##STR00455## 4-(2-(ethylamino)ethoxy]-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C F T 5.68, 282, D
(DMSO-D.sub.6, 400 MHz): 8.97 (s, 1H), 8.57 (s, 1H), 8.54 (d, J =
5.7 Hz, 1H), 8.28 (s, 1H), 7.05 (d, J = 5.8 Hz, 1H), 4.41 (t, J =
5.5 Hz, 2H), 3.13 (t, J = 5.6 Hz, 2H), 2.72 (q, J = 7.1 Hz, 2H),
1.08 (t, J = 7.1 Hz, 3H). 221 ##STR00456## (R)-4-(Pyrrolidin-2-
ylmethoxy)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile C F T
5.94, 294, D (DMSO-D.sub.6, 400 MHz): 8.98 (s, 1H), 8.63 (s, 1H),
8.56 (d, J = 5.7 Hz, 1H), 7.06 (d, J = 5.8 Hz, 1H), 4.41 (m, 4.4
Hz, 1H), 4.27 (m, 1H), 3.86 (m, 1H), 3.07 (m, 2H), 2.08 (m, 1H),
1.84 (m, 2H), 1.65 (m, 1H). 222 ##STR00457## (S)-4-(Pyrrolidin-2-
ylmethoxy)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile C F T
5.87, 294, D (DMSO-D.sub.6, 400 MHz): 8.97 (s, 1H), 8.55 (s, 1H),
8.53 (d, J = 5.7 Hz, 1H), 7.03 (d, J = 5.8 Hz, 1H), 4.23 (m, 1H),
4.15 (m, 1H), 3.70-3.55 (m, 1H), 2.90 (t, J = 6.5 Hz, 2H), 1.98 (m,
1H), 1.85- 1.64 (m, 2H), 1.65-1.45 (m, 1H). 223 ##STR00458##
4-(Azetidin-3-yloxy)-9H- dipyrido[2,3-b;4',3'-d]
pyrrole-6-carbonitrile C F T 5.27, 266, D (DMSO-D.sub.6, 400 MHz):
8.98 (d, J = 0.8 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H),
6.75 (d, J = 5.7 Hz, 1H), 5.46-5.30 (m, 1H), 4.01-3.86 (m, 2H),
3.86-3.72 (m, 2H). 224 ##STR00459## (R)-4-(Pyrrolidin-3-yloxy)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C F T 5.56, 280, D
(DMSO-D.sub.6, 500 MHz): 8.95 (s, 1H), 8.60 (s, 1H), 8.53 (d, J =
5.7 Hz, 1H), 7.01 (d, J = 5.8 Hz, 1H), 5.27 (s, 1H), 3.13 (m, 2H),
3.10-3.05 (m, 1H), 2.85 (d, J = 8.0 Hz, 1H), 2.19 (m, 1H), 2.01 (m,
1H). 225 ##STR00460## (S)-4-(Pyrrolidin-3-
ylmethoxy)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile C F T
5.53, 280, D (DMSO-D.sub.6, 500 MHz): 8.95 (s, 1H), 8.60 (s, 1H),
8.53 (d, J = 5.7 Hz, 1H), 7.01 (d, J = 5.8 Hz, 1H), 5.28 (m, 1H),
3.18 (m, 1H), 3.16-3.13 (m, 1H), 3.13-3.08 (m, 1H), 2.88 (m, 1H),
2.21 (m, 1H), 2.07-1.99 (m, 1H). 226 ##STR00461##
(R)-(Piperidin-3-yloxy)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile C F T 6.10, 294, D (DMSO-D.sub.6, 500 MHz): 8.96 (d,
J = 1.0 Hz, 1H), 8.53 (d, J= 0.9 Hz, 1H), 8.51 (d, J = 5.8 Hz, 1H),
7.07 (d, J = 5.9 Hz, 1H), 4.72 (m, 1H), 3.19 (m, 1H), 2.85 (m, 1H),
2.82- 2.76 (m, 1H), 2.68-2.61 (m, 1H), 2.13 (s, 1H), 1.85 (m, 1H),
1.76 (m, 1H), 1.53 (m, 1H). 227 ##STR00462##
(R)-4-(Piperidin-3-ylmethoxy)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile C F T 6.26, 308, D (DMSO-D.sub.6, 400
MHz): 8.97 (s, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.02
(d, J = 5.8 Hz, 1H), 4.23 (d, J = 6.4 Hz, 2H), .delta. 3.16 (m,
1H), 2.89 (m, 1H), 2.15 (m, 2H), 1.91 (d, J = 9.6 Hz, 1H), 1.64 (m,
1H), 1.57-1.19 (m, 3H). 228 ##STR00463##
(S)-4-(Piperidin-3-ylmethoxy)- 9H-dipyrido[2,3-b;4',3'-
d]pyrrole-6-carbonitrile C F T 6.31, 308, D (DMSO-D.sub.6, 400
MHz): 8.97 (s, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.03
(d, J = 5.8 Hz, 1H), 4.23 (d, J = 6.5 Hz, 2H), 3.17 (m, 1H), 2.89
(m, 1H), 2.15 (m, 2H), 1.90 (m, 1H), 1.65 (m, 1H), 1.54- 1.20 (m,
3H). 229 ##STR00464## (R)-4-(Pyrrolidin-3-
ylmethoxy)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile C F T
2.61, 294, E (DMSO-D.sub.6, 400 MHz): 8.98 (s, 1H), 8.55 (d, J =
5.7 Hz, 1H), 8.45 (s, 1H), 7.04 (d, J = 5.8 Hz, 1H), 4.32 (m, 2H),
3.21 (m, 1H), 3.05 (m, 1H), 3.00-2.92 (m, 1H), 2.92- 2.85 (m, 1H),
2.79 (m, 1H), 2.06 (m, 1H), 1.65 (m, 1H). 230 ##STR00465##
(S)-4-(Pyrrolidin-3- ylmethoxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile C F T 2.66, 294, E (DMSO-D.sub.6,
400 MHz): 8.96 (d, J = 0.9 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.42
(s, 1H), 7.01 (d, J = 5.7 Hz, 1H), 4.28 (m, 2H), 3.06 (m, 1H), 2.91
(m, 9.1, 1H), 2.88- 2.64 (m, 3H), 1.98 (m, 7.9, 1H), 1.56 (m, 1H).
231 ##STR00466## 4-(Piperidin-4-ylmethoxy)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C F T 2.67, 308, E
(DMSO-D.sub.6, 400 MHz): 8.97 (d, J = 0.8 Hz, 1H), 8.54 (d, J = 5.7
Hz, 1H), 8.41 (s, 1H), 7.05 (d, J = 5.8 Hz, 1H), 4.22 (d, J = 6.3
Hz, 2H), 3.05 (d, J = 11.8 Hz, 2H), 2.60 (m, 2H), 2.10 (m, 1H),
1.83 (d, J = 10.9 Hz, 2H), 1.41-1.26 (m, 2H).
Example 232
4-(Piperidin-4-ylamino)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00467##
[0788] Step 1: tert-Butyl
4-{6-cyano-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrr-
ol-4-ylamino}piperidine-1-carboxylate
##STR00468##
[0790] A mixture of
4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile with
4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile (6.5:1, 85 mg, 0.24 mmol), tert-butyl
4-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.04 mmol),
tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol), and
cesium carbonate (150 mg, 0.47 mmol) in 1,4-dioxane (2 mL) was
sealed and heated at 110.degree. C. for 2 h. The mixture was
diluted with water (20 mL) and ethyl acetate (50 mL). The organic
layer was separated, dried over sodium sulfate, filtered,
concentrated in vacuo, and purified flash chromatography (silica,
40 g, ISCO, 5-75% ethyl acetate in heptane) to afford the title
compound as a yellow solid (80 mg, 60%).
Step 2:
4-(Piperidin-4-ylamino)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbon-
itrile
##STR00469##
[0792] tert-Butyl
4-{6-cyano-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4',3'-d]pyrr-
ol-4-ylamino}piperidine-1-carboxylate (80 mg, 0.14 mmol) was
dissolved in 1,4-dioxane (0.4 mL) and then treated with 48%
HBr.sub.(aq)(0.5 mL) and heated at 75.degree. C. for 15 minutes.
The cooled reaction mixture was then basified to pH 6.about.12 by
dropwise addition of 6N sodium hydroxide and then immediately
acidified to pH .about.8-9 by dropwise addition of concentrated
hydrochloric acid, producing a cloudy precipitate. The solid was
collected by centrifugation, dissolved in dimethylsulfoxide (2 mL),
and purified by preparative HPLC (5-85% methanol in water (0.1%
formic acid) over 30 min, 35 mL/min) to afford the title compound
as a pale yellow solid (20 mg, 30% over two steps). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 9.08 (s, 1H), 8.83 (s, 1H), 8.20 (d, J=5.9
Hz, 1H), 6.63 (d, J=6.0 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 3.74 (m,
1H), 3.11 (m, 2H), 2.71 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H). LCMS
(Method E): R.sub.T=2.28 min, M+H.sup.+=293.
[0793] The compounds of the Examples in Table 11 were prepared via
general Suzuki procedures described above.
TABLE-US-00012 TABLE 11 Ex- Halide or Depro- LCMS R.sub.T, am-
Coupling Mesylate tection Purification M + H.sup.+, ple
Structure/Name Method displacement Method Method(s) Method .sup.1H
NMR (ppm) 233 ##STR00470## 5-(3-Methylamino-propyl)-3-(1- meth
l-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile L D/E -- B 5.21, 346, A (DMSO-D.sub.6, 400 MHz):
8.99 (d, J = 2.0 Hz, 1H), 8.92 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H),
8.42 (s, 1H), 8.14 (d, J = 0.8 Hz, 1H), 3.92 (s, 3H), 3.53 (t, J =
7.7 Hz, 2H), 3.10 (t, J = 7.8 Hz, 2H), 2.54 (s, 3H), 2.16-2.06 (m,
2H). 234 ##STR00471## 3-(1-Methyl-1H-pyrazol-4-yl)-5-(3-
pyrrolidin-1-yl-propyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile L D -- B 5.35, 385, A
(CD.sub.3OD, 400 MHz): 8.84 (d, J = 2.1 Hz, 1H), 8.82-8.79 (m, 1H),
8.68 (d, J = 2.1 Hz, 1H), 8.13-8.10 (m, 1H), 7.97 (d, J = 0.8 Hz,
1H), 3.96 (s, 3H), 3.53 (t, J = 7.8 Hz, 2H), 2.75 (t, J = 7.6 Hz,
2H), 2.57 (m, 4H), 2.09 (m, J = 7.7 Hz, 2H), 1.78-1.71 (m, 4H). 235
##STR00472## 3-(1-Methyl-1H-pyrazol-4-yl)-5-(3-
orpholin-4-yl-propyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile L D/E -- B 5.50, 402, F (DMSO-D.sub.6, 400 MHz):
12.83 (s, 1H), 8.96 (t, J = 2.1 Hz, 1H), 8.88 (s, 1H), 8.70 (d, J =
2.1 Hz, 1H), 8.36 (s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 3.97- 3.90 (m,
3H), 3.52 (t, J = 7.4 Hz, 2H), 3.43 (t, J = 4.4 Hz, 4H), 2.47 (t, J
= 6.7 Hz, 2H), 2.27 (s, 4H), 2.03-1.93 (m, 2H). 236 ##STR00473##
3-(1-Methyl-1H-pyrazol-4-yl)-5- pip ridin-4-ylmethyl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile M NA E B 6.08, 372, F
(DMSO-D.sub.6, 400 MHz): 12.99 (s, 1H), 12.66 (s, 1H), 9.01 (d, J =
2.0 Hz, 1H), 8.96 (s, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H),
8.12 (s, 1H), 3.97 (s, 3H), 3.50 (d, J = 7.2 Hz, 2H), 3.30 (d, J =
12.5 Hz, 2H), 2.86 (t, J = 12.4 Hz, 2H), 2.20 (s, 1H), 1.90 (d, J =
13.9 Hz, 2H), 1.71 (t, J = 13.0 Hz, 2H). 237 ##STR00474##
5-(1-Ethyl-piperidin-4-ylmethyl)-3- (1-methyl-1H-pyrazol-4-yl)-9H-
dipy ido[2,3-b;4',3'-d]pyrrole-6- carbonitrile M F D C 5.96, 400, F
(DMSO-D.sub.6, 400 MHz): 12.82 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H),
8.87 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.32 (s, 1H), 8.04 (d, J =
0.8 Hz, 1H), 3.92 (s, 3H), 3.40 (d, J = 7.0 Hz, 2H), 2.82 (d, J =
10.9 Hz, 2H), 2.23 (q, J = 7.2 Hz, 2H), 1.82-1.61 (m, 5H),
1.55-1.41 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H). 238 ##STR00475##
5-(1-Ethyl-piperidin-4-ylmethyl)- - pyridin-4-yl-9H-dipyrido[2,3-
b;4', '-d]pyrrole-6-carbonitrile M.sup..dagger. F D C 3.73, 397, F
(DMSO-D.sub.6, 400 MHz): 13.03 (s, 1H), 9.14 (d, J = 2.1 Hz, 1H),
8.94 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.75-8.70 (m, 2), 7.94-7.89
(m, 2H), 3.46 (d, J = 7.1 Hz, 2H), 2.87-2.79 (m, 2H), 2.24 (q, J =
7.2 Hz, 2H), 1.90-1.59 (m, 5H), 1.57- 1.42 (m, 2H), 0.94 (t, J =
7.1 Hz, 3). .sup..dagger.Deviation from method: 9-Benzenesulfonyl
5-bromo-3-pyridin-4-yl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
was used in place of
9-benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile. indicates data missing or illegible
when filed
[0794] The compounds of the Examples in Table 12 were prepared via
general Mitsunobu procedures followed by general Suzuki coupling
described above.
TABLE-US-00013 TABLE 12 LCMS Depro- Puri- R.sub.T, Cou- tec- ficat-
M + Ex- pling tion ion H.sup.+, am- Amino Mitsunobu Meth- Meth-
Meth- Meth- ple Structure/Name alcohol Method od od od(s) od
.sup.1H NMR (ppm) 239 ##STR00476## 3-(1-Methyl-1H-pyrazol-4-yl)-5-
(piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic
acid tert- butyl ester A N F R.sup.3 5.38, 374, A (DMSO-D.sub.6,
400 MHz): 13.07 (s, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.95 (s, 2H),
8.85 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.43 (s, 1H), 8.07 (d, J =
0.8 Hz, 1H), 5.01-4.94 (m, 1H), 3.95 (s, 3H), 3.42 (d, J = 12.0 Hz,
2H), 3.12 (s, 2H), 2.34- 2.18 (m, 4H). 240 ##STR00477##
3-(1-Methyl-1H-pyrazol-4-yl)-5-((S)-
piperidin-3-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile 3-(S)- Hydroxy- piperidine
carboxylic acid tert- butyl ester A N F R.sup.3 5.37, 374, A
(DMSO-D.sub.6, 400 MHz): 13.14 (s, 1H), 9.42 (s, 2H), 9.00 (d, J =
2.0 Hz, 1H), 8.86 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H),
8.12 (s, 1H), 5.01 (m, 1H), 3.95 (s, 3H), 3.72 (d, J = 11.5 Hz,
1H), 3.51 (d, J = 10.1 Hz, 1H), 3.24-3.11 (m, 1H), 3.09 (d, J = 9.9
Hz, 1H), 2.18 (s, 1H), 2.13-1.93 (m, 2H), 1.75 (d, J = 12.3 Hz,
1H). 241 ##STR00478## 5-(1-Ethyl-piperidin-4-yloxy)-3-(1-
methyl-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-
6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N NA E.sup.2 5.44,
402, A (DMSO-D.sub.6, 400 MHz): 12.92 (s, 1H), 8.97 (d, J = 2.1 Hz,
1H), 8.78 (s, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.32 (s, 1H), 8.01 (d,
J = 0.8 Hz, 1H), 4.81- 4.74 (m, 1H), 3.94 (s, 3H), 2.91-2.83 (m,
2H), 2.35 (q, J = 7.2 Hz, 2H), 2.12 (d, J = 11.7 Hz, 4H), 2.05-1.94
(m, 2H), 1.01 (t, J = 7.1 Hz, 3H). 242 ##STR00479##
3-(4-Morpholin-4-ylmethyl-phenyl)-5-
(piperidin-4-yloxy)-9H-dipyrido[2,
3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic
acid tert- butyl ester A N A S 4.55, 469, A (DMSO-D.sub.6, 400
MHz): 13.23 (s, 1H), 11.52 (s, 1H), 9.07 (d, J = 2.4 Hz, 2H), 8.88
(s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.82
(d, J = 7.8 Hz, 2H), 5.07- 4.99 (m, 1H), 4.42 (d, J = 5.3 Hz, 2H),
3.97 (d, J = 12.7 Hz, 2H), 3.85 (t, J = 12.1 Hz, 2H), 3.43- 3.35
(m, 2H), 3.28 (d, J = 12.6 Hz, 2H), 3.12 (s, 4H), 2.33-2.16 (m,
4H). 243 ##STR00480## 3-[4-(4,4-Difluoro-piperidin-1-ylmethyl)-
phenyl]-5-(piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N A S 4.93, 503, A
(DMSO-D.sub.6, 400 MHz): 13.21 (s, 1H), 11.75 (s, 1H), 9.10-8.96
(m, 3H), 8.86-8.82 (m, 1H), 8.66 (d, J = 2.2 Hz, 1H), 7.96 (d, J =
7.8 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H), 5.06- 4.97 (m, 1H), 4.45 (s,
2H), 3.52-3.30 (m, 4H), 3.21-3.15 (m, 2H), 3.10 (d, J = 12.4 Hz,
2H), 2.36 (s, 3H), 2.33-2.17 (m, 5H). 244 ##STR00481##
5-(Piperidin-4-yloxy)-3-[4-(4-trifluoromethyl-
piperidin-1-ylmethyl)-phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N A S 5.14, 535, A
(DMSO-D.sub.6, 400 MHz): 13.25 (s, 1H), 11.25 (s, 1H), 9.10 (d, J =
2.4 Hz, 3H), 8.89 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.00 (d, J =
7.9 Hz, 2H), 7.83 (d, J = 7.9 Hz, 2H), 5.09- 5.02 (m, 1H), 4.39 (d,
J = 5.0 Hz, 2H), 3.50 (d, J = 12.2 Hz, 2H), 3.46- 3.36 (m, 2H),
3.19-2.96 (m, 4H), 2.69 (s, 1H), 2.35-2.19 (m, 4H), 2.10- 1.91 (m,
4H). 245 ##STR00482## 3-(4-Hydroxymethyl-phenyl)-5-
(piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic
acid tert- butyl ester A N A S 5.62, 400, A (DMSO-D.sub.6, 400
MHz): 13.17 (s, 1H) 9.07 (d, J = 10.0 Hz, 1H), 9.02 (t, J = 2.2 Hz,
1H), 8.95-8.84 (m, 1H), 8.91-8.82 (m, 1H), 8.61 (d, J = 2.2 Hz,
1H), 7.81 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 5.06-4.98
(m, 1H), 4.59 (s, 2H), 3.39 (m, 2H), 3.10 (d, J = 11.3 Hz, 2H)
2.31-2.12 (m, 4H). 246 ##STR00483##
5-(Piperidin-4-yloxy)-3-pyridin-4-yl-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile 4-Hydroxy-
piperidine carboxylic acid tert- butyl ester A N A R.sup.7 4.16,
371, A (DMSO-D.sub.6, 400 MHz): 13.52 (s, 1H), 9.33 (d, J = 2.2 Hz,
1H), 9.30 (s, 1H); 9.19 (s, 1H), 8.96 (d, J = 6.2 Hz, 2H), 8.94-
8.90 (m, 2H), 8.53 (d, J = 6.0 Hz, 2H), 5.12-5.03 (m, 1H), 3.39 (s,
2H), 3.11 (t, J = 8.8 Hz, 2H) 2.34-2.28 (m, 4H). 247 ##STR00484##
5-(Piperidin-4-yloxy)-3-pyridin-3-yl-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile 4-Hydroxy-
piperidine carboxylic acid tert- butyl ester A N A R.sup.7 4.58,
371, A (DMSO-D.sub.6, 400 MHz): 13.36 (s, 1H), 9.36 (s, 1H), 9.16
(d, J = 2.3 Hz, 2H), 8.90 (s, 1H), 8.84- 8.77 (m, 3H), 7.95 (dd, J
= 8.1, 5.3 Hz, 1H), 5.09- 5.01 (m, 1H), 3.38 (d, J = 11.8 Hz, 2H),
3.10 (d, J = 10.4 Hz, 2H), 2.31- 2.22 (m, 4H). 248 ##STR00485##
3-(4-Methoxy-pyridin-3-yl)-5-(piperidin-
4-yloxy)-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile
4-Hydroxy- piperidine carboxylic acid tert- butyl ester A N A
R.sup.7 4.11, 401, A (DMSO-D.sub.6, 400 MHz): 13.35 (s, 1H), 9.19
(s, 2H), 9.04 (s, 1H), 8.95- 8.93 (m, 1H), 8.91-8.82 (m, 2H), 8.73
(d, J = 2.1 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1 H), 5.04-4.97 (m, 1H),
4.16 (s, 3H), 3.38 (m, 2H), 3.09 (d, J = 10.8 Hz, 2H), 2.32- 2.16
(m, 4H). 249 ##STR00486## 3-(5-Methoxy-pyridin-3-yl)-5-
(piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic
acid tert- butyl ester A N A R.sup.7 5.23, 401, A (DMSO-D.sub.6,
400 MHz): 13.35 (s, 1H), 9.16 (d, J = 2.2 Hz, 2H), 8.99 (s, 1H),
8.90-8.86 (m, 2H), 8.76 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 2.6 Hz,
1H), 8.22 (s, 1H), 5.10-5.02 (m, 1H), 4.04 (s, 3H), 3.38 (m, 2H),
3.11 (d, J = 11.0 Hz, 2H), 2.34- 2.17 (m, 4H). 250 ##STR00487##
3-(2-Methoxy-pyridin-3-yl)- 5-(piperidin-4-yloxy)-9H-
dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile 4-Hydroxy-
piperidine carboxylic acid tert- butyl ester A N B C.sup.2 5.78,
401, A (DMSO-D.sub.6, 400 MHz): 8.86 (t, J = 2.2 Hz, 1H), 8.81 (s,
1H), 8.78 (d, J = 2.2 Hz, 1H), 8.26 (dd, J = 5.0, 1.8 Hz, 1H),
7.99- 7.94 (m, 1H), 7.20 (dd, J = 7.3, 5.0 Hz, 1H), 4.83- 4.75 (m,
1H), 3.99-3.92 (m, 3H), 3.08-3.01 (m, 2H), 2.59-2.52 (m, 2H), 2.06
(d, J = 11.9 Hz, 2H), 1.85-1.74 (m, 2H). 251 ##STR00488##
3-(6-Methoxy-pyridin-3-yl)-5- (piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N B C.sup.2 7.36, 401, F
(DMSO-D.sub.6, 400 MHz): 8.99 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H),
8.63 (d, J = 2.3 Hz, 1H), 8.60 (dd, J = 2.6, 0.8 Hz, 1H), 8.15 (dd,
J = 8.6, 2.6 Hz, 1H), 7.01 (dd, J = 8.6, 0.7 Hz, 1H), 4.86-4.77 (m,
1H), 3.94 (s, 3H), 3.10-3.01 (m, 2H), 2.62-2.52 (m, 2H), 2.07 (d, J
= 11.9 Hz, 2H), 1.87-1.76 (m, 2H). 252 ##STR00489##
3-(3-Methoxy-pyridin-4-yl)-5-(piperidin- 4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N A R.sup.1 5.10, 401, F
(DMSO-D.sub.6, 400 MHz): 13.38 (s, 1H), 9.14 (s, 2H), 9.02 (d, J =
2.1 Hz, 1H), 8.89 (s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.75 (s, 1H),
8.59 (d, J = 5.4 Hz, 1H), 8.10 (d, J = 5.4 Hz, 1H) 5.03-4.96 (m,
1H), 4.07 (s, 3H), 3.37 (m, 2H), 3.08 (d, J = 10.6 Hz, 2H), 2.32-
2.14 (m, 4H). 253 ##STR00490## 3-(2-Methoxy-pyridin-4-yl)-5-
(piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N B E.sup.5 7.33, 401, F
(DMSO-D.sub.6, 400 MHz): 9.09 (d, J = 2.2 Hz, 1H), 8.81 (s, 1H),
8.72 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.44 (dd, J =
5.4, 1.6 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 4.87- 4.78 (m, 1H),
3.94 (s, 3H), 3.12-3.01 (m, 2H), 2.62-2.52 (m, 2H), 2.08 (d, J =
11.9 Hz, 2H), 1.88-1.77 (m, 2H). 254 ##STR00491##
5-(1-Ethyl-piperidin-4-yloxy)-3-(4-
hydroxymethyl-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy-
piperidine A N.sup.2 D B.sup.8 6.89, 428, F (CDCl.sub.3 and
CD.sub.3OD, 400 MHz): 8.90 (d, J = 2.2 Hz, 1 H), 8.79 (d, J = 2.2
Hz, 1H), 8.75 (s, 1H), 7.73-7.69 (m, 2H), 7.57-7.52 (m, 2H), 5.04-
4.94 (m, 1H), 4.72 (s, 2H), 3.04-2.95 (m, 2H), 2.49 (q, J = 7.2 Hz,
2H), 2.38-2.19 (m, 4H), 2.18- 2.07 (m, 2H), 1.12 (t, J = 7.2 Hz,
3H). 255 ##STR00492## 5-(1-Ethyl-piperidin-4-yloxy)-3-p-
tolyl-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile N-Ethyl 4-
hydroxy- piperidine A N.sup.2 D B.sup.5 8.41, 412, F (CDCl.sub.3
and CD.sub.3OD, 400 MHz): 8.85 (d, J = 2.2 Hz, 1H), 8.76 (d, J =
2.1 Hz, 1H), 8.73 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.36 (d, J =
7.9 Hz, 2H), 5.06-4.96 (m, 1H), 3.04-2.92 (m, 2H), 2.54- 2.43 (m,
5H), 2.38-2.20 (m, 4H), 2.18-2.07 (m, 2H), 1.12 (t, J = 7.2 Hz,
3H). 256 ##STR00493## 5-(1-Ethyl-piperidin-4-yloxy)-3-[4-(1-
hydroxy-1-methyl-ethyl)-phenyl]-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile N-Ethyl 4- hydroxy-
piperidine A N.sup.2 D B.sup.5 7.87, 456, F (CDCl.sub.3 and
CD.sub.3OD, 400 MHz): 8.90 (d, J = 2.2 Hz, 1 H), 8.79 (d, J = 2.2
Hz, 1H), 8.76 (s, 1H), 7.68-7.67 (s, 4H), 5.06-4.95 (m, 1H), 3.05-
2.96 (m, 2H), 2.50 (q, J = 7.2 Hz, 2H), 2.38-2.20 (m, 4H),
2.19-2.08 (m, 2H), 1.63 (s, 6H), 1.13 (t, J = 7.2 Hz, 3H). 257
##STR00494## 5-(1-Ethyl-piperidin-4-yloxy)-3-(4-
hydroxymethyl-3-methoxy-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile N-Ethyl 4- hydroxy-
piperidine A N.sup.2 D B.sup.5 7.29, 458, F (CDCl.sub.3 and
CD.sub.3OD, 400 MHz): 8.91 (d, J = 2.2 Hz, 1 H), 8.78 (d, J = 2.2
Hz, 1H), 8.76 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 7.7,
1.7 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 5.05-4.95 (m, 1H), 4.74 (s,
2H), 3.98 (s, 3H), 3.03-2.94 (m, 2H), 2.49 (q, J = 7.2 Hz, 2H),
2.40-2.29 (m, 2H), 2.28-2.20 (m, 2H), 2.19-2.08 (m, 2H), 1.12 (t, J
= 7.2 Hz, 3H). 258 ##STR00495## 3-(4-tert-Butyl-phenyl)-5-(1-ethyl-
piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A
N.sup.2 D B.sup.5 9.86, 454, F (DMSO-D.sub.6, 400 MHz): 13.03 (s,
1H), 9.00 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.68 (d, J = 2.3 z,
1H), 7.75-7.70 (m, 2H), 7.61-7.55 (m, 2H), 4.88 (m, 1H), 2.92- 2.80
(m, 2H), 2.40-2.29 (m, 2H), 2.21-2.04 (m, 4H), 2.02-1.89 (m, 2H),
1.35 (s, 9H), 0.99 (t, J = 7.1 Hz, 3H). 259 ##STR00496##
3-(4-tert-Butyl-3-methoxy-phenyl)-5-
(1-ethyl-piperidin-4-yloxy)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile N-Ethyl 4- hydroxy- piperidine A N.sup.2 D B.sup.5
10.17, 484, F (DMSO-D.sub.6, 400 MHz): 13.05 (s, 1H), 9.05 (d, J =
2.2 Hz, 1H), 8.80 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 7.39 (d, J =
8.0 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.0, 1.8 Hz,
1H), 4.87-4.77 (m, 1H), 3.96 (s, 3H), 2.87-2.79 (m, 2H), 2.33 (q, J
= 7.1 Hz, 2H), 2.21- 2.05 (m, 4H), 2.03-1.90 (m, 2H), 1.39 (s, 9H),
0.98 (t, J = 7.2 Hz, 3 H). 260 ##STR00497##
5-(1-Ethyl-piperidin-4-yloxy)-3-(4-
hydroxymethyl-3-trifluoromethoxy-
phenyl)-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile N-Ethyl
4- hydroxy- piperidine A N.sup.2 D B.sup.1 8.49, 512, F
(DMSO-D.sub.6, 400 MHz): 13.10 (s, 1H), 9.06 (d, J = 2.2 Hz, 1H),
8.82 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.1, 1.7 Hz,
1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 5.46 (t, J = 5.7 Hz,
1H), 4.90-4.81 (m, 1H), 4.65 (d, J = 5.6 Hz, 2H), 2.86-2.76 (m,
2,H), 2.34 (q, J = 7.1 Hz, 2H), 2.23- 2.04 (m, 4H), 2.03-1.90 (m,
2H), 0.99 (t, J = 7.1 Hz, 3H). 261 ##STR00498##
5-(1-Ethyl-piperidin-4-yloxy)-3-
pyridin-4-yl-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile
N-Ethyl 4- hydroxy- piperidine A N NA B/ C.sup.2 4.42, 399, F
(DMSO-D.sub.6, 400 MHz): 13.07 (s, 1H), 9.14 (d, J = 2.2 Hz, 1H),
8.84-8.79 (m, 2H), 8.72 (d, J = 5.3 Hz, 2H), 7.87 (dd, J = 4.8, 1.6
Hz, 2H), 4.89- 4.80 (m, 1H), 2.92-2.81 (m, 2H), 2.36 (q, J = 7.2
Hz, 2H), 2.23-2.06 (m, 4H), 2.04-1.93 (m, 2H), 1.00 (t, J = 7.1 Hz,
3H). 262 ##STR00499## 5-(1-Ethyl-piperidin-4-yloxy)-3-(6-
methoxy-pyridin-3-yl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy-
piperidine A N NA B.sup.2 7.45, 429, F (DMSO-D.sub.6, 400 MHz):
13.02 (s, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.66 (d, J =
2.3 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 8.15 (dd, J = 8.6, 2.6 Hz,
1H), 7.01 (d, J = 8.6 Hz, 1H), 4.86-4.75 (m, 1H), 3.94 (s, 3H),
2.92-2.79 (m, 2H), 2.35 (q, J = 7.2 Hz, 2H), 2.21- 2.04 (m, 4H),
2.03-1.90 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 263 ##STR00500##
5-(1-Ethyl-piperidin-4-yloxy)-3-
pyridin-3-yl-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile
N-Ethyl 4- hydroxy- piperidine A N NA B.sup.2/6 5.53, 399, F
(DMSO-D.sub.6, 400 MHz): 13.21 (s, 1H), 9.09 (d, J = 2.2 Hz, 1H),
9.06 (d, J = 2.4 Hz, 1H), 8.86 (s, 1H), 8.73 (d, J = 2.2 Hz, 1H)
8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.61-7.56
(m, 1H), 4.95 (s, 1 H), 3.22-2.63 (m, 4H), 2.38- 2.03 (m, 4H),
1.27-1.06 (m, 3H). 264 ##STR00501##
5-(1-Ethyl-piperidin-4-yloxy)-3-[4-(4-
trifluoromethyl-piperidin-1-ylmethyl)- phenyl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy-
piperidine A N.sup.2 NA B.sup.8 5.68, 563, F (CDCl.sub.3 and
CD.sub.3OD, 400 MHz): 8.85 (s, 1H), 8.78 (s, 1H), 8.73 (s, 1H),
7.63 (d, J = 7.7 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 5.02 (s, 1H),
3.61 (s, 2H), 3.09-3.01 (m, 2H), 3.01-2.93 (m, 2H), 2.53-2.42 (m,
2H), 2.33- 2.19 (m, 4H), 2.16-1.98 (m, 5H), 1.92-1.83 (m, 2H),
1.76-1.62 (m, 2H), 1.17-1.06 (m, 3H). 265 ##STR00502##
3-[4-(4,4-Difluoro-piperidin-1- ylmethyl)-phenyl]-5-(1-ethyl-
piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy-
piperidine A N.sup.2 NA B 5.46, 531, F (CDCl.sub.3, 400 MHz): 10.67
(s, 1H), 8.92 (d, J = 2.1 Hz, 1 H), 8.81 (s, 1H) 8.78 (s, 1,H),
7.62 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 5.11- 5.01 (m,
1H), 3.66 (s, 2H), 3.09-2.94 (m, 2H), 2.68-2.59 (m, 4H), 2.56- 2.42
(m, 2H), 2.37-2.18 (m, 4H), 2.17-1.98 (s, 6H), 1.18-1.05 (m, 3H).
266 ##STR00503## 3-(4-Chloro-phenyl)-5-(1-ethyl-
piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A
N.sup.2 NA B 8.58, 432, F (CDCl.sub.3 and CD.sub.3OD, 400 MHz):
8.82 (d, J = 2.2 Hz, 1H), 8.76 (s, 1H), 8.74 (s, 1H), 7.65- 7.58
(m, 2H), 7.55-7.50 (m, 2H), 5.08-4.97 (m, 1H), 3.02-2.91 (m, 2H),
2.52-2.42 (m, 2H), 2.34- 2.19 (m, 4H), 2.17-2.03 (m, 2H), 1.16-1.07
(m, 3H).
267 ##STR00504## 5-(1-Ethyl-piperidin-4-yloxy)-3-(4-
fluoro-phenyl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
N-Ethyl 4- hydroxy- piperidine A N.sup.2 NA B.sup.3 8.04, 416, F
(CDCl.sub.3 and DMSO-D.sub.6, 400 MHz): 12.39 (s, 1H), 8.84 (d, J =
2.2 Hz, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 7.66-7.58 (m, 2H),
7.27-7.20 (m, 2H), 4.96 (s, 1H), 3.06-2.91 (m, 2H), 2.53-2.39 (m,
2H), 2.30-1.99 (m, 6H), 1.16- 1.04 (m, 3H). 268 ##STR00505##
5-(1-Ethyl-piperidin-4-yloxy)-3-(3- fluorophenyl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A
N.sup.2 NA B 8.23, 416, F (CDCl.sub.3, 400 MHz): 10.20 (s, 1H),
8.89 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.78 (s, 1H), 7.56- 7.48
(m, 1H), 7.46-7.42 (m, 1H), 7.36 (dt, J = 9.8, 2.0 Hz, 1H), 7.19-
7.13 (m, 1H), 5.14-5.04 (m, 1H), 3.03-2.90 (m, 2H), 2.53-2.41 (m,
2H), 2.33-2.19 (m, 4H), 2.16- 2.03 (m, 2H), 1.11 (t, J = 7.2 Hz,
3H). 269 ##STR00506## 3-(4-Cyano-phenyl)-5-(1-ethyl-
piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A
N.sup.2 NA B.sup.3 7.51, 423, F (CDCl.sub.3 and DMSO-D.sub.6, 400
MHz): 12.54 (s, 1H) 8.89 (d, J = 2.2 Hz, 1H), 8.79 (s, 1H),
8.77-8.68 (m, 1H), 7.87-7.74 (m, 4H), 5.05-4.92 (m, 1H), 3.10-2.87
(m, 2H), 2.57- 2.37 (m, 2H), 2.35-1.97 (m, 6H), 1.22-1.02 (m, 3H).
270 ##STR00507## 5-(1-Ethyl-piperidin-4-yloxy)-3-
phenyl-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile N-Ethyl 4-
hydroxy- piperidine A N.sup.2 NA B.sup.3 7.92, 398, F (CDCl.sub.3
and DMSO-D.sub.6, 400 MHz): 12.37 (s, 1H), 8.89 (d, J = 2.2 Hz,
1H), 8.78 (s, 1H), 8.75-8.65 (m, 1H), 7.69-7.62 (m, 2H), 7.57-7.50
(m, 2H), 7.47-7.40 (m, 1H), 4.97 (s, 1H), 3.10-2.87 (m, 2H),
2.55-2.37 (m, 2H), 2.34-2.05 (m, 6H), 1.21- 1.03 (m, 3H). 271
##STR00508## 3-(2-Chloro-phenyl)-5-(1-ethyl-
piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A
N.sup.2 NA B.sup.3 8.08, 432, F (CDCl.sub.3, 400 MHz): 10.64 (s,
1H), 8.82 (s, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.73 (s, 1H), 7.61-
7.56 (m, 1H), 7.48-7.39 (m, 3H), 5.08-4.96 (m, 1H), 3.06-2.88 (m,
2H), 2.53-2.38 (m, 2H), 2.32- 2.00 (m, 6H), 1.16-1.01 (m, 3H). 272
##STR00509## 3-(3-Chloro-phenyl)-5-(1-ethyl-
piperidin-4-yloxy)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A
N.sup.2 NA B.sup.3 8.66, 432, F (CDCl.sub.3, 400 MHz): 10.34 (s,
1H), 8.88 (d, J = 2.2 Hz, 1H), 8.82 (s, 1H), 8.77 (s, 1H), 7.64 (s,
1H), 7.56-7.41 (m, 3H), 5.17-5.05 (m, 1H), 3.06-2.88 (m, 2H), 2.56-
2.40 (m, 2H), 2.38-2.20 (m, 4H), 2.19-2.05 (m, 2H), 1.17-1.05 (m,
3H). 273 ##STR00510## 3-Bromo-5-(1-ethyl-piperidin-4-
yloxy-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4-
hydroxy- piperidine A N A D B 6.43, 400/ 402, F (400 MHz,
CD.sub.3OD): 8.71 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.66 (d, J =
2.3 Hz, 1H), 5.00-4.91 (m, 1H), 3.03-2.95 (m, 2H), 2.51 (q, J = 7.3
Hz, 2H), 2.36-2.25 (m, 2H), 2.24-2.15 (m, 2H), 2.12- 2.00 (m, 2H),
1.14 (t, J = 7.2 Hz, 3H). 274 ##STR00511##
3-(1-Isopropyl-1H-pyrazol-4-yl)-5- (piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A Stille C B .sup.1C 7.27, 402, F
(DMSO-D.sub.6, 400 MHz): 13.03 (s, 1H), 9.01 (d, J = 2.1 Hz, 1H),
8.83 (s, 1H), 8.55 (br s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.41 (s,
1H), 8.05 (s, 1H), 5.02-4.93 (m, 1H), 4.63-4.51 (m, 1H), 3.47- 3.38
(m, 2H), 3.18-3.06 (m, 2H), 2.35-2.24 (m, 2H), 2.22-2.10 (m, 2H),
1.49 (d, J = 6.7 Hz, 6H). 275 ##STR00512##
3-(3-Methoxy-4-methyl-phenyl)-5- (piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N B C.sup.2 8.66, 414, F
(CD.sub.3OD and CDCl.sub.3, 400 MHz): 8.84 (d, J = 2.0 Hz, 1H),
8.73 (d, J = 8.7 Hz, 2H), 7.34-7.27 (m, 1H), 7.14 (d, J = 7.7 Hz,
1H), 7.08 (s, 1H), 5.06-4.96 (m, 1H), 3.95 (s, 3H), 3.27-3.17 (m,
2H), 2.79-2.68 (m, 2H), 2.31 (s, 3H), 2.29- 2.19 (m, 2H), 2.01-1.89
(m, 2H). 276 ##STR00513## 5-(1-Ethyl-piperidin-4-yloxy)-3-(3-
methoxy-4-methyl-phenyl)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy-
piperidine A N NA B 8.79, 442, F (CDCl.sub.3, 400 MHz): 10.81 (s,
1H), 8.91 (d, J = 2.1 Hz, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 7.30 (d,
J = 7.6 Hz, 1H), 7.14 (dd, J = 7.6, 1.7 Hz, 1H), 7.08 (d, J = 1.6
Hz, 1H), 5.11-5.02 (m, 1H), 3.96 (s, 3H), 3.09-2.88 (m, 2H),
2.57-2.40 (m, 3H), 2.38-2.05 (m, 8H), 1.20- 1.02 (m, 3H). 277
##STR00514## 3-(4-Hydroxymethyl-3-methoxy-phenyl)-
5-(piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine
carboxylic acid tert- butyl ester A N B C 5.86, 430, A
(DMSO-D.sub.6, 400 MHz): 9.05 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H),
8.66 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.36 (dd, J =
7.8, 1.6 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 4.88- 4.78 (m, 1H),
4.57 (s, 2H), 3.92 (s, 3H), 3.10- 3.01 (m, 2H), 2.60-2.51 (m, 2H),
2.13-2.04 (m, 2H), 1.88-1.75 (m, 2H). 278 ##STR00515##
5-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-
3-(1-methyl-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile 3- Quinuclininol A N NA C.sup.8 6.25, 400, F
(DMSO-D.sub.6, 300 MHz): 12.90 (s, 1H); 8.95 (d, J = 2.1 Hz, 1H),
8.75 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H),
5.06-4.98 (m, 1H), 3.93 (s, 3H), 3.45- 3.26 (m, 1H), 3.17-2.95 (m,
2H), 2.92-2.78 (m, 1H), 2.77-2.56 (m, 2H), 2.29-2.10 (m, 2H), 1.77-
1.63 (m, 1H), 1.56-1.42 (m, 2H). 279 ##STR00516##
5-(1-Ethyl-piperidin-4-yloxy)-3-(4-
morpholin-4-ylmethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile N-Ethyl 4- hydroxy- piperidine A N NA B.sup.5 4.72,
497, F (CDCl.sub.3, 400 MHz): 10.01 (s, 1H), 8.91 (s, 1H),
8.84-8.71 (m, 2H), 7.65-7.56 (m, 2H), 7.55- 7.49 (m, 2H), 5.12-5.01
(m, 1H), 3.77 (t, J = 4.5 Hz, 4H), 3.61 (s, 2H), 2.99 (s, 2H),
2.57- 2.41 (m, 5H), 2.37-2.00 (m, 4H), 1.73-1.50 (br s, 4H),
1.20-1.04 (br s, 2H). 280 ##STR00517##
3-(1-Methyl-1H-pyrazol-4-yl)-5-(1-
propyl-piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N-Propyl 4- hydroxy-
piperidine A N NA Q 6.75, 416, F (DMSO-D.sub.6, 300 MHz): 12.91 (br
s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 0.5 Hz, 1H), 8.56
(d, J = 2.2 Hz, 1H), 8.30 (s, 1 H), 7.99 (s, 1H), 4.83- 4.71 (m,
1H), 3.92 (s, 3H), 2.89-2.77 (m, 2H), 2.24 (t, J = 7.4 Hz, 2H),
2.18-1.88 (m, 6H), 1.51- 1.35 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H).
281 ##STR00518## 5-((S)-1-Ethyl-pyrrolidin-3-yloxy)-
3-pyridin-4-yl-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
(R)-1-Ethyl- pyrrolidin- 3-ol A N NA B 3.40, 385, F (DMSO-D.sub.6,
400 MHz): 13.11 (s, 1H), 9.15 (d, J = 2.3 Hz, 1H), 9.06 (d, J = 2.3
Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J = 4.7, 1.6 Hz, 2H), 7.85 (dd, J
= 4.6, 1.7 Hz, 2H), 5.49- 5.44 (m, 1H), 3.20-3.13 (m, 1H),
3.10-3.03 (m, 1H), 2.55-2.22 (m, 5H), 2.21-2.11 (m, 1H), 0.94 (t, J
= 7.2 Hz, 3H). 282 ##STR00519##
trans-3-[4-(4,4-Difluoro-piperidin-1-
ylmethyl)-phenyl]-5-(-1-ethyl-3- fluoro-piperidin-4-yloxy)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile cis-1-Ethyl-
3-fluoro- piperidin- 4-ol A N NA B.sup.4 4.73, 340, F (CDCl.sub.3
400 MHz): 10.70 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.85 (s, 1H),
8.83 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H),
5.14- 4.79 (m, 2H), 3.74-3.60 (m, 2H), 3.38-3.23 (m, 1H), 3.07-2.93
(m, 1H), 2.74-2.41 (m, 6H), 2.26- 1.96 (m, 6H), 1.69-1.48 (m, 2H),
1.18-1.03 (m, 3H). 283 ##STR00520##
3-Pyridin-4-yl-5-[1-(2,2,2-trifluoro- ethyl)-piperidin-4-yloxy]-9H-
dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile 1-(2,2,2- Tri-
fluoroethyl) piperidin- 4-ol A N NA B, Q.sup.1 9.41, 453, F
(CDCl.sub.3 and CD.sub.3OD, 300 MHz): 9.00 (d, J = 2.2 Hz, 1H),
8.87 (d, J = 2.3 Hz, 1H), 8.78 (s, 1H), 8.74-8.67 (m, 2H),
7.80-7.74 (m, 2H), 5.09- 4.96 (m, 1H), 3.18-3.02 (m, 4H), 2.72-2.57
(m, 2H), 2.32-2.07 (m, 4H). 284 ##STR00521##
5-(8-Methyl-8-aza-bicyclo[3.2.1]oct-
3-yloxy)-3-pyridin-4-yl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 8-Methyl-8- azabicyclo
[3.2.1] octan-3-ol A N NA E.sup.1 4.40, 411, F (DMSO-D.sub.6, 300
MHz): 13.03 (br s, 1H), 9.14 (d, J = 2.2 Hz, 1H), 8.81- 8.78 (m,
2H), 8.75-8.71 (m, 2H), 7.88-7.83 (m, 2H), 5.15-4.99 (m, 1H),
3.25-3.17 (m, 2H), 2.25 (s, 3H), 2.06 (dd, J = 8.4, 2.9 Hz, 4H),
1.94- 1.86 (m, 2H), 1.54-1.43 (m, 2H). 285 ##STR00522##
5-(1-Isopropyl-piperidin-4-yloxy)-3- pyridin-4-yl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 1-Isopropyl- piperidin- 4-ol
A N NA E 4.93, 413, F (CDCl.sub.3 and CD.sub.3OD, 300 MHz): 8.99
(d, J = 2.3 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H), 8.78 (s, 1H),
8.73-8.66 (m, 2H), 7.81-7.75 (m, 2H), 5.09- 4.93 (m, 1H), 3.05-2.90
(m, 2H), 2.88-2.71 (m, 1H), 2.53-2.35 (m, 2H), 2.33-2.00 (m, 4H),
1.09 (d, J = 6.5 Hz, 6H). 286 ##STR00523##
5-(1-(2-Methoxy-ethyl)-piperidin-4-
yloxy]-3-pyridin-4-yl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile 1-(2- Methoxy- ethyl)- 4-
piperidinol A N NA E.sup.2 4.76, 429, F (CDCl.sub.3 and CD.sub.3OD,
300 MHz): 9.01 (d, J = 2.2 Hz, 1 H), 8.91 (d, J = 2.3 Hz, 1H), 8.78
(s, 1H), 8.73-8.66 (m, 2H), 7.84-7.78 (m, 2H), 5.08- 4.95 (m, 1H),
3.56 (t, J = 5.5 Hz, 2H), 3.10-2.97 (m, 2H), 2.65 (t, J = 5.5 Hz,
2H), 2.45-2.32 (m, 2H), 2.31-2.07 (m, 4H).
[0795] The compounds of the Examples in Table 13 were prepared via
the general alkylation procedure followed by the general bromide
displacement procedures described above.
TABLE-US-00014 TABLE 13 Ex- Bromide LCMS am- Akylation Displacement
Purification R.sub.T, M + H.sup.+, ple Structure/Name Method Method
Method(s) Method .sup.1H NMR (ppm) 287 ##STR00524##
5-(3-Methylamino-propoxy)-3-(1-
methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile A E Q 5.29, 362, A (CD.sub.3OD,
400 MHz): 8.84 (d, J = 2.2 Hz, 1H), 8.73- 8.69 (m, 1H), 8.62 (d, J
= 2.2 Hz, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 4.70 (t, J = 6.1 Hz,
2H), 4.05-3.96 (m, 3H), 3.00 (t, J = 7.2 Hz, 2H), 2.51 (s, 3H)
2.32-2.22 (m, 2H). 288 ##STR00525##
5-(3-Dimethylamino-propoxy)-3-(1-methyl-
1H-pyrazol-4-yl)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile
A E Q 4.96, 362, A (CD.sub.3OD, 400 MHz): 8.83 (s, 2H), 8.71 (s,
1H), 8.08 (s, 1H), 7.94-7.92 (m, 1H), 4.70 (t, J = 5.4 Hz, 2H),
4.02-3.97 (m, 3H), 3.00 (t, J = 5.4 Hz, 2H), 2.44 (s, 6H). 289
##STR00526## 5-(3-Dimethylamino-propoxy)-3-(1-
methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile A E Q 5.20, 388, A (DMSO-D.sub.6,
400 MHz, DMSO-d.sub.6): 12.89 (s, 1H), 8.95 (d, J = 2.2 Hz, 1H),
8.80 (d, J = 2.2 Hz, 1H), 8.79-8.75 (m, 1H), 8.28 (s, 1H), 7.99 (d,
J = 0.8 Hz, 1H), 4.66 (t, J = 5.4 Hz, 2H), 3.93 (s, 3H), 3.00 (t, J
= 5.3 Hz, 2H), 2.54 (s, 4H), 1.66-1.50 (m, 4H).
[0796] The compounds of the Examples in Table 14 were prepared via
the general bromide displacement procedures described above.
TABLE-US-00015 TABLE 14 Ex- Bromide LCMS am- Displacement
Purification R.sub.T, M + H.sup.+, ple Structure/Name Method
Method(s) Method .sup.1H NMR (ppm) 290 ##STR00527##
5-(1-Ethyl-piperidin-4-ylamino)-3- (1-methyl-1H-pyrazol-4-yl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile B C, Q, B 5.85, 401,
F (CDCl.sub.3 and MeOD, 400 MHz): 8.73 (d, J = 2.0 Hz, 1 H); 8.62
(d, J = 2.0 Hz, 1 H); 8.40 (s, 1 H); 8.03 (s, 1 H); 7.95 (d, J =
0.8 Hz, 1 H); 4.17-4.07 (m, 1 H); 4.02 (s, 3 H); 3.11-3.01 (m, 2
H); 2.51 (q, J = 7.2 Hz, 2 H); 2.29-2.12 (m, 4 H); 1.92- 1.78 (m, 2
H); 1.16 (t, J = 7.2 Hz, 3 H). 291 ##STR00528##
3-(1-Methyl-1H-pyrazol-4-yl)-5-(2- pyrrolidin-1-yl-ethylamino)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile B C, B.sup.1 5.84,
387, F (CDCl.sub.3 and MeOD, 400 MHz): 8.75 (d, J = 2.0 Hz, 1 H);
8.72 (d, J = 2.0 Hz, 1 H); 8.37 (s, 1 H); 8.03 (s, 1 H); 7.91 (s, 1
H); 4.02-3.97 (m, 5 H); 2.98 (t, J = 6.1 Hz, 2 H); 2.76-2.68 (m, 4
H); 1.86-1.77 (m, 4 H). 292 ##STR00529##
5-(3-Dimethylamino-propylamino)-3- (1-methyl-1H-pyrazol-4-yl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile B C, B.sup.2 6.09,
375, F (CDCl.sub.3 and MeOD, 400 MHz): 8.87 (d, J = 2.0 Hz, 1 H);
8.73 (d, J = 2.0 Hz, 1 H); 8.38 (s, 1 H); 8.07 (s, 1 H); 7.96 (d, J
= 0.8 Hz, 1 H); 4.02 (s, 3 H); 3.99 (t, J = 6.9 Hz, 2 H); 2.72 (t,
J = 7.1 Hz, 2 H); 2.44 (s, 6 H); 2.16-2.06 (m, 2 H). 293
##STR00530## 5-(4-Ethyl-piperazin-1-yl)-3-(1-
methyl-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole-6-
carbonitrile A Q.sup.1 5.15, 387, F (CDCl.sub.3 and MeOD, 400 MHz):
8.82 (d, J = 2.1 Hz, 1 H); 8.74- 8.71 (m, 2 H); 8.05 (s, 1 H); 7.90
(d, J = 0.8 Hz, 1 H); 4.02 (s, 3 H); 3.71-3.64 (m, 4 H); 2.94-2.84
(m, 4 H); 2.67 (q, J = 7.2 Hz, 2 H); 1.25 (t, J = 7.2 Hz, 3 H). 294
##STR00531## 3-Bromo-5-(4-ethyl-piperazin-1-yl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile C B.sup.1 4.62,
385, F (CDCl.sub.3 and MeOD, 400 MHz): 8.78 (d, J = 2.2 Hz, 1 H);
8.75 (s, 1 H); 8.70 (d, J = 2.2 Hz, 1 H); 3.68-3.61 (m, 4 H); 2.90-
2.81 (m, 4 H); 2.65 (q, J = 7.25 Hz, 2 H); 1.24 (t, J = 7.2 Hz, 3
H). 295 ##STR00532## 3-Bromo-5-(1-ethyl-piperidin-4-
ylamino)-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile C C, Q
2.84, 399, G (CDCl.sub.3 and MeOD, 400 MHz): 8.70 (d, J = 2.1 Hz, 1
H); 8.62 (d, J = 2.1 Hz, 1 H); 8.43 (s, 1 H); 4.22-4.08 (m, 1 H);
3.12- 3.01 (m, 2 H); 2.52 (q, J = 7.2 Hz, 2 H); 2.31-2.14 (m, 4 H);
1.93-1.74 (m, 2 H); 1.16 (t, J = 7.2 Hz, 3 H). 296 ##STR00533##
3-Bromo-5-(4-diethylamino- piperidin-1-yl)-9H-dipyrido[2,3-
b;4',3'-d]pyrrole-6-carbonitrile D C, B 2.57, 427, G (CDCl.sub.3
and MeOD, 400 MHz): 8.73-8.71 (m, 2 H); 8.69 (d, J = 2.2 Hz, 1 H);
3.68-3.54 (m, 4H); 2.96-2.86 (m, 1 H); 2.80 (q, J = 7.2 Hz, 4 H);
2.19-2.11 (m, 2 H); 1.99-1.86 (m, 2 H); 1.17 (t, J = 7.2 Hz, 6 H).
297 ##STR00534## 3-Bromo-5-[4-(2-methoxy-ethyl)-
piperazin-1-yl]-9H-dipyrido [2,3-b;4',3'-d]pyrrole-6-carbonitrile D
C, B.sup.1 5.42, 415, F (CDCl.sub.3 and MeOD, 400 MHz): 8.80 (d, J
= 2.2 Hz, 1 H); 8.74 (s, 1 H); 8.70 (d, J = 2.2 Hz, 1 H); 3.69-3.60
(m, 6 H); 3.42 (s, 3 H); 2.94-2.87 (m, 4 H); 2.79 (t, J = 5.45 Hz,
2 H). 298 ##STR00535## 3-Bromo-5-[4-(2,2,2-trifluoro-ethyl)-
piperazin-1-yl]-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile D
C, B.sup.1 4.60, 439, G (CDCl.sub.3 and MeOD, 300 MHz): 8.76 (d, J
= 2.2 Hz, 1 H); 8.75 (s, 1 H); 8.69 (d, J = 2.2 Hz, 1 H); 3.66-3.60
(m, 4 H); 3.25 (q, J = 9.6 Hz, 2 H); 3.10-3.04 (m, 4 H). 299
##STR00536## 3-Bromo-5-[4-(2-methanesulfonyl-
ethyl)-piperazin-1-yl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile D 2.45, 463, G
[0797] The compounds of the Examples in Table 15 were prepared via
the general Mitsunobu or the general Bromide Displacement Methods
followed by the general reduction procedure described above.
TABLE-US-00016 TABLE 15 Puri- LCMS Ex- Bromide Depro- fication
R.sub.T, M + am- Mitsunobu Displacement Reduction tection Meth-
H.sup.+, ple Structure/Name Method Method Method Method od Method
.sup.1H NMR (ppm) 300 ##STR00537##
5-(Piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A NA A B C.sup.2 4.74, 294, F
(MeOD and CDCl.sub.3, 300 MHz): 8.73 (s, 1 H); 8.66 (s, 1 H);
8.65-8.63 (m, 1 H); 7.46-7.41 (m, 1 H); 4.96-4.87 (m, 1 H); 3.21-
3.13 (m, 2 H); 2.72-2.62 (m, 2 H); 2.23-2.13 (m, 2 H); 1.99-1.88
(m, 2 H). 301 ##STR00538## 5-(1-Ethyl-piperidin-4-yloxy)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile A NA A E B.sup.4
5.10, 322, F (DMSO-D.sub.6, 400 MHz): 12.94 (s, 1H); 8.79 (s, 1 H);
8.71 (dd, J = 6.0, 1.7 Hz, 1 H); 8.60 (dd, J = 9.4, 1.7 Hz, 1 H);
7.47 (dd, J = 12.5, 4.7 Hz, 1 H); 4.78- 4.66 (m, 1 H); 2.90-2.78
(m, 2 H); 2.34 (q, J = 7.2 Hz, 2 H); 2.13-2.00 (m, 4 H); 1.99-1.86
(m, 2 H); 1.00 (t, J = 7.2 Hz, 3 H). 302 ##STR00539##
5-((S)-1-Ethyl-pyrrolidin-3-yloxy)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile A NA B E B.sup.2
4.28, 308, F (DMSO-D.sub.6, 400 MHz): 12.92 (s, 1 H); 8.78 (s, 1
H); 8.74-8.68 (m, 2 H); 7.45 (dd, J = 7.9, 4.8 Hz, 1 H); 5.43-5.36
(m, 1 H); 3.05-2.94 (m, 2 H); 2.71- 2.62 (m, 1 H); 2.57-2.42 (m, 2
H); 2.41-2.26 (m, 2 H); 2.21-2.09 (m, 1 H); 1.06 (t, J = 7.2 Hz, 3
H). 303 ##STR00540## 5-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile A NA B E C,
Q.sup.2 4.88, 320, F (DMSO-D.sub.6, 300 MHz): 13.27-12.47 (br s, 1
H); 8.76 (s, 1 H); 8.70 (dd, J = 4.8, 1.6 Hz, 1 H); 8.53 (dd, J =
7.9, 1.7 Hz, 1 H); 7.48 (dd, J = 7.9, 4.8 Hz, 1 H); 5.09-4.98 (m, 1
H); 3.11- 2.97 (m, 2 H); 2.89-2.54 (s, 4 H); 2.26-2.18 (m, 1 H);
2.17-2.03 (m, 1 H); 1.76 (m, 1 H); 1.56-1.39 (m, 2 H). 304
##STR00541## 5-(1-Isopropyl-piperidin-4-yloxy)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile A NA B E C,
Q.sup.2 2.25, 336, H (CDCl.sub.3 and MeOD, 300 MHz): 8.74 (s, 1 H);
8.68-8.66 (m, 1 H); 8.65 (s, 1 H); 7.46-7.40 (m, 1 H); 4.99-4.86
(m, 1 H); 3.05- 2.94 (m, 2 H); 2.87-2.74 (m, 1 H); 2.50-2.38 (m, 2
H); 2.29-2.02 (m, 4 H); 1.11 (d, J = 6.6 Hz, 6 H). 305 ##STR00542##
5-[1-(2-Methoxy-ethyl)-piperidin-4-
yloxy]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile A NA B E
C, Q.sup.2 5.46, 352, F (CDCl.sub.3 and MeOD, 300 MHz): 8.74 (s, 1
H); 8.68-8.63 (m, 2 H); 7.45- 7.40 (m, 1 H); 5.00-4.86 (m, 1 H);
3.57 (t, J = 5.5 Hz, 2 H); 3.37 (s, 3 H); 3.07- 2.97 (m, 2 H); 2.66
(t, J = 5.55 Hz, 2 H); 2.44-2.31 (m, 2 H); 2.28-2.04 (m, 4 H). 306
##STR00543## 5-[(S)-(1-Aza-bicyclo[2.2.2]oct-3-yl)
oxy]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile A NA B E
B.sup.1 5.02, 320, F (DMSO-D.sub.6, 300 MHz): 13.01 (br s, 1 H);
8.82 (d, J = 0.5 Hz, 1 H); 8.73 (dd, J = 4.8, 1.6 Hz, 1 H); 8.56
(dd, J = 7.9, 1.6 Hz, 1 H); 7.49 (dd, J = 7.9, 4.8 Hz, 1 H);
5.27-5.17 (m, 1 H); 4.14-3.99 (m, 1 H); 3.83- 3.69 (m, 1 H);
3.55-2.92 (m, 5 H); 2.42-2.23 (m, 1 H); 1.97-1.62 (m, 3 H). 307
##STR00544## 5-(4-Ethyl-piperazin-1-yl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile N A C A N A R.sup.7
3.29, 307, F (CDCl.sub.3 and CD.sub.3OD, 400 MHz): 8.86 (s, 1 H);
8.84 (dd, J = 8.0, 1.6 Hz, 1 H); 8.69 (dd, J = 4.8, 1.6 Hz, 1 H);
7.50 (dd, J = 8.0, 4.8 Hz, 1 H); 4.01-3.76 (m, 4 H); 3.74-3.57 (m,
4 H); 3.42 (q, J = 7.3 Hz, 2 H); 1.49 (t, J = 7.3 Hz, 3 H). 308
##STR00545## 5-(1-Ethyl-piperidin-4-ylamino)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile N A C A N A R.sup.7
4.27, 321, F (CDCl.sub.3 and CD.sub.3OD, 400 MHz): 8.71 (d, J = 8.0
Hz, 1 H); 8.62 (dd, J = 4.9, 1.5 Hz, 1 H); 8.53 (s, 1 H); 7.43 (dd,
J = 8.0, 4.9 Hz, 1 H); 4.44-4.32 (m, 1 H); 3.74-3.61 (m, 2 H);
3.27- 3.03 (m, 4 H); 2.56-2.41 (m, 2 H); 2.30-2.14 (m, 2 H); 1.42
(t, J = 7.3 Hz, 3 H). 309 ##STR00546##
5-(4-Diethylamino-piperidin-1-yl)-
9H-dipyrido[2,3-b;4',3'-d]pyrrole-6- carbonitrile N A D A N A
R.sup.7 5.05, 349, F (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 8.78
(s, 1H), 8.72 (dd, J = 8.0, 1.5 Hz, 1H), 8.66 (dd, J = 4.9, 1.8 Hz,
1H), 7.48 (dd, J = 8.0, 4.9 Hz, 1H), 3.75-3.61 (m, 5H), 3.46-3.35
(m, 4H), 2.37-2.29 (m, 2H), 2.28-2.15 (m, 2H), 1.44 (t, J = 7.3 Hz,
6H). 310 ##STR00547## 5-[4-(2-Methoxy-ethyl)-piperazin-1-
yl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole- 6-carbonitrile N A D A N A
R.sup.7 4.17, 337, F (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 8.84
(s, 1H), 8.80 (dd, J = 8.0, 1.6 Hz, 1H), 8.68 (dd, J = 4.9, 1.6 Hz,
1H), 7.49 (dd, J = 8.0, 4.9 Hz, 1H), 3.87-3.76 (m, 6H), 3.66-3.50
(m, 4H), 3.47 (s, 3H), 3.45-3.36 (m, 2H). 311 ##STR00548##
5-[4-(2,2,2-Trifluoro-ethyl)-piperazin-
1-yl]-9H-dipyrido[2,3-b;4',3'-d] pyrrole-6-carbonitrile N A D A N A
R.sup.7 10.56, 361, F (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 8.75
(s, 1H), 8.72 (dd, J = 8.0, 1.6 Hz, 1H), 8.65 (dd, J = 6.3, 1.6 Hz,
1H), 7.45 (dd, J = 8.0, 4.9 Hz, 1H), 3.66-3.60 (m, 4H), 3.24 (q, J
= 9.7 Hz, 2H), 3.10-3.05 (m, 4H). 312 ##STR00549##
5-[4-(2-Methanesulfonyl-ethyl)- piperazin-1-yl]-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile N A D A N A R.sup.7 4.53,
385, F (CDCl.sub.3 plus CD.sub.3OD, 400 MHz): 8.77 (s, 1H), 8.74
(dd, J = 8.0, 1.6 Hz, 1H), 8.65 (dd, J = 6.2, 1.6 Hz, 1H), 7.46
(dd, J = 8.0, 4.9 Hz, 1H), 3.73-3.62 (m, 4H), 3.51-3.39 (m, 2H),
3.24-3.12 (m, 4H), 3.10-2.94 (m, 5H). 313 ##STR00550##
trans-5-(-1-Ethyl-3-fluoro- piperidin-4-yloxy)-9H-dipyrido
[2,3-b;4',3'-d]pyrrole-6-carbonitrile A NA A E R.sup.5 4.73, 340, F
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.75 (s, 1H), 8.69 (dd, J =
7.9, 1.6 Hz, 1H), 8.63 (dd, J = 4.9, 1.6 Hz, 1H), 7.38 (dd, J =
7.9, 4.9 Hz, 1H), 5.15-4.74 (m, 2H), 3.36-3.23 (m, 1H), 3.04- 2.94
(m, 1H), 2.62-2.35 (m, 3H), 2.28-2.04 (m, 3H), 1.13 (t, J = 7.2 Hz,
3H).
Example 314
5-Bromo-6-chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole
##STR00551##
[0798] Step 1: 5-Bromo-6-chloro-4-iodonicotinic acid
##STR00552##
[0800] n-Butyllithium (1.6M in hexanes, 172 mL, 276 mmol) was added
to a solution of 2,2,6,6-tetramethylpiperidine (48.5 mL, 285 mmol)
in anhydrous THF (200 mL) at -50.degree. C. After 20 min, solid
5-bromo-6-chloronicotinic acid (21.6 g, 92 mmol) was added
portionwise and the resultant slurry was allowed to warm to
-20.degree. C. over 1 h and stirred at that temperature for 1 h.
After this time, the reaction mixture was cooled to -60.degree. C.
and transferred via cannula to a solution of iodine (70 g, 276
mmol) in anhydrous THF (100 mL) at -60.degree. C. at such a rate
that the internal temperature of the solution remained below
-40.degree. C. On complete addition, the reaction mixture was
allowed to warm slowly to ambient temperature and stirred for 18 h.
The reaction mixture was concentrated in vacuo and the resultant
dark red slurry was dissolved in water (500 mL) and washed with
diethyl ether (3.times.200 mL). The pH of aqueous layer was
adjusted to 2 by the addition of 1M aqueous hydrochloric acid and
the resulting beige precipitate was collected by filtration and
dried under vacuum to afford the title compound (17.7 g, 53%).
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 8.30 (s, 1H).
Step 2: (5-Bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid
tert-butyl ester
##STR00553##
[0802] Triethylamine (20.6 mL, 147 mmol) was added to a solution of
5-bromo-6-chloro-4-iodo-nicotinic acid (17.7 g, 49 mmol) and
diphenylphosphorazide (15.8 mL, 73 mmol) in toluene (100 mL) and
t-BuOH (90 mL) and the resultant solution was heated at 110.degree.
C. for 3 h. The reaction mixture was allowed to cool and then
concentrated in vacuo and the resultant residue was purified by
flash chromatography (silica, 330 g column, ISCO, 0-100% ethyl
acetate in cyclohexane) to afford the title compound as a white
solid (21.1 g, 90%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 9.04 (s,
1H), 8.25 (s, 1H), 1.47 (s, 9H).
Step 3: 5-Bromo-6-chloro-4-iodo-pyridin-3-ylamine
##STR00554##
[0804] Trifluoroacetic acid (30 mL) was added to a solution of
(5-bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester (19.0 g, 44 mmol) in DCM (120 mL) and the resultant solution
was stirred at ambient temperature for 2 h then concentrated in
vacuo. The resultant residue was loaded onto an SCX-2 cartridge (70
g) eluting with acetonitrile (100 mL) then 2N ammonia in methanol
(100 mL). The basic fraction was concentrated in vacuo to afford
the title compound (11.5 g, 78%). .sup.1H NMR (DMSO-D.sub.6, 400
MHz): 7.23 (s, 1H), 5.92 (s, 2H).
Step 4: 2-Fluoro-5-(4-piperidin-1-ylmethylphenyl)-pyridine
##STR00555##
[0806] A degassed mixture of 5-bromo-2-fluoropyridine (578 .mu.L,
5.60 mmol), 4-piperidin-1-ylmethyl-boronic acid (1.23 g, 5.6 mmol),
1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (205
mg, 5 mol %) in 1N potassium fluoride solution (4 mL) and
acetonitrile (9 mL) was heated under microwave irradiaition at
100.degree. C. for 15 min. The resultant crude mixture was diluted
with water (10 mL) and extracted with DCM (3.times.20 mL). The
combined organic layer was purified by flash chromatography
(silica, 40 g column, ISCO, 0-10% (2N ammonia in MeOH) in DCM) to
afford the title compound (1.27 g, 84%). .sup.1H NMR (CDCl.sub.3,
400 MHz): 8.41 (d, J=2.5 Hz, 1H), 7.96 (td, J=8.5, 2.5 Hz, 1H),
7.48 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.99 (dd, J=8.5,
3.0 Hz, 1H), 3.52 (s, 2H), 2.40 (br. s, 4H), 1.59 (p, J=6.0 Hz,
4H), 1.44 (t, J=6.0 Hz, 2H). LCMS (Method B): R.sub.T=2.05 min,
M+H.sup.+=271.
Step 5: 2-Fluoro-3-boronic
acid-5-(4-piperidin-1-ylmethylphenyl)-pyridine
##STR00556##
[0808] Lithium diisopropylamine (7.1 mL, 14.1 mmol) was added to a
solution of 2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-pyridine
(1.27 g, 4.70 mmol) and triisopropyl borate (3.26 mL, 14.1 mmol) in
anhydrous THF (12 mL) at -10.degree. C. The resultant solution was
stirred between -10.degree. C. and 0.degree. C. for 1 h, and then
quenched by the addition of saturated aqueous ammonium chloride (10
mL). The reaction mixture was diluted with water (20 mL) and
extracted with DCM (3.times.20 mL). The combined organic layer was
dried over magnesium sulfate and concentrated in vacuo. The crude
oil was triturated with cyclohexane:DCM (3:1) to afford the title
compound as a beige solid (677 mg, 46%). NMR (DMSO-D.sub.6, 300
MHz): 8.53 (s, 1H), 8.35-8.31 (m, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.41
(d, J=8.0 Hz, 2H), 3.54-3.42 (m, 2H), 2.44-2.24 (m, 4H), 1.57-1.45
(m, 4H), 1.44-1.36 (m, 2H), 1.20 (d, J=6.5 Hz, 2H). LCMS (Method
B): R.sub.T=1.79 min, M+H.sup.+=315.
Step 6:
5'-Bromo-6'-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4-
']bipyridinyl-3'-ylamine
##STR00557##
[0810] A mixture of 2-fluoro-3-boronic
acid-5-(4-piperidin-1-ylmethylphenyl)-pyridine (515 mg, 1.6 mmol),
5-bromo-6-chloro-4-iodo-pyridin-3-ylamine (546 mg, 1.6 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (60
mg, 5 mol %) in 1N potassium fluoride solution (5 mL) and
acetonitrile (15 mL) was heated under microwave irradiation at
110.degree. C. for 20 min. The reaction mixture was allowed to cool
to ambient temperature, diluted with water (10 mL) and extracted
with DCM (3.times.20 mL). The combined organic layer was
concentrated in vacuo and the residue was purified by flash
chromatography (silica, 12 g column, ISCO, 0-10% MeOH in DCM) to
afford the title compound (189 mg, 24%). .sup.1H NMR (CDCl.sub.3,
300 MHz): 8.57 (dd, J=2.5, 1.0 Hz, 1H), 7.96 (s, 1H), 7.90 (dd,
J=8.5, 2.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H),
3.72 (s, 2H), 3.54 (s, 2H), 2.41 (br. s, 4H), 1.64-1.58 (m, 4H),
1.48-1.44 (m, 2H). LCMS (Method B): R.sub.T=2.41 min,
M+H.sup.+=475/477.
Step 7:
5-Bromo-6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole
##STR00558##
[0812] Sodium bis(trimethylsilyl)amide (3.9 mL, 3.90 mmol) was
added to a solution of
5'-bromo-6'-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyri-
dinyl-3'-ylamine (187 mg, 0.39 mmol) in anhydrous THF (7.0 mL) and
the resultant solution stirred at ambient temperature for 20 min.
The reaction mixture was diluted with water (20 mL) and extracted
with DCM: MeOH (4:1, 3.times.20 mL). The combined organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated
in vacuo. The resultant residue was purified by flash
chromatography (silica, 4 g column, ISCO, 0-15% MeOH in DCM) to
afford the title compound as a beige powder (30 mg, 17%). .sup.1H
NMR (CDCl.sub.3, 400 MHz): 9.17 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0
Hz, 1H), 8.67 (s, 1H), 7.65 (d, J=7.5 Hz, 2H), 7.49 (d, J=7.5 Hz,
2H), 3.59 (s, 2H), 2.51-2.47 (m, 4H), 1.68-1.59 (m, 4H), 1.51-1.45
(m, 2H). LCMS (Method A): R.sub.T=7.10 min, M+H+=455/457.
Example 315
6-Chloro-3-(4-piperidin-1-ylmethyl-phenyl)-5-vinyl-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole
##STR00559##
[0813] Step 1:
6'-Chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-5'-vinyl-[3,4]bipyri-
dinyl-3'-ylamine
##STR00560##
[0815] A mixture of
5'-bromo-6'-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4']bipyr-
idinyl-3'-ylamine (93 mg, 0.19 mmol), vinyltributyl tin (63 .mu.L,
0.21 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol
%) and lithium chloride (25 mg, 0.59 mmol) in 1,4-dioxane (1.0 mL)
was heated under reflux for 3.5 h. The reaction mixture was allowed
to cool to ambient temperature, diluted with water (10 mL) and
extracted with DCM (3.times.20 mL). The combined organic layer was
concentrated in vacuo and the resultant residue purified by flash
chromatography (silica, 4 g column, ISCO, 0-10% MeOH in DCM) to
afford the title compound as a beige powder (77 mg, 82%). .sup.1H
NMR (CDCl.sub.3, 400 MHz): 8.50 (dd, J=2.5, 1.0 Hz, 1H), 7.94 (s,
1H), 7.88 (dd, J=8.5, 2.5 Hz, 1H), 7.54-7.47 (m, 4H), 6.53 (dd,
J=18.0, 11.5 Hz, 1H), 5.37 (dd, J=11.5, 1.0 Hz, 1H), 5.11 (dd,
J=18.0, 1.0 Hz, 1H), 3.60 (s, 2H), 3.55-3.50 (m, 2H), 2.48-2.35 (m,
4H), 1.68-1.58 (m, 4H), 1.50-1.44 (m, 2H). LCMS (Method B):
R.sub.T=2.32 min, M+H.sup.+=423/425.
Step 2:
6-Chloro-3-(4-piperidin-1-ylmethyl-phenyl)-5-vinyl-9H-dipyrido[2,3-
-b;4',3'-d]pyrrole
##STR00561##
[0817] Sodium bis(trimethylsilyl)amide (1.3 mL, 1.3 mmol) was added
to a solution of
6'-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-5'-vinyl-[3,4]
bipyridinyl-3'-ylamine (53 mg, 0.13 mmol) in anhydrous THF (1 mL)
and the resultant solution stirred at ambient temperature for 20
min. The reaction mixture was diluted with brine (5 mL) and ethyl
acetate (5 mL). The resultant precipitate was collected by
filtration to afford the title compound as a beige powder (13 mg,
26%). NMR (CDCl.sub.3, 400 MHz): 8.85 (d, J=2.0 Hz, 1H), 8.77 (d,
J=2.0 Hz, 1H), 8.61 (s, 1H), 7.58-7.55 (m, 2H), 7.46 (d, J=8.0 Hz,
2H), 7.22-7.14 (m, 1H), 6.03-6.01 (m, 1H), 5.99-5.97 (m, 1H), 3.56
(s, 2H), 2.47-2.37 (m, 4H), 1.64-1.59 (m, 4H), 1.52-1.44 (m, 2H).
LCMS (Method A): R.sub.T=6.81 min, M+H.sup.+=403/405.
Example 316
5-Ethyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-
-6-carbonitrile
##STR00562##
[0818] Step 1: Trifluoromethanesulfonic acid
9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yl
ester
##STR00563##
[0820] Trifluoromethanesulfonic anhydride (0.91 g, 0.54 mL, 3.22
mmol) was added dropwise to a suspension of
9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitr-
ile (1.03 g, 2.93 mmol) in pyridine (1.2 mL, 14.7 mmol) and dry DCM
(20 mL) at 0.degree. C. The reaction mixture was then allowed to
warm to ambient temperature and stirred for 2 h. The reaction
mixture was treated with 1N hydrochloric acid (10 mL) and the
phases were separated. The aqueous phase was extracted with DCM
(2.times.10 mL), the combined organic phase was dried over
anhydrous magnesium sulfate and concentrated in vacuo. The
resultant residue was purified by chromatography (silica, 5 g
column, Si-SPE, DCM) to afford the title compound as a white solid
(855 mg, 60%). LCMS (Method B): R.sub.T=4.22 min,
M+H.sup.+=483.
Step 2:
9-Benzenesulfonyl-5-vinyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
onitrile
##STR00564##
[0822] A mixture of trifluoromethanesulfonic acid
9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yl
ester (150 mg, 0.31 mmol), tributyl(vinyl)stannane (102 .mu.L, 0.35
mmol), lithium chloride (40 mg, 0.93 mmol) and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 6.0 .mu.mol) in
dioxane (1.5 mL) was degassed with argon and heated under reflux
for 18 h. The reaction mixture was allowed to cool to ambient
temperature then diluted with DCM (9 mL) and methanol (1 mL). The
resultant residue was purified by chromatography (silica, 2 g
column, Si-SPE, 0-2% MeOH in DCM) and triturated with pentane
(2.times.2 mL) to afford the title compound as a white solid (60
mg, 52%). LCMS (Method B): R.sub.T=3.73 min, M+H.sup.+=361.
Step 3:
9-Benzenesulfonyl-5-ethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
onitrile
##STR00565##
[0824] A mixture of
9-benzenesulfonyl-5-vinyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitril-
e (60 mg 0.16 mmol) and 10% palladium on carbon (20 mg) in THF (4
mL) and IMS (3 mL) was stirred under an atmosphere of hydrogen for
3 h. The reaction vessel was then purged with nitrogen then the
reaction mixture was filtered through celite. The celite pad was
washed with DCM and then ethyl acetate and the combined filtrate
was concentrated in vacuo to yield the title compound as a beige
solid (60 mg, 99%). LCMS (Method B): R.sub.T=3.78 min,
M+H.sup.+=363.
Step 4:
5-Ethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00566##
[0826] A mixture of
9-benzenesulfonyl-5-ethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitril-
e (60 mg, 0.16 mmol), DCM (3.0 mL) and 7N ammonia in methanol (3
mL) was stirred at room temperature for 5 days. The reaction
mixture was then concentrated in vacuo and the resultant residue
was triturated with methanol (2 mL) and dried in vacuo to give the
title compound as an off-white solid (28 mg, 81%). LCMS (Method B):
R.sub.T=2.81 min, M+H.sup.+=223.
Step 5:
3-Bromo-5-ethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00567##
[0828] To a solution of
5-ethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (48 mg,
0.21 mmol) in DMF (1 mL) was added NBS (54 mg, 0.30 mmol) then the
reaction mixture was stirred for 18 h at ambient temperature. The
reaction mixture was then diluted with ethyl acetate (20 mL) and
washed with saturated aqueous sodium carbonate (10 mL). The aqueous
phase was washed with DCM (2.times.10 mL), the combined organic
phase was washed with saturated brine (2.times.10 mL) and
concentrated in vacuo to afford the title compound as a yellow
solid (50 mg, 79%). LCMS (Method B): R.sub.T=3.34 min,
M+H.sup.+=301/303.
Step 6:
5-Ethyl-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole-6-carbonitrile
##STR00568##
[0830] A mixture of
3-bromo-5-ethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
(48 mg, 0.16 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (56
mg, 0.26 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg,
0.016 mmol) in 2N aqueous sodium carbonate (0.5 mL) and
acetonitrile (0.63 mL) was heated under microwave irradiation at
140.degree. C. for 35 minutes. The reaction mixture was allowed to
cool to ambient temperature, diluted with water (5 mL) and
extracted with ethyl acetate (3.times.5 mL). The combined organic
layer was dried over anhydrous magnesium sulfate, filtered and
evaporated in vacuo. The resultant residue was purified by flash
chromatography (silica, 2 g column, ISCO, 0-5% methanol in DCM) and
trituration with diethyl ether (2.times.1 mL) to afford the title
compound as a beige solid (29 mg, 46%). .sup.1H NMR (DMSO-D.sub.6,
400 MHz): 12.93 (br. s, 1H), 8.99 (d, J=2.2 Hz, 1H), 8.91 (s, 1H),
8.79 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz,
2H), 3.53-3.43 (m, 4H), 2.42-2.33 (m, 4H), 1.55-1.47 (m, 4H),
1.46-1.37 (m, 5H). LCMS (Method A): R.sub.T=6.23 min,
M+H.sup.+=396.
Example 317
5-Hydroxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole-6-carbonitrile
##STR00569##
[0831] Step 1:
9-Benzenesulfonyl-5-hydroxy-3-(4-piperidin-1-ylmethyl
phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00570##
[0833] A mixture of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (150 mg, 0.35 mmol), 4-piperidin-1-ylmethylphenyl
boronic acid (126 mg, 0.6 mmol) and [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) (27 mg, 0.04 mmol) in 2N aqueous
potassium acetate (1.1 mL) and acetonitrile (1.4 mL) was heated
under microwave irradiation at 140.degree. C., for 30 minutes. The
reaction mixture was diluted with ethyl acetate (10 mL) and water
(10 mL) resulting in the formation of a precipitate. The
supernatant liquors were decanted and the precipitate was dissolved
in 10% methanol in DCM. The decanted liquors were partitioned and
the aqueous phase was washed with 10% methanol in DCM (2.times.10
mL). The combined organic phases were concentrated in vacuo and the
resultant residue purified by column chromatography (silica, 2 g
cartridge, Si-SPE, 0-20% MeOH in DCM) afforded the crude product
which was triturated with acetonitrile (1 mL) and methanol (1 mL)
to afford the title compound as a beige solid (60 mg, 31%). LCMS
(Method B): R.sub.T=2.65 min, M+H.sup.+=524.
Step 2:
5-Hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b:4',3'-
-d]pyrrole-6-carbonitrile
##STR00571##
[0835]
9-Benzenesulfonyl-5-hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dip-
yrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (50 mg, 0.01 mmol) was
dissolved in 0.15N potassium hydroxide solution in methanol (7 mL).
The reaction mixture was stirred for 2.5 h then treated with a
solution of monobasic potassium phosphate (136 mg, 1.0 mmol) in
water (2 mL). The resultant mixture was concentrated in vacuo and
the resultant residue was diluted with water (5 mL). The pH of the
aqueous phase was adjusted to 7 by the addition of 1N hydrochloric
acid. The aqueous phase was extracted with ethyl acetate, DCM and
THF. The combined organic phase was concentrated in vacuo and the
residue purified by flash chromatography (silica, 500 mg column,
Si-SPE, 10-20% methanol in DCM) to afford the title compound as its
hydrochloride salt (25 mg, 63%). NMR (DMSO-D.sub.6, 400 MHz): 12.91
(s, 1H), 11.86 (br. s, 1H), 10.41 (s, 1H), 9.13 (d, J=2.2 Hz, 1H),
9.00 (d, J=2.2 Hz, 1H), 8.60 (s, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.76
(d, J=8.1 Hz, 2H), 4.33 (d, J=5.2 Hz, 2H), 3.39-3.29 (m, 2H),
2.92-2.83 (m, 2H), 1.85-1.63 (m, 5H), 1.45-1.31 (m, 1H). LCMS
(Method A): R.sub.T=5.32 min, M+H.sup.+=384.
Example 318
5-Ethoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le-6-carbonitrile hydrochloride
##STR00572##
[0836] Step 1:
9-Benzenesulfonyl-3-bromo-5-ethoxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-ca-
rbonitrile
##STR00573##
[0838] A solution of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (120 mg, 0.28 mmol) in anhydrous THF (5 mL) was cooled
to 0.degree. C. and treated with sodium hydride (60% dispersion in
mineral oil; 12 mg, 0.30 mmol). After gas evolution had ceased,
iodoethane (424 .mu.L, 4.10 mmol) was added and the mixture stirred
at ambient temperature overnight then heated at 60.degree. C. for 5
h. The reaction was then allowed to cool, diluted with toluene and
concentrated in vacuo. The residue was purified by column
chromatography (silica, 2 g column, Si II SPE, 10-100% ethyl
acetate in DCM) to afford the title compound as a yellow solid (30
mg, 23%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 8.86 (s, 1H), 8.77
(s, 2H), 8.24-8.22 (m, 1H), 8.22-8.20 (m, 1H), 7.81-7.75 (m, 1H),
7.68-7.61 (m, 2H), 4.75 (q, J=7.2 Hz, 2H), 1.64 (t, J=7.2 Hz, 3H).
LCMS (Method B): R.sub.T=3.30 min, M+H.sup.+=457/459.
Step 2:
5-Ethoxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole-6-carbonitrile hydrochloride
##STR00574##
[0840] A degassed mixture of
9-benzenesulfonyl-3-bromo-5-ethoxy-9H-dipyrido[2,3-b;4',3'
d]pyrrole-6-carbonitrile (60 mg, 0.13 mmol),
4-piperidin-1-ylmethylphenyl boronic acid (48 mg, 0.22 mmol) and
[1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (10
mg, 0.013 mmol) in 2N aqueous sodium carbonate (0.42 mL) and
acetonitrile (0.53 mL) was heated under microwave irradiation at
140.degree. C. for 30 minutes. The reaction mixture was allowed to
cool to ambient temperature, diluted with ethyl acetate (5 mL) and
THF (5 mL) and washed with sodium hydrogen carbonate (5 mL). The
aqueous phase was extracted with THF (2.times.5 mL) then the
combined organic layer was concentrated in vacuo. The resultant
residue was taken up in 1:1 DCM:MeOH containing 0.5 mL 1M
hydrochloric acid and purified by flash chromatography (silica, 2 g
column, Si-SPE, 5-25% methanol in DCM) and trituration with
acetonitrile and 20% MeOH in acetonitrile to afford the title
compound as the hydrochloride salt as a brown powder (24 mg, 41%).
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 8.98 (d, J=2.3 Hz, 1H), 8.94
(d, J=2.3 Hz, 1H), 8.44 (s, 1H), 7.84 (d, J=7.8 Hz, 2H), 7.62 (d,
J=7.8 Hz, 2H), 4.64 (q, J=7.2 Hz, 2H), 4.34 (s, 2H), 3.54-3.45 (m,
4H), 3.44-3.26 (m, 1H), 3.02-2.82 (m, 2H), 1.91-1.66 (m, 4H), 1.62
(t, J=7.2 Hz, 3H). LCMS (Method A): R.sub.T=4.94 min,
M+H.sup.+=412.
Example 319
5-(2-Methoxyethoxy)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4'-
,3'-d]pyrrole-6-carbonitrile
##STR00575##
[0841] Step 1:
9-Benzenesulfonyl-3-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4',3'-d]-
pyrrole-6-carbonitrile
##STR00576##
[0843] A solution of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (120 mg, 0.28 mmol), 2-methoxyethanol (128 .mu.L, 1.60
mmol) and triphenylphosphine (315 mg, 1.60 mmol) in anhydrous DMF
(1.25 mL) was treated dropwise with diethyl azodicarboxylate (252
.mu.L, 1.60 mmol) and the mixture stirred at ambient temperature
for 9 h. The mixture was diluted with ethyl acetate (15 mL) and
washed with brine (3.times.10 mL), dried over anhydrous magnesium
sulfate, filtered and evaporated in vacuo. The crude material was
purified by column chromatography (silica, 5 g column, Si-SPE,
30-50% DCM in pentane) to afford the title compound (50 mg, 37%).
.sup.1H NMR (CDCl.sub.3, 400 MHz): 9.58 (s, 1H), 8.97 (d, J=2.3 Hz,
1H), 8.76 (d, J=2.3 Hz, 1H), 8.24-8.22 (m, 1H), 8.22-8.00 (m, 1H),
7.66-7.60 (m, 1H), 7.54-7.48 (m, 2H), 4.74-4.69 (m, 2H), 3.87-3.83
(m, 2H), 3.48 (s, 3H). LCMS (Method B): R.sub.T=4.25 min,
M+H.sup.+=487/489.
Step 2:
5-(2-Methoxyethoxy)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2-
,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00577##
[0845] A degassed mixture of
3-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonit-
rile (50 mg, 0.10 mmol), 4-piperidin-1-ylmethylphenyl boronic acid
(31 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (9 mg, 0.012 mmol) in 2N aqueous sodium
carbonate solution (0.42 mL) and acetonitrile (0.53 mL) were heated
under microwave irradiation at 140.degree. C. for 30 minutes. The
reaction mixture was diluted with water (2 mL) and extracted with
10% MeOH in DCM. The combined organic phase was concentrated in
vacuo and the resultant residue was purified by flash
chromatography (silica, 500 mg column, Si-SPE, 0-20% methanol in
DCM). The resultant residue was dissolved in a solution of 0.15M
potassium hydroxide in methanol (7 mL) and stirred for 45 minutes.
1N Potassium dihydrogen phosphate (1 mL) was added then the mixture
concentrated in vacuo. The resultant residue was diluted with water
and the pH adjusted to 7 by the addition of 1N potassium dihydrogen
phosphate. The aqueous phase was extracted with DCM (3.times.10 mL)
and 20% ethanol in DCM (10 mL), the combined organic phase was
dried over magnesium sulfate and concentrated in vacuo. The
resultant residue was purified by flash chromatography (silica, 500
mg column, Si-SPE, 2-4% methanol in DCM) and trituration with
acetonitrile to afford the title compound as a brown solid (14 mg,
32%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 9.91 (s, 1H), 9.09 (d,
J=2.2 Hz, 1H), 8.93 (d, J=2.2 Hz, 1H), 8.80 (s, 1H), 7.67 (d, J=8.1
Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.75-4.69 (m, 2H), 3.95-3.89 (m,
2H), 3.58 (s, 2H), 3.47 (s, 3H), 2.51-2.37 (m, 4H), 1.68-1.54 (m,
4H), 1.52-1.41 (m, 2H). LCMS (Method A): R.sub.T=6.27 min,
M+H.sup.+=442.
Example 320
3-(1-Methyl-1H-pyrazol-4-yl)-5-(pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole-6-carbonitrile hydrochloride
##STR00578##
[0846] Step 1:
3-(9-Benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-y-
loxy)pyrrolidine-1-carboxylic acid tert-butyl ester
##STR00579##
[0848] A solution of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (200 mg, 0.46 mmol), 3-hydroxypyrrolidine-1-carboxylic
acid tert-butyl ester (670 mg, 3.56 mmol) and triphenylphosphine
(724 mg, 2.76 mmol) in anhydrous DMF (2 mL) was treated dropwise
with diethyl azodicarboxylate (0.53 mL, 3.40 mmol) and the mixture
stirred at ambient temperature for 3 h then left to stand
overnight. The mixture was diluted with ethyl acetate (20 mL) and
washed with brine (3.times.15 mL), dried over magnesium sulfate and
concentrated in vacuo. The crude material was purified by flash
chromatography (silica, 20 g column, Si-SPE, 0-20% methanol in
DCM). Collecting appropriate fractions afforded the title compound
(160 mg, 57%). NMR (CDCl.sub.3, 400 MHz): 9.57 (s, 1H), 8.76 (d,
J=2.3 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 1H), 8.23-8.21
(m, 1H), 7.71-7.61 (m, 1H), 7.58-7.45 (m, 2H), 5.88-5.83 (m, 1H),
4.36-4.11 (m, 1H), 3.87-3.36 (m, 2H), 2.48-2.26 (m, 2H), 2.13-2.05
(m, 1H), 1.46 (s, 9H). LCMS (Method B): R.sub.T=4.51 min,
M+H.sup.+=598/600.
Step 2:
3-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]-
pyrrol-5-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
##STR00580##
[0850] A degassed mixture of
3-(3-bromo-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yloxy)-pyrrolidine--
1-carboxylic acid tert-butyl ester (160 mg, 0.20 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(54 mg, 0.26 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg,
0.026 mmol) in 1N aqueous potassium fluoride (0.60 mL, 0.60 mmol)
and acetonitrile (0.60 mL) was heated at 130.degree. C. under
microwave irradiation for 30 minutes. The reaction mixture was
allowed to cool to ambient temperature diluted with water (5 mL)
and saturated aqueous sodium carbonate (5 mL) then extracted with
ethyl acetate (3.times.10 mL). The combined organic phase was dried
over magnesium sulfate and concentrated in vacuo. The resultant was
purified by flash chromatography (silica, 2 g column, Si-SPE
cartridge, 0-100% ethyl acetate in DCM then methanol) and
trituration with acetonitrile to afford the title compound as a
white solid (28 mg, 30%). .sup.1H NMR (CDCl.sub.3, 400 MHz):
8.78-8.71 (m, 2H), 8.46 (s, 1H), 7.90 (s, 1H), 7.85-7.80 (m, 1H),
5.81 (s, 0.5H), 5.73 (s, 0.5H), 4.01 (s, 3H), 3.86-3.57 (m, 3H),
2.58-2.40 (m, 1H), 2.37-2.17 (m, 2H), 1.39 (s, 4H), 1.33 (s, 5H).
LCMS (Method B): R.sub.T=3.09 min, M+H.sup.+=460.
Step 3:
3-(1-Methyl-1H-pyrazol-4-yl)-5-(pyrrolidin-3-yloxy)-9H-dipyrido[2,-
3-b;4',3'-d]pyrrole-6-carbonitrile, hydrochloride salt
##STR00581##
[0852]
3-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]p-
yrrol-5-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (28
mg, 0.06 mmol) was treated with a mixture of acetyl chloride and
methanol (2:5, 1 mL). After 1 h the mixture was concentrated in
vacuo and the resultant residue was triturated with acetonitrile,
the solid collected by filtration and dried in vacuo to afford the
compound as a yellow solid (25 mg, 100%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 13.07 (s, 1H), 9.83 (s, 1H), 9.63 (s, 1H),
8.99 (d, J=2.1 Hz, 1H), 8.82 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.45
(s, 1H), 8.11 (d, J=0.8 Hz, 1H), 5.68-5.61 (m, 1H), 3.98-3.88 (m,
5H), 3.62-3.43 (m, 2H), 2.43-2.34 (m, 1H), 2.29-2.17 (m, 1H). LCMS
(Method A): R.sub.T=4.97 min, M+H.sup.+=360.
Example 321
3-(1-Methyl-1H-pyrazol-4-yl)-5-(S)-pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4-
',3'-d]pyrrole-6-carbonitrile Hydrochloride salt
##STR00582##
[0854] The title compound was prepared using the procedure
described in Example 320 using
(R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester.
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 13.06 (s, 1H), 9.67 (s, 1H),
9.43 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.82 (s, 1H), 8.58 (d, J=2.1
Hz, 1H), 8.41 (s, 1H), 8.09 (d, J=0.8 Hz, 1H), 5.68-5.60 (m, 1H),
3.99-3.89 (m, 4H), 3.80-3.70 (m, 1H), 2.44-2.34 (m, 1H), 2.30-2.17
(m, 1H). LCMS (Method A): R.sub.T=5.07 min, M+H.sup.+=360.
Example 322
3-(1-Methyl-1H-pyrazol-4-yl)-5-((R)-pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile, hydrochloride salt
##STR00583##
[0856] The title compound was prepared using the procedure
described in Example 320 using
(S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 13.07 (s, 1H), 9.83 (s, 1H),
9.63 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.82 (s, 1H), 8.58 (d, J=2.1
Hz, 1H), 8.45 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 5.68-5.61 (m, 1H),
3.98-3.88 (m, 5H), 3.62-3.43 (m, 2H), 2.43-2.34 (m, 1H), 2.29-2.17
(m, 1H). LCMS (Method A): R.sub.T=4.97 min, M+H.sup.+=360.
Example 323
5-(2-Methoxyethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d-
]pyrrole-6-carbonitrile
##STR00584##
[0857] Step 1:
9-Benzenesulfonyl-3-bromo-5-(2-methoxyethoxy)-9H-dipyrido[2,3-b;4',3'-d]p-
yrrole-6-carbonitrile
##STR00585##
[0859] A solution of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (145 mg, 0.3 mmol), 2-methoxyethanol (158 .mu.L, 2.0
mmol) and triphenylphosphine (525 mg, 2.0 mmol) in anhydrous DMF
(1.25 mL) was treated with diethyl azodicarboxylate (0.315 mL, 2.0
mmol) and the mixture stirred at ambient temperature for 30 min
then left to stand for 4 days. The mixture was diluted with ethyl
acetate (20 mL) and washed with brine (3.times.10 mL) then the
aqueous phase was extracted with ethyl acetate (10 mL). The
combined organic phase was dried over magnesium sulfate and
concentrated in vacuo. The resultant residue was purified by flash
chromatography (silica, 5 g column, Si-SPE, 0-100% ethyl acetate in
DCM) to afford the title compound (35 mg, 23%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 9.58 (s, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.76
(d, J=2.3 Hz, 1H), 8.26-8.18 (m, 2H), 7.68-7.60 (m, 1H), 7.57-7.47
(m, 2H), 4.74-4.69 (m, 2H), 3.89-3.80 (m, 2H), 3.49 (s, 3H).
Step 2:
5-(2-Methoxyethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b-
;4',3'-d]pyrrole-6-carbonitrile
##STR00586##
[0861] A mixture of
9-benzenesulfonyl-3-bromo-5-(2-methoxyethoxy)-9H-dipyrido[2,3-b;4',3'-d]p-
yrrole-6-carbonitrile (35 mg, 0.07 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(20 mg, 0.096 mmol), [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) (7 mg) in 1N aqueous potassium
fluoride solution (0.30 mL) and acetonitrile (0.30 mL) was degassed
and heated under microwave irradiation at 130.degree. C. for 30
minutes. The reaction mixture was allowed to cool to ambient
temperature and ethyl acetate (5 mL) added. The solid was collected
by filtration, washed with water (5 mL) and acetonitrile (5 mL) and
left to air dry. The resultant solid was purified by flash
chromatography (silica, 500 mg column, Si-SPE, 10% MeOH in DCM) and
trituration with acetonitrile (2.times.0.25 mL) to afford the title
compound as a grey solid (12 mg, 50%). .sup.1H NMR (DMSO-D6, 400
MHz): 12.91 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.81 (d, J=2.2 Hz,
1H), 8.77 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 4.66-4.62 (m, 2H),
3.92 (s, 3H), 3.87-3.83 (m, 2H), 3.36 (s, 3H). LCMS (Method A):
R.sub.T=7.66 min, M+H.sup.+=349.
Example 324
3-(1-Methyl-1H-pyrazol-4-yl)-5-(piperidin-4-ylsulfanyl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile
Step 1:
5-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
role-6-carbonitrile
##STR00587##
[0863] A mixture of
9-benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-bipyrido[2,3-b;-
4',3'-d]pyrrole-6-carbonitrile (575 mg, 1.2 mmol) and
tetrabutylammonium fluoride (1.0M in THF, 25 mL, 25 mmol) in THF
(25 mL) was stirred at ambient temperature for 15 min. The reaction
mixture was evaporated in vacuo to afford a residue that was
suspended in water and sonicated. The resultant solid was collected
by filtration and triturated with methanol to afford the title
compound as a white solid (420 mg, 100%). .sup.1H NMR
(DMSO-D.sub.6, 300 MHz): 9.02 (d, J=2.2 Hz, 1H), 8.98 (s, 1H), 8.93
(d, J=2.2 Hz, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 3.92 (s, 3H).
Step 2:
5-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxym-
ethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00588##
[0865] To a solution of
5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6--
carbonitrile (547 mg, 1.55 mmol) in DMF (25 ml) under a flow of
nitrogen was added sodium hydride (93 mg, 60% dispersion in mineral
oil, 2.39 mmol). After 20 min, a yellow solution had formed and
(2-chloromethoxyethyl)-trimethyl-silane (358 .mu.L, 2.02 mmol) was
added. The reaction mixture was stirred at ambient temperature for
3 days, then diluted with water and sonicated. The resultant solid
was collected by filtration and triturated with methanol to afford
the title compound as a yellow solid (404 mg, 54%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): .delta. 9.13 (s, 1H), 9.04 (d, J=2.2 Hz,
1H), 8.95 (d, J=2.1 Hz, 1H), 7.93-7.88 (m, 1H), 7.83-7.77 (m, 1H),
6.06 (s, 2H), 4.06 (s, 3H), 3.70-3.59 (m, 2H), 1.03-0.92 (m, 2H),
-0.03 (s, 9H).
Step 3:
4-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethox-
y
methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-ylsulfanyl]-piperidine-1-carb-
oxylic acid tert-butyl ester
##STR00589##
[0867] To a degassed suspension of
5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9-
H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (120 mg, 0.25
mmol), 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (54
mg, 0.25 mmol) and sodium tert-butoxide (26.4 mg, 0.28 mmol) in
dimethoxyethane (0.4 mL) in a sealed 5 ml microwave vial was added
a degassed solution of palladium(II) acetate (2.2 mg, 0.01 mmol)
and
(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphos-
phine (5.5 mg, 0.01 mmol) in dimethoxyethane (1.0 mL). The reaction
mixture was heated at 100.degree. C. for 22 h then cooled to
ambient temperature and concentrated in vacuo. The resultant
residue was adsorbed onto HM-N then purified by flash
chromatography (silica, 50 g column, Si-SPE, 0-10% (2M ammonia in
MeOH) in DCM) to afford the title compound as a yellow solid (106
mg, 68%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 9.33 (s, 1H),
9.11-9.06 (m, 2H), 8.35 (s, 1H), 8.05-8.01 (m, 1H), 6.05 (s, 2H),
3.93 (s, 3H), 3.86-3.73 (m, 2H), 3.64-3.53 (m, 2H), 2.97-2.78 (m,
3H), 1.97-1.83 (m, 2H), 1.64-1.45 (m, 2H), 1.35 (s, 9H), 0.87-0.78
(m, 2H), -0.17 (s, 9H).
Step 4:
3-(1-Methyl-1H-pyrazol-4-yl)-5-(piperidin-4-ylsulfanyl)-9H-dipyrid-
o[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00590##
[0869] A mixture of
4-[6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethy-
l)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-ylsulfanyl]-piperidine-1-carboxylic
acid tert-butyl ester (106 mg, 0.17 mmol) and trifluoroacetic acid
(1 mL) in dichloromethane (9 mL) was stirred at ambient temperature
for 22 h. The reaction mixture was concentrated in vacuo and the
resultant residue partitioned between dichloromethane (10 mL) and a
saturated aqueous solution of sodium hydrogen carbonate (10 mL).
The organic phase was concentrated in vacuo and the residue was
adsorbed onto HM-N then purified by flash chromatography (silica,
25 g column, Si-SPE, 0-13% (2M ammonia in MeOH) in DCM) to afford
the title compound as a pale yellow solid (21.5 mg, 25%). .sup.1H
NMR (DMSO-D.sub.6, 300 MHz): 9.04 (d, J=2.2 Hz, 1H), 9.02-8.97 (m,
2H), 8.29 (s, 1H), 7.98 (s, 1H), 3.93 (s, 3H), 3.54-3.21 (m, 1H),
2.97-2.86 (m, 2H), 2.49-2.36 (m, 2H), 1.89-1.77 (m, 2H), 1.65-1.47
(m, 2H). LCMS (Method F): R.sub.T=7.08 min, M+H.sup.+=390.
Example 325
5-(1-Ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbo-
nitrile
##STR00591##
[0870] Step 1:
9-Benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitr-
ile
##STR00592##
[0872] A suspension of
9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-c-
arbonitrile (5.0 g, 11.7 mmol) and 10% palladium on carbon (500 mg)
in industrial methylated spirits (120 mL), ethyl acetate (25 mL),
dimethylformamide (25 mL) and triethylamine (25 mL) was stirred at
ambient temperature under an atmosphere of hydrogen for 20 h. The
reaction vessel was purged with nitrogen then the reaction mixture
was filtered through celite. The filtrate was evaporated in vacuo.
The resultant brown residue was suspended in aqueous hydrochloric
acid (1M, 40 mL) and sonicated for 20 minutes then filtered to
afford the title compound as a beige solid (4.0 g, 98%). .sup.1H
NMR (DMSO-D.sub.6, 300 MHz): 9.27 (d, J=0.8 Hz, 1H), 8.73-8.65 (m,
2H), 8.19 (d, J=7.9 Hz, 2H), 7.78-7.69 (m, 1H), 7.65-7.54 (m,
3H).
Step 2: 1,1,2,2,3,3,4,4,4-Nonafluoro-butane-1-sulfonic acid
9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yl
ester
##STR00593##
[0874] To a suspension of
9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitr-
ile (4.0 g, 11.4 mmol) in dichloromethane (250 ml) was added
pyridine (8.9 mL, 114 mmol). The reaction mixture was stirred at
ambient temperature for 10 min then cooled to 0.degree. C. and
nonafluorobutanesulfonic anhydride (7.01 mL, 22.9 mmol) added over
10 minutes. The mixture was allowed to warm to ambient temperature
and stirred for 2.5 h. After this time, the reaction was cooled to
0.degree. C., aqueous hydrochloric acid (1M, 120 mL) was added and
the resulting mixture extracted with dichloromethane (3.times.100
mL). The combined organic phase was dried over sodium sulfate,
filtered and concentrated in vacuo. The resultant residue was
purified by flash chromatography (silica, 50 g column, Si-SPE, DCM)
to afford the title compound as a pale yellow solid (5.34 g, 74%).
.sup.1H NMR (CDCl.sub.3, 300 MHz): 9.93 (s, 1H), 8.84 (dd, J=4.8,
1.65 Hz, 1H), 8.67 (dd, J=8.1, 1.65 Hz, 1H), 8.33-8.28 (m, 2H),
7.71-7.63 (m, 1H), 7.59-7.51 (m, 3H).
Step 3:
9-Benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
onitrile
##STR00594##
[0876] A mixture of 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic
acid
9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-yl
ester (5.43 g, 8.4 mmol) and tetrabutylammonium bromide (10.0 g, 31
mmol) in 1,4-dioxane (175 mL) was heated at 100.degree. C. for 30
min. The reaction mixture was allowed to cool to ambient
temperature then evaporated in vacuo to afford the title compound
as a white solid (2.38 g, 68%). .sup.1H NMR (DMSO-D.sub.6, 300
MHz): 9.74 (s, 1H), 9.02 (dd, J=8.1, 1.6 Hz, 1H), 8.84 (dd, J=4.8,
1.6 Hz, 1H), 8.29-8.22 (m, 2H), 7.78-7.68 (m, 2H), 7.67-7.58 (m,
2H).
Step 4:
9-Benzenesulfonyl-5-(1-ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-
-b;4', 3'-d]pyrrole-6-carbonitrile
##STR00595##
[0878] A mixture of 1-ethyl-4-methylene-piperidine (540 mg, 4.32
mmol) and 9-borabicyclo[3.3.1]nonane (0.5M in THF, 8.0 mL, 4.0
mmol) was heated at 65.degree. C. for 3.5 h. The resultant cooled
solution was then added portionwise to a degassed suspension of
9-benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitril-
e (420 mg, 1 mmol), bis(diphenylphosphino)ferrocene
dichloropalladium(II) (90 mg, 0.11 mmol) and potassium carbonate
(180 mg, 1.3 mmol) in water (1 mL) and dimethylformamide (10 mL).
The resultant orange solution was heated at 65.degree. C. for 2 h
then allowed to cool to ambient temperature and partitioned between
dichloromethane (20 mL) and a saturated aqueous solution of sodium
chloride (15 mL). The aqueous phase was extracted with
dichloromethane (3.times.10 mL) and the combined organic phase was
washed with a saturated aqueous solution of sodium chloride (20
mL), dried over magnesium sulfate and concentrated in vacuo. The
resultant residue was purified by flash chromatography (silica, 10
g column, Si-SPE, 0-20% MeOH in DCM) to afford the title compound
(200 mg, 43%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.81 (s, 1H),
8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.29-8.24 (m,
2H), 7.66-7.60 (m, 1H), 7.58-7.48 (m, 3H), 3.41 (d, J=7.2 Hz, 2H),
2.89 (q, J=7.3 Hz, 2H), 2.56-2.44 (m, 2H), 2.33-2.08 (m, 3H),
1.94-1.74 (m, 4H), 1.35 (t, J=7.3 Hz, 3H). LCMS (Method G):
R.sub.T=3.01 min, M+H.sup.+=460.
Step 5:
5-(1-Ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-
-6-carbonitrile
##STR00596##
[0880] A solution of
9-benzenesulfonyl-5-(1-ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole-6-carbonitrile (200 mg, 0.4 mmol) and triethylamine (4
mL) in methanol (40 mL) was stirred at ambient temperature for 6
days. The mixture was concentrated in vacuo and the residue
purified by flash chromatography (silica, 2 g column, Si-SPE, 0-20%
MeOH in DCM). The resultant material was triturated with
acetonitrile and methanol to afford the title compound as a white
solid (65 mg, 51%). NMR (DMSO-D.sub.6, 400 MHz): 12.85 (s, 1H),
8.90 (s, 1H), 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.65 (dd, J=8.0, 1.6
Hz, 1H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 2.86-2.77 (m, 2H), 2.24 (q,
J=7.2 Hz, 2H), 1.84-1.58 (m, 5H), 1.54-1.40 (m, 2H), 0.95 (t, J=7.1
Hz, 3H). LCMS (Method H): R.sub.T=4.56 min, M+H.sup.+=320.
Example 326
6-Cyano-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-3-c-
arboxylic acid methyl ester
##STR00597##
[0882]
9-Benzenesulfonyl-3-bromo-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[-
2,3-b:4',3'-d]pyrrole-6-carbonitrile (150 mg, 0.278 mmol),
molybdenum hexacarbonyl (73 mg, 0.278 mmol), Herman's catalyst
(trans-di(.mu.-acetato)bis[(2-di-o-tolylphosphino)benzyl]dipalladium(II),
26 mg, 0.028 mmol) and tri-tert-butylphosphonium tetrafluoroborate
(20 mg, 0.069 mmol) were placed in a 5 mL microwave vial. Dioxane
(3 mL), methanol (1.5 mL) followed by
1,8-diazabicyclo(5.4.0)undec-7-ene (0.12 mL, 0.833 mmol) were added
to the mixture, the tube sealed and heated under microwave
irradiation at 150.degree. C. for 15 min. The cooled reaction
mixture was diluted with water and extracted into ethyl acetate
(4.times.50 mL). The combined organic phase was washed with brine,
dried over sodium sulfate and concentrated in vacuo to afford a
residue that was purified by flash chromatography (silica, 12 g
column, ISCO, 0-10% MeOH in DCM). The resultant material was
triturated with MeOH and collected by filtration to afford the
title compound as a pale yellow powder (29 mg, 28%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 9.35 (d, J=2.1 Hz, 1H), 9.23 (s, 1H), 8.83
(s, 1H), 5.21-5.06 (m, 1H), 4.05 (s, 3H), 3.07-2.88 (m, 2H),
2.59-2.44 (m, 2H), 2.41-2.06 (m, 6H), 1.20-1.07 (m, 3H). LCMS
(Method H): R.sub.T=6.56 min, M+H.sup.+=380.
Example 327
5-(1-Ethylpiperidin-4-yloxy)-3-isopropyl-9H-dipyrido[2,3-b:4',3'-d]pyrrole-
-6-carbonitrile
##STR00598##
[0883] Step 1:
5-(1-Ethylpiperidin-4-yloxy)-3-isopropenyl-9H-dipyrido[2,3-b:4',3'-d]pyrr-
ole-6-carbonitrile
##STR00599##
[0885]
9-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido-
[2,3-b:4',3'-d]pyrrole-6-carbonitrile (147 mg, 0.272 mmol) and
[1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (11
mg, 0.014 mmol) were dissolved in THF (9 mL) and 1N aqueous sodium
carbonate (3 mL) added followed by isopropenylboronic acid pinacol
ester (0.076 mL, 0.408 mmol) and placed under an argon atmosphere.
The reaction mixture was heated under microwave irradiation at
140.degree. C. for 50 min. The cooled reaction mixture was diluted
with saturated aqueous sodium hydrogen carbonate solution (20 mL)
and extracted into ethyl acetate (4.times.20 mL). The combined
organic phase was washed with brine (20 mL), dried over sodium
sulfate and concentrated in vacuo to afford the title compound as a
brown solid (163 mg) which was used without further purification in
the next step. .sup.1H NMR (CDCl.sub.3, 300 MHz): 12.05 (br s, 1H),
8.81 (d, J=2.2 Hz, 1H), 8.77 (s, 1H), 8.64 (d, J=2.2 Hz, 1H), 5.48
(s, 1H), 5.28-5.24 (m, 1H), 5.09-4.97 (m, 1H), 3.02-2.91 (m, 2H),
2.49 (q, J=7.2 Hz, 2H), 2.35-2.20 (m, 7H), 2.19-2.07 (m, 2H), 1.12
(t, J=7.2 Hz, 3H).
Step 2:
5-(1-Ethylpiperidin-4-yloxy)-3-isopropyl-9H-dipyrido[2,3-b:4',3'-d-
]pyrrole-6-carbonitrile
##STR00600##
[0887] A suspension of
5-(1-ethylpiperidin-4-yloxy)-3-isopropenyl-9H-dipyrido[2,3-b:4',3'-d]pyrr-
ole-6-carbonitrile (98 mg, 0.271 mmol), 10% palladium on carbon (50
mg) and triethylamine (0.5 mL) in IMS (5 mL) was stirred at ambient
temperature under a hydrogen atmosphere for 18 h. The mixture was
filtered through a PTFE filter and the filtrate concentrated in
vacuo to give a brown solid. The resultant solid was purified by
flash chromatography (silica, 12 g column, ISCO, 0-5% MeOH in DCM)
to afford the title compound as a white solid (27 mg, 27%). .sup.1H
NMR (DMSO-D.sub.6, 300 MHz): 12.96 (s, 1H), 8.82 (s, 1H), 8.68 (s,
1H), 8.32 (s, 1H), 5.11-4.77 (m, 1H), 3.65-3.48 (m, 2H), 3.28-3.18
(m, 2H), 3.14-2.90 (m, 3H), 2.42-2.18 (m, 4H), 1.37 (d, J=6.9 Hz,
6H), 1.29-1.17 (m, 3H). LCMS (Method H): R.sub.T=7.10 min,
M+H.sup.+=364.
Example 328
5-(1-Ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-3,6-dicarbo-
nitrile
##STR00601##
[0889] DMF (8 mL) was added to a mixture of
9-benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b-
:4',3'-d]pyrrole-6-carbonitrile (200 mg, 0.37 mmol), zinc cyanide
(217 mg, 1.85 mmol) and tetrakis(triphenylphosphine) palladium(0)
(43 mg, 0.04 mmol) and the reaction mixture heated under microwave
irradiation at 150.degree. C. for 30 min. Triethylamine (2 mL) was
then added and the reaction mixture heated at 50.degree. C. for 24
h. The mixture was diluted with saturated aqueous sodium
bicarbonate solution (100 mL) and extracted into 10% MeOH in DCM
(2.times.25 mL). The combined organic phase was adsorbed onto HM-N
then purified by flash chromatography (silica, 12 g column, ISCO,
0-10% MeOH in DCM) to afford the title compound as a cream solid (6
mg, 5%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 9.07 (d, J=2.0 Hz,
1H), 8.99 (d, J=1.9 Hz, 1H), 8.84 (s, 1H), 4.86-4.76 (m, 1H),
2.97-2.87 (m, 2H), 2.42 (q, J=7.2 Hz, 2H), 2.23-2.13 (m, 2H),
2.12-1.94 (m, 4H), 1.03 (t, J=7.2 Hz, 3H). LCMS (Method H):
R.sub.T=5.27 min, m+H.sup.+=347.
Example 329
5-[1-(2,22-Trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3-b;4',3'-d-
]pyrrole-6-carbonitrile
##STR00602##
[0890] Step 1:
4-(9-Benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-ylmethyl)-
-piperidine-1-carboxylic acid tert-butyl ester
##STR00603##
[0892] A mixture of 4-methylene-piperidine-1-carboxylic acid
tert-butyl ester (0.70 g, 3.55 mmol) and 9-borabicyclo[3,3,1]nonane
(0.5M solution in THF, 7 mL, 3.5 mmol) were heated at reflux for
1.5 h. The reaction mixture was cooled and added to a degassed
mixture of
9-benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitril-
e (0.41 g, 1.0 mmol), [1,1-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) (0.090 g, 0.11 mmol) and potassium
carbonate (0.18 g, 1.3 mmol) in water (1 mL) and DMF (10 mL) and
the reaction mixture was then heated at 65.degree. C. for 1.25 h.
After cooling to ambient temperature the reaction mixture was then
diluted with water (5 mL) and dichloromethane (10 mL). The aqueous
phase was extracted with dichloromethane (2.times.15 mL) and the
combined organic phase was washed with brine (15 mL), dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was triturated with pentane (10 mL) and the resultant material was
purified by flash chromatography (silica, 5 g column, SPE-Si II,
0-2% methanol in DCM) to afford title compound as a yellow solid
(202 mg, 38%). NMR (CDCl.sub.3, 400 MHz): 9.81 (s, 1H), 8.79 (dd,
J=4.8, 1.6 Hz, 1H), 8.33-8.27 (m, 3H), 7.66-7.60 (m, 1H), 7.55-7.46
(m, 3H), 4.22-4.01 (m, 2H), 3.34-3.27 (m, 2H), 2.62-2.50 (m, 2H),
1.97-1.76 (m, 2H), 1.72-1.46 (m, 3H), 1.45 (s, 9H).
Step 2:
9-Benzenesulfonyl-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4',3'-d-
]pyrrole-6-carbonitrile
##STR00604##
[0894] A solution of
4-(9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4',3'-d]pyrrol-5-ylmethyl)-
-piperidine-1-carboxylic acid tert-butyl ester (202 mg, 0.38 mmol)
in dichloromethane (6 mL) was treated with trifluoroacetic acid (2
mL) and the resultant mixture stirred for 1 h then concentrated in
vacuo. The residue was purified by flash chromatography (silica, 5
g column, SPE-NH.sub.2, 0-8% methanol in DCM) to give title
compound as an off white solid (150 mg, 80%). LCMS (Method G):
R.sub.T=3.07 min, M+H.sup.+=432.
Step 3:
9-Benzenesulfonyl-5-[1-(2,2,2-trifluoroethyl)-piperidin-4-ylmethyl-
]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00605##
[0896] N,N-Diisopropylethylamine (100 mg, 0.77 mmol) and
trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (100 mg,
0.43 mmol) in THF (1 mL) were added to a solution of
9-benzenesulfonyl-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e-6-carbonitrile in THF (4 mL) and resultant mixture stirred at
ambient temperature for 30 min. The mixture was then filtered
through a 2 g SiII SPE cartridge, eluting with THF. The THF
washings were concentrated in vacuo and the resultant residue was
purified by flash chromatography (silica, 2 g column, Si II SPE,
0-20% ethyl acetate in DCM) to afford title compound as a white
solid (0.16 g, 85%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.81 (d,
J=2.9 Hz, 1H), 8.81-8.75 (m, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.28 (d,
J=7.9 Hz, 2H), 7.66-7.59 (m, 1H), 7.55-7.45 (m, 3H), 3.35-3.27 (m,
2H), 3.02-2.88 (m, 5H), 2.32-2.21 (m, 2H), 1.86-1.60 (m, 4H).
Step 4:
5-[1-(2,2,2-Trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile
##STR00606##
[0898]
9-Benzenesulfonyl-5-[1-(2,2,2-trifluoroethyl)-piperidin-4-ylmethyl]-
-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (0.16 g, 0.3
mmol) was dissolved in tetrabutylammonium fluoride (1M in THF, 5
mL, 5 mmol) and stirred at ambient temperature for 24 h. The
solution was filtered through 2 g NH.sub.2 cartridge, eluting with
1:1 methanol/dichloromethane. The filtrate was concentrated in
vacuo and the residue diluted with water (10 mL) and the resultant
precipitate collected by filtration. Purification of the solid by
flash chromatography (silica, 5 g column, SPE Si-II, 0-6% methanol
in DCM) afforded the title compound as a white solid (90 mg, 80%).
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.88 (s, 1H), 8.91 (s, 1H),
8.72-8.64 (m, 2H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 3.09 (q, J=10.3
Hz, 2H), 2.92-2.83 (m, 2H), 2.25-2.15 (m, 2H), 1.85-1.72 (m, 1H),
1.66-1.58 (m, 2H), 1.57-1.43 (m, 2H). LCMS (Method H): R.sub.T=9.20
min, M+H.sup.+=374.
Example 330
5-(Azetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole-6-carbonitrile
##STR00607##
[0899] Step 1:
9-Benzenesulfonyl-5-(1-benzhydrylazetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-
-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile
##STR00608##
[0901] A mixture of
9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole-6-carbonitrile (210 mg, 0.50 mmol), cesium
carbonate (320 mg, 0.98 mmol) and sodium iodide (37 mg, 0.24 mmol)
in DMF (10 mL) were heated at 130.degree. C. for 10 minutes. After
cooling to ambient temperature the reaction mixture was then
diluted with water (5 mL) and ethyl acetate(3.times.10 mL). The
combined organic phase was washed with brine (15 mL), dried over
magnesium sulfate, filtered and concentrated in vacuo. Purification
of the residue by flash chromatography (silica, 12 g column, SPE
Si--II, 0-10% methanol in DCM) afforded the title compound as a
white solid (240 mg, 76%). LCMS (Method G): R.sub.T=4.12 min,
M+H.sup.+=652.
Step 2:
5-(Azetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3--
b:4',3'-d]pyrrole-6-carbonitrile
##STR00609##
[0903] To a stirred solution of
9-benzenesulfonyl-5-(1-benzhydrylazetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-
-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile (238 mg,
0.37 mmol) in methanol (10 mL) at 0.degree. C. was added a solution
of 1-chloroethyl chloroformate (120 .mu.L, 1.1 mmol) in DCM (10
mL). The reaction mixture was allowed to warm to ambient
temperature then heated at 40.degree. C. for 4 h. The reaction was
cooled to ambient temperature and then concentrated in vacuo.
Purification of the residue by flash chromatography (silica, 11 g
column, SPE NH.sub.2, 0-20% methanol in DCM) afforded the title
compound as a white solid (5 mg, 5%). .sup.1H NMR (CDCl.sub.3 plus
CD.sub.3OD, 400 MHz): 8.85 (s, 1H), 8.74-8.69 (m, 2H), 8.08 (s,
1H), 7.93 (s, 1H), 5.73-5.64 (m, 1H), 4.19-4.05 (m, 4H), 4.01 (s,
3H). LCMS (Method G): R.sub.T=5.59 min, M+H.sup.+=346.
[0904] The compounds of the Examples in Table 16 were prepared
using the methods described above from commercially available
starting materials and the general Suzuki Methods.
TABLE-US-00017 TABLE 16 Suzuki Puri- LCMS Ex- Cou- fication
R.sub.T, am- pling Meth- M + H.sup.+, ple Structure/Name Method
od(s) Method .sup.1H NMR (ppm) 331 ##STR00610##
6-(1-Methyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole I B.sup.1 4.7, 423, A (CD.sub.3OD,
300 MHz): 8.85 (d, J = 1.1 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.77
(d, J = 2.2 Hz, 1H), 8.31 (d, J = 1.1 Hz, 1H), 8.07 (s, 1H), 8.05
(s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.01
(s, 3H), 3.60 (s, 2H), 2.56-2.44 (m, 4H), 1.71-1.58 (m, 4H),
1.55-1.45 (m, 2H). 332 ##STR00611##
6-(1-Ethyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole I C, B, E, D 4.9, 437, A
(DMSO-D.sub.6, 400 MHz): 12.12 (s, 1H), 8.92 (d, J = 2.3 Hz, 1H),
8.90 (d, J = 2.3 Hz, 1H), 8.85 (d, J = 1.1 Hz, 1H), 8.51 (d, J =
1.1 Hz, 1H), 8.26 (d, J = 0.7 Hz, 1H), 8.00 (d, J = 0.7 Hz, 1H),
7.76 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 4.21 (q, J =
7.3 Hz, 2H), 3.50 (s, 2H), 2.41- 2.34 (m, 4H), 1.58-1.48 (m, 4H),
1.47- 1.37 (m, 5H). 333 ##STR00612##
3-(4-Piperidin-1-ylmethyl-phenyl)- 6-(1-propyl-1H-pyrazol-4-yl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole I C, B, D 951, 451, A (DMSO-D.sub.6,
400 MHz): 12.13 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.90 (d, J = 2.3
Hz, 1H), 8.86 (d, J = 1.1 Hz, 1H), 8.52 (d, J = 1.1 Hz, 1H), 8.25
(d, J = 0.7 Hz, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.76 (d, J = 8.0 Hz,
2H), 7.45 (d, J = 8.0 Hz, 2H), 4.14 (t, J = 6.9 Hz, 2H), 3.49 (s,
2H), 2.40-2.34 (m, 4H), 1.91-1.80 (m, 2H), 1.56-1.48 (m, 4H),
1.43-1.38 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 334 ##STR00613##
6-(1-Isobutyl-1H-pyrazol-4-yl)-3-(4-
piperidin-1-ylmethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole J B
5.5, 465, A (CD.sub.3OD, 300 MHz): 8.85 (d, J = 1.0 Hz, 1H), 8.81
(d, J = 2.2 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 1.1 Hz,
1H), 8.08 (s, 1H), 8.07 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.51 (d,
J = 8.0 Hz, 2H), 4.02 (d, J = 7.3 Hz, 2H), 3.74 (s, 2H), 2.70-2.58
(m, 4H), 2.35-2.19 (m, 1H), 1.73-1.64 (m, 4H), 1.59-1.48 (m, 2H),
0.98 (d, J = 6.7 Hz, 6H). 335 ##STR00614##
6-(1-Benzyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-
dipyrido[2,3-b;4',3'-d]pyrrole J N, O, P, Q.sup.3 5.8, 499, A
(CD.sub.3OD, 300 MHz): 8.84 (d, J = 1.1 Hz, 1H), 8.81 (d, J = 2.2
Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 1.1 Hz, 1H), 8.13
(d, J = 0.7 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 7.69 (d, J = 8.1 Hz,
2H), 7.48 (d, J = 8.0 Hz, 2H), 7.42-7.29 (m, 5H), 5.42 (s, 2H),
3.60 (s, 2H), 2.55- 2.45 (m, 4H), 1.68-1.60 (m, 4H), 1.53- 1.47 (m,
2H). 336 ##STR00615## 6-(1,5-Dimethyl-1H-pyrazol-4-yl)-3-
(4-piperidin-1-ylmethyl-phenyl)-9H- dipyrido[2,3-b;4',3'-d]pyrrole
J O 4.7, 437, A (CD.sub.3OD, 300 MHz): 8.93 (d, J = 1.1 Hz, 1H),
8.81 (d, J = 2.2 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.15 (d, J =
1.1 Hz, 1H), 7.82 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.47 (d, J =
8.0 Hz, 2H), 3.89 (s, 3H), 3.59 (s, 2H), 2.60 (s, 3H), 2.52-2.45
(m, 4H), 1.69-1.59 (m, 4H), 1.54-1.45 (m, 2H). 337 ##STR00616##
3-(4-Piperidin-1-ylmethyl-phenyl)-6- thiazol-5-yl-9H-dipyrido
[2,3-b;4',3'-d]pyrrole 6.02, 426, A (CDCl.sub.3 plus CD.sub.3OD,
300 MHz): 8.93 (d, J = 1.1 Hz, 1H), 8.92 (d, J = 0.7 Hz, 1H), 8.85
(d, J = 2.2 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 1.1 Hz,
1H), 8.43 (d, J = 0.7 Hz, 1H), 7.75-7.70 (m, 2H), 7.55-7.49 (m,
2H), 3.71 (s, 2H), 2.67- 2.53 (m, 4H), 1.74-1.63 (m, 4H), 1.59-
1.47 (m, 2H) plus one exchangeable not observed.
Example 338
3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00617##
[0905] Step 1: 5-Bromo-2-fluoro-[3,4']bipyridinyl-3'-ylamine
##STR00618##
[0907] A mixture of 4-iodo-pyridin-3-ylamine (1.027 g, 4.67 mmol),
2-fluoro-5-bromopyridine-3-boronic acid (2.05 g, 9.33 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
complex with dichloromethane (1:1) (191 mg, 0.233 mmol) in
acetonitrile (12 mL) and 1N aqueous potassium fluoride solution (12
mL) was heated at 95.degree. C. for 3 h. The reaction mixture was
allowed to cool, treated with additional portions of the boronic
acid (0.5 eq) and of catalyst (5.0 mol %), and heated under reflux
overnight under a nitrogen atmosphere. The mixture was allowed to
cool, diluted with DCM and water, and filtered to remove the
solids. The filtrate layers were separated and the aqueous phase
was extracted into DCM, and the combined organic phase concentrated
in vacuo. The resultant residue was redissolved in 20% methanol in
DCM and absorbed onto silica gel for purification by flash
chromatography (silica, 100 g column, Biotage, 1-20% methanol in
DCM) to afford the title compound as a brown solid (861 mg, 69%).
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 8.43 (d, J=1.1 Hz, 1H), 8.18
(dd, J=8.3 Hz, 2.5 Hz, 1H) 8.11 (s, 1H), 7.81 (d, J=4.8 Hz, 1H),
7.01 (d, J=4.8 Hz, 1H), 5.37 (s, 2H). LCMS (Method B): R.sub.T=0.95
min, M+H.sup.+=268/270.
Step 2:
5-(4-Piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4']bipyridinyl-3'-yl-
amine
##STR00619##
[0909] A degassed mixture of
5-bromo-2-fluoro-[3,4']bipyridinyl-3'-ylamine (861 mg, 3.21 mmol),
4-piperidin-1-ylmethyl-phenyl boronic acid (816 mg, 3.72 mmol) and
bis(triphenylphosphine)palladium(II) chloride (169 mg, 0.241 mmol)
in acetonitrile (14 mL) and 1N aqueous potassium fluoride solution
(8.0 mL) was heated under microwave irradiation at 100.degree. C.
for 25 minutes. The cooled reaction mixture was diluted with water
and 20% methanol in DCM, the layers separated, and the aqueous
phase extracted into 20% methanol in DCM. The combined organic
phase was concentrated in vacuo, and the resultant residue
dissolved in DCM/methanol, absorbed onto celite, and purified by
flash chromatography (silica, 100 g column, Biotage, 0-20% methanol
in DCM) to afford the title compound as a dark orange foam (753 mg,
65%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 8.58 (s, 1H), 8.20 (d,
J=7.1 Hz, 1H), 8.13 (s, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.74 (m, 2H),
7.43 (m, 2H), 7.07 (d, J=4.9 Hz, 1H), 5.31 (s, 2H), 3.29 (s, 2H),
2.35 (m, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method B):
R.sub.T=1.27 min, M+H.sup.+=363.
Step 3:
3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e
##STR00620##
[0911] A 1N solution of bis(trimethylsilyl)amide in THF (2.78 mL,
2.80 mmol) was added dropwise to a solution of
5-(4-piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4']bipyridinyl-3'-ylamine
(101 mg, 0.278 mmol) in THF (5.0 mL) at ambient temperature. The
mixture was stirred for 1 h at ambient temperature and then treated
with water. The resultant brown solution was partitioned between
DCM and water, the layers separated, and the aqueous phase
extracted into 20% methanol in DCM. The combined organic phase was
concentrated in vacuo. The resultant residue was absorbed onto
silica gel, and purified by flash chromatography (silica, 1-20%
methanol in DCM) to provide a light orange-yellow solid (39.9 mg,
42%). .sup.1H NMR (DMSO-D.sub.6, 500 MHz): 12.24 (s, 1H), 8.99 (d,
J=1.8 Hz, 1H), 8.93 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.45 (d, J=5.2
Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.45 (d,
J=7.5 Hz, 2H), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m 4H), 1.41 (m,
2H). LCMS (Method D): R.sub.T=4.64 min, M+H.sup.+=343.
Example 339
3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6--
carboxylic acid
##STR00621##
[0913] A degassed mixture of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid (37.7
mg, 0.13 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid,
pinacol ester (58.5 mg, 0.194 mmol) and
bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 6.4
.mu.mol) in acetonitrile (2 mL) and aqueous sodium carbonate
solution (2 mL) was heated under microwave irradiation at
140.degree. C. for 10 minutes. The cooled reaction mixture was
acidified with 10% aqueous sulfuric acid, filtered, and the crude
solution was purified by preparative HPLC (0-30% MeCN over 30 min,
35 mL/min) to afford the title compound. .sup.1H NMR (DMSO-D.sub.6,
400 MHz): 12.62 (s, 1H), 9.66 (s, 1H), 9.14-8.95 (m, 4H), 7.77 (d,
J=8.7 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 3.97 (d, J=13.4 Hz, 2H),
3.55 (d, J=11.6 Hz, 2H), 3.20 (q, J=11.1 Hz, 2H), 3.04 (t, J=11.9
Hz, 2H), 2.89 (s, 3H). LCMS (Method D): R.sub.T=5.09 min,
M+H.sup.+=388.
Example 340
3-(1-Methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxyli-
c acid
##STR00622##
[0915] A degassed mixture of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid methyl
ester (30.4 mg, 99.3 .mu.mol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(31.0 mg, 0.149 mmol), and bis(triphenylphosphine)palladium(II)
dichloride (3.5 mg, 5.0 .mu.mol) in acetonitrile (2.5 mL) and 2N
aqueous sodium carbonate solution (2.5 mL) was heated under under
microwave irradiation at 140.degree. C. for 10 minutes. The cooled
reaction mixture was acidified with 10% aqueous sulfuric acid, the
solid removed by filtration and the resultant filtrate purified by
preparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the
title compound. .sup.1H NMR (DMSO-D.sub.6, 500 MHz): 12.84 (s, 1H),
9.04 (d, J=2.1 Hz, 1H), 8.95 (s, 2H), 8.91 (d, J=2.1 Hz, 1H), 8.25
(s, 1H), 8.00 (s, 1H), 6.48 (s, 1H), 3.92 (s, 3H). LCMS (Method D):
R.sub.T=5.24 min, M+H.sup.+=294.
Example 341
3-(3-Trifluoromethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic
acid
##STR00623##
[0917] A degassed mixture of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid (20.0
mg, 68.5 .mu.mol), 3-(trifluoromethyl)phenylboronic acid (19.5 mg,
0.103 mmol), and bis(triphenylphosphine)palladium(II) dichloride
(2.4 mg, 3.4 .mu.mol) in acetonitrile (0.3 mL) and 2N aqueous
sodium carbonate solution (0.3 mL) was heated under microwave
irradiation at 140.degree. C. for 10 minutes. The cooled reaction
mixture was acidified with 10% aqueous sulfuric acid. The solid was
removed by filtration and the resultant filtrate was purified by
preparative HPLC (5-45% MeCN over 45 min, 35 mL/min) to afford the
title compound. .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.75 (s, 1H),
9.38-9.00 (m, 3H), 8.21 (m, 1H), 7.78 (m, 2H), 7.65-7.60 (m, 2H).
LCMS (Method D): R.sub.1=10.76 min, M+H.sup.+=358.
Example 342
3-(3-{N-[(4-Methoxyphenyl)methyl]aminocarbonyl}phenyl)-9H-dipyrido[2,3-b;4-
',3'-d]pyrrole-6-carboxylic acid
##STR00624##
[0918] Step 1: 3-{N-[(4-Methoxyphenyl)methyl]aminocarbonyl}
phenylboronic acid
##STR00625##
[0920] 3-Carboxyphenylboronic acid (140 mg, 0.84 mmol), PyBOP (376
mg, 0.72 mmol) and HOBt (97.7 mg, 0.72 mmol) were dissolved in DMF
(3.18 mL) and treated with DIPEA (420 .mu.L, 2.41 mmol). After 5
min at ambient temperature, 4-methoxybenzenemethanamine (78 .mu.L,
0.60 mmol) was added. The homogeneous reaction mixture was stirred
at ambient temperature for 16 h, the solvent was removed under
reduced pressure, and the residue purified by preparative HPLC
(5-40% MeCN over 40 min, 35 mL/min) to afford the product as a
white solid.
Step 2:
3-(3-{N-[(4-Methoxyphenyl)methyl]aminocarbonyl}phenyl)-9H-dipyrido-
[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
[0921] A degassed mixture of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid methyl
ester (40.4 mg, 0.13 mmol),
N-[(4-methoxyphenyl)methyl]aminocarbonyl}phenylboronic acid (41.4
mg, 0.15 mmol) and bis(triphenylphosphine)palladium(II) dichloride
(4.6 mg, 66 mmol) in acetonitrile (3.3 mL) and 2N aqueous sodium
carbonate solution (3.3 mL) was heated under microwave irradiation
at 140.degree. C. for 10 minutes. The cooled reaction mixture was
acidified with 10% aqueous sulfuric acid. The solid was removed by
filtration, and the resultant filtrate was purified by preparative
HPLC (5-40% MeCN over 40 min, 35 mL/min) to afford the title
compound. .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.74 (s, 1H), 9.28
(m, 1H), 9.13 (m, 1H), 9.07 (m, 1H), 9.00 (m, 1H), 8.35 (m, 1H),
8.02 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.65 (t, J=7.7 Hz,
1H), 7.30 (q, J=8.6 Hz, 2H), 6.91 (q, J=8.6 Hz, 2H), 4.48 (d, J=5.8
Hz, 2H), 3.73 (s, 3H). LCMS (Method D): R.sub.T=9.61 min,
M+H.sup.+=423.
Example 343
3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
oxamide
##STR00626##
[0923] A solution of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-car-
boxylic acid methyl ester (67.3 mg, 0.168 mmol) in 7M ammonia in
methanol (8.0 mL) was heated to 70.degree. C. for 24 h in a sealed
tube. The mixture was allowed to cool and concentrated in vacuo.
The residue was dissolved in DMSO and purified by preparative HPLC
(2-60% MeCN/water modified with 0.1% ammonium hydroxide) to afford
a light-yellow fluffy solid (10.3 mg, 16%). .sup.1H NMR
(DMSO-D.sub.6, 500 MHz): 12.56 (s, 1H), 9.18 (d, J=2.2 Hz, 1H),
9.00 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.90 (s, 1H), 8.10 (s, 1H),
7.79 (d, J=8.1 Hz, 2H), 7.53 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.49
(s, 2H), 2.36 (m, 4H), 1.56-1.47 (m, 4H), 1.40 (m, 2H). LCMS
(Method D): R.sub.T=5.88 min, M+H.sup.+=386.
Example 344
N-Ethyl-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e-6-carboxamide
##STR00627##
[0925] A solution of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-car-
boxylic acid methyl ester (152 mg, 0.380 mmol) in 2-Methylamine in
THF (8.0 mL) was heated to 80.degree. C. for 4 days in a sealed
tube. The mixture was allowed to cool and concentrated in vacuo.
The residue was redissolved in DMSO and purified by preparative
HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to
afford a dark brown solid (74.9 mg, 48%). .sup.1H NMR
(DMSO-D.sub.6, 500 MHz): 9.19 (d, J=2.2 Hz, 1H), 8.99 (s, 1H), 8.97
(d, J=2.2 Hz, 1H), 8.91 (s, 1H), 8.72 (m, 1H), 8.24 (s, 1H), 7.81
(d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.47-3.33 (m, 2H), 2.38
(m, 4H), 1.53 (m, 4H), 1.42 (m, 2H), 1.18 (t, J=7.2 Hz, 3H). LCMS
(Method E): R.sub.T=3.30 min, M+H.sup.+=414.
Example 345
N-(2-Aminoethyl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole-6-carboxamide
##STR00628##
[0927] A solution of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-car-
boxylic acid methyl ester (152 mg, 0.380 mmol) in ethylenediamine
(8.0 mL) was heated to 80.degree. C. for 16 h in a sealed tube. The
mixture was allowed to cool and concentrated in vacuo. The residue
was dissolved in DMSO and purified by preparative HPLC (2-60%
MeCN/water modified with 0.1% ammonium hydroxide) to afford a light
brown solid (45.4 mg, 28%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
9.19 (d, J=2.1 Hz, 1H), 8.99 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.92
(s, 1H), 8.74 (m, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz,
2H), 3.50 (s, 2H), 3.41-3.33 (m, 2H), 2.76 (t, J=6.4 Hz, 2H), 2.38
(m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): R.sub.T=6.45
min, M+H.sup.+=429.
Example 346
3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6--
carboxylic acid amide
##STR00629##
[0929] DIPEA (14 .mu.L, 77 .mu.mol) was added to a solution of
3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-
-carboxylic acid (20.0 mg, 51.6 .mu.mol), PyBOP (28.2 mg, 54.2
.mu.mol) and HOBt (8.4 mg, 62 .mu.mol) in DMF (1 mL). After 10 min
at ambient temperature, a solution of 0.5M ammonia in 1,4-dioxane
(500 .mu.L, 0.258 mmol) was added to the reaction mixture. After 30
min the reaction mixture was acidified with 10% aqueous sulfuric
acid and made homogeneous with the addition of DMSO. The crude
solution was purified by preparative HPLC (0-30% MeCN over 30 min,
35 mL/min) to afford the title compound. .sup.1H NMR (DMSO-D.sub.6,
400 MHz): 12.48 (s, 1H), 9.11-8.89 (m, 4H), 7.77 (d, J=8.9 Hz, 2H),
7.18 (d, J=8.9 Hz, 2H), 3.97 (d, J=13.5 Hz, 2H), 3.55 (q, J=12.2
Hz, 2H), 3.20 (q, J=11.4 Hz, 2H), 3.03 (t, J=12.0 Hz, 2H), 2.89 (s,
3H). LCMS (Method D): R.sub.T=6.35 min, M+H.sup.+=387.
Example 347
3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6--
carboxylic acid dimethylamide
##STR00630##
[0931] DIPEA (14 .mu.L, 77 .mu.mol) was added to a solution of
3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-
-carboxylic acid (20.0 mg, 51.6 mop, PyBOP (28.2 mg, 54.2 mop and
HOBt (8.4 mg, 62 .mu.mol) in DMF (0.6 mL). After 10 min at ambient
temperature, dimethylamine hydrochloride (20.0 mg, 0.258 mmol) and
DIPEA (45 .mu.L, 0.26 mmol) were added to the reaction mixture.
After 30 min the reaction mixture was acidified with 10% aqueous
sulfuric acid, the solid removed by filtration and the resultant
filtrate was purified by preparative HPLC (0-30% MeCN over 30 min,
35 mL/min) to afford the title compound. .sup.1H NMR (DMSO-D.sub.6,
400 MHz): 12.40 (s, 1H), 9.03 (m, 1H), 8.92 (m, 1H), 8.89 (m, 1H),
8.55 (m, 1H), 7.75 (d, J=8.9 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 3.97
(d, J=12.2 Hz, 2H), 3.56 (d, J=12.2 Hz, 2H), 3.21 (m, 2H), 3.08 (m,
6H), 3.02 (m, 2H), 2.98 (s, 3H). LCMS (Method D): R.sub.T=6.19 min,
M+H.sup.+=415.
Example 348
3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6--
carboxylic acid (2-hydroxy-ethyl)amide
##STR00631##
[0933] DIPEA (13.5 .mu.L, 77.4 .mu.mol) was added to a solution of
3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-
-carboxylic acid (20.0 mg, 51.6 .mu.mol), PyBOP (28.2 mg, 54.2
.mu.mol) and HOBt (8.4 mg, 62 .mu.mol) in DMF (0.6 mL). After 10
min at ambient temperature, ethanolamine (16 .mu.L, 0.26 mmol) was
added to the reaction mixture. After 30 min the resultant mixture
was acidified with 10% aqueous sulfuric acid and concentrated in
vacuo. The resultant residue was dissolved in DMF, water and 10%
aqueous sulfuric acid and purified by preparative HPLC (0-30% MeCN
over 30 min, 35 mL/min) to afford the title compound. .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.49 (s, 1H), 9.71 (br.s, 1H), 9.14 (d,
J=2.1 Hz, 1H), 8.90 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.66 (t, J=5.8
Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 3.97 (d,
J=13.4 Hz, 2H), 3.57 (m, 4H), 3.45 (m, 2H), 3.20 (m, 2H), 3.04 (m,
2H), 2.89 (s. 3H), LCMS (Method D): R.sub.T=6.31 min,
M+H.sup.+=431.
Example 349
6-(Pyrrolidinylcarbonyl)-3-[4-(4-methylpiperizin-1-yl)-phenyl]-9H-dipyrido-
[2,3-b;4',3'-d]pyrrole
##STR00632##
[0934] Step 1:
6-(Pyrrolidinylcarbonyl)-3-bromo-9H-dipyrido[2,3-b:4',3'-d]pyrrole
##STR00633##
[0936] 3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
methyl ester (140 mg, 0.458 mmol) was dissolved in pyrrolidine (6
mL) and the mixture heated to reflux for 2 h. The mixture was
allowed to cool and concentrated in vacuo to afford a bright orange
oily solid. The residue was used without purification.
Step 2:
6-(Pyrrolidinylcarbonyl)-3-[4-(4-methylpiperizin-1-yl)-phenyl]-9H--
dipyrido[2,3-b;4',3'-d]pyrrole
##STR00634##
[0938] A degassed mixture of
6-(pyrrolidinylcarbonyl)-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
(158 mg, 0.457 mmol), 4-(4-methylpiperizin-1-yl)-phenyl-1-boronic
acid, pinacol ester (597 mg, 1.98 mmol), and
bis(triphenylphosphine)palladium(II) chloride (69.0 mg, 99.0
.mu.mol, 5.0 mol %) in acetonitrile (2.5 mL) and 1.0M aqueous
sodium carbonate (2.5 mL) was heated under microwave irradiation at
120.degree. C. for 10 minutes, allowed to cool, and partitioned
between ethyl acetate and water. The organic layer was dried over
sodium sulfate filtered and concentrated in vacuo. The resultant
residue was purified by preparative HPLC (0-30% MeCN/water modified
with 0.1% formic acid) to afford an off-white solid (10.0 mg, 5%).
.sup.1H NMR (DMSO-D.sub.5, 400 MHz) 12.39-12.29 (s, 1H), 9.01 (d,
J=2.2 Hz, 1H), 8.88 (d, J=2.2 Hz, 31), 8.86 (s, 1H), 8.70 (s, 1H),
7.69 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 3.78 (t, J=6.2 Hz,
2H), 3.57 (t, J=6.2 Hz, 2H), 3.25-3.18 (m, 4H), 2.47 (m, 3H), 2.24
(m, 4H), 1.87 (m, 4H). LCMS (Method D): R.sub.T=7.36 min,
M+H.sup.+=441.
Example 350
3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-meth-
anol
##STR00635##
[0940] A 1M solution of lithium aluminum hydride in THF (1.2 mL,
1.2 mmol) was slowly added to a suspension of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-car-
boxylic acid methyl ester (48.0 mg, 0.120 mmol) in THF at 0.degree.
C. The mixture was slowly warmed to ambient temperature. A further
portion of 1M solution of lithium aluminum hydride in THF (1.2 mL,
1.2 mmol) was added slowly to the bright orange-yellow, homogeneous
mixture at ambient temperature. After 1 h, the mixture was treated
with aqueous ammonium chloride, and diluted with water and 50%
DCM/methanol. The resulting mixture was treated with Rochelle's
salt and allowed to stir vigorously for 2 h. The solids were
removed by filtration, and the filtrate layers were separated. The
aqueous phase was extracted with 20% methanol in DCM and the
combined organic phase concentrated in vacuo. The residue was
dissolved in DMSO and purified by preparative HPLC (2-60%
MeCN/water modified with 0.1% ammonium hydroxide) to provide a
light-yellow solid (7.1 mg, 16%). .sup.1H NMR (DMSO-D.sub.6, 400
MHz): 12.10 (s, 1H), 9.02 (m, 1H), 8.90 (m, 1H), 8.82 (m, 1H), 8.28
(m, 1H), 7.79 (m, 2H), 7.46 (m, 2H), 5.40 (t, J=5.7 Hz, 1H), 4.74
(d, J=5.6 Hz, 2H), 3.59-3.41 (m, 2H), 2.38 (m, 4H), 1.54 (m, 414),
1.42 (m, 2H). LCMS (Method D): R.sub.T=4.48 min, M+H.sup.+=373.
Example 351
{3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6--
yl}-methanol
##STR00636##
[0941] Step 1:
3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-methanol
##STR00637##
[0943] Lithium aluminium hydride (1M solution in THF, 16.3 mL, 16.3
mmol) was added dropwise to a suspension of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid methyl
ester (500 mg, 1.63 mmol) in THF (10 mL). After 10 minutes the
reaction mixture was quenched with a solution of saturated ammonium
chloride, diluted with DCM and water and the solid removed by
filtration. The layers of the resultant filtrate were separated and
the aqueous phase was further extracted with DCM. The combined
organic layer was concentrated in vacuo and purified by flash
chromatography (silica, 1-15% methanol in DCM).
Step 2:
{3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]p-
yrrol-6-yl}-methanol
##STR00638##
[0945] A suspension of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-methanol (40.7 mg,
0.146 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol
ester (46.4 mg, 0.154 mmol) and
bis(triphenylphosphine)palladium(II) dichloride (5.1 mg, 7.3 mmol)
in acetonitrile (0.73 mL) and 2N aqueous sodium carbonate solution
(0.73 mL) was heated at 150.degree. C. under microwave irradiation
for 20 minutes. The cooled reaction mixture was diluted with THF,
the solid removed by filtration, and washed with THF and DCM. The
combined filtrate was concentrated in vacuo and the resultant
residue purified by flash chromatography (silica, 1-15% (2N ammonia
methanol) in DCM) to afford the title compound. .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.46 (s, 1H), 9.76 (s, 1H), 9.07 (d,
J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J=8.7
Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 3.38-3.30 (m, 8H),
2.89 (s, 3H). LCMS (Method D): R.sub.T=5.24 min, M+H.sup.+=374.
Example 352
2-{3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrol--
6-yl}-propan-2-ol
##STR00639##
[0946] Step 1:
3-[4-(4-Methyl-piperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole--
6-carboxylic acid methyl ester
##STR00640##
[0948] 3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
methyl ester (100 mg, 0.327 mmol),
4-(4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester (104
mg, 0.343 mmol) and bis(triphenylphosphine)palladium(II) dichloride
(11.5 mg, 0.016 mmol) were suspended in acetonitrile (1.8 mL) and
1N aqueous potassium acetate solution (1.8 mL) and heated under
microwave irradiation at 140.degree. C. for 30 minutes. The cooled
reaction mixture was diluted with saturated sodium bicarbonate
solution and DCM, and the solid removed by filtration. The layers
of the resultant filtrate were separated and the aqueous phase was
further extracted with DCM. The combined organic phase was dried
over sodium sulfate, filtered and concentrated in vacuo. The
resultant residue was purified by flash chromatography (silica,
0-20% (MeOH containing 1% triethylamine) in DCM).
Step 2:
2-{3-[4-(4-Methyl-piperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'--
d]pyrrol-6-yl}-propan-2-ol
##STR00641##
[0950] A solution of 3N methylmagnesium chloride in THF (545 .mu.L,
1.6 mmol) was added to a suspension of
3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-
-carboxylic acid methyl ester (54.7 mg, 0.136 mmol) in THF (4 mL)
at ambient temperature. After 5 minutes the reaction mixture was
quenched with saturated ammonium chloride solution and diluted with
DCM and water. The layers were separated and the aqueous phase was
further extracted with DCM. The combined organic phase was dried
over sodium sulfate, filtered, and concentrated in vacuo. The
resultant residue was dissolved in water, DMF, and 10% aqueous
sulfuric acid and purified by preparative HPLC (0-30% MeCN over 40
min, 35 mL/min) to afford the title compound. .sup.1H NMR
(DMSO-D.sub.6,400 MHz): 12.85 (s, 1H), 9.78 (s, 1H), 9.15-8.84 (m,
4H), 7.78 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 3.98 (d,
J=13.6 Hz, 2H), 3.60 (m, 2H), 3.20 (q, J=10.0 Hz, 2H), 3.03 (t,
J=12.4 Hz, 2H), 2.89 (s, 3H), 1.65 (s, 6H). LCMS (Method D):
R.sub.T=2.91 min, M+H.sup.+=402.
Example 353
6-Bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e
##STR00642##
[0952] Method 1: Step 1:
6'-Bromo-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4']bipyridinyl-3'--
ylamine
##STR00643##
[0953] A mixture of 6-bromo-4-iodopyridin-3-amine (3.3 g, 8.0
mmol), 2-fluoro-3-boronic
acid-5-(4-piperidin-1-ylmethylphenyl)pyridine (3.2 g, 10.0 mmol),
and 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(360 mg, 0.44 mmol) in 1N aqueous potassium fluoride (21 mL) and
acetonitrile (45 mL) was heated at 90.degree. C. for 4 h. The
cooled reaction was diluted with water (100 mL) and extracted with
DCM (3.times.50 mL). The combined organic layer was dried over
sodium sulfate, filtered, and evaporated to afford a residue which
was purified by flash chromotagraphy (silica, 25 g column, Biotage,
0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to
afford the title compound as a yellow/orange solid (3.2 g, 91%).
.sup.1H NMR (DMSO-D.sub.6, 500 MHz,): 8.62 (s, 1H), 8.25 (d, J=7.3
Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H), 7.42 (d, J=6.5 Hz),
7.35 (s, 1H), 5.57 (s, 2H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s,
4H), 1.40 (s, 2H).
Step 2:
6-Bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole
[0954] To a solution of
6'-bromo-2-fluoro-[3,4']bipyridinyl-3'-ylamine (1.5 g, 3.4 mmol) in
anhydrous tetrahydrofuran (41 mL) was added sodium
bis(trimethylsilyl)amide (1N solution in THF, 10.5 mL, 10 mmol)
under a flow of nitrogen. The reaction mixture was left to stir at
room temperature for 1 h then quenched by the addition of acetic
acid (1 mL). The reaction mixture was evaporated in vacuo to afford
a residue that was purified by flash chromotagraphy (silica, 25 g
column, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia in
methanol) to afford the title compound as an off-white solid (620
mg, 43%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz) 12.37 (s, 1H), 9.03
(d, J=2.5 Hz, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.71 (s, 1H), 8.52 (s,
1H), 7.75 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 3.51 (s, 2H),
2.38 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D):
R.sub.T=8.63 min, M+H.sup.+=422/424.
Method 2: Step 1:
6'-Chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3'--
ylamine
##STR00644##
[0956] A degassed mixture of
5-bromo-6'-chloro-2-fluoro-[3,4']bipyridinyl-3'-ylamine (1.35 g,
4.46 mmol), 4-(piperidin-1-ylmethyl)phenylboronic acid hydrobromide
(2.28 g, 7.59 mmol) and bis(triphenylphosphine)palladium(II)
chloride (0.29 g, 0.35 mmol) in acetonitrile (70 mL) and 1N aqueous
potassium fluoride solution (12 mL) was heated under microwave
irradiation at 100.degree. C. for 30 minutes. The cooled reaction
was diluted with water (100 mL) and extracted with DCM (3.times.50
mL). The combined organic layer was dried over sodium sulfate,
filtered, and evaporated to afford a residue which was purified by
flash chromotagraphy (silica, 25 g column, Biotage, 0-10% methanol
in (DCM containing 1% 2M ammonia in methanol)) to afford the title
compound as a yellow/orange solid (0.95 g, 54%).
Step 2:
6-Bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole
##STR00645##
[0958] To a solution of
6'-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4']bipyridinyl-3'-
-ylamine (1.6 g, 0.004 mol) in 1,4-dioxane (30 mL) was added
bromotrimethylsilane (27 mL, 0.2 mol) which immediately produced a
white precipitate. The reaction was heated at 100.degree. C. for 48
h. The solid from the cooled reaction mixture was collected by
filtration and washed with ethyl acetate (2.times.20 mL). The
resultant solid was then purified by flash chromotagraphy (silica,
25 g column, Biotage, 0-10% methanol in (DCM containing 1% 2M
ammonia in methanol)) to afford the title compound as an off-white
solid (1.1 g, 45%). .sup.1H NMR (DMSO-D.sub.6, 500 MHz,): 8.62 (s,
1H), 8.25 (d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H),
7.42 (d, J=6.5 Hz), 7.35 (s, 1H), 5.57 (s, 2H), 3.47 (s, 2H), 2.34
(s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).
Example 354
6-Chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le
##STR00646##
[0960] A degassed mixture of
3-bromo-6-chloro-9H-dipyrido[2,3-b;4',3'-d]pyrrole (1.00 g, 3.55
mmol),
1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine
hydrochloride (1.24 g, 3.67 mmol) and 1,1'-[bis(diphenylphosphino)
ferrocene]dichloro palladium(II) (0.29 g, 0.35 mmol) in
acetonitrile (20 mL) and 2N aqueous potassium fluoride solution (10
mL) was heated under microwave irradiation at 140.degree. C. for 30
minutes. The cooled reaction mixture was concentrated under reduced
pressure and taken up in DCM/methanol and loaded onto an SCX-2
cartridge (20 g) which was then washed with methanol (50 mL) then
2N ammonia in methanol (50 mL). The combined basic fractions were
concentrated in vacuo and the residue purified by flash
chromatography (silica, 80 g column, ISCO, 0-10% methanol in DCM)
to afford the title compound as a pink solid (0.87 g, 66%). .sup.1H
NMR (DMSO-D.sub.6, 400 MHz): 12.38 (s, 1H), 9.03 (d, J=2.3 Hz, 1H),
8.95 (d, J=2.3 Hz, 1H), 8.71 (d, J=1.0 Hz, 1H), 8.38 (d, J=0.9 Hz,
1H), 7.75 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 3.49 (s, 2H),
2.39-2.33 (m, 4H), 1.56-1.48 (m, 4H), 1.45-1.37 (m, 2H). LCMS
(Method B): R.sub.T=2.27 min, M+H.sup.+=377.
Example 355
6-Chloro-3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]p-
yrrole
##STR00647##
[0962] A degassed mixture of
3-bromo-6-chloro-9H-dipyrido[2,3-b;4',3'-d]pyrrole (43.0 mg, 0.152
mmol), 4-(4-methylpiperizin-1-yl)-phenyl-1-boronic acid, pinacol
ester (48.2 mg, 0.159 mmol) and
bis(triphenylphosphine)palladium(II) chloride (5.3 mg, 7.6 .mu.mol,
5.0 mol %) in acetonitrile (0.63 mL) and 1M aqueous potassium
acetate (0.63 mL) was heated under microwave irradiation at
140.degree. C. for 30 minutes, allowed to cool and concentrated in
vacuo. The residue was dissolved in water, DMF, and 10% sulfuric
acid and purified by preparative HPLC (0-30% MeCN/water modified
with 0.1% formic acid) to afford a light yellow solid (21.3 mg,
35%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.34 (s, 1H), 8.96 (d,
J=2.2 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.70 (s, 1H), 8.38 (s, 1H),
7.66 (d, J=8.7, 3H), 7.09 (d, J=8.8, 3H), 3.26-3.17 (m, 4H), 2.47
(m, 4H), 2.24 (s, 3H). LCMS (Method D): R.sub.T=8.90 min,
M+H.sup.+=378.
Example 356
6-Chloro-3-(1-methylpyrazol-4-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e
##STR00648##
[0964] A degassed mixture of
3-bromo-6-chloro-9H-dipyrido[2,3-b;4',3'-d]pyrrole (34.6 mg, 0.122
mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(26.8 mg, 0.129 mmol), and bis(triphenylphosphine)palladium(II)
chloride (4.3 mg, 6.1 .mu.mol, 5.0 mol %) in acetonitrile (0.51 mL)
and 1M aqueous potassium acetate (0.51 mL) was heated under
microwave irradiation at 140.degree. C. for 30 minutes, allowed to
cool and concentrated in vacuo. The residue was dissolved in water,
DMF, and 10% sulfuric acid and purified by preparative HPLC (0-30%
MeCN/water modified with 0.1% formic acid) to afford an off-white
solid (15.4 mg, 44%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.32
(s, 1H), 8.89 (s, 2H), 8.69 (d, J=0.7 Hz, 1H), 8.28 (d, J=0.7 Hz,
1H), 8.22 (s, 1H), 7.96 (s, 1H), 3.90 (s, 3H). LCMS (Method D):
R.sub.T=9.61 min, M+H.sup.+=284.
Example 357
6-Fluoro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e
##STR00649##
[0965] Step 1: 6-Fluoro-4-iodopyridin-3-ylamine
##STR00650##
[0967] (6-Fluoro-4-iodopyridin-3-yl)-carbamic acid tert-butyl ester
(1.75 g, 5.18 mmol) was dissolved in DCM (25 mL) and TFA (5 mL)
added. The mixture was stirred at ambient temperature for 1 h and
then evaporated in vacuo. The resultant residue was treated with
saturated aqueous sodium hydrogen carbonate solution (25 mL),
diluted with water (100 mL) and extracted into ethyl acetate
(2.times.100 mL). The organic layer was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford the
title compound as an orange oil, which crystallized on standing
(1.23 g, 99%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.61 (d, J=1.6
Hz, 1H), 7.28-7.25 (m, 1H), 3.99 (s, 2H). LCMS (Method B):
R.sub.T=2.52 min, M+H.sup.+=239.
Step 2: 5-Bromo-2,6'-difluoro-[3,4']bipyridinyl-3'-ylamine
##STR00651##
[0969] A mixture of 6-fluoro-4-iodopyridin-3-ylamine (1.57 g, 6.59
mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.17 g, 9.89 mmol)
and 1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(0.43 g, 0.53 mmol) in acetonitrile (25 mL) and 1N aqueous
potassium fluoride solution (25 mL) was degassed with nitrogen for
20 minutes. The reaction mixture was heated at 80.degree. C. for 3
h, allowed to cool to ambient temperature and then partitioned
between ethyl acetate (100 mL) and water (75 mL). The organic layer
was separated, dried over sodium sulfate, filtered and evaporated
in vacuo. The resultant residue was purified by flash
chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in
cyclohexane) to afford the title compound as an brown solid (0.54
g, 29%). .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.37 (dd, J=2.5, 1.4
Hz, 1H), 7.99 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 6.74
(d, J=2.8 Hz, 1H), 3.62 (s, 2H). LCMS (Method B): R.sub.T=3.01 min,
M+H.sup.+=286/288.
Step 3: 3-Bromo-6-fluoro-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00652##
[0971] A solution of
5-bromo-2,6'-difluoro-[3,4']bipyridinyl-3'-ylamine (0.79 g, 2.76
mmol) in THF (15 mL) was added dropwise over 10 minutes to sodium
bis(trimethylsilyl)amide (1N solution in THF, 5.5 mL, 5.52 mmol).
The reaction mixture was left to stir for 20 minutes then quenched
by the addition of water (2 mL). The resultant black solution was
partitioned between ethyl acetate (75 mL) and water (50 mL) and the
layers separated. The organic phase was dried over sodium sulfate,
filtered and evaporated in vacuo to give an off white solid. The
resultant solid was triturated with ethyl acetate (30 mL),
collected by filtration, washed with diethyl ether (5 mL) and left
to air dry to afford the title compound as an off white solid (0.51
g, 65%), .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 9.00 (d, J=2.3 Hz,
1H), 8.69 (d, J=2.3 Hz, 1H), 8.51 (dd, J=1.7, 0.9 Hz, 1H), 7.95
(dd, J=2.4, 0.9 Hz, 1H). LCMS (Method B): R.sub.T=3.10 min,
M+H.sup.+=266/268.
Step 4:
6-Fluoro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole
##STR00653##
[0973] A mixture of
3-bromo-6-fluoro-9H-dipyrido[2,3-b;4',3'-d]pyrrole (100 mg, 0.38
mmol), 4-benzylpiperidine boronic acid (123 mg, 0.56 mmol) and
1,1'-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (31
mg, 0.038 mmol) in acetonitrile (1.5 mL) and 2N aqueous potassium
fluoride solution (1.5 mL) was degassed with nitrogen for 20
minutes. The reaction mixture was then heated under microwave
irradiation at 150.degree. C. for 30 minutes, allowed to cool to
ambient temperature and diluted with water (3 mL). The resultant
precipitate was collected by filtration, washed with water (5 mL)
and ethyl acetate (10 mL). The resultant solid residue was purified
by flash chromatography (silica, 4 g column, ISCO, 0-20% methanol
in DCM) to afford the title compound as an off white solid (90 mg,
67%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 12.27 (s, 1H), 9.00 (d,
J=2.3 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.98
(d, J=2.3 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H),
3.48 (s, 2H), 2.42-2.29 (m, 4H), 1.54-1.47 (m, 4H), 1.44-1.34 (m,
2H). LCMS (Method A): R.sub.T=5.87 min, M+H.sup.+=361.
Example 358
6-oxo-3-(4-piperidin-1-ylmethyl-phenyl)-6,7-dihydro-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole
##STR00654##
[0975] To
6-methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4'-
,3'-d]pyrrole (200 mg, 0.5 mmol) was added HBr (33% in acetic acid,
5 mL) and the reaction was heated at 100.degree. C. for 16 h. The
cooled reaction mixture was then evaporated in vacuo to afford a
residue that was purified by preparative HPLC [0-30% MeCN in water
(0.1% formic acid) over 30 min, 35 mL/min] to afford the title
compound as a bright yellow solid (50 mg, 30%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 11.51 (s, 1H), 8.91-8.74 (m, 2H), 8.28 (s,
1H), 7.72 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.29 (s, 1H),
6.68-6.44 (s, 1H), 3.48 (s, 2H), 2.36 (s, 4H), 1.51 (m, 4H), 1.40
(m, 2H). LCMS (Method D): R.sub.T=4.97 min, M+H.sup.+=359.
Example 359
6-Methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole
##STR00655##
[0976] Step 1: tert-Butyl 6-methoxypyridin-3-ylcarbamate
##STR00656##
[0978] A mixture of 6-methoxypyridin-3-amine (14 g, 0.11 mol) and
di-tert-butyldicarbonate (32 g, 0.15 mol) in 1,4-dioxane (100 mL)
was heated at 75.degree. C. for 16 h. The cooled reaction mixture
was diluted with ethyl acetate (200 mL) and washed with water (150
mL). The organic phase was separated, dried over sodium sulfate,
filtered and evaporated in vacuo to afford a residue that was
purified by flash chromotagraphy (silica, 120 g column, ISCO, 0-40%
ethyl acetate in hexanes) to afford the title compound as a pink
solid (20 g, 80%).
Step 2: (6-Methoxy-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester
##STR00657##
[0980] n-Butyllithium (2.5M in hexanes, 100 mL, 240 mmol) was added
dropwise over 1 h to a cooled (-78.degree. C.) mixture of
tert-butyl-6-methoxypyridin-3-ylcarbamate (16 g, 71 mmol) and
N,N,N',N'-tetramethylethylenediamine (34 mL, 221 mmol) in diethyl
ether (100 mL). The reaction was stirred at -78.degree. C. for 30
minutes, then warmed to -20.degree. C. and left stirring for 3 h.
The reaction mixture was transferred via cannula over fifteen
minutes to a cold (-78.degree. C.) solution of
1-chloro-2-iodoethane (48 g, 243 mmol) in diethyl ether (50 mL). On
complete addition, the reaction mixture was allowed to warm to room
temperature and left stirring at this temperature for 16 h. The
reaction was quenched with saturated aqueous ammonium chloride (30
mL) and water (200 mL) then extracted with ethyl acetate
(2.times.100 mL). The combined organic layer was washed with
saturated sodium sulfite (50 mL), 1N hydrochloric acid (100 mL),
water (100 mL), saturated sodium bicarbonate solution (100 mL) and
brine (50 mL), dried over sodium sulfate, and evaporated to give a
residue which was purified by flash chromatography (silica, 120 g
column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title
compound as a white cyrstaline solid (18 g, 72%).
Step 3: 6-Methoxy-4-iodopyridin-3-amine
##STR00658##
[0982] A solution of (6-methoxy-4-iodo-pyridin-3-yl)-carbamic acid
tert-butyl ester (18 g, 51 mmol) in DCM (50 mL) and TFA (50 mL) was
stirred at ambient temperature for 1 h and then evaporated in
vacuo. The resultant residue was treated with saturated aqueous
sodium hydrogen carbonate solution (25 mL), diluted with water (100
mL) and extracted into ethyl acetate (2.times.100 mL). The organic
layer was separated, dried over sodium sulfate, filtered and
evaporated in vacuo to afford the title compound as a brown foam
(10 g, 60%).
Step 4:
5-Bromo-6'-methoxy-2-fluoro-[3,4']bipyridinyl-3'-ylamine
##STR00659##
[0984] A mixture of 6-methoxy-4-iodopyridin-3-amine (9.5 g, 38
mmol), 5-bromo-2-fluoropyridin-3-ylboronic acid (16.7 g, 76 mmol),
and 1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(1.5 g, 2 mmol) in 1N aqueous potassium fluoride (95 mL) and
acetonitrile (200 mL) was heated at 95.degree. C. for 16 h. The
cooled reaction mixture was diluted with water (100 mL) and
extracted with DCM (3.times.100 mL). The combined organic layer was
dried over sodium sulfate, filtered, and evaporated to afford a
residue which was purified by flash chromotagraphy (silica, 120 g
column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title
compound as a yellow/orange solid (8.0 g, 71%).
Step 5:
6'-Methoxy-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4']bipyri-
dinyl-3'-ylamine
##STR00660##
[0986] A mixture of
6'-methoxy-2-fluoro-[3,4']bipyridinyl-3'-ylamine (1.0 g, 3.4 mmol),
4-(piperidin-1-ylmethyl)phenylboronic acid hydrobromide (1.7 g, 5.7
mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.18 g,
0.25 mmol) in 1N aqueous potassium fluoride (8.4 mL) and
acetonitrile (12 mL) was heated under microwave irradiation at
100.degree. C. for 25 minutes. The cooled reaction was diluted with
water (100 mL) and extracted with DCM (3.times.50 mL). The combined
organic layer was, dried over sodium sulfate, filtered, and
purified by flash chromotagraphy (silica, 25 g column, Biotage,
0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to
afford the title compound as a yellow/orange solid (1.0 g, 77%).
.sup.1H NMR (DMSO-D.sub.6, 500 MHz): 8.59 (s, 1H), 8.22 (d, J=8.0
Hz, 1H), 7.74 (s, 3H), 7.42 (s, 2H), 6.65 (s, 1H), 4.71 (s, 2H),
3.77 (s, 3H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s,
2H).
Step 6:
6-Methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole
##STR00661##
[0988] To a solution of
6'-methoxy-2-fluoro-[3,4']bipyridinyl-3'-ylamine (43 mg, 0.11 mmol)
in anhydrous tetrahydrofuran (1.8 mL) was added sodium
bis(trimethylsilyl)amide (1N solution in THF, 0.33 mL, 0.332 mmol)
under a flow of nitrogen. The reaction was left to stir at room
temperature for 1 h then quenched with acetic acid (1 mL). The
reaction mixture was evaporated in vacuo to afford a residue that
was purified by preparative HPLC [0-30% MeCN in water (0.1% formic
acid) over 30 min, 35 mL/min] to afford the title compound as a
beige solid (10 mg, 20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
11.82 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.47
(s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.64 (s, 1H), 7.42 (d, J=8.2 Hz,
2H), 3.92 (s, 3H), 3.48 (s, 2H), 2.36 (s, 4H), 1.51 (m, 4H), 1.40
(m, 2H). LCMS (Method E): R.sub.T=2.40, M+H.sup.+=373.
Example 360
6-Methoxy-3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]-
pyrrole
##STR00662##
[0989] Step 1:
6-Methoxy-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00663##
[0991] A 1N solution of bis(trimethylsilyl)amide in THF (6.81 mL,
6.81 mmol) was added dropwise to a solution of
5-bromo-2-fluoro-6'-methoxy-[3,4]bipyridinyl-3'-ylamine (203 mg,
0.681 mmol) in THF (12.0 mL). The reaction mixture was stirred for
30 minutes at ambient temperature, diluted with water, and
extracted into ethyl acetate. The organic phase was dried over
sodium sulfate, filtered, and concentrated in vacuo. The crude
residue was dissolved in ethyl acetate and methanol, absorbed onto
silica gel, and purified by flash chromatography (silica, 12 g
column, ISCO, 0-100% ethyl acetate in hexanes) to provide the title
compound as an orange-tan solid (89.0 mg, 47%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.44-12.12 (m, 1H), 7.79 (d, J=2.6 Hz,
1H), 7.66 (d, J=3.5 Hz, 2H), 6.56 (s, 1H), 3.75 (s, 3H). LCMS
(Method B): R.sub.T=1.83 min, M+H.sup.+=278/280.
Step 2:
6-Methoxy-3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole
##STR00664##
[0993] A degassed mixture of
6-methoxy-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (89.0 mg, 0.320
mmol), 4-(4-methylpiperazin-1-yl)-phenyl-1-boronic acid, pinacol
ester (102 mg, 0.336 mmol) and bis(triphenylphosphine)palladium(II)
chloride (11.2 mg, 16.0 umol, 5.0 mol %) in acetonitrile (1.3 mL)
and 1M aqueous potassium acetate (1.3 mL) was heated under
microwave irradiation at 140.degree. C. for 30 minutes, allowed to
cool to room temperature and concentrated. The residue was
dissolved in water, DMF, and 10% sulfuric acid and purified by
preparative HPLC [0-25% MeCN/water modified with 0.1% formic acid]
to afford a light yellow solid (17.3 mg, 15%). NMR (DMSO-D.sub.6,
500 MHz): 11.72 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.80 (d, J=2.3 Hz,
1H), 8.46 (m, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.63 (s, 1H), 7.09 (d,
J=8.8 Hz, 2H), 3.92 (s, 3H), 3.28 (s, 3H), 2.71 (m, 4H), 2.41 (m,
4H). LCMS (Method D): R.sub.T=6.70 min, M+H.sup.+=374.
Example 361
3,6-Bis(1-methyl-4-pyrazolyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00665##
[0994] Step 1:
3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
hydrazide
##STR00666##
[0996] A solution of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid methyl
ester (582 mg, 1.90 mmol) and hydrazine hydrate (2.29 mL, 47.0
mmol) in ethanol (4.6 mL) was heated under reflux in an inert
atmosphere. After 1 h, the reaction mixture was allowed to cool to
ambient temperature. The resultant precipitate was collected by
filtration, washed with ethanol, and left to air-dry to afford the
title compound as a tan-yellow solid.
Step 2: 3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
azide
##STR00667##
[0998] Hydrogen chloride (3.0 mL, 90 mmol) was added dropwise to a
suspension of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid
hydrazide (530 mg, 1.73 mmol) in water (12.4 mL). Once homogeneous,
the solution was cooled to 0.degree. C. and a solution of 3N sodium
nitrite in water (0.60 mL, 2.0 mmol) was added to the mixture.
After 1 h, added another 1.03 eq. of 3N sodium nitrite in water
(0.60 mL, 2.0 mmol) and allowed the reaction to warm to ambient
temperature over night. After 17 h at room temperature, the
reaction was cooled to 0.degree. C. and a solution of 3N sodium
nitrite in water (0.60 mL, 2.0 mmol) was added and then warmed to
room temperature. The reaction was made basic with a solution of
saturated sodium bicarbonate, and the solid precipitate was
collected by filtration, washed with water, and dried in a
dessicator under vacuum to provide a solid material that was 70%
pure by LCMS analysis.
Step 3: 6-Amino-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00668##
[1000] A suspension of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carboxylic acid azide
(1.09 g, 3.44 mmol) in a mixture of 1:1 water-acetic acid (3.52 mL)
was heated under reflux for 1 h. The reaction was allowed to cool
to ambient temperature and the mixture concentrated in vacuo. The
resultant residue was purified by flash chromatography (silica,
1-20% (MeOH containing 1% of 2N ammonia in MeOH) in DCM) and
recrystallized from pyridine to afford the title compound.
Step 4: 3,6-Dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00669##
[1002] A solution of hydrogen bromide (33%) in acetic acid (1.10
mL, 6.08 mmol) was added to
6-amino-3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (80.1 mg, 0.304
mmol) at 0.degree. C. To the resulting suspension was added bromine
(18 .mu.L, 0.34 mmol), and then a 1N solution of sodium nitrite in
water (0.43 mL, 0.43 mmol), and the mixture was allowed to warm to
ambient temperature. After 1 h, the reaction mixture was diluted
with concentrated ammonium hydroxide-water (1:1) and DCM, filtered
to remove the solid, and the filtrate layers separated. The aqueous
phase was extracted into DCM and the combined organic phase was
concentrated in vacuo. The residue was purified by flash
chromatography (silica, 0-100% ethyl acetate in hexanes).
Step 5:
3,6-Bis(1-Methyl-4-pyrazolyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00670##
[1004] A suspension of
3,6-dibromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (9.3 mg, 28 .mu.mol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(17.8 mg, 85.3 .mu.mol) and bis(triphenylphosphine)palladium(II)
dichloride (1.0 mg, 14 mop in acetonitrile (0.18 mL) and 2N aqueous
sodium carbonate solution was heated under microwave irradiation at
140.degree. C. for 20 minutes. The reaction mixture was allowed to
cool to ambient temperature and the resultant precipitate collected
by filtration, and the solid washed sequentially with water, DCM,
and 20% MeOH in DCM. The filtrate was combined, the layers
separated, and the aqueous phase extracted into 20% MeOH in DCM.
The combined organic phase was concentrated in vacuo and the
resultant residue purified by flash chromatography (silica, 0-20%
MeOH in DCM) to afford the title compound. .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.01 (s, 1H), 8.83 (m, 2H), 8.78 (m, 1H),
8.39 (s, 1H), 8.21 (d, J=9.4 Hz, 2H), 7.97 (d, J=7.0 Hz, 2H),
3.98-3.91 (s, 6H). LCMS (Method D): R.sub.T=7.53 min,
M+H.sup.+=330.
Example 362
3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-amin-
e
##STR00671##
[1005] Step 1:
tert-Butyl-{3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl}-carbamate
##STR00672##
[1007] A suspension of
3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonyl azide (50.0
mg, 0.158 mmol) in toluene (3.0 mL) was treated with tert-butyl
alcohol (1.00 mL, 10.4 mmol) and heated under reflux for 1 h under
a nitrogen atmosphere. The solution was allowed to cool to ambient
temperature and the resulting precipitate was collected by
filtration, washed with DCM, and dried under vacuum to afford an
orange solid (55.9 mg, 98%). The solid was used without
purification. .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.12 (s, 1H),
9.57 (s, 1H), 8.99 (d, J=2.2 Hz, 1H), 8.62 (d, J=2 Hz2, 1H), 8.59
(s, 1H), 8.49 (s, 1H), 1.51 (s, 9H).
Step 2:
tert-Butyl-{3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4'-
,3'-d]pyrrol-6-yl}-carbamate
##STR00673##
[1009] A degassed mixture of
tert-butyl-{3-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl}-carbamate
(229 mg, 0.631 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid
(207 mg, 0.946 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (51.5 mg, 6.31 .mu.mol, 10.0 mol %) in
1,4-dioxane (12.4 mL) and 2M aqueous cesium carbonate (1.32 mL) was
heated under reflux for 5 h. The mixture was allowed to cool to
room temperature, diluted with DCM and water, and filtered to
remove the precipitate. The filtrate layers were separated and the
aqueous phase was extracted with DCM, and the combined organic
phase concentrated in vacuo. The resultant residue was dissolved in
20% methanol in DCM and absorbed onto silica gel for purification
by flash chromatography (silica, 11 g column, Biotage, 1-20%
methanol in DCM) to afford the title compound as a beige solid
(86.9 mg, 30%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 11.96 (s, 1H),
9.55 (s, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.57
(d, J=7.8 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H),
3.50 (s, 2H), 2.35 (m, 4H), 1.55-1.45 (m, 4H), 1.52 (s, 9H), 1.39
(m, 2H). LCMS (Method D): R.sub.T=9.11 min, M+H.sup.+=458.
Step 3:
3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e-6-amine
##STR00674##
[1011] A degassed mixture of
tert-butyl-{3-Bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl}-carbamate
(105 mg, 0.290 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid
(73.7 mg, 0.336 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (17.8 mg, 2.18 .mu.mol, 7.5 mol %) in
acetonitrile (1.3 mL) and 1M aqueous potassium acetate (1.3 mL) was
heated under microwave irradiation at 140.degree. C. for 30
minutes. The cooled reaction mixture was diluted with 20% MeOH in
DCM and water, and filtered to remove the solids. The filtrate
layers were separated and the aqueous phase was extracted into 20%
MeOH in DCM, and the combined organic phase concentrated in vacuo.
The resultant residue was purified by preparative HPLC (0-30% MeCN
in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the
title compound as a yellow solid (41 mg, 40%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 11.47 (s, 1H), 8.77 (d, J=2.0 Hz, 1H),
8.73 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.73 (d, J=8.1
Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.18 (s, 1H), 3.48 (s, 2H), 2.38
(m, 4H), 1.57-1.47 (m, 4H), 1.41 (m, 2H). LCMS (Method D):
R.sub.T=6.20 min, M+H.sup.+=358.
Example 363
N-{3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl-
-methanesulfonamide
##STR00675##
[1013] A solution of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-amin-
e (82.1 mg, 0.230 mmol) in pyridine (8.2 mL) was treated with
methanesulfonyl chloride (58.7 .mu.L, 0.758 mmol) and heated at
50.degree. C. for 15 h. The cooled reaction mixture was treated
with saturated sodium bicarbonate solution and diluted with 20%
MeOH in DCM and water. The layers were separated, the aqueous phase
extracted into 20% MeOH in DCM, and the combined organic phases
were dried over sodium sulfate and concentrated in vacuo. The
resultant residue was purified by preparative HPLC (0-30% MeCN in
water (0.1% formic acid) over 30 min, 35 mL/min) to afford the
title compound as a tan solid (38 mg, 38%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.03 (s, 1H), 8.96 (d, J=2.1 Hz, 1H),
8.88 (d, J=2.1 Hz, 1H), 8.64 (s, 1H), 7.85 (s, 1H), 7.77 (d, J=8.1
Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 3.48 (s, 2H), 3.22 (s, 3H), 2.36
(m, 4H), 1.55-1.46 (m, 4H), 1.41 (m, 2H). LCMS (Method D):
R.sub.T=7.37 min, M+H.sup.+=436.
Example 364
1-Ethyl-3-{3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4'.,
3'-d]pyrrol-6-yl}-urea
##STR00676##
[1015] A suspension of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-amin-
e (91.6 mg, 0.256 mmol) in DCM (9.1 mL) was treated with pyridine
(22.8 .mu.L, 0.282 mmol) and ethylisocyanate (33.2 .mu.L, 0.423
mmol) and then the reaction mixture was heated under reflux for 5
h. The cooled reaction mixture was treated with saturated sodium
bicarbonate and diluted with 20% MeOH in DCM and water. The layers
were separated, the aqueous phase extracted into 20% MeOH in DCM,
and the combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The resultant residue was purified by
preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30
min, 35 mL/min) to afford the title compound as a yellow solid (34
mg, 31%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 9.66 (t, J=5.4 Hz,
1H), 9.19 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.91 (d, J=2.1 Hz, 1H),
7.80 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.20 (s, 1H),
3.53-3.44 (m, 4H), 2.36 (m, 4H), 1.58-1.46 (m, 4H), 1.41 (m, 2H),
1.31-1.21 (m, 3H). LCMS (Method D): R.sub.T=8.06 min,
M+H.sup.+=429.
Example 365
N-{3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl-
}-isobutyramide
##STR00677##
[1017] A suspension of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-amin-
e (80.9 mg, 0.226 mmol) in DCM (1.8 mL) was treated with isobutyryl
chloride (26.3 .mu.L, 0.249 mmol) and DIPEA (118 .mu.L, 0.679
mmol). The reaction mixture was treated with saturated sodium
bicarbonate and diluted with 20% MeOH in DCM and water. The layers
were separated, the aqueous phase extracted into 20% MeOH in DCM,
and the combined organic phase was dried over sodium sulfate and
concentrated in vacuo. The resultant residue was dissolved in
DCM/methanol, absorbed onto celite, and purified by preparative
HPLC (0-30% MeCN/water modified with 0.1% formic acid) to afford an
off-white solid (12 mg, 12%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
12.03 (s, 1H), 10.32 (s, 1H), 8.95 (d, J=2.2 Hz, 1H), 8.90-8.85 (m,
2H), 8.62 (s, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H),
3.48 (s, 2H), 2.79 (dt, J=6.7, 13.5 Hz, 1H), 2.36 (m, 4H),
1.58-1.46 (m, 4H), 1.41 (m, 2H), 1.14 (d, J=6.8 Hz, 6H). LCMS
(Method D): R.sub.T=7.73 min, M+H.sup.+=428.
Example 366
3-(4-Piperidin-1-ylmethyl-phenyl)-6-(1H-imidazol-1-yl)-9H-dipyrido[2,3-b;4-
',3'-d]pyrrole
##STR00678##
[1019] A mixture of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-amin-
e (101.1 mg, 0.283 mmol), paraformaldehyde (9.65 .mu.L, 0.283
mmol), glyoxal (13.0 .mu.L, 0.283 mmol) and 0.17M aqueous ammonium
chloride (5.0 mL) in 1,4-dioxane (8.4 mL) and water (8.4 mL) was
heated at 100.degree. C. for 18 h. The cooled reaction mixture was
treated with saturated sodium bicarbonate and diluted with 20% MeOH
in DCM and water. The layers were separated, the aqueous phase
extracted into 20% MeOH in DCM, and the combined organic phase was
dried over sodium sulfate and concentrated in vacuo. The resultant
residue was purified by preparative HPLC (0-30% MeCN in water (0.1%
formic acid) over 30 min, 35 mL/min) to afford the title compound
as a white solid (20 mg, 17%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
12.37 (s, 1H), 8.96 (s, 2H), 8.82 (s, 1H), 8.67 (s, 1H). 8.49 (s,
1H), 7.94 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H),
7.16 (s, 1H), 3.50 (s, 2H), 2.37 (m, 4H), 1.58-1.46 (m, 4H), 1.41
(m, 2H). LCMS (Method D): R.sub.T=6.62 min, M+H.sup.+=409
Example 367
3-(4-piperidin-1-ylmethyl-phenyl)-6-(4H-1,2,4-triazol-4-yl)-9H-dipyrido[2,-
3-b;4',3'-d]pyrrole
##STR00679##
[1021] A mixture of
3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-amin-
e (22.3 mg, 62.4 .mu.mol), 1,2-diformylhydrazine (16.5 mg, 0.187
mmol), chloro-trimethylsilane (119 .mu.L, 0.936 mmol) in
triethylamine (60.9 .mu.L, 0.437 mmol) and pyridine (340 .mu.L) was
heated under reflux for 30 minutes. The cooled reaction mixture was
diluted with water, DCM, methanol and water. The layers were
separated; the aqueous phase extracted with 20% MeOH in DCM, and
the combined organic phase was concentrated in vacuo. The resultant
residue was purified by preparative HPLC (0-30% MeCN in water (0.1%
formic acid) over 30 min, 35 mL/min) to afford the title compound
as a yellow solid (21 mg, 81%). .sup.1H NMR (DMSO-D.sub.6, 400
MHz): 12.50 (s, 1H), 9.25 (s, 2H), 8.99 (d, J=2.1 Hz, 1H), 8.94 (d,
J=2.2 Hz, 1H), 8.86 (s, 1H), 8.73 (s, 1H), 7.76 (d, J=8.1 Hz, 2H),
7.46 (d, J=8.1 HZ, 2H), 3.50 (s, 2H), 2.35 (m, 4H), 1.58-1.46 (m,
4H), 1.41 (m, 2H). LCMS (Method D): R.sub.T=7.46 min,
M+H.sup.+=410.
Example 368
6-(1-Methyl-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-di-
pyrido[2,3-b;4',3'-d]pyrrole
##STR00680##
[1022] Step 1:
6-Iodo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e
##STR00681##
[1024] A mixture of
6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (250 mg, 0.6 mmol), copper (I) iodide (23 mg, 0.12 mmol),
N,N'-dimethyl-1,2-ethanediamine (0.013 mL, 0.12 mmol), and sodium
iodide (360 mg, 2.4 mmol) in 1,4-dioxane was heated at 110.degree.
C. for 3 days. The reaction was diluted with dichloromethane (20
mL), filtered, and concentrated to afford a residue that was
purified by flash chromatography (silica, 10 g column, Biotage,
0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to
afford the title compound as an orange solid (280 mg, 100%).
Step 2:
6-(1-Methyl-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-pheny-
l)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00682##
[1026] A degassed mixture of
6-iodo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e (100 mg, 0.21 mmol),
1-methyl-5-(trimethylstannyl)-1H-1,2,3-triazole (158 mg, 0.64 mmol)
and bis(triphenylphosphine)palladium(II) dichloride (15 mg, 0.021
mmol) in N,N-diisopropylethylamine (0.74 mL, 0.43 mmol) in
1,4-dioxane (1.7 mL) was heated at 100.degree. C. for 1 h. The
cooled reaction mixture was diluted with DCM (20 mL) and methanol
(2 mL) and washed with water (15 mL). The organic phase was
separated, dried over sodium sulfate, filtered and evaporated in
vacuo to afford a residue that was purified by preparative HPLC
(20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35
mL/min) to afford the title compound as a pale yellow solid (20 mg,
20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.47 (s, 1H), 9.05 (s,
1H), 9.04 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.78 (s, 1H),
8.18 (s, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 4.37
(s, 3H), 3.50 (s, 2H), 2.35 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H).
LCMS (method D): R.sub.T=8.04 min, M+H.sup.+=424.
Example 369
6-((5-1H-1,2,3-Triazol-4-yl)methanol)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-
-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00683##
[1027] Step 1:
6-(1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazol-5-yl)-
-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00684##
[1029] The title compound was prepared following a similar
procedure to Example 368 using
1-benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)-1H-1-
,2,3-triazole. The crude reaction mixture was purified by flash
chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in DCM
containing 1% 7M ammonia in methanol) to afford a residue that was
used in the next step without further purification.
Step 2:
6-((5-1H-1,2,3-Triazol-4-yl)methanol)-3-(4-piperidin-1-ylmethyl-ph-
enyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00685##
[1031] A solution of 6-(1-benzyl-4-((tert-butyldimethylsilyloxy)
methyl)-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyr-
ido[2,3-b;4',3'-d]pyrrole in 48% aqueous hydrobromic acid (1.5 mL)
was heated at 110.degree. C. in a sealed tube for 7 h. The cooled
reaction mixture was then neutralized by dropwise addition of 6N
sodium hydroxide solution. The solvent was evaporated to afford a
residue that was dissolved in DMF and purified by preparative HPLC
(20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35
mL/min) to afford the title compound as a pale yellow solid (20 mg,
20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.29 (s, 1H), 9.13 (d,
J=2.1 Hz, 1H), 8.97 (s, 1H), 8.95-8.91 (m, 2H), 7.80 (d, J=8.1 Hz,
2H), 7.44 (d, J=8.1 Hz, 2H), 6.00 (s, 1H), 4.90 (s, 2H), 3.49 (s,
2H), 2.35 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (method D):
R.sub.T=6.83 min, M+H.sup.+=440.
Example 370
3-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-6-(1-methyl-1H-pyr-
azol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00686##
[1032] Step 1:
6'-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4'-
]bipyridinyl-3'-ylamine
##STR00687##
[1034] A degassed mixture of
5-bromo-6'-chloro-2-fluoro-[3,4']bipyridinyl-3'-ylamine (2.0 g,
6.60 mmol), bis(pinacolato)diborane (1.84 g, 7.30 mmol),
1,1'-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (270
mg, 0.33 mmol) and potassium acetate (1.94 g, 19.8 mmol) in dioxane
(20 mL) and DMSO (2 mL) was heated under microwave irradiation at
150.degree. C. for 30 minutes. The cooled reaction mixture was
diluted with ethyl acetate (50 mL) the solid removed by filtration
and the filtrate was washed with water (75 mL). The organic phase
was dried over sodium sulfate, filtered and evaporated in vacuo to
afford a residue that was purified by flash chromatography (silica,
40 g column, ISCO, 0-50% ethyl acetate in DCM) to afford the title
compound as a white solid (737 mg, 32%). .sup.1H NMR (CDCl.sub.3,
300 MHz): 8.67 (dd, J=2.0, 0.8 Hz, 1H), 8.18 (dd, J=10.0, 2.0 Hz,
1H), 7.97 (d, J=0.5 Hz, 1H), 7.10 (s, 1H), 1.36 (s, 12H).
Step 2:
6'-Chloro-5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)--
2-fluoro-[3,4']bipyridinyl-3'-ylamine
##STR00688##
[1036] A degassed mixture of
6'-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4'-
]bipyridinyl-3'-ylamine (1.99 g, 5.70 mmol),
2-bromo-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.54 g,
6.30 mmol), 1,1'-[bis(diphenylphosphino)
ferrocene]dichloropalladium(II) (466 mg, 0.57 mmol) in 1N aqueous
potassium fluoride solution (22.5 mL) and acetonitrile (22.5 mL)
was heated under microwave irradiation at 100.degree. C. for 30
minutes. The cooled reaction mixture was loaded onto an SCX-2
cartridge (50 g) and eluted with 2N ammonia in methanol to afford
impure product as a brown solid. The resultant brown residue was
purified by flash chromatography (silica, 40 g column, ISCO, 0-10%
methanol in DCM) to afford the title compound as an off-white solid
(1.05 g, 47%). .sup.1H NMR (DMSO-D.sub.6, 300 MHz): 8.48 (d, J=2.4
Hz, 1H), 8.12 (dd, J=9.0, 2.6 Hz, 1H), 7.89 (s, 1H), 7.36 (s, 1H),
7.21 (s, 1H), 5.54 (s, 2H), 3.45 (s, 2H), 2.86-2.79 (m, 2H),
2.75-2.68 (m, 2H), 2.58-2.51 (m, 2H), 1.08 (t, J=7.1 Hz, 3H).
Step 3:
5-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-6-
'-(1-methyl-1H-pyrazol-4-yl)-[3,4']bipyridinyl-3'-ylamine
##STR00689##
[1038] A degassed mixture of
6'-chloro-5-(5-ethyl-4,5,6,7-tetrahydro
thieno[3,2-c]pyridin-2-yl)-2-fluoro-[3,4']bipyridinyl-3'-ylamine
(1.05 g, 2.70 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(842 mg, 4.10 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (221
mg, 0.27 mmol) in 1N aqueous potassium fluoride solution (9 mL) and
acetonitrile (9 mL) was heated under microwave irradiation at
120.degree. C. for 20 minutes. The cooled reaction mixture was
diluted with ethyl acetate (100 mL) then washed with water (75 mL).
The organic phase was dried over sodium sulfate, filtered and
evaporated in vacuo to afford a residue that was purified by flash
chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM)
to afford the title compound as a white solid (641 mg, 55%). NMR
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.44 (dd, J=2.5, 1.1 Hz,
1H), 8.13 (d, J=0.6 Hz, 1H), 8.07 (dd, J=8.7, 2.5 Hz, 1H), 7.89 (s,
1H), 7.85 (d, J=0.8 Hz, 1H), 7.32 (s, 1H), 7.12 (s, 1H), 3.94 (s,
3H), 3.61 (s, 2H), 3.00-2.94 (m, 2H), 2.93-2.85 (m, 2H), 2.68 (q,
J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Step 4:
3-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-6-(1-methy-
l-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00690##
[1040] A solution of sodium bis(trimethylsilyl)amide (1N solution
in THF, 4.5 mL, 4.5 mmol) was added dropwise over 10 minutes to a
solution of
5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-6'-(1-me-
thyl-1H-pyrazol-4-yl)-[3,4']bipyridinyl-3'-ylamine (638 mg, 1.50
mmol) in anhydrous THF (26 mL). After 30 minutes, the reaction was
quenched by the addition of aqueous saturated aqueous potassium
fluoride solution (10 mL). The resultant brown solution was
partitioned between DCM (75 mL) and brine (50 mL). The organic
phase was separated, dried over sodium sulfate, filtered and
evaporated in vacuo to afford a residue that was purified by flash
chromatography (silica, 50 g column, Biotage, 0-15% methanol in
DCM) to afford the title compound as a white solid (96 mg, 16%).
.sup.1H NMR (CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.82 (s, 1H),
8.76 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.29 (s, 1H), 8.07
(s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 4.00 (s, 3H), 3.64 (s, 2H),
3.02-2.95 (m, 2H), 2.93-2.86 (m, 2H), 2.70 (q, J=7.2 Hz, 2H), 1.24
(t, J=7.2 Hz, 3H).
Example 371
3-(3,5-Dimethoxy-4-piperidin-1-ylmethylphenyl)-6-(1-methyl-1H-pyrazol-4-yl-
)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00691##
[1041] Step 1:
6'-Chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4']b-
ipyridinyl-3'-ylamine
##STR00692##
[1043] A degassed mixture of
6'-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4]-
bipyridinyl-3'-ylamine (630 mg, 1.80 mmol),
trifluoromethanesulfonic acid
3,5-dimethoxy-4-piperidin-1-ylmethylphenyl ester (1.06 g, 1.98
mmol), 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(147 mg, 0.18 mmol) in 1N aqueous potassium fluoride solution (10
mL) and acetonitrile (8 mL) was heated under microwave irradiation
at 100.degree. C. for 30 minutes. The cooled reaction mixture was
partitioned between DCM (50 mL) and brine (50 mL). The organic
phase was separated, dried over sodium sulfate, filtered and
evaporated in vacuo to afford a residue that was purified by flash
chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM)
to afford the title compound as a white solid (830 mg, 76%).
.sup.1H NMR (CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.52-8.57 (m,
1H), 8.12-8.19 (m, 1H), 7.98 (s, 1H), 7.19 (s, 1H), 6.91 (s, 2H),
4.34 (s, 2H), 4.01 (s, 6H), 2.87-3.64 (v br m, 4H), 1.63-2.02 (s,
6H).
Step 2:
5-(3,5-Dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-6'-(1-meth-
yl-1H-pyrazol-4-yl)-[3,4']bipyridinyl-3'-ylamine
##STR00693##
[1045] A degassed mixture of
6'-chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4']b-
ipyridinyl-3'-ylamine (830 mg, 1.40 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(577 mg, 2.78 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (151
mg, 0.19 mmol) in 1N aqueous potassium fluoride solution (10 mL)
and acetonitrile (6 mL) was heated under microwave irradiation at
100.degree. C. for 20 minutes. The cooled reaction mixture was
diluted with ethyl acetate (100 mL) then washed with water (75 mL).
The organic phase was separated, dried over sodium sulfate,
filtered and evaporated in vacuo to afford a residue that was
purified by flash chromatography (silica, 20 g column, ISCO, 0-10%
methanol in DCM) to afford the title compound as a white solid (494
mg, 54%). NMR (CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.55 (dd,
J=2.5, 1.0 Hz, 1H), 8.22 (dd, J=8.8, 2.5 Hz, 1H), 8.16 (d, J=0.6
Hz, 1H), 7.92 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 6.95
(s, 2H), 4.35 (s, 2H), 4.01 (s, 6H), 3.95 (s, 3H), 3.61-3.22 (br m,
2H), 3.19-2.90 (br m, 2H), 2.02-1.47 (br m, 6H).
Step 3:
3-(3,5-Dimethoxy-4-piperidin-1-ylmethyl-phenyl)-6-(1-methyl-1H-pyr-
azol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00694##
[1047] A solution of
5-(3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl)-2-fluoro-6'-(1-methyl-1H--
pyrazol-4-yl)-[3,4]bipyridinyl-3'-ylamine (490 mg, 0.98 mmol) in
anhydrous THF (16.7 mL) was added dropwise over 10 minutes to a
solution of sodium bis(trimethylsilyl)amide (1N solution in THF,
2.9 mL, 2.9 mmol). After 30 minutes, the reaction was quenched by
the addition of saturated aqueous potassium fluoride solution (5
mL) and concentrated under reduced pressure to afford a brown
residue. The resultant brown residue was partitioned between ethyl
acetate (75 mL) and water (50 mL). The organic phase was separated,
dried over sodium sulfate, filtered and evaporated in vacuo to
afford a residue that was purified by flash chromatography (silica,
50 g column, Biotage, 0-20% methanol in DCM) to afford the title
compound as an off-white solid (69 mg, 15%). .sup.1H NMR
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H),
8.84-8.80 (m, 2H), 8.37 (d, J=1.1 Hz, 1H), 8.09 (s, 1H), 8.06 (d,
J=0.8 Hz, 1H), 6.91 (s, 2H), 4.01 (s, 3H), 3.96 (s, 6H), 3.74 (s,
2H), 2.64-2.50 (m, 4H), 1.65-1.56 (m, 4H), 1.49-1.37 (m, 2H).
Example 372
3-[4-(4,4-Dimethylpiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-y-
l)-9H-dipyrido[2,3-b:4',3'-d]pyrrole
##STR00695##
[1048] Step 1:
6-Bromo-3-[4-(4,4-dimethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b-
;4',3'-d]pyrrole
##STR00696##
[1050] A degassed mixture of
4,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]--
piperidine (836 mg, 2.5 mmol),
3-iodo-6-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (500 mg, 1.3
mmol), 1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(109 mg, 0.13 mmol) in 1N aqueous potassium fluoride solution (25
mL) and acetonitrile (25 mL) was heated at 80.degree. C. for 18 h.
The cooled reaction mixture was diluted with ethyl acetate (100 mL)
then washed with water (75 mL). The organic phase was separated,
dried over sodium sulfate, filtered and evaporated in vacuo to
afford a residue that was purified by flash chromatography (silica,
120 g column, ISCO, 0-15% methanol in DCM) to afford the title
compound as an off-white solid (190 mg, 33%). .sup.1H NMR
(CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.76
(d, J=2.2 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H), 8.32 (d, J=0.9 Hz, 1H),
7.73 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 3.82 (s, 2H),
2.77-2.63 (m, 4H), 1.52 (t, J=5.6 Hz, 4H), 1.00 (s, 6H).
Step 2:
3-[4-(4,4-Dimethylpiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyr-
azol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00697##
[1052] A degassed mixture of
6-bromo-3-[4-(4,4-dimethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b-
;4',3'-d]pyrrole (200 mg, 0.45 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(185 mg, 0.89 mmol), 1,1'-[bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (37 mg, 0.05 mmol) in 2N aqueous sodium
carbonate solution (5 mL) and acetonitrile (5 mL) was heated under
microwave irradiation at 130.degree. C. for 20 minutes. The cooled
reaction mixture was diluted with ethyl acetate (100 mL) and washed
with water (75 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by flash chromatography (silica, 10 g
column, Biotage, 0-15% methanol in DCM) to afford the title
compound as a white solid (78 mg, 38%). .sup.1H NMR (CDCl.sub.3
plus CD.sub.3OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2
Hz, 1H), 8.79 (d, J=2.2 Hz, 1H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s,
1H), 8.06 (d, J=08 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1
Hz, 2H), 4.00 (s, 3H), 3.63 (s, 2H), 2.51 (t, J=5.0 Hz, 4H), 1.46
(t, J=5.6 Hz, 4H), 0.96 (s, 6H).
Example 373
3-[4-((2S,6R)-2,6-Dimethyl-piperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-py-
razol-4-yl)-9H-dipyrido[2,3-b:4',3'-d]pyrrole
##STR00698##
[1053] Step 1:
6-Bromo-3-[4-((2S,6R)-2,6-dimethylpiperidin-1-ylmethy)-phenyl]-9H-dipyrid-
o[2,3-b;4',3'-d]pyrrole
##STR00699##
[1055] A degassed mixture of
(2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)b-
enzyl]piperidine (685 mg, 2.08 mmol),
3-iodo-6-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (389 mg, 1.04
mmol), 1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(127 mg, 0.16 mmol) in saturated sodium carbonate solution (1 mL)
and THF (10 mL) was heated under reflux for 18 h. The cooled
reaction mixture was diluted with DCM (50 mL) and washed with water
(25 mL). The organic phase was separated, dried over sodium
sulfate, filtered and evaporated in vacuo to afford a residue that
was purified by flash chromatography (silica, 40 g column, ISCO,
0-15% methanol in DCM) to afford the title compound as an off-white
solid (181 mg, 39%). .sup.1H NMR (CDCl.sub.3 plus CD.sub.3OD, 300
MHz): 8.85 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.69 (d,
J=0.9 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.68-7.63 (d, J=8.1 Hz, 2H),
7.56-7.50 (m, 2H), 4.00 (s, 2H), 2.65-2.51 (m, 2H), 1.72-1.56 (m,
4H), 1.46-1.30 (m, 2H), 1.25 (d, J=6.2 Hz, 6H).
Step 2:
3-[4-(2S,6R)-2,6-Dimethylpiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-
-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00700##
[1057] A degassed mixture of
6-bromo-3-[4-((2S,6R)-2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyr-
ido[2,3-b;4',3'-d]pyrrole (223 mg, 0.50 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(208 mg, 1.0 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg,
0.05 mmol) in 2N aqueous sodium carbonate solution (6 mL) and
acetonitrile (6 mL) was heated under microwave irradiation at
130.degree. C. for 20 minutes. The cooled reaction mixture was
diluted with ethyl acetate (100 mL) and washed with water (75 mL).
The organic phase was separated, dried over sodium sulfate,
filtered and evaporated in vacuo to afford a residue that was
purified by flash chromatography (silica, 25 g column, Biotage,
0-15% methanol in DCM) to afford the title compound as a white
solid (70 mg, 31%). NMR (CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.85
(d, J=1.1 Hz, 1H), 8.82-8.77 (m, 2H), 8.33 (d, J=1.1 Hz, 1H), 8.08
(s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.71-7.65 (m, 2H), 7.56-7.51 (m,
2H), 4.00 (d, J=1.9 Hz, 5H), 2.65-2.52 (m, 2H), 1.72-1.60 (m, 3H),
1.47-1.30 (m, 3H), 1.25 (d, J=6.2 Hz, 6H).
Example 374
6-(1-Methyl-1H-pyrazol-4-yl)-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido-
[2,3-b;4',3'-d]pyrrole
##STR00701##
[1058] Step 1:
6-Bromo-3-(4-morpholin-4-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e
##STR00702##
[1060] A degassed mixture of 4-(4-morpholinomethyl)phenylboronic
acid pinacol ester (486 mg, 1.61 mmol),
3-iodo-6-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (400 mg, 1.07
mmol), 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(131 mg, 0.16 mmol) in 2N aqueous sodium carbonate solution (8 mL)
and 2-methyltetrahyrdofuran (16 mL) was heated at 85.degree. C. for
18 h. The cooled reaction mixture was diluted with ethyl acetate
(100 mL) and washed with water (75 mL). The organic phase was
separated, dried over sodium sulfate, filtered and evaporated in
vacuo to afford a residue that was purified by flash chromatography
(silica, 50 g column, Biotage, 0-15% methanol in DCM) to afford the
title compound as an off-white solid (137 mg, 30%). .sup.1H NMR
(CDCl.sub.3, 300 MHz): 12.41 (s, 1H), 9.04 (d, J=2.3 Hz, 1H), 8.95
(d, J=2.3 Hz, 1H), 8.72 (d, J=1.0 Hz, 1H), 8.53 (s, 1H), 7.76 (d,
J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 3.65-3.56 (m, 4H), 3.53 (s,
2H), 2.44-2.29 (m, 4H).
Step 2:
6-(1-Methyl-1H-pyrazol-4-yl)-3-(4-morpholin-4-ylmethyl-phenyl)-9H--
dipyrido[2,3-b;4',3'-d]pyrrole
##STR00703##
[1062] A degassed mixture of
6-bromo-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (245 mg, 0.58 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(241 mg, 1.16 mmol), 1,1'-[bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (47 mg, 0.06 mmol) in 2N aqueous sodium
carbonate solution (7 mL) and acetonitrile (7 mL) was heated under
microwave irradiation at 130.degree. C. for 20 minutes. The cooled
reaction mixture was diluted with ethyl acetate (75 mL) and washed
with water (50 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by flash chromatography (silica, 10 g
column, Biotage, 0-10% methanol in DCM) to afford the title
compound as a white solid (61 mg, 25%). .sup.1H NMR (CDCl.sub.3,
300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (d,
J=2.2 Hz, 1H), 8.31 (d, J=1.1 Hz, 1H), 8.07 (s, 1H), 8.05 (d, J=0.8
Hz, 1H), 7.73-7.67 (m, 2H), 7.54-7.48 (m, 2H), 4.01 (s, 3H),
3.80-3.73 (m, 4H), 3.63 (s, 2H), 2.60-2.52 (m, 4H).
Example 375
6-(1-Methyl-1H-pyrazol-4-yl)-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)--
phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00704##
[1063] Step 1:
1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluorome-
thylpiperidine
##STR00705##
[1065] A degassed mixture of
1-(4-bromobenzyl)-4-trifluoromethylpiperidine (1.0 g, 3.1 mmol),
bis(pinacolato)diborane (0.95 g, 3.7 mmol),
1,1'-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.13
g, 0.16 mmol) and potassium acetate (0.91 g, 9.3 mmol) in
1,4-dioxane (15 mL) and DMSO (1 mL) was heated under microwave
irradiation at 150.degree. C. for 30 minutes. The cooled reaction
mixture was partitioned between ethyl acetate and water and the
organic phase was separated, dried over sodium sulfate, filtered
and evaporated to afford the title compound as a black oil (1.9 g)
which was used without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.79-7.74 (m, 2H), 7.32 (d, J=7.7 Hz, 2H),
3.71 (s, 2H), 3.01-2.91 (m, 2H), 2.04-1.90 (m, 3H), 1.85-1.76 (m,
2H), 1.72-1.60 (m, 2H), 1.34 (s, 12H). LCMS (Method B):
R.sub.T=2.53 min, M+H.sup.+=370.
Step 2:
6-Bromo-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-di-
pyrido[2,3-b;4',3'-d]pyrrole
##STR00706##
[1067] A degassed mixture of
6-bromo-3-iodo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (0.64 g, 1.7
mmol),
1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluorome-
thyl piperidine (1.14 g, 3.1 mmol) and 1,1'-[bis(diphenyl
phosphino)ferrocene]dichloropalladium(II) (0.21 g, 0.26 mmol) in
2-methyl-THF (26 mL) and saturated aqueous sodium carbonate
solution (12 mL) was heated at 85.degree. C. for 16 h. The cooled
reaction mixture was filtered through celite and partitioned
between DCM and water and the phases were separated. The organic
phase was dried over sodium sulfate, filtered and evaporated then
the residue was purified by flash chromatography (silica, 40 g
column, ISCO, 0-15% methanol in DCM). Trituration of the resultant
residue with acetonitrile afforded the title compound as a tan
solid (57 mg, 7%). .sup.1H NMR (CD.sub.3OD, 300 MHz): 8.84 (d,
J=2.2 Hz, 1H), 8.70-8.67 (m, 2H), 8.27 (d, J=1.0 Hz, 1H), 7.67 (d,
J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.11-3.02 (m,
2H), 2.14-2.02 (m, 3H), 1.94-1.84 (m, 2H), 1.76-1.59 (m, 2H. LCMS
(Method B): R.sub.T=2.55 min, M+H.sup.+=489.
Step 3:
6-(1-Methyl-1H-pyrazol-4-yl)-3-[4-(4-trifluoromethylpiperidin-1-yl-
methyl)-phenyl]-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00707##
[1069] A degassed mixture of
6-bromo-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[-
2,3-b;4',3'-d]pyrrole (0.15 g, 0.30 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(0.13 g, 0.60 mmol) and 1,1'-[bis(diphenyl
phosphino)ferrocene]dichloropalladium(II)(25 mg, 0.03 mmol) in
acetonitrile (3 mL) and saturated aqueous sodium carbonate solution
(3 mL) was heated under microwave irradiation at 130.degree. C. for
30 minutes. The cooled reaction mixture was partitioned between DCM
and water then separated on a hydrophobic frit. The organic phase
was evaporated then the resultant residue was purified by flash
chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM)
to afford a residue which was purified by HPLC (C 18 column, 50-98%
MeCN in water (plus 20 mM triethylamine) to afford the title
compound (46 mg, 31%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.15
(s, 1H), 8.94-8.88 (m, 2H), 8.86 (d, J=1.1 Hz, 1H), 8.51 (d, J=1.1
Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.78 (d, J=8.0 Hz,
2H), 7.46 (d, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.56 (s, 2H), 2.99-2.88
(m, 2H), 2.39-2.19 (m, 1H), 2.00 (t, J=1.5 Hz, 2H), 1.85-1.94 (m,
2H), 1.57-1.38 (m, 2H). LCMS (Method A): R.sub.T=5.22 min,
M+H.sup.+=491.
Example 376
3-[4-(4-Methoxypiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)--
9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00708##
[1071] Step 1:
4-Methoxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-pip-
eridine
##STR00709##
[1072] A degassed mixture of 1-(4-bromobenzyl)-4-methoxypiperidine
(0.90 g, 3.18 mmol), bis(pinacolato)diborane (0.89 g, 3.5 mmol),
1,1'-[bis(diphenyl phosphino)ferrocene] dichloropalladium(II) (0.13
g, 0.16 mmol) and potassium acetate (0.94 g, 9.5 mmol) in
1,4-dioxane (16 mL) was heated under microwave irradiation at
150.degree. C. for 30 minutes. The cooled reaction mixture was
partitioned between ethyl acetate and water, the organic phase was
separated, dried over sodium sulfate, filtered through celite and
evaporated to afford the title compound as a brown oil (1.07 g)
which was used without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): 7.78 (d, J=7.5 Hz, 2H), 7.38 (d, J=7.5 Hz,
2H), 3.71 (s, 2H), 3.64 (br s, 1H), 3.31 (s, 3H), 2.83-2.71 (m,
2H), 2.34 (br s, 2H), 1.98 (br s, 2H), 1.69 (br s, 2H), 1.34 (s,
12H). LCMS (Method G): R.sub.T=3.00 min, M+H.sup.+=332.
Step 2:
6-Bromo-3-[4-(4-methoxypiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2-
,3-b;4',3'-d]pyrrole
##STR00710##
[1074] A degassed mixture of
6-bromo-3-iodo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (0.50 g, 1.3
mmol),
4-methoxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-pip-
eridine (0.80 g, 2.4 mmol) and
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.16
g, 0.2 mmol) in 2-methyl THF (20 mL) and saturated aqueous sodium
carbonate (10 mL) was heated at 85.degree. C. for 3 h. The material
was partitioned between DCM, water and methanol and the phases were
separated. The organic phase was separated, dried over sodium
sulfate, filtered and evaporated to afford a residue which was
purified by flash chromatography (silica, 50 g column, Biotage,
0-10% methanol in DCM). The resultant material was triturated with
methanol to afford the title compound as a tan solid (0.165 g,
28%). .sup.1H NMR (CDCl.sub.3 plus CD.sub.3OD, 300 MHz): 8.84 (d,
J=2.2 Hz, 1H), 8.73 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.30
(d, J=1.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H),
3.63 (s, H), 2.89-2.76 (m, 2H), 2.37-2.22 (m, 2H), 2.02-1.89 (m,
2H), 1.73-1.56 (m, 2H). LCMS (Method G): R.sub.T=3.30 min,
M+H.sup.+=451.
Step 3:
3-[4-(4-Methoxypiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazo-
l-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00711##
[1076] A degassed mixture of
6-bromo-3-[4-(4-methoxypiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4'-
,3'-d]pyrrole (0.16 g, 0.36 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(0.15 g, 0.72 mmol) and 1,1'-[bis(diphenyl
phosphino)ferrocene]dichloropalladium(II) (29 mg, 0.036 mmol) in
acetonitrile (3.6 mL) and saturated aqueous sodium carbonate
solution (3.6 mL). The reaction mixture was heated under microwave
irradiation at 130.degree. C. for 20 minutes. The cooled reaction
mixture was partitioned between DCM and water. The organic phase
was dried over sodium sulfate, filtered and evaporated and the
resultant residue was purified by flash chromatography (silica, 12
g column, ISCO, 0-15% methanol in DCM) to afford the title compound
as a yellow solid (68 mg, 42%). .sup.1H NMR (CDCl.sub.3 plus
CD.sub.3OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz,
1H), 8.77 (d, J=2.2 Hz, 1H), 8.30 (d, J=1.1 Hz, 1H), 8.06-8.04 (m,
2H), 7.71 (d, J=7.9 Hz, 2H), 7.52 (d, J=2.0 Hz, 2H), 4.01 (s, 3H),
3.74-3.63 (m, 2H), 2.94-2.79 (m, 2H), 2.47-2.25 (m, 2H), 2.04-1.90
(m, 2H), 1.78-1.58 (m, 2H). LCMS (Method A): R.sub.T=4.76 min,
M+H.sup.+=453.
Example 377
3-(3-Methoxy-4-piperidin-1-ylmethyl-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-9-
H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00712##
[1077] Step 1:
6-Bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole
##STR00713##
[1079] A degassed mixture of
1-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-pip-
eridine (885 mg, 2.7 mmol),
3-iodo-6-bromo-9H-dipyrido[2,3-b;4',3'-d]pyrrole (500 mg, 1.3
mmol), 1,1'-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
(163 mg, 0.2 mmol) in 2N aqueous sodium carbonate solution (10 mL)
and 2-methyltetrahydrofuran (20 mL) was heated at 85.degree. C. for
18 h. The cooled reaction mixture was diluted with DCM (100 mL) and
washed with water (75 mL). The organic phase was separtated, dried
over sodium sulfate, filtered and evaporated in vacuo to afford a
residue (357 mg, 61%) that was used in the next step without
purification. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.83 (d, J=2.0 Hz,
1H), 8.70 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 7.45 (d,
J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 3.96 (s, 3H),
3.65 (s, 2H), 2.56-2.48 (m, 4H), 1.67-1.59 (m, 4H), 1.52-1.41 (m,
2H).
Step 2:
3-(3-Methoxy-4-piperidin-1-ylmethylphenyl)-6-(1-methyl-1H-pyrazol--
4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00714##
[1081] A degassed mixture of
6-bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole (350 mg, 0.78 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(242 mg, 1.16 mmol), 1,1'-[bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (64 mg, 0.08 mmol) in 2N aqueous sodium
carbonate solution (8 mL) and acetonitrile (8 mL) was heated under
microwave irradiation at 130.degree. C. for 20 minutes. The cooled
reaction mixture was diluted with ethyl acetate (75 mL) and washed
with water (50 mL). The organic phase was separtated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by flash chromatography (silica, 50 g
column, Biotage, 0-25% methanol in DCM) to afford the title
compound as an off-white solid (61 mg, 17%). .sup.1H NMR
(DMSO-D.sub.6, 300 MHz): 8.95-8.92 (m, 2H), 8.85 (d, J=1.0 Hz, 1H),
8.49 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=7.7
Hz, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.48 (s,
2H), 2.44-2.34 (m, 4H), 1.55-1.48 (m, 4H), 1.45-1.37 (m, 2H).
Example 378
6-(Oxazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole
##STR00715##
[1083] A mixture of
6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (150 mg, 0.36 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (140 mg,
0.71 mmol),
1,1'-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (29
mg, 0.004 mmol) in saturated aqueous sodium carbonate solution (0.5
mL) and acetonitrile (5 mL) was heated under microwave irradiation
at 130.degree. C. for 30 minutes. The cooled reaction mixture was
diluted with DCM (20 mL) and methanol (2 mL) and washed with water
(15 mL). The organic phase was separated, dried over sodium
sulfate, filtered and evaporated in vacuo to afford a residue that
was purified by preparative HPLC [20-60% MeCN in water (0.1%
ammonium hydroxide) over 30 min, 35 mL/min] to afford the title
compound as an off-white solid (42 mg, 29%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.42 (s, 1H), 9.12 (d, J=2.2 Hz, 1H),
8.96 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.67 (s, 1H), 8.52 (s, 1H),
7.78 (d, J=8.1 Hz, 2H), 7.66 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.50
(s, 2H), 2.37 (s, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method D):
R.sub.T=7.76 min, M+H.sup.+=410.
Example 379
6-(1-Methyl-1H-pyrazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido-
[2,3-b;4',3'-d]pyrrole
##STR00716##
[1085] The title compound was prepared following a similar
procedure to the previous example using
1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
to yield a yellow/orange solid (20%). .sup.1H NMR (DMSO-D.sub.6,
400 MHz): 12.34 (s, 1H), 9.05 (d, J=2.2 Hz, 1H), 9.00 (s, 1H), 8.94
(d, J=2.3 Hz, 1H), 8.65 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.50 (d,
J=1.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.72 (d, J=1.9 Hz, 1H), 4.17
(s, 3H), 3.49 (s, 2H), 2.35 (s, 4H), 1.51 (m, 4H), 1.42 (m, 2H).
LCMS (Method D): R.sub.T=6.48 min, M+H.sup.+=423.
Example 380
6-(1-Methyl-1H-imidazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido-
[2,3-b;4',3'-d]pyrrole
##STR00717##
[1087] A mixture of
6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (100 mg, 0.16 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole
(120 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (18
mg, 0.016 mmol) and lithium chloride (68 mg, 1.6 mmol) in
1,4-dioxane (3 mL) was degassed and flushed with nitrogen and the
reaction heated at 100.degree. C. for 16 h. The cooled reaction
mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed
with water (15 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by flash chromotagraphy (silica, 10 g
column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia in
methanol)) to afford a residue that was purified by preparative
HPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min,
35 mL/min] to afford the title compound as a pale orange solid (13
mg, 20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.26 (s, 1H), 9.04
(d, J=2.2 Hz, 1H), 8.95 (d, J=0.9 Hz, 1H), 8.92 (d, J=2.2 Hz, 1H),
8.58 (d, J=0.9 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.72 (s, 1H), 7.44
(d, J=8.1 Hz, 2H), 7.39 (d, J=1.0 Hz, 1H), 3.96 (s, 3H), 3.49 (s,
2H), 2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method
D): R.sub.T=6.54 min, M+H.sup.+=423.
Example 381
6-(Thiazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole
##STR00718##
[1089] The title compound was prepared following a similar
procedure as to the previous example using
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole to yield a
beige solid (21%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.32 (s,
1H), 9.08 (s, 1H), 9.00 (d, J=2.4 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H),
8.92 (s, 1H), 8.89 (s, 1H), 8.49 (s, 1H), 8.25 (s, 2H), 7.78 (d,
J=8.2 Hz, 2H), 7.46 (d, J=8.1 Hz, 3H), 3.50 (s, 2H), 2.37 (s, 4H),
1.53 (m, 4H), 1.40 (m, 2H). LCMS (Method D): R.sub.T=8.36 min,
M+H.sup.+=426.
Example 382
6-(Isoxazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole
##STR00719##
[1091] A mixture of
6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e (130 mg, 0.18 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (140 mg,
0.74 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18
mg, 0.002 mmol) in 1N aqueous potassium acetate solution (0.62 mL)
and acetonitrile (3 mL) was heated under microwave irradiation at
85.degree. C. for 18 minutes. The cooled reaction mixture was
diluted with DCM (20 mL) and methanol (2 mL) and washed with water
(15 mL). The organic phase was separated, dried over sodium
sulfate, filtered and evaporated in vacuo to afford a residue that
was purified by preparative HPLC [0-30% MeCN in water (0.1% formic
acid) over 30 min, 35 mL/min] to afford the title compound as a
beige solid (10 mg, 10%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
12.32 (s, 1H), 9.47 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.94 (d,
J=2.3 Hz, 1H), 8.89 (d, J=2.2 Hz, 1H), 8.68 (s, 1H), 7.76 (d, J=8.1
Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.52
(m, 4H), 1.41 (m, 2H). LCMS (Method D): R.sub.T=6.55 min,
M+H.sup.+=410.
Example 383
6-(3,5-Dimethylisoxazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido-
[2,3-b:4',3'-d]pyrrole
##STR00720##
[1093] The title compound was prepared following a similar
procedure to the previous example using
3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole
to yield an off-white solid (20%). .sup.1H NMR (DMSO-D.sub.6, 500
MHz): 12.32 (s, 1H), 9.09 (d, J=2.3 Hz, 1H), 9.00 (d, J=1.0 Hz,
1H), 8.93 (d, J=2.3 Hz, 1H), 8.41 (s, 1H), 7.77 (d, J=8.2 Hz, 2H),
7.45 (d, J =8.2 Hz, 2H), 3.49 (s, 2H), 2.63 (s, 3H), 2.45 (s, 3H),
2.36 (s, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method D):
R.sub.T=6.44 min, M+H.sup.+=438.
Example 384
6-(2-Methylthiazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole
##STR00721##
[1095] The title compound was prepared following a similar
procedure to the previous example using
2-methyl-5-(trimethylstannyl)thiazole to yield a pale yellow solid
(20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.35 (s, 1H), 8.99 (d,
J=2.2 Hz, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.89 (s, 1H), 8.82 (s, 1H),
8.21 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.49
(s, 2H), 2.69 (s, 3H), 2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.41 (m,
2H). LCMS (Method D): R.sub.T=7.42 min, M+H.sup.+=440.
Example 385
6-(1,2-Dimethyl-1H-imidazol-5-yl-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipy-
rido[2,3-b;4',3'-d]pyrrole
##STR00722##
[1097] The title compound was prepared following a similar
procedure to the previous example using
1,2-dimethyl-5-(tributylstannyl)-1H-imidazole to yield a pale
yellow solid (20%). .sup.1H NMR (DMSO-D.sub.6, 500 MHz): 12.25 (s,
1H), 9.04 (d, J=2.1 Hz, 1H), 8.95 (s, 1H), 8.92 (d, J=2.1 Hz, 1H),
8.51 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.21
(s, 1H), 3.86 (s, 3H), 3.49 (s, 2H), 2.38 (s, 3H), 2.36 (s, 4H),
1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method D): R.sub.T=6.72 min,
M+H.sup.+=437.
Example 386
6-(1,3,4-Thiadiazol-2-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,-
3-b;4',3'-d]pyrrole
##STR00723##
[1099] Step 1:
3-(4-Piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
hydrazide
##STR00724##
[1100] A solution of
3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
oxylic acid methyl ester (425 mg, 1.06 mmol) and hydrazine hydrate
(1.29 mL, 26.5 mmol) in ethanol (4.6 mL) was heated under reflux
for 1 h under a nitrogen atmosphere. The solution was allowed to
cool to ambient temperature and the resulting precipitate was
collected by filtration, washed with ethanol, and dried under
vacuum to afford a yellow solid (337 mg, 79%). The solid was used
without purification.
[1101] Step 2:
6-(1,3,4-Thiadiazol-2-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,-
3-b;4',3'-d]pyrrole
##STR00725##
[1102] A solution of
3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
hydrazide (87.3 mg, 0.218 mmol) in formic acid (1.0 mL) was heated
under reflux for 30 minutes then allowed to cool to room
temperature, diluted with xylenes (4.4 mL) and treated with
phosphorus pentasulfide (174 mg, 0.392 mmol). The mixture was
heated under reflux under a nitrogen atmosphere for 24 h, then
allowed to cool to ambient temperature and treated with additional
phosphorus pentasulfide (116 mg, 0.263 mmol) and formic acid (1.0
mL). The mixture was heated under reflux for an additional 24 h,
allowed to cool, and concentrated in vacuo. The resulting residue
was purified by preparative HPLC (2-60% MeCN/water modified with
0.1% ammonium hydroxide) to afford the title compound as an orange
fluffy solid (9.5 mg, 10%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
12.63-12.59 (s, 1H), 9.62 (s, 1H), 9.26 (s, 1H), 9.24 (d, J=2.2 Hz,
1H), 9.02 (s, 1H), 8.98 (d, J=2.2 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H),
7.45 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.38 (m, 4H), 1.52 (m, 4H),
1.41 (m, 2H). LCMS (Method D): R.sub.T=8.71 min, M+H.sup.+=427.
Example 387
6-(1,3,4-Oxadiazol-2-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3--
b;4',3'-d]pyrrole
##STR00726##
[1104] A solution of
3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carb-
hydrazide (53.8 mg, 0.134 mmol) and trimethoxymethane (1.21 mL,
11.0 mmol) in DMF (0.81 mL) was heated at 120.degree. C. for 24 h.
The mixture was cooled, treated with trimethoxymethane (1.0 mL) and
a few drops of acetic acid and heated under reflux for 48 h. The
mixture was allowed to cool, treated with saturated aqueous sodium
bicarbonate solution, and the resultant white precipitate collected
by filtration and washed with water. The filtrate was extracted
with DCM, 20% methanol in DCM, and the combined organic phases
dried over sodium sulfate, combined with the isolated solid and
concentrated in vacuo. The resultant residue was purified by
preprative HPLC [2-60% MeCN/water modified with 0.1% ammonium
hydroxide] to afford a light-yellow flaky solid (6.0 mg, 27%).
.sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.77-12.69 (s, 1H), 9.41 (s,
1H), 9.26 (d, J=2.2 Hz, 1H), 9.18 (s, 1H), 9.08 (s, 1H), 9.00 (d,
J=2.2 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1
Hz, 2H), 3.50 (s, 2H), 2.37 (m, 414), 1.52 (m, 4H), 1.41 (m, 2H).
LCMS (Method D): R.sub.T=7.69 min, M+H.sup.+=411.
Example 388
6-(1-Benzyl-1H-1,2,3-triazol-4-yl).sub.3-(4-piperidin-1-ylmethyl-phenyl)-9-
H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00727##
[1106] Step 1:
64(Trimethylsilyl)ethynyl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2-
,3-b;4',3'-d]pyrrole
##STR00728##
[1107] A mixture of
6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-
e (170 mg, 0.40 mmol), copper(I) iodide (7.7 mg, 0.04 mmol), and A
N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) in anhydrous
1,4-dioxane (3 mL) was degassed and flushed with nitrogen.
Tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.04 mmol) and
(trimethylsilyl)acetylene (0.34 mL, 2.4 mmol) were added and the
reaction mixture heated at 110.degree. C. for 1 h. The cooled
reaction mixture was diluted with DCM (20 mL) and methanol (2 mL)
and washed with water (15 mL). The organic phase was separated,
dried over sodium sulfate, filtered and evaporated in vacuo to
afford a residue that was purified by flash chromotagraphy (silica,
10 g column, Biotage, 0-10% methanol in (DCM containing 1% 7M
ammomia in methanol) to afford a brown residue that was taken to
the next step without further purification.
[1108] Step 2:
6-Ethynyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole
##STR00729##
[1109] A mixture of
6-((trimethylsilyl)ethynyl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[-
2,3-b;4',3'-d]pyrrole (120 mg, 0.3 mmol) and potassium carbonate
(170 mg, 1.2 mmol) in methanol (2 mL) was stirred at ambient
temperature for 1 h. The reaction mixture was diluted with DCM (20
mL) and methanol (2 mL) and washed with water (15 mL). The organic
phase was separated, dried over sodium sulfate, filtered and
evaporated in vacuo to afford a brown residue that was taken to the
next step without purification.
Step 3:
6-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl-
)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00730##
[1111] A mixture of
6-ethynyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrr-
ole (90 mg, 0.2 mmol), copper (I) iodide (4.7 mg, 0.02 mmol), and
azidomethyl-benzene (36 mg, 0.27 mmol) in N,N-dimethylformamide (2
mL) was heated at 60.degree. C. for 2 h. The cooled reaction
mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed
with water (15 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by preparative HPLC [20-60% MeCN in water
(0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the
title compound as an off-white solid (20 mg, 20%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.30 (s, 1H), 9.16 (d, J=2.2 Hz, 1H),
8.93 (s, 2H), 8.91 (s, 1H), 8.61 (s, 1H), 7.80 (d, J=8.1 Hz, 2H),
7.40 (m, 7H), 5.69 (s, 2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.57-1.46
(m, 4H), 1.40 (m, 2H). LCMS (Method D): R.sub.T=9.35 min,
M+H.sup.+=500.
Example 389
6-(1H-1,2,3-Triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-
-b;4',3'-d]pyrrole
##STR00731##
[1112] Step 1:
6'-((Trimethylsilyl)ethynyl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3-
,4']bipyridinyl-3'-ylamine
##STR00732##
[1114] A mixture of
6'-bromo-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4'b]ipyridinyl-3'-y-
lamine (100 mg, 0.23 mmol), copper (I) iodide (4.3 mg, 0.02 mmol),
and N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) in anhydrous
1,4-dioxane (2.5 mL) was degassed and flushed with nitrogen.
Tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.02 mmol) and
(trimethylsilyl)acetylene (0.16 mL, 1:1 mmol) were added and the
reaction was heated at 100.degree. C. for 5 h. The cooled reaction
mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed
with water (15 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by flash chromotagraphy (silica, 10 g
column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia in
ammonia)) to afford a brown residue that was taken to the next step
without further purification.
Step 2:
6'-Ethynyl-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4']bipyrid-
inyl-3'-ylamine
##STR00733##
[1116] A mixture of
6'-((trimethylsilyl)ethynyl)-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[-
3,4']bipyridinyl-3'-ylamine (90 mg, 0.2 mmol) and potassium
carbonate (150 mg, 1.1 mmol) in methanol (2 mL) was stirred at
ambient temperature for 1 h. The cooled reaction mixture was
diluted with DCM (20 mL) and methanol (2 mL) and washed with water
(15 mL). The organic phase was separated, dried over sodium
sulfate, filtered and evaporated in vacuo to afford a brown residue
that was taken to the next step without purification.
Step 3:
6-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl-
)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00734##
[1118] A mixture of
6'-ethynyl-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4]bipyridinyl-3'--
ylamine (60 mg, 0.16 mmol), copper (I) iodide (3.0 mg, 0.016 mmol),
and azidomethylbenzene (29 mg, 0.22 mmol) in N,N-dimethylformamide
(2 mL) was heated at 60.degree. C. for 2 h. The cooled reaction
mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed
with water (15 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a brown
residue that was taken to the next step without purification.
Step 4:
6-(1H-1,2,3-Triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipy-
rido[2,3-b;4',3'-d]pyrrole
##STR00735##
[1120] To a solution of
6'-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-fluoro-5-(4-piperidin-1-ylmethylphe-
nyl)-[3,4']bipyridinyl-3'-ylamine (80 mg, 0.16 mmol) in anhydrous
tetrahydrofuran (2 mL) was added sodium bis(trimethylsilyl)amide
(1N solution in THF, 0.46 mL, 0.46 mmol) under a flow of nitrogen
and the reaction mixture was stirred at room temperature for 2 h.
The reaction mixture was then evaporated in vacuo to afford a
residue that was purified by preparative HPLC (20-60% MeCN in water
(0.1% ammonium hydroxide) over 30 min, 35 mL/min) to afford the
title compound as an orange solid (10 mg, 10%). .sup.1H NMR
(DMSO-D.sub.6, 500 MHz):12.33 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H),
8.94 (d, J=2.2 Hz, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1
Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.52
(m, 4H), 1.41 (m, 2H), triazole NH not observed. LCMS (Method D):
R.sub.T=6.68 min, M+H.sup.+=410.
Example 390
6-(Tetrazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole
##STR00736##
[1122] A mixture of
6-carbonitrile-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d-
]pyrrole (269 mg, 0.732 mmol) and azidotrimethyltin(IV) (1.51 g,
7.32 mmol) in a mixture of N,N-dimethylacetamide (5 mL) and toluene
(24 mL) was heated 110.degree. C. for 24 hours. The reaction
mixture was allowed to cool and concentrated in vacuo. The
resultant residue was dissolved in 20% methanol in DCM, absorbed
onto celite in vacuo, and purified by flash chromatography (Amino
Silica, Snap KP-NH, Biotage, 1-20% methanol in (DCM containing 0 1%
7M ammonia in methanol) to yield a dark yellow solid (80.5 mg). The
solid was further purified by preparative HPLC (2-60% MeCN/water
containing 0.1% ammonium hydroxide) to afford the title compound as
a pale yellow solid (36.9 mg, 12%). .sup.1H NMR (DMSO-D.sub.6, 400
MHz): 12.52 (s, 1H), 9.22 (d, J=2.2 Hz, 1H), 9.10 (s, 1H), 9.02 (s,
1H), 8.98 (d, J=2.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.1
Hz, 2H), 3.69 (s, 2H), 2.55 (m, 4H), 1.58 (m, 4H), 1.44 (m, 2H).
LCMS (Method E): R.sub.1=3.04 min, M+H.sup.+=411.
Example 391
6-Pyridin-3-yl-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dip-
yrido[2,3-b;4',3'-d]pyrrole
##STR00737##
[1124] To a mixture of pyridine-2-boronic acid (27 mg, 0.22 mmol),
6-bromo-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido-
[2,3-b;4',3'-d]pyrrole (55 mg, 0.11 mmol) and
1,1'-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9 mg,
0.011 mmol) in acetonitrile (1 mL) and saturated aqueous sodium
carbonate solution (1 mL) was heated under microwave irradiation at
140.degree. C. for 30 minutes. The cooled reaction mixture was
partitioned between DCM and water and the phases were separated
using a hydrophobic fit and the organic phase evaporated. The
residue was purified HPLC (C18 column, 50-98% MeCN in water
(containing 20 mM triethylamine) over 30 minutes and the fractions
containing pure product combined and concentrated then freeze-dried
to afford the title compound (6 mg, 11%). .sup.1H NMR (CDCl.sub.3
plus CD.sub.3OD, 400 MHz): 9.22 (dd, J=2.3, 0.8 Hz, 1H), 9.05 (d,
J=1.1 Hz, 1H), 8.86-8.83 (m, 2H), 8.59-8.56 (m, 2H), 8.48-8.44 (m,
1H), 7.73-7.69 (m, 2H), 7.58-7.54 (m, 1H), 7.50 (d, J=8.0 Hz, 2H),
3.64 (s, 2H), 3.11-3.03 (m, 2H), 2.17-2.04 (m, 3H), 1.93-1.85 (m,
2H), 1.74-1.61 (m, 2H). LCMS (Method A): R.sub.T=5.43 min,
M+H.sup.+=488.
Example 392
6-(Pyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole
##STR00738##
[1126] The title compound was prepared following a similar
procedure to the previous example using
3-(1,3,2-dioxaborinan-2-yl)pyridine to yield a beige solid (40%).
NMR (DMSO-D.sub.6, 400 MHz): 12.30 (s, 1H), 9.36 (d, J=2.0 Hz, 1H),
9.05 (d, J=2.3 Hz, 1H), 9.04 (s, 1H), 8.99 (s, 1H), 8.94 (d, J=2.2
Hz, 1H), 8.60 (dd, J=1.6 Hz, 3.2, 1H), 8.50 (dt, J=8.0, 2.0 Hz,
1H), 7.78 (d, J=8.2 Hz, 2H), 7.55 (s, 1H), 7.46 (d, J=8.1 Hz, 2H),
3.51 (s, 2H), 2.38 (s, 4H), 1.53 (m, 4H), 1.41 (m, 2H). LCMS
(Method D): R.sub.T=6.92 min, M+H.sup.+=420.
Example 393
6-(Pyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'--
d]pyrrole
##STR00739##
[1128] The title compound was prepared following a similar
procedure to the previous example using pyridin-4-ylboronic acid to
yield a beige solid (40%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz):
12.48 (s, 1H), 9.10 (s, 1H), 9.07 (d, J=2.2 Hz, 1H), 9.06 (s, 1H),
8.96 (d, J=2.2 Hz, 1H), 8.70 (d, J=6.1 Hz, 2H), 8.15 (d, J=6.1 Hz,
2H), 7.78 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H),
2.37 (s, 4H), 1.58-1.47 (m, 4H), 1.41 (m, 2H). LCMS (Method D):
R.sub.T=7.01 min, M+H.sup.+=420.
Example 394
6-(4-Methoxypyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-
-b;4',3'-d]pyrrole
##STR00740##
[1130] The title compound was prepared following a similar
procedure to the previous example using
5-4-methoxypyridin-3-ylboronic acid to yield a beige solid (20%).
.sup.1H NMR (DMSO-D.sub.6, 500 MHz): 12.36 (s, 1H), 9.05 (d, J=2.2
Hz, 1H), 9.03 (s, 1H), 8.93 (d, J=2.1 Hz, 1H), 8.87 (s, 1H), 8.71
(s, 1H), 8.48 (d, J=5.7 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.44 (d,
J=8.1 Hz, 2H), 7.24 (d, J=5.8 Hz, 1H), 3.99 (s, 3H), 3.49 (s, 2H),
2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D):
R.sub.T=6.56 min, M+H.sup.+=450.
Example 395
6-(5-Methoxypyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-
-bl4',3'-d]pyrrole
##STR00741##
[1132] The title compound was prepared following a similar
procedure to the previous example using
3-methoxy-5-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)pyridine
to afford a beige solid (20%). .sup.1H NMR (DMSO-D.sub.6, 500 MHz):
12.39 (s, 1H), 9.05 (d, J=2.5 Hz, 1H), 9.04 (s, 1H), 9.03 (s, 1H),
8.99 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H), 8.08
(s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.96 (s,
3H), 3.50 (s, 2H), 2.36 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS
(Method D): R.sub.T=7.68 min, M+H.sup.+=450.
Example 396
3-(1-Methyl-1H-pyrazol-4-yl)-6-[4-(piperidin-4-yloxy)-pyridin-3-yl]-9H-dip-
yrido[2,3-b;4',3'-d]pyrrole
##STR00742##
[1134] Step 1:
6-Iodo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9-
H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00743##
[1135] A degassed mixture of
6-bromo-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl
ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole (0.20 g, 0.44
mmol), copper (I) iodide (8.9 mg, 0.044 mmol),
N,N'-dimethylethylenediamine (9.4 .mu.L, 0.088 mmol) and sodium
iodide (0.264 mg, 1.76 mmol) in 1,4-dioxane (2 mL) was heated at
110.degree. C. for 3 days. The cooled reaction mixture was
partitioned between water and ethyl acetate, the organic layer was
separated, dried over sodium sulfate, filtered and evaporated to
afford the title compound as a yellow solid (0.205 g, 92%). 1H NMR
(CDCl.sub.3, 300 MHz): 8.88 (d, J=0.9 Hz, 1H), 8.78 (d, J=2.1 Hz,
1H), 8.41-8.36 (m, 2H), 7.84 (s, 1H), 7.71 (s, 1H), 5.92 (s, 2H),
4.02 (s, 3H), 3.58 (t, J=8.2 Hz, 2H), 0.92 (t, J=8.2 Hz, 2H), -0.09
(s, 9H).
[1136] Step 2:
6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsila-
nylethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00744##
[1137]
6-Iodo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymeth-
yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole (0.21 g, 0.41 mmol),
4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-pyridine
(0.15 g, 0.615 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (17
mg, 0.021 mmol) in saturated aqueous sodium carbonate solution (1
mL) and acetonitrile (4 mL) were placed under an atmosphere of
argon and heated with microwave irradiation at 100.degree. C. for
45 minutes. The cooled reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was separated,
dried over sodium sulfate, filtered and evaporated to afford a
residue which was purified by flash chromatography (silica, 12 g
column, ISCO, 0-10% methanol in DCM) to afford the title compound
as a yellow oil (0.13 g, 66%). .sup.1H NMR (CDCl.sub.3, 400 MHz):
9.22 (d, J=1.1 Hz, 1H), 8.91 (d, J=0.5 Hz, 1H), 8.79 (d, J=2.1 Hz,
1H), 8.53 (d, J=5.4 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.32 (d, J=1.1
Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.73 (s, 1H), 7.48 (dd, J=5.4, 0.5
Hz, 1H), 6.01 (s, 2H), 4.01 (s, 3H), 3.70-3.63 (m, 2H), 1.02-0.94
(m, 2H), -0.06 (s, 9H). LCMS (Method G): R.sub.T=4.8 min,
M+H.sup.+=491.
Step 3:
4-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymet-
hyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl]-pyridin-4-yloxy}-piperidine-1--
carboxylic acid tert-butyl ester
##STR00745##
[1139] Sodium hydride (60% dispersion in mineral oil, 42 mg, 1.06
mmol) was added to a solution of
tert-butyl-4-hydroxy-1-piperidinecarboxaldehyde (0.16 g, 0.795
mmol) in DMF (2.5 mL) and the reaction mixture was stirred at
ambient temperature for 30 minutes.
6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsila-
nyl-ethoxymethyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole (0.13 g, 0.265
mmol) was added as a solution in DMF (2.5 mL) and the reaction
mixture was heated at 80.degree. C. for 1.5 h. The material was
partitioned between water and ethyl acetate. The organic layer was
separated, dried over sodium sulfate, filtered and evaporated in
vacuo. The resultant residue was purified by flash chromatography
(silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the
title compound as a yellow oil which crystallised on standing (0.1
g, 58%). .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.19 (d, J=1.1 Hz, 1H),
9.01 (s, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.45
(d, J=1.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 7.85 (s, 1H), 7.76 (s,
1H), 6.97 (d, J=5.8 Hz, 1H), 6.01 (s, 2H), 4.84-4.73 (br s, 1H),
4.02 (s, 3H), 3.71-3.62 (m, 2H), 3.60-3.39 (m, 4H), 1.97 (br s,
2H), 1.88 (br s, 2H), 1.41 (s, 9H), 1.01-0.93 (m, 2H), -0.07 (s,
9H).
Step 4:
3-(1-Methyl-1H-pyrazol-4-yl)-6-[4piperidin-4-yloxy)-pyridin-3-yl]--
9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00746##
[1141] A mixture of
4-{3-[3(1-methyl-1H-pyrazol-4-yl)-942-trimethylsilanylethoxy
methyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrol-6-yl]-pyridin-4-yloxy}-piperidin-
e-1-carboxylic acid tert-butyl ester (0.1 g, 0.15 mmol) in TBAF (1N
in THF, 10 mL) was heated at 50.degree. C. for 19 h. The cooled
reaction mixture was partitioned between water and ethyl acetate.
The organic layer was separated, dried over sodium sulfate,
filtered and concentrated in vacuo, to afford a residue which was
purified by flash chromatography (silica, 12 g column, ISCO, 0-10%
methanol in DCM). This resultant residue was dissolved in DCM (5
mL) and TFA (1 mL) and left to stir for 30 minutes. The mixture was
diluted with DCM and water. The aqueous layer was separated,
evaporated and the resultant residue was loaded onto an SCX-2
cartridge and washed with methanol and 2M ammonia in methanol. The
combined basic fraction was purified by HPLC (C18 column, eluting
with 5-60% MeCN in water (with 20 mM triethylamine) over 20
minutes) to afford the title compound as a white solid (25 mg,
39%). .sup.1H NMR (MeOD, 400 MHz): 8.97 (s, 1H), 8.83-8.78 (m, 2H),
8.72 (s, 1H), 8.58 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 8.12 (s, 1H),
7.98 (s, 1H), 7.28 (d, J=6.0 Hz, 1H), 4.91-4.80 (m, 1H), 3.98 (s,
3H), 3.01-2.91 (m, 2H), 2.80-2.70 (m, 2H), 2.11-2.00 (m, 2H),
1.83-1.73 (m, 2H) plus 2 exchangeables not observed. LCMS (Method
A): R.sub.T=4.0 min, M+H.sup.+=426.
Example 397
6-[4-(1-Ethyl-piperidin-4-yloxy)-pyridin-3-yl]-3-(1-methyl-1H-pyrazol-4-yl-
)-9H-dipyrido[2,3-b;4',3'-d]pyrrole
##STR00747##
[1143] Sodium hydride (60% dispersion in mineral oil, 0.133 g, 3.32
mmol) was added to a solution of 1-ethyl-piperidin-4-ol (0.306 g,
2.37 mmol) in DMF (5 mL) and the reaction mixture was stirred at
ambient temperature for 45 minutes.
6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole (0.121 g, 0.474 mmol) was added and the reaction
mixture was heated at 80.degree. C. for 5 h. The material was
partitioned between water and ethyl acetate. The solid suspended in
the aqueous layer was removed by filtration then the aqueous layer
was separated, adsorbed onto HM-N and purified by flash
chromatography (silica, 12 g column, ISCO, 0-10% (2N ammonia in
methanol) in DCM). The resultant residue was triturated with ethyl
acetate and cyclohexane to afford the title compound as a yellow
solid (28 mg, 13%). .sup.1H NMR (MeOD, 400 MHz): 8.97 (d, J=1.1 Hz,
1H), 8.83-8.80 (m, 2H), 8.73 (s, 1H), 8.60 (d, J=1.1 Hz, 1H); 8.43
(d, J=5.9 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.28 (d, J
=6.0 Hz, 1H), 3.98 (s, 3H), 2.65-2.54 (m, 2H), 2.53-2.43 (m, 2H),
2.39 (q, J=7.3 Hz, 2H), 2.13-2.03 (m, 2H), 1.97-1.86 (m, 2H), 1.02
(t, J=7.2 Hz, 3H). LCMS (Method A): R.sub.T=4.0 min,
M+H.sup.+=454.
Example 398
Dimethyl-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyr-
rol-6-yl]-pyridin-4-yloxy}-ethyl)-amine
##STR00748##
[1145] Sodium hydride (60% dispersion in mineral oil, 38 mg, 0.96
mmol) was added to a solution of N,N-dimethylethanolamine (63 mg,
0.71 mmol) in DMF (5 mL) and the mixture stirred at ambient
temperature for 75 minutes.
6-(4-chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;-
4',3'-d]pyrrole (85 mg, 0.24 mmol) was added and the reaction
mixture was stirred at ambient temperature for 26 h then at
80.degree. C. for 2 h. After this time, the reaction mixture was
added to a solution of N,N-dimethylethanolamine (0.48 mL) and
sodium hydride (60% dispersion in mineral oil, 288 mg) in DMF (2
mL), which had been pre-stirred for 15 minutes. The reaction
mixture was stirred at 80.degree. C. overnight before being poured
onto water and the resultant solid collected by filtration. The
material was purified by flash chromatography (silica, 12 g column,
ISCO, 0-20% methanol in DCM then 20% (2N ammonia in methanol) in
DCM) to afford the title compound as a yellow oil which
crystallised on standing (0.1 g, 58%). .sup.1H NMR (CD.sub.3OD, 400
MHz): 8.94 (d, J=1.1 Hz, 1H), 8.81-8.77 (m, 2H), 8.71 (s, 1H), 8.58
(d, J=1.1 Hz, 1H), 8.48 (d, J=5.9 Hz, 1H), 8.09 (s, 1H), 7.94 (s,
1H), 7.28 (d, J=5.9 Hz, 1H), 4.42 (t, J=5.2 Hz, 2H), 3.98 (s, 3H),
3.03 (t, J=5.1 Hz, 2H), 2.42 (s, 6H). LCMS (Method A): R.sub.T=3.93
min, M+H.sup.+=414.
Example 399
6-(Pyrazin-2-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4',3'-
-d]pyrrole
##STR00749##
[1147] The title compound was prepared following a similar
procedure to the previous example using 2-(tributylstannyl)pyrazine
to yield a pale orange solid (20%). .sup.1H NMR (DMSO-D.sub.6, 500
MHz): 12.43 (s, 1H), 9.62 (d, J=1.4 Hz, 1H), 9.28 (s, 1H), 9.19 (d,
J=2.3 Hz, 1H), 9.06 (s, 1H), 8.95 (d, J=2.2 Hz, 1H), 8.78-8.72 (m,
1H), 8.66 (d, J=2.5 Hz, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1
Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.58-1.48 (m, 4H), 1.41 (m,
2H). LCMS (Method E): R.sub.T=2.93 min, M+H.sup.+=421.
Example 400
6-(Pyridazin-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole
##STR00750##
[1149] Step 1:
6'-(Pyridazin-4-yl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4']bipyr-
idinyl-3'-ylamine
##STR00751##
[1150] A mixture of
6'-bromo-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4]bipyridinyl-3'-yl-
amine (200 mg, 0.45 mmol), 4-(tributylstannyl)pyridazine (334 mg,
0.91 mmol) and lithium chloride (192 mg, 4.5 mmol) in 1,4-dioxane
(5 mL) was degassed and flushed with nitrogen.
Tetrakis(triphenylphosphine)-palladium(0) (39 mg, 0.034 mmol) was
added and the reaction was heated at 110.degree. C. for 24 h. The
cooled reaction mixture was diluted with DCM (20 mL) and methanol
(2 mL) and washed with water (15 mL). The organic phase was
separated, dried over sodium sulfate, filtered and evaporated in
vacuo to afford a residue that was purified by flash chromotagraphy
(silica, 10 g column, Biotage, 0-10% methanol in DCM containing 0
1% ammonia) to afford a brown residue that was taken to the next
step without further purification.
Step 2:
6-(Pyridazin-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,-
3-b;4',3'-d]pyrrole
##STR00752##
[1152] To a solution of
6'-(pyridazin-4-yl)-2-fluoro-[3,4']bipyridinyl-3'-ylamine (120 mg,
0.27 mmol) in anhydrous tetrahydrofuran (5 mL) was added sodium
bis-(trimethylsilyl)amide (1N solution in THF, 1.4 mL, 1.4 mmol)
under a flow of nitrogen. The reaction was left to stir at room
temperature for 5 h then quenched with acetic acid (1 mL). The
reaction mixture was then evaporated in vacuo to afford a residue
that was purified by preparative HPLC [20-60% MeCN in water (0.1%
ammonium hydroxide) over 30 min, 35 mL/min] to afford the title
compound as a pale orange solid (37 mg, 20%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.58 (s, 1H), 10.01 (s, 1H), 9.35 (d,
J=5.4 Hz, 1H), 9.25 (s, 1H), 9.12 (s, 1H), 9.05 (d, J=2.1 Hz, 1H),
8.98 (d, J=2.1 Hz, 1H), 8.34 (m, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.47
(d, J=8.1 Hz, 2H), 3.52 (s, 2H), 2.38 (s, 4H), 1.53 (m, 4H), 1.41
(m, 2H). LCMS (Method D): R.sub.T=7.78 min, M+H.sup.+=421.
Example 401
6-(pyrimidin-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3-
'-d]pyrrole
##STR00753##
[1154] A mixture of
6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (40 mg, 0.08 mmol), pyrimidin-5-yl boronic acid (20 mg, 0.16
mmol), 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(3.2 mg, 0.004 mmol) in saturated aqueous sodium carbonate solution
(0.15 mL) and acetonitrile (1.50 mL) was heated under microwave
irradiation at 130.degree. C. for 30 minutes. The cooled reaction
mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed
with water (15 mL). The organic phase was separated, dried over
sodium sulfate, filtered and evaporated in vacuo to afford a
residue that was purified by preparative HPLC [0-30% MeCN in water
(0.1% formic acid) over 30 min, 35 mL/min] to afford the title
compound as a yellow/orange solid (10 mg, 23%). .sup.1H NMR
(DMSO-D.sub.6, 400 MHz): 12.44 (s, 1H), 9.52 (s, 2H), 9.21 (s, 1H),
9.08 (d, J=1.7 Hz, 2H), 9.02 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz,
1H), 7.77 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H),
2.37 (s, 4H), 1.53 (m, 4H), 1.41 (m, 2H). LCMS (Method D):
R.sub.T=6.84 min, M+H.sup.+=421.
Example 402
6-(2-Aminopyrimidin-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-
-b;4',3'-d]pyrrole
##STR00754##
[1156] A degassed mixture of
6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrro-
le (74.4 mg, 0.197 mmol), 2-aminopyrimidine-5-boronic acid, pinacol
ester (45.8 mg, 0.207 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
complex with dichloromethane (1:1) (8.1 mg, 9.87 umol, 5.0 mol %)
in acetonitrile (0.74 mL) and 1M aqueous potassium carbonate
solution (0.74 mL) was heated under microwave irradiation
(140.degree. C.) for 30 minutes. Further portions of the boronate
ester (1.0 eq) and catalyst (5 mol %), acetonitrile (0.74 mL), and
1M aqueous potassium carbonate solution (0.74 mL) were added and
the mixture heated under microwave irradiation (140.degree. C.) for
an additional 30 minutes. The mixture was concentrated in vacuo and
the residue dissolved in water and DMF, and acidified with 10%
(v/v) sulfuric acid. The resultant solid was removed by filtration
and the filtrate concentrated in vacuo. The resultant residue was
dissolved in DMSO and purified by preparative HPLC [0-30%
MeCN/water modified with 0.1% formic acid] to afford an orange
fluffy solid (5.1 mg, 14%). LCMS (Method E): R.sub.T=5.45 min,
M+H.sup.+=436.
Example 403
6-(Imidazo[1,2-a]pyrimidin-3-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipy-
rido[2,3-b;4',3'-d]pyrrole
##STR00755##
[1158] The title compound was prepared following a similar
procedure to the previous example using
3-(trimethylstannyl)imidazo[1,2-a]pyrimidine to yield a pale yellow
solid (20%). .sup.1H NMR (DMSO-D.sub.6, 400 MHz): 12.34 (s, 1H),
10.23 (dd, J=6.8, 2.0 Hz, 1H), 9.05 (s, 1H), 9.04 (d, J=2.4 Hz,
1H), 8.97 (d, J=2.4 Hz, 1H), 8.95 (s, 1H), 8.64 (s, 1H), 8.46 (s,
1H), 7.79 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.25 (s, 1H),
3.52 (s, 2H), 2.39 (s, 4H), 1.54 (m, 4H), 1.42 (m, 2H). LCMS
(Method D): R.sub.T=7.32 min, M+H.sup.+=460.
Example i
Chk1 and Chk2 Assays (Chk Primary Assays)
[1159] Full length human mutant recombinant protein, histidine
tagged and expressed in insect cells is used as source of enzymatic
activity (Invitrogen, chk1 from product PV3982 and chk2 from
product PV3983).
[1160] The chk1 AlphaScreen assay is carried out for 30 minutes in
the presence of 10 .mu.M ATP using biotinylated Akt substrate-1
peptide (Cell Signalling Technology, product #1065) as a substrate.
Phosphorylation of the substrate is detected and quantified using
AlphaScreen technology. This consists of an anti-phospho-Akt
substrate-1 antibody (Cell Signalling technology Product #9611) and
two AlphaScreen beads (Perkin Elmer), one product coated with
Protein A which binds the antibody Ig chain (Product 6760137), and
one coated with Streptavidin which binds the biotin on the
biotinylated Akt substrate peptide-1 (Product 6760002). Chk1
activity results in the production of phosphorylated Akt substrate
peptide-1 an event which causes the two bead species to be brought
into close proximity in the presence of antibody leading to the
generation of luminescence which is detected on a Perkin Elmer
reader (Fusion).
[1161] The ATP Radiometric ChK1 assay is carried out by incubation
for 30 minutes in the presence of 10 .mu.M ATP containing 0.3
.mu.Ci .sup.33P-ATP per sample and using ChKTide (peptide sequence
KKKVSRSGLYRSPSMPENLNRPR) as a substrate. Following acidification
with 1% phosphoric acid and washing to remove unincorporated ATP,
phosphorylation of the substrate is detected and quantified by
measurement of radioactivity incorporated using a Perkin Elmer
Topcount.
[1162] The chk2 AlphaScreen assay is carried out for 30 minutes in
the presence of 30 .mu.M ATP using biotinylated tyrosine
hydroxylase (ser 40) peptide (Cell Signalling Technology, product
#1132) as a substrate. Phosphorylation of the substrate is detected
and quantified using AlphaScreen technology. This consists of an
anti-phospho-tyrosine hydroxylase (ser 40) peptide antibody (Cell
Signalling technology Product #2791) and two AlphaScreen beads
(Perkin Elmer), one product coated with Protein A which binds the
antibody Ig chain (Product 6760137), and one coated with
Streptavidin which binds the biotin on the biotinylated tyrosine
hydroxylase (ser 40) peptide (Product 6760002). Chk2 activity
results in the production of phosphorylated tyrosine hydroxylase
peptide an event which causes the two bead species to be brought
into close proximity in the presence of antibody leading to the
generation of luminescence which is detected on a Perkin Elmer
reader (Fusion).
[1163] The ATP Radiometric ChK2 assay is carried out by incubation
for 30 minutes in the presence of 30 .mu.M ATP containing 0.3
.mu.Ci .sup.33P-ATP per sample and using ChKTide (peptide sequence
KKKVSRSGLYRSPSMPENLNRPR) as a substrate. Following acidification
with 1% phosphoric acid and washing to remove unincorporated ATP,
phosphorylation of the substrate is detected and quantified by
measurement of radioactivity incorporated using a Perkin Elmer
Topcount.
[1164] Test compounds are diluted in DMSO prior to addition to
assay buffer, the final DMSO concentration in the assay is 1%.
[1165] The IC.sub.50 is defined as the concentration at which a
given test compound achieved 50% inhibition of the control.
IC.sub.50 values are calculated using the XLfit software package
(version 2.0.5).
[1166] Title compounds of EXAMPLES 1-119, 121-141, 143, 145-146,
148-171, 173, 175-178, 180-181, 184, and 186-403 exhibited an
IC.sub.50 of less than 5 .mu.M in the assays described in EXAMPLE i
against chk1.
Example ii
Cellular Assay (Checkpoint Abrogation)
[1167] Compounds are tested in a cellular assay using the human
colorectal adenocarcinoma derived cell line HT-29 (ATCC
HTB-38).
[1168] The cell line is maintained in DMEM/F12 (1:1) media
(Invitrogen Gibco, #31331) supplemented with 10% FCS at 37.degree.
C. in a 5% CO.sub.2 humidified incubator.
[1169] Cells are seeded in 96-well plates at 30,000 cells/well and
after 24 h they are exposed to 20 nM SN-38 in 0.4% DMSO. One column
of 8 wells on each plate was used to generate a maximum signal
control. These cells are treated with 0.4% DMSO without SN-38.
Cells are grown for a further 16 h, then the media containing DMSO
plus or minus SN-38 is removed and replaced with media containing
300 nM nocodazole alone (to determine baseline) or in combination
with ten concentrations of chk1 inhibitor (final DMSO concentration
is 0.4%). Cells are grown for a further 24 h. The media is removed
and replaced with 50 .mu.l lysis buffer containing protease
inhibitors and phosphatase inhibitors. This buffer contains
detergent to bring about cellular disruption. Following complete
cellular disruption, 25 .mu.l lysate is transferred to a MesoScale
96 well 4-spot plate coated with an antibody to Histone H3
(MesoScale Discovery (MSD) Product K110EWA-3) which have been
previously blocked with 3% bovine serum albumin in Tris buffered
saline. Following the transfer of lysate to the MSD plate, Histone
H3 in the lysate is captured on the coated antibody by incubation
at room temperature for 2 h. Following the capture step the plate
is washed and then incubated with an antibody to phosphorylated
Histone H3 which is conjugated with a Sulfo-Tag. This tag gives a
signal when in proximity to the electrode on the base of the MSD
plate. Binding the tagged antibody to the captured protein allow
detection on a MSD reader.
[1170] The EC.sub.50 is defined as the concentration at which a
given compound achieves 50% decrease of the measured levels of
phospho-Histone H3 within the range of a normal sigmoidal dose
response curve compared to the signal generated by 300 nM
nocodazole alone. EC.sub.50 values are calculated using the XLfit
software package (version 2.0.5) or Graphpad Prism, (version 3.03)
fitting a sigmoidal curve with a variable slope.
[1171] Title compounds of EXAMPLES 1, 4-7, 9-13, 15-30, 32-41,
43-46, 48-55, 58-62, 64-77, 80, 84-90, 93-117, 119, 125, 127,
130-133, 135, 138, 157, 160, 166, 176, 180, 186, 188, 190, 194-195,
198-209, 211-212, 214, 216-282, 284-316, 319-322, 324-338, 343-344,
350-351, 353-362, 366, 368, 370-389, 391-395, 397-402 exhibited an
EC.sub.50 of less than 10 .mu.M in the assay described in EXAMPLE
ii.
* * * * *